DIAGNOSTIC AND STATISTICAL
MANUAL OF 
MENTAL DISORDERS
FIFTH  EDITION
DSM-5TM

American Psychiatric Association
Officers 2012-2013  
President  Dilip V. J este , M.D.
President -Elect  Jeffrey  A. L ieberman , M.D.
Treasurer  David  Fassler , M.D.
Secretary  Rcxser  Peele , M.D.
Assembly  
Speaker  R. S cott  Benson , M.D.
Speaker -Elect  Melinda  L. Y oung , M.D.
Board of Trustees  
Jeffrey  Akaka , M.D.
Carol  A. B ernstein , M.D.
BrL ·^ ^  C rowley , M.D.
Anita  S. E verett , M.D.
Jeffrey  Geller , M.D., M.P.H.
M ^ c  David  Graff , M.D.
' J ^ e&A. G i^eneVM.D.
Judith  F. K ashtan , M.D.
Molly  K. M cVoy, M.D.
James  E. N ininger , M.D.
John  M. O ldham , M.D.
Alan  F. S chatzberg , M.D.
Alik s. W idge , M.D., P h.D.
Erik R. V anderlip , M.D.,  
Member -in-Training  Trustee -Elect

MANUAL OF 
MENTAL DISORDERS7
FIFTH EDITION
DSM-5TM
New School Library
/«44
Amcriccin
Osvchiatric
ADivi«ono(AmCT»MlVhijtiKAMod<tk>n
W ashington, DC 
London, England

Copyright © 2013 American Psychiatric Association
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The correct citation for this book is American Psychiatric Association: Diagnostic and Statisti­

cal Manual of Mental Disorders, Fifth Edition. Arlington, VA, American Psychiatric Associa­
tion, 2013.
Library of Congress Cataloging-in-Publication Data
Diagnostic and statistical manual of mental disorders : DSM-5. — 5th ed.
p. ; cm.
DSM-5
DSM-V
Includes index.
ISBN 978-0-89042-554-1 (hardcover : alk. paper) — ISBN 978-0-89042-555-8 (pbk. : alk. paper)
I. American Psychiatric Association. II. American Psychiatric Association. DSM-5 Task Force, 
m . Title: DSM-5. IV. Title: DSM-V.
[DNLM: 1. Diagnostic and statistical manual of mental disorders. 5th ed. 2. Mental Disorders— 
classification. 3. Mental Disorders—diagnosis. WM 15]
RC455.2.C4 
616.89Ό75—dc23
2013011061
British Library Cataloguing in Publication Data ^ n
A CIP record is available from the British Library. ^

Text Design—Tammy J. Cordova
Manufacturing—Edwards Brothers Malloy ^
cH

Contents
DSM-5 Classification..................................................................xiii
Preface......................................................................................... xli
Section I
DSM-5 Basics
Introduction................................................................................... 5
Use of the Manual........................................................................19
Cautionary Statement for Forensic Use of DSM-5 ..................... 25
Section II
Diagnostic Criteria and Codes
Neurodevelopmental Disorders .................................................. 31
Schizophrenia Spectrum and Other Psychotic Disorders .......... 87
Bipolar and Related Disorders .................................................. 123
Depressive Disorders................................................................155
Anxiety Disorders........................................................................189

Obsessive-Compulsive and Related Disorders ....................... 235
Trauma- and Stressor-Related Disorders ................................. 265
Dissociative Disorders.............................................................. 291
Somatic Symptom and Related Disorders............................... 309
Feeding and Eating Disorders.................................................. 329
Elimination Disorders................................................................355
Sleep-Wake Disorders................................................................361
Sexual Dysfunctions..................................................................423
Gender Dysphoria......................................................................451

Disruptive, Impulse-Control, and Conduct Disorders..............461
Substance-Related and Addictive Disorders ........................... 481
Neurocognitive Disorders.......................................................... 591
Personality Disorders................................................................ 645
Paraphilic Disorders..................................................................685
Other Mental Disorders............................................................ 707
Medication-Induced Movement Disorders  
and Other Adverse Effects of Medication ............................. 709
Other Conditions That May Be a Focus of Clinical Attention .. 715
Section III
Emerging Measures and Models
Assessment Measures.............................................................. 733
Cultural Formulation..................................................................749
Alternative DSM-5 Model for Personality Disorders................761

Conditions for Further Study .................................................... 783
Appendix
Highlights of Changes From DSM-IV to DSM-5 ....................... 809
Glossary of Technical Terms .................................................... 817
Glossary of Cultural Concepts of Distress ............................... 833
Alphabetical Listing of DSM-5 Diagnoses and Codes  
(ICD-9-CM and ICD-10-CM) .................................................... 839
Numerical Listing of DSM-5 Diagnoses and Codes  
(ICD-9-CM) ............................................................................. 863
(ICD-10-CM)............................................................................877
DSM-5 Advisors and Other Contributors................................. 897

Index........................................................................................... 917

DSM-5 Task Force
David  J. K upfer , M.D.
Task Force Chair
Darrel  A. R egier , M.D., M.P.H.
Task Force Vice-Chair
William E. Narrow, M.D.,
Research Director
Dan G. Blazer, M.D., Ph.D., M.P.H. 
Jack D. Burke Jr., M.D., M.P.H. 
William T. Carpenter Jr., M.D.
F. Xavier Castellanos, M.D.
Wilson M. Compton, M.D., M.P.E. 
Joel E. Dimsdale, M.D.
Javier I. Escobar, M.D., M.Sc.
Jan A. Fawcett, M.D.
Bridget F. Grant, Ph.D., Ph.D. (2009-)  
Steven E. Hyman, M.D. (2007-2012)  
Dilip V. Jeste, M.D. (2007-2011)  
Helena C. Kraemer, Ph.D.
Daniel T. Mamah, M.D., M.P.E.
James P. McNulty, A.B., Sc.B. 
Howard B. Moss, M.D. (2007-2009)Susan K. Schultz, M.D., Text Editor  
Emily A. Kuhl, Ph.D., APA Text Editor
Charles P. O'Brien, M.D., Ph.D.
Roger Peele, M.D.
Katharine A. Phillips, M.D.
Daniel S. Pine, M.D.
Charles F. Reynolds III, M.D.
Maritza Rubio-Stipec, Sc.D.
David Shaffer, M.D.
Andrew E. Skodol II, M.D.
Susan E. Swedo, M.D.
B. Timothy Walsh, M.D.
Philip Wang, M.D., Dr.P.H. (2007-2012)

Philip Wang, M.D., Dr.P.H. (2007-2012)  
William M. Womack, M.D.
Kimberly A. Yonkers, M.D.
Kenneth J. Zucker, Ph.D.
Norman Sartorius, M.D., Ph.D., Consultant
APA Division of Research Staff on DSIVI-5
Darrel A. Regier, M.D., M.P.H., 
Director, Division of Research  
William E. Narrow, M.D., M.P.H., 
Associate Director  
Emily A. Kuhl, Ph.D., Senior Science  
Writer; Staff Text Editor  
Diana E. Clarke, Ph.D., M.Sc., Research  
Statistician
Lisa H. Greiner, M.S.S.A., DSM-5 Field  
Trials Project Manager  
Eve K. Moscicki, Sc.D., M.P.H.,
Director, Practice Research Network  
S. Janet Kuramoto, Ph.D. M.H.S.,
Senior Scientific Research Associate,  
Practice Research Network
Amy Porfiri, M.B.A.
Director of Finance and AdministrationJennifer J. Shupinka, Assistant Director,  
DSM Operations  
Seung-Hee Hong, DSM Senior Research  
Associate

Associate
Anne R. Hiller, DSM Research Associate  
Alison S. Beale, DSM Research Associate  
Spencer R. Case, DSM Research Associate
Joyce C. West, Ph.D., M.P.P.,
Health Policy Research Director, Practice  
Research Network  
Farifteh F. Duffy, Ph.D.,
Quality Care Research Director, Practice  
Lisa M. Countis, Field Operations  
Manager, Practice Research Network
Christopher M. Reynolds,
Executive Assistant
APA Office of the IVIedlcal Director
James H. S c u lly  Jr., M.D. 
Medical Director and CEO

Editorial and Coding Consultants
Michael B. First, M.D. Maria N. Ward, M.Ed., RHIT, CCS-P
DSM-5 Work Groups
ADHD and Disruptive Behavior Disorders
David  Shaffer , M.D.
Chair
F. X avier  Castellanos , M.D.
Co-Chair
Paul J. Frick, Ph.D., Text Coordinator  Luis Augusto Rohde, M.D., Sc.D.
Glorisa Canino, Ph.D. Rosemary Tannock, Ph.D.
Terrie E. Moffitt, Ph.D. Eric A. Taylor, M.B.
Joel T. Nigg, Ph.D. Richard Todd, Ph.D., M.D. (d. 2008)
Anxiety, Obsessive-Compulsive Spectrum, Posttraumatic, 
and Dissociative Disorders
Katharine  A. P hillips , M.D.
Chair
Michelle G. Craske, Ph.D., Text  Scott L. Rauch, M.D.
Coordinator  H. Blair Simpson, M.D., Ph.D.
J. Gavin Andrews, M.D. David Spiegel, M.D.
Susan M. Bögels, Ph.D. Dan J. Stein, M.D., Ph.D.
Matthew J. Friedman, M.D., Ph.D. Murray B. Stein, M.D.
Eric Hollander, M.D. (2007-2009)  Robert J. Ursano, M.D.
Roberto Lewis-Fernandez, M.D., M.T.S. Hans-Ulrich Wittchen, Ph.D.
Robert S. Pynoos, M.D., M.P.H.
Childhood and Adolescent Disorders

Daniel  S. P ine, M.D.
Chair
Ronald E. Dahl, M.D. James F. Leckman, M.D.
E. Jane Costello, Ph.D. (2007-2009)  Ellen Leibenluft, M.D.
Regina Smith James, M.D. Judith H. L. Rapoport, M.D.
Rachel G. Klein, Ph.D. Charles H. Zeanah, M.D.
Eating Disorders
B. T imothy  Walsh , M.D.
Chair
Stephen A. Wonderlich, Ph.D., Richard E. Kreipe, M.D.
Text Coordinator  Marsha D. Marcus, Ph.D.
Evelyn Attia, M.D. James E. Mitchell, M.D.
Anne E. Becker, M.D., Ph.D., Sc.M. Ruth H. Striegel-Moore, Ph.D.
Rachel Bryant-Waugh, M.D. G. Terence Wilson, Ph.D.
Hans W. Hoek, M.D., Ph.D. Barbara E. Wolfe, Ph.D. A.P.R.N.

Mood Disorders
Ja n  a . F a w ce tt, M.D. 
Chair
Ellen Frank, Ph.D., Text Coordinator  
Jules Angst, M.D. (2007-2008)  
William H. Coryell, M.D.
Lori L. Davis, M.D.
Raymond J. DePaulo, M.D.
Sir David Goldberg, M.D.
James S. Jackson, Ph.D.Kenneth S. Kendler, M.D., Ph.D.
(2007-2010)
Mario Maj, M.D., Ph.D.
Husseini K. Manji, M.D. (2007-2008)  
Michael R. Phillips, M.D.
Trisha Suppes, M.D., Ph.D.
Carlos A. Zarate, M.D.
Neurocognitive Disorders
Dilip V. Jeste, M.D. (2007-2011) 
Chair Emeritus
Dan G. B lazer , M.D., P h.D., M.P.H.
Chair
R o n a ld  C. P etersen, M.D., Ph.D. 
Co-Chair
Mary Ganguli, M.D., M.P.H.,
Text Coordinator  
Deborah Blacker, M.D., Sc.D. 
Warachal Faison, M.D. (2007-2008)Igor Grant, M.D.
Eric J. Lenze, M.D.
Jane S. Paulsen, Ph.D.
Perminder S. Sachdev, M.D., Ph.D.
Neurodevelopmental Disorders
Susan  E. S wedo , M.D.
Chair
Gillian Baird, M.A., M.B., B.Chir., 
Edwin H. Cook Jr., M.D. 
Francesca G. Happé, Ph.D.
James C. Harris, M.D.

Chair
Walter E. Kaufmann, M.D.
Bryan H. King, M.D.Catherine E. Lord, Ph.D.
Joseph Piven, M.D.
Sally J. Rogers, Ph.D.
Sarah J. Spence, M.D., Ph.D. 
Fred Volkmar, M.D. (2007-2009)  
Amy M. Wetherby, Ph.D.
Harry H. Wright, M.D.
Personality and Personality Disorders^
Andrew  E. S kodol , M.D.
Chair
Co-Chair
Robert F. Krueger, Ph.D., Text 
Coordinator  
Renato D. Alarcon, M.D., M.P.H. 
Carl C. Bell, M.D.
Donna S. Bender, Ph.D.Lee Anna Clark, Ph.D.
W. John Livesley, M.D., Ph.D. (2007-2012)  
Leslie C. Morey, Ph.D.
Larry J. Siever, M.D.
Roel Verheul, Ph.D. (2008-2012)
^  The members of the Personality and Personality Disorders W ork Group are responsible for the 
alternative DSM-5 model for personality disorders that is included in Section III. The Section II

alternative DSM-5 model for personality disorders that is included in Section III. The Section II 
personality disorders criteria and text (with updating of the text) are retained from DSM-IV-TR.

Psychotic Disorders
William  T. C arpenter  Jr., M.D.
Chair
Deanna M. Barch, Ph.D., Text Dolores Malaspina, M.D., M.S.P.H.
Coordinator  Michael J. Owen, M.D., Ph.D.
Juan R. Bustillo, M.D. Susan K. Schultz, M.D.
Wolfgang Gaebel, M.D. Rajiv Tandon, M.D.
Raquel E. Gur, M.D., Ph.D. Ming T. Tsuang, M.D., Ph.D.
Stephan H. Heckers, M.D. Jim van Os, M.D.
Sexual and Gender Identity Disorders
Kenneth  J. Z ucker , Ph.D.
Chair
Lori Brotto, Ph.D., Text Coordinator  Martin P. Kafka, M.D.
Irving M. Binik, Ph.D. Richard B. Krueger, M.D.
Ray M. Blanchard, Ph.D. Niklas Langström, M.D., Ph.D.
Peggy T. Cohen-Kettenis, Ph.D. Heino F.L. Meyer-Bahlburg, Dr. rer. nat.
Jack Drescher, M.D. Friedemann Pfäfflin, M.D.
Cynthia A. Graham, Ph.D. Robert Taylor Segraves, M.D., Ph.D.
Sleep-Wake Disorders
Charles  F. R eynolds  III, M.D.
Chair
Ruth M. O'Hara, Ph.D., Text Coordinator  Kathy P. Parker, Ph.D., R.N.
Charles M. Morin, Ph.D. Susan Redline, M.D., M.P.H.
Allan I. Pack, Ph.D. Dieter Riemann, Ph.D.

Chair
Somatic Symptom Disorders
Joel E. D imsdale , M.D.
Chair
James L. Levenson, M.D., Text  Michael R. Irwin, M.D.
Coordinator  Francis J. Keefe, Ph.D. (2007-2011)
Arthur J. Barsky III, M.D. Sing Lee, M.D.
Francis Creed, M.D. Michael Sharpe, M.D.
Nancy Frasure-Smith, Ph.D. (2007-2011)  Lawson R. Wulsin, M.D.
Substance-Related Disorders
Charles  P. O 'B rien , M.D., P h.D.
Chair
Thomas  J. C rowley , M.D.
Co-Chair
Wilson M. Compton, M.D., M.P.E., Thomas R. Kosten, M.D. (2007-2008)
Text Coordinator  Walter Ling, M.D.
Marc Auriacombe, M.D. Spero M. Manson, Ph.D. (2007-2008)
Guilherme L. G. Borges, M.D., Dr .Sc. A. Thomas McLellan, Ph.D. (2007-2008)  
Kathleen K. Bucholz, Ph.D. Nancy M. Petry, Ph.D.
Alan J. Budney, Ph.D. Marc A. Schuckit, M.D.
Bridget F. Grant, Ph.D., Ph.D. Wim van den Brink, M.D., Ph.D.

Deborah S. Hasin, Ph.D. (2007-2008)

DSM-5 Study Groups
Diagnostic Spectra and DSM/ICD Harmonization
Steven  E. H yman , M.D.
Chair (2007-2012)
William T. Carpenter Jr., M.D. William E. Narrow, M.D., M.P.H.
Wilson M. Compton, M.D., M.P.E. Charles P. O'Brien, M.D., Ph.D.
Jan A. Fawcett, M.D. John M. Oldham, M.D.
Helena C. Kraemer, Ph.D. Katharine A. Phillips, M.D.
David J. Kupfer, M.D. Darrel A. Regier, M.D., M.P.H.
Lifespan Developmental Approaches
Eric J. L enze , M.D.
Chair
Susan  K. S chultz , M.D.
Dan G. Blazer, M.D., Ph.D., M.P.H.
Wilson M. Compton, M.D., M.P.E.Daniel T. Mamah, M.D., M.P.E. 
Andrew E. Skodol II, M.D. 
Gender and Cross-Cultural Issues
Kimberly  A. Y onkers , M.D.
Chair
Roberto  Lewis -Fernândez , M.D., M.T.S.
Co-Chair, Cross-Cultural Issues
Diana E. Clarke, Ph.D., M.Sc.
Ellen Frank, Ph.D.
James S. Jackson, Ph.D.

Spiro M. Manson, Ph.D. (2007-2008)  
James P. McNulty, A.B., Sc.B.Leslie C. Morey, Ph.D.
William E. Narrow, M.D., M.P.H.
Kermeth J. Zucker, Ph.D.
Psychiatric/General Medical Interface
Lawson  R. W ulsin , M.D.
Chair
Ronald E. Dahl, M.D.
Javier I. Escobar, M.D., M.Sc. 
Walter E. Kaufmann, M.D.Richard E. Kreipe, M.D.
Ronald C. Petersen, Ph.D., M.D. 
Robert Taylor Segraves, M.D., Ph.D. 

Impairment and Disability
Jan e S. P au lsen , Ph.D. 
Chair
J. Gavin Andrews, M.D. 
Glorisa Canino, Ph.D.
Lee Anna Clark, Ph.D.
Diana E. Clarke, Ph.D., M.Sc. 
Michelle G. Craske, Ph.D.Hans W. Hoek, M.D., Ph.D. 
Helena C. Kraemer, Ph.D. 
William E. Narrow, M.D., M.P.H. 
Diagnostic Assessment Instruments
Jack  D. B urke  Jr., M.D., M.P.H.
Chair
Bridget F. Grant, Ph.D., Ph.D.Helena C. Kraemer, Ph.D. 
DSM-5 Research Group
William  E. N arrow , M.D., M.P.H.
Chair
Helena C. Kraemer, Ph.D.David J. Kupfer, M.D.
Darrel A. Regier, M.D., M.P.H. 
Course Specifiers and Glossary
Wolfgang  Gaebel , M.D.
Chair
Charles P. O'Brien, M.D., Ph.D. 
Norman Sartorius, M.D., Ph.D., 
Consultant  
Susan K. Schultz, M.D.Dan J. Stein, M.D., Ph.D.
Eric A. Taylor, M.B.
David J. Kupfer, M.D.

Chair
Darrel A. Regier, M.D., M.P.H.

Before each disorder name, ICD-9-CM codes are provided, followed by ICD-IO-CM codes 
in parentheses. Blank lines indicate that either the ICD-9-CM or the ICD-IO-CM code is not 
applicable. For some disorders, the code can be indicated only according to the subtype or 
specifier.
ICD-9-CM codes are to be used for coding purposes in the United States through Sep­
tember 30,2014. ICD-IO-CM codes are to be used starting October 1,2014.
Following chapter titles and disorder names, page numbers for the corresponding text 
or criteria are included in parentheses.
Note for all mental disorders due to another medical condition: Indicate the name of 
the other medical condition in the name of the mental disorder due to [the medical condi­
tion]. The code and name for the other medical condition should be listed first immedi­
ately before the mental disorder due to the medical condition.
Neurodevelopm ental Disorders (31)
Intellectual Disabilities (33)

319 (___.__) Intellectual Disability (Intellectual Developmental Disorder) (33)
Specify  current severity;
(F70) Mild
(F71) Moderate
(F72) Severe
(F73) Profound
315.8 (F88) Global Developmental Delay (41)
319 (F79) Unspecified Intellectual Disability (Intellectual Developmental
Disorder) (41)
Communication Disorders (41)
315.39 (F80.9) Language Disorder (42)
315.39 (F80.0) Speech Sound Disorder (44)
315.35 (F80.81) Childhood-Onset Fluency Disorder (Stuttering) (45)
Note: Later-onset cases are diagnosed as 307.0 (F98.5) adult-onset fluency 
disorder.
315.39 (F80.89) Social (Pragmatic) Communication Disorder (47)
307.9 (F80.9) Unspecified Communication Disorder (49)

Autism Spectrum Disorder (50)
299.00 (F84.0) Autism Spectrum Disorder (50)
Specify  if: Associated with a known medical or genetic condition or envi­
ronmental factor; Associated with another neurodevelopmental, men­
tal, or behavioral disorder 
Specify  current severity for Criterion A and Criterion B: Requiring very 
substantial support. Requiring substantial support. Requiring support 
Specify  if: With or without accompanying intellectual impairment. With 
or without accompanying language impairment. With catatonia (use 
additional code 293.89 [F06.1])
Attention-Deficit/Hyperactivity Disorder (59)
___.__ (_ _.__) Attention-Deficit/Hyperactivity Disorder (59)
Specify  whether:
314.01 (F90.2) Combined presentation
314.00 (F90.0) Predominantly inattentive presentation
314.01 (F90.1) Predominantly hyperactive/impulsive presentation
Specify  if: In partial remission
Specify  current severity: Mild, Moderate, Severe

314.01  (F90.8) Other Specified Attention-Deficit/Hyperactivity Disorder (65)
314.01  (F90.9) Unspecified Attention-Deficit/Hyperactivity Disorder (66)
Specific Learning Disorder (66)
___.__ (___.__) Specific Learning Disorder (66)
Specify  if:
315.00  (F81.0) With impairment in reading {specify  if with word reading
accuracy, reading rate or fluency, reading comprehension)
315.2  (F81.81 ) With impairment in written expression {specify  if with spelling
accuracy, grammar and punctuation accuracy, clarity or 
organization of written expression)
315.1  (F81.2) With impairment in mathematics {specify  if with number sense,
memorization of arithmetic facts, accurate or fluent 
calculation, accurate math reasoning)
Motor Disorders (74)
315.4 (F82) Developmental Coordination Disorder (74)

307.3  (F98.4) Stereotypic Movement Disorder (77)
Specify  if: With self-injurious behavior. Without self-injurious behavior 
Specify  if: Associated with a known medical or genetic condition, neuro­
developmental disorder, or environmental factor 
Tic Disorders
307.23 (F95.2) Tourette's Disorder (81)
307.22 (F95.1) Persistent (Chronic) Motor or Vocal Tic Disorder (81)
Specify  if: With motor tics only. With vocal tics only

307.21 (F95.0) Provisional Tic Disorder (81)
307.20 (F95.8) , Other Specified Tic Disorder (85)
307.20 (F95.9) Urispecified Tic Disorder (85)
Other Neurodevelopmental Disorders (86)
315.8 (FSB) Other Specified Neurodevelopmental Disorder (86)
315.9 (F89) Unspecified Neurodevelopmental Disorder (86)
Schizophrenia Spectrum  
and Other Psychotic Disorders (87)
The following specifiers apply to Schizophrenia Spectrum and Other Psychotic Disorders 
where indicated:
^Specify  if: The following course specifiers are only to be used after a 1-year duration of the dis­
order: First episode, currently in acute episode; First episode, currently in partial remission; 
First episode, currently in full remission; Multiple episodes, currently in acute episode; Mul­
tiple episodes, currently in partial remission; Multiple episodes, currently in full remission; 
Continuous; Unspecified 
^Specify  if: With catatonia (use additional code 293.89 [F06.1])

^Specify  current severity of delusions, hallucinations, disorganized speech, abnormal psycho­
motor behavior, negative symptoms, impaired cognition, depression, and mania symptoms
301.22 (F21)  
297.1 (F22)
298.8 (F23)
295.40 (F20.81)
295.90 (F20.9)
295.70 (F25.0)
295.70 (F25.1)
293.81 (F06.2)
293.82 (F06.0)Schizotypal (Personality) Disorder (90)
Delusional Disorder^' ^  (90)
Specify  whether: Erotomanie type. Grandiose type. Jealous type. Persecu­
tory type. Somatic type. Mixed type. Unspecified type 
Specify  if: With bizarre content
Brief Psychotic Disorder^' ^  (94)
Specify  if: With marked stressor(s). Without marked stressor(s). With 
postpartum onset
Schizophreniform Disorder^' ^  (96)
Specify  if: With good prognostic features. Without good prognostic fea­
tures
Schizophrenia^' ^  (99)

tures
Schizoaffective Disorder^' ^  (105)
Bipolar type 
Depressive type
Substance/Medication-Induced Psychotic Disorder^ (110)
Note: See the criteria set and corresponding recording procedures for 
substance-specific codes and ICD-9-CM and ICD-IO-CM coding. 
Specify  if: With onset during intoxication. With onset during withdrawal
Psychotic Disorder Due to Another Medical Condition^ (115) 
With delusions 
With hallucinations

293.89 (F06.1) Catatonia Associated With Another Mental Disorder (Catatonia
Specifier) (119)
293.89 (F06.1) Catatonic Disorder Due to Another Medical Condition (120)
293.89 (F06.1) Unspecified Catatonia (121)
Note: Code first 781.99 (R29.818) other symptoms involving nervous and 
musculoskeletal systems.
298.8 (F28) Other Specified Schizophrenia Spectrum and Other Psychotic
Disorder (122)
298.9 (F29) Unspecified Schizophrenia Spectrum and Other Psychotic
Bipolar and Related Disorders (123)
The following specifiers apply to Bipolar and Related Disorders where indicated:
^Specify:  With anxious distress (specify  current severity: mild, moderate, moderate-severe, severe); 
With mixed features; With rapid cycling; With melancholic features; With atypical features; 
With mood-congruent psychotic features; With mood-incongruent psychotic features; With 
catatonia (use additional code 293.89 [F06.1]); With péripartum onset; With seasonal pattem
296.41
296.42
296.43
296.44

296.41
296.42
296.43
296.44
296.45
296.46
296.40
296.40
296.45
296.46
296.40
296.51
296.52
296.53
296.54
296.55
296.56  
296.50  
296.7(F31.11)
(F31.12)
(F31.13)
(F31.2)
(F31.73)
(F31.74)
(F31.9)
(F31.0)
(F31.73)
(F31.74)
(F31.9)
(F31.31)
(F31.32)
(F31.4)
(F31.5)
(F31.75)
(F31.76)
(F31.9)
(F31.9)
296.89 (F31.81)Bipolar I Disorder® (123)
Current or most recent episode manic 
Mild
Moderate
Severe
With psychotic features 
In partial remission 
In full remission 
Unspecified 
Current or most recent episode hypomanie 
In kill remission 
Current or most recent episode depressed 
Mild
Moderate
Severe
Current or most recent episode unspecified 
Bipolar II Disorder® (132)
Specify  current or most recent episode: Hypomanie, Depressed

Specify  current or most recent episode: Hypomanie, Depressed 
Specify  course if full criteria for a mood episode are not currently met: In 
partial remission. In full remission 
Specify  severity if full criteria for a mood episode are not currently met: 
Mild, Moderate, Severe

301.13 (F34.0)
y
293.83 ( __._ )
(F06.33)  
(F06.33)  
(F06.34)  
296.89 (F31.89)  
296.80 (F31.9)Cyclothymic Disorder (139)
Specify  if: With anxious distress
Substance/Medication-Induced Bipolar and Related Disorder (142) 
Bipolar and Related Disorder Due to Another Medical Condition 
(145)
With manic features 
With manic- or hypomanic-like episode 
With mixed features 
Other Specified Bipolar and Related Disorder (148)
Unspecified Bipolar and Related Disorder (149)
Depressive Disorders (155)
The following specifiers apply to Depressive Disorders where indicated:
^Specify:  With anxious distress (specify  current severity: mild, moderate, moderate-severe, 
severe); With mixed features; With melancholic features; With atypical features; With mood-

severe); With mixed features; With melancholic features; With atypical features; With mood- 
congruent psychotic features; With mood-incongruent psychotic features; With catatonia 
(use additional code 293.89 [F06.1]); With péripartum onset; With seasonal pattern
296.99 (F34.8) Disruptive Mood Dysregulation Disorder (156)
. (_ ■  ) Major Depressive Disorder® (160)
. ( _ .  ) Single episode
296.21 (F32.0) Mild
296.22 (F32.1) Moderate
296.23 (F32.2) Severe
296.24 (F32.3) With psychotic features
296.25 (F32.4) In partial remission
296.26 (F32.5) In full remission
296.20 (F32.9) Unspecified
. ( _ ·  ) Recurrent episode
296.31 (F33.0) Mild
296.32 (F33.1) Moderate
296.33 (F33.2) Severe
296.34 (F33.3) With psychotic features
296.35 (F33.41) In partial remission
296.36 (F33.42) In full remission
296.30 (F33.9) Unspecified
300.4 (F34.1) Persistent Depressive Disorder (Dysthymia)® (168)

Specify  if: In partial remission. In full remission 
Specify  if: Early onset. Late onset
Specify  if: With pure dysthymic syndrome; With persistent major depres­
sive episode; With intermittent major depressive episodes, with current

625.4 (N94.3)  
(__■_)
293.83 ( _ _._ )
(F06.31)  
(F06.32)  
(F06.34)  
311 (F32.8)  
311 (F32.9)episode; With intermittent major depressive episodes, without current 
episode
Specify  current severity: Mild, Moderate, Severe 
Premenstrual Dysphoric Disorder (171)
Substance/Medication-Induced Depressive Disorder (175)
Depressive Disorder Due to Another Medical Condition (180) 
With depressive features 
With major depressive-like episode 
Other Specified Depressive Disorder (183)
Unspecified Depressive Disorder (184)
Anxiety Disorders (189)
309.21 (F93.0)
312.23 (F94.0)  
300.29 ( _ _._ )
(F40.218)
(F40.228)
( _ · _ )
(F40.230)
(F40.231)
(F40.232)
(F40.233)
(F40.248)
(F40.298)
300.23 (F40.10)
300.01 (F41.0)
300.22 (F40.00)

(F40.218)
(F40.228)
( _ · _ )
(F40.230)
(F40.231)
(F40.232)
(F40.233)
(F40.248)
(F40.298)
300.02 (F41.1)Separation Anxiety Disorder (190)
Selective Mutism (195)
Specific Phobia (197)
Animal
Natural environment 
Blood-injection-injury 
Fear of blood
Fear of injections and transfusions 
Fear of other medical care 
Fear of injury 
Situational 
Other
Social Anxiety Disorder (Social Phobia) (202)
Specify  if: Performance only
Panic Disorder (208)
Panic Attack Specifier (214)
Agoraphobia (217)
Generalized Anxiety Disorder (222)
Substance/Medication-Induced Anxiety Disorder (226)
Specify  if: With onset during intoxication. With onset during withdrawal. 
With onset after medication use

293.84 (F06.4) Anxiety Disorder Due to Another Medical Condition (230)
300.09 (F41.8) \  Other Specified Anxiety Disorder (233)
300.00 (F41 .9) Unspecified Anxiety Disorder (233)
Obsessive-Compulsive and Related Disorders (235)
The following specifier applies to Obsessive-Compulsive and Related Disorders where indicated: 
^Specify  if: With good or fair insight. With poor insight. With absent insight/delusional beliefs
300.3 (F42)
300.7 (F45.22)
312.39 (F63.2)
698.4 (L98.1)
(_._J
294.8 (F06.8)
300.3 (F42)Obsessive-Compulsive Disorder^ (237)
Specify  if: Tic-related
Body Dysmorphic Disorder^ (242)
Specify  if: With muscle dysmorphia
Hoarding Disorder^ (247)
Specify  if: With excessive acquisition
Trichotillomania (Hair-Pulling Disorder) (251)
Excoriation (Skin-Picking) Disorder (254)
Substance/Medication-Induced Obsessive-Compulsive and 
Related Disorder (257)
Note: See the criteria set and corresponding recording procedures for

Obsessive-Compulsive and Related Disorder Due to Another 
Medical Condition (260)
Specify  if: With obsessive-compulsive disorder-like symptoms. With 
appearance preoccupations. With hoarding symptoms. With hair- 
pulling symptoms. With skin-picking symptoms
Other Specified Obsessive-Compulsive and Related Disorder 
(263)
Unspecified Obsessive-Compulsive and Related Disorder (264)
Trauma- and Stressor-Related Disorders (265)
313.89 (F94.1)
313.89 (F94.2)
309.81 (F43.10)
308.3 (F43.0)Reactive Attachment Disorder (265)
Specify  if: Persistent
Specify  current severity: Severe
Disinhibited Social Engagement Disorder (268)

Posttraumatic Stress Disorder (includes Posttraumatic Stress 
Disorder for Children 6 Years and Younger) (271) 
Specify  whether: With dissociative symptoms 
Specify  if: With delayed expression
Acute Stress Disorder (280)

XX DSM-5 Classification
( ■_) Adjustment Disorders (286)
309.0 (F43.21) With depressed mood
309.24 (F43.22) With anxiety
309.28 (F43.23) With mixed anxiety and depressed mood
309.3 (F43.24) With disturbance of conduct
309.4 (F43.25) With mixed disturbance of emotions and conduct
309.9 (F43.20) Unspecified
309.89 (F43.8) Other Specified Trauma- and Stressor-Related Disorder (289)
309.9 (F43.9) Unspecified Trauma- and Stressor-Related Disorder (290)
Dissociative Disorders (291)
300.14 (F44.81) Dissociative Identity Disorder (292)
300.12 (F44.0) Dissociative Amnesia (298)
300.13 (F44.1) With dissociative fugue
300.6 (F48.1) Depersonalization/Derealization Disorder (302)
300.15 {F44.89) Other Specified Dissociative Disorder (306)
300.15 (F44.9) Unspecified Dissociative Disorder (307)
Somatic Symptom and Related Disorders (309)
300.82 (F45.1) Somatic Symptom Disorder (311)
Specify  if: With predominant pain

300.7 (F45.21) Illness Anxiety Disorder (315)
Specify  whether: Care seeking type. Care avoidant type
300.11 ( ._ ) Conversion Disorder (Functional Neurological Symptom
Disorder) (318)
Specify  symptom type:
(F44.4) With weakness or paralysis
(F44.4) With abnormal movement
(F44.4) With swallowing symptoms
(F44.4) With speech symptom
{F44.5) With attacks or seizures
(F44.6) With anesthesia or sensory loss
(F44.6) With special sensory symptom
(F44.7) With mixed symptoms
Specify  if: Acute episode, Persistent
Specify  if: With psychological stressor (specify stressor). Without psycho­
logical stressor

316 (F54)  
300.19 (F68.10)
300.89 (F45.8)  
300.82 (F45.9)Psychological Factors Affecting Other Medical Conditions (322) 
Specify  current severity: Mild, Moderate, Severe, Extreme
Factitious Disorder (includes Factitious Disorder Imposed on Self, 
Factitious Disorder Imposed on Another) (324)
Specify  Single episode. Recurrent episodes
Other Specified Somatic Symptom and Related Disorder (327) 
Unspecified Somatic Symptom and Related Disorder (327)
Feeding and Eating Disorders (329)
The following specifiers apply to Feeding and Eating Disorders where indicated:
^Specify  if: In remission
^Specify  if: In partial remission, In full remission
^Specify  current severity: Mild, Moderate, Severe, Extreme
307.52 ( . ) Pica® (329)
(F98.3) In children
(F50.8) In adults
307.53 (F98.21) Rumination Disorder^ (332)
307.59 {F50.8) Avoidant/Restrictive Food Intake Disorder^ (334)
307.1 ( . ) Anorexia Nervosa^' ^  (338) 
(F50.01) Restricting type
(F50.02) Binge-eating/purging type

307.51 (F50.2) Bulimia Nervosa^' ^  (345)
307.51 (F50.8) Binge-Eating Disorder^' ^  (350)
307.59 (F50.8) Other Specified Feeding or Eating Disorder (353)
307.50 (F50.9) Unspecified Feeding or Eating Disorder (354)
Elimination Disorders (355)
307.6 (F98.0) Enuresis (355)
Specify  whether: Nocturnal only. Diurnal only. Nocturnal and diurnal
307.7 (F98.1) Encopresis (357)
Specify  whether: With constipation and overflow incontinence. Without 
constipation and overflow incontinence
. ( _ .  ) Other Specified Elimination Disorder (359)
788.39 (N39.498) With urinary symptoms
787.60 (R15.9) With fecal symptoms
. ( . ) Unspecified Elimination Disorder (360)
788.30 (R32) With urinary symptoms

Sleep-Wake Disorders (361)
The following specifiers apply to Sleep-Wake Disorders where indicated:
^Specify  if: Episodic, Persistent, Recurrent 
^Specify  if: Acute, Subacute, Persistent 
^Specify  current severity: Mild, Moderate, Severe
780.52 (G47.00) Insomnia Disorder^ (362)
Specify  if: With non-sleep disorder mental comorbidity. With other 
medical comorbidity. With other sleep disorder
Hypersoninolence Disorder^' ^  (368)
Specify  if: With mental disorder. With medical condition. With another 
sleep disorder
Narcolepsy^ (372)
Narcolepsy v^ithout cataplexy but with hypocretin deficiency 
Narcolepsy with cataplexy but without hypocretin deficiency 
Autosomal dominant cerebellar ataxia, deafness, and 
narcolepsy
Autosomal dominant narcolepsy, obesity, and type 2 diabetes 
Narcolepsy secondary to another medical condition780.54 (G47.10)
347.00 (G47.419)
347.01 (G47.411)
347.00 (G47.419)  
347.10 (G47.429)
Breathing-Related Sleep Disorders (378)

327.23 (G47.33) Obstructive Sleep Apnea Hypopnea^ (378)
327.21 (G47.31)  
786.04 (R06.3)  
780.57 (G47.37)
327.24 (G47.34)
327.25 (G47.35)
327.26 (G47.36)
307.45 (G47.21)
307.45 (G47.22)
307.45 (G47.23)
307.45 (G47.24)Central Sleep Apnea (383)
Idiopathic central sleep apnea 
Cheyne-Stokes breathing 
Central sleep apnea comorbid with opioid use 
Note: First code opioid use disorder, if present.
Specify  current severity
Sleep-Related Hypoventilation (387)
Idiopathic hypoventilation 
Congenital central alveolar hypoventilation 
Comorbid sleep-related hypoventilation 
Circadian Rhythm Sleep-Wake Disorders^ (390)
Delayed sleep phase type (391)
Specify  if: Familial, Overlapping with non-24-hour sleep-wake type

Specify  if: Familial, Overlapping with non-24-hour sleep-wake type 
Advanced sleep phase type (393)
Specify  if: Familial
Irregular sleep-wake type (394)
Non-24-hour sleep-wake type (396)

307.45 (G47.26)
307.45 (G47.20)
Parasomnias (399)Shift work type (397) 
Unspecified type
307.46 (F51.3)
307.46 (F51.4)
307.47 (F51.5)
327.42 (G47.52)  
333.94 (025.81)
( _ . _ )
780.52 (G47.09)
780.52 (G47.00)
780.54 (G47.19)
780.54 (G47.10)
780.59 (G47.8)
780.59 (G47.9)Non-Rapid Eye Movement Sleep Arousal Disorders (399)
Sleepwalking type
Specify  if: With sleep-related eating. With sleep-related sexual 
behavior (sexsomnia)
Sleep terror type
Nightmare Disorder^' ^  (404)
Specify  if: During sleep onset
Specify  if: With associated non-sleep disorder. With associated other 
medical condition. With associated other sleep disorder
Rapid Eye Movement Sleep Behavior Disorder (407)
Restless Legs Syndrome (410)
Substance/Medication-Induced Sleep Disorder (413)
Specify  whether: Insomnia type. Daytime sleepiness type, Parasomnia

Specify  whether: Insomnia type. Daytime sleepiness type, Parasomnia 
type. Mixed type
Specify  if: With onset during intoxication. With onset during discontinua­
tion/withdrawal
Other Specified Insomnia Disorder (420)
Unspecified Insonmia Disorder (420)
Other Specified Hypersomnolence Disorder (421)
Unspecified Hypersomnolence Disorder (421)
Other Specified Sleep-Wake Disorder (421)
Unspecified Sleep-Wake Disorder (422)
Sexual Dysfunctions (423)
The following specifiers apply to Sexual Dysfunctions where indicated:
^Specify  whether: Lifelong, Acquired 
^Specify  whether: Generalized, Situational 
302.74 (F52.32) Delayed Ejaculation®' ^ (424)
Erectile Disorder®' (426)
Female Orgasmic Disorder®' * ^ ' (429)
Specify  if: Never experienced an orgasm under any situation
Female Sexual Interest/Arousal Disorder®' (433)

Female Sexual Interest/Arousal Disorder®' (433) 
Genito-Pelvic Pain/Penetration Disorder®' ^ (437)302.72 (F52.21)
302.73 (F52.31)
302.72 (F52.22)  
302.76 (F52.6)

302.71 (F52.0)  
302.75 (F52.4)
302.79 (F52.8)  
302.70 (F52.9)Male Hypoactive Sexual Desire Disorder^' ^  (440)
Premature (Early) Ejaculation^' ^ (443)
Substance/Medication-Induced Sexual Dysfunction^ (446)
Other Specified Sexual Dysfunction (450)
Unspecified Sexual Dysfunction (450)
Gender Dysplioria (451)
. { ·  ) Gender Dysphoria (452)
302.6 (F64.2) Gender Dysphoria in Children
Specify  if: With a disorder of sex development
302.85 (F64.1) Gender Dysphoria in Adolescents and Adults 
Specify  if: With a disorder of sex development 
Specify  if: Posttransition 
Note: Code the disorder of sex development if present, in addition to 
gender dysphoria.
302.6 (F64.8) Other Specified Gender Dysphoria (459)
302.6 (F64.9) Unspecified Gender Dysphoria (459)

Disruptive, impuise-Control, and Conduct Disorders (461)
313.81 (F91.3) Oppositional Defiant Disorder (462)
312.34 (F63.81) Intermittent Explosive Disorder (466)
■ 'Conduct Disorder (469) 
312.81 (F91.1) Childhood-onset type
312.32 (F91.2) Adolescent-onset type
312.89 (F91.9) Unspecified onset 
Specify  if: With limited prosocial emotions 
301.7 (F60.2) Antisocial Personality Disorder (476)
312.33 {F63.1) Pyromania (476)
312.32 (F63.3) Kleptomania (478)
312.89 (F91.8) Other Specified Disruptive, Impulse-Control, and Conduct 
Disorder (479)
312.9 (F91.9) Unspecified Disruptive, Impulse-Control, and Conduct Disorder 
(480)

Substance-Related and Addictive Disorders (481)
The following specifiers and note apply to Substance-Related and Addictive Disorders where 
indicated:
^Specify  if: In early remission. In sustained remission 
^Specify  if: In a controlled environment 
^Specify  if: With perceptual disturbances
^The ICD-IO-CM code indicates the comorbid presence of a moderate or severe substance use 
disorder, which must be present in order to apply the code for substance withdrawal.
Substance-Related Disorders (483)
Alcohol-Related Disorders (490)
. ( . ) Alcohol Use Disorder®' (490)
Specify  current severity:
305.00 (F10.10) Mild
303.90 (FI 0.20) Moderate
303.90 (F10.20) Severe
303.00 ( . ) Alcohol Intoxication (497)
(F10.129) With use disorder, mild
(F10.229) With use disorder, moderate or severe
(F10.929) Without use disorder
291.81 ( ._ ) Alcohol Withdrawal^' ^  (499)
(FI0.239) Without perceptual disturbances
(FI 0.232) With perceptual disturbances
. ( ._ ) Other Alcohol-Induced Disorders (502)

291.9 (FI 0.99) Unspecified Alcohol-Related Disorder (503)
Caffeine-Related Disorders (503)
305.90 (F15.929) Caffeine Intoxication (503)
292.0 (F15.93) Caffeine Withdrawal (506)
. ( _ ·  ) Other Caffeine-Induced Disorders (508)
292.9 (FI 5.99) Unspecified Caffeine-Related Disorder (509)
Cannabis-Related Disorders (509)
. ( ■  ) Cannabis Use Disorder^' ^  (509)
305.20 (F12.10) Mild
304.30 (F12.20) Moderate
304.30 (F12.20) Severe

292.89 ( _ _
(F12.129)  
(Fl 2.229)  
(F12.929)
(F12.122)  
(F12.222)  
(F12.922)
(F12.288)  
( _ . _ )292.0
292.9 (F12.99)
Hallucinogen-Related Disorders (520)Cannabis Intoxication‘s  (516)
Without perceptual disturbances 
With use disorder, mild 
With use disorder, moderate or severe 
Without use disorder 
With perceptual disturbances 
Without use disorder
Cannabis Withdrawal*^ (517)
Other Cannabis-Induced Disorders (519) 
Unspecified Cannabis-Related Disorder (519)
305.90 (F16.10)
304.60 (F16.20)
( _ ■ _ )
305.30 (F16.10)
304.50 (F16.20)
292.89 ( _ _._)
(F16.129)  
(F16.229)  
(F16.929)
292.89 ( _ _._ )Phencyclidine Use Disorder®' (520)
Mild
Moderate
Severe
Other Hallucinogen Use Disorder®' (523) 
Specify  the particular hallucinogen 
Mild
Moderate
Severe
Phencyclidine Intoxication (527)
With use disorder, mild

Moderate
Severe
Mild
Moderate
Severe
With use disorder, moderate or severe
Other Hallucinogen Intoxication (529)
Hallucinogen Persisting Perception Disorder (531) 
Other Phencyclidine-Induced Disorders (532) 
Other Hallucinogen-Induced Disorders (532) 
Unspecified Phencyclidine-Related Disorder (533) 
Unspecified Hallucinogen-Related Disorder (533) 
Inhalant-Related Disorders (533)
___. _  ( _ _._ ) Inhalant Use Disorder®' (533)
Specify  the particular inhalant 
305.90 (F18.10) Mild(F16.129)  
(F16.229)  
(F16.929)  
292.89 (F16.983)  
( _ . _ )
292.9
292.9(F16.99)
(F16.99)

304.60 (F18.20)
(F18.129)  
(F18.229)  
(F18.929)
( _ ■ _ )  
292.9 (F18.99)Moderate
Severe
Inhalant Intoxication (538)
Other Inhalant-Induced Disorders (540) 
Unspecified Inhalant-Related Disorder (540)
Opioid-Related Disorders (540)
___.__ (___. __) Opioid Use Disorder® (541)
Specify  if: On maintenance therapy, In a controlled environment 
305.50 (F11.10) Mild
304.00 (F11.20) Moderate
304.00 (F11.20) Severe
292.89 ( . ) Opioid Intoxication‘ s  (546)
Without perceptual disturbances
(F11.129) With use disorder, mild
(F11.229) With use disorder, moderate or severe
(F11.929) Without use disorder
With perceptual disturbances
(F11.122) With use disorder, mild
(F11.222) With use disorder, moderate or severe
(F11.922) Without use disorder
292.0 (F11.23) Opioid Withdrawal‘ s (547)
. ( ■  ) Other Opioid-Induced Disorders (549)

292.9 (F11.99) Unspecified Opioid-Related Disorder (550)
Sedative-, Hypnotic-, or Anxiolytic-Related Disorders (550)
■  ( -  ) Sedative, Hypnotic, or Anxiolytic Use Disorder^' ^  (550)
305.40 (F13.10) Mild
304.10 (F13.20) Moderate
304.10 (F13.20) Severe
292.89 ( . ) Sedative, Hypnotic, or Anxiolytic Intoxication (556)
(F13.129) With use disorder, mild
(F13.229) With use disorder, moderate or severe
(F13.929) Without use disorder
292.0 ( . ) Sedative, Hypnotic, or Anxiolytic Withdrawal^' ^  (557)
(FI 3.239) Without perceptual disturbances
(F13.232) With perceptual disturbances

___.__ (_ _.__) Other Sedative-, Hypnotic-, or Anxiolytic-Induced Disorders
(560)
292.9 (F13.99) Unspecified Sedative-, Hypnotic-, or Anxiolytic-Related Disorder
(560)
305.70  
305.60
305.70Stimulant-Related
( _ ■ _ )
(F15.10)
(F14.10)
(F15.10)
( _ ■ _ )
(F15.20)
(F14.20)
(F15.20)
( _ . _ )
(F15.20)
(F14.20)
(F15.20)304.40  
304.20
304.40
304.40  
304.20
304.40
292.89 ( _ _._ )
(F15.129)  
(F15.229)  
(F15.929)
292.89 ( _ _._J
(F14.129)  
(F14.229)  
(F14.929)
(F15.122)  
(F15.222)  
(F15.922)
292.89 ( __._ )
(F14.122)  
(F14.222)  
(F14.922)
292.0 ( _ _._ )
(F15.23)  
(FI 4.23)
( _ . _ )Disorders (561)
Stimulant Use Disorder®'*^ (561)
Mild
Amphetamine-t)φe substance 
Cocaine
Other or unspecified stimulant 
Moderate
Amphetamine-type substance 
Cocaine
Severe
Cocaine
Other or unspecified stimulant
Stimulant Intoxication‘ s  (567)
Specify  the specific intoxicant

Cocaine
Severe
Cocaine
Amphetamine or other stimulant. Without perceptual 
disturbances 
Cocaine, Without perceptual disturbances 
Amphetamine or other stimulant. With perceptual 
Cocaine, With perceptual disturbances 
Stimulant Withdrawal*^ (569)
Specify  the specific substance causing the withdrawal syndrome 
Amphetamine or other stimulant 
Cocaine
Other Stimulant-Induced Disorders (570)

292.9 (_ _.__) Unspecified Stimulant-Related Disorder (570)
(FI 5.9^ 9) Amphetamine or other stimulant
(FI 4.99) Cocaine
Tobacco-Related Disorders (571)
■ ( ._ ) Tobacco Use Disorder® (571)
Specify  if: On maintenance therapy. In a controlled environment 
305.1 (Z72.0) Mild
305.1 (F17.200) Moderate
305.1 (F17.200) Severe
292.0 (F17.203) Tobacco Withdrawal*^ (575)
■ ( . ) Other Tobacco-Induced Disorders (576)
292.9 (FI 7.209) Unspecified Tobacco-Related Disorder (577)
Other (or Unknown) Substance-Related Disorders (577)
— ■ - (_ _ . ) Other (or Unknown) Substance Use Disorder®' (577) 
305.90 (F19.10) Mild
304.90 (F19.20) Moderate
304.90 (F19.20) Severe
292.89 ( _ .  ) Other (or Unknown) Substance Intoxication (581)
(FI 9.129) With use disorder, mild
(F19.229) With use disorder, moderate or severe
(F19.929) Without use disorder
292.0 (F19.239) Other (or Unknown) Substance Withdrawal*^ (583)

■ ( ._ ) Other (or Unknown) Substance-Induced Disorders (584)
292.9 (F19.99) Unspecified Other (or Unknovm) Substance-Related Disorder (585)
Non-Substance-Related Disorders (585)
312.31 (F63.0) Gambling Disorder^ (585)
Specify  if: Episodic, Persistent
Neurocognitive Disorders (591)
292.81 ( _ _._J
293.0 (F05)Delirium (596)
^Note: See the criteria set and corresponding recording procedures for 
Substance intoxication delirium^
Substance withdrawal delirium^
Medication-induced delirium^
Delirium due to another medical condition

293.0 (F05) Delirium due to multiple etiologies
Specify  if: Acute, Persistent
Specify  if: Hyperactive, Hypoactive, Mixed level of activity
780.09  (R41.0) Other Specified Delirium (602)
780.09 (R41.0) Unspecified Delirium (602)
Major and Mild Neurocognitive Disorders (602)
Specify  whether due to: Alzheimer's disease, Frontotemporal lobar degeneration, Lewy body 
disease. Vascular disease. Traumatic brain injury. Substance/medication use, HIV infection. 
Prion disease, Parkinson's disease, Huntington's disease. Another medical condition. Multi­
ple etiologies. Unspecified 
^Specify  Without behavioral disturbance. With behavioral disturbance. For possible major neuro­
cognitive disorder and for mild neurocognitive disorder, behavioral disturbance cannot be coded but  
should still be indicated in writing.
^Specify  current severity: Mild, Moderate, Severe. This specifier applies only to major neurocogni­
tive disorders (including probable and possible).

Note: As indicated for each subtype, an additional medical code is needed for probable major 
neurocognitive disorder or major neurocognitive disorder. An additional medical code should 
not be used for possible major neurocognitive disorder or mild neurocognitive disorder.
Major or Mild Neurocognitive Disorder Due to Alzheimer’s Disease (611)
___.__ (___. __) Probable Major Neurocognitive Disorder Due to Alzheimer's
Disease^
Note: Code first 331.0 (G30.9) Alzheimer's disease.
294.11 (F02.81 ) With behavioral disturbance
294.10 (F02.80) Without behavioral disturbance
331.9 (G31.9) Possible Major Neurocognitive Disorder Due to Alzheimer's
Disease^' ^
331.83 (G31.84) Mild Neurocognitive Disorder Due to Alzheimer's Disease^ 
Major or Mild Frontotemporal Neurocognitive Disorder (614)

___.__ (_ _.__) Probable Major Neurocognitive Disorder Due to Frontotemporal
Lobar Degeneration^
Note: Code first 331.19 (G31.09) frontotemporal disease.
294.11  (F02.81 ) With behavioral disturbance
294.10  (F02.80) Without behavioral disturbance
331.9  (G31.9) Possible Major Neurocognitive Disorder Due to Frontotemporal
Lobar Degeneration^' ^
331.83  (G31,84) Mild Neurocognitive Disorder Due to Frontotemporal Lobar
Degeneration^
Major or Mild Neurocognitive Disorder With Lewy Bodies (618)
___.__ (_ _.__) Probable Major Neurocognitive Disorder With Lew ^y Bodies^
Note: Code first 331.82 (G31.83) Lewy body disease.

—■—( ·_)
290.40 (FOI .51)
290.40 (FOI .50)
331.9 (G31.9)
331.83 (G31.84)331.9 (G31.9) Possible Major Neurocognitive Disorder With Lewy Bodies^' ^ 
331 -83 (G31.84) Mild Neurocognitive Disorder With Lewy Bodies^
Major or Mild Vascular Neurocognitive Disorder (621)
Probable Major Vascular Neurocognitive Disorder^
Note: No additional medical code for vascular disease.
With behavioral disturbance 
Without behavioral disturbance 
Possible Major Vascular Neurocognitive Disorder^' ^
Mild Vascular Neurocognitive Disorder^
Major or Mild Neurocognitive Disorder Due to Traumatic Brain Injury (624)
___.__ (_ _.__) Major Neurocognitive Disorder Due to Traumatic Brain Injury^
Note: For ICD-9-CM, code first 907.0 late effect of intracranial injury without 
skull fracture. For ICD-IO-CM, code first S06.2X9S diffuse traumatic brain 
injury with loss of consciousness of unspecified duration, sequela.

331.83 (G31.84) Mild Neurocognitive Disorder Due to Traumatic Brain Injury^
Substance/Medication-Induced Major or Mild Neurocognitive Disorder^ (627)
Note: No additional medical code. See the criteria set and corresponding recording procedures 
for substance-specific codes and ICD-9-CM and ICD-IO-CM coding.
Major or Mild Neurocognitive Disorder Due to HIV Infection (632)
Major Neurocognitive Disorder Due to HIV Infection^
Note: Code first 042 (B20) HIV infection.
Mild Neurocognitive Disorder Due to HIV Infection^
Major or Mild Neurocognitive Disorder Due to Prion Disease (634)
___.__ (___.__) Major Neurocognitive Disorder Due to Prion Disease^
Note: Code first 046.79 (A81.9) prion disease.

331.83  (G31.84) Mild Neurocognitive Disorder Due to Prion Disease^
Major or Mild Neurocognitive Disorder Due to Parkinson’s Disease (636)
_ _.__ (_ _.__) Major Neurocognitive Disorder Probably Due to Parkinson's
Disease^
Note: Code first 332.0 (G20) Parkinson's disease.
294.10 (F02.80) Without behavioral disturbance----■—( ._)
294.11 (F02.81)
294.10 (F02.80)
331.83 (G31.84)

331.9 (G31 .9) Major Neurocognitive Disorder Possibly Due to Parkir\son's
Disease®' ^
331.83 (G31.84) Mild Neurocognitive Disorder Due to Parkinson's Disease®
Major or Mild Neurocognitive Disorder Due to Huntington’s Disease (638)
___.__ (_ _.__) Major Neurocognitive Disorder Due to Huntington's Disease*’
Note: Code first 333.4 (G IO ) Huntington's disease.
331 -83 (G31.84) Mild Neurocognitive Disorder Due to Huntington's Disease^
Major or Mild Neurocognitive Disorder Due to Another Medical Condition (641)
___.__ (___. __) Major Neurocognitive Disorder Due to Another Medical
Condition^
Note: Code first the other medical condition.
331.83 (G31.84) Mild Neurocognitive Disorder Due to Another Medical
Major or Mild Neurocognitive Disorder Due to Multiple Etiologies (642)

___.__ (_ _.__) Major Neurocognitive Disorder Due to Multiple Etiologies^
Note: Code first all the etiological medical conditions (with the exception 
of vascular disease).
331.83  (G31.84) Mild Neurocognitive Disorder Due to Multiple Etiologies^
Unspecified Neurocognitive Disorder (643)
799.59 (R41.9) Unspecified Neurocognitive Disorder^
Personality Disorders (645)
Cluster A Personality Disorders
301.0 (F60.0) Paranoid Personality Disorder (649)
301.20 (F60.1) Schizoid Personality Disorder (652)
301.22 (F21) Schizotypal Personality Disorder (655)
Cluster B Personality Disorders
301.7 (F60.2) Antisocial Personality Disorder (659)
301.83 (F60.3) Borderline Personality Disorder (663)

301.50 (F60.4) Histrionic Personality Disorder (667)
301.81 (F60.81) Narcissistic Personality Disorder (669)

Cluster C Personality Disorders
301.82 (F60.6V Avoidant Personality Disorder (672)
301.6 (F60.7) Dependent Personality Disorder (675)
301.4 (F60.5) Obsessive-Compulsive Personality Disorder (678)
Other Personality Disorders
310.1 (F07.0) Personality Change Due to Another Medical Condition (682)
Specify  whether: Labile type, Disinhibited type. Aggressive type, Apathetic 
type. Paranoid type. Other type. Combined type. Unspecified type
301.89 (F60.89) Other Specified Personality Disorder (684)
301.9 (F60.9) Unspecified Personality Disorder (684)
Paraphilic Disorders (685)
The following specifier applies to Paraphilic Disorders where indicated: 
^Specify  if: In a controlled environment. In full remission
302.82 (F65.3)  
302.4 (F65.2)
302.89 (F65.81)
302.83 (F65.51)
302.84 (F65.52)  
302.2 (F65.4)
302.81 (F65.0)
302.3 (F65.1)
302.89 (F65.89)
302.9 (F65.9)Voyeuristic Disorder® (686)
Exhibitionistic Disorder® (689)
Specify  whether: Sexually aroused by exposing genitals to prepubertal

Specify  whether: Sexually aroused by exposing genitals to prepubertal 
children. Sexually aroused by exposing genitals to physically mature 
individuals. Sexually aroused by exposing genitals to prepubertal chil­
dren and to physically mature individuals
Frotteuristic Disorder® (691)
Sexual Masochism Disorder® (694)
Specify  if: With asphyxiophilia
Sexual Sadism Disorder® (695)
Pedophilic Disorder (697)
Specify  whether: Exclusive type. Nonexclusive type 
Specify  if: Sexually attracted to males. Sexually attracted to females. Sexu­
ally attracted to both 
Specify  if: Limited to incest
Fetishistic Disorder® (700)
Specify:  Body part(s). Nonliving object(s). Other 
Transvestic Disorder® (702)
Specify  if: With fetishism. With autogynephilia 
Other Specified Paraphilic Disorder (705)
Unspecified Paraphilic Disorder (705)
Other Mental Disorders (707)

294.8 (F06.8) Other Specified Mental Disorder Due to Another Medical
Condition (707)
294.9 (F09) Unspecified Mental Disorder Due to Another Medical Condition
(708)
300.9 (F99) Other Specified Mental Disorder (708)
300.9 (F99) Unspecified Mental Disorder (708)

Medication-Induced iVlovement Disorders and  
Other Adverse Effects of iVledication (709)
332.1 (G21.11) Neuroleptic-Induced Parkinsonism (709)
332.1 (G21.19) Other Medication-Induced Parkinsonism (709)
333.92 (G21.0) Neuroleptic Malignant Syndrome (709)
333.72 (G24.02) Medication-Induced Acute Dystonia (711)
333.99 (G25.71) Medication-Induced Acute Akathisia (711)
333.85 (G24.01) Tardive Dyskinesia (712)
333.72 (G24.09) Tardive Dystonia (712)
333.99 (G25.71) Tardive Akathisia (712)
333.1 (G25.1) Medication-Induced Postural Tremor (712)
333.99 (G25.79) Other Medication-Induced Movement Disorder (712)
. ( . ) Antidepressant Discontinuation Syndrome (712)
995.29 (T43.205A) Initial encounter
995.29 (T43.205D) Subsequent encounter
995.29 (T43.205S) Sequelae
. ( ■  ) Other Adverse Effect of Medication (714)
995.20 (T50.905A) Initial encounter
995.20 (T50.905D) Subsequent encounter
995.20 (T50.905S) Sequelae
Other Conditions That iVlay Be a Focus  
of Ciinicai Attention (715)

Relational Problems (715)
Problems Related to Family Upbringing (715)
V61.20 (Z62.820) Parent-Child Relational Problem (715)
V61.8 (Z62.891 ) Sibling Relational Problem (716)
V61.8 (Z62.29) Upbringing Away From Parents (716)
V61.29 (Z62.898) Child Affected by Parental Relationship Distress (716)
Other Problems Related to Primary Support Group (716)
V61.10 (Z63.0) Relationship Distress With Spouse or Intimate Partner (716) 
V61.03 (Z63.5) Disruption of Family by Separation or Divorce (716)
V61.8 (Z63.8) High Expressed Emotion Level Within Family (716)
V62.82 (Z63.4) Uncomplicated Bereavement (716)

Abuse and Neglect (717)
Child ΜβΙίΓ63ίφ6ηΙ and Neglect Problems (717)
Child Physical Abuse (717)
Child Physical Abuse, Confirmed (717)
995.54 (T74.12XA) Initialencounter
995.54 {T74.12XD) Subsequent encounter
Child Physical Abuse, Suspected (717)
995.54 (T76.12XA) Initialencounter
995.54 (T76.12XD) Subsequent encounter
Other Circumstances Related to Child Physical Abuse (718)
V61.21 (Z69.01 0) Encounter for mental health services for victim of child abuse
by parent
V61.21 (Z69.020) Encounter for mental health services for victim of nonparental
child abuse
VI 5.41 (Z62.810) Personal history (past history) of physical abuse in childhood 
V61.22 (Z69.011  ) Encounter for mental health services for perpetrator of parental
V62.83 (Z69.021) Encounter for mental health services for perpetrator of
nonparental child abuse
Child Sexual Abuse (718)
Child Sexual Abuse, Confirmed (718)
995.53 (T74.22XA) Initial encounter
995.53 (T74.22XD) Subsequent encounter

Child Sexual Abuse, Suspected (718)
995.53 (T76.22XA) Initialencounter
995.53 (T76.22XD) Subsequent encounter
Other Circumstances Related to Child Sexual Abuse (718)
V61.21 (Z69.010) Encounter for mental health services for victim of child sexual
abuse by parent
child sexual abuse
V15.41 (Z62.810) Personal history (past history) of sexual abuse in childhood 
nonparental child sexual abuse
Child Neglect (718)
Child Neglect, Confirmed (718)
995.52 (T74.02XA) Initial encounter
995.52 (T74.02XD) Subsequent encounter

Child Neglect, Suspected (719)
995.52 (T76.02XA) Initialencounter
995.52 (T76.02XD) Subsequent encounter 
Other Circumstances Related to Child Neglect (719)
V61.21 (Z69.010) Encounter for mental health services for victim of child neglect
by parent
child neglect
VI 5.42 (Z62.812) Personal history (past history) of neglect in childhood
nonparental child neglect
Child Psychological Abuse (719)
Child Psychological Abuse, Confirmed (719)
995.51 (T74.32XA) Initial encounter
995.51 (T74.32XD) Subsequent encounter
Child Psychological Abuse, Suspected (719)
995.51 (T76.32XA) Initial encounter
995.51 (T76.32XD) Subsequent encounter
Other Circumstances Related to Child Psychological Abuse (719)

V61.21 (Z69.010) Encounter for mental health services for victim of child
psychological abuse by parent 
child psychological abuse 
VI 5.42 (Z62.811) Personal history (past history) of psychological abuse in
childhood
nonparental child psychological abuse
Adult Maltreatment and Neglect Problems (720)
Spouse or Partner Violence, Physical (720)
Spouse or Partner Violence, Physical, Confirmed (720)
995.81 (T74.11XA) Initial encounter
995.81 (T74.11XD) Subsequent encounter
Spouse or Partner Violence, Physical, Suspected (720)

995.81 (T76.11XA) Initialencounter
995.81 (T76.11XD) Subsequent encounter
Other Circumstances Related to Spouse or Partner Violence, Physical (720)
V61.11 (Z69.11) Encounter for mental health services for victim of spouse or
partner violence, physical

V15.41 (Z91.410) Personal history (past history) of spouse or partner violence,
physical
V61.12 (Z69.12) Encounter for mental health services for perpetrator of spouse
or partner violence, physical
Spouse or Partner Violence, Sexual (720)
Spouse or Partner Violence, Sexual, Confirmed (720)
995.83 (T74.21XA) Irûtial encounter
995.83 (T74.21XD) Subsequent encounter
Spouse or Partner Violence, Sexual, Suspected (720)
995.83 (T76.21XA) Initialencounter
995.83 (T76.21XD) Subsequent encounter
Other Circumstances Related to Spouse or Partner Violence, Sexual (720)
V61.11 (Z69.81 ) Encounter for mental health services for victim of spouse or
partner violence, sexual 
VI 5.41 (Z91.410) Personal history (past history) of spouse or partner violence,
sexual
or partner violence, sexual
Spouse or Partner, Neglect (721)
Spouse or Partner Neglect, Confirmed (721)
995.85 (T74.01XA) Initialencounter

995.85 (T74.01XD) Subsequent encounter
Spouse or Partner Neglect, Suspected (721)
995.85 (T76.01XA) Initialencounter
995.85 (T76.01XD) Subsequent encounter
Other Circumstances Related to Spouse or Partner Neglect (721)
partner neglect
VI 5.42 (Z91.412) Personal history (past history) of spouse or partner neglect 
or partner neglect
Spouse or Partner Abuse, Psychological (721)
Spouse or Partner Abuse, Psychological, Confirmed (721)
995.82 (T74.31XA) Initialencounter
995.82 (T74.31XD) Subsequent encounter
Spouse or Partner Abuse, Psychological, Suspected (721)
995.82 (T76.31XA) Initialencounter
995.82 (T76.31XD) Subsequent encounter

Other Circumstances Related to Spouse or Partner Abuse, Psychological (721)
V61.11 (Z69.11  ) Encounter for mental health services for victim of spouse or
partner psychological abuse

V15.42 (Z91.411) Personal history (past history) of spouse or partner
psychological abuse
or partner psychological abuse
Adult Abuse by Nonspouse or Nonpartner (722)
Adult Physical Abuse by Nonspouse or Nonpartner, Confirmed (722)
995.81 (T74.11XA) Initialencounter
Adult Physical Abuse by Nonspouse or Nonpartner, Suspected (722)
Adult Sexual Abuse by Nonspouse or Nonpartner, Confirmed (722)
995.83 (T74.21XA) Initialencounter
Adult Sexual Abuse by Nonspouse or Nonpartner, Suspected (722)
995.83 (T76.21XA) Irütial encounter
Adult Psychological Abuse by Nonspouse or Nonpartner, Confirmed (722)

Adult Psychological Abuse by Nonspouse or Nonpartner, Suspected (722)
Other Circumstances Related to Adult Abuse by Nonspouse or Nonpartner (722) 
V65.49 (Z69.81) Encoxmter for mental health services for victim of nonspousal
adult abuse
V62.83 (Z69.82) Encovmter for mental health services for perpetrator of
nonspousal adult abuse
Educational and Occupational Problems (723)
Educational Problems (723)
V62.3 (Z55.9) Academic or Educational Problem (723)
Occupational Problems (723)
V62.21 (Z56.82) Problem Related to Current Military Deployment Status (723) 
V62.29 (Z56.9) Other Problem Related to Employment (723)
Housing and Economic Problems (723)
Housing Problems (723)
V60.0 (Z59.0) Homelessness (723)

V60.1 (Z59.1) Inadequate Housing (723)

V60.89 (Z59.2) Discord With Neighbor, Lodger, or Landlord (723)
V60.6 (Z59.3V Problem Related to Living in a Residential Institution (724)
Economic Problems (724)
V60.2 (Z59.4) Lack of Adequate Food or Safe Drinking Water (724)
V60.2 (Z59.5) Extreme Poverty (724)
V60.2 (Z59.6) Low Income (724)
V60.2 (Z59.7) Insufficient Social Insurance or Welfare Support (724)
V60.9 (Z59.9) Unspecified Housing or Economic Problem (724)
Other Problems Related to the Social Environment (724)
V62.89 (Z60.0) Phase of Life Problem (724)
V60.3 (Z60.2) Problem Related to Living Alone (724)
V62.4 (Z60.3) Acculturation Difficulty (724)
V62.4 (Z60.4) Social Exclusion or Rejection (724)
V62.4 (Z60.5) Target of (Perceived) Adverse Discrimination or Persecution (724)
V62.9 (Z60.9) Unspecified Problem Related to Social Environment (725)
Problems Related to Crime or Interaction With the Legal System (725)
V62.89 (Z65.4) Victim of Crime (725)
V62.5 (Z65.0) Conviction in Civil or Criminal Proceedings Without

V62.5 (Z65.0) Conviction in Civil or Criminal Proceedings Without 
Imprisonment (725)
V62.5 (Z65.1) Imprisonment or Other Incarceration (725)
V62.5 (Z65.2) Problems Related to Release From Prison (725)
V62.5 (Z65.3) Problems Related to Other Legal Circumstances (725)
Other Health Service Encounters for Counseling and Medical Advice (725)  
V65.49 (Z70.9) Sex Counseling (725)
V65.40 (271.9) Other Counseling or Consultation (725)
Problems Related to Other Psychosocial, Personal, and Environmental  
Circumstances (725)
V62.89 (Z65.8) Religious or Spiritual Problem (725)
V61.7 (Z64.0) Problems Related to Unwanted Pregnancy (725)
V61.5 (Z64.1) Problems Related to Multiparity (725)
V62.89 (Z64.4) Discord With Social Service Provider, Including Probation
Officer, Case Manager, or Social Services Worker (725)
V62.89 (Z65.4) Victim of Terrorism or Torture (725)

V62.22 (Z65.5) Exposure to Disaster, War, or Other Hostilities (725)
V62.89 (Z65.8) Other Problem Related to Psychosocial Circumstances (725)
V62.9 (Z65.9) Unspecified Problem Related to Unspecified Psychosocial

V15.49 (Z91.49)
V15.59 (Z91.5)
V62.22 (Z91.82)
V15.89 (Z91.89)
V69.9 (Z72.9)
V71.01 (Z72.811)
V71.02 (Z72.810)Other Circumstances of Personal History (726)
Other Personal History of Psychological Trauma (726)
Personal History of Self-Harm (726)
Personal History of Military Deployment (726)
Other Personal Risk Factors (726)
Problem Related to Lifestyle (726)
Adult Antisocial Behavior (726)
Child or Adolescent Antisocial Behavior (726)
Problems Related to Access to Medical and Other Health Care (726)
V63.9 (Z75.3) Unavailability or Inaccessibility of Health Care Facilities (726) 
V63.8 (Z75.4) Unavailability or Inaccessibility of Other Helping Agencies (726)
Nonadherence to Medical Treatment (726)
V15.81 (Z91.19) Nonadherence to Medical Treatment (726)
278.00 (E66.9) Overweight or Obesity (726)
V65.2 (Z76.5) Malingering (726)
V40.31 (Z91.83) Wandering Associated With a Mental Disorder (727)
V62.89 (R41.83) Borderline Intellectual Functioning (727)

Preface
ΤΙΊΘ A m G riC Sn P s y c h iâ t r ic  Association's Diagnostic and Statistical Manual of  
Mental Disorders  (DSM) is a classification of mental disorders with associated criteria de­
signed to facilitate more reliable diagnoses of these disorders. With successive editions 
over the past 60 years, it has become a standard reference for clinical practice in the mental 
health field. Since a complete description of the underlying pathological processes is not 
possible for most mental disorders, it is important to emphasize that the current diagnos­
tic criteria are the best available description of how mental disorders are expressed and 
can be recognized by trained clinicians. DSM is intended to serve as a practical, functional, 
and flexible guide for organizing information that can aid in the accurate diagnosis and 
treatment of mental disorders. It is a tool for clinicians, an essential educational resource

treatment of mental disorders. It is a tool for clinicians, an essential educational resource 
for students and practitioners, and a reference for researchers in the field.
Although this edition of DSM was designed first and foremost to be a useful guide to 
clinical practice, as an official nomenclature it must be applicable in a wide diversity of 
contexts. DSM has been used by clinicians and researchers from different orientations (bi­
ological, psychodynamic, cognitive, behavioral, interpersonal, family/systems), all of 
whom strive for a common language to communicate the essential characteristics of men­
tal disorders presented by their patients. The information is of value to all professionals 
associated with various aspects of mental health care, including psychiatrists, other 
physicians, psychologists, social workers, nurses, counselors, forensic and legal special­

ists, occupational and rehabilitation therapists, and other health professionals. The criteria 
are concise and explicit and intended to facilitate an objective assessment of symptom pre­
sentations in a variety of clinical settings—inpatient, outpatient, partial hospital, consul­
tation-liaison, clinical, private practice, and primary care—as well in general community 
epidemiological studies of mental disorders. DSM-5 is also a tool for collecting and com­
municating accurate public health statistics on mental disorder morbidity and mortality 
rates. Finally, the criteria and corresponding text serve as a textbook for students early in 
their profession who need a structured way to understand and diagnose mental disorders

their profession who need a structured way to understand and diagnose mental disorders 
as well as for seasoned professionals encountering rare disorders for the first time. Fortu­
nately, all of these uses are mutually compatible.
These diverse needs and interests were taken into consideration in planning DSM-5. 
The classification of disorders is harmonized with the World Health Organization's Inter­
national Classification of Diseases  (ICD), the official coding system used in the United States, 
so that the DSM criteria define disorders identified by ICD diagnostic names and code 
numbers. In DSM-5, both ICD-9-CM and ICD-IO-CM codes (the latter scheduled for adop­
tion in October 2014) are attached to the relevant disorders in the classification.
Although DSM-5 remains a categorical classification of separate disorders, we recog­

nize that mental disorders do not always fit completely within the boundaries of a single 
disorder. Some symptom domains, such as depression and anxiety, involve multiple di­
agnostic categories and may reflect common underlying vulnerabilities for a larger group 
of disorders. In recognition of this reality, the disorders included in DSM-5 were reordered 
into a revised organizational structure meant to stimulate new clinical perspectives. This 
new structure corresponds with the organizational arrangement of disorders planned for 
ICD-11 scheduled for release in 2015. Other enhancements have been introduced to pro­
mote ease of use across all settings:
xli

•  Representation of developmental issues related to diagnosis. The change in chapter 
organization better reflects a lifespan approach, with disorders more frequently diag­
nosed in childhood (e.g., neurodevelopmental disorders) at the beginning of the man­
ual and disorders more applicable to older adulthood (e.g., neurocognitive disorders) 
at the end of the manual. Also, within the text, subheadings on development and course 
provide descriptions of how disorder presentations may change across the lifespan. 
Age-related factors specific to diagnosis (e.g., symptom presentation and prevalence 
differences in certain age groups) are also included in the text. For added emphasis, 
these age-related factors have been added to the criteria themselves where applicable 
(e.g., in the criteria sets for insomnia disorder and posttraumatic stress disorder, spe­
cific criteria describe how symptoms might be expressed in children). Likewise, gender

cific criteria describe how symptoms might be expressed in children). Likewise, gender 
and cultural issues have been integrated into the disorders where applicable.
•  Integration of scientific findings from the latest research in genetics and neuroimag­
ing. The revised chapter structure was informed by recent research in neuroscience and 
by emerging genetic linkages between diagnostic groups. Genetic and physiological 
risk factors, prognostic indicators, and some putative diagnostic markers are high­
lighted in the text. This new structure should improve clinicians' ability to identify di­
agnoses in a disorder spectrum based on common neurocircuitry, genetic vulnerability, 
and environmental exposures.
•  Consolidation of autistic disorder, Asperger's disorder, and pervasive developmen­
tal disorder into autism spectrum disorder. Symptoms of these disorders represent a

tal disorder into autism spectrum disorder. Symptoms of these disorders represent a 
single continuum of mild to severe impairments in the two domains of social commu­
nication and restrictive repetitive behaviors/interests rather than being distinct disor­
ders. This change is designed to improve the sensitivity and specificity of the criteria for 
the diagnosis of autism spectrum disorder and to identify more focused treatment tar­
gets for the specific impairments identified.
•  Streamlined classification of bipolar and depressive disorders. Bipolar and depres­
sive disorders are the most commonly diagnosed conditions in psychiatry. It was there­
fore important to streamline the presentation of these disorders to enhance both clinical 
and educational use. Rather than separating the definition of manic, hypomanie, and

and educational use. Rather than separating the definition of manic, hypomanie, and 
major depressive episodes from the definition of bipolar I disorder, bipolar II disorder, 
and major depressive disorder as in the previous edition, we included all of the com­
ponent criteria within the respective criteria for each disorder. This approach will facil­
itate bedside diagnosis and treatment of these important disorders. Likewise, the 
explanatory notes for differentiating bereavement and major depressive disorders will 
provide far greater clinical guidance than was previously provided in the simple be­
reavement exclusion criterion. The new specifiers of anxious distress and mixed fea­
tures are now fully described in the narrative on specifier variations that accompanies 
the criteria for these disorders.
•  Restructuring of substance use disorders for consistency and clarity. The categories

•  Restructuring of substance use disorders for consistency and clarity. The categories 
of substance abuse and substance dependence have been eliminated and replaced with 
an overarching new category of substance use disorders—with the specific substance 
used defining the specific disorders. "Dependence" has been easily confused with the 
term "addiction" when, in fact, the tolerance and withdrawal that previously defined 
dependence are actually very normal responses to prescribed medications that affect 
the central nervous system and do not necessarily indicate the presence of an addiction. 
By revising and clarifying these criteria in DSM-5, we hope to alleviate some of the 
widespread misunderstanding about these issues.
•  Enhanced specificity for major and mild neurocognitive disorders. Given the explo­
sion in neuroscience, neuropsychology, and brain imaging over the past 20 years, it was

sion in neuroscience, neuropsychology, and brain imaging over the past 20 years, it was 
critical to convey the current state-of-the-art in the diagnosis of specific types of disor­
ders that were previously referred to as the "dementias" or organic brain diseases. Bi­
ological markers identified by imaging for vascular and traumatic brain disorders and

specific molecular genetic findings for rare variants of Alzheimer's disease and Hun­
tington's disease have greatly advanced clinical diagnoses, and these disorders and 
others have now been separated into specific subtypes.
•  Transition in conceptualizing personality disorders. Although the benefits of a more 
dimensional approach to personality disorders have been identified in previous edi­
tions, the transition from a categorical diagnostic system of individual disorders to one 
based on the relative distribution of personality traits has not been widely accepted. In 
DSM-5, the categorical personality disorders are virtually unchanged from the previous 
edition. However, an alternative "hybrid" model has been proposed in Section III to 
guide future research that separates interpersonal functioning assessments and the ex­
pression of pathological personality traits for six specific disorders. A more dimensional

pression of pathological personality traits for six specific disorders. A more dimensional 
profile of personality trait expression is also proposed for a trait-specified approach.
•  Section III: new disorders and features. A new section (Section III) has been added to 
highlight disorders that require further study but are not sufficiently well established to 
be a part of the official classification of mental disorders for routine clinical use. Dimen­
sional measures of symptom severity in 13 symptom domains have also been incorpo­
rated to allow for the measurement of symptom levels of varying severity across all 
diagnostic groups. Likewise, the WHO Disability Assessment Schedule (WHODAS), a 
standard method for assessing global disability levels for mental disorders that is based 
on the International Classification of Functioning, Disability and Health (ICF) and is ap­

plicable in all of medicine, has been provided to replace the more limited Global As­
sessment of Functioning scale. It is our hope that as these measures are implemented 
over time, they will provide greater accuracy and flexibility in the clinical description of 
individual symptomatic presentations and associated disability during diagnostic as­
sessments.
•  Online enhancements. DSM-5 features online supplemental information. 
Additional cross-cutting and diagnostic severity measures are available online 
(www.psychiatry.org/dsm5), linked to the relevant disorders. In addition, the Cul­
tural Formulation Interview, Cultural Formulation Interview—Informant Version, and 
supplementary modules to the core Cultural Formulation Interview are also included 
online at www.psychiatry.org/dsm5.

These innovations were designed by the leading authorities on mental disorders in the 
world and were implemented on the basis of their expert review, public commentary, and 
independent peer review. The 13 work groups, under the direction of the DSM-5 Task 
Force, in conjunction with other review bodies and, eventually, the APA Board of Trust­
ees, collectively represent the global expertise of the specialty. This effort was supported 
by an extensive base of advisors and by the professional staff of the APA Division of Re­
search; the names of everyone involved are too numerous to mention here but are listed in 
the Appendix. We owe tremendous thanks to those who devoted countless hours and in­
valuable expertise to this effort to improve the diagnosis of mental disorders.
We would especially like to acknowledge the chairs, text coordinators, and members of

We would especially like to acknowledge the chairs, text coordinators, and members of 
the 13 work groups, listed in the front of the manual, who spent many hours in this vol­
unteer effort to improve the scientific basis of clinical practice over a sustained 6-year pe­
riod. Susan K. Schultz, M.D., who served as text editor, worked tirelessly with Emily A. 
Kuhl, Ph.D., senior science writer and DSM-5 staff text editor, to coordinate the efforts of 
the work groups into a cohesive whole. William E. Narrow, M.D., M.P.H., led the research 
group that developed the overall research strategy for DSM-5, including the field trials, 
that greatly enhanced the evidence base for this revision. In addition, we are grateful to 
those who contributed so much time to the independent review of the revision proposals, 
including Kenneth S. Kendler, M.D., and Robert Freedman, M.D., co-chairs of the Scien­

tific Review Committee; John S. McIntyre, M.D., and Joel Yager, M.D., co-chairs of the 
Clinical and Public Health Committee; and Glenn Martin, M.D., chair of the APA Assem­

bly review process. Special thanks go to Helena C. Kraemer, Ph.D., for her expert statistical 
consultation; Michael B. First, M.D., for his valuable input on the coding and review of cri­
teria; and Paul S. Appelbaum, M.D., for feedback on forensic issues. Maria N. Ward, 
M.Ed., RHIT, CCS-P, also helped in verifying all ICD coding. The Summit Group, which 
included these consultants, the chairs of all review groups, the task force chairs, and the 
APA executive officers, chaired by Dilip V. Jeste, M.D., provided leadership and vision in 
helping to achieve compromise and consensus. This level of commitment has contributed 
to the balance and objectivity that we feel are hallmarks of DSM-5.
We especially wish to recognize the outstanding APA Division of Research staff— 
identified in the Task Force and Work Group listing at the front of this manual—who 
worked tirelessly to interact with the task force, work groups, advisors, and reviewers to

worked tirelessly to interact with the task force, work groups, advisors, and reviewers to 
resolve issues, serve as liaisons between the groups, direct and manage the academic and 
routine clinical practice field trials, and record decisions in this important process. In par­
ticular, we appreciate the support and guidance provided by James H. Scully Jr., M.D., 
Medical Director and CEO of the APA, through the years and travails of the development 
process. Finally, we thank the editorial and production staff of American Psychiatric Pub­
lishing—specifically, Rebecca Rinehart, Publisher; John McDuffie, Editorial Director; Ann 
Eng, Senior Editor; Greg Kuny, Managing Editor; and Tammy Cordova, Graphics Design 
Manager—for their guidance in bringing this all together and creating the final product. It 
is the culmination of efforts of many talented individuals who dedicated their time, exper­

tise, and passion that made DSM-5 possible.
DSM-5 Task Force Chair
DSM-5 Task Force Vice-Chair 
December 19, 2012

Introduction.................................................................................................. 5
Use of the Manual .................................................................................... 19
Cautionary Statement for Forensic Use of DSM-5 .................................. 25

This section is a basic orientation to the purpose, structure, content, and  
use of DSM-5. It is not intended to provide an exhaustive account of the evo­
lution of DSM-5, but rather to give readers a succinct overview of its key ele­
ments. The introductory section describes the public, professional, and expert  
review process that was used to extensively evaluate the diagnostic criteria  
presented in Section II. A summary of the DSM-5 structure, harmonization with  
ICD-11, and the transition to a non-axial system with a new approach to as­
sessing disability is also presented. “ Use of the Manual”  includes “Definition of  
a Mental Disorder,”  forensic considerations, and a brief overview of the diag­
nostic process and use of coding and recording procedures.

Introduction
ΤΙΊΘ C rG âtion of the fifth edition of Diagnostic and Statistical Manual of Mental Disorders  
(DSM-5) was a massive undertaking that involved hundreds of people working toward a 
common goal over a 12-year process. Much thought and deliberation were involved in 
evaluating the diagnostic criteria, considering the organization of every aspect of the man­
ual, and creating new features believed to be most useful to clinicians. All of these efforts 
were directed toward the goal of enhancing the clinical usefulness of DSM-5 as a guide in 
the diagnosis of mental disorders.
Reliable diagnoses are essential for guiding treatment recommendations, identifying 
prevalence rates for mental health service planning, identifying patient groups for clinical 
and basic research, and documenting important public health information such as mor­
bidity and mortality rates. As the understanding of mental disorders and their treatments

bidity and mortality rates. As the understanding of mental disorders and their treatments 
has evolved, medical, scientific, and clinical professionals have focused on the character­
istics of specific disorders and their implications for treatment and research.
While DSM has been the cornerstone of substantial progress in reliability, it has been well 
recognized by both the American Psychiatric Association (APA) and the broad scientific com­
munity working on mental disorders that past science was not mature enough to yield fully 
validated diagnoses—that is, to provide consistent, strong, and objective scientific validators 
of individual DSM disorders. The science of mental disorders continues to evolve. However, 
the last two decades since DSM-IV was released have seen real and durable progress in such 
areas as cognitive neuroscience, brain imaging, epidemiology, and genetics. The DSM-5 Task

areas as cognitive neuroscience, brain imaging, epidemiology, and genetics. The DSM-5 Task 
Force overseeing the new edition recognized that research advances will require careful, iter­
ative changes if DSM is to maintain its place as the touchstone classification of mental disor­
ders. Finding the right balance is critical. Speculative results do not belong in an official 
nosology, but at the same time, DSM must evolve in the context of other clinical research ini­
tiatives in the field. One important aspect of this transition derives from the broad recognition 
that a too-rigid categorical system does not capture clinical experience or important scientific 
observations. The results of numerous studies of comorbidity and disease transmission in fam­
ilies, including twin studies and molecular genetic studies, make strong arguments for what

ilies, including twin studies and molecular genetic studies, make strong arguments for what 
many astute clinicians have long observed: the boundaries between many disorder "catego­
ries" are more fluid over the life course than DSM-IV recognized, and many symptoms as­
signed to a single disorder may occur, at varying levels of severity, in many other disorders. 
These findings mean that DSM, like other medical disease classifications, should accommo­
date ways to introduce dimensional approaches to mental disorders, including dimensions 
that cut across current categories. Such an approach should permit a more accurate description 
of patient presentations and increase the validity of a diagnosis (i.e., the degree to which diag­
nostic criteria reflect the comprehensive manifestation of an underlying psychopathological

nostic criteria reflect the comprehensive manifestation of an underlying psychopathological 
disorder). DSM-5 is designed to better fill the need of clinicians, patients, families, and re­
searchers for a clear and concise description of each mental disorder organized by explicit di­
agnostic criteria, supplemented, when appropriate, by dimensional measures that cross 
diagnostic boundaries, and a brief digest of information about the diagnosis, risk factors, as­
sociated features, research advances, and various expressions of the disorder.
Clinical training and experience are needed to use DSM for determining a diagnosis. The 
diagnostic criteria identify symptoms, behaviors, cognitive functions, personality traits, phys­
ical signs, syndrome combinations, and durations that require clinical expertise to differenti­

ate from normal life variation and transient responses to stress. To facilitate a thorough

examination of the range of symptoms present, DSM can serve clinicians as a guide to identify 
the most prominent symptoms that should be assessed when diagnosing a disorder. Although 
some mental disorders may have well-defined boundaries around symptom clusters, scien­
tific evidence now places many, if not most, disorders on a spectrum with closely related dis­
orders that have shared symptoms, shared genetic and environmental risk factors, and 
possibly shared neural substrates (perhaps most strongly established for a subset of anxiety 
disorders by neuroimaging and animal models). In short, we have come to recognize that the 
boundaries between disorders are more porous than originally perceived.
Many health profession and educational groups have been involved in the development 
and testing of DSM-5, including physicians, psychologists, social workers, nurses, counselors, 
epidemiologists, statisticians, neuroscientists, and neuropsychologists. Finally, patients, fam­

ilies, lawyers, consumer organizations, and advocacy groups have all participated in revising 
DSM-5 by providing feedback on the mental disorders described in this volume. Their moni­
toring of the descriptions and explanatory text is essential to improve understanding, reduce 
stigma, and advance the treatment and eventual cures for these conditions.
A Brief History
The APA first published a predecessor of DSM in 1844, as a statistical classification of in­
stitutionalized mental patients. It was designed to improve communication about the 
types of patients cared for in these hospitals. This forerunner to DSM also was used as a 
component of the full U.S. census. After World War II, DSM evolved through four major

component of the full U.S. census. After World War II, DSM evolved through four major 
editions into a diagnostic classification system for psychiatrists, other physicians, and 
other mental health professionals that described the essential features of the full range of 
mental disorders. The current edition, DSM-5, builds on the goal of its predecessors (most 
recently, DSM-IV-TR, or Text Revision, published in 2000) of providing guidelines for di­
agnoses that can inform treatment and management decisions.
DSM-5 Revision Process
In 1999, the APA launched an evaluation of the strengths and weaknesses of DSM based on 
emerging research that did not support the boundaries established for some mental disor­
ders. This effort was coordinated with the World Health Organization (WHO) Division of 
Mental Health, the World Psychiatric Association, and the National Institute of Mental

Mental Health, the World Psychiatric Association, and the National Institute of Mental 
Health (NIMH) in the form of several conferences, the proceedings of which were published 
in 2002 in a monograph entitled A Research Agenda for DSM-V.  Thereafter, from 2003 to 2008, 
a cooperative agreement with the APA and the WHO was supported by the NIMH, the Na­
tional Institute on Drug Abuse (NIDA), and the National Institute on Alcoholism and Alco­
hol Abuse (NI A A A) to convene 13 international DSM-5 research planning conferences, 
involving 400 participants from 39 countries, to review the world literature in specific diag­
nostic areas to prepare for revisions in developing both DSM-5 and the International Classi­
fication of Diseases,  11th Revision (ICD-11). Reports from these conferences formed the basis 
for future DSM-5 Task Force reviews and set the stage for the new edition of DSM.

In 2006, the APA named David J. Kupfer, M.D., as Chair and Darrel A. Regier, M.D., 
M.P.H., as Vice-Chair of the DSM-5 Task Force. They were charged with recommending 
chairs for the 13 diagnostic work groups and additional task force members with a multi­
disciplinary range of expertise who would oversee the development of DSM-5. An addi­
tional vetting process was initiated by the APA Board of Trustees to disclose sources of 
income and thus avoid conflicts of interest by task force and work group members. The full 
disclosure of all income and research grants from commercial sources, including the phar­
maceutical industry, in the previous 3 years, the imposition of an income cap from all com­
mercial sources, and the publication of disclosures on a Web site set a new standard for the

field. Thereafter, the task force of 28 members was approved in 2007, and appointments of 
more than 130 work group members were approved in 2008. More than 400 additional 
work group advisors with no voting authority were also approved to participate in the pro­
cess. A clear concept of the next evolutionary stage for the classification of mental disorders 
was central to the efforts of the task force and the work groups. This vision emerged as the 
task force and work groups recounted the history of DSM-IV's classification, its current 
strengths and limitations, and strategic directions for its revision. An intensive 6-year pro­
cess involved conducting literature reviews and secondary analyses, publishing research 
reports in scientific journals, developing draft diagnostic criteria, posting preliminary 
drafts on the DSM-5 Web site for public comment, presenting preliminary findings at pro­
fessional meetings, performing field trials, and revising criteria and text.

Proposals for Revisions
Proposals for the revision of DSM-5 diagnostic criteria were developed by members of the 
work groups on the basis of rationale, scope of change, expected impact on clinical man­
agement and public health, strength of the supporting research evidence, overall clarity, 
and clinical utility. Proposals encompassed changes to diagnostic criteria; the addition of 
new disorders, subtypes, and specifiers; and the deletion of existing disorders.
In the proposals for revisions, strengths and weaknesses in the current criteria and no­
sology were first identified. Novel scientific findings over the previous two decades were 
considered, leading to the creation of a research plan to assess potential changes through 
literature reviews and secondary data analyses. Four principles guided the draft revisions:

literature reviews and secondary data analyses. Four principles guided the draft revisions: 
1) DSM-5 is primarily intended to be a manual to be used by clinicians, and revisions must 
be feasible for routine clinical practice; 2) recommendations for revisions should be guided 
by research evidence; 3) where possible, continuity should be maintained with previous 
editions of DSM; and 4) no a priori constraints should be placed on the degree of change 
between DSM-IV and DSM-5.
Building on the initial literature reviews, work groups identified key issues within 
their diagnostic areas. Work groups also examined broader methodological concerns, 
such as the presence of contradictory findings within the literature; development of a re­
fined definition of mental disorder; cross-cutting issues relevant to all disorders; and the

fined definition of mental disorder; cross-cutting issues relevant to all disorders; and the 
revision of disorders categorized in DSM-IV as '"not otherwise specified." Inclusion of a 
proposal for revision in Section II was informed by consideration of its advantages and 
disadvantages for public health and clinical utility, the strength of the evidence, and the 
magnitude of the change. New diagnoses and disorder subtypes and specifiers were sub­
ject to additional stipulations, such as demonstration of reliability (i.e., the degree to which 
two clinicians could independently arrive at the same diagnosis for a given patient). Dis­
orders with low clinical utility and weak validity were considered for deletion. Placement 
of conditions in ''Conditions for Further Study" in Section III was contingent on the

of conditions in ''Conditions for Further Study" in Section III was contingent on the 
amount of empirical evidence generated on the diagnosis, diagnostic reliability or valid­
ity, presence of clear clinical need, and potential benefit in advancing research.
DSIVI-5 Fieid Triais
The use of field trials to empirically demonstrate reliability was a noteworthy improvement in­
troduced in DSM-III. The design and implementation strategy of the DSM-5 Field Trials rep­
resent several changes over approaches used for DSM-III and DSM-IV, particularly in 
obtaining data on the precision of kappa reliability estimates (a statistical measure that assesses 
level of agreement between raters that corrects for chance agreement due to prevalence rates) 
in the context of clinical settings with high levels of diagnostic comorbidity. For DSM-5, field

in the context of clinical settings with high levels of diagnostic comorbidity. For DSM-5, field 
trials were extended by using two distinctive designs: one in large, diverse medical-academic 
settings, and the other in routine clinical practices. The former capitalized on the need for large 
sample sizes to test hypotheses on reliability and clinical utility of a range of diagnoses in a

variety of patient populations; the latter supplied valuable information about how proposed 
revisions performed in everyday clinical settings among a diverse sample of DSM users. It is 
anticipated that future clinical and basic research studies will focus on the validity of the re­
vised categorical diagnostic criteria and the underlying dimensional features of these disor­
ders (including those now being explored by the N IB/IH  Research Domain Criteria initiative).
The medical-academic field trials were conducted at 11 North American medical-academic 
sites and assessed the reliability, feasibility, and clinical utility of select revisions, with priority 
given to those that represented the greatest degree of change from DSM-IV or those potentially 
having the greatest public health impact. The full clinical patient populations coming to each 
site were screened for DSM-IV diagnoses or qualifying symptoms likely to predict several spe­

cific DSM-5 disorders of interest. Stratified samples of four to seven specific disorders, plus a 
stratum containing a representative sample of all other diagnoses, were identified for each site. 
Patients consented to the study and were randomly assigned for a clinical interview by a cli­
nician blind to the diagnosis, followed by a second interview with a clinician blind to previous 
diagnoses. Patients first filled out a computer-assisted inventory of cross-cutting symptoms in 
more than a dozen psychological domains. These inventories were scored by a central server, 
and results were provided to cliniciai\s before they conducted a typical clinical interview (with 
no structured protocol). Clinicians were required to score the presence of qualifying criteria on

no structured protocol). Clinicians were required to score the presence of qualifying criteria on 
a computer-assisted DSM-5 diagnostic checklist, determine diagnoses, score the severity of the 
diagnosis, and submit all data to the central Web-based server. This study design allowed the 
calculation of the degree to which two independent clinicians could agree on a diagnosis (us­
ing the intraclass kappa statistic) and the agreement of a single patient or two different clini­
cians on two separate ratings of cross-cutting symptoms, personality traits, disability, and 
diagnostic severity measures (using intraclass correlation coefficients) along with information 
on tiie precision of these estimates of reliability. It was also possible to assess the prevalence 
rates of both DSM-IV and DSM-5 conditions in the respective clinical populations.

The routine clinical practice field trials involved recruitment of individual psychiatrists 
and other mental health clinicians. A volunteer sample was recruited that included gener­
alist and specialty psychiatrists, psychologists, licensed clinical social workers, counselors, 
marriage and family therapists, and advanced practice psychiatric mental health nurses. 
The field trials provided exposure of the proposed DSM-5 diagnoses and dimensional mea­
sures to a wide range of clinicians to assess their feasibility and clinical utility.
Public and Professional Review
In 2010, the APA launched a unique Web site to facilitate public and professional input into 
DSM-5. All draft diagnostic criteria and proposed changes in organization were posted on

DSM-5. All draft diagnostic criteria and proposed changes in organization were posted on 
www.dsm5.org for a 2-month comment period. Feedback totaled more than 8,000 submis­
sions, which were systematically reviewed by each of the 13 work groups, whose members, 
where appropriate, integrated questions and comments into discussions of draft revisions 
and plans for field trial testing. After revisions to the initial draft criteria and proposed 
chapter organization, a second posting occurred in 2011. Work groups considered feedback 
from both Web postings and the results of the DSM-5 Field Trials when drafting proposed 
final criteria, which were posted on the Web site for a third and final time in 2012. These 
three iterations of external review produced more than 13,000 individually signed com­
ments on the Web site that were received and reviewed by the work groups, plus thousands

ments on the Web site that were received and reviewed by the work groups, plus thousands 
of organized petition signers for and against some proposed revisions, all of which allowed 
the task force to actively address concerns of DSM users, as well as patients and advocacy 
groups, and ensure that clinical utility remained a high priority.
Expert Review
The members of the 13 work groups, representing expertise in their respective areas, col­
laborated with advisors and reviewers under the overall direction of the DSM-5 Task

Force to draft the diagnostic criteria and accompanying text. This effort was supported by 
a team of APA Division of Research staff and developed through a network of text coor­
dinators from each work group. The preparation of the text was coordinated by the text 
editor, working in close collaboration with the work groups and under the direction of the 
task force chairs. The Scientific Review Committee (SRC) was established to provide a sci­
entific peer review process that was external to that of the work groups. The SRC chair, 
vice-chair, and six committee members were charged with reviewing the degree to which 
the proposed changes from DSM-IV could be supported with scientific evidence. Each 
proposal for diagnostic revision required a memorandum of evidence for change pre­
pared by the work group and accompanied by a summary of supportive data organized 
around validators for the proposed diagnostic criteria (i.e., antecedent validators such as

around validators for the proposed diagnostic criteria (i.e., antecedent validators such as 
familial aggregation, concurrent validators such as biological markers, and prospective 
validators such as response to treatment or course of illness). The submissions were re­
viewed by the SRC and scored according to the strength of the supportive scientific data. 
Other justifications for change, such as those arising from clinical experience or need or 
from a conceptual reframing of diagnostic categories, were generally seen as outside the 
purview of the SRC. The reviewers' scores, which varied substantially across the different 
proposals, and an accompanying brief commentary were then returned to the APA Board 
of Trustees and the work groups for consideration and response.
The Clinical and Public Health Committee (CPHC), composed of a chair, vice-chair, and

The Clinical and Public Health Committee (CPHC), composed of a chair, vice-chair, and 
six members, was appointed to consider additional clinical utility, public health, and log­
ical clarification issues for criteria that had not yet accumulated the type or level of evi­
dence deemed sufficient for change by the SRC. This review process was particularly 
important for DSM-IV disorders with known deficiencies for which proposed remedies 
had neither been previously considered in the DSM revision process nor been subjected to 
replicated research studies. These selected disorders were evaluated by four to five exter­
nal reviewers, and the blinded results were reviewed by CPHC members, who in turn 
made recommendations to the APA Board of Trustees and the work groups.
Forensic reviews by the members of the APA Council on Psychiatry and Law were con­

ducted for disorders frequently appearing in forensic environments and ones with high 
potential for influencing civil and criminal judgments in courtroom settings. Work groups 
also added forensic experts as advisors in pertinent areas to complement expertise pro­
vided by the Council on Psychiatry and Law.
The work groups themselves were charged with the responsibility to review the entire re­
search literature surrounding a diagnostic area, including old, revised, and new diagnostic cri­
teria, in an intensive 6-year review process to assess the pros and cons of making either small 
iterative changes or major conceptual changes to address the inevitable reification that occurs 
with diagnostic conceptual approaches that persist over several decades. Such changes in­

cluded the merger of previously separate diagnostic areas into more dimensional spectra, such 
as that which occurred with autism spectrum disorder, substance use disorders, sexual dys­
functions, and somatic symptom and related disorders. Other changes included correcting 
flaws that had become apparent over time in the choice of operational criteria for some disor­
ders. These types of changes posed particular challenges to the SRC and CPHC review pro­
cesses, which were not constructed to evaluate the validity of DSM-IV diagnostic criteria. 
However, the DSM-5 Task Force, which had reviewed proposed changes and had responsi­
bility for reviewing the text describing each disorder contemporaneously with the work

bility for reviewing the text describing each disorder contemporaneously with the work 
groups during this period, was in a unique position to render an ir\formed judgment on the sci­
entific merits of such revisions. Furthermore, many of these major changes were subject to field 
trial testing, although comprehensive testing of all proposed changes could not be accommo­
dated by such testing because of time limitations and availability of resources.
A final recommendation from the task force was then provided to the APA Board of 
Trustees and the APA Assembly's Committee on DSM-5 to consider some of the clinical 
utility and feasibility features of the proposed revisions. The assembly is a deliberative

body of the APA representing the district branches and wider membership that is com­
posed of psychiatrists from throughout the United States who provide geographic, prac­
tice size, and interest-based diversity. The Committee on DSM-5 is a committee made up 
of a diverse group of assembly leaders.
Following all of the preceding review steps, an executive "summit committee" session 
was held to consolidate input from review and assembly committee chairs, task force 
chairs, a forensic advisor, and a statistical advisor, for a preliminary review of each disor­
der by the assembly and APA Board of Trustees executive committees. This preceded a 
preliminary review by the full APA Board of Trustees. The assembly voted, in November 
2012, to recommend that the board approve the publication of DSM-5, and the APA Board 
of Trustees approved its publication in December 2012. The many experts, reviewers, and 
advisors who contributed to this process are listed in the Appendix.

Organizational Structure
The individual disorder definitions that constitute the operationalized sets of diagnostic 
criteria provide the core of DSM-5 for clinical and research purposes. These criteria have 
been subjected to scientific review, albeit to varying degrees, and many disorders have un­
dergone field testing for interrater reliability. In contrast, the classification of disorders (the 
way in which disorders are grouped, which provides a high-level organization for the man­
ual) has not generally been thought of as scientifically significant, despite the fact that judg­
ments had to be made when disorders were initially divided into chapters for DSM-III.
DSM is a medical classification of disorders and as such serves as a historically deter­

mined cognitive schema imposed on clinical and scientific information to increase its com­
prehensibility and utility. Not surprisingly, as the foundational science that ultimately led 
to DSM-III has approached a half-century in age, challenges have begun to emerge for cli­
nicians and scientists alike that are inherent in the DSM structure rather than in the de­
scription of any single disorder. These challenges include high rates of comorbidity within 
and across DSM chapters, an excessive use of and need to rely on "not otherwise specified" 
(NOS) criteria, and a growing inability to integrate DSM disorders with the results of ge­
netic studies and other scientific findings.
As the APA and the WHO began to plan their respective revisions of the DSM and the

As the APA and the WHO began to plan their respective revisions of the DSM and the 
International Classification of Disorders  (ICD), both considered the possibility of improving 
clinical utility (e.g., by helping to explain apparent comorbidity) and facilitating scientific 
investigation by rethinking the organizational structures of both publications in a linear 
system designated by alphanumeric codes that sequence chapters according to some ra­
tional and relational structure. It was critical to both the DSM-5 Task Force and the WHO 
International Advisory Group on the revision of the ICD-10 Section on Mental and Behav­
ioral Disorders that the revisions to the organization enhance clinical utility and remain 
within the bounds of well-replicated scientific information. Although the need for reform 
seemed apparent, it was important to respect the state of the science as well as the chal­

lenge that overly rapid change would pose for the clinical and research communities. In 
that spirit, revision of the organization was approached as a conservative, evolutionary di­
agnostic reform that would be guided by emerging scientific evidence on the relationships 
between disorder groups. By reordering and regrouping the existing disorders, the re­
vised structure is meant to stimulate new clinical perspectives and to encourage research­
ers to identify the psychological and physiological cross-cutting factors that are not bound 
by strict categorical designations.
The use of DSM criteria has the clear virtue of creating a common language for com­
munication between clinicians about the diagnosis of disorders. The official criteria and

munication between clinicians about the diagnosis of disorders. The official criteria and 
disorders that were determined to have accepted clinical applicability are located in Sec­
tion II of the manual. However, it should be noted that these diagnostic criteria and their

relationships within the classification are based on current research and may need to be 
modified as new evidence is gathered by future research both within and across the do­
mains of proposed disorders. "Conditions for Further Study," described in Section III, are 
those for which we determined that the scientific evidence is not yet available to support 
widespread clinical use. These diagnostic criteria are included to highlight the evolution 
and direction of scientific advances in these areas to stimulate further research.
With any ongoing review process, especially one of this complexity, different viewpoints 
emerge, and an effort was made to consider various viewpoints and, when warranted, ac­
commodate them. For example, personality disorders are included in both Sections II and 
III. Section II represents an update of the text associated with the same criteria found in 
DSM-IV-TR, whereas Section III includes the proposed research model for personality dis­

order diagnosis and conceptualization developed by the DSM-5 Personality and Personality 
Disorders Work Group. As this field evolves, it is hoped that both versions will serve clin­
ical practice and research initiatives.
Harmonization With ICD-11
The groups tasked with revising the DSM and ICD systems shared the overarching goal of 
harmonizing the two classifications as much as possible, for the following reasons:
•  The existence of two major classifications of mental disorders hinders the collection and 
use of national health statistics, the design of clinical trials aimed at developing new 
treatments, and the consideration of global applicability of the results by international 
regulatory agencies.
•  More broadly, the existence of two classifications complicates attempts to replicate sci­

entific results across national boundaries.
•  Even when the intention was to identify identical patient populations, DSM-IV and 
ICD-10 diagnoses did not always agree.
Early in the course of the revisions, it became apparent that a shared organizational 
structure would help harmonize the classifications. In fact, the use of a shared framework 
helped to integrate the work of DSM and ICD work groups and to focus on scientific is­
sues. The DSM-5 organization and the proposed linear structure of the ICD-11 have been 
endorsed by the leadership of the NIMH Research Domain Criteria (RDoC) project as con­
sistent with the initial overall structure of that project.
Of course, principled disagreements on the classification of psychopathology and on 
specific criteria for certain disorders were expected given the current state of scientific

specific criteria for certain disorders were expected given the current state of scientific 
knowledge. However, most of the salient differences between the DSM and the ICD classi­
fications do not reflect real scientific differences, but rather represent historical by-products 
of independent committee processes.
To the surprise of participants in both revision processes, large sections of the content 
fell relatively easily into place, reflecting real strengths in some areas of the scientific lit­
erature, such as epidemiology, analyses of comorbidity, twin studies, and certain other ge­
netically informed designs. When disparities emerged, they almost always reflected the 
need to make a judgment about where to place a disorder in the face of incomplete—or, 
more often, conflicting—data. Thus, for example, on the basis of patterns of symptoms, co­

morbidity, and shared risk factors, attention-deficit/hyperactivity disorder (ADHD) was 
placed with neurodevelopmental disorders, but the same data also supported strong ar­
guments to place ADHD within disruptive, impulse-control, and conduct disorders. 
These issues were settled with the preponderance of evidence (most notably validators ap­
proved by the DSM-5 Task Force). The work groups recognize, however, that future dis­
coveries might change the placement as well as the contours of individual disorders and, 
furthermore, that the simple and linear organization that best supports clinical practice

may not fully capture the complexity and heterogeneity of mental disorders. The revised 
organization is coordinated with the mental and behavioral disorders chapter (Chapter V) 
of ICD-11, which will utilize an expanded numeric-alphanumeric coding system. How­
ever, the official coding system in use in the United States at the time of publication of this 
manual is that of the International Classification of Diseases, Ninth Revision, Clinical Modifica­
tion (ICD-9-CM)—the U.S. adaptation of ICD-9. International Classification of Diseases, Tenth  
Revision, Clinical Modification  (ICD-IO-CM), adapted from ICD-10, is scheduled for imple­
mentation in the United States in October 2014. Given the impending release of ICD-11, it 
was decided that this iteration, and not ICD-10, would be the most relevant on which to focus 
harmonization. However, given that adoption of the ICD-9-CM coding system will remain

harmonization. However, given that adoption of the ICD-9-CM coding system will remain 
at the time of the DSM-5 release, it will be necessary to use the ICD-9-CM codes. Further­
more, given that DSM-5's organizational structure reflects the anticipated structure of 
ICD-11, the eventual ICD-11 codes will follow the sequential order of diagnoses in the 
DSM-5 chapter structure more closely. At present, both the ICD-9-CM and the ICD-IO-CM 
codes have been indicated for each disorder. These codes will not be in sequential order 
throughout the manual because they were assigned to complement earlier organizational 
structures.
Dimensional Approach to Diagnosis
Structural problems rooted in the basic design of the previous DSM classification, con­
structed of a large number of narrow diagnostic categories, have emerged in both clinical

structed of a large number of narrow diagnostic categories, have emerged in both clinical 
practice and research. Relevant evidence comes from diverse sources, including shidies of 
comorbidity and the substantial need for not otherwise specified diagnoses, which repre­
sent the majority of diagnoses in areas such as eating disorders, personality disorders, and 
autism spectrum disorder. Studies of both genetic and environmental risk factors, whether 
based on twin designs, familial transmission, or molecular analyses, also raise concerns 
about the categorical structure of the DSM system. Because the previous DSM approach 
considered each diagnosis as categorically separate from health and from other diagnoses, 
it did not capture the widespread sharing of symptoms and risk factors across many dis­
orders that is apparent in studies of comorbidity. Earlier editions of DSM focused on ex­

cluding false-positive results from diagnoses; thus, its categories were overly narrow, as is 
apparent from the widespread need to use NOS diagnoses. Indeed, the once plausible goal 
of identifying homogeneous populations for treatment and research resulted in narrow di­
agnostic categories that did not capture clinical reality, symptom heterogeneity within dis­
orders, and significant sharing of symptoms across multiple disorders. The historical 
aspiration of achieving diagnostic homogeneity by progressive subtyping within disorder 
categories no longer is sensible; like most common human ills, mental disorders are het­
erogeneous at many levels, ranging from genetic risk factors to symptoms.
Related to recommendations about alterations in the chapter structure of DSM-5, mem­

bers of the diagnostic spectra study group examined whether scientific validators could 
inform possible new groupings of related disorders within the existing categorical frame­
work. Eleven such indicators were recommended for this purpose: shared neural sub­
strates, family traits, genetic risk factors, specific environmental risk factors, biomarkers, 
temperamental antecedents, abnormalities of emotional or cognitive processing, symptom 
similarity, course of illness, high comorbidity, and shared treatment response. These indi­
cators served as empirical guidelines to inform decision making by the work groups and 
the task force about how to cluster disorders to maximize their validity and clinical utility.
A series of papers was developed and published in a prominent international journal

A series of papers was developed and published in a prominent international journal 
(Psychological Medicine,  Vol. 39,2009) as part of both the DSM-5 and the ICD-11 develop­
mental processes to document that such validators were most useful for suggesting large 
groupings of disorders rather than for "validating" individual disorder diagnostic criteria. 
The regrouping of mental disorders in DSM-5 is intended to enable future research to en-

hance understanding of disease origins and pathophysiological commonalities between 
disorders and provide a base for future replication wherein data can be reanalyzed over 
time to continually assess validity. Ongoing revisions of DSM-5 will make it a ''living doc­
ument," adaptable to future discoveries in neurobiology, genetics, and epidemiology.
On the basis of the published findings of this common DSM-5 and ICD-11 analysis, it 
was demonstrated that clustering of disorders according to what has been termed internal­
izing  and externalizing factors represents an empirically supported framework. Within both 
the internalizing group (representing disorders with prominent anxiety, depressive, and 
somatic symptoms) and the externalizing group (representing disorders with prominent 
impulsive, disruptive conduct, and substance use symptoms), the sharing of genetic and 
environmental risk factors, as shown by twin studies, likely explains much of the system­

atic comorbidities seen in both clinical and community samples. The adjacent placement of 
"internalizing disorders," characterized by depressed mood, anxiety, and related physio­
logical and cognitive symptoms, should aid in developing new diagnostic approaches, in­
cluding dimensional approaches, while facilitating the identification of biological markers. 
Similarly, adjacencies of the "externalizing group," including disorders exhibiting antiso­
cial behaviors, conduct disturbances, addictions, and impulse-control disorders, should en­
courage advances in identifying diagnoses, markers, and underlying mechanisms.
Despite the problem posed by categorical diagnoses, the DSM-5 Task Force recognized 
that it is premature scientifically to propose alternative definitions for most disorders. The

that it is premature scientifically to propose alternative definitions for most disorders. The 
organizational structure is meant to serve as a bridge to new diagnostic approaches with­
out disrupting current clinical practice or research. With support from DSM-associated 
training materials, the National Institutes of Health other funding agencies, and scientific 
publications, the more dimensional DSM-5 approach and organizational structure can fa­
cilitate research across current diagnostic categories by encouraging broad investigations 
within the proposed chapters and across adjacent chapters. Such a reformulation of re­
search goals should also keep DSM-5 central to the development of dimensional approaches 
to diagnosis that will likely supplement or supersede current categorical approaches in 
coming years.
Developmental and Lifespan Considerations

To improve clinical utility, DSM-5 is organized on developmental and lifespan consider­
ations. It begins with diagnoses thought to reflect developmental processes that manifest 
early in life (e.g., neurodevelopmental and schizophrenia spectrum and other psychotic 
disorders), followed by diagnoses that more commonly manifest in adolescence and 
young adulthood (e.g., bipolar, depressive, and anxiety disorders), and ends with diagno­
ses relevant to adulthood and later life (e.g., neurocognitive disorders). A similar approach 
has been taken, where possible, within each chapter. This organizational structure facili­
tates the comprehensive use of lifespan information as a way to assist in diagnostic deci­
sion making.
The proposed organization of chapters of DSM-5, after the neurodevelopmental disor­

ders, is based on groups of internalizing (emotional and somatic) disorders, externalizing 
disorders, neurocognitive disorders, and other disorders. It is hoped that this organization 
will encourage further study of underlying pathophysiological processes that give rise to 
diagnostic comorbidity and symptom heterogeneity. Furthermore, by arranging disorder 
clusters to mirror clinical reality, DSM-5 should facilitate identification of potential diag­
noses by non-mental health specialists, such as primary care physicians.
The organizational structure of DSM-5, along with ICD harmonization, is designed to 
provide better and more flexible diagnostic concepts for the next epoch of research and to 
serve as a useful guide to clinicians in explaining to patients why they might have received

serve as a useful guide to clinicians in explaining to patients why they might have received 
multiple diagnoses or why they might have received additional or altered diagnoses over 
their lifespan.

Cultural Issues
Mental disorders are defined in relation to cultural, social, and familial norms and values. 
Culture provides interpretive frameworks that shape the experience and expression of the 
symptoms, signs, and behaviors that are criteria for diagnosis. Culture is transmitted, re­
vised, and recreated within the family and other social systems and institutions. Diagnostic 
assessment must therefore consider whether an individual's experiences, symptoms, and 
behaviors differ from sociocultural norms and lead to difficulties in adaptation in the cul­
tures of origin and in specific social or familial contexts. Key aspects of culture relevant to di­
agnostic classification and assessment have been considered in the development of DSM-5.
In Section III, the "Cultural Formulation" contains a detailed discussion of culture and 
diagnosis in DSM-5, including tools for in-depth cultural assessment. In the Appendix, the

diagnosis in DSM-5, including tools for in-depth cultural assessment. In the Appendix, the 
"Glossary of Cultural Concepts of Distress" provides a description of some common cul­
tural syndromes, idioms of distress, and causal explanations relevant to clinical practice.
The boundaries between normality and pathology vary across cultures for specific types 
of behaviors. Thresholds of tolerance for specific symptoms or behaviors differ across cul­
tures, social settings, and families. Hence, the level at which an experience becomes prob­
lematic or pathological will differ. The judgment that a given behavior is abnormal and 
requires clinical attention depends on cultural norms that are internalized by the individual 
and applied by others around them, including family members and clinicians. Awareness of

and applied by others around them, including family members and clinicians. Awareness of 
the significance of culture may correct mistaken interpretations of psychopathology, but cul­
ture may also contribute to vulnerability and suffering (e.g., by amplifying fears that main­
tain panic disorder or health anxiety). Cultural meanings, habits, and traditions can also 
contribute to either stigma or support in the social and familial response to mental illness. 
Culture may provide coping strategies that enhance resilience in response to illness, or sug­
gest help seeking and options for accessing health care of various types, including alterna­
tive and complementary health systems. Culture may influence acceptance or rejection of a 
diagnosis and adherence to treatments, affecting the course of illness and recovery. Culture

diagnosis and adherence to treatments, affecting the course of illness and recovery. Culture 
also affects the conduct of the clinical encounter; as a result, cultural differences between the 
clinician and the patient have implications for the accuracy and acceptance of diagnosis as 
well as for treatment decisions, prognostic considerations, and clinical outcomes.
Historically, the construct of the culture-bound syndrome has been a key interest of 
cultural psychiatry. In DSM-5, this construct has been replaced by three concepts that offer 
greater clinical utility:
1. Cultural syndrome is a cluster or group of co-occurring, relatively invariant symptoms 
found in a specific cultural group, community, or context (e.g., ataque de nervios).  The 
syndrome may or may not be recognized as an illness within the culture (e.g., it might

syndrome may or may not be recognized as an illness within the culture (e.g., it might 
be labeled in various ways), but such cultural patterns of distress and features of illness 
may nevertheless be recognizable by an outside observer.
2. Cultural idiom of distress  is a linguistic term, phrase, or way of talking about suffering 
among individuals of a cultural group (e.g., similar ethnicity and religion) referring to 
shared concepts of pathology and ways of expressing, communicating, or naming es­
sential features of distress (e.g., kufiingisisa).  An idiom of distress need not be associated 
with specific symptoms, syndromes, or perceived causes. It may be used to convey a 
wide range of discomfort, including everyday experiences, subclinical conditions, or 
suffering due to social circumstances rather than mental disorders. For example, most

suffering due to social circumstances rather than mental disorders. For example, most 
cultures have common bodily idioms of distress used to express a wide range of suf­
fering and concerns.
3. Cultural explanation or perceived cause is a label, attribution, or feature of an explanatory 
model that provides a culturally conceived etiology or cause for symptoms, illness, or 
distress (e.g., maladi moun).  Causal explanations may be salient features of folk classi­
fications of disease used by laypersons or healers.

These three concepts (for which discussion and examples are provided in Section III 
and the Appenc^ix) suggest cultural ways of understanding and describing illness experi­
ences that can be elicited in the clinical encounter. They influence symptomatology, help 
seeking, clinical presentations, expectations of treatment, illness adaptation, and treat­
ment response. The same cultural term often serves more than one of these functions.
Gender Differences
Sex and gender differences as they relate to the causes and expression of medical conditions 
are established for a number of diseases, including selected mental disorders. Revisions to 
DSM-5 included review of potential differences between men and women in the expression 
of mental illness. In terms of nomenclature, sex differences  are variations attributable to an 
individual's reproductive organs and XX or XY chromosomal complement. Gender differ­

ences  are variations that result from biological sex as well as an individual's self-represen­
tation that includes the psychological, behavioral, and social consequences of one's 
perceived gender. The term gender differences  is used in DSM-5 because, more commonly, 
the differences between men and women are a result of both biological sex and individual 
self-representation. However, some of the differences are based on only biological sex.
Gender can influence illness in a variety of ways. First, it may exclusively determine 
whether an individual is at risk for a disorder (e.g., as in premenstrual dysphoric disor­
der). Second, gender may moderate the overall risk for development of a disorder as 
shown by marked gender differences in the prevalence and incidence rates for selected

shown by marked gender differences in the prevalence and incidence rates for selected 
mental disorders. Third, gender may influence the likelihood that particular symptoms of 
a disorder are experienced by an individual. Attention-def icit/hyper activity disorder is 
an example of a disorder with differences in presentation that are most commonly expe­
rienced by boys or girls. Gender likely has other effects on the experience of a disorder that 
are indirectly relevant to psychiatric diagnosis. It may be that certain symptoms are more 
readily endorsed by men or women, and that this contributes to differences in service pro­
vision (e.g., women may be more likely to recognize a depressive, bipolar, or anxiety dis­
order and endorse a more comprehensive list of symptoms than men).
Reproductive life cycle events, including estrogen variations, also contribute to gender

Reproductive life cycle events, including estrogen variations, also contribute to gender 
differences in risk and expression of illness. Thus, a specifier for postpartum onset of mania 
or major depressive episode denotes a time frame wherein women may be at increased risk 
for the onset of an illness episode. In the case of sleep and energy, alterations are often nor­
mative postpartum and thus may have lower diagnostic reliability in postpartum women.
The manual is configured to include information on gender at multiple levels. If there 
are gender-specific symptoms, they have been added to the diagnostic criteria. A gender- 
related specifier, such as perinatal onset of a mood episode, provides additional informa­
tion on gender and diagnosis. Finally, other issues that are pertinent to diagnosis and gen­
der considerations can be found in the section "Gender-Related Diagnostic Issues."

Use of Other Specified and Unspecified Disorders
To enhance diagnostic specificity, DSM-5 replaces the previous NOS designation with two 
options for clinical use: other specified disorder  and unspecified disorder.  The other specified 
disorder category is provided to allow the clinician to communicate the specific reason 
that the presentation does not meet the criteria for any specific category within a diagnos­
tic class. This is done by recording the name of the category, followed by the specific rea­
son. For example, for an individual with clinically significant depressive symptoms 
lasting 4 weeks but whose symptomatology falls short of the diagnostic threshold for a 
major depressive episode, the clinician would record "other specified depressive disorder,

major depressive episode, the clinician would record "other specified depressive disorder, 
depressive episode with insufficient symptoms." If the clinician chooses not to specify the

reason that the criteria are not met for a specific disorder, then "unspecified depressive 
disorder" would be diagnosed. Note that the differentiation between other specified and 
unspecified disorders is based on the clinician's decision, providing maximum flexibility 
for diagnosis. Clinicians do not have to differentiate between other specified and unspec­
ified disorders based on some feature of the presentation itself. When the clinician deter­
mines that there is evidence to specify the nature of the clinical presentation, the other 
specified diagnosis can be given. When the clinician is not able to further specify and de­
scribe the clinical presentation, the unspecified diagnosis can be given. This is left entirely 
up to clinical judgment.
For a more detailed discussion of how to use other specified and unspecified designa­
tions, see "Use of the Manual" in Section I.
The Multiaxial System

Despite widespread use and its adoption by certain insurance and governmental agencies, 
the multiaxial system in DSM-IV was not required to make a mental disorder diagnosis. A 
nonaxial assessment system was also included that simply listed the appropriate Axis I, II, 
and III disorders and conditions without axial designations. DSM-5 has moved to a nonax­
ial documentation of diagnosis (formerly Axes I, II, and III), with separate notations for 
important psychosocial and contextual factors (formerly Axis IV) and disability (formerly 
Axis V). This revision is consistent with the DSM-IV text that states, "The multiaxial dis­
tinction among Axis I, Axis II, and Axis III disorders does not imply that there are funda­
mental differences in their conceptualization, that mental disorders are unrelated to

mental differences in their conceptualization, that mental disorders are unrelated to 
physical or biological factors or processes, or that general medical conditions are unrelated 
to behavioral or psychosocial factors or processes." The approach of separately noting di­
agnosis from psychosocial and contextual factors is also consistent with established WHO 
and ICD guidance to consider the individual's functional status separately from his or her 
diagnoses or symptom status. In DSM-5, Axis III has been combined with Axes I and II. 
Clinicians should continue to list medical conditions that are important to the understand­
ing or management of an individual's mental disorder(s).
DSM-IV Axis IV covered psychosocial and environmental problems that may affect the 
diagnosis, treatment, and prognosis of mental disorders. Although this axis provided

diagnosis, treatment, and prognosis of mental disorders. Although this axis provided 
helpful information, even if it was not used as frequently as intended, the DSM-5 Task 
Force recommended that DSM-5 should not develop its own classification of psychosocial 
and environmental problems, but rather use a selected set of the ICD-9-CM V codes and 
the new Z codes contained in ICD-IO-CM. The ICD-10 Z codes were examined to deter­
mine which are most relevant to mental disorders and also to identify gaps.
DSM-IV Axis V consisted of the Global Assessment of Functioning (GAF) scale, repre­
senting the clinician's judgment of the individual's overall level of "functioning on a hy­
pothetical continuum of mental health-illness." It was recommended that the GAF be 
dropped from DSM-5 for several reasons, including its conceptual lack of clarity (i.e., in­

cluding symptoms, suicide risk, and disabilities in its descriptors) and questionable psy­
chometrics in routine practice. In order to provide a global measure of disability, the WHO 
Disability Assessment Schedule (WHODAS) is included, for further study, in Action III of 
DSM-5 (see the chapter "Assessment Measures"). The WHODAS is based on the Interna­
tional Classification of Functioning, Disability and Health (ICF) for use across all of medicine 
and health care. The WHODAS (version 2.0), and a modification developed for children/ 
adolescents and their parents by the Impairment and Disability Study Group were in­
cluded in the DSM-5 field trial.

Online Enhancements
It was challenging to determine what to include in the print version of DSM-5 to be most 
clinically relevant and useful and at the same time maintain a manageable size. For this 
reason, the inclusion of clinical rating scales and measures in the print edition is limited to 
those considered most relevant. Additional assessment measures used in the field trials 
are available online (www.psychiatry.org/dsm5), linked to the relevant disorders. The 
Cultural Formulation Interview, Cultural Formulation Interview—Informant Version, and 
supplementary modules to the core Cultural Formulation Interview are also available on­
line at www.psychiatry.org/dsm5.
DSM-5 is available as an online subscription at PsychiatryOnline.org as well as an e­
book. The online component contains modules and assessment tools to enhance the diag­
nostic criteria and text. Also available online is a complete set of supportive references as

nostic criteria and text. Also available online is a complete set of supportive references as 
well as additional helpful information. The organizational structure of DSM-5, its use of 
dimensional measures, and compatibility with ICD codes will allow it to be readily adapt­
able to future scientific discoveries and refinements in its clinical utility. DSM-5 will be an­
alyzed over time to continually assess its validity and enhance its value to clinicians.

Use of the Manual
T h e  in tr o d u c tio n  contains much of the history and developmental process of the 
DSM-5 revision. This section is designed to provide a practical guide to using DSM-5, par­
ticularly in clinical practice. The primary purpose of DSM-5 is to assist trained clinicians 
in the diagnosis of their patients' mental disorders as part of a case formulation assess­
ment that leads to a fully informed treatment plan for each individual. The symptoms con­
tained in the respective diagnostic criteria sets do not constitute comprehensive 
definitions of underlying disorders, which encompass cognitive, emotional, behavioral, 
and physiological processes that are far more complex than can be described in these brief 
summaries. Rather, they are intended to summarize characteristic syndromes of signs and 
symptoms that point to an underlying disorder with a characteristic developmental his­

tory, biological and environmental risk factors, neuropsychological and physiological cor­
relates, and typical clinical course.
Approach to Clinical Case Formulation
The case formulation for any given patient must involve a careful clinical history and con­
cise summary of the social, psychological, and biological factors that may have contrib­
uted to developing a given mental disorder. Hence, it is not sufficient to simply check off 
the symptoms in the diagnostic criteria to make a mental disorder diagnosis. Although a 
systematic check for the presence of these criteria as they apply to each patient will assure 
a more reliable assessment, the relative severity and valence of individual criteria and 
their contribution to a diagnosis require clinical judgment. The symptoms in our diagnos­

tic criteria are part of the relatively limited repertoire of human emotional responses to in­
ternal and external stresses that are generally maintained in a homeostatic balance without 
a disruption in normal functioning. It requires clinical training to recognize when the com­
bination of predisposing, precipitating, perpetuating, and protective factors has resulted 
in a psychopathological condition in which physical signs and symptoms exceed normal 
ranges. The ultimate goal of a clinical case formulation is to use the available contextual 
and diagnostic information in developing a comprehensive treatment plan that is in­
formed by the individual's cultural and social context. However, recommendations for the 
selection and use of the most appropriate evidence-based treatment options for each dis­

order are beyond the scope of this manual.
Although decades of scientific effort have gone into developing the diagnostic criteria 
sets for the disorders included in Section II, it is well recognized that this set of categorical 
diagnoses does not fully describe the full range of mental disorders that individuals ex­
perience and present to clinicians on a daily basis throughout the world. As noted previ­
ously in the introduction, the range of genetic/environmental interactions over the course 
of human development affecting cognitive, emotional and behavioral function is virtually 
limitless. As a result, it is impossible to capture the full range of psychopathology in the 
categorical diagnostic categories that we are now using. Hence, it is also necessary to in­

clude "other specified/unspecified" disorder options for presentations that do not fit 
exactly into the diagnostic boundaries of disorders in each chapter. In an emergency de­
partment setting, it may be possible to identify only the most prominent symptom ex­
pressions associated with a particular chapter—for example, delusions, hallucinations.

mania, depression, anxiety, substance intoxication, or neurocognitive symptoms—so that 
an "unspecified" disorder in that category is identified until a fuller differential diagnosis 
is possible.
Definition of a Mental Disorder
Each disorder identified in Section II of the manual (excluding those in the chapters enti­
tled "Medication-Induced Movement Disorders and Other Adverse Effects of Medica­
tion" and "Other Conditions That May Be a Focus of Clinical Attention") must meet the 
definition of a mental disorder. Although no definition can capture all aspects of all dis­
orders in the range contained in DSM-5, the following elements are required:
A mental disorder is a syndrome characterized by clinically significant distur­
bance in  an individual’s cognition, emotion regulation, or behavior that reflects  
a dysfunction in  the psychological, biological, or developmental processes un­
derlying mental functioning. Mental disorders are usually associated with signif­

icant distress or disability in social, occupational, or other important activities.
An expectable or culturally approved response to a common stressor or loss,  
such as the death of a loved one, is not a mental disorder. Socially deviant be­
havior (e.g., political, religious, or sexual) and conflicts that are primarily be­
tween the individual and society are not mental disorders unless the deviance  
or conflict results from a dysfunction in  the individual, as described above.
The diagnosis of a mental disorder should have clinical utility: it should help clinicians 
to determine prognosis, treatment plans, and potential treatment outcomes for their pa­
tients. However, the diagnosis of a mental disorder is not equivalent to a need for treat­

ment. Need for treatment is a complex clinical decision that takes into consideration 
symptom severity, symptom salience (e.g., the presence of suicidal ideation), the patient's 
distress (mental pain) associated with the symptom(s), disability related to the patient's 
symptoms, risks and benefits of available treatments, and other factors (e.g., psychiatric 
symptoms complicating other illness). Clinicians may thus encounter individuals whose 
symptoms do not meet full criteria for a mental disorder but who demonstrate a clear need 
for treatment or care. The fact that some individuals do not show all symptoms indicative 
of a diagnosis should not be used to justify limiting their access to appropriate care.
Approaches to validating diagnostic criteria for discrete categorical mental disorders

Approaches to validating diagnostic criteria for discrete categorical mental disorders 
have included the following types of evidence: antecedent validators (similar genetic mark­
ers, family traits, temperament, and environmental exposure), concurrent validators (simi­
lar neural substrates, biomarkers, emotional and cognitive processing, and symptom 
similarity), and predictive validators (similar clinical course and treatment response). In 
DSM-5, we recognize that the current diagnostic criteria for any single disorder will not nec­
essarily identify a homogeneous group of patients who can be characterized reliably with all 
of these validators. Available evidence shows that these validators cross existing diagnostic 
boundaries but tend to congregate more frequently within and across adjacent DSM-5 chap­

ter groups. Until incontrovertible etiological or pathophysiological mechanisms are identi­
fied to fully validate specific disorders or disorder spectra, the most important standard for 
the DSM-5 disorder criteria will be their clinical utility for the assessment of clinical course 
and treatment response of individuals grouped by a given set of diagnostic criteria.
This definition of mental disorder was developed for clinical, public health, and re­
search purposes. Additional information is usually required beyond that contained in the 
DSM-5 diagnostic criteria in order to make legal judgments on such issues as criminal re­
sponsibility, eligibility for disability compensation, and competency (see "Cautionary 
Statement for Forensic Use of DSM-5" elsewhere in this manual).

Criterion for Ciinical Significance
There have beeh substantial efforts by the DSM-5 Task Force and the World Health Orga­
nization (WHO) to separate the concepts of mental disorder and disability (impairment in 
social, occupational, or other important areas of functioning). In the WHO system, the In­
ternational Classification of Diseases (ICD) covers all diseases and disorders, while the In­
ternational Classification of Functioning, Disability and Health (ICF) provides a separate 
classification of global disability. The WHO Disability Assessment Schedule (WHODAS) 
is based on the ICF and has proven useful as a standardized measure of disability for men­
tal disorders. However, in the absence of clear biological markers or clinically useful mea­
surements of severity for many mental disorders, it has not been possible to completely 
separate normal and pathological symptom expressions contained in diagnostic criteria.

separate normal and pathological symptom expressions contained in diagnostic criteria. 
This gap in information is particularly problematic in clinical situations in which the pa­
tient's symptom presentation by itself (particularly in mild forms) is not inherently path­
ological and may be encountered in individuals for whom a diagnosis of "mental 
disorder" would be inappropriate. Therefore, a generic diagnostic criterion requiring dis­
tress or disability has been used to establish disorder thresholds, usually worded "the dis­
turbance causes clinically significant distress or impairment in social, occupational, or 
other important areas of functioning." The text following the revised definition of a mental 
disorder acknowledges that this criterion may be especially helpful in determining a pa­
tient's need for treatment. Use of information from family members and other third parties

tient's need for treatment. Use of information from family members and other third parties 
(in addition to the individual) regarding the individual's performance is recommended 
when necessary.
Elements of a Diagnosis 
Diagnostic Criteria and Descriptors
Diagnostic criteria are offered as guidelines for making diagnoses, and their use should be 
informed by clinical judgment. Text descriptions, including introductory sections of each 
diagnostic chapter, can help support diagnosis (e.g., providing differential diagnoses; de­
scribing the criteria more fully under "Diagnostic Features").
Following the assessment of diagnostic criteria, clinicians should consider the applica­
tion of disorder subtypes and/or specifiers as appropriate. Severity and course specifiers 
should be applied to denote the individual's current presentation, but only when the full

should be applied to denote the individual's current presentation, but only when the full 
criteria are met. When full criteria are not met, clinicians should consider whether the 
symptom presentation meets criteria for an "other specified" or "unspecified" designa­
tion. Where applicable, specific criteria for defining disorder severity (e.g., mild, moder­
ate, severe, extreme), descriptive features (e.g., with good to fair insight; in a controlled 
environment), and course (e.g., in partial remission, in full remission, recurrent) are pro­
vided with each diagnosis. On the basis of the clinical interview, text descriptions, criteria, 
and clinician judgment, a final diagnosis is made.
The general convention in DSM-5 is to allow multiple diagnoses to be assigned for 
those presentations that meet criteria for more than one DSM-5 disorder.
Subtypes and Specifiers

Subtypes and specifiers (some of which are coded in the fourth, fifth, or sixth digit) are 
provided for increased specificity. Subtypes  define mutually exclusive and jointly exhaus­
tive phenomenological subgroupings within a diagnosis and are indicated by the instruc­
tion "Specify  whether" in the criteria set. In contrast, specifiers  are not intended to be 
mutually exclusive or jointly exhaustive, and as a consequence, more than one specifier 
may be given. Specifiers are indicated by the instruction "Specify"  or "Specify  if" in the cri­
teria set. Specifiers provide an opportunity to define a more homogeneous subgrouping of

individuals with the disorder who share certain features (e.g., major depressive disorder, 
with mixed features) and to convey information that is relevant to the management of the 
individual's disorder, such as the "with other medical comorbidity" specifier in sleep- 
wake disorders. Although a fifth digit is sometimes assigned to code a subtype or specifier 
(e.g., 294.11 [F02.81] major neurocognitive disorder due to Alzheimer's disease, with be­
havioral disturbance) or severity (296.21 [F32.0] major depressive disorder, single episode, 
mild), the majority of subtypes and specifiers included in DSM-5 cannot be coded within 
the ICD-9-CM and ICD-IO-CM systems and are indicated only by including the subtype or 
specifier after the name of the disorder (e.g., social anxiety disorder [social phobia], per­
formance type). Note that in some cases, a specifier or subtype is codable in ICD-IO-CM 
but not in ICD-9-CM. Accordingly, in some cases the 4th or 5th character codes for the sub­

types or specifiers are provided only for the ICD-IO-CM coding designations.
A DSM-5 diagnosis is usually applied to the individual's current presentation; previ­
ous diagnoses from which the individual has recovered should be clearly noted as such. 
Specifiers indicating course  (e.g., in partial remission, in full remission) may be listed after 
the diagnosis and are indicated in a number of criteria sets. Where available, severity spec­
ifiers  are provided to guide clinicians in rating the intensity, frequency, duration, symptom 
count, or other severity indicator of a disorder. Severity specifiers are indicated by the in­
struction "Specify  current severity" in the criteria set and include disorder-specific defini­

tions. Descriptive features specifiers  have also been provided in the criteria set and convey 
additional information that can inform treatment planning (e.g., obsessive-compulsive 
disorder, with poor insight). Not all disorders include course, severity, and/or descriptive 
features specifiers.
Medication-Induced iVlovement Disorders and Other  
Conditions That iViay Be a Focus of Ciinicai Attention
In addition to important psychosocial and environmental factors (see "The Multiaxial Sys­
tem" in the "Introduction" elsewhere in this manual), these chapters in Section II also con­
tain other conditions that are not mental disorders but may be encountered by mental 
health clinicians. These conditions may be listed as a reason for clinical visit in addition to,

health clinicians. These conditions may be listed as a reason for clinical visit in addition to, 
or in place of, the mental disorders listed in Section II. A separate chapter is devoted to 
medication-induced disorders and other adverse effects of medication that may be as­
sessed and treated by clinicians in mental health practice such as akathisia, tardive dyski­
nesia, and dystonia. The description of neuroleptic malignant syndrome is expanded from 
that provided in DSM-IV-TR to highlight the emergent and potentially life-threatening na­
ture of this condition, and a new entry on antidepressant discontinuation syndrome is pro­
vided. An additional chapter discusses other conditions that may be a focus of clinical 
attention. These include relational problems, problems related to abuse and neglect, prob­
lems with adherence to treatment regimens, obesity, antisocial behavior, and malingering.

Principal Diagnosis
When more than one diagnosis for an individual is given in an inpatient setting, the prin­
cipal diagnosis is the condition established after study to be chiefly responsible for occa­
sioning the admission of the individual. When more than one diagnosis is given for an 
individual in an outpatient setting, the reason for visit is the condition that is chiefly re­
sponsible for the ambulatory care medical services received during the visit. In most cases, 
the principal diagnosis or the reason for visit is also the main focus of attention or treat­
ment. It is often difficult (and somewhat arbitrary) to determine which diagnosis is the 
principal diagnosis or the reason for visit, especially when, for example, a substance-

principal diagnosis or the reason for visit, especially when, for example, a substance- 
related diagnosis such as alcohol use disorder is accompanied by a non-substance-related 
diagnosis such as schizophrenia. For example, it may be unclear which diagnosis should

be considered "principal" for an individual hospitalized with both schizophrenia and al­
cohol use disorder, because each condition may have contributed equally to the need for 
admission and treatment. The principal diagnosis is indicated by listing it first, and the re­
maining disorders are listed in order of focus of attention and treatment. When the prin­
cipal diagnosis or reason for visit is a mental disorder due to another medical condition 
(e.g., major neurocognitive disorder due to Alzheimer's disease, psychotic disorder due to 
malignant lung neoplasm), ICD coding rules require that the etiological medical condition 
be listed first. In that case, the principal diagnosis or reason for visit would be the mental 
disorder due to the medical condition, the second listed diagnosis. In most cases, the dis­
order listed as the principal diagnosis or the reason for visit is followed by the qualifying 
phrase "(principal diagnosis)" or "(reason for visit)."
Provisional Diagnosis

The specifier "provisional" can be used when there is a strong presumption that the full 
criteria will ultimately be met for a disorder but not enough information is available to 
make a firm diagnosis. The clinician can indicate the diagnostic uncertainty by recording 
"(provisional)" following the diagnosis. For example, this diagnosis might be used when 
an individual who appears to have a major depressive disorder is unable to give an ade­
quate history, and thus it cannot be established that the full criteria are met. Another use of 
the term provisional  is for those situations in which differential diagnosis depends exclu­
sively on the duration of illness. For example, a diagnosis of schizophreniform disorder re­
quires a duration of less than 6 months but of at least 1 month and can only be given

quires a duration of less than 6 months but of at least 1 month and can only be given 
provisionally if assigned before remission has occurred.
Coding and Reporting Procedures
Each disorder is accompanied by an identifying diagnostic and statistical code, which is 
typically used by institutions and agencies for data collection and billing purposes. There 
are specific recording protocols for these diagnostic codes (identified as coding notes in 
the text) that were established by WHO, the U.S. Centers for Medicare and Medicaid Ser­
vices (CMS), and the Centers for Disease Control and Prevention's National Center for 
Health Statistics to ensure consistent international recording of prevalence and mortality 
rates for identified health conditions. For most clinicians, the codes are used to identify the 
diagnosis or reason for visit for CMS and private insurance service claims. The official

diagnosis or reason for visit for CMS and private insurance service claims. The official 
coding system in use in the United States as of publication of this manual is ICD-9-CM. Of­
ficial adoption of ICD-IO-CM is scheduled to take place on October 1, 2014, and these 
codes, which are shown parenthetically in this manual, should not be used until the offi­
cial implementation occurs. Both ICD-9-CM and ICD-IO-CM codes have been listed 1) pre­
ceding the name of the disorder in the classification and 2) accompanying the criteria set 
for each disorder. For some diagnoses (e.g., neurocognitive and substance/medication- 
induced disorders), the appropriate code depends on further specification and is listed 
within the criteria set for the disorder, as coding notes, and, in some cases, further clarified 
in a section on recording procedures. The names of some disorders are followed by alter­

native terms enclosed in parentheses, which, in most cases, were the DSM-IV names for 
the disorders.
Looking to the Future: 
Assessment and Monitoring Tools
The various components of DSM-5 are provided to facilitate patient assessment and to aid 
in developing a comprehensive case formulation. Whereas the diagnostic criteria in Sec­
tion II are well-established measures that have undergone extensive review, the assess-

ment tools, a cultural formulation interview, and conditions for further study included in 
Section III are those for which we determined that the scientific evidence is not yet avail­
able to support widespread clinical use. These diagnostic aids and criteria are included to 
highlight the evolution and direction of scientific advances in these areas and to stimulate 
further research.
Each of the measures in Section III is provided to aid in a comprehensive assessment of 
individuals that will contribute to a diagnosis and treatment plan tailored to the individ­
ual presentation and clinical context. Where cultural dynamics are particularly important 
for diagnostic assessment, the cultural formulation interview should be considered as a 
useful aid to communication with the individual. Cross-cutting symptom and diagnosis- 
specific severity measures provide quantitative ratings of important clinical areas that are

specific severity measures provide quantitative ratings of important clinical areas that are 
designed to be used at the initial evaluation to establish a baseline for comparison with rat­
ings on subsequent encounters to monitor changes and inform treatment planning.
The use of such measures will undoubtedly be facilitated by digital apphcations, and 
the measures are included in Section III to provide for further evaluation and develop­
ment. As with each DSM edition, the diagnostic criteria and the DSM-5 classification of 
mental disorders reflect the current consensus on the evolving knowledge in our field.

Cautionary Statement for 
Forensic Use of DSiVi-5
A lth o u g h  th e  D S M - 5  diagnostic criteria and text are primarily designed to assist 
clinicians in conducting clinical assessment, case formulation, and treatment planning, 
DSM-5 is also used as a reference for the courts and attorneys in assessing the forensic con­
sequences of mental disorders. As a result, it is important to note that the definition of 
mental disorder included in DSM-5 was developed to meet the needs of clinicians, public 
health professionals, and research investigators rather than all of the technical needs of the 
courts and legal professionals. It is also important to note that DSM-5 does not provide 
treatment guidelines for any given disorder.
When used appropriately, diagnoses and diagnostic information can assist legal deci­
sion makers in their determinations. For example, when the presence of a mental disorder

sion makers in their determinations. For example, when the presence of a mental disorder 
is the predicate for a subsequent legal determination (e.g., involuntary civil commitment), 
the use of an established system of diagnosis enhances the value and reliability of the de­
termination. By providing a compendium based on a review of the pertinent clinical and 
research literature, DSM-5 may facilitate legal decision makers' understanding of the rel­
evant characteristics of mental disorders. The literature related to diagnoses also serves as 
a check on ungrounded speculation about mental disorders and about the functioning of a 
particular individual. Finally, diagnostic information about longitudinal course may im­
prove decision making when the legal issue concerns an individual's mental functioning 
at a past or future point in time.

However, the use of DSM-5 should be informed by an awareness of the risks and lim­
itations of its use in forensic settings. When DSM-5 categories, criteria, and textual descrip­
tions are employed for forensic purposes, there is a risk that diagnostic information will be 
misused or misunderstood. These dangers arise because of the imperfect fit between the 
questions of ultimate concern to the law and the information contained in a clinical diagno­
sis. In most situations, the clinical diagnosis of a DSM-5 mental disorder such as intellec­
tual disability (intellectual developmental disorder), schizophrenia, major neurocognitive 
disorder, gambling disorder, or pedophilic disorder does not imply that an individual 
with such a condition meets legal criteria for the presence of a mental disorder or a speci­

fied legal standard (e.g., for competence, criminal responsibility, or disability). For the latter, 
additional information is usually required beyond that contained in the DSM-5 diagnosis, 
which might include information about the individual's functional impairments and how 
these impairments affect the particular abilities in question. It is precisely because impair­
ments, abilities, and disabilities vary widely within each diagnostic category that assign­
ment of a particular diagnosis does not imply a specific level of impairment or disability.
Use of DSM-5 to assess for the presence of a mental disorder by nonclinical, nonmed­
ical, or otherwise insufficiently trained individuals is not advised. Nonclinical decision

ical, or otherwise insufficiently trained individuals is not advised. Nonclinical decision 
makers should also be cautioned that a diagnosis does not carry any necessary implica­
tions regarding the etiology or causes of the individual's mental disorder or the individ­
ual's degree of control over behaviors that may be associated with the disorder. Even 
when diminished control over one's behavior is a feature of the disorder, having the diag­
nosis in itself does not demonstrate that a particular individual is (or was) unable to con­
trol his or her behavior at a particular time.

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"3ôfe^  riDiagnostic '
Neurodevelopmental Disorders ................................................................ 31
Schizophrenia Spectrum and Other Psychotic Disorders ...................... 87
Bipolar and Related Disorders ................................................................ 123
Depressive Disorders.............................................................................. 155
Anxiety Disorders.................................................................................... 189
Obsessive-Compulsive and Related Disorders...................................... 235
Trauma- and Stressor-Related Disorders.............................................. 265

Dissociative Disorders............................................................................ 291
Somatic Symptom and Related Disorders............................................ 309
Feeding and Eating Disorders................................................................ 329
Elimination Disorders.............................................................................. 355
Sleep-Wake Disorders............................................................................ 361
Sexual Dysfunctions................................................................................ 423
Gender Dysphoria.................................................................................... 451
Disruptive, Impulse-Control, and Conduct Disorders ............................ 461

Substance-Related and Addictive Disorders ........................................ 481
Neurocognitive Disorders ........................................................................ 591
Personality Disorders.............................................................................. 645
Paraphilic Disorders................................................................................ 685
Other Mental Disorders.......................................................................... 707
Medication-Induced Movement Disorders and  
Other Adverse Effects of Medication.................................................. 709
Other Conditions That May Be a Focus of Clinical Attention ................ 715

I his s e c tio n  contains the diagnostic criteria approved for routine clinical  
use along with the ICD-9-CM codes (ICD-10 codes are shown parenthetically).  
For each mental disorder, the diagnostic criteria are followed by descriptive  
text to assist in diagnostic decision making. Where needed, specific recording  
procedures are presented with the diagnostic criteria to provide guidance in  
selecting the most appropriate code. In some cases, separate recording pro­
cedures for ICD-9-CM and ICD-10-CM are provided. Although not considered  
as official DSM-5 disorders, medication-induced movement disorders and other  
adverse effects of medication, as well as other conditions that may be a focus  
of clinical attention (including additional ICD-9-CM V codes and forthcoming  
ICD-10-CM Z codes), are provided to indicate other reasons for a clinical visit  
such as environmental factors and relational problems. These codes are adapted

such as environmental factors and relational problems. These codes are adapted  
from ICD-9-CM and 1CD-10-CM and were neither reviewed nor approved as  
official DSM-5 diagnoses, but can provide additional context for a clinical for­
mulation and treatment plan. These three components—^ th e  criteria and their  
descriptive text, the medication-induced movement disorders and other ad­
verse effects of medication, and the descriptions of other conditions that may  
be a focus of clinical attention—represent the key elements of the clinical di­
agnostic process and thus are presented together.

ΤΙίΘ Π θυΓΟ όθνθΙορΓΠ Θ Π ΐάΙ disorders are a group of conditions with onset in the 
developmental period. The disorders typically manifest early in development, often be­
fore the child enters grade school, and are characterized by developmental deficits that 
produce impairments of personal, social, academic, or occupational functioning. The 
range of developmental deficits varies from very specific limitations of learning or control 
of executive functions to global impairments of social skills or intelligence. The neurode- 
velopmental disorders frequently co-occur; for example, individuals with autism spec­
trum disorder often have intellectual disability (intellectual developmental disorder), and 
many children with attention-deficit/hyperactivity disorder (ADHD) also have a specific 
learning disorder. For some disorders, the clinical presentation includes symptoms of ex­
cess as well as deficits and delays in achieving expected milestones. For example, autism

cess as well as deficits and delays in achieving expected milestones. For example, autism 
spectrum disorder is diagnosed only when the characteristic deficits of social communi­
cation are accompanied by excessively repetitive behaviors, restricted interests, and insis­
tence on sameness.
Intellectual disability (intellectual developmental disorder) is characterized by deficits 
in general mental abilities, such as reasoning, problem solving, planning, abstract thinking, 
judgment, academic learning, and learning from experience. The deficits result in impair­
ments of adaptive functioning, such that the individual fails to meet standards of personal 
independence and social responsibility in one or more aspects of daily life, including com- 
mimication, social participation, academic or occupational functioning, and personal inde­

pendence at home or in community settings. Global developmental delay, as its name 
implies, is diagnosed when an individual fails to meet expected developmental milestones 
in several areas of intellectual functioning. The diagnosis is used for individuals who are 
imable to undergo systematic assessments of intellectual functioning, including children 
who are too young to participate in standardized testing. Intellectual disability may result 
from an acquired insult during the developmental period from, for example, a severe head 
injury, in which case a neurocognitive disorder also may be diagnosed.
Tlie communication disorders include language disorder, speech sound disorder, so­
cial (pragmatic) communication disorder, and childhood-onset fluency disorder (stutter­

ing). The first three disorders are characterized by deficits in the development and use of 
language, speech, and social communication, respectively. Childhood-onset fluency dis­
order is characterized by disturbances of the normal fluency and motor production of 
speech, including repetitive sounds or syllables, prolongation of consonants or vowel 
sounds, broken words, blocking, or words produced with an excess of physical tension. 
Like other neurodevelopmental disorders, communication disorders begin early in life 
and may produce lifelong functional impairments.
Autism spectrum disorder is characterized by persistent deficits in social communica­
tion and social interaction across multiple contexts, including deficits in social reciprocity,

tion and social interaction across multiple contexts, including deficits in social reciprocity, 
nonverbal communicative behaviors used for social interaction, and skills in developing, 
maintaining, and understanding relationships. In addition to the social communication 
deficits, the diagnosis of autism spectrum disorder requires the presence of restricted, re­
petitive patterns of behavior, interests, or activities. Because symptoms change with de­
velopment and may be masked by compensatory mechanisms, the diagnostic criteria may

be met based on historical information, although the current presentation must cause sig­
nificant impairment.
Within the diagnosis of autism spectrum disorder, individual clinical characteristics 
are noted through the use of specifiers (with or without accompanying intellectual impair­
ment; with or without accompanying structural language impairment; associated with a 
known medical/genetic or environmental/acquired condition; associated with another 
neurodevelopmental, mental, or behavioral disorder), as well as specifiers that describe 
the autistic symptoms (age at first concern; with or without loss of established skills; sever­
ity). These specifiers provide clinicians with an opportunity to individualize the diagnosis 
and communicate a richer clinical description of the affected individuals. For example, many 
individuals previously diagnosed with Asperger's disorder would now receive a diagnosis 
of autism spectrum disorder without language or intellectual impairment.

ADHD is a neurodevelopmental disorder defined by impairing levels of inattention, dis­
organization, and/or hyperactivity-impulsivity. Inattention and disorganization entail inabil­
ity to stay on task, seeming not to listen, and losing materials, at levels that are inconsistent 
with age or developmental level. Hyperactivity-impulsivity entails overactivity, fidgeting, in­
ability to stay seated, intruding into other people's activities, and inability to wait—symptoms 
that are excessive for age or developmental level. In childhood, ADHD frequently overlaps 
with disorders that are often considered to be "externalizing disorders," such as oppositional 
defiant disorder and conduct disorder. ADHD often persists into adulthood, witii resultant 
impairments of social, academic and occupational functioning.

The neurodevelopmental motor disorders include developmental coordination disor­
der, stereotypic movement disorder, and tic disorders. Developmental coordination dis­
order is characterized by deficits in the acquisition and execution of coordinated motor 
skills and is manifested by clumsiness and slowness or inaccuracy of performance of mo­
tor skills that cause interference with activities of daily living. Stereotypic movement dis­
order is diagnosed when an individual has repetitive, seemingly driven, and apparently 
purposeless motor behaviors, such as hand flapping, body rocking, head banging, self- 
biting, or hitting. The movements interfere with social, academic, or other activities. If the 
behaviors cause self-injury, this should be specified as part of the diagnostic description.

behaviors cause self-injury, this should be specified as part of the diagnostic description. 
Tic disorders are characterized by the presence of motor or vocal tics, which are sudden, 
rapid, recurrent, nonrhythmic, sterotyped motor movements or vocalizations. The dura­
tion, presumed etiology, and clinical presentation define the specific tic disorder that is di­
agnosed: Tourette's disorder, persistent (chronic) motor or vocal tic disorder, provisional 
tic disorder, other specified tic disorder, and unspecified tic disorder. Tourette's disorder 
is diagnosed when the individual has multiple motor and vocal tics that have been present 
for at least 1 year and that have a waxing-waning symptom course.
Specific learning disorder, as the name implies, is diagnosed when there are specific defi­

cits in an individual's ability to perceive or process information efficiently and accurately. This 
neurodevelopmental disorder first manifests during the years of formal schooling and is 
characterized by persistent and impairing difficulties with learning foimdational academic 
skills in reading, writing, and/or math. The individual's performance of the affected academic 
skills is well below average for age, or acceptable performance levels are achieved only with 
extraordinary effort. Specific learning disorder may occur in individuals identified as intellec­
tually gifted and manifest only when the learning demands or assessment procedures (e.g., 
timed tests) pose barriers that cannot be overcome by their innate intelligence and compensa­

tory strategies. For all individuals, specific learning disorder can produce lifelong impairments 
in activities dependent on the skills, including occupational performance.
The use of specifiers for the neurodevelopmental disorder diagnoses enriches the clin­
ical description of the individual's clinical course and current symptomatology. In addi­
tion to specifiers that describe the clinical presentation, such as age at onset or severity 
ratings, the neurodevelopmental disorders may include the specifier "associated with a 
known medical or genetic condition or environmental factor." This specifier gives clini­

cians an opportunity to document factors that may have played a role in the etiology of the 
disorder, as v^^ll as those that might affect the clinical course. Examples include genetic 
disorders, such as fragile X syndrome, tuberous sclerosis, and Rett syndrome; medical con­
ditions such as epilepsy; and environmental factors, including very low birth weight and 
fetal alcohol exposure (even in the absence of stigmata of fetal alcohol syndrome).
Intellectual Disabilities
Intellectual Disability  
(Intellectual Developmental Disorder)
Diagnostic Criteria
Intellectual disability (intellectual developmental disorder) is a disorder with onset during  
the developmental period that includes both intellectual and adaptive functioning deficits  
in conceptual, social, and practical domains. The following three criteria must be met:
A. Deficits in  intellectual functions, such as reasoning, problem solving, planning, abstract

A. Deficits in  intellectual functions, such as reasoning, problem solving, planning, abstract  
thinking, judgment, academic learning, and learning from experience, confirmed by  
both clinical assessment and individualized, standardized intelligence testing.
B. Deficits in adaptive functioning that result in failure to meet developmental and socio­
cultural standards for personal independence and social responsibility. Without ongo­
ing support, the adaptive deficits lim it functioning in one or more activities of daily life,  
such as communication, social participation, and independent living, across multiple  
environments, such as home, school, work, and community.
C. Onset of intellectual and adaptive deficits during the developmental period.
Note: The diagnostic term intellectual disability  is the equivalent term for the ICD-11  diag­

nosis of intellectual developmental disorders.  Although the term intellectual disability  is 
used throughout this manual, both terms are used in the title to clarify relationships with  
other classification systems. Moreover, a federal statute in the United States (Public Law  
111 -256, Rosa’s Law) replaces the term mental retardation  with intellectual disability,  and 
research journals use the term intellectual disability.  Thus, intellectual disability  is the  
term in common use by medical, educational, and other professions and by the lay public  
and advocacy groups.
Coding note: The ICD-9-CM code for intellectual disability (intellectual developmental  
disorder) is 319, which is assigned regardless of the severity specifier. The ICD-10-CM code  
depends on the severity specifier (see below).

Specify  current severity (see Table 1  ):
(F70) Mild  
(F71) lUloderate  
(F72) Severe  
Specifiers
The various levels of severity are defined on the basis of adaptive functioning, and not IQ 
scores, because it is adaptive functioning that determines the level of supports required. 
Moreover, IQ measures are less valid in the lower end of the IQ range.

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Diagnostic Features
The essential fèatures of intellectual disability (intellectual developmental disorder) are 
deficits in general mental abilities (Criterion A) and impairment in everyday adaptive 
functioning, in comparison to an individual's age-, gender-, and socioculturally matched 
peers (Criterion B). Onset is during the developmental period (Criterion C). The diagnosis 
of intellectual disability is based on both clinical assessment and standardized testing of 
intellectual and adaptive functions.
Criterion A refers to intellectual functions that involve reasoning, problem solving, 
planning, abstract thinking, judgment, learning from instruction and experience, and 
practical understanding. Critical components include verbal comprehension, working 
memory, perceptual reasoning, quantitative reasoning, abstract thought, and cognitive ef­
ficacy. Intellectual functioning is typically measured with individually administered and

ficacy. Intellectual functioning is typically measured with individually administered and 
psychometrically valid, comprehensive, culturally appropriate, psychometrically sound 
tests of intelligence. Individuals with intellectual disability have scores of approximately 
two standard deviations or more below the population mean, including a margin for mea­
surement error (generally +5 points). On tests with a standard deviation of 15 and a mean 
of 100, this involves a score of 65-75 (70 ± 5). Clinical training and judgment are required 
to interpret test results and assess intellectual performance.
Factors that may affect test scores include practice effects and the "Flynn effect' (i.e., 
overly high scores due to out-of-date test norms). Invalid scores may result from the use of 
brief intelligence screening tests or group tests; highly discrepant individual subtest scores

brief intelligence screening tests or group tests; highly discrepant individual subtest scores 
may make an overall IQ score invalid. Instruments must be normed for the individual's so­
ciocultural background and native language. Co-occurring disorders that affect communi­
cation, language, and/or motor or sensory function may affect test scores. Individual 
cognitive profiles based on neuropsychological testing are more useful for understanding 
intellectual abilities than a single IQ score. Such testing may identify areas of relative 
strengths and weaknesses, an assessment important for academic and vocational planning.
IQ test scores are approximations of conceptual functioning but may be insufficient to 
assess reasoning in real-life situations and mastery of practical tasks. For example, a per­
son with an IQ score above 70 may have such severe adaptive behavior problems in social

son with an IQ score above 70 may have such severe adaptive behavior problems in social 
judgment, social understanding, and other areas of adaptive functioning that the person's 
actual functioning is comparable to that of individuals with a lower IQ score. Thus, clinical 
judgment is needed in interpreting the results of IQ tests.
Deficits in adaptive functioning (Criterion B) refer to how well a person meets community 
standards of personal independence and social responsibility, in comparison to others of sim­
ilar age and sociocultural background. Adaptive functioning involves adaptive reasoning in 
three domains: conceptual, social, and practical. The conceptual (academic) domain  involves 
competence in memory, language, reading, writing, math reasoning, acquisition of practical 
knowledge, problem solving, and judgment in novel situations, among others. The social do­

main  involves awareness of others' thoughts, feelings, and experiences; empathy; interper­
sonal communication skills; friendship abilities; and social judgment, among others. The 
practical domain  involves learning and self-management across life settings, including personal 
care, job responsibilities, money management, recreation, self-management of behavior, and 
school and work task organization, among others. Intellectual capacity, education, motivation, 
socialization, personality features, vocational opportunity, cultural experience, and coexisting 
general medical conditions or mental disorders influence adaptive functioning.
Adaptive functioning is assessed using both clinical evaluation and individualized, 
culturally appropriate, psychometrically sound measures. Standardized measures are

culturally appropriate, psychometrically sound measures. Standardized measures are 
used with knowledgeable informants (e.g., parent or other family member; teacher; coun­
selor; care provider) and the individual to the extent possible. Additional sources of infor­
mation include educational, developmental, medical, and mental health evaluations. 
Scores from standardized measures and interview sources must be interpreted using clin­
ical judgment. When standardized testing is difficult or impossible, because of a variety of

factors (e.g., sensory impairment, severe problem behavior), the individual may be diag­
nosed with unspecified intellectual disability. Adaptive functioning may be difficult to 
assess in a controlled setting (e.g., prisons, detention centers); if possible, corroborative in­
formation reflecting functioning outside those settings should be obtained.
Criterion B is met when at least one domain of adaptive functioning—conceptual, so­
cial, or practical—is sufficiently impaired that ongoing support is needed in order for the 
person to perform adequately in one or more life settings at school, at work, at home, or in 
the community. To meet diagnostic criteria for intellectual disability, the deficits in adap­
tive functioning must be directly related to the intellectual impairments described in Cri­
terion A. Criterion C, onset during the developmental period, refers to recognition that 
intellectual and adaptive deficits are present during childhood or adolescence.

Associated Features Supporting Diagnosis
Intellectual disability is a heterogeneous condition with multiple causes. There may be 
associated difficulties with social judgment; assessment of risk; self-management of behav­
ior, emotions, or interpersonal relationships; or motivation in school or work environments. 
Lack of communication skills may predispose to disruptive and aggressive behaviors. Gull­
ibility is often a feature, involving naiveté in social situations and a tendency for being easily 
led by others. Gullibility and lack of awareness of risk may result in exploitation by others 
and possible victimization, fraud, unintentional criminal involvement, false confessions, 
and risk for physical and sexual abuse. These associated features can be important in crim­

inal cases, including Atkins-type hearings involving the death penalty.
Individuals with a diagnosis of intellectual disability with co-occurring mental disor­
ders are at risk for suicide. They think about suicide, make suicide attempts, and may die 
from them. Thus, screening for suicidal thoughts is essential in the assessment process. Be­
cause of a lack of awareness of risk and danger, accidental injury rates may be increased.
Prevalence
Intellectual disability has an overall general population prevalence of approximately 1%, 
and prevalence rates vary by age. Prevalence for severe intellectual disability is approxi­
mately 6 per 1,000.
Deveiopment and Course
Onset of intellectual disability is in the developmental period. The age and characteristic

Onset of intellectual disability is in the developmental period. The age and characteristic 
features at onset depend on the etiology and severity of brain dysfunction. Delayed motor, 
language, and social milestones may be identifiable within the first 2 years of life among 
those with more severe intellectual disability, while mild levels may not be identifiable un­
til school age when difficulty with academic learning becomes apparent. All criteria (in­
cluding Criterion C) must be fulfilled by history or current presentation. Some children 
under age 5 years whose presentation will eventually meet criteria for intellectual disabil­
ity have deficits that meet criteria for global developmental delay.
When intellectual disability is associated with a genetic syndrome, there may be a char­
acteristic physical appearance (as in, e.g.. Down syndrome). Some syndromes have a

acteristic physical appearance (as in, e.g.. Down syndrome). Some syndromes have a 
behavioral phenotype,  which refers to specific behaviors that are characteristic of particular 
genetic disorder (e.g., Lesch-Nyhan syndrome). In acquired forms, the onset may be 
abrupt following an illness such as meningitis or encephalitis or head trauma occurring 
during the developmental period. When intellectual disability results from a loss of pre­
viously acquired cognitive skills, as in severe traumatic brain injury, the diagnoses of in­
tellectual disability and of a neurocognitive disorder may both be assigned.
Although intellectual disability is generally nonprogressive, in certain genetic disor­
ders (e.g., Rett syndrome) there are periods of worsening, followed by stabilization, and in

others (e.g., San Phillippo syndrome) progressive worsening of intellectual function. After 
early childhood^ the disorder is generally lifelong, although severity levels may change 
over time. The course may be influenced by underlying medical or genetic conditions and 
co-occurring conditions (e.g., hearing or visual impairments, epilepsy). Early and ongoing in­
terventions may improve adaptive functioning throughout childhood and adulthood. In 
some cases, these result in significant improvement of intellectual functioning, such that 
the diagnosis of intellectual disability is no longer appropriate. Thus, it is common practice 
when assessing infants and young children to delay diagnosis of intellectual disability un­
til after an appropriate course of intervention is provided. For older children and adults, 
the extent of support provided may allow for full participation in all activities of daily liv­

ing and improved adaptive function. Diagnostic assessments must determine whether im­
proved adaptive skills are the result of a stable, generalized new skill acquisition (in which 
case the diagnosis of intellectual disability may no longer be appropriate) or whether the 
improvement is contingent on the presence of supports and ongoing interventions (in 
which case the diagnosis of intellectual disability may still be appropriate).
Risk and Prognostic Factors
Genetic and physiological. Prenatal etiologies include genetic syndromes (e.g., se­
quence variations or copy number variants involving one or more genes; chromosomal 
disorders), inborn errors of metabolism, brain malformations, maternal disease (including

disorders), inborn errors of metabolism, brain malformations, maternal disease (including 
placental disease), and environmental influences (e.g., alcohol, other drugs, toxins, terato­
gens). Perinatal causes include a variety of labor and delivery-related events leading to 
neonatal encephalopathy. Postnatal causes include hypoxic ischemic injury, traumatic 
brain injury, infections, demyelinating disorders, seizure disorders (e.g., infantile spasms), 
severe and chronic social deprivation, and toxic metabolic syndromes and intoxications 
(e.g., lead, mercury).
Culture-Reiated Diagnostic issues
Intellectual disability occurs in all races and cultures. Cultural sensitivity and knowledge 
are needed during assessment, and the individual's ethnic, cultural, and linguistic back­
ground, available experiences, and adaptive functioning within his or her community and

ground, available experiences, and adaptive functioning within his or her community and 
cultural setting must be taken into account.
Gender-Reiated Diagnostic issues
Overall, males are more likely than females to be diagnosed with both mild (average 
maleifemale ratio 1.6:1) and severe (average male:female ratio 1.2:1) forms of intellectual 
disability. However, gender ratios vary widely in reported studies. Sex-linked genetic fac­
tors and male vulnerability to brain insult may accoimt for some of the gender differences.
Diagnostic iVlaricers
A comprehensive evaluation includes an assessment of intellectual capacity and adaptive 
functioning; identification of genetic and nongenetic etiologies; evaluation for associated 
medical conditions (e.g., cerebral palsy, seizure disorder); and evaluation for co-occurring

medical conditions (e.g., cerebral palsy, seizure disorder); and evaluation for co-occurring 
mental, emotional, and behavioral disorders. Components of the evaluation may include 
basic pre- and perinatal medical history, three-generational family pedigree, physical exam­
ination, genetic evaluation (e.g., karyotype or chromosomal microarray analysis and testing 
for specific genetic syndromes), and metabolic screening and neuroimaging assessment.
Differential Diagnosis
The diagnosis of intellectual disability should be made whenever Criteria A, B, and C are 
met. A diagnosis of intellectual disability should not be assumed because of a particular

genetic or medical condition. A genetic syndrome linked to intellectual disability should 
be noted as a concurrent diagnosis with the intellectual disability.
Major and mild neurocognitive disorders. Intellectual disability is categorized as a neu­
rodevelopmental disorder and is distinct from the neurocognitive disorders, which are 
characterized by a loss of cognitive functioning. Major neurocognitive disorder may co­
occur with intellectual disability (e.g., an individual with Down syndrome who develops 
Alzheimer's disease, or an individual with intellectual disability who loses further cogni­
tive capacity following a head injury). In such cases, the diagnoses of intellectual disability 
and neurocognitive disorder may both be given.
Communication disorders and specific learning disorder. These neurodevelopmental 
disorders are specific to the communication and learning domains and do not show defi­

cits in intellectual and adaptive behavior. They may co-occur with intellectual disability. 
Both diagnoses are made if full criteria are met for intellectual disability and a communi­
cation disorder or specific learning disorder.
Autism spectrum disorder. Intellectual disability is common among individuals with 
autism spectrum disorder. Assessment of intellectual ability may be complicated by so- 
cial-communication and behavior deficits inherent to autism spectrum disorder, which 
may interfere with understanding and complying with test procedures. Appropriate as­
sessment of intellectual functioning in autism spectrum disorder is essential, with reas­
sessment across the developmental period, because IQ scores in autism spectrum disorder 
may be unstable, particularly in early childhood.
Comorbidity

Co-occurring mental, neurodevelopmental, medical, and physical conditions are frequent 
in intellectual disability, with rates of some conditions (e.g., mental disorders, cerebral 
palsy, and epilepsy) three to four times higher than in the general population. The prognosis 
and outcome of co-occurring diagnoses may be influenced by the presence of intellectual 
disability. Assessment procedures may require modifications because of associated disor­
ders, including communication disorders, autism spectrum disorder, and motor, sensory, 
or other disorders. Knowledgeable informants are essential for identifying symptoms 
such as irritability, mood dysregulation, aggression, eating problems, and sleep problems, 
and for assessing adaptive functioning in various community settings.

The most common co-occurring mental and neurodevelopmental disorders are atten- 
tion-deficit/hyperactivity disorder; depressive and bipolar disorders; anxiety disorders; 
autism spectrum disorder; stereotypic movement disorder (with or without self-injurious 
behavior); impulse-control disorders; and major neurocognitive disorder. Major depres­
sive disorder may occur throughout the range of severity of intellectual disability. Self- 
injurious behavior requires prompt diagnostic attention and may warrant a separate di­
agnosis of stereotypic movement disorder. Individuals with intellectual disability, partic­
ularly those with more severe intellectual disability, may also exhibit aggression and 
disruptive behaviors, including harm of others or property destruction.
Reiationship to Other Classifications

ICD-11 (in development at the time of this publication) uses the term intellectual develop­
mental disorders  to indicate that these are disorders that involve impaired brain functioning 
early in life. These disorders are described in ICD-11 as a metasyndrome occurring in the 
developmental period analogous to dementia or neurocognitive disorder in later life. 
There are four subtypes in ICD-11: mild, moderate, severe, and profound.
The American Association on Intellectual and Developmental Disabilities (AAIDD) 
also uses the term intellectual disability  with a similar meaning to the term as used in this

manual. The AAIDD's classification is multidimensional rather than categorical and is 
based on the disability construct. Rather than listing specifiers as is done in DSM-5, the 
AAIDD emphasizes a profile of supports based on severity.
Global Developmental Delay
315.8 (F88)
This diagnosis is reserved for individuals under  the age of 5 years when the clinical severity  
level cannot be reliably assessed during early childhood. This category is diagnosed when  
an individual fails to meet expected developmental milestones in  several areas of intellec­
tual functioning, and applies to individuals who are unable to undergo systematic assess­
ments of intellectual functioning, including children who are too young to participate in  
standardized testing. This category requires reassessment after a period of time.
Unspecified Intellectual Disability  
319 (F79)
This category is reserved for individuals over the age of 5 years when assessment of the

319 (F79)
This category is reserved for individuals over the age of 5 years when assessment of the  
degree of intellectual disability (intellectual developmental disorder) by means of locally  
available procedures is rendered difficult or impossible because of associated sensory or  
physical impairments, as in  blindness or prelingual deafness; locomotor disability; or pres­
ence of severe problem behaviors or co-occurring mental disorder. This category should  
only be used in exceptional circumstances and requires reassessment after a period of time.
Communication Disorders
Disorders of communication include deficits in language, speech, and communication. 
Speech  is the expressive production of sounds and includes an individual's articulation, 
fluency, voice, and resonance quality. Language includes the form, function, and use of a

fluency, voice, and resonance quality. Language includes the form, function, and use of a 
conventional system of symbols (i.e., spoken words, sign language, written words, pic­
tures) in a rule-governed manner for communication. Communication  includes any verbal 
or nonverbal behavior (whether intentional or unintentional) that influences the behavior, 
ideas, or attitudes of another individual. Assessments of speech, language and communi­
cation abilities must take into account the individual’s cultural and language context, 
particularly for individuals growing up in bilingual environments. The standardized mea­
sures of language development and of nonverbal intellectual capacity must be relevant for 
the cultural and linguistic group (i.e., tests developed and standardized for one group may 
not provide appropriate norms for a different group). The diagnostic category of commu­

nication disorders includes the following: language disorder, speech sound disorder, 
childhood-onset fluency disorder (stuttering), social (pragmatic) communication disor­
der, and other specified and unspecified communication disorders.

Language Disorder
Diagnostic Criteria 315.39 (F80.9)
A. Persistent difficulties in the acquisition and use of language across modalities (i.e.,  
spoken, written, sign language, or other) due to deficits in comprehension or produc­
tion that include the following:
1. Reduced vocabulary (word knowledge and use).
2. Limited sentence structure (ability to put words and word endings together to form  
sentences based on the rules of grammar and morphology).
3. Impairments in discourse (ability to use vocabulary and connect sentences to ex­
plain or describe a topic or series of events or have a conversation).
B. Language abilities are substantially and quantifiably below those expected for age, re­
sulting in functional limitations in  effective communication, social participation, aca­
demic achievement, or occupational performance, individually or in any combination.
C. Onset of symptoms is in the early developmental period.

D. The difficulties are not attributable to hearing or other sensory impairment, motor dys­
function, or another medical or neurological condition and are not better explained by in­
tellectual disability (intellectual developmental disorder) or global developmental delay.
The core diagnostic features of language disorder are difficulties in the acquisition and use 
of language due to deficits in the comprehension or production of vocabulary, sentence 
structure, and discourse. The language deficits are evident in spoken communication, 
written communication, or sign language. Language learning and use is dependent on 
both receptive and expressive skills. Expressive ability  refers to the production of vocal, ges­
tural, or verbal signals, while receptive ability  refers to the process of receiving and com­

prehending language messages. Language skills need to be assessed in both expressive 
and receptive modalities as these may differ in severity. For example, an individual's ex­
pressive language may be severely impaired, while his receptive language is hardly im­
paired at all.
Language disorder usually affects vocabulary and grammar, and these effects then 
limit the capacity for discourse. The child's first words and phrases are likely to be delayed 
in onset; vocabulary size is smaller and less varied than expected; and sentences are 
shorter and less complex with grammatical errors, especially in past tense. Deficits in com­
prehension of language are frequently underestimated, as children may be good at using

prehension of language are frequently underestimated, as children may be good at using 
context to infer meaning. There may be word-finding problems, impoverished verbal def­
initions, or poor understanding of synonyms, multiple meanings, or word play appro­
priate for age and culture. Problems with remembering new words and sentences are 
manifested by difficulties following instructions of increasing length, difficulties rehears­
ing strings of verbal information (e.g., remembering a phone number or a shopping list), 
and difficulties remembering novel sound sequences, a skill that may be important for 
learning new words. Difficulties with discourse are shown by a reduced ability to provide 
adequate information about the key events and to narrate a coherent story.
The language difficulty is manifest by abilities substantially and quantifiably below

The language difficulty is manifest by abilities substantially and quantifiably below 
that expected for age and significantly interfering with academic achievement, occupa­
tional performance, effective communication, or socialization (Criterion B). A diagnosis of 
language disorder is made based on the synthesis of the individual's history, direct clinical 
observation in different contexts (i.e., home, school, or work), and scores from standard­
ized tests of language ability that can be used to guide estimates of severity.

A positive family history of language disorders is often present. Individuals, even chil­
dren, can be adept at accommodating to their limited language. They may appear to be shy 
or reticent to talk. Affected individuals may prefer to communicate only with family mem­
bers or other familiar individuals. Although these social indicators are not diagnostic of a 
language disorder, if they are notable and persistent, they warrant referral for a full lan­
guage assessment. Language disorder, particularly expressive deficits, may co-occur with 
speech sound disorder.
Language acquisition is marked by changes from onset in toddlerhood to the adult level of 
competency that appears during adolescence. Changes appear across the dimensions of 
language (sounds, words, grammar, narratives/expository texts, and conversational 
skills) in age-graded increments and synchronies. Language disorder emerges during the

skills) in age-graded increments and synchronies. Language disorder emerges during the 
early developmental period; however, there is considerable variation in early vocabulary 
acquisition and early word combinations, and individual differences are not, as single 
indicators, highly predictive of later outcomes. By age 4 years, individual differences in 
language ability are more stable, with better measurement accuracy, and are highly pre­
dictive of later outcomes. Language disorder diagnosed from 4 years of age is likely to be 
stable over time and typically persists into adulthood, although the particular profile of 
language strengths and deficits is likely to change over the course of development.
Risic and Prognostic Factors
Children with receptive language impairments have a poorer prognosis than those with 
predominantly expressive impairments. They are more resistant to treatment, and diffi­

culties with reading comprehension are frequently seen.
Genetic and physiological. Language disorders are highly heritable, and family mem­
bers are more likely to have a history of language impairment.
Differentiai Diagnosis
Normal variations in language. Language disorder needs to be distinguished from nor­
mal developmental variations, and this distinction may be difficult to make before 4 years 
of age. Regional, social, or cultural/ethnic variations of language (e.g., dialects) must be 
considered when an individual is being assessed for language impairment.
Hearing or other sensory impairment. Hearing impairment needs to be excluded as the 
primary cause of language difficulties. Language deficits may be associated with a hearing

primary cause of language difficulties. Language deficits may be associated with a hearing 
impairment, other sensory deficit, or a speech-motor deficit. When language deficits are in 
excess of those usually associated with these problems, a diagnosis of language disorder 
may be made.
Intellectual disability (intellectual developmental disorder). Language delay is often the 
presenting feature of intellectual disability, and the definitive diagnosis may not be made 
until the child is able to complete standardized assessments. A separate diagnosis is not 
given unless the language deficits are clearly in excess of the intellectual limitations.
Neurological disorders. Language disorder can be acquired in association with neuro­
logical disorders, including epilepsy (e.g., acquired aphasia or Landau-Kleffner syndrome).

Language regression. Loss of speech and language in a child younger than 3 years may 
be a sign of autism spectrum disorder (with developmental regression) or a specific neuro­
logical condition, such as Landau-Kleffner syndrome. Among children older than 3 years, 
language loss may be a symptom of seizures, and a diagnostic assessment is necessary to 
exclude the presence of epilepsy (e.g., routine and sleep electroencephalogram).

Language disorder is strongly associated with other neurodevelopmental disorders in 
terms of specific learning disorder (literacy and numeracy), attention-deficit/hyperactiv­
ity disorder, autism spectrum disorder, and developmental coordination disorder. It is 
also associated with social (pragmatic) communication disorder. A positive family history 
of speech or language disorders is often present.
Speech Sound Disorder
Diagnostic Criteria 315.39 (F80.0)
A. Persistent difficulty with speech sound production that interferes with speech intelligi­
bility or prevents verbal communication of messages.
B. The disturbance causes limitations in effective communication that interfere with social  
participation, academic achievement, or occupational performance, individually or in  
any combination.
D. The difficulties are not attributable to congenital or acquired conditions, such as cere­

bral palsy, cleft palate, deafness or hearing loss, traumatic brain injury, or other medi­
cal or neurological conditions.
Speech sound production describes the clear articulation of the phonemes (i.e., individual 
sounds) that in combination make up spoken words. Speech sound production requires both 
the phonological knowledge of speech sounds and the ability to coordinate the movements of 
the articulators (i.e., the jaw, tongue, and lips,) with breathing and vocalizing for speech. Chil­
dren with speech production difficulties may experience difficulty with phonological knowl­
edge of speech sounds or the ability to coordinate movements for speech in varying degrees. 
Speech sound disorder is thus heterogeneous in its underlying mechanisms and includes pho­

nological disorder and articulation disorder. A speech sound disorder is diagnosed when 
speech sound production is not what would be expected based on the child's age and devel­
opmental stage and when the deficits are not the result of a physical, structural, neurological, 
or hearing impairment. Among typically developing children at age 4 years, overall speech 
should be intelligible, whereas at age 2 years, only 50% may be understandable.
Language disorder, particularly expressive deficits, may be found to co-occur with speech 
sound disorder. A positive family history of speech or language disorders is often present.
If the ability to rapidly coordinate the articulators is a particular aspect of difficulty,

If the ability to rapidly coordinate the articulators is a particular aspect of difficulty, 
there may be a history of delay or incoordination in acquiring skills that also utilize the 
articulators and related facial musculature; among others, these skills include chewing, 
maintaining mouth closure, and blowing the nose. Other areas of motor coordination may 
be impaired as in developmental coordination disorder. Verbal dyspraxia  is a term also 
used for speech production problems.
Speech may be differentially impaired in certain genetic conditions (e.g.. Down syn­
drome, 22q deletion, FoxPZ  gene mutation). If present, these should also be coded.
Learning to produce speech sounds clearly and accurately and learning to produce con­
nected speech fluently are developmental skills. Articulation of speech sounds follows a

developmental pattern, which is reflected in the age norms of standardized tests. It is not 
unusual for typically developing children to use developmental processes for shortening 
words and syllables as they are learning to talk, but their progression in mastering speech 
sound production should result in mostly inteUigible speech by age 3 years. Children with 
speech sound disorder continue to use immature phonological simplification processes 
past the age when most children can produce words clearly.
Most speech sounds should be produced clearly and most words should be pronounced 
accurately according to age and community norms by age 7 years. The most frequently mis- 
articulated sounds also tend to be learned later, leading them to be called the ''late eight" ( / , r, 
s, z, th, ch, dzh,  and zh). Misarticulation of any of these sounds by itself could be considered 
within normal limits up to age 8 years. When multiple sounds are involved, it may be appro­

priate to target some of those sounds as part of a plan to improve intelligibility prior to the age 
at which almost all children can produce them accurately. Lisping (i.e., misarticulating sibi­
lants) is particularly common and may involve frontal or lateral patterns of airstream direc­
tion. It may be associated with an abnormal tongue-thrust swallowing pattern.
Most children with speech sound disorder respond well to treatment, and speech dif­
ficulties improve over time, and thus the disorder may not be lifelong. However, when a 
language disorder is also present, the speech disorder has a poorer prognosis and may be 
associated with specific learning disorders.
Normal variations in speech. Regional, social, or cultural/ethnic variations of speech

Normal variations in speech. Regional, social, or cultural/ethnic variations of speech 
should be considered before making the diagnosis.
Hearing or other sensory impairment. Hearing impairment or deafness may result in 
abnormalities of speech. Deficits of speech sound production may be associated with a 
hearing impairment, other sensory deficit, or a speech-motor deficit. When speech deficits 
are in excess of those usually associated with these problems, a diagnosis of speech sound 
disorder may be made.
Structural deficits. Speech impairment may be due to structural deficits (e.g., cleft palate).
Dysarthria. Speech impairment may be attributable to a motor disorder, such as cerebral 
palsy. Neurological signs, as well as distinctive features of voice, differentiate dysarthria 
from speech sound disorder, although in young children (under 3 years) differentiation

from speech sound disorder, although in young children (under 3 years) differentiation 
may be difficult, particularly when there is no or minimal general body motor involve­
ment (as in, e.g., Worster-Drought syndrome).
Selective mutism. Limited use of speech may be a sign of selective mutism, an anxiety 
disorder that is characterized by a lack of speech in one or more contexts or settings. Se­
lective mutism may develop in children with a speech disorder because of embarassment 
about their impairments, but many children with selective mutism exhibit normal speech 
in "safe" settings, such as at home or with close friends.
Childhood-Onset Fluency Disorder (Stuttering)
Diagnostic Criteria 315.35 (F80.81)
A. Disturbances in the normal fluency and time patterning of speech that are inappropri­
ate for the individual’s age and language skills, persist over time, and are characterized

ate for the individual’s age and language skills, persist over time, and are characterized  
by frequent and marked occurrences of one (or more) of the following:
1. Sound and syllable repetitions.
2. Sound prolongations of consonants as well as vowels.

3. Broken words (e.g., pauses within a word).
4. Audible or silent blocking (filled or unfilled pauses in speech).
5. Circumlocutions (word substitutions to avoid problematic words).
6. Words produced with an excess of physical tension.
7. Monosyllabic whole-word repetitions (e.g., “I-I-I-I see him” ).
B. The disturbance causes anxiety about speaking or limitations in  effective communica­
tion, social participation, or academic or occupational performance, individually or in  
C. The onset of symptoms is in the early developmental period. (Note: Later-onset cases  
are diagnosed as 307.0 [F98.5] adult-onset fluency disorder.)
D. The disturbance is not attributable to a speech-motor or sensory deficit, dysfluency as­
sociated with neurological insult (e.g., stroke, tumor, trauma), or another medical con­
dition and is not better explained by another mental disorder.

The essential feature of childhood-onset fluency disorder (stuttering) is a disturbance in 
the normal fluency and time patterning of speech that is inappropriate for the individual's 
age. This disturbance is characterized by frequent repetitions or prolongations of sounds 
or syllables and by other types of speech dysfluencies, including broken words (e.g., 
pauses within a word), audible or silent blocl^g (i.e., filled or unfilled pauses in speech), 
circumlocutions (i.e., word substitutions to avoid problematic words), words produced 
with an excess of physical tension, and monosyllabic whole-word repetitions (e.g., 'T-I-I-I 
see him"). The disturbance in fluency interferes with academic or occupational achieve­
ment or with social communication. The extent of the disturbance varies from situation to

ment or with social communication. The extent of the disturbance varies from situation to 
situation and often is more severe when there is special pressure to communicate (e.g., giv­
ing a report at school, interviewing for a job). Dysfluency is often absent during oral read­
ing, singing, or talking to inanimate objects or to pets.
Fearful anticipation of the problem may develop. The speaker may attempt to avoid dys­
fluencies by linguistic mechanisms (e.g., altering the rate of speech, avoiding certain 
words or sounds) or by avoiding certain speech situations, such as telephoning or public 
speaking. In addition to being features of the condition, stress and anxiety have been 
shown to exacerbate dysfluency.
Childhood-onset fluency disorder may also be accompanied by motor movements

Childhood-onset fluency disorder may also be accompanied by motor movements 
(e.g., eye blinks, tics, tremors of the lips or face, jerking of the head, breathing movements, 
fist clenching). Children with fluency disorder show a range of language abilities, and the 
relationship between fluency disorder and language abilities is unclear.
Childhood-onset fluency disorder, or developmental stuttering, occurs by age 6 for 80%- 
90% of affected individuals, with age at onset ranging from 2 to 7 years. The onset can be 
insidious or more sudden. Typically, dysfluencies start gradually, with repetition of initial 
consonants, first words of a phrase, or long words. The child may not be aware of dysflu­
encies. As the disorder progresses, the dysfluencies become more frequent and interfering,

encies. As the disorder progresses, the dysfluencies become more frequent and interfering, 
occurring on the most meaningful words or phrases in the utterance. As the child becomes 
aware of the speech difficulty, he or she may develop mechanisms for avoiding the dys­
fluencies and emotional responses, including avoidance of public speaking and use of 
short and simple utterances. Longitudinal research shows that 65%-85% of children re­

cover from the dysfluency, with severity of fluency disorder at age 8 years predicting re­
covery or persisjence into adolescence and beyond.
Genetic and physiological. The risk of stuttering among first-degree biological rela­
tives of individuals with childhood-onset fluency disorder is more than three times the 
risk in the general population.
Functional Consequences of  
Childhood-Onset Fiuency Disorder (Stuttering)
In addition to being features of the condition, stress and anxiety can exacerbate dysflu­
ency. Impairment of social functioning may result from this anxiety.
Sensory deficits. Dysfluencies of speech may be associated with a hearing impairment 
or other sensory deficit or a speech-motor deficit. When the speech dysfluencies are in ex­
cess of those usually associated with these problems, a diagnosis of childhood-onset flu­
ency disorder may be made.

Normal speech dysfluencies. The disorder must be distinguished from normal dysflu­
encies that occur frequently in young children, which include whole-word or phrase rep­
etitions (e.g., 'T want, I want ice cream"), incomplete phrases, interjections, unfilled 
pauses, and parenthetical remarks. If these difficulties increase in frequency or complexity 
as the child grows older, a diagnosis of childhood-onset fluency disorder is appropriate.
Medication side effects. Stuttering may occur as a side effect of medication and may be 
detected by a temporal relationship with exposure to the medication.
Adult-onset dysfluencies. If onset of dysfluencies is during or after adolescence, it is an 
"adult-onset dysfluency" rather than a neurodevelopmental disorder. Adult-onset dysflu­
encies are associated with specific neurological insults and a variety of medical conditions

encies are associated with specific neurological insults and a variety of medical conditions 
and mental disorders and may be specified with them, but they are not a DSM-5 diagnosis.
Tourette’s disorder. Vocal tics and repetitive vocalizations of Tourette's disorder 
should be distinguishable from the repetitive sounds of childhood-onset fluency disorder 
by their nature and timing.
Social (Pragmatic) Communication Disorder
Diagnostic Criteria 315.39 (F80.89)
A. Persistent difficulties in the social use of verbal and nonverbal communication as man­
ifested by all of the following:
1. Deficits in  using communication for social purposes, such as greeting and sharing  
information, in a manner that is appropriate for the social context.
2. Impairment of the ability to change communication to match context or the needs of

2. Impairment of the ability to change communication to match context or the needs of  
the listener, such as speaking differently in  a classroom than on a playground, talk­
ing differently to a child than to an adult, and avoiding use of overly formal language.
3. Difficulties following rules for conversation and storytelling, such as taking turns in  
conversation, rephrasing when misunderstood, and knowing how to use verbal and  
nonverbal signals to regulate interaction.

4. Difficulties understanding wliat is not explicitly stated (e.g., making inferences) and  
nonliteral or ambiguous meanings of language (e.g., idioms, humor, metaphors,  
multiple meanings that depend on the context for interpretation).
B. The deficits result in functional limitations in effective communication, social participa­
tion, social relationships, academic achievement, or occupational performance, indi­
vidually or in combination.
C. The onset of the symptoms is in the early developmental period (but deficits may not  
become fully manifest until social communication demands exceed limited capacities).
D. The symptoms are not attributable to another medical or neurological condition or to low  
abilities in  the domains of word structure and grammar, and are not better explained by  
autism spectrum disorder, intellectual disability (intellectual developmental disorder),  
global developmental delay, or another mental disorder.

Social (pragmatic) communication disorder is characterized by a primary difficulty with 
pragmatics, or the social use of language and communication, as manifested by deficits in 
understanding and following social rules of verbal and nonverbal communication in nat­
uralistic contexts, changing language according to the needs of the listener or situation, 
and following rules for conversations and storytelling. The deficits in social communica­
tion result in functional limitations in effective communication, social participation, devel­
opment of social relationships, academic achievement, or occupational performance. The 
deficits are not better explained by low abilities in the domains of structural language or 
cognitive abihty.

The most common associated feature of social (pragmatic) communication disorder is lan­
guage impairment, which is characterized by a history of delay in reaching language mile­
stones, and historical, if not current, structural language problems (see ''Language Disorder" 
earlier in this chapter). Individuals with social communication deficits may avoid social inter­
actions. Attention-deficit/hyperactivity disorder (ADHD), behavioral problems, and specific 
learning disorders are also more common among affected individuals.
Development and Course
Because social (pragmatic) communication depends on adequate developmental progress 
in speech and language, diagnosis of social (pragmatic) communication disorder is rare 
among children younger than 4 years. By age 4 or 5 years, most children should possess

among children younger than 4 years. By age 4 or 5 years, most children should possess 
adequate speech and language abilities to permit identification of specific deficits in social 
communication. Milder forms of the disorder may not become apparent until early ado­
lescence, when language and social interactions become more complex.
The outcome of social (pragmatic) communication disorder is variable, with some chil­
dren improving substantially over time and others continuing to have difficulties persist­
ing into adulthood. Even among those who have significant improvements, the early 
deficits in pragmatics may cause lasting impairments in social relationships and behavior 
and also in acquisition of other related skills, such as written expression.
Genetic and physiological. A family history of autism spectrum disorder, communica­

tion disorders, or specific learning disorder appears to increase the risk for social (prag­
matic) communication disorder.

Autism spectrum disorder. Autism spectrum disorder is the primary diagnostic con­
sideration for individuals presenting with social communication deficits. The two disor­
ders can be differentiated by the presence in autism spectrum disorder of restricted/ 
repetitive patterns of behavior, interests, or activities and their absence in social (prag­
matic) communication disorder. Individuals with autism spectrum disorder may only dis­
play the restricted/repetitive patterns of behavior, interests, and activities during the early 
developmental period, so a comprehensive history should be obtained. Current absence of 
symptoms would not preclude a diagnosis of autism spectrum disorder, if the restricted 
interests and repetitive behaviors were present in the past. A diagnosis of social (prag­
matic) communication disorder should be considered only if the developmental history

matic) communication disorder should be considered only if the developmental history 
fails to reveal any evidence of restricted/repetitive patterns of behavior, interests, or ac­
tivities.
Attention-deficit/hyperactivity disorder. Primary deficits of ADHD may cause impair­
ments in social communication and functional limitations of effective communication, so­
cial participation, or academic achievement.
Social anxiety disorder (social phobia). The symptoms of social communication disor­
der overlap with those of social anxiety disorder. The differentiating feature is the timing 
of the onset of symptoms. In social (pragmatic) communication disorder, the individual 
has never had effective social communication; in social anxiety disorder, the social com­
munication skills developed appropriately but are not utilized because of anxiety, fear, or 
distress about social interactions.

Intellectual disability (intellectual developmental disorder) and global developmental  
delay. Social communication skills may be deficient among individuals with global de­
velopmental delay or intellectual disability, but a separate diagnosis is not given unless 
the social communication deficits are clearly in excess of the intellectual limitations.
Unspecified Communication Disorder
307.9 (F80.9)
This category applies to presentations in which symptoms characteristic of communication  
disorder that cause clinically significant distress or impairment in social, occupational, or  
other important areas of functioning predominate but do not meet the full criteria for com­
munication disorder or for any of the disorders in the neurodevelopmental disorders diag­
nostic class. The unspecified communication disorder category is used in situations in

nostic class. The unspecified communication disorder category is used in situations in  
which the clinician chooses not to specify the reason that the criteria are not met for com­
munication disorder or for a specific neurodevelopmental disorder, and includes presen­
tations in which there is insufficient information to make a more specific diagnosis.

Autism Spectrum Disorder
Diagnostic Criteria 299.00 (F84.0)
A. Persistent deficits in  social communication and social interaction across multiple con­
texts, as manifested by the following, currently or by history (examples are illustrative,  
not exhaustive; see text):
1. Deficits in social-emotional reciprocity, ranging, for example, from abnormal social  
approach and failure of normal back-and-forth conversation; to reduced sharing of  
interests, emotions, or affect; to failure to initiate or respond to social interactions.
2. Deficits in  nonverbal communicative behaviors used for social interaction, ranging,  
for example, from poorly integrated verbal and nonverbal communication; to abnor­
malities in eye contact and body language or deficits in understanding and use of  
gestures: to a total lack of facial expressions and nonverbal communication.
3. Deficits in  developing, maintaining, and understanding relationships, ranging, for ex­

ample, from difficulties adjusting behavior to suit various social contexts; to difficulties  
in  sharing imaginative play or in  making friends; to absence of interest in  peers.
Severity is based on social communication impairments and restricted, re­
petitive patterns of behavior (seeTable 2).
B. Restricted, repetitive patterns of behavior, interests, or activities, as manifested by at  
least two of the following, currently or by history (examples are illustrative, not exhaus­
tive; see text):
1. Stereotyped or repetitive motor movements, use of objects, or speech (e.g., simple  
motor stereotypies, lining up toys or flipping objects, echolalia, idiosyncratic  
phrases).
2. Insistence on sameness, inflexible adherence to routines, or ritualized patterns of

phrases).
2. Insistence on sameness, inflexible adherence to routines, or ritualized patterns of  
verbal or nonverbal behavior (e.g., extreme distress at small changes, difficulties  
with transitions, rigid thinking patterns, greeting rituals, need to take same route or  
eat same food every day).
3. Highly restricted, fixated interests that are abnormal in intensity or focus (e.g.,  
strong attachment to or preoccupation with unusual objects, excessively circum­
scribed or perseverative interests).
4. Hyper- or hyporeactivity to sensory input or unusual interest in sensory aspects of  
the environment (e.g., apparent indifference to pain/temperature, adverse re­
sponse to specific sounds or textures, excessive smelling or touching of objects,  
visual fascination with lights or movement).

petitive patterns of behavior (see Table 2).
C. Symptoms must be present in the early developmental period (but may not become  
fully manifest until social demands exceed limited capacities, or may be masked by  
learned strategies in later life).
D. Symptoms cause clinically significant impairment in  social, occupational, or other im­
portant areas of current functioning.

E. These disturbances are not better explained by intellectual disability (intellectual devel­
opmental disorder) or global developmental delay. Intellectual disability and autism  
spectrum disorder frequently co-occur; to make comorbid diagnoses of autism spec­
trum disorder and intellectual disability, social communication should be below that ex­
pected for general developmental level.
Note: Individuals with a well-established DSM-IV diagnosis of autistic disorder, Asperger’s  
disorder, or pervasive developmental disorder not otherwise specified should be given the  
diagnosis of autism spectrum disorder. Individuals who have marked deficits in social  
communication, but whose symptoms do not othenwise meet criteria for autism spectrum  
disorder, should be evaluated for social (pragmatic) communication disorder.
Specify  if;
With or without accompanying inteliectual impairment  
With or without accompanying language impairment

Associated with a icnown medicai or genetic condition or environmental factor  
(Coding note: Use additional code to identify the associated medical or genetic condition.)  
Associated with another neurodevelopmental, mental, or behavioral disorder  
(Coding note: Use additional code[s] to identify the associated neurodevelopmental,  
mental, or behavioral disorder[s].)
With catatonia (refer to the criteria for catatonia associated with another mental dis­
order, pp. 119-120, for definition) (Coding note: Use additional code 293.89 [F06.1]  
catatonia associated with autism spectrum disorder to indicate the presence of the co­
morbid catatonia.)
Recording Procedures
For autism spectrum disorder that is associated with a known medical or genetic condition

For autism spectrum disorder that is associated with a known medical or genetic condition 
or environmental factor, or with another neurodevelopmental, mental, or behavioral dis­
order, record autism spectrum disorder associated with (name of condition, disorder, or 
factor) (e.g., autism spectrum disorder associated with Rett syndrome). Severity should be 
recorded as level of support needed for each of the two psychopathological domains in 
Table 2 (e.g., "requiring very substantial support for deficits in social communication and 
requiring substantial support for restricted, repetitive behaviors"). Specification of "with 
accompanying intellectual impairment" or "without accompanying intellectual impair­
ment" should be recorded next. Language impairment specification should be recorded 
thereafter. If there is accompanying language impairment, the current level of verbal func­

tioning should be recorded (e.g., "with accompanying language impairment—no intelligi­
ble speech" or "with accompanying language impairment—phrase speech"). If catatonia is 
present, record separately "catatonia associated with autism spectrum disorder."
The severity specifiers (see Table 2) may be used to describe succinctly the current symp­
tomatology (which might fall below level 1), with the recognition that severity may vary by 
context and fluctuate over time. Severity of social communication difficulties and re­
stricted, repetitive behaviors should be separately rated. The descriptive severity categories 
should not be used to determine eligibility for and provision of services; these can only be 
developed at an individual level and through discussion of personal priorities and targets.

Regarding the specifier "with or without accompanying intellectual impairment," un­
derstanding the (often uneven) intellectual profile of a child or adult with autism spectrum 
disorder is necessary for interpreting diagnostic features. Separate estimates of verbal and 
nonverbal skill are necessary (e.g., using untimed nonverbal tests to assess potential 
strengths in individuals with limited language).

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To use the specifier "with or without accompanying language impairment," the cur­
rent level of verbal functioning should be assessed and described. Examples of the specific 
descriptions for "with accompanying language impairment" might include no intelligible 
speech (nonverbal), single words only, or phrase speech. Language level in individuals 
"without accompanying language impairment" might be further described by speaks in 
full sentences or has fluent speech. Since receptive language may lag behind expressive 
language development in autism spectrum disorder, receptive and expressive language 
skills should be considered separately.
The specifier "associated with a known medical or genetic condition or environmental fac­
tor" should be used when the individual has a known genetic disorder (e.g., Rett syndrome. 
Fragile X syndrome. Down syndrome), a medical disorder (e.g. epilepsy), or a history of envi­

ronmental exposure (e.g., valproate, fetal alcohol syndrome, very low birth weight).
Additional neurodevelopmental, mental or behavioral conditions should also be noted 
(e.g., attention-deficit/hyperactivity disorder; developmental coordination disorder; dis­
ruptive behavior, impulse-control, or conduct disorders; anxiety, depressive, or bipolar 
disorders; tics or Tourette's disorder; self-injury; feeding, elimination, or sleep disorders).
The essential features of autism spectrum disorder are persistent impairment in reciprocal 
social communication and social interaction (Criterion A), and restricted, repetitive pat­
terns of behavior, interests, or activities (Criterion B). These symptoms are present from

terns of behavior, interests, or activities (Criterion B). These symptoms are present from 
early childhood and limit or impair everyday functioning (Criteria C and D). The stage at 
which functional impairment becomes obvious will vary according to characteristics of 
the individual and his or her environment. Core diagnostic features are evident in the 
developmental period, but intervention, compensation, and current supports may mask 
difficulties in at least some contexts. Manifestations of the disorder also vary greatly de­
pending on the severity of the autistic condition, developmental level, and chronological age; 
hence, the term spectrum.  Autism spectrum disorder encompasses disorders previously re­
ferred to as early infantile autism, childhood autism, Kanner's autism, high-functioning 
autism, atypical autism, pervasive developmental disorder not otherwise specified, child­

hood disintegrative disorder, and Asperger's disorder.
The impairments in communication and social interaction specified in Criterion A are 
pervasive and sustained. Diagnoses are most valid and reliable when based on multiple 
sources of information, including clinician's observations, caregiver history, and, when 
possible, self-report. Verbal and nonverbal deficits in social communication have varying 
manifestations, depending on the individual's age, intellectual level, and language ability, 
as well as other factors such as treatment history and current support. Many individuals 
have language deficits, ranging from complete lack of speech through language delays, 
poor comprehension of speech, echoed speech, or stilted and overly literal language. Even

poor comprehension of speech, echoed speech, or stilted and overly literal language. Even 
when formal language skills (e.g., vocabulary, grammar) are intact, the use of language for 
reciprocal social communication is impaired in autism spectrum disorder.
Deficits in social-emotional reciprocity (i.e., the ability to engage with others and share 
thoughts and feelings) are clearly evident in young children with the disorder, who may 
show little or no initiation of social interaction and no sharing of emotions, along with re­
duced or absent imitation of others' behavior. What language exists is often one-sided, 
lacking in social reciprocity, and used to request or label rather than to comment, share 
feelings, or converse. In adults without intellectual disabilities or language delays, deficits 
in social-emotional reciprocity may be most apparent in difficulties processing and re­

sponding to complex social cues (e.g., when and how to join a conversation, what not to 
say). Adults who have developed compensation strategies for some social challenges still 
struggle in novel or unsupported situations and suffer from the effort and anxiety of con­
sciously calculating what is socially intuitive for most individuals.

Deficits in nonverbal communicative behaviors used for social interaction are mani­
fested by absent, reduced, or atypical use of eye contact (relative to cultural norms), ges­
tures, facial expressions, body orientation, or speech intonation. An early feature of autism 
spectrum disorder is impaired joint attention as manifested by a lack of pointing, showing, 
or bringing objects to share interest with others, or failure to follow someone's pointing or 
eye gaze. Individuals may learn a few functional gestures, but their repertoire is smaller 
than that of others, and they often fail to use expressive gestures spontaneously in com­
munication. Among adults with fluent language, the difficulty in coordinating nonverbal 
communication with speech may give the impression of odd, wooden, or exaggerated 
"body language" during interactions. Impairment may be relatively subtle within indi­
vidual modes (e.g., someone may have relatively good eye contact when speaking) but

vidual modes (e.g., someone may have relatively good eye contact when speaking) but 
noticeable in poor integration of eye contact, gesture, body posture, prosody, and facial ex­
pression for social communication.
Deficits in developing, maintaining, and understanding relationships should be 
judged against norms for age, gender, and culture. There may be absent, reduced, or atyp­
ical social interest, manifested by rejection of others, passivity, or inappropriate ap­
proaches that seem aggressive or disruptive. These difficulties are particularly evident in 
young children, in whom there is often a lack of shared social play and imagination (e.g., 
age-appropriate flexible pretend play) and, later, insistence on playing by very fixed rules. 
Older individuals may struggle to understand what behavior is considered appropriate in

Older individuals may struggle to understand what behavior is considered appropriate in 
one situation but not another (e.g., casual behavior during a job interview), or the different 
ways that language may be used to communicate (e.g., irony, white lies). There may be an 
apparent preference for solitary activities or for interacting with much younger or older 
people. Frequently, there is a desire to establish friendships without a complete or realistic 
idea of what friendship entails (e.g., one-sided friendships or friendships based solely on 
shared special interests). Relationships with siblings, co-workers, and caregivers are also 
important to consider (in terms of reciprocity).
Autism spectrum disorder is also defined by restricted, repetitive patterns of behavior, 
interests, or activities (as specified in Criterion B), which show a range of manifestations

interests, or activities (as specified in Criterion B), which show a range of manifestations 
according to age and ability, intervention, and current supports. Stereotyped or repetitive 
behaviors include simple motor stereotypies (e.g., hand flapping, finger flicking), repeti­
tive use of objects (e.g., spinning coins, lining up toys), and repetitive speech (e.g., echola- 
lia, the delayed or immediate parroting of heard words; use of "you" when referring to 
self; stereotyped use of words, phrases, or prosodic patterns). Excessive adherence to rou­
tines and restricted patterns of behavior may be manifest in resistance to change (e.g., dis­
tress at apparently small changes, such as in packaging of a favorite food; insistence on 
adherence to rules; rigidity of thinking) or ritualized patterns of verbal or nonverbal be­

havior (e.g., repetitive questioning, pacing a perimeter). Highly restricted, fixated interests 
in autism spectrum disorder tend to be abnormal in intensity or focus (e.g., a toddler 
strongly attached to a pan; a child preoccupied with vacuum cleaners; an adult spending 
hours writing out timetables). Some fascinations and routines may relate to apparent hy­
per- or hyporeactivity to sensory input, manifested through extreme responses to specific 
sounds or textures, excessive smelling or touching of objects, fascination with lights or 
spinning objects, and sometimes apparent indifference to pain, heat, or cold. Extreme re­
action to or rituals involving taste, smell, texture, or appearance of food or excessive food 
restrictions are common and may be a presenting feature of autism spectrum disorder.

Many adults with autism spectrum disorder without intellectual or language disabili­
ties learn to suppress repetitive behavior in public. Special interests may be a source of 
pleasure and motivation and provide avenues for education and employment later in life. 
Diagnostic criteria may be met when restricted, repetitive patterns of behavior, interests, 
or activities were clearly present during childhood or at some time in the past, even if 
symptoms are no longer present.

Criterion D requires that the features must cause clinically significant impairment in so­
cial, occupational, or other important areas of current functioning. Criterion E specifies that 
the social communication deficits, although sometimes accompanied by intellectual disabil­
ity (intellectual developmental disorder), are not in line with the individual's developmental 
level; impairments exceed difficulties expected on the basis of developmental level.
Standardized behavioral diagnostic instruments with good psychometric properties, 
including caregiver interviews, questionnaires and clinician observation measures, are 
available and can improve reliability of diagnosis over time and across clinicians.
Many individuals with autism spectrum disorder also have intellectual impairment and/or 
language impairment (e.g., slow to talk, language comprehension behind production). Even

language impairment (e.g., slow to talk, language comprehension behind production). Even 
those with average or high intelligence have an uneven profile of abilities. The gap between 
intellectual and adaptive functional skills is often large. Motor deficits are often present, in­
cluding odd gait, clumsiness, and other abnormal motor signs (e.g., walking on tiptoes). Self­
injury (e.g., head banging, biting the wrist) may occur, and disruptive/challenging behav­
iors are more common in children and adolescents with autism spectrum disorder than 
other disorders, including intellectual disability. Adolescents and adults with autism spec­
trum disorder are prone to anxiety and depression. Some individuals develop catatonic-like 
motor behavior (slowing and "freezing" mid-action), but these are typically not of the mag­

nitude of a catatonic episode. However, it is possible for individuals with autism spectrum 
disorder to experience a marked deterioration in motor symptoms and display a full cata­
tonic episode with symptoms such as mutism, posturing, grimacing and waxy flexibility. 
The risk period for comorbid catatonia appears to be greatest in the adolescent years.
In recent years, reported frequencies for autism spectrum disorder across U.S. and non- 
U.S. countries have approached 1% of the population, with similar estimates in child and 
adult samples. It remains unclear whether higher rates reflect an expansion of the diag­
nostic criteria of DSM-IV to include subthreshold cases, increased awareness, differences 
in study methodology, or a true increase in the frequency of autism spectrum disorder.

The age and pattern of onset also should be noted for autism spectrum disorder. Symptoms 
are typically recognized during the second year of life (12-24 months of age) but may be seen 
earlier than 12 months if developmental delays are severe, or noted later than 24 months if 
symptoms are more subtle. The pattern of onset description might include information 
about early developmental delays or any losses of social or language skills. In cases where 
skills have been lost, parents or caregivers may give a history of a gradual or relatively 
rapid deterioration in social behaviors or language skills. Typically, this would occur be­
tween 12 and 24 months of age and is distinguished from the rare instances of developmen­

tal regression occurring after at least 2 years of normal development (previously described 
as childhood disintegrative disorder).
The behavioral features of autism spectrum disorder first become evident in early 
childhood, with some cases presenting a lack of interest in social interaction in the first 
year of life. Some children with autism spectrum disorder experience developmental pla­
teaus or regression, with a gradual or relatively rapid deterioration in social behaviors or 
use of language, often during the first 2 years of life. Such losses are rare in other disor­
ders and may be a useful "red flag" for autism spectrum disorder. Much more unusual 
and warranting more extensive medical investigation are losses of skills beyond social

and warranting more extensive medical investigation are losses of skills beyond social 
communication (e.g., loss of self-care, toileting, motor skills) or those occurring after the

second birthday (see also Rett syndrome in the section "Differential Diagnosis" for this 
disorder).
First symptoms of autism spectrum disorder frequently involve delayed language de­
velopment, often accompanied by lack of social interest or unusual social interactions (e.g., 
pulling individuals by the hand without any attempt to look at them), odd play patterns 
(e.g., carrying toys around but never playing with them), and unusual communication 
patterns (e.g., knowing the alphabet but not responding to own name). Deafness may be 
suspected but is typically ruled out. During the second year, odd and repetitive behaviors 
and the absence of typical play become more apparent. Since many typically developing 
young children have strong preferences and enjoy repetition (e.g., eating the same foods, 
watching the same video multiple times), distinguishing restricted and repetitive behav­
iors that are diagnostic of autism spectrum disorder can be difficult in preschoolers. The

iors that are diagnostic of autism spectrum disorder can be difficult in preschoolers. The 
clinical distinction is based on the type, frequency, and intensity of the behavior (e.g., a 
child who daily lines up objects for hours and is very distressed if any item is moved).
Autism spectrum disorder is not a degenerative disorder, and it is typical for learning 
and compensation to continue throughout life. Symptoms are often most marked in early 
childhood and early school years, with developmental gains typical in later childhood in 
at least some areas (e.g., increased interest in social interaction). A small proportion of in­
dividuals deteriorate behaviorally during adolescence, whereas most others improve. 
Only a minority of individuals with autism spectrum disorder live and work indepen­
dently in adulthood; those who do tend to have superior language and intellectual abilities

dently in adulthood; those who do tend to have superior language and intellectual abilities 
and are able to find a niche that matches their special interests and skills. In general, indi­
viduals with lower levels of impairment may be better able to function independently. 
However, even these individuals may remain socially naive and vulnerable, have difficul­
ties organizing practical demands without aid, and are prone to anxiety and depression. 
Many adults report using compensation strategies and coping mechanisms to mask their 
difficulties in public but suffer from the stress and effort of maintaining a socially accept­
able facade. Scarcely anything is known about old age in autism spectrum disorder.
Some individuals come for first diagnosis in adulthood, perhaps prompted by the diagno­
sis of autism in a child in the family or a breakdown of relations at work or home. Obtaining de­

tailed developmental history in such cases may be difficult, and it is important to consider self­
reported difficulties. Where clinical observation suggests criteria are currently met, autism 
spectrum disorder may be diagnosed, provided there is no evidence of good social and com­
munication skills in childhood. For example, the report (by parents or another relative) that the 
individual had ordinary and sustained reciprocal friendships and good nonverbal communi­
cation skills throughout childhood would rule out a diagnosis of autism spectrum disorder; 
however, the absence of developmental information in itself should not do so.
Manifestations of the social and communication impairments and restricted/repeti­

tive behaviors that define autism spectrum disorder are clear in the developmental period. 
In later life, intervention or compensation, as well as current supports, may mask these dif­
ficulties in at least some contexts. However, symptoms remain sufficient to cause current 
impairment in social, occupational, or other important areas of functioning.
The best established prognostic factors for individual outcome within autism spectrum 
disorder are presence or absence of associated intellectual disability and language impair­
ment (e.g., functional language by age 5 years is a good prognostic sign) and additional 
mental health problems. Epilepsy, as a comorbid diagnosis, is associated with greater in­
tellectual disability and lower verbal ability.

Environmental. A variety of nonspecific risk factors, such as advanced parental age, low 
birth weight, or fetal exposure to valproate, may contribute to risk of aufism spectrum dis­
order.

Genetic and physiological. Heritability estimates for autism spectrum disorder have 
ranged from 3 7 °/ ^  to higher than 90%, based on twin concordance rates. Currently, as many 
as 15% of cases of autism spectrum disorder appear to be associated with a known genetic 
mutation, with different de novo copy number variants or de novo mutations in specific 
genes associated with the disorder in different families. However, even when an autism 
spectrum disorder is associated with a known genetic mutation, it does not appear to be 
fully penetrant. Risk for the remainder of cases appears to be polygenic, with perhaps hun­
dreds of genetic loci making relatively small contributions.
Culture-Related Diagnostic Issues
Cultural differences will exist in norms for social interaction, nonverbal communication, 
and relationships, but individuals with autism spectrum disorder are markedly impaired 
against the norms for their cultural context. Cultural and socioeconomic factors may affect

against the norms for their cultural context. Cultural and socioeconomic factors may affect 
age at recognition or diagnosis; for example, in the United States, late or underdiagnosis of 
autism spectrum disorder among African American children may occur.
Gender-Related Diagnostic Issues
Autism spectrum disorder is diagnosed four times more often in males than in females. In 
clinic samples, females tend to be more likely to show accompanying intellectual disabil­
ity, suggesting that girls without accompanying intellectual impairments or language 
delays may go unrecognized, perhaps because of subtler manifestation of social and com­
munication difficulties.
Functional Consequences of Autism Spectrum Disorder
In young children with autism spectrum disorder, lack of social and communication abil­
ities may hamper learning, especially learning through social interaction or in settings

ities may hamper learning, especially learning through social interaction or in settings 
with peers. In the home, insistence on routines and aversion to change, as well as sensory 
sensitivities, may interfere with eating and sleeping and make routine care (e.g., haircuts, 
dental work) extremely difficult. Adaptive skills are typically below measured IQ. Ex­
treme difficulties in planning, organization, and coping with change negatively impact 
academic achievement, even for students with above-average intelligence. During adult­
hood, these individuals may have difficulties establishing independence because of con­
tinued rigidity and difficulty with novelty.
Many individuals with autism spectrum disorder, even without intellectual disability, 
have poor adult psychosocial functioning as indexed by measures such as independent

have poor adult psychosocial functioning as indexed by measures such as independent 
living and gainful employment. Functional consequences in old age are unknown, but so­
cial isolation and communication problems (e.g., reduced help-seeking) are likely to have 
consequences for health in older adulthood.
Rett syndrome. Disruption of social interaction may be observed during the regressive 
phase of Rett syndrome (typically between 1-4 years of age); thus, a substantial proportion 
of affected young girls may have a presentation that meets diagnostic criteria for autism 
spectrum disorder. However, after this period, most individuals with Rett syndrome im­
prove their social communication skills, and autistic features are no longer a major area of 
concern. Consequently, autism spectrum disorder should be considered only when all di­
agnostic criteria are met.

Selective mutism. In selective mutism, early development is not typically disturbed. 
The affected child usually exhibits appropriate communication skills in certain contexts 
and settings. Even in settings where the child is mute, social reciprocity is not impaired, 
nor are restricted or repetitive patterns of behavior present.

Language disorders and social (pragmatic) communication disorder. In some forms 
of language disorder, there may be problems of communication and some secondary so­
cial difficulties. However, specific language disorder is not usually associated with abnor­
mal nonverbal communication, nor with the presence of restricted, repetitive patterns of 
behavior, interests, or activities.
When an individual shows impairment in social communication and social interactions 
but does not show restricted and repetitive behavior or interests, criteria for social (prag­
matic) communication disorder, instead of autism spectrum disorder, may be met. The di­
agnosis of autism spectrum disorder supersedes that of social (pragmatic) communication 
disorder whenever the criteria for autism spectrum disorder are met, and care should be 
taken to enquire carefully regarding past or current restricted/repetitive behavior.

Intellectual disability (intellectual developmental disorder) without autism spectrum  
disorder. Intellectual disability without autism spectrum disorder may be difficult to 
differentiate from autism spectrum disorder in very young children. Individuals with in­
tellectual disability who have not developed language or symbolic skills also present a 
challenge for differential diagnosis, since repetitive behavior often occurs in such individ­
uals as well. A diagnosis of autism spectrum disorder in an individual with intellectual 
disability is appropriate when social communication and interaction are significantly im­
paired relative to the developmental level of the individual's nonverbal skills (e.g., fine 
motor skills, nonverbal problem solving). In contrast, intellectual disability is the appropri­

ate diagnosis when there is no apparent discrepancy between the level of social-commu­
nicative skills and other intellectual skills.
Stereotypic movement disorder. Motor stereotypies are among the diagnostic charac­
teristics of autism spectrum disorder, so an additional diagnosis of stereotypic movement 
disorder is not given when such repetitive behaviors are better explained by the presence 
of autism spectrum disorder. However, when stereotypies cause self-injury and become a 
focus of treatment, both diagnoses may be appropriate.
Attention-deficit/hyperactivity disorder. Abnormalities of attention (overly focused or 
easily distracted) are common in individuals with autism spectrum disorder, as is hy­
peractivity. A diagnosis of attention-deficit/hyperactivity disorder (ADHD) should be

peractivity. A diagnosis of attention-deficit/hyperactivity disorder (ADHD) should be 
considered when attentional difficulties or hyperactivity exceeds that typically seen in in­
dividuals of comparable mental age.
Schizophrenia. Schizophrenia with childhood onset usually develops after a period of 
normal, or near normal, development. A prodromal state has been described in which so­
cial impairment and atypical interests and beliefs occur, which could be confused with the 
social deficits seen in autism spectrum disorder. Hallucinations and delusions, which are 
defining features of schizophrenia, are not features of autism spectrum disorder. How­
ever, clinicians must take into account the potential for individuals with autism spectrum 
disorder to be concrete in their interpretation of questions regarding the key features of

disorder to be concrete in their interpretation of questions regarding the key features of 
schizophrenia (e.g., "Do you hear voices when no one is there?" "Yes [on the radio]").
Autism spectrum disorder is frequently associated with intellectual impairment and struc­
tural language disorder (i.e., an inability to comprehend and construct sentences with proper 
grammar), which should be noted under the relevant specifiers when applicable. Many in­
dividuals with autism spectrum disorder have psychiatric symptoms that do not form part of 
the diagnostic criteria for the disorder (about 70% of individuals with autism spectrum dis­
order may have one comorbid mental disorder, and 40% may have two or more comorbid 
mental disorders). When criteria for both ADHD and autism spectrum disorder are met, both

mental disorders). When criteria for both ADHD and autism spectrum disorder are met, both 
diagnoses should be given. This same principle applies to concurrent diagnoses of autism 
spectrum disorder and developmental coordination disorder, anxiety disorders, depressive

disorders, and other comorbid diagnoses. Among individuals who are nonverbal or have 
language deficits, observable signs such as changes in sleep or eating and increases in chal­
lenging behavior should trigger an evaluation for anxiety or depression. Specific learning dif­
ficulties (literacy and numeracy) are common, as is developmental coordination disorder. 
Medical conditions commonly associated with autism spectrum disorder should be noted 
under the "associated with a known medical/genetic or environmental/acquired condition" 
specifier. Such medical conditions include epilepsy, sleep problems, and constipation. 
Avoidant-restrictive food intake disorder is a fairly frequent presenting feature of autism 
spectrum disorder, and extreme and narrow food preferences may persist.
Attention-Deficit/Hyperactivity  
Disorder
Attention-Deficit/Hyperactivity Disorder
A. A persistent pattern of inattention and/or hyperactivity-impulsivity that interferes with

Disorder
A. A persistent pattern of inattention and/or hyperactivity-impulsivity that interferes with  
functioning or development, as characterized by (1) and/or (2):
1. Inattention: Six (or more) of the following symptoms have persisted for at least  
6 months to a degree that is inconsistent with developmental level and that nega­
tively impacts directly on social and academic/occupational activities:
Note: The symptoms are not solely a manifestation of oppositional behavior, defi­
ance, hostility, or failure to understand tasks or instructions. For older adolescents  
and adults (age 17 and older), at least five symptoms are required.
a. Often fails to give close attention to details or makes careless mistakes in  
schoolwork, at work, or during other activities (e.g., overlooks or misses details,  
work is inaccurate).

b. Often has difficulty sustaining attention in tasks or play activities (e.g., has diffi­
culty remaining focused during lectures, conversations, or lengthy reading).
c. Often does not seem to listen when spoken to directly (e.g., mind seems else­
where, even in the absence of any obvious distraction).
d. Often does not follow through on instructions and fails to finish schoolwork,  
chores, or duties in the workplace (e.g., starts tasks but quickly loses focus and  
is easily sidetracked).
e. Often has difficulty organizing tasks and activities (e.g., difficulty managing se­
quential tasks; difficulty keeping materials and belongings in order; messy, dis­
organized work; has poor time management; fails to meet deadlines).

f. Often avoids, dislikes, or is reluctant to engage in  tasks that require sustained  
mental effort (e.g., schoolwork or homework; for older adolescents and adults,  
preparing reports, completing forms, reviewing lengthy papers).
g. Often loses things necessary for tasks or activities (e.g., school materials, pen­
cils, books, tools, wallets, keys, papenwork, eyeglasses, mobile telephones).
h. Is often easily distracted by extraneous stimuli (for older adolescents and  
adults, may include unrelated thoughts).
i. Is often forgetful in daily activities (e.g., doing chores, running errands; for older  
adolescents and adults, returning calls, paying bills, keeping appointments).

2. Hyperactivity and impuisivity: Six (or more) of the following symptoms have per­
sisted for at least 6 months to a degree that is inconsistent with developmental level  
and that negatively impacts directly on social and academic/occupational activities:  
ance, hostility, or a failure to understand tasks or instructions. For older adolescents  
a. Often fidgets with or taps hands or feet or squirms in seat.
b. Often leaves seat in situations when remaining seated is expected (e.g., leaves  
his or her place in the classroom, in the office or other workplace, or in other  
situations that require remaining in place).
c. Often runs about or climbs in situations where it is inappropriate. (Note: In ad­
olescents or adults, may be limited to feeling restless.)
d. Often unable to play or engage in leisure activities quietly.

e. Is often “ on the go,”  acting as if “ driven by a motor”  (e.g., is unable to be or un­
comfortable being still for extended time, as in restaurants, meetings; may be  
experienced by others as being restless or difficult to keep up with).
f. Often talks excessively.
g. Often blurts out an answer before a question has been completed (e.g., com­
pletes people’s sentences; cannot wait for turn in conversation).
h. Often has difficulty waiting his or her turn (e.g., while waiting in line).
i. Often interrupts or intrudes on others (e.g., butts into conversations, games, or  
activities; may start using other people’s things without asking or receiving per­
mission; for adolescents and adults, may intrude into or take over what others  
are doing).
B. Several inattentive or hyperactive-impulsive symptoms were present prior to age  
12 years.

12 years.
C. Several inattentive or hyperactive-impulsive symptoms are present in two or more set­
tings (e.g., at home, school, or work; with friends or relatives; in other activities).
D. There is clear evidence that the symptoms interfere with, or reduce the quality of, so­
cial, academic, or occupational functioning.
E. The symptoms do not occur exclusively during the course of schizophrenia or another  
psychotic disorder and are not better explained by another mental disorder (e.g., mood  
disorder, anxiety disorder, dissociative disorder, personality disorder, substance intox­
ication or withdrawal).
314.01 (F90.2) Combined presentation: If both Criterion A1 (inattention) and Crite­
rion A2 (hyperactivity-impulsivity) are met for the past 6 months.

314.00 (F90.0) Predominantly inattentive presentation: If Criterion A1 (inattention)  
is met but Criterion A2 (hyperactivity-impulsivity) is not met for the past 6 months.
314.01 (F90.1) Predominantly hyperactive/impulsive presentation: If Criterion A2 (hy­
peractivity-im pulsivity) is met and Criterion A 1 (inattention) is not met for the past 6 months.
in partial remission: When full criteria were previously met, fewer than the full criteria  
have been met for the past 6 months, and the symptoms still result in impairment in  
social, academic, or occupational functioning.
lUlild: Few, if any, symptoms in excess of those required to make the diagnosis are  
present, and symptoms result in no more than minor impairments in social or occupa­

tional functioning.
Moderate: Symptoms or functional impairment between “ mild”  and “ severe”  are present.

Severe: Many symptoms in excess of tliose required to m al<e tlie diagnosis, or several  
symptoms that are particularly severe, are present, or the symptoms result in marked  
impairment in social or occupational functioning.
The essential feature of attention-deficit/hyperactivity disorder (ADHD) is a persistent 
pattern of inattention and/or hyperactivity-impulsivity that interferes with functioning or 
development. Inattention  manifests behaviorally in ADHD as wandering off task, lacking 
persistence, having difficulty sustaining focus, and being disorganized and is not due to 
defiance or lack of comprehension. Hyperactivity  refers to excessive motor activity (such as 
a child running about) when it is not appropriate, or excessive fidgeting, tapping, or talk­
ativeness. In adults, hyperactivity may manifest as extreme restlessness or wearing others 
out with their activity. Impulsivity  refers to hasty actions that occur in the moment without

out with their activity. Impulsivity  refers to hasty actions that occur in the moment without 
forethought and that have high potential for harm to the individual (e.g., darting into the 
street without looking). Impulsivity may reflect a desire for immediate rewards or an in­
ability to delay gratification. Impulsive behaviors may manifest as social intrusiveness 
(e.g., interrupting others excessively) and/or as making important decisions without con­
sideration of long-term consequences (e.g., taking a job without adequate information).
ADHD begins in childhood. The requirement that several symptoms be present before 
age 12 years conveys the importance of a substantial clinical presentation during child­
hood. At the same time, an earlier age at onset is not specified because of difficulties in es­
tablishing precise childhood onset retrospectively. Adult recall of childhood symptoms

tablishing precise childhood onset retrospectively. Adult recall of childhood symptoms 
tends to be unreliable, and it is beneficial to obtain ancillary information.
Manifestations of the disorder must be present in more than one setting (e.g., home and 
school, work). Confirmation of substantial symptoms across settings typically cannot be 
done accurately without consulting informants who have seen the individual in those set­
tings. Typically, symptoms vary depending on context within a given setting. Signs of the 
disorder may be minimal or absent when the individual is receiving frequent rewards for 
appropriate behavior, is under close supervision, is in a novel setting, is engaged in espe­
cially interesting activities, has consistent external stimulation (e.g., via electronic screens), 
or is interacting in one-on-one situations (e.g., the clinician's office).

Mild delays in language, motor, or social development are not specific to ADHD but often co­
occur. Associated features may include low frustration tolerance, irritability, or mood lability. 
Even in the absence of a specific learning disorder, academic or work performance is often im­
paired. Inattentive behavior is associated with various underlying cognitive processes, and in­
dividuals with ADHD may exhibit cognitive problems on tests of attention, executive 
function, or memory, although these tests are not sufficiently sensitive or specific to serve as di­
agnostic indices. By early adulthood, ADHD is associated with an increased risk of suicide at­
tempt, primarily when comorbid with mood, conduct, or substance use disorders.

No biological marker is diagnostic for ADHD. As a group, compared with peers, chil­
dren with ADHD display increased slow wave electroencephalograms, reduced total 
brain volume on magnetic resonance imaging, and possibly a delay in posterior to anterior 
cortical maturation, but these findings are not diagnostic. In the uncommon cases where 
there is a known genetic cause (e.g.. Fragile X syndrome, 22qll deletion syndrome), the 
ADHD presentation should still be diagnosed.
Population surveys suggest that ADHD occurs in most cultures in about 5% of children 
and about 2.5% of adults.

Many parents first observe excessive motor activity when the child is a toddler, but symp­
toms are difficult to distinguish from highly variable normative behaviors before age 4 
years. ADHD is most often identified during elementary school years, and inattention be­
comes more prominent and impairing. The disorder is relatively stable through early ad­
olescence, but some individuals have a worsened course with development of antisocial 
behaviors. In most individuals with ADHD, symptoms of motoric hyperactivity become 
less obvious in adolescence and adulthood, but difficulties with restlessness, inattention, 
poor planning, and impulsivity persist. A substantial proportion of children with ADHD 
remain relatively impaired into adulthood.
In preschool, the main manifestation is hyperactivity. Inattention becomes more prom­
inent during elementary school. During adolescence, signs of hyperactivity (e.g., running

inent during elementary school. During adolescence, signs of hyperactivity (e.g., running 
and climbing) are less common and may be confined to fidgetiness or an inner feeling of 
jitteriness, restlessness, or impatience. In adulthood, along with inattention and restless­
ness, impulsivity may remain problematic even when hyperactivity has diminished.
Temperamental. ADHD is associated with reduced behavioral inhibition, effortful con­
trol, or constraint; negative emotionality; and/or elevated novelty seeking. These traits 
may predispose some children to ADHD but are not specific to the disorder.
Environmental. Very low birth weight (less than 1,500 grams) conveys a two- to three­
fold risk for ADHD, but most children with low birth weight do not develop ADHD. Al­
though ADHD is correlated with smoking during pregnancy, some of this association

though ADHD is correlated with smoking during pregnancy, some of this association 
reflects common genetic risk. A minority of cases may be related to reactions to aspects of 
diet. There may be a history of child abuse, neglect, multiple foster placements, neurotoxin 
exposure (e.g., lead), infections (e.g., encephalitis), or alcohol exposure in utero. Exposure 
to environmental toxicants has been correlated with subsequent ADHD, but it is not 
known whether these associations are causal.
Genetic and physiological. ADHD is elevated in the first-degree biological relatives of 
individuals with ADHD. The heritability of ADHD is substantial. While specific genes 
have been correlated with ADHD, they are neither necessary nor sufficient causal factors. 
Visual and hearing impairments, metabolic abnormalities, sleep disorders, nutritional de­

ficiencies, and epilepsy should be considered as possible influences on ADHD symptoms.
ADHD is not associated with specific physical features, although rates of minor phys­
ical anomalies (e.g., hypertelorism, highly arched palate, low-set ears) may be relatively 
elevated. Subtle motor delays and other neurological soft signs may occur. (Note that 
marked co-occurring clumsiness and motor delays should be coded separately [e.g., de­
velopmental coordination disorder].)
Course modifiers. Family interaction patterns in early childhood are unlikely to cause 
ADHD but may influence its course or contribute to secondary development of conduct 
problems.
Cuiture-Reiated Diagnostic Issues
Differences in ADHD prevalence rates across regions appear attributable mainly to differ­

problems.
ent diagnostic and methodological practices. However, there also may be cultural varia­
tion in attitudes toward or interpretations of children's behaviors. Clinical identification 
rates in the United States for African American and Latino populations tend to be lower 
than for Caucasian populations. Informant symptom ratings may be influenced by cul­
tural group of the child and the informant, suggeshng that culturally appropriate practices 
are relevant in assessing ADHD.

ADHD is more frequent in males than in females in the general population, with a ratio of 
approximately 2:1 in children and 1.6:1 in adults. Females are more likely than males to 
present primarily with inattentive features.
ADHD is associated with reduced school performance and academic attainment, social re­
jection, and, in adults, poorer occupational performance, attainment, attendance, and 
higher probability of unemployment as well as elevated interpersonal conflict. Children 
with ADHD are significantly more likely than their peers without ADHD to develop con­
duct disorder in adolescence and antisocial personality disorder in adulthood, conse­
quently increasing the likelihood for substance use disorders and incarceration. The risk of 
subsequent substance use disorders is elevated, especially when conduct disorder or an­

tisocial personality disorder develops. Individuals with ADHD are more likely than peers 
to be injured. Traffic accidents and violations are more frequent in drivers with ADHD. 
There may be an elevated likelihood of obesity among individuals with ADHD.
Inadequate or variable self-application to tasks that require sustained effort is often in­
terpreted by others as laziness, irresponsibility, or failure to cooperate. Family relation­
ships may be characterized by discord and negative interactions. Peer relationships afe 
often disrupted by peer rejection, neglect, or teasing of the individual with ADHD. On av­
erage, individuals with ADHD obtain less schooling, have poorer vocational achievement, 
and have reduced intellectual scores than their peers, although there is great variability. In

and have reduced intellectual scores than their peers, although there is great variability. In 
its severe form, the disorder is markedly impairing, affecting social, familial, and scholas­
tic/occupational adjustment.
Academic deficits, school-related problems, and peer neglect tend to be most associ­
ated with elevated symptoms of inattention, whereas peer rejection and, to a lesser extent, 
accidental injury are most salient with marked symptoms of hyperactivity or impulsivity.
Oppositional defiant disorder. Individuals with oppositional defiant disorder may re­
sist work or school tasks that require self-application because they resist conforming to 
others' demands. Their behavior is characterized by negativity, hostility, and defiance. 
These symptoms must be differentiated from aversion to school or mentally demanding

These symptoms must be differentiated from aversion to school or mentally demanding 
tasks due to difficulty in sustaining mental effort, forgetting instructions, and impulsivity 
in individuals with ADHD. Complicating the differential diagnosis is the fact that some 
individuals with ADHD may develop secondary oppositional attitudes toward such tasks 
and devalue their importance.
Intermittent explosive disorder. ADHD and intermittent explosive disorder share high 
levels of impulsive behavior. However, individuals with intermittent explosive disorder 
show serious aggression toward others, which is not characteristic of ADHD, and they do 
not experience problems with sustaining attention as seen in ADHD. In addition, intermit­
tent explosive disorder is rare in childhood. Intermittent explosive disorder may be diag­
nosed in the presence of ADHD.

Other neurodevelopmental disorders. The increased motoric activity that may occur in 
ADHD must be distinguished from the repetitive motor behavior that characterizes stereo­
typic movement disorder and some cases of autism spectrum disorder. In stereotypic 
movement disorder, the motoric behavior is generally fixed and repetitive (e.g., body rock­
ing, self-biting), whereas the fidgetiness and restlessness in ADHD are typically general­
ized and not characterized by repetitive stereotypic movements. In Tourette's disorder,

frequent multiple tics can be mistaken for the generalized fidgetiness of ADHD. Prolonged 
observation may be needed to differentiate fidgetiness from bouts of multiple tics.
Specific learning disorder. Children with specific learning disorder may appear inat­
tentive because of frustration, lack of interest, or limited ability. However, inattention in 
individuals with a specific learning disorder who do not have ADHD is not impairing out­
side of academic work.
Intellectual disability (intellectual developmental disorder). Symptoms of ADHD are 
common among children placed in academic settings that are inappropriate to their intel­
lectual ability. In such cases, the symptoms are not evident during non-academic tasks. A 
diagnosis of ADHD in intellectual disability requires that inattention or hyperactivity be 
excessive for mental age.
Autism spectrum disorder. Individuals with ADHD and those with autism spectrum

Autism spectrum disorder. Individuals with ADHD and those with autism spectrum 
disorder exhibit inattention, social dysfunction, and difficult-to-manage behavior. The so­
cial dysfunction and peer rejection seen in individuals with ADHD must be distinguished 
from the social disengagement, isolation, and indifference to facial and tonal communica­
tion cues seen in individuals with autism spectrum disorder. Children with autism spec­
trum disorder may display tantrums because of an inability to tolerate a change from their 
expected course of events. In contrast, children with ADHD may misbehave or have a tan­
trum during a major transition because of impulsivity or poor self-control.
Reactive attachment disorder. Children with reactive attachment disorder may show 
social disinhibition, but not the full ADHD symptom cluster, and display other features

social disinhibition, but not the full ADHD symptom cluster, and display other features 
such as a lack of enduring relationships that are not characteristic of ADHD.
Anxiety disorders. ADHD shares symptoms of inattention with anxiety disorders. Indi­
viduals with ADHD are inattentive because of their attraction to external stimuli, new 
activities, or preoccupation with enjoyable activities. This is distinguished from the inat­
tention due to worry and rumination seen in anxiety disorders. Restlessness might be seen 
in anxiety disorders. However, in ADHD, the symptom is not associated with worry and 
rumination.
Depressive disorders. Individuals with depressive disorders may present with inabil­
ity to concentrate. However, poor concentration in mood disorders becomes prominent 
only during a depressive episode.
Bipolar disorder. Individuals with bipolar disorder may have increased activity, poor

Bipolar disorder. Individuals with bipolar disorder may have increased activity, poor 
concentration, and increased impulsivity, but these features are episodic, occurring sev­
eral days at a time. In bipolar disorder, increased impulsivity or inattention is accompa­
nied by elevated mood, grandiosity, and other specific bipolar features. Children with 
ADHD may show significant changes in mood within the same day; such lability is dis­
tinct from a manic episode, which must last 4 or more days to be a clinical indicator of bi­
polar disorder, even in children. Bipolar disorder is rare in preadolescents, even when 
severe irritability and anger are prominent, whereas ADHD is common among children 
and adolescents who display excessive anger and irritability.
Disruptive mood dysregulation disorder. Disruptive mood dysregulation disorder is 
characterized by pervasive irritability, and intolerance of frustration, but impulsiveness

characterized by pervasive irritability, and intolerance of frustration, but impulsiveness 
and disorganized attenhon are not essential features. However, most children and adoles­
cents with the disorder have symptoms that also meet criteria for ADHD, which is diag­
nosed separately.
Substance use disorders. Differentiating ADHD from substance use disorders may be 
problematic if the first presentation of ADHD symptoms follows the onset of abuse or fre­
quent use. Clear evidence of ADHD before substance misuse from informants or previous 
records may be essential for differential diagnosis.

Personality disorders. In adolescents and adults, it may be difficult to distinguish ADHD 
from borderline, narcissistic, and other personality disorders. All these disorders tend to 
share the features of disorganization, social intrusiveness, emotional dysregulation, and 
cognitive dysregulation. However, ADHD is not characterized by fear of abandonment, 
self-injury, extreme ambivalence, or other features of personality disorder. It may take 
extended clinical observation, informant interview, or detailed history to distinguish im­
pulsive, socially intrusive, or inappropriate behavior from narcissistic, aggressive, or dom­
ineering behavior to make this differential diagnosis.
Psychotic disorders. ADHD is not diagnosed if the symptoms of inattention and hyperac­
tivity occur exclusively during the course of a psychotic disorder.
Medication-induced symptoms of ADHD. Symptoms of inattention, hyperactivity, or

Medication-induced symptoms of ADHD. Symptoms of inattention, hyperactivity, or 
impulsivity attributable to the use of medication (e.g., bronchodilators, isoniazid, neuro­
leptics [resulting in akathisia], thyroid replacement medication) are diagnosed as other 
specified or unspecified other (or unknown) substance-related disorders.
Neurocognitive disorders. Early major neurocognitive disorder (dementia) and/or 
mild neurocognitive disorder are not known to be associated with ADHD but may present 
with similar clinical features. These conditions are distinguished from ADHD by their late 
onset.
In clinical settings, comorbid disorders are frequent in individuals whose symptoms meet 
criteria for ADHD. In the general population, oppositional defiant disorder co-occurs with 
ADHD in approximately half of children with the combined presentation and about a

ADHD in approximately half of children with the combined presentation and about a 
quarter with the predominantly inattentive presentation. Conduct disorder co-occurs in 
about a quarter of children or adolescents with the combined presentation, depending on 
age and setting. Most children and adolescents with disruptive mood dysregulation dis­
order have symptoms that also meet criteria for ADHD; a lesser percentage of children 
with ADHD have symptoms that meet criteria for disruptive mood dysregulation disor­
der. Specific learning disorder commonly co-occurs with ADHD. Anxiety disorders and 
major depressive disorder occur in a minority of individuals with ADHD but more often 
than in the general population. Intermittent explosive disorder occurs in a minority of 
adults with ADHD, but at rates above population levels. Although substance use disor­

ders are relatively more frequent among adults with ADHD in the general population, the 
disorders are present in only a minority of adults with ADHD. In adults, antisocial and 
other personality disorders may co-occur with ADHD. Other disorders that may co-occur 
with ADHD include obsessive-compulsive disorder, tic disorders, and autism spectrum 
disorder.
Other Specified Attention-Deficit/  
Hyperactivity Disorder
314.01 (F90.8)
This category applies to presentations in which symptoms characteristic of attention-  
deficit/hyperactivity disorder that cause clinically significant distress or impairment in so­
cial, occupational or other important areas of functioning predominate but do not meet the  
full criteria for attention-deficit/hyperactivity disorder or any of the disorders in the neuro-

full criteria for attention-deficit/hyperactivity disorder or any of the disorders in the neuro-  
developmental disorders diagnostic class. The other specified attention-deficit/hyperactiv-  
ity disorder category is used in situations in  which the clinician chooses to communicate

the specific reason that the presentation does not meet the criteria for attention-deficit/  
hyperactivity disorder or any specific neurodevelopmental disorder. This is done by re­
cording “ other specified attention-deficit/hyperactivity disorder”  followed by the specific  
reason (e.g., “ with insufficient inattention symptoms” ).
Unspecified Attention-Deficit/  
314.01 (F90.9)
cial, occupational, or other important areas of functioning predominate but do not meet the  
full criteria for attention-deficit/hyperactivity disorder or any of the disorders in the neuro­
developmental disorders diagnostic class. The unspecified attention-deficit/hyperactivity  
disorder category is used in situations in which the clinician chooses not to specify the rea­

son that the criteria are not met for attention-deficit/hyperactivity disorder or for a specific  
neurodevelopmental disorder, and includes presentations in which there is insufficient in­
formation to make a more specific diagnosis.
Specific Learning Disorder
A. Difficulties learning and using academic skills, as indicated by the presence of at least
one of the following symptoms that have persisted for at least 6 months, despite the
provision of interventions that target those difficulties:
1. Inaccurate or slow and effortful word reading (e.g., reads single words aloud incor­
rectly or slowly and hesitantly, frequently guesses words, has difficulty sounding  
out words).

2. Difficulty understanding the meaning of what is read (e.g., may read text accurately  
but not understand the sequence, relationships, inferences, or deeper meanings of  
what is read).
3. Difficulties with spelling (e.g., may add, omit, or substitute vowels or consonants).
4. Difficulties with written expression (e.g., makes multiple grammatical or punctua­
tion errors within sentences; employs poor paragraph organization; written expres­
sion of ideas lacks clarity).
5. Difficulties mastering number sense, number facts, or calculation (e.g., has poor  
understanding of numbers, their magnitude, and relationships; counts on fingers to  
add single-digit numbers instead of recalling the math fact as peers do; gets lost in  
the midst of arithmetic computation and may switch procedures).

6. Difficulties with mathematical reasoning (e.g., has severe difficulty applying math­
ematical concepts, facts, or procedures to solve quantitative problems).

B. The affected academic skills are substantially and quantifiably below those expected  
for the individual’s chronological age, and cause significant interference with academic  
or occupational performance, or with activities of daily living, as confirmed by individu­
ally administered standardized achievement measures and comprehensive clinical  
assessment. For individuals age 17 years and older, a documented history of impairing  
learning difficulties may be substituted for the standardized assessment.
C. The learning difficulties begin during school-age years but may not become fully man­
ifest until the demands for those affected academic sl< ills exceed the individual’s lim­
ited capacities (e.g., as in timed tests, reading or writing lengthy complex reports for a  
tight deadline, excessively heavy academic loads).
D. The learning difficulties are not better accounted for by intellectual disabilities, uncor­

rected visual or auditory acuity, other mental or neurological disorders, psychosocial  
adversity, lack of proficiency in the language of academic instruction, or inadequate  
educational instruction.
Note; The four diagnostic criteria are to be met based on a clinical synthesis of the indi­
vidual’s history (developmental, medical, family, educational), school reports, and psycho-  
educational assessment.
Coding note: Specify all academic domains and subskills that are impaired. When more  
than one domain is impaired, each one should be coded individually according to the fol­
lowing specifiers.
315.00 (F81.0) With impairment in reading:
Word reading accuracy  
Reading rate or fluency  
Reading comprehension
Note: Dyslexia  is an alternative term used to refer to a pattern of learning difficulties

Note: Dyslexia  is an alternative term used to refer to a pattern of learning difficulties  
characterized by problems with accurate or fluent word recognition, poor decoding,  
and poor spelling abilities. If dyslexia is used to specify this particular pattern of dif­
ficulties, it is important also to specify any additional difficulties that are present,  
such as difficulties with reading comprehension or math reasoning.
315.2 (F81.81) Witli impairment in written expression:
Spelling accuracy
Grammar and punctuation accuracy  
Clarity or organization of written expression
315.1 (FBI .2) With impairment in mathematics:
Number sense
Memorization of arithmetic facts  
Accurate or fluent calculation  
Accurate math reasoning
Note: Dyscalculia  is an altemative term used to refer to a pattern of difficulties char­
acterized by problems processing numerical information, learning arithmetic facts,

acterized by problems processing numerical information, learning arithmetic facts,  
and performing accurate or fluent calculations. If dyscalculia is used to specify this  
particular pattern of mathematic difficulties, it is important also to specify any addi­
tional difficulties that are present, such as difficulties with math reasoning or word rea­
soning accuracy.
lUliid: Some difficulties learning skills in  one or two academic domains, but of m ild enough  
severity that the individual may be able to compensate or function well when provided with  
appropriate accommodations or support services, especially during the school years.

Moderate: Marked difficulties learning skills in one or more academic domains, so that  
the individual is unlikely to become proficient without some intervals of intensive and  
specialized teaching during the school years. Some accommodations or supportive  
services at least part of the day at school, in the workplace, or at home may be needed  
to complete activities accurately and efficiently.
Severe: Severe difficulties learning skills, affecting several academic domains, so that  
the individual is unlikely to learn those skills without ongoing intensive individualized  
and specialized teaching for most of the school years. Even with an array of appropri­
ate accommodations or services at home, at school, or in the workplace, the individual  
may not be able to complete all activities efficiently.
Each impaired academic domain and subskill of specific learning disorder should be re­

corded. Because of ICD coding requirements, impairments in reading, impairments in writ­
ten expression, and impairments in mathematics, with their corresponding impairments in 
subskills, must be coded separately. For example, impairments in reading and mathematics 
and impairments in the subskills of reading rate or fluency, reading comprehension, accu­
rate or fluent calculation, and accurate math reasoning would be coded and recorded as 
315.00 (F81.0) specific learning disorder with impairment in reading, with impairment in 
reading rate or fluency and impairment in reading comprehension; 315.1 (F81.2) specific 
learning disorder with impairment in mathematics, with impairment in accurate or fluent 
calculation and impairment in accurate math reasoning.

Specific learning disorder is a neurodevelopmental disorder with a biological origin that is 
the basis for abnormalities at a cognitive level that are associated with the behavioral signs 
of the disorder. The biological origin includes an interaction of genetic, epigenetic, and en­
vironmental factors, which affect the brain's ability to perceive or process verbal or non­
verbal information efficiently and accurately.
One essential feature of specific learning disorder is persistent difficulties learning key­
stone academic skills (Criterion A), with onset during the years of formal schooling (i.e., the de­
velopmental period). Key academic skills include reading of single words accurately and 
fluently, reading comprehension, written expression and spelling, arithmetic calculation, and

fluently, reading comprehension, written expression and spelling, arithmetic calculation, and 
mathematical reasoning (solving mathematical problems). In contrast to talking or walking, 
which are acquired developmental milestones that emerge with brain maturation, academic 
skills (e.g., reading, spelling, writing, mathematics) have to be taught and learned explicitly. 
Specific learning disorder disrupts the normal pattern of learning academic skills; it is not sim­
ply a consequence of lack of opportunity of learning or inadequate instruction. Difficulties 
mastering these key academic skills may also impede learning in other academic subjects (e.g., 
history, science, social studies), but those problems are attributable to difficulties learning the 
underlying academic skills. Difficulties learning to map letters with the sounds of one's lan­

guage—^ t o  read printed words (often called dyslexia )—is one of the most common manifesta­
tions of specific learning disorder. The learning difficulties manifest as a range of observable, 
descriptive behaviors or symptoms (as listed in Criteria A1-A6). These clinical symptoms may 
be observed, probed by means of the clinical interview, or ascertained from school reports, rat­
ing scales, or descriptions in previous educational or psychological assessments. The learning 
difficulties are persistent, not transitory. In children and adolescents, persistence  is defined as 
restricted progress in learning (i.e., no evidence that the individual is catching up with class­
mates) for at least 6 months despite the provision of extra help at home or school. For example,

mates) for at least 6 months despite the provision of extra help at home or school. For example, 
difficulties learning to read single words that do not fully or rapidly remit with the provision of 
instruction in phonological skills or word identification strategies may indicate a specific

learning disorder. Evidence of persistent learning difficulties may be derived from cumulative 
school reports, portfolios of the child's evaluated work, curriculum-based measures, or clinical 
interview. In adults, persistent difficulty refers to ongoing difficulties in literacy or numeracy 
skills that manifest during childhood or adolescence, as indicated by cumulative evidence 
from school reports, evaluated portfolios of work, or previous assessments.
A second key feature is that the individual's performance of the affected academic skills is 
well below average for age (Criterion B). One robust clinical indicator of difficulties learning 
academic skills is low academic achievement for age or average achievement that is sustain­
able only by extraordinarily high levels of effort or support. In children, the low academic skills 
cause significant interference in school performance (as indicated by school reports and

cause significant interference in school performance (as indicated by school reports and 
teacher's grades or ratings). Another clinical indicator, particularly in adults, is avoidance of 
activities that require the academic skills. Also in adulthood, low academic skills interfere with 
occupational performance or everyday activities requiring those skills (as indicated by self-re­
port or report by others). However, this criterion also requires psychometric evidence from an 
individually administered, psychometrically sound and culturally appropriate test of aca­
demic achievement that is norm-referenced or criterion-referenced. Academic skills are dis­
tributed along a continuum, so there is no natural cutpoint that can be used to differentiate 
individuals with and without specific learning disorder. Thus, any threshold used to specify

individuals with and without specific learning disorder. Thus, any threshold used to specify 
what constitutes significantly low academic achievement (e.g., academic skills weU below age 
expectation) is to a large extent arbitrary. Low achievement scores on one or more standard­
ized tests or subtests within an academic domain (i.e., at least 1.5 standard deviations [SD] be­
low the population mean for age, which translates to a standard score of 78 or less, which is 
below the 7th percentile) are needed for the greatest diagnostic certainty. However, precise 
scores will vary according to the particular standardized tests that are used. On the basis of 
clinical judgment, a more lenient threshold may be used (e.g., 1.0-2.5 SD below the pop­
ulation mean for age), when learning difficulties are supported by converging evidence

ulation mean for age), when learning difficulties are supported by converging evidence 
from clinical assessment, academic history, school reports, or test scores. Moreover, since 
standardized tests are not available in all languages, the diagnosis may then be based in 
part on clinical judgment of scores on available test measures.
A third core feature is that the learning difficulties are readily apparent in the early 
school years in most individuals (Criterion C). However, in others, the learning difficulties 
may not manifest fully until later school years, by which time learning demands have in­
creased and exceed the individual's limited capacities.
Another key diagnostic feature is that the learning difficulties are considered "spe­
cific," for four reasons. First, they are not attributable to intellectual disabilities (intellec­

tual disability [intellectual developmental disorder]); global developmental delay; 
hearing or vision disorders, or neurological or motor disorders) (Criterion D). Specific 
learning disorder affects learning in individuals who otherwise demonstrate normal lev­
els of intellectual functioning (generally estimated by an IQ score of greater than about 70 
[±5 points allowing for measurement error]). The phrase "unexpected academic under­
achievement" is often cited as the defining characteristic of specific learning disorder in 
that the specific learning disabilities are not part of a more general learning difficulty as 
manifested in intellectual disability or global developmental delay. Specific learning dis­
order may also occur in individuals identified as intellectually "gifted." These individuals

order may also occur in individuals identified as intellectually "gifted." These individuals 
may be able to sustain apparentiy adequate academic functioning by using compensatory 
strategies, extraordinarily high effort, or support, until the learning demands or assess­
ment procedures (e.g., timed tests) pose barriers to their demonstrating their learning or 
accomplishing required tasks. Second, the learning difficulty cannot be attributed to more 
general external factors, such as economic or environmental disadvantage, chronic absen­
teeism, or lack of education as typically provided in the individual's community context. 
Third, the learning difficulty cannot be attributed to a neurological (e.g., pediatric stroke) 
or motor disorders or to vision or hearing disorders, which are often associated with prob­

lems learning academic skills but are distinguishable by presence of neurological signs.

Finally, the learning difficulty may be restricted to one academic skill or domain (e.g., read­
ing single words, retrieving or calculating number facts).
Comprehensive assessment is required. Specific learning disorder can only be diagnosed 
after formal education starts but can be diagnosed at any point afterward in children, adoles­
cents, or adults, providing there is evidence of onset during the years of formal schooling (i.e., 
the developmental period). No single data source is sufficient for a diagnosis of specific learn­
ing disorder. Rather, specific learning disorder is a clinical diagnosis based on a synthesis of 
the individual's medical, developmental, educational, and family history; the history of the 
learning difficulty, including its previous and current manifestation; the impact of the diffi­
culty on academic, occupational, or social functioning; previous or current school reports;

culty on academic, occupational, or social functioning; previous or current school reports; 
portfolios of work requiring academic skills; curriculum-based assessments; and previous or 
current scores from individual standardized tests of academic achievement. If an intellectual, 
sensory, neurological, or motor disorder is suspected, then the clinical assessment for specific 
learning disorder should also include methods appropriate for these disorders. Thus, compre­
hensive assessment will involve professionals with expertise in specific learning disorder and 
psychological/cognitive assessment. Since specific learning disorder typically persists into 
adulthood, reassessment is rarely necessary, unless indicated by marked changes in the learn­
ing difficulties (amelioration or worsening) or requested for specific purposes.

Specific learning disorder is frequently but not invariably preceded, in preschool years, by 
delays in attention, language, or motor skills that may persist and co-occur with specific 
learning disorder. An uneven profile of abilities is common, such as above-average abili­
ties in drawing, design, and other visuospatial abilities, but slow, effortful, and inaccurate 
reading and poor reading comprehension and written expression. Individuals with spe­
cific learning disorder typically (but not invariably) exhibit poor performance on psycho­
logical tests of cognitive processing. However, it remains unclear whether these cognitive 
abnormalities are the cause, correlate, or consequence of the learning difficulties. Also, al­
though cognitive deficits associated with difficulties learning to read words are well doc­

umented, those associated with other manifestations of specific learning disorder (e.g., 
reading comprehension, arithmetic computation, written expression) are underspecified 
or unknown. Moreover, individuals with similar behavioral symptoms or test scores are 
found to have a variety of cognitive deficits, and many of these processing deficits are also 
found in other neurodevelopmental disorders (e.g., attention-deficit/hyperactivity disor­
der [ADHD], autistic spectrum disorder, communication disorders, developmental coor­
dination disorder). Thus, assessment of cognitive processing deficits is not required for 
diagnostic assessment. Specific learning disorder is associated with increased risk for sui­
cidal ideation and suicide attempts in children, adolescents, and adults.

There are no known biological markers of specific learning disorder. As a group, indi­
viduals with the disorder show circumscribed alterations in cognitive processing and 
brain structure and function. Genetic differences are also evident at the group level. But 
cognitive testing, neuroimaging, or genetic testing are not useful for diagnosis at this time.
The prevalence of specific learning disorder across the academic domains of reading, writ­
ing, and mathematics is 5%-15% among school-age children across different languages 
and cultures. Prevalence in adults is unknown but appears to be approximately 4%.
Onset, recognition, and diagnosis of specific learning disorder usually occurs during the

Onset, recognition, and diagnosis of specific learning disorder usually occurs during the 
elementary school years when children are required to learn to read, spell, write, and learn

mathematics. However, precursors such as language delays or deficits, difficulties in 
rhyming or counting, or difficulties with fine motor skills required for writing commonly 
occur in early childhood before the start of formal schooling. Manifestations may be be­
havioral (e.g., a reluctance to engage in learning; oppositional behavior). Specific learning 
disorder is lifelong, but the course and clinical expression are variable, in part depending 
on the interactions among the task demands of the environment, the range and severity of 
the individual's learning difficulties, the individual's learning abilities, comorbidity, and 
the available support systems and intervention. Nonetheless, problems with reading flu­
ency and comprehension, spelling, written expression, and numeracy skills in everyday life 
typically persist into adulthood.
Changes in manifestation of symptoms occur with age, so that an individual may have

Changes in manifestation of symptoms occur with age, so that an individual may have 
a persistent or shifting array of learning difficulties across the lifespan.
Examples of symptoms that may be observed among preschool-age children include a lack 
of interest in playing games with language sounds (e.g., repetition, rhyming), and they may 
have trouble learning nursery rhymes. Preschool children with specific learning disorder may 
frequently use baby talk, mispronounce words, and have trouble remembering names of let­
ters, numbers, or days of the week. They may fail to recognize letters in their own names and 
have trouble learning to count. Kindergarten-age children with specific learning disorder may 
be unable to recognize and write letters, may be unable to write their own names, or may use 
invented spelling. They may have trouble breaking down spoken words into syllables (e.g.,

invented spelling. They may have trouble breaking down spoken words into syllables (e.g., 
"cowboy" into "cow" and "boy") and trouble recognizing words that rhyme (e.g., cat, bat, hat). 
Kindergarten-age children also may have trouble cormecting letters with their sounds (e.g., let­
ter b makes the sound /b/) and may be unable to recognize phonemes (e.g., do not know 
which in a set of words [e.g., dog, man, car] starts with the same sound as "cat").
Specific learning disorder in elementary school-age children typically manifests as 
marked difficulty learning letter-sound correspondence (particularly in English-speaking 
children), fluent word decoding, spelling, or math facts; reading aloud is slow, inaccurate, 
and effortful, and some children struggle to understand the magnitude that a spoken or 
written number represents. Children in primary grades (grades 1-3) may continue to have

written number represents. Children in primary grades (grades 1-3) may continue to have 
problems recognizing and manipulating phonemes, be unable to read common one-sylla­
ble words (such as mat or top), and be unable recognize common irregularly spelled 
words (e.g., said, two). They may commit reading errors that indicate problems in con­
necting sounds and letters (e.g., "big" for "got") and have difficulty sequencing numbers 
and letters. Children in grades 1-3 also may have difficulty remembering number facts or 
arithmetic procedures for adding, subtracting, and so forth, and may complain that read­
ing or arithmetic is hard and avoid doing it. Children with specific learning disorder in the 
middle grades (grades 4-6) may mispronounce or skip parts of long, multisyllable words 
(e.g., say "conible" for "convertible," "aminal" for "animal") and confuse words that

(e.g., say "conible" for "convertible," "aminal" for "animal") and confuse words that 
sound alike (e.g., "tornado" for "volcano"). They may have trouble remembering dates, 
names, and telephone numbers and may have trouble completing homework or tests on 
time. Children in the middle grades also may have poor comprehension with or without 
slow, effortful, and inaccurate reading, and they may have trouble reading small function 
words (e.g., that, the, an, in). They may have very poor spelling and poor written work. 
They may get the first part of a word correctly, then guess wildly (e.g., read "clover" as 
"clock"), and may express fear of reading aloud or refuse to read aloud.
By contrast, adolescents may have mastered word decoding, but reading remains slow 
and effortful, and they are likely to show marked problems in reading comprehension and

and effortful, and they are likely to show marked problems in reading comprehension and 
written expression (including poor spelling) and poor mastery of math facts or mathemat­
ical problem solving. During adolescence and into adulthood, individuals with specific 
learning disorder may continue to make numerous spelling mistakes and read single 
words and connected text slowly and with much effort, with trouble pronouncing multi­
syllable words. They may frequently need to reread material to understand or get the main 
point and have trouble making inferences from written text. Adolescents and adults may

avoid activities that demand reading or arithmetic (reading for pleasure, reading instruc­
tions). Adults with specific learning disorder have ongoing spelling problems, slow  and 
effortful reading, or problems making important inferences from numerical information 
in work-related written documents. They may avoid both leisure and work-related activ­
ities that demand reading or writing or use alternative approaches to access print (e.g., 
text-to-speech/speech-to-text software, audiobooks, audiovisual media).
An alternative clinical expression is that of circumscribed learning difficulties that per­
sist across the lifespan, such as an inability to master the basic sense of number (e.g., to 
know which of a pair of numbers or dots represents the larger magnitude), or lack of pro­
ficiency in word identification or spelling. Avoidance of or reluctance to engage in activi­
ties requiring academic skills is common in children, adolescents, and adults. Episodes of

ties requiring academic skills is common in children, adolescents, and adults. Episodes of 
severe anxiety or anxiety disorders, including somatic complaints or panic attacks, are 
common across the lifespan and accompany both the circumscribed and the broader ex­
pression of learning difficulties.
Environmental. Prematurity or very low birth weight increases the risk for specific 
learning disorder, as does prenatal exposure to nicotine.
Genetic and physiological. Specific learning disorder appears to aggregate in families, 
particularly when affecting reading, mathematics, and spelling. The relative risk of spe­
cific learning disorder in reading or mathematics is substantially higher (e.g., 4-8 times 
and 5-10 times higher, respectively) in first-degree relatives of individuals with these

and 5-10 times higher, respectively) in first-degree relatives of individuals with these 
learning difficulties compared with those without them. Family history of reading diffi­
culties (dyslexia) and parental literacy skills predict literacy problems or specific learning 
disorder in offspring, indicating the combined role of genetic and environmental factors.
There is high heritability for both reading ability and reading disability in alphabetic and 
nonalphabetic languages, including high heritability for most manifestations of learning abil­
ities and disabilities (e.g., heritability estimate values greater than 0.6). Covariation between 
various manifestations of learning difficulties is high, suggesting that genes related to one 
presentation are highly correlated with genes related to another manifestation.

Course modifiers. Marked problems with inattentive behavior in preschool years is pre­
dictive of later difficulties in reading and mathematics (but not necessarily specific learn­
ing disorder) and nonresponse to effective academic interventions. Delay or disorders in 
speech or language, or impaired cognitive processing (e.g., phonological awareness, 
working memory, rapid serial naming) in preschool years, predicts later specific learning 
disorder in reading and written expression. Comorbidity with ADHD is predictive of 
worse mental health outcome than that associated with specific learning disorder without 
ADHD. Systematic, intensive, individualized instruction, using evidence-based interven­
tions, may improve or ameliorate the learning difficulties in some individuals or promote

tions, may improve or ameliorate the learning difficulties in some individuals or promote 
the use of compensatory strategies in others, thereby mitigating the otherwise poor out­
comes.
Culture-Related Diagnostic issues
Specific learning disorder occurs across languages, cultures, races, and socioeconomic 
conditions but may vary in its manifestation according to the nature of the spoken and 
written symbol systems and cultural and educational practices. For example, the cognitive 
processing requirements of reading and of working with numbers vary greatly across or­
thographies. In the English language, the observable hallmark clinical symptom of diffi­
culties learning to read is inaccurate and slow reading of single words; in other alphabetic 
languages that have more direct mapping between sounds and letters (e.g., Spanish, Ger­

man) and in non-alphabetic languages (e.g., Chinese, Japanese), the hallmark feature is

slow but accurate reading. In English-language learners, assessment should include con­
sideration of whether the source of reading difficulties is a limited proficiency with Eng­
lish or a specific learning disorder. Risk factors for specific learning disorder in English- 
language learners include a family history of specific learning disorder or language delay 
in the native language, as well as learning difficulties in English and failure to catch up 
with peers. If there is suspicion of cultural or language differences (e.g., as in an English- 
language learner), the assessment needs to take into account the individual's language 
proficiency in his or her first or native language as well as in the second language (in this 
example, English). Also, assessment should consider the linguistic and cultural context in 
which the individual is living, as well as his or her educational and learning history in the 
original culture and language.
Gender-Related Diagnostic issues

Specific learning disorder is more common in males than in females (ratios range from 
about 2:1 to 3:1) and cannot be attributed to factors such as ascertainment bias, definitional 
or measurement variation, language, race, or socioeconomic status.
Functionai Consequences of  
Specific learning disorder can have negative functional consequences across the lifespan, 
including lower academic attainment, higher rates of high school dropout, lower rates of 
postsecondary education, high levels of psychological distress and poorer overall mental 
health, higher rates of unemployment and under-employment, and lower incomes. School 
dropout and co-occurring depressive symptoms increase the risk for poor mental health

dropout and co-occurring depressive symptoms increase the risk for poor mental health 
outcomes, including suicidality, whereas high levels of social or emotional support predict 
better mental health outcomes.
Normal variations in academic attainment. Specific learning disorder is distinguished 
from normal variations in academic attainment due to external factors (e.g., lack of edu­
cational opportunity, consistently poor instruction, learning in a second language), be­
cause the learning difficulties persist in the presence of adequate educational opportunity 
and exposure to the same instruction as the peer group, and competency in the language of 
instruction, even when it is different from one's primary spoken language.
Intellectual disability (intellectual developmental disorder). Specific learning disorder

Intellectual disability (intellectual developmental disorder). Specific learning disorder 
differs from general learning difficulties associated with intellectual disability, because the 
learning difficulties occur in the presence of normal levels of intellectual functioning (i.e., 
IQ score of at least 70 ± 5). If intellectual disability is present, specific learning disorder can 
be diagnosed only when the learning difficulties are in excess of those usually associated 
with the intellectual disability.
Learning difficulties due to neurological or sensory disorders. Specific learning dis­
order is distinguished from learning difficulties due to neurological or sensory disorders 
(e.g., pediatric stroke, traumatic brain injury, hearing impairment, vision impairment), be­
cause in these cases there are abnormal findings on neurological examination.

Neurocognitive disorders. Specific learning disorder is distinguished from learning 
problems associated with neurodegenerative cognitive disorders, because in specific 
learning disorder the clinical expression of specific learning difficulties occurs during the 
developmental period, and the difficulties do not manifest as a marked decline from a for­
mer state.

Attention-deficit/hyperactivity disorder. Specific learning disorder is distinguished from 
the poor academic performance associated with ADHD, because in the latter condition the 
problems may not necessarily reflect specific difficulties in learning academic skills but 
rather may reflect difficulties in performing those skills. However, the co-occurrence of 
specific learning disorder and ADHD is more frequent than expected by chance. If criteria 
for both disorders are met, both diagnoses can be given.
Psychotic disorders. Specific learning disorder is distinguished from the academic and 
cognitive-processing difficulties associated with schizophrenia or psychosis, because with 
these disorders there is a decline (often rapid) in these functional domains.
Specific learning disorder commonly co-occurs with neurodevelopmental (e.g., ADHD, 
communication disorders, developmental coordination disorder, autistic spectrum disor­

der) or other mental disorders (e.g., anxiety disorders, depressive and bipolar disorders). 
These comorbidities do not necessarily exclude the diagnosis specific learning disorder 
but may make testing and differential diagnosis more difficult, because each of the co­
occurring disorders independently interferes with the execution of activities of daily liv­
ing, including learning. Thus, clinical judgment is required to attribute such impairment to 
learning difficulties. If there is an indication that another diagnosis could account for the 
difficulties learning keystone academic skills described in Criterion A, specific learning 
disorder should not be diagnosed.
Motor Disorders
Developmental Coordination Disorder
Diagnostic Criteria 315.4 (F82)

A. The acquisition and execution of coordinated motor skills is substantially below that ex­
pected given the individual’s chronological age and opportunity for skill learning and  
use. Difficulties are manifested as clumsiness (e.g., dropping or bumping into objects)  
as well as slowness and inaccuracy of performance of motor skills (e.g., catching an  
object, using scissors or cutlery, handwriting, riding a bike, or participating in sports).
B. The motor skills deficit in Criterion A significantly and persistently interferes with activ­
ities of daily living appropriate to chronological age (e.g., self-care and self-mainte­
nance) and impacts academic/school productivity, prevocational and vocational  
activities, leisure, and play.
C. Onset of symptoms is in  the early developmental period.

D. The motor skills deficits are not better explained by intellectual disability (Intellectual devel­
opmental disorder) or visual impairment and are not attributable to a neurological condi­
tion affecting movement (e.g., cerebral palsy, muscular dystrophy, degenerative disorder).
The diagnosis of developmental coordinahon disorder is made by a clinical synthesis of the
history (developmental and medical), physical examination, school or workplace report, and
individual assessment using psychometrically sound and culturally appropriate standardized
tests. The manifestation of impaired skills requiring motor coordination (Criterion A) varies

with age. Young children may be delayed in achieving motor milestones (i.e., sitting, crawling, 
walking), although many achieve typical motor milestones. They also may be delayed in de­
veloping skills such as negotiating stairs, pedaling, buttoning shirts, completing puzzles, and 
using zippers. Even when the skill is achieved, movement execution may appear awkward, 
slow, or less precise than that of peers. Older children and adults may display slow speed or in­
accuracy with motor aspects of activities such as assembling puzzles, building models, playing 
ball games (especially in teams), handwriting, typing, driving, or carrying out self-care sldlls.
Developmental coordination disorder is diagnosed only if the impairment in motor 
skills significantly interferes with the performance of, or participation in, daily activities in 
family, social, school, or community life (Criterion B). Examples of such activities include

family, social, school, or community life (Criterion B). Examples of such activities include 
getting dressed, eating meals with age-appropriate utensils and without mess, engaging 
in physical games with others, using specific tools in class such as rulers and scissors, and 
participating in team exercise activities at school. Not only is ability to perform these ac­
tions impaired, but also marked slowness in execution is common. Handwriting compe­
tence is frequently affected, consequently affecting legibility and/or speed of written output 
and affecting academic achievement (the impact is distinguished from specific learning 
difficulty by the emphasis on the motoric component of written output skills). In adults, 
everyday skills in education and work, especially those in which speed and accuracy are 
required, are affected by coordination problems.

Criterion C states that the onset of symptoms of developmental coordination disorder 
must be in the early developmental period. However, developmental coordination disorder is 
typically not diagnosed before age 5 years because there is considerable variation in the age at 
acquisition of many motor skills or a lack of stability of measurement in early childhood (e.g., 
some children catch up) or because other causes of motor delay may not have fully manifested.
Criterion D specifies that the diagnosis of developmental coordination disorder is 
made if the coordination difficulties are not better explained by visual impairment or at­
tributable to a neurological condition. Thus, visual function examination and neurological 
examination must be included in the diagnostic evaluation. If intellectual disability (intel­

lectual developmental disorder) is present, the motor difficulties are in excess of those ex­
pected for the mental age; however, no IQ cut-off or discrepancy criterion is specified.
Developmental coordination disorder does not have discrete subtypes; however, indi­
viduals may be impaired predominantly in gross motor skills or in fine motor skills, in­
cluding handwriting skills.
Other terms used to describe developmental coordination disorder include childhood  
dyspraxia, specific developmental disorder of motor function,  and clumsy child syndrome.
Some children with developmental coordination disorder show additional (usually sup­
pressed) motor activity, such as choreiform movements of unsupported limbs or mirror

pressed) motor activity, such as choreiform movements of unsupported limbs or mirror 
movements. These "overflow" movements are referred to as neurodevelopmental immaturities  or 
neurological soft signs  rather than neurological abnormalities. In both current literature and 
clinical practice, their role in diagnosis is still unclear, requiring further evaluation.
Prevaience
The prevalence of developmental coordination disorder in children ages 5-11 years is 5%- 
6% (in children age 7 years, 1.8% are diagnosed with severe developmental coordination 
disorder and 3% with probable developmental coordination disorder). Males are more of­
ten affected than females, with a maleifemale ratio between 2:1 and 7:1.
The course of developmental coordination disorder is variable but stable at least to 1  year

The course of developmental coordination disorder is variable but stable at least to 1  year 
follow-up. Although there may be improvement in the longer term, problems with coor­

dinated movements continue through adolescence in an estimated 50%-70% of children. 
Onset is in early childhood. Delayed motor milestones may be the first signs, or the disor­
der is first recognized when the child attempts tasks such as holding a knife and fork, but­
toning clothes, or playing ball games. In middle childhood, there are difficulties with 
motor aspects of assembling puzzles, building models, playing ball, and handwriting, as 
well as with organizing belongings, when motor sequencing and coordination are re­
quired. In early adulthood, there is continuing difficulty in learning new tasks involving 
complex/automatic motor skills, including driving and using tools. Inability to take notes 
and handwrite quickly may affect performance in the workplace. Co-occurrence with 
other disorders (see the section "Comorbidity" for this disorder) has an additional impact 
on presentation, course, and outcome.

Environmental. Developmental coordination disorder is more common following pre­
natal exposure to alcohol and in preterm and low-birth-weight children.
Genetic and physiological. Impairments in underlying neurodevelopmental processes— 
particularly in visual-motor skills, both in visual-motor perception and spatial mentalizing— 
have been found and affect the ability to make rapid motoric adjustments as the complexity of 
the required movements increases. Cerebellar dysfunction has been proposed, but the neural 
basis of developmental coordination disorder remains unclear. Because of the co-occurrence of 
developmental coordination disorder with attention-deficit/hyperactivity disorder (ADHD), 
specific learning disabilities, and autism spectrum disorder, shared genetic effect has been pro­

posed. However, consistent co-occurrence in twins appears only in severe cases.
Course modifiers. Individuals with ADHD and with developmental coordination dis­
order demonstrate more impairment than individuals with ADHD without developmen­
tal coordination disorder.
Developmental coordination disorder occurs across cultures, races, and socioeconomic 
conditions. By definition, "activities of daily living" implies cultural differences necessi­
tating consideration of the context in which the individual child is living as well as 
whether he or she has had appropriate opportunities to learn and practice such activities.

Developmental coordination disorder leads to impaired functional performance in activ­
ities of daily living (Criterion B), and the impairment is increased with co-occurring con­
ditions. Consequences of developmental coordination disorder include reduced 
participation in team play and sports; poor self-esteem and sense of self-worth; emotional 
or behavior problems; impaired academic achievement; poor physical fitness; and re­
duced physical activity and obesity.
Motor impairments due to another medical condition. Problems in coordination may 
be associated with visual function impairment and specific neurological disorders (e.g., 
cerebral palsy, progressive lesions of the cerebellum, neuromuscular disorders). In such 
cases, there are additional findings on neurological examination.

Intellectual disability (intellectual developmental disorder). If intellectual disability is 
present, motor competences may be impaired in accordance with the intellectual disabil-

ity. However, if the motor difficulties are in excess of what could be accounted for by the 
intellectual disability, and criteria for developmental coordination disorder are met, de­
velopmental coordination disorder can be diagnosed as well.
Attention-deficit/hyperactivity disorder. Individuals with ADHD may fall, bump into 
objects, or knock things over. Careful observation across different contexts is required to 
ascertain if lack of motor competence is attributable to distractibility and impulsiveness 
rather than to developmental coordination disorder. If criteria for both ADHD and devel­
opmental coordination disorder are met, both diagnoses can be given.
Autism spectrum disorder. Individuals with autism spectrum disorder may be uninter­
ested in participating in tasks requiring complex coordination skills, such as ball sports, 
which will affect test performance and function but not reflect core motor competence. Co­

occurrence of developmental coordination disorder and autism spectrum disorder is com­
mon. If criteria for both disorders are met, both diagnoses can be given.
Joint hypermobility syndrome. Individuals with syndromes causing hyperextensible 
joints (found on physical examination; often with a complaint of pain) may present with 
symptoms similar to those of developmental coordination disorder.
Disorders that commonly co-occur with developmental coordination disorder include 
speech and language disorder; specific learning disorder (especially reading and writing); 
problems of inattention, including ADHD (the most frequent coexisting condition, with 
about 50% co-occurrence); autism spectrum disorder; disruptive and emotional behavior

about 50% co-occurrence); autism spectrum disorder; disruptive and emotional behavior 
problems; and joint hypermobility syndrome. Different clusters of co-occurrence may be 
present (e.g., a cluster with severe reading disorders, fine motor problems, and handwriting 
problems; another cluster with impaired movement control and motor planning). Presence 
of other disorders does not exclude developmental coordination disorder but may make 
testing more difficult and may independently interfere with the execution of activities of 
daily living, thus requiring examiner judgment in ascribing impairment to motor skills.
Stereotypic Movement Disorder
Diagnostic Criteria 307.3 (F98.4)
A. Repetitive, seemingly driven, and apparently purposeless motor behavior (e.g., hand  
shaking or waving, body rocking, head banging, self-biting, hitting own body).

B. The repetitive motor behavior interferes with social, academic, or other activities and  
may result in self-injury.
C. Onset is in the early developmental period.
D. The repetitive motor behavior is not attributable to the physiological effects of a sub­
stance or neurological condition and is not better explained by another neurodevel-  
opmental or mental disorder (e.g., trichotillomania [hair-pulling disorder], obsessive-  
compulsive disorder).
With self-injurious behavior (or behavior that would result in an injury if preventive  
measures were not used)
Without self-injurious behavior
Associated with a known medical or genetic condition, neurodevelopmental dis­
order, or environmental factor (e.g., Lesch-Nyhan syndrome, intellectual disability

order, or environmental factor (e.g., Lesch-Nyhan syndrome, intellectual disability  
[intellectual developmental disorder], intrauterine alcohol exposure)

Coding note: Use additional code to identify the associated medical or genetic  
condition, or neurodevelopmental disorder.
Mild: Symptoms are easily suppressed by sensory stimulus or distraction.
Moderate: Symptoms require explicit protective measures and behavioral m odification.  
Severe: Continuous monitoring and protective measures are required to prevent seri­
ous injury.
For stereotypic movement disorder that is associated with a known medical or genetic 
condition, neurodevelopmental disorder, or environmental factor, record stereotypic 
movement disorder associated with (name of condition, disorder, or factor) (e.g., stereo­
typic movement disorder associated with Lesch-Nyhan syndrome).
The severity of non-self-injurious stereotypic movements ranges from mild presentations 
that are easily suppressed by a sensory stimulus or distraction to continuous movements

that are easily suppressed by a sensory stimulus or distraction to continuous movements 
that markedly interfere with all activities of daily living. Self-injurious behaviors range in se­
verity along various dimensions, including the frequency, impact on adaptive functioning, 
and severity of bodily injury (from mild bruising or erythema from hitting hand against 
body, to lacerations or amputation of digits, to retinal detachment from head banging).
The essential feature of stereotypic movement disorder is repetitive, seemingly driven, 
and apparently purposeless motor behavior (Criterion A). These behaviors are often 
rhythmical movements of the head, hands, or body without obvious adaptive function. 
The movements may or may not respond to efforts to stop them. Among typically devel­

oping children, the repetitive movements may be stopped when attention is directed to 
them or when the child is distracted from performing them. Among children with neuro­
developmental disorders, the behaviors are typically less responsive to such efforts. In 
other cases, the individual demonstrates self-restraining behaviors (e.g., sitting on hands, 
wrapping arms in clothing, finding a protective device).
The repertoire of behaviors is variable; each individual presents with his or her own in­
dividually patterned, "signature" behavior. Examples of non-self-injurious stereotypic 
movements include, but are not limited to, body rocking, bilateral flapping or rotating 
hand movements, flicking or fluttering fingers in front of the face, arm waving or flapping,

hand movements, flicking or fluttering fingers in front of the face, arm waving or flapping, 
and head nodding. Stereotyped self-injurious behaviors include, but are not limited to, re­
petitive head banging, face slapping, eye poking, and biting of hands, lips, or other body 
parts. Eye poking is particularly concerning; it occurs more frequently among children 
with visual impairment. Multiple movements may be combined (e.g., cocking the head, 
rocking the torso, waving a small string repetitively in front of the face).
Stereotypic movements may occur many times during a day, lasting a few seconds to 
several minutes or longer. Frequency can vary from many occurrences in a single day to 
several weeks elapsing between episodes. The behaviors vary in context, occurring when 
the individual is engrossed in other activities, when excited, stressed, fatigued, or bored.

the individual is engrossed in other activities, when excited, stressed, fatigued, or bored. 
Criterion A requires that the movements be "apparently" purposeless. However, some 
functions may be served by the movements. For example, stereotypic movements might 
reduce anxiety in response to external stressors.
Criterion B states that the stereotypic movements interfere with social, academic, or 
other activities and, in some children, may result in self-injury (or would if protective mea­
sures were not used). If self-injury is present, it should be coded using the specifier. Onset

of stereotypic movements is in the early developmental period (Criterion C). Criterion D 
states that the repetitive, stereotyped behavior in stereotypic movement disorder is not at­
tributable to the^physiological effects of a substance or neurological condition and is not 
better explained by another neurodevelopmental or mental disorder. The presence of 
stereotypic movements may indicate an undetected neurodevelopmental problem, espe­
cially in children ages 1-3 years.
Simple stereotypic movements (e.g., rocking) are common in young typically developing chil­
dren. Complex stereotypic movements are much less common (occurring in approximately 
3%-4%). Between 4% and 16°/« of individuals v^ith intellectual disability (intellectual develop­
mental disorder) engage in stereotypy and self-injury. The risk is greater in individuals with 
severe intellectual disability. Among individuals with intellectual disability living in res­

idential facilities, 10%-15% may have stereotypic movement disorder with self-injury.
Stereotypic movements typically begin within the first 3 years of life. Simple stereotypic move­
ments are common in infancy and may be involved in acquisition of motor mastery. In chil­
dren who develop complex motor stereotypies, approximately 80% exhibit symptoms before 
24 months of age, 12% between 24 and 35 months, and 8% at 36 months or older. In most typ­
ically developing children, these movements resolve over time or can be suppressed. Onset of 
complex motor stereotypies may be in infancy or later in the developmental period. Among 
individuals with intellectual disability, the stereotyped, self-injurious behaviors may persist

individuals with intellectual disability, the stereotyped, self-injurious behaviors may persist 
for years, even though the typography or pattern of self-injury may change.
Environmental. Social isolation is a risk factor for self-stimulation that may progress to 
stereotypic movements with repetitive self-injury. Environmental stress may also trigger 
stereotypic behavior. Fear may alter physiological state, resulting in increased frequency 
of stereotypic behaviors.
Genetic and physiological. Lower cognitive functioning is linked to greater risk for stereo­
typic behaviors and poorer response to interventions. Stereotypic movements are more fre­
quent among individuals with moderate-to-severe/profound intellectual disability, who by 
virtue of a particular syndrome (e.g., Rett syndrome) or environmental factor (e.g., an environ­

ment with relatively insufficient stimulation) seem to be at higher risk for stereotypies. Repet­
itive self-injurious behavior may be a behavioral phenotype in neurogenetic syndromes. For 
example, in Lesch-Nyhan syndrome, there are both stereotypic dystonie movements and self­
mutilation of fingers, lip biting, and other forms of self-injury unless the individual is re­
strained, and in Rett syndrome and Cornelia de Lange syndrome, self-injury may result from 
the hand-to-mouth stereotypies. Stereotypic behaviors may result from a painful medical con­
dition (e.g., middle ear infection, dental problems, gastroesophageal reflux).
Stereotypic movement disorder, with or without self-injury, occurs in all races and cultures.

Stereotypic movement disorder, with or without self-injury, occurs in all races and cultures. 
Cultural attitudes toward unusual behaviors may result in delayed diagnosis. Overall cultural 
tolerance and attitudes toward stereotypic movement vary and must be considered.
Normal development. Simple stereotypic movements are common in infancy and early 
childhood. Rocking may occur in the transition from sleep to awake, a behavior that usu­

ally resolves with age. Complex stereotypies are less common in typically developing 
children and can usually be suppressed by distraction or sensory stimulation. The indi­
vidual's daily routine is rarely affected, and the movements generally do not cause the 
child distress. The diagnosis would not be appropriate in these circumstances.
Autism spectrum disorder. Stereotypic movements may be a presenting symptom of 
autism spectrum disorder and should be considered when repetitive movements and be­
haviors are being evaluated. Deficits of social communication and reciprocity manifesting 
in autism spectrum disorder are generally absent in stereotypic movement disorder, and 
thus social interaction, social communication, and rigid repetitive behaviors and interests 
are distinguishing features. When autism spectrum disorder is present, stereotypic move­
ment disorder is diagnosed only when there is self-injury or when the stereotypic behav­

iors are sufficiently severe to become a focus of treatment.
Tic disorders. Typically, stereotypies have an earlier age at onset (before 3 years) than 
do tics, which have a mean age at onset of 5-7 years. They are consistent and fixed in their 
pattern or topography compared with tics, which are variable in their presentation. Ste­
reotypies may involve arms, hands, or the entire body, while tics commonly involve eyes, 
face, head, and shoulders. Stereotypies are more fixed, rhythmic, and prolonged in dura­
tion than tics, which, generally, are brief, rapid, random, and fluctuating. Tics and stereo­
typic movements are both reduced by distraction.
Obsessive-compulsive and related disorders. Stereotypic movement disorder is dis­

tinguished from obsessive-compulsive disorder (OCD) by the absence of obsessions, as 
well as by the nature of the repetitive behaviors. In OCD the individual feels driven to per­
form repetitive behaviors in response to an obsession or according to rules that must be ap­
plied rigidly, whereas in stereotypic movement disorder the behaviors are seemingly 
driven but apparently purposeless. Trichotillomania (hair-pulling disorder) and excoria­
tion (skin-picking) disorder are characterized by body-focused repetitive behaviors (i.e., 
hair pulling and skin picking) that may be seemingly driven but that are not apparently 
purposeless, and that may not be patterned or rhythmical. Furthermore, onset in tricho­
tillomania and excoriation disorder is not typically in the early developmental period, but 
rather around puberty or later.

Other neurological and medical conditions. The diagnosis of stereotypic movements 
requires the exclusion of habits, mannerisms, paroxysmal dyskinesias, and benign he­
reditary chorea. A neurological history and examination are required to assess features 
suggestive of other disorders, such as myoclonus, dystonia, tics, and chorea. Involuntary 
movements associated with a neurological condition may be distinguished by their signs 
and symptoms. For example, repetitive, stereotypic movements in tardive dyskinesia can 
be distinguished by a history of chronic neuroleptic use and characteristic oral or facial 
dyskinesia or irregular trunk or limb movements. These types of movements do not result 
in self-injury. A diagnosis of stereotypic movement disorder is not appropriate for repet­

itive skin picking or scratching associated with amphetamine intoxication or abuse (e.g., 
patients are diagnosed with substance/medication-induced obsessive-compulsive and re­
lated disorder) and repetitive choreoathetoid movements associated with other neurolog­
ical disorders.
Stereotypic movement disorder may occur as a primary diagnosis or secondary to another 
disorder. For example, stereotypies are a common manifestation of a variety of neuro- 
genetic disorders, such as Lesch-Nyhan syndrome, Rett syndrome, fragile X syndrome, 
Cornelia de Lange syndrome, and Smith-Magenis syndrome. When stereotypic move­
ment disorder co-occurs with another medical condition, both should be coded.

------------------------ ----------------------------------------------------------------------------------------------------------------
Note: A tic is a sudden, rapid, recurrent, nonrhythmic motor movement or vocalization.
Tourette’s Disorder 307.23 (F95.2)
A. Both multiple motor and one or more vocal tics have been present at some time during  
the illness, although not necessarily concurrently.
B. The tics may wax and wane in frequency but have persisted for more than 1  year since  
first tic onset.
C. Onset is before age 18 years.
D. The disturbance is not attributable to the physiological effects of a substance (e.g., co­
caine) or another medical condition (e.g., Huntington’s disease, postviral encephalitis).
Persistent (Chronic) Motor  or Vocal Tic Disorder 307.22 (F95.1 )
A. Single or multiple motor or vocal tics have been present during the illness, but not both  
motor and vocal.

E. Criteria have never been met for Tourette’s disorder.
With motor tics only  
With vocal tics only
Provisional Tic Disorder 307.21 (F95.0)
A. Single or multiple motor and/or vocal tics.
B. The tics have been present for less than 1  year since first tic onset.

E. Criteria have never been met for Tourette’s disorder or persistent (chronic) motor or  
vocal tic disorder.______________________________________________________
The "motor tics only" or "vocal tics only" specifier is only required for persistent (chronic) 
motor or vocal tic disorder.
Tic disorders comprise four diagnostic categories: Tourette's disorder, persistent (chronic) 
motor or vocal tic disorder, provisional tic disorder, and the other specified and unspecified 
tic disorders. Diagnosis for any tic disorder is based on the presence of motor and/or vocal 
tics (Criterion A), duration of tic symptoms (Criterion B), age at onset (Criterion C), and ab­
sence of any known cause such as another medical condition or substance use (Criterion D).

sence of any known cause such as another medical condition or substance use (Criterion D). 
The tic disorders are hierarchical in order (i.e., Tourette's disorder, followed by persistent 
[chronic] motor or vocal tic disorder, followed by provisional tic disorder, followed by the

other specified and unspecified tic disorders), such that once a tic disorder at one level of the 
hierarchy is diagnosed, a lower hierarchy diagnosis cannot be made (Criterion E).
Tics are sudden, rapid, recurrent, nonrhythmic motor movements or vocalizations. An 
individual may have various tic symptoms over time, but at any point in time, the tic rep­
ertoire recurs in a characteristic fashion. Although tics can include almost any muscle group 
or vocalization, certain tic symptoms, such as eye blinking or throat clearing, are common 
across patient populations. Tics are generally experienced as involuntary but can be vol­
untarily suppressed for varying lengths of time.
Tics can be either simple or complex. Simple motor tics  are of short duration (i.e., milli­
seconds) and can include eye blinking, shoulder shrugging, and extension of the extrem­
ities. Simple vocal tics include throat clearing, sniffing, and grunting often caused by

ities. Simple vocal tics include throat clearing, sniffing, and grunting often caused by 
contraction of the diaphragm or muscles of the oropharynx. Complex motor tics  are of lon­
ger duration (i.e., seconds) and often include a combination of simple tics such as simul­
taneous head turning and shoulder shrugging. Complex tics can appear purposeful, such 
as a tic-like sexual or obscene gesture (copropraxia)  or a tic-like imitation of someone else's 
movements (echopraxia).  Similarly, complex vocal tics include repeating one's own sounds 
or words {palilalia),  repeating the last-heard word or phrase (echolalia),  or uttering socially 
unacceptable words, including obscenities, or ethnic, racial, or religious slurs (coprolalia).  
Importantly, coprolalia is an abrupt, sharp bark or grunt utterance and lacks the prosody 
of similar inappropriate speech observed in human interactions.

The presence of motor and/or vocal tics varies across the four tic disorders (Criterion 
A). For Tourette's disorder, both motor and vocal tics must be present, whereas for per­
sistent (chronic) motor or vocal tic disorder, only motor or only vocal tics are present. For 
provisional tic disorder, motor and/or vocal tics may be present. For other specified or un­
specified tic disorders, the movement disorder symptoms are best characterized as tics but 
are atypical in presentation or age at onset, or have a known etiology.
The 1-year minimum duration criterion (Criterion B) assures that individuals diag­
nosed with either Tourette's disorder or persistent (chronic) motor or vocal tic disorder 
have had persistent symptoms. Tics wax and wane in severity, and some individuals may

have had persistent symptoms. Tics wax and wane in severity, and some individuals may 
have tic-free periods of weeks to months; however, an individual who has had tic symp­
toms of greater than 1  year's duration since first tic onset would be considered to have per­
sistent symptoms regardless of duration of tic-free periods. For an individual with motor 
and/or vocal tics of less than 1  year since first tic onset, a provisional tic disorder diagnosis 
can be considered. There is no duration specification for other specified and unspecified tic 
disorders. The onset of tics must occur prior to age 18 years (Criterion C). Tic disorders 
typically begin in the prepubertal period, with an average age at onset between 4 and 6 
years, and with the incidence of new-onset tic disorders decreasing in the teen years. New

years, and with the incidence of new-onset tic disorders decreasing in the teen years. New 
onset of tic symptoms in adulthood is exceedingly rare and is often associated with expo­
sures to drugs (e.g., excessive cocaine use) or is a result of a central nervous system insult 
(e.g., postviral encephalitis). Although tic onset is uncommon in teenagers and adults, it is 
not uncommon for adolescents and adults to present for an initial diagnostic assessment 
and, when carefully evaluated, provide a history of milder symptoms dating back to child­
hood. New-onset abnormal movements suggestive of tics outside of the usual age range 
should result in evaluation for other movement disorders or for specific etiologies.
Tic symptoms cannot be attributable to the physiological effects of a substance or an­
other medical condition (Criterion D). When there is strong evidence from the history,

other medical condition (Criterion D). When there is strong evidence from the history, 
physical examination, and/or laboratory results to suggest a plausible, proximal, and 
probable cause for a tic disorder, a diagnosis of other specified tic disorder should be used.
Having previously met diagnostic criteria for Tourette's disorder negates a possible di­
agnosis of persistent (chronic) motor or vocal tic disorder (Criterion E). Similarly, a previ­
ous diagnosis of persistent (chronic) motor or vocal tic disorder negates a diagnosis of 
provisional tic disorder or other specified or unspecified tic disorder (Criterion E).

Tics are common in childhood but transient in most cases. The estimated prevalence of 
Tourette's disorder ranges from 3 to 8 per 1,000 in school-age children. Males are more 
commonly affected than females, with the ratio varying from 2:1 to 4:1. A national survey 
in the United States estimated 3 per 1,000 for the prevalence of clinically identified cases. 
The frequency of identified cases was lower among African Americans and Hispanic 
Americans, which may be related to differences in access to care.
Onset of tics is typically between ages 4 and 6 years. Peak severity occurs between ages 10 
and 12 years, with a decline in severity during adolescence. Many adults with tic disorders 
experience diminished symptoms. A small percentage of individuals will have persis­
tently severe or worsening symptoms in adulthood.
Tic symptoms manifest similarly in all age groups and across the lifespan. Tics wax and

Tic symptoms manifest similarly in all age groups and across the lifespan. Tics wax and 
wane in severity and change in affected muscle groups and vocalizations over time. As 
children get older, they begin to report their tics being associated with a premonitory 
urge—a somatic sensation that precedes the tic—and a feeling of tension reduction follow­
ing the expression of the tic. Tics associated with a premonitory urge may be experienced 
as not completely ''involuntary" in that the urge and the tic can be resisted. An individual 
may also feel the need to perform a tic in a specific way or repeat it until he or she achieves 
the feeling that the tic has been done "'just right."
The vulnerability toward developing co-occurring conditions changes as individuals 
pass through the age of risk for various co-occurring conditions. For example, prepubertal

pass through the age of risk for various co-occurring conditions. For example, prepubertal 
children with tic disorders are more likely to experience attention-deficit/hyperactivity 
disorder (ADHD), obsessive-compulsive disorder (OCD), and separation anxiety disorder 
than are teenagers and adults, who are more likely to experience the new onset of major 
depressive disorder, substance use disorder, or bipolar disorder.
Temperamental. Tics are worsened by anxiety, excitement, and exhaustion and are better 
during calm, focused activities. Individuals may have fewer tics when engaged in schoolwork 
or tasks at work than when relaxing at home after school or in the evening. Stressful/exciting 
events (e.g., taking a test, participating in exciting activities) often make tics worse.
Environmental. Observing a gesture or sound in another person may result in an indi­

vidual with a tic disorder making a similar gesture or sound, which may be incorrectly 
perceived by others as purposeful. This can be a particular problem when the individual is 
interacting with authority figures (e.g., teachers, supervisors, police).
Genetic and physiological. Genetic and environmental factors influence tic symptom 
expression and severity. Important risk alleles for Tourette's disorder and rare genetic 
variants in families with tic disorders have been identified. Obstetrical complications, 
older paternal age, lower birth weight, and maternal smoking during pregnancy are as­
sociated with worse tic severity.
Tic disorders do not appear to vary in clinical characteristics, course, or etiology by race,

Tic disorders do not appear to vary in clinical characteristics, course, or etiology by race, 
ethnicity, and culture. However, race, ethnicity, and culture may impact how tic disorders 
are perceived and managed in the family and community, as well as influencing patterns 
of help seeking, and choices of treatment.

Males are more commonly affected than females, but there are no gender differences in the 
kinds of tics, age at onset, or course. Women with persistent tic disorders may be more 
likely to experience anxiety and depression.
Functional Consequences of Tic Disorders
Many individuals with mild to moderate tic severity experience no distress or impairment 
in functioning and may even be unaware of their tics. Individuals with more severe symp­
toms generally have more impairment in daily living, but even individuals with moderate 
or even severe tic disorders may function well. The presence of a co-occurring condition, 
such as ADHD or OCD, can have greater impact on functioning. Less commonly, tics dis­
rupt functioning in daily activities and result in social isolation, interpersonal conflict, 
peer victimization, inability to work or to go to school, and lower quality of life. The indi­

vidual also may experience substantial psychological distress. Rare complications of Tou- 
rette's disorder include physical injury, such as eye injury (from hitting oneself in the face), 
and orthopedic and neurological injury (e.g., disc disease related to forceful head and neck 
movements).
Abnormal movements that may accompany other medical conditions and stereotypic  
movement disorder. Motor stereotypies are defined as involuntary rhythmic, repetitive, 
predictable movements that appear purposeful but serve no obvious adaptive function or 
purpose and stop with distraction. Examples include repetitive hand waving/rotating, 
arm flapping, and finger wiggling. Motor stereotypies can be differentiated from tics based

arm flapping, and finger wiggling. Motor stereotypies can be differentiated from tics based 
on the former's earlier age at onset (younger than 3 years), prolonged duration (seconds to 
minutes), constant repetitive fixed form and location, exacerbation when engrossed in ac­
tivities, lack of a premonitory urge, and cessation with distraction (e.g., name called or 
touched). Chorea  represents rapid, random, continual, abrupt, irregular, unpredictable, 
nonstereotyped actions that are usually bilateral and affect all parts of the body (i.e., face, 
trunk, and limbs). The timing, direction, and distribution of movements vary from mo­
ment to moment, and movements usually worsen during attempted voluntary action. Dys­
tonia  is the simultaneous sustained contracture of both agonist and antagonist muscles, 
resulting in a distorted posture or movement of parts of the body. Dystonie postures are of­

ten triggered by attempts at voluntary movements and are not seen during sleep.
Substance-induced and paroxysmal dyskinesias. Paroxysmal dyskinesias usually oc­
cur as dystonie or choreoathetoid movements that are precipitated by voluntary move­
ment or exertion and less commonly arise from normal background activity.
Myoclonus. Myoclonus is characterized by a sudden unidirectional movement that is 
often nonrhythmic. It may be worsened by movement and occur during sleep. Myoclonus 
is differentiated from tics by its rapidity, lack of suppressibility, and absence of a premon­
itory urge.
Obsessive-compulsive and related disorders. Differentiating obsessive-compulsive 
behaviors from tics may be difficult. Clues favoring an obsessive-compulsive behavior in­

clude a cognitive-based drive (e.g., fear of contamination) and the need to perform the ac­
tion in a particular fashion a certain number of times, equally on both sides of the body, or 
until a "just right" feeling is achieved. Impulse-control problems and other repetitive be­
haviors, including persistent hair pulling, skin picking, and nail biting, appear more goal 
directed and complex than tics.

Many medical and psychiatric conditions have been described as co-occurring with tic disor­
ders, with ADHD and obsessive-compulsive and related disorders being particularly com­
mon. The obsessive-compulsive symptoms observed in tic disorder tend to be characterized 
by more aggressive symmetry and order symptoms and poorer response to pharmacotherapy 
with selective serotonin reuptake inhibitors. Children with ADHD may demonstrate disrup­
tive behavior, social immaturity, and learning difficulties that may interfere with academic 
progress and interpersonal relationships and lead to greater impairment than that caused by a 
tic disorder. Individuals with tic disorders can also have other movement disorders and other 
mental disorders, such as depressive, bipolar, or substance use disorders.
Other Specified Tic Disorder
307.20 (F95.8)
This category applies to presentations in which symptoms characteristic of a tic disorder

This category applies to presentations in which symptoms characteristic of a tic disorder  
that cause clinically significant distress or impairment in social, occupational, or other im­
portant areas of functioning predominate but do not meet the full criteria for a tic disorder  
or any of the disorders in  the neurodevelopmental disorders diagnostic class. The other  
specified tic disorder category is used in situations in  which the clinician chooses to com­
municate the specific reason that the presentation does not meet the criteria for a tic disor­
der or any specific neurodevelopmental disorder. This is done by recording “ other specified  
tic disorder”  followed by the specific reason (e.g., “ with onset after age 18 years” ).
Unspecified Tic Disorder
307.20 (F95.9)

or for any of the disorders in the neurodevelopmental disorders diagnostic class. The un­
specified tic disorder category is used in situations in which the clinician chooses not to 
specify the reason that the criteria are not met for a tic disorder or for a specific neurode­
velopmental disorder, and includes presentations in which there is insufficient information  
to make a more specific diagnosis.

Other Neurodevelopmental Disorders
Other Specified Neurodevelopmental Disorder
This category applies to presentations in which symptoms characteristic of a neurodevel­
opmental disorder that cause impairment in  social, occupational, or other important areas  
of functioning predominate but do not meet the full criteria for any of the disorders in the  
neurodevelopmental disorders diagnostic class. The other specified neurodevelopmental  
disorder category is used in  situations in which the clinician chooses to communicate the  
specific reason that the presentation does not meet the criteria for any specific neurode­
velopmental disorder. This is done by recording “ other specified neurodevelopmental dis­
order”  followed by the specific reason (e.g., “ neurodevelopmental disorder associated with  
prenatal alcohol exposure” ).
An example of a presentation that can be specified using the “ other specified”  desig­
nation is the following:

Neurodevelopmental disorder associated with prenatal alcohol exposure: Neu­
rodevelopmental disorder associated with prenatal alcohol exposure is characterized  
by a range of developmental disabilities following exposure to alcohol in utero.
Unspecified Neurodevelopmental Disorder
315.9 (F89)
opmental disorder that cause impairment in social, occupational, or other important areas  
neurodevelopmental disorders diagnostic class. The unspecified neurodevelopmental dis­
order category is used in situations in which the clinician chooses not to  specify the reason  
that the criteria are not met for a specific neurodevelopmental disorder, and includes pre­

sentations in which there is insufficient information to make a more specific diagnosis  
(e.g., in emergency room settings).

S^izophrenïa Spectrum and 
Other Psychotic Disorder·
SchiZOphreniâ spectrum and other psychotic disorders include schizophrenia, 
other psychotic disorders, and schizotypal (personality) disorder. They are defined by ab­
normalities in one or more of the following five domains: delusions, hallucinations, disor­
ganized thinking (speech), grossly disorganized or abnormal motor behavior (including 
catatonia), and negative symptoms.
Key Features That Define the Psychotic Disorders 
Delusions
Delusions  are fixed beliefs that are not amenable to change in light of conflicting evidence. 
Their content may include a variety of themes (e.g., persecutory, referential, somatic, reli­
gious, grandiose). Persecutory delusions  (i.e., belief that one is going to be harmed, harassed, 
and so forth by an individual, organization, or other group) are most common. Referential  
delusions  (i.e., belief that certain gestures, comments, environmental cues, and so forth are

delusions  (i.e., belief that certain gestures, comments, environmental cues, and so forth are 
directed at oneself) are also common. Grandiose delusions  (i.e., when an individual believes 
that he or she has exceptional abilities, wealth, or fame) and érotomanie delusions  (i.e., when 
an individual believes falsely that another person is in love with him or her) are also seen. 
Nihilistic delusions  involve the conviction that a major catastrophe will occur, and somatic  
delusions  focus on preoccupations regarding health and organ function.
Delusions are deemed bizarre  if they are clearly implausible and not understandable to 
same-culture peers and do not derive from ordinary life experiences. An example of a bi­
zarre delusion is the belief that an outside force has removed his or her internal organs and

zarre delusion is the belief that an outside force has removed his or her internal organs and 
replaced them with someone else's organs without leaving any wounds or scars. An ex­
ample of a nonbizarre delusion is the belief that one is under surveillance by the police, de­
spite a lack of convincing evidence. Delusions that express a loss of control over mind or 
body are generally considered to be bizarre; these include the belief that one's thoughts 
have been "removed" by some outside force {thought withdrawal),  that alien thoughts have 
been put into one's mind (thought insertion),  or that one's body or actions are being acted on 
or manipulated by some outside force (delusions of control).  The distinction between a de­
lusion and a strongly held idea is sometimes difficult to make and depends in part on the

lusion and a strongly held idea is sometimes difficult to make and depends in part on the 
degree of conviction with which the belief is held despite clear or reasonable contradictory 
evidence regarding its veracity.
Hallucinations
Hallucinations  are perception-like experiences that occur without an external stimulus. 
They are vivid and clear, with the full force and impact of normal perceptions, and not 
under voluntary control. They may occur in any sensory modality, but auditory halluci­
nations are the most common in schizophrenia and related disorders. Auditory hallucina­
tions are usually experienced as voices, whether familiar or unfamiliar, that are perceived 
as distinct from the individual's own thoughts. The hallucinations must occur in the con­
text of a clear sensorium; those that occur while falling asleep (hypnagogic)  or waking up

(hypnopompic)  are considered to be within the range of normal experience. Hallucinations 
may be a normal part of religious experience in certain cultural contexts.
Disorganized Thinking (Speech)
Disorganized thinking (formal thought disorder)  is typically inferred from the individual's 
speech. The individual may switch from one topic to another {derailment or loose associa­
tions).  Answers to questions may be obliquely related or completely unrelated (tangential-  
ity). Rarely, speech may be so severely disorganized that it is nearly incomprehensible and 
resembles receptive aphasia in its linguistic disorganization {incoherence  or "word salad"). 
Because mildly disorganized speech is common and nonspecific, the symptom must be se­
vere enough to substantially impair effective communication. The severity of the impair­
ment may be difficult to evaluate if the person making the diagnosis comes from a

ment may be difficult to evaluate if the person making the diagnosis comes from a 
different linguistic background than that of the person being examined. Less severe dis­
organized thinking or speech may occur during the prodromal and residual periods of 
schizophrenia.
Grossly Disorganized or Abnormai iViotor Behavior  
(inciuding Catatonia)
Grossly disorganized or abnormal motor behavior  may manifest itself in a variety of ways, 
ranging from childlike "silliness" to unpredictable agitation. Problems may be noted in 
any form of goal-directed behavior, leading to difficulties in performing activities of daily 
living.
Catatonic behavior is a marked decrease in reactivity to the environment. This ranges 
from resistance to instructions {negativism);  to maintaining a rigid, inappropriate or bi­
zarre posture; to a complete lack of verbal and motor responses {mutism  and stupor).  It can

zarre posture; to a complete lack of verbal and motor responses {mutism  and stupor).  It can 
also include purposeless and excessive motor activity without obvious cause {catatonic 
excitement).  Other features are repeated stereotyped movements, staring, grimacing, 
mutism, and the echoing of speech. Although catatonia has historically been associated 
with schizophrenia, catatonic symptoms are nonspecific and may occur in other mental 
disorders (e.g., bipolar or depressive disorders with catatonia) and in medical conditions 
(catatonic disorder due to another medical condition).
Negative Symptoms
Negative symptoms  account for a substantial portion of the morbidity associated with 
schizophrenia but are less prominent in other psychotic disorders. Two negative symp­
toms are particularly prominent in schizophrenia: diminished emotional expression and

toms are particularly prominent in schizophrenia: diminished emotional expression and 
avolition. Diminished emotional expression  includes reductions in the expression of emo­
tions in the face, eye contact, intonation of speech (prosody), and movements of the hand, 
head, and face that normally give an emotional emphasis to speech. Avolition  is a decrease 
in motivated self-initiated purposeful activities. The individual may sit for long periods of 
time and show little interest in participating in work or social activities. Other negative 
symptoms include alogia, anhedonia, and asociality. Alogia  is manifested by diminished 
speech output. Anhedonia  is the decreased ability to experience pleasure from positive 
stimuli or a degradation in the recollection of pleasure previously experienced. Asociality

stimuli or a degradation in the recollection of pleasure previously experienced. Asociality  
refers to the apparent lack of interest in social interactions and may be associated with avo­
lition, but it can also be a manifestation of limited opportunities for social interactions.
Disorders in Tliis CInapter
This chapter is organized along a gradient of psychopathology. Clinicians should first con­
sider conditions that do not reach full criteria for a psychotic disorder or are limited to one

domain of psychopathology. Then they should consider time-limited conditions. Finally, 
the diagnosis of a schizophrenia spectrum disorder requires the exclusion of another con­
dition that may give rise to psychosis.
Schizotypal personality disorder is noted within this chapter as it is considered within 
the schizophrenia spectrum, although its full description is found in the chapter "Person­
ality Disorders." The diagnosis schizotypal personality disorder captures a pervasive pat­
tern of social and interpersonal deficits, including reduced capacity for close relationships; 
cognitive or perceptual distortions; and eccentricities of behavior, usually beginning by 
early adulthood but in some cases first becoming apparent in childhood and adolescence. 
Abnormalities of beliefs, thinking, and perception are below the threshold for the diagno­
sis of a psychotic disorder.
Two conditions are defined by abnormalities limited to one domain of psychosis: delu­

sions or catatonia. Delusional disorder is characterized by at least 1  month of delusions but 
no other psychotic symptoms. Catatonia is described later in the chapter and further in this 
discussion.
Brief psychotic disorder lasts more than 1 day and remits by 1 month. Schizophreni­
form disorder is characterized by a symptomatic presentation equivalent to that of schizo­
phrenia except for its duration (less than 6 months) and the absence of a requirement for a 
decline in functioning.
Schizophrenia lasts for at least 6 months and includes at least 1  month of active-phase 
symptoms. In schizoaffective disorder, a mood episode and the active-phase symptoms of 
schizophrenia occur together and were preceded or are followed by at least 2 weeks of de­
lusions or hallucinations without prominent mood symptoms.

Psychotic disorders may be induced by another condition. In substance/medication- 
induced psychotic disorder, the psychotic symptoms are judged to be a physiological con­
sequence of a drug of abuse, a medication, or toxin exposure and cease after removal of the 
agent. In psychotic disorder due to another medical condition, the psychotic symptoms 
are judged to be a direct physiological consequence of another medical condition.
Catatonia can occur in several disorders, including neurodevelopmental, psychotic, bi­
polar, depressive, and other mental disorders. This chapter also includes the diagnoses 
catatonia associated with another mental disorder (catatonia specifier), catatonic disorder 
due to another medical condition, and unspecified catatonia, and the diagnostic criteria for 
all three conditions are described together.

Other specified and unspecified schizophrenia spectrum and other psychotic disor­
ders are included for classifying psychotic presentations that do not meet the criteria for 
any of the specific psychotic disorders, or psychotic symptomatology about which there is 
inadequate or contradictory information.
Clinician-Rated Assessment of Symptoms and 
Related Clinical Phenomena in Psychosis
Psychotic disorders are heterogeneous, and the severity of symptoms can predict impor­
tant aspects of the illness, such as the degree of cognitive or neurobiological deficits. To 
move the field forward, a detailed framework for the assessment of severity is included in 
Section III "Assessment Measures," which may help with treatment planning, prognostic 
decision making, and research on pathophysiological mechanisms. Section III "Assess­

ment Measures" also contains dimensional assessments of the primary symptoms of psy­
chosis, including hallucinations, delusions, disorganized speech (except for substance/ 
medication-induced psychotic disorder and psychotic disorder due to another medical 
condition), abnormal psychomotor behavior, and negative symptoms, as well as dimen­
sional assessments of depression and mania. The severity of mood symptoms in psychosis 
has prognostic value and guides treatment. There is growing evidence that schizoaffective

disorder is not a distinct nosological category. Thus, dimensional assessments of depres­
sion and mania for all psychotic disorders alert clinicians to mood pathology and the need 
to treat where appropriate. The Section III scale also includes a dimensional assessment of 
cognitive impairment. Many individuals with psychotic disorders have impairments in a 
range of cognitive domains that predict functional status. Clinical neuropsychological as­
sessment can help guide diagnosis and treatment, but brief assessments without formal 
neuropsychological assessment can provide useful information that can be sufficient for 
diagnostic purposes. Formal neuropsychological testing, when conducted, should be ad­
ministered and scored by personnel trained in the use of testing instruments. If a formal 
neuropsychological assessment is not conducted, the clinician should use the best avail­
able information to make a judgment. Further research on these assessments is necessary

able information to make a judgment. Further research on these assessments is necessary 
in order to determine their clinical utility; thus, the assessments available in Section III 
should serve as a prototype to stimulate such research.
Schizotypal (Personality) Disorder
Criteria and text for schizotypal personality disorder can be found in the chapter "Person­
ality Disorders." Because this disorder is considered part of the schizophrenia spectrum of 
disorders, and is labeled in this section of ICD-9 and ICD-10 as schizotypal disorder, it is 
listed in this chapter and discussed in detail in the DSM-5 chapter "Personality Disorders."
Delusional Disorder
Diagnostic Criteria 297.1 (F22)
A. The presence of one (or more) delusions with a duration of 1  month or longer.
B. Criterion A for schizophrenia has never been met.

Note: Hallucinations, if present, are not prominent and are related to the delusional  
theme (e.g., the sensation of being infested with insects associated with delusions of  
infestation).
C. Apart from the impact of the delusion(s) or its ramifications, functioning is not markedly  
impaired, and behavior is not obviously bizarre or odd.
D. If manic or major depressive episodes have occurred, these have been brief relative  
to the duration of the delusional periods.
E. The disturbance is not attributable to the physiological effects of a substance or an­
other medical condition and is not better explained by another mental disorder, such  
as body dysmorphic disorder or obsessive-compulsive disorder.

Erotomanie type: This subtype applies when the central theme of the delusion is that  
another person is in love with the individual.
Grandiose type: This subtype applies when the central theme of the delusion is the  
conviction of having some great (but unrecognized) talent or insight or having made  
some important discovery.
Jeaious type: This subtype applies when the central theme of the individual’s delusion  
is that his or her spouse or lover is unfaithful.
Persecutory type: This subtype applies when the central theme of the delusion in­
volves the individual’s belief that he or she is being conspired against, cheated, spied  
on, followed, poisoned or drugged, maliciously maligned, harassed, or obstructed in  
the pursuit of long-term goals.

Somatic type: This subtype applies when the central theme of the delusion involves  
bodily functions or sensations.

Mixed type: This subtype applies when no one delusional theme predominates.  
Unspecified type: This subtype applies when the dominant delusional belief cannot  
be clearly determined or is not described in the specific types (e.g., referential delu­
sions without a prominent persecutory or grandiose component).
With bizarre content: Delusions are deemed bizarre if they are clearly implausible, not  
understandable, and not derived from ordinary life experiences (e.g., an individual’s be­
lief that a stranger has removed his or her internal organs and replaced them with some­
one else’s organs without leaving any wounds or scars).
The following course specifiers are only to be used after a 1  -year duration of the disorder:  
First episode, currently in acute episode: First manifestation of the disorder meet­
ing the defining diagnostic symptom and time criteria. An acute episode  is a time pe­
riod in which the symptom criteria are fulfilled.

First episode, currently in partial remission: Partial remission  is a time period dur­
ing which an improvement after a previous episode is maintained and in which the de­
fining criteria of the disorder are only partially fulfilled.
First episode, currently in full remission: Full remission  is a period of time after a  
previous episode during which no disorder-specific symptoms are present.  
lUlultiple episodes, currently in acute episode  
Multiple episodes, currently in partial remission  
Multiple episodes, currently in full remission
Continuous: Symptoms fulfilling the diagnostic symptom criteria of the disorder are  
remaining for the majority of the illness course, with subthreshold symptom periods be­
ing very brief relative to the overall course.
Unspecified  

Severity is rated by a quantitative assessment of the primary symptoms of psychosis,  
including delusions, hallucinations, disorganized speech, abnormal psychomotor be­
havior, and negative symptoms. Each of these symptoms may be rated for its current  
severity (most severe in the last 7 days) on a 5-point scale ranging from 0 (not present)  
to 4 (present and severe). (See Clinician-Rated Dimensions of Psychosis Symptom  
Severity in the chapter “ Assessment Measures.” )
Note: Diagnosis of delusional disorder can be made without using this severity specifier.
Subtypes
In érotomanie type,  the central theme of the delusion is that another person is in love with 
the individual. The person about whom this conviction is held is usually of higher status

Subtypes
the individual. The person about whom this conviction is held is usually of higher status 
(e.g., a famous individual or a superior at work) but can be a complete stranger. Efforts to 
contact the object of the delusion are common. In grandiose type,  the central theme of the de­
lusion is the conviction of having some great talent or insight or of having made some im­
portant discovery. Less commonly, the individual may have the delusion of having a 
special relationship with a prominent individual or of being a prominent person (in which 
case the actual individual may be regarded as an impostor). Grandiose delusions may 
have a religious content. In jealous type,  the central theme of the delusion is that of an un­
faithful partner. This belief is arrived at without due cause and is based on incorrect infer­

ences supported by small bits of "evidence" (e.g., disarrayed clothing). The individual 
with the delusion usually confronts the spouse or lover and attempts to intervene in the 
imagined infidelity. In persecutory type,  the central theme of the delusion involves the in­

dividual's belief of being conspired against, cheated, spied on, followed, poisoned, mali­
ciously maligned, harassed, or obstructed in the pursuit of long-term goals. Small slights 
may be exaggerated and become the focus of a delusional system. The affected individual 
may engage in repeated attempts to obtain satisfaction by legal or legislative action. Indi­
viduals with persecutory delusions are often resentful and angry and may resort to vio­
lence against those they believe are hurting them. In somatic type,  the central theme of the 
delusion involves bodily functions or sensations. Somatic delusions can occur in several 
forms. Most common is the belief that the individual emits a foul odor; that there is an in­
festation of insects on or in the skin; that there is an internal parasite; that certain parts of 
the body are misshapen or ugly; or that parts of the body are not functioning.

The essential feature of delusional disorder is the presence of one or more delusions that 
persist for at least 1  month (Criterion A). A diagnosis of delusional disorder is not given if 
the individual has ever had a symptom presentation that met Criterion A for schizophre­
nia (Criterion B). Apart from the direct impact of the delusions, impairments in psychoso­
cial functioning may be more circumscribed than those seen in other psychotic disorders 
such as schizophrenia, and behavior is not obviously bizarre or odd (Criterion C). If mood 
episodes occur concurrently with the delusions, the total duration of these mood episodes 
is brief relative to the total duration of the delusional periods (Criterion D). The delusions

is brief relative to the total duration of the delusional periods (Criterion D). The delusions 
are not attributable to the physiological effects of a substance (e.g., cocaine) or another 
medical condition (e.g., Alzheimer's disease) and are not better explained by another men­
tal disorder, such as body dysmorphic disorder or obsessive-compulsive disorder (Crite­
rion E).
In addition to the five symptom domain areas identified in the diagnostic criteria, the 
assessment of cognition, depression, and mania symptom domains is vital for making crit­
ically important distinctions between the various schizophrenia spectrum and other psy­
chotic disorders.
Social, marital, or work problems can result from the delusional beliefs of delusional dis­
order. Individuals with delusional disorder may be able to factually describe that others

order. Individuals with delusional disorder may be able to factually describe that others 
view their beliefs as irrational but are unable to accept this themselves (i.e., there may be 
"factual insight" but no true insight). Many individuals develop irritable or dysphoric 
mood, which can usually be understood as a reaction to their delusional beliefs. Anger and 
violent behavior can occur with persecutory, jealous, and érotomanie types. The individ­
ual may engage in htigious or antagonistic behavior (e.g., sending hundreds of letters of 
protest to the government). Legal difficulties can occur, particularly in jealous and éroto­
manie types.
The lifetime prevalence of delusional disorder has been estimated at around 0.2%, and the 
most frequent subtype is persecutory. Delusional disorder, jealous type, is probably more

most frequent subtype is persecutory. Delusional disorder, jealous type, is probably more 
common in males than in females, but there are no major gender differences in the overall 
frequency of delusional disorder.
On average, global function is generally better than that observed in schizophrenia. Al­
though the diagnosis is generally stable, a proportion of individuals go on to develop

schizophrenia. Delusional disorder has a significant familial relationship with both 
schizophrenia and schizotypal personality disorder. Although it can occur in younger age 
groups, the condition may be more prevalent in older individuals.
An individual's cultural and religious background must be taken into account in evaluat­
ing the possible presence of delusional disorder. The content of delusions also varies 
across cultural contexts.
Functional Consequences of Delusional Disorder
The functional impairment is usually more circumscribed than that seen with other psy­
chotic disorders, although in some cases, the impairment may be substantial and include 
poor occupational functioning and social isolation. When poor psychosocial functioning is 
present, delusional beliefs themselves often play a significant role. A common character­
istic of individuals with delusional disorder is the apparent normality of their behavior

istic of individuals with delusional disorder is the apparent normality of their behavior 
and appearance when their delusional ideas are not being discussed or acted on.
Obsessive-compulsive and related disorders. If an individual with obsessive-compul­
sive disorder is completely convinced that his or her obsessive-compulsive disorder beliefs 
are true, then the diagnosis of obsessive-compulsive disorder, with absent insight/delu­
sional beliefs specifier, should be given rather than a diagnosis of delusional disorder. 
Similarly, if an individual with body dysmorphic disorder is completely convinced that 
his or her body dysmorphic disorder beliefs are true, then the diagnosis of body dysmor­
phic disorder, with absent insight/delusional beliefs specifier, should be given rather than 
a diagnosis of delusional disorder.

Delirium, major neurocognitive disorder, psychotic disorder due to another medical con­
dition, and substance/medication-induced psychotic disorder. Individuals with these 
disorders may present with symptoms that suggest delusional disorder. For example, sim­
ple persecutory delusions in the context of major neurocognitive disorder would be di­
agnosed as major neurocognitive disorder, with behavioral disturbance. A substance/ 
medication-induced psychotic disorder cross-sectionally may be identical in symptom­
atology to delusional disorder but can be distinguished by the chronological relationship 
of substance use to the onset and remission of the delusional beliefs.
Schizophrenia and schizophreniform disorder. Delusional disorder can be distinguished 
from schizophrenia and schizophreniform disorder by the absence of the other character­

istic symptoms of the active phase of schizophrenia.
Depressive and bipolar disorders and schizoaffective disorder. These disorders may 
be distinguished from delusional disorder by the temporal relationship between the mood 
disturbance and the delusions and by the severity of the mood symptoms. If delusions oc­
cur exclusively during mood episodes, the diagnosis is depressive or bipolar disorder with 
psychotic features. Mood symptoms that meet full criteria for a mood episode can be su­
perimposed on delusional disorder. Delusional disorder can be diagnosed only if the total 
duration of all mood episodes remains brief relative to the total duration of the delusional 
disturbance. If not, then a diagnosis of other specified or unspecified schizophrenia spec­

trum and other psychotic disorder accompanied by other specified depressive disorder, 
unspecified depressive disorder, other specified bipolar and related disorder, or unspeci­
fied bipolar and related disorder is appropriate.

Brief Psychotic Disorder
Diagnostic Criteria 298.8 (F23)
A. Presence of one (or more) of the following symptoms. At least one of these must be  
(1), (2), or (3):
1. Delusions.
2. Hallucinations.
3. Disorganized speech (e.g., frequent derailment or incoherence).
4. Grossly disorganized or catatonic behavior.
Note: Do not include a symptom if it is a culturally sanctioned response.
B. Duration of an episode of the disturbance is at least 1  day but less than 1  month, with  
eventual full return to premorbid level of functioning.
C. The disturbance is not better explained by major depressive or bipolar disorder with  
psychotic features or another psychotic disorder such as schizophrenia or catatonia,  
and is not attributable to the physiological effects of a substance (e.g., a drug of abuse,  
a medication) or another medical condition.
With marked stressor(s) (brief reactive psychosis): If symptoms occur in  response to

With marked stressor(s) (brief reactive psychosis): If symptoms occur in  response to  
events that, singly or together, would be markedly stressful to almost anyone in similar  
circumstances in the individual’s culture.
Without marited stressor(s): If symptoms do not occur in  response to events that,  
singly or together, would be markedly stressful to almost anyone in similar circum­
stances in the individual’s culture.
With postpartum onset: If onset is during pregnancy or within 4 weeks postpartum.  
order, pp. 119-120, for definition)
Coding note: Use additional code 293.89 (F06.1) catatonia associated with brief  
psychotic disorder to indicate the presence of the comorbid catatonia.
Severity is rated by a quantitative assessment of the primary symptoms of psychosis,

Severity in the chapter “ Assessment Measures.”)
Note: Diagnosis of brief psychotic disorder can be made without using this severity  
specifier._____________________________________________________________
The essential feature of brief psychotic disorder is a disturbance that involves the sudden 
onset of at least one of the following positive psychotic symptoms: delusions, hallucina­

tions, disorganized speech (e.g., frequent derailment or incoherence), or grossly abnormal 
psychomotor behavior, including catatonia (Criterion A). Sudden onset  is defined as 
change from a nonpsychotic state to a clearly psychotic state within 2 weeks, usually with­
out a prodrome. An episode of the disturbance lasts at least 1  day but less than 1  month, 
and the individual eventually has a full return to the premorbid level of functioning (Cri­

terion B). The disturbance is not better explained by a depressive or bipolar disorder with 
psychotic features, by schizoaffective disorder, or by schizophrenia and is not attributable 
to the physiological effects of a substance (e.g., a hallucinogen) or another medical condi­
tion (e.g., subdural hematoma) (Criterion C).
Individuals with brief psychotic disorder typically experience emotional turmoil or over­
whelming confusion. They may have rapid shifts from one intense affect to another. 
Although the disturbance is brief, the level of impairment may be severe, and supervision

Although the disturbance is brief, the level of impairment may be severe, and supervision 
may be required to ensure that nutritional and hygienic needs are met and that the indi­
vidual is protected from the consequences of poor judgment, cognitive impairment, or act­
ing on the basis of delusions. There appears to be an increased risk of suicidal behavior, 
particularly during the acute episode.
In the United States, brief psychotic disorder may account for 9% of cases of first-onset 
psychosis. Psychotic disturbances that meet Criteria A and C, but not Criterion B, for brief 
psychotic disorder (i.e., duration of active symptoms is 1-6 months as opposed to remis­
sion within 1  month) are more common in developing countries than in developed coun­
tries. Brief psychotic disorder is twofold more common in females than in males.

Brief psychotic disorder may appear in adolescence or early adulthood, and onset can oc­
cur across the lifespan, with the average age at onset being the mid 30s. By definition, a 
diagnosis of brief psychotic disorder requires a full remission of all symptoms and an 
eventual full return to the premorbid level of functioning within 1  month of the onset of the 
disturbance. In some individuals, the duration of psychotic symptoms may be quite brief 
(e.g., a few days).
Temperamental. Preexisting personality disorders and traits (e.g., schizotypal person­
ality disorder; borderline personality disorder; or traits in the psychoticism domain, such 
as perceptual dysregulation, and the negative affectivity domain, such as suspiciousness)

as perceptual dysregulation, and the negative affectivity domain, such as suspiciousness) 
may predispose the individual to the development of the disorder.
Cuiture-Reiated Diagnostic issues
It is important to distinguish symptoms of brief psychotic disorder from culturally sanc­
tioned response patterns. For example, in some religious ceremonies, an individual may 
report hearing voices, but these do not generally persist and are not perceived as abnormal 
by most members of the individual's community. In addition, cultural and religious back­
ground must be taken into account when considering whether beliefs are delusional.
Functionai Consequences of Brief Psycliotic Disorder
Despite high rates of relapse, for most individuals, outcome is excellent in terms of social 
functioning and symptomatology.

Other medical conditions. A variety of medical disorders can manifest with psychotic 
symptoms of short duration. Psychotic disorder due to another medical condition or a de­
lirium is diagnosed when there is evidence from the history, physical examination, or lab­
oratory tests that the delusions or hallucinations are the direct physiological consequence 
of a specific medical condition (e.g., Cushing's syndrome, brain tumor) (see 'Tsychotic 
Disorder Due to Another Medical Condition" later in this chapter).
Substance-related disorders. Substance/medication-induced psychotic disorder, sub­
stance-induced delirium, and substance intoxication are distinguished from brief psychotic 
disorder by the fact that a substance (e.g., a drug of abuse, a medication, exposure to a toxin) 
is judged to be etiologically related to the psychotic symptoms (see ''Substance/Medication- 
Induced Psychotic Disorder" later in this chapter). Laboratory tests, such as a urine drug

Induced Psychotic Disorder" later in this chapter). Laboratory tests, such as a urine drug 
screen or a blood alcohol level, may be helpful in making this determination, as may a care­
ful history of substance use with attention to temporal relationships between substance in­
take and onset of the symptoms and to the nature of the substance being used.
Depressive and bipolar disorders. The diagnosis of brief psychotic disorder cannot be 
made if the psychotic symptoms are better explained by a mood episode (i.e., the psychotic 
symptoms occur exclusively during a full major depressive, manic, or mixed episode).
Other psychotic disorders. If the psychotic symptoms persist for 1  month or longer, the 
diagnosis is either schizophreniform disorder, delusional disorder, depressive disorder 
with psychotic features, bipolar disorder with psychotic features, or other specified or un­

specified schizophrenia spectrum and other psychotic disorder, depending on the other 
symptoms in the presentation. The differential diagnosis between brief psychotic disorder 
and schizophreniform disorder is difficult when the psychotic symptoms have remitted be­
fore 1 month in response to successful treatment with medication. Careful attention should 
be given to the possibility that a recurrent disorder (e.g., bipolar disorder, recurrent acute ex­
acerbations of schizophrenia) may be responsible for any recurring psychotic episodes.
Malingering and factitious disorders. An episode of factitious disorder, with predomi­
nantly psychological signs and symptoms, may have the appearance of brief psychotic 
disorder, but in such cases there is evidence that the symptoms are intentionally produced.

disorder, but in such cases there is evidence that the symptoms are intentionally produced. 
When malingering involves apparently psychotic symptoms, there is usually evidence 
that the illness is being feigned for an understandable goal.
Personality disorders. In certain individuals with personality disorders, psychosocial 
stressors may precipitate brief periods of psychotic symptoms. These symptoms are usu­
ally transient and do not warrant a separate diagnosis. If psychotic symptoms persist for at 
least 1 day, an additional diagnosis of brief psychotic disorder may be appropriate.
Schizophreniform Disorder
Diagnostic Criteria 295.40 (F20.81)
A. Two (or more) of the following, each present for a significant portion of time during a  
1-month period (or less if successfully treated). At least one of these must be (1), (2),  
or (3):

or (3):
5. Negative symptoms (i.e., diminished emotional expression or avolition).

B. An episode of the disorder lasts at least 1  month but less than 6 months. When the  
diagnosis must be made without waiting for recovery, it should be qualified as “ provi­
sional.”  '
C. Schizoaffective disorder and depressive or bipolar disorder with psychotic features have  
been ruled out because either 1  ) no major depressive or manic episodes have occurred  
concurrently with the active-phase symptoms, or 2) if mood episodes have occurred dur­
ing active-phase symptoms, they have been present for a minority of the total duration  
of the active and residual periods of the illness.
D. The disturbance is not attributable to the physiological effects of a substance (e.g., a  
drug of abuse, a medication) or another medical condition.
With good prognostic features: This specifier requires the presence of at least two  
of the following features: onset of prominent psychotic symptoms within 4 weeks of the

of the following features: onset of prominent psychotic symptoms within 4 weeks of the  
first noticeable change in  usual behavior or functioning; confusion or perplexity: good  
premorbid social and occupational functioning; and absence of blunted or flat affect.  
Without good prognostic features: This specifier is applied if two or more of the  
above features have not been present.
With catatonia (refer to the criteria for catatonia associated with another mental disor­
der, pp. 119-120, for definition).
Coding note: Use additional code 293.89 (F06.1) catatonia associated with schizo­
phreniform disorder to indicate the presence of the comorbid catatonia.

Note: Diagnosis of schizophreniform disorder can be made without using this severity  
Note: For additional information on Associated Features Supporting Diagnosis, Develop­
ment and Course (age-related factors), Culture-Related Diagnostic Issues, Gender-Related 
Diagnostic Issues, Differential Diagnosis, and Comorbidity, see the corresponding sec­
tions in schizophrenia.

The characteristic symptoms of schizophreniform disorder are identical to those of schizo­
phrenia (Criterion A). Schizophreniform disorder is distinguished by its difference in du­
ration: the total duration of the illness, including prodromal, active, and residual phases, is 
at least 1  month but less than 6 months (Criterion B). The duration requirement for schizo­
phreniform disorder is intermediate between that for brief psychotic disorder, which lasts 
more than 1  day and remits by 1  month, and schizophrenia, which lasts for at least 6 months. 
The diagnosis of schizophreniform disorder is made under two conditions. 1) when an ep­
isode of illness lasts between 1  and 6 months and the individual has already recovered, 
and 2) when an individual is symptomatic for less than the 6 months' duration required for

and 2) when an individual is symptomatic for less than the 6 months' duration required for 
the diagnosis of schizophrenia but has not yet recovered. In this case, the diagnosis should 
be noted as "schizophreniform disorder (provisional)" because it is uncertain if the indi­
vidual will recover from the disturbance within the 6-month period. If the disturbance per­
sists beyond 6 months, the diagnosis should be changed to schizophrenia.

Another distinguishing feature of schizophreniform disorder is the lack of a criterion 
requiring impaired social and occupational functioning. While such impairments may po­
tentially be present, they are not necessary for a diagnosis of schizophreniform disorder.
As with schizophrenia, currently there are no laboratory or psychometric tests for schizo­
phreniform disorder. There are multiple brain regions where neuroimaging, neuropa- 
thological, and neurophysiological research has indicated abnormalities, but none are 
diagnostic.
Incidence of schizophreniform disorder across sociocultural settings is likely similar to

Incidence of schizophreniform disorder across sociocultural settings is likely similar to 
that observed in schizophrenia. In the United States and other developed countries, the in­
cidence is low, possibly fivefold less than that of schizophrenia. In developing countries, 
the incidence may be higher, especially for the specifier ''with good prognostic features"; 
in some of these settings schizophreniform disorder may be as common as schizophrenia.
The development of schizophreniform disorder is similar to that of schizophrenia. About 
one-third of individuals with an initial diagnosis of schizophreniform disorder (provi­
sional) recover within the 6-month period and schizophreniform disorder is their final di­
agnosis. The majority of the remaining two-thirds of individuals will eventually receive a 
diagnosis of schizophrenia or schizoaffective disorder.

Genetic and physiological. Relatives of individuals with schizophreniform disorder 
have an increased risk for schizophrenia.
Sciiizophreniform Disorder
For the majority of individuals with schizophreniform disorder who eventually receive a 
diagnosis of schizophrenia or schizoaffective disorder, the functional consequences are 
similar to the consequences of those disorders. Most individuals experience dysfunction in 
several areas of daily functioning, such as school or work, interpersonal relationships, and 
self-care. Individuals who recover from schizophreniform disorder have better functional 
outcomes.
Other mental disorders and medical conditions. A wide variety of mental and medical

outcomes.
Other mental disorders and medical conditions. A wide variety of mental and medical 
conditions can manifest with psychotic symptoms that must be considered in the differ­
ential diagnosis of schizophreniform disorder. These include psychotic disorder due to 
another medical condition or its treatment; delirium or major neurocognitive disorder; 
substance/medication-induced psychotic disorder or delirium; depressive or bipolar 
disorder with psychotic features; schizoaffective disorder; other specified or unspecified bi­
polar and related disorder; depressive or bipolar disorder with catatonic features; schizophre-

nia; brief psychotic disorder; delusional disorder; other specified or unspecified schizo­
phrenia spectrum and other psychotic disorder; schizotypal, schizoid, or paranoid 
personality disorders; autism spectrum disorder; disorders presenting in childhood with 
disorganized speech; attention-deficit/hyperactivity disorder; obsessive-compulsive dis­
order; posttraumatic stress disorder; and traumatic brain injury.
Since the diagnostic criteria for schizophreniform disorder and schizophrenia differ 
primarily in duration of illness, the discussion of the differential diagnosis of schizophre­
nia also applies to schizophreniform disorder.
Brief psychotic disorder. Schizophreniform disorder differs in duration from brief psy­
chotic disorder, which has a duration of less than 1  month.
Schizophrenia
Diagnostic Criteria 295.90 (F20.9)
A. Two (or more) of the following, each present for a significant portion of time during a

1  -month period (or less if successfully treated). At least one of these must be (1  ), (2), or (3):
B. For a significant portion of the time since the onset of the disturbance, level of function­
ing in one or more major areas, such as work, interpersonal relations, or self-care, is  
markedly below the level achieved prior to the onset (or when the onset is in childhood  
or adolescence, there is failure to achieve expected level of interpersonal, academic,  
or occupational functioning).
C. Continuous signs of the disturbance persist for at least 6 months. This 6-month period

C. Continuous signs of the disturbance persist for at least 6 months. This 6-month period  
must include at least 1  month of symptoms (or less if successfully treated) that meet Cri­
terion A (i.e., active-phase symptoms) and may include periods of prodromal or residual  
symptoms. During these prodromal or residual periods, the signs of the disturbance may  
be manifested by only negative symptoms or by two or more symptoms listed in Criterion  
A present in  an attenuated form (e.g., odd beliefs, unusual perceptual experiences).
D. Schizoaffective disorder and depressive or bipolar disorder with psychotic features  
have been ruled out because either 1  ) no major depressive or manic episodes have  
occurred concurrently with the active-phase symptoms, or 2) if mood episodes have  
occurred during active-phase symptoms, they have been present for a minority of the  
total duration of the active and residual periods of the illness.

E. The disturbance is not attributable to the physiological effects of a substance (e.g., a  
F. If there is a history of autism spectrum disorder or a communication disorder of child­
hood onset, the additional diagnosis of schizophrenia is made only if prominent delu­
sions or hallucinations, in addition to the other required symptoms of schizophrenia,  
are also present for at least 1  month (or less if successfully treated).
The following course specifiers are only to be used after a 1-year duration of the disorder  
and if they are not in contradiction to the diagnostic course criteria.

First episode, currently in partial remission: Partial remission  is a period of time  
during which an improvement after a previous episode is maintained and in which the  
defining criteria of the disorder are only partially fulfilled.
previous episode during which no disorder-specific symptoms are present.
Multiple episodes, currently in acute episode: Multiple episodes may be deter­
mined after a minimum of two episodes (i.e., after a first episode, a remission and a  
minimum of one relapse).
■Multiple episodes, currently in partial remission  

With catatonia (refer to the criteria for catatonia associated with another mental disorder,  
pp. 119-120, for definition).
Coding note: Use additional code 293.89 (F06.1) catatonia associated with  
schizophrenia to indicate the presence of the comorbid catatonia.

Note: Diagnosis of schizophrenia can be made without using this severity specifier.
The characteristic symptoms of schizophrenia involve a range of cognitive, behavioral, and 
emotional dysfunctions, but no single symptom is pathognomonic of the disorder. The di­
agnosis involves the recognition of a constellation of signs and symptoms associated with 
impaired occupational or social functioning. Individuals with the disorder will vary sub­
stantially on most features, as schizophrenia is a heterogeneous clinical syndrome.
At least two Criterion A symptoms must be present for a significant portion of time 
during a 1-month period or longer. At least one of these symptoms must be the clear pres­
ence of delusions (Criterion Al), hallucinations (Criterion A2), or disorganized speech

ence of delusions (Criterion Al), hallucinations (Criterion A2), or disorganized speech 
(Criterion A3). Grossly disorganized or catatonic behavior (Criterion A4) and negative 
symptoms (Criterion A5) may also be present. In those situations in which the active- 
phase symptoms remit within a month in response to treatment. Criterion A is still met if the 
clinician estimates that they would have persisted in the absence of treatment.
Schizophrenia involves impairment in one or more major areas of functioning (Crite­
rion B). If the disturbance begins in childhood or adolescence, the expected level of func­
tion is not attained. Comparing the individual with unaffected siblings may be helpful. The 
dysfunction persists for a substantial period during the course of the disorder and does not 
appear to be a direct result of any single feature. Avolition (i.e., reduced drive to pursue

appear to be a direct result of any single feature. Avolition (i.e., reduced drive to pursue 
goal-directed behavior; Criterion A5) is linked to the social dysfunction described under 
Criterion B. There is also strong evidence for a relationship between cognitive impairment 
(see the section "Associated Features Supporting Diagnosis" for this disorder) and func­
tional impairment in individuals with schizophrenia.

Some signs of the disturbance must persist for a continuous period of at least 6 months 
(Criterion C). Pi;odromal symptoms often precede the active phase, and residual symp­
toms may follow it, characterized by mild or subthreshold forms of hallucinations or 
delusions. Individuals may express a variety of unusual or odd beliefs that are not of de­
lusional proportions (e.g., ideas of reference or magical thinking); they may have unusual 
perceptual experiences (e.g., sensing the presence of an unseen person); their speech may 
be generally understandable but vague; and their behavior may be unusual but not grossly 
disorganized (e.g., mumbling in public). Negative symptoms are common in the pro­
dromal and residual phases and can be severe. Individuals who had been socially active 
may become withdrawn from previous routines. Such behaviors are often the first sign of 
a disorder.
Mood symptoms and full mood episodes are common in schizophrenia and may be con­

current with active-phase symptomatology. However, as distinct from a psychotic mood dis­
order, a schizophrenia diagnosis requires the presence of delusions or hallucinations in the 
absence of mood episodes. In addition, mood episodes, taken in total, should be present for 
only a minority of the total duration of the active and residual periods of the illness.
Individuals with schizophrenia may display inappropriate affect (e.g., laughing in the ab­

sence of an appropriate stimulus); a dysphoric mood that can take the form of depression, 
anxiety, or anger; a disturbed sleep pattern (e.g., daytime sleeping and nighttime activity); 
and a lack of interest in eating or food refusal. Depersonalization, derealization, and so­
matic concerns may occur and sometimes reach delusional proportions. Anxiety and pho­
bias are common. Cognitive deficits in schizophrenia are conrmion and are strongly linked 
to vocational and functional impairments. These deficits can include decrements in declar­
ative memory, working memory, language function, and other executive functions, as well 
as slower processing speed. Abnormalities in sensory processing and inhibitory capacity, 
as well as reductions in attention, are also found. Some individuals with schizophrenia

as well as reductions in attention, are also found. Some individuals with schizophrenia 
show social cognition deficits, including deficits in the ability to infer the intentions of 
other people (theory of mind), and may attend to and then inteφret irrelevant events or 
stimuli as meaningful, perhaps leading to the generation of explanatory delusions. These 
impairments frequently persist during symptomatic remission.
Some individuals with psychosis may lack insight or awareness of their disorder (i.e., 
anosognosia). This lack of "'insight" includes unawareness of symptoms of schizophrenia 
and may be present throughout the entire course of the illness. Unawareness of illness is 
typically a symptom of schizophrenia itself rather than a coping strategy. It is comparable 
to the lack of awareness of neurological deficits following brain damage, termed anoso­

gnosia.  This symptom is the most common predictor of non-adherence to treatment, and it 
predicts higher relapse rates, increased number of involuntary treatments, poorer psycho­
social functioning, aggression, and a poorer course of illness.
Hostility and aggression can be associated with schizophrenia, although spontaneous 
or random assault is uncommon. Aggression is more frequent for younger males and for 
individuals with a past history of violence, non-adherence with treatment, substance 
abuse, and impulsivity. It should be noted that the vast majority of persons with schizo­
phrenia are not aggressive and are more frequently victimized than are individuals in the 
general population.
Currently, there are no radiological, laboratory, or psychometric tests for the disorder.

Currently, there are no radiological, laboratory, or psychometric tests for the disorder. 
Differences are evident in multiple brain regions between groups of healthy individuals

and persons with schizophrenia, including evidence from neuroimaging, neuropatholog- 
ical, and neurophysiological studies. Differences are also evident in cellular architecture, 
white matter connectivity, and gray matter volume in a variety of regions such as the pre- 
frontal and temporal cortices. Reduced overall brain volume has been observed, as well as 
increased brain volume reduction with age. Brain volume reductions with age are more 
pronounced in individuals with schizophrenia than in healthy individuals. Finally, indi­
viduals with schizophrenia appear to differ from individuals without the disorder in eye- 
tracking and electrophysiological indices.
Neurological soft signs common in individuals with schizophrenia include impairments 
in motor coordination, sensory integration, and motor sequencing of complex movements; 
left-right confusion; and disinhibition of associated movements. In addition, minor phys­
ical anomalies of the face and limbs may occur.

The lifetime prevalence of schizophrenia appears to be approximately 0.3%-0.7%, al­
though there is reported variation by race/ethnicity, across countries, and by geographic 
origin for immigrants and children of immigrants. The sex ratio differs across samples and 
populations: for example, an emphasis on negative symptoms and longer duration of dis­
order (associated with poorer outcome) shows higher incidence rates for males, whereas 
definitions allowing for the inclusion of more mood symptoms and brief presentations 
(associated with better outcome) show equivalent risks for both sexes.
The psychotic features of schizophrenia typically emerge between the late teens and the 
mid-30s; onset prior to adolescence is rare. The peak age at onset for the first psychotic ep­

isode is in the early- to mid-20s for males and in the late-20s for females. The onset may be 
abrupt or insidious, but the majority of individuals manifest a slow and gradual develop­
ment of a variety of clinically significant signs and symptoms. Half of these individuals 
complain of depressive symptoms. Earlier age at onset has traditionally been seen as a pre­
dictor of worse prognosis. However, the effect of age at onset is likely related to gender, 
with males having worse premorbid adjustment, lower educational achievement, more 
prominent negative symptoms and cognitive impairment, and in general a worse out­
come. Impaired cognition is common, and alterations in cognition are present during de­
velopment and precede the emergence of psychosis, taking the form of stable cognitive

velopment and precede the emergence of psychosis, taking the form of stable cognitive 
impairments during adulthood. Cognitive impairments may persist when other symptoms 
are in remission and contribute to the disability of the disease.
The predictors of course and outcome are largely unexplained, and course and outcome 
may not be reliably predicted. The course appears to be favorable in about 20% of those 
with schizophrenia, and a small number of individuals are reported to recover completely. 
However, most individuals with schizophrenia still require formal or informal daily living 
supports, and many remain chronically ill, with exacerbations and remissions of active 
symptoms, while others have a course of progressive deterioration.
Psychotic symptoms tend to diminish over the life course, perhaps in association with

Psychotic symptoms tend to diminish over the life course, perhaps in association with 
normal age-related declines in dopamine activity. Negative symptoms are more closely re­
lated to prognosis than are positive symptoms and tend to be the most persistent. Further­
more, cognitive deficits associated with the illness may not improve over the course of the 
illness.
The essential features of schizophrenia are the same in childhood, but it is more diffi­
cult to make the diagnosis. In children, delusions and hallucinations may be less elaborate 
than in adults, and visual hallucinations are more common and should be distinguished 
from normal fantasy play. Disorganized speech occurs in many disorders with childhood 
onset (e.g., autism spectrum disorder), as does disorganized behavior (e.g., attention-deficit/

hyperactivity disorder). These symptoms should not be attributed to schizophrenia with­
out due consideration of the more common disorders of childhood. Childhood-onset cases 
tend to resemble poor-outcome adult cases, with gradual onset and prominent negative 
symptoms. Children who later receive the diagnosis of schizophrenia are more likely to 
have experienced nonspecific emotional-behavioral disturbances and psychopathology, 
intellectual and language alterations, and subtle motor delays.
Late-onset cases (i.e., onset after age 40 years) are overrepresented by females, who 
may have married. Often, the course is characterized by a predominance of psychotic 
symptoms with preservation of affect and social functioning. Such late-onset cases can still 
meet the diagnostic criteria for schizophrenia, but it is not yet clear whether this is the 
same condition as schizophrenia diagnosed prior to mid-life (e.g., prior to age 55 years).

Environmental. Season of birth has been linked to the incidence of schizophrenia, in­
cluding late winter/early spring in some locations and summer for the deficit form of the 
disease. The incidence of schizophrenia and related disorders is higher for children grow­
ing up in an urban environment and for some minority ethnic groups.
Genetic and physiological. There is a strong contribution for genetic factors in deter­
mining risk for schizophrenia, although most individuals who have been diagnosed with 
schizophrenia have no family history of psychosis. Liability is conferred by a spectrum of 
risk alleles, common and rare, with each allele contributing only a small fraction to the to­
tal population variance. The risk alleles identified to date are also associated with other 
mental disorders, including bipolar disorder, depression, and autism spectrum disorder.

Pregnancy and birth complications with hypoxia and greater paternal age are associated 
with a higher risk of schizophrenia for the developing fetus. In addition, other prenatal 
and perinatal adversities, including stress, infection, malnutrition, maternal diabetes, and 
other medical conditions, have been linked with schizophrenia. However, the vast major­
ity of offspring with these risk factors do not develop schizophrenia.
Cultural and socioeconomic factors must be considered, particularly when the individual 
and the clinician do not share the same cultural and socioeconomic background. Ideas that 
appear to be delusional in one culture (e.g., witchcraft) may be commonly held in another.

appear to be delusional in one culture (e.g., witchcraft) may be commonly held in another. 
In some cultures, visual or auditory hallucinations with a religious content (e.g., hearing 
God's voice) are a normal part of religious experience. In addition, the assessment of dis­
organized speech may be made difficult by linguistic variation in narrative styles across 
cultures. The assessment of affect requires sensitivity to differences in styles of emotional 
expression, eye contact, and body language, which vary across cultures. If the assessment 
is conducted in a language that is different from the individual's primary language, care 
must be taken to ensure that alogia is not related to linguistic barriers. In certain cultures, 
distress may take the form of hallucinations or pseudo-hallucinations and overvalued

distress may take the form of hallucinations or pseudo-hallucinations and overvalued 
ideas that may present clinically similar to true psychosis but are normative to the pa­
tient's subgroup.
A number of features distinguish the clinical expression of schizophrenia in females and 
males. The general incidence of schizophrenia tends to be slightly lower in females, par­
ticularly among treated cases. The age at onset is later in females, with a second mid-life 
peak as described earlier (see the section "Development and Course" for this disorder). 
Symptoms tend to be more affect-laden among females, and there are more psychotic 
symptoms, as well as a greater propensity for psychotic symptoms to worsen in later life.

Other symptom differences include less frequent negative symptoms and disorganization. 
Finally, social functioning tends to remain better preserved in females. There are, how­
ever, frequent exceptions to these general caveats.
Suicide Risic
Approximately 5%-6% of individuals with schizophrenia die by suicide, about 20% attempt 
suicide on one or more occasions, and many more have significant suicidal ideation. Suicidal 
behavior is sometimes in response to command hallucinations to harm oneself or others. 
Suicide risk remains high over the whole lifespan for males and females, although it may be 
especially high for younger males with comorbid substance use. Other risk factors include 
having depressive symptoms or feelings of hopelessness and being unemployed, and the 
risk is higher, also, in the period after a psychotic episode or hospital discharge.
Functional Consequences of Schizoplirenia
Schizophrenia is associated with significant social and occupational dysfunction. Making

Schizophrenia is associated with significant social and occupational dysfunction. Making 
educational progress and maintaining employment are frequently impaired by avolition 
or other disorder manifestations, even when the cognitive skills are sufficient for the tasks 
at hand. Most individuals are employed at a lower level than their parents, and most, par­
ticularly men, do not marry or have limited social contacts outside of their family.
Major depressive or bipolar disorder with psychotic or catatonic features. The distinc­
tion between schizophrenia and major depressive or bipolar disorder with psychotic 
features or with catatonia depends on the temporal relationship between the mood distur­
bance and the psychosis, and on the severity of the depressive or manic symptoms. If de­
lusions or hallucinations occur exclusively during a major depressive or manic episode,

lusions or hallucinations occur exclusively during a major depressive or manic episode, 
the diagnosis is depressive or bipolar disorder with psychotic features.
Schizoaffective disorder. A diagnosis of schizoaffective disorder requires that a major 
depressive or manic episode occur concurrently with the active-phase symptoms and that 
the mood symptoms be present for a majority of the total duration of the active periods.
Schizophreniform disorder and brief psychotic disorder. These disorders are of shorter 
duration than schizophrenia as specified in Criterion C, which requires 6 months of symp­
toms. In schizophreniform disorder, the disturbance is present less than 6 months, and in 
brief psychotic disorder, symptoms are present at least 1 day but less than 1  month.
Delusional disorder. Delusional disorder can be distinguished from schizophrenia by

Delusional disorder. Delusional disorder can be distinguished from schizophrenia by 
the absence of the other symptoms characteristic of schizophrenia (e.g., delusions, prom­
inent auditory or visual hallucinations, disorganized speech, grossly disorganized or cata­
tonic behavior, negative symptoms).
Schizotypal personality disorder. Schizotypal personality disorder may be distinguished 
from schizophrenia by subthreshold symptoms that are associated with persistent person­
ality features.
Obsessive-compulsive disorder and body dysmorphic disorder. Individuals with 
obsessive-compulsive disorder and body dysmorphic disorder may present with poor or 
absent insight, and the preoccupations may reach delusional proportions. But these 
disorders are distinguished from schizophrenia by their prominent obsessions, compul­

sions, preoccupations with appearance or body odor, hoarding, or body-focused repeti­
tive behaviors.
Posttraumatic stress disorder. Posttraumatic stress disorder may include flashbacks that 
have a hallucinatory quality, and hypervigilance may reach paranoid proportions. But a trau-

matic event and characteristic symptom features relating to reliving or reacting to the event 
are required to make the diagnosis.
Autism spectrum disorder or communication disorders. These disorders may also have 
symptoms resembling a psychotic episode but are distinguished by their respective defi­
cits in social interaction with repetitive and restricted behaviors and other cognitive and 
communication deficits. An individual v^ith autism spectrum disorder or communication 
disorder must have symptoms that meet full criteria for schizophrenia, w ^ ith  prominent 
hallucinations or delusions for at least 1  month, in order to be diagnosed with schizophre­
nia as a comorbid condition.
Other mental disorders associated with a psychotic episode. The diagnosis of schizo­
phrenia is made only when the psychotic episode is persistent and not attributable to the 
physiological effects of a substance or another medical condition. Individuals with a de­

lirium or major or minor neurocognitive disorder may present with psychotic symptoms, 
but these would have a temporal relationship to the onset of cognitive changes consistent 
with those disorders. Individuals with substance/medication-induced psychotic disorder 
may present with symptoms characteristic of Criterion A for schizophrenia, but the sub­
stance/medication-induced psychotic disorder can usually be distinguished by the chron­
ological relationship of substance use to the onset and remission of the psychosis in the 
absence of substance use.
Rates of comorbidity with substance-related disorders are high in schizophrenia. Over 
half of individuals with schizophrenia have tobacco use disorder and smoke cigarettes

half of individuals with schizophrenia have tobacco use disorder and smoke cigarettes 
regularly. Comorbidity with anxiety disorders is increasingly recognized in schizophre­
nia. Rates of obsessive-compulsive disorder and panic disorder are elevated in individuals 
with schizophrenia compared with the general population. Schizotypal or paranoid per­
sonality disorder may sometimes precede the onset of schizophrenia.
Life expectancy is reduced in individuals with schizophrenia because of associated 
medical conditions. Weight gain, diabetes, metabolic syndrome, and cardiovascular and 
pulmonary disease are more common in schizophrenia than in the general population. 
Poor engagement in health maintenance behaviors (e.g., cancer screening, exercise) in­
creases the risk of chronic disease, but other disorder factors, including medications, life­

style, cigarette smoking, and diet, may also play a role. A shared vulnerability for 
psychosis and medical disorders may explain some of the medical comorbidity of schizo­
phrenia.
Schizoaffective Disorder
A. An uninterrupted period of illness during which there is a major mood episode (major  
depressive or manic) concurrent with Criterion A of schizophrenia.
Note: The major depressive episode must include Criterion A1 :  Depressed mood.
B. Delusions or hallucinations for 2 or more weeks in the absence of a major mood epi­
sode (depressive or manic) during the lifetime duration of the illness.
C. Symptoms that meet criteria for a major mood episode are present for the majority of  
the total duration of the active and residual portions of the illness.

D. The disturbance is not attributable to the effects of a substance (e.g., a drug of abuse,  

295.70 (F25.0) Bipolar type: This subtype applies if a manic episode is part of the pre­
sentation. Major depressive episodes may also occur.
295.70 (F25.1) Depressive type: This subtype applies if only major depressive epi­
sodes are part of the presentation.
schizoaffective disorder to indicate the presence of the comorbid catatonia.
The following course specifiers are only to be used after a 1  -year duration of the disorder  

Note: Diagnosis of schizoaffective disorder can be made without using this severity  
Note: For additional information on Development and Course (age-related factors). Risk

Note: For additional information on Development and Course (age-related factors). Risk 
and Prognostic Factors (environmental risk factors), Culture-Related Diagnostic Issues, 
and Gender-Related Diagnostic Issues, see the corresponding sections in schizophrenia, 
bipolar I and II disorders, and major depressive disorder in their respective chapters.
The diagnosis of schizoaffective disorder is based on the assessment of an uninterrupted 
period of illness during which the individual continues to display active or residual symp­
toms of psychotic illness. The diagnosis is usually, but not necessarily, made during the 
period of psychotic illness. At some time during the period. Criterion A for schizophrenia

has to be met. Criteria B (social dysfunction) and F (exclusion of autism spectrum disorder 
or other commimication disorder of childhood onset) for schizophrenia do not have to be 
met. In addition to meeting Criterion A for schizophrenia, there is a major mood episode 
(major depressive or manic) (Criterion A for schizoaffective disorder). Because loss of in­
terest or pleasure is common in schizophrenia, to meet Criterion A for schizoaffective dis­
order, the major depressive episode must include pervasive depressed mood (i.e., the 
presence of markedly diminished interest or pleasure is not sufficient). Episodes of de­
pression or mania are present for the majority of the total duration of the illness (i.e., after 
Criterion A has been met) (Criterion C for schizoaffective disorder). To separate schizoaf­
fective disorder from a depressive or bipolar disorder with psychotic features, delusions

fective disorder from a depressive or bipolar disorder with psychotic features, delusions 
or hallucinations must be present for at least 2 w ^eeks in the absence of a major mood epi­
sode (depressive or manic) at some point during the lifetime duration of the illness (Cri­
terion B for schizoaffective disorder). The symptoms must not be attributable to the effects 
of a substance or another medical condition (Criterion D for schizoaffective disorder).
Criterion C for schizoaffective disorder specifies that mood symptoms meeting criteria 
for a major mood episode must be present for the majority of the total duration of the ac­
tive and residual portion of the illness. Criterion C requires the assessment of mood symp­
toms for the entire course of a psychotic illness, which differs from the criterion in DSM-IV,

toms for the entire course of a psychotic illness, which differs from the criterion in DSM-IV, 
which required only an assessment of the current period of illness. If the mood symptoms 
are present for only a relatively brief period, the diagnosis is schizophrenia, not schizoaf­
fective disorder. When deciding whether an individual's presentation meets Criterion C, 
the clinician should review the total duration of psychotic illness (i.e., both active and re­
sidual symptoms) and determine when significant mood symptoms (untreated or in need 
of treatment with antidepressant and/or mood-stabilizing medication) accompanied the 
psychotic symptoms. This determination requires sufficient historical information and 
clinical judgment. For example, an individual with a 4-year history of active and residual 
symptoms of schizophrenia develops depressive and manic episodes that, taken together,

symptoms of schizophrenia develops depressive and manic episodes that, taken together, 
do not occupy more than 1  year during the 4-year history of psychotic illness. This presen­
tation would not meet Criterion C.
Occupational functioning is frequently impaired, but this is not a defining criterion (in 
contrast to schizophrenia). Restricted social contact and difficulties with self-care are as­
sociated with schizoaffective disorder, but negative symptoms may be less severe and less 
persistent than those seen in schizophrenia. Anosognosia (i.e., poor insight) is also com­

mon in schizoaffective disorder, but the deficits in insight may be less severe and perva­
sive than those in schizophrenia. Individuals with schizoaffective disorder may be at 
increased risk for later developing episodes of major depressive disorder or bipolar disor­
der if mood symptoms continue following the remission of symptoms meeting Criterion A 
for schizophrenia. There may be associated alcohol and other substance-related disorders.
There are no tests or biological measures that can assist in making the diagnosis of 
schizoaffective disorder. Whether schizoaffective disorder differs from schizophrenia 
with regard to associated features such as structural or functional brain abnormalities, 
cognitive deficits, or genetic risk factors is not clear.

Schizoaffective disorder appears to be about one-third as common as schizophrenia. Life­
time prevalence of schizoaffective disorder is estimated to be 0.3%. The incidence of

schizoaffective disorder is higher in females than in males, mainly due to an increased in­
cidence of the depressive type among females.
The typical age at onset of schizoaffective disorder is early adulthood, although onset can 
occur anywhere from adolescence to late in life. A significant number of individuals diag­
nosed with another psychotic illness initially will receive the diagnosis schizoaffective dis­
order later when the pattern of mood episodes has become more apparent. With the 
current diagnostic Criterion C, it is expected that the diagnosis for some individuals will 
convert from schizoaffective disorder to another disorder as mood symptoms become less 
prominent. The prognosis for schizoaffective disorder is somewhat better than the prog­
nosis for schizophrenia but worse than the prognosis for mood disorders.
Schizoaffective disorder may occur in a variety of temporal patterns. The following is

Schizoaffective disorder may occur in a variety of temporal patterns. The following is 
a typical pattern: An individual may have pronounced auditory hallucinations and per­
secutory delusions for 2 months before the onset of a prominent major depressive episode. 
The psychotic symptoms and the full major depressive episode are then present for 3 months. 
Then, the individual recovers completely from the major depressive episode, but the psy­
chotic symptoms persist for another month before they too disappear. During this period 
of illness, the individual's symptoms concurrently met criteria for a major depressive ep­
isode and Criterion A for schizophrenia, and during this same period of illness, auditory 
hallucinations and delusions were present both before and after the depressive phase. The 
total period of illness lasted for about 6 months, with psychotic symptoms alone present

total period of illness lasted for about 6 months, with psychotic symptoms alone present 
during the initial 2 months, both depressive and psychotic symptoms present during the 
next 3 months, and psychotic symptoms alone present during the last month. In this in­
stance, the duration of the depressive episode was not brief relative to the total duration of 
the psychotic disturbance, and thus the presentation qualifies for a diagnosis of schizoaf­
fective disorder.
The expression of psychotic symptoms across the lifespan is variable. Depressive or 
manic symptoms can occur before the onset of psychosis, during acute psychotic episodes, 
during residual periods, and after cessation of psychosis. For example, an individual 
might present with prominent mood symptoms during the prodromal stage of schizo­

phrenia. This pattern is not necessarily indicative of schizoaffective disorder, since it is the 
co-occurrence of psychotic and mood symptoms that is diagnostic. For an individual with 
symptoms that clearly meet the criteria for schizoaffective disorder but who on further fol­
low-up only presents with residual psychotic symptoms (such as subthreshold psychosis 
and/or prominent negative symptoms), the diagnosis may be changed to schizophrenia, 
as the total proportion of psychotic illness compared with mood symptoms becomes more 
prominent. Schizoaffective disorder, bipolar type, may be more common in young adults, 
whereas schizoaffective disorder, depressive type, may be more common in older adults.
Genetic and physiological. Among individuals with schizophrenia, there may be an in­

creased risk for schizoaffective disorder in first-degree relatives. The risk for schizoaffec­
tive disorder may be increased among individuals who have a first-degree relative with 
schizophrenia, bipolar disorder, or schizoaffective disorder.
Culture-Reiated Diagnostic Issues
and the clinician do not share the same cultural and economic background. Ideas that ap­
pear to be delusional in one culture (e.g., witchcraft) may be commonly held in another. 
There is also some evidence in the literature for the overdiagnosis of schizophrenia com­

pared with schizoaffective disorder in African American and Hispanic populations, so 
care must be tal^en to ensure a culturally appropriate evaluation that includes both psy­
chotic and affective symptoms.
The lifetime risk of suicide for schizophrenia and schizoaffective disorder is 5%, and the 
presence of depressive symptoms is correlated w ^ ith  a higher risk for suicide. There is ev­
idence that suicide rates are higher in North American populations than in European, 
Eastern European, South American, and Indian populations of individuals with schizo­
phrenia or schizoaffective disorder.
Functional Consequences of Scliizoaffective Disorder
Schizoaffective disorder is associated with social and occupational dysfunction, but dys­
function is not a diagnostic criterion (as it is for schizophrenia), and there is substantial 
variability between individuals diagnosed with schizoaffective disorder.

Other mental disorders and medical conditions. A wide variety of psychiatric and med­
ical conditions can manifest with psychotic and mood symptoms that must be considered 
in the differential diagnosis of schizoaffective disorder. These include psychotic disorder 
due to another medical condition; delirium; major neurocognitive disorder; substance/ 
medication-induced psychotic disorder or neurocognitive disorder; bipolar disorders 
with psychotic features; major depressive disorder with psychotic features; depressive or 
bipolar disorders with catatonic features; schizotypal, schizoid, or paranoid personality 
disorder; brief psychotic disorder; schizophreniform disorder; schizophrenia; delusional 
disorder; and other specified and unspecified schizophrenia spectrum and other psychotic

disorder; and other specified and unspecified schizophrenia spectrum and other psychotic 
disorders. Medical conditions and substance use can present with a combination of psy­
chotic and mood symptoms, and thus psychotic disorder due to another medical condition 
needs to be excluded. Distinguishing schizoaffective disorder from schizophrenia and 
from depressive and bipolar disorders with psychotic features is often difficult. Criterion 
C is designed to separate schizoaffective disorder from schizophrenia, and Criterion B is 
designed to distinguish schizoaffective disorder from a depressive or bipolar disorder 
with psychotic features. More specifically, schizoaffective disorder can be distinguished 
from a depressive or bipolar disorder with psychotic features due to the presence of prom­
inent delusions and/or hallucinations for at least 2 weeks in the absence of a major mood

inent delusions and/or hallucinations for at least 2 weeks in the absence of a major mood 
episode. In contrast, in depressive or bipolar disorders with psychotic features, the psy­
chotic features primarily occur during the mood episode(s). Because the relative propor­
tion of mood to psychotic symptoms may change over time, the appropriate diagnosis 
may change from and to schizoaffective disorder (e.g., a diagnosis of schizoaffective dis­
order for a severe and prominent major depressive episode lasting 3 months during the 
first 6 months of a persistent psychotic illness would be changed to schizophrenia if active 
psychotic or prominent residual symptoms persist over several years without a recurrence 
of another mood episode).
Psychotic disorder due to another medical condition. Other medical conditions and 
substance use can manifest with a combination of psychotic and mood symptoms, and

substance use can manifest with a combination of psychotic and mood symptoms, and 
thus psychotic disorder due to another medical condition needs to be excluded.
Schizophrenia, bipolar, and depressive disorders. Distinguishing schizoaffective dis­
order from schizophrenia and from depressive and bipolar disorders with psychotic fea­
tures is often difficult. Criterion C is designed to separate schizoaffective disorder from 
schizophrenia, and Criterion B is designed to distinguish schizoaffective disorder from a

depressive or bipolar disorder with psychotic features. More specifically, schizoaffective 
disorder can be distinguished from a depressive or bipolar disorder with psychotic features 
based on the presence of prominent delusions and/or hallucinations for at least 2 weeks in 
the absence of a major mood episode. In contrast, in depressive or bipolar disorder with 
psychotic features, the psychotic features primarily occur during the mood episode(s). Be­
cause the relative proportion of mood to psychotic symptoms may change over time, the 
appropriate diagnosis may change from and to schizoaffective disorder. (For example, a 
diagnosis of schizoaffective disorder for a severe and prominent major depressive episode 
lasting 3 months during the first 6 months of a chronic psychotic illness would be changed 
to schizophrenia if active psychotic or prominent residual symptoms persist over several 
years without a recurrence of another mood episode.)

Many individuals diagnosed with schizoaffective disorder are also diagnosed with other 
mental disorders, especially substance use disorders and anxiety disorders. Similarly, the 
incidence of medical conditions is increased above base rate for the general population 
and leads to decreased life expectancy.
Substance/Medication-Induced  
Psychotic Disorder
A. Presence of one or both of the following symptoms:
B. There is evidence from the history, physical examination, or laboratory findings of both  
(1)and (2):
1. The symptoms in Criterion A developed during or soon after substance intoxication  
or withdrawal or after exposure to a medication.
2. The involved substance/medication is capable of producing the symptoms in Crite­
rion A.

rion A.
C. The disturbance is not better explained by a psychotic disorder that is not substance/  
medication-induced. Such evidence of an independent psychotic disorder could in­
clude the following:
The symptoms preceded the onset of the substance/medication use; the symptoms  
persist for a substantial period of time (e.g., about 1  month) after the cessation of  
acute withdrawal or severe intoxication: or there is other evidence of an indepen­
dent non-substance/medication-induced psychotic disorder (e.g., a history of recur­
rent non-substance/medication-related episodes).
D. The disturbance does not occur exclusively during the course of a delirium.
E. The disturbance causes clinically significant distress or impairment in social, occupa­
tional, or other important areas of functioning.

Note: This diagnosis should be made instead of a diagnosis of substance intoxication or  
substance withdrawal only when the symptoms in Criterion A predominate in the clinical  
picture and when they are sufficiently severe to warrant clinical attention.

Coding note: The ICD-9-CM and ICD-10-CIVI codes for the [specific substance/medica-  
tion]-induced psychotic disorders are indicated in the table below. Note that the ICD-10-  
CM code depends on whether or not there is a comorbid substance use disorder present  
for the same class of substance. If a mild substance use disorder is comorbid with the sub­
stance-induced psychotic disorder, the 4th position character is “ 1 a n d  the clinician should  
record “ m ild [substance] use disorder”  before the substance-induced psychotic disorder  
(e.g., “ m ild cocaine use disorder with cocaine-induced psychotic disorder” ). If a moderate or  
severe substance use disorder is comorbid with the substance-induced psychotic disor­
der, the 4th position character is “ 2,”  and the clinician should record “ moderate [substance]  
use disorder”  or “ severe [substance] use disorder,”  depending on the severity of the co­

morbid substance use disorder. If there is no comorbid substance use disorder (e.g., after  
a one-time heavy use of the substance), then the 4th position character is “ 9,”  and the cli­
nician should record only the substance-induced psychotic disorder.
ICD-10-CM
ICD-9-CMWith use  
disorder,  
mildWith use  
disorder,  
moderate  
or severeWithout
use
disorder
Alcohol 291.9 F10.159 FI 0.259 FI 0.959
Cannabis 292.9 F12.159 FI 2.259 FI 2.959
Phencyclidine 292.9 F16.159 FI 6.259 FI 6.959
Other hallucinogen 292.9 FI 6.159 FI 6.259 FI 6.959
Inhalant 292.9 F18.159 FI 8.259 FI 8.959
Sedative, hypnotic, or  
anxiolytic292.9 FI 3.159 FI 3.259 FI 3.959
Amphetamine (or other  
stimulant)292.9 FI 5.159 FI 5.259 FI 5.959
Cocaine 292.9 F14.159 FI 4.259 FI 4.959

Other (or unknown) substance 292.9 FI 9.159 FI 9.259 FI 9.959
Specify  if (see Table 1  in  the chapter “ Substance-Related and Addictive Disorders”  for diag­
noses associated with substance class):
With onset during intoxication: If the criteria are met for intoxication with the sub­
stance and the symptoms develop during intoxication.
With onset during withdrawal: If the criteria are met for withdrawal from the sub­
stance and the symptoms develop during, or shortly after, withdrawal.
including delusions, hallucinations, abnormal psychomotor behavior, and negative  
symptoms. Each of these symptoms may be rated for its current severity (most severe

symptoms. Each of these symptoms may be rated for its current severity (most severe  
in the last 7 days) on a 5-point scale ranging from 0 (not present) to 4 (present and  
severe). (See Clinician-Rated Dimensions of Psychosis Symptom Severity in the chap­
ter “ Assessment Measures.”)
Note: Diagnosis of substance/medication-induced psychotic disorder can be made  
without using this severity specifier.

ICD-9-CM. The name of the substance/medication-induced psychotic disorder begins 
with the specific substance (e.g., cocaine, dexamethasone) that is presumed to be causing 
the delusions or hallucinations. The diagnostic code is selected from the table included in 
the criteria set, which is based on the drug class. For substances that do not fit into any of 
the classes (e.g., dexamethasone), the code for ''other substance" should be used; and in 
cases in which a substance is judged to be an etiological factor but the specific class of sub­
stance is unknown, the category "unknown substance" should be used.
The name of the disorder is followed by the specification of onset (i.e., onset during in­
toxication, onset during withdrawal). Unlike the recording procedures for ICD-IO-CM, 
which combine the substance-induced disorder and substance use disorder into a single 
code, for ICD-9-CM a separate diagnostic code is given for the substance use disorder. For

code, for ICD-9-CM a separate diagnostic code is given for the substance use disorder. For 
example, in the case of delusions occurring during intoxication in a man with a severe co­
caine use disorder, the diagnosis is 292.9 cocaine-induced psychotic disorder, with onset 
during intoxication. An additional diagnosis of 304.20 severe cocaine use disorder is also 
given. When more than one substance is judged to play a significant role in the development 
of psychotic symptoms, each should be listed separately (e.g., 292.9 cannabis-induced psy­
chotic disorder with onset during intoxication, with severe cannabis use disorder; 292.9 
phencyclidine-induced psychotic disorder, with onset during intoxication, with mild 
phencyclidine use disorder).
ICD-10-CM. The name of the substance/medication-induced psychotic disorder begins

ICD-10-CM. The name of the substance/medication-induced psychotic disorder begins 
the criteria set, which is based on the drug class and presence or absence of a comorbid 
substance use disorder. For substances that do not fit into any of the classes (e.g., dexa­
methasone), the code for "other substance" with no comorbid substance use should be 
used; and in cases in which a substance is judged to be an etiological factor but the specific 
class of substance is unknown, the category "unknown substance" with no comorbid sub­
stance use should be used.
When recording the name of the disorder, the comorbid substance use disorder (if any)

When recording the name of the disorder, the comorbid substance use disorder (if any) 
is listed first, followed by the word "with," followed by the name of the substance-induced 
psychotic disorder, followed by the specification of onset (i.e., onset during intoxication, 
onset during withdrawal). For example, in the case of delusions occurring during intoxi­
cation in a man with a severe cocaine use disorder, the diagnosis is F14.259 severe cocaine 
use disorder with cocaine-induced psychotic disorder, with onset during intoxication. A 
separate diagnosis of the comorbid severe cocaine use disorder is not given. If the sub­
stance-induced psychotic disorder occurs without a comorbid substance use disorder 
(e.g., after a one-time heavy use of the substance), no accompanying substance use disor­

der is noted (e.g., F16.959 phencyclidine-induced psychotic disorder, with onset during in­
toxication). When more than one substance is judged to play a significant role in the 
development of psychotic symptoms, each should be listed separately (e.g., F12.259 severe 
cannabis use disorder with cannabis-induced psychotic disorder, with onset during intox­
ication; F16.159 mild phencyclidine use disorder with phencyclidine-induced psychotic 
disorder, with onset during intoxication).
The essential features of substance/medication-induced psychotic disorder are prominent 
delusions and/or hallucinations (Criterion A) that are judged to be due to the physiolog­
ical effects of a substance/medication (i.e., a drug of abuse, a medication, or a toxin expo­

sure) (Criterion B). Hallucinations that the individual realizes are substance/medication- 
induced are not included here and instead would be diagnosed as substance intoxication

or substance withdrawal with the accompanying specifier "with perceptual disturbances" 
(applies to alcohpl withdrawal; cannabis intoxication; sedative, hypnotic, or anxiolytic 
withdrawal; and stimulant intoxication).
A substance/medication-induced psychotic disorder is distinguished from a primary 
psychotic disorder by considering the onset, course, and other factors. For drugs of abuse, 
there must be evidence from the history, physical examination, or laboratory findings of 
substance use, intoxication, or withdrawal. Substance/medication-induced psychotic 
disorders arise during or soon after exposure to a medication or after substance intoxica­
tion or withdrawal but can persist for weeks, whereas primary psychotic disorders may 
precede the onset of substance/medication use or may occur during times of sustained ab­
stinence. Once initiated, the psychotic symptoms may continue as long as the substance/

stinence. Once initiated, the psychotic symptoms may continue as long as the substance/ 
medication use continues. Another consideration is the presence of features that are atyp­
ical of a primary psychotic disorder (e.g., atypical age at onset or course). For example, the 
appearance of delusions de novo in a person older than 35 years without a known history 
of a primary psychotic disorder should suggest the possibility of a substance/medication- 
induced psychotic disorder. Even a prior history of a primary psychotic disorder does not 
rule out the possibility of a substance/medication-induced psychotic disorder. In contrast, 
factors that suggest that the psychotic symptoms are better accounted for by a primary 
psychotic disorder include persistence of psychotic symptoms for a substantial period of

psychotic disorder include persistence of psychotic symptoms for a substantial period of 
time (i.e., a month or more) after the end of substance intoxication or acute substance with­
drawal or after cessation of medication use; or a history of prior recurrent primary psy­
chotic disorders. Other causes of psychotic symptoms must be considered even in an 
individual with substance intoxication or withdrawal, because substance use problems are 
not uncommon among individuals with non-substance/medication-induced psychotic 
disorders.
In addition to the four symptom domain areas identified in the diagnostic criteria, the 

Psychotic disorders can occur in association with intoxication with the following classes of 
substances: alcohol; cannabis; hallucinogens, including phencyclidine and related sub­
stances; inhalants; sedatives, hypnotics, and anxiolytics; stimulants (including cocaine); 
and other (or unknown) substances. Psychotic disorders can occur in association with with­
drawal from the following classes of substances: alcohol; sedatives, hypnotics, and anxio­
lytics; and other (or unknown) substances.
Some of the medications reported to evoke psychotic symptoms include anesthetics 
and analgesics, anticholinergic agents, anticonvulsants, antihistamines, antihypertensive 
and cardiovascular medications, antimicrobial medications, antiparkinsonian medica­
tions, chemotherapeutic agents (e.g., cyclosporine, procarbazine), corticosteroids, gastro­

intestinal medications, muscle relaxants, nonsteroidal anti-inflammatory medications, 
other over-the-counter medications (e.g., phenylephrine, pseudoephedrine), antidepres­
sant medication, and disulfiram. Toxins reported to induce psychotic symptoms include 
anticholinesterase, organophosphate insecticides, sarin and other nerve gases, carbon 
monoxide, carbon dioxide, and volatile substances such as fuel or paint.
Prevalence of substance/medication-induced psychotic disorder in the general popula­
tion is unknown. Between 7% and 25% of individuals presenting with a first episode of 
psychosis in different settings are reported to have substance/medication-induced psy­
chotic disorder.

The initiation of the disorder may vary considerably with the substance. For example, 
smoking a high dose of cocaine may produce psychosis within minutes, whereas days or 
weeks of high-dose alcohol or sedative use may be required to produce psychosis. Alco­
hol-induced psychotic disorder, with hallucinations, usually occurs only after prolonged, 
heavy ingestion of alcohol in individuals who have moderate to severe alcohol use disorder, 
and the hallucinations are generally auditory in nature.
Psychotic disorders induced by amphetamine and cocaine share similar clinical fea­
tures. Persecutory delusions may rapidly develop shortly after use of amphetamine or a 
similarly acting sympathomimetic. The hallucination of bugs or vermin crawling in or un­
der the skin (formication) can lead to scratching and extensive skin excoriations. Cannabis- 
induced psychotic disorder may develop shortly after high-dose cannabis use and usually

induced psychotic disorder may develop shortly after high-dose cannabis use and usually 
involves persecutory delusions, marked anxiety, emotional lability, and depersonalization. 
The disorder usually remits within a day but in some cases may persist for a few days.
Substance/medication-induced psychotic disorder may at times persist when the offend­
ing agent is removed, such that it may be difficult initially to distinguish it from an indepen­
dent psychotic disorder. Agents such as amphetamines, phencyclidine, and cocaine have been 
reported to evoke temporary psychotic states that can sometimes persist for weeks or longer 
despite removal of the agent and treatment with neuroleptic medication. In later life, poly­
pharmacy for medical conditions and exposure to medications for parkinsonism, cardiovas­

cular disease, and other medical disorders may be associated with a greater likelihood of 
psychosis induced by prescription medications as opposed to substances of abuse.
Diagnostic iVlarlcers
With substances for which relevant blood levels are available (e.g., blood alcohol level, 
other quantifiable blood levels such as digoxin), the presence of a level consistent with tox­
icity may increase diagnostic certainty.
Substance/iVledication-induced Psycliotic Disorder
Substance/medication-induced psychotic disorder is typically severely disabling and 
consequently is observed most frequently in emergency rooms, as individuals are often 
brought to the acute-care setting when it occurs. However, the disability is typically self­

limited and resolves upon removal of the offending agent.
Substance intoxication or substance withdrawal. Individuals intoxicated with stimu­
lants, cannabis, the opioid meperidine, or phencyclidine, or those withdrawing from alco­
hol or sedatives, may experience altered perceptions that they recognize as drug effects. If 
reality testing for these experiences remains intact (i.e., the individual recognizes that the 
perception is substance induced and neither believes in nor acts on it), the diagnosis is not 
substance/medication-induced psychotic disorder. Instead, substance intoxication or 
substance withdrawal, with perceptual disturbances, is diagnosed (e.g., cocaine intoxica­
tion, with perceptual disturbances). "Flashback" hallucinations that can occur long after

tion, with perceptual disturbances). "Flashback" hallucinations that can occur long after 
the use of hallucinogens has stopped are diagnosed as hallucinogen persisting perception 
disorder. If substance/medication-induced psychotic symptoms occur exclusively during 
the course of a delirium, as in severe forms of alcohol withdrawal, the psychotic symptoms 
are considered to be an associated feature of the delirium and are not diagnosed sepa­
rately. Delusions in the context of a major or mild neurocognitive disorder would be di­
agnosed as major or mild neurocognitive disorder, with behavioral disturbance.

Primary psychotic disorder. A substance/medication-induced psychotic disorder is 
distinguished from a primary psychotic disorder, such as schizophrenia, schizoaffective 
disorder, delusional disorder, brief psychotic disorder, other specified schizophrenia 
spectrum and other psychotic disorder, or unspecified schizophrenia spectrum and other 
psychotic disorder, by the fact that a substance is judged to be etiologically related to the 
symptoms.
Psychotic disorder due to another medical condition. A substance/medication-induced 
psychotic disorder due to a prescribed treatment for a mental or medical condition must 
have its onset while the individual is receiving the medication (or during withdrawal, if 
there is a withdrawal syndrome associated with the medication). Because individuals with 
medical conditions often take medications for those conditions, the clinician must con­
sider the possibility that the psychotic symptoms are caused by the physiological conse­

quences of the medical condition rather than the medication, in which case psychotic 
disorder due to another medical condition is diagnosed. The history often provides the 
primary basis for such a judgment. At times, a change in the treatment for the medical con­
dition (e.g., medication substitution or discontinuation) may be needed to determine em­
pirically for that individual whether the medication is the causative agent. If the clinician 
has ascertained that the disturbance is attributable to both a medical condition and sub­
stance/medication use, both diagnoses (i.e., psychotic disorder due to another medical 
condition and substance/medication-induced psychotic disorder) may be given.
Psychotic Disorder  
Due to Another Medical Condition
A. Prominent hallucinations or delusions.

B. There is evidence from the history, physical examination, or laboratory findings that the  
disturbance is the direct pathophysiological consequence of another medical condi­
tion.
C. The disturbance is not better explained by another mental disorder.
Code based on predominant symptom:
293.81 (F06.2) With delusions: If delusions are the predominant symptom.
293.82 (F06.0) With hallucinations: If hallucinations are the predominant symptom.
Coding note: Include the name of the other medical condition in the name of the mental

Coding note: Include the name of the other medical condition in the name of the mental  
disorder (e.g., 293.81 [F06.2] psychotic disorder due to malignant lung neoplasm, with de­
lusions). The other medical condition should be coded and listed separately immediately  
before the psychotic disorder due to the medical condition (e.g., 162.9 [C34.90] malignant  
lung neoplasm; 293.81 [F06.2] psychotic disorder due to malignant lung neoplasm, with  
delusions).
in the last 7 days) on a 5-point scale ranging from 0 (not present) to 4 (present and

ter “ Assessment Measures.” )
Note: Diagnosis of psychotic disorder due to another medical condition can be made  
In addition to the symptom domain areas identified in the diagnostic criteria, the assess­
ment of cognition, depression, and mania symptom domains is vital for making critically 
important distinctions between the various schizophrenia spectrum and other psychotic 
The essential features of psychotic disorder due to another medical condition are promi­
nent delusions or hallucinations that are judged to be attributable to the physiological ef­
fects of another medical condition and are not better explained by another mental disorder 
(e.g., the symptoms are not a psychologically mediated response to a severe medical con­

dition, in which case a diagnosis of brief psychotic disorder, with marked stressor, would 
be appropriate).
Hallucinations can occur in any sensory modality (i.e., visual, olfactory, gustatory, tac­
tile, or auditory), but certain etiological factors are likely to evoke specific hallucinatory 
phenomena. Olfactory hallucinations are suggestive of temporal lobe epilepsy. Hallucina­
tions may vary from simple and unformed to highly complex and organized, depending 
on etiological and environmental factors. Psychotic disorder due to another medical con­
dition is generally not diagnosed if the individual maintains reality testing for the hallu­
cinations and appreciates that they result from the medical condition. Delusions may have

cinations and appreciates that they result from the medical condition. Delusions may have 
a variety of themes, including somatic, grandiose, religious, and, most commonly, perse­
cutory. On the whole, however, associations between delusions and particular medical 
conditions appear to be less specific than is the case for hallucinations.
In determining whether the psychotic disturbance is attributable to another medical 
condition, the presence of a medical condition must be identified and considered to be the 
etiology of the psychosis through a physiological mechanism. Although there are no 
infallible guidelines for determining whether the relationship between the psychotic distur­
bance and the medical condition is etiological, several considerations provide some guidance. 
One consideration is the presence of a temporal association between the onset, exacerba­

tion, or remission of the medical condition and that of the psychotic disturbance. A second 
consideration is the presence of features that are atypical for a psychotic disorder (e.g., 
atypical age at onset or presence of visual or olfactory hallucinations). The disturbance must 
also be distinguished from a substance/medication-induced psychotic disorder or an­
other mental disorder (e.g., an adjustment disorder).
The temporal association of the onset or exacerbation of the medical condition offers the 
greatest diagnostic certainty that the delusions or hallucinations are attributable to a med­
ical condition. Additional factors may include concomitant treatments for the underlying

ical condition. Additional factors may include concomitant treatments for the underlying 
medical condition that confer a risk for psychosis independently, such as steroid treatment 
for autoimmune disorders.
Prevalence rates for psychotic disorder due to another medical condition are difficult to es­
timate given the wide variety of underlying medical etiologies. Lifetime prevalence has

been estimated to range from 0.21% to 0.54%. When the prevalence findings are stratified 
by age group, individuals older than 65 years have a significantly greater prevalence of 
0.74% compared with those in younger age groups. Rates of psychosis also vary according 
to the underlying medical condition; conditions most commonly associated with psy­
chosis include untreated endocrine and metabolic disorders, autoimmune disorders (e.g., 
systemic lupus erythematosus, N-methyl-D-aspartate (NMDA) receptor autoimmune en­
cephalitis), or temporal lobe epilepsy. Psychosis due to epilepsy has been further differ­
entiated into ictal, postictal, and interictal psychosis. The most common of these is postictal 
psychosis, observed in 2%-7.8% of epilepsy patients. Among older individuals, there may 
be a higher prevalence of the disorder in females, although additional gender-related fea­
tures are not clear and vary considerably with the gender distributions of the underlying

tures are not clear and vary considerably with the gender distributions of the underlying 
medical conditions.
Psychotic disorder due to another medical condition may be a single transient state or it 
may be recurrent, cycling with exacerbations and remissions of the underlying medical 
condition. Although treatment of the underlying medical condition often results in a res­
olution of the psychosis, this is not always the case, and psychotic symptoms may persist 
long after the medical event (e.g., psychotic disorder due to focal brain injury). In the con­
text of chronic conditions such as multiple sclerosis or chronic interictal psychosis of epi­
lepsy, the psychosis may assume a long-term course.
The expression of psychotic disorder due to another medical condition does not differ 
substantially in phenomenology depending on age at occurrence. However, older age

substantially in phenomenology depending on age at occurrence. However, older age 
groups have a higher prevalence of the disorder, which is most likely due to the increasing 
medical burden associated with advanced age and the cumulative effects of deleterious 
exposures and age-related processes (e.g., atherosclerosis). The nature of the underlying 
medical conditions is likely to change across the lifespan, with younger age groups more 
affected by epilepsy, head trauma, autoimmune, and neoplastic diseases of early to mid­
life, and older age groups more affected by stroke disease, anoxic events, and multiple sys­
tem comorbidities. Underlying factors with increasing age, such as preexisting cognitive 
impairment as well as vision and hearing impairments, may incur a greater risk for psy­
chosis, possibly by serving to lower the threshold for experiencing psychosis.

Course modifiers. Identification and treatment of the underlying medical condition has 
the greatest impact on course, although preexisting central nervous system injury may 
confer a worse course outcome (e.g., head trauma, cerebrovascular disease).
The diagnosis of psychotic disorder due to another medical condition depends on the clin­
ical condition of each individual, and the diagnostic tests will vary according to that con­
dition. A variety of medical conditions may cause psychotic symptoms. These include 
neurological conditions (e.g., neoplasms, cerebrovascular disease, Huntington's disease, 
multiple sclerosis, epilepsy, auditory or visual nerve injury or impairment, deafness,

multiple sclerosis, epilepsy, auditory or visual nerve injury or impairment, deafness, 
migraine, central nervous system infections), endocrine conditions (e.g., hyper- and hypo­
thyroidism, hyper- and hypoparathyroidism, hyper- and hypoadrenocorticism), metabolic 
conditions (e.g., hypoxia, hypercarbia, hypoglycemia), fluid or electrolyte imbalances, 
hepatic or renal diseases, and autoimmune disorders with central nervous system involve­
ment (e.g., systemic lupus erythematosus). The associated physical examination findings, 
laboratory findings, and patterns of prevalence or onset reflect the etiological medical 
condition.

Suicide Risl(
Suicide risk in the context of psychotic disorder due to another medical condition is not 
clearly delineated, although certain conditions such as epilepsy and multiple sclerosis are 
associated with increased rates of suicide, which may be further increased in the presence 
of psychosis.
Functional Consequences of Psycliotic Disorder  
Due to Another IVIedical Condition
Functional disability is typically severe in the context of psychotic disorder due to another 
medical condition but will vary considerably by the type of condition and likely improve 
with successful resolution of the condition.
Delirium. Hallucinations and delusions commonly occur in the context of a delirium; 
however, a separate diagnosis of psychotic disorder due to another medical condition is 
not given if the disturbance occurs exclusively during the course of a delirium. Delusions 
in the context of a major or mild neurocognitive disorder would be diagnosed as major or

in the context of a major or mild neurocognitive disorder would be diagnosed as major or 
mild neurocognitive disorder, with behavioral disturbance.
Substance/medication-induced psychotic disorder. If there is evidence of recent or 
prolonged substance use (including medications with psychoactive effects), withdrawal 
from a substance, or exposure to a toxin (e.g., LSD [lysergic acid diethylamide] intoxica­
tion, alcohol withdrawal), a substance/medication-induced psychotic disorder should be 
considered. Symptoms that occur during or shortly after (i.e., within 4 weeks) of substance 
intoxication or withdrawal or after medication use may be especially indicative of a sub­
stance-induced psychotic disorder, depending on the character, duration, or amount of 
the substance used. If the clinician has ascertained that the disturbance is due to both a

the substance used. If the clinician has ascertained that the disturbance is due to both a 
medical condition and substance use, both diagnoses (i.e., psychotic disorder due to an­
other medical condition and substance/medication-induced psychotic disorder) can be 
given.
Psychotic disorder. Psychotic disorder due to another medical condition must be distin­
guished from a psychotic disorder (e.g., schizophrenia, delusional disorder, schizoaffective 
disorder) or a depressive or bipolar disorder, with psychotic features. In psychotic disor­
ders and in depressive or bipolar disorders, with psychotic features, no specific and direct 
causative physiological mechanisms associated with a medical condition can be demon­
strated. Late age at onset and the absence of a personal or family history of schizophrenia 
or delusional disorder suggest the need for a thorough assessment to rule out the diagno­

sis of psychotic disorder due to another medical condition. Auditory hallucinations that 
involve voices speaking complex sentences are more characteristic of schizophrenia than 
of psychotic disorder due to a medical condition. Other types of hallucinations (e.g., vi­
sual, olfactory) commonly signal a psychotic disorder due to another medical condition or 
a substance/medication-induced psychotic disorder.
Psychotic disorder due to another medical condition in individuals older than 80 years is 
associated with concurrent major neurocognitive disorder (dementia).

Catatonia
Catatonia can occur in the context of several disorders, including neurodevelopmental, 
psychotic, bipolar, depressive disorders, and other medical conditions (e.g., cerebral folate 
deficiency, rare autoimmune and paraneoplastic disorders. The manual does not treat 
catatonia as an independent class but recognizes a) catatonia associated with another men­
tal disorder (i.e., a neurodevelopmental, psychotic disorder, a bipolar disorder, a depres­
sive disorder, or other mental disorder), b) catatonic disorder due to another medical 
condition, and c) unspecified catatonia.
Catatonia is defined by the presence of three or more of 12 psychomotor features in the 
diagnostic criteria for catatonia associated with another mental disorder and catatonic dis­
order due to another medical condition. The essential feature of catatonia is a marked psy­
chomotor disturbance that may involve decreased motor activity, decreased engagement

chomotor disturbance that may involve decreased motor activity, decreased engagement 
during interview or physical examination, or excessive and peculiar motor activity. The 
clinical presentation of catatonia can be puzzling, as the psychomotor disturbance may 
range from marked unresponsiveness to marked agitation. Motoric immobility may be se­
vere (stupor) or moderate (catalepsy and waxy flexibility). Similarly, decreased engage­
ment may be severe (mutism) or moderate (negativism). Excessive and peculiar motor 
behaviors can be complex (e.g., stereotypy) or simple (agitation) and may include echola- 
lia and echopraxia. In extreme cases, the same individual may wax and wane between de­
creased and excessive motor activity. The seemingly opposing clinical features and 
variable manifestations of the diagnosis contribute to a lack of awareness and decreased

variable manifestations of the diagnosis contribute to a lack of awareness and decreased 
recognition of catatonia. During severe stages of catatonia, the individual may need care­
ful supervision to avoid self-harm or harming others. There are potential risks from mal­
nutrition, exhaustion, hyperpyrexia and self-inflicted injury.
Catatonia Associated With Another  
Mental Disorder (Catatonia Specifier)
293.89 (F06.1)
A. The clinical picture is dominated by three (or more) of the following symptoms:
1. Stupor (i.e., no psychomotor activity; not actively relating to environment).
2. Catalepsy (i.e., passive induction of a posture held against gravity).
3. Waxy flexibility (i.e., slight, even resistance to positioning by examiner).
4. Mutism (i.e., no, or very little, verbal response [exclude if known aphasia]).
5. Negativism (i.e., opposition or no response to instructions or external stimuli).

6. Posturing (i.e., spontaneous and active maintenance of a posture against gravity).
7. Mannerism (i.e., odd, circumstantial caricature of normal actions).
8. Stereotypy (i.e., repetitive, abnormally frequent, non-goal-directed movements).
9. Agitation, not influenced by external stimuli.
10. Grimacing.
11. Echolalia (i.e., mimicking another’s speech).
12. Echopraxia (i.e., mimicking another’s movements).
Coding note: Indicate the name of the associated mental disorder when recording the  
name of the condition (i.e., 293.89 [F06.1] catatonia associated with major depressive dis­
order). Code first the associated mental disorder (e.g., neurodevelopmental disorder, brief

psychotic disorder, schizophreniform disorder, schizophrenia, schizoaffective disorder,  
bipolar disorder, major depressive disorder, or other mental disorder) (e.g., 295.70 [F25.1]  
schizoaffective disorder, depressive type; 293.89 [F06.1] catatonia associated with  
schizoaffective disorder).
Catatonia associated with another mental disorder (catatonia specifier) may be used when 
criteria are met for catatonia during the course of a neurodevelopmental, psychotic, bipo­
lar, depressive, or other mental disorder. The catatonia specifier is appropriate when the 
clinical picture is characterized by marked psychomotor disturbance and involves at least 
three of the 12 diagnostic features listed in Criterion A. Catatonia is typically diagnosed in 
an inpatient setting and occurs in up to 35% of individuals with schizophrenia, but the ma­
jority of catatonia cases involve individuals with depressive or bipolar disorders. Before

jority of catatonia cases involve individuals with depressive or bipolar disorders. Before 
the catatonia specifier is used in neurodevelopmental, psychotic, bipolar, depressive, or 
other mental disorders, a wide variety of other medical conditions need to be ruled out; 
these conditions include, but are not limited to, medical conditions due to infectious, met­
abolic, or neurological conditions (see '"Catatonic Disorder Due to Another Medical Con­
dition"). Catatonia can also be a side effect of a medication (see the chapter "Medication- 
Induced Movement Disorders and Other Adverse Effects of Medication"). Because of the 
seriousness of the complications, particular attention should be paid to the possibility that 
the catatonia is attributable to 333.92 (G21.0) neuroleptic malignant syndrome.
Catatonic Disorder Due to  
Another IVIedical Condition
Diagnostic Criteria 293.89 (F06.1)

4. Mutism (i.e., no, or very little, verbal response [Note: not applicable if there is an  
established aphasia]).

disturbance is the direct pathophysiological consequence of another medical condition.
C. The disturbance is not better explained by another mental disorder (e.g., a manic episode).

Coding note: Include the name of the medical condition in the name of the mental disor­
der (e.g., 293.89 [F06.1]) catatonic disorder due to hepatic encephalopathy). The other  
medical condition should be coded and listed separately immediately before the cata­
tonic disorder due to the medical condition (e.g., 572.2 [K71.90] hepatic encephalopathy;  
293.89 [F06.1] catatonic disorder due to hepatic encephalopathy).
The essential feature of catatonic disorder due to another medical condition is the presence 
of catatonia that is judged to be attributed to the physiological effects of another medical 
condition. Catatonia can be diagnosed by the presence of at least three of the 12 clinical fea­
tures in Criterion A. There must be evidence from the history, physical examination, or 
laboratory findings that the catatonia is attributable to another medical condition (Crite­
rion B). The diagnosis is not given if the catatonia is better explained by another mental

rion B). The diagnosis is not given if the catatonia is better explained by another mental 
disorder (e.g., manic episode) (Criterion C) or if it occurs exclusively during the course of 
a delirium (Criterion D).
A variety of medical conditions may cause catatonia, especially neurological conditions 
(e.g., neoplasms, head trauma, cerebrovascular disease, encephalitis) and metabolic con­
ditions (e.g., hypercalcemia, hepatic encephalopathy, homocystinuria, diabetic ketoacido­
sis). The associated physical examination findings, laboratory findings, and patterns of 
prevalence and onset reflect those of the etiological medical condition.
A separate diagnosis of catatonic disorder due to another medical condition is not given if 
the catatonia occurs exclusively during the course of a delirium or neuroleptic malignant

the catatonia occurs exclusively during the course of a delirium or neuroleptic malignant 
syndrome. If the individual is currently taking neuroleptic medication, consideration 
should be given to medication-induced movement disorders (e.g., abnormal positioning 
may be due to neuroleptic-induced acute dystonia) or neuroleptic malignant syndrome 
(e.g., catatonic-like features may be present, along with associated vital sign and/or labo­
ratory abnormalities). Catatonic symptoms may be present in any of the following five 
psychotic disorders: brief psychotic disorder, schizophreniform disorder, schizophrenia, 
schizoaffective disorder, and substance/medication-induced psychotic disorder. It may 
also be present in some of the neurodevelopmental disorders, in all of the bipolar and de­
pressive disorders, and in other mental disorders.
Unspecified Catatonia

This category applies to presentations in which symptoms characteristic of catatonia  
cause clinically significant distress or impairment in social, occupational, or other impor­
tant areas of functioning but either the nature of the underlying mental disorder or other  
medical condition is unclear, full criteria for catatonia are not met, or there is insufficient  
information to make a more specific diagnosis (e.g., in emergency room settings).
Coding note: Code first 781.99 (R29.818) other symptoms involving nervous and muscu­
loskeletal systems, followed by 293.89 (F06.1) unspecified catatonia.

Other Specified Schizophrenia Spectrum and  
Other Psychotic Disorder
298.8 (F28)
This category applies to presentations in which symptoms characteristic of a schizophre­
nia spectrum and other psychotic disorder that cause clinically significant distress or im­
pairment in social, occupational, or other important areas of functioning predominate but  
do not meet the full criteria for any of the disorders in the schizophrenia spectrum and other  
psychotic disorders diagnostic class. The other specified schizophrenia spectrum and oth­
er psychotic disorder category is used in situations in which the clinician chooses to com­
municate the specific reason that the presentation does not meet the criteria for any  
specific schizophrenia spectrum and other psychotic disorder. This is done by recording “ oth­
er specified schizophrenia spectrum and other psychotic disorder”  followed by the specific  
reason (e.g., “ persistent auditory hallucinations” ).

Examples of presentations that can be specified using the “ other specified”  designation  
include the following:
1. Persistent auditory liallucinations occurring in the absence of any other features.
2. Deiusions with significant overlapping mood episodes: This includes persistent  
delusions with periods of overlapping mood episodes that are present for a substantial  
portion of the delusional disturbance (such that the criterion stipulating only brief mood  
disturbance in  delusional disorder is not met).
3. Attenuated psychiosis syndrome: This syndrome is characterized by psychotic-like  
symptoms that are below a threshold for full psychosis (e.g., the symptoms are less  
severe and more transient, and insight is relatively maintained).
4. Deiusionai symptoms in partner of individuai witii deiusionai disorder: In the

4. Deiusionai symptoms in partner of individuai witii deiusionai disorder: In the  
context of a relationship, the delusional material from the dominant partner provides  
content for delusional belief by the individual who may not othenwise entirely meet cri­
teria for delusional disorder.
Unspecified Schizophrenia Spectrum and  
298.9 (F29)
do not meet the full criteria for any of the disorders in the schizophrenia spectrum and oth­
er psychotic disorders diagnostic class. The unspecified schizophrenia spectrum and oth­
er psychotic disorder category is used in situations in which the clinician chooses not to

er psychotic disorder category is used in situations in which the clinician chooses not to 
specify the reason that the criteria are not met for a specific schizophrenia spectrum and  
other psychotic disorder, and includes presentations in which there is insufficient informa­
tion to make a more specific diagnosis (e.g., in emergency room settings).

^  ~  Bipolar and 
Related Disorders
B ip o ls r  S n d  rG lâ ted  disorders are separated from the depressive disorders in 
DSM-5 and placed between the chapters on schizophrenia spectrum and other psychotic 
disorders and depressive disorders in recognition of their place as a bridge between the 
two diagnostic classes in terms of symptomatology, family history, and genetics. The di­
agnoses included in this chapter are bipolar I disorder, bipolar II disorder, cyclothymic 
disorder, substance/medication-induced bipolar and related disorder, bipolar and relat­
ed disorder due to another medical condition, other specified bipolar and related disor­
der, and unspecified bipolar and related disorder.
The bipolar I disorder criteria represent the modern understanding of the classic 
manic-depressive disorder or affective psychosis described in the nineteenth century, dif­
fering from that classic description only to the extent that neither psychosis nor the lifetime

fering from that classic description only to the extent that neither psychosis nor the lifetime 
experience of a major depressive episode is a requirement. However, the vast majority of 
individuals whose symptoms meet the criteria for a fully syndromal manic episode also 
experience major depressive episodes during the course of their lives.
Bipolar II disorder, requiring the lifetime experience of at least one episode of major de­
pression and at least one hypomanie episode, is no longer thought to be a "milder" condition 
than bipolar I disorder, largely because of the amount of time individuals with this con­
dition spend in depression and because the instability of mood experienced by individuals 
with bipolar II disorder is typically accompanied by serious impairment in work and social 
functioning.
The diagnosis of cyclothymic disorder is given to adults who experience at least 2 years

The diagnosis of cyclothymic disorder is given to adults who experience at least 2 years 
(for children, a full year) of both hypomanie and depressive periods without ever fulfilling 
the criteria for an episode of mania, hypomania, or major depression.
A large number of substances of abuse, some prescribed medications, and several 
medical conditions can be associated with manic-like phenomena. This fact is recognized 
in the diagnoses of substance/medication-induced bipolar and related disorder and bipo­
lar and related disorder due to another medical condition.
The recognition that many individuals, particularly children and, to a lesser extent, ad­
olescents, experience bipolar-like phenomena that do not meet the criteria for bipolar I, bi­
polar II, or cyclothymic disorder is reflected in the availability of the other specified

polar II, or cyclothymic disorder is reflected in the availability of the other specified 
bipolar and related disorder category. Indeed, specific criteria for a disorder involving 
short-duration hypomania are provided in Section III in the hope of encouraging further 
study of this disorder.
Bipolar I Disorder
For a diagnosis of bipolar I disorder, it is necessary to meet tlie following criteria for a manic  
episode. The manic episode may have been preceded by and may be followed by hypo-  
manic or major depressive episodes.

Manic Episode
A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood  
and abnormally and persistently increased goal-directed activity or energy, lasting at  
least 1  week and present most of the day, nearly every day (or any duration if hospi­
talization is necessary).
B. During the period of mood disturbance and increased energy or activity, three (or  
more) of the following symptoms (four if the mood is only irritable) are present to a sig­
nificant degree and represent a noticeable change from usual behavior:
1. Inflated self-esteem or grandiosity.
2. Decreased need for sleep (e.g., feels rested after only 3 hours of sleep).
3. More talkative than usual or pressure to keep talking.
4. Flight of ideas or subjective experience that thoughts are racing.
5. Distractibility (i.e., attention too easily drawn to unimportant or irrelevant external  
stimuli), as reported or observed.

6. Increase in goal-directed activity (either socially, at work or school, or sexually) or  
psychomotor agitation (i.e., puφoseless non-goal-directed activity).
7. Excessive involvement in activities that have a high potential for painful conse­
quences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or  
foolish business investments).
C. The mood disturbance is sufficiently severe to cause marked impairment in social or  
occupational functioning or to necessitate hospitalization to prevent harm to self or oth­
ers, or there are psychotic features.
D. The episode is not attributable to the physiological effects of a substance (e.g., a drug  
of abuse, a medication, other treatment) or to another medical condition.

Note: A full manic episode that emerges during antidepressant treatment (e.g., medi­
cation, electroconvulsive therapy) but persists at a fully syndromal level beyond the  
physiological effect of that treatment is sufficient evidence for a manic episode and,  
therefore, a bipolar I diagnosis.
Note: Criteria A-D constitute a manic episode. At least one lifetime manic episode is re­
quired for the diagnosis of bipolar I disorder.
Hypomanie Episode
and abnormally and persistently increased activity or energy, lasting at least 4 consec­
utive days and present most of the day, nearly every day.
B. During the period of mood disturbance and increased energy and activity, three (or

B. During the period of mood disturbance and increased energy and activity, three (or  
more) of the following symptoms (four if the mood is only irritable) have persisted, rep­
resent a noticeable change from usual behavior, and have been present to a significant  
degree:
psychomotor agitation.
quences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or

C. The episode is associated with an unequivocal change in functioning that is uncharac­
teristic of the individual when not symptomatic.
D. The disturbance in mood and the change in functioning are observable by others.
E. The episode is not severe enough to cause marked impairment in social or occupa­
tional functioning or to necessitate hospitalization. If there are psychotic features, the  
episode is, by definition, manic.
F. The episode is not attributable to the physiological effects of a substance (e.g., a drug  
of abuse, a medication, other treatment).
Note: A full hypomanie episode that emerges during antidepressant treatment (e.g.,  
medication, electroconvulsive therapy) but persists at a fully syndromal level beyond  
the physiological effect of that treatment is sufficient evidence for a hypomanie episode  
diagnosis. However, caution is indicated so that one or two symptoms (particularly in­

creased irritability, edginess, or agitation following antidepressant use) are not taken  
as sufficient for diagnosis of a hypomanie episode, nor necessarily indicative of a bi­
polar diathesis.
Note: Criteria A-'F constitute a hypomanie episode. Hypomanie episodes are common in  
bipolar I  disorder but are not required for the diagnosis of bipolar I disorder.
Major Depressive Episode
A. Five (or more) of the following symptoms have been present during the same 2-week  
period and represent a change from previous functioning; at least one of the symptoms  
is either (1) depressed mood or (2) loss of interest or pleasure.
Note: Do not include symptoms that are clearly attributable to another medical condi­
tion.
1. Depressed mood most of the day, nearly every day, as indicated by either subjec­

tion.
tive report (e.g., feels sad, empty, or hopeless) or observation made by others (e.g.,  
appears tearful). (Note: In children and adolescents, can be irritable mood.)
2. Markedly diminished interest or pleasure in all, or almost all, activities most of the  
day, nearly every day (as indicated by either subjective account or observation).
3. Significant weight loss when not dieting or weight gain (e.g., a change of more than  
5% of body weight in a month), or decrease or increase in appetite nearly every  
day. (Note: In children, consider failure to make expected weight gain.)
4. Insomnia or hypersomnia nearly every day.
5. Psychomotor agitation or retardation nearly every day (observable by others; not  
merely subjective feelings of restlessness or being slowed down).

6. Fatigue or loss of energy nearly every day.
7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delu­
sional) nearly every day (not merely self-reproach or guilt about being sick).
8. Diminished ability to think or concentrate, or indecisiveness, nearly every day (ei­
ther by subjective account or as observed by others).
9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation with­
out a specific plan, or a suicide attempt or a specific plan for committing suicide.
B. The symptoms cause clinically significant distress or impairment in social, occupa­
C. The episode is not attributable to the physiological effects of a substance or another  
medical condition.

Note: Criteria A-C constitute a major depressive episode. Major depressive episodes are  
common in bipolar I disorder but are not required for the diagnosis of bipolar I  disorder.  
Note: Responses to a significant loss (e.g., bereavement, financial ruin, losses from a  
natural disaster, a serious medical illness or disability) may include the feelings of intense

sadness, rumination about the loss, insomnia, poor appetite, and weight loss noted in Cri­
terion A, which may resemble a depressive episode. Although such symptoms may be un­
derstandable or considered appropriate to the loss, the presence of a major depressive  
episode in addition to the normal response to a significant loss should also be carefully  
considered. This decision inevitably requires the exercise of clinical judgment based on  
the individual’s history and the cultural norms for the expression of distress in the context  
of loss.^
A. Criteria have been met for at least one manic episode (Criteria A-D under “Manic Ep­
isode”  above).
B. The occurrence of the manic and major depressive episode(s) is not better explained  
by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional dis­
order, or other specified or unspecified schizophrenia spectrum and other psychotic  
disorder.
Coding and Recording Procedures

disorder.
The diagnostic code for bipolar I  disorder is based on type of current or most recent epi­
sode and its status with respect to current severity, presence of psychotic features, and  
remission status. Current severity and psychotic features are only indicated if full criteria  
are currently met for a manic or major depressive episode. Remission specifiers are only  
indicated if the full criteria are not currently met for a manic, hypomanie, or major depres­
sive episode. Codes are as follows:
Bipolar 1  disorderCurrent or  
most recent  
episode  
manicCurrent or  
episode  
hypomanie*Current or  
episode  
depressedCurrent or  
episode  
unspecified**
Mild (p. 154) 296.41 ΝΑ 296.51 NA
(F31.11) (F31.31)
Moderate (p. 154) 296.42 ΝΑ 296.52 NA
(F31.12) (F31.32)
Severe (p. 154) 296.43 ΝΑ 296.53 NA
(F31.13) (F31.4)

episode  
^  In distinguishing grief from a major depressive episode (MDE), it is useful to consider that in  
grief the predominant affect is feelings of emptiness and loss, while in MDE it is persistent  
depressed mood and the inability to anticipate happiness or pleasure. The dysphoria in grief is  
likely to decrease in intensity over days to W feeks and occurs in waves, the so-called pangs of  
grief. These waves tend to be associated with thoughts or reminders of the deceased. The  
depressed mood of a MDE is more persistent and not tied to specific thoughts or preoccupations.  
The pain of grief may be accompanied by positive emotions and humor that are uncharacteristic  
of the pervasive unhappiness and misery characteristic of a major depressive episode. The

of the pervasive unhappiness and misery characteristic of a major depressive episode. The  
thought content associated with grief generally features a preoccupation with thoughts and  
memories of the deceased, rather than the self-critical or pessimistic ruminations seen in a MDE.  
In grief, self-esteem is generally preserved, whereas in a MDE, feelings of worthlessness and self­
loathing are common. If self-derogatory ideation is present in grief, it typically involves per­
ceived failings vis-à-vis the deceased (e.g., not visiting frequently enough, not telling the  
deceased how much he or she was loved). If a bereaved individual thinks about death and dying,  
such thoughts are generally focused on the deceased and possibly about "joining" the deceased,  
whereas in a major depressive episode such thoughts are focused on ending one's own life

whereas in a major depressive episode such thoughts are focused on ending one's own life  
because of feeling worthless, undeserving of life, or unable to cope with the pain of depression.

episode  
episode  
episode  
episode  
With psychotic 296.44 ΝΑ 296.54 NA
features*** (F31.2) (F31.5)
(p. 152)
In partial 296.45 296.45 296.55 NA
remission (p. 154) (F31.73) (F31.73) (F31.75)
In full remission 296.46 296.46 296.56 NA
(p. 154) (F31.74) (F31.74) (F31.76)
Unspecified 296.40 296.40 296.50 NA
(F31.9) (F31.9) (F31.9)
Severity and psychotic specifiers do not apply; code 296.40 (F31.0) for cases not in remission.  
Severity, psychotic, and remission specifiers do not apply. Code 296.7 (F31.9).
***If psychotic features are present, code the "with psychotic features" specifier irrespective of epi­
sode severity.
In recording the name of a diagnosis, terms should be listed in the following order: bipolar  
I disorder, type of current or most recent episode, severity/psychotic/remission specifiers,

I disorder, type of current or most recent episode, severity/psychotic/remission specifiers,  
followed by as many specifiers without codes as apply to the current or most recent epi­
sode.
Specify.
With anxious distress (p. 149)
With mixed features (pp. 149-150)
With rapid cycling (pp. 150-151)
With meianchoiic features (p. 151)
With atypicai features (pp. 151-152)
With mood-congruent psychotic features (p. 152)
With mood-incongruent psychotic features (p. 152)
With catatonia (p. 152). Coding note: Use additional code 293.89 (F06.1).
With péripartum onset (pp. 152-153)
With seasonal pattern (pp. 153-154)
The essential feature of a manic episode is a distinct period during which there is an ab­
normally, persistently elevated, expansive, or irritable mood and persistently increased

normally, persistently elevated, expansive, or irritable mood and persistently increased 
activity or energy that is present for most of the day, nearly every day, for a period of at 
least 1  week (or any duration if hospitalization is necessary), accompanied by at least three 
additional symptoms from Criterion B. If the mood is irritable rather than elevated or ex­
pansive, at least four Criterion B symptoms must be present.
Mood in a manic episode is often described as euphoric, excessively cheerful, high, or 
"feeling on top of the world." In some cases, the mood is of such a highly infectious quality 
that it is easily recognized as excessive and may be characterized by unlimited and hap­
hazard enthusiasm for interpersonal, sexual, or occupational interactions. For example, 
the individual may spontaneously start extensive conversations with strangers in public.

the individual may spontaneously start extensive conversations with strangers in public. 
Often the predominant mood is irritable rather than elevated, particularly when the indi­
vidual's wishes are denied or if the individual has been using substances. Rapid shifts in 
mood over brief periods of time may occur and are referred to as lability (i.e., the alterna-

tion among euphoria, dysphoria, and irritability). In children, happiness, silliness and 
"goofiness" are normal in the context of special occasions; however, if these symptoms are 
recurrent, inappropriate to the context, and beyond what is expected for the developmen­
tal level of the child, they may meet Criterion A. If the happiness is unusual for a child (i.e., 
distinct from baseline), and the mood change occurs at the same time as symptoms that 
meet Criterion B for mania, diagnostic certainty is increased; however, the mood change 
must be accompanied by persistently increased activity or energy levels that are obvious 
to those who know the child well.
During the manic episode, the individual may engage in multiple overlapping new 
projects. The projects are often initiated with little knowledge of the topic, and nothing seems 
out of the individual's reach. The increased activity levels may manifest at unusual hours of 
the day.

the day.
Inflated self-esteem is typically present, ranging from uncritical self-confidence to marked 
grandiosity, and may reach delusional proportions (Criterion Bl). Despite lack of any partic­
ular experience or talent, the individual may embark on complex tasks such as writing a novel 
or seeing publicity for some impractical invention. Grandiose delusions (e.g., of having a 
special relationship to a famous person) are common. In children, overestimation of abilities 
and belief that, for example, they are the best at a sport or the smartest in the class is normal; 
however, when such beliefs are present despite clear evidence to the contrary or the child at­
tempts feats that are clearly dangerous and, most important, represent a change from the 
child's normal behavior, the grandiosity criterion should be considered satisfied.

One of the most common features is a decreased need for sleep (Criterion B2) and is 
distinct from insomnia in which the individual wants to sleep or feels the need to sleep but 
is unable. The individual may sleep httle, if at all, or may awaken several hours earlier than 
usual, feeling rested and full of energy. When the sleep disturbance is severe, the individ­
ual may go for days without sleep, yet not feel tired. Often a decreased need for sleep her­
alds the onset of a manic episode.
Speech can be rapid, pressured, loud, and difficult to interrupt (Criterion B3). Individ­
uals may talk continuously and without regard for others' wishes to communicate, often 
in an intrusive manner or without concern for the relevance of what is said. Speech is

in an intrusive manner or without concern for the relevance of what is said. Speech is 
sometimes characterized by jokes, puns, amusing irrelevancies, and theatricality, with 
dramatic mannerisms, singing, and excessive gesturing. Loudness and forcefulness of 
speech often become more important than what is conveyed. If the individual's mood is 
more irritable than expansive, speech may be marked by complaints, hostile comments, or 
angry tirades, particularly if attempts are made to interrupt the individual. Both Criterion 
A and Criterion B symptoms may be accompanied by symptoms of the opposite (i.e., de­
pressive) pole (see "with mixed features" specifier, pp. 149-150).
Often the individual's thoughts race at a rate faster than they can be expressed through 
speech (Criterion B4). Frequently there is flight of ideas evidenced by a nearly continuous flow

speech (Criterion B4). Frequently there is flight of ideas evidenced by a nearly continuous flow 
of accelerated speech, with abrupt shifts from one topic to another. When flight of ideas is se­
vere, speech may become disorganized, incoherent, and particularly distressful to the individ­
ual. Sometimes thoughts are experienced as so crowded that it is very difficult to speak.
Distractibility (Criterion B5) is evidenced by an inability to censor immaterial external 
stimuli (e.g., the interviewer's attire, background noises or conversations, furnishings in 
the room) and often prevents individuals experiencing mania from holding a rational con­
versation or attending to instructions.
The increase in goal-directed activity often consists of excessive planning and partici­
pation in multiple activities, including sexual, occupational, political, or religious activi­

ties. Increased sexual drive, fantasies, and behavior are often present. Individuals in a manic 
episode usually show increased sociability (e.g., renewing old acquaintances or calling or 
contacting friends or even strangers), without regard to the intrusive, domineering, and 
demanding nature of these interactions. They often display psychomotor agitation or rest­
lessness (i.e., purposeless activity) by pacing or by holding multiple conversations simulta­

neously. Some individuals write excessive letters, e-mails, text messages, and so forth, on 
many different topics to friends, public figures, or the media.
The increased activity criterion can be difficult to ascertain in children; however, when 
the child takes on many tasks simultaneously, starts devising elaborate and unrealistic 
plans for projects, develops previously absent and developmentally inappropriate sexual 
preoccupations (not accounted for by sexual abuse or exposure to sexually explicit mate­
rial), then Criterion B might be met based on clinical judgment. It is essential to determine 
whether the behavior represents a change from the child's baseline behavior; occurs most 
of the day, nearly every day for the requisite time period; and occurs in temporal associa­
tion with other symptoms of mania.
The expansive mood, excessive optimism, grandiosity, and poor judgment often lead 
to reckless involvement in activities such as spending sprees, giving away possessions,

to reckless involvement in activities such as spending sprees, giving away possessions, 
reckless driving, foolish business investments, and sexual promiscuity that is unusual for 
the individual, even though these activities are likely to have catastrophic consequences 
(Criterion B7). The individual may purchase many unneeded items without the money to 
pay for them and^ in some cases, give them away. Sexual behavior may include infidelity 
or indiscriminate sexual encounters with strangers, often disregarding the risk of sexually 
transmitted diseases or interpersonal consequences.
The manic episode must result in marked impairment in social or occupational func­
tioning or require hospitalization to prevent harm to self or others (e.g., financial losses, il­
legal activities, loss of employment, self-injurious behavior). By definition, the presence of

legal activities, loss of employment, self-injurious behavior). By definition, the presence of 
psychotic features during a manic episode also satisfies Criterion C.
Manic symptoms or syndromes that are attributable to the physiological effects of a 
drug of abuse (e.g., in the context of cocaine or amphetamine intoxication), the side effects 
of medications or treatments (e.g., steroids, L-dopa, antidepressants, stimulants), or an­
other medical condition do not count toward the diagnosis of bipolar I disorder. However, 
a fully syndromal manic episode that arises during treatment (e.g., with medications, elec- 
troconvulsive therapy, light therapy) or drug use and persists beyond the physiological ef­
fect of the inducing agent (i.e., after a medication is fully out of the individual's system or 
the effects of electroconvulsive therapy would be expected to have dissipated completely)

the effects of electroconvulsive therapy would be expected to have dissipated completely) 
is sufficient evidence for a manic episode diagnosis (Criterion D). Caution is indicated so 
that one or two symptoms (particularly increased irritability, edginess, or agitation follow­
ing antidepressant use) are not taken as sufficient for diagnosis of a manic or hypomanie 
episode, nor necessarily an indication of a bipolar disorder diathesis. It is necessary to 
meet criteria for a manic episode to make a diagnosis of bipolar I disorder, but it is not re­
quired to have hypomanie or major depressive episodes. However, they may precede or 
follow a manic episode. Full descriptions of the diagnostic features of a hypomanie epi­
sode may be found within the text for bipolar II disorder, and the features of a major de­
pressive episode are described within the text for major depressive disorder.

E>uring a manic episode, individuals often do not perceive that they are ill or in need of treat­
ment and vehemently resist efforts to be treated. Individuals may change their dress, makeup, 
or personal appearance to a more sexually suggestive or flamboyant style. Some perceive a 
sharper sense of smell, hearing, or vision. Gambling and antisocial behaviors may accompany 
the manic episode. Some individuals may become hostile and physically threatening to others 
and, when delusional, may become physically assaultive or suicidal. Catastrophic conse­
quences of a manic episode (e.g., involuntary hospitalization, difficulties with the law, serious 
financial difficulties) often result from poor judgment, loss of insight, and hyperactivity.

Mood may shift very rapidly to anger or depression. Depressive symptoms may occur 
during a manic episode and, if present, may last moments, hours, or, more rarely, days (see 
"with mixed features" specifier, pp. 149-150).

The 12-month prevalence estimate in the continental United States was 0.6% for bipolar I 
disorder as defined in DSM-IV. Twelve-month prevalence of bipolar I disorder across 11 
countries ranged from 0.0% to 0.6%. The lifetime male-to-female prevalence ratio is ap­
proximately 1.1:1.
Mean age at onset of the first manic, hypomanie, or major depressive episode is approxi­
mately 18 years for bipolar I disorder. Special considerations are necessary to detect the di­
agnosis in children. Since children of the same chronological age may be at different 
developmental stages, it is difficult to define with precision what is ''normal" or "ex­
pected" at any given point. Therefore, each child should be judged according to his or her 
own baseline. Onset occurs throughout the life cycle, including first onsets in the 60s or 
70s. Onset of manic symptoms (e.g., sexual or social disinhibition) in late mid-life or late-

70s. Onset of manic symptoms (e.g., sexual or social disinhibition) in late mid-life or late- 
life should prompt consideration of medical conditions (e.g., frontotemporal neurocogni- 
tive disorder) and of substance ingestion or withdrawal.
More than 90% of individuals who have a single manic episode go on to have recurrent 
mood episodes. Approximately 60% of manic episodes occur immediately before a major 
depressive episode. Individuals with bipolar I disorder who have multiple (four or more) 
mood episodes (major depressive, manic, or hypomanie) within 1  year receive the speci­
fier "with rapid cycling."
Environmental. Bipolar disorder is more common in high-income than in low-income 
countries (1.4 vs. 0.7%). Separated, divorced, or widowed individuals have higher rates of 
bipolar I disorder than do individuals who are married or have never been married, but

bipolar I disorder than do individuals who are married or have never been married, but 
the direction of the association is unclear.
Genetic and physiological. A family history of bipolar disorder is one of the strongest and 
most consistent risk factors for bipolar disorders. There is an average 10-fold increased risk 
among adult relatives of individuals with bipolar I and bipolar II disorders. Magnitude of 
risk increases with degree of kinship. Schizophrenia and bipolar disorder likely share a ge­
netic origin, reflected in familial co-aggregation of schizophrenia and bipolar disorder.
Course modifiers. After an individual has a manic episode with psychotic features, subse­
quent manic episodes are more likely to include psychotic features. Incomplete inter­
episode recovery is more common when the current episode is accompanied by mood- 
incongruent psychotic features.

Little information exists on specific cultural differences in the expression of bipolar I dis­
order. One possible explanation for this may be that diagnostic instruments are often 
translated and applied in different cultures with no transcultural validation. In one U.S. 
study, 12-month prevalence of bipolar I disorder was significantly lower for Afro-Carib- 
beans than for African Americans or whites.
Females are more likely to experience rapid cycling and mixed states, and to have patterns of 
comorbidity that differ from those of males, including higher rates of lifetime eating disor­
ders. Females with bipolar I or II disorder are more likely to experience depressive symptoms

ders. Females with bipolar I or II disorder are more likely to experience depressive symptoms 
than males. They also have a higher lifetime risk of alcohol use disorder than are males and a 
much greater likelihood of alcohol use disorder than do females in the general population.

Suicide Risk
The lifetime risk of suicide in individuals with bipolar disorder is estimated to be at least 
15 times that of the general population. In fact, bipolar disorder may account for one-quar­
ter of all completed suicides. A past history of suicide attempt and percent days spent de­
pressed in the past year are associated with greater risk of suicide attempts or completions.
Functional Consequences of Bipoiar I Disorder
Although many individuals with bipolar disorder return to a fully functional level be­
tween episodes, approximately 30% show severe impairment in work role function. Func­
tional recovery lags substantially behind recovery from symptoms, especially with respect 
to occupational recovery, resulting in lower socioeconomic status despite equivalent lev­
els of education when compared with the general population. Individuals with bipolar I 
disorder perform more poorly than healthy individuals on cognitive tests. Cognitive im­

pairments may contribute to vocational and interpersonal difficulties and persist through 
the lifespan, evex^  during euthymie periods.
Major depressive disorder. Major depressive disorder may also be accompanied by hy­
pomanie or manic symptoms (i.e., fewer symptoms or for a shorter duration than required 
for mania or hypomania). When the individual presents in an episode of major depression, 
one must depend on corroborating history regarding past episodes of mania or hypoma­
nia. Symptoms of irritability may be associated with either major depressive disorder or 
bipolar disorder, adding to diagnostic complexity.
Other bipolar disorders. Diagnosis of bipolar I disorder is differentiated from bipolar II

Other bipolar disorders. Diagnosis of bipolar I disorder is differentiated from bipolar II 
disorder by determining whether there have been any past episodes of mania. Other spec­
ified and unspecified bipolar and related disorders should be differentiated from bipolar I 
and II disorders by considering whether either the episodes involving manic or hypo- 
manic symptoms or the episodes of depressive symptoms fail to meet the full criteria for 
those conditions.
Bipolar disorder due to another medical condition may be distinguished from bipolar
I and II disorders by identifying, based on best clinical evidence, a causally related medical 
Generalized anxiety disorder, panic disorder, posttraumatic stress disorder, or other  
anxiety disorders. These disorders need to be considered in the differential diagnosis as 
either the primary disorder or, in some cases, a comorbid disorder. A careful history of

either the primary disorder or, in some cases, a comorbid disorder. A careful history of 
symptoms is needed to differentiate generalized anxiety disorder from bipolar disorder, 
as anxious ruminations may be mistaken for racing thoughts, and efforts to minimize anx­
ious feelings may be taken as impulsive behavior. Similarly, symptoms of posttraumatic 
stress disorder need to be differentiated from bipolar disorder. It is helpful to assess the ep­
isodic nature of the symptoms described, as well as to consider symptom triggers, in mak­
ing this differential diagnosis.
Substance/medication-induced bipolar disorder. Substance use disorders may mani­
fest with substance.medication-induced manic symptoms that must be distinguished 
from bipolar I disorder; response to mood stabilizers during a substance/medication-

from bipolar I disorder; response to mood stabilizers during a substance/medication- 
induced mania may not necessarily be diagnostic for bipolar disorder. There may be sub­
stantial overlap in view of the tendency for individuals with bipolar I disorder to overuse 
substances during an episode. A primary diagnosis of bipolar disorder must be estab­
lished based on symptoms that remain once substances are no longer being used.
Attention-deficit/hyperactivity disorder. This disorder may be misdiagnosed as bipolar 
disorder, especially in adolescents and children. Many symptoms overlap with the symp­

toms of mania, such as rapid speech, racing thoughts, distractibihty, and less need for 
sleep. The "double counting" of symptoms toward both ADHD and bipolar disorder can 
be avoided if the clinician clarifies whether the symptom(s) represents a distinct episode.
Personality disorders. Personality disorders such as borderline personality disorder 
may have substantial symptomatic overlap with bipolar disorders, since mood lability 
and impulsivity are common in both conditions. Symptoms must represent a distinct ep­
isode, and the noticeable increase over baseline required for the diagnosis of bipolar dis­
order must be present. A diagnosis of a personality disorder should not be made during an 
untreated mood episode.
Disorders with prominent irritability. In individuals with severe irritability, particularly 
children and adolescents, care must be taken to apply the diagnosis of bipolar disorder

children and adolescents, care must be taken to apply the diagnosis of bipolar disorder 
only to those who have had a clear episode of mania or hypomania—that is, a distinct time 
period, of the required duration, during which the irritability was clearly different from 
the individual's baseline and was accompanied by the onset of Criterion B symptoms. 
When a child's irritability is persistent and particularly severe, the diagnosis of disruptive 
mood dysregulation disorder would be more appropriate. Indeed, when any child is being 
assessed for mania, it is essential that the symptoms represent a clear change from the 
child's typical behavior.
Co-occurring mental disorders are common, with the most frequent disorders being any 
anxiety disorder (e.g., panic attacks, social anxiety disorder [social phobia], specific pho­

bia), occurring in approximately three-fourths of individuals; ADHD, any disruptive, im- 
pulse-control, or conduct disorder (e.g., intermittent explosive disorder, oppositional 
defiant disorder, conduct disorder), and any substance use disorder (e.g., alcohol use dis­
order) occur in over half of individuals with bipolar I disorder. Adults with bipolar I dis­
order have high rates of serious and/or untreated co-occurring medical conditions. 
Metabolic s)nidrome and migraine are more common among individuals with bipolar dis­
order than in the general population. More than half of individuals whose symptoms meet 
criteria for bipolar disorder have an alcohol use disorder, and those with both disorders 
are at greater risk for suicide attempt.
Bipolar II Disorder

Diagnostic Criteria 296.89 (F31.81)
For a diagnosis of bipolar II disorder, it is necessary to meet the following criteria for a cur­
rent or past hypomanie episode and the following criteria for a current or past major de­
pressive episode:
B. During the period of mood disturbance and increased energy and activity, three (or more)  
of the following symptoms have persisted (four if the mood is only irritable), represent a no­
ticeable change from usual behavior, and have been present to a significant degree:

stimuli), as reported or obsen/ed.
6. Increase in  goal-directed activity (either socially, at work or school, or sexually) or  
C. The episode is associated with an unequivocal change in  functioning that is uncharac­

of abuse, a medication or other treatment).
A. Five (or more) of the following symptoms have been present during the same 2-week

is either (1 ) depressed mood or (2) loss of interest or pleasure.
Note: Do not include symptoms that are clearly attributable to a medical condition.
5% of body weight in a month), or decrease or increase in appetite nearly every

out a specific plan, a suicide attempt, or a specific plan for committing suicide.

Note: Criteria A-C above constitute a major depressive episode.
Note: Responses to a significant loss (e.g., bereavement, financial ruin, losses from a nat­
ural disaster, a serious medical illness or disability) may include the feelings of intense sad­
ness, rumination about the loss, insomnia, poor appetite, and weight loss noted in Criterion  
A, which may resemble a depressive episode. Although such symptoms may be under­
standable or considered appropriate to the loss, the presence of a major depressive episode  
in addition to the normal response to a significant loss should be carefully considered. This  
decision inevitably requires the exercise of clinical judgment based on the individual’s history  
and the cultural norms for the expression of distress in the context of loss.^
A. Criteria have been met for at least one hypomanie episode (Criteria A-F under “Hypo-  
manic Episode”  above) and at least one major depressive episode (Criteria A-C under

manic Episode”  above) and at least one major depressive episode (Criteria A-C under  
“Major Depressive Episode”  above).
B. There has never been a manic episode.
C. The occurrence of the hypomanie episode(s) and major depressive episode(s) is not  
better explained by schizoaffective disorder, schizophrenia, schizophreniform disor­
der, delusional disorder, or other specified or unspecified schizophrenia spectrum and  
other psychotic disorder.
D. The symptoms of depression or the unpredictability caused by frequent alternation be­
tween periods of depression and hypomania causes clinically significant distress or im­
pairment in social, occupational, or other important areas of functioning.
Bipolar II disorder has one diagnostic code: 296.89 (F31.81 ). Its status with respect to cur­

rent severity, presence of psychotic features, course, and other specifiers cannot be  
coded but should be indicated in writing (e.g., 296.89 [F31.81] bipolar II disorder, current  
episode depressed, moderate severity, with mixed features; 296.89 [F31.81] bipolar II dis­
order, most recent episode depressed, in partial remission).
Specify  current or most recent episode:
Hypomanie  
Depressed  
^  In distinguishing grief from a major depressive episode (MDE), it is useful to consider that in grief  
the predominant affect is feelings of emptiness and loss, while in a MDE it is persistent depressed  
mood and the inability to anticipate happiness or pleasure. The dysphoria in grief is likely to

mood and the inability to anticipate happiness or pleasure. The dysphoria in grief is likely to  
decrease in intensity over days to weeks and occurs in waves, the so-called pangs of grief. These  
waves tend to be associated with thoughts or reminders of the deceased. The depressed mood of a  
MDE is more persistent and not tied to specific thoughts or preoccupations. The pain of grief may  
be accompanied by positive emotions and humor that are uncharacteristic of the pervasive unhap­
piness and misery characteristic of a MDE. The thought content associated with grief generally fea­
tures a preoccupation with thoughts and memories of the deceased, rather than the self-critical or  
pessinüstic ruminations seen in a MDE. In grief, self-esteem is generally preserved, whereas in a  
MDE feelings of worthlessness and self-loathing are common. If self-derogatory ideation is present

MDE feelings of worthlessness and self-loathing are common. If self-derogatory ideation is present  
in grief, it typically involves perceived failings vis-à-vis the deceased (e.g., not visiting frequently  
enough, not telling the deceased how much he or she was loved). If a bereaved individual thinks  
about death and dying, such thoughts are generally focused on the deceased and possibly about  
"’ joining" the deceased, whereas in a MDE such thoughts are focused on ending one's own life  
because of feeling worthless, undeserving of üfe, or unable to cope with the pain of depression.

Withi mood-congruent psychotic features (p. 152)
With seasonal pattern (pp. 153-154): Applies only to the pattern of major depressive  
episodes.
Specify  course if full criteria for a mood episode are not currently met:  
in partial remission (p. 154)
In full remission (p. 154)
Specify  severity if full criteria for a mood episode are currently met:  
lUlild (p. 154)  
lUloderate (p. 154)
Severe (p. 154) _______________________________________________________
Bipolar II disorder is characterized by a clinical course of recurring mood episodes con­
sisting of one or more major depressive episodes (Criteria A-C under "Major Depressive 
Episode") and at least one hypomanie episode (Criteria A-F under "Hypomanie Epi­

sode"). The major depressive episode must last at least 2 weeks, and the hypomarüc epi­
sode must last at least 4 days, to meet the diagnostic criteria. During the mood episode(s), 
the requisite number of symptoms must be present most of the day, nearly every day, and 
represent a noticeable change from usual behavior and functioning. The presence of a 
manic episode during the course of illness precludes the diagnosis of bipolar II disorder 
(Criterion B under "Bipolar II Disorder"). Episodes of substance/medication-induced de­
pressive disorder or substance/medication-induced bipolar and related disorder (repre­
senting the physiological effects of a medication, other somatic treatments for depression, 
drugs of abuse, or toxin exposure) or of depressive and related disorder due to another

drugs of abuse, or toxin exposure) or of depressive and related disorder due to another 
medical condition or bipolar and related disorder due to another medical condition do not 
count toward a diagnosis of bipolar II disorder unless they persist beyond the physiolog­
ical effects of the treatment or substance and then meet duration criteria for an episode. In 
addition, the episodes must not be better accounted for by schizoaffective disorder and are 
not superimposed on schizophrenia, schizophreniform disorder, delusional disorder, or 
other specified or unspecified schizophrenia spectrum or other psychotic disorders (Cri­
terion C under "Bipolar II Disorder"). The depressive episodes or hypomanie fluctuations 
must cause clinically significant distress or impairment in social, occupational, or other 
important areas of functioning (Criterion D under "Bipolar II Disorder"); however, for hy­

pomanie episodes, this requirement does not have to be met. A hypomanie episode that 
causes significant impairment would likely qualify for the diagnosis of manic episode and, 
therefore, for a lifetime diagnosis of bipolar I disorder. The recurrent major depressive ep­
isodes are often more frequent and lengthier than those occurring in bipolar I disorder.
Individuals with bipolar II disorder typically present to a clinician during a major de­
pressive episode and are unlikely to complain initially of hypomania. Typically, the hy­
pomanie episodes themselves do not cause impairment. Instead, the impairment results 
from the major depressive episodes or from a persistent pattern of unpredictable mood 
changes and fluctuating, unreliable interpersonal or occupational functioning. Individu­

als with bipolar II disorder may not view the hypomanie episodes as pathological or dis­
advantageous, although others may be troubled by the individual's erratic behavior. 
Clinical information from other informants, such as close friends or relatives, is often use­
ful in establishing the diagnosis of bipolar II disorder.

A hypomanie episode should not be confused with the several days of euthymia and re­
stored energy or activity that may follow remission of a major depressive episode. Despite the 
substantial differences in duration and severity between a manic and hypomanie episode, bi­
polar II disorder is not a "milder form" of bipolar I disorder. Compared with individuals with 
bipolar I disorder, individuals with bipolar II disorder have greater chronicity of illness and 
spend, on average, more time in the depressive phase of their illness, which can be severe and/ 
or disabling. Depressive symptoms co-occurring with a hypomanie episode or hypomanie 
symptoms co-occurring with a depressive episode are common in individuals with bipolar Π  
disorder and are overrepresented in females, particularly hypomania with mixed features. In­
dividuals experiencing hypomania with mixed features may not label their symptoms as hy­

pomania, but instead experience them as depression with increased energy or irritability.
A common feature of bipolar II disorder is impulsivity, which can contribute to suicide at­
tempts and substance use disorders. Impulsivity may also stem from a concurrent person­
ality disorder, substance use disorder, anxiety disorder, another mental disorder, or a 
medical condition. There may be heightened levels of creativity in some individuals with 
a bipolar disorder. However, that relationship may be nonlinear; that is, greater lifetime 
creative accomplishments have been associated with milder forms of bipolar disorder, and 
higher creativity has been found in unaffected family members. The individual's attach­

ment to heightened creativity during hypomanie episodes may contribute to ambivalence 
about seeking treatment or undermine adherence to treatment.
The 12-month prevalence of bipolar II disorder, internationally, is 0.3%. In the United 
States, 12-month prevalence is 0.8%. The prevalence rate of pediatric bipolar II disorder is 
difficult to establish. DSM-IV bipolar I, bipolar II, and bipolar disorder not otherwise spec­
ified yield a combined prevalence rate of 1.8% in U.S. and non-U.S. community samples, 
with higher rates (2.7% inclusive) in youths age 12 years or older.
Although bipolar II disorder can begin in late adolescence and throughout adulthood, av­
erage age at onset is the mid-20s, which is slightly later than for bipolar I disorder but ear­

lier than for major depressive disorder. The illness most often begins with a depressive 
episode and is not recognized as bipolar II disorder until a hypomanie episode occurs; this 
happens in about 12% of individuals with the initial diagnosis of major depressive disor­
der. Anxiety, substance use, or eating disorders may also precede the diagnosis, compli­
cating its detection. Many individuals experience several episodes of major depression 
prior to the first recognized hypomanie episode.
The number of lifetime episodes (both hypomanie and major depressive episodes) 
tends to be higher for bipolar II disorder than for major depressive disorder or bipolar I 
disorder. However, individuals with bipolar I disorder are actually more likely to experi­

ence hypomanie symptoms than are individuals with bipolar II disorder.The interval 
between mood episodes in the course of bipolar II disorder tends to decrease as the indi­
vidual ages. While the hypomanie episode is the feature that defines bipolar II disorder, 
depressive episodes are more enduring and disabling over time. Despite the predomi­
nance of depression, once a hypomanie episode has occurred, the diagnosis becomes bi­
polar II disorder and never reverts to major depressive disorder.
Approximately 5%-15% of individuals with bipolar II disorder have multiple (four or 
more) mood episodes (hypomanie or major depressive) within the previous 12 months. If

this pattern is present, it is noted by the specifier "with rapid cycling." By definition, psy­
chotic symptoms do not occur in hypomanie episodes, and they appear to be less frequent 
in the major depressive episodes in bipolar II disorder than in those of bipolar I disorder.
Switching from a depressive episode to a manic or hypomanie episode (with or with­
out mixed features) may occur, both spontaneously and during treatment for depression. 
About 5%-15% of individuals with bipolar II disorder will ultimately develop a manic ep­
isode, which changes the diagnosis to bipolar I disorder, regardless of subsequent course.
Making the diagnosis in children is often a challenge, especially in those with irritabil­
ity and hyperarousal that is nonepisodic  (i.e., lacks the well-demarcated periods of altered 
mood). Nonepisodic irritability in youth is associated with an elevated risk for anxiety dis­
orders and major depressive disorder, but not bipolar disorder, in adulthood. Persistently

orders and major depressive disorder, but not bipolar disorder, in adulthood. Persistently 
irritable youths have lower familial rates of bipolar disorder than do youths who have bi­
polar disorder. For a hypomanie episode to be diagnosed, the child's symptoms must ex­
ceed what is expected in a given environment and culture for the child's developmental 
stage. Compared with adult onset of bipolar II disorder, childhood or adolescent onset of 
the disorder may be associated with a more severe lifetime course. The 3-year incidence 
rate of first-onset bipolar II disorder in adults older than 60 years is 0.34%. However, dis­
tinguishing individuals older than 60 years with bipolar II disorder by late versus early 
age at onset does not appear to have any clinical utility.
Genetic and physiological. The risk of bipolar II disorder tends to be highest among rel­

atives of individuals with bipolar II disorder, as opposed to individuals with bipolar I dis­
order or major depressive disorder. There may be genetic factors influencing the age at 
onset for bipolar disorders.
Course modifiers. A rapid-cycling pattern is associated with a poorer prognosis. Return 
to previous level of social function for individuals with bipolar II disorder is more likely 
for individuals of younger age and with less severe depression, suggesting adverse effects 
of prolonged illness on recovery. More education, fewer years of illness, and being mar­
ried are independently associated with functional recovery in individuals with bipolar 
disorder, even after diagnostic type (I vs. II), current depressive symptoms, and presence 
of psychiatric comorbidity are taken into account.

Whereas the gender ratio for bipolar I disorder is equal, findings on gender differences in 
bipolar II disorder are mixed, differing by type of sample (i.e., registry, community, or 
clinical) and country of origin. There is little to no evidence of bipolar gender differences, 
whereas some, but not all, clinical samples suggest that bipolar II disorder is more com­
mon in females than in males, which may reflect gender differences in treatment seeking 
or other factors.
Patterns of illness and comorbidity, however, seem to differ by gender, with females 
being more likely than males to report hypomania with mixed depressive features and a 
rapid-cycling course. Childbirth may be a specific trigger for a hypomanie episode, which

rapid-cycling course. Childbirth may be a specific trigger for a hypomanie episode, which 
can occur in 10%-20% of females in nonelinieal populations and most typically in the early 
postpartum period. Distinguishing hypomania from the elated mood and reduced sleep 
that normally accompany the birth of a child may be challenging. Postpartum hypomania 
may foreshadow the onset of a depression that occurs in about half of females who expe­
rience postpartum "highs." Accurate detection of bipolar II disorder may help in estab­
lishing appropriate treatment of the depression, which may reduce the risk of suicide and 
infanticide.

Suicide risk is high in bipolar II disorder. Approximately one-third of individuals with bi­
polar II disorder report a lifetime history of suicide attempt. The prevalence rates of life­
time attempted suicide in bipolar II and bipolar I disorder appear to be similar (32.4% and 
36.3%, respectively). However, the lethality of attempts, as defined by a lower ratio of at­
tempts to completed suicides, may be higher in individuals with bipolar II disorder com­
pared with individuals with bipolar I disorder. There may be an association between 
genetic markers and increased risk for suicidal behavior in individuals with bipolar dis­
order, including a 6.5-fold higher risk of suicide among first-degree relatives of bipolar II 
probands compared with those with bipolar I disorder.
Functional Consequences of Bipolar II Disorder
Although many individuals with bipolar II disorder return to a fully functional level be­

tween mood episodes, at least 15% continue to have some inter-episode dysfunction, and 
20% transition directly into another mood episode without inter-episode recovery. Func­
tional recovery lags substantially behind recovery from symptoms of bipolar II disorder, 
especially in regard to occupational recovery, resulting in lower socioeconomic status de­
spite equivalent levels of education with the general population. Individuals with bipolar
II disorder perform more poorly than healthy individuals on cognitive tests and, with the 
exception of memory and semantic fluency, have similar cognitive impairment as do in­
dividuals with bipolar I disorder. Cognitive impairments associated with bipolar II disor­
der may contribute to vocational difficulties. Prolonged unemployment in individuals

der may contribute to vocational difficulties. Prolonged unemployment in individuals 
with bipolar disorder is associated with more episodes of depression, older age, increased 
rates of current panic disorder, and lifetime history of alcohol use disorder.
Major depressive disorder. Perhaps the most challenging differential diagnosis to con­
sider is major depressive disorder, which may be accompanied by hypomanie or manic 
symptoms that do not meet full criteria (i.e., either fewer symptoms or a shorter duration 
than required for a hypomanie episode). This is especially true in evaluating individuals 
with symptoms of irritability, which may be associated with either major depressive dis­
order or bipolar II disorder.
Cyclothymic disorder. In cyclothymic disorder, there are numerous periods of hypo-

Cyclothymic disorder. In cyclothymic disorder, there are numerous periods of hypo- 
manic symptoms and numerous periods of depressive symptoms that do not meet symp­
tom or duration criteria for a major depressive episode. Bipolar II disorder is distinguished 
from cyclothymic disorder by the presence of one or more major depressive episodes. If a 
major depressive episode occurs after the first 2 years of cyclothymic disorder, the addi­
tional diagnosis of bipolar II disorder is given.
Schizophrenia spectrum and other related psychotic disorders. Bipolar II disorder must 
be distinguished from psychotic disorders (e.g., schizoaffective disorder, schizophrenia, 
and delusional disorder). Schizophrenia, schizoaffective disorder, and delusional disor­
der are all characterized by periods of psychotic symptoms that occur in the absence of 
prominent mood symptoms. Other helpful considerations include the accompanying

prominent mood symptoms. Other helpful considerations include the accompanying 
symptoms, previous course, and family history.
Panic disorder or other anxiety disorders. Anxiety disorders need to be considered in 
the differential diagnosis and may frequently be present as co-occurring disorders.
Substance use disorders. Substance use disorders are included in the differential diag­
nosis.
Attention-deficit/hyperactivity disorder. Attention-deficit/hyperactivity disorder (ADHD) 
may be misdiagnosed as bipolar II disorder, especially in adolescents and children. Many

symptoms of ADHD, such as rapid speech, racing thoughts, distractibility, and less need 
for sleep, overlap with the symptoms of hypomania. The double counting of symptoms to­
ward both ADHD and bipolar II disorder can be avoided if the clinician clarifies whether 
the symptoms represent a distinct episode and if the noticeable increase over baseline re­
quired for the diagnosis of bipolar II disorder is present.
Personality disorders. The same convention as applies for ADHD also applies when 
evaluating an individual for a personality disorder such as borderline personality disor­
der, since mood lability and impulsivity are common in both personality disorders and bi­
polar II disorder. Symptoms must represent a distinct episode, and the noticeable increase 
over baseline required for the diagnosis of bipolar II disorder must be present. A diagnosis 
of a personality disorder should not be made during an untreated mood episode unless

of a personality disorder should not be made during an untreated mood episode unless 
the lifetime history supports the presence of a personality disorder.
Other bipolar disorders. Diagnosis of bipolar II disorder should be differentiated from 
bipolar I disorder by carefully considering whether there have been any past episodes of 
mania and from other specified and unspecified bipolar and related disorders by confirm­
ing the presence of fully syndromal hypomania and depression.
Bipolar II disorder is more often than not associated with one or more co-occurring mental 
disorders, with anxiety disorders being the most common. Approximately 60% of individ­
uals with bipolar II disorder have three or more co-occurring mental disorders; 75% have 
an anxiety disorder; and 37% have a substance use disorder. Children and adolescents

an anxiety disorder; and 37% have a substance use disorder. Children and adolescents 
with bipolar II disorder have a higher rate of co-occurring anxiety disorders compared 
with those with bipolar I disorder, and the anxiety disorder most often predates the bi­
polar disorder. Anxiety and substance use disorders occur in individuals with bipolar II 
disorder at a higher rate than in the general population. Approximately 14% of individuals 
with bipolar II disorder have at least one lifetime eating disorder, with binge-eating dis­
order being more common than bulimia nervosa and anorexia nervosa.
These commonly co-occurring disorders do not seem to follow a course of illness that 
is truly independent from that of the bipolar disorder, but rather have strong associations 
with mood states. For example, anxiety and eating disorders tend to associate most with

with mood states. For example, anxiety and eating disorders tend to associate most with 
depressive symptoms, and substance use disorders are moderately associated with manic 
symptoms.
Cyclothymic Disorder
Diagnostic Criteria 301.13 (F34.0)
A. For at least 2 years (at least 1  year in children and adolescents) there have been nu­
merous periods with hypomanie symptoms that do not meet criteria for a hypomanie  
episode and numerous periods with depressive symptoms that do not meet criteria for  
a major depressive episode.
B. During the above 2-year period (1 year in children and adolescents), the hypomanie  
and depressive periods have been present for at least half the time and the individual  
has not been without the symptoms for more than 2 months at a time.
C. Criteria for a major depressive, manic, or hypomanie episode have never been met.

D. The symptoms in Criterion A are not better explained by schizoaffective disorder,  
schizophrenia, schizophreniform disorder, delusional disorder, or other specified or un­
specified schizophrenia spectrum and other psychotic disorder.
E. The symptoms are not attributable to the physiological effects of a substance (e.g., a  
drug of abuse, a medication) or another medical condition (e.g., hyperthyroidism).

F. The symptoms cause clinically significant distress or impairment in social, occupa­
With anxious distress (see p. 149) _______________________________________
The essential feature of cyclothymic disorder is a chronic, fluctuating mood disturbance 
involving numerous periods of hypomanie symptoms and periods of depressive symp­
toms that are distinct from each other (Criterion A). The hypomanie symptoms are of 
insufficient number, severity, pervasiveness, or duration to meet full criteria for a hypo- 
manic episode, and the depressive symptoms are of insufficient number, severity, perva­
siveness, or duration to meet full criteria for a major depressive episode. During the initial 
2-year period (1 year for children or adolescents), the symptoms must be persistent (pres­
ent more days than not), and any symptom-free intervals last no longer than 2 months

ent more days than not), and any symptom-free intervals last no longer than 2 months 
(Criterion B). The diagnosis of cyclothymic disorder is made only if the criteria for a major 
depressive, manic, or hypomanie episode have never been met (Criterion C).
If an individual with cyclothymic disorder subsequently (i.e., after the initial 2 years in 
adults or 1  year in children or adolescents) experiences a major depressive, manic, or hy­
pomanie episode, the diagnosis changes to major depressive disorder, bipolar I disorder, 
or other specified or unspecified bipolar and related disorder (subclassified as hypomanie 
episode without prior major depressive episode), respectively, and the cyclothymic disor­
der diagnosis is dropped.
The cyclothymic disorder diagnosis is not made if the pattern of mood swings is better

The cyclothymic disorder diagnosis is not made if the pattern of mood swings is better 
explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delu­
sional disorder, or other specified and unspecified schizophrenia spectrum and other 
psychotic disorders (Criterion D), in which ease the mood symptoms are considered asso­
ciated features of the psychotic disorder. The mood disturbance must also not be attribut­
able to the physiological effects of a substance (e.g., a drug of abuse, a medication) or 
another medical condition (e.g., hyperthyroidism) (Criterion E). Although some individ­
uals may function particularly well during some of the periods of hypomania, over the 
prolonged course of the disorder, there must be clinically significant distress or impair­
ment in social, occupational, or other important areas of functioning as a result of the

ment in social, occupational, or other important areas of functioning as a result of the 
mood disturbance (Criterion F). The impairment may develop as a result of prolonged pe­
riods of cyclical, often unpredictable mood changes (e.g., the individual may be regarded 
as temperamental, moody, unpredictable, inconsistent, or unreliable).
The lifetime prevalence of cyclothymic disorder is approximately 0.4%-l%. Prevalence in 
mood disorders clinics may range from 3% to 5%. In the general population, cyclothymic 
disorder is apparently equally common in males and females. In clinical settings, females 
with cyclothymic disorder may be more likely to present for treatment than males.
Cyclothymic disorder usually begins in adolescence or early adult life and is sometimes 
considered to reflect a temperamental predisposition to other disorders in this chapter.

considered to reflect a temperamental predisposition to other disorders in this chapter. 
Cyclothymic disorder usually has an insidious onset and a persistent course. There is a 
15%-50% risk that an individual with cyclothymic disorder will subsequently develop bi­
polar I disorder or bipolar II disorder. Onset of persistent, fluctuating hypomanie and de­
pressive symptoms late in adult life needs to be clearly differentiated from bipolar and

related disorder due to another medical condition and depressive disorder due to another 
medical condition (e.g., multiple sclerosis) before the cyclothymic disorder diagnosis is as­
signed. Among children with cyclothymic disorder, the mean age at onset of symptoms is 
6.5 years of age.
Genetic and physiological. Major depressive disorder, bipolar I disorder, and bipolar II 
disorder are more common among first-degree biological relatives of individuals with cyclo­
thymic disorder than in the general population. There may also be an increased familial risk of 
substance-related disorders. Cyclotiiymic disorder may be more common in the first-degree 
biological relatives of individuals w itiK  bipolar I disorder than in the general population.
Bipolar and related disorder due to another medical condition and depressive disorder  
due to another medical condition. The diagnosis of bipolar and related disorder due to

due to another medical condition. The diagnosis of bipolar and related disorder due to 
another medical condition or depressive disorder due to another medical condition is 
made when the mood disturbance is judged to be attributable to the physiological effect of 
a specific, usually chronic medical condition (e.g., hyperthyroidism). This determination 
is based on the history, physical examination, or laboratory findings. If it is judged that the 
hypomanie and depressive symptoms are not the physiological consequence of the med­
ical condition, then the primary mental disorder (i.e., cyclothymic disorder) and the med­
ical condition are coded. For example, this would be the case if the mood symptoms are 
considered to be the psychological (not the physiological) consequence of having a chronic

considered to be the psychological (not the physiological) consequence of having a chronic 
medical condition, or if there is no etiological relationship between the hypomanie and de­
pressive symptoms and the medical condition.
Substance/medication-induced bipolar and related disorder and substance/medica­
tion-induced depressive disorder. Substance/medication-induced bipolar and related 
disorder and substance/medication-induced depressive disorder are distinguished from 
cyclothymic disorder by the judgment that a substance/medication (especially stimu­
lants) is etiologically related to the mood disturbance. The frequent mood swings in these 
disorders that are suggestive of cyclothymic disorder usually resolve following cessation 
of substance/medication use.
Bipolar I disorder, with rapid cycling, and bipolar II disorder, with rapid cycling.

Both disorders may resemble cyclothymic disorder by virtue of the frequent marked shifts 
in mood. By definition, in cyclothymic disorder the criteria for a major depressive, manic, 
or hypomanie episode has never been met, whereas the bipolar I disorder and bipolar II 
disorder specifier "with rapid cycling" requires that full mood episodes be present.
Borderline personality disorder. Borderline personality disorder is associated with 
marked shifts in mood that may suggest cyclothymic disorder. If the criteria are met for 
both disorders, both borderline personality disorder and cyclothymic disorder may be di­
agnosed.
Substance-related disorders and sleep disorders (i.e., difficulties in initiating and main­
taining sleep) may be present in individuals with cyclothymic disorder. Most children

agnosed.
taining sleep) may be present in individuals with cyclothymic disorder. Most children 
with cyclothymic disorder treated in outpatient psychiatric settings have comorbid mental 
conditions; they are more likely than other pediatric patients with mental disorders to 
have comorbid attention-deficit/hyperactivity disorder.

Bipolar and Related Disorder
A. A prominent and persistent disturbance in  mood that predominates in  the clinical picture  
and is characterized by elevated, expansive, or irritable mood, with or without depressed  
mood, or markedly diminished interest or pleasure in  all, or almost all, activities.
rion A.
C. The disturbance is not better explained by a bipolar or related disorder that is not sub­
stance/medication-induced. Such evidence of an independent bipolar or related disor­
der could include the following:
The symptoms precede the onset of the substance/medication use; the symptoms per­

sist for a substantial period of time (e.g., about 1  month) after the cessation of acute  
withdrawal or severe intoxication; or there is other evidence suggesting the existence  
of an independent non-substance/medication-induced bipolar and related disorder  
(e.g., a history of recurrent non-substance/medication-related episodes).
Coding note: The ICD-9-CM and ICD-10-CM codes for the [specific substance/medication]-  
induced bipolar and related disorders are indicated in  the table below. Note that the ICD-10-

induced bipolar and related disorders are indicated in  the table below. Note that the ICD-10-  
CM code depends on whether or not there is a comorbid substance use disorder present for  
the same class of substance. If a m ild substance use disorder is  comorbid with the substance-  
induced bipolar and related disorder, the 4th position character is “1,”  and the clinician should  
record “ m ild [substance] use disorder'’ before the substance-induced bipolar and related dis­
order (e.g., “ m ild cocaine use disorder with cocaine-induced bipolar and related disorder” ). If a  
moderate or severe substance use disorder is comorbid with the substance-induced bipolar  
and related disorder, the 4th position character is “ 2,”  and the clinician should record “ moder­
ate [substance] use disorder'’ or “ severe [substance] use disorder,”  depending on the severity

ate [substance] use disorder'’ or “ severe [substance] use disorder,”  depending on the severity  
of the comorbid substance use disorder. If there is  no comorbid substance use disorder (e.g.,  
after a one-time heavy use of the substance), then the 4th position character is “ 9,”  and the  
clinician should record only the substance-induced bipolar and related disorder.
ICD-10-CM
With use  
disorder,  
ICD-9-CIVI mildWith use  
disorder,  
moderate  
use
disorder
Alcohol  
Phencyclidine  
Other hallucinogen291.89
292.84
292.84F10.14
F16.14
F16.14F10.24  
FI 6.24  
FI 6.24FI 0.94  
F16.94  
F16.94

ICD-10-CM
disorder,  
disorder,  
moderate  
use
disorder
Sedative, hypnotic, or anxiolytic 292.84 F13.14 F13.24 F13.94
stimulant)292.84 F15.14 F15.24 FI 5.94
Cocaine 292.84 F14.14 F14.24 F14.94
Other (or unknown) substance 292.84 F19.14 F19.24 FI 9.94
Specify  if (see Table 1  in the chapter “ Substance-Related and Addictive Disorders”  for di­
agnoses associated with substance class):
With onset during withdrawal: If criteria are met for withdrawal from the substance  
and the symptoms develop during, or shortly after, withdrawal.
ICD-9-CM. The name of the substance/medication-induced bipolar and related disor­
der begins with the specific substance (e.g., cocaine, dexamethasone) that is presumed to

der begins with the specific substance (e.g., cocaine, dexamethasone) that is presumed to 
be causing the bipolar mood symptoms. The diagnostic code is selected from the table in­
cluded in the criteria set, which is based on the drug class. For substances that do not fit 
into any of the classes (e.g., dexamethasone), the code for "other substance" should be 
class of substance is unknown, the category "unknown substance" should be used.

example, in the case of irritable symptoms occurring during intoxication in a man with a 
severe cocaine use disorder, the diagnosis is 292.84 cocaine-induced bipolar and related 
disorder, with onset during intoxication. An additional diagnosis of 304.20 severe cocaine 
use disorder is also given. When more than one substance is judged to play a significant 
role in the development of bipolar mood symptoms, each should be listed separately (e.g., 
292.84 methylphenidate-induced bipolar and related disorder, with onset during intoxi­
cation; 292.84 dexamethasone-induced bipolar and related disorder, with onset during in­
toxication).
ICD-10-CM. The name of the substance/medication-induced bipolar and related disor­

cluded in the criteria set, which is based on the drug class and presence or absence of a co- 
morbid substance use disorder. For substances that do not fit into any of the classes (e.g., 
dexamethasone), the code for "other substance" should be used; and in cases in which a 
substance is judged to be an etiological factor but the specific class of substance is un­
known, the category "unknown substance" should be used.
is listed first, followed by the word "with," followed by the name of the substance-induced

bipolar and related disorder, followed by the specification of onset (i.e., onset during in­
toxication, onset during withdrawal). For example, in the case of irritable symptoms oc­
curring during intoxication in a man with a severe cocaine use disorder, the diagnosis is 
F14.24 severe cocaine use disorder with cocaine-induced bipolar and related disorder, 
with onset during intoxication. A separate diagnosis of the comorbid severe cocaine use 
disorder is not given. If the substance-induced bipolar and related disorder occurs without 
a comorbid substance use disorder (e.g., after a one-time heavy use of the substance), no 
accompanying substance use disorder is noted (e.g., F15.94 amphetamine-induced bipolar 
and related disorder, with onset during intoxication). When more than one substance is 
judged to play a significant role in the development of bipolar mood symptoms, each 
should be listed separately (e.g., F15.24 severe methylphenidate use disorder with meth-

should be listed separately (e.g., F15.24 severe methylphenidate use disorder with meth- 
ylphenidate-induced bipolar and related disorder, with onset during intoxication; F19.94 
dexamethasone-induced bipolar and related disorder, with onset during intoxication).
The diagnostic features of substance/medication-induced bipolar and related disorder are es­
sentially the same as those for mania, hypomania, or depression. A key exception to the diag­
nosis of substance/medication-induced bipolar and related disorder is the case of hypomania 
or mania that occurs after antidepressant medication use or other treatments and persists be­
yond the physiological effects of the medication. This condition is considered an indicator of 
true bipolar disorder, not substance/medication-induced bipolar and related disorder. Simi­

larly, individuals with apparent electroconvulsive therapy-induced manic or hypomanie ep­
isodes that persist beyond the physiological effects of the treatment are diagnosed with 
bipolar disorder, not substance/medication-induced bipolar ^ d  related disorder.
Side effects of some antidepressants and other psychotropic drugs (e.g., edginess, ag­
itation) may resemble the primary symptoms of a manic syndrome, but they are funda­
mentally distinct from bipolar symptoms and are insufficient for the diagnosis. That is, the 
criterion symptoms of mania/hypomania have specificity (simple agitation is not the same 
as excess involvement in purposeful activities), and a sufficient number of symptoms 
must be present (not just one or two symptoms) to make these diagnoses. In particular, the

must be present (not just one or two symptoms) to make these diagnoses. In particular, the 
appearance of one or two nonspecific sjonptoms—irritability, edginess, or agitation during 
antidepressant treatment—in the absence of a full manic or hypomanie syndrome should 
not be taken to support a diagnosis of a bipolar disorder.
Etiology (causally related to the use of psychotropic medications or substances of abuse 
based on best clinical evidence) is the key variable in this etiologically specified form of bi­
polar disorder. Substances/medications that are typically considered to be associated 
with substance/medication-induced bipolar and related disorder include the stimulant 
class of drugs, as well as phencyclidine and steroids; however, a number of potential sub­
stances continue to emerge as new compounds are synthesized (e.g., so-called bath salts).

stances continue to emerge as new compounds are synthesized (e.g., so-called bath salts). 
A history of such substance use may help increase diagnostic certainty.
There are no epidemiological studies of substance/medication-induced mania or bipolar 
disorder. Each etiological substance may have its own individual risk of inducing a bipo­
lar (manic/hypomanie) disorder.
In phencyclidine-induced mania, the initial presentation may be one of a delirium with af­
fective features, which then becomes an atypically appearing manic or mixed manic state.

This condition follows the ingestion or inhalation quickly, usually within hours or, at the 
most, a few dayâ^ In stimulant-induced manic or hypomanie states, the response is in min­
utes to 1  hour after one or several ingestions or injections. The episode is very brief and 
typically resolves over 1-2 days. With corticosteroids and some immunosuppressant 
medications, the mania (or mixed or depressed state) usually follows several days of in­
gestion, and the higher doses appear to have a much greater likelihood of producing bi­
polar symptoms.
Diagnostic iVlari(ers
Determination of the substance of use can be made through markers in the blood or urine 
to corroborate diagnosis.
Substance/medication-induced bipolar and related disorder should be differentiated 
from other bipolar disorders, substance intoxication or substance-induced delirium, and 
medication side effects (as noted earlier). A full manic episode that emerges during anti­

depressant treatment (e.g., medication, electroconvulsive therapy) but persists at a fully 
syndromal level beyond the physiological effect of that treatment is sufficient evidence for 
a bipolar I diagnosis. A full hypomanie episode that emerges during antidepressant treat­
ment (e.g., medication, electroconvulsive therapy) but persists at a fully syndromal level 
beyond the physiological effect of that treatment is sufficient evidence for a bipolar II di­
agnosis only if preceded by a major depressive episode.
Comorbidities are those associated with the use of illicit substances (in the case of illegal 
stimulants or phencyclidine) or diversion of prescribed stimulants. Comorbidities related 
to steroid or immunosuppressant medications are those medical indications for these

to steroid or immunosuppressant medications are those medical indications for these 
preparations. Delirium can occur before or along with manic symptoms in individuals in­
gesting phencyclidine or those who are prescribed steroid medications or other immuno­
suppressant medications.
Bipolar and Related Disorder  
A. A prominent and persistent period of abnormally elevated, expansive, or irritable mood  
and abnormally increased activity or energy that predominates in the clinical picture.
B. There is evidence from the history, physical examination, or laboratory findings that the dis­
turbance is the direct pathophysiological consequence of another medical condition.

tional, or other important areas of functioning, or necessitates hospitalization to pre­
vent harm to self or others, or there are psychotic features.
Coding note: The ICD-9-CM code for bipolar and related disorder due to another medical  
condition is 293.83, which is assigned regardless of the specifier. The ICD-10-CM code  
depends on the specifier (see below).

(F06.33) With manic features: Full criteria are not met for a manic or hypomanie ep­
isode.
(F06.33) With manic- or hypomanic-iii<e episode: Full criteria are met except Crite­
rion D for a manic episode or except Criterion F for a hypomanie episode.
(F06.34) With mixed features: Symptoms of depression are also present but do not  
predominate in the clinical picture.
disorder (e.g., 293.83 [F06.33] bipolar disorder due to hyperthyroidism, with manic fea­
tures). The other medical condition should also be coded and listed separately immedi­
ately before the bipolar and related disorder due to the medical condition (e.g., 242.90  
[E05.90] hyperthyroidism; 293.83 [F06.33] bipolar disorder due to hyperthyroidism, with  
manic features).
The essential features of bipolar and related disorder due to another medical condition are

The essential features of bipolar and related disorder due to another medical condition are 
presence of a prominent and persistent period of abnormally elevated, expansive, or irri­
table mood and abnormally increased activity or energy predominating in the clinical pic­
ture that is attributable to another medical condition (Criterion B). In most cases the manic 
or hypomanie picture may appear during the initial presentation of the medical condition 
(i.e., within 1  month); however, there are exceptions, especially in chronic medical condi­
tions that might worsen or relapse and herald the appearance of the manic or hypomanie 
picture. Bipolar and related disorder due to another medical condition would not be diag­
nosed when the manic or hypomanie episodes definitely preceded the medical condition, 
since the proper diagnosis would be bipolar disorder (except in the unusual circumstance

since the proper diagnosis would be bipolar disorder (except in the unusual circumstance 
in which all preceding manic or hypomanie episodes—or, when only one such episode has 
occurred, the preceding manic or hypomanie episode—were associated with ingestion of 
a substance/medication). The diagnosis of bipolar and related disorder due to another 
medical condition should not be made during the course of a delirium (Criterion D). The 
manic or hypomanie episode in bipolar and related disorder due to another medical con­
dition must cause clinically significant distress or impairment in social, occupational, or 
other important areas of functioning to qualify for this diagnosis (Criterion E).
Etiology (i.e., a causal relationship to another medical condition based on best clinical ev­

idence) is the key variable in this etiologically specified form of bipolar disorder. The list­
ing of medical conditions that are said to be able to induce mania is never complete, and 
the clinician's best judgment is the essence of this diagnosis. Among the best known of the 
medical conditions that can cause a bipolar manic or hypomanie condition are Cushing's 
disease and multiple sclerosis, as well as stroke and traumatic brain injuries.
Bipolar and related disorder due to another medical condition usually has its onset acutely 
or subacutely within the first weeks or month of the onset of the associated medical con­
dition. However, this is not always the case, as a worsening or later relapse of the associ­
ated medical condition may precede the onset of the manic or hypomanie syndrome. The

ated medical condition may precede the onset of the manic or hypomanie syndrome. The 
clinician must make a clinical judgment in these situations about whether the medical con­
dition is causative, based on temporal sequence as well as plausibility of a causal relation­

ship. Finally, the condition may remit before or just after the medical condition remits, 
particularly wh^n treatment of the manic/hypomanie symptoms is effective.
Culture-related differences, to the extent that there is any evidence, pertain to those asso­
ciated with the medical condition (e.g., rates of multiple sclerosis and stroke vary around 
the world based on dietary, genetic factors, and other environmental factors).
Gender differences pertain to those associated with the medical condition (e.g., systemic 
lupus erythematosus is more common in females; stroke is somewhat more common in 
middle-age males compared with females).
Diagnostic Markers
Diagnostic markers pertain to those associated with the medical condition (e.g., steroid 
levels in blood or urine to help corroborate the diagnosis of Cushing's disease, which can 
be associated with manic or depressive syndromes; laboratory tests confirming the diag­

nosis of multiple sclerosis).
Functional Consequences of Bipolar and Related  
Disorder Due to Another Medical Condition
Functional consequences of the bipolar symptoms may exacerbate impairments associ­
ated with the medical condition and may incur worse outcomes due to interference with 
medical treatment. In general, it is believed, but not established, that the illness, when in­
duced by Cushing's disease, will not recur if the Cushing's disease is cured or arrested. 
However, it is also suggested, but not established, that mood syndromes, including de­
pressive and manic/hypomanie ones, may be episodic (i.e., recurring) with static brain in­
juries and other central nervous system diseases.
Symptoms of delirium, catatonia, and acute anxiety. It is important to differentiate

Symptoms of delirium, catatonia, and acute anxiety. It is important to differentiate 
symptoms of mania from excited or hypervigilant delirious symptoms; from excited cata­
tonic symptoms; and from agitation related to acute anxiety states.
Medication-induced depressive or manic symptoms. An important differential diag­
nostic observation is that the other medical condition may be treated with medications 
(e.g., steroids or alpha-interferon) that can induce depressive or manic symptoms. In these 
cases, clinical judgment using all of the evidence in hand is the best way to try to separate 
the most likely and/or the most important of two etiological factors (i.e., association with 
the medical condition vs. a substance/medication-induced syndrome). The differential di­
agnosis of the associated medical conditions is relevant but largely beyond the scope of the 
present manual.

Conditions comorbid with bipolar and related disorder due to another medical condition 
are those associated with the medical conditions of etiological relevance. Delirium can oc­
cur before or along with manic symptoms in individuals with Cushing's disease.

Other Specified Bipolar and Related Disorder
296.89 (F31.89)
This category applies to presentations in which symptoms characteristic of a bipolar and  
related disorder that cause clinically significant distress or impairment in social, occupa­
tional, or other important areas of functioning predominate but do not meet the full criteria  
for any of the disorders in the bipolar and related disorders diagnostic class. The other  
specified bipolar and related disorder category is used in situations in which the clinician  
chooses to communicate the specific reason that the presentation does not meet the cri­
teria for any specific bipolar and related disorder. This is done by recording “ other speci­
fied bipolar and related disorder”  followed by the specific reason (e.g., “ short-duration  
cyclothymia” ).

1. Short-duration hypomanie episodes (2-3 days) and major depressive episodes: A
lifetime history of one or more major depressive episodes in  individuals whose presenta­
tion has never met full criteria for a manic or hypomanie episode but who have experienced  
two or more episodes of short-duration hypomania that meet the full symptomatic criteria  
for a hypomanie episode but that only last for 2-3 days. The episodes of hypomanie symp­
toms do not overlap in  time with the major depressive episodes, so the disturbance does  
not meet criteria for major depressive episode, with mixed features.
2. Hypomanie episodes with insufficient symptoms and major depressive epi­
sodes: A lifetime history of one or more major depressive episodes in individuals  
whose presentation has never met full criteria for a manic or hypomanie episode but

whose presentation has never met full criteria for a manic or hypomanie episode but  
who have experienced one or more episodes of hypomania that do not meet full symp­
tomatic criteria (i.e., at least 4 consecutive days of elevated mood and one or two of  
the other symptoms of a hypomanie episode, or irritable mood and two or three of the  
other symptoms of a hypomanie episode). The episodes of hypomanie symptoms do  
not overlap in  time with the major depressive episodes, so the disturbance does not  
meet criteria for major depressive episode, with mixed features.
3. Hypomanie episode without prior major depressive episode: One or more hypo-  
manic episodes in an individual whose presentation has never met full criteria for a ma­
jor depressive episode or a manic episode. If this occurs in an individual with an

jor depressive episode or a manic episode. If this occurs in an individual with an  
established diagnosis of persistent depressive disorder (dysthymia), both diagnoses  
can be concurrently applied during the periods when the full criteria for a hypomanie  
episode are met.
4. Short-duration eyelothymia (less than 24 months): Multiple episodes of hypomanie  
symptoms that do not meet criteria for a hypomanie episode and multiple episodes of de­
pressive symptoms that do not meet criteria for a major depressive episode that persist  
over a period of less than 24 months (less than 12 months for children or adolescents)  
in an individual whose presentation has never met full criteria for a major depressive,  
manic, or hypomanie episode and does not meet criteria for any psychotic disorder. Dur­
ing the course of the disorder, the hypomanie or depressive symptoms are present for

ing the course of the disorder, the hypomanie or depressive symptoms are present for  
more days than not, the individual has not been without symptoms for more than 2 months  
at a time, and the symptoms cause clinically significant distress or impairment.

Unspecified Bipolar and Related Disorder
_________________________________V_______________________________________________________________________________________________________________________________________________________
296.80 (F31.9)
This category applies to presentations in  which symptoms characteristic of a bipolar and  
for any of the disorders in the bipolar and related disorders diagnostic class. The unspec­
ified bipolar and related disorder category is used in situations in which the clinician choos­
es not to specify the reason that the criteria are not met for a specific bipolar and related  
disorder, and includes presentations in which there is insufficient information to make a  
more specific diagnosis (e.g., in  emergency room settings).

Specifiers for Bipolar and Related Disorders
With anxious distress: The presence of at least two of the following symptoms during  
the majority of days of the current or most recent episode of mania, hypomania, or de­
pression:
1. Feeling keyed up or tense.
2. Feeling unusually restless.
3. Difficulty concentrating because of worry.
4. Fear that something awful may happen.
5. Feeling that the individual might lose control of himself or herself.
Specify  current severity:  
lUlild: Two symptoms.  
lUloderate: Three symptoms.
Moderate-severe: Four or five symptoms.
Severe: Four or five symptoms with motor agitation.
Note: Anxious distress has been noted as a prominent feature of both bipolar and  
major depressive disorder in both primary care and specialty mental health set­

tings. High levels of anxiety have been associated with higher suicide risk, longer  
duration of illness, and greater likelihood of treatment nonresponse. As a result, it  
is clinically useful to specify accurately the presence and severity levels of anxious  
distress for treatment planning and monitoring of response to treatment.
With mixed features: The mixed features specifier can apply to the current manic, hy­
pomanie, or depressive episode in  bipolar I or bipolar II disorder:
IManic or hypomanie episode, with mixed features:
A. Full criteria are met for a manic episode or hypomanie episode, and at least  
three of the following symptoms are present during the majority of days of the  
current or most recent episode of mania or hypomania:
1. Prominent dysphoria or depressed mood as indicated by either subjective

1. Prominent dysphoria or depressed mood as indicated by either subjective  
report (e.g., feels sad or empty) or observation made by others (e.g., ap­
pears tearful).
2. Diminished interest or pleasure in all, or almost all, activities (as indicated by  
either subjective account or observation made by others).
3. Psychomotor retardation nearly every day (observable by others; not merely  
subjective feelings of being slowed down).

4. Fatigue or loss of energy.
5. Feelings of worthlessness or excessive or inappropriate guilt (not merely  
self-reproach or guilt about being sick).
6. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ide­
ation without a specific plan, or a suicide attempt or a specific plan for com­
mitting suicide.
B. Mixed symptoms are observable by others and represent a change from the  
person’s usual behavior.
C. For individuals whose symptoms meet full episode criteria for both mania and  
depression simultaneously, the diagnosis should be manic episode, with mixed  
features, due to the marked impairment and clinical severity of full mania.
D. The mixed symptoms are not attributable to the physiological effects of a sub­
stance (e.g., a drug of abuse, a medication, other treatment).
Depressive episode, witli mixed features:
A. Full criteria are met for a major depressive episode, and at least three of the fol­

lowing manic/hypomanic symptoms are present during the majority of days of  
the current or most recent episode of depression:
1. Elevated, expansive mood.
2. Inflated self-esteem or grandiosity.
5. Increase in energy or goal-directed activity (either socially, at work or school,  
or sexually).
6. Increased or excessive involvement in activities that have a high potential  
for painful consequences (e.g., engaging in unrestrained buying sprees,  
sexual indiscretions, or foolish business investments).
7. Decreased need for sleep (feeling rested despite sleeping less than usual;  
to be contrasted with insomnia).

features.
stance (e.g., a drug of abuse, a medication, or other treatment).
Note: Mixed features associated with a major depressive episode have been found  
to be a significant risk factor for the development of bipolar I or bipolar II disorder.  
As a result, it is clinically useful to note the presence of this specifier for treatment  
planning and monitoring of response to treatment.
Witli rapid cycling (can be applied to bipolar I  or bipolar II disorder): Presence of at

Witli rapid cycling (can be applied to bipolar I  or bipolar II disorder): Presence of at  
least four mood episodes in the previous 12 months that meet the criteria for manic,  
hypomanie, or major depressive episode.
Note: Episodes are demarcated by either partial or full remissions of at least 2 months  
or a switch to an episode of the opposite polarity (e.g., major depressive episode to  
manic episode).
Note: The essential feature of a rapid-cycling bipolar disorder is the occurrence of  
at least four mood episodes during the previous 12 months. These episodes can  
occur in any combination and order. The episodes must meet both the duration and

symptom number criteria for a major depressive, manic, or hypomanie episode and  
must be demarcated by either a period of full remission or a switch to an episode  
of the opposite polarity. Manic and hypomanie episodes are counted as being on  
the same pole. Except for the fact that they occur more frequently, the episodes that  
occur in a rapid-cycling pattern are no different from those that occur in a non-rapid-  
cycling pattern. Mood episodes that count toward defining a rapid-cycling pattern  
exclude those episodes directly caused by a substance (e.g., cocaine, corticoste­
roids) or another medical condition.
With melancholic features:
A. One of the following is present during the most severe period of the current episode;
1. Loss of pleasure in all, or almost all, activities.
2. Lack of reactivity to usually pleasurable stimuli (does not feel much better, even  
temporarily, when something good happens).
B. Three (or more) of the following:

1. A distinct quality of depressed mood characterized by profound despondency,  
despair, and/or moroseness or by so-called empty mood.
2. Depression that is regularly worse in the morning.
3. Early-morning awakening (i.e., at least 2 hours before usual awakening).
4. Marked psychomotor agitation or retardation.
5. Significant anorexia or weight loss.
6. Excessive or inappropriate guilt.
Note: The specifier “ with melancholic features”  is applied if these features are pres­
ent at the most severe stage of the episode. There is a near-complete absence of  
the capacity for pleasure, not merely a diminution. A guideline for evaluating the  
lack of reactivity of mood is that even highly desired events are not associated with  
marked brightening of mood. Either mood does not brighten at all, or it brightens

marked brightening of mood. Either mood does not brighten at all, or it brightens  
only partially (e.g., up to 20% -40%  of normal for only minutes at a time). The “ dis­
tinct quality”  of mood that is characteristic of the “ with melancholic features”  speci­
fier is experienced as qualitatively different from that during a nonmelancholic  
depressive episode. A depressed mood that is described as merely more severe,  
longer lasting, or present without a reason is not considered distinct in quality. Psy­
chomotor changes are nearly always present and are observable by others.
Melancholic features exhibit only a modest tendency to repeat across episodes  
in the same individual. They are more frequent in inpatients, as opposed to outpa­
tients; are less likely to occur in milder than in more severe major depressive epi­
sodes; and are more likely to occur in those with psychotic features.

With atypical features: This specifier can be applied when these features predomi­
nate during the majority of days of the current or most recent major depressive epi­
sode.
A. Mood reactivity (i.e., mood brightens in response to actual or potential positive  
events).
B. Two (or more) of the following features:
1. Significant weight gain or increase in appetite.
2. Hypersomnia.
3. Leaden paralysis (i.e., heavy, leaden feelings in arms or legs).
4. A long-standing pattern of interpersonal rejection sensitivity (not limited to epi­
sodes of mood disturbance) that results in significant social or occupational  
impairment.

C. Criteria are not met for “ with melancholic features”  or “ with catatonia”  during the  
same episode.
Note: “ Atypical depression”  has historical significance (i.e., atypical in contradis­
tinction to the more classical agitated, “ endogenous”  presentations of depression  
that were the norm when depression was rarely diagnosed in outpatients and al­
most never in adolescents or younger adults) and today does not connote an un­
common or unusual clinical presentation as the term might imply.
Mood reactivity is the capacity to be cheered up when presented with positive  
events (e.g., a visit from children, compliments from others). Mood may become  
euthymie (not sad) even for extended periods of time if the external circumstances  
remain favorable. Increased appetite may be manifested by an obvious increase in  
food intake or by weight gain. Hypersomnia may include either an extended period

food intake or by weight gain. Hypersomnia may include either an extended period  
of nighttime sleep or daytime napping that totals at least 10 hours of sleep per day  
(or at least 2 hours more than when not depressed). Leaden paralysis is defined as  
feeling heavy, leaden, or weighted down, usually in the arms or legs. This sensation  
is generally present for at least an hour a day but often lasts for many hours at a  
time. Unlike the other atypical features, pathological sensitivity to perceived inter­
personal rejection is a trait that has an early onset and persists throughout most of  
adult life. Rejection sensitivity occurs both when the person is and is not depressed,  
though it may be exacerbated during depressive periods.
With psychotic features: Delusions or hallucinations are present at any time in the

With psychotic features: Delusions or hallucinations are present at any time in the  
episode. If psychotic features are present, specify if mood-congruent or mood-incon-  
gruent:
With mood-congruent psychotic features: During manic episodes, the con­
tent of all delusions and hallucinations is consistent with the typical manic  
themes of grandiosity, invulnerability, etc., but may also include themes of sus­
piciousness or paranoia, especially with respect to others’ doubts about the in­
dividual’s capacities, accomplishments, and so forth.
With mood-incongruent psychotic features: The content of delusions and  
hallucinations is inconsistent with the episode polarity themes as described  
above, or the content is a mixture of mood-incongruent and mood-congruent  
themes.
With catatonia: This specifier can apply to an episode of mania or depression if cata­

themes.
tonic features are present during most of the episode. See criteria for catatonia asso­
ciated with a mental disorder in the chapter “ Schizophrenia Spectrum and Other  
Psychotic Disorders.”
With péripartum onset: This specifier can be applied to the current or, if the full crite­
ria are not currently met for a mood episode, most recent episode of mania, hypoma-  
nia, or major depression in  bipolar I  or bipolar I! disorder if onset of mood symptoms  
occurs during pregnancy or in the 4 weeks following delivery.
Note: Mood episodes can have their onset either during pregnancy or postpartum.  
Although the estimates differ according to the period of follow-up after delivery, be­
tween 3% and 6% of women will experience the onset of a major depressive epi­

sode during pregnancy or in the weeks or months following delivery. Fifty percent  
of “ postpartum”  major depressive episodes actually begin prior to delivery. Thus,  
these episodes are referred to collectively as péripartum  episodes. Women with  
péripartum major depressive episodes often have severe anxiety and even panic  
attacks. Prospective studies have demonstrated that mood and anxiety symptoms  
during pregnancy, as well as the “ baby blues,”  increase the risk for a postpartum  
major depressive episode.

Peripartum-onset mood episodes can present either with or without psychotic  
features^ Infanticide is most often associated with postpartum psychotic episodes  
that are characterized by command hallucinations to kill the infant or delusions that  
the infant is possessed, but psychotic symptoms can also occur in severe postpar­
tum mood episodes without such specific delusions or hallucinations.
Postpartum mood (major depressive or manic) episodes with psychotic features  
appear to occur in from 1  in 500 to 1  in 1,000 deliveries and may be more common  
in primiparous women. The risk of postpartum episodes with psychotic features is  
particularly increased for women with prior postpartum mood episodes but is also  
elevated for those with a prior history of a depressive or bipolar disorder (especially  
bipolar I  disorder) and those with a family history of bipolar disorders.
Once a woman has had a postpartum episode with psychotic features, the risk

Once a woman has had a postpartum episode with psychotic features, the risk  
of recurrence with each subsequent delivery is between 30% and 50%. Postpartum  
episodes must be differentiated from delirium occurring in the postpartum period,  
which is distinguished by a fluctuating level of awareness or attention. The postpar­
tum period is unique with respect to the degree of neuroendocrine alterations and  
psychosocial adjustments, the potential impact of breast-feeding on treatment plan­
ning, and the long-term implications of a history of postpartum mood disorder on sub­
sequent family planning.
With seasonal pattern: This specifier applies to the lifetime pattern of mood episodes.  
The essential feature is a regular seasonal pattern of at least one type of episode (i.e.,  
mania, hypomania, or depression). The other types of episodes may not follow this pat­

tern. For example, an individual may have seasonal manias, but his or her depressions  
do not regularly occur at a specific time of year.
A. There has been a regular temporal relationship between the onset of manic, hypo-  
manic, or major depressive episodes and a particular time of the year (e.g., in  the  
fall or winter) in bipolar I or bipolar II disorder.
Note: Do not include cases in which there is an obvious effect of seasonally related  
psychosocial stressors (e.g., regularly being unemployed every winter).
B. Full remissions (or a change from major depression to mania or hypomania or vice  
versa) also occur at a characteristic time of the year (e.g., depression disappears  
in the spring).
C. In the last 2 years, the individual’s manic, hypomanie, or major depressive episodes

C. In the last 2 years, the individual’s manic, hypomanie, or major depressive episodes  
have demonstrated a temporal seasonal relationship, as defined above, and no  
non-seasonal episodes of that polarity have occurred during that 2-year period.
D. Seasonal manias, hypomanias, or depressions (as described above) substantially  
outnumber any nonseasonal manias, hypomanias, or depressions that may have  
occurred over the individual’s lifetime.
Note: This specifier can be applied to the pattern of major depressive episodes in  
bipolar I  disorder, bipolar II disorder, or major depressive disorder, recurrent. The  
essential feature is the onset and remission of major depressive episodes at char­
acteristic times of the year. In most cases, the episodes begin in fall or winter and  
remit in spring. Less commonly, there may be recurrent summer depressive epi­

sodes. This pattern of onset and remission of episodes must have occurred during  
at least a 2-year period, without any nonseasonal episodes occurring during this  
period. In addition, the seasonal depressive episodes must substantially outnum­
ber any nonseasonal depressive episodes over the individual’s lifetime.
This specifier does not apply to those situations in which the pattern is better ex­
plained by seasonally linked psychosocial stressors (e.g., seasonal unemployment  
or school schedule). Major depressive episodes that occur in a seasonal pattern

are often characterized by prominent energy, hypersomnia, overeating, weight  
gain, and a craving for carbohydrates. It is unclear whether a seasonal pattern is  
more likely in  recurrent major depressive disorder or in bipolar disorders. However,  
within the bipolar disorders group, a seasonal pattern appears to be more likely in  
bipolar II disorder than in  bipolar I  disorder. In some individuals, the onset of manic  
or hypomanie episodes may also be linked to a particular season.
The prevalence of winter-type seasonal pattern appears to vary with latitude,  
age, and sex. Prevalence increases with higher latitudes. Age is also a strong pre­
dictor of seasonality, with younger persons at higher risk for winter depressive epi­
sodes.
In partial remission: Symptoms of the immediately previous manic, hypomanie, or  
depressive episode are present, but fu ll criteria are not met, or there is a period lasting

sodes.
depressive episode are present, but fu ll criteria are not met, or there is a period lasting  
less than 2 months without any significant symptoms of a manic, hypomanie, or major  
depressive episode following the end of such an episode.
In full remission: During the past 2 months, no significant signs or symptoms of the  
disturbance were present.
Severity is based on the number of criterion symptoms, the severity of those symptoms,
and the degree of functional disability.
Mild: Few, if any, symptoms in excess of those required to meet the diagnostic criteria  
are present, the intensity of the symptoms is distressing but manageable, and the  
symptoms result in minor impairment in  social or occupational functioning.
Moderate: The number of symptoms, intensity of symptoms, and/or functional impair­

ment are between those specified for “ mild”  and “ severe.”
Severe: The number of symptoms is substantially in excess of those required to make  
the diagnosis, the intensity of the symptoms is seriously distressing and unmanage­
able, and the symptoms markedly interfere with social and occupational functioning.

D eprG SSiV G  diSO rdG rS include disruptive mood dysregulation disorder, major 
depressive disorder (including major depressive episode), persistent depressive disorder 
(dysthymia), premenstrual dysphoric disorder, substance/medication-induced depres­
sive disorder, depressive disorder due to another medical condition, other specified de­
pressive disorder, and imspecified depressive disorder. Unlike in DSM-IV, this chapter 
"Depressive Disorders" has been separated from the previous chapter "Bipolar and Re­
lated Disorders." The common feature of all of these disorders is the presence of sad, 
empty, or irritable mood, accompanied by somatic and cognitive changes that signifi­
cantly affect the individual's capacity to function. What differs among them are issues of 
duration, timing, or presumed etiology.
In order to address concerns about the potential for the overdiagnosis of and treatment

In order to address concerns about the potential for the overdiagnosis of and treatment 
for bipolar disorder in children, a new diagnosis, disruptive mood dysregulation disorder, 
referring to the presentation of children with persistent irritability and frequent episodes 
of extreme behavioral dyscontrol, is added to the depressive disorders for children up to 
12 years of age. Its placement in this chapter reflects the finding that children with this 
symptom pattern typically develop unipolar depressive disorders or anxiety disorders, 
rather than bipolar disorders, as they mature into adolescence and adulthood.
Major depressive disorder represents the classic condition in this group of disorders. It 
is characterized by discrete episodes of at least 2 weeks' duration (although most episodes 
last considerably longer) involving clear-cut changes in affect, cognition, and neurovege-

last considerably longer) involving clear-cut changes in affect, cognition, and neurovege- 
tative functions and inter-episode remissions. A diagnosis based on a single episode is 
possible, although the disorder is a recurrent one in the majority of cases. Careful consid­
eration is given to the delineation of normal sadness and grief from a major depressive ep­
isode. Bereavement may induce great suffering, but it does not typically induce an episode 
of major depressive disorder. When they do occur together, the depressive symptoms and 
functional impairment tend to be more severe and the prognosis is worse compared with 
bereavement that is not accompanied by major depressive disorder. Bereavement-related 
depression tends to occur in persons with other vulnerabilities to depressive disorders, 
and recovery may be facilitated by antidepressant treatment.

A more chronic form of depression, persistent depressive disorder (dysthymia), can be 
diagnosed when the mood disturbance continues for at least 2 years in adults or 1 year in 
children. This diagnosis, new in DSM-5, includes both the DSM-IV diagnostic categories of 
chronic major depression and dysthymia.
After careful scientific review of the evidence, premenstrual dysphoric disorder has 
been moved from an appendix of DSM-IV ("Criteria Sets and Axes Provided for Further 
Study") to Section II of DSM-5. Almost 20 years of additional of research on this condition 
has confirmed a specific and treatment-responsive form of depressive disorder that begins 
sometime following ovulation and remits within a few days of menses and has a marked 
impact on functioning.

medical conditions can be associated with depression-like phenomena. This fact is recog­
nized in the diagnoses of substance/medication-induced depressive disorder and depres­
sive disorder due to another medical condition.

Disruptive Mood Dysregulation Disorder
Diagnostic Criteria 296.99 (F34.8)
A. Severe recurrent temper outbursts manifested verbally (e.g., verbal rages) and/or be­
haviorally (e.g., physical aggression toward people or property) that are grossly out of  
proportion in intensity or duration to the situation or provocation.
B. The temper outbursts are inconsistent with developmental level.
C. The temper outbursts occur, on average, three or more times per week.
D. The mood between temper outbursts is persistently irritable or angry most of the day,  
nearly every day, and is observable by others (e.g., parents, teachers, peers).
E. Criteria A-D have been present for 12 or more months. Throughout that time, the indi­
vidual has not had a period lasting 3 or more consecutive months without all of the  
symptoms in Criteria A-D.
F. Criteria A and D are present in at least two of three settings (i.e., at home, at school,  
with peers) and are severe in at least one of these.

G. The diagnosis should not be made for the first time before age 6 years or after age 18  
years.
H. By history or observation, the age at onset of Criteria A-E is before 10 years.
I. There has never been a distinct period lasting more than 1  day during which the full  
symptom criteria, except duration, for a manic or hypomanie episode have been met.  
Note: Developmentally appropriate mood elevation, such as occurs in the context of a  
highly positive event or its anticipation, should not be considered as a symptom of ma­
nia or hypomania.
J. The behaviors do not occur exclusively during an episode of major depressive disorder  
and are not better explained by another mental disorder (e.g., autism spectrum disor­
der, posttraumatic stress disorder, separation anxiety disorder, persistent depressive

der, posttraumatic stress disorder, separation anxiety disorder, persistent depressive  
disorder [dysthymia]).
Note: This diagnosis cannot coexist with oppositional defiant disorder, intermittent ex­
plosive disorder, or bipolar disorder, though it can coexist with others, including major  
depressive disorder, attention-deficit/hyperactivity disorder, conduct disorder, and  
substance use disorders. Individuals whose symptoms meet criteria for both disruptive  
mood dysregulation disorder and oppositional defiant disorder should only be given the  
diagnosis of disruptive mood dysregulation disorder. If an individual has ever experi­
enced a manic or hypomanie episode, the diagnosis of disruptive mood dysregulation  
disorder should not be assigned.
K. The symptoms are not attributable to the physiological effects of a substance or to an­
other medical or neurological condition.

The core feature of disruptive mood dysregulation disorder is chronic, severe persistent ir- 
ritabihty. This severe irritability has two prominent clinical manifestations, the first of 
which is frequent temper outbursts. These outbursts typically occur in response to frus­
tration and can be verbal or behavioral (the latter in the form of aggression against prop­
erty, self, or others). They must occur frequently (i.e., on average, three or more times per 
week) (Criterion C) over at least 1  year in at least two settings (Criteria E and F), such as in 
the home and at school, and they must be developmentally inappropriate (Criterion B). 
The second manifestation of severe irritability consists of chronic, persistently irritable or

The second manifestation of severe irritability consists of chronic, persistently irritable or 
angry mood that is present between the severe temper outbursts. This irritable or angry 
mood must be characteristic of the child, being present most of the day, nearly every day, 
and noticeable by others in the child's environment (Criterion D).

The clinical presentation of disruptive mood dysregulation disorder must be carefully 
distinguished from presentations of other, related conditions, particularly pediatric bi­
polar disorder. In fact, disruptive mood dysregulation disorder was added to DSM-5 to 
address the considerable concern about the appropriate classification and treatment of 
children who present with chronic, persistent irritability relative to children who present 
with classic (i.e., episodic) bipolar disorder.
Some researchers view severe, non-episodic irritability as characteristic of bipolar dis­
order in children, although both DSM-IV and DSM-5 require that both children and adults 
have distinct episodes of mania or hypomania to qualify for the diagnosis of bipolar I dis­
order. During the latter decades of the 20th century, this contention by researchers that 
severe, nonepisodic irritability is a manifestation of pediatric mania coincided with an up­

surge in the rates at which clinicians assigned the diagnosis of bipolar disorder to their 
pediatric patients. This sharp increase in rates appears to be attributable to clinicians com­
bining at least two clinical presentations into a single category. That is, both classic, epi­
sodic presentations of mania and non-episodic presentations of severe irritability have 
been labeled as bipolar disorder in children. In DSM-5, the term bipolar disorder  is explicitly 
reserved for episodic presentations of bipolar symptoms. DSM-IV did not include a diagno­
sis designed to capture youths whose hallmark symptoms consisted of very severe, non- 
episodic irritability, whereas DSM-5, with the inclusion of disruptive mood dysregulation 
disorder, provides a distinct category for such presentations.

Disruptive mood dysregulation disorder is common among children presenting to pedi­
atric mental health clinics. Prevalence estimates of the disorder in the community are un­
clear. Based on rates of chronic and severe persistent irritability, which is the core feature 
of the disorder, the overall 6-month to 1-year period-prevalence of disruptive mood dys­
regulation disorder among children and adolescents probably falls in the 2%-5% range. 
However, rates are expected to be higher in males and school-age children than in females 
and adolescents.
The onset of disruptive mood dysregulation disorder must be before age 10 years, and the 
diagnosis should not be applied to children with a developmental age of less than 6 years.

diagnosis should not be applied to children with a developmental age of less than 6 years. 
It is unknown whether the condition presents only in this age-delimited fashion. Because 
the symptoms of disruptive mood dysregulation disorder are likely to change as children 
mature, use of the diagnosis should be restricted to age groups similar to those in which 
validity has been established (7-18 years). Approximately half of children with severe, 
chronic irritability will have a presentation that continues to meet criteria for the condition
1  year later. Rates of conversion from severe, nonepisodic irritability to bipolar disorder 
are very low. Instead, children with chronic irritability are at risk to develop unipolar de­
pressive and/or anxiety disorders in adulthood.
Age-related variations also differentiate classic bipolar disorder and disruptive mood

Age-related variations also differentiate classic bipolar disorder and disruptive mood 
dysregulation disorder. Rates of bipolar disorder generally are very low prior to adoles­
cence (<1%), with a steady increase into early adulthood (l%-2% prevalence). Disruptive 
mood dysregulation disorder is more common than bipolar disorder prior to adolescence, 
and symptoms of the condition generally become less common as children transition into 
adulthood.
Temperamental. Children with chronic irritability typically exhibit complicated psy­
chiatric histories. In such children, a relatively extensive history of chronic irritability is

common, typically manifesting before full criteria for the syndrome are met. Such predi­
agnostic presentations may have qualified for a diagnosis of oppositional defiant disorder. 
Many children with disruptive mood dysregulation disorder have symptoms that also 
meet criteria for attention-deficit/hyperactivity disorder (ADHD) and for an anxiety dis­
order, with such diagnoses often being present from a relatively early age. For some chil­
dren, the criteria for major depressive disorder may also be met.
Genetic and physiological. In terms of familial aggregation and genetics, it has been 
suggested that children presenting with chronic, non-episodic irritability can be differen­
tiated from children with bipolar disorder in their family-based risk. However, these two 
groups do not differ in familial rates of anxiety disorders, unipolar depressive disorders, 
or substance abuse. Compared with children with pediatric bipolar disorder or other men­

tal illnesses, those with disruptive mood dysregulation disorder exhibit both commonal­
ities and differences in information-processing deficits. For example, face-emotion 
labeling deficits, as well as perturbed decision making and cognitive control, are present in 
children with bipolar disorder and chronically irritable children, as well as in children 
with some other psychiatric conditions. There is also evidence for disorder-specific dys­
function, such as during tasks assessing attention deployment in response to emotional 
stimuli, which has demonstrated unique signs of dysfunction in children with chronic ir­
ritability.
Children presenting to clinics with features of disruptive mood dysregulation disorder are

Children presenting to clinics with features of disruptive mood dysregulation disorder are 
predominantly male. Among community samples, a male preponderance appears to be 
supported. This difference in prevalence between males and females differentiates disrup­
tive mood dysregulation disorder from bipolar disorder, in which there is an equal gender 
prevalence.
In general, evidence documenting suicidal behavior and aggression, as well as other se­
vere functional consequences, in disruptive mood dysregulation disorder should be noted 
when evaluating children with chronic irritability.
Disruptive iVlood Dysreguiation Disorder
Chronic, severe irritability, such as is seen in disruptive mood dysregulation disorder, is 
associated with marked disruption in a child's family and peer relationships, as well as in 
school performance. Because of their extremely low frustration tolerance, such children

school performance. Because of their extremely low frustration tolerance, such children 
generally have difficulty succeeding in school; they are often unable to participate in the 
activities typically enjoyed by healthy children; their family life is severely disrupted by 
their outbursts and irritability; and they have trouble initiating or sustaining friendships. 
Levels of dysfunction in children with bipolar disorder and disruptive mood dysregulation 
disorder are generally comparable. Both conditions cause severe disruption in the lives of 
the affected individual and their families. In both disruptive mood dysregulation disorder 
and pediatric bipolar disorder, dangerous behavior, suicidal ideation or suicide attempts, 
severe aggression, and psychiatric hospitalization are common.

Because chronically irritable children and adolescents typically present with complex histo­
ries, the diagnosis of disruptive mood dysregulation disorder must be made while consid­
ering the presence or absence of multiple other conditions. Despite the need to consider

many other syndromes, differentiation of disruptive mood dysregulation disorder from bi­
polar disorder and oppositional defiant disorder requires particularly careful assessment.
Bipolar disorders. The central feature differentiating disruptive mood dysregulation disor­
der and bipolar disorders in children involves the longitudinal course of the core s}nTiptoms. In 
children, as in adults, bipolar I disorder and bipolar Π  disorder manifest as an episodic illness 
with discrete episodes of mood perturbation that can be differentiated from the child's typical 
presentation. The mood perturbation that occurs during a manic episode is distinctly different 
from the child's usual mood. In addition, during a manic episode, the change in mood must be 
accompanied by the onset, or worsening, of associated cognitive, behavioral, and physical 
symptoms (e.g., distractibility, increased goal-directed activity), which are also present to a de­

gree that is distinctly different from the child's usual baseline. Thus, in the case of a manic ep­
isode, parents (and, depending on developmental level, children) should be able to identify a 
distinct time period during which the child's mood and behavior were markedly different 
from usual. In contrast, the irritability of disruptive mood dysregulation disorder is persistent 
and is present over many months; while it may wax and wane to a certain degree, severe irri­
tability is characteristic of the child with disruptive mood dysregulation disorder. Thus, while 
bipolar disorders are episodic conditions, disruptive mood dysregulation disorder is not. In 
fact, the diagnosis of disruptive mood dysregulation disorder cannot be assigned to a child

fact, the diagnosis of disruptive mood dysregulation disorder cannot be assigned to a child 
who has ever experienced a fuU-duration hypomanie or manic episode (irritable or euphoric) 
or who has ever had a manic or hypomanie episode lasting more than 1 day. Another central 
differentiating feature between bipolar disorders and disruptive mood dysregulation disorder 
is the presence of elevated or expansive mood and grandiosity. These symptoms are common 
features of mania but are not characteristic of disruptive m ood  dysregulation disorder.
Oppositional defiant disorder. While symptoms of oppositional defiant disorder typi­
cally do occur in children with disruptive mood dysregulation disorder, mood symptoms 
of disruptive mood dysregulation disorder are relatively rare in children with opposi­
tional defiant disorder. The key features that warrant the diagnosis of disruptive mood

tional defiant disorder. The key features that warrant the diagnosis of disruptive mood 
dysregulation disorder in children whose symptoms also meet criteria for oppositional de­
fiant disorder are the presence of severe and frequently recurrent outbursts and a persis­
tent disruption in mood between outbursts. In addition, the diagnosis of disruptive mood 
dysregulation disorder requires severe impairment in at least one setting (i.e., home, 
school, or among peers) and mild to moderate impairment in a second setting. For this rea­
son, while most children whose symptoms meet criteria for disruptive mood dysregula­
tion disorder will also have a presentation that meets criteria for oppositional defiant 
disorder, the reverse is not the case. That is, in only approximately 15% of individuals with 
oppositional defiant disorder would criteria for disruptive mood dysregulation disorder

oppositional defiant disorder would criteria for disruptive mood dysregulation disorder 
be met. Moreover, even for children in whom criteria for both disorders are met, only the 
diagnosis of disruptive mood dysregulation disorder should be made. Finally, both the 
prominent mood symptoms in disruptive mood dysregulation disorder and the high risk 
for depressive and anxiety disorders in follow-up studies justify placement of disruptive 
mood dysregulation disorder among the depressive disorders in DSM-5. (Oppositional 
defiant disorder is included in the chapter "Disruptive, Impulse-Control, and Conduct 
Disorders.") This reflects the more prominent mood component among individuals with 
disruptive mood dysregulation disorder, as compared with individuals with oppositional 
defiant disorder. Nevertheless, it also should be noted that disruptive mood dysregulation

defiant disorder. Nevertheless, it also should be noted that disruptive mood dysregulation 
disorder appears to carry a high risk for behavioral problems as well as mood problems.
Attention-deficit/hyperactivity disorder, major depressive disorder, anxiety disorders,  
and autism spectrum disorder. Unlike children diagnosed with bipolar disorder or op­
positional defiant disorder, a child whose symptoms meet criteria for disruptive mood 
dysregulation disorder also can receive a comorbid diagnosis of ADHD, major depressive 
disorder, and/or anxiety disorder. However, children whose irritability is present only in 
the context of a major depressive episode or persistent depressive disorder (dysthymia)

should receive one of those diagnoses rather than disruptive mood dysregulation disor­
der. Children with disruptive mood dysregulation disorder may have symptoms that also 
meet criteria for an anxiety disorder and can receive both diagnoses, but children whose ir­
ritability is manifest only in the context of exacerbation of an anxiety disorder should re­
ceive the relevant anxiety disorder diagnosis rather than disruptive mood dysregulation 
disorder. In addition, children with autism spectrum disorders frequently present with 
temper outbursts when, for example, their routines are disturbed. In that instance, the 
temper outbursts would be considered secondary to the autism spectrum disorder, and 
the child should not receive the diagnosis of disruptive mood dysregulation disorder.
Intermittent explosive disorder. Children with symptoms suggestive of intermittent 
explosive disorder present with instances of severe temper outbursts, much like children

explosive disorder present with instances of severe temper outbursts, much like children 
with disruptive mood dysregulation disorder. However, unlike disruptive mood dysreg­
ulation disorder, intermittent explosive disorder does not require persistent disruption in 
mood between outbursts. In addition, intermittent explosive disorder requires only 3 months 
of active symptoms, in contrast to the 12-month requirement for disruptive mood dys­
regulation disorder. Thus, these two diagnoses should not be made in the same child. For 
children with outbursts and intercurrent, persistent irritability, only the diagnosis of dis­
ruptive mood dysregulation disorder should be made.
Rates of comorbidity in disruptive mood dysregulation disorder are extremely high. It is 
rare to find individuals whose symptoms meet criteria for disruptive mood dysregulation

rare to find individuals whose symptoms meet criteria for disruptive mood dysregulation 
disorder alone. Comorbidity between disruptive mood dysregulation disorder and other 
DSM-defined syndromes appears higher than for many other pediatric mental illnesses; 
the strongest overlap is with oppositional defiant disorder. Not only is the overall rate of 
comorbidity high in disruptive mood dysregulation disorder, but also the range of comor- 
bid illnesses appears particularly diverse. These children typically present to the clinic 
with a wide range of disruptive behavior, mood, anxiety, and even autism spectrum 
symptoms and diagnoses. However, children with disruptive mood dysregulation disor­
der should not have symptoms that meet criteria for bipolar disorder, as in that context, 
only the bipolar disorder diagnosis should be made. If children have symptoms that meet

only the bipolar disorder diagnosis should be made. If children have symptoms that meet 
criteria for oppositional defiant disorder or intermittent explosive disorder and disruptive 
mood dysregulation disorder, only the diagnosis of disruptive mood dysregulation disor­
der should be assigned. Also, as noted earlier, the diagnosis of disruptive mood dysregu­
lation disorder should not be assigned if the symptoms occur only in an anxiety- 
provoking context, when the routines of a child with autism spectrum disorder or obses­
sive-compulsive disorder are disturbed, or in the context of a major depressive episode.
Major Depressive Disorder
period and represent a change from previous functioning: at least one of the symptoms  

Note: Do not include symptoms that are clearly attributable to another medical condition.
tive report (e.g., feels sad, empty, hopeless) or observation made by others (e.g.,  

5% of body weight in  a month), or decrease or increase in appetite nearly every day.  
(Note: In children, consider failure to make expected weight gain.)
5. Psychomotor agitation or retardation nearly every day (observable by others, not  

B. The symptoms cause clinically significant distress or impairment in  social, occupa­
C. The episode is not attributable to the physiological effects of a substance or to another  
Note: Criteria A-C represent a major depressive episode.
ness, rumination about the loss, insomnia, poor appetite, and weight loss noted in  Criterion A,  
which may resemble a depressive episode. Although such symptoms may be understand­
able or considered appropriate to the loss, the presence of a major depressive episode in

able or considered appropriate to the loss, the presence of a major depressive episode in  
addition to the normal response to a significant loss should also be carefully considered. This  
and the cultural norms for the expression of distress in  the context of loss.^
D. The occurrence of the major depressive episode is not better explained by schizoaf­
fective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or  
other specified and unspecified schizophrenia spectrum and other psychotic disorders.
E. There has never been a manic episode or a hypomanie episode.
Note: This exclusion does not apply if all of the manic-like or hypomanic-like episodes  
are substance-induced or are attributable to the physiological effects of another med­
ical condition.

’ In distinguishing grief from a major depressive episode (MDE), it is useful to consider that in  
likely to decrease in intensity over days to weeks and occurs in waves, the so-called pangs of  
depressed mood of MDE is more persistent and not tied to specific thoughts or preoccupations.  
of the pervasive unhappiness and misery characteristic of MDE. The thought content associated

of the pervasive unhappiness and misery characteristic of MDE. The thought content associated  
with grief generally features a preoccupation with thoughts and memories of the deceased,  
rather than the self-critical or pessimistic ruminations seen in MDE. In grief, self-esteem is gener­
ally preserved, whereas in MDE feelings of worthlessness and self-loathing are common. If self­
derogatory ideation is present in grief, it typically involves perceived failings vis-à-vis the  
deceased (e.g., not visiting frequently enough, not telling the deceased how much he or she was  
loved). If a bereaved individual thinks about death and dying, such thoughts are generally  
focused on the deceased and possibly about "joining" the deceased, whereas in MDE such  
thoughts are focused on ending one's own life because of feeling worthless, undeserving of life,

thoughts are focused on ending one's own life because of feeling worthless, undeserving of life,  
or unable to cope with the pain of depression.

The diagnostic code for major depressive disorder is based on whether this is a single or  
recurrent episode, current severity, presence of psychotic features, and remission status.  
Current severity and psychotic features are only indicated if full criteria are currently met  
for a major depressive episode. Remission specifiers are only indicated if the full criteria  
are not currently met for a major depressive episode. Codes are as follows:
Severity/course specifier Single episode Recurrent episode*
Mild (p. 188) 296.21 (F32.0) 296.31 (F33.0)
Moderate (p. 188) 296.22 (F32.1) 296.32 (F33.1)
Severe (p. 188) 296.23 (F32.2) 296.33 (F33.2)
With psychotic features** (p. 186) 296.24 (F32.3) 296.34 (F33.3)
In partial remission (p. 188) 296.25 (F32.4) 296.35 (F33.41)
In full remission (p. 188) 296.26 (F32.5) 296.36 (F33.42)
Unspecified 296.20 (F32.9) 296.30 (F33.9)

*For an episode to be considered recurrent, there must be an interval of at least 2 consecutive months  
between separate episodes in which criteria are not met for a major depressive episode. The defini­
tions of specifiers are found on the indicated pages.
**If psychotic features are present, code the "with psychotic features" specifier irrespective of epi­
In recording the name of a diagnosis, terms should be listed in the following order: major  
depressive disorder, single or recurrent episode, severity/psychotic/remission specifiers,  
followed by as many of the following specifiers without codes that apply to the current  
episode.
Specify:
With anxious distress (p. 184)
With mixed features (pp. 184-185)
With melancholic features (p. 185)
With atypical features (pp. 185-186)

episode.
Specify:
With mood-congruent psychotic features (p. 186)
With mood-incongruent psychotic features (p. 186)
With catatonia (p. 186). Coding note: Use additional code 293.89 (F06.1).
With péripartum onset (pp. 186-187)
With seasonal pattern (recurrent episode only) (pp. 187-188)
The criterion symptoms for major depressive disorder must be present nearly every day to 
be considered present, with the exception of weight change and suicidal ideation. De­
pressed mood must be present for most of the day, in addition to being present nearly ev­
ery day. Often insomnia or fatigue is the presenting complaint, and failure to probe for 
accompanying depressive symptoms will result in underdiagnosis. Sadness may be de­
nied at first but may be elicited through interview or inferred from facial expression and

nied at first but may be elicited through interview or inferred from facial expression and 
demeanor. With individuals who focus on a somatic complaint, clinicians should de­
termine whether the distress from that complaint is associated with specific depressive 
symptoms. Fatigue and sleep disturbance are present in a high proportion of cases; psy­
chomotor disturbances are much less common but are indicative of greater overall sever­
ity, as is the presence of delusional or near-delusional guilt.

The essential feature of a major depressive episode is a period of at least 2 weeks during 
w ^hich there is either depressed mood or the loss of interest or pleasure in nearly all activi­
ties (Criterion A). In children and adolescents, the mood may be irritable rather than sad. 
The individual must also experience at least four additional symptoms drawn from a list 
that includes changes in appetite or weight, sleep, and psychomotor activity; decreased en­
ergy; feelings of worthlessness or guilt; difficulty thinking, concentrating, or making deci­
sions; or recurrent thoughts of death or suicidal ideation or suicide plans or attempts. To 
count toward a major depressive episode, a symptom must either be newly present or must 
have clearly worsened compared with the person's pre-episode status. The symptoms 
must persist for most of the day, nearly every day, for at least 2 consecutive weeks. The ep­

isode must be accompanied by clinically significant distress or impairment in social, occu­
pational, or other important areas of functioning. For some individuals with milder 
episodes, functioning may appear to be normal but requires markedly increased effort.
The mood in a major depressive episode is often described by the person as depressed, 
sad, hopeless, discouraged, or "down in the dumps" (Criterion Al). In some cases, sadness 
may be denied at first but may subsequently be elicited by interview (e.g., by pointing out 
that the individual looks as if he or she is about to cry). In some individuals who complain 
of feeling "blah," having no feelings, or feeling anxious, the presence of a depressed mood 
can be inferred from the person's facial expression and demeanor. Some individuals em­

phasize somatic complaints (e.g., bodily aches and pains) rather than reporting feelings of 
sadness. Many individuals report or exhibit increased irritability (e.g., persistent anger, a 
tendency to respond to events with angry outbursts or blaming others, an exaggerated 
sense of frustration over minor matters). In children and adolescents, an irritable or cranky 
mood may develop rather than a sad or dejected mood. This presentation should be dif­
ferentiated from a pattern of irritability when frustrated.
Loss of interest or pleasure is nearly always present, at least to some degree. Individ­
uals may report feeling less interested in hobbies, "not caring anymore," or not feeling any 
enjoyment in activities that were previously considered pleasurable (Criterion A2). Family

enjoyment in activities that were previously considered pleasurable (Criterion A2). Family 
members often notice social withdrawal or neglect of pleasurable avocations (e.g., a for­
merly avid golfer no longer plays, a child who used to enjoy soccer finds excuses not to 
practice). In some individuals, there is a significant reduction from previous levels of sex­
ual interest or desire.
Appetite change may involve either a reduction or increase. Some depressed individ­
uals report that they have to force themselves to eat. Others may eat more and may crave 
specific foods (e.g., sweets or other carbohydrates). When appetite changes are severe (in 
either direction), there may be a significant loss or gain in weight, or, in children, a failure 
to make expected weight gains may be noted (Criterion A3).
Sleep disturbance may take the form of either difficulty sleeping or sleeping exces­

sively (Criterion A4). When insomnia is present, it typically takes the form of middle in- 
sonrmia (i.e., waking up during the night and then having difficulty returning to sleep) or 
terminal insomnia (i.e., waking too early and being unable to return to sleep). Initial in­
somnia (i.e., difficulty falling asleep) may also occur. Individuals who present with over­
sleeping (hypersomnia) may experience prolonged sleep episodes at night or increased 
daytime sleep. Sometimes the reason that the individual seeks treatment is for the dis­
turbed sleep.
Psychomotor changes include agitation (e.g., the inability to sit still, pacing, hand- 
wringing; or pulling or rubbing of the skin, clothing, or other objects) or retardation (e.g., 
slowed speech, thinking, and body movements; increased pauses before answering;

slowed speech, thinking, and body movements; increased pauses before answering; 
speech that is decreased in volume, inflection, amount, or variety of content, or muteness) 
(Criterion A5). The psychomotor agitation or retardation must be severe enough to be ob­
servable by others and not represent merely subjective feelings.
Decreased energy, tiredness, and fatigue are common (Criterion A6). A person may re­
port sustained fatigue without physical exertion. Even the smallest tasks seem to require

substantial effort. The efficiency with which tasks are accomplished may be reduced. For 
example, an individual may complain that washing and dressing in the morning are ex­
hausting and take twice as long as usual.
The sense of worthlessness or guilt associated with a major depressive episode may in­
clude unrealistic negative evaluations of one's worth or guilty preoccupations or rumina­
tions over minor past failings (Criterion A7). Such individuals often misinterpret neutral 
or trivial day-to-day events as evidence of personal defects and have an exaggerated sense 
of responsibility for untoward events. The sense of worthlessness or guilt may be of delu­
sional proportions (e.g., an individual who is convinced that he or she is personally re­
sponsible for world poverty). Blaming oneself for being sick and for failing to meet 
occupational or inteφersonal responsibilities as a result of the depression is very common

occupational or inteφersonal responsibilities as a result of the depression is very common 
and, unless delusional, is not considered sufficient to meet this criterion.
Many individuals report impaired ability to think, concentrate, or make even minor 
decisions (Criterion A8). They may appear easily distracted or complain of memory diffi­
culties. Those engaged in cognitively demanding pursuits are often unable to function. In 
children, a precipitous drop in grades may reflect poor concentration. In elderly individ­
uals, memory difficulties may be the chief complaint and may be mistaken for early signs 
of a dementia (''pseudodementia"). When the major depressive episode is successfully 
treated, the memory problems often fully abate. However, in some individuals, particu­
larly elderly persons, a major depressive episode may sometimes be the initial presenta­
tion of an irreversible dementia.

Thoughts of death, suicidal ideation, or suicide attempts (Criterion A9) are common. 
They may range from a passive wish not to awaken in the morning or a belief that others 
would be better off if the individual were dead, to transient but recurrent thoughts of com­
mitting suicide, to a specific suicide plan. More severely suicidal individuals may have put 
their affairs in order (e.g., updated wills, settled debts), acquired needed materials (e.g., a 
rope or a gun), and chosen a location and time to accomplish the suicide. Motivations for 
suicide may include a desire to give up in the face of perceived insurmountable obstacles, 
an intense wish to end what is perceived as an unending and excruciatingly painful emo­
tional state, an inability to foresee any enjoyment in life, or the wish to not be a burden to

tional state, an inability to foresee any enjoyment in life, or the wish to not be a burden to 
others. The resolution of such thinking may be a more meaningful measure of diminished 
suicide risk than denial of further plans for suicide.
The evaluation of the symptoms of a major depressive episode is especially difficult 
when they occur in an individual who also has a general medical condition (e.g., cancer, 
stroke, myocardial infarction, diabetes, pregnancy). Some of the criterion signs and symp­
toms of a major depressive episode are identical to those of general medical conditions 
(e.g., weight loss with untreated diabetes; fatigue with cancer; hypersomnia early in preg­
nancy; insonmia later in pregnancy or the postpartum). Such symptoms count toward a 
major depressive diagnosis except when they are clearly and fully attributable to a general

major depressive diagnosis except when they are clearly and fully attributable to a general 
medical condition. Nonvegetative symptoms of dysphoria, anhedonia, guilt or worthless­
ness, impaired concentration or indecision, and suicidal thoughts should be assessed with 
particular care in such cases. Definitions of major depressive episodes that have been mod­
ified to include only these nonvegetative symptoms appear to identify nearly the same in­
dividuals as do the full criteria.
Major depressive disorder is associated with high mortality, much of which is accounted 
for by suicide; however, it is not the only cause. For example, depressed individuals ad­
mitted to nursing homes have a markedly increased likelihood of death in the first year. In­
dividuals frequently present with tearfulness, irritability, brooding, obsessive rumination,

dividuals frequently present with tearfulness, irritability, brooding, obsessive rumination, 
anxiety, phobias, excessive worry over physical health, and complaints of pain (e.g., head­
aches; joint, abdominal, or other pains). In children, separation anxiety may occur.

Although an extensive literature exists describing neuroanatomical, neuroendocrino­
logical, and neurophysiological correlates of major depressive disorder, no laboratory test 
has yielded results of sufficient sensitivity and specificity to be used as a diagnostic tool for 
this disorder. Until recently, hypothalamic-pituitary-adrenal axis hyperactivity had been 
the most extensively investigated abnormality associated v^ith major depressive episodes, 
and it appears to be associated with melancholia, psychotic features, and risks for eventual 
suicide. Molecular studies have also implicated peripheral factors, including genetic vari­
ants in neurotrophic factors and pro-inflammatory cytokines. Additionally, functional 
magnetic resonance imaging studies provide evidence for functional abnormalities in spe­
cific neural systems supporting emotion processing, reward seeking, and emotion regula­
tion in adults with major depression.

Twelve-month prevalence of major depressive disorder in the United States is approximately 
7%, with marked differences by age group such that the prevalence in 18- to 29-year-old indi­
viduals is threefold higher than the prevalence in individuals age 60 years or older. Females ex­
perience 1.5- to 3-fold higher rates than males beginning in early adolescence.
Major depressive disorder may first appear at any age, but the likelihood of onset in­
creases markedly with puberty. In the United States, incidence appears to peak in the 20s; 
however, first onset in late life is not uncommon.
The course of major depressive disorder is quite variable, such that some individuals 
rarely, if ever, experience remission (a period of 2 or more months with no symptoms, or

rarely, if ever, experience remission (a period of 2 or more months with no symptoms, or 
only one or two symptoms to no more than a mild degree), while others experience many 
years with few or no symptoms between discrete episodes. It is important to distinguish 
individuals who present for treatment during an exacerbation of a chronic depressive ill­
ness from those whose symptoms developed recently. Chronicity of depressive symptoms 
substantially increases the likelihood of underlying personality, anxiety, and substance 
use disorders and decreases the likelihood that treatment will be followed by full symp­
tom resolution. It is therefore useful to ask individuals presenting with depressive symp­
toms to identify the last period of at least 2 months during which they were entirely free of 
depressive symptoms.

Recovery typically begins within 3 months of onset for two in five individuals with ma­
jor depression and within 1  year for four in five individuals. Recency of onset is a strong 
determinant of the likelihood of near-term recovery, and many individuals who have been 
depressed only for several months can be expected to recover spontaneously. Features as­
sociated with lower recovery rates, other than current episode duration, include psychotic 
features, prominent anxiety, personality disorders, and symptom severity.
The risk of recurrence becomes progessively lower over time as the duration of re­
mission increases. The risk is higher in individuals whose preceding episode was severe, 
in younger individuals, and in individuals who have already experienced multiple epi­
sodes. The persistence of even mild depressive symptoms during remission is a powerful

sodes. The persistence of even mild depressive symptoms during remission is a powerful 
predictor of recurrence.
Many bipolar illnesses begin with one or more depressive episodes, and a substantial 
proportion of individuals who initially appear to have major depressive disorder will 
prove, in time, to instead have a bipolar disorder. This is more likely in individuals with 
onset of the illness in adolescence, those with psychotic features, and those with a family 
history of bipolar illness. The presence of a "'with mixed features" specifier also increases 
the risk for future manic or hypomanie diagnosis. Major depressive disorder, particularly 
with psychotic features, may also transition into schizophrenia, a change that is much 
more frequent than the reverse.

Despite consistent differences between genders in prevalence rates for depressive disor­
ders, there appear to be no clear differences by gender in phenomenology, course, or treat­
ment response. Similarly, there are no clear effects of current age on the course or treatment 
response of major depressive disorder. Some symptom differences exist, though, such that 
hypersomnia and hyperphagia are more likely in younger individuals, and melancholic 
symptoms, particularly psychomotor disturbances, are more common in older individuals. 
The likelihood of suicide attempts lessens in middle and late life, although the risk of com­
pleted suicide does not. Depressions with earlier ages at onset are more familial and more 
likely to involve personality disturbances. The course of major depressive disorder within 
individuals does not generally change with aging. Mean times to recovery appear to be sta­

ble over long periods, and the likelihood of being in an episode does not generally increase 
or decrease with time.
Temperamental. Neuroticism (negative affectivity) is a well-established risk factor for the 
onset of major depressive disorder, and high levels appear to render individuals more likely 
to develop depressive episodes in response to stressful life events.
Environmental. Adverse childhood experiences, particularly when there are multiple 
experiences of diverse types, constitute a set of potent risk factors for major depressive dis­
order. Stressful life events are well recognized as précipitants of major depressive epi­
sodes, but the presence or absence of adverse life events near the onset of episodes does

sodes, but the presence or absence of adverse life events near the onset of episodes does 
not appear to provide a useful guide to prognosis or treatment selection.
Genetic and physiological. First-degree family members of individuals with major de­
pressive disorder have a risk for major depressive disorder two- to fourfold higher than 
that of the general population. Relative risks appear to be higher for early-onset and re­
current forms. Heritability is approximately 40%, and the personality trait neuroticism ac­
counts for a substantial portion of this genetic liability.
Course modifiers. Essentially all major nonmood disorders increase the risk of an indi­
vidual developing depression. Major depressive episodes that develop against the back­
ground of another disorder often follow a more refractory course. Substance use, anxiety,

ground of another disorder often follow a more refractory course. Substance use, anxiety, 
and borderline personality disorders are among the most common of these, and the pre­
senting depressive symptoms may obscure and delay their recognition. However, sus­
tained clinical improvement in depressive symptoms may depend on the appropriate 
treatment of underlying illnesses. Chronic or disabling medical conditions also increase 
risks for major depressive episodes. Such prevalent illnesses as diabetes, morbid obesity, 
and cardiovascular disease are often complicated by depressive episodes, and these epi­
sodes are more likely to become chronic than are depressive episodes in medically healthy 
individuals.
Surveys of major depressive disorder across diverse cultures have shown sevenfold dif­

ferences in 12-month prevalence rates but much more consistency in female-to-male raho, 
mean ages at onset, and the degree to which presence of the disorder raises the likelihood 
of comorbid substance abuse. While these findings suggest substantial cultural differences 
in the expression of major depressive disorder, they do not permit simple linkages be­
tween particular cultures and the likelihood of specific symptoms. Rather, clinicians 
should be aware that in most countries the majority of cases of depression go unrecog­
nized in primary care settings and that in many cultures, somatic symptoms are very likely 
to constitute the presenting complaint. Among the Criterion A symptoms, insomnia and 
loss of energy are the most uniformly reported.

Although the möst reproducible finding in the epidemiology of major depressive disorder 
has been a higher prevalence in females, there are no clear differences between genders in 
symptoms, course, treatment response, or functional consequences. In w ^om en, the risk for 
suicide attempts is higher, and the risk for suicide completion is lower. The disparity in 
suicide rate by gender is not as great among those with depressive disorders as it is in the 
population as a whole.
The possibility of suicidal behavior exists at all times during major depressive episodes. 
The most consistently described risk factor is a past history of suicide attempts or threats, 
but it should be remembered that most completed suicides are not preceded by unsuccess­
ful attempts. Other features associated with an increased risk for completed suicide 
include male sex, being single or living alone, and having prominent feelings of hopeless­

ness. The presence of borderline personality disorder markedly increases risk for future 
suicide attempts.
iVlajor Depressive Disorder
Many of the functional consequences of major depressive disorder derive from individual 
symptoms. Impairment can be very mild, such that many of those who interact with the af­
fected individual are unaware of depressive symptoms. Impairment may, however, range 
to complete incapacity such that the depressed individual is unable to attend to basic self­
care needs or is mute or catatonic. Among individuals seen in general medical settings, 
those with major depressive disorder have more pain and physical illness and greater de­
creases in physical, social, and role functioning.

Manic episodes with irritable mood or mixed episodes. Major depressive episodes 
with prominent irritable mood may be difficult to distinguish from manic episodes with 
irritable mood or from mixed episodes. This distinction requires a careful clinical evalua­
tion of the presence of manic symptoms.
Mood disorder due to another medical condition. A major depressive episode is the 
appropriate diagnosis if the mood disturbance is not judged, based on individual history, 
physical examination, and laboratory findings, to be the direct pathophysiological conse­
quence of a specific medical condition (e.g., multiple sclerosis, stroke, hypothyroidism).
Substance/medication-induced depressive or bipolar disorder. This disorder is distin­
guished from major depressive disorder by the fact that a substance (e.g., a drug of abuse,

guished from major depressive disorder by the fact that a substance (e.g., a drug of abuse, 
a medication, a toxin) appears to be etiologically related to the mood disturbance. For ex­
ample, depressed mood that occurs only in the context of withdrawal from cocaine would 
be diagnosed as cocaine-induced depressive disorder.
Attention-deficit/hyperactivity disorder. Distractibility and low frustration tolerance 
can occur in both attention-deficit/ hyperactivity disorder and a major depressive epi­
sode; if the criteria are met for both, attention-deficit/hyperactivity disorder may be diag­
nosed in addition to the mood disorder. However, the clinician must be cautious not to 
overdiagnose a major depressive episode in children with attention-deficit/hyperactivity 
disorder whose disturbance in mood is characterized by irritability rather than by sadness 
or loss of interest.

Adjustment disorder with depressed mood. A major depressive episode that occurs in 
response to a psychosocial stressor is distinguished from adjustment disorder w ^ ith  de­
pressed mood by the fact that the full criteria for a major depressive episode are not met in 
adjustment disorder.
Sadness. Finally, periods of sadness are inherent aspects of the human experience. 
These periods should not be diagnosed as a major depressive episode unless criteria are 
met for severity (i.e., five out of nine symptoms), duration (i.e., most of the day, nearly ev­
ery day for at least 2 w ^eeks), and clinically significant distress or impairment. The diagno­
sis other specified depressive disorder may be appropriate for presentations of depressed 
mood wiih  clinically significant impairment that do not meet criteria for duration or se­
verity.
Other disorders with which major depressive disorder frequently co-occurs are substance-

verity.
Other disorders with which major depressive disorder frequently co-occurs are substance- 
related disorders, panic disorder, obsessive-compulsive disorder, anorexia nervosa, buli­
mia nervosa, and borderline personality disorder.
Persistent Depressive Disorder (Dysthymia)
Diagnostic Criteria 300.4 (F34.1)
This disorder represents a consolidation of DSM-lV-defined chronic major depressive dis­
order and dysthymic disorder.
A. Depressed mood for most of the day, for more days than not, as indicated by either  
subjective account or observation by others, for at least 2 years.
Note: In children and adolescents, mood can be irritable and duration must be at least  
1  year.
B. Presence, while depressed, of two (or more) of the following:
1. Poor appetite or overeating.
2. Insomnia or hypersomnia.
3. Low energy or fatigue.
4. Low self-esteem.
5. Poor concentration or difficulty making decisions.
6. Feelings of hopelessness.

C. During the 2-year period ( 1  year for children or adolescents) of the disturbance, the individ­
ual has never been without the symptoms in  Criteria A and B for more than 2 months at a  
time.
D. Criteria for a major depressive disorder may be continuously present for 2 years.
E. There has never been a manic episode or a hypomanie episode, and criteria have  
never been met for cyclothymic disorder.
F. The disturbance is not better explained by a persistent schizoaffective disorder,  
schizophrenia, delusional disorder, or other specified or unspecified schizophrenia  
spectrum and other psychotic disorder.
G. The symptoms are not attributable to the physiological effects of a substance (e.g., a  
drug of abuse, a medication) or another medical condition (e.g. hypothyroidism).

H. The symptoms cause clinically significant distress or impairment in  social, occupational,  
or other important areas of functioning.
Note: Because the criteria for a major depressive episode include four symptoms that are  
absent from the symptom list for persistent depressive disorder (dysthymia), a very limited

number of individuals w ill have depressive symptoms that have persisted longer than 2 years  
but w ill not mee| criteria for persistent depressive disorder. If full criteria for a major de­
pressive episode have been met at some point during the current episode of illness, they  
should be given a diagnosis of major depressive disorder. Othenwise, a diagnosis of other  
specified depressive disorder or unspecified depressive disorder is warranted.
In partial remission (p. 188)
In full remission (p. 188)
Early onset: If onset is before age 21 years.
Late onset: If onset is at age 21 years or older.
Specify  if (for most recent 2 years of persistent depressive disorder):

With pure dysthymic syndrome: Full criteria for a major depressive episode have not  
been met in  at least the preceding 2 years.
With persistent major depressive episode: Full criteria for a major depressive epi­
sode have been met throughout the preceding 2-year period.
With intermittent major depressive episodes, with current episode: Full criteria for  
a major depressive episode are currently met, but there have been periods of at least  
8 weeks in at least the preceding 2 years with symptoms below the threshold for a full  
With intermittent major depressive episodes, without current episode: Full crite­
ria for a major depressive episode are not currently met, but there has been one or  
more major depressive episodes in  at least the preceding 2 years.

Mild (p. 188)
Moderate (p. 188)
Severe (p. 188)
The essential feature of persistent depressive disorder (dysthymia) is a depressed mood 
that occurs for most of the day, for more days than not, for at least 2 years, or at least 1 year 
for children and adolescents (Criterion A). This disorder represents a consolidation of 
DSM-IV-defined chronic major depressive disorder and dysthymic disorder. Major de­
pression may precede persistent depressive disorder, and major depressive episodes may 
occur during persistent depressive disorder. Individuals whose symptoms meet major de­
pressive disorder criteria for 2 years should be given a diagnosis of persistent depressive 
disorder as well as major depressive disorder.

Individuals with persistent depressive disorder describe their mood as sad or "down 
in the dumps." During periods of depressed mood, at least two of the six symptoms from 
Criterion B are present. Because these symptoms have become a part of the individual's 
day-to-day experience, particularly in the case of early onset (e.g., "I've always been this

way"), they may not be reported unless the individual is directly prompted. E>uring the 2-year 
period (1 year for children or adolescents), any symptom-free intervals last no longer than
2 months (Criterion C).
Persistent depressive disorder is effectively an amalgam of DSM-IV dysthymic disorder and 
chronic major depressive episode. The 12-month prevalence in the United States is approxi­
mately 0.5% for persistent depressive disorder and 1.5% for chronic major depressive disorder.
Persistent depressive disorder often has an early and insidious onset (i.e., in childhood, 
adolescence, or early adult life) and, by definition, a chronic course. Among individuals 
with both persistent depressive disorder and borderline personality disorder, the covari­
ance of the corresponding features over time suggests the operation of a common mecha­
nism. Early onset (i.e., before age 21 years) is associated with a higher likelihood of

nism. Early onset (i.e., before age 21 years) is associated with a higher likelihood of 
comorbid personality disorders and substance use disorders.
When symptoms rise to the level of a major depressive episode, they are likely to sub­
sequently revert to a lower level. However, depressive symptoms are much less likely to 
resolve in a given period of time in the context of persistent depressive disorder than they 
are in a major depressive episode.
Temperamental. Factors predictive of poorer long-term outcome include higher levels 
of neuroticism (negative affectivity), greater symptom severity, poorer global functioning, 
and presence of anxiety disorders or conduct disorder.
Environmental. Childhood risk factors include parental loss or separation.
Genetic and physiological. There are no clear differences in illness development, course,

Genetic and physiological. There are no clear differences in illness development, course, 
or family history between DSM-IV dysthymic disorder and chronic major depressive dis­
order. Earlier findings pertaining to either disorder are therefore likely to apply to per­
sistent depressive disorder. It is thus likely that individuals with persistent depressive 
disorder will have a higher proportion of first-degree relatives with persistent depressive 
disorder than do individuals with major depressive disorder, and more depressive disor­
ders in general.
A number of brain regions (e.g., prefrontal cortex, anterior cingulate, amygdala, hip­
pocampus) have been implicated in persistent depressive disorder. Possible polysomno- 
graphic abnormalities exist as well.
Persistent Depressive Disorder
The degree to which persistent depressive disorder impacts social and occupational func­

tioning is likely to vary widely, but effects can be as great as or greater than those of major 
depressive disorder.
Major depressive disorder. If there is a depressed mood plus two or more symptoms 
meeting criteria for a persistent depressive episode for 2 years or more, then the diagnosis of 
persistent depressive disorder is made. The diagnosis depends on the 2-year duration, 
which distinguishes it from episodes of depression that do not last 2 years. If the symptom

criteria are sufficient for a diagnosis of a major depressive episode at any time during this pe­
riod, then the diagnosis of major depression should be noted, but it is coded not as a separate 
diagnosis but rather as a specifier with the diagnosis of persistent depressive disorder. If the 
individual's symptoms currently meet full criteria for a major depressive episode, then the 
specifier of "with intermittent major depressive episodes, with current episode" would be 
made. If the major depressive episode has persisted for at least a 2-year duration and re­
mains present, then the specifier "with persistent major depressive episode" is used. When 
full major depressive episode criteria are not currently met but there has been at least one 
previous episode of major depression in the context of at least 2 years of persistent depres­
sive symptoms, then the specifier of "with intermittent major depressive episodes, without

sive symptoms, then the specifier of "with intermittent major depressive episodes, without 
current episode" is used. If the individual has not experienced an episode of major depres­
sion in the last 2 years, then the specifier "with pure dysthymic syndrome" is used.
Psychotic disorders. Depressive symptoms are a common associated feature of chronic 
psychotic disorders (e.g., schizoaffective disorder, schizophrenia, delusional disorder). A 
separate diagnosis of persistent depressive disorder is not made if the symptoms occur 
only during the course of the psychotic disorder (including residual phases).
Depressive or bipolar and related disorder due to another medical condition. Persistent 
depressive disorder must be distinguished from a depressive or bipolar and related dis­
order due to another medical condition. The diagnosis is depressive or bipolar and related

order due to another medical condition. The diagnosis is depressive or bipolar and related 
disorder due to another medical condition if the mood disturbance is judged, based on his­
tory, physical examination, or laboratory findings, to be attributable to the direct patho­
physiological effects of a specific, usually chronic, medical condition (e.g., multiple 
sclerosis). If it is judged that the depressive symptoms are not attributable to the physiolog­
ical effects of another medical condition, then the primary mental disorder (e.g., persistent 
depressive disorder) is recorded, and the medical condition is noted as a concomitant med­
ical condition (e.g., diabetes mellitus).
Substance/medication-induced depressive or bipolar disorder. A substance/medi­
cation-induced depressive or bipolar and related disorder is distinguished from persis­

tent depressive disorder when a substance (e.g., a drug of abuse, a medication, a toxin) is 
judged to be etiologically related to the mood disturbance.
Personality disorders. Often, there is evidence of a coexisting personality disturbance. 
When an individual's presentation meets the criteria for both persistent depressive disor­
der and a personality disorder, both diagnoses are given.
In comparison to individuals with major depressive disorder, those with persistent de­
pressive disorder are at higher risk for psychiatric comorbidity in general, and for anxiety 
disorders and substance use disorders in particular. Early-onset persistent depressive dis­
order is strongly associated with DSM-IV Cluster B and C personality disorders.
Premenstrual Dysphoric Disorder
Diagnostic Criteria 625.4 (N94.3)

A. In the majority of menstrual cycles, at least five symptoms must be present in the final  
week before the onset of menses, start to improve  within a few days after the onset of  
menses, and become minimal  or absent in the week postmenses.
B. One (or more) of the following symptoms must be present:
1. Marked affective lability (e.g., mood swings: feeling suddenly sad or tearful, or in­
creased sensitivity to rejection).

2. Marked irritability or anger or increased interpersonal conflicts.
3. Marked depressed mood, feelings of hopelessness, or self-deprecating thoughts.
4. Marked anxiety, tension, and/or feelings of being keyed up or on edge.
C. One (or more) of the following symptoms must additionally be present, to reach a total  
of five symptoms when combined with symptoms from Criterion B above.
1. Decreased interest in usual activities (e.g., work, school, friends, hobbies).
2. Subjective difficulty in concentration.
3. Lethargy, easy fatigability, or marked lack of energy.
4. Marked change in appetite; overeating; or specific food cravings.
5. Hypersomnia or insomnia.
6. A sense of being ovenwhelmed or out of control.
7. Physical symptoms such as breast tenderness or swelling, joint or muscle pain, a  
sensation of “ bloating,”  or weight gain.
Note: The symptoms in Criteria A-C must have been met for most menstrual cycles that  
occurred in the preceding year.

D. The symptoms are associated with clinically significant distress or interference with  
work, school, usual social activities, or relationships with others (e.g., avoidance of so­
cial activities; decreased productivity and efficiency at work, school, or home).
E. The disturbance is not merely an exacerbation of the symptoms of another disorder,  
such as major depressive disorder, panic disorder, persistent depressive disorder  
(dysthymia), or a personality disorder (although it may co-occur with any of these dis­
orders).
F. Criterion A should be confirmed by prospective daily ratings during at least two symptom­
atic cycles. (Note: The diagnosis may be made provisionally prior to this confirmation.)
G. The symptoms are not attributable to the physiological effects of a substance (e.g., a

drug of abuse, a medication, other treatment) or another medical condition (e.g., hy­
perthyroidism).
If symptoms have not been confirmed by prospective daily ratings of at least two symp­
tomatic cycles, "provisional" should be noted after the name of the diagnosis (i.e., "pre­
menstrual dysphoric disorder, provisional").
The essential features of premenstrual dysphoric disorder are the expression of mood la­
bility, irritability, dysphoria, and anxiety symptoms that occur repeatedly during the pre­
menstrual phase of the cycle and remit around the onset of menses or shortly thereafter. 
These symptoms may be accompanied by behavioral and physical symptoms. Symptoms 
must have occurred in most of the menstrual cycles during the past year and must have an

must have occurred in most of the menstrual cycles during the past year and must have an 
adverse effect on work or social functioning. The intensity and/or expressivity of the ac­
companying symptoms may be closely related to social and cultural background charac­
teristics of the affected female, family perspectives, and more specific factors such as 
religious beliefs, social tolerance, and female gender role issues.
Typically, symptoms peak around the time of the onset of menses. Although it is not 
uncommon for symptoms to linger into the first few days of menses, the individual must 
have a symptom-free period in the follicular phase after the menstrual period begins. 
While the core symptoms include mood and anxiety symptoms, behavioral and somatic 
symptoms commonly also occur. However, the presence of physical and/or behavioral

symptoms commonly also occur. However, the presence of physical and/or behavioral 
symptoms in the absence of mood and/or anxious symptoms is not sufficient for a diag­

nosis. Symptoms are of comparable severity (but not duration) to those of another mental 
disorder, such a^  a major depressive episode or generalized anxiety disorder. In order to 
confirm a provisional diagnosis, daily prospective symptom ratings are required for at 
least two symptomatic cycles.
Delusions and hallucinations have been described in the late luteal phase of the menstrual 
cycle but are rare. The premenstrual phase has been considered by some to be a risk period 
for suicide.
Twelve-month prevalence of premenstrual dysphoric disorder is between 1.8% and 5.8% 
of menstruating women. Estimates are substantially inflated if they are based on retro­
spective reports rather than prospective daily ratings. However, estimated prevalence 
based on a daily record of symptoms for 1-2 months may be less representative, as indi­
viduals with the most severe symptoms may be unable to sustain the rating process. The

viduals with the most severe symptoms may be unable to sustain the rating process. The 
most rigorous estimate of premenstrual dysphoric disorder is 1.8% for women whose 
symptoms meet the full criteria without functional impairment and 1.3% for women 
whose symptoms meet the current criteria with functional impairment and without co-oc­
curring symptoms from another mental disorder.
Onset of premenstrual dysphoric disorder can occur at any point after menarche. Inci­
dence of new cases over a 40-month follow-up period is 2.5% (95% confidence interval = 
1.7-3.7). Anecdotally, many individuals, as they approach menopause, report that symp­
toms worsen. Symptoms cease after menopause, although cyclical hormone replacement 
can trigger the re-expression of symptoms.
Environmental. Environmental factors associated with the expression of premenstrual

Environmental. Environmental factors associated with the expression of premenstrual 
dysphoric disorder include stress, history of interpersonal trauma, seasonal changes, and 
sociocultural aspects of female sexual behavior in general, and female gender role in par­
ticular.
Genetic and physiological. Heritability of premenstrual dysphoric disorder is unknown. 
However, for premenstrual symptoms, estimates for heritability range between 30% and 
80%, with the most stable component of premenstrual symptoms estimated to be about 
50% heritable.
Course modifiers. Women who use oral contraceptives may have fewer premenstrual 
complaints than do women who do not use oral contraceptives.
Premenstrual dysphoric disorder is not a culture-bound syndrome and has been observed 
in individuals in the United States, Europe, India, and Asia. It is unclear as to whether rates

in individuals in the United States, Europe, India, and Asia. It is unclear as to whether rates 
differ by race. Nevertheless, frequency, intensity, and expressivity of symptoms and help- 
seeking patterns may be significantly influenced by cultural factors.
As indicated earlier, the diagnosis of premenstrual dysphoric disorder is appropriately 
confirmed by 2 months of prospective symptom ratings. A number of scales, including the

Daily Rating of Severity of Problems and the Visual Analogue Scales for Premenstrual 
Mood Symptoms, have undergone validation and are commonly used in clinical trials for 
premenstrual dysphoric disorder. The Premenstrual Tension Syndrome Rating Scale has a 
self-report and an observer version, both of v^hich have been validated and used widely to 
measure illness severity in women who have premenstrual dysphoric disorder.
Symptoms must be associated with clinically meaningful distress and/or an obvious and 
marked impairment in the ability to function socially or occupationally in the week prior 
to menses. Impairment in social functioning may be manifested by marital discord and 
problems with children, other family members, or friends. Chronic marital or job prob­
lems should not be confused with dysfunction that occurs only in association with pre­
menstrual dysphoric disorder.

Premenstrual syndrome. Premenstrual syndrome differs from premenstrual dysphoric 
disorder in that a minimum of five symptoms is not required, and there is no stipulation of 
affective symptoms for individuals who have premenstrual syndrome. This condition 
may be more common than premenstrual dysphoric disorder, although the estimated 
prevalence of premenstrual syndrome varies. While premenstrual syndrome shares the 
feature of symptom expression during the premenstrual phase of the menstrual cycle, it is 
generally considered to be less severe than premenstrual dysphoric disorder. The pres­
ence of physical or behavioral symptoms in the premenstruum, without the required 
affective symptoms, likely meets criteria for premenstrual syndrome and not for premen­
strual dysphoric disorder.

Dysmenorrhea. Dysmenorrhea is a syndrome of painful menses, but this is distinct from a 
syndrome characterized by affective changes. Moreover, symptoms of dysmenorrhea begin 
with the onset of menses, whereas symptoms of premenstrual dysphoric disorder, by defini­
tion, begin before the onset of menses, even if they linger into the first few days of menses.
Bipolar disorder, major depressive disorder, and persistent depressive disorder  
(dysthymia). Many women with (either naturally occurring or substance/medication- 
induced) bipolar or major depressive disorder or persistent depressive disorder believe 
that they have premenstrual dysphoric disorder. However, when they chart symptoms, 
they realize that the symptoms do not follow a premenstrual pattern. Women with an­

other mental disorder may experience chronic symptoms or intermittent symptoms that 
are unrelated to menstrual cycle phase. However, because the onset of menses constitutes 
a memorable event, they may report that symptoms occur only during the premenstruum 
or that symptoms worsen premenstrually. This is one of the rationales for the requirement 
that symptoms be confirmed by daily prospective ratings. The process of differential di­
agnosis, particularly if the clinician relies on retrospective symptoms only, is made more 
difficult because of the overlap between symptoms of premenstrual dysphoric disorder 
and some other diagnoses. The overlap of symptoms is particularly salient for differenti­
ating premenstrual dysphoric disorder from major depressive episodes, persistent de­

pressive disorder, bipolar disorders, and borderline personality disorder. However, the 
rate of personality disorders is no higher in individuals with premenstrual dysphoric dis­
order than in those without the disorder.
Use of hormonal treatments. Some women who present with moderate to severe pre­
menstrual symptoms may be using hormonal treatments, including hormonal contracep­
tives. If such symptoms occur after initiation of exogenous hormone use, the symptoms

may be due to the use of hormones rather than to the underlying condition of premen­
strual dysphoriq disorder. If the woman stops hormones and the symptoms disappear, 
this is consistent with substance/medication-induced depressive disorder.
A major depressive episode is the most frequently reported previous disorder in individuals 
presenting with premenstrual dysphoric disorder. A wide range of medical (e.g., migraine, 
asthma, allergies, seizure disorders) or other mental disorders (e.g., depressive and bipolar 
disorders, anxiety disorders, bulimia nervosa, substance use disorders) may worsen in the 
premenstrual phase; however, the absence of a symptom-free period during the postmen- 
strual interval obviates a diagnosis of premenstrual dysphoric disorder. These conditions 
are better considered premenstrual exacerbation of a current mental or medical disorder. Al­
though the diagnosis of premenstrual dysphoric disorder should not be assigned in situa­

tions in which an individual only experiences a premenstrual exacerbation of another 
mental or physical disorder, it can be considered in addition to the diagnosis of another men­
tal or physical disorder if the individual experiences symptoms and changes in level of func­
tioning that are characteristic of premenstrual dysphoric disorder and markedly different 
from the symptoms experienced as part of the ongoing disorder.
Depressive Disorder
A. A prominent and persistent disturbance in mood that predominates in  the clinical pic­
ture and is characterized by depressed mood or markedly diminished interest or plea­
sure in all, or almost all, activities.
B. There is evidence from the history, physical examination, or laboratory findings of both

(1)and(2):
rion A.
C. The disturbance is not better explained by a depressive disorder that is not substance/  
medication-induced. Such evidence of an independent depressive disorder could in­
persist for a substantial period of time (e.g., about 1  month) after the cessation of acute  
of an independent non-substance/medication-induced depressive disorder (e.g., a his­
tory of recurrent non-substance/medication-related episodes).

Coding note: The ICD-9-CM and ICD-10-CM codes for the [specific substance/medica-  
tion]-induced depressive disorders are indicated in the table below. Note that the ICD-10-

CM code depends on wliether or not there is a comorbid substance use disorder present for  
induced depressive disorder, the 4th position character is “ 1 a n d  the clinician should record  
“ m ild [substance] use disorder”  before the substance-induced depressive disorder (e.g.,  
“ m ild cocaine use disorder with cocaine-induced depressive disorder” ). If a moderate or se­
vere substance use disorder is comorbid with the substance-induced depressive disorder,  
the 4th position character is “ 2,”  and the clinician should record “ moderate [substance] use  
disorder”  or “ severe [substance] use disorder,”  depending on the severity of the comorbid  
substance use disorder. If there is no comorbid substance use disorder (e.g., after a one­
time heavy use of the substance), then the 4th position character is “ 9,”  and the clinician should

time heavy use of the substance), then the 4th position character is “ 9,”  and the clinician should  
record only the substance-induced depressive disorder.
ICD-10-CM
disorder,  
disorder,  
moderate  
use
disorder
Alcohol 291.89 F10.14 F10.24 FI 0.94
Phencyclidine 292.84 F16.14 F16.24 F16.94
Other hallucinogen 292.84 F16.14 F16.24 FI 6.94
Inhalant 292.84 F18.14 F18.24 FI 8.94
Opioid 292.84 F11.14 F11.24 F11.94
Sedative, hypnotic, or anxiolytic 292.84 F13.14 FI 3.24 FI 3.94
stimulant)292.84 F15.14 FI 5.24 FI 5.94
Cocaine 292.84 F14.14 FI 4.24 FI 4.94
Specify  if (see Table 1  in  the chapter “ Substance-Related and Addictive Disorders”  for di­

With onset during intoxication: If criteria are met for intoxication with the substance  
and the symptoms develop during intoxication.
ICD-9-CM. The name of the substance/medication-induced depressive disorder begins 
the depressive symptoms. The diagnostic code is selected from the table included in the 
criteria set, which is based on the drug class. For substances that do not fit into any of the 
classes (e.g., dexamethasone), the code for ''other substance" should be used; and in cases

classes (e.g., dexamethasone), the code for ''other substance" should be used; and in cases 
in which a substance is judged to be an etiological factor but the specific class of substance 
is unknown, the category "unknown substance" should be used.
which combine the substance-induced disorder and substance use disorder into a single

example, in the qase of depressive symptoms occurring during withdrawal in a man with 
a severe cocaine use disorder, the diagnosis is 292.84 cocaine-induced depressive disorder, 
with onset during withdrawal. An additional diagnosis of 304.20 severe cocaine use dis­
order is also given. When more than one substance is judged to play a significant role in 
the development of depressive mood symptoms, each should be listed separately (e.g.,
292.84 methylphenidate-induced depressive disorder, with onset during withdrawal;
292.84 dexamethasone-induced depressive disorder, with onset during intoxication).
ICD-10-CM. The name of the substance/medication-induced depressive disorder begins 
the depressive symptoms. The diagnostic code is selected from the table included in the

criteria set, which is based on the drug class and presence or absence of a comorbid sub­
stance use disorder. For substances that do not fit into any of the classes (e.g., dexameth­
asone), the code for "other substance" should be used; and in cases in which a substance is 
judged to be an etiological factor but the specific class of substance is unknown, the category 
"unknown substance" should be used.
When recording the name of the disorder, the comorbid substance use disorder (if any) is 
listed first, followed by the word "with," followed by the name of the substance-induced de­
pressive disorder, followed by the specification of onset (i.e., onset during intoxication, onset 
during withdrawal). For example, in the case of depressive symptoms occurring during with­

drawal in a man with a severe cocaine use disorder, the diagnosis is F14.24 severe cocaine use 
disorder with cocaine-induced depressive disorder, with onset during withdrawal. A separate 
diagnosis of the comorbid severe cocaine use disorder is not given. If the substance-induced 
depressive disorder occurs without a comorbid substance use disorder (e.g., after a one-time 
heavy use of the substance), no accompanying substance use disorder is noted (e.g., F16.94 
phencyclidine-induced depressive disorder, with onset during intoxication). When more than 
one substance is judged to play a significant role in the development of depressive mood 
symptoms, each should be listed separately (e.g., F15.24 severe methylphenidate use disorder

symptoms, each should be listed separately (e.g., F15.24 severe methylphenidate use disorder 
with methylphenidate-induced depressive disorder, with onset during withdrawal; F19.94 
dexamethasone-induced depressive disorder, with onset during intoxication).
The diagnostic features of substance/medication-induced depressive disorder include the 
symptoms of a depressive disorder, such as major depressive disorder; however, the de­
pressive symptoms are associated with the ingestion, injection, or inhalation of a sub­
stance (e.g., drug of abuse, toxin, psychotropic medication, other medication), and the 
depressive symptoms persist beyond the expected length of physiological effects, intoxi­
cation, or withdrawal period. As evidenced by clinical history, physical examination, or 
laboratory findings, the relevant depressive disorder should have developed during or

laboratory findings, the relevant depressive disorder should have developed during or 
within 1  month after use of a substance that is capable of producing the depressive disor­
der (Criterion Bl). In addition, the diagnosis is not better explained by an independent 
depressive disorder. Evidence of an independent depressive disorder includes the de­
pressive disorder preceded the onset of ingestion or withdrawal from the substance; the 
depressive disorder persists beyond a substantial period of time after the cessation of sub­
stance use; or other evidence suggests the existence of an independent non-substance/ 
medication-induced depressive disorder (Criterion C). This diagnosis should not be made 
when symptoms occur exclusively during the course of a delirium (Criterion D). The de­
pressive disorder associated with the substance use, intoxication, or withdrawal must

pressive disorder associated with the substance use, intoxication, or withdrawal must 
tant areas of functioning to qualify for this diagnosis (Criterion E).
Some medications (e.g., stimulants, steroids, L-dopa, antibiotics, central nervous  
system drugs, dermatological agents, chemotherapeutic drugs, immunological agents)

can induce depressive mood disturbances. Clinical judgment is essential to determine 
whether the medication is truly associated with inducing the depressive disorder or 
whether a primary depressive disorder happened to have its onset while the person was 
receiving the treatment. For example, a depressive episode that developed within the first 
several weeks of beginning alpha-methyldopa (an antihypertensive agent) in an individ­
ual with no history of major depressive disorder would qualify for the diagnosis of med­
ication-induced depressive disorder. In some cases, a previously established condition 
(e.g., major depressive disorder, recurrent) can recur while the individual is coincidentally 
taking a medication that has the capacity to cause depressive symptoms (e.g., L-dopa, oral 
contraceptives). In such cases, the clinician must make a judgment as to whether the med­
ication is causative in this particular situation.

A substance/medication-induced depressive disorder is distinguished from a primary 
depressive disorder by considering the onset, course, and other factors associated with the 
substance use. There must be evidence from the history, physical examination, or labora­
tory findings of substance use, abuse, intoxication, or withdrawal prior to the onset of the 
depressive disorder. The withdrawal state for some substances can be relatively pro­
tracted, and thus intense depressive symptoms can last for a long period after the cessation 
of substance use.
In a nationally representative U.S. adult population, the lifetime prevalence of substance/ 
medication-induced depressive disorder is 0.26%.
A depressive disorder associated with the use of substance (i.e., alcohol, illicit drugs, or a

A depressive disorder associated with the use of substance (i.e., alcohol, illicit drugs, or a 
prescribed treatment for a mental disorder or another medical condition) must have its on­
set while the individual is using the substance or during withdrawal, if there is a with­
drawal syndrome associated with the substance. Most often, the depressive disorder has 
its onset within the first few weeks or 1  month of use of the substance. Once the substance 
is discontinued, the depressive symptoms usually remit within days to several weeks, de­
pending on the half-life of the substance/medication and the presence of a withdrawal 
syndrome. If symptoms persist 4 weeks beyond the expected time course of withdrawal of 
a particular substance/medication, other causes for the depressive mood symptoms 
should be considered.
Although there are a few prospective controlled trials examining the association of de­

pressive symptoms with use of a medication, most reports are from postmarketing sur­
veillance studies, retrospective observational studies, or case reports, making evidence of 
causality difficult to determine. Substances implicated in medication-induced depressive 
disorder, with varying degrees of evidence, include antiviral agents (efavirenz), cardio­
vascular agents (clonidine, guanethidine, methyldopa, reserpine), retinoic acid deriva­
tives (isotretinoin), antidepressants, anticonvulsants, anti-migraine agents (triptans), 
antipsychotics, hormonal agents (corticosteroids, oral contraceptives, gonadotropin- 
releasing hormone agonists, tamoxifen), smoking cessation agents (varenicline), and im­
munological agents (interferon). However, other potential substances continue to emerge

munological agents (interferon). However, other potential substances continue to emerge 
as new compounds are synthesized. A history of such substance use may help increase di­
agnostic certainty.
Temperamental. Factors that appear to increase the risk of substance/medication- 
induced depressive disorder can be conceptualized as pertaining to the specific type of 
drug or to a group of individuals with underlying alcohol or drug use disorders. Risk fac­

tors common to all drugs include history of major depressive disorder, history of drug- 
induced depression, and psychosocial stressors.
Environmental, There are also risks factors pertaining to a specific type of medication 
(e.g., increased immune activation prior to treatment for hepatitis C associated with inter- 
feron-alfa-induced depression); high doses (greater than 80 mg/day prednisone-equiva- 
lents) of corticosteroids or high plasma concentrations of efavirenz; and high estrogen/ 
progesterone content in oral contraceptives.
Course modifiers. In a representative U.S. adult population, compared with individuals 
with major depressive disorder who did not have a substance use disorder, individuals 
with substance-induced depressive disorder were more likely to be male, to be black, to 
have at most a high school diploma, to lack insurance, and to have lower family income. 
They were also more likely to report higher family history of substance use disorders and

They were also more likely to report higher family history of substance use disorders and 
antisocial behavior, higher 12-month history of stressful life events, and a greater number 
of DSM-rV major depressive disorder criteria. They were more likely to report feelings of 
worthlessness, insomnia/hypersomnia, and thoughts of death and suicide attempts, but 
less likely to report depressed mood and parental loss by death before age 18 years.
Diagnostic iViarlcers
Determination of the substance of use can sometimes be made through laboratory assays 
of the suspected substance in the blood or urine to corroborate the diagnosis.
Drug-induced or treatment-emergent suicidality represents a marked change in thoughts 
and behavior from the person's baseline, is usually temporally associated with initiation of

and behavior from the person's baseline, is usually temporally associated with initiation of 
a substance, and must be distinguished from the underlying primary mental disorders.
In regard to the treatment-emergent suicidality associated with antidepressants, a U.S. 
Food and Drug Administration (FDA) advisory committee considered meta-analyses of 
99,839 participants enrolled in 372 randomized clinical trials of antidepressants in trials for 
mental disorders. The analyses showed that when the data were pooled across all adult 
age groups, there was no perceptible increased risk of suicidal behavior or ideation. How­
ever, in age-stratified analyses, the risk for patients ages 18-24 years was elevated, albeit 
not significantly (odds ratio [OR] = 1.55; 95% confidence interval [Cl] = 0.91-2.70). The

not significantly (odds ratio [OR] = 1.55; 95% confidence interval [Cl] = 0.91-2.70). The 
FDA meta-analyses reveal an absolute risk of suicide in patients taking investigational an­
tidepressants of 0.01%. In conclusion, suicide is clearly an extremely rare treatment-emer­
gent phenomenon, but the outcome of suicide was serious enough to prompt the FDA to 
issue an expanded black-box warning in 2007 regarding the importance of careful moni­
toring of treatment-emergent suicidal ideation in patients receiving antidepressants.
Substance intoxication and withdrawal. Depressive symptoms occur commonly in sub­
stance intoxicahon and substance withdrawal, and the diagnosis of the substance-specific 
intoxication or withdrawal will usually suffice to categorize the symptom presentation. A 
diagnosis of substance-induced depressive disorder should be made instead of a diag­

nosis of substance intoxication or substance withdrawal when the mood symptoms are 
sufficiently severe to warrant independent clinical attention. For example, dysphoric 
mood is a characteristic feature of cocaine withdrawal. Substance/medication-induced 
depressive disorder should be diagnosed instead of cocaine withdrawal only if the mood 
disturbance is substantially more intense or longer lasting than what is usually encountered 
with cocaine withdrawal and is sufficiently severe to be a separate focus of attention and 
treatment.

Primary depressive disorder. A substance/medication-induced depressive disorder is 
distinguished from a primary depressive disorder by the fact that a substance is judged to 
be etiologically related to the symptoms, as described earlier (see section "Development 
and Course" for this disorder).
Depressive disorder due to another medical condition. Because individuals with other 
medical conditions often take medications for those conditions, the clinician must consider the 
possibility that the mood symptoms are caused by the physiological consequences of the med­
ical condition rather than the medication, in which case depressive disorder due to another 
medical condition is diagnosed. The history often provides Üie primary basis for such a judg­
ment. At times, a change in the treatment for the other medical condition (e.g., medication sub­
stitution or discontinuation) may be needed to determine empirically whether the medication

stitution or discontinuation) may be needed to determine empirically whether the medication 
is the causative agent. If the clinician has ascertained that the disturbance is a function of both 
another medical condition and substance use or withdrawal, both diagnoses (i.e., depressive 
disorder due to another medical condition and substance/medication-induced depressive 
disorder) may be given. When there is insufficient evidence to determine whether the depres­
sive symptoms are associated with substance (including a medication) ingestion or with­
drawal or with another medical condition or are primary (i.e., not a function of either a 
substance or another medical condition), a diagnosis of other specified depressive disorder or 
unspecified depressive disorder would be indicated.
Compared with individuals with major depressive disorder and no comorbid substance

Compared with individuals with major depressive disorder and no comorbid substance 
use disorder, those with substance/medication-induced depressive disorder have higher 
rates of comorbidity with any DSM-IV mental disorder; are more likely to have specific 
DSM-IV disorders of pathological gambling and paranoid, histrionic, and antisocial per­
sonality disorders; and are less likely to have persistent depressive disorder (dysthymia). 
Compared with individuals with major depressive disorder and a comorbid substance use 
disorder, individuals with substance/medication-induced depressive disorder are more 
likely to have alcohol use disorder, any other substance use disorder, and histrionic per­
sonality disorder; however, they are less likely to have persistent depressive disorder.
Depressive Disorder 
Due to Another l\/ledical Condition

A. A prominent and persistent period of depressed mood or markedly diminished interest  
or pleasure in all, or almost all, activities that predominates in the clinical picture.
tion.
C. The disturbance is not better explained by another mental disorder (e.g., adjustment  
disorder, with depressed mood, in which the stressor is a serious medical condition).

Coding note: The ICD-9-CM code for depressive disorder due to another medical condi­
tion is 293.83, which is assigned regardless of the specifier. The ICD-10-CM code de­
pends on the specifier (see below).

(F06.31) With depressive features: Full criteria are not met for a major depressive  
episode. '
(F06.32) Witli major depressive-iilce episode: Full criteria are met (except Criterion  
C) for a major depressive episode.
(F06.34) With mixed features: Symptoms of mania or hypomania are also present but  
do not predominate in  the clinical picture.
Coding note: Include the name of the other medical condition in  the name of the mental dis­
order (e.g., 293.83 [F06.31] depressive disorder due to hypothyroidism, with depressive fea­
tures). The other medical condition should also be coded and listed separately immediately  
before the depressive disorder due to the medical condition (e.g., 244.9 [E03.9] hypothyroid­
ism ; 293.83 [F06.31] depressive disorder due to hypothyroidism, w ith depressive features).
The essential feature of depressive disorder due to another medical condition is a promi­

nent and persistent period of depressed mood or markedly diminished interest or plea­
sure in all, or almost all, activities that predominates in the clinical picture (Criterion A) 
and that is thought to be related to the direct physiological effects of another medical con­
dition (Criterion B). In determining whether the mood disturbance is due to a general 
medical condition, the clinician must first establish the presence of a general medical con­
dition. Further, the clinician must establish that the mood disturbance is etiologically re­
lated to the general medical condition through a physiological mechanism. A careful and 
comprehensive assessment of multiple factors is necessary to make this judgment. Al­
though there are no infallible guidelines for determining whether the relationship

though there are no infallible guidelines for determining whether the relationship 
between the mood disturbance and the general medical condition is etiological, several 
considerations provide some guidance in this area. One consideration is the presence of a 
temporal association between the onset, exacerbation, or remission of the general medical 
condition and that of the mood disturbance. A second consideration is the presence of fea­
tures that are atypical of primary Mood Disorders (e.g., atypical age at onset or course or 
absence of family history). Evidence from the literature that suggests that there can be a di­
rect association between the general medical condition in question and the development 
of mood symptoms can provide a useful context in the assessment of a particular situation.

idence) is the key variable in depressive disorder due to another medical condition. The 
listing of the medical conditions that are said to be able to induce major depression is never 
complete, and the clinician's best judgment is the essence of this diagnosis.
There are clear associations, as well as some neuroanatomical correlates, of depression 
with stroke, Huntington's disease, Parkinson's disease, and traumatic brain injury. Among 
the neuroendocrine conditions most closely associated with depression are Cushing's dis­
ease and hypothyroidism. There are numerous other conditions thought to be associated 
with depression, such as multiple sclerosis. However, the literature's support for a causal

with depression, such as multiple sclerosis. However, the literature's support for a causal 
association is greater with some conditions, such as Parkinson's disease and Huntington's 
disease, than with others, for which the differential diagnosis may be adjustment disorder, 
with depressed mood.
Following stroke, the onset of depression appears to be very acute, occurring within 1  day 
or a few days of the cerebrovascular accident (CVA) in the largest case series. However, in

some cases, onset of the depression is weeks to months following the CVA. In the largest 
series, the duration of the major depressive episode following stroke was 9-11 months on 
average. Similarly, in Huntington's disease the depressive state comes quite early in the 
course of the illness. With Parkinson's disease and Huntington's disease, it often precedes 
the major motor impairments and cognitive impairments associated with each condition. 
This is more prominently the case for Huntington's disease, in which depression is con­
sidered to be the first neuropsychiatric symptom. There is some observational evidence 
that depression is less common as the dementia of Huntington's disease progresses.
The risk of acute onset of a major depressive disorder following a CVA (within 1  day to a 
week of the event) appears to be strongly correlated with lesion location, with greatest risk

week of the event) appears to be strongly correlated with lesion location, with greatest risk 
associated with left frontal strokes and least risk apparently associated with right frontal 
lesions in those individuals who present within days of the stroke. The association with 
frontal regions and laterality is not observed in depressive states that occur in the 2-6 months 
following stroke.
be associated with manic or depressive syndromes).

There are no epidemiological studies that provide evidence to differentiate the risk of sui­
cide from a major depressive episode due to another medical condition compared with the 
risk from a major depressive episode in general. There are case reports of suicides in 
association with major depressive episodes associated with another medical condition. 
There is a clear association between serious medical illnesses and suicide, particularly 
shortly after onset or diagnosis of the illness. Thus, it would be prudent to assume that the 
risk of suicide for major depressive episodes associated with medical conditions is not less 
than that for other forms of major depressive episode, and might even be greater.
Functional Consequences of Depressive Disorder  
Due to Another iViedicai Condition

Functional consequences pertain to those associated with the medical condition. In gen­
eral, it is believed, but not established, that a major depressive episode induced by Cush­
ing's disease will not recur if the Cushing's disease is cured or arrested. However, it is also 
suggested, but not established, that mood syndromes, including depressive and manic/ 
hypomanie ones, may be episodic (i.e., recurring) in some individuals with static brain in­
Depressive disorders not due to another medical condition. Determination of whether 
a medical condition accompanying a depressive disorder is causing the disorder depends 
on a) the absence of an episode(s) of depressive episodes prior to the onset of the medical

condition, b) the probability that the associated medical condition has a potential to pro­
mote or cause a depressive disorder, and c) a course of the depressive symptoms shortly 
after the onset o i^  worsening of the medical condition, especially if the depressive symp­
toms remit near the time that the medical disorder is effectively treated or remits.
Medication-induced depressive disorder. An important caveat is that some medical con­
ditions are treated with medications (e.g., steroids or alpha-interferon) that can induce depres­
sive or manic symptoms. In these cases, clinical judgment, based on all the evidence in hand, is 
the best way to try to separate the most likely and/or the most important of two etiological fac­
tors (i.e., association with the medical condition vs. a substance-induced syndrome).
Adjustment disorders. It is important to differentiate a depressive episode from an ad­

justment disorder, as the onset of the medical condition is in itself a life stressor that could 
bring on either an adjustment disorder or an episode of major depression. The major dif­
ferentiating elements are the pervasiveness the depressive picture and the number and 
quality of the depressive symptoms that the patient reports or demonstrates on the mental 
status examination. The differential diagnosis of the associated medical conditions is rel­
evant but largely beyond the scope of the present manual.
Conditions comorbid with depressive disorder due to another medical condition are those 
associated with the medical conditions of etiological relevance. It has been noted that de­
lirium can occur before or along with depressive symptoms in individuals with a variety

lirium can occur before or along with depressive symptoms in individuals with a variety 
of medical conditions, such as Cushing's disease. The association of anxiety symptoms, 
usually generalized symptoms, is common in depressive disorders, regardless of cause.
Other Specified Depressive Disorder
311 (F32.8)
This category applies to presentations in which symptoms characteristic of a depressive  
disorder that cause clinically significant distress or impairment in  social, occupational, or  
other important areas of functioning predominate but do not meet the full criteria for any of  
the disorders in the depressive disorders diagnostic class. The other specified depressive  
specific reason that the presentation does not meet the criteria for any specific depressive

specific reason that the presentation does not meet the criteria for any specific depressive  
disorder. This is done by recording “ other specified depressive disorder”  followed by the  
specific reason (e.g., “ short-duration depressive episode” ).
1. Recurrent brief depression: Concurrent presence of depressed mood and at least  
four other symptoms of depression for 2-13 days at least once per month (not associ­
ated with the menstrual cycle) for at least 12 consecutive months in an individual  
whose presentation has never met criteria for any other depressive or bipolar disorder  
and does not currently meet active or residual criteria for any psychotic disorder.
2. Short-duration depressive episode (4-13 days): Depressed affect and at least four

2. Short-duration depressive episode (4-13 days): Depressed affect and at least four  
of the other eight symptoms of a major depressive episode associated with clinically  
significant distress or impairment that persists for more than 4 days, but less than 14 days,  
in an individual whose presentation has never met criteria for any other depressive or  
bipolar disorder, does not currently meet active or residual criteria for any psychotic dis­
order, and does not meet criteria for recurrent brief depression.
3. Depressive episode with insufficient symptoms: Depressed affect and at least one  
of the other eight symptoms of a major depressive episode associated with clinically

significant distress or impairment tliat persist for at least 2 weeks in an individual  
whose presentation has never met criteria for any other depressive or bipolar disorder,  
does not currently meet active or residual criteria for any psychotic disorder, and does  
not meet criteria for mixed anxiety and depressive disorder symptoms.
Unspecified Depressive Disorder
311 (F32.9)
This category applies to presentations in  which symptoms characteristic of a depressive dis­
order that cause clinically significant distress or impairment in  social, occupational, or other im ­
portant areas of functioning predominate but do not meet the full criteria for any of the disorders  
in  the depressive disorders diagnostic class. The unspecified depressive disorder category is  
used in  situations in which the clinician chooses not to specify the reason that the criteria are  
not met for a specific depressive disorder, and includes presentations for which there is insuf­

ficient inform ation to make a more specific diagnosis (e.g., in emergency room settings).
Specifiers for Depressive Disorders
With anxious distress: Anxious distress is defined as the presence of at least two of  
the following symptoms during the majority of days of a major depressive episode or  
persistent depressive disorder (dysthymia):
IMild: Two symptoms.
■Moderate: Three symptoms.
■Moderate-severe: Four or five symptoms.
Severe: Four or five symptoms and with motor agitation.

Note: Anxious distress has been noted as a prominent feature of both bipolar and ma­
jor depressive disorder in both primary care and specialty mental health settings. High  
levels of anxiety have been associated with higher suicide risk, longer duration of ill­
ness, and greater likelihood of treatment nonresponse. As a result, it is clinically useful  
to specify accurately the presence and severity levels of anxious distress for treatment  
Witli mixed features:
A. At least three of the following manic/hypomanic symptoms are present nearly every  
day during the majority of days of a major depressive episode:

5. Increase in energy or goal-directed activity (either socially, at work or school, or  
sexually).

6. Increased or excessive involvement in activities that have a high potential for  
painful consequences (e.g., engaging in unrestrained buying sprees, sexual in­
discretions, foolish business investments).
7. Decreased need for sleep (feeling rested despite sleeping less than usual; to be  
contrasted with insomnia).
B. Mixed symptoms are observable by others and represent a change from the per­
son’s usual behavior.
C. For individuals whose symptoms meet full criteria for either mania or hypomania,  
the diagnosis should be bipolar I or bipolar II disorder.
D. The mixed symptoms are not attributable to the physiological effects of a substance  
(e.g., a drug of abuse, a medication or other treatment).
to be a significant risk factor for the development of bipolar I  or bipolar II disorder.  
As a result, it is clinically useful to note the presence of this specifier for treatment

A. One of the following is present during the most severe period of the current epi­
sode:
B. Three (or more) of the following;

Note: The specifier “ with melancholic features”  is applied if these features are present  
at the most severe stage of the episode. There is a near-complete absence of the ca­
pacity for pleasure, not merely a diminution. A guideline for evaluating the lack of reac­
tivity of mood is that even highly desired events are not associated with marked  
brightening of mood. Either mood does not brighten at all, or it brightens only partially  
(e.g., up to 20%-^0% of normal for only minutes at a time). The “ distinct quality”  of mood  
that is characteristic of the “ with melancholic features”  specifier is experienced as qual­
itatively different from that during a nonmelancholic depressive episode. A depressed  
mood that is described as merely more severe, longer lasting, or present without a rea­

son is not considered distinct in  quality. Psychomotor changes are nearly always pres­
ent and are observable by others.
Melancholic features exhibit only a modest tendency to repeat across episodes in the  
same individual. They are more frequent in inpatients, as opposed to outpatients; are  
less likely to occur in  milder than in  more severe major depressive episodes; and are  
more likely to occur in those with psychotic features.
nate during the majority of days of the current or most recent major depressive episode  
or persistent depressive disorder.
events).

B. Two (or more) of the following:
3. Leaden paralysis (i.e., heavy, leaden feelings in  arms or legs).
sodes of mood disturbance) that results in significant social or occupational im­
pairment.
Note: “ Atypical depression”  has historical significance (i.e., atypical in contradistinction  
to the more classical agitated, “ endogenous”  presentations of depression that were the  
norm when depression was rarely diagnosed in outpatients and almost never in ado­
lescents or younger adults) and today does not connote an uncommon or unusual clin­
ical presentation as the term might imply.
Mood reactivity is the capacity to be cheered up when presented with positive events

Mood reactivity is the capacity to be cheered up when presented with positive events  
(e.g., a visit from children, compliments from others). Mood may become euthymie (not  
sad) even for extended periods of time if the external circumstances remain favorable.  
Increased appetite may be manifested by an obvious increase in food intake or by  
weight gain. Hypersomnia may include either an extended period of nighttime sleep or  
daytime napping that totals at least 10 hours of sleep per day (or at least 2 hours more  
than when not depressed). Leaden paralysis is defined as feeling heavy, leaden, or  
weighted down, usually in the arms or legs. This sensation is generally present for at  
least an hour a day but often lasts for many hours at a time. Unlike the other atypical  
features, pathological sensitivity to perceived interpersonal rejection is a trait that has

features, pathological sensitivity to perceived interpersonal rejection is a trait that has  
an early onset and persists throughout most of adult life. Rejection sensitivity occurs  
both when the person is and is not depressed, though it may be exacerbated during  
depressive periods.
With psychotic features: Delusions and/or hallucinations are present.
With mood-congruent psychotic features: The content of all delusions and hal­
lucinations is consistent with the typical depressive themes of personal inade­
quacy, guilt, disease, death, nihilism, or deserved punishment.
With mood-incongruent psychotic features: The content of the delusions or hal­
lucinations does not involve typical depressive themes of personal inadequacy,  
guilt, disease, death, nihilism, or deserved punishment, or the content is a mixture  
of mood-incongruent and mood-congruent themes.

With catatonia: The catatonia specifier can apply to an episode of depression if cata­
ciated with a mental disorder (for a description of catatonia, see the chapter  
“ Schizophrenia Spectrum and Other Psychotic Disorders”).
With péripartum onset: This specifier can be applied to the current or, if full criteria  
are not currently met for a major depressive episode, most recent episode of major de­
pression if onset of mood symptoms occurs during pregnancy or in  the 4 weeks follow­
ing delivery.
tween 3% and 6% of women w ill experience the onset of a major depressive epi­

péripartum major depressive episodes often have severe anxiety and even panic

attacl<s. Prospective studies have demonstrated that mood and anxiety symptoms  
major depVessive episode.
features. Infanticide is most often associated with postpartum psychotic episodes  
particularly increased for women with prior postpartum mood episodes but is also

bipolar I disorder) and those with a family history of bipolar disorders.
psychosocial adjustments, the potential impact of breast-feeding on treatment  
planning, and the long-term implications of a history of postpartum mood disorder  
on subsequent family planning.

With seasonal pattern: This specifier applies to recurrent major depressive disorder.
A. There has been a regular temporal relationship between the onset of major depres­
sive episodes in major depressive disorder and a particular time of the year (e.g.,  
in  the fall or winter).
B . Full remissions (or a change from major depression to mania or hypomania) also  
occur at a characteristic time of the year (e.g., depression disappears in the spring).
C. In the last 2 years, two major depressive episodes have occurred that demonstrate  
the temporal seasonal relationships defined above and no nonseasonal major de­

pressive episodes have occurred during that same period.
D. Seasonal major depressive episodes (as described above) substantially outnum­
ber the nonseasonal major depressive episodes that may have occurred over the  
individual’s lifetime.
Note: The specifier “ with seasonal pattern”  can be applied to the pattern of major de­
pressive episodes in major depressive disorder, recurrent. The essential feature is the  
onset and remission of major depressive episodes at characteristic times of the year.  
In most cases, the episodes begin in fall or winter and remit in spring. Less commonly,  
there may be recurrent summer depressive episodes. This pattern of onset and remis­
sion of episodes must have occurred during at least a 2-year period, without any non­

seasonal episodes occurring during this period. In addition, the seasonal depressive  
episodes must substantially outnumber any nonseasonal depressive episodes over  
the individual’s lifetime.
plained by seasonally linked psychosocial stressors (e.g., seasonal unemployment or  
school schedule). Major depressive episodes that occur in a seasonal pattern are often  
characterized by prominent energy, hypersomnia, overeating, weight gain, and a crav­
ing for carbohydrates. It is unclear whether a seasonal pattern is more likely in recur­
rent major depressive disorder or in bipolar disorders. However, within the bipolar  
disorders group, a seasonal pattern appears to be more likely in bipolar II disorder than

in bipolar I  disorder. In some individuals, the onset of manic or hypomanie episodes  
may also be linked to a particular season.
The prevalence of winter-type seasonal pattern appears to vary with latitude, age,  
and sex. Prevalence increases with higher latitudes. Age is also a strong predictor of  
seasonality, with younger persons at higher risk for winter depressive episodes.
In partial remission: Symptoms of the immediately previous major depressive episode  
are present, but full criteria are not met, or there is a period lasting less than 2 months  
without any significant symptoms of a major depressive episode following the end of  
such an episode.
Severity is based on the number of criterion symptoms, the severity of those symptoms,  

Mild: Few, if any, symptoms in excess of those required to make the diagnosis are  
present, the intensity of the symptoms is distressing but manageable, and the symp­
toms result in  minor impairment in social or occupational functioning.
Severe: The number of symptoms is substantially in excess of that required to make  

A n x ie ty  diSOrdGrS include disorders that share features of excessive fear and anxi­
ety and related behavioral disturbances. Fear is the emotional response to real or per­
ceived imminent threat, whereas anxiety  is anticipation of future threat. Obviously, these 
two states overlap, but they also differ, with fear more often associated with surges of au­
tonomic arousal necessary for fight or flight, thoughts of immediate danger, and escape 
behaviors, and anxiety more often associated with muscle tension and vigilance in prep­
aration for future danger and cautious or avoidant behaviors. Sometimes the level of fear 
or anxiety is reduced by pervasive avoidance behaviors. Panic attacks  feature prominently 
within the anxiety disorders as a particular type of fear response. Panic attacks are not lim­
ited to anxiety disorders but rather can be seen in other mental disorders as well.
The anxiety disorders differ from one another in the types of objects or situations that

The anxiety disorders differ from one another in the types of objects or situations that 
induce fear, anxiety, or avoidance behavior, and the associated cognitive ideation. Thus, 
while the anxiety disorders tend to be highly comorbid with each other, they can be dif­
ferentiated by close examination of the types of situations that are feared or avoided and 
the content of the associated thoughts or beliefs.
Anxiety disorders differ from developmentally normative fear or anxiety by being ex­
cessive or persisting beyond developmentally appropriate periods. They differ from tran­
sient fear or anxiety, often stress-induced, by being persistent (e.g., typically lasting 6 months 
or more), although the criterion for duration is intended as a general guide with allowance 
for some degree of flexibility and is sometimes of shorter duration in children (as in sepa­

ration anxiety disorder and selective mutism). Since individuals with anxiety disorders 
typically overestimate the danger in situations they fear or avoid, the primary determina­
tion of whether the fear or anxiety is excessive or out of proportion is made by the clinician, 
taking cultural contextual factors into account. Many of the anxiety disorders develop in 
childhood and tend to persist if not treated. Most occur more frequently in females than in 
males (approximately 2:1 ratio). Each anxiety disorder is diagnosed only when the symp­
toms are not attributable to the physiological effects of a substance/medication or to another 
medical condition or are not better explained by another mental disorder.
The chapter is arranged developmentally, with disorders sequenced according to the

The chapter is arranged developmentally, with disorders sequenced according to the 
typical age at onset. The individual with separation anxiety disorder is fearful or anxious 
about separation from attachment figures to a degree that is developmentally inappro­
priate. There is persistent fear or anxiety about harm coming to attachment figures and 
events that could lead to loss of or separation from attachment figures and reluctance to go 
away from attachment figures, as well as nightmares and physical symptoms of distress. Al­
though the symptoms often develop in childhood, they can be expressed throughout adult­
hood as well.
Selective mutism is characterized by a consistent failure to speak in social situations in 
which there is an expectation to speak (e.g., school) even though the individual speaks in 
other situations. The failure to speak has significant consequences on achievement in aca­

demic or occupational settings or otherwise interferes with normal social communication.
Individuals with specific phobia are fearful or anxious about or avoidant of circum­
scribed objects or situations. A specific cognitive ideation is not featured in this disorder, 
as it is in other anxiety disorders. The fear, anxiety, or avoidance is almost always imme-

diately induced by the phobic situation, to a degree that is persistent and out of proportion 
to the actual risk posed. There are various types of specific phobias: animal; natural envi­
ronment; blood-injection-injury; situational; and other situations.
In social anxiety disorder (social phobia), the individual is fearful or anxious about or 
avoidant of social interactions and situations that involve the possibility of being scruti­
nized. These include social interactions such as meeting unfamiliar people, situations in 
which the individual may be observed eating or drinking, and situations in which the in­
dividual performs in front of others. The cognitive ideation is of being negatively evalu­
ated by others, by being embarrassed, humiliated, or rejected, or offending others.
In panic disorder, the individual experiences recurrent unexpected panic attacks and is 
persistently concerned or worried about having more panic attacks or changes his or her

persistently concerned or worried about having more panic attacks or changes his or her 
behavior in maladaptive ways because of the panic attacks (e.g., avoidance of exercise or of 
unfamiliar locations). Panic attacks are abrupt surges of intense fear or intense discomfort 
that reach a peak within minutes, accompanied by physical and/or cognitive symptoms. 
Limited-symptom panic attacks include fewer than four symptoms. Panic attacks may be 
expected,  such as in response to a typically feared object or situation, or unexpected,  meaning 
that the panic attack occurs for no apparent reason. Panic attacks function as a marker and 
prognostic factor for severity of diagnosis, course, and comorbidity across an array of dis­
orders, including, but not limited to, the anxiety disorders (e.g., substance use, depressive

orders, including, but not limited to, the anxiety disorders (e.g., substance use, depressive 
and psychotic disorders). Panic attack may therefore be used as a descriptive specifier for 
any anxiety disorder as well as other mental disorders.
Individuals with agoraphobia are fearful and anxious about two or more of the follow­
ing situations: using public transportation; being in open spaces; being in enclosed places; 
standing in line or being in a crowd; or being outside of the home alone in other situations. 
The individual fears these situations because of thoughts that escape might be difficult or 
help might not be available in the event of developing panic-like symptoms or other inca­
pacitating or embarrassing symptoms. These situations almost always induce fear or anx­
iety and are often avoided and require the presence of a companion.

The key features of generalized anxiety disorder are persistent and excessive anxiety 
and worry about various domains, including work and school performance, that the indi­
vidual finds difficult to control. In addition, the individual experiences physical symptoms, 
including restlessness or feeling keyed up or on edge; being easily fatigued; difficulty con­
centrating or mind going blank; irritability; muscle tension; and sleep disturbance.
Substance/medication-induced anxiety disorder involves anxiety due to substance in­
toxication or withdrawal or to a medication treatment. In anxiety disorder due to another 
medical condition, anxiety symptoms are the physiological consequence of another med­
Disorder-specific scales are available to better characterize the severity of each anxiety

Disorder-specific scales are available to better characterize the severity of each anxiety 
disorder and to capture change in severity over time. For ease of use, particularly for in­
dividuals with more than one anxiety disorder, these scales have been developed to have 
the same format (but different focus) across the anxiety disorders, with ratings of behav­
ioral symptoms, cognitive ideation symptoms, and physical symptoms relevant to each 
disorder.
Separation Anxiety Disorder
Diagnostic Criteria 309.21 (F93.0)
A. Developmentally inappropriate and excessive fear or anxiety concerning separation from  
those to whom the individual is attached, as evidenced by at least three of the following:
1. Recurrent excessive distress when anticipating or experiencing separation from  
home or from major attachment figures.

2. Persistent and excessive worry about losing major attachment figures or about pos­
sible harm to them, such as illness, injury, disasters, or death.
3. Persistent and excessive worry about experiencing an untoward event (e.g., getting  
lost, being kidnapped, having an accident, becoming ill) that causes separation  
from a major attachment figure.
4. Persistent reluctance or refusal to go out, away from home, to school, to work, or  
elsewhere because of fear of separation.
5. Persistent and excessive fear of or reluctance about being alone or without major  
attachment figures at home or in other settings.
6. Persistent reluctance or refusal to sleep away from home or to go to sleep without  
being near a major attachment figure.
7. Repeated nightmares involving the theme of separation.
8. Repeated complaints of physical symptoms (e.g., headaches, stomachaches, nau­
sea, vomiting) when separation from major attachment figures occurs or is antici­
pated.

pated.
B. The fear, anxiety, or avoidance is persistent, lasting at least 4 weeks in children and  
adolescents and typically 6 months or more in adults.
C. The disturbance causes clinically significant distress or impairment in social, aca­
demic, occupational, or other important areas of functioning.
D. The disturbance is not better explained by another mental disorder, such as refusing  
to leave home because of excessive resistance to change in autism spectrum disorder;  
delusions or hallucinations concerning separation in psychotic disorders; refusal to go  
outside without a trusted companion in  agoraphobia; worries about ill health or other  
harm befalling significant others in generalized anxiety disorder; or concerns about  
having an illness in illness anxiety disorder.

The essential feature of separation anxiety disorder is excessive fear or anxiety concerning 
separation from home or attachment figures. The anxiety exceeds what may be expected 
given the person's developmental level (Criterion A). Individuals with separation anxiety 
disorder have symptoms that meet at least three of the following criteria: They experience 
recurrent excessive distress when separation from home or major attachment figures is an­
ticipated or occurs (Criterion Al). They worry about the well-being or death of attachment 
figures, particularly when separated from them, and they need to know the whereabouts 
of their attachment figures and want to stay in touch with them (Criterion A2). They also 
worry about untoward events to themselves, such as getting lost, being kidnapped, or

worry about untoward events to themselves, such as getting lost, being kidnapped, or 
having an accident, that would keep them from ever being reunited with their major at­
tachment figure (Criterion A3). Individuals with separation anxiety disorder are reluctant 
or refuse to go out by themselves because of separation fears (Criterion A4). They have 
persistent and excessive fear or reluctance about being alone or without major attachment 
figures at home or in other settings. Children with separation anxiety disorder may be un­
able to stay or go in a room by themselves and may display "clinging" behavior, staying 
close to or "shadowing" the parent around the house, or requiring someone to be with 
them when going to another room in the house (Criterion A5). They have persistent reluc­
tance or refusal to go to sleep without being near a major attachment figure or to sleep

tance or refusal to go to sleep without being near a major attachment figure or to sleep 
away from home (Criterion A6). Children with this disorder often have difficulty at bed­
time and may insist that someone stay with them until they fall asleep. During the night, 
they may make their way to their parents' bed (or that of a significant other, such as a sib­
ling). Children may be reluctant or refuse to attend camp, to sleep at friends' homes, or to 
go on errands. Adults may be uncomfortable when traveling independently (e.g., sleeping 
in a hotel room). There may be repeated nightmares in which the content expresses the in­

dividual's separation anxiety (e.g., destruction of the family through fire, murder, or other 
catastrophe) (Criterion A7). Physical symptoms (e.g., headaches, abdominal complaints, 
nausea, vomiting) are common in children when separation from major attachment fig­
ures occurs or is anticipated (Criterion A8). Cardiovascular symptoms such as palpitations, 
dizziness, and feeling faint are rare in younger children but may occur in adolescents and 
adults.
The disturbance must last for a period of at least 4 weeks in children and adolescents 
younger than 18 years and is typically 6 months or longer in adults (Criterion B). However, 
the duration criterion for adults should be used as a general guide, with allowance for 
some degree of flexibility. The disturbance must cause clinically significant distress or im­
pairment in social, academic, occupational, or other important areas of functioning (Cri­
terion C).

terion C).
When separated from major attachment figures, children with separation anxiety disorder 
may exhibit social withdrawal, apathy, sadness, or difficulty concentrating on work or 
play. Depending on their age, individuals may have fears of animals, monsters, the dark, 
muggers, burglars, kidnappers, car accidents, plane travel, and other situations that are 
perceived as presenting danger to the family or themselves. Some individuals become 
homesick and uncomfortable to the point of misery when away from home. Separation 
anxiety disorder in children may lead to school refusal, which in turn may lead to academic 
difficulties and social isolation. When extremely upset at the prospect of separation, chil­
dren may show anger or occasionally aggression toward someone who is forcing separa­

tion. When alone, especially in the evening or the dark, young children may report unusual 
perceptual experiences (e.g., seeing people peering into their room, frightening creatures 
reaching for them, feeling eyes staring at them). Children with this disorder may be de­
scribed as demanding, intrusive, and in need of constant attention, and, as adults, may ap­
pear dependent and overprotective. The individual's excessive demands often become a 
source of frustration for family members, leading to resentment and conflict in the family.
The 12-month prevalence of separation anxiety disorder among adults in the United States 
is 0.9%-1.9%. In children, 6- to 12-month prevalence is estimated to be approximately 4%.

is 0.9%-1.9%. In children, 6- to 12-month prevalence is estimated to be approximately 4%. 
In adolescents in the United States, the 12-month prevalence is 1.6%. Separation anxiety 
disorder decreases in prevalence from childhood through adolescence and adulthood and 
is the most prevalent anxiety disorder in children younger than 12 years. In clinical sam­
ples of children, the disorder is equally common in males and females. In the community, 
the disorder is more frequent in females.
Periods of heightened separation anxiety from attachment figures are part of normal early 
development and may indicate the development of secure attachment relationships (e.g., 
around 1  year of age, when infants may suffer from stranger anxiety). Onset of separation 
anxiety disorder may be as early as preschool age and may occur at any time during child­

hood and more rarely in adolescence. Typically there are periods of exacerbation and re­
mission. In some cases, both the anxiety about possible separation and the avoidance of 
situations involving separation from the home or nuclear family (e.g., going away to col­
lege, moving away from attachment figures) may persist through adulthood. However, 
the majority of children with separation anxiety disorder are free of impairing anxiety dis­
orders over their lifetimes. Many adults with separation anxiety disorder do not recall a 
childhood onset of separation anxiety disorder, although they may recall symptoms.

The manifestations of separation anxiety disorder vary with age. Younger children are 
more reluctant to go to school or may avoid school altogether. Younger children may not 
express worries 6r specific fears of definite threats to parents, home, or themselves, and the 
anxiety is manifested only when separation is experienced. As children age, worries 
emerge; these are often worries about specific dangers (e.g., accidents, kidnapping, mug­
ging, death) or vague concerns about not being reunited with attachment figures. In adults, 
separation anxiety disorder may limit their ability to cope with changes in circumstances 
(e.g., moving, getting married). Adults with the disorder are typically overconcemed about 
their offspring and spouses and experience marked discomfort when separated from them. 
They may also experience significant disruption in work or social experiences because of 
needing to continuously check on the whereabouts of a significant other.

Environmental. Separation anxiety disorder often develops after life stress, especially a 
loss (e.g., the death of a relative or pet; an illness of the individual or a relative; a change of 
schools; parental divorce; a move to a new neighborhood; immigration; a disaster that in­
volved periods of separation from attachment figures). In young adults, other examples of 
life stress include leaving the parental home, entering into a romantic relationship, and be­
coming a parent. Parental overprotection and intrusiveness may be associated with sepa­
ration anxiety disorder.
Genetic and physiological. Separation anxiety disorder in children may be heritable. 
Heritability was estimated at 73% in a community sample of 6-year-old twins, with higher

Heritability was estimated at 73% in a community sample of 6-year-old twins, with higher 
rates in girls. Children with separation anxiety disorder display particularly enhanced 
sensitivity to respiratory stimulation using C 02-enriched air.
Cuiture-Related Diagnostic issues
There are cultural variations in the degree to which it is considered desirable to tolerate 
separation, so that demands and opportunities for separation between parents and chil­
dren are avoided in some cultures. For example, there is wide variation across countries 
and cultures with respect to the age at which it is expected that offspring should leave the 
parental home. It is important to differentiate separation anxiety disorder from the high 
value some cultures place on strong interdependence among family members.

Girls manifest greater reluctance to attend or avoidance of school than boys. Indirect ex­
pression of fear of separation may be more common in males than in females, for example, 
by limited independent activity, reluctance to be away from home alone, or distress when 
spouse or offspring do things independently or when contact with spouse or offspring is 
not possible.
Separation anxiety disorder in children may be associated with an increased risk for sui­
cide. In a community sample, the presence of mood disorders, anxiety disorders, or sub­
stance use has been associated with suicidal ideation and attempts. However, this 
association is not specific to separation anxiety disorder and is found in several anxiety 

Functionai Consequences of Separation Anxiety Disorder
Individuals with separation anxiety disorder often limit independent activities away from 
home or attachment figures (e.g., in children, avoiding school, not going to camp, having

difficulty sleeping alone; in adolescents, not going away to college; in adults, not leaving the 
parental home, not traveling, not working outside the home).
Generalized anxiety disorder. Separation anxiety disorder is distinguished from gener­
alized anxiety disorder in that the anxiety predominantly concerns separation from attach­
ment figures, and if other worries occur, they do not predominate the clinical picture.
Panic disorder. Threats of separation may lead to extreme anxiety and even a panic at­
tack. In separation anxiety disorder, in contrast to panic disorder, the anxiety concerns the 
possibility of being away from attachment figures and worry about untoward events be­
falling them, rather than being incapacitated by an unexpected panic attack.
Agoraphobia. Unlike individuals with agoraphobia, those with separation anxiety dis­
order are not anxious about being trapped or incapacitated in situations from which es­

cape is perceived as difficult in the event of panic-like symptoms or other incapacitating 
symptoms.
Conduct disorder. School avoidance (truancy) is common in conduct disorder, but anx­
iety about separation is not responsible for school absences, and the child or adolescent 
usually stays away from, rather than returns to, the home.
Social anxiety disorder. School refusal may be due to social anxiety disorder (social pho­
bia). In such instances, the school avoidance is due to fear of being judged negatively by oth­
ers rather than to worries about being separated from the attachment figures.
Posttraumatic stress disorder. Fear of separation from loved ones is common after trau­
matic events such as a disasters, particularly when periods of separation from loved ones

matic events such as a disasters, particularly when periods of separation from loved ones 
were experienced during the traumatic event. In posttraumatic stress disorder (PTSD), the 
central symptoms concern intrusions about, and avoidance of, memories associated with 
the traumatic event itself, whereas in separation anxiety disorder, the worries and avoid­
ance concern the well-being of attachment figures and separation from them.
Illness anxiety disorder. Individuals with illness anxiety disorder worry about specific 
illnesses they may have, but the main concern is about the medical diagnosis itself, not 
about being separated from attachment figures.
Bereavement. Intense yearning or longing for the deceased, intense sorrow and emo­
tional pain, and preoccupation with the deceased or the circumstances of the death are ex­

pected responses occurring in bereavement, whereas fear of separation from other 
attachment figures is central in separation anxiety disorder.
Depressive and bipolar disorders. These disorders may be associated with reluctance 
to leave home, but the main concern is not worry or fear of untoward events befalling at­
tachment figures, but rather low motivation for engaging with the outside world. How­
ever, individuals with separation anxiety disorder may become depressed while being 
separated or in anticipation of separation.
Oppositional defiant disorder. Children and adolescents with separation anxiety disor­
der may be oppositional in the context of being forced to separate from attachment figures. 
Oppositional defiant disorder should be considered only when there is persistent opposi­

tional behavior unrelated to the anticipation or occurrence of separation from attachment 
figures.
Psychotic disorders. Unlike the hallucinations in psychotic disorders, the unusual per­
ceptual experiences that may occur in separation anxiety disorder are usually based on a 
misperception of an actual stimulus, occur only in certain situations (e.g., nighttime), and 
are reversed by the presence of an attachment figure.

Personality disorders. Dependent personality disorder is characterized by an indis­
criminate tendency to rely on others, whereas separation anxiety disorder involves con­
cern about the proximity and safety of main attachment figures. Borderline personality 
disorder is characterized by fear of abandonment by loved ones, but problems in identity, 
self-direction, interpersonal functioning, and impulsivity are additionally central to that 
disorder, whereas they are not central to separation anxiety disorder.
In children, separation anxiety disorder is highly comorbid with generahzed anxiety dis­
order and specific phobia. In adults, common comorbidities include specific phobia, 
PTSD, panic disorder, generalized anxiety disorder, social anxiety disorder, agoraphobia, 
obsessive-compulsive disorder, and personality disorders. Depressive and bipolar disor­
ders are also comorbid with separation anxiety disorder in adults.
Selective Mutism
Diagnostic Criteria 312.23 (F94.0)

A. Consistent failure to speak in  specific social situations in which there is an expectation  
for speaking (e.g., at school) despite speaking in other situations.
B. The disturbance interferes with educational or occupational achievement or with social  
communication.
C. The duration of the disturbance is at least 1  month (not limited to the first month of  
school).
D. The failure to speak is not attributable to a lack of knowledge of, or comfort with, the  
spoken language required in the social situation.
E. The disturbance is not better explained by a communication disorder (e.g., childhood-  
onset fluency disorder) and does not occur exclusively during the course of autism  
spectrum disorder, schizophrenia, or another psychotic disorder.
When encountering other individuals in social interactions, children with selective mut­

ism do not initiate speech or reciprocally respond when spoken to by others. Lack of 
speech occurs in social interactions with children or adults. Children with selective mut­
ism will speak in their home in the presence of immediate family members but often not 
even in front of close friends or second-degree relatives, such as grandparents or cousins. 
The disturbance is often marked by high social anxiety. Children with selective mutism of­
ten refuse to speak at school, leading to academic or educational impairment, as teachers 
often find it difficult to assess skills such as reading. The lack of speech may interfere with 
social communication, although children with this disorder sometimes use nonspoken or 
nonverbal means (e.g., grunting, pointing, writing) to communicate and may be willing or

nonverbal means (e.g., grunting, pointing, writing) to communicate and may be willing or 
eager to perform or engage in social encounters when speech is not required (e.g., nonver­
bal parts in school plays).
Associated features of selective mutism may include excessive shyness, fear of social em­
barrassment, social isolation and withdrawal, clinging, compulsive traits, negativism, 
temper tantrums, or mild oppositional behavior. Although children with this disorder 
generally have normal language skills, there may occasionally be an associated commu-

nication disorder, although no particular association with a specific communication dis­
order has been identified. Even when these disorders are present, anxiety is present as 
well. In clinical settings, children with selective mutism are almost always given an addi­
tional diagnosis of another anxiety disorder—most commonly, social anxiety disorder (so­
cial phobia).
Selective mutism is a relatively rare disorder and has not been included as a diagnostic cat­
egory in epidemiological studies of prevalence of childhood disorders. Point prevalence 
using various clinic or school samples ranges between 0.03% and 1% depending on the set­
ting (e.g., clinic vs. school vs. general population) and ages of the individuals in the sample. 
The prevalence of the disorder does not seem to vary by sex or race/ethnicity. The disor­
der is more likely to manifest in young children than in adolescents and adults.

The onset of selective mutism is usually before age 5 years, but the disturbance may not 
come to clinical attention until entry into school, where there is an increase in social inter­
action and performance tasks, such as reading aloud. The persistence of the disorder is 
variable. Although clinical reports suggest that many individuals "'outgrow" selective 
mutism, the longitudinal course of the disorder is unknown. In some cases, particularly in 
individuals with social anxiety disorder, selective mutism may disappear, but symptoms 
of social anxiety disorder remain.
Temperamental. Temperamental risk factors for selective mutism are not well identi­
fied. Negative affectivity (neuroticism) or behavioral inhibition may play a role, as may

fied. Negative affectivity (neuroticism) or behavioral inhibition may play a role, as may 
parental history of shyness, social isolation, and social anxiety. Children with selective 
mutism may have subtle receptive language difficulties compared with their peers, al­
though receptive language is still within the normal range.
Environmental. Social inhibition on the part of parents may serve as a model for social 
reticence and selective mutism in children. Furthermore, parents of children with selective 
mutism have been described as overprotective or more controlling than parents of chil­
dren with other anxiety disorders or no disorder.
Genetic and physiological factors. Because of the significant overlap between selective 
mutism and social anxiety disorder, there may be shared genetic factors between these 
conditions.

Children in families who have immigrated to a country where a different language is spo­
ken may refuse to speak the new language because of lack of knowledge of the language. 
If comprehension of the new language is adequate but refusal to speak persists, a diagno­
sis of selective mutism may be warranted.
Functional Consequences of Selective Mutism
Selective mutism may result in social impairment, as children may be too anxious to en­
gage in reciprocal social interaction with other children. As children with selective mutism 
mature, they may face increasing social isolation. In school settings, these children may 
suffer academic impairment, because often they do not communicate with teachers re­
garding their academic or personal needs (e.g., not understanding a class assignment, not

asking to use the restroom). Severe impairment in school and social functioning, including 
that resulting from teasing by peers, is common. In certain instances, selective mutism 
may serve as a compensatory strategy to decrease anxious arousal in social encounters.
Communication disorders. Selective mutism should be distinguished from speech dis­
turbances that are better explained by a communication disorder, such as language 
disorder, speech sound disorder (previously phonological disorder), childhood-onset 
fluency disorder (stuttering), or pragmatic (social) communication disorder. Unlike selec­
tive mutism, the speech disturbance in these conditions is not restricted to a specific social 
situation.
Neurodevelopmental disorders and schizophrenia and other psychotic disorders.
Individuals with an autism spectrum disorder, schizophrenia or another psychotic disor­
der, or severe intellectual disability may have problems in social communication and be

der, or severe intellectual disability may have problems in social communication and be 
unable to speak appropriately in social situations. In contrast, selective mutism should be 
diagnosed only when a child has an established capacity to speak in some social situations 
(e.g., typically at home).
Social anxiety disorder (social phobia). The social anxiety and social avoidance in so­
cial anxiety disorder may be associated with selective mutism. In such cases, both diagno­
ses may be given.
The most common comorbid conditions are other anxiety disorders, most commonly so­
cial anxiety disorder, followed by separation anxiety disorder and specific phobia. Oppo­
sitional behaviors have been noted to occur in children with selective mutism, although 
oppositional behavior may be limited to situations requiring speech. Communication de­

lays or disorders also may appear in some children with selective mutism.
Specific Phobia
A. Marked fear or anxiety about a specific object or situation (e.g., flying, heights, animals,  
receiving an injection, seeing blood).
Note: In children, the fear or anxiety may be expressed by crying, tantrums, freezing,  
or clinging.
B. The phobic object or situation almost always provokes immediate fear or anxiety.
C. The phobic object or situation is actively avoided or endured with intense fear or anxiety.
D. The fear or anxiety is out of proportion to the actual danger posed by the specific object  
or situation and to the sociocultural context.
E. The fear, anxiety, or avoidance is persistent, typically lasting for 6 months or more.

F. The fear, anxiety, or avoidance causes clinically significant distress or impairment in  
social, occupational, or other important areas of functioning.
G. The disturbance is not better explained by the symptoms of another mental disorder,  
including fear, anxiety, and avoidance of situations associated with panic-like symptoms  
or other incapacitating symptoms (as in agoraphobia): objects or situations related to  
obsessions (as in obsessive-compulsive disorder); reminders of traumatic events (as in  
posttraumatic stress disorder); separation from home or attachment figures (as in sep­
aration anxiety disorder); or social situations (as in social anxiety disorder).

Code based on the phobic stimulus:
300.29 (F40.218) Animal (e.g., spiders, insects, dogs).
300.29 (F40.228) Natural environment (e.g., heights, storms, water).
300.29 (F40.23X) Blood-injection-injury (e.g., needles, invasive medical procedures).
Coding note: Select specific ICD-10-CM code as follows: F40.230 fear of blood;
F40.231 fear of injections and transfusions; F40.232 fear of other medical care; or
F40.233 fear of injury.
300.29 (F40.248) Situational (e.g., airplanes, elevators, enclosed places).
300.29 (F40.298) Other (e.g., situations that may lead to choking or vomiting: in chil­
dren, e.g., loud sounds or costumed characters).
Coding note: When more than one phobic stimulus is present, code all ICD-10-CM codes  
that apply (e.g., for fear of snakes and flying, F40.218 specific phobia, animal, and  
F40.248 specific phobia, situational).
It is common for individuals to have multiple specific phobias. The average individual with

It is common for individuals to have multiple specific phobias. The average individual with 
specific phobia fears three objects or situations, and approximately 75% of individuals with 
specific phobia fear more than one situation or object. In such cases, multiple specific phobia 
diagnoses, each with its own diagnostic code reflecting the phobic stimulus, would need to be 
given. For example, if an individual fears thunderstorms and flying, then two diagnoses 
would be given: specific phobia, natural environment, and specific phobia, situational.
A key feature of this disorder is that the fear or anxiety is circumscribed to the presence of a 
particular situation or object (Criterion A), which may be termed the phobic stimulus.  The cat­
egories of feared situations or objects are provided as specifiers. Many individuals fear objects

egories of feared situations or objects are provided as specifiers. Many individuals fear objects 
or situations from more than one category, or phobic stimulus. For the diagnosis of specific 
phobia, the response must differ from normal, transient fears that commonly occur in the pop­
ulation. To meet the criteria for a diagnosis, the fear or anxiety must be intense or severe (i.e., 
"marked") (Criterion A). The amount of fear experienced may vary with proximity to the 
feared object or situation and may occur in anticipation of or in the actual presence of the object 
or situation. Also, the fear or anxiety may take the form of a full or limited symptom panic at­
tack (i.e., expected panic attack). Another characteristic of specific phobias is that fear or anxi­
ety is evoked nearly every time the individual comes into contact with the phobic stimulus

ety is evoked nearly every time the individual comes into contact with the phobic stimulus 
(Criterion B). Thus, an individual who becomes anxious only occasionally upon being con­
fronted with the situation or object (e.g., becomes anxious when flying only on one out of every 
five airplane flights) would not be diagnosed with specific phobia. However, the degree of fear 
or anxiety expressed may vary (from anticipatory anxiety to a full panic attack) across different 
occasions of encountering the phobic object or situation because of various contextual factors 
such as the presence of others, duration of exposure, and other threatening elements such as 
turbulence on a flight for individuals who fear flying. Fear and anxiety are often expressed dif­
ferently between children and adults. Also, the fear or anxiety occurs as soon as the phobic ob­

ject or situation is encountered (i.e., immediately rather than being delayed).
The individual actively avoids the situation, or if he or she either is unable or decides 
not to avoid it, the situation or object evokes intense fear or anxiety (Criterion C). Active  
avoidance means the individual intentionally behaves in ways that are designed to prevent 
or minimize contact with phobic objects or situations (e.g., takes tunnels instead of bridges 
on daily commute to work for fear of heights; avoids entering a dark room for fear of spi­
ders; avoids accepting a job in a locale where a phobic stimulus is more common). Avoid-

ance behaviors are often obvious (e.g., an individual who fears blood refusing to go to the 
doctor) but are sometimes less obvious (e.g., an individual who fears snakes refusing to 
look at pictures ihat resemble the form or shape of snakes). Many individuals with specific 
phobias have suffered over many years and have changed their living circumstances in 
ways designed to avoid the phobic object or situation as much as possible (e.g., an indi­
vidual diagnosed with specific phobia, animal, who moves to reside in an area devoid of 
the particular feared animal). Therefore, they no longer experience fear or anxiety in their 
daily life. In such instances, avoidance behaviors or ongoing refusal to engage in activities 
that would involve exposure to the phobic object or situation (e.g., repeated refusal to ac­
cept offers for work-related travel because of fear of flying) may be helpful in confirming 
the diagnosis in the absence of overt anxiety or panic.

The fear or anxiety is out of proportion to the actual danger that the object or situation 
poses, or more intense than is deemed necessary (Criterion D). Although individuals with 
specific phobia often recognize their reactions as disproportionate, they tend to overesti­
mate the danger in their feared situations, and thus the judgment of being out of propor­
tion is made by the clinician. The individual's sociocultural context should also be taken 
into account. For example, fears of the dark may be reasonable in a context of ongoing 
violence, and fear of insects may be more disproportionate in settings where insects are 
consumed in the diet. The fear, anxiety, or avoidance is persistent, typically lasting for 
6 months or more (Criterion E), which helps distinguish the disorder from transient fears

6 months or more (Criterion E), which helps distinguish the disorder from transient fears 
that are common in the population, particularly among children. However, the duration 
criterion should be used as a general guide, with allowance for some degree of flexibility. 
The specific phobia must cause clinically significant distress or impairment in social, oc­
cupational, or other important areas of functioning in order for the disorder to be diag­
nosed (Criterion F).
Individuals with specific phobia typically experience an increase in physiological arousal 
in anticipation of or during exposure to a phobic object or situation. However, the physi­
ological response to the feared situation or object varies. Whereas individuals with situa­
tional, natural environment, and animal specific phobias are likely to show sympathetic

tional, natural environment, and animal specific phobias are likely to show sympathetic 
nervous system arousal, individuals with blood-injection-injury specific phobia often 
demonstrate a vasovagal fainting or near-fainting response that is marked by initial brief 
acceleration of heart rate and elevation of blood pressure followed by a deceleration of 
heart rate and a drop in blood pressure. Current neural systems models for specific phobia 
emphasize the amygdala and related structures, much as in other anxiety disorders.
In the United States, the 12-month community prevalence estimate for specific phobia is 
approximately 7%-9%. Prevalence rates in European countries are largely similar to those 
in the United States (e.g., about 6%), but rates are generally lower in Asian, African, and 
Latin American countries (2%-4%). Prevalence rates are approximately 5% in children and

Latin American countries (2%-4%). Prevalence rates are approximately 5% in children and 
are approximately 16% in 13- to 17-year-olds. Prevalence rates are lower in older individ­
uals (about 3%-5%), possibly reflecting diminishing severity to subclinical levels. Females 
are more frequently affected than males, at a rate of approximately 2:1, although rates vary 
across different phobic stimuli. That is, animal, natural environment, and situational spe­
cific phobias are predominantly experienced by females, whereas blood-injection-injury 
phobia is experienced nearly equally by both genders.
Specific phobia sometimes develops following a traumatic event (e.g., being attacked by 
an animal or stuck in an elevator), observation of others going through a traumatic event (e.g.,

watching someone drown), an unexpected panic attack in the to be feared situation (e.g., 
an unexpected panic attack while on the subway), or informational transmission (e.g., ex­
tensive media coverage of a plane crash). However, many individuals with specific phobia 
are unable to recall the specific reason for the onset of their phobias. Specific phobia usu­
ally develops in early childhood, with the majority of cases developing prior to age 10 
years. The median age at onset is between 7 and 11 years, with the mean at about 10 years. 
Situational specific phobias tend to have a later age at onset than natural environment, an­
imal, or blood-injection-injury specific phobias. Specific phobias that develop in child­
hood and adolescence are likely to wax and wane during that period. However, phobias 
that do persist into adulthood are unlikely to remit for the majority of individuals.
When specific phobia is being diagnosed in children, two issues should be considered.

When specific phobia is being diagnosed in children, two issues should be considered. 
First, young children may express their fear and anxiety by crying, tantrums, freezing, 
or clinging. Second, young children typically are not able to understand the concept of 
avoidance. Therefore, the clinician should assemble additional information from parents, 
teachers, or others who know the child well. Excessive fears are quite common in young 
children but are usually transitory and only mildly impairing and thus considered devel­
opmentally appropriate. In such cases a diagnosis of specific phobia would not be made. 
When the diagnosis of specific phobia is being considered in a child, it is important to 
assess the degree of impairment and the duration of the fear, anxiety, or avoidance, and 
whether it is typical for the child's particular developmental stage.

Although the prevalence of specific phobia is lower in older populations, it remains 
one of the more commonly experienced disorders in late life. Several issues should be con­
sidered when diagnosing specific phobia in older populations. First, older individuals 
may be more likely to endorse natural environment specific phobias, as well as phobias of 
falling. Second, specific phobia (like all anxiety disorders) tends to co-occur with medical 
concerns in older individuals, including coronary heart disease and chronic obstructive 
pulmonary disease. Third, older individuals may be more likely to attribute the symptoms 
of anxiety to medical conditions. Fourth, older individuals may be more likely to manifest 
anxiety in an atypical manner (e.g., involving symptoms of both anxiety and depression)

anxiety in an atypical manner (e.g., involving symptoms of both anxiety and depression) 
and thus be more likely to warrant a diagnosis of unspecified anxiety disorder. Addition­
ally, the presence of specific phobia in older adults is associated with decreased quality of 
life and may serve as a risk factor for major neurocognitive disorder.
Although most specific phobias develop in childhood and adolescence, it is possible for a 
specific phobia to develop at any age, often as the result of experiences that are traumatic. For 
example, phobias of choking almost always follow a near-choking event at any age.
Temperamental. Temperamental risk factors for specific phobia, such as negative affec- 
tivity (neuroticism) or behavioral inhibition, are risk factors for other anxiety disorders as 
well.

well.
Environmental. Environmental risk factors for specific phobias, such as parental over­
protectiveness, parental loss and separation, and physical and sexual abuse, tend to pre­
dict other anxiety disorders as well. As noted earlier, negative or traumatic encounters 
with the feared object or situation sometimes (but not always) precede the development of 
specific phobia.
Genetic and physiological. There may be a genetic susceptibility to a certain category of 
specific phobia (e.g., an individual with a first-degree relative with a specific phobia of an­
imals is significantly more likely to have the same specific phobia than any other category 
of phobia). Individuals with blood-injection-injury phobia show a unique propensity to

of phobia). Individuals with blood-injection-injury phobia show a unique propensity to 
vasovagal syncope (fainting) in the presence of the phobic stimulus.

In the United States, Asians and Latinos report significantly lower rates of specific phobia 
than non-Latino whites, African Americans, and Native Americans. In addition to having 
lower prevalence rates of specific phobia, some countries outside of the United States, par­
ticularly Asian and African countries, show differing phobia content, age at onset, and 
gender ratios.
Individuals with specific phobia are up to 60% more likely to make a suicide attempt than 
are individuals without the diagnosis. However, it is likely that these elevated rates are 
primarily due to comorbidity with personality disorders and other anxiety disorders.
Functional Consequences of Specific Phobia
Individuals with specific phobia show similar patterns of impairment in psychosocial 
functioning and decreased quality of life as individuals with other anxiety disorders and 
alcohol and substance use disorders, including impairments in occupational and inter­

personal functioning. In older adults, impairment may be seen in caregiving duties and 
volunteer activities. Also, fear of falling in older adults can lead to reduced mobility and 
reduced physical and social functioning, and may lead to receiving formal or informal 
home support. The distress and impairment caused by specific phobias tend to increase 
with the number of feared objects and situations. Thus, an individual who fears four ob­
jects or situations is likely to have more impairment in his or her occupational and social 
roles and a lower quality of life than an individual who fears only one object or situation. 
Individuals with blood-injection-injury specific phobia are often reluctant to obtain med­
ical care even when a medical concern is present. Additionally, fear of vomiting and chok­

ing may substantially reduce dietary intake.
Agoraphobia. Situational specific phobia may resemble agoraphobia in its clinical pre­
sentation, given the overlap in feared situations (e.g., flying, enclosed places, elevators). If 
an individual fears only one of the agoraphobia situations, then specific phobia, situa­
tional, may be diagnosed. If two or more agoraphobic situations are feared, a diagnosis of 
agoraphobia is likely warranted. For example, an individual who fears airplanes and ele­
vators (which overlap with the '"public transportation" agoraphobic situation) but does 
not fear other agoraphobic situations would be diagnosed with specific phobia, situa­
tional, whereas an individual who fears airplanes, elevators, and crowds (which overlap

tional, whereas an individual who fears airplanes, elevators, and crowds (which overlap 
with two agoraphobic situations, "using public transportation" and "standing in line and 
or being in a crowd") would be diagnosed with agoraphobia. Criterion B of agoraphobia 
(the situations are feared or avoided "because of thoughts that escape might be difficult or 
pacitating or embarrassing symptoms") can also be useful in differentiating agoraphobia 
from specific phobia. If the situations are feared for other reasons, such as fear of being 
harmed directly by the object or situations (e.g., fear of the plane crashing, fear of the an­
imal biting), a specific phobia diagnosis may be more appropriate.
Social anxiety disorder. If the situations are feared because of negative evaluation, so­

cial anxiety disorder should be diagnosed instead of specific phobia.
Separation anxiety disorder. If the situations are feared because of separation from a 
primary caregiver or attachment figure, separation anxiety disorder should be diagnosed 
instead of specific phobia.

Panic disorder. Individuals with specific phobia may experience panic attacks when con­
fronted with their feared situation or object. A diagnosis of specific phobia would be given if 
the panic attacks only occurred in response to the specific object or situation, whereas a di­
agnosis of panic disorder would be given if the individual also experienced panic attacks 
that were unexpected (i.e., not in response to the specific phobia object or situation).
Obsessive-compulsive disorder. If an individual's primary fear or anxiety is of an ob­
ject or situation as a result of obsessions (e.g., fear of blood due to obsessive thoughts about 
contamination from blood-borne pathogens [i.e., HIV]; fear of driving due to obsessive im­
ages of harming others), and if other diagnostic criteria for obsessive-compulsive disorder 
are met, then obsessive-compulsive disorder should be diagnosed.
Trauma- and stressor-related disorders. If the phobia develops following a traumatic

Trauma- and stressor-related disorders. If the phobia develops following a traumatic 
event, posttraumatic stress disorder (PTSD) should be considered as a diagnosis. How­
ever, traumatic events can precede the onset of PTSD and specific phobia. In this case, a di­
agnosis of specific phobia would be assigned only if all of the criteria for PTSD are not met.
Eating disorders. A diagnosis of specific phobia is not given if the avoidance behavior is 
exclusively limited to avoidance of food and food-related cues, in which case a diagnosis 
of anorexia nervosa or bulimia nervosa should be considered.
Schizophrenia spectrum and other psychotic disorders. When the fear and avoidance 
are due to delusional thinking (as in schizophrenia or other schizophrenia spectrum and 
other psychotic disorders), a diagnosis of specific phobia is not warranted.

Specific phobia is rarely seen in medical-clinical settings in the absence of other psycho­
pathology and is more frequently seen in nonmedical mental health settings. Specific pho­
bia is frequently associated with a range of other disorders, especially depression in older 
adults. Because of early onset, specific phobia is typically the temporally primary disorder. 
Individuals with specific phobia are at increased risk for the development of other dis­
orders, including other anxiety disorders, depressive and bipolar disorders, substance- 
related disorders, somatic symptom and related disorders, and personality disorders (par­
ticularly dependent personality disorder).
Social Anxiety Disorder (Social Phobia)
Diagnostic Criteria 300.23 (F40.10)

A. Marked fear or anxiety about one or more social situations in which the individual is  
exposed to possible scrutiny by others. Examples include social interactions (e.g., hav­
ing a conversation, meeting unfamiliar people), being observed (e.g., eating or drink­
ing), and performing in front of others (e.g., giving a speech).
Note: In children, the anxiety must occur in  peer settings and not just during interac­
tions with adults.
B. The individual fears that he or she w ill act in a way or show anxiety symptoms that will  
be negatively evaluated (i.e., will be humiliating or embarrassing: will lead to rejection  
or offend others).
C. The social situations almost always provoke fear or anxiety.
clinging, shrinking, or failing to speak in social situations.

D. The social situations are avoided or endured with intense fear or anxiety.

E. The fear or anxiety is out of proportion to the actual threat posed by the social situation  
and to the sociocultural context.
F. The fear, anxiety, or avoidance is persistent, typically lasting for 6 months or more.
G. The fear, anxiety, or avoidance causes clinically significant distress or impairment in  
H. The fear, anxiety, or avoidance is not attributable to the physiological effects of a sub­
stance (e.g., a drug of abuse, a medication) or another medical condition.
I. The fear, anxiety, or avoidance is not better explained by the symptoms of another  
mental disorder, such as panic disorder, body dysmoφhic disorder, or autism spectrum  
disorder.
J. If another medical condition (e.g., Parkinson’s disease, obesity, disfigurement from bums  
or injury) is present, the fear, anxiety, or avoidance is clearly unrelated or is excessive.

Performance only: If the fear is restricted to speaking or performing in public.
Individuals with the performance only type of social anxiety disorder have performance 
fears that are typically most impairing in their professional lives (e.g., musicians, dancers, 
performers, athletes) or in roles that require regular public speaking. Performance fears 
may also manifest in work, school, or academic settings in which regular public presenta­
tions are required. Individuals with performance only social anxiety disorder do not fear 
or avoid nonperformance social situations.
The essential feature of social anxiety disorder is a marked, or intense, fear or anxiety of so­
cial situations in which the individual may be scrutinized by others. In children the fear or

cial situations in which the individual may be scrutinized by others. In children the fear or 
anxiety must occur in peer settings and not just during interactions with adults (Criterion 
A). When exposed to such social situations, the individual fears that he or she will be neg­
atively evaluated. The individual is concerned that he or she will be judged as anxious, 
weak, crazy, stupid, boring, intimidating, dirty, or unlikable. The individual fears that 
he or she will act or appear in a certain way or show anxiety symptoms, such as blushing, 
trembling, sweating, stumbling over one's words, or staring, that will be negatively eval­
uated by others (Criterion B). Some individuals fear offending others or being rejected as 
a result. Fear of offending others—for example, by a gaze or by showing anxiety symp­

toms—may be the predominant fear in individuals from cultures with strong collectivistic 
orientations. An individual with fear of trembling of the hands may avoid drinking, eat­
ing, writing, or pointing in public; an individual with fear of sweating may avoid shaking 
hands or eating spicy foods; and an individual with fear of blushing may avoid public per­
formance, bright lights, or discussion about intimate topics. Some individuals fear and 
avoid urinating in public restrooms when other individuals are present (i.e., paruresis, or 
"shy bladder syndrome").
The social situations almost always provoke fear or anxiety (Criterion C). Thus, an in­
dividual who becomes anxious only occasionally in the social situation(s) would not be di­

agnosed with social anxiety disorder. However, the degree and type of fear and anxiety 
may vary (e.g., anticipatory anxiety, a panic attack) across different occasions. The antici­
patory anxiety may occur sometimes far in advance of upcoming situations (e.g., worrying 
every day for weeks before attending a social event, repeating a speech for days in advance). 
In children, the fear or anxiety may be expressed by crying, tantrums, freezing, clinging, or 
shrinking in social situations. The individual will often avoid the feared social situations. 
Alternatively, the situations are endured with intense fear or anxiety (Criterion D). Avoid-

ance can be extensive (e.g., not going to parties, refusing school) or subtle (e.g., overpre­
paring the text of a speech, diverting attention to others, limiting eye contact).
The fear or anxiety is judged to be out of proportion to the actual risk of being nega­
tively evaluated or to the consequences of such negative evaluation (Criterion E). Some­
times, the anxiety may not be judged to be excessive, because it is related to an actual 
danger (e.g., being bullied or tormented by others). However, individuals with social anx­
iety disorder often overestimate the negative consequences of social situations, and thus 
the judgment of being out of proportion is made by the clinician. The individual's socio­
cultural context needs to be taken into account when this judgment is being made. For ex­
ample, in certain cultures, behavior that might otherwise appear socially anxious may be 
considered appropriate in social situations (e.g., might be seen as a sign of respect).

The duration of the disturbance is typically at least 6 months (Criterion F). This dura­
tion threshold helps distinguish the disorder from transient social fears that are com­
mon, particularly among children and in the community. However, the duration criterion 
should be used as a general guide, with allowance for some degree of flexibility. The fear, 
anxiety, and avoidance must interfere significantly with the individual's normal routine, 
occupational or academic functioning, or social activities or relationships, or must cause 
clinically significant distress or impairment in social, occupational, or other important ar­
eas of functioning (Criterion G). For example, an individual who is afraid to speak in pub­

lic would not receive a diagnosis of social anxiety disorder if this activity is not routinely 
encountered on the job or in classroom work, and if the individual is not significantly dis­
tressed about it. However, if the individual avoids, or is passed over for, the job or educa­
tion he or she really wants because of social anxiety symptoms. Criterion G is met.
Individuals with social anxiety disorder may be inadequately assertive or excessively sub­
missive or, less commonly, highly controlling of the conversation. They may show overly 
rigid body posture or inadequate eye contact, or speak with an overly soft voice. These in­
dividuals may be shy or withdrawn, and they may be less open in conversations and dis­

close little about themselves. They may seek employment in jobs that do not require social 
contact, although this is not the case for individuals with social anxiety disorder, perfor­
mance only. They may live at home longer. Men may be delayed in marrying and having 
a family, whereas women who would want to work outside the home may live a life as 
homemaker and mother. Self-medication with substances is common (e.g., drinking be­
fore going to a party). Social anxiety among older adults may also include exacerbation of 
symptoms of medical illnesses, such as increased tremor or tachycardia. Blushing is a hall­
mark physical response of social anxiety disorder.
The 12-month prevalence estimate of social anxiety disorder for the United States is ap­

proximately 7%. Lower 12-month prevalence estimates are seen in much of the world us­
ing the same diagnostic instrument, clustering around 0.5%-2.0%; median prevalence in 
Europe is 2.3%. The 12-month prevalence rates in children and adolescents are comparable 
to those in adults. Prevalence rates decrease with age. The 12-month prevalence for older 
adults ranges from 2% to 5%. In general, higher rates of social anxiety disorder are found 
in females than in males in the general population (with odds ratios ranging from 1.5 to 
2.2), and the gender difference in prevalence is more pronounced in adolescents and 
young adults. Gender rates are equivalent or slightly higher for males in clinical samples, 
and it is assumed that gender roles and social expectations play a significant role in ex­

plaining the heightened help-seeking behavior in male patients. Prevalence in the United 
States is higher in American Indians and lower in persons of Asian, Latino, African Amer­
ican, and Afro-Caribbean descent compared with non-Hispanic whites.

Median age at onset of social anxiety disorder in the United States is 13 years, and 75% of 
individuals have an age at onset between 8 and 15 years. The disorder sometimes emerges 
out of a childhood history of social inhibition or shyness in U.S. and European studies. On­
set can also occur in early childhood. Onset of social anxiety disorder may follow a stress­
ful or humiliating experience (e.g., being bullied, vomiting during a public speech), or it 
may be insidious, developing slowly. First onset in adulthood is relatively rare and is more 
likely to occur after a stressful or humiliating event or after life changes that require new 
social roles (e.g., marrying someone from a different social class, receiving a job promo­
tion). Social anxiety disorder may diminish after an individual with fear of dating marries 
and may reemerge after divorce. Among individuals presenting to clinical care, the disor­
der tends to be particularly persistent.

Adolescents endorse a broader pattern of fear and avoidance, including of dating, 
compared with younger children. Older adults express social anxiety at lower levels but 
across a broader range of situations, whereas younger adults express higher levels of so­
cial anxiety for specific situations. In older adults, social anxiety may concern disability 
due to declining sensory functioning (hearing, vision) or embarrassment about one's ap­
pearance (e.g., tremor as a symptom of Parkinson's disease) or functioning due to medical 
conditions, incontinence, or cognitive impairment (e.g., forgetting people's names). In the 
community approximately 30% of individuals with social anxiety disorder experience re­
mission of symptoms within 1  year, and about 50% experience remission within a few

mission of symptoms within 1  year, and about 50% experience remission within a few 
years. For approximately 60% of individuals without a specific treatment for social anxiety 
disorder, the course takes several years or longer.
Detection of social anxiety disorder in older adults may be challenging because of sev­
eral factors, including a focus on somatic symptoms, comorbid medical illness, limited 
insight, changes to social environment or roles that may obscure impairment in social 
functioning, or reticence about describing psychological distress.
Temperamental. Underlying traits that predispose individuals to social anxiety disor­
der include behavioral inhibition and fear of negative evaluation.
Environmental. There is no causative role of increased rates of childhood maltreatment or

Environmental. There is no causative role of increased rates of childhood maltreatment or 
other early-onset psychosocial adversity in the development of social anxiety disorder. How­
ever, childhood maltreatment and adversity are risk factors for social anxiety disorder.
Genetic and physiological. Traits predisposing individuals to social anxiety disorder, 
such as behavioral inhibition, are strongly genetically influenced. The genetic influence is 
subject to gene-environment interaction; that is, children with high behavioral inhibition 
are more susceptible to environmental influences, such as socially anxious modeling by 
parents. Also, social anxiety disorder is heritable (but performance-only anxiety less so). 
First-degree relatives have a two to six times greater chance of having social anxiety dis­
order, and liability to the disorder involves the interplay of disorder-specific (e.g., fear of

order, and liability to the disorder involves the interplay of disorder-specific (e.g., fear of 
negative evaluation) and nonspecific (e.g., neuroticism) genetic factors.
The syndrome of taijin kyofusho  (e.g., in Japan and Korea) is often characterized by social- 
evaluative concerns, fulfilling criteria for social anxiety disorder, that are associated with 
the fear that the individual makes other  people uncomfortable (e.g., "My gaze upsets peo­
ple so they look away and avoid me"), a fear that is at times experienced with delusional 
intensity. This symptom may also be found in non-Asian settings. Other presentations 
of taijin kyofusho  may fulfill criteria for body dysmorphic disorder or delusional disorder.

Immigrant status is associated with significantly lower rates of social anxiety disorder in 
both Latino and non-Latino white groups. Prevalence rates of social anxiety disorder may 
not be in line with self-reported social anxiety levels in the same culture—that is, societies 
with strong collectivistic orientations may report high levels of social anxiety but low prev­
alence of social anxiety disorder.
Females with social anxiety disorder report a greater number of social fears and comorbid 
depressive, bipolar, and anxiety disorders, whereas males are more likely to fear dating, 
have oppositional defiant disorder or conduct disorder, and use alcohol and illicit drugs to 
relieve symptoms of the disorder. Paruresis is more common in males.
Functional Consequences of Social Anxiety Disorder
Social anxiety disorder is associated with elevated rates of school dropout and with de­

creased well-being, employment, workplace productivity, socioeconomic status, and quality 
of life. Social anxiety disorder is also associated with being single, unmarried, or divorced 
and with not having children, particularly among men. In older adults, there may be impair­
ment in caregiving duties and volunteer activities. Social anxiety disorder also impedes lei­
sure activities. Despite the extent of distress and social impairment associated with social 
anxiety disorder, only about half of individuals with the disorder in Western societies ever 
seek treatment, and they tend to do so only after 15-20 years of experiencing symptoms. Not 
being employed is a strong predictor for ihe persistence of social aimety disorder.
Normative shyness. Shyness (i.e., social reticence) is a common personality trait and is

Normative shyness. Shyness (i.e., social reticence) is a common personality trait and is 
not by itself pathological. In some societies, shyness is even evaluated positively. How­
ever, when there is a significant adverse impact on social, occupational, and other impor­
tant areas of functioning, a diagnosis of social anxiety disorder should be considered, and 
when full diagnostic criteria for social anxiety disorder are met, the disorder should be di­
agnosed. Only a minority (12%) of self-identified shy individuals in the United States have 
symptoms that meet diagnostic criteria for social anxiety disorder.
Agoraphobia. Individuals with agoraphobia may fear and avoid social situations (e.g., go­
ing to a movie) because escape might be difficult or help might not be available in the event of

ing to a movie) because escape might be difficult or help might not be available in the event of 
incapacitation or panic-like symptoms, whereas individuals with social anxiety disorder are 
most fearful of scrutiny by others. Moreover, individuals with social anxiety disorder are likely 
to be calm when left entirely alone, which is often not the case in agoraphobia.
Panic disorder. Individuals with social anxiety disorder may have panic attacks, but the 
concern is about fear of negative evaluation, whereas in panic disorder the concern is 
about the panic attacks themselves.
Generalized anxiety disorder. Social worries are common in generalized anxiety disorder, 
but the focus is more on the nature of ongoing relationships rather than on fear of negative 
evaluation. Individuals with generalized anxiety disorder, particularly children, may have ex­

cessive worries about the quality of their social performance, but these worries also pertain to 
nonsocial performance and when the individual is not being evaluated by others. In social anx­
iety disorder, the worries focus on social performance and others' evaluation.
Separation anxiety disorder. Individuals with separation anxiety disorder may avoid 
social settings (including school refusal) because of concerns about being separated from 
attachment figures or, in children, about requiring the presence of a parent when it is not 
developmentally appropriate. Individuals with separation anxiety disorder are usually 
comfortable in social settings when their attachment figure is present or when they are at

home, whereas those with social anxiety disorder may be uncomfortable when social sit­
uations occur at home or in the presence of attachment figures.
Specific phobias. Individuals with specific phobias may fear embarrassment or humil­
iation (e.g., embarrassment about fainting when they have their blood drawn), but they do 
not generally fear negative evaluation in other social situations.
Selective mutism. Individuals with selective mutism may fail to speak because of fear of 
negative evaluation, but they do not fear negative evaluation in social situations where no 
speaking is required (e.g., nonverbal play).
Major depressive disorder. Individuals with major depressive disorder may be con­
cerned about being negatively evaluated by others because they feel they are bad or not 
worthy of being liked. In contrast, individuals with social anxiety disorder are worried 
about being negatively evaluated because of certain social behaviors or physical symptoms.

Body dysmorphic disorder. Individuals with body dysmorphic disorder are preoccu­
pied with one or more perceived defects or flaws in their physical appearance that are not 
observable or appear slight to others; this preoccupation often causes social anxiety and 
avoidance. If their social fears and avoidance are caused only by their beliefs about their 
appearance, a separate diagnosis of social anxiety disorder is not warranted.
Delusional disorder. Individuals with delusional disorder may have nonbizarre delu­
sions and/or hallucinations related to the delusional theme that focus on being rejected by 
or offending others. Although extent of insight into beliefs about social situations may 
vary, many individuals with social anxiety disorder have good insight that their beliefs are

vary, many individuals with social anxiety disorder have good insight that their beliefs are 
out of proportion to the actual threat posed by the social situation.
Autism spectrum disorder. Social anxiety and social communication deficits are hall­
marks of autism spectrum disorder. Individuals with social anxiety disorder typically 
have adequate age-appropriate social relationships and social communication capacity, 
although they may appear to have impairment in these areas when first interacting with 
unfamiliar peers or adults.
Personality disorders. Given its frequent onset in childhood and its persistence into and 
through adulthood, social anxiety disorder may resemble a personality disorder. The most 
apparent overlap is with avoidant personality disorder. Individuals with avoidant person­
ality disorder have a broader avoidance pattern than those with social anxiety disorder.

ality disorder have a broader avoidance pattern than those with social anxiety disorder. 
Nonetheless, social anxiety disorder is typically more comorbid with avoidant personality 
disorder than with other personality disorders, and avoidant personality disorder is more 
comorbid with social anxiety disorder than with other anxiety disorders.
Other mental disorders. Social fears and discomfort can occur as part of schizophrenia, 
but other evidence for psychotic symptoms is usually present. In individuals with an eat­
ing disorder, it is important to determine that fear of negative evaluation about eating 
disorder symptoms or behaviors (e.g., purging and vomiting) is not the sole source of so­
cial anxiety before applying a diagnosis of social anxiety disorder. Similarly, obsessive- 
compulsive disorder may be associated with social anxiety, but the additional diagnosis of

compulsive disorder may be associated with social anxiety, but the additional diagnosis of 
social anxiety disorder is used only when social fears and avoidance are independent of 
the foci of the obsessions and compulsions.
Other medical conditions. Medical conditions may produce symptoms that may be em­
barrassing (e.g. trembling in Parkinson's disease). When the fear of negative evaluation 
due to other medical conditions is excessive, a diagnosis of social anxiety disorder should 
be considered.
Oppositional defiant disorder. Refusal to speak due to opposition to authority figures 
should be differentiated from failure to speak due to fear of negative evaluation.

Social anxiety disorder is often comorbid with other anxiety disorders, major depressive 
disorder, and substance use disorders, and the onset of social anxiety disorder generally 
precedes that of the other disorders, except for specific phobia and separation anxiety dis­
order. Chronic social isolation in the course of a social anxiety disorder may result in major 
depressive disorder. Comorbidity with depression is high also in older adults. Substances 
may be used as self-medication for social fears, but the symptoms of substance intoxica­
tion or withdrawal, such as trembling, may also be a source of (further) social fear. Social 
anxiety disorder is frequently comorbid with bipolar disorder or body dysmorphic disor­
der; for example, an individual has body dysmorphic disorder concerning a preoccupa­
tion with a slight irregularity of her nose, as well as social anxiety disorder because of a

tion with a slight irregularity of her nose, as well as social anxiety disorder because of a 
severe fear of sounding unintelligent. The more generalized form of social anxiety disor­
der, but not social anxiety disorder, performance only, is often comorbid with avoidant 
personality disorder. In children, comorbidities with high-functioning autism and selec­
tive mutism are common.
Panic Disorder
Diagnostic Criteria 300.01 (F41.0)
A. Recurrent unexpected panic attacks. A panic attack is an abrupt surge of intense fear  
or intense discomfort that reaches a peak within minutes, and during which time four  
(or more) of the following symptoms occur;
Note: The abrupt surge can occur from a calm state or an anxious state.
1. Palpitations, pounding heart, or accelerated heart rate.
2. Sweating.
3. Trembling or shaking.
4. Sensations of shortness of breath or smothering.
5. Feelings of choking.

6. Chest pain or discomfort.
7. Nausea or abdominal distress.
8. Feeling dizzy, unsteady, light-headed, or faint.
9. Chills or heat sensations.
10. Paresthesias (numbness or tingling sensations).
11. Derealization (feelings of unreality) or depersonalization (being detached from one­
self).
12. Fear of losing control or “ going crazy.”
13. Fear of dying.
Note: Culture-specific symptoms (e.g., tinnitus, neck soreness, headache, uncontrol­
lable screaming or crying) may be seen. Such symptoms should not count as one of  
the four required symptoms.
B. At least one of the attacks has been followed by 1  month (or more) of one or both of  
the following:
1. Persistent concern or worry about additional panic attacks or their consequences  
(e.g., losing control, having a heart attack, “ going crazy”).

2. A significant maladaptive change in behavior related to the attacks (e.g., behaviors  
designed to avoid having panic attacks, such as avoidance of exercise or unfamiliar  
situations).

C. The disturbance is not attributable to the physiological effects of a substance (e.g., a  
drug of abuse, a medication) or another medical condition (e.g., hyperthyroidism, car­
diopulmonary disorders).
D. The disturbance is not better explained by another mental disorder (e.g., the panic at­
tacks do not occur only in response to feared social situations, as in social anxiety dis­
order: in response to circumscribed phobic objects or situations, as in specific phobia:  
in response to obsessions, as in obsessive-compulsive disorder: in response to re­
minders of traumatic events, as in posttraumatic stress disorder: or in response to sep­
aration from attachment figures, as in separation anxiety disorder).
Panic disorder  refers to recurrent unexpected panic attacks (Criterion A). A panic attack is 
an abrupt surge of intense fear or intense discomfort that reaches a peak within minutes,

an abrupt surge of intense fear or intense discomfort that reaches a peak within minutes, 
and during which time four or more of a list of 13 physical and cognitive symptoms occur. 
The term recurrent  literally means more than one unexpected panic attack. The term unex­
pected  refers to a panic attack for which there is no obvious cue or trigger at the time of oc­
currence—that is, the attack appears to occur from out of the blue, such as when the 
individual is relaxing or emerging from sleep (nocturnal panic attack). In contrast, expected  
panic attacks are attacks for which there is an obvious cue or trigger, such as a situation in 
which panic attacks typically occur. The determination of whether panic attacks are ex­
pected or unexpected is made by the clinician, who makes this judgment based on a com­

bination of careful questioning as to the sequence of events preceding or leading up to the 
attack and the individual's own judgment of whether or not the attack seemed to occur for 
no apparent reason. Cultural interpretations may influence the assignment of panic at­
tacks as expected or unexpected (see section "Culture-Related Diagnostic Issues" for this 
disorder). In the United States and Europe, approximately one-half of individuals with 
panic disorder have expected panic attacks as well as unexpected panic attacks. Thus, the 
presence of expected panic attacks does not rule out the diagnosis of panic disorder. For 
more details regarding expected versus unexpected panic attacks, see the text accompa­
nying panic attacks (pp. 214-217).

The frequency and severity of panic attacks vary widely. In terms of frequency, there 
may be moderately frequent attacks (e.g., one per week) for months at a time, or short 
bursts of more frequent attacks (e.g., daily) separated by weeks or months without any at­
tacks or with less frequent attacks (e.g., two per month) over many years. Persons who 
have infrequent panic attacks resemble persons with more frequent panic attacks in terms 
of panic attack symptoms, demographic characteristics, comorbidity with other disorders, 
family history, and biological data. In terms of severity, individuals with panic disorder 
may have both full-symptom (four or more symptoms) and limited-symptom (fewer than 
four symptoms) attacks, and the number and type of panic attack symptoms frequently

four symptoms) attacks, and the number and type of panic attack symptoms frequently 
differ from one panic attack to the next. However, more than one unexpected full-symp­
tom panic attack is required for the diagnosis of panic disorder.
The worries about panic attacks or their consequences usually pertain to physical con­
cerns, such as worry that panic attacks reflect the presence of life-threatening illnesses 
(e.g., cardiac disease, seizure disorder); social concerns, such as embarrassment or fear of 
being judged negatively by others because of visible panic symptoms; and concerns about 
mental functioning, such as ''going crazy" or losing control (Criterion B). The maladaptive 
changes in behavior represent attempts to minimize or avoid panic attacks or their conse­
quences. Examples include avoiding physical exertion, reorganizing daily life to ensure

quences. Examples include avoiding physical exertion, reorganizing daily life to ensure 
that help is available in the event of a panic attack, restricting usual daily activities, and 
avoiding agoraphobia-type situations, such as leaving home, using public transportation, 
or shopping. If agoraphobia is present, a separate diagnosis of agoraphobia is given.

One type of unexpected panic attack is a nocturnal  panic attack (i.e., waking from sleep in 
a state of panic, which differs from panicking after fully waking from sleep). In the United 
States, this type of panic attack has been estimated to occur at least one time in roughly 
one-quarter to one-third of individuals with panic disorder, of whom the majority also 
have daytime panic attacks. In addition to worry about panic attacks and their conse­
quences, many individuals with panic disorder report constant or intermittent feelings of 
anxiety that are more broadly related to health and mental health concerns. For example, 
individuals with panic disorder often anticipate a catastrophic outcome from a mild phys­
ical symptom or medication side effect (e.g., thinking that they may have heart disease or 
that a headache means presence of a brain tumor). Such individuals often are relatively in­

tolerant of medication side effects. In addition, there may be pervasive concerns about 
abilities to complete daily tasks or withstand daily stressors, excessive use of drugs (e.g., 
alcohol, prescribed medications or illicit drugs) to control panic attacks, or extreme behav­
iors aimed at controlling panic attacks (e.g., severe restrictions on food intake or avoidance 
of specific foods or medications because of concerns about physical symptoms that pro­
voke panic attacks).
In the general population, the 12-month prevalence estimate for panic disorder across the 
United States and several European countries is about 2%-3% in adults and adolescents. In 
the United States, significantly lower rates of panic disorder are reported among Latinos,

the United States, significantly lower rates of panic disorder are reported among Latinos, 
African Americans, Caribbean blacks, and Asian Americans, compared with non-Latino 
whites; American Indians, by contrast, have significantly higher rates. Lower estimates 
have been reported for Asian, African, and Latin American countries, ranging from 0.1% 
to 0.8%. Females are more frequently affected than males, at a rate of approximately 2:1. The 
gender differentiation occurs in adolescence and is already observable before age 14 years. 
Although panic attacks occur in children, the overall prevalence of panic disorder is low 
before age 14 years (<0.4%). The rates of panic disorder show a gradual increase during ad­
olescence, particularly in females, and possibly following the onset of puberty, and peak dur­

ing adulthood. The prevalence rates decline in older individuals (i.e., 0.7% in adults over 
the age of 64), possibly reflecting diminishing severity to subclinical levels.
The median age at onset for panic disorder in the United States is 20-24 years. A small 
number of cases begin in childhood, and onset after age 45 years is unusual but can occur. 
The usual course, if the disorder is untreated, is chronic but waxing and waning. Some in­
dividuals may have episodic outbreaks with years of remission in between, and others 
may have continuous severe symptomatology. Only a minority of individuals have full 
remission without subsequent relapse within a few years. The course of panic disorder

remission without subsequent relapse within a few years. The course of panic disorder 
typically is complicated by a range of other disorders, in particular other anxiety disor­
ders, depressive disorders, and substance use disorders (see section "Comorbidity" for 
this disorder).
Although panic disorder is very rare in childhood, first occurrence of "fearful spells" is 
often dated retrospectively back to childhood. As in adults, panic disorder in adolescents 
tends to have a chronic course and is frequently comorbid with other anxiety, depressive, 
and bipolar disorders. To date, no differences in the clinical presentation between adoles­
cents and adults have been found. However, adolescents may be less worried about addi­
tional panic attacks than are young adults. Lower prevalence of panic disorder in older 
adults appears to be attributable to age-related "dampening" of the autonomic nervous

adults appears to be attributable to age-related "dampening" of the autonomic nervous 
system response. Many older individuals with "panicky feelings" are observed to have a 
"hybrid" of limited-symptom panic attacks and generalized anxiety. Also, older adults

tend to attribute their panic attacks to certain stressful situations, such as a medical pro­
cedure or social setting. Older individuals may retrospectively endorse explanations for 
the panic attack^which would preclude the diagnosis of panic disorder), even if an attack 
might actually have been unexpected in the moment (and thus qualify as the basis for a 
panic disorder diagnosis). This may result in under-endorsement of unexpected panic at­
tacks in older individuals. Thus, careful questioning of older adults is required to assess 
whether panic attacks were expected before entering the situation, so that unexpected 
panic attacks and the diagnosis of panic disorder are not overlooked.
While the low rate of panic disorder in children could relate to difficulties in symptom 
reporting, this seems unlikely given that children are capable of reporting intense fear or 
panic in relation to separation and to phobic objects or phobic situations. Adolescents

panic in relation to separation and to phobic objects or phobic situations. Adolescents 
might be less willing than adults to openly discuss panic attacks. Therefore, clinicians 
should be aware that unexpected panic attacks do occur in adolescents, much as they do in 
adults, and be attuned to this possibility when encountering adolescents presenting with 
episodes of intense fear or distress.
Temperamental. Negative affectivity (neuroticism) (i.e., proneness to experiencing neg­
ative emotions) and anxiety sensitivity (i.e., the disposition to believe that symptoms of 
anxiety are harmful) are risk factors for the onset of panic attacks and, separately, for 
worry about panic, although their risk status for the diagnosis of panic disorder is un­
known. History of "fearful spells" (i.e., limited-symptom attacks that do not meet full cri­

teria for a panic attack) may be a risk factor for later panic attacks and panic disorder. 
Although separation anxiety in childhood, especially when severe, may precede the later 
development of panic disorder, it is not a consistent risk factor.
Environmental. Reports of childhood experiences of sexual and physical abuse are more 
common in panic disorder than in certain other anxiety disorders. Smoking is a risk factor 
for panic attacks and panic disorder. Most individuals report identifiable stressors in the 
months before their first panic attack (e.g., interpersonal stressors and stressors related to 
physical well-being, such as negative experiences with illicit or prescription drugs, dis­
ease, or death in the family).

Genetic and physiological. It is believed that multiple genes confer vulnerability to panic 
disorder. However, the exact genes, gene products, or functions related to the genetic re­
gions implicated remain unknown. Current neural systems models for panic disorder em­
phasize the amygdala and related structures, much as in other anxiety disorders. There is 
an increased risk for panic disorder among offspring of parents with anxiety, depressive, 
and bipolar disorders. Respiratory disturbance, such as asthma, is associated with panic 
disorder, in terms of past history, comorbidity, and family history.
The rate of fears about mental and somatic symptoms of anxiety appears to vary across 
cultures and may influence the rate of panic attacks and panic disorder. Also, cultural ex­

pectations may influence the classification of panic attacks as expected or unexpected. For 
example, a Vietnamese individual who has a panic attack after walking out into a windy 
environment (trilng gio;  "hit by the wind") may attribute the panic attack to exposure to 
wind as a result of the cultural syndrome that links these two experiences, resulting in clas­
sification of the panic attack as expected. Various other cultural syndromes are associated 
with panic disorder, including ataque de nervios  ("attack of nerves") among Latin Ameri­
cans and khyal  attacks and "soul loss" among Cambodians. Ataque de nervios  may involve 
trembling, uncontrollable screaming or crying, aggressive or suicidal behavior, and deper­

sonalization or derealization, which may be experienced longer than the few minutes typical

of panic attacks. Some clinical presentations of ataque de nervios  fulfill criteria for condi­
tions other than panic attack (e.g., other specified dissociative disorder). These syndromes 
impact the symptoms and frequency of panic disorder, including the individual's attribu­
tion of unexpectedness, as cultural syndromes may create fear of certain situations, rang­
ing from interpersonal arguments (associated with ataque de nervios),  to types of exertion 
(associated with khyâl  attacks), to atmospheric wind (associated with trùng gio  attacks). 
Clarification of the details of cultural attributions may aid in distinguishing expected and 
unexpected panic attacks. For more information regarding cultural syndromes, refer to the 
"Glossary of Cultural Concepts of Distress" in the Appendix.
The specific worries about panic attacks or their consequences are likely to vary from 
one culture to another (and across different age groups and gender). For panic disorder,

one culture to another (and across different age groups and gender). For panic disorder, 
U.S. community samples of non-Latino whites have significantly less functional impair­
ment than African Americans. There are also higher rates of objectively defined severity in 
non-Latino Caribbean blacks with panic disorder, and lower rates of panic disorder over­
all in both African American and Afro-Caribbean groups, suggesting that among individ­
uals of African descent, the criteria for panic disorder may be met only when there is 
substantial severity and impairment.
The clinical features of panic disorder do not appear to differ between males and females. 
There is some evidence for sexual dimorphism, with an association between panic disor­
der and the catechol-O-methyltransferase (COMT) gene in females only.
Diagnostic IVIarkers

Agents with disparate mechanisms of action, such as sodium lactate, caffeine, isoprotere­
nol, yohimbine, carbon dioxide, and cholecystokinin, provoke panic attacks in individuals 
with panic disorder to a much greater extent than in healthy control subjects (and in some 
cases, than in individuals with other anxiety, depressive, or bipolar disorders without 
panic attacks). Also, for a proportion of individuals with panic disorder, panic attacks are 
related to hypersensitive medullary carbon dioxide detectors, resulting in hypocapnia and 
other respiratory irregularities. However, none of these laboratory findings are consid­
ered diagnostic of panic disorder.
Panic attacks and a diagnosis of panic disorder in the past 12 months are related to a higher

Panic attacks and a diagnosis of panic disorder in the past 12 months are related to a higher 
rate of suicide attempts and suicidal ideation in the past 12 months even when comorbid­
ity and a history of childhood abuse and other suicide risk factors are taken into account.
Functional Consequences of Panic Disorder
Panic disorder is associated with high levels of social, occupational, and physical disabil­
ity; considerable economic costs; and the highest number of medical visits among the anx­
iety disorders, although the effects are strongest with the presence of agoraphobia. 
Individuals with panic disorder may be frequently absent from work or school for doctor 
and emergency room visits, which can lead to unemployment or dropping out of school. 
In older adults, impairment may be seen in caregiving duties or volunteer activities. Full- 
symptom panic attacks typically are associated with greater morbidity (e.g., greater health

symptom panic attacks typically are associated with greater morbidity (e.g., greater health 
care utilization, more disability, poorer quality of life) than limited-symptom attacks.
other specified anxiety disorder or unspecified anxiety disorder. Panic disorder should 
not be diagnosed if full-symptom (unexpected) panic attacks have never been experienced. In

the case of only limited-symptom unexpected panic attacks, an other specified anxiety dis­
order or unspecified anxiety disorder diagnosis should be considered.
Anxiety disorder due to another medical condition. Panic disorder is not diagnosed if 
the panic attacks are judged to be a direct physiological consequence of another medical 
condition. Examples of medical conditions that can cause panic attacks include hyperthy­
roidism, hyperparathyroidism, pheochromocytoma, vestibular dysfunctions, seizure dis­
orders, and cardiopulmonary conditions (e.g., arrhythmias, supraventricular tachycardia, 
asthma, chronic obstructive pulmonary disease [COPD]). Appropriate laboratory tests 
(e.g., serum calcium levels for hyperparathyroidism; Holter monitor for arrhythmias) or 
physical examinations (e.g., for cardiac conditions) may be helpful in determining the eti­
ological role of another medical condition.
Substance/medication-induced anxiety disorder. Panic disorder is not diagnosed if

Substance/medication-induced anxiety disorder. Panic disorder is not diagnosed if 
the panic attacks are judged to be a direct physiological consequence of a substance. In­
toxication with central nervous system stimulants (e.g., cocaine, amphetamines, caffeine) 
or cannabis and withdrawal from central nervous system depressants (e.g., alcohol, bar­
biturates) can precipitate a panic attack. However, if panic attacks continue to occur out­
side of the context of substance use (e.g., long after the effects of intoxication or withdrawal 
have ended), a diagnosis of panic disorder should be considered. In addition, because 
panic disorder may precede substance use in some individuals and may be associated 
with increased substance use, especially for purposes of self-medication, a detailed history 
should be taken to determine if the individual had panic attacks prior to excessive sub­

stance use. If this is the case, a diagnosis of panic disorder should be considered in addition 
to a diagnosis of substance use disorder. Features such as onset after age 45 years or the 
presence of atypical symptoms during a panic attack (e.g., vertigo, loss of consciousness, 
loss of bladder or bowel control, slurred speech, armiesia) suggest the possibility that an­
other medical condition or a substance may be causing the panic attack symptoms.
Other mental disorders with panic attacks as an associated feature (e.g., other anxiety  
disorders and psychotic disorders). Panic attacks that occur as a symptom of other anx­
iety disorders are expected (e.g., triggered by social situations in social anxiety disorder, by

iety disorders are expected (e.g., triggered by social situations in social anxiety disorder, by 
phobic objects or situations in specific phobia or agoraphobia, by worry in generalized anx­
iety disorder, by separation from home or attachment figures in separation anxiety disorder) 
and thus would not meet criteria for panic disorder. (Note: Sometimes an unexpected panic 
attack is associated with the onset of another anxiety disorder, but then the attacks become 
expected, whereas panic disorder is characterized by recurrent unexpected panic attacks.) If 
the panic attacks occur only in response to specific triggers, then only the relevant anxiety 
disorder is assigned. However, if the individual experiences unexpected panic attacks as 
well and shows persistent concern and worry or behavioral change because of the attacks, 
then an additional diagnosis of panic disorder should be considered.

Panic disorder infrequently occurs in clinical settings in the absence of other psychopa­
thology. The prevalence of panic disorder is elevated in individuals with other disorders, 
particularly other anxiety disorders (and especially agoraphobia), major depression, bipo­
lar disorder, and possibly mild alcohol use disorder. While panic disorder often has an ear­
lier age at onset than the comorbid disorder(s), onset sometimes occurs after the comorbid 
disorder and may be seen as a severity marker of the comorbid illness.
Reported lifetime rates of comorbidity between major depressive disorder and panic 
disorder vary widely, ranging from 10% to 65% in individuals with panic disorder. In ap­
proximately one-third of individuals with both disorders, the depression precedes the on­

set of panic disorder. In the remaining two-thirds, depression occurs coincident with or 
following the onset of panic disorder. A subset of individuals with panic disorder develop 
a substance-related disorder, which for some represents an attempt to treat their anxiety

with alcohol or medications. Comorbidity with other anxiety disorders and illness anxiety 
disorder is also common.
Panic disorder is significantly comorbid with numerous general medical symptoms 
and conditions, including, but not limited to, dizziness, cardiac arrhythmias, hyperthy­
roidism, asthma, COPD, and irritable bowel syndrome. However, the nature of the asso­
ciation (e.g., cause and effect) between panic disorder and these conditions remains 
unclear. Although mitral valve prolapse and thyroid disease are more common among in­
dividuals with panic disorder than in the general population, the differences in prevalence 
are not consistent.
Panic Attack Specifier
Note: Symptoms are presented for the purpose of identifying a panic attacl<; however,  
panic attack is not a mental disorder and cannot be coded. Panic attacl<s can occur in  the  
context of any anxiety disorder as well as other mental disorders (e.g., depressive disor­

ders, posttraumatic stress disorder, substance use disorders) and some medical condi­
tions (e.g., cardiac, respiratory, vestibular, gastrointestinal). When the presence of a panic  
attack is identified, it should be noted as a specifier (e.g., “ posttraumatic stress disorder  
with panic attacks” ). For panic disorder, the presence of panic attack is contained within  
the criteria for the disorder and panic attack is not used as a specifier.
An abrupt surge of intense fear or intense discomfort that reaches a peak within minutes,  
and during which time four (or more) of the following symptoms occur:

9. Chilis or heat sensations.
11. Derealization (feelings of unreality) or depersonalization (being detached from oneself).
Note: Culture-specific symptoms (e.g., tinnitus, neck soreness, headache, uncontrollable  
screaming or crying) may be seen. Such symptoms should not count as one of the four  
required symptoms.
Features
The essential feature of a panic attack is an abrupt surge of intense fear or intense discomfort 
that reaches a peak within minutes and during which time four or more of 13 physical and cog­

nitive symptoms occur. Eleven of these 13 symptoms are physical (e.g., palpitations, sweat­
ing), while two are cognitive (i.e., fear of losing control or going crazy, fear of dying). 'Tear of 
going crazy" is a colloquialism often used by individuals with panic attacks and is not in­
tended as a pejorative or diagnostic term. The term within minutes  means that the time to peak

intensity is literally only a few minutes. A panic attack can arise from either a calm state or an 
anxious state, and time to peak intensity should be assessed independently of any preceding 
anxiety. That is, the start of the panic attack is the point at which there is an abrupt increase in 
discomfort rather than the point at which armety first developed. Likewise, a panic attack can 
return to either an anxious state or a calm state and possibly peak again. A panic attack is dis­
tinguished from ongoing anxiety by its time to peak intensity, which occurs within minutes; its 
discrete nature; and its typically greater severity. Attacks that meet all other criteria but have 
fewer than four physical and/or cognitive symptoms are referred to as limited-symptom attacks.
There are two characteristic types of panic attacks: expected and unexpected. Expected  
panic attacks  are attacks for which there is an obvious cue or trigger, such as situations in

panic attacks  are attacks for which there is an obvious cue or trigger, such as situations in 
which panic attacks have typically occurred. Unexpected panic attacks  are those for which 
there is no obvious cue or trigger at the time of occurrence (e.g., when relaxing or out of 
sleep [nocturnal panic attack]). The determination of whether panic attacks are expected 
or unexpected is made by the clinician, who makes this judgment based on a combination 
of careful questioning as to the sequence of events preceding or leading up to the attack 
and the individual's own judgment of whether or not the attack seemed to occur for no ap­
parent reason. Cultural interpretations may influence their determination as expected or 
unexpected. Culture-specific symptoms (e.g., tinnitus, neck soreness, headache, uncon­
trollable screaming or crying) may be seen; however, such symptoms should not count as

trollable screaming or crying) may be seen; however, such symptoms should not count as 
one of the four required symptoms. Panic attacks can occur in the context of any mental 
disorder (e.g., anxiety disorders, depressive disorders, bipolar disorders, eating disorders, 
obsessive-compulsive and related disorders, personality disorders, psychotic disorders, 
substance use disorders) and some medical conditions (e.g., cardiac, respiratory, vestibu­
lar, gastrointestinal), with the majority never meeting criteria for panic disorder. Recur­
rent unexpected panic attacks are required for a diagnosis of panic disorder.
Associated Features
One type of unexpected panic attack is a nocturnal panic attack  (i.e., waking from sleep in a 
state of panic), which differs from panicking after fully waking from sleep. Panic attacks

state of panic), which differs from panicking after fully waking from sleep. Panic attacks 
are related to a higher rate of suicide attempts and suicidal ideation even when comorbid­
ity and other suicide risk factors are taken into account.
In the general population, 12-month prevalence estimates for panic attacks in the United 
States is 11.2% in adults. Twelve-month prevalence estimates do not appear to differ sig­
nificantly among African Americans, Asian Americans, and Latinos. Lower 12-month 
prevalence estimates for European countries appear to range from 2.7% to 3.3%. Females 
are more frequently affected than males, although this gender difference is more pro­
nounced for panic disorder. Panic attacks can occur in children but are relatively rare until 
the age of puberty, when the prevalence rates increase. The prevalence rates decline in

the age of puberty, when the prevalence rates increase. The prevalence rates decline in 
older individuals, possibly reflecting diminishing severity to subclinical levels.
The mean age at onset for panic attacks in the United States is approximately 22-23 years 
among adults. However, the course of panic attacks is likely influenced by the course of 
any co-occurring mental disorder(s) and stressful life events. Panic attacks are uncommon, 
and unexpected panic attacks are rare, in preadolescent children. Adolescents might be 
less willing than adults to openly discuss panic attacks, even though they present with ep­
isodes of intense fear or discomfort. Lower prevalence of panic attacks in older individuals 
may be related to a weaker autonomic response to emotional states relative to younger in­

dividuals. Older individuals may be less inclined to use the word "fear" and more inclined

to use the word "discomfort" to describe panic attacks. Older individuals with "panicky 
feelings" may have a hybrid of limited-symptom attacks and generalized anxiety. In 
addition, older individuals tend to attribute panic attacks to certain situations that are 
stressful (e.g., medical procedures, social settings) and may retrospectively endorse expla­
nations for the panic attack even if it was unexpected in the moment. This may result in un­
der-endorsement of unexpected panic attacks in older individuals.
anxiety are harmful) are risk factors for the onset of panic attacks. History of "fearful 
spells" (i.e., limited-symptom attacks that do not meet full criteria for a panic attack) may 
be a risk factor for later panic attacks.

Environmental. Smoking is a risk factor for panic attacks. Most individuals report iden­
tifiable stressors in the months before their first panic attack (e.g., interpersonal stressors 
and stressors related to physical well-being, such as negative experiences with illicit or 
prescription drugs, disease, or death in the family).
Cultural interpretations may influence the determination of panic attacks as expected or 
unexpected. Culture-specific symptoms (e.g., tinnitus, neck soreness, headache, and un­
controllable screaming or crying) may be seen; however, such symptoms should not count 
as one of the four required symptoms. Frequency of each of the 13 symptoms varies cross- 
culturally (e.g., higher rates of paresthesias in African Americans and of dizziness in sev­

eral Asian groups). Cultural syndromes also influence the cross-cultural presentation of 
panic attacks, resulting in different symptom profiles across different cultural groups. Ex­
amples include khyal  (wind) attacks, a Cambodian cultural syndrome involving dizziness, 
tinnitus, and neck soreness; and trùnggiô  (wind-related) attacks, a Vietnamese cultural 
syndrome associated with headaches. Ataque de nervios  (attack of nerves) is a cultural syn­
drome among Latin Americans that may involve trembling, uncontrollable screaming or 
crying, aggressive or suicidal behavior, and depersonalization or derealization, and which 
may be experienced for longer than only a few minutes. Some clinical presentations of

may be experienced for longer than only a few minutes. Some clinical presentations of 
ataque de nervios  fulfill criteria for conditions other than panic attack (e.g., other specified 
dissociative disorder). Also, cultural expectations may influence the classification of panic 
attacks as expected or unexpected, as cultural syndromes may create fear of certain situa­
tions, ranging from interpersonal arguments (associated with ataque de nervios),  to types of 
exertion (associated with khyâl  attacks), to atmospheric wind (associated with trùnggiô  at­
tacks). Clarification of the details of cultural attributions may aid in distinguishing ex­
pected and unexpected panic attacks. For more information about cultural syndromes, see 
"Glossary of Cultural Concepts of Distress" in the Appendix to this manual.

Panic attacks are more common in females than in males, but clinical features or symp­
toms of panic attacks do not differ between males and females.
Physiological recordings of naturally occurring panic attacks in individuals with panic 
disorder indicate abrupt surges of arousal, usually of heart rate, that reach a peak within 
minutes and subside within minutes, and for a proportion of these individuals the panic 
attack may be preceded by cardiorespiratory instabilities.

Functional Consequences of Panic Attaclcs
In the context of^co-occurring mental disorders, including anxiety disorders, depressive 
disorders, bipolar disorder, substance use disorders, psychotic disorders, and personality 
disorders, panic attacks are associated with increased symptom severity, higher rates of 
comorbidity and suicidality, and poorer treatment response. Also, full-symptom panic at­
tacks typically are associated with greater morbidity (e.g., greater health care utilization, 
more disability, poorer quality of life) than limited-symptom attacks.
Other paroxysmal episodes (e.g., “anger attacks”). Panic attacks should not be diag­
nosed if the episodes do not involve the essential feature of an abrupt surge of intense fear 
or intense discomfort, but rather other emotional states (e.g., anger, grief).
Anxiety disorder due to another medical condition. Medical conditions that can cause

Anxiety disorder due to another medical condition. Medical conditions that can cause 
or be misdiagnosed as panic attacks include hyperthyroidism, hyperparathyroidism, pheo- 
chromocytoma, vestibular dysfunctions, seizure disorders, and cardiopulmonary con­
ditions (e.g., arrhythmias, supraventricular tachycardia, asthma, chronic obstructive 
pulmonary disease). Appropriate laboratory tests (e.g., serum calcium levels for hyperpara­
thyroidism; Holter monitor for arrhythmias) or physical examinations (e.g., for cardiac con­
ditions) may be helpful in determining the etiological role of another medical condition.
Substance/medication-induced anxiety disorder. Intoxication with central nervous 
system stimulants (e.g., cocaine, amphetamines, caffeine) or cannabis and withdrawal 
from central nervous system depressants (e.g., alcohol, barbiturates) can precipitate a

from central nervous system depressants (e.g., alcohol, barbiturates) can precipitate a 
panic attack. A detailed history should be taken to determine if the individual had panic 
attacks prior to excessive substance use. Features such as onset after age 45 years or the 
loss of bladder or bowel control, slurred speech, or amnesia) suggest the possibility that a 
medical condition or a substance may be causing the panic attack symptoms.
Panic disorder. Repeated unexpected panic attacks are required but are not sufficient for 
the diagnosis of panic disorder (i.e., full diagnostic criteria for panic disorder must be met).
Panic attacks are associated with increased likelihood of various comorbid mental dis­
orders, including anxiety disorders, depressive disorders, bipolar disorders, impulse­

control disorders, and substance use disorders. Panic attacks are associated with increased 
likelihood of later developing anxiety disorders, depressive disorders, bipolar disorders, 
and possibly other disorders.
Agoraphobia
Diagnostic Criteria 300.22 (F40.00)
A. Marked fear or anxiety about two (or more) of the following five situations:
1. Using public transportation (e.g., automobiles, buses, trains, ships, planes).
2. Being in open spaces (e.g., parking lots, marketplaces, bridges).
3. Being in enclosed places (e.g., shops, theaters, cinemas).
4. Standing in line or being in a crowd.
5. Being outside of the home alone.
B. The individual fears or avoids these situations because of thoughts that escape might  
be difficult or help might not be available in  the event of developing panic-like symp­

toms or other incapacitating or embarrassing symptoms (e.g., fear of falling in the el­
derly; fear of incontinence).
C. The agoraphobic situations almost always provoke fear or anxiety.
D. The agoraphobic situations are actively avoided, require the presence of a companion,  
or are endured with intense fear or anxiety.
E. The fear or anxiety is out of proportion to the actual danger posed by the agoraphobic  
situations and to the sociocultural context.
H. If another medical condition (e.g., inflammatory bowel disease, Parkinson’s disease)  
is present, the fear, anxiety, or avoidance is clearly excessive.
I. The fear, anxiety, or avoidance is not better explained by the symptoms of another men­

tal disorder—for example, the symptoms are not confined to specific phobia, situational  
type; do not involve only social situations (as in  social anxiety disorder): and are not re­
lated exclusively to obsessions (as in obsessive-compulsive disorder), perceived defects  
or flaws in  physical appearance (as in body dysmoφhic disorder), reminders of traumatic  
events (as in  posttraumatic stress disorder), or fear of separation (as in separation anx­
iety disorder).
Note: Agoraphobia is diagnosed irrespective of the presence of panic disorder. If an indi­
vidual’s presentation meets criteria for panic disorder and agoraphobia, both diagnoses  
should be assigned.
The essential feature of agoraphobia is marked, or intense, fear or anxiety triggered by the

The essential feature of agoraphobia is marked, or intense, fear or anxiety triggered by the 
real or anticipated exposure to a wide range of situations (Criterion A). The diagnosis re­
quires endorsement of symptoms occurring in at least two of the following five situations: 
1) using public transporation, such as automobiles, buses, trains, ships, or planes; 2) being 
in open spaces, such as parking lots, marketplaces, or bridges; 3) being in enclosed spaces, 
such as shops, theaters, or cinemas; 4) standing in line or being in a crowd; or 5) being out­
side of the home alone. The examples for each situation are not exhaustive; other situations 
may be feared. When experiencing fear and anxiety cued by such situations, individuals 
typically experience thoughts that something terrible might happen (Criterion B). Individ­
uals frequently believe that escape from such situations might be difficult (e.g., "can't get

uals frequently believe that escape from such situations might be difficult (e.g., "can't get 
out of here") or that help might be unavailable (e.g., "there is nobody to help me") when 
panic-like symptoms or other incapacitating or embarrassing symptoms occur. "Panic-like 
symptoms" refer to any of the 13 symptoms included in the criteria for panic attack, such as 
dizziness, faintness, and fear of dying. "Other incapacitating or embarrassing symptoms" 
include symptoms such as vomiting and inflammatory bowel symptoms, as well as, in 
older adults, a fear of falling or, in children, a sense of disorientation and getting lost.
The amount of fear experienced may vary with proximity to the feared situation and 
may occur in anticipation of or in the actual presence of the agoraphobic situation. Also, 
the fear or anxiety may take the form of a full- or limited-symptom panic attack (i.e., an ex­

pected panic attack). Fear or anxiety is evoked nearly every time the individual comes into 
contact with the feared situation (Criterion C). Thus, an individual who becomes anxious 
only occasionally in an agoraphobic situation (e.g., becomes anxious when standing in line 
on only one out of every five occasions) would not be diagnosed with agoraphobia. The in­
dividual actively avoids the situation or, if he or she either is unable or decides not to avoid 
it, the situation evokes intense fear or anxiety (Criterion D). Active avoidance  means the in­
dividual is currently behaving in ways that are intentionally designed to prevent or min­
imize contact with agoraphobic situations. Avoidance can be behavioral (e.g., changing

daily routines, choosing a job nearby to avoid using public transportation, arranging for 
food delivery to avoid entering shops and supermarkets) as well as cognitive (e.g., using 
distraction to get through agoraphobic situations) in nature. The avoidance can become so 
severe that the person is completely homebound. Often, an individual is better able to con­
front a feared situation when accompanied by a companion, such as a partner, friend, or 
health professional.
The fear, anxiety, or avoidance must be out of proportion to the actual danger posed by 
the agoraphobic situations and to the sociocultural context (Criterion E). Differentiating 
clinically significant agoraphobic fears from reasonable fears (e.g., leaving the house dur­
ing a bad storm) or from situations that are deemed dangerous (e.g., walking in a parking 
lot or using public transportation in a high-crime area) is important for a number of reasons.

lot or using public transportation in a high-crime area) is important for a number of reasons. 
First, what constitutes avoidance may be difficult to judge across cultures and sociocultural 
contexts (e.g., it is socioculturally appropriate for orthodox Muslim women in certain parts 
of the world to avoid leaving the house alone, and thus such avoidance would not be con­
sidered indicative of agoraphobia). Second, older adults are likely to overattribute their 
fears to age-related constraints and are less likely to judge their fears as being out of pro­
portion to the actual risk. Third, individuals with agoraphobia are likely to overestimate 
danger in relation to panic-like or other bodily symptoms. Agoraphobia should be diag­
nosed only if the fear, anxiety, or avoidance persists (Criterion F) and if it causes clinically

nosed only if the fear, anxiety, or avoidance persists (Criterion F) and if it causes clinically 
significant distress or impairment in social, occupational, or other important areas of func­
tioning (Criterion G). The duration of "typically lasting for 6 months or more" is meant to 
exclude individuals with short-lived, transient problems. However, the duration criterion 
should be used as a general guide, with allowance for some degree of flexibility.
In its most severe forms, agoraphobia can cause individuals to become completely home- 
bound, unable to leave their home and dependent on others for services or assistance to pro­
vide even for basic needs. Demoralization and depressive symptoms, as well as abuse of 
alcohol and sedative medication as inappropriate self-medication strategies, are common.

Every year approximately 1.7% of adolescents and adults have a diagnosis of agoraphobia. 
Females are twice as likely as males to experience agoraphobia. Agoraphobia may occur in 
childhood, but incidence peaks in late adolescence and early adulthood. Twelve-month 
prevalence in individuals older than 65 years is 0.4%. Prevalence rates do not appear to 
vary systematically across cultural/racial groups.
The percentage of individuals with agoraphobia reporting panic attacks or panic disorder 
preceding the onset of agoraphobia ranges from 30% in community samples to more than 
50% in clinic samples. The majority of individuals with panic disorder show signs of anx­
iety and agoraphobia before the onset of panic disorder.

In two-thirds of all cases of agoraphobia, initial onset is before age 35 years. There is a 
substantial incidence risk in late adolescence and early adulthood, with indications for 
a second high incidence risk phase after age 40 years. First onset in childhood is rare. The 
overall mean age at onset for agoraphobia is 17 years, although the age at onset without 
preceding panic attacks or panic disorder is 25-29 years.
The course of agoraphobia is typically persistent and chronic. Complete remission is 
rare (10%), unless the agoraphobia is treated. With more severe agoraphobia, rates of full 
remission decrease, whereas rates of relapse and chronicity increase. A range of other dis­
orders, in particular other anxiety disorders, depressive disorders, substance use disor­

ders, and personality disorders, may complicate the course of agoraphobia. The long-term

course and outcome of agoraphobia are associated with substantially elevated risk of sec­
ondary major depressive disorder, persistent depressive disorder (dysthymia), and sub­
stance use disorders.
The clinical features of agoraphobia are relatively consistent across the lifespan, although 
the type of agoraphobic situations triggering fear, anxiety, or avoidance, as well as the type of 
cognitions, may vary. For example, in children, being outside of the home alone is the most fre­
quent situation feared, whereas in older adults, being in shops, standing in line, and being in 
open spaces are most often feared. Also, cognitions often pertain to becoming lost (in children), 
to experiencing panic-like symptoms (in adults), to falling (in older adults).
TTie low prevalence of agoraphobia in children could reflect difficulties in symptom re­
porting, and thus assessments in young children may require solicitation of information

porting, and thus assessments in young children may require solicitation of information 
from multiple sources, including parents or teachers. Adolescents, particularly males, 
may be less willing than adults to openly discuss agoraphobic fears and avoidance; how­
ever, agoraphobia can occur prior to adulthood and should be assessed in children and 
adolescents. In older adults, comorbid somatic symptom disorders, as well as motor dis­
turbances (e.g., sense of falling or having medical complications), are frequently men­
tioned by individuals as the reason for their fear and avoidance. In these instances, care is 
to be taken in evaluating whether the fear and avoidance are out of proportion to the real 
danger involved.
Temperamental. Behavioral inhibition and neurotic disposition (i.e., negative affectivity

Temperamental. Behavioral inhibition and neurotic disposition (i.e., negative affectivity 
[neuroticism] and anxiety sensitivity) are closely associated with agoraphobia but are rel­
evant to most anxiety disorders (phobic disorders, panic disorder, generalized anxiety dis­
order). Anxiety sensitivity (the disposition to believe that symptoms of anxiety are 
harmful) is also characteristic of individuals with agoraphobia.
Environmental. Negative events in childhood (e.g., separation, death of parent) and other 
stressful events, such as being attacked or mugged, are associated with the onset of agorapho­
bia. Furthermore, individuals with agoraphobia describe the fannily climate and child-rearing 
behavior as being characterized by reduced warmth and increased overprotection.
Genetic and physiological. Heritability for agoraphobia is 61%. Of the various phobias,

Genetic and physiological. Heritability for agoraphobia is 61%. Of the various phobias, 
agoraphobia has the strongest and most specific association with the genetic factor that 
represents proneness to phobias.
Gender-Reiated Diagnostic Issues
Females have different patterns of comorbid disorders than males. Consistent with gender 
differences in the prevalence of mental disorders, males have higher rates of comorbid 
substance use disorders.
Functional Consequences of Agoraphobia
Agoraphobia is associated with considerable impairment and disability in terms of role 
functioning, work productivity, and disability days. Agoraphobia severity is a strong de­
terminant of the degree of disability, irrespective of the presence of comorbid panic disor­
der, panic attacks, and other comorbid conditions. More than one-third of individuals 
with agoraphobia are completely homebound and unable to work.

When diagnostic criteria for agoraphobia and another disorder are fully met, both diagnoses 
should be assigned, unless the fear, anxiety, or avoidance of agoraphobia is attributable to the 
other disorder. Weighting of criteria and clinical judgment may be helpful in some cases.

Specific phobia, situational type. Differentiating agoraphobia from situational specific 
phobia can be challenging in some cases, because these conditions share several symptom 
characteristics and criteria. Specific phobia, situational type, should be diagnosed versus ago­
raphobia if the fear, anxiety, or avoidance is limited to one of the agoraphobic situations. 
Requiring fears from two or more of the agoraphobic situations is a robust means for differen­
tiating agoraphobia from specific phobias, particularly the situational subtype. Additional dif­
ferentiating features include the cognitive ideation. Thus, if the situation is feared for reasons 
other than panic-like symptoms or other incapacitating or embarrassing symptoms (e.g., fears 
of being directly harmed by the situation itself, such as fear of the plane crashing for individ­
uals who fear flying), then a diagnosis of specific phobia may be more appropriate.

Separation anxiety disorder. Separation anxiety disorder can be best differentiated 
from agoraphobia by examining cognitive ideation. In separation anxiety disorder, the 
thoughts are about detachment from significant others and the home environment (i.e., 
parents or other attachment figures), whereas in agoraphobia the focus is on panic-like 
symptoms or other incapacitating or embarrassing symptoms in the feared situations.
Social anxiety disorder (social phobia). Agoraphobia should be differentiated from so­
cial anxiety disorder based primarily on the situational clusters that trigger fear, anxiety, 
or avoidance and the cognitive ideation. In social anxiety disorder, the focus is on fear of 
being negatively evaluated.

Panic disorder. When criteria for panic disorder are met, agoraphobia should not be di­
agnosed if the avoidance behaviors associated with the panic attacks do not extend to avoid­
ance of two or more agoraphobic situations.
Acute stress disorder and posttraumatic stress disorder. Acute stress disorder and 
posttraumatic stress disorder (PTSD) can be differentiated from agoraphobia by examin­
ing whether the fear, anxiety, or avoidance is related only to situations that remind the 
individual of a traumatic event. If the fear, anxiety, or avoidance is restricted to trauma re­
minders, and if the avoidance behavior does not extend to two or more agoraphobic situ­
ations, then a diagnosis of agoraphobia is not warranted.
Major depressive disorder. In major depressive disorder, the individual may avoid leav­

ing home because of apathy, loss of energy, low self-esteem, and anhedonia. If the avoid­
ance is unrelated to fears of panic-like or other incapacitating or embarrassing symptoms, 
then agoraphobia should not be diagnosed.
Other medical conditions. Agoraphobia is not diagnosed if the avoidance of situations 
is judged to be a physiological consequence of a medical condition. This determination is 
based on history, laboratory findings, and a physical examination. Other relevant medical 
conditions may include neurodegenerative disorders with associated motor disturbances 
(e.g., Parkinson's disease, multiple sclerosis), as well as cardiovascular disorders. Individ­
uals with certain medical conditions may avoid situations because of realistic concerns

uals with certain medical conditions may avoid situations because of realistic concerns 
about being incapacitated (e.g., fainting in an individual with transient ischemic attacks) 
or being embarrassed (e.g., diarrhea in an individual with Crohn's disease). The diagnosis 
of agoraphobia should be given only when the fear or avoidance is clearly in excess of that 
usually associated with these medical conditions.
The majority of individuals with agoraphobia also have other mental disorders. The most 
frequent additional diagnoses are other anxiety disorders (e.g., specific phobias, panic dis­
order, social anxiety disorder), depressive disorders (major depressive disorder), PTSD, 
and alcohol use disorder. Whereas other anxiety disorders (e.g., separation anxiety disor­
der, specific phobias, panic disorder) frequently precede onset of agoraphobia, depressive

der, specific phobias, panic disorder) frequently precede onset of agoraphobia, depressive 
disorders and substance use disorders typically occur secondary to agoraphobia.

Generalized Anxiety Disorder
Diagnostic Criteria 300.02 (F41.1)
A. Excessive anxiety and worry (apprehensive expectation), occurring more days than  
not for at least 6 months, about a number of events or activities (such as work or school  
performance).
B. The individual finds it difficult to control the worry.
C. The anxiety and worry are associated with three (or more) of the following six symp­
toms (with at least some symptoms having been present for more days than not for the  
past 6 months);
Note: Only one item is required in children.
1. Restlessness or feeling keyed up or on edge.
2. Being easily fatigued.
3. Difficulty concentrating or mind going blank.
4. Irritability.
5. Muscle tension.
6. Sleep disturbance (difficulty falling or staying asleep, or restless, unsatisfying  
sleep).
D. The anxiety, worry, or physical symptoms cause clinically significant distress or impair­
ment in social, occupational, or other important areas of functioning.

sleep).
F. The disturbance is not better explained by another mental disorder (e.g., anxiety or  
worry about having panic attacks in panic disorder, negative evaluation in social anxi­
ety disorder [social phobia], contamination or other obsessions in obsessive-compul­
sive disorder, separation from attachment figures in separation anxiety disorder,  
reminders of traumatic events in posttraumatic stress disorder, gaining weight in an­
orexia nervosa, physical complaints in somatic symptom disorder, perceived appear­
ance flaws in body dysmorphic disorder, having a serious illness in illness anxiety

ance flaws in body dysmorphic disorder, having a serious illness in illness anxiety  
disorder, or the content of delusional beliefs in schizophrenia or delusional disorder).
The essential feature of generalized anxiety disorder is excessive anxiety and worry (ap­
prehensive expectation) about a number of events or activities. The intensity, duration, or 
frequency of the anxiety and worry is out of proportion to the actual likelihood or impact 
of the anticipated event. The individual finds it difficult to control the worry and to keep 
worrisome thoughts from interfering with attention to tasks at hand. Adults with gener­
alized anxiety disorder often worry about everyday, routine life circumstances, such as 
possible job responsibilities, health and finances, the health of family members, misfor­

tune to their children, or minor matters (e.g., doing household chores or being late for ap­
pointments). Children with generalized anxiety disorder tend to worry excessively about 
their competence or the quality of their performance. During the course of the disorder, 
the focus of worry may shift from one concern to another.
Several features distinguish generalized anxiety disorder from nonpathological anxiety. 
First, the worries associated with generalized anxiety disorder are excessive and typically in­
terfere significantly with psychosocial functioning, whereas the worries of everyday life 
are not excessive and are perceived as more manageable and may be put off when more 
pressing matters arise. Second, the worries associated with generalized anxiety disorder are

more pervasive, pronounced, and distressing; have longer duration; and frequently occur 
without précipitants. The greater the range of life circumstances about which a person 
worries (e.g., finances, children's safety, job performance), the more likely his or her symp­
toms are to meet criteria for generalized anxiety disorder. Third, everyday worries are much 
less likely to be accompanied by physical symptoms (e.g., restlessness or feeling keyed up 
or on edge). Individuals with generalized anxiety disorder report subjective distress due 
to constant worry and related impairment in social, occupational, or other important areas 
of functioning.
The anxiety and worry are accompanied by at least three of the following additional 
symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty 
concentrating or mind going blank, irritability, muscle tension, and disturbed sleep, al­
though only one additional symptom is required in children.

Associated with muscle tension, there may be trembling, twitching, feeling shaky, and 
muscle aches or soreness. Many individuals with generalized anxiety disorder also expe­
rience somatic symptoms (e.g., sweating, nausea, diarrhea) and an exaggerated startle re­
sponse. Symptoms of autonomic hyperarousal (e.g., accelerated heart rate, shortness of 
breath, dizziness) are less prominent in generalized anxiety disorder than in other anxiety 
disorders, such as panic disorder. Other conditions that may be associated with stress (e.g., 
irritable bowel syndrome, headaches) frequently accompany generalized anxiety disorder.
The 12-month prevalence of generalized anxiety disorder is 0.9% among adolescents and

The 12-month prevalence of generalized anxiety disorder is 0.9% among adolescents and 
2.9% among adults in the general community of the United States. The 12-month preva­
lence for the disorder in other countries ranges from 0.4% to 3.6%. The lifetime morbid risk 
is 9.0%. Females are twice as likely as males to experience generalized anxiety disorder. The 
prevalence of the diagnosis peaks in middle age and declines across the later years of life.
Individuals of European descent tend to experience generalized anxiety disorder more 
frequently than do individuals of non-European descent (i.e., Asian, African, Native 
American and Pacific Islander). Furthermore, individuals from developed countries are 
more likely than individuals from nondeveloped countries to report that they have expe­
rienced symptoms that meet criteria for generalized anxiety disorder in their lifetime.

Many individuals with generalized anxiety disorder report that they have felt anxious and 
nervous all of their lives. The median age at onset for generalized anxiety disorder is 30 
years; however, age at onset is spread over a very broad range. The median age at onset is 
later than that for the other anxiety disorders. The symptoms of excessive worry and anx­
iety may occur early in life but are then manifested as an anxious temperament. Onset of 
the disorder rarely occurs prior to adolescence. The symptoms of generalized anxiety dis­
order tend to be chronic and wax and wane across the lifespan, fluctuating between syn- 
dromal and subsyndromal forms of the disorder. Rates of full remission are very low.

The clinical expression of generalized anxiety disorder is relatively consistent across 
the lifespan. The primary difference across age groups is in the content of the individual's 
worry. Children and adolescents tend to worry more about school and sporting perfor­
mance, whereas older adults report greater concern about the well-being of family or their 
own physical heath. Thus, the content of an individual's worry tends to be age appropri­
ate. Younger adults experience greater severity of symptoms than do older adults.
The earlier in life individuals have symptoms that meet criteria for generalized anxiety 
disorder, the more comorbidity they tend to have and the more impaired they are likely to

be. The advent of chronic physical disease can be a potent issue for excessive worry in the 
elderly. In the frail elderly, worries about safety—and especially about falling—may limit 
activities. In those with early cognitive impairment, what appears to be excessive worry 
about, for example, the whereabouts of things is probably better regarded as realistic 
given the cognitive impairment.
In children and adolescents with generalized anxiety disorder, the anxieties and wor­
ries often concern the quality of their performance or competence at school or in sporting 
events, even when their performance is not being evaluated by others. There may be ex­
cessive concerns about punctuality. They may also worry about catastrophic events, such 
as earthquakes or nuclear war. Children with the disorder may be overly conforming, per­
fectionist, and unsure of themselves and tend to redo tasks because of excessive dissatis­

faction with less-than-perfect performance. They are typically overzealous in seeking 
reassurance and approval and require excessive reassurance about their performance and 
other things they are worried about.
Generalized anxiety disorder may be overdiagnosed in children. When this diagnosis 
is being considered in children, a thorough evaluation for the presence of other childhood 
anxiety disorders and other mental disorders should be done to determine whether the 
worries may be better explained by one of these disorders. Separation anxiety disorder, so­
cial anxiety disorder (social phobia), and obsessive-compulsive disorder are often accom­
panied by worries that may mimic those described in generalized anxiety disorder. For

panied by worries that may mimic those described in generalized anxiety disorder. For 
example, a child with social anxiety disorder may be concerned about school performance 
because of fear of humiliation. Worries about illness may also be better explained by sep­
aration anxiety disorder or obsessive-compulsive disorder.
Temperamental. Behavioral inhibition, negative affectivity (neuroticism), and harm 
avoidance have been associated with generalized anxiety disorder.
Environmental. Although childhood adversities and parental overprotection have been 
associated with generalized anxiety disorder, no environmental factors have been identi­
fied as specific to generalized anxiety disorder or necessary or sufficient for making the di­
agnosis.
Genetic and physiological. One-third of the risk of experiencing generalized anxiety

agnosis.
Genetic and physiological. One-third of the risk of experiencing generalized anxiety 
disorder is genetic, and these genetic factors overlap with the risk of neuroticism and are 
shared with other anxiety and mood disorders, particularly major depressive disorder.
There is considerable cultural variation in the expression of generalized anxiety disorder. 
For example, in some cultures, somatic symptoms predominate in the expression of the 
disorder, whereas in other cultures cognitive symptoms tend to predominate. This differ­
ence may be more evident on initial presentation than subsequently, as more symptoms 
are reported over time. There is no information as to whether the propensity for excessive 
worrying is related to culture, although the topic being worried about can be culture spe­

cific. It is important to consider the social and cultural context when evaluating whether 
worries about certain situations are excessive.
In clinical settings, generalized anxiety disorder is diagnosed somewhat more frequently 
in females than in males (about 55%-60% of those presenting with the disorder are 
female). In epidemiological studies, approximately two-thirds are female. Females and 
males who experience generalized anxiety disorder appear to have similar symptoms but

demonstrate different patterns of comorbidity consistent with gender differences in the 
prevalence of disorders. In females, comorbidity is largely confined to the anxiety disor­
ders and unipolar depression, whereas in males, comorbidity is more likely to extend to 
the substance use disorders as well.
Excessive worrying impairs the individual's capacity to do things quickly and efficiently, 
whether at home or at work. The worrying takes time and energy; the associated symp­
toms of muscle tension and feeling keyed up or on edge, tiredness, difficulty concentrat­
ing, and disturbed sleep contribute to the impairment. Importantly the excessive worrying 
may impair the ability of individuals with generalized anxiety disorder to encourage con­
fidence in their children.
Generalized anxiety disorder is associated with significant disability and distress that is

Generalized anxiety disorder is associated with significant disability and distress that is 
independent of comorbid disorders, and most non-institutionalized adults with the disorder 
are moderately to seriously disabled. Generalized anxiety disorder accounts for 110 mil­
lion disability days per annum in the U.S. population.
Anxiety disorder due to another medical condition. The diagnosis of anxiety disorder 
associated with another medical condition should be assigned if the individual's anxiety 
and worry are judged, based on history, laboratory findings, or physical examination, to 
be a physiological effect of another specific medical condition (e.g., pheochromocytoma, 
hyperthyroidism).
Substance/medication-induced anxiety disorder. A substance/medication-induced 
anxiety disorder is distinguished from generalized anxiety disorder by the fact that a sub­

stance or medication (e.g., a drug of abuse, exposure to a toxin) is judged to be etiologically 
related to the anxiety. For example, severe anxiety that occurs only in the context of heavy 
coffee consumption would be diagnosed as caffeine-induced anxiety disorder.
Social anxiety disorder. Individuals with social anxiety disorder often have anticipa­
tory anxiety that is focused on upcoming social situations in which they must perform or 
be evaluated by others, whereas individuals with generalized anxiety disorder worry, 
whether or not they are being evaluated.
Obsessive-compulsive disorder. Several features distinguish the excessive worry of 
generalized anxiety disorder from the obsessional thoughts of obsessive-compulsive dis­

order. In generalized anxiety disorder the focus of the worry is about forthcoming prob­
lems, and it is the excessiveness of the worry about future events that is abnormal. In 
obsessive-compulsive disorder, the obsessions are inappropriate ideas that take the form of 
intrusive and unwanted thoughts, urges, or images.
Posttraumatic stress disorder and adjustment disorders. Anxiety is invariably pres­
ent in posttraumatic stress disorder. Generalized anxiety disorder is not diagnosed if the 
anxiety and worry are better explained by symptoms of posttraumatic stress disorder. 
Anxiety may also be present in adjustment disorder, but this residual category should be 
used only when the criteria are not met for any other disorder (including generalized anx­

iety disorder). Moreover, in adjustment disorders, the anxiety occurs in response to an 
identifiable stressor within 3 months of the onset of the stressor and does not persist for 
more than 6 months after the termination of the stressor or its consequences.
Depressive, bipolar, and psychotic disorders. Generalized anxiety/worry is a common 
associated feature of depressive, bipolar, and psychotic disorders and should not be di-

agnosed separately if the excessive worry has occurred only during the course of these 
Individuals whose presentation meets criteria for generalized anxiety disorder are likely 
to have met, or currently meet, criteria for other anxiety and unipolar depressive disor­
ders. The neuroticism or emotional liability that underpins this pattern of comorbidity is 
associated with temperamental antecedents and genetic and environmental risk factors 
shared between these disorders, although independent pathways are also possible. Co­
morbidity with substance use, conduct, psychotic, neurodevelopmental, and neurocogni- 
tive disorders is less common.
Anxiety Disorder
A. Panic attacks or anxiety is predominant in  the clinical picture.

or withdrawal or atter exposure to a medication.
rion A.
C. The disturbance is not better explained by an anxiety disorder that is not substance/  
medication-induced. Such evidence of an independent anxiety disorder could include  
The symptoms precede the onset of the substance/medication use; the symptoms  
persist for a substantial period of time (e.g., about 1  month) atter the cessation of  
acute withdrawal or severe intoxication: or there is other evidence suggesting the  
existence of an independent non-substance/medication-induced anxiety disorder

existence of an independent non-substance/medication-induced anxiety disorder  
picture and they are sufficiently severe to warrant clinical attention.
tion]-induced anxiety disorders are indicated in the table below. Note that the ICD-10-CM  
code depends on whether or not there is a comorbid substance use disorder present for

code depends on whether or not there is a comorbid substance use disorder present for  
the same class of substance. If a mild substance use disorder is comorbid with the sub­
stance-induced anxiety disorder, the 4th position character is “1,”  and the clinician should  
record “ mild [substance] use disorder”  before the substance-induced anxiety disorder  
(e.g., “ mild cocaine use disorder with cocaine-induced anxiety disorder” ). If a moderate or  
severe substance use disorder is comorbid with the substance-induced anxiety disorder,  
disorder or “ severe [substance] use disorder,”  depending on the severity of the comorbid  

time heavy use of the substance), then the 4th position character is “ 9,”  and the clinician  
should record only the substance-induced anxiety disorder.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ s  -. ,  - ,
ICD-10-CM
disorder,  
disorder,  
moderate  
use
disorder
Alcohol 291.89 F10.180 FI 0.280 FI 0.980
Caffeine 292.89 F15.180 FI 5.280 FI 5.980
Cannabis 292.89 F12.180 FI 2.280 FI 2.980
Phencyclidine 292.89 F16.180 FI 6.280 FI 6.980
Other hallucinogen 292.89 F16.180 F16.280 F16.980
Inhalant 292.89 FI 8.180 FI 8.280 F18.980
Opioid 292.89 F11.188 F11.288 F11.988
Sedative, hypnotic, or anxiolytic 292.89 FI 3.180 FI 3.280 FI 3.980
stimulant)292.89 FI 5.180 FI 5.280 FI 5.980
Cocaine 292.89 FI 4.180 FI 4.280 FI 4.980
Other (or unl<nown) substance 292.89 FI 9.180 FI 9.280 FI 9.980

With onset during intoxication: This specifier applies if criteria are met for intoxica­
tion with the substance and the symptoms develop during intoxication.
Witli onset during withdrawai: This specifier applies if criteria are met for withdrawal  
from the substance and the symptoms develop during, or shortly after, withdrawal.  
Witli onset after medication use: Symptoms may appear either at initiation of medi­
cation or after a modification or change in use.
ICD-9-CM. The name of the substance/medication-induced anxiety disorder begins 
with the specific substance (e.g., cocaine, salbutamol) that is presumed to be causing the 
anxiety symptoms. The diagnostic code is selected from the table included in the criteria 
set, which is based on the drug class. For substances that do not fit into any of the classes

set, which is based on the drug class. For substances that do not fit into any of the classes 
(e.g., salbutamol), the code for "other substance" should be used; and in cases in which 
a substance is judged to be an etiological factor but the specific class of substance is un­
toxication, onset during withdrawal, with onset during medication use). Unlike the record­
ing procedures for ICD-IO-CM, which combine the substance-induced disorder and 
substance use disorder into a single code, for ICD-9-CM a separate diagnostic code is given 
for the substance use disorder. For example, in the case of anxiety symptoms occurring dur­
ing withdrawal in a man with a severe lorazepam use disorder, the diagnosis is 292.89 loraz-

ing withdrawal in a man with a severe lorazepam use disorder, the diagnosis is 292.89 loraz- 
epam-induced anxiety disorder, with onset during withdrawal. An additional diagnosis of 
304.10 severe lorazepam use disorder is also given. When more than one substance is judged 
to play a significant role in the development of anxiety symptoms, each should be listed sep-

arately (e.g., 292.89 methylphenidate-induced anxiety disorder, with onset during intoxica­
tion; 292.89 salbutamol-induced anxiety disorder, with onset after medication use).
ICD-10-CM. The name of the substance/medication-induced anxiety disorder begins 
set, which is based on the drug class and presence or absence of a comorbid substance use 
disorder. For substances that do not fit into any of the classes (e.g., salbutamol), the code 
for "other substance" should be used; and in cases in which a substance is judged to be an 
etiological factor but the specific class of substance is unknown, the category "unknown 
substance" should be used.

anxiety disorder, followed by the specification of onset (i.e., onset during intoxication, 
onset during withdrawal, with onset during medication use). For example, in the case of 
anxiety symptoms occurring during withdrawal in a man with a severe lorazepam use dis­
order, the diagnosis is F13.280 severe lorazepam use disorder with lorazepam-induced 
anxiety disorder, with onset during withdrawal. A separate diagnosis of the comorbid se­
vere lorazepam use disorder is not given. If the substance-induced anxiety disorder occurs 
without a comorbid substance use disorder (e.g., after a one-time heavy use of the substance), 
no accompanying substance use disorder is noted (e.g., F16.980 psilocybin-induced anxi­

ety disorder, with onset during intoxication). When more than one substance is judged to 
play a significant role in the development of anxiety symptoms, each should be listed sep­
arately (e.g., F15.280 severe methylphenidate use disorder with methylphenidate-induced 
anxiety disorder, with onset during intoxication; F19.980 salbutamol-induced anxiety dis­
order, with onset after medication use).
The essential features of substance/medication-induced anxiety disorder are prominent 
symptoms of panic or anxiety (Criterion A) that are judged to be due to the effects of a sub­
stance (e.g., a drug of abuse, a medication, or a toxin exposure). The panic or anxiety symp­
toms must have developed during or soon after substance intoxication or withdrawal or

toms must have developed during or soon after substance intoxication or withdrawal or 
after exposure to a medication, and the substances or medications must be capable of pro­
ducing the symptoms (Criterion B2). Substance/medication-induced anxiety disorder 
due to a prescribed treatment for a mental disorder or another medical condition must 
have its onset while the individual is receiving the medication (or during withdrawal, if a 
withdrawal is associated with the medication). Once the treatment is discontinued, the 
panic or anxiety symptoms will usually improve or remit within days to several weeks to 
a month (depending on the half-life of the substance/medication and the presence of with­
drawal). The diagnosis of substance/medication-induced anxiety disorder should not be 
given if the onset of the panic or anxiety symptoms precedes the substance/medication in­

toxication or withdrawal, or if the symptoms persist for a substantial period of time (i.e., 
usually longer than 1  month) from the time of severe intoxication or withdrawal. If the 
panic or anxiety symptoms persist for substantial periods of time, other causes for the 
symptoms should be considered.
The substance/medication-induced anxiety disorder diagnosis should be made in­
stead of a diagnosis of substance intoxication or substance withdrawal only when the 
symptoms in Criterion A are predominant in the clinical picture and are sufficiently severe 
to warrant independent clinical attention.
Panic or anxiety can occur in association with intoxication with the following classes of sub­

stances: alcohol, caffeine, cannabis, phencyclidine, other hallucinogens, inhalants, stimu­

lants (including cocaine), and other (or unknown) substances. Panic or anxiety can occur in 
association with withdrawal from the following classes of substances: alcohol; opioids; sed­
atives, hypnotics, and anxiolytics; stimulants (including cocaine); and other (or unknown) 
substances. Some medications that evoke anxiety symptoms include anesthetics and anal­
gesics, sympathomimetics or other bronchodilators, anticholinergics, insulin, thyroid prep­
arations, oral contraceptives, antihistamines, antiparkinsonian medications, corticosteroids, 
antihypertensive and cardiovascular medications, anticonvulsants, lithium carbonate, an­
tipsychotic medications, and antidepressant medications. Heavy metals and toxins (e.g., 
organophosphate insecticide, nerve gases, carbon monoxide, carbon dioxide, volatile sub­
stances such as gasoline and paint) may also cause panic or anxiety symptoms.
The prevalence of substance/medication-induced anxiety disorder is not clear. General

The prevalence of substance/medication-induced anxiety disorder is not clear. General 
population data suggest that it may be rare, with a 12-month prevalence of approximately 
0.002%. However, in clinical populations, the prevalence is likely to be higher.
Laboratory assessments (e.g., urine toxicology) may be useful to measure substance intox­
ication as part of an assessment for substance/medication-induced anxiety disorder.
Substance intoxication and substance withdrawal. Anxiety symptoms commonly oc­
cur in substance intoxication and substance withdrawal. The diagnosis of the substance- 
specific intoxication or substance-specific withdrawal will usually suffice to categorize the 
symptom presentation. A diagnosis of substance/medication-induced anxiety disorder 
should be made in addition to substance intoxication or substance withdrawal when the

should be made in addition to substance intoxication or substance withdrawal when the 
panic or anxiety symptoms are predominant in the clinical picture and are sufficiently se­
vere to warrant independent clinical attention. For example, panic or anxiety symptoms 
are characteristic of alcohol withdrawal.
Anxiety disorder (i.e., not induced by a substance/medication). Substance/medication- 
induced anxiety disorder is judged to be etiologically related to the substance/medication. 
Substance/medication-induced anxiety disorder is distinguished from a primary anxiety 
disorder based on the onset, course, and other factors with respect to substances/medica­
tions. For drugs of abuse, there must be evidence from the history, physical examination, or 
laboratory findings for use, intoxication, or withdrawal. Substance/medication-induced

laboratory findings for use, intoxication, or withdrawal. Substance/medication-induced 
anxiety disorders arise only in association with intoxication or withdrawal states, whereas 
primary anxiety disorders may precede the onset of substance/medication use. The pres­
ence of features that are atypical of a primary anxiety disorder, such as atypical age at onset 
(e.g., onset of panic disorder after age 45 years) or symptoms (e.g., atypical panic attack 
symptoms such as true vertigo, loss of balance, loss of consciousness, loss of bladder con­
trol, headaches, slurred speech) may suggest a substance/medication-induced etiology. A 
primary anxiety disorder diagnosis is warranted if the panic or anxiety symptoms persist 
for a substantial period of time (about 1  month or longer) after the end of the substance in­
toxication or acute withdrawal or there is a history of an anxiety disorder.

Delirium. If panic or anxiety symptoms occur exclusively during the course of delirium, 
they are considered to be an associated feature of the delirium and are not diagnosed sep­
arately.
Anxiety disorder due to another medical condition. If the panic or anxiety symptoms 
are attributed to the physiological consequences of another medical condition (i.e., rather 
than to the medication taken for the medical condition), anxiety disorder due to another

medical condition should be diagnosed. The history often provides the basis for such a 
judgment. At times, a change in the treatment for the other medical condition (e.g., med­
ication substitution or discontinuation) may be needed to determine whether the medica­
tion is the causative agent (in which case the symptoms may be better explained by 
substance/medication-induced anxiety disorder). If the disturbance is attributable to both 
another medical condition and substance use, both diagnoses (i.e., anxiety disorder due to 
another medical condition and substance/medication-induced anxiety disorder) may be 
given. When there is insufficient evidence to determine whether the panic or anxiety symp­
toms are attributable to a substance/medication or to another medical condition or are pri­
mary (i.e., not attributable to either a substance or another medical condition), a diagnosis 
of other specified or unspecified anxiety disorder would be indicated.
Anxiety Disorder Due to

Anxiety Disorder Due to  
Another Medical Condition
Diagnostic Criteria 293.84 (F06.4)
B . There is evidence from the history, physical examination, or laboratory findings that the dis­
E. The disturbance causes clinically significant distress or impairment in  social, occupa­
Coding note: Include the name of the other medical condition within the name of the men­
tal disorder (e.g., 293.84 [F06.4] anxiety disorder due to pheochromocytoma). The other

tal disorder (e.g., 293.84 [F06.4] anxiety disorder due to pheochromocytoma). The other  
medical condition should be coded and listed separately immediately before the anxiety  
disorder due to the medical condition (e.g., 227.0 [D35.00] pheochromocytoma; 293.84  
[F06.4] anxiety disorder due to pheochromocytoma. _____________________________
The essential feature of anxiety disorder due to another medical condition is clinically signifi­
cant anxiety that is judged to be best explained as a physiological effect of another medical con­
dition. Symptoms can include prominent anxiety symptoms or panic attacks (Criterion A). 
The judgment that the symptoms are best explained by the associated physical condition must 
be based on evidence from the history, physical examination, or laboratory findings (Criterion

be based on evidence from the history, physical examination, or laboratory findings (Criterion 
B). Additionally, it must be judged that the symptoms are not better accounted for by another 
mental disorder, in particular, adjustment disorder, with anxiety, in which the stressor is the 
medical condition (Criterion C). In this case, an individual with adjustment disorder is espe­
cially distressed about the meaning or the consequences of the associated medical condition. 
By contrast, there is often a prominent physical component to the anxiety (e.g., shortness of 
breath) when the anxiety is due to another medical condition. The diagnosis is not made if the 
anxiety symptoms occur only during the course of a delirium (Criterion D). The anxiety symp­
toms must cause clinically significant distress or impairment in social, occupational, or other 
important areas of functioning (Criterion E).

In determining whether the anxiety symptoms are attributable to another medical con­
dition, the clinician must first establish the presence of the medical condition. Further­
more, it must be established that anxiety symptoms can be etiologically related to the 
medical condition through a physiological mechanism before making a judgment that this 
is the best explanation for the symptoms in a specific individual. A careful and compre­

hensive assessment of multiple factors is necessary to make this judgment. Several aspects 
of the clinical presentation should be considered: 1) the presence of a clear temporal asso­
ciation between the onset, exacerbation, or remission of the medical condition and the anx­
iety symptoms; 2) the presence of features that are atypical of a primary anxiety disorder 
(e.g., atypical age at onset or course); and 3) evidence in the literature that a known phys­
iological mechanism (e.g., hyperthyroidism) causes anxiety. In addition, the disturbance 
must not be better explained by a primary anxiety disorder, a substance/medication- 
induced anxiety disorder, or another primary mental disorder (e.g., adjustment disorder).
A number of medical conditions are known to include anxiety as a symptomatic manifes­
tation. Examples include endocrine disease (e.g., hyperthyroidism, pheochromocytoma,

tation. Examples include endocrine disease (e.g., hyperthyroidism, pheochromocytoma, 
hypoglycemia, hyperadrenocortisolism), cardiovascular disorders (e.g., congestive heart 
failure, pulmonary embolism, arrhythmia such as atrial fibrillation), respiratory illness 
(e.g., chronic obstructive pulmonary disease, asthma, pneumonia), metabolic distur­
bances (e.g., vitamin B ^ 2 deficiency, porphyria), and neurological illness (e.g., neoplasms, 
vestibular dysfunction, encephalitis, seizure disorders). Anxiety due to another medical 
condition is diagnosed when the medical condition is known to induce anxiety and when 
the medical condition preceded the onset of the anxiety.
The prevalence of anxiety disorder due to another medical condition is unclear. There ap­
pears to be an elevated prevalence of anxiety disorders among individuals with a variety

pears to be an elevated prevalence of anxiety disorders among individuals with a variety 
of medical conditions, including asthma, hypertension, ulcers, and arthritis. However, this 
increased prevalence may be due to reasons other than the anxiety disorder directly caus­
ing the medical condition.
The development and course of anxiety disorder due to another medical condition gen­
erally follows the course of the underlying illness. This diagnosis is not meant to include 
primary anxiety disorders that arise in the context of chronic medical illness. This is im­
portant to consider with older adults, who may experience chronic medical illness and 
then develop independent anxiety disorders secondary to the chronic medical illness.
Laboratory assessments and/or medical examinations are necessary to confirm the diag­

nosis of the associated medical condition.
Delirium. A separate diagnosis of anxiety disorder due to another medical condition is 
not given if the anxiety disturbance occurs exclusively during the course of a delirium. 
However, a diagnosis of anxiety disorder due to another medical condition may be given 
in addition to a diagnosis of major neurocognitive disorder (dementia) if the etiology of 
anxiety is judged to be a physiological consequence of the pathological process causing the 
neurocognitive disorder and if anxiety is a prominent part of the clinical presentation.
Mixed presentation of symptoms (e.g., mood and anxiety). If the presentation includes 
a mix of different types of symptoms, the specific mental disorder due to another medical

a mix of different types of symptoms, the specific mental disorder due to another medical 
condition depends on which symptoms predominate in the clinical picture.
Substance/medication-induced anxiety disorder. If there is evidence of recent or pro­
longed substance use (including medications with psychoactive effects), withdrawal from

a substance, or exposure to a toxin, a substance/medication-induced anxiety disorder 
should be considered. Certain medications are known to increase anxiety (e.g., corticoste­
roids, estrogens, metoclopramide), and when this is the case, the medication may be the 
most likely etiology, although it may be difficult to distinguish whether the anxiety is at­
tributable to the medications or to the medical illness itself. When a diagnosis of substance- 
induced anxiety is being made in relation to recreational or nonprescribed drugs, it may be 
useful to obtain a urine or blood drug screen or other appropriate laboratory evaluation. 
Symptoms that occur during or shortly after (i.e., within 4 weeks of) substance intoxication 
or withdrawal or after medication use may be especially indicative of a substance/medi­
cation-induced anxiety disorder, depending on the type, duration, or amount of the sub­
stance used. If the disturbance is associated with both another medical condition and

stance used. If the disturbance is associated with both another medical condition and 
substance use, both diagnoses (i.e., anxiety disorder due to another medical condition and 
substance/medication-induced anxiety disorder) can be given. Features such as onset af­
ter age 45 years or the presence of atypical symptoms during a panic attack (e.g., vertigo, 
loss of consciousness, loss of bladder or bowel control, slurred speech, amnesia) suggest 
the possibility that another medical condition or a substance may be causing the panic at­
tack symptoms.
Anxiety disorder (not due to a known medical condition). Anxiety disorder due to an­
other medical condition should be distinguished from other anxiety disorders (especially 
panic disorder and generalized anxiety disorder). In other anxiety disorders, no specific 
and direct causative physiological mechanisms associated with another medical condition

and direct causative physiological mechanisms associated with another medical condition 
can be demonstrated. Late age at onset, atypical symptoms, and the absence of a personal 
or family history of anxiety disorders suggest the need for a thorough assessment to rule 
out the diagnosis of anxiety disorder due to another medical condition. Anxiety disorders 
can exacerbate or pose increased risk for medical conditions such as cardiovascular events 
and myocardial infarction and should not be diagnosed as anxiety disorder due to another 
medical condition in these cases.
Illness anxiety disorder. Anxiety disorder due to another medical condition should be 
distinguished from illness anxiety disorder. Illness anxiety disorder is characterized by 
worry about illness, concern about pain, and bodily preoccupations. In the case of illness

worry about illness, concern about pain, and bodily preoccupations. In the case of illness 
anxiety disorder, individuals may or may not have diagnosed medical conditions. Al­
though an individual with illness anxiety disorder and a diagnosed medical condition is 
likely to experience anxiety about the medical condition, the medical condition is not 
physiologically related to the anxiety symptoms.
Adjustment disorders. Anxiety disorder due to another medical condition should be 
distinguished from adjustment disorders, with anxiety, or with anxiety and depressed 
mood. Adjustment disorder is warranted when individuals experience a maladaptive re­
sponse to the stress of having another medical condition. The reaction to stress usually 
concerns the meaning or consequences of the stress, as compared with the experience of

concerns the meaning or consequences of the stress, as compared with the experience of 
anxiety or mood symptoms that occur as a physiological consequence of the other medical 
condition. In adjustment disorder, the anxiety symptoms are typically related to coping 
with the stress of having a general medical condition, whereas in anxiety disorder due to 
another medical condition, individuals are more likely to have prominent physical symp­
toms and to be focused on issues other than the stress of the illness itself.
Associated feature of another mental disorder. Anxiety symptoms may be an associ­
ated feature of another mental disorder (e.g., schizophrenia, anorexia nervosa).
Other specified or unspecified anxiety disorder. This diagnosis is given if it cannot be 
determined whether the anxiety symptoms are primary, substance-induced, or associated 
with another medical condition.

Other Specified Anxiety Disorder
^  300.09 (F41.8)
This category applies to presentations in which symptoms characteristic of an anxiety dis­
order that cause clinically significant distress or impairment in social, occupational, or oth­
er important areas of functioning predominate but do not meet the full criteria for any of the  
disorders in the anxiety disorders diagnostic class. The other specified anxiety disorder  
category is used in situations in which the clinician chooses to communicate the specific  
reason that the presentation does not meet the criteria for any specific anxiety disorder.  
This is done by recording “ other specified anxiety disorder”  followed by the specific reason  
(e.g., “ generalized anxiety not occurring more days than not” ).
include the following;
1. Limited-symptom attacks.
2. Generalized anxiety not occurring more days than not.

3. Khyâl  cap (wind attacks): See “ Glossary of Cultural Concepts of Distress”  in the Ap­
pendix.
4. Ataque de nervios  (attack of nerves): See “ Glossary of Cultural Concepts of Distress”  
in  the Appendix.
Unspecified Anxiety Disorder
300.00 (F41.9)
disorders in the anxiety disorders diagnostic class. The unspecified anxiety disorder cate­
gory is used in  situations in which the clinician chooses not to specify the reason that the

gory is used in  situations in which the clinician chooses not to specify the reason that the  
criteria are not met for a specific anxiety disorder, and includes presentations in which  
there is insufficient information to make a more specific diagnosis (e.g., in emergency room  
settings).

Obsessive-Coinpiilsive and 
O bSG SSiV G -C O m p u lsiV G  and related disorders include obsessive-compulsive 
disorder (OCD), body dysmorphic disorder, hoarding disorder, trichotillomania (hair- 
pulling disorder), excoriation (skin-picking) disorder, substance/medication-induced ob­
sessive-compulsive and related disorder, obsessive-compulsive and related disorder due 
to another medical condition, and other specified obsessive-compulsive and related dis­
order and unspecified obsessive-compulsive and related disorder (e.g., body-focused re­
petitive behavior disorder, obsessional jealousy).
OCD is characterized by the presence of obsessions and/or compulsions. Obsessions  
are recurrent and persistent thoughts, urges, or images that are experienced as intrusive 
and unwanted, whereas compulsions  are repetitive behaviors or mental acts that an indi­
vidual feels driven to perform in response to an obsession or according to rules that must

vidual feels driven to perform in response to an obsession or according to rules that must 
be applied rigidly. Some other obsessive-compulsive and related disorders are also char­
acterized by preoccupations and by repetitive behaviors or mental acts in response to the 
preoccupations. Other obsessive-compulsive and related disorders are characterized pri­
marily by recurrent body-focused repetitive behaviors (e.g., hair pulling, skin picking) and 
repeated attempts to decrease or stop the behaviors.
The inclusion of a chapter on obsessive-compulsive and related disorders in DSM-5 re­
flects the increasing evidence of these disorders' relatedness to one another in terms of a 
range of diagnostic validators as well as the clinical utility of grouping these disorders in 
the same chapter. Clinicians are encouraged to screen for these conditions in individuals

the same chapter. Clinicians are encouraged to screen for these conditions in individuals 
who present with one of them and be aware of overlaps between these conditions. At the 
same time, there are important differences in diagnostic validators and treatment ap­
proaches across these disorders. Moreover, there are close relationships between the anx­
iety disorders and some of the obsessive-compulsive and related disorders (e.g., OCD), 
which is reflected in the sequence of DSM-5 chapters, with obsessive-compulsive and re­
lated disorders following anxiety disorders.
The obsessive-compulsive and related disorders differ from developmentally norma­
tive preoccupations and rituals by being excessive or persisting beyond developmentally 
appropriate periods. The distinction between the presence of subclinical symptoms and a

appropriate periods. The distinction between the presence of subclinical symptoms and a 
clinical disorder requires assessment of a number of factors, including the individual's 
level of distress and impairment in functioning.
The chapter begins with OCD. It then covers body dysmorphic disorder and hoarding 
disorder, which are characterized by cognitive symptoms such as perceived defects or 
flaws in physical appearance or the perceived need to save possessions, respectively. The 
chapter then covers trichotillomania (hair-pulling disorder) and excoriation (skin-picking) 
disorder, which are characterized by recurrent body-focused repetitive behaviors. Finally, 
it covers substance/medication-induced obsessive-compulsive and related disorder, 
obsessive-compulsive and related disorder due to another medical condition, and other

obsessive-compulsive and related disorder due to another medical condition, and other 
specified obsessive-compulsive and related disorder and unspecified obsessive-compul­
sive and related disorder.
While the specific content of obsessions and compulsions varies among individuals, 
certain symptom dimensions are common in OCD, including those of cleaning (contami­
nation obsessions and cleaning compulsions); symmetry (symmetry obsessions and repeat-

ing, ordering, and counting compulsions); forbidden or taboo thoughts (e.g., aggressive, 
sexual, and religious obsessions and related compulsions); and harm (e.g., fears of harm to 
oneself or others and related checking compulsions). The tic-related specifier of OCD is 
used v^hen an individual has a current or past history of a tic disorder.
Body dysmorphic disorder is characterized by preoccupation with one or more per­
ceived defects or flav^s in physical appearance that are not observable or appear only slight 
to others, and by repetitive behaviors (e.g., mirror checking, excessive grooming, skin 
picking, or reassurance seeking) or mental acts (e.g., comparing one's appearance v^ith that 
of other people) in response to the appearance concerns. The appearance preoccupations 
are not better explained by concerns with body fat or weight in an individual with an eat­
ing disorder. Muscle dysmoφhia is a form of body dysmorphic disorder that is character­

ized by the belief that one's body build is too small or is insufficiently muscular.
Hoarding disorder is characterized by persistent difficulty discarding or parting with 
possessions, regardless of their actual value, as a result of a strong perceived need to save 
the items and to distress associated with discarding them. Hoarding disorder differs from 
normal collecting. For example, symptoms of hoarding disorder result in the accumula­
tion of a large number of possessions that congest and clutter active living areas to the ex­
tent that their intended use is substantially compromised. The excessive acquisition form 
of hoarding disorder, which characterizes most but not all individuals with hoarding dis­
order, consists of excessive collecting, buying, or stealing of items that are not needed or

order, consists of excessive collecting, buying, or stealing of items that are not needed or 
for which there is no available space.
Trichotillomania (hair-pulling disorder) is characterized by recurrent pulling out of 
one's hair resulting in hair loss, and repeated attempts to decrease or stop hair pulling. 
Excoriation (skin-picking) disorder is characterized by recurrent picking of one's skin re­
sulting in skin lesions and repeated attempts to decrease or stop skin picking. The body- 
focused repetitive behaviors that characterize these two disorders are not triggered by ob­
sessions or preoccupations; however, they may be preceded or accompanied by various 
emotional states, such as feelings of anxiety or boredom. They may also be preceded by an 
increasing sense of tension or may lead to gratification, pleasure, or a sense of relief when

increasing sense of tension or may lead to gratification, pleasure, or a sense of relief when 
the hair is pulled out or the skin is picked. Individuals with these disorders may have vary­
ing degrees of conscious awareness of the behavior while engaging in it, with some indi­
viduals displaying more focused attention on the behavior (with preceding tension and 
subsequent relief) and other individuals displaying more automatic behavior (with the be­
haviors seeming to occur without full awareness).
Substance/medication-induced obsessive-compulsive and related disorder consists of 
symptoms that are due to substance intoxication or withdrawal or to a medication. Obses­
sive-compulsive and related disorder due to another medical condition involves symptoms 
characteristic of obsessive-compulsive and related disorders that are the direct pathophysio­

logical consequence of a medical disorder. Other specified obsessive-compulsive and related 
disorder and unspecified obsessive-compulsive and related disorder consist of symptoms 
that do not meet criteria for a specific obsessive-compulsive and related disorder because of 
atypical presentation or uncertain etiology; these categories are also used for other specific 
syndromes that are not listed in Section Π  and when insufficient information is available to di­
agnose the presentation as another obsessive-compulsive and related disorder. Examples of 
specific syndromes not listed in Section Π , and therefore diagnosed as other specified obses­
sive-compulsive and related disorder or as unspecified obsessive-compulsive and related

sive-compulsive and related disorder or as unspecified obsessive-compulsive and related 
disorder include body-focused repetitive behavior disorder and obsessional jealousy.
Obsessive-compulsive and related disorders that have a cognitive component have in­
sight as the basis for specifiers; in each of these disorders, insight ranges from "good or fair 
insight" to "poor insight" to "absent insight/delusional beliefs" with respect to disorder- 
related beliefs. For individuals whose obsessive-compulsive and related disorder symp­
toms warrant the "with absent insight/delusional beliefs" specifier, these symptoms 
should not be diagnosed as a psychotic disorder.

Obsessive-Compulsive Disorder
-------------------- i-------------------------------------------------------------------------------------------
Diagnostic Criteria 300.3 (F42)
A. Presence of obsessions, compulsions, or both:
Obsessions are defined by (1) and (2):
1. Recurrent and persistent thoughts, urges, or images that are experienced, at some  
time during the disturbance, as intrusive and unwanted, and that in most individuals  
cause marked anxiety or distress.
2. The individual attempts to ignore or suppress such thoughts, urges, or images, or to  
neutralize them with some other thought or action (i.e., by performing a compulsion).
Compulsions are defined by (1) and (2):
1. Repetitive behaviors (e.g., hand washing, ordering, checking) or mental acts (e.g.,  
praying, counting, repeating words silently) that the individual feels driven to per­
form in response to an obsession or according to rules that must be applied rigidly.

2. The behaviors or mental acts are aimed at preventing or reducing anxiety or dis­
tress, or preventing some dreaded event or situation; however, these behaviors or  
mental acts are not connected in  a realistic way with what they are designed to neu­
tralize or prevent, or are clearly excessive.
Note: Young children may not be able to articulate the aims of these behaviors or  
mental acts.
B. The obsessions or compulsions are time-consuming (e.g., take more than 1  hour per  
day) or cause clinically significant distress or impairment in  social, occupational, or  
other important areas of functioning.
C. The obsessive-compulsive symptoms are not attributable to the physiological effects  
of a substance (e.g., a drug of abuse, a medication) or another medical condition.

D. The disturbance is not better explained by the symptoms of another mental disorder  
(e.g., excessive worries, as in generalized anxiety disorder; preoccupation with ap­
pearance, as in body dysmorphic disorder; difficulty discarding or parting with posses­
sions, as in hoarding disorder; hair pulling, as in trichotillomania [hair-pulling disorder];  
skin picking, as in excoriation [skin-picking] disorder; stereotypies, as in stereotypic  
movement disorder; ritualized eating behavior, as in eating disorders; preoccupation  
with substances or gambling, as in substance-related and addictive disorders; preoc­
cupation with having an illness, as in  illness anxiety disorder; sexual urges or fantasies,  
as in paraphilic disorders; impulses, as in disruptive, impulse-control, and conduct dis­

orders; guilty ruminations, as in major depressive disorder; thought insertion or delu­
sional preoccupations, as in  schizophrenia spectrum and other psychotic disorders; or  
repetitive patterns of behavior, as in autism spectrum disorder).
With good or fair insiglit: The individual recognizes that obsessive-compulsive dis­
order beliefs are definitely or probably not true or that they may or may not be true.  
With poor insight: The individual thinks obsessive-compulsive disorder beliefs are  
probably true.
With absent insight/deiusionai beiiefs: The individual is completely convinced that  
obsessive-compulsive disorder beliefs are true.
Tic-reiated: The individual has a current or past history of a tic disorder.

Many individuals with obsessive-compulsive disorder (OCD) have dysfunctional beliefs. 
These beliefs can include an inflated sense of responsibility and the tendency to overesti­
mate threat; perfectionism and intolerance of uncertainty; and over-importance of thoughts 
(e.g., believing that having a forbidden thought is as bad as acting on it) and the need to 
control thoughts.
Individuals with OCD vary in the degree of insight they have about the accuracy of the 
beliefs that underlie their obsessive-compulsive symptoms. Many individuals have good or  
fair insight  (e.g., the individual believes that the house definitely will not, probably will not, 
or may or may not bum down if the stove is not checked 30 times). Some have poor insight  
(e.g., the individual believes that the house will probably burn down if the stove is not 
checked 30 times), and a few (4% or less) have absent insight/delusional beliefs  (e.g., the in­

dividual is convinced that the house will bum down if the stove is not checked 30 times). 
Insight can vary within an individual over the course of the illness. Poorer insight has been 
linked to worse long-term outcome.
Up to 30% of individuals with OCD have a lifetime tic disorder. This is most common 
in males with onset of OCD in childhood. These individuals tend to differ from those with­
out a history of tic disorders in the themes of their OCD symptoms, comorbidity, course, 
and pattem of familial transmission.
The characteristic symptoms of OCD are the presence of obsessions and compulsions (Cri­
terion A). Obsessions  are repetitive and persistent thoughts (e.g., of contamination), images

terion A). Obsessions  are repetitive and persistent thoughts (e.g., of contamination), images 
(e.g., of violent or horrific scenes), or urges (e.g., to stab someone). Importantly, obsessions 
are not pleasurable or experienced as voluntary: they are intrusive and unwanted and 
cause marked distress or anxiety in most individuals. The individual attempts to ignore or 
suppress these obsessions (e.g., avoiding triggers or using thought suppression) or to neu­
tralize them with another thought or action (e.g., performing a compulsion). Compulsions  
(or rituals) are repetitive behaviors (e.g., washing, checking) or mental acts (e.g., counting, 
repeating words silently) that the individual feels driven to perform in response to an 
obsession or according to rules that must be applied rigidly. Most individuals with OCD

obsession or according to rules that must be applied rigidly. Most individuals with OCD 
have both obsessions and compulsions. Compulsions are typically performed in response 
to an obsession (e.g., thoughts of contamination leading to washing rituals or that some­
thing is incorrect leading to repeating rituals until it feels "just right")· The aim is to reduce 
the distress triggered by obsessions or to prevent a feared event (e.g., becoming ill). How­
ever, these compulsions either are not connected in a realistic way to the feared event (e.g., 
arranging items symmetrically to prevent harm to a loved one) or are clearly excessive 
(e.g., showering for hours each day). Compulsions are not done for pleasure, although some 
individuals experience relief from anxiety or distress.
Criterion B emphasizes that obsessions and compulsions must be time-consuming (e.g.,

Criterion B emphasizes that obsessions and compulsions must be time-consuming (e.g., 
more than 1 hour per day) or cause clinically significant distress or impairment to warrant 
a diagnosis of OCD. This criterion helps to distinguish the disorder from the occasional in- 
tmsive thoughts or repetitive behaviors that are common in the general population (e.g., 
double-checking that a door is locked). The frequency and severity of obsessions and com­
pulsions vary across individuals with OCD (e.g., some have mild to moderate symptoms, 
spending 1-3 hours per day obsessing or doing compulsions, whereas others have nearly 
constant intmsive thoughts or compulsions that can be incapacitating).
The specific content of obsessions and compulsions varies between individuals. However, 
certain themes, or dimensions, are common, including those of cleaning (contamination

certain themes, or dimensions, are common, including those of cleaning (contamination 
obsessions and cleaning compulsions); symmetry (symmetry obsessions and repeating.

ordering, and counting compulsions); forbidden or taboo thoughts (e.g., aggressive, sexual, 
or religious obsessions and related compulsions); and harm (e.g., fears of harm to oneself 
or others and checking compulsions). Some individuals also have difficulties discarding 
and accumulate (hoard) objects as a consequence of typical obsessions and compulsions, 
such as fears of harming others. These themes occur across different cultures, are rela­
tively consistent over time in adults w ^ ith  the disorder, and may be associated v^ith differ­
ent neural substrates. Importantly, individuals often have symptoms in more than one 
dimension.
Individuals with OCD experience a range of affective responses when confronted with 
situations that trigger obsessions and compulsions. For example, many individuals expe­
rience marked anxiety that can include recurrent panic attacks. Others report strong feel­
ings of disgust. While performing compulsions, some individuals report a distressing

ings of disgust. While performing compulsions, some individuals report a distressing 
sense of "incompleteness" or uneasiness until things look, feel, or sound "just right."
It is common for individuals with the disorder to avoid people, places, and things that 
trigger obsessions and compulsions. For example, individuals with contamination con­
cerns might avoid public situations (e.g., restaurants, public restrooms) to reduce ex­
posure to feared contaminants; individuals with intrusive thoughts about causing harm 
might avoid social interactions.
The 12-month prevalence of OCD in the United States is 1.2%, with a similar prevalence in­
ternationally (1.1%-1.8%). Females are affected at a shghtly higher rate than males in 
adulthood, although males are more commonly affected in childhood.

In the United States, the mean age at onset of OCD is 19.5 years, and 25% of cases start by 
age 14 years. Onset after age 35 years is unusual but does occur. Males have an earlier age 
at onset than females: nearly 25% of males have onset before age 10 years. The onset of 
symptoms is typically gradual; however, acute onset has also been reported.
If OCD is untreated, the course is usually chronic, often with waxing and waning symp­
toms. Some individuals have an episodic course, and a minority have a deteriorating 
course. Without treatment, remission rates in adults are low (e.g., 20% for those reevalu­
ated 40 years later). Onset in childhood or adolescence can lead to a lifetime of OCD. How­
ever, 40% of individuals with onset of OCD in childhood or adolescence may experience

ever, 40% of individuals with onset of OCD in childhood or adolescence may experience 
remission by early adulthood. The course of OCD is often complicated by the co-occurrence 
of other disorders (see section "Comorbidity" for this disorder).
Compulsions are more easily diagnosed in children than obsessions are because com­
pulsions are observable. However, most children have both obsessions and compulsions 
(as do most adults). The pattern of symptoms in adults can be stable over time, but it is 
more variable in children. Some differences in the content of obsessions and compulsions 
have been reported when children and adolescent samples have been compared with 
adult samples. These differences likely reflect content appropriate to different develop­
mental stages (e.g., higher rates of sexual and religious obsessions in adolescents than in

mental stages (e.g., higher rates of sexual and religious obsessions in adolescents than in 
children; higher rates of harm obsessions [e.g., fears of catastrophic events, such as death 
or illness to self or loved ones] in children and adolescents than in adults).
Temperamental. Greater internalizing symptoms, higher negative emotionality, and 
behavioral inhibition in childhood are possible temperamental risk factors.
Environmental. Physical and sexual abuse in childhood and other stressful or traumatic 
events have been associated with an increased risk for developing OCD. Some children

may develop the sudden onset of obsessive-compulsive symptoms, v^hich has been asso­
ciated with different environmental factors, including various infectious agents and a 
post-infectious autoimmune syndrome.
Genetic and physiological. The rate of OCD among first-degree relatives of adults with 
OCD is approximately two times that among first-degree relatives of those without the 
disorder; however, among first-degree relatives of individuals with onset of OCD in child­
hood or adolescence, the rate is increased 10-fold. Familial transmission is due in part to 
genetic factors (e.g., a concordance rate of 0.57 for monozygotic vs. 0.22 for dizygotic twins). 
Dysfunction in the orbitofrontal cortex, anterior cingulate cortex, and striatum have been 
most strongly implicated.
OCD occurs across the world. There is substantial similarity across cultures in the gender

OCD occurs across the world. There is substantial similarity across cultures in the gender 
distribution, age at onset, and comorbidity of OCD. Moreover, around the globe, there is a 
similar symptom structure involving cleaning, symmetry, hoarding, taboo thoughts, or 
fear of harm. However, regional variation in symptom expression exists, and cultural 
factors may shape the content of obsessions and compulsions.
Males have an earlier age at onset of OCD than females and are more likely to have co- 
morbid tic disorders. Gender differences in the pattern of symptom dimensions have been 
reported, with, for example, females more likely to have symptoms in the cleaning dimen­
sion and males more likely to have symptoms in the forbidden thoughts and symmetry di­
mensions. Onset or exacerbation of OCD, as well as symptoms that can interfere with the

mensions. Onset or exacerbation of OCD, as well as symptoms that can interfere with the 
mother-infant relationship (e.g., aggressive obsessions leading to avoidance of the infant), 
have been reported in the péripartum period.
Suicidal thoughts occur at some point in as many as about half of individuals with OCD. 
Suicide attempts are also reported in up to one-quarter of individuals with OCD; the pres­
ence of comorbid major depressive disorder increases the risk.
OCD is associated with reduced quality of life as well as high levels of social and occupa­
tional impairment. Impairment occurs across many different domains of life and is asso­
ciated with symptom severity. Impairment can be caused by the time spent obsessing and 
doing compulsions. Avoidance of situations that can trigger obsessions or compulsions

doing compulsions. Avoidance of situations that can trigger obsessions or compulsions 
can also severely restrict functioning. In addition, specific symptoms can create specific 
obstacles. For example, obsessions about harm can make relationships with family and 
friends feel hazardous; the result can be avoidance of these relationships. Obsessions 
about symmetry can derail the timely completion of school or work projects because the 
project never feels "just right," potentially resulting in school failure or job loss. Health 
consequences can also occur. For example, individuals with contamination concerns may 
avoid doctors' offices and hospitals (e.g., because of fears of exposure to germs) or develop 
dermatological problems (e.g., skin lesions due to excessive washing). Sometimes the 
symptoms of the disorder interfere with its own treatment (e.g., when medications are con­

sidered contaminated). When the disorder starts in childhood or adolescence, individuals 
may experience developmental difficulties. For example, adolescents may avoid socializ­
ing with peers; young adults may struggle when they leave home to live independently.

The result can be few significant relationships outside the family and a lack of autonomy 
and financial independence from their family of origin. In addition, some individuals with 
OCD try to impose rules and prohibitions on family members because of their disorder 
(e.g., no one in the family can have visitors to the house for fear of contamination), and this 
can lead to family dysfunction.
Anxiety disorders. Recurrent thoughts, avoidant behaviors, and repetitive requests for 
reassurance can also occur in anxiety disorders. However, the recurrent thoughts that are 
present in generalized anxiety disorder (i.e., worries) are usually about real-life concerns, 
whereas the obsessions of OCD usually do not involve real-life concerns and can include 
content that is odd, irrational, or of a seemingly magical nature; moreover, compulsions 
are often present and usually linked to the obsessions. Like individuals with OCD, indi­

viduals with specific phobia can have a fear reaction to specific objects or situations; how­
ever, in specific phobia the feared object is usually much more circumscribed, and rituals 
are not present. In social anxiety disorder (social phobia), the feared objects or situations 
are limited to social interactions, and avoidance or reassurance seeking is focused on re­
ducing this social fear.
Major depressive disorder. OCD can be distinguished from the rumination of major 
depressive disorder, in which thoughts are usually mood-congruent and not necessarily 
experienced as intrusive or distressing; moreover, ruminations are not linked to compul­
sions, as is typical in OCD.
Other obsessive-compulsive and related disorders. In body dysmorphic disorder, the

Other obsessive-compulsive and related disorders. In body dysmorphic disorder, the 
obsessions and compulsions are limited to concerns about physical appearance; and in 
trichotillomania (hair-pulling disorder), the compulsive behavior is limited to hair pulling 
in the absence of obsessions. Hoarding disorder symptoms focus exclusively on the per­
sistent difficulty discarding or parting with possessions, marked distress associated with 
discarding items, and excessive accumulation of objects. However, if an individual has ob­
sessions that are typical of OCD (e.g., concerns about incompleteness or harm), and these 
obsessions lead to compulsive hoarding behaviors (e.g., acquiring all objects in a set to at­
tain a sense of completeness or not discarding old newspapers because they may contain 
information that could prevent harm), a diagnosis of OCD should be given instead.

Eating disorders. OCD can be distinguished from anorexia nervosa in that in OCD the 
obsessions and compulsions are not limited to concerns about weight and food.
Tics (in tic disorder) and stereotyped movements. A tic is a sudden, rapid, recurrent, 
nonrhythmic motor movement or vocalization (e.g., eye blinking, throat clearing). A ste­
reotyped movement  is a repetitive, seemingly driven, nonfunctional motor behavior (e.g., 
head banging, body rocking, self-biting). Tics and stereotyped movements are typically 
less complex than compulsions and are not aimed at neutralizing obsessions. However, 
distinguishing between complex tics and compulsions can be difficult. Whereas compul­
sions are usually preceded by obsessions, tics are often preceded by premonitory sensory

sions are usually preceded by obsessions, tics are often preceded by premonitory sensory 
urges. Some individuals have symptoms of both OCD and a tic disorder, in which case 
both diagnoses may be warranted.
Psychotic disorders. Some individuals with OCD have poor insight or even delusional 
OCD beliefs. However, they have obsessions and compulsions (distinguishing their 
condition from delusional disorder) and do not have other features of schizophrenia or 
schizoaffective disorder (e.g., hallucinations or formal thought disorder).
Other compulsive-like behaviors. Certain behaviors are sometimes described as ''com­
pulsive," including sexual behavior (in the case of paraphilias), gambling (i.e., gambling

disorder), and substance use (e.g., alcohol use disorder). However, these behaviors differ 
from the compulsions of OCD in that the person usually derives pleasure from the activity 
and may wish to resist it only because of its deleterious consequences.
Obsessive-compulsive personality disorder. Although obsessive-compulsive person­
ality disorder and OCD have similar names, the clinical manifestations of these disorders 
are quite different. Obsessive-compulsive personality disorder is not characterized by in­
trusive thoughts, images, or urges or by repetitive behaviors that are performed in re­
sponse to these intrusions; instead, it involves an enduring and pervasive maladaptive 
pattern of excessive perfectionism and rigid control. If an individual manifests symptoms 
of both OCD and obsessive-compulsive personality disorder, both diagnoses can be given.
Individuals with OCD often have other psychopathology. Many adults with the disorder

Individuals with OCD often have other psychopathology. Many adults with the disorder 
have a lifetime diagnosis of an anxiety disorder (76%; e.g., panic disorder, social anxiety 
disorder, generalized anxiety disorder, specific phobia) or a depressive or bipolar disorder 
(63% for any depressive or bipolar disorder, with the most common being major depres­
sive disorder [41%]). Onset of OCD is usually later than for most comorbid anxiety disor­
ders (with the exception of separation anxiety disorder) and PTSD but often precedes that 
of depressive disorders. Comorbid obsessive-compulsive personality disorder is also 
common in individuals with OCD (e.g., ranging from 23% to 32%).
Up to 30% of individuals with OCD also have a lifetime tic disorder. A comorbid tic 
disorder is most common in males with onset of OCD in childhood. These individuals

disorder is most common in males with onset of OCD in childhood. These individuals 
tend to differ from those without a history of tic disorders in the themes of their OCD 
symptoms, comorbidity, course, and pattern of familial transmission. A triad of OCD, tic 
disorder, and attention-deficit/hyperactivity disorder can also be seen in children.
Disorders that occur more frequently in individuals with OCD than in those without 
the disorder include several obsessive-compulsive and related disorders such as body 
dysmorphic disorder, trichotillomania (hair-pulling disorder), and excoriation (skin-pick­
ing) disorder. Finally, an association between OCD and some disorders characterized by 
impulsivity, such as oppositional defiant disorder, has been reported.
OCD is also much more common in individuals with certain other disorders than

OCD is also much more common in individuals with certain other disorders than 
would be expected based on its prevalence in the general population; when one of those 
other disorders is diagnosed, the individual should be assessed for OCD as well. For ex­
ample, in individuals with schizophrenia or schizoaffective disorder, the prevalence of 
OCD is approximately 12%. Rates of OCD are also elevated in bipolar disorder; eating dis­
orders, such as anorexia nervosa and bulimia nervosa; and Tourette's disorder.
Body Dysmorphic Disorder
Diagnostic Criteria 300.7 (F45.22)
A. Preoccupation with one or more perceived defects or flaws in  physical appearance that  
are not observable or appear slight to others.
B. At some point during the course of the disorder, the individual has performed repetitive  
behaviors (e.g., mirror checking, excessive grooming, skin picking, reassurance seek­

ing) or mental acts (e.g., comparing his or her appearance with that of others) in re­
sponse to the appearance concerns.
C. The preoccupation causes clinically significant distress or impairment in social, occu­
pational, or other important areas of functioning.
D. The appearance preoccupation is not better explained by concerns with body fat or  
weight in an individual whose symptoms meet diagnostic criteria for an eating disorder.

With muscle dysmorphia: The individual is preoccupied with the idea that his or her  
body build is too small or insufficiently muscular. This specifier is used even if the indi­
vidual is preoccupied with other body areas, which is often the case.
Indicate degree of insight regarding body dysmorphic disorder beliefs (e.g., “I look ugly”  or  
“I lo o l<  deformed” ).
With good or fair insight: The individual recognizes that the body dysmorphic disor­
der beliefs are definitely or probably not true or that they may or may not be true.
With poor insight: The individual thinks that the body dysmorphic disorder beliefs are  
With absent insight/delusionai beliefs: The individual is completely convinced that  
the body dysmorphic disorder beliefs are true.
Individuals with body dysmorphic disorder (formerly known as dysmorphophobia)  are pre­

occupied with one or more perceived defects or flaws in their physical appearance, which 
they believe look ugly, unattractive, abnormal, or deformed (Criterion A). The perceived 
flaws are not observable or appear only slight to other individuals. Concerns range from 
looking "unattractive" or "not right" to looking "hideous" or "like a monster." Preoccu­
pations can focus on one or many body areas, most commonly the skin (e.g., perceived 
acne, scars, lines, wrinkles, paleness), hair (e.g., "thinning" hair or "excessive" body or fa­
cial hair), or nose (e.g., size or shape). However, any body area can be the focus of concern 
(e.g., eyes, teeth, weight, stomach, breasts, legs, face size or shape, lips, chin, eyebrows, 
genitals). Some individuals are concerned about perceived asymmetry of body areas. The

genitals). Some individuals are concerned about perceived asymmetry of body areas. The 
preoccupations are intrusive, unwanted, time-consuming (occurring, on average, 3-8 
hours per day), and usually difficult to resist or control.
Excessive repetitive behaviors or mental acts (e.g., comparing) are performed in re­
sponse to the preoccupation (Criterion B). The individual feels driven to perform these be­
haviors, which are not pleasurable and may increase anxiety and dysphoria. They are 
typically time-consuming and difficult to resist or control. Common behaviors are com­
paring one's appearance with that of other individuals; repeatedly checking perceived 
defects in mirrors or other reflecting surfaces or examining them directly; excessively 
grooming (e.g., combing, styling, shaving, plucking, or pulling hair); camouflaging (e.g.,

grooming (e.g., combing, styling, shaving, plucking, or pulling hair); camouflaging (e.g., 
repeatedly applying makeup or covering disliked areas with such things as a hat, clothing, 
makeup, or hair); seeking reassurance about how the perceived flaws look; touching dis­
liked areas to check them; excessively exercising or weight lifting; and seeking cosmetic 
procedures. Some individuals excessively tan (e.g., to darken "pale" skin or diminish per­
ceived acne), repeatedly change their clothes (e.g., to camouflage perceived defects), or 
compulsively shop (e.g., for beauty products). Compulsive skin picking intended to 
improve perceived skin defects is common and can cause skin damage, infections, or 
ruptured blood vessels. The preoccupation must cause clinically significant distress or im­
pairment in social, occupational, or other important areas of functioning (Criterion C);

pairment in social, occupational, or other important areas of functioning (Criterion C); 
usually both are present. Body dysmoφhic disorder must be differentiated from an eating 
disorder.
Muscle dysmorphia,  a form of body dysmoφhic disorder occurring almost exclusively 
in males, consists of preoccupation with the idea that one's body is too small or insuffi­
ciently lean or muscular. Individuals with this form of the disorder actually have a nor­
mal-looking body or are even very muscular. They may also be preoccupied with other 
body areas, such as skin or hair. A majority (but not all) diet, exercise, and/or lift weights 
excessively, sometimes causing bodily damage. Some use potentially dangerous anabolic-

androgenic steroids and other substances to try to make their body bigger and more mus­
cular. Body dysmorphic disorder by proxy is a form of body dysmorphic disorder in 
which individuals are preoccupied with defects they perceive in another person's appear­
ance.
Insight regarding body dysmorphic disorder beliefs can range from good to absent/ 
delusional (i.e., delusional beliefs consisting of complete conviction that the individual's 
view of their appearance is accurate and undistorted). On average, insight is poor; one- 
third or more of individuals currently have delusional body dysmorphic disorder beliefs. 
Individuals with delusional body dysmorphic disorder tend to have greater morbidity in 
some areas (e.g., suicidality), but this appears accounted for by their tendency to have 
more severe body dysmorphic disorder symptoms.
Many individuals with body dysmorphic disorder have ideas or delusions of reference,

Many individuals with body dysmorphic disorder have ideas or delusions of reference, 
believing that other people take special notice of them or mock them because of how they 
look. Body dysmorphic disorder is associated with high levels of anxiety, social anxiety, 
social avoidance, depressed mood, neuroticism, and perfectionism as well as low extro­
version and low self-esteem. Many individuals are ashamed of their appearance and their 
excessive focus on how they look, and are reluctant to reveal their concerns to others. A 
majority of individuals receive cosmetic treatment to try to improve their perceived de­
fects. Dermatological treatment and surgery are most common, but any type (e.g., dental, 
electrolysis) may be received. Occasionally, individuals may perform surgery on them­
selves. Body dysmorphic disorder appears to respond poorly to such treatments and

selves. Body dysmorphic disorder appears to respond poorly to such treatments and 
sometimes becomes worse. Some individuals take legal action or are violent toward the 
clinician because they are dissatisfied with the cosmetic outcome.
Body dysmorphic disorder has been associated with executive dysfunction and visual 
processing abnormalities, with a bias for analyzing and encoding details rather than ho­
listic or configurai aspects of visual stimuli. Individuals with this disorder tend to have a 
bias for negative and threatening interpretations of facial expressions and ambiguous sce­
narios.
The point prevalence among U.S. adults is 2.4% (2.5% in females and 2.2% in males). Out­
side the United States (i.e., Germany), current prevalence is approximately 1.7%-1,8%, 
with a gender distribution similar to that in the United States. The current prevalence is

with a gender distribution similar to that in the United States. The current prevalence is 
9%-15% among dermatology patients, 7%-8% among U.S. cosmetic surgery patients, 3%- 
16% among international cosmetic surgery patients (most studies), 8% among adult orth­
odontia patients, and 10% among patients presenting for oral or maxillofacial surgery.
The mean age at disorder onset is 16-17 years, the median age at onset is 15 years, and the 
most common age at onset is 12-13 years. Two-thirds of individuals have disorder onset 
before age 18. Subclinical body dysmorphic disorder symptoms begin, on average, at age 
12 or 13 years. Subclinical concerns usually evolve gradually to the full disorder, although 
some individuals experience abrupt onset of body dysmorphic disorder. The disorder 
appears to usually be chronic, although improvement is likely when evidence-based

appears to usually be chronic, although improvement is likely when evidence-based 
treatment is received. The disorder's clinical features appear largely similar in children/ 
adolescents and adults. Body dysmoφhic disorder occurs in the elderly, but little is known 
about the disorder in this age group. Individuals with disorder onset before age 18 years 
are more likely to attempt suicide, have more comorbidity, and have gradual (rather than 
acute) disorder onset than those with adult-onset body dysmorphic disorder.

Environmental. "  Body dysmorphic disorder has been associated with high rates of child­
hood neglect and abuse.
Genetic and physiological. The prevalence of body dysmorphic disorder is elevated in 
first-degree relatives of individuals with obsessive-compulsive disorder (OCD).
Body dysmorphic disorder has been reported internationally. It appears that the disorder 
may have more similarities than differences across races and cultures but that cultural 
values and preferences may influence symptom content to some degree. Taijin kyofusho,  
included in the traditional Japanese diagnostic system, has a subtype similar to body dys­
morphic disorder: shubo-kyofu  ("the phobia of a deformed body").
Females and males appear to have more similarities than differences in terms of most clin­
ical features— for example, disliked body areas, types of repehtive behaviors, symptom

ical features— for example, disliked body areas, types of repehtive behaviors, symptom 
severity, suicidality, comorbidity, illness course, and receipt of cosmetic procedures for 
body dysmorphic disorder. However, males are more likely to have genital preoccupa­
tions, and females are more likely to have a comorbid eating disorder. Muscle dysmorphia 
occurs almost exclusively in males.
Rates of suicidal ideation and suicide attempts are high in both adults and children/ado­
lescents with body dysmorphic disorder. Furthermore, risk for suicide appears high in ad­
olescents. A substantial proportion of individuals attribute suicidal ideation or suicide 
attempts primarily to their appearance concerns. Individuals with body dysmorphic dis­
order have many risk factors for completed suicide, such as high rates of suicidal ideation

order have many risk factors for completed suicide, such as high rates of suicidal ideation 
and suicide attempts, demographic characteristics associated with suicide, and high rates 
of comorbid major depressive disorder.
Nearly all individuals with body dysmorphic disorder experience impaired psychosocial 
functioning because of their appearance concerns. Impairment can range from moderate 
(e.g., avoidance of some social situations) to extreme and incapacitating (e.g., being com­
pletely housebound). On average, psychosocial functioning and quality of life are mark­
edly poor. More severe body dysmorphic disorder symptoms are associated with poorer 
functioning and quality of life. Most individuals experience impairment in their job, aca­
demic, or role functioning (e.g., as a parent or caregiver), which is often severe (e.g., per­

forming poorly, missing school or work, not working). About 20% of youths with body 
dysmorphic disorder report dropping out of school primarily because of their body dys­
morphic disorder symptoms. Impairment in social functioning (e.g., social activities, rela­
tionships, intimacy), including avoidance, is common. Individuals may be housebound 
because of their body dysmorphic disorder symptoms, sometimes for years. A high pro­
portion of adults and adolescents have been psychiatrically hospitalized.
Normal appearance concerns and clearly noticeable physical defects. Body dysmor­
phic disorder differs from normal appearance concerns in being characterized by exces­

sive appearance-related preoccupations and repetitive behaviors that are time-consuming, 
are usually difficult to resist or control, and cause clinically significant distress or impair­
ment in functioning. Physical defects that are clearly noticeable (i.e., not slight) are not 
diagnosed as body dysmorphic disorder. However, skin picking as a symptom of body 
dysmoφhic disorder can cause noticeable skin lesions and scarring; in such cases, body dys­
morphic disorder should be diagnosed.
Eating disorders. In an individual with an eating disorder, concerns about being fat are 
considered a symptom of the eating disorder rather than body dysmorphic disorder. 
However, weight concerns may occur in body dysmorphic disorder. Eating disorders and 
body dysmorphic disorder can be comorbid, in which case both should be diagnosed.
Other obsessive-compulsive and related disorders. The preoccupations and repetitive

Other obsessive-compulsive and related disorders. The preoccupations and repetitive 
behaviors of body dysmorphic disorder differ from obsessions and compulsions in OCD 
in that the former focus only on appearance. These disorders have other differences, such 
as poorer insight in body dysmoφhic disorder. When skin picking is intended to improve 
the appearance of perceived skin defects, body dysmorphic disorder, rather than excoria­
tion (skin-picking) disorder, is diagnosed. When hair removal (plucking, pulling, or other 
types of removal) is intended to improve perceived defects in the appearance of facial 
or body hair, body dysmoφhic disorder is diagnosed rather than trichotillomania (hair- 
pulling disorder).
Illness anxiety disorder. Individuals with body dysmorphic disorder are not preoccu­
pied with having or acquiring a serious illness and do not have particularly elevated levels

pied with having or acquiring a serious illness and do not have particularly elevated levels 
of somatization.
Major depressive disorder. The prominent preoccupation with appearance and exces­
sive repetitive behaviors in body dysmorphic disorder differentiate it from major de­
pressive disorder. However, major depressive disorder and depressive symptoms are 
common in individuals with body dysmoφhic disorder, often appearing to be secondary 
to the distress and impairment that body dysmorphic disorder causes. Body dysmoφhic 
disorder should be diagnosed in depressed individuals if diagnostic criteria for body dys- 
moφhic disorder are met.
Anxiety disorders. Social anxiety and avoidance are common in body dysmorphic dis­
order. However, unlike social anxiety disorder (social phobia), agoraphobia, and avoidant

order. However, unlike social anxiety disorder (social phobia), agoraphobia, and avoidant 
personality disorder, body dysmorphic disorder includes prominent appearance-related 
preoccupation, which may be delusional, and repetitive behaviors, and the social anxiety 
and avoidance are due to concerns about perceived appearance defects and the belief or 
fear that other people will consider these individuals ugly, ridicule them, or reject them be­
cause of their physical features. Unlike generalized anxiety disorder, anxiety and worry in 
body dysmoφhic disorder focus on perceived appearance flaws.
Psychotic disorders. Many individuals with body dysmorphic disorder have delu­
sional appearance beliefs (i.e., complete conviction that their view of their perceived de­
fects is accurate), which is diagnosed as body dysmoφhic disorder, with absent insight/

fects is accurate), which is diagnosed as body dysmoφhic disorder, with absent insight/ 
delusional beliefs, not as delusional disorder. Appearance-related ideas or delusions of 
reference are common in body dysmorphic disorder; however, unlike schizophrenia or 
schizoaffective disorder, body dysmoφhic disorder involves prominent appearance pre­
occupations and related repetitive behaviors, and disorganized behavior and other psy­
chotic symptoms are absent (except for appearance beliefs, which may be delusional).
Other disorders and symptoms. Body dysmorphic disorder should not be diagnosed if 
the preoccupation is limited to discomfort with or a desire to be rid of one's primary and/ 
or secondary sex characteristics in an individual with gender dysphoria or if the preoccu­
pation focuses on the belief that one emits a foul or offensive body odor as in olfactory

pation focuses on the belief that one emits a foul or offensive body odor as in olfactory 
reference syndrome (which is not a DSM-5 disorder). Body identity integrity disorder

(apotemnophilia) (which is not a DSM-5 disorder) involves a desire to have a limb ampu­
tated to correct ^n experience of mismatch between a person's sense of body identity and 
his or her actual anatomy. However, the concern does not focus on the limb's appearance, 
as it would in body dysmorphic disorder. Koro,  a culturally related disorder that usually 
occurs in epidemics in Southeastern Asia, consists of a fear that the penis (labia, nipples, or 
breasts in females) is shrinking or retracting and will disappear into the abdomen, often 
accompanied by a belief that death will result. Koro differs from body dysmorphic disor­
der in several ways, including a focus on death rather than preoccupation with perceived 
ugliness. Dysmorphic concern  (which is not a DSM-5 disorder) is a much broader construct 
than, and is not equivalent to, body dysmorphic disorder. It involves symptoms reflecting 
an overconcern with slight or imagined flaws in appearance.

Major depressive disorder is the most common comorbid disorder, with onset usually af­
ter that of body dysmorphic disorder. Comorbid social anxiety disorder (social phobia), 
OCD, and substance-related disorders are also common.
Hoarding Disorder
A. Persistent difficulty discarding or parting with possessions, regardless of their actual value.
B. This difficulty is due to a perceived need to save the items and to distress associated  
with discarding them.
C. The difficulty discarding possessions results in  the accumulation of possessions that  
congest and clutter active living areas and substantially compromises their intended  
use. If living areas are uncluttered, it is only because of the interventions of third parties  
(e.g., family members, cleaners, authorities).

D. The hoarding causes clinically significant distress or impairment in social, occupa­
tional, or other important areas of functioning (including maintaining a safe environ­
ment for self and others).
E. The hoarding is not attributable to another medical condition (e.g., brain injury, cere­
brovascular disease, Prader-Willi syndrome).
F. The hoarding is not better explained by the symptoms of another mental disorder (e.g.,  
obsessions in obsessive-compulsive disorder, decreased energy in major depressive  
disorder, delusions in  schizophrenia or another psychotic disorder, cognitive deficits in  
major neurocognitive disorder, restricted interests in autism spectrum disorder).
With excessive acquisition: If difficulty discarding possessions is accompanied by ex­

cessive acquisition of items that are not needed or for which there is no available space.
With good or fair insight: The individual recognizes that hoarding-related beliefs and  
behaviors (pertaining to difficulty discarding items, clutter, or excessive acquisition) are  
problematic.
With poor insight: The individual is mostly convinced that hoarding-related beliefs  
and behaviors (pertaining to difficulty discarding items, clutter, or excessive acquisi­
tion) are not problematic despite evidence to the contrary.
With absent insight/deiusionai beliefs: The individual is completely convinced that  
hoarding-related beliefs and behaviors (pertaining to difficulty discarding items, clutter,  
or excessive acquisition) are not problematic despite evidence to the contrary.

With excessive acquisition. Approximately 80%-90% of individuals with hoarding 
disorder display excessive acquisition. The most frequent form of acquisition is excessive 
buying, followed by acquisition of free items (e.g., leaflets, items discarded by others). 
Stealing is less common. Some individuals may deny excessive acquisition when first as­
sessed, yet it may appear later during the course of treatment. Individuals with hoarding 
disorder typically experience distress if they are unable to or are prevented from acquiring 
items.
The essential feature of hoarding disorder is persistent difficulties discarding or parting 
with possessions, regardless of their actual value (Criterion A). The term persistent  indi­
cates a long-standing difficulty rather than more transient life circumstances that may lead 
to excessive clutter, such as inheriting property. The difficulty in discarding possessions

to excessive clutter, such as inheriting property. The difficulty in discarding possessions 
noted in Criterion A refers to any form of discarding, including throwing away, selling, 
giving away, or recycling. The main reasons given for these difficulties are the perceived 
utility or aesthetic value of the items or strong sentimental attachment to the possessions. 
Some individuals feel responsible for the fate of their possessions and often go to great 
lengths to avoid being wasteful. Fears of losing important information are also common. 
The most commonly saved items are newspapers, magazines, old clothing, bags, books, 
mail, and paperwork, but virtually any item can be saved. The nature of items is not lim­
ited to possessions that most other people would define as useless or of limited value. 
Many individuals collect and save large numbers of valuable things as well, which are of­

ten found in piles mixed with other less valuable items.
Individuals with hoarding disorder purposefully save possessions and experience dis­
tress when facing the prospect of discarding them (Criterion B). This criterion emphasizes 
that the saving of possessions is intentional, which discriminates hoarding disorder from 
other forms of psychopathology that are characterized by the passive accumulation of 
items or the absence of distress when possessions are removed.
Individuals accumulate large numbers of items that fill up and clutter active living ar­
eas to the extent that their intended use is no longer possible (Criterion C). For example, 
the individual may not be able to cook in the kitchen, sleep in his or her bed, or sit in a

the individual may not be able to cook in the kitchen, sleep in his or her bed, or sit in a 
chair. If the space can be used, it is only with great difficulty. Clutter  is defined as a large 
group of usually unrelated or marginally related objects piled together in a disorganized 
fashion in spaces designed for other purposes (e.g., tabletops, floor, hallway). Criterion C 
emphasizes the ''active" living areas of the home, rather than more peripheral areas, such 
as garages, attics, or basements, that are sometimes cluttered in homes of individuals with­
out hoarding disorder. However, individuals with hoarding disorder often have posses­
sions that spill beyond the active living areas and can occupy and impair the use of other 
spaces, such as vehicles, yards, the workplace, and friends' and relatives' houses. In some

spaces, such as vehicles, yards, the workplace, and friends' and relatives' houses. In some 
cases, living areas may be uncluttered because of the intervention of third parties (e.g., 
family members, cleaners, local authorities). Individuals who have been forced to clear 
their homes still have a symptom picture that meets criteria for hoarding disorder because 
the lack of clutter is due to a third-party intervention. Hoarding disorder contrasts with 
normative collecting behavior, which is organized and systematic, even if in some cases 
the actual amount of possessions may be similar to the amount accumulated by an indi­
vidual with hoarding disorder. Normative collecting does not produce the clutter, dis­
tress, or impairment typical of hoarding disorder.
Symptoms (i.e., difficulties discarding and/or clutter) must cause clinically significant

Symptoms (i.e., difficulties discarding and/or clutter) must cause clinically significant 
distress or impairment in social, occupational, or other important areas of functioning, in­
cluding maintaining a safe environment for self and others (Criterion D). In some cases.

particularly when there is poor insight, the individual may not report distress, and the im­
pairment may apparent only to those around the individual. Hov^ever, any attempts to 
discard or clear the possessions by third parties result in high levels of distress.
Other common features of hoarding disorder include indecisiveness, perfectionism, 
avoidance, procrastination, difficulty planning and organizing tasks, and distractibility. 
Some individuals with hoarding disorder live in unsanitary conditions that may be a log­
ical consequence of severely cluttered spaces and/or that are related to planning and or­
ganizing difficulties. Animal hoarding  can be defined as the accumulation of a large number 
of animals and a failure to provide minimal standards of nutrition, sanitation, and veter­
inary care and to act on the deteriorating condition of the animals (including disease, star­

vation, or death) and the environment (e.g., severe overcrowding, extremely unsanitary 
conditions). Animal hoarding may be a special manifestation of hoarding disorder. Most 
individuals who hoard animals also hoard inanimate objects. The most prominent differ­
ences between animal and object hoarding are the extent of unsanitary conditions and the 
poorer insight in animal hoarding.
Nationally representative prevalence studies of hoarding disorder are not available. Com­
munity surveys estimate the point prevalence of clinically significant hoarding in the 
United States and Europe to be approximately 2%-6%. Hoarding disorder affects both 
males and females, but some epidemiological studies have reported a significantly greater

males and females, but some epidemiological studies have reported a significantly greater 
prevalence among males. This contrasts with clinical samples, which are predominantly 
female. Hoarding symptoms appear to be almost three times more prevalent in older 
adults (ages 55-94 years) compared with younger adults (ages 34-44 years).
Hoarding appears to begin early in life and spans well into the late stages. Hoarding symp­
toms may first emerge around ages 11-15 years, start interfering with the individual's ev­
eryday functioning by the mid-20s, and cause clinically significant impairment by the 
mid-30s. Participants in clinical research studies are usually in their 50s. Thus, the severity 
of hoarding increases with each decade of life. Once symptoms begin, the course of hoard­
ing is often chronic, with few individuals reporting a waxing and waning course.

Pathological hoarding in children appears to be easily distinguished from develop­
mentally adaptive saving and collecting behaviors. Because children and adolescents 
typically do not control their living environment and discarding behaviors, the possible 
intervention of third parties (e.g., parents keeping the spaces usable and thus reducing in­
terference) should be considered when making the diagnosis.
Temperamental. Indecisiveness is a prominent feature of individuals with hoarding dis­
order and their first-degree relatives.
Environmental. Individuals with hoarding disorder often retrospectively report stressful 
and traumatic life events preceding the onset of the disorder or causing an exacerbation.

Genetic and physiological. Hoarding behavior is familial, with about 50% of individu­
als who hoard reporting having a relative who also hoards. Twin studies indicate that ap­
proximately 50% of the variability in hoarding behavior is attributable to additive genetic 
factors.

While most of the research has been done in Western, industrialized countries and urban 
communities, the available data from non-Western and developing countries suggest that 
hoarding is a universal phenomenon with consistent clinical features.
The key features of hoarding disorder (i.e., difficulties discarding, excessive amount of 
clutter) are generally comparable in males and females, but females tend to display more 
excessive acquisition, particularly excessive buying, than do males.
Functional Consequences of Hoarding Disorder
Clutter impairs basic activities, such as moving through the house, cooking, cleaning, per­
sonal hygiene, and even sleeping. Appliances may be broken, and utilities such as water 
and electricity may be disconnected, as access for repair work may be difficult. Quality of 
life is often considerably impaired. In severe cases, hoarding can put individuals at risk for

life is often considerably impaired. In severe cases, hoarding can put individuals at risk for 
fire, falling (especially elderly individuals), poor sanitation, and other health risks. Hoard­
ing disorder is associated with occupational impairment, poor physical health, and high 
social service utilization. Family relationships are frequently under great strain. Conflict 
with neighbors and local authorities is common, and a substantial proportion of individ­
uals with severe hoarding disorder have been involved in legal eviction proceedings, and 
some have a history of eviction.
Other medical conditions. Hoarding disorder is not diagnosed if the symptoms are 
judged to be a direct consequence of another medical condition (Criterion E), such as trau­
matic brain injury, surgical resection for treatment of a tumor or seizure control, cerebro­

vascular disease, infections of the central nervous system (e.g., herpes simplex encephalitis), 
or neurogenetic conditions such as Prader-Willi syndrome. Damage to the anterior ven­
tromedial prefrontal and cingulate cortices has been particularly associated with the ex­
cessive accumulation of objects. In these individuals, the hoarding behavior is not present 
prior to the onset of the brain damage and appears shortly after the brain damage occurs. 
Some of these individuals appear to have little interest in the accumulated items and are 
able to discard them easily or do not care if others discard them, whereas others appear to 
be very reluctant to discard anything.
Neurodevelopmental disorders. Hoarding disorder is not diagnosed if the accumula­

tion of objects is judged to be a direct consequence of a neurodevelopmental disorder, such 
as autism spectrum disorder or intellectual disability (intellectual developmental disorder).
Schizophrenia spectrum and other psychotic disorders. Hoarding disorder is not di­
agnosed if the accumulation of objects is judged to be a direct consequence of delusions or 
negative symptoms in schizophrenia spectrum and other psychotic disorders.
Major depressive episode. Hoarding disorder is not diagnosed if the accumulation of 
objects is judged to be a direct consequence of psychomotor retardation, fatigue, or loss of 
energy during a major depressive episode.
Obsessive-compulsive disorder. Hoarding disorder is not diagnosed if the symptoms 
are judged to be a direct consequence of typical obsessions or compulsions, such as fears

are judged to be a direct consequence of typical obsessions or compulsions, such as fears 
of contamination, harm, or feelings of incompleteness in obsessive-compulsive disorder 
(OCD). Feelings of incompleteness (e.g., losing one's identity, or having to document and 
preserve all life experiences) are the most frequent OCD symptoms associated with this 
form of hoarding. The accumulation of objects can also be the result of persistently avoid­

ing onerous rituals (e.g., not discarding objects in order to avoid endless washing or check­
ing rituals). \
In OCD, the behavior is generally unwanted and highly distressing, and the individual ex­
periences no pleasure or reward from it. Excessive acquisition is usually not present; if exces­
sive acquisition is present, items are acquired because of a specific obsession (e.g., the need to 
buy items that have been accidentally touched in order to avoid contaminating other people), 
not because of a genuine desire to possess the items. Individuals who hoard in the context of 
OCD are also more likely to accumulate bizarre items, such as trash, feces, urine, nails, hair, 
used diapers, or rotten food. Accumulation of such items is very unusual in hoarding disorder.
When severe hoarding appears concurrently with other typical symptoms of OCD but 
is judged to be independent from these symptoms, both hoarding disorder and OCD may 
be diagnosed.

Neurocognitive disorders. Hoarding disorder is not diagnosed if the accumulation of 
objects is judged to be a direct consequence of a degenerative disorder, such as neurocog­
nitive disorder associated with frontotemporal lobar degeneration or Alzheimer's disease. 
Typically, onset of the accumulating behavior is gradual and follows onset of the neuro­
cognitive disorder. The accumulating behavior may be accompanied by self-neglect and 
severe domestic squalor, alongside other neuropsychiatric symptoms, such as disinhibi­
tion, gambling, rituals/stereotypies, tics, and self-injurious behaviors.
Approximately 75% of individuals with hoarding disorder have a comorbid mood or anx­
iety disorder. The most common comorbid conditions are major depressive disorder (up

iety disorder. The most common comorbid conditions are major depressive disorder (up 
to 50% of cases), social anxiety disorder (social phobia), and generalized anxiety disorder. 
Approximately 20% of individuals with hoarding disorder also have symptoms that meet 
diagnostic criteria for OCD. These comorbidities may often be the main reason for consul­
tation, because individuals are unlikely to spontaneously report hoarding symptoms, and 
these symptoms are often not asked about in routine clinical interviews.
Trichotillomania (Hair-Pulling Disorder)
Diagnostic Criteria 312.39 (F63.2)
A. Recurrent pulling out of one’s hair, resulting in hair loss.
B. Repeated attempts to decrease or stop hair pulling.
C. The hair pulling causes clinically significant distress or impairment in social, occupa­

D. The hair pulling or hair loss is not attributable to another medical condition (e.g., a der-  
matological condition).
E. The hair pulling is not better explained by the symptoms of another mental disorder  
(e.g., attempts to improve a perceived defect or flaw in appearance in body dysmorphic  
The essential feature of trichotillomania (hair-pulling disorder) is the recurrent pulling out 
of one's own hair (Criterion A). Hair pulling may occur from any region of the body in 
which hair grows; the most common sites are the scalp, eyebrows, and eyelids, while less 
common sites are axillary, facial, pubic, and peri-rectal regions. Hair-pulling sites may 
vary over time. Hair pulling may occur in brief episodes scattered throughout the day or

vary over time. Hair pulling may occur in brief episodes scattered throughout the day or 
during less frequent but more sustained periods that can continue for hours, and such hair

pulling may endure for months or years. Criterion A requires that hair pulling lead to hair 
loss, although individuals with this disorder may pull hair in a widely distributed pattern 
(i.e., pulling single hairs from all over a site) such that hair loss may not be clearly visible. 
Alternatively, individuals may attempt to conceal or camouflage hair loss (e.g., by using 
makeup, scarves, or wigs). Individuals with trichotillomania have made repeated at­
tempts to decrease or stop hair pulling (Criterion B). Criterion C indicates that hair pulling 
causes clinically significant distress or impairment in social, occupational, or other impor­
tant areas of functioning. The term distress  includes negative affects that may be experi­
enced by individuals with hair pulling, such as feeling a loss of control, embarrassment, 
and shame. Significant impairment may occur in several different areas of functioning

and shame. Significant impairment may occur in several different areas of functioning 
(e.g., social, occupational, academic, and leisure), in part because of avoidance of work, 
school, or other public situations.
Hair pulling may be accompanied by a range of behaviors or rituals involving hair. Thus, 
individuals may search for a particular kind of hair to pull (e.g., hairs with a specific tex­
ture or color), may try to pull out hair in a specific way (e.g., so that the root comes out in­
tact), or may visually examine or tactilely or orally manipulate the hair after it has been 
pulled (e.g., rolling the hair between the fingers, pulling the strand between the teeth, bit­
ing the hair into pieces, or swallowing the hair).
Hair pulling may also be preceded or accompanied by various emotional states; it may

Hair pulling may also be preceded or accompanied by various emotional states; it may 
be triggered by feelings of anxiety or boredom, may be preceded by an increasing sense of 
tension (either immediately before pulling out the hair or when attempting to resist the 
urge to pull), or may lead to gratification, pleasure, or a sense of relief when the hair is 
pulled out. Hair-pulling behavior may involve varying degrees of conscious awareness, 
with some individuals displaying more focused attention on the hair pulling (with pre­
ceding tension and subsequent relief), and other individuals displaying more automatic 
behavior (in which the hair pulling seems to occur without full awareness). Many individ­
uals report a mix of both behavioral styles. Some individuals experience an "itch-like" or 
tingling sensation in the scalp that is alleviated by the act of pulling hair. Pain does not 
usually accompany hair pulling.

Patterns of hair loss are highly variable. Areas of complete alopecia, as well as areas of 
thinned hair density, are common. When the scalp is involved, there may be a predilection 
for pulling out hair in the crown or parietal regions. There may be a pattern of nearly com­
plete baldness except for a narrow perimeter around the outer margins of the scalp, par­
ticularly at the nape of the neck ("tonsure trichotillomania"). Eyebrows and eyelashes may 
be completely absent.
Hair pulling does not usually occur in the presence of other individuals, except imme­
diate family members. Some individuals have urges to pull hair from other individuals 
and may sometimes try to find opportunities to do so surreptitiously. Some individuals 
may pull hairs from pets, dolls, and other fibrous materials (e.g., sweaters or carpets).

may pull hairs from pets, dolls, and other fibrous materials (e.g., sweaters or carpets). 
Some individuals may deny their hair pulling to others. The majority of individuals with 
trichotillomania also have one or more other body-focused repetitive behaviors, including 
skin picking, nail biting, and lip chewing.
In the general population, the 12-month prevalence estimate for trichotillomania in adults 
and adolescents is l%-2%. Females are more frequently affected than males, at a ratio of 
approximately 10:1. This estimate likely reflects the true gender ratio of the condition, al­
though it may also reflect differential treatment seeking based on gender or cultural at­
titudes regarding appearance (e.g., acceptance of normative hair loss among males). 
Among children with trichotillomania, males and females are more equally represented.

Hair pulling maÿ be seen in infants, and this behavior typically resolves during early devel­
opment. Onset of hair pulling in trichotillomania most commonly coincides with, or follows 
the onset of, puberty. Sites of hair pulling may vary over time. The usual course of trichotillo­
mania is chronic, with some waxing and waning if the disorder is untreated. Symptoms may 
possibly worsen in females accompanying hormonal changes (e.g., menstruation, perimeno­
pause). For some individuals, the disorder may come and go for weeks, months, or years at a 
time. A minority of individuals remit without subsequent relapse within a few years of onset.
Genetic and physiological. There is evidence for a genetic vulnerability to trichotillo­
mania. The disorder is more common in individuals with obsessive-compulsive disorder 
(OCD) and their first-degree relatives than in the general population.

Trichotillomania appears to manifest similarly across cultures, although there is a paucity 
of data from non-Westem regions.
Most individuals with trichotillomania admit to hair pulling; thus, dermatopathological 
diagnosis is rarely required. Skin biopsy and dermoscopy (or trichoscopy) of trichotillo­
mania are able to differentiate the disorder from other causes of alopecia. In trichotil­
lomania, dermoscopy shows a range of characteristic features, including decreased hair 
density, short vellus hair, and broken hairs with different shaft lengths.
Triciiotiiiomania (Hair-Puliing Disorder)
Trichotillomania is associated with distress as well as with social and occupational impair­

ment. There may be irreversible damage to hair growth and hair quality. Infrequent med­
ical consequences of trichotillomania include digit purpura, musculoskeletal injury (e.g., 
carpal tunnel syndrome; back, shoulder and neck pain), blepharitis, and dental damage 
(e.g., worn or broken teeth due to hair biting). Swallowing of hair (trichophagia) may lead 
to trichobezoars, with subsequent anemia, abdominal pain, hematemesis, nausea and 
vomiting, bowel obstruction, and even perforation.
Normative hair removal/manipulation. Trichotillomania should not be diagnosed when 
hair removal is performed solely for cosmetic reasons (i.e., to improve one's physical ap­
pearance). Many individuals twist and play with their hair, but this behavior does not usu­

ally qualify for a diagnosis of trichotillomania. Some individuals may bite rather than pull 
hair; again, this does not qualify for a diagnosis of trichotillomania.
Other obsessive-compulsive and related disorders. Individuals with OCD and sym­
metry concerns may pull out hairs as part of their symmetry rituals, and individuals with 
body dysmorphic disorder may remove body hair that they perceive as ugly, asymmetri­
cal, or abnormal; in such cases a diagnosis of trichotillomania is not given. The description 
of body-focused repetitive behavior disorder in other specified obsessive-compulsive and 
related disorder excludes individuals who meet diagnostic criteria for trichotillomania.

Neurodevelopmental disorders. In neurodevelopmental disorders, hair pulling may 
meet the definition of stereotypies (e.g., in stereotypic movement disorder). Tics (in tic dis­
orders) rarely lead to hair pulling.
Psychotic disorder. Individuals with a psychotic disorder may remove hair in response 
to a delusion or hallucination. Trichotillomania is not diagnosed in such cases.
Another medical condition. Trichotillomania is not diagnosed if the hair pulling or hair 
loss is attributable to another medical condition (e.g., inflammation of the skin or other der- 
matological conditions). Other causes of scarring alopecia (e.g., alopecia areata, androgenic 
alopecia, telogen effluvium) or nonscarring alopecia (e.g., chronic discoid lupus erythema­
tosus, lichen planopilaris, central centrifugal cicatricial alopecia, pseudopelade, folliculitis 
decalvans, dissecting foUiculitis, acne keloidalis nuchae) should be considered in individu­

als with hair loss who deny hair pulling. Skin biopsy or dermoscopy can be used to differ­
entiate individuals with trichotillomania from those with dermatological disorders.
Substance-related disorders. Hair-pulling symptoms may be exacerbated by certain 
substances—for example, stimulants—^ b u t it is less likely that substances are the primary 
cause of persistent hair pulling.
Trichotillomania is often accompanied by other mental disorders, most commonly major 
depressive disorder and excoriation (skin-picking) disorder. Repetitive body-focused 
symptoms other than hair pulling or skin picking (e.g. nail biting) occur in the majority of 
individuals with trichotillomania and may deserve an additional diagnosis of other spec­

ified obsessive-compulsive and related disorder (i.e., body-focused repetitive behavior 
Excoriation (Skin-Picking) Disorder
Diagnostic Criteria 698.4 (L98.1)
A. Recurrent skin picking resulting in skin lesions.
B. Repeated attempts to decrease or stop skin picking.
C. The skin picking causes clinically significant distress or impairment in social, occupa­
D. The skin picking is not attributable to the physiological effects of a substance (e.g., co­
caine) or another medical condition (e.g., scabies).
E. The skin picking is not better explained by symptoms of another mental disorder (e.g.,  
delusions or tactile hallucinations in a psychotic disorder, attempts to improve a per­

ceived defect or flaw in appearance in body dysmorphic disorder, stereotypies in ste­
reotypic movement disorder, or intention to harm oneself in nonsuicidal self-injury).
The essential feature of excoriation (skin-picking) disorder is recurrent picking at one's 
own skin (Criterion A). The most commonly picked sites are the face, arms, and hands, but 
many individuals pick from multiple body sites. Individuals may pick at healthy skin, at 
minor skin irregularities, at lesions such as pimples or calluses, or at scabs from previous 
picking. Most individuals pick with their fingernails, although many use tweezers, pins, 
or other objects. In addition to skin picking, there may be skin rubbing, squeezing, lancing,

or other objects. In addition to skin picking, there may be skin rubbing, squeezing, lancing, 
and biting. Individuals with excoriation disorder often spend significant amounts of time 
on their picking behavior, sometimes several hours per day, and such skin picking may

endure for months or years. Criterion A requires that skin picking lead to skin lesions, al­
though individu^als with this disorder often attempt to conceal or camouflage such lesions 
(e.g., with makeup or clothing). Individuals with excoriation disorder have made repeated 
attempts to decrease or stop skin picking (Criterion B).
Criterion C indicates that skin picking causes clinically significant distress or impair­
ment in social, occupational, or other important areas of functioning. The term distress  in­
cludes negative affects that may be experienced by individuals with skin picking, such as 
feeling a loss of control, embarrassment, and shame. Significant impairment may occur in 
several different areas of functioning (e.g., social, occupational, academic, and leisure), in 
part because of avoidance of social situations.
Skin picking may be accompanied by a range of behaviors or rihials involving skin or scabs.

Skin picking may be accompanied by a range of behaviors or rihials involving skin or scabs. 
Thus, individuals may search for a particular kind of scab to pull, and they may examine, 
play with, or mouth or swallow the skin after it has been pulled. Skin picking may also be pre­
ceded or accompanied by various emotional states. Skin picking may be triggered by feelings 
of anxiety or boredom, may be preceded by an increasing sense of tension (either immedi­
ately before picking the skin or when attempting to resist the urge to pick), and may lead to 
gratification, pleasure, or a sense of relief when the skin or scab has been picked. Some indi­
viduals report picking in response to a minor skin irregularity or to relieve an uncomfortable 
bodily sensation. Pain is not routinely reported to accompany skin picking. Some individuals

bodily sensation. Pain is not routinely reported to accompany skin picking. Some individuals 
engage in skin picking that is more focused (i.e., with preceding tension and subsequent re­
lief), whereas others engage in more automatic picking (i.e., when skin picking occurs with­
out preceding tension and without full awareness), and many have a mix of both behavioral 
styles. Skin picking does not usually occur in the presence of other individuals, except im­
mediate faniily members. Some individuals report picking the skin of others.
In the general population, the lifetime prevalence for excoriation disorder in adults is 1.4% 
or somewhat higher. Three-quarters or more of individuals with the disorder are female. 
This likely reflects the true gender ratio of the condition, although it may also reflect dif­

ferential treatment seeking based on gender or cultural attitudes regarding appearance.
Although individuals with excoriation disorder may present at various ages, the skin pick­
ing most often has onset during adolescence, commonly coinciding with or following the 
onset of puberty. The disorder frequently begins with a dermatological condition, such 
as acne. Sites of skin picking may vary over time. The usual course is chronic, with some 
waxing and waning if untreated. For some individuals, the disorder may come and go for 
weeks, months, or years at a time.
R isk  and Prognostic Factors
Genetic and physiological. Excoriation disorder is more common in individuals with 
obsessive-compulsive disorder (OCD) and their first-degree family members than in the 

Most individuals with excoriation disorder admit to skin picking; therefore, dermato- 
pathological diagnosis is rarely required. However, the disorder may have characteristic 
features on histopathology.

Excoriation (Sl(in-Picicing) Disorder
Excoriation disorder is associated with distress as well as with social and occupational im­
pairment. The majority of individuals with this condition spend at least 1  hour per day 
picking, thinking about picking, and resisting urges to pick. Many individuals report 
avoiding social or entertainment events as well as going out in public. A majority of indi­
viduals with the disorder also report experiencing work interference from skin picking on 
at least a daily or weekly basis. A significant proportion of students with excoriation disor­
der report having missed school, having experienced difficulties managing responsibilities 
at school, or having had difficulties studying because of skin picking. Medical complica­
tions of skin picking include tissue damage, scarring, and infection and can be life-threaten­
ing. Rarely, synovitis of the wrists due to chronic picking has been reported. Skin picking

ing. Rarely, synovitis of the wrists due to chronic picking has been reported. Skin picking 
often results in significant tissue damage and scarring. It frequently requires antibiotic treat­
ment for infection, and on occasion it may require surgery.
Psychotic disorder. Skin picking may occur in response to a delusion (i.e., parasitosis) 
or tactile hallucination (i.e., formication) in a psychotic disorder. In such cases, excoriation 
Other obsessive-compulsive and related disorders. Excessive washing compulsions 
in response to contamination obsessions in individuals with OCD may lead to skin lesions, 
and skin picking may occur in individuals with body dysmorphic disorder who pick their 
skin solely because of appearance concerns; in such cases, excoriation disorder should not

skin solely because of appearance concerns; in such cases, excoriation disorder should not 
be diagnosed. The description of body-focused repetitive behavior disorder in other spec­
ified obsessive-compulsive and related disorder excludes individuals whose symptoms 
meet diagnostic criteria for excoriation disorder.
Neurodevelopmental disorders. While stereotypic movement disorder may be charac­
terized by repetitive self-injurious behavior, onset is in the early developmental period. 
For example, individuals with the neurogenetic condition Prader-Willi syndrome may 
have early onset of skin picking, and their symptoms may meet criteria for stereotypic 
movement disorder. While tics in individuals with Tourette's disorder may lead to self­
injury, the behavior is not tic-like in excoriation disorder.
Somatic symptom and related disorders. Excoriation disorder is not diagnosed if the

Somatic symptom and related disorders. Excoriation disorder is not diagnosed if the 
skin lesion is primarily attributable to deceptive behaviors in factitious disorder.
Other disorders. Excoriation disorder is not diagnosed if the skin picking is primarily 
attributable to the intention to harm oneself that is characteristic of nonsuicidal self-injury.
Other medical conditions. Excoriation disorder is not diagnosed if the skin picking is 
primarily attributable to another medical condition. For example, scabies is a dermatolog- 
ical condition invariably associated with severe itching and scratching. However, excori­
ation disorder may be precipitated or exacerbated by an underlying dermatological 
condition. For example, acne may lead to some scratching and picking, which may also be 
associated with comorbid excoriation disorder. The differentiation between these two

associated with comorbid excoriation disorder. The differentiation between these two 
clirücal situations (acne with some scratching and picking vs. acne with comorbid excori­
ation disorder) requires an assessment of the extent to which the individual's skin picking 
has become independent of the underlying dermatological condition.
Substance/medication-induced disorders. Skin-picking symptoms may also be induced 
by certain substances (e.g., cocaine), in which case excoriation disorder should not be di­
agnosed. If such skin picking is clinically significant, then a diagnosis of substance/med­
ication-induced obsessive-compulsive and related disorder should be considered.

Excoriation disorder is often accompanied by other mental disorders. Such disorders in­
clude OCD and trichotillomania (hair-pulling disorder), as well as major depressive dis­
order. Repetitive body-focused symptoms other than skin picking and hair pulling (e.g., 
nail biting) occur in many individuals with excoriation disorder and may deserve an ad­
ditional diagnosis of other specified obsessive-compulsive and related disorder (i.e., 
body-focused repetitive behavior disorder).
Obsessive-Compulsive and Related Disorder
A. Obsessions, compulsions, skin picking, hair pulling, other body-focused repetitive be­
haviors, or other symptoms characteristic of the obsessive-compulsive and related dis­
orders predominate in the clinical picture.

rion A.
C. The disturbance is not better explained by an obsessive-compulsive and related disor­
der that is not substance/medication-induced. Such evidence of an independent ob­
sessive-compulsive and related disorder could include the following:
withdrawal or severe intoxication; or there is other evidence suggesting the exis­
tence of an independent non-substance/medication-induced obsessive-compul­

sive and related disorder (e.g., a history of recurrent non-substance/medication-  
related episodes).
E. The disturiiance causes clinically significant distress or impairment in  social, occupa­
Note: This diagnosis should be made in addition to a diagnosis of substance intoxication  
or substance withdrawal only when the symptoms in Criterion A predominate in the clinical  
picture and are sufficiently severe to warrant clinical attention.
tion]-induced obsessive-compulsive and related disorders are indicated in the table below.  
Note that the ICD-10-CM code depends on whether or not there is a comorbid substance

Note that the ICD-10-CM code depends on whether or not there is a comorbid substance  
use disorder present for the same class of substance. If a mild substance use disorder is  
comorbid with the substance-induced obsessive-compulsive and related disorder, the 4th  
position character is “ 1 a n d  the clinician should record “ mild [substance] use disorder”  
before the substance-induced obsessive-compulsive and related disorder (e.g., “ mild co­
caine use disorder with cocaine-induced obsessive-compulsive and related disorder"). If  
a moderate or severe substance use disorder is comorbid with the substance-induced ob­
sessive-compulsive and related disorder, the 4th position character is “ 2,”  and the clinician  
should record “ moderate [substance] use disorder”  or “ severe [substance] use disorder,”

should record “ moderate [substance] use disorder”  or “ severe [substance] use disorder,”  
depending on the severity of the comorbid substance use disorder. If there Is no comorbid

substance use disorder (e.g., after a one-time heavy use of the substance), then the 4th  
position character is “ 9,”  and the clinician should record only the substance-induced ob­
sessive-compulsive and related disorder.
ICD-10-CM
ICD-9-CIVIWith use  
disorder,  
disorder,  
moderate  
use
disorder
stimulant)292.89 F15.188 F15.288 F15.988
Cocaine 292.89 F14.188 FI 4.288 F14.988
Other (or unknown) substance 292.89 F19.188 F19.288 F19.988
Witii onset during withdrawai: If criteria are met for withdrawal from the substance  

ICD-9-CM. The name of the substance/medication-induced obsessive-compulsive and 
related disorder begins with the specific substance (e.g., cocaine) that is presumed to be 
causing the obsessive-compulsive and related symptoms. The diagnostic code is selected 
from the table included in the criteria set, which is based on the drug class. For substances 
that do not fit into any of the classes, the code for "other substance" should be used; and in 

toxication, onset during withdrawal, with onset after medication use). Unlike the record­
substance use disorder into a single code, for ICD-9-CM a separate diagnostic code is 
given for the substance use disorder. For example, in the case of repetitive behaviors oc­
292.89 cocaine-induced obsessive-compulsive and related disorder, with onset during in­
toxication. An additional diagnosis of 304.20 severe cocaine use disorder is also given. 
When more than one substance is judged to play a significant role in the development of

When more than one substance is judged to play a significant role in the development of 
the obsessive-compulsive and related disorder, each should be listed separately.
ICD-10-CM. The name of the substance/medication-induced obsessive-compulsive and re­
lated disorder begins with the specific substance (e.g., cocaine) that is presumed to be causing 
the obsessive-compulsive and related symptoms. The diagnostic code is selected from the ta­
ble included in the criteria set, which is based on the drug class and presence or absence of a 
comorbid substance use disorder. For substances that do not fit into any of the classes, 
the code for "other substance" with no comorbid substance use should be used; and in cases in 
which a substance is judged to be an etiological factor but the specific class of substance is un­

known, the category "unknown substance" with no comorbid substance use should be used.

listed first, followed by the word "with," followed by the name of the substance-induced ob­
sessive-compulsive and related disorder, followed by the specification of onset (i.e., onset dur­
ing intoxication, onset during withdrawal, with onset after medication use). For example, in 
the case of repetitive behaviors occurring during intoxication in a man with a severe cocaine 
use disorder, the diagnosis is F14.288 severe cocaine use disorder with cocaine-induced obses­
sive-compulsive and related disorder, with onset during intoxication. A separate diagnosis of 
the comorbid severe cocaine use disorder is not given. If the substance-induced obsessive- 
compulsive and related disorder occurs without a comorbid substance use disorder (e.g., after 
a one-time heavy use of the substance), no accompanying substance use disorder is noted (e.g.,

a one-time heavy use of the substance), no accompanying substance use disorder is noted (e.g., 
F15.988 amphetamine-induced obsessive-compulsive and related disorder, with onset during 
intoxication). When more than one substance is judged to play a significant role in the devel­
opment of the obsessive-compulsive and related disorder, each should be listed separately.
The essential features of substance/medication-induced obsessive-compulsive and related 
disorder are prominent symptoms of an obsessive-compulsive and related disorder (Criterion 
A) that are judged to be attributable to the effects of a substance (e.g., drug of abuse, medica­
tion). The obsessive-compulsive and related disorder symptoms must have developed during 
or soon after substance intoxication or withdrawal or after exposure to a medication or toxin,

or soon after substance intoxication or withdrawal or after exposure to a medication or toxin, 
and the substance/medication must be capable of producing the symptoms (Criterion B). Sub­
stance/medication-induced obsessive-compulsive and related disorder due to a prescribed 
treatment for a mental disorder or general medical condition must have its onset while the in­
dividual is receiving the medication. Once the treatment is discontinued, the obsessive-com­
pulsive and related disorder symptoms will usually improve or remit within days to several 
weeks to 1  month (depending on the half-life of the substance/medication). The diagnosis of 
substance/medication-induced obsessive-compulsive and related disorder should not be 
given if onset of the obsessive-compulsive and related disorder symptoms precedes the sub­

stance intoxication or medication use, or if the symptoms persist for a substantial period of 
time, usually longer than 1  month, from the time of severe intoxication or withdrawal. If the 
obsessive-compulsive and related disorder symptoms persist for a substantial period of time, 
other causes for the symptoms should be considered. The substance/medication-induced ob­
sessive-compulsive and related disorder diagnosis should be made in addition to a diagnosis 
of substance intoxication only when the symptoms in Criterion A predominate in the clinical 
picture and are sufficiently severe to warrant independent clinical attention
Obsessions, compulsions, hair pulling, skin picking, or other body-focused repetitive be­

haviors can occur in association with intoxication with the following classes of substances: 
stimulants (including cocaine) and other (or unknown) substances. Heavy metals and tox­
ins may also cause obsessive-compulsive and related disorder symptoms. Laboratory as­
sessments (e.g., urine toxicology) may be useful to measure substance intoxication as part 
of an assessment for obsessive-compulsive and related disorders.
In the general population, the very limited data that are available indicate that substance- 
induced obsessive-compulsive and related disorder is very rare.
Substance intoxication. Obsessive-compulsive and related disorder symptoms may oc­
cur in substance intoxication. The diagnosis of the substance-specific intoxication will usu­

ally suffice to categorize the symptom presentation. A diagnosis of an obsessive-compulsive 
and related disorder should be made in addition to substance intoxication when the symp­
toms are judged to be in excess of those usually associated with intoxication and are suf­
ficiently severe to warrant independent clinical attention.
Obsessive-compulsive and related disorder (i.e., not induced by a substance). Sub­
stance/medication-induced obsessive-compulsive and related disorder is judged to be 
etiologically related to the substance/medication. Substance/medication-induced obses­
sive-compulsive and related disorder is distinguished from a primary obsessive-compul­
sive and related disorder by considering the onset, course, and other factors with respect 
to substances/medications. For drugs of abuse, there must be evidence from the history, 
physical examination, or laboratory findings for use or intoxication. Substance/medica­

tion-induced obsessive-compulsive and related disorder arises only in association with in­
toxication, whereas a primary obsessive-compulsive and related disorder may precede the 
onset of substance/medication use. The presence of features that are atypical of a primary 
obsessive-compulsive and related disorder, such as atypical age at onset of symptoms, 
may suggest a substance-induced etiology. A primary obsessive-compulsive and related 
disorder diagnosis is warranted if the symptoms persist for a substantial period of time 
(about 1  month or longer) after the end of the substance intoxication or the individual has 
a history of an obsessive-compulsive and related disorder.
Obsessive-compulsive and related disorder due to another medical condition. If the

obsessive-compulsive and related disorder symptoms are attributable to another medical 
condition (i.e., rather than to the medication taken for the other medical condition), obses­
sive-compulsive and related disorder due to another medical condition should be diag­
nosed. The history often provides the basis for judgment. At times, a change in the 
treatment for the other medical condition (e.g., medication substitution or discontinua­
tion) may be needed to determine whether or not the medication is the causative agent (in 
which case the symptoms may be better explained by substance/medication-induced ob­
sessive-compulsive and related disorder). If the disturbance is attributable to both another 
medical condition and substance use, both diagnoses (i.e., obsessive-compulsive and related

medical condition and substance use, both diagnoses (i.e., obsessive-compulsive and related 
disorder due to another medical condition and substance/medication-induced obsessive- 
compulsive and related disorder) may be given. When there is insufficient evidence to de­
termine whether the symptoms are attributable to either a substance/medication or an­
other medical condition or are primary (i.e., attributable to neither a substance/medication 
nor another medical condition), a diagnosis of other specified or unspecified obsessive- 
compulsive and related disorder would be indicated.
Delirium. If obsessive-compulsive and related disorder symptoms occur exclusively 
during the course of delirium, they are considered to be an associated feature of the delir­
ium and are not diagnosed separately.
Obsessive-Compulsive and Related Disorder  

Diagnostic Criteria 294.8 (F06.8)
A. Obsessions, compulsions, preoccupations with appearance, hoarding, s l< in  picking,  
hair pulling, other body-focused repetitive behaviors, or other symptoms characteristic  
of obsessive-compulsive and related disorder predominate in  the clinical picture.

With obsessive-compulsive disorder-lil<e symptoms: If obsessive-compulsive dis­
order-like symptoms predominate in the clinical presentation.
Witli appearance preoccupations: If preoccupation with perceived appearance de­
fects or flaws predominates in the clinical presentation.
Witli hoarding symptoms: If hoarding predominates in the clinical presentation.
With hair-pulling symptoms: If hair pulling predominates in the clinical presentation.  
With sl(in-picl(ing symptoms: If skin picking predominates in the clinical presenta­
tion.
disorder (e.g., 294.8 [F06.8] obsessive-compulsive and related disorder due to cerebral

tion.
disorder (e.g., 294.8 [F06.8] obsessive-compulsive and related disorder due to cerebral  
infarction). The other medical condition should be coded and listed separately immediately  
before the obsessive-compulsive and related disorder due to the medical condition (e.g.,  
438.89 [169.398] cerebral infarction; 294.8 [F06.8] obsessive-compulsive and related dis­
order due to cerebral infarction)._____________________________________________
The essential feature of obsessive-compulsive and related disorder due to another medical 
condition is clinically significant obsessive-compulsive and related symptoms that are 
judged to be best explained as the direct pathophysiological consequence of another med­
ical condition. Symptoms can include prominent obsessions, compulsions, preoccu­
pations with appearance, hoarding, hair pulling, skin picking, or other body-focused

pations with appearance, hoarding, hair pulling, skin picking, or other body-focused 
repetitive behaviors (Criterion A). The judgment that the symptoms are best explained by 
the associated medical condition must be based on evidence from the history, physical ex­
amination, or laboratory findings (Criterion B). Additionally, it must be judged that the 
symptoms are not better explained by another mental disorder (Criterion C). The diagno­
sis is not made if the obsessive-compulsive and related symptoms occur only during the 
course of a delirium (Criterion D). The obsessive-compulsive and related symptoms must 
tant areas of functioning (Criterion E).
In determining whether the obsessive-compulsive and related symptoms are attribut­

able to another medical condition, a relevant medical condition must be present. Further­
more, it must be established that obsessive-compulsive and related symptoms can be 
etiologically related to the medical condition through a pathophysiological mechanism 
and that this best explains the symptoms in the individual. Although there are no infallible 
guidelines for determining whether the relationship between the obsessive-compulsive 
and related symptoms and the medical condition is etiological, considerations that may 
provide some guidance in making this diagnosis include the presence of a clear temporal 
association between the onset, exacerbation, or remission of the medical condition and the 
obsessive-compulsive and related symptoms; the presence of features that are atypical of

obsessive-compulsive and related symptoms; the presence of features that are atypical of 
a primary obsessive-compulsive and related disorder (e.g., atypical age at onset or course); 
and evidence in the literature that a known physiological mechanism (e.g., striatal dam­
age) causes obsessive-compulsive and related symptoms. In addition, the disturbance 
cannot be better explained by a primary obsessive-compulsive and related disorder, a sub­
stance/medication-induced obsessive-compulsive and related disorder, or another men­
tal disorder.
There is some controversy about whether obsessive-compulsive and related disorders 
can be attributed to Group A streptococcal infection. Sydenham's chorea is the neurolog­

ical manifestation of rheumatic fever, which is in turn due to Group A streptococcal in­
fection. Sydenham's chorea is characterized by a combination of motor and nonmotor 
features. Nonmotor features include obsessions, compulsions, attention deficit, and emo­
tional lability. Although individuals w ^ ith Sydenham's chorea may present with non­
neuropsychiatric features of acute rheumatic fever, such as carditis and arthritis, they may 
present with obsessive-compulsive disorder-like symptoms; such individuals should 
be diagnosed with obsessive-compulsive and related disorder due to another medical 
Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infec­
tions (PANDAS) has been identified as another post-infectious autoimmune disorder 
characterized by the sudden onset of obsessions, compulsions, and/or tics accompanied 
by a variety of acute neuropsychiatric symptoms in the absence of chorea, carditis, or ar­

thritis, after Group A streptococcal infection. Although there is a body of evidence that 
supports the existence of PANDAS, it remains a controversial diagnosis. Given this ongo­
ing controversy, the description of PANDAS has been modified to eliminate etiological 
factors and to designate an expanded clinical entity: pediatric acute-onset neuropsychiat­
ric syndrome (PANS) or idiopathic childhood acute neuropsychiatric symptoms (CANS), 
which deserves further study.
A number of other medical disorders are known to include obsessive-compulsive and re­
lated symptoms as a manifestation. Examples include disorders leading to striatal dam­
age, such as cerebral infarction.

The development and course of obsessive-compulsive and related disorder due to another 
medical condition generally follows the course of the underlying illness.
Diagnostic iViaricers
nosis of another medical condition.
Delirium. A separate diagnosis of obsessive-compulsive and related disorder due to an­
other medical condition is not given if the disturbance occurs exclusively during the 
course of a delirium. However, a diagnosis of obsessive-compulsive and related disorder 
due to another medical condition may be given in addition to a diagnosis of major neuro- 
cognitive disorder (dementia) if the etiology of the obsessive-compulsive symptoms is

cognitive disorder (dementia) if the etiology of the obsessive-compulsive symptoms is 
judged to be a physiological consequence of the pathological process causing the dementia 
and if obsessive-compulsive symptoms are a prominent part of the clinical presentation.
Mixed presentation of symptoms (e.g., mood and obsessive-compulsive and related  
disorder symptoms). If the presentation includes a mix of different types of symptoms, 
the specific mental disorder due to another medical condition depends on which symp­
toms predominate in the clinical picture.
Substance/medication-induced obsessive-compulsive and related disorders. If there 
is evidence of recent or prolonged substance use (including medications with psychoac­
tive effects), withdrawal from a substance, or exposure to a toxin, a substance/medication- 
induced obsessive-compulsive and related disorder should be considered. When a sub­

stance/medication-induced obsessive-compulsive and related disorder is being diag­
nosed in relation to drugs of abuse, it may be useful to obtain a urine or blood drug screen

or other appropriate laboratory evaluation. Symptoms that occur during or shortly after 
(i.e., within 4 v^eeks of) substance intoxication or withdrawal or after medication use may 
be especially indicative of a substance/medication-induced obsessive-compulsive and re­
lated disorder, depending on the type, duration, or amount of the substance used.
Obsessive-compulsive and related disorders (primary). Obsessive-compulsive and re­
lated disorder due to another medical condition should be distinguished from a primary 
obsessive-compulsive and related disorder. In primary mental disorders, no specific and 
direct causative physiological mechanisms associated with a medical condition can be 
demonstrated. Late age at onset or atypical symptoms suggest the need for a thorough as­
sessment to rule out the diagnosis of obsessive-compulsive and related disorder due to an­
other medical condition.
Illness anxiety disorder. Illness anxiety disorder is characterized by a preoccupation with

Illness anxiety disorder. Illness anxiety disorder is characterized by a preoccupation with 
having or acquiring a serious illness. In the case of illness anxiety disorder, individuals 
may or may not have diagnosed medical conditions.
Associated feature of another mental disorder. Obsessive-compulsive and related symp­
toms may be an associated feature of another mental disorder (e.g., schizophrenia, an­
orexia nervosa).
Other specified obsessive-compulsive and related disorder or unspecified obsessive-  
compulsive and related disorder. These diagnoses are given if it is unclear whether the 
obsessive-compulsive and related symptoms are primary, substance-induced, or due to 
another medical condition.
Other Specified Obsessive-Compulsive  
and Related Disorder
This category applies to presentations in which symptoms characteristic of an obsessive-  
compulsive and related disorder that cause clinically significant distress or impairment in

compulsive and related disorder that cause clinically significant distress or impairment in  
social, occupational, or other important areas of functioning predominate but do not meet  
the full criteria for any of the disorders in the obsessive-compulsive and related disorders  
diagnostic class. The other specified obsessive-compulsive and related disorder category  
is used in situations in which the clinician chooses to communicate the specific reason that  
the presentation does not meet the criteria for any specific obsessive-compulsive and re­
lated disorder. This is done by recording “ other specified obsessive-compulsive and relat­
ed disorder”  followed by the specific reason (e.g., “ body-focused repetitive behavior  
disorder”).

1. Body dysmorphic-like disorder witli actual flaws: This is similar to body dysmor­
phic disorder except that the defects or flaws in physical appearance are clearly ob­
servable by others (i.e., they are more noticeable than “ slight” ). In such cases, the  
preoccupation with these flaws is clearly excessive and causes significant impairment  
or distress.
2. Body dysmorphic-like disorder without repetitive behaviors: Presentations that  
meet body dysmorphic disorder except that the individual has not performed repetitive  
behaviors or mental acts in response to the appearance concerns.
3. Body-focused repetitive behavior disorder: This is characterized by recurrent body-  
focused repetitive behaviors (e.g., nail biting, lip biting, cheek chewing) and repeated  
attempts to decrease or stop the behaviors. These symptoms cause clinically significant

distress or impairment in  social, occupational, or other important areas of functioning  
and are not better explained by trichotillomania (hair-pulling disorder), excoriation (skin-  
picking) disorder, stereotypic movement disorder, or nonsuicidal self-injury.
4. Obsessional jealousy: This is characterized by nondelusional preoccupation with a  
partner’s perceived infidelity. The preoccupations may lead to repetitive behaviors or  
mental acts in response to the infidelity concerns; they cause clinically significant dis­
tress or impairment in  social, occupational, or other important areas of functioning; and  
they are not better explained by another mental disorder such as delusional disorder,  
jealous type, or paranoid personality disorder.
5. Shubo-kyofu:  A variant of taijin kyofusho  (see “ Glossary of Cultural Concepts of Dis­
tress”  in  the Appendix) that is similar to body dysmorphic disorder and is characterized  
by excessive fear of having a bodily deformity.

6. Koro:  Related to dhat syndrome  (see “ Glossary of Cultural Concepts of Distress”  in  
the Appendix), an episode of sudden and intense anxiety that the penis (or the vulva  
and nipples in females) will recede into the body, possibly leading to death.
7. Jikoshu-kyofu:  A variant of taijin l<yofusho  (see “ Glossary of Cultural Concepts of Dis­
tress”  in the Appendix) characterized by fear of having an offensive body odor (also  
termed olfactory reference syndrome).
Unspecified Obsessive-Compulsive  
This category applies to presentations in  which symptoms characteristic of an obsessive-  
social, occupational, or other important areas of functioning predominate but do not meet

diagnostic class. The unspecified obsessive-compulsive and related disorder category is  
used in  situations in  which the clinician chooses not to specify the reason that the criteria  
are not met for a specific obsessive-compulsive and related disorder, and includes presen­
tations in  which there is insufficient information to make a more specific diagnosis (e.g., in  
emergency room settings).

Trauma- and 
Stressor-Related Disorders
T r3 U m 3 - â n d  StrG SSO r-rG lâÎG d disorders include disorders in which exposure to 
a traumatic or stressful event is listed explicitly as a diagnostic criterion. These include reactive 
attachment disorder, disinhibited social engagement disorder, posttraumatic stress disor­
der (PTSD), acute stress disorder, and adjustment disorders. Placement of this chapter reflects 
the close relationship between these diagnoses and disorders in the surrounding chapters on 
anxiety disorders, obsessive-compulsive and related disorders, and dissociative disorders.
Psychological distress following exposure to a traumatic or stressful event is quite vari­
able. In some cases, symptoms can be well understood within an anxiety- or fear-based 
context. It is clear, however, that many individuals who have been exposed to a traumatic 
or stressful event exhibit a phenotype in which, rather than anxiety- or fear-based symp­

toms, the most prominent clinical characteristics are anhedonic and dysphoric symptoms, 
externalizing angry and aggressive symptoms, or dissociative symptoms. Because of these 
variable expressions of clinical distress following exposure to catastrophic or aversive 
events, the aforementioned disorders have been grouped under a separate category: 
trauma- and stressor-related disorders.  Furthermore, it is not uncommon for the clinical pic­
ture to include some combination of the above symptoms (with or without anxiety- or 
fear-based symptoms). Such a heterogeneous picture has long been recognized in adjust­
ment disorders, as well. Social neglect—that is, the absence of adequate caregiving during 
childhood—is a diagnostic requirement of both reactive attachment disorder and disin­

hibited social engagement disorder. Although the two disorders share a common etiology, 
the former is expressed as an internalizing disorder with depressive symptoms and with­
drawn behavior, while the latter is marked by disinhibition and externalizing behavior.
Reactive Attachment Disorder
Diagnostic Criteria 313.89 (F94.1)
A. A consistent pattern of inhibited, emotionally withdrawn behavior toward adult caregiv­
ers, manifested by both of the following:
1. The child rarely or minimally seeks comfort when distressed.
2. The child rarely or minimally responds to comfort when distressed.
B . A persistent social and emotional disturbance characterized by at least two of the following:
1. Minimal social and emotional responsiveness to others.
2. Limited positive affect.

3. Episodes of unexplained irritability, sadness, or fearfulness that are evident even  
during nonthreatening interactions with adult caregivers.
C. The child has experienced a pattern of extremes of insufficient care as evidenced by
at least one of the following:
1. Social neglect or deprivation in the form of persistent laci< of having basic emotional  
needs for comfort, stimulation, and affection met by caregiving adults.

2. Repeated changes of primary caregivers that limit opportunities to form stable at­
tachments (e.g., frequent changes in foster care).
3. Rearing in unusual settings that severely lim it opportunities to form selective at­
tachments (e.g., institutions with high child-to-caregiver ratios).
D. The care in Criterion C is presumed to be responsible for the disturbed behavior in Cri­
terion A (e.g., the disturbances in Criterion A began following the lack of adequate care  
in  Criterion C).
E. The criteria are not met for autism spectrum disorder.
F. The disturbance is evident before age 5 years.
G. The child has a developmental age of at least 9 months.
Persistent: The disorder has been present for more than 12 months.
Reactive attachment disorder is specified as severe when a child exhibits all symp­
toms of the disorder, with each symptom manifesting at relatively high levels.

Reactive attachment disorder of infancy or early childhood is characterized by a pattern of 
markedly disturbed and developmentally inappropriate attachment behaviors, in which a 
child rarely or minimally turns preferentially to an attachment figure for comfort, support, 
protection, and nurturance. The essential feature is absent or grossly underdeveloped at­
tachment between the child and putative caregiving adults. Children with reactive attach­
ment disorder are believed to have the capacity to form selective attachments. However, 
because of limited opportunities during early development, they fail to show the behavioral 
manifestations of selective attachments. That is, when distressed, they show no consistent

manifestations of selective attachments. That is, when distressed, they show no consistent 
effort to obtain comfort, support, nurturance, or protection from caregivers. Furthermore, 
when distressed, children with this disorder do not respond more than minimally to com­
forting efforts of caregivers. Thus, the disorder is associated with the absence of expected 
comfort seeking and response to comforting behaviors. As such, children with reactive 
attachment disorder show diminished or absent expression of positive emotions during 
routine interactions with caregivers. In addition, their emotion regulation capacity is com­
promised, and they display episodes of negative emotions of fear, sadness, or irritability 
that are not readily explained. A diagnosis of reactive attachment disorder should not be 
made in children who are developmentally unable to form selective attachments. For this

made in children who are developmentally unable to form selective attachments. For this 
reason, the child must have a developmental age of at least 9 months.
Because of the shared etiological association with social neglect, reactive attachment dis­
order often co-occurs with developmental delays, especially in delays in cognition and 
language. Other associated features include stereotypies and other signs of severe neglect 
(e.g., malnutrition or signs of poor care).
The prevalence of reactive attachment disorder is unknown, but the disorder is seen rela­
tively rarely in clinical settings. The disorder has been found in young children exposed to 
severe neglect before being placed in foster care or raised in institutions. However, even in 
populations of severely neglected children, the disorder is uncommon, occurring in less

populations of severely neglected children, the disorder is uncommon, occurring in less 
than 10% of such children.

Conditions of sotial neglect are often present in the first months of life in children diag­
nosed with reactive attachment disorder, even before the disorder is diagnosed. The clin­
ical features of the disorder manifest in a similar fashion between the ages of 9 months and 
5 years. That is, signs of absent-to-minimal attachment behaviors and associated emotion­
ally aberrant behaviors are evident in children throughout this age range, although differ­
ing cognitive and motor abilities may affect how these behaviors are expressed. Without 
remediation and recovery through normative caregiving environments, it appears that signs 
of the disorder may persist, at least for several years.
It is unclear whether reactive attachment disorder occurs in older children and, if so, how 
it differs from its presentation in young children. Because of this, the diagnosis should be 
made with caution in children older than 5 years.

Environmental. Serious social neglect is a diagnostic requirement for reactive attach­
ment disorder and is also the only known risk factor for the disorder. However, the ma­
jority of severely neglected children do not develop the disorder. Prognosis appears to 
depend on the quality of the caregiving environment following serious neglect.
Cuiture-Related Diagnostic Issues
Similar attachment behaviors have been described in young children in many different 
cultures around the world. However, caution should be exercised in making the diagnosis 
of reactive attachment disorder in cultures in which attachment has not been studied.
Reactive attachment disorder significantly impairs young children's abilities to relate in-

Reactive attachment disorder significantly impairs young children's abilities to relate in- 
teφersonally to adults or peers and is associated with functional impairment across many 
domains of early childhood.
Autism spectrum disorder. Aberrant social behaviors manifest in young children with 
reactive attachment disorder, but they also are key features of autism spectrum disorder. 
Specifically, young children with either condition can manifest dampened expression of 
positive emotions, cognitive and language delays, and impairments in social reciprocity. 
As a result, reactive attachment disorder must be differentiated from autism spectrum dis­
order. These two disorders can be distinguished based on differential histories of neglect 
and on the presence of restricted interests or ritualized behaviors, specific deficit in social

and on the presence of restricted interests or ritualized behaviors, specific deficit in social 
communication, and selective attachment behaviors. Children with reactive attachment 
disorder have experienced a history of severe social neglect, although it is not always pos­
sible to obtain detailed histories about the precise nature of their experiences, especially in 
initial evaluations. Children with autistic spectrum disorder will only rarely have a history 
of social neglect. The restricted interests and repetitive behaviors characteristic of autism 
spectrum disorder are not a feature of reactive attachment disorder. These clinical features 
manifest as excessive adherence to rituals and routines; restricted, fixated interests; and 
unusual sensory reactions. However, it is important to note that children with either con­

dition can exhibit stereotypic behaviors such as rocking or flapping. Children with either 
disorder also may exhibit a range of intellectual functioning, but only children with autis-

tic spectrum disorder exhibit selective impairments in social communicative behaviors, 
such as intentional communication (i.e., impairment in communication that is deliberate, 
goal-directed, and aimed at influencing the behavior of the recipient). Children with reac­
tive attachment disorder show social communicative functioning comparable to their 
overall level of intellectual functioning. Finally, children with autistic spectrum disorder 
regularly show attachment behavior typical for their developmental level. In contrast, 
children with reactive attachment disorder do so only rarely or inconsistently, if at all.
Intellectual disability (intellectual developmental disorder). Developmental delays of­
ten accompany reactive attachment disorder, but they should not be confused with the 
disorder. Children with intellectual disability should exhibit social and emotional skills 
comparable to their cognitive skills and do not demonstrate the profound reduction in

comparable to their cognitive skills and do not demonstrate the profound reduction in 
positive affect and emotion regulation difficulties evident in children with reactive attach­
ment disorder. In addition, developmentally delayed children who have reached a cogni­
tive age of 7-9 months should demonstrate selective attachments regardless of their 
chronological age. In contrast, children with reactive attachment disorder show lack of 
preferred attachment despite having attained a developmental age of at least 9 months.
Depressive disorders. Depression in young children is also associated with reductions 
in positive affect. There is limited evidence, however, to suggest that children with depres­
sive disorders have impairments in attachment. That is, young children who have been di­
agnosed with depressive disorders still should seek and respond to comforting efforts by 
caregivers.

Conditions associated with neglect, including cognitive delays, language delays, and ste­
reotypies, often co-occur with reactive attachment disorder. Medical conditions, such as 
severe malnutrition, may accompany signs of the disorder. Depressive symptoms also 
may co-occur with reactive attachment disorder.
Disinhiblted Social Engagement Disorder
Diagnostic Criteria 313.89 (F94.2)
A. A pattern of behavior in which a child actively approaches and interacts with unfamiliar  
adults and exhibits at least two of the following:
1. Reduced or absent reticence in approaching and interacting with unfamiliar adults.
2. Overly familiar verbal or physical behavior (that is not consistent with culturally  
sanctioned and with age-appropriate social boundaries).

3. Diminished or absent checking back with adult caregiver after venturing away, even  
in unfamiliar settings.
4. Willingness to go off with an unfamiliar adult with minimal or no hesitation.
B. The behaviors in Criterion A are not limited to impulsivity (as in attention-deficit/hyper-  
activity disorder) but include socially disinhiblted behavior.
C. The child has experienced a pattern of extremes of insufficient care as evidenced by  
1. Social neglect or deprivation in the form of persistent lack of having basic emotional  

3. Rearing in unusual settings that severely limit opportunities to form selective at­

terion A (e.g:, the disturbances in Criterion A began following the pathogenic care in  
Criterion C).
E. The child has a developmental age of at least 9 months.
Disinhibited social engagement disorder is specified as severe when the child exhibits  
all symptoms of the disorder, with each symptom manifesting at relatively high levels.
The essential feature of disinhibited social engagement disorder is a pattern of behavior 
that involves culturally inappropriate, overly familiar behavior with relative strangers 
(Criterion A). This overly familiar behavior violates the social boundaries of the culture. A 
diagnosis of disinhibited social engagement disorder should not be made before children

diagnosis of disinhibited social engagement disorder should not be made before children 
are developmentally able to form selective attachments. For this reason, the child must 
have a developmental age of at least 9 months.
Because of the shared etiological association with social neglect, disinhibited social en­
gagement disorder may co-occur with developmental delays, especially cognitive and lan­
guage delays, stereotypies, and other signs of severe neglect, such as malnutrition or poor 
care. However, signs of the disorder often persist even after these other signs of neglect are 
no longer present. Therefore, it is not uncommon for children with the disorder to present 
with no current signs of neglect. Moreover, the condition can present in children who 
show no signs of disordered attachment. Thus, disinhibited social engagement disorder

show no signs of disordered attachment. Thus, disinhibited social engagement disorder 
may be seen in children with a history of neglect who lack attachments or whose attach­
ments to their caregivers range from disturbed to secure.
The prevalence of disinhibited social attachment disorder is unknown. Nevertheless, the 
disorder appears to be rare, occurring in a minority of children, even those who have been 
severely neglected and subsequently placed in foster care or raised in institutions. In such 
high-risk populations, the condition occurs in only about 20% of children. The condition is 
seen rarely in other clinical settings.
Conditions of social neglect are often present in the first months of life in children diag­
nosed with disinhibited social engagement disorder, even before the disorder is diag­

nosed. However, there is no evidence that neglect beginning after age 2 years is associated 
with manifestations of the disorder. If neglect occurs early and signs of the disorder 
appear, clinical features of the disorder are moderately stable over time, particularly if 
conditions of neglect persist. Indiscriminate social behavior and lack of reticence with un­
familiar adults in toddlerhood are accompanied by attention-seeking behaviors in pre­
schoolers. When the disorder persists into middle childhood, clinical features manifest as 
verbal and physical overfamiliarity as well as inauthentic expression of emotions. These 
signs appear particularly apparent when the child interacts with adults. Peer relationships 
are most affected in adolescence, with both indiscriminate behavior and conflicts appar­

ent. The disorder has not been described in adults.

Disinhibited social engagement disorder has been described from the second year of 
life through adolescence. There are some differences in manifestations of the disorder 
from early childhood through adolescence. At the youngest ages, across many cultures, 
children show reticence when interacting with strangers. Young children with the disorder 
fail to show reticence to approach, engage with, and even accompany adults. In preschool 
children, verbal and social intrusiveness appear most prominent, often accompanied by 
attention-seeking behavior. Verbal and physical overfamiliarity continue through middle 
childhood, accompanied by inauthentic expressions of emotion. In adolescence, indis­
criminate behavior extends to peers. Relative to healthy adolescents, adolescents with the 
disorder have more "superficial" peer relationships and more peer conflicts. Adult man­
ifestations of the disorder are unknown.

Environmental. Serious social neglect is a diagnostic requirement for disinhibited social 
engagement disorder and is also the only known risk factor for the disorder. However, the 
majority of severely neglected children do not develop the disorder. Neurobiological vul­
nerability may differentiate neglected children who do and do not develop the disorder. 
However, no clear link with any specific neurobiological factors has been established. The 
disorder has not been identified in children who experience social neglect only after age 
2 years. Prognosis is only modestly associated with quality of the caregiving environment 
following serious neglect. In many cases, the disorder persists, even in children whose 
caregiving environment becomes markedly improved.

Course modifiers. Caregiving quality seems to moderate the course of disinhibited so­
cial engagement disorder. Nevertheless, even after placement in normative caregiving 
environments, some children show persistent signs of the disorder, at least through ado­
lescence.
Disinhibited Sociai Engagement Disorder
Disinhibited social engagement disorder significantly impairs young children's abilities to 
relate interpersonally to adults and peers.
Attention-deficit/hyperactivity disorder. Because of social impulsivity that sometimes 
accompanies attention-deficit/hyperactivity disorder (ADHD), it is necessary to differ­
entiate the two disorders. Children with disinhibited social engagement disorder may be 
distinguished from those with ADHD because the former do not show difficulties with at­

tention or hyperactivity.
Limited research has examined the issue of disorders comorbid with disinhibited social 
engagement disorder. Conditions associated with neglect, including cognitive delays, 
language delays, and stereotypies, may co-occur with disinhibited social engagement dis­
order. In addition, children may be diagnosed with ADHD and disinhibited social engage­
ment disorder concurrently.

Posttraumatic Stress Disorder
Diagnostic Criteria 309.81 (F43.10)
Note: The following criteria apply to adults, adolescents, and children older than 6 years.  
For children 6 years and younger, see corresponding criteria below.
A. Exposure to actual or threatened death, serious injury, or sexual violence in one (or  
more) of the following ways:
1. Directly experiencing the traumatic event(s).
2. Witnessing, in person, the event(s) as it occurred to others.
3. Learning that the traumatic event(s) occurred to a close family member or close  
friend. In cases of actual or threatened death of a family member or friend, the  
event(s) must have been violent or accidental.
4. Experiencing repeated or extreme exposure to aversive details of the traumatic  
event(s) (e.g., first responders collecting human remains: police officers repeatedly  
exposed to details of child abuse).
Note: Criterion A4 does not apply to exposure through electronic media, television,

Note: Criterion A4 does not apply to exposure through electronic media, television,  
movies, or pictures, unless this exposure is work related.
B. Presence of one (or more) of the following intrusion symptoms associated with the  
traumatic event(s), beginning after the traumatic event(s) occurred:
1. Recurrent, involuntary, and intrusive distressing memories of the traumatic event(s).
Note: In children older than 6 years, repetitive play may occur in which themes or  
aspects of the traumatic event(s) are expressed.
2. Recurrent distressing dreams in which the content and/or affect of the dream are  
related to the traumatic event(s).
Note: In children, there may be frightening dreams without recognizable content.
3. Dissociative reactions (e.g., flashbacks) in which the individual feels or acts as if  
the traumatic event(s) were recurring. (Such reactions may occur on a continuum,

the traumatic event(s) were recurring. (Such reactions may occur on a continuum,  
with the most extreme expression being a complete loss of awareness of present  
surroundings.)
Note: In children, trauma-specific reenactment may occur in play.
4. Intense or prolonged psychological distress at exposure to internal or external cues  
that symbolize or resemble an aspect of the traumatic event(s).
5. Marked physiological reactions to internal or external cues that symbolize or re­
semble an aspect of the traumatic event(s).
C. Persistent avoidance of stimuli associated with the traumatic event(s), beginning after  
the traumatic event(s) occurred, as evidenced by one or both of the following:
1. Avoidance of or efforts to avoid distressing memories, thoughts, or feelings about  
or closely associated with the traumatic event(s).

2. Avoidance of or efforts to avoid external reminders (people, places, conversations,  
activities, objects, situations) that arouse distressing memories, thoughts, or feel­
ings about or closely associated with the traumatic event(s).
D. Negative alterations in  cognitions and mood associated with the traumatic event(s),  
beginning or worsening after the traumatic event(s) occurred, as evidenced by two (or  
more) of the following:
1. Inability to remember an important aspect of the traumatic event(s) (typically due to dis­
sociative amnesia and not to other factors such as head injury, alcohol, or drugs).

2. Persistent and exaggerated negative beliefs or expectations about oneself, others,  
or the world (e.g., “I  am bad,”  “ No one can be trusted,”  ‘The world is completely  
dangerous,”  “My whole nervous system is permanently ruined”).
3. Persistent, distorted cognitions about the cause or consequences of the traumatic  
event(s) that lead the individual to blame himself/herself or others.
4. Persistent negative emotional state (e.g., fear, horror, anger, guilt, or shame).
5. Markedly diminished interest or participation in  significant activities.
6. Feelings of detachment or estrangement from others.
7. Persistent inability to experience positive emotions (e.g., inability to experience  
happiness, satisfaction, or loving feelings).
E. Marked alterations in arousal and reactivity associated with the traumatic event(s), be­
ginning or worsening after the traumatic event(s) occurred, as evidenced by two (or  

1. Irritable behavior and angry outbursts (with little or no provocation) typically ex­
pressed as verbal or physical aggression toward people or objects.
2. Reckless or self-destructive behavior.
3. Hypervigilance.
4. Exaggerated startle response.
5. Problems with concentration.
6. Sleep disturbance (e.g., difficulty falling or staying asleep or restless sleep).
F. Duration of the disturbance (Criteria B, C, D, and E) is more than 1  month.
G. The disturbance causes clinically significant distress or impairment in social, occupa­
H. The disturbance is not attributable to the physiological effects of a substance (e.g.,  
medication, alcohol) or another medical condition.
With dissociative symptoms: The individual’s symptoms meet the criteria for post­

traumatic stress disorder, and in addition, in response to the stressor, the individual ex­
periences persistent or recurrent symptoms of either of the following:
1. Depersonalization: Persistent or recurrent experiences of feeling detached from,  
and as if one were an outside observer of, one’s mental processes or body (e.g.,  
feeling as though one were in a dream; feeling a sense of unreality of self or body  
or of time moving slowly).
2. Dereaiization: Persistent or recurrent experiences of unreality of surroundings  
(e.g., the world around the individual is experienced as unreal, dreamlike, distant,  
or distorted).
Note: To use this subtype, the dissociative symptoms must not be attributable to the  
physiological effects of a substance (e.g., blackouts, behavior during alcohol intoxica­

tion) or another medical condition (e.g., complex partial seizures).
With delayed expression: If the full diagnostic criteria are not met until at least 6 months  
after the event (although the onset and expression of some symptoms may be immediate).
Posttraumatic Stress Disorder for Children 6 Years and Younger
A. In children 6 years and younger, exposure to actual or threatened death, serious injury,  
or sexual violence in one (or more) of the following ways:
2. Witnessing, in person, the event(s) as it occurred to others, especially primary care­
givers.

Note: Witnessing does not include events that are witnessed only in electronic me­
dia, television, movies, or pictures.
3. Learning that the traumatic event(s) occurred to a parent or caregiving figure.
1. Recurrent, involuntary, and intrusive distressing memories of the traumatic  
event(s).
Note: Spontaneous and intrusive memories may not necessarily appear distress­
ing and may be expressed as play reenactment.
Note: It may not be possible to ascertain that the frightening content is related to  
the traumatic event.
3. Dissociative reactions (e.g., flashbacks) in which the child feels or acts as if the  
traumatic event(s) were recurring. (Such reactions may occur on a continuum, with

traumatic event(s) were recurring. (Such reactions may occur on a continuum, with  
the most extreme expression being a complete loss of awareness of present sur­
roundings.) Such trauma-specific reenactment may occur in play.
5. Marked physiological reactions to reminders of the traumatic event(s).
C. One (or more) of the following symptoms, representing either persistent avoidance of  
stimuli associated with the traumatic event(s) or negative alterations in cognitions and  
mood associated with the traumatic event(s), must be present, beginning after the  
event(s) or worsening after the event(s):
Persistent Avoidance of Stimuli
1. Avoidance of or efforts to avoid activities, places, or physical reminders that arouse

1. Avoidance of or efforts to avoid activities, places, or physical reminders that arouse  
recollections of the traumatic event(s).
2. Avoidance of or efforts to avoid people, conversations, or interpersonal situations  
that arouse recollections of the traumatic event(s).
Negative Alterations in Cognitions
3. Substantially increased frequency of negative emotional states (e.g., fear, guilt,  
sadness, shame, confusion).
4. Markedly diminished interest or participation in significant activities, including con­
striction of play.
5. Socially withdrawn behavior.
6. Persistent reduction in expression of positive emotions.
D. Alterations in arousal and reactivity associated with the traumatic event(s), beginning  
or worsening after the traumatic event(s) occurred, as evidenced by two (or more) of  

pressed as verbal or physical aggression toward people or objects (including ex­
treme temper tantrums).
2. Hypervigilance.
3. Exaggerated startle response.
4. Problems with concentration.
5. Sleep disturbance (e.g., difficulty falling or staying asleep or restless sleep).
E. The duration of the disturbance is more than 1  month.

F. The disturbance causes clinically significant distress or impairment in relationships  
with parents, siblings, peers, or other caregivers or with school behavior.
G. The disturbance is not attributable to the physiological effects of a substance (e.g.,  
medication or alcohol) or another medical condition.
traumatic stress disorder, and the individual experiences persistent or recurrent symp­
toms of either of the following:
2. Derealization: Persistent or recurrent experiences of unreality of surroundings  
(e.g., the world around the individual is experienced as unreal, dreamlike, distant,

physiological effects of a substance (e.g., blackouts) or another medical condition  
(e.g., complex partial seizures).
With delayed expression: If the full diagnostic criteria are not met until at least  
6 months after the event (although the onset and expression of some symptoms may  
be immediate).
The essential feature of posttraumatic stress disorder (PTSD) is the development of char­
acteristic symptoms following exposure to one or more traumatic events. Emotional re­
actions to the traumatic event (e.g., fear, helplessness, horror) are no longer a part of 
Criterion A. The clinical presentation of PTSD varies. In some individuals, fear-based re-

Criterion A. The clinical presentation of PTSD varies. In some individuals, fear-based re- 
experiencing, emotional, and behavioral symptoms may predominate. In others, anhe- 
donic or dysphoric mood states and negative cognitions may be most distressing. In some 
other individuals, arousal and reactive-externalizing symptoms are prominent, while in 
others, dissociative symptoms predominate. Finally, some individuals exhibit combina­
tions of these symptom patterns.
The directly experienced traumatic events in Criterion A include, but are not limited 
to, exposure to war as a combatant or civilian, threatened or actual physical assault (e.g., 
physical attack, robbery, mugging, childhood physical abuse), threatened or actual sexual 
violence (e.g., forced sexual penetration, alcohol/drug-facilitated sexual penetration, abu­

sive sexual contact, noncontact sexual abuse, sexual trafficking), being kidnapped, being 
taken hostage, terrorist attack, torture, incarceration as a prisoner of war, natural or hu­
man-made disasters, and severe motor vehicle accidents. For children, sexually violent 
events may include developmentally inappropriate sexual experiences without physical 
violence or injury. A life-threatening illness or debilitating medical condition is not neces­
sarily considered a traumatic event. Medical incidents that qualify as traumatic events in­
volve sudden, catastrophic events (e.g., waking during surgery, anaphylactic shock). 
Witnessed events include, but are not limited to, observing threatened or serious injury, 
unnatural death, physical or sexual abuse of another person due to violent assault, domes­

tic violence, accident, war or disaster, or a medical catastrophe in one's child (e.g., a life- 
threatening hemorrhage). Indirect exposure through learning about an event is limited to 
experiences affecting close relatives or friends and experiences that are violent or acciden­
tal (e.g., death due to natural causes does not qualify). Such events include violent per­

sonal assault, suicide, serious accident, and serious injury. The disorder may be especially 
severe or long-lasting when the stressor is interpersonal and intentional (e.g., torture, sex­
ual violence). ^
The traumatic event can be reexperienced in various ways. Commonly, the individual 
has recurrent, involuntary, and intrusive recollections of the event (Criterion Bl). Intrusive 
recollections in PTSD are distinguished from depressive rumination in that they apply 
only to involuntary and intrusive distressing memories. The emphasis is on recurrent 
memories of the event that usually include sensory, emotional, or physiological behavioral 
components. A common reexperiencing symptom is distressing dreams that replay the 
event itself or that are representative or thematically related to the major threats involved 
in the traumatic event (Criterion B2). The individual may experience dissociative states

in the traumatic event (Criterion B2). The individual may experience dissociative states 
that last from a few seconds to several hours or even days, during which components of 
the event are relived and the individual behaves as if the event were occurring at that mo­
ment (Criterion B3). Such events occur on a continuum from brief visual or other sensory 
intrusions about part of the traumatic event without loss of reality orientation, to complete 
loss of awareness of present surroundings. These episodes, often referred to as "flash­
backs," are typically brief but can be associated with prolonged distress and heightened 
arousal. For young children, reenactment of events related to trauma may appear in play 
or in dissociative states. Intense psychological distress (Criterion B4) or physiological re­

activity (Criterion B5) often occurs when the individual is exposed to triggering events that 
resemble or symbolize an aspect of the traumatic event (e.g., windy days after a hurricane; 
seeing someone who resembles one's perpetrator). The triggering cue could be a physical 
sensation (e.g., dizziness for survivors of head trauma; rapid heartbeat for a previously 
traumatized child), particularly for individuals with highly somatic presentations.
Stimuli associated with the trauma are persistently (e.g., always or almost always) 
avoided. The individual commonly makes deliberate efforts to avoid thoughts, memories, 
feelings, or talking about the traumatic event (e.g., utilizing distraction techniques to avoid 
internal reminders) (Criterion Cl) and to avoid activities, objects, situations, or people

internal reminders) (Criterion Cl) and to avoid activities, objects, situations, or people 
who arouse recollections of it (Criterion C2).
Negative alterations in cognitions or mood associated with the event begin or worsen 
after exposure to the event. These negative alterations can take various forms, including an 
inability to remember an important aspect of the traumatic event; such amnesia is typically 
due to dissociative amnesia and is not due to head injury, alcohol, or drugs (Criterion Dl). 
Another form is persistent (i.e., always or almost always) and exaggerated negative ex­
pectations regarding important aspects of life applied to oneself, others, or the future (e.g., 
"I have always had bad judgment"; "People in authority can't be trusted") that may man­
ifest as a negative change in perceived identity since the trauma (e.g., "I can't trust anyone

ifest as a negative change in perceived identity since the trauma (e.g., "I can't trust anyone 
ever again"; Criterion D2). Individuals with PTSD may have persistent erroneous cogni­
tions about the causes of the traumatic event that lead them to blame themselves or others 
(e.g., "It's all my fault that my uncle abused me") (Criterion D3). A persistent negative 
mood state (e.g., fear, horror, anger, guilt, shame) either began or worsened after exposure 
to the event (Criterion D4). The individual may experience markedly diminished interest 
or participation in previously enjoyed activities (Criterion D5), feeling detached or es­
tranged from other people (Criterion D6), or a persistent inability to feel positive emotions 
(especially happiness, joy, satisfaction, or emotions associated with intimacy, tenderness, 
and sexuality) (Criterion D7).

Individuals with PTSD may be quick tempered and may even engage in aggressive 
verbal and/or physical behavior with little or no provocation (e.g., yelling at people, get­
ting into fights, destroying objects) (Criterion El). They may also engage in reckless or self­
destructive behavior such as dangerous driving, excessive alcohol or drug use, or self- 
injurious or suicidal behavior (Criterion E2). PTSD is often characterized by a heightened 
sensitivity to potential threats, including those that are related to the traumatic experience 
(e.g., following a motor vehicle accident, being especially sensitive to the threat potentially

caused by cars or trucks) and those not related to the traumatic event (e.g., being fearful of 
suffering a heart attack) (Criterion E3). Individuals with PTSD may be very reactive to un­
expected stimuli, displaying a heightened startle response, or jumpiness, to loud noises or 
unexpected movements (e.g., jumping markedly in response to a telephone ringing) (Cri­
terion E4). Concentration difficulties, including difficulty remembering daily events (e.g., 
forgetting one's telephone number) or attending to focused tasks (e.g., following a conver­
sation for a sustained period of time), are commonly reported (Criterion E5). Problems 
with sleep onset and maintenance are common and may be associated with nightmares 
and safety concerns or with generalized elevated arousal that interferes with adequate sleep 
(Criterion E6). Some individuals also experience persistent dissociative symptoms of de­
tachment from their bodies (depersonalization) or the world around them (derealization);

tachment from their bodies (depersonalization) or the world around them (derealization); 
this is reflected in the ''with dissociative symptoms" specifier.
Developmental regression, such as loss of language in young children, may occur. Audi­
tory pseudo-hallucinations, such as having the sensory experience of hearing one's 
thoughts spoken in one or more different voices, as well as paranoid ideation, can be pres­
ent. Following prolonged, repeated, and severe traumatic events (e.g., childhood abuse, 
torture), the individual may additionally experience difficulties in regulating emotions or 
maintaining stable interpersonal relationships, or dissociative symptoms. When the trau­
matic event produces violent death, symptoms of both problematic bereavement and PTSD 
may be present.

In the United States, projected lifetime risk for PTSD using DSM-IV criteria at age 75 years 
is 8.7%. Twelve-month prevalence among U.S. adults is about 3.5%. Lower estimates are 
seen in Europe and most Asian, African, and Latin American countries, clustering around 
0.5%-L0%. Although different groups have different levels of exposure to traumatic 
events, the conditional probability of developing PTSD following a similar level of expo­
sure may also vary across cultural groups. Rates of PTSD are higher among veterans and 
others whose vocation increases the risk of traumatic exposure (e.g., police, firefighters, 
emergency medical personnel). Highest rates (ranging from one-third to more than one- 
half of those exposed) are found among survivors of rape, military combat and captivity,

half of those exposed) are found among survivors of rape, military combat and captivity, 
and ethnically or politically motivated internment and genocide. The prevalence of PTSD 
may vary across development; children and adolescents, including preschool children, 
generally have displayed lower prevalence following exposure to serious traumatic 
events; however, this may be because previous criteria were insufficiently developmen­
tally informed. The prevalence of full-threshold PTSD also appears to be lower among 
older adults compared with the general population; there is evidence that subthreshold 
presentations are more common than full PTSD in later life and that these symptoms are 
associated with substantial clinical impairment. Compared with U.S. non-Latino whites, 
higher rates of PTSD have been reported among U.S. Latinos, African Americans, and

higher rates of PTSD have been reported among U.S. Latinos, African Americans, and 
American Indians, and lower rates have been reported among Asian Americans, after ad­
justment for traumatic exposure and demographic variables.
PTSD can occur at any age, beginning after the first year of life. Symptoms usually begin 
within the first 3 months after the trauma, although there may be a delay of months, or 
even years, before criteria for the diagnosis are met. There is abundant evidence for what 
DSM-IV called "delayed onset" but is now called "delayed expression," with the recogni­
tion that some symptoms typically appear immediately and that the delay is in meeting 
full criteria.

Frequently, an individual's reaction to a trauma initially meets criteria for acute stress 
disorder in the immediate aftermath of the trauma. The symptoms of PTSD and the rela­
tive predominance of different symptoms may vary over time. Duration of the symptoms 
also varies, with complete recovery within 3 months occurring in approximately one-half 
of adults, while some individuals remain symptomatic for longer than 12 months and 
sometimes for more than 50 years. Symptom recurrence and intensification may occur in 
response to reminders of the original trauma, ongoing life stressors, or newly experienced 
traumatic events. For older individuals, declining health, worsening cognitive function­
ing, and social isolation may exacerbate PTSD symptoms.
The clinical expression of reexperiencing can vary across development. Young children 
may report new onset of frightening dreams without content specific to the traumatic event.

may report new onset of frightening dreams without content specific to the traumatic event. 
Before age 6 years (see criteria for preschool subtype), young children are more likely to ex­
press reexperiencing symptoms through play that refers directly or symbolically to the 
trauma. They may not manifest fearful reactions at the time of the exposure or during reex­
periencing. Parents may report a wide range of emotional or behavioral changes in young 
children. Children may focus on imagined interventions in their play or storytelling. In ad­
dition to avoidance, children may become preoccupied with reminders. Because of young 
children's limitations in expressing thoughts or labeling emotions, negative alterations in 
mood or cognition tend to involve primarily mood changes. Children may experience co­
occurring traumas (e.g., physical abuse, witnessing domestic violence) and in chronic cir­

cumstances may not be able to identify onset of symptomatology. Avoidant behavior may 
be associated with restricted play or exploratory behavior in young children; reduced par­
ticipation in new activities in school-age children; or reluctance to pursue developmental op­
portunities in adolescents (e.g., dating, driving). Older children and adolescents may judge 
themselves as cowardly. Adolescents may harbor beliefs of being changed in ways that 
make them socially undesirable and estrange them from peers (e.g., '"Now I'll never fit in") 
and lose aspirations for the future. Irritable or aggressive behavior in children and adoles­
cents can interfere with peer relationships and school behavior. Reckless behavior may lead

cents can interfere with peer relationships and school behavior. Reckless behavior may lead 
to accidental injury to self or others, thrill-seeking, or high-risk behaviors. Individuals who 
continue to experience PTSD into older adulthood may express fewer symptoms of hy­
perarousal, avoidance, and negative cognitions and mood compared with younger adults 
with PTSD, although adults exposed to traumatic events during later life may display more 
avoidance, hyperarousal, sleep problems, and crying spells than do younger adults exposed 
to the same traumatic events. In older individuals, the disorder is associated with negative 
health perceptions, primary care utilization, and suicidal ideation.
Risk (and protective) factors are generally divided into pretraumatic, peritraumatic, and 
posttraumatic factors.
Pretraumatic factors

Temperamental. These include childhood emotional problems by age 6 years (e.g., prior 
traumatic exposure, externalizing or anxiety problems) and prior mental disorders (e.g., 
panic disorder, depressive disorder, PTSD, or obsessive-compulsive disorder [OCD]).
Environmental. These include lower socioeconomic status; lower education; exposure to 
prior trauma (especially during childhood); childhood adversity (e.g., economic depriva­
tion, family dysRinction, parental separation or death); cultural characteristics (e.g., fatal­
istic or self-blaming coping strategies); lower intelligence; minority racial/ethnic status; 
and a family psychiatric history. Social support prior to event exposure is protective.
Genetic and physiological. These include female gender and younger age at the time of

Genetic and physiological. These include female gender and younger age at the time of 
trauma exposure (for adults). Certain genotypes may either be protective or increase risk 
of PTSD after exposure to traumatic events.

Peritraumatic factors
Environmental. These include severity (dose) of the trauma (the greater the magnitude 
of trauma, the greater the likelihood of PTSD), perceived life threat, personal injury, in­
terpersonal violence (particularly trauma peφetrated by a caregiver or involving a wit­
nessed threat to a caregiver in children), and, for military personnel, being a perpetrator, 
witnessing atrocities, or killing the enemy. Finally, dissociation that occurs during the trauma 
and persists afterward is a risk factor.
Posttraumatic factors
Temperamental. These include negative appraisals, inappropriate coping strategies, 
and development of acute stress disorder.
Environmental. These include subsequent exposure to repeated upsetting reminders, subse­
quent adverse life events, and financial or other trauma-related losses. Social support (includ­
ing family stability, for children) is a protective factor that moderates outcome after trauma.

The risk of onset and severity of PTSD may differ across cultural groups as a result of vari­
ation in the type of traumatic exposure (e.g., genocide), the impact on disorder severity of 
the meaning attributed to the traumatic event (e.g., inability to perform funerary rites after 
a mass killing), the ongoing sociocultural context (e.g., residing among unpunished per­
petrators in postconflict settings), and other cultural factors (e.g., acculturative stress in 
immigrants). The relative risk for PTSD of particular exposures (e.g., religious persecu­
tion) may vary across cultural groups. The clinical expression of the symptoms or symp­
tom clusters of PTSD may vary culturally, particularly with respect to avoidance and 
numbing symptoms, distressing dreams, and somatic symptoms (e.g., dizziness, short­
ness of breath, heat sensations).

Cultural syndromes and idioms of distress influence the expression of PTSD and the 
range of comorbid disorders in different cultures by providing behavioral and cognitive 
templates that link traumatic exposures to specific symptoms. For example, panic attack 
symptoms may be salient in PTSD among Cambodians and Latin Americans because of 
the association of traumatic exposure with panic-like khyâl  attacks and ataque de nervios.  
Comprehensive evaluation of local expressions of PTSD should include assessment of cul­
tural concepts of distress (see the chapter "Cultural Formulation" in Section III).
PTSD is more prevalent among females than among males across the lifespan. Females in 
the general population experience PTSD for a longer duration than do males. At least some

the general population experience PTSD for a longer duration than do males. At least some 
of the increased risk for PTSD in females appears to be attributable to a greater likelihood 
of exposure to traumatic events, such as rape, and other forms of interpersonal violence. 
Within populations exposed specifically to such stressors, gender differences in risk for 
PTSD are attenuated or nonsignificant.
Traumatic events such as childhood abuse increase a person's suicide risk. PTSD is associated 
with suicidal ideation and suicide attempts, and presence of the disorder may indicate which 
individuals with ideation eventually make a suicide plan or actually attempt suicide.
PTSD is associated with high levels of social, occupational, and physical disability, as well

PTSD is associated with high levels of social, occupational, and physical disability, as well 
as considerable economic costs and high levels of medical utilization. Impaired function­

ing is exhibited across social, inteq:)ersonal, developmental, educational, physical health, 
and occupational domains. In community and veteran samples, PTSD is associated with 
poor social and family relationships, absenteeism from work, lower income, and lower ed­
ucational and occupational success.
Adjustment disorders. In adjustment disorders, the stressor can be of any severity or 
type rather than that required by PTSD Criterion A. The diagnosis of an adjustment dis­
order is used when the response to a stressor that meets PTSD Criterion A does not meet 
all other PTSD criteria (or criteria for another mental disorder). An adjustment disorder is 
also diagnosed when the symptom pattern of PTSD occurs in response to a stressor that 
does not meet PTSD Criterion A (e.g., spouse leaving, being fired).
Other posttraumatic disorders and conditions. Not all psychopathology that occurs in

Other posttraumatic disorders and conditions. Not all psychopathology that occurs in 
individuals exposed to an extreme stressor should necessarily be attributed to PTSD. The 
diagnosis requires that trauma exposure precede the onset or exacerbation of pertinent 
symptoms. Moreover, if the symptom response pattern to the extreme stressor meets cri­
teria for another mental disorder, these diagnoses should be given instead of, or in addi­
tion to, PTSD. Other diagnoses and conditions are excluded if they are better explained by 
PTSD (e.g., symptoms of panic disorder that occur only after exposure to traumatic re­
minders). If severe, symptom response patterns to the extreme stressor may warrant a sep­
arate diagnosis (e.g., dissociative amnesia).
Acute stress disorder. Acute stress disorder is distinguished from PTSD because the

Acute stress disorder. Acute stress disorder is distinguished from PTSD because the 
symptom pattern in acute stress disorder is restricted to a duration of 3 days to 1  month 
following exposure to the traumatic event.
Anxiety disorders and obsessive-compulsive disorder. In OCD, there are recurrent 
intrusive thoughts, but these meet the definition of an obsession. In addition, the intrusive 
thoughts are not related to an experienced traumatic event, compulsions are usually pres­
ent, and other symptoms of PTSD or acute stress disorder are typically absent. Neither the 
arousal and dissociative symptoms of panic disorder nor the avoidance, irritability, and 
anxiety of generalized anxiety disorder are associated with a specific traumatic event. The 
symptoms of separation anxiety disorder are clearly related to separation from home or 
family, rather than to a traumatic event.

Major depressive disorder. Major depression may or may not be preceded by a trau­
matic event and should be diagnosed if other PTSD symptoms are absent. Specifically, ma­
jor depressive disorder does not include any PTSD Criterion B or C symptoms. Nor does it 
include a number of symptoms from PTSD Criterion D or E.
Personality disorders. Interpersonal difficulties that had their onset, or were greatly ex­
acerbated, after exposure to a traumatic event may be an indication of PTSD, rather than a 
personality disorder, in which such difficulties would be expected independently of any 
traumatic exposure.
Dissociative disorders. Dissociative amnesia, dissociative identity disorder, and de- 
personalization-derealization disorder may or may not be preceded by exposure to a trau­

matic event or may or may not have co-occurring PTSD symptoms. When full PTSD criteria 
are also met, however, the PTSD ''with dissociative symptoms" subtype should be considered.
Conversion disorder (functional neurological symptom disorder). New onset of somatic 
symptoms within the context of posttraumatic distress might be an indication of PTSD 
rather than conversion disorder (functional neurological symptom disorder).
Psychotic disorders. Flashbacks in PTSD must be distinguished from illusions, halluci­
nations, and other perceptual disturbances that may occur in schizophrenia, brief psy­
chotic disorder, and other psychotic disorders; depressive and bipolar disorders with

psychotic features; delirium; substance/medication-induced disorders; and psychotic dis­
orders due to another medical condition.
Traumatic brain injury. When a brain injury occurs in the context of a traumatic event (e.g., 
traumatic accident, bomb blast, acceleration/deceleration trauma), sjmnptoms of PTSD may 
appear. An event causing head trauma may also constitute a psychological traumatic event, 
and tramautic brain injury (TBI)-related neurocognitive symptoms are not mutually exclusive 
and may occur concurrently. Symptoms previously termed postconcussive  (e.g., headaches, 
dizziness, sensitivity to light or sound, irritability, concentration deficits) can occur in brain- 
injured and non-brain-injured populations, including individuals with PTSD. Because symp­
toms of PTSD and TBI-related neurocognitive symptoms can overlap, a differential diagnosis 
between PTSD and neurocognitive disorder symptoms attributable to TBI may be possible

between PTSD and neurocognitive disorder symptoms attributable to TBI may be possible 
based on the presence of symptoms that are distinctive to each presentation. Whereas reexpe- 
riencing and avoidance are characteristic of PTSD and not the effects of TBI, persistent disori­
entation and confusion are more specific to TBI (neurocognitive effects) than to PTSD.
Individuals with PTSD are 80% more likely than those without PTSD to have symptoms 
that meet diagnostic criteria for at least one other mental disorder (e.g., depressive, bipo­
lar, anxiety, or substance use disorders). Comorbid substance use disorder and conduct 
disorder are more common among males than among females. Among U.S. military per­
sonnel and combat veterans who have been deployed to recent wars in Afghanistan and 
Iraq, co-occurrence of PTSD and mild TBI is 48%. Although most young children with

Iraq, co-occurrence of PTSD and mild TBI is 48%. Although most young children with 
PTSD also have at least one other diagnosis, the patterns of comorbidity are different than 
in adults, with oppositional defiant disorder and separation anxiety disorder predominat­
ing. Finally, there is considerable comorbidity between PTSD and major neurocognitive 
disorder and some overlapping symptoms between these disorders.
Acute Stress Disorder
Diagnostic Criteria 308.3 (F43.0)
A. Exposure to actual or threatened death, serious injury, or sexual violation in  one (or  
3. Learning that the event(s) occurred to a close family member or close friend. Note:  
In cases of actual or threatened death of a family member or friend, the event(s)

In cases of actual or threatened death of a family member or friend, the event(s)  
must have been violent or accidental.
event(s) (e.g., first responders collecting human remains, police officers repeatedly  
Note: This does not apply to exposure through electronic media, television, mov­
ies, or pictures, unless this exposure is work related.
B. Presence of nine (or more) of the following symptoms from any of the five categories  
of intrusion, negative mood, dissociation, avoidance, and arousal, beginning or wors­
ening after the traumatic event(s) occurred:
Intrusion Symptoms
event(s). Note: In children, repetitive play may occur in which themes or aspects of

event(s). Note: In children, repetitive play may occur in which themes or aspects of  
the traumatic event(s) are expressed.

related to the event(s). Note: In children, there may be frightening dreams without  
recognizable content.
surroundings.) Note: In children, trauma-specific reenactment may occur in play.
4. Intense or prolonged psychological distress or marked physiological reactions in re­
sponse to internal or external cues that symbolize or resemble an aspect of the  
traumatic event(s).
Negative Mood
5. Persistent inability to experience positive emotions (e.g., inability to experience  
Dissociative Symptoms
6. An altered sense of the reality of one’s surroundings or oneself (e.g., seeing oneself

6. An altered sense of the reality of one’s surroundings or oneself (e.g., seeing oneself  
from another’s perspective, being in a daze, time slowing).
7. Inability to remember an important aspect of the traumatic event(s) (typically due to  
dissociative amnesia and not to other factors such as head injury, alcohol, or  
drugs).
Avoidance Symptoms
8. Efforts to avoid distressing memories, thoughts, or feelings about or closely asso­
ciated with the traumatic event(s).
9. Efforts to avoid external reminders (people, places, conversations, activities, ob­
jects, situations) that arouse distressing memories, thoughts, or feelings about or  
closely associated with the traumatic event(s).
Arousal Symptoms
10. Sleep disturbance (e.g., difficulty falling or staying asleep, restless sleep).
11. Irritable behavior and angry outbursts (with little or no provocation), typically ex­

12. Hypervigilance.
13. Problems with concentration.
14. Exaggerated startle response.
C. Duration of the disturbance (symptoms in Criterion B) is 3 days to 1  month after trauma  
exposure.
Note: Symptoms typically begin immediately after the trauma, but persistence for at  
least 3 days and up to a month is needed to meet disorder criteria.
D. The disturbance causes clinically significant distress or impairment in social, occupa­
E. The disturbance is not attributable to the physiological effects of a substance (e.g.,  
medication or alcohol) or another medical condition (e.g., mild traumatic brain injury)

medication or alcohol) or another medical condition (e.g., mild traumatic brain injury)  
and is not better explained by brief psychotic disorder._________________________
The essential feature of acute stress disorder is the development of characteristic symp­
toms lasting from 3 days to 1  month following exposure to one or more traumatic events.
Traumatic events that are experienced directly include, but are not limited to, exposure
to war as a combatant or civilian, threatened or actual violent personal assault (e.g., sexual

violence, physical attack, active combat, mugging, childhood physical and/or sexual vio­
lence, being kidnapped, being taken hostage, terrorist attack, torture), natural or human­
made disasters (e.g., earthquake, hurricane, airplane crash), and severe accident (e.g., 
severe motor vehicle, industrial accident). For children, sexually traumatic events may 
include inappropriate sexual experiences without violence or injury. A life-threatening 
illness or debilitating medical condition is not necessarily considered a traumatic event. 
Medical incidents that qualify as traumatic events involve sudden, catastrophic events (e.g., 
waking during surgery, anaphylactic shock). Stressful events that do not possess the severe 
and traumatic components of events encompassed by Criterion A may lead to an adjust­
ment disorder but not to acute stress disorder.
The clinical presentation of acute stress disorder may vary by individual but typically

The clinical presentation of acute stress disorder may vary by individual but typically 
involves an anxiety response that includes some form of reexperiencing of or reactivity to 
the traumatic event. In some individuals, a dissociative or detached presentation can pre­
dominate, although these individuals typically will also display strong emotional or phys­
iological reactivity in response to trauma reminders. In other individuals, there can be a 
strong anger response in which reactivity is characterized by irritable or possibly aggres­
sive responses. The full symptom picture must be present for at least 3 days after the trau­
matic event and can be diagnosed only up to 1 month after the event. Symptoms that occur 
immediately after the event but resolve in less than 3 days would not meet criteria for 
acute stress disorder.
Witnessed events include, but are not limited to, observing threatened or serious in­

jury, unnatural death, physical or sexual violence inflicted on another individual as a re­
sult of violent assault, severe domestic violence, severe accident, war, and disaster; it may 
also include witnessing a medical catastrophe (e.g., a life-threatening hemorrhage) involv­
ing one's child. Events experienced indirectly through learning about the event are limited 
to close relatives or close friends. Such events must have been violent or accidental—death 
due to natural causes does not qualify—and include violent personal assault, suicide, se­
rious accident, or serious injury. The disorder may be especially severe when the stressor 
is interpersonal and intentional (e.g., torture, rape). The likelihood of developing this dis­

order may increase as the intensity of and physical proximity to the stressor increase.
has recurrent and intrusive recollections of the event (Criterion Bl). The recollections are 
spontaneous or triggered recurrent memories of the event that usually occur in response 
to a stimulus that is reminiscent of the traumatic experience (e.g., the sound of a backfiring 
car triggering memories of gunshots). These intrusive memories often include sensory 
(e.g., sensing the intense heat that was perceived in a house fire), emotional (e.g., experi­
encing the fear of believing that one was about to be stabbed), or physiological (e.g., expe­
riencing the shortness of breath that one suffered during a near-drowning) components.

Distressing dreams may contain themes that are representative of or thematically re­
lated to the major threats involved in the traumatic event. (For example, in the case of a 
motor vehicle accident survivor, the distressing dreams may involve crashing cars gener­
ally; in the case of a combat soldier, the distressing dreams may involve being harmed in 
ways other than combat.)
Dissociative states may last from a few seconds to several hours, or even days, during 
which components of the event are relived and the individual behaves as though experi­
encing the event at that moment. While dissociative responses are common during a trau­
matic event, only dissociative responses that persist beyond 3 days after trauma exposure

matic event, only dissociative responses that persist beyond 3 days after trauma exposure 
are considered for the diagnosis of acute stress disorder. For young children, reenactment 
of events related to trauma may appear in play and may include dissociative moments 
(e.g., a child who survives a motor vehicle accident may repeatedly crash toy cars during 
play in a focused and distressing manner). These episodes, often referred to as flashbacks,  
are typically brief but involve a sense that the traumatic event is occurring in the present 
rather than being remembered in the past and are associated with significant distress.

Some individuals with the disorder do not have intrusive memories of the event itself, 
but instead experience intense psychological distress or physiological reactivity when 
they are exposed to triggering events that resemble or symbolize an aspect of the traumatic 
event (e.g., windy days for children after a hurricane, entering an elevator for a male or fe­
male who was raped in an elevator, seeing someone who resembles one's perpetrator). 
The triggering cue could be a physical sensation (e.g., a sense of heat for a bum victim, diz­
ziness for survivors of head trauma), particularly for individuals with highly somatic pre­
sentations. The individual may have a persistent inability to feel positive emotions (e.g., 
happiness, joy, satisfaction, or emotions associated with intimacy, tenderness, or sexual­
ity) but can experience negative emotions such as fear, sadness, anger, guilt, or shame.

Alterations in awareness can include depersonalization,  a detached sense of oneself (e.g., 
seeing oneself from the other side of the room), or derealization,  having a distorted view of 
one's surroundings (e.g., perceiving that things are moving in slow motion, seeing things 
in a daze, not being aware of events that one would normally encode). Some individuals 
also report an inability to remember an important aspect of the traumatic event that was 
presumably encoded. This symptom is attributable to dissociative amnesia and is not at­
tributable to head injury, alcohol, or drugs.
Stimuli associated with the trauma are persistently avoided. The individual may refuse 
to discuss the traumatic experience or may engage in avoidance strategies to minimize

to discuss the traumatic experience or may engage in avoidance strategies to minimize 
awareness of emotional reactions (e.g., excessive alcohol use when reminded of the ex­
perience). This behavioral avoidance may include avoiding watching news coverage of 
the traumatic experience, refusing to return to a workplace where the trauma occurred, or 
avoiding interacting with others who shared the same traumatic experience.
It is very common for individuals with acute stress disorder to experience problems 
with sleep onset and maintenance, which may be associated with nightmares or with gen­
eralized elevated arousal that prevents adequate sleep. Individuals with acute stress dis­
order may be quick tempered and may even engage in aggressive verbal and/or physical 
behavior with little provocation. Acute stress disorder is often characterized by a height­

ened sensitivity to potential threats, including those that are related to the traumatic ex­
perience (e.g., a motor vehicle accident victim may be especially sensitive to the threat 
potentially caused by any cars or trucks) or those not related to the traumatic event (e.g., 
fear of having a heart attack). Concentration difficulties, including difficulty remembering 
daily events (e.g., forgetting one's telephone number) or attending to focused tasks (e.g., 
following a conversation for a sustained period of time), are commonly reported. Individ­
uals with acute stress disorder may be very reactive to unexpected stimuli, displaying a 
heightened startle response or jumpiness to loud noises or unexpected movements (e.g., 
the individual may jump markedly in the response to a telephone ringing).

Individuals with acute stress disorder commonly engage in catastrophic or extremely neg­
ative thoughts about their role in the traumatic event, their response to the traumatic ex­
perience, or the likelihood of future harm. For example, an individual with acute stress 
disorder may feel excessively guilty about not having prevented the traumatic event or 
about not adapting to the experience more successfully. Individuals with acute stress dis­
order may also interpret their symptoms in a catastrophic manner, such that flashback 
memories or emotional numbing may be interpreted as a sign of diminished mental ca­
pacity. It is common for individuals with acute stress disorder to experience panic attacks

pacity. It is common for individuals with acute stress disorder to experience panic attacks 
in the initial month after trauma exposure that may be triggered by trauma reminders or 
may apparently occur spontaneously. Additionally, individuals with acute stress disorder 
may display chaotic or impulsive behavior. For example, individuals may drive reck­
lessly, make irrational decisions, or gamble excessively. In children, there may be sig­
nificant separation anxiety, possibly manifested by excessive needs for attention from

caregivers. In the case of bereavement following a death that occurred in traumatic cir­
cumstances, the symptoms of acute stress disorder can involve acute grief reactions. In 
such cases, reexperiencing, dissociative, and arousal symptoms may involve reactions to 
the loss, such as intrusive memories of the circumstances of the individual's death, disbe­
lief that the individual has died, and anger about the death. Postconcussive symptoms 
(e.g., headaches, dizziness, sensitivity to light or sound, irritability, concentration deficits), 
which occur frequently following mild traumatic brain injury, are also frequently seen in 
individuals with acute stress disorder. Postconcussive symptoms are equally common in 
brain-injured and non-brain-injured populations, and the frequent occurrence of postcon­
cussive symptoms could be attributable to acute stress disorder symptoms.
The prevalence of acute stress disorder in recently trauma-exposed populations (i.e.,

The prevalence of acute stress disorder in recently trauma-exposed populations (i.e., 
within 1  month of trauma exposure) varies according to the nature of the event and the 
context in which it is assessed. In both U.S. and non-U.S. populations, acute stress disorder 
tends to be identified in less than 20% of cases following traumatic events that do not in­
volve interpersonal assault; 13%-21% of motor vehicle accidents, 14% of mild traumatic 
brain injury, 19% of assault, 10% of severe burns, and 6%-12% of industrial accidents. 
Higher rates (i.e., 20%-50%) are reported following interpersonal traumatic events, in­
cluding assault, rape, and witnessing a mass shooting.
Acute stress disorder cannot be diagnosed until 3 days after a traumatic event. Although 
acute stress disorder may progress to posttraumatic stress disorder (PTSD) after 1 month,

acute stress disorder may progress to posttraumatic stress disorder (PTSD) after 1 month, 
it may also be a transient stress response that remits within 1  month of trauma exposure 
and does not result in PTSD. Approximately half of individuals who eventually develop 
PTSD initially present with acute stress disorder. Symptom worsening during the initial 
month can occur, often as a result of ongoing life stressors or further traumatic events.
The forms of reexperiencing can vary across development. Unlike adults or adoles­
cents, young children may report frightening dreams without content that clearly reflects 
aspects of the trauma (e.g., waking in fright in the aftermath of the trauma but being unable 
to relate the content of the dream to the traumatic event). Children age 6 years and younger 
are more likely than older children to express reexperiencing symptoms through play that

are more likely than older children to express reexperiencing symptoms through play that 
refers directly or symbolically to the trauma. For example, a very young child who sur­
vived a fire may draw pictures of flames. Young children also do not necessarily manifest 
fearful reactions at the time of the exposure or even during reexperiencing. Parents typi­
cally report a range of emotional expressions, such as anger, shame, or withdrawal, and 
even excessively bright positive affect, in young children who are traumatized. Although 
children may avoid reminders of the trauma, they sometimes become preoccupied with 
reminders (e.g., a young child bitten by a dog may talk about dogs constantly yet avoid go­
ing outside because of fear of coming into contact with a dog).
Temperamental. Risk factors include prior mental disorder, high levels of negative af-

Temperamental. Risk factors include prior mental disorder, high levels of negative af- 
fectivity (neuroticism), greater perceived severity of the traumatic event, and an avoidant 
coping style. Catastrophic appraisals of the traumatic experience, often characterized by 
exaggerated appraisals of future harm, guilt, or hopelessness, are strongly predictive of 
Environmental. First and foremost, an individual must be exposed to a traumatic event to 
be at risk for acute stress disorder. Risk factors for the disorder include a history of prior 
trauma.

Genetic and physiological. Females are at greater risk for developing acute stress dis­
order.
\
Elevated reactivity, as reflected by acoustic startle response, prior to trauma exposure 
increases the risk for developing acute stress disorder.
The profile of symptoms of acute stress disorder may vary cross-culturally, particularly 
with respect to dissociative symptoms, nightmares, avoidance, and somatic symptoms 
(e.g., dizziness, shortness of breath, heat sensations). Cultural syndromes and idioms of 
distress shape the local symptom profiles of acute stress disorder. Some cultural groups 
may display variants of dissociative responses, such as possession or trancelike behaviors 
in the initial month after trauma exposure. Panic symptoms may be salient in acute stress 
disorder among Cambodians because of the association of traumatic exposure with panic­
like khyâl  attacks, and ataque de nervios  among Latin Americans may also follow a traumatic

like khyâl  attacks, and ataque de nervios  among Latin Americans may also follow a traumatic 
exposure.
Acute stress disorder is more prevalent among females than among males. Sex-linked neu- 
robiological differences in stress response may contribute to females' increased risk for 
acute stress disorder. The increased risk for the disorder in females may be attributable in 
part to a greater likelihood of exposure to the types of traumatic events with a high con­
ditional risk for acute stress disorder, such as rape and other interpersonal violence.
Functional Consequences of Acute Stress Disorder
Impaired functioning in social, interpersonal, or occupational domains has been shown 
across survivors of accidents, assault, and rape who develop acute stress disorder. The ex­
treme levels of anxiety that may be associated with acute stress disorder may interfere

treme levels of anxiety that may be associated with acute stress disorder may interfere 
with sleep, energy levels, and capacity to attend to tasks. Avoidance in acute stress dis­
order can result in generalized withdrawal from many situations that are perceived as 
potentially threatening, which can lead to nonattendance of medical appointments, avoid­
ance of driving to important appointments, and absenteeism from work.
Adjustment disorders. In acute stress disorder, the stressor can be of any severity rather 
than of the severity and type required by Criterion A of acute stress disorder. The diagnosis of 
an adjustment disorder is used when the response to a Criterion A event does not meet the cri­
teria for acute stress disorder (or another specific mental disorder) and when the symptom pat­

tern of acute stress disorder occurs in response to a stressor that does not meet Criterion A for 
exposure to actual or threatened death, serious injury, or sexual violence (e.g., spouse leaving, 
being fired). For example, severe stress reactions to life-threatening illnesses that may include 
some acute stress disorder symptoms may be more appropriately described as an adjustment 
disorder. Some forms of acute stress response do not include acute stress disorder symptoms 
and may be characterized by anger, depression, or guilt. These responses are more appro­
priately described as primarily an adjustment disorder. Depressive or anger responses in an 
adjustment disorder may involve rumination about the traumatic event, as opposed to invol­

untary and intrusive distressing memories in acute stress disorder.
Panic disorder. Spontaneous panic attacks are very common in acute stress disorder. 
However, panic disorder is diagnosed only if panic attacks are unexpected and there is 
anxiety about future attacks or maladaptive changes in behavior associated with fear of 
dire consequences of the attacks.

Dissociative disorders. Severe dissociative responses (in the absence of characteristic 
acute stress disorder symptoms) may be diagnosed as derealization/depersonalization 
disorder. If severe amnesia of the trauma persists in the absence of characteristic acute 
stress disorder symptoms, the diagnosis of dissociative amnesia may be indicated.
Posttraumatic stress disorder. Acute stress disorder is distinguished from PTSD because 
the symptom pattern in acute stress disorder must occur within 1 month of the traumatic event 
and resolve within that 1-month period. If the symptoms persist for more than 1  month and 
meet criteria for PTSD, the diagnosis is changed from acute stress disorder to PTSD.
Obsessive-compulsive disorder. In obsessive-compulsive disorder, there are recurrent 

ent, and other symptoms of acute stress disorder are typically absent.
Psychotic disorders. Flashbacks in acute stress disorder must be distinguished from il­
lusions, hallucinations, and other perceptual disturbances that may occur in schizophre­
nia, other psychotic disorders, depressive or bipolar disorder with psychotic features, a 
delirium, substance/medication-induced disorders, and psychotic disorders due to an­
other medical condition. Acute stress disorder flashbacks are distinguished from these 
other perceptual disturbances by being directly related to the traumatic experience and by 
occurring in the absence of other psychotic or substance-induced features.
Traumatic brain injury. When a brain injury occurs in the context of a traumatic event

Traumatic brain injury. When a brain injury occurs in the context of a traumatic event 
(e.g., traumatic accident, bomb blast, acceleration/deceleration trauma), symptoms of 
acute stress disorder may appear. An event causing head trauma may also constitute a 
psychological traumatic event, and tramautic brain injury (TBI)-related neurocognitive 
symptoms are not mutually exclusive and may occur concurrently. Symptoms previously 
termed postconcussive  (e.g., headaches, dizziness, sensitivity to light or sound, irritability, 
concentration deficits) can occur in brain-injured and non-brain injured populations, in­
cluding individuals with acute stress disorder. Because symptoms of acute stress disorder 
and TBI-related neurocognitive symptoms can overlap, a differential diagnosis between 
acute stress disorder and neurocognitive disorder symptoms attributable to TBI may be

acute stress disorder and neurocognitive disorder symptoms attributable to TBI may be 
possible based on the presence of symptoms that are distinctive to each presenta­
tion. Whereas reexperiencing and avoidance are characteristic of acute stress disorder and 
not the effects of TBI, persistent disorientation and confusion are more specific to TBI (neu­
rocognitive effects) than to acute stress disorder. Furthermore, differential is aided by the 
fact that symptoms of acute stress disorder persist for up to only 1  month following trauma 
exposure.
Adjustment Disorders
A. The development of emotional or behavioral symptoms in response to an identifiable  
stressor(s) occurring within 3 months of the onset of the stressor(s).
B. These symptoms or behaviors are clinically significant, as evidenced by one or both of  

1. Marked distress that is out of proportion to the severity or intensity of the stressor,  
taking into account the external context and the cultural factors that might influence  
symptom severity and presentation.
2. Significant impairment in  social, occupational, or other important areas of functioning.
C. The stress-related disturbance does not meet the criteria for another mental disorder  
and is not merely an exacerbation of a preexisting mental disorder.

D. The symptoms do not represent normal bereavement.
E. Once the stressor or its consequences have terminated, the symptoms do not persist  
for more than an additional 6 months.
309.0 (F43.21) With depressed mood: Low mood, tearfulness, or feelings of hope­
lessness are predominant.
309.24 (F43.22) With anxiety: Nervousness, worry, jitteriness, or separation anxiety  
is predominant.
309.28 (F43.23) With mixed anxiety and depressed mood: A combination of de­
pression and anxiety is predominant.
309.3 (F43.24) With disturbance of conduct: Disturbance of conduct is predominant.
309.4 (F43.25) With mixed disturbance of emotions and conduct: Both emotional  
symptoms (e.g., depression, anxiety) and a disturbance of conduct are predominant.  
309.9 (F43.20) Unspecified: For maladaptive reactions that are not classifiable as one  
of the specific subtypes of adjustment disorder. ______________________________

The presence of emotional or behavioral symptoms in response to an identifiable stressor 
is the essential feature of adjustment disorders (Criterion A). The stressor may be a single 
event (e.g., a termination of a romantic relationship), or there may be multiple stressors 
(e.g., marked business difficulties and marital problems). Stressors may be recurrent (e.g., 
associated with seasonal business crises, unfulfilling sexual relationships) or continuous 
(e.g., a persistent painful illness with increasing disability, living in a crime-ridden neigh­
borhood). Stressors may affect a single individual, an entire family, or a larger group or 
community (e.g., a natural disaster). Some stressors may accompany specific developmen­

tal events (e.g., going to school, leaving a parental home, reentering a parental home, get­
ting married, becoming a parent, failing to attain occupational goals, retirement).
Adjustment disorders may be diagnosed following the death of a loved one when the 
intensity, quality, or persistence of grief reactions exceeds what normally might be ex­
pected, when cultural, religious, or age-appropriate norms are taken into account. A more 
specific set of bereavement-related symptoms has been designated persistent complex be­
reavement disorder.
Adjustment disorders are associated with an increased risk of suicide attempts and 
completed suicide.
Adjustment disorders are common, although prevalence may vary widely as a function of

Adjustment disorders are common, although prevalence may vary widely as a function of 
the population studied and the assessment methods used. The percentage of individuals 
in outpatient mental health treatment with a principal diagnosis of an adjustment disorder 
ranges from approximately 5% to 20%. In a hospital psychiatric consultation setting, it is 
often the most common diagnosis, frequently reaching 50%.
By definition, the disturbance in adjustment disorders begins within 3 months of onset of 
a stressor and lasts no longer than 6 months after the stressor or its consequences have 
ceased. If the stressor is an acute event (e.g., being fired from a job), the onset of the dis­
turbance is usually immediate (i.e., within a few days) and the duration is relatively brief 
(i.e., no more than a few months). If the stressor or its consequences persist, the adjustment

(i.e., no more than a few months). If the stressor or its consequences persist, the adjustment 
disorder may also continue to be present and become the persistent form.

Environmental. Individuals from disadvantaged life circumstances experience a high 
rate of stressors and may be at increased risk for adjustment disorders.
The context of the individual's cultural setting should be taken into account in making the 
clinical judgment of whether the individual's response to the stressor is maladaptive or 
whether the associated distress is in excess of what would be expected. The nature, mean­
ing, and experience of the stressors and the evaluation of the response to the stressors may 
vary across cultures.
Functional Consequences of Adjustment Disorders
The subjective distress or impairment in functioning associated with adjustment disorders 
is frequently manifested as decreased performance at work or school and temporary 
changes in social relationships. An adjustment disorder may complicate the course of ill­

ness in individuals who have a general medical condition (e.g., decreased compliance with 
the recommended medical regimen; increased length of hospital stay).
Major depressive disorder. If an individual has symptoms that meet criteria for a major 
depressive disorder in response to a stressor, the diagnosis of an adjustment disorder is 
not applicable. The symptom profile of major depressive disorder differentiates it from ad­
justment disorders.
Posttraumatic stress disorder and acute stress disorder. In adjustment disorders, the 
stressor can be of any severity rather than of the severity and type required by Criterion A 
of acute stress disorder and posttraumatic stress disorder (PTSD). In distinguishing ad­

justment disorders from these two posttraumatic diagnoses, there are both timing and 
symptom profile considerations. Adjustment disorders can be diagnosed immediately 
and persist up to 6 months after exposure to the traumatic event, whereas acute stress dis­
order can only occur between 3 days and 1 month of exposure to the stressor, and PTSD 
cannot be diagnosed until at least 1 month has passed since the occurrence of the traumatic 
stressor. The required symptom profile for PTSD and acute stress disorder differentiates 
them from the adjustment disorders. With regard to symptom profiles, an adjustment dis­
order may be diagnosed following a traumatic event when an individual exhibits symptoms 
of either acute stress disorder or PTSD that do not meet or exceed the diagnostic threshold

of either acute stress disorder or PTSD that do not meet or exceed the diagnostic threshold 
for either disorder. An adjustment disorder should also be diagnosed for individuals who 
have not been exposed to a traumatic event but who otherwise exhibit the full symptom pro­
file of either acute stress disorder or PTSD.
Personality disorders. With regard to personality disorders, some personality features 
may be associated with a vulnerability to situational distress that may resemble an adjust­
ment disorder. The lifetime history of personality functioning will help inform the in­
terpretation of distressed behaviors to aid in distinguishing a long-standing personality 
disorder from an adjustment disorder. In addition to some personality disorders incurring 
vulnerability to distress, stressors may also exacerbate personality disorder symptoms. In

vulnerability to distress, stressors may also exacerbate personality disorder symptoms. In 
the presence of a personality disorder, if the symptom criteria for an adjustment disorder 
are met, and the stress-related disturbance exceeds what may be attributable to maladap­
tive personality disorder symptoms (i.e.. Criterion C is met), then the diagnosis of an ad­
justment disorder should be made.

Psychological factors affecting other medical conditions. In psychological factors af­
fecting other medical conditions, specific psychological entities (e.g., psychological symp­
toms, behaviors, other factors) exacerbate a medical condition. These psychological 
factors can precipitate, exacerbate, or put an individual at risk for medical illness, or they 
can worsen an existing condition. In contrast, an adjustment disorder is a reaction to the 
stressor (e.g., having a medical illness).
Normative stress reactions. When bad things happen, most people get upset. This is 
not an adjustment disorder. The diagnosis should only be made when the magnitude of 
the distress (e.g., alterations in mood, anxiety, or conduct) exceeds what would normally 
be expected (which may vary in different cultures) or when the adverse event precipitates 
functional impairment.
Adjustment disorders can accompany most mental disorders and any medical disorder.

Adjustment disorders can accompany most mental disorders and any medical disorder. 
Adjustment disorders can be diagnosed in addition to another mental disorder only if the 
latter does not explain the particular symptoms that occur in reaction to the stressor. For 
example, an individual may develop an adjustment disorder, with depressed mood, after 
losing a job and at the same time have a diagnosis of obsessive-compulsive disorder. Or, 
an individual may have a depressive or bipolar disorder and an adjustment disorder as 
long as the criteria for both are met. Adjustment disorders are common accompaniments 
of medical illness and may be the major psychological response to a medical disorder.
Other Specified Trauma- and  
Stressor-Related Disorder
309.89 (F43.8)
This category applies to presentations in which symptoms characteristic of a trauma- and  
stressor-related disorder that cause clinically significant distress or impairment in social,

stressor-related disorder that cause clinically significant distress or impairment in social,  
occupational, or other important areas of functioning predominate but do not meet the full  
criteria for any of the disorders in the trauma- and stressor-related disorders diagnostic  
class. The other specified trauma- and stressor-related disorder category is used in situa­
tions in which the clinician chooses to communicate the specific reason that the presenta­
tion does not meet the criteria for any specific trauma- and stressor-related disorder. This  
is done by recording “ other specified trauma- and stressor-related disorder”  followed by  
the specific reason (e.g., “ persistent complex bereavement disorder”).

1. Adjustment-like disorders with delayed onset of symptoms that occur more than  
3 months after the stressor.
2. Adjustment-like disorders with prolonged duration of more than 6 months with­
out prolonged duration of stressor.
3. Ataque de nervios:  See “ Glossary of Cultural Concepts of Distress”  in the Appendix.
4. Other cultural syndromes: See “ Glossary of Cultural Concepts of Distress”  in the Ap­
pendix.
5. Persistent complex bereavement disorder: This disorder is characterized by severe  
and persistent grief and mourning reactions (see the chapter “ Conditions for Further  
Study” ).

Unspecified Trauma- and  
309.9 (F43.9)
This category applies to presentations in  which symptoms characteristic of a trauma- and  
stressor-related disorder that cause clinically significant distress or impairment in social, oc­
cupational, or other important areas of functioning predominate but do not meet the full cri­
teria for any of the disorders in the trauma- and stressor-related disorders diagnostic class.  
The unspecified trauma- or stressor-related disorder category is used in situations in which  
the clinician chooses not to specify the reason that the criteria are not met for a specific  
trauma- and stressor-related disorder, and includes presentations in which there is insuffi­
cient information to make a more specific diagnosis (e.g., in  emergency room settings).

DiSSOCiâtiVG d isorders are characterized by a disruption of and/or discontinuity 
in the normal integration of consciousness, memory, identity, emotion, perception, body 
representation, motor control, and behavior. Dissociative symptoms can potentially dis­
rupt every area of psychological functioning. This chapter includes dissociative identity 
disorder, dissociative amnesia, depersonalization/derealization disorder, other specified 
dissociative disorder, and unspecified dissociative disorder.
Dissociative symptoms are experienced as a) unbidden intrusions into awareness and 
behavior, with accompanying losses of continuity in subjective experience (i.e., "positive" 
dissociative symptoms such as fragmentation of identity, depersonalization, and dereal­
ization) and/or b) inability to access information or to control mental functions that nor­
mally are readily amenable to access or control (i.e., '"negative" dissociative symptoms such 
as amnesia).

The dissociative disorders are frequently found in the aftermath of trauma, and many 
of the symptoms, including embarrassment and confusion about the symptoms or a desire 
to hide them, are influenced by the proximity to trauma. In DSM-5, the dissociative disor­
ders are placed next to, but are not part of, the trauma- and stressor-related disorders, re­
flecting the close relationship between these diagnostic classes. Both acute stress disorder 
and posttraumatic stress disorder contain dissociative symptoms, such as amnesia, flash­
backs, numbing, and depersonalization/derealization.
Depersonalization/derealization disorder  is characterized by clinically significant persis­
tent or recurrent depersonalization (i.e., experiences of unreality or detachment from one's

tent or recurrent depersonalization (i.e., experiences of unreality or detachment from one's 
mind, self, or body) and/or derealization (i.e., experiences of imreality or detachment from 
one's surroundings). These alterations of experience are accompanied by intact reality 
testing. There is no evidence of any distinction between individuals with predominantly 
depersonalization versus derealization symptoms. Therefore, individuals with this disor­
der can have depersonalization, derealization, or both.
Dissociative amnesia  is characterized by an inability to recall autobiographical informa­
tion. This amnesia may be localized (i.e., an event or period of time), selective (i.e., a specific 
aspect of an event), or generalized (i.e., identity and life history). Dissociative amnesia is fun­
damentally an inability to recall autobiographical information that is inconsistent with nor­

mal forgetting. It may or may not involve purposeful travel or bewildered wandering (i.e., 
fugue). Although some individuals with amnesia promptly notice that they have "lost time" 
or that they have a gap in their memory, most individuals with dissociative disorders are ini­
tially unaware of their amnesias. For them, awareness of amnesia occurs only when personal 
identity is lost or when circumstances make these individuals aware that autobiographical 
information is missing (e.g., when they discover evidence of events they cannot recall or 
when others tell them or ask them about events they cannot recall). Until and unless this hap­
pens, these individuals have "amnesia for their amnesia." Amnesia is experienced as an es­

sential feature of dissociative amnesia; individuals may experience localized or selective 
amnesia most commonly, or generalized amnesia rarely. Dissociative fugue is rare in per­
sons with dissociative amnesia but common in dissociative identity disorder.
Dissociative identity disorder is characterized by a) the presence of two or more distinct 
personality states or an experience of possession and b) recurrent episodes of amnesia. The

fragmentation of identity may vary v^ith culture (e.g., possession-form presentations) and cir­
cumstance. Thus, individuals may experience discontinuities in identity and memory that 
may not be immediately evident to others or are obscured by attempts to hide dysfunction. In­
dividuals with dissociative identity disorder experience a) recurrent, inexplicable intrusions 
into their conscious functioning and sense of self (e.g., voices; dissociated actions and speech; 
intrusive thoughts, emotions, and impulses), b) alterations of sense of self (e.g., attitudes, pref­
erences, and feeling like one's body or actions are not one's own), c) odd changes of perception 
(e.g., depersonalization or derealization, such as feeling detached from one's body while cut­
ting), and d) intermittent functional neurological symptoms. Stress often produces transient 
exacerbation of dissociative symptoms that makes them more evident.

The residual category of other specified dissociative disorder has seven examples: chronic 
or recurrent mixed dissociative symptoms that approach, but fall short of, the diagnostic cri­
teria for dissociative identity disorder; dissociative states secondary to brainwashing or 
thought reform; two acute presentations, of less than 1  month's duration, of mixed dissociative 
symptoms, one of which is also marked by the presence of psychotic symptoms; and three sin­
gle-symptom dissociative presentations—dissociative trance, dissociative stupor or coma, and 
Ganser's syndrome (the giving of approximate and vague answers).
Dissociative Identity Disorder
Diagnostic Criteria 300.14 (F44.81)
A. Disruption of identity characterized by two or more distinct personality states, which

A. Disruption of identity characterized by two or more distinct personality states, which  
may be described in some cultures as an experience of possession. The disruption in  
identity involves marked discontinuity in sense of self and sense of agency, accompa­
nied by related alterations in affect, behavior, consciousness, memory, perception,  
cognition, and/or sensory-motor functioning. These signs and symptoms may be ob­
served by others or reported by the individual.
B. Recurrent gaps in the recall of everyday events, important personal information, and/  
or traumatic events that are inconsistent with ordinary forgetting.
C. The symptoms cause clinically significant distress or impairment in social, occupa­
D. The disturbance is not a normal part of a broadly accepted cultural or religious practice.

D. The disturbance is not a normal part of a broadly accepted cultural or religious practice.  
Note: In children, the symptoms are not better explained by imaginary playmates or  
other fantasy play.
E. The symptoms are not attributable to the physiological effects of a substance (e.g.,  
blacl<outs or chaotic behavior during alcohol intoxication) or another medical condition  
The defining feature of dissociative identity disorder is the presence of two or more dis­
tinct personality states or an experience of possession (Criterion A). The overtness or 
covertness of these personality states, however, varies as a function of psychological 
motivation, current level of stress, culture, internal conflicts and dynamics, and emotional 
resilience. Sustained periods of identity disruption may occur when psychosocial pres­

sures are severe and/or prolonged. In many possession-form cases of dissociative identity 
disorder, and in a small proportion of non-possession-form cases, manifestations of alter­
nate identities are highly overt. Most individuals with non-possession-form dissociative 
identity disorder do not overtly display their discontinuity of identity for long periods of 
time; only a small minority present to clinical attention with observable alternation of

identities. When alternate personality states are not directly observed, the disorder can be 
identified by two clusters of symptoms: 1) sudden alterations or discontinuities in sense of 
self and sense οί agency (Criterion A), and 2) recurrent dissociative amnesias (Criterion B).
Criterion A symptoms are related to discontinuities of experience that can affect any 
aspect of an individual's functioning. Individuals v^ith dissociative identity disorder may 
report the feeling that they have suddenly become depersonalized observers of their 
"own" speech and actions, which they may feel powerless to stop (sense of self). Such in­
dividuals may also report perceptions of voices (e.g., a child's voice; crying; the voice of a 
spiritual being). In some cases, voices are experienced as multiple, perplexing, indepen­
dent thought streams over which the individual experiences no control. Strong emotions, 
impulses, and even speech or other actions may suddenly emerge, without a sense of per­

sonal ownership or control (sense of agency). These emotions and impulses are frequently 
reported as ego-dystonic and puzzling. Attitudes, outlooks, and personal preferences 
(e.g., about food, activities, dress) may suddenly shift and then shift back. Individuals may 
report that their bodies feel different (e.g., like a small child, like the opposite gender, huge 
and muscular). Alterations in sense of self and loss of personal agency may be accompa­
nied by a feeling that these attitudes, emotions, and behaviors—even one's body—are 
"not mine" and/or are "not under my control." Although most Criterion A symptoms are 
subjective, many of these sudden discontinuities in speech, affect, and behavior can be wit­
nessed by family, friends, or the clinician. Non-epileptic seizures and other conversion

nessed by family, friends, or the clinician. Non-epileptic seizures and other conversion 
symptoms are prominent in some presentations of dissociative identity disorder, espe­
cially in some non-Westem settings.
The dissociative amnesia of individuals with dissociative identity disorder manifests in 
three primary ways: as 1) gaps in remote memory of personal life events (e.g., periods of 
childhood or adolescence; some important life events, such as the death of a grandparent, 
getting married, giving birth); 2) lapses in dependable memory (e.g., of what happened 
today, of well-leamed skills such as how to do their job, use a computer, read, drive); and 
3) discovery of evidence of their everyday actions and tasks that they do not recollect do­
ing (e.g., finding unexplained objects in their shopping bags or among their possessions;

ing (e.g., finding unexplained objects in their shopping bags or among their possessions; 
finding perplexing writings or drawings that they must have created; discovering injuries; 
"coming to" in the midst of doing something). Dissociative fugues, wherein the person 
discovers dissociated travel, are common. Thus, individuals with dissociative identity dis­
order may report that they have suddenly found themselves at the beach, at work, in a night­
club, or somewhere at home (e.g., in the closet, on a bed or sofa, in the corner) with no 
memory of how they came to be there. Amnesia in individuals with dissociative identity dis­
order is not limited to stressful or traumatic events; these individuals often cannot recall 
everyday events as well.
Individuals with dissociative identity disorder vary in their awareness and attitude to­

ward their amnesias. It is common for these individuals to minimize their amnestic symp­
toms. Some of their amnestic behaviors may be apparent to others—as when these persons 
do not recall something they were witnessed to have done or said, when they cannot 
remember their own name, or when they do not recognize their spouse, children, or close 
friends.
Possession-form identities in dissociative identity disorder typically manifest as be­
haviors that appear as if a "spirit," supernatural being, or outside person has taken control, 
such that the individual begins speaking or acting in a distinctly different manner. For ex­
ample, an individual's behavior may give the appearance that her identity has been 
replaced by the "ghost" of a girl who committed suicide in the same community years

replaced by the "ghost" of a girl who committed suicide in the same community years 
before, speaking and acting as though she were still alive. Or an individual may be "taken 
over" by a demon or deity, resulting in profound impairment, and demanding that the in­
dividual or a relative be punished for a past act, followed by more subtle periods of iden­
tity alteration. However, the majority of possession states around the world are normal, 
usually part of spiritual practice, and do not meet criteria for dissociative identity disor-

der. The identities that arise during possession-form dissociative identity disorder present 
recurrently, are unvs^anted and involuntary, cause clinically significant distress or impair­
ment (Criterion C), and are not a normal part of a broadly accepted cultural or religious 
practice (Criterion D).
Individuals with dissociative identity disorder typically present v^ith comorbid depression, 
anxiety, substance abuse, self-injury, non-epileptic seizures, or another common symp­
tom. They often conceal, or are not fully aware of, disruptions in consciousness, amnesia, 
or other dissociative symptoms. Many individuals with dissociative identity disorder re­
port dissociative flashbacks during which they undergo a sensory reliving of a previous 
event as though it were occurring in the present, often with a change of identity, a partial 
or complete loss of contact with or disorientation to current reality during the flashback,

or complete loss of contact with or disorientation to current reality during the flashback, 
and a subsequent amnesia for the content of the flashback. Individuals with the disorder 
typically report multiple types of interpersonal maltreatment during childhood and adult­
hood. Nonmaltreatment forms of overwhelming early life events, such as multiple long, 
painful, early-life medical procedures, also may be reported. Self-mutilation and suicidal 
behavior are frequent. On standardized measures, these individuals report higher levels 
of hypnotizability and dissociativity compared with other clinical groups and healthy con­
trol subjects. Some individuals experience transient psychotic phenomena or episodes. 
Several brain regions have been implicated in the pathophysiology of dissociative identity 
disorder, including the orbitofrontal cortex, hippocampus, parahippocampal gyrus, and

disorder, including the orbitofrontal cortex, hippocampus, parahippocampal gyrus, and 
amygdala.
The 12-month prevalence of dissociative identity disorder among adults in a small U.S. 
community study was 1.5%. The prevalence across genders in that study was 1.6% for 
males and 1.4% for females.
Dissociative identity disorder is associated with overwhelming experiences, traumatic 
events, and/or abuse occurring in childhood. The full disorder may first manifest at al­
most any age (from earliest childhood to late life). Dissociation in children may generate 
problems with memory, concentration, attachment, and traumatic play. Nevertheless, chil­
dren usually do not present with identity changes; instead they present primarily with over­
lap and interference among mental states (Criterion A phenomena), wiüi symptoms related

lap and interference among mental states (Criterion A phenomena), wiüi symptoms related 
to discontinuities of experience. Sudden changes in identity during adolescence may ap­
pear to be just adolescent turmoil or the early stages of another mental disorder. Older 
individuals may present to treatment with what appear to be late-life mood disorders, ob­
sessive-compulsive disorder, paranoia, psychotic mood disorders, or even cognitive dis­
orders due to dissociative amnesia. In some cases, disruptive affects and memories may 
increasingly intrude into awareness with advancing age.
Psychological decompensation and overt changes in identity may be triggered by 1) re­
moval from the traumatizing situation (e.g., through leaving home); 2) the individual's 
children reaching the same age at which the individual was originally abused or trauma­

tized; 3) later traumatic experiences, even seemingly inconsequential ones, like a minor 
motor vehicle accident; or 4) the death of, or the onset of a fatal illness in, their abuser(s).
Environmental. Inteφersonal physical and sexual abuse is associated with an increased 
risk of dissociative identity disorder. Prevalence of childhood abuse and neglect in the

United States, Canada, and Europe among those with the disorder is about 90%. Other 
forms of traumatizing experiences, including childhood medical and surgical procedures, 
war, childhood prostitution, and terrorism, have been reported.
Course modifiers. Ongoing abuse, later-life retraumatization, comorbidity with mental 
disorders, severe medical illness, and delay in appropriate treatment are associated with 
poorer prognosis.
Many features of dissociative identity disorder can be influenced by the individual's cul­
tural background. Individuals with this disorder may present with prominent medically 
unexplained neurological symptoms, such as non-epileptic seizures, paralyses, or sensory 
loss, in cultural settings where such symptoms are common. Similarly, in settings where 
normative possession is common (e.g., rural areas in the developing world, among certain

normative possession is common (e.g., rural areas in the developing world, among certain 
religious groups in the United States and Europe), the fragmented identities may take the 
form of possessing spirits, deities, demons, animals, or mythical figures. Acculturation or 
prolonged intercultural contact may shape the characteristics of the other identities (e.g., 
identities in India may speak English exclusively and wear Western clothes). Possession­
form dissociative identity disorder can be distinguished from culturally accepted posses­
sion states in that the former is involuntary, distressing, uncontrollable, and often recur­
rent or persistent; involves conflict between the individual and his or her surrounding 
family, social, or work milieu; and is manifested at times and in places that violate the 
norms of the culture or religion.

Females with dissociative identity disorder predominate in adult clinical settings but not 
in child clinical settings. Adult males with dissociative identity disorder may deny their 
symptoms and trauma histories, and this can lead to elevated rates of false negative di­
agnosis. Females with dissociative identity disorder present more frequently with acute 
dissociative states (e.g., flashbacks, amnesia, fugue, functional neurological [conversion] 
symptoms, hallucinations, self-mutilation). Males commonly exhibit more criminal or vi­
olent behavior than females; among males, common triggers of acute dissociative states in­
clude combat, prison conditions, and physical or sexual assaults.
Over 70% of outpatients with dissociative identity disorder have attempted suicide; mul­

tiple attempts are common, and other self-injurious behavior is frequent. Assessment of 
suicide risk may be complicated when there is amnesia for past suicidal behavior or when 
the presenting identity does not feel suicidal and is unaware that other dissociated iden­
tities do.
Dissociative identity Disorder
Impairment varies widely, from apparently minimal (e.g., in high-functioning profession­
als) to profound. Regardless of level of disability, individuals with dissociative identity 
disorder commonly minimize the impact of their dissociative and posttraumatic symp­
toms. The symptoms of higher-functioning individuals may impair their relational, mar­
ital, family, and parenting functions more than their occupational and professional life

ital, family, and parenting functions more than their occupational and professional life 
(although the latter also may be affected). With appropriate treatment, many impaired in­
dividuals show marked improvement in occupational and personal functioning. How­
ever, some remain highly impaired in most activities of living. These individuals may only 
respond to treatment very slowly, with gradual reduction in or improved tolerance of

their dissociative and posttraumatic symptoms. Long-term supportive treatment may 
slowly increase these individuals' ability to manage their symptoms and decrease use of 
more restrictive levels of care.
Other specified dissociative disorder. The core of dissociative identity disorder is the 
division of identity, v^ith recurrent disruption of conscious functioning and sense of self. 
This central feature is shared with one form of other specified dissociative disorder, which 
may be distinguished from dissociative identity disorder by the presence of chronic or re­
current mixed dissociative symptoms that do not meet Criterion A for dissociative identity 
disorder or are not accompanied by recurrent amnesia.
Major depressive disorder. Individuals with dissociative identity disorder are often de­
pressed, and their symptoms may appear to meet the criteria for a major depressive episode.

pressed, and their symptoms may appear to meet the criteria for a major depressive episode. 
Rigorous assessment indicates that this depression in some cases does not meet full criteria for 
major depressive disorder. Other specified depressive disorder in individuals with dissocia­
tive identity disorder often has an important feature: the depressed mood and cognitions fluc­
tuate  because they are experienced in some identity states but not others.
Bipolar disorders. Individuals with dissociative identity disorder are often misdiag­
nosed with a bipolar disorder, most often bipolar II disorder. The relatively rapid shifts in 
mood in individuals with this disorder—typically within minutes or hours, in contrast to 
the slower mood changes typically seen in individuals with bipolar disorders—are due to 
the rapid, subjective shifts in mood commonly reported across dissociative states, some­

times accompanied by fluctuation in levels of activation. Furthermore, in dissociative 
identity disorder, elevated or depressed mood may be displayed in conjunction with overt 
identities, so one or the other mood may predominate for a relatively long period of time 
(often for days) or may shift within minutes.
Posttraumatic stress disorder. Some traumatized individuals have both posttraumatic 
stress disorder (PTSD) and dissociative identity disorder. Accordingly, it is crucial to dis­
tinguish between individuals with PTSD only and individuals who have both PTSD and 
dissociative identity disorder. This differential diagnosis requires that the clinician estab­
lish the presence or absence of dissociative symptoms that are not characteristic of acute

lish the presence or absence of dissociative symptoms that are not characteristic of acute 
stress disorder or PTSD. Some individuals with PTSD manifest dissociative symptoms that 
also occur in dissociative identity disorder: 1) amnesia for some aspects of trauma, 2) dis­
sociative flashbacks (i.e., reliving of the trauma, with reduced awareness of one's current 
orientation), and 3) symptoms of intrusion and avoidance, negative alterations in cogni­
tion and mood, and hyperarousal that are focused around the traumatic event. On the other 
hand, individuals with dissociative identity disorder manifest dissociative symptoms that 
are not a manifestation of PTSD: 1) amnesias for many everyday (i.e., nontraumatic) events,
2) dissociative flashbacks that may be followed by amnesia for the content of the flashback,

3) disruptive intrusions (unrelated to traumatic material) by dissociated identity states 
into the individual's sense of self and agency, and 4) infrequent, full-blown changes 
among different identity states.
Psychotic disorders. Dissociative identity disorder may be confused with schizophre­
nia or other psychotic disorders. The personified, internally communicative inner voices 
of dissociative identity disorder, especially of a child (e.g., "I hear a little girl crying in a 
closet and an angry man yelling at her"), may be mistaken for psychotic hallucinations. 
Dissociative experiences of identity fragmentation or possession, and of perceived loss of 
control over thoughts, feelings, impulses, and acts, may be confused with signs of formal

control over thoughts, feelings, impulses, and acts, may be confused with signs of formal 
thought disorder, such as thought insertion or withdrawal. Individuals with dissociative 
identity disorder may also report visual, tactile, olfactory, gustatory, and somatic halluci­
nations, which are usually related to posttraumatic and dissociative factors, such as partial

flashbacks. Individuals with dissociative identity disorder experience these symptoms as 
caused by alternate identities, do not have delusional explanations for the phenomena, 
and often describe the symptoms in a personified way (e.g., "I feel like someone else wants 
to cry with my eyes"). Persecutory and derogatory internal voices in dissociative identity 
disorder associated with depressive symptoms may be misdiagnosed as major depression 
with psychotic features. Chaotic identity change and acute intrusions that disrupt thought 
processes may be distinguished from brief psychotic disorder by the predominance of dis­
sociative symptoms and amnesia for the episode, and diagnostic evaluation after cessation 
of the crisis can help confirm the diagnosis.
Substance/medication-induced disorders. Symptoms associated with the physiological 
effects of a substance can be distinguished from dissociative identity disorder if the sub­

stance in question is judged to be etiologically related to the disturbance.
Personality disorders. Individuals with dissociative identity disorder often present identi­
ties that appear to encapsulate a variety of severe personality disorder features, suggesting a 
differential diagnosis of personality disorder, especially of tiie borderline type. Importantly, 
however, the individual's longitudinal variability in personality style (due to inconsistency 
among identities) differs from the pervasive and persistent dysfunction in affect management 
and inteφersonal relationships typical of those with personality disorders.
Conversion disorder (functional neurological symptom disorder). This disorder may be 
distinguished from dissociative identity disorder by the absence of an identity disruption

distinguished from dissociative identity disorder by the absence of an identity disruption 
characterized by two or more distinct personality states or an experience of possession. 
Dissociative amnesia in conversion disorder is more limited and circumscribed (e.g., am­
nesia for a non-epileptic seizure).
Seizure disorders. Individuals with dissociative identity disorder may present with sei­
zurelike symptoms and behaviors that resemble complex partial seizures with temporal 
lobe foci. These include déjà vu, jamais vu, depersonalization, derealization, out-of-body 
experiences, amnesia, disruptions of consciousness, hallucinations, and other intrusion 
phenomena of sensation, affect, and thought. Normal electroencephalographic findings, 
including telemetry, differentiate non-epileptic seizures from the seizurelike symptoms of

including telemetry, differentiate non-epileptic seizures from the seizurelike symptoms of 
dissociative identity disorder. Also, individuals with dissociative identity disorder obtain 
very high dissociation scores, whereas individuals with complex partial seizures do not.
Factitious disorder and malingering. Individuals who feign dissociative identity disor­
der do not report the subtle symptoms of intrusion characteristic of the disorder; instead 
they tend to overreport well-publicized symptoms of the disorder, such as dissociative 
amnesia, while underreporting less-publicized comorbid symptoms, such as depression. 
Individuals who feign dissociative identity disorder tend to be relatively undisturbed by 
or may even seem to enjoy "having" the disorder. In contrast, individuals with genuine 
dissociative identity disorder tend to be ashamed of and overwhelmed by their symptoms

dissociative identity disorder tend to be ashamed of and overwhelmed by their symptoms 
and to underreport their symptoms or deny their condition. Sequential observation, cor­
roborating history, and intensive psychometric and psychological assessment may be 
helpful in assessment.
Individuals who malinger dissociative identity disorder usually create limited, stereo­
typed alternate identities, with feigned amnesia, related to the events for which gain is 
sought. For example, they may present an "all-good" identity and an "all-bad" identity in 
hopes of gaining exculpation for a crime.
Many individuals with dissociative identity disorder present with a comorbid disorder. If 
not assessed and treated specifically for the dissociative disorder, these individuals often 
receive prolonged treatment for the comorbid diagnosis only, with limited overall treat­

ment response and resultant demoralization, and disability.

Individuals with dissociative identity disorder usually exhibit a large number of co- 
morbid disorders. In particular, most develop PTSD. Other disorders that are highly co- 
morbid with dissociative identity disorder include depressive disorders, trauma- and 
stressor-related disorders, personality disorders (especially avoidant and borderline per­
sonality disorders), conversion disorder (functional neurological symptom disorder), 
somatic symptom disorder, eating disorders, substance-related disorders, obsessive- 
compulsive disorder, and sleep disorders. Dissociative alterations in identity, memory, 
and consciousness may affect the symptom presentation of comorbid disorders.
Dissociative Amnesia
Diagnostic Criteria 300.12 (F44.0)
A. An inability to recall important autobiographical information, usually of a traumatic or  
stressful nature, that is inconsistent with ordinary forgetting.
Note: Dissociative amnesia most often consists of localized or selective amnesia for a

Note: Dissociative amnesia most often consists of localized or selective amnesia for a  
specific event or events; or generalized amnesia for identity and life history.
C. The disturbance is not attributable to the physiological effects of a substance (e.g., al­
cohol or other drug of abuse, a medication) or a neurological or other medical condition  
(e.g., partial complex seizures, transient global amnesia, sequelae of a closed head in­
jury/traumatic brain injury, other neurological condition).
D. The disturbance is not better explained by dissociative identity disorder, posttraumatic  
stress disorder, acute stress disorder, somatic symptom disorder, or major or mild neu-  
rocognitive disorder.
Coding note: The code for dissociative amnesia without dissociative fugue is 300.12

Coding note: The code for dissociative amnesia without dissociative fugue is 300.12  
(F44.0). The code for dissociative amnesia with dissociative fugue is 300.13 (F44.1).
Specify  if ;
300.13 (F44.1) With dissociative fugue: Apparently purposeful travel or bewildered  
wandering that is associated with amnesia for identity or for other important autobio­
graphical information.___________________________________________________
The defining characteristic of dissociative amnesia is an inability to recall important auto­
biographical information that 1) should be successfully stored in memory and 2) ordinar­
ily would be readily remembered (Criterion A). Dissociative amnesia differs from the 
permanent amnesias due to neurobiological damage or toxicity that prevent memory stor­

age or retrieval in that it is always potentially reversible because the memory has been suc­
cessfully stored.
Localized amnesia,  a failure to recall events during a circumscribed period of time, is the 
most common form of dissociative amnesia. Localized amnesia may be broader than am­
nesia for a single traumatic event (e.g., months or years associated with child abuse or in­
tense combat). In selective amnesia,  the individual can recall some, but not all, of the events 
during a circumscribed period of time. Thus, the individual may remember part of a trau­
matic event but not other parts. Some individuals report both localized and selective am­
nesias.
Generalized amnesia,  a complete loss of memory for one's life history, is rare. Individuals

nesias.
Generalized amnesia,  a complete loss of memory for one's life history, is rare. Individuals 
with generalized amnesia may forget personal identity. Some lose previous knowledge 
about the world (i.e., semantic knowledge) and can no longer access well-learned skills

(i.e., procedural knowledge). Generalized amnesia has an acute onset; the perplexity, dis­
orientation, an4 purposeless wandering of individuals with generalized amnesia usually 
bring them to the attention of the police or psychiatric emergency services. Generalized 
amnesia may be more common among combat veterans, sexual assault victims, and indi­
viduals experiencing extreme emotional stress or conflict.
Individuals with dissociative amnesia are frequently unaware (or only partially aware) 
of their memory problems. Many, especially those with localized amnesia, minimize the 
importance of their memory loss and may become uncomfortable when prompted to ad­
dress it. In systematized amnesia,  the individual loses memory for a specific category of in­
formation (e.g., all memories relating to one's family, a particular person, or childhood 
sexual abuse). In continuous amnesia,  an individual forgets each new event as it occurs.

Many individuals with dissociative amnesia are chronically impaired in their ability to 
form and sustain satisfactory relationships. Histories of trauma, child abuse, and victim­
ization are common. Some individuals with dissociative amnesia report dissociative flash­
backs (i.e., behavioral reexperiencing of traumatic events). Many have a history of self­
mutilation, suicide attempts, and other high-risk behaviors. Depressive and functional 
neurological symptoms are common, as are depersonalization, auto-hypnotic symptoms, 
and high hypnotizability. Sexual dysfunctions are common. Mild traumatic brain injury 
may precede dissociative amnesia.
The 12-month prevalence for dissociative amnesia among adults in a small U.S. commu­
nity study was 1.8% (1.0% for males; 2.6% for females).

Onset of generalized amnesia is usually sudden. Less is known about the onset of localized 
and selective amnesias because these amnesias are seldom evident, even to the individual. 
Although overwhelming or intolerable events typically precede localized amnesia, its on­
set may be delayed for hours, days, or longer.
Individuals may report multiple episodes of dissociative amnesia. A single episode 
may predispose to future episodes. In between episodes of amnesia, the individual may or 
may not appear to be acutely symptomatic. The duration of the forgotten events can range 
from minutes to decades. Some episodes of dissociative amnesia resolve rapidly (e.g., 
when the person is removed from combat or some other stressful situation), whereas other

when the person is removed from combat or some other stressful situation), whereas other 
episodes persist for long periods of time. Some individuals may gradually recall the dis­
sociated memories years later. Dissociative capacities may decline with age, but not al­
ways. As the amnesia remits, there may be considerable distress, suicidal behavior, and 
symptoms of posttrauma tic stress disorder (PTSD).
Dissociative amnesia has been observed in young children, adolescents, and adults. 
Children may be the most difficult to evaluate because they often have difficulty under­
standing questions about amnesia, and interviewers may find it difficult to formulate child- 
friendly questions about memory and amnesia. Observations of apparent dissociative am­
nesia are often difficult to differentiate from inattention, absorption, anxiety, oppositional

nesia are often difficult to differentiate from inattention, absorption, anxiety, oppositional 
behavior, and learning disorders. Reports from several different sources (e.g., teacher, 
therapist, case worker) may be needed to diagnose amnesia in children.
Risl( and Prognostic Factors
Environmental. Single or repeated traumatic experiences (e.g., war, childhood maltreat­
ment, natural disaster, internment in concentration camps, genocide) are common ante­

cedents. Dissociative amnesia is more likely to occur with 1) a greater number of adverse 
childhood experiences, particularly physical and/or sexual abuse, 2) interpersonal vio­
lence; and 3) increased severity, frequency, and violence of the trauma.
Genetic and physiological. There are no genetic studies of dissociative amnesia. Stud­
ies of dissociation report significant genetic and environmental factors in both clinical and 
nonclinical samples.
Course modifiers. Removal from the traumatic circumstances underlying the dissociative 
amnesia (e.g., combat) may bring about a rapid return of memory. The memory loss of indi­
viduals with dissociative fugue may be particularly refractory. Onset of PTSD symptoms may 
decrease localized, selective, or systematized amnesia. The returning memory, however, may 
be experienced as flashbacks that alternate with amnesia for the content of the flashbacks.

In Asia, the Middle East, and Latin America, non-epileptic seizures and other functional 
neurological symptoms may accompany dissociative amnesia. In cultures with highly re­
strictive social traditions, the précipitants of dissociative amnesia often do not involve 
frank trauma. Instead, the amnesia is preceded by severe psychological stresses or con­
flicts (e.g., marital conflict, other family disturbances, attachment problems, conflicts due 
to restriction or oppression).
Suicidal and other self-destructive behaviors are common in individuals with dissociative 
amnesia. Suicidal behavior may be a particular risk when the amnesia remits suddenly 
and overwhelms the individual with intolerable memories.
Functional Consequences of Dissociative Amnesia
The impairment of individuals with localized, selective, or systematized dissociative am­

nesia ranges from limited to severe. Individuals with chronic generalized dissociative am­
nesia usually have impairment in all aspects of functioning. Even when these individuals 
"re-leam" aspects of their life history, autobiographical memory remains very impaired. 
Most become vocationally and interpersonally disabled.
Dissociative identity disorder. Individuals with dissociative amnesia may report de­
personalization and auto-hypnotic symptoms. Individuals with dissociative identity dis­
order report pervasive discontinuities in sense of self and agency, accompanied by many 
other dissociative symptoms. The amnesias of individuals with localized, selective, and/ 
or systematized dissociative amnesias are relatively stable. Anmesias in dissociative iden­

tity disorder include amnesia for everyday events, finding of unexplained possessions, 
sudden fluctuations in skills and knowledge, major gaps in recall of life history, and brief 
amnesic gaps in interpersonal interactions.
Posttraumatic stress disorder. Some individuals with PTSD cannot recall part or all of 
a specific traumatic event (e.g., a rape victim with depersonalization and/or derealization 
symptoms who cannot recall most events for the entire day of the rape). When that amne­
sia extends beyond the immediate time of the trauma, a comorbid diagnosis of dissociative 
amnesia is warranted.
Neurocognitive disorders. In neurocognitive disorders, memory loss for personal infor­
mation is usually embedded in cognitive, linguistic, affective, attentional, and behavioral

disturbances. In dissociative amnesia, memory deficits are primarily for autobiographical 
information; intellectual and cognitive abilities are preserved.
Substance-related disorders. In the context of repeated intoxication with alcohol or 
other substances/medications, there may be episodes of "^lack outs" or periods for which the 
individual has no memory. To aid in distinguishing these episodes from dissociative am­
nesia, a longitudinal history noting that the amnestic episodes occur only in the context of 
intoxication and do not occur in other situations would help identify the source as sub­
stance-induced; however the distinction may be difficult when the individual with dis­
sociative amnesia may also misuse alcohol or other substances in the context of stressful 
situations that may also exacerbate dissociative symptoms. Some individuals with comor- 
bid dissociative amnesia and substance use disorders will attribute their memory prob­

lems solely to the substance use. Prolonged use of alcohol or other substances may result in 
a substance-induced neurocognitive disorder that may be associated with impaired cog­
nitive function, but in this context the protracted history of substance use and the persis­
tent deficits associated with the neurocognitive disorder would serve to distinguish it 
from dissociative amnesia, where there is typically no evidence of persistent impairment in 
intellectual functioning.
Posttraumatic amnesia due to brain injury. Amnesia may occur in the context of a trau­
matic brain injury (TBI) when there has been an impact to the head or other mechaiüsms of 
rapid movement or displacement of the brain within the skull TBI. Other characteristics of

rapid movement or displacement of the brain within the skull TBI. Other characteristics of 
TBI include loss of consciousness, disorientation and confusion, or, in more severe cases, 
neurological signs (e.g., abnormalities on neuroimaging, a new onset of seizures or a marked 
worsening of a preexisting seizure disorder, visual field cuts, anosmia). A neurocognitive 
disorder attributable to TBI must present either immediately after brain injury occurs or im­
mediately after the individual recovers consciousness after the injury, and persist past the 
acute post-injury period. The cognitive presentation of a neurocognitive disorder following 
TBI is variable and includes difficulties in the domains of complex attention, executive func­
tion, learning and memory as well as slowed speed of information processing and distur­

bances in social cognition. These additional features help distinguish it from dissociative 
amnesia.
Seizure disorders. Individuals with seizure disorders may exhibit complex behavior dur­
ing seizures or post-ictally with subsequent amnesia. Some individuals with a seizure disorder 
engage in nonpurposive wandering that is limited to the period of seizure activity. Con­
versely, behavior during a dissociative fugue is usually purposeful, complex, and goal- 
directed and may last for days, weeks, or longer. Occasionally, individuals with a seizure dis­
order will report that earlier autobiographical memories have been "wiped out" as the seizure 
disorder progresses. Such memory loss is not associated with traumatic circumstances and ap­

pears to occur randomly. Serial electroencephalograms usually show abnormalities. Telemet­
ric electroencephalographic monitoring usually shows an association between the episodes of 
amnesia and seizure activity. Dissociative and epileptic amnesias may coexist.
Catatonic stupor. Mutism in catatonic stupor may suggest dissociative amnesia, but fail­
ure of recall is absent. Other catatonic symptoms (e.g., rigidity, posturing, negativism) are 
usually present.
Factitious disorder and malingering. There is no test, battery of tests, or set of procedures 
that invariably distinguishes dissociative amnesia from feigned amnesia. Individuals with 
factitious disorder or malingering have been noted to continue their deception even during

factitious disorder or malingering have been noted to continue their deception even during 
hypnotic or barbiturate-facilitated interviews. Feigned amnesia is more common in individ­
uals with 1) acute, florid dissociative amnesia; 2) financial, sexual, or legal problems; or 3) a 
wish to escape stressful circumstances. True amnesia can be associated with those same cir­
cumstances. Many individuals who malinger confess spontaneously or when confronted.

Normal and age-related changes in memory. Memory decrements in major and mild 
neurocognitive disorders differ from those of dissociative amnesia, which are usually as­
sociated with stressful events and are more specific, extensive, and/or complex.
As dissociative anmesia begins to remit, a wide variety of affective phenomena may sur­
face: dysphoria, grief, rage, shame, guilt, psychological conflict and turmoil, and suicidal 
and homicidal ideation, impulses, and acts. These individuals may have symptoms that 
then meet diagnostic criteria for persistent depressive disorder (dysthymia); major de­
pressive disorder; other specified or unspecified depressive disorder; adjustment disor­
der, with depressed mood; or adjustment disorder, with mixed disturbance of emotions 
and conduct. Many individuals with dissociative amnesia develop PTSD at some point 
during their life, especially when the traumatic antecedents of their amnesia are brought 
into conscious awareness.

Many individuals with dissociative amnesia have symptoms that meet diagnostic cri­
teria for a comorbid somatic symptom or related disorder (and vice versa), including so­
matic symptom disorder and conversion disorder (functional neurological symptom 
disorder). Many individuals with dissociative amnesia have symptoms that meet diagnos­
tic criteria for a personality disorder, especially dependent, avoidant, and borderline.
Depersonalization/Dereallzation Disorder
Diagnostic Criteria 300.6 (F48.1)
A. The presence of persistent or recurrent experiences of depersonalization, derealiza­
tion, or both:
1. Depersonalization: Experiences of unreality, detachment, or being an outside ob­
server with respect to one’s thoughts, feelings, sensations, body, or actions (e.g.,  
perceptual alterations, distorted sense of time, unreal or absent self, emotional and/

perceptual alterations, distorted sense of time, unreal or absent self, emotional and/  
or physical numbing).
2. Derealization: Experiences of unreality or detachment with respect to surround­
ings (e.g., individuals or objects are experienced as unreal, dreamlike, foggy, life­
less, or visually distorted).
B. During the depersonalization or derealization experiences, reality testing remains intact.
drug of abuse, medication) or another medical condition (e.g., seizures).
E. The disturbance is not better explained by another mental disorder, such as schizo­
phrenia, panic disorder, major depressive disorder, acute stress disorder, posttrau­

matic stress disorder, or another dissociative disorder.
The essential features of depersonalization/derealization disorder are persistent or recur­
rent episodes of depersonalization, derealization, or both. Episodes of depersonalization 
are characterized by a feeling of unreality or detachment from, or unfamiliarity with, one's 
whole self or from aspects of the self (Criterion Al). The individual may feel detached 
from his or her entire being (e.g., "I am no one," "I have no self"). He or she may also feel 
subjectively detached from aspects of the self, including feelings (e.g., hypoemotionality:

"I know I have feelings but I don't feel them"), thoughts (e.g., "My thoughts don't feel like 
my own," "head^filled with cotton"), whole body or body parts, or sensations (e.g., touch, 
proprioception, hunger, thirst, libido). There may also be a diminished sense of agency 
(e.g., feeling robotic, like an automaton; lacking control of one's speech or movements). 
The depersonalization experience can sometimes be one of a split self, with one part ob­
serving and one participating, known as an "out-of-body experience" in its most extreme 
form. The unitary symptom of "depersonalization" consists of several symptom factors: 
anomalous body experiences (i.e., unreality of the self and perceptual alterations); emo­
tional or physical numbing; and temporal distortions with anomalous subjective recall.
Episodes of derealization are characterized by a feeling of unreality or detachment 
from, or unfamiliarity with, the world, be it individuals, inanimate objects, or all surround­

ings (Criterion A2). TTie individual may feel as if he or she were in a fog, dream, or bubble, or 
as if there were a veil or a glass wall between the individual and world around. Surround­
ings may be experienced as artificial, colorless, or lifeless. Derealization is commonly ac­
companied by subjective visual distortions, such as blurriness, heightened acuity, widened 
or narrowed visual field, two-dimensionality or flatness, exaggerated three-dimensional­
ity, or altered distance or size of objects (i.e., macropsia or micropsia). Auditory distortions 
can also occur, whereby voices or sounds are muted or heightened. In addition. Criterion 
C requires the presence of clinically significant distress or impairment in social, occupa­

tional, or other important areas of fimctioning, and Criteria D and E describe exclusionary 
diagnoses.
Individuals with depersonalization/derealization disorder may have difficulty describ­
ing their symptoms and may think they are "crazy" or "going crazy". Another common 
experience is the fear of irreversible brain damage. A commonly associated symptom is a 
subjectively altered sense of time (i.e., too fast or too slow), as well as a subjective difficulty 
in vividly recalling past memories and owning them as personal and emotional. Vague so­
matic symptoms, such as head fullness, tingling, or lightheadedness, are not uncommon. 
Individuals may suffer extreme rumination or obsessional preoccupation (e.g., constantly

Individuals may suffer extreme rumination or obsessional preoccupation (e.g., constantly 
obsessing about whether they really exist, or checking their perceptions to determine 
whether they appear real). Varying degrees of anxiety and depression are also common as­
sociated features. Individuals with the disorder have been found to have physiological 
hyporeactivity to emotional stimuli. Neural substrates of interest include the hypotha­
lamic-pituitary-adrenocortical axis, inferior parietal lobule, and prefrontal cortical-limbic 
circuits.
Transient depersonalization/derealization symptoms lasting hours to days are common 
in the general population. The 12-month prevalence of depersonalization/derealization 
disorder is thought to be markedly less than for transient symptoms, although precise es­
timates for the disorder are unavailable. In general, approximately one-half of all adults

timates for the disorder are unavailable. In general, approximately one-half of all adults 
have experienced at least one lifetime episode of depersonalization/derealization. How­
ever, symptomatology that meets full criteria for depersonalization/derealization disor­
der is markedly less common than transient symptoms. Lifetime prevalence in U.S. and 
non-U.S. countries is approximately 2% (range of 0.8% to 2.8%). TÎie gender ratio for the 
disorder is 1:1.
The mean age at onset of depersonalization/derealization disorder is 16 years, although the 
disorder can start in early or middle childhood; a minority cannot recall ever not having had

the symptoms. Less than 20% of individuals experience onset after age 20 years and only 
5% after age 25 years. Onset in the fourth decade of life or later is highly unusual. Onset can 
range from extremely sudden to gradual. Duration of depersonalization/derealization 
disorder episodes can vary greatly, from brief (hours or days) to prolonged (weeks, 
months, or years). Given the rarity of disorder onset after age 40 years, in such cases the in­
dividual should be examined more closely for underlying medical conditions (e.g., brain 
lesions, seizure disorders, sleep apnea). The course of the disorder is often persistent. 
About one-third of cases involve discrete episodes; another third, continuous symptoms 
from the start; and still another third, an initially episodic course that eventually becomes 
continuous.
While in some individuals the intensity of symptoms can wax and wane considerably,

While in some individuals the intensity of symptoms can wax and wane considerably, 
others report an unwavering level of intensity that in extreme cases can be constantly pres­
ent for years or decades. Internal and external factors that affect symptom intensity vary 
between individuals, yet some typical patterns are reported. Exacerbations can be trig­
gered by stress, worsening mood or anxiety symptoms, novel or overstimulating settings, 
and physical factors such as lighting or lack of sleep.
Temperamental. Individuals with depersonalization/derealization disorder are charac­
terized by harm-avoidant temperament, immature defenses, and both disconnection and 
overconnection schemata. Immature defenses such as idealization/devaluation, projec­
tion and acting out result in denial of reality and poor adaptation. Cognitive disconnection

tion and acting out result in denial of reality and poor adaptation. Cognitive disconnection  
schemata  reflect defectiveness and emotional inhibition and subsume themes of abuse, ne­
glect, and deprivation. Overconnection schemata  involve impaired autonomy with themes 
of dependency, vulnerability, and incompetence.
Environmental. There is a clear association between the disorder and childhood interper­
sonal traumas in a substantial portion of individuals, although this association is not as prev­
alent or as extreme in the nature of the traumas as in other dissociative disorders, such as 
dissociative identity disorder. In particular, emotional abuse and emotional neglect have been 
most strongly and consistently associated with the disorder. Other stressors can include phys­
ical abuse; witnessing domestic violence; growing up with a seriously impaired, mentally ill

ical abuse; witnessing domestic violence; growing up with a seriously impaired, mentally ill 
parent; or unexpected death or suicide of a family member or close Wend. Sexual abuse is a 
much less common antecedent but can be encountered. The most common proximal précipi­
tants of the disorder are severe stress (interpersonal, financial, occupational), depression, anx­
iety (particularly panic attacks), and illicit drug use. Symptoms may be specifically induced by 
substances such as tetrahydrocannabinol, hallucinogens, ketamine, MDMA (3,4-methylene­
dioxymethamphetamine; "ecstasy") and salvia. Marijuana use may precipitate new-onset 
panic attacks and depersonalization/derealization symptoms simultaneously.
Volitionally induced experiences of depersonalization/derealization can be a part of med­

itative practices that are prevalent in many religions and cultures and should not be diag­
nosed as a disorder. However, there are individuals who initially induce these states 
intentionally but over time lose control over them and may develop a fear and aversion for 
related practices.
Depersonaiization/Dereaiization Disorder
Symptoms of depersonalization/derealization disorder are highly distressing and are as­
sociated with major morbidity. The affectively flattened and robotic demeanor that these

individuals often demonstrate may appear incongruent with the extreme emotional pain 
reported by those with the disorder. Impairment is often experienced in both interpersonal 
and occupational spheres, largely due to the hypoemotionaHty with others, subjective diffi­
culty in focusing and retaining information, and a general sense of disconnectedness from 
life.
Illness anxiety disorder. Although individuals with depersonalization/derealization dis­
order can present with vague somatic complaints as well as fears of permanent brain dam­
age, the diagnosis of depersonalization/derealization disorder is characterized by the 
presence of a constellation of typical depersonalization/derealization symptoms and the ab­
sence of other manifestations of illness anxiety disorder.
Major depressive disorder. Feelings of numbness, deadness, apathy, and being in a 
dream are not uncommon in major depressive episodes. However, in depersonalization/

dream are not uncommon in major depressive episodes. However, in depersonalization/ 
derealization disorder, such symptoms are associated with further symptoms of the dis­
order. If the depersonalization/derealization clearly precedes the onset of a major depres­
sive episode or clearly continues after its resolution, the diagnosis of depersonalization/ 
derealization disorder applies.
Obsessive-compulsive disorder. Some individuals with depersonalization/dereal­
ization disorder can become obsessively preoccupied with their subjective experience or 
develop rituals checking on the status of their symptoms. However, other symptoms of 
obsessive-compulsive disorder unrelated to depersonalization/derealization are not 
present.
Other dissociative disorders. In order to diagnose depersonalization/derealization 
disorder, the symptoms should not occur in the context of another dissociative disorder,

present.
disorder, the symptoms should not occur in the context of another dissociative disorder, 
such as dissociative identity disorder. Differentiation from dissociative amnesia and con­
version disorder (functional neurological symptom disorder) is simpler, as the symptoms 
of these disorders do not overlap with those of depersonalization/derealization disorder.
Anxiety disorders. Depersonalization/derealization is one of the symptoms of panic at­
tacks, increasingly common as panic attack severity increases. Therefore, depersonal­
ization/dereahzation disorder should not be diagnosed when the symptoms occur only 
during panic attacks that are part of panic disorder, social anxiety disorder, or specific 
phobia. In addition, it is not uncommon for depersonalization/derealization symptoms 
to first begin in the context of new-onset panic attacks or as panic disorder progresses and

to first begin in the context of new-onset panic attacks or as panic disorder progresses and 
worsens. In such presentations, the diagnosis of depersonalization/derealization disorder 
can be made if 1) the depersonalization/derealization component of the presentation is 
very prominent from the start, clearly exceeding in duration and intensity the occurrence 
of actual panic attacks; or 2) the depersonalization/derealization continues after panic dis­
order has remitted or has been successfully treated.
Psychotic disorders. The presence of intact reality testing specifically regarding the 
depersonalization/derealization symptoms is essential to differentiating depersonal­
ization/derealization disorder from psychotic disorders. Rarely, positive-symptom 
schizophrenia can pose a diagnostic challenge when nihilistic delusions are present. For

schizophrenia can pose a diagnostic challenge when nihilistic delusions are present. For 
example, an individual may complain that he or she is dead or the world is not real; this 
could be either a subjective experience that the individual knows is not true or a delusional 
conviction.
Substance/medication-induced disorders. Depersonalization/derealization associated 
with the physiological effects of substances during acute intoxication or withdrawal is not 
diagnosed as depersonalization/derealization disorder. The most common precipitating 
substances are the illicit drugs marijuana, hallucinogens, ketamine, ecstasy, and salvia. In

about 15% of all cases of depersonalization/derealization disorder, the symptoms are pre­
cipitated by ingestion of such substances. If the symptoms persist for some time in the ab­
sence of any further substance or medication use, the diagnosis of depersonalization/ 
derealization disorder applies. This diagnosis is usually easy to establish since the vast ma­
jority of individuals with this presentation become highly phobic and aversive to the trig­
gering substance and do not use it again.
Mental disorders due to another medical condition. Features such as onset after age 
40 years or the presence of atypical symptoms and course in any individual suggest the 
possibility of an underlying medical condition. In such cases, it is essential to conduct a 
thorough medical and neurological evaluation, which may include standard laboratory 
studies, viral titers, an electroencephalogram, vestibular testing, visual testing, sleep stud­

ies, and/or brain imaging. When the suspicion of an underlying seizure disorder proves 
difficult to confirm, an ambulatory electroencephalogram may be indicated; although 
temporal lobe epilepsy is most commonly implicated, parietal and frontal lobe epilepsy 
may also be associated.
In a convenience sample of adults recruited for a number of depersonalization research 
studies, lifetime comorbidities were high for unipolar depressive disorder and for any 
anxiety disorder, with a significant proportion of the sample having both disorders. Comor­
bidity with posttraumatic stress disorder was low. The three most commonly co-occurring 
personality disorders were avoidant, borderline, and obsessive-compulsive.
Other Specified Dissociative Disorder
300.15 (F44.89)

This category applies to presentations in  which symptoms characteristic of a dissociative  
the disorders in the dissociative disorders diagnostic class. The other specified dissocia­
tive disorder category is used in situations in which the clinician chooses to communicate  
the specific reason that the presentation does not meet the criteria for any specific disso­
ciative disorder. This is done by recording “ other specified dissociative disorder”  followed  
by the specific reason (e.g., “ dissociative trance” ).

1. Chronic and recurrent syndromes of mixed dissociative symptoms: This cate­
gory includes identity disturbance associated with less-than-marked discontinuities in  
sense of self and agency, or alterations of identity or episodes of possession in an in­
dividual who reports no dissociative amnesia.
2. identity disturbance due to proionged and intense coercive persuasion: Individ­
uals who have been subjected to intense coercive persuasion (e.g., brainwashing,  
thought reform, indoctrination while captive, torture, long-term political imprisonment,  
recruitment by sects/cults or by terror organizations) may present with prolonged  
changes in, or conscious questioning of, their identity.
3. Acute dissociative reactions to stressfui events: This category is for acute, tran­

sient conditions that typically last less than 1  month, and sometimes only a few hours  
or days. These conditions are characterized by constriction of consciousness; deper­
sonalization; derealization; perceptual disturbances (e.g., time slowing, macropsia);

micro-amnesias; transient stupor; and/or alterations in sensory-motor functioning (e.g.,  
analgesia, paralysis).
4. Dissociative trance: This condition is characterized by an acute narrowing or com­
plete loss of awareness of immediate surroundings that manifests as profound unre­
sponsiveness or insensitivity to environmental stimuli. The unresponsiveness may be  
accompanied by minor stereotyped behaviors (e.g., finger movements) of which the in­
dividual is unaware and/or that he or she cannot control, as well as transient paralysis  
or loss of consciousness. The dissociative trance is not a normal part of a broadly ac­
cepted collective cultural or religious practice.
Unspecified Dissociative Disorder
300.15 (F44.9)
This category applies to presentations in which symptoms characteristic of a dissociative  
disorder that cause clinically significant distress or impairment in social, occupational, or

the disorders in the dissociative disorders diagnostic class. The unspecified dissociative  
son that the criteria are not met for a specific dissociative disorder, and includes presen­
tations for which there is insufficient information to make a more specific diagnosis (e.g.,  
in emergency room settings).

Somatic Symptom 
Related
SomStiC symptom disorder and other disorders with prominent somatic symp­
toms constitute a new category in DSM-5 called somatic symptom and related disorders.  This 
chapter includes the diagnoses of somatic symptom disorder, illness anxiety disorder, con­
version disorder (functional neurological symptom disorder), psychological factors affect­
ing other medical conditions, factitious disorder, other specified somatic sjnnptom and 
related disorder, and unspecified somatic symptom and related disorder. All of the disor­
ders in this chapter share a common feature: the prominence of somatic symptoms associ­
ated with significant distress and impairment. Individuals with disorders with prominent 
somatic symptoms are commonly encoimtered in primary care and other medical settings 
but are less commonly encountered in psychiatric and otiier mental health settings. These 
reconceptualized diagnoses, based on a reorganization of DSM-IV somatoform disorder di­

agnoses, are more useful for primary care and other medical (nonpsychiatric) clinicians.
The major diagnosis in this diagnostic class, somatic symptom disorder, emphasizes 
diagnosis made on the basis of positive symptoms and signs (distressing somatic symp­
toms plus abnormal thoughts, feelings, and behaviors in response to these symptoms) 
rather than the absence of a medical explanation for somatic symptoms. A distinctive char­
acteristic of many individuals with somatic symptom disorder is not the somatic symp­
toms per se, but instead the way they present and interpret them. Incorporating affective, 
cognitive, and behavioral components into the criteria for somatic symptom disorder pro­
vides a more comprehensive and accurate reflection of the true clinical picture than can be

vides a more comprehensive and accurate reflection of the true clinical picture than can be 
achieved by assessing the somatic complaints alone.
The principles behind the changes in the somatic symptom and related diagnoses from 
DSM-IV are crucial in imderstanding the DSM-5 diagnoses. The DSM-IV term somatoform  
disorders  was confusing and is replaced by somatic symptom and related disorders.  In DSM-IV 
there was a great deal of overlap across the somatoform disorders and a lack of clarity 
about the boundaries of diagnoses. Although individuals with these disorders primarily 
present in medical rather than mental health settings, nonpsychiatric physicians foimd the 
DSM-IV somatoform diagnoses difficult to understand and use. The current DSM-5 clas­
sification recogrüzes this overlap by reducing the total number of disorders as well as their 
subcategories.

The previous criteria overemphasized the centrality of medically unexplained symptoms. 
Such symptoms are present to various degrees, particularly in conversion disorder, but so­
matic symptom disorders can also accompany diagnosed medical disorders. The reli­
ability of determining that a somatic symptom is medically unexplained is limited, and 
grounding a diagnosis on the absence of an explanation is problematic and reinforces 
mind-body dualism. It is not appropriate to give an individual a mental disorder diagnosis 
solely because a medical cause cannot be demonstrated. Furthermore, the presence of a 
medical diagnosis does not exclude the possibility of a comorbid mental disorder, includ­
ing a somatic symptom and related disorder. Perhaps because of the predominant focus

ing a somatic symptom and related disorder. Perhaps because of the predominant focus 
on lack of medical explanation, individuals regarded these diagnoses as pejorative and de­
meaning, implying that their physical symptoms were not "real." The new classification 
defines the major diagnosis, somatic symptom disorder, on the basis of positive symptoms 
(distressing somatic symptoms plus abnormal thoughts, feelings, and behaviors in response

to these symptoms). However, medically unexplained symptoms remain a key feature in 
conversion disorder and pseudocyesis (other specified somatic symptom and related dis­
order) because it is possible to demonstrate definitively in such disorders that the symp­
toms are not consistent with medical pathophysiology.
It is important to note that some other mental disorders may initially manifest with pri­
marily somatic symptoms (e.g., major depressive disorder, panic disorder). Such diagno­
ses may account for the somatic symptoms, or they may occur alongside one of the somatic 
symptom and related disorders in this chapter. There is also considerable medical comor­
bidity among somatizing individuals. Although somatic symptoms are frequently associ­
ated with psychological distress and psychopathology, some somatic symptom and 
related disorders can arise spontaneously, and their causes can remain obscure. Anxiety

related disorders can arise spontaneously, and their causes can remain obscure. Anxiety 
disorders and depressive disorders may accompany somatic symptom and related disor­
ders. The somatic component adds severity and complexity to depressive and anxiety dis­
orders and results in higher severity, functional impairment, and even refractoriness to 
traditional treatments. In rare instances, the degree of preoccupation may be so severe as 
to warrant consideration of a delusional disorder diagnosis.
A number of factors may contribute to somatic symptom and related disorders. These 
include genetic and biological vulnerability (e.g., increased sensitivity to pain), early trau­
matic experiences (e.g., violence, abuse, deprivation), and learning (e.g., attention ob­
tained from illness, lack of reinforcement of nonsomatic expressions of distress), as well as

tained from illness, lack of reinforcement of nonsomatic expressions of distress), as well as 
cultural/social norms that devalue and stigmatize psychological suffering as compared 
with physical suffering. Differences in medical care across cultures affect the presentation, 
recognition, and management of these somatic presentations. Variations in symptom pre­
sentation are likely the result of the interaction of multiple factors within cultural con­
texts that affect how individuals identify and classify bodily sensations, perceive illness, 
and seek medical attention for them. Thus, somatic presentations can be viewed as expres­
sions of personal suffering inserted in a cultural and social context.
All of these disorders are characterized by the prominent focus on somatic concerns 
and their iiütial presentation mainly in medical rather than mental health care settings. So­

matic symptom disorder offers a more clinically useful method of characterizing individ­
uals who may have been considered in the past for a diagnosis of somatization disorder. 
Furthermore, approximately 75% of individuals previously diagnosed with hypochon­
driasis are subsumed under the diagnosis of somatic symptom disorder. However, about 
25% of individuals with hypochondriasis have high health anxiety in the absence of so­
matic symptoms, and many such individuals' symptoms would not qualify for an anxiety 
disorder diagnosis. The DSM-5 diagnosis of illness anxiety disorder is for this latter group 
of individuals. Illness anxiety disorder can be considered either in this diagnostic section 
or as an anxiety disorder. Because of the strong focus on somatic concerns, and because ill­

ness anxiety disorder is most often encountered in medical settings, for utility it is listed 
with the somatic symptom and related disorders. In conversion disorder, the essential fea­
ture is neurological symptoms that are found, after appropriate neurological assessment, 
to be incompatible with neurological pathophysiology. Psychological factors affecting 
other medical conditions is also included in this chapter. Its essential feature is the pres­
ence of one or more clinically significant psychological or behavioral factors that adversely 
affect a medical condition by increasing the risk for suffering, death, or disability. Like the 
other somatic symptom and related disorders, factitious disorder embodies persistent

other somatic symptom and related disorders, factitious disorder embodies persistent 
problems related to illness perception and identity. In the great majority of reported cases 
of factitious disorder, both imposed on self and imposed on another, individuals present 
with somatic symptoms and medical disease conviction. Consequently, DSM-5 factitious 
disorder is included among the somatic symptom and related disorders. Other specified 
somatic symptom and related disorder and unspecified somatic symptom and related dis­
order include conditions for which some, but not all, of the criteria for somatic symptom 
disorder or illness anxiety disorder are met, as well as pseudocyesis.

Somatic Symptom Disorder
Diagnostic Criteria 300.82 (F45.1)
A. One or more somatic symptoms that are distressing or result in significant disruption  
of daily life.
B. Excessive thoughts, feelings, or behaviors related to the somatic symptoms or associ­
ated health concerns as manifested by at least one of the following:
1. Disproportionate and persistent thoughts about the seriousness of one’s symptoms.
2. Persistently high level of anxiety about health or symptoms.
3. Excessive time and energy devoted to these symptoms or health concerns.
C. Although any one somatic symptom may not be continuously present, the state of be­
ing symptomatic is persistent (typically more than 6 months).
Witli predominant pain (previously pain disorder): This specifier is for individuals  
whose somatic symptoms predominantly involve pain.
Persistent: A persistent course is characterized by severe symptoms, marked impair­
ment, and long duration (more than 6 months).

Mild: Only one of the symptoms specified in Criterion B is fulfilled.
Moderate: Two or more of the symptoms specified in Criterion B are fulfilled.
Severe: Two or more of the symptoms specified in Criterion B are fulfilled, plus there  
are multiple somatic complaints (or one very severe somatic symptom).
Individuals with somatic symptom disorder typically have multiple, current, somatic symp­
toms that are distressing or result in significant disruption of daily life (Criterion A), al­
though sometimes only one severe symptom, most commonly pain, is present. Symptoms 
may be specific (e.g., localized pain) or relatively nonspecific (e.g., fatigue). The symptoms

may be specific (e.g., localized pain) or relatively nonspecific (e.g., fatigue). The symptoms 
sometimes represent normal bodily sensations or discomfort that does not generally sig­
nify serious disease. Somatic symptoms without an evident medical explanation are not 
sufficient to make this diagnosis. The individual's suffering is authentic, whether or not it 
is medically explained.
The symptoms may or may not be associated with another medical condition. The di­
agnoses of somatic symptom disorder and a concurrent medical illness are not mutually 
exclusive, and these frequently occur together. For example, an individual may become se­
riously disabled by symptoms of somatic symptom disorder after an uncomplicated myo­
cardial infarction even if the myocardial infarction itself did not result in any disability. If

cardial infarction even if the myocardial infarction itself did not result in any disability. If 
another medical condition or high risk for developing one is present (e.g., strong family 
history), the thoughts, feelings, and behaviors associated with this condition are excessive 
(Criterion B).
Individuals with somatic symptom disorder tend to have very high levels of worry 
about illness (Criterion B). They appraise their bodily symptoms as unduly threatening, 
harmful, or troublesome and often think the worst about their health. Even when there is 
evidence to the contrary, some patients still fear the medical seriousness of their symp­
toms. In severe somatic symptom disorder, health concerns may assume a central role in 
the individual's life, becoming a feature of his or her identity and dominating interper­
sonal relationships.

Individuals typically experience distress that is principally focused on somatic symp­
toms and their significance. When asked directly about their distress, some individuals de­
scribe it in relation to other aspects of their lives, while others deny any source of distress 
other than the somatic symptoms. Health-related quality of life is often impaired, both 
physically and mentally. In severe somatic symptom disorder, the impairment is marked, 
and when persistent, the disorder can lead to invalidism.
There is often a high level of medical care utilization, which rarely alleviates the individ­
ual's concerns. Consequently, the patient may seek care from multiple doctors for the same 
symptoms. These individuals often seem unresponsive to medical interventions, and new 
interventions may only exacerbate the presenting symptoms. Some individuals with the dis­
order seem unusually sensitive to medication side effects. Some feel that their medical as­

sessment and treatment have been inadequate.
Cognitive features include attention focused on somatic symptoms, attribution of normal 
bodily sensations to physical illness (possibly with catastrophic interpretations), worry 
about illness, and fear that any physical activity may damage the body. The relevant as­
sociated behavioral features may include repeated bodily checking for abnormalities, re­
peated seeking of medical help and reassurance, and avoidance of physical activity. These 
behavioral features are most pronounced in severe, persistent somatic symptom disorder. 
These features are usually associated with frequent requests for medical help for different 
somatic symptoms. This may lead to medical consultations in which individuals are so fo­

cused on their concerns about somatic symptom(s) that they cannot be redirected to other 
matters. Any reassurance by the doctor that the symptoms are not indicative of serious 
physical illness tends to be short-lived and/or is experienced by the individuals as the 
doctor not taking their symptoms with due seriousness. As the focus on somatic symp­
toms is a primary feature of the disorder, individuals with somatic symptom disorder typ­
ically present to general medical health services rather than mental health services. The 
suggestion of referral to a mental health specialist may be met with surprise or even frank 
refusal by individuals with somatic symptom disorder.
Since somatic symptom disorder is associated with depressive disorders, there is an in­

creased suicide risk. It is not known whether somatic symptom disorder is associated with 
suicide risk independent of its association with depressive disorders.
The prevalence of somatic symptom disorder is not known. However, the prevalence of 
somatic symptom disorder is expected to be higher than that of the more restrictive DSM- 
IV somatization disorder (<1%) but lower than that of undifferentiated somatoform dis­
order (approximately 19%). The prevalence of somatic symptom disorder in the general 
adult population may be around 5%-7%. Females tend to report more somatic symptoms 
than do males, and the prevalence of somatic symptom disorder is consequently likely to 
be higher in females.
In older individuals, somatic symptoms and concurrent medical illnesses are common,

In older individuals, somatic symptoms and concurrent medical illnesses are common, 
and a focus on Criterion B is crucial for making the diagnosis. Somatic symptom disorder 
may be underdiagnosed in older adults either because certain somatic symptoms (e.g., 
pain, fatigue) are considered part of normal aging or because illness worry is considered 
"understandable" in older adults who have more general medical illnesses and medica­
tions than do younger people. Concurrent depressive disorder is common in older people 
who present with numerous somatic symptoms.

In children, the most common symptoms are recurrent abdominal pain, headache, fa­
tigue, and nausea. A single prominent symptom is more common in children than in 
adults. While young children may have somatic complaints, they rarely worry about "ill­
ness" per se prior to adolescence. The parents' response to the symptom is important, as 
this may determine the level of associated distress. It is the parent who may determine the 
interpretation of symptoms and the associated time off school and medical help seeking.
Temperamental. The personality trait of negative affectivity (neuroticism) has been identi­
fied as an independent correlate/risk factor of a high number of somatic symptoms. Comorbid 
anxiety or depression is common and may exacerbate symptoms and impairment.
Environmental. Somatic symptom disorder is more frequent in individuals with few years 
of education and low socioeconomic status, and in those who have recently experienced

of education and low socioeconomic status, and in those who have recently experienced 
stressful life events.
Course modifiers. Persistent somatic symptoms are associated with demographic fea­
tures (female sex, older age, fewer years of education, lower socioeconomic status, un­
employment), a reported history of sexual abuse or other childhood adversity, concurrent 
chronic physical illness or psychiatric disorder (depression, anxiety, persistent depressive 
disorder [dysthymia], panic), social stress, and reinforcing social factors such as illness 
benefits. Cognitive factors that affect clinical course include sensitization to pain, height­
ened attention to bodily sensations, and attribution of bodily symptoms to a possible med­
ical illness rather than recognizing them as a normal phenomenon or psychological stress.

Somatic sjmnptoms are prominent in various "culture-bound syndromes." High numbers 
of somatic symptoms are found in population-based and primary care studies aroimd the 
world, with a similar pattern of the most commonly reported somatic symptoms, impair­
ment, and treatment seeking. The relationship between number of somatic symptoms and 
illness worry is similar in different cultures, and marked illness worry is associated with 
impairment and greater treatment seeking across cultures. The relationship between nu­
merous somatic symptoms and depression appears to be very similar around the world 
and between different cultures within one country.
Despite these similarities, there are differences in somatic symptoms among cultures 
and ethnic groups. The description of somatic symptoms varies with linguistic and other

and ethnic groups. The description of somatic symptoms varies with linguistic and other 
local cultural factors. These somatic presentations have been described as "idioms of dis­
tress" because somatic symptoms may have special meanings and shape patient-clinician 
interactions in the particular cultural contexts. "Burnout," the sensation of heaviness or 
the complaints of "gas"; too much heat in the body; or burning in the head are examples of 
symptoms that are common in some cultures or ethnic groups but rare in others. Explan­
atory models also vary, and somatic symptoms may be attributed variously to particular 
family, work, or environmental stresses; general medical illness; the suppression of feel­
ings of anger and resentment; or certain culture-specific phenomena, such as semen loss. 
There may also be differences in medical treatment seeking among cultural groups, in ad­

dition to differences due to variable access to medical care services. Seeking treatment for 
multiple somatic symptoms in general medical clinics is a worldwide phenomenon and 
occurs at similar rates among ethnic groups in the same country.
Functional Consequences of Somatic Symptom Disorder
The disorder is associated with marked impairment of health status. Many individuals 
with severe somatic symptom disorder are likely to have impaired health status scores 
more than 2 standard deviations below population norms.

If the somatic symptoms are consistent with another mental disorder (e.g., panic disorder), 
and the diagnostic criteria for that disorder are fulfilled, then that mental disorder should 
be considered as an alternative or additional diagnosis. A separate diagnosis of somatic 
symptom disorder is not made if the somatic symptoms and related thoughts, feelings, or 
behaviors occur only during major depressive episodes. If, as commonly occurs, the crite­
ria for both somatic symptom disorder and another mental disorder diagnosis are ful­
filled, then both should be coded, as both may require treatment.
Other medical conditions. The presence of somatic symptoms of unclear etiology is not 
in itself sufficient to make the diagnosis of somatic symptom disorder. The symptoms of 
many individuals with disorders like irritable bowel syndrome or fibromyalgia would not 
satisfy the criterion necessary to diagnose somatic symptom disorder (Criterion B). Con­

versely, the presence of somatic symptoms of an established medical disorder (e.g., diabe­
tes or heart disease) does not exclude the diagnosis of somatic symptom disorder if the 
criteria are otherwise met.
Panic disorder. In panic disorder, somatic symptoms and anxiety about health tend to 
occur in acute episodes, whereas in somatic symptom disorder, anxiety and somatic symp­
toms are more persistent.
Generalized anxiety disorder. Individuals with generalized anxiety disorder worry about 
multiple events, situations, or activities, only one of which may involve their health. The 
main focus is not usually somatic symptoms or fear of illness as it is in somatic symptom 
disorder.
Depressive disorders. Depressive disorders are commonly accompanied by somatic

disorder.
Depressive disorders. Depressive disorders are commonly accompanied by somatic 
symptoms. However, depressive disorders are differentiated from somatic symptom dis­
order by the core depressive symptoms of low (dysphoric) mood and anhedonia.
Illness anxiety disorder. If the individual has extensive worries about health but no or 
minimal somatic symptoms, it may be more appropriate to consider illness anxiety disorder.
Conversion disorder (functional neurological symptom disorder). In conversion disor­
der, the presenting symptom is loss of function (e.g., of a limb), whereas in somatic symp­
tom disorder, the focus is on the distress that particular symptoms cause. The features 
listed under Criterion B of somatic symptom disorder may be helpful in differentiating the 
two disorders.
Delusional disorder. In somatic symptom disorder, the individual's beliefs that somatic

Delusional disorder. In somatic symptom disorder, the individual's beliefs that somatic 
symptoms might reflect serious underlying physical illness are not held with delusional 
intensity. Nonetheless, the individual's beliefs concerning the somatic symptoms can be 
firmly held. In contrast, in delusional disorder, somatic subtype, the somatic symptom be­
liefs and behavior are stronger than those found in somatic symptom disorder.
Body dysmorphic disorder. In body dysmorphic disorder, the individual is excessively 
concerned about, and preoccupied by, a perceived defect in his or her physical features. In 
contrast, in somatic symptom disorder, the concern about somatic symptoms reflects fear 
of underlying illness, not of a defect in appearance.
Obsessive-compulsive disorder. In somatic symptom disorder, the recurrent ideas about

Obsessive-compulsive disorder. In somatic symptom disorder, the recurrent ideas about 
somatic symptoms or illness are less intrusive, and individuals with this disorder do not 
exhibit the associated repetitive behaviors aimed at reducing anxiety that occur in obses­
sive-compulsive disorder.
Somatic symptom disorder is associated with high rates of comorbidity with medical dis­
orders as well as anxiety and depressive disorders. When a concurrent medical illness is

present, the degree of impairment is more marked than would be expected from the phys­
ical illness alone. When an individual's symptoms meet diagnostic criteria for somatic 
symptom disorder, the disorder should be diagnosed; however, in view of the frequent co­
morbidity, especially with anxiety and depressive disorders, evidence for these concur­
rent diagnoses should be sought.
Illness Anxiety Disorder
Diagnostic Criteria 300.7 (F45.21)
A. Preoccupation with having or acquiring a serious illness.
B. Somatic symptoms are not present or, if present, are only mild in intensity. If another  
medical condition is present or there is a high risk for developing a medical condition  
(e.g., strong family history is present), the preoccupation is clearly excessive or dispro­
portionate.
C. There is a high level of anxiety about health, and the individual is easily alarmed about  
personal health status.
D. The individual performs excessive health-related behaviors (e.g., repeatedly checks

D. The individual performs excessive health-related behaviors (e.g., repeatedly checks  
his or her body for signs of illness) or exhibits maladaptive avoidance (e.g., avoids doc­
tor appointments and hospitals).
E. Illness preoccupation has been present for at least 6 months, but the specific illness  
that is feared may change over that period of time.
F. The illness-related preoccupation is not better explained by another mental disorder, such  
as somatic symptom disorder, panic disorder, generalized anxiety disorder, body dysmor­
phic disorder, obsessive-compulsive disorder, or delusional disorder, somatic type.
Care-seeking type: Medical care, including physician visits or undergoing tests and  
procedures, is frequently used.
Care-avoidant type: Medical care is rarely used.
Most individuals with hypochondriasis are now classified as having somatic symptom

Most individuals with hypochondriasis are now classified as having somatic symptom 
disorder; however, in a minority of cases, the diagnosis of illness anxiety disorder applies 
instead. Illness anxiety disorder entails a preoccupation with having or acquiring a seri­
ous, undiagnosed medical illness (Criterion A). Somatic symptoms are not present or, if 
present, are only mild in intensity (Criterion B). A thorough evaluation fails to identify a 
serious medical condition that accounts for the individual's concerns. While the concern 
may be derived from a nonpathological physical sign or sensation, the individual's dis­
tress emanates not primarily from the physical complaint itself but rather from his or her 
anxiety about the meaning, significance, or cause of the complaint (i.e., the suspected med­

ical diagnosis). If a physical sign or symptom is present, it is often a normal physiological 
sensation (e.g., orthostatic dizziness), a benign and self-limited dysfunction (e.g., transient 
tinnitus), or a bodily discomfort not generally considered indicative of disease (e.g., belch­
ing). If a diagnosable medical condition is present, the individual's anxiety and preoccu­
pation are clearly excessive and disproportionate to the severity of the condition (Criterion 
B). Empirical evidence and existing literature pertain to previously defined DSM hypo­
chondriasis, and it is unclear to what extent and how precisely they apply to the descrip­
tion of this new diagnosis.
The preoccupation with the idea that one is sick is accompanied by substantial anxiety

The preoccupation with the idea that one is sick is accompanied by substantial anxiety 
about health and disease (Criterion C). Individuals with illness anxiety disorder are easily

alarmed about illness, such as by hearing about someone else falling ill or reading a health- 
related news story. Their concerns about undiagnosed disease do not respond to appro­
priate medical reassurance, negative diagnostic tests, or benign course. The physician's at­
tempts at reassurance and symptom palliation generally do not alleviate the individual's 
concerns and may heighten them. Illness concerns assume a prominent place in the indi­
vidual's life, affecting daily activities, and may even result in invalidism. Illness becomes 
a central feature of the individual's identity and self-image, a frequent topic of social dis­
course, and a characteristic response to stressful life events. Individuals with the disorder 
often examine themselves repeatedly (e.g., examining one's throat in the mirror) (Crite­
rion D). They research their suspected disease excessively (e.g., on the Internet) and re­

peatedly seek reassurance from family, friends, or physicians. This incessant worrying often 
becomes frustrating for others and may result in considerable strain within the family. In 
some cases, the anxiety leads to maladaptive avoidance of situations (e.g., visiting sick 
family members) or activities (e.g., exercise) that these individuals fear might jeopardize 
their health.
Because they believe they are medically ill, individuals with illness anxiety disorder are 
encountered far more frequently in medical than in mental health settings. The majority of 
individuals with illness anxiety disorder have extensive yet unsatisfactory medical care, 
though some may be too anxious to seek medical attention. They generally have elevated

though some may be too anxious to seek medical attention. They generally have elevated 
rates of medical utilization but do not utilize mental health services more than the general 
population. They often consult multiple physicians for the same problem and obtain re­
peatedly negative diagnostic test results. At times, medical attention leads to a paradoxical 
exacerbation of anxiety or to iatrogenic complications from diagnostic tests and proce­
dures. Individuals with the disorder are generally dissatisfied with their medical care and 
find it unhelpful, often feeling they are not being taken seriously by physicians. At times, 
these concerns may be justified, since physicians sometimes are dismissive or respond 
with frustration or hostility. This response can occasionally result in a failure to diagnose 
a medical condition that is present.

Prevalence estimates of illness anxiety disorder are based on estimates of the DSM-III and 
DSM-rV diagnosis hypochondriasis.  The 1- to 2-year prevalence of health anxiety and/or 
disease conviction in community surveys and population-based samples ranges fiOm 1.3% 
to 10%. In ambulatory medical populations, the 6-month/1-year prevalence rates are be­
tween 3% and 8%. The prevalence of the disorder is similar in males and females.
The development and course of illness anxiety disorder are unclear. Illness anxiety disor­
der is generally thought to be a chronic and relapsing condition with an age at onset in 
early and middle adulthood. In population-based samples, health-related anxiety in­
creases with age, but the ages of individuals with high health anxiety in medical settings

creases with age, but the ages of individuals with high health anxiety in medical settings 
do not appear to differ from those of other patients in those settings. In older individuals, 
health-related anxiety often focuses on memory loss; the disorder is thought to be rare in 
children.
Environmental. Illness anxiety disorder may sometimes be precipitated by a major life 
stress or a serious but ultimately benign threat to the individual's health. A history of child­

hood abuse or of a serious childhood ilhiess may predispose to development of the disor­
der in adulthood^
Course modifiers. Approximately one-third to one-half of individuals with illness anx­
iety disorder have a transient form, which is associated with less psychiatric comorbidity, 
more medical comorbidity, and less severe illness aiixiety disorder.
The diagnosis should be made with caution in individuals whose ideas about disease are 
congruent with widely held, culturally sanctioned beliefs. Little is known about the phe­
nomenology of the disorder across cultures, although the prevalence appears to be similar 
across different countries with diverse cultures.
Functional Consequences of Illness Anxiety Disorder
Illness anxiety disorder causes substantial role impairment and decrements in physical 
function and health-related quality of life. Health concerns often interfere with interper­

sonal relationships, disrupt family life, and damage occupational performance.
Other medical conditions. The first differential diagnostic consideration is an underly­
ing medical condition, including neurological or endocrine conditions, occult malignan­
cies, and other diseases that affect multiple body systems. The presence of a medical 
condition does not rule out the possibility of coexisting illness anxiety disorder. If a med­
ical condition is present, the health-related anxiety and disease concerns are clearly dis­
proportionate to its seriousness. Transient preoccupations related to a medical condition 
do not constitute illness anxiety disorder.
Adjustment disorders. Health-related anxiety is a normal response to serious illness

Adjustment disorders. Health-related anxiety is a normal response to serious illness 
and is not a mental disorder. Such nonpathological health anxiety is clearly related to the 
medical condition and is typically time-limited. If the health anxiety is severe enough, an 
adjustment disorder may be diagnosed. However, only when the health anxiety is of suf­
ficient duration, severity, and distress can illness anxiety disorder be diagnosed. Thus, the 
diagnosis requires the continuous persistence of disproportionate health-related anxiety 
for at least 6 months.
Somatic symptom disorder. Somatic symptom disorder is diagnosed when significant 
somatic symptoms are present. In contrast, individuals with illness anxiety disorder have 
minimal somatic symptoms and are primarily concerned with the idea they are ill.
Anxiety disorders. In generalized anxiety disorder, individuals worry about multiple

Anxiety disorders. In generalized anxiety disorder, individuals worry about multiple 
events, situations, or activities, only one of which may involve health. In panic disorder, 
the individual may be concerned that the panic attacks reflect the presence of a medical ill­
ness; however, although these individuals may have health anxiety, their anxiety is typi­
cally very acute and episodic. In illness anxiety disorder, the health anxiety and fears are 
more persistent and enduring. Individuals with illness anxiety disorder may experience 
panic attacks that are triggered by their illness concerns.
Obsessive-compulsive and related disorders. Individuals with illness anxiety disor­
der may have intrusive thoughts about having a disease and also may have associated 
compulsive behaviors (e.g., seeking reassurance). However, in illness anxiety disorder, the

compulsive behaviors (e.g., seeking reassurance). However, in illness anxiety disorder, the 
preoccupations are usually focused on having a disease, whereas in obsessive-compulsive 
disorder (OCD), the thoughts are intrusive and are usually focused on fears of getting a 
disease in the future. Most individuals with OCD have obsessions or compulsions involv­
ing other concerns in addition to fears about contracting disease. In body dysmorphic dis-

order, concerns are limited to the individual's physical appearance, which is viewed as 
defective or flawed.
Major depressive disorder. Some individuals with a major depressive episode rumi­
nate about their health and worry excessively about illness. A separate diagnosis of illness 
anxiety disorder is not made if these concerns occur only during major depressive epi­
sodes. However, if excessive illness worry persists after remission of an episode of major 
depressive disorder, the diagnosis of illness anxiety disorder should be considered.
Psychotic disorders. Individuals with illness anxiety disorder are not delusional and 
can acknowledge the possibility that the feared disease is not present. Their ideas do not 
attain the rigidity and intensity seen in the somatic delusions occurring in psychotic dis­
orders (e.g., schizophrenia; delusional disorder, somatic type; major depressive disorder,

orders (e.g., schizophrenia; delusional disorder, somatic type; major depressive disorder, 
with psychotic features). True somatic delusions are generally more bizarre (e.g., that an 
organ is rotting or dead) than the concerns seen in illness anxiety disorder. The concerns 
seen in illness anxiety disorder, though not founded in reality, are plausible.
Because illness anxiety disorder is a new disorder, exact comorbidities are unknown. Hy­
pochondriasis co-occurs with anxiety disorders (in particular, generalized anxiety disor­
der, panic disorder, and OCD) and depressive disorders. Approximately two-thirds of 
individuals with illness anxiety disorder are likely to have at least one other comorbid ma­
jor mental disorder. Individuals with illness anxiety disorder may have an elevated risk 
for somatic symptom disorder and personality disorders.
Conversion Disorder

Conversion Disorder  
(Functional Neurological Symptom Disorder)
A. One or more symptoms of altered voluntary motor or sensory function.
B. Clinical findings provide evidence of incompatibility between the symptom and recog­
nized neurological or medical conditions.
C. The symptom or deficit is not better explained by another medical or mental disorder.
D. The symptom or deficit causes clinically significant distress or impairment in social, oc­
cupational, or other important areas of functioning or warrants medical evaluation.
Coding note: The ICD-9-CM code for conversion disorder is 300.11, which is assigned  
regardless of the symptom type. The ICD-10-CM code depends on the symptom type (see  
below).
(F44.4) With wealcness or paralysis

below).
(F44.4) With abnormal movement (e.g., tremor, dystonie movement, myoclonus, gait  
disorder)
(F44.4) With speech symptom (e.g., dysphonia, slurred speech)
(F44.5) With attacks or seizures  
(F44.6) With special sensory symptom (e.g., visual, olfactory, or hearing distur­
bance)

Acute episode; Symptoms present for less than 6 months.
Persistent: Symptoms occurring for 6 months or more.
With psyctiological stressor (specify stressor)
Without psychoiogicai stressor
Many clinicians use the alternative names of "functional" (referring to abnormal central 
nervous system functioning) or "psychogenic" (referring to an assumed etiology) to de­
scribe the symptoms of conversion disorder (functional neurological symptom disor­
der). In conversion disorder, there may be one or more symptoms of various types. Motor 
symptoms include weakness or paralysis; abnormal movements, such as tremor or dys­
tonie movements; gait abnormalities; and abnormal limb posturing. Sensory symptoms 
include altered, reduced, or absent skin sensation, vision, or hearing. Episodes of abnor­
mal generalized limb shaking with apparent impaired or loss of consciousness may resem­

ble epileptic seizures (also called psychogenic  or non-epileptic seizures).  There may be 
episodes of unresponsiveness resembling syncope or coma. Other symptoms include re­
duced or absent speech volume (dysphonia/aphonia), altered articulation (dysarthria), a 
sensation of a lump in the throat (globus), and diplopia.
Although the diagnosis requires that the symptom is not explained by neurological 
disease, it should not be made simply because results from investigations are normal or 
because the symptom is "bizarre." There must be clinical findings that show clear evidence 
of incompatibility with neurological disease. Internal inconsistency at examination is one 
way to demonstrate incompatibility (i.e., demonstrating that physical signs elicited

way to demonstrate incompatibility (i.e., demonstrating that physical signs elicited 
through one examination method are no longer positive when tested a different way). Ex­
amples of such examination findings include
•  Hoover's sign, in which weakness of hip extension returns to normal strength with con­
tralateral hip flexion against resistance.
•  Marked weakness of ankle plantar-flexion when tested on the bed in an individual who 
is able to walk on tiptoes;
•  Positive findings on the tremor entrainment test. On this test, a unilateral tremor may 
be identified as functional if the tremor changes when the individual is distracted away 
from it. This may be observed if the individual is asked to copy the examiner in making 
a rhythmical movement with their unaffected hand and this causes the functional

a rhythmical movement with their unaffected hand and this causes the functional 
tremor to change such that it copies or "entrains" to the rhythm of the unaffected hand 
or the functional tremor is suppressed, or no longer makes a simple rhythmical move­
ment.
•  In attacks resembling epilepsy or syncope ("psychogenic" non-epileptic attacks), the 
occurrence of closed eyes with resistance to opening or a normal simultaneous electro­
encephalogram (although this alone does not exclude all forms of epilepsy or syncope).
•  For visual symptoms, a tubular visual field (i.e., tunnel vision).
It is important to note that the diagnosis of conversion disorder should be based on the 
overall clinical picture and not on a single clinical finding.
A number of associated features can support the diagnosis of conversion disorder. There

A number of associated features can support the diagnosis of conversion disorder. There 
may be a history of multiple similar somatic symptoms. Onset may be associated with 
stress or trauma, either psychological or physical in nature. The potential etiological rele­

vance of this stress or trauma may be suggested by a close temporal relationship. However, 
while assessment for stress and trauma is important, the diagnosis should not be withheld 
if none is found.
Conversion disorder is often associated with dissociative symptoms, such as deperson­
alization, derealization, and dissociative amnesia, particularly at symptom onset or during 
attacks.
The diagnosis of conversion disorder does not require the judgment that the symptoms 
are not intentionally produced (i.e., not feigned), as the definite absence of feigning may 
not be reliably discerned. The phenomenon of la belle indifférence  (i.e., lack of concern about 
the nature or implications of the symptom) has been associated with conversion disorder 
but it is not specific for conversion disorder and should not be used to make the diagnosis. 
Similarly the concept of secondary gain  (i.e., when individuals derive external benefits such

Similarly the concept of secondary gain  (i.e., when individuals derive external benefits such 
as money or release from responsibilities) is also not specific to conversion disorder and 
particularly in the context of definite evidence for feigning, the diagnoses that should be 
considered instead would include factitious disorder or malingering (see the section "Dif­
ferential Diagnosis" for this disorder).
Transient conversion symptoms are common, but the precise prevalence of the disorder is 
unknown. This is partly because the diagnosis usually requires assessment in secondary 
care, where it is found in approximately 5% of referrals to neurology clinics. The incidence 
of individual persistent conversion symptoms is estimated to be 2-5/100,000 per year.
Onset has been reported throughout the life course. The onset of non-epileptic attacks

Onset has been reported throughout the life course. The onset of non-epileptic attacks 
peaks in the third decade, and motor symptoms have their peak onset in the fourth decade. 
The symptoms can be transient or persistent. The prognosis may be better in younger chil­
dren than in adolescents and adults.
Temperamental. Maladaptive personality traits are commonly associated with conver­
sion disorder.
Environmental. There may be a history of childhood abuse and neglect. Stressful life 
events are often, but not always, present.
Genetic and physiological. The presence of neurological disease that causes similar symp­
toms is a risk factor (e.g., non-epileptic seizures are more common in patients who also 
have epilepsy).
Course modifiers. Short duration of symptoms and acceptance of the diagnosis are pos­

itive prognostic factors. Maladaptive personality traits, the presence of comorbid physical 
disease, and the receipt of disability benefits may be negative prognostic factors.
Changes resembling conversion (and dissociative) symptoms are common in certain 
culturally sanctioned rituals. If the symptoms are fully explained within the particular 
cultural context and do not result in clinically significant distress or disability, then the di­
agnosis of conversion disorder is not made.
Conversion disorder is two to three times more common in females.

Functional Consequences of Conversion Disorder
Individuals with conversion symptoms may have substantial disability. The severity of dis­
ability can be similar to that experienced by individuals with comparable medical diseases.
If another mental disorder better explains the symptoms, that diagnosis should be made. 
However the diagnosis of conversion disorder may be made in the presence of another 
mental disorder.
Neurological disease. The main differential diagnosis is neurological disease that might 
better explain the symptoms. After a thorough neurological assessment, an unexpected 
neurological disease cause for the symptoms is rarely found at follow up. However, reas­
sessment may be required if the symptoms appear to be progressive. Conversion disorder 
may coexist with neurological disease.
Somatic symptom disorder. Conversion disorder may be diagnosed in addition to so­

matic symptom disorder. Most of the somatic symptoms encountered in somatic symptom 
disorder cannot be demonstrated to be clearly incompatible with pathophysiology (e.g., 
pain, fatigue), whereas in conversion disorder, such incompatibility is required for the di­
agnosis. The excessive thoughts, feelings, and behaviors characterizing somatic symptom 
disorder are often absent in conversion disorder.
Factitious disorder and malingering. The diagnosis of conversion disorder does not re­
quire the judgment that the symptoms are not intentionally produced (i.e., not feigned), 
because assessment of conscious intention is unreliable. However definite evidence of 
feigning (e.g., clear evidence that loss of function is present during the examination but not 
at home) would suggest a diagnosis of factitious disorder if the individual's apparent aim

at home) would suggest a diagnosis of factitious disorder if the individual's apparent aim 
is to assume the sick role or malingering if the aim is to obtain an incentive such as money.
Dissociative disorders. Dissociative symptoms are common in individuals with con­
version disorder. If both conversion disorder and a dissociative disorder are present, both 
diagnoses should be made.
Body dysmorphic disorder. Individuals with body dysmorphic disorder are exces­
sively concerned about a perceived defect in their physical features but do not complain of 
symptoms of sensory or motor functioning in the affected body part.
Depressive disorders. In depressive disorders, individuals may report general heavi­
ness of their limbs, whereas the weakness of conversion disorder is more focal and prom­
inent. Depressive disorders are also differentiated by the presence of core depressive 
symptoms.

symptoms.
Panic disorder. Episodic neurological symptoms (e.g., tremors and paresthesias) can 
occur in both conversion disorder and panic attacks. In panic attacks, the neurological 
symptoms are typically transient and acutely episodic with characteristic cardiorespira­
tory symptoms. Loss of awareness with amnesia for the attack and violent limb move­
ments occur in non-epileptic attacks, but not in panic attacks.
Anxiety disorders, especially panic disorder, and depressive disorders commonly co-occur 
with conversion disorder. Somatic symptom disorder may co-occur as well. Psychosis, sub­
stance use disorder, and alcohol misuse are uncommon. Personality disorders are more 
common in individuals with conversion disorder than in the general population. Neuro­

logical or other medical conditions commonly coexist with conversion disorder as well.

Psychological Factors Affecting  
Other Medical Conditions
Diagnostic Criteria 316 (F54)
A. A medical symptom or condition (other than a mental disorder) is present.
B. Psychological or behavioral factors adversely affect the medical condition in one of the  
following ways:
1. The factors have influenced the course of the medical condition as shown by a  
close temporal association between the psychological factors and the development  
or exacerbation of, or delayed recovery from, the medical condition.
2. The factors interfere with the treatment of the medical condition (e.g., poor adher­
ence).
3. The factors constitute additional well-established health risks for the individual.
4. The factors influence the underlying pathophysiology, precipitating or exacerbating  
symptoms or necessitating medical attention.
C. The psychological and behavioral factors in Criterion B are not better explained by an­

other mental disorder (e.g., panic disorder, major depressive disorder, posttraumatic  
stress disorder).
Mild: Increases medical risk (e.g., inconsistent adherence with antihypertension treat­
ment).
Moderate: Aggravates underlying medical condition (e.g., anxiety aggravating  
asthma).
Severe: Results in medical hospitalization or emergency room visit.
Extreme: Results in severe, life-threatening risk (e.g., ignoring heart attack symp­
toms).
The essential feature of psychological factors affecting other medical conditions is the 
presence of one or more clinically significant psychological or behavioral factors that ad­
versely affect a medical condition by increasing the risk for suffering, death, or disability

versely affect a medical condition by increasing the risk for suffering, death, or disability 
(Criterion B). These factors can adversely affect the medical condition by influencing its 
course or treatment, by constituting an additional well-established health risk factor, or by 
influencing the underlying pathophysiology to precipitate or exacerbate symptoms or to 
necessitate medical attention.
Psychological or behavioral factors include psychological distress, patterns of interper­
sonal interaction, coping styles, and maladaptive health behaviors, such as denial of symp­
toms or poor adherence to medical recommendations. Common clinical examples are 
anxiety-exacerbating asthma, denial of need for treatment for acute chest pain, and manip­
ulation of insulin by an individual v^ith diabetes wishing to lose weight. Many different

ulation of insulin by an individual v^ith diabetes wishing to lose weight. Many different 
psychological factors have been demonstrated to adversely influence medical conditions— 
for example, symptoms of depression or anxiety, stressful life events, relationship style, 
personality traits, and coping styles. The adverse effects can range from acute, with imme­
diate medical consequences (e.g., Takotsubo cardiomyopathy) to chronic, occurring over a 
long period of time (e.g., chronic occupational stress increasing risk for hypertension). Af­
fected medical conditions can be those with clear pathophysiology (e.g., diabetes, cancer, 
coronary disease), functional syndromes (e.g., migraine, irritable bowel syndrome, fibro­
myalgia), or idiopathic medical symptoms (e.g., pain, fatigue, dizziness).

This diagnosis should be reserved for situations in which the effect of the psychological 
factor on the medical condition is evident and the psychological factor has clinically sig­
nificant effects on the course or outcome of the medical condition. Abnormal psychologi­
cal or behavioral symptoms that develop in response to a medical condition are more 
properly coded as an adjustment disorder (a clinically significant psychological response 
to an identifiable stressor). There must be reasonable evidence to suggest an association 
between the psychological factors and the medical condition, although it may often not be 
possible to demonstrate direct causality or the mechanisms underlying the relationship.
The prevalence of psychological factors affecting other medical conditions is unclear. In 
U.S. private insurance billing data, it is a more common diagnosis than somatic symptom 

Psychological factors affecting other medical conditions can occur across the lifespan. Par­
ticularly with young children, corroborative history from parents or school can assist the di­
agnostic evaluation. Some conditions are characteristic of particular life stages (e.g., in older 
individuals, the stress associated with acting as a caregiver for an ill spouse or partner).
Many differences between cultures may influence psychological factors and their effects 
on medical conditions, such as those in language and communication style, explanatory 
models of illness, patterns of seeking health care, service availability and organization, 
doctor-patient relationships and other healing practices, family and gender roles, and at­
titudes toward pain and death. Psychological factors affecting other medical conditions

titudes toward pain and death. Psychological factors affecting other medical conditions 
must be differentiated from culturally specific behaviors such as using faith or spiritual 
healers or other variations in illness management that are acceptable within a culture and 
represent an attempt to help the medical condition rather than interfere with it. These local 
practices may complement rather than obstruct evidence-based interventions. If they do 
not adversely affect outcomes, they should not be pathologized as psychological factors 
affecting other medical conditions.
Functional Consequences of Psychological Factors  
Affecting Other Medical Conditions
Psychological and behavioral factors have been demonstrated to affect the course of many 
medical diseases.
Mental disorder due to another medical condition. A temporal association between

Mental disorder due to another medical condition. A temporal association between 
symptoms of a mental disorder and those of a medical condition is also characteristic of a 
mental disorder due to another medical condition, but the presumed causality is in the op­
posite direction. In a mental disorder due to another medical condition, the medical 
condition is judged to be causing the mental disorder through a direct physiological mech­
anism. In psychological factors affecting other medical conditions, the psychological or be­
havioral factors are judged to affect the course of the medical condition.
Adjustment disorders. Abnormal psychological or behavioral symptoms that develop in 
response to a medical condition are more properly coded as an adjustment disorder (a clin­
ically significant psychological response to an identifiable stressor). For example, an indi­

vidual with angina that is precipitated whenever he becomes enraged would be diagnosed 
as having psychological factors affecting other medical conditions, whereas an individual 
with angina who developed maladaptive anticipatory anxiety would be diagnosed as hav­
ing an adjustment disorder with anxiety. In clinical practice, however, psychological fac­
tors and a medical condition are often mutually exacerbating (e.g., anxiety as both a 
precipitant and a consequence of angina), in which case the distinction is arbitrary. Other 
mental disorders frequently result in medical complications, most notably substance use 
disorders (e.g., alcohol use disorder, tobacco use disorder). If an individual has a coexisting 
major mental disorder that adversely affects or causes another medical condition, diagno­
ses of the mental disorder and the medical condition are usually sufficient. Psychological 
factors affecting other medical conditions is diagnosed when the psychological traits or

factors affecting other medical conditions is diagnosed when the psychological traits or 
behaviors do not meet criteria for a mental diagnosis.
Somatic symptom disorder. Somatic symptom disorder is characterized by a combina­
tion of distressing somatic symptoms and excessive or maladaptive thoughts, feelings, 
and behavior in response to these symptoms or associated health concerns. The individual 
may or may not have a diagnosable medical condition. In contrast, in psychological factors 
affecting other medical conditions, the psychological factors adversely affect a medical 
condition; the individual's thoughts, feelings, and behavior are not necessarily excessive. 
The difference is one of emphasis, rather than a clear-cut distinction. In psychological fac­
tors affecting other medical conditions, the emphasis is on the exacerbation of the medical

tors affecting other medical conditions, the emphasis is on the exacerbation of the medical 
condition (e.g., an individual with angina that is precipitated whenever he becomes anx­
ious). In somatic symptom disorder, the emphasis is on maladaptive thoughts, feelings, 
and behavior (e.g., an individual with angina who worries constantly that she will have a 
heart attack, takes her blood pressure multiple times per day, and restricts her activities).
Illness anxiety disorder. Illness anxiety disorder is characterized by high illness anxiety 
that is distressing and/or disruptive to daily life with minimal somatic symptoms. The fo­
cus of clinical concern is the individual's worry about having a disease; in most cases, no 
serious disease is present. In psychological factors affecting other medical conditions, anx­

iety may be a relevant psychological factor affecting a medical condition, but the clinical 
concern is the adverse effects on the medical condition.
By definition, the diagnosis of psychological factors affecting other medical conditions entails 
a relevant psychological or behavioral syndrome or trait and a comorbid medical condition.
Factitious Disorder
Diagnostic Criteria 300.19 (F68.10)
Factitious Disorder Imposed on Self
A. Falsification of physical or psychological signs or symptoms, or induction of injury or  
disease, associated with identified deception.
B. The individual presents himself or herself to others as ill, impaired, or injured.
C. The deceptive behavior is evident even in the absence of obvious external rewards.

D. The behavior is not better explained by another mental disorder, such as delusional  
disorder or another psychotic disorder.
Specify:
Single episode
Recurrent episodes (two or more events of falsification of illness and/or induction of  
injury)

Factitious Disorder Imposed on Another  
(Previously Factitious Disorder by Proxy)
disease, in another, associated with identified deception.
B. The individual presents another individual (victim) to others as ill, impaired, or injured.
Note: The perpetrator, not the victim, receives this diagnosis.
Specify.
injury)
When an individual falsifies illness in another (e.g., children, adults, pets), the diagnosis is 
factitious disorder imposed on another. The perpetrator, not the victim, is given the diag­

nosis. The victim may be given an abuse diagnosis (e.g., 995.54 [T74.12X]; see the chapter 
'Other Conditions That May Be a Focus of Clinical Attention").
The essential feature of factitious disorder is the falsification of medical or psychological signs 
and symptoms in oneself or others that are associated with the identified deception. Indi­
viduals with factitious disorder can also seek treatment for themselves or another following 
induction of injury or disease. The diagnosis requires demonstrating that the individual is 
taking surreptitious actions to misrepresent, simulate, or cause signs or symptoms of ill­
ness or injury in the absence of obvious external rewards. Methods of illness falsification

ness or injury in the absence of obvious external rewards. Methods of illness falsification 
can include exaggeration, fabrication, simulation, and induction. While a preexisting med­
ical condition may be present, the deceptive behavior or induction of injury associated 
with deception causes others to view such individuals (or another) as more ill or impaired, 
and this can lead to excessive clinical intervention. Individuals with factitious disorder 
might, for example, report feelings of depression and suicidality following the death of a 
spouse despite the death not being true or the individual's not having a spouse; decep­
tively report episodes of neurological symptoms (e.g., seizures, dizziness, or blacking out); 
manipulate a laboratory test (e.g., by adding blood to urine) to falsely indicate an abnor­

mality; falsify medical records to indicate an illness; ingest a substance (e.g., insulin or 
warfarin) to induce an abnormal laboratory result or illness; or physically injure them­
selves or induce illness in themselves or anotiier (e.g., by injecting fecal material to produce 
an abscess or to induce sepsis).
Individuals with factitious disorder imposed on self or factitious disorder imposed on an­
other are at risk for experiencing great psychological distress or functional impairment by 
causing harm to themselves and others. Family, friends, and health care professionals are 
also often adversely affected by their behavior. Factitious disorders have similarities to

also often adversely affected by their behavior. Factitious disorders have similarities to 
substance use disorders, eating disorders, impulse-control disorders, pedophilic disorder, 
and some other established disorders related to both the persistence of the behavior and 
the intentional efforts to conceal the disordered behavior through deception. Whereas 
some aspects of factitious disorders might represent criminal behavior (e.g., factitious dis-

order imposed on another, in which the parent's actions represent abuse and maltreat­
ment of a child), such criminal behavior and mental illness are not mutually exclusive. The 
diagnosis of factitious disorder emphasizes the objective identification of falsification of 
signs and symptoms of illness, rather than an inference about intent or possible underly­
ing motivation. Moreover, such behaviors, including the induction of injury or disease, are 
associated with deception.
The prevalence of factitious disorder is unknown, likely because of the role of deception in 
this population. Among patients in hospital settings, it is estimated that about 1% of indi­
viduals have presentations that meet the criteria for factitious disorder.
The course of factitious disorder is usually one of intermittent episodes. Single episodes 
and episodes that are characterized as persistent and unremitting are both less common.

and episodes that are characterized as persistent and unremitting are both less common. 
Onset is usually in early adulthood, often after hospitalization for a medical condition or a 
mental disorder. When imposed on another, the disorder may begin after hospitalization 
of the individual's child or other dependent. In individuals with recurrent episodes of fal­
sification of signs and symptoms of illness and/or induction of injury, this pattern of suc­
cessive deceptive contact with medical personnel, including hospitalizations, may become 
lifelong.
Caregivers who lie about abuse injuries in dependents solely to protect themselves from lia­
bility are not diagnosed with factitious disorder imposed on anotiier because protection from 
liability is an external reward (Criterion C, the deceptive behavior is evident even in the ab­

sence of obvious external rewards). Such caregivers who, upon observation, analysis of med­
ical records, and/or interviews with others, are found to lie more extensively than needed for 
immediate self-protection are diagnosed with factitious disorder imposed on another.
Somatic symptom disorder. In somatic symptom disorder, there may be excessive at­
tention and treatment seeking for perceived medical concerns, but there is no evidence that 
the individual is providing false information or behaving deceptively.
Malingering. Malingering is differentiated from factitious disorder by the intentional re­
porting of symptoms for personal gain (e.g., money, time off work). In contrast, the diag­
nosis of factitious disorder requires the absence of obvious rewards.

Conversion disorder (functional neurological symptom disorder). Conversion disorder 
is characterized by neurological symptoms that are inconsistent with neurological patho­
physiology. Factitious disorder with neurological symptoms is distinguished from con­
version disorder by evidence of deceptive falsification of symptoms.
Borderiine personality disorder. Deliberate physical self-harm in the absence of suicidal 
intent can also occur in association with other mental disorders such as borderline person­
ality disorder. Factitious disorder requires that the induction of injury occur in association 
with deception.
Medical condition or mental disorder not associated with intentional symptom falsifi­
cation. Presentation of signs and symptoms of illness that do not conform to an identi­

fiable medical condition or mental disorder increases the likelihood of the presence of a 
factitious disorder. However, the diagnosis of factitious disorder does not exclude the 
presence of true medical condition or mental disorder, as comorbid illness often occurs in 
the individual along with factitious disorder. For example, individuals who might manip­
ulate blood sugar levels to produce symptoms may also have diabetes.

Other Specified Somatic Symptom and  
Related Disorder
300.89 (F45.8)
This category applies to presentations in which symptoms characteristic of a somatic  
symptom and related disorder that cause clinically significant distress or impairment in  so­
full criteria for any of the disorders in the somatic symptom and related disorders diagnos­
tic class.
1. Brief somatic symptom disorder: Duration of symptoms is less than 6 months.
2. Brief illness anxiety disorder: Duration of symptoms is less than 6 months.
3. Illness anxiety disorder without excessive health-related behaviors: Criterion D  
for illness anxiety disorder is not met.
4. Pseudocyesis: A false belief of being pregnant that is associated with objective signs  
and reported symptoms of pregnancy.

Unspecified Somatic Symptom and  
300.82 (F45.9)
symptom and related disorder that cause clinically significant distress or impairment in so­
tic class. The unspecified somatic symptom and related disorder category should not be  
used unless there are decidedly unusual situations where there is insufficient information  

pGGdiriQ ând GSting disorders are characterized by a persistent disturbance of eat­
ing or eating-related behavior that results in the altered consumption or absorption of 
food and that significantly impairs physical health or psychosocial functioning. Diagnos­
tic criteria are provided for pica, rumination disorder, avoidant/restrictive food intake 
disorder, anorexia nervosa, bulimia nervosa, and binge-eating disorder.
The diagnostic criteria for rumination disorder, avoidant/restrictive food intake dis­
order, anorexia nervosa, bulimia nervosa, and binge-eating disorder result in a classifica­
tion scheme that is mutually exclusive, so that during a single episode, only one of these 
diagnoses can be assigned. The rationale for this approach is that, despite a number of 
common psychological and behavioral features, the disorders differ substantially in clin­
ical course, outcome, and treatment needs. A diagnosis of pica, however, may be assigned

ical course, outcome, and treatment needs. A diagnosis of pica, however, may be assigned 
in the presence of any other feeding and eating disorder.
Some individuals with disorders described in this chapter report eating-related symp­
toms resembling those typically endorsed by individuals with substance use disorders, 
such as craving and patterns of compulsive use. This resemblance may reflect the involve­
ment of the same neural systems, including those implicated in regulatory self-control and 
reward, in both groups of disorders. However, the relative contributions of shared and 
distinct factors in the development and perpetuation of eating and substance use disor­
ders remain insufficiently understood.
Finally, obesity is not included in DSM-5 as a mental disorder. Obesity (excess body fat) 
results from the long-term excess of energy intake relative to energy expenditure. A range

results from the long-term excess of energy intake relative to energy expenditure. A range 
of genetic, physiological, behavioral, and environmental factors that vary across individ­
uals contributes to the development of obesity; thus, obesity is not considered a mental 
disorder. However, there are robust associations between obesity and a number of mental 
disorders (e.g., binge-eating disorder, depressive and bipolar disorders, schizophrenia). 
The side effects of some psychotropic medications contribute importantly to the develop­
ment of obesity, and obesity may be a risk factor for the development of some mental dis­
orders (e.g., depressive disorders).
Pica
A. Persistent eating of nonnutritive, nonfood substances over a period of at least 1  month.
B . The eating of nonnutritive, nonfood substances is inappropriate to the developmental  
level of the individual.

C. The eating behavior is not part of a culturally supported or socially normative practice.
D. If the eating behavior occurs in  the context of another mental disorder (e.g., intellectual  
disability [intellectual developmental disorder], autism spectrum disorder, schizophre­
nia) or medical condition (including pregnancy), it is sufficiently severe to warrant ad­
ditional clinical attention.

Coding note: The ICD-9-CIVI code for pica is 307.52 and is used for children or adults.  
The ICD-10-CM codes for pica are (F98.3) in children and (F50.8) in adults.
In remission: After full criteria for pica were previously met, the criteria have not been  
met for a sustained period of time. ________________________________________
The essential feature of pica is the eating of one or more nonnutritive, nonfood substances on a 
persistent basis over a period of at least 1  month (Criterion A) that is severe enough to warrant 
clinical attention. Typical substances ingested tend to vary with age and availability and might 
include paper, soap, cloth, hair, string, wool, soil, chalk, talcum powder, paint, gum, metal, 
pebbles, charcoal or coal, ash, clay, starch, or ice. The term nonfood  is included because the di­
agnosis of pica does not apply to ingestion of diet products that have minimal nutritional con­

tent. There is typically no aversion to food in general. The eating of nonnutritive, nonfood 
substances must be developmentally inappropriate (Criterion B) and not part of a culturally 
supported or socially normative practice (Criterion C). A minimum age of 2 years is suggested 
for a pica diagnosis to exclude developmentally normal mouthing of objects by infants that re­
sults in ingestion. The eating of nonnutritive, nonfood substances can be an associated feature 
of other mental disorders (e.g., intellectual disability [intellectual developmental disorder], 
autism spectrum disorder, schizophrenia). If the eating behavior occurs exclusively in the con­
text of another mental disorder, a separate diagnosis of pica should be made only if the eating

text of another mental disorder, a separate diagnosis of pica should be made only if the eating 
behavior is sufficientiy severe to warrant additional clinical attention (Criterion D).
Although deficiencies in vitamins or minerals (e.g., zinc, iron) have been reported in some 
instances, often no specific biological abnormalities are found. In some cases, pica comes 
to clinical attention only following general medical complications (e.g., mechanical bowel 
problems; intestinal obstruction, such as that resulting from a bezoar; intestinal perfora­
tion; infections such as toxoplasmosis and toxocariasis as a result of ingesting feces or dirt; 
poisoning, such as by ingestion of lead-based paint).
The prevalence of pica is unclear. Among individuals with intellectual disability, the prev­

alence of pica appears to increase with the severity of the condition,
Onset of pica can occur in childhood, adolescence, or adulthood, although childhood onset 
is most commonly reported. Pica can occur in otherwise normally developing children, 
whereas in adults, it appears more likely to occur in the context of intellectual disability or 
other mental disorders. The eating of nonnutritive, nonfood substances may also manifest 
in pregnancy, when specific cravings (e.g., chalk or ice) might occur. The diagnosis of pica 
during pregnancy is only appropriate if such cravings lead to the ingestion of nonnutri­
tive, nonfood substances to the extent that the eating of these substances poses potential 
medical risks. The course of the disorder can be protracted and can result in medical emer­

gencies (e.g., intestinal obstruction, acute weight loss, poisoning). The disorder can poten­
tially be fatal depending on substances ingested.
Environmental. Neglect, lack of supervision, and developmental delay can increase the 
risk for this condition.

In some populations, the eating of earth or other seemingly nonnutritive substances is believed 
to be of spiritual, medicinal, or other social value, or may be a culturally supported or socially 
normative practice. Such behavior does not warrant a diagnosis of pica (Criterion C).
Pica occurs in both males and females. It can occur in females during pregnancy; however, 
little is known about the course of pica in the postpartum period.
Abdominal flat plate radiography, ultrasound, and other scanning methods may reveal 
obstructions related to pica. Blood tests and other laboratory tests can be used to ascertain 
levels of poisoning or the nature of infection.
Functional Consequences of Pica
Pica can significantly impair physical functioning, but it is rarely the sole cause of impair­
ment in social functioning. Pica often occurs with other disorders associated with im­
paired social functioning.

Eating of nonnutritive, nonfood substances may occur during the course of other mental 
disorders (e.g., autism spectrum disorder, schizophrenia) and in Kleine-Levin syndrome. 
In any such instance, an additional diagnosis of pica should be given only if the eating be­
havior is sufficiently persistent and severe to warrant additional clinical attention.
Anorexia nervosa. Pica can usually be distinguished from the other feeding and eating 
disorders by the consumption of nonnutritive, nonfood substances. It is important to note, 
however, that some presentations of anorexia nervosa include ingestion of nonnutritive, 
nonfood substances, such as paper tissues, as a means of attempting to control appetite. In 
such cases, when the eating of nonnutritive, nonfood substances is primarily used as a

such cases, when the eating of nonnutritive, nonfood substances is primarily used as a 
means of weight control, anorexia nervosa should be the primary diagnosis.
Factitious disorder. Some individuals with factitious disorder may intentionally ingest 
foreign objects as part of the pattern of falsification of physical symptoms. In such in­
stances, there is an element of deception that is consistent with deliberate induction of in­
jury or disease.
Nonsuicidal self-injury and nonsuicidal self-injury behaviors in personality disorders.
Some individuals may swallow potentially harmful items (e.g., pins, needles, knives) in 
the context of maladaptive behavior patterns associated with personality disorders or 
nonsuicidal self-injury.
Disorders most commonly comorbid with pica are autism spectrum disorder and intellec­

tual disability (intellectual developmental disorder), and, to a lesser degree, schizophrenia 
and obsessive-compulsive disorder. Pica can be associated with trichotillomania (hair- 
pulling disorder) and excoriation (skin-picking) disorder. In comorbid presentations, the 
hair or skin is typically ingested. Pica can also be associated with avoidant/restrictive food 
intake disorder, particularly in individuals with a strong sensory component to their pre­
sentation. When an individual is known to have pica, assessment should include con­
sideration of the possibility of gastrointestinal complications, poisoning, infection, and 
nutritional deficiency.

Rumination Disorder
Diagnostic Criteria 307.53 (F98.21)
A. Repeated regurgitation of food over a period of at least 1  month. Regurgitated food  
may be re-chewed, re-swallowed, or spit out.
B. The repeated regurgitation is not attributable to an associated gastrointestinal or other  
medical condition (e.g., gastroesophageal reflux, pyloric stenosis).
C. The eating disturbance does not occur exclusively during the course of anorexia nervosa,  
bulimia nervosa, binge-eating disorder, or avoidant/restrictive food intal<e disorder.
D. If the symptoms occur in the context of another mental disorder (e.g., intellectual dis­
ability [Intellectual developmental disorder] or another neurodevelopmental disorder),  
they are sufficiently severe to warrant additional clinical attention.
In remission: After full criteria for rumination disorder were previously met, the criteria  
have not been met for a sustained period of time.

The essential feature of rumination disorder is the repeated regurgitation of food occur­
ring after feeding or eating over a period of at least 1  month (Criterion A). Previously swal­
lowed food that may be partially digested is brought up into the mouth without apparent 
nausea, involuntary retching, or disgust. The food may be re-chewed and then ejected 
from the mouth or re-swallowed. Regurgitation in rumination disorder should be fre­
quent, occurring at least several times per week, typically daily. The behavior is not better 
explained by an associated gastrointestinal or other medical condition (e.g., gastroesoph­
ageal reflux, pyloric stenosis) (Criterion B) and does not occur exclusively during the 
course of anorexia nervosa, bulimia nervosa, binge-eating disorder, or avoidant/restric­

tive food intake disorder (Criterion C). If the symptoms occur in the context of another 
mental disorder (e.g., intellectual disability [intellectual developmental disorder], neuro­
developmental disorder), they must be sufficiently severe to warrant additional clinical 
attention (Criterion D) and should represent a primary aspect of the individual's presen­
tation requiring intervention. The disorder may be diagnosed across the life span, par­
ticularly in individuals who also have intellectual disability. Many individuals with 
rumination disorder can be directly observed engaging in the behavior by the clinician. In 
other instances diagnosis can be made on the basis of self-report or corroborative informa­
tion from parents or caregivers. Individuals may describe the behavior as habitual or out­

side of their control.
Infants with rumination disorder display a characteristic position of straining and arching 
the back with the head held back, making sucking movements with their tongue. They 
may give the impression of gaining satisfaction from the activity. They may be irritable 
and hungry between episodes of regurgitation. Weight loss and failure to make expected 
weight gains are common features in infants with rumination disorder. Malnutrition may 
occur despite the infant's apparent hunger and the ingestion of relatively large amounts of 
food, particularly in severe cases, when regurgitation immediately follows each feeding 
episode and regurgitated food is expelled. Malnutrition might also occur in older children

episode and regurgitated food is expelled. Malnutrition might also occur in older children 
and adults, particularly when the regurgitation is accompanied by restriction of intake. 
Adolescents and adults may attempt to disguise the regurgitation behavior by placing a

hand over the mouth or coughing. Some will avoid eating with others because of the ac­
knowledged soqal undesirability of the behavior. This may extend to an avoidance of eat­
ing prior to social situations, such as work or school (e.g., avoiding breakfast because it 
may be followed by regurgitation).
Prevalence data for rumination disorder are inconclusive, but the disorder is commonly 
reported to be higher in certain groups, such as individuals with intellectual disability.
Onset of rumination disorder can occur in infancy, childhood, adolescence, or adulthood. 
The age at onset in infants is usually between ages 3 and 12 months. In infants, the disorder 
frequently remits spontaneously, but its course can be protracted and can result in medical 
emergencies (e.g., severe malnutrition). It can potentially be fatal, particularly in infancy. 
Rumination disorder can have an episodic course or occur continuously until treated. In

Rumination disorder can have an episodic course or occur continuously until treated. In 
infants, as well as in older individuals with intellectual disability (intellectual developmen­
tal disorder) or other neurodevelopmental disorders, the regurgitation and rumination be­
havior appears to have a self-soothing or self-stimulating function, similar to that of other 
repetitive motor behaviors such as head banging.
Environmental. Psychosocial problems such as lack of stimulation, neglect, stressful life 
situations, and problems in the parent-child relationship may be predisposing factors in 
infants and young children.
Functional Consequences of Rumination Disorder
Malnutrition secondary to repeated regurgitation may be associated with growth delay 
and have a negative effect on development and learning potential. Some older individuals

and have a negative effect on development and learning potential. Some older individuals 
with rumination disorder deliberately restrict their food intake because of the social un­
desirability of regurgitation. They may therefore present with weight loss or low weight. 
In older children, adolescents, and adults, social functioning is more likely to be adversely 
affected.
Gastrointestinal conditions. It is important to differentiate regurgitation in rumination 
disorder from other conditions characterized by gastroesophageal reflux or vomiting. Con­
ditions such as gastroparesis, pyloric stenosis, hiatal hernia, and Sandifer syndrome in in­
fants should be ruled out by appropriate physical examinations and laboratory tests.
Anorexia nervosa and bulimia nervosa. Individuals with anorexia nervosa and bulimia

Anorexia nervosa and bulimia nervosa. Individuals with anorexia nervosa and bulimia 
nervosa may also engage in regurgitation with subsequent spitting out of food as a means 
of disposing of ingested calories because of concerns about weight gain.
Regurgitation with associated rumination can occur in the context of a concurrent medical 
condition or another mental disorder (e.g., generalized anxiety disorder). When the regur­
gitation occurs in this context, a diagnosis of rumination disorder is appropriate only when 
the severity of the disturbance exceeds that routinely associated with such conditions or 
disorders and warrants additional clinical attention.

Avoidant/Restrictive Food Intake Disorder
Diagnostic Criteria 307.59 (F50.8)
A. An eating or feeding disturbance (e.g., apparent lack of interest in eating or food; avoid­
ance based on tlie sensory ciiaracteristics of food; concern about aversive conse­
quences of eating) as manifested by persistent failure to meet appropriate nutritional  
and/or energy needs associated with one (or more) of the following:
1. Significant weight loss (or failure to achieve expected weight gain or faltering  
growth in children).
2. Significant nutritional deficiency.
3. Dependence on enteral feeding or oral nutritional supplements.
4. Marked interference with psychosocial functioning.
B. The disturbance is not better explained by lack of available food or by an associated  
culturally sanctioned practice.
C. The eating disturbance does not occur exclusively during the course of anorexia ner­
vosa or bulimia nervosa, and there is no evidence of a disturbance in the way in which

vosa or bulimia nervosa, and there is no evidence of a disturbance in the way in which  
one’s body weight or shape is experienced.
D. The eating disturbance is not attributable to a concurrent medical condition or not bet­
ter explained by another mental disorder. When the eating disturbance occurs in the  
context of another condition or disorder, the severity of the eating disturbance exceeds  
that routinely associated with the condition or disorder and warrants additional clinical  
attention.
In remission: After full criteria for avoidant/restrictive food intake disorder were previ­
ously met, the criteria have not been met for a sustained period of time.
Avoidant/restrictive food intake disorder replaces and extends the DSM-IV diagnosis of 
feeding disorder of infancy or early childhood. The main diagnostic feature of avoidant/

feeding disorder of infancy or early childhood. The main diagnostic feature of avoidant/ 
restrictive food intake disorder is avoidance or restriction of food intake (Criterion A) 
manifested by clinically significant failure to meet requirements for nutrition or insuffi­
cient energy intake through oral intake of food. One or more of the following key features 
must be present: significant weight loss, significant nutritional deficiency (or related 
health impact), dependence on enteral feeding or oral nutritional supplements, or marked 
interference with psychosocial functioning. The determination of whether weight loss is 
significant (Criterion Al) is a clinical judgment; instead of losing weight, children and ad­
olescents who have not completed growth may not maintain weight or height increases 
along their developmental trajectory.

Determination of significant nutritional deficiency (Criterion A2) is also based on clin­
ical assessment (e.g., assessment of dietary intake, physical examination, and laboratory 
testing), and related impact on physical health can be of a similar severity to that seen in 
anorexia nervosa (e.g., hypothermia, bradycardia, anemia). In severe cases, particularly in 
infants, malnutrition can be life threatening. "Dependence" on enteral feeding or oral nu­
tritional supplements (Criterion A3) means that supplementary feeding is required to sus­
tain adequate intake. Examples of individuals requiring supplementary feeding include 
infants with failure to thrive who require nasogastric tube feeding, children with neuro- 
developmental disorders who are dependent on nutritionally complete supplements, and

developmental disorders who are dependent on nutritionally complete supplements, and 
individuals who rely on gastrostomy tube feeding or complete oral nutrition supplements 
in the absence of an underlying medical condition. Inability to participate in normal social

activities, such as eating with others, or to sustain relationships as a result of the distur­
bance would inculcate marked interference with psychosocial functioning (Criterion A4).
Avoidant/restrictive food intake disorder does not include avoidance or restriction of 
food intake related to lack of availability of food or to cultural practices (e.g., religious fast­
ing or normal dieting) (Criterion B), nor does it include developmentally normal behaviors 
(e.g., picky eating in toddlers, reduced intake in older adults). The disturbance is not better 
explained by excessive concern about body weight or shape (Criterion C) or by concurrent 
medical factors or mental disorders (Criterion D).
In some individuals, food avoidance or restriction may be based on the sensory char­
acteristics of qualities of food, such as extreme sensitivity to appearance, color, smell, 
texture, temperature, or taste. Such behavior has been described as "restrictive eating,"

texture, temperature, or taste. Such behavior has been described as "restrictive eating," 
"selective eating," "choosy eating," "perseverant eating," "chronic food refusal," and 
"food neophobia" and may manifest as refusal to eat particular brands of foods or to tol­
erate the smell of food being eaten by others. Individuals with heightened sensory sensi­
tivities associated with autism may show similar behaviors.
Food avoidance or restriction may also represent a conditioned negative response as­
sociated with food intake following, or in anticipation of, an aversive experience, such as 
choking; a traumatic investigation, usually involving the gastrointestinal tract (e.g., esoph- 
agoscopy); or repeated vomiting. The terms frinctional dysphagia and globus hystericus  have 
also been used for such conditions.

Several features may be associated with food avoidance or reduced food intake, including 
a lack of interest in eating or food, leading to weight loss or faltering growth. Very young 
infants may present as being too sleepy, distressed, or agitated to feed. Infants and young 
children may not engage with the primary caregiver during feeding or communicate hun­
ger in favor of other activities. In older children and adolescents, food avoidance or restric­
tion may be associated with more generalized emotional difficulties that do not meet 
diagnostic criteria for an anxiety, depressive, or bipolar disorder, sometimes called "food 
avoidance emotional disorder."
Food avoidance or restriction associated with insufficient intake or lack of interest in eat­

ing most commonly develops in infancy or early childhood and may persist in adulthood. 
Likewise, avoidance based on sensory characteristics of food tends to arise in the first de­
cade of life but may persist into adulthood. Avoidance related to aversive consequences 
can arise at any age. The scant literature regarding long-term outcomes suggests that food 
avoidance or restriction based on sensory aspects is relatively stable and long-standing, 
but when persisting into adulthood, such avoidance/restriction can be associated with rel­
atively normal functioning. There is currently insufficient evidence directly linking avoid­
ant/restrictive food intake disorder and subsequent onset of an eating disorder.
Infants with avoidant/restrictive food intake disorder may be irritable and difficult to

Infants with avoidant/restrictive food intake disorder may be irritable and difficult to 
console during feeding, or may appear apathetic and withdrawn. In some instances, par­
ent-child interaction may contribute to the infant's feeding problem (e.g., presenting food 
inappropriately, or interpreting the infant's behavior as an act of aggression or rejection). 
Inadequate nutritional intake may exacerbate the associated features (e.g., irritability, de­
velopmental lags) and further contribute to feeding difficulties. Associated factors include 
infant temperament or developmental impairments that reduce an infant's responsiveness 
to feeding. Coexisting parental psychopathology, or child abuse or neglect, is suggested if 
feeding and weight improve in response to changing caregivers. In infants, children, and 
prepubertal adolescents, avoidant/restrictive food intake disorder may be associated with

prepubertal adolescents, avoidant/restrictive food intake disorder may be associated with 
growth delay, and the resulting malnutrition negatively affects development and learning

potential. In older children, adolescents, and adults, social functioning tends to be ad­
versely affected. Regardless of the age, family function may be affected, with heightened 
stress at mealtimes and in other feeding or eating contexts involving friends and relatives.
Avoidant/restrictive food intake disorder manifests more commonly in children than 
in adults, and there may be a long delay between onset and clinical presentation. Triggers 
for presentation vary considerably and include physical, social, and emotional difficulties.
Temperamental. Anxiety disorders, autism spectrum disorder, obsessive-compulsive 
disorder, and attention-deficit/hyperactivity disorder may increase risk for avoidant or 
restrictive feeding or eating behavior characteristic of the disorder.
Environmental. Environmental risk factors for avoidant/restrictive food intake disor­
der include familial anxiety. Higher rates of feeding disturbances may occur in children of

der include familial anxiety. Higher rates of feeding disturbances may occur in children of 
mothers with eating disorders.
Genetic and physiological. History of gastrointestinal conditions, gastroesophageal re­
flux disease, vomiting, and a range of other medical problems has been associated with 
feeding and eating behaviors characteristic of avoidant/restrictive food intake disorder.
Presentations similar to avoidant/restrictive food intake disorder occur in various popu­
lations, including in the United States, Canada, Australia, and Europe. Avoidant/restrictive 
food intake disorder should not be diagnosed when avoidance of food intake is solely re­
lated to specific religious or cultural practices.
Avoidant/restrictive food intake disorder is equally common in males and females in in­

fancy and early childhood, but avoidant/restrictive food intake disorder comorbid with 
autism spectrum disorder has a male predominance. Food avoidance or restriction related 
to altered sensory sensitivities can occur in some physiological conditions, most notably 
pregnancy, but is not usually extreme and does not meet full criteria for the disorder.
Diagnostic markers include malnutrition, low weight, growth delay, and the need for ar­
tificial nutrition in the absence of any clear medical condition other than poor intake.
Functionai Consequences of Avoidant/Restrictive  
Food Intaice Disorder
Associated developmental and functional limitations include impairment of physical de­
velopment and social difficulties that can have a significant negative impact on family 
function.

function.
Appetite loss preceding restricted intake is a nonspecific symptom that can accompany a 
number of mental diagnoses. Avoidant/restrictive food intake disorder can be diagnosed 
concurrently with the disorders below if all criteria are met, and the eating disturbance re­
quires specific clinical attention.
Other medical conditions (e.g., gastrointestinal disease, food allergies and Intoler­
ances, occult malignancies). Restriction of food intake may occur in other medical condi-

tiens, especially those with ongoing symptoms such as vomiting, loss of appetite, nausea, ab­
dominal pain, o^ diarrhea. A diagnosis of avoidant/restrictive food intake disorder requires 
that the disturbance of intake is beyond that directly accounted for by physical symptoms con­
sistent with a medical condition; tiie eating disturbance may also persist after being triggered 
by a medical condition and following resolution of the medical condition.
Underlying medical or comorbid mental conditions may complicate feeding and eating. 
Because older individuals, postsurgical patients, and individuals receiving chemotherapy 
often lose their appetite, an additional diagnosis of avoidant/restrictive food intake dis­
order requires that the eating disturbance is a primary focus for intervention.
Specific neurological/neuromuscular, structural, or congenital disorders and condi­
tions associated with feeding difficulties. Feeding difficulties are common in a number

tions associated with feeding difficulties. Feeding difficulties are common in a number 
of congenital and neurological conditions often related to problems with oral/esophageal/ 
pharyngeal structure and function, such as hypotonia of musculature, tongue protrusion, 
and unsafe swallowing. Avoidant/restrictive food intake disorder can be diagnosed in in­
dividuals with such presentations as long as all diagnostic criteria are met.
Reactive attachment disorder. Some degree of withdrawal is characteristic of reactive 
attachment disorder and can lead to a disturbance in the caregiver-child relationship that 
can affect feeding and the child's intake. Avoidant/restrictive food intake disorder should 
be diagnosed concurrently only if all criteria are met for both disorders and the feeding 
disturbance is a primary focus for intervention.

Autism spectrum disorder. Individuals with autism spectrum disorder often present with 
rigid eating behaviors and heightened sensory sensitivities. However, these features do 
not always result in the level of impairment that would be required for a diagnosis of 
avoidant/restrictive food intake disorder. Avoidant/restrictive food intake disorder should 
be diagnosed concurrently only if all criteria are met for both disorders and when the eat­
ing disturbance requires specific treatment.
Specific phobia, social anxiety disorder (social phobia), and other anxiety disorders.
Specific phobia, other type, specifies "situations that may lead to choking or vomiting" and 
can represent the primary trigger for the fear, anxiety, or avoidance required for diagnosis.

can represent the primary trigger for the fear, anxiety, or avoidance required for diagnosis. 
Distinguishing specific phobia from avoidant/restrictive food intake disorder can be dif­
ficult when a fear of choking or vomiting has resulted in food avoidance. Although avoid­
ance or restriction of food intake secondary to a pronounced fear of choking or vomiting 
can be conceptualized as specific phobia, in situations when the eating problem becomes 
the primary focus of clinical attention, avoidant/restrictive food intake disorder becomes 
the appropriate diagnosis. In social anxiety disorder, the individual may present with a 
fear of being observed by others while eating, which can also occur in avoidant/restrictive 
food intake disorder.
Anorexia nervosa. Restriction of energy intake relative to requirements leading to sig­

nificantly low body weight is a core feature of anorexia nervosa. However, individuals 
with anorexia nervosa also display a fear of gaining weight or of becoming fat, or persis­
tent behavior that interferes with weight gain, as well as specific disturbances in relation to 
perception and experience of their own body weight and shape. These features are not 
present in avoidant/restrictive food intake disorder, and the two disorders should not be 
diagnosed concurrently. Differential diagnosis between avoidant/restrictive food intake 
disorder and anorexia nervosa may be difficult, especially in late childhood and early ad­
olescence, because these disorders may share a number of common symptoms (e.g., food 
avoidance, low weight). Differential diagnosis is also potentially difficult in individuals

avoidance, low weight). Differential diagnosis is also potentially difficult in individuals 
with anorexia nervosa who deny any fear of fatness but nonetheless engage in persistent 
behaviors that prevent weight gain and who do not recognize the medical seriousness of 
their low weight—a presentation sometimes termed "non-fat phobic anorexia nervosa." 
Full consideration of symptoms, course, and family history is advised, and diagnosis may

be best made in the context of a clinical relationship over time. In some individuals, avoid­
ant/restrictive food intake disorder might precede the onset of anorexia nervosa.
Obsessive-compulsive disorder. Individuals with obsessive-compulsive disorder may 
present with avoidance or restriction of intake in relation to preoccupations with food or 
ritualized eating behavior. Avoidant/restrictive food intake disorder should be diagnosed 
concurrently only if all criteria are met for both disorders and when the aberrant eating is 
a major aspect of the clinical presentation requiring specific intervention.
Major depressive disorder. In major depressive disorder, appetite might be affected to 
such an extent that individuals present with significantly restricted food intake, usually in 
relation to overall energy intake and often associated with weight loss. Usually appetite 
loss and related reduction of intake abate with resolution of mood problems. Avoidant/

loss and related reduction of intake abate with resolution of mood problems. Avoidant/ 
restrictive food intake disorder should only be used concurrently if full criteria are met for 
both disorders and when the eating disturbance requires specific treatment.
Schizophrenia spectrum disorders. Individuals with schizophrenia, delusional disor­
der, or other psychotic disorders may exhibit odd eating behaviors, avoidance of specific 
foods because of delusional beliefs, or other manifestations of avoidant or restrictive in­
take. In some cases, delusional beliefs may contribute to a concern about negative conse­
quences of ingesting certain foods. Avoidant/restrictive food intake disorder should be 
used concurrently only if all criteria are met for both disorders and when the eating dis­
turbance requires specific treatment.

Factitious disorder or factitious disorder imposed on another. Avoidant/restrictive 
food intake disorder should be differentiated from factitious disorder or factitious disor­
der imposed on another. In order to assume the sick role, some individuals with factitious 
disorder may intentionally describe diets that are much more restrictive than those they 
are actually able to consume, as well as complications of such behavior, such as a need for 
enteral feedings or nutritional supplements, an inability to tolerate a normal range of 
foods, and/or an inability to participate normally in age-appropriate situations involving 
food. The presentation may be impressively dramatic and engaging, and the symptoms re­
ported inconsistently. In factitious disorder imposed on another, the caregiver describes

ported inconsistently. In factitious disorder imposed on another, the caregiver describes 
symptoms consistent with avoidant/restrictive food intake disorder and may induce 
physical symptoms such as failure to gain weight. As with any diagnosis of factitious dis­
order imposed on another, the caregiver receives the diagnosis rather than the affected in­
dividual, and diagnosis should be made only on the basis of a careful, comprehensive 
assessment of the affected individual, the caregiver, and their interaction.
The most commonly observed disorders comorbid with avoidant/restrictive food intake 
disorder are anxiety disorders, obsessive-compulsive disorder, and neurodevelopmental 
disorders (specifically autism spectrum disorder, attention-deficit/hyperactivity disor­
der, and intellectual disability [intellectual developmental disorder]).
Anorexia Nervosa

A. Restriction of energy intal<e relative to requirements, leading to a significantly low body  
weigfit in tfie context of age, sex, developmental trajectory, and physical health. Sig­
nificantly low weight  is defined as a weight that is less than minimally normal or, for  
children and adolescents, less than that minimally expected.
B. Intense fear of gaining weight or of becoming fat, or persistent behavior that interferes  
with weight gain, even though at a significantly low weight.

C. Disturbance in tlie way in  which one’s body weight or shape is experienced, undue in­
fluence of body weight or shape on self-evaluation, or persistent lack of recognition of  
the seriousness of the current low body weight.
Coding note: The ICD-9-CM code for anorexia nervosa is 307.1 , which is assigned re­
gardless of the subtype. The ICD-10-CM code depends on the subtype (see below).  
(F50.01) Restricting type: During the last 3 months, the individual has not engaged in  re­
current episodes of binge eating or purging behavior (i.e., self-induced vomiting or the mis­
use of laxatives, diuretics, or enemas). This subtype describes presentations in  which  
weight loss is accomplished primarily through dieting, fasting, and/or excessive exercise.  
(F50.02) Binge-eating/purging type: During the last 3 months, the individual has en­
gaged in  recurrent episodes of binge eating or purging behavior (i.e., self-induced

gaged in  recurrent episodes of binge eating or purging behavior (i.e., self-induced  
vomiting or the misuse of laxatives, diuretics, or enemas).
In partial remission: After full criteria for anorexia nervosa were previously met. Cri­
terion A (low body weight) has not been met for a sustained period, but either Criterion  
B (intense fear of gaining weight or becoming fat or behavior that interferes with weight  
gain) or Criterion C (disturbances in  self-perception of weight and shape) is still met.  
In full remission: After full criteria for anorexia nervosa were previously met, none of  
the criteria have been met for a sustained period of time.
The minimum level of severity is based, for adults, on current body mass index (BMI) (see  
below) or, for children and adolescents, on BMI percentile. The ranges below are derived

below) or, for children and adolescents, on BMI percentile. The ranges below are derived  
from World Health Organization categories for thinness in adults; for children and adoles­
cents, corresponding BMI percentiles should be used. The level of severity may be in­
creased to reflect clinical symptoms, the degree of functional disability, and the need for  
supervision.
Mild: BMI>17kg/m2  
Moderate: BM116-16.99 kg/m^
Severe: BM115-15.99 kg/m^
Extreme: BMI < 15 kg/m^
Subtypes
Most individuals with the binge-eating/purging type of anorexia nervosa who binge eat 
also purge through self-induced vomiting or the misuse of laxatives, diuretics, or enemas. 
Some individuals with this subtype of anorexia nervosa do not binge eat but do regularly 
purge after the consumption of small amounts of food.
Crossover between the subtypes over the course of the disorder is not uncommon;

Crossover between the subtypes over the course of the disorder is not uncommon; 
therefore, subtype description should be used to describe current symptoms rather than 
longitudinal course.
There are three essential features of anorexia nervosa: persistent energy intake restriction; 
intense fear of gaining weight or of becoming fat, or persistent behavior that interferes 
with weight gain; and a disturbance in self-perceived weight or shape. The individual main­
tains a body weight that is below a minimally normal level for age, sex, developmental tra­
jectory, and physical health (Criterion A). Individuals' body weights frequently meet this 
criterion following a significant weight loss, but among children and adolescents, there 
may alternatively be failure to make expected weight gain or to maintain a normal devel­
opmental trajectory (i.e., while growing in height) instead of weight loss.

Criterion A requires that the individual's weight be significantly low (i.e., less than 
minimally normal or, for children and adolescents, less than that minimally expected). 
Weight assessment can be challenging because normal weight range differs among indi­
viduals, and different thresholds have been published defining thinness or underweight 
status. Body mass index (BMI; calculated as weight in kilograms/height in meters^) is a 
useful measure to assess body weight for height. For adults, a BMI of 18.5 kg/m^ has been 
employed by the Centers for Disease Control and Prevention (CDC) and the World Health 
Organization (WHO) as the lower limit of normal body weight. Therefore, most adults with 
a BMI greater than or equal to 18.5 kg/m^ would not be considered to have a significantly 
low body weight. On the other hand, a BMI of lower than 17.0 kg/m^ has been considered 
by the WHO to indicate moderate or severe thinness; therefore, an individual with a BMI

by the WHO to indicate moderate or severe thinness; therefore, an individual with a BMI 
less than 17.0 kg/m^ would likely be considered to have a significantly low weight. An 
adult with a BMI between 17.0 and 18.5 kg/m^, or even above 18.5 kg/m , might be consid­
ered to have a significantly low weight if clinical history or other physiological informa­
tion supports this judgment.
For children and adolescents, determining a BMI-for-age percentile is useful (see, e.g., 
the CDC BMI percentile calculator for children and teenagers. As for adults, it is not pos­
sible to provide definitive standards forjudging whether a child's or an adolescent's weight 
is significantly low, and variations in developmental trajectories among youth limit the 
utility of simple numerical guidelines. The CDC has used a BMI-for-age below the 5th per­

centile as suggesting underweight; however, children and adolescents with a BMI above 
this benchmark may be judged to be significantly underweight in light of failure to main­
tain their expected growth trajectory. In summary, in determining whether Criterion A is 
met, the clinician should consider available numerical guidelines, as well as the individual's 
body build, weight history, and any physiological disturbances.
Individuals with this disorder typically display an intense fear of gaining weight or of 
becoming fat (Criterion B). This intense fear of becoming fat is usually not alleviated by 
weight loss. In fact, concern about weight gain may increase even as weight falls. Younger 
individuals with anorexia nervosa, as well as some adults, may not recognize or acknowl­

edge a fear of weight gain. In the absence of another explanation for the significantly low 
weight, clinician inference drawn from collateral history, observational data, physical and 
laboratory findings, or longitudinal course either indicating a fear of weight gain or sup­
porting persistent behaviors that prevent it may be used to establish Criterion B.
The experience and significance of body weight and shape are distorted in these indi­
viduals (Criterion C). Some individuals feel globally overweight. Others realize that they 
are thin but are still concerned that certain body parts, particularly the abdomen, buttocks, 
and thighs, are "too fat." They may employ a variety of techniques to evaluate their body 
size or weight, including frequent weighing, obsessive measuring of body parts, and per­

sistent use of a mirror to check for perceived areas of "fat." The self-esteem of individuals 
with anorexia nervosa is highly dependent on their perceptions of body shape and weight. 
Weight loss is often viewed as an impressive achievement and a sign of extraordinary self­
discipline, whereas weight gain is perceived as an unacceptable failure of self-control. Al­
though some individuals with this disorder may acknowledge being thin, they often do 
not recognize the serious medical implications of their malnourished state.
Often, the individual is brought to professional attention by family members after marked 
weight loss (or failure to make expected weight gains) has occurred. If individuals seek help 
on their own, it is usually because of distress over the somatic and psychological sequelae

on their own, it is usually because of distress over the somatic and psychological sequelae 
of starvation. It is rare for an individual with anorexia nervosa to complain of weight loss 
per se. In fact, individuals with anorexia nervosa frequently either lack insight into or deny 
the problem. It is therefore often important to obtain information from family members or 
other sources to evaluate the history of weight loss and other features of the illness.

The semi-starvation of anorexia nervosa, and the purging behaviors sometimes associated 
with it, can result in significant and potentially life-threatening medical conditions. The 
nutritional compromise associated with this disorder affects most major organ systems 
and can produce a variety of disturbances. Physiological disturbances, including amenor­
rhea and vital sign abnormalities, are common. While most of the physiological distur­
bances associated with malnutrition are reversible with nutritional rehabilitation, some, 
including loss of bone mineral density, are often not completely reversible. Behaviors such 
as self-induced vomiting and misuse of laxatives, diuretics, and enemas may cause a num­
ber of disturbances that lead to abnormal laboratory findings; however, some individuals 
with anorexia nervosa exhibit no laboratory abnormalities.
When seriously underweight, many individuals with anorexia nervosa have depressive

When seriously underweight, many individuals with anorexia nervosa have depressive 
signs and symptoms such as depressed mood, social withdrawal, irritability, insomnia, and 
diminished interest in sex. Because these features are also observed in individuals without 
anorexia nervosa who are significantly undernourished, many of the depressive features 
may be secondary to the physiological sequelae of semi-starvation, although they may also 
be sufficiently severe to warrant an additional diagnosis of major depressive disorder.
Obsessive-compulsive features, both related and unrelated to food, are often prominent. 
Most individuals with anorexia nervosa are preoccupied with thoughts of food. Some col­
lect recipes or hoard food. Observations of behaviors associated with other forms of star­
vation suggest that obsessions and compulsions related to food may be exacerbated by

vation suggest that obsessions and compulsions related to food may be exacerbated by 
imdemutrition. When individuals with anorexia nervosa exhibit obsessions and compul­
sions that are not related to food, body shape, or weight, an additional diagnosis of obses­
sive-compulsive disorder (OCD) may be warranted.
Other features sometimes associated with anorexia nervosa include concerns about 
eating in public, feelings of ineffectiveness, a strong desire to control one's environment, 
inflexible thinking, limited social spontaneity, and overly restrained emotional ex­
pression. Compared with individuals with anorexia nervosa, restricting type, those with 
binge-eating/purging type have higher rates of impulsivity and are more likely to abuse 
alcohol and other drugs.
A subgroup of individuals with anorexia nervosa show excessive levels of physical ac­

tivity. Increases in physical activity often precede onset of the disorder, and over the 
course of the disorder increased activity accelerates weight loss. During treatment, exces­
sive activity may be difficult to control, thereby jeopardizing weight recovery.
Individuals with anorexia nervosa may misuse medications, such as by manipulating 
dosage, in order to achieve weight loss or avoid weight gain. Individuals with diabetes 
mellitus may omit or reduce insulin doses in order to minimize carbohydrate metabolism.
The 12-month prevalence of anorexia nervosa among young females is approximately 
0.4%. Less is known about prevalence among males, but anorexia nervosa is far less com­
mon in males than in females, with clinical populations generally reflecting approximately

mon in males than in females, with clinical populations generally reflecting approximately 
a 10 :1 female-to-male ratio.
Anorexia nervosa commonly begins during adolescence or young adulthood. It rarely be­
gins before puberty or after age 40, but cases of both early and late onset have been de­
scribed. The onset of this disorder is often associated with a stressful life event, such as 
leaving home for college. The course and outcome of anorexia nervosa are highly variable. 
Younger individuals may manifest atypical features, including denying "fear of fat." Older

individuals more likely have a longer duration of illness, and their clinical presentation may 
include more signs and symptoms of long-standing disorder. Clinicians should not exclude 
anorexia nervosa from the differential diagnosis solely on the basis of older age.
Many individuals have a period of changed eating behavior prior to full criteria for the 
disorder being met. Some individuals with anorexia nervosa recover fully after a single 
episode, with some exhibiting a fluctuating pattern of weight gain followed by relapse, 
and others experiencing a chronic course over many years. Hospitalization may be re­
quired to restore weight and to address medical complications. Most individuals with an­
orexia nervosa experience remission within 5 years of presentation. Among individuals 
admitted to hospitals, overall remission rates may be lower. The crude mortality rate (CMR) 
for anorexia nervosa is approximately 5% per decade. Death most commonly results from

for anorexia nervosa is approximately 5% per decade. Death most commonly results from 
medical complications associated with the disorder itself or from suicide.
Temperamental. Individuals who develop anxiety disorders or display obsessional 
traits in childhood are at increased risk of developing anorexia nervosa.
Environmental. Historical and cross-cultural variability in the prevalence of anorexia 
nervosa supports its association with cultures and settings in which thinness is valued. Oc­
cupations and avocations that encourage thinness, such as modeling and elite athletics, are 
also associated with increased risk.
Genetic and physiological. There is an increased risk of anorexia nervosa and bulimia 
nervosa among first-degree biological relatives of individuals with the disorder. An in­

creased risk of bipolar and depressive disorders has also been found among first-degree 
relatives of individuals with anorexia nervosa, particularly relatives of individuals with 
the binge-eating/purging type. Concordance rates for anorexia nervosa in monozygotic 
twins are significantly higher than those for dizygotic twins. A range of brain abnormali­
ties has been described in anorexia nervosa using functional imaging technologies (func­
tional magnetic resonance imaging, positron emission tomography). The degree to which 
these findings reflect changes associated with malnutrition versus primary abnormalities 
associated with the disorder is unclear.
Anorexia nervosa occurs across culturally and socially diverse populations, although available

Anorexia nervosa occurs across culturally and socially diverse populations, although available 
evidence suggests cross-cultural variation in its occurrence and presentation. Anorexia ner­
vosa is probably most prevalent in post-industrialized, high-income countries such as in the 
United States, many European countries, Australia, New Zealand, and Japan, but its incidence 
in most low- and middle-income countries is uncertain. Whereas the prevalence of anorexia 
nervosa appears comparatively low among Latinos, African Americans, and Asians in the 
United States, clinicians should be aware that mental health service utilization among individ­
uals with an eating disorder is significantly lower in these ethnic groups and that the low rates 
may reflect an ascertainment bias. The presentation of weight concerns among individuals

may reflect an ascertainment bias. The presentation of weight concerns among individuals 
with eating and feeding disorders varies substantially across cultural contexts. The absence of 
an expressed intense fear of weight gain, sometimes referred to as "fat phobia," appears to be 
relatively more common in populations in Asia, where the rationale for dietary restriction is 
commonly related to a more culturally sanctioned complaint such as gastrointestinal discom­
fort. Within the United States, presentations without a stated intense fear of weight gain may 
be comparatively more common among Latino groups.
Diagnostic IVIaricers
The following laboratory abnormalities may be observed in anorexia nervosa; their pres­
ence may serve to increase diagnostic confidence.

Hematology. Leukopenia is common, with the loss of all cell types but usually with ap­
parent lympho<^ytosis. Mild anemia can occur, as well as thrombocytopenia and, rarely, 
bleeding problems.
Serum chemistry. Dehydration may be reflected by an elevated blood urea nitrogen 
level. Hypercholesterolemia is common. Hepatic enzyme levels may be elevated. Hypo­
magnesemia, hypozincemia, hypophosphatemia, and hyperamylasemia are occasionally 
observed. Self-induced vomiting may lead to metabolic alkalosis (elevated serum bicarbon­
ate), hypochloremia, and hypokalemia; laxative abuse may cause a mild metabolic acidosis.
Endocrine. Serum thyroxine (T 4) levels are usually in the low-normal range; triiodothy­
ronine (T 3) levels are decreased, while reverse T 3 levels are elevated. Females have low se­
rum estrogen levels, whereas males have low levels of serum testosterone.
Electrocardiography. Sinus bradycardia is common, and, rarely, arrhythmias are noted.

Electrocardiography. Sinus bradycardia is common, and, rarely, arrhythmias are noted. 
Significant prolongation of the QTc interval is observed in some individuals.
Bone mass. Low bone mineral density, with specific areas of osteopenia or osteoporo­
sis, is often seen. The risk of fracture is significantly elevated.
Electroencephalography. Diffuse abnormalities, reflecting a metabolic encephalopa­
thy, may result from significant fluid and electrolyte disturbances.
Resting energy expenditure. There is often a significant reduction in resting energy ex­
penditure.
Physical signs and symptoms. Many of the physical signs and symptoms of anorexia 
nervosa are attributable to starvation. Amenorrhea is commonly present and appears to 
be an indicator of physiological dysfunction. If present, amenorrhea is usually a conse­
quence of the weight loss, but in a minority of individuals it may actually precede the

quence of the weight loss, but in a minority of individuals it may actually precede the 
weight loss. In prepubertal females, menarche maybe delayed. In addition to amenorrhea, 
there may be complaints of constipation, abdominal pain, cold intolerance, lethargy, and 
excess energy.
The most remarkable finding on physical examination is emaciation. Commonly, there 
is also significant hypotension, hypothermia, and bradycardia. Some individuals develop 
lanugo, a fine downy body hair. Some develop peripheral edema, especially during 
weight restoration or upon cessation of laxative and diuretic abuse. Rarely, petechiae or 
ecchymoses, usually on the extremities, may indicate a bleeding diathesis. Some individ­
uals evidence a yellowing of the skin associated with hypercarotenemia. As may be seen in 
individuals with bulimia nervosa, individuals with anorexia nervosa who self-induce

individuals with bulimia nervosa, individuals with anorexia nervosa who self-induce 
vomiting may have hypertrophy of the salivary glands, particularly the parotid glands, as 
well as dental enamel erosion. Some individuals may have scars or calluses on the dorsal 
surface of the hand from repeated contact with the teeth while inducing vomiting.
Suicide risk is elevated in anorexia nervosa, with rates reported as 12 per 100,000 per year. 
Comprehensive evaluation of individuals with anorexia nervosa should include assess­
ment of suicide-related ideation and behaviors as well as other risk factors for suicide, in­
cluding a history of suicide attempt(s).
Functional Consequences of Anorexia Nervosa
Individuals with anorexia nervosa may exhibit a range of functional limitations associated 
with the disorder. While some individuals remain active in social and professional func­

tioning, others demonstrate significant social isolation and/or failure to fulfill academic or 
career potential.

Other possible causes of either significantly low body weight or significant weight loss 
should be considered in the differential diagnosis of anorexia nervosa, especially when the 
presenting features are atypical (e.g., onset after age 40 years).
Medical conditions (e.g., gastrointestinal disease, hypeiihyroidism, occult malignan­
cies, and acquired immunodeficiency syndrome [AIDS]). Serious weight loss may oc­
cur in medical conditions, but individuals with these disorders usually do not also mani­
fest a disturbance in the way their body weight or shape is experienced or an intense fear 
of weight gain or persist in behaviors that interfere with appropriate weight gain. Acute 
weight loss associated with a medical condition can occasionally be followed by the onset 
or recurrence of anorexia nervosa, which can initially be masked by the comorbid medical 
condition. Rarely, anorexia nervosa develops after bariatric surgery for obesity.

Major depressive disorder. In major depressive disorder, severe weight loss may occur, 
but most individuals with major depressive disorder do not have either a desire for exces­
sive weight loss or an intense fear of gaining weight.
Schizophrenia. Individuals with schizophrenia may exhibit odd eating behavior and oc­
casionally experience significant weight loss, but they rarely show the fear of gaining 
weight and the body image disturbance required for a diagnosis of anorexia nervosa.
Substance use disorders. Individuals with substance use disorders may experience low 
weight due to poor nutritional intake but generally do not fear gaining weight and do not 
manifest body image disturbance. Individuals who abuse substances that reduce appetite

manifest body image disturbance. Individuals who abuse substances that reduce appetite 
(e.g., cocaine, stimulants) and who also endorse fear of weight gain should be carefully 
evaluated for the possibility of comorbid anorexia nervosa, given that the substance use 
may represent a persistent behavior that interferes with weight gain (Criterion B).
Social anxiety disorder (social phobia), obsessive-compulsive disorder, and body dys­
morphic disorder. Some of the features of anorexia nervosa overlap with the criteria for 
social phobia, OCD, and body dysmorphic disorder. Specifically, individuals may feel hu­
miliated or embarrassed to be seen eating in public, as in social phobia; may exhibit obses­
sions and compulsions related to food, as in OCD; or may be preoccupied with an imagined 
defect in bodily appearance, as in body dysmorphic disorder. If the individual with anorexia

defect in bodily appearance, as in body dysmorphic disorder. If the individual with anorexia 
nervosa has social fears that are limited to eating behavior alone, the diagnosis of social pho­
bia should not be made, but social fears unrelated to eating behavior (e.g., excessive fear of 
speaking in public) may warrant an additional diagnosis of social phobia. Similarly, an ad­
ditional diagnosis of OCD should be considered only if the individual exhibits obsessions 
and compulsions unrelated to food (e.g., an excessive fear of contamination), and an addi­
tional diagnosis of body dysmorphic disorder should be considered only if the distortion is 
unrelated to body shape and size (e.g., preoccupation that one's nose is too big).
Bulimia nervosa. Individuals with bulimia nervosa exhibit recurrent episodes of binge

Bulimia nervosa. Individuals with bulimia nervosa exhibit recurrent episodes of binge 
eating, engage in inappropriate behavior to avoid weight gain (e.g., self-induced vomit­
ing), and are overly concerned with body shape and weight. However, unlike individuals 
with anorexia nervosa, binge-eating/purging type, individuals with bulimia nervosa main­
tain body weight at or above a minimally normal level.
Avoidant/restrictive food intake disorder. Individuals with this disorder may exhibit 
significant weight loss or significant nutritional deficiency, but they do not have a fear of 
gaining weight or of becoming fat, nor do they have a disturbance in the way they expe­
rience their body shape and weight.
Bipolar, depressive, and anxiety disorders commonly co-occur with anorexia nervosa. 
Many individuals with anorexia nervosa report the presence of either an anxiety disorder

or symptoms prior to onset of their eating disorder. OCD is described in some individuals 
with anorexia nervosa, especially those with the restricting type. Alcohol use disorder and 
other substance use disorders may also be comorbid with anorexia nervosa, especially 
among those with the binge-eating/purging type.
Bulimia Nervosa
Diagnostic Criteria 307.51 (F50.2)
A. Recurrent episodes of binge eating. An episode of binge eating is characterized by  
both of the following:
1. Eating, in a discrete period of time (e.g., within any 2-hour period), an amount of  
food that is definitely larger than what most individuals would eat in a similar period  
of time under similar circumstances.
2. A sense of lack of control over eating during the episode (e.g., a feeling that one  
cannot stop eating or control what or how much one is eating).
B. Recurrent inappropriate compensatory behaviors in order to prevent weight gain, such

B. Recurrent inappropriate compensatory behaviors in order to prevent weight gain, such  
as self-induced vomiting; misuse of laxatives, diuretics, or other medications; fasting;  
or excessive exercise.
C. The binge eating and inappropriate compensatory behaviors both occur, on average,  
at least once a week for 3 months.
D. Self-evaluation is unduly influenced by body shape and weight.
E. The disturbance does not occur exclusively during episodes of anorexia nervosa.
In partial remission: After full criteria for bulimia nervosa were previously met, some,  
but not all, of the criteria have been met for a sustained period of time.
In full remission: After full criteria for bulimia nervosa were previously met, none of  
The minimum level of severity is based on the frequency of inappropriate compensatory

The minimum level of severity is based on the frequency of inappropriate compensatory  
behaviors (see below). The level of severity may be increased to reflect other symptoms  
lUlild: An average of 1-3 episodes of inappropriate compensatory behaviors per week.  
■Moderate: An average of 4-7 episodes of inappropriate compensatory behaviors per  
week.
Severe: An average of 8-13 episodes of inappropriate compensatory behaviors per  
week.
Extreme: An average of 14 or more episodes of inappropriate compensatory behav­
iors per week.
There are three essential features of bulimia nervosa: recurrent episodes of binge eating 
(Criterion A), recurrent inappropriate compensatory behaviors to prevent weight gain 
(Criterion B), and self-evaluation that is unduly influenced by body shape and weight

(Criterion B), and self-evaluation that is unduly influenced by body shape and weight 
(Criterion D). To qualify for the diagnosis, the binge eating and inappropriate compensa­
tory behaviors must occur, on average, at least once per week for 3 months (Criterion C).
An "episode of binge eating" is defined as eating, in a discrete period of time, an 
amount of food that is definitely larger than most individuals would eat in a similar period 
of time under similar circumstances (Criterion Al). The context in which the eating occurs

may affect the clinician's estimation of whether the intake is excessive. For example, a 
quantity of food that might be regarded as excessive for a typical meal might be consid­
ered normal during a celebration or holiday meal. A "discrete period of time" refers to a 
limited period, usually less than 2 hours. A single episode of binge eating need not be re­
stricted to one setting. For example, an individual may begin a binge in a restaurant and 
then continue to eat on returning home. Continual snacking on small amounts of food 
throughout the day would not be considered an eating binge.
An occurrence of excessive food consumption must be accompanied by a sense of lack 
of control (Criterion A2) to be considered an episode of binge eating. An indicator of loss 
of control is the inability to refrain from eating or to stop eating once started. Some indi­
viduals describe a dissociative quality during, or following, the binge-eating episodes. The

viduals describe a dissociative quality during, or following, the binge-eating episodes. The 
impairment in control associated with binge eating may not be absolute; for example, an 
individual may continue binge eating while the telephone is ringing but will cease if a 
roommate or spouse unexpectedly enters the room. Some individuals report that their 
binge-eating episodes are no longer characterized by an acute feeling of loss of control but 
rather by a more generalized pattern of uncontrolled eating. If individuals report that they 
have abandoned efforts to control their eating, loss of control should be considered as 
present. Binge eating can also be planned in some instances.
The type of food consumed during binges varies both across individuals and for a 
given individual. Binge eating appears to be characterized more by an abnormality in the

given individual. Binge eating appears to be characterized more by an abnormality in the 
amount of food consumed than by a craving for a specific nutrient. However, during binges, 
individuals tend to eat foods they would otherwise avoid.
Individuals with bulimia nervosa are typically ashamed of their eating problems and 
attempt to conceal their symptoms. Binge eating usually occurs in secrecy or as inconspic­
uously as possible. The binge eating often continues until the individual is uncomfortably, 
or even painfully, full. The most common antecedent of binge eating is negative affect. 
Other triggers include interpersonal stressors; dietary restraint; negative feelings related 
to body weight, body shape, and food; and boredom. Binge eating may minimize or mit­
igate factors that precipitated the episode in the short-term, but negative self-evaluation

igate factors that precipitated the episode in the short-term, but negative self-evaluation 
and dysphoria often are the delayed consequences.
Another essential feature of bulimia nervosa is the recurrent use of inappropriate com­
pensatory behaviors to prevent weight gain, collectively referred to as purge behaviors  or 
purging  (Criterion B). Many individuals with bulimia nervosa employ several methods to 
compensate for binge eating. Vomiting is the most common inappropriate compensatory 
behavior. The immediate effects of vomiting include relief from physical discomfort and re­
duction of fear of gaining weight. In some cases, vomiting becomes a goal in itself, and the 
individual will binge eat in order to vomit or will vomit after eating a small amount of food. 
Individuals with bulimia nervosa may use a variety of methods to induce vomiting, includ­

ing the use of fingers or instruments to stimulate the gag reflex. Individuals generally 
become adept at inducing vomiting and are eventually able to vomit at will. Rarely, indi­
viduals consume syrup of ipecac to induce vomiting. Other purging behaviors include the 
misuse of laxatives and diuretics. A number of other compensatory methods may also be 
used in rare cases. Individuals with bulimia nervosa may misuse enemas following epi­
sodes of binge eating, but this is seldom the sole compensatory method employed. Individ­
uals with this disorder may take thyroid hormone in an attempt to avoid weight gain. 
Individuals with diabetes mellitus and bulimia nervosa may omit or reduce insulin doses in 
order to reduce the metabolism of food consumed during eating binges. Individuals with

order to reduce the metabolism of food consumed during eating binges. Individuals with 
bulimia nervosa may fast for a day or more or exercise excessively in an attempt to prevent 
weight gain. Exercise may be considered excessive when it significantly interferes with im­
portant activities, when it occurs at inappropriate times or in inappropriate settings, or 
when the individual continues to exercise despite injury or other medical complications.
Individuals with bulimia nervosa place an excessive emphasis on body shape or weight 
in their self-evaluation, and these factors are typically extremely important in determining

self-esteem (Criterion D). Individuals with this disorder may closely resemble those w ^ ith  
anorexia nervosa in their fear of gaining weight, in their desire to lose weight, and in the 
level of dissatisfaction with their bodies. However, a diagnosis of bulimia nervosa should 
not be given when the disturbance occurs only during episodes of anorexia nervosa (Cri­
terion E).
Individuals with bulimia nervosa typically are within the normal weight or overweight 
range (body mass index [BMI] >  18.5 and < 30 in adults). The disorder occurs but is un­
common among obese individuals. Between eating binges, individuals with bulimia ner­
vosa typically restrict their total caloric consumption and preferentially select low-calorie 
("diet") foods while avoiding foods that they perceive to be fattening or likely to trigger a 
binge.
Menstrual irregularity or amenorrhea often occurs among females with bulimia ner­

binge.
vosa; it is uncertain whether such disturbances are related to weight fluctuations, to nu­
tritional deficiencies, or to emotional distress. The fluid and electrolyte disturbances 
resulting from the purging behavior are sometimes sufficiently severe to constitute med­
ically serious problems. Rare but potentially fatal complications include esophageal tears, 
gastric rupture, and cardiac arrhythmias. Serious cardiac and skeletal myopathies have 
been reported among individuals following repeated use of syrup of ipecac to induce vom­
iting. Individuals who chronically abuse laxatives may become dependent on their use to 
stimulate bowel movements. Gastrointestinal symptoms are commonly associated with 
bulimia nervosa, and rectal prolapse has also been reported among individuals with this 
disorder.

disorder.
Twelve-month prevalence of bulimia nervosa among young females is 1%-1.5%. Point 
prevalence is highest among young adults since the disorder peaks in older adolescence 
and young adulthood. Less is known about the point prevalence of bulimia nervosa in 
males, but bulimia nervosa is far less common in males than it is in females, with an ap­
proximately 10 :1 female-to-male ratio.
Bulimia nervosa commonly begins in adolescence or young adulthood. Onset before pu­
berty or after age 40 is uncommon. The binge eating frequently begins during or after an 
episode of dieting to lose weight. Experiencing multiple stressful life events also can pre­
cipitate onset of bulimia nervosa.
Disturbed eating behavior persists for at least several years in a high percentage of

Disturbed eating behavior persists for at least several years in a high percentage of 
clinic samples. The course may be chronic or intermittent, with periods of remission 
alternating with recurrences of binge eating. However, over longer-term follow-up, the 
symptoms of many individuals appear to diminish with or without treatment, although 
treatment clearly impacts outcome. Periods of remission longer than 1 year are associated 
with better long-term outcome.
Significantly elevated risk for mortality (all-cause and suicide) has been reported for 
individuals with bulimia nervosa. The CMR (crude mortality rate) for bulimia nervosa is 
nearly 2% per decade.
Diagnostic cross-over from initial bulimia nervosa to anorexia nervosa occurs in a mi­
nority of cases (10%-15%). Individuals who do experience cross-over to anorexia nervosa 
commonly will revert back to bulimia nervosa or have multiple occurrences of cross-overs

commonly will revert back to bulimia nervosa or have multiple occurrences of cross-overs 
between these disorders. A subset of individuals with bulimia nervosa continue to binge 
eat but no longer engage in inappropriate compensatory behaviors, and therefore their

symptoms meet criteria for binge-eating disorder or other specified eating disorder. Diag­
nosis should be based on the current (i.e., past 3 months) clinical presentation.
Temperamental. Weight concerns, low self-esteem, depressive symptoms, social anxi­
ety disorder, and overanxious disorder of childhood are associated with increased risk for 
the development of bulimia nervosa.
Environmental. Internalization of a thin body ideal has been found to increase risk for 
developing weight concerns, which in turn increase risk for the development of bulimia 
nervosa. Individuals who experienced childhood sexual or physical abuse are at increased 
risk for developing bulimia nervosa.
Genetic and physiological. Childhood obesity and early pubertal maturation increase 
risk for bulimia nervosa. Familial transmission of bulimia nervosa may be present, as well 
as genetic vulnerabilities for the disorder.

Course modifiers. Severity of psychiatric comorbidity predicts worse long-term outcome 
of bulimia nervosa.
Bulimia nervosa has been reported to occur with roughly similar frequencies in most in­
dustrialized countries, including the United States, Canada, many European countries, 
Australia, Japan, New Zealand, and South Africa. In clinical studies of bulimia nervosa in 
the United States, individuals presenting with this disorder are primarily white. However, 
the disorder also occurs in other ethnic groups and with prevalence comparable to esti­
mated prevalences observed in white samples.
Bulimia nervosa is far more common in females than in males. Males are especially under­
represented in treatment-seeking samples, for reasons that have not yet been systemati­
cally examined.

Diagnostic IViarkers
No specific diagnostic test for bulimia nervosa currently exists. However, several labora­
tory abnormalities may occur as a consequence of purging and may increase diagnostic 
certainty. These include fluid and electrolyte abnormalities, such as hypokalemia (which 
can provoke cardiac arrhythmias), hypochloremia, and hyponatremia. The loss of gastric 
acid through vomiting may produce a metabolic alkalosis (elevated serum bicarbonate), 
and the frequent induction of diarrhea or dehydration through laxative and diuretic abuse 
can cause metabolic acidosis. Some individuals with bulimia nervosa exhibit mildly ele­
vated levels of serum amylase, probably reflecting an increase in the salivary isoenzyme.

Physical examination usually yields no physical findings. However, inspection of the 
mouth may reveal significant and permanent loss of dental enamel, especially from lin­
gual surfaces of the front teeth due to recurrent vomiting. These teeth may become 
chipped and appear ragged and "moth-eaten." There may also be an increased frequency 
of dental caries. In some individuals, the salivary glands, particularly the parotid glands, 
may become notably enlarged. Individuals who induce vomiting by manually stimulating 
the gag reflex may develop calluses or scars on the dorsal surface of the hand from re­
peated contact with the teeth. Serious cardiac and skeletal myopathies have been reported 
among individuals following repeated use of syrup of ipecac to induce vomiting.

Suicide risk is elevated in bulimia nervosa. Comprehensive evaluation of individuals with 
this disorder should include assessment of suicide-related ideation and behaviors as well 
as other risk factors for suicide, including a history of suicide attempts.
Functional Consequences of Buiimia Nervosa
Individuals with bulimia nervosa may exhibit a range of functional limitations associated 
with the disorder. A minority of individuals report severe role impairment, with the so­
cial-life domain most likely to be adversely affected by bulimia nervosa.
Anorexia nervosa, binge-eating/purging type. Individuals whose binge-eating behav­
ior occurs only during episodes of anorexia nervosa are given the diagnosis anorexia ner­
vosa, binge-eating/purging type, and should not be given the additional diagnosis of 
bulimia nervosa. For individuals with an initial diagnosis of anorexia nervosa who binge

bulimia nervosa. For individuals with an initial diagnosis of anorexia nervosa who binge 
and purge but whose presentation no longer meets the full criteria for anorexia nervosa, 
binge-eating/purging type (e.g., when weight is normal), a diagnosis of bulimia ner­
vosa should be given only when all criteria for bulimia nervosa have been met for at least 
3 months.
Binge-eating disorder. Some individuals binge eat but do not engage in regular inap­
propriate compensatory behaviors. In these cases, the diagnosis of binge-eating disorder 
Kleine-Levin syndrome. In certain neurological or other medical conditions, such as 
Kleine-Levin syndrome, there is disturbed eating behavior, but the characteristic psycho­
logical features of bulimia nervosa, such as overconcem with body shape and weight, are 
not present.

Major depressive disorder, with atypical features. Overeating is common in major de­
pressive disorder, with atypical features, but individuals with this disorder do not engage 
in inappropriate compensatory behaviors and do not exhibit the excessive concern with 
body shape and weight characteristic of bulimia nervosa. If criteria for both disorders are 
met, both diagnoses should be given.
Borderline personality disorder. Binge-eating behavior is included in the impulsive be­
havior criterion that is part of the definition of borderline personality disorder. If the cri­
teria for both borderline personality disorder and bulimia nervosa are met, both diagnoses 
should be given.
Comorbidity with mental disorders is common in individuals with bulimia nervosa, with

Comorbidity with mental disorders is common in individuals with bulimia nervosa, with 
most experiencing at least one other mental disorder and many experiencing multiple co­
morbidities. Comorbidity is not limited to any particular subset but rather occurs across a 
wide range of mental disorders. There is an increased frequency of depressive symptoms 
(e.g., low self-esteem) and bipolar and depressive disorders (particularly depressive dis­
orders) in individuals with bulimia nervosa. In many individuals, the mood disturbance 
begins at the same time as or following the development of bulimia nervosa, and individ­
uals often ascribe their mood disturbances to the bulimia nervosa. However, in some in­
dividuals, the mood disturbance clearly precedes the development of bulimia nervosa. 
There may also be an increased frequency of anxiety symptoms (e.g., fear of social situa­

tions) or anxiety disorders. These mood and anxiety disturbances frequently remit follow­

ing effective treatment of the bulimia nervosa. The lifetime prevalence of substance use, 
particularly alcohol or stimulant use, is at least 30% among individuals with bulimia ner­
vosa. Stimulant use often begins in an attempt to control appetite and weight. A substan­
tial percentage of individuals with bulimia nervosa also have personality features that 
meet criteria for one or more personality disorders, most frequently borderline personality 
disorder.
Binge-Eating Disorder
Diagnostic Criteria 307.51 (F50.8)
A. Recurrent episodes of binge eating. An episode of binge eating is characterized  
by both of the following:
food that is definitely larger than what most people would eat in a similar period of  
time under similar circumstances.

B. The binge-eating episodes are associated with three (or more) of the following:
1. Eating much more rapidly than normal.
2. Eating until feeling uncomfortably full.
3. Eating large amounts of food when not feeling physically hungry.
4. Eating alone because of feeling embarrassed by how much one is eating.
5. Feeling disgusted with oneself, depressed, or very guilty afterward.
C. Marked distress regarding binge eating is present.
D. The binge eating occurs, on average, at least once a week for 3 months.
E. The binge eating is not associated with the recurrent use of inappropriate compensa­
tory behavior as in bulimia nen/osa and does not occur exclusively during the course  
of bulimia nervosa or anorexia nervosa.

In partial remission: After full criteria for binge-eating disorder were previously met,  
binge eating occurs at an average frequency of less than one episode per week for a  
sustained period of time.
In full remission: After full criteria for binge-eating disorder were previously met, none  
of the criteria have been met for a sustained period of time.
The minimum level of severity is based on the frequency of episodes of binge eating (see  
below). The level of severity may be increased to reflect other symptoms and the degree  
of functional disability.
Mild: 1-3 binge-eating episodes per week.  
lUloderate: 4-7 binge-eating episodes per week.
Severe: 8-13 binge-eating episodes per week.
Extreme: 14 or more binge-eating episodes per week.

The essential feature of binge-eating disorder is recurrent episodes binge eating that must 
occur, on average, at least once per week for 3 months (Criterion D). An "episode of binge 
eating" is defined as eating, in a discrete period of time, an amount of food that is defi­

nitely larger than most people would eat in a similar period of time under similar circum­
stances (Criterion Al). The context in which the eating occurs may affect the clinician's 
estimation of whether the intake is excessive. For example, a quantity of food that might be 
regarded as excessive for a typical meal might be considered normal during a celebration 
or holiday meal. A ''discrete period of time" refers to a limited period, usually less than 
2 hours. A single episode of binge eating need not be restricted to one setting. For example, 
an individual may begin a binge in a restaurant and then continue to eat on returning 
home. Continual snacking on small amounts of food throughout the day would not be con­
sidered an eating binge.
of control (Criterion A2) to be considered an episode of binge eating. An indicator of loss

have abandoned efforts to control their eating, loss of control may still be considered as 

The type of food consumed during binges varies both across individuals and for a given 
individual. Binge eating appears to be characterized more by an abnormality in the amount 
of food consumed than by a craving for a specific nutrient.
Binge eating must be characterized by marked distress (Criterion C) and at least three 
of the following features: eating much more rapidly than normal; eating until feeling un­
comfortably full; eating large amoimts of food when not feeling physically hungry; eating 
alone because of feeling embarrassed by how much one is eating; and feeling disgusted 
with oneself, depressed, or very guilty afterward (Criterion B).
Individuals with binge-eating disorder are typically ashamed of their eating problems 
and attempt to conceal their symptoms. Binge eating usually occurs in secrecy or as incon­

spicuously as possible. The most common antecedent of binge eating is negative affect. 
Other triggers include inteφersonal stressors; dietary restraint; negative feelings related 
to body weight, body shape, and food; and boredom. Binge eating may miriimize or mit­
Binge-eating disorder occurs in normal-weight/overweight and obese individuals. It is re­
liably associated with overweight and obesity in treatment-seeking individuals. Never­
theless, binge-eating disorder is distinct from obesity. Most obese individuals do not 
engage in recurrent binge eating. In addition, compared with weight-matched obese indi­

viduals without binge-eating disorder, those with the disorder consume more calories in 
laboratory studies of eating behavior and have greater functional impairment, lower qual­
ity of life, more subjective distress, and greater psychiatric comorbidity.
Twelve-month prevalence of binge-eating disorder among U.S. adult (age 18 or older) fe­
males and males is 1.6% and 0.8%, respectively. The gender ratio is far less skewed in binge- 
eating disorder than in bulimia nervosa. Binge-eating disorder is as prevalent among fe­
males from racial or ethnic minority groups as has been reported for white females. The 
disorder is more prevalent among individuals seeking weight-loss treatment than in the 

Little is known about the development of binge-eating disorder. Both binge eating and 
loss-of-control eating without objectively excessive consumption occur in children and are 
associated with increased body fat, weight gain, and increases in psychological symptoms. 
Binge eating is common in adolescent and college-age samples. Loss-of-control eating or 
episodic binge eating may represent a prodromal phase of eating disorders for some indi­
viduals.
Dieting follows the development of binge eating in many individuals with binge- 
eating disorder. (This is in contrast to bulimia nervosa, in which dysfunctional dieting 
usually precedes the onset of binge eating.) Binge-eating disorder typically begins in ad­
olescence or young adulthood but can begin in later adulthood. Individuals with binge- 
eating disorder who seek treatment usually are older than individuals with either bulimia 
nervosa or anorexia nervosa who seek treatment.

Remission rates in both natural course and treatment outcome studies are higher for 
binge-eating disorder than for bulimia nervosa or anorexia nervosa. Binge-eating disorder 
appears to be relatively persistent, and the course is comparable to that of bulimia nervosa 
in terms of severity and duration. Crossover from binge-eating disorder to other eating 
disorders is uncommon.
Genetic and physiological. Binge-eating disorder appears to run in families, which may 
reflect additive genetic influences.
Binge-eating disorder occurs with roughly similar frequencies in most industrialized 
countries, including the United States, Canada, many European countries, Australia, and 
New Zealand. In the United States, the prevalence of binge-eating disorder appears com­

parable among non-Latino whites. Latinos, Asians, and African Americans.
Functionai Consequences of Binge-Eating Disorder
Binge-eating disorder is associated with a range of functional consequences, including so­
cial role adjustment problems, impaired health-related quality of life and life satisfaction, 
increased medical morbidity and mortality, and associated increased health care utiliza­
tion compared with body mass index (BMI)-matched control subjects. It may also be as­
sociated with an increased risk for weight gain and the development of obesity.
Bulimia neivosa. Binge-eating disorder has recurrent binge eating in common with bu­
limia nervosa but differs from the latter disorder in some fundamental respects. In terms of

limia nervosa but differs from the latter disorder in some fundamental respects. In terms of 
clinical presentation, the recurrent inappropriate compensatory behavior (e.g., purging, 
driven exercise) seen in bulimia nervosa is absent in binge-eating disorder. Unlike in­
dividuals with bulimia nervosa, individuals with binge-eating disorder typically do not 
show marked or sustained dietary restriction designed to influence body weight and 
shape between binge-eating episodes. They may, however, report frequent attempts at 
dieting. Binge-eating disorder also differs from bulimia nervosa in terms of response to treat­
ment. Rates of improvement are consistently higher among individuals with binge-eating 
disorder than among those with bulimia nervosa.
Obesity. Binge-eating disorder is associated with overweight and obesity but has

Obesity. Binge-eating disorder is associated with overweight and obesity but has 
several key features that are distinct from obesity. First, levels of overvaluation of body

weight and shape are higher in obese individuals with the disorder than in those without 
the disorder. Second, rates of psychiatric comorbidity are significantly higher among 
obese individuals with the disorder compared with those without the disorder. Third, the 
long-term successful outcome of evidence-based psychological treatments for binge- 
eating disorder can be contrasted with the absence of effective long-term treatments for 
obesity.
Bipolar and depressive disorders. Increases in appetite and weight gain are included 
in the criteria for major depressive episode and in the atypical features specifiers for de­
pressive and bipolar disorders. Increased eating in the context of a major depressive epi­
sode may or may not be associated with loss of control. If the full criteria for both disorders 
are met, both diagnoses can be given. Binge eating and other symptoms of disordered eat­

ing are seen in association with bipolar disorder. If the full criteria for both disorders are 
Borderline personality disorder. Binge eating is included in the impulsive behavior cri­
terion that is part of the definition of borderline personality disorder. If the full criteria for 
both disorders are met, both diagnoses should be given.
Binge-eating disorder is associated with significant psychiatric comorbidity that is com­
parable to that of bulimia nervosa and anorexia nervosa. The most common comorbid dis­
orders are bipolar disorders, depressive disorders, anxiety disorders, and, to a lesser 
degree, substance use disorders. The psychiatric comorbidity is linked to the severity of 
binge eating and not to the degree of obesity.

Other Specified Feeding or Eating Disorder
307.59 (F50.8)
This category applies to presentations in which symptoms characteristic of a feeding and  
eating disorder that cause clinically significant distress or impairment in social, occupation­
al, or other important areas of functioning predominate but do not meet the full criteria for  
any of the disorders in the feeding and eating disorders diagnostic class. The other spec­
ified feeding or eating disorder category is used in situations in which the clinician chooses  
to communicate the specific reason that the presentation does not meet the criteria for any  
specific feeding and eating disorder. This is done by recording “ other specified feeding or  
eating disorder”  followed by the specific reason (e.g., “ bulimia nervosa of low frequency” ).

1. Atypical anorexia nervosa: All of the criteria for anorexia nervosa are met, except  
that despite significant weight loss, the individual’s weight is within or above the normal  
range.
2. Bulimia nervosa (of low frequency and/or limited duration): All of the criteria for  
bulimia nervosa are met, except that the binge eating and inappropriate compensatory  
behaviors occur, on average, less than once a week and/or for less than 3 months.
3. Binge-eating disorder (of low frequency and/or limited duration): All of the criteria  
for binge-eating disorder are met, except that the binge eating occurs, on average, less  
than once a week and/or for less than 3 months.

4. Purging disorder: Recurrent purging behavior to influence weight or shape (e.g., self­
induced vomiting: misuse of laxatives, diuretics, or other medications) in the absence  
of binge eating.

5. Night eating syndrome: Recurrent episodes of night eating, as manifested by eating  
after awakening from sleep or by excessive food consumption after the evening meal.  
There Is awareness and recall of the eating. The night eating is not better explained by  
external influences such as changes in the individual’s sleep-wake cycle or by local so­
cial norms. The night eating causes significant distress and/or impairment in function­
ing. The disordered pattern of eating is not better explained by binge-eating disorder  
or another mental disorder, including substance use, and is not attributable to another  
medical disorder or to an effect of medication.
Unspecified Feeding or Eating Disorder
307.50 (F50.9)

any of the disorders in the feeding and eating disorders diagnostic class. The unspecified  
feeding and eating disorder category is used in situations in  which the clinician chooses  
not to specify the reason that the criteria are not met for a specific feeding and eating dis­
order, and includes presentations in which there is insufficient information to make a more  
specific diagnosis (e.g., in emergency room settings).

Elimination 
Disorders
Elimin3t ion diSOrdGrSall  involve the inappropriate elimination of urine or feces 
and are usually first diagnosed in childhood or adolescence. This group of disorders in­
cludes enuresis,  the repeated voiding of urine into inappropriate places, and encopresis,  the 
repeated passage of feces into inappropriate places. Subtypes are provided to differentiate 
nocturnal from diurnal (i.e., during waking hours) voiding for enuresis and the presence or 
absence of constipation and overflow incontinence for encopresis. Although there are min­
imum age requirements for diagnosis of both disorders, these are based on developmental 
age and not solely on chronological age. Both disorders may be volimtary or involuntary. 
Although these disorders typically occur separately, co-occurrence may also be observed.
Enuresis
Diagnostic Criteria 307.6 (F98.0)
A. Repeated voiding of urine into bed or clothes, whether involuntary or intentional.

Enuresis
B . The behavior is clinically significant as manifested by either a frequency of at least twice a  
week for at least 3 consecutive months or the presence of clinically significant distress or  
impairment in social, academic (occupational), or other important areas of functioning.
C. Chronological age is at least 5 years (or equivalent developmental level).
D. The behavior is not attributable to the physiological effects of a substance (e.g., a di­
uretic, an antipsychotic medication) or another medical condition (e.g., diabetes, spina  
bifida, a seizure disorder).
Nocturnal only: Passage of urine only during nighttime sleep.
Diurnal only: Passage of urine during waking hours.
Nocturnal and diurnal: A combination of the two subtypes above.
Subtypes
The noctumal-only subtype of enuresis, sometimes referred to as monosymptomatic enure­

Subtypes
sis, is the most common subtype and involves incontinence only during nighttime sleep, 
typically during the first one-third of the night. The diurnal-only subtype occurs in the 
absence of nocturnal enuresis and may be referred to simply as urinary incontinence.  Indi­
viduals with this subtype can be divided into two groups. Individuals with ''urge incon­
tinence" have sudden urge symptoms and detrusor instability, whereas individuals with 
"voiding postponement" consciously defer micturition urges until incontinence results. 
The noctumal-and-diurnal subtype is also known as nonmonosymptomatic enuresis.
The essential feature of enuresis is repeated voiding of urine during the day or at night into 
bed or clothes (Criterion A). Most often the voiding is involuntary, but occasionally it may

be intentional. To qualify for a diagnosis of enuresis, the voiding of urine must occur at 
least twice a week for at least 3 consecutive months or must cause clinically significant dis­
tress or impairment in social, academic (occupational), or other important areas of func­
tioning (Criterion B). The individual must have reached an age at which continence is 
expected (i.e., a chronological age of at least 5 years or, for children with developmental 
delays, a mental age of at least 5 years) (Criterion C). The urinary incontinence is not at­
tributable to the physiological effects of a substance (e.g., a diuretic, an antipsychotic med­
ication) or another medical condition (e.g., diabetes, spina bifida, a seizure disorder) 
(Criterion D).
Ehiring nocturnal enuresis, occasionally the voiding takes place during rapid eye movement 
(REM) sleep, and the child may recall a dream that involved the act of urinating. During day­

time (diurnal) enuresis, the child defers voiding until incontinence occurs, sometimes because 
of a reluctance to use the toilet as a result of social anxiety or a preoccupation with school or 
play activity. The enuretic event most commonly occurs in the early afternoon on school days 
and may be associated with symptoms of disruptive behavior. The enuresis commonly per­
sists after appropriate treatment of an associated infection.
The prevalence of enuresis is 5%-10% among 5-year-olds, 3%-5% among 10-year-olds, 
and around 1% among individuals 15 years or older.
Two types of course of enuresis have been described: a "primary" type, in which the indi­
vidual has never established urinary continence, and a "secondary" type, in which the dis­

turbance develops after a period of established urinary continence. There are no differences 
in prevalence of comorbid mental disorders between the two types. By definition, primary 
enuresis begins at age 5 years. The most common time for the onset of secondary enuresis 
is between ages 5 and 8 years, but it may occur at any time. After age 5 years, the rate of spon­
taneous remission is 5%-10% per year. Most children with the disorder become continent 
by adolescence, but in approximately 1% of cases the disorder continues into adulthood. 
Diurnal enuresis is uncommon after age 9 years. While occasional diurnal incontinence is 
not uncommon in middle childhood, it is substantially more common in those who also 
have persistent nocturnal enuresis. When enuresis persists into late childhood or adoles­

cence, the frequency of incontinence may increase, whereas continence in early childhood 
is usually associated with a declining frequency of wet nights.
Environmental. A number of predisposing factors for enuresis have been suggested, in­
cluding delayed or lax toilet training and psychosocial stress.
Genetic and physiological. Enuresis has been associated with delays in the develop­
ment of normal circadian rhythms of urine production, with resulting nocturnal polyuria 
or abnormalities of central vasopressin receptor sensitivity, and reduced functional blad­
der capacities with bladder hyperreactivity (unstable bladder syndrome). Nocturnal en­
uresis is a genetically heterogeneous disorder. Heritability has been shown in family, twin,

uresis is a genetically heterogeneous disorder. Heritability has been shown in family, twin, 
and segregation analyses. Risk for childhood nocturnal enuresis is approximately 3.6 times 
higher in offspring of enuretic mothers and 10 .1 times higher in the presence of paternal 
urinary incontinence. The risk magnitudes for nocturnal enuresis and diurnal incontinence 
are similar.

Enuresis has beeh reported in a variety of European, African, and Asian countries as well 
as in the United States. At a national level, prevalence rates are remarkably similar, and 
there is great similarity in the developmental trajectories found in different countries. 
There are very high rates of enuresis in orphanages and other residential institutions, 
likely related to the mode and environment in which toilet training occurs.
Nocturnal enuresis is more common in males. Diurnal incontinence is more common in fe­
males. The relative risk of having a child who develops enuresis is greater for previously 
enuretic fathers than for previously enuretic mothers.
Functional Consequences of Enuresis
The amount of impairment associated with enuresis is a function of the limitation on the 
child's social activities (e.g., ineligibility for sleep-away camp) or its effect on the child's

child's social activities (e.g., ineligibility for sleep-away camp) or its effect on the child's 
self-esteem, the degree of social ostracism by peers, and the anger, punishment, and rejec­
tion on the part of caregivers.
Neurogenic bladder or another medical condition. The diagnosis of enuresis is not made 
in the presence of a neurogenic bladder or another medical condition that causes polyuria or 
urgency (e.g., untreated diabetes mellitus or diabetes insipidus) or during an acute urinary 
tract infection. However, a diagnosis is compatible with such conditions if urinary inconti­
nence was regularly present prior to the development of another medical condition or if it per­
sists after the institution of appropriate treatment of the medical condition.
Medication side effects. Enuresis may occur during treatment with antipsychotic med­

ications, diuretics, or other medications that may induce incontinence. In this case, the di­
agnosis should not be made in isolation but may be noted as a medication side effect. 
However, a diagnosis of enuresis may be made if urinary incontinence was regularly pres­
ent prior to treatment with the medication.
Although most children with enuresis do not have a comorbid mental disorder, the prevalence 
of comorbid behavioral symptoms is higher in children with enuresis than in children without 
enuresis. Developmental delays, including speech, language, learning, and motor skills 
delays, are also present in a portion of children with enuresis. Encopresis, sleepwalking, and 
sleep terror disorder may be present. Urinary tract infections are more common in children

sleep terror disorder may be present. Urinary tract infections are more common in children 
with enuresis, especially the diurnal subtype, than in those who are continent.
Encopresis
Diagnostic Criteria 307.7 (F98.1)
A. Repeated passage of feces into inappropriate places (e.g., clothing, floor), whether in­
voluntary or intentional.
B. At least one such event occurs each month for at least 3 months.
C. Chronological age is at least 4 years (or equivalent developmental level).
D. The behavior is not attributable to the physiological effects of a substance (e.g., laxa­
tives) or another medical condition except through a mechanism involving constipation.

With constipation and overflow incontinence: There is evidence of constipation on  
physical examination or by history.
Without constipation and overflow incontinence: There is no evidence of constipa­
tion on physical examination or by history.
Subtypes
Feces in the with constipation and overflow incontinence subtype are characteristically 
(but not invariably) poorly formed, and leakage can be infrequent to continuous, occur­
ring mostly during the day and rarely during sleep. Only part of the feces is passed during 
toileting, and the incontinence resolves after treatment of the constipation.
In the without constipation and overflow incontinence subtype, feces are likely to be of 
normal form and consistency, and soiling is intermittent. Feces may be deposited in a 
prominent location. This is usually associated with the presence of oppositional defiant 
disorder or conduct disorder or may be the consequence of anal masturbation. Soiling

disorder or conduct disorder or may be the consequence of anal masturbation. Soiling 
without constipation appears to be less common than soiling with constipation.
The essential feature of encopresis is repeated passage of feces into inappropriate places (e.g., 
clothing or floor) (Criterion A). Most often the passage is involimtary but occasionally may be 
intentional. The event must occur at least once a month for at least 3 months (Criterion B), and 
the chronological age of the child must be at least 4 years (or for children with developmental 
delays, the mental age must be at least 4 years) (Criterion C). The fecal incontinence must not 
be exclusively attributable to the physiological effects of a substance (e.g., laxatives) or another 
medical condition except through a mechanism involving constipation (Criterion D).

When the passage of feces is involuntary rather than intentional, it is often related to 
constipation, impaction, and retention with subsequent overflow. The constipation may 
develop for psychological reasons (e.g., anxiety about defecating in a particular place, a 
more general pattern of anxious or oppositional behavior), leading to avoidance of defeca­
tion. Physiological predispositions to constipation include ineffectual straining or paradox­
ical defecation dynamics, with contraction rather than relaxation of the external sphincter 
or pelvic floor during straining for defecation. Dehydration associated with a febrile ill­
ness, hypothyroidism, or a medication side effect can also induce constipation. Once con­

stipation has developed, it may be complicated by an anal fissure, painful defecation, and 
further fecal retention. The consistency of the stool may vary. In some individuals the stool 
may be of normal or near-normal consistency. In other individuals—such as those with 
overflow incontinence secondary to fecal retention—it may be liquid.
The child with encopresis often feels ashamed and may wish to avoid situations (e.g., 
camp, school) that might lead to embarrassment. The amount of impairment is a function 
of the effect on the child's self-esteem, the degree of social ostracism by peers, and the an­
ger, punishment, and rejection on the part of caregivers. Smearing feces may be deliberate

ger, punishment, and rejection on the part of caregivers. Smearing feces may be deliberate 
or accidental, resulting from the child's attempt to clean or hide feces that were passed in­
voluntarily. When the incontinence is clearly deliberate, features of oppositional defiant 
disorder or conduct disorder may also be present. Many children with encopresis and 
chronic constipation also have enuresis symptoms and may have associated urinary reflux 
in the bladder or ureters that may lead to chronic urinary infections, the symptoms of 
which may remit with treatment of the constipation.

It is estimated thiht approximately 1% of 5-year-olds have encopresis, and the disorder is 
more common in males than in females.
Encopresis is not diagnosed until a child has reached a chronological age of at least 4 years 
(or for children with developmental delays, a mental age of at least 4 years). Inadequate, 
inconsistent toilet training and psychosocial stress (e.g., entering school, the birth of a sib­
ling) may be predisposing factors. Two types of course have been described: a "primary" 
type, in which the individual has never established fecal continence, and a "secondary" 
type, in which the disturbance develops after a period of established fecal continence. En­
copresis can persist, with intermittent exacerbations, for years.
Genetic and physiological. Painful defecation can lead to constipation and a cycle of with­
holding behaviors that make encopresis more likely. Use of some medications (e.g., anti­

convulsants, cough suppressants) may increase constipation and make encopresis more 
likely.
In addition to physical examination, gastrointestinal imaging (e.g., abdominal radiograph) 
may be informative to assess retained stool and gas in the colon. Additional tests, such as 
barium enema and anorectal manography, may be used to help exclude other medical 
conditions, such as Hirschsprung's disease.
A diagnosis of encopresis in the presence of another medical condition is appropriate only 
if the mechanism involves constipation that cannot be explained by other medical condi­
tions. Fecal incontinence related to other medical conditions (e.g., chronic diarrhea, spina 
bifida, anal stenosis) would not warrant a DSM-5 diagnosis of encopresis.

Urinary tract infections can be comorbid with encopresis and are more common in females.
Other Specified Elimination Disorder
This category applies to presentations in which symptoms characteristic of an elimination  
the disorders in the elimination disorders diagnostic class. The other specified elimination  
disorder category is used in situations in which the clinician chooses to communicate the  
specific reason that the presentation does not meet the criteria for any specific elimination  
disorder. This is done by recording “ other specified elimination disorder”  followed by the

disorder. This is done by recording “ other specified elimination disorder”  followed by the  
specific reason (e.g., “low-frequency enuresis” ).
Coding note: Code 788.39 (N39.498) for other specified elimination disorder with urinary  
symptoms: 787.60 (R15.9) for other specified elimination disorder with fecal symptoms.

Unspecified Elimination Disorder
This category applies to presentations in  which symptoms characteristic of an elimination  
the disorders in the elimination disorders diagnostic class. The unspecified elimination dis­
order category is used in situations in which the clinician chooses nof to specify the reason  
that the criteria are not met for a specific elimination disorder, and includes presentations  
in  which there is insufficient information to make a more specific diagnosis (e.g., in emer­
gency room settings).
Coding note: Code 788.30 (R32) for unspecified elimination disorder with urinary symp­
toms; 787.60 (R15.9) for unspecified elimination disorder with fecal symptoms.

Sleep-W&k^
ThG DSM-5 Cl3SSifiC3tion of sleep-wake disorders is intended for use by general 
mental health and medical clinicians (those caring for adult, geriatric, and pediatric pa­
tients). Sleep-wake disorders encompass 10 disorders or disorder groups: insomrüa disor­
der, hypersomjiolence disorder, narcolepsy, breathing-related sleep disorders, circadian 
rhythm sleep-wake disorders, non-rapid eye movement (NREM) sleep arousal disorders, 
nightmare disorder, rapid eye movement (REM) sleep behavior disorder, restless legs syn­
drome, and substance/medication-induced sleep disorder. Individuals with these disor­
ders typically present with sleep-wake complaints of dissatisfaction regarding the quality, 
timing, and amount of sleep. Resulting daytime distress and impairment are core features 
shared by all of these sleep-wake disorders.
The organization of this chapter is designed to facilitate differential diagnosis of sleep-

The organization of this chapter is designed to facilitate differential diagnosis of sleep- 
wake complaints and to clarify when referral to a sleep specialist is appropriate for further 
assessment and treatment planning. The DSM-5 sleep disorders nosology uses a simple, 
clinically useful approach, while also reflecting scientific advances in epidemiology, ge­
netics, pathophysiology, assessment, and interventions research since DSM-IV. In some 
cases (e.g., insomnia disorder), a "lumping" approach has been adopted, whereas in oth­
ers (e.g., narcolepsy), a "splitting" approach has been taken, reflecting the availability of 
validators derived from epidemiological, neurobiological, and interventions research.
Sleep disorders are often accompanied by depression, anxiety, and cognitive changes 
that must be addressed in treatment planning and management. Furthermore, persistent

that must be addressed in treatment planning and management. Furthermore, persistent 
sleep disturbances (both insomnia and excessive sleepiness) are established risk factors for 
the subsequent development of mental illnesses and substance use disorders. They may 
also represent a prodromal expression of an episode of mental illness, allowing the possi­
bility of early intervention to preempt or to attenuate a full-blown episode.
The differential diagnosis of sleep-wake complaints necessitates a multidimensional 
approach, with consideration of possibly coexisting medical and neurological conditions. 
Coexisting clinical conditions are the rule, not the exception. Sleep disturbances furnish a 
clinically useful indicator of medical and neurological conditions that often coexist with 
depression and other common mental disorders. Prominent among these comorbidities

depression and other common mental disorders. Prominent among these comorbidities 
are breathing-related sleep disorders, disorders of the heart and lungs (e.g., congestive 
heart failure, chronic obstructive pulmonary disease), neurodegenerative disorders (e.g., 
Alzheimer's disease), and disorders of the musculoskeletal system (e.g., osteoarthritis). 
These disorders not only may disturb sleep but also may themselves be worsened during 
sleep (e.g., prolonged apneas or electrocardiographic arrhythmias during REM sleep; con- 
fusional arousals in patients with dementing illness; seizures in persons with complex 
partial seizures). REM sleep behavior disorder is often an early indicator of neurodegen­
erative disorders (alpha synucleinopathies) like Parkinson's disease. For all of these rea­
sons—related to differential diagnosis, clinical comorbidity, and facilitation of treatment

sons—related to differential diagnosis, clinical comorbidity, and facilitation of treatment 
planning—sleep disorders are included in DSM-5.
The approach taken to the classification of sleep-wake disorders in DSM-5 can be under­
stood within the context of "lumping versus splitting." DSM-IV represented an effort to 
simplify sleep-wake disorders classification and thus aggregated diagnoses under broader, 
less differentiated labels. At the other pole, the International Classification of Sleep Disorders,

2nd Edition (ICSD-2) elaborated numerous diagnostic subtypes. DSM-IV was prepared for 
use by mental health and general medical clinicians who are not experts in sleep medicine. 
ICSD-2 reflected the science and opinions of the sleep specialist community and was pre­
pared for use by specialists.
The weight of available evidence supports the superior performance characteristics 
(interrater reliability, as well as convergent, discriminant, and face validity) of simpler, less- 
differentiated approaches to diagnosis of sleep-wake disorders. The text accompanying 
each set of diagnostic criteria provides linkages to the corresponding disorders included in 
ICSD-2. The DSM-5 sleep-wake disorders classification also specifies corresponding non­
psychiatric listings (e.g., neurology codes) from the International Classification of Diseases  
(ICD).
The field of sleep disorders medicine has progressed in this direction since the publi­

(ICD).
cation of DSM-IV. The use of biological validators is now embodied in the DSM-5 classi­
fication of sleep-wake disorders, particularly for disorders of excessive sleepiness, such as 
narcolepsy; for breathing-related sleep disorders, for which formal sleep studies (i.e., 
polysomnography) are indicated; and for restless legs syndrome, which can often coexist 
with periodic limb movements during sleep, detectable via polysomnography.
Insomnia Disorder
Diagnostic Criteria 780.52 (G47.00)
A . A  predominant complaint of dissatisfaction witli sleep quantity or quality, associated  
with one (or more) of the following symptoms:
1. Difficulty initiating sleep. (In children, this may manifest as difficulty initiating sleep  
without caregiver intervention.)

2. Difficulty maintaining sleep, characterized by frequent awakenings or problems re­
turning to sleep after awakenings. (In children, this may manifest as difficulty return­
ing to sleep without caregiver intervention.)
3. Early-morning awakening with inability to return to sleep.
B. The sleep disturbance causes clinically significant distress or impairment in social, oc­
cupational, educational, academic, behavioral, or other important areas of functioning.
C. The sleep difficulty occurs at least 3 nights per week.
D. The sleep difficulty is present for at least 3 months.
E. The sleep difficulty occurs despite adequate opportunity for sleep.
F. The insomnia is not better explained by and does not occur exclusively during the

F. The insomnia is not better explained by and does not occur exclusively during the  
course of another sleep-wake disorder (e.g., narcolepsy, a breathing-related sleep dis­
order, a circadian rhythm sleep-wake disorder, a parasomnia).
G. The insomnia is not attributable to the physiological effects of a substance (e.g., a drug  
of abuse, a medication).
H. Coexisting mental disorders and medical conditions do not adequately explain the pre­
dominant complaint of insomnia.
With non-sleep disorder mental comorbidity, including substance use disorders  
With other medical comorbidity  
With other sleep disorder
Coding note: The code 780.52 (G47.00) applies to all three specifiers. Code also the  
relevant associated mental disorder, medical condition, or other sleep disorder imme­
diately after the code for insomnia disorder in  order to indicate the association.

Episodic: Sy(nptoms last at least 1  month but less than 3 months.
Persistent: Symptoms last 3 months or longer.
Recurrent: Two (or more) episodes within the space of 1  year.
Note: Acute and short-term insomnia (i.e., symptoms lasting less than 3 months but oth-  
enA /ise meeting all criteria with regard to frequency, intensity, distress, and/or impairment)  
should be coded as an other specified insomnia disorder.
Note. The diagnosis of insomnia disorder is given whether it occurs as an independent 
condition or is comorbid with another mental disorder (e.g., major depressive disorder), 
medical condition (e.g., pain), or another sleep disorder (e.g., a breathing-related sleep dis­
order). For instance, insomnia may develop its own course with some anxiety and depres­
sive features but in the absence of criteria being met for any one mental disorder. Insomnia 
may also manifest as a clinical feature of a more predominant mental disorder. Persistent

may also manifest as a clinical feature of a more predominant mental disorder. Persistent 
insomnia may even be a risk factor for depression and is a common residual symptom af­
ter treatment for this condition. With comorbid insomnia and a mental disorder, treatment 
may also need to target both conditions. Given these different courses, it is often impossi­
ble to establish the precise nature of the relationship between these clinical entities, and 
this relationship may change over time. Therefore, in the presence of insomnia and a co­
morbid disorder, it is not necessary to make a causal attribution between the two condi­
tions. Rather, the diagnosis of insomnia disorder is made with concurrent specification of 
the clinically comorbid conditions. A concurrent insomnia diagnosis should only be con­

sidered when the insomnia is sufficiently severe to warrant independent clinical attention; 
otherwise, no separate diagnosis is necessary.
The essential feature of insomnia disorder is dissatisfaction with sleep quantity or quality 
with complaints of difficulty initiating or maintaining sleep. The sleep complaints are ac­
companied by clinically significant distress or impairment in social, occupational, or other 
important areas of functioning. The sleep disturbance may occur during the course of an­
other mental disorder or medical condition, or it may occur independently.
Different manifestations of insomnia can occur at different times of the sleep period. Sleep-  
onset insomnia  (or initial insomnia)  involves difficulty initiating sleep at bedtime. Sleep mainte­

nance insomnia  (or middle insomnia)  involves frequent or prolonged awakenings throughout 
the night. Late insomnia  involves early-morning awakening with an inability to return to sleep. 
Difficulty maintaining sleep is the most common single symptom of insomnia, followed by 
difficulty falling asleep, while a combination of these symptoms is the most common presen­
tation overall. The specific type of sleep complaint often varies over time. Individuals who 
complain of difficulty falling asleep at one time may later complain of difficulty maintaining 
sleep, and vice versa. Symptoms of difficulty falling asleep and difficulty maintaining sleep 
can be quantified by the individual's retrospective self-report, sleep diaries, or other methods,

can be quantified by the individual's retrospective self-report, sleep diaries, or other methods, 
such as actigraphy or polysomnography, but the diagnosis of insomnia disorder is based on 
the individual's subjective perception of sleep or a caretaker's report.
Nonrestorative sleep,  a complaint of poor sleep quality that does not leave the individual 
rested upon awakening despite adequate duration, is a common sleep complaint usually 
occurring in association with difficulty initiating or maintaining sleep, or less frequently in 
isolation. This complaint can also be reported in association with other sleep disorders 
(e.g., breathing-related sleep disorder). When a complaint of nonrestorative sleep occurs 
in isolation (i.e., in the absence of difficulty initiating and/or maintaining sleep) but all di­

agnostic criteria with regard to frequency, duration, and daytime distress and impairments 
are otherwise met, a diagnosis of other specified insomnia disorder or unspecified insom­
nia disorder is made.

Aside from the frequency and duration criteria required to make the diagnosis, addi­
tional criteria are useful to quantify insomnia severity. These quantitative criteria, while 
arbitrary, are provided for illustrative purpose only. For instance, difficulty initiating sleep 
is defined by a subjective sleep latency greater than 20-30 minutes, and difficulty maintain­
ing sleep is defined by a subjective time awake after sleep onset greater than 20-30 min­
utes. Although there is no standard definition of early-morning awakening, this symptom 
involves awakening at least 30 minutes before the scheduled time and before total sleep 
time reaches hours. It is essential to take into account not only the final awakening time 
but also the bedtime on the previous evening. Awakening at 4:00 A.M. does not have the 
same clinical significance in those who go to bed at 9:00 P.M. as in those who go to bed at

same clinical significance in those who go to bed at 9:00 P.M. as in those who go to bed at 
11:00 P.M. Such a symptom may also reflect an age-dependent decrease in the ability to sus­
tain sleep or an age-dependent shift in the timing of the main sleep period.
Insomnia disorder involves daytime impairments as well as nighttime sleep difficulties. 
These include fatigue or, less commonly, daytime sleepiness; the latter is more common 
among older individuals and when insomnia is comorbid with another medical condition 
(e.g., chronic pain) or sleep disorder (e.g., sleep apnea). Impairment in cognitive performance 
may include difficulties with attention, concentration and memory, and even with performing 
simple manual skills. Associated mood disturbances are typically described as irritability or 
mood lability and less commonly as depressive or anxiety symptoms. Not all individuals with

mood lability and less commonly as depressive or anxiety symptoms. Not all individuals with 
nighttime sleep disturbances are distressed or have functional impairment. For example, sleep 
continuity is often interrupted in healthy older adults who nevertheless identify themselves 
as good sleepers. A diagnosis of insomnia disorder should be reserved for those individuals 
with significant daytime distress or impairment related to their nighttime sleep difficulties.
Insomnia is often associated with physiological and cognitive arousal and conditioning 
factors that interfere with sleep. A preoccupation with sleep and distress due to the inabil­
ity to sleep may lead to a vicious cycle: the more the individual strives to sleep, the more 
frustration builds and further impairs sleep. Thus, excessive attention and efforts to sleep,

frustration builds and further impairs sleep. Thus, excessive attention and efforts to sleep, 
which override normal sleep-onset mechanisms, may contribute to the development of in­
somnia. Individuals with persistent insomnia may also acquire maladaptive sleep habits 
(e.g., spending excessive time in bed; following an erratic sleep schedule; napping) and 
cognitions (e.g., fear of sleeplessness; apprehensions of daytime impairments; clock mon­
itoring) during the course of the disorder. Engaging in such activities in an environment in 
which the individual has frequently spent sleepless nights may further compound the con­
ditioned arousal and perpetuate sleep difficulties. Conversely, the individual may fall asleep 
more easily when not trying to do so. Some individuals also report better sleep when away 
from their own bedrooms and their usual routines.

Insomnia may be accompanied by a variety of daytime complaints and symptoms, in­
cluding fatigue, decreased energy, and mood disturbances. Symptoms of anxiety or de­
pression that do not meet criteria for a specific mental disorder may be present, as well as 
an excessive focus on the perceived effects of sleep loss on daytime functioning.
Individuals with insomnia may have elevated scores on self-report psychological or 
personality inventories with profiles indicating mild depression and anxiety, a worrisome 
cognitive style, an emotion-focused and internalizing style of conflict resolution, and a so­
matic focus. Patterns of neurocognitive impairment among individuals with insomnia dis­
order are inconsistent, although there may be impairments in performing tasks of higher

order are inconsistent, although there may be impairments in performing tasks of higher 
complexity and those requiring frequent changes in performance strategy. Individuals 
with insomnia often require more effort to maintain cognitive performance.
Population-based estimates indicate that about one-third of adults report insomnia symp­
toms, 10%-15% experience associated daytime impairments, and 6% -10% have symptoms

that meet criteria for insonmia disorder. Insomnia disorder is the most prevalent of all 
sleep disorders. ù;i primary care settings, approximately 10%-2 0% of individuals complain 
of significant insomnia symptoms. Insomnia is a more prevalent complaint among fe­
males than among males, with a gender ratio of about 1.44:1. Although insomnia can be a 
symptom or an independent disorder, it is most frequently observed as a comorbid con­
dition with another medical condition or mental disorder. For instance, 40%-50% of indi­
viduals with insomnia also present with a comorbid mental disorder.
The onset of insomnia symptoms can occur at any time during life, but the first episode is 
more common in young adulthood. Less frequently, insomnia begins in childhood or ad­
olescence. In women, new-onset insomnia may occur during menopause and persist even 
after other symptoms (e.g., hot flashes) have resolved. Insomnia may have a late-life onset,

after other symptoms (e.g., hot flashes) have resolved. Insomnia may have a late-life onset, 
which is often associated with the onset of other health-related conditions.
Insomnia can be situational, persistent, or recurrent. Situational or acute insomnia usu­
ally lasts a few days or a few weeks and is often associated with life events or rapid changes 
in sleep schedules or environment. It usually resolves once the initial precipitating event 
subsides. For some individuals, perhaps those more vulnerable to sleep disturbances, in­
somnia may persist long after the initial triggering event, possibly because of conditioning 
factors and heightened arousal. The factors that precipitate insomnia may differ from 
those that perpetuate it. For example, an individual who is bedridden with a painful injury 
and has difficulty sleeping may then develop negative associations for sleep. Conditioned

and has difficulty sleeping may then develop negative associations for sleep. Conditioned 
arousal may then persist and lead to persistent insomnia. A similar course may develop in 
the context of an acute psychological stress or a mental disorder. For instance, insomnia that 
occurs during an episode of major depressive disorder can become a focus of attention, 
with consequent negative conditioning, and persist even after resolution of the depressive 
episode. In some cases, insomnia may also have an insidious onset without any identifi­
able precipitating factor.
The course of insomnia may also be episodic, with recurrent episodes of sleep difficul­
ties associated with the occurrence of stressful events. Chronicity rates range from 45% 
to 75% for follow-ups of 1-7 years. Even when the course of the insomnia has become

to 75% for follow-ups of 1-7 years. Even when the course of the insomnia has become 
chronic, there is night-to-night variability in sleep patterns, with an occasional restful night's 
sleep interspersed with several nights of poor sleep. The characteristics of insomnia may 
also change over time. Many individuals with insomnia have a history of "light" or easily 
disturbed sleep prior to onset of more persistent sleep problems.
Insomnia complaints are more prevalent among middle-age and older adults. The type 
of insomnia symptom changes as a function of age, with difficulties initiating sleep being 
more common among young adults and problems maintaining sleep occurring more fre­
quently among middle-age and older individuals.
Difficulties initiating and maintaining sleep can also occur in children and adolescents,

Difficulties initiating and maintaining sleep can also occur in children and adolescents, 
but there are more limited data on prevalence, risk factors, and comorbidity during these 
developmental phases of the lifespan. Sleep difficulties in childhood can result from con­
ditioning factors (e.g., a child who does not learn to fall asleep or return to sleep without 
the presence of a parent) or from the absence of consistent sleep schedules and bedtime 
routines. Insomnia in adolescence is often triggered or exacerbated by irregular sleep sched­
ules (e.g., phase delay). In both children and adolescents, psychological and medical fac­
tors can contribute to insomnia.
The increased prevalence of insomnia in older adults is partly explained by the higher 
incidence of physical health problems with aging. Changes in sleep patterns associated with 
the normal developmental process must be differentiated from those exceeding age-related

the normal developmental process must be differentiated from those exceeding age-related 
changes. Although polysomnography is of limited value in the routine evaluation of in­
somnia, it may be more useful in the differential diagnosis among older adults because the 
etiologies of insomnia (e.g., sleep apnea) are more often identifiable in older individuals.

While the risk and prognostic factors discussed in this section increase vuhierability to in­
somnia, sleep disturbances are more likely to occur when predisposed individuals are ex­
posed to precipitating events, such as major life events (e.g., illness, separation) or less 
severe but more chronic daily stress. Most individuals resume normal sleep patterns after 
the initial triggering event has disappeared, but others—perhaps those more vulnerable to 
insomnia—continue experiencing persistent sleep difficulties. Perpetuating factors such as 
poor sleep habits, irregular sleep scheduling, and the fear of not sleeping feed into the in­
somnia problem and may contribute to a vicious cycle that may induce persistent insomnia.
Temperamental . Anxiety or worry-prone personality or cognitive styles, increased arousal 
predisposition, and tendency to repress emotions can increase vulnerability to insomnia.

Environmental. Noise, light, uncomfortably high or low temperature, and high altitude 
may also increase vulnerability to insomnia.
Genetic and physiological. Female gender and advancing age are associated with in­
creased vulnerability to insomnia. Disrupted sleep and insomnia display a familial dispo­
sition. The prevalence of insomnia is higher among monozygotic twins relative to 
dizygotic twins; it is also higher in first-degree family members compared with the general 
population. The extent to which this link is inherited through a genetic predisposition, 
learned by observations of parental models, or established as a by-product of another psy­
chopathology remains undetermined.
Course modifiers. Deleterious course modifiers include poor sleep hygiene practices

Course modifiers. Deleterious course modifiers include poor sleep hygiene practices 
(e.g., excessive caffeine use, irregular sleep schedules).
Insomnia is a more prevalent complaint among females than among males, with first onset 
often associated with the birth of a new child or with menopause. Despite higher preva­
lence among older females, polysomnographic studies suggest better preservation of 
sleep continuity and slow-wave sleep in older females than in older males.
Polysomnography usually shows impairments of sleep continuity (e.g., increased sleep la­
tency and time awake after sleep onset and decreased sleep efficiency [percentage of time 
in bed asleep] and may show increased stage 1 sleep and decreased stages 3 and 4 sleep. 
The severity of these sleep impairments does not always match the individual's clinical

The severity of these sleep impairments does not always match the individual's clinical 
presentation or subjective complaint of poor sleep, as individuals with insomnia often un­
derestimate sleep duration and overestimate wakefulness relative to polysomnography. 
Quantitative electroencephalographic analyses may indicate that individuals with insom­
nia have greater high-frequency electroencephalography power relative to good sleepers 
both around the sleep onset period and during non-rapid eye movement sleep, a feature 
suggestive of increased cortical arousal. Individuals with insomnia disorder may have a 
lower sleep propensity and typically do not show increased daytime sleepiness on objec­
tive sleep laboratory measures compared with individuals without sleep disorders.
Other laboratory measures show evidence, although not consistently, of increased

Other laboratory measures show evidence, although not consistently, of increased 
arousal and a generalized activation of the hypothalamic-pituitary-adrenal axis (e.g., in­
creased cortisol levels, heart rate variability, reactivity to stress, metabolic rate). In general, 
findings are consistent with the hypothesis that increased physiological and cognitive 
arousal plays a significant role in insomnia disorder.
Individuals with insomnia disorder may appear either fatigued or haggard or, con­
versely, overaroused and "wired." However, there are no consistent or characteristic 
abnormalities on physical examination. There may be an increased incidence of stress-

related psychophysiological symptoms (e.g., tension headache, muscle tension or pain, 
gastrointestinal symptoms).
Functional Consequences of Insomnia Disorder
Interpersonal, social, and occupational problems may develop as a result of insomnia or 
excessive concern with sleep, increased daytime irritability, and poor concentration. De­
creased attention and concentration are common and may be related to higher rates of ac­
cidents observed in insomnia. Persistent insomnia is also associated with long-term 
consequences, including increased risks of major depressive disorder, hypertension, and 
myocardial infarction; increased absenteeism and reduced productivity at work; reduced 
quality of life; and increased economic burden.
Normal sleep variations. Normal sleep duration varies considerably across individuals. 
Some individuals who require little sleep ("short sleepers") may be concerned about their

Some individuals who require little sleep ("short sleepers") may be concerned about their 
sleep duration. Short sleepers differ from individuals with insomnia disorder by the lack of 
difficulty falling or staying asleep and by the absence of characteristic daytime symptoms 
(e.g., fatigue, concentration problems, irritability). However, some short sleepers may desire 
or attempt to sleep for a longer period of time and, by prolonging time in bed, may create an 
insomnia-like sleep pattern. Clinical insomnia also should be distinguished from normal, 
age-related sleep changes. Insomnia must also be distinguished from sleep deprivation due 
to inadequate opportunity or circumstance for sleep resulting, for example, from an emer­
gency or from professional or family obligations forcing the individual to stay awake.

Situational/acute insomnia. Situational/acute insomnia  is a condition lasting a few days 
to a few weeks, often associated with life events or with changes in sleep schedules. These 
acute or short-term insomnia symptoms may also produce significant distress and inter­
fere with social, personal, and occupational functioning. When such symptoms are fre­
quent enough and meet all other criteria except for the 3-month duration, a diagnosis of 
other specified insomnia disorder or unspecified insomnia disorder is made.
Delayed sleep phase and shift work types of circadian rhythm sleep-wake disorder.
Individuals with the delayed sleep phase type of circadian rhythm sleep-wake disorder re­
port sleep-onset insomnia only when they try to sleep at socially normal times, but they do

port sleep-onset insomnia only when they try to sleep at socially normal times, but they do 
not report difficulty falling asleep or staying asleep when their bed and rising times are 
delayed and coincide with their endogenous circadian rhythm. Shift work type differs from 
insomnia disorder by the history of recent shift work.
Restless legs syndrome. Restless legs syndrome often produces difficulties initiating 
and maintaining sleep. However, an urge to move the legs and any accompanying unpleas­
ant leg sensations are features that differentiate this disorder from insomnia disorder.
Breathing-related sleep disorders. Most individuals with a breathing-related sleep dis­
order have a history of loud snoring, breathing pauses during sleep, and excessive daytime 
sleepiness. Nonetheless, as many as 50% of individuals with sleep apnea may also report

sleepiness. Nonetheless, as many as 50% of individuals with sleep apnea may also report 
insomnia symptoms, a feature that is more common among females and older adults.
Narcolepsy. Narcolepsy may cause insomnia complaints but is distinguished from in­
somnia disorder by the predominance of symptoms of excessive daytime sleepiness, cat­
aplexy, sleep paralysis, and sleep-related hallucinations.
Parasomnias. Parasomnias are characterized by a complaint of unusual behavior or events 
during sleep that may lead to intermittent awakenings and difficulty resuming sleep. 
However, it is these behavioral events, rather than the insomnia per se, that dominate the 
clinical picture.

Substance/medication-induced sleep disorder, insomnia type. Substance/medication- 
induced sleep disorder, insomnia type, is distinguished from insomnia disorder by the fact 
that a substance (i.e., a drug of abuse, a medication, or exposure to a toxin) is judged to be 
etiologically related to the insomnia (see "Substance/Medication-Induced Sleep Disor­
der" later in this chapter). For example, insomnia occurring only in the context of heavy 
coffee consumption would be diagnosed as caffeine-induced sleep disorder, insomnia 
type, with onset during intoxication.
Insomnia is a common comorbidity of many medical conditions, including diabetes, cor­
onary heart disease, chronic obstructive pulmonary disease, arthritis, fibromyalgia, and 
other chronic pain conditions. The risk relationship appears to be bidirectional: insomnia 
increases the risk of medical conditions, and medical problems increase the risk of insom­

nia. The direction of the relationship is not always clear and may change over time; for this 
reason, comorbid insomnia is the preferred terminology in the presence of coexisting in­
somnia with another medical condition (or mental disorder).
Individuals with insomnia disorder frequently have a comorbid mental disorder, par­
ticularly bipolar, depressive, and anxiety disorders. Persistent insomnia represents a risk 
factor or an early symptom of subsequent bipolar, depressive, anxiety, and substance use 
disorders. Individuals with insomnia may misuse medications or alcohol to help with 
nighttime sleep, anxiolytics to combat tension or anxiety, and caffeine or other stimulants 
to combat excessive fatigue. In addition to worsening the insomnia, this type of substance

to combat excessive fatigue. In addition to worsening the insomnia, this type of substance 
use may in some cases progress to a substance use disorder.
Relationship to international Classification of  
Sleep Disorders
There are several distinct insomnia phenotypes relating to the perceived source of the in­
somnia that are recognized by the International Classification of Sleep Disorders,  2nd Edition 
(ICSD-2). These include psychophysiological insomnia, idiopathic insomnia, sleep-state mispercep­
tion, and inadequate sleep hygiene.  Despite their clinical appeal and heuristic value, there is 
limited evidence to support these distinct phenotypes.
Hypersomnolence Disorder
Diagnostic Criteria 780.54 (G47.10)
A. Self-reported excessive sleepiness (hypersomnolence) despite a main sleep period  
lasting at least 7 hours, with at least one of the following symptoms:

1. Recurrent periods of sleep or lapses into sleep within the same day.
2. A prolonged main sleep episode of more than 9 hours per day that is nonrestorative  
(i.e., unrefreshing).
3. Difficulty being fully awake after abrupt awakening.
B. The hypersomnolence occurs at least three times per week, for at least 3 months.
C. The hypersomnolence is accompanied by significant distress or impairment in cogni­
tive, social, occupational, or other important areas of functioning.
D. The hypersomnolence is not better explained by and does not occur exclusively during  
the course of another sleep disorder (e.g., narcolepsy, breathing-related sleep disor­
der, circadian rhythm sleep-wake disorder, or a parasomnia).
E. The hypersomnolence is not attributable to the physiological effects of a substance

E. The hypersomnolence is not attributable to the physiological effects of a substance  
(e.g., a drug of abuse, a medication).

F. Coexisting mental and medical disorders do not adequately explain the predominant  
complaint of t^ypersomnolence.
With mental disorder, including substance use disorders  
With medicai condition  
With another sleep disorder
Coding note: The code 780.54 (G47.10) applies to all three specifiers. Code also the  
relevant associated mental disorder, medical condition, or other sleep disorder im­
mediately after the code for hypersomnolence disorder in order to indicate the associ­
ation.
Acute: Duration of less than 1  month.
Subacute: Duration of 1-3 months.  
Persistent: Duration of more than 3 months.
Specify severity based on degree of difficulty maintaining daytime alertness as manifested  
by the occurrence of multiple attacks of irresistible sleepiness within any given day occur­
ring, for example, while sedentary, driving, visiting with friends, or working.
Mild: Difficulty maintaining daytime alertness 1-2 days/week.

Moderate: Difficulty maintaining daytime alertness 3-^ days/week.
Severe: Difficulty maintaining daytime alertness 5-7 days/week.
Hypersomnolence  is a broad diagnostic term and includes symptoms of excessive quantity 
of sleep (e.g., extended nocturnal sleep or involuntary daytime sleep), deteriorated quality 
of wakefulness (i.e., sleep propensity during wakefulness as shown by difficulty awaken­
ing or inability to remain awake when required), and sleep inertia (i.e., a period of im­
paired performance and reduced vigilance following awakening from the regular sleep 
episode or from a nap) (Criterion A). Individuals with this disorder fall asleep quickly and 
have a good sleep efficiency (>90%). They may have difficulty waking up in the morning,

have a good sleep efficiency (>90%). They may have difficulty waking up in the morning, 
sometimes appearing confused, combative, or ataxic. This prolonged impairment of alert­
ness at the sleep-wake transition is often referred to as sleep inertia  (i.e., sleep drunkenness). 
It can also occur upon awakening from a daytime nap. During that period, the individual 
appears awake, but there is a decline in motor dexterity, behavior may be very inappro­
priate, and memory deficits, disorientation in time and space, and feelings of grogginess 
may occur. This period may last some minutes to hours.
The persistent need for sleep can lead to automatic behavior (usually of a very routine, 
low-complexity type) that the individual carries out with little or no subsequent recall. For 
example, individuals may find themselves having driven several miles from where they

example, individuals may find themselves having driven several miles from where they 
thought they were, unaware of the "automatic" driving they did in the preceding minutes. 
For some individuals with hypersomnolence disorder, the major sleep episode (for most 
individuals, nocturnal sleep) has a duration of 9 hours or more. However, the sleep is often 
nonrestorative and is followed by difficulty awakening in the morning. For other individ­
uals with hypersomnolence disorder, the major sleep episode is of normal nocturnal sleep 
duration (6-9 hours). In these cases, the excessive sleepiness is characterized by several un­
intentional daytime naps. These daytime naps tend to be relatively long (often lasting 1 hour 
or more), are experienced as nonrestorative (i.e., unrefreshing), and do not lead to improved

or more), are experienced as nonrestorative (i.e., unrefreshing), and do not lead to improved 
alertness. Individuals with hypersomnolence have daytime naps nearly everyday regard­
less of the nocturnal sleep duration. Subjective sleep quality may or may not be reported as 
good. Individuals typically feel sleepiness developing over a period of time, rather than

experiencing a sudden sleep "attack." Unintentional sleep episodes typically occur in low- 
stimulation and low-activity situations (e.g., while attending lectures, reading, watching 
television, or driving long distances), but in more severe cases they can manifest in high- 
attention situations such as at work, in meetings, or at social gatherings.
Nonrestorative sleep, automatic behavior, difficulties awakening in the morning, and 
sleep inertia, although common in hypersomnolence disorder, may also be seen in a variety 
of conditions, including narcolepsy. Approximately 80% of individuals with hyper­
somnolence report that their sleep is nonrestorative, and as many have difficulties awak­
ening in the morning. Sleep inertia, though less common (i.e., observed in 36%-50% of 
individuals with hypersomnolence disorder), is highly specific to h)φersomnolence. Short

individuals with hypersomnolence disorder), is highly specific to h)φersomnolence. Short 
naps (i.e., duration of less than 30 minutes) are often unrefreshing. Individuals with hy­
persomnolence often appear sleepy and may even fall asleep in the clinician's waiting 
area.
A subset of individuals with hypersomnolence disorder have a family history of hy­
persomnolence and also have symptoms of autonomic nervous system dysfunction, in­
cluding recurrent vascular-type headaches, reactivity of the peripheral vascular system 
(Raynaud's phenomenon), and fainting.
Approximately 5%-10% of individuals who consult in sleep disorders clinics with com­
plaints of daytime sleepiness are diagnosed as having hypersomnolence disorder. It is es­
timated that about 1% of the European and U.S. general population has episodes of sleep

timated that about 1% of the European and U.S. general population has episodes of sleep 
inertia. Hypersomnolence occurs with relatively equal frequency in males and females.
Hypersomnolence disorder has a persistent course, with a progressive evolution in the se­
verity of symptoms. In most extreme cases, sleep episodes can last up to 20 hours. How­
ever, the average nighttime sleep duration is around 9Vi hours. While many individuals 
with hypersomnolence are able to reduce their sleep time during working days, weekend 
and holiday sleep is greatly increased (by up to 3 hours). Awakenings are very difficult 
and accompanied by sleep inertia episodes in nearly 40% of cases. Hypersomnolence fully 
manifests in most cases in late adolescence or early adulthood, with a mean age at onset of

manifests in most cases in late adolescence or early adulthood, with a mean age at onset of 
17-24 years. Individuals with hypersomnolence disorder are diagnosed, on average, 10-15 
years after the appearance of the first symptoms. Pediatric cases are rare.
Hypersomnolence has a progressive onset, with symptoms beginning between ages 15 
and 25 years, with a gradual progression over weeks to months. For most individuals, the 
course is then persistent and stable, unless treatment is initiated. The development of other 
sleep disorders (e.g., breathing-related sleep disorder) may worsen the degree of sleepi­
ness. Although hyperactivity may be one of the presenting signs of daytime sleepiness in 
children, voluntary napping increases with age. This normal phenomenon is distinct from 
hypersomnolence.

Environmental. Hypersomnolence can be increased temporarily by psychological stress 
and alcohol use, but they have not been documented as environmental precipitating 
factors. Viral infections have been reported to have preceded or accompanied hyper­
somnolence in about 10% of cases. Viral infections, such as HIV pneumonia, infectious 
mononucleosis, and Guillain-Barré syndrome, can also evolve into hypersomnolence within

months after the infection. Hypersomnolence can also appear within 6-18 months follow­
ing a head traum;^.
Genetic and physiological. Hypersomnolence may be familial, with an autosomal­
dominant mode of inheritance.
Nocturnal polysomnography demonstrates a normal to prolonged sleep duration, short 
sleep latency, and normal to increased sleep continuity. The distribution of rapid eye 
movement (REM) sleep is also normal. Sleep efficiency is mostly greater than 90%. Some 
individuals with hypersomnolence disorder have increased amounts of slow-wave sleep. 
The multiple sleep latency test documents sleep tendency, typically indicated by mean 
sleep latency values of less than 8 minutes. In hypersomnolence disorder, the mean sleep 
latency is typically less than 10 minutes and frequently 8 minutes or less. Sleep-onset REM 
periods (SOREMPs; i.e., the occurrence of REM sleep within 20 minutes of sleep onset)

periods (SOREMPs; i.e., the occurrence of REM sleep within 20 minutes of sleep onset) 
may be present but occur less than two times in four to five nap opportunities.
Functional Consequences of Hypersomnoience Disorder
The low level of alertness that occurs while an individual fights the need for sleep can lead 
to reduced efficiency, diminished concentration, and poor memory during daytime activ­
ities. Hypersomnoience can lead to significant distress and dysfunction in work and social 
relationships. Prolonged nocturnal sleep and difficulty awakening can result in difficulty 
in meeting morning obligations, such as arriving at work on time. Unintentional daytime 
sleep episodes can be embarrassing and even dangerous, if, for instance, the individual is 
driving or operating machinery when the episode occurs.

Normative variation in sleep. "Normal" sleep duration varies considerably in the general 
population. "Long sleepers" (i.e., individuals who require a greater than average amount 
of sleep) do not have excessive sleepiness, sleep inertia, or automatic behavior when they 
obtain their required amount of nocturnal sleep. Sleep is reported to be refreshing. If social 
or occupational demands lead to shorter nocturnal sleep, daytime symptoms may appear. 
In hypersomnoience disorder, by contrast, symptoms of excessive sleepiness occur regard­
less of nocturnal sleep duration. An inadequate amount of nocturnal sleep, or behaviorally  
induced insufficient sleep syndrome,  can produce symptoms of daytime sleepiness very similar 
to those of hypersomnoience. An average sleep duration of fewer than 7 hours per night

to those of hypersomnoience. An average sleep duration of fewer than 7 hours per night 
strongly suggests inadequate nocturnal sleep, and an average of more than 9-10 hours of 
sleep per 24-hour period suggests hypersomnoience. Individuals with inadequate noctur­
nal sleep typically "catch up" with longer sleep durations on days when they are free from 
social or occupational demands or on vacations. Unlike hypersomnoience, insufficient 
nocturnal sleep is unlikely to persist unabated for decades. A diagnosis of hypersomno­
ience disorder should not be made if there is a question regarding the adequacy of noctur­
nal sleep duration. A diagnostic and therapeutic trial of sleep extension for 10-14 days can 
often clarify the diagnosis.
Poor sleep quality and fatigue. Hypersomnoience disorder should be distinguished

Poor sleep quality and fatigue. Hypersomnoience disorder should be distinguished 
from excessive sleepiness related to insufficient sleep quantity or quality and fatigue (i.e., 
tiredness not necessarily relieved by increased sleep and unrelated to sleep quantity or 
quality). Excessive sleepiness and fatigue are difficult to differentiate and may overlap 
considerably.
Breathing-related sleep disorders. Individuals with hypersomnoience and breathing- 
related sleep disorders may have similar patterns of excessive sleepiness. Breathing-

related sleep disorders are suggested by a history of loud snoring, pauses in breathing 
during sleep, brain injury, or cardiovascular disease and by the presence of obesity, oro­
pharyngeal anatomical abnormalities, hypertension, or heart failure on physical examina­
tion. Polysomnographie studies can confirm the presence of apneic events in breathing- 
related sleep disorder (and their absence in hypersomnolence disorder).
Circadian rhythm sleep-wake disorders. Circadian rhythm sleep-wake disorders are 
often characterized by daytime sleepiness. A history of an abnormal sleep-wake schedule 
(with shifted or irregular hours) is present in individuals with a circadian rhythm sleep- 
wake disorder.
Parasomnias. Parasomnias rarely produce the prolonged, undisturbed nocturnal sleep 
or daytime sleepiness characteristic of hypersomnolence disorder.
Other mental disorders. Hypersomnolence disorder must be distinguished from mental

Other mental disorders. Hypersomnolence disorder must be distinguished from mental 
disorders that include hypersomnolence as an essential or associated feature. In particular, 
complaints of daytime sleepiness may occur in a major depressive episode, with atypical fea­
tures, and in the depressed phase of bipolar disorder. Assessment for other mental disorders is 
essential before a diagnosis of hypersomnolence disorder is considered. A diagnosis of hyper­
somnolence disorder can be made in the presence of another current or past mental disorder.
H)φersomnolence can be associated with depressive disorders, bipolar disorders (during a 
depressive episode), and major depressive disorder, with seasonal pattern. Many individu­
als with hypersomnolence disorder have symptoms of depression that may meet criteria for 
a depressive disorder. This presentation may be related to the psychosocial consequences of

a depressive disorder. This presentation may be related to the psychosocial consequences of 
persistent increased sleep need. Individuals with hyper somnolence disorder are also at 
risk for substance-related disorders, particularly related to self-medication with stimulants. 
This general lack of specificity may contribute to very heterogeneous profiles among indi­
viduals whose symptoms meet the same diagnostic criteria for hypersomnolence disorder. 
Neurodegenerative conditions, such as Alzheimer's disease, Parkinson's disease, and mul­
tiple system atrophy, may also be associated with hypersomnolence.
Reiationship to internatlonai Classification of  
The International Classification of Sleep Disorders,  2nd Edition (ICSD-2), differentiates nine 
subtypes of "hypersomnias of central origin," including recurrent hypersomnia (Kleine­
Levin syndrome).
Narcolepsy

A. Recurrent periods of an irrepressible need to sleep, lapsing into sleep, or napping oc­
curring within the same day. These must have been occurring at least three times per  
week over the past 3 months.
B. The presence of at least one of the following:
1. Episodes of cataplexy, defined as either (a) or (b), occurring at least a few times  
per month:
a. In individuals with long-standing disease, brief (seconds to minutes) episodes  
of sudden bilateral loss of muscle tone with maintained consciousness that are  
precipitated by laughter or joking.

b. In children or in individuals within 6 months of onset, spontaneous grimaces or  
jaw-opening episodes with tongue thrusting or a global hypotonia, without any  
obvious emotional triggers.
2. Hypocretin deficiency, as measured using cerebrospinal fluid (CSF) hypocretin-1  
immunoreactivity values (less than or equal to one-third of values obtained in  
healthy subjects tested using the same assay, or less than or equal to 110 pg/mL).  
Low CSF levels of hypocretin-1 must not be observed in the context of acute brain  
injury, inflammation, or infection.
3. Nocturnal sleep polysomnography showing rapid eye movement (REM) sleep la­
tency less than or equal to 15 minutes, or a multiple sleep latency test showing a  
mean sleep latency less than or equal to 8 minutes and two or more sleep-onset  
REM periods.
347.00 (G47.419) Narcolepsy without cataplexy but with hypocretin deficiency: Cri­

terion B requirements of low CSF hypocretin-1 levels and positive polysomnography/  
multiple sleep latency test are met, but no cataplexy is present (Criterion B 1 not met).
347.01 (G47.411) Narcolepsy with cataplexy but without hypocretin deficiency:
In this rare subtype (less than 5% of narcolepsy cases), Criterion B requirements of  
cataplexy and positive polysomnography/multiple sleep latency test are met, but CSF  
hypocretin-1 levels are normal (Criterion B2 not met).
347.00 (G47.419) Autosomal dominant cerebellar ataxia, deafness, and narco­
lepsy: This subtype is caused by exon 21 DNA (cytosine-5)-methyltransferase-1 mu­
tations and is characterized by late-onset (age 30-40 years) narcolepsy (with low or

tations and is characterized by late-onset (age 30-40 years) narcolepsy (with low or  
intermediate CSF hypocretin-1 levels), deafness, cerebellar ataxia, and eventually de­
mentia.
347.00 (G47.419) Autosomal dominant narcolepsy, obesity, and type 2 diabetes:
Narcolepsy, obesity, and type 2 diabetes and low CSF hypocretin-1 levels have been  
described in rare cases and are associated with a mutation in the myelin oligodendro­
cyte glycoprotein gene.
347.10 (G47.429) Narcolepsy secondary to another medical condition: This sub­
type is for narcolepsy that develops secondary to medical conditions that cause infec­
tious (e.g., Whipple’s disease, sarcoidosis), traumatic, or tumoral destruction of  
hypocretin neurons.
Coding note (for ICD-9-CM code 347.10 only): Code first the underlying medical con­
dition (e.g., 040.2 Whipple’s disease; 347.10 narcolepsy secondary to Whipple’s dis­
ease).

ease).
IMild: Infrequent cataplexy (less than once per week), need for naps only once or twice  
per day, and less disturbed nocturnal sleep.
Moderate: Cataplexy once daily or every few days, disturbed nocturnal sleep, and  
need for multiple naps daily.
Severe: Drug-resistant cataplexy with multiple attacks daily, nearly constant sleepi­
ness, and disturbed noctumal sleep (i.e., movements, insomnia, and vivid dreaming).
Subtypes
In narcolepsy without cataplexy but with hypocretin deficiency, unclear ''cataplexy-like" 
symptoms may be reported (e.g., the symptoms are not triggered by emotions and are un­
usually long lasting). In extremely rare cases, cerebrospinal fluid (CSF) levels of hypocre­

tin-1 are low, and polysomnographic/multiple sleep latency test (MSLT) results are 
negative: repeating the test is advised before establishing the subtype diagnosis. In narco­

lepsy with cataplexy but without hypocretin deficiency, test results for human leukocyte 
antigen (HLA) DQBl’ ^06:02 may be negative. Seizures, falls of other origin, and conversion 
disorder (functional neurological symptom disorder) should be excluded. In narcolepsy 
secondary to infectious (e.g., Whipple's disease, sarcoidosis), traumatic, or tumoral de­
struction of hypocretin neurons, test results for HLA DQBl *06:02 may be positive and may 
result from the insult triggering the autoimmune process. In other cases, the destruction of 
hypocretin neurons may be secondary to trauma or hypothalamic surgery. Head trauma 
or infections of the central nervous system can, however, produce transitory decreases in 
CSF hypocretin-1 levels without hypocretin cell loss, complicating the diagnosis.
The essential features of sleepiness in narcolepsy are recurrent daytime naps or lapses into

The essential features of sleepiness in narcolepsy are recurrent daytime naps or lapses into 
sleep. Sleepiness typically occurs daily but must occur at a minimum three times a week 
for at least 3 months (Criterion A). Narcolepsy generally produces cataplexy, which most 
commonly presents as brief episodes (seconds to minutes) of sudden, bilateral loss of mus­
cle tone precipitated by emotions, typically laughing and joking. Muscles affected may 
include those of the neck, jaw, arms, legs, or whole body, resulting in head bobbing, jaw 
dropping, or complete falls. Individuals are awake and aware during cataplexy. To meet 
Criterion Bl(a), cataplexy must be triggered by laughter or joking and must occur at least 
a few times per month when the condition is untreated or in the past.
Cataplexy should not be confused with ''weakness" occurring in the context of athletic

Cataplexy should not be confused with ''weakness" occurring in the context of athletic 
activities (physiological) or exclusively after unusual emotional triggers such as stress or 
anxiety (suggesting possible psychopathology). Episodes lasting hours or days, or those not 
triggered by emotions, are unlikely to be cataplexy, nor is rolling on the floor while laugh­
ing hysterically.
In children close to onset, genuine cataplexy can be atypical, affecting primarily the 
face, causing grimaces or jaw opening with tongue thrusting ("cataplectic faces"). Alter­
natively, cataplexy may present as low-grade continuous hypotonia, yielding a wobbling 
walk. In these cases. Criterion Bl(b) can be met in children or in individuals within 6 months 
of a rapid onset.
Narcolepsy-cataplexy nearly always results from the loss of hypothalamic hypocretin

Narcolepsy-cataplexy nearly always results from the loss of hypothalamic hypocretin 
(orexin)-producing cells, causing hypocretin deficiency (less than or equal to one-third of 
control values, or 110 pg/mL in most laboratories). Cell loss is likely autoimmune, and ap­
proximately 99% of affected individuals carry HLA-DQBl*06:02 (vs. 12%-38% of control 
subjects). Thus, checking for the presence of DQB1*06:02 prior to a lumbar puncture for eval­
uation of CSF hypocretin-1 immunoreactivity may be useful. Rarely, low CSF levels of hypo­
cretin-1 occur without cataplexy, notably in youths who may develop cataplexy later. CSF 
hypocretin -1 measurement represents the gold standard, excepting associated severe con­
ditions (neurological, inflammatory, infectious, trauma) that can interfere with the assay.

A nocturnal polysonrmographic sleep study followed by an MSLT can also be used to 
confirm the diagnosis (Criterion B3). These tests must be performed after the individual 
has stopped all psychotropic medications, following 2 weeks of adequate sleep time (as 
documented with sleep diaries, actigraphy). Short rapid eye movement (REM) latency 
(sleep-onset REM period, REM latency less than or equal to 15 minutes) during polysom­
nography is sufficient to confirm the diagnosis and meets Criterion B3. Alternatively, the 
MSLT result must be positive, showing a mean sleep latency of less than or equal to 8 min­
utes and two or more sleep-onset REM periods in four to five naps.
When sleepiness is severe, automatic behaviors may occur, with the individual continuing

When sleepiness is severe, automatic behaviors may occur, with the individual continuing 
his or her activities in a semi-automatic, hazelike fashion without memory or conscious­
ness. Approximately 20%-60% of individuals experience vivid hypnagogic hallucinations

before or upon falling asleep or hypnopompic hallucinations just after awakening. These 
hallucinations are distinct from the less vivid, nonhallucinatory dreamlike mentation at 
sleep onset that occurs in normal sleepers. Nightmares and vivid dreaming are also fre­
quent in narcolepsy, as is REM sleep behavior disorder. Approximately 20%-60% of indi­
viduals experience sleep paralysis upon falling asleep or awakening, leaving them awake 
but unable to move or speak. However, many normal sleepers also report sleep paralysis, 
especially with stress or sleep deprivation. Nocturnal eating may occur. Obesity is com­
mon. Nocturnal sleep disruption with frequent long or short awakenings is common and 
can be disabling.
Individuals may appear sleepy or fall asleep in the waiting area or during clinical ex­
amination. During cataplexy, individuals may slump in a chair and have slurred speech or 
drooping eyelids. If the clinician has time to check reflexes during cataplexy (most attacks

drooping eyelids. If the clinician has time to check reflexes during cataplexy (most attacks 
are less than 10 seconds), reflexes are abolished—an important finding distinguishing gen­
uine cataplexy from conversion disorder.
Narcolepsy-cataplexy affects 0.02%-0.04% of the general population in most countries. 
Narcolepsy affects both genders, with possibly a slight male preponderance.
Onset is typically in children and adolescents/young adults but rarely in older adults. 
Two peaks of onset are suggested, at ages 15-25 years and ages 30-35 years. Onset can be 
abrupt or progressive (over years). Severity is highest when onset is abrupt in children, 
and then decreases with age or with treatment, so that symptoms such as cataplexy can oc­
casionally disappear. Abrupt onset in young, prepubescent children can be associated

casionally disappear. Abrupt onset in young, prepubescent children can be associated 
with obesity and premature puberty, a phenotype more frequently observed since 2009. In 
adolescents, onset is more difficult to pinpoint. Onset in adults is often unclear, with some 
individuals reporting having had excessive sleepiness since birth. Once the disorder has 
manifested, the course is persistent and lifelong.
In 90% of cases, the first symptom to manifest is sleepiness or increased sleep, followed 
by cataplexy (within 1 year in 50% of cases, within 3 years in 85%). Sleepiness, hypnagogic 
hallucinations, vivid dreaming, and REM sleep behavior disorder (excessive movements 
during REM sleep) are early symptoms. Excessive sleep rapidly progresses to an inability 
to stay awake during the day, and to maintain good sleep at night, without a clear increase

to stay awake during the day, and to maintain good sleep at night, without a clear increase 
in total 24-hour sleep needs. In the first months, cataplexy may be atypical, especially in 
children. Sleep paralysis usually develops around puberty in children with prepubertal 
onset. Exacerbations of symptoms suggest lack of compliance with medications or devel­
opment of a concurrent sleep disorder, notably sleep apnea.
Young children and adolescents with narcolepsy often develop aggression or behav­
ioral problems secondary to sleepiness and/or nighttime sleep disruption. Workload and 
social pressure increase through high school and college, reducing available sleep time at 
night. Pregnancy does not seem to modify symptoms consistently. After retirement, indi­
viduals typically have more opportunity for napping, reducing the need for stimulants.

viduals typically have more opportunity for napping, reducing the need for stimulants. 
Maintaining a regular schedule benefits individuals at all ages.
Temperamental. Parasomnias, such as sleepwalking, bruxism, REM sleep behavior dis­
order, and enuresis, may be more common in individuals who develop narcolepsy. Indi­
viduals commonly report that they need more sleep than other family members.
Environmental. Group A streptococcal throat infection, influenza (notably pandemic 
H lN l 2009), or other winter infections are likely triggers of the autoimmune process, pro­

ducing narcolepsy a few months later. Head trauma and abrupt changes in sleep-wake 
patterns (e.g., job changes, stress) may be additional triggers.
Genetic and physiological. Monozygotic twins are 25%-32% concordant for narcolepsy. 
The prevalence of narcolepsy is l%-2% in first-degree relatives (a 10- to 40-fold increase 
overall). Narcolepsy is strongly associated with DQB1*06:02 (99% vs. 12%-38% in control 
subjects of various ethnic groups; 25% in the general U.S. population). DQB1*03:01 in­
creases, while DQBl’ OSiOl, DQBl’ OôiOl, and DQB1*06:03 reduce risk in the presence of 
DQB1’ ^06:02, but the effect is small. Polymorphisms within the T-cell receptor alpha gene 
and other immune modulating genes also modulate risk slightly.
Narcolepsy has been described in all ethnic groups and in many cultures. Among African 
Americans, more cases present without cataplexy or with atypical cataplexy, complicating

Americans, more cases present without cataplexy or with atypical cataplexy, complicating 
diagnosis, especially in the presence of obesity and obstructive sleep apnea.
Functional imaging suggests impaired hypothalamic responses to humorous stimuli. 
Nocturnal polysomnography followed by an MSLT is used to confirm the diagnosis of 
narcolepsy, especially when the disorder is first being diagnosed and before treatment has 
begun, and if hypocretin deficiency has not been documented biochemically. The poly­
somnography/MSLT should be performed after the individual is no longer taking any 
psychotropic drugs and after regular sleep-wake patterns, without shift work or sleep de­
privation, have been documented.
A sleep-onset REM period during the polysomnography (REM sleep latency less than 
or equal to 15 minutes) is highly specific (approximately 1% positive in control subjects)

or equal to 15 minutes) is highly specific (approximately 1% positive in control subjects) 
but moderately sensitive (approximately 50%). A positive MSLT result displays an aver­
age sleep latency of less than or equal to 8 minutes, and sleep-onset REM periods in two or 
more naps on a four- or five-nap test. The MSLT result is positive in 90%-95% of individ­
uals with narcolepsy versus 2%-4% of control subjects or individuals with other sleep dis­
orders. Additional polysomnographic findings often include frequent arousals, decreased 
sleep efficiency, and increased stage 1 sleep. Periodic limb movements (found in about 
40% of individuals with narcolepsy) and sleep apnea are often noted.
Hypocretin deficiency is demonstrated by measuring CSF hypocretin-1 immunoreac- 
tivity. The test is particularly useful in individuals with suspected conversion disorder

tivity. The test is particularly useful in individuals with suspected conversion disorder 
and those without typical cataplexy, or in treatment-refractory cases. The diagnostic value 
of the test is not affected by medications, sleep deprivation, or circadian time, but the find­
ings are uninteφretable when the individual is severely ill with a concurrent infection or 
head trauma or is comatose. CSF cytology, protein, and glucose are within normal range 
even when sampled within weeks of rapid onset. CSF hypocretin-1 in these incipient cases 
is typically already very diminished or undetectable.
Functional Consequences of Narcolepsy
Driving and working are impaired, and individuals with narcolepsy should avoid jobs 
that place themselves (e.g., working with machinery) or others (e.g., bus driver, pilot) in 
danger. Once the narcolepsy is controlled with therapy, patients can usually drive, al­

though rarely long distances alone. Untreated individuals are also at risk for social isola­
tion and accidental injury to themselves or others. Social relations may suffer as these 
individuals strive to avert cataplexy by exerting control over emotions.
Other hypersomnias. Hypersomnolence and narcolepsy are similar with respect to the 
degree of daytime sleepiness, age at onset, and stable course over time but can be distin­

guished based on distinctive clinical and laboratory features. Individuals with hypersom­
nolence typically have longer and less disrupted nocturnal sleep, greater difficulty 
awakening, more persistent daytime sleepiness (as opposed to more discrete "sleep at­
tacks" in narcolepsy), longer and less refreshing daytime sleep episodes, and little or no 
dreaming during daytime naps. By contrast, individuals with narcolepsy have cataplexy 
and recurrent intrusions of elements of REM sleep into the transition between sleep and 
wakefulness (e.g., sleep-related hallucinations and sleep paralysis). The MSLT typically 
demonstrates shorter sleep latencies (i.e., greater physiological sleepiness) as well as the 
presence of multiple sleep-onset REM periods in individuals with narcolepsy.
Sleep deprivation and insufficient nocturnal sleep. Sleep deprivation and insufficient 
nocturnal sleep are common in adolescents and shift workers. In adolescents, difficulties

nocturnal sleep are common in adolescents and shift workers. In adolescents, difficulties 
falling asleep at night are common, causing sleep deprivation. The MSLT result may be 
positive if conducted while the individual is sleep deprived or while his or her sleep is 
phase delayed.
Sleep apnea syndromes. Sleep apneas are especially likely in the presence of obesity. 
Because obstructive sleep apnea is more frequent than narcolepsy, cataplexy may be over­
looked (or absent), and the individual is assumed to have obstructive sleep apnea unre­
sponsive to usual therapies.
Major depressive disorder. Narcolepsy or hypersomnia may be associated or confused 
with depression. Cataplexy is not present in depression. The MSLT results are most often 
normal, and there is dissociation between subjective and objective sleepiness, as measured 
by the mean sleep latency during the MSLT.

Conversion disorder (functional neurological symptom disorder). Atypical features, 
such as long-lasting cataplexy or unusual triggers, may be present in conversion disorder 
(functional neurological symptom disorder). Individuals may report sleeping and dream­
ing, yet the MSLT does not show the characteristic sleep-onset REM period. Full-blown, 
long-lasting pseudocataplexy may occur during consultation, allowing the examining 
physician enough time to verify reflexes, which remain intact.
Attention-deficit/hyperactivity disorder or other behavioral problems. In children and 
adolescents, sleepiness can cause behavioral problems, including aggressiveness and in­
attention, leading to a misdiagnosis of attention-deficit/hyperactivity disorder.
Seizures. In young children, cataplexy can be misdiagnosed as seizures. Seizures are not

Seizures. In young children, cataplexy can be misdiagnosed as seizures. Seizures are not 
conmionly triggered by emotions, and when they are, the trigger is not usually laughing or 
joking. During a seizure, individuals are more likely to hurt themselves when falling. Sei­
zures characterized by isolated atonia are rarely seen in isolation of other seizures, and 
they also have signatures on the electroencephalogram.
Chorea and movement disorders. In young children, cataplexy can be misdiagnosed as 
chorea or pediatric autoimmune neuropsychiatric disorders associated with streptococcal 
infections, especially in the context of a strep throat infection and high antistreptolysin O 
antibody levels. Some children may have an overlapping movement disorder close to on­
set of the cataplexy.
Schizophrenia. In the presence of florid and vivid hypnagogic hallucinations, individuals

Schizophrenia. In the presence of florid and vivid hypnagogic hallucinations, individuals 
may think these experiences are real—a feature that suggests schizophrenia. Similarly, 
with stimulant treatment, persecutory delusions may develop. If cataplexy is present, the 
clinician should first assume that these symptoms are secondary to narcolepsy before con­
sidering a co-occurring diagnosis of schizophrenia.
Narcolepsy can co-occur with bipolar, depressive, and anxiety disorders, and in rare cases 
with schizophrenia. Narcolepsy is also associated with increased body mass index or obe­

sity, especially when the narcolepsy is untreated. Rapid weight gain is common in young 
children with a sudden disease onset. Comorbid sleep apnea should be considered if there 
is a sudden aggravation of preexisting narcolepsy.
The International Classification of Sleep Disorders,  2nd Edition (ICSD-2), differentiates five 
subtypes of narcolepsy.
Breathing-Related Sleep Disorders
The breathing-related sleep disorders category encompasses three relatively distinct dis­
orders: obstructive sleep apnea hypopnea, central sleep apnea, and sleep-related hypo­
ventilation.
Obstructive Sleep Apnea Hypopnea
Diagnostic Criteria 327.23 (G47.33)
A. Either (1) or (2):
1. Evidence by polysomnography of at least five obstructive apneas or hypopneas per  
hour of sleep and either of the following sleep symptoms:
a. Nocturnal breathing disturbances: snoring, snorting/gasping, or breathing  
pauses during sleep.

b. Daytime sleepiness, fatigue, or unrefreshing sleep despite sufficient opportuni­
ties to sleep that is not better explained by another mental disorder (including a  
sleep disorder) and is not attributable to another medical condition.
2. Evidence by polysomnography of 15 or more obstructive apneas and/or hypopneas  
per hour of sleep regardless of accompanying symptoms.
Mild: Apnea hypopnea index is less than 15.
■Moderate: Apnea hypopnea Index is 15-30.
Severe: Apnea hypopnea index is greater than 30.
Disease severity is measured by a count of the number of apneas plus hypopneas per hour 
of sleep (apnea hypopnea index) using polysomnography or other overnight monitoring. 
Overall severity is also informed by levels of nocturnal desaturation and sleep fragmen­

tation (measured by brain cortical arousal frequency and sleep stages) and degree of as­
sociated symptoms and daytime impairment. However, the exact number and thresholds 
may vary according to the specific measurement techniques used, and these numbers may 
change over time. Regardless of the apnea hypopnea index (count) per se, the disorder is 
considered to be more severe when apneas and hypopneas are accompanied by significant 
oxygen hemoglobin desaturation (e.g., when more than 10% of the sleep time is spent at 
desaturation levels of less than 90%) or when sleep is severely fragmented as shown by an

elevated arousal index (arousal index greater than 30) or reduced stages in deep sleep (e.g., 
percentage stage N3 [slow-v^ave sleep] less than 5%).
Obstructive sleep apnea hypopnea is the most common breathing-related sleep disorder. 
It is characterized by repeated episodes of upper (pharyngeal) airw ^ay obstruction (apneas 
and hypopneas) during sleep. Apnea refers to the total absence of airflow, and hypopnea  re­
fers to a reduction in airflow. Each apnea or hypopnea represents a reduction in breathing 
of at least 10 seconds in duration in adults or two missed breaths in children and is typi­
cally associated with drops in oxygen saturation of 3% or greater and/or an electroenceph- 
alographic arousal. Both sleep-related (nocturnal) and wake-time symptoms are common. 
The cardinal symptoms of obstructive sleep apnea hypopnea are snoring and daytime 
sleepiness.
Obstructive sleep apnea hypopnea in adults is diagnosed on the basis of polysom-

Obstructive sleep apnea hypopnea in adults is diagnosed on the basis of polysom- 
nographic findings and symptoms. The diagnosis is based on symptoms of 1) nocturnal 
breathing disturbances (i.e., snoring, snorting/gasping, breathing pauses during sleep), or 
2) daytime sleepiness, fatigue, or unrefreshing sleep despite sufficient opportunities to 
sleep that are not better explained by another mental disorder and not attributable to an­
other medical condition, along with 3) evidence by polysomnography of five or more ob­
structive apneas or hypopneas per hour of sleep (Criterion Al). Diagnosis can be made in 
the absence of these symptoms if there is evidence by polysomnography of 15 or more ob­
structive apneas and/or hypopneas per hour of sleep (Criterion A2).
Specific attention to disturbed sleep occurring in association with snoring or breathing

Specific attention to disturbed sleep occurring in association with snoring or breathing 
pauses and physical findings that increase risk of obstructive sleep apnea hypopnea (e.g., 
central obesity, crowded pharyngeal airway, elevated blood pressure) is needed to reduce 
the chance of misdiagnosing this treatable condition.
Because of the frequency of nocturnal awakenings that occur with obstructive sleep apnea 
hypopnea, individuals may report symptoms of insomnia. Other common, though non­
specific, symptoms of obstructive sleep apnea hypopnea are heartburn, nocturia, morning 
headaches, dry mouth, erectile dysfunction, and reduced libido. Rarely, individuals may 
complain of difficulty breathing while lying supine or sleeping. Hypertension may occur 
in more than 60% of individuals with obstructive sleep apnea hypopnea.

Obstructive sleep apnea hypopnea is a very common disorder, affecting at least l% - 2% of 
children, 2%-15% of middle-age adults, and more than 20% of older individuals. In the 
general community, prevalence rates of undiagnosed obstructive sleep apnea hypopnea 
may be very high in elderly individuals. Since the disorder is strongly associated with obe­
sity, increases in obesity rates are likely to be accompanied by an increased prevalence of 
this disorder. Prevalence may be particularly high among males, older adults, and certain 
racial/ethnic groups. In adults, the male-to-female ratio of obstructive sleep apnea hypop­
nea ranges from 2:1 to 4:1. Gender differences decline in older age, possibly because of an 
increased prevalence in females after menopause. There is no gender difference among

increased prevalence in females after menopause. There is no gender difference among 
prepubertal children.
The age distribution of obstructive sleep apnea hypopnea likely follows a J-shaped distri­
bution. There is a peak in children ages 3-8 years when the nasopharynx may be compro­
mised by a relatively large mass of tonsillar tissue compared with the size of the upper

airway. With growth of the airway and regression of lymphoid tissue during later child­
hood, there is reduction in prevalence. Then, as obesity prevalence increases in midlife and 
females enter menopause, obstructive sleep apnea hypopnea again increases. The course 
in older age is unclear; the disorder may level off after age 65 years, but in other individ­
uals, prevalence may increase with aging. Because there is some age dependency of the oc­
currence of apneas and hypopneas, polysomnographic results must be interpreted in light 
of other clinical data. In particular, significant clinical symptoms of insomnia or hyper­
somnia should be investigated regardless of the individual's age.
Obstructive sleep apnea hypopnea usually has an insidious onset, gradual progression, 
and persistent course. Typically the loud snoring has been present for many years, often since 
childhood, but an increase in its severity may lead the individual to seek evaluation. Weight

childhood, but an increase in its severity may lead the individual to seek evaluation. Weight 
gain may precipitate an increase in symptoms. Although obstructive sleep apnea hypopnea 
can occur at any age, it most commonly manifests among individuals ages 40-60 years. Over 
4-5 years, the average apnea hypopnea index increases in adults and older individuals by ap­
proximately two apneas/hypopneas per hour. The apnea hypopnea index is increased and in­
cident obstructive sleep apnea hypopnea is greater among individuals who are older, who are 
male, or who have a higher baseline body mass index (BMI) or increase their BMI over time. 
Spontaneous resolution of obstructive sleep apnea hypopnea has been reported with weight 
loss, particularly after bariatric surgery. In children, seasonal variation in obstructive sleep ap­

nea hypopnea has been observed, as has improvement with overall growth.
In young children, the signs and symptoms of obstructive sleep apnea hypopnea may be 
more subtle than in adults, making diagnosis more difficult to establish. Polysomnography is 
useful in confirming diagnosis. Evidence of fragmentation of sleep on the polysomnogram 
may not be as apparent as in studies of older individuals, possibly because of the high homeo­
static drive in young individuals. Symptoms such as snoring are usually parent-reported and 
thus have reduced sensitivity. Agitated arousals and unusual sleep postures, such as sleeping 
on the hands and knees, may occur. Nocturnal enuresis also may occur and should raise the

on the hands and knees, may occur. Nocturnal enuresis also may occur and should raise the 
suspicion of obstructive sleep apnea hypopnea if it recurs in a child who was previously dry at 
night. Children may also manifest excessive daytime sleepiness, although this is not as com­
mon or pronounced as in adults. Daytime mouth breathing, difficulty in swallowing, and poor 
speech articulation are also common features in children. Children younger than 5 years more 
often present with nighttime symptoms, such as observed apneas or labored breathing, than 
with l^havioral symptoms (i.e., the nighttime symptoms are more noticeable and more often 
bring the child to clinical attention). In children older than 5 years, daytime symptoms such as 
sleepiness and behavioral problems (e.g., impulsivity and hyperactivity), attention-deficit/

sleepiness and behavioral problems (e.g., impulsivity and hyperactivity), attention-deficit/ 
hyperactivity disorder, learning difficulties, and morning headaches are more often the focus 
of concern. Children with obstructive sleep apnea hypopnea also may present with failure to 
thrive and developmental delays. In young children, obesity is a less common risk factor, 
while delayed growth and "failure to thrive" may be present.
Genetic and physiological. The major risk factors for obstructive sleep apnea hypopnea 
are obesity and male gender. Others include maxillary-mandibular retrognathia or micro­
gnathia, positive family history of sleep apnea, genetic syndromes that reduce upper 
airway patency (e.g., Down's syndrome, Treacher Collin's syndrome), adenotonsillar hy­
pertrophy (especially in young children), menopause (in females), and various endocrine

pertrophy (especially in young children), menopause (in females), and various endocrine 
syndromes (e.g., acromegaly). Compared with premenopausal females, males are at in­
creased risk for obstructive sleep apnea hypopnea, possibly reflecting the influences of sex 
hormones on ventilatory control and body fat distribution, as well as because of gender 
differences in airway structure. Medications for mental disorders and medical conditions 
that tend to induce somnolence may worsen the course of apnea symptoms if these med­
ications are not managed carefully.

Obstructive sleep apnea hypopnea has a strong genetic basis, as evidenced by the sig­
nificant familial aggregation of the apnea hypopnea index. The prevalence of obstructive 
sleep apnea hypopnea is approximately twice as high among the first-degree relatives of 
probands with obstructive sleep apnea hypopnea as compared with members of control 
families. One-third of the variance in the apnea hypopnea index is explained by shared fa­
milial factors. Although genetic markers with diagnostic or prognostic value are not yet 
available for use, eliciting a family history of obstructive sleep apnea hypopnea should in­
crease the clinical suspicion for the disorder.
There is a potential for sleepiness and fatigue to be reported differently across cultures. In 
some groups, snoring may be considered a sign of health and thus may not trigger con­
cerns. Individuals of Asian ancestry may be at increased risk for obstructive sleep apnea

cerns. Individuals of Asian ancestry may be at increased risk for obstructive sleep apnea 
hypopnea despite relatively low BMI, possibly reflecting the influence of craniofacial risk 
factors that narrow the nasopharynx.
Gender-Related Issues
Females may more commonly report fatigue rather than sleepiness and may underreport 
snoring.
Polysomnography provides quantitative data on frequency of sleep-related respiratory 
disturbances and associated changes in oxygen saturation and sleep continuity. Polysom­
nographie findings in children differ from those in adults in that children demonstrate 
labored breathing, partial obstructive hypoventilation with cyclical desaturations, hyper- 
capnia and paradoxical movements. Apnea hypopnea index levels as low as 2 are used to 
define thresholds of abnormality in children.

Arterial blood gas measurements while the individual is awake are usually normal, but 
some individuals can have waking hypoxemia or hypercapnia. This pattern should alert the 
clinician to the possibility of coexisting lung disease or hypoventilation. Imaging procedures 
may reveal narrowing of the upper airway. Cardiac testing may show evidence of impaired 
ventricular function. Individuals with severe nocturnal oxygen desaturation may also have el­
evated hemoglobin or hematocrit values. Validated sleep measures (e.g., multiple sleep la­
tency test [MSLT], maintenance of wakefulness test) may identify sleepiness.
More than 50% of individuals with moderate to severe obstructive sleep apnea hypopnea 
report symptoms of daytime sleepiness. A twofold increased risk of occupational accidents

report symptoms of daytime sleepiness. A twofold increased risk of occupational accidents 
has been reported in association with symptoms of snoring and sleepiness. Motor vehicle 
crashes also have been reported to be as much as sevenfold higher among individuals with 
elevated apnea hypopnea index values. Clinicians should be cognizant of state govern­
ment requirements for reporting this disorder, especially in relationship to commercial 
drivers. Reduced scores on measures of health-related quality of life are common in individ­
uals with obstructive sleep apnea hypopnea, with the largest decrements observed in the 
physical and vitality subscales.
Primary snoring and other sleep disorders. Individuals with obstructive sleep apnea 
hypopnea must be differentiated from individuals with primary snoring (i.e., otherwise

asjnnptomatic individuals who snore and do not have abnormalities on overnight polysom­
nography). Individuals with obstructive sleep apnea hypopnea may additionally report 
nocturnal gasping and choking. The presence of sleepiness or other daytime symptoms 
not explained by other etiologies suggests the diagnosis of obstructive sleep apnea hypop­
nea, but this differentiation requires polysomnography. Definitive differential diagnosis 
between hypersomnia, central sleep apnea, sleep-related hypoventilation, and obstructive 
sleep apnea hypopnea also requires polysomnographic studies.
Obstructive sleep apnea hypopnea must be differentiated from other causes of sleepi­
ness, such as narcolepsy, hypersonmia, and circadian rhythm sleep disorders. Obstructive 
sleep apnea hypopnea can be differentiated from narcolepsy by the absence of cataplexy, 
sleep-related hallucinations, and sleep paralysis and by the presence of loud snoring,

sleep-related hallucinations, and sleep paralysis and by the presence of loud snoring, 
gasping during sleep, or observed apneas in sleep. Daytime sleep episodes in narcolepsy 
are characteristically shorter, more refreshing, and more often associated with dreaming. 
Obstructive sleep apnea hypopnea shows characteristic apneas and hypopneas and oxy­
gen desaturation during nocturnal polysomnographic studies. Narcolepsy results in mul­
tiple sleep-onset rapid eye movement (REM) periods during the MSLT. Narcolepsy, like 
obstructive sleep apnea hypopnea, may be associated with obesity, and some individuals 
have concurrent narcolepsy and obstructive sleep apnea hypopnea. A diagnosis of narco­
lepsy does not exclude the diagnosis of obstructive sleep apnea hypopnea, as the two con­
ditions may co-occur.
Insomnia disorder. For individuals complaining of difficulty initiating or maintaining

Insomnia disorder. For individuals complaining of difficulty initiating or maintaining 
sleep or early-moming awakenings, insomnia disorder can be differentiated from obstruc­
tive sleep apnea hypopnea by the absence of snoring and the absence of the history, signs, 
and symptoms characteristic of the latter disorder. However, insomnia and obstructive 
sleep apnea hypopnea may coexist, and if so, both disorders may need to be addressed 
concurrently to improve sleep.
Panic attacks. Nocturnal panic attacks may include symptoms of gasping or choking 
during sleep that may be difficult to distinguish clinically from obstructive sleep apnea hy­
popnea. However, the lower frequency of episodes, intense autonomic arousal, and lack of 
excessive sleepiness differentiate nocturnal panic attacks from obstructive sleep apnea hy­

popnea. Polysomnography in individuals with nocturnal panic attacks does not reveal the 
typical pattern of apneas or oxygen desaturation characteristic of obstructive sleep apnea 
hypopnea. Individuals with obstructive sleep apnea hypopnea do not provide a history of 
daytime panic attacks.
Attention-deficit/hyperactivity disorder. Attention-defidt/hyperactivity disorder in chil­
dren may include symptoms of inattention, academic impairment, hyperactivity, and in­
ternalizing behaviors, all of which may also be symptoms of childhood obstructive sleep 
apnea hypopnea. The presence of other symptoms and signs of childhood obstructive 
sleep apnea hypopnea (e.g., labored breathing or snoring during sleep and adenotonsillar 
hypertrophy) would suggest the presence of obstructive sleep apnea hypopnea. Obstruc­

tive sleep apnea hypopnea and attention-deficit/hyperactivity disorder may commonly 
co-occur, and there may be causal links between them; therefore, risk factors such as en­
larged tonsils, obesity, or a family history of sleep apnea may help alert the clinician to 
their co-occurrence.
Substance/medication-induced insomnia or hypersomnia. Substance use and substance 
withdrawal (including medications) can produce insomnia or hypersomnia. A careful his­
tory is usually sufficient to identify the relevant substance/medication, and follow-up 
shows improvement of the sleep disturbance after discontinuation of the substance/med­
ication. In other cases, the use of a substance/medication (e.g., alcohol, barbiturates, ben­
zodiazepines, tobacco) has been shown to exacerbate obstructive sleep apnea hypopnea.

zodiazepines, tobacco) has been shown to exacerbate obstructive sleep apnea hypopnea. 
An individual with symptoms and signs consistent with obstructive sleep apnea hypop-

nea should receive that diagnosis, even in the presence of concurrent substance use that is
exacerbating the condition.
\
Systemic hypertension, coronary artery disease, heart failure, stroke, diabetes, and increased 
mortality are consistently associated with obstructive sleep apnea hypopnea. Risk esti­
mates vary from 30% to as much as 300% for moderate to severe obstructive sleep apnea 
hypopnea. Evidence of pulmonary hypertension and right heart failure (e.g., cor pulmo­
nale, ankle edema, hepatic congestion) are rare in obstructive sleep apnea hypopnea and 
when present indicate either very severe disease or associated hypoventilation or cardio­
pulmonary comorbidities. Obstructive sleep apnea hypopnea also may occur with in­
creased frequency in association with a number of medical or neurological conditions (e.g., 
cerebrovascular disease, Parkinson's disease). Physical findings reflect the co-occurrence of 
these conditions.

As many as one-third of individuals referred for evaluation of obstructive sleep apnea 
hypopnea report symptoms of depression, with as many of 10% having depression scores 
consistent with moderate to severe depression. Severity of obstructive sleep apnea hypop­
nea, as measured by the apnea hypopnea index, has been foimd to be correlated w i^ se­
verity of symptoms of depression. This association may be stronger in males than in 
females.
Reiationsliip to internationai Ciassification of  
Sieep Disorders
The International Classification of Sleep Disorders,  2nd Edition (ICSD-2), differentiates 11 sub­
types of "sleep-related breathing disorders," including primary central sleep apnea, ob­
structive sleep apnea, and sleep-related hypoventilation.
Central Sleep Apnea
A. Evidence by polysomnography of five or more central apneas per hour of sleep.

B. The disorder is not better explained by another current sleep disorder.
327.21 (G47.31) Idiopathic central sleep apnea: Characterized by repeated epi­
sodes of apneas and hypopneas during sleep caused by variability in respiratory effort  
but without evidence of ainway obstruction.
786.04 (R06.3) Clieyne-Stokes breathing: A pattern of periodic crescendo-  
decrescendo variation in  tidal volume that results in central apneas and hypopneas at  
a frequency of at least five events per hour, accompanied by frequent arousal.
780.57 (G47.37) Central sleep apnea comorbid with opioid use: The pathogenesis  
of this subtype is attributed to the effects of opioids on the respiratory rhythm genera­
tors in the medulla as well as the differential effects on hypoxic versus hypercapnic re­

spiratory drive.
Coding note (for 780.57 [G47.37] code only): When an opioid use disorder is present, first  
code the opioid use disorder: 305.50 (F11.10) mild opioid use disorder or 304.00 (F11.20)  
moderate or severe opioid use disorder; then code 780.57 (G47.37) central sleep apnea  
comorbid with opioid use. When an opioid use disorder is not present (e.g., after a one­
time heavy use of the substance), code only 780.57 (G47.37) central sleep apnea comor­
bid with opioid use.

Note: See the section “Diagnostic Features”  in text.
Severity of central sleep apnea is graded according to the frequency of the breathing  
disturbances as well as the extent of associated oxygen desaturation and sleep frag­
mentation that occur as a consequence of repetitive respiratory disturbances.
Subtypes
Idiopathic central sleep apnea and Cheyne-Stokes breathing are characterized by increased 
gain of the ventilatory control system, also referred to as high loop gain,  which leads to in­
stability in ventilation and PaC 02 levels. This instability is termed periodic breathing  and 
can be recognized by hyperventilation alternating with hypoventilation. Individuals with 
these disorders typically have pC 02 levels while awake that are slightly hypocapneic or 
normocapneic. Central sleep apnea may also manifest during initiation of treatment of ob­
structive sleep apnea hypopnea or may occur in association with obstructive sleep apnea

structive sleep apnea hypopnea or may occur in association with obstructive sleep apnea 
hypopnea syndrome (termed complex sleep apnea).  The occurrence of central sleep apnea in 
association with obstructive sleep apnea is also considered to be due to high loop gain. In 
contrast, the pathogenesis of central sleep apnea comorbid with opioid use has been at­
tributed to the effects of opioids on the respiratory rhythm generators in the medulla as 
well as to its differential effects on hypoxic versus hypercapneic respiratory drive. These 
individuals may have elevated pC 02 levels while awake. Individuals receiving chronic 
methadone maintenance therapy have been noted to have increased sonmolence and de­
pression, although the role of breathing disorders associated with opioid medication in caus­
ing these problems has not been studied.

An increase in the central apnea index (i.e., number of central apneas per hour of sleep) re­
flects an increase in severity of central sleep apnea. Sleep continuity and quality may be 
markedly impaired with reductions in restorative stages of non-rapid eye movement (REM) 
sleep (i.e., decreased slow-wave sleep [stage N3]). In individuals with severe Cheyne- 
Stokes breathing, the pattern can also be observed during resting wakefulness, a finding 
that is thought to be a poor prognostic marker for mortality.
Central sleep apnea disorders are characterized by repeated episodes of apneas and hy- 
popneas during sleep caused by variability in respiratory effort. These are disorders of 
ventilatory control in which respiratory events occur in a periodic or intermittent pattern.

ventilatory control in which respiratory events occur in a periodic or intermittent pattern. 
Idiopathic central sleep apnea  is characterized by sleepiness, insomnia, and awakenings due 
to dyspnea in association with five or more central apneas per hour of sleep. Central sleep 
apnea occurring in individuals with heart failure, stroke, or renal failure typically have a 
breathing pattern called Cheyne-Stokes breathing,  which is characterized by a pattern of 
periodic crescendo-decrescendo variation in tidal volume that results in central apneas 
and hypopneas occurring at a frequency of at least five events per hour that are accompa­
nied by frequent arousals. Central and obstructive sleep apneas may coexist; the ratio of 
central to obstructive apneas/hypopneas may be used to identify which condition is pre­
dominant.

dominant.
Alterations in neuromuscular control of breathing can occur in association with med­
ications or substances used in individuals with mental health conditions, which can cause 
or exacerbate impairments of respiratory rhythm and ventilation. Individuals taking these 
medications have a sleep-related breathing disorder that could contribute to sleep distur­
bances and symptoms such as sleepiness, confusion, and depression. Specifically, chronic

use of long-acting opioid medications  is often associated with impairment of respiratory con­
trol leading to central sleep apnea.
Individuals with central sleep apnea hypopneas can manifest with sleepiness or insomnia. 
There can be complaints of sleep fragmentation, including awakening with dyspnea. 
Some individuals are asymptomatic. Obstructive sleep apnea hypopnea can coexist with 
Cheyne-Stokes breathing, and thus snoring and abruptly terminating apneas may be ob­
served during sleep.
The prevalence of idiopathic central sleep apnea is unknown but thought to be rare. The 
prevalence of Cheyne-Stokes breathing is high in individuals with depressed cardiac ven­
tricular ejection fraction. In individuals with an ejection fraction of less than 45%, the prev­
alence has been reported to be 20% or higher. The male-to-female ratio for prevalence is 
even more highly skewed toward males than for obstructive sleep apnea hypopnea. Prev­

alence increases with age, and most patients are older than 60 years. Cheyne-Stokes breath­
ing occurs in approximately 20% of individuals with acute stroke. Central sleep apnea 
comorbid with opioid use occurs in approximately 30% of individuals taking chronic opi­
oids for nonmalignant pain and similarly in individuals receiving methadone mainte­
nance therapy.
The onset of Cheyne-Stokes breathing appears tied to the development of heart failure. The 
Cheyne-Stokes breathing pattern is associated with oscillations in heart rate, blood pres­
sure and oxygen desaturation, and elevated sympathetic nervous system activity that can 
promote progression of heart failure. The clinical significance of Cheyne-Stokes breathing

promote progression of heart failure. The clinical significance of Cheyne-Stokes breathing 
in the setting of stroke is not known, but Cheyne-Stokes breathing may be a transient find­
ing that resolves with time after acute stroke. Central sleep apnea comorbid with opioid 
use has been documented with chronic use (i.e., several months).
Genetic and physiological. Cheyne-Stokes breathing is frequently present in individu­
als with heart failure. The coexistence of atrial fibrillation further increases risk, as do older 
age and male gender. Cheyne-Stokes breathing is also seen in association with acute stroke 
and possibly renal failure. The underlying ventilatory instability in the setting of heart fail­
ure has been attributed to increased ventilatory chemosensitivity and hyperventilation

ure has been attributed to increased ventilatory chemosensitivity and hyperventilation 
due to pulmonary vascular congestion and circulatory delay. Central sleep apnea is seen 
in individuals taking long-acting opioids.
Diagnostic l\/larl(ers
Physical findings seen in individuals with a Cheyne-Stokes breathing pattern relate to its 
risk factors. Findings consistent with heart failure, such as jugular venous distension, S 3 
heart sound, lung crackles, and lower extremity edema, may be present. Polysonmogra- 
phy is used to characterize the breathing characteristics of each breathing-related sleep 
disorder subtype. Central sleep apneas are recorded when periods of breathing cessation 
for longer than 10 seconds occur. Cheyne-Stokes breathing is characterized by a pattern of 
periodic crescendo-decrescendo variation in tidal volume that results in central apneas

nied by frequent arousals. The cycle length of Cheyne-Stokes breathing (or time from end 
of one central apnea to the end of the next apnea) is about 60 seconds.

Functional Consequences of Central Sleep Apnea
Idiopathic central sleep apnea has been reported to cause symptoms of disrupted sleep, in­
cluding insomnia and sleepiness. Cheyne-Stokes breathing with comorbid heart failure 
has been associated with excessive sleepiness, fatigue, and insomnia, although many in­
dividuals may be asymptomatic. Coexistence of heart failure and Cheyne-Stokes breath­
ing may be associated with increased cardiac arrhythmias and increased mortality or 
cardiac transplantation. Individuals with central sleep apnea comorbid with opioid use 
may present with symptoms of sleepiness or insomnia.
Idiopathic central sleep apnea must be distinguished from other breathing-related sleep 
disorders, other sleep disorders, and medical conditions and mental disorders that cause 
sleep fragmentation, sleepiness, and fatigue. This is achieved using polysomnography.
Other breathing-related sleep disorders and sleep disorders. Central sleep apnea can

Other breathing-related sleep disorders and sleep disorders. Central sleep apnea can 
be distinguished from obstructive sleep apnea hypopnea by the presence of at least five 
central apneas per hour of sleep. These conditions may co-occur, but central sleep apnea is 
considered to predominate when the ratio of central to obstructive respiratory events ex­
ceeds 50%.
Cheyne-Stokes breathing can be distinguished from other mental disorders, including 
other sleep disorders, and other medical conditions that cause sleep fragmentation, sleep­
iness, and fatigue based on the presence of a predisposing condition (e.g., heart failure or 
stroke) and signs and polysomnographic evidence of the characteristic breathing pattern. 
Polysomnographie respiratory findings can help distinguish Cheyne-Stokes breathing 
from insomnia due to other medical conditions. High-altitude periodic breathing has a

from insomnia due to other medical conditions. High-altitude periodic breathing has a 
pattern that resembles Cheyne-Stokes breathing but has a shorter cycle time, occurs only 
at high altitude, and is not associated with heart failure.
Central sleep apnea comorbid with opioid use can be differentiated from other types of 
breathing-related sleep disorders based on the use of long-acting opioid medications in 
conjunction with polysomnographic evidence of central apneas and periodic or ataxic 
breathing. It can be distinguished from insomnia due to drug or substance use based on 
polysomnographic evidence of central sleep apnea.
Central sleep apnea disorders are frequently present in users of long-acting opioids, such 
as methadone. Individuals taking these medications have a sleep-related breathing disor­

der that could contribute to sleep disturbances and symptoms such as sleepiness, confu­
sion, and depression. While the individual is asleep, breathing patterns such as central 
apneas, periodic apneas, and ataxic breathing may be observed. Obstructive sleep apnea 
hypopnea may coexist with central sleep apnea, and features consistent with this condi­
tion can also be present (see 'Obstructive Sleep Apnea Hypopnea" earlier in this chapter). 
Cheyne-Stokes breathing is more commonly observed in association with conditions that 
include heart failure, stroke, and renal failure and is seen more frequently in individuals 
with atrial fibrillation. Individuals with Cheyne-Stokes breathing are more likely to be 
older, to be male, and to have lower weight than individuals with obstructive sleep apnea

older, to be male, and to have lower weight than individuals with obstructive sleep apnea 
hypopnea.

Sleep-Related Hypoventilation
--------------------1 -------------------------------------------------------------------------------------------
A. Polysomnograpy demonstrates episodes of decreased respiration associated with el­
evated CO 2 levels. (Note: In the absence of objective measurement of CO 2, persistent  
low levels of hemoglobin oxygen saturation unassociated with apneic/hypopneic  
events may indicate hypoventilation.)
B. The disturbance is not better explained by another current sleep disorder.
327.24 (G47.34) Idiopathic liypoventilation: This subtype is not attributable to any  
readily identified condition.
327.25 (G47.35) Congenital central alveolar hypoventilation: This subtype is a rare  
congenital disorder in which the individual typically presents in the perinatal period with  
shallow breathing, or cyanosis and apnea during sleep.
327.26 (G47.36) Comorbid sleep-related hypoventilation: This subtype occurs as a

327.26 (G47.36) Comorbid sleep-related hypoventilation: This subtype occurs as a  
consequence of a medical condition, such as a pulmonary disorder (e.g., interstitial  
lung disease, chronic obstructive pulmonary disease) or a neuromuscular or chest wall  
disorder (e.g., muscular dystrophies, postpolio syndrome, cervical spinal cord injury,  
kyphoscoliosis), or medications (e.g., benzodiazepines, opiates). It also occurs with  
obesity (obesity hypoventilation disorder), where it reflects a combination of increased  
work of breathing due to reduced chest wall compliance and ventilation-perfusion mis­
match and variably reduced ventilatory drive. Such individuals usually are character­
ized by body mass index of greater than 30 and hypercapnia during wakefulness (with  
a PCO 2 of greater than 45), without other evidence of hypoventilation.

Severity is graded according to the degree of hypoxemia and hypercarbia present dur­
ing sleep and evidence of end organ impairment due to these abnormalities (e.g., right­
sided heart failure). The presence of blood gas abnormalities during wakefulness is an  
indicator of greater severity.
Subtypes
Regarding obesity hypoventilation disorder, the prevalence of obesity hypoventilation in 
the general population is not known but is thought to be increasing in association with the 
increased prevalence of obesity and extreme obesity.
Sleep-related hypoventilation can occur independently or, more frequently, comorbid 
with medical or neurological disorders, medication use, or substance use disorder. Al­
though symptoms are not mandatory to make this diagnosis, individuals often report

though symptoms are not mandatory to make this diagnosis, individuals often report 
excessive daytime sleepiness, frequent arousals and awakenings during sleep, morning 
headaches, and insomnia complaints.
Individuals with sleep-related hypoventilation can present with sleep-related complaints 
of insomnia or sleepiness. Episodes of orthopnea can occur in individuals with diaphragm 
weakness. Headaches upon awakening may be present. During sleep, episodes of shallow 
breathing may be observed, and obstructive sleep apnea hypopnea or central sleep apnea 
may coexist. Consequences of ventilatory insufficiency, including pulmonary hyperten­
sion, cor pulmonale (right heart failure), polycythemia, and neurocognitive dysfunction.

can be present. With progression of ventilatory insufficiency, blood gas abnormalities ex­
tend into wakefulness. Features of the medical condition causing sleep-related hypoven­
tilation can also be present. Episodes of hypoventilation may be associated with frequent 
arousals or bradytachycardia. Individuals may complain of excessive sleepiness and in­
somnia or morning headaches or may present with findings of neurocognitive dysfunction 
or depression. Hypoventilation may not be present during wakefulness.
Idiopathic sleep-related hypoventilation in adults is very uncommon. The prevalence of 
congenital central alveolar hypoventilation is unknown, but the disorder is rare. Comor- 
bid sleep-related hypoventilation (i.e., hypoventilation comorbid with other conditions, 
such as chronic obstructive pulmonary disease [COPD], neuromuscular disorders, or obe­
sity) is more common.

Idiopathic sleep-related hypoventilation is thought to be a slowly progressive disorder of 
respiratory impairment. When this disorder occurs comorbidly with other disorders (e.g., 
COPD, neuromuscular disorders, obesity), disease severity reflects the severity of the un­
derlying condition, and the disorder progresses as the condition worsens. Complications 
such as pulmonary hypertension, cor pulmonale, cardiac dysrhythmias, polycythemia, 
neurocognitive dysfunction, and worsening respiratory failure can develop with increas­
ing severity of blood gas abnormalities.
Congenital central alveolar hypoventilation usually manifests at birth with shallow, 
erratic, or absent breathing. This disorder can also manifest during infancy, childhood, 
and adulthood because of variable penetrance of the PHOX2B  mutation. Children with

and adulthood because of variable penetrance of the PHOX2B  mutation. Children with 
congenital central alveolar hypoventilation are more likely to have disorders of the auto­
nomic nervous system, Hirschsprung's disease, neural crest tumors, and characteristic box­
shaped face (i.e., the face is short relative to its width).
Environmental. Ventilatory drive can be reduced in individuals using central nervous 
system depressants, including benzodiazepines, opiates, and alcohol.
Genetic and physiological. Idiopathic sleep-related hypoventilation is associated with 
reduced ventilatory drive due to a blunted chemoresponsiveness to CO 2 (reduced respi­
ratory drive; i.e., "won't breathe"), reflecting underlying neurological deficits in centers 
governing the control of ventilation. More commonly, sleep-related hypoventilation is co­

morbid with another medical condition, such as a pulmonary disorder, a neuromuscular 
or chest wall disorder, or hypothyroidism, or with use of medications (e.g., benzodiaze­
pines, opiates). In these conditions, the hypoventilation may be a consequence of in­
creased work of breathing and/or impairment of respiratory muscle function (i.e., "can't 
breathe") or reduced respiratory drive (i.e., "won't breathe").
Neuromuscular disorders influence breathing through impairment of respiratory mo­
tor innervation or respiratory muscle function. They include conditions such as amyo­
trophic lateral sclerosis, spinal cord injury, diaphragmatic paralysis, myasthenia gravis, 
Lambert-Eaton syndrome, toxic or metabolic myopathies, postpolio syndrome, and Char- 
cot-Marie-Tooth syndrome.

Congenital central alveolar hypoventilation is a genetic disorder attributable to muta­
tions of PH0X2B,  a gene that is crucial for the development of the embryonic autonomic 
nervous system and neural crest derivatives. Children with congenital central alveolar hy­
poventilation show blunted ventilatory responses to hypercapnia, especially in non-rapid 
eye movement sleep.

Gender distributions for sleep-related hypoventilation occurring in association with co- 
morbid conditions reflect the gender distributions of the comorbid conditions. For exam­
ple, COPD is more frequently present in males and with increasing age.
Sleep-related hypoventilation is diagnosed using polysomnography showing sleep-related 
hypoxemia and hypercapnia that is not better explained by another breathing-related sleep 
disorder. The documentation of increased arterial pC 02 levels to greater than 55 mmHg 
during sleep or a 10 mmHg or greater increase in pC 02 levels (to a level that also exceeds 
50 mmHg) during sleep in comparison to awake supine values, for 10 minutes or longer, is 
the gold standard for diagnosis. However, obtaining arterial blood gas determinations dur­
ing sleep is impractical, and non-invasive measures of pC 02 have not been adequately val­

idated during sleep and are not widely used during polysomnography in adults. Prolonged 
and sustained decreases in oxygen saturation (oxygen saturation of less than 90% for more 
than 5 minutes with a nadir of at least 85%, or oxygen saturation of less than 90% for at least 
30% of sleep time) in the absence of evidence of upper airway obstruction are often used as 
an indication of sleep-related hypoventilation; however, this finding is not specific, as there 
are other potential causes of hypoxemia, such as that due to lung disease.
The consequences of sleep-related hypoventilation are related to the effects of chronic ex­
posure to hypercapnia and hypoxemia. These blood gas derangements cause vasocon­

striction of the pulmonary vasculature leading to pulmonary hypertension, which, if 
severe, can result in right-sided heart failure (cor pulmonale). Hypoxemia can lead to dys­
function of organs such as the brain, blood, and heart, leading to outcomes such as cog­
nitive dysfunction, polycythemia, and cardiac arrhythmias. Hypercapnia can depress 
ventilatory drive, leading to progressive respiratory failure.
Other medical conditions affecting ventilation. In adults, the idiopathic variety of sleep- 
related hypoventilation is very uncommon and is determined by excluding the presence of 
lung diseases, skeletal malformations, neuromuscular disorders, and other medical and 
neurological disorders or medications that affect ventilation. Sleep-related hypoventila­

tion must be distinguished from other causes of sleep-related hypoxemia, such as that due 
to lung disease.
Other breathing-related sleep disorders. Sleep-related hypoventilation can be distin­
guished from obstructive sleep apnea hypopnea and central sleep apnea based on clinical 
features and findings on polysomnography. Sleep-related hypoventilation typically shows 
more sustained periods of oxygen desaturation rather that the periodic episodes seen in 
obstructive sleep apnea hypopnea and central sleep apnea. Obstructive sleep apnea hy­
popnea and central sleep apnea also show a pattern of discrete episodes of repeated air­
flow decreases that can be absent in sleep-related hypoventilation.
Sleep-related hypoventilation often occurs in association with a pulmonary disorder (e.g., in­

terstitial lung disease, COPD), with a neuromuscular or chest wall disorder (e.g., muscular 
dystrophies, post-polio syndrome, cervical spinal cord injury, obesity, kyphoscoliosis), or.

most relevant to the mental health provider, with medication use (e.g., benzodiazepines, opi­
ates). Congenital central alveolar hypoventilation often occurs in association with autonomic 
dysfunction and may occur in association with Hirschsprung's disease. COPD, a disorder of 
lower airway obstruction usually associated with cigarette smoking, can result in sleep- 
related hypoventilation and hypoxemia. The presence of coexisting obstructive sleep apnea 
hypopnea is thought to exacerbate hypoxemia and hypercapnia during sleep and wakeful­
ness. The relationship between congenital central alveolar hypoventilation and idiopathic 
sleep-related hypoventilation is unclear; in some individuals, idiopathic sleep-related hy­
poventilation may represent cases of late-onset congenital central alveolar hypoventilation.
Relationship to internationai Ciassification of  
The International Classification of Sleep Disorders,  2nd Edition (ICSD-2), combines sleep-

The International Classification of Sleep Disorders,  2nd Edition (ICSD-2), combines sleep- 
related hypoventilation and sleep-related hypoxemia under the category of sleep-related 
hypoventilation/hypoxemic syndromes. This approach to classification reflects the fre­
quent co-occurrence of disorders that lead to hypoventilation and hypoxemia. In contrast, 
the classification used in DSM-5 reflects evidence that there are distinct sleep-related 
pathogenetic processes leading to hypoventilation.
Circadian Rhythm Sleep-Wake Disorders
A. A persistent or recurrent pattern of sleep disruption that is primarily due to an alteration  
of the circadian system or to a misalignment between the endogenous circadian  
rhythm and the sleep-wake schedule required by an individual’s physical environment  
or social or professional schedule.

B. The sleep disruption leads to excessive sleepiness or insomnia, or both.
C. The sleep disturbance causes clinically significant distress or impairment in social, oc­
cupational, and other important areas of functioning.
Coding note: For ICD-9-CM, code 307.45 for all subtypes. For ICD-10-CM, code is based  
on subtype.
307.45 (G47.21) Delayed sleep phase type: A pattern of delayed sleep onset and  
awakening times, with an inability to fall asleep and awaken at a desired or convention­
ally acceptable earlier time.
Familial: A family history of delayed sleep phase is present.
Overlapping with non-24-hour sleep-wake type: Delayed sleep phase type  
may overlap with another circadian rhythm sleep-wake disorder, non-24-hour  
sleep-wake type.

307.45 (G47.22) Advanced sleep phase type: A pattern of advanced sleep onset and  
awakening times, with an inability to remain awake or asleep until the desired or con­
ventionally acceptable later sleep or wake times.
Familial: A family history of advanced sleep phase is present.
307.45 (G47.23) Irregular sleep-walte type: A temporally disorganized sleep-wake  
pattern, such that the timing of sleep and wake periods is variable throughout the 24-  
hour period.

307.45 (G47.24) Non-24-hour sleep-wake type: A pattern of sleep-wal<e cycles that  
is not synchronized to the 24-hour environment, with a consistent daily drift (usually to  
later and later times) of sleep onset and wake times.
307.45 (G47.26) Shift work type: Insomnia during the major sleep period and/or ex­
cessive sleepiness (including inadvertent sleep) during the major awake period asso­
ciated with a shift work schedule (i.e., requiring unconventional work hours).
307.45 (G47.20) Unspecified type
Episodic: Symptoms last at least 1  month but less than 3 months.
Recurrent: Two or more episodes occur within the space of 1  year.
Delayed Sleep Phase Type
The delayed sleep phase type is based primarily on a history of a delay in the timing of the 
major sleep period (usually more than 2 hours) in relation to the desired sleep and wake-

major sleep period (usually more than 2 hours) in relation to the desired sleep and wake- 
up time, resulting in symptoms of insomnia and excessive sleepiness. When allowed to set 
their own schedule, individuals with delayed sleep phase type exhibit normal sleep qual­
ity and duration for age. Symptoms of sleep-onset insomnia, difficulty waking in the 
morning, and excessive early day sleepiness are prominent.
Common associated features of delayed sleep phase type include a history of mental dis­
orders or a concurrent mental disorder. Extreme and prolonged difficulty awakening with 
morning confusion is also common. Psychophysiological insomnia may develop as a re­
sult of maladaptive behaviors that impair sleep and increase arousal because of repeated 
attempts to fall asleep at an earlier time.

Prevalence of delayed sleep phase type in the general population is approximately 0.17% 
but appears to be greater than 7% in adolescents. Although the prevalence of familial de­
layed sleep phase type has not been established, a family history of delayed sleep phase is 
present in individuals with delayed sleep phase type.
Course is persistent, lasting longer than 3 months, with intermittent exacerbations through­
out adulthood. Although age at onset is variable, symptoms begin typically in adolescence 
and early adulthood and persist for several months to years before diagnosis is estab­
lished. Severity may decrease with age. Relapse of symptoms is common.
Clinical expression may vary across the lifespan depending on social, school, and work

Clinical expression may vary across the lifespan depending on social, school, and work 
obligations. Exacerbation is usually triggered by a change in work or school schedule that 
requires an early rise time. Individuals who can alter their work schedules to accommo­
date the delayed circadian sleep and wake timing can experience remission of symptoms.
Increased prevalence in adolescence may be a consequence of both physiological and be­
havioral factors. Hormonal changes may be involved specifically, as delayed sleep phase is as­
sociated with the onset of puberty. Thus, delayed sleep phase type in adolescents should be 
differentiated from the common delay in the timing of circadian rhythms in this age group. In 
the familial form, the course is persistent and may not improve sig^iificantly with age.

Genetic and physiological. Predisposing factors may include a longer than average cir­
cadian period, changes in light sensitivity, and impaired homeostatic sleep drive. Some in­
dividuals with delayed sleep phase type may be hypersensitive to evening light, which 
can serve as a delay signal to the circadian clock, or they may be hyposensitive to morning 
light such that its phase-advancing effects are reduced. Genetic factors may play a role in 
the pathogenesis of familial and sporadic forms of delayed sleep phase type, including 
mutations in circadian genes (e.g., PER3, CKle).
Diagnostic i\/larl(ers
Confirmation of the diagnosis includes a complete history and use of a sleep diary or actigra- 
phy (i.e., a wrist-wom motion detector that monitors motor activity for prolonged periods and 
can be used as a proxy for sleep-wake patterns for at least 7 days). The period covered should

can be used as a proxy for sleep-wake patterns for at least 7 days). The period covered should 
include weekends, when social and occupational obligations are less strict, to ensure that the 
individual exhibits a consistently delayed sleep-wake pattern. Biomarkers such as salivary 
dim light melatonin onset should be obtained only when the diagnosis is unclear.
Functional Consequences of Delayed Sleep Phase Type
Excessive early day sleepiness is prominent. Extreme and prolonged difficulty awakening 
with morning confusion (i.e., sleep inertia) is also common. The severity of insomnia and 
excessive sleepiness symptoms varies substantially among individuals and largely de­
pends on the occupational and social demands on the individual.
Normative variations in sleep. Delayed sleep phase type must be distinguished from

Normative variations in sleep. Delayed sleep phase type must be distinguished from 
"normal" sleep patterns in which an individual has a late schedule that does not cause 
personal, social, or occupational distress (most commonly seen in adolescents and young 
adults).
Other sleep disorders. Insomnia disorder and other circadian rhythm sleep-wake dis­
orders should be included in the differential. Excessive sleepiness may also be caused by 
other sleep disturbances, such as breathing-related sleep disorders, insomnias, sleep- 
related movement disorders, and medical, neurological, and mental disorders. Overnight 
polysomnography may help in evaluating for other comorbid sleep disorders, such as 
sleep apnea. The circadian nature of delayed sleep phase type, however, should differen­
tiate it from other disorders with similar complaints.

Delayed sleep phase type is strongly associated with depression, personality disorder, and 
somatic symptom disorder or illness anxiety disorder. In addition, comorbid sleep disor­
ders, such as insomnia disorder, restless legs syndrome, and sleep apnea, as well as depres­
sive and bipolar disorders and anxiety disorders, can exacerbate symptoms of insomnia 
and excessive sleepiness. Delayed sleep phase type may overlap with another circadian 
rhythm sleep-wake disorder, non-24-hour sleep-wake type. Sighted individuals with non- 
24-hour sleep-wake type disorder commonly also have a history of delayed circadian sleep 
phase.

Advanced Sleep Phase Type
\
Advanced sleep phase type may be documented with the specified "famihal." Although 
the prevalence of familial advanced sleep phase type has not been established, a family 
history of advanced sleep phase is present in individuals with advanced sleep phase type. 
In this type, specific mutations demonstrate an autosomal dominant mode of inheritance. 
In the familial form, onset of symptoms may occur earlier (during childhood and early 
adulthood), the course is persistent, and the severity of symptoms may increase with age.
Advanced sleep phase type is characterized by sleep-wake times that are several hours 
earlier than desired or conventional times. Diagnosis is based primarily on a history of an 
advance in the timing of the major sleep period (usually more than 2 hours) in relation to 
the desired sleep and wake-up time, with symptoms of early morning insomnia and ex­

cessive daytime sleepiness. When allowed to set their schedule, individuals with ad­
vanced sleep phase type will exhibit normal sleep quality and duration for age.
Individuals with advanced sleep phase type are "morning types," having earlier sleep- 
wake times, with the timing of circadian biomarkers such as melatonin and core body tem­
perature rhythms occurring 2-A hours earlier than normal. When required to keep a con­
ventional schedule requiring a delay of bedtime, these individuals will continue to have an 
early rise time, leading to persistent sleep deprivation and daytime sleepiness. Use of hyp­
notics or alcohol to combat sleep-maintenance insomnia and stimulants to reduce daytime 
sleepiness may lead to substance abuse in these individuals.

The estimated prevalence of advanced sleep phase type is approximately 1% in middle- 
age adults. Sleep-wake times and circadian phase advance in older individuals, probably 
accounting for increased prevalence in this population.
Onset is usually in late adulthood. In the familial form, onset can be earlier. The course is typ­
ically persistent, lasting more than 3 months, but the severity may increase depending on work 
and social schedules. The advanced sleep phase type is more common in older adults.
obligations. Individuals who can alter their work schedules to accommodate the advanced 
circadian sleep and wake timing can experience remission of symptoms. Increasing age

circadian sleep and wake timing can experience remission of symptoms. Increasing age 
tends to advance the sleep phase, however, it is unclear whether the common age-associ­
ated advanced sleep phase type is due solely to a change in circadian timing (as seen in the 
familial form) or also to age-related changes in the homeostatic regulation of sleep, result­
ing in earlier awakening. Severity, remission, and relapse of symptoms suggest lack of ad­
herence to behavioral and environmental treatments designed to control sleep and wake 
structure and light exposure.

Environmental. Decreased late aftemoon/early evening exposure to light and/or expo­
sure to early morning light due to early morning awakening can increase the risk of ad­
vanced sleep phase type by advancing circadian rhythms. By going to bed early, these 
individuals are not exposed to light in the phase delay region of the curve, resulting in per­
petuation of advanced phase. In familial advanced sleep phase type, a shortening of the 
endogenous circadian period can result in an advanced sleep phase, although circadian pe­
riod does not appear to systematically decrease with age.
Genetic and physiological. Advanced sleep phase type has demonstrated an autoso­
mal dominant mode of inheritance, including a PER2  gene mutation causing hypophos- 
phorylation of the PER2 protein and a missense mutation in CKL
African Americans may have a shorter circadian period and larger magnitude phase ad­

vances to light than do Caucasians, possibly increasing the risk for development of ad­
vanced sleep phase type in this population.
A sleep diary and actigraphy may be used as diagnostic markers, as described earlier for 
delayed sleep phase type.
Functionai Consequences of Advanced Sieep Pliase Type
Excessive sleepiness associated with advanced sleep phase can have a negative effect on 
cognitive performance, social interaction, and safety. Use of wake-promoting agents to 
combat sleepiness or sedatives for early morning awakening may increase potential for 
substance abuse.
Other sleep disorders. Behavioral factors such as irregular sleep schedules, voluntary 
early awakening, and exposure to light in the early morning should be considered, partic­

ularly in older adults. Careful attention should be paid to rule out other sleep-wake dis­
orders, such as insomnia disorder, and other mental disorders and medical conditions that 
can cause early morning awakening.
Depressive and bipolar disorders. Because early morning awakening, fatigue, and sleep­
iness are prominent features of major depressive disorder, depressive and bipolar disor­
ders must also be considered.
Medical conditions and mental disorders with the symptom of early morning awakening, 
such as insomnia, can co-occur with the advance sleep phase type.
Irregular Sleep-Wake Type
The diagnosis of irregular sleep-wake type is based primarily on a history of symptoms of 
insomnia at night (during the usual sleep period) and excessive sleepiness (napping) dur­

ing the day. Irregular sleep-wake type is characterized by a lack of discernable sleep-wake

circadian rhythm. There is no major sleep period, and sleep is fragmented into at least 
three periods d\iring the 24-hour day.
Individuals with irregular sleep-wake type typically present with insomnia or excessive 
sleepiness, depending on the time of day. Sleep and wake periods across 24 hours are frag­
mented, although the longest sleep period tends to occur between 2:00 A.M. and 6:00 A.M.  
and is usually less than 4 hours. A history of isolation or reclusion may occur in association 
with the disorder and contribute to the symptoms via a lack of external stimuli to help en­
train a normal pattern. Individuals or their caregivers report frequent naps throughout the 
day. Irregular sleep-wake type is most commonly associated with neurodegenerative dis­
orders, such as major neurocognitive disorder, and many neurodevelopmental disorders 
in children.
Prevalence of irregular sleep-wake type in the general population is unknown.

The course of irregular sleep-wake type is persistent. Age at onset is variable, but the dis­
order is more common in older adults.
Temperamental. Neurodegenerative disorders, such as Alzheimer's disease, Parkinson's 
disease, and Huntington's disease, and neurodevelopmental disorders in children in­
crease the risk for irregular sleep-wake type.
Environmental. Decreased exposure to environmental light and structured daytime ac­
tivity can be associated with a low-amplitude circadian rhythm. Hospitalized individuals 
are especially prone to such weak external entraining stimuli, and even outside the hospi­
tal setting, individuals with major neurocognitive disorder (i.e., dementia) are exposed to 
significantly less bright light.

A detailed sleep history and a sleep diary (by a caregiver) or actigraphy help confirm the 
irregular sleep-wake pattern.
irregular Sleep-Wake Type
Lack of a clearly discernible major sleep and wake period in irregular sleep-wake type re­
sults in insomnia or excessive sleepiness, depending on the time of day. Disruption of the 
caregiver's sleep also often occurs and is an important consideration.
Normative variations in sleep. Irregular sleep-wake type should be distinguished from 
a voluntary irregular sleep-wake schedule and poor sleep hygiene, which can result in in­
somnia and excessive sleepiness.
Other medical conditions and mental disorders. Other causes of insomnia and daytime 
sleepiness, including comorbid medical conditions and mental disorders or medication,

sleepiness, including comorbid medical conditions and mental disorders or medication, 

Irregular sleep-wake type is often comorbid with neurodegenerative and neurodevelop- 
mental disorders, such as major neurocognitive disorder, intellectual disability (intellec­
tual developmental disorder), and traumatic brain injury. It is also comorbid with other 
medical conditions and mental disorders in which there is social isolation and/or lack of 
light and structured activities.
Non-24-Hour Sleep-Wake Type
The diagnosis of non-24-hour sleep-wake type is based primarily on a history of symp­
toms of insomnia or excessive sleepiness related to abnormal synchronization between the 
24-hour light-dark cycle and the endogenous circadian rhythm. Individuals typically pre­
sent with periods of insomnia, excessive sleepiness, or both, which alternate with short 
asymptomatic periods. Starting with the asymptomatic period, when the individual's 
sleep phase is aligned to the external environment, sleep latency will gradually increase

sleep phase is aligned to the external environment, sleep latency will gradually increase 
and the individual will complain of sleep-onset insomnia. As the sleep phase continues to 
drift so that sleep time is now in the daytime, the individual will have trouble staying 
awake during the day and will complain of sleepiness. Because the circadian period is not 
aligned to the external 24-hour environment, symptoms will depend on when an individ­
ual tries to sleep in relation to the circadian rhythm of sleep propensity.
Non-24-hour sleep-wake type is most common among blind or visually impaired individ­
uals who have decreased light perception. In sighted individuals, there is often a history of 
delayed sleep phase and of decreased exposure to light and structured social and physical

delayed sleep phase and of decreased exposure to light and structured social and physical 
activity. Sighted individuals with non-24-hour sleep-wake type also demonstrate in­
creased sleep duration.
Prevalence of non-24-hour sleep-wake type in the general population is unclear, but the 
disorder appears rare in sighted individuals. The prevalence in blind individuals is esti­
mated to be 50%.
Course of non-24-hour sleep-wake type is persistent, with intermittent remission and ex­
acerbations due to changes in work and social schedules throughout the lifespan. Age at 
onset is variable, depending on the onset of visual impairment. In sighted individuals, be­
cause of the overlap with delayed sleep phase type, non-24-hour sleep-wake type may de­
velop in adolescence or early adulthood. Remission and relapse of symptoms in blind and

velop in adolescence or early adulthood. Remission and relapse of symptoms in blind and 
sighted individuals largely depend on adherence to treatments designed to control sleep 
and wake structure and light exposure.
obligations. In adolescents and adults, irregular sleep-wake schedules and exposure to 
light or lack of light at critical times of the day can exacerbate the effects of sleep loss and 
disrupt circadian entrainment. Consequently, symptoms of insomnia, daytime sleepiness, 
and school, professional, and interpersonal functioning may worsen.
Environmental. In sighted individuals, decreased exposure or sensitivity to light and so­
cial and physical activity cues may contribute to a free-running circadian rhythm. With the

high frequency of mental disorders involving social isolation and cases of non-24-hour 
sleep-wake type developing after a change in sleep habits (e.g., night shift work, job loss), 
behavioral factors in combination with physiological tendency may precipitate and per­
petuate this disorder in sighted individuals. Hospitalized individuals with neurological and 
psychiatric disorders can become insensitive to social cues, predisposing them to the de­
velopment of non-24-hour sleep-wake type.
Genetic and physiological. Blindness is a risk factor for non-24-hour sleep-wake type. 
Non-24-hour sleep-wake type has been associated with traumatic brain injury.
Diagnosis is confirmed by history and sleep diary or actigraphy for an extended period. 
Sequential measurement of phase markers (e.g., melatonin) can help determine circadian 
phase in both sighted and blind individuals.
Non-24-Hour Sieep-Walce Type

Complaints of insomnia (sleep onset and sleep maintenance), excessive sleepiness, or both 
are prominent. The unpredictability of sleep and wake times (typically a daily delay drift) 
results in an inability to attend school or maintain a steady job and may increase potential 
for social isolation.
Circadian rhythm sleep-wake disorders. In sighted individuals, non-24-hour sleep-wake 
type should be differentiated from delayed sleep phase type, as individuals with delayed 
sleep phase type may display a similar progressive delay in sleep period for several days.
Depressive disorders. Depressive symptoms and depressive disorders may result in 
similar circadian dysregulation and symptoms.

Blindness is often comorbid with non-24-hour sleep-wake type, as are depressive and bi­
polar disorders with social isolation.
Shift Work Type
Diagnosis is primarily based on a history of the individual working outside of the normal 
8:00 A.M. to 6:00 P.M. daytime window (particularly at night) on a regularly scheduled (i.e., 
non-overtime) basis. Symptoms of excessive sleepiness at work, and impaired sleep at 
home, on a persistent basis are prominent. Presence of both sets of symptoms are usually 
required for a diagnosis of shift work type. Typically, when the individual reverts to a day­
work routine, symptoms resolve. Although the etiology is slightly different, individuals 
who travel across many time zones on a very frequent basis may experience effects similar

who travel across many time zones on a very frequent basis may experience effects similar 
to those experienced by individuals with shift work type who work rotating shifts.
The prevalence of shift work type is unclear, but the disorder is estimated to affect 5%-10% 
of the night worker population (16%-20% of the workforce). Prevalence rises with advance­
ment into middle-age and beyond (Drake et al. 2004).

Shift work type can appear in individuals of any age but is more prevalent in individuals 
older than 50 years and typically worsens with the passage of time if the disruptive work 
hours persist. Although older adults may show similar rates of circadian phase adjust­
ment to a change in routine as do younger adults, they appear to experience significantly 
more sleep disruption as a consequence of the circadian phase shift.
Temperamental. Predisposing factors include a morning-type disposition, a need for 
long (i.e., more than 8 hours) sleep durations in order to feel well rested, and strong com­
peting social and domestic needs (e.g., parents of young children). Individuals who are able 
to commit to a nocturnal lifestyle, with few competing day-oriented demands, appear at 
lower risk for shift work type.
Genetic and physiological. Because shift workers are more likely than day workers to

Genetic and physiological. Because shift workers are more likely than day workers to 
be obese, obstructive sleep apnea may be present and may exacerbate the symptoms.
A history and sleep diary or actigraphy may be useful in diagnosis, as discussed earlier for 
Functional Consequences of Shift Worl( Type
Individuals with shift work type not only may perform poorly at work but also appear to 
be at risk for accidents both at work and on the drive home. They may also be at risk for 
poor mental health (e.g., alcohol use disorder, substance use disorder, depression) and 
physical health (e.g., gastrointestinal disorders, cardiovascular disease, diabetes, cancer). 
Individuals with a history of bipolar disorder are particularly vulnerable to shift work 
type-related episodes of mania resulting from missed nights of sleep. Shift work type of­
ten results in interpersonal problems.

Normative variations in sleep with shift work. The diagnosis of shift work type, as op­
posed to the ''normal" difficulties of shift work, must depend to some extent on the sever­
ity of symptoms and/or level of distress experienced by the individual. Presence of shift 
work type symptoms even when the individual is able to live on a day-oriented routine for 
several weeks at a time may suggest the presence of other sleep disorders, such as sleep ap­
nea, insomnia, and narcolepsy, which should be ruled out.
Shift work type has been associated with increased alcohol use disorder, other substance 
use disorders, and depression. A variety of physical health disorders (e.g., gastrointestinal 
disorders, cardiovascular disease, diabetes, cancer) have been found to be associated with 
prolonged exposure to shift work.

Relationship to International Classification of  
circadian rhythm sleep disorders, including jet lag type.

Parasomnias
Parasomnias  are disorders characterized by abnormal behavioral, experiential, or physio­
logical events occurring in association with sleep, specific sleep stages, or sleep-wake tran­
sitions. The most common parasomnias—non-rapid eye movement (NREM) sleep 
arousal disorders and rapid eye movement (REM) sleep behavior disorder—represent ad­
mixtures of wakefulness and NREM sleep and wakefulness and REM sleep, respectively. 
These conditions serve as a reminder that sleep and wakefulness are not mutually exclu­
sive and that sleep is not necessarily a global, whole-brain phenomenon.
Non-Rapid Eye Movement  
Sleep Arousal Disorders
A. Recurrent episodes of incomplete awakening from sleep, usually occurring during the  
first third of the major sleep episode, accompanied by either one of the following:
1. Sleepwalking: Repeated episodes of rising from bed during sleep and walking

1. Sleepwalking: Repeated episodes of rising from bed during sleep and walking  
about. While sleepwalking, the individual has a blank, staring face; is relatively un­
responsive to the efforts of others to communicate with him or her; and can be  
awakened only with great difficulty.
2. Sleep terrors: Recurrent episodes of abrupt terror arousals from sleep, usually be­
ginning with a panicky scream. There is intense fear and signs of autonomic  
arousal, such as mydriasis, tachycardia, rapid breathing, and sweating, during  
each episode. There is relative unresponsiveness to efforts of others to comfort the  
individual during the episodes.
B. No or little (e.g., only a single visual scene) dream imagery is recalled.
C. Amnesia for the episodes is present.
D. The episodes cause clinically significant distress or impairment in social, occupational,  

drug of abuse, a medication).
F. Coexisting mental and medical disorders do not explain the episodes of sleepwalking  
or sleep terrors.
Coding note: For ICD-9-CM, code 307.46 for all subtypes. For ICD-10-CM, code is based
307.46 (F51.3) Sleepwalking type  
With sleep-related eating
With sleep-related sexual behavior (sexsomnia)
307.46 (F51.4) Sleep terror type

The essential feature of non-rapid eye movement (NREM) sleep arousal disorders is the 
repeated occurrence of incomplete arousals, usually beginning during the first third of the 
major sleep episode (Criterion A), that typically are brief, lasting 1-10 minutes, but may be 
protracted, lasting up to 1  hour. The maximum duration of an event is unknown. The eyes 
are typically open during these events. Many individuals exhibit both subtypes of arousals 
on different occasions, which underscores the unitary underlying pathophysiology. The 
subtypes reflect varying degrees of simultaneous occurrence of wakefulness and NREM 
sleep, resulting in complex behaviors arising from sleep with varying degrees of conscious 
awareness, motor activity, and autonomic activation.
The essential feature of sleepwalking  is repeated episodes of complex motor behavior 
initiated during sleep, including rising from bed and walking about (Criterion Al). Sleep­

walking episodes begin during any stage of NREM sleep, most commonly during slow- 
wave sleep and therefore most often occurring during the first third of the night. During 
episodes, the individual has reduced alertness and responsiveness, a blank stare, and rel­
ative unresponsiveness to communication with others or efforts by others to awaken the 
individual. If awakened during the episode (or on awakening the following morning), the 
individual has limited recall for the episode. After the episode, there may initially be a brief 
period of confusion or difficulty orienting, followed by full recovery of cognitive function 
and appropriate behavior.
The essential feature of sleep terrors  is the repeated occurrence of precipitous awaken­

ings from sleep, usually beginning with a panicky scream or cry (Criterion A 2). Sleep ter­
rors usually begin during the first third of the major sleep episode and last 1-10  minutes, 
but they may last considerably longer, particularly in children. The episodes are accom­
panied by impressive autonomic arousal and behavioral manifestations of intense fear. 
During an episode, the individual is difficult to awaken or comfort. If the individual awak­
ens after the sleep terror, little or none of the dream, or only fragmentary, single images, 
are recalled. During a typical episode of sleep terrors, the individual abruptly sits up in 
bed screaming or crying, with a frightened expression and autonomic signs of intense anx­
iety (e.g., tachycardia, rapid breathing, sweating, dilation of the pupils). The individual

iety (e.g., tachycardia, rapid breathing, sweating, dilation of the pupils). The individual 
may be inconsolable and is usually unresponsive to the efforts of others to awaken or com­
fort him or her. Sleep terrors are also called "night terrors" or "pavor nocturnus."
Sleepwalking episodes can include a wide variety of behaviors. Episodes may begin with 
confusion: the individual may simply sit up in bed, look about, or pick at the blanket or 
sheet. This behavior then becomes progressively complex. The individual may actually 
leave the bed and walk into closets, out of the room, and even out of buildings. Individuals 
may use the bathroom, eat, talk, or engage in more complex behaviors. Running and fran­
tic attempts to escape some apparent threat can also occur. Most behaviors during sleep­

walking episodes are routine and of low complexity. However, cases of unlocking doors 
and even operating machinery (driving an automobile) have been reported. Sleepwalking 
can also include inappropriate behavior (e.g., commonly, urinating in a closet or waste­
basket). Most episodes last for several minutes to a half hour but may be more protracted. 
Inasmuch as sleep is a state of relative analgesia, painful injuries sustained during sleep­
walking may not be appreciated until awakening after the fact.
There are two "specialized" forms of sleepwalking: sleep-related eating behavior and 
sleep-related sexual behavior (sexsomnia or sleep sex). Individuals with sleep-related eating  
experience unwanted recurrent episodes of eating with varying degrees of amnesia, rang­

ing from no awareness to full awareness without the ability to not eat. During these epi­
sodes, inappropriate foods may be ingested. Individuals witii sleep-related eating disorder 
may find evidence of their eating only the next morning. In sexsomnia,  varying degrees of

sexual activity (e.g., masturbation, fondling, groping, sexual intercourse) occur as complex 
behaviors arising from sleep without conscious awareness. This condition is more common 
in males and may result in serious interpersonal relationship problems or medicolegal 
consequences.
During a typical episode of sleep terrors, there is often a sense of overwhelming dread, 
with a compulsion to escape. Although fragmentary vivid dream images may occur, a story­
like dream sequence (as in nightmares) is not reported. Most commonly, the individual does 
not awaken fully, but returns to sleep and has amnesia for the episode on awakening the next 
morning. Usually only one episode will occur on any one night. Occasionally several episodes 
may occur at intervals throughout the night. These events rarely arise during daytime naps.
Isolated or infrequent NREM sleep arousal disorders are very common in the general pop­

ulation. From 10% to 30% of children have had at least one episode of sleepwalking, and 
2%-3% sleepwalk often. The prevalence of sleepwalking disorder, marked by repeated ep­
isodes and impairment or distress, is much lower, probably in the range of l%-5%. The 
prevalence of sleepwalking episodes (not sleepwalking disorder) is 1.0%-7.0% among 
adults, with weekly to monthly episodes occurring in 0.5%-0.7%. The lifetime prevalence 
of sleepwalking in adults is 29.2%, with a past-year prevalence of sleepwalking of 3.6%.
The prevalence of sleep terrors in the general population is unknown. The prevalence 
of sleep terror episodes (as opposed to sleep terror disorder, in which there is recurrence 
and distress or impairment) is approximately 36.9% at 18 months of age, 19.7% at 30 months

and distress or impairment) is approximately 36.9% at 18 months of age, 19.7% at 30 months 
of age, and 2.2% in adults.
NREM sleep arousal disorders occur most commonly in childhood and diminish in fre­
quency with increasing age. The onset of sleepwalking in adults with no prior history of 
sleepwalking as children should prompt a search for specific etiologies, such as obstruc­
tive sleep apnea, nocturnal seizures, or effect of medication.
Environmental. Sedative use, sleep deprivation, sleep-wake schedule disruptions, fa­
tigue, and physical or emotional stress increase the likelihood of episodes. Fever and sleep 
deprivation can produce an increased frequency of NREM sleep arousal disorders.
Genetic and physiological. A family history for sleepwalking or sleep terrors may oc­

cur in up to 80% of individuals who sleepwalk. The risk for sleepwalking is further in­
creased (to as much as 60% of offspring) when both parents have a history of the disorder.
Individuals with sleep terrors frequently have a positive family history of either sleep 
terrors or sleepwalking, with as high as a 10-fold increase in the prevalence of the disorder 
among first-degree biological relatives. Sleep terrors are much more common in monozy­
gotic twins as compared with dizygotic twins. The exact mode of inheritance is unknown.
Violent or sexual activity during sleepwalking episodes is more likely to occur in adults. 
Eating during sleepwalking episodes is more commonly seen in females. Sleepwalking oc­

curs more often in females during childhood but more often in males during adulthood.
Older children and adults provide a more detailed recollection of fearful images asso­
ciated with sleep terrors than do younger children, who are more likely to have complete 
amnesia or report only a vague sense of fear. Among children, sleep terrors are more com­
mon in males than in females. Among adults, the sex ratio is even.

NREM sleep arousal disorders arise from any stage of NREM sleep but most commonly 
from deep NREM sleep (slow-wave sleep). They are most likely to appear in the first third 
of the night and do not commonly occur during daytime naps. During the episode, the 
polysomnogram may be obscured with movement artifact. In the absence of such artifact, 
the electroencephalogram typically shows theta or alpha frequency activity during the ep­
isode, indicating partial or incomplete arousal.
Polysomnography in conjunction with audiovisual monitoring can be used to document 
episodes of sleepwalking. In the absence of actually capturing an event during a polysomno- 
graphic recording, there are no polysomnographic features that can serve as a marker for 
sleepwalking. Sleep deprivation may increase the likelihood of capturing an event. As a group, 
individuals who sleepwalk show instability of deep NREM sleep, but the overlap in findings

individuals who sleepwalk show instability of deep NREM sleep, but the overlap in findings 
with individuals who do not sleepwalk is great enough to preclude use of this indicator in es­
tablishing a diagnosis. Unlike arousals from REM sleep associated with nightmares, in which 
there is an increase in heart rate and respiration prior to the arousal, the NREM sleep arousals 
of sleep terrors begin precipitously from sleep, without anticipatory autonomic changes. The 
arousals are associated with impressive autonomic activity, with doubling or tripling of 
the heart rate. The pathophysiology is poorly understood, but there appears to be instability in 
the deeper stages of NREM sleep. Absent capturing an event during a formal sleep study, 
there are no reliable polysomnographic indicators of the tendency to experience sleep terrors.
Functional Consequences of

Non-REIVI Sleep Arousal Disorders
For the diagnosis of a NREM sleep arousal disorder to be made, the individual or house­
hold members must experience clinically significant distress or impairment, although pa- 
rasomnia symptoms may occur occasionally in nonclinical populations and would be 
subthreshold for the diagnosis. Embarrassment concerning the episodes can impair social 
relationships. Social isolation or occupational difficulties can result. The determination of a 
"disorder" depends on a number of factors, which may vary on an individual basis and 
will depend on the frequency of events, potential for violence or injurious behaviors, em­
barrassment, or disruption/distress of other household members. Severity determination 
is best made based on the nature or consequence of the behaviors rather than simply on fre­

quency. Uncommonly, NREM sleep arousal disorders may result in serious injury to the 
individual or to someone trying to console the individual. Injuries to others are confined to 
those in close proximity; individuals are not "sought out." Typically, sleepwalking in both 
children and adults is not associated with significant mental disorders. For individuals 
with sleep-related eating behaviors, unknowingly preparing or eating food during the 
sleep period may create problems such as poor diabetes control, weight gain, injury (cuts 
and bums), or consequences of eating dangerous or toxic inedibles. NREM sleep arousal 
disorders may rarely result in violent or injurious behaviors with forensic implications.

Nightmare disorder. In contrast to individuals with NREM sleep arousal disorders, in­
dividuals with nightmare disorder typically awaken easily and completely, report vivid 
storyhke dreams accompanying the episodes, and tend to have episodes later in the night. 
NREM sleep arousal disorders occur during NREM sleep, whereas nightmares usually oc­
cur during REM sleep. Parents of children with NREM sleep arousal disorders may mis­
interpret reports of fragmentary imagery as nightmares.
Breathing-related sleep disorders. Breathing disorders during sleep can also produce 
confusional arousals with subsequent amnesia. However, breathing-related sleep disor­
ders are also characterized by characteristic symptoms of snoring, breathing pauses, and

daytime sleepiness. In some individuals, a breathing-related sleep disorder may precipi­
tate episodes of sleepwalking.
\
REM sleep behavior disorder. REM sleep behavior disorder may be difficult to distin­
guish from NREM sleep arousal disorders. REM sleep behavior disorder is characterized 
by episodes of prominent, complex movements, often involving personal injury arising 
from sleep. In contrast to NREM sleep arousal disorders, REM sleep behavior disorder oc­
curs during REM sleep. Individuals v^ith REM sleep behavior disorder awaken easily and 
report more detailed and vivid dream content than do individuals with NREM sleep arousal 
disorders. They often report that they "act out dreams."
Parasomnia overlap syndrome. Parasomnia overlap syndrome consists of clinical and 
polysomnographic features of both sleepwalking and REM sleep behavior disorder.
Sleep-related seizures. Some types of seizures can produce episodes of very unusual

Sleep-related seizures. Some types of seizures can produce episodes of very unusual 
behaviors that occur predominantly or exclusively during sleep. Nocturnal seizures may 
closely mimic NREM sleep arousal disorders but tend to be more stereotypic in nature, oc­
cur multiple times nightly, and be more likely to occur from daytime naps. The presence of 
sleep-related seizures does not preclude the presence of NREM sleep arousal disorders. 
Sleep-related seizures should be classified as a form of epilepsy.
Alcohol-induced blackouts. Alcohol-induced blackouts may be associated with extremely 
complex behaviors in the absence of other suggestions of intoxication. They do not involve 
the loss of consciousness but rather reflect an isolated disruption of memory for events 
during a drinking episode. By history, these behaviors may be indistinguishable from those 
seen in NREM sleep arousal disorders.

Dissociative amnesia, with dissociative fugue. Dissociative fugue may be extremely 
difficult to distinguish from sleepwalking. Unlike all other parasomnias, nocturnal disso­
ciative fugue arises from a period of wakefulness during sleep, rather than precipitously 
from sleep without intervening wakefulness. A history of recurrent childhood physical or 
sexual abuse is usually present (but may be difficult to obtain).
Malingering or other voluntary behavior occurring during wakefulness. As with disso­
ciative fugue, malingering or other voluntary behavior occurring during wakefulness 
arises from wakefulness.
Panic disorder. Panic attacks may also cause abrupt awakenings from deep NREM sleep 
accompanied by fearfulness, but these episodes produce rapid and complete awakening with­

out the confusion, amnesia, or motor activity typical of NREM sleep arousal disorders.
Medication-induced complex behaviors. Behaviors similar to those in NREM sleep 
arousal disorders can be induced by use of, or withdrawal from, substances or medica­
tions (e.g., benzodiazepines, nonbenzodiazepine sedative-hypnotics, opiates, cocaine, nic­
otine, antipsychotics, tricyclic antidepressants, chloral hydrate). Such behaviors may arise 
from the sleep period and may be extremely complex. The underlying pathophysiology 
appears to be a relatively isolated amnesia. In such cases, substance/medication-induced 
sleep disorder, parasomnia type, should be diagnosed (see "Substance/Medication- 
Induced Sleep Disorder" later in this chapter).

Night eating syndrome. The sleep-related eating disorder form of sleepwalking is to be 
differentiated from night eating syndrome, in which there is a delay in the circadian rhythm 
of food ingestion and an association with insomnia and/or depression.
In adults, there is an association between sleepwalking and major depressive episodes and 
obsessive-compulsive disorder. Children or adults with sleep terrors may have elevated 
scores for depression and anxiety on personality inventories.

The International Classification of Sleep Disorders,  2nd Edition, includes "confusional 
arousal" as a NREM sleep arousal disorder.
Nightmare Disorder
Diagnostic Criteria 307.47 (F51.5)
A. Repeated occurrences of extended, extremely dysphoric, and well-remembered  
dreams that usually involve efforts to avoid threats to survival, security, or physical in­
tegrity and that generally occur during the second half of the major sleep episode.
B. On awakening from the dysphoric dreams, the individual rapidly becomes oriented and  
alert.
0. The sleep disturbance causes clinically significant distress or impairment in social, oc­
cupational, or other important areas of functioning.
D. The nightmare symptoms are not attributable to the physiological effects of a sub­
stance (e.g., a drug of abuse, a medication).
E. Coexisting mental and medical disorders do not adequately explain the predominant  
complaint of dysphoric dreams.

During sleep onset
With associated non-sleep disorder, including substance use disorders  
With associated other medical condition  
With associated other sleep disorder
Coding note: The code 307.47 (F51.5) applies to all three specifiers. Code also the  
diately after the code for nightmare disorder in order to indicate the association.
Acute: Duration of period of nightmares is 1  month or less.
Subacute: Duration of period of nightmares is greater than 1  month but less than  
6 months.
Persistent: Duration of period of nightmares is 6 months or greater.
Severity can be rated by the frequency with which the nightmares occur:

6 months.
Mild: Less than one episode per week on average.
Moderate: One or more episodes per week but less than nightly.
Severe: Episodes nightly.
Nightmares  are typically lengthy, elaborate, story like sequences of dream imagery that 
seem real and that incite anxiety, fear, or other dysphoric emotions. Nightmare content 
typically focuses on attempts to avoid or cope with imminent danger but may involve 
themes that evoke other negative emotions. Nightmares occurring after traumatic experi­
ences may replicate the threatening situation ("'replicative nightmares"), but most do not. 
On awakening, nightmares are well remembered and can be described in detail. They arise

almost exclusively during rapid eye movement (REM) sleep and can thus occur through­
out sleep but are; more likely in the second half of the major sleep episode when dreaming 
is longer and more intense. Factors that increase early-night REM intensity, such as sleep 
fragmentation or deprivation, jet lag, and REM-sensitive medications, might facilitate 
nightmares earlier in the night, including at sleep onset.
Nightmares usually terminate with awakening and rapid return of full alertness. How­
ever, the dysphoric emotions may persist into wakefulness and contribute to difficulty re­
turning to sleep and lasting daytime distress. Some nightmares, known as "bad dreams," 
may not induce awakening and are recalled only later. If nightmares occur during sleep- 
onset REM periods (hypnagogic),  the dysphoric emotion is frequently accompanied by a 
sense of being both awake and unable to move voluntarily {isolated sleep paralysis).

Mild autonomic arousal, including sweating, tachycardia, and tachypnea, may character­
ize nightmares. Body movements and vocalizations are not characteristic because of REM 
sleep-related loss of skeletal muscle tone, but such behaviors may occur under situations 
of emotional stress or sleep fragmentation and in posttraumatic stress disorder (PTSD). 
When talking or emoting occurs, it is typically a brief event terminating the nightmare.
Individuals with frequent nightmares are at substantially greater risk for suicidal ide­
ation and suicide attempts, even when gender and mental illness are taken into account.
Prevalence of nightmares increases through childhood into adolescence. From 1.3% to 
3.9% of parents report that their preschool children have nightmares "often" or "always".

3.9% of parents report that their preschool children have nightmares "often" or "always". 
Prevalence increases from ages 10 to 13 for both males and females but continues to in­
crease to ages 20-29 for females (while decreasing for males), when it can be twice as high 
for females as for males. Prevalence decreases steadily with age for both sexes, but the gen­
der difference remains. Among adults, prevalence of nightmares at least monthly is 6%, 
whereas prevalence for frequent nightmares is l%-2%. Estimates often combine idio­
pathic and posttraumatic nightmares indiscriminately.
Nightmares often begin between ages 3 and 6 years but reach a peak prevalence and se­
verity in late adolescence or early adulthood. Nightmares most likely appear in children 
exposed to acute or chronic psychosocial stressors and thus may not resolve spontane­

ously. In a minority, frequent nightmares persist into adulthood, becoming virtually a life­
long disturbance. Although specific nightmare content may reflect the individual's age, 
the essential features of the disorder are the same across age groups.
Temperamental. Individuals who experience nightmares report more frequent past ad­
verse events, but not necessarily trauma, and often display personality disturbances or 
psychiatric diagnosis.
Environmental. Sleep deprivation or fragmentation, and irregular sleep-wake schedules 
that alter the timing, intensity, or quantity of REM sleep, can put individuals at risk for 
nightmares.
Genetic and physiological. Twin studies have identified genetic effects on the disposi­

tion to nightmares and their co-occurrence with other parasomnias (e.g., sleeptalking).
Course modifiers. Adaptive parental bedside behaviors, such as soothing the child fol­
lowing nightmares, may protect against developing chronic nightmares.

The significance attributed to nightmares may vary by culture, and sensitivity to such be­
liefs may facilitate disclosure.
Adult females report having nightmares more frequently than do adult males. Nightmare 
content differs by sex, with adult females tending to report themes of sexual harassment or 
of loved ones disappearing/dying, and adult males tending to report themes of physical 
aggression or war/terror.
Polysomnographie studies demonstrate abrupt awakenings from REM sleep, usually during 
the second half of the night, prior to report of a nightmare. Heart, respiratory, and eye move­
ment rates may quicken or increase in variability before awakening. Nightmares following 
traumatic events may also arise during non-REM (NREM), particularly stage 2, sleep. The typ­
ical sleep of individuals with nightmares is mildly impaired (e.g., reduced efficiency, less slow-

ical sleep of individuals with nightmares is mildly impaired (e.g., reduced efficiency, less slow- 
wave sleep, more awakenings), with more frequent periodic leg movements in sleep and rel­
ative sympathetic nervous system activation after REM sleep deprivation.
Functional Consequences of Niglitmare Disorder
Nightmares cause more significant subjective distress than demonstrable social or occu­
pational impairment. However, if awakenings are frequent or result in sleep avoidance, 
individuals may experience excessive daytime sleepiness, poor concentration, depression, 
anxiety, or irritability. Frequent childhood nightmares (e.g., several per week), may cause 
significant distress to parents and child.
Sleep terror disorder. Both nightmare disorder and sleep terror disorder include awak­

enings or partial awakenings with fearfulness and autonomic activation, but the two dis­
orders are differentiable. Nightmares typically occur later in the night, during REM sleep, 
and produce vivid, storylike, and clearly recalled dreams; mild autonomic arousal; and 
complete awakenings. Sleep terrors typically arise in the first third of the night during 
stage 3 or 4 NREM sleep and produce either no dream recall or images without an elabo­
rate storylike quality. The terrors lead to partial awakenings that leave the individual con­
fused, disoriented, and only partially responsive and with substantial autonomic arousal. 
There is usually amnesia for the event in the morning.
REM sleep behavior disorder. The presence of complex motor activity during fright­

ening dreams should prompt further evaluation for REM sleep behavior disorder, which 
occurs more typically among late middle-age males and, unlike nightmare disorder, is as­
sociated with often violent dream enactments and a history of nocturnal injuries. The 
dream disturbance of REM sleep behavior disorder is described by patients as nightmares 
but is controlled by appropriate medication.
Bereavement. Dysphoric dreams may occur during bereavement but typically involve 
loss and sadness and are followed by self-reflection and insight, rather than distress, on 
awakening.
Narcolepsy. Nightmares are a frequent complaint in narcolepsy, but the presence of ex­
cessive sleepiness and cataplexy differentiates this condition from nightmare disorder.
Nocturnal seizures. Seizures may rarely manifest as nightmares and should be evalu­

ated with polysomnography and continuous video electroencephalography. Nocturnal 
seizures usually involve stereotypical motor activity. Associated nightmares, if recalled.

are often repetitive in nature or reflect epileptogenic features such as the content of diurnal 
auras (e.g., unmotivated dread), phosphenes, or ictal imagery. Disorders of arousal, espe­
cially confusional arousals, may also be present.
Breathing-related sleep disorders. Breathing-related sleep disorders can lead to av^aken- 
ings with autonomic arousal, but these are not usually accompanied by recall of nightmares.
Panic disorder. Attacks arising during sleep can produce abrupt awakenings with au­
tonomic arousal and fearfulness, but nightmares are typically not reported and symptoms 
are similar to panic attacks arising during wakefulness.
Sleep-related dissociative disorders. Individuals may recall actual physical or emo­
tional trauma as a "dream" during electroencephalography-documented awakenings.
Medication or substance use. Numerous substances/medications can precipitate night­
mares, including dopaminergics; beta-adrenergic antagonists and other antihypertensives;

mares, including dopaminergics; beta-adrenergic antagonists and other antihypertensives; 
amphetamine, cocaine, and other stimulants; antidepressants; smoking cessation aids; 
and melatonin. Withdrawal of REM sleep-suppressant medications (e.g., antidepressants) 
and alcohol can produce REM sleep rebound accompanied by nightmares. If nightmares 
are sufficiently severe to warrant independent clinical attention, a diagnosis of substance/ 
medication-induced sleep disorder should be considered.
Nightmares may be comorbid with several medical conditions, including coronary heart 
disease, cancer, parkinsonism, and pain, and can accompany medical treatments, such as he­
modialysis, or withdrawal from medications or substances of abuse. Nightmares frequently 
are comorbid with other mental disorders, including PTSD; insomnia disorder; schizophrenia;

are comorbid with other mental disorders, including PTSD; insomnia disorder; schizophrenia; 
psychosis; mood, anxiety, adjustment, and personality disorders; and grief during be­
reavement. A concurrent nightmare disorder diagnosis should only be considered when in­
dependent clinical attention is warranted (i.e.. Criteria A-C are met). Otherwise, no separate 
diagnosis is necessary. These conditions should be listed under the appropriate comorbid 
category specifier. However, nightmare disorder may be diagnosed as a separate disorder in 
individuals with PTSD if the nightmares are temporally unrelated to PTSD (i.e., preceding 
other PTSD symptoms or persisting after other PTSD symptoms have resolved).
Nightmares are normally characteristic of REM sleep behavior disorder, PTSD, and acute 
stress disorder, but nightmare disorder may be independently coded if nightmares preceded

stress disorder, but nightmare disorder may be independently coded if nightmares preceded 
the condition and their frequency or severity necessitates independent clinical attention. The 
latter may be determined by asking whether nightmares were a problem before onset of the 
other disorder and whether they continued after other symptoms had remitted.
Relationsliip to internationai Ciassification of  
The International Classification of Sleep Disorders,  2nd Edition (ICSD-2), presents similar di­
agnostic criteria for nightmare disorder.
Rapid Eye Movement Sleep Behavior Disorder
Diagnostic Criteria 327.42 (G47.52)
A. Repeated episodes of arousal during sleep associated with vocalization and/or com­
plex motor behaviors.
B. These behaviors arise during rapid eye movement (REM) sleep and therefore usually

B. These behaviors arise during rapid eye movement (REM) sleep and therefore usually  
occur more than 90 minutes after sleep onset, are more frequent during the later por­
tions of the sleep period, and uncommonly occur during daytime naps.

C. Upon awakening from these episodes, the individual is completely awake, alert, and  
not confused or disoriented.
D. Either of the following:
1. REM sleep without atonia on polysomnographic recording.
2. A history suggestive of REM sleep behavior disorder and an established synuclein-  
opathy diagnosis (e.g., Parkinson’s disease, multiple system atrophy).
E. The behaviors cause clinically significant distress or impairment in social, occupa­
tional, or other important areas of functioning (which may include injury to self or the  
bed partner).
F. The disturbance is not attributable to the physiological effects of a substance (e.g., a  
G. Coexisting mental and medical disorders do not explain the episodes.
The essential feature of rapid eye movement (REM) sleep behavior disorder is repeated 
episodes of arousal, often associated with vocalizations and/or complex motor behaviors

episodes of arousal, often associated with vocalizations and/or complex motor behaviors 
arising from REM sleep (Criterion A). These behaviors often reflect motor responses to the 
content of action-filled or violent dreams of being attacked or trying to escape from a 
threatening situation, which may be termed dream enacting behaviors.  The vocalizations are 
often loud, emotion-filled, and profane. These behaviors may be very bothersome to the 
individual and the bed partner and may result in significant injury (e.g., falling, jumping, 
or flying out of bed; running, punching, thrusting, hitting, or kicking). Upon awakening, 
the individual is immediately awake, alert, and oriented (Criterion C) and is often able to 
recall dream mentation, which closely correlates with the observed behavior. The eyes

recall dream mentation, which closely correlates with the observed behavior. The eyes 
typically remain closed during these events. The diagnosis of REM sleep behavior disor­
der requires clinically significant distress or impairment (Criterion E); this determination 
will depend on a number of factors, including the frequency of events, the potential for vi­
olence or injurious behaviors, embarrassment, and distress in other household members.
Severity determination is best made based on the nature or consequence of the behavior 
rather than simply on frequency. Although the behaviors are typically prominent and vi­
olent, lesser behaviors may also occur.
The prevalence of REM sleep behavior disorder is approximately 0.38%-0.5% in the gen­
eral population. Prevalence in patients with psychiatric disorders may be greater, possibly

eral population. Prevalence in patients with psychiatric disorders may be greater, possibly 
related to medications prescribed for the psychiatric disorder.
The onset of REM sleep behavior disorder may be gradual or rapid, and the course is usu­
ally progressive. REM sleep behavior disorder associated with neurodegenerative disor­
ders may improve as the underlying neurodegenerative disorder progresses. Because of 
the very high association with the later appearance of an underlying neurodegenerative 
disorder, most notably one of the synucleinopathies (Parkinson's disease, multiple system 
atrophy, or major or mild neurocognitive disorder with Lewy bodies), the neurological 
status of individuals with REM sleep behavior disorder should be closely monitored.
REM sleep behavior disorder overwhelmingly affects males older than 50 years, but in­

creasingly this disorder is being identified in females and in younger individuals. Symp­

toms in young individuals, particularly young females, should raise the possibility of 
narcolepsy or medication-induced REM sleep behavior disorder.
Genetic and physiologicaL Many widely prescribed medications, including tricyclic 
antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reup­
take inhibitors, and beta-blockers, may result in polysomnographic evidence of REM sleep 
w^ithout atonia and in frank REM sleep behavior disorder. It is not known whether the 
medications per se result in REM sleep behavior disorder or they unmask an underlying 
predisposition.
Associated laboratory findings from polysomnography indicate increased tonic and/or 
phasic electromyographic activity during REM sleep that is normally associated with mus­
cle atonia. The increased muscle activity variably affects different muscle groups, mandating

cle atonia. The increased muscle activity variably affects different muscle groups, mandating 
more extensive electromyographic monitoring than is employed in conventional sleep stud­
ies. For this reason, it is suggested that electromyographic monitoring include the submen- 
talis, bilateral extensor digitorum, and bilateral anterior tibialis muscle groups. Continuous 
video monitoring is mandatory. Other polysomnographic findings may include very fre­
quent periodic and aperiodic extremity electromyography activity during non-REM 
(NREM) sleep. This polysomnography observation, termed REM sleep without atonia,  is pres­
ent in virtually all cases of REM sleep behavior disorder but may also be an asymptomatic 
polysomnographic finding. Clinical dream-enacting behaviors coupled with the polysom­
nographic finding of REM without atonia is necessary for the diagnosis of REM sleep behav­

ior disorder. REM sleep without atonia without a clinical history of dream-enacting 
behaviors is simply an asymptomatic polysomnographic observation. It is not known 
whether isolated REM sleep without atonia is a precursor to REM sleep behavior disorder.
Rapid Eye IViovement Sieep Behavior Disorder
REM sleep behavior disorder may occur in isolated occasions in otherwise unaffected in­
dividuals. Embarrassment concerning the episodes can impair social relationships. Indi­
viduals may avoid situations in which others might become aware of the disturbance, 
visiting friends overnight, or sleeping with bed partners. Social isolation or occupational 
difficulties can result. Uncommonly, REM sleep behavior disorder may result in serious 
injury to the victim or to the bed partner.

Other parasomnias. Confusional arousals, sleepwalking, and sleep terrors can easily be 
confused with REM sleep behavior disorder. In general, these disorders occur in younger 
individuals. Unlike REM sleep behavior disorder, they arise from deep NREM sleep and 
therefore tend to occur in the early portion of the sleep period. Awakening from a confu­
sional arousal is associated with confusion, disorientation, and incomplete recall of dream 
mentation accompanying the behavior. Polysomnographic monitoring in the disorders of 
arousal reveals normal REM atonia.
Nocturnal seizures. Nocturnal seizures may perfectly mimic REM sleep behavior disor­
der, but the behaviors are generally more stereotyped. Polysomnographic monitoring em­
ploying a full electroencephalographic seizure montage may differentiate the two. REM

ploying a full electroencephalographic seizure montage may differentiate the two. REM 
sleep without atonia is not present on polysomnographic monitoring.

Obstructive sleep apnea. Obstructive sleep apnea may result in behaviors indistin­
guishable from REM sleep behavior disorder. Polysomnographie monitoring is necessary 
to differentiate between the two. In this case, the symptoms resolve following effective 
treatment of the obstructive sleep apnea, and REM sleep without atonia is not present on 
polysomnography monitoring.
Other specified dissociative disorder (sleep-related psychogenic dissociative disorder).
Unlike virtually all other parasomnias, which arise precipitously from NREM or REM 
sleep, psychogenic dissociative behaviors arise from a period of well-defined wakefulness 
during the sleep period. Unlike REM sleep behavior disorder, this condition is more prev­
alent in young females.
Malingering. Many cases of malingering in which the individual reports problematic 
sleep movements perfectly mimic the clinical features of REM sleep behavior disorder, 
and polysonmographic documentation is mandatory.

REM sleep behavior disorder is present concurrently in approximately 30% of patients 
with narcolepsy. When it occurs in narcolepsy, the demographics reflect the younger age 
range of narcolepsy, with equal frequency in males and females. Based on findings from 
individuals presenting to sleep clinics, most individuals (>50%) with initially "'idiopathic" 
REM sleep behavior disorder will eventually develop a neurodegenerative disease—most 
notably, one of the synucleinopathies (Parkinson's disease, multiple system atrophy, or 
major or mild neurocognitive disorder with Lewy bodies). REM sleep behavior disorder 
often predates any other sign of these disorders by many years (often more than a decade).

REM sleep behavior disorder is virtually identical to REM sleep behavior disorder in the 
International Classification of Sleep Disorders,  2nd Edition (ICSD-2).
Restless Legs Syndrome
Diagnostic Criteria 333.94 (G25.81)
A. An urge to move the legs, usually accompanied by or in response to uncomfortable and  
unpleasant sensations in the legs, characterized by all of the following:
1. The urge to move the legs begins or worsens during periods of rest or inactivity.
2. The urge to move the legs is partially or totally relieved by movement.
3. The urge to move the legs is worse in the evening or at night than during the day,  
or occurs only in the evening or at night.
B. The symptoms in Criterion A occur at least three times per week and have persisted  
for at least 3 months.

C. The symptoms in Criterion A are accompanied by significant distress or impairment in  
social, occupational, educational, academic, behavioral, or other important areas of  
D. The symptoms in  Criterion A are not attributable to another mental disorder or medical  
condition (e.g., arthritis, leg edema, peripheral ischemia, leg cramps) and are not better  
explained by a behavioral condition (e.g., positional discomfort, habitual foot tapping).
E. The symptoms are not attributable to the physiological effects of a drug of abuse or  
medication (e.g., akathisia).

Restless legs syndrome (RLS) is a sensorimotor, neurological sleep disorder characterized 
by a desire to move the legs or arms, usually associated with uncomfortable sensations 
typically described as creeping, crawling, tingling, burning, or itching (Criterion A). The 
diagnosis of RLS is based primarily on patient self-report and history. Symptoms are 
worse when the individual is at rest, and frequent movements of the legs occur in an effort 
to relieve the uncomfortable sensations. Symptoms are worse in the evening or night, and 
in some individuals they occur only in the evening or night. Evening worsening occurs in­
dependently of any differences in activity. It is important to differentiate RLS from other 
conditions such as positional discomfort and leg cramps (Criterion D).
The symptoms of RLS can delay sleep onset and awaken the individual from sleep and 
are associated with significant sleep fragmentation. The relief obtained from moving the

are associated with significant sleep fragmentation. The relief obtained from moving the 
legs may no longer be apparent in severe cases. RLS is associated with daytime sleepiness 
and is frequently accompanied by significant clinical distress or functional impairment.
Periodic leg movements in sleep (PLMS) can serve as corroborating evidence for RLS, with 
up to 90% of individuals diagnosed with RLS demonstrating PLMS when recordings are 
taken over multiple nights. Periodic leg movements during wakefulness are supportive of 
an RLS diagnosis. Reports of difficulty initiating and maintaining sleep and of excessive 
daytime sleepiness may also support the diagnosis of RLS. Additional supportive features 
include a family history of RLS among first-degree relatives and a reduction in symptoms, 
at least initially, with dopaminergic treatment.

Prevalence rates of RLS vary widely when broad criteria are utilized but range from 2% to 
7.2% when more defined criteria are employed. When frequency of symptoms is at least 
three times per week with moderate or severe distress, the prevalence rate is 1.6%; when 
frequency of symptoms is a minimum of one time per week, the prevalence rate is 4.5%. 
Females are 1.5-2 times more likely than males to have RLS. RLS also increases with age. 
The prevalence of RLS may be lower in Asian populations.
The onset of RLS typically occurs in the second or third decade. Approximately 40% of in­
dividuals diagnosed with RLS during adulthood report having experienced symptoms 
before age 2 0 years, and 2 0% report having experienced symptoms before age 10 years.

before age 2 0 years, and 2 0% report having experienced symptoms before age 10 years. 
Prevalence rates of RLS increase steadily with age until about age 60 years, with symptoms 
remaining stable or decreasing slightly in older age groups. Compared with nonfamilial 
cases, familial RLS usually has a younger age at onset and a slower progressive course. The 
clinical course of RLS differs by age at onset. When onset occurs before age 45, there is of­
ten a slow progression of symptoms. In late-onset RLS, rapid progression is typical, and 
aggravating factors are common. Symptoms of RLS appear similar across the lifespan, re­
maining stable or decreasing slightly in older age groups.
Diagnosis of RLS in children can be difficult because of the self-report component. 
While Criterion A for adults assumes that the description of "urge to move" is by the pa­

tient, pediatric diagnosis requires a description in the child's own words rather than by a 
parent or caretaker. Typically children age 6 years or older are able to provide detailed, ad­
equate descriptors of RLS. However, children rarely use or understand the word "urge," 
reporting instead that their legs "have to" or "got to" move. Also, potentially related to 
prolonged periods of sitting during class, two-thirds of children and adolescents report 
daytime leg sensations. Thus, for diagnostic Criterion A3, it is important to compare equal

duration of sitting or lying down in the day to sitting or lying down in the evening or night. 
Nocturnal worsening tends to persist even in the context of pediatric RLS. As with RLS in 
adults, there is a significant negative impact on sleep, mood, cognition, and function. Im­
pairment in children and adolescents is manifested more often in behavioral and educa­
tional domains.
Genetic and physiological. Predisposing factors include female gender, advancing 
age, genetic risk variants, and family history of RLS. Precipitating factors are often time- 
limited, such as iron deficiency, with most individuals resuming normal sleep patterns 
after the initial triggering event has disappeared. Genetic risk variants also play a role in 
RLS secondary to such disorders as uremia, suggesting that individuals with a genetic sus­
ceptibility develop RLS in the presence of further risk factors. RLS has a strong familial 
component.

There are defined pathophysiological pathways subserving RLS. Genome-wide asso­
ciation studies have found that RLS is significantly associated with common genetic vari­
ants in intronic or intergenic regions in MEISl, BTBD9,  and ΜΛΡ2Κ5  on chromosomes 2p, 
6p, and 15q, respectively. The association of these three variants with RLS has been inde­
pendently replicated. BTBD9  confers a very large (80%) excessive risk when even a single 
allele is present. Because of the high frequency of this variant in individuals of European 
descent, the population attributable risk (PAR) approximates 50%. At-risk alleles associ­
ated with MEISl  and BTBD9  are less common in individuals of African or Asian descent, 
perhaps suggesting lower risk for RLS in these populations.

Pathophysiological mechanisms in RLS also include disturbances in the central dopa­
minergic system and disturbances in iron metabolism. The endogenous opiate system 
may also be involved. Treatment effects of dopaminergic drugs (primarily D 2 and D 3 non­
ergot agonists) provide further support that RLS is grounded in dysfunctional central 
dopaminergic pathways. While the effective treatment of RLS has also been shown to sig­
nificantly reduce depressive symptoms, serotonergic antidepressants can induce or aggra­
vate RLS in some individuals.
Although RLS is more prevalent in females than in males, there are no diagnostic differ­
ences according to gender. However, the prevalence of RLS during pregnancy is two to 
three times greater than in the general population. RLS associated with pregnancy peaks

three times greater than in the general population. RLS associated with pregnancy peaks 
during the third trimester and improves or resolves in most cases soon after delivery. The 
gender difference in prevalence of RLS is explained at least in part by parity, with nullipa- 
rous females being at the same risk of RLS as age-matched males.
Polysomnography demonstrates significant abnormalities in RLS, commonly increased 
latency to sleep, and higher arousal index. Polysomnography with a preceding immobili­
zation test may provide an indicator of the motor sign of RLS, periodic limb movements, 
under standard conditions of sleep and during quiet resting, both of which can provoke RLS 
symptoms.
Functionai Consequences of Restless Legs Syndrome
Forms of RLS severe enough to significantly impair functioning or associated with mental dis­

symptoms.
orders, including depression and anxiety, occur in approximately 2%-3% of the population.
Although the impact of milder symptoms is less well characterized, individuals with 
RLS complain of disruption in at least one activity of daily living, with up to 50% reporting

a negative impact on mood, and 47.6% reporting a lack of energy. The most common conse­
quences of RLS are sleep disturbance, including reduced sleep time, sleep fragmentation, 
and overall disturbance; depression, generalized anxiety disorder, panic disorder, and post­
traumatic stress disorder; and quality-of-life impairments. RLS can result in daytime sleep­
iness or fatigue and is frequently accompanied by significant distress or impairment in 
affective, social, occupational, educational, academic, behavioral, or cognitive functioning.
The most important conditions in the differential diagnosis of RLS are leg cramps, posi­
tional discomfort, arthralgias/arthritis, myalgias, positional ischemia (numbness), leg 
edema, peripheral neuropathy, radiculopathy, and habitual foot tapping. ''Knotting" of 
the muscle (cramps), relief with a single postural shift, limitation to joints, soreness to pal­

pation (myalgias), and other abnormalities on physical examination are not characteristic 
of RLS. Unlike RLS, nocturnal leg cramps do not typically present with the desire to move 
the limbs nor are there frequent limb movements. Less common conditions to be differen­
tiated from RLS include neuroleptic-induced akathisia, myelopathy, symptomatic venous 
insufficiency, peripheral artery disease, eczema, other orthopedic problems, and anxiety- 
induced restlessness. Worsening at night and periodic limb movements are more connmon 
in RLS than in medication-induced akathisia or peripheral neuropathy.
While is it important that RLS symptoms not be solely accounted for by another medical 
or behavioral condition, it should also be appreciated that any of these similar conditions can

or behavioral condition, it should also be appreciated that any of these similar conditions can 
occur in an individual with RLS. This necessitates a separate focus on each possible condi­
tion in the diagnostic process and when assessing impact. For cases in which tiie diagnosis of 
RLS is not certain, evaluation for the supportive features of RLS, particularly PLMS or a fam­
ily history of RLS, may be helpful. Clinical features, such as response to a dopaminergic 
agent and positive family history for RLS, can help with the differential diagnosis.
Depressive disorders, anxiety disorders, and attentional disorders are commonly comor- 
bid with RLS and are discussed in the section "Functional Consequences of Restless Legs 
Syndrome." The main medical disorder comorbid with RLS is cardiovascular disease.

Syndrome." The main medical disorder comorbid with RLS is cardiovascular disease. 
There may be an association with numerous other medical disorders, including hyperten­
sion, narcolepsy, migraine, Parkinson's disease, multiple sclerosis, peripheral neuropathy, 
obstructive sleep apnea, diabetes mellitus, fibromyalgia, osteoporosis, obesity, thyroid 
disease, and cancer. Iron deficiency, pregnancy, and chronic renal failure are also comor­
bid with RLS.
The International Classification of Sleep Disorders,  2nd Edition (ICSD-2), presents similar diag­
nostic criteria for RLS but does not contain a criterion specifying frequency or duration of 
symptoms.
Substance/Medication-Induced Sleep Disorder
A. A prominent and severe disturbance in  sleep.

symptoms.
B. There is evidence from tiie history, physical examination, or laboratory findings of both  

or after withdrawal from or exposure to a medication.
rion A.
C. The disturbance is not better explained by a sleep disorder that is not substance/  
medication-induced. Such evidence of an independent sleep disorder could include  
acute withdrawal or severe intoxication; or there is other evidence suggesting the  
existence of an independent non-substance/medication-induced sleep disorder  

substance withdrawal only when the symptoms in  Criterion A predominate in the clinical  
tion]-induced sleep disorders are indicated in  the table below. Note that the ICD-10-CM  
stance-induced sleep disorder, the 4th position character is “ 1 a n d  the clinician should

stance-induced sleep disorder, the 4th position character is “ 1 a n d  the clinician should  
record “ mild [substance] use disorder”  before the substance-induced sleep disorder (e.g.,  
“ mild cocaine use disorder with cocaine-induced sleep disorder”). If a moderate or severe  
substance use disorder is comorbid with the substance-induced sleep disorder, the 4th po­
sition character is “ 2,”  and the clinician should record “ moderate [substance] use disorder”  
or “ severe [substance] use disorder,”  depending on the severity of the comorbid substance  
use disorder. If there is no comorbid substance use disorder (e.g., after a one-time heavy  
use of the substance), then the 4th position character is “ 9,”  and the clinician should record  
only the substance-induced sleep disorder. A moderate or severe tobacco use disorder is

only the substance-induced sleep disorder. A moderate or severe tobacco use disorder is  
required in order to code a tobacco-induced sleep disorder; it is not permissible to code a  
comorbid mild tobacco use disorder or no tobacco use disorder with a tobacco-induced  
sleep disorder.
Insomnia type: Characterized by difficulty falling asleep or maintaining sleep, frequent  
nocturnal awakenings, or nonrestorative sleep.
Daytime sleepiness type: Characterized by predominant complaint of excessive  
sleepiness/fatigue during waking hours or, less commonly, a long sleep period.  
Parasomnia type: Characterized by abnormal behavioral events during sleep.  
lUlixed type: Characterized by a substance/medication-induced sleep problem charac­
terized by multiple types of sleep symptoms, but no symptom clearly predominates.

With onset during intoxication: This specifier should be used if criteria are met for  
intoxication with the substance/medication and symptoms developed during the intox­
ication period.
With onset during discontinuation/withdrawal: This specifier should be used if cri­
teria are met for discontinuation/withdrawal from the substance/medication and symp­
toms developed during, or shortly after, discontinuation of the substance/medication.

disorder,  
mildICD-IO-CM
With use  
disorder,  
moderate  
use
disorder
Alcohol 291.82 F10.182 F10.282 FI 0.982
Caffeine 292.85 F15.182 FI 5.282 F15.982
Cannabis 292.85 F12.188 FI 2.288 FI 2.988
Opioid 292.85 F11.182 F11.282 F11.982
Sedative, hypnotic, or anxiolytic 292.85 F13.182 FI 3.282 FI 3.982
stimulant)292.85 F15.182 FI 5.282 FI 5.982
Cocaine 292.85 F14.182 FI 4.282 FI 4.982
Tobacco 292.85 NA F17.208 NA
Other (or unknown) substance 292.85 FI 9.182 FI 9.282 FI 9.982
ICD-9-CM. The name of the substance/medication-induced sleep disorder begins with 
the specific substance (e.g., cocaine, bupropion) that is presumed to be causing the sleep 
disturbance. The diagnostic code is selected from the table included in the criteria set, 
which is based on the drug class. For substances that do not fit into any of the classes (e.g.,

which is based on the drug class. For substances that do not fit into any of the classes (e.g., 
bupropion), the code for "other substance" should be used; and in cases in which a sub­
stance is judged to be an etiological factor but the specific class of substance is unknown, 
the category "unknown substance" should be used.
toxication, onset during discontinuation/withdrawal), followed by the subtype designa­
tion (i.e., insomnia type, daytime sleepiness type, parasomnia type, mixed type). Unlike 
the recording procedures for ICD-IO-CM, which combine the substance-induced disorder 
and substance use disorder into a single code, for ICD-9-CM a separate diagnostic code 
is given for the substance use disorder. For example, in the case of insomnia occurring

is given for the substance use disorder. For example, in the case of insomnia occurring 
during withdrawal in a man with a severe lorazepam use disorder, the diagnosis is 292.85 
lorazepam-induced sleep disorder, with onset during withdrawal, insomnia type. An ad­
ditional diagnosis of 304.10 severe lorazepam use disorder is also given. When more than 
one substance is judged to play a significant role in the development of the sleep distur­
bance, each should be listed separately (e.g., 292.85 alcohol-induced sleep disorder, with 
onset during intoxication, insonmia type; 292.85 cocaine-induced sleep disorder, with on­
set during intoxication, insomnia type).
ICD-10-CM . The name of the substance/medication-induced sleep disorder begins with the 
specific substance (e.g., cocaine, bupropion) that is presumed to be causing the sleep distur­

bance. The diagnostic code is selected from the table included in the criteria set, which is based 
on the drug class and presence or absence of a comorbid substance use disorder. For sub­
stances that do not fit into any of the classes (e.g., bupropion), the code for "other substance" 
should be used; and in cases in which a substance is judged to be an etiological factor but the 
specific class of substance is unknown, the category "unknown substance" should be used.
sleep disorder, followed by the specification of onset (i.e., onset during intoxication, onset

during discontinuation/withdrawal), followed by the subtype designation (i.e., insomnia 
type, daytime sleepiness type, parasomnia type, mixed type). For example, in the case of 
insomnia occurring during withdrawal in a man with a severe lorazepam use disorder, the 
diagnosis is F13.282 severe lorazepam use disorder with lorazepam-induced sleep disor­
der, with onset during withdrawal, insomnia type. A separate diagnosis of the comorbid 
severe lorazepam use disorder is not given. If the substance-induced sleep disorder occurs 
without a comorbid substance use disorder (e.g., with medication use), no accompanying 
substance use disorder is noted (e.g., F19.982 bupropion-induced sleep disorder, with on­
set during medication use, insomnia type). When more than one substance is judged to 
play a significant role in the development of the sleep disturbance, each should be listed 
separately (e.g., F10.282 severe alcohol use disorder with alcohol-induced sleep disorder,

separately (e.g., F10.282 severe alcohol use disorder with alcohol-induced sleep disorder, 
with onset during intoxication, insomnia type; F14.282 severe cocaine use disorder with 
cocaine-induced sleep disorder, with onset during intoxication, insomnia type).
The essential feature of substance/medication-induced sleep disorder is a prominent sleep 
disturbance that is sufficiently severe to warrant independent clinical attention (Criterion A) 
and that is judged to be primarily associated with the pharmacological effects of a substance 
(i.e., a drug of abuse, a medication, toxin exposure) (Criterion B). Depending on the sub­
stance involved, one of four types of sleep disturbances is reported. Insomnia type and day­
time sleepiness type are most common, while parasomnia type is seen less often. The mixed

time sleepiness type are most common, while parasomnia type is seen less often. The mixed 
type is noted when more than one type of sleep disturbance-related symptom is present and 
none predominates. The disturbance must not be better explained by another sleep disorder 
(Criterion C). A substance/medication-induced sleep disorder is distinguished from insom­
nia disorder or a disorder associated with excessive daytime sleepiness by considering onset 
and course. For drugs of abuse, there must be evidence of intoxication or withdrawal from 
the history, physical examination, or laboratory findings. Substance/medication-induced 
sleep disorder arises only in association with intoxication or discontinuation/withdrawal 
states, whereas other sleep disorders may precede the onset of substance use or occur during

states, whereas other sleep disorders may precede the onset of substance use or occur during 
times of sustained abstinence. As discontinuation/withdrawal states for some substances 
can be protracted, onset of the sleep disturbance can occur 4 weeks after cessation of sub­
stance use, and the disturbance may have features atypical of other sleep disorders (e.g., 
atypical age at onset or course). The diagnosis is not made if the sleep disturbance occurs 
only during a delirium (Criterion D). The symptoms must cause clinically significant dis­
tress or impairment in social, occupational, or other important areas of functioning (Crite­
rion E). This diagnosis should be made instead of a diagnosis of substance intoxication or 
substance withdrawal only when the symptoms in Criterion A predominate in the clinical 
picture and when the symptoms warrant independent clinical attention.

During periods of substance/medication use, intoxication, or withdrawal, individuals fre­
quently complain of dysphoric mood, including depression and anxiety, irritability, cog­
nitive impairment, inability to concentrate, and fatigue.
Prominent and severe sleep disturbances can occur in association with intoxication 
with the following classes of substances: alcohol; caffeine; cannabis; opioids; sedatives, 
hypnotics, or anxiolytics; stimulants (including cocaine); and other (or unknown) sub­
stances. Prominent and severe sleep disturbances can occur in association with withdrawal 
from the following classes of substances: alcohol; caffeine; cannabis; opioids; sedatives, 
hypnotics, or anxiolytics; stimulant (including cocaine); tobacco; and other (or unknown)

hypnotics, or anxiolytics; stimulant (including cocaine); tobacco; and other (or unknown) 
substances. Some medications that invoke sleep disturbances include adrenergic agonists 
and antagonists, dopamine agonists and antagonists, cholinergic agonists and antagonists, 
serotonergic agonists and antagonists, antihistamines, and corticosteroids.

Alcohol. Alcohol-induced sleep disorder typically occurs as insomnia type. During 
acute intoxication, alcohol produces an immediate sedative effect depending on dose, ac­
companied by increased stages 3 and 4 non-rapid eye movement (NREM) sleep and re­
duced rapid eye movement (REM) sleep. Following these initial effects, there may be 
increased wakefulness, restless sleep, and vivid and anxiety-laden dreams for the remain­
ing sleep period. In parallel, stages 3 and 4 sleep are reduced, and wakefulness and REM 
sleep are increased. Alcohol can aggravate breathing-related sleep disorder. With habitual 
use, alcohol continues to show a short-lived sedative effect in the first half of the night, fol­
lowed by sleep continuity disruption in the second half. During alcohol withdrawal, there 
is extremely disrupted sleep continuity, and an increased amount and intensity of REM 
sleep, associated frequently with vivid dreaming, which in extreme form, constitutes part

sleep, associated frequently with vivid dreaming, which in extreme form, constitutes part 
of alcohol withdrawal delirium. After acute withdrawal, chronic alcohol users may con­
tinue to complain of light, fragmented sleep for weeks to years associated with a persistent 
deficit in slow-wave sleep.
Caffeine. Caffeine-induced sleep disorder produces insomnia in a dose-dependent man­
ner, with some individuals presenting with daytime sleepiness related to withdrawal.
Cannabis. Acute administration of cannabis may shorten sleep latency, though arous­
ing effects with increments in sleep latency also occur. Cannabis enhances slow-wave 
sleep and suppresses REM sleep after acute administration. In chronic users, tolerance to 
the sleep-inducing and slow-wave sleep-enhancing effects develops. Upon withdrawal, 
sleep difficulties and unpleasant dreams have been reported lasting for several weeks.

sleep difficulties and unpleasant dreams have been reported lasting for several weeks. 
Polysomnography studies demonstrate reduced slow-wave sleep and increased REM sleep 
during this phase.
Opioids. Opioids may produce an increase in sleepiness and in subjective depth of sleep, 
and reduced REM sleep, during acute short-term use. With continued administration, tol­
erance to the sedative effects of opioids develops and there are complaints of insomnia. 
Consistent with their respiratory depressant effects, opioids exacerbate sleep apnea.
Sedative, hypnotic, or anxiolytic substances. Sedatives, hypnotics, and anxiolytics (e.g., 
barbiturates, benzodiazepines receptor agonists, meprobamate, glutethimide, methypry- 
lon) have similar effects as opioids on sleep. During acute intoxication, sedative-hypnotic 
drugs produce the expected increase in sleepiness and decrease in wakefulness. Chronic

drugs produce the expected increase in sleepiness and decrease in wakefulness. Chronic 
use (particularly of barbiturates and the older nonbarbiturate, nonbenzodiazepine drugs) 
may cause tolerance with subsequent return of insomnia. Daytime sleepiness may occur. 
Sedative-hypnotic drugs can increase the frequency and severity of obstructive sleep ap­
nea events. Parasomnias are associated with use of benzodiazepine receptor agonists, es­
pecially when these medications are taken at higher doses and when they are combined 
with other sedative drugs. Abrupt discontinuation of chronic sedative, hypnotic, or anx­
iolytic use can lead to withdrawal but more commonly rebound insomnia, a condition of 
an exacerbation of insomnia upon drug discontinuation for 1-2 days reported to occur 
even with short-term use. Sedative, hypnotic, or anxiolytic drugs with short durations of

even with short-term use. Sedative, hypnotic, or anxiolytic drugs with short durations of 
action are most likely to produce complaints of rebound insomnia, whereas those with 
longer durations of action are more often associated with daytime sleepiness. Any sedative, 
hypnotic, or anxiolytic drug can potentially cause daytime sedation, withdrawal, or re­
bound insomnia.
Amphetamines and related substances and other stimulants. Sleep disorders induced 
by amphetamine and related substances and other stimulants are characterized by insomnia 
during intoxication and excessive sleepiness during withdrawal. During acute intoxication, 
stimulants reduce the total amount of sleep, increase sleep latency and sleep continuity distur­
bances, and decrease REM sleep. Slow-wave sleep tends to be reduced. During withdrawal

bances, and decrease REM sleep. Slow-wave sleep tends to be reduced. During withdrawal 
from chronic stimulant use, there is both prolonged nocturnal sleep duration and excessive 
daytime sleepiness. Multiple sleep latency tests may show increased daytime sleepiness dur-

ing the withdrawal phase. Drugs like 34-methylenedioxyrnethamphetamine (MDMA; "ec­
stasy") and related substances lead to restless and disturbed sleep within 48 hours of intake; 
frequent use of these compounds is associated with persisting symptoms of anxiety, depres­
sion, and sleep disturbances, even during longer-term abstinence.
Tobacco. Chronic tobacco consumption is associated primarily with symptoms of insom­
nia, decreased slow-wave sleep with a reduction of sleep efficiency, and increased daytime 
sleepiness. Withdrawal from tobacco can lead to impaired sleep. Individuals who smoke 
heavily may experience regular nocturnal awakenings caused by tobacco craving.
Other or unknown substances/medications. Other substances/medications may pro­
duce sleep disturbances, particularly medications that affect the central or autonomic 
nervous systems (e.g., adrenergic agonists and antagonists, dopamine agonists and antag­

onists, cholinergic agonists and antagonists, serotonergic agonists and antagonists, anti­
histamines, corticosteroids).
Insomnia in children can be identified by either a parent or the child. Often the child has a 
clear sleep disturbance associated with initiation of a medication but may not report 
symptoms, although parents observe the sleep disturbances. The use of some illicit sub­
stances (e.g., cannabis, ecstasy) is prevalent in adolescence and early adulthood. Insomnia 
or any other sleep disturbance encountered in this age group should prompt careful con­
sideration of whether the sleep disturbance is due to consumption of these substances. 
Help-seeking behavior for the sleep disturbance in these age groups is limited, and thus

Help-seeking behavior for the sleep disturbance in these age groups is limited, and thus 
corroborative report may be elicited from a parent, caregiver, or teacher. Older individuals 
take more medications and are at increased risk for developing a substance/medication- 
induced sleep disorder. They may interpret sleep disturbance as part of normal aging and 
fail to report symptoms. Individuals with major neurocognitive disorder (e.g., dementia) 
are at risk for substance/medication-induced sleep disorders but may not report symp­
toms, making corroborative report from caregiver(s) particularly important.
Risk and prognostic factors involved in substance abuse/dependence or medication use 
are normative for certain age groups. They are relevant for, and likely applicable to, the 
type of sleep disturbance encountered (see the chapter "Substance-Related and Addictive

type of sleep disturbance encountered (see the chapter "Substance-Related and Addictive 
Disorders" for descriptions of respective substance use disorders).
Temperamental. Substance use generally precipitates or accompanies insomnia in vul­
nerable individuals. Thus, presence of insomnia in response to stress or change in sleep en­
vironment or timing can represent a risk for developing substance/medication-induced 
sleep disorder. A similar risk may be present for individuals with other sleep disorders 
(e.g., individuals with hypersomnia who use stimulants).
The consumption of substances, including prescribed medications, may depend in part on 
cultural background and specific local drug regulations.
Gender-specific prevalences (i.e., females affected more than males at a ratio of about 2:1) exist

Gender-specific prevalences (i.e., females affected more than males at a ratio of about 2:1) exist 
for patterns of consumption of some substances (e.g., alcohol). The same amount and duration 
of consumption of a given substance may lead to highly different sleep-related outcomes in 
males and females based on, for example, gender-specific differences in hepatic functioning.

Each of the substance/medication-induced sleep disorders produces electroencephalo- 
graphic sleep patterns that are associated with, but cannot be considered diagnostic of, other 
disorders. The electroencephalographic sleep profile for each substance is related to the 
stage of use, whether intake/intoxication, chronic use, or withdrawal following discontinu­
ation of the substance. All-night polysomnography can help define the severity of insomnia 
complaints, while the multiple sleep latency test provides information about Üie severity of 
daytime sleepiness. Monitoring of nocturnal respiration and periodic limb movements with 
polysomnography may verify a substance's impact on nocturnal breathing and motor be­
havior. Sleep diaries for 2 weeks and actigraphy are considered helpful in confirming the 
presence of substance/medication-induced sleep disorder. Drug screening can be of use

presence of substance/medication-induced sleep disorder. Drug screening can be of use 
when the individual is not aware or unwilling to relate information about substance intake.
Substance/iVledication-induced Sleep Disorder
While there are many functional consequences associated with sleep disorders, the only 
unique consequence for substance/medication-induced sleep disorder is increased risk 
for relapse. The degree of sleep disturbance during alcohol withdrawal (e.g., REM sleep 
rebound predicts risk of relapse of drinking). Monitoring of sleep quality and daytime 
sleepiness during and after withdrawal may provide clinically meaningful information on 
whether an individual is at increased risk for relapse.
Substance intoxication or substance withdrawal. Sleep disturbances are commonly en­

countered in the context of substance intoxication or substance discontinuation/with­
drawal. A diagnosis of substance/medication-induced sleep disorder should be made 
instead of a diagnosis of substance intoxication or substance withdrawal only when the 
sleep disturbance is predominant in the clinical picture and is sufficiently severe to war­
rant independent clinical attention.
Delirium. If the substance/medication-induced sleep disturbance occurs exclusively dur­
ing the course of a delirium, it is not diagnosed separately.
Other sleep disorders. A substance/medication-induced sleep disorder is distinguished 
from another sleep disorder if a substance/medication is judged to be etiologically related to 
the symptoms. A substance/medication-induced sleep disorder attributed to a prescribed

the symptoms. A substance/medication-induced sleep disorder attributed to a prescribed 
medication for a mental disorder or medical condition must have its onset while the individual 
is receiving the medication or during discontinuation, if there is a discontinuation/with­
drawal syndrome associated with the medication. Once treatment is discontinued, the sleep 
disturbance will usually remit within days to several weeks. If symptoms persist beyond 
4 weeks, other causes for the sleep disturbance-related symptoms should be considered. Not 
infrequently, individuals with another sleep disorder use medications or drugs of abuse to 
self-medicate their symptoms (e.g., alcohol for management of insomnia). If the substance/ 
medication is judged to play a significant role in the exacerbation of the sleep disturbance, an

medication is judged to play a significant role in the exacerbation of the sleep disturbance, an 
additional diagnosis of a substance/medication-induced sleep disorder may be warranted.
Sleep disorder due to another medical condition. Substance/medication-induced sleep 
disorder and sleep disorder associated with another medical condition may produce sim­
ilar symptoms of insomnia, daytime sleepiness, or a parasomnia. Many individuals with 
other medical conditions that cause sleep disturbance are treated with medications that 
may also cause sleep disturbances. The chronology of symptoms is the most important fac­
tor in distinguishing between these two sources of sleep symptoms. Difficulties with sleep 
that clearly preceded the use of any medication for treatment of a medical condition would

suggest a diagnosis of sleep disorder associated with another medical condition. Con­
versely, sleep symptoms that appear only after the initiation of a particular medication/ 
substance suggest a substance/medication-induced sleep disorder. If the disturbance is 
comorbid with another medical condition and is also exacerbated by substance use, both 
diagnoses (i.e., sleep disorder associated with another medical condition and substance/ 
medication-induced sleep disorder) are given. When there is insufficient evidence to de­
termine whether the sleep disturbance is attributable to a substance/medication or to an­
other medical condition or is primary (i.e., not due to either a substance/medication or 
another medical condition), a diagnosis of other specified sleep-wake disorder or unspec­
ified sleep-wake disorder is indicated.
See the "Comorbidity" sections for other sleep disorders in this chapter, including insom­

nia, hypersomnolence, central sleep apnea, sleep-related hypoventilation, and circadian 
rhythm sleep-wake disorders, shift work type.
The International Classification of Sleep Disorders,  2nd Edition (ICSD-2), lists sleep disorders 
"due to drug or substance" under their respective phenotypes (e.g., insonmia, hypersomnia).
Other Specified Insomnia Disorder
This category applies to presentations in  which symptoms characteristic of insomnia disorder  
that cause clinically significant distress or impairment in  social, occupational, or other important  
areas of functioning predominate but do not meet the full criteria for insomnia disorder or any  
of the disorders In the sleep-wake disorders diagnostic class. The other specified insomnia dis­

order category is used in situations in  which the clinician chooses to communicate the specific  
reason that the presentation does not meet the criteria for insomnia disorder or any specific  
sleep-wake disorder. This is done by recording “ other specified insomnia disorder”  followed by  
the specific reason (e.g., “ brief insomnia disorder).
1. Brief insomnia disorder: Duration is less than 3 months.
2. Restricted to nonrestorative sleep: Predominant complaint is nonrestorative sleep  
unaccompanied by other sleep symptoms such as difficulty falling asleep or remaining  
asleep.
Unspecified Insomnia Disorder

asleep.
This category applies to presentations in  which symptoms characteristic of insomnia disor­
der that cause clinically significant distress or impairment in social, occupational, or other  
important areas of functioning predominate but do not meet the full criteria for insomnia dis­
order or any of the disorders in  the sleep-wake disorders diagnostic class. The unspecified

insomnia disorder category is used in situations in which the clinician chooses not to specify  
the reason that the criteria are not met for insomnia disorder or a specific sleep-wake dis­
specific diagnosis.
Other Specified Hypersomnolence Disorder
This category applies to presentations in  which symptoms characteristic of hypersomno­
lence disorder that cause clinically significant distress or impairment in social, occupation­
hypersomnolence disorder or any of the disorders in the sleep-wake disorders diagnostic  
class. The other specified hypersomnolence disorder category is used in situations in  
which the clinician chooses to communicate the specific reason that the presentation does  
not meet the criteria for hypersomnolence disorder or any specific sleep-wake disorder.

not meet the criteria for hypersomnolence disorder or any specific sleep-wake disorder.  
This is done by recording “ other specified hypersomnolence disorder”  followed by the spe­
cific reason (e.g., “ brief-duration hypersomnolence,”  as in Kieine-Levin syndrome).
Unspecified Hypersomnolence Disorder
This category applies to presentations in which symptoms characteristic of hypersomno­
class. The unspecified hypersomnolence disorder category is used in situations in which  
the clinician chooses not to specify the reason that the criteria are not met for hypersom­

nolence disorder or a specific sleep-wake disorder, and includes presentations in which  
there is insufficient information to make a more specific diagnosis.
Other Specified Sleep-Wake Disorder
This category applies to presentations in which symptoms characteristic of a sleep-wake  
the disorders in  the sleep-wake disorders diagnostic class and do not qualify for a diagno­
sis of other specified insomnia disorder or other specified hypersomnolence disorder. The  
other specified sleep-wake disorder category is used in situations in which the clinician

other specified sleep-wake disorder category is used in situations in which the clinician  
chooses to communicate the specific reason that the presentation does not meet the  
criteria for any specific sleep-wake disorder. This is done by recording “ other specified  
sleep-wake disorder”  followed by the specific reason (e.g., “ repeated arousals during rapid  
eye movement sleep without polysomnography or history of Parkinson’s disease or other  
synucleinopathy” ).

Unspecified Sleep-Wake Disorder
780.59 (G47.9)
other Important areas of functioning predominate but do not meet the full criteria for any of  
the disorders in the sleep-wake disorders diagnostic class and do not qualify for a diagno­
sis of unspecified insomnia disorder or unspecified hypersomnolence disorder. The un­
specified sleep-wake disorder category is used in situations in  which the clinician chooses  
not to specify the reason that the criteria are not met for a specific sleep-wake disorder,  
and includes presentations in which there is insufficient information to make a more spe­
cific diagnosis.

Sexual dysfunctions include delayed ejaculation, erectile disorder, female orgasmic 
disorder, female sexual interest/arousal disorder, genito-pelvic pain/penetration disorder, 
male hypoactive sexual desire disorder, premature (early) ejaculation, substance/medication- 
induced sexual dysfunction, other specified sexual dysfunction, and unspecified sexual dys­
function. Sexual dysfunctions are a heterogeneous group of disorders that are typically char­
acterized by a clinically significant disturbance in a person's ability to respond sexually or to 
experience sexual pleasure. An individual may have several sexual dysfunctions at the same 
time. In such cases, all of the dysfunctions should be diagnosed.
Clinical judgment should be used to determine if the sexual difficulties are the result of 
inadequate sexual stimulation; in these cases, there may still be a need for care, but a di­
agnosis of a sexual dysfimction would not be made. These cases may include, but are not

agnosis of a sexual dysfimction would not be made. These cases may include, but are not 
limited to, conditions in which lack of knowledge about effective stimulation prevents the 
experience of arousal or orgasm.
Subtypes are used to designate the onset of the difficulty. In many individuals with 
sexual dysfunctions, the time of onset may indicate different etiologies and interventions. 
Lifelong  refers to a sexual problem that has been present from first sexual experiences, and 
acquired  applies to sexual disorders that develop after a period of relatively normal sexual 
function. Generalized  refers to sexual difficulties that are not limited to certain types of 
stimulation, situations, or partners, and situational  refers to sexual difficulties that only oc­
cur with certain types of stimulation, situations, or partners.

In addition to the lifelong/ acquired and generalized/situational subtypes, a number 
of factors must be considered during the assessment of sexual dysfunction, given that they 
may be relevant to etiology and/or treatment, and that may contribute, to varying degrees, 
across individuals: 1) partner factors (e.g., partner's sexual problems; partner's health sta­
tus); 2) relationship factors (e.g., poor communication; discrepancies in desire for sexual 
activity); 3) individual vulnerability factors (e.g., poor body image; history of sexual or emo­
tional abuse), psychiatric comorbidity (e.g., depression, anxiety), or stressors (e.g., job loss, 
bereavement); 4) cultural or religious factors (e.g., inhibitions related to prohibitions against

bereavement); 4) cultural or religious factors (e.g., inhibitions related to prohibitions against 
sexual activity or pleasure; attitudes toward sexuality); and 5) medical factors relevant to 
prognosis, course, or treatment.
Clinical judgment about the diagnosis of sexual dysfunction should take into consideration 
cultural factors that may influence expectations or engender prohibitions about the experience 
of sexual pleasure. Aging may be associated with a normative decrease in sexual response.
Sexual response has a requisite biological undeφinning, yet is usually experienced in 
an intrapersonal, interpersonal, and cultural context. Thus, sexual function involves a com­
plex interaction among biological, sociocultural, and psychological factors. In many clinical 
contexts, a precise understanding of the etiology of a sexual problem is unknown. Nonethe­

less, a sexual dysfunction diagnosis requires ruling out problems that are better explained 
by a nonsexual mental disorder, by the effects of a substance (e.g., drug or medication), by 
a medical condition (e.g., due to pelvic nerve damage), or by severe relationship distress, 
partner violence, or other stressors.
If the sexual dysfunction is mostly explainable by another nonsexual mental disorder (e.g., 
depressive or bipolar disorder, anxiety disorder, posttraumatic stress disorder, psychotic dis-

order), then only the other mental disorder diagnosis should be made. If the problem is 
thought to be better explained by the use/misuse or discontinuation of a drug or substance, it 
should be diagnosed accordingly as a substance/medication-induced sexual dysfunction. If 
the sexual dysfunction is attributable to another medical condition (e.g., peripheral neuropa­
thy), the individual would not receive a psychiatric diagnosis. If severe relationship distress, 
partner violence, or significant stressors better explain the sexual difficulties, then a sexual dys­
function diagnosis is not made, but an appropriate V or Z code for the relationship problem or 
stressor may be listed. In many cases, a precise etiological relationship between another con­
dition (e.g., a medical condition) and a sexual dysfunction cannot be established.
Delayed Ejaculation
Diagnostic Criteria 302.74 (F52.32)
A. Either of the following symptoms must be experienced on almost all or all occasions

A. Either of the following symptoms must be experienced on almost all or all occasions  
(approximately 75%-100%) of partnered sexual activity (in identified situational con­
texts or, if generalized, in  all contexts), and without the individual desiring delay:
1. Marked delay in ejaculation.
2. Marked infrequency or absence of ejaculation.
B. The symptoms in  Criterion A have persisted for a minimum duration of approximately  
6 months.
C. The symptoms in Criterion A cause clinically significant distress in the individual.
D. The sexual dysfunction is not better explained by a nonsexual mental disorder or as a  
consequence of severe relationship distress or other significant stressors and is not at­
tributable to the effects of a substance/medication or another medical condition.
Lifelong: The disturbance has been present since the individual became sexually active.

Lifelong: The disturbance has been present since the individual became sexually active.  
Acquired: The disturbance began after a period of relatively normal sexual function.  
Generalized: Not limited to certain types of stimulation, situations, or partners.  
Situational: Only occurs with certain types of stimulation, situations, or partners.  
Mild: Evidence of mild distress over the symptoms in Criterion A.
Moderate: Evidence of moderate distress over the symptoms in Criterion A.
Severe: Evidence of severe or extreme distress over the symptoms in  Criterion A.
The distinguishing feature of delayed ejaculation is a marked delay in or inability to 
achieve ejaculation (Criterion A). The man reports difficulty or inability to ejaculate de­

spite the presence of adequate sexual stimulation and the desire to ejaculate. The present­
ing complaint usually involves partnered sexual activity. In most cases, the diagnosis will 
be made by self-report of the individual. The definition of "delay" does not have precise 
boundaries, as there is noconsensus as to what constitutes a reasonable time to reach or­
gasm or what is unacceptably long for most men and their sexual partners.
The man and his partner may report prolonged thrusting to achieve orgasm to the point of 
exhaustion or genital discomfort and then ceasing efforts. Some men may report avoiding

sexual activity because of a repetitive pattern of difficulty ejaculating. Some sexual partners 
may report feeliAg less sexually attractive because their partner cannot ejaculate easily.
In addition to the subtypes "lifelong/acquired" and "generalized/situational," the fol­
lowing five factors must be considered during assessment and diagnosis of delayed ejacu­
lation, given that they may be relevant to etiology and/or treatment: 1) partner factors (e.g., 
partner's sexual problems, partner's health status); 2) relationship factors (e.g., poor com­
munication, discrepancies in desire for sexual activity); 3) individual vulnerability factors 
(e.g., poor body image; history of sexual or emotional abuse), psychiatric comorbidity (e.g., 
depression, anxiety), or stressors (e.g., job loss, bereavement); 4) cultural/religious factors 
(e.g., inhibitions related to prohibitions against sexual activity; attitudes toward sexuality);

(e.g., inhibitions related to prohibitions against sexual activity; attitudes toward sexuality); 
and 5) medical factors relevant to prognosis, course, or treatment. Each of these factors may 
contribute differently to the presenting symptoms of different men with this disorder.
Prevalence is unclear because of the lack of a precise definition of this syndrome. It is the 
least common male sexual complaint. Only 75% of men report always ejaculating during 
sexual activity, and less than 1% of men will complain of problems with reaching ejacula­
tion that last more than 6 months.
Lifelong delayed ejaculation begins with early sexual experiences and continues through­
out life. By definition, acquired delayed ejaculation begins after a period of normal sexual 
function. There is minimal evidence concerning the course of acquired delayed ejacula­

tion. The prevalence of delayed ejaculation appears to remain relatively constant until 
around age 50 years, when the incidence begins to increase significantly. Men in their 80s 
report twice as much difficulty ejaculating as men younger than 59 years.
Genetic and physiological. Age-related loss of the fast-conducting peripheral sensory 
nerves and age-related decreased sex steroid secretion may be associated with the increase 
in delayed ejaculation in men older than 50 years.
Complaints of ejaculatory delay vary across countries and cultures. Such complaints are 
more common among men in Asian populations than in men living in Europe, Australia, 
or the United States. This variation may be attributable to cultural or genetic differences

or the United States. This variation may be attributable to cultural or genetic differences 
between cultures.
Functional Consequences of Delayed Ejaculation
Difficulty with ejaculation may contribute to difficulties in conception. Delayed ejacula­
tion is often associated with considerable psychological distress in one or both partners.
Another medical condition. The major differential diagnosis is between delayed ejacu­
lation fully explained by another medical illness or injury and delayed ejaculation with a 
psychogenic, idiopathic, or combined psychological and medical etiology. A situational 
aspect to the complaint is suggestive of a psychological basis for the problem (e.g., men 
who can ejaculate during sexual activity with one sex but not the other; men who can ejac­
ulate with one partner but not another of the same sex; men with paraphilic arousal pat­

terns; men who require highly ritualized activity to ejaculate during partnered sexual 
activity). Another medical illness or injury may produce delays in ejaculation independent 
of psychological issues. For example, inability to ejaculate can be caused by interruption of 
the nerve supply to the genitals, such as can occur after traumatic surgical injury to the 
lumbar sympathetic ganglia, abdominoperitoneal surgery, or lumbar sympathectomy. 
Ejaculation is thought to be under autonomic nervous system control involving the hypo­
gastric (sympathetic) and pudendal (parasympathetic) nerves. A number of neurodegen- 
erative diseases, such as multiple sclerosis and diabetic and alcoholic neuropathy, can 
cause inability to ejaculate. Delayed ejaculation should also be differentiated from retro­
grade ejaculation (i.e., ejaculation into the bladder), which may follow transurethral pros­
tatic resection.
Substance/medication use. A number of pharmacological agents, such as antidepres­

sants, antipsychotics, alpha sympathetic drugs, and opioid drugs, can cause ejaculatory 
problems.
Dysfunction with orgasm. It is important in the history to ascertain whether the com­
plaint concerns delayed ejaculation or the sensation of orgasm, or both. Ejaculation occurs 
in the genitals, whereas the experience of orgasm is believed to be primarily subjective. 
Ejaculation and orgasm usually occur together but not always. For example, a man with a 
normal ejaculatory pattern may complain of decreased pleasure (i.e., anhedonic ejacula­
tion). Such a complaint would not be coded as delayed ejaculation but could be coded as 
other specified sexual dysfunction or unspecified sexual dysfunction.
There is some evidence to suggest that delayed ejaculation may be more common in severe

There is some evidence to suggest that delayed ejaculation may be more common in severe 
forms of major depressive disorder.
Erectile Disorder
Diagnostic Criteria 302.72 (F52.21)
A. At least one of the three following symptoms must be experienced on almost all or all  
(approximately 75%-100%) occasions of sexual activity (in identified situational con­
texts or, if generalized, in all contexts):
1. Marked difficulty in obtaining an erection during sexual activity.
2. Marked difficulty in maintaining an erection until the completion of sexual activity.
3. Marked decrease in erectile rigidity.
B. The symptoms in Criterion A have persisted for a minimum duration of approximately  
6 months.
D. The sexual dysfunction is not better explained by a nonsexual mental disorder or as a

6 months.
Lifelong: The disturbance has been present since the individual became sexually ac­
tive.
Generaiized: Not limited to certain types of stimulation, situations, or partners.  
Situationai: Only occurs with certain types of stimulation, situations, or partners.

Severe: Evidence of severe or extreme distress over the symptoms in Criterion A.
The essential feature of erectile disorder is the repeated failure to obtain or maintain erec­
tions during partnered sexual activities (Criterion A). A careful sexual history is necessary 
to ascertain that the problem has been present for a significant duration of time (i.e., at least 
approximately 6 months) and occurs on the majority of sexual occasions (i.e., at least 75% 
of the time). Symptoms may occur only in specific situations involving certain types of 
stimulation or partners, or they may occur in a generalized manner in all types of situa­
tions, stimulation, or partners.
Many men with erectile disorder may have low self-esteem, low self-confidence, and a de­

creased sense of masculinity, and may experience depressed affect. Fear and/or avoid­
ance of future sexual encounters may occur. Decreased sexual satisfaction and reduced 
sexual desire in the individual's partner are common.
lowing five factors must be considered during assessment and diagnosis of erectile disorder 
given that they may be relevant to etiology and/or treatment: 1) partner factors (e.g., part­
ner's sexual problems, partner's health status); 2) relationship factors (e.g., poor communi­
cation, discrepancies in desire for sexual activity); 3) individual vulnerability factors (e.g., 
poor body image, history of sexual or emotional abuse), psychiatric comorbidity (e.g., de­

pression, anxiety), or stressors (e.g., job loss, bereavement); 4) cultural/religious factors (e.g., 
inhibitions related to prohibitions against sexual activity; attitudes toward sexuality); and 
5) medical factors relevant to prognosis, course, or treatment. Each of these factors may con­
tribute differentiy to the presenting symptoms of different men with this disorder.
The prevalence of lifelong versus acquired erectile disorder is unknown. There is a strong 
age-related increase in both prevalence and incidence of problems with erection, particu­
larly after age 50 years. Approximately 13%-21% of men ages 40-80 years complain of oc­
casional problems with erections. Approximately 2% of men younger than age 40-50 years

casional problems with erections. Approximately 2% of men younger than age 40-50 years 
complain of frequent problems with erections, whereas 40%-50% of men older than 60-70 
years may have significant problems with erections. About 20% of men fear erectile prob­
lems on their first sexual experience, whereas approximately 8% experienced erectile prob­
lems that hindered penetration during their first sexual experience.
Erectile failure on first sexual attempt has been found to be related to having sex with a 
previously unknown partner, concomitant use of drugs or alcohol, not wanting to have 
sex, and peer pressure. There is minimal evi-2t most of these problems spontaneously re­
mit without professional intervention, but some men may continue to have episodic prob­
lems. In contrast, acquired erectile disorder is often associated with biological factors such

lems. In contrast, acquired erectile disorder is often associated with biological factors such 
as diabetes and cardiovascular disease. Acquired erectile disorder is likely to be persistent 
in most men.
The natural history of lifelong erectile disorder is unknown. Clinical observation sup­
ports the association of lifelong erectile disorder with psychological factors that are self-

limiting or responsive to psychological interventions, whereas, as noted above, acquired 
erectile disorder is more likely to be related to biological factors and to be persistent. The 
incidence of erectile disorder increases with age. A minority of men diagnosed as having 
moderate erectile failure may experience spontaneous remission of symptoms without 
medical intervention. Distress associated with erectile disorder is lower in older men as 
compared with younger men.
Temperamental. Neurotic personality traits may be associated with erectile problems in col­
lege students, and submissive personality traits may be associated with erectile problems in 
men age 40 years and older. Alexithymia  (i.e., deficits in cognitive processing of emotions) is 
common in men diagnosed with "psychogenic" erectile dysfunction. Erectile problems are 
common in men diagnosed with depression and posttraumatic stress disorder.

Course modifiers. Risk factors for acquired erectile disorder include age, smoking to­
bacco, lack of physical exercise, diabetes, and decreased desire.
Complaints of erectile disorder have been found to vary across countries. It is unclear to 
what extent these differences represent differences in cultural expectations as opposed to 
genuine differences in the frequency of erectile failure.
Nocturnal penile tumescence testing and measured erectile turgidity during sleep can be 
employed to help differentiate organic from psychogenic erectile problems on the as­
sumption that adequate erections during rapid eye movement sleep indicate a psycholog­
ical etiology to the problem. A number of other diagnostic procedures may be employed

ical etiology to the problem. A number of other diagnostic procedures may be employed 
depending on the clinician's assessment of their relevance given the individual's age, co- 
morbid medical problems, and clinical presentation. Doppler ultrasonography and intra- 
vascular injection of vasoactive drugs, as well as invasive diagnostic procedures such as 
dynamic infusion cavernosography, can be used to assess vascular integrity. Pudendal 
nerve conduction studies, including somatosensory evoked potentials, can be employed 
when a peripheral neuropathy is suspected. In men also complaining of decreased sexual 
desire, serum bioavailable or free testosterone is frequently assessed to determine if the 
difficulty is secondary to endocrinological factors. Thyroid function may also be assessed. 
Determination of fasting serum glucose is useful to screen for the presence of diabetes mel­

litus. The assessment of serum lipids is important, as erectile disorder in men 40 years and 
older is predictive of the future risk of coronary artery disease.
Functionai Consequences of Erectiie Disorder
Erectile disorder can interfere with fertility and produce both individual and interpersonal 
distress. Fear and/or avoidance of sexual encounters may interfere with the ability to de­
velop intimate relationships.
Nonsexual mental disordei^. Major depressive disorder and erectile disorder are closely 
associated, and erectile disorder accompanying severe depressive disorder may occur.
Normal erectile function. The differential should include consideration of normal erec­
tile function in men with excessive expectations.

Substance/medication use. Another major differential diagnosis is whether the erectile 
problem is secondary to substance/medication use. An onset that coincides with the be­
ginning of substance/medication use and that dissipates with discontinuation of the sub­
stance/medication or dose reduction is suggestive of a substance/medication-induced 
sexual dysfunction.
Another medical condition. The most difficult aspect of the differential diagnosis of erec­
tile disorder is ruling out erectile problems that are fully explained by medical factors. Such 
cases would not receive a diagnosis of a mental disorder. The distinction between erectile 
disorder as a mental disorder and erectile dysfunction as the result of another medical con­
dition is usually unclear, and many cases will have complex, interactive biological and psy­
chiatric etiologies. If the individual is older than 40-50 years and/or has concomitant

chiatric etiologies. If the individual is older than 40-50 years and/or has concomitant 
medical problems, the differential diagnosis should include medical etiologies, especially 
vascular disease. The presence of an organic disease known to cause erectile problems does 
not confirm a causal relationship. For example, a man with diabetes mellitus can develop 
erectile disorder in response to psychological stress. In general, erectile dysfunction due to 
organic factors is generalized and gradual in onset. An exception would be erectile problems 
after traumatic injury to the nervous innervation of the genital organs (e.g., spinal cord injury). 
Erectile problems that are situational and inconsistent and that have an acute onset after a 
stressful life event are most often due to psychological events. An age of less than 40 years is

stressful life event are most often due to psychological events. An age of less than 40 years is 
also suggestive of a psychological etiology to the difficulty.
Other sexual dysfunctions. Erectile disorder may coexist with premature (early) ejacu­
lation and male hypoactive sexual desire disorder.
Erectile disorder can be comorbid with other sexual diagnoses, such as premature (early) 
ejaculation and male hypoactive sexual desire disorder, as well as with anxiety and de­
pressive disorders. Erectile disorder is common in men with lower urinary tract symptoms 
related to prostatic hypertrophy. Erectile disorder may be comorbid with dyslipidemia, car­
diovascular disease, hypogonadism, multiple sclerosis, diabetes mellitus, and other diseases 
that interfere with the vascular, neurological, or endocrine function necessary for normal 
erectile function.

Relationship to internationai Classification of Diseases
Erectile response is coded as failure of genital response in ICD-10 (F2.2).
Female Orgasmic Disorder
Diagnostic Criteria 302.73 (F52.31)
A. Presence of either of the following symptoms and experienced on almost all or all (ap­
proximately 75%-100%) occasions of sexual activity (in identified situational contexts  
or, if generalized, in all contexts):
1. Marked delay in, marked infrequency of, or absence of orgasm.
2. Markedly reduced intensity of orgasmic sensations.
6 months.

6 months.
consequence of severe relationship distress (e.g., partner violence) or other significant

stressors and is not attributable to the effects of a substance/medication or another  
Never experienced an orgasm under any situation.
Female orgasmic disorder is characterized by difficulty experiencing orgasm and/or 
markedly reduced intensity of orgasmic sensations (Criterion A). Women show wide vari­

ability in the type or intensity of stimulation that elicits orgasm. Similarly, subjective descrip­
tions of orgasm are extremely varied, suggesting that it is experienced in very different 
ways, both across women and on different occasions by the same woman. For a diagnosis 
of female orgasmic disorder, symptoms must be experienced on almost all or all (approx­
imately 75%-100%) occasions of sexual activity (in identified situational contexts or, if 
generalized, in all contexts) and have a minimum duration of approximately 6 months. 
The use of the minimum severity and duration criteria is intended to distinguish transient 
orgasm difficulties from more persistent orgasmic dysfunction. The inclusion of "approx­

imately" in Criterion B allows for clinician judgment in cases in which symptom duration 
does not meet the recommended 6-month threshold.
For a woman to have a diagnosis of female orgasmic disorder, clinically significant dis­
tress must accompany the symptoms (Criterion C). In many cases of orgasm problems, the 
causes are multifactorial or cannot be determined. If female orgasmic disorder is deemed 
to be better explained by another mental disorder, the effects of a substance/medication, 
or a medical condition, then a diagnosis of female orgasmic disorder would not be made. 
Finally, if interpersonal or significant contextual factors, such as severe relationship dis­
tress, intimate partner violence, or other significant stressors, are present, then a diagnosis

tress, intimate partner violence, or other significant stressors, are present, then a diagnosis 
of female orgasmic disorder would not be made.
Many women require clitoral stimulation to reach orgasm, and a relatively small pro­
portion of women report that they always experience orgasm during penile-vaginal inter­
course. Thus, a woman's experiencing orgasm through clitoral stimulation but not during 
intercourse does not meet criteria for a clinical diagnosis of female orgasmic disorder. It is 
also important to consider whether orgasmic difficulties are the result of inadequate sex­
ual stimulation; in these cases, there may still be a need for care, but a diagnosis of female 
orgasmic disorder would not be made.
Associations between specific patterns of personality traits or psychopathology and orgas­

mic dysfunction have generally not been supported. Compared with women without the 
disorder, some women with female orgasmic disorder may have greater difficulty com­
municating about sexual issues. Overall sexual satisfaction, however, is not strongly cor­
related with orgasmic experience. Many women report high levels of sexual satisfaction

despite rarely or never experiencing orgasm. Orgasmic difficulties in women often co­
occur with problems related to sexual interest and arousal.
In addition to the subtypes "lifelong/acquired" and "generalized/situational/' the fol­
lowing five factors must be considered during assessment and diagnosis of female orgas­
mic disorder given that they may be relevant to etiology and/or treatment: 1) partner 
factors (e.g., partner's sexual problems, partner's health status); 2) relationship factors 
(e.g., poor communication, discrepancies in desire for sexual activity); 3) individual vul­
nerability factors (e.g., poor body image, history of sexual or emotional abuse), psychiatric 
comorbidity (e.g., depression, anxiety), or stressors (e.g., job loss, bereavement); (4) cul­
tural/religious factors (e.g., inhibitions related to prohibitions against sexual activity; 
attitudes toward sexuality); and 5) medical factors relevant to prognosis, course, or treat­

ment. Each of these factors may contribute differently to the presenting symptoms of dif­
ferent women with this disorder.
Reported prevalence rates for female orgasmic problems in women vary widely, from 10% 
to 42%, depending on multiple factors (e.g., age, culture, duration, and severity of symp­
toms); however, these estimates do not take into account the presence of distress. Only a 
proportion of women experiencing orgasm difficulties also report associated distress. 
Variation in how symptoms are assessed (e.g., the duration of symptoms and the recall pe­
riod) also influence prevalence rates. Approximately 10% of women do not experience or­
gasm throughout their lifetime.

By definition, lifelong female orgasmic disorder indicates that the orgasmic difficulties have 
always been present, whereas the acquired subtype would be assigned if the woman's or­
gasmic difficulties developed after a period of normal orgasmic functioning.
A woman's first experience of orgasm can occur any time from the prepubertal period 
to well into adulthood. Women show a more variable pattern in age at first orgasm than do 
men, and women's reports of having experienced orgasm increase with age. Many women 
learn to experience orgasm as they experience a wide variety of stimulation and acquire 
more knowledge about their bodies. Women's rates of orgasm consistency (defined as 
"usually or always" experiencing orgasm) are higher during masturbation than during 
sexual activity with a partner.

Temperamental. A wide range of psychological factors, such as anxiety and concerns 
about pregnancy, can potentially interfere with a woman's ability to experience orgasm.
Environmental. There is a strong association between relationship problems, physical 
health, and mental health and orgasm difficulties in women. Sociocultural factors (e.g., 
gender role expectations and religious norms) are also important influences on the expe­
rience of orgasmic difficulties.
Genetic and physiological. Many physiological factors may influence a woman's expe­
rience of orgasm, including medical conditions and medications. Conditions such as mul­
tiple sclerosis, pelvic nerve damage from radical hysterectomy, and spinal cord injury can 
all influence orgasmic functioning in women. Selective serotonin reuptake irüiibitors are

all influence orgasmic functioning in women. Selective serotonin reuptake irüiibitors are 
known to delay or inhibit orgasm in women. Women with vulvovaginal atrophy (charac­
terized by symptoms such as vaginal dryness, itching, and pain) are significantly more 
likely to report orgasm difficulties than are women without this condition. Menopausal 
status is not consistently associated with the likelihood of orgasm difficulties. There may 
be a significant genetic contribution to variation in female orgasmic function. However,

psychological, sociocultural, and physiological factors likely interact in complex ways to 
influence women's experience of orgasm and of orgasm difficulties.
The degree to which lack of orgasm in women is regarded as a problem that requires treat­
ment may vary depending on cultural context. In addition, women differ in how important 
orgasm is to their sexual satisfaction. There may be marked sociocultural and generational 
differences in women's orgasmic ability. For example, the prevalence of inability to reach or­
gasm has ranged from 17.7% (in Northern Europe) to 42.2% (in Southeast Asia).
Although measurable physiological changes occur during female orgasm, including 
changes in hormones, pelvic floor musculature, and brain activation, there is significant 
variability in these indicators of orgasm across women. In clinical situations, the diagnosis 
of female orgasmic disorder is based on a woman's self-report.

Functional Consequences of Female Orgasmic Disorder
The functional consequences of female orgasmic disorder are unclear. Although there is a 
strong association between relationship problems and orgasmic difficulties in women, it is 
unclear whether relationship factors are risk factors for orgasmic difficulties or are conse­
quences of those difficulties.
Nonsexual mental disorders. Nonsexual mental disorders, such as major depressive 
disorder, which is characterized by markedly diminished interest or pleasure in all, or al­
most all, activities, may explain female orgasmic disorder. If the orgasmic difficulties are 
better explained by another mental disorder, then a diagnosis of female orgasmic disorder 
would not be made.
Substance/nfiedlcation-induced sexual dysfunction. Substance/medication use may

Substance/nfiedlcation-induced sexual dysfunction. Substance/medication use may 
explain the orgasmic difficulties.
Another medical condition. If the disorder is due to another medical condition (e.g., 
multiple sclerosis, spinal cord injury), then a diagnosis of female orgasmic disorder would 
not be made.
Interpersonal factors. If interpersonal or significant contextual factors, such as severe 
relationship distress, intimate partner violence, or other significant stressors, are associ­
ated with the orgasmic difficulties, then a diagnosis of female orgasmic disorder would 
Other sexual dysfunctions. Female orgasmic disorder may occur in association with other 
sexual dysfunctions (e.g., female sexual interest/arousal disorder). The presence of another 
sexual dysfunction does not rule out a diagnosis of female orgasmic disorder. Occasional or­

gasmic difficulties that are short-term or infrequent and are not accompanied by clinically sig­
nificant distress or impairment are not diagnosed as female orgasmic disorder. A diagnosis is 
also not appropriate if the problems are the result of inadequate sexual stimulation.
Comorbldlty
Women with female orgasmic disorder may have co-occurring sexual interest/arousal 
difficulties. Women with diagnoses of other nonsexual mental disorders, such as major de­
pressive disorder, may experience lower sexual interest/arousal, and this may indirectly 
increase the likelihood of orgasmic difficulties.

Female Sexual Interest/Arousal Disorder
__________________________________________________________________________
Diagnostic Criteria 302.72 (F52.22)
A. Lack of, or significantly reduced, sexual interest/arousal, as manifested by at least  
three of the following:
1. Absent/reduced interest in  sexual activity.
2. Absent/reduced sexual/erotic thoughts or fantasies.
3. No/reduced initiation of sexual activity, and typically unreceptive to a partner’s at­
tempts to initiate.
4. Absent/reduced sexual excitement/pleasure during sexual activity in almost all or  
all (approximately 75%-100%) sexual encounters (in identified situational contexts  
or, if generalized, in all contexts).
5. Absent/reduced sexual interest/arousal in response to any internal or external sex­
ual/erotic cues (e.g., written, verbal, visual).
6. Absent/reduced genital or nongenital sensations during sexual activity in almost all  
or all (approximately 75%-100%) sexual encounters (in identified situational con­

texts or, if generalized, in  all contexts).
6 months.
C. The symptoms in  Criterion A cause clinically significant distress in the individual.
D. The sexual dysfunction is not better explained by a nonsexuai mental disorder or as a  
consequence of severe relationship distress (e.g., partner violence) or other significant  
Lifelong: The disturbance has been present since the individual became sexually  
active.
Generalized: Not limited to certain types of stimulation, situations, or partners.

active.
In assessing female sexual interest/arousal disorder, interpersonal context must be taken 
into account. A "desire discrepancy," in which a woman has lower desire for sexual activ­
ity than her partner, is not sufficient to diagnose female sexual interest/arousal disorder. 
In order for the criteria for the disorder to be met, there must be absence or reduced fre­

quency or intensity of at least three of six indicators (Criterion A) for a minimum duration 
of approximately 6 months (Criterion B). There may be different symptom profiles across 
women, as well as variability in how sexual interest and arousal are expressed. For exam­
ple, in one woman, sexual interest/arousal disorder may be expressed as a lack of interest 
in sexual activity, an absence of erotic or sexual thoughts, and reluctance to initiate sexual 
activity and respond to a partner's sexual invitations. In another woman, an inability to be­
come sexually excited, to respond to sexual stimuli with sexual desire, and a correspond-

ing lack of signs of physical sexual arousal may be the primary features. Because sexual 
desire and arousal frequently coexist and are elicited in response to adequate sexual cues, 
the criteria for female sexual interest/arousal disorder take into account that difficulties in 
desire and arousal often simultaneously characterize the complaints of women with this 
disorder. Short-term changes in sexual interest or arousal are common and may be adaptive 
responses to events in a woman's life and do not represent a sexual dysfunction. Diagnosis 
of female sexual interest/arousal disorder requires a minimum duration of symptoms of 
approximately 6 months as a reflection that the symptoms must be a persistent problem. 
The estimation of persistence may be determined by clinical judgment when a duration of 
6 months cannot be ascertained precisely.
There may be absent or reduced frequency or intensity of interest in sexual activity (Crite­

rion Al), which was previously termed hypoactive sexual desire disorder.  The frequency or inten­
sity of sexual and erotic thoughts or fantasies may be absent or reduced (Criterion A2). The 
expression of fantasies varies widely across women and may include memories of past sexual 
experiences. The normative decline in sexual thoughts with age should be taken into account 
when this criterion is being assessed. Absence or reduced frequency of initiating sexual activ­
ity and of receptivity to a partner's sexual invitations (Criterion A3) is a behaviorally focused 
criterion. A couple's beliefs and preferences for sexual initiation patterns are highly relevant to 
the assessment of this criterion. There may be absent or reduced sexual excitement or pleasure 
during sexual activity in almost all or all (approximately 75%-100%) sexual encounters (Cri­

terion A4). Lack of pleasure is a common presenting clinical complaint in women with low de­
sire. Among women who report low sexual desire, there are fewer sexual or erotic cues that 
elicit sexual interest or arousal (i.e., there is a lack of "responsive desire"). Assessment of the 
adequacy of sexual stimuli will assist in determining if there is a difficulty with responsive sex­
ual desire (Criterion A5). Frequency or intensity of genital or nongenital sensations during sex­
ual activity may be reduced or absent (Criterion A 6). This may include reduced vaginal 
lubrication/vasocongestion, but because physiological measures of genital sexual response do 
not differentiate women who report sexual arousal concerns from those who do not, the self­

report of reduced or absent genital or nongenital sensations is sufficient.
For a diagnosis of female sexual interest/arousal disorder to be made, clinically signif­
icant distress must accompany the symptoms in Criterion A. Distress may be experienced 
as a result of the lack of sexual interest Arousal or as a result of significant interference in 
a woman's life and well-being. If a lifelong lack of sexual desire is better explained by one's 
self-identification as "asexual," then a diagnosis of female sexual interest/arousal disor­
der would not be made.
Female sexual interest/arousal disorder is frequently associated with problems in experi­
encing orgasm, pain experienced during sexual activity, infrequent sexual activity, and

encing orgasm, pain experienced during sexual activity, infrequent sexual activity, and 
couple-level discrepancies in desire. Relationship difficulties and mood disorders are also 
frequently associated features of female sexual interest/arousal disorder. Unrealistic ex­
pectations and norms regarding the "appropriate" level of sexual interest or arousal, along 
with poor sexual techniques and lack of information about sexuality, may also be evident 
in women diagnosed with female sexual interest/arousal disorder. The latter, as well as 
normative beliefs about gender roles, are important factors to consider.
In addition to the subtypes "lifelong/acquired" and "generalized/situational," the follow­
ing five factors must be considered during assessment and diagnosis of female sexual interest/ 
arousal disorder given that they may be relevant to etiology and/or treatment: 1) partner fac­

tors (e.g., partner's sexual problems, partner's health status); 2) relationship factors (e.g., poor 
communication, discrepancies in desire for sexual activity); 3) individual vulnerability factors 
(e.g., poor body image, history of sexual or emotional abuse), psychiatric comorbidity (e.g., de­
inhibitions related to prohibitions against sexual activity; attitudes toward sexuality); and

5) medical factors relevant to prognosis, course, or treatment. Note that each of these factors 
may contribute differently to the presenting symptoms of different women with this disorder.
The prevalence of female sexual interest/arousal disorder, as defined in this manual, is 
unknown. The prevalence of low sexual desire and of problems with sexual arousal (with 
and without associated distress), as defined by DSM-IV or ICD-10, may vary markedly in 
relation to age, cultural setting, duration of symptoms, and presence of distress. Regard­
ing duration of symptoms, there are striking differences in prevalence estimates between 
short-term and persistent problems related to lack of sexual interest. When distress about 
sexual functioning is required, prevalence estimates are markedly lower. Some older 
women report less distress about low sexual desire than younger women, although sexual 
desire may decrease with age.

By definition, lifelong female sexual interest/arousal disorder suggests that the lack of 
sexual interest or arousal has been present for the woman's entire sexual life. For Criteria 
A3, A4, and A 6, which assess functioning during sexual activity, a subtype of lifelong 
would mean presence of symptoms since the individual's first sexual experiences. The ac­
quired subtype would be assigned if the difficulties with sexual interest or arousal de­
veloped after a period of nonproblematic sexual functioning. Adaptive and normative 
changes in sexual functioning may result from partner-related, interpersonal, or personal 
events and may be transient in nature. However, persistence of symptoms for approxi­
mately 6 months or more would constitute a sexual dysfunction.

There are normative changes in sexual interest and arousal across the life span. Fur­
thermore, women in relationships of longer duration are more likely to report engaging in 
sex despite no obvious feelings of sexual desire at the outset of a sexual encounter com­
pared with women in shorter-duration relationships. Vaginal dryness in older women is 
related to age and menopausal status.
Temperamental. Temperamental factors include negative cognitions and attitudes about 
sexuality and past history of mental disorders. Differences in propensity for sexual excitation 
and sexual inhibition may also predict the likelihood of developing sexual problems.
Environmental. Environmental factors include relationship difficulties, partner sexual

Environmental. Environmental factors include relationship difficulties, partner sexual 
functioning, and developmental history, such as early relationships with caregivers and 
childhood stressors.
Genetic and physiological. Some medical conditions (e.g., diabetes mellitus, thyroid 
dysfunction) can be risk factors for female sexual interest/arousal disorder. There appears 
to be a strong influence of genetic factors on vulnerability to sexual problems in women. 
Psychophysiological research using vaginal photoplethysmography has not found differ­
ences between women with and without perceived lack of genital arousal.
There is marked variability in prevalence rates of low desire across cultures. Lower rates of 
sexual desire may be more common among East Asian women compared with Euro-

sexual desire may be more common among East Asian women compared with Euro- 
Canadian women. Although the lower levels of sexual desire and arousal found in men 
and women from East Asian countries compared with Euro-American groups may reflect 
less interest in sex in those cultures, the possibility remains that such group differences are 
an artifact of the measures used to quantify desire. A judgment about whether low sexual

desire reported by a woman from a certain ethnocultural group meets criteria for female 
sexual interest/arousal disorder must take into account the fact that different cultures may 
pathologize some behaviors and not others.
By definition, the diagnosis of female sexual interest/arousal disorder is only given to 
women. Distressing difficulties with sexual desire in men would be considered under 
male hypoactive sexual desire disorder.
Difficulties in sexual interest/arousal are often associated with decreased relationship sat­
isfaction.
disorder, in which there is '"markedly diminished interest or pleasure in all, or almost all, 
activities most of the day, nearly every day," may explain the lack of sexual interest/

activities most of the day, nearly every day," may explain the lack of sexual interest/ 
arousal. If the lack of interest or arousal is completely attributable to another mental dis­
order, then a diagnosis of female sexual interest/arousal disorder would not be made.
Substance/medication use. Substance or medication use may explain the lack of inter­
est/arousal.
Another medical condition. If the sexual symptoms are considered to be almost exclu­
sively associated with the effects of another medical condition (e.g., diabetes mellitus, en­
dothelial disease, thyroid dysfunction, central nervous system disease), then a diagnosis 
of female sexual interest/arousal disorder would not be made.
relationship distress, intimate partner violence, or other significant stressors, explain the

relationship distress, intimate partner violence, or other significant stressors, explain the 
sexual interest/arousal symptoms, then a diagnosis of female sexual interest/arousal dis­
order would not be made.
Other sexual dysfunctions. The presence of another sexual dysfunction does not rule 
out a diagnosis of female sexual interest/arousal disorder. It is common for women to ex­
perience more than one sexual dysfunction. For example, the presence of chronic genital 
pain may lead to a lack of desire for the (painful) sexual activity. Lack of interest and 
arousal during sexual activity may impair orgasmic ability. For some women, all aspects 
of the sexual response may be unsatisfying and distressing.
Inadequate or absent sexual stimuli. When differential diagnoses are being considered, 
it is important to assess the adequacy of sexual stimuli within the woman's sexual experi­

ence. In cases where inadequate or absent sexual stimuli are contributing to the clinical pic­
ture, there may be evidence for clinical care, but a sexual dysfunction diagnosis would not 
be made. Similarly, transient and adaptive alterations in sexual functioning that are second­
ary to a significant life or personal event must be considered in the differential diagnosis.
Comorbidity between sexual interest/arousal problems and other sexual difficulties is 
extremely common. Sexual distress and dissatisfaction with sex life are also highly cor­
related in women with low sexual desire. Distressing low desire is associated with depres­
sion, thyroid problems, anxiety, urinary incontinence, and other medical factors. Arthritis

sion, thyroid problems, anxiety, urinary incontinence, and other medical factors. Arthritis 
and inflammatory or irritable bowel disease are also associated with sexual arousal prob-

lems. Low desire appears to be comorbid with depression, sexual and physical abuse in 
adulthood, global mental functioning, and use of alcohol.
Genlto-Pelvic Pain/Penetration Disorder
Diagnostic Criteria 302.76 (F52.6)
A. Persistent or recurrent difficulties with one (or more) of the following:
1. Vaginal penetration during intercourse.
2. Marked vulvovaginal or pelvic pain during vaginal intercourse or penetration attempts.
3. Marl<ed fear or anxiety about vulvovaginal or pelvic pain in  anticipation of, during,  
or as a result of vaginal penetration.
4. Marl<ed tensing or tightening of the pelvic floor muscles during attempted vaginal  
penetration.
6 months.

6 months.
consequence of a severe relationship distress (e.g., partner violence) or other signifi­
cant stressors and is not attributable to the effects of a substance/medication or an­
lUlild: Evidence of mild distress over the symptoms in  Criterion A.  
lUloderate: Evidence of moderate distress over the symptoms in Criterion A.
Genito-pelvic pain/penetration disorder refers to four commonly comorbid symptom di­

mensions: 1) difficulty having intercourse, 2) genito-pelvic pain, 3) fear of pain or vaginal 
penetration, and 4) tension of the pelvic floor muscles (Criterion A). Because major diffi­
culty in any one of these symptom dimensions is often sufficient to cause clinically sig­
nificant distress, a diagnosis can be made on the basis of marked difficulty in only one 
symptom dimension. However, all four symptom dimensions should be assessed even if a 
diagnosis can be made on the basis of only one symptom dimension.
Marked dijficulty having vaginal intercourse/penetration  (Criterion Al) can vary from a total in­
ability to experience vaginal penetration in any situation (e.g., intercourse, gynecological ex­
aminations, tampon insertion) to the ability to easily experience penetration in one situation

aminations, tampon insertion) to the ability to easily experience penetration in one situation 
and but not in another. Although the most common clinical situation is when a woman is un­
able to experience intercourse or penetration with a partner, difficulties in undergoing re­
quired gynecological examinations may also be present. Marked vulvovaginal or pelvic pain  
during vaginal intercourse or penetration attempts  (Criterion A2) refers to pain occurring in differ­
ent locations in the genito-pelvic area. Location of pain as well as intensity should be assessed. 
Typically, pain can be characterized as superficial (vulvovaginal or occurring during penetra­
tion) or deep (pelvic; i.e., not felt until deeper penetration). The intensity of the pain is often not 
linearly related to distress or interference with sexual intercourse or other sexual activities.

linearly related to distress or interference with sexual intercourse or other sexual activities. 
Some genito-pelvic pain only occurs when provoked (i.e., by intercourse or mechanical stim-

Illation); other genito-pelvic pain may be spontaneous as well as provoked. Genito-pelvic pain 
can also be usefully characterized qualitatively (e.g., "burning," "cutting," "shooting," "throb­
bing"). The pain may persist for a period after intercourse is completed and may also occur 
during urination. Typically, the pain experienced during sexual intercourse can be reproduced 
during a gynecological examination.
Marked fear or anxiety about vulvovaginal or pelvic pain either in anticipation of, or during, or  
as a result of vaginal penetration (Criterion A3) is commonly reported by women who have 
regularly experienced pain during sexual intercourse. This "normal" reaction may lead to 
avoidance of sexual/intimate situations. In other cases, this marked fear does not appear 
to be closely related to the experience of pain but nonetheless leads to avoidance of inter­
course and vaginal penetration situations. Some have described this as similar to a phobic

course and vaginal penetration situations. Some have described this as similar to a phobic 
reaction except that the phobic object may be vaginal penetration or the fear of pain.
Marked tensing or tightening of the pelvic floor muscles during attempted vaginal penetration  
(Criterion A4) can vary from reflexive-like spasm of the pelvic floor in response to at­
tempted vaginal entry to "normal/voluntary" muscle guarding in response to the antici­
pated or the repeated experience of pain or to fear or anxiety. In the case of "normal/ 
guarding" reactions, penetration may be possible under circumstances of relaxation. The 
characterization and assessment of pelvic floor dysfunction is often best undertaken by a 
specialist gynecologist or by a pelvic floor physical therapist.

Genito-pelvic pain/penetration disorder is frequently associated with other sexual dysfunc­
tions, particularly reduced sexual desire and interest (female sexual interest/arousal disor­
der). ä)metimes desire and interest are preserved in sexual situations that are not painful or 
do not require penetration. Even when individuals with genito-pelvic pain/penetration dis­
order report sexual interest/motivation, there is often behavioral avoidance of sexual situ­
ations and opportunities. Avoidance of gynecological examinations despite medical 
recommendations is also frequent. The pattern of avoidance is similar to that seen in phobic 
disorders. It is common for women who have not succeeded in having sexual intercourse to

disorders. It is common for women who have not succeeded in having sexual intercourse to 
come for treatment only when they wish to conceive. Many women with genito-pelvic pain/ 
penetration disorder will experience associated relationship/marital problems; they also of­
ten report that the sjnnptoms significantly diminish their feelings of femininity.
In addition to the subtype "lifelong/acquired," five factors should be considered dur­
ing assessment and diagnosis of genito-pelvic pain/penetration disorder because they 
may be relevant to etiology and/or treatment: 1) partner factors (e.g., partner's sexual 
problems, partner's health status); 2) relationship factors (e.g., poor communication, dis­
crepancies in desire for sexual activity); 3) individual vulnerability factors (e.g., poor body 
image, history of sexual or emotional abuse), psychiatric comorbidity (e.g., depression,

image, history of sexual or emotional abuse), psychiatric comorbidity (e.g., depression, 
anxiety), or stressors (e.g., job loss, bereavement); 4) cultural/religious factors (e.g., inhi­
bitions related to prohibitions against sexual activity; attitudes toward sexuality); and 
5) medical factors relevant to prognosis, course, or treatment. Each of these factors may 
contribute differently to the presenting symptoms of different women with this disorder.
There are no valid physiological measures of any of the component symptom dimen­
sions of genito-pelvic pain/penetration disorder. Validated psychometric inventories may 
be used to formally assess the pain and anxiety components related to genito-pelvic pain/ 
penetration disorder.
The prevalence of genito-pelvic pain/penetration disorder is unknown. However, approx­

imately 15% of women in North America report recurrent pain during intercourse. Diffi­
culties having intercourse appear to be a frequent referral to sexual dysfunction clinics and 
to specialist clinicians.

The developmeAt and course of genito-pelvic pain/penetration disorder is unclear. Because 
women generally do not seek treatment until they experience problems in sexual functioning, 
it can, in general, be difficult to characterize genito-pelvic pain/penetration disorder as life­
long (primary) or acquired (secondary). Although women typically come to clinical atten­
tion after the initiation of sexual activity, there are often earlier clinical signs. For example, 
difficulty with or the avoidance of use of tampons is an important predictor of later problems. 
Difficulties with vaginal penetration (inability or fear or pain) may not be obvious until sex­
ual intercourse is attempted. Even once intercourse is attempted, the frequency of attempts 
may not be significant or regular. In cases where it is difficult to establish whether symptom­
atology is lifelong or acquired, it is useful to determine the presence of any consistent period

atology is lifelong or acquired, it is useful to determine the presence of any consistent period 
of successful pain-, fear-, and tension-free intercourse. If the experience of such a period can 
be established, then genito-pelvic pain/penetration disorder can be characterized as ac­
quired. Once symptomatology is well established for a period of approximately 6 months, 
the probability of spontaneous and significant symptomatic remission appears to diminish.
Complaints related to genito-pelvic pain peak during early adulthood and in the peri- 
and postmenopausal period. Women with complaints about difficulty having intercourse 
appear to be primarily premenopausal. There may also be an increase in genito-pelvic 
pain-related symptoms in the postpartum period.
Environmental. Sexual and/or physical abuse have often been cited as predictors of the

Environmental. Sexual and/or physical abuse have often been cited as predictors of the 
DSM-IV-defined sexual pain disorders dyspareunia and vaginismus. This is a matter of con­
troversy in the current literature.
Genetic and physiological. Women experiencing superficial pain during sexual inter­
course often report the onset of the pain after a history of vaginal infections. Even after the in­
fections have resolved and there are no known residual physical findings, the pain persists. 
Pain during tampon insertion or the inability to insert tampons before any sexual contact has 
been attempted is an important risk factor for genito-pelvic pain/penetration disorder.
In the past, inadequate sexual education and religious orthodoxy have often been consid­
ered to be culturally related predisposing factors to the DSM-IV diagnosis of vaginismus.

ered to be culturally related predisposing factors to the DSM-IV diagnosis of vaginismus. 
This perception appears to be confirmed by recent reports from Turkey, a primarily Mus­
lim country, indicating a strikingly high prevalence for the disorder. However, most avail­
able research, although limited in scope, does not support this notion (Lahaie et al. 2010).
By definition, the diagnosis of genito-pelvic pain/penetration disorder is only given to 
women. There is relatively new research concerning urological chronic pelvic pain syn­
drome in men, suggesting that men may experience some similar problems. The research 
and clinical experience are not sufficiently developed yet to justify the application of this 
diagnosis to men. Other specified sexual dysfunction or unspecified sexual dysfunction 
may be diagnosed in men appearing to fit this pattern.

Genito-Pelvic Pain/Penetration Disorder
Functional difficulties in genito-pelvic pain/penetration disorder are often associated 
with interference in relationship satisfaction and sometimes with the ability to conceive 
via penile/vaginal intercourse.

Another medical condition. In many instances, women with genito-pelvic pain/pene­
tration disorder will also be diagnosed with another medical condition (e.g., lichen scle- 
rosus, endometriosis, pelvic inflammatory disease, vulvovaginal atrophy). In some cases, 
treating the medical condition may alleviate the genito-pelvic pain/penetration disorder. 
Much of the time, this is not the case. There are no reliable tools or diagnostic methods to 
allow clinicians to know whether the medical condition or genito-pelvic pain/penetration 
disorder is primary. Often, the associated medical conditions are difficult to diagnose and 
treat. For example, the increased incidence of postmenopausal pain during intercourse 
may sometimes be attributable to vaginal dryness or vulvovaginal atrophy associated with 
declining estrogen levels. The relationship, however, between vulvovaginal atrophy/dry­
ness, estrogen, and pain is not well understood.

Somatic symptom and related disorders. Some women with genito-pelvic pain/pene­
tration disorder may also be diagnosable with somatic symptom disorder. Since both 
genito-pelvic pain/penetration disorder and the somatic symptom and related disorders 
are new diagnoses, it is not yet clear whether they can be reliably differentiated. Some 
women diagnosed with genito-pelvic pain/penetration disorder will also be diagnosed 
with a specific phobia.
Inadequate sexual stimuli. It is important that the clinician, in considering differential diag­
noses, assess the adequacy of sexual stimuli within the woman's sexual experience. Sexual sit­
uations in which there is inadequate foreplay or arousal may lead to difficiilties in penetration, 
pain, or avoidance. Erectile dysfunction or premature ejaculation in the male partner may

pain, or avoidance. Erectile dysfunction or premature ejaculation in the male partner may 
result in difficulties with penetration. These conditions should be carefully assessed. In some 
situations, a diagnosis of genito-pelvic pain/penetration disorder may not be appropriate.
Comorbidity between genito-pelvic pain/penetration disorder and other sexual difficul­
ties appears to be common. Comorbidity with relationship distress is also common. This is 
not surprising, since in Western cultures the inability to have (pain-free) intercourse with 
a desired partner and the avoidance of sexual opportunities may be either a contributing 
factor to or the result of other sexual or relationship problems. Because pelvic floor symp­
toms are implicated in the diagnosis of genito-pelvic pain/penetration disorder, there is

toms are implicated in the diagnosis of genito-pelvic pain/penetration disorder, there is 
likely to be a higher prevalence of other disorders related to the pelvic floor or reproduc­
tive organs (e.g., interstitial cystitis, constipation, vaginal infection, endometriosis, irrita­
ble bowel syndrome).
Male Hypoactive Sexual Desire Disorder
Diagnostic Criteria 302.71 (F52.0)
A. Persistently or recurrently deficient (or absent) sexual/erotic thoughts or fantasies and  
desire for sexual activity. The judgment of deficiency is made by the clinician, taking  
into account factors that affect sexual functioning, such as age and general and socio­
cultural contexts of the individual’s life.
6 months.

6 months.
tributable to thes effects of a substance/medication or another medical condition.

Lifelong: The disturbance has been present since the Individual became sexually
active.
Acquired; The disturbance began after a period of relatively normal sexual function.  
Generaiized: Not limited to certain types of stimulation, situations, or partners.
Moderate: Evidence of moderate distress over the symptoms In Criterion A.
When an assessment for male hypoactive sexual desire disorder is being made, inter­
personal context must be taken into account. A "desire discrepancy," in which a man has 
lower desire for sexual activity than his partner, is not sufficient to diagnose male hypo­

active sexual desire disorder. Both low/absent desire for sex and deficient/absent sexual 
thoughts or fantasies are required for a diagnosis of the disorder. There may be variation 
across men in how sexual desire is expressed.
The lack of desire for sex and deficient/absent erotic thoughts or fantasies must be per­
sistent or recurrent and must occur for a minimum duration of approximately 6 months. 
The inclusion of this duration criterion is meant to safeguard against making a diagnosis in 
cases in which a man's low sexual desire may represent an adaptive response to adverse 
life conditions (e.g., concern about a partner's pregnancy when the man is considering ter­
minating the relationship). The introduction of "approximately" in Criterion B allows for

minating the relationship). The introduction of "approximately" in Criterion B allows for 
clinician judgment in cases in which symptom duration does not meet the recommended 
6-month threshold.
Male hypoactive sexual desire disorder is sometimes associated with erectile and/or ejac- 
ulatory concerns. For example, persistent difficulties obtaining an erection may lead a man 
to lose interest in sexual activity. Men with hypoactive sexual desire disorder often report 
that they no longer initiate sexual activity and that they are minimally receptive to a part­
ner's attempt to initiate. Sexual activities (e.g., masturbation or partnered sexual activity) 
may sometimes occur even in the presence of low sexual desire. Relationship-specific pref­
erences regarding patterns of sexual initiation must be taken into account when making a

erences regarding patterns of sexual initiation must be taken into account when making a 
diagnosis of male hypoactive sexual desire disorder. Although men are more likely to ini­
tiate sexual activity, and thus low desire may be characterized by a pattern of non-initiation, 
many men may prefer to have their partner initiate sexual activity. In such situations, the 
man's lack of receptivity to a partner's initiation should be considered when evaluating low 
desire.
lowing five factors must be considered during assessment and diagnosis of male hypo­
active sexual desire disorder given that they may be relevant to etiology and/or treatment: 
1) partner factors (e.g., partner's sexual problems, partner's health status); 2) relationship

1) partner factors (e.g., partner's sexual problems, partner's health status); 2) relationship 
factors (e.g., poor communication, discrepancies in desire for sexual activity); 3) individ­
ual vulnerability factors (e.g., poor body image, history of sexual or emotional abuse), psy­
chiatric comorbidity (e.g., depression, anxiety), or stressors (e.g., job loss, bereavement); 
4) cultural/religious factors (e.g., inhibitions related to prohibitions against sexual activity; 
attitudes toward sexuality); and 5) medical factors relevant to prognosis, course, or treat-

ferent men with this disorder.
The prevalence of male hypoactive sexual desire disorder varies depending on country of 
origin and method of assessment. Approximately 6% of younger men (ages 18-24 years) 
and 41% of older men (ages 66-74 years) have problems with sexual desire. However, a 
persistent lack of interest in sex, lasting 6 months or more, affects only a small proportion 
of men ages 16-44 (1.8%).
By definition, lifelong male hypoactive sexual desire disorder indicates that low or no sex­
ual desire has always been present, whereas the acquired subtype would be assigned if the 
man's low desire developed after a period of normal sexual desire. There is a requirement 
that low desire persist for approximately 6 months or more; thus, short-term changes in 
sexual desire should not be diagnosed as male hypoactive sexual desire disorder.

There is a normative age-related decline in sexual desire. Like women, men identify a 
variety of triggers for their sexual desire, and they describe a wide range of reasons that 
they choose to engage in sexual activity. Although erotic visual cues may be more potent 
elicitors of desire in younger men, the potency of sexual cues may decrease with age and 
must be considered when evaluating men for hypoactive sexual desire disorder.
Temperamental. Mood and anxiety symptoms appear to be strong predictors of low de­
sire in men. Up to half of men with a past history of psychiatric symptoms may have mod­
erate or severe loss of desire, compared with only 15% of those without such a history. A 
man's feelings about himself, his perception of his partner's sexual desire toward him,

man's feelings about himself, his perception of his partner's sexual desire toward him, 
feelings of being emotionally connected, and contextual variables may all negatively (as 
well as positively) affect sexual desire.
Environmental. Alcohol use may increase the occurrence of low desire. Among gay men, 
self-directed homophobia, interpersonal problems, attitudes, lack of adequate sex educa­
tion, and trauma resulting from early life experiences must be taken into account in ex­
plaining the low desire. Social and cultural contextual factors should also be considered.
Genetic and physiological. Endocrine disorders such as hyperprolactinemia signifi­
cantly affect sexual desire in men. Age is a significant risk factor for low desire in men. It is 
unclear whether or not men with low desire also have abnormally low levels of testoster­

one; however, among hypogonadal men, low desire is conmion. There also may be a crit­
ical threshold below which testosterone will affect sexual desire in men and above which 
there is little effect of testosterone on men's desire.
There is marked variability in prevalence rates of low desire across cultures, ranging from 
12.5% in Northern European men to 28% in Southeast Asian men ages 40-80 years. Just as 
there are higher rates of low desire among East Asian subgroups of women, men of East 
Asian ancestry also have higher rates of low desire. Guilt about sex may mediate this as­
sociation between East Asian ethnicity and sexual desire in men.

In contrast to the classification of sexual disorders in women, desire and arousal disorders 
have been retained as separate constructs in men. Despite some similarities in the experi­

ence of desire across men and women, and the fact that desire fluctuates over time and is 
dependent on contextual factors, men do report a significantly higher intensity and fre­
quency of sexual desire compared with women.
disorder, which is characterized by "markedly diminished interest or pleasure in all, or al­
most all, activities," may explain the lack of sexual desire. If the lack of desire is better 
explained by another mental disorder, then a diagnosis of male hypoactive sexual desire 
disorder would not be made.
Substance/medication use. Substance/medication use may explain the lack of sexual 
desire.
Another medical condition. If the low/absent desire and deficient/absent erotic thoughts 
or fantasies are better explained by the effects of another medical condition (e.g., hypogo­
nadism, diabetes mellitus, thyroid dysfunction, central nervous system disease), then a di­

agnosis of male hypoactive sexual desire disorder would not be made.
lnteφersonal factors. If interpersonal or significant contextual factors, such as severe 
relationship distress or other significant stressors, are associated with the loss of desire in 
the man, then a diagnosis of male hypoactive sexual desire disorder would not be made.
Other sexual dysfunctions. The presence of another sexual dysfunction does not rule out a 
diagnosis of male hypoactive sexual desire disorder; there is some evidence that up to one-half 
of men with low sexual desire also have erectile difficulties, and slightly fewer may also have 
early ejaculation difficulties. If the man's low desire is explained by self-identification as an 
asexual, then a diagnosis of male hypoactive sexual desire disorder is not made.

Depression and other mental disorders, as well as endocrinological factors, are often co- 
morbid with male hypoactive sexual desire disorder.
Premature (Early) Ejaculation
Diagnostic Criteria 302.75 (F52.4)
A. A persistent or recurrent pattern of ejaculation occurring during partnered sexual activ­
ity within approximately 1  minute following vaginal penetration and before the individ­
ual wishes it.
Note: Although the diagnosis of premature (early) ejaculation may be applied to indi­
viduals engaged in nonvaginal sexual activities, specific duration criteria have not been  
established for these activities.
B. The symptom in Criterion A must have been present for at least 6 months and must be  
experienced on almost all or all (approximately 75%-100%) occasions of sexual activ­

ity (in identified situational contexts or, if generalized, in all contexts).
C. The symptom in Criterion A causes clinically significant distress in the individual.
Specify  whether;
Acquired: The disturbance began after a period of relatively normal sexual function.

iUlild: Ejaculation occurring within approximately 30 seconds to 1  minute of vaginal  
Moderate: Ejaculation occurring within approximately 15-30 seconds of vaginal pen­
etration.
Severe: Ejaculation occurring prior to sexual activity, at the start of sexual activity, or  
within approximately 15 seconds of vaginal penetration. _______________________
Premature (early) ejaculation is manifested by ejaculation that occurs prior to or shortly af­
ter vaginal penetration, operationalized by an individual's estimate of ejaculatory latency 
(i.e., elapsed time before ejaculation) after vaginal penetration. Estimated and measured 
intravaginal ejaculatory latencies are highly correlated as long as the ejaculatory latency is

intravaginal ejaculatory latencies are highly correlated as long as the ejaculatory latency is 
of short duration; therefore, self-reported estimates of ejaculatory latency are sufficient for 
diagnostic puφoses. A 60-second intravaginal ejaculatory latency time is an appropriate 
cutoff for the diagnosis of lifelong premature (early) ejaculation in heterosexual men. 
There are insufficient data to determine if this duration criterion can be applied to ac­
quired premature (early) ejaculation. The durational definition may apply to males of 
varying sexual orientations, since ejaculatory latencies appear to be similar across men of 
different sexual orientations and across different sexual activities.
Many males with premature (early) ejaculation complain of a sense of lack of control over

Many males with premature (early) ejaculation complain of a sense of lack of control over 
ejaculation and report apprehension about their anticipated inability to delay ejaculation 
on future sexual encounters.
The following factors may be relevant in the evaluation of any sexual dysfunction: 
1) partner factors (e.g., partner's sexual problems, partner's health status); 2) relationship fac­
tors (e.g., poor conrmiunication, discrepancies in desire for sexual activity); 3) individual 
vulnerability factors (e.g., poor body image, history of sexual or emotional abuse), psychiatric 
comorbidity (e.g., depression, anxiety), and stressors (e.g., job loss, bereavement); 4) cultural/ 
religious factors (e.g., inhibitions related to prohibitions against sexual activity; attitudes 
toward sexuality); and 5) medical factors relevant to prognosis, course, or treatment.

Estimates of the prevalence of premature (early) ejaculation vary widely depending on the 
definition utilized. Internationally, more than 20%-30% of men ages 18-70 years report 
concern about how rapidly they ejaculate. With the new definition of premature (early) 
ejaculation (i.e., ejaculation occurring within approximately 1 minute of vaginal penetra­
tion), only l%-3% of men would be diagnosed with the disorder. Prevalence of premature 
(early) ejaculation may increase with age.
By definition, lifelong premature (early) ejaculation starts during a male's initial sexual ex­
periences and persists thereafter. Some men may experience premature (early) ejaculation 
during their initial sexual encounters but gain ejaculatory control over time. It is the persis­

tence of ejaculatory problems for longer than 6 months that determines the diagnosis of pre­
mature (early) ejaculation. In contrast, some men develop the disorder after a period of

having a normal ejaculatory latency, known as acquired premature (early) ejaculation.  There is 
far less known about acquired premature (early) ejaculation than about lifelong premahire 
(early) ejaculation. The acquired form likely has a later onset, usually appearing during or af­
ter the fourth decade of life. Lifelong is relatively stable throughout life. Little is known about 
the course of acquired premature (early) ejaculation. Reversal of medical conditions such as 
hyperthyroidism and prostatitis appears to restore ejaculatory latencies to baseline values. 
Lifelong premature (early) ejaculation begins with early sexual experiences and persists 
throughout an individual's life. In approximately 20% of men with premature (early) ejacu­
lation, ejaculatory latencies decrease further with age. Age and relationship length have been 
found to be negatively associated with prevalence of premature (early) ejaculation.

Temperamental. Premature (early) ejaculation may be more common in men with anx­
iety disorders, especially social anxiety disorder (social phobia).
Genetic and physiological. There is a moderate genetic contribution to lifelong prema­
ture (early) ejaculation. Premature (early) ejaculation may be associated with dopamine 
transporter gene polymorphism or serotonin transporter gene polymorphism. Thyroid 
disease, prostatitis, and drug withdrawal are associated with acquired premature (early) 
ejaculation. Positron emission tomography measures of regional cerebral blood flow dur­
ing ejaculation have shown primary activation in the mesocephalic transition zone, includ­
ing the ventral tegmental area.
Perception of what constitutes a normal ejaculatory latency is different in many cultures.

Perception of what constitutes a normal ejaculatory latency is different in many cultures. 
Measured ejaculatory latencies may differ in some countries. Such differences may be ex­
plained by cultural or religious factors as well as genetic differences between populations.
Premature (early) ejaculation is a sexual disorder in males. Males and their sexual partners 
may differ in their perception of what constitutes an acceptable ejaculatory latency. There 
may be increasing concerns in females about early ejaculation in their sexual partners, 
which may be a reflection of changing societal attitudes concerning female sexual activity.
Ejaculatory latency is usually monitored in research settings by the sexual partner utilizing 
a timing device (e.g., stopwatch), though this is not ideal in real-life sexual situations. For

a timing device (e.g., stopwatch), though this is not ideal in real-life sexual situations. For 
vaginal intercourse, the time between intravaginal penetration and ejaculation is measured.
Premature (Eariy) Ejaculation
A pattern of premature (early) ejaculation may be associated with decreased self-esteem, a 
sense of lack of control, and adverse consequences for partner relationships. It may also 
cause personal distress in the sexual partner and decreased sexual satisfaction in the sexual 
partner. Ejaculation prior to penetration may be associated with difficulties in conception.
Substance/medication-induced sexual dysfunction. When problems with premature 
ejaculation are due exclusively to substance use, intoxication, or withdrawal, substance/ 
medication-induced sexual dysfunction should be diagnosed.

Ejaculatory concerns that do not meet diagnostic criteria. It is necessary to identify 
males with normal ejaculatory latencies who desire longer ejaculatory latencies and males 
who have episodic premature (early) ejaculation (e.g., during the first sexual encounter 
with a new partner when a short ejaculatory latency may be common or normative). Neither 
of these situations would lead to a diagnosis of premature (early) ejaculation, even though 
these situations may be distressing to some males.
Premature (early) ejaculation may be associated with erectile problems. In many cases, it 
may be difficult to determine which difficulty preceded the other. Lifelong premature 
(early) ejaculation may be associated with certain anxiety disorders. Acquired premature 
(early) ejaculation may be associated with prostatitis, thyroid disease, or drug withdrawal 
(e.g., during opioid withdrawal).
Sexual Dysfunction

A. A clinically significant disturbance in  sexual function is  predominant in  the clinical picture.
2. The involved substance/medication is capable of producing the symptoms in  Crite­
rion A.
C. The disturbance is not better explained by a sexual dysfunction that is not substance/  
medication-induced. Such evidence of an independent sexual dysfunction could in­
persist for a substantial period of time (e.g., about 1  month) after the cessation of

existence of an independent non-substance/medication-induced sexual dysfunc­
tion (e.g., a history of recurrent non-substance/medication-related episodes).
E. The disturbance causes clinically significant distress in the individual.
Coding note: The ICD-9-CM and ICD-10-CM codes for the [specific substance/medica-

tion]-induced sexual dysfunctions are indicated in  the table below. Note that the ICD-10-CM  
code depends on whether or not there is a comorbid substance use disorder present for the  
same class of substance. If a mild substance use disorder is comorbid with the substance-  
induced sexual dysfunction, the 4th position character is “1,”  and the clinician should record  
“ m ild [substance] use disorder”  before the substance-induced sexual dysfunction (e.g., “ m ild  
cocaine use disorder with cocaine-induced sexual dysfunction” ). If a moderate or severe  
substance use disorder is comorbid with the substance-induced sexual dysfunction, the 4th  
position character is “ 2,”  and the clinician should record “ moderate [substance] use disorder'’

position character is “ 2,”  and the clinician should record “ moderate [substance] use disorder'’  
or “ severe [substance] use disorder,”  depending on the severity of the comorbid substance

only the substance-induced sexual dysfunction.
ICD-10-CM
disorder,  
disorder,  
moderate  
use
disorder
Alcohol 291.89 F10.181 F10.281 F10.981
Opioid 292.89 F11.181 F11.281 F11.981
anxiolytic292.89 F13.181 FI 3.281 FI 3.981
stimulant)292.89 F15.181 FI 5.281 FI 5.981
Cocaine 292.89 F14.181 FI 4.281 FI 4.981
Other (or unknown) substance 292.89 F19.181 FI 9.281 FI 9.981

With onset during withdrawai: If criteria are met for withdrawal from the substance  
With onset after medication use: Symptoms may appear either at initiation of medi­
Mild: Occurs on 25%-50% of occasions of sexual activity.
■Moderate: Occurs on 50%-75% of occasions of sexual activity.
Severe: Occurs on 75% or more of occasions of sexual activity.
ICD-9-CM. The name of the substance/medication-induced sexual dysfunction begins 
with the specific substance (e.g., alcohol, fluoxetine) that is presumed to be causing the 
sexual dysfunction. The diagnostic code is selected from the table included in the criteria

sexual dysfunction. The diagnostic code is selected from the table included in the criteria 
(e.g., fluoxetine), the code for "other substance" should be used; and in cases in which a 
toxication, onset during withdrawal, with onset after medication use), followed by the se­
verity specifier (e.g., mild, moderate, severe). Unlike the recording procedures for ICD-10- 
CM, which combine the substance-induced disorder and substance use disorder into a sin­
gle code, for ICD-9-CM a separate diagnostic code is given for the substance use disorder.

gle code, for ICD-9-CM a separate diagnostic code is given for the substance use disorder. 
For example, in the case of erectile dysfunction occurring during intoxication in a man 
with a severe alcohol use disorder, the diagnosis is 291.89 alcohol-induced sexual dysfunc­
tion, with onset during intoxication, moderate. An additional diagnosis of 303.90 severe 
alcohol use disorder is also given. When more than one substance is judged to play a sig-

nificant role in the development of the sexual dysfunction, each should be listed separately 
(e.g., 292.89 cocaine-induced sexual dysfunction with onset during intoxication, moderate; 
292.89 fluoxetine-induced sexual dysfunction, with onset after medication use).
ICD-10-CM. The name of the substance/medication-induced sexual dysfunction begins 
disorder. For substances that do not fit into any of the classes (e.g., fluoxetine), the code for 
"other substance" should be used; and in cases in which a substance is judged to be an eti­
ological factor but the specific class of substance is unknown, the category "unknown sub­
stance" should be used.

sexual dysfunction, followed by the specification of onset (i.e., onset during intoxication, 
onset during withdrawal, with onset after medication use), followed by the severity spec­
ifier (e.g., mild, moderate, severe). For example, in the case of erectile dysfunction occur­
ring during intoxication in a man with a severe alcohol use disorder, the diagnosis is 
F10.281 moderate alcohol use disorder with alcohol-induced sexual dysfunction, with on­
set during intoxication, moderate. A separate diagnosis of the comorbid severe alcohol use 
disorder is not given. If the substance-induced sexual dysfunction occurs without a co­

morbid substance use disorder (e.g., after a one-time heavy use of the substance), no ac­
companying substance use disorder is noted (e.g., F15.981 amphetamine-induced sexual 
dysfunction, with onset during intoxication). When more than one substance is judged to 
play a significant role in the development of the sexual dysfunction, each should be listed 
separately (e.g., F14.181 mild cocaine use disorder with cocaine-induced sexual dysfunc­
tion, with onset during intoxication, moderate; F19.981 fluoxetine-induced sexual dys­
function, with onset after medication use, moderate).
The major feature is a disturbance in sexual function that has a temporal relationship with 
substance/medication initiation, dose increase, or substance/medication discontinuation.

Sexual dysfunctions can occur in association with intoxication with the following classes of 
substances: alcohol; opioids; sedatives, hypnotics, or anxiolytics; stimulants (including co­
caine); and other (or unknown) substances. Sexual dysfunctions can occur in association 
with withdrawal from the following classes of substances: alcohol; opioids; sedatives, hyp­
notics, or anxiolytics; and other (or unknown) substances. Medications that can induce sex­
ual dysfunctions include antidepressants, antipsychotics, and hormonal contraceptives.
The most commonly reported side effect of antidepressant drugs is difficulty with or­
gasm or ejaculation. Problems with desire and erection are less frequent. Approximately

gasm or ejaculation. Problems with desire and erection are less frequent. Approximately 
30% of sexual complaints are clinically significant. Certain agents, such as bupropion and 
mirtazapine, appear not to be associated with sexual side effects.
The sexual problems associated with antipsychotic drugs, including problems with 
sexual desire, erection, lubrication, ejaculation, or orgasm, have occurred with typical as 
well as atypical agents. However, problems are less common with prolactin-sparing anti­
psychotics than with agents that cause significant prolactin elevation.
Although the effects of mood stabilizers on sexual function are unclear, it is possible 
that lithium and anticonvulsants, with the possible exception of lamotrigine, have adverse 
effects on sexual desire. Problems with orgasm may occur with gabapentin. Similarly, there

effects on sexual desire. Problems with orgasm may occur with gabapentin. Similarly, there 
may be a higher prevalence of erectile and orgasmic problems associated with benzodiaz­
epines. There have not been such reports with buspirone.

Many nonpsychiatric medications, such as cardiovascular, cytotoxic, gastrointestinal, 
and hormonal agents, are associated with disturbances in sexual function. Illicit substance 
use is associated with decreased sexual desire, erectile dysfunction, and difficulty reach­
ing orgasm. Sexual dysfunctions are also seen in individuals receiving methadone but are 
seldom reported by patients receiving buprenoφhine. Chronic alcohol abuse and chronic 
nicotine abuse are associated with erectile problems.
The prevalence and the incidence of substance/medication-induced sexual dysfunction 
are unclear, likely because of underreporting of treatment-emergent sexual side effects. 
Data on substance/medication-induced sexual dysfunction typically concern the effects of 
antidepressant drugs. The prevalence of antidepressant-induced sexual dysfunction var­
ies in part depending on the specific agent. Approximately 25%-80% of individuals taking

ies in part depending on the specific agent. Approximately 25%-80% of individuals taking 
monoamine oxidase inhibitors, tricyclic antidepressants, serotonergic antidepressants, 
and combined serotonergic-adrenergic antidepressants report sexual side effects. There 
are differences in the incidence of sexual side effects between some serotonergic and com­
bined adrenergic-serotonergic antidepressants, although it is unclear if these differences 
are clinically significant.
Approximately 50% of individuals taking antipsychotic medications will experience 
adverse sexual side effects, including problems with sexual desire, erection, lubrication, 
ejaculation, or orgasm. The incidence of these side effects among different antipsychotic 
agents is unclear.
Exact prevalence and incidence of sexual dysfunctions among users of nonpsychiatric

Exact prevalence and incidence of sexual dysfunctions among users of nonpsychiatric 
medications such as cardiovascular, cytotoxic, gastrointestinal, and hormonal agents are 
unknown. Elevated rates of sexual dysfunction have been reported with methadone or 
high-dose opioid drugs for pain. There are increased rates of decreased sexual desire, erec­
tile dysfunction, and difficulty reaching orgasm associated with illicit substance use. The 
prevalence of sexual problems appears related to chronic drug abuse and appears higher 
in individuals who abuse heroin (approximately 60%-70%) than in individuals who abuse 
amphetamines or 3,4-methylenedioxymethamphetamine (i.e., MDMA, ecstasy). Elevated 
rates of sexual dysfunction are also seen in individuals receiving methadone but are sel­
dom reported by patients receiving buprenorphine. Chronic alcohol abuse and chronic

dom reported by patients receiving buprenorphine. Chronic alcohol abuse and chronic 
nicotine abuse are related to higher rates of erectile problems.
The onset of antidepressant-induced sexual dysfunction may be as early as 8 days after the 
agent is first taken. Approximately 30% of individuals with mild to moderate orgasm de­
lay will experience spontaneous remission of the dysfunction within 6 months. In some 
cases, serotonin reuptake inhibitor-induced sexual dysfunction may persist after the 
agent is discontinued. The time to onset of sexual dysfunction after initiation of antipsy­
chotic drugs or drugs of abuse is unknown. It is probable that the adverse effects of nico­
tine and alcohol may not appear until after years of use. Premature (early) ejaculation can 
sometimes occur after cessation of opioid use. There is some evidence that disturbances in

sometimes occur after cessation of opioid use. There is some evidence that disturbances in 
sexual function related to substance/medication use increase with age.
There may be an interaction among cultural factors, the influence of medications on sexual 
functioning, and the response of the individual to those changes.
Some gender differences in sexual side effects may exist.

Substance/Medication-Induced Sexual Dysfunction
Medication-induced sexual dysfunction may result in medication noncompliance.
Non-substance/medication-induced sexual dysfunctions. Many mental conditions, such 
as depressive, bipolar, anxiety, and psychotic disorders, are associated with disturbances 
of sexual function. Thus, differentiating a substance/medication-induced sexual dys­
function from a manifestation of the underlying mental disorder can be quite difficult. The 
diagnosis is usually established if a close relationship between substance/medication ini­
tiation or discontinuation is observed. A clear diagnosis can be established if the problem 
occurs after substance/medication initiation, dissipates with substance/medication dis­
continuation, and recurs with introduction of the same agent. Most substance/medication-in­
duced side effects occur shortly after initiation or discontinuation. Sexual side effects that

duced side effects occur shortly after initiation or discontinuation. Sexual side effects that 
only occur after chronic use of a substance/medication may be extremely difficult to di­
agnose with certainty.
Other Specified Sexual Dysfunction
302.79 (F52.8)
This category applies to presentations in  which symptoms characteristic of a sexual dys­
function that cause clinically significant distress in the individual predominate but do not  
meet the full criteria for any of the disorders in the sexual dysfunctions diagnostic class.  
The other specified sexual dysfunction category is used in situations in which the clinician  
teria for any specific sexual dysfunction. This is done by recording “ other specified sexual  
dysfunction”  followed by the specific reason (e.g., “ sexual aversion” ).

Unspecified Sexual Dysfunction
302.70 (F52.9)
This category applies to presentations in which symptoms characteristic of a sexual dys­
The unspecified sexual dysfunction category is used in situations in which the clinician  
chooses not to specify the reason that the criteria are not met for a specific sexual dys­
function, and includes presentations for which there is insufficient information to make a  
more specific diagnosis.

elender 
Dysphoria
In th is  C h s p te r , there is one overarching diagnosis of gender dysphoria, with sepa­
rate developmentally appropriate criteria sets for children and for adolescents and adults. 
The area of sex and gender is highly controversial and has led to a proliferation of terms 
whose meanings vary over time and within and between disciplines. An additional source 
of confusion is that in English "sex" connotes both male/female and sexuality. This chapter 
employs constructs and terms as they are widely used by clinicians from various disci­
plines with specialization in this area. In this chapter, sex and sexual  refer to the biological 
indicators of male and female (understood in the context of reproductive capacity), such 
as in sex chromosomes, gonads, sex hormones, and nonambiguous internal and external 
genitalia. Disorders of sex development denote conditions of inborn somatic deviations of

genitalia. Disorders of sex development denote conditions of inborn somatic deviations of 
the reproductive tract from the norm and/or discrepancies among the biological indica­
tors of male and female. Cross-sex hormone treatment denotes the use of feminizing hor­
mones in an individual assigned male at birth based on traditional biological indicators or 
the use of masculinizing hormones in an individual assigned female at birth.
The need to introduce the term gender  arose with the realization that for individuals 
with conflicting or ambiguous biological indicators of sex (i.e., "intersex"), the lived role in 
society and/or the identification as male or female could not be uniformly associated with 
or predicted from the biological indicators and, later, that some individuals develop an 
identity as female or male at variance with their uniform set of classical biological indica­

tors. Thus, gender  is used to denote the public (and usually legally recognized) lived role as 
boy or girl, man or woman, but, in contrast to certain social constructionist theories, biolog­
ical factors are seen as contributing, in interaction with social and psychological factors, to 
gender development. Gender assignment  refers to the initial assignment as male or female. 
This occurs usually at birth and, thereby, yields the "natal gender." Gender-atypical  refers to 
somatic features or behaviors that are not typical (in a statistical sense) of individuals with 
the same assigned gender in a given society and historical era; for behavior, gender-noncon­
forming  is an alternative descriptive term. Gender reassignment  denotes an official (and usu­

ally legal) change of gender. Gender identity  is a category of social identity and refers to an 
individual's identification as male, female, or, occasionally, some category other than male 
or female. Gender dysphoria  as a general descriptive term refers to an individual's affective/ 
cognitive discontent with the assigned gender but is more specifically defined when used 
as a diagnostic category. Transgender  refers to the broad spectrum of individuals who tran­
siently or persistently identify with a gender different from their natal gender. Transsexual  
denotes an individual who seeks, or has undergone, a social transition from male to female 
or female to male, which in many, but not all, cases also involves a somatic transition by

or female to male, which in many, but not all, cases also involves a somatic transition by 
cross-sex hormone treatment and genital surgery (sex reassignment surgery).
Gender dysphoria  refers to the distress that may accompany the incongruence between 
one's experienced or expressed gender and one's assigned gender. Although not all indi­
viduals will experience distress as a result of such incongruence, many are distressed if the 
desired physical interventions by means of hormones and/or surgery are not available. 
The current term is more descriptive than the previous DSM-IV term gender identity disor­
der and focuses on dysphoria as the clinical problem, not identity per se.

Gender Dysphoria
Gender Dysphoria in Children 302.6 (F64.2)
A. A marked incongruence between one’s experienced/expressed gender and assigned  
gender, of at least 6 months’ duration, as manifested by at least six of the following  
(one of which must be Criterion A1):
1. A strong desire to be of the other gender or an insistence that one is the other gen­
der (or some alternative gender different from one’s assigned gender).
2. In boys (assigned gender), a strong preference for cross-dressing or simulating fe­
male attire: or in girls (assigned gender), a strong preference for wearing only typ­
ical masculine clothing and a strong resistance to the wearing of typical feminine  
clothing.
3. A strong preference for cross-gender roles in  make-believe play or fantasy play.
4. A strong preference for the toys, games, or activities stereotypically used or en­
gaged in by the other gender.
5. A strong preference for playmates of the other gender.

6. In boys (assigned gender), a strong rejection of typically masculine toys, games,  
and activities and a strong avoidance of rough-and-tumble play; or in  girls (as­
signed gender), a strong rejection of typically feminine toys, games, and activities.
7. A strong dislike of one’s sexual anatomy.
8. A strong desire for the primary and/or secondary sex characteristics that match  
one’s experienced gender.
B. The condition is associated with clinically significant distress or impairment in social,  
school, or other important areas of functioning.
With a disorder of sex development (e.g., a congenital adrenogenital disorder such  
as 255.2 [E25.0] congenital adrenal hyperplasia or 259.50 [E34.50] androgen insensi­
tivity syndrome).

Coding note: Code the disorder of sex development as well as gender dysphoria.
Gender Dysphoria in Adolescents and Adults 302.85 (F64.1 )
gender, of at least 6 months’ duration, as manifested by at least two of the following:
1. A marked incongruence between one’s experienced/expressed gender and pri­
mary and/or secondary sex characteristics (or in young adolescents, the antici­
pated secondary sex characteristics).
2. A strong desire to be rid of one’s primary and/or secondary sex characteristics be­
cause of a marked incongruence with one’s experienced/expressed gender (or in  
young adolescents, a desire to prevent the development of the anticipated second­
ary sex characteristics).

3. A strong desire for the primary and/or secondary sex characteristics of the other  
gender.
4. A strong desire to be of the other gender (or some alternative gender different from  
one’s assigned gender).
5. A strong desire to be treated as the other gender (or some alternative gender dif­
ferent from one’s assigned gender).
6. A strong conviction that one has the typical feelings and reactions of the other gen­

B. The condition is associated with clinically significant distress or impairment in  social,  
occupationali^or other important areas of functioning.
Coding note: Code the disorder of sex development as well as gender dysphoria.  
Posttransttion: The individual has transitioned to full-time living in the desired gender  
(with or without legalization of gender change) and has undergone (or is preparing to  
have) at least one cross-sex medical procedure or treatment regimen—namely, regu­
lar cross-sex hormone treatment or gender reassignment surgery confirming the desired  
gender (e.g., penectomy, vaginoplasty in a natal male; mastectomy or phalloplasty in  
a natal female).

The posttransition specifier may be used in the context of continuing treatment procedures 
that serve to support the new gender assignment.
Individuals with gender dysphoria have a marked incongruence between the gender they 
have been assigned to (usually at birth, referred to as natal gender)  and their experienced/ 
expressed gender. This discrepancy is the core component of the diagnosis. There must 
also be evidence of distress about this incongruence. Experienced gender may include al­
ternative gender identities beyond binary stereotypes. Consequently, the distress is not 
limited to a desire to simply be of the other gender, but may include a desire to be of an al­
ternative gender, provided that it differs from the individual's assigned gender.
Gender dysphoria manifests itself differently in different age groups. Prepubertal natal

Gender dysphoria manifests itself differently in different age groups. Prepubertal natal 
girls with gender dysphoria may express the wish to be a boy, assert they are a boy, or as­
sert they will grow up to be a man. They prefer boys' clothing and hairstyles, are often 
perceived by strangers as boys, and may ask to be called by a boy's name. Usually, they dis­
play intense negative reactions to parental attempts to have them wear dresses or other 
feminine attire. Some may refuse to attend school or social events where such clothes are 
required. These girls may demonstrate marked cross-gender identification in role-playing, 
dreams, and fantasies. Contact sports, rough-and-tumble play, traditional boyhood games, 
and boys as playmates are most often preferred. They show little interest in stereotypically 
feminine toys (e.g., dolls) or activities (e.g., feminine dress-up or role-play). Occasionally,

feminine toys (e.g., dolls) or activities (e.g., feminine dress-up or role-play). Occasionally, 
they refuse to urinate in a sitting position. Some natal girls may express a desire to have a 
penis or claim to have a penis or that they will grow one when older. They may also state that 
they do not want to develop breasts or menstruate.
Prepubertal natal boys with gender dysphoria may express the wish to be a girl or as­
sert they are a girl or that they will grow up to be a woman. They have a preference for 
dressing in girls' or women's clothes or may improvise clothing from available materials 
(e.g., using towels, aprons, and scarves for long hair or skirts). These children may role- 
play female figures (e.g., playing "mother") and often are intensely interested in female 
fantasy figures. Traditional feminine activities, stereotypical games, and pastimes (e.g.,

fantasy figures. Traditional feminine activities, stereotypical games, and pastimes (e.g., 
"playing house"; drawing feminine pictures; watching television or videos of favorite fe­
male characters) are most often preferred. Stereotypical female-type dolls (e.g.. Barbie) are 
often favorite toys, and girls are their preferred playmates. They avoid rough-and-tumble 
play and competitive sports and have little interest in stereotypically masculine toys (e.g., 
cars, trucks). Some may pretend not to have a penis and insist on sitting to urinate. More

rarely, they may state that they find their penis or testes disgusting, that they wish them re­
moved, or that they have, or wish to have, a vagina.
In young adolescents with gender dysphoria, clinical features may resemble those of 
children or adults with the condition, depending on developmental level. As secondary 
sex characteristics of young adolescents are not yet fully developed, these individuals may 
not state dislike of them, but they are concerned about imminent physical changes.
In adults with gender dysphoria, the discrepancy between experienced gender and 
physical sex characteristics is often, but not always, accompanied by a desire to be rid of 
primary and/or secondary sex characteristics and/or a strong desire to acquire some pri­
mary and/or secondary sex characteristics of the other gender. To varying degrees, adults 
with gender dysphoria may adopt the behavior, clothing, and mannerisms of the experi­

enced gender. They feel uncomfortable being regarded by others, or functioning in soci­
ety, as members of their assigned gender. Some adults may have a strong desire to be of a 
different gender and treated as such, and they may have an inner certainty to feel and re­
spond as the experienced gender without seeking medical treatment to alter body char­
acteristics. They may find other ways to resolve the incongruence between experienced/ 
expressed and assigned gender by partially living in the desired role or by adopting a gen­
der role neither conventionally male nor conventionally female.
When visible signs of puberty develop, natal boys may shave their legs at the first signs of

When visible signs of puberty develop, natal boys may shave their legs at the first signs of 
hair growth. They sometimes bind their genitals to make erections less visible. Girls may 
bind their breasts, walk with a stoop, or use loose sweaters to make breasts less visible. In­
creasingly, adolescents request, or may obtain without medical prescription and supervi­
sion, hormonal suppressors ("blockers") of gonadal steroids (e.g., gonadotropin-releasing 
hormone [GnRH] analog, spironolactone). Clinically referred adolescents often want hor­
mone treatment and many also wish for gender reassignment surgery. Adolescents living in 
an accepting environment may openly express the desire to be and be treated as the experi­
enced gender and dress partly or completely as the experienced gender, have a hairstyle typ­

ical of the experienced gender, preferentially seek friendships with peers of the other gender, 
and/or adopt a new first name consistent with the experienced gender. Older adolescents, 
when sexually active, usually do not show or allow partners to touch their sexual organs. For 
adults with an aversion toward their genitals, sexual activity is constrained by the preference 
that their genitals not be seen or touched by their partners. Some adults may seek hormone 
treatment (sometimes without medical prescription and supervision) and gender reassign­
ment surgery. Others are satisfied with either hormone treatment or surgery alone.
Adolescents and adults with gender dysphoria before gender reassignment are at in­
creased risk for suicidal ideation, suicide attempts, and suicides. After gender reassign­

ment, adjustment may vary, and suicide risk may persist.
For natal adult males, prevalence ranges from 0.005% to 0.014%, and for natal females, 
from 0.002% to 0.003%. Since not all adults seeking hormone treatment and surgical reas­
signment attend specialty clinics, these rates are likely modest underestimates. Sex differ­
ences in rate of referrals to specialty clinics vary by age group. In children, sex ratios of 
natal boys to girls range from 2:1 to 4.5:1. In adolescents, the sex ratio is close to parity; in 
adults, the sex ratio favors natal males, with ratios ranging from 1:1 to 6.1:1. In two coun­
tries, the sex ratio appears to favor natal females (Japan: 2.2:1; Poland: 3.4:1).
Because expression of gender dysphoria varies with age, there are separate criteria sets for

Because expression of gender dysphoria varies with age, there are separate criteria sets for 
children versus adolescents and adults. Criteria for children are defined in a more con-

crete, behavioral manner than those for adolescents and adults. Many of the core criteria 
draw on well-dofumented behavioral gender differences between typically developing 
boys and girls. Young children are less likely than older children, adolescents, and adults 
to express extreme and persistent anatomic dysphoria. In adolescents and adults, incon­
gruence between experienced gender and somatic sex is a central feature of the diagnosis. 
Factors related to distress and impairment also vary with age. A very young child may 
show signs of distress (e.g., intense crying) only when parents tell the child that he or she 
is "really" not a member of the other gender but only "desires" to be. Distress may not be 
manifest in social environments supportive of the child's desire to live in the role of the 
other gender and may emerge only if the desire is interfered with. In adolescents and 
adults, distress may manifest because of strong incongruence between experienced gender

adults, distress may manifest because of strong incongruence between experienced gender 
and somatic sex. Such distress may, however, be mitigated by supportive environments and 
knowledge that biomedical treatments exist to reduce incongruence. Impairment (e.g., 
school refusal, development of depression, anxiety, and substance abuse) may be a conse­
quence of gender dysphoria.
Gender dysphoria without a disorder of sex development. For clinic-referred children, 
onset of cross-gender behaviors is usually between ages 2 and 4 years. This corresponds to 
the developmental time period in which most typically developing children begin ex­
pressing gendered behaviors and interests. For some preschool-age children, both perva­
sive cross-gender behaviors and the expressed desire to be the other gender may be 
present, or, more rarely, labeling oneself as a member of the other gender may occur. In

present, or, more rarely, labeling oneself as a member of the other gender may occur. In 
some cases, the expressed desire to be the other gender appears later, usually at entry into 
elementary school. A small minority of children express discomfort with their sexual anat­
omy or will state the desire to have a sexual anatomy corresponding to the experienced 
gender ("anatomic dysphoria"). Expressions of anatomic dysphoria become more com­
mon as children with gender dysphoria approach and anticipate puberty.
Rates of persistence of gender dysphoria from childhood into adolescence or adulthood 
vary. In natal males, persistence has ranged from 2.2% to 30%. In natal females, persistence 
has ranged from 12% to 50%. Persistence of gender dysphoria is modestly correlated with 
dimensional measures of severity ascertained at the time of a childhood baseline assess­

ment. In one sample of natal males, lower socioeconomic background was also modestly 
correlated with persistence. It is unclear if particular therapeutic approaches to gender 
dysphoria in children are related to rates of long-term persistence. Extant follow-up sam­
ples consisted of children receiving no formal therapeutic intervention or receiving ther­
apeutic interventions of various types, ranging from active efforts to reduce gender 
dysphoria to a more neutral, "watchful waiting" approach. It is unclear if children "en­
couraged" or supported to live socially in the desired gender will show higher rates of per­
sistence, since such children have not yet been followed longitudinally in a systematic 
manner. For both natal male and female children showing persistence, almost all are

manner. For both natal male and female children showing persistence, almost all are 
sexually attracted to individuals of their natal sex. For natal male children whose gender 
dysphoria does not persist, the majority are androphilic  (sexually attracted to males) and of­
ten self-identify as gay or homosexual (ranging from 63% to 100%). In natal female chil­
dren whose gender dysphoria does not persist, the percentage who are gynephilic  (sexually 
attracted to females) and self-identify as lesbian is lower (ranging from 32% to 50%).
In both adolescent and adult natal males, there are two broad trajectories for develop­
ment of gender dysphoria: early onset and late onset. Early-onset gender dysphoria  starts in 
childhood and continues into adolescence and adulthood; or, there is an intermittent pe­
riod in which the gender dysphoria desists and these individuals self-identify as gay or ho­

mosexual, followed by recurrence of gender dysphoria. Late-onset gender dysphoria  occurs 
around puberty or much later in life. Some of these individuals report having had a desire 
to be of the other gender in childhood that was not expressed verbally to others. Others do 
not recall any signs of childhood gender dysphoria. For adolescent males with late-onset 
gender dysphoria, parents often report surprise because they did not see signs of gender

dysphoria during childhood. Expressions of anatomic dysphoria are more common and 
salient in adolescents and adults once secondary sex characteristics have developed.
Adolescent and adult natal males with early-onset gender dysphoria are almost al­
ways sexually attracted to men (androphilic). Adolescents and adults with late-onset gen­
der dysphoria frequently engage in transvestic behavior with sexual excitement. The 
majority of these individuals are gynephilic or sexually attracted to other posttransition 
natal males with late-onset gender dysphoria. A substantial percentage of adult males 
with late-onset gender dysphoria cohabit with or are married to natal females. After gen­
der transition, many self-identify as lesbian. Among adult natal males with gender dyspho­
ria, the early-onset group seeks out clinical care for hormone treatment and reassignment 
surgery at an earlier age than does the late-onset group. The late-onset group may have more

surgery at an earlier age than does the late-onset group. The late-onset group may have more 
fluctuations in the degree of gender dysphoria and be more ambivalent about and less 
likely satisfied after gender reassignment surgery.
In both adolescent and adult natal females, the most common course is the early-onset 
form of gender dysphoria. The late-onset form is much less common in natal females com­
pared with natal males. As in natal males with gender dysphoria, there may have been a 
period in which the gender dysphoria desisted and these individuals self-identified as les­
bian; however, with recurrence of gender dysphoria, clinical consultation is sought, often 
with the desire for hormone treatment and reassignment surgery. Parents of natal adoles­
cent females with the late-onset form also report surprise, as no signs of childhood gender

cent females with the late-onset form also report surprise, as no signs of childhood gender 
dysphoria were evident. Expressions of anatomic dysphoria are much more common and 
salient in adolescents and adults than in children.
Adolescent and adult natal females with early-onset gender dysphoria are almost 
always gynephilic. Adolescents and adults with the late-onset form of gender dysphoria 
are usually androphilic and after gender transition self-identify as gay men. Natal females 
with the late-onset form do not have co-occurring transvestic behavior with sexual ex­
citement.
Gender dysphoria in association with a disorder of sex development. Most individuals 
with a disorder of sex development who develop gender dysphoria have already come to 
medical attention at an early age. For many, starting at birth, issues of gender assignment

medical attention at an early age. For many, starting at birth, issues of gender assignment 
were raised by physicians and parents. Moreover, as infertility is quite common for this 
group, physicians are more willing to perform cross-sex hormone treatments and genital 
surgery before adulthood.
Disorders of sex development in general are frequently associated with gender-atypi­
cal behavior starting in early childhood. However, in the majority of cases, this does not 
lead to gender dysphoria. As individuals with a disorder of sex development become 
aware of their medical history and condition, many experience uncertainty about their 
gender, as opposed to developing a firm conviction that they are another gender. How­
ever, most do not progress to gender transition. Gender dysphoria and gender transition 
may vary considerably as a function of a disorder of sex development, its severity, and as­

signed gender.
Temperamental. For individuals with gender dysphoria without a disorder of sex de­
velopment, atypical gender behavior among individuals with early-onset gender dyspho­
ria develops in early preschool age, and it is possible that a high degree of atypicality 
makes the development of gender dysphoria and its persistence into adolescence and 
adulthood more likely.
Environmental. Among individuals with gender dysphoria without a disorder of sex de­
velopment, males with gender dysphoria (in both childhood and adolescence) more com­
monly have older brothers than do males without the condition. Additional predisposing

factors under consideration, especially in individuals with late-onset gender dysphoria (ad­
olescence, adulthpod), include habitual fetishistic transvestism developing into autogyne- 
philia (i.e., sexual arousal associated with the thought or image of oneself as a woman) and 
other forms of more general social, psychological, or developmental problems.
Genetic and physiological. For individuals with gender dysphoria without a disorder of 
sex development, some genetic contribution is suggested by evidence for (weak) familial- 
ity of transsexualism among nontwin siblings, increased concordance for transsexualism 
in monozygotic compared with dizygotic same-sex twins, and some degree of heritability 
of gender dysphoria. As to endocrine findings, no endogenous systemic abnormalities in 
sex-hormone levels have been found in 46,XY individuals, whereas there appear to be in­
creased androgen levels (in the range found in hirsute women but far below normal male

creased androgen levels (in the range found in hirsute women but far below normal male 
levels) in 46,XX individuals. Overall, current evidence is insufficient to label gender dys­
phoria without a disorder of sex development as a form of intersexuality limited to the cen­
tral nervous system.
In gender dysphoria associated with a disorder of sex development, the likelihood of 
later gender dysphoria is increased if prenatal production and utilization (via receptor 
sensitivity) of androgens are grossly atypical relative to what is usually seen in individuals 
with the same assigned gender. Examples include 46,XY individuals with a history of nor­
mal male prenatal hormone milieu but inborn nonhormonal genital defects (as in cloacal 
bladder exstrophy or penile agenesis) and who have been assigned to the female gender.

bladder exstrophy or penile agenesis) and who have been assigned to the female gender. 
The likelihood of gender dysphoria is further enhanced by additional, prolonged, highly 
gender-atypical postnatal androgen exposure with somatic virilization as may occur in fe­
male-raised and noncastrated 46,XY individuals with 5-alpha reductase-2 deficiency or
17-beta-hydroxysteroid dehydrogenase-3 deficiency or in female-raised 46,XX individuals 
with classical congenital adrenal hyperplasia with prolonged periods of non-adherence to 
glucocorticoid replacement therapy. However, the prenatal androgen milieu is more 
closely related to gendered behavior than to gender identity. Many individuals with dis­
orders of sex development and markedly gender-atypical behavior do not develop gender 
dysphoria. Thus, gender-atypical behavior by itself should not be inteφreted as an indi­

cator of current or future gender dysphoria. There appears to be a higher rate of gender 
dysphoria and patient-initiated gender change from assigned female to male than from as­
signed male to female in 46,XY individuals with a disorder of sex development.
Individuals with gender dysphoria have been reported across many countries and cul­
tures. The equivalent of gender dysphoria has also been reported in individuals living in 
cultures with institutionalized gender categories other than male or female. It is unclear 
whether with these individuals the diagnostic criteria for gender dysphoria would be met.
Individuals with a somatic disorder of sex development show some correlation of final

Individuals with a somatic disorder of sex development show some correlation of final 
gender identity outcome with the degree of prenatal androgen production and utilization. 
However, the correlation is not robust enough for the biological factor, where ascertain­
able, to replace a detailed and comprehensive diagnostic interview evaluation for gender 
dysphoria.
Functional Consequences of Gender Dysphoria
Preoccupation with cross-gender wishes may develop at all ages after the first 2-3 years of 
childhood and often interfere with daily activities. In older children, failure to develop 
age-typical same-sex peer relationships and skills may lead to isolation from peer groups 
and to distress. Some children may refuse to attend school because of teasing and harass-

ment or pressure to dress in attire associated with their assigned sex. Also in adolescents 
and adults, preoccupation with cross-gender wishes often interferes with daily activities. 
Relationship difficulties, including sexual relationship problems, are common, and func­
tioning at school or at work may be impaired. Gender dysphoria, along with atypical 
gender expression, is associated with high levels of stigmatization, discrimination, and 
victimization, leading to negative self-concept, increased rates of mental disorder comor­
bidity, school dropout, and economic marginalization, including unemployment, with at­
tendant social and mental health risks, especially in individuals from resource-poor family 
backgrounds. In addition, these individuals' access to health services and mental health 
services may be impeded by structural barriers, such as institutional discomfort or inex­
perience in working with this patient population.

Nonconfonnity to gender roles. Gender dysphoria should be distinguished from sim­
ple nonconformity to stereotypical gender role behavior by the strong desire to be of an­
other gender than the assigned one and by the extent and pervasiveness of gender-variant 
activities and interests. The diagnosis is not meant to merely describe nonconformity to 
stereotypical gender role behavior (e.g., "tomboyism" in girls, "girly-boy" behavior in 
boys, occasional cross-dressing in adult men). Given the increased openness of atypical 
gender expressions by individuals across the entire range of the transgender spectrum, it 
is important that the clinical diagnosis be limited to those individuals whose distress and 
impairment meet the specified criteria.

Transvestic disorder. Transvestic disorder occurs in heterosexual (or bisexual) adoles­
cent and adult males (rarely in females) for whom cross-dressing behavior generates sex­
ual excitement and causes distress and/or impairment without drawing their primary 
gender into question. It is occasionally accompanied by gender dysphoria. An individual 
with transvestic disorder who also has clinically significant gender dysphoria can be given 
both diagnoses. In many cases of late-onset gender dysphoria in gynephilic natal males, 
transvestic behavior with sexual excitement is a precursor.
Body dysmoφhic disorder. An individual with body dysmorphic disorder focuses on 
the alteration or removal of a specific body part because it is perceived as abnormally formed, 
not because it represents a repudiated assigned gender. When an individual's presenta­

tion meets criteria for both gender dysphoria and body dysmorphic disorder, both diag­
noses can be given. Individuals wishing to have a healthy limb amputated (termed by 
some body integrity identity disorder)  because it makes them feel more "complete" usually 
do not wish to change gender, but rather desire to live as an amputee or a disabled person.
Schizophrenia and other psychotic disorders. In schizophrenia, there may rarely be 
delusions of belonging to some other gender. In the absence of psychotic symptoms, in­
sistence by an individual with gender dysphoria that he or she is of some other gender is 
not considered a delusion. Schizophrenia (or other psychotic disorders) and gender dys­
phoria may co-occur.
Other clinical presentations. Some individuals with an emasculinization desire who

Other clinical presentations. Some individuals with an emasculinization desire who 
develop an alternative, nonmale/nonfemale gender identity do have a presentation that 
meets criteria for gender dysphoria. However, some males seek castration and/or penec­
tomy for aesthetic reasons or to remove psychological effects of androgens without chang­
ing male identity; in these cases, the criteria for gender dysphoria are not met.
Clinically referred children with gender dysphoria show elevated levels of emotional and 
behavioral problems—most commonly, anxiety, disruptive and impulse-control, and de-

pressive disorders. In prepubertal children, increasing age is associated with having more 
behavioral or emotional problems; this is related to the increasing non-acceptance of gen­
der-variant behavior by others. In older children, gender-variant behavior often leads to 
peer ostracism, which may lead to more behavioral problems. The prevalence of mental 
health problems differs among cultures; these differences may also be related to differences 
in attitudes toward gender variance in children. However, also in some non-Westem cul­
tures, anxiety has been found to be relatively common in individuals with gender dysphoria, 
even in cultures with accepting attitudes toward gender-variant behavior. Autism spec­
trum disorder is more prevalent in clinically referred children with gender dysphoria than 
in the general population. Clinically referred adolescents with gender dysphoria appear to 
have comorbid mental disorders, with anxiety and depressive disorders being the most

have comorbid mental disorders, with anxiety and depressive disorders being the most 
common. As in children, autism spectrum disorder is more prevalent in clinically referred 
adolescents with gender dysphoria than in the general population. Clinically referred 
adults with gender dysphoria may have coexisting mental health problems, most commonly 
anxiety and depressive disorders.
Other Specified Gender Dysphoria
302.6 (F64.8)
This category applies to presentations in which symptoms characteristic of gender dys­
phoria that cause clinically significant distress or impairment in social, occupational, or other  
important areas of functioning predominate but do not meet the full criteria for gender dys­
phoria. The other specified gender dysphoria category is used in situations in which the  
clinician chooses to communicate the specific reason that the presentation does not meet

clinician chooses to communicate the specific reason that the presentation does not meet  
the criteria for gender dysphoria. This is done by recording “ other specified gender dys­
phoria”  followed by the specific reason (e.g., “ brief gender dysphoria” ).
The current disturbance meets symptom criteria for gender dysphoria, but the  
duration is iess than 6 months.
Unspecified Gender Dysphoria
302.6 (F64.9)
phoria that cause clinically significant distress or impairment in social, occupational, or oth­
er important areas of functioning predominate but do not meet the full criteria for gender  
dysphoria. The unspecified gender dysphoria category is used in situations in which the

dysphoria. The unspecified gender dysphoria category is used in situations in which the  
clinician chooses not to specify the reason that the criteria are not met for gender dyspho­
ria, and includes presentations in which there is insufficient information to make a more  

Disruptive, ImpTUse-ContAly 
and Conduct Disorders
D is r u p tiv e , im p u ls e -C O n tro l, and conduct disorders include conditions involv­
ing problems in the self-control of emotions and behaviors. While other disorders in DSM-
5 may also involve problems in emotional and/or behavioral regulation, the disorders in 
this chapter are unique in that these problems are manifested in behaviors that violate the 
rights of others (e.g., aggression, destruction of property) and/or that bring the individual 
into significant conflict with societal norms or authority figures. The underlying causes of 
the problems in the self-control of emotions and behaviors can vary greatly across the dis­
orders in this chapter and among individuals within a given diagnostic category.
The chapter includes oppositional defiant disorder, intermittent explosive disorder, con­
duct disorder, antisocial personality disorder (which is described in the chapter ''Personality

duct disorder, antisocial personality disorder (which is described in the chapter ''Personality 
Disorders"), pyromania, kleptomania, and other specified and unspecified disruptive, im- 
pulse-control, and conduct disorders. Although all the disorders in the chapter involve 
problems in both emotional and behavioral regulation, the source of variation among the 
disorders is the relative emphasis on problems in the two types of self-control. For example, 
the criteria for conduct disorder focus largely on poorly controlled behaviors that violate the 
rights of others or that violate major societal norms. Many of the behavioral symptoms (e.g., 
aggression) can be a result of poorly controlled emotions such as anger. At the other extreme, 
the criteria for intermittent explosive disorder focus largely on such poorly controlled emo­

tion, outbursts of anger that are disproportionate to the interpersonal or other provocation 
or to other psychosocial stressors. Intermediate in impact to these two disorders is opposi­
tional defiant disorder, in which the criteria are more evenly distributed between emotions 
(anger and irritation) and behaviors (argumentativeness and defiance). Pyromania and 
kleptomania are less commonly used diagnoses characterized by poor impulse control re­
lated to specific behaviors (fire setting or stealing) that relieve internal tension. Other speci­
fied disruptive, impulse-control, and conduct disorder is a category for conditions in which 
there are symptoms of conduct disorder, oppositional defiant disorder, or other disruptive,

there are symptoms of conduct disorder, oppositional defiant disorder, or other disruptive, 
impulse-control, and conduct disorders, but the number of symptoms does not meet ^ e di­
agnostic threshold for any of the disorders in this chapter, even though there is evidence of 
clinically significant impairment associated with the symptoms.
The disruptive, impulse-control, and conduct disorders all tend to be more common in 
males than in females, although the relative degree of male predominance may differ both 
across disorders and within a disorder at different ages. The disorders in this chapter tend to 
have first onset in childhood or adolescence. In fact, it is very rare for either conduct disorder or 
oppositional defiant disorder to first emerge in adulthood. There is a developmental relation­
ship between oppositional defiant disorder and conduct disorder, in that most cases of con­

duct disorder previously would have met criteria for oppositional defiant disorder, at least in 
those cases in which conduct disorder emerges prior to adolescence. However, most children 
with oppositional defiant disorder do not eventually develop conduct disorder. Furthermore, 
children with oppositional defiant disorder are at risk for eventually developing other prob­
lems besides conduct disorder, including anxiety and depressive disorders.
Many of the symptoms that define the disruptive, impulse-control, and conduct disor­
ders are behaviors that can occur to some degree in typically developing individuals. 
Thus, it is critical that the frequency, persistence, pervasiveness across situations, and im-

pairment associated with the behaviors indicative of the diagnosis be considered relative 
to v^hat is normative for a person's age, gender, and culhire when determining if they are 
symptomatic of a disorder.
The disruptive, impulse-control, and conduct disorders have been linked to a common 
externalizing spectrum associated with the personality dimensions labeled as disinhibition  
and (inversely) constraint  and, to a lesser extent, negative emotionality. These shared per­
sonality dimensions could account for the high level of comorbidity among these disorders 
and their frequent comorbidity with substance use disorders and antisocial personality 
disorder. However, the specific nature of the shared diathesis that constitutes the exter­
nalizing spectrum remains unknown.
Oppositional Defiant Disorder
Diagnostic Criteria 313.81 (F91.3)
A. A pattern of angry/irritable mood, argumentative/defiant behavior, or vindictiveness lasting

A. A pattern of angry/irritable mood, argumentative/defiant behavior, or vindictiveness lasting  
at least 6 months as evidenced by at least four symptoms from any of the following cate­
gories, and exhibited during interaction with at least one individual who is not a sibling.
Angry/Irritable Mood
1. Often loses temper.
2. Is often touchy or easily annoyed.
3. Is often angry and resentful.
Argumentative/Defiant Behavior
4. Often argues with authority figures or, for children and adolescents, with adults.
5. Often actively defies or refuses to comply with requests from authority figures or  
with rules.
6. Often deliberately annoys others.
7. Often blames others for his or her mistakes or misbehavior.
Vindictiveness
8. Has been spiteful or vindictive at least twice within the past 6 months.
Note: The persistence and frequency of these behaviors should be used to distinguish

Note: The persistence and frequency of these behaviors should be used to distinguish  
a behavior that is within normal limits from a behavior that is symptomatic. For children  
younger than 5 years, the behavior should occur on most days for a period of at least  
6 months unless otherwise noted (Criterion A8). For individuals 5 years or older, the  
behavior should occur at least once per week for at least 6 months, unless othenwise  
noted (Criterion AS). While these frequency criteria provide guidance on a minimal lev­
el of frequency to define symptoms, other factors should also be considered, such as  
whether the frequency and intensity of the behaviors are outside a range that is nor­
mative for the individual’s developmental level, gender, and culture.
B. The disturbance in behavior is associated with distress in  the individual or others in his or

B. The disturbance in behavior is associated with distress in  the individual or others in his or  
her immediate social context (e.g., family, peer group, work colleagues), or it impacts neg­
atively on social, educational, occupational, or other important areas of functioning.
C. The behaviors do not occur exclusively during the course of a psychotic, substance  
use, depressive, or bipolar disorder. Also, the criteria are not met for disruptive mood  
dysregulation disorder.
iU liid: Symptoms are confined to only one setting (e.g., at home, at school, at work, with  
peers).

Moderate: Some symptoms are present in at least two settings.
Severe: Son\e symptoms are present in three or more settings.
It is not uncommon for individuals with oppositional defiant disorder to show symptoms 
only at home and only with family members. However, the pervasiveness of the symp­
toms is an indicator of the severity of the disorder.
The essential feature of oppositional defiant disorder is a frequent and persistent pattern 
of angry/irritable mood, argumentative/defiant behavior, or vindictiveness (Criterion 
A). It is not unusual for individuals with oppositional defiant disorder to show the behav­
ioral features of the disorder without problems of negative mood. However, individuals 
with the disorder who show the angry/irritable mood symptoms typically show the be­
havioral features as well.
The symptoms of oppositional defiant disorder may be confined to only one setting,

The symptoms of oppositional defiant disorder may be confined to only one setting, 
and this is most frequently the home. Individuals who show enough symptoms to meet 
the diagnostic threshold, even if it is only at home, may be significantly impaired in their 
social functioning. However, in more severe cases, the symptoms of the disorder are pres­
ent in multiple settings. Given that the pervasiveness of symptoms is an indicator of the 
severity of the disorder, it is critical that the individual's behavior be assessed across mul­
tiple settings and relationships. Because these behaviors are common among siblings, they 
must be observed during interactions with persons other than siblings. Also, because 
symptoms of the disorder are typically more evident in interactions with adults or peers

symptoms of the disorder are typically more evident in interactions with adults or peers 
whom the individual knows well, they may not be apparent during a clinical examination.
The symptoms of oppositional defiant disorder can occur to some degree in individu­
als without this disorder. There are several key considerations for determining if the be­
haviors are symptomatic of oppositional defiant disorder. First, the diagnostic threshold 
of four or more symptoms within the preceding 6 months must be met. Second, the per­
sistence and frequency of the symptoms should exceed what is normative for an individ­
ual's age, gender, and culture. For example, it is not unusual for preschool children to 
show temper tantrums on a weekly basis. Temper outbursts for a preschool child would be 
considered a symptom of oppositional defiant disorder only if they occurred on most days

considered a symptom of oppositional defiant disorder only if they occurred on most days 
for the preceding 6 months, if they occurred with at least three other symptoms of the dis­
order, and if the temper outbursts contributed to the significant impairment associated 
with the disorder (e.g., led to destruction of property during outbursts, resulted in the 
child being asked to leave a preschool).
The symptoms of the disorder often are part of a pattern of problematic interactions 
with others. Furthermore, individuals with this disorder typically do not regard themselves 
as angry, oppositional, or defiant. Instead, they often justify their behavior as a response to 
unreasonable demands or circumstances. Thus, it can be difficult to disentangle the rela­
tive contribution of the individual with the disorder to the problematic interactions he or

tive contribution of the individual with the disorder to the problematic interactions he or 
she experiences. For example, children with oppositional defiant disorder may have ex­
perienced a history of hostile parenting, and it is often impossible to determine if the 
child's behavior caused the parents to act in a more hostile manner toward the child, if the 
parents' hostility led to the child's problematic behavior, or if there was some combination 
of both. Whether or not the clinician can separate the relative contributions of potential 
causal factors should not influence whether or not the diagnosis is made. In the event that 
the child may be living in particularly poor conditions where neglect or mistreatment may 
occur (e.g., in institutional settings), clinical attention to reducing the contribution of the 
environment may be helpful.

In children and adolescents, oppositional defiant disorder is more prevalent in families in 
which child care is disrupted by a succession of different caregivers or in families in which 
harsh, inconsistent, or neglectful child-rearing practices are common. Two of the most 
common co-occurring conditions with oppositional defiant disorder are attention-deficit/ 
hyperactivity disorder (ADHD) and conduct disorder (see the section "Comorbidity" for 
this disorder). Oppositional defiant disorder has been associated with increased risk for 
suicide attempts, even after comorbid disorders are controlled for.
The prevalence of oppositional defiant disorder ranges from 1% to 11%, with an average 
prevalence estimate of around 3.3%. The rate of oppositional defiant disorder may vary 
depending on the age and gender of the child. The disorder appears to be somewhat more

depending on the age and gender of the child. The disorder appears to be somewhat more 
prevalent in males than in females (1.4:1) prior to adolescence. This male predominance is 
not consistently found in samples of adolescents or adults.
The first symptoms of oppositional defiant disorder usually appear during the preschool 
years and rarely later than early adolescence. Oppositional defiant disorder often precedes 
the development of conduct disorder, especially for those with the childhood-onset type 
of conduct disorder. However, many children and adolescents with oppositional defiant 
disorder do not subsequently develop conduct disorder. Oppositional defiant disorder 
also conveys risk for the development of anxiety disorders and major depressive disorder, 
even in the absence of conduct disorder. The defiant, argumentative, and vindictive symp­

toms carry most of the risk for conduct disorder, whereas the angry-irritable mood symp­
toms carry most of the risk for emotional disorders.
Manifestations of the disorder across development appear consistent. Children and 
adolescents with oppositional defiant disorder are at increased risk for a number of prob­
lems in adjustment as adults, including antisocial behavior, impulse-control problems, 
substance abuse, anxiety, and depression.
Many of the behaviors associated with oppositional defiant disorder increase in fre­
quency during the preschool period and in adolescence. Thus, it is especially critical dur­
ing these development periods that the frequency and intensity of these behaviors be 
evaluated against normative levels before it is decided that they are symptoms of opposi­

tional defiant disorder.
Risl( and Prognostic Features
Temperamental. Temperamental factors related to problems in emotional regulation 
(e.g., high levels of emotional reactivity, poor frustration tolerance) have been predictive 
of the disorder.
Environmental. Harsh, inconsistent, or neglectful child-rearing practices are common in 
families of children and adolescents with oppositional defiant disorder, and these parent­
ing practices play an important role in many causal theories of the disorder.
Genetic and physiological. A number of neurobiological markers (e.g., lower heart rate 
and skin conductance reactivity; reduced basal cortisol reactivity; abnormalities in the pre- 
frontal cortex and amygdala) have been associated with oppositional defiant disorder.

frontal cortex and amygdala) have been associated with oppositional defiant disorder. 
However, the vast majority of studies have not separated children with oppositional de­
fiant disorder from those with conduct disorder. Thus, it is unclear whether there are 
markers specific to oppositional defiant disorder.

The prevalence of the disorder in children and adolescents is relatively consistent across 
countries that differ in race and ethnicity.
When oppositional defiant disorder is persistent throughout development, individuals 
with the disorder experience frequent conflicts with parents, teachers, supervisors, peers, 
and romantic partners. Such problems often result in significant impairments in the indi­
vidual's emotional, social, academic, and occupational adjustment.
Conduct disorder. Conduct disorder and oppositional defiant disorder are both related 
to conduct problems that bring the individual in conflict with adults and other authority 
figures (e.g., teachers, work supervisors). The behaviors of oppositional defiant disorder 
are typically of a less severe nature than those of conduct disorder and do not include ag­

gression toward people or animals, destruction of property, or a pattern of theft or deceit. 
Furthermore, oppositional defiant disorder includes problems of emotional dysregulation 
(i.e., angry and irritable mood) that are not included in the definition of conduct disorder.
Attention-deficit/hyperactivity disorder. ADHD is often comorbid with oppositional de­
fiant disorder. To make the additional diagnosis of oppositional defiant disorder, it is impor­
tant to determine that the individual's failure to conform to requests of others is not solely in 
situations that demand sustained effort and attention or demand that the individual sit still.
Depressive and bipolar disorders. Depressive and bipolar disorders often involve neg­

ative affect and irritability. As a result, a diagnosis of oppositional defiant disorder should 
not be made if the symptoms occur exclusively during the course of a mood disorder.
Disruptive mood dysregulation disorder. Oppositional defiant disorder shares with dis­
ruptive mood dysregulation disorder the symptoms of chronic negative mood and temper 
outbursts. However, the severity, frequency, and chronicity of temper outbursts are more 
severe in individuals with disruptive mood dysregulation disorder than in those with 
oppositional defiant disorder. Thus, only a minority of children and adolescents whose 
symptoms meet criteria for oppositional defiant disorder would also be diagnosed with dis­
ruptive mood dysregulation disorder. When the mood disturbance is severe enough to meet

ruptive mood dysregulation disorder. When the mood disturbance is severe enough to meet 
criteria for disruptive mood dysregulation disorder, a diagnosis of oppositional defiant dis­
order is not given, even if all criteria for oppositional defiant disorder are met.
Intermittent explosive disorder. Intermittent explosive disorder also involves high 
rates of anger. However, individuals with this disorder show serious aggression toward 
others that is not part of the definition of oppositional defiant disorder.
Intellectual disability (intellectual developmental disorder). In individuals with intel­
lectual disability, a diagnosis of oppositional defiant disorder is given only if the opposi­
tional behavior is markedly greater than is commonly observed among individuals of 
comparable mental age and with comparable severity of intellectual disability.

Language disorder. Oppositional defiant disorder must also be distinguished from a 
failure to follow directions that is the result of impaired language comprehension (e.g., 
hearing loss).
Social anxiety disorder (social phobia). Oppositional defiant disorder must also be dis­
tinguished from defiance due to fear of negative evaluation associated with social anxiety 
disorder.

Rates of oppositional defiant disorder are much higher in samples of children, adoles­
cents, and adults with ADHD, and this may be the result of shared temperamental risk fac­
tors. Also, oppositional defiant disorder often precedes conduct disorder, although this 
appears to be most common in children with the childhood-onset subtype. Individuals 
with oppositional defiant disorder are also at increased risk for anxiety disorders and ma­
jor depressive disorder, and this seems largely attributable to the presence of the angry- 
irritable mood symptoms. Adolescents and adults with oppositional defiant disorder also 
show a higher rate of substance use disorders, although it is unclear if this association is in­
dependent of the comorbidity with conduct disorder.
Intermittent Explosive Disorder
Diagnostic Criteria 312.34 (F63.81)
A. Recurrent behavioral outbursts representing a failure to control aggressive impulses  
as manifested by either of the following;

1. Verbal aggression (e.g., temper tantrums, tirades, verbal arguments or fights) or  
physical aggression toward property, animals, or other individuals, occurring twice  
weekly, on average, for a period of 3 months. The physical aggression does not re­
sult in damage or destruction of property and does not result in physical injury to  
animals or other individuals.
2. Three behavioral outbursts involving damage or destruction of property and/or  
physical assault involving physical injury against animals or other individuals occur­
ring within a 12-month period.
B. The magnitude of aggressiveness expressed during the recurrent outbursts is grossly  
out of proportion to the provocation or to any precipitating psychosocial stressors.

C. The recurrent aggressive outbursts are not premeditated (i.e., they are impulsive and/  
or anger-based) and are not committed to achieve some tangible objective (e.g.,  
money, power, intimidation).
D. The recurrent aggressive outbursts cause either marked distress in the individual or  
impairment in occupational or interpersonal functioning, or are associated with finan­
cial or legal consequences.
E. Chronological age is at least 6 years (or equivalent developmental level).
F. The recurrent aggressive outbursts are not better explained by another mental disor­
der (e.g., major depressive disorder, bipolar disorder, disruptive mood dysregulation  
disorder, a psychotic disorder, antisocial personality disorder, borderline personality

disorder, a psychotic disorder, antisocial personality disorder, borderline personality  
disorder) and are not attributable to another medical condition (e.g., head trauma, Alz­
heimer’s disease) or to the physiological effects of a substance (e.g., a drug of abuse,  
a medication). For children ages 6-18 years, aggressive behavior that occurs as part  
of an adjustment disorder should not be considered for this diagnosis.
Note: This diagnosis can be made in addition to the diagnosis of attention-deficit/hyper-  
activity disorder, conduct disorder, oppositional defiant disorder, or autism spectrum dis­
order when recurrent impulsive aggressive outbursts are in excess of those usually seen  
in these disorders and warrant independent clinical attention.
The impulsive (or anger-based) aggressive outbursts in intermittent explosive disorder have

The impulsive (or anger-based) aggressive outbursts in intermittent explosive disorder have 
a rapid onset and, typically, little or no prodromal period. Outbursts typically last for less

than 30 minutes and commonly occur in response to a minor provocation by a close intimate 
or associate. Individuals with intermittent explosive disorder often have less severe epi­
sodes of verbal and/or nondamaging, nondestructive, or noninjurious physical assault (Cri­
terion Al) in between more severe destructive/assaultive episodes (Criterion A2). Criterion 
A1 defines frequent (i.e., twice weekly, on average, for a period of 3 months) aggressive out­
bursts characterized by temper tantrums, tirades, verbal arguments or fights, or assault 
without damage to objects or without injury to animals or other individuals. Criterion A2 
defines infrequent (i.e., three in a 1-year period) impulsive aggressive outbursts character­
ized by damaging or destroying an object, regardless of its tangible value, or by assaulting/ 
striking or otherwise causing physical injury to an animal or to another individual. Regard­

less of the nature of the impulsive aggressive outburst, the core feature of intermittent 
explosive disorder is failure to control impulsive aggressive behavior in response to subjec­
tively experienced provocation (i.e., psychosocial stressor) that would not typically result in 
an aggressive outburst (Criterion B). The aggressive outbursts are generally impulsive and/ 
or anger-based, rather than premeditated or instrumental (Criterion C) and are associated 
with significant distress or impairment in psychosocial function (Criterion D). A diagnosis 
of intermittent explosive disorder should not be given to individuals younger than 6 years, 
or the equivalent developmental level (Criterion E), or to individuals whose aggressive out­

bursts are better explained by another mental disorder (Criterion F). A diagnosis of intermit­
tent explosive disorder should not be given to individuals with disruptive mood 
dysregulation disorder or to individuals whose impulsive aggressive outbursts are attribut­
able to another medical condition or to the physiological effects of a substance (Criterion F). 
In addition, children ages 6-18 years should not receive this diagnosis when impulsive ag­
gressive outbursts occur in the context of an adjustment disorder (Criterion F).
Mood disorders (unipolar), anxiety disorders, and substance use disorders are associated 
with intermittent explosive disorder, although onset of these disorders is typically later 
than that of intermittent explosive disorder.

One-year prevalence data for intermittent explosive disorder in the United States is about 
2.7% (narrow definition). Intermittent explosive disorder is more prevalent among 
younger individuals (e.g., younger than 35-40 years), compared with older individuals 
(older than 50 years), and in individuals with a high school education or less.
The onset of recurrent, problematic, impulsive aggressive behavior is most common in late 
childhood or adolescence and rarely begins for the first time after age 40 years. The core 
features of intermittent explosive disorder, typically, are persistent and continue for many 
years.
The course of the disorder may be episodic, with recurrent periods of impulsive ag­
gressive outbursts. Intermittent explosive disorder appears to follow a chronic and persis­

years.
tent course over many years. It also appears to be quite common regardless of the presence 
or absence of attention-deficit/hyperactivity disorder (ADHD) or disruptive, impulse­
control, and conduct disorders (e.g., conduct disorder, oppositional defiant disorder).
Environmental. Individuals with a history of physical and emotional trauma during the 
first two decades of life are at increased risk for intermittent explosive disorder.

Genetic and physiological. First-degree relatives of individuals v^ith intermittent ex­
plosive disorder are at increased risk for intermittent explosive disorder, and twin studies 
have demonstrated a substantial genetic influence for impulsive aggression.
Research provides neurobiological support for the presence of serotonergic abnormal­
ities, globally and in the brain, specifically in areas of the limbic system (anterior cingulate) 
and orbitofrontal cortex in individuals with  intermittent explosive disorder. Amygdala 
responses to anger stimuli, during functional magnetic resonance imaging scanning, are 
greater in individuals with  intermittent explosive disorder compared with healthy indi­
viduals.
The lower prevalence of intermittent explosive disorder in some regions (Asia, Middle 
East) or countries (Romania, Nigeria), compared with the United States, suggests that in­

formation about recurrent, problematic, impulsive aggressive behaviors either is not elic­
ited on questioning or is less likely to be present, because of cultural factors.
In some studies the prevalence of intermittent explosive disorder is greater in males than 
in females (odds ratio = 1.4-2.3); other studies have found no gender difference.
Interm ittent Explosive Disorder
Social (e.g., loss of friends, relatives, marital instability), occupational (e.g., demotion, loss 
of employment), financial (e.g., due to value of objects destroyed), and legal (e.g., civil 
suits as a result of aggressive behavior against person or property; criminal charges for as­
sault) problems often develop as a result of intermittent explosive disorder.

A diagnosis of intermittent explosive disorder should not be made when Criteria A1 and/ 
or A2 are only met during an episode of another mental disorder (e.g., major depressive 
disorder, bipolar disorder, psychotic disorder), or when impulsive aggressive outbursts 
are attributable to another medical condition or to the physiological effects of a substance 
or medication. This diagnosis also should not be made, particularly in children and ado­
lescents ages 6-18 years, when the impulsive aggressive outbursts occur in the context of 
an adjustment disorder. Other examples in which recurrent, problematic, impulsive ag­
gressive outbursts may, or may not, be diagnosed as intermittent explosive disorder in­
clude the following.

Disruptive mood dysregulation disorder. In contrast to intermittent explosive disorder, 
disruptive mood dysregulation disorder is characterized by a persistently negative mood state 
(i.e., irritability, anger) most of the day, nearly every day, between impulsive aggressive out­
bursts. A diagnosis of disruptive mood dysregulation disorder can only be given when the on­
set of recurrent, problematic, impulsive aggressive outbursts is before age 10 years. Finally, a 
diagnosis of disruptive mood dysregulation disorder should not be made for the first time 
after age 18 years. Otherwise, these diagnoses are mutually exclusive.
Antisocial personality disorder or borderline personality disorder. Individuals with an­

tisocial personahty disorder or borderline personality disorder often display recurrent, 
problematic impulsive aggressive outbursts. However, the level of impulsive aggression 
in individuals with antisocial personality disorder or borderline personality disorder is 
lower than that in individuals with intermittent explosive disorder.

Delirium, major neurocognitive disorder, and personality change due to another med­
ical condition, aggressive type. A diagnosis of intermittent explosive disorder should not 
be made when aggressive outbursts are judged to result from the physiological effects of an­
other diagnosable medical condition (e.g., brain injury associated with a change in personality 
characterized by aggressive outbursts; complex partial epilepsy). Nonspecific abnormalities 
on neurological examination (e.g., "soft signs") and nonspecific electroencephalographic 
changes are compatible with a diagnosis of intermittent explosive disorder unless there is a di­
agnosable medical condition that better explains the impulsive aggressive outbursts.
Substance intoxication or substance withdrawal. A diagnosis of intermittent explosive 
disorder should not be made when impulsive aggressive outbursts are nearly always as­
sociated with intoxication with or withdrawal from substances (e.g., alcohol, phencyclidine,

sociated with intoxication with or withdrawal from substances (e.g., alcohol, phencyclidine, 
cocaine and other stimulants, barbiturates, inhalants). However, when a sufficient number 
of impulsive aggressive outbursts also occur in the absence of substance intoxication or 
withdrawal, and these warrant independent clinical attention, a diagnosis of intermittent 
explosive disorder may be given.
Attention-deficit/hyperactivity disorder, conduct disorder, oppositional defiant disor­
der, or autism spectrum disorder. Individuals with any of these childhood-onset dis­
orders may exhibit impulsive aggressive outbursts. Individuals with ADHD are typically 
impulsive and, as a result, may also exhibit impulsive aggressive outbursts. While indi­
viduals with conduct disorder can exhibit impulsive aggressive outbursts, the form of ag­

gression characterized by the diagnostic criteria is proactive and predatory. Aggression in 
oppositional defiant disorder is typically characterized by temper tantrums and verbal ar­
guments with authority figures, whereas impulsive aggressive outbursts in intermittent 
explosive disorder are in response to a broader array of provocation and include physical 
assault. The level of impulsive aggression in individuals with a history of one or more of 
these disorders has been reported as lower than that in comparable individuals whose 
symptoms also meet intermittent explosive disorder Criteria A through E. Accordingly, if 
Criteria A through E are also met, and the impulsive aggressive outbursts warrant inde­
pendent clinical attention, a diagnosis of intermittent explosive disorder may be given.

Depressive disorders, anxiety disorders, and substance use disorders are most commonly 
comorbid with intermittent explosive disorder. In addition, individuals with antisocial 
personality disorder or borderline personality disorder, and individuals with a history of 
disorders with disruptive behaviors (e.g., ADHD, conduct disorder, oppositional defiant 
disorder), are at greater risk for comorbid intermittent explosive disorder.
Conduct Disorder
A. A repetitive and persistent pattern of behavior in which the basic rights of others or ma­
jor age-appropriate societal norms or rules are violated, as manifested by the presence  
of at least three of the following 15 criteria in the past 12 months from any of the cate­

gories below, with at least one criterion present in the past 6 months:
Aggression to People and Animals
1. Often bullies, threatens, or intimidates others.
2. Often initiates physical fights.
3. Has used a weapon that can cause serious physical harm to others (e.g., a bat,  
brick, broken bottle, knife, gun).

4. Has been physically cruel to people.
5. Has been physically cruel to animals.
6. Has stolen while confronting a victim (e.g., mugging, purse snatching, extortion,  
armed robbery).
7. Has forced someone into sexual activity.
Destruction of Property
8. Has deliberately engaged in  fire setting with the intention of causing serious damage.
9. Has deliberately destroyed others’ property (other than by fire setting).
Deceitful ness or Theft
10. Has broken into someone else’s house, building, or car.
11. Often lies to obtain goods or favors or to avoid obligations (i.e., “ cons”  others).
12. Has stolen items of nontrivial value without confronting a victim (e.g., shoplifting,  
but without breaking and entering: forgery).
Serious Violations of Rules
13. Often stays out at night despite parental prohibitions, beginning before age 13 years.
14. Has run away from home overnight at least twice while living in the parental or pa­

rental surrogate home, or once without returning for a lengthy period.
15. Is often truant from school, beginning before age 13 years.
B. The disturbance in behavior causes clinically significant impairment in social, aca­
demic, or occupational functioning.
C. If the individual is age 18 years or older, criteria are not met for antisocial personality  
disorder.
312.81 (F91.1) Childhood-onset type: Individuals show at least one symptom char­
acteristic of conduct disorder prior to age 10 years.
312.82 (F91.2) Adolescent-onset type: Individuals show no symptom characteristic  
of conduct disorder prior to age 10 years.
312.89 (F91.9) Unspecified onset: Criteria for a diagnosis of conduct disorder are  
met, but there is not enough information available to determine whether the onset of

met, but there is not enough information available to determine whether the onset of  
the first symptom was before or after age 10 years.
With limited prosocial emotions: To qualify for this specifier, an individual must have dis­
played at least two of the following characteristics persistently over at least 12 months and  
in  multiple relationships and settings. These characteristics reflect the individual’s typical  
pattern of interpersonal and emotional functioning over this period and not just occasional  
occurrences in some situations. Thus, to assess the criteria for the specifier, multiple infor­
mation sources are necessary. In addition to the individual’s self-report, it is necessary to  
consider reports by others who have known the individual for extended periods of time  
(e.g., parents, teachers, co-workers, extended family members, peers).

Lack of remorse or guilt: Does not feel bad or guilty when he or she does some­
thing wrong (exclude remorse when expressed only when caught and/or facing  
punishment). The individual shows a general lack of concern about the negative  
consequences of his or her actions. For example, the individual is not remorseful  
after hurting someone or does not care about the consequences of breaking rules.  
Callous —lack of empathy: Disregards and is unconcerned about the feelings of  
others. The individual is described as cold and uncaring. The person appears more  
concerned about the effects of his or her actions on himself or herself, rather than  
their effects on others, even when they result in substantial harm to others.

Unconcerned about performance: Does not show concern about poor/problem­
atic performance at school, at work, or in  other important activities. The individual  
does not put forth the effort necessary to perform well, even when expectations are  
clear, and typically blames others for his or her poor performance.
Shallow or deficient affect: Does not express feelings or show emotions to others,  
except in  ways that seem shallow, insincere, or superficial (e.g., actions contradict the  
emotion displayed; can turn emotions “ on”  or “ off’ quickly) or when emotional expres­
sions are used for gain (e.g., emotions displayed to manipulate or intimidate others).
Mild: Few if any conduct problems in  excess of those required to make the diagnosis  
are present, and conduct problems cause relatively minor harm to others (e.g., lying,  
truancy, staying out after dark without permission, other rule breaking).

Moderate: The number of conduct problems and the effect on others are intermediate  
between those specified in “ mild”  and those in “ severe”  (e.g., stealing without confront­
ing a victim, vandalism).
Severe: Many conduct problems in  excess of those required to make the diagnosis are  
present, or conduct problems cause considerable harm to others (e.g., forced sex, physical  
cruelty, use of a weapon, stealing while confronting a victim , breaking and entering).
Subtypes
Three subtypes of conduct disorder are provided based on the age at onset of the disorder. 
Onset is most accurately estimated with information from both the youth and the care­
giver; estimates are often 2 years later than actual onset. Both subtypes can occur in a mild,

giver; estimates are often 2 years later than actual onset. Both subtypes can occur in a mild, 
moderate, or severe form. An unspecified-onset subtype is designated when there is in­
sufficient information to determine age at onset.
In childhood-onset conduct disorder, individuals are usually male, frequently display 
physical aggression toward others, have disturbed peer relationships, may have had op­
positional defiant disorder during early childhood, and usually have symptoms that meet 
full criteria for conduct disorder prior to puberty. Many children with this subtype also 
have concurrent attention-deficit/hyperactivity disorder (ADHD) or other neurodevel- 
opmental difficulties. Individuals with childhood-onset type are more likely to have per­
sistent conduct disorder into adulthood than are those with adolescent-onset type. As

sistent conduct disorder into adulthood than are those with adolescent-onset type. As 
compared with individuals with childhood-onset type, individuals with adolescent-onset 
conduct disorder are less likely to display aggressive behaviors and tend to have more 
normative peer relationships (although they often display conduct problems in the com­
pany of others). These individuals are less likely to have conduct disorder that persists into 
adulthood. The ratio of males to females with conduct disorder is more balanced for the 
adolescent-onset type than for the childhood-onset type.
A minority of individuals with conduct disorder exhibit characteristics that qualify for the 
"with limited prosocial emotions" specifier. The indicators of this specifier are those that 
have often been labeled as callous and unemotional traits in research. Other personality

have often been labeled as callous and unemotional traits in research. Other personality 
features, such as thrill seeking, fearlessness, and insensitivity to punishment, may also dis­
tinguish those with characteristics described in the specifier. Individuals with character­
istics described in this specifier may be more likely than other individuals with conduct 
disorder to engage in aggression that is planned for instrumental gain. Individuals with 
conduct disorder of any subtype or any level of severity can have characteristics that qual­
ify for the specifier "with limited prosocial emotions," although individuals with the spec­
ifier are more likely to have childhood-onset type and a severity specifier rating of severe.

Although the validity of self-report to assess the presence of the specifier has been sup­
ported in some research contexts, individuals with conduct disorder with this specifier 
may not readily admit to the traits in a clinical interview. Thus, to assess the criteria for the 
specifier, multiple information sources are necessary. Also, because the indicators of the 
specifier are characteristics that reflect the individual's typical pattern of interpersonal and 
emotional functioning, it is important to consider reports by others who have known the 
individual for extended periods of time and across relationships and settings (e.g., par­
ents, teachers, co-workers, extended family members, peers).
The essential feature of conduct disorder is a repetitive and persistent pattern of behavior 
in which the basic rights of others or major age-appropriate societal norms or rules are vi­

olated (Criterion A). These behaviors fall into four main groupings: aggressive conduct 
that causes or threatens physical harm to other people or animals (Criteria A1-A7); non­
aggressive conduct that causes property loss or damage (Criteria A8-A9); deceitfulness or 
theft (Criteria A10-A12); and serious violations of rules (Criteria A13-A15). Three or more 
characteristic behaviors must have been present during the past 12 months, with at least 
one behavior present in the past 6 months. The disturbance in behavior causes clinically 
significant impairment in social, academic, or occupational functioning (Criterion B). The 
behavior pattern is usually present in a variety of settings, such as home, at school, or in

behavior pattern is usually present in a variety of settings, such as home, at school, or in 
the community. Because individuals with conduct disorder are likely to minimize their 
conduct problems, the clinician often must rely on additional informants. However, infor­
mants' knowledge of the individual's conduct problems may be limited if they have inad­
equately supervised the individual or the individual has concealed symptom behaviors.
Individuals with conduct disorder often initiate aggressive behavior and react aggres­
sively to others. They may display bullying, threatening, or intimidating behavior (includ­
ing bullying via messaging on Web-based social media) (Criterion Al); initiate frequent 
physical fights (Criterion A2); use a weapon that can cause serious physical harm (e.g., a bat, 
brick, broken bottle, knife, gun) (Criterion A3); be physically cruel to people (Criterion A4)

brick, broken bottle, knife, gun) (Criterion A3); be physically cruel to people (Criterion A4) 
or animals (Criterion A5); steal while confronting a victim (e.g., mugging, purse snatching, 
extortion, armed robbery) (Criterion A 6); or force someone into sexual activity (Criterion AT). 
Physical violence may take the form of rape, assault, or, in rare cases, homicide. Deliberate 
destruction of others' property may include deliberate fire setting with the intention of caus­
ing serious damage (Criterion A 8) or deliberate destroying of other people's property in 
other ways (e.g., smashing car windows, vandalizing school property) (Criterion A9). Acts of 
deceitfulness or theft may include breaking into someone else's house, building, or car (Crite­
rion AlO); frequently lying or breaking promises to obtain goods or favors or to avoid debts

rion AlO); frequently lying or breaking promises to obtain goods or favors or to avoid debts 
or obligations (e.g., "conning" other individuals) (Criterion A ll); or stealing items of non­
trivial value without confronting the victim (e.g., shoplifting, forgery, fraud) (Criterion A12).
Individuals with conduct disorder may also frequently commit serious violations of 
rules (e.g., school, parental, workplace). Children with conduct disorder often have a pat­
tern, beginning before age 13 years, of staying out late at night despite parental prohi­
bitions (Criterion A13). Children may also show a pattern of running away from home 
overnight (Criterion A14). To be considered a symptom of conduct disorder, the running 
away must have occurred at least twice (or only once if the individual did not return for a

away must have occurred at least twice (or only once if the individual did not return for a 
lengthy period). Runaway episodes that occur as a direct consequence of physical or sex­
ual abuse do not typically qualify for this criterion. Children with conduct disorder may 
often be truant from school, beginning prior to age 13 years (Criterion A15).
Especially in ambiguous situations, aggressive individuals with conduct disorder fre­
quently misperceive the intentions of others as more hostile and threatening than is the

case and respond with aggression that they then feel is reasonable and justified. Person­
ality features of trait negative emotionality and poor self-control, including poor frustra­
tion tolerance, irritability, temper outbursts, suspiciousness, insensitivity to punishment, 
thrill seeking, and recklessness, frequently co-occur with conduct disorder. Substance 
misuse is often an associated feature, particularly in adolescent females. Suicidal ideation, 
suicide attempts, and completed suicide occur at a higher-than-expected rate in individu­
als with conduct disorder.
One-year population prevalence estimates range from 2% to more than 10%, with a median 
of 4%. The prevalence of conduct disorder appears to be fairly consistent across various 
countries that differ in race and ethnicity. Prevalence rates rise from childhood to adoles­
cence and are higher among males than among females. Few children with impairing con­
duct disorder receive treatment.

The onset of conduct disorder may occur as early as the preschool years, but the first sig­
nificant symptoms usually emerge during the period from middle childhood through 
middle adolescence. Oppositional defiant disorder is a common precursor to the child- 
hood-onset type of conduct disorder. Conduct disorder may be diagnosed in adults, how­
ever, symptoms of conduct disorder usually emerge in childhood or adolescence, and 
onset is rare after age 16 years. The course of conduct disorder after onset is variable. In a 
majority of individuals, the disorder remits by adulthood. Many individuals with conduct 
disorder—particularly those with adolescent-onset type and those with few and milder 
symptoms—achieve adequate social and occupational adjustment as adults. However, the

symptoms—achieve adequate social and occupational adjustment as adults. However, the 
early-onset type predicts a worse prognosis and an increased risk of criminal behavior, 
conduct disorder, and substance-related disorders in adulthood. Individuals with conduct 
disorder are at risk for later mood disorders, anxiety disorders, posttraumatic stress dis­
order, impulse-control disorders, psychotic disorders, somatic symptom disorders, and 
substance-related disorders as adults.
Symptoms of the disorder vary with age as the individual develops increased physical 
strength, cognitive abilities, and sexual maturity. Symptom behaviors that emerge first 
tend to be less serious (e.g., lying, shoplifting), whereas conduct problems that emerge last 
tend to be more severe (e.g., rape, theft while confronting a victim). However, there are

tend to be more severe (e.g., rape, theft while confronting a victim). However, there are 
wide differences among individuals, with some engaging in the more damaging behaviors 
at an early age (which is predictive of a worse prognosis). When individuals with conduct 
disorder reach adulthood, symptoms of aggression, property destruction, deceitfulness, 
and rule violation, including violence against co-workers, partners, and children, may be ex­
hibited in the workplace and the home, such that antisocial personality disorder may be 
considered.
Temperamental. Temperamental risk factors include a difficult undercontrolled infant 
temperament and lower-than-average intelligence, particularly with regard to verbal IQ.
Environmental. Family-level risk factors include parental rejection and neglect, inconsis­

tent child-rearing practices, harsh discipline, physical or sexual abuse, lack of supervision, 
early institutional living, frequent changes of caregivers, large family size, parental criminal­
ity, and certain kinds of familial psychopathology (e.g., substance-related disorders). Com­
munity-level risk factors include peer rejection, association with a delinquent peer group, 
and neighborhood exposure to violence. Both types of risk factors tend to be more common 
and severe among individuals with the childhood-onset subtype of conduct disorder.

Genetic and physiological. Conduct disorder is influenced by both genetic and envi­
ronmental factors. The risk is increased in children v^ith a biological or adoptive parent or 
a sibling with conduct disorder. The disorder also appears to be more common in children 
of biological parents with severe alcohol use disorder, depressive and bipolar disorders, or 
schizophrenia or biological parents who have a history of ADHD or conduct disorder. 
Family history particularly characterizes individuals with the childhood-onset subtype of 
conduct disorder. Slower resting heart rate has been reliably noted in individuals with 
conduct disorder compared with those without the disorder, and this marker is not char­
acteristic of any other mental disorder. Reduced autonomic fear conditioning, particularly 
low skin conductance, is also well documented. However, these psychophysiological find­
ings are not diagnostic of the disorder. Structural and functional differences in brain areas

ings are not diagnostic of the disorder. Structural and functional differences in brain areas 
associated with affect regulation and affect processing, particularly frontotemporal-limbic 
connections involving the brain's ventral prefrontal cortex and amygdala, have been con­
sistently noted in individuals with conduct disorder compared with those without the dis­
order. However, neuroimaging findings are not diagnostic of the disorder.
Course modifiers. Persistence is more likely for individuals with behaviors that meet 
criteria for the childhood-onset subtype and qualify for the specifier ''with limited pro­
social emotions". The risk that conduct disorder will persist is also increased by co-occurring 
ADHD and by substance abuse.
Conduct disorder diagnosis may at times be potentially misapplied to individuals in set­

tings where patterns of disruptive behavior are viewed as near-normative (e.g., in very 
threatening, high-crime areas or war zones). Therefore, the context in which the undesir­
able behaviors have occurred should be considered.
Males with a diagnosis of conduct disorder frequently exhibit fighting, stealing, vandalism, 
and school discipline problems. Females with a diagnosis of conduct disorder are more likely 
to exhibit lying, truancy, running away, substance use, and prostitution. Whereas males tend 
to exhibit both physical aggression and relational aggression (behavior that harms social re­
lationships of others), females tend to exhibit relatively more relational aggression.
Functional Consequences of Conduct Disorder

Conduct disorder behaviors may lead to school suspension or expulsion, problems in 
work adjustment, legal difficulties, sexually transmitted diseases, unplanned pregnancy, 
and physical injury from accidents or fights. These problems may preclude attendance in 
ordinary schools or living in a parental or foster home. Conduct disorder is often associ­
ated with an early onset of sexual behavior, alcohol use, tobacco smoking, use of illegal 
substances, and reckless and risk-taking acts. Accident rates appear to be higher among in­
dividuals with conduct disorder compared with those without the disorder. These func­
tional consequences of conduct disorder may predict health difficulties when individuals 
reach midlife. It is not uncommon for individuals with conduct disorder to come into con­

tact with the criminal justice system for engaging in illegal behavior. Conduct disorder is 
a common reason for treatment referral and is frequently diagnosed in mental health fa­
cilities for children, especially in forensic practice. It is associated with impairment that is 
more severe and chronic than that experienced by other clinic-referred children.
Oppositional defiant disorder. Conduct disorder and oppositional defiant disorder are 
both related to symptoms that bring the individual in conflict with adults and other au-

thority figures (e.g., parents, teachers, work supervisors). The behaviors of oppositional 
defiant disorder ^re typically of a less severe nature than those of individuals with conduct 
disorder and do not include aggression toward individuals or animals, destruction of 
property, or a pattern of theft or deceit. Furthermore, oppositional defiant disorder in­
cludes problems of emotional dysregulation (i.e., angry and irritable mood) that are not in­
cluded in the definition of conduct disorder. When criteria are met for both oppositional 
defiant disorder and conduct disorder, both diagnoses can be given.
Attention-deficit/hyperactivity disorder. Although children with ADHD often exhibit 
hyperactive and impulsive behavior that may be disruptive, this behavior does not by it­
self violate societal norms or the rights of others and therefore does not usually meet cri­
teria for conduct disorder. When criteria are met for both ADHD and conduct disorder, both 
diagnoses should be given.

Depressive and bipolar disorders. Irritability, aggression, and conduct problems can 
occur in children or adolescents with a major depressive disorder, a bipolar disorder, or 
disruptive mood dysregulation disorder. The behaviorial problems associated with these 
mood disorders can usually be distinguished from the pattern of conduct problems seen in 
conduct disorder based on their course. Specifically, persons with conduct disorder will 
display substantial levels of aggressive or non-aggressive conduct problems during peri­
ods in which there is no mood disturbance, either historically (i.e., a history of conduct 
problems predating the onset of the mood disturbance) or concurrently (i.e., display of 
some conduct problems that are premeditated and do not occur during periods of intense

some conduct problems that are premeditated and do not occur during periods of intense 
emotional arousal). In those cases in which criteria for conduct disorder and a mood dis­
order are met, both diagnoses can be given.
Intermittent explosive disorder. Both conduct disorder and intermittent explosive dis­
order involve high rates of aggression. However, the aggression in individuals with inter­
mittent explosive disorder is limited to impulsive aggression and is not premeditated, and 
it is not committed in order to achieve some tangible objective (e.g., money, power, intim­
idation). Also, the definition of intermittent explosive disorder does not include the non­
aggressive symptoms of conduct disorder. If criteria for both disorders are met, the diag­
nosis of intermittent explosive disorder should be given only when the recurrent impul­

sive aggressive outbursts warrant independent clinical attention.
Adjustment disorders. The diagnosis of an adjustment disorder (with disturbance of con­
duct or with mixed disturbance of emotions and conduct) should be considered if clinically 
significant conduct problems that do not meet the criteria for another specific disorder de­
velop in clear association with the onset of a psychosocial stressor and do not resolve within
6  months of the termination of the stressor (or its consequences). Conduct disorder is diag­
nosed only when the conduct problems represent a repetitive and persistent pattern that is 
associated with impairment in social, academic, or occupational functioning.
ADHD and oppositional defiant disorder are both common in individuals with conduct

ADHD and oppositional defiant disorder are both common in individuals with conduct 
disorder, and this comorbid presentation predicts worse outcomes. Individuals who show 
the personality features associated with antisocial personality disorder often violate the 
basic rights of others or violate major age-appropriate societal norms, and as a result their 
pattern of behavior often meets criteria for conduct disorder. Conduct disorder may also 
co-occur with one or more of the following mental disorders: specific learning disorder, 
anxiety disorders, depressive or bipolar disorders, and substance-related disorders. Aca­
demic achievement, particularly in reading and other verbal skills, is often below the level 
expected on the basis of age and intelligence and may justify the additional diagnosis of 
specific learning disorder or a communication disorder.

Antisocial Personality Disorder
Criteria and text for antisocial personality disorder can be found in the chapter ''Person­
ality Disorders." Because this disorder is closely connected to the spectrum of "external­
izing" conduct disorders in this chapter, as well as to the disorders in the adjoining chapter 
"Substance-Related and Addictive Disorders," it is dual coded here as well as in the chap­
ter "Personality Disorders."
Pyromania
Diagnostic Criteria 312.33 (F63.1)
A. Deliberate and purposeful fire setting on more than one occasion.
B. Tension or affective arousal before the act.
C. Fascination with, interest in, curiosity about, or attraction to fire and its situational con­
texts (e.g., paraphernalia, uses, consequences).
D. Pleasure, gratification, or relief when setting fires or when witnessing or participating  
in their aftermath.
E. The fire setting is not done for monetary gain, as an expression of sociopolitical ideol­

ogy, to conceal criminal activity, to express anger or vengeance, to improve one’s living  
circumstances, in response to a delusion or hallucination, or as a result of impaired  
judgment (e.g., in  major neurocognitive disorder, intellectual disability [intellectual de­
velopmental disorder], substance intoxication).
F. The fire setting is not better explained by conduct disorder, a manic episode, or anti­
social personality disorder.
The essential feature of pyromania is the presence of multiple episodes of deliberate and 
purposeful fire setting (Criterion A). Individuals with this disorder experience tension or af­
fective arousal before setting a fire (Criterion B). There is a fascination with, interest in, cu­
riosity about, or attraction to fire and its situational contexts (e.g., paraphernalia, uses,

riosity about, or attraction to fire and its situational contexts (e.g., paraphernalia, uses, 
consequences) (Criterion C). Individuals with this disorder are often regular "watchers" at 
fires in their neighborhoods, may set off false alarms, and derive pleasure from institutions, 
equipment, and personnel associated with fire. They may spend time at the local fire depart­
ment, set fires to be affiliated with the fire department, or even become firefighters. Individ­
uals with this disorder experience pleasure, gratification, or relief when setting the fire, 
witnessing its effects, or participating in its aftermath (Criterion D). The fire setting is not 
done for monetary gain, as an expression of sociopolitical ideology, to conceal criminal ac­
tivity, to express anger or vengeance, to improve one's living circumstances, or in response

tivity, to express anger or vengeance, to improve one's living circumstances, or in response 
to a delusion or a hallucination (Criterion E). The fire setting does not result from impaired 
judgment (e.g., in major neurocognitive disorder or intellectual disability [intellectual devel­
opmental disorder]). The diagnosis is not made if the fire setting is better explained by con­
duct disorder, a manic episode, or antisocial personality disorder (Criterion F).
Individuals with pyromania may make considerable advance preparation for starting a 
fire. They may be indifferent to the consequences to life or property caused by the fire, or

they may derive satisfaction from the resulting property destruction. The behaviors may 
lead to property damage, legal consequences, or injury or loss of life to the fire setter or to 
others. Individuals who impulsively set fires (who may or may not have pyromania) often 
have a current or past history of alcohol use disorder.
The population prevalence of pyromania is not known. The lifetime prevalence of fire set­
ting, which is just one component of pyromania and not sufficient for a diagnosis by itself, 
was reported as 1.13% in a population sample, but the most common comorbidities were 
antisocial personality disorder, substance use disorder, bipolar disorder, and pathological 
gambling (gambling disorder). In contrast, pyromania as a primary diagnosis appears to 
be very rare. Among a sample of persons reaching the criminal system with repeated fire 
setting, only 3.3% had symptoms that met full criteria for pyromania.

There are insufficient data to establish a typical age at onset of pyromania. The relation­
ship between fire setting in childhood and pyromania in adulthood has not been docu­
mented. In individuals with pyromania, fire-setting incidents are episodic and may wax 
and wane in frequency. Longitudinal course is unknown. Although fire setting is a major 
problem in children and adolescents (over 40% of those arrested for arson offenses in the 
United States are younger than 18 years), pyromania in childhood appears to be rare. Ju­
venile fire setting is usually associated with conduct disorder, attention-deficit/hyperac- 
tivity disorder, or an adjustment disorder.
Pyromania occurs much more often in males, especially those with poorer social skills and 
learning difficulties.

Other causes of intentional fire setting. It is important to rule out other causes of fire 
setting before giving the diagnosis of pyromania. Intentional fire setting may occur for 
profit, sabotage, or revenge; to conceal a crime; to make a political statement (e.g., an act of 
terrorism or protest); or to attract attention or recognition (e.g., setting a fire in order to dis­
cover it and save the day). Fire setting may also occur as part of developmental experi­
mentation in childhood (e.g., playing with matches, lighters, or fire).
Other mental disorders. A separate diagnosis of pyromania is not given when fire set­
ting occurs as part of conduct disorder, a manic episode, or antisocial personality disorder,

ting occurs as part of conduct disorder, a manic episode, or antisocial personality disorder, 
or if it occurs in response to a delusion or a hallucination (e.g., in schizophrenia) or is at­
tributable to the physiological effects of another medical condition (e.g., epilepsy). The di­
agnosis of pyromania should also not be given when fire setting results from impaired 
judgment associated with major neurocognitive disorder, intellectual disability, or sub­
stance intoxication.
There appears to be a high co-occurrence of substance use disorders, gambling disorder, 
depressive and bipolar disorders, and other disruptive, impulse-control, and conduct dis­
orders with pyromania.

Kleptomania
Diagnostic Criteria 312.32 (F63.3)
A. Recurrent failure to resist impulses to steal objects tliat are not needed for personal  
use or for their monetary value.
B. Increasing sense of tension immediately before committing the theft.
C. Pleasure, gratification, or relief at the time of committing the theft.
D. The stealing is not committed to express anger or vengeance and is not in response  
to a delusion or a hallucination.
E. The stealing is not better explained by conduct disorder, a manic episode, or antisocial  
personality disorder.
The essential feature of kleptomania is the recurrent failure to resist impulses to steal items 
even though the items are not needed for personal use or for their monetary value (Criterion 
A). The individual experiences a rising subjective sense of tension before the theft (Criterion B) 
and feels pleasure, gratification, or relief when committing the theft (Criterion C). The stealing

and feels pleasure, gratification, or relief when committing the theft (Criterion C). The stealing 
is not committed to express anger or vengeance, is not done in response to a delusion or hal­
lucination (Criterion D), and is not better explained by conduct disorder, a manic episode, or 
antisocial personality disorder (Criterion E). The objects are stolen despite the fact that they are 
typically of little value to the individual, who could have afforded to pay for them and often 
gives them away or discards them. Occasionally the individual may hoard the stolen objects or 
surreptitiously return them. Although individuals with this disorder will generally avoid 
stealing when immediate arrest is probable (e.g., in full view of a police officer), they usually 
do not preplan the thefts or fully take into account the chances of apprehension. The stealing is

do not preplan the thefts or fully take into account the chances of apprehension. The stealing is 
done without assistance from, or collaboration with, others.
Individuals with kleptomania typically attempt to resist the impulse to steal, and they are 
aware that the act is wrong and senseless. The individual frequently fears being appre­
hended and often feels depressed or guilty about the thefts. Neurotransmitter pathways 
associated with behavioral addictions, including those associated with the serotonin, do­
pamine, and opioid systems, appear to play a role in kleptomania as well.
Kleptomania occurs in about 4%-24% of individuals arrested for shoplifting. Its preva­
lence in the general population is very rare, at approximately 0.3%-0.6%. Females outnum­
ber males at a ratio of 3:1.

Age at onset of kleptomania is variable, but the disorder often begins in adolescence. How­
ever, the disorder may begin in childhood, adolescence, or adulthood, and in rare cases 
in late adulthood. There is little systematic information on the course of kleptomania, but 
three typical courses have been described: sporadic with brief episodes and long periods 
of remission; episodic with protracted periods of stealing and periods of remission; and 
chronic with some degree of fluctuation. The disorder may continue for years, despite 
multiple convictions for shoplifting.

Genetic and physiological. There are no controlled family history studies of kleptoma­
nia. However, first-degree relatives of individuals with kleptomania may have higher 
rates of obsessive-compulsive disorder than the general population. There also appears to 
be a higher rate of substance use disorders, including alcohol use disorder, in relatives of 
individuals with kleptomania than in the general population.
Functionai Consequences of Kleptomania
The disorder may cause legal, family, career, and personal difficulties.
Ordinaiy theft. Kleptomania should be distinguished from ordinary acts of theft or 
shoplifting. Ordinary theft (whether planned or impulsive) is deliberate and is motivated 
by the usefulness of the object or its monetary worth. Some individuals, especially adoles­
cents, may also steal on a dare, as an act of rebellion, or as a rite of passage. The diagnosis

cents, may also steal on a dare, as an act of rebellion, or as a rite of passage. The diagnosis 
is not made unless other characteristic features of kleptomania are also present. Klepto­
mania is exceedingly rare, whereas shoplifting is relatively common.
Malingering. In malingering, individuals may simulate the symptoms of kleptomania to 
avoid criminal prosecution.
Antisocial personality disorder and conduct disorder. Antisocial personality disorder 
and conduct disorder are distinguished from kleptomania by a general pattern of antiso­
cial behavior.
Manic episodes, psychotic episodes, and major neurocognitive disorder. Kleptomania 
should be distinguished from intentional or inadvertent stealing that may occur during a 
manic episode, in response to delusions or hallucinations (as in, e.g., schizophrenia), or as 
a result of a major neurocognitive disorder.

Kleptomania may be associated with compulsive buying as well as with depressive and 
bipolar disorders (especially major depressive disorder), anxiety disorders, eating disor­
ders (particularly bulimia nervosa), personality disorders, substance use disorders (espe­
cially alcohol use disorder), and other disruptive, impulse-control, and conduct disorders.
Other Specified Disruptive, Impulse-Control,  
and Conduct Disorder
312.89 (F91.8)
This category applies to presentations in which symptoms characteristic of a disruptive,  
impulse-control, and conduct disorder that cause clinically significant distress or impair­
ment in social, occupational, or other important areas of functioning predominate but do  
not meet the full criteria for any of the disorders in the disruptive, impulse-control, and con­

duct disorders diagnostic class. The other specified disruptive, impulse-control, and con­
duct disorder category is used in situations in which the clinician chooses to communicate  
the specific reason that the presentation does not meet the criteria for any specific disrup­
tive, impulse-control, and conduct disorder. This is done by recording “ other specified dis­
ruptive, impulse-control, and conduct disorder”  followed by the specific reason (e.g.,  
“recurrent behavioral outbursts of insufficient frequency” ).

Unspecified Disruptive, Impulse-Control,  
312.9 (F91.9)
This category applies to presentations in  which symptoms characteristic of a disruptive,  
duct disorders diagnostic class. The unspecified disruptive, impulse-control, and conduct  
disorder category is used in situations in  which the clinician chooses not to specify the rea­
son that the criteria are not met for a specific disruptive, impulse-control, and conduct dis­
order, and includes presentations in which there is insufficient information to m al<e a more  

Substance-Related and 
Addictive Disorders
T h e  SU bStSnCG -rG lâtG C l disorders encompass 10 separate classes of drugs: alco­
hol; caffeine; cannabis; hallucinogens (with separate categories for phencyclidine [or sim­
ilarly acting arylcyclohexylamines] and other hallucinogens); inhalants; opioids; 
sedatives, hypnotics, and anxiolytics; stimulants (amphetamine-type substances, cocaine, 
and other stimulants); tobacco; and other (or unknown) substances. These 10 classes are 
not fully distinct. All drugs that are taken in excess have in common direct activation of 
the brain reward system, which is involved in the reinforcement of behaviors and the pro­
duction of memories. They produce such an intense activation of the reward system that 
normal activities may be neglected. Instead of achieving reward system activation 
through adaptive behaviors, drugs of abuse directly activate the reward pathways. The

through adaptive behaviors, drugs of abuse directly activate the reward pathways. The 
pharmacological mechanisms by which each class of drugs produces reward are different, 
but the drugs typically activate the system and produce feelings of pleasure, often re­
ferred to as a ''high." Furthermore, individuals with lower levels of self-control, which 
may reflect impairments of brain inhibitory mechanisms, may be particularly predisposed 
to develop substance use disorders, suggesting that the roots of substance use disorders 
for some persons can be seen in behaviors long before the onset of actual substance use 
itself.
In addition to the substance-related disorders, this chapter also includes gambling dis­
order, reflecting evidence that gambling behaviors activate reward systems similar to 
those activated by drugs of abuse and produce some behavioral symptoms that appear

those activated by drugs of abuse and produce some behavioral symptoms that appear 
comparable to those produced by the substance use disorders. Other excessive behavioral 
patterns, such as Internet gaming, have also been described, but the research on these and 
other behavioral syndromes is less clear. Thus, groups of repetitive behaviors, which some 
term behavioral addictions,  with such subcategories as "sex addiction," "exercise addiction," 
or "shopping addiction," are not included because at this time there is insufficient peer-re­
viewed evidence to establish the diagnostic criteria and course descriptions needed to 
identify these behaviors as mental disorders.
The substance-related disorders are divided into two groups: substance use disorders 
and substance-induced disorders. The following conditions may be classified as sub­

stance-induced: intoxication, withdrawal, and other substance/medication-induced men­
tal disorders (psychotic disorders, bipolar and related disorders, depressive disorders, 
anxiety disorders, obsessive-compulsive and related disorders, sleep disorders, sexual dys­
functions, delirium, and neurocognitive disorders).
The current section begins with a general discussion of criteria sets for a substance 
use disorder, substance intoxication and withdrawal, and other substance/medication- 
induced mental disorders, at least some of which are applicable across classes of sub­
stances. Reflecting some unique aspects of the 10 substance classes relevant to this chapter, 
the remainder of the chapter is organized by the class of substance and describes their

the remainder of the chapter is organized by the class of substance and describes their 
unique aspects. To facilitate differential diagnosis, the text and criteria for the remaining 
substance/medication-induced mental disorders are included with disorders with which 
they share phenomenology (e.g., substance/medication-induced depressive disorder is in 
the chapter "Depressive Disorders"). The broad diagnostic categories associated with each 
specific group of substances are shown in Table 1.

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Substance-Related Disorders  
Substance Use Disorders
Features
The essential feature of a substance use disorder is a cluster of cognitive, behavioral, and 
physiological symptoms indicating that the individual continues using the substance de­
spite significant substance-related problems. As seen in Table 1, the diagnosis of a sub­
stance use disorder can be applied to all 10 classes included in this chapter except caffeine. 
For certain classes some symptoms are less salient, and in a few instances not all symptoms 
apply (e.g., withdrawal symptoms are not specified for phencyclidine use disorder, other 
hallucinogen use disorder, or inhalant use disorder).
An important characteristic of substance use disorders is an underlying change in brain cir­
cuits that may persist beyond detoxification, particularly in individuals with severe disorders. 
The behavioral effects of these brain changes may be exhibited in the repeated relapses and in­

tense drug craving when the individuals are exposed to drug-related stimuli. These persistent 
drug effects may benefit from long-term approaches to treatment.
Overall, the diagnosis of a substance use disorder is based on a pathological pattern of 
behaviors related to use of the substance. To assist with organization. Criterion A criteria can 
be considered to fit within overall groupings of impaired control, social impairment, risky use,  
and pharmacological criteria.  Impaired control over substance use is the first criteria grouping 
(Criteria 1-4). The individual may take the substance in larger amounts or over a longer pe­
riod than was originally intended (Criterion 1). The individual may express a persistent de­

sire to cut down or regulate substance use and may report multiple unsuccessful efforts to 
decrease or discontinue use (Criterion 2). The individual may spend a great deal of time ob­
taining the substance, using the substance, or recovering from its effects (Criterion 3). In 
some instances of more severe substance use disorders, virtually all of the individual's daily 
activities revolve around the substance. Craving (Criterion 4) is manifested by an intense de­
sire or urge for the drug that may occur at any time but is more likely when in an environ­
ment where the drug previously was obtained or used. Craving has also been shown to 
involve classical conditioning and is associated with activation of specific reward structures

involve classical conditioning and is associated with activation of specific reward structures 
in the brain. Craving is queried by asking if there has ever been a time when they had such 
strong urges to take the drug that they could not think of anything else. Current craving is of­
ten used as a treatment outcome measure because it may be a signal of impending relapse.
Social impairment is the second grouping of criteria (Criteria 5-7). Recurrent substance 
use may result in a failure to fulfill major role obligations at work, school, or home (Crite­
rion 5). The individual may continue substance use despite having persistent or recurrent 
social or interpersonal problems caused or exacerbated by the effects of the substance (Cri­
terion 6). Important social, occupational, or recreational activities may be given up or re­

duced because of substance use (Criterion 7). The individual may withdraw from family 
activities and hobbies in order to use the substance.
Risky use of the substance is the third grouping of criteria (Criteria 8-9). This may take 
the form of recurrent substance use in situations in which it is physically hazardous (Cri­
terion 8). The individual may continue substance use despite knowledge of having a per­
sistent or recurrent physical or psychological problem that is likely to have been caused or 
exacerbated by the substance (Criterion 9). The key issue in evaluating this criterion is not 
the existence of the problem, but rather the individual's failure to abstain from using the 
substance despite the difficulty it is causing.

Pharmacological criteria are the final grouping (Criteria 10 and 11). Tolerance (Crite­
rion 10) is signaled by requiring a markedly increased dose of the substance to achieve the 
desired effect or a markedly reduced effect when the usual dose is consumed. The degree 
to which tolerance develops varies greatly across different individuals as well as across 
substances and may involve a variety of central nervous system effects. For example, tol­
erance to respiratory depression and tolerance to sedating and motor coordination may 
develop at different rates, depending on the substance. Tolerance may be difficult to de­
termine by history alone, and laboratory tests may be helpful (e.g., high blood levels of the 
substance coupled with little evidence of intoxication suggest that tolerance is likely). Tol­
erance must also be distinguished from individual variability in the initial sensitivity to 
the effects of particular substances. For example, some first-time alcohol drinkers show

the effects of particular substances. For example, some first-time alcohol drinkers show 
very little evidence of intoxication with three or four drinks, whereas others of similar 
weight and drinking histories have slurred speech and incoordination.
Withdrawal (Criterion 11) is a syndrome that occurs when blood or tissue concentra­
tions of a substance decline in an individual who had maintained prolonged heavy use of 
the substance. After developing withdrawal symptoms, the individual is likely to con­
sume the substance to relieve the symptoms. Withdrawal symptoms vary greatly across 
the classes of substances, and separate criteria sets for withdrawal are provided for the 
drug classes. Marked and generally easily measured physiological signs of withdrawal are 
common with alcohol, opioids, and sedatives, hypnotics, and anxiolytics. Withdrawal

common with alcohol, opioids, and sedatives, hypnotics, and anxiolytics. Withdrawal 
signs and symptoms with stimulants (amphetamines and cocaine), as well as tobacco and 
cannabis, are often present but may be less apparent. Significant withdrawal has not been 
documented in humans after repeated use of phencyclidine, other hallucinogens, and in­
halants; therefore, this criterion is not included for these substances. Neither tolerance nor 
withdrawal is necessary for a diagnosis of a substance use disorder. However, for most 
classes of substances, a past history of withdrawal is associated with a more severe clinical 
course (i.e., an earlier onset of a substance use disorder, higher levels of substance intake, 
and a greater number of substance-related problems).
Symptoms of tolerance and withdrawal occurring during appropriate medical treat­

ment with prescribed medications (e.g., opioid analgesics, sedatives, stimulants) are spe­
cifically not counted when diagnosing a substance use disorder. The appearance of normal, 
expected pharmacological tolerance and withdrawal during the course of medical treat­
ment has been known to lead to an erroneous diagnosis of "addiction" even when these 
were the only symptoms present. Individuals whose only symptoms are those that occur 
as a result of medical treatment (i.e., tolerance and withdrawal as part of medical care 
when the medications are taken as prescribed) should not receive a diagnosis solely on the 
basis of these symptoms. However, prescription medications can be used inappropriately, 
and a substance use disorder can be correctly diagnosed when there are other symptoms 
of compulsive, drug-seeking behavior.
Severity and Specifiers

Substance use disorders occur in a broad range of severity, from mild to severe, with se­
verity based on the number of symptom criteria endorsed. As a general estimate of sever­
ity, a mild substance use disorder is suggested by the presence of two to three symptoms, 
moderate  by four to five symptoms, and severe  by six or more symptoms. Changing severity 
across time is also reflected by reductions or increases in the frequency and/or dose of 
substance use, as assessed by the individual's own report, report of knowledgeable others, 
clinician's observations, and biological testing. The following course specifiers and descrip­
tive features specifiers are also available for substance use disorders: "in early remission," 
"in sustained remission," "on maintenance therapy," and "in a controlled environment."

"in sustained remission," "on maintenance therapy," and "in a controlled environment." 
Definitions of each are provided within respective criteria sets.

Recording Procedures for Substarice Use Disorders
\
The clinician should use the code that applies to the class of substances but record the 
name of the specific substance.  For example, the clinician should record 304.10 (F13.20) 
moderate alprazolam use disorder (rather than moderate sedative, hypnotic, or anxiolytic 
use disorder) or 305.70 (F15.10) mild methamphetamine use disorder (rather than mild 
stimulant use disorder). For substances that do not fit into any of the classes (e.g., anabolic 
steroids), the appropriate code for "other substance use disorder" should be used and the 
specific substance indicated (e.g., 305.90 [F19.10] mild anabolic steroid use disorder). If the 
substance taken by the individual is unknown, the code for the class "other (or unknown)" 
should be used (e.g., 304.90 [F19.20] severe unknown substance use disorder). If criteria 
are met for more than one substance use disorder, all should be diagnosed (e.g., 304.00

are met for more than one substance use disorder, all should be diagnosed (e.g., 304.00 
[FI 1.20] severe heroin use disorder; 304.20 [F14.20] moderate cocaine use disorder).
The appropriate ICD-IO-CM code for a substance use disorder depends on whether 
there is a comorbid substance-induced disorder (including intoxication and withdrawal). In 
the above example, the diagnostic code for moderate alprazolam use disorder, F13.20, re­
flects the absence of a comorbid alprazolam-induced mental disorder. Because ICD-IO-CM 
codes for substance-induced disorders indicate both the presence (or absence) and severity 
of the substance use disorder, ICD-IO-CM codes for substance use disorders can be used 
only in the absence of a substance-induced disorder. See the individual substance-specific 
sections for additional coding information.

Note that the word addiction  is not applied as a diagnostic term in this classification, 
although it is in common usage in many countries to describe severe problems related to 
compulsive and habitual use of substances. The more neutral term substance use disorder  is 
used to describe the wide range of the disorder, from a mild form to a severe state of chron­
ically relapsing, compulsive drug taking. Some clinicians will choose to use the word ad­
diction  to describe more extreme presentations, but the word is omitted from the official 
DSM-5 substance use disorder diagnostic terminology because of its uncertain definition 
and its potentially negative connotation.
Substance-Induced Disorders
The overall category of substance-induced disorders includes intoxication, withdrawal,

The overall category of substance-induced disorders includes intoxication, withdrawal, 
and other substance/medication-induced mental disorders (e.g., substance-induced psy­
chotic disorder, substance-induced depressive disorder).
Substance Intoxication and Withdrawal
Criteria for substance intoxication are included within the substance-specific sections of 
this chapter. The essential feature is the development of a reversible substance-specific 
syndrome due to the recent ingestion of a substance (Criterion A). The clinically significant 
problematic behavioral or psychological changes associated with intoxication (e.g., bellig­
erence, mood lability, impaired judgment) are attributable to the physiological effects of 
the substance on the central nervous system and develop during or shortly after use of the 
substance (Criterion B). The symptoms are not attributable to another medical condition

substance (Criterion B). The symptoms are not attributable to another medical condition 
and are not better explained by another mental disorder (Criterion D). Substance intoxi­
cation is common among those with a substance use disorder but also occurs frequently in 
individuals without a substance use disorder. This category does not apply to tobacco.
The most common changes in intoxication involve disturbances of perception, wake­
fulness, attention, thinking, judgment, psychomotor behavior, and interpersonal behav­
ior. Short-term, or "acute," intoxications may have different signs and symptoms than

sustained, or "chronic," intoxications. For example, moderate cocaine doses may initially 
produce gregariousness, but social withdrawal may develop if such doses are frequently 
repeated over days or weeks.
When used in the physiological sense, the term intoxication  is broader than substance 
intoxication as defined here. Many substances may produce physiological or psychologi­
cal changes that are not necessarily problematic. For example, an individual with tachy­
cardia from substance use has a physiological effect, but if this is the only symptom in the 
absence of problematic behavior, the diagnosis of intoxication would not apply. Intoxica­
tion may sometimes persist beyond the time when the substance is detectable in the body. 
This may be due to enduring central nervous system effects, the recovery of which takes 
longer than the time for elimination of the substance. These longer-term effects of intoxi­

cation must be distinguished from withdrawal (i.e., symptoms initiated by a decline in 
blood or tissue concentrations of a substance).
Criteria for substance withdrawal are included within the substance-specific sections of 
this chapter. The essential feature is the development of a substance-specific problematic be­
havioral change, with physiological and cognitive concomitants, that is due to the cessation of, 
or reduction in, heavy and prolonged substance use (Criterion A). The substance-specific syn­
drome causes clinically significant distress or impairment in social, occupational, or other im­
portant areas of functioning (Criterion C). The symptoms are not due to another medical 
condition and are not better explained by another mental disorder (Criterion D). Withdrawal

condition and are not better explained by another mental disorder (Criterion D). Withdrawal 
is usually, but not always, associated with a substance use disorder. Most individuals with 
withdrawal have an urge to re-administer the substance to reduce the symptoms.
Route of Administration and Speed of Substance Effects
Routes of administration that produce more rapid and efficient absorption into the blood­
stream (e.g., intravenous, smoking, intranasal "snorting") tend to result in a more intense 
intoxication and an increased likelihood of an escalating pattern of substance use leading 
to withdrawal. Similarly, rapidly acting substances are more likely than slower-acting 
substances to produce immediate intoxication.
Duration of Effects
Within the same drug category, relatively short-acting substances tend to have a higher

Within the same drug category, relatively short-acting substances tend to have a higher 
potential for the development of withdrawal than do those with a longer duration of ac­
tion. However, longer-acting substances tend to have longer withdrawal duration. The 
half-life of the substance parallels aspects of withdrawal: the longer the duration of action, 
the longer the time between cessation and the onset of withdrawal symptoms and the lon­
ger the withdrawal duration. In general, the longer the acute withdrawal period, the less 
intense the syndrome tends to be.
Use of iVluitipie Substances
Substance intoxication and withdrawal often involve several substances used simultane­
ously or sequentially. In these cases, each diagnosis should be recorded separately.
Associated Laboratory Findings
Laboratory analyses of blood and urine samples can help determine recent use and the specific

Laboratory analyses of blood and urine samples can help determine recent use and the specific 
substances involved. However, a positive laboratory test result does not by itself indicate that 
the individual has a pattern of substance use that meets criteria for a substance-induced or sub­
stance use disorder, and a negative test result does not by itself rule out a diagnosis.
Laboratory tests can be useful in identifying withdrawal. If the individual presents 
with withdrawal from an unknown substance, laboratory tests may help identify the sub­
stance and may also be helpful in differentiating withdrawal from other mental disorders.

In addition, normal functioning in the presence of high blood levels of a substance sug­
gests considerakjle tolerance.
Individuals ages 18-24 years have relatively high prevalence rates for the use of virtually 
every substance. Intoxication is usually the initial substance-related disorder and often be­
gins in the teens. Withdrawal can occur at any age as long as the relevant drug has been 
taken in sufficient doses over an extended period of time.
Recording Procedures for Intoxication and Withdrawal
name of the specific substance.  For example, the clinician should record 292.0 (F13.239) seco­
barbital withdrawal (rather than sedative, hypnotic, or anxiolytic withdrawal) or 292.89 
(F15.129) methamphetamine intoxication (rather than stimulant intoxication). Note that 
the appropriate ICD-IO-CM diagnostic code for intoxication depends on whether there is

the appropriate ICD-IO-CM diagnostic code for intoxication depends on whether there is 
a comorbid substance use disorder. In this case, the F15.129 code for methamphetamine in­
dicates the presence of a comorbid mild methamphetamine use disorder. If there had been 
no comorbid methamphetamine use disorder, the diagnostic code would have been 
F15.929. ICD-IO-CM coding rules require that all withdrawal codes imply a comorbid 
moderate to severe substance use disorder for that substance. In the above case, the code 
for secobarbital withdrawal (F13.239) indicates the comorbid presence of a moderate to se­
vere secobarbital use disorder. See the coding note for the substance-specific intoxication 
and withdrawal syndromes for the actual coding options.
For substances that do not fit into any of the classes (e.g., anabolic steroids), the appropriate

For substances that do not fit into any of the classes (e.g., anabolic steroids), the appropriate 
code for "other substance intoxication" should be used and the specific substance indicated 
(e.g., 292.89 [F19.929] anabolic steroid intoxication). If the substance taken by the individual is 
unknown, the code for the class "other (or unknown)" should be used (e.g., 292.89 [F19.929] 
unknown substance intoxication). If there are symptoms or problems associated with a partic­
ular substance but criteria are not met for any of the substance-specific disorders, the unspec­
ified category can be used (e.g., 292.9 [F12.99] unspecified cannabis-related disorder).
As noted above, the substance-related codes in ICD-IO-CM combine the substance use dis­
order aspect of the clinical picture and the substance-induced aspect into a single combined 
code. Thus, if both heroin withdrawal and moderate heroin use disorder are present, the single

code. Thus, if both heroin withdrawal and moderate heroin use disorder are present, the single 
code FI 1.23 is given to cover both presentations. In ICD-9-CM, separate diagnostic codes 
(292.0 and 304.00) are given to indicate withdrawal and a moderate heroin use disorder, re­
spectively. See the individual substance-specific sections for additional coding information.
Substance/Medication-Induced Mental Disorders
The substance/medication-induced mental disorders are potentially severe, usually tem­
porary, but sometimes persisting central nervous system (CNS) syndromes that develop 
in the context of the effects of substances of abuse, medications, or several toxins. They are 
distinguished from the substance use disorders, in which a cluster of cognitive, behav­
ioral, and physiological symptoms contribute to the continued use of a substance despite

ioral, and physiological symptoms contribute to the continued use of a substance despite 
significant substance-related problems. The substance/medication-induced mental disor­
ders may be induced by the 10 classes of substances that produce substance use disorders, 
or by a great variety of other medications used in medical treatment. Each substance- 
induced mental disorder is described in the relevant chapter (e.g., "Depressive Disorders," 
"Neurocognitive Disorders"), and therefore, only a brief description is offered here. All 
substance/medication-induced disorders share common characteristics. It is important to 
recognize these common features to aid in the detection of these disorders. These features 
are described as follows:

A. The disorder represents a clinically significant symptomatic presentation of a relevant 
B. There is evidence from the history, physical examination, or laboratory findings of 
both of the follov^ing:
1. The disorder developed during or within 1  month of a substance intoxication or 
v^ithdrawal or taking a medication; and
2. The involved substance/medication is capable of producing the mental disorder.
C. The disorder is not better explained by an independent mental disorder (i.e., one that is 
not substance- or medication-induced). Such evidence of an independent mental dis­
order could include the following:
1. The disorder preceded the onset of severe intoxication or withdrawal or exposure 
to the medication; or
2. The full mental disorder persisted for a substantial period of time (e.g., at least 1 month) 
after the cessation of acute withdrawal or severe intoxication or taking the medica­

tion. This criterion does not apply to substance-induced neurocognitive disorders 
or hallucinogen persisting perception disorder, which persist beyond the cessation 
of acute intoxication or withdrawal.
D. The disorder does not occur exclusively during the course of a delirium.
E. The disorder causes clinically significant distress or impairment in social, occupa­
Features
Some generalizations can be made regarding the categories of substances capable of produc­
ing clinically relevant substance-induced mental disorders. In general, the more sedating 
drugs (sedative, hypnotics, or anxiolytics, and alcohol) can produce prominent and clini­
cally significant depressive disorders during intoxication, while anxiety conditions are likely

cally significant depressive disorders during intoxication, while anxiety conditions are likely 
to be observed during withdrawal syndromes from these substances. Also, during intoxica­
tion, the more stimulating substances (e.g., amphetamines and cocaine) are likely to be as­
sociated with substance-induced psychotic disorders and substance-induced anxiety 
disorders, with substance-induced major depressive episodes observed during withdrawal. 
Both the more sedating and more stimulating drugs are likely to produce significant but 
temporary sleep and sexual disturbances. An overview of the relationship between specific 
categories of substances and specific psychiatric syndromes is presented in Table 1.
The medication-induced conditions include what are often idiosyncratic CNS reac­
tions or relatively extreme examples of side effects for a wide range of medications taken

tions or relatively extreme examples of side effects for a wide range of medications taken 
for a variety of medical concerns. These include neurocognitive complications of anesthet­
ics, antihistamines, antihypertensives, and a variety of other medications and toxins (e.g., 
organophosphates, insecticides, carbon monoxide), as described in the chapter on neuro­
cognitive disorders. Psychotic syndromes may be temporarily experienced in the context 
of anticholinergic, cardiovascular, and steroid drugs, as well as during use of stimulant­
like and depressant-like prescription or over-the-counter drugs. Temporary but severe 
mood disturbances can be observed with a wide range of medications, including steroids, 
antihypertensives, disulfiram, and any prescription or over-the-counter depressant or 
stimulant-like substances. A similar range of medications can be associated with tempo­

rary anxiety syndromes, sexual dysfunctions, and conditions of disturbed sleep.
In general, to be considered a substance/medication-induced mental disorder, there 
must be evidence that the disorder being observed is not likely to be better explained by an 
independent mental condition. The latter are most likely to be seen if the mental disorder 
was present before the severe intoxication or withdrawal or medication administration, or, 
with the exception of several substance-induced persisting disorders listed in Table 1, con­
tinued more than 1 month after cessation of acute withdrawal, severe intoxication, or use

of the medications. When symptoms are only observed during a delirium (e.g., alcohol 
withdrawal del|rium), the mental disorder should be diagnosed as a delirium, and the 
psychiatric syndrome occurring during the delirium should not also be diagnosed sepa­
rately, as many symptoms (including disturbances in mood, anxiety, and reality testing) 
are commonly seen during agitated, conhised states. The features associated with each rel­
evant major mental disorder are similar whether observed with independent or sub­
stance/medication-induced mental disorders. However, individuals with substance/ 
medication-induced mental disorders are likely to also demonstrate the associated fea­
tures seen with the specific category of substance or medication, as listed in other subsec­
tions of this chapter.
Substance-induced mental disorders develop in the context of intoxication or withdrawal

Substance-induced mental disorders develop in the context of intoxication or withdrawal 
from substances of abuse, and medication-induced mental disorders are seen with pre­
scribed or over-the-counter medications that are taken at the suggested doses. Both condi­
tions are usually temporary and likely to disappear within 1 month or so of cessation of acute 
withdrawal, severe intoxication, or use of the medication. Exceptions to these generaliza­
tions occur for certain long-duration substance-induced disorders: substance-associated 
neurocognitive disorders that relate to conditions such as alcohol-induced neurocognitive 
disorder, inhalant-induced neurocognitive disorder, and sedative-, hypnotic-, or anxiolytic- 
induced neurocognitive disorder; and hallucinogen persisting perception disorder ("flash­
backs"; see the section "Hallucinogen-Related Disorders" later in this chapter). However,

backs"; see the section "Hallucinogen-Related Disorders" later in this chapter). However, 
most other substance/medication-induced mental disorders, regardless of the severity of 
the symptoms, are likely to improve relatively quickly with abstinence and unlikely to re­
main clinically relevant for more than 1 month after complete cessation of use.
As is true of many consequences of heavy substance use, some individuals are more 
and others less prone toward specific substance-induced disorders. Similar types of pre­
dispositions may make some individuals more likely to develop psychiatric side effects of 
some types of medications, but not others. However, it is unclear whether individuals 
with family histories or personal prior histories with independent psychiatric syndromes 
are more likely to develop the induced syndrome once the consideration is made as to

are more likely to develop the induced syndrome once the consideration is made as to 
whether the quantity and frequency of the substance was sufficient to lead to the devel­
opment of a substance-induced syndrome.
There are indications that the intake of substances of abuse or some medications with 
psychiatric side effects in the context of a preexisting mental disorder is likely to result in 
an intensification of the preexisting independent syndrome. The risk for substance/med­
ication-induced mental disorders is likely to increase with both the quantity and the fre­
quency of consumption of the relevant substance.
The symptom profiles for the substance/medication-induced mental disorders resem­
ble independent mental disorders. While the symptoms of substance/medication-in­
duced mental disorders can be identical to those of independent mental disorders (e.g.,

duced mental disorders can be identical to those of independent mental disorders (e.g., 
delusions, hallucinations, psychoses, major depressive episodes, anxiety syndromes), and 
although they can have the same severe consequences (e.g., suicide), most induced mental 
disorders are likely to improve in a matter of days to weeks of abstinence.
The substance/medication-induced mental disorders are an important part of the dif­
ferential diagnoses for the independent psychiatric conditions. The importance of recog­
nizing an induced mental disorder is similar to the relevance of identifying the possible 
role of some medical conditions and medication reactions before diagnosing an indepen­
dent mental disorder. Symptoms of substance- and medication-induced mental disorders 
may be identical cross-sectionally to those of independent mental disorders but have dif­

ferent treatments and prognoses from the independent condition.

Functional Consequences of Substance/Medication-  
Induced Mental Disorders
The same consequences related to the relevant independent mental disorder (e.g., suicide 
attempts) are likely to apply to the substance/medication-induced mental disorders, but 
these are likely to disappear within 1  month after abstinence. Similarly, the same func­
tional consequences associated with the relevant substance use disorder are likely to be seen 
for the substance-induced mental disorders.
Recording Procedures for Substance/Medication-  
induced Mental Disorders
Coding notes and separate recording procedures for ICD-9-CM and ICD-IO-CM codes for 
other specific substance/medication-induced mental disorders are provided in other 
chapters of the manual with disorders with which they share phenomenology (see the sub­
stance/medication-induced mental disorders in these chapters: '"Schizophrenia Spectrum 
and Other Psychotic Disorders," "Bipolar and Related Disorders," "Depressive Disor­

ders," "Anxiety Disorders," "Obsessive-Compulsive and Related Disorders," "Sleep- 
Wake Disorders," "Sexual Dysfunctions," and "Neurocognitive Disorders"). Generally, 
for ICD-9-CM, if a mental disorder is induced by a substance use disorder, a separate di­
agnostic code is given for the specific substance use disorder, in addition to the code for the 
substance/medication-induced mental disorder. For ICD-IO-CM, a single code combines 
the substance-induced mental disorder with the substance use disorder. A separate diag­
nosis of the comorbid substance use disorder is not given, although the name and severity 
of the specific substance use disorder (when present) are used when recording the sub­
stance/medication-induced mental disorder. ICD-IO-CM codes are also provided for sit­

uations in which the substance/medication-induced mental disorder is not induced by a 
substance use disorder (e.g., when a disorder is induced by one-time use of a substance or 
medication). Additional information needed to record the diagnostic name of the sub­
stance/medication-induced mental disorder is provided in the section "Recording Proce­
dures" for each substance/medication-induced mental disorder in its respective chapter.
Alcohol-Related Disorders
Alcohol Use Disorder  
Alcohol Intoxication  
Alcohol Withdrawal  
Other Alcohol-induced Disorders  
Unspecified Alcohol-Related Disorder
Alcohol Use Disorder
A. A problematic pattern of alcohol use leading to clinically significant impairment or dis­

tress, as manifested by at least two of the following, occurring within a 12-month period:
1. Alcohol is often taken in larger amounts or over a longer period than was intended.
2. There is a persistent desire or unsuccessful efforts to cut down or control alcohol use.

3. A great deal of time is spent in activities necessary to obtain alcohol, use alcohol,  
or recovôr from its effects.
4. Craving, or a strong desire or urge to use alcohol.
5. Recurrent alcohol use resulting in a failure to fulfill major role obligations at work,  
school, or home.
6. Continued alcohol use despite having persistent or recurrent social or interpersonal  
problems caused or exacerbated by the effects of alcohol.
7. Important social, occupational, or recreational activities are given up or reduced be­
cause of alcohol use.
8. Recurrent alcohol use in situations in which it is physically hazardous.
9. Alcohol use is continued despite knowledge of having a persistent or recurrent  
physical or psychological problem that is likely to have been caused or exacerbated  
by alcohol.
10. Tolerance, as defined by either of the following:
a. A need for markedly increased amounts of alcohol to achieve intoxication or de­
sired effect.

b. A markedly diminished effect with continued use of the same amount of alcohol.
11. Withdrawal, as manifested by either of the following:
a. The characteristic withdrawal syndrome for alcohol (refer to Criteria A and B of  
the criteria set for alcohol withdrawal, pp. 499-500).
b. Alcohol (or a closely related substance, such as a benzodiazepine) is taken to  
relieve or avoid withdrawal symptoms.
In early remission: After full criteria for alcohol use disorder were previously met,  
none of the criteria for alcohol use disorder have been met for at least 3 months but for  
less than 12 months (with the exception that Criterion A4, “ Craving, or a strong desire  
or urge to use alcohol,”  may be met).
In sustained remission: After full criteria for alcohol use disorder were previously

In sustained remission: After full criteria for alcohol use disorder were previously  
met, none of the criteria for alcohol use disorder have been met at any time during a  
period of 12 months or longer (with the exception that Criterion A4, “ Craving, or a  
strong desire or urge to use alcohol,”  may be met).
In a controlled environment: This additional specifier is used if the individual is in an  
environment where access to alcohol is restricted.
Code based on current severity: Note for ICD-10-CM codes: If an alcohol intoxication,  
alcohol withdrawal, or another alcohol-induced mental disorder is also present, do not use  
the codes below for alcohol use disorder. Instead, the comorbid alcohol use disorder is  
indicated in the 4th character of the alcohol-induced disorder code (see the coding note  
for alcohol intoxication, alcohol withdrawal, ora specific alcohol-induced mental disorder).

for alcohol intoxication, alcohol withdrawal, ora specific alcohol-induced mental disorder).  
For example, if there is comorbid alcohol intoxication and alcohol use disorder, only the  
alcohol intoxication code is given, with the 4th character indicating whether the comorbid  
alcohol use disorder is mild, moderate, or severe: F10.129 for mild alcohol use disorder  
with alcohol intoxication or FI 0.229 for a moderate or severe alcohol use disorder with al­
cohol intoxication.
305.00 (FI 0.10) Mild: Presence of 2-3 symptoms.
303.90 (FI 0.20) Moderate: Presence of 4-5 symptoms.
303.90 (FI 0.20) Severe: Presence of 6 or more symptoms.

"In a controlled environment" applies as a further specifier of remission if the individual is 
both in remission and in a controlled environment (i.e., in early remission in a controlled 
environment or in sustained remission in a controlled environment). Examples of these 
environments are closely supervised and substance-free jails, therapeutic communities, 
and locked hospital units.
Severity of the disorder is based on the number of diagnostic criteria endorsed. For a 
given individual, changes in severity of alcohol use disorder across time are also reflected 
by reductions in the frequency (e.g., days of use per month) and/or dose (e.g., number of 
standard drinks consumed per day) of alcohol used, as assessed by the individual's self­
report, report of knowledgeable others, clinician observations, and, when practical, bio­
logical testing (e.g., elevations in blood tests as described in the section "Diagnostic Mark­
ers" for this disorder).

Alcohol use disorder is defined by a cluster of behavioral and physical symptoms, which 
can include withdrawal, tolerance, and craving. Alcohol withdrawal is characterized by 
withdrawal symptoms that develop approximately 4-12 hours after the reduction of in­
take following prolonged, heavy alcohol ingestion. Because withdrawal from alcohol can 
be unpleasant and intense, individuals may continue to consume alcohol despite adverse 
consequences, often to avoid or to relieve withdrawal symptoms. Some withdrawal symp­
toms (e.g., sleep problems) can persist at lower intensities for months and can contribute to 
relapse. Once a pattern of repetitive and intense use develops, individuals with alcohol 
use disorder may devote substantial periods of time to obtaining and consuming alcoholic 
beverages.

Craving for alcohol is indicated by a strong desire to drink that makes it difficult to 
think of anything else and that often results in the onset of drinking. School and job per­
formance may also suffer either from the aftereffects of drinking or from actual intoxica­
tion at school or on the job; child care or household responsibilities may be neglected; and 
alcohol-related absences may occur from school or work. The individual may use alcohol 
in physically hazardous circumstances (e.g., driving an automobile, swimming, operating 
machinery while intoxicated). Finally, individuals with an alcohol use disorder may con­
tinue to consume alcohol despite the knowledge that continued consumption poses sig­

nificant physical (e.g., blackouts, liver disease), psychological (e.g., depression), social, or 
interpersonal problems (e.g., violent arguments with spouse while intoxicated, child 
abuse).
Alcohol use disorder is often associated with problems similar to those associated with 
other substances (e.g., cannabis; cocaine; heroin; amphetamines; sedatives, hypnotics, or 
anxiolytics). Alcohol may be used to alleviate the unwanted effects of these other 
substances or to substitute for them when they are not available. Symptoms of conduct 
problems, depression, anxiety, and insomnia frequently accompany heavy drinking and 
sometimes precede it.
Repeated intake of high doses of alcohol can affect nearly every organ system, espe­

cially the gastrointestinal tract, cardiovascular system, and the central and peripheral ner­
vous systems. Gastrointestinal effects include gastritis, stomach or duodenal ulcers, and, 
in about 15% of individuals who use alcohol heavily, liver cirrhosis and/or pancreatitis. 
There is also an increased rate of cancer of the esophagus, stomach, and other parts of the 
gastrointestinal tract. One of the most commonly associated conditions is low-grade hy­
pertension. Cardiomyopathy and other myopathies are less common but occur at an in­

creased rate among those who drink very heavily. These factors, along with marked 
increases in levels of triglycerides and low-density lipoprotein cholesterol, contribute to 
an elevated risk of heart disease. Peripheral neuropathy may be evidenced by muscular 
weakness, paresthesias, and decreased peripheral sensation. More persistent central ner­
vous system effects include cognitive deficits, severe memory impairment, and degener­
ative changes in the cerebellum. These effects are related to the direct effects of alcohol or 
of trauma and to vitamin deficiencies (particularly of the B vitamins, including thiamine). 
One devastating central nervous system effect is the relatively rare alcohol-induced per­
sisting amnestic disorder, or Wemicke-Korsakoff syndrome, in which the ability to encode 
new memory is severely impaired. This condition would now be described within the chap­
ter "Neurocognitive Disorders" and would be termed a substance/medication-induced neuro-

ter "Neurocognitive Disorders" and would be termed a substance/medication-induced neuro-  
cognitive disorder.
Alcohol use disorder is an important contributor to suicide risk during severe intoxi­
cation and in the context of a temporary alcohol-induced depressive and bipolar disorder. 
There is an increased rate of suicidal behavior as well as of completed suicide among in­
dividuals with the disorder.
Alcohol use disorder is a common disorder. In the United States, the 12-month prevalence 
of alcohol use disorder is estimated to be 4.6% among 12- to 17-year-olds and 8.5% among 
adults age 18 years and older in the United States. Rates of the disorder are greater among 
adult men (12.4%) than among adult women (4.9%). Twelve-month prevalence of alcohol 
use disorder among adults decreases in middle age, being greatest among individuals 18-

use disorder among adults decreases in middle age, being greatest among individuals 18- 
to 29-years-old (16.2%) and lowest among individuals age 65 years and older (1.5%).
Twelve-month prevalence varies markedly across race/ethnic subgroups of the U.S. 
population. For 12- to 17-year-olds, rates are greatest among Hispanics (6.0%) and Native 
Americans and Alaska Natives (5.7%) relative to whites (5.0%), African Americans (1.8%), 
and Asian Americans and Pacific Islanders (1.6%). In contrast, among adults, the 12-month 
prevalence of alcohol use disorder is clearly greater among Native Americans and Alaska 
Natives (12.1%) than among whites (8.9%), Hispanics (7.9%), African Americans (6.9%), 
and Asian Americans and Pacific Islanders (4.5%).
The first episode of alcohol intoxication is likely to occur during the mid-teens. Alcohol-

The first episode of alcohol intoxication is likely to occur during the mid-teens. Alcohol- 
related problems that do not meet full criteria for a use disorder or isolated problems may 
occur prior to age 2 0 years, but the age at onset of an alcohol use disorder with two or more 
of the criteria clustered together peaks in the late teens or early to mid 20s. The large ma­
jority of individuals who develop alcohol-related disorders do so by their late 30s. The first 
evidence of withdrawal is not likely to appear until after many other aspects of an alcohol 
use disorder have developed. An earlier onset of alcohol use disorder is observed in ado­
lescents with preexisting conduct problems and those with an earlier onset of intoxication.
Alcohol use disorder has a variable course that is characterized by periods of remission

Alcohol use disorder has a variable course that is characterized by periods of remission 
and relapse. A decision to stop drinking, often in response to a crisis, is likely to be followed 
by a period of weeks or more of abstinence, which is often followed by limited periods of 
controlled or nonproblematic drinking. However, once alcohol intake resumes, it is highly 
likely that consumption will rapidly escalate and that severe problems will once again 
develop.
Alcohol use disorder is often erroneously perceived as an intractable condition, per­
haps based on the fact that individuals who present for treatment typically have a history 
of many years of severe alcohol-related problems. However, these most severe cases rep­
resent only a small proportion of individuals with this disorder, and the typical individual 
with the disorder has a much more promising prognosis.

Among adolescents, conduct disorder and repeated antisocial behavior often co-occur 
with alcohol- and w ^ ith  other substance-related disorders. While most individuals v^ith al­
cohol use disorder develop the condition before age 40 years, perhaps 10% have later 
onset. Age-related physical changes in older individuals result in increased brain suscep­
tibility to the depressant effects of alcohol; decreased rates of liver metabolism of a variety 
of substances, including alcohol; and decreased percentages of body water. These changes 
can cause older people to develop more severe intoxication and subsequent problems at 
lower levels of consumption. Alcohol-related problems in older people are also especially 
likely to be associated with other medical complications.
Environmental. Environmental risk and prognostic factors may include cultural atti­
tudes toward drinking and intoxication, the availability of alcohol (including price),

tudes toward drinking and intoxication, the availability of alcohol (including price), 
acquired personal experiences with alcohol, and stress levels. Additional potential medi­
ators of how alcohol problems develop in predisposed individuals include heavier peer 
substance use, exaggerated positive expectations of the effects of alcohol, and suboptimal 
ways of coping with stress.
Genetic and physiological. Alcohol use disorder runs in families, with 40%-60% of the 
variance of risk explained by genetic influences. The rate of this condition is three to four 
times higher in close relatives of individuals with alcohol use disorder, with values highest 
for individuals with a greater number of affected relatives, closer genetic relationships to 
the affected person, and higher severity of the alcohol-related problems in those relatives.

the affected person, and higher severity of the alcohol-related problems in those relatives. 
A significantly higher rate of alcohol use disorders exists in the monozygotic twin than in 
the dizygotic twin of an individual with the condition. A three- to fourfold increase in risk 
has been observed in children of individuals with alcohol use disorder, even when these 
children were given up for adoption at birth and raised by adoptive parents who did not 
have the disorder.
Recent advances in our understanding of genes that operate through intermediate 
characteristics (or phenotypes) to affect the risk of alcohol use disorder can help to identify 
individuals who might be at particularly low or high risk for alcohol use disorder. Among 
the low-risk phenotypes are the acute alcohol-related skin flush (seen most prominently in

the low-risk phenotypes are the acute alcohol-related skin flush (seen most prominently in 
Asians). High vulnerability is associated with preexisting schizophrenia or bipolar disor­
der, as well as impulsivity (producing enhanced rates of all substance use disorders and 
gambling disorder), and a high risk specifically for alcohol use disorder is associated with 
a low level of response (low sensitivity) to alcohol. A number of gene variations may ac­
count for low response to alcohol or modulate the dopamine reward systems; it is impor­
tant to note, however, that any one gene variation is likely to explain only l% - 2% of the risk 
for these disorders.
Course modifiers. In general, high levels of impulsivity are associated with an earlier 
onset and more severe alcohol use disorder.

In most cultures, alcohol is the most frequently used intoxicating substance and contrib­
utes to considerable morbidity and mortality. An estimated 3.8% of all global deaths and 
4.6% of global disability-adjusted life-years are attributable to alcohol. In the United States, 
80% of adults (age 18 years and older) have consumed alcohol at some time in their lives, 
and 65% are current drinkers (last 12 months). An estimated 3.6% of the world population 
(15-64 years old) has a current (12-month) alcohol use disorder, with a lower prevalence 
(1.1%) found in the African region, a higher rate (5.2%) found in the American region (North, 
South, and Central America and the Caribbean), and the highest rate (10.9%) found in the 
Eastern Europe region.

Polymorphisms of genes for the alcohol-metabolizing enzymes alcohol dehydroge­
nase and aldehyde dehydrogenase are most often seen in Asians and affect the response to 
alcohol. When consuming alcohol, individuals with these gene variations can experience a 
flushed face and palpitations, reactions that can be so severe as to limit or preclude future 
alcohol consumption and diminish the risk for alcohol use disorder. These gene variations 
are seen in as many as 40% of Japanese, Chinese, Korean, and related groups worldwide 
and are related to lower risks for the disorder.
Despite small variations regarding individual criterion items, the diagnostic criteria 
perform equally well across most race/ethnicity groups.
Males have higher rates of drinking and related disorders than females. However, because 
females generally weigh less than males, have more fat and less water in their bodies, and

females generally weigh less than males, have more fat and less water in their bodies, and 
metabolize less alcohol in their esophagus and stomach, they are likely to develop higher 
blood alcohol levels per drink than males. Females who drink heavily may also be more 
vulnerable than males to some of the physical consequences associated with alcohol, in­
cluding liver disease.
Individuals whose heavier drinking places them at elevated risk for alcohol use disorder 
can be identified both through standardized questionnaires and by elevations in blood test 
results likely to be seen with regular heavier drinking. These measures do not establish a 
diagnosis of an alcohol-related disorder but can be useful in highlighting individuals for 
whom more information should be gathered. The most direct test available to measure al­

cohol consumption cross-sectionally is blood alcohol concentration,  which can also be used to 
judge tolerance to alcohol. For example, an individual with a concentration of 150 mg of 
ethanol per deciliter (dL) of blood who does not show signs of intoxication can be pre­
sumed to have acquired at least some degree of tolerance to alcohol. At 200 mg/dL, most 
nontolerant individuals demonstrate severe intoxication.
Regarding laboratory tests, one sensitive laboratory indicator of heavy drinking is a 
modest elevation or high-normal levels (>35 units) of gamma-glutamyltransferase (GGT). 
This may be the only laboratory finding. At least 70% of individuals with a high GGT level 
are persistent heavy drinkers (i.e., consuming eight or more drinks daily on a regular basis).

are persistent heavy drinkers (i.e., consuming eight or more drinks daily on a regular basis). 
A second test with comparable or even higher levels of sensitivity and specificity is carbo­
hydrate-deficient transferrin (CDT), with levels of 20 units or higher useful in identifying in­
dividuals who regularly consume eight or more drinks daily. Since both GGT and CDT 
levels return toward normal within days to weeks of stopping drinking, both state markers 
may be useful in monitoring abstinence, especially when the clinician observes increases, 
rather than decreases, in these values over time—a finding indicating that the person is 
likely to have returned to heavy drinking. The combination of tests for CDT and GGT may 
have even higher levels of sensitivity and specificity than either test used alone. Additional

have even higher levels of sensitivity and specificity than either test used alone. Additional 
useful tests include the mean corpuscular volume (MCV), which may be elevated to high­
normal values in individuals who drink heavily—a change that is due to the direct toxic ef­
fects of alcohol on erythropoiesis. Although the MCV can be used to help identify those who 
drink heavily, it is a poor method of monitoring abstinence because of the long half-life of 
red blood cells. Liver function tests (e.g., alanine aminotransferase [ALT] and alkaline phos­
phatase) can reveal liver injury that is a consequence of heavy drinking. Other potential 
markers of heavy drinking that are more nonspecific for alcohol but can help the clinician 
think of the possible effects of alcohol include elevations in blood levels or lipids (e.g., tri­

glycerides and high-density lipoprotein cholesterol) and high-normal levels of uric acid.
Additional diagnostic markers relate to signs and symptoms that reflect the consequences 
often associated with persistent heavy drinking. For example, dyspepsia, nausea, and bloat­

ing can accompany gastritis, and hepatomegaly, esophageal varices, and hemorrhoids may 
reflect alcohol-induced changes in the liver. Other physical signs of heavy drinking include 
tremor, unsteady gait, insomnia, and erectile dysfunction. Males with chronic alcohol use dis­
order may exhibit decreased testicular size and feminizing effects associated with reduced 
testosterone levels. Repeated heavy drinking in females is associated with menstrual irregu­
larities and, during pregnancy, spontaneous abortion and fetal alcohol syndrome. Individu­
als with preexisting histories of epilepsy or severe head trauma are more likely to develop 
alcohol-related seizures. Alcohol withdrawal may be associated with nausea, vomiting, gas­
tritis, hematemesis, dry mouth, puffy blotchy complexion, and mild peripheral edema.
Functional Consequences of Alcohol Use Disorder
The diagnostic features of alcohol use disorder highlight major areas of life functioning

The diagnostic features of alcohol use disorder highlight major areas of life functioning 
likely to be impaired. These include driving and operating machinery, school and work, 
interpersonal relationships and communication, and health. Alcohol-related disorders 
contribute to absenteeism from work, job-related accidents, and low employee productiv­
ity. Rates are elevated in homeless individuals, perhaps reflecting a downward spiral in 
social and occupational functioning, although most individuals with alcohol use disorder 
continue to live with their families and function within their jobs.
Alcohol use disorder is associated with a significant increase in the risk of accidents, vi­
olence, and suicide. It is estimated that one in five intensive care unit admissions in some 
urban hospitals is related to alcohol and that 40% of individuals in the United States ex­

perience an alcohol-related adverse event at some time in their lives, with alcohol account­
ing for up to 55% of fatal driving events. Severe alcohol use disorder, especially in 
individuals with antisocial personality disorder, is associated with the commission of 
criminal acts, including homicide. Severe problematic alcohol use also contributes to dis­
inhibition and feelings of sadness and irritability, which contribute to suicide attempts and 
completed suicides.
Unanticipated alcohol withdrawal in hospitalized individuals for whom a diagnosis of 
alcohol use disorder has been overlooked can add to the risks and costs of hospitalization 
and to time spent in the hospital.
Nonpathological use of alcohol. The key element of alcohol use disorder is the use of

Nonpathological use of alcohol. The key element of alcohol use disorder is the use of 
heavy doses of alcohol with resulting repeated and significant distress or impaired func­
tioning. While most drinkers sometimes consume enough alcohol to feel intoxicated, only 
a minority (less than 20%) ever develop alcohol use disorder. Therefore, drinking, even 
daily, in low doses and occasional intoxication do not by themselves make this diagnosis.
Sedative, hypnotic, or anxiolytic use disorder. The signs and symptoms of alcohol use 
disorder are similar to those seen in sedative, hypnotic, or anxiolytic use disorder. The two 
must be distinguished, however, because the course may be different, especially in rela­
tion to medical problems.
Conduct disorder in childhood and adult antisocial personality disorder. Alcohol use 
disorder, along with other substance use disorders, is seen in the majority of individuals

disorder, along with other substance use disorders, is seen in the majority of individuals 
with antisocial personality and preexisting conduct disorder. Because these diagnoses are 
associated with an early onset of alcohol use disorder as well as a worse prognosis, it is im­
portant to establish both conditions.
Bipolar disorders, schizophrenia, and antisocial personality disorder are associated with a 
markedly increased rate of alcohol use disorder, and several anxiety and depressive disorders

may relate to alcohol use disorder as well. At least a part of the reported association between 
depression and i^oderate to severe alcohol use disorder may be attributable to temporary, al­
cohol-induced comorbid depressive symptoms resulting from the acute effects of intoxication 
or withdrawal. Severe, repeated alcohol intoxication may also suppress immune mechanisms 
and predispose individuals to infections and increase the risk for cancers.
Alcohol Intoxication
A. Recent ingestion of alcohol.
B. Clinically significant problematic beliavioral or psychological changes (e.g., inappropri­
ate sexual or aggressive behavior, mood lability, impaired judgment) that developed  
during, or shortly after, alcohol ingestion.
C. One (or more) of the following signs or symptoms developing during, or shortly after,  
alcohol use:
1. Slurred speech.
2. Incoordination.
3. Unsteady gait.
4. Nystagmus.
5. Impairment in attention or memory.
6. Stupor or coma.

D. The signs or symptoms are not attributable to another medical condition and are not better  
explained by another mental disorder, including intoxication with another substance.
Coding note: The ICD-9-CM code is 303.00. The ICD-10-CM code depends on whether  
there is a comorbid alcohol use disorder. If a mild alcohol use disorder is comorbid, the  
ICD-10-CM code is FI 0.129, and if a moderate or severe alcohol use disorder is comorbid,  
the ICD-10-CM code is FI 0.229. If there is no comorbid alcohol use disorder, then the  
ICD-10-CM code is F10.929. _______________________________________________
The essential feature of alcohol intoxication is the presence of clinically significant problematic 
behavioral or psychological changes (e.g., inappropriate sexual or aggressive behavior, mood

behavioral or psychological changes (e.g., inappropriate sexual or aggressive behavior, mood 
lability, impaired judgment, impaired social or occupational functioning) that develop during, 
or shortly after, alcohol ingestion (Criterion B). These changes are accompanied by evidence of 
impaired functioning and judgment and, if intoxication is intense, can result in a life-threaten­
ing coma. The symptoms must not be attributable to another medical condition (e.g., diabetic 
ketoacidosis), are not a reflection of conditions such as delirium, and are not related to intoxi­
cation with other depressant drugs (e.g., benzodiazepines) (Criterion D). The levels of incoor­
dination can interfere with driving abilities and performance of usual activities to the point of 
causing accidents. Evidence of alcohol use can be obtained by smelling alcohol on the individ­

ual's breath, eliciting a history from the individual or another observer, and, when needed, 
having the individual provide breath, blood, or urine samples for toxicology analyses.
Alcohol intoxication is sometimes associated with amnesia for the events that occurred 
during the course of the intoxication ("blackouts"). This phenomenon may be related to 
the presence of a high blood alcohol level and, perhaps, to the rapidity with which this 
level is reached. During even mild alcohol intoxication, different symptoms are likely to be

observed at different time points. Evidence of mild intoxication with alcohol can be seen in 
most individuals after approximately two drinks (each standard drink is approximately 
10-12  grams of ethanol and raises the blood alcohol concentration approximately 2 0 mg/ 
dL). Early in the drinking period, when blood alcohol levels are rising, symptoms often 
include talkativeness, a sensation of well-being, and a bright, expansive mood. Later, es­
pecially when blood alcohol levels are falling, the individual is likely to become progres­
sively more depressed, withdrawn, and cognitively impaired. At very high blood alcohol 
levels (e.g., 200-300 mg/dL), an individual who has not developed tolerance for alcohol is 
likely to fall asleep and enter a first stage of anesthesia. Higher blood alcohol levels (e.g., in 
excess of 300-400 mg/dL) can cause inhibition of respiration and pulse and even death in 
nontolerant individuals. The duration of intoxication depends on how much alcohol was

nontolerant individuals. The duration of intoxication depends on how much alcohol was 
consumed over what period of time. In general, the body is able to metabolize approxi­
mately one drink per hour, so that the blood alcohol level generally decreases at a rate of 
15-20 mg/dL per hour. Signs and symptoms of intoxication are likely to be more intense 
when the blood alcohol level is rising than when it is falling.
Alcohol intoxication is an important contributor to suicidal behavior. There appears to 
be an increased rate of suicidal behavior, as well as of completed suicide, among persons 
intoxicated by alcohol.
The large majority of alcohol consumers are likely to have been intoxicated to some degree at 
some point in their lives. For example, in 2010,44% of 12th-grade students admitted to having

some point in their lives. For example, in 2010,44% of 12th-grade students admitted to having 
been "drunk in the past year," with more than 70% of college students reporting the same.
Intoxication usually occurs as an episode usually developing over minutes to hours and typi­
cally lasting several hours. In the United States, the average age at first intoxication is approx­
imately 15 years, with the highest prevalence at approximately 18-25 years. Frequency and 
intensity usually decrease with further advancing age. The earlier the onset of regular intoxi­
cation, the greater the likelihood the individual w iU go on to develop alcohol use disorder.
Temperamental. Episodes of alcohol intoxication increase with personality characteris­
tics of sensation seeking and impulsivity.

Environmental. Episodes of alcohol intoxication increase with a heavy drinking envi­
ronment.
The major issues parallel the cultural differences regarding the use of alcohol overall. 
Thus, college fraternities and sororities may encourage alcohol intoxication. This condi­
tion is also frequent on certain dates of cultural significance (e.g.. New Year's Eve) and, for 
some subgroups, during specific events (e.g., wakes following funerals). Other subgroups 
encourage drinking at religious celebrations (e.g., Jewish and Catholic holidays), while 
still others strongly discourage all drinking or intoxication (e.g., some religious groups, 
such as Mormons, fundamentalist Christians, and Muslims).

Historically, in many Western societies, acceptance of drinking and drunkenness is more 
tolerated for males, but such gender differences may be much less prominent in recent 
years, especially during adolescence and young adulthoocj.

Intoxication is usually established by observing an individual's behavior and smelling alcohol 
on the breath. The degree of intoxication increases with an individual's blood or breath alcohol 
level and with the ingestion of other substances, especially those with sedating effects.
Functional Consequences of Alcoliol intoxication
Alcohol intoxication contributes to the more than 30,000 alcohol-related drinking deaths in 
the United States each year. In addition, intoxication with this drug contributes to huge 
costs associated with drunk driving, lost time from school or work, as well as interpersonal 
arguments and physical fights.
Other medical conditions. Several medical (e.g., diabetic acidosis) and neurological condi­
tions (e.g., cerebellar ataxia, multiple sclerosis) can temporarily resemble alcohol intoxication.
Sedative, hypnotic, or anxiolytic intoxication. Intoxication with sedative, hypnotic, or

Sedative, hypnotic, or anxiolytic intoxication. Intoxication with sedative, hypnotic, or 
anxiolytic drugs or with other sedating substances (e.g., antihistamines, anticholinergic 
drugs) can be mistaken for alcohol intoxication. The differential requires observing alco­
hol on the breath, measuring blood or breath alcohol levels, ordering a medical workup, 
and gathering a good history. The signs and symptoms of sedative-hypnotic intoxication 
are very similar to those observed with alcohol and include similar problematic behavioral 
or psychological changes. These changes are accompanied by evidence of impaired func­
tioning and judgment—which, if intense, can result in a life-threatening coma—and levels 
of incoordination that can interfere with driving abilities and with performing usual 
activities. However, there is no smell as there is with alcohol, but there is likely to be evi­

dence of misuse of the depressant drug in the blood or urine toxicology analyses.
Alcohol intoxication may occur comorbidly with other substance intoxication, especially 
in individuals with conduct disorder or antisocial personality disorder.
Alcohol Withdrawal
A. Cessation of (or reduction in) alcohol use that has been heavy and prolonged.
B. Two (or more) of the following, developing within several hours to a few days after the  
cessation of (or reduction in) alcohol use described in Criterion A:
1. Autonomic hyperactivity (e.g., sweating or pulse rate greater than 100 bpm).
2. Increased hand tremor.
3. Insomnia.
4. Nausea or vomiting.
5. Transient visual, tactile, or auditory hallucinations or illusions.
6. Psychomotor agitation.
7. Anxiety.

8. Generalized tonic-clonic seizures.
C. The signs or symptoms in Criterion B cause clinically significant distress or impairment  
in social, occupational, or other important areas of functioning.

D. The signs or symptoms are not attributable to another medical condition and are not  
better explained by another mental disorder, including intoxication or withdrawal from  
another substance.
With perceptual disturbances: This specifier applies in the rare instance when hal­
lucinations (usually visual or tactile) occur with intact reality testing, or auditory, visual,  
or tactile illusions occur in the absence of a delirium.
Coding note: The ICD-9-CM code is 291.81. The ICD-10-CM code for alcohol withdrawal  
without perceptual disturbances is  FI 0.239, and the ICD-10-CM code for alcohol withdrawal  
with perceptual disturbances is FI 0.232. Note that the ICD-10-CM code indicates the comor-  
bid presence of a moderate or severe alcohol use disorder, reflecting the fact that alcohol with­
drawal can only occur in  the presence of a moderate or severe alcohol use disorder. It is  not

drawal can only occur in  the presence of a moderate or severe alcohol use disorder. It is  not  
permissible to code a comorbid m ild alcohol use disorder with alcohol withdrawal.
When hallucinations occur in the absence of delirium (i.e., in a clear sensorium), a diagno­
sis of substance/medication-induced psychotic disorder should be considered.
The essential feature of alcohol withdrawal is the presence of a characteristic withdrawal 
syndrome that develops within several hours to a few days after the cessation of (or re­
duction in) heavy and prolonged alcohol use (Criteria A and B). The withdrawal syn­
drome includes two or more of the symptoms reflecting autonomic hyperactivity and 
anxiety listed in Criterion B, along with gastrointestinal symptoms.
Withdrawal symptoms cause clinically significant distress or impairment in social, oc­

cupational, or other important areas of functioning (Criterion C). The symptoms must not 
be attributable to another medical condition and are not better explained by another men­
tal disorder (e.g., generalized anxiety disorder), including intoxication or withdrawal 
from another substance (e.g., sedative, hypnotic, or anxiolytic withdrawal) (Criterion D).
Symptoms can be relieved by administering alcohol or benzodiazepines (e.g., diazepam). 
The withdrawal symptoms typically begin when blood concentrations of alcohol decline 
sharply (i.e., within 4-12 hours) after alcohol use has been stopped or reduced. Reflecting the 
relatively fast metabolism of alcohol, symptoms of alcohol withdrawal usually peak in inten­
sity during the second day of abstinence and are likely to improve markedly by the fourth or

sity during the second day of abstinence and are likely to improve markedly by the fourth or 
fifth day. Following acute withdrawal, however, symptoms of anxiety, insomnia, and auto­
nomic dysfunction may persist for up to 3-6 months at lower levels of intensity.
Fewer than 10% of individuals who develop alcohol withdrawal will ever develop dra­
matic symptoms (e.g., severe autonomic hyperactivity, tremors, alcohol withdrawal delir­
ium). Tonic-clonic seizures occur in fewer than 3% of individuals.
Although confusion and changes in consciousness are not core criteria for alcohol with­
drawal, alcohol withdrawal delirium (see "Delirium" in the chapter "Neurocognitive Dis­
orders") may occur in the context of withdrawal. As is true for any agitated, confused state,

orders") may occur in the context of withdrawal. As is true for any agitated, confused state, 
regardless of the cause, in addition to a disturbance of consciousness and cognition, with­
drawal delirium can include visual, tactile, or (rarely) auditory hallucinations (delirium tre­
mens). When alcohol withdrawal delirium develops, it is likely that a clinically relevant 
medical condition may be present (e.g., liver failure, pneumonia, gastrointestinal bleeding, 
sequelae of head trauma, hypoglycemia, an electrolyte imbalance, postoperative status).

It is estimated that approximately 50% of middle-class, highly functional individuals with 
alcohol use disorder have ever experienced a full alcohol withdrawal syndrome. Among 
individuals with alcohol use disorder who are hospitalized or homeless, the rate of al­
cohol withdrawal may be greater than 80%. Less than 10% of individuals in withdrawal 
ever demonstrate alcohol withdrawal delirium or withdrawal seizures.
Acute alcohol withdrawal occurs as an episode usually lasting 4-5 days and only after 
extended periods of heavy drinking. Withdrawal is relatively rare in individuals younger 
than 30 years, and the risk and severity increase with increasing age.
Environmental. The probability of developing alcohol withdrawal increases with the 
quantity and frequency of alcohol consumption. Most individuals with this condition are 
drinking daily, consuming large amounts (approximately more than eight drinks per day)

drinking daily, consuming large amounts (approximately more than eight drinks per day) 
for multiple days. However, there are large inter-individual differences, with enhanced 
risks for individuals with concurrent medical conditions, those with family histories of al­
cohol withdrawal (i.e., a genetic component), those with prior withdrawals, and individ­
uals who consume sedative, hypnotic, or anxiolytic drugs.
Autonomic hyperactivity in the context of moderately high but falling blood alcohol levels 
and a history of prolonged heavy drinking indicate a likelihood of alcohol withdrawal.
Functional Consequences of Alcohol Withdrawal
Symptoms of withdrawal may serve to perpetuate drinking behaviors and contribute to 
relapse, resulting in persistently impaired social and occupational functioning. Symptoms

relapse, resulting in persistently impaired social and occupational functioning. Symptoms 
requiring medically supervised detoxification result in hospital utilization and loss of 
work productivity. Overall, the presence of withdrawal is associated with greater func­
tional impairment and poor prognosis.
Other medical conditions. The symptoms of alcohol withdrawal can also be mimicked 
by some medical conditions (e.g., hypoglycemia and diabetic ketoacidosis). Essential 
tremor, a disorder that frequently runs in families, may erroneously suggest the tremu­
lousness associated with alcohol withdrawal.
Sedative, hypnotic, or anxiolytic withdrawal. Sedative, hypnotic, or anxiolytic with­
drawal produces a syndrome very similar to that of alcohol withdrawal.
Withdrawal is more likely to occur with heavier alcohol intake, and that might be most of­

ten observed in individuals with conduct disorder and antisocial personality disorder. 
Withdrawal states are also more severe in older individuals, individuals who are also de­
pendent on other depressant drugs (sedative-hypnotics), and individuals who have had 
more alcohol withdrawal experiences in the past.

Other Alcohol-Induced Disorders
The following alcohol-induced disorders are described in other chapters of the manual with 
disorders with which they share phenomenology (see the substance/medication-induced 
mental disorders in these chapters): alcohol-induced psychotic disorder (''Schizophrenia Spec­
trum and Other Psychotic Disorders"); alcohol-induced bipolar disorder ("Bipolar and 
Related Disorders"); alcohol-induced depressive disorder ("Depressive Disorders"); alcohol- 
induced anxiety disorder ("Anxiety Disorders"); alcohol-induced sleep disorder ("Sleep- 
Wake Disorders"); alcohol-induced sexual dysfunction ("Sexual Dysfunctions"); and alcohol- 
induced major or mild neurocognitive disorder ("Neurocognitive Disorders"). For alcohol 
intoxication delirium and alcohol withdrawal delirium, see the criteria and discussion of de­
lirium in the chapter "Neurocognitive Disorders." These alcohol-induced disorders are diag­

nosed instead of alcohol intoxication or alcohol withdrawal only when the symptoms are 
sufficiently severe to warrant independent clinical attention.
Features
The symptom profiles for an alcohol-induced condition resemble independent mental disor­
ders as described elsewhere in DSM-5. However, the alcohol-induced disorder is temporary 
and observed after severe intoxication with and/or withdrawal from alcohol. While the symp­
toms can be identical to those of independent mental disorders (e.g., psychoses, major depres­
sive disorder), and while they can have the same severe consequences (e.g., suicide attempts), 
alcohol-induced conditions are likely to improve without formal treatment in a matter of days 
to weeks after cessation of severe intoxication and/or withdrawal.

Each alcohol-induced mental disorder is listed in the relevant diagnostic section and there­
fore only a brief description is offered here. Alcohol-induced disorders must have developed 
in the context of severe intoxication and/or withdrawal from the substance capable of produc­
ing the mental disorder. In addition, there must be evidence that the disorder being observed 
is not likely to be better explained by another non-alcohol-induced mental disorder. The latter 
is likely to occur if the mental disorder was present before the severe intoxication or with­
drawal, or continued more than 1 month after the cessation of severe intoxication and/or with­
drawal. When symptoms are observed only during a delirium, they should be considered part

drawal. When symptoms are observed only during a delirium, they should be considered part 
of the delirium and not diagnosed separately, as many sjmiptoms (including disturbances in 
mood, anxiety, and reality testing) are commonly seen during agitated, confused states. The al­
cohol-induced disorder must be clinically relevant, causing significant levels of distress or sig­
nificant functional impairment. Finally, there are indications that the intake of substances of 
abuse in the context of a preexisting mental disorder are likely to result in an intensification of 
the preexisting independent syndrome.
The features associated with each relevant major mental disorder (e.g., psychotic epi­
sodes, major depressive disorder) are similar whether observed with an independent or an 
alcohol-induced condition. However, individuals with alcohol-induced disorders are

alcohol-induced condition. However, individuals with alcohol-induced disorders are 
likely to also demonstrate the associated features seen with an alcohol use disorder, as 
listed in the subsections of this chapter.
Rates of alcohol-induced disorders vary somewhat by diagnostic category. For exam­
ple, the lifetime risk for major depressive episodes in individuals with alcohol use disorder 
is approximately 40%, but only about one-third to one-half of these represent independent 
major depressive syndromes observed outside the context of intoxication. Similar rates of 
alcohol-induced sleep and anxiety conditions are likely, but alcohol-induced psychotic ep­
isodes are fairly rare.
Once present, the symptoms of an alcohol-induced condition are likely to remain clinically 
relevant as long as the individual continues to experience severe intoxication and/or with­

drawal. While the symptoms are identical to those of independent mental disorders (e.g., 
psychoses, majqr depressive disorder), and while they can have the same severe conse­
quences (e.g., suicide attempts), all alcohol-induced syndromes other than alcohol- 
induced neurocognitive disorder, amnestic confabulatory type (alcohol-induced persist­
ing amnestic disorder), regardless of the severity of the symptoms, are likely to improve 
relatively quickly and unlikely to remain clinically relevant for more than 1 month after 
cessation of severe intoxication and/or withdrawal.
The alcohol-induced disorders are an important part of the differential diagnoses for 
the independent mental conditions. Independent schizophrenia, major depressive disor­
der, bipolar disorder, and anxiety disorders, such as panic disorder, are likely to be asso­
ciated with much longer-lasting periods of symptoms and often require longer-term

ciated with much longer-lasting periods of symptoms and often require longer-term 
medications to optimize the probability of improvement or recovery. The alcohol-induced 
conditions, on the other hand, are likely to be much shorter in duration and disappear 
within several days to 1 month after cessation of severe intoxication and/or withdrawal, 
even without psychotropic medications.
The importance of recognizing an alcohol-induced disorder is similar to the relevance 
of identifying the possible role of some endocrine conditions and medication reactions be­
fore diagnosing an independent mental disorder. In light of the high prevalence of alcohol 
use disorders worldwide, it is important that these alcohol-induced diagnoses be consid­
ered before independent mental disorders are diagnosed.
291.9 (F10.99)

This category applies to presentations in which symptoms characteristic of an alcohol-  
for any specific alcohol-related disorder or any of the disorders in the substance-related  
and addictive disorders diagnostic class.
Caffeine-Related Disorders
Caffeine Intoxication  
Caffeine Withdrawal  
Other Caffeine-Induced Disorders  
Unspecified Caffeine-Related Disorder
Caffeine Intoxication
Diagnostic Criteria 305.90 (F15.929)
A. Recent consumption of caffeine (typically a high dose well in excess of 250 mg).
B. Five (or more) of the following signs or symptoms developing during, or shortly after,

B. Five (or more) of the following signs or symptoms developing during, or shortly after,  
caffeine use:
1. Restlessness.
2. Nervousness.

3. Excitement.
4. Insomnia.
5. Flushed face.
6. Diuresis.
7. Gastrointestinal disturbance.
8. Muscle twitching.
9. Rambling flow of thought and speech.
10. Tachycardia or cardiac arrhythmia.
11. Periods of inexhaustibility.
12. Psychomotor agitation.
D. The signs or symptoms are not attributable to another medical condition and are not bet­
ter explained by another mental disorder, including intoxication with another substance.
Caffeine can be consumed from a number of different sources, including coffee, tea, caf- 
feinated soda, "energy" drinks, over-the-counter analgesics and cold remedies, energy 
aids (e.g., drinks), weight-loss aids, and chocolate. Caffeine is also increasingly being used 
as an additive to vitamins and to food products. More than 85% of children and adults con­

sume caffeine regularly. Some caffeine users display symptoms consistent with problem­
atic use, including tolerance and withdrawal (see "Caffeine Withdrawal" later in this 
chapter); the data are not available at this time to determine the clinical significance of a 
caffeine use disorder and its prevalence. In contrast, there is evidence that caffeine with­
drawal and caffeine intoxication are clinically significant and sufficiently prevalent.
The essential feature of caffeine intoxication is recent consumption of caffeine and five 
or more signs or symptoms that develop during or shortly after caffeine use (Criteria A 
and B). Symptoms include restlessness, nervousness, excitement, insomnia, flushed face,

and B). Symptoms include restlessness, nervousness, excitement, insomnia, flushed face, 
diuresis, and gastrointestinal complaints, which can occur with low doses (e.g., 2 0 0 mg) in 
vulnerable individuals such as children, the elderly, or individuals who have not been ex­
posed to caffeine previously. Symptoms that generally appear at levels of more than 1 g/ 
day include muscle twitching, rambling flow of thought and speech, tachycardia or car­
diac arrhythmia, periods of inexhaustibility, and psychomotor agitation. Caffeine intoxi­
cation may not occur despite high caffeine intake because of the development of tolerance. 
The signs or symptoms must cause clinically significant distress or impairment in social, 
occupational, or other important areas of functioning (Criterion C). The signs or symp­
toms must not be attributable to another medical condition and are not better explained by

toms must not be attributable to another medical condition and are not better explained by 
another mental disorder (e.g., an anxiety disorder) or intoxication with another substance 
Mild sensory disturbances (e.g., ringing in the ears and flashes of light) may occur with high 
doses of caffeine. Although large doses of caffeine can increase heart rate, smaller doses can 
slow heart rate. Whether excess caffeine intake can cause headaches is unclear. On physical 
examination, agitation, restlessness, sweating, tachycardia, flushed face, and increased 
bowel motility may be seen. Caffeine blood levels may provide important information for 
diagnosis, particularly when the individual is a poor historian, although these levels are not 
diagnostic by themselves in view of the individual variation in response to caffeine.

The prevalence of caffeine intoxication in the general population is unclear. In the United 
States, approximately 7% of individuals in the population may experience five or more symp­
toms along with functional impairment consistent with a diagnosis of caffeine intoxication.
Consistent with a half-life of caffeine of approximately 4-6 hours, caffeine intoxication 
symptoms usually remit within the first day or so and do not have any known long-lasting 
consequences. However, individuals who consume very high doses of caffeine (i.e., 5-10 
g) may require immediate medical attention, as such doses can be lethal.
With advancing age, individuals are likely to demonstrate increasingly intense reac­
tions to caffeine, with greater complaints of interference with sleep or feelings of hyper­
arousal. Caffeine intoxication among young individuals after consumption of highly 
caffeinated products, including energy drinks, has been observed. Children and adoles­

cents may be at increased risk for caffeine intoxication because of low body weight, lack of 
tolerance, and lack of knowledge about the pharmacological effects of caffeine.
Environmental. Caffeine intoxication is often seen among individuals who use caffeine 
less frequently or in those who have recently increased their caffeine intake by a substan­
tial amount. Furthermore, oral contraceptives significantly decrease the elimination of caf­
feine and consequently may increase the risk of intoxication.
Genetic and physiological. Genetic factors may affect risk of caffeine intoxication.
Functional Consequences of Caffeine Intoxication
Impairment from caffeine intoxication may have serious consequences, including dys­

function at work or school, social indiscretions, or failure to fulfill role obligations. More­
over, extremely high doses of caffeine can be fatal. In some cases, caffeine intoxication may 
precipitate a caffeine-induced disorder.
Other mental disorders. Caffeine intoxication may be characterized by symptoms (e.g., 
panic attacks) that resemble primary mental disorders. To meet criteria for caffeine intoxica­
tion, the symptoms must not be associated with another medical condition or another mental 
disorder, such as an anxiety disorder, that could better explain them. Manic episodes; panic 
disorder; generalized anxiety disorder; amphetamine intoxication; sedative, h 3φnotic, or anx­
iolytic witiidrawal or tobacco withdrawal; sleep disorders; and medication-induced side ef­

fects (e.g., akathisia) can cause a clinical picture that is similar to that of caffeine intoxication.
Other caffeine-induced disorders. The temporal relationship of the symptoms to increased 
caffeine use or to abstinence from caffeine helps to establish the diagnosis. Caffeine intoxica­
tion is differentiated from caffeine-induced anxiety disorder, with onset during intoxication 
(see "Substance/Medication-Induced AiOciety Disorder" in the chapter "Anxiety Disorders"), 
and caffeine-induced sleep disorder, with onset during intoxication (see "Substance/Medica­
tion-Induced Sleep Disorder" in the chapter "Sleep-Wake Disorders"), by the fact that the 
symptoms in these latter disorders are in excess of those usually associated with caffeine in­

toxication and are severe enough to warrant independent clinical attention.

Typical dietary doses of caffeine have not been consistently associated with medical prob­
lems. However, heavy use (e.g., >400 mg) can cause or exacerbate anxiety and somatic 
symptoms and gastrointestinal distress. With acute, extremely high doses of caffeine, 
grand mal seizures and respiratory failure may result in death. Excessive caffeine use is as­
sociated with depressive disorders, bipolar disorders, eating disorders, psychotic disor­
ders, sleep disorders, and substance-related disorders, whereas individuals with anxiety 
disorders are more likely to avoid caffeine.
Caffeine Withdrawal
Diagnostic Criteria 292.0 (F15.93)
A. Prolonged daily use of caffeine.
B. Abrupt cessation of or reduction in caffeine use, followed within 24 hours by three (or  
more) of the following signs or symptoms:
1. Headache.
2. Marked fatigue or drowsiness.
3. Dysphoric mood, depressed mood, or irritability.
4. Difficulty concentrating.

5. Flu-like symptoms (nausea, vomiting, or muscle pain/stiffness).
D. The signs or symptoms are not associated with the physiological effects of another  
medical condition (e.g., migraine, viral illness) and are not better explained by another  
mental disorder, including intoxication or withdrawal from another substance.
The essential feature of caffeine withdrawal is the presence of a characteristic withdrawal 
syndrome that develops after the abrupt cessation of (or substantial reduction in) pro­
longed daily caffeine ingestion (Criterion B). The caffeine withdrawal syndrome is indi­

cated by three or more of the following (Criterion B): headache; marked fatigue or 
drowsiness; dysphoric mood, depressed mood, or irritability; difficulty concentrating; 
and flu-hke symptoms (nausea, vomiting, or muscle pain/stiffness). The withdrawal syn­
drome causes clinical significant distress or impairment in social, occupational, or other 
important areas of functioning (Criterion C). The symptoms must not be associated with 
the physiological effects of another medical condition and are not better explained by an­
other mental disorder (Criterion D).
Headache is the hallmark feature of caffeine withdrawal and may be diffuse, gradual 
in development, throbbing, severe, and sensitive to movement. However, other symptoms

in development, throbbing, severe, and sensitive to movement. However, other symptoms 
of caffeine withdrawal can occur in the absence of headache. Caffeine is the most widely 
used behaviorally active drug in the world and is present in many different types of bev­
erages (e.g., coffee, tea, maté, soft drinks, energy drinks), foods, energy aids, medications, 
and dietary supplements. Because caffeine ingestion is often integrated into social customs 
and daily rituals (e.g., coffee break, tea time), some caffeine consumers may be unaware of 
their physical dependence on caffeine. Thus, caffeine withdrawal symptoms could be un­
expected and misattributed to other causes (e.g., the flu, migraine). Furthermore, caffeine 
withdrawal symptoms may occur when individuals are required to abstain from foods 
and beverages prior to medical procedures or when a usual caffeine dose is missed be­

cause of a change in routine (e.g., during travel, weekends).

The probability and severity of caffeine withdrawal generally increase as a function of 
usual daily caffeine dose. However, there is large variability among individuals and 
within individuals across different episodes in the incidence, severity, and time course of 
withdrawal symptoms. Caffeine withdrawal symptoms may occur after abrupt cessation 
of relatively low chronic daily doses of caffeine (i.e., 10 0 mg).
Caffeine abstinence has been shown to be associated with impaired behavioral and cogni­
tive performance (e.g., sustained attention). Electroencephalographic studies have shown 
that caffeine withdrawal symptoms are significantly associated with increases in theta 
power and decreases in beta-2 power. Decreased motivation to work and decreased socia­
bility have also been reported during caffeine withdrawal. Increased analgesic use during 
caffeine withdrawal has been documented.

More than 85% of adults and children in the United States regularly consume caffeine, 
with adult caffeine consumers ingesting about 280 mg/day on average. The incidence and 
prevalence of the caffeine withdrawal syndrome in the general population are unclear. In 
the United States, headache may occur in approximately 50% of cases of caffeine absti­
nence. In attempts to permanently stop caffeine use, more than 70% of individuals may ex­
perience at least one caffeine withdrawal symptom (47% may experience headache), and 
24% may experience headache plus one or more other symptoms as well as functional 
impairment due to withdrawal. Among individuals who abstain from caffeine for at least 
24 hours but are not trying to permanently stop caffeine use, 11% may experience head­

ache plus one or more other symptoms as well as functional impairment. Caffeine con­
sumers can decrease the incidence of caffeine withdrawal by using caffeine daily or only 
infrequently (e.g., no more than 2 consecutive days). Gradual reduction in caffeine over a 
period of days or weeks may decrease the incidence and severity of caffeine withdrawal.
Symptoms usually begin 12-24 hours after the last caffeine dose and peak after 1-2 days 
of abstinence. Caffeine withdrawal symptoms last for 2-9 days, with the possibility of 
withdrawal headaches occurring for up to 21 days. Symptoms usually remit rapidly 
(within 30-60 minutes) after re-ingestion of caffeine.
Caffeine is unique in that it is a behaviorally active drug that is consumed by individ­

uals of nearly all ages. Rates of caffeine consumption and overall level of caffeine con­
sumption increase with age until the early to mid-30s and then level off. Although caffeine 
withdrawal among children and adolescents has been documented, relatively little is 
known about risk factors for caffeine withdrawal among this age group. The use of highly 
caffeinated energy drinks is increasing with in young individuals, which could increase 
the risk for caffeine withdrawal.
Temperamental. Heavy caffeine use has been observed among individuals with mental 
disorders, including eating disorders; smokers; prisoners; and drug and alcohol abusers. 
Thus, these individuals could be at higher risk for caffeine withdrawal upon acute caffeine 
abstinence.

Environmental. The unavailability of caffeine is an environmental risk factor for incipi­
ent withdrawal symptoms. While caffeine is legal and usually widely available, there are 
conditions in which caffeine use may be restricted, such as during medical procedures, 
pregnancy, hospitalizations, religious observances, wartime, travel, and research partici­

pation. These external environmental circumstances may precipitate a withdrawal syn­
drome in vulnerable individuals.
Genetic and physiological factors. Genetic factors appear to increase vulnerability to 
caffeine withdrawal, but no specific genes have been identified.
Course modifiers. Caffeine withdrawal symptoms usually remit within 30-60 minutes 
of reexposure to caffeine. Doses of caffeine significantly less than one's usual daily dose 
may be sufficient to prevent or attenuate caffeine withdrawal symptoms (e.g., consump­
tion of 25 mg by an individual who typically consumes 300 mg).
Habitual caffeine consumers who fast for religious reasons may be at increased risk for caf­
feine withdrawal.
Caffeine Withdrawal Disorder
Caffeine withdrawal symptoms can vary from mild to extreme, at times causing functional 
impairment in normal daily activities. Rates of functional impairment range from 10% to

impairment in normal daily activities. Rates of functional impairment range from 10% to 
55% (median 13%), with rates as high as 73% found among individuals who also show 
other problematic features of caffeine use. Examples of functional impairment include be­
ing unable to work, exercise, or care for children; staying in bed all day; missing religious 
services; ending a vacation early; and cancelling a social gathering. Caffeine withdrawal 
headaches may be described by individuals as "the worst headaches" ever experienced. 
Decrements in cognitive and motor performance have also been observed.
Other medical disorders and medical side effects. Several disorders should be consid­
ered in the differential diagnosis of caffeine withdrawal. Caffeine withdrawal can mimic 
migraine and other headache disorders, viral illnesses, sinus conditions, tension, other

migraine and other headache disorders, viral illnesses, sinus conditions, tension, other 
drug withdrawal states (e.g., from amphetamines, cocaine), and medication side effects. 
The final determination of caffeine withdrawal should rest on a determination of the pat­
tern and amount consumed, the time interval between caffeine abstinence and onset of 
symptoms, and the particular clinical features presented by the individual. A challenge 
dose of caffeine followed by symptom remission may be used to confirm the diagnosis.
Caffeine withdrawal may be associated with major depressive disorder, generalized anx­
iety disorder, panic disorder, antisocial personality disorder in adults, moderate to severe 
alcohol use disorder, and cannabis and cocaine use.
Other Caffeine-Induced Disorders
The following caffeine-induced disorders are described in other chapters of the manual

The following caffeine-induced disorders are described in other chapters of the manual 
with disorders with which they share phenomenology (see the substance/medication- 
induced mental disorders in these chapters): caffeine-induced anxiety disorder ("Anxiety 
Disorders") and caffeine-induced sleep disorder ("Sleep-Wake Disorders"). These caf­
feine-induced disorders are diagnosed instead of caffeine intoxication or caffeine with­
drawal only when the symptoms are sufficiently severe to warrant independent clinical 

Unspecified Caffeine-Related Disorder____________ \______________________________________________________
______________________________________ 292.9 (F15.99)
This category applies to presentations in  whicfi symptoms characteristic of a caffeine-  
for any specific caffeine-related disorder or any of the disorders in the substance-related  
Cannabis-Related Disorders
Cannabis Use Disorder  
Cannabis Intoxication  
Cannabis Withdrawal  
Other Cannabis-Induced Disorders  
Unspecified Cannabis-Related Disorder
Cannabis Use Disorder
A. A problematic pattern of cannabis use leading to clinically significant impairment or dis­

1. Cannabis is often taken in larger amounts or over a longer period than was intended.
2. There is a persistent desire or unsuccessful efforts to cut down or control cannabis use.
3. A great deal of time is spent in activities necessary to obtain cannabis, use canna­
bis, or recover from its effects.
4. Craving, or a strong desire or urge to use cannabis.
5. Recurrent cannabis use resulting in a failure to fulfill major role obligations at work,  
6. Continued cannabis use despite having persistent or recurrent social or interper­
sonal problems caused or exacerbated by the effects of cannabis.
cause of cannabis use.
8. Recurrent cannabis use in situations in which it is physically hazardous.

9. Cannabis use is continued despite knowledge of having a persistent or recurrent  
by cannabis.
a. A need for markedly increased amounts of cannabis to achieve intoxication or  
desired effect.
b. Markedly diminished effect with continued use of the same amount of cannabis.
a. The characteristic withdrawal syndrome for cannabis (refer to Criteria A and B  
of the criteria set for cannabis withdrawal, pp. 517-518).

b. Cannabis (or a closely related substance) is tal<en to relieve or avoid withdrawal  
symptoms.
In early remission: After full criteria for cannabis use disorder were previously met,  
none of the criteria for cannabis use disorder have been met for at least 3 months but  
for less than 12 months (with the exception that Criterion A4, “ Craving, or a strong de­
sire or urge to use cannabis,”  may be met).
In sustained remission; After full criteria for cannabis use disorder were previously  
met, none of the criteria for cannabis use disorder have been met at any time during a  
strong desire or urge to use cannabis,”  may be present).
In a controlled environment: This additional specifier is used if the individual is in  an  
environment where access to cannabis is restricted.
Code based on current severity: Note for ICD-10-CM codes: If a cannabis intoxication,

Code based on current severity: Note for ICD-10-CM codes: If a cannabis intoxication,  
cannabis withdrawal, or another cannabis-induced mental disorder is also present, do not  
use the codes below for cannabis use disorder. Instead, the comorbid cannabis use disorder  
is indicated in  the 4th character of the cannabis-induced disorder code (see the coding note  
for cannabis intoxication, cannabis withdrawal, or a specific cannabis-induced mental disor­
der). For example, if there is comorbid cannabis-induced anxiety disorder and cannabis use  
disorder, only the cannabis-induced anxiety disorder code is given, with the 4th character  
indicating whether the comorbid cannabis use disorder is mild, moderate, or severe:  
F12.180 for m ild cannabis use disorder with cannabis-induced anxiety disorder or F12.280  
for a moderate or severe cannabis use disorder with cannabis-induced anxiety disorder.

305.20 (F12.10) Mild: Presence of 2-3 symptoms.
304.30 (F12.20) Moderate: Presence of 4-5 symptoms.
304.30 (F12.20) Severe: Presence of 6 or more symptoms.
Changing severity across time in an individual may also be reflected by changes in the 
frequency (e.g., days of use per month or times used per day) and/or dose (e.g., amount 
used per episode) of cannabis, as assessed by individual self-report, report of knowledge­

able others, clinician's observations, and biological testing.
Cannabis use disorder and the other cannabis-related disorders include problems that are 
associated with substances derived from the cannabis plant and chemically similar syn­
thetic compounds. Over time, this plant material has accumulated many names (e.g., 
weed, pot, herb, grass, reefer, mary jane, dagga, dope, bhang, skunk, boom, gangster, kif, 
and ganja). A concentrated extraction of the cannabis plant that is also commonly used is 
hashish. Cannabis  is the generic and perhaps the most appropriate scientific term for the 
psychoactive substance(s) derived from the plant, and as such it is used in this manual 
to refer to all forms of cannabis-like substances, including synthetic cannabinoid com­
pounds.

Synthetic oral formulations (pill/capsules) of delta-9-tetrahydrocannabinol (delta-9- 
THC) are availal^le by prescription for a number of approved medical indications (e.g., for 
nausea and vomiting caused by chemotherapy; for anorexia and weight loss in individuals 
with AIDS). Other synthetic cannabinoid compounds have been manufactured and dis­
tributed for nonmedical use in the form of plant material that has been sprayed with a can­
nabinoid formulation (e.g., K 2, Spice, JWH-018, JWH-073).
The cannabinoids have diverse effects in the brain, prominent among which are actions 
on CBl and CB2 cannabinoid receptors that are found throughout the central nervous sys­
tem. Endogenous ligands for these receptors behave essentially like neurotransmitters. 
The potency of cannabis (delta-9-THC concentration) that is generally available varies 
greatly, ranging from 1% to approximately 15% in typical cannabis plant material and

greatly, ranging from 1% to approximately 15% in typical cannabis plant material and 
10%-20% in hashish. During the past two decades, a steady increase in the potency of 
seized cannabis has been observed.
Cannabis is most commonly smoked via a variety of methods: pipes, water pipes 
(bongs or hookahs), cigarettes (joints or reefers), or, most recently, in the paper from hol­
lowed out cigars (blunts). Cannabis is also sometimes ingested orally, typically by mixing 
it into food. More recently, devices have been developed in which cannabis is "vapor­
ized." Vaporization involves heating the plant material to release psychoactive cannabi­
noids for inhalation. As with other psychoactive substances, smoking (and vaporization) 
typically produces more rapid onset and more intense experiences of the desired effects.

Individuals who regularly use cannabis can develop all the general diagnostic features 
of a substance use disorder. Cannabis use disorder is commonly observed as the only sub­
stance use disorder experienced by the individual; however, it also frequently occurs con­
currently with other types of substance use disorders (i.e., alcohol, cocaine, opioid). In 
cases for which multiple types of substances are used, many times the individual may 
minimize the symptoms related to cannabis, as the symptoms may be less severe or cause 
less harm than those directly related to the use of the other substances. Pharmacological 
and behavioral tolerance to most of the effects of cannabis has been reported in individuals 
who use cannabis persistently. Generally, tolerance is lost when cannabis use is discontin­

ued for a significant period of time (i.e., for at least several months).
New to DSM-5 is the recognition that abrupt cessation of daily or near-daily cannabis 
use often results in the onset of a cannabis withdrawal syndrome. Common symptoms of 
withdrawal include irritability, anger or aggression, anxiety, depressed mood, restless­
ness, sleep difficulty, and decreased appetite or weight loss. Although typically not as 
severe as alcohol or opiate withdrawal, the cannabis withdrawal syndrome can cause sig­
nificant distress and contribute to difficulty quitting or relapse among those trying to 
abstain.
Individuals with cannabis use disorder may use cannabis throughout the day over a 
period of months or years, and thus may spend many hours a day under the influence.

abstain.
period of months or years, and thus may spend many hours a day under the influence. 
Others may use less frequently, but their use causes recurrent problems related to family, 
school, work, or other important activities (e.g., repeated absences at work; neglect of fam­
ily obligations). Periodic cannabis use and intoxication can negatively affect behavioral 
and cognitive functioning and thus interfere with optimal performance at work or school, 
or place the individual at increased physical risk when performing activities that could be 
physically hazardous (e.g., driving a car; playing certain sports; performing manual work 
activities, including operating machinery). Arguments with spouses or parents over the 
use of cannabis in the home, or its use in the presence of children, can adversely impact 
family functioning and are common features of those with cannabis use disorder. Last, in­

dividuals with cannabis use disorder may continue using despite knowledge of physical 
problems (e.g., chronic cough related to smoking) or psychological problems (e.g., exces­
sive sedation or exacerbation of other mental health problems) associated with its use.
Whether or not cannabis is being used for legitimate medical reasons may also affect 
diagnosis. When a substance is taken as indicated for a medical condition, symptoms of

tolerance and withdrawal will naturally occur and should not be used as the primary cri­
teria for determining a diagnosis of a substance use disorder. Although medical uses of 
cannabis remain controversial and equivocal, use for medical circumstances should be 
considered when a diagnosis is being made.
Individuals who regularly use cannabis often report that it is being used to cope with 
mood, sleep, pain, or other physiological or psychological problems, and those diagnosed 
with cannabis use disorder frequently do have concurrent other mental disorders. Careful 
assessment typically reveals reports of cannabis use contributing to exacerbation of these 
same symptoms, as well as other reasons for frequent use (e.g., to experience euphoria, to 
forget about problems, in response to anger, as an enjoyable social activity). Related to this 
issue, some individuals who use cannabis multiple times per day for the aforementioned

issue, some individuals who use cannabis multiple times per day for the aforementioned 
reasons do not perceive themselves as (and thus do not report) spending an excessive 
amount of time under the influence or recovering from the effects of cannabis, despite be­
ing intoxicated on cannabis or coming down from it effects for the majority of most days. 
An important marker of a substance use disorder diagnosis, particularly in milder cases, is 
continued use despite a clear risk of negative consequences to other valued activities or re­
lationships (e.g., school, work, sport activity, partner or parent relationship).
Because some cannabis users are motivated to minimize their amount or frequency of 
use, it is important to be aware of common signs and symptoms of cannabis use and intox­
ication so as to better assess the extent of use. As with other substances, experienced users

ication so as to better assess the extent of use. As with other substances, experienced users 
of cannabis develop behavioral and pharmacological tolerance such that it can be difficult 
to detect when they are under the influence. Signs of acute and chronic use include red eyes 
(conjunctival injection), cannabis odor on clothing, yellowing of finger tips (from smoking 
joints), chronic cough, burning of incense (to hide the odor), and exaggerated craving and 
impulse for specific foods, sometimes at unusual times of the day or night.
Cannabinoids, especially cannabis, are the most widely used illicit psychoactive sub­
stances in the United States. The 12-month prevalence of cannabis use disorder (DSM-IV 
abuse and dependence rates combined) is approximately 3.4% among 12- to 17-year-olds 
and 1.5% among adults age 18 years and older. Rates of cannabis use disorder are greater

and 1.5% among adults age 18 years and older. Rates of cannabis use disorder are greater 
among adult males (2.2%) than among adult females (0.8%) and among 12- to 17-year-old 
males (3.8%) than among 12- to 17-year-old females (3.0%). Twelve-month prevalence 
rates of cannabis use disorder among adults decrease with age, with rates highest among
18- to 29-year-olds (4.4%) and lowest among individuals age 65 years and older (0.01%). 
The high prevalence of cannabis use disorder likely reflects the much more widespread 
use of cannabis relative to other illicit drugs rather than greater addictive potential.
Ethnic and racial differences in prevalence are moderate. Twelve-month prevalences 
of cannabis use disorder vary markedly across racial-ethnic subgroups in the United 
States. For 12- to 17-year-olds, rates are highest among Native American and Alaska Na­

tives (7.1%) compared with Hispanics (4.1%), whites (3.4%), African Americans (2.7%), 
and Asian Americans and Pacific Islanders (0.9%). Among adults, the prevalence of can­
nabis use disorder is also highest among Native Americans and Alaska Natives (3.4%) rel­
ative to rates among African Americans (1.8%), whites (1.4%), Hispanics (1.2%), and Asian 
and Pacific Islanders (1.2%). During the past decade the prevalence of cannabis use disor­
der has increased among adults and adolescents. Gender differences in cannabis use dis­
order generally are concordant with those in other substance use disorders. Cannabis use 
disorder is more commonly observed in males, although the magnitude of this difference 
is less among adolescents.

The onset of canhabis use disorder can occur at any time during or following adolescence, 
but onset is most commonly during adolescence or young adulthood. Although much less 
frequent, onset of cannabis use disorder in the preteen years or in the late 2 0s or older can 
occur. Recent acceptance by some of the use and availability of "medical marijuana" may 
increase the rate of onset of cannabis use disorder among older adults.
Generally, cannabis use disorder develops over an extended period of time, although 
the progression appears to be more rapid in adolescents, particularly those with pervasive 
conduct problems. Most people who develop a cannabis use disorder typically establish a 
pattern of cannabis use that gradually increases in both frequency and amount. Cannabis, 
along with tobacco and alcohol, is traditionally the first substance that adolescents try. 
Many perceive cannabis use as less harmful than alcohol or tobacco use, and this percep­

tion likely contributes to increased use. Moreover, cannabis intoxication does not typically 
result in as severe behavioral and cognitive dysfunction as does significant alcohol intox­
ication, which may increase the probability of more frequent use in more diverse situa­
tions than with alcohol. These factors likely contribute to the potential rapid transition 
from cannabis use to a cannabis use disorder among some adolescents and the common 
pattern of using throughout the day that is commonly observed among those with more 
severe carmabis use disorder.
Cannabis use disorder among preteens, adolescents, and young adults is typically ex­
pressed as excessive use with peers that is a component of a pattern of other delinquent

pressed as excessive use with peers that is a component of a pattern of other delinquent 
behaviors usually associated with conduct problems. Milder cases primarily reflect con­
tinued use despite clear problems related to disapproval of use by other peers, school ad­
ministration, or family, which also places the youth at risk for physical or behavioral 
consequences. In more severe cases, there is a progression to using alone or using through­
out the day such that use interferes with daily functioning and takes the place of previ­
ously established, prosocial activities.
With adolescent users, changes in mood stability, energy level, and eating patterns are 
commonly observed. These signs and symptoms are likely due to the direct effects of can­
nabis use (intoxication) and the subsequent effects following acute intoxication (coming

nabis use (intoxication) and the subsequent effects following acute intoxication (coming 
down), as well as attempts to conceal use from others. School-related problems are com­
monly associated with cannabis use disorder in adolescents, particularly a dramatic drop 
in grades, truancy, and reduced interest in general school activities and outcomes.
Cannabis use disorder among adults typically involves well-established patterns of daily 
cannabis use that continue despite clear psychosocial or medical problems. Many adults have 
experienced repeated desire to stop or have failed at repeated cessation attempts. Milder adult 
cases may resemble the more common adolescent cases in that cannabis use is not as frequent 
or heavy but continues despite potential significant consequences of sustained use. The rate of

or heavy but continues despite potential significant consequences of sustained use. The rate of 
use among middle-age and older adults appears to be increasing, likely because of a cohort ef­
fect resulting from high prevalence of use in the late 1960s and the 1970s.
Early onset of cannabis use (e.g., prior to age 15 years) is a robust predictor of the de­
velopment of cannabis use disorder and other types of substance use disorders and mental 
disorders during young adulthood. Such early onset is likely related to concurrent other 
externalizing problems, most notably conduct disorder symptoms. However, early onset 
is also a predictor of internalizing problems and as such probably reflects a general risk 
factor for the development of mental health disorders.
Temperamental. A history of conduct disorder in childhood or adolescence and antiso­

cial personality disorder are risk factors for the development of many substance-related 
disorders, including cannabis-related disorders. Other risk factors include externalizing

or internalizing disorders during childhood or adolescence. Youths with high behavioral 
disinhibition scores show early-onset substance use disorders, including cannabis use dis­
order, multiple substance involvement, and early conduct problems.
Environmental. Risk factors include academic failure, tobacco smoking, unstable or abu­
sive family situation, use of cannabis among immediate family members, a family history 
of a substance use disorder, and low socioeconomic status. As with all substances of abuse, 
the ease of availability of the substance is a risk factor; cannabis is relatively easy to obtain 
in most cultures, which increases the risk of developing a cannabis use disorder.
Genetic and physiological. Genetic influences contribute to the development of canna­
bis use disorders. Heritable factors contribute between 30% and 80% of the total variance 
in risk of cannabis use disorders. It should be noted that common genetic and shared en­

vironmental influences between cannabis and other types of substance use disorders sug­
gest a common genetic basis for adolescent substance use and conduct problems.
Cannabis is probably the world's most commonly used illicit substance. Occurrence of 
cannabis use disorder across countries is unknown, but the prevalence rates are likely sim­
ilar among developed countries. It is frequently among the first drugs of experimentation 
(often in the teens) of all cultural groups in the United States.
Acceptance of cannabis for medical purposes varies widely across and within cultures. 
Cultural factors (acceptability and legal status) that might impact diagnosis relate to dif­
ferential consequences across cultures for detection of use (i.e., arrest, school suspensions,

ferential consequences across cultures for detection of use (i.e., arrest, school suspensions, 
or employment suspension). The general change in substance use disorder diagnostic cri­
teria from DSM-IV to DSM-5 (i.e., removal of the recurrent substance-related legal prob­
lems criterion) mitigates this concern to some degree.
Biological tests for cannabinoid metabolites are useful for determining if an individual has 
recently used cannabis. Such testing is helpful in making a diagnosis, particularly in 
milder cases if an individual denies using while others (family, work, school) purport con­
cern about a substance use problem. Because cannabinoids are fat soluble, they persist in 
bodily fluids for extended periods of time and are excreted slowly. Expertise in urine test­
ing methods is needed to reliably interpret results.
Functional Consequences of Cannabis Use Disorder

Functional consequences of cannabis use disorder are part of the diagnostic criteria. Many 
areas of psychosocial, cognitive, and health functioning may be compromised in relation 
to cannabis use disorder. Cognitive function, particularly higher executive function, ap­
pears to be compromised in cannabis users, and this relationship appears to be dose de­
pendent (both acutely and chronically). This may contribute to increased difficulty at 
school or work. Cannabis use has been related to a reduction in prosocial goal-directed ac­
tivity, which some have labeled an amotivational syndrome,  that manifests itself in poor 
school performance and employment problems. These problems may be related to perva­

sive intoxication or recovery from the effects of intoxication. Similarly, cannabis-associated 
problems with social relationships are commonly reported in those with cannabis use dis­
order. Accidents due to engagement in potentially dangerous behaviors while under the 
influence (e.g., driving, sport, recreational or employment activities) are also of concern. 
Cannabis smoke contains high levels of carcinogenic compounds that place chronic users 
at risk for respiratory illnesses similar to those experienced by tobacco smokers. Chronic 
cannabis use may contribute to the onset or exacerbation of many other mental disorders. 
In particular, concern has been raised about cannabis use as a causal factor in schizophrenia 
and other psychotic disorders. Cannabis use can contribute to the onset of an acute psy­

chotic episode, can exacerbate some symptoms, and can adversely affect treatment of a 
major psychotic \llness.
Nonproblematic use of cannabis. The distinction between nonproblematic use of can­
nabis and cannabis use disorder can be difficult to make because social, behavioral, or psy­
chological problems may be difficult to attribute to the substance, especially in the context 
of use of other substances. Also, denial of heavy cannabis use and the attribution that can­
nabis is related to or causing substantial problems are common among individuals who 
are referred to treatment by others (i.e., school, family, employer, criminal justice system).
Other mental disorders. Cannabis-induced disorder may be characterized by symp­
toms (e.g., anxiety) that resemble primary mental disorders (e.g., generalized anxiety dis­
order vs. cannabis-induced anxiety disorder, with generalized anxiety, with onset during

order vs. cannabis-induced anxiety disorder, with generalized anxiety, with onset during 
intoxication). Chronic intake of cannabis can produce a lack of motivation that resembles 
persistent depressive disorder (dysthymia). Acute adverse reactions to cannabis should be 
differentiated from the symptoms of panic disorder, major depressive disorder, delusional 
disorder, bipolar disorder, or schizophrenia, paranoid type. Physical examination will 
usually show an increased pulse and conjunctival injection. Urine toxicological testing can 
be helpful in making a diagnosis.
Cannabis has been commonly thought of as a "gateway" drug because individuals who 
frequently use cannabis have a much greater lifetime probability than nonusers of using 
what are commonly considered more dangerous substances, like opioids or cocaine. Can­

nabis use and cannabis use disorder are highly comorbid with other substance use disor­
ders. Co-occurring mental conditions are common in cannabis use disorder. Cannabis use 
has been associated with poorer life satisfaction; increased mental health treatment and 
hospitalization; and higher rates of depression, anxiety disorders, suicide attempts, and 
conduct disorder. Individuals with past-year or lifetime cannabis use disorder have high 
rates of alcohol use disorder (greater than 50%) and tobacco use disorder (53%). Rates of 
other substance use disorders are also likely to be high among individuals with cannabis 
use disorder. Among those seeking treatment for a cannabis use disorder, 74% report 
problematic use of a secondary or tertiary substance: alcohol (40%), cocaine (12%), meth-

problematic use of a secondary or tertiary substance: alcohol (40%), cocaine (12%), meth- 
amphetamine ( 6%), and heroin or other opiates (2%). Among those younger than 18 years, 
61% reported problematic use of a secondary substance: alcohol (48%), cocaine (4%), meth- 
amphetamine (2%), and heroin or other opiates (2%). Cannabis use disorder is also often 
observed as a secondary problem among those with a primary diagnosis of other substance 
use disorders, with approximately 25%-80% of those in treatment for another substance 
use disorder reporting use of cannabis.
Individuals with past-year or lifetime diagnoses of cannabis use disorder also have 
high rates of concurrent mental disorders other than substance use disorders. Major de­
pressive disorder (11%), any anxiety disorder (24%), and bipolar I disorder (13%) are quite

pressive disorder (11%), any anxiety disorder (24%), and bipolar I disorder (13%) are quite 
common among individuals with a past-year diagnosis of a cannabis use disorder, as are 
antisocial (30%), obsessive-compulsive, (19%), and paranoid (18%) personality disorders. 
Approximately 33% of adolescents with cannabis use disorder have internalizing disor­
ders (e.g., anxiety, depression, posttraumatic stress disorder), and 60% have externalizing 
disorders (e.g., conduct disorder, attention-deficit/hyperactivity disorder).
Although cannabis use can impact multiple aspects of normal human functioning, in­
cluding the cardiovascular, immune, neuromuscular, ocular, reproductive, and respira­
tory systems, as well as appetite and cognition/perception, there are few clear medical 
conditions that commonly co-occur with cannabis use disorder. The most significant health

effects of cannabis involve the respiratory system, and chronic cannabis smokers exhibit 
high rates of respiratory symptoms of bronchitis, sputum production, shortness of breath, 
and wheezing.
Cannabis Intoxication
A. Recent use of cannabis.
B. Clinically significant problematic behavioral or psychological changes (e.g., impaired  
motor coordination, euphoria, anxiety, sensation of slowed time, impaired judgment,  
social withdrawal) that developed during, or shortly after, cannabis use.
C. Two (or more) of the following signs or symptoms developing within 2 hours of canna­
bis use:
1. Conjunctival injection.
2. Increased appetite.
3. Dry mouth.
4. Tachycardia.
With perceptual disturbances: Hallucinations with intact reality testing or auditory, vi­

sual, or tactile illusions occur in the absence of a delirium.
Coding note: The ICD-9-CM code is 292.89. The ICD-10-CM code depends on whether  
or not there is a comorbid cannabis use disorder and whether or not there are perceptual  
disturbances.
For cannabis intoxication, without perceptual disturbances: If a mild cannabis use  
disorder is comorbid, the ICD-10-CM code is F12.129, and if a moderate or severe  
cannabis use disorder is comorbid, the ICD-10-CM code is F12.229. If there is no co­
morbid cannabis use disorder, then the ICD-10-CM code is F12.929.
For cannabis intoxication, with perceptual disturbances: If a mild cannabis use  
disorder is comorbid, the ICD-10-CM code is F I 2.122, and if a moderate or severe

disorder is comorbid, the ICD-10-CM code is F I 2.122, and if a moderate or severe  
cannabis use disorder is comorbid, the ICD-10-CM code is FI 2.222. If there is no co­
morbid cannabis use disorder, then the ICD-10-CM code is FI 2.922.
When hallucinations occur in the absence of intact reality testing, a diagnosis of substance/ 
medication-induced psychotic disorder should be considered.
The essential feature of cannabis intoxication is the presence of clinically significant prob­
lematic behavioral or psychological changes that develop during, or shortly after, canna­
bis use (Criterion B). Intoxication typically begins with a ''high" feeling followed by 
symptoms that include euphoria with inappropriate laughter and grandiosity, sedation, 
lethargy, impairment in short-term memory, difficulty carrying out complex mental pro­

cesses, impaired judgment, distorted sensory perceptions, impaired motor performance, 
and the sensation that time is passing slowly. Occasionally, anxiety (which can be severe),

dysphoria, or social withdrawal occurs. These psychoactive effects are accompanied by 
two or more of the following signs, developing within 2 hours of cannabis use: conjuncti­
val injection, increased appetite, dry mouth, and tachycardia (Criterion C).
Intoxication develops within minutes if the cannabis is smoked but may take a few 
hours to develop if the cannabis is ingested orally. The effects usually last 3-4 hours, with 
the duration being somewhat longer when the substance is ingested orally. The magnitude 
of the behavioral and physiological changes depends on the dose, the method of adminis­
tration, and the characteristics of the individual using the substance, such as rate of absorp­
tion, tolerance, and sensitivity to the effects of the substance. Because most cannabinoids, 
including delta-9-tetrahydrocannabinol (delta-9-THC), are fat soluble, the effects of canna­
bis or hashish may occasionally persist or reoccur for 12-24 hours because of the slow re­

lease of psychoactive substances from fatty tissue or to enterohepatic circulation.
The prevalence of actual episodes of cannabis intoxication in the general population is un­
known. However, it is probable that most cannabis users would at some time meet criteria 
for cannabis intoxication. Given this, the prevalence of cannabis users and the prevalence 
of individuals experiencing cannabis intoxication are likely similar.
Functional Consequences of Cannabis Intoxication
Impairment from cannabis intoxication may have serious consequences, including dys­
function at work or school, social indiscretions, failure to fulfill role obligations, traffic ac­
cidents, and having unprotected sex. In rare cases, cannabis intoxication may precipitate a 
psychosis that may vary in duration.

Note that if the clinical presentation includes hallucinations in the absence of intact reality 
testing, a diagnosis of substance/medication-induced psychotic disorder should be con­
sidered.
Other substance intoxication. Cannabis intoxication may resemble intoxication with 
other types of substances. However, in contrast to carmabis intoxication, alcohol intoxica­
tion and sedative, hypnotic, or anxiolytic intoxication frequently decrease appetite, in­
crease aggressive behavior, and produce nystagmus or ataxia. Hallucinogens in low doses 
may cause a clinical picture that resembles cannabis intoxication. Phencyclidine, like can­
nabis, can be smoked and also causes perceptual changes, but phencyclidine intoxication 
is much more likely to cause ataxia and aggressive behavior.

Other cannabis-induced disorders. Cannabis intoxication is distinguished from the other 
cannabis-induced disorders (e.g., cannabis-induced anxiety disorder, with onset during 
intoxication) because the symptoms in these latter disorders predominate the clinical pre­
sentation and are severe enough to warrant independent clinical attention.
Cannabis Withdrawal
Diagnostic Criteria 292.0 (F12.288)
A. Cessation of cannabis use tliat lias been heavy and prolonged (i.e., usually daily or  
almost daily use over a period of at least a few months).
B. Three (or more) of the following signs and symptoms develop within approximately 1  week  
after Criterion A :

1. Irritability, anger, or aggression.
2. Nervousness or anxiety.
3. Sleep difficulty (e.g., insomnia, disturbing dreams).
4. Decreased appetite or weight loss.
5. Restlessness.
6. Depressed mood.
7. At least one of the following physical symptoms causing significant discomfort: ab­
dominal pain, shakiness/tremors, sweating, fever, chills, or headache.
Coding note: The ICD-9-CM code is 292.0. The ICD-10-CM code for cannabis withdrawal  
is F12.288. Note that the ICD-10-CM code indicates the comorbid presence of a moderate  
or severe cannabis use disorder, reflecting the fact that cannabis withdrawal can only oc­

cur in the presence of a moderate or severe cannabis use disorder. It is not permissible to  
code a comorbid mild cannabis use disorder with cannabis withdrawal.
The essential feature of cannabis withdrawal is the presence of a characteristic withdrawal 
syndrome that develops after the cessation of or substantial reduction in heavy and pro­
longed cannabis use. In addition to the symptoms in Criterion B, the following may also be 
observed postabstinence: fatigue, yawning, difficulty concentrating, and rebound periods 
of increased appetite and hypersomnia that follow initial periods of loss of appetite and in­
somnia. For the diagnosis, withdrawal symptoms must cause clinically significant distress

somnia. For the diagnosis, withdrawal symptoms must cause clinically significant distress 
or impairment in social, occupational, or other important areas of functioning (Criterion 
C). Many cannabis users report smoking cannabis or taking other substances to help re­
lieve withdrawal symptoms, and many report that withdrawal symptoms make quitting 
difficult or have contributed to relapse. The symptoms typically are not of sufficient se­
verity to require medical attention, but medication or behavioral strategies may help alle­
viate symptoms and improve prognosis in those trying to quit using cannabis.
Cannabis withdrawal is commonly observed in individuals seeking treatment for can­
nabis use as well as in heavy cannabis users who are not seeking treatment. Among indi­
viduals who have used cannabis regularly during some period of their lifetime, up to one-

viduals who have used cannabis regularly during some period of their lifetime, up to one- 
third report having experienced cannabis withdrawal. Among adults and adolescents en­
rolled in treatment or heavy cannabis users, 50%-95% report cannabis withdrawal. These 
findings indicate that cannabis withdrawal occurs among a substantial subset of regular 
cannabis users who try to quit.
The amount, duration, and frequency of cannabis smoking that is required to produce an 
associated withdrawal disorder during a quit attempt are unknown. Most symptoms have 
their onset within the first 24-72 hours of cessation, peak within the first week, and last 
approximately 1-2 weeks. Sleep difficulties may last more than 30 days. Cannabis with­
drawal has been documented among adolescents and adults. Withdrawal tends to be more

drawal has been documented among adolescents and adults. Withdrawal tends to be more 
common and severe among adults, most likely related to the more persistent and greater 
frequency and quantity of use among adults.

\
Environmental. Most likely, the prevalence and severity of cannabis withdrawal are 
greater among heavier cannabis users, and particularly among those seeking treatment for 
cannabis use disorders. Withdrawal severity also appears to be positively related to the se­
verity of comorbid symptoms of mental disorders.
Functional Consequences of Cannabis Withdrawal
Cannabis users report using cannabis to relieve withdrawal symptoms, suggesting that 
withdrawal might contribute to ongoing expression of cannabis use disorder. Worse out­
comes may be associated with greater withdrawal. A substantial proportion of adults and 
adolescents in treatment for moderate to severe cannabis use disorder acknowledge mod­
erate to severe withdrawal symptoms, and many complain that these symptoms make ces­
sation more difficult. Cannabis users report having relapsed to cannabis use or initiating

sation more difficult. Cannabis users report having relapsed to cannabis use or initiating 
use of other drugs (e.g., tranquilizers) to provide relief from cannabis withdrawal symp­
toms. Last, individuals living with cannabis users observe significant withdrawal effects, 
suggesting that such symptoms are disruptive to daily living.
Because many of the symptoms of cannabis withdrawal are also symptoms of other sub­
stance withdrawal syndromes or of depressive or bipolar disorders, careful evaluation 
should focus on ensuring that the symptoms are not better explained by cessation from an­
other substance (e.g., tobacco or alcohol withdrawal), another mental disorder (general­
ized anxiety disorder, major depressive disorder), or another medical condition.
Other Cannabis-Induced Disorders

The following cannabis-induced disorders are described in other chapters of the manual with 
mental disorders in these chapters): cannabis-induced psychotic disorder ("Schizophrenia 
Spectrum and Other Psychotic Disorders"); cannabis-induced anxiety disorder (''Anxiety 
Disorders"); and cannabis-induced sleep disorder ("Sleep-Wake Disorders"). For cannabis 
intoxication delirium, see the criteria and discussion of delirium in the chapter "Neurocog- 
nitive Disorders." These cannabis-induced disorders are diagnosed instead of cannabis in­
toxication or cannabis withdrawal when the symptoms are sufficiently severe to warrant 
independent clinical attention.

This category applies to presentations in whicii symptoms characteristic of a cannabis-  
for any specific cannabis-related disorder or any of the disorders in  the substance-related  

Hallucinogen-Related Disorders
Phencyclidine Use Disorder  
Other Hallucinogen Use Disorder  
Phencyclidine Intoxication  
Other Hallucinogen Intoxication  
Hallucinogen Persisting Perception Disorder  
Other Phencyclidine-induced Disorders  
Other Hallucinogen-induced Disorders  
Unspecified Phencyclidine-Related Disorder  
Unspecified Hallucinogen-Related Disorder
Phencyclidine Use Disorder
A. A pattern of phencyclidine (or a pharmacologically similar substance) use leading to
clinically significant impairment or distress, as manifested by at least two of the follow­
ing, occurring within a 12-month period:
1. Phencyclidine is often taken in larger amounts or over a longer period than was in­
tended.
2. There is a persistent desire or unsuccessful efforts to cut down or control phency­
clidine use.
3. A great deal of time is spent in activities necessary to obtain phencyclidine, use the  
phencyclidine, or recover from its effects.

4. Craving, or a strong desire or urge to use phencyclidine.
5. Recurrent phencyclidine use resulting in a failure to fulfill major role obligations at  
work, school, or home (e.g., repeated absences from work or poor work performance  
related to phencyclidine use; phencyclidine-related absences, suspensions, or ex­
pulsions from school; neglect of children or household).
6. Continued phencyclidine use despite having persistent or recurrent social or inter­
personal problems caused or exacerbated by the effects of the phencyclidine (e.g.,  
arguments with a spouse about consequences of intoxication; physical fights).
cause of phencyclidine use.
8. Recurrent phencyclidine use in situations in which it is physically hazardous (e.g.,

8. Recurrent phencyclidine use in situations in which it is physically hazardous (e.g.,  
driving an automobile or operating a machine when impaired by a phencyclidine).
9. Phencyclidine use is continued despite knowledge of having a persistent or recur­
rent physical or psychological problem that is likely to have been caused or exac­
erbated by the phencyclidine.
a. A need for markedly increased amounts of the phencyclidine to achieve intoxi­
cation or desired effect.
b. A markedly diminished effect with continued use of the same amount of the  
phencyclidine.

Note: Withdrawal symptoms and signs are not established for phencyclidines, and so this  
criterion does not apply. (Withdrawal from phencyclidines has been reported in animals  
but not documented in human users.)
In early remission: After full criteria for phencyclidine use disorder were previously  
met, none of the criteria for phencyclidine use disorder have been met for at least  
3 months but for less than 12 months (with the exception that Criterion A4, “ Craving,  
or a strong desire or urge to use the phencyclidine,”  may be met).
In sustained remission: After full criteria for phencyclidine use disorder were previ­
ously met, none of the criteria for phencyclidine use disorder have been met at any time  
during a period of 12 months or longer (with the exception that Criterion A4, “ Craving,  

environment where access to phencyclidines is restricted.
Coding based on current severity: Note for ICD-10-CM codes: If a phencyclidine intoxica­
tion or another phencyclidine-induced mental disorder is also present, do not use the codes  
below for phencyclidine use disorder. Instead, the comorbid phencyclidine use disorder is in­
dicated in  the 4th character of the phencyclidine-induced disorder code (see the coding note  
for phencyclidine intoxication or a specific phencyclidine-induced mental disorder). For ex­
ample, if there is comorbid phencyclidine-induced psychotic disorder, only the phencyclidine-  
induced psychotic disorder code is given, with the 4th character indicating whether the co­

morbid phencyclidine use disorder is m ild, moderate, or severe: F16.159 for m ild phencycli­
dine use disorder with phencyclidine-induced psychotic disorder or F16.259 for a moderate  
or severe phencyclidine use disorder with phencyclidine-induced psychotic disorder.
305.90 (F I6.10) Mild: Presence of 2-3 symptoms.
304.60 (FI 6.20) Moderate: Presence of 4-5 symptoms.
304.60 (F16.20) Severe: Presence of 6 or more symptoms.
environment or in sustained remission in a controlled environment). Examples of these

The phencyclidines (or phencyclidine-like substances) include phencyclidine (e.g., PCP, 
"angel dust") and less potent but similarly acting compounds such as ketamine, cyclohex- 
amine, and dizocilpine. These substances were first developed as dissociative anesthetics 
in the 1950s and became street drugs in the 1960s. They produce feelings of separation 
from mind and body (hence "dissociative") in low doses, and at high doses, stupor and 
coma can result. These substances are most commonly smoked or taken orally, but they 
may also be snorted or injected. Although the primary psychoactive effects of PCP last for

may also be snorted or injected. Although the primary psychoactive effects of PCP last for 
a few hours, the total elimination rate of this drug from the body typically extends 8 days 
or longer. The hallucinogenic effects in vulnerable individuals may last for weeks and may 
precipitate a persistent psychotic episode resembling schizophrenia. Ketamine has been 
observed to have utility in the treatment of major depressive disorder. Withdrawal symp­

toms have not been clearly established in humans, and therefore the withdraw^al criterion 
is not included in the diagnosis of phencyclidine use disorder.
Phencyclidine may be detected in urine for up to 8 days or even longer at very high doses. In 
addition to laboratory tests to detect its presence, characteristic symptoms resulting from 
intoxication v^ith phencyclidine or related substances may aid in its diagnosis. Phencycli­
dine is likely to produce dissociative symptoms, analgesia, nystagmus, and hypertension, 
with risk of hypotension and shock. Violent behavior can also occur with phencyclidine 
use, as intoxicated persons may believe that they are being attacked. Residual symptoms 
following use may resemble schizophrenia.
The prevalence of phencyclidine use disorder is unknown. Approximately 2.5% of the pop­
ulation reports having ever used phencyclidine. The proportion of users increases with

ulation reports having ever used phencyclidine. The proportion of users increases with 
age, from 0.3% of 12- to 17-year-olds, to 1.3% of 18- to 25-year-olds, to 2.9% of those age 26 
years and older reporting ever using phencyclidine. There appears to have been an in­
crease among 12th graders in both ever used (to 2.3% from 1.8%) and past-year use (to 1.3% 
from 1.0%) of phencyclidine. Past-year use of ketamine appears relatively stable among 
12th graders (1.6%-1.7% over the past 3 years).
There is little information about risk factors for phencyclidine use disorder. Among indi­
viduals admitted to substance abuse treatment, those for whom phencyclidine was the 
primary substance were younger than those admitted for other substance use, had lower 
educational levels, and were more likely to be located in the West and Northeast regions of

educational levels, and were more likely to be located in the West and Northeast regions of 
the United States, compared with other admissions.
Ketamine use in youths ages 16-23 years has been reported to be more common among 
whites (0.5%) than among other ethnic groups (range 0%-0.3%). Among individuals ad­
mitted to substance abuse treatment, those for whom phencyclidine was the primary sub­
stance were predominantly black (49%) or Hispanic (29%).
Males make up about three-quarters of those with phencyclidine-related emergency room 
visits.
Laboratory testing may be useful, as phencyclidine is present in the urine in intoxicated in­
dividuals up to 8 days after ingestion. The individual's history, along with certain physical

dividuals up to 8 days after ingestion. The individual's history, along with certain physical 
signs, such as nystagmus, analgesia and prominent hypertension, may aid in distinguish­
ing the phencyclidine clinical picture from that of other hallucinogens.
Functional Consequences of Pliencyclidine Use Disorder
In individuals with phencyclidine use disorder, there may be physical evidence of injuries 
from accidents, fights, and falls. Chronic use of phencyclidine may lead to deficits in mem­
ory, speech, and cognition that may last for months. Cardiovascular and neurological tox- 
icities (e.g., seizures, dystonias, dyskinesias, catalepsy, hypothermia or hyperthermia) 
may result from intoxication with phencyclidine. Other consequences include intracranial 
hemorrhage, rhabdomyolysis, respiratory problems, and (occasionally) cardiac arrest.

\
Other substance use disorders. Distinguishing the effects of phencychdine from those 
of other substances is important, since it may be a common additive to other substances 
(e.g., cannabis, cocaine).
Schizophrenia and other mental disorders. Some of the effects of phencychdine and 
related substance use may resemble symptoms of other psychiatric disorders, such as psy­
chosis (schizophrenia), low mood (major depressive disorder), violent aggressive be­
haviors (conduct disorder, antisocial personality disorder). Discerning whether these 
behaviors occurred before the intake of the drug is important in the differentiation of acute 
drug effects from preexisting mental disorder. Phencyclidine-induced psychotic disorder 
should be considered when there is impaired reality testing in individuals experiencing 
disturbances in perception resulting from ingestion of phencyclidine.
Other Hallucinogen Use Disorder

A. A problematic pattern of hallucinogen (other than phencyclidine) use leading to clini­
cally significant impairment or distress, as manifested by at least two of the following,
occurring within a 12-month period:
1. The hallucinogen is often taken in larger amounts or over a longer period than was  
intended.
2. There is a persistent desire or unsuccessful efforts to cut down or control halluci­
nogen use.
3. A great deal of time is spent in activities necessary to obtain the hallucinogen, use  
the hallucinogen, or recover from its effects.
4. Craving, or a strong desire or urge to use the hallucinogen.
5. Recurrent hallucinogen use resulting in a failure to fulfill major role obligations at  
work, school, or home (e.g., repeated absences from work or poor work perfor­
mance related to hallucinogen use; hallucinogen-related absences, suspensions,

mance related to hallucinogen use; hallucinogen-related absences, suspensions,  
or expulsions from school; neglect of children or household).
6. Continued hallucinogen use despite having persistent or recurrent social or inter­
personal problems caused or exacerbated by the effects of the hallucinogen (e.g.,  
cause of hallucinogen use.
8. Recurrent hallucinogen use in situations in  which it is physically hazardous (e.g.,  
driving an automobile or operating a machine when impaired by the hallucinogen).
9. Hallucinogen use is continued despite knowledge of having a persistent or recur­
erbated by the hallucinogen.

a. A need for markedly increased amounts of the hallucinogen to achieve intoxi­
b. A markedly diminished effect with continued use of the same amount of the hal­
lucinogen.
Note: Withdrawal symptoms and signs are not established for hallucinogens, and so this  
criterion does not apply.

Specify  the particular hallucinogen.
In early remission: After full criteria for other hallucinogen use disorder were previ­
ously met, none of the criteria for other hallucinogen use disorder have been met for  
at least 3 months but for less than 12 months (with the exception that Criterion A4,  
“ Craving, or a strong desire or urge to use the hallucinogen,”  may be met).
In sustained remission: After full criteria for other hallucinogen use disorder were  
previously met, none of the criteria for other hallucinogen use disorder have been met  
at any time during a period of 12 months or longer (with the exception that Criterion A4,  
environment where access to hallucinogens is restricted.
Coding based on current severity: Note for ICD-10-CM codes: If a hallucinogen intoxication

Coding based on current severity: Note for ICD-10-CM codes: If a hallucinogen intoxication  
or another hallucinogen-induced mental disorder is also present, do not use the codes below  
for hallucinogen use disorder. Instead, the comorbid hallucinogen use disorder is indicated in  
the 4th character of the hallucinogen-induced disorder code (see the coding note for halluci­
nogen intoxication or specific hallucinogen-induced mental disorder). For example, if there is  
comorbid hallucinogen-induced psychotic disorder and hallucinogen use disorder, only the  
hallucinogen-induced psychotic disorder code is given, with the 4th character indicating wheth­
er the comorbid hallucinogen use disorder is m ild, moderate, or severe: F16.159 for m ild hal­
lucinogen use disorder with hallucinogen-induced psychotic disorder or F16.259 for a  
moderate or severe hallucinogen use disorder with hallucinogen-induced psychotic disorder.

305.30 (FI 6.10) IWild: Presence of 2-3 symptoms.
304.50 (F16.20) Moderate: Presence of 4-5 symptoms.
304.50 (F16.20) Severe: Presence of 6 or more symptoms.
Hallucinogens comprise a diverse group of substances that, despite having different chem­
ical structures and possibly involving different molecular mechanisms, produce similar

ical structures and possibly involving different molecular mechanisms, produce similar 
alterations of perception, mood, and cognition in users. Hallucinogens included are phenyl­
alkylamines (e.g., mescaline, DOM [2,5-dimethoxy-4-methylamphetamine], and MDMA 
[3,4-methylenedioxymethamphetamine; also called "ecstasy"]); the indoleamines, includ­
ing psilocybin (i.e., psilocin) and dimethyltryptamine (DMT); and the ergolines, such as LSD 
(lysergic acid diethylamide) and morning glory seeds. In addition, miscellaneous other 
ethnobotanical compounds are classified as "hallucinogens," of which Salvia divinorum  and 
jimsonweed are two examples. Excluded from the hallucinogen group are cannabis and its 
active compound, delta-9-tetrahydrocannabinol (THC) (see the section "Cannabis-Related 
Disorders"). These substances can have hallucinogenic effects but are diagnosed separately

Disorders"). These substances can have hallucinogenic effects but are diagnosed separately 
because of significant differences in their psychological and behavioral effects.
Hallucinogens are usually taken orally, although some forms are smoked (e.g., DMT, 
salvia) or (rarely) taken intranasally or by injection (e.g., ecstasy). Duration of effects varies

across types of hallucinogens. Some of these substances (i.e., LSD, MDMA) have a long 
half-life and extended duration such that users may spend hours to days using and/or re­
covering from the effects of these drugs. However, other hallucinogenic drugs (e.g., DMT, 
salvia) are short acting. Tolerance to hallucinogens develops with repeated use and has 
been reported to have both autonomic and psychological effects. Cross-tolerance exists be­
tween LSD and other hallucinogens (e.g., psilocybin, mescaline) but does not extend to 
other drug categories such as amphetamines and cannabis.
MDMA/ecstasy as a hallucinogen may have distinctive effects attributable to both its hal­
lucinogenic and its stimulant properties. Among heavy ecstasy users, continued use despite 
physical or psychological problems, tolerance, hazardous use, and spending a great deal of 
time obtaining the substance are the most commonly reported criteria—over 50% in adults

time obtaining the substance are the most commonly reported criteria—over 50% in adults 
and over 30% in a younger sample, while legal problems related to substance use and persis­
tent desire/inability to quit are rarely reported. As found for other substances, diagnostic cri­
teria for other hallucinogen use disorder are arrayed along a single continuum of severity.
One of the generic criteria for substance use disorders, a clinically significant with­
drawal syndrome, has not been consistently documented in humans, and therefore the di­
agnosis of hallucinogen withdrawal syndrome is not included in DSM-5. However, there 
is evidence of withdrawal from MDMA, with endorsement of two or more withdrawal 
symptoms observed in 59%-98% in selected samples of ecstasy users. Both psychological 
and physical problems have been commonly reported as withdrawal problems.

The characteristic symptom features of some of the hallucinogens can aid in diagnosis if 
urine or blood toxicology results are not available. For example, individuals who use LSD 
tend to experience visual hallucinations that can be frightening. Individuals intoxicated 
with hallucinogens may exhibit a temporary increase in suicidality.
Of all substance use disorders, other hallucinogen use disorder is one of the rarest. The 
12-month prevalence is estimated to be 0.5% among 12- to 17-year-olds and 0.1% among 
adults age 18 and older in the United States. Rates are higher in adult males (0.2%) compared 
with females (0.1%), but the opposite is observed in adolescent samples ages 12-17, in which

with females (0.1%), but the opposite is observed in adolescent samples ages 12-17, in which 
the 12-month rate is slightly higher in females (0.6%) than in males (0.4%). Rates are highest in 
individuals younger than 30 years, with the peak occurring in individuals ages 18-29 years 
(0.6%) and decreasing to virtually 0.0% among individuals age 45 and older.
There are marked ethnic differences in 12-month prevalence of other hallucinogen use 
disorder. Among youths ages 12-17 years, 12-month prevalence is higher among Native 
Americans and Alaska Natives (1.2%) than among Hispanics (0.6%), whites (0.6%), Afri­
can Americans (0.2%), and Asian Americans and Pacific Islanders (0.2%). Among adults, 
12-month prevalence of other hallucinogen use disorder is similar for Native Americans 
and Alaska Natives, whites, and Hispanics (all 0.2%) but somewhat lower for Asian Amer­

icans and Pacific Islanders (0.07%) and African Americans (0.03%). Past-year prevalence is 
higher in clinical samples (e.g., 19% in adolescents in treatment). Among individuals cur­
rently using hallucinogens in the general population, 7.8% (adult) to 17% (adolescent) had 
a problematic pattern of use that met criteria for past-year other hallucinogen use disorder. 
Among select groups of individuals who use hallucinogens (e.g., recent heavy ecstasy 
use), 73.5% of adults and 77% of adolescents have a problematic pattern of use that may 
meet other hallucinogen use disorder criteria.
Unlike most substances where an early age at onset is associated with elevations in risk for 
the corresponding use disorder, it is unclear whether there is an association of an early age

at onset with elevations in risk for other hallucinogen use disorder. However, patterns of 
drug consumption have been found to differ by age at onset, with early-onset ecstasy users 
more likely to be polydrug users than their later-onset counterparts. There may be a dis­
proportionate influence of use of specific hallucinogens on risk of developing other hallu­
cinogen use disorder, with use of ecstasy/MDMA increasing the risk of the disorder 
relative to use of other hallucinogens.
Little is knovm regarding the course of other hallucinogen use disorder, but it is generally 
thought to have low incidence, low persistence, and high rates of recovery. Adolescents are es­
pecially at risk for using these drugs, and it is estimated that 2.7% of youths ages 12-17 years 
have used one or more of these drugs in the past 12 months, with 44% having used ecstasy/ 
MDMA. Other hallucinogen use disorder is a disorder observed primarily in individuals

MDMA. Other hallucinogen use disorder is a disorder observed primarily in individuals 
younger than 30 years, with rates vanishingly rare among older adults.
Temperamental. In adolescents but not consistently in adults, MDMA use is associated with 
an elevated rate of other hallucinogen use disorder. Other substance use disorders, particu­
larly alcohol, tobacco, and cannabis, and major depressive disorder are associated with ele­
vated rates of other hallucinogen use disorder. Antisocial personality disorder may be 
elevated among individuals who use more than two other drugs in addition to hallucinogens, 
compared with their counterparts with less extensive use history. The influence of adult anti­
social behaviors—^ b u t not conduct disorder or antisocial personality disorder—on other hal­

lucinogen use disorder may be stronger in females than in males. Use of specific hallucinogens 
(e.g., salvia) is prominent among individuals ages 18-25 years with other risk-taking behaviors 
and illegal activities. Cannabis use has also been implicated as a precursor to initiation of use of 
hallucinogens (e.g., ecstasy), along with early use of alcohol and tobacco. Higher drug use by 
peers and high sensation seeking have also been associated with elevated rates of ecstasy use. 
MDMA/ecstasy use appears to signify a more severe group of hallucinogen users.
Genetic and physiological. Among male twins, total variance due to additive genetics 
has been estimated to range from 26% to 79%, with inconsistent evidence for shared envi­
ronmental influences.

Historically, hallucinogens have been used as part of established religious practices, such 
as the use of peyote in the Native American Church and in Mexico. Ritual use by indige­
nous populations of psilocybin obtained from certain types of mushrooms has occurred in 
South America, Mexico, and some areas in the United States, or of ayahuasca in the Santo 
Daime and Uniäo de Vegetal sects. Regular use of peyote as part of religious rituals is not 
linked to neuropsychological or psychological deficits. For adults, no race or ethnicity dif­
ferences for the full criteria or for any individual criterion are apparent at this time.
In adolescents, females may be less likely than males to endorse ''hazardous use," and fe­
male gender may be associated with increased odds of other hallucinogen use disorder.

Laboratory testing can be useful in distinguishing among the different hallucinogens. 
However, because some agents (e.g., LSD) are so potent that as little as 75 micrograms can 
produce severe reactions, typical toxicological examination will not always reveal which 
substance has been used.

There is evidence for long-term neuro toxic effects of MDMA/ecstasy use, including im­
pairments in memory, psychological function, and neuroendocrine function; serotonin 
system dysfunction; and sleep disturbance; as well as adverse effects on brain microvas­
culature, white matter maturation, and damage to axons. Use of MDMA/ecstasy may di­
minish functional connectivity among brain regions.
Other substance use disorders. The effects of hallucinogens must be distinguished from 
those of other substances (e.g., amphetamines), especially because contamination of the 
hallucinogens with other drugs is relatively common.
Schizophrenia. Schizophrenia also must be ruled out, as some affected individuals (e.g., 
individuals with schizophrenia who exhibit paranoia) may falsely attribute their symp­
toms to use of hallucinogens.

Other mental disorders or medical conditions. Other potential disorders or conditions 
to consider include panic disorder, depressive and bipolar disorders, alcohol or sedative 
withdrawal, hypoglycemia and other metabolic conditions, seizure disorder, stroke, oph- 
thalmological disorder, and central nervous system tumors. Careful history of drug tak­
ing, collateral reports from family and friends (if possible), age, clinical history, physical 
examination, and toxicology reports should be useful in arriving at the final diagnostic de­
cision.
Adolescents who use MDMA/ecstasy and other hallucinogens, as well as adults who have 
recently used ecstasy, have a higher prevalence of other substance use disorders compared 
with nonhallucinogen substance users. Individuals who use hallucinogens exhibit eleva­

tions of nonsubstance mental disorders (especially anxiety, depressive, and bipolar disor­
ders), particularly with use of ecstasy and salvia. Rates of antisocial personality disorder (but 
not conduct disorder) are significantly elevated among individuals with other hallucinogen 
use disorder, as are rates of adult antisocial behavior. However, it is unclear whether the 
mental illnesses may be precursors to rather than consequences of other hallucinogen use 
disorder (see the section "Risk and Prognostic Factors" for this disorder). Both adults and 
adolescents who use ecstasy are more likely than other drug users to be polydrug users and 
to have other drug use disorders.
Phencyclidine Intoxication
A. Recent use of phencyclidine (or a pharmacologically similar substance).

B. Clinically significant problematic behavioral changes (e.g., belligerence, assaultive­
ness, impulsiveness, unpredictability, psychomotor agitation, impaired judgment) that  
developed during, or shortly after, phencyclidine use.
C. Within 1  hour, two (or more) of the following signs or symptoms:
Note: When the drug is smoked, “ snorted,”  or used intravenously, the onset may be  
particularly rapid.
1. Vertical or horizontal nystagmus.
2. Hypertension or tachycardia.

3. Numbness or diminished responsiveness to pain.
4. Ataxia.
5. Dysarthria.
6. Muscle rigidity.
7. Seizures or coma.
8. Hyperacusis.
explained by another mental disorder, including Intoxication with another substance.
there is a comorbid phencyclidine use disorder. If a mild phencyclidine use disorder is co-  
morbid, the ICD-10-CM code is F16.129, and if a moderate or severe phencyclidine use  
disorder is comorbid, the ICD-10-CM code is F16.229. If there is no comorbid phencycli­
dine use disorder, then the ICD-10-CM code is F16.929.
Note: In addition to the section "Functional Consequences of Phencyclidine Intoxication," 
see the corresponding section in phencyclidine use disorder.
Phencyclidine intoxication reflects the clinically significant behavioral changes that occur

Phencyclidine intoxication reflects the clinically significant behavioral changes that occur 
shortly after ingestion of this substance (or a pharmacologically similar substance). The 
most common clinical presentations of phencyclidine intoxication include disorientation, 
confusion without hallucinations, hallucinations or delusions, a catatonic-like syndrome, 
and coma of varying severity. The intoxication typically lasts for several hours but, de­
pending on the type of clinical presentation and whether other drugs besides phencycli­
dine were consumed, may last for several days or longer.
Use of phencyclidine or related substances may be taken as an estimate of the prevalence 
of intoxication. Approximately 2.5% of the population reports having ever used phency­
clidine. Among high school students, 2.3% of 12th graders report ever using phencycli­

dine, with 57% having used in the past 12 months. This represents an increase from prior 
to 2011. Past-year use of ketamine, which is assessed separately from other substances, has 
remained stable over time, with about 1.7% of 12th graders reporting use.
Diagnostic IVIarlcers
Laboratory testing may be useful, as phencyclidine is detectable in urine for up to 8 days 
following use, although the levels are only weakly associated with an individual's clinical 
presentation and may therefore not be useful for case management. Creatine phosphoki- 
nase and aspartate aminotransferase levels may be elevated.
Functional Consequences of Phencyclidine Intoxication
Phencyclidine intoxication produces extensive cardiovascular and neurological (e.g., sei­

zures, dystonias, dyskinesias, catalepsy, hypothermia or hyperthermia) toxicity.
In particular, in the absence of intact reality testing (i.e., without insight into any percep­
tual abnormalities), an additional diagnosis of phencyclidine-induced psychotic disorder 
Other substance intoxication. Phencyclidine intoxication should be differentiated from 
intoxication due to other substances, including other hallucinogens; amphetamine, co­

caine, or other stimulants; and anticholinergics, as well as withdrawal from benzodiaze­
pines. Nystagm\is and bizarre and violent behavior may distinguish intoxication due to 
phencyclidine from that due to other substances. Toxicological tests may be useful in mak­
ing this distinction, since phencyclidine is detectable in urine for up to 8 days after use. 
However, there is a weak correlation between quantitative toxicology levels of phencycli­
dine and clinical presentation that diminishes the utility of the laboratory findings for pa­
tient management.
Other conditions. Other conditions to be considered include schizophrenia, depression, 
withdrawal from other drugs (e.g., sedatives, alcohol), certain metabolic disorders like hy­
poglycemia and hyponatremia, central nervous system tumors, seizure disorders, sepsis, 
neuroleptic malignant syndrome, and vascular insults.
Other Hallucinogen Intoxication
A. Recent use of a hallucinogen (other than phencyclidine).

B. Clinically significant problematic behavioral or psychological changes (e.g., marked  
anxiety or depression, ideas of reference, fear of “ losing one’s mind,”  paranoid ide­
ation, impaired judgment) that developed during, or shortly after, hallucinogen use.
C. Perceptual changes occurring in a state of full wakefulness and alertness (e.g., sub­
jective intensification of perceptions, depersonalization, derealization, illusions, hallu­
cinations, synesthesias) that developed during, or shortly after, hallucinogen use.
D. Two (or more) of the following signs developing during, or shortly after, hallucinogen  
use:
1. Pupillary dilation.
2. Tachycardia.
3. Sweating.
4. Palpitations.
5. Blurring of vision.
6. Tremors.
7. Incoordination.

use:
E. The signs or symptoms are not attributable to another medical condition and are not  
better explained by another mental disorder, including intoxication with another sub­
stance.
there is a comorbid hallucinogen use disorder. If a mild hallucinogen use disorder is co-  
morbid, the ICD-10-CM code is FI 6.129, and if a moderate or severe hallucinogen use  
disorder is comorbid, the ICD-10-CM code is F16.229. If there is no comorbid hallucinogen  
use disorder, then the ICD-10-CM code is F16.929. _________________________________
Note; For information on Associated Features Supporting Diagnosis and Culture-Related 
Diagnostic Issues, see the corresponding sections in other hallucinogen use disorder.

Other hallucinogen intoxication reflects the clinically significant behavioral or psycholog­
ical changes that occur shortly after ingestion of a hallucinogen. Depending on the specific 
hallucinogen, the intoxication may last only minutes (e.g., for salvia) or several hours or 
longer (e.g., for LSD [lysergic acid diethylamide] or MDMA [3,4-methylenedioxymetham­
phetamine]).

The prevalence of other hallucinogen intoxication may be estimated by use of those sub­
stances. In the United States, 1.8% of individuals age 12 years or older report using hallu­
cinogens in the past year. Use is more prevalent among younger individuals, with 3.1% of 
12- to 17-year-olds and 7.1% of 18- to 25-year-olds using hallucinogens in the past year, 
compared with only 0.7% of individuals age 26 years or older. Twelve-month prevalence 
for hallucinogen use is more common in males (2.4%) than in females (1.2%), and even 
more so among 18- to 25-year-olds (9.2% for males vs. 5.0% for females). In contrast, 
among individuals ages 12-17 years, there are no gender differences (3.1% for both gen­
ders). These figures may be used as proxy estimates for gender-related differences in the 
prevalence of other hallucinogen intoxication.
Other hallucinogen intoxication may lead to increased suicidality, although suicide is rare 
among users of hallucinogens.

Otiier Hallucinogen Intoxication
Other hallucinogen intoxication can have serious consequences. The perceptual distur­
bances and impaired judgment associated with other hallucinogen intoxication can result 
in injuries or fatalities from automobile crashes, physical fights, or unintentional self­
injury (e.g., attempts to "fly" from high places). Environmental factors and the personality 
and expectations of the individual using the hallucinogen may contribute to the nature of 
and severity of hallucinogen intoxication. Continued use of hallucinogens, particularly 
MDMA, has also been linked with neurotoxic effects.
Other substance intoxication. Other hallucinogen intoxication should be differentiated

Other substance intoxication. Other hallucinogen intoxication should be differentiated 
from intoxication with amphetamines, cocaine, or other stimulants; anticholinergics; in­
halants; and phencyclidine. Toxicological tests are useful in making this distinction, and 
determining the route of administration may also be useful.
Other conditions. Other disorders and conditions to be considered include schizophre­
nia, depression, withdrawal from other drugs (e.g., sedatives, alcohol), certain metabolic 
disorders (e.g., hypoglycemia), seizure disorders, tumors of the central nervous system, 
and vascular insults.
Hallucinogen persisting perception disorder. Other hallucinogen intoxication is dis­
tinguished from hallucinogen persisting perception disorder because the symptoms in the 
latter continue episodically or continuously for weeks (or longer) after the most recent in­
toxication.

Other hallucinogen-induced disorders. Other hallucinogen intoxication is distinguished 
from the other hallucinogen-induced disorders (e.g., hallucinogen-induced anxiety disor­
der, with onset during intoxication) because the symptoms in these latter disorders pre­
dominate the clinical presentation and are severe enough to warrant independent clinical 

Hallucinogen Persisting Perception Disorder
_____________ \ ____________________________________________________________
Diagnostic Criteria 292.89 (F16.983)
A. Following cessation of use of a hallucinogen, the reexperiencing of one or more of the  
perceptual symptoms that were experienced while intoxicated with the hallucinogen  
(e.g., geometric hallucinations, false perceptions of movement in the peripheral visual  
fields, flashes of color, intensified colors, trails of images of moving objects, positive  
afterimages, halos around objects, macropsia and micropsia).
B. The symptoms in Criterion A cause clinically significant distress or impairment in  so­
cial, occupational, or other important areas of functioning.
C. The symptoms are not attributable to another medical condition (e.g., anatomical le­
sions and infections of the brain, visual epilepsies) and are not better explained by an­
other mental disorder (e.g., delirium, major neurocognitive disorder, schizophrenia) or

other mental disorder (e.g., delirium, major neurocognitive disorder, schizophrenia) or  
hypnopompic hallucinations.
The hallmark of hallucinogen persisting perception disorder is the reexperiencing, when the 
individual is sober, of the perceptual disturbances that were experienced while the individ­
ual was intoxicated with the hallucinogen (Criterion A). The symptoms may include any 
perceptual perturbations, but visual disturbances tend to be predominant. Typical of the ab­
normal visual perceptions are geometric hallucinations, false perceptions of movement in 
the peripheral visual fields, flashes of color, intensified colors, trails of images of moving ob­
jects (i.e., images left suspended in the path of a moving object as seen in stroboscopic pho­
tography), perceptions of entire objects, positive afterimages (i.e., a same-colored or

tography), perceptions of entire objects, positive afterimages (i.e., a same-colored or 
complementary-colored "shadow" of an object remaining after removal of the object), halos 
around objects, or misperception of images as too large (macropsia) or too small (micropsia). 
Duration of the visual disturbances may be episodic or nearly continuous and must cause 
clinically significant distress or impairment in social, occupational, or other important areas 
of functioning (Criterion B). The disturbances may last for weeks, months, or years. Other 
explanations for the disturbances (e.g., brain lesions, preexisting psychosis, seizure disor­
ders, migraine aura without headaches) must be ruled out (Criterion C).
Hallucinogen persisting perception disorder occurs primarily after LSD (lysergic acid 
diethylamide) use, but not exclusively. There does not appear to be a strong correlation be­

tween hallucinogen persisting perception disorder and number of occasions of hallucino­
gen use, with some instances of hallucinogen persisting perception disorder occurring in 
individuals with minimal exposure to hallucinogens. Some instances of hallucinogen per­
sisting perception disorder may be triggered by use of other substances (e.g., cannabis or 
alcohol) or in adaptation to dark environments.
Reality testing remains intact in individuals with hallucinogen persisting perception dis­
order (i.e., the individual is aware that the disturbance is linked to the effect of the drug). 
If this is not the case, another disorder might better explain the abnormal perceptions.

Prevalence estimates of hallucinogen persisting perception disorder are unknown. Initial 
prevalence estimates of the disorder among individuals who use hallucinogens is approx­
imately 4.2%.

Little is known about the development of hallucinogen persisting perception disorder. Its 
course, as suggested by its name, is persistent, lasting for weeks, months, or even years in 
certain individuals.
There is little evidence regarding risk factors for hallucinogen persisting perception dis­
order, although genetic factors have been suggested as a possible explanation underlying 
the susceptibility to LSD effects in this condition.
Haliucinogen Persisting Perception Disorder
Although hallucinogen persisting perception disorder remains a chronic condition in 
some cases, many individuals with the disorder are able to suppress the disturbances and 
continue to function normally.
Conditions to be ruled out include schizophrenia, other drug effects, neurodegenerative 
disorders, stroke, brain tumors, infections, and head trauma. Neuroimaging results in hal­

lucinogen persisting perception disorder cases are typically negative. As noted earlier, re­
ality testing remains intact (i.e., the individual is aware that the disturbance is linked to the 
effect of the drug); if this is not the case, another disorder (e.g., psychotic disorder, another 
medical condition) might better explain the abnormal perceptions.
Common comorbid mental disorders accompanying hallucinogen persisting perception 
disorder are panic disorder, alcohol use disorder, and major depressive disorder.
Other Phencyclidine-Induced Disorders
Other phencyclidine-induced disorders are described in other chapters of the manual with 
disorders with which they share phenomenology (see the substance/medication-induced

mental disorders in these chapters): phencyclidine-induced psychotic disorder ("Schizo­
phrenia Spectrum and Other Psychotic Disorders"); phencyclidine-induced bipolar dis­
order ("Bipolar and Related Disorders"); phencyclidine-induced depressive disorder 
("Depressive Disorders"); and phencyclidine-induced anxiety disorder ("Anxiety Disor­
ders"). For phencyclidine-induced intoxication delirium, see the criteria and discussion of 
delirium in the chapter "Neurocognitive Disorders." These phencyclidine-induced disor­
ders are diagnosed instead of phencyclidine intoxication only when the symptoms are suf­
Other Hallucinogen-Induced Disorders
The following other hallucinogen-induced disorders are described in other chapters of the

The following other hallucinogen-induced disorders are described in other chapters of the 
manual with disorders with which they share phenomenology (see the substance/medi­
cation-induced mental disorders in these chapters): other hallucinogen-induced psychotic 
disorder ("Schizophrenia Spectrum and Other Psychotic Disorders"); other hallucinogen- 
induced bipolar disorder ("Bipolar and Related Disorders"); other hallucinogen-induced

depressive disorder ("Depressive Disorders"); and other hallucinogen-induced anxiety 
disorder ("Anxiety Disorders"). For other hallucinogen intoxication delirium, see the cri­
teria and discussion of delirium in the chapter "Neurocognitive Disorders." These hallu­
cinogen-induced disorders are diagnosed instead of other hallucinogen intoxication only 
when the symptoms are sufficiently severe to warrant independent clinical attention.
Unspecified Phencyclidine-Related Disorder
292.9 (F16.99)
This category applies to presentations in  which symptoms characteristic of a phencycli­
dine-related disorder that cause clinically significant distress or impairment in social, oc­
cupational, or other important areas of functioning predominate but do not meet the full  
criteria for any specific phencyclidine-related disorder or any of the disorders in the sub­
stance-related and addictive disorders diagnostic class.

This category applies to presentations in which symptoms characteristic of a hallucinogen-  
for any specific hallucinogen-related disorder or any of the disorders in the substance-  
related and addictive disorders diagnostic class.
Inhalant-Related Disorders
Inhalant Use Disorder  
Inhalant Intoxication  
Other Inhalant-Induced Disorders  
Unspecified Inhalant-Related Disorder
Inhalant Use Disorder
A. A problematic pattern of use of a hydrocarbon-based inhalant substance leading to  

1. The inhalant substance is often taken in larger amounts or over a longer period than  
was intended.
2. There is a persistent desire or unsuccessful efforts to cut down or control use of the  
inhalant substance.

3. A great deal of time is spent in activities necessary to obtain the inhalant substance,  
use it, or recover from its effects.
4. Craving, or a strong desire or urge to use the inhalant substance.
5. Recurrent use of the inhalant substance resulting in a failure to fulfill major role ob­
ligations at work, school, or home.
6. Continued use of the inhalant substance despite having persistent or recurrent so­
cial or interpersonal problems caused or exacerbated by the effects of its use.
cause of use of the inhalant substance.
8. Recurrent use of the inhalant substance in  situations in which it is physically haz­
ardous.
9. Use of the inhalant substance is continued despite knowledge of having a persis­
tent or recurrent physical or psychological problem that is likely to have been  
caused or exacerbated by the substance.

a. A need for markedly increased amounts of the inhalant substance to achieve  
intoxication or desired effect.
b. A markedly diminished effect with continued use of the same amount of the in­
halant substance.
Specify  the particular inhalant: When possible, the particular substance involved should  
be named (e.g., “ solvent use disorder'’).
in early remission: After full criteria for inhalant use disorder were previously met,  
none of the criteria for inhalant use disorder have been met for at least 3 months but  
sire or urge to use the inhalant substance,”  may be met).
In sustained remission: After full criteria for inhalant use disorder were previously

In sustained remission: After full criteria for inhalant use disorder were previously  
met, none of the criteria for inhalant use disorder have been met at any time during a  
strong desire or urge to use the inhalant substance,”  may be met).
environment where access to inhalant substances is restricted.
Coding based on current severity: Note for ICD-10-CM codes: If an inhalant intoxication  
or another inhalant-induced mental disorder is also present, do not use the codes below  
for inhalant use disorder. Instead, the comorbid inhalant use disorder is indicated in the  
4th character of the inhalant-induced disorder code (see the coding note for inhalant intox­

ication or a specific inhalant-induced mental disorder). For example, if there is comorbid  
inhalant-induced depressive disorder and inhalant use disorder, only the inhalant-induced  
depressive disorder code is given, with the 4th character indicating whether the comorbid  
inhalant use disorder is mild, moderate, or severe: F18.14 for mild inhalant use disorder  
with inhalant-induced depressive disorder or FI 8.24 for a moderate or severe inhalant use  
disorder with inhalant-induced depressive disorder.
305.90 (F18.10) Mild: Presence of 2-3 symptoms.
304.60 (F18.20) lUloderate: Presence of 4-5 symptoms.
304.60 (FI 8.20) Severe: Presence of 6 or more symptoms.

This manual reà^gnizes volatile hydrocarbon use meeting the above diagnostic criteria as 
inhalant use disorder. Volatile hydrocarbons are toxic gases from glues, fuels, paints, and 
other volatile compounds. When possible, the particular substance involved should be 
named (e.g., "toluene use disorder"). However, most compounds that are inhaled are a 
mixture of several substances that can produce psychoactive effects, and it is often difficult 
to ascertain the exact substance responsible for the disorder. Unless there is clear evidence 
that a single, unmixed substance has been used, the general term inhalant should be used 
in recording the diagnosis. Disorders arising from inhalation of nitrous oxide or of amyl-, 
butyl-, or isobutylnitrite are considered as other (or unknown) substance use disorder.
"In a controlled environment" applies as a further specifier of remission if the individ­

ual is both in remission and in a controlled environment (i.e., in early remission in a con­
trolled environment or in sustained remission in a controlled environment). Examples of 
these environments are closely supervised and substance-free jails, therapeutic communi­
ties, and locked hospital units.
The severity of individuals' inhalant use disorder is assessed by the number of diag­
nostic criteria endorsed. Changing severity of individuals' inhalant use disorder across 
time is reflected by reductions in the frequency (e.g., days used per month) and/or dose 
(e.g., tubes of glue per day) used, as assessed by the individual's self-report, report of oth­
ers, clinician's observations, and biological testing (when practical).

Features of inhalant use disorder include repeated use of an inhalant substance despite the 
individual's knowing that the substance is causing serious problems for the individual 
(Criterion A9). Those problems are reflected in the diagnostic criteria.
Missing work or school or inability to perform t)^ical responsibilities at work or school 
(Criterion A5), and continued use of the inhalant substance even though it causes arguments 
with family or friends, fights, and other social or interpersonal problems (Criterion A6), may 
be seen in inhalant use disorder. Limiting family contact, work or school obligations, or rec­
reational activities (e.g., sports, games, hobbies) may also occur (Criterion A7). Use of inhal­
ants when driving or operating dangerous equipment (Criterion A8) is also seen.

Tolerance (Criterion AlO) and mild withdrawal are each reported by about 10% of in­
dividuals who use inhalants, and a few individuals use inhalants to avoid withdrawal. 
However, because the withdrawal symptoms are mild, this manual neither recognizes a 
diagnosis of inhalant withdrawal nor counts withdrawal complaints as a diagnostic crite­
rion for inhalant use disorder.
A diagnosis of inhalant use disorder is supported by recurring episodes of intoxication 
with negative results in standard drug screens (which do not detect inhalants); possession, 
or lingering odors, of inhalant substances; peri-oral or peri-nasal "glue-sniffer's rash"; as­
sociation with other individuals known to use inhalants; membership in groups with prev­

alent irüialant use (e.g., some native or aboriginal communities, homeless children in street 
gangs); easy access to certain inhalant substances; paraphernalia possession; presence of 
the disorder's characteristic medical complications (e.g., brain white matter pathology, 
rhabdomyolysis); and the presence of multiple substance use disorders. Inhalant use and 
inhalant use disorder are associated with past suicide attempts, especially among adults 
reporting previous episodes of low mood or anhedonia.
About 0.4% of Americans ages 12-17 years have a pattern of use that meets criteria for in­
halant use disorder in the past 12 months. Among those youths, the prevalence is highest

in Native Americans and lowest in African Americans. Prevalence falls to about 0.1% among 
Americans ages 18-29 years, and only 0.02% w ^hen all Americans 18 years or older are con­
sidered, v^ith almost no females and a preponderance of European Americans. Of course, 
in isolated subgroups, prevalence may differ considerably from these overall rates.
About 10% of 13-year-old American children report having used inhalants at least once; 
that percentage remains stable through age 17 years. Among those 12- to 17-year-olds who 
use inhalants, the more-used substances include glue, shoe polish, or toluene; gasoline or 
lighter fluid; or spray paints.
Only 0.4% of 12- to 17-year-olds progress to inhalant use disorder; those youths tend to 
exhibit multiple other problems. The declining prevalence of inhalant use disorder after 
adolescence indicates that this disorder usually remits in early adulthood.

Volatile hydrocarbon use disorder is rare in prepubertal children, most common in ad­
olescents and young adults, and uncommon in older persons. Calls to poison-control cen­
ters for ''intentional abuse" of inhalants peak with calls involving individuals at age 14 years. 
Of adolescents who use inhalants, perhaps one-fifth develop inhalant use disorder; a few 
die from inhalant-related accidents, or "sudden sniffing death". But the disorder apparently 
remits in many individuals after adolescence. Prevalence declines dramatically among in­
dividuals in their 20s. Those with inhalant use disorder extending into adulthood often 
have severe problems: substance use disorders, antisocial personality disorder, and sui­
cidal ideation with attempts.

Temperamental. Predictors of progression from nonuse of inhalants, to use, to inhalant 
use disorder include comorbid non-inhalant substance use disorders and either conduct 
disorder or antisocial personality disorder. Other predictors are earlier onset of inhalant 
use and prior use of mental health services.
Environmental. Inhalant gases are widely and legally available, increasing the risk of mis­
use. Childhood maltreatment or trauma also is associated with youthful progression from 
inhalant non-use to inhalant use disorder.
Genetic and physiological. Behavioral disinhihition  is a highly heritable general propensity 
to not constrain behavior in socially acceptable ways, to break social norms and rules, and to 
take dangerous risks, pursuing rewards excessively despite dangers of adverse consequences.

take dangerous risks, pursuing rewards excessively despite dangers of adverse consequences. 
Youths with strong behavioral disinhibition show risk factors for inhalant use disorder: early- 
onset substance use disorder, multiple substance involvement, and early conduct problems. 
Because behavioral disinhibition is under strong genetic influence, youths in families with 
substance and antisocial problems are at elevated risk for inhalant use disorder.
Certain native or aboriginal communities have experienced a high prevalence of inhalant 
problems. Also, in some countries, groups of homeless children in street gangs have ex­
tensive inhalant use problems.
Although the prevalence of inhalant use disorder is almost identical in adolescent males 
and females, the disorder is very rare among adult females.

Urine, breath, or saliva tests may be valuable for assessing concurrent use of non-inhalant 
substances by individuals with inhalant use disorder. However, technical problems and

the considerable expense of analyses make frequent biological testing for inhalants them­
selves impractic^al.
Functional Consequences of Inhalant Use Disorder
Because of inherent toxicity, use of butane or propane is not infrequently fatal. Moreover, 
any inhaled volatile hydrocarbons may produce "sudden sniffing death" from cardiac ar­
rhythmia. Fatalities may occur even on the first inhalant exposure and are not thought to 
be dose-related. Volatile hydrocarbon use impairs neurobehavioral function and causes 
various neurological, gastrointestinal, cardiovascular, and pulmonary problems.
Long-term inhalant users are at increased risk for tuberculosis, HIV /  AIDS, sexually 
transmitted diseases, depression, anxiety, bronchitis, asthma, and sinusitis. Deaths may 
occur from respiratory depression, arrhythmias, asphyxiation, aspiration of vomitus, or 
accident and injury.
Inhalant exposure (unintentional) from industrial or other accidents. This designation

Inhalant exposure (unintentional) from industrial or other accidents. This designation 
is used when findings suggest repeated or continuous inhalant exposure but the involved 
individual and other informants deny any history of purposeful inhalant use.
Inhalant use (intentional), without meeting criteria for inhalant use disorder. Inhalant use 
is common among adolescents, but for most of those individuals, the inhalant use does not 
meet the diagnostic standard of two or more Criterion A items for inhalant use disorder in 
the past year.
Inhalant intoxication, without meeting criteria for inhalant use disorder. Inhalant intox­
ication occurs frequently during inhalant use disorder but also may occur among individ­
uals whose use does not meet criteria for inhalant use disorder, which requires at least two 
of the 10 diagnostic criteria in the past year.
Inhalant-induced disorders (i.e., inhalant-induced psychotic disorder, depressive dis­

order, anxiety disorder, neurocognitive disorder, other inhalant-induced disorders)  
without meeting criteria for inhalant use disorder. Criteria are met for a psychotic, de­
pressive, anxiety, or major neurocognitive disorder, and there is evidence from history, 
physical examination, or laboratory findings that the deficits are etiologically related to 
the effects of inhalant substances. Yet, criteria for inhalant use disorder may not be met 
(i.e., fewer than 2 of the 10 criteria were present).
Other substance use disorders, especially those involving sedating substances (e.g.,  
alcohol, benzodiazepines, barbiturates). Inhalant use disorder commonly co-occurs 
with other substance use disorders, and the symptoms of the disorders may be similar and 
overlapping. To disentangle symptom patterns, it is helpful to inquire about which symp­

toms persisted during periods when some of the substances were not being used.
Other toxic, metabolic, traumatic, neoplastic, or infectious disorders impairing central or  
peripheral nervous system function. Individuals with inhalant use disorder may pre­
sent with symptoms of pernicious anemia, subacute combined degeneration of the spinal 
cord, psychosis, major or minor cognitive disorder, brain atrophy, leukoencephalopathy, 
and many other nervous system disorders. Of course, these disorders also may occur in 
the absence of inhalant use disorder. A history of little or no inhalant use helps to exclude 
inhalant use disorder as the source of these problems.
Disorders of other organ systems. Individuals with inhalant use disorder may present

Disorders of other organ systems. Individuals with inhalant use disorder may present 
with symptoms of hepatic or renal damage, rhabdomyolysis, methemoglobinemia, or symp­
toms of other gastrointestinal, cardiovascular, or pulmonary diseases. A history of little or no 
inhalant use helps to exclude inhalant use disorder as the source of such medical problems.

Individuals with inhalant use disorder receiving clinical care often have numerous other 
substance use disorders. Inhalant use disorder commonly co-occurs with adolescent con­
duct disorder and adult antisocial personality disorder. Adult inhalant use and inhalant 
use disorder also are strongly associated with suicidal ideation and suicide attempts.
Inhalant Intoxication
A. Recent intended or unintended short-term, high-dose exposure to inhalant sub­
stances, including volatile hydrocarbons such as toluene or gasoline.
B. Clinically significant problematic behavioral or psychological changes (e.g., belliger­
ence, assaultiveness, apathy, impaired judgment) that developed during, or shortly af­
ter, exposure to inhalants.
C. Two (or more) of the following signs or symptoms developing during, or shortly after,  
inhalant use or exposure:
1. Dizziness.
2. Nystagmus.
3. Incoordination.
4. Slurred speech.
5. Unsteady gait.
6. Lethargy.

7. Depressed reflexes.
8. Psychomotor retardation.
9. Tremor.
10. Generalized muscle weakness.
11. Blurred vision or diplopia.
12. Stupor or coma.
13. Euphoria.
there is a comorbid inhalant use disorder. If a mild inhalant use disorder is comorbid, the  
ICD-10-CM code is F18.129, and if a moderate or severe inhalant use disorder is comor­
bid, the ICD-10-CM code is F18.229. If there is no comorbid inhalant use disorder, then  
the ICD-10-CM code is FI 8.929. ____________________________________________
Note: For information on Development and Course, Risk and Prognostic Factors, Culture-

Note: For information on Development and Course, Risk and Prognostic Factors, Culture- 
Related Diagnostic Issues, and Diagnostic Markers, see the corresponding sections in in­
halant use disorder.
Inhalant intoxication is an inhalant-related, clinically significant mental disorder that de­
velops during, or immediately after, intended or unintended inhalation of a volatile hy­
drocarbon substance. Volatile hydrocarbons are toxic gases from glues, fuels, paints, and 
other volatile compounds. When it is possible to do so, the particular substance involved 
should be named (e.g., toluene intoxication). Among those who do, the intoxication clears 
within a few minutes to a few hours after the exposure ends. Thus, inhalant intoxication 
usually occurs in brief episodes that may recur.

Inhalant intoxicàtion may be indicated by evidence of possession, or lingering odors, of in­
halant substances (e.g., glue, paint thinner, gasoline, butane lighters); apparent intoxica­
tion occurring in the age range with the highest prevalence of inhalant use (12-17 years); 
and apparent intoxication with negative results from the standard drug screens that usu­
ally fail to identify inhalants.
The prevalence of actual episodes of inhalant intoxication in the general population is un­
known, but it is probable that most inhalant users would at some time exhibit use that 
would meet criteria for inhalant intoxication disorder. Therefore, the prevalence of inhal­
ant use and the prevalence of inhalant intoxication disorder are likely similar. In 2009 and 
2010, inhalant use in the past year was reported by 0.8% of all Americans older than 12 years;

2010, inhalant use in the past year was reported by 0.8% of all Americans older than 12 years; 
the prevalence was highest in younger age groups (3.6% for individuals 12 to 17 years old, 
and 1.7% for individuals 18 to 25 years old).
Gender differences in the prevalence of inhalant intoxication in the general population are 
unknown. However, if it is assumed that most inhalant users eventually experience inhal­
ant intoxication, gender differences in the prevalence of inhalant users  likely approximate 
those in the proportions of males and females experiencing inhalant intoxication. Regard­
ing gender differences in the prevalence of inhalant users in the United States, 1% of males 
older than 12 years and 0.7% of females older than 12 years have used inhalants in the pre­
vious year, but in the younger age groups more females than males have used inhalants

vious year, but in the younger age groups more females than males have used inhalants 
(e.g., among 12- to 17-year-olds, 3.6% of males and 4.2% of females).
Functional Consequences of inhalant intoxication
Use of inhaled substances in a closed container, such as a plastic bag over the head, may 
lead to unconsciousness, anoxia, and death. Separately, "sudden sniffing death," likely 
from cardiac arrhythmia or arrest, may occur with various volatile inhalants. The en­
hanced toxicity of certain volatile inhalants, such as butane or propane, also causes fatal­
ities. Although inhalant intoxication itself is of short duration, it may produce persisting 
medical and neurological problems, especially if the intoxications are frequent.
Inhalant exposure, without meeting the criteria for inhalant intoxication disorder.

The individual intentionally or unintentionally inhaled substances, but the dose was in­
sufficient for the diagnostic criteria for inhalant use disorder to be met.
Intoxication and other substance/medication-induced disorders from other sub­
stances, especially from sedating substances (e.g., alcohol, benzodiazepines, barbi­
turates). These disorders may have similar signs and symptoms, but the intoxication is 
attributable to other intoxicants that may be identified via a toxicology screen. Differenti­
ating the source of the intoxication may involve discerning evidence of inhalant exposure 
as described for inhalant use disorder. A diagnosis of inhalant intoxication may be sug­
gested by possession, or lingering odors, of inhalant substances (e.g., glue, paint thinner,

gested by possession, or lingering odors, of inhalant substances (e.g., glue, paint thinner, 
gasoline, butane lighters,); paraphernalia possession (e.g., rags or bags for concentrating 
glue fumes); perioral or perinasal "glue-sniffer's rash"; reports from family or friends that 
the intoxicated individual possesses or uses inhalants; apparent intoxication despite neg- 
ahve results on standard drug screens (which usually fail to identify inhalants); apparent 
intoxication occurring in that age range with the highest prevalence of inhalant use (12-17

years); association with others known to use inhalants; membership in certain small com­
munities with prevalent inhalant use (e.g., some native or aboriginal communities, home­
less street children and adolescents); or unusual access to certain inhalant substances.
Other inhalant-related disorders. Episodes of inhalant intoxication do occur during, 
but are not identical with, other inhalant-related disorders. Those inhalant-related disorders 
are recognized by their respective diagnostic criteria: inhalant use disorder, inhalant- 
induced neurocognitive disorder, inhalant-induced psychotic disorder, inhalant-induced 
depressive disorder, inhalant-induced anxiety disorder, and other inhalant-induced dis­
orders.
Other toxic, metabolic, traumatic, neoplastic, or infectious disorders that impair brain  
function and cognition. Numerous neurological and other medical conditions may pro­
duce the clinically significant behavioral or psychological changes (e.g., belligerence, as­

saultiveness, apathy, impaired judgment) that also characterize inhalant intoxication.
Other Inhalant-Induced Disorders
The following inhalant-induced disorders are described in other chapters of the manual 
induced mental disorders in these chapters): inhalant-induced psychotic disorder ("Schizo­
phrenia Spectrum and Other Psychotic Disorders"); inhalant-induced depressive disorder 
("Depressive Disorders"); inhalant-induced anxiety disorder ("Anxiety Disorders"); and in­
halant-induced major or mild neurocognitive disorder ("Neurocognitive Disorders"). For 
inhalant intoxication delirium, see the criteria and discussion of delirium in the chapter

inhalant intoxication delirium, see the criteria and discussion of delirium in the chapter 
"Neurocognitive Disorders." These inhalant-induced disorders are diagnosed instead of in­
halant intoxication only when symptoms are sufficiently severe to warrant independent 
clinical attention.
292.9 (F18.99)
This category applies to presentations in wliich symptoms characteristic of an inhalant-  
for any specific inhalant-related disorder or any of the disorders in the substance-related  
Opioid-Related Disorders
Opioid Use Disorder  
Opioid Intoxication  
Opioid Withdrawai  
Other Opioid-induced Disorders

Other Opioid-induced Disorders  
Unspecified Opioid-Reiated Disorder

Opioid Use Disorder
_________________________________ \ —
A. A problematic pattern of opioid use leading to clinically significant impairment or distress,  
as manifested by at least two of the following, occurring within a 12-month period:
1. Opioids are often taken in larger amounts or over a longer period than was in­
tended.
2. There is a persistent desire or unsuccessful efforts to cut down or control opioid use.
3. A great deal of time is spent in activities necessary to obtain the opioid, use the opi­
oid, or recover from its effects.
4. Craving, or a strong desire or urge to use opioids.
5. Recurrent opioid use resulting in a failure to fulfill major role obligations at work,  
6. Continued opioid use despite having persistent or recurrent social or interpersonal  
problems caused or exacerbated by the effects of opioids.
cause of opioid use.

8. Recurrent opioid use in situations in which it is physically hazardous.
9. Continued opioid use despite knowledge of having a persistent or recurrent physi­
cal or psychological problem that is likely to have been caused or exacerbated by  
the substance.
a. A need for markedly increased amounts of opioids to achieve intoxication or de­
b. A markedly diminished effect with continued use of the same amount of an opioid.
Note: This criterion is not considered to be met for those taking opioids solely under  
appropriate medical supervision.
a. The characteristic opioid withdrawal syndrome (refer to Criteria A and B of the  
criteria set for opioid withdrawal, pp. 547-548).

b. Opioids (or a closely related substance) are taken to relieve or avoid withdrawal  
symptoms.
Note: This criterion is not considered to be met for those individuals taking opioids  
solely under appropriate medical supervision.
In early remission: After full criteria for opioid use disorder were previously met, none  
of the criteria for opioid use disorder have been met for at least 3 months but for less  
than 12 months (with the exception that Criterion A4, “ Craving, or a strong desire or  
urge to use opioids,”  may be met).
In sustained remission: After full criteria for opioid use disorder were previously met,  
none of the criteria for opioid use disorder have been met at any time during a period

none of the criteria for opioid use disorder have been met at any time during a period  
of 12 months or longer (with the exception that Criterion A4, “ Craving, or a strong de­
sire or urge to use opioids,”  may be met).
On maintenance therapy: This additional specifier is used if the individual is taking a  
prescribed agonist medication such as methadone or buprenorphine and none of the  
criteria for opioid use disorder have been met for that class of medication (except tol­
erance to, or withdrawal from, the agonist). This category also applies to those Individ­

uals being maintained on a partial agonist, an agonist/antagonist, or a full antagonist  
such as oral naltrexone or depot naltrexone.
environment where access to opioids is restricted.
Coding based on current severity: Note for ICD-10-CM codes: If an opioid intoxication,  
opioid withdrawal, or another opioid-induced mental disorder is also present, do not use  
the codes below for opioid use disorder. Instead, the comorbid opioid use disorder is indi­
cated in the 4th character of the opioid-induced disorder code (see the coding note for opi­
oid intoxication, opioid withdrawal, or a specific opioid-induced mental disorder). For  
example, if there is comorbid opioid-induced depressive disorder and opioid use disorder,  
only the opioid-induced depressive disorder code is given, with the 4th character indicating

only the opioid-induced depressive disorder code is given, with the 4th character indicating  
whether the comorbid opioid use disorder is mild, moderate, or severe: F11.14 for mild opi­
oid use disorder with opioid-induced depressive disorder or F11.24 for a moderate or se­
vere opioid use disorder with opioid-induced depressive disorder.
305.50 (F11.10) Mild: Presence of 2 -3  symptoms.
304.00 (F11.20) Moderate: Presence of 4-5 symptoms.
304.00 (F11.20) Severe: Presence of 6 or more symptoms.
The "on maintenance therapy" specifier applies as a further specifier of remission if the in­
dividual is both in remission and receiving maintenance therapy. "In a controlled environ­
ment" applies as a further specifier of remission if the individual is both in renüssion and in

ment" applies as a further specifier of remission if the individual is both in renüssion and in 
a controlled environment (i.e., in early remission in a controlled environment or in sustained 
remission in a controlled environment). Examples of these environments are closely super­
vised and substance-free jails, therapeutic communities, and locked hospital units.
Changing severity across time in an individual is also reflected by reductions in the fre­
quency (e.g., days of use per month) and/or dose (e.g., injections or number of pills) of an 
opioid, as assessed by the individual's self-report, report of knowledgeable others, clini­
cian's observations, and biological testing.
Opioid use disorder includes signs and symptoms that reflect compulsive, prolonged self­
administration of opioid substances that are used for no legitimate medical purpose or, if

administration of opioid substances that are used for no legitimate medical purpose or, if 
another medical condition is present that requires opioid treatment, that are used in doses 
greatly in excess of the amount needed for that medical condition. (For example, an indi­
vidual prescribed analgesic opioids for pain relief at adequate dosing will use significantly 
more than prescribed and not only because of persistent pain.) Individuals with opioid use 
disorder tend to develop such regular patterns of compulsive drug use that daily activities 
are planned around obtaining and administering opioids. Opioids are usually purchased 
on the illegal market but may also be obtained from physicians by falsifying or exagger­
ating general medical problems or by receiving simultaneous prescriptions from several

ating general medical problems or by receiving simultaneous prescriptions from several 
physicians. Health care professionals with opioid use disorder will often obtain opioids by 
writing prescriptions for themselves or by diverting opioids that have been prescribed for 
patients or from pharmacy supplies. Most individuals with opioid use disorder have 
significant levels of tolerance and will experience withdrawal on abrupt discontinuation 
of opioid substances. Individuals with opioid use disorder often develop conditioned 
responses to drug-related stimuli (e.g., craving on seeing any heroin powder-like sub­
stance)—a phenomenon that occurs with most drugs that cause intense psychological 
changes. These responses probably contribute to relapse, are difficult to extinguish, and typ­
ically persist long after detoxification is completed.

Opioid use disoMer can be associated with a history of drug-related crimes (e.g., posses­
sion or distribution of drugs, forgery, burglary, robbery, larceny, receiving stolen goods). 
Among health care professionals and individuals who have ready access to controlled 
substances, there is often a different pattern of illegal activities involving problems with 
state licensing boards, professional staffs of hospitals, or other administrative agencies. 
Marital difficulties (including divorce), unemployment, and irregular employment are of­
ten associated with opioid use disorder at all socioeconomic levels.
The 12-month prevalence of opioid use disorder is approximately 0.37% among adults age 
18 years and older in the community population. This may be an underestimate because of 
the large number of incarcerated individuals with opioid use disorders. Rates are higher in

the large number of incarcerated individuals with opioid use disorders. Rates are higher in 
males than in females (0.49% vs. 0.26%), with the male-to-female ratio typically being 1.5:1 
for opioids other than heroin (i.e., available by prescription) and 3:1 for heroin. Female ad­
olescents may have a higher likelihood of developing opioid use disorders. The preva­
lence decreases with age, with the prevalence highest (0.82%) among adults age 29 years or 
younger, and decreasing to 0.09% among adults age 65 years and older. Among adults, the 
prevalence of opioid use disorder is lower among African Americans at 0.18% and over­
represented among Native Americans at 1.25%. It is close to average among whites (0.38%), 
Asian or Pacific Islanders (0.35%), and Hispanics (0.39%).
Among individuals in the United States ages 12-17 years, the overall 12-month prev­

alence of opioid use disorder in the community population is approximately 1.0%, but the 
prevalence of heroin use disorder is less than 0.1%. By contrast, analgesic use disorder is 
prevalent in about 1.0% of those ages 12-17 years, speaking to the importance of opioid an­
algesics as a group of substances with significant health consequences.
The 12-month prevalence of problem opioid use in European countries in the commu­
nity population ages 15-64 years is between 0.1% and 0.8%. The average prevalence of 
problem opioid use in the European Union and Norway is between 0.36% and 0.44%.
Opioid use disorder can begin at any age, but problems associated with opioid use are 
most commonly first observed in the late teens or early 20s. Once opioid use disorder

most commonly first observed in the late teens or early 20s. Once opioid use disorder 
develops, it usually continues over a period of many years, even though brief periods of 
abstinence are frequent. In treated populations, relapse following abstinence is common. 
Even though relapses do occur, and while some long-term mortality rates may be as high 
as 2% per year, about 20%-30% of individuals with opioid use disorder achieve long-term 
abstinence. An exception concerns that of military service personnel who became depen­
dent on opioids in Vietnam; over 90% of this population who had been dependent on opi­
oids during deployment in Vietnam achieved abstinence after they returned, but they 
experienced increased rates of alcohol or amphetamine use disorder as well as increased 
suicidality.

Increasing age is associated with a decrease in prevalence as a result of early mortality 
and the remission of symptoms after age 40 years (i.e., "maturing out"). However, many 
individuals continue have presentations that meet opioid use disorder criteria for decades.
Genetic and physiological. The risk for opiate use disorder can be related to individual, 
family, peer, and social environmental factors, but within these domains, genetic factors 
play a particularly important role both directly and indirectly. For instance, impulsivity 
and novelty seeking are individual temperaments that relate to the propensity to develop

a substance use disorder but may themselves be genetically determined. Peer factors may 
relate to genetic predisposition in terms of how an individual selects his or her environ­
ment.
Despite small variations regarding individual criterion items, opioid use disorder diag­
nostic criteria perform equally well across most race/ethnicity groups. Individuals from 
ethnic minority populations living in economically deprived areas have been overrep­
resented among individuals with opioid use disorder. However, over time, opioid use 
disorder is seen more often among white middle-class individuals, especially females, 
suggesting that differences in use reflect the availability of opioid drugs and that other so­
cial factors may impact prevalence. Medical personnel who have ready access to opioids 
may be at increased risk for opioid use disorder.

Routine urine toxicology test results are often positive for opioid drugs in individuals with 
opioid use disorder. Urine test results remain positive for most opioids (e.g., heroin, mor­
phine, codeine, oxycodone, propoxyphene) for 12-36 hours after administration. Fentanyl 
is not detected by standard urine tests but can be identified by more specialized proce­
dures for several days. Methadone, buprenorphine (or buprenorphine/naloxone combi­
nation), and LA AM (L-alpha-acetylmethadol) have to be specifically tested for and will not 
cause a positive result on routine tests for opiates. They can be detected for several days up 
to more than 1  week. Laboratory evidence of the presence of other substances (e.g., co­
caine, marijuana, alcohol, amphetamines, benzodiazepines) is common. Screening test re­

sults for hepatitis A, B, and C virus are positive in as many as 80%-90% of injection opioid 
users, either for hepatitis antigen (signifying active infection) or for hepatitis antibody (sig­
nifying past infection). HIV is prevalent in injection opioid users as well. Mildly elevated 
liver function test results are common, either as a result of resolving hepatitis or from toxic 
injury to the liver due to contaminants that have been mixed with the injected opioid. Sub­
tle changes in cortisol secretion patterns and body temperature regulation have been ob­
served for up to 6 months following opioid detoxification.
Similar to the risk generally observed for all substance use disorders, opioid use disorder 
is associated with a heightened risk for suicide attempts and completed suicides. Particu­

larly notable are both accidental and deliberate opioid overdoses. Some suicide risk factors 
overlap with risk factors for an opioid use disorder. In addition, repeated opioid intoxica­
tion or withdrawal may be associated with severe depressions that, although temporary, 
can be intense enough to lead to suicide attempts and completed suicides. Available data 
suggest that nonfatal accidental opioid overdose (which is common) and attempted sui­
cide are distinct clinically significant problems that should not be mistaken for each other.
Functional Consequences of Opioid Use Disorder
Opioid use is associated with a lack of mucous membrane secretions, causing dry mouth 
and nose. Slowing of gastrointestinal activity and a decrease in gut motility can produce

and nose. Slowing of gastrointestinal activity and a decrease in gut motility can produce 
severe constipation. Visual acuity may be impaired as a result of pupillary constriction 
with acute administration. In individuals who inject opioids, sclerosed veins ("tracks") 
and puncture marks on the lower portions of the upper extremities are common. Veins 
sometimes become so severely sclerosed that peripheral edema develops, and individuals 
switch to injecting in veins in the legs, neck, or groin. When these veins become unusable, 
individuals often inject directly into their subcutaneous tissue ("skin-popping"), resulting

in cellulitis, abscesses, and circular-appearing scars from healed skin lesions. Tetanus and 
Clostridium botulinum  infections are relatively rare but extremely serious consequences of 
injecting opioids, especially with contaminated needles. Infections may also occur in other 
organs and include bacterial endocarditis, hepatitis, and HIV infection. Hepatitis C infec­
tions, for example, may occur in up to 90% of persons who inject opioids. In addition, the 
prevalence of HIV infection can be high among individuals who inject drugs, a large pro­
portion of whom are individuals with opioid use disorder. HIV infection rates have been 
reported to be as high as 60% among heroin users with opioid use disorder in some areas 
of the United States or the Russian Federation. However, the incidence may also be 10% or 
less in other areas, especially those where access to clean injection material and parapher­
nalia is facilitated.

Tuberculosis is a particularly serious problem among individuals who use drugs in­
travenously, especially those who are dependent on heroin; infection is usually asymptom­
atic and evident only by the presence of a positive tuberculin skin test. However, many cases 
of active tuberculosis have been found, especially among those who are infected with HIV. 
These individuals often have a newly acquired infection but also are likely to experience 
reactivation of a prior infection because of impaired immune function.
Individuals who sniff heroin or other opioids into the nose ("snorting") often develop 
irritation of the nasal mucosa, sometimes accompanied by perforation of the nasal septum. 
Difficulties in sexual functioning are cormnon. Males often experience erectile dysfunction 
during intoxication or chronic use. Females commonly have disturbances of reproductive

during intoxication or chronic use. Females commonly have disturbances of reproductive 
function and irregular menses.
In relation to infections such as cellulitis, hepatitis, HIV infection, tuberculosis, and en­
docarditis, opioid use disorder is associated with a mortality rate as high as 1.5%-2% per 
year. Death most often results from overdose, accidents, injuries, AIDS, or other general 
medical complications. Accidents and injuries due to violence that is associated with buy­
ing or selling drugs are common. In some areas, violence accounts for more opioid-related 
deaths than overdose or HIV infection. Physiological dependence on opioids may occur in 
about half of the infants born to females with opioid use disorder; this can produce a se­
vere withdrawal syndrome requiring medical treatment. Although low birth weight is

vere withdrawal syndrome requiring medical treatment. Although low birth weight is 
also seen in children of mothers with opioid use disorder, it is usually not marked and is 
generally not associated with serious adverse consequences.
Opioid-induced mental disorders. Opioid-induced disorders occur frequently in individ­
uals with opioid use disorder. Opioid-induced disorders may be characterized by symptoms 
(e.g., depressed mood) that resemble primary mental disorders (e.g., persistent depressive dis­
order [dysthymia] vs. opioid-induced depressive disorder, with depressive features, with on­
set during intoxication). Opioids are less likely to produce symptoms of mental disturbance 
than are most other drugs of abuse. Opioid intoxication and opioid withdrawal are distin­
guished from the other opioid-induced disorders (e.g., opioid-induced depressive disorder,

guished from the other opioid-induced disorders (e.g., opioid-induced depressive disorder, 
with onset during intoxication) because the symptoms in these latter disorders predominate 
the clinical presentation and are severe enough to warrant independent clinical attention.
Other substance intoxication. Alcohol intoxication and sedative, hypnotic, or anxiolytic 
intoxication can cause a clinical picture that resembles that for opioid intoxication. A diag­
nosis of alcohol or sedative, hypnotic, or anxiolytic intoxication can usually be made based 
on the absence of pupillary constriction or the lack of a response to naloxone challenge. In 
some cases, intoxication may be due both to opioids and to alcohol or other sedatives. In 
these cases, the naloxone challenge will not reverse all of the sedative effects.
Other withdrawal disorders. The anxiety and restlessness associated with opioid with­

drawal resemble symptoms seen in sedative-hypnotic withdrawal. However, opioid 
withdrawal is also accompanied by rhinorrhea, lacrimation, and pupillary dilation, which

are not seen in sedative-type withdrav^al. Dilated pupils are also seen in hallucinogen 
intoxication and stimulant intoxication. However, other signs or symptoms of opioid 
withdrav^al, such as nausea, vomiting, diarrhea, abdominal cramps, rhinorrhea, or lacri­
ma tion, are not present.
The most common medical conditions associated v/ith  opioid use disorder are viral (e.g., 
HIV, hepatitis C virus) and bacterial infections, particularly among users of opioids by in­
jection. These infections are less common in opioid use disorder v^ith prescription opioids. 
Opioid use disorder is often associated w ^ ith  other substance use disorders, especially those 
involving tobacco, alcohol, cannabis, stimulants, and benzodiazepines, which are often 
taken to reduce symptoms of opioid withdrawal or craving for opioids, or to enhance the ef­
fects of administered opioids. Individuals with opioid use disorder are at risk for the devel­

opment of mild to moderate depression that meets symptomatic and duration criteria for 
persistent depressive disorder (dysthymia) or, in some cases, for major depressive disorder. 
These symptoms may represent an opioid-induced depressive disorder or an exacerbation 
of a preexisting primary depressive disorder. Periods of depression are especially common 
during chronic intoxication or in association with physical or psychosocial stressors that are 
related to the opioid use disorder. Insomnia is common, especially during withdrawal. An­
tisocial personality disorder is much more common in individuals with opioid use disorder 
than in the general population. Posttraumatic stress disorder is also seen with increased fre­

quency. A history of conduct disorder in childhood or adolescence has been identified as a 
significant risk factor for substance-related disorders, especially opioid use disorder.
Opioid Intoxication
A. Recent use of an opioid.
B. Clinically significant problematic behavioral or psychological changes (e.g., initial eu­
phoria followed by apathy, dysphoria, psychomotor agitation or retardation, impaired  
judgment) that developed during, or shortly after, opioid use.
C. Pupillary constriction (or pupillary dilation due to anoxia from severe overdose) and  
one (or more) of the following signs or symptoms developing during, or shortly after,  
opioid use:
1. Drowsiness or coma.
2. Slurred speech.
3. Impairment in attention or memory.

stance.
With perceptual disturbances: This specifier may be noted in the rare instance in  
which hallucinations with intact reality testing or auditory, visual, or tactile illusions oc­
cur in the absence of a delirium.
or not there is a comorbid opioid use disorder and whether or not there are perceptual dis­
turbances.
For opioid intoxication without perceptual disturbances: If a mild opioid use dis­
order is comorbid, the ICD-10-CM code is F11.129, and if a moderate or severe opioid

use disorder is comorbid, the ICD-10-CM code is F11.229. If there is no comorbid opi­
oid use disorder, then the ICD-10-CM code is F11.929.\
For opioid intoxication with perceptual disturbances: If a mild opioid use disorder  
is comorbid, the ICD-10-CM code is F11.122, and if a moderate or severe opioid use  
disorder is comorbid, the ICD-10-CM code is F11.222. If there is no comorbid opioid  
use disorder, then the ICD-10-CM code is F11.922.
The essential feature of opioid intoxication is the presence of clinically significant prob­
lematic behavioral or psychological changes (e.g., initial euphoria followed by apathy, 
dysphoria, psychomotor agitation or retardation, impaired judgment) that develop dur­
ing, or shortly after, opioid use (Criteria A and B). Intoxication is accompanied by pupil­
lary constriction (unless there has been a severe overdose with consequent anoxia and

lary constriction (unless there has been a severe overdose with consequent anoxia and 
pupillary dilation) and one or more of the following signs: drowsiness (described as be­
ing "on the nod"), slurred speech, and impairment in attention or memory (Criterion C); 
drowsiness may progress to coma. Individuals with opioid intoxication may demonstrate 
inattention to the environment, even to the point of ignoring potentially harmful events. 
The signs or symptoms must not be attributable to another medical condition and are not 
better explained by another mental disorder (Criterion D).
Other substance intoxication. Alcohol intoxication and sedative-hypnotic intoxication 
can cause a clinical picture that resembles opioid intoxication. A diagnosis of alcohol or 
sedative-hypnotic intoxication can usually be made based on the absence of pupillary con­

striction or the lack of a response to a naloxone challenge. In some cases, intoxication may 
be due both to opioids and to alcohol or other sedatives. In these cases, the naloxone chal­
lenge will not reverse all of the sedative effects.
Other opioid-related disorders. Opioid intoxication is distinguished from the other 
opioid-induced disorders (e.g., opioid-induced depressive disorder, with onset during in­
toxication) because the symptoms in the latter disorders predominate in the clinical pre­
sentation and meet full criteria for the relevant disorder.
Opioid Withdrawal
Diagnostic Criteria 292.0 (F11.23)
A. Presence of either of the following;
1. Cessation of (or reduction in) opioid use that has been heavy and prolonged (i.e.,  
several weeks or longer).

2. Administration of an opioid antagonist after a period of opioid use.
B. Three (or more) of the following developing within minutes to several days after Criterion A:
1. Dysphoric mood.
2. Nausea or vomiting.
3. Muscle aches.
4. Lacrimation or rhinorrhea.
5. Pupillary dilation, piloerection, or sweating.

6. Diarrhea.
7. Yawning.
8. Fever.
9. Insomnia.
Coding note: The ICD-9-CM code is 292.0. The ICD-10-CM code for opioid withdrawal is  
F11.23. Note that the ICD-10-CM code indicates the comorbid presence of a moderate or  
severe opioid use disorder, reflecting the fact that opioid withdrawal can only occur in the  
presence of a moderate or severe opioid use disorder. It is not permissible to code a co­
morbid mild opioid use disorder with opioid withdrawal.
The essential feature of opioid withdrawal is the presence of a characteristic withdrawal

The essential feature of opioid withdrawal is the presence of a characteristic withdrawal 
syndrome that develops after the cessation of (or reduction in) opioid use that has been 
heavy and prolonged (Criterion Al). The withdrawal syndrome can also be precipitated 
by administration of an opioid antagonist (e.g., naloxone or naltrexone) after a period of 
opioid use (Criterion A2). This may also occur after administration of an opioid partial ag­
onist such as buprenorphine to a person currently using a full opioid agonist.
Opioid withdrawal is characterized by a pattern of signs and symptoms that are oppo­
site to the acute agonist effects. The first of these are subjective and consist of complaints of 
anxiety, restlessness, and an "achy feeling" that is often located in the back and legs, along 
with irritability and increased sensitivity to pain. Three or more of the following must be

with irritability and increased sensitivity to pain. Three or more of the following must be 
present to make a diagnosis of opioid withdrawal: dysphoric mood; nausea or vomiting; 
muscle aches; lacrimation or rhinorrhea; pupillary dilation, piloerection, or increased 
sweating; diarrhea; yawning; fever; and insonmia (Criterion B). Piloerection and fever are 
associated with more severe withdrawal and are not often seen in routine clinical practice 
because individuals with opioid use disorder usually obtain substances before with­
drawal becomes that far advanced. These symptoms of opioid withdrawal must cause 
eas of functioning (Criterion C). The symptoms must not be attributable to another med­
ical condition and are not better explained by another mental disorder (Criterion D).

ical condition and are not better explained by another mental disorder (Criterion D). 
Meeting diagnostic criteria for opioid withdrawal alone is not sufficient for a diagnosis of 
opioid use disorder, but concurrent symptoms of craving and drug-seeking behavior are 
suggestive of comorbid opioid use disorder. ICD-IO-CM codes only allow a diagnosis of 
opioid withdrawal in the presence of comorbid moderate to severe opioid use disorder.
The speed and severity of withdrawal associated with opioids depend on the half-life of 
the opioid used. Most individuals who are physiologically dependent on short-acting drugs 
such as heroin begin to have withdrawal symptoms within 6-12 hours after the last dose. 
Symptoms may take 2-4 days to emerge in the case of longer-acting drugs such as metha­
done, LAAM (L-alpha-acetylmethadol), or buprenorphine. Acute withdrawal symptoms for

done, LAAM (L-alpha-acetylmethadol), or buprenorphine. Acute withdrawal symptoms for 
a short-acting opioid such as heroin usually peak within 1-3 days and gradually subside 
over a period of 5-7 days. Less acute withdrawal symptoms can last for weeks to months. 
These more chronic symptoms include anxiety, dysphoria, anhedonia, and insomnia.

Males with opioid withdrawal may experience piloerection, sweating, and spontaneous 
ejaculations while awake. Opioid withdrawal is distinct from opioid use disorder and 
does not necessarily occur in the presence of the drug-seeking behavior associated with 
opioid use disorder. Opioid withdrawal may occur in any individual after cessation of re­
peated use of an opioid, whether in the setting of medical management of pain, during 
opioid agonist therapy for opioid use disorder, in the context of private recreational use, or 
following attempts to self-treat symptoms of mental disorders with opioids.
Among individuals from various clinical settings, opioid withdrawal occurred in 60% of 
individuals who had used heroin at least once in the prior 12 months.
Opioid withdrawal is typical in the course of an opioid use disorder. It can be part of an es­

calating pattern in which an opioid is used to reduce withdrawal symptoms, in turn lead­
ing to more withdrawal at a later time. For persons with an established opioid use 
disorder, withdrawal and attempts to relieve withdrawal are typical.
drawal resemble symptoms seen in sedative-hypnotic withdrawal. However, opioid with­
drawal is also accompanied by rhinorrhea, lacrimation, and pupillary dilation, which are 
not seen in sedative-type withdrawal.
Other substance intoxication. Dilated pupils are also seen in hallucinogen intoxication 
and stimulant intoxication. However, other signs or symptoms of opioid withdrawal, such

and stimulant intoxication. However, other signs or symptoms of opioid withdrawal, such 
as nausea, vomiting, diarrhea, abdominal cramps, rhinorrhea, and lacrimation, are not 
present.
Other opioid-induced disorders. Opioid withdrawal is distinguished from the other 
opioid-induced disorders (e.g., opioid-induced depressive disorder, with onset during 
withdrawal) because the symptoms in these latter disorders are in excess of those usually 
associated with opioid withdrawal and meet full criteria for the relevant disorder.
Other Opioid-Induced Disorders
The following opioid-induced disorders are described in other chapters of the manual with 
mental disorders in these chapters): opioid-induced depressive disorder ("Depressive Dis­

orders"); opioid-induced anxiety disorder ("Anxiety Disorders"); opioid-induced sleep 
disorder ("Sleep-Wake Disorders"); and opioid-induced sexual dysfunction ("Sexual Dys­
functions"). For opioid intoxication delirium and opioid withdrawal delirium, see the crite­
ria and discussion of delirium in the chapter "Neurocognitive Disorders." These opioid- 
induced disorders are diagnosed instead of opioid intoxication or opioid withdrawal only 

Unspecified Opioid-Related Disorder
292.9 (F11.99)
This category applies to presentations in  which symptoms characteristic of an opioid-  
for any specific opioid-related disorder or any of the disorders in the substance-related and  
addictive disorders diagnostic class.
Sedative-, Hypnotic-,  
or Anxiolytic-Related Disorders
Sedative, Hypnotic, or Anxiolytic Use Disorder  
Sedative, Hypnotic, or Anxiolytic Intoxication  
Sedative, Hypnotic, or Anxiolytic Withdrawal  
Other Sedative·, Hypnotic-, or Anxiolytic-Induced Disorders  
Unspecified Sedative-, Hypnotic-, or Anxiolytic-Related Disorder
Sedative, Hypnotic, or Anxiolytic Use Disorder
A. A problematic pattern of sedative, hypnotic, or anxiolytic use leading to clinically signif­

icant impairment or distress, as manifested by at least two of the following, occurring
within a 12-month period:
1. Sedatives, hypnotics, or anxiolytics are often taken in larger amounts or over a lon­
ger period than was intended.
2. There is a persistent desire or unsuccessful efforts to cut down or control sedative,  
hypnotic, or anxiolytic use.
3. A great deal of time is spent in activities necessary to obtain the sedative, hypnotic,  
or anxiolytic; use the sedative, hypnotic, or anxiolytic; or recover from its effects.
4. Craving, or a strong desire or urge to use the sedative, hypnotic, or anxiolytic.
5. Recurrent sedative, hypnotic, or anxiolytic use resulting in  a failure to fulfill major  
role obligations at work, school, or home (e.g., repeated absences from work or

role obligations at work, school, or home (e.g., repeated absences from work or  
poor work performance related to sedative, hypnotic, or anxiolytic use; sedative-,  
hypnotic-, or anxiolytic-related absences, suspensions, or expulsions from school;  
neglect of children or household).
6. Continued sedative, hypnotic, or anxiolytic use despite having persistent or re­
current social or interpersonal problems caused or exacerbated by the effects of  
sedatives, hypnotics, or anxiolytics (e.g., arguments with a spouse about conse­
quences of intoxication; physical fights).
cause of sedative, hypnotic, or anxiolytic use.

8. Recurrent sedative, hypnotic, or anxiolytic use in situations in which it is physically  
hazardous (e.g., driving an automobile or operating a machine when impaired by  
sedative, hypnotic, or anxiolytic use).
9. Sedative, hypnotic, or anxiolytic use is continued despite knowledge of having a  
persistent or recurrent physical or psychological problem that is likely to have been  
caused or exacerbated by the sedative, hypnotic, or anxiolytic.
10. Tolerance, as defined by either of the following;
a. A need for markedly increased amounts of the sedative, hypnotic, or anxiolytic  
to achieve intoxication or desired effect.
b. A markedly diminished effect with continued use of the same amount of the sed­
ative, hypnotic, or anxiolytic.
Note: This criterion is not considered to be met for individuals taking sedatives,  
hypnotics, or anxiolytics under medical supervision.

a. The characteristic withdrawal syndrome for sedatives, hypnotics, or anxiolytics  
(refer to Criteria A and B of the criteria set for sedative, hypnotic, or anxiolytic  
withdrawal, pp. 557-558).
b. Sedatives, hypnotics, or anxiolytics (or a closely related substance, such as al­
cohol) are taken to relieve or avoid withdrawal symptoms.
In early remission: After full criteria for sedative, hypnotic, or anxiolytic use disorder  
were previously met, none of the criteria for sedative, hypnotic, or anxiolytic use disor­
der have been met for at least 3 months but for less than 12 months (with the exception

der have been met for at least 3 months but for less than 12 months (with the exception  
that Criterion A4, “ Craving, or a strong desire or urge to use the sedative, hypnotic, or  
anxiolytic,”  may be met).
In sustained remission: After full criteria for sedative, hypnotic, or anxiolytic use dis­
order were previously met, none of the criteria for sedative, hypnotic, or anxiolytic use  
disorder have been met at any time during a period of 12 months or longer (with the  
exception that Criterion A4, “ Craving, or a strong desire or urge to use the sedative,  
hypnotic, or anxiolytic,”  may be met).
environment where access to sedatives, hypnotics, or anxiolytics is restricted.
Coding based on current severity: Note for ICD-10-CM codes: If a sedative, hypnotic, or

Coding based on current severity: Note for ICD-10-CM codes: If a sedative, hypnotic, or  
anxiolytic intoxication; sedative, hypnotic, or anxiolytic withdrawal; or another sedative-,  
hypnotic-, or anxiolytic-induced mental disorder is also present, do not use the codes be­
low for sedative, hypnotic, or anxiolytic use disorder. Instead the comorbid sedative, hyp­
notic, or anxiolytic use disorder is indicated in the 4th character of the sedative-, hypnotic-,  
or anxiolytic-induced disorder (see the coding note for sedative, hypnotic, or anxiolytic in­
toxication; sedative, hypnotic, or anxiolytic withdrawal; or specific sedative-, hypnotic-, or  
anxiolytic-induced mental disorder). For example, if there is comorbid sedative-, hypnotic-,  
or anxiolytic-induced depressive disorder and sedative, hypnotic, or anxiolytic use disor­

der, only the sedative-, hypnotic-, or anxiolytic-induced depressive disorder code is given  
with the 4th character indicating whether the comorbid sedative, hypnotic, or anxiolytic use  
disorder is mild, moderate, or severe: F13.14 for m ild sedative, hypnotic, or anxiolytk: use  
disorder with sedative-, hypnotic-, or anxiolytic-induced depressive disorder or FI 3.24 for  
a moderate or severe sedative, hypnotic, or anxiolytic use disorder with sedative-, hypnotic-,  
or anxiolytic-induced depressive disorder.

305.40 (F13.10) Mild: Presence of 2-3 symptoms.
304.10 (F13.20) Moderate: Presence of 4 -5  symptoms.
304.10 (FI 3.20) Severe: Presence of 6 or more symptoms.
Sedative, hypnotic, or anxiolytic substances include benzodiazepines, benzodiazepine­
like drugs (e.g., zolpidem, zaleplon), carbamates (e.g., glutethimide, meprobamate), 
barbiturates (e.g., secobarbital), and barbiturate-like hypnotics (e.g., glutethimide, meth- 
aqualone). This class of substances includes all prescription sleeping medications and

aqualone). This class of substances includes all prescription sleeping medications and 
almost all prescription antianxiety medications. Nonbenzodiazepine antianxiety agents 
(e.g., buspirone, gepirone) are not included in this class because they do not appear to be 
associated with significant misuse.
Like alcohol, these agents are brain depressants and can produce similar substance/ 
medication-induced and substance use disorders. Sedative, hypnotic, or anxiolytic sub­
stances are available both by prescription and illegally. Some individuals who obtain these 
substances by prescription will develop a sedative, hypnotic, or anxiolytic use disorder, 
while others who misuse these substances or use them for intoxication will not develop a 
use disorder. In particular, sedatives, hypnotics, or anxiolytics with rapid onset and/or

use disorder. In particular, sedatives, hypnotics, or anxiolytics with rapid onset and/or 
short to intermediate lengths of action may be taken for intoxication purposes, although 
longer acting substances in this class may be taken for intoxication as well.
Craving (Criterion A4), either while using or during a period of abstinence, is a typical 
feature of sedative, hypnotic, or anxiolytic use disorder. Misuse of substances from this 
class may occur on its own or in conjunction with use of other substances. For example, in­
dividuals may use intoxicating doses of sedatives or benzodiazepines to "come down" 
from cocaine or amphetamines or use high doses of benzodiazepines in combination with 
methadone to "boost" its effects.
Repeated absences or poor work performance, school absences, suspensions or expul­

sions, and neglect of children or household (Criterion A5) may be related to sedative, hyp­
notic, or anxiolytic use disorder, as may the continued use of the substances despite 
arguments with a spouse about consequences of intoxication or despite physical fights 
(Criterion A6). Limiting contact with family or friends, avoiding work  or school, or stop­
ping participation in hobbies, sports, or games (Criterion A7) and recurrent sedative, 
hypnotic, or anxiolytic use when driving an automobile or operating a machine when im­
paired by sedative, hypnotic, or anxiolytic use (Criterion A8) are also seen in sedative, 
hypnotic, or anxiolytic use disorder.
Very significant levels of tolerance and withdrawal can develop to the sedative, hyp­
notic, or anxiolytic. There may be evidence of tolerance and withdrawal in the absence of

notic, or anxiolytic. There may be evidence of tolerance and withdrawal in the absence of 
a diagnosis of a sedative, hypnotic, or anxiolytic use disorder in an individual who has 
abruptly discontinued use of benzodiazepines that were taken for long periods of time at 
prescribed and therapeutic doses. In these cases, an additional diagnosis of sedative, hyp­
notic, or anxiolytic use disorder is made only if other criteria are met. That is, sedative, 
hypnotic, or anxiolytic medications may be prescribed for appropriate medical purposes, 
and depending on the dose regimen, these drugs may then produce tolerance and with­

drawal. If these drugs are prescribed or recommended for appropriate medical purposes, 
and if they are uöed as prescribed, the resulting tolerance or withdrawal does not meet the 
criteria for diagnosing a substance use disorder. However, it is necessary to determine 
whether the drugs were appropriately prescribed and used (e.g., falsifying medical symp­
toms to obtain the medication; using more medication than prescribed; obtaining the med­
ication from several doctors without informing them of the others' involvement).
Given the unidimensional nature of the symptoms of sedative, hypnotic, or anxiolytic 
use disorder, severity is based on the number of criteria endorsed.
Sedative, hypnotic, or anxiolytic use disorder is often associated with other substance use dis­
orders (e.g., alcohol, cannabis, opioid, stimulant use disorders). Sedatives are often used to al­

leviate the unwanted effects of these other substances. With repeated use of the substance, 
tolerance develops to the sedative effects, and a progressively higher dose is used. However, 
tolerance to brain stem depressant effects develops much more slowly, and as the individual 
takes more substance to achieve euphoria or other desired effects, there may be a sudden onset 
of respiratory depression and hypotension, which may result in death. Intense or repeated 
sedative, hypnotic, or anxiolytic intoxication may be associated with severe depression that, 
although temporary, can lead to suicide attempt and completed suicide.
The 12-month prevalences of DSM-IV sedative, hypnotic, or anxiolytic use disorder are es­

timated to be 0.3% among 12- to 17-year-olds and 0.2% among adults age 18 years and 
older. Rates of DSM-IV sedative, hypnotic, or anxiolytic use disorder are slightly greater 
among adult males (0.3%) than among adult females, but for 12- to 17-year-olds, the rate 
for females (0.4%) exceeds that for males (0.2%). The 12-month prevalence of DSM-IV 
sedative, hypnotic, or anxiolytic use disorder decreases as a function of age and is great­
est among 18- to 29-year-olds (0.5%) and lowest among individuals 65 years and older 
(0.04%).
Twelve-month prevalence of sedative, hypnotic, or anxiolytic use disorder varies across 
racial/ethnic subgroups of the U.S. population. For 12- to 17-year-olds, rates are greatest 
among whites (0.3%) relative to African Americans (0.2%), Hispanics (0.2%), Native Amer­

icans (0.1%), and Asian Americans and Pacific Islanders (0.1%). Among adults, 12-month 
prevalence is greatest among Native Americans and Alaska Natives (0.8%), with rates of 
approximately 0.2% among African Americans, whites, and Hispanics and 0.1% among 
Asian Americans and Pacific Islanders.
The usual course of sedative, hypnotic, or anxiolytic use disorder involves individuals in 
their teens or 20s who escalate their occasional use of sedative, hypnotic, or anxiolytic 
agents to the point at which they develop problems that meet criteria for a diagnosis. This 
pattern may be especially likely among individuals who have other substance use disor­
ders (e.g., alcohol, opioids, stimulants). An initial pattern of intermittent use socially (e.g.,

ders (e.g., alcohol, opioids, stimulants). An initial pattern of intermittent use socially (e.g., 
at parties) can lead to daily use and high levels of tolerance. Once this occurs, an increasing 
level of interpersonal difficulties, as well as increasingly severe episodes of cognitive dys­
function and physiological withdrawal, can be expected.
The second and less frequently observed clinical course begins with an individual who 
originally obtained the medication by prescription from a physician, usually for the treat­
ment of anxiety, insomnia, or somatic complaints. As either tolerance or a need for higher 
doses of the medication develops, there is a gradual increase in the dose and frequency of 
self-administration. The individual is likely to continue to justify use on the basis of his or 
her original symptoms of anxiety or insomnia, but substance-seeking behavior becomes

more prominent, and the individual may seek out multiple physicians to obtain sufficient 
supplies of the medication. Tolerance can reach high levels, and withdrawal (including 
seizures and withdrawal delirium) may occur.
As with many substance use disorders, sedative, hypnotic, or anxiolytic use disorder gen­
erally has an onset during adolescence or early adult life. There is an increased risk for misuse 
and problems from many psychoactive substances as individuals age. In particular, cognitive 
impairment increases as a side effect with age, and the metabolism of sedatives, hypnotics, or 
anxiolytics decreases with age among older individuals. Both acute and chronic toxic effects 
of these substances, especially effects on cognition, memory, and motor coordination, are 
likely to increase with age as a consequence of pharmacodynamic and pharmacokinetic age- 
related changes. Individuals with major neurocognitive disorder (dementia) are more likely

related changes. Individuals with major neurocognitive disorder (dementia) are more likely 
to develop intoxication and impaired physiological functioning at lower doses.
Deliberate intoxication to achieve a ''high" is most likely to be observed in teenagers 
and individuals in their 20s. Problems associated with sedatives, hypnotics, or anxiolytics 
are also seen in individuals in their 40s and older who escalate the dose of prescribed med­
ications. In older individuals, intoxication can resemble a progressive dementia.
Temperamental. Impulsivity and novelty seeking are individual temperaments that re­
late to the propensity to develop a substance use disorder but may themselves be geneti­
cally determined.
Environmental. Since sedatives, hypnotics, or anxiolytics are all pharmaceuticals, a key

Environmental. Since sedatives, hypnotics, or anxiolytics are all pharmaceuticals, a key 
risk factor relates to availability of the substances. In the United States, the historical pat­
terns of sedative, hypnotic, or anxiolytic misuse relate to the broad prescribing patterns. 
For instance, a marked decrease in prescription of barbiturates was associated with an in­
crease in benzodiazepine prescribing. Peer factors may relate to genetic predisposition in 
terms of how individuals select their environment. Other individuals at heightened risk 
might include those with alcohol use disorder who may receive repeated prescriptions in 
response to their complaints of alcohol-related anxiety or insomnia.
Genetic and physiological. As for other substance use disorders, the risk for sedative, 
hypnotic, or anxiolytic use disorder can be related to individual, family, peer, social, and

hypnotic, or anxiolytic use disorder can be related to individual, family, peer, social, and 
environmental factors. Within these domains, genetic factors play a particularly important 
role both directly and indirectly. Overall, across development, genetic factors seem to play 
a larger role in the onset of sedative, hypnotic, or anxiolytic use disorder as individuals age 
through puberty into adult life.
Course modifiers. Early onset of use is associated with greater likelihood for develop­
ing a sedative, hypnotic, or anxiolytic use disorder.
There are marked variations in prescription patterns (and availability) of this class of sub­
stances in different countries, which may lead to variations in prevalence of sedative, hyp­
notic, or anxiolytic use disorders.

Females may be at higher risk than males for prescription drug misuse of sedative, hyp­
notic, or anxiolytic substances.
Almost all sedative, hypnotic, or anxiolytic substances can be identified through labora­
tory evaluations of urine or blood (the latter of which can quantify the amounts of these

agents in the body). Urine tests are likely to remain positive for up to approximately 1 week 
after the use of long-acting substances, such as diazepam or flurazepam.
Sedative, Hypnotic, or Anxioiytic Use Disorder
The social and interpersonal consequences of sedative, hypnotic, or anxiolytic use disorder 
mimic those of alcohol in terms of the potential for disinhibited behavior. Accidents, interper­
sonal difficulties (such as arguments or fights), and interference with work or school perfor­
mance are all common outcomes. Physical examination is likely to reveal evidence of a mild 
decrease in most aspects of autonomic nervous system functioning, including a slower pulse, 
a slightly decreased respiratory rate, and a slight drop in blood pressure (most likely to occur 
with postural changes). At high doses, sedative, hypnotic, or anxiolytic substances can be le­
thal, particularly when mixed with alcohol, although the lethal dosage varies considerably

thal, particularly when mixed with alcohol, although the lethal dosage varies considerably 
among the specific substances. Overdoses may be associated with a deterioration in vital signs 
that signals an impending medical emergency (e.g., respiratory arrest from barbiturates). 
There may be consequences of trauma (e.g., internal bleeding or a subdural hematoma) from 
accidents that occur while intoxicated. Intravenous use of these substances can result in med­
ical complications related to the use of contaminated needles (e.g., hepatitis and HIV).
Acute intoxication can result in accidental injuries and automobile accidents. For elderly 
individuals, even short-term use of these sedating medications at prescribed doses can be as­
sociated with an increased risk for cognitive problems and falls. The disinhibiting effects of

sociated with an increased risk for cognitive problems and falls. The disinhibiting effects of 
these agents, H ke alcohol, may potentially contribute to overly aggressive behavior, with sub­
sequent interpersonal and legal problems. Accidental or deliberate overdoses, similar to those 
observed for alcohol use disorder or repeated alcohol intoxication, can occur. In contrast to 
their wide margin of safety when used alone, benzodiazepines taken in combination with al­
cohol can be particularly dangerous, and accidental overdoses are reported commonly. Acci­
dental overdoses have also been reported in individuals who deliberately misuse barbiturates 
and other nonbenzodiazepine sedatives (e.g., methaqualone), but since these agents are much 
less available than the benzodiazepines, the frequency of overdosing is low in most settings.

Other mental disorders or medical conditions. Individuals with sedative-, hypnotic-, 
or anxiolytic-induced disorders may present with symptoms (e.g., anxiety) that resemble 
primary mental disorders (e.g., generalized anxiety disorder vs. sedative-, hypnotic-, or 
anxiolytic-induced anxiety disorder, with onset during withdrawal). The slurred speech, 
incoordination, and other associated features characteristic of sedative, hypnotic, or anx­
iolytic intoxication could be the result of another medical condition (e.g., multiple sclero­
sis) or of a prior head trauma (e.g., a subdural hematoma).
Alcohol use disorder. Sedative, hypnotic, or anxiolytic use disorder must be differenti­
ated from alcohol use disorder.
Clinically appropriate use of sedative, hypnotic, or anxiolytic medications. Individuals

Clinically appropriate use of sedative, hypnotic, or anxiolytic medications. Individuals 
may continue to take benzodiazepine medication according to a physician's direction for a 
legitimate medical indication over extended periods of time. Even if physiological signs of 
tolerance or withdrawal are manifested, many of these individuals do not develop symp­
toms that meet the criteria for sedative, hypnotic, or anxiolytic use disorder because they 
are not preoccupied with obtaining the substance and its use does not interfere with their 
performance of usual social or occupational roles.
Nonmedical use of sedative, hypnotic, or anxiolytic agents is associated with alcohol use 
disorder, tobacco use disorder, and, generally, illicit drug use. There may also be an over­

lap between sedative, hypnotic, or anxiolytic use disorder and antisocial personality dis­
order; depressive, bipolar, and anxiety disorders; and other substance use disorders, such 
as alcohol use disorder and illicit drug use disorders. Antisocial behavior and antisocial 
personality disorder are especially associated v^ith sedative, hypnotic, or anxiolytic use 
disorder w ^hen the substances are obtained illegally.
Sedative, Hypnotic, or Anxiolytic Intoxication
A. Recent use of a sedative, hypnotic, or anxiolytic.
B. Clinically significant maladaptive behavioral or psychological changes (e.g., inappro­
priate sexual or aggressive behavior, mood lability, impaired judgment) that developed  
during, or shortly after, sedative, hypnotic, or anxiolytic use.
sedative, hypnotic, or anxiolytic use:

5. Impairment in cognition (e.g., attention, memory).
stance.
there is a comorbid sedative, hypnotic, or anxiolytic use disorder. If a mild sedative, hyp­
notic, or anxiolytic use disorder is comorbid, the ICD-10-CM code is F13.129, and if a mod­
erate or severe sedative, hypnotic, or anxiolytic use disorder is comorbid, the ICD-10-CM  
code is FI 3.229. If there is no comorbid sedative, hypnotic, or anxiolytic use disorder, then  
the ICD-10-CM code is FI 3.929.__________________________________________________

Note: For information on Development and Course; Risk and Prognostic Factors; Culture- 
Related Diagnostic Issues; Diagnostic Markers; Functional Consequences of Sedative, 
Hypnotic, or Anxiolytic Intoxication; and Comorbidity, see the corresponding sections in 
sedative, hypnotic, or anxiolytic use disorder.
The essential feature of sedative, hypnotic, or anxiolytic intoxication is the presence of clini­
cally significant maladaptive behavioral or psychological changes (e.g., inappropriate sexual 
or aggressive behavior, mood lability, impaired judgment, impaired social or occupational 
functioning) that develop during, or shortly after, use of a sedative, hypnotic, or anxiolytic 
(Criteria A and B). As with other brain depressants, such as alcohol, these behaviors may be ac­

companied by slurred speech, incoordination (at levels that can interfere with driving abilities 
and with performing usual activities to the point of causing falls or automobile accidents), an 
unsteady gait, nystagmus, impairment in cognition (e.g., attentional or memory problems), 
and stupor or coma (Criterion C). Memory impairment is a prominent feature of sedative, hyp­
notic, or anxiolytic intoxication and is most often characterized by an anterograde amnesia tiiat 
resembles "alcoholic blackouts," which can be disturbing to the individual. The symptoms 
must not be attributable to another medical condition and are not better explained by another

mental disorder (Criterion D). Intoxication may occur in individuals who are receiving these 
substances by prescription, are borrov^ing the medication from friends or relatives, or are de­
liberately taking the substance to achieve intoxication.
Associated features include taking more medication than prescribed, taking multiple dif­
ferent medications, or mixing sedative, hypnotic, or anxiolytic agents with alcohol, which 
can markedly increase the effects of these agents.
The prevalence of sedative, hypnotic, or anxiolytic intoxication in the general population 
is unclear. However, it is probable that most nonmedical users of sedatives, hypnotics, or 
anxiolytics would at some time have signs or symptoms that meet criteria for sedative, 
hypnotic, or anxiolytic intoxication; if so, then the prevalence of nonmedical sedative, 
hypnotic, or anxiolytic use in the general population may be similar to the prevalence of

hypnotic, or anxiolytic use in the general population may be similar to the prevalence of 
sedative, hypnotic, or anxiolytic intoxication. For example, tranquilizers are used non- 
medically by 2.2% of Americans older than 12 years.
Alcohol use disorders. Since the clinical presentations may be identical, distinguishing sed­
ative, hypnotic, or anxiolytic intoxication from alcohol use disorders requires evidence for re­
cent ingestion of sedative, hypnotic, or anxiolytic medications by self-report, informant report, 
or toxicological testing. Many individuals who misuse sedatives, hypnotics, or anxiolytics may 
also misuse alcohol and other substances, and so multiple intoxication diagnoses are possible.
Alcohol intoxication. Alcohol intoxication may be distinguished from sedative, hypnotic,

Alcohol intoxication. Alcohol intoxication may be distinguished from sedative, hypnotic, 
or anxiolytic intoxication by the smell of alcohol on the breath. Otherwise, the features of 
the two disorders may be similar.
Other sedative-, hypnotic-, or anxiolytic-induced disorders. Sedative, hypnotic, or anx­
iolytic intoxication is distinguished from the other sedative-, hypnotic-, or anxiolytic- 
induced disorders (e.g., sedative-, hypnotic-, or anxiolytic-induced anxiety disorder, with 
onset during withdrawal) because the symptoms in the latter disorders predominate in 
the clinical presentation and are severe enough to warrant clinical attention.
Neurocognitive disorders. In situations of cognitive impairment, traumatic brain in­
jury, and delirium from other causes, sedatives, hypnotics, or anxiolytics may be intoxi­

cating at quite low dosages. The differential diagnosis in these complex settings is based 
on the predominant syndrome. An additional diagnosis of sedative, hypnotic, or anxio­
lytic intoxication may be appropriate even if the substance has been ingested at a low dos­
age in the setting of these other (or similar) co-occurring conditions.
Sedative, Hypnotic, or Anxiolytic Withdrawal
A. Cessation of (or reduction in) sedative, liypnotic, or anxiolytic use that has been pro­
longed.
B. Two (or more) of the following, developing within several hours to a few days after the ces­
sation of (or reduction in) sedative, hypnotic, or anxiolytic use described in  Criterion A:
2. Hand tremor.

8. Grand mal seizures.
With perceptual disturbances: This specifier may be noted when hallucinations with in­
tact reality testing or auditory, visual, or tactile illusions occur in  the absence of a delirium.
Coding note: The ICD-9-CM code is 292.0. The ICD-10-CM code for sedative, hypnotic,  
or anxiolytic withdrawal depends on whether or not there is a comorbid moderate or se­
vere sedative, hypnotic, or anxiolytic use disorder and whether or not there are perceptual

vere sedative, hypnotic, or anxiolytic use disorder and whether or not there are perceptual  
disturbances. For sedative, hypnotic, or anxiolytic withdrawal without perceptual distur­
bances, the ICD-10-CM code is F13.239. For sedative, hypnotic, or anxiolytic withdrawal  
with perceptual disturbances, the ICD-10-CM code is F13.232. Note that the ICD-10-CM  
codes indicate the comorbid presence of a moderate or severe sedative, hypnotic, or anx­
iolytic use disorder, reflecting the fact that sedative, hypnotic, or anxiolytic withdrawal can  
only occur in the presence of a moderate or severe sedative, hypnotic, or anxiolytic use  
disorder. It is not permissible to code a comorbid mild sedative, hypnotic, or anxiolytic use  
disorder with sedative, hypnotic, or anxiolytic withdrawal.
Note: For information on Development and Course; Risk and Prognostic Factors; Culture-

Related Diagnostic Issues; Functional Consequences of Sedative, Hypnotic, or Anxiolytic 
Withdrawal; and Comorbidity, see the corresponding sections in sedative, hypnotic, or 
anxiolytic use disorder.
The essential feature of sedative, hypnotic, or anxiolytic withdrawal is the presence of a char­
acteristic syndrome that develops after a marked decrease in or cessation of intake after several 
weeks or more of regular use (Criteria A and B). This withdrawal syndrome is characterized by 
two or more symptoms (similar to alcohol withdrawal) that include autonomic hyperactivity 
(e.g., increases in heart rate, respiratory rate, blood pressure, or body temperature, along with 
sweating); a tremor of the hands; insomnia; nausea, sometimes accompanied by vomiting;

sweating); a tremor of the hands; insomnia; nausea, sometimes accompanied by vomiting; 
anxiety; and psychomotor agitation. A grand mal seizure may occur in perhaps as many as 
20%-30% of individuals undergoing untreated withdrawal from these substances. In severe 
withdrawal, visual, tactile, or auditory hallucinations or illusions can occur but are usually in 
the context of a delirium. If the individual's reality testing is intact (i.e., he or she knows the 
substance is causing the hallucinations) and the illusions occur in a clear sensorium, the spec­
ifier 'Vith perceptual disturbances" can be noted. When hallucinations occur in the absence of 
intact reality testing, a diagnosis of substance/medication-induced psychotic disorder should 
be considered. The symptoms cause clinically significant distress or impairment in social, oc­

cupational, or other important areas of functioning (Criterion C). The symptoms must not be 
attributable to another medical condition and are not better explained by another mental dis­
order (e.g., alcohol withdrawal or generalized anxiety disorder) (Criterion D). Relief of with­
drawal symptoms with administration of any sedative-hypnotic agent would support a 
diagnosis of sedative, hypnotic, or anxiolytic withdrawal.

The timing and severity of the withdrawal syndrome will differ depending on the specific 
substance and its pharmacokinetics and pharmacodynamics. For example, withdrawal 
from shorter-acting substances that are rapidly absorbed and that have no active metabo­
lites (e.g., triazolam) can begin within hours after the substance is stopped; withdrawal 
from substances with long-acting metabolites (e.g., diazepam) may not begin for 1-2 days 
or longer. The withdrawal syndrome produced by substances in this class may be charac­
terized by the development of a delirium that can be life-threatening. There may be evi­
dence of tolerance and withdrawal in the absence of a diagnosis of a substance use 
disorder in an individual who has abruptly discontinued benzodiazepines that were taken 
for long periods of time at prescribed and therapeutic doses. However, ICD-IO-CM codes

for long periods of time at prescribed and therapeutic doses. However, ICD-IO-CM codes 
only allow a diagnosis of sedative, hypnotic, or anxiolytic withdrawal in the presence of 
comorbid moderate to severe sedative, hypnotic, or anxiolytic use disorder.
The time course of the withdrawal syndrome is generally predicted by the half-life of 
the substance. Medications whose actions typically last about 10 hours or less (e.g., loraz- 
epam, oxazepam, temazepam) produce withdrawal symptoms within 6-8 hours of de­
creasing blood levels that peak in intensity on the second day and improve markedly by 
the fourth or fifth day. For substances with longer half-lives (e.g., diazepam), symptoms 
may not develop for more than 1  week, peak in intensity during the second week, and de­
crease markedly during the third or fourth week. There may be additional longer-term

crease markedly during the third or fourth week. There may be additional longer-term 
symptoms at a much lower level of intensity that persist for several months.
The longer the substance has been taken and the higher the dosages used, the more likely 
it is that there will be severe withdrawal. However, withdrawal has been reported with as little 
as 15 mg of diazepam (or its equivalent in other benzodiazepines) when taken daily for several 
months. Doses of approximately 40 mg of diazepam (or its equivalent) daily are more likely to 
produce clinically relevant withdrawal symptoms, and even higher doses (e.g., 100 mg of di­
azepam) are more likely to be followed by withdrawal seizures or delirium. Sedative, hyp­
notic, or anxiolytic withdrawal delirium is characterized by disturbances in consciousness and

notic, or anxiolytic withdrawal delirium is characterized by disturbances in consciousness and 
cognition, with visual, tactile, or auditory hallucinations. When present, sedative, hypnotic, or 
anxiolytic withdrawal delirium should be diagnosed instead of withdrawal.
The prevalence of sedative, hypnotic, or anxiolytic withdrawal is unclear.
Diagnostic iVlarkers
Seizures and autonomic instability in the setting of a history of prolonged exposure to sed­
ative, hypnotic, or anxiolytic medications suggest a high likelihood of sedative, hypnotic, 
or anxiolytic withdrawal.
Other medical disorders. The symptoms of sedative, hypnotic, or anxiolytic with­
drawal may be mimicked by other medical conditions (e.g., hypoglycemia, diabetic keto­
acidosis). If seizures are a feature of the sedative, hypnotic, or anxiolytic withdrawal, the

acidosis). If seizures are a feature of the sedative, hypnotic, or anxiolytic withdrawal, the 
differential diagnosis includes the various causes of seizures (e.g., infections, head injury, 
poisonings).
Essential tremor. Essential tremor, a disorder that frequently runs in families, may 
erroneously suggest the tremulousness associated with sedative, hypnotic, or anxiolytic 
withdrawal.
Alcohol withdrawal. Alcohol withdrawal produces a syndrome very similar to that of 
sedative, hypnotic, or anxiolytic withdrawal.

iolytic withdrawal is distinguished from the other sedative-, hypnotic-, or anxiolytic- 
Anxiety disorders. Recurrence or worsening of an underlying anxiety disorder pro­
duces a syndrome similar to sedative, hypnotic, or anxiolytic withdrawal. Withdrawal 
would be suspected with an abrupt reduction in the dosage of a sedative, hypnohc, or anx­
iolytic medication. When a taper is under way, distinguishing the withdrawal syndrome 
from the underlying anxiety disorder can be difficult. As with alcohol, lingering with­
drawal symptoms (e.g., anxiety, moodiness, and trouble sleeping) can be mistaken for

drawal symptoms (e.g., anxiety, moodiness, and trouble sleeping) can be mistaken for 
non-substance/medication-induced anxiety or depressive disorders (e.g., generalized 
anxiety disorder).
Other Sedative-, Hypnotic-,  
or Anxiolytic-Induced Disorders
The following sedative-, hypnotic-, or anxiolytic-induced disorders are described in other 
stance/medication-induced mental disorders in these chapters): sedative-, hypnotic-, or 
anxiolytic-induced psychotic disorder (''Schizophrenia Spectrum and Other Psychotic 
Disorders"); sedative-, hypnotic-, or anxiolytic-induced bipolar disorder ("Bipolar and Re­
lated Disorders"); sedative-, hypnotic-, or anxiolytic-induced depressive disorder ("De­
pressive Disorders"); sedative-, hypnotic-, or anxiolytic-induced anxiety disorder

pressive Disorders"); sedative-, hypnotic-, or anxiolytic-induced anxiety disorder 
("Anxiety Disorders"); sedative-, hypnotic-, or anxiolytic-induced sleep disorder ("Sleep- 
Wake Disorders"); sedative-, hypnotic-, or anxiolytic-induced sexual dysfunction ("Sex­
ual Dysfunctions"); and sedative-, hypnotic-, or anxiolytic-induced major or mild neuro- 
cognitive disorder ("Neurocognitive Disorders"). For sedative, hypnotic, or anxiolytic 
intoxication delirium and sedative, hypnotic, or anxiolytic withdrawal delirium, see the 
criteria and discussion of delirium in the chapter "Neurocognitive Disorders." These sed­
ative-, hypnotic-, or anxiolytic-induced disorders are diagnosed instead of sedative, hyp­
notic, or anxiolytic intoxication or sedative, hypnotic, or anxiolytic withdrawal only when 
the symptoms are sufficiently severe to warrant independent clinical attention.

Unspecified Sedative-, Hypnotic-,  
or Anxiolytic-Related Disorder
292.9 (F13.99)
This category applies to presentations in  which symptoms characteristic of a sedative-,  
hypnotic-, or anxiolytic-related disorder that cause clinically significant distress or impair­
not meet the full criteria for any specific sedative-, hypnotic-, or anxiolytic-related disorder  
or any of the disorders in the substance-related and addictive disorders diagnostic class.

Stimulant-Related Disorders
Stimulant Use Disorder  
Stimulant Intoxication  
Stimulant Withdrawal  
Other Stimulant-Induced Disorders  
Unspecified Stimulant-Related Disorder
Stimulant Use Disorder
A. A pattern of amphetamine-type substance, cocaine, or other stimulant use leading to  
1. The stimulant is often taken in larger amounts or over a longer period than was in­
tended.
2. There is a persistent desire or unsuccessful efforts to cut down or control stimulant use.
3. A great deal of time is spent in activities necessary to obtain the stimulant, use the  
stimulant, or recover from its effects.
4. Craving, or a strong desire or urge to use the stimulant.
5. Recurrent stimulant use resulting in a failure to fulfill major role obligations at work,  

6. Continued stimulant use despite having persistent or recurrent social or inteφer-  
sonal problems caused or exacerbated by the effects of the stimulant.
cause of stimulant use.
8. Recurrent stimulant use in situations in which it is physically hazardous.
9. Stimulant use is continued despite knowledge of having a persistent or recurrent  
by the stimulant.
a. A need for markedly increased amounts of the stimulant to achieve intoxication  
or desired effect.
stimulant.

Note: This criterion is not considered to be met for those taking stimulant medica­
tions solely under appropriate medical supervision, such as medications for atten-  
tion-deficit/hyperactivity disorder or narcolepsy.
a. The characteristic withdrawal syndrome for the stimulant (refer to Criteria A and  
B of the criteria set for stimulant withdrawal, p. 569).
b. The stimulant (or a closely related substance) is taken to relieve or avoid with­
drawal symptoms.

Note; This criterion is not considered to be met for those taking stimulant medica­
tion-deficii'hyperactivity disorder or narcolepsy.
In early remission: After full criteria for stimulant use disorder were previously met,  
none of the criteria for stimulant use disorder have been met for at least 3 months but  
sire or urge to use the stimulant,”  may be met).
In sustained remission: After full criteria for stimulant use disorder were previously  
met, none of the criteria for stimulant use disorder have been met at any time during a  
strong desire or urge to use the stimulant,”  may be met).
In a controlled environment: This additional specifier is used if the individual is in an

environment where access to stimulants is restricted.
Coding based on current severity: Note for ICD-10-CM codes: If an amphetamine in­
toxication, amphetamine withdrawal, or another amphetamine-induced mental disorder is  
also present, do not use the codes below for amphetamine use disorder. Instead, the co-  
morbid amphetamine use disorder is indicated in  the 4th character of the amphetamine-  
induced disorder code (see the coding note for amphetamine intoxication, amphetamine  
withdrawal, or a specific amphetamine-induced mental disorder). For example, if there is  
comorbid amphetamine-type or other stimulant-induced depressive disorder and amphet­
amine-type or other stimulant use disorder, only the amphetamine-type or other stimulant-

amine-type or other stimulant use disorder, only the amphetamine-type or other stimulant-  
induced depressive disorder code is given, with the 4th character indicating whether the  
comorbid amphetamine-type or other stimulant use disorder is mild, moderate, or severe:  
FI 5.14 for mild amphetamine-type or other stimulant use disorder with amphetamine-type  
or other stimulant-induced depressive disorder or FI 5.24 for a moderate or severe am­
phetamine-type or other stimulant use disorder with amphetamine-type or other stimulant-  
induced depressive disorder. Similarly, if there is comorbid cocaine-induced depressive  
disorder and cocaine use disorder, only the cocaine-induced depressive disorder code is  
given, with the 4th character indicating whether the comorbid cocaine use disorder is mild,  
moderate, or severe: F14.14 for mild cocaine use disorder with cocaine-induced depressive

moderate, or severe: F14.14 for mild cocaine use disorder with cocaine-induced depressive  
disorder or FI 4.24 for a moderate or severe cocaine use disorder with cocaine-induced  
Mild: Presence of 2-3 symptoms.
305.70 (FI 5.10) Amphetamine-type substance
305.60 (FI 4.10) Cocaine
305.70 (F I5.10) Other or unspecified stimulant
iVloderate: Presence of 4-5 symptoms.
304.40 (FI 5.20) Amphetamine-type substance
304.20 (FI 4.20) Cocaine
304.40 (F15.20) Other or unspecified stimulant
Severe: Presence of 6 or more symptoms.
304.40 (FI 5.20) Other or unspecified stimulant

The amphetamine and amphetamine-type stimulants include substances with a substi- 
tuted-phenylethylamine structure, such as amphetamine, dextroamphetamine, and meth- 
amphetamine. Also included are those substances that are structurally different but have 
similar effects, such as methylphenidate. These substances are usually taken orally or in­
travenously, although methamphetamine is also taken by the nasal route. In addition to 
the synthetic amphetamine-type compounds, there are naturally occurring, plant-derived

the synthetic amphetamine-type compounds, there are naturally occurring, plant-derived 
stimulants such as khât.  Amphetamines and other stimulants may be obtained by prescrip­
tion for the treatment of obesity, attention-deficit/hyperactivity disorder, and narcolepsy. 
Consequently, prescribed stimulants may be diverted into the illegal market. The effects of 
amphetamines and amphetamine-like drugs are similar to those of cocaine, such that the 
criteria for stimulant use disorder are presented here as a single disorder with the ability to 
specify the particular stimulant used by the individual. Cocaine may be consumed in sev­
eral preparations (e.g., coca leaves, coca paste, cocaine hydrochloride, and cocaine alka­
loids such as freebase and crack) that differ in potency because of varying levels of purity

loids such as freebase and crack) that differ in potency because of varying levels of purity 
and speed of onset. However, in all forms of the substance, cocaine is the active ingredient. 
Cocaine hydrochloride powder is usually "snorted" through the nostrils or dissolved in 
water and injected intravenously.
Individuals exposed to amphetamine-type stimulants or cocaine can develop stimu­
lant use disorder as rapidly as 1  week, although the onset is not always this rapid. Re­
gardless of the route of administration, tolerance occurs with repeated use. Withdrawal 
symptoms, particularly hypersomnia, increased appetite, and dysphoria, can occur and 
can enhance craving. Most individuals with stimulant use disorder have experienced tol­
erance or withdrawal.
Use patterns and course are similar for disorders involving amphetamine-type stimu­

lants and cocaine, as both substances are potent central nervous system stimulants with 
similar psychoactive and sympathomimetic effects. Amphetamine-type stimulants are 
longer acting than cocaine and thus are used fewer times per day. Usage may be chronic or 
episodic, with binges punctuated by brief non-use periods. Aggressive or violent behavior 
is common when high doses are smoked, ingested, or administered intravenously. Intense 
temporary anxiety resembling panic disorder or generalized anxiety disorder, as well as 
paranoid ideation and psychotic episodes that resemble schizophrenia, is seen with high­
dose use.
Withdrawal states are associated with temporary but intense depressive symptoms that 
can resemble a major depressive episode; the depressive symptoms usually resolve within

dose use.
can resemble a major depressive episode; the depressive symptoms usually resolve within 
1 week. Tolerance to amphetamine-type stimulants develops and leads to escalation of the 
dose. Conversely, some users of amphetamine-type stimulants develop sensitization, 
characterized by enhanced effects.
When injected or smoked, stimulants typically produce an instant feeling of well-being, 
confidence, and euphoria. Dramatic behavioral changes can rapidly develop with stimu­
lant use disorder. Chaotic behavior, social isolation, aggressive behavior, and sexual dys­
function can result from long-term stimulant use disorder.

Individuals v^ith acute intoxication may present with rambling speech, headache, tran­
sient ideas of reference, and tinnitus. There may be paranoid ideation, auditory halluci­
nations in a clear sensorium, and tactile hallucinations, which the individual usually 
recognizes as drug effects. Threats or acting out of aggressive behavior may occur. Depres­
sion, suicidal ideation, irritability, anhedonia, emotional lability, or disturbances in atten­
tion and concentration commonly occur during withdrawal. Mental disturbances associated 
with cocaine use usually resolve hours to days after cessation of use but can persist for 
1  month. Physiological changes during stimulant withdrawal are opposite to those of the 
intoxication phase, sometimes including bradycardia. Temporary depressive symptoms 
may meet symptomatic and duration criteria for major depressive episode. Histories con­
sistent with repeated panic attacks, social anxiety disorder (social phobia)-like behavior,

sistent with repeated panic attacks, social anxiety disorder (social phobia)-like behavior, 
and generalized anxiety-like syndromes are common, as are eating disorders. One ex­
treme instance of stimulant toxicity is stimulant-induced psychotic disorder, a disorder 
that resembles schizophrenia, with delusions and hallucinations.
Individuals with stimulant use disorder often develop conditioned responses to drug- 
related stimuli (e.g., craving on seeing any white powderlike substance). These responses 
contribute to relapse, are difficult to extinguish, and persist after detoxification.
Depressive symptoms with suicidal ideation or behavior can occur and are generally 
the most serious problems seen during stimulant withdrawal.
Stimulant use disorder: amphetamine-type stimulants. Estimated 12-month prevalence

Stimulant use disorder: amphetamine-type stimulants. Estimated 12-month prevalence 
of amphetamine-type stimulant use disorder in the United States is 0.2% among 12- to 17- 
year-olds and 0.2% among individuals 18 years and older. Rates are similar among adult 
males and females (0.2%), but among 12- to 17-year-olds, the rate for females (0.3%) is 
greater than that for males (0.1%). Intravenous stimulant use has a male-to-female ratio of 
3:1 or 4:1, but rates are more balanced among non-injecting users, with males representing 
54% of primary treatment admissions. Twelve-month prevalence is greater among 18- to 
29-year-olds (0.4%) compared with 45- to 64-year-olds (0.1%). For 12- to 17-year-olds, rates 
are highest among whites and African Americans (0.3%) compared with Hispanics (0.1%) 
and Asian Americans and Pacific Islanders (0.01%), with amphetamine-type stimulant use

and Asian Americans and Pacific Islanders (0.01%), with amphetamine-type stimulant use 
disorder virtually absent among Native Americans. Among adults, rates are highest among 
Native Americans and Alaska Natives (0.6%) compared with whites (0.2%) and Hispanics 
(0.2%), with amphetamine-type stimulant use disorder virtually absent among African 
Americans and Asian Americans and Pacific Islanders. Past-year nonprescribed use of 
prescription stimulants occurred among 5%-9% of children through high school, with 
5%-35% of college-age persons reporting past-year use.
Stimulant use disorder: cocaine. Estimated 12-month prevalence of cocaine use disorder 
in the United States is 0.2% among 12- to 17-year-olds and 0.3% among individuals 18 years 
and older. Rates are higher among males (0.4%) than among females (0.1%). Rates are

and older. Rates are higher among males (0.4%) than among females (0.1%). Rates are 
highest among 18- to 29-year-olds (0.6%) and lowest among 45- to 64-year-olds (0.1%). Among 
adults, rates are greater among Native Americans (0.8%) compared with African Ameri­
cans (0.4%), Hispanics (0.3%), whites (0.2%), and Asian Americans and Pacific Islanders 
(0.1%). In contrast, for 12- to 17-year-olds, rates are similar among Hispanics (0.2%), whites 
(0.2%), and Asian Americans and Pacific Islanders (0.2%); and lower among African Amer­
icans (0.02%); with cocaine use disorder virtually absent among Native Americans and 
Alaska Natives.
Stimulant use disorders occur throughout all levels of society and are more common among 
individuals ages 12-25 years compared with individuals 26 years and older. First regular use

among individuals in treatment occurs, on average, at approximately age 23 years. For pri­
mary methamphetamine-primary treatment admissions, Ûie  average age is 31 years.
Some individuals begin stimulant use to control weight or to improve performance in 
school, work, or athletics. This includes obtaining medications such as methylphenidate or 
amphetamine salts prescribed to others for the treatment of attention-deficit/hyperac­
tivity disorder. Stimulant use disorder can develop rapidly with intravenous or smoked 
administration; among primary admissions for amphetamine-type stimulant use, 66% re­
ported smoking, 18% reported injecting, and 10% reported snorting.
Patterns of stimulant administration include episodic or daily (or almost daily) use. 
Episodic use tends to be separated by 2 or more days of non-use (e.g., intense use over a 
weekend or on one or more weekdays). "'Binges" involve continuous high-dose use over

weekend or on one or more weekdays). "'Binges" involve continuous high-dose use over 
hours or days and are often associated with physical dependence. Binges usually termi­
nate only when stimulant supplies are depleted or exhaustion ensues. Chronic daily use 
may involve high or low doses, often with an increase in dose over time.
Stimulant smoking and intravenous use are associated with rapid progression to se­
vere-level stimulant use disorder, often occurring over weeks to months. Intranasal use of 
cocaine and oral use of amphetamine-type stimulants result in more gradual progression 
occurring over months to years. With continuing use, there is a diminution of pleasurable 
effects due to tolerance and an increase in dysphoric effects.
Temperamental. Comorbid bipolar disorder, schizophrenia, antisocial personality disor­

der, and other substance use disorders are risk factors for developing stimulant use disorder 
and for relapse to cocaine use in treatment samples. Also, impulsivity and similar personality 
traits may affect treatment outcomes. Childhood conduct disorder and adult antisocial per­
sonality disorder are associated with the later development of stimulant-related disorders.
Environmental. Predictors of cocaine use among teenagers include prenatal cocaine ex­
posure, postnatal cocaine use by parents, and exposure to community violence during 
childhood. For youths, especially females, risk factors include living in an unstable home 
environment, having a psychiatric condition, and associating with dealers and users.

Stimulant use-attendant disorders affect all racial/ethnic, socioeconomic, age, and gender 
groups. Diagnostic issues may be related to societal consequences (e.g., arrest, school sus­
pensions, employment suspension). Despite small variations, cocaine and other stimulant 
use disorder diagnostic criteria perform equally across gender and race/ethnicity groups.
Chronic use of cocaine impairs cardiac left ventricular function in African Americans. 
Approximately 66% of individuals admitted for primary methamphetamine/amphet- 
amine-related disorders are non-Hispanic white, followed by 21% of Hispanic origin, 3% 
Asian and Pacific Islander, and 3% non-Hispanic black.
Benzoylecgonine, a metabolite of cocaine, typically remains in the urine for 1-3 days after 
a single dose and may be present for 7-12 days in individuals using repeated high doses.

a single dose and may be present for 7-12 days in individuals using repeated high doses. 
Mildly elevated liver function tests can be present in cocaine injectors or users with con­
comitant alcohol use. There are no neurobiological markers of diagnostic utility. Discon­
tinuation of chronic cocaine use may be associated with electroencephalographic changes, 
suggesting persistent abnormalities; alterations in secretion patterns of prolactin; and 
downregulation of dopamine receptors.
Short-half-life amphetamine-type stimulants (MDMA [3,4-methylenedioxy-JV-methyl- 
amphetamine], methamphetamine) can be detected for 1-3 days, and possibly up to 4 days

depending on dosage and nnetabolism. Hair samples can be used to detect presence of am­
phetamine-type stimulants for up to 90 days. Other laboratory findings, as well as physical 
findings and other medical conditions (e.g., weight loss, malnutrition; poor hygiene), are 
similar for both cocaine and amphetamine-type stimulant use disorder.
Functional Consequences of Stimulant Use Disorder
Various medical conditions may occur depending on the route of administration. Intrana­
sal users often develop sinusitis, irritation, bleeding of the nasal mucosa, and a perforated 
nasal septum. Individuals who smoke the drugs are at increased risk for respiratory prob­
lems (e.g., coughing, bronchitis, and pneumonitis). Injectors have puncture marks and 
"tracks," most commonly on their forearms. Risk of HIV infection increases with frequent 
intravenous injections and unsafe sexual activity. Other sexually transmitted diseases,

intravenous injections and unsafe sexual activity. Other sexually transmitted diseases, 
hepatitis, and tuberculosis and other lung infections are also seen. Weight loss and mal­
nutrition are common.
Chest pain may be a common symptom during stimulant intoxication. Myocardial in­
farction, palpitations and arrhythmias, sudden death from respiratory or cardiac arrest, 
and stroke have been associated with stimulant use among young and otherwise healthy 
individuals. Seizures can occur with stimulant use. Pneumothorax can result from per­
forming Valsalva-like maneuvers done to better absorb inhaled smoke. Traumatic injuries 
due to violent behavior are common among individuals trafficking drugs. Cocaine use is 
associated with irregularities in placental blood flow, abruptio placentae, premahire labor 
and delivery, and an increased prevalence of infants with very low birth weights.

Individuals with stimulant use disorder may become involved in theft, prostitution, or 
drug dealing in order to acquire drugs or money for drugs.
Neurocognitive impairment is common among methamphetamine users. Oral health 
problems include "meth mouth" with gum disease, tooth decay, and mouth sores related 
to the toxic effects of smoking the drug and to bruxism while intoxicated. Adverse pulmo­
nary effects appear to be less common for amphetamine-type stimulants because they are 
smoked fewer times per day. Emergency department visits are common for stimulant-re­
lated mental disorder symptoms, injury, skin infections, and dental pathology.
Primary mental disorders. Stimulant-induced disorders may resemble primary mental

Primary mental disorders. Stimulant-induced disorders may resemble primary mental 
disorders (e.g., major depressive disorder) (for discussion of this differential diagnosis, see 
"Stimulant Withdrawal"). The mental disturbances resulting from the effects of stimulants 
should be distinguished from the symptoms of schizophrenia; depressive and bipolar dis­
orders; generalized anxiety disorder; and panic disorder.
Phencyclidine intoxication. Intoxication with phencyclidine ("PCP" or "angel dust") or 
synthetic "designer drugs" such as mephedrone (known by different names, including 
"bath salts") may cause a similar clinical picture and can only be distinguished from stim­
ulant intoxication by the presence of cocaine or amphetamine-type substance metabolites 
in a urine or plasma sample.
Stimulant intoxication and withdrawal. Stimulant intoxication and withdrawal are dis­

tinguished from the other stimulant-induced disorders (e.g., anxiety disorder, with onset 
during intoxication) because the symptoms in the latter disorders predominate the clinical 
presentation and are severe enough to warrant independent clinical attention.
Stimulant-related disorders often co-occur with other substance use disorders, especially 
those involving substances with sedative properties, which are often taken to reduce in-

somnia, nervousness, and other unpleasant side effects. Cocaine users often use alcohol, 
while amphetamine-type stimulant users often use cannabis. Stimulant use disorder may 
be associated with posttraumatic stress disorder, antisocial personality disorder, atten- 
tion-deficit/hyperactivity disorder, and gambling disorder. Cardiopulmonary problems 
are often present in individuals seeking treatment for cocaine-related problems, with chest 
pain being the most common. Medical problems occur in response to adulterants used as 
"cutting" agents. Cocaine users who ingest cocaine cut with levamisole, an antimicrobial 
and veterinary medication, may experience agranulocytosis and febrile neutropenia.
Stimulant Intoxication
A. Recent use of an amphetamine-type substance, cocaine, or other stimulant.
B. Clinically significant problematic behavioral or psychological changes (e.g., euphoria

B. Clinically significant problematic behavioral or psychological changes (e.g., euphoria  
or affective blunting: changes in sociability: hypervigilance: interpersonal sensitivity:  
anxiety, tension, or anger; stereotyped behaviors: impaired judgment) that developed  
during, or shortly after, use of a stimulant.
C. Two (or more) of the following signs or symptoms, developing during, or shortly after,  
stimulant use:
1. Tachycardia or bradycardia.
2. Pupillary dilation.
3. Elevated or lowered blood pressure.
4. Perspiration or chills.
5. Nausea or vomiting.
6. Evidence of weight loss.
7. Psychomotor agitation or retardation.
8. Muscular weakness, respiratory depression, chest pain, or cardiac arrhythmias.
9. Confusion, seizures, dyskinesias, dystonias, or coma.
D. The signs or symptoms are not attributable to another medical condition and are not

stance.
Specify  the specific intoxicant (i.e., amphetamine-type substance, cocaine, or other  
stimulant).
Witli perceptual disturbances: This specifier may be noted when hallucinations with  
intact reality testing or auditory, visual, or tactile illusions occur in the absence of a de­
lirium .
the stimulant is an amphetamine, cocaine, or other stimulant: whether there is a comorbid  
amphetamine, cocaine, or other stimulant use disorder; and whether or not there are per­
ceptual disturbances.
For amphetamine, cocaine, or other stimulant intoxication, without perceptual dis­
turbances: If a mild amphetamine or other stimulant use disorder is comorbid, the ICD-

turbances: If a mild amphetamine or other stimulant use disorder is comorbid, the ICD-  
10-CM code is FI 5.129, and if a moderate or severe amphetamine or other stimulant use  
disorder is comorbid, the ICD-10-CM code is F I 5.229. If there is no comorbid amphet­
amine or other stimulant use disorder, then the ICD-10-CM code is F15.929. Similarly, if  
a mild cocaine use disorder is comorbid, the ICD-10-CM code is FI 4.129, and if a mod­
erate or severe cocaine use disorder is comorbid, the ICD-10-CM code is F I4.229. If 
there is no comorbid cocaine use disorder, then the ICD-10-CM code is F14.929.

For amphetamine, cocaine, or other stimulant intoxication, with perceptual distur­
bances: If a m ild amphetamine or other stimulant use disorder is comorbid, the ICD-10-  
CM code is FI 5.122, and if a moderate or severe amphetamine or other stimulant use  
disorder is comorbid, the ICD-10-CM code is FI 5.222. If there is no comorbid amphet­
amine or other stimulant use disorder, then the ICD-10-CM code is F15.922. Similarly, if  
a m ild cocaine use disorder is comorbid, the ICD-10-CM code is FI 4.122, and if a mod­
erate or severe cocaine use disorder is comorbid, the ICD-10-CM code is FI 4.222. If 
there is no comorbid cocaine use disorder, then the ICD-10-CM code is F14.922.
The essential feature of stimulant intoxication, related to amphetamine-type stimulants 
and cocaine, is the presence of clinically significant behavioral or psychological changes 
that develop during, or shortly after, use of stimulants (Criteria A and B). Auditory hallu­

cinations may be prominent, as may paranoid ideation, and these symptoms must be dis­
tinguished from an independent psychotic disorder such as schizophrenia. Stimulant 
intoxication usually begins with a "high" feeling and includes one or more of the follow­
ing: euphoria with enhanced vigor, gregariousness, hyperactivity, restlessness, hypervig­
ilance, interpersonal sensitivity, talkativeness, anxiety, tension, alertness, grandiosity, 
stereotyped and repetitive behavior, anger, impaired judgment, and, in the case of chronic 
intoxication, affective blunting with fatigue or sadness and social withdrawal. These be­
havioral and psychological changes are accompanied by two or more of the following 
signs and symptoms that develop during or shortly after stimulant use: tachycardia or bra­

dycardia; pupillary dilation; elevated or lowered blood pressure; perspiration or chills; 
nausea or vomiting; evidence of weight loss; psychomotor agitation or retardation; mus­
cular weakness, respiratory depression, chest pain, or cardiac arrhythmias; and confu­
sion, seizures, dyskinesias, dystonias, or coma (Criterion C). Intoxication, either acute or 
chronic, is often associated with impaired social or occupational functioning. Severe in­
toxication can lead to convulsions, cardiac arrhythmias, hyperpyrexia, and death. For the 
diagnosis of stimulant intoxication to be made, the symptoms must not be attributable 
to another medical condition and not better explained by another mental disorder (Crite­
rion D). While stimulant intoxication occurs in individuals with stimulant use disorders, in­

toxication is not a criterion for stimulant use disorder, which is confirmed by the presence 
of two of the 11 diagnostic criteria for use disorder.
The magnitude and direction of the behavioral and physiological changes depend on many 
variables, including the dose used and the characteristics of the individual using the sub­
stance or the context (e.g., tolerance, rate of absorption, chronicity of use, context in which 
it is taken). Stimulant effects such as euphoria, increased pulse and blood pressure, and 
psychomotor activity are most commonly seen. Depressant effects such as sadness, brady­
cardia, decreased blood pressure, and decreased psychomotor activity are less common 
and generally emerge only with chronic high-dose use.

Stimulant-induced disorders. Stimulant intoxication is distinguished from the other 
stimulant-induced disorders (e.g., stimulant-induced depressive disorder, bipolar disor­
der, psychotic disorder, anxiety disorder) because the severity of the intoxication symp­
toms exceeds that associated with the stimulant-induced disorders, and the symptoms 
warrant independent clinical attention. Stimulant intoxication delirium would be distin­
guished by a disturbance in level of awareness and change in cognition.

Other mental disorders. Salient mental disturbances associated with stimulant intoxi­
cation should be distinguished from the symptoms of schizophrenia, paranoid type; bi­
polar and depressive disorders; generalized anxiety disorder; and panic disorder as 
described in DSM-5.
Stimulant Withdrawal
A. Cessation of (or reduction in) prolonged amphetamine-type substance, cocaine, or  
other stimulant use.
B. Dysphoric mood and two (or more) of the following physiological changes, developing  
within a few hours to several days after Criterion A :
1. Fatigue.
2. Vivid, unpleasant dreams.
3. Insomnia or hypersomnia.
4. Increased appetite.
5. Psychomotor retardation or agitation.

Specify  tlie specific substance tiiat causes the withdrawai syndrome (i.e., amphet­
amine-type substance, cocaine, or other stimulant).
Coding note: The ICD-9-CM code is 292.0. The ICD-10-CM code depends on whether  
the stimulant is an amphetamine, cocaine, or other stimulant. The ICD-10-CM code for  
amphetamine or an other stimulant withdrawal is FI 5.23, and the ICD-10-CM for cocaine  
withdrawal is F14.23. Note that the ICD-10-CM code indicates the comorbid presence of  
a moderate or severe amphetamine, cocaine, or other stimulant use disorder, reflecting  
the fact that amphetamine, cocaine, or other stimulant withdrawal can only occur in the

the fact that amphetamine, cocaine, or other stimulant withdrawal can only occur in the  
presence of a moderate or severe amphetamine, cocaine, or other stimulant use disorder.  
It is not permissible to code a comorbid m ild amphetamine, cocaine, or other stimulant use  
disorder with amphetamine, cocaine, or other stimulant withdrawal. _________________
The essential feature of stimulant withdrawal is the presence of a characteristic with­
drawal syndrome that develops within a few hours to several days after the cessation of 
(or marked reduction in) stimulant use (generally high dose) that has been prolonged (Cri­
terion A). The withdrawal syndrome is characterized by the development of dysphoric 
mood accompanied by two or more of the following physiological changes: fatigue, vivid 
and unpleasant dreams, insomnia or hypersomnia, increased appetite, and psychomotor

and unpleasant dreams, insomnia or hypersomnia, increased appetite, and psychomotor 
retardation or agitation (Criterion B). Bradycardia is often present and is a reliable mea­
sure of stimulant withdrawal.
Anhedonia and drug craving can often be present but are not part of the diagnostic cri­
teria. These symptoms cause clinically significant distress or impairment in social, occu­
pational, or other important areas of functioning (Criterion C). The symptoms must not be 
attributable to another medical condition and are not better explained by another mental 
disorder (Criterion D).

Acute withdrawal symptoms ("a crash") are often seen after periods of repetitive high-dose 
use ("runs" or 'l^inges"). These periods are characterized by intense and unpleasant feelings of 
lassitude and depression and increased appetite, generally requiring several days of rest and 
recuperation. Depressive symptoms with suicidal ideation or behavior can occur and are gen­
erally the most serious problems seen during "crashing" or other forms of stimulant with­
drawal. The majority of individuals with stimulant use disorder experience a withdrawal 
syndrome at some point, and virtually all individuals with the disorder report tolerance.
Stimulant use disorder and other stimulant-induced disorders. Stimulant withdrawal 
is distinguished from stimulant use disorder and from the other stimulant-induced disor­
ders (e.g., stimulant-induced intoxication delirium, depressive disorder, bipolar disorder,

ders (e.g., stimulant-induced intoxication delirium, depressive disorder, bipolar disorder, 
psychotic disorder, anxiety disorder, sexual dysfunction, sleep disorder) because the 
symptoms of withdrawal predominate the clinical presentation and are severe enough to 
warrant independent clinical attention.
Other Stimulant-Induced Disorders
The following stimulant-induced disorders (which include amphetamine-, cocaine-, and 
other stimulant-induced disorders) are described in other chapters of the manual with dis­
orders with which they share phenomenology (see the substance/medication-induced 
mental disorders in these chapters): stimulant-induced psychotic disorder ("Schizophrenia 
Spectrum and Other Psychotic Disorders"); stimulant-induced bipolar disorder ("Bipolar 
and Related Disorders"); stimulant-induced depressive disorder ("Depressive Disorders");

and Related Disorders"); stimulant-induced depressive disorder ("Depressive Disorders"); 
stimulant-induced anxiety disorder ("Anxiety Disorders"); stimulant-induced obsessive- 
compulsive disorder ("Obsessive-Compulsive and Related Disorders"); stimulant-induced 
sleep disorder ("Sleep-Wake Disorders"); and stimulant-induced sexual dysfunction ("Sex­
ual Dysfunctions"). For stimulant intoxication delirium, see the criteria and discussion of 
delirium in the chapter "Neurocognitive Disorders." These stimulant-induced disorders 
are diagnosed instead of stimulant intoxication or stimulant withdrawal only when the 
symptoms are sufficiently severe to warrant independent clinical attention.
This category applies to presentations in which symptoms characteristic of a stimulant-

This category applies to presentations in which symptoms characteristic of a stimulant-  
for any specific stimulant-related disorder or any of the disorders in the substance-related  
Coding note: The ICD-9-CM code is 292.9. The ICD-10-CM code depends on whether  
the stimulant is an amphetamine, cocaine, or another stimulant. The ICD-10-CM code for  
an unspecified amphetamine- or other stimulant-related disorder is F15.99. The ICD-10-  
CM code for an unspecified cocaine-related disorder is FI 4.99.

Tobacco-Related Disorders
Tobacco Use Disorder  
Tobacco Withdrawal  
Other Tobacco-Induced Disorders  
Unspecified Tobacco-Related Disorder
Tobacco Use Disorder
A. A problematic pattern of tobacco use leading to clinically significant impairment or dis­
1. Tobacco is often taken in larger amounts or over a longer period than was intended.
2. There is a persistent desire or unsuccessful efforts to cut down or control tobacco use.
3. A great deal of time is spent in activities necessary to obtain or use tobacco.
4. Craving, or a strong desire or urge to use tobacco.
5. Recurrent tobacco use resulting in a failure to fulfill major role obligations at work,  
school, or home (e.g., interference with work).
6. Continued tobacco use despite having persistent or recurrent social or interper­
sonal problems caused or exacerbated by the effects of tobacco (e.g., arguments

sonal problems caused or exacerbated by the effects of tobacco (e.g., arguments  
with others about tobacco use).
7. important social, occupational, or recreational activities are given up or reduced be­
cause of tobacco use.
8. Recurrent tobacco use in  situations in which it is physically hazardous (e.g., smok­
ing in bed).
9. Tobacco use is continued despite knowledge of having a persistent or recurrent  
by tobacco.
a. A need for markedly increased amounts of tobacco to achieve the desired effect.
b. A markedly diminished effect with continued use of the same amount of tobacco.
a. The characteristic withdrawal syndrome for tobacco (refer to Criteria A and B of  
the criteria set for tobacco withdrawal).

b. Tobacco (or a closely related substance, such as nicotine) is taken to relieve or  
avoid withdrawal symptoms.
In early remission: After full criteria for tobacco use disorder were previously met,  
none of the criteria for tobacco use disorder have been met for at least 3 months but  
sire or urge to use tobacco,”  may be met).
In sustained remission: After full criteria for tobacco use disorder were previously  
met, none of the criteria for tobacco use disorder have been met at any time during a  
strong desire or urge to use tobacco," may be met).

On maintenance therapy: The individual is taking a long-term maintenance medica­
tion, such as nicotine replacement medication, and no criteria for tobacco use disorder  
have been met for that class of medication (except tolerance to, or withdrawal from,  
the nicotine replacement medication).
environment where access to tobacco is restricted.
Coding based on current severity: Note for ICD-10-CM codes; If a tobacco withdrawal or  
tobacco-induced sleep disorder is also present, do not use the codes below for tobacco use  
disorder. Instead, the comorbid tobacco use disorder is  indicated in  the 4th character of the  
tobacco-induced disorder code (see the coding note for tobacco withdrawal or tobacco-  
induced sleep disorder). For example, if there is comorbid tobacco-induced sleep disorder and

induced sleep disorder). For example, if there is comorbid tobacco-induced sleep disorder and  
tobacco use disorder, only the tobacco-induced sleep disorder code is given, with the 4th char­
acter indicating whether the comorbid tobacco use disorder is moderate or severe: F17.208  
for moderate or severe tobacco use disorder with tobacco-induced sleep disorder. It is  not per­
missible to code a comorbid m ild tobacco use disorder with a tobacco-induced sleep disorder.
305.1 (Z72.0) Mild: Presence of 2-3 symptoms.
305.1 (F I7.200) Moderate: Presence of 4-5 symptoms.
305.1 (F I 7.200) Severe: Presence of 6 or more symptoms.
"On maintenance therapy" applies as a further specifier to individuals being maintained on 
other tobacco cessation medication (e.g., bupropion, varenicline) and as a further specifier of

other tobacco cessation medication (e.g., bupropion, varenicline) and as a further specifier of 
remission if the individual is both in remission and on maintenance therapy. "In a controlled 
environment" applies as a further specifier of remission if the individual is both in remission 
and in a controlled environment (i.e., in early remission in a controlled environment or in sus­
tained remission in a controlled environment). Examples of these environments are closely su­
pervised and substance-free jails, therapeutic conununities, and locked hospital units.
Tobacco use disorder is common among individuals who use cigarettes and smokeless to­
bacco daily and is uncommon among individuals who do not use tobacco daily or who use 
nicotine medications. Tolerance to tobacco is exemplified by the disappearance of nausea

nicotine medications. Tolerance to tobacco is exemplified by the disappearance of nausea 
and dizziness after repeated intake and with a more intense effect of tobacco the first time 
it is used during the day. Cessation of tobacco use can produce a well-defined withdrawal 
syndrome. Many individuals with tobacco use disorder use tobacco to relieve or to avoid 
withdrawal symptoms (e.g., after being in a situation where use is restricted). Many indi­
viduals who use tobacco have tobacco-related physical symptoms or diseases and con­
tinue to smoke. The large majority report craving when they do not smoke for several hours. 
Spending excessive time using tobacco can be exemplified by chain-smoking (i.e., smok­
ing one cigarette after another with no time between cigarettes). Because tobacco sources 
are readily and legally available, and because nicotine intoxication is very rare, spending a

are readily and legally available, and because nicotine intoxication is very rare, spending a 
great deal of time attempting to procure tobacco or recovering from its effects is uncom­
mon. Giving up important social, occupational, or recreational activities can occur when 
an individual forgoes an activity because it occurs in tobacco use-restricted areas. Use of 
tobacco rarely results in failure to fulfill major role obligations (e.g., interference with 
work, interference with home obligations), but persistent social or inteφersonal problems 
(e.g., having arguments with others about tobacco use, avoiding social situations because 
of others' disapproval of tobacco use) or use that is physically hazardous (e.g., smoking in

bed, smoking around flammable chemicals) occur at an intermediate prevalence. Although 
these criteria are less often endorsed by tobacco users, if endorsed, they can indicate a 
more severe disorder.
Smoking within 30 minutes of waking, smoking daily, smoking more cigarettes per day, 
and waking at night to smoke are associated with tobacco use disorder. Environmental 
cues can evoke craving and withdrawal. Serious medical conditions, such as lung and 
other cancers, cardiac and pulmonary disease, perinatal problems, cough, shortness of 
breath, and accelerated skin aging, often occur.
Cigarettes are the most commonly used tobacco product, representing over 90% of to­
bacco/nicotine use. In the United States, 57% of adults have never been smokers, 22% are 
former smokers, and 21% are current smokers. Approximately 20% of current U.S. smok­
ers are nondaily smokers. The prevalence of smokeless tobacco use is less than 5%, and the

ers are nondaily smokers. The prevalence of smokeless tobacco use is less than 5%, and the 
prevalence of tobacco use in pipes and cigars is less than 1%.
DSM-IV nicotine dependence criteria can be used to estimate the prevalence of tobacco 
use disorder, but since they are a subset of tobacco use disorder criteria, the prevalence of 
tobacco use disorder will be somewhat greater. The 12-month prevalence of DSM-IV nic­
otine dependence in the United States is 13% among adults age 18 years and older. Rates 
are similar among adult males (14%) and females (12%) and decline in age from 17% 
among 18- to 29-year-olds to 4% among individuals age 65 years and older. The prevalence 
of current nicotine dependence is greater among Native American and Alaska Natives 
(23%) than among whites (14%) but is less among African Americans (10%), Asian Amer­

icans and Pacific Islanders (6%), and Hispanics (6%). The prevalence among current daily 
smokers is approximately 50%.
In many developing nations, the prevalence of smoking is much greater in males than 
in females, but this is not the case in developed nations. However, there often is a lag in the 
demographic transition such that smoking increases in females at a later time.
The majority of U.S. adolescents experiment with tobacco use, and by age 18 years, about 
20% smoke at least monthly. Most of these individuals become daily tobacco users. Initi­
ation of smoking after age 21 years is rare. In general, some of the tobacco use disorder cri­
teria symptoms occur soon after beginning tobacco use, and many individuals' pattern of

teria symptoms occur soon after beginning tobacco use, and many individuals' pattern of 
use meets current tobacco use disorder criteria by late adolescence. More than 80% of in­
dividuals who use tobacco attempt to quit at some time, but 60% relapse within 1  week 
and less than 5% remain abstinent for life. However, most individuals who use tobacco 
make multiple attempts such that one-half of tobacco users eventually abstain. Individuals 
who use tobacco who do quit usually do not do so until after age 30 years. Although non­
daily smoking in the United States was previously rare, it has become more prevalent in 
the last decade, especially among younger individuals who use tobacco.
Temperamental. Individuals with externalizing personality traits are more likely to 
initiate tobacco use. Children with attention-deficit/hyperactivity disorder or conduct

initiate tobacco use. Children with attention-deficit/hyperactivity disorder or conduct 
disorder, and adults with depressive, bipolar, anxiety, personality, psychotic, or other 
substance use disorders, are at higher risk of starting and continuing tobacco use and of to­
bacco use disorder.

Environmental. Individuals with low incomes and low educational levels are more likely 
to initiate tobacco use and are less likely to stop.
Genetic and physiological. Genetic factors contribute to the onset of tobacco use, the 
continuation of tobacco use, and the development of tobacco use disorder, with a degree of 
heritability equivalent to that observed with other substance use disorders (i.e., about 
50%). Some of this risk is specific to tobacco, and some is common with the vulnerability to 
developing any substance use disorder.
Cultures and subcultures vary widely in their acceptance of the use of tobacco. The prev­
alence of tobacco use declined in the United States from the 1960s through the 1990s, but 
this decrease has been less evident in African American and Hispanic populations. Also, 
smoking in developing countries is more prevalent than in developed nations. The degree

smoking in developing countries is more prevalent than in developed nations. The degree 
to which these cultural differences are due to income, education, and tobacco control ac­
tivities in a country is unclear. Non-Hispanic white smokers appear to be more likely to 
develop tobacco use disorder than are smokers. Some ethnic differences may be biologi­
cally based. African American males tend to have higher nicotine blood levels for a given 
number of cigarettes, and this might contribute to greater difficulty in quitting. Also, the 
speed of nicotine metabolism is significantly different for whites compared with African 
Americans and can vary by genotypes associated with ethnicities.
Carbon monoxide in the breath, and nicotine and its metabolite cotinine in blood, saliva, or 
urine, can be used to measure the extent of current tobacco or nicotine use; however, these

urine, can be used to measure the extent of current tobacco or nicotine use; however, these 
are only weakly related to tobacco use disorder.
Functional Consequences of Tobacco Use Disorder
Medical consequences of tobacco use often begin when tobacco users are in their 40s and 
usually become progressively more debilitating over time. One-half of smokers who do 
not stop using tobacco will die early from a tobacco-related illness, and smoking-related 
morbidity occurs in more than one-half of tobacco users. Most medical conditions result 
from exposure to carbon monoxide, tars, and other non-nicotine components of tobacco. 
The major predictor of reversibility is duration of smoking. Secondhand smoke increases 
the risk of heart disease and cancer by 30%. Long-term use of nicotine medications does 
not appear to cause medical harm.

The most common medical diseases from smoking are cardiovascular illnesses, chronic 
obstructive pulmonary disease, and cancers. Smoking also increases perinatal problems, 
such as low birth weight and miscarriage. The most common psychiatric comorbidities are 
alcohol/substance, depressive, bipolar, anxiety, personality, and attention-deficit/hyper- 
activity disorders. In individuals with current tobacco use disorder, the prevalence of cur­
rent alcohol, drug, anxiety, depressive, bipolar, and personality disorders ranges from 
22% to 32%. Nicotine-dependent smokers are 2.7-8.1 times more likely to have these dis­
orders than nondependent smokers, never-smokers, or ex-smokers.

Tobacco Withdrawal
_____________ ^ ____________________________________________________________
Diagnostic Criteria 292.0 (F17.203)
A. Daily use of tobacco for at least several weeks.
B. Abrupt cessation of tobacco use, or reduction in the amount of tobacco used, followed  
within 24 hours by four (or more) of the following signs or symptoms:
1. Irritability, frustration, or anger.
2. Anxiety.
3. Difficulty concentrating.
7. Insomnia.
D. The signs or symptoms are not attributed to another medical condition and are not bet­
ter explained by another mental disorder, including intoxication or withdrawal from an­
other substance.
Coding note: The ICD-9-CM code is 292.0. The ICD-10-CM code for tobacco withdrawal

Coding note: The ICD-9-CM code is 292.0. The ICD-10-CM code for tobacco withdrawal  
is F17.203. Note that the ICD-10-CM code indicates the comorbid presence of a moderate  
or severe tobacco use disorder, reflecting the fact that tobacco withdrawal can only occur  
in the presence of a moderate or severe tobacco use disorder. It is not permissible to code  
a comorbid mild tobacco use disorder with tobacco withdrawal. ____________________
Withdrawal symptoms impair the ability to stop tobacco use. The symptoms after absti­
nence from tobacco are in large part due to nicotine deprivation. Symptoms are much 
more intense among individuals who smoke cigarettes or use smokeless tobacco than 
among those who use nicotine medications. This difference in symptom intensity is likely

among those who use nicotine medications. This difference in symptom intensity is likely 
due to the more rapid onset and higher levels of nicotine with cigarette smoking. Tobacco 
withdrawal is common among daily tobacco users who stop or reduce but can also occur 
among nondaily users. Typically, heart rate decreases by 5-12 beats per minute in the first 
few days after stopping smoking, and weight increases an average of 4-7 lb (2-3 kg) over 
the first year after stopping smoking. Tobacco withdrawal can produce clinically signifi­
cant mood changes and functional impairment.
Craving for sweet or sugary foods and impaired performance on tasks requiring vigilance 
are associated with tobacco withdrawal. Abstinence can increase constipation, coughing, 
dizziness, dreaming/nightmares, nausea, and sore throat. Smoking increases the metab­

olism of many medications used to treat mental disorders; thus, cessation of smoking can 
increase the blood levels of these medications, and this can produce clinically significant 
outcomes. This effect appears to be due not to nicotine but rather to other compounds in 
tobacco.

Approximately 50% of tobacco users who quit for 2 or more days will have symptoms that 
meet criteria for tobacco withdrawal. The most commonly endorsed signs and symptoms 
are anxiety, irritability, and difficulty concentrating. The least commonly endorsed symp­
toms are depression and insomnia.
Tobacco withdrawal usually begins within 24 hours of stopping or cutting down on to­
bacco use, peaks at 2-3 days after abstinence, and lasts 2-3 weeks. Tobacco withdrawal 
symptoms can occur among adolescent tobacco users, even prior to daily tobacco use. Pro­
longed symptoms beyond 1  month are uncommon.
Temperamental. Smokers with depressive disorders, bipolar disorders, anxiety disor­
ders, attention-deficit/hyperactivity disorder, and other substance use disorders have 
more severe withdrawal.
Genetic and physiological. Genotype can influence the probability of withdrawal upon 

urine, can be used to measure the extent of tobacco or nicotine use but are only weakly re­
lated to tobacco withdrawal.
Functional Consequences of Tobacco Withdrawal
Abstinence from cigarettes can cause clinically significant distress. Withdrawal impairs 
the ability to stop or control tobacco use. Whether tobacco withdrawal can prompt a new 
mental disorder or recurrence of a mental disorder is debatable, but if this occurs, it would 
be in a small minority of tobacco users.
The symptoms of tobacco withdrawal overlap with those of other substance withdrawal 
syndromes (e.g., alcohol withdrawal; sedative, hypnotic, or anxiolytic withdrawal; stim­

ulant withdrawal; caffeine withdrawal; opioid withdrawal); caffeine intoxication; anxiety, 
depressive, bipolar, and sleep disorders; and medication-induced akathisia. Admission to 
smoke-free inpatient units or voluntary smoking cessation can induce withdrawal symp­
toms that mimic, intensify, or disguise other disorders or adverse effects of medications 
used to treat mental disorders (e.g., irritability thought to be due to alcohol withdrawal 
could be due to tobacco withdrawal). Reduction in symptoms with the use of nicotine 
medications confirms the diagnosis.
Other Tobacco-Induced Disorders
Tobacco-induced sleep disorder is discussed in the chapter "Sleep-Wake Disorders" (see 
''Substance/Medication-Induced Sleep Disorder").

^  292.9 (F17.209)
This category applies to presentations in  which symptoms characteristic of a tobacco-  
related disorder that cause clinically significant distress or impairment in  social, occupa­
for any specific tobacco-related disorder or any of the disorders in the substance-related  
Other (or Unknown)  
Other (or Unknown) Substance Use Disorder  
Other (or Unknown) Substance Intoxication  
Other (or Unknown) Substance Withdrawal  
Other (or Unknown) Substance-Induced Disorders  
Unspecified Other (or Unknown) Substance-Related Disorder
Other (or Unknown) Substance Use Disorder
A. A problematic pattern of use of an intoxicating substance not able to be classified  
within the alcohol; caffeine; cannabis; hallucinogen (phencyclidine and others); inhal­

ant; opioid; sedative, hypnotic, or anxiolytic; stimulant; or tobacco categories and lead­
ing to clinically significant impairment or distress, as manifested by at least two of the  
following, occurring within a 12-month period:
1. The substance is often taken in larger amounts or over a longer period than was  
intended.
substance.
3. A great deal of time is spent in activities necessary to obtain the substance, use the  
substance, or recover from its effects.
4. Craving, or a strong desire or urge to use the substance.
5. Recurrent use of the substance resulting in a failure to fulfill major role obligations  
at work, school, or home.

6. Continued use of the substance despite having persistent or recurrent social or in­
terpersonal problems caused or exacerbated by the effects of its use.
cause of use of the substance.
8. Recurrent use of the substance in situations in which it is physically hazardous.
9. Use of the substance is continued despite knowledge of having a persistent or re­
current physical or psychological problem that is likely to have been caused or ex­
acerbated by the substance.

a. A need for markedly increased amounts of the substance to achieve intoxication  
b. A markedly diminished effect with continued use of the same amount of the sub­
stance.
a. The characteristic withdrawal syndrome for other (or unknown) substance (refer to  
Criteria A and B of the criteria sets for other [or unknown] substance withdrawal,  
p. 583).
b. The substance (or a closely related substance) is taken to relieve or avoid with­
In early remission: After full criteria for other (or unknown) substance use disorder were  
previously met, none of the criteria for other (or unknown) substance use disorder have  
been met for at least 3 months but for less than 12 months (with the exception that Cri­
terion A4, “ Craving, or a strong desire or urge to use the substance,”  may be met).

In sustained remission: After full criteria for other (or unknown) substance use disor­
der were previously met, none of the criteria for other (or unknown) substance use dis­
order have been met at any time during a period of 12 months or longer (with the  
exception that Criterion A4, “ Craving, or a strong desire or urge to use the substance,”  
may be met).
environment where access to the substance is restricted.
Coding based on current severity: Note for ICD-10-CM codes: If an other (or unknown) sub­
stance intoxication, other (or unknown) substance withdrawal, or another other (or unknown)  
substance-induced mental disorder is present, do not use the codes below for other (or un­

known) substance use disorder. Instead, the comorbid other (or unknown) substance use dis­
order is indicated in the 4th character of the other (or unknown) substance-induced disorder  
code (see the coding note for other (or unknown) substance intoxication, other (or unknown)  
substance withdrawal, or specific other (or unknown) substance-induced mental disorder).  
For example, if there is comotbid other (or unknown) substance-induced depressive disorder  
and other (or unknown) substance use disorder, only the other (or unknown) substance-  
induced depressive disorder code is given, with the 4th character indicating whether the co­
m orbid other (or unknown) substance use disorder is m ild, moderate, or severe: FI 9.14 for

m orbid other (or unknown) substance use disorder is m ild, moderate, or severe: FI 9.14 for  
other (or unknown) substance use disorder with other (or unknown) substance-induced de­
pressive disorder or FI 9.24 for a moderate or severe other (or unknown) substance use dis­
order with other (or unknown) substance-induced depressive disorder.
305.90 (FI 9.10) Mild: Presence of 2 -3  symptoms.
304.90 (FI 9.20) Moderate: Presence of 4-5 symptoms.
304.90 (F19.20) Severe: Presence of 6 or more symptoms.
environments are closely supervised and substance-free jails, therapeutic communities,

The diagnostic dass other (or unknown) substance use and related disorders comprises 
substance-related disorders unrelated to alcohol; caffeine; cannabis; hallucinogens (phen­
cyclidine and others); inhalants; opioids; sedative, hypnotics, or anxiolytics; stimulants 
(including amphetamine and cocaine); or tobacco. Such substances include anabolic ste­
roids; nonsteroidal anti-inflammatory drugs; cortisol; antiparkinsonian medications; an­
tihistamines; nitrous oxide; amyl-, butyl-, or isobutyl-nitrites; betel nut, which is chewed 
in many cultures to produce mild euphoria and a floating sensation; kava (from a South 
Pacific pepper plant), which produces sedation, incoordination, weight loss, mild hepati­
tis, and lung abnormalities; or cathinones (including khât plant agents and synthetic chem­
ical derivatives) that produce stimulant effects. Unknown substance-related disorders are

ical derivatives) that produce stimulant effects. Unknown substance-related disorders are 
associated with unidentified substances, such as intoxications in which the individual can­
not identify the ingested drug, or substance use disorders involving either new, black mar­
ket drugs not yet identified or familiar drugs illegally sold under false names.
Other (or unknown) substance use disorder is a mental disorder in which repeated use 
of an other or unknown substance typically continues, despite the individual's knowing 
that the substance is causing serious problems for the individual. Those problems are re­
flected in the diagnostic criteria. When the substance is known, it should be reflected in the 
name of the disorder upon coding (e.g., nitrous oxide use disorder).

A diagnosis of other (or unknown) substance use disorder is supported by the individual's 
statement that the substance involved is not among the nine classes listed in this chapter; by re­
curring episodes of intoxication with negative results in standard drug screens (which may not 
detect new or rarely used substances); or by the presence of symptoms characteristic of an un­
identified substance that has newly appeared in the individual's community.
Because of increased access to nitrous oxide ("laughing gas"), membership in certain 
populations is associated with diagnosis of nitrous oxide use disorder. The role of this gas 
as an anesthetic agent leads to misuse by some medical and dental professionals. Its use as 
a propellant for commercial products (e.g., whipped cream dispensers) contributes to

a propellant for commercial products (e.g., whipped cream dispensers) contributes to 
misuse by food service workers. With recent widespread availability of the substance in 
"whippet" cartridges for use in home whipped cream dispensers, nitrous oxide misuse by 
adolescents and young adults is significant, especially among those who also inhale vola­
tile hydrocarbons. Some continuously using individuals, inhaling from as many as 240 
whippets per day, may present with serious medical complications and mental conditions, 
including myeloneuropathy, spinal cord subacute combined degeneration, peripheral 
neuropathy, and psychosis. These conditions are also associated with a diagnosis of ni­
trous oxide use disorder.
Use of amyl-, butyl-, and isobutyl nitrite gases has been observed among homosexual 
men and some adolescents, especially those with conduct disorder. Membership in these

men and some adolescents, especially those with conduct disorder. Membership in these 
populations may be associated with a diagnosis of amyl-, butyl-, or isobutyl-nitrite use dis­
order. However, it has not been determined that these substances produce a substance use 
disorder. Despite tolerance, these gases may not alter behavior through central effects, and 
they may be used only for their peripheral effects.
Substance use disorders generally are associated with elevated risks of suicide, but there 
is no evidence of unique risk factors for suicide with other (or unknown) substance use 
disorder.
Based on extremely limited data, the prevalence of other (or unknown) substance use disorder 
is likely lower than that of use disorders involving the nine substance classes in this chapter.

No single pattern of development or course characterizes the pharmacologically varied 
other (or unknown) substance use disorders. Often unknown substance use disorders will 
be reclassified when the unknown substance eventually is identified.
Risk and prognostic factors for other (or unknown) substance use disorders are thought to 
be similar to those for most substance use disorders and include the presence of any other 
substance use disorders, conduct disorder, or antisocial personality disorder in the indi­
vidual or the individual's family; early onset of substance problems; easy availability of 
the substance in the individual's environment; childhood maltreatment or trauma; and ev­
idence of limited early self-control and behavioral disinhibition.
Certain cultures may be associated with other (or unknown) substance use disorders in­

volving specific indigenous substances within the cultural region, such as betel nut.
Urine, breath, or saliva tests may correctly identify a commonly used substance falsely 
sold as a novel product. However, routine clinical tests usually cannot identify truly un­
usual or new substances, which may require testing in specialized laboratories.
Use of Other or unknown substances without meeting criteria for other (or unknown)  
substance use disorder. Use of unknown substances is not rare among adolescents, but 
most use does not meet the diagnostic standard of two or more criteria for other (or un­
known) substance use disorder in the past year.
Substance use disorders. Other (or unknown) substance use disorder may co-occur

Substance use disorders. Other (or unknown) substance use disorder may co-occur 
with various substance use disorders, and the symptoms of the disorders may be similar 
and overlapping. To disentangle symptom patterns, it is helpful to inquire about which 
symptoms persisted during periods when some of the substances were not being used.
Other (or unknown) substance/medication-induced disorder. This diagnosis should 
be differentiated from instances when the individual's symptoms meet full criteria for one 
of the following disorders, and that disorder is caused by an other or unknown substance: 
delirium, major or mild neurocognitive disorder, psychotic disorder, depressive disorder, 
anxiety disorder, sexual dysfunction, or sleep disorder.
Other medical conditions. Individuals with substance use disorders, including other 
(or unknown) substance use disorder, may present with symptoms of many medical dis­

orders. These disorders also may occur in the absence of other (or unknown) substance use 
disorder. A history of little or no use of other or unknown substances helps to exclude 
other (or unknown) substance use disorder as the source of these problems.
Substance use disorders, including other (or unknown) substance use disorder, are com­
monly comorbid with one another, with adolescent conduct disorder and adult antisocial 
personality disorder, and with suicidal ideation and suicide attempts.

Other (or Unknown) Substance Intoxication
------------------- ^______________________________________________________
A. The development of a reversible substance-specific syndrome attributable to recent in­
gestion of (or exposure to) a substance that is not listed elsewhere or is unknown.
B. Clinically significant problematic behavioral or psychological changes that are attribut­
able to the effect of the substance on the central nervous system (e.g., impaired motor  
coordination, psychomotor agitation or retardation, euphoria, anxiety, belligerence,  
mood lability, cognitive impairment, impaired judgment, social withdrawal) and develop  
during, or shortly after, use of the substance.
C. The signs or symptoms are not attributable to another medical condition and are not bet­
Coding note: The ICD-9-CM code is 292.89. The ICD-10-CM code depends on whether

there is a comorbid other (or unknown) substance use disorder involving the same sub­
stance. If a mild other (or unknown) substance use disorder is comorbid, the ICD-10-CM  
code is FI 9.129, and if a moderate or severe other (or unknown) substance use disorder is  
comorbid, the ICD-10-CM code is FI 9.229. If there is no comorbid other (or unknown) sub­
stance use disorder involving the same substance, then the ICD-10-CM code is F19.929.
Note: For information on Risk and Prognostic Factors, Culture-Related Diagnostic Issues, 
and Diagnostic Markers, see the corresponding sections in other (or unknown) substance 
use disorder.
Other (or unknown) substance intoxication is a clinically significant mental disorder that

Other (or unknown) substance intoxication is a clinically significant mental disorder that 
develops during, or immediately after, use of either a) a substance not elsewhere ad­
dressed in this chapter (i.e., alcohol; caffeine; cannabis; phencyclidine and other halluci­
nogens; inhalants; opioids; sedatives, hypnotics, or anxiolytics; stimulants; or tobacco) or 
b) an unknown substance. If the substance is known, it should be reflected in the name of 
the disorder upon coding.
Application of the diagnostic criteria for other (or unknown) substance intoxication is 
very challenging. Criterion A requires development of a reversible "substance-specific 
syndrome," but if the substance is unknown, that syndrome usually will be unknown. To 
resolve this conflict, clinicians may ask the individual or obtain collateral history as to 
whether the individual has experienced a similar episode after using substances with the

whether the individual has experienced a similar episode after using substances with the 
same "street" name or from the same source. Similarly, hospital emergency departments 
sometimes recognize over a few days numerous presentations of a severe, unfamiliar in­
toxication syndrome from a newly available, previously unknown substance. Because of 
the great variety of intoxicating substances. Criterion B can provide only broad examples 
of signs and symptoms from some intoxications, with no threshold for the number of 
symptoms required for a diagnosis; clinical judgment guides those decisions. Criterion C 
requires ruling out other medical conditions, mental disorders, or intoxications.
The prevalence of other (or unknown) substance intoxication is unknown.
Intoxications usually appear and then peak minutes to hours after use of the substance, but

Intoxications usually appear and then peak minutes to hours after use of the substance, but 
the onset and course vary with the substance and the route of administration. Generally,

substances used by pulmonary inhalation and intravenous injection have the most rapid 
onset of action, while those ingested by mouth and requiring metabolism to an active 
product are much slower. (For example, after ingestion of certain mushrooms, the first 
signs of an eventually fatal intoxication may not appear for a few days.) Intoxication ef­
fects usually resolve within hours to a very few days. However, the body may completely 
eliminate an anesthetic gas such as nitrous oxide just minutes after use ends. At the other 
extreme, some "hit-and-run" intoxicating substances poison systems, leaving permanent 
impairments. For example, MPTP (l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine), a con­
taminating by-product in the synthesis of a certain opioid, kills dopaminergic cells and in­
duces permanent parkinsonism in users who sought opioid intoxication.

Impairment from intoxication with any substance may have serious consequences, includ­
ing dysfunction at work, social indiscretions, problems in interpersonal relationships, fail­
ure to fulfill role obligations, traffic accidents, fighting, high-risk behaviors (i.e., having 
unprotected sex), and substance or medication overdose. The pattern of consequences will 
vary with the particular substance.
Use of Other or unknown substance, without meeting criteria for other (or unknown)  
substance intoxication. The individual used an other or unknown substance(s), but the 
dose was insufficient to produce symptoms that meet the diagnostic criteria required for 
the diagnosis.
Substance intoxication or other substance/medication-induced disorders. Familiar sub­

stances may be sold in the black market as novel products, and individuals may experience 
intoxication from those substances. History, toxicology screens, or chemical testing of the 
substance itself may help to identify it.
Different types of other (or unknown) substance-related disorders. Episodes of other 
(or unknown) substance intoxication may occur during, but are distinct from, other (or un­
known) substance use disorder, unspecified other (or unknown) substance-related disor­
der, and other (or unknown) substance-induced disorders.
Other toxic, metabolic, traumatic, neoplastic, vascular, or infectious disorders that impair  
brain function and cognition. Numerous neurological and other medical conditions may

brain function and cognition. Numerous neurological and other medical conditions may 
produce rapid onset of signs and symptoms mimicking those of intoxications, including the 
examples in Criterion B. Paradoxically, drug withdrawals also must be ruled out, because, for 
example, lethargy may indicate withdrawal from one drug or intoxication with another drug.
As with all substance-related disorders, adolescent conduct disorder, adult antisocial per­
sonality disorder, and other substance use disorders tend to co-occur with other (or un­
known) substance intoxication.

Other (or Unknown) Substance Withdrawal
Diagnostic Criteria 292.0 (F19.239)
A. Cessation of (or reduction in) use of a substance that has been heavy and prolonged.
B. The development of a substance-specific syndrome shortly after the cessation of (or  
reduction in) substance use.
C. The substance-specific syndrome causes clinically significant distress or impairment  
D. The symptoms are not attributable to another medical condition and are not better ex­
plained by another mental disorder, including withdrawal from another substance.
E. The substance involved cannot be classified under any of the other substance catego­
ries (alcohol; caffeine; cannabis; opioids; sedatives, hypnotics, or anxiolytics; stimu­
lants; or tobacco) or is unknown.
Coding note: The ICD-9-CM code is 292.0. The ICD-10-CM code for other (or unknown) sub­
stance withdrawal is F19.239. Note that the ICD-10-CM code indicates the comorbid presence

stance withdrawal is F19.239. Note that the ICD-10-CM code indicates the comorbid presence  
of a moderate or severe other (or unknown) substance use disorder. It is not permissible to  
code a comorbid m ild other (or unknown) substance use disorder with other (or unknown) sub­
stance withdrawal.
Note: For information on Risk and Prognostic Factors and Diagnostic Markers, see the cor­
responding sections in other (or unknown) substance use disorder.
Other (or unknown) substance withdrawal is a clinically significant mental disorder that 
develops during, or within a few hours to days after, reducing or terminating dosing with 
a substance (Criteria A and B). Although recent dose reduction or termination usually is 
clear in the history, other diagnostic procedures are very challenging if the drug is un­

known. Criterion B requires development of a "substance-specific syndrome" (i.e., the in­
dividual's signs and symptoms must correspond with the known withdrawal syndrome 
for the recently stopped drug)—a requirement that rarely can be met with an unknown 
substance. Consequently, clinical judgment must guide such decisions when information 
is this limited. Criterion D requires ruling out other medical conditions, mental disorders, 
or withdrawals from familiar substances. When the substance is known, it should be re­
flected in the name of the disorder upon coding (e.g., betel nut withdrawal).
The prevalence of other (or unknown) substance withdrawal is unknown.
Withdrawal signs commonly appear some hours after use of the substance is terminated,

Withdrawal signs commonly appear some hours after use of the substance is terminated, 
but the onset and course vary greatly, depending on the dose typically used by the person 
and the rate of elimination of the specific substance from the body. At peak severity, with­
drawal symptoms from some substances involve only moderate levels of discomfort, 
whereas withdrawal from other substances may be fatal. Withdrawal-associated dyspho­
ria often motivates relapse to substance use. Withdrawal symptoms slowly abate over 
days, weeks, or months, depending on the particular drug and doses to which the indi­
vidual became tolerant.
Culture-related issues in diagnosis will vary with the particular substance.

Withdrawal from any substance may have serious consequences, including physical signs 
and symptoms (e.g., malaise, vital sign changes, abdominal distress, headache), intense 
drug craving, anxiety, depression, agitation, psychotic symptoms, or cognitive impairments. 
These consequences may lead to problems such as dysfunction at work, problems in in­
terpersonal relationships, failure to fulfill role obligations, traffic accidents, fighting, high­
risk behavior (e.g., having unprotected sex), suicide attempts, and substance or medica­
tion overdose. The pattern of consequences will vary with the particular substance.
Dose reduction after extended dosing, but not meeting the criteria for other (or un­
known) substance withdrawal. The individual used other (or unknown) substances, 
but the dose that was used was insufficient to produce symptoms that meet the criteria re­
quired for the diagnosis.

Substance withdrawal or other substance/medication-induced disorders. Familiar 
substances may be sold in the black market as novel products, and individuals may expe­
rience withdrawal when discontinuing those substances. History, toxicology screens, or 
chemical testing of the substance itself may help to identify it.
(or unknown) substance withdrawal may occur during, but are distinct from, other (or un­
der, and unspecified other (or unknown) substance-induced disorders.
Other toxic, metabolic, traumatic, neoplastic, vascular, or infectious disorders that im­

pair brain function and cognition. Numerous neurological and other medical condi­
tions may produce rapid onset of signs and symptoms mimicking those of withdrawals. 
Paradoxically, drug intoxications also must be ruled out, because, for example, lethargy 
may indicate withdrawal from one drug or intoxication with another drug.
sonality disorder, and other substance use disorders likely co-occur with other (or un­
known) substance withdrawal.
Other (or Unknown) 
Because the category of other or unknown substances is inherently ill-defined, the extent 
and range of induced disorders are uncertain. Nevertheless, other (or unknown) sub­

stance-induced disorders are possible and are described in other chapters of the manual 
induced mental disorders in these chapters): other (or unknown) substance-induced psy­
chotic disorder ("Schizophrenia Spectrum and Other Psychotic Disorders"); other (or un­
known substance-induced bipolar disorder ("Bipolar and Related Disorders"); other (or 
unknown) substance-induced depressive disorder ("Depressive Disorders"); other (or 
unknown) substance-induced anxiety disorders ("Anxiety Disorders"); other (or un­
known) substance-induced obsessive-compulsive disorder ("Obsessive-Compulsive and 
Related Disorders"); other (or unknown) substance-induced sleep disorder ("Sleep-Wake

Disorders"); other (or unknown) substance-induced sexual dysfunction ("Sexual Dys­
functions"); an(J other (or unknown) substance/medication-induced major or mild neu- 
rocognitive disorder ("Neurocognitive Disorders"). For other (or unknown) substance- 
induced intoxication delirium and other (or unknown) substance-induced withdrawal 
delirium, see the criteria and discussion of delirium in the chapter "Neurocognitive Dis­
orders." These other (or unknown) substance-induced disorders are diagnosed instead of 
other (or unknown) substance intoxication or other (or unknown) substance withdrawal 
only when the symptoms are sufficiently severe to warrant independent clinical attention.
Unspecified Other (or Unknown)  
Substance-Related Disorder
292.9 (F19.99)
This category applies to presentations in  which symptoms characteristic of an other (or un­
known) substance-related disorder that cause clinically significant distress or impairment

known) substance-related disorder that cause clinically significant distress or impairment  
in social, occupational, or other important areas of functioning predominate but do not  
meet the full criteria for any specific other (or unknown) substance-related disorder or any  
of the disorders in  the substance-related disorders diagnostic class.
Non-Substance-Related Disorders
Gambling Disorder
Diagnostic Criteria 312.31 (F63.0)
A. Persistent and recurrent problematic gambling behavior leading to clinically significant
impairment or distress, as indicated by the individual exhibiting four (or more) of the fol­
lowing in a 12-month period:
1. Needs to gamble with increasing amounts of money in  order to achieve the desired  
excitement.
2. Is restless or irritable when attempting to cut down or stop gambling.
3. Has made repeated unsuccessful efforts to control, cut back, or stop gambling.

4. Is often preoccupied with gambling (e.g., having persistent thoughts of reliving past  
gambling experiences, handicapping or planning the next venture, thinking of ways  
to get money with which to gamble).
5. Often gambles when feeling distressed (e.g., helpless, guilty, anxious, depressed).
6. After losing money gambling, often returns another day to get even (“ chasing”  one’s  
losses).
7. Lies to conceal the extent of involvement with gambling.
8. Has jeopardized or lost a significant relationship, job, or educational or career op­
portunity because of gambling.
9. Relies on others to provide money to relieve desperate financial situations caused  
by gambling.
B. The gambling behavior is not better explained by a manic episode.

Episodic: Meeting diagnostic criteria at more than one time point, witli symptoms sub­
siding between periods of gambling disorder for at least several months.
Persistent: Experiencing continuous symptoms, to meet diagnostic criteria for multiple  
years.
in eariy remission: After full criteria for gambling disorder were previously met, none  
of the criteria for gambling disorder have been met for at least 3 months but for less  
than 12 months.
in sustained remission: After full criteria for gambling disorder were previously met,  
none of the criteria for gambling disorder have been met during a period of 12 months  
or longer.
Mild: 4-5 criteria met.  
iModerate: 6-7 criteria met.
Severe: 8-9 criteria met.
Note: Although some behavioral conditions that do not involve ingestion of substances 
have similarities to substance-related disorders, only one disorder—gambling disorder— 
has sufficient data to be included in this section.

Severity is based on the number of criteria endorsed. Individuals with mild gambling dis­
order may exhibit only 4-5 of the criteria, with the most frequently endorsed criteria usu­
ally related to preoccupation with gambling and "chasing" losses. Individuals with 
moderately severe gambling disorder exhibit more of the criteria (i.e., 6-7). Individuals 
with the most severe form will exhibit all or most of the nine criteria (i.e., 8-9). Jeopardiz­
ing relationships or career opportunities due to gambling and relying on others to provide 
money for gambling losses are typically the least often endorsed criteria and most often oc­
cur among those with more severe gambling disorder. Furthermore, individuals present­
ing for treatment of gambling disorder typically have moderate to severe forms of the 
disorder.

disorder.
Gambling involves risking something of value in the hopes of obtaining something of 
greater value. In many cultures, individuals gamble on games and events, and most do so 
without experiencing problems. However, some individuals develop substantial impair­
ment related to their gambling behaviors. The essential feature of gambling disorder is 
persistent and recurrent maladaptive gambling behavior that disrupts personal, family, 
and/or vocational pursuits (Criterion A). Gambling disorder is defined as a cluster of four 
or more of the symptoms listed in Criterion A occurring at any time in the same 12-month 
period.
A pattern of "chasing one's losses" may develop, with an urgent need to keep gam­
bling (often with the placing of larger bets or the taking of greater risks) to undo a loss or

period.
bling (often with the placing of larger bets or the taking of greater risks) to undo a loss or 
series of losses. The individual may abandon his or her gambling strategy and try to win 
back losses all at once. Although many gamblers may "chase" for short periods of time, it 
is the frequent, and often long-term, "chase" that is characteristic of gambling disorder 
(Criterion A 6). Individuals may lie to family members, therapists, or others to conceal the 
extent of involvement with gambling; these instances of deceit may also include, but 
are not limited to, covering up illegal behaviors such as forgery, fraud, theft, or embez­
zlement to obtain money with which to gamble (Criterion A7). Individuals may also en-

gage in "bailout" behavior, turning to family or others for help with a desperate financial 
situation that w,as caused by gambling (Criterion A9).
Distortions in thinking (e.g., denial, superstitions, a sense of power and control over the 
outcome of chance events, overconfidence) may be present in individuals with gambling 
disorder. Many individuals with gambling disorder believe that money is both the cause 
of and the solution to their problems. Some individuals with gambling disorder are im­
pulsive, competitive, energetic, restless, and easily bored; they may be overly concerned 
with the approval of others and may be generous to the point of extravagance when win­
ning. Other individuals with gambling disorder are depressed and lonely, and they may 
gamble when feeling helpless, guilty, or depressed. Up to half of individuals in treatment 
for gambling disorder have suicidal ideation, and about 17% have attempted suicide.

The past-year prevalence rate of gambling disorder is about 0.2%-0.3% in the general pop­
ulation. In the general population, the lifetime prevalence rate is about 0.4%-1.0%. For fe­
males, the lifetime prevalence rate of gambling disorder is about 0.2%, and for males it is 
about 0.6%. The lifetime prevalence of pathological gambling among African Americans is 
about 0.9%, among whites about 0.4%, and among Hispanics about 0.3%.
The onset of gambling disorder can occur during adolescence or young adulthood, but in 
other individuals it manifests during middle or even older adulthood. Generally, gam­
bling disorder develops over the course of years, although the progression appears to be 
more rapid in females than in males. Most individuals who develop a gambling disorder

more rapid in females than in males. Most individuals who develop a gambling disorder 
evidence a pattern of gambling that gradually increases in both frequency and amount of 
wagering. Certainly, milder forms can develop into more severe cases. Most individuals 
with gambling disorder report that one or two types of gambling are most problematic for 
them, although some individuals participate in many forms of gambling. Individuals are 
likely to engage in certain types of gambling (e.g., buying scratch tickets daily) more fre­
quently than others (e.g., playing slot machines or blackjack at the casino weekly). Fre­
quency of gambling can be related more to the type of gambling than to the severity of the 
overall gambling disorder. For example, purchasing a single scratch ticket each day may 
not be problematic, while less frequent casino, sports, or card gambling may be part of a

not be problematic, while less frequent casino, sports, or card gambling may be part of a 
gambling disorder. Similarly, amounts of money spent wagering are not in themselves in­
dicative of gambling disorder. Some individuals can wager thousands of dollars per 
month and not have a problem with gambling, while others may wager much smaller 
amounts but experience substantial gambling-related difficulties.
Gambling patterns may be regular or episodic, and gambling disorder can be persis­
tent or in remission. Gambling can increase during periods of stress or depression and 
during periods of substance use or abstinence. There may be periods of heavy gambling 
and severe problems, times of total abstinence, and periods of nonproblematic gambling. 
Gambling disorder is sometimes associated with spontaneous, long-term remissions.

Gambling disorder is sometimes associated with spontaneous, long-term remissions. 
Nevertheless, some individuals underestimate their vulnerability to develop gambling 
disorder or to return to gambling disorder following remission. When in a period of re­
mission, they may incorrectly assume that they will have no problem regulating gambling 
and that they may gamble on some forms nonproblematically, only to experience a return 
to gambling disorder.
Early expression of gambling disorder is more common among males than among fe­
males. Individuals who begin gambling in youth often do so with family members or

friends. Development of early-life gambling disorder appears to be associated v^ith impul- 
sivity and substance abuse. Many high school and college shidents who  develop gambling 
disorder grow out of the disorder over time, although it remains a lifelong problem for 
some. Mid- and later-life onset of gambling disorder is more common among females than 
among males.
There are age and gender variations in the type of gambling activities and the preva­
lence rates of gambling disorder. Gambling disorder is more common among younger and 
middle-age persons than among older adults. Among adolescents and young adults, the 
disorder is more prevalent in males than in females. Younger individuals prefer different 
forms of gambling (e.g., sports betting), while older adults are more likely to develop 
problems with slot machine and bingo gambling. Although the proportions of individuals 
who seek treatment for gambling disorder are low across all age groups, younger individ­

uals are especially unlikely to present for treatment.
Males are more likely to begin gambling earlier in life and to have a younger age at on­
set of gambling disorder than females, who are more likely to begin gambling later in life 
and to develop gambling disorder in a shorter time frame. Females with gambling disor­
der are more likely than males with gambling disorder to have depressive, bipolar, and 
anxiety disorders. Females also have a later age at onset of the disorder and seek treatment 
sooner, although rates of treatment seeking are low (< 10%) among individuals with gam­
bling disorder regardless of gender.
Temperamental. Gambling that begins in childhood or early adolescence is associated

Temperamental. Gambling that begins in childhood or early adolescence is associated 
with increased rates of gambling disorder. Gambling disorder also appears to aggregate 
with antisocial personality disorder, depressive and bipolar disorders, and other sub­
stance use disorders, particularly with alcohol disorders.
Genetic and physiological. Gambling disorder can aggregate in families, and this effect 
appears to relate to both environmental and genetic factors. Gambling problems are more 
frequent in monozygotic than in dizygotic twins. Gambling disorder is also more preva­
lent among first-degree relatives of individuals with moderate to severe alcohol use dis­
order than among the general population.
Course modifiers. Many individuals, including adolescents and young adults, are likely to 
resolve their problems with gambling disorder over time, although a strong predictor of

resolve their problems with gambling disorder over time, although a strong predictor of 
future gambling problems is prior gambling problems.
Individuals from specific cultures and races/ethnicities are more likely to participate in 
some types of gambling activities than others (e.g., pai gow, cockfights, blackjack, horse rac­
ing). Prevalence rates of gambling disorder are higher among African Americans than 
among European Americans, with rates for Hispanic Americans similar to those of Euro­
pean Americans. Indigenous populations have high prevalence rates of gambling disorder.
Males develop gambling disorder at higher rates than females, although this gender gap 
may be narrowing. Males tend to wager on different forms of gambling than females, with

may be narrowing. Males tend to wager on different forms of gambling than females, with 
cards, sports, and horse race gambling more prevalent among males, and slot machine and 
bingo gambling more common among females.

Functional Consequences of Gambling Disorder
Areas of psychosocial, health, and mental health functioning may be adversely affected by 
gambling disorder. Specifically, individuals with gambling disorder may, because of their 
involvement with gambling, jeopardize or lose important relationships with family mem­
bers or friends. Such problems may occur from repeatedly lying to others to cover up the 
extent of gambling or from requesting money that is used for gambling or to pay off gam­
bling debts. Employment or educational activities may likewise be adversely impacted by 
gambling disorder; absenteeism or poor work or school performance can occur with gam­
bling disorder, as individuals may gamble during work or school hours or be preoccupied 
with gambling or its adverse consequence when they should be working or studying. In­
dividuals with gambling disorder have poor general health and utilize medical services at 
high rates.

Nondisordered gambling. Gambling disorder must be distinguished from professional 
and social gambling. In professional gambling, risks are limited and discipline is central. 
Social gambling typically occurs with friends or colleagues and lasts for a limited period of 
time, with acceptable losses. Some individuals can experience problems associated with 
gambling (e.g., short-term chasing behavior and loss of control) that do not meet the full 
criteria for gambling disorder.
Manic episode. Loss of judgment and excessive gambling may occur during a manic ep­
isode. An additional diagnosis of gambling disorder should be given only if the gambling 
behavior is not better explained by manic episodes (e.g., a history of maladaptive gam­
bling behavior at times other than during a manic episode). Alternatively, an individual

bling behavior at times other than during a manic episode). Alternatively, an individual 
with gambling disorder may, during a period of gambling, exhibit behavior that resembles 
a manic episode, but once the individual is away from the gambling, these manic-like fea­
tures dissipate.
Personality disorders. Problems with gambling may occur in individuals with antisocial 
personality disorder and other personality disorders. If the criteria are met for both disor­
ders, both can be diagnosed.
Other medical conditions. Some patients taking dopaminergic medications (e.g., for 
Parkinson's disease) may experience urges to gamble. If such symptoms dissipate when 
dopaminergic medications are reduced in dosage or ceased, then a diagnosis of gambling 
disorder would not be indicated.
Gambling disorder is associated with poor general health. In addition, some specific med­

ical diagnoses, such as tachycardia and angina, are more common among individuals with 
gambling disorder than in the general population, even when other substance use disor­
ders, including tobacco use disorder, are controlled for. Individuals with gambling disor­
der have high rates of comorbidity with other mental disorders, such as substance use 
disorders, depressive disorders, anxiety disorders, and personality disorders. In some in­
dividuals, other mental disorders may precede gambling disorder and be either absent or 
present during the manifestation of gambling disorder. Gambling disorder may also occur 
prior to the onset of other mental disorders, especially anxiety disorders and substance use 

The neurocognitive disorders (NCDs) (referred to in DSM-IV as "Dementia,
Delirium, Amnestic, and Other Cognitive Disorders") begin with delirium, followed by 
the syndromes of major NCD, mild NCD, and their etiological subtypes. The major or 
mild NCD subtypes are NCD due to Alzheimer's disease; vascular NCD; NCD with Lewy 
bodies; NCD due to Parkinson's disease; frontotemporal NCD; NCD due to traumatic 
brain injury; NCD due to HIV infection; substance/medication-induced NCD; NCD due 
to Huntington's disease; NCD due to prion disease; NCD due to another medical condi­
tion; NCD due to multiple etiologies; and unspecified NCD. The NCD category encom­
passes the group of disorders in which the primary clinical deficit is in cognitive function, 
and that are acquired rather than developmental. Although cognitive deficits are present 
in many if not all mental disorders (e.g., schizophrenia, bipolar disorders), only disorders

in many if not all mental disorders (e.g., schizophrenia, bipolar disorders), only disorders 
whose core features are cognitive are included in the NCD category. The NCDs are those 
in which impaired cognition has not been present since birth or very early life, and thus 
represents a decline from a previously attained level of functioning.
The NCDs are unique among DSM-5 categories in that these are syndromes for which 
the underlying pathology, and frequently the etiology as well, can potentially be deter­
mined. The various underlying disease entities have all been the subject of extensive re­
search, clinical experience, and expert consensus on diagnostic criteria. The DSM-5 criteria 
for these disorders have been developed in close consultation with the expert groups for 
each of the disease entities and align as closely as possible with the current consensus cri­

teria for each of them. The potential utility of biomarkers is also discussed in relation to 
diagnosis. Dementia is subsumed imder the newly named entity major neurocognitive dis­
order,  although the term dementia  is not precluded from use in the etiological subtypes in 
which that term is standard. Furthermore, DSM-5 recognizes a less severe level of cogni­
tive impairment, mild neurocognitive disorder,  which can also be a focus of care, and which 
in DSM-IV was subsumed under "Cognitive Disorder Not Otherwise Specified." Diagnos­
tic criteria are provided for both these syndromic entities, followed by diagnostic criteria 
for the different etiological subtypes. Several of the NCDs frequently coexist with one an­

other, and their relationships may be multiply characterized under different chapter sub­
headings, including "Differential Diagnosis" (e.g., NCD due to Alzheimer's disease vs. 
vascular NCD), "Risk and Prognostic Factors" (e.g., vascular pathology increasing the 
clinical expression of Alzheimer's disease), and/or "Comorbidity" (e.g., mixed Alzhei­
mer's disease-vascular pathology).
The term dementia  is retained in DSM-5 for continuity and may be used in settings 
where physicians and patients are accustomed to this term. Although dementia is the cus­
tomary term for disorders like the degenerative dementias that usually affect older adults, 
the term neurocognitive disorder  is widely used and often preferred for conditions affect­

ing younger individuals, such as impairment secondary to traumatic brain injury or HIV 
infection. Furthermore, the major NCD definition is somewhat broader than the term 
dementia,  in that individuals with substantial decline in a single domain can receive this di­
agnosis, most notably the DSM-IV category of "Amnestic Disorder," which would now be 
diagnosed as major NCD due to another medical condition and for which the term demen­
tia would not be used.

Neurocognitive Domains
The criteria for the various NCDs are all based on defined cognitive domains. Table 1 pro­
vides for each of the key domains a working definition, examples of symptoms or obser­
vations regarding impairments in everyday activities, and examples of assessments. The 
domains thus defined, along with guidelines for clinical thresholds, form the basis on 
which the NCDs, their levels, and their subtypes may be diagnosed.

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Delirium
A.
B.A disturbance in attention (i.e., reduced ability to direct, focus, sustain, and shift atten­
tion) and awareness (reduced orientation to the environment).
The disturbance develops over a short period of time (usually hours to a few days), rep­
resents a change from baseline attention and awareness, and tends to fluctuate in se­
verity during the course of a day.
C. An additional disturbance in cognition (e.g., memory deficit, disorientation, language,  
visuospatial ability, or perception).
D. The disturbances in Criteria A and C are not better explained by another preexisting,  
established, or evolving neurocognitive disorder and do not occur in the context of a  
severely reduced level of arousal, such as coma.
E. There is evidence from the history, physical examination, or laboratory findings that the  
disturbance is a direct physiological consequence of another medical condition, sub­

stance intoxication or withdrawal (i.e., due to a drug of abuse or to a medication), or  
exposure to a toxin, or is due to multiple etiologies.
Substance intoxication delirium: This diagnosis should be made instead of sub­
stance intoxication when the symptoms in Criteria A and C predominate in the clinical  
Coding note: The ICD-9-CM and ICD-10-CM codes for the [specific substance] in­
toxication delirium are indicated in the table below. Note that the ICD-10-CM code  
depends on whether or not there is a comorbid substance use disorder present for  
the same class of substance. If a mild substance use disorder is comorbid with the

the same class of substance. If a mild substance use disorder is comorbid with the  
substance intoxication delirium, the 4th position character is “1,”  and the clinician  
should record “mild [substance] use disorder”  before the substance intoxication de­
lirium (e.g., “ mild cocaine use disorder with cocaine intoxication delirium” ). If a mod­
erate or severe substance use disorder is comorbid with the substance intoxication  
delirium, the 4th position character is “ 2,”  and the clinician should record “ moderate  
[substance] use disorder”  or “ severe [substance] use disorder,”  depending on the  
severity of the comorbid substance use disorder. If there is no comorbid substance  
use disorder (e.g., after a one-time heavy use of the substance), then the 4th posi­
tion character is “ 9,”  and the clinician should record only the substance intoxication  
delirium.
ICD-10-CM
ICD-9-CMWith use

delirium.
ICD-10-CM
disorder,  
disorder,  
moderate or  
severeWithout use  
disorder
Alcohol 291.0 F10.121 F10.221 FI 0.921
Cannabis 292.81 F12.121 F12.221 F12.921
Phencyclidine 292.81 F16.121 FI 6.221 FI 6.921
Other hallucinogen 292.81 F16.121 FI 6.221 FI 6.921
Inhalant 292.81 F18.121 F18.221 FI 8.921
Opioid 292.81 F11.121 F11.221 F11.921

ICD-10-CM
disorder,  
disorder,  
disorder
Sedative, hypnotic, or anxiolytic 292.81 F13.121 F13.221 FI 3.921
stimulant)292.81 F15.121 F15.221 F15.921
Cocaine 292.81 F14.121 FI 4.221 F14.921
Other (or unknown) substance 292.81 F19.121 F19.221 FI 9.921
Substance withdrawal delirium: Tliis diagnosis should be made instead of sub­
stance withdrawal when the symptoms in Criteria A and C predominate in the clinical  
Code [specific substance] withdrawal delirium: 291.0 (F I0.231) alcohol; 292.0  
(F11.23) opioid: 292.0 (F I3.231) sedative, hypnotic, or anxiolytic; 292.0 (F19.231)  
other (or unknown) substance/medication.
Medication-induced delirium: This diagnosis applies when the symptoms in Criteria  
A and C arise as a side effect of a medication taken as prescribed.

Coding note: The ICD-9-CM code for [specific medication]-induced delirium is  
292.81 . The ICD-10-CM code depends on the type of medication. If the medication  
is an opioid taken as prescribed, the code is F11.921. If the medication is a seda­
tive, hypnotic, or anxiolytic taken as prescribed, the code is FI 3.921. If the medica­
tion is an amphetamine-type or other stimulant taken as prescribed, the code is  
F I5.921. For medications that do not fit into any of the classes (e.g., dexametha-  
sone) and in cases in which a substance is judged to be an etiological factor but the  
specific class of substance is unknown, the code is F19.921.
293.0 (F05) Delirium due to another medical condition: There is evidence from the

293.0 (F05) Delirium due to another medical condition: There is evidence from the  
history, physical examination, or laboratory findings that the disturbance is attributable  
to the physiological consequences of another medical condition.
Coding note: Include the name of the other medical condition in the name of the  
delirium (e.g., 293.0 [F05] delirium due to hepatic encephalopathy). The other med­
ical condition should also be coded and listed separately immediately before the  
delirium due to another medical condition (e.g., 572.2 [K72.90] hepatic encepha­
lopathy; 293.0 [F05] delirium due to hepatic encephalopathy).
293.0 (F05) Delirium due to multiple etiologies: There is evidence from the history,  
physical examination, or laboratory findings that the delirium has more than one etiol­
ogy (e.g., more than one etiological medical condition; another medical condition plus

ogy (e.g., more than one etiological medical condition; another medical condition plus  
substance intoxication or medication side effect).
Coding note: Use multiple separate codes reflecting specific delirium etiologies  
(e.g., 572.2 [K72.90] hepatic encephalopathy, 293.0 [F05] delirium due to hepatic  
failure; 291.0 [FI 0.231] alcohol withdrawal delirium). Note that the etiological med­
ical condition both appears as a separate code that precedes the delirium code and  
is substituted into the delirium due to another medical condition rubric.
Acute: Lasting a few hours or days.
Persistent: Lasting weeks or months.

Hyperactive: The individual has a hyperactive level of psychomotor activity that may be  
accompanied by mood lability, agitation, and/or refusal to cooperate with medical care.  
Hypoactive: The individual has a hypoactive level of psychomotor activity that may be  
accompanied by sluggishness and lethargy that approaches stupor.
Mixed level of activity; The individual has a normal level of psychomotor activity even  
though attention and awareness are disturbed. Also includes individuals whose activity  
level rapidly fluctuates.
Substance intoxication delirium
ICD-9-CM,  The name of the substance/medication intoxication delirium begins with 
the specific substance (e.g., cocaine, dexamethasone) that is presumed to be causing the 
delirium. The diagnostic code is selected from the table included in the criteria set, which 
is based on the drug class. For substances that do not fit into any of the classes (e.g., dexa­

methasone), the code for "other substance" should be used; and in cases in which a sub­
The name of the disorder is followed by the course (i.e., acute, persistent), followed by 
the specifier indicating level of psychomotor activity (i.e., hyperactive, hypoactive, mixed 
level of activity). Unlike the recording procedures for ICD-IO-CM, which combine the sub­
stance/medication intoxication delirium and substance use disorder into a single code, for 
ICD-9-CM a separate diagnostic code is given for the substance use disorder. For example, 
in the case of acute hyperactive intoxication delirium occurring in a man with a severe co­

caine use disorder, the diagnosis is 292.81 cocaine intoxication delirium, acute, hyperac­
tive. An additional diagnosis of 304.20 severe cocaine use disorder is also given. If the 
intoxication delirium occurs without a comorbid substance use disorder (e.g., after a one­
time heavy use of the substance), no accompanying substance use disorder is noted (e.g., 
292.81 phencyclidine intoxication delirium, acute, hypoactive).
ICD-IO-CM.  The name of the substance/medication intoxication delirium begins with the 
specific substance (e.g., cocaine, dexamethasone) that is presumed to be causing the delirium. 
The diagnostic code is selected from the table included in the criteria set, which is based on the 
drug class and presence or absence of a comorbid substance use disorder. For substances that

drug class and presence or absence of a comorbid substance use disorder. For substances that 
do not fit into any of the classes (e.g., dexamethasone), the code for "other substance" should 
be used; and in cases in which a substance is judged to be an etiological factor but the specific 
listed first, followed by the word "with," followed by the name of the substance intoxication 
delirium, followed by the course (i.e., acute, persistent), followed by the specifier indicating 
level of psychomotor activity (i.e., hyperactive, hypoactive, mixed level of activity). For exam­
ple, in the case of acute hyperactive intoxication delirium occurring in a man with a severe co­

caine use disorder, the diagnosis is F14.221 severe cocaine use disorder with cocaine 
intoxication delirium, acute, hyperactive. A separate diagnosis of the comorbid severe cocaine 
use disorder is not given. If the intoxication delirium occurs without a comorbid substance use 
disorder (e.g., after a one-time heavy use of the substance), no accompanying substance use 
disorder is noted (e.g., F16.921 phencyclidine intoxication delirium, acute, hypoactive).
Substance withdrawal delirium
ICD-9~CM,  The name of the substance/medication withdrawal delirium begins with the 
specific substance (e.g., alcohol) that is presumed to be causing the withdrawal delirium. The 
diagnostic code is selected from substance-specific codes included in the coding note included

in the criteria set. The name of the disorder is followed by the course (i.e., acute, persistent), fol­
lowed by the specifier indicating level of psychomotor activity (i.e., hyperactive, hypoactive, 
mixed level of activity). Unlike the recording procedures for ICD-IO-CM, which combine the 
substance/medication withdrawal delirium and substance use disorder into a single code, for 
ICD-9-CM a separate diagnostic code is given for the substance use disorder. For example, in 
the case of acute h 3φeractive withdrawal delirium occurring in a man with a severe alcohol use 
disorder, the diagnosis is 291.0 alcohol withdrawal delirium, acute, hyperactive. An additional 
diagnosis of 303.90 severe alcohol use disorder is also given.
ICD-10~CM.  The name of the substance/medication withdrawal delirium begins with 
the specific substance (e.g., alcohol) that is presumed to be causing the withdrawal delir­

ium. The diagnostic code is selected from substance-specific codes included in the coding 
note included in the criteria set. When recording the name of the disorder, the comorbid 
moderate or severe substance use disorder (if any) is listed first, followed by the word 
"with," followed by the substance withdrawal delirium, followed by the course (i.e., acute, 
persistent), followed by the specifier indicating level of psychomotor activity (i.e., hyper­
active, hypoactive, mixed level of activity). For example, in the case of acute hyperactive 
withdrawal delirium occurring in a man with a severe alcohol use disorder, the diagnosis 
is F10.231 severe alcohol use disorder with alcohol withdrawal delirium, acute, hyperac­
tive. A separate diagnosis of the comorbid severe alcohol use disorder is not given.

Medication-induced delirium. The name of the medication-induced delirium begins 
with the specific substance (e.g., dexamethasone) that is presumed to be causing the de­
lirium. The name of the disorder is followed by the course (i.e., acute, persistent), followed 
by the specifier indicating level of psychomotor activity (i.e., hyperactive, hypoactive, 
mixed level of activity). For example, in the case of acute hyperactive medication-induced 
delirium occurring in a man using dexamethasone as prescribed, the diagnosis is 292.81 
(F19.921) dexamethasone-induced delirium, acute, hyperactive.
Regarding course, in hospital settings, delirium usually lasts about 1  week, but some 
symptoms often persist even after individuals are discharged from the hospital.

Individuals with delirium may rapidly switch between hyperactive and hypoactive 
states. The hyperactive state may be more common or more frequently recognized and 
often is associated with medication side effects and drug withdrawal. The hypoactive state 
may be more frequent in older adults.
The essential feature of delirium is a disturbance of attention or awareness that is accom­
panied by a change in baseline cognition that cannot be better explained by a preexisting 
or evolving neurocognitive disorder (NCD). The disturbance in attention (Criterion A) is 
manifested by reduced ability to direct, focus, sustain, and shift attention. Questions must 
be repeated because the individual's attention wanders, or the individual may perseverate

be repeated because the individual's attention wanders, or the individual may perseverate 
with an answer to a previous question rather than appropriately shift attention. The indi­
vidual is easily distracted by irrelevant stimuli. The disturbance in awareness is mani­
fested by a reduced orientation to the environment or at times even to oneself.
The disturbance develops over a short period of time, usually hours to a few days, and 
tends to fluctuate during the course of the day, often with worsening in the evening and 
night when external orienting stimuli decrease (Criterion B). There is evidence from the 
history, physical examination, or laboratory findings that the disturbance is a physiologi­
cal consequence of an underlying medical condition, substance intoxication or with­
drawal, use of a medication, or a toxin exposure, or a combination of these factors

drawal, use of a medication, or a toxin exposure, or a combination of these factors 
(Criterion E). The etiology should be coded according to the etiologically appropriate sub­
type (i.e., substance or medication intoxication, substance withdrawal, another medical

condition, or multiple etiologies). Delirium often occurs in the context of an underlying 
NCD. The impaired brain function of individuals with mild and major NCD renders them 
more vulnerable to delirium.
There is an accompanying change in at least one other area that may include memory 
and learning (particularly recent memory), disorientation (particularly to time and place), 
alteration in language, or perceptual distortion or a perceptual-motor disturbance (Crite­
rion C). The perceptual disturbances accompanying delirium include misinterpretations, 
illusions, or hallucinations; these disturbances are typically visual, but may occur in other 
modalities as well, and range from simple and uniform to highly complex. Normal atten­
tion/arousal, delirium, and coma lie on a continuum, with coma defined as the lack of any 
response to verbal stimuli. The ability to evaluate cognition to diagnose delirium depends

response to verbal stimuli. The ability to evaluate cognition to diagnose delirium depends 
on there being a level of arousal sufficient for response to verbal stimulation; hence, delir­
ium should not be diagnosed in the context of coma (Criterion D). Many noncoma tose pa­
tients have a reduced level of arousal. Those patients who show only minimal responses to 
verbal stimulation are incapable of engaging with attempts at standardized testing or even 
interview. This inability to engage should be classified as severe inattention. Low-arousal 
states (of acute onset) should be recognized as indicating severe inattention and cognitive 
change, and hence delirium. They are clinically indistinguishable from delirium diag­
nosed on the basis of inattention or cognitive change elicited through cognitive testing and 
interview.

Delirium is often associated with a disturbance in the sleep-wake cycle. This disturbance 
can include daytime sleepiness, nighttime agitation, difficulty falling asleep, excessive 
sleepiness throughout the day, or wakefulness throughout the night. In some cases, com­
plete reversal of the night-day sleep-wake cycle can occur. Sleep-wake cycle disturbances 
are very common in delirium and have been proposed as a core criterion for the diagnosis.
The individual with delirium may exhibit emotional disturbances, such as anxiety, 
fear, depression, irritability, anger, euphoria, and apathy. There may be rapid and unpre­
dictable shifts from one emotional state to another. The disturbed emotional state may also 
be evident in calling out, screaming, cursing, muttering, moaning, or making other

be evident in calling out, screaming, cursing, muttering, moaning, or making other 
sounds. These behaviors are especially prevalent at night and under conditions in which 
stimulation and environmental cues are lacking.
The prevalence of delirium is highest among hospitalized older individuals and varies 
depending on the individuals' characteristics, setting of care, and sensitivity of the detec­
tion method. The prevalence of delirium in the community overall is low (l%-2%) but in­
creases with age, rising to 14% among individuals older than 85 years. The prevalence is 
10%-30% in older individuals presenting to emergency departments, where the delirium 
often indicates a medical illness.
The prevalence of delirium when individuals are admitted to the hospital ranges from 
14% to 24%, and estimates of the incidence of delirium arising during hospitalization

14% to 24%, and estimates of the incidence of delirium arising during hospitalization 
range from 6% to 56% in general hospital populations. Delirium occurs in 15%-53% of 
older individuals postoperatively and in 70%-87% of those in intensive care. Delirium oc­
curs in up to 60% of individuals in nursing homes or post-acute care settings and in up to 
83% of all individuals at the end of life.
While the majority of individuals with delirium have a full recovery with or without 
treatment, early recognition and intervention usually shortens the duration of the delir-

ium. Delirium may progress to stupor, coma, seizures, or death, particularly if the under­
lying cause remains untreated. Mortality among hospitalized individuals with delirium is 
high, and as many as 40% of individuals with delirium, particularly those with malignan­
cies and other significant underlying medical illness, die within a year after diagnosis.
Environmental. Delirium may be increased in the context of functional impairment, im­
mobility, a history of falls, low levels of activity, and use of drugs and medications with 
psychoactive properties (particularly alcohol and anticholinergics).
Genetic and physiological. Both major and mild NCDs can increase the risk for delir­
ium and complicate the course. Older individuals are especially susceptible to delirium 
compared with younger adults. Susceptibility to delirium in infancy and through child­
hood may be greater than in early and middle adulthood. In childhood, delirium may be

hood may be greater than in early and middle adulthood. In childhood, delirium may be 
related to febrile illnesses and certain medications (e.g., anticholinergics).
In addition to laboratory findings characteristic of underlying medical conditions (or in­
toxication or withdrawal states), there is often generalized slowing on electroencephalog­
raphy, and fast activity is occasionally found (e.g., in some cases of alcohol withdrawal 
delirium). However, electroencephalography is insufficiently sensitive and specific for di­
agnostic use.
Functional Consequences of Deiirium
Delirium itself is associated with increased functional decline and risk of institutional 
placement. Hospitalized individuals 65 years or older with delirium have three times the 
risk of nursing home placement and about three times the functional decline as hospital­

ized patients without delirium at both discharge and 3 months postdischarge.
Psychotic disorders and bipolar and depressive disorders with psychotic features.
Delirium that is characterized by vivid hallucinations, delusions, language disturbances, 
and agitation must be distinguished from brief psychotic disorder, schizophrenia, schizo­
phreniform disorder, and other psychotic disorders, as well as from bipolar and depres­
sive disorders with psychotic features.
Acute stress disorder. Delirium associated with fear, anxiety, and dissociative symptoms, 
such as depersonalization, must be distinguished from acute stress disorder, which is pre­
cipitated by exposure to a severely traumatic event.
Malingering and factitious disorder. Delirium can be distinguished from these disor­

ders on the basis of the often atypical presentation in malingering and factitious disorder 
and the absence of another medical condition or substance that is etiologically related to 
the apparent cognitive disturbance.
Other neurocognitive disorders. The most common differential diagnostic issue when 
evaluating confusion in older adults is disentangling symptoms of delirium and dementia. 
The clinician must determine whether the individual has delirium; a delirium superim­
posed on a preexisting NCD, such as that due to Alzheimer's disease; or an NCD without 
delirium. The traditional distinction between delirium and dementia according to acute­
ness of onset and temporal course is particularly difficult in those elderly individuals who 
had a prior NCD that may not have been recognized, or who develop persistent cognitive

had a prior NCD that may not have been recognized, or who develop persistent cognitive 
impairment following an episode of delirium.

Other Specified Delirium
780.09 (R41.0)
This category applies to presentations in which symptoms characteristic of delirium that  
tant areas of functioning predominate but do not meet the full criteria for delirium or any of  
the disorders in  the neurocognitive disorders diagnostic class. The other specified delirium  
category is used in  situations in which the clinician chooses to communicate the specific  
reason that the presentation does not meet the criteria for delirium or any specific neuro­
cognitive disorder. This is done by recording “ other specified delirium”  followed by the spe­
cific reason (e.g., “ attenuated delirium syndrome” ).
Attenuated delirium syndrome: This syndrome applies in cases of delirium in which

Attenuated delirium syndrome: This syndrome applies in cases of delirium in which  
the severity of cognitive impairment falls short of that required for the diagnosis, or in  
which some, but not all, diagnostic criteria for delirium are met.
Unspecified Delirium
the disorders in the neurocognitive disorders diagnostic class. The unspecified delirium  
category is used in situations in which the clinician chooses not to specify the reason that  
the criteria are not met for delirium, and includes presentations for which there is insuffi­

cient information to make a more specific diagnosis (e.g., in emergency room settings).
Major and Mild Neurocognitive Disorders
Major Neurocognitive Disorder
A. Evidence of significant cognitive decline from a previous level of performance in one  
or more cognitive domains (complex attention, executive function, learning and mem­
ory, language, perceptual-motor, or social cognition) based on:
1. Concern of the individual, a knowledgeable informant, or the clinician that there has  
been a significant decline in cognitive function; and
2. A substantial impairment in cognitive performance, preferably documented by stan­
dardized neuropsychological testing or, in its absence, another quantified clinical  
assessment.

B. The cognitive deficits interfere with independence in everyday activities (i.e., at a min­
imum, requiring assistance with complex instrumental activities of daily living such as  
paying bills or managing medications).
C. The cognitive deficits do not occur exclusively in the context of a delirium.

D. The cognitive deficits are not better explained by another mental disorder (e.g., major  
depressive disorder, schizophrenia).
Specify  whether due to:
Alzheimer’s disease (pp. 611-614)
Frontotemporal lobar degeneration (pp. 614-618)
Lewy body disease (pp. 618-621)
Vascular disease (pp. 621-624)
Traumatic brain injury (pp. 624-627)
Substance/medication use (pp. 627-632)
HIV infection (pp. 632-634)
Prion disease (pp. 634-636)
Parkinson’s disease (pp. 636-638)
Huntington’s disease (pp. 638-641)
Anotlier medical condition (pp. 641-642)
Multiple etiologies (pp. 642-643)
Unspecified (p. 643)
Coding note: Code based on medical or substance etiology. In some cases, there Is need  
for an additional code for the etiological medical condition, which must immediately pre­
cede the diagnostic code for major neurocognitive disorder, as follows:
Associated etiological
medical code for major Major neurocogni- Mild neurocogni-

medical code for major Major neurocogni- Mild neurocogni-  
Etiological subtype neurocognitive disorder® tive disorder code^ tive disorder code®
Alzheimer’s Probable: 331.0 (G30.9) Probable: 294.1x 331.83 (G31.84)
disease Possible: no additional (F02.8X) (Do not use addi­
medical code Possible: 331.9 tional code for
(G31.9)‘= Alzheimer’s
disease.)
Frontotemporal Probable: 331.19 Probable: 294.1x 331.83(031.84)
lobar degeneration (G31.09) (F02.8X) (Do not use addi­
Possible: no additional Possible: 331.9 tional code for
medical code (031.9)*= frontotemporal
disease.)
Lewy body disease Probable: 331.82 Probable: 294.1x 331.83(031.84)
(G31.83) (F02.8X) (Do n ot use addi­
medical code (031.9)*= Lewy body disease.)
Vascular disease No additional medical Probable: 290.40 331.83 (031.84)
code (F01.5X) (Do not use addi­

Possible: 331.9 tional code for the
(G31 .9 f vascular disease.)
Traumatic brain 907.0 (S06.2X9S) 294.1x (F02.8X) 331.83 (031.84)
injury (Do n ot use ad d itio n al
code for the trau­
m atic brain injury.)
Substance/ No additional m edical Code based on the Code based on the
medication- code type of substance type of substance
induced causing the major causing the m ild
neurocognitive neurocognitive
disorder‘d ’ disorder^

Etiological subtype neurocognitive disorder^ tive disorder code^ tive disorder code^
HIV infection 042 (B20) 294.1x(F02.8x) 331.83 (G31.84)  
(Do not use addi­
tional code for HIV  
infection.)
Prion disease 046.79 (A81.9) 294.1x (F02.8X) 331.83 (G31.84)  
tional code for  
prion disease.)
Parkinson’s
diseaseProbable: 332.0 (G20)  
Possible: No additional  
medical codeProbable: 294.1x  
(F02.8X)  
Possible: 331.9  
(G31.9)''331.83 (G31.84)  
Parkinson’s  
disease.)
Huntington’s
disease333.4 (G10) 294.1x (F02.8X) 331.83 (G31.84)  
Huntington’s  
disease.)
Due to another  
medical conditionCode the other m edical  
condition first  
(e.g., 340 [G35]  
multiple sclerosis)294.1x (F02.8X) 331.83 (G31.84)  
tional codes for the  
presumed etiologi­
cal medical condi­
tions.)
Due to m ultiple

tions.)
Due to m ultiple  
etiologiesCode all of the etiological  
medical conditions first  
(with the exception of  
vascular disease)294.1x (F02.8X)  
(Plus the code for  
the relevant sub­
stance/medication-  
induced major neu­
rocognitive disor­
ders if substances  
or medications  
play a role in  the  
etiology.)331.83 (G31.84)  
stance/m edication-  
induced m ild neuro­
cognitive disor­
or m edications play  
a role in  the etiol­
ogy. Do not use ad­
ditional codes for  
the presum ed  
etiological m edical  
conditions.)
Unspecified neuro­
cognitive disorderNo additional m edical  
code799.59 (R41.9) 799.59 (R41.9)
^Code first, before code for major neurocognitive disorder.

^Code fifth character based on symptom specifier: .xO  without behavioral disturbance; .xl with be­
havioral disturbance (e.g., psychotic symptoms, mood disturbance, agitation, apathy, or other be­
havioral symptoms).
^N ote: Behavioral disturbance specifier cannot be coded but should still be indicated in writing.  
^See "'Substance/Medication-Induced Major or Mild Neurocognitive Disorder."

Specify:
Without behjavioral disturbance: If the cognitive disturbance is not accompanied by  
any clinically significant behavioral disturbance.
With behavioral disturbance (specify disturbance):  If the cognitive disturbance is ac­
companied by a clinically significant behavioral disturbance (e.g., psychotic symptoms,  
mood disturbance, agitation, apathy, or other behavioral symptoms).
iUlild: Difficulties with instrumental activities of daily living (e.g., housework, managing  
money).
Moderate: Difficulties with basic activities of daily living (e.g., feeding, dressing).  
Severe: Fully dependent.
ild Neurocognitive Disorder
A. Evidence of modest cognitive decline from a previous level of performance in one or  
more cognitive domains (complex attention, executive function, learning and memory,  
language, perceptual motor, or social cognition) based on:

been a mild decline in cognitive function; and
2. A modest impairment in cognitive performance, preferably documented by stan­
B. The cognitive deficits do not interfere with capacity for independence in everyday  
activities (i.e., complex instrumental activities of daily living such as paying bills or  
managing medications are preserved, but greater effort, compensatory strategies, or  
accommodation may be required).

Another medical condition (pp. 641-642)
Coding note: For mild neurocognitive disorder due to any of the medical etiologies listed  
above, code 331.83 (G31.84). Do not use additional codes for the presumed etiological  
medical conditions. For substance/medication-induced mild neurocognitive disorder, code  
based on type of substance; see “ Substance/Medication-Induced Major or Mild Neurocog­

nitive Disorder.”  For unspecified mild neurocognitive disorder, code 799.59 (R41.9).

Specify:
Without behavioral disturbance: If the cognitive disturbance is not accompanied by  
Subtypes
Major and mild neurocognitive disorders (NCDs) are primarily subtyped according to the 
known or presumed etiological/pathological entity or entities underlying the cognitive de­
cline. These subtypes are distinguished on the basis of a combination of time course, charac­
teristic domains affected, and associated symptoms. For certain etiological subtypes, the 
diagnosis depends substantially on the presence of a potentially causative entity, such as Par­
kinson's or Huntington's disease, or a traumatic brain injury or stroke in the appropriate time

kinson's or Huntington's disease, or a traumatic brain injury or stroke in the appropriate time 
period. For other etiological subtypes (generally the neurodegenerative diseases like Alzhei­
mer's disease, frontotemporal lobar degeneration, and Lewy body disease), the diagnosis is 
based primarily on the cognitive, behavioral, and functional symptoms. Typically, the differ­
entiation among these syndromes that lack an independentiy recognized etiological entity is 
clearer at the level of major NCD than at the level of mild NCD, but sometimes characteristic 
symptoms and associated features are present at the mild level as well.
NCDs are frequently managed by clinicians in multiple disciplines. For many sub­
types, multidisciplinary international expert groups have developed specialized consen­
sus criteria based on clinicopathological correlation with underlying brain pathology. The

sus criteria based on clinicopathological correlation with underlying brain pathology. The 
subtype criteria here have been harmonized with those expert criteria.
Evidence for distinct behavioral features in NCDs has been recognized, particularly in the 
areas of psychotic symptoms and depression. Psychotic features are common in many 
NCDs, particularly at the mild-to-moderate stage of major NCDs due to Alzheimer's dis­
ease, Lewy body disease, and frontotemporal lobar degeneration. Paranoia and other 
delusions are common features, and often a persecutory theme may be a prominent aspect 
of delusional ideation. In contrast to psychotic disorders with onset in earlier life (e.g., 
schizophrenia), disorganized speech and disorganized behavior are not characteristic of 
psychosis in NCDs. Hallucinations may occur in any modality, although visual hallucina­

tions are more common in NCDs than in depressive, bipolar, or psychotic disorders.
Mood disturbances, including depression, anxiety, and elation, may occur. Depression 
is common early in the course (including at the mild NCD level) of NCD due to Alzhei­
mer's disease and Parkinson's disease, while elation may occur more commonly in fron­
totemporal lobar degeneration. When a full affective syndrome meeting diagnostic criteria 
for a depressive or bipolar disorder is present, that diagnosis should be coded as well. 
Mood symptoms are increasingly recognized to be a significant feature in the earliest stages 
of mild NCDs such that clinical recognition and intervention may be important.
Agitation is common in a wide variety of NCDs, particularly in major NCD of moder­

ate to severe severity, and often occurs in the setting of confusion or frustration. It may 
arise as combative behaviors, particularly in the context of resisting caregiving duties such 
as bathing and dressing. Agitation is characterized as disruptive motor or vocal activity 
and tends to occur with advanced stages of cognitive impairment across all of the NCDs.
Individuals with NCD can present with a wide variety of behavioral symptoms that 
are the focus of treatment. Sleep disturbance is a common symptom that can create a need 
for clinical attention and may include symptoms of insomnia, hypersomnia, and circadian 
rhythm disturbances.

Apathy is common in mild and mild major NCD. It is observed particularly in NCD due 
to Alzheimer's disease and may be a prominent feature of NCD due to frontotemporal 
lobar degeneration. Apathy is typically characterized by diminished motivation and re­
duced goal-directed behavior accompanied by decreased emotional responsiveness. 
Symptoms of apathy may manifest early in the course of NCDs when a loss of motivation 
to pursue daily activities or hobbies may be observed.
Other important behavioral symptoms include wandering, disinhibition, hyperpha- 
gia, and hoarding. Some of these symptoms are characteristic of specific disorders, as dis­
cussed in the relevant sections. When more than one behavioral disturbance is observed, 
each type should be noted in writing with the specifier "with behavioral symptoms."
Major and mild NCDs exist on a spectrum of cognitive and functional impairment. Major

Major and mild NCDs exist on a spectrum of cognitive and functional impairment. Major 
NCD corresponds to the condition referred to in DSM-IV as dementia,  retained as an alter­
native in this volume. The core feature of NCDs is acquired cognitive decline in one or 
more cognitive domains (Criterion A) based on both 1) a concern about cognition on the 
part of the individual, a knowledgeable informant, or the clinician, and 2) performance on 
an objective assessment that falls below the expected level or that has been observed to de­
cline over time. Both a concern and objective evidence are required because they are com­
plementary. When there is an exclusive focus on objective testing, a disorder may go 
undiagnosed in high-functioning individuals whose currently "normal" performance ac­
tually represents a substantial decline in abilities, or an illness may be incorrectly diag­

nosed in individuals whose currently "low" performance does not represent a change 
from their own baseline or is a result of extraneous factors like test conditions or a passing 
illness. Alternatively, excessive focus on subjective symptoms may fail to diagnose illness 
in individuals with poor insight, or whose informants deny or fail to notice their symptoms, 
or it may be overly sensitive in the so-called worried well.
A cognitive concern differs from a complaint in that it may or may not be voiced spon­
taneously. Rather, it may need to be elicited by careful questioning about specific symp­
toms that commonly occur in individuals with cognitive deficits (see Table 1 in the 
introduction to this chapter). For example, memory concerns include difficulty remember­

ing a short grocery list or keeping track of the plot of a television program; executive con­
cerns include difßculty resuming a task when interrupted, organizing tax records, or 
planning a holiday meal. At the mild NCD level, the individual is likely to describe these 
tasks as being more difficult or as requiring extra time or effort or compensatory strategies. 
At the major NCD level, such tasks may only be completed with assistance or may be 
abandoned altogether. At the mild NCD level, individuals and their families may not no­
tice such symptoms or may view them as normal, particularly in the elderly; thus, careful 
history taking is of paramount importance. The difficulties must represent changes rather 
than lifelong patterns: the individual or informant may clarify this issue, or the clinician

than lifelong patterns: the individual or informant may clarify this issue, or the clinician 
can infer change from prior experience with the patient or from occupational or other 
clues. It is also critical to determine that the difficulties are related to cognitive loss rather 
than to motor or sensory limitations.
Neuropsychological testing, with performance compared with norms appropriate to 
the patient's age, educational attainment, and cultural background, is part of the standard 
evaluation of NCDs and is particularly critical in the evaluation of mild NCD. For major 
NCD, performance is typically 2 or more standard deviations below appropriate norms 
(3rd percentile or below). For mild NCD, performance typically lies in the 1-2 standard de­
viation range (between the 3rd and 16th percentiles). However, neuropsychological test­

ing is not available in all settings, and neuropsychological thresholds are sensitive to the 
specific test(s) and norms employed, as well as to test conditions, sensory limitations, and 
intercurrent illness. A variety of brief office-based or "bedside" assessments, as described

in Table 1, can also supply objective data in settings where such testing is unavailable or 
infeasible. In any case, as with cognitive concerns, objective performance must be inter­
preted in light of the individual's prior performance. Optimally, this information would 
be available from a prior administration of the same test, but often it must be inferred 
based on appropriate norms, along with the individual's educational history, occupation, 
and other factors. Norms are more challenging to interpret in individuals with very high 
or very low levels of education and in individuals being tested outside their own language 
or cultural background.
Criterion B relates to the individual's level of independence in everyday functioning. 
Individuals with major NCD will have impairment of sufficient severity so as to interfere 
with independence, such that others will have to take over tasks that the individuals were

with independence, such that others will have to take over tasks that the individuals were 
previously able to complete on their own. Individuals with mild NCD will have preserved 
independence, although there may be subtle interference with function or a report that 
tasks require more effort or take more time than previously.
The distinction between major and mild NCD is inherently arbitrary, and the disorders 
exist along a continuum. Precise thresholds are therefore difficult to determine. Careful 
history taking, observation, and integration with other findings are required, and the im­
plications of diagnosis should be considered when an individual's clinical manifestations 
lie at a boundary.
Typically the associated features that support a diagnosis of major or mild NCD will be

Typically the associated features that support a diagnosis of major or mild NCD will be 
specific to the etiological subtype (e.g., neuroleptic sensitivity and visual hallucinations in 
NCD due to Lewy body disease). Diagnostic features specific to each of the subtypes are 
found in the relevant sections.
The prevalence of NCD varies widely by age and by etiological subtype. Overall preva­
lence estimates are generally only available for older populations. Among individuals 
older than 60 years, prevalence increases steeply with age, so prevalence estimates are 
more accurate for narrow age bands than for broad categories such as "over 65" (where the 
mean age can vary greatly with the life expectancy of the given population). For those eti­
ological subtypes occurring across the lifespan, prevalence estimates for NCD are likely to

ological subtypes occurring across the lifespan, prevalence estimates for NCD are likely to 
be available, if at all, only as the fraction of individuals who develop NCD among those 
with the relevant condition (e.g., traumatic brain injury, HIV infection).
Overall prevalence estimates for dementia (which is largely congruent with major 
NCD) are approximately l%-2% at age 65 years and as high as 30% by age 85 years. The 
prevalence of mild NCD is very sensitive to the definition of the disorder, particularly in 
community settings, where evaluations are less detailed. In addition, in contrast with clin­
ical settings, where cognitive concern must be high to seek and locate care, there may be a 
less clear decline from baseline functioning. Estimates of the prevalence of mild cognitive 
impairment (which is substantially congruent with mild NCD) among older individuals

impairment (which is substantially congruent with mild NCD) among older individuals 
are fairly variable, ranging from 2% to 10% at age 65 and 5% to 25% by age 85.
The course of NCD varies across etiological subtypes, and this variation can be useful in 
differential diagnosis. Some subtypes (e.g., those related to traumatic brain injury or 
stroke) typically begin at a specific time and (at least after initial symptoms related to in­
flammation or swelling subside) remain static. Others may fluctuate over time (although 
if this occurs, the possibility of delirium superimposed on NCD should be considered). 
NCDs due to neurodegenerative diseases like Alzheimer's disease or frontotemporal 
lobar degeneration typically are marked by insidious onset and gradual progression, and

the pattem of onset of cognitive deficits and associated features helps to distinguish among 
them.
NCDs with onset in childhood and adolescence may have broad repercussions for so­
cial and intellectual development, and in this setting intellectual disability (intellectual 
developmental disorder) and/or other neurodevelopmental disorders may also be diag­
nosed to capture the full diagnostic picture and ensure the provision of a broad range of 
services. In older individuals, NCDs often occur in the setting of medical illnesses, frailty, 
and sensory loss, which complicate the clinical picture for diagnosis and treatment.
When cognitive loss occurs in youth to midlife, individuals and families are likely to 
seek care. NCDs are typically easiest to identify at younger ages, although in some settings 
malingering or other factitious disorders may be a concern. Very late in life, cognitive 
symptoms may not cause concern or may go unnoticed. In late life, mild NCD must also be

symptoms may not cause concern or may go unnoticed. In late life, mild NCD must also be 
distinguished from the more modest deficits associated with "normal aging," although a 
substantial fraction of what has been ascribed to normal aging likely represents prodromal 
phases of various NCDs. In addition, it becomes harder to recognize mild NCD with age 
because of the increasing prevalence of medical illness and sensory deficits. It becomes 
harder to differentiate among subtypes with age because there are multiple potential sources 
of neurocognitive decline.
Risk factors vary not only by etiological subtype but also by age at onset within etiological 
subtypes. Some subtypes are distributed throughout the lifespan, whereas others occur 
exclusively or primarily in late life. Even within the NCDs of aging, the relative prevalence

exclusively or primarily in late life. Even within the NCDs of aging, the relative prevalence 
varies with age: Alzheimer's disease is uncommon before age 60 years, and the prevalence 
increases steeply thereafter, while the overall less common frontotemporal lobar degener­
ation has earlier onset and represents a progressively smaller fraction of NCDs with age.
Genetic and physiological. The strongest risk factor for major and mild NCDs is age, 
primarily because age increases the risk of neurodegenerative and cerebrovascular dis­
ease. Female gender is associated with higher prevalence of dementia overall, and especially 
Alzheimer's disease, but this difference is largely, if not wholly, attributable to greater lon­
gevity in females.
Individuals' and families' level of awareness and concern about neurocognitive symp­

toms may vary across ethnic and occupational groups. Neurocognitive symptoms are 
more likely to be noticed, particularly at the mild level, in individuals who engage in com­
plex occupational, domestic, or recreational activities. In addition, norms for neuropsy­
chological testing tend to be available only for broad populations, and thus they may not 
be easily applicable to individuals with less than high school education or those being 
evaluated outside their primary language or culture.
Like age, culture, and occupation, gender issues may affect the level of concern and aware­
ness of cognitive symptoms. In addition, for late-life NCDs, females are likely to be older, 
to have more medical comorbidity, and to live alone, which can complicate evaluation and

to have more medical comorbidity, and to live alone, which can complicate evaluation and 
treatment. In addition, there are gender differences in the frequency of some of the etio­
logical subtypes.
In addition to a careful history, neuropsychological assessments are the key measures for 
diagnosis of NCDs, particularly at the mild level, where functional changes are minimal

and symptoms more subtle. Ideally, individuals will be referred for formal neuropsycho­
logical testing, which will provide a quantitative assessment of all relevant domains and 
thus help with diagnosis; provide guidance to the family on areas where the individual 
may require more support; and serve as a benchmark for further decline or response to 
therapies. When such testing is unavailable or not feasible, the brief assessments in Table 1  
can provide insight into each domain. More global brief mental status tests may be helpful 
but may be insensitive, particularly to modest changes in a single domain or in those with 
high premorbid abilities, and may be overly sensitive in those with low premorbid abilities.
In distinguishing among etiological subtypes, additional diagnostic markers may 
come into play, particularly neuroimaging studies such as magnetic resonance imaging 
scans and positron emission tomography scans. In addition, specific markers may be in­

volved in the assessment of specific subtypes and may become more important as addi­
tional research findings accumulate over time, as discussed in the relevant sections.
By definition, major and mild NCDs affect functioning, given the central role of cognition in 
human life. Thus, the criteria for the disorders, and the threshold for differentiating mild 
from major NCD, are based in part on functional assessment. Within major NCD there is a 
broad range of functional impairment, as implemented in the severity specifiers. In addition, 
the specific functions that are compromised can help identify the cognitive domains affected, 
particularly when neuropsychological testing is not available or is difficult to interpret.

Normal cognition. The differential diagnosis between normal cognition and mild NCD, 
as between mild and major NCD, is challenging because the boundaries are inherently ar­
bitrary. Careful history taking and objective assessment are critical to these distinctions. A 
longitudinal evaluation using quantified assessments may be key in detecting mild NCD.
Delirium. Both mild and major NCD may be difficult to distinguish from a persistent de­
lirium, which can co-occur. Careful assessment of attention and arousal will help to make 
the distinction.
Major depressive disorder. The distinction between mild NCD and major depressive 
disorder, which may co-occur with NCD, can also be challenging. Specific patterns of cog­
nitive deficits may be helpful. For example, consistent memory and executive function

nitive deficits may be helpful. For example, consistent memory and executive function 
deficits are typical of Alzheimer's disease, whereas nonspecific or more variable perfor­
mance is seen in major depression. Alternatively, treatment of the depressive disorder 
with repeated observation over time may be required to make the diagnosis.
Specific learning disorder and other neurodevelopmental disorders. A careful clari­
fication of the individual's baseline status will help distinguish an NCD from a specific 
learning disorder or other neurodevelopmental disorders. Additional issues may enter the 
differential for specific etiological subtypes, as described in the relevant sections.
NCDs are common in older individuals and thus often co-occur with a wide variety of age- 
related diseases that may complicate diagnosis or treatment. Most notable of these is

related diseases that may complicate diagnosis or treatment. Most notable of these is 
delirium, for which NCD increases the risk. In older individuals, a delirium during hos­
pitalization is, in many cases, the first time that an NCD is noticed, although a careful his­
tory will often reveal evidence of earlier decline. Mixed NCDs are also common in older 
individuals, as many etiological entities increase in prevalence with age. In younger indi­
viduals, NCD often co-occurs with neurodevelopmental disorders; for example, a head in­

jury in a preschool child may also lead to significant developmental and learning issues. 
Additional comorbidity of NCD is often related to the etiological subtype, as discussed in 
the relevant sections.
Major or Mild Neurocognitive Disorder  
Due to Alzheimer’s Disease
A. The criteria are met for major or mild neurocognitive disorder.
B . There is insidious onset and gradual progression of impairment in  one or more cognitive  
domains (for major neurocognitive disorder, at least two domains must be impaired).
C. Criteria are met for either probable or possible Alzheimer’s disease as follows:
For major neurocognitive disorder:
Probable Alzheimer’s disease is diagnosed if either of the following is present; oth­
erwise, possible Alzheimer’s disease should be diagnosed.
1. Evidence of a causative Alzheimer’s disease genetic mutation from family history  
or genetic testing.
2. All three of the following are present:

a. Clear evidence of decline in memory and learning and at least one other cogni­
tive domain (based on detailed history or serial neuropsychological testing).
b. Steadily progressive, gradual decline in cognition, without extended plateaus.
c. No evidence of mixed etiology (i.e., absence of other neurodegenerative or  
cerebrovascular disease, or another neurological, mental, or systemic disease  
or condition likely contributing to cognitive decline).
For mild neurocognitive disorder:
Probable Alzheimer’s disease is diagnosed if there is evidence of a causative Alz­
heimer’s disease genetic mutation from either genetic testing or family history.
Possible Alzheimer’s disease is diagnosed if there is no evidence of a causative Alz­
heimer’s disease genetic mutation from either genetic testing or family history, and all

heimer’s disease genetic mutation from either genetic testing or family history, and all  
three of the following are present:
1. Clear evidence of decline in memory and learning.
2. Steadily progressive, gradual decline in cognition, without extended plateaus.
3. No evidence of mixed etiology (i.e., absence of other neurodegenerative or cere­
brovascular disease, or another neurological or systemic disease or condition likely  
contributing to cognitive decline).
D. The disturbance is not better explained by cerebrovascular disease, another neurode­
generative disease, the effects of a substance, or another mental, neurological, or sys­
temic disorder.
Coding note: For probable major neurocognitive disorder due to Alzheimer’s disease,  
with behavioral disturbance, code first 331.0 (G30.9) Alzheimer’s disease, followed by

294.11 (F02.81) major neurocognitive disorder due to Alzheimer’s disease. For probable  
neurocognitive disorder due to Alzheimer’s disease, without behavioral disturbance, code  
first 331.0 (G30.9) Alzheimer’s disease, followed by 294.10 (F02.80) major neurocognitive  
disorder due to Alzheimer’s disease, without behavioral disturbance.
For possible major neurocognitive disorder due to Alzheimer’s disease, code 331.9  
(G31.9) possible major neurocognitive disorder due to Alzheimer’s disease. (Note: Do not 
use the additional code for Alzheimer’s disease. Behavioral disturbance cannot be coded  
but should still be indicated in  writing.)

For mild neurocognitive disorder due to Alzheimer’s disease, code 331.83 (G31.84).  
(Note: Do not use the additional code for Alzheimer’s disease. Behavioral disturbance  
cannot be coded but should still be indicated in writing.)
Beyond the neurocognitive disorder (NCD) syndrome (Criterion A), the core features of ma­
jor or mild NCD due to Alzheimer's disease include an insidious onset and gradual pro­
gression of cognitive and behavioral symptoms (Criterion B). The typical presentation is 
amnestic (i.e., with impairment in memory and learning). Unusual nonamnestic presen­
tations, particularly visuospatial and logopenic aphasie variants, also exist. At the mild 
NCD phase, Alzheimer's disease manifests typically with impairment in memory and learn­
ing, sometimes accompanied by deficits in executive function. At the major NCD phase, 
visuoconstructional/perceptual motor ability and language will also be impaired, partic­

ularly when the NCD is moderate to severe. Social cognition tends to be preserved until 
late in the course of the disease.
A level of diagnostic certainty must be specified denoting Alzheimer's disease as the 
"probable" or "possible" etiology (Criterion C). Probable Alzheimer's disease  is diagnosed in 
both major and mild NCD if there is evidence of a causative Alzheimer's disease gene, ei­
ther from genetic testing or from an autosomal dominant family history coupled with au­
topsy confirmation or a genetic test in an affected family member. For major NCD, a 
typical clinical picture, without extended plateaus or evidence of mixed etiology, can also 
be diagnosed as due to probable Alzheimer's disease. For mild NCD, given the lesser de­

gree of certainty that the deficits will progress, these features are only sufficient for a 
possible  Alzheimer's etiology. If the etiology appears mixed, mild NCD due to multiple eti­
ologies should be diagnosed. In any case, for both mild and major NCD due to Alzhei­
mer's disease, the clinical features must not suggest another primary etiology for the NCD 
In specialty clinical settings, approximately 80% of individuals with major NCD due to 
Alzheimer's disease have behavioral and psychological manifestations; these features are 
also frequent at the mild NCD stage of impairment. These symptoms are as or more dis­
tressing than cognitive manifestations and are frequently the reason that health care is

tressing than cognitive manifestations and are frequently the reason that health care is 
sought. At the mild NCD stage or the mildest level of major NCD, depression and/or ap­
athy are often seen. With moderately severe major NCD, psychotic features, irritability, 
agitation, combativeness, and wandering are common. Late in the illness, gait distur­
bance, dysphagia, incontinence, myoclonus, and seizures are observed.
The prevalence of overall dementia (major NCD) rises steeply with age. In high-income 
countries, it ranges from 5% to 10% in the seventh decade to at least 25% thereafter. U.S. 
census data estimates suggest that approximately 7% of individuals diagnosed with Alz­
heimer's disease are between ages 65 and 74 years, 53% are between ages 75 and 84 years, 
and 40% are 85 years and older. The percentage of dementias attributable to Alzheimer's

and 40% are 85 years and older. The percentage of dementias attributable to Alzheimer's 
disease ranges from about 60% to over 90%, depending on the setting and diagnostic cri­
teria. Mild NCD due to Alzheimer's disease is likely to represent a substantial fraction of 
mild cognitive impairment (MCI) as well.
Major or mild NCD due to Alzheimer's disease progresses gradually, sometimes with 
brief plateaus, through severe dementia to death. The mean duration of survival after di­

agnosis is approximately 10 years, reflecting the advanced age of the majority of individ­
uals rather than the course of the disease; some individuals can live with the disease for as 
long as 20 years. Y.ate-stage individuals are eventually mute and bedbound. Death most 
commonly results from aspiration in those who survive through the full course. In mild 
NCD due to Alzheimer's disease, impairments increase over time, and functional status 
gradually declines until symptoms reach the threshold for the diagnosis of major NCD.
The onset of symptoms is usually in the eighth and ninth decades; early-onset forms 
seen in the fifth and sixth decades are often related to known causative mutations. Symp­
toms and pathology do not differ markedly at different onset ages. However, younger in­
dividuals are more likely to survive the full course of the disease, while older individuals 
are more likely to have numerous medical comorbidities that affect the course and man­

agement of the illness. Diagnostic complexity is higher in older adults because of the in­
creased likelihood of comorbid medical illness and mixed pathology.
Environmental. Traumatic brain injury increases risk for major or mild NCD due to Alz­
heimer's disease.
Genetic and physiological. Age is the strongest risk factor for Alzheimer's disease. The 
genetic susceptibility polymorphism apolipoprotein E4 increases risk and decreases age 
at onset, particularly in homozygous individuals. There are also extremely rare causative 
Alzheimer's disease genes. Individuals with Down's syndrome (trisomy 21) develop Alz­
heimer's disease if they survive to midlife. Multiple vascular risk factors influence risk for

heimer's disease if they survive to midlife. Multiple vascular risk factors influence risk for 
Alzheimer's disease and may act by increasing cerebrovascular pathology or also through 
direct effects on Alzheimer pathology.
Detection of an NCD may be more difficult in cultural and socioeconomic settings where 
memory loss is considered normal in old age, where older adults face fewer cognitive de­
mands in everyday life, or where very low educational levels pose greater challenges to 
objective cognitive assessment.
Cortical atrophy, amyloid-predominant neuritic plaques, and tau-predominant neurofibril­
lary tangles are hallinarks of the pathological diagnosis of Alzheimer's disease and may be 
confirmed via postmortem histopathological examination. For early-onset cases with auto­

somal dominant inheritance, a mutation in one of the known causative Alzheimer's disease 
genes—amyloid precursor protein (APP), presenilin 1 (PSENl), or presenilin 2 (PSEN2)— 
may be involved, and genetic testing for such mutations is commercially available, at least 
for PSENl. Apolipoprotein E4 cannot serve as a diagnostic marker because it is only a risk 
factor and neither necessary nor sufficient for disease occurrence.
Since amyloid beta-42 deposition in the brain occurs early in the pathophysiological 
cascade, amyloid-based diagnostic tests such as amyloid imaging on brain positron emis­
sion tomography (PET) scans and reduced levels of amyloid beta-42 in the cerebrospinal 
fluid (CSF) may have diagnostic value. Signs of neuronal injury, such as hippocampal and

fluid (CSF) may have diagnostic value. Signs of neuronal injury, such as hippocampal and 
temporoparietal cortical atrophy on a magnetic resonance image scan, temporoparietal 
hypometabolism on a fluorodeoxyglucose PET scan, and evidence for elevated total tau 
and phospho-tau levels in CSF, provide evidence of neuronal damage but are less specific 
for Alzheimer's disease. At present, these biomarkers are not fully validated, and many 
are available only in tertiary care settings. However, some of them, along with novel bio­
markers, will likely move into wider clinical practice in the coming years.

Functional Consequences of Major or Mild  
Neurocognitive Disorder Due to Alzheimer’s Disease
The prominence of memory loss can cause significant difficulties relatively early in the 
course. Social cognition (and thus social functioning) and procedural memory (e.g., danc­
ing, playing musical instruments) may be relatively preserved for extended periods.
Other neurocognitive disorders. Major and mild NCDs due to other neurodegenera- 
tive processes (e.g., Lewy body disease, frontotemporal lobar degeneration) share the in­
sidious onset and gradual decline caused by Alzheimer's disease but have distinctive core 
features of their own. In major or mild vascular NCD, there is typically history of stroke 
temporally related to the onset of cognitive impairment, and infarcts or white matter hy­
perintensities are judged sufficient to account for the clinical picture. However, particu­

larly when there is no clear history of stepwise decline, major or mild vascular NCD can 
share many clinical features with Alzheimer's disease.
Other concurrent, active neurological or systemic illness. Other neurological or sys­
temic illness should be considered if there is an appropriate temporal relationship and 
severity to account for the clinical picture. At the mild NCD level, it may be difficult to dis­
tinguish an Alzheimer's disease etiology from that of another medical condition (e.g., thy­
roid disorders, vitamin Bj 2 deficiency).
Major depressive disorder. Particularly at the mild NCD level, the differential diagnosis 
also includes major depression. The presence of depression may be associated with re­
duced daily functioning and poor concentration that may resemble an NCD, but improve­

ment with treatment of depression may be useful in making the distinction.
Most individuals with Alzheimer's disease are elderly and have multiple medical conditions 
that can complicate diagnosis and influence the clinical course. Major or mild NCD due to 
Alzheimer's disease commonly co-occurs with cerebrovascular disease, which contributes 
to the clinical picture. When a comorbid condition contributes to the NCD in an individual 
with Alzheimer's disease, then NCD due to multiple etiologies should be diagnosed.
Major or Mild Frontotemporal  
Neurocognitive Disorder
B. The disturbance has insidious onset and gradual progression.
C. Either (1) or (2);
1. Behavioral variant;

a. Three or more of the following behavioral symptoms:
i. Behavioral disinhibition.
ii. Apathy or inertia.
iii. Loss of sympathy or empathy.
iv. Perseverative, stereotyped or compulsive/ritualistic behavior.
v. Hyperorality and dietary changes.
b. Prominent decline in social cognition and/or executive abilities.

2. Language variant:
a. Prom i(Qent decline in language ability, in the form of speech production, word  
finding, object naming, grammar, or word comprehension.
D. Relative sparing of learning and memory and perceptual-motor function.
E. The disturbance is not better explained by cerebrovascular disease, another neurode-  
Probable frontotemporal neurocognitive disorder is diagnosed if either of the following  
is present; othenwise, possible frontotemporal neurocognitive disorder should be di­
agnosed:
1. Evidence of a causative frontotemporal neurocognitive disorder genetic mutation, from  
either family history or genetic testing.
2. Evidence of disproportionate frontal and/or temporal lobe involvement from neuroim­
aging.
Possible frontotemporal neurocognitive disorder is diagnosed if there is no evidence  
of a genetic mutation, and neuroimaging has not been performed.

aging.
Coding note: For probable major neurocognitive disorder due to frontotemporal lobar de­
generation, with behavioral disturbance, code first 331.19 (G31.09) frontotemporal dis­
ease, followed by 294.11 (F02.81) probable major neurocognitive disorder due to  
frontotemporal lobar degeneration, with behavioral disturbance. For probable major neu­
rocognitive disorder due to frontotemporal lobar degeneration, without behavioral distur­
bance, code first 331.19 (G31.09) frontotemporal disease, followed by 294.10 (F02.80)  
probable major neurocognitive disorder due to frontotemporal lobar degeneration, without  
behavioral disturbance.
For possible major neurocognitive disorder due to frontotemporal lobar degeneration, code  
331.9 (G31.9) possible major neurocognitive disorder due to frontotemporal lobar degen­

eration. (Note: Do not use the additional code for frontotemporal disease. Behavioral distur­
bance cannot be coded but should still be indicated in writing.)
For mild neurocognitive disorder due to frontotemporal lobar degeneration, code 331.83  
(031.84). (Note: Do not use the additional code for frontotemporal disease. Behavioral  
disturbance cannot be coded but should still be indicated in writing.)
Major or mild frontotemporal neurocognitive disorder (NCD) comprises a number of syn­
dromic variants characterized by the progressive development of behavioral and personality 
change and/or language impairment. The behavioral variant and three language variants (se­
mantic, agrammatic/nonfluent, and logopenic) exhibit distinct patterns of brain atrophy and

mantic, agrammatic/nonfluent, and logopenic) exhibit distinct patterns of brain atrophy and 
some distinctive neuropathology. The criteria must be met for either the behavioral or the lan­
guage variant to make the diagnosis, but many individuals present with features of both.
Individuals with behavioral-variant major or mild frontotemporal NCD present with 
varying degrees of apathy or disinhibition. They may lose interest in socialization, self­
care, and personal responsibilities, or display socially inappropriate behaviors. Insight is 
usually impaired, and this often delays medical consultation. The first referral is often to a 
psychiatrist. Individuals may develop changes in social style, and in religious and political 
beliefs, with repetitive movements, hoarding, changes in eating behavior, and hyperoral-

beliefs, with repetitive movements, hoarding, changes in eating behavior, and hyperoral- 
ity. In later stages, loss of sphincter control may occur. Cognitive decline is less prominent, 
and formal testing may show relatively few deficits in the early stages. Common neuro­
cognitive symptoms are lack of planning and organization, distractibility, and poor judg­
ment. Deficits in executive function, such as poor performance on tests of mental

flexibility, abstract reasoning, and response inhibition, are present, but learning and mem­
ory are relatively spared, and perceptual motor abilities are almost always preserved in 
the early stages.
Individuals with language-variant major or mild frontotemporal NCD present with pri­
mary progressive aphasia with gradual onset, with three subtypes commonly described: 
semantic variant, agrammatic/nonfluent variant, and logopenic variant, and each variant 
has distinctive features and corresponding neuropathology.
"Probable" is distinguished from "possible" frontotemporal NCD by the presence of 
causative genetic factors (e.g., mutations in the gene coding for microtubule-associated pro­
tein tau) or by the presence of distinctive atrophy or reduced activity in frontotemporal re­
gions on structural or functional imaging.
Extrapyramidal features may be prominent in some cases, with an overlap with syn­

dromes such as progressive supranuclear palsy and corticobasal degeneration. Features of 
motor neuron disease may be present in some cases (e.g., muscle atrophy, weakness). A 
subset of individuals develop visual hallucinations.
Major or mild frontotemporal NCD is a common cause of early-onset NCD in individuals 
younger than 65 years. Population prevalence estimates are in the range of 2-10 per 
100,000. Approximately 20%-25% of cases of frontotemporal NCD occur in individuals 
older than 65 years. Frontotemporal NCD accounts for about 5% of all cases of dementia in 
unselected autopsy series. Prevalence estimates of behavioral variant and semantic lan­
guage variant are higher among males, and prevalence estimates of nonfluent language 
variant are higher among females.

Individuals with major or mild frontotemporal NCD commonly present in the sixth de­
cade of life, although the age at onset varies from the third to the ninth decades. The dis­
ease is gradually progressive, with median survival being 6-11  years after symptom onset 
and 3-4 years after diagnosis. Survival is shorter and decline is faster in major or mild fron­
totemporal NCD than in typical Alzheimer's disease.
Genetic and physiological. Approximately 40% of individuals with major or mild fron­
totemporal NCD have a family history of early-onset NCD, and approximately 10% show an 
autosomal dominant inheritance pattern. A number of genetic factors have been identified, 
such as mutations in the gene encoding the microtubule associated protein tau (MAPT), the

such as mutations in the gene encoding the microtubule associated protein tau (MAPT), the 
granulin gene (CRN), and the C90RF72 gene. A number of families with causative muta­
tions have been identified (see the section "Diagnostic Markers" for this disorder), but many 
individuals with known familial transmission do not have a known mutation. The presence 
of motor neuron disease is associated with a more rapid deterioration.
Computed tomography (CT) or structural magnetic resonance imaging (MRI) may show 
distinct patterns of atrophy. In behavioral-variant major or mild frontotemporal NCD, 
both frontal lobes (especially the medial frontal lobes) and the anterior temporal lobes are 
atrophic. In semantic language-variant major or mild frontotemporal NCD, the middle, 
inferior, and anterior temporal lobes are atrophic bilaterally but asymmetrically, with the

left side usually being more affected. Nonfluent language-variant major or mild fronto­
temporal NCD is associated with predominantly left posterior frontal-insular atrophy. 
The logopenic variant of major or mild frontotemporal NCD is associated with predomi­
nantly left posterior perisylvian or parietal atrophy. Functional imaging demonstrates hy­
poperfusion and/or cortical hypometabolism in the corresponding brain regions, which 
may be present in the early stages in the absence of structural abnormality. Emerging bio­
markers for Alzheimer's disease (e.g., cerebrospinal fluid amyloid-beta and tau levels, and 
amyloid imaging) may help in the differential diagnosis, but the distinction from Alzhei­
mer's disease can remain difficult (the logopenic variant is in fact often a manifestation of 
Alzheimer's disease).
In familial cases of frontotemporal NCD, the identification of genetic mutations may 
help confirm the diagnosis. Mutations associated with frontotemporal NCD include

help confirm the diagnosis. Mutations associated with frontotemporal NCD include 
the genes encoding microtubule-associated protein tau (MAPT) and granulin (GRN), 
C90RF72, transactive response DNA-binding protein of 43 kDa (TDP-43, or TARDBP), 
valosin-containing protein (VCP), chromatin modifying protein 2B (CHMP2B), and fused 
in sarcoma protein (PUS).
Frontotemporal Neurocognitive Disorder
Because of the relative early age at onset of the disorder, the disorder oftens affects work­
place and family life. Because of the involvement of language and/or behavior, function is 
often more severely impaired relatively early in the course. For individuals with the be­
havioral variant, prior to diagnostic clarification there may be significant family disrup­

tion, legal involvement, and problems in the workplace because of socially inappropriate 
behaviors. The functional impairment due to behavioral change and language dysfunc­
tion, which can include hyperorality, impulsive wandering, and other dishinhibited be­
haviors, may far exceed that due to the cognitive disturbance and may lead to nursing 
home placement or institutionalization. These behaviors can be severely disruptive, even 
in structured care settings, particularly when the individuals are otherwise healthy, non­
frail, and free of other medical comorbidities.
Other neurocognitive disorders. Other neurodegenerative diseases may be distinguished 
from major or mild frontotemporal NCD by their characteristic features. In major or mild

from major or mild frontotemporal NCD by their characteristic features. In major or mild 
NCD due to Alzheimer's disease, decline in learning and memory is an early feature. 
However, 10%-30% of patients presenting with a syndrome suggestive of major or mild 
frontotemporal NCD are found at autopsy to have Alzheimer's disease pathology. This oc­
curs more frequently in individuals who present with progressive dysexecutive syn­
dromes in the absence of behavioral changes or movement disorder or in those with the 
logopenic variant.
In major or mild NCD with Lewy bodies, core and suggestive features of Lewy bodies 
must be present. In major or mild NCD due to Parkinson's disease, spontaneous parkin­
sonism emerges well before the cognitive decline. In major or mild vascular NCD, depend­
ing on affected brain regions, there may also be loss of executive ability and behavioral

ing on affected brain regions, there may also be loss of executive ability and behavioral 
changes such as apathy, and this disorder should be considered in the differential diagno­
sis. However, history of a cerebrovascular event is temporally related to the onset of cog­
nitive impairment in major or mild vascular NCD, and neuroimaging reveals infarctions 
or white matter lesions sufficient to account for the clinical picture.
Other neurological conditions. Major or mild frontotemporal NCD overlaps with pro­
gressive supranuclear palsy, corticobasal degeneration, and motor neuron disease 
clinically as well as pathologically. Progressive supranuclear palsy is characterized by

supranuclear gaze palsies and axial-predominant parkinsonism. Pseudobulbar signs may 
be present, and rétropulsion is often prominent. Neurocognitive assessment shows psy­
chomotor slowing, poor working memory, and executive dysfunction. Corticobasal degen­
eration presents with asymmetric rigidity, limb apraxia, postural instability, myoclonus, 
alien limb phenomenon, and cortical sensory loss. Many individuals with behavioral-variant 
major or mild frontotemporal NCD show features of motor neuron disease, which tend to 
be mixed upper and predominantly lower motor neuron disease.
Other mental disorders and medical conditions. Behavioral-variant major or mild fron­
totemporal NCD may be mistaken for a primary mental disorder, such as major depression, 
bipolar disorders, or schizophrenia, and individuals with this variant often present initially 
to psychiatry. Over time, the development of progressive neurocognitive difficulties will

to psychiatry. Over time, the development of progressive neurocognitive difficulties will 
help to make the distinction. A careful medical evaluation will help to exclude treatable 
causes of NCDs, such as metabolic disturbances, nutritional deficiencies, and infections.
With Lewy Bodies
A. The criteria are met for major or m ild neurocognitive disorder.
B. The disorder has an insidious onset and gradual progression.
C. The disorder meets a combination of core diagnostic features and suggestive diagnos­
tic features for either probable or possible neurocognitive disorder with Lewy bodies.  
For probable major or mild neurocognitive disorder with Lewy bodies, the indi­
vidual has two core features, or one suggestive feature with one or more core features.

vidual has two core features, or one suggestive feature with one or more core features.  
For possible major or mild neurocognitive disorder with Lewy bodies, the individ­
ual has only one core feature, or one or more suggestive features.
1. Core diagnostic features:
a. Fluctuating cognition with pronounced variations in attention and alertness.
b. Recurrent visual hallucinations that are well formed and detailed.
c. Spontaneous features of parkinsonism, with onset subsequent to the develop­
ment of cognitive decline.
2. Suggestive diagnostic features;
a. Meets criteria for rapid eye movement sleep behavior disorder.
b. Severe neuroleptic sensitivity.
D. The disturbance is not better explained by cerebrovascular disease, another neurode-  

Coding note: For probable major neurocognitive disorder with Lewy bodies, with behav­
ioral disturbance, code first 331.82 (G31.83) Lewy body disease, followed by 294.11  
(F02.81 ) probable major neurocognitive disorder with Lewy bodies, with behavioral distur­
bance. For probable major neurocognitive disorder with Lewy bodies, without behavioral  
disturbance, code first 331.82 (G31.83) Lewy body disease, followed by 294.10 (F02.80)  
probable major neurocognitive disorder with Lewy bodies, without behavioral disturbance.  
For possible major neurocognitive disorder with Lewy bodies, code 331.9 (G31.9) possible  
major neurocognitive disorder with Lewy bodies. (Note: Do not use the additional code for  
Lewy body disease. Behavioral disturbance cannot be coded but should still be indicated

Lewy body disease. Behavioral disturbance cannot be coded but should still be indicated  
in writing.)

For mild neurocognitive disorder with Lewy bodies, code 331.83 (G31.84). (Note: Do not 
use the additional code for Lewy body disease. Behavioral disturbance cannot be coded  
but should still be indicated in writing.)
Major or mild neurocognitive disorder with Lewy bodies (NCDLB), in the case of major 
neurocognitive disorder (NCD), corresponds to the condition known as dementia with 
Lewy bodies (DLB). The disorder includes not only progressive cognitive impairment 
(with early changes in complex attention and executive function rather than learning and 
memory) but also recurrent complex visual hallucinations; and concurrent symptoms of 
rapid eye movement (REM) sleep behavior disorder (which can be a very early manifes­
tation); as well as hallucinations in other sensory modalities, depression, and delusions. 
The symptoms fluctuate in a pattern that can resemble a delirium, but no adequate under­

lying cause can be found. The variable presentation of NCDLB symptoms reduces the like­
lihood of all symptoms being observed in a brief clinic visit and necessitates a thorough 
assessment of caregiver observations. The use of assessment scales specifically designed to 
assess fluctuation may aid in diagnosis. Another core feature is spontaneous parkinson­
ism, which must begin after the onset of cognitive decline; by convention, major cognitive 
deficits are observed at least 1  year before the motor symptoms. The parkinsonism must 
also be distinguished from neuroleptic-induced extrapyramidal signs. Accurate diagnosis 
is essential to safe treatment planning, as up to 50% of individuals with NCDLB have se­
vere sensitivity to neuroleptic drugs, and these medications should be used with extreme

vere sensitivity to neuroleptic drugs, and these medications should be used with extreme 
caution in managing the psychotic manifestations.
The diagnosis of mild NCDLB is appropriate for individuals who present with the core 
or suggestive features at a stage when cognitive or functional impairments are not of suf­
ficient severity to fulfill criteria for major NCD. However, as for all mild NCDs, there will 
often be insufficient evidence to justify any single etiology, and use of the unspecified di­
agnosis is most appropriate.
Individuals with NCDLB frequently experience repeated falls and syncope and transient 
episodes of unexplained loss of consciousness. Autonomic dysfunction, such as ortho­
static hypotension and urinary incontinence, may be observed. Auditory and other

static hypotension and urinary incontinence, may be observed. Auditory and other 
nonvisual hallucinations are common, as are systematized delusions, delusional misiden- 
tification, and depression.
The few population-based prevalence estimates for NCDLB available range from 0.1% to 
5% of the general elderly population, and from 1.7% to 30.5% of all dementia cases. In 
brain bank (autopsy) series, the pathological lesions known as Lewy bodies are present in 
20%-35% of cases of dementia. The male-to-female ratio is approximately 1.5:1.
NCDLB is a gradually progressive disorder with insidious onset. However, there is often 
a prodromal history of confusional episodes (delirium) of acute onset, often precipitated 
by illness or surgery. The distinction between NCDLB, in which Lewy bodies are primar­

ily cortical in location, and major or mild NCD due to Parkinson's disease, in which the pa­
thology is primarily in the basal ganglia, is the order in which the cognitive and motor 
symptoms emerge. In NCDLB, the cognitive decline is manifested early in the course of ill­
ness, at least a year before the onset of motor symptoms (see the section "Differential Di­

agnosis" for this disorder). Disease course may be characterized by occasional plateaus 
but eventually progresses through severe dementia to death. Average duration of survival 
is 5-7 years in clinical series. Onset of symptoms is typically observed from the sixth 
through the ninth decades of life, with most cases having their onset when affected indi­
viduals are in their mid-70s.
Genetic and physiological. Familial aggregation may occur, and several risk genes have 
been identified, but in most cases of NCDLB, there is no family history.
The underlying neurodegenerative disease is primarily a synucleinopathy due to alpha- 
synuclein misfolding and aggregation. Cognitive testing beyond the use of a brief screen­
ing instrument may be necessary to define deficits clearly. Assessment scales developed to 
measure fluctuation can be useful. The associated condition REM sleep behavior disorder

measure fluctuation can be useful. The associated condition REM sleep behavior disorder 
may be diagnosed through a formal sleep study or identified by questioning the patient or 
informant about relevant symptoms. Neuroleptic sensitivity (challenge) is not recom­
mended as a diagnostic marker but raises suspicion of NCDLB if it occurs. A diagnosti- 
cally suggestive feature is low striatal dopamine transporter uptake on single photon 
emission computed tomography (SPECT) or positron emission tomography (PET) scan. 
Other clinically useful markers potentially include relative preservation of medial tempo­
ral structures on computed tomography (CT)/magnetic resonance imaging (MRI) brain 
scan; reduced striatal dopamine transporter uptake on SPECT/PET scan; generalized low 
uptake on SPECT/PET perfusion scan with reduced occipital activity; abnormal (low up­

take) MIBG myocardial scintigraphy suggesting sympathetic denervation; and prominent 
slow-wave activity on the electroencephalogram with temporal lobe transient waves.
Functional Consequences of iVlajor or iVliid  
Neurocognitive Disorder With Lewy Bodies
Individuals with NCDLB are more functionally impaired than would be expected for their 
cognitive deficits when contrasted to individuals with other neurodegenerative diseases, 
such as Alzheimer's disease. This is largely a result of motor and autonomic impairments, 
which cause problems with toileting, transferring, and eating. Sleep disorders and prom­
inent psychiatric symptoms may also add to functional difficulties. Consequently, the qual­
ity of life of individuals with NCDLB is often significantly worse than that of individuals 
with Alzheimer's disease.

Major or mild neurocognitive disorder due to Parkinson’s disease. A key differenti­
ating feature in clinical diagnosis is the temporal sequence in which the parkinsonism and 
the NCD appear. For NCD due to Parkinson's disease, the individual must develop cog­
nitive decline in the context of established Parkinson's disease; by convention, the decline 
should not reach the stage of major NCD until at least 1  year after Parkinson's is diagnosed. 
If less than a year has passed since the onset of motor symptoms, the diagnosis is NCDLB. 
This distinction is clearer at the major NCD level than at the mild NCD level.
The timing and sequence of parkinsonism and mild NCD may be more difficult to de­
termine because the onset and clinical presentation can be ambiguous, and unspecified

termine because the onset and clinical presentation can be ambiguous, and unspecified 
mild NCD should be diagnosed if the other core and suggestive features are absent.

Lewy body pathology frequently coexists with Alzheimer's disease and cerebrovascular 
disease pathology, particularly among the oldest age groups. In Alzheimer's disease, there 
is concomitant synuclein pathology in 60% of cases (if amygdala-restricted cases are in­
cluded). In general, there is a higher rate of Lewy body pathology in individuals with de­
mentia than in older individuals without dementia.
Major or Mild Vascular Neurocognitive Disorder
B. The clinical features are consistent with a vascular etiology, as suggested by either of  
1. Onset of the cognitive deficits is temporally related to one or more cerebrovascular  
events.
2. Evidence for decline is prominent in complex attention (including processing  
speed) and frontal-executive function.
0. There is evidence of the presence of cerebrovascular disease from history, physical

0. There is evidence of the presence of cerebrovascular disease from history, physical  
examination, and/or neuroimaging considered sufficient to account for the neurocog­
nitive deficits.
D. The symptoms are not better explained by another brain disease or systemic disorder.
Probable vascular neurocognitive disorder is diagnosed if one of the following is pres­
ent; othenvise possible vascular neurocognitive disorder should be diagnosed:
1. Clinical criteria are supported by neuroimaging evidence of significant parenchymal in­
jury attributed to cerebrovascular disease (neuroimaging-supported).
2. The neurocognitive syndrome is temporally related to one or more documented cere­
brovascular events.
3. Both clinical and genetic (e.g., cerebral autosomal dominant arteriopathy with subcortical  
infarcts and leukoencephalopathy) evidence of cerebrovascular disease is present.

Possible vascular neurocognitive disorder is diagnosed if the clinical criteria are met  
but neuroimaging is not available and the temporal relationship of the neurocognitive syn­
drome with one or more cerebrovascular events is not established.
Coding note: For probable major vascular neurocognitive disorder, with behavioral dis­
turbance, code 290.40 (F01.51). For probable major vascular neurocognitive disorder,  
without behavioral disturbance, code 290.40 (FOI .50). For possible major vascular neuro­
cognitive disorder, with or without behavioral disturbance, code 331.9 (G31.9). An addi­
tional medical code for the cerebrovascular disease is not needed.
For mild vascular neurocognitive disorder, code 331.83 (G31.84). (Note: Do not use an

For mild vascular neurocognitive disorder, code 331.83 (G31.84). (Note: Do not use an  
additional code for the vascular disease. Behavioral disturbance cannot be coded but  
should still be indicated in writing.)
The diagnosis of major or mild vascular neurocognitive disorder (NCD) requires the es­
tablishment of an NCD (Criterion A) and the determination that cerebrovascular disease is 
the dominant if not exclusive pathology that accounts for the cognitive deficits (Criteria B 
and C). Vaiscular etiology may range from large vessel stroke to microvascular disease; the

presentation is therefore very heterogeneous, stemming from the types of vascular lesions 
and their extent and location. The lesions may be focal, multifocal, or diffuse and occur in 
various combinations.
Many individuals with major or mild vascular NCD present with multiple infarctions, 
with an acute stepwise or fluctuating decline in cognition, and intervening periods of 
stability and even some improvement. Others may have gradual onset with slow pro­
gression, a rapid development of deficits followed by relative stability, or another complex 
presentation. Major or mild vascular NCD with a gradual onset and slow progression is 
generally due to small vessel disease leading to lesions in the white matter, basal ganglia, 
and/or thalamus. The gradual progression in these cases is often punctuated by acute 
events that leave subtle neurological deficits. The cognitive deficits in these cases can be at­

tributed to disruption of cortical-subcortical circuits, and complex attention, particularly 
speed of information processing, and executive ability are likely to be affected.
Assessing for the presence of sufficient cerebrovascular disease relies on history, phys­
ical examination, and neuroimaging (Criterion C). Etiological certainty requires the dem­
onstration of abnormalities on neuroimaging. The lack of neuroimaging can result in 
significant diagnostic inaccuracy by overlooking "silent" brain infarction and white mat­
ter lesions. However, if the neurocognitive impairment is temporally associated with one 
or more well-documented strokes, a probable diagnosis can be made in the absence of neu­
roimaging. Clinical evidence of cerebrovascular disease includes documented history of

roimaging. Clinical evidence of cerebrovascular disease includes documented history of 
stroke, with cognitive decline temporally associated with the event, or physical signs con­
sistent with stroke (e.g., hemiparesis; pseudobulbar syndrome, visual field defect). Neuro­
imaging (magnetic resonance imaging [MRI] or computed tomography [CT]) evidence of 
cerebrovascular disease comprises one or more of the following: one or more large vessel 
infarcts or hemorrhages, a strategically placed single infarct or hemorrhage (e.g., in angu­
lar gyrus, thalamus, basal forebrain), two or more lacunar infarcts outside the brain stem, 
or extensive and confluent white matter lesions. The latter is often termed small vessel dis­
ease or subcortical ischemic changes  on clinical neuroimaging evaluations.
For mild vascular NCD, history of a single stroke or extensive white matter disease is gen­

erally sufficient. For major vascular NCD, two or more strokes, a strategically placed stroke, 
or a combination of white matter disease and one or more lacunes is generally necessary.
The disorder must not be better explained by another disorder. For example, promi­
nent memory deficit early in the course might suggest Alzheimer's disease, early and 
prominent parkinsonian features would suggest Parkinson's disease, and a close associa­
tion between onset and depression would suggest depression.
A neurological assessment often reveals history of stroke and/or transient ischemic epi­
sodes, and signs indicative of brain infarctions. Also commonly associated are personality 
and mood changes, abulia, depression, and emotional lability. The development of late-

and mood changes, abulia, depression, and emotional lability. The development of late- 
onset depressive symptoms accompanied by psychomotor slowing and executive dys­
function is a common presentation among older adults with progressive small vessel isch­
emic disease ("vascular depression").
Major or mild vascular NCD is the second most common cause of NCD after Alzheimer's 
disease. In the United States, population prevalence estimates for vascular dementia range 
from 0.2% in the 65-70 years age group to 16% in individuals 80 years and older. Within 
3 months following stroke, 20%-30% of individuals are diagnosed with dementia. In neu­
ropathology series, the prevalence of vascular dementia increases from 13% at age 70 years 
to 44.6% at age 90 years or older, in comparison with Alzheimer's disease (23.6%-51%) and

to 44.6% at age 90 years or older, in comparison with Alzheimer's disease (23.6%-51%) and 
combined vascular dementia and Alzheimer's disease (2%-46.4%). Higher prevalence has

been reported in African Americans compared with Caucasians, and in East Asian countries 
(e.g., Japan, Chii;ia). Prevalence is higher in males than in females.
Major or mild vascular NCD can occur at any age, although the prevalence increases ex­
ponentially after age 65 years. In older individuals, additional pathologies may partly ac­
count for the neurocognitive deficits. The course may vary from acute onset with partial 
improvement to stepwise decline to progressive decline, with fluctuations and plateaus of 
varying durations. Pure subcortical major or mild vascular NCD can have a slowly pro­
gressive course that simulates major or mild NCD due to Alzheimer's disease.
Environmental. The neurocognitive outcomes of vascular brain injury are influenced by 
neuroplasticity factors such as education, physical exercise, and mental activity.
Genetic and physiological. The major risk factors for major or mild vascular NCD are the

Genetic and physiological. The major risk factors for major or mild vascular NCD are the 
same as those for cerebrovascular disease, including hypertension, diabetes, smoking, obesity, 
high cholesterol levels, high homocysteine levels, other risk factors for atherosclerosis and ar- 
teriolosclerosis, atrial fibrillation, and other conditions increasing the risk of cerebral emboli. 
Cerebral amyloid angiopathy is an important risk factor in which amyloid deposits occur 
within arterial vessels. Another key risk factor is the hereditary condition cerebral autosomal 
dominant arteriopathy with subcortical infarcts and leukoencephalopathy, or CADASIL.
Structural neuroimaging, using MRI or CT, has an important role in the diagnostic pro­
cess. There are no other established biomarkers of major or mild vascular NCD.

Major or mild vascular NCD is commonly associated with physical deficits that cause ad­
ditional disability.
Other neurocognitive disorders. Since incidental brain infarctions and white matter le­
sions are common in older individuals, it is important to consider other possible etiologies 
when an NCD is present. A history of memory deficit early in the course, and progressive 
worsening of memory, language, executive function, and perceptual-motor abilities in the 
absence of corresponding focal lesions on brain imaging, are suggestive of Alzheimer's 
disease as the primary diagnosis. Potential biomarkers currently being validated for Alz­

heimer's disease, such as cerebrospinal fluid levels of beta-amyloid and phosphorylated 
tau, and amyloid imaging, may prove to be helpful in the differential diagnosis. NCD with 
Lewy bodies is distinguished from major or mild vascular NCD by its core features of fluc­
tuating cognition, visual hallucinations, and spontaneous parkinsonism. While deficits in 
executive function and language occur in major or mild vascular NCD, the insidious onset 
and gradual progression of behavioral features or language impairment are characteristic 
of frontotemporal NCD and are not typical of vascular etiology.
Other medical conditions. A diagnosis of major or mild vascular NCD is not made if 
other diseases (e.g., brain tumor, multiple sclerosis, encephalitis, toxic or metabolic disor­

ders) are present and are of sufficient severity to account for the cognitive impairment.

Other mental disorders. A diagnosis of major or mild vascular NCD is inappropriate if 
the symptoms can be entirely attributed to delirium, although delirium may sometimes be 
superimposed on a preexisting major or mild vascular NCD, in which case both diagnoses 
can be made. If the criteria for major depressive disorder are met and the cognitive impair­
ment is temporally related to the likely onset of the depression, major or mild vascular 
NCD should not be diagnosed. However, if the NCD preceded the development of the de­
pression, or the severity of the cognitive impairment is out of proportion to the severity of 
the depression, both should be diagnosed.
Major or mild NCD due to Alzheimer's disease commonly co-occurs with major or mild 
vascular NCD, in which case both diagnoses should be made. Major or mild vascular NCD 
and depression frequently co-occur.
Due to Traumatic Brain Injury

B. There is evidence of a traumatic brain injury—that is, an impact to the head or other  
mechanisms of rapid movement or displacement of the brain within the skull, with one  
or more of the following:
1. Loss of consciousness.
2. Posttraumatic amnesia.
3. Disorientation and confusion.
4. Neurological signs (e.g., neuroimaging demonstrating injury; a new onset of sei­
zures; a marked worsening of a preexisting seizure disorder; visual field cuts; an­
osmia; hemiparesis).
C. The neurocognitive disorder presents immediately after the occurrence of the trau­
matic brain injury or immediately after recovery of consciousness and persists past the  
acute post-injury period.
Coding note: For major neurocognitive disorder due to traumatic brain injury, with behavioral

Coding note: For major neurocognitive disorder due to traumatic brain injury, with behavioral  
disturbance: For ICD-9-CM, first code 907.0 late effect of intracranial injury without skull frac­
ture, followed by 294.11 major neurocognitive disorder due to traumatic brain injury, with be­
havioral disturbance. For ICD-10-CM, first code S06.2X9S diffuse traumatic brain injury with  
loss of consciousness of unspecified duration, sequela; followed by F02.81 major neurocog­
nitive disorder due to traumatic brain injury, with behavioral disturbance.
For major neurocognitive disorder due to traumatic brain injury, without behavioral distur­
bance: For ICD-9-CM, first code 907.0 late effect of intracranial injury without skull fracture,  
followed by 294.10 major neurocognitive disorder due to traumatic brain injury, without be­
havioral disturbance. For ICD-10-CM, first code S06.2X9S diffuse traumatic brain injury with

loss of consciousness of unspecified duration, sequela; followed by F02.80 major neurocog­
nitive disorder due to traumatic brain injury, without behavioral disturbance.
For mild neurocognitive disorder due to traumatic brain injury, code 331.83 (G31.84).  
(Note: Do not use the additional code for traumatic brain injury. Behavioral disturbance  

Rate the severity of the neurocognitive disorder (NCD), not the underlying traumatic brain 
injury (see the section "Development and Course" for this disorder).
Major or mild NCD due to traumatic brain injury (TBI) is caused by an impact to the head, 
or other mechanisms of rapid movement or displacement of the brain within the skull, as 
can happen with blast injuries. Traumatic brain injury  is defined as brain trauma with spe­
cific characteristics that include at least one of the following: loss of consciousness, post­
traumatic amnesia, disorientation and confusion, or, in more severe cases, neurological 
signs (e.g., positive neuroimaging, a new onset of seizures or a marked worsening of a pre­
existing seizure disorder, visual field cuts, anosmia, hemiparesis) (Criterion B). To be at­
tributable to TBI, the NCD must present either immediately after the brain injury occurs or

tributable to TBI, the NCD must present either immediately after the brain injury occurs or 
immediately after the individual recovers consciousness after the injury and persist past 
the acute post-injury period (Criterion C).
The cognitive presentation is variable. Difficulties in the domains of complex attention, 
executive ability^, learning, and memory are common as well as slowing in speed of infor­
mation processing and disturbances in social cognition. In more severe TBI in which there 
is brain contusion, intracranial hemorrhage, or penetrating injury, there may be additional 
neurocognitive deficits, such as aphasia, neglect, and constructional dyspraxia.
Major or mild NCD due to TBI may be accompanied by disturbances in emotional function 
(e.g., irritability, easy frustration, tension and anxiety, affective lability); personality

(e.g., irritability, easy frustration, tension and anxiety, affective lability); personality 
changes (e.g., disinhibition, apathy, suspiciousness, aggression); physical disturbances 
(e.g., headache, fatigue, sleep disorders, vertigo or dizziness, tinnitus or hyperacusis, pho­
tosensitivity, anosmia, reduced tolerance to psychotropic medications); and, particularly 
in more severe TBI, neurological symptoms and signs (e.g., seizures, hemiparesis, visual 
disturbances, cranial nerve deficits) and evidence of orthopedic injuries.
In the United States, 1.7 million TBIs occur annually, resulting in 1.4 million emergency de­
partment visits, 275,000 hospitalizations, and 52,000 deaths. About 2% of the population 
lives with TBI-associated disability. Males account for 59% of TBIs in the United States. 
The most common etiologies of TBI in the United States are falls, vehicular accidents, and

The most common etiologies of TBI in the United States are falls, vehicular accidents, and 
being struck on the head. Collisions and blows to the head that occur in the course of con­
tact sports are increasingly recognized as sources of mild TBI, with a concern that repeated 
mild TBI may have cumulatively persisting sequelae.
The severity of a TBI is rated at the time of injury/initial assessment as mild, moderate, or 
severe according to the thresholds in Table 2.
The severity rating of the TBI itself does not necessarily correspond to the severity of 
the resulting NCD. The course of recovery from TBI is variable, depending not only on the 
specifics of the injury but also on cofactors, such as age, prior history of brain damage, or 
substance abuse, that may favor or impede recovery.

TABLE 2 Severity ratings for traumatic brain injury
Injury characteristic M ild TBI Moderate TBI Severe TBI
Loss of consciousness <30 n n in  30 minutes-24 hours >24 hours
Posttraumatic amnesia <24 hours 24 hours-7 days >7 days
Disorientation and confusion 13-15 (not below 13 9-12 3-8
at initial assessment at 30 minutes)
(Glasgow Coma Scale  
Score)
Neurobehavioral symptoms tend to be most severe in the immediate aftermath of the 
TBI. Except in the case of severe TBI, the typical course is that of complete or substantial 
improvement in associated neurocognitive, neurological, and psychiatric symptoms and 
signs. Neurocognitive symptoms associated with mild TBI tend to resolve within days to 
weeks after the injury with complete resolution typical by 3 months. Other symptoms that 
may potentially co-occur with the neurological symptoms (e.g., depression, irritability, 
fatigue, headache, photosensitivity, sleep disturbance) also tend to resolve in the weeks

fatigue, headache, photosensitivity, sleep disturbance) also tend to resolve in the weeks 
following mild TBI. Substantial subsequent deterioration in these areas should trigger con­
sideration of additional diagnoses. However, repeated mild TBI may be associated with 
persisting neurocognitive disturbance.
With moderate and severe TBI, in addition to persistence of neurocognitive deficits, 
there may be associated neurophysiological, emotional, and behavioral complications. 
These include seizures (particularly in the first year), photosensitivity, h)φeracusis, irritabil­
ity, aggression, depression, sleep disturbance, fatigue, apathy, inability to resume occu­
pational and social functioning at pre-injury level, and deterioration in interpersonal 
relationships. Moderate and severe TBI have been associated with increased risk of depres­

sion, aggression, and possibly neurodegenerative diseases such as Alzheimer's disease.
The features of persisting major or mild NCD due to TBI will vary by age, specifics of 
the injury, and cofactors. Persisting TBI-related impairment in an infant or child may be re­
flected in delays in reaching developmental milestones (e.g., language acquisition), worse 
academic performance, and possibly impaired social development. Among older teenag­
ers and adults, persisting symptoms may include various neurocognitive deficits, irrita­
bility, hypersensitivity to light and sound, easy fatigability, and mood changes, including 
depression, anxiety, hostility, or apathy. In older individuals with depleted cognitive re­
serve, mild TBI is more likely to result in incomplete recoveries.

Risk factors for traumatic brain injury. Traumatic brain injury rates vary by age, with 
the highest prevalence among individuals younger than 4 years, older adolescents, and in­
dividuals older than 65 years. Falls are the most common cause of TBI, with motor vehicle 
accidents being second. Sports concussions are frequent causes of TBI in older children, 
teenagers, and young adults.
Risk factors for neurocognitive disorder after traumatic brain injury. Repeated con­
cussions can lead to persistent NCD and neuropathological evidence of traumatic enceph­
alopathy. Co-occurring intoxication with a substance may increase the severity of a TBI 
from a motor vehicle accident, but whether intoxication at the time of injury worsens neu­
rocognitive outcome is unknown.

Course modifiers. Mild TBI generally resolves within a few weeks to months, although res­
olution may be delayed or incomplete in the context of repeated TBI. Worse outcome from

moderate to severe TBI is associated with older age (older than 40 years) and initial clinical pa­
rameters, such a^ low Glasgow Coma Scale score; worse motor function; pupillary nonreac­
tivity; and computed tomography (CT) evidence of brain injury (e.g., petechial hemorrhages, 
subarachnoid hemorrhage, midline shift, obliteration of third ventricle).
Diagnostic IViarlcers
Beyond neuropsychological testing, CT scanning may reveal petechial hemorrhages, 
subarachnoid hemorrhage, or evidence of contusion. Magnetic resonance image scanning 
may also reveal hyperintensities suggestive of microhemorrhages.
Functionai Consequences of iViajor or IViiid  
Neurocognitive Disorder Due to Traumatic Brain injury
With mild NCD due to TBI, individuals may report reduced cognitive efficiency, difficulty 
concentrating, and lessened ability to perform usual activities. With major NCD due to TBI, an 
individual may have difficulty in independent living and self-care. Prominent neuromotor

individual may have difficulty in independent living and self-care. Prominent neuromotor 
features, such as severe incoordination, ataxia, and motor slowing, may be present in major 
NCD due to TBI and may add to functional difficulties. Individuals with TBI histories report 
more depressive symptoms, and these can amplify cognitive complaints and worsen func­
tional outcome. Additionally, loss of emotional control, including aggressive or inappropriate 
affect and apathy, may be present after more severe TBI with greater neurocognitive impair­
ment. These features may compound difficulties with independent living and self-care.
In some instances, severity of neurocognitive symptoms may appear to be inconsistent 
with the severity of the TBI. After previously undetected neurological complications (e.g.,

with the severity of the TBI. After previously undetected neurological complications (e.g., 
chronic hematoma) are excluded, the possibility of diagnoses such as somatic symptom 
disorder or factitious disorder need to be considered. Posttraumatic stress disorder (PTSD) 
can co-occur with the NCD and have overlapping symptoms (e.g., difficulty concentrat­
ing, depressed mood, aggressive behavioral disinhibition).
Among individuals with substance use disorders, the neurocognitive effects of the sub­
stance contribute to or compound the TBI-associated neurocognitive change. Some symp­
toms associated with TBI may overlap with symptoms found in cases of PTSD, and the two 
disorders may co-occur, especially in military populations.
Major or Mild Neurocognitive Disorder

B. The neurocognitive impairments do not occur exclusively during the course of a delir­
ium and persist beyond the usual duration of intoxication and acute withdrawal.
C. The involved substance or medication and duration and extent of use are capable of  
producing the neurocognitive impairment.
D. The temporal course of the neurocognitive deficits is consistent with the timing of sub­
stance or medication use and abstinence (e.g., the deficits remain stable or improve  
after a period of abstinence).

E. The neurocognitive disorder is not attributable to another medical condition or is not  
better explained by another mental disorder.
tion]-induced neurocognitive disorders are indicated in  the table below. Note that the ICD-  
10-CM code depends on whether or not there is a comorbid substance use disorder present  
for the same class of substance. If a m ild substance use disorder is comorbid with the sub­
stance-induced neurocognitive disorder, the 4th position character is “ 1 a n d  the clinician  
should record “ m ild [substance] use disorder”  before the substance-induced neurocognitive  
disorder (e.g., “ m ild inhalant use disorder with inhalant-induced major neurocognitive disor­
der”). If a moderate or severe substance use disorder is comorbid with the substance-  
induced neurocognitive disorder, the 4th position character is “ 2,”  and the clinician should

induced neurocognitive disorder, the 4th position character is “ 2,”  and the clinician should  
record “ moderate [substance] use disorder”  or “ severe [substance] use disorder,”  depending  
on the severity of the comorbid substance use disorder. If there is no comorbid substance  
use disorder, then the 4th position character is “ 9,”  and the clinician should record only the  
substance-induced neurocognitive disorder. For some classes of substances (i.e., alcohol;  
sedatives, hypnotics, anxiolytics), it is not permissible to code a comorbid m ild substance  
use disorder with a substance-induced neurocognitive disorder; only a comorbid moderate  
or severe substance use disorder, or no substance use disorder, can be diagnosed. Behav­
ioral disturbance cannot be coded but should still be indicated in  writing.
ICD-10-CM
disorder,  
disorder,  
moderate or

ICD-10-CM
disorder,  
disorder,  
disorder
Alcohol (major neurocognitive  
disorder), nonamnestic-  
confabulatory type291.2 NA FI 0.27 FI 0.97
disorder), amnestic-  
confabulatory type291.1 NA FI 0.26 FI 0.96
Alcohol (m ild neurocognitive  
disorder)291.89 NA FI 0.288 FI 0.988
Inhalant (major neurocognitive  
disorder)292.82 F18.17 FI 8.27 FI 8.97
Inhalant (m ild neurocognitive  
disorder)292.89 FI 8.188 FI 8.288 FI 8.988
Sedative, hypnotic, or anxiolytic  
(major neurocognitive disorder)292.82 NA FI 3.27 FI 3.97
(m ild neurocognitive disorder)292.89 NA FI 3.288 FI 3.988
Other (or unknown) substance  
(major neurocognitive disorder)292.82 F19.17 FI 9.27 FI 9.97
(m ild neurocognitive disorder)292.89 F19.188 FI 9.288 FI 9.988

Persistent:,Neurocognitive impairment continues to be significant after an extended  
period of abstinence.
ICD-9-CM. The name of the substance/medication-induced neurocognitive disorder be­
gins with the specific substance/medication (e.g., alcohol) that is presumed to be causing 
the neurocognitive symptoms. The diagnostic code is selected from the table included in 
the classes, the code for "other substance" should be used; and in cases in which a substance 
is judged to be an etiological factor but the specific class of substance is unknown, the cat­
egory "unknown substance" should be used.
The name of the disorder (i.e., [specific substance]-induced major neurocognitive dis­
order or [specific substance]-induced mild neurocognitive disorder) is followed by the 
type in the case of alcohol (i.e., nonamnestic-confabulatory type, amnestic-confabulatory

type in the case of alcohol (i.e., nonamnestic-confabulatory type, amnestic-confabulatory 
type), followed by specification of duration (i.e., persistent). Unlike the recording procedures 
for ICD-IO-CM, which combine the substance/medication-induced disorder and sub­
stance use disorder into a single code, for ICD-9-CM a separate diagnostic code is given for 
the substance use disorder. For example, in the case of persistent amnestic-confabulatory 
symptoms in a man with a severe alcohol use disorder, the diagnosis is 291.1 alcohol- 
induced major neurocognitive disorder, amnestic-confabulatory type, persistent. An addi­
tional diagnosis of 303.90 severe alcohol use disorder is also given. If the substance/medi­
cation-induced neurocognitive disorder occurs without a comorbid substance use disorder 
(e.g., after a sporadic heavy use of inhalants), no accompanying substance use disorder is

(e.g., after a sporadic heavy use of inhalants), no accompanying substance use disorder is 
noted (e.g., 292.82 inhalant-induced mild neurocognitive disorder).
ICD-10-CM. The name of the substance/medication-induced neurocognitive disorder 
begins with the specific substance (e.g., alcohol) that is presumed to be causing the neuro­
cognitive symptoms. The diagnostic code is selected from the table included in the criteria 
disorder. For substances that do not fit into any of the classes, the code for "other sub­
stance" should be used; and in cases in which a substance is judged to be an etiological fac­
tor but the specific class of substance is unknown, the category "unknown substance" 
should be used.
When recording the name of the disorder, the comorbid substance use disorder (if any) is

listed first, followed by the word "with," followed by the name of the disorder (i.e., [specific 
substance]-induced major neurocognitive disorder or [specific substance]-induced mild 
neurocognitive disorder), followed by the type in the case of alcohol (i.e., nonamnestic-con­
fabulatory type, amnestic-confabulatory type), followed by specification of duration (i.e., 
persistent). For example, in the case of persistent amnestic-confabulatory symptoms in a 
man with a severe alcohol use disorder, the diagnosis is F10.26 severe alcohol use disorder 
with alcohol-induced major neurocognitive disorder, amnestic-confabulatory type, persis­
tent. A separate diagnosis of the comorbid severe alcohol use disorder is not given. If the

tent. A separate diagnosis of the comorbid severe alcohol use disorder is not given. If the 
substance-induced neurocognitive disorder occurs without a comorbid substance use dis­
order (e.g., after a sporadic heavy use of inhalants), no accompanying substance use disor­
der is noted (e.g., F18.988 inhalant-induced mild neurocognitive disorder).
Substance/medication-induced major or mild NCD is characterized by neurocognitive 
impairments that persist beyond the usual duration of intoxication and acute withdrawal 
(Criterion B). Initially, these manifestations can reflect slow recovery of brain functions 
from a period of prolonged substance use, and improvements in neurocognitive as well as

brain imaging indicators may be seen over many months. If the disorder continues for an 
extended period, persistent  should be specified. The given substance and its use must be 
known to be capable of causing the observed impairments (Criterion C). While nonspecific 
decrements in a range of cognitive abilities can occur with nearly any substance of abuse 
and a variety of medications, some patterns occur more frequently with selected drug 
classes. For example, NCD due to sedative, hypnotic, or anxiolytic drugs (e.g., benzodiaz­
epines, barbiturates) may show greater disturbances in memory than in other cognitive 
functions. NCD induced by alcohol frequently manifests with a combination of impair­
ments in executive-function and memory and learning domains. The temporal course of 
the substance-induced NCD must be consistent with that of use of the given substance 
(Criterion D). In alcohol-induced amnestic confabulatory (Korsakoff's) NCD, the features

(Criterion D). In alcohol-induced amnestic confabulatory (Korsakoff's) NCD, the features 
include prominent amnesia (severe difficulty learning new information with rapid forget­
ting) and a tendency to confabulate. These manifestations may co-occur with signs of thi­
amine encephalopathy (Wernicke's encephalopathy) with associated features such as 
nystagmus and ataxia. Ophthalmoplegia of Wernicke's encephalopathy is typically charac­
terized by a lateral gaze paralysis.
In addition to or independent of the more common neurocognitive symptoms related 
to methamphetamine use (e.g., difficulties with learning and memory; executive func­
tion), methamphetamine use can also be associated with evidence of vascular injury (e.g., 
focal weakness, unilateral incoordination, asymmetrical reflexes). The most common neu­
rocognitive profile approximates that seen in vascular NCD.

Intermediate-duration NCD induced by drugs with central nervous system depressant effects 
may manifest with added symptoms of increased irritability, anxiety, sleep disturbance, and 
dysphoria. Intermediate-duration NCD induced by stimulant drugs may manifest with re­
bound depression, hypersomnia, and apathy. In severe forms of substance/medication- 
induced major NCD (e.g., associated with long-term alcohol use), there may be prominent 
neuromotor features, such as incoordination, ataxia, and motor slowing. There may also be 
loss of emotional control, including aggressive or inappropriate affect, or apathy.
The prevalence of these conditions is not known. Prevalence figures for substance abuse are

The prevalence of these conditions is not known. Prevalence figures for substance abuse are 
available, and substance/medication-induced major or mild NCDs are more likely in those 
who are older, have longer use, and have other risk factors such as nutritional deficits.
For alcohol abuse, the rate of mild NCD of intermediate duration is approximately 30%- 
40% in the first 2 months of abstinence. Mild NCD may persist, particularly in those who do 
not achieve stable abstinence until after age 50 years. Major NCD is rare and may result from 
concomitant nutritional deficits, as in alcohol-induced amnestic confabulatory NCD.
For individuals quitting cocaine, methamphetamine, opioids, phencyclidine, and sed­
ative, hypnotics, or anxiolytics, substance/medication-induced mild NCD of intermediate 
duration may occur in one-third or more, and there is some evidence that these substances

duration may occur in one-third or more, and there is some evidence that these substances 
may also be associated with persistent mild NCD. Major NCD associated with these sub­
stances is rare, if it occurs at all. In the case of methamphetamine, cerebrovascular disease 
can also occur, resulting in diffuse or focal brain injury that can be of mild or major neu­
rocognitive levels. Solvent exposure has been linked to both major and mild NCD of both 
intermediate and persistent duration.
The presence of NCD induced by cannabis and various hallucinogens is controversial. 
With cannabis, intoxication is accompanied by various neurocognitive disturbances, but 
these tend to clear with abstinence.

Substance use disorders tend to commence during adolescence and peak in the 20s and 
30s. Although longer history of severe substance use disorder is associated with greater 
likelihood of NCD, the relationships are not straightforward, with substantial and even 
complete recovery of neurocognitive functions being common among individuals who 
achieve stable abstinence prior to age 50 years. Substance/medication-induced major or 
mild NCD is most likely to become persistent in individuals who continue abuse of sub­
stances past age 50 years, presumably because of a combination of lessened neural plas­
ticity and beginnings of other age-related brain changes. Earlier commencement of abuse, 
particularly of alcohol, may lead to defects in later neural development (e.g., later stages of 
maturation of frontal circuitries), which may have effects on social cognition as well as 
other neurocognitive abilities. For alcohol-induced NCD, there may be an additive effect

other neurocognitive abilities. For alcohol-induced NCD, there may be an additive effect 
of aging and alcohol-induced brain injury.
Risk factors for substance/medication-induced NCDs include older age, longer use, and 
persistent use past age 50 years. In addition, for alcohol-induced NCD, long-term nutri­
tional deficiencies, liver disease, vascular risk factors, and cardiovascular and cerebrovas­
cular disease may contribute to risk.
Magnetic resonance imaging (MRI) of individuals with chronic alcohol abuse frequently 
reveals cortical thinning, white matter loss, and enlargement of sulci and ventricles. While 
neuroimaging abnormalities are more common in those with NCDs, it is possible to ob­
serve NCDs without neuroimaging abnormalities, and vice versa. Specialized techniques

serve NCDs without neuroimaging abnormalities, and vice versa. Specialized techniques 
(e.g., diffusion tensor imaging) may reveal damage to specific white matter tracts. Mag­
netic resonance spectroscopy may reveal reduction in N-acetylaspartate, and increase in 
markers of inflammation (e.g., myoinositol) or white matter injury (e.g., choline). Many of 
these brain imaging changes and neurocognitive manifestations reverse following suc­
cessful abstinence. In individuals with methamphetamine use disorder, MRI may also re­
veal hyperintensities suggestive of microhemorrhages or larger areas of infarction.
Functional Consequences of Substance/lVledication-  
induced iViajor or iVliid Neurocognitive Disorder
The functional consequences of substance/medication-induced mild NCD are sometimes 
augmented by reduced cognitive efficiency and difficulty concentrating beyond that seen

augmented by reduced cognitive efficiency and difficulty concentrating beyond that seen 
in many other NCDs. In addition, at both major and mild levels, substance/medication- 
induced NCDs may have associated motor syndromes that increase the level of functional 
Individuals with substance use disorders, substance intoxication, and substance withdrawal 
are at increased risk for other conditions that may independently, or through a compounding 
effect, result in neurocognitive disturbance. These include history of traumatic brain injury 
and infections that can accompany substance use disorder (e.g., MV, hepatitis C virus, syph­
ilis). Therefore, presence of substance/medication-induced major or mild NCD should be 
differentiated from NCDs arising outside the context of substance use, intoxication, and with­

drawal, including these accompanying conditions (e.g., traumatic brain injury).

Substance use disorders, substance intoxication, and substance withdrawal are highly co- 
morbid with other mental disorders. Comorbid posttraumatic stress disorder, psychotic 
disorders, depressive and bipolar disorders, and neurodevelopmental disorders can con­
tribute to neurocognitive impairment in substance users. Traumatic brain injury occurs 
more frequently with substance use, complicating efforts to determine the etiology of NCD 
in such cases. Severe, long-term alcohol use disorder can be associated with major organ 
system disease, including cerebrovascular disease and cirrhosis. Amphetamine-induced 
NCD may be accompanied by major or mild vascular NCD, also secondary to amphet­
amine use.
Due to HIV Infection
B. Tliere is documented infection witfi human immunodeficiency virus (HIV).

C. The neurocognitive disorder is not better explained by non-HIV conditions, including  
secondary brain diseases such as progressive multifocal leukoencephalopathy or  
cryptococcal meningitis.
D. The neurocognitive disorder is not attributable to another medical condition and is not  
better explained by a mental disorder.
Coding note: For major neurocognitive disorder due to HIV infection, with behavioral dis­
turbance, code first 042 (B20) HIV infection, followed by 294.11 (F02.81) major neurocog­
nitive disorder due to HIV infection, with behavioral disturbance. For major neurocognitive  
disorder due to HIV infection, without behavioral disturbance, code first 042 (820) HIV in­
fection, followed by 294.10 (F02.80) major neurocognitive disorder due to HIV infection,

fection, followed by 294.10 (F02.80) major neurocognitive disorder due to HIV infection,  
without behavioral disturbance.
For mild neurocognitive disorder due to HIV infection, code 331.83 (G31.84). (Note: Do 
not use the additional code for HIV infection. Behavioral disturbance cannot be coded but  
should still be indicated in  writing.)
HIV disease is caused by infection with human immunodeficiency virus type-1 (HIV-1), 
which is acquired through exposure to bodily fluids of an infected person through injection 
drug use, unprotected sexual contact, or accidental or iatrogenic exposure (e.g., contami­
nated blood supply, needle puncture injury to medical personnel). HIV infects several types 
of cells, most particularly immune cells. Over time, the infection can cause severe depletion

of cells, most particularly immune cells. Over time, the infection can cause severe depletion 
of "T-helper" (CD4) lymphocytes, resulting in severe immunocompromise, often leading to 
opportunistic infections and neoplasms. This advanced form of HIV infection is termed 
acquired immune deficiency syndrome (AIDS). Diagnosis of HIV is confirmed by established 
laboratory methods such as enzyme-linked immunosorbent assay for HIV antibody with 
Western blot confirmation and/or polymerase chain reaction-based assays for HIV.
Some individuals with HIV infection develop an NCD, which generally shows a "sub­
cortical pattern" with prominently impaired executive function, slowing of processing 
speed, problems with more demanding attentional tasks, and difficulty in learning new 
information, but fewer problems with recall of learned information. In major NCD, slow­

ing may be prominent. Language difficulties, such as aphasia, are uncommon, although 
reductions in fluency may be observed. HIV pathogenic processes can affect any part of 
the brain; therefore, other patterns are possible.

Major or mild NCD due to HIV infection is usually more prevalent in individuals with 
prior episodes of severe immunosuppression, high viral loads in the cerebrospinal fluid, 
and indicators of advanced HIV disease such as anemia and hypoalbuminemia. Individ­
uals with advanced NCD may experience prominent neuromotor features such as severe 
incoordination, ataxia, and motor slowing. There may be loss of emotional control, includ­
ing aggressive or inappropriate affect or apathy.
Depending on stage of HIV disease, approximately one-third to over one-half of HIV- 
infected individuals have at least mild neurocognitive disturbance, but some of these dis­
turbances may not meet the full criteria for mild NCD. An estimated 25% of individuals 
with HIV will have signs and symptoms that meet criteria for mild NCD, and in fewer than 
5% would criteria for major NCD be met.

An NCD due to HIV infection can resolve, improve, slowly worsen, or have a fluctuating 
course. Rapid progression to profound neurocognitive impairment is uncommon in the 
context of currently available combination antiviral treatment; consequently, an abrupt 
change in mental status in an individual with HIV may prompt an evaluation of other 
medical sources for the cognitive change, including secondary infections. Because HIV in­
fection preferentially affects subcortical regions over the course of illness, including deep 
white matter, the progression of the disorder follows a "subcortical" pattern. Since HIV 
can affect a variety of brain regions, and the illness can take on many different trajectories 
depending on associated comorbidities and consequences of HIV, the overall course of an

depending on associated comorbidities and consequences of HIV, the overall course of an 
NCD due to HIV infection has considerable heterogeneity. A subcortical neurocognitive 
profile may interact with age over the life course, when psychomotor slowing and motor 
impairments such as slowed gait may occur as a consequence of other age-related condi­
tions so that the overall progression may appear more pronounced in later life.
In developed countries, HIV disease is primarily a condition of adults, with acquisition 
via risky behaviors (e.g., unprotected sex, injection drug use) beginning in late adolescence 
and peaking during young and middle adulthood. In developing countries, particularly 
sub-Saharan Africa, where HIV testing and antiretroviral treatments for pregnant women 
are not readily available, perinatal transmission is common. The NCD in such infants and

are not readily available, perinatal transmission is common. The NCD in such infants and 
children may present primarily as neurodevelopmental delay. As individuals treated for 
HIV survive into older age, additive and interactive neurocognitive effects of HIV and 
aging, including other NCDs (e.g., due to Alzheimer's disease, due to Parkinson's dis­
ease), are possible.
R is k  and Prognostic Factors
Risk and prognostic factors for HIV infection. Risk factors for HIV infection include injec­
tion drug use, unprotected sex, and unprotected blood supply and other iatrogenic factors.
Risk and prognostic factors for major or mild neurocognitive disorder due to HIV in­
fection. Paradoxically, NCD due to HIV infection has not declined significantly with the 
advent of combined antiretroviral therapy, although the most severe presentations (con­

sistent with the diagnosis of major NCD) have decreased sharply. Contributory factors 
may include inadequate control of HIV in the central nervous system (CNS), the evolution 
of drug-resistant viral strains, the effects of chronic long-term systemic and brain inflam­
mation, and the effects of comorbid factors such as aging, drug abuse, past history of CNS 
trauma, and co-infections, such as with the hepatitis C virus. Chronic exposure to antiret­
roviral drugs also raises the possibility of neurotoxicity, although this has not been defin­
itively established.

Serum HIV testing is required for the diagnosis. In addition, HIV characterization of the cere­
brospinal fluid may be helpful if it reveals a disproportionately high viral load in cerebrospinal 
fluid versus in the plasma. Neuroimaging (i.e., magnetic resonance imaging [MRI]) may reveal 
reduction in total brain volume, cortical thinning, reduction in white matter volume, and 
patchy areas of abnormal white matter (hyperintensities). MRI or lumbar puncture may be 
helpful to exclude a specific medical condition such as cryptococcus infection or herpes en­
cephalitis that may contribute to CNS changes in the context of AIDS. Specialized techniques 
such as diffusion tensor imaging may reveal damage to specific white matter tracts.
Functionai Consequences of iVlajor or iVliid  
Neurocognitive Disorder Due to HIV infection
Functional consequences of major or mild NCD due to HIV infection are variable across

Functional consequences of major or mild NCD due to HIV infection are variable across 
individuals. Thus, impaired executive abilities and slowed information processing may 
substantially interfere with the complex disease management decisions required for ad­
herence to the combined antiretroviral therapy regimen. The likelihood of comorbid dis­
ease may further create functional challenges.
In the presence of comorbidities, such as other infections (e.g., hepatitis C virus, syphilis), 
drug abuse (e.g., methamphetamine abuse), or prior head injury or neurodevelopmental 
conditions, major or mild NCD due to HIV infection can be diagnosed provided there is ev­
idence that infection with HIV has worsened any NCDs due to such preexisting or comorbid 
conditions. Among older adults, onset of neurocognitive decline related to cerebrovascular

conditions. Among older adults, onset of neurocognitive decline related to cerebrovascular 
disease or neurodegeneration (e.g., major or mild NCD due to Alzheimer's disease) may 
need to be differentiated. In general, stable, fluctuating (without progression) or improving 
neurocognitive status would favor an HIV etiology, whereas steady or stepwise deter­
ioration would suggest neurodegenerative or vascular etiology. Because more severe im­
munodeficiency can result in opportunistic infections of the brain (e.g., toxoplasmosis; 
cryptococcosis) and neoplasia (e.g., CNS lymphoma), sudden onset of an NCD or sudden 
worsening of that disorder demands active investigation of non-HIV etiologies.
HIV disease is accompanied by chronic systemic and neuro-inflammation that can be as­
sociated with cerebrovascular disease and metabolic syndrome. These complications can

sociated with cerebrovascular disease and metabolic syndrome. These complications can 
be part of the pathogenesis of major or mild NCD due to HIV infection. HIV frequently co­
occurs with conditions such as substance use disorders when the substance has been in­
jected and other sexually transmitted disorders.
Due to Prion Disease
B. There is insidious onset, and rapid progression of impairment is common.
C. There are motor features of prion disease, such as myoclonus or ataxia, or biomarker  
evidence.

better expiated by another mental disorder.
Coding note: For major neurocognitive disorder due to prion disease, with behavioral dis­
turbance, code first 046.79 (A81.9) prion disease, followed by 294.11 (F02.81) major  
neurocognitive disorder due to prion disease, with behavioral disturbance. For major neu­
rocognitive disorder due to prion disease, without behavioral disturbance, code first  
046.79 (A81.9) prion disease, followed by 294.10 (F02.80) major neurocognitive disorder  
due to prion disease, without behavioral disturbance.
For mild neurocognitive disorder due to prion disease, code 331.83 (G31.84). (Note: Do 
not use the additional code for prion disease. Behavioral disturbance cannot be coded but  
The classification of major or mild neurocognitive disorder (NCD) due to prion disease in­

cludes NCDs due to a group of subacute spongiform encephalopathies (including Creutz­
feldt-Jakob disease, variant Creutzfeldt-Jakob disease, kuru, Gerstmann-Sträussler- 
Scheinker syndrome, and fatal insomnia) caused by transmissible agents known as prions.  
The most common type is sporadic Creutzfeldt-Jakob disease, typically referred to as 
Creutzfeldt-Jakob disease (CJD). Variant CJD is much rarer and is associated with trans­
mission of bovine spongiform encephalopathy, also called "mad cow disease." Typically, 
individuals with CJD present with neurocognitive deficits, ataxia, and abnormal move­
ments such as myoclonus, chorea, or dystonia; a startle reflex is also common. Typically, 
the history reveals rapid progression to major NCD over as little as 6 months, and thus the

the history reveals rapid progression to major NCD over as little as 6 months, and thus the 
disorder is typically seen only at the major level. However, many individuals with the dis­
order may have atypical presentations, and the disease can be confirmed only by biopsy or 
at autopsy. Individuals with variant CJD may present with a greater preponderance of 
psychiatric symptoms, characterized a by low mood, withdrawal, and anxiety. Prion dis­
ease is typically not diagnosed without at least one of the characteristic biomarker fea­
tures: recognized lesions on magnetic resonance imaging with DWI (diffusion-weighted 
imaging) or FLAIR (fluid-attenuated inversion recovery), tau or 14-3-3 protein in cerebro­
spinal fluid, characteristic triphasic waves on electroencephalogram, or, for rare familial 
forms, family history or genetic testing.

The annual incidence of sporadic CJD is approximately one or two cases per million peo­
ple. Prevalence is unknown but very low given the short survival.
Prion disease may develop at any age in adults—the peak age for the sporadic CJD is ap­
proximately 67 years—although it has been reported to occur in individuals spaniüng the 
teenage years to late life. Prodromal symptoms of prion disease may include fatigue, anx­
iety, problems with appetite or sleeping, or difficulties with concentration. After several 
weeks, these symptoms may be followed by incoordination, altered vision, or abnormal 
gait or other movements that may be myoclonic, choreoathetoid, or ballistic, along with a 
rapidly progressive dementia. The disease typically progresses very rapidly to the major

rapidly progressive dementia. The disease typically progresses very rapidly to the major 
level of impairment over several months. More rarely, it can progress over 2 years and ap­
pear similar in its course to other NCDs.

Risk Factors and Prognosis
Environmental. Cross-species transmission of prion infections, with agents that are 
closely related to the human form, has been demonstrated (e.g., the outbreak of bovine 
spongiform encephalopathy inducing variant CJD in the United Kingdom during the mid- 
1990s). Transmission by comeal transplantation and by human growth factor injection has 
been documented, and anecdotal cases of transmission to health care workers have been 
reported.
Genetic and physiological. There is a genetic component in up to 15% of cases, associ­
ated with an autosomal dominant mutation.
Prion disease can be definitively confirmed only by biopsy or at autopsy. Although there are 
no distinctive findings on cerebrospinal fluid analysis across the prion diseases, reliable bio­
markers are being developed and include 14-3-3 protein (particularly for sporadic CJD) as 
well as tau protein. Magnetic resonance brain imaging is currently considered the most sen­

sitive diagnostic test when DWI is performed, with the most common finding being multi­
focal gray matter hyperintensities in subcortical and cortical regions. In some individuals, 
the electroencephalogram reveals periodic sharp, often triphasic and synchronous dis­
charges at a rate of 0.5-2 Hz at some point during the course of the disorder.
Other major neurocognitive disorders. Major NCD due to prion disease may appear 
similar in its course to other NCDs, but prion diseases are typically distinguished by their 
rapid progression and prominent cerebellar and motor symptoms.
Due to Parkinson’s Disease

B. The disturbance occurs in the setting of established Parkinson’s disease.
C. There is insidious onset and gradual progression of impairment.
Major or mild neurocognitive disorder probably due to Parkinson’s disease should  
be diagnosed if 1  and 2 are both met. iUlajor or miid neurocognitive disorder possibly  
due to Parltinson’s disease should be diagnosed if 1  or 2 is met:
1. There is no evidence of mixed etiology (i.e., absence of other neurodegenerative or  
cerebrovascular disease or another neurological, mental, or systemic disease or con­
dition likely contributing to cognitive decline).
2. The Parkinson’s disease clearly precedes the onset of the neurocognitive disorder.

Coding note: For major neurocognitive disorder probably due to Parkinson’s disease,  
with behavioral disturbance, code first 332.0 (G20) Parkinson’s disease, followed by
294.11 (F02.81) major neurocognitive disorder probably due to Parkinson’s disease, with  
behavioral disturbance. For major neurocognitive disorder probably due to Parkinson’s  
disease, without behavioral disturbance, code first 332.0 (G20) Parkinson’s disease, fol­

lowed by 294.10 (F02.80) major neurocognitive disorder probably due to Parkinson’s dis­
ease, without be^havioral disturbance.
For major neurocognitive disorder possibly due to Parkinson’s disease, code 331.9  
(G31.9) major neurocognitive disorder possibly due to Parkinson’s disease. (Note: Do not 
use the additional code for Parkinson’s disease. Behavioral disturbance cannot be coded  
For mild neurocognitive disorder due to Parkinson’s disease, code 331.83 (G31.84).  
(Note: Do not use the additional code for Parkinson’s disease. Behavioral disturbance  
The essential feature of major or mild neurocognitive disorder (NCD) due to Parkinson's 
disease is cognitive decline following the onset of Parkinson's disease. The disturbance 
must occur in the setting of established Parkinson's disease (Criterion B), and deficits must

must occur in the setting of established Parkinson's disease (Criterion B), and deficits must 
have developed gradually (Criterion C). The NCD is viewed as probably  due to Parkinson's 
disease when there is no evidence of another disorder that might be contributing to the 
cognitive decline and when the Parkinson's disease clearly precedes onset of the NCD. The 
NCD is considered possibly  due to Parkinson's disease either  when there is no evidence of 
another disorder that might be contributing to the cognitive decline or when the Parkin­
son's disease precedes onset of the NCD, but not both.
Frequently present features include apathy, depressed mood, anxious mood, hallucina­
tions, delusions, personality changes, rapid eye movement sleep behavior disorder, and 
excessive daytime sleepiness.

The prevalence of Parkinson's disease in the United States steadily increases with age from 
approximately 0.5% between ages 65 and 69 to 3% at age 85 years and older. Parkinson's 
disease is more common in males than in females. Among individuals with Parkinson's 
disease, as many as 75% will develop a major NCD sometime in the course of their disease. 
The prevalence of mild NCD in Parkinson's disease has been estimated at 27%.
Onset of Parkinson's disease is typically between the sixth and ninth decades of life, with 
most expression in the early 60s. Mild NCD often develops relatively early in the course of 
Parkinson's disease, whereas major impairment typically does not occur until late.
Environmental. Risk factors for Parkinson's disease include exposure to herbicides and 
pesticides.

Genetic and physiological. Potential risk factors for NCD among individuals with Par­
kinson's disease include older age at disease onset and increasing duration of disease.
Neuropsychological testing, with a focus on tests that do not rely on motor function, is crit­
ical in detecting the core cognitive deficits, particularly at the mild NCD phase. Structural 
neuroimaging and dopamine transporter scans, such as DaT scans, may differentiate 
Lewy body-related dementias (Parkinson's and dementia with Lewy bodies) from non-

Lewy body-related dementias (e.g., Alzheimer's disease) and can sometimes be helpful in 
the evaluation of major or mild NCD due to Parkinson's disease.
Major or mild neurocognitive disorder with Lewy bodies. This distinction is based sub­
stantially on the timing and sequence of motor and cognitive symptoms. For NCD to be at­
tributed to Parkinson's disease, the motor and other symptoms of Parkinson's disease must 
be present well before (by convention, at least 1 year prior) cognitive decline has reached 
the level of major NCD, whereas in major or mild NCD with Lewy bodies, cognitive symp­
toms begin shortly before, or concurrent with, motor symptoms. For mild NCD, the timing 
is harder to establish because the diagnosis itself is less clear and the two disorders exist on 
a continuum. Unless Parkinson's disease has been established for some time prior to the 
onset of cognitive decline, or typical features of major or mild NCD with Lewy bodies are

onset of cognitive decline, or typical features of major or mild NCD with Lewy bodies are 
present, it is preferable to diagnose unspecified mild NCD.
Major or mild neurocognitive disorder due to Alzheimer’s disease. The motor features 
are the key to distinguishing major or mild NCD due to Parkinson's disease from major or 
mild NCD due to Alzheimer's disease. However, the two disorders can co-occur.
Major or mild vascular neurocognitive disorder. Major or mild vascular NCD may pre­
sent with parkinsonian features such as psychomotor slowing that may occur as a conse­
quence of subcortical small vessel disease. However, the parkinsonian features typically 
are not sufficient for a diagnosis of Parkinson's disease, and the course of the NCD usually 
has a clear association with cerebrovascular changes.
Neurocognitive disorder due to another medical condition (e.g., neurodegenerative

Neurocognitive disorder due to another medical condition (e.g., neurodegenerative  
disorders). When a diagnosis of major or mild NCD due to Parkinson's disease is being 
considered, the distinction must also be made from other brain disorders, such as progres­
sive supranuclear palsy, corticobasal degeneration, multiple system atrophy, tumors, and 
hydrocephalus.
Neuroleptic-induced parkinsonism. Neuroleptic-induced parkinsonism can occur in 
individuals with other NCDs, particularly when dopamine-blocking drugs are prescribed 
for the behavioral manifestations of such disorders
Other medical conditions. Delirium and NCDs due to side effects of dopamine-blocking 
drugs and other medical conditions (e.g., sedation or impaired cognition, severe hypothy­
roidism, Bi 2 deficiency) must also be ruled out.
Parkinson's disease may coexist with Alzheimer's disease and cerebrovascular disease, espe­

cially in older individuals. The compounding of multiple pathological features may diminish 
the functional abilities of individuals with Parkinson's disease. Motor symptoms and frequent 
co-occurrence of depression or apathy can make functional impairment worse.
Due to Huntington’s Disease
B. There is insidious onset and gradual progression.
C. There is clinically established Huntington’s disease, or risk for Huntington’s disease  
based on family history or genetic testing.

Coding note: For major neurocognitive disorder due to Huntington’s disease, with behav­
ioral disturbance, code first 333.4 (G10) Huntington’s disease, followed by 294.11  
(F02.81) major neurocognitive disorder due to Huntington’s disease, with behavioral dis­
turbance. For major neurocognitive disorder due to Huntington’s disease, without behav­
ioral disturbance, code first 333.4 (G10) Huntington’s disease, followed by 294.10 (F02.80)  
major neurocognitive disorder due to Huntington’s disease, without behavioral disturbance.  
For mild neurocognitive disorder due to Huntington’s disease, code 331.83 (G31.84).  
(Note: Do not use the additional code for Huntington’s disease. Behavioral disturbance  

Progressive cognitive impairment is a core feature of Huntington's disease, with early changes 
in executive function (i.e., processing speed, organization, and planning) rather than learn­
ing and memory. Cognitive and associated behavioral changes often precede the emergence 
of the typical motor abnormalities of bradykinesia (i.e., slowing of voluntary movement) 
and chorea (i.e., involuntary jerking movements). A diagnosis of definite Huntington's dis­
ease is given in the presence of unequivocal, extrapyramidal motor abnormalities in an in­
dividual with either a family history of Huntington's disease or genetic testing showing a 
CAG trinucleotide repeat expansion in the HIT gene, located on chromosome 4.

Depression, irritability, anxiety, obsessive-compulsive symptoms, and apathy are fre­
quently, and psychosis more rarely, associated with Huntington's disease and often pre­
cede the onset of motor symptoms.
Neurocognitive deficits are an eventual outcome of Huntington's disease; the worldwide 
prevalence is estimated to be 2.7 per 100,000. The prevalence of Huntington's disease in 
North America, Europe, and Australia is 5.7 per 100,000, with a much lower prevalence of 
0.40 per 100,000 in Asia.
The average age at diagnosis of Huntington's disease is approximately 40 years, although 
this varies widely. Age at onset is inversely correlated with CAG expansion length. Juve­
nile Huntington's disease (onset before age 20) may present more commonly with brady­

kinesia, dystonia, and rigidity than with the choreic movements characteristic of the adult- 
onset disorder. The disease is gradually progressive, with median survival approximately 
15 years after motor symptom diagnosis.
Phenotypic expression of Huntington's disease varies by presence of motor, cognitive, 
and psychiatric symptoms. Psychiatric and cognitive abnormalities can predate the motor 
abnormality by at least 15 years. Initial symptoms requiring care often include irritabity, 
anxiety, or depressed mood. Other behavioral disturbances may include pronounced ap­
athy, disinhibition, impulsivity, and impaired insight, with apathy often becoming more 
progressive over time. Early movement symptoms may involve the appearance of fidget­

iness of the extremities as well as mild apraxia  (i.e., difficulty with purposeful movements), 
particularly with fine motor tasks. As the disorder progresses, other motor problems in­
clude impaired gait (ataxia)  and postural instability. Motor impairment eventually affects 
speech production (dysarthria)  such that the speech becomes very difficult to understand.

which may result in significant distress resulting from the communication barrier in the 
context of comparatively intact cognition. Advanced motor disease severely affects gait 
with progressive ataxia. Eventually individuals become nonambulatory. End-stage motor 
disease impairs motor control of eating and swallowing, typically a major contributor to 
the death of the individual from aspiration pneumonia.
Genetic and physiological. The genetic basis of Huntington's disease is a fully penetrant 
autosomal dominant expansion of the CAG trincleotide, often called a CAG repeat  in the 
huntingtin gene. A repeat length of 36 or more is invariably associated with Huntington's 
disease, with longer repeat lengths associated with early age at onset. A CAG repeat length 
of 36 or more is invariably associated with Huntington's disease.
Genetic testing is the primary laboratory test for the determination of Huntington's dis­

ease, which is an autosomal dominant disorder with complete penetrance. The trinucleo­
tide CAG is observed to have a repeat expansion in the gene that encodes huntingtin 
protein on chromosome 4. A diagnosis of Huntington's disease is not made in the presence 
of the gene expansion alone, but the diagnosis is made only after symptoms become man­
ifest. Some individuals with a positive family history request genetic testing in a presymp- 
tomatic stage. Associated features may also include neuroimaging changes; volume loss in 
the basal ganglia, particularly the caudate nucleus and putamen, is well known to occur 
and progresses over the course of illness. Other structural and functional changes have 
been observed in brain imaging but remain research measures.
Functionai Consequences of iViajor or IVliid

Functionai Consequences of iViajor or IVliid  
Neurocognitive Disorder Due to Huntington’s Disease
In the prodromal phase of illness and at early diagnosis, occupational decline is most com­
mon, with most individuals reporting some loss of ability to engage in their typical work. 
The emotional, behavioral, and cognitive aspects of Huntington's disease, such as disin­
hibition and personality changes, are highly associated with functional decline. Cognitive 
deficits that contribute most to functional decline may include speed of processing, initi­
ation, and attention rather than memory impairment. Given that Huntington's disease on­
set occurs in productive years of life, it may have a very disruptive effect on performance 
in the work setting as well as social and family life. As the disease progresses, disability

in the work setting as well as social and family life. As the disease progresses, disability 
from problems such as impaired gait, dysarthria, and impulsive or irritable behaviors may 
substantially add to the level of impairment and daily care needs, over and above the care 
needs attributable to the cognitive decline. Severe choreic movements may substantially 
interfere with provision of care such as bathing, dressing, and toileting.
Other mental disorders. Early symptoms of Huntington's disease may include instabil­
ity of mood, irritability, or compulsive behaviors that may suggest another mental disor­
der. However, genetic testing or the development of motor symptoms will distinguish the 
presence of Huntington's disease.
Other neurocognitive disorders. The early symptoms of Huntington's disease, particu­

larly symptoms of executive dysfunction and impaired psychomotor speed, may resemble 
other neurocognitive disorders (NCDs), such as major or mild vascular NCD.

Other movement disorders. Huntington's disease must also be differentiated from other 
disorders or conditions associated with chorea, such as Wilson's disease, drug-induced 
tardive dyskinesia, Sydenham's chorea, systemic lupus erythematosus, or senile chorea. 
Rarely, individuals may present with a course similar to that of Huntington's disease but 
without positive genetic testing; this is considered to be a Huntington's disease pheno- 
copy that results from a variety of potential genetic factors.
neurocognitive disorder is the pathophysiological consequence of another medical  
C. The cognitive deficits are not better explained by another mental disorder or another

C. The cognitive deficits are not better explained by another mental disorder or another  
specific neurocognitive disorder (e.g., Alzheimer’s disease, HIV infection).
Coding note: For major neurocognitive disorder due to another medical condition, with  
behavioral disturbance, code first the other medical condition, followed by the major neu­
rocognitive disorder due to another medical condition, with behavioral disturbance (e.g.,  
340 [G35] multiple sclerosis, 294.11 [F02.81] major neurocognitive disorder due to multi­
ple sclerosis, with behavioral disturbance). For major neurocognitive disorder due to an­
other medical condition, without behavioral disturbance, code first the other medical  
condition, followed by the major neurocognitive disorder due to another medical condition,  
without behavioral disturbance (e.g., 340 [G35] multiple sclerosis, 294.10 [F02.80] major

without behavioral disturbance (e.g., 340 [G35] multiple sclerosis, 294.10 [F02.80] major  
neurocognitive disorder due to multiple sclerosis, without behavioral disturbance).
For m ild neürocognitive disorder due to another medical condition, code 331.83 (G31.84).  
(Note: Do not use the additional code for the other medical condition. Behavioral distur­
A number of other medical conditions can cause neurocognitive disorders (NCDs). These 
conditions include structural lesions (e.g., primary or secondary brain tumors, subdural 
hematoma, slowly progressive or normal-pressure hydrocephalus), hypoxia related to hy­
poperfusion from heart failure, endocrine conditions (e.g., hypothyroidism, hypercalce­
mia, hypoglycemia), nutritional conditions (e.g., deficiencies of thiamine or niacin), other

mia, hypoglycemia), nutritional conditions (e.g., deficiencies of thiamine or niacin), other 
infectious conditions (e.g., neurosyphilis, cryptococcosis), immune disorders (e.g., tempo­
ral arteritis, systemic lupus erythematosus), hepatic or renal failure, metabolic conditions 
(e.g., Kufs' disease, adrenoleukodystrophy, metachromatic leukodystrophy, other storage 
diseases of adulthood and childhood), and other neurological conditions (e.g., epilepsy, 
multiple sclerosis). Unusual causes of central nervous system injury, such as electrical 
shock or intracranial radiation, are generally evident from the history. The temporal asso­
ciation between the onset or exacerbation of the medical condition and the development of 
the cognitive deficit offers the greatest support that the NCD is induced by the medical

the cognitive deficit offers the greatest support that the NCD is induced by the medical 
condition. Diagnostic certainty regarding this relationship may be increased if the neuro­
cognitive deficits ameliorate partially or stabilize in the context of treatment of the medical 

Typically the course of the NCD progresses in a manner that is commensurate with progres­
sion of the underlying medical disorder. In circumstances where the medical disorder is treat­
able (e.g., hypothyroidism), the neurocognitive deficit may improve or at least not progress. 
When the medical condition has a deteriorative course (e.g., secondary progressive multiple 
sclerosis), the neurocognitive deficits will progress along with the temporal course of illness.
Associated physical examination and laboratory findings and other clinical features de­
pend on the nature and severity of the medical condition.
Other major or mild neurocognitive disorder. The presence of an attributable medical 
condition does not entirely exclude the possibility of another major or mild NCD. If cog­
nitive deficits persist following successful treatment of an associated medical condition,

nitive deficits persist following successful treatment of an associated medical condition, 
then another etiology may be responsible for the cognitive decline.
Due to Multiple Etiologies
neurocognitive disorder is the pathophysiological consequence of more than one etio­
logical process, excluding substances (e.g., neurocognitive disorder due to Alzhei­
mer’s disease with subsequent development of vascular neurocognitive disorder).  
Note: Please refer to the diagnostic criteria for the various neurocognitive disorders due  
to specific medical conditions for guidance on establishing the particular etiologies.

C. The cognitive deficits are not better explained by another mental disorder and do not  
occur exclusively during the course of a delirium.
Coding note: For major neurocognitive disorder due to multiple etiologies, with behavioral  
disturbance, code 294.11 (F02.81); for major neurocognitive disorder due to multiple etiolo­
gies, without behavioral disturbance, code 294.10 (F02.80). All of the etiological medical  
conditions (with the exception of vascular disease) should be coded and listed separately  
immediately before major neurocognitive disorder due to multiple etiologies (e.g., 331.0  
[G30.9] Alzheimer’s disease; 331.82 [G31.83] Lewy body disease; 294.11 [F02.81] major  
neurocognitive disorder due to multiple etiologies, with behavioral disturbance).

When a cerebrovascular etiology is contributing to the neurocognitive disorder, the diagno­
sis of vascular neurocognitive disorder should be listed in addition to major neurocognitive  
disorder due to multiple etiologies. For example, for a presentation of major neurocognitive  
disorder due to both Alzheimer’s disease and vascular disease, with behavioral disturbance,  
code the following: 331.0 (G30.9) Alzheimer’s disease; 294.11 (F02.81) major neurocogni­
tive disorder due to multiple etiologies, with behavioral disturbance; 290.40 (FOI .51) major  
vascular neurocognitive disorder, with behavioral disturbance.
For mild neurocognitive disorder due to multiple etiologies, code 331.83 (G31.84). (Note:  
Do not use the additional codes for the etiologies. Behavioral disturbance cannot be coded

Do not use the additional codes for the etiologies. Behavioral disturbance cannot be coded  

This category is included to cover the clinical presentation of a neurocognitive disorder (NCD) 
for v^hich there is^ ^ evid en ce that multiple medical conditions have played a probable role in the 
development of the NCD. In addition to evidence indicative of the presence of multiple med­
ical conditions that are known to cause NCD (i.e., findings from the history and physical ex­
amination, and laboratory findings), it may be helpful to refer to the diagnostic criteria and text 
for the various medical etiologies (e.g., NCD due to Parkinson's disease) for more information 
on establishing the etiological connection for that particular medical condition.
Unspecified Neurocognitive Disorder
799.59 (R41.9)
This category applies to presentations in which symptoms characteristic of a neurocogni­
tive disorder that cause clinically significant distress or impairment in social, occupational,  
or other important areas of functioning predominate but do not meet the full criteria for any

or other important areas of functioning predominate but do not meet the full criteria for any  
of the disorders in the neurocognitive disorders diagnostic class. The unspecified neuro­
cognitive disorder category is used in situations in which the precise etiology cannot be  
determined with sufficient certainty to make an etiological attribution.
Coding note: For unspecified major or mild neurocognitive disorder, code 799.59 (R41.9).  
(Note: Do not use additional codes for any presumed etiological medical conditions. Be­
havioral disturbance cannot be coded but may be indicated in writing.)

Personality 
Disordet#
T h is  C h s p te r  b eg in s  with a general definition of personaliiy disorder that applies 
to each of the 10 specific personality disorders. A personality disorder  is an enduring pattern 
of inner experience and behavior that deviates markedly from the expectations of the in­
dividual's culture, is pervasive and inflexible, has an onset in adolescence or early adult­
hood, is stable over time, and leads to distress or impairment.
With any ongoing review process, especially one of this complexity, different view­
points emerge, and an effort was made to accommodate them. Thus, personality disorders 
are included in both Sections II and III. The material in Section II represents an update of 
text associated with the same criteria found in DSM-IV-TR, whereas Section III includes 
the proposed research model for personality disorder diagnosis and conceptualization de­
veloped by the DSM-5 Personality and Personality Disorders Work Group. As this field

veloped by the DSM-5 Personality and Personality Disorders Work Group. As this field 
evolves, it is hoped that both versions will serve clinical practice and research initiatives, 
respectively.
The following personality disorders are included in this chapter.
•  Paranoid personality disorder is a pattern of distrust and suspiciousness such that oth­
ers' motives are interpreted as malevolent.
•  Schizoid personality disorder is a pattern of detachment from social relationships and 
a restricted range of emotional expression.
•  Schizotypal personality disorder is a pattern of acute discomfort in close relationships, 
cognitive or perceptual distortions, and eccentricities of behavior.
•  Antisocial personality disorder is a pattern of disregard for, and violation of, the rights 
of others.
•  Borderline personality disorder is a pattern of instability in interpersonal relation­

of others.
ships, self-image, and affects, and marked impulsivity.
•  Histrionic personality disorder is a pattern of excessive emotionality and attention 
seeking.
• Narcissistic personality disorder is a pattern of grandiosity, need for admiration, and 
lack of empathy.
• Avoidant personality disorder is a pattern of social inhibition, feelings of inadequacy, 
and hypersensitivity to negative evaluation.
• Dependent personality disorder is a pattern of submissive and clinging behavior re­
lated to an excessive need to be taken care of.
• Obsessive-compulsive personality disorder is a pattern of preoccupation with order­
liness, perfectionism, and control.
• Personality change due to another medical condition is a persistent personality dis­

turbance that is judged to be due to the direct physiological effects of a medical condi­
tion (e.g., frontal lobe lesion).
• Other specified personality disorder and unspecified personality disorder is a cate­
gory provided for two situations: 1) the individual's personality pattern meets the gen­
eral criteria for a personality disorder, and traits of several different personality 
disorders are present, but the criteria for any specific personality disorder are not met;

or 2) the individual's personality pattern meets the general criteria for a personality dis­
order, but the individual is considered to have a personality disorder that is not in­
cluded in the DSM-5 classification (e.g., passive-aggressive personality disorder).
The personality disorders are grouped into three clusters based on descriptive similarities. 
Cluster A includes paranoid, schizoid, and schizotypal personality disorders. Individuals with 
these disorders often appear odd or eccentric. Cluster B includes antisocial, borderline, histri­
onic, and narcissistic personality disorders. Individuals with these disorders often appear dra­
matic, emotional, or erratic. Cluster C includes avoidant, dependent, and obsessive- 
compulsive personality disorders. Individuals with these disorders often appear anxious or 
fearful. It should be noted that this clustering system, although useful in some research and ed­

ucational situations, has serious limitations and has not been consistently validated.
Moreover, individuals frequently present with co-occurring personality disorders 
from different clusters. Prevalence estimates for the different clusters suggest 5.7% for dis­
orders in Cluster A, 1.5% for disorders in Cluster B, 6.0% for disorders in Cluster C, and 
9.1% for any personality disorder, indicating frequent co-occurrence of disorders from dif­
ferent clusters. Data from the 2001-2002 National Epidemiologic Survey on Alcohol and 
Related Conditions suggest that approximately 15% of U.S. adults have at least one per­
sonality disorder.
Dimensional Models for Personality Disorders
The diagnostic approach used in this manual represents the categorical perspective that

The diagnostic approach used in this manual represents the categorical perspective that 
personality disorders are qualitatively distinct clinical syndromes. An alternative to the 
categorical approach is the dimensional perspective that personality disorders represent 
maladaptive variants of personality traits that merge imperceptibly into normality and 
into one another. See Section III for a full description of a dimensional model for person­
ality disorders. The DSM-IV personality disorder clusters (i.e., odd-eccentric, dramatic­
emotional, and anxious-fearful) may also be viewed as dimensions representing spectra of 
personality dysfunction on a continuum with other mental disorders. The alternative di­
mensional models have much in common and together appear to cover the important ar­
eas of personality dysfunction. Their integration, clinical utility, and relationship with the

eas of personality dysfunction. Their integration, clinical utility, and relationship with the 
personality disorder diagnostic categories and various aspects of personality dysfunction 
are under active investigation.
General Personality Disorder
Criteria
A. An enduring pattern of inner experience and behavior that deviates markedly from the  
expectations of the individual’s culture. This pattern is manifested in two (or more) of  
the following areas:
1. Cognition (i.e., ways of perceiving and interpreting self, other people, and events).
2. Affectivity (i.e., the range, intensity, lability, and appropriateness of emotional re­
sponse).
3. Interpersonal functioning.
4. Impulse control.
B. The enduring pattern is inflexible and pervasive across a broad range of personal and  
social situations.
C. The enduring pattern leads to clinically significant distress or impairment in  social, oc­

D. The pattern is stable and cf long duration, and Its onset can be traced back at least to  
adolescence or early adulthood.
E. The enduring pattern is not better explained as a manifestation or consequence of an­
other mental disorder.
F. The enduring pattern is not attributable to the physiological effects of a substance (e.g.,  
a drug of abuse, a medication) or another medical condition (e.g., head trauma).
Personality traits  are enduring patterns of perceiving, relating to, and thinking about the en­
vironment and oneself that are exhibited in a wide range of social and personal contexts. 
Only when personality traits are inflexible and maladaptive and cause significant func­
tional impairment or subjective distress do they constitute personality disorders. The essen­
tial feature of a personality disorder is an enduring pattern of inner experience and behavior 
that deviates markedly from the expectations of the individual's culture and is manifested

that deviates markedly from the expectations of the individual's culture and is manifested 
in at least two of the following areas: cognition, affectivity, interpersonal functioning, or im­
pulse control (Criterion A). This enduring pattern is inflexible and pervasive across a broad 
range of personal and social situations (Criterion B) and leads to clinically significant dis­
rion C). The pattern is stable and of long duration, and its onset can be traced back at least 
to adolescence or early adulthood (Criterion D). The pattern is not better explained as a 
manifestation or consequence of another mental disorder (Criterion E) and is not attribut­
able to the physiological effects of a substance (e.g., a drug of abuse, a medication, exposure

able to the physiological effects of a substance (e.g., a drug of abuse, a medication, exposure 
to a toxin) or another medical condition (e.g., head trauma) (Criterion F). Specific diagnostic 
criteria are also provided for each of the personality disorders included in this chapter.
The diagnosis of personality disorders requires an evaluation of the individual's long­
term patterns of functioning, and the particular personality features must be evident by 
early adulthood. The personality traits that define these disorders must also be distin­
guished from characteristics that emerge in response to specific situational stressors or 
more transient mental states (e.g., bipolar, depressive, or anxiety disorders; substance in­
toxication). The clinician should assess the stability of personality traits over time and

toxication). The clinician should assess the stability of personality traits over time and 
across different situations. Although a single interview with the individual is sometimes 
sufficient for making the diagnosis, it is often necessary to conduct more than one inter­
view and to space these over time. Assessment can also be complicated by the fact that the 
characteristics that define a personality disorder may not be considered problematic by 
the individual (i.e., the traits are often ego-syntonic). To help overcome this difficulty, sup­
plementary information from other informants may be helpful.
The features of a personality disorder usually become recognizable during adolescence or 
early adult life. By definition, a personality disorder is an enduring pattern of thinking,

early adult life. By definition, a personality disorder is an enduring pattern of thinking, 
feeling, and behaving that is relatively stable over time. Some types of personality disorder 
(notably, antisocial and borderline personality disorders) tend to become less evident or to 
remit with age, whereas this appears to be less true for some other types (e.g., obsessive- 
compulsive and schizotypal personality disorders).
Personality disorder categories may be applied with children or adolescents in those 
relatively unusual instances in which the individual's particular maladaptive personality 
traits appear to be pervasive, persistent, and unlikely to be limited to a particular devel­
opmental stage or another mental disorder. It should be recognized that the traits of a per­
sonality disorder that appear in childhood will often not persist unchanged into adult life.

sonality disorder that appear in childhood will often not persist unchanged into adult life. 
For a personality disorder to be diagnosed in an individual younger than 18 years, the fea­
tures must have been present for at least 1  year. The one exception to this is antisocial per-

sonality disorder, which cannot be diagnosed in individuals younger than 18 years. Al­
though, by definition, a personality disorder requires an onset no later than early 
adulthood, individuals may not come to clinical attention until relatively late in life. A per­
sonality disorder may be exacerbated following the loss of significant supporting persons 
(e.g., a spouse) or previously stabilizing social situations (e.g., a job). However, the devel­
opment of a change in personality in middle adulthood or later life warrants a thorough 
evaluation to determine the possible presence of a personality change due to another med­
ical condition or an unrecognized substance use disorder.
Judgments about personality functioning must take into account the individual's ethnic, cul­
tural, and social background. Personality disorders should not be confused with problems as­

sociated with acculturation following immigration or with the expression of habits, customs, 
or religious and political values professed by the individual's culture of origin. It is useful for 
the clinician, especially when evaluating someone from a different background, to obtain ad­
ditional information from informants who are familiar with the person's cultural background.
Certain personality disorders (e.g., antisocial personality disorder) are diagnosed more 
frequently in males. Others (e.g., borderline, histrionic, and dependent personality disor­
ders) are diagnosed more frequently in females. Although these differences in prevalence 
probably reflect real gender differences in the presence of such patterns, clinicians must be

probably reflect real gender differences in the presence of such patterns, clinicians must be 
cautious not to overdiagnose or underdiagnose certain personality disorders in females or 
in males because of social stereotypes about typical gender roles and behaviors.
Other mental disorders and personality traits. Many of the specific criteria for the per­
sonality disorders describe features (e.g., suspiciousness, dependency, insensitivity) that 
are also characteristic of episodes of other mental disorders. A personality disorder should 
be diagnosed only when ihe defining characteristics appeared before early adulthood, are 
typical of the individual's long-term functioning, and do not occur exclusively during an 
episode of another mental disorder. It may be particularly difficult (and not particularly

episode of another mental disorder. It may be particularly difficult (and not particularly 
useful) to distinguish personality disorders from persistent mental disorders such as per­
sistent depressive disorder that have an early onset and an enduring, relatively stable 
course. Some personality disorders may have a "spectrum" relationship to other mental 
disorders (e.g., schizotypal personality disorder with schizophrenia; avoidant personality 
disorder with social anxiety disorder [social phobia]) based on phenomenological or bio­
logical similarities or familial aggregation.
Personality disorders must be distinguished from personality traits that do not reach 
the threshold for a personality disorder. Personality traits are diagnosed as a personality 
disorder only when they are inflexible, maladaptive, and persisting and cause significant 
functional impairment or subjective distress.

Psychotic disorders. For the three personality disorders that may be related to the psy­
chotic disorders (i.e., paranoid, schizoid, and schizotypal), there is an exclusion criterion 
stating that the pattern of behavior must not have occurred exclusively during the course 
of schizophrenia, a bipolar or depressive disorder with psychotic features, or another psy­
chotic disorder. When an individual has a persistent mental disorder (e.g., schizophrenia) 
that was preceded by a preexisting personality disorder, the personality disorder should 
also be recorded, followed by "premorbid" in parentheses.
Anxiety and depressive disorders. The clinician must be cautious in diagnosing per­
sonality disorders during an episode of a depressive disorder or an anxiety disorder, be-

cause these conditions may have cross-sectional symptom features that mimic personality 
traits and may m^ke it more difficult to evaluate retrospectively the individual's long-term 
patterns of functioning.
Posttraumatic stress disorder. When personality changes emerge and persist after an 
individual has been exposed to extreme stress, a diagnosis of posttraumatic stress disorder 
Substance use disorders. When an individual has a substance use disorder, it is impor­
tant not to make a personality disorder diagnosis based solely on behaviors that are con­
sequences of substance intoxication or withdrawal or that are associated with activities in 
the service of sustaining substance use (e.g., antisocial behavior).
Personality change due to another medical condition. When enduring changes in per­
sonality arise as a result of the physiological effects of another medical condition (e.g.,

sonality arise as a result of the physiological effects of another medical condition (e.g., 
brain tumor), a diagnosis of personality change due to another medical condition should 
Paranoid Personality Disorder
Diagnostic Criteria 301.0 (F60.0)
A. A pervasive distrust and suspiciousness of others such that their nfiotives are inter­
preted as malevolent, beginning by early adulthood and present in a variety of con­
texts, as indicated by four (or more) of the following:
1. Suspects, without sufficient basis, that others are exploiting, harming, or deceiving  
him or her.
2. Is preoccupied with unjustified doubts about the loyalty or trustworthiness of friends  
or associates.
3. Is reluctant to confide in others because of unwarranted fear that the information  
will be used maliciously against him or her.

4. Reads hidden demeaning or threatening meanings into benign remarks or events.
5. Persistently bears grudges (i.e., is unforgiving of insults, injuries, or slights).
6. Perceives attacks on his or her character or reputation that are not apparent to oth­
ers and is quick to react angrily or to counterattack.
7. Has recurrent suspicions, without justification, regarding fidelity of spouse or sexual  
partner.
B. Does not occur exclusively during the course of schizophrenia, a bipolar disorder or  
depressive disorder with psychotic features, or another psychotic disorder and is not  
attributable to the physiological effects of another medical condition.
Note: If criteria are met prior to the onset of schizophrenia, add “ premorbid,”  i.e., “ paranoid
personality disorder (premorbid).”

The essential feature of paranoid personality disorder is a pattern of pervasive distrust 
and suspiciousness of others such that their motives are interpreted as malevolent. This 
pattern begins by early adulthood and is present in a variety of contexts.

Individuals with this disorder assume that other people will exploit, harm, or deceive 
them, even if no evidence exists to support this expectation (Criterion Al). They suspect on 
the basis of little or no evidence that others are plotting against them and may attack them 
suddenly, at any time and without reason. They often feel that they have been deeply and 
irreversibly injured by another person or persons even when there is no objective evidence 
for this. They are preoccupied with unjustified doubts about the loyalty or trustworthiness 
of their friends and associates, whose actions are minutely scrutinized for evidence of hos­
tile intentions (Criterion A2). Any perceived deviation from trustworthiness or loyalty 
serves to support their underlying assumptions. They are so amazed when a friend or as­
sociate shows loyalty that they cannot trust or believe it. If they get into trouble, they ex­
pect that friends and associates will either attack or ignore them.

Individuals with paranoid personality disorder are reluctant to confide in or become 
close to others because they fear that the information they share will be used against them 
(Criterion A3). They may refuse to answer personal questions, saying that the information 
is "nobody's business." They read hidden meanings that are demeaning and threatening 
into benign remarks or events (Criterion A4). For example, an individual with this disor­
der may misinterpret an honest mistake by a store clerk as a deliberate attempt to short­
change, or view a casual humorous remark by a co-worker as a serious character attack. 
Compliments are often misinterpreted (e.g., a compliment on a new acquisition is mis­
interpreted as a criticism for selfishness; a compliment on an accomplishment is misinter­

preted as an attempt to coerce more and better performance). They may view an offer of 
help as a criticism that they are not doing well enough on their own.
Individuals with this disorder persistently bear grudges and are unwilling to forgive 
the insults, injuries, or slights that they think they have received (Criterion A5). Minor 
slights arouse major hostility, and the hostile feelings persist for a long time. Because they 
are constantly vigilant to the harmful intentions of others, they very often feel that their 
character or reputation has been attacked or that they have been slighted in some other 
way. They are quick to counterattack and react with anger to perceived insults (Criterion 
A6). Individuals with this disorder may be pathologically jealous, often suspecting that

A6). Individuals with this disorder may be pathologically jealous, often suspecting that 
their spouse or sexual partner is unfaithful without any adequate justification (Criterion 
A7). They may gather trivial and circumstantial "evidence" to support their jealous beliefs. 
They want to maintain complete control of intimate relationships to avoid being betrayed 
and may constantly question and challenge the whereabouts, actions, intentions, and fi­
delity of their spouse or partner.
Paranoid personality disorder should not be diagnosed if the pattern of behavior oc­
curs exclusively during the course of schizophrenia, a bipolar disorder or depressive dis­
order with psychotic features, or another psychotic disorder, or if it is attributable to the 
physiological effects of a neurological (e.g., temporal lobe epilepsy) or another medical 
condition (Criterion B).

Individuals with paranoid personality disorder are generally difficult to get along with 
and often have problems with close relationships. Their excessive suspiciousness and hos­
tility may be expressed in overt argumentativeness, in recurrent complaining, or by quiet, 
apparently hostile aloofness. Because they are hypervigilant for potential threats, they 
may act in a guarded, secretive, or devious manner and appear to be "cold" and lacking in 
tender feelings. Although they may appear to be objective, rational, and unemotional, they 
more often display a labile range of affect, with hostile, stubborn, and sarcastic expressions 
predominating. Their combative and suspicious nature may elicit a hostile response in 
others, which then serves to confirm their original expectations.

Because individuals with paranoid personality disorder lack trust in others, they have 
an excessive need to be self-sufficient and a strong sense of autonomy. They also need to

have a high degree of control over those around them. They are often rigid, critical of oth­
ers, and unable to collaborate, although they have great difficulty accepting criticism them­
selves. They may blame others for their own shortcomings. Because of their quickness to 
counterattack in response to the threats they perceive around them, they may be litigious 
and frequently become involved in legal disputes. Individuals with this disorder seek to 
confirm their preconceived negative notions regarding people or situations they encounter, 
attributing malevolent motivations to others that are projections of their own fears. They 
may exhibit thinly hidden, unrealistic grandiose fantasies, are often attuned to issues of 
power and rank, and tend to develop negative stereotypes of others, particularly those 
from population groups distinct from their own. Attracted by simplistic formulations of the

from population groups distinct from their own. Attracted by simplistic formulations of the 
world, they are often wary of ambiguous situations. They may be perceived as "fanatics" 
and form tightly knit "cults" or groups with others who share their paranoid belief systems.
Particularly in response to stress, individuals with this disorder may experience very 
brief psychotic episodes (lasting minutes to hours). In some instances, paranoid personal­
ity disorder may appear as the premorbid antecedent of delusional disorder or schizo­
phrenia. Individuals with paranoid personality disorder may develop major depressive 
disorder and may be at increased risk for agoraphobia and obsessive-compulsive dis­
order. Alcohol and other substance use disorders frequently occur. The most common co­
occurring personality disorders appear to be schizotypal, schizoid, narcissistic, avoidant, 
and borderline.

A prevalence estimate for paranoid personality based on a probability subsample from 
Part II of the National Comorbidity Survey Replication suggests a prevalence of 2.3%, 
while the National Epidemiologic Survey on Alcohol and Related Conditions data suggest 
a prevalence of paranoid personality disorder of 4.4%.
Paranoid personality disorder may be first apparent in childhood and adolescence with 
solitariness, poor peer relationships, social anxiety, underachievement in school, hyper­
sensitivity, peculiar thoughts and language, and idiosyncratic fantasies. These children 
may appear to be "odd" or "eccentric" and attract teasing. In clinical samples, this disorder 
appears to be more commonly diagnosed in males.

Genetic and physiological. There is some evidence for an increased prevalence of par­
anoid personality disorder in relatives of probands with schizophrenia and for a more spe­
cific familial relationship with delusional disorder, persecutory type.
Some behaviors that are influenced by sociocultural contexts or specific life circumstances 
may be erroneously labeled paranoid and may even be reinforced by the process of clinical 
evaluation. Members of minority groups, immigrants, political and economic refugees, or 
individuals of different ethnic backgrounds may display guarded or defensive behaviors 
because of unfamiliarity (e.g., language barriers or lack of knowledge of rules and regula­

tions) or in response to the perceived neglect or indifference of the majority society. These 
behaviors can, in turn, generate anger and frustration in those who deal with these indi­
viduals, thus setting up a vicious cycle of mutual mistrust, which should not be confused 
with paranoid personality disorder. Some ethnic groups also display culturally related be­
haviors that can be misinterpreted as paranoid.

Other mental disorders with psychotic symptoms. Paranoid personality disorder can 
be distinguished from delusional disorder, persecutory type; schizophrenia; and a bipolar or 
depressive disorder with psychotic features because these disorders are all characterized by a 
period of persistent psychotic symptoms (e.g., delusions and hallucinations). For an additional 
diagnosis of paranoid personality disorder to be given, the personality disorder must have 
been present before the onset of psychotic symptoms and must persist when the psychotic 
symptoms are in remission. When an individual has another persistent mental disorder (e.g., 
schizophrenia) that was preceded by paranoid personality disorder, paranoid personality dis­
order should also be recorded, followed by "premorbid" in parentheses.
Personality change due to another medical condition. Paranoid personality disorder 
must be distinguished from personality change due to another medical condition, in

must be distinguished from personality change due to another medical condition, in 
which the traits that emerge are attributable to the direct effects of another medical condi­
tion on the central nervous system.
Substance use disorders. Paranoid personality disorder must be distinguished from 
symptoms that may develop in association with persistent substance use.
Paranoid traits associated with physical handicaps. The disorder must also be distin­
guished from paranoid traits associated with the development of physical handicaps (e.g., 
a hearing impairment).
Other personality disorders and personality traits. Other personality disorders may be 
confused with paranoid personality disorder because they have certain features in common. 
It is therefore important to distinguish among these disorders based on differences in their

It is therefore important to distinguish among these disorders based on differences in their 
characteristic features. However, if an individual has personality features that meet criteria 
for one or more personality disorders in addition to paranoid personality disorder, all can be 
diagnosed. Paranoid personality disorder and schizotypal personality disorder share the 
traits of suspiciousness, interpersonal aloofness, and paranoid ideation, but schizotypal per­
sonality disorder also includes symptoms such as magical thinking, unusual perceptual ex­
periences, and odd thinking and speech. Individuals with behaviors that meet criteria for 
schizoid personality disorder are often perceived as strange, eccentric, cold, and aloof, but 
they do not usually have prominent paranoid ideation. The tendency of individuals with

they do not usually have prominent paranoid ideation. The tendency of individuals with 
paranoid personality disorder to react to minor stimuli with anger is also seen in borderline 
and histrionic personality disorders. However, these disorders are not necessarily associ­
ated with pervasive suspiciousness. People with avoidant personality disorder may also be 
reluctant to confide in others, but more from fear of being embarrassed or found inadequate 
than from fear of others' malicious intent. Although antisocial behavior may be present in 
some individuals with paranoid personality disorder, it is not usually motivated by a desire 
for personal gain or to exploit others as in antisocial personality disorder, but rather is more 
often attributable to a desire for revenge. Individuals with narcissistic personality disorder

often attributable to a desire for revenge. Individuals with narcissistic personality disorder 
may occasionally display suspiciousness, social withdrawal, or alienation, but this derives 
primarily from fears of having their imperfections or flaws revealed.
Paranoid traits may be adaptive, particularly in threatening environments. Paranoid 
personality disorder should be diagnosed only when these traits are inflexible, maladap­
tive, and persisting and cause significant functional impairment or subjective distress.
Schizoid Personality Disorder
Diagnostic Criteria 301.20 (F60.1)
A. A pervasive pattern of detachment from social relationships and a restricted range of  
expression of emotions in interpersonal settings, beginning by early adulthood and  
present in  a variety of contexts, as indicated by four (or more) of the following:

1. Neither desires nor enjoys close relationships, including being part of a family.
2. Almost always  chooses solitary activities.
3. Has little, if any, interest in having sexual experiences with another person.
4. Tal<es pleasure in few, if any, activities.
5. Lacks close friends or confidants other than first-degree relatives.
6. Appears indifferent to the praise or criticism of others.
7. Shows emotional coldness, detachment, or flattened affectivity.
depressive disorder with psychotic features, another psychotic disorder, or autism  
spectrum disorder and is not attributable to the physiological effects of another medical  
Note: If criteria are met prior to the onset of schizophrenia, add “ premorbid,”  i.e., “ schiz­
oid personality disorder (premorbid).”
The essential feature of schizoid personality disorder is a pervasive pattern of detachment

The essential feature of schizoid personality disorder is a pervasive pattern of detachment 
from social relationships and a restricted range of expression of emotions in interpersonal 
settings. This pattern begins by early adulthood and is present in a variety of contexts.
Individuals with schizoid personality disorder appear to lack a desire for intimacy, 
seem indifferent to opportunities to develop close relationships, and do not seem to derive 
much satisfaction from being part of a family or other social group (Criterion Al). They 
prefer spending time by themselves, rather than being with other people. They often ap­
pear to be socially isolated or "loners" and almost always choose solitary activities or hob­
bies that do not include interaction with others (Criterion A2). They prefer mechanical or 
abstract tasks, such as computer or mathematical games. They may have very little interest

abstract tasks, such as computer or mathematical games. They may have very little interest 
in having sexual experiences with another person (Criterion A3) and take pleasure in few, 
if any, activities (Criterion A4). There is usually a reduced experience of pleasure from sen­
sory, bodily, or interpersonal experiences, such as walking on a beach at sunset or having 
sex. These individuals have no close friends or confidants, except possibly a first-degree 
relative (Criterion A5).
Individuals with schizoid personality disorder often seem indifferent to the approval 
or criticism of others and do not appear to be bothered by what others may think of them 
(Criterion A6). They may be oblivious to the normal subtleties of social interaction and of­
ten do not respond appropriately to social cues so that they seem socially inept or super­

ficial and self-absorbed. They usually display a "bland" exterior without visible emotional 
reactivity and rarely reciprocate gestures or facial expressions, such as smiles or nods (Cri­
terion A7). They claim that they rarely experience strong emotions such as anger and joy. 
They often display a constricted affect and appear cold and aloof. However, in those very 
unusual circumstances in which these individuals become at least temporarily comfort­
able in revealing themselves, they may acknowledge having painful feelings, particularly 
related to social interactions.
Schizoid personality disorder should not be diagnosed if the pattern of behavior occurs 
exclusively during the course of schizophrenia, a bipolar or depressive disorder with psy­

chotic features, another psychotic disorder, or autism spectrum disorder, or if it is attrib­
utable to the physiological effects of a neurological (e.g., temporal lobe epilepsy) or another 
medical condition (Criterion B).
Individuals with schizoid personality disorder may have particular difficulty expressing 
anger, even in response to direct provocation, which contributes to the impression that

they lack emotion. Their lives sometimes seem directionless, and they may appear to 
"drift" in their goals. Such individuals often react passively to adverse circumstances and 
have difficulty responding appropriately to important life events. Because of their lack of 
social skills and lack of desire for sexual experiences, individuals with this disorder have 
few friendships, date infrequently, and often do not marry. Occupational functioning may 
be impaired, particularly if interpersonal involvement is required, but individuals with 
this disorder may do well when they work under conditions of social isolation. Particu­
larly in response to stress, individuals with this disorder may experience very brief psy­
chotic episodes (lasting minutes to hours). In some instances, schizoid personality 
disorder may appear as the premorbid antecedent of delusional disorder or schizophre­
nia. Individuals with this disorder may sometimes develop major depressive disorder.

nia. Individuals with this disorder may sometimes develop major depressive disorder. 
Schizoid personality disorder most often co-occurs with schizotypal, paranoid, and avoid­
ant personality disorders.
Schizoid personality disorder is uncommon in clinical settings. A prevalence estimate for 
schizoid personality based on a probability subsample from Part II of the National Co­
morbidity Survey Replication suggests a prevalence of 4.9%. Data from the 2001-2002 
National Epidemiologic Survey on Alcohol and Related Conditions suggest a prevalence of 
3.1%.
Schizoid personality disorder may be first apparent in childhood and adolescence with 
solitariness, poor peer relationships, and underachievement in school, which mark these 
children or adolescents as different and make them subject to teasing.

Genetic and physiological. Schizoid personality disorder may have increased preva­
lence in the relatives of individuals with schizophrenia or schizotypal personality disorder.
Individuals from a variety of cultural backgrounds sometimes exhibit defensive behaviors 
and inteφersonal styles that may be erroneously labeled as "schizoid." For example, those 
who have moved from rural to metropolitan environments may react with "emotional 
freezing" that may last for several months and manifest as solitary activities, constricted 
affect, and other deficits in communication. Immigrants from other countries are some­
times mistakenly perceived as cold, hostile, or indifferent.

Schizoid personality disorder is diagnosed slightly more often in males and may cause 
more impairment in them.
Other mental disorders with psychotic symptoms. Schizoid personality disorder can 
be distinguished from delusional disorder, schizophrenia, and a bipolar or depressive dis­
order with psychotic features because these disorders are all characterized by a period of 
persistent psychotic symptoms (e.g., delusions and hallucinations). To give an additional 
diagnosis of schizoid personality disorder, the personality disorder must have been present 
before the onset of psychotic symptoms and must persist when the psychotic symptoms

are in remission. When an individual has a persistent psychotic disorder (e.g., schizophre­
nia) that was preceded by schizoid personality disorder, schizoid personality disorder 
should also be recorded, followed by "premorbid" in parentheses.
Autism spectrum disorder. There may be great difficulty differentiating individuals with 
schizoid personality disorder from those with milder forms of autism spectrum disorder, 
which may be differentiated by more severely impaired social interaction and stereotyped 
behaviors and interests.
Personality change due to another medical condition. Schizoid personality disorder 
which the traits that emerge are attributable to the effects of another medical condition on 
the central nervous system.
Substance use disorders. Schizoid personality disorder must also be distinguished 
from symptoms that may develop in association with persistent substance use.

confused with schizoid personality disorder because they have certain features in com­
mon. It is, therefore, important to distinguish among these disorders based on differences 
in their characteristic features. However, if an individual has personality features that 
meet criteria for one or more personality disorders in addition to schizoid personality dis­
order, all can be diagnosed. Although characteristics of social isolation and restricted af- 
fectivity are common to schizoid, schizotypal, and paranoid personality disorders, 
schizoid personality disorder can be distinguished from schizotypal personality disorder 
by the lack of cognitive and perceptual distortions and from paranoid personality disorder

by the lack of cognitive and perceptual distortions and from paranoid personality disorder 
by the lack of suspiciousness and paranoid ideation. The social isolation of schizoid per­
sonality disorder can be distinguished from that of avoidant personality disorder, which is 
attributable to fear of being embarrassed or found inadequate and excessive anticipation 
of rejection. In contrast, people with schizoid personality disorder have a more pervasive 
detachment and limited desire for social intimacy. Individuals with obsessive-compulsive 
personality disorder may also show an apparent social detachment stemming from devo­
tion to work and discomfort with emotions, but they do have an underlying capacity for 
intimacy.
Individuals who are "loners" may display personality traits that might be considered 
schizoid. Only when these traits are inflexible and maladaptive and cause significant func­

intimacy.
tional impairment or subjective distress do they constitute schizoid personality disorder.
Schizotypal Personality Disorder
Diagnostic Criteria 301.22 (F21)
A. A pervasive pattern of social and interpersonal deficits marked by acute discomfort  
with, and reduced capacity for, close relationships as well as by cognitive or perceptual  
distortions and eccentricities of behavior, beginning by early adulthood and present in  
a variety of contexts, as indicated by five (or more) of the following:
1. Ideas of reference (excluding delusions of reference).
2. Odd beliefs or magical thinking that influences behavior and is inconsistent with  
subcultural norms (e.g., superstitiousness, belief in clairvoyance, telepathy, or

subcultural norms (e.g., superstitiousness, belief in clairvoyance, telepathy, or  
“ sixth sense”:  in children and adolescents, bizarre fantasies or preoccupations).
3. Unusual perceptual experiences, including bodily illusions.
4. Odd thinking and speech (e.g., vague, circumstantial, metaphorical, overelaborate,  
or stereotyped).
5. Suspiciousness or paranoid ideation.

6. Inappropriate or constricted affect.
7. Behavior or appearance that is odd, eccentric, or peculiar.
8. Lack of close friends or confidants other than first-degree relatives.
9. Excessive social anxiety that does not diminish with familiarity and tends to be as­
sociated with paranoid fears rather than negative judgments about self.
B. Does not occur exclusively during the course of schizophrenia, a bipolar disorder or
spectrum disorder.
Note: If criteria are met prior to the onset of schizophrenia, add “ premorbid,”  e.g., “ schizo­
typal personality disorder (premorbid).”
The essential feature of schizotypal personality disorder is a pervasive pattern of social 
and interpersonal deficits marked by acute discomfort with, and reduced capacity for, 
close relationships as well as by cognitive or perceptual distortions and eccentricities of be­

havior. This pattern begins by early adulthood and is present in a variety of contexts.
Individuals with schizotypal personality disorder often have ideas of reference (i.e., in­
correct interpretations of casual incidents and external events as having a particular and 
unusual meaning specifically for the person) (Criterion Al). These should be distin­
guished from delusions of reference, in which the beliefs are held with delusional convic­
tion. These individuals may be superstitious or preoccupied with paranormal phenomena 
that are outside the norms of their subculture (Criterion A2). They may feel that they have 
special powers to sense events before they happen or to read others' thoughts. They may 
believe that they have magical control over others, which can be implemented directly

believe that they have magical control over others, which can be implemented directly 
(e.g., believing that their spouse's taking the dog out for a walk is the direct result of think­
ing an hour earlier it should be done) or indirectly through compliance with magical rit­
uals (e.g., walking past a specific object three times to avoid a certain harmful outcome). 
Perceptual alterations may be present (e.g., sensing that another person is present or hear­
ing a voice murmuring his or her name) (Criterion A3). Their speech may include unusual 
or idiosyncratic phrasing and construction. It is often loose, digressive, or vague, but with­
out actual derailment or incoherence (Criterion A4). Responses can be either overly con­
crete or overly abstract, and words or concepts are sometimes applied in unusual ways 
(e.g., the individual may state that he or she was not "talkable" at work).

Individuals with this disorder are often suspicious and may have paranoid ideation 
(e.g., believing their colleagues at work are intent on undermining their reputation with 
the boss) (Criterion A5). They are usually not able to negotiate the full range of affects and 
interpersonal cuing required for successful relationships and thus often appear to interact 
with others in an inappropriate, stiff, or constricted fashion (Criterion A6). These individ­
uals are often considered to be odd or eccentric because of unusual mannerisms, an often 
unkempt manner of dress that does not quite "fit together," and inattention to the usual 
social conventions (e.g., the individual may avoid eye contact, wear clothes that are ink 
stained and ill-fitting, and be unable to join in the give-and-take banter of co-workers) 
(Criterion A7).

Individuals with schizotypal personality disorder experience interpersonal related­
ness as problematic and are uncomfortable relating to other people. Although they may 
express unhappiness about their lack of relationships, their behavior suggests a decreased 
desire for intimate contacts. As a result, they usually have no or few close friends or con­
fidants other than a first-degree relative (Criterion A8). They are anxious in social situa­
tions, particularly those involving unfamiliar people (Criterion A9). They will interact 
with other individuals when they have to but prefer to keep to themselves because they 
feel that they are different and just do not "fit in." Their social anxiety does not easily abate.

even when they spend more time in the setting or become more familiar with the other 
people, because t^ h eir anxiety tends to be associated with suspiciousness regarding others' 
motivations. For example, when attending a dinner party, the individual with schizotypal 
personality disorder will not become more relaxed as time goes on, but rather may become 
increasingly tense and suspicious.
Schizotypal personality disorder should not be diagnosed if the pattern of behavior oc­
curs exclusively during the course of schizophrenia, a bipolar or depressive disorder with 
psychotic features, another psychotic disorder, or autism spectrum disorder (Criterion B).
Individuals with schizotypal personality disorder often seek treatment for the associated 
symptoms of anxiety or depression rather than for the personality disorder features per se. 
Particularly in response to stress, individuals with this disorder may experience transient

Particularly in response to stress, individuals with this disorder may experience transient 
psychotic episodes (lasting minutes to hours), although they usually are insufficient in du­
ration to warrant an additional diagnosis such as brief psychotic disorder or schizophreni­
form disorder. In some cases, clinically significant psychotic symptoms may develop that 
meet criteria for brief psychotic disorder, schizophreniform disorder, delusional disorder, 
or schizophrenia. Over half may have a history of at least one major depressive episode. 
From 30% to 50% of individuals diagnosed with this disorder have a concurrent diagnosis 
of major depressive disorder when admitted to a clinical setting. There is considerable co­
occurrence with schizoid, paranoid, avoidant, and borderline personality disorders.

In community studies of schizotypal personality disorder, reported rates range from 0.6% 
in Norwegian samples to 4.6% in a U.S. community sample. The prevalence of schizotypal 
personality disorder in clinical populations seems to be infrequent (0%-1.9%), with a 
higher estimated prevalence in the general population (3.9%) found in the National Epi­
demiologic Survey on Alcohol and Related Conditions.
Schizotypal personality disorder has a relatively stable course, with only a small propor­
tion of individuals going on to develop schizophrenia or another psychotic disorder. 
Schizotypal personality disorder may be first apparent in childhood and adolescence with 

sensitivity, peculiar thoughts and language, and bizarre fantasies. These children may ap­
pear "odd" or "eccentric" and attract teasing.
Genetic and physiological. Schizotypal personality disorder appears to aggregate fa­
milially and is more prevalent among the first-degree biological relatives of individuals 
with schizophrenia than among the general population. There may also be a modest in­
crease in schizophrenia and other psychotic disorders in the relatives of probands with 
schizotypal personality disorder.
Cultural-Related Diagnostic issues
Cognitive and perceptual distortions must be evaluated in the context of the individual's 
cultural milieu. Pervasive culturally determined characteristics, particularly those regard­

ing religious beliefs and rituals, can appear to be schizotypal to the uninformed outsider 
(e.g., voodoo, speaking in tongues, life beyond death, shamanism, mind reading, sixth 
sense, evil eye, magical beliefs related to health and illness).

Schizotypal personality disorder may be slightly more common in males.
Other mental disorders with psychotic symptoms. Schizotypal personality disorder 
can be distinguished from delusional disorder, schizophrenia, and a bipolar or depressive 
disorder with psychotic features because these disorders are all characterized by a period 
of persistent psychotic symptoms (e.g., delusions and hallucinations). To give an addi­
tional diagnosis of schizotypal personality disorder, the personality disorder must have 
been present before the onset of psychotic symptoms and persist when the psychotic 
symptoms are in remission. When an individual has a persistent psychotic disorder (e.g., 
schizophrenia) that was preceded by schizotypal personality disorder, schizotypal per­
sonality disorder should also be recorded, followed by "premorbid" in parentheses.
Neurodevelopmental disorders. There may be great difficulty differentiating children

Neurodevelopmental disorders. There may be great difficulty differentiating children 
with schizotypal personality disorder from the heterogeneous group of solitary, odd chil­
dren whose behavior is characterized by marked social isolation, eccentricity, or peculiar­
ities of language and whose diagnoses would probably include milder forms of autism 
spectrum disorder or language communication disorders. Communication disorders may 
be differentiated by the primacy and severity of the disorder in language and by the char­
acteristic features of impaired language found in a specialized language assessment. 
Milder forms of autism spectrum disorder are differentiated by the even greater lack of so­
cial awareness and emotional reciprocity and stereotyped behaviors and interests.
Personality change due to another medical condition. Schizotypal personality disor­

der must be distinguished from personality change due to another medical condition, in 
Substance use disorders. Schizotypal personality disorder must also be distinguished 
Other personality disorders and personality traits. Other personality disorders may 
be confused with schizotypal personality disorder because they have certain features in 
common. It is, therefore, important to distinguish among these disorders based on differ­
ences in their characteristic features. However, if an individual has personality features 
that meet criteria for one or more personality disorders in addition to schizotypal person­

ality disorder, all can be diagnosed. Although paranoid and schizoid personality disor­
ders may also be characterized by social detachment and restricted affect, schizotypal 
personality disorder can be distinguished from these two diagnoses by the presence of 
cognitive or perceptual distortions and marked eccentricity or oddness. Close relation­
ships are limited in both schizotypal personality disorder and avoidant personality dis­
order; however, in avoidant personality disorder an active desire for relationships is 
constrained by a fear of rejection, whereas in schizotypal personality disorder there is 
a lack of desire for relationships and persistent detachment. Individuals with narcissistic 
personality disorder may also display suspiciousness, social withdrawal, or alienation,

personality disorder may also display suspiciousness, social withdrawal, or alienation, 
but in narcissistic personality disorder these qualities derive primarily from fears of hav­
ing imperfections or flaws revealed. Individuals with borderline personality disorder may 
also have transient, psychotic-like symptoms, but these are usually more closely related to 
affective shifts in response to stress (e.g., intense anger, anxiety, disappointment) and are 
usually more dissociative (e.g., derealization, depersonalization). In contrast, individuals 
with schizotypal personality disorder are more likely to have enduring psychotic-like symp­
toms that may worsen under stress but are less likely to be invariably associated with pro­
nounced affective symptoms. Although social isolation may occur in borderline personality

disorder, it is usually secondary to repeated interpersonal failures due to angry outbursts 
and frequent mood shifts, rather than a result of a persistent lack of social contacts and de­
sire for intimacy. Furthermore, individuals with schizotypal personality disorder do not 
usually demonstrate the impulsive or manipulative behaviors of the individual with bor­
derline personality disorder. However, there is a high rate of co-occurrence between the 
two disorders, so that making such distinctions is not always feasible. Schizotypal features 
during adolescence may be reflective of transient emotional turmoil, rather than an endur­
ing personality disorder.
Diagnostic Criteria 301.7 (F60.2)
A. A pervasive pattern of disregard for and violation of the rights of others, occurring since  
age 15 years, as indicated by three (or more) of the following:

1. Failure to conform to social norms with respect to lawful behaviors, as indicated by  
repeatedly performing acts that are grounds for arrest.
2. Deceitfulness, as indicated by repeated lying, use of aliases, or conning others for  
personal profit or pleasure.
3. Impulsivity or failure to plan ahead.
4. Irritability and aggressiveness, as indicated by repeated physical fights or assaults.
5. Reckless disregard for safety of self or others.
6. Consistent irresponsibility, as indicated by repeated failure to sustain consistent  
work behavior or honor financial obligations.
7. Lack of remorse, as indicated by being indifferent to or rationalizing having hurt,  
mistreated, or stolen from another.
B. The individual is at least age 18 years.

C. There is evidence of conduct disorder with onset before age 15 years.
D. The occurrence of antisocial behavior is not exclusively during the course of schizo­
phrenia or bipolar disorder.
The essential feature of antisocial personality disorder is a pervasive pattern of disregard 
for, and violation of, the rights of others that begins in childhood or early adolescence and 
continues into adulthood. This pattern has also been referred to as psychopathy, sociopathy,  
or dyssocial personality disorder.  Because deceit and manipulation are central features of an­
tisocial personality disorder, it may be especially helpful to integrate information acquired 
from systematic clinical assessment with information collected from collateral sources.

For this diagnosis to be given, the individual must be at least age 18 years (Criterion B) 
and must have had a history of some symptoms of conduct disorder before age 15 years 
(Criterion C). Conduct disorder involves a repetitive and persistent pattern of behavior in 
which the basic rights of others or major age-appropriate societal norms or rules are vio­
lated. The specific behaviors characteristic of conduct disorder fall into one of four cate­
gories: aggression to people and animals, destruction of property, deceitfulness or theft, or 
serious violation of rules.

The pattern of antisocial behavior continues into adulthood. Individuals with antiso­
cial personality disorder fail to conform to social norms with respect to lawful behavior 
(Criterion Al). They may repeatedly perform acts that are grounds for arrest (whether 
they are arrested or not), such as destroying property, harassing others, stealing, or pur­
suing illegal occupations. Persons with this disorder disregard the wishes, rights, or feel­
ings of others. They are frequently deceitful and manipulative in order to gain personal 
profit or pleasure (e.g., to obtain money, sex, or power) (Criterion A2). They may repeat­
edly lie, use an alias, con others, or malinger. A pattern of impulsivity may be manifested 
by a failure to plan ahead (Criterion A3). Decisions are made on the spur of the moment, 
without forethought and without consideration for the consequences to self or others; this 
may lead to sudden changes of jobs, residences, or relationships. Individuals with antiso­

cial personality disorder tend to be irritable and aggressive and may repeatedly get into 
physical fights or commit acts of physical assault (including spouse beating or child beat­
ing) (Criterion A4). (Aggressive acts that are required to defend oneself or someone else 
are not considered to be evidence for this item.) These individuals also display a reckless 
disregard for the safety of themselves or others (Criterion A5). This may be evidenced in 
their driving behavior (i.e., recurrent speeding, driving while intoxicated, multiple acci­
dents). They may engage in sexual behavior or substance use that has a high risk for harm­
ful consequences. They may neglect or fail to care for a child in a way that puts the child in 
danger.

danger.
Individuals with antisocial personality disorder also tend to be consistently and ex­
tremely irresponsible (Criterion A6). Irresponsible work behavior may be indicated by sig­
nificant periods of unemployment despite available job opportunities, or by abandonment 
of several jobs without a realistic plan for getting another job. There may also be a pattern 
of repeated absences from work that are not explained by illness either in themselves or in 
their family. Financial irresponsibility is indicated by acts such as defaulting on debts, fail­
ing to provide child support, or failing to support other dependents on a regular basis. In­
dividuals with antisocial personality disorder show little remorse for the consequences of

dividuals with antisocial personality disorder show little remorse for the consequences of 
their acts (Criterion A7). They may be indifferent to, or provide a superficial rationaliza­
tion for, having hurt, mistreated, or stolen from someone (e.g., 'Tife's unfair," "losers de­
serve to lose"). These individuals may blame the victims for being foolish, helpless, or 
deserving their fate (e.g., "he had it coming anyway"); they may minimize the harmful 
consequences of their actions; or they may simply indicate complete indifference. They 
generally fail to compensate or make amends for their behavior. They may believe that 
everyone is out to "help number one" and that one should stop at nothing to avoid being 
pushed around.
The antisocial behavior must not occur exclusively during the course of schizophrenia 
or bipolar disorder (Criterion D).

Individuals with antisocial personality disorder frequently lack empathy and tend to be 
callous, cynical, and contemptuous of the feelings, rights, and sufferings of others. They 
may have an inflated and arrogant self-appraisal (e.g., feel that ordinary work is beneath 
them or lack a realistic concern about their current problems or their future) and may be 
excessively opinionated, self-assured, or cocky. They may display a glib, superficial charm 
and can be quite voluble and verbally facile (e.g., using technical terms or jargon that 
might impress someone who is unfamiliar with the topic). Lack of empathy, inflated self­
appraisal, and superficial charm are features that have been commonly included in tradi­
tional conceptions of psychopathy that may be particularly distinguishing of the disorder

tional conceptions of psychopathy that may be particularly distinguishing of the disorder 
and more predictive of recidivism in prison or forensic settings, where criminal, delin­
quent, or aggressive acts are likely to be nonspecific. These individuals may also be irre­
sponsible and exploitative in their sexual relationships. They may have a history of many

sexual partners and may never have sustained a monogamous relationship. They may be 
irresponsible as parents, as evidenced by malnutrition of a child, an illness in the child re­
sulting from a \aèk of minimal hygiene, a child's dependence on neighbors or nonresident 
relatives for food or shelter, a failure to arrange for a caretaker for a young child when the 
individual is away from home, or repeated squandering of money required for household 
necessities. These individuals may receive dishonorable discharges from the armed ser­
vices, may fail to be self-supporting, may become impoverished or even homeless, or may 
spend many years in penal institutions. Individuals with antisocial personality disorder 
are more likely than people in the general population to die prematurely by violent means 
(e.g., suicide, accidents, homicides).
Individuals with antisocial personality disorder may also experience dysphoria, in­

cluding complaints of tension, inability to tolerate boredom, and depressed mood. They 
may have associated anxiety disorders, depressive disorders, substance use disorders, so­
matic symptom disorder, gambling disorder, and other disorders of impulse control. In­
dividuals with antisocial personality disorder also often have personality features that 
meet criteria for other personality disorders, particularly borderline, histrionic, and nar­
cissistic personality disorders. The likelihood of developing antisocial personality disor­
der in adult life is increased if the individual experienced childhood onset of conduct 
disorder (before age 10 years) and accompanying attention-deficit/hyperactivity disorder. 
Child abuse or neglect, unstable or erratic parenting, or inconsistent parental discipline

Child abuse or neglect, unstable or erratic parenting, or inconsistent parental discipline 
may increase the likelihood that conduct disorder will evolve into antisocial personality 
disorder.
Twelve-month prevalence rates of antisocial personality disorder, using criteria from pre­
vious DSMs, are between 0.2% and 3.3%. The highest prevalence of antisocial personality 
disorder (greater than 70%) is among most severe samples of males with alcohol use dis­
order and from substance abuse clinics, prisons, or other forensic settings. Prevalence is 
higher in samples affected by adverse socioeconomic (i.e., poverty) or sociocultural (i.e., 
migration) factors.
Antisocial personality disorder has a chronic course but may become less evident or remit 
as the individual grows older, particularly by the fourth decade of life. Although this re­

mission tends to be particularly evident with respect to engaging in criminal behavior, 
there is likely to be a decrease in the full spectrum of antisocial behaviors and substance 
use. By definition, antisocial personality cannot be diagnosed before age 18 years.
Genetic and physiological. Antisocial personality disorder is more common among the 
first-degree biological relatives of those with the disorder than in the general population. 
The risk to biological relatives of females with the disorder tends to be higher than the risk 
to biological relatives of males with the disorder. Biological relatives of individuals with 
this disorder are also at increased risk for somatic symptom disorder and substance use

this disorder are also at increased risk for somatic symptom disorder and substance use 
disorders. Within a family that has a member with antisocial personality disorder, males 
more often have antisocial personality disorder and substance use disorders, whereas fe­
males more often have somatic symptom disorder. However, in such families, there is an 
increase in prevalence of all of these disorders in both males and females compared with 
the general population. Adoption studies indicate that both genetic and environmental 
factors contribute to the risk of developing antisocial personality disorder. Both adopted 
and biological children of parents with antisocial personality disorder have an increased

risk of developing antisocial personality disorder, somatic symptom disorder, and sub­
stance use disorders. Adopted-away children resemble their biological parents more than 
their adoptive parents, but the adoptive family environment influences the risk of devel­
oping a personality disorder and related psychopathology.
Antisocial personality disorder appears to be associated with low socioeconomic status 
and urban settings. Concerns have been raised that the diagnosis may at times be misap­
plied to individuals in settings in which seemingly antisocial behavior may be part of a 
protective survival strategy. In assessing antisocial traits, it is helpful for the clinician to 
consider the social and economic context in which the behaviors occur.
Antisocial personality disorder is much more common in males than in females. There has 
been some concern that antisocial personality disorder may be underdiagnosed in fe­

males, particularly because of the emphasis on aggressive items in the definition of con­
duct disorder.
The diagnosis of antisocial personality disorder is not given to individuals younger than 
18 years and is given only if there is a history of some symptoms of conduct disorder be­
fore age 15 years. For individuals older than 18 years, a diagnosis of conduct disorder is 
given only if the criteria for antisocial personality disorder are not met.
Substance use disorders. When antisocial behavior in an adult is associated with a 
substance use disorder, the diagnosis of antisocial personality disorder is not made unless 
the signs of antisocial personality disorder were also present in childhood and have con­

tinued into adulthood. When substance use and antisocial behavior both began in childhood 
and continued into adulthood, both a substance use disorder and antisocial personality 
disorder should be diagnosed if the criteria for both are met, even though some antisocial 
acts may be a consequence of the substance use disorder (e.g., illegal selling of drugs, thefts 
to obtain money for drugs).
Schizophrenia and bipolar disorders. Antisocial behavior that occurs exclusively dur­
ing the course of schizophrenia or a bipolar disorder should not be diagnosed as antisocial 
Other personality disorders. Other personality disorders may be confused with antiso­
cial personality disorder because they have certain features in common. It is therefore im­

portant to distinguish among these disorders based on differences in their characteristic 
features. However, if an individual has personality features that meet criteria for one or 
more personality disorders in addition to antisocial personality disorder, all can be diag­
nosed. Individuals with antisocial personality disorder and narcissistic personality disor­
der share a tendency to be tough-minded, glib, superficial, exploitative, and lack empathy. 
However, narcissistic personality disorder does not include characteristics of impulsivity, 
aggression, and deceit. In addition, individuals with antisocial personality disorder may 
not be as needy of the admiration and envy of others, and persons with narcissistic per­

sonality disorder usually lack the history of conduct disorder in childhood or criminal 
behavior in adulthood. Individuals with antisocial personality disorder and histrionic 
personality disorder share a tendency to be impulsive, superficial, excitement seeking, 
reckless, seductive, and manipulative, but persons with histrionic personality disorder 
tend to be more exaggerated in their emotions and do not characteristically engage in an­
tisocial behaviors. Individuals with histrionic and borderline personality disorders are

manipulative to gain nurturance, whereas those with antisocial personality disorder are 
manipulative to gain profit, power, or some other material gratification. Individuals with 
antisocial personality disorder tend to be less emotionally unstable and more aggressive 
than those with borderline personality disorder. Although antisocial behavior may be 
present in some individuals with paranoid personality disorder, it is not usually moti­
vated by a desire for personal gain or to exploit others as in antisocial personality disorder, 
but rather is more often attributable to a desire for revenge.
Criminal behavior not associated with a personality disorder. Antisocial personality 
disorder must be distinguished from criminal behavior undertaken for gain that is not ac­
companied by the personality features characteristic of this disorder. Only when antisocial 
personality traits are inflexible, maladaptive, and persistent and cause significant func­

tional impairment or subjective distress do they constitute antisocial personality disorder.
Borderline Personality Disorder
Diagnostic Criteria 301.83 (F60.3)
A pervasive pattern of instability of interpersonal relationships, self-image, and affects,  
and marked impulsivity, beginning by early adulthood and present in a variety of contexts,  
as indicated by five (or more) of the following:
1. Frantic efforts to avoid real or imagined abandonment. (Note: Do not include suicidal  
or self-mutilating behavior covered in Criterion 5.)
2. A pattern of unstable and intense interpersonal relationships characterized by alternat­
ing between extremes of idealization and devaluation.
3. Identity disturbance: markedly and persistently unstable self-image or sense of self.

4. Impulsivity in at least two areas that are potentially self-damaging (e.g., spending, sex,  
substance abuse, reckless driving, binge eating). (Note: Do not include suicidal or self-  
mutilating behavior covered in Criterion 5.)
5. Recurrent suicidal behavior, gestures, or threats, or self-mutilating behavior.
6. Affective instability due to a marked reactivity of mood (e.g., intense episodic dysphoria,  
irritability, or anxiety usually lasting a few hours and only rarely more than a few days).
7. Chronic feelings of emptiness.
8. Inappropriate, intense anger or difficulty controlling anger (e.g., frequent displays of  
temper, constant anger, recurrent physical fights).
9. Transient, stress-related paranoid ideation or severe dissociative symptoms. _______

The essential feature of borderline personality disorder is a pervasive pattern of instability 
of interpersonal relationships, self-image, and affects, and marked impulsivity that begins 
by early adulthood and is present in a variety of contexts.
Individuals with borderline personality disorder make frantic efforts to avoid real or 
imagined abandonment (Criterion 1). The perception of impending separation or rejection, 
or the loss of external structure, can lead to profound changes in self-image, affect, cognition, 
and behavior. These individuals are very sensitive to environmental circumstances. They ex­
perience intense abandonment fears and inappropriate anger even when faced with a real­
istic time-limited separation or when there are unavoidable changes in plans (e.g., sudden

istic time-limited separation or when there are unavoidable changes in plans (e.g., sudden 
despair in reaction to a clinician's announcing the end of the hour; panic or fury when some­
one important to them is just a few minutes late or must cancel an appointment). They may 
believe that this "abandonment" implies they are "bad." These abandonment fears are re­
lated to an intolerance of being alone and a need to have other people with them. Their frantic

efforts to avoid abandonment may include impulsive actions such as self-mutilating or sui­
cidal behaviors, which are described separately in Criterion 5.
Individuals with borderline personality disorder have a pattern of unstable and intense 
relationships (Criterion 2). They may idealize potential caregivers or lovers at the first or 
second meeting, demand to spend a lot of time together, and share the most intimate details 
early in a relationship. However, they may switch quickly from idealizing other people to 
devaluing them, feeling that the other person does not care enough, does not give enough, 
or is not "there" enough. These individuals can empathize with and nurture other people, 
but only with the expectation that the other person will "be there" in return to meet their 
own needs on demand. These individuals are prone to sudden and dramatic shifts in their 
view of others, who may alternatively be seen as beneficent supports or as cruelly punitive.

view of others, who may alternatively be seen as beneficent supports or as cruelly punitive. 
Such shifts often reflect disillusionment with a caregiver whose nurturing qualities had 
been idealized or whose rejection or abandonment is expected.
There may be an identity disturbance characterized by markedly and persistently un­
stable self-image or sense of self (Criterion 3). There are sudden and dramatic shifts in self­
image, characterized by shifting goals, values, and vocational aspirations. There may be 
sudden changes in opinions and plans about career, sexual identity, values, and types of 
friends. These individuals may suddenly change from the role of a needy supplicant for 
help to that of a righteous avenger of past mistreatment. Although they usually have a self­
image that is based on being bad or evil, individuals with this disorder may at times have

image that is based on being bad or evil, individuals with this disorder may at times have 
feelings that they do not exist at all. Such experiences usually occur in situations in which 
the individual feels a lack of a meaningful relationship, nurturing, and support. These in­
dividuals may show worse performance in unstructured work or school situations.
Individuals with borderline personality disorder display impulsivity in at least two areas 
that are potentially self-damaging (Criterion 4). They may gamble, spend money irrespon­
sibly, binge eat, abuse substances, engage in unsafe sex, or drive recklessly. Individuals 
with this disorder display recurrent suicidal behavior, gestures, or threats, or self-mutilat­
ing behavior (Criterion 5). Completed suicide occurs in 8%-10% of such individuals, and 
self-mutilative acts (e.g., cutting or burning) and suicide threats and attempts are very

self-mutilative acts (e.g., cutting or burning) and suicide threats and attempts are very 
common. Recurrent suicidality is often the reason that these individuals present for help. 
These self-destructive acts are usually precipitated by threats of separation or rejection or 
by expectations that the individual assumes increased responsibility. Self-mutilation may 
occur during dissociative experiences and often brings relief by reaffirming the ability to 
feel or by expiating the individual's sense of being evil.
Individuals with borderline personality disorder may display affective instability that 
is due to a marked reactivity of mood (e.g., intense episodic dysphoria, irritability, or anx­
iety usually lasting a few hours and only rarely more than a few days) (Criterion 6). The 
basic dysphoric mood of those with borderline personality disorder is often disrupted by

basic dysphoric mood of those with borderline personality disorder is often disrupted by 
periods of anger, panic, or despair and is rarely relieved by periods of well-being or satis­
faction. These episodes may reflect the individual's extreme reactivity to interpersonal 
stresses. Individuals with borderline personality disorder may be troubled by chronic feel­
ings of emptiness (Criterion 7). Easily bored, they may constantly seek something to do. 
Individuals with this disorder frequently express inappropriate, intense anger or have dif­
ficulty controlling their anger (Criterion 8). They may display extreme sarcasm, enduring 
bitterness, or verbal outbursts. The anger is often elicited when a caregiver or lover is seen 
as neglectful, withholding, uncaring, or abandoning. Such expressions of anger are often

as neglectful, withholding, uncaring, or abandoning. Such expressions of anger are often 
followed by shame and guilt and contribute to the feeling they have of being evil. During 
periods of extreme stress, transient paranoid ideation or dissociative symptoms (e.g., de­
personalization) may occur (Criterion 9), but these are generally of insufficient severity or 
duration to warrant an additional diagnosis. These episodes occur most frequently in re­
sponse to a real or imagined abandonment. Symptoms tend to be transient, lasting min­
utes or hours. The real or perceived return of the caregiver's nurturance may result in a 
remission of symptoms.

Individuals with borderline personality disorder may have a pattern of undermining 
themselves at the moment a goal is about to be realized (e.g., dropping out of school just 
before graduation; regressing severely after a discussion of how well therapy is going; de­
stroying a good relationship just when it is clear that the relationship could last). Some in­
dividuals develop psychotic-like symptoms (e.g., hallucinations, body-image distortions, 
ideas of reference, hypnagogic phenomena) during times of stress. Individuals with this 
disorder may feel more secure with transitional objects (i.e., a pet or inanimate possession) 
than in interpersonal relationships. Premature death from suicide may occur in individu­
als with this disorder, especially in those with co-occurring depressive disorders or sub­
stance use disorders. Physical handicaps may result from self-inflicted abuse behaviors or

stance use disorders. Physical handicaps may result from self-inflicted abuse behaviors or 
failed suicide attempts. Recurrent job losses, interrupted education, and separation or di­
vorce are common. Physical and sexual abuse, neglect, hostile conflict, and early parental 
loss are more common in the childhood histories of those with borderline personality dis­
order. Common co-occurring disorders include depressive and bipolar disorders, sub­
stance use disorders, eating disorders (notably bulimia nervosa), posttraumatic stress 
disorder, and attention-deficit/hyperactivity disorder. Borderline personahty disorder 
also frequently co-occurs with the other personality disorders.
The median population prevalence of borderline personality disorder is estimated to be 
1.6% but may be as high as 5.9%. The prevalence of borderline personality disorder is

1.6% but may be as high as 5.9%. The prevalence of borderline personality disorder is 
about 6% in primary care settings, about 10% among individuals seen in outpatient mental 
health clinics, and about 20% among psychiatric inpatients. The prevalence of borderline 
personality disorder may decrease in older age groups.
There is considerable variability in the course of borderline personahty disorder. The most 
common pattern is one of chronic instability in early adulthood, with episodes of serious 
affective and impulsive dyscontrol and high levels of use of health and mental health re­
sources. The impairment from the disorder and the risk of suicide are greatest in the 
young-adult years and gradually wane with advancing age. Although the tendency to­
ward intense emotions, impulsivity, and intensity in relationships is often lifelong, indi­

viduals who engage in therapeutic intervention often show improvement beginning 
sometime during the first year. During their 30s and 40s, the majority of individuals with 
this disorder attain greater stability in their relationships and vocational functioning. Fol­
low-up studies of individuals identified through outpatient mental health clinics indicate 
that after about 10 years, as many as half of the individuals no longer have a pattern of be­
havior that meets full criteria for borderline personality disorder.
Genetic and physiological. Borderline personality disorder is about five times more 
common among first-degree biological relatives of those with the disorder than in the gen­
eral population. There is also an increased familial risk for substance use disorders, anti­

social personality disorder, and depressive or bipolar disorders.
The pattern of behavior seen in borderline personality disorder has been identified in many 
settings around the world. Adolescents and young adults with identity problems (especially 
when accompanied by substance use) may transiently display behaviors that misleadingly

give the impression of borderline personality disorder. Such situations are characterized by 
emotional instability, "existential" dilemmas, uncertainty, anxiety-provoking choices, con­
flicts about sexual orientation, and competing social pressures to decide on careers.
Borderline personality disorder is diagnosed predominantly (about 75%) in females.
Depressive and bipolar disorders. Borderline personality disorder often co-occurs with 
depressive or bipolar disorders, and when criteria for both are met, both may be diagnosed. 
Because the cross-sectional presentation of borderline personality disorder can be mimicked 
by an episode of depressive or bipolar disorder, the clinician should avoid giving an addi­
tional diagnosis of borderline personality disorder based only on cross-sectional presenta­
tion without having documented that the pattern of behavior had an early onset and a long­
standing course.

Other personality disorders. Other personality disorders may be confused with border­
line personality disorder because they have certain features in common. It is therefore im­
more personality disorders in addition to borderline personality disorder, all can be diag­
nosed. Although histrionic personality disorder can also be characterized by attention seek­
ing, manipulative behavior, and rapidly shifting emotions, borderline personality disorder 
is distinguished by self-destructiveness, angry disruptions in close relationships, and

is distinguished by self-destructiveness, angry disruptions in close relationships, and 
chronic feelings of deep emptiness and loneliness. Paranoid ideas or illusions may be pres­
ent in both borderline personality disorder and schizotypal personality disorder, but these 
symptoms are more transient, interpersonally reactive, and responsive to external structur­
ing in borderline personality disorder. Although paranoid personality disorder and narcis­
sistic personality disorder may also be characterized by an angry reaction to minor stimuli, 
the relative stability of self-image, as well as the relative lack of self-destructiveness, impul- 
sivity, and abandonment concerns, distinguishes these disorders from borderline person­
ality disorder. Although antisocial personality disorder and borderline personality disorder

ality disorder. Although antisocial personality disorder and borderline personality disorder 
are both characterized by manipulative behavior, individuals with antisocial personality 
disorder are manipulative to gain profit, power, or some other material gratification, 
whereas the goal in borderline personality disorder is directed more toward gaining the con­
cern of caretakers. Both dependent personality disorder and borderline personality disorder 
are characterized by fear of abandonment; however, the individual with borderline person­
ality disorder reacts to abandonment with feelings of emotional emptiness, rage, and de­
mands, whereas the individual with dependent personality disorder reacts with increasing 
appeasement and submissiveness and urgently seeks a replacement relationship to provide 
caregiving and support. Borderline personality disorder can further be distinguished from

caregiving and support. Borderline personality disorder can further be distinguished from 
dependent personality disorder by the typical pattern of unstable and intense relationships.
Personality change due to another medical condition. Borderline personality disor­
Substance use disorders. Borderline personality disorder must also be distinguished 
Identity problems. Borderline personality disorder should be distinguished from an 
identity problem, which is reserved for identity concerns related to a developmental phase 
(e.g., adolescence) and does not qualify as a mental disorder.

Histrionic Personality Disorder
Diagnostic Criteria 301.50 (F60.4)
A pervasive pattern of excessive emotionality and attention seeking, beginning by early adult­
hood and present in  a variety of contexts, as indicated by five (or more) of the following:
1. Is uncomfortable in situations in which he or she is not the center of attention.
2. Interaction with others is often characterized by inappropriate sexually seductive or  
provocative behavior.
3. Displays rapidly shifting and shallow expression of emotions.
4. Consistently uses physical appearance to draw attention to self.
5. Has a style of speech that is excessively impressionistic and lacking in detail.
6. Shows self-dramatization, theatricality, and exaggerated expression of emotion.
7. Is suggestible (i.e., easily influenced by others or circumstances).
8. Considers relationships to be more intimate than they actually are.

The essential feature of histrionic personality disorder is pervasive and excessive emotion­
ality and attention-seeking behavior. This pattern begins by early adulthood and is pres­
ent in a variety of contexts.
Individuals with histrionic personality disorder are uncomfortable or feel unappreci­
ated when they are not the center of attention (Criterion 1). Often lively and dramatic, they 
tend to draw attention to themselves and may initially charm new acquaintances by their 
enthusiasm, apparent openness, or flirtatiousness. These qualities wear thin, however, as 
these individuals continually demand to be the center of attention. They commandeer the 
role of "the life of the party." If they are not the center of attention, they may do something

role of "the life of the party." If they are not the center of attention, they may do something 
dramatic (e.g., make up stories, create a scene) to draw the focus of attention to themselves. 
This need is often apparent in their behavior with a clinician (e.g., being flattering, bring­
ing gifts, providing dramatic descriptions of physical and psychological symptoms that 
are replaced by new symptoms each visit).
The appearance and behavior of individuals with this disorder are often inappropri­
ately sexually provocative or seductive (Criterion 2). This behavior not only is directed to­
ward persons in whom the individual has a sexual or romantic interest but also occurs in 
a wide variety of social, occupational, and professional relationships beyond what is ap­
propriate for the social context. Emotional expression may be shallow and rapidly shifting

propriate for the social context. Emotional expression may be shallow and rapidly shifting 
(Criterion 3). Individuals with this disorder consistently use physical appearance to draw 
attention to themselves (Criterion 4). They are overly concerned with impressing others by 
their appearance and expend an excessive amount of time, energy, and money on clothes 
and grooming. They may "fish for compliments" regarding appearance and may be easily 
and excessively upset by a critical conunent about how they look or by a photograph that 
they regard as unflattering.
These individuals have a style of speech that is excessively impressionistic and lacking 
in detail (Criterion 5). Strong opinions are expressed with dramatic flair, but underlying 
reasons are usually vague and diffuse, without supporting facts and details. For example,

reasons are usually vague and diffuse, without supporting facts and details. For example, 
an individual with histrionic personality disorder may comment that a certain individual 
is a wonderful human being, yet be unable to provide any specific examples of good qual­
ities to support this opinion. Individuals with this disorder are characterized by self­
dramatization, theatricality, and an exaggerated expression of emotion (Criterion 6). They 
may embarrass friends and acquaintances by an excessive public display of emotions (e.g., 
embracing casual acquaintances with excessive ardor, sobbing uncontrollably on minor

sentimental occasions, having temper tantrums). However, their emotions often seem to 
be turned on and off too quickly to be deeply felt, which may lead others to accuse the in­
dividual of faking these feelings.
Individuals with histrionic personality disorder have a high degree of suggestibility (Cri­
terion 7). Their opinions and feelings are easily influenced by others and by current fads. 
They may be overly trusting, especially of strong authority figures whom they see as mag­
ically solving their problems. They have a tendency to play hunches and to adopt convic­
tions quickly. Individuals with this disorder often consider relationships more intimate 
than they actually are, describing almost every acquaintance as "my dear, dear friend" or 
referring to physicians met only once or twice under professional circumstances by their 
first names (Criterion 8).

Individuals with histrionic personality disorder may have difficulty achieving emotional in­
timacy in romantic or sexual relationships. Without being aware of it, they often act out a 
role (e.g., "victim" or "princess") in their relationships to others. They may seek to control 
their partner through emotional manipulation or seductiveness on one level, while display­
ing a marked dependency on them at another level. Individuals with this disorder often 
have impaired relationships with same-sex friends because their sexually provocative inter­
personal style may seem a threat to their friends' relationships. These individuals may also 
alienate friends with demands for constant attention. They often become depressed and up­
set when they are not the center of attention. They may crave novelty, stimulation, and ex­

citement and have a tendency to become bored with their usual routine. These individuals 
are often intolerant of, or frustrated by, situations that involve delayed gratification, and 
their actions are often directed at obtaining immediate satisfaction. Although they often ini­
tiate a job or project with great enthusiasm, their interest may lag quickly. Longer-term re­
lationships may be neglected to make way for the excitement of new relationships.
The actual risk of suicide is not known, but clinical experience suggests that individu­
als with this disorder are at increased risk for suicidal gestures and threats to get attention 
and coerce better caregiving. Histrionic personality disorder has been associated with 
higher rates of somatic symptom disorder, conversion disorder (functional neurological

higher rates of somatic symptom disorder, conversion disorder (functional neurological 
symptom disorder), and major depressive disorder. Borderline, narcissistic, antisocial, and 
dependent personality disorders often co-occur.
Data from the 2001-2002 National Epidemiologic Survey on Alcohol and Related Condi­
tions suggest a prevalence of histrionic personality of 1.84%.
Norms for interpersonal behavior, personal appearance, and emotional expressiveness 
vary widely across cultures, genders, and age groups. Before considering the various traits 
(e.g., emotionality, seductiveness, dramatic interpersonal style, novelty seeking, sociabil­
ity, charm, impressionability, a tendency to somatization) to be evidence of histrionic per­
sonality disorder, it is important to evaluate whether they cause clinically significant 
impairment or distress.

In clinical settings, this disorder has been diagnosed more frequently in females; however, 
the sex ratio is not significantly different from the sex ratio of females within the respective 
clinical setting. In contrast, some studies using structured assessments report similar prev­
alence rates among males and females.

be confused with histrionic personality disorder because they have certain features in 
common. It is therefore important to distinguish among these disorders based on differ­
that meet criteria for one or more personality disorders in addition to histrionic personal­
ity disorder, all can be diagnosed. Although borderline personality disorder can also be 
characterized by attention seeking, manipulative behavior, and rapidly shifting emotions, 
it is distinguished by self-destructiveness, angry disruptions in close relationships, and 
chronic feelings of deep emptiness and identity disturbance. Individuals with antisocial 
personality disorder and histrionic personality disorder share a tendency to be impulsive,

personality disorder and histrionic personality disorder share a tendency to be impulsive, 
superficial, excitement seeking, reckless, seductive, and manipulative, but persons with 
histrionic personality disorder tend to be more exaggerated in their emotions and do not 
characteristically engage in antisocial behaviors. Individuals with histrionic personality 
disorder are manipulative to gain nurturance, whereas those with antisocial personality 
disorder are manipulative to gain profit, power, or some other material gratification. Al­
though individuals with narcissistic personality disorder also crave attention from others, 
they usually want praise for their '"superiority," whereas individuals with histrionic per­
sonality disorder are willing to be viewed as fragile or dependent if this is instrumental in

sonality disorder are willing to be viewed as fragile or dependent if this is instrumental in 
getting attention. Individuals with narcissistic personality disorder may exaggerate the 
intimacy of their relationships with other people, but they are more apt to emphasize the 
"VIP" status or wealth of their friends. In dependent personality disorder, the individual 
is excessively dependent on others for praise and guidance, but is without the flamboyant, 
exaggerated, emotional features of individuals with histrionic personality disorder.
Many individuals may display histrionic personality traits. Only when these traits are 
inflexible, maladaptive, and persisting and cause significant functional impairment or 
subjective distress do they constitute histrionic personality disorder.
Personality change due to another medical condition. Histrionic personality disorder

Personality change due to another medical condition. Histrionic personality disorder 
Substance use disorders. The disorder must also be distinguished from sjonptoms that 
may develop in association with persistent substance use.
Narcissistic Personality Disorder
Diagnostic Criteria 301.81 (F60.81)
A pervasive pattern of grandiosity (in fantasy or behavior), need for admiration, and lack  
of empathy, beginning by early adulthood and present in a variety of contexts, as indicated  
by five (or more) of the following:
1. Has a grandiose sense of self-importance (e.g., exaggerates achievements and talents,  
expects to be recognized as superior without commensurate achievements).

2. Is preoccupied with fantasies of unlimited success, power, brilliance, beauty, or ideal  
love.
3. Believes that he or she is “ special”  and unique and can only be understood by, or  
should associate with, other special or high-status people (or institutions).
4. Requires excessive admiration.
5. Has a sense of entitlement (i.e., unreasonable expectations of especially favorable  
treatment or automatic compliance with his or her expectations).

6. Is interpersonally exploitative (i.e., takes advantage of others to achieve his or her own  
ends).
7. Lacks empathy: is unwilling to recognize or identify with the feelings and needs of others.
8. Is often envious of others or believes that others are envious of him or her.
9. Shows arrogant, haughty behaviors or attitudes.
The essential feature of narcissistic personality disorder is a pervasive pattern of grandi­
osity, need for admiration, and lack of empathy that begins by early adulthood and is pres­
Individuals with this disorder have a grandiose sense of self-importance (Criterion 1). 
They routinely overestimate their abilities and inflate their accomplishments, often appearing 
boastful and pretentious. They may blithely assume that others attribute the same value to 
their efforts and may be surprised when the praise they expect and feel they deserve is not

their efforts and may be surprised when the praise they expect and feel they deserve is not 
forthcoming. Often implicit in the inflated judgments of their own accomplishments is an un­
derestimation (devaluation) of the contributions of others. Individuals with narcissistic per­
sonality disorder are often preoccupied with fantasies of unlimited success, power, brilliance, 
beauty, or ideal love (Criterion 2). They may ruminate about "'long overdue" admiration and 
privilege and compare themselves favorably with famous or privileged people.
Individuals with narcissistic personality disorder believe that they are superior, spe­
cial, or unique and expect others to recognize them as such (Criterion 3). They may feel 
that they can only be understood by, and should only associate with, other people who are

that they can only be understood by, and should only associate with, other people who are 
special or of high status and may attribute "unique," "perfect," or "gifted" qualities to those 
with whom they associate. Individuals with this disorder believe that their needs are spe­
cial and beyond the ken of ordinary people. Their own self-esteem is enhanced (i.e., "mir­
rored") by the idealized value that they assign to those with whom they associate. They are 
likely to insist on having only the "top" person (doctor, lawyer, hairdresser, instructor) or 
being affiliated with the "best" institutions but may devalue the credentials of those who dis­
appoint them.
Individuals with this disorder generally require excessive admiration (Criterion 4). Their 
self-esteem is almost invariably very fragile. Tliey may be preoccupied with how well they

self-esteem is almost invariably very fragile. Tliey may be preoccupied with how well they 
are doing and how favorably they are regarded by others. This often takes the form of a need 
for constant attention and admiration. They may expect their arrival to be greeted with great 
farifare and are astonished if others do not covet their possessions. They may constantly fish 
for compliments, often with great charm. A sense of entitlement is evident in these individ­
uals' unreasonable expectation of especially favorable treatment (Criterion 5). They expect 
to be catered to and are puzzled or furious when this does not happen. For example, they 
may assume that they do not have to wait in line and that their priorities are so important 
that others should defer to them, and then get irritated when others fail to assist "in their

that others should defer to them, and then get irritated when others fail to assist "in their 
very important work." This sense of entitlement, combined with a lack of sensitivity to the 
wants and needs of others, may result in the conscious or unwitting exploitation of others 
(Criterion 6). They expect to be given whatever they want or feel they need, no matter what 
it might mean to others. For example, these individuals may expect great dedication from 
others and may overwork them without regard for the impact on their lives. They tend to 
form friendships or romantic relationships only if the other person seems likely to advance 
their purposes or otherwise enhance their self-esteem. They often usuφ special privileges 
and extra resources that they believe they deserve because they are so special.
Individuals with narcissistic personality disorder generally have a lack of empathy and

Individuals with narcissistic personality disorder generally have a lack of empathy and 
have difficulty recognizing the desires, subjective experiences, and feelings of others (Crite­
rion 7). They may assume that others are totally concerned about their welfare. They tend to 
discuss their own concerns in inappropriate and lengthy detail, while failing to recognize 
that others also have feelings and needs. They are often contemptuous and impatient with

others who talk about their own problems and concerns. These individuals may be oblivious 
to the hurt their remarks may inflict (e.g., exuberantly telling a former lover that "I am now 
in the relationship of a lifetime!"; boasting of health in front of someone who is sick). When 
recognized, the needs, desires, or feelings of others are likely to be viewed disparagingly as 
signs of weakness or vulnerability. Those who relate to individuals with narcissistic person­
ality disorder typically find an emotional coldness and lack of reciprocal interest.
These individuals are often envious of others or believe that oéiers are envious of them 
(Criterion 8). They may begrudge others their successes or possessions, feeling that they better 
deserve those achievements, admiration, or privileges. They may harshly devalue the contri­
butions of others, particularly when those individuals have received acknowledgment or

butions of others, particularly when those individuals have received acknowledgment or 
praise for their accomplishments. Arrogant, haughty behaviors characterize these individuals; 
they often display snobbish, disdainful, or patronizing attitudes (Criterion 9). For example, an 
individual with this disorder may complain about a clumsy waiter's "rudeness" or "stupidity" 
or conclude a medical evaluation with a condescending evaluation of the physician.
Vulnerability in self-esteem makes individuals with narcissistic personality disorder very 
sensitive to "injury" from criticism or defeat. Although they may not show it outwardly, 
criticism may haunt these individuals and may leave them feeling humiliated, degraded, 
hollow, and empty. They may react with disdain, rage, or defiant counterattack. Such ex­

periences often lead to social withdrawal or an appearance of humility that may mask and 
protect the grandiosity. Interpersonal relations are typically impaired because of problems 
derived from entitlement, the need for admiration, and the relative disregard for the sen­
sitivities of others. Though overweening ambition and confidence may lead to high 
achievement, performance may be disrupted because of intolerance of criticism or defeat. 
Sometimes vocational functioning can be very low, reflecting an unwillingness to take a 
risk in competitive or other situations in which defeat is possible. Sustained feelings of 
shame or humiliation and the attendant self-criticism may be associated with social with­
drawal, depressed mood, and persistent depressive disorder (dysthymia) or major de­

pressive disorder. In contrast, sustained periods of grandiosity may be associated with a 
hypomanie mood. Narcissistic personality disorder is also associated with anorexia ner­
vosa and substance use disorders (especially related to cocaine). Histrionic, borderline, 
antisocial, and paranoid personality disorders may be associated with narcissistic person­
ality disorder.
Prevalence estimates for narcissistic personality disorder, based on DSM-IV definitions, 
range from 0% to 6.2% in community samples.
Narcissistic traits may be particularly common in adolescents and do not necessarily in­
dicate that the individual will go on to have narcissistic personality disorder. Individuals 
with narcissistic personality disorder may have special difficulties adjusting to the onset of

with narcissistic personality disorder may have special difficulties adjusting to the onset of 
physical and occupational limitations that are inherent in the aging process.
Of those diagnosed with narcissistic personality disorder, 50%-75% are male.
be confused with narcissistic personality disorder because they have certain features in

that meet criteria for one or more personality disorders in addition to narcissistic person­
ality disorder, all can be diagnosed. The most useful feature in discriminating narcissistic 
personality disorder from histrionic, antisocial, and borderline personality disorders, in 
which the interactive styles are coquettish, callous, and needy, respectively, is the grandi­
osity characteristic of narcissistic personality disorder. The relative stability of self-image 
as well as the relative lack of self-destructiveness, impulsivity, and abandonment concerns 
also help distinguish narcissistic personality disorder from borderline personality disor­
der. Excessive pride in achievements, a relative lack of emotional display, and disdain for

der. Excessive pride in achievements, a relative lack of emotional display, and disdain for 
others' sensitivities help distinguish narcissistic personality disorder from histrionic 
personality disorder. Although individuals with borderline, histrionic, and narcissistic 
personality disorders may require much attention, those with narcissistic personality dis­
order specifically need that attention to be admiring. Individuals with antisocial and nar­
cissistic personality disorders share a tendency to be tough-minded, glib, superficial, 
exploitative, and unempathic. However, narcissistic personality disorder does not neces­
sarily include characteristics of impulsivity, aggression, and deceit. In addition, individu­
als with antisocial personality disorder may not be as needy of the admiration and envy of

als with antisocial personality disorder may not be as needy of the admiration and envy of 
others, and persons with narcissistic personality disorder usually lack the history of con­
duct disorder in childhood or criminal behavior in adulthood. In both narcissistic person­
ality disorder and obsessive-compulsive personality disorder, the individual may profess 
a commitment to perfectionism and believe that others cannot do things as well. In con­
trast to the accompanying self-criticism of those with obsessive-compulsive personality 
disorder, individuals with narcissistic personality disorder are more likely to believe that 
they have achieved perfection. Suspiciousness and social withdrawal usually distinguish 
those with schizotypal or paranoid personality disorder from those with narcissistic per­

sonality disorder. When these qualities are present in individuals with narcissistic person­
ality disorder, they derive primarily from fears of having imperfections or flaws revealed.
Many highly successful individuals display personality traits that might be considered 
narcissistic. Only when these traits are inflexible, maladaptive, and persisting and cause 
significant functional impairment or subjective distress do they constitute narcissistic per­
Mania or hypomania. Grandiosity may emerge as part of manic or hypomanie episodes, 
but the association with mood change or functional impairments helps distinguish these 
episodes from narcissistic personality disorder.
Substance use disorders. Narcissistic personality disorder must also be distinguished

Substance use disorders. Narcissistic personality disorder must also be distinguished 
Avoidant Personality Disorder
Diagnostic Criteria 301.82 (F60.6)
A pervasive pattern of social inhibition, feelings of inadequacy, and hypersensitivity to neg­
ative evaluation, beginning by early adulthood and present in a variety of contexts, as in­
dicated by four (or more) of the following:
1. Avoids occupational activities that involve significant interpersonal contact because of  
fears of criticism, disapproval, or rejection.

2. Is unwilling to get involved with people unless certain of being liked.
3. Shows restraint within intimate relationships because of the fear of being shamed or  
ridiculed. '
4. Is preoccupied with being criticized or rejected in social situations.
5. Is inhibited in new interpersonal situations because of feelings of inadequacy.
6. Views self as socially inept, personally unappealing, or inferior to others.
7. Is unusually reluctant to take personal risks or to engage in any new activities because  
they may prove embarrassing.
The essential feature of avoidant personality disorder is a pervasive pattern of social inhi­
bition, feelings of inadequacy, and hypersensitivity to negative evaluation that begins by 
early adulthood and is present in a variety of contexts.
Individuals with avoidant personality disorder avoid work activities that involve sig­
nificant interpersonal contact because of fears of criticism, disapproval, or rejection (Cri­

terion 1). Offers of job promotions may be declined because the new responsibilities might 
result in criticism from co-workers. These individuals avoid making new friends unless 
they are certain they will be liked and accepted without criticism (Criterion 2). Until they 
pass stringent tests proving the contrary, other people are assumed to be critical and dis­
approving. Individuals with this disorder will not join in group activities unless there are 
repeated and generous offers of support and nurturance. Interpersonal intimacy is often 
difficult for these individuals, although they are able to establish intimate relationships 
when there is assurance of uncritical acceptance. They may act with restraint, have diffi­

culty talking about themselves, and withhold intimate feelings for fear of being exposed, 
ridiculed, or shamed (Criterion 3).
Because individuals with this disorder are preoccupied with being criticized or re­
jected in social situations, they may have a markedly low threshold for detecting such re­
actions (Criterion 4). If someone is even slightly disapproving or critical, they may feel 
extremely hurt. They tend to be shy, quiet, inhibited, and "invisible" because of the fear 
that any attention would be degrading or rejecting. They expect that no matter what they 
say, others will see it as "wrong," and so they may say nothing at all. They react strongly 
to subtle cues that are suggestive of mockery or derision. Despite their longing to be active

to subtle cues that are suggestive of mockery or derision. Despite their longing to be active 
participants in social life, they fear placing their welfare in the hands of others. Individuals 
with avoidant personality disorder are inhibited in new interpersonal situations because 
they feel inadequate and have low self-esteem (Criterion 5). Doubts concerning social 
competence and personal appeal become especially manifest in settings involving inter­
actions with strangers. These individuals believe themselves to be socially inept, person­
ally unappealing, or inferior to others (Criterion 6). They are unusually reluctant to take 
personal risks or to engage in any new activities because these may prove embarrassing 
(Criterion 7). They are prone to exaggerate the potential dangers of ordinary situations,

(Criterion 7). They are prone to exaggerate the potential dangers of ordinary situations, 
and a restricted lifestyle may result from their need for certainty and security. Someone 
with this disorder may cancel a job interview for fear of being embarrassed by not dressing 
appropriately. Marginal somatic symptoms or other problems may become the reason for 
avoiding new activities.
Individuals with avoidant personality disorder often vigilantly appraise the movements 
and expressions of those with whom they come into contact. Their fearful and tense de­
meanor may elicit ridicule and derision from others, which in turn confirms their self­
doubts. These individuals are very anxious about the possibility that they will react to crit­
icism with blushing or crying. They are described by others as being "shy," "timid,"

"lonely," and "isolated." The major problems associated with this disorder occur in social 
and occupational functioning. The low self-esteem and hypersensitivity to rejection are 
associated with restricted interpersonal contacts. These individuals may become relatively 
isolated and usually do not have a large social support network that can help them weather 
crises. They desire affection and acceptance and may fantasize about idealized relation­
ships with others. The avoidant behaviors can also adversely affect occupational function­
ing because these individuals try to avoid the types of social situations that may be 
important for meeting the basic demands of the job or for advancement.
Other disorders that are commonly diagnosed with avoidant personality disorder in­
clude depressive, bipolar, and anxiety disorders, especially social anxiety disorder (social 
phobia). Avoidant personality disorder is often diagnosed with dependent personality

phobia). Avoidant personality disorder is often diagnosed with dependent personality 
disorder, because individuals with avoidant personality disorder become very attached to 
and dependent on those few other people with whom they are friends. Avoidant per­
sonality disorder also tends to be diagnosed with borderline personality disorder and with 
the Cluster A personality disorders (i.e., paranoid, schizoid, or schizotypal personality 
disorders).
tions suggest a prevalence of about 2.4% for avoidant personality disorder.
The avoidant behavior often starts in infancy or childhood with shyness, isolation, and 
fear of strangers and new situations. Although shyness in childhood is a common precur­

sor of avoidant personality disorder, in most individuals it tends to gradually dissipate as 
they get older. In contrast, individuals who go on to develop avoidant personality disor­
der may become increasingly shy and avoidant during adolescence and early adulthood, 
when social relationships with new people become especially important. There is some 
evidence that in adults, avoidant personality disorder tends to become less evident or to 
remit with age. This diagnosis should be used with great caution in children and adoles­
cents, for whom shy and avoidant behavior may be developmentally appropriate.
There may be variation in the degree to which different cultural and ethnic groups regard

There may be variation in the degree to which different cultural and ethnic groups regard 
diffidence and avoidance as appropriate. Moreover, avoidant behavior may be the result 
of problems in acculturation following immigration.
Avoidant personality disorder appears to be equally frequent in males and females.
Anxiety disorders. There appears to be a great deal of overlap between avoidant person­
ality disorder and social anxiety disorder (social phobia), so much so that they may be 
alternative conceptualizations of the same or similar conditions. Avoidance also character­
izes both avoidant personality disorder and agoraphobia, and they often co-occur.
be confused with avoidant personality disorder because they have certain features in com­

meet criteria for one or more personality disorders in addition to avoidant personality dis-

order, all can be diagnosed. Both avoidant personality disorder and dependent personal­
ity disorder are characterized by feelings of inadequacy, hypersensitivity to criticism, and 
a need for reassurance. Although the primary focus of concern in avoidant personality 
disorder is avoidance of humiliation and rejection, in dependent personality disorder the 
focus is on being taken care of. However, avoidant personality disorder and dependent 
personality disorder are particularly likely to co-occur. Like avoidant personality disor­
der, schizoid personality disorder and schizotypal personality disorder are characterized 
by social isolation. However, individuals with avoidant personality disorder want to have 
relationships with others and feel their loneliness deeply, whereas those with schizoid or 
schizotypal personality disorder may be content with and even prefer their social isola­
tion. Paranoid personality disorder and avoidant personality disorder are both character­

ized by a reluctance to confide in others. However, in avoidant personality disorder, this 
reluctance is attributable more to a fear of being embarrassed or being found inadequate 
than to a fear of others' malicious intent.
Many individuals display avoidant personality traits. Only when these traits are in­
flexible, maladaptive, and persisting and cause significant functional impairment or sub­
jective distress do they constitute avoidant personality disorder.
Personality change due to another medical condition. Avoidant personality disorder 

Substance use disorders. Avoidant personality disorder must also be distinguished 
Dependent Personality Disorder
Diagnostic Criteria 301.6(F60.7)
A pervasive and excessive need to be taken care of that leads to submissive and clinging  
behavior and fears of separation, beginning by early adulthood and present in a variety of  
contexts, as indicated by five (or more) of the following:
1. Has difficulty making everyday decisions without an excessive amount of advice and  
reassurance from others.
2. Needs others to assume responsibility for most major areas of his or her life.
3. Has difficulty expressing disagreement with others because of fear of loss of support  
or approval. (Note: Do not include realistic fears of retribution.)

4. Has difficulty initiating projects or doing things on his or her own (because of a lack of  
self-confidence in judgment or abilities rather than a lack of motivation or energy).
5. Goes to excessive lengths to obtain nurturance and support from others, to the point  
of volunteering to do things that are unpleasant.
6. Feels uncomfortable or helpless when alone because of exaggerated fears of being  
unable to care for himself or herself.
7. Urgently seeks another relationship as a source of care and support when a close re­
lationship ends.
8. Is unrealistically preoccupied with fears of being left to take care of himself or herself.
The essential feature of dependent personality disorder is a pervasive and excessive need

The essential feature of dependent personality disorder is a pervasive and excessive need 
to be taken care of that leads to submissive and clinging behavior and fears of separation. 
This pattern begins by early adulthood and is present in a variety of contexts. The dependent

and submissive behaviors are designed to elicit caregiving and arise from a self-perception 
of being unable to function adequately without the help of others.
Individuals with dependent personality disorder have great difficulty making every­
day decisions (e.g., what color shirt to wear to work or whether to carry an umbrella) without 
an excessive amount of advice and reassurance from others (Criterion 1). These individu­
als tend to be passive and to allow other people (often a single other person) to take the ini­
tiative and assume responsibility for most major areas of their lives (Criterion 2). Adults 
with this disorder typically depend on a parent or spouse to decide where they should 
live, what kind of job they should have, and which neighbors to befriend. Adolescents 
with this disorder may allow their parent(s) to decide what they should wear, with whom 
they should associate, how they should spend their free time, and what school or college

they should associate, how they should spend their free time, and what school or college 
they should attend. This need for others to assume responsibility goes beyond age-appro­
priate and situation-appropriate requests for assistance from others (e.g., the specific 
needs of children, elderly persons, and handicapped persons). Dependent personality dis­
order may occur in an individual who has a serious medical condition or disability, but in 
such cases the difficulty in taking responsibility must go beyond what would normally be 
associated with that condition or disability.
Because they fear losing support or approval, individuals with dependent personality 
disorder often have difficulty expressing disagreement with other individuals, especially 
those on whom they are dependent (Criterion 3). These individuals feel so unable to func­

tion alone that they will agree with things that they feel are wrong rather than risk losing 
the help of those to whom they look for guidance. They do not get appropriately angry at 
others whose support and nurturance they need for fear of alienating them. If the individ­
ual's concerns regarding the consequences of expressing disagreement are realistic (e.g., 
realistic fears of retribution from an abusive spouse), the behavior should not be consid­
ered to be evidence of dependent personality disorder.
Individuals with this disorder have difficulty initiating projects or doing things inde­
pendently (Criterion 4). They lack self-confidence and believe that they need help to begin 
and carry through tasks. They will wait for others to start things because they believe that

and carry through tasks. They will wait for others to start things because they believe that 
as a rule others can do them better. These individuals are convinced that they are incapable 
of functioning independently and present themselves as inept and requiring constant as­
sistance. They are, however, likely to function adequately if given the assurance that some­
one else is supervising and approving. There may be a fear of becoming or appearing to be 
more competent, because they may believe that this will lead to abandonment. Because 
they rely on others to handle their problems, they often do not leam the skills of indepen­
dent living, thus perpetuating dependency.
Individuals with dependent personality disorder may go to excessive lengths to obtain 
nurturance and support from others, even to the point of volunteering for unpleasant

nurturance and support from others, even to the point of volunteering for unpleasant 
tasks if such behavior will bring the care they need (Criterion 5). They are willing to submit 
to what others want, even if the demands are unreasonable. Their need to maintain an im­
portant bond will often result in imbalanced or distorted relationships. They may make ex­
traordinary self-sacrifices or tolerate verbal, physical, or sexual abuse. (It should be noted 
that this behavior should be considered evidence of dependent personality disorder only 
when it can clearly be established that other options are available to the individual.) Indi­
viduals with this disorder feel uncomfortable or helpless when alone, because of their ex­
aggerated fears of being unable to care for themselves (Criterion 6). They will "tag along"

aggerated fears of being unable to care for themselves (Criterion 6). They will "tag along" 
with important others just to avoid being alone, even if they are not interested or involved 
in what is happening.
When a close relationship ends (e.g., a breakup with a lover; the death of a caregiver), in­
dividuals with dependent personality disorder may urgently seek another relationship to 
provide the care and support they need (Criterion 7). Their belief that they are unable to 
function in the absence of a close relationship motivates these individuals to become quickly 
and indiscriminately attached to another individual. Individuals with this disorder are often

preoccupied with fears of being left to care for themselves (Criterion 8). They see themselves 
as so totally dependent on the advice and help of an important other person that they worry 
about being abandoned by that person when there are no grounds to justify such fears. To be 
considered as evidence of this criterion, the fears must be excessive and unrealistic. For ex­
ample, an elderly man with cancer who moves into his son's household for care is exhibiting 
dependent behavior that is appropriate given this person's life circumstances.
Individuals with dependent personality disorder are often characterized by pessimism 
and self-doubt, tend to belittle their abilities and assets, and may constantly refer to them­
selves as "stupid." They take criticism and disapproval as proof of their worthlessness and 
lose faith in themselves. They may seek overprotection and dominance from others. Oc­

cupational functioning may be impaired if independent initiative is required. They may 
avoid positions of responsibility and become anxious when faced with decisions. Social re­
lations tend to be limited to those few people on whom the individual is dependent. There 
may be an increased risk of depressive disorders, anxiety disorders, and adjustment dis­
orders. Dependent personality disorder often co-occurs with other personality disorders, 
especially borderline, avoidant, and histrionic personality disorders. Chronic physical ill­
ness or separation anxiety disorder in childhood or adolescence may predispose the indi­
vidual to the development of this disorder.

tions yielded an estimated prevalence of dependent personality disorder of 0.49%, and de­
pendent personality was estimated, based on a probability subsample from Part II of the 
National Comorbidity Survey Replication, to be 0.6%.
This diagnosis should be used with great caution, if at all, in children and adolescents, for 
whom dependent behavior may be developmentally appropriate.
The degree to which dependent behaviors are considered to be appropriate varies sub­
stantially across different age and sociocultural groups. Age and cultural factors need to 
be considered in evaluating the diagnostic threshold of each criterion. Dependent behav­
ior should be considered characteristic of the disorder only when it is clearly in excess of

ior should be considered characteristic of the disorder only when it is clearly in excess of 
the individual's cultural norms or reflects unrealistic concerns. An emphasis on passivity, 
politeness, and deferential treatment is characteristic of some societies and may be mis­
interpreted as traits of dependent personality disorder. Similarly, societies may differen­
tially foster and discourage dependent behavior in males and females.
In clinical settings, dependent personality disorder has been diagnosed more frequently in 
females, although some studies report similar prevalence rates among males and females.
Other mental disorders and medical conditions. Dependent personality disorder must 
be distinguished from dependency arising as a consequence of other mental disorders (e.g.,

be distinguished from dependency arising as a consequence of other mental disorders (e.g., 
depressive disorders, panic disorder, agoraphobia) and as a result of other medical conditions.

confused with dependent personality disorder because they have certain features in com­
mon. It is therefore important to distinguish among these disorders based on differences in 
their characteristic features. However, if an individual has personality features that meet cri­
teria for one or more personality disorders in addition to dependent personality disorder, all 
can be diagnosed. Although many personality disorders are characterized by dependent 
features, dependent personality disorder can be distinguished by its predominantly submis­
sive, reactive, and clinging behavior. Both dependent personality disorder and borderline 
personality disorder are characterized by fear of abandonment; however, the individual 
with borderline personality disorder reacts to abandonment with feelings of emotional emp­
tiness, rage, and demands, whereas the individual with dependent personality disorder re­

acts with increasing appeasement and submissiveness and urgently seeks a replacement 
relationship to provide caregiving and support. Borderline personality disorder can further 
be distinguished from dependent personality disorder by a typical pattern of unstable and 
intense relationships. Individuals with histrionic personality disorder, like those with de­
pendent personality disorder, have a strong need for reassurance and approval and may ap­
pear childlike and clinging. However, unlike dependent personality disorder, which is 
characterized by self-effacing and docile behavior, histrionic personality disorder is charac­
terized by gregarious flamboyance with active demands for attention. Both dependent 
personality disorder and avoidant personality disorder are characterized by feelings of in­

adequacy, hypersensitivity to criticism, and a need for reassurance; however, individuals 
with avoidant personality disorder have such a strong fear of humiliation and rejection that 
they withdraw until they are certain they will be accepted. In contrast, individuals with de­
pendent personality disorder have a pattern of seeking and maintaining connections to im­
portant others, rather than avoiding and withdrawing from relationships.
Many individuals display dependent personality traits. Orüy when these traits are in­
jective distress do they constitute dependent personality disorder.
Personality change due to another medical condition. Dependent personality disor­

Substance use disorders. Dependent personality disorder must also be distinguished 
Obsessive-Compulsive Personality Disorder
Diagnostic Criteria 301.4 (F60.5)
A pervasive pattern of preoccupation with orderliness, perfectionism, and mental and in-  
teφersonal control, at the expense of flexibility, openness, and efficiency, beginning by  
early adulthood and present in a variety of contexts, as indicated by four (or more) of the  
following:
1. Is preoccupied with details, rules, lists, order, organization, or schedules to the extent

1. Is preoccupied with details, rules, lists, order, organization, or schedules to the extent  
that the major point of the activity is lost.
2. Shows perfectionism that interferes with task completion (e.g., is unable to complete a  
project because his or her own overly strict standards are not met).
3. Is excessively devoted to work and productivity to the exclusion of leisure activities and  
friendships (not accounted for by obvious economic necessity).
4. Is overconscientious, scrupulous, and inflexible about matters of morality, ethics, or  
values (not accounted for by cultural or religious identification).

5. Is unable to discard worn-out or worthless objects even when they have no sentimental  
value.
6. Is reluctant to delegate tasks or to work with others unless they submit to exactly his  
or her way of doing things.
7. Adopts a miserly spending style toward both self and others; money is viewed as  
something to be hoarded for future catastrophes.
8. Shows rigidity and stubbornness.
The essential feature of obsessive-compulsive personality disorder is a preoccupation 
with orderliness, perfectionism, and mental and interpersonal control, at the expense of 
flexibility, openness, and efficiency. This pattern begins by early adulthood and is present 
in a variety of contexts.
Individuals with obsessive-compulsive personality disorder attempt to maintain a 
sense of control through painstaking attention to rules, trivial details, procedures, lists, 
schedules, or form to the extent that the major point of the activity is lost (Criterion 1). They

schedules, or form to the extent that the major point of the activity is lost (Criterion 1). They 
are excessively careful and prone to repetition, paying extraordinary attention to detail 
and repeatedly checking for possible mistakes. They are oblivious to the fact that other 
people tend to become very annoyed at the delays and inconveniences that result from this 
behavior. For example, when such individuals misplace a list of things to be done, they 
will spend an inordinate amount of time looking for the list rather than spending a few 
moments re-creating it from memory and proceeding to accomplish the tasks. Time is 
poorly allocated, and the most important tasks are left to the last moment. The perfection­
ism and self-imposed high standards of performance cause significant dysfunction and 
distress in these individuals. They may become so involved in making every detail of a

distress in these individuals. They may become so involved in making every detail of a 
project absolutely perfect that the project is never finished (Criterion 2). For example, the 
completion of a written report is delayed by numerous time-consuming rewrites that all 
come up short of "perfection." Deadlines are missed, and aspects of the individual's life 
that are not the current focus of activity may fall into disarray.
Individuals with obsessive-compulsive personality disorder display excessive devotion 
to work and productivity to the exclusion of leisure activities and friendships (Criterion 3). 
This behavior is not accounted for by economic necessity. They often feel that they do not 
have time to take an evening or a weekend day off to go on an outing or to just relax. They 
may keep postponing a pleasurable activity, such as a vacation, so that it may never occur.

may keep postponing a pleasurable activity, such as a vacation, so that it may never occur. 
When they do take time for leisure activities or vacations, they are very uncomfortable un­
less they have taken along something to work on so they do not "waste time." There may be 
a great concentration on household chores (e.g., repeated excessive cleaning so that "one 
could eat off the floor"). If they spend time with friends, it is likely to be in some kind of for­
mally organized activity (e.g., sports). Hobbies or recreational activities are approached as 
serious tasks requiring careful organization and hard work to master. The emphasis is on 
perfect performance. These individuals turn play into a structured task (e.g., correcting an 
infant for not putting rings on the post in the right order; telling a toddler to ride his or her tri­

cycle in a straight line; turning a baseball game into a harsh "lesson").
Individuals with obsessive-compulsive personality disorder may be excessively con­
scientious, scrupulous, and inflexible about matters of morality, ethics, or values (Crite­
rion 4). They may force themselves and others to follow rigid moral principles and very 
strict standards of performance. They may also be mercilessly self-critical about their own 
mistakes. Individuals with this disorder are rigidly deferential to authority and rules and 
insist on quite literal compliance, with no rule bending for extenuating circumstances. For 
example, the individual will not lend a quarter to a friend who needs one to make a tele­
phone call because "neither a borrower nor a lender be" or because it would be "bad" for

the person's character. These qualities should not be accounted for by the individual's cul­
tural or religious identification.
Individuals with this disorder may be unable to discard worn-out or worthless objects, 
even when they have no sentimental value (Criterion 5). Often these individuals will ad­
mit to being "pack rats." They regard discarding objects as wasteful because "you never 
know when you might need something" and will become upset if someone tries to get rid of 
the things they have saved. Their spouses or roommates may complain about the amount of 
space taken up by old parts, magazines, broken appliances, and so on.
Individuals with obsessive-compulsive personality disorder are reluctant to delegate 
tasks or to work with others (Criterion 6). They stubbornly and unreasonably insist that 
everything be done their way and that people conform to their way of doing things. They 
often give very detailed instructions about how things should be done (e.g., there is one

often give very detailed instructions about how things should be done (e.g., there is one 
and only one way to mow the lawn, wash the dishes, build a doghouse) and are surprised 
and irritated if others suggest creative alternatives. At other times they may reject offers of 
help even when behind schedule because they believe no one else can do it right.
Individuals with this disorder may be miserly and stingy and maintain a standard of 
living far below what they can afford, believing that spending must be tightly controlled to 
provide for future catastrophes (Criterion 7). Obsessive-compulsive personality disorder 
is characterized by rigidity and stubbornness (Criterion 8). Individuals with this disorder 
are so concerned about having things done the one "correct" way that they have trouble 
going along with anyone else's ideas. These individuals plan ahead in meticulous detail

going along with anyone else's ideas. These individuals plan ahead in meticulous detail 
and are unwilling to consider changes. Totally wrapped up in their own perspective, they 
have difficulty acknowledging the viewpoints of others. Friends and colleagues may be­
come frustrated by this constant rigidity. Even when individuals with obsessive-compul­
sive personality disorder recognize that it may be in their interest to compromise, they 
may stubbornly refuse to do so, arguing that it is "the principle of the thing."
When rules and established procedures do not dictate the correct answer, decision making 
may become a time-consuming, often painful process. Individuals with obsessive- 
compulsive personality disorder may have such difficulty deciding which tasks take pri­

ority or what is the best way of doing some particular task that they may never get started 
on anything. They are prone to become upset or angry in situations in which they are not 
able to maintain control of their physical or interpersonal environment, although the an­
ger is typically not expressed directly. For example, an individual may be angry when ser­
vice in a restaurant is poor, but instead of complaining to the management, the individual 
ruminates about how much to leave as a tip. C 3n  other occasions, anger may be expressed 
with righteous indignation over a seemingly minor matter. Individuals with this disorder 
may be especially attentive to their relative status in dominance-submission relationships 
and may display excessive deference to an authority they respect and excessive resistance

and may display excessive deference to an authority they respect and excessive resistance 
to authority they do not respect.
Individuals with this disorder usually express affection in a highly controlled or stilted 
fashion and may be very uncomfortable in the presence of others who are emotionally ex­
pressive. Their everyday relationships have a formal and serious quality, and they may be 
stiff in situations in which others would smile and be happy (e.g., greeting a lover at the 
airport). They carefully hold themselves back until they are sure that whatever they say 
will be perfect. They may be preoccupied with logic and intellect, and intolerant of affec­
tive behavior in others. They often have difficulty expressing tender feelings, rarely pay­
ing compliments. Individuals with this disorder may experience occupational difficulties

ing compliments. Individuals with this disorder may experience occupational difficulties 
and distress, particularly when confronted with new situations that demand flexibility 
and compromise.
Individuals with anxiety disorders, including generalized anxiety disorder, social anx­
iety disorder (social phobia), and specific phobias, and obsessive-compulsive disorder (OCD)

have an increased likelihood of having a personality disturbance that meets criteria for ob- 
sessive-compulçive personality disorder. Even so, it appears that the majority of individ­
uals with OCD do not have a pattern of behavior that meets criteria for this personality 
disorder. Many of the features of obsessive-compulsive personality disorder overlap with 
"type A" personality characteristics (e.g., preoccupation with work, competitiveness, time 
urgency), and these features may be present in people at risk for myocardial infarction. 
There may be an association between obsessive-compulsive personality disorder and de­
pressive and bipolar disorders and eating disorders.
Obsessive-compulsive personality disorder is one of the most prevalent personality dis­
orders in the general population, with estimated prevalence ranging from 2.1% to 7.9%.
In assessing an individual for obsessive-compulsive personality disorder, the clinician

In assessing an individual for obsessive-compulsive personality disorder, the clinician 
should not include those behaviors that reflect habits, customs, or interpersonal styles that 
are culturally sanctioned by the individual's reference group. Certain cultures place sub­
stantial emphasis on work and productivity; the resulting behaviors in members of those 
societies need not be considered indications of obsessive-compulsive personality disorder.
In systematic studies, obsessive-compulsive personality disorder appears to be diagnosed 
about twice as often among males.
Obsessive-compulsive disorder. Despite the similarity in names, OCD is usually easily 
distinguished from obsessive-compulsive personality disorder by the presence of true ob­
sessions and compulsions in OCD. When criteria for both obsessive-compulsive person­
ality disorder and OCD are met, both diagnoses should be recorded.

Hoarding disorder. A diagnosis of hoarding disorder should be considered especially 
when hoarding is extreme (e.g., accumulated stacks of worthless objects present a fire haz­
ard and make it difficult for others to walk through the house). When criteria for both ob­
sessive-compulsive personality disorder and hoarding disorder are met, both diagnoses 
should be recorded.
be confused with obsessive-compulsive personality disorder because they have certain 
features in common. It is, therefore, important to distinguish among these disorders based 
on differences in their characteristic features. However, if an individual has personality 
features that meet criteria for one or more personality disorders in addition to obsessive-

features that meet criteria for one or more personality disorders in addition to obsessive- 
compulsive personality disorder, all can be diagnosed. Individuals with narcissistic per­
sonality disorder may also profess a commitment to perfectionism and believe that others 
cannot do things as well, but these individuals are more likely to believe that they have 
achieved perfection, whereas those with obsessive-compulsive personahty disorder are 
usually self-critical. Individuals with narcissistic or antisocial personality disorder lack 
generosity but will indulge themselves, whereas those with obsessive-compulsive person­
ality disorder adopt a miserly spending style toward both self and others. Both schizoid 
personality disorder and obsessive-compulsive personality disorder may be characterized 
by an apparent formality and social detachment. In obsessive-compulsive personality dis­

order, this stems from discomfort with emotions and excessive devotion to work, whereas 
in schizoid personality disorder there is a fundamental lack of capacity for intimacy.

Obsessive-compulsive personality traits in moderation may be especially adaptive, par­
ticularly in situations that reward high performance. Only when these traits are inflexible, 
maladaptive, and persisting and cause significant functional impairment or subjective dis­
tress do they constitute obsessive-compulsive personality disorder.
Personality change due to another medical condition. Obsessive-compulsive person­
ality disorder must be distinguished from personality change due to another medical con­
dition, in which the traits emerge attributable to the effects of another medical condition 
on the central nervous system.
Substance use disorders. Obsessive-compulsive personality disorder must also be dis­
tinguished from symptoms that may develop in association with persistent substance use.
Personality Change  
Diagnostic Criteria 310.1 (F07.0)

A. A persistent personality disturbance that represents a change fro n n  the individual’s pre­
vious characteristic personality pattern.
Note: In children, the disturbance involves a marked deviation from normal devel­
opment or a significant change in the child’s usual behavior patterns, lasting at least  
1  year.
C. The disturbance is not better explained by another mental disorder (including another  
mental disorder due to another medical condition).

Labile type: If the predominant feature is affective lability.
Disinhibited type: If the predominant feature is poor impulse control as evidenced by  
sexual indiscretions, etc.
Aggressive type: If the predominant feature is aggressive behavior.
Apathetic type: If the predominant feature is marked apathy and indifference.  
Paranoid type: If the predominant feature is suspiciousness or paranoid ideation.  
Other type: If the presentation is not characterized by any of the above subtypes.  
Combined type: If more than one feature predominates in the clinical picture.  
Coding note: Include the name of the other medical condition (e.g., 310.1 [F07.0] person­
ality change due to temporal lobe epilepsy). The other medical condition should be coded

ality change due to temporal lobe epilepsy). The other medical condition should be coded  
and listed separately immediately before the personality disorder due to another medical  
condition (e.g., 345.40 [G40.209] temporal lobe epilepsy; 310.1 [F07.0] personality  
change due to temporal lobe epilepsy).

Subtypes
The particular {Personality change can be specified by indicating the symptom presenta­
tion that predominates in the clinical presentation.
The essential feature of a personality change due to another medical condition is a persis­
tent personality disturbance that is judged to be due to the direct pathophysiological ef­
fects of a medical condition. The personality disturbance represents a change from the 
individual's previous characteristic personality pattern. In children, this condition may be 
manifested as a marked deviation from normal development rather than as a change in a 
stable personality pattern (Criterion A). There must be evidence from the history, physical 
examination, or laboratory findings that the personality change is the direct physiological 
consequence of another medical condition (Criterion B). The diagnosis is not given if the 
disturbance is better explained by another mental disorder (Criterion C). The diagnosis is

disturbance is better explained by another mental disorder (Criterion C). The diagnosis is 
not given if the disturbance occurs exclusively during the course of a delirium (Criterion 
D). The disturbance must also cause clinically significant distress or impairment in social, 
occupational, or other important areas of functioning (Criterion E).
Common manifestations of the personality change include affective instability, poor 
impulse control, outbursts of aggression or rage grossly out of proportion to any precipi­
tating psychosocial stressor, marked apathy, suspiciousness, or paranoid ideation. The 
phenomenology of the change is indicated using the subtypes listed in the criteria set. An 
individual with the disorder is often characterized by others as "not himself [or herself]." 
Although it shares the term "personality" with the other personality disorders, this diag­

nosis is distinct by virtue of its specific etiology, different phenomenology, and more vari­
able onset and course.
The clinical presentation in a given individual may depend on the nature and localiza­
tion of the pathological process. For example, injury to the frontal lobes may yield symp­
toms such as lack of judgment or foresight, facetiousness, disinhibition, and euphoria. 
Right hemisphere strokes have often been shown to evoke personality changes in asso­
ciation with unilateral spatial neglect, anosognosia (i.e., inability of the individual to 
recognize a bodily or functional deficit, such as the existence of hemiparesis), motor im- 
persistence, and other neurological deficits.

A variety of neurological and other medical conditions may cause personality changes, 
including central nervous system neoplasms, head trauma, cerebrovascular disease, 
Huntington's disease, epilepsy, infectious conditions with central nervous system in­
volvement (e.g., HIV), endocrine conditions (e.g., hypothyroidism, hypo- and hyperadre- 
nocorticism), and autoimmune conditions with central nervous system involvement (e.g., 
systemic lupus erythematosus). The associated physical examination findings, laboratory 
findings, and patterns of prevalence and onset reflect those of the neurological or other 
medical condition involved.
Chronic medical conditions associated with pain and disability. Chronic medical con­

ditions associated with pain and disability can also be associated with changes in person­
ality. The diagnosis of personality change due to another medical condition is given only 
if a direct pathophysiological mechanism can be established. This diagnosis is not given if 
the change is due to a behavioral or psychological adjustment or response to another med­
ical condition (e.g., dependent behaviors that result from a need for the assistance of others 
following a severe head trauma, cardiovascular disease, or dementia).

Delirium or major neurocognitive disorder. Personality change is a frequently associated 
feature of a delirium or major neurocognitive disorder. A separate diagnosis of personal­
ity change due to another medical condition is not given if the change occurs exclusively 
during the course of a delirium. However, the diagnosis of personality change due to an­
other medical condition may be given in addition to the diagnosis of major neurocognitive 
disorder if the personality change is a prominent part of the clinical presentation.
Another mental disorder due to another medical condition. The diagnosis of person­
ality change due to another medical condition is not given if the disturbance is better ex­
plained by another mental disorder due to another medical condition (e.g., depressive 
disorder due to brain tumor).
Substance use disorders. Personality changes may also occur in the context of substance

Substance use disorders. Personality changes may also occur in the context of substance 
use disorders, especially if the disorder is long-standing. The clinician should inquire carefully 
about the nature and extent of substance use. If the clinician wishes to indicate an etiological re­
lationship between the personality change and substance use, the unspecified category for the 
specific substance (e.g., unspecified stimulant-related disorder) can be used.
Other mental disorders. Marked personality changes may also be an associated feature 
of other mental disorders (e.g., schizophrenia; delusional disorder; depressive and bipolar 
disorders; other specified and unspecified disruptive behavior, impulse-control, and con­
duct disorders; panic disorder). However, in these disorders, no specific physiological fac­
tor is judged to be etiologically related to the personality change.

Other personality disorders. Personality change due to another medical condition can 
be distinguished from a personality disorder by the requirement for a clinically significant 
change from baseline personality functioning and the presence of a specific etiological 
Other Specified Personality Disorder
301.89 (F60.89)
This category applies to presentations in wliich symptoms characteristic of a personality  
the disorders in the personality disorders diagnostic class. The other specified personality  
disorder category is used in  situations in  which the clinician chooses to communicate the

disorder category is used in  situations in  which the clinician chooses to communicate the  
specific reason that the presentation does not meet the criteria for any specific personality  
disorder. This is done by recording “ other specified personality disorder”  followed by the  
specific reason (e.g., “ mixed personality features” ).
Unspecified Personality Disorder
301.9 (F60.9)
This category applies to presentations in which symptoms characteristic of a personality  
the disorders in the personality disorders diagnostic class. The unspecified personality  

son that the criteria are not met for a specific personality disorder, and includes presenta­
tions in which there is insufficient information to make a more specific diagnosis.

ParapKilic 
Disorders
Psrsphilic disorders included in this manual are voyeuristic disorder (spying on 
others in private activities), exhibitionistic disorder (exposing the genitals), frotteuristic 
disorder (touching or rubbing against a nonconsenting individual), sexual masochism 
disorder (undergoing humiliation, bondage, or suffering), sexual sadism disorder (inflict­
ing humiliation, bondage, or suffering), pedophilic disorder (sexual focus on children), fe- 
tishistic disorder (using nonliving objects or having a highly specific focus on nongenital 
body parts), and transvestic disorder (engaging in sexually arousing cross-dressing). 
These disorders have traditionally been selected for specific listing and assignment of ex­
plicit diagnostic criteria in DSM for two main reasons: they are relatively common, in re­
lation to other paraphilic disorders, and some of them entail actions for their satisfaction

lation to other paraphilic disorders, and some of them entail actions for their satisfaction 
that, because of their noxiousness or potential harm to others, are classed as criminal of­
fenses. The eight listed disorders do not exhaust the list of possible paraphilic disorders. 
Many dozens of distinct paraphilias have been identified and named, and almost any of 
them could, by virtue of its negative consequences for the individual or for others, rise to 
the level of a paraphilic disorder. The diagnoses of the other specified and unspecified 
paraphilic disorders are therefore indispensable and will be required in many cases.
In this chapter, the order of presentation of the listed paraphilic disorders generally 
corresponds to common classification schemes for these conditions. The first group of 
disorders is based on anomalous activity preferences. These disorders are subdivided into

disorders is based on anomalous activity preferences. These disorders are subdivided into 
courtship disorders,  which resemble distorted components of human courtship behavior 
(voyeuristic disorder, exhibitionistic disorder, and frotteuristic disorder), and algolagnie  
disorders,  which involve pain and suffering (sexual masochism disorder and sexual sadism 
disorder). The second group of disorders is based on anomalous target preferences.  These 
disorders include one directed at other humans (pedophilic disorder) and two directed 
elsewhere (fetishistic disorder and transvestic disorder).
The term paraphilia denotes any intense and persistent sexual interest other than sexual 
interest in genital stimulation or preparatory fondling with phenotypically normal, phys­
ically mature, consenting human partners. In some circumstances, the criteria "intense

ically mature, consenting human partners. In some circumstances, the criteria "intense 
and persistent" may be difficult to apply, such as in the assessment of persons who are 
very old or medically ill and who may not have "intense" sexual interests of any kind. In 
such circumstances, the term paraphilia  may be defined as any sexual interest greater than 
or equal to normophilic sexual interests. There are also specific paraphilias that are gen­
erally better described as preferential  sexual interests than as intense sexual interests.
Some paraphilias primarily concern the individual's erotic activities, and others pri­
marily concern the individual's erotic targets. Examples of the former would include in­
tense and persistent interests in spanking, whipping, cutting, binding, or strangulating 
another person, or an interest in these activities that equals or exceeds the individual's in­

terest in copulation or equivalent interaction with another person. Examples of the latter 
would include intense or preferential sexual interest in children, corpses, or amputees (as 
a class), as well as intense or preferential interest in nonhuman animals, such as horses or 
dogs, or in inanimate objects, such as shoes or articles made of rubber.
A paraphilic disorder  is a paraphilia that is currently causing distress or impairment to the 
individual or a paraphilia whose satisfaction has entailed personal harm, or risk of harm, to

others. A paraphilia is a necessary but not a sufficient condition for having a paraphilic dis­
order, and a paraphilia by itself does not necessarily justify or require clinical intervention.
In the diagnostic criteria set for each of the listed paraphilic disorders. Criterion A specifies 
the qualitative nature of the paraphilia (e.g., an erotic focus on children or on exposing tiie gen­
itals to strangers), and Criterion B specifies the negative consequences of the paraphilia (i.e., 
distress, impairment, or harm to others). In keeping with the distinction between paraphilias 
and paraphilic disorders, the term diagnosis  should be reserved for individuals who meet both 
Criteria A and B (i.e., individuals who have a paraphilic disorder). If an individual meets Cri­
terion A but not Criterion B for a particular paraphilia—a circumstance that might arise when 
a benign paraphilia is discovered during the clinical investigation of some other condition—

a benign paraphilia is discovered during the clinical investigation of some other condition— 
then the individual may be said to have that paraphilia but not a paraphilic disorder.
It is not rare for an individual to manifest two or more paraphilias. In some cases, the para­
philic foci are closely related and the connection between the paraphilias is intuitively com­
prehensible (e.g., foot fetishism and shoe fetishism). In other cases, the connection between the 
paraphilias is not obvious, and the presence of multiple paraphilias may be coincidental or else 
related to some generalized vulnerability to anomalies of psychosexual development. In any 
event, comorbid diagnoses of separate paraphilic disorders may be warranted if more than 
one paraphilia is causing suffering to the individual or harm to others.

Because of the two-pronged nature of diagnosing paraphilic disorders, clinician-rated 
or self-rated measures and severity assessments could address either the strength of the 
paraphilia itself or the seriousness of its consequences. Although the distress and impair­
ment stipulated in the Criterion B are special in being the immediate or ultimate result of 
the paraphilia and not primarily the result of some other factor, the phenomena of reactive 
depression, anxiety, guilt, poor work history, impaired social relations, and so on are not 
unique in themselves and may be quantified with multipurpose measures of psychosocial 
functioning or quality of life.
The most widely applicable framework for assessing the strength of a paraphilia itself

The most widely applicable framework for assessing the strength of a paraphilia itself 
is one in which examinees' paraphilic sexual fantasies, urges, or behaviors are evaluated in 
relation to their normophilic sexual interests and behaviors. In a clinical interview or on 
self-administered questionnaires, examinees can be asked whether their paraphilic sexual 
fantasies, urges, or behaviors are weaker than, approximately equal to, or stronger than 
their normophilic sexual interests and behaviors. This same type of comparison can be, 
and usually is, employed in psychophysiological measures of sexual interest, such as pe­
nile plethysmography in males or viewing time in males and females.
Voyeuristic Disorder
Diagnostic Criteria 302.82 (F65.3)
A. Over a period of at least 6 months, recurrent and intense sexual arousal from observ­
ing an unsuspecting person who is naked, in the process of disrobing, or engaging in

ing an unsuspecting person who is naked, in the process of disrobing, or engaging in  
sexual activity, as manifested by fantasies, urges, or behaviors.
B. The individual has acted on these sexual urges with a nonconsenting person, or the  
sexual urges or fantasies cause clinically significant distress or impairment in social,  
occupational, or other important areas of functioning.
0. The individual experiencing the arousal and/or acting on the urges is at least 18 years  
of age.
In a controlled environment: This specifier is primarily applicable to individuals living  
in institutional or other settings where opportunities to engage in voyeuristic behavior  
are restricted.

In full remission: The individual lias not acted on the urges with a nonconsenting per­
son, and there has been no distress or impairment in social, occupational, or other ar­
eas of functioning, for at least 5 years while in an uncontrolled environment.
The "in full remission" specifier does not address the continued presence or absence of 
voyeurism per se, which may still be present after behaviors and distress have remitted.
The diagnostic criteria for voyeuristic disorder can apply both to individuals who more or less 
freely disclose this paraphilic interest and to those who categorically deny any sexual arousal 
from observing an unsuspecting person who is naked, disrobing, or engaged in sexual activity 
despite substantial objective evidence to the contrary. If disclosing individuals also report dis­
tress or psychosocial problems because of their voyeuristic sexual preferences, they could be

tress or psychosocial problems because of their voyeuristic sexual preferences, they could be 
diagnosed with voyeuristic disorder. On the other hand, if they declare no distress, demon­
strated by lack of anxiety, obsessions, guilt, or shame, about these paraphilic impulses and are 
not impaired in other important areas of functioning because of tids sexual interest, and their 
psychiatric or legal histories indicate that they do not act on it, they could be ascertained as 
having voyeuristic sexual interest but should not be diagnosed with voyeuristic disorder.
Nondisclosing individuals include, for example, individuals known to have been spy­
ing repeatedly on unsuspecting persons who are naked or engaging in sexual activity on 
separate occasions but who deny any urges or fantasies concerning such sexual behavior,

separate occasions but who deny any urges or fantasies concerning such sexual behavior, 
and who may report that known episodes of watching unsuspecting naked or sexually ac­
tive persons were all accidental and nonsexual. Others may disclose past episodes of ob­
serving unsuspecting naked or sexually active persons but contest any significant or 
sustained sexual interest in this behavior. Since these individuals deny having fantasies or 
impulses about watching others nude or involved in sexual activity, it follows that they 
would also reject feeling subjectively distressed or socially impaired by such impulses. De­
spite their nondisclosing stance, such individuals may be diagnosed with voyeuristic dis­
order. Recurrent voyeuristic behavior constitutes sufficient support for voyeurism (by 
fulfilling Criterion A) and simultaneously demonstrates that this paraphilically motivated

fulfilling Criterion A) and simultaneously demonstrates that this paraphilically motivated 
behavior is causing harm to others (by fulfilling Criterion B).
"Recurrent" spying on unsuspecting persons who are naked or engaging in sexual ac­
tivity (i.e., multiple victims, each on a separate occasion) may, as a general rule, be inter­
preted as three or more victims on separate occasions. Fewer victims can be interpreted as 
satisfying this criterion if there were multiple occasions of watching the same victim or if 
there is corroborating evidence of a distinct or preferential interest in secret watching of 
naked or sexually active unsuspecting persons. Note that multiple victims, as suggested 
earlier, are a sufficient but not a necessary condition for diagnosis; the criteria may also be 
met if the individual acknowledges intense voyeuristic sexual interest.

The Criterion A time frame, indicating that signs or symptoms of voyeurism must have 
persisted for at least 6 months, should also be understood as a general guideline, not a 
strict threshold, to ensure that the sexual interest in secretly watching unsuspecting naked 
or sexually active others is not merely transient.
Adolescence and puberty generally increase sexual curiosity and activity. To alleviate 
the risk of pathologizing normative sexual interest and behavior during pubertal adoles­
cence, the minimum age for the diagnosis of voyeuristic disorder is 18 years (Criterion C).
Voyeuristic acts are the most common of potentially law-breaking sexual behaviors. The 
population prevalence of voyeuristic disorder is unknown. However, based on voyeuris­

tic sexual acts in nonclinical samples, the highest possible lifetime prevalence for voyeuris­
tic disorder is approximately 12% in males and 4% in females.
Adult males with voyeuristic disorder often first become aware of their sexual interest in 
secretly watching unsuspecting persons during adolescence. However, the minimum age 
for a diagnosis of voyeuristic disorder is 18 years because there is substantial difficulty in 
differentiating it from age-appropriate puberty-related sexual curiosity and activity. The 
persistence of voyeurism over time is unclear. Voyeuristic disorder, however, per defini­
tion requires one or more contributing factors that may change over time with or without 
treatment: subjective distress (e.g., guilt, shame, intense sexual frustration, loneliness), 
psychiatric morbidity, hypersexuality, and sexual impulsivity; psychosocial impairment; 
and/or the propensity to act out sexually by spying on unsuspecting naked or sexually ac­

tive persons. Therefore, the course of voyeuristic disorder is likely to vary with age.
Iemperamental. Voyeurism is a necessary precondition for voyeuristic disorder; hence, 
risk factors for voyeurism should also increase the rate of voyeuristic disorder.
Environmental. Childhood sexual abuse, substance misuse, and sexual preoccupation/ 
hypersexuality have been suggested as risk factors, although the causal relationship to 
voyeurism is uncertain and the specificity unclear.
Voyeuristic disorder is very uncommon among females in clinical settings, while the male- 
to-female ratio for single sexually arousing voyeuristic acts might be 3:1.
Conduct disorder and antisocial personality disorder. Conduct disorder in adolescents

Conduct disorder and antisocial personality disorder. Conduct disorder in adolescents 
and antisocial personality disorder would be characterized by additional norm-breaking 
and antisocial behaviors, and the specific sexual interest in secretly watching unsuspect­
ing others who are naked or engaging in sexual activity should be lacking.
Substance use disorders. Substance use disorders might involve single voyeuristic ep­
isodes by intoxicated individuals but should not involve the typical sexual interest in se­
cretly watching unsuspecting persons being naked or engaging in sexual activity. Hence, 
recurrent voyeuristic sexual fantasies, urges, or behaviors that occur also when the indi­
vidual is not intoxicated suggest that voyeuristic disorder might be present.
Known comorbidities in voyeuristic disorder are largely based on research with males

Known comorbidities in voyeuristic disorder are largely based on research with males 
suspected of or convicted for acts involving the secret watching of unsuspecting nude or 
sexually active persons. Hence, these comorbidities might not apply to all individuals with 
voyeuristic disorder. Conditions that occur comorbidly with voyeuristic disorder include 
hypersexuality and other paraphilic disorders, particularly exhibitionistic disorder. De­
pressive, bipolar, anxiety, and substance use disorders; attention-deficit/hyperactivity 
disorder; and conduct disorder and antisocial personality disorder are also frequent co- 
morbid conditions.

Exhibitionistic Disorder
Diagnostic Criteria 302.4 (F65.2)
A. Over a period of at least 6 months, recurrent and intense sexual arousal from the ex­
posure of one’s genitals to an unsuspecting person, as manifested by fantasies, urges,  
or behaviors.
Sexually aroused by exposing genitals to prepubertal children  
Sexually aroused by exposing genitals to physically mature individuals  
Sexually aroused by exposing genitals to prepubertal children and to physically  
mature individuals
In a controlled environment: This specifier is primarily applicable to individuals living in  
institutional or other settings where opportunities to expose one’s genitals are restricted.

institutional or other settings where opportunities to expose one’s genitals are restricted.  
In full remission: The individual has not acted on the urges with a nonconsenting per­
Subtypes
The subtypes for exhibitionistic disorder are based on the age or physical maturity of the non­
consenting individuals to whom the individual prefers to expose his or her genitals. The non­
consenting individuals could be prepubescent children, adults, or both. This specifier should 
help draw adequate attention to characteristics of victims of individuals with exhibitionistic 
disorder to prevent co-occurring pedophilic disorder from being overlooked. However, indi­

cations that the individual with exhibitionistic disorder is sexually attracted to exposing his or 
her genitals to children should not preclude a diagnosis of pedophilic disorder.
The "in full remission" specifier does not address the continued presence or absence of ex­
hibitionism per se, which may still be present after behaviors and distress have remitted.
The diagnostic criteria for exhibitionistic disorder can apply both to individuals who more or 
less freely disclose this paraphilia and to those who categorically deny any sexual attraction to 
exposing their genitals to unsuspecting persons despite substantial objective evidence to the 
contrary. If disclosing individuals also report psychosocial difficulties because of their sexual

contrary. If disclosing individuals also report psychosocial difficulties because of their sexual 
attractions or preferences for exposing, they may be diagnosed with exhibitionistic disorder. In 
contrast, if they declare no distress (exemplified by absence of anxiety, obsessions, and guilt or 
shame about these paraphilic impulses) and are not impaired by this sexual interest in other 
important areas of functioning, and their self-reported, psychiatric, or legal histories indicate 
that they do not act on them, they could be ascertained as having exhibitionistic sexual interest 
but not be diagnosed with exhibitionistic disorder.
Examples of nondisclosing individuals include those who have exposed themselves 
repeatedly to unsuspecting persons on separate occasions but who deny any urges or fan­

tasies about such sexual behavior and who report that known episodes of exposure were 
all accidental and nonsexual. Others may disclose past episodes of sexual behavior involv­
ing genital exposure but refute any significant or sustained sexual interest in such behav­
ior. Since these individuals deny having urges or fantasies involving genital exposure, it 
follows that they would also deny feeling subjectively distressed or socially impaired by 
such impulses. Such individuals may be diagnosed with exhibitionistic disorder despite 
their negative self-report. Recurrent exhibitionistic behavior constitutes sufficient support 
for exhibitionism (Criterion A) and simultaneously demonstrates that this paraphilically 
motivated behavior is causing harm to others (Criterion B).
"Recurrent" genital exposure to unsuspecting others (i.e., multiple victims, each on a 
separate occasion) may, as a general rule, be interpreted as three or more victims on sep­

arate occasions. Fewer victims can be interpreted as satisfying this criterion if there were 
multiple occasions of exposure to the same victim, or if there is corroborating evidence of 
a strong or preferential interest in genital exposure to unsuspecting persons. Note that 
multiple victims, as suggested earlier, are a sufficient but not a necessary condition for di­
agnosis, as criteria may be met by an individual's acknowledging intense exhibitionistic 
sexual interest with distress and/or impairment.
The Criterion A time frame, indicating that signs or symptoms of exhibitionism must 
have persisted for at least 6 months, should also be understood as a general guideline, not 
a strict threshold, to ensure that the sexual interest in exposing one's genitals to unsuspect­

ing others is not merely transient. This might be expressed in clear evidence of repeated 
behaviors or distress over a nontransient period shorter than 6 months.
The prevalence of exhibitionistic disorder is unknown. However, based on exhibitionistic 
sexual acts in nonclinical or general populations, the highest possible prevalence for exhi­
bitionistic disorder in the male population is 2%-4%. The prevalence of exhibitionistic dis­
order in females is even more uncertain but is generally believed to be much lower than in 
males.
Adult males with exhibitionistic disorder often report that they first became aware of sex­
ual interest in exposing their genitals to unsuspecting persons during adolescence, at a

ual interest in exposing their genitals to unsuspecting persons during adolescence, at a 
somewhat later time than the typical development of normative sexual interest in women 
or men. Although there is no minimum age requirement for the diagnosis of exhibitionis­
tic disorder, it may be difficult to differentiate exhibitionistic behaviors from age-appro­
priate sexual curiosity in adolescents. Whereas exhibitionistic impulses appear to emerge 
in adolescence or early adulthood, very little is known about persistence over time. By def­
inition, exhibitionistic disorder requires one or more contributing factors, which may 
change over time with or without treatment; subjective distress (e.g., guilt, shame, intense 
sexual frustration, loneliness), mental disorder comorbidity, hypersexuality, and sexual 
impulsivity; psychosocial impairment; and/or the propensity to act out sexually by expos­

ing the genitals to unsuspecting persons. Therefore, the course of exhibitionistic disorder 
is likely to vary with age. As with other sexual preferences, advancing age may be associ­
ated with decreasing exhibitionistic sexual preferences and behavior.
Temperamental. Since exhibitionism is a necessary precondition for exhibitionistic dis­
order, risk factors for exhibitionism should also increase the rate of exhibitionistic disor­
der. Antisocial history, antisocial personality disorder, alcohol misuse, and pedophilic 
sexual preference might increase risk of sexual recidivism in exhibitionistic offenders.

Hence, antisocial personality disorder, alcohol use disorder, and pedophilic interest may 
be considered ri^k factors for exhibitionistic disorder in males with exhibitionistic sexual 
preferences.
Environmental. Childhood sexual and emotional abuse and sexual preoccupation/hyper­
sexuality have been suggested as risk factors for exhibitionism, although the causal rela­
tionship to exhibitionism is uncertain and the specificity unclear.
Exhibitionistic disorder is highly unusual in females, whereas single sexually arousing ex­
hibitionistic acts might occur up to half as often among women compared with men.
Functionai Consequences of Exiiibitionistic Disorder
The functional consequences of exhibitionistic disorder have not been addressed in re­
search involving individuals who have not acted out sexually by exposing their genitals to 
unsuspecting strangers but who fulfill Criterion B by experiencing intense emotional dis­
tress over these preferences.

Potential differential diagnoses for exhibitionistic disorder sometimes occur also as co- 
morbid disorders. Therefore, it is generally necessary to evaluate the evidence for exhibi­
tionistic disorder and other possible conditions as separate questions.
and antisocial personality disorder would be characterized by additional norm-breaking and 
antisocial behaviors, and the specific sexual interest in exposing the genitals should be lacking.
Substance use disorders. Alcohol and substance use disorders might involve single 
exhibitionistic episodes by intoxicated individuals but should not involve the typical sex­
ual interest in exposing the genitals to unsuspecting persons. Hence, recurrent exhibition­

istic sexual fantasies, urges, or behaviors that occur also when the individual is not 
intoxicated suggest that exhibitionistic disorder might be present.
Known comorbidities in exhibitionistic disorder are largely based on research with indi­
viduals (almost all males) convicted for criminal acts involving genital exposure to non­
consenting individuals. Hence, these comorbidities might not apply to all individuals who 
qualify for a diagnosis of exhibitionistic disorder. Conditions that occur comorbidly with 
exhibitionistic disorder at high rates include depressive, bipolar, anxiety, and substance 
use disorders; hypersexuality; attention-deficit/hyperactivity disorder; other paraphilic 
disorders; and antisocial personality disorder.
Frotteuristic Disorder

Diagnostic Criteria 302.89 (F65.81)
A. Over a period of at least 6 months, recurrent and intense sexual arousal from touching  
or rubbing against a nonconsenting person, as manifested by fantasies, urges, or be­
haviors.

in institutional or other settings where opportunities to touch or rub against a noncon­
senting person are restricted.
The "in remission" specifier does not address the continued presence or absence of frot- 
teurism per se, which may still be present after behaviors and distress have remitted.
The diagnostic criteria for frotteuristic disorder can apply both to individuals who relatively 
freely disclose this paraphilia and to those who firmly deny any sexual attraction from touch­
ing or rubbing against a nonconsenting individual regardless of considerable objective evi­

dence to the contrary. If disclosing individuals also report psychosocial impairment due to 
their sexual preferences for touching or rubbing against a nonconsenting individual, they 
could be diagnosed with frotteuristic disorder. In contrast, if they declare no distress (demon­
strated by lack of anxiety, obsessions, guilt, or shame) about these paraphilic impulses and are 
not impaired in other important areas of functioning because of this sexual interest, and their 
having frotteuristic sexual interest but should not be diagnosed with frotteuristic disorder.
Nondisclosing individuals include, for instance, individuals known to have been

Nondisclosing individuals include, for instance, individuals known to have been 
touching or rubbing against nonconsenting individuals on separate occasions but who 
contest any urges or fantasies concerning such sexual behavior. Such individuals may re­
port that identified episodes of touching or rubbing against an unwilling individual were 
all unintentional and nonsexual. Others may disclose past episodes of touching or rubbing 
against nonconsenting individuals but contest any major or persistent sexual interest in 
this. Since these individuals deny having fantasies or impulses about touching or rubbing, 
they would consequently reject feeling distressed or psychosocially impaired by such 
impulses. Despite their nondisclosing position, such individuals may be diagnosed with 
frotteuristic disorder. Recurrent  frotteuristic behavior constitutes satisfactory support for

frotteuristic disorder. Recurrent  frotteuristic behavior constitutes satisfactory support for 
frotteurism (by fulfilling Criterion A) and concurrently demonstrates that this paraphili- 
cally motivated behavior is causing harm to others (by fulfilling Criterion B).
"Recurrent" touching or rubbing against a nonconsenting individual (i.e., multiple vic­
tims, each on a separate occasion) may, as a general rule, be inteφreted as three or more vic­
tims on separate occasions. Fewer victims can be inteφreted as satisfying this criterion if 
there were multiple occasions of touching or rubbing against the same unwilling individ­
ual, or corroborating evidence of a strong or preferential interest in touching or rubbing 
against nonconsenting individuals. Note that multiple victims are a sufficient but not a nec­
essary condition for diagnosis; criteria may also be met if the individual acknowledges in­

tense frotteuristic sexual interest with clinically significant distress and/or impairment.
The Criterion A time frame, indicating that signs or symptoms of frotteurism must persist 
for at least 6 months, should also be inteφreted as a general guideline, not a strict threshold, to 
ensure that the sexual interest in touching or rubbing against a nonconsenting individual is not 
transient. Hence, the duration part of Criterion A may also be met if there is clear evidence of 
recurrent behaviors or distress over a shorter but nontransient time period.
Frotteuristic acts, including the uninvited sexual touching of or rubbing against another 
individual, may occur in up to 30% of adult males in the general population. Approximately

10%-14% of adult males seen in outpatient settings for paraphilic disorders and hypersex­
uality have a presentation that meets diagnostic criteria for frotteuristic disorder. Hence, 
whereas the population prevalence of frotteuristic disorder  is unknown, it is not likely that 
it exceeds the rate found in selected clinical settings.
Adult males with frotteuristic disorder often report first becoming aware of their sexual in­
terest in surreptitiously touching unsuspecting persons during late adolescence or emerging 
adulthood. However, children and adolescents may also touch or rub against unwilling oth­
ers in the absence of a diagnosis of frotteuristic disorder. Although there is no minimum age 
for the diagnosis, frotteuristic disorder can be difficult to differentiate from conduct-disor­
dered behavior without sexual motivation in individuals at younger ages. The persistence of

dered behavior without sexual motivation in individuals at younger ages. The persistence of 
frotteurism over time is unclear. Frotteuristic disorder, however, by definition requires one 
or more contributing factors that may change over time with or without treatment: subjec­
tive distress (e.g., guilt, shame, intense sexual frustration, loneliness); psychiatric morbidity; 
hypersexuality and sexual impulsivity; psychosocial impairment; and/or the propensity to 
act out sexually by touching or rubbing against unconsenting persons. Therefore, the course 
of frotteuristic disorder is likely to vary with age. As with other sexual preferences, advanc­
ing age may be associated with decreasing frotteuristic sexual preferences and behavior.
Temperamental. Nonsexual antisocial behavior and sexual preoccupation/hypersexuality

Temperamental. Nonsexual antisocial behavior and sexual preoccupation/hypersexuality 
might be nonspecific risk factors, although the causal relationship to frotteurism is uncertain 
and the specificity unclear. However, frotteurism is a necessary precondition for frotteuristic 
disorder, so risk factors for frotteurism should also increase the rate of frotteuristic disorder.
There appear to be substantially fewer females with frotteuristic sexual preferences than 
males.
and antisocial behaviors, and the specific sexual interest in touching or rubbing against a 
nonconsenting individual should be lacking.
Substance use disorders. Substance use disorders, particularly those involving stimu­

lants such as cocaine and amphetamines, might involve single frotteuristic episodes by in­
toxicated individuals but should not involve the typical sustained sexual interest in 
touching or rubbing against unsuspecting persons. Hence, recurrent frotteuristic sexual 
fantasies, urges, or behaviors that occur also when the individual is not intoxicated sug­
gest that frotteuristic disorder might be present.
Known comorbidities in frotteuristic disorder are largely based on research with males 
suspected of or convicted for criminal acts involving sexually motivated touching of or 
rubbing against a nonconsenting individual. Hence, these comorbidities might not apply 
to other individuals with a diagnosis of frotteuristic disorder based on subjective distress

to other individuals with a diagnosis of frotteuristic disorder based on subjective distress 
over their sexual interest. Conditions that occur comorbidly with frotteuristic disorder in­
clude hypersexuality and other paraphilic disorders, particularly exhibitionistic disorder 
and voyeuristic disorder. Conduct disorder, antisocial personality disorder, depressive

disorders, bipolar disorders, anxiety disorders, and substance use disorders also co-occur. 
Potential differential diagnoses for frotteuristic disorder sometimes occur also as comor- 
bid disorders. Therefore, it is generally necessary to evaluate the evidence for frotteuristic 
disorder and possible comorbid conditions as separate questions.
Sexual Masochism Disorder
Diagnostic Criteria 302.83 (F65.51)
A. Over a period of at least 6 months, recurrent and intense sexual arousal from the act  
of being humiliated, beaten, bound, or othenwise made to suffer, as manifested by fan­
tasies, urges, or behaviors.
B. The fantasies, sexual urges, or behaviors cause clinically significant distress or impair­
With asphyxiophilia: If the individual engages in the practice of achieving sexual  
arousal related to restriction of breathing.

in institutional or other settings where opportunities to engage in masochistic sexual  
behaviors are restricted.
In full remission: There has been no distress or impairment in social, occupational,  
or other areas of functioning for at last 5 years while in an uncontrolled environment.
The diagnostic criteria for sexual masochism disorder are intended to apply to individuals 
who freely admit to having such paraphilic interests. Such individuals openly acknowl­
edge intense sexual arousal from the act of being humiliated, beaten, bound, or otherwise 
made to suffer, as manifested by fantasies, urges, or behaviors. If these individuals also re­

port psychosocial difficulties because of their sexual attractions or preferences for being 
humiliated, beaten, bound, or otherwise made to suffer, they may be diagnosed with sex­
ual masochism disorder. In contrast, if they declare no distress, exemplified by anxiety, ob­
sessions, guilt, or shame, about these paraphilic impulses, and are not hampered by them 
in pursuing other personal goals, they could be ascertained as having masochistic sexual 
interest but should not be diagnosed with sexual masochism disorder.
The Criterion A time frame, indicating that the signs or symptoms of sexual masoch­
ism must have persisted for at least 6 months, should be understood as a general guideline, 
not a strict threshold, to ensure that the sexual interest in being humiliated, beaten, bound,

not a strict threshold, to ensure that the sexual interest in being humiliated, beaten, bound, 
or otherwise made to suffer is not merely transient. However, the disorder can be diag­
nosed in the context of a clearly sustained but shorter time period.
The extensive use of pornography involving the act of being humiliated, beaten, bound, or oth­
erwise made to suffer is sometimes an associated feature of sexual masochism disorder.
The population prevalence of sexual masochism disorder is unknown. In Australia, it has 
been estimated that 2.2% of males and 1.3% of females had been involved in bondage and 
discipline, sadomasochism, or dominance and submission in the past 12 months.

Community individuals with paraphilias have reported a mean age at onset for masoch­
ism of 19.3 years, although earlier ages, including puberty and childhood, have also been 
reported for the onset of masochistic fantasies. Very little is known about persistence over 
time. Sexual masochism disorder per definition requires one or more contributing factors, 
which may change over time with or without treatment. These include subjective distress 
(e.g., guilt, shame, intense sexual frustration, loneliness), psychiatric morbidity, hypersex­
uality and sexual impulsivity, and psychosocial impairment. Therefore, the course of sex­
ual masochism disorder is likely to vary with age. Advancing age is likely to have the same 
reducing effect on sexual preference involving sexual masochism as it has on other para- 
philic or normophilic sexual behavior.
Functional Consequences of Sexual Masochism Disorder

The functional consequences of sexual masochism disorder are unknown. However, mas- 
ochists are at risk of accidental death while practicing asphyxiophilia or other autoerotic 
procedures.
Many of the conditions that could be differential diagnoses for sexual masochism disorder 
(e.g., transvestic fetishism, sexual sadism disorder, hypersexuality, alcohol and substance 
use disorders) sometimes occur also as comorbid diagnoses. Therefore, it is necessary to 
carefully evaluate the evidence for sexual masochism disorder, keeping the possibility of 
other paraphilias or other mental disorders as part of the differential diagnosis. Sexual 
masochism in the absence of distress (i.e., no disorder) is also included in the differential,

masochism in the absence of distress (i.e., no disorder) is also included in the differential, 
as individuals who conduct the behaviors may be satisfied with their masochistic orienta­
tion.
Known comorbidities with sexual masochism disorder are largely based on individuals in 
treatment. Disorders that occur comorbidly with sexual masochism disorder typically in­
clude other paraphilic disorders, such as transvestic fetishism.
Sexual Sadism Disorder
Diagnostic Criteria 302.84 (F65.52)
A. Over a period of at least 6 months, recurrent and intense sexual arousal from the phys­
ical or psychological suffering of another person, as manifested by fantasies, urges, or  
behaviors.
sexual urges or fantasies cause clinically significant distress or impairment in social,

in  institutional or other settings where opportunities to engage in sadistic sexual behav­
iors are restricted.
eas of functioning, for at least 5 years while in  an uncontrolled environment.

The diagnostic criteria for sexual sadism disorder are intended to apply both to individuals 
who freely admit to having such paraphilic interests and to those who deny any sexual interest 
in the physical or psychological suffering of another individual despite substantial objective 
evidence to the contrary. Individuals who openly acknowledge intense sexual interest in the 
physical or psychological suffering of others are referred to as "admitting individuals." If these 
individuals also report psychosocial difficulties because of their sexual attractions or prefer­
ences for the physical or psychological suffering of another individual, they may be diagnosed 
with sexual sadism disorder. In contrast, if admitting individuals declare no distress, exempli­
fied by anxiety, obsessions, guilt, or shame, about these paraphilic impulses, and are not ham­
pered by them in pursuing other goals, and their self-reported, psychiatric, or legal histories

pered by them in pursuing other goals, and their self-reported, psychiatric, or legal histories 
indicate that they do not act on them, then they could be ascertained as having sadistic sexual 
interest but they would not meet criteria for sexual sadism disorder.
Examples of individuals who deny any interest in the physical or psychological suffering 
of another individual include individuals known to have inflicted pain or suffering on mul­
tiple victims on separate occasions but who deny any urges or fantasies about such sexual 
behavior and who may further claim that known episodes of sexual assault were either un­
intentional or nonsexual. Others may admit past episodes of sexual behavior involving the 
infliction of pain or suffering on a nonconsenting individual but do not report any significant

infliction of pain or suffering on a nonconsenting individual but do not report any significant 
or sustained sexual interest in the physical or psychological suffering of another individual. 
Since these individuals deny having urges or fantasies involving sexual arousal to pain and 
suffering, it follows that they would also deny feeling subjectively distressed or socially im­
paired by such impulses. Such individuals may be diagnosed with sexual sadism disorder 
despite their negative self-report. Their recurrent behavior constitutes clinical support for 
the presence of the paraphilia of sexual sadism (by satisfying Criterion A) and simultane­
ously demonstrates that their paraphilically motivated behavior is causing clinically signif­
icant distress, harm, or risk of harm to others (satisfying Criterion B).

"Recurrent" sexual sadism involving nonconsenting others (i.e., multiple victims, each 
on a separate occasion) may, as general rule, be interpreted as three or more victims on 
separate occasions. Fewer victims can be interpreted as satisfying this criterion, if there are 
multiple instances of infliction of pain and suffering to the same victim, or if there is cor­
roborating evidence of a strong or preferential interest in pain and suffering involving 
multiple victims. Note that multiple victims, as suggested earlier, are a sufficient but not 
a necessary condition for diagnosis, as the criteria may be met if the individual acknowl­
edges intense sadistic sexual interest.
The Criterion A time frame, indicating that the signs or symptoms of sexual sadism

The Criterion A time frame, indicating that the signs or symptoms of sexual sadism 
must have persisted for at least 6 months, should also be understood as a general guide­
line, not a strict threshold, to ensure that the sexual interest in inflicting pain and suffering 
on nonconsenting victims is not merely transient. However, the diagnosis may be met if 
there is a clearly sustained but shorter period of sadistic behaviors.
The extensive use of pornography involving the infliction of pain and suffering is some­
times an associated feature of sexual sadism disorder.
The population prevalence of sexual sadism disorder is unknown and is largely based on 
individuals in forensic settings. Depending on the criteria for sexual sadism, prevalence 
varies widely, from 2% to 30%. Among civilly committed sexual offenders in the United

varies widely, from 2% to 30%. Among civilly committed sexual offenders in the United 
States, less than 10% have sexual sadism. Among individuals who have committed sexu­
ally motivated homicides, rates of sexual sadism disorder range from 37% to 75%.

Individuals with sexual sadism in forensic samples are almost exclusively male, but a rep­
resentative sample of the population in Australia reported that 2.2% of men and 1.3% of 
women said they had been involved in bondage and discipline, "sadomasochism," or dom­
inance and submission in the previous year. Information on the development and course 
of sexual sadism disorder is extremely limited. One study reported that females became 
aware of their sadomasochistic orientation as young adults, and another reported that the 
mean age at onset of sadism in a group of males was 19.4 years. Whereas sexual sadism per 
se is probably a lifelong characteristic, sexual sadism disorder may fluctuate according to 
the individual's subjective distress or his or her propensity to harm nonconsenting others. 
Advancing age is likely to have the same reducing effect on this disorder as it has on other 
paraphilic or normophilic sexual behavior.

Many of the conditions that could be differential diagnoses for sexual sadism disorder 
(e.g., antisocial personality disorder, sexual masochism disorder, hypersexuality, sub­
stance use disorders) sometimes occur also as comorbid diagnoses. Therefore, it is neces­
sary to carefully evaluate the evidence for sexual sadism disorder, keeping the possibility 
of other paraphilias or mental disorders as part of the differential diagnosis. The majority 
of individuals who are active in community networks that practice sadistic and masoch­
istic behaviors do not express any dissatisfaction with their sexual interests, and their be­
havior would not meet DSM-5 criteria for sexual sadism disorder. Sadistic interest, but not 
the disorder, may be considered in the differential diagnosis.

Known comorbidities with sexual sadism disorder are largely based on individuals (al­
most all males) convicted for criminal acts involving sadistic acts against nonconsenting 
victims. Hence, these comorbidities might not apply to all individuals who never engaged 
in sadistic activity with a nonconsenting victim but who qualify for a diagnosis of sexual 
sadism disorder based on subjective distress over their sexual interest. Disorders that are 
commonly comorbid with sexual sadism disorder include other paraphilic disorders.
Pedophilic Disorder
Diagnostic Criteria 302.2 (F65.4)
A. Over a period of at least 6 months, recurrent, intense sexually arousing fantasies, sex­
ual urges, or behaviors involving sexual activity with a prepubescent child or children  
(generally age 13 years or younger).

B. The individual has acted on these sexual urges, or the sexual urges or fantasies cause  
marked distress or interpersonal difficulty.
C. The individual is at least age 16 years and at least 5 years older than the child or chil­
dren in Criterion A.
Note: Do not include an individual in  late adolescence involved in an ongoing sexual  
relationship with a 12- or 13-year-old.
Exclusive type (attracted only to children)
Nonexclusive type

Sexually attracted to males  
Sexually attracted to females  
Sexually attracted to both
Limited to incest
The diagnostic criteria for pedophilic disorder are intended to apply both to individuals who 
freely disclose this paraphilia and to individuals who deny any sexual attraction to prepuber­
tal children (generally age 13 years or younger), despite substantial objective evidence to the 
contrary. Examples of disclosing this paraphilia include candidly acknowledging an intense 
sexual interest in children and indicating that sexual interest in children is greater than or equal 
to sexual interest in physically mature individuals. If individuals also complain that their sex­
ual attractions or preferences for children are causing psychosocial difficulties, they may be di­
agnosed with pedophilic disorder. However, if they report an absence of feelings of guilt,

agnosed with pedophilic disorder. However, if they report an absence of feelings of guilt, 
shame, or anxiety about these impulses and are not functionally limited by their paraphilic im­
pulses (according to self-report, objective assessment, or both), and their self-reported and le­
gally recorded histories indicate that they have never acted on their impulses, then these 
individuals have a pedophilic sexual orientation but not pedophilic disorder.
Examples of individuals who deny attraction to children include individuals who are 
known to have sexually approached multiple children on separate occasions but who deny 
any urges or fantasies about sexual behavior involving children, and who may further claim 
that the known episodes of physical contact were all unintentional and nonsexual. Other indi­

viduals may acknowledge past episodes of sexual behavior involving children but deny any 
significant or sustained sexual interest in children. Since these individuals may deny experi­
ences impulses or fantasies involving children, they may also deny feeling subjectively dis­
tressed. Such individuals may still be diagnosed with pedophilic disorder despite the absence 
of self-reported distress, provided that there is evidence of recurrent behaviors persisting for 
6 months (Criterion A) and evidence that the individual has acted on sexual urges or experi­
enced interpersonal difficulties as a consequence of the disorder (Criterion B).
Presence of multiple victims, as discussed above, is sufficient but not necessary for di­

agnosis; that is, the individual can still meet Criterion A by merely acknowledging intense 
or preferential sexual interest in children.
The Criterion A clause, indicating that the signs or symptoms of pedophilia have per­
sisted for 6 months or longer, is intended to ensure that the sexual attraction to children is 
not merely transient. However, the diagnosis may be made if there is clinical evidence of 
sustained persistence of the sexual attraction to children even if the 6-month duration can­
not be precisely determined.
The extensive use of pornography depicting prepubescent children is a useful diagnostic 
indicator of pedophilic disorder. This is a specific instance of the general case that individ­

uals are likely to choose the kind of pornography that corresponds to their sexual interests.
The population prevalence of pedophilic disorder is unknown. The highest possible prev­
alence for pedophilic disorder in the male population is approximately 3%-5%. The pop­
ulation prevalence of pedophilic disorder in females is even more uncertain, but it is likely 
a small fraction of the prevalence in males.

Adult males \νιψ pedophilic disorder may indicate that they become aware of strong or 
preferential sexual interest in children around the time of puberty—the same time frame 
in which males who later prefer physically mature partners became aware of their sexual 
interest in women or men. Attempting to diagnose pedophilic disorder at the age at which 
it first manifests is problematic because of the difficulty during adolescent development in 
differentiating it from age-appropriate sexual interest in peers or from sexual curiosity. 
Hence, Criterion C requires for diagnosis a minimum age of 16 years and at least 5 years 
older than the child or children in Criterion A.
Pedophilia per se appears to be a lifelong condition. Pedophilic disorder, however, 
necessarily includes other elements that may change over time with or without treatment: 
subjective distress (e.g., guilt, shame, intense sexual frustration, or feelings of isolation) or

subjective distress (e.g., guilt, shame, intense sexual frustration, or feelings of isolation) or 
psychosocial impairment, or the propensity to act out sexually with children, or both. 
Therefore, the course of pedophilic disorder may fluctuate, increase, or decrease with age.
Adults with pedophilic disorder may report an awareness of sexual interest in children 
that preceded engaging in sexual behavior involving children or self-identification as a pedo­
phile. Advanced age is as likely to similarly diminish the frequency of sexual behavior involv­
ing children as it does other paraphilically motivated and normophilic sexual behavior.
Temperamental. There appears to be an interaction between pedophilia and antisocial­
ity, such that males with both traits are more likely to act out sexually with children. Thus,

ity, such that males with both traits are more likely to act out sexually with children. Thus, 
antisocial personality disorder may be considered a risk factor for pedophilic disorder in 
males with pedophilia.
Environmental. Adult males with pedophilia often report that they were sexually abused 
as children. It is unclear, however, whether this correlation reflects a causal influence of 
childhood sexual abuse on adult pedophilia.
Genetic and physiological. Since pedophilia is a necessary condition for pedophilic dis­
order, any factor that increases the probability of pedophilia also increases the risk of pe­
dophilic disorder. There is some evidence that neurodevelopmental perturbation in utero 
increases the probability of development of a pedophilic orientation.
Psychophysiological laboratory measures of sexual interest, which are sometimes useful in di­

agnosing pedophilic disorder in males, are not necessarily useful in diagnosing this disorder in 
females, even when an identical procedure (e.g., viewing time) or analogous procedures (e.g., 
penile plethysmography and vaginal photoplethysmography) are available.
Psychophysiological measures of sexual interest may sometimes be useful when an indi­
vidual's history suggests the possible presence of pedophilic disorder but the individual 
denies strong or preferential attraction to children. The most thoroughly researched and 
longest used of such measures is penile plethysmography,  although the sensitivity and spec­
ificity of diagnosis may vary from one site to another. Viewing time,  using photographs of

ificity of diagnosis may vary from one site to another. Viewing time,  using photographs of 
nude or minimally clothed persons as visual stimuli, is also used to diagnose pedophilic 
disorder, especially in combination with self-report measures. Mental health professionals 
in the United States, however, should be aware that possession of such visual stimuli, even 
for diagnostic purposes, may violate American law regarding possession of child pornog­
raphy and leave the mental health professional susceptible to criminal prosecution.

Many of the conditions that could be differential diagnoses for pedophilic disorder also 
sometimes occur as comorbid diagnoses. It is therefore generally necessary to evaluate the 
evidence for pedophilic disorder and other possible conditions as separate questions.
Antisocial personality disorder. This disorder increases the likelihood that a person who 
is primarily attracted to the mature physique will approach a child, on one or a few occa­
sions, on the basis of relative availability. The individual often shows other signs of this 
personality disorder, such as recurrent law-breaking.
Alcohol and substance use disorders. The disinhibiting effects of intoxication may also 
increase the likelihood that a person who is primarily attracted to the mature physique will 
sexually approach a child.
Obsessive-compulsive disorder. There are occasional individuals who complain about

Obsessive-compulsive disorder. There are occasional individuals who complain about 
ego-dystonic thoughts and worries about possible attraction to children. Clinical inter­
viewing usually reveals an absence of sexual thoughts about children during high states of 
sexual arousal (e.g., approaching orgasm during masturbation) and sometimes additional 
ego-dystonic, intrusive sexual ideas (e.g., concerns about homosexuality).
Psychiatric comorbidity of pedophilic disorder includes substance use disorders; depres­
sive, bipolar, and anxiety disorders; antisocial personality disorder; and other paraphilic 
disorders. However, findings on comorbid disorders are largely among individuals con­
victed for sexual offenses involving children (almost all males) and may not be general- 
izable to other individuals with pedophilic disorder (e.g., individuals who have never

izable to other individuals with pedophilic disorder (e.g., individuals who have never 
approached a child sexually but who qualify for the diagnosis of pedophilic disorder on 
the basis of subjective distress).
Fetishistic Disorder
Diagnostic Criteria 302.81 (F65.0)
A. Over a period of at least 6 months, recurrent and intense sexual arousal from either  
the use of nonliving objects or a highly specific focus on nongenital body part(s), as  
manifested by fantasies, urges, or behaviors.
C. The fetish objects are not limited to articles of clothing used in cross-dressing (as in  
transvestic disorder) or devices specifically designed for the puφose of tactile genital  
stimulation (e.g., vibrator).
Specify:
Body part(s)

Specify:
Body part(s)  
Nonliving object(s)  
Other
in a controiied environment: This specifier is primarily applicable to individuals living  
in institutional or other settings where opportunities to engage in fetishistic behaviors  
in fuii remission: There has been no distress or impairment in social, occupational,  
or other areas of functioning for at least 5 years while in an uncontrolled environment.

Although individuals with fetishistic disorder may report intense and recurrent sexual 
arousal to inanimate objects or a specific body part, it is not unusual for non-mutually ex­
clusive combinations of fetishes to occur. Thus, an individual may have fetishistic disorder 
associated with an inanimate object (e.g., female undergarments) or an exclusive focus on 
an intensely eroticized body part (e.g., feet, hair), or their fetishistic interest may meet cri­
teria for various combinations of these specifiers (e.g., socks, shoes and feet).
The paraphilic focus of fetishistic disorder involves the persistent and repetitive use of or de­
pendence on nonliving objects or a highly specific focus on a (typically nongenital) body part 
as primary elements associated with sexual arousal (Criterion A). A diagnosis of fetishistic dis­
order must include clinically significant personal distress or psychosocial role impairment

order must include clinically significant personal distress or psychosocial role impairment 
(Criterion B). Common fetish objects include female undergarments, male or female footwear, 
rubber articles, leather clothing, or other wearing apparel. Highly eroticized body parts asso­
ciated with fetishistic disorder include feet, toes, and hair. It is not uncommon for sexualized 
fetishes to include both inanimate objects and body parts (e.g., dirty socks and feet), and for 
this reason the definition of fetishistic disorder now re-incorporates partialism  (i.e., an exclusive 
focus on a body part) into its boundaries. Partialism, previously considered a paraphilia not 
otherwise specified disorder, had historically been subsumed in fetishism prior to DSM-Π Ι.
Many individuals who self-identify as fetishist practitioners do not necessarily report

Many individuals who self-identify as fetishist practitioners do not necessarily report 
clinical impairment in association with their fetish-associated behaviors. Such individuals 
could be considered as having a fetish but not fetishistic disorder. A diagnosis of fetishistic 
disorder requires concurrent fulfillment of both the behaviors in Criterion A and the clin­
ically significant distress or impairment in functioning noted in Criterion B.
Fetishistic disorder can be a multisensory experience, including holding, tasting, rubbing, 
inserting, or smelling the fetish object while masturbating, or preferring that a sexual part­
ner wear or utilize a fetish object during sexual encounters. Some individuals may acquire 
extensive collections of highly desired fetish objects.

Usually paraphilias have an onset during puberty, but fetishes can develop prior to ado­
lescence. Once established, fetishistic disorder tends to have a continuous course that fluc­
tuates in intensity and frequency of urges or behavior.
Knowledge of and appropriate consideration for normative aspects of sexual behavior are 
important factors to explore to establish a clinical diagnosis of fetishistic disorder and to 
distinguish a clinical diagnosis from a socially acceptable sexual behavior.
Fetishistic disorder has not been systematically reported to occur in females. In clinical 
samples, fetishistic disorder is nearly exclusively reported in males.
Functionai Consequences of Fetishistic Disorder

Typical impairments associated with fetishistic disorder include sexual dysfunction 
during romantic reciprocal relationships when the preferred fetish object or body part is

unavailable during foreplay or coitus. Some individuals with fetishistic disorder may pre­
fer solitary sexual activity associated with their fetishistic preference(s) even while in­
volved in a meaningful reciprocal and affectionate relationship.
Although fetishistic disorder is relatively uncommon among arrested sexual offenders 
with paraphilias, males with fetishistic disorder may steal and collect their particular fe­
tishistic objects of desire. Such individuals have been arrested and charged for nonsexual 
antisocial behaviors (e.g., breaking and entering, theft, burglary) that are primarily moti­
vated by the fetishistic disorder.
Transvestic disorder. The nearest diagnostic neighbor of fetishistic disorder is transves- 
tic disorder. As noted in the diagnostic criteria, fetishistic disorder is not diagnosed when 
fetish objects are limited to articles of clothing exclusively worn during cross-dressing (as

fetish objects are limited to articles of clothing exclusively worn during cross-dressing (as 
in transvestic disorder), or when the object is genitally stimulating because it has been de­
signed for that purpose (e.g., a vibrator).
Sexual masochism disorder or other paraphilic disorders. Fetishes can co-occur with 
other paraphilic disorders, especially "sadomasochism" and transvestic disorder. When 
an individual fantasizes about or engages in "forced cross-dressing" and is primarily sex­
ually aroused by the domination or humiliation associated with such fantasy or repetitive 
activity, the diagnosis of sexual masochism disorder should be made.
Fetishistic behavior without fetishistic disorder. Use of a fetish object for sexual arousal 
without any associated distress or psychosocial role impairment or other adverse conse­

quence would not meet criteria for fetishistic disorder, as the threshold required by Crite­
rion B would not be met. For example, an individual whose sexual partner either shares or 
can successfully incorporate his interest in caressing, smelling, or licking feet or toes as an 
important element of foreplay would not be diagnosed with fetishistic disorder; nor 
would an individual who prefers, and is not distressed or impaired by, solitary sexual be­
havior associated with wearing rubber garments or leather boots.
Fetishistic disorder may co-occur with other paraphilic disorders as well as hypersexual­
ity. Rarely, fetishistic disorder may be associated with neurological conditions.
Transvestic Disorder
Diagnostic Criteria 302.3 (F65.1)

A. Over a period of at least 6 months, recurrent and intense sexual arousal from cross­
dressing, as manifested by fantasies, urges, or behaviors.
With fetishism: If sexually aroused by fabrics, materials, or garments.
With autogynephiiia: If sexually aroused by thoughts or images of self as female.  
in institutional or other settings where opportunities to cross-dress are restricted,  

The presence of fetishism decreases the likelihood of gender dysphoria in men with trans­
vestic disorder. The presence of autogynephilia increases the likelihood of gender dyspho­
ria in men with transvestic disorder.
The diagnosis of transvestic disorder does not apply to all individuals who dress as the op­
posite sex, even those who do so habitually. It applies to individuals whose cross-dressing 
or thoughts of cross-dressing are always or often accompanied by sexual excitement (Cri­
terion A) and who are emotionally distressed by this pattern or feel it impairs social or in­
terpersonal functioning (Criterion B). The cross-dressing may involve only one or two 
articles of clothing (e.g., for men, it may pertain only to women's undergarments), or it 
may involve dressing completely in the iimer and outer garments of the other sex and (in 
men) may include the use of women's wigs and make-up. Transvestic disorder is nearly

men) may include the use of women's wigs and make-up. Transvestic disorder is nearly 
exclusively reported in males. Sexual arousal, in its most obvious form of penile erection, 
may co-occur with cross-dressing in various ways. In younger males, cross-dressing often 
leads to masturbation, following which any female clothing is removed. Older males often 
leam to avoid masturbating or doing anything to stimulate the penis so that the avoidance 
of ejaculation allows them to prolong their cross-dressing session. Males with female part­
ners sometimes complete a cross-dressing session by having intercourse with their part­
ners, and some have difficulty maintaining a sufficient erection for intercourse without 
cross-dressing (or private fantasies of cross-dressing).
Clinical assessment of distress or impairment, like clinical assessment of transvestic

Clinical assessment of distress or impairment, like clinical assessment of transvestic 
sexual arousal, is usually dependent on the individual's self-report. The pattern of behav­
ior "purging and acquisition" often signifies the presence of distress in individuals with 
transvestic disorder. During this behavioral pattern, an individual (usually a man) who 
has spent a great deal of money on women's clothes and other apparel (e.g., shoes, wigs) 
discards the items (i.e., purges them) in an effort to overcome urges to cross-dress, and 
then begins acquiring a woman's wardrobe all over again.
Transvestic disorder in men is often accompanied by autogynephilia  (i.e., a male's para- 
philic tendency to be sexually aroused by the thought or image of himself as a woman). 
Autogynephilic fantasies and behaviors may focus on the idea of exhibiting female phys­

iological functions (e.g., lactation, menstruation), engaging in stereotypically feminine be­
havior (e.g., knitting), or possessing female anatomy (e.g., breasts).
The prevalence of transvestic disorder is unknown. Transvestic disorder is rare in males 
and extremely rare in females. Fewer than 3% of males report having ever been sexually 
aroused by dressing in women's attire. The percentage of individuals who have cross­
dressed with sexual arousal more than once or a few times in their lifetimes would be even 
lower. The majority of males with transvestic disorder identify as heterosexual, although 
some individuals have occasional sexual interaction with other males, especially when 
they are cross-dressed.

In males, the first signs of transvestic disorder may begin in childhood, in the form of 
strong fascination with a particular item of women's attire. Prior to puberty, cross-dress­
ing produces generalized feelings of pleasurable excitement. With the arrival of puberty, 
dressing in women's clothes begins to elicit penile erection and, in some cases, leads di­

rectly to first ejaculation. In many cases, cross-dressing elicits less and less sexual ex­
citement as the individual grows older; eventually it may produce no discernible penile 
response at all. The desire to cross-dress, at the same time, remains the same or grows even 
stronger. Individuals who report such a diminution of sexual response typically report 
that the sexual excitement of cross-dressing has been replaced by feelings of comfort or 
well-being.
In some cases, the course of transvestic disorder is continuous, and in others it is epi­
sodic. It is not rare for men with transvestic disorder to lose interest in cross-dressing when 
they first fall in love with a woman and begin a relationship, but such abatement usually 
proves temporary. When the desire to cross-dress returns, so does the associated distress.
Some cases of transvestic disorder progress to gender dysphoria. The males in these

Some cases of transvestic disorder progress to gender dysphoria. The males in these 
cases, who may be indistinguishable from others with transvestic disorder in adolescence 
or early childhood, gradually develop desires to remain in the female role for longer pe­
riods and to feminize their anatomy. The development of gender dysphoria is usually ac­
companied by a (self-reported) reduction or elimination of sexual arousal in association 
with cross-dressing.
The manifestation of transvestism in penile erection and stimulation, like the manifesta­
tion of other paraphilic as well as normophiHc sexual interests, is most intense in adolescence 
and early adulthood. The severity of transvestic disorder is highest in adulthood, when the 
transvestic drives are most likely to conflict with performance in heterosexual intercourse

transvestic drives are most likely to conflict with performance in heterosexual intercourse 
and desires to marry and start a family. Middle-age and older men with a history of trans­
vestism are less likely to present with transvestic disorder than with gender dysphoria.
Functional Consequences of Transvestic Disorder
Engaging in transvestic behaviors can interfere with, or detract from, heterosexual rela­
tionships. This can be a source of distress to men who wish to maintain conventional mar­
riages or romantic partnerships with women.
Fetishistic disorder. This disorder may resemble transvestic disorder, in particular, in 
men with fetishism who put on women's undergarments while masturbating with them. 
Distinguishing transvestic disorder depends on the individual's specific thoughts during

Distinguishing transvestic disorder depends on the individual's specific thoughts during 
such activity (e.g., are there any ideas of being a woman, being like a woman, or being 
dressed as a woman?) and on the presence of other fetishes (e.g., soft, silky fabrics, whether 
these are used for garments or for something else).
Gender dysphoria. Individuals with transvestic disorder do not report an incongruence be­
tween their experienced gender and assigned gender nor a desire to be of the other gender; and 
they typically do not have a history of childhood cross-gender behaviors, which would be 
present in individuals with gender dysphoria. Individuals with a presentation that meets fuU  
criteria for transvestic disorder as weU as gender dysphoria should be given both diagnoses.
Transvestism (and thus transvestic disorder) is often found in association with other para­

philias. The most frequently co-occurring paraphilias are fetishism and masochism. One 
particularly dangerous form of masochism, autoerotic asphyxia,  is associated with transves­
tism in a substantial proportion of fatal cases.

Other Specified Paraphilic Disorder
This category applies to presentations in  which symptoms characteristic of a paraphilic disor­
der that cause clinically significant distress or impairment in  social, occupational, or other im­
in the paraphilic disorders diagnostic class. The other specified paraphilic disorder category is  
used in  situations in  which the clinician chooses to communicate the specific reason that the  
presentation does not meet the criteria for any specific paraphilic disorder. This is done by re­
cording “ other specified paraphilic disorder'’ followed by the specific reason (e.g., “ zoophilia” ).
include, but are not limited to, recurrent and intense sexual arousal involving telephone

include, but are not limited to, recurrent and intense sexual arousal involving telephone  
scatologia  (obscene phone calls), necrophilia  (coφses), zoophilia  (animals), coprophilia  
(feces), klismaphilia  (enemas), or urophilia  (urine) that has been present for at least 6 months  
and causes marked distress or impairment in social, occupational, or other important ar­
eas of functioning. Other specified paraphilic disorder can be specified as in  remission  
and/or as occurring in a controlled environment.
Unspecified Paraphilic Disorder
302.9 (F65.9)
This category applies to presentations in which symptoms characteristic of a paraphilic  
other important areas of functioning predominate but do not meet the full criteria for any of

the disorders in the paraphilic disorders diagnostic class. The unspecified paraphilic dis­
order category is used in situations in  which the clinician chooses not to specify the reason  
that the criteria are not met for a specific paraphilic disorder, and includes presentations  
in which there is insufficient information to make a more specific diagnosis.

F o u r d iSO rd G fS are included in this chapter: other specified mental disorder due to 
another medical condition; unspecified mental disorder due to another medical condition; 
other specified mental disorder; and unspecified mental disorder. This residual category 
applies to presentations in which symptoms characteristic of a mental disorder that cause 
eas of functioning predominate but do not meet the full criteria for any other mental dis­
order in DSM-5. For other specified and unspecified mental disorders due to another 
medical condition, it must be established that the disturbance is caused by the physiolog­
ical effects of another medical condition. If other specified and unspecified mental disor­
ders are due to another medical condition, it is necessary to code and list the medical 
condition first (e.g., 042 [B20] HIV disease), followed by the other specified or unspecified

condition first (e.g., 042 [B20] HIV disease), followed by the other specified or unspecified 
mental disorder (use appropriate code).
Other Specified IVIental Disorder  
This category applies to presentations in which symptoms characteristic of a mental dis­
order due to another medical condition that cause clinically significant distress or impair­
not meet the full criteria for any specific mental disorder attributable to another medical  
condition. The other specified mental disorder due to another medical condition category  
is used in  situations in which the clinician chooses to communicate the specific reason that  
the presentation does not meet the criteria for any specific mental disorder attributable to

the presentation does not meet the criteria for any specific mental disorder attributable to  
another medical condition. This is done by recording the name of the disorder, with the  
specific etiological medical condition inserted in place of “ another medical condition,”  fol­
lowed by the specific symptomatic manifestation that does not meet the criteria for any  
specific mental disorder due to another medical condition. Furthermore, the diagnostic  
code for the specific medical condition must be listed immediately before the code for the  
other specified mental disorder due to another medical condition. For example, dissocia­
tive symptoms due to complex partial seizures would be coded and recorded as 345.40  
(G40.209), complex partial seizures 294.8 (F06.8) other specified mental disorder due to  
complex partial seizures, dissociative symptoms.

Dissociative symptoms: This includes symptoms occurring, for example, in the con­
text of complex partial seizures.

Unspecified IVIental Disorder 
294.9 (F09)
not meet the full criteria for any specific mental disorder due to another medical condition.  
The unspecified mental disorder due to another medical condition category is used in  sit­
uations in which the clinician chooses nof to specify the reason that the criteria are not met  
for a specific mental disorder due to another medical condition, and includes presentations  
for which there is insufficient information to make a more specific diagnosis (e.g., in  emer­
gency room settings). This is done by recording the name of the disorder, with the specific

gency room settings). This is done by recording the name of the disorder, with the specific  
etiological medical condition inserted in  place of “ another medical condition.”  Furthermore,  
the diagnostic code for the specific medical condition must be listed immediately before  
the code for the unspecified mental disorder due to another medical condition. For exam­
ple, dissociative symptoms due to complex partial seizures would be coded and recorded  
as 345.40 (G40.209) complex partial seizures, 294.9 (F06.9) unspecified mental disorder  
due to complex partial seizures.
Other Specified Mental Disorder
300.9 (F99)
er important areas of functioning predominate but do not meet the full criteria for any

er important areas of functioning predominate but do not meet the full criteria for any  
specific mental disorder. The other specified mental disorder category is used in  situations  
in which the clinician chooses to communicate the specific reason that the presentation  
does not meet the criteria for any specific mental disorder. This is done by recording “ other  
specified mental disorder”  followed by the specific reason.
Unspecified Mental Disorder
mental disorder. The unspecified mental disorder category is used in situations in  which

mental disorder. The unspecified mental disorder category is used in situations in  which  
mental disorder, and includes presentations for which there is insufficient information to  
make a more specific diagnosis (e.g., in  emergency room settings).

Medication-Induced Movement 
Disorders and Otiier Adverse 
Effects of Medication
MGCliCâtiOn-indUCGCl movement disorders are included in Section II because of 
their frequent importance in 1) the management by medication of mental disorders or oth­
er medical conditions and 2) the differential diagnosis of mental disorders (e.g., anxiety 
disorder versus neuroleptic-induced akathisia; malignant catatonia versus neuroleptic 
malignant syndrome). Although these movement disorders are labeled "medication in­
duced," it is often difficult to establish the causal relationship between medication expo­
sure and the development of the movement disorder, especially because some of these 
movement disorders also occur in the absence of medication exposure. The conditions 
and problems listed in this chapter are not mental disorders.
The term neuroleptic  is becoming outdated because it highlights the propensity of an­

tipsychotic medications to cause abnormal movements, and it is being replaced with the 
term antipsychotic  in many contexts. Nevertheless, the term neuroleptic  remains appropri­
ate in this context. Although newer antipsychotic medications may be less likely to cause 
some medication-induced movement disorders, those disorders still occur. Neuroleptic 
medications include so-called conventional, "typical," or first-generation antipsychotic 
agents (e.g., chlorpromazine, haloperidol, fluphenazine); "atypical" or second-generation 
antipsychotic agents (e.g., clozapine, risperidone, olanzapine, quetiapine); certain dopa­
mine receptor-blocking drugs used in the treatment of symptoms such as nausea and gas- 
troparesis (e.g., prochlorperazine, promethazine, trimethobenzamide, thiethylperazine,

troparesis (e.g., prochlorperazine, promethazine, trimethobenzamide, thiethylperazine, 
metoclopramide); and amoxapine, which is marketed as an antidepressant.
Neuroleptic-Induced Parkinsonism 
Other Medication-Induced Parkinsonism
332.1 (G21.11 ) Neuroleptic-Induced Parkinsonism
332.1 (G21.19) Other Medication-Induced Parkinsonism
Parkinsonian tremor, muscular rigidity, akinesia (i.e., loss of movement or difficulty ini­
tiating movement), or bradykinesia (i.e., slowing movement) developing within a few 
weeks of starting or raising the dosage of a medication (e.g., a neuroleptic) or after reduc­
ing the dosage of a medication used to treat extrapyramidal symptoms.
Neuroleptic Malignant Syndrome
333.92 (G21.0) Neuroleptic Malignant Syndrome
Although neuroleptic malignant syndrome is easily recognized in its classic full-blown

Although neuroleptic malignant syndrome is easily recognized in its classic full-blown 
form, it is often heterogeneous in onset, presentation, progression, and outcome. The clin­
ical features described below are those considered most important in making the diagno­
sis of neuroleptic malignant syndrome based on consensus recommendations.

Patients have generally been exposed to a dopamine antagonist within 72 hours prior to 
symptom development. Hyperthermia (>100.4°F or >38.0°C on at least two occasions, 
measured orally), associated with profuse diaphoresis, is a distinguishing feature of neu­
roleptic malignant syndrome, setting it apart from other neurological side effects of anti­
psychotic medications. Extreme elevations in temperature, reflecting a breakdown in 
central thermoregulation, are more likely to support the diagnosis of neuroleptic malig­
nant syndrome. Generalized rigidity, described as "lead pipe" in its most severe form and 
usually unresponsive to antiparkinsonian agents, is a cardinal feature of the disorder and 
may be associated with other neurological symptoms (e.g., tremor, sialorrhea, akinesia, 
dystonia, trismus, myoclonus, dysarthria, dysphagia, rhabdomyolysis). Creatine kinase 
elevation of at least four times the upper limit of normal is commonly seen. Changes in

elevation of at least four times the upper limit of normal is commonly seen. Changes in 
mental status, characterized by delirium or altered consciousness ranging from stupor to 
coma, are often an early sign. Affected individuals may appear alert but dazed and unre­
sponsive, consistent with catatonic stupor. Autonomic activation and instability—mani­
fested by tachycardia (rate >25% above baseline), diaphoresis, blood pressure elevation 
(systolic or diastolic >25% above baseline) or fluctuation (>20 mmHg diastolic change or 
>25 mmHg systolic change within 24 hours), urinary incontinence, and pallor—may be 
seen at any time but provide an early clue to the diagnosis. Tachypnea (rate >50% above 
baseline) is common, and respiratory distress—resulting from metabolic acidosis, hyper­
metabolism, chest wall restriction, aspiration pneumonia, or pulmonary emboli—can oc­

cur and lead to sudden respiratory arrest.
A workup, including laboratory investigation, to exclude other infectious, toxic, met­
abolic, and neuropsychiatric etiologies or complications is essential (see the section "Dif­
ferential Diagnosis" later in this discussion). Although several laboratory abnormalities 
are associated with neuroleptic malignant syndrome, no single abnormality is specific to 
the diagnosis. Individuals with neuroleptic malignant syndrome may have leukocytosis, 
metabolic acidosis, hypoxia, decreased serum iron concentrations, and elevations in se­
rum muscle enzymes and catecholamines. Findings from cerebrospinal fluid analysis and 
neuroimaging studies are generally normal, whereas electroencephalography shows gen­

eralized slowing. Autopsy findings in fatal cases have been nonspecific and variable, de­
pending on complications.
Evidence from database studies suggests incidence rates for neuroleptic malignant syn­
drome of 0.01%-0.02% among individuals treated with antipsycho tics. The temporal pro­
gression of signs and symptoms provides important clues to the diagnosis and prognosis 
of neuroleptic malignant syndrome. Alteration in mental status and other neurological 
signs typically precede systemic signs. The onset of symptoms varies from hours to days 
after drug initiation. Some cases develop within 24 hours after drug initiation, most within 
the first week, and virtually all cases within 30 days. Once the syndrome is diagnosed and

the first week, and virtually all cases within 30 days. Once the syndrome is diagnosed and 
oral antipsychotic drugs are discontinued, neuroleptic malignant syndrome is self-limited 
in most cases. The mean recovery time after drug discontinuation is 7-10 days, with most 
individuals recovering within 1 week and nearly all within 30 days. The duration may be 
prolonged when long-acting antipsychotics are implicated. There have been reports of in­
dividuals in whom residual neurological signs persisted for weeks after the acute hyper- 
metabolic symptoms resolved. Total resolution of symptoms can be obtained in most 
cases of neuroleptic malignant syndrome; however, fatality rates of 10%-20% have been 
reported when the disorder is not recognized. Although many individuals do not experi­
ence a recurrence of neuroleptic malignant syndrome when rechallenged with antipsy­

chotic medication, some do, especially when antipsychotics are reinstituted soon after an 
episode.

Neuroleptic malignant syndrome is a potential risk in any individual after antipsychotic 
drug administration. It is not specific to any neuropsychiatric diagnosis and may occur in 
individuals without a diagnosable mental disorder who receive dopamine antagonists. 
Clinical, systemic, and metabolic factors associated with a heightened risk of neuroleptic 
malignant syndrome include agitation, exhaustion, dehydration, and iron deficiency. A 
prior episode associated with antipsychotics has been described in 15%-20% of index 
cases, suggesting underlying vulnerability in some patients; however, genetic findings 
based on neurotransmitter receptor polymorphisms have not been replicated consistently.
Nearly all dopamine antagonists have been associated with neuroleptic malignant 
sjmdrome, although high-potency antipsychotics pose a greater risk compared with low- 
potency agents and newer atypical antipsychotics. Partial or milder forms may be associ­

ated with newer antipsychotics, but neuroleptic malignant syndrome varies in severity 
even with older drugs. Dopamine antagonists used in medical settings (e.g., metoclopra­
mide, prochlorperazine) have also been implicated. Parenteral administration routes, 
rapid titration rates, and higher total drug dosages have been associated with increased 
risk; however, neuroleptic malignant syndrome usually occurs within the therapeutic dos­
age range of antipsychotics.
Neuroleptic malignant syndrome must be distinguished from other serious neurological 
or medical conditions, including central nervous system infections, inflammatory or au­
toimmune conditions, status epilepticus, subcortical structural lesions, and systemic con­

ditions (e.g., pheochromocytoma, thyrotoxicosis, tetanus, heat stroke).
Neuroleptic malignant syndrome also must be distinguished from similar syndromes 
resulting from the use of other substances or medications, such as serotonin syndrome; 
parkinsonian hyperthermia syndrome following abrupt discontinuation of dopamine ag­
onists; alcohol or sedative withdrawal; malignant hyperthermia occurring during anes­
thesia; hyperthermia associated with abuse of stimulants and hallucinogens; and atropine 
poisoning from anticholinergics.
In rare instances, individuals with schizophrenia or a mood disorder may present with 
malignant catatonia, which may be indistinguishable from neuroleptic malignant syn­
drome. Some investigators consider neuroleptic malignant syndrome to be a drug-

drome. Some investigators consider neuroleptic malignant syndrome to be a drug- 
induced form of malignant catatonia.
Medication-Induced Acute Dystonia
333.72 (G24.02) Medication-Induced Acute Dystonia
Abnormal and prolonged contraction of the muscles of the eyes (oculogyric crisis), head, 
neck (torticollis or retrocollis), limbs, or trunk developing within a few days of starting or 
raising the dosage of a medication (such as a neuroleptic) or after reducing the dosage of a 
medication used to treat extrapyramidal symptoms.
IVledication-lnduced Acute Al<atlnisia
333.99 (G25.71) Medication-Induced Acute Akathisia
Subjective complaints of restlessness, often accompanied by observed excessive move­
ments (e.g., fidgety movements of the legs, rocking from foot to foot, pacing, inability to sit 
or stand still), developing within a few weeks of starting or raising the dosage of a medi­

cation (such as a neuroleptic) or after reducing the dosage of a medication used to treat ex­
trapyramidal symptoms.

Tardive Dyskinesia
333.85 (G24.01) Tardive Dyskinesia
Involuntary athetoid or choreiform movements (lasting at least a few weeks) generally of 
the tongue, lower face and jaw, and extremities (but sometimes involving the pharyngeal, 
diaphragmatic, or trunk muscles) developing in association with the use of a neuroleptic 
medication for at least a few months.
Symptoms may develop after a shorter period of medication use in older persons. In 
some patients, movements of this type may appear after discontinuation, or after change 
or reduction in dosage, of neuroleptic medications, in which case the condition is called 
neuroleptic withdrawal-emergent dyskinesia.  Because withdrawal-emergent dyskinesia is 
usually time-limited, lasting less than 4-8 weeks, dyskinesia that persists beyond this win­
dow is considered to be tardive dyskinesia.
Tardive Dystonia 
Tardive Akathisia
333.72 (G24.09) Tardive Dystonia
333.99 (G25.71 ) Tardive Akathisia

Tardive syndrome involving other types of movement problems, such as dystonia or 
akathisia, which are distinguished by their late emergence in the course of treatment and 
their potential persistence for months to years, even in the face of neuroleptic discontinu­
ation or dosage reduction.
Medication-Induced Postural Tremor
333.1 (G25.1) Medication-Induced Postural Tremor
Fine tremor (usually in the range of 8-12 Hz) occurring during attempts to maintain a pos­
ture and developing in association with the use of medication (e.g., lithium, antidepres­
sants, valproate). This tremor is very similar to the tremor seen with anxiety, caffeine, and 
other stimulants.
Other Medication-Induced Movement Disorder
333.99 (G25.79) Other Medication-Induced Movement Disorder

This category is for medication-induced movement disorders not captured by any of the 
specific disorders listed above. Examples include 1) presentations resembling neuroleptic 
malignant syndrome that are associated with medications other than neuroleptics and 
2) other medication-induced tardive conditions.
Antidepressant Discontinuation Syndrome
Antidepressant discontinuation syndrome is a set of symptoms that can occur after an 
abrupt cessation (or marked reduction in dose) of an antidepressant medication that was 
taken continuously for at least 1 month. Symptoms generally begin within 2-4 days and 
typically include specific sensory, somatic, and cognitive-emotional manifestations. Fre­

quently reported sensory and somatic symptoms include flashes of lights, "electric shock" 
sensations, nausea, and hyperresponsivity to noises or lights. Nonspecific anxiety and 
feelings of dread may also be reported. Symptoms are alleviated by restarting the same 
medication or starting a different medication that has a similar mechanism of action— 
for example, discontinuation symptoms after withdrawal from a serotonin-norepineph- 
rine reuptake inhibitor may be alleviated by starting a tricyclic antidepressant. To qualify 
as antidepressant discontinuation syndrome, the symptoms should not have been present 
before the antidepressant dosage was reduced and are not better explained by another 
mental disorder (e.g., manic or hypomanie episode, substance intoxication, substance 
withdrawal, somatic symptom disorder).
Discontinuation symptoms may occur following treatment with tricyclic antidepressants

Discontinuation symptoms may occur following treatment with tricyclic antidepressants 
(e.g., imipramine, amitriptyline, desipramine), serotonin reuptake inhibitors (e.g., fluox­
etine, paroxetine, sertraline), and monoamine oxidase inhibitors (e.g., phenelzine, selegi­
line, pargyline). The incidence of this syndrome depends on the dosage and half-life of the 
medication being taken, as well as the rate at which the medication is tapered. Short-acting 
medications that are stopped abruptly rather than tapered gradually may pose the great­
est risk. The short-acting selective serotonin reuptake inhibitor (SSRI) paroxetine is the 
agent most commonly associated with discontinuation symptoms, but such symptoms oc­
cur for all types of antidepressants.
Unlike withdrawal syndromes associated with opioids, alcohol, and other substances 
of abuse, antidepressant discontinuation syndrome has no pathognomonic symptoms. In­

stead, the symptoms tend to be vague and variable and typically begin 2-A days after the 
last dose of the antidepressant. For SSRIs (e.g., paroxetine), symptoms such as dizziness, 
ringing in the ears, "electric shocks in the head," an inability to sleep, and acute anxiety are 
described. The antidepressant use prior to discontinuation must not have incurred hypo- 
mania or euphoria (i.e., there should be confidence that the discontinuation syndrome is 
not the result of fluctuations in mood stability associated with the previous treatment). 
The antidepressant discontinuation syndrome is based solely on pharmacological factors 
and is not related to the reinforcing effects of an antidepressant. Also, in the case of stim­
ulant augmentation of an antidepressant, abrupt cessation may result in stimulant with­

drawal symptoms (see "Stimulant Withdrawal" in the chapter "Substance-Related and 
Addictive Disorders") rather than the antidepressant discontinuation syndrome described 
here.
The prevalence of antidepressant discontinuation syndrome is unknown but is thought to 
vary according to the dosage prior to discontinuation, the half-life and receptor-binding 
affinity of the medication, and possibly the individual's genetically influenced rate of me­
tabolism for this medication.
Course and Development
Because longitudinal studies are lacking, litfle is known about the clinical course of anti­
depressant discontinuation syndrome. Symptoms appear to abate over time with very 
gradual dosage reductions. After an episode, some individuals may prefer to resume med­
ication indefinitely if tolerated.

The differential diagnosis of antidepressant discontinuation syndrome includes anxiety 
and depressive disorders, substance use disorders, and tolerance to medications.

Anxiety and depressive disorders. Discontinuation symptoms often resemble symptoms 
of a persistent anxiety disorder or a return of somatic symptoms of depression for which 
the medication was initially given.
Substance use disorders. Antidepressant discontinuation syndrome differs from sub­
stance withdrawal in that antidepressants themselves have no reinforcing or euphoric ef­
fects. The medication dosage has usually not been increased without the clinician's 
permission, and the individual generally does not engage in drug-seeking behavior to ob­
tain additional medication. Criteria for a substance use disorder are not met.
Tolerance to medications. Tolerance and discontinuation symptoms can occur as a 
normal physiological response to stopping medication after a substantial duration of 
exposure. Most cases of medication tolerance can be managed through carefully con­
trolled tapering.

Typically, the individual was initially started on the medication for a major depressive dis­
order; the original symptoms may return during the discontinuation syndrome.
Other Adverse Effect of Medication
This category is available for optional use by clinicians to code side effects of medication 
(other than movement symptoms) when these adverse effects become a main focus of clin­
ical attention. Examples include severe hypotension, cardiac arrhythmias, and priapism.

other Conditions That May Be 
a Focus of Ciinicai Attention
T h is  d is c u s s io n  covers other conditions and problems that may be a focus of clini­
cal attention or that may otherwise affect the diagnosis, course, prognosis, or treatment of 
a patient's mental disorder. These conditions are presented with their corresponding 
codes from ICD-9-CM (usually V codes) and ICD-IO-CM (usually Z codes). A condition 
or problem in this chapter may be coded if it is a reason for the current visit or helps to 
explain the need for a test, procedure, or treatment. Conditions and problems in this chap­
ter may also be included in the medical record as useful information on circumstances that 
may affect the patient's care, regardless of their relevance to the current visit.
The conditions and problems listed in this chapter are not mental disorders. Their in­
clusion in DSM-5 is meant to draw attention to the scope of additional issues that may be

clusion in DSM-5 is meant to draw attention to the scope of additional issues that may be 
encountered in routine clinical practice and to provide a systematic listing that may be 
useful to clinicians in documenting these issues.
Relational Problems
Key relationships, especially intimate adult partner relationships and parent/caregiver- 
child relationships, have a significant impact on the health of the individuals in these re­
lationships. These relationships can be health promoting and protective, neutral, or detri­
mental to health outcomes. In the extreme, these close relationships can be associated with 
maltreatment or neglect, which has significant medical and psychological consequences 
for the affected individual. A relational problem may come to clinical attention either as 
the reason that the individual seeks health care or as a problem that affects the course,

the reason that the individual seeks health care or as a problem that affects the course, 
prognosis, or treatment of the individual's mental or other medical disorder.
Problems Related to Family Upbringing
V61.20 (Z62.820) Parent-Child Relational Problem
For this category, the term parent is used to refer to one of the child's primary caregivers, 
who may be a biological, adoptive, or foster parent or may be another relative (such as a 
grandparent) who fulfills a parental role for the child. This category should be used when 
the main focus of clinical attention is to address the quality of the parent-child relationship 
or when the quality of the parent-child relationship is affecting the course, prognosis, or 
treatment of a mental or other medical disorder. Typically, the parent-child relational 
problem is associated with impaired functioning in behavioral, cognitive, or affective do­

mains. Examples of behavioral problems include inadequate parental control, supervision, 
and involvement with the child; parental overprotection; excessive parental pressure; ar­
guments that escalate to threats of physical violence; and avoidance without resolution of 
problems. Cognitive problems may include negative attributions of the other's intentions, 
hostility toward or scapegoating of the other, and unwarranted feelings of estrangement. 
Affective problems may include feelings of sadness, apathy, or anger about the other in­
dividual in the relationship. Clinicians should take into account the developmental needs 
of the child and the cultural context.

V61.8 (Z62.891 ) Sibling Relational Problem
This category should be used when the focus of clinical attention is a pattern of interaction 
among siblings that is associated with significant impairment in individual or family function­
ing or with development of symptoms in one or more of the siblings, or when a sibling relational 
problem is affecting the course, prognosis, or treatment of a sibling's mental or other medical 
disorder. This category can be used for either children or adults if the focus is on the sibling re­
lationship. Siblings in this context include full, half-, step-, foster, and adopted siblings.
V61.8 (Z62.29) Upbringing Away From Parents
This category should be used when the main focus of clinical attention pertains to issues 
regarding a child being raised away from the parents or when this separate upbringing af­
fects the course, prognosis, or treatment of a mental or other medical disorder. The child

fects the course, prognosis, or treatment of a mental or other medical disorder. The child 
could be one who is under state custody and placed in kin care or foster care. The child 
could also be one who is living in a nonparental relative's home, or with friends, but whose 
out-of-home placement is not mandated or sanctioned by the courts. Problems related to a 
child living in a group home or orphanage are also included. This category excludes issues 
related to V60.6 (Z59.3) children in boarding schools.
V61.29 (Z62.898) Child Affected by Parental Relationship Distress
This category should be used when the focus of clinical attention is the negative effects of 
parental relationship discord (e.g., high levels of conflict, distress, or disparagement) on a 
child in the family, including effects on the child's mental or other medical disorders.
o th e r Problems Related to Primary Support Group

V61.10 (Z63.0) Relationship Distress With Spouse or Intimate Partner
This category should be used when the major focus of the clinical contact is to address the 
quality of the intimate (spouse or partner) relationship or when the quality of that rela­
tionship is affecting the course, prognosis, or treatment of a mental or other medical dis­
order. Partners can be of the same or different genders. Typically, the relationship distress 
is associated with impaired functioning in behavioral, cognitive, or affective domains. Ex­
amples of behavioral problems include conflict resolution difficulty, withdrawal, and 
overinvolvement. Cognitive problems can manifest as chronic negative attributions of the 
other's intentions or dismissals of the partner's positive behaviors. Affective problems

other's intentions or dismissals of the partner's positive behaviors. Affective problems 
would include chronic sadness, apathy, and/or anger about the other partner.
Note: This category excludes clinical encounters for V61.1x (Z69.1x) mental health ser­
vices for spousal or partner abuse problems and V65.49 (Z70.9) sex counseling.
V61.03 (Z63.5) Disruption of Family by Separation or Divorce
This category should be used when partners in an intimate adult couple are living apart 
due to relationship problems or are in the process of divorce.
V61.8 (Z63.8) High Expressed Emotion Level Within Family
Expressed emotion  is a construct used as a qualitative measure of the "amount" of emo­
tion—in particular, hostility, emotional overinvolvement, and criticism directed toward a 
family member who is an identified patient—displayed in the family environment. This

family member who is an identified patient—displayed in the family environment. This 
category should be used when a family's high level of expressed emotion is the focus of 
clinical attention or is affecting the course, prognosis, or treatment of a family member's 
mental or other medical disorder.
V62.82 (Z63.4) Uncomplicated Bereavement
This category can be used when the focus of clinical attention is a normal reaction to the 
death of a loved one. As part of their reaction to such a loss, some grieving individuals 
present with symptoms characteristic of a major depressive episode—for example, feel­

ings of sadness and associated symptoms such as insomnia, poor appetite, and weight 
loss. The berea>(ed individual typically regards the depressed mood as "normal," al­
though the individual may seek professional help for relief of associated symptoms such 
as insomnia or anorexia. The duration and expression of "normal" bereavement vary con­
siderably among different cultural groups. Further guidance in distinguishing grief from 
a major depressive episode is provided in the criteria for major depressive episode.
Abuse and Neglect
Maltreatment by a family member (e.g., caregiver, intimate adult partner) or by a nonrel­
ative can be the area of current clinical focus, or such maltreatment can be an important 
factor in the assessment and treatment of patients with mental or other medical disorders. 
Because of the legal implications of abuse and neglect, care should be used in assessing 
these conditions and assigning these codes. Having a past history of abuse or neglect can

these conditions and assigning these codes. Having a past history of abuse or neglect can 
influence diagnosis and treatment response in a number of mental disorders, and may also 
be noted along with the diagnosis.
For the following categories, in addition to listings of the confirmed or suspected event 
of abuse or neglect, other codes are provided for use if the current clinical encounter is to 
provide mental health services to either the victim or the perpetrator of the abuse or ne­
glect. A separate code is also provided for designating a past history of abuse or neglect.
Coding Note for ICD-IO-CM Abuse and Neglect Conditions
For T codes only, the 7th character should be coded as follows:
A (initial encounter)—Use while the patient is receiving active treatment for 
the condition (e.g., surgical treatment, emergency department encounter, eval­
uation and treatment by a new clinician); or

D (subsequent encounter)—Use for encounters after the patient has received 
active treatment for the condition and when he or she is receiving routine care 
for the condition during the healing or recovery phase (e.g., cast change or re­
moval, removal of external or internal fixation device, medication adjustment, 
other aftercare and follow-up visits).
Child M altreatm ent and Neglect Problems
Child Physical Abuse
Child physical abuse is nonaccidental physical injury to a child—^ranging from minor bruises 
to severe fractures or death—occurring as a result of punching, beating, kicking, biting, 
shaking, throwing, stabbing, choking, hitting (with a hand, stick, strap, or other object), 
burning, or any other method that is inflicted by a parent, caregiver, or other individual who

burning, or any other method that is inflicted by a parent, caregiver, or other individual who 
has responsibility for the child. Such injury is considered abuse regardless of whether the 
caregiver intended to hurt the child. Physical discipline, such as spanking or paddling, is not 
considered abuse as long as it is reasonable and causes no bodily injury to the child.
Child Physical Abuse, Confirmed
995.54 (T74.12XA) Initial encounter
995.54 (T74.12XD) Subsequent encounter
Child Physical Abuse, Suspected
995.54 (T76.12XA) Initial encounter

Other Circumstances Related to Child Physical Abuse
V61.21 (Z69.010) Encounter for mental health services for victim of child abuse by parent
V61.21 (Z69.020) Encounter for mental health services for victim of nonparental child 
abuse
V I 5.41 (Z62.810) Personal history (past history) of physical abuse in childhood
V61.22 (Z69.011  ) Encounter for mental health services for perpetrator of parental child 
abuse
V62.83 (Z69.021) Encounter for mental health services for perpetrator of nonparental 
Child Sexual Abuse
Child sexual abuse encompasses any sexual act involving a child that is intended to pro­
vide sexual gratification to a parent, caregiver, or other individual who has responsibility 
for the child. Sexual abuse includes activities such as fondling a child's genitals, penetra­
tion, incest, rape, sodomy, and indecent exposure. Sexual abuse also includes noncontact 
exploitation of a child by a parent or caregiver—for example, forcing, tricking, enticing,

exploitation of a child by a parent or caregiver—for example, forcing, tricking, enticing, 
threatening, or pressuring a child to participate in acts for the sexual gratification of others, 
without direct physical contact between child and abuser.
Child Sexual Abuse, Confirmed
Child Sexual Abuse, Suspected
995.53 (T76.22XA) Initial encounter
Other Circumstances Related to Child Sexual Abuse
V61.21 (Z69.010) Encounter for mental health services for victim of child sexual abuse 
by parent
sexual abuse
V I 5.41 (Z62.810) Personal history (past history) of sexual abuse in childhood

V62.83 (Z69.021) Encounter for mental health services for peφetrator of nonparental 
Child Neglect
Child neglect is defined as any confirmed or suspected egregious act or omission by a 
child's parent or other caregiver that deprives the child of basic age-appropriate needs and 
thereby results, or has reasonable potential to result, in physical or psychological harm to 
the child. Child neglect encompasses abandonment; lack of appropriate supervision; fail­
ure to attend to necessary emotional or psychological needs; and failure to provide neces­
sary education, medical care, nourishment, shelter, and/or clothing.
Child Neglect, Confirmed

Child Neglect, Suspected
995.52 (T76.02XA) Initial encounter
995.52 (T76.02XD) Subsequent encounter
Other Circumstances Related to Child Neglect
V61.21 (Z69.010) Encounter for mental health services for victim of child neglect by 
parent
neglect
V I 5.42 (Z62.812) Personal history (past history) of neglect in childhood
neglect
Child Psychological Abuse
Child psychological abuse is nonaccidental verbal or symbolic acts by a child's parent or 
caregiver that result, or have reasonable potential to result, in significant psychological 
harm to the child. (Physical and sexual abusive acts are not included in this category.) Ex­
amples of psychological abuse of a child include berating, disparaging, or humiliating

amples of psychological abuse of a child include berating, disparaging, or humiliating 
the child; threatening the child; harming/abandoning—or indicating that the alleged 
offender will harm/abandon—people or things that the child cares about; confining the 
child (as by tying a child's arms or legs together or binding a child to furrüture or another 
object, or confining a child to a small enclosed area [e.g., a closet]); egregious scapegoating 
of the child; coercing the child to inflict pain on himself or herself; and disciplining the 
child excessively (i.e., at an extremely high frequency or duration, even if not at a level of 
physical abuse) through physical or nonphysical means.
Child Psychological Abuse, Confirmed
Child Psychological Abuse, Suspected
995.51 (T76.32XA) Inihal encounter

Other Circumstances Related to Child Psychological Abuse
V61.21 (Z69.010) Encounter for mental health services for victim of child psychological 
V I 5.42 (Z62.811  ) Personal history (past history) of psychological abuse in childhood
V61.22 (Z69.011  ) Encounter for mental health services for peφetrator of parental child 
V62.83 (Z69.021 ) Encounter for mental health services for perpetrator of nonparental 
child psychological abuse

Adult M altreatm ent and Neglect Problems
Spouse or Partner Violence, Physical
This category should be used when nonaccidental acts of physical force that result, or have 
reasonable potential to result, in physical harm to an intimate partner or that evoke signif­
icant fear in the partner have occurred during the past year. Nonaccidental acts of physical 
force include shoving, slapping, hair pulling, pinching, restraining, shaking, throwing, 
biting, kicking, hitting with the fist or an object, burning, poisoning, applying force to the 
throat, cutting off the air supply, holding the head under water, and using a weapon. Acts 
for the purpose of physically protecting oneself or one's partner are excluded.
Spouse or Partner Violence, Physical, Confirmed
Spouse or Partner Violence, Physical, Suspected

Other Circumstances Related to Spouse or Partner Violence, Physical
V61.11 (Z69.11) Encounter for mental health services for victim of spouse or partner 
violence, physical
VI 5.41 (Z91.410) Personal history (past history) of spouse or partner violence, physical
V61.12 (Z69.12) Encounter for mental health services for perpetrator of spouse or 
Spouse or Partner Violence, Sexual
This category should be used when forced or coerced sexual acts with an intimate partner 
have occurred during the past year. Sexual violence may involve the use of physical force 
or psychological coercion to compel the partner to engage in a sexual act against his or her 
will, whether or not the act is completed. Also included in this category are sexual acts

will, whether or not the act is completed. Also included in this category are sexual acts 
with an intimate partner who is unable to consent.
Spouse or Partner Violence, Sexual, Confirmed
995.83 (T74.21 XA) Initial encounter
Spouse or Partner Violence, Sexual, Suspected
995.83 (T76.21 XA) Initial encounter
Other Circumstances Related to Spouse or Partner Violence, Sexual
V61.11 (Z69.81) Encounter for mental health services for victim of spouse or partner 
violence, sexual
VI 5.41 (Z91.410) Personal history (past history) of spouse or partner violence, sexual
partner violence, sexual

Spouse or Partner Neglect
Partner neglect is any egregious act or omission in the past year by one partner that de­
prives a dependent partner of basic needs and thereby results, or has reasonable potential 
to result, in physical or psychological harm to the dependent partner. This category is used 
in the context of relationships in which one partner is extremely dependent on the other 
partner for care or for assistance in navigating ordinary daily activities—for example, a 
partner who is incapable of self-care owing to substantial physical, psychological/intel­
lectual, or cultural limitations (e.g., inability to communicate with others and manage ev­
eryday activities due to living in a foreign culture).
Spouse or Partner Neglect, Confirmed
995.85 (T74.01 XA ) Initial encounter
995.85 (T74.01 XD ) Subsequent encounter
Spouse or Partner Neglect, Suspected
995.85 (T76.01 XA ) Initial encounter

Other Circumstances Related to Spouse or Partner Neglect
neglect
V15.42 (Z91.412) Personal history (past history) of spouse or partner neglect
Spouse or Partner Abuse, Psychological
Partner psychological abuse encompasses nonaccidental verbal or symbolic acts by one 
partner that result, or have reasonable potential to result, in significant harm to the other 
partner. This category should be used when such psychological abuse has occurred during 
the past year. Acts of psychological abuse include berating or humiliating the victim; inter­

rogating the victim; restricting tiie victim's ability to come and go freely; obstructing the vic­
tim's access to assistance (e.g., law enforcement; legal, protective, or medical resources); 
threatening the victim with physical harm or sexual assault; harming, or threatening to 
harm, people or things that the victim cares about; unwarranted restriction of the victim's ac­
cess to or use of economic resources; isolating the victim from family, friends, or social sup­
port resources; stalking the victim; and trying to make the victim think that he or she is crazy.
Spouse or Partner Abuse, Psychological, Confirmed
995.82 (T74.31 XA ) Initial encounter
995.82 (174.31 XD ) Subsequent encounter
Spouse or Partner Abuse, Psychological, Suspected
995.82 (T76.31 XA ) Initial encounter

Other Circumstances Related to Spouse or Partner Abuse, Psychological

V15.42 (Z91.411 ) Personal history (past history) of spouse or partner psychological abuse
V61.12 (Z69.12) Encounter for mental health services for perpetrator of spouse or part­
ner psychological abuse
Adult Abuse by Nonspouse or Nonpartner
These categories should be used when an adult has been abused by another adult who is 
not an intimate partner. Such maltreatment may involve acts of physical, sexual, or emo­
tional abuse. Examples of adult abuse include nonaccidental acts of physical force (e.g., 
pushing/shoving, scratching, slapping, throwing something that could hurt, punching, 
biting) that have resulted—or have reasonable potential to result—in physical harm or 
have caused significant fear; forced or coerced sexual acts; and verbal or symbolic acts 
with the potential to cause psychological harm (e.g., berating or humiliating the person; 
interrogating the person; restricting the person's ability to come and go freely; obstructing

interrogating the person; restricting the person's ability to come and go freely; obstructing 
the person's access to assistance; threatening the person; harming or threatening to harm 
people or things that the person cares about; restricting the person's access to or use of eco­
nomic resources; isolating the person from family, friends, or social support resources; 
stalking the person; trying to make the person think that he or she is crazy). Acts for the 
purpose of physically protecting oneself or the other person are excluded.
Adult Physical Abuse by Nonspouse or Nonpartner, Confirmed
Adult Physical Abuse by Nonspouse or Nonpartner, Suspected
Adult Sexual Abuse by Nonspouse or Nonpartner, Confirmed

995.83 (T74.21 XD) Subsequent encounter
Adult Sexual Abuse by Nonspouse or Nonpartner, Suspected
995.83 (T76.21XA) Initial encounter
Adult Psychological Abuse by Nonspouse or Nonpartner, Confirmed
995.82 (T74.31 XD) Subsequent encounter
Adult Psychological Abuse by Nonspouse or Nonpartner, Suspected
995.82 (T76.31XA) Initial encounter
Other Circumstances Related to Adult Abuse by Nonspouse or Nonpartner
V65.49 (Z69.81 ) Encounter for mental health services for victim of nonspousal or non­
partner adult abuse
V62.83 (Z69.82) Encounter for mental health services for perpetrator of nonspousal or 
nonpartner adult abuse

Educational and Occupational Problems
\
Educational Problems
V62.3 (Z55.9) Academic or Educational Problem
This category should be used when an academic or educational problem is the focus of 
clinical attention or has an impact on the individual's diagnosis, treatment, or prognosis. 
Problems to be considered include illiteracy or low-level literacy; lack of access to school­
ing owing to unavailability or unattainability; problems with academic performance (e.g., 
failing school examinations, receiving failing marks or grades) or underachievement (be­
low what would be expected given the individual's intellectual capacity); discord with 
teachers, school staff, or other students; and any other problems related to education and/ 
or literacy.
Occupational Problems
V62.21 (Z56.82) Problem Related to Current Military Deployment Status
This category should be used when an occupational problem directly related to an indi­

vidual's military deployment status is the focus of clinical attention or has an impact on the 
individual's diagnosis, treatment, or prognosis. Psychological reactions to deployment are 
not included in this category; such reactions would be better captured as an adjustment 
disorder or another mental disorder.
V62.29 (Z56.9) Other Problem Related to Employment
This category should be used when an occupational problem is the focus of clinical atten­
tion or has an impact on the individual's treatment or prognosis. Areas to be considered 
include problems with employment or in the work environment, including unemploy­
ment; recent change of job; threat of job loss; job dissatisfaction; stressful work schedule;

ment; recent change of job; threat of job loss; job dissatisfaction; stressful work schedule; 
uncertainty about career choices; sexual harassment on the job; other discord with boss, 
supervisor, co-workers, or others in the work environment; uncongenial or hostile work 
environments; other psychosocial stressors related to work; and any other problems re­
lated to employment and/or occupation.
Housing and Economic Problems
Housing Problems
V60.0 (Z59.0) Homelessness
This category should be used when lack of a regular dwelling or living quarters has an im­
pact on an individual's treatment or prognosis. An individual is considered to be homeless 
if his or her primary nighttime residence is a homeless shelter, a warming shelter, a do­
mestic violence shelter, a public space (e.g., tunnel, transportation station, mall), a build­

ing not intended for residential use (e.g., abandoned structure, unused factory), a 
cardboard box or cave, or some other ad hoc housing situation.
V60.1 (Z59.1) Inadequate Housing
This category should be used when lack of adequate housing has an impact on an individ­
ual's treatment or prognosis. Examples of inadequate housing conditions include lack of 
heat (in cold temperatures) or electricity, infestation by insects or rodents, inadequate 
plumbing and toilet facilities, overcrowding, lack of adequate sleeping space, and exces­
sive noise. It is important to consider cultural norms before assigning this category.
V60.89 (Z59.2) Discord With Neighbor, Lodger, or Landlord
This category should be used when discord with neighbors, lodgers, or a landlord is a fo­

cus of clinical attention or has an impact on the individual's treatment or prognosis.

V60.6 (Z59.3) Problem Related to Living in a Residential Institution
This category should be used when a problem (or problems) related to living in a residen­
tial institution is a focus of clinical attention or has an impact on the individual's treatment 
or prognosis. Psychological reactions to a change in living situation are not included in this 
category; such reactions would be better captured as an adjustment disorder.
Economic Problems
V60.2 (Z59.4) Lack of Adequate Food or Safe Drinking Water  
V60.2 (Z59.5) Extreme Poverty  
V60.2 (Z59.6) Low Income
V60.2 (Z59.7) Insufficient Social Insurance or Welfare Support
This category should be used for individuals who meet eligibility criteria for social or wel­
fare support but are not receiving such support, who receive support that is insufficient to 
address their needs, or who otherwise lack access to needed insurance or support pro­
grams. Examples include inability to qualify for welfare support owing to lack of proper

grams. Examples include inability to qualify for welfare support owing to lack of proper 
documentation or evidence of address, inability to obtain adequate health insurance be­
cause of age or a preexisting condition, and denial of support owing to excessively strin­
gent income or other requirements.
V60.9 (Z59.9) Unspecified Housing or Economic Problem
This category should be used when there is a problem related to housing or economic cir­
cumstances other than as specified above.
Other Problems Related to the Social Enviroriment
V62.89 (Z60.0) Phase of Life Problem
This category should be used when a problem adjusting to a life-cycle transition (a partic­
ular developmental phase) is the focus of clinical attention or has an impact on the indi­
vidual's treatment or prognosis. Examples of such transitions include entering or

vidual's treatment or prognosis. Examples of such transitions include entering or 
completing school, leaving parental control, getting married, starting a new career, be­
coming a parent, adjusting to an "empty nest" after children leave home, and retiring.
V60.3 (Z60.2) Problem Related to Living Alone
This category should be used when a problem associated with living alone is the focus of 
clinical attention or has an impact on the individual's treatment or prognosis. Examples of 
such problems include chronic feelings of loneliness, isolation, and lack of structure in car­
rying out activities of daily living (e.g., irregular meal and sleep schedules, inconsistent 
performance of home maintenance chores).
V62.4 (Z60.3) Acculturation Difficulty
This category should be used when difficulty in adjusting to a new culture (e.g., following

This category should be used when difficulty in adjusting to a new culture (e.g., following 
migration) is the focus of clinical attention or has an impact on the individual's treatment 
or prognosis.
V62.4 (Z60.4) Social Exclusion or Rejection
This category should be used when there is an imbalance of social power such that there is 
recurrent social exclusion or rejection by others. Examples of social rejection include bul­
lying, teasing, and intimidation by others; being targeted by others for verbal abuse and 
humiliation; and being purposefully excluded from the activities of peers, workmates, or 
others in one's social environment.
V62.4 (Z60.5) Target of (Perceived) Adverse Discrimination or Persecution
This category should be used when there is perceived or experienced discrimination 
against or persecution of the individual based on his or her membership (or perceived

membership) in a specific category. Typically, such categories include gender or gender 
identity, race, ethnicity, religion, sexual orientation, country of origin, political beliefs, dis­
ability status, caste, social status, weight, and physical appearance.
V62.9 (Z60.9) Unspecified Problem Related to Social Environment
This category should be used when there is a problem related to the individual's social en­
vironment other than as specified above.
Problems Related to Crime or Interaction 
With the Legal System
V62.89 (Z65.4) Victim of Crime
V62.5 (Z65.0) Conviction in Civil or Criminal Proceedings Without Imprisonment  
V62.5 (Z65.1) Imprisonment or Other Incarceration  
V62.5 (Z65.2) Problems Related to Release From Prison  
V62.5 (Z65.3) Problems Related to Other Legal Circumstances
Other Health Service Encounters for 
Counseling and Medical Advice
V65.49 (Z70.9) Sex Counseling
This category should be used when the individual seeks counseling related to sex educa­

tion, sexual behavior, sexual orientation, sexual attitudes (embarrassment, timidity), oth­
ers' sexual behavior or orientation (e.g., spouse, partner, child), sexual enjoyment, or any 
other sex-related issue.
V65.40 (Z71.9) Other Counseling or Consultation
This category should be used when counseling is provided or advice/consultation is 
sought for a problem that is not specified above or elsewhere in this chapter. Examples in­
clude spiritual or religious counseling, dietary counseling, and counseling on nicotine use.
Problems Related to Other Psychosocial, Personal, 
and Environmental Circumstances
V62.89 (Z65.8) Religious or Spiritual Problem
This category can be used when the focus of clinical attention is a religious or spiritual

This category can be used when the focus of clinical attention is a religious or spiritual 
problem. Examples include distressing experiences that involve loss or questioning of 
faith, problems associated with conversion to a new faith, or questioning of spiritual val­
ues that may not necessarily be related to an organized church or religious institution.
V61.7 (Z64.0) Problems Related to Unwanted Pregnancy
V61.5 (Z64.1) Problems Related to Multiparity
V62.89 (Z64.4) Discord With Social Service Provider, Including Probation Officer,  
Case Manager, or Social Services Worker
V62.89 (Z65.4) Victim of Terrorism or Torture
V62.22 (Z65.5) Exposure to Disaster, War, or Other Hostilities
V62.89 (Z65.8) Other Problem Related to Psychosocial Circumstances
V62.9 (Z65.9) Unspecified Problem Related to Unspecified Psychosocial Circum­
stances

Other Circumstances of Personal History
V15.49 (Z91.49) Other Personal History of Psychological Trauma
V15.59 (Z91.5) Personal History of Self-Harm
V62.22 (Z91.82) Personal History of Military Deployment
V15.89 (Z91.89) Other Personal Risk Factors
V69.9 (Z72.9) Problem Related to Lifestyle
This category should be used when a lifestyle problem is a specific focus of treatment or di­
rectly affects the course, prognosis, or treatment of a mental or other medical disorder. Ex­
amples of lifestyle problems include lack of physical exercise, inappropriate diet, high-risk 
sexual behavior, and poor sleep hygiene. A problem that is attributable to a symptom of a 
mental disorder should not be coded unless that problem is a specific focus of treatment or 
directly affects the course, prognosis, or treatment of the individual. In such cases, both the 
mental disorder and the lifestyle problem should be coded.
V71.01 (Z72.811  ) Adult Antisocial Behavior

This category can be used when the focus of clinical attention is adult antisocial behavior 
that is not due to a mental disorder (e.g., conduct disorder, antisocial personality disor­
der). Examples include the behavior of some professional thieves, racketeers, or dealers in 
illegal substances.
V71.02 (Z72.810) Child or Adolescent Antisocial Behavior
This category can be used when the focus of clinical attention is antisocial behavior in a 
child or adolescent that is not due to a mental disorder (e.g., intermittent explosive disor­
der, conduct disorder). Examples include isolated antisocial acts by children or adoles­
cents (not a pattern of antisocial behavior).
Problems Related to Access to Medical  
and Other Health Care
V63.9 (Z75.3) Unavailability or Inaccessibility of Health Care Facilities  
V63.8 (Z75.4) Unavailability or Inaccessibility of Other Helping Agencies

Nonadherence to M edical Treatm ent
V15.81 (Z91.19) Nonadherence to Medical Treatment
This category can be used when the focus of clinical attention is nonadherence to an im­
portant aspect of treatment for a mental disorder or another medical condition. Reasons 
for such nonadherence may include discomfort resulting from treatment (e.g., medication 
side effects), expense of treatment, personal value judgments or religious or cultural be­
liefs about the proposed treatment, age-related debility, and the presence of a mental dis­
order (e.g., schizophrenia, personality disorder). This category should be used only when 
the problem is sufficiently severe to warrant independent clinical attention and does not 
meet diagnostic criteria for psychological factors affecting other medical conditions.

278.00 (E66.9) Overweight or Obesity
This category may be used when overweight or obesity is a focus of clinical attention. 
V65.2 (Z76.5) Malingering
The essential feature of malingering is the intentional production of false or grossly exag­
gerated physical or psychological symptoms, motivated by external incentives such as 
avoiding military duty, avoiding work, obtaining financial compensation, evading crimi­
nal prosecution, or obtaining drugs. Under some circumstances, malingering may repre­

sent adaptive behavior—for example, feigning illness while a captive of the enemy during 
wartime. Malingering should be strongly suspected if any combination of the following is 
noted:
1. Medicolegal context of presentation (e.g., the individual is referred by an attorney to 
the clinician for examination, or the individual self-refers while litigation or criminal 
charges are pending).
2. Marked discrepancy between the individual's claimed stress or disability and the ob­
jective findings and observations.
3. Lack of cooperation during the diagnostic evaluation and in complying with the pre­
scribed treatment regimen.
4. The presence of antisocial personality disorder.
Malingering differs from factitious disorder in that the motivation for the symptom 
production in malingering is an external incentive, whereas in factitious disorder external 
incentives are absent. Malingering is differentiated from conversion disorder and somatic

incentives are absent. Malingering is differentiated from conversion disorder and somatic 
symptom-related mental disorders by the intentional production of symptoms and by the 
obvious external incentives associated with it. Definite evidence of feigning (such as clear 
evidence that loss of function is present during the examination but not at home) would 
suggest a diagnosis of factitious disorder if the individual's apparent aim is to assume the 
sick role, or malingering if it is to obtain an incentive, such as money.
V40.31 (Z91.83) Wandering Associated With a Mental Disorder
This category is used for individuals with a mental disorder whose desire to walk about 
leads to significant clinical management or safety concerns. For example, individuals with 
major neurocognitive or neurodevelopmental disorders may experience a restless urge to

major neurocognitive or neurodevelopmental disorders may experience a restless urge to 
wander that places them at risk for falls and causes them to leave supervised settings with­
out needed accompaniment. This category excludes individuals whose intent is to escape 
an unwanted housing situation (e.g., children who are running away from home, patients 
who no longer wish to remain in the hospital) or those who walk or pace as a result of med­
ication-induced akathisia.
Coding note: First code associated mental disorder (e.g., major neurocognitive disor­
der, autism spectrum disorder), then code V40.31 (Z91.83) wandering associated with 
[specific mental disorder].
V62.89 (R41.83) Borderline Intellectual Functioning
This category can be used when an individual's borderline intellectual functioning is the fo­

cus of clinical attention or has an impact on the individual's treatment or prognosis. Differ­
entiating borderline intellectual functioning and mild intellectual disability (intellectual 
developmental disorder) requires careful assessment of intellectual and adaptive functions 
and their discrepancies, particularly in the presence of co-occurring mental disorders that 
may affect patient compliance with standardized testing procedures (e.g., schizophrenia or 
attention-deficit/hyperactivity disorder with severe impulsivity).

: -ζ ' - ' i ; -  ---- -S E C T I Q I I l l l
Eilniefgmg MçasUrés and Mogels
Assessment Measures............................................................................ 733
Cross-Cutting Symptom Measures .................................................... 734
DSM-5 Self-Rated Level 1  Cross-Cutting  
Symptom Measure—Adult........................................................ 738
Parent/Guardian-Rated DSM-5 Level 1  Cross-Cutting  
Symptom Measure—Child Age 6 -1 7 ...................................... 740
Clinician-Rated Dimensions of Psychosis Symptom Severity .......... 742
World Health Organization Disability Assessment Schedule 2.0  
(WHODAS 2.0).................................................................................. 745
Cultural Formulation................................................................................ 749
Cultural Formulation Interview (CFI) .................................................... 750

Cultural Formulation Interview (CFI)—Informant Version .................. 755
Alternative DSM-5 Model for Personality Disorders .............................. 761
Conditions for Further Study.................................................................. 783
Attenuated Psychosis Syndrome ........................................................ 783
Depressive Episodes With Short-Duration Hypomania .................... 786
Persistent Complex Bereavement Disorder ...................................... 789
Caffeine Use Disorder.......................................................................... 792
Internet Gaming Disorder.................................................................... 795
Neurobehavioral Disorder Associated With

Neurobehavioral Disorder Associated With  
Prenatal Alcohol Exposure .............................................................. 798
Suicidal Behavior Disorder.................................................................. 801
Nonsuicidal Self-Injury........................................................................ 803

This section contains tools and techniques to enhance the clinical deci­
sion-making process, understand the cultural context of mental disorders, and  
recognize emerging diagnoses for further study. It provides strategies to en­
hance clinical practice and new criteria to stimulate future research, represent­
ing a dynamic DSM-5 that will evolve with advances in  the field.
Among the tools in Section III is a Level 1  cross-cutting self/informant-rated  
measure that serves as a review of systems across mental disorders. A clini­
cian-rated severity scale for schizophrenia and other psychotic disorders also  
is provided, as well as the World Health Organization Disability Assessment  
Schedule, Version 2 (WHODAS 2.0). Level 2 severity measures are available  
online (www.psychiatry.org/dsm5) and may be used to explore significant re­
sponses to the Level 1  screen. A comprehensive review of the cultural context

sponses to the Level 1  screen. A comprehensive review of the cultural context  
of mental disorders, and the Cultural Formulation Interview (CFI) for clinical use,  
are provided.
Proposed disorders for future study are provided, which include a new  
model for the diagnosis of personality disorders as an alternative to the estab­
lished diagnostic criteria; the proposed model incorporates impairments in per­
sonality functioning as well as pathological personality traits. Also included are  
new conditions that are the focus of active research, such as attenuated psy­
chosis syndrome and nonsuicidal self-injury.

Assessrilbnt 
Measures
A growing body of scientific evidence favors dimensional concepts in the diagnosis 
of mental disorders. The limitations of a categorical approach to diagnosis include the fail­
ure to find zones of rarity between diagnoses (i.e., delineation of mental disorders from one 
another by natural boundaries), the need for intermediate categories like schizoaffective dis­
order, high rates of comorbidity, frequent not-otherwise-specified (NOS) diagnoses, relative 
lack of utility in furthering the identification of unique antecedent validators for most men­
tal disorders, and lack of treatment specificity for the various diagnostic categories.
From both clinical and research perspectives, there is a need for a more dimensional 
approach that can be combined with DSM's set of categorical diagnoses. Such an approach 
incorporates variations of features within an individual (e.g., differential severity of indi­

vidual symptoms both within and outside of a disorder's diagnostic criteria as measured 
by intensity, duration, or number of symptoms, along with other features such as type and 
severity of disabilities) rather than relying on a simple yes-or-no approach. For diagnoses 
for which all symptoms are needed for a diagnosis (a monothetic criteria set), different se­
verity levels of the constituent symptoms may be noted. If a threshold endorsement of 
multiple symptoms is needed, such as at least five of nine symptoms for major depressive 
disorder (a polythetic criteria set), both severity levels and different combinations of the 
criteria may identify more homogeneous diagnostic groups.
A dimensional approach depending primarily on an individual's subjective reports of

A dimensional approach depending primarily on an individual's subjective reports of 
symptom experiences along with the clinician's interpretation is consistent with current 
diagnostic practice. It is expected that as our understanding of basic disease mechanisms 
based on pathophysiology, neurocircuitry, gene-environment interactions, and laboratory 
tests increases, approaches that integrate both objective and subjective patient data will be 
developed to supplement and enhance the accuracy of the diagnostic process.
Cross-cutting symptom measures modeled on general medicine's review of systems can 
serve as an approach for reviewing critical psychopathological domains. The general med­
ical review of systems is crucial to detecting subtle changes in different organ systems that 
can facilitate diagnosis and treatment. A similar review of various mental functions can

can facilitate diagnosis and treatment. A similar review of various mental functions can 
aid in a more comprehensive mental status assessment by drawing attention to symptoms 
that may not fit neatly into the diagnostic criteria suggested by the individual's presenting 
symptoms, but may nonetheless be important to the individual's care. The cross-cutting 
measures have two levels: Level 1 questions are a brief survey of 13 symptom domains for 
adult patients and 12 domains for child and adolescent patients. Level 2 questions provide 
a more in-depth assessment of certain domains. These measures were developed to be 
administered both at initial interview and over time to track the patient's symptom status 
and response to treatment.
Severity measures  are disorder-specific, corresponding closely to the criteria that consti­

tute the disorder definition. They may be administered to individuals who have received 
a diagnosis or who have a clinically significant syndrome that falls short of meeting full 
criteria for a diagnosis. Some of the assessments are self-completed by the individual, 
while others require a clinician to complete. As with the cross-cutting symptom measures, 
these measures were developed to be administered both at initial interview and over time 
to track the severity of the individual's disorder and response to treatment.

The World Health Organization Disability Assessment Schedule,  Version 2.0 (WHODAS 2.0) 
was developed to assess a patient's ability to perform activities in six areas: understanding 
and communicating; getting around; self-care; getting along with people; life activities 
(e.g., household, work/school); and participation in society. The scale is self-administered 
and was developed to be used in patients with any medical disorder. It corresponds to 
concepts contained in the WHO International Classification of Functioning, Disability 
and Health. This assessment can also be used over time to track changes in a patient's dis­
abilities.
This chapter focuses on the DSM-5 Level 1 Cross-Cutting Symptom Measure (adult 
self-rated and parent/guardian versions); the Clinician-Rated Dimensions of Psychosis 
Symptom Severity; and the WHODAS 2.0. Clinician instructions, scoring information, 
and interpretation guidelines are included for each. These measures and additional

and interpretation guidelines are included for each. These measures and additional 
dimensional assessments, including those for diagnostic severity, can be found online at 
www.psychiatry.org/dsmS.
Cross-Cutting Symptom Measures 
Level 1 Cross-Cutting Symptom Measure
The DSM-5 Level 1 Cross-Cutting Symptom Measure is a patient- or informant-rated mea­
sure that assesses mental health domains that are important across psychiatric diagnoses. 
It is intended to help clinicians identify additional areas of inquiry that may have signifi­
cant impact on the individual's treatment and prognosis. In addition, the measure may be 
used to track changes in the individual's symptom presentation over time.
The adult version of the measure consists of 23 questions that assess 13 psychiatric do­
mains, including depression, anger, mania, anxiety, somatic symptoms, suicidal ideation,

mains, including depression, anger, mania, anxiety, somatic symptoms, suicidal ideation, 
psychosis, sleep problems, memory, repetitive thoughts and behaviors, dissociation, per­
sonality functioning, and substance use (Table 1). Each domain consists of one to three 
questions. Each item inquires about how much (or how often) the individual has been 
bothered by the specific symptom during the past 2 weeks. If the individual is of impaired 
capacity and unable to complete the form (e.g., an individual with dementia), a laiowl- 
edgeable adult informant may complete this measure. The measure was found to be clin­
ically useful and to have good reliability in the DSM-5 field trials that were conducted in 
adult clinical samples across the United States and in Canada.
The parent/guardian-rated version of the measure (for children ages 6-17) consists of

The parent/guardian-rated version of the measure (for children ages 6-17) consists of 
25 questions that assess 12 psychiatric domains, including depression, anger, irritability, 
mania, anxiety, somatic symptoms, inattention, suicidal ideation/attempt, psychosis, 
sleep disturbance, repetitive thoughts and behaviors, and substance use (Table 2). Each 
item asks the parent or guardian to rate how much (or how often) his or her child has been 
bothered by the specific psychiatric symptom during the past 2 weeks. The measure was 
also found to be clinically useful and to have good reliability in the DSM-5 field trials that 
were conducted in pediatric clinical samples across the United States. For children ages 
11-17, along with the parent/guardian rating of the child's symptoms, the clinician may 
consider having the child complete the child-rated version of the measure. The child-rated

consider having the child complete the child-rated version of the measure. The child-rated 
version of the measure can be found online at www.psychiatry.org/dsm5.
Scoring and interpretation. On the adult self-rated version of the measure, each item is 
rated on a 5-point scale (O=none or not at all; l=slight or rare, less than a day or two; 2=mild 
or several days; 3=moderate or more than half the days; and 4=severe or nearly every day). 
The score on each item within a domain should be reviewed. However, a rating of mild (i.e., 
2) or greater on any item within a domain, except for substance use, suicidal ideation, and 
psychosis, may serve as a guide for additional inquiry and follow-up to determine if a more 
detailed assessment is necessary, which may include the Level 2 cross-cutting symptom as­
sessment for the domain (see Table 2). For substance use, suicidal ideahon, and psychosis, a

TA B LE  1 Adult DSM-5 Self-Rated Level 1  Cross-Cutting Symptom Measure:  
13 domains, thresholds for further inquiry, and associated DSM-5  
Level 2 measures
Dom ain Domain nameThreshold to guide DSM-5 Level 2 Cross-Cutting Symptom 
further inquiry M easure®
I. Depression Mild or greater Level 2—Depression—Adult (PROMIS  
Emotional Distress—Short Form)
II. Anger Mild or greater Level 2—Anger—Adult (PROMIS Emo­
tional Distress—Anger—Short Form)
III. Mania Mild or greater Level 2—Mania—Adult (Altman Self-Rating  
Mania Scale [ASRM])
IV. Anxiety Mild or greater Level 2—Anxiety—Adult (PROMIS  
Emotional Distress—Anxiety—Short  
Form)
V . Somatic symptoms Mild or greater Level 2—Somatic Symptom—Adult (Patient  
Health Questionnaire-15  
[PHQ-15] Somatic Symptom Severity  
Scale)
VI. Suicidal ideation Slight or greater None
VII. Psychosis Slight or greater None
VIII. Sleep problems Mild or greater Level 2—Sleep Disturbance—Adult  
(PROMIS Sleep Disturbance—Short Form)

Scale)
IX. Memory Mild or greater None
X. Repetitive thoughts  
and behaviorsMild or greater Level 2—Repetitive Thoughts and  
Behaviors—Adult (Florida Obsessive-  
Compulsive Inventory [FOCI] Severity  
Scale)
XI. Dissociation Mild or greater None
XII. Personality
functioningMild or greater None
XIII. Substance use Slight or greater Level 2—Substance Use—Adult (adapted  
from the NIDA-Modified ASSIST)
Note.  NIDA=National Institute on Drug Abuse.  
^Available at www.psychiatry.org/dsm5.
rating of slight (i.e., 1) or greater on any item within the domain may serve as a guide for ad­
ditional inquiry and follow-up to determine if a more detailed assessment is needed. As 
such, indicate the highest score within a domain in the "Highest domain score" column.

such, indicate the highest score within a domain in the "Highest domain score" column. 
Table 1  outlines threshold scores that may guide further inquiry for the remaining domains.
On the parent/guardian-rated version of the measure (for children ages 6-17), 19 of the 25 
items are each rated on a 5-point scale (O=none or not at aU ; l=slight or rare, less than a day or 
two; 2=mild or several days; 3=moderate or more than half the days; and 4=severe or nearly 
every day). The suicide ideation, suicide attempt, and substance abuse items are each rated on 
a "Yes, No, or Don't Know" scale. The score on each item within a domain should be re­
viewed. However, with the exception of inattention and psychosis, a rating of mild (i.e., 2) or 
greater on any item within a domain that is scored on the 5-point scale may serve as a guide

greater on any item within a domain that is scored on the 5-point scale may serve as a guide 
for additional inquiry and follow-up to determine if a more detailed assessment is necessary, 
which may include the Level 2 cross-cutting symptom assessment for the domain (see 
Table 2). For inattention or psychosis, a rating of slight or greater (i.e., 1  or greater) may be

TABLE 2 Parent/guardian-rated DSM-5 Level 1  Cross-Cutting Symptom Measure  
for child age 6 -1 7 :1 2  domains, thresholds for further inquiry, and  
associated Level 2 measures
I. Somatic symptoms Mild or greater Level 2—Somatic Symptoms—Parent/Guard­
ian of Child Age 6-17 (Patient Health  
Questionnaire-15 Somatic Symptom Sever­
ity Scale [PHQ-15])
II. Sleep problems Mild or greater Level 2—Sleep Disturbance—Parent/Guard­
ian of Child Age 6-17 (PROMIS Sleep  
Disturbance—Short Form)^
III. Inattention Slight or greater Level 2—Inattention—Parent/Guardian of  
Child Age 6-17 (Swanson, Nolan, and Pel­
ham, Version IV [SNAP-IV])
IV. Depression Mild or greater Level 2—Depression—Parent/Guardian of  
Child Age 6-17 (PROMIS Emotional Dis­
tress—Depression—Parent Item Bank)
V. Anger Mild or greater Level 2—Anger—Parent/Guardian of Child  
(PROMIS Calibrated Anger Measure—Parent)

VI. Irritability Mild or greater Level 2—Irritability—Parent/Guardian of  
Child (Affective Reactivity Index [ARI])
VII. Mania Mild or greater Level 2—Mania—Parent/Guardian of Child  
Age 6-17 (Altman Self-Rating Mania Scale  
[ASRM])
VIII. Anxiety Mild or greater Level 2—Anxiety—Parent/Guardian of Child  
Age 6-17 (PROMIS Emotional Distress— 
Anxiety—Parent Item Bank)
IX. Psychosis Slight or greater None
X. Repetitive thoughts Mild or greater  
and behaviorsNone
XI. Substance use Yes
Don't KnowLevel 2—Substance Use—Parent/Guardian of  
Child (adapted from the NIDA-modified  
ASSIST)
NIDA-modified ASSIST (adapted)—  
Child-Rated (age 11-17 years)
XII. Suicidal ideation/  
suicide attemptsYes
Don't KnowNone
None

None
used as an indicator for additional inquiry. A parent or guardian's rating of "Don't Know" on 
the suicidal ideation, suicide attempt, and any of the substance use items, especially for chil­
dren ages 11-17 years, may result in additional probing of the issues with the child, including 
using tiie child-rated Level 2 Cross-Cutting Symptom Measure for the relevant domain. Be­
cause additional inquiry is made on the basis of the highest score on any item within a do­
main, clinicians should indicate that score in the "Highest Domain Score" column. Table 2 
outlines threshold scores that may guide further inquiry for the remaining domains.

Level 2 Cross-Cutting Symptom Measures
Any threshold scores on the Level 1  Cross-Cutting Symptom Measure (as noted in Tables 
1  and 2 and described in "Scoring and Interpretation" indicate a possible need for detailed 
clinical inquiry. Level 2 Cross-Cutting Symptom Measures provide one method of obtain­
ing more in-depth information on potentially significant symptoms to inform diagnosis, 
treatment planning, and follow-up. They are available online at www.psychiatry.org/ 
dsmS. Tables 1 and 2 outline each Level 1 domain and identify the domains for which 
DSM-5 Level 2 Cross-Cutting Symptom Measures are available for more detailed assess­
ments. Adult and pediatric (parent and child) versions are available online for most Level 
1 symptom domains at www.psychiatry.org/dsm5.
Frequency of Use of the Cross-Cutting  
Symptom iVleasures
To track change in the individual's symptom presentation over time, the Level 1 and rel­

evant Level 2 cross-cutting symptom measures may be completed at regular intervals as 
clinically indicated, depending on the stability of the individual's symptoms and treat­
ment status. For individuals with impaired capacity and for children ages 6-17 years, it is 
preferable for the measures to be completed at follow-up appointments by the same 
knowledgeable informant and by the same parent or guardian. Consistently high scores 
on a particular domain may indicate significant and problematic symptoms for the indi­
vidual that might warrant further assessment, treatment, and follow-up. Clinical judg­
ment should guide decision making.

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Clinician-Rated Dimensions of 
Psychosis Symptom Severity
As described in the chapter "Schizophrenia Spectrum and Other Psychotic Disorders," 
psychotic disorders are heterogeneous, and symptom severity can predict important as­
pects of the illness, such as the degree of cognitive and/or neurobiological deficits. Dimen­
sional assessments capture meaningful variation in the severity of symptoms, which may 
help with treatment planning, prognostic decision-making, and research on pathophysi­
ological mechanisms. The Clinician-Rated Dimensions of Psychosis Symptom Severity 
provides scales for the dimensional assessment of the primary symptoms of psychosis, in­
cluding hallucinations, delusions, disorganized speech, abnormal psychomotor behavior, 
and negative symptoms. A scale for the dimensional assessment of cognitive impairment 
is also included. Many individuals with psychotic disorders have impairments in a range

is also included. Many individuals with psychotic disorders have impairments in a range 
of cogrutive domains, which predict functional abilities. In addition, scales for dimensional 
assessment of depression and mania are provided, which may alert clinicians to mood pa­
thology. The severity of mood symptoms in psychosis has prognostic value and guides 
The Clinician-Rated Dimensions of Psychosis Symptom Severity is an 8-item measure 
that may be completed by the clinician at the time of the clinical assessment. Each item asks 
the clinician to rate the severity of each symptom as experienced by the individual during 
the past 7 days.
Scoring and Interpretation
Each item on the measure is rated on a 5-point scale (O=none; l=equivocal; 2=present, but 
mild; 3=present and moderate; and 4=present and severe) with a symptom-specific defi­

nition of each rating level. The clinician may review all of the individual's available infor­
mation and, based on clinical judgment, select (by circling) the level that most accurately 
describes the severity of the individual's condition. The clinician then indicates the score 
for each item in the "Score" column provided.
Frequency of Use
To track changes in the individual's symptom severity over time, the measure may be 
completed at regular intervals as clinically indicated, depending on the stability of the in­
dividual's symptoms and treatment status. Consistently high scores on a particular do­
main may indicate significant and problematic areas for the individual that might warrant 
further assessment, treatment, and follow-up. Clinical judgment should guide decision 
making.

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World Health Organization 
' Disability Assessment Schedule 2.0
The adult self-administered version of the World Health Organization Disability Assessment 
Schedule 2.0 (WHODAS 2.0) is a 36-item measure that assesses disability in adults age 18 
years and older. It assesses disability across six domains, including understanding and 
communicating, getting around, sel^care, getting along with people, life activities (i.e., 
household, work, and/or school activities), and participation in society. If the adult indi­
vidual is of impaired capacity and unable to complete the form (e.g., a patient with demen­
tia), a knowledgeable informant may complete the proxy-administered version of the 
measure, which is available at www.psychiatry.org/dsm5. Each item on the self-administered 
version of the WHODAS 2.0 asks the individual to rate how much difficulty he or she has 
had in specific areas of functioning during the past 30 days.
WHODAS 2.0 Scoring Instructions Provided by WHO

WHODAS 2.0 summary scores. There are two basic options for computing the summary 
scores for the WHODAS 2.0 36-item full version.
Simple: The scores assigned to each of the items—"none" (1), "mild" (2), "moderate" (3), 
"severe" (4), and "extreme" (5)—are summed. This method is referred to as simple scoring 
because the scores from each of the items are simply added up without recoding or collaps­
ing of response categories; thus, there is no weighting of individual items. This approach is 
practical to use as a hand-scoring approach, and may be the method of choice in busy clin­
ical settings or in paper-and-pencil interview situations. As a result, the simple sum of the 
scores of the items across all domains constitutes a statistic that is sufficient to describe the

scores of the items across all domains constitutes a statistic that is sufficient to describe the 
degree of functional limitations.
Complex: The more complex method of scoring is called "item-response-theory" 
(IRT)-based scoring. It takes into account multiple levels of difficulty for each WHODAS
2.0 item. It takes the coding for each item response as "none," "mild," "moderate," "se­
vere," and "extreme" separately, and then uses a computer to determine the summary 
score by differentially weighting the items and the levels of severity. The computer pro­
gram is available from the WHO Web site. The scoring has three steps:
•  Step 1—Summing of recoded item scores within each domain.
•  Step 2—Summing of all six domain scores.
•  Step 3—Converting the summary score into a metric ranging from 0 to 100 
(where 0=no disability; 100=full disability).

WHODAS 2.0 domain scores. WHODAS 2.0 produces domain-specific scores for six 
different functioning domains: cognition, mobility, self-care, getting along, life activities 
(household and work/school), and participation.
WHODAS 2.0 population nomris. For the population norms for IRT-based scoring of the 
WHODAS 2.0 and for the population distribution of IRT-based scores for WHODAS 2.0, 
please see www.who.int/classifications/icf/Pop_norms_distrib_IRT_scores.pdf.
Additional Scoring and interpretation Guidance for  
DSiVI-5 Users
The clinician is asked to review the individual's response on each item on the measure 
during the clinical interview and to indicate the self-reported score for each item in the sec­
tion provided for "Clinician Use Only." However, if the clinician determines that the score

tion provided for "Clinician Use Only." However, if the clinician determines that the score 
on an item should be different based on the clinical interview and other information avail­

able, he or she may indicate a corrected score in the raw item score box. Based on findings 
from the DSM-5 Field Trials in adult patient samples across six sites in the United States 
and one in Canada, DSM-5 recommends calculation and use of average scores for each domain  
and for general disability.  The average scores are comparable to the WHODAS 5-point scale, 
which allows the clinician to think of the individual's disability in terms of none ( 1), mild 
(2), moderate (3), severe (4), or extreme (5). The average domain and general disability 
scores were found to be reliable, easy to use, and clinically useful to the clinicians in the 
DSM-5 Field Trials. The average domain score  is calculated by dividing the raw domain score 
by the number of items in the domain (e.g., if all the items within the "understanding and 
communicating" domain are rated as being moderate then the average domain score

communicating" domain are rated as being moderate then the average domain score 
would be 18/6=3, indicating moderate disability). The average general disability score  is cal­
culated by dividing the raw overall score by number of items in the measure (i.e., 36). The 
individual should be encouraged to complete all of the items on the WHODAS 2.0. If no re­
sponse is given on 10 or more items of the measure (i.e., more than 25% of the 36 total 
items), calculation of the simple and average general disability scores may not be helpful. 
If 10 or more of the total items on the measure are missing but the items for some of the do­
mains are 75%-100% complete, the simple or average domain scores may be used for those 
domains.
Frequency of use. To track change in the individual's level of disability over time, the

domains.
Frequency of use. To track change in the individual's level of disability over time, the 
measure may be completed at regular intervals as clinically indicated, depending on the 
stabihty of the individual's symptoms and treatment status. Consistently high scores on a 
particular domain may indicate significant and problematic areas for the individual that 
might warrant further assessment and intervention.

Patient Name:WHODAS 2.0
World Health Organization Disability Assessment Schedule 2.0
3 6 -ite m  version , self-ad m in istered
_________________ A g e: _______  Sex: □  Male □  Female Date: __________
This q u estio n n aire asks a b o u t difficulties d u e to  h e a lth /m e n ta l h ealth co n d itio n s. H ealth con d itio n s include d is e a se s o r  
illn esses, o th e r  h e a lth  p ro b le m s th a t m ay  b e s h o rt o r long lastin g, in ju ries, m e n ta l o r e m o tio n a l p ro b le m s, an d  p ro b lem s  
w ith  alcoh o l o r d ru g s. Think back o ver th e  p a st 3 0  d a y s and an sw er th e s e  q u estio n s thinking ab o u t how  m uch difficulty you  
had doing th e  follow ing activities. For each  q u estio n , p lease circle only o n e  resp o n se.
Numeric scores assigned to each of the items: j  ^  j 1 |  ^ |  3 j 4 5
In th e  last 30 d avs. how  m u ch  difficulty did you h ave in:
Understanding and communicating

D l.l Concentrating on doing something for ten minutes? None Mild M oderate SevereExtreme or  
cannot do
D1.2 Remembering to do imoortant things? None Mild Moderate SevereExtreme or  
cannot do
013Analvzinfi and finding solutions to oroblems in day-None Mild Moderate SevereIxtrem eo r  
cannot doto-day life? “ “
D1.4Learning a new task, for example, learning how to  
get to a new place?None Mild M oderate SevereExtreme or  
cannot do
D1.5 Generally understanding what people say? None Mild M oderate Severe^Extreme or  
cannot do
D1.6 Starting and maintaining a conversation? None Mild M oderate SevereExtreme or  
cannot do
Getti ng around
D2.1 Standing for long periods, such as 30 minutes? 1 None Mild Moderate SevereExtreme or  
cannot do
D2.2 Standing u d from sitting down? None Mild M oderate SevereExtreme or

cannot do
D2.2 Standing u d from sitting down? None Mild M oderate SevereExtreme or  
cannot do
D2.3 IMovIng around inside vour home? None Mild M oderate SevereExtreme or  
cannot do
D2.4 Gettingoutof vour home? None Mild M oderate SevereExtreme or  
cannot do
Walking a lone distance, such as a kilometer (or  
E g a le n t)?None Mild M oderate SevereExtreme or  
cannot do :
Self-care
D3:i washing vour whole bodv? None Mild M oderate SevereExtreme or  
cannot do
D3.2 Getting dressed?None Mild Moderate SevereExtreme or  
cannot do
D3.3None Mild M oderate SevereExtreme or  
cannot do
D3.4 Staving bv yourself for a few days? None Mild M oderate SevereExtreme or  
cannot do
Getting along with people
D4.1 Dealing with people vou do not know? None M ild M oderate SevereExtreme or  
cannot do
D4.2 Maintaining a friendship?None Mild Moderate SevereExtreme or  
cannot do

cannot do
cannot do
D4.3 Getting along with people who are close to you? None Mild Moderate SevereExtreme or  
cannot do
D4.4 Making new friends?None Mild M oderate SevereExtreme or  
cannot do
D4.5 Sexual activities?None M ild M oderate SevereExtreme or  
cannot doClinician Use  
Only
3 0
2 5
20

Clinician Use  
Only  -
Numeric scores assigned to each of the items: j  1 j ^  I  ^ 1  I  5
1 «| i sIIIIn th e  last 30 days, h ow  m uch difficulty did you h ave in:
Life activities—Household
D5.1 Taking care of your household responsibilities? None ^  Mild M oderate SevereExtreme or  
cann otd o
20 5 ;■D5.2 Doing most important household tasks well? None Mild M oderate SevereExtreme or  
cannot do
053Getting ail of the household work done that you  
needed to do?None ”  M l # M oderate SevereExtreme or  
cannot do
D5.4Getting vour household work done as auickiv as  
needed?None Mild M oderate SevereExtreme or  
cannot do
Life activities—School/Work
If you work (paid, non-paid, self-employed) or go to school, complete questions D5.5-D5.8, below.  
Otherwise, skip to D6.1.
Because of vour health condition, in the oast 30 days, how much difficultN did you have in:
0S.5 Your dav-to-dav work/school? - : None Miid M ^ ierate“ Severe“Extreme or  
can no t d o

can no t d o
iD5.6 Doing your most important work/school tasks well? None Mild M oderate SevereExtreme or  
cannot do-
D5 7 Setting ail of the work done that you need to do? ~ None Mild M oderate SevereExtreme or  
cannot do20 5
D5.8 Getting vour work done as auickiv as needed? None Mild M oderate SevereExtreme or  
cannot do
Participation in society
In the past 30 days:
06,1How much of a problem did vou have In joining in  
commimltv activities (for example, festivities. - ™
None Mild " Modeirate SevereExtreme or  
cannot do
40 5retigious, or other activities) in the same way as.  
anyone else can?
D6.2How much of a problem did you have because of
None Mild M oderate SevereExtreme or  
cannot do
£^3How much of a problem did vou have living with  
dfgnitv because of the attitudes and actions of

cannot do
p i» ? . ,  V  '  ' ,None Mild M oderate SevereExtreme or  
cannot do
D6.4How much time did you spend on your health  
condition or its consequences?None Some M oderate A LotExtreme or  
cannot do
D6.5much have vou been emotionaliv affected bv
None Mild SevereExtreme or  
cannot do health condition?M oderate
D6.6How much has vour health been a drain on the  
inancial resources of you or your family?None Mild M oderate SevereExtreme or  
cannot do
D6.7How much of a problem did your family have  
because of your health problems?None Mitd M oderate SevereExtreme or  
cannot do
D6.8How much of a problem did you have in doing
cannot do
G en eral Disability S co re (T otal):180 5

cannot do
cannot do
© World Health Organization, 2012. All rights reserved. Measuring health and disability: manual for WHO Disability  
Assessment Schedule (WHODAS 2.0), World Health Organization, 2010, Geneva.
The World Health Organization has granted the Publisher permission for the reproduction of this instrument. This material can  
be reproduced without permission by clinicians for use with their own patients. Any other use, including electronic use,  
requires written permission from WHO.

Cuitural
Formulation
UndGrStânding the cultursl context of niness experience is essential for effec­
tive diagnostic assessment and clinical management. Culture  refers to systems of knowl­
edge, concepts, rules, and practices that are learned and transmitted across generations. 
Culture includes language, religion and spirituality, family structures, life-cycle stages, 
ceremonial rituals, and customs, as well as moral and legal systems. Cultures are open, 
dynamic systems that undergo continuous change over time; in the contemporary world, 
most individuals and groups are exposed to multiple cultures, which they use to fashion 
their own identities and make sense of experience. These features of culture make it cru­
cial not to overgeneralize cultural information or stereotype groups in terms of fixed cul­
tural traits.
Race  is a culturally constructed category of identity that divides humanity into groups

Race  is a culturally constructed category of identity that divides humanity into groups 
based on a variety of superficial physical traits attributed to some hypothetical intrinsic, 
biological characteristics. Racial categories and constructs have varied widely over history 
and across societies. The construct of race has no consistent biological definition, but it is 
socially important because it supports racial ideologies, racism, discrimination, and social 
exclusion, which can have strong negative effects on mental health. There is evidence that 
racism can exacerbate many psychiatric disorders, contributing to poor outcome, and that 
racial biases' can affect diagnostic assessment.
Ethnicity  is a culturally constructed group identity used to define peoples and communi­
ties. It may be rooted in a common history, geography, language, religion, or other shared

ties. It may be rooted in a common history, geography, language, religion, or other shared 
characteristics of a group, which distinguish that group from others. Ethrücity may be self­
assigned or attributed by outsiders. Increasing mobility, intermarriage, and intermixing of 
cultures has defined new mixed, multiple, or hybrid ethnic identities.
Culture, race, and ethnicity are related to economic inequities, racism, and discrimina­
tion that result in health disparities. Cultural, ethnic, and racial identities can be sources of 
strength and group support that enhance resilience, but they may also lead to psycholog­
ical, interpersonal, and intergenerational conflict or difficulties in adaptation that require 
diagnostic assessment.
Outline for Cultural Formulation
The Outline for Cultural Formulation introduced in DSM-IV provided a framework for as­

sessing information about cultural features of an individual's mental health problem and 
how it relates to a social and cultural context and history. DSM-5 not only includes an up­
dated version of the Outline but also presents an approach to assessment, using the Cul­
tural Formulation Interview (CFI), which has been field-tested for diagnostic usefulness 
among clinicians and for acceptability among patients.
The revised Outline for Cultural Formulation calls for systematic assessment of the fol­
lowing categories:
•  Cultural identity of the individual: Describe the individual's racial, ethnic, or cultural 
reference groups that may influence his or her relationships with others, access to re­

sources, and developmental and current challenges, conflicts, or predicaments. For im­
migrants and racial or ethnic minorities, the degree and kinds of involvement with both 
the culture of origin and the host culture or majority culture should be noted separately. 
Language abilities, preferences, and patterns of use are relevant for identifying difficul­
ties with access to care, social integration, and the need for an interpreter. Other clini­
cally relevant aspects of identity may include religious affiliation, socioeconomic 
background, personal and family places of birth and growing up, migrant status, and 
sexual orientation.
•  Cultural conceptualizations of distress: Describe the cultural constructs that influence 
how the individual experiences, understands, and communicates his or her symptoms 
or problems to others. These constructs may include cultural syndromes, idioms of dis­
tress, and explanatory models or perceived causes. The level of severity and meaning of

tress, and explanatory models or perceived causes. The level of severity and meaning of 
the distressing experiences should be assessed in relation to the norms of the individ­
ual's cultural reference groups. Assessment of coping and help-seeking patterns should 
consider the use of professional as well as traditional, alternative, or complementary 
sources of care.
•  Psychosocial stressors and cultural features of vulnerability and resilience: Identify 
key stressors and supports in the individual's social environment (which may include 
both local and distant events) and the role of religion, family, and other social networks 
(e.g., friends, neighbors, coworkers) in providing emotional, instrumental, and infor­
mational support. Social stressors and social supports vary with cultural interpreta­
tions of events, family structure, developmental tasks, and social context. Levels of

tions of events, family structure, developmental tasks, and social context. Levels of 
functioning, disability, and resilience should be assessed in light of the individual's cul­
tural reference groups.
•  Cultural features of the relationship between the individual and the clinician: Iden­
tify differences in culture, language, and social status between an individual and clini­
cian that may cause difficulties in communication and may influence (diagnosis and 
treatment. Experiences of racism and discrimination in the larger society may impede 
establishing trust and safety in the clinical diagnostic encounter. Effects may include 
problems eliciting symptoms, misunderstanding of the cultural and clinical signifi­
cance of symptoms and behaviors, and difficulty establishing or maintaining the rap­
port needed for an effective clinical alliance.

•  Overall cultural assessment: Summarize the implications of the components of the cul­
tural formulation identified in earlier sections of the Outline for diagnosis and other 
clinically relevant issues or problems as well as appropriate management and treat­
ment intervention.
Cultural Formulation Interview (CFI)
The Cultural Formulation Interview (CFI) is a set of 16 questions that clinicians may use to 
obtain information during a mental health assessment about the impact of culture on key 
aspects of an individual's clinical presentation and care. In the CFI, culture  refers to
•  The values, orientations, knowledge, and practices that individuals derive from mem­
bership in diverse social groups (e.g., ethnic groups, faith communities, occupational 
groups, veterans groups).

•  Aspects of an individual's background, developmental experiences, and current social 
contexts that may affect his or her perspective, such as geographical origin, migration, 
language, religion, sexual orientation, or race/ethnicity.
•  The influence of family, friends, and other community members (the individual's social  
network)  on the individual's illness experience.

The CFI is a brief semistructured interview for systematically assessing cultural factors 
in the clinical enc;ounter that may be used with any individual. The CFI focuses on the in­
dividual's experience and the social contexts of the clinical problem. The CFI follows a per­
son-centered approach to cultural assessment by eliciting information from the individual 
about his or her own views and those of others in his or her social network. This approach 
is designed to avoid stereotyping, in that each individual's cultural knowledge affects how 
he or she interprets illness experience and guides how he or she seeks help. Because the 
CFI concerns the individual's personal views, there are no right or wrong answers to these 
questions. The interview follows and is available online at www.psychiatry.org/dsm5.
The CFI is formatted as two text columns. The left-hand column contains the instruc­
tions for administering the CFI and describes the goals for each interview domain. The

tions for administering the CFI and describes the goals for each interview domain. The 
questions in the right-hand column illustrate how to explore these domains, but they are 
not meant to be exhaustive. Follow-up questions may be needed to clarify individuals' an­
swers. Questions may be rephrased as needed. The CFI is intended as a guide to cultural as­
sessment and should be used flexibly to maintain a natural flow of the interview and rapport 
with the individual.
The CFI is best used in conjunction with demographic information obtained prior to 
the interview in order to tailor the CFI questions to address the individual's background 
and current situation. Specific demographic domains to be explored with the CFI will vary 
across individuals and settings. A comprehensive assessment may include place of birth,

across individuals and settings. A comprehensive assessment may include place of birth, 
age, gender, racial/ethnic origin, marital status, family composition, education, language 
fluencies, sexual orientation, religious or spiritual affiliation, occupation, employment, in­
come, and migration history.
The CFI can be used in the initial assessment of individuals in all clinical settings, regard­
less of the cultural background of the individual or of the clinician. Individuals and clini­
cians who appear to share the same cultural background may nevertheless differ in ways 
that are relevant to care. The CFI may be used in its entirety, or components may be incor­
porated into a clinical evaluation as needed. The CFI may be especially helpful when there is
•  Difficulty in diagnostic assessment owing to significant differences in the cultural, re­

ligious, or socioeconomic backgrounds of clinician and the individual.
•  Uncertainty about the fit between culturally distinctive symptoms and diagnostic criteria.
•  Difficulty in judging illness severity or impairment.
•  Disagreement between the individual and clinician on the course of care.
•  Limited engagement in and adherence to treatment by the individual.
The CFI emphasizes four domains of assessment: Cultural Definition of the Problem 
(questions 1-3); Cultural Perceptions of Cause, Context, and Support (questions 4-10); Cul­
tural Factors Affecting Self-Coping and Past Help Seeking (questions 11-13); and Cultural 
Factors Affecting Current Help Seeking (questions 14-16). Both the person-centered process

Factors Affecting Current Help Seeking (questions 14-16). Both the person-centered process 
of conducting the CFI and the information it elicits are intended to enhance the cultural va­
lidity of diagnostic assessment, facilitate treatment planning, and promote the individual's 
engagement and satisfaction. To achieve these goals, the information obtained from the CFI 
should be integrated with all other available clinical material into a comprehensive clinical 
and contextual evaluation. An Informant version of the CFI can be used to collect collateral 
information on the CFI domains from family members or caregivers.
Supplementary modules have been developed that expand on each domain of the CFI 
and guide clinicians who wish to explore these domains in greater depth. Supplementary 
modules have also been developed for specific populations, such as children and adoles­

cents, elderly individuals, and immigrants and refugees. These supplementary modules 
are referenced in the CFI under the pertinent subheadings and are available online at 
www.psychiatry.org/dsm5.

Supplementary modules used to expand each CFI subtopic are noted in parentheses.  
GUIDE TO INTERVIEWERINSTRUCTIONS TO THE INTERVIEWER ARE  
ITALICIZED,
The following questions aim to clarify key aspects of INTRODUCTION FOR THE INDIVIDUAL:
the presenting clinical problem from the point of  
view of the individual and other members of the  
individual's social network (i.e., family, friends, or  
others involved in current problem). This includes  
the problem's meaning, potential sources of help,  
and expectations for services.I would like to understand the problems that  
bring you here so that I can help you more  
effectively. I want to know about your  experi­
ence and ideas. I will ask some questions  
about what is going on and how you are deal­
ing with it. Please remember there are no  
right or wrong answers.
CULTURAL DEFINITION OF THE PROBLEM
Cultural  Οερινιήον  of the Problem
(Explanatory Model, Level of Functioning)
Elicit the individual's view o f core problems and key

Elicit the individual's view o f core problems and key  
concerns.
Focus on the individual's own way of understand­
ing the problem.
Use the term, expression, or brief description elicited  
in question 1  to identify the problem in subsequent  
questions (e.g., "your conflict with your son").
Ask how individual frames the problem for members  
of the social network.
Focus on the aspects o f the problem that matter most  
to the individual.2.
3.What brings you here today?
IF INDIVIDUAL GIVES FEW DETAILS OR  
ONLY MENTIONS SYMPTOMS OR A  
MEDICAL DIAGNOSIS, PROBE:
People often understand their problems in  
their own way, which may be similar to or  
different from how doctors describe the  
problem. How would you describe your  
problem?
Sometimes people have different ways of  
describing their problem to their family,

problem?
describing their problem to their family,  
friends, or others in their community. How  
would you describe your problem to them?  
What troubles you most about your prob­
lem?
CULTURAL PERCEPTIONS OF CAUSE, CONTEXT, AND SUPPORT
Causes
(Explanatory Model, Social Network, Older Adults)
This question indicates the meaning of the condition  4.  
for the individual, which may be relevant for clin­
ical care.
Note that individuals may identify multiple causes,  
depending on the facet of the problem they are con­
sidering.
Focus on the views of members of the individual's  
social network. These may be diverse and vary from  
the individual's.Why do you think this is happening to  
you? What do you think are the causes of  
your [PROBLEM]?
PROMPT FURTHER IF REQUIRED:
Some people may explain their problem as  
the result of bad things that happen in their

the result of bad things that happen in their  
life, problems with others, a physical ill­
ness, a spiritual reason, or many other  
causes.
What do others in your family, your  
friends, or others in your community think  
is causing your [PROBLEM]?

GUIDE TO INTERVIEWERINSTRUCTIONS TO TH E IN TERVIEW ER ARE 
ITALICIZED.
Stressors  and Supports  
(Social Network, Caregivers, Psychosocial Stressors, Religion and Spirituality, Immigrants and  
Refugees, Cultural Identity, Older Adults, Coping and Help Seeking)
Elicit information on the individual's life context,  
focusing on resources, social supports, and resil­
ience. May also probe other supports (e.g., from co­
workers, from participation in religion or spiritu­
ality).
Focus on stressful aspects o f the individuals envi­
ronment. Can also probe, e.g., relationship prob­
lems, difficulties at work or school, or  
discrimination.6. Are there any kinds of support that make  
your [PROBLEM] better, such as support  
from family, friends, or others?
7. Are there any kinds of stresses that make  
your [PROBLEM] worse, such as difficul­
ties with money, or family problems?
Role of Cultural  Identity

Role of Cultural  Identity  
(Cultural Identity, Psychosocial Stressors, Religion and Spirituality, Immigrants and Refugees,
Older Adults, Children and Adolescents)
Ask the individual to reflect on the most salient ele­
ments of his or her cultural identity. Use this  
information to tailor questions 9-10 as needed.
Elicit aspects o f identity that make the problem bet­
ter or worse.
Probe as needed (e.g., clinical worsening as a result  
of discrimination due to migration status, race!  
ethnicity, or sexual orientation).
Probe as needed (e.g., migration-related problems;  
conflict across generations or due to gender roles).Sometimes, aspects of people's back­
ground or identity can make their [PROB­
LEM] better or worse. By background  or 
identity,  I mean, for example, the commu­
nities you belong to, the languages you

nities you belong to, the languages you  
speak, where you or your family are from,  
your race or ethnic background, your gen­
der or sexual orientation, or your faith or  
religion.
8. For you, what are the most important  
aspects of your background or identity?
9. Are there any aspects of your background  
or identity that make a difference to your  
[PROBLEM]?
10. Are there any aspects of your background  
or identity that are causing other concerns  
or difficulties for you?
CULTURAL FACTORS AFFECTING SELF-COPING A N D  PAST HELP SEEKING
Self-Coping
(Coping and Help Seeking, Religion and Spirituality, Older Adults, Caregivers,
Psychosocial Stressors)
Clarify self-coping for the problem.  11. Sometimes people have various ways of
dealing with problems like [PROBLEM].  
What have you done on your own to cope  
with your [PROBLEM]?

Supplementary modules used to expand each CFI subtopic are noted in parentheses.
Past Help Seeking
(Coping and Help Seeking, Religion and Spirituality, Older Adults, Caregivers, Psychosocial  
Stressors, Immigrants and Refugees, Social Network, Clinician-Patient Relationship)
Elicit various sources of help (e.g., medical care, 12. Often, people look for help from many dif-
mental health treatment, support groups, work-  
based counseling, folk healing, religious or spiri­
tual counseling, other forms of traditional or alter­
native healing).
Probe as needed (e.g., "What other sources of help  
have you used?").
Clarify the individual's experience and regard for  
previous help.ferent sources, including different kinds of  
doctors, helpers, or healers. In the past,  
what kinds of treatment, help, advice, or  
healing have you sought for your [PROB­
LEM]?
PROBE IF DOES NOT DESCRIBE USE­
FULNESS OF HELP RECEIVED:
What types of help or treatment were most  
useful? Not useful?
Barriers

LEM]?
Barriers
(Coping and Help Seeking, Religion and Spirituality, Older Adults, Psychosocial Stressors, Immi­
grants and Refugees, Social Network, Clinician-Patient Relationship)
Clarify the role of social barriers to help seeking,  13. Has anything prevented you from getting  
access to care, and problems engaging in previous  
Probe details as needed (e.g., "What got in the  
way?").the help you need?
PROBE AS NEEDED:
For example, money, work or family com­
mitments, stigma or discrimination, or lack  
of services that understand your language  
or background?
CULTURAL FACTORS AFFECTING CURRENT HELP SEEKING
Preferences
(Social Network, Caregivers, Religion and Spirituality, Older Adults, Coping and Help Seeking)
Clarify individual's current perceived needs and  
expectations o f help, broadly defined.

Probe if individual lists only one source o f help (e.g., 
"What other kinds of help would be useful to you  
at this time?").
Focus on the views of the social network regarding  
help seeking.Now let's talk some more about the help  
you need.
14. What kinds of help do you think would be  
most useful to you at this time for your  
15. Are there other kinds of help that your fam­
ily, friends, or other people have suggested  
would be helpful for you now?
Clinician -Ραήεντ  Relationship
(Clinician-Patient Relationship, Older Adults)
Elicit possible concerns about the clinic or the clini­
cian-patient relationship, including perceived rac­
ism, language barriers, or cultural differences that  
may undermine goodwill, communication, or care  
delivery.

delivery.
Probe details as needed (e.g., "In what way?").
Address possible barriers to care or concerns about  
the clinic and the clinician-patient relationship  
raised previously.Sometimes doctors and patients misunder­
stand each other because they come from  
different backgrounds or have different  
expectations.
16. Have you been concerned about this and is  
there anything that we can do to provide  
you with the care you need?

Cultural Formulation Interview (CFI)—Informant Version
\
The CFI-Informant Version collects collateral information from an informant who is 
knowledgeable about the clinical problems and life circumstances of the identified indi­
vidual. This version can be used to supplement information obtained from the core CFI or 
can be used instead of the core CFI when the individual is unable to provide information— 
as might occur, for example, with children or adolescents, floridly psychotic individuals, 
or persons with cognitive impairment.
Cultural Formulation Interview (CFI)— Informant Version
The following questions aim to clarify key aspects of  
the presenting clinical problem from the infor­
mant's point of view. This includes the problem's  
meaning, potential sources of help, and expecta­
tions for services.INTRODUCTION FOR THE INFORMANT:
I would like to understand the problems that

I would like to understand the problems that  
bring your family member/friend here so  
that I can help you and him/her more effec­
tively. I want to know about your  experience  
and ideas. I will ask some questions about  
what is going on and how you and your fam­
ily member/friend are dealing with it. There  
are no right or wrong answers.
RELATIONSHIP WITH THE PATIENT
Clarify the informant's relationship with the indi­
vidual and/or the individual's family.1. How would you describe your relationship  
to [INDIVIDUAL OR TO FAMILY]?  
PROBE IF NOT CLEAR:
How often do you see [INDIVIDUAL]?
Elicit the informant's view o f core problems and key  2.  
concerns.
Focus on the informant's way of understanding the  
individual's problem.
Use the term, expression, or brief description elicited

concerns.
questions (e.g., "her conflict with her son").
Ask how informant frames the problem for members  3.  
Focus on the aspects of the problem that matter most  4.  
to the informant.What brings your family member/friend  
here today?
IF INFORMANT GIVES FEW DETAILS OR  
People often understand problems in their  
own way, which may be similar or differ­
ent from how doctors describe the prob­
lem. How would you describe  
[INDIVIDUAL'S] problem?
describing the problem to family, friends,  
or others in their conmiunity. How would  
you describe [INDIVIDUAL'S] problem to  
them?
What troubles you most about [INDIVID­
UAL'S] problem?

Causes
This question indicates the meaning o f the condition  5.  
for the informant, which may be relevant for clini­
cal care.
Note that informants may identify multiple causes  
sidering.Why do you think this is happening to  
[INDIVIDUAL]? What do you think are the  
causes of his/her [PROBLEM]?
Some people may explain the problem as the  
result of bad things that happen in their life,  
problems with others, a physical illness, a  
spiritual reason, or many other causes.
What do others in [INDIVIDUAL'S] fam­
ily, his/her friends, or others in the com­
munity think is causing [INDIVIDUAL'S]  
Supports
Elicit information on the individual's life context,  7. Are there any kinds of supports that makeFocus on the views of members of the individual's  6.  
social network. These may be diverse and vary  
from the informant's.
Stressors  and

ality).
Focus on stressful aspects of the individual's environ­
ment. Can also probe, e.g., relationship problems, dif­
ficulties at work or school, or discrimination.8.his/her [PROBLEM] better, such as from  
family, friends, or others?
Are there any kinds of stresses that make  
his/her [PROBLEM] worse, such as diffi­
culties with money, or family problems?
Ask the informant to reflect on the most salient ele­
ments of the individual's cultural identity. Use this  
information to tailor questions 10-11 as needed.  
of discrimination due to migration status, race!

conflict across generations or due to gender roles).Sometimes, aspects of people's background  
or identity can make the [PROBLEM] better  
or worse. By background  or identity,  I mean,  
for example, the communities you belong to,  
the languages you speak, where you or your  
family are from, your race or ethnic back­
ground, your gender or sexual orientation,  
and your faith or religion.
9. For you, what are the most important  
aspects of [INDIVIDUAL'S] background or  
identity?
10. Are there any aspects of [INDIVIDUAL'S]  
background or identity that make a differ­
ence to his/her [PROBLEM]?
11. Are there any aspects of [INDIVIDUAL'S]  
background or identity that are causing

background or identity that are causing  
other concerns or difficulties for him/her?

CULTURAL FACTORS AFFECTING SELF-COPING AND PAST HELP SEEKING
Clarify individual's self-coping for the problem. 12. Sometimes people have various ways of  
What has [INDIVIDUAL] done on his/her  
own to cope with his/her [PROBLEM]?  
Elicit various sources o f help (e.g., medical care,  
tual counseling, other alternative healing).
has he/she used?").
previous help.13. Often, people also look for help from many  
different sources, including different kinds  
of doctors, helpers, or healers. In the past,  
healing has [INDIVIDUAL] sought for his/  
her [PROBLEM]?
What types of help or treatment were most

Barriers
Clarify the role of social barriers to help-seeking,  14.  
way?").Has anything prevented [INDIVIDUAL]  
from getting the help he/she needs?
of services that understand his/her lan­
guage or background?
expectations of help, broadly defined, from the  
point of view of the informant.
Probe if informant lists only one source o f help (e.g.,  
"What other kinds o f help would be useful to  
IINDIVIDUALI at this time?").
Focus on the views o f the social network regarding

Focus on the views o f the social network regarding  
help seeking.Now let's talk about the help [INDIVID­
UAL] needs.
15. What kinds of help would be most useful to  
him/her at this time for his/her [PROB­
LEM]?
16. Are there other kinds of help that [INDI­
VIDUAL'S] family, friends, or other people  
have suggested would be helpful for him/  
her now?
Clinician -Patient  Relationship
delivery.
raised previously.Sometimes doctors and patients nüsunder-

raised previously.Sometimes doctors and patients nüsunder-  
17. Have you been concerned about this, and is  
[INDIVIDUAL] with the care he/she  
needs?

Cultural Concepts of Distress
Cultural concepts of distress  refers to ways that cultural groups experience, understand, and 
communicate suffering, behavioral problems, or troubling thoughts and emotions. Three 
main types of cultural concepts may be distinguished. Cultural syndromes  are clusters of 
symptoms and attributions that tend to co-occur among individuals in specific cultural 
groups, communities, or contexts and that are recognized locally as coherent patterns of 
experience. Cultural idioms of distress  are ways of expressing distress that may not involve 
specific symptoms or syndromes, but that provide collective, shared ways of experiencing 
and talking about personal or social concerns. For example, everyday talk about "nerves" 
or "depression" may refer to widely varying forms of suffering without mapping onto a 
discrete set of symptoms, syndrome, or disorder. Cultural explanations  or perceived causes

discrete set of symptoms, syndrome, or disorder. Cultural explanations  or perceived causes  
are labels, attributions, or features of an explanatory model that indicate culturally recog­
nized meaning or etiology for symptoms, illness, or distress.
These three concepts—syndromes, idioms, and explanations—are more relevant to 
clinical practice than the older formulation culture-bound syndrome.  Specifically, the term 
culture-bound syndrome  ignores the fact that clinically important cultural differences often 
involve explanations or experience of distress rather than culturally distinctive configura­
tions of symptoms. Furthermore, the term culture-bound  overemphasizes the local partic­
ularity and limited distribution of cultural concepts of distress. The current formulation 
acknowledges that all forms of distress are locally shaped, including the DSM disorders.

acknowledges that all forms of distress are locally shaped, including the DSM disorders. 
From this perspective, many DSM diagnoses can be understood as operationalized proto­
types that started out as cultural syndromes, and became widely accepted as a result of 
their clinical and research utility. Across groups there remain culturally patterned differ­
ences in symptoms, ways of talking about distress, and locally perceived causes, which are 
in turn associated with coping strategies and patterns of help seeking.
Cultural concepts arise from local folk or professional diagnostic systems for mental 
and emotional distress, and they may also reflect the influence of biomedical concepts. 
Cultural concepts have four key features in relation to the DSM-5 nosology:
•  There is seldom a one-to-one correspondence of any cultural concept with a DSM diag­

nostic entity; the correspondence is more likely to be one-to-many in either direction. 
Symptoms or behaviors that might be sorted by DSM-5 into several disorders may be 
included in a single folk concept, and diverse presentations that might be classified by 
DSM-5 as variants of a single disorder may be sorted into several distinct concepts by an 
indigenous diagnostic system.
•  Cultural concepts may apply to a wide range of severity, including presentations that 
do not meet DSM criteria for any mental disorder. For example, an individual with acute 
grief or a social predicament may use the same idiom of distress or display the same 
cultural syndrome as another individual with more severe psychopathology.
•  In common usage, the same cultural term frequently denotes more than one type of

•  In common usage, the same cultural term frequently denotes more than one type of 
cultural concept. A familiar example may be the concept of "depression," which may 
be used to describe a syndrome (e.g., major depressive disorder), an idiom of distress 
(e.g., as in the common expression "I feel depressed"), or a perceived cause (similar to 
"stress").
•  Like culture and DSM itself, cultural concepts may change over time in response to both 
local and global influences.
Cultural concepts are important to psychiatric diagnosis for several reasons:
•  To avoid misdiagnosis: Cultural variation in symptoms and in explanatory models as­
sociated with these cultural concepts may lead clinicians to misjudge the severity of a

problem or assign the wrong diagnosis (e.g., unfamiliar spiritual explanations may be 
misunderstood as psychosis).
•  To obtain useful clinical information: Cultural variations in symptoms and attribu­
tions may be associated with particular features of risk, resilience, and outcome.
•  To improve clinical rapport and engagement: "Speaking the language of the patient," 
both linguistically and in terms of his or her dominant concepts and metaphors, can re­
sult in greater communication and satisfaction, facilitate treatment negotiation, and 
lead to higher retention and adherence.
•  To improve therapeutic efficacy: Culture influences the psychological mechanisms of 
disorder, which need to be understood and addressed to improve clinical efficacy. For 
example, culturally specific catastrophic cognitions can contribute to symptom escala­
tion into panic attacks.
•  To guide clinical research: Locally perceived connections between cultural concepts

•  To guide clinical research: Locally perceived connections between cultural concepts 
may help identify patterns of comorbidity and underlying biological substrates.
•  To clarify the cultural epidemiology: Cultural concepts of distress are not endorsed 
uniformly by everyone in a given culture. Distinguishing syndromes, idioms, and ex­
planations provides an approach for studying the distribution of cultural features of ill­
ness across settings and regions, and over time. It also suggests questions about cultural 
determinants of risk, course, and outcome in clinical and community settings to en­
hance the evidence base of cultural research.
DSM-5 includes information on cultural concepts in order to improve the accuracy of 
diagnosis and the comprehensiveness of clinical assessment. Clinical assessment of indi­

viduals presenting with these cultural concepts should determine whether they meet 
DSM-5 criteria for a specified disorder or an other specified or unspecified  diagnosis. Once the 
disorder is diagnosed, the cultural terms and explanations should be included in case for­
mulations; they may help clarify symptoms and etiological attributions that could other­
wise be confusing. Individuals whose symptoms do not meet DSM criteria for a specific 
mental disorder may still expect and require treatment; this should be assessed on a case- 
by-case basis. In addition to the CFI and its supplementary modules, DSM-5 contains the 
following information and tools that may be useful when integrating cultural information 
in clinical practice:

•  Data in DSM-5 criteria and text for specific disorders: The text includes information 
on cultural variations in prevalence, symptomatology, associated cultural concepts, 
and other clinical aspects. It is important to emphasize that there is no one-to-one cor­
respondence at the categorical level between DSM disorders and cultural concepts. Dif­
ferential diagnosis for individuals must therefore incorporate information on cultural 
variation with information elicited by the CFI.
•  Other Conditions That May Be a Focus of Clinical Attention: Some of the clinical con­
cerns identified by the CFI may correspond to V codes or Z codes—for example, accul­
turation problems, parent-child relational problems, or religious or spiritual problems.
• Glossary of Cultural Concepts of Distress: Located in the Appendix, this glossary pro­

vides examples of well-studied cultural concepts of distress that illustrate the relevance 
of cultural information for clinical diagnosis and some of the interrelationships among 
cultural syndromes, idioms of distress, and causal explanations.

Alternative DSM-5 Model 
Pereonality b Îs o rÉ iii
ThG current approach to personality disorders appears in Section II of DSM- 5, 
and an alternative model developed for DSM-5 is presented here in Section III. The inclu­
sion of both models in DSM-5 reflects the decision of the APA Board of Trustees to pre­
serve continuity with current clinical practice, while also introducing a new approach that 
aims to address numerous shortcomings of the current approach to personality disorders. 
For example, the typical patient meeting criteria for a specific personality disorder fre­
quently also meets criteria for other personality disorders. Similarly, other specified or un­
specified personality disorder is often the correct (but mostly uninformative) diagnosis, in 
the sense that patients do not tend to present with patterns of symptoms that correspond 
with one and only one personality disorder.
In the following alternative DSM-5 model, personality disorders are characterized by

In the following alternative DSM-5 model, personality disorders are characterized by 
impairments in personality functioning  and pathological personality traits.  The specific 
personality disorder diagnoses that may be derived from this model include antisocial, 
avoidant, borderline, narcissistic, obsessive-compulsive, and schizotypal personality dis­
orders. This approach also includes a diagnosis of personality disorder—trait specified 
(PD-TS) that can be made when a personality disorder is considered present but the crite­
ria for a specific disorder are not met.
General Criteria for Personality Disorder
The essential features of a personality disorder are
A. Moderate or greater impairment in personality (self/interpersonal) functioning.
B. One or more pathological personality traits.
C. The impairments in personality functioning and the individual’s personality trait expres­

sion are relatively inflexible and pervasive across a broad range of personal and social  
situations.
D. The impairments in personality functioning and the individual’s personality trait expres­
sion are relatively stable across time, with onsets that can be traced back to at least  
E. The impairments in personality functioning and the individual’s personality trait expres­
sion are not better explained by another mental disorder.
F. The impairments in personality functioning and the individual’s personality trait expres­
sion are not solely attributable to the physiological effects of a substance or another  
medical condition (e.g., severe head trauma).
G. The impairments in personality functioning and the individual’s personality trait expres­

sion are not better understood as normal for an individual’s developmental stage or so­
ciocultural environment.

A diagnosis of a personality disorder requires two determinations: 1) an assessment of 
the level of impairment in personality functioning, w ^hich is needed for Criterion A, and 2) 
an evaluation of pathological personality traits, which is required for Criterion B. The im­
pairments in personality functioning and personality trait expression are relatively inflex­
ible and pervasive across a broad range of personal and social situations (Criterion C); 
relatively stable across time, with onsets that can be traced back to at least adolescence or 
early adulthood (Criterion D); not better explained by another mental disorder (Criterion 
E); not attributable to the effects of a substance or another medical condition (Criterion F); 
and not better understood as normal for an individual's developmental stage or sociocul­
tural environment (Criterion G). All Section III personality disorders described by criteria 
sets, as well as PD-TS, meet these general criteria, by definition.

Criterion A: Levei of Personaiity Functioning
Disturbances in self and interpersonal functioning constitute the core of personality psy­
chopathology and in this alternative diagnostic model they are evaluated on a continuum. 
Self functioning involves identity and self-direction; interpersonal functioning involves 
empathy and intimacy (see Table 1). The Level of Personality Functioning Scale (LPFS; see 
Table 2, pp. 775-778) uses each of these elements to differentiate five levels of impairment, 
ranging from little or no impairment (i.e., healthy, adaptive functioning; Level 0) to some 
(Level 1), moderate (Level 2), severe (Level 3), and extreme (Level 4) impairment.
TABLE 1 Elements of personality functioning
"selfi ^
1. Identity:  Experience of oneself as unique, with clear boundaries between self and others; sta­

"selfi ^
bility of self-esteem and accuracy of self-appraisal; capacity for, and ability to regulate, a  
range of emotional experience.
2. Self-direction:  Pursuit of coherent and meaningful short-term and life goals; utilization of  
constructive and prosocial internal standards of behavior; ability to self-reflect productively.
Interpersonal:
1. Empathy:  Comprehension and appreciation of others' experiences and motivations; tolerance  
of differing perspectives; understanding the effects of one's own behavior on others.
2. Intim acy:  Depth and duration of connection with others; desire and capacity for closeness;  
mutuality of regard reflected in interpersonal behavior.
Impairment in personality functioning predicts the presence of a personality disorder,

Impairment in personality functioning predicts the presence of a personality disorder, 
and the severity of impairment predicts whether an individual has more than one person­
ality disorder or one of the more typically severe personality disorders. A moderate level 
of impairment in personality functioning is required for the diagnosis of a personality dis­
order; this threshold is based on empirical evidence that the moderate level of impairment 
maximizes the ability of clinicians to accurately and efficiently identify personality disor­
der pathology.
Criterion B: Pathoiogicai Personaiity Traits
Pathological personality traits are organized into five broad domains: Negative Affectiv- 
ity. Detachment, Antagonism, Disinhibition, and Psychoticism. Within the five broad trait 
domains are 25 specific trait facets that were developed initially from a review of existing

domains are 25 specific trait facets that were developed initially from a review of existing 
trait models and subsequently through iterative research with samples of persons who 
sought mental health services. The full trait taxonomy is presented in Table 3 (see pp. 779­
781). The B criteria for the specific personality disorders comprise subsets of the 25 trait

facets, based on meta-analytic reviews and empirical data on the relationships of the traits 
to DSM-IV personality disorder diagnoses.
Criteria C and D: Pervasiveness and Stability
Impairments in personality functioning and pathological personality traits are relatively  per­
vasive across a range of personal and social contexts, as personality is defined as a pattern of 
perceiving, relating to, and thinking about the environment and oneself. The term relatively  
reflects the fact that all except the most extremely pathological personalities show some de­
gree of adaptability. The pattern in personality disorders is maladaptive and relatively inflex­
ible, which leads to disabilities in social, occupational, or other important pursuits, as 
individuals are unable to modify their thinking or behavior, even in the face of evidence that 
their approach is not working. The impairments in functioning and personality traits are also

their approach is not working. The impairments in functioning and personality traits are also 
relatively  stable. Personality traits—the dispositions to behave or feel in certain ways—are 
more stable than the symptomatic expressions of these dispositions, but personality traits can 
also change. Impairments in personality functioning are more stable than symptoms.
Criteria E, F, and G: Alternative Explanations for  
Personality Pathology (Differential Diagnosis)
On some occasions, what appears to be a personality disorder may be better explained by 
another mental disorder, the effects of a substance or another medical condition, or a nor­
mal developmental stage (e.g., adolescence, late life) or the individual's sociocultural en­
vironment. When another mental disorder is present, the diagnosis of a personality

vironment. When another mental disorder is present, the diagnosis of a personality 
disorder is not made, if the manifestations of the personality disorder clearly are an ex­
pression of the other mental disorder (e.g., if features of schizotypal personality disorder 
are present only in the context of schizophrenia). On the other hand, personality disorders 
can be accurately diagnosed in the presence of another mental disorder, such as major de­
pressive disorder, and patients with other mental disorders should be assessed for comor- 
bid personality disorders because personality disorders often impact the course of other 
mental disorders. Therefore, it is always appropriate to assess personality functioning and 
pathological personality traits to provide a context for other psychopathology.
Specific Personality Disorders

Section III includes diagnostic criteria for antisocial, avoidant, borderline, narcissistic, ob­
sessive-compulsive, and schizotypal personality disorders. Each personality disorder is 
defined by typical impairments in personality functioning (Criterion A) and characteristic 
pathological personality traits (Criterion B):
•  Typical features of antisocial personality disorder are a failure to conform to lawful 
and ethical behavior, and an egocentric, callous lack of concern for others, accompanied 
by deceitfulness, irresponsibility, manipulativeness, and/or risk taking.
•  Typical features of avoidant personality disorder are avoidance of social situations and 
inhibition in interpersonal relationships related to feelings of ineptitude and inade­
quacy, anxious preoccupation with negative evaluation and rejection, and fears of rid­
icule or embarrassment.

•  Typical features of borderline personality disorder are instability of self-image, per­
sonal goals, interpersonal relationships, and affects, accompanied by impulsivity, risk 
taking, and/or hostility.
•  Typical features of narcissistic personality disorder are variable and vulnerable self­
esteem, with attempts at regulation through attention and approval seeking, and either 
overt or covert grandiosity.

•  Typical features of obsessive-compulsive personality disorder are difficulties in estab­
lishing and sustaining close relationships, associated with rigid perfectionism, inflexi­
bility, and restricted emotional expression.
•  Typical features of schizotypal personality disorder are impairments in the capacity 
for social and close relationships, and eccentricities in cognition, perception, and behav­
ior that are associated with distorted self-image and incoherent personal goals and ac­
companied by suspiciousness and restricted emotional expression.
The A and B criteria for the six specific personality disorders and for PD-TS follow. All 
personality disorders also meet criteria C through G of the General Criteria for Personality 
Disorder.
Typical features of antisocial personality disorder are a failure to conform to lawful and 
ethical behavior, and an egocentric, callous lack of concern for others, accompanied by de­

ceitfulness, irresponsibility, manipulativeness, and/or risk taking. Characteristic difficul­
ties are apparent in identity, self-direction, empathy, and/or intimacy, as described below, 
along with specific maladaptive traits in the domains of Antagonism and Disinhibition.
Proposed Diagnostic Criteria
A. Moderate or greater impairment in personality functioning, manifested by characteristic  
difficulties in two or more of the following four areas:
1. Identity:  Egocentrism; self-esteem derived from personal gain, power, or pleasure.
2. Self-direction:  Goal setting based on personal gratification; absence of prosocial  
internal standards, associated with failure to conform to lawful or culturally norma­
tive ethical behavior.

3. Empathy:  Lack of concern for feelings, needs, or suffering of others; lack of re­
morse after hurting or mistreating another.
4. Intimacy:  Incapacity for mutually intimate relationships, as exploitation is a primary  
means of relating to others, including by deceit and coercion; use of dominance or  
intimidation to control others.
B. Six or more of the following seven pathological personality traits:
1. Manipulativeness  (an aspect of Antagonism): Frequent use of subterfuge to in­
fluence or control others; use of seduction, charm, glibness, or ingratiation to  
achieve one’s ends.
2. Callousness  (an aspect of Antagonism): Lack of concern for feelings or problems  
of others; lack of guilt or remorse about the negative or harmful effects of one’s ac­

tions on others; aggression; sadism.
3. Deceitfulness  (an aspect of Antagonism): Dishonesty and fraudulence; misrepre­
sentation of self; embellishment or fabrication when relating events.
4. Hostility  (an aspect of Antagonism): Persistent or frequent angry feelings; anger or  
irritability in  response to minor slights and insults; mean, nasty, or vengeful behavior.
5. Risk taking  (an aspect of Disinliibition): Engagement in dangerous, risky, and poten­
tially self-damaging activities, unnecessarily and without regard for consequences;  
boredom proneness and thoughtless initiation of activities to counter boredom; lack of  
concern for one’s lim itations and denial of the reality of personal danger.
6. Impulsivity  (an aspect of Disinhibition): Acting on the spur of the moment in re­

sponse to immediate stimuli; acting on a momentary basis without a plan or consid­
eration of outcomes; difficulty establishing and following plans.

7. Irresponsibility  (an aspect of Disinhibition); Disregard for—and failure to honor-  
financial ^nd other obligations or commitments; lack of respect for—and lack of fol­
low-through on—agreements and promises.
Note. The individual is at least 18 years of age.
With psychopathic features.
Specifiers. A distinct variant often termed psychopathy  (or "primary" psychopathy) is 
marked by a lack of anxiety or fear and by a bold inteφersonal style that may mask mal­
adaptive behaviors (e.g., fraudulence). This psychopathic variant is characterized by low 
levels of anxiousness (Negative Affectivity domain) and withdrawal (Detachment do­
main) and high levels of attention seeking (Antagonism domain). High attention seeking 
and low withdrawal capture the social potency (assertive/dominant) component of psy­
chopathy, whereas low anxiousness captures the stress immunity (emotional stability/re­
silience) component.

In addition to psychopathic features, trait and personality functioning specifiers may be 
used to record other personality features that may be present in antisocial personality dis­
order but are not required for the diagnosis. For example, traits of Negative Affectivity (e.g., 
anxiousness), are not diagnostic criteria for antisocial personality disorder (see Criterion B) 
but can be specified when appropriate. Furthermore, although moderate or greater impair­
ment in personality functioning is required for the diagnosis of antisocial personality disor­
der (Criterion A), the level of personality functioning can also be specified.
Typical features of avoidant personality disorder are avoidance of social situations and in­

hibition in interpersonal relationships related to feelings of ineptitude and inadequacy, 
anxious preoccupation with negative evaluation and rejection, and fears of ridicule or em­
barrassment. Characteristic difficulties are apparent in identity, self-direction, empathy, 
and/or intimacy, as described below, along with specific maladaptive traits in the do­
mains of Negative Affectivity and Detachment.
A. Moderate or greater impairment in personality functioning, manifest by characteristic  
difficulties in  two or more of the following four areas:
1. Identity:  Low self-esteem associated with self-appraisal as socially inept, person­
ally unappealing, or inferior; excessive feelings of shame.
2. Self-direction:  Unrealistic standards for behavior associated with reluctance to

2. Self-direction:  Unrealistic standards for behavior associated with reluctance to  
pursue goals, take personal risks, or engage in new activities involving inteφer-  
sonal contact.
3. Empathy:  Preoccupation with, and sensitivity to, criticism or rejection, associated  
with distorted inference of others’ perspectives as negative.
4. Intimacy:  Reluctance to get involved with people unless being certain of being  
liked: diminished mutuality within intimate relationships because of fear of being  
shamed or ridiculed.
B. Three or more of the following four pathological personality traits, one of which must  
be (1) Anxiousness:
1. Anxiousness  (an aspect of Negative Affectivity): Intense feelings of nervous­
ness, tenseness, or panic, often in  reaction to social situations: worry about the  
negative effects of past unpleasant experiences and future negative possibilities;

feeling fearful, apprehensive, or threatened by uncertainty; fears of embarrass­
ment.
2. Withdrawal  (an aspect of Detachment); Reticence in  social situations; avoidance  
of social contacts and activity; lack of initiation of social contact.
3. Anhedonia  (an aspect of Detachment): Lack of enjoyment from, engagement in,  
or energy for life’s experiences; deficits in  the capacity to feel pleasure or take in­
terest in things.
4. Intimacy avoidance  (an aspect of Detachment); Avoidance of close or romantic  
relationships, interpersonal attachments, and intimate sexual relationships.
Specifiers. Considerable heterogeneity in the form of additional personality traits is 
found among individuals diagnosed with avoidant personality disorder. Trait and level of 
personality functioning specifiers can be used to record additional personality features 
that may be present in avoidant personality disorder. For example, other Negative Affec-

that may be present in avoidant personality disorder. For example, other Negative Affec- 
tivity traits (e.g., depressivity, separation insecurity, submissiveness, suspiciousness, hos­
tility) are not diagnostic criteria for avoidant personality disorder (see Criterion B) but can 
be specified when  appropriate. Furthermore, although moderate or greater impairment in 
personality functioning is required for the diagnosis of avoidant personality disorder (Cri­
terion A), the level of personality functioning also can be specified.
Typical features of borderline personality disorder are instability of self-image, personal 
goals, interpersonal relationships, and affects, accompanied by impulsivity, risk taking, 
and/or hostility. Characteristic difficulties are apparent in identity, self-direction, empa­

thy, and/or intimacy, as described below, along with specific maladaptive traits in the do­
main of Negative Affectivity, and also Antagonism and/or Disinhibition.
A. Moderate or greater impairment in personality functioning, manifested by characteristic
1.  Identity:  Markedly impoverished, poorly developed, or unstable self-image, often  
associated with excessive self-criticism; chronic feelings of emptiness; dissociative  
states under stress.
2. Self-direction:  Instability in goals, aspirations, values, or career plans.
3. Empathy:  Compromised ability to recognize the feelings and needs of others asso­
ciated with inteφersonal hypersensitivity (i.e., prone to feel slighted or insulted); per­

ceptions of others selectively biased toward negative attributes or vulnerabilities.
4. Intimacy:  Intense, unstable, and conflicted close relationships, marked by mistrust,  
neediness, and anxious preoccupation with real or imagined abandonment; close  
relationships often viewed in extremes of idealization and devaluation and alternat­
ing between overinvolvement and withdrawal.
B. Four or more of the following seven pathological personality traits, at least one of which
must be (5) Impulsivity, (6) Risk taking, or (7) Hostility:
1. Emotional lability  (an aspect of Negative Affectivity): Unstable emotional expe­
riences and frequent mood changes; emotions that are easily aroused, intense,  
and/or out of proportion to events and circumstances.

2. Anxiousness  (an aspect of Negative Affectivity): Intense feelings of nervous­
ness, tenseness, or panic, often in  reaction to interpersonal stresses; worry about  
the negative effects of past unpleasant experiences and future negative possibili-

ties; feeling fearful, apprehensive, or threatened by uncertainty; fears of falling  
apart or Ipsing control.
3. Separation insecurity  (an aspect of Negative Affectivity): Fears of rejection by—  
and/or separation from—significant others, associated with fears of excessive de­
pendency and complete loss of autonomy.
4. Depressivity  (an aspect of Negative Affectivity): Frequent feelings of being down,  
miserable, and/or hopeless; difficulty recovering from such moods; pessimism  
about the future; pervasive shame; feelings of inferior self-worth; thoughts of sui­
cide and suicidal behavior.
5. Impulsivity  (an aspect of Disiniiibition): Acting on the spur of the moment in re­
eration of outcomes; difficulty establishing or following plans; a sense of urgency  
and self-harming behavior under emotional distress.
6. taking  (an aspect of Disiniiibition): Engagement in  dangerous, risky, and po­

tentially self-damaging activities, unnecessarily and without regard to conse­
quences; lack of concern for one’s limitations and denial of the reality of personal  
danger.
7. Hostility  (an aspect of Antagonism): Persistent or frequent angry feelings; anger  
or irritability in response to minor slights and insults.
Specifiers. Trait and level of personality functioning specifiers may be used to record ad­
ditional personality features that may be present in borderline personality disorder but are 
not required for the diagnosis. For example, traits of Psychoticism (e.g., cognitive and per­
ceptual dysregulation) are not diagnostic criteria for borderline personality disorder (see 
Criterion B) but can be specified when appropriate. Furthermore, although moderate or

Criterion B) but can be specified when appropriate. Furthermore, although moderate or 
greater impairment in personality functioning is required for the diagnosis of borderline 
personality disorder (Criterion A), the level of personality functioning can also be specified.
Narcissistic Personaiity Disorder
Typical features of narcissistic personality disorder are variable and vulnerable self-esteem, 
with attempts at regulation through attention and approval seeking, and either overt or 
covert grandiosity. Characteristic difficulties are apparent in identity, self-direction, em­
pathy, and/or intimacy, as described below, along with specific maladaptive traits in the 
domain of Antagonism.

1.  Identity:  Excessive reference to others for self-definition and self-esteem regula­
tion; exaggerated self-appraisal inflated or deflated, or vacillating between extremes;  
emotional regulation mirrors fluctuations in self-esteem.
2. Self-direction:  Goal setting based on gaining approval from others; personal stan­
dards unreasonably high in order to see oneself as exceptional, or too low based  
on a sense of entitlement; often unaware of own motivations.
3. Empathy:  Impaired ability to recognize or identify with the feelings and needs of  
others; excessively attuned to reactions of others, but only if perceived as relevant  
to self; over- or underestimate of own effect on others.
4. Intimacy:  Relationships largely superficial and exist to serve self-esteem regula­

tion; mutuality constrained by little genuine interest in others’ experiences and pre­
dominance of a need for personal gain.

B. Both of the following pathological personality traits:
1.  Grandiosity  (an aspect of Antagonism); Feelings of entitlement, either overt or co­
vert; self-centeredness; firmly holding to the belief that one is better than others;  
condescension toward others.
2. Attention seeldng  (an aspect of Antagonism): Excessive attempts to attract and  
be the focus of the attention of others; admiration seeking.
Specifiers. Trait and personality functioning specifiers may be used to record additional 
personality features that may be present in narcissistic personality disorder but are not re­
quired for the diagnosis. For example, other traits of Antagonism (e.g., manipulativeness, de­
ceitfulness, callousness) are not diagnostic criteria for narcissistic personality disorder (see 
Criterion B) but can be specified v^hen more pervasive antagonistic feahires (e.g., "malignant 
narcissism") are present. Other traits of Negative Affectivity (e.g., depressivity, anxiousness)

narcissism") are present. Other traits of Negative Affectivity (e.g., depressivity, anxiousness) 
can be specified to record more "vulnerable" presentations. Furtiiermore, although moderate 
or greater impairment in personality functioning is required for the diagnosis of narcissistic 
Obsessive-Compulsive Personaiity Disorder
Typical features of obsessive-compulsive personality disorder are difficulties in establish­
ing and sustaining close relationships, associated with rigid perfectionism, inflexibility, 
and restricted emotional expression. Characteristic difficulties are apparent in identity, 
self-direction, empathy, and/or intimacy, as described below, along v^ith specific mal­
adaptive traits in the domains of Negative Affectivity and/or Detachment.

1. Identity:  Sense of self derived predominantly from work or productivity; constricted  
experience and expression of strong emotions.
2. Self-direction:  Difficulty completing tasks and realizing goals, associated with rigid  
and unreasonably high and inflexible internal standards of behavior; overly consci­
entious and moralistic attitudes.
3. Empathy:  Difficulty understanding and appreciating the ideas, feelings, or behav­
iors of others.
4. Intimacy:  Relationships seen as secondary to work and productivity; rigidity and  
stubbornness negatively affect relationships with others.

B. Three or more of the following four pathological personality traits, one of which must
be (1) Rigid perfectionism:
1. Rigid perfectionism  (an aspect of extreme Conscientiousness [the opposite pole  
of Detachment]): Rigid insistence on everything being flawless, perfect, and without  
errors or faults, including one’s own and others’ performance; sacrificing of timeli­
ness to ensure correctness in every detail; believing that there is only one right way  
to do things; difficulty changing ideas and/or viewpoint; preoccupation with details,  
organization, and order.
2. Perseveration  (an aspect of Negative Affectivity): Persistence at tasks long after  
the behavior has ceased to be functional or effective; continuance of the same be­
havior despite repeated failures.

3. intimacy avoidance  (an aspect of Detachment): Avoidance of close or romantic  

4. Restricted affectivity  (an aspect of Detachment); Little reaction to emotionally  
arousing situations; constricted emotional experience and expression; indifference  
or coldness.
personality features that may be present in obsessive-compulsive personality disorder but are 
not required for the diagnosis. For example, other traits of Negative Affectivity (e.g., anxious­
ness) are not diagnostic criteria for obsessive-compulsive personality disorder (see Criterion B) 
ment in personality functioning is required for the diagnosis of obsessive-compulsive person­
ality disorder (Criterion A), the level of personality functioning can also be specified.
Typical features of schizotypal personality disorder are impairments in the capacity for so­

cial and close relationships and eccentricities in cognition, perception, and behavior that 
are associated with distorted self-image and incoherent personal goals and accompanied 
by suspiciousness and restricted emotional expression. Characteristic difficulties are ap­
parent in identity, self-direction, empathy, and/or intimacy, along with specific maladap­
tive traits in the domains of Psychoticism and Detachment.
1.  Identity:  Confused boundaries between self and others; distorted self-concept;  
emotional expression often not congruent with context or internal experience.
2. Self-direction:  Unrealistic or incoherent goals; no clear set of internal standards.

3. Empathy:  Pronounced difficulty understanding impact of own behaviors on others;  
frequent misinterpretations of others’ motivations and behaviors.
4. Intimacy:  Marked impairments in developing close relationships, associated with  
mistrust and anxiety.
B. Four or more of the following six pathological personality traits:
1.  Cognitive and perceptual dysregulation  (an aspect of Psychoticism): Odd or
unusual thought processes; vague, circumstantial, metaphorical, overelaborate, or  
stereotyped thought or speech; odd sensations in various sensory modalities.
2. Unusual beliefs and experiences  (an aspect of Psychoticism): Thought content  
and views of reality that are viewed by others as bizarre or idiosyncratic; unusual  
experiences of reality.

3. Eccentricity  (an aspect of Psychoticism): Odd, unusual, or bizarre behavior or  
appearance; saying unusual or inappropriate things.
4. Restricted affectivity  (an aspect of Detachment): Little reaction to emotionally  
5. Withdrawal  (an aspect of Detachment): Preference for being alone to being with  
others; reticence in social situations; avoidance of social contacts and activity; lack  
of initiation of social contact.
6. Suspiciousness  (an aspect of Detachment): Expectations of—and heightened  
sensitivity to—signs of interpersonal ill-intent or harm; doubts about loyalty and fi­
delity of others; feelings of persecution.

personality features that may be present in schizotypal personality disorder but are not re­
quired for the diagnosis. For example, traits of Negative Affectivity (e.g., depressivity, 
anxiousness) are not diagnostic criteria for schizotypal personality disorder (see Criterion 
B) but can be specified when appropriate. Furthermore, although moderate or greater im­
pairment in personality functioning is required for the diagnosis of schizotypal personal­
ity disorder (Criterion A), the level of personality functioning can also be specified.
Personality Disorder—Trait Specified
A. Moderate or greater impairment in personality functioning, manifested by difficulties in
two or more of the following four areas:
1. Identity
2. Self-direction
3. Empathy
4. Intimacy
B. One or more pathological personality trait domains OR specific trait facets within do­

3. Empathy
mains, considering ALL of the following domains:
1. Negative Affectivity (vs. Emotional Stability): Frequent and intense experiences  
of high levels of a wide range of negative emotions (e.g., anxiety, depression, guilt/  
shame, worry, anger), and their behavioral (e.g., self-harm) and interpersonal (e.g.,  
dependency) manifestations.
2. Detachment'(vs. Extraversion): Avoidance of socioemotional experience, includ­
ing both withdrawal from inteφersonal interactions, ranging from casual, daily in­
teractions to friendships to intimate relationships, as well as restricted affective  
experience and expression, particularly limited hedonic capacity.
3. Antagonism (vs. Agreeableness): Behaviors that put the individual at odds with

3. Antagonism (vs. Agreeableness): Behaviors that put the individual at odds with  
other people, including an exaggerated sense of self-importance and a concomi­
tant expectation of special treatment, as well as a callous antipathy toward others,  
encompassing both unawareness of others’ needs and feelings, and a readiness  
to use others in the service of self-enhancement.
4. Disinfiibition (vs. Conscientiousness): Orientation toward immediate gratification,  
leading to impulsive behavior driven by current thoughts, feelings, and external  
stimuli, without regard for past learning or consideration of future consequences.
5. Psychoticism (vs. Lucidity): Exhibiting a wide range of culturally incongruent odd,  
eccentric, or unusual behaviors and cognitions, including both process (e.g., per­
ception, dissociation) and content (e.g., beliefs).

Subtypes. Because personality features vary continuously along multiple trait dimen­
sions, a comprehensive set of potential expressions of PD-TS can be represented by DBM­
S's dimensional model of maladaptive personality trait variants (see Table 3, pp. 779-781). 
Thus, subtypes are unnecessary for PD-TS, and instead, the descriptive elements that con­
stitute personality are provided, arranged in an empirically based model. This arrange­
ment allows clinicians to tailor the description of each individual's personality disorder 
profile, considering all five broad domains of personality trait variation and drawing on 
the descriptive features of these domains as needed to characterize the individual.

Specifiers, The specific personality features of individuals are always recorded in eval­
uating Criterion Ç, so the combination of personality features characterizing an individual 
directly constitutes the specifiers in each case. For example, two individuals who are both 
characterized by emotional lability, hostility, and depressivity may differ such that the 
first individual is characterized additionally by callousness, whereas the second is not.
Personality Disorder Sooring Algorithms
The requirement for any two of the four A criteria for each of the six personality disorders 
was based on maximizing the relationship of these criteria to their corresponding person­
ality disorder. Diagnostic thresholds for the B criteria were also set empirically to miiümize 
change in prevalence of the disorders from DSM-IV and overlap with other personality 
disorders, and to maximize relationships with functional impairment. The resulting diag­

nostic criteria sets represent clinically useful personality disorders with high fidelity, in 
terms of core impairments in personality functioning of varying degrees of severity and 
constellations of pathological personality traits.
Personality Disorder Diagnosis
Individuals who have a pattern of impairment in personality functioning and maladaptive 
traits that matches one of the six defined personality disorders should be diagnosed with 
that personality disorder. If an individual also has one or even several prominent traits that 
may have clinical relevance in addition to those required for the diagnosis (e.g., see narcis­
sistic personality disorder), the option exists for these to be noted as specifiers. Individuals

sistic personality disorder), the option exists for these to be noted as specifiers. Individuals 
whose personality functioning or trait pattern is substantially different from that of any of 
the six specific personality disorders should be diagnosed with PD-TS. The individual may 
not meet the required number of A or B criteria and, thus, have a subthreshold presentation 
of a personality disorder. The individual may have a mix of features of personality disorder 
types or some features that are less characteristic of a type and more accurately considered 
a mixed or atypical presentation. The specific level of impairment in personality function­
ing and the pathological personality traits that characterize the individual's personality can 
be specified for PD-TS, using the Level of Personality Functioning Scale (Table 2) and the

be specified for PD-TS, using the Level of Personality Functioning Scale (Table 2) and the 
pathological trait taxonomy (Table 3). The current diagnoses of paranoid, schizoid, histri­
onic, and dependent personality disorders are represented also by the diagnosis of PD-TS; 
these are defined by moderate or greater impairment in personality functioning and can be 
specified by the relevant pathological personality trait combinations.
Level of Personality Functioning
Like most human tendencies, personality functioning is distributed on a continuum. Cen­
tral to functioning and adaptation are individuals' characteristic ways of thinking about 
and understanding themselves and their interactions with others. An optimally function­
ing individual has a complex, fully elaborated, and well-integrated psychological world

ing individual has a complex, fully elaborated, and well-integrated psychological world 
that includes a mostly positive, volitional, and adaptive self-concept; a rich, broad, and ap­
propriately regulated emotional life; and the capacity to behave as a productive member of 
society with reciprocal and fulfilling interpersonal relationships. At the opposite end of 
the continuum, an individual with severe personality pathology has an impoverished, dis- 
orgarüzed, and/or conflicted psychological world that includes a weak, unclear, and mal­
adaptive self-concept; a propensity to negative, dysregulated emotions; and a deficient 
capacity for adaptive interpersonal functioning and social behavior.

S e lf -  and I n t e r p e r s o n a l  Functioning  
Dimensional Definition
Generalized severity may be the most important single predictor of concurrent and pro­
spective dysfunction in assessing personality psychopathology. Personality disorders are 
optimally characterized by a generalized personality severity continuum with additional 
specification of stylistic elements, derived from personality disorder symptom constella­
tions and personality traits. At the same time, the core of personality psychopathology is 
impairment in ideas and feelings regarding self and interpersonal relationships; this no­
tion is consistent with multiple theories of personality disorder and their research bases. The 
components of the Level of Personality Functioning Scale—identity, self-direction, empa­
thy, and intimacy (see Table 1)—are particularly central in describing a personality func­
tioning continuum.
Mental representations of the self and interpersonal relationships are reciprocally in­

fluential and inextricably tied, affect the nature of interaction with mental health pro­
fessionals, and can have a significant impact on both treatment efficacy and outcome, 
underscoring the importance of assessing an individual's characteristic self-concept as 
well as views of other people and relationships. Although the degree of disturbance in the 
self and interpersonal functioning is continuously distributed, it is useful to consider the 
level of impairment in functioning for clinical characterization and for treatment planning 
and prognosis.
Rating Levei of Personaiity Functioning
To use the Level of Personality Functioning Scale (LPFS), the clinician selects the level that 
most closely captures the individual's current overall  level of impairment in personality func­

tioning. The rating is necessary for the diagnosis of a personality disorder (moderate or greater 
impairment) and can be used to specify the severity of impairment present for an individual 
with any personality disorder at a given point in time. The LPFS may also be used as a global 
indicator of personality functioning without specification of a personality disorder diagnosis, 
or in the event that personality impairment is subthreshold for a disorder diagnosis.
Personality Traits
Definition and Description
Criterion B in the alternative model involves assessments of personality traits that are 
grouped into five domains. A personality trait  is a tendency to feel, perceive, behave, and 
think in relatively consistent ways across time and across situations in which the trait may

think in relatively consistent ways across time and across situations in which the trait may 
manifest. For example, individuals with a high level of the personality trait of anxiousness  
would tend to feel  anxious readily, including in circumstances in which most people 
would be calm and relaxed. Individuals high in trait anxiousness also would perceive  sit­
uations to be anxiety-provoking more frequently than would individuals with lower lev­
els of this trait, and those high in the trait would tend to behave  so as to avoid situations that 
they think  would make them anxious. They would thereby tend to think  about the world as 
more anxiety provoking than other people.
Importantly, individuals high in trait anxiousness would not necessarily be anxious at 
all times and in all situations. Individuals' trait levels also can and do change throughout

all times and in all situations. Individuals' trait levels also can and do change throughout 
life. Some changes are very general and reflect maturation (e.g., teenagers generally are 
higher on trait impulsivity than are older adults), whereas other changes reflect individ­
uals' life experiences.
Dimensionality of peiOonality traits. All individuals can be located on the spectrum of 
trait dimensions; that is, personality traits apply to everyone in different degrees rather

than being present versus absent. Moreover, personality traits, including those identified 
specifically in tl^ e Section III model, exist on a spectrum v^ith two opposing poles. For ex­
ample, the opposite of the trait of callousness  is the tendency to be empathie and kind- 
hearted, even in circumstances in w ^hich most persons would not feel that way. Hence, al­
though in Section III this trait is labeled callousness,  because that pole of the dimension is 
the primary focus, it could be described in full as callousness versus kind-heartedness.  More­
over, its opposite pole can be recognized and may not be adaptive in all circumstances 
(e.g., individuals who, due to extreme kind-heartedness, repeatedly allow themselves to 
be taken advantage of by unscrupulous others).
Hierarchical structure of personality. Some trait terms are quite specific (e.g., "talkative") 
and describe a narrow range of behaviors, whereas others are quite broad (e.g.. Detach­

ment) and characterize a wide range of behavioral propensities. Broad trait dimensions 
are called domains,  and specific trait dimensions are called facets.  Personality trait domains  
comprise a spectrum of more specific personality facets  that tend to occur together. For ex­
ample, withdrawal and anhedonia are specific trait facets  in the trait domain  of Detachment. 
Despite some cross-cultural variation in personality trait facets, the broad domains they 
collectively comprise are relatively consistent across cultures.
The Personality Trait IVlodel
The Section III personality trait system includes five broad domains of personality trait 
variation—Negative Affectivity (vs. Emotional Stability), Detachment (vs. Extraversion),

variation—Negative Affectivity (vs. Emotional Stability), Detachment (vs. Extraversion), 
Antagonism (vs. Agreeableness), Disinhibition (vs. Conscientiousness), and Psychoticism 
(vs. Lucidity)—comprising 25 specific personality trait facets. Table 3 provides definitions 
of all personality domains and facets. These five broad domains are maladaptive variants 
of the five domains of the extensively validated and replicated personality model known 
as the "Big Five", or Five Factor Model of personality (FFM), and are also similar to the do­
mains of the Personality Psychopathology Five (PSY-5). The specific 25 facets represent a 
list of personality facets chosen for their clinical relevance.
Although the Trait Model focuses on personality traits associated with psychopathol­
ogy, there are healthy, adaptive, and resilient personality traits identified as the polar

ogy, there are healthy, adaptive, and resilient personality traits identified as the polar 
opposites of these traits, as noted in the parentheses above (i.e.. Emotional Stability, Ex­
tra version, Agreeableness, Conscientiousness, and Lucidity). Their presence can greatly 
mitigate the effects of mental disorders and facilitate coping and recovery from traumatic 
injuries and other medical illness.
Distinguishing Traits, Symptoms, and Specific Behaviors
Although traits are by no means immutable and do change throughout the life span, they 
show relative consistency compared with symptoms and specific behaviors. For example, 
a person may behave impulsively at a specific time for a specific reason (e.g., a person who 
is rarely impulsive suddenly decides to spend a great deal of money on a particular item 
because of an unusual opportunity to purchase something of unique value), but it is only

because of an unusual opportunity to purchase something of unique value), but it is only 
when behaviors aggregate across time and circumstance, such that a pattern of behavior 
distinguishes between individuals, that they reflect traits. Nevertheless, it is important to 
recognize, for example, that even people who are impulsive are not acting impulsively all 
of the time. A trait is a tendency or disposition toward specific behaviors; a specific behav­
ior is an instance or manifestation of a trait.
Similarly, traits are distinguished from most symptoms because symptoms tend to 
wax and wane, whereas traits are relatively more stable. For example, individuals with 
higher levels of depressivity  have a greater likelihood of experiencing discrete episodes of a 
depressive disorder and of showing the symptoms of these disorders, such difficulty con­

centrating. However, even patients who have a trait propensity to depressivity  typically cy­
cle through distinguishable episodes of mood disturbance, and specific symptoms such as

difficulty concentrating tend to wax and wane in concert with specific episodes, so they do 
not form part of the trait definition. Importantly, however, symptoms and traits are both 
amenable to intervention, and many interventions targeted at symptoms can affect the 
longer term patterns of personality functioning that are captured by personality traits.
Assessment of the DSM-5 Section III  
Personality Trait Model
The clinical utility of the Section ΙΠ  multidimensional personality trait model lies in its ability 
to focus attention on multiple relevant areas of personality variation in each individual patient. 
Rather than focusing attention on the identification of one and only one optimal diagnostic 
label, clinical application of the Section III personality trait model involves reviewing all five 
broad personality domains portrayed in Table 3. The clinical approach to personality is similar

broad personality domains portrayed in Table 3. The clinical approach to personality is similar 
to the well-known review of systems in clinical medicine. For example, an individual's pre­
senting complaint may focus on a specific neurological symptom, yet during an initial 
evaluation clinicians still systematically review functioning in all relevant systems (e.g., car­
diovascular, respiratory, gastrointestinal), lest an important area of diminished functioning 
and corresponding opportunity for effective intervention be missed.
Clinical use of the Section III personality trait model proceeds similarly. An initial in­
quiry reviews all five broad domains of personality. This systematic review is facilitated 
by the use of formal psychometric instruments designed to measure specific facets and do­
mains of personality. For example, the personality trait model is operationalized in the

mains of personality. For example, the personality trait model is operationalized in the 
Personality Inventory for DSM-5 (PID-5), which can be completed in its self-report form by 
patients and in its informant-report form by those who know the patient well (e.g., a 
spouse). A detailed clinical assessment would involve collection of both patient- and in­
formant-report data on all 25 facets of the personality trait model. However, if this is not 
possible, due to time or other constraints, assessment focused at the five-domain level is an 
acceptable clinical option when only a general (vs. detailed) portrait of a patient's person­
ality is needed (see Criterion B of PD-TS). However, if personality-based problems are the 
focus of treatment, then it will be important to assess individuals' trait facets as well as do­
mains.

mains.
Because personality traits are continuously distributed in the population, an approach 
to making the judgment that a specific trait is elevated (and therefore is present for diag­
nostic purposes) could involve comparing individuals' personality trait levels with pop­
ulation norms and/or clinical judgment. If a trait is elevated—that is, formal psychometric 
testing and/or interview data support the clinical judgment of elevation—then it is con­
sidered as contributing to meeting Criterion B of Section III personality disorders.
Clinical Utility of the Multidimensional Personality  
Functioning and Trait Model
Disorder and trait constructs each add value to the other in predicting important anteced­

ent (e.g., family history, history of child abuse), concurrent (e.g., functional impairment, 
medication use), and predictive (e.g., hospitalization, suicide attempts) variables. DSM-5 
impairments in personality functioning and pathological personality traits each contrib­
ute independently to clinical decisions about degree of disability; risks for self-harm, vio­
lence, and criminality; recommended treatment type and intensity; and prognosis—all 
important aspects of the utility of psychiatric diagnoses. Notably, knowing the level of an 
individual's personality functioning and his or her pathological trait profile also provides 
the clinician with a rich base of information and is valuable in treatment planning and in 
predicting the course and outcome of many mental disorders in addition to personality

predicting the course and outcome of many mental disorders in addition to personality 
disorders. Therefore, assessment of personality functioning and pathological personality 
traits may be relevant whether an individual has a personality disorder or not.

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TABLE 3 Dc^finitions of DSM-5 personality disorder trait domains  
and facets
D O M A IN S (Polar Opposites)
and Facets Definitions
NEGATIVEAFFECTIVITY  
(vs. Em otional Stability)
Emotional lability
Anxiousness
Separation insecurity
Submissiveness
Hostility
Perseveration
Depressivity  
Suspiciousness  
Restricted affectivity  
(lack of)
DETACHMENT  
(vs. Extraversion)
Withdrawal
Intimacy avoidance
Anhedonia
Depressivity
SuspiciousnessFrequent and intense experiences of high levels of a wide range of  
negative emotions (e.g., anxiety, depression, guilt/ shame, worry,  
anger) and their behavioral (e.g., self-harm) and interpersonal (e.g.,  
Instability of emotional experiences and mood; emotions that are  
easily aroused, intense, and/or out of proportion to events and cir­
cumstances.
Feelings of nervousness, tenseness, or panic in reaction to diverse situa­
tions; frequent worry about the negative effects of past unpleasant

tions; frequent worry about the negative effects of past unpleasant  
experiences and future negative possibilities; feeling fearful and  
apprehensive about uncertainty; expecting the worst to happen.
Fears of being alone due to rejection by—and/or separation from—  
significant others, based in a lack of confidence in one's ability to  
care for oneself, both physically and emotionally.
Adaptation of one's behavior to the actual or perceived interests and  
desires of others even when doing so is antithetical to one's own  
interests, needs, or desires.
Persistent or frequent angry feelings; anger or irritability in response  
to minor slights and insults; mean, nasty, or vengeful behavior. See 
also Antagonism.
Persistence at tasks or in a particular way of doing things long after the  
behavior has ceased to be functional or effective; continuance of the

behavior has ceased to be functional or effective; continuance of the  
same behavior despite repeated failures or clear reasons for stopping.
See Detachment.
The lack  o/this facet characterizes low levels  of Negative Affectivity.  
See Detachment for definition of this facet.
Avoidance of socioemotional experience, including both withdrawal  
from interpersonal interactions (ranging from casual, daily interac­
tions to friendships to intimate relationships) and restricted affective  
Preference for being alone to being with others; reticence in social sit­
uations; avoidance of social contacts and activity; lack of initiation  
of social contact.
Avoidance of close or romantic relationships, interpersonal attach­
ments, and intimate sexual relationships.

Lack of enjoyment from, engagement in, or energy for life's experiences;  
deficits in the capacity to feel pleasure and take interest in things.
Feelings of being down, nüserable, and/or hopeless; difficulty recov­
ering from such moods; pessimism about the future; pervasive  
shame and/or guilt; feelings of inferior self-worth; thoughts of sui­
Little reaction to emotionally arousing situations; constricted emo­
tional experience and expression; indifference and aloofness in nor­
matively engaging situations.
Expectations of—and sensitivity to—signs of inteφersonal ill-  
intent or harm; doubts about loyalty and fidelity of others; feelings  
of being mistreated, used, and/or persecuted by others.

TABLE 3  Definitions of DSIVI-S personality disorder trait domains  
and facets (continued)
D O M A IN S (Polar Opposites) 
ANTAGONISM (vs.  
Agreeableness)
Manipulativeness
Deceitfulness
Grandiosity
Attention seeking  
Callousness
Hostility
DISINHIBITION  
(vs. Conscientiousness)
Irresponsibility
Impulsivity
Distractibility  
Risk taking
Rigid perfectionism (lack of)Behaviors that put the individual at odds with other people, includ­
ing an exaggerated sense of self-importance and a concomitant  
expectation of special treatment, as well as a callous antipathy  
toward others, encompassing both an unawareness of others'  
needs and feelings and a readiness to use others in the service of  
self-enhancement.
Use of subterfuge to influence or control others; use of seduction,  
charm, glibness, or ingratiation to achieve one's ends.
Dishonesty and fraudulence; misrepresentation of self; embellish­
ment or fabrication when relating events.

Believing that one is superior to others and deserves special treat­
ment; self-centeredness; feelings of entitlement; condescension  
toward others.
Engaging in behavior designed to attract notice and to make oneself  
the focus of others' attention and admiration.
Lack of concern for the feelings or problems of others; lack of guilt  
or remorse about the negative or harmful effects of one's actions  
on others.
See Negative Affectivity.
Orientation toward immediate gratification, leading to impulsive  
behavior driven by current thoughts, feelings, and external stim­
uli, without regard for past learning or consideration of future  
Disregard for—and failure to honor—financial and other obliga­
tions or commitments; lack of respect for—and lack of follow-

tions or commitments; lack of respect for—and lack of follow-  
through on—agreements and promises; carelessness with others'  
property.
Acting on the spur of the moment in response to immediate stimuli;  
acting on a momentary basis without a plan or consideration of  
outcomes; difficulty establishing and following plans; a sense of  
urgency and self-harming behavior under emotional distress.
Difficulty concentrating and focusing on tasks; attention is easily  
diverted by extraneous stimuli; difficulty maintaining goal-  
focused behavior, including both planning and completing tasks.
Engagement in dangerous, risky, and potentially self-damaging  
activities, unnecessarily and without regard to consequences; lack  
of concern for one's limitations and denial of the reality of per­
sonal danger; reckless pursuit of goals regardless of the level of  
risk involved.

Rigid insistence on everything being flawless, perfect, and without  
errors or faults, including one's own and others' performance; sac­
rificing of timeliness to ensure correctness in every detail; believ­
ing that there is only one right way to do things; difficulty  
changing ideas and/or viewpoint; preoccupation with details,  
organization, and order. The lack o/this facet characterizes low 
levels  of Disinhibition.

TABLE 3  Definitions of DSM-5 personality disorder trait domains  
PSYCHOTICISM  
(vs. Lucidity)
Unusual beliefs and  
experiences
Eccentricity
Cognitive and perceptual  
dysregulationExhibiting a wide range of culturally incongruent odd, eccentric, or  
unusual behaviors and cognitions, including both process (e.g.,  
perception, dissociation) and content (e.g., beliefs).
Belief that one has unusual abilities, such as mind reading, telekine­
sis, thought-action fusion, unusual experiences of reality, includ­
ing hallucination-like experiences.
Odd, unusual, or bizarre behavior, appearance, and/or speech;  
having strange and unpredictable thoughts; saying unusual or  
inappropriate things.
Odd or unusual thought processes and experiences, including  
depersonalization, derealization, and dissociative experiences;  
mixed sleep-wake state experiences; thought-control experiences.

P r o p o s e d  C riteriâ sets are presented for conditions on which future research is en­
couraged. The specific items, thresholds, and durations contained in these research crite­
ria sets were set by expert consensus—informed by literature review, data reanalysis, and 
field trial results, where available—and are intended to provide a common language for 
researchers and clinicians who are interested in studying these disorders. It is hoped that 
such research will allow the field to better understand these conditions and will inform 
decisions about possible placement in forthcoming editions of DSM. The DSM-5 Task 
Force and Work Groups subjected each of these proposed criteria sets to a careful empir­
ical review and invited wide commentary from the field as well as from the general public. 
The Task Force determined that there was insufficient evidence to warrant inclusion of 
these proposals as official mental disorder diagnoses in Section II. These proposed criteria

these proposals as official mental disorder diagnoses in Section II. These proposed criteria  
sets are not intended fo r clinical use; only the criteHa sets and disorders in Section I I  of  
D S M -5  are officially recognized and can be used fo r clinical purposes.
Attenuated Psychosis Syndrome
Proposed Criteria
A. At least one of the following symptoms is present in attenuated form, with relatively in­
tact reality testing, and is of sufficient severity or frequency to warrant clinical attention:
3. Disorganized speech.
B. Symptom(s) must have been present at least once per week for the past month.
C. Symptom(s) must have begun or worsened in the past year.
D. Symptom(s) is sufficiently distressing and disabling to the individual to warrant clinical  
E. Symptom(s) is not better explained by another mental disorder, including a depressive

E. Symptom(s) is not better explained by another mental disorder, including a depressive  
or bipolar disorder with psychotic features, and is not attributable to the physiological  
effects of a substance or another medical condition.
F. Criteria for any psychotic disorder have never been met. _______________________
Attenuated psychotic symptoms, as defined in Criterion A, are psychosis-like but below the 
threshold for a full psychotic disorder. Compared with psychotic disorders, the symptoms 
are less severe and more transient, and insight is relatively maintained. A diagnosis of atten­
uated psychosis syndrome requires state psychopathology associated with functional 
impairment rather than long-standing trait pathology. The psychopathology has not pro­
gressed to full psychotic severity. Attenuated psychosis syndrome is a disorder based on the

gressed to full psychotic severity. Attenuated psychosis syndrome is a disorder based on the 
manifest pathology and impaired function and distress. Changes in experiences and behav-

iors are noted by the individual and/or others, suggesting a change in mental state (i.e., the 
symptoms are of sufficient severity or frequency to warrant clinical attention) (Criterion A). 
Attenuated delusions (Criterion Al) may have suspiciousness/persecutory ideational con­
tent, including persecutory ideas of reference. The individual may have a guarded, distrust­
ful attitude. When the delusions are moderate in severity, the individual views others as 
untrustworthy and may be hypervigilant or sense ill will in others. When the delusions are 
severe but still within the attenuated range, the individual entertains loosely organized be­
liefs about danger or hostile intention, but the delusions do not have the fixed nature that is 
necessary for the diagnosis of a psychotic disorder. Guarded behavior in the interview can 
interfere with the ability to gather information. Reality testing and perspective can be elic­

ited with nonconfirming evidence, but the propensity for viewing the world as hostile and 
dangerous remains strong. Attenuated delusions may have grandiose content presenting as 
an unrealistic sense of superior capacity. When the delusions are moderate, the individual 
harbors notions of being gifted, influential, or special. When the delusions are severe, the in­
dividual has beliefs of superiority that often alienate friends and worry relatives. Thoughts 
of being special may lead to unrealistic plans and investments, yet skepticism about these at­
titudes can be elicited with persistent questioning and confrontation.
Attenuated hallucinations (Criterion A2) include alterations in sensory perceptions, 
usually auditory and/or visual. When the hallucinations are moderate, the sounds and

usually auditory and/or visual. When the hallucinations are moderate, the sounds and 
images are often unformed (e.g., shadows, trails, halos, murmurs, rumbling), and they are 
experienced as unusual or puzzling. When the hallucinations are severe, these experiences 
become more vivid and frequent (i.e., recurring illusions or hallucinations that capture at­
tention and affect thinking and concentration). These perceptual abnormalities may dis­
rupt behavior, but skepticism about their reality can still be induced.
Disorganized communication (Criterion A3) may manifest as odd speech (vague, meta­
phorical, overelaborate, stereotyped), unfocused speech (confused, muddled, too fast or too 
slow, wrong words, irrelevant context, off track), or meandering speech (circumstantial, tan­
gential). When the disorganization is moderately severe, the individual frequently gets into

gential). When the disorganization is moderately severe, the individual frequently gets into 
irrelevant topics but responds easily to clarifying questions. Speech may be odd but under­
standable. At the moderately severe level, speech becomes meandering and circumstantial, 
and when the disorganization is severe, the individual fails to get to the point without 
external guidance (tangential). At the severe level, some thought blocking and/or loose as­
sociations may occur infrequently, especially when the individual is under pressure, but re­
orienting questions quickly return structure and organization to the conversation.
The individual realizes that changes in mental state and/or in relationships are taking 
place. He or she maintains reasonable insight into the psychotic-like experiences and gen­

erally appreciates that altered perceptions are not real and magical ideation is not compel­
ling. The individual must experience distress and/or impaired performance in social or role 
functioning (Criterion D), and the individual or responsible others must note the changes 
and express concern, such that clinical care is sought (Criterion A).
The individual may experience magical thinking, perceptual aberrations, difficulty in con­
centration, some disorganization in thought or behavior, excessive suspiciousness, anxi­
ety, social withdrawal, and disruption in sleep-wake cycle. Impaired cognitive function 
and negative symptoms are often observed. Neuroimaging variables distinguish cohorts

and negative symptoms are often observed. Neuroimaging variables distinguish cohorts 
with attenuated psychosis syndrome from normal control cohorts with patterns similar to, 
but less severe than, that observed in schizophrenia. However, neuroimaging data is not 
diagnostic at the individual level.
The prevalence of attenuated psychosis syndrome is unknown. Symptoms in Criterion A 
are not uncommon in the non-help-seeking population, ranging from 8%-13% for hallu­

cinatory experiences and delusional thinking. There appears to be a slight male prepon­
derance for attei^uated psychosis syndrome.
Onset of attenuated psychosis syndrome is usually in mid-to-late adolescence or early 
adulthood. It may be preceded by normal development or evidence for impaired cogni­
tion, negative symptoms, and/or impaired social development. In help-seeking cohorts, 
approximately 18% in 1  year and 32% in 3 years may progress symptomatically and met 
criteria for a psychotic disorder. In some cases, the syndrome may transition to a depres­
sive or bipolar disorder with psychotic features, but development to a schizophrenia spec­
trum disorder is more frequent. It appears that the diagnosis is best applied to individuals 
ages 15-35 years. Long-term course is not yet described beyond 7-12 years.
Temperamental. Factors predicting prognosis of attenuated psychosis syndrome have

Temperamental. Factors predicting prognosis of attenuated psychosis syndrome have 
not been definitively characterized, but the presence of negative symptoms, cognitive im­
pairment, and poor functioning are associated with poor outcome and increase risk of 
transition to psychosis.
Genetic and physiological. A family history of psychosis places the individual with at­
tenuated psychosis syndrome at increased risk for developing a full psychotic disorder. 
Structural, functional, and neurochemical imaging data are associated with increased risk 
of transition to psychosis.
Attenuated Psycliosis Syndrome
Many individuals may experience functional impairments. Modest-to-moderate impair­
ment in social and role functioning may persist even with abatement of symptoms. A sub­

stantial portion of individuals with the diagnosis will improve over time; many continue 
to have mild symptoms and impairment, and many others will have a full recovery.
Brief psychotic disorder. When symptoms of attenuated psychosis syndrome initially 
manifest, they may resemble symptoms of brief psychotic disorder. However, in attenu­
ated psychosis syndrome, the symptoms do not cross the psychosis threshold and reality 
testing/insight remains intact.
Schizotypal personality disorder. Schizotypal personality disorder, although having 
symptomatic features that are similar to those of attenuated psychosis syndrome, is a rel­
atively stable trait disorder not meeting the state-dependent aspects (Criterion C) of atten­

uated psychosis syndrome. In addition, a broader array of symptoms is required for 
schizotypal personality disorder, although in the early stages of presentation it may re­
semble attenuated psychosis syndrome.
Depressive or bipolar disorders. Reality distortions that are temporally limited to an 
episode of a major depressive disorder or bipolar disorder and are descriptively more 
characteristic of those disorders do not meet Criterion E for attenuated psychosis syn­
drome. For example, feelings of low self-esteem or attributions of low regard from others 
in the context of major depressive disorder would not qualify for comorbid attenuated 
psychosis syndrome.
Anxiety disorders. Reality distortions that are temporally limited to an episode of an

Anxiety disorders. Reality distortions that are temporally limited to an episode of an 
anxiety disorder and are descriptively more characteristic of an anxiety disorder do not

meet Criterion E for attenuated psychosis syndrome. For example, a feeling of being the 
focus of undesired attention in the context of social anxiety disorder would not qualify for 
comorbid attenuated psychosis syndrome.
Bipolar II disorder. Reality distortions that are temporally limited to an episode of ma­
nia or hypomania and are descriptively more characteristic of bipolar disorder do not meet 
Criterion E for attenuated psychosis syndrome. For example, inflated self-esteem in the 
context of pressured speech and reduced need for sleep would not qualify for comorbid at­
tenuated psychosis syndrome.
Borderline personality disorder. Reality distortions that are concomitant with border­
line personality disorder and are descriptively more characteristic of it do not meet Crite­
rion E for attenuated psychosis syndrome. For example, a sense of being unable to 
experience feelings in the context of an intense fear of real or imagined abandonment and

experience feelings in the context of an intense fear of real or imagined abandonment and 
recurrent self-mutilation would not qualify for comorbid attenuated psychosis syndrome.
Adjustment reaction of adolescence. Mild, transient symptoms typical of normal de­
velopment and consistent with the degree of stress experienced do not qualify for attenu­
ated psychosis syndrome.
Extreme end of perceptual aberration and magical thinking in the non-ill population.
This diagnostic possibility should be strongly entertained when reality distortions are not 
associated with distress and functional impairment and need for care.
Substance/medication-induced psychotic disorder. Substance use is common among 
individuals whose symptoms meet attenuated psychosis syndrome criteria. When other­
wise qualifying characteristic symptoms are strongly temporally related to substance use

wise qualifying characteristic symptoms are strongly temporally related to substance use 
episodes. Criterion E for attenuated psychosis syndrome may not be met, and a diagnosis 
of substance/medication-induced psychotic disorder may be preferred.
Attention-deficit/hyperactivity disorder. A history of attentional impairment does not 
exclude a current attenuated psychosis syndrome diagnosis. Earlier attentional impair­
ment may be a prodromal condition or comorbid attention-deficit/hyperactivity disorder.
Individuals with attenuated psychosis syndrome often experience anxiety and/or depres­
sion. Some individuals with an attenuated psychosis syndrome diagnosis will progress to 
another diagnosis, including anxiety, depressive, bipolar, and personality disorders. In such 
cases, the psychopathology associated with the attenuated psychosis syndrome diagnosis is

cases, the psychopathology associated with the attenuated psychosis syndrome diagnosis is 
reconceptualized as the prodromal phase of another disorder, not a comorbid condition.
Depressive Episodes With Short-Duration Hypomania
Lifetime experience of at least one major depressive episode meeting the foiiowing  
criteria:
A. Five (or more) of the following criteria have been present during the same 2-week pe­
riod and represent a change from previous functioning; at least one of the symptoms  
is either (1) depressed mood or (2) loss of interest or pleasure. (Note: Do not include  
symptoms that are clearly attributable to a medical condition.)
tive report (e.g., feels sad, empty, or hopeless) or observation made by others (e.g.,

5% of bqdy weight in  a month), or decrease or increase in appetite nearly every  

C. The disturbance is not attributable to the physiological effects of a substance or an­
D. The disturbance is not better explained by schizoaffective disorder and is not superim­
posed on schizophrenia, schizophreniform disorder, delusional disorder, or other spec­
ified or unspecified schizophrenia spectrum and other psychotic disorder.
At least two lifetime episodes of hypomanie periods that involve the required crite­
rion symptoms below but are of insufficient duration (at least 2 days but less than  
4 consecutive days) to meet criteria for a hypomanie episode. The criterion symp­
toms are as follows:

and abnormally and persistently increased goal-directed activity or energy.
B . During the period of mood disturbance and increased energy and activity, three (or more)  
3. More talkative than usual or pressured to keep talking.
5. Distractibility (i.e., attention too easily drawn to unimportant or irrelevant external

quences (e.g., the individual engages in unrestrained buying sprees, sexual indis­
cretions, or foolish business investments).

Individuals with short-duration hypomania have experienced at least one major depres­
sive episode as well as at least two episodes of 2-3 days' duration in which criteria for a hy­
pomanie episode were met (except for symptom duration). These episodes are of sufficient 
intensity to be categorized as a hypomanie episode but do not meet the 4-day duration re­
quirement. Symptoms are present to a significant degree, such that they represent a no­
ticeable change from the individual's normal behavior.
An individual with a history of a syndromal hypomanie episode and a major depres­
sive episode by definition has bipolar II disorder, regardless of current duration of hypo- 
manic symptoms.
Individuals who have experienced both short-duration hypomania and a major depres­
sive episode, with their increased comorbidity with substance use disorders and a greater

sive episode, with their increased comorbidity with substance use disorders and a greater 
family history of bipolar disorder, more closely resemble individuals with bipolar disor­
der than those with major depressive disorder.
Differences have also been found between individuals with short-duration hypomania 
and those with syndromal bipolar disorder. Work impairment was greater for individuals 
with syndromal bipolar disorder, as was the estimated average number of episodes. Indi­
viduals with short-duration hypomania may exhibit less severity than individuals with 
syndromal hypomanie episodes, including less mood lability.
The prevalence of short-duration hypomania is unclear, since the criteria are new as of this 
edition of the manual. Using somewhat different criteria, however, it has been estimated 
that short-duration hypomania occurs in 2.8% of the population (compared with hypoma­

nia or mania in 5.5% of the population). Short-duration hypomania may be more common 
in females, who may present with more features of atypical depression.
Genetic and physiological. A family history of mania is two to three times more common in 
individuals with short-duration hypomania compared with the general population, but less 
than half as common as in individuals with a history of syndromal mania or hypomania.
Individuals with short-duration hypomania have higher rates of suicide attempts than 
healthy individuals, although not as high as the rates in individuals with syndromal bipo­
lar disorder.
Functional Consequences of Short-Duration Hypomania
Functional impairments associated specifically with short-duration hypomania are as yet

Functional impairments associated specifically with short-duration hypomania are as yet 
not fully determined. However, research suggests that individuals with this disorder have 
less work impairment than individuals with syndromal bipolar disorder but more comor- 
bid substance use disorders, particularly alcohol use disorder, than individuals with major 
Bipolar II disorder. Bipolar II disorder is characterized by a period of at least 4 days of 
hypomanie symptoms, whereas short-duration hypomania is characterized by periods of

2-3 days of hypomanie symptoms. Once an individual has experienced a hypomanie ep­
isode (4 days o i* more), the diagnosis becomes and remains bipolar II disorder regardless 
of future duration of hypomanie symptom periods.
Major depressive disorder. Major depressive disorder is also characterized by at least 
one lifetime major depressive episode. However, the additional presence of at least two life­
time periods of 2-3 days of hypomanie symptoms leads to a diagnosis of short-duration hy- 
pomania rather than to major depressive disorder.
Major depressive disorder with mixed features. Both major depressive disorder with 
mixed features and short-duration hypomania are characterized by the presence of some 
hypomanie symptoms and a major depressive episode. However, major depressive disor­
der with mixed features is characterized by hypomanie features present concurrently  with 
a major depressive episode, while individuals with short-duration hypomania experience

a major depressive episode, while individuals with short-duration hypomania experience 
subsyndromal hypomania and fully syndromal major depression at different times.
Bipolar I disorder. Bipolar I disorder is differentiated from short-duration hypomania 
by at least one lifetime manic episode, which is longer (at least 1 week) and more severe 
(causes more impaired social functioning) than a hypomanie episode. An episode (of any 
duration) that involves psychotic symptoms or necessitates hospitalization is by definition 
a manic episode rather than a hypomanie one.
Cyclothymic disorder. While cyclothymic disorder is characterized by periods of de­
pressive symptoms and periods of hypomanie symptoms, the lifetime presence of a major 
depressive episode precludes the diagnosis of cyclothymic disorder.

Short-duration hypomania, similar to full hypomanie episodes, has been associated with 
higher rates of comorbid anxiety disorders and substance use disorders than are found in 
the general population.
Persistent Confiplex Bereavement Disorder
A. The individual experienced the death of someone with whom he or she had a close re­
lationship.
B. Since the death, at least one of the following symptoms is experienced on more days  
than not and to a clinically significant degree and has persisted for at least 12 months  
after the death in the case of bereaved adults and 6 months for bereaved children:
1. Persistent yearning/longing for the deceased. In young children, yearning may be  
expressed in play and behavior, including behaviors that reflect being separated

expressed in play and behavior, including behaviors that reflect being separated  
from, and also reuniting with, a caregiver or other attachment figure.
2. Intense sorrow and emotional pain in response to the death.
3. Preoccupation with the deceased.
4. Preoccupation with the circumstances of the death. In children, this preoccupation  
with the deceased may be expressed through the themes of play and behavior and  
may extend to preoccupation with possible death of others close to them.
C. Since the death, at least six of the following symptoms are experienced on more days  
than not and to a clinically significant degree, and have persisted for at least 12 months  

Reactive distress to the death
1. Marked difficulty accepting the death. In children, this is dependent on the child’s  
capacity to comprehend the meaning and permanence of death.
2. Experiencing disbelief or emotional numbness over the loss.
3. Difficulty with positive reminiscing about the deceased.
4. Bitterness or anger related to the loss.
5. Maladaptive appraisals about oneself in  relation to the deceased or the death (e.g.,  
self-blame).
6. Excessive avoidance of reminders of the loss (e.g., avoidance of individuals,  
places, or situations associated with the deceased; in children, this may include  
avoidance of thoughts and feelings regarding the deceased).
Social/identity disruption
7. A desire to die in order to be with the deceased.
8. Difficulty trusting other individuals since the death.
9. Feeling alone or detached from other individuals since the death.
10. Feeling that life is meaningless or empty without the deceased, or the belief that

10. Feeling that life is meaningless or empty without the deceased, or the belief that  
one cannot function without the deceased.
11. Confusion about one’s role in life, or a diminished sense of one’s identity (e.g., feel­
ing that a part of oneself died with the deceased).
12. Difficulty or reluctance to pursue interests since the loss or to plan for the future  
(e.g., friendships, activities).
E. The bereavement reaction is out of proportion to or inconsistent with cultural, religious,  
or age-appropriate norms.
With traumatic bereavement: Bereavement due to homicide or suicide with persis­
tent distressing preoccupations regarding the traumatic nature of the death (often in re­

sponse to loss reminders), including the deceased’s last moments, degree of suffering  
and mutilating injury, or the malicious or intentional nature of the death.
Persistent complex bereavement disorder is diagnosed only if at least 12 months ( 6 months 
in children) have elapsed since the death of someone with whom the bereaved had a close 
relationship (Criterion A). This time frame discriminates normal grief from persistent 
grief. The condition typically involves a persistent yearning/longing for the deceased 
(Criterion Bl), which may be associated with intense sorrow and frequent crying (Crite­
rion B2) or preoccupation with the deceased (Criterion B3). The individual may also be 
preoccupied with the manner in which the person died (Criterion B4).

Six additional symptoms are required, including marked difficulty accepting that the in­
dividual has died (Criterion Cl) (e.g. preparing meals for them), disbelief that the individual is 
dead (Criterion C2), distressing memories of the deceased (Criterion C3), anger over the loss 
(Criterion C4), maladaptive appraisals about oneself in relation to the deceased or the death 
(Criterion C5), and excessive avoidance of reminders of the loss (Criterion C 6). Individuals 
may also report a desire to die because they wish to be with the deceased (Criterion C7); be dis­
trustful of others (Criterion C 8); feel isolated (Criterion C9); believe that life has no meaning or 
purpose without the deceased (Criterion CIO); experience a diminished sense of identity in

purpose without the deceased (Criterion CIO); experience a diminished sense of identity in 
which they feel a part of themselves has died or been lost (Criterion Cll); or have difficulty en­
gaging in activities, pursuing relationships, or planning for the future (Criterion C12).

Persistent complex bereavement disorder requires clinically significant distress or im­
pairment in psychosocial functioning (Criterion D). The nature and severity of grief must 
be beyond expected norms for the relevant cultural setting, religious group, or develop­
mental stage (Criterion E). Although there are variations in how grief can manifest, the 
symptoms of persistent complex bereavement disorder occur in both genders and in di­
verse social and cultural groups.
Some individuals with persistent complex bereavement disorder experience hallucina­
tions of the deceased (auditory or visual) in which they temporarily perceive the deceased's 
presence (e.g., seeing the deceased sitting in his or her favorite chair). They may also ex­
perience diverse somatic complaints (e.g., digestive complaints, pain, fatigue), including 
symptoms experienced by the deceased.

The prevalence of persistent complex bereavement disorder is approximately 2A%-4.S%.  
The disorder is more prevalent in females than in males.
Persistent complex bereavement disorder can occur at any age, begirming after the age of 
1 year. Symptoms usually begin within the initial months after the death, although there 
may be a delay of months, or even years, before the full syndrome appears. Although grief 
responses commonly appear immediately following bereavement, these reactions are not 
diagnosed as persistent complex bereavement disorder unless the symptoms persist be­
yond 12 months ( 6 months for children).
Young children may experience the loss of a primary caregiver as traumatic, given the 
disorganizing effects the caregiver's absence can have on a child's coping response. In chil­

dren, the distress may be expressed in play and behavior, developmental regressions, and 
anxious or protest behavior at times of separation and reunion. Separation distress may be 
predominant in younger children, and social/identity distress and risk for comorbid de­
pression can increasingly manifest in older children and adolescents.
Environmental. Risk for persistent complex bereavement disorder is heightened by in­
creased dependency on the deceased person prior to the death and by the death of a child. 
Disturbances in caregiver support increase the risk for bereaved children.
Genetic and physiological. Risk for the disorder is heightened by the bereaved individ­
ual being female.

The symptoms of persistent complex bereavement disorder are observed across cultural 
settings, but grief responses may manifest in culturally specific ways. Diagnosis of the dis­
order requires that the persistent and severe responses go beyond cultural norms of grief 
responses and not be better explained by culturally specific mourning rituals.
Individuals with persistent complex bereavement disorder frequently report suicidal 
ideation.

Persistent Compiex Bereavement Disorder
Persistent complex bereavement disorder is associated with deficits in work and social func­
tioning and with harmful health behaviors, such as increased tobacco and alcohol use. It is also 
associated with marked increases in risks for serious medical conditions, including cardiac dis­
ease, hypertension, cancer, immunological deficiency, and reduced quality of life.
Normal grief. Persistent complex bereavement disorder is distinguished from normal 
grief by the presence of severe grief reactions that persist at least 12 months (or 6 months in 
children) after the death of the bereaved. It is only when severe levels of grief response per­
sist at least 12 months following the death and interfere with the individual's capacity to 
function that persistent complex bereavement disorder is diagnosed.
Depressive disorders. Persistent complex bereavement disorder, major depressive dis­

order, and persistent depressive disorder (dysthymia) share sadness, crying, and suicidal 
thinking. Whereas major depressive disorder and persistent depressive disorder can share 
depressed mood with persistent complex bereavement disorder, the latter is characterized 
by a focus on the loss.
Posttraumatic stress disorder. Individuals who experience bereavement as a result of trau­
matic death may develop both posttraumatic stress disorder (PTSD) and persistent complex 
bereavement disorder. Both conditions can involve intrusive thoughts and avoidance. 
Whereas intrusions in PTSD revolve around the traumatic event, intrusive memories in per­
sistent complex bereavement disorder focus on thoughts about many aspects of the relation­
ship with the deceased, including positive aspects of the relationship and distress over the

ship with the deceased, including positive aspects of the relationship and distress over the 
separation. In individuals with the traumatic bereavement specifier of persistent complex be­
reavement disorder, the distressing thoughts or feelings may be more overtly related to the 
manner of death, with distressing fantasies of what happened. Both persistent complex be­
reavement disorder and PTSD can involve avoidance of reminders of distressing events. 
Whereas avoidance in PTSD is characterized by consistent avoidance of internal and external 
reminders of the traumatic experience, in persistent complex bereavement disorder, there is 
also a preoccupation with the loss and yearning for the deceased, which is absent in PTSD.
Separation anxiety disorder. Separation anxiety disorder is characterized by anxiety

Separation anxiety disorder. Separation anxiety disorder is characterized by anxiety 
about separation from current attachment figures, whereas persistent complex bereavement 
disorder involves distress about separation from a deceased individual.
The most common comorbid disorders with persistent complex bereavement disorder are 
major depressive disorder, PTSD, and substance use disorders. PTSD is more frequently 
comorbid with persistent complex bereavement disorder when the death occurred in trau­
matic or violent circumstances.
Caffeine Use Disorder
A problematic pattern of caffeine use leading to clinically significant impainnent or distress, as  
manifested by at least the first three of the following criteria occurring within a 12-month period:
1. A persistent desire or unsuccessful efforts to cut down or control caffeine use.

2. Continued caffeine use despite knowledge of having a persistent or recurrent physical  
or psychological problem that is likely to have been caused or exacerbated by caffeine.

3. Withdrawal, as manifested by either of the following:
a. The characteristic withdrawal syndronne for caffeine.
b. Caffeine (or a closely related) substance is taken to relieve or avoid withdrawal  
symptoms.
4. Caffeine is often taken in  larger amounts or over a longer period than was intended.
5. Recurrent caffeine use resulting in  a failure to fulfill major role obligations at work,  
school, or home (e.g., repeated tardiness or absences from work or school related to  
caffeine use or withdrawal).
6. Continued caffeine use despite having persistent or recurrent social or interpersonal  
problems caused or exacerbated by the effects of caffeine (e.g., arguments with  
spouse about consequences of use, medical problems, cost).
7. Tolerance, as defined by either of the following:
a. A need for markedly increased amounts of caffeine to achieve desired effect.
b. Markedly diminished effect with continued use of the same amount of caffeine.

8. A great deal of time is spent in  activities necessary to obtain caffeine, use caffeine, or  
recover from its effects.
9. Craving or a strong desire or urge to use caffeine.
A diagnosis of substance dependence due to caffeine is recognized by the World Health 
Organization in ICD-10. Since the publication of DSM-IV in 1994, considerable research on 
caffeine dependence has been published, and several recent review^s provide a current 
analysis of this literature. There is now sufficient evidence to warrant inclusion of caffeine 
use disorder as a research diagnosis in DSM-5 to encourage additional research. The work­
ing diagnostic algorithm proposed for the study of caffeine use disorder differs from that 
of the other substance use disorders, reflecting the need to identify only cases that have

of the other substance use disorders, reflecting the need to identify only cases that have 
sufficient clinical importance to warrant the labeling of a mental disorder. A key goal of in­
cluding caffeine use disorder in this section of DSM-5 is to stimulate research that will 
determine the reliability, validity, and prevalence of caffeine use disorder based on the 
proposed diagnostic schema, with particular attention to the association of the diagnosis 
with functional impairments as part of validity testing.
The proposed criteria for caffeine use disorder reflect the need for a diagnostic thresh­
old higher than that used for the other substance use disorders. Such a threshold is in­
tended to prevent overdiagnosis of caffeine use disorder due to the high rate of habitual 
nonproblematic daily caffeine use in the general population.

Caffeine use disorder is characterized by the continued use of caffeine and failure to con­
trol use despite negative physical and/or psychological consequences. In a survey of the 
general population, 14% of caffeine users met the criterion of use despite harm, with most 
reporting that a physician or counselor had advised them to stop or reduce caffeine use 
within the last year. Medical and psychological problems attributed to caffeine included 
heart, stomach, and urinary problems, and complaints of anxiety, depression, insomnia, 
irritability, and difficulty thinking. In the same survey, 45% of caffeine users reported de­
sire or unsuccessful efforts to control caffeine use, 18% reported withdrawal, 8% reported 
tolerance, 28% used more than intended, and 50% reported spending a great deal of time

tolerance, 28% used more than intended, and 50% reported spending a great deal of time 
using caffeine. In addition, 19% reported a strong desire for caffeine that they could not re­
sist, and less than 1% reported that caffeine had interfered with social activities.
Among those seeking treatment for quitting problematic caffeine use, 8 8% reported 
having made prior serious attempts to modify caffeine use, and 43% reported having been 
advised by a medical professional to reduce or eliminate caffeine. Ninety-three percent 
endorsed signs and symptoms meeting DSM-IV criteria for caffeine dependence, with the

most commonly endorsed criteria being withdrawal (96%), persistent desire or unsuccess­
ful efforts to control use (89%), and use despite knowledge of physical or psychological 
problems caused by caffeine (87%). The most common reasons for wanting to modify caf­
feine use were health-related (59%) and a desire to not be dependent on caffeine (35%).
The DSM-5 discussion of caffeine withdrawal in the Section II chapter "Substance- 
Related and Addictive Disorders" provides information on the features of the withdrawal 
criterion. It is well documented that habitual caffeine users can experience a well-defined 
withdrawal syndrome upon acute abstinence from caffeine, and many caffeine-dependent 
individuals report continued use of caffeine to avoid experiencing withdrawal symptoms.
The prevalence of caffeine use disorder in the general population is unclear. Based on all 
seven generic DSM-IV-TR criteria for dependence, 30% of current caffeine users may have

seven generic DSM-IV-TR criteria for dependence, 30% of current caffeine users may have 
met DSM-IV criteria for a diagnosis of caffeine dependence, with endorsement of three or 
more dependence criteria, during the past year. When only four of the seven criteria (the 
three primary criteria proposed above plus tolerance) are used, the prevalence appears to 
drop to 9%. Thus, the expected prevalence of caffeine use disorder among regular caffeine 
users is likely less than 9%. Given that approximately 75%-80% of the general population 
uses caffeine regularly, the estimated prevalence would be less than 7%. Among regular 
caffeine drinkers at higher risk for caffeine use problems (e.g., high school and college stu­
dents, individuals in drug treatment, and individuals at pain clinics who have recent his­

tories of alcohol or illicit drug misuse), approximately 2 0% may have a pattern of use that 
meets all three of the proposed criteria in Criterion A.
Individuals whose pattern of use meets criteria for a caffeine use disorder have shown a 
wide range of daily caffeine intake and have been consumers of various types of caffein- 
ated products (e.g., coffee, soft drinks, tea) and medications. A diagnosis of caffeine use 
disorder has been shown to prospectively predict a greater incidence of caffeine reinforce­
ment and more severe withdrawal.
There has been no longitudinal or cross-sectional lifespan research on caffeine use dis­
order. Caffeine use disorder has been identified in both adolescents and adults. Rates of

order. Caffeine use disorder has been identified in both adolescents and adults. Rates of 
caffeine consumption and overall level of caffeine consumption tend to increase with age 
until the early to mid-30s and then level off. Age-related factors for caffeine use disorder 
are unknown, although concern is growing related to excessive caffeine consumption 
among adolescents and young adults through use of caffeinated energy drinks.
Genetic and physiological. Heritabilities of heavy caffeine use, caffeine tolerance, and 
caffeine withdrawal range from 35% to 77%. For caffeine use, alcohol use, and cigarette 
smoking, a common genetic factor (polysubstance use) underlies the use of these three 
substances, with 28%^1% of the heritable effects of caffeine use (or heavy use) shared 
with alcohol and smoking. Caffeine and tobacco use disorders are associated and substan­

tially influenced by genetic factors unique to these licit drugs. The magnitude of heritabil- 
ity for caffeine use disorder markers appears to be similar to that for alcohol and tobacco 
use disorder markers.
Functional Consequences of Caffeine Use Disorder
Caffeine use disorder may predict greater use of caffeine during pregnancy. Caffeine with­
drawal, a key feature of caffeine use disorder, has been shown to produce functional im-

pairment in normal daily activities. Caffeine intoxication may include symptoms of 
nausea and vomijing, as well as impairment of normal activities. Significant disruptions in 
normal daily activities may occur during caffeine abstinence.
Nonproblematic use of caffeine. The distinction between nonproblematic use of caf­
feine and caffeine use disorder can be difficult to make because social, behavioral, or psy­
chological problems may be difficult to attribute to the substance, especially in the context of 
use of other substances. Regular, heavy caffeine use that can result in tolerance and with­
drawal is relatively common, which by itself should not be sufficient for making a diagnosis.
Other stimulant use disorder. Problems related to use of other stimulant medications 
or substances may approximate the features of caffeine use disorder.
Anxiety disorders. Chronic heavy caffeine use may mimic generalized anxiety disorder,

Anxiety disorders. Chronic heavy caffeine use may mimic generalized anxiety disorder, 
and acute caffeine consumption may produce and mimic panic attacks.
There may be comorbidity between caffeine use disorder and daily cigarette smoking, a 
family or personal history of alcohol use disorder. Features of caffeine use disorder (e.g., 
tolerance, caffeine withdrawal) may be positively associated with several diagnoses: ma­
jor depression, generalized anxiety disorder, panic disorder, adult antisocial personality 
disorder, and alcohol, cannabis, and cocaine use disorders.
Internet Gaming Disorder
Persistent and recurrent use of the Internet to engage in games, often with other players,  
leading to clinically significant impairment or distress as indicated by five (or more) of the  
following in a 12-month period:

1. Preoccupation with Internet games. (The individual thinks about previous gaming  
activity or anticipates playing the next game; Internet gaming becomes the dominant  
activity in daily life).
Note: This disorder is distinct from Internet gambling, which is included under gam­
bling disorder.
2. Withdrawal symptoms when Internet gaming is taken away. (These symptoms are typ­
ically described as irritability, anxiety, or sadness, but there are no physical signs of  
pharmacological withdrawal.)
3. Tolerance—the need to spend increasing amounts of time engaged in Internet games.
4. Unsuccessful attempts to control the participation in Internet games.
5. Loss of interests in previous hobbies and entertainment as a result of, and with the ex­
ception of, Internet games.
6. Continued excessive use of Internet games despite knowledge of psychosocial problems.

7. Has deceived family members, therapists, or others regarding the amount of Internet  
gaming.
8. Use of Internet games to escape or relieve a negative mood (e.g., feelings of helpless­
ness, guilt, anxiety).
9. Has jeopardized or lost a significant relationship, job, or educational or career oppor­
tunity because of participation in Internet games.

Note: Only nongambling Internet games are included in this disorder. Use of the Internet  
for required activities in a business or profession is not included; nor is the disorder intend­
ed to include other recreational or social Internet use. Similarly, sexual Internet sites are  
excluded.
Specify current severity:
Internet gaming disorder can be mild, moderate, or severe depending on the degree  
of disruption of normal activities. Individuals with less severe Internet gaming disorder  
may exhibit fewer symptoms and less disruption of their lives. Those with severe Inter­
net gaming disorder w ill have more hours spent on the computer and more severe loss  
of relationships or career or school opportunities.
Subtypes
There are no well-researched subtypes for Internet gaming disorder to date. Internet gam­
ing disorder most often involves specific Internet games, but it could involve non-Intemet

Subtypes
ing disorder most often involves specific Internet games, but it could involve non-Intemet 
computerized games as well, although these have been less researched. It is likely that pre­
ferred games will vary over time as new games are developed and popularized, and it is 
unclear if behaviors and consequence associated with Internet gaming disorder vary by 
game type.
Gambling disorder is currently the only non-substance-related disorder proposed for in­
clusion with DSM-5 substance-related and addictive disorders. However, there are other 
behavioral disorders that show some similarities to substance use disorders and gambling 
disorder for which the word addiction  is commonly used in nonmedical settings, and the 
one condition with a considerable literature is the compulsive playing of Internet games.

one condition with a considerable literature is the compulsive playing of Internet games. 
Internet gaming has been reportedly defined as an "addiction" by the Chinese govern­
ment, and a treatment system has been set up. Reports of treatment of this condition have 
appeared in medical journals, mostly from Asian countries and some in the United States.
The DSM-5 work group reviewed more than 240 articles and found some behavioral 
similarities of Internet gaming to gambling disorder and to substance use disorders. The 
literature suffers, however, from lack of a standard definition from which to derive prev­
alence data. An understanding of the natural histories of cases, with or without treatment, 
is also missing. The literature does describe many underlying similarities to substance ad­
dictions, including aspects of tolerance, withdrawal, repeated unsuccessful attempts to cut

dictions, including aspects of tolerance, withdrawal, repeated unsuccessful attempts to cut 
back or quit, and impairment in normal functioning. Further, the seemingly high preva­
lence rates, both in Asian countries and, to a lesser extent, in the West, justified inclusion of 
this disorder in Section III of DSM-5.
Internet gaming disorder has significant public health importance, and additional re­
search may eventually lead to evidence that Internet gaming disorder (also commonly re­
ferred to as Internet use disorder, Internet addiction,  or gaming addiction)  has merit as an 
independent disorder. As with gambling disorder, there should be epidemiological stud­
ies to determine prevalence, clinical course, possible genetic influence, and potential bio­
logical factors based on, for example, brain imaging data.

Internet gaming disorder is a pattern of excessive and prolonged Internet gaming that re­
sults in a cluster of cognitive and behavioral symptoms, including progressive loss of control 
over gaming, tolerance, and withdrawal symptoms, analogous to the symptoms of sub­
stance use disorders. As with substance-related disorders, individuals with Internet gaming 
disorder continue to sit at a computer and engage in gaming activities despite neglect of 
other activities. They typically devote 8-10 hours or more per day to this activity and at least 
30 hours per week. If they are prevented from using a computer and returning to the game, 
they become agitated and angry. They often go for long periods without food or sleep. Nor-

mal obligations, such as school or work, or family obligations are neglected. This condition is 
separate from gambling disorder involving the Internet because money is not at risk.
The essential feature of Internet gaming disorder is persistent and recurrent participa­
tion in computer gaming, typically group games, for many hours. These games involve 
competition between groups of players (often in different global regions, so that duration 
of play is encouraged by the time-zone independence) participating in complex structured 
activities that include a significant aspect of social interactions during play. Team aspects 
appear to be a key motivation. Attempts to direct the individual toward schoolwork or in­
terpersonal activities are strongly resisted. Thus personal, family, or vocational pursuits 
are neglected. When individuals are asked, the major reasons given for using the com­
puter are more likely to be "avoiding boredom" rather than commimicating or searching

puter are more likely to be "avoiding boredom" rather than commimicating or searching 
for information.
The description of criteria related to this condition is adapted from a study in China. Un­
til the optimal criteria and threshold for diagnosis are determined empirically, conserva­
tive definitions ought to be used, such that diagnoses are considered for endorsement of 
five or more of nine criteria.
No consistent personality types associated with Internet gaming disorder have been iden­
tified. Some authors describe associated diagnoses, such as depressive disorders, atten- 
tion-deficit/hyperactivity disorder (ADHD), or obsessive-compulsive disorder (OCD). 
Individuals with compulsive Internet gaming have demonstrated brain activation in spe­
cific regions triggered by exposure to the Internet game but not limited to reward system 
structures

The prevalence of Internet gaming disorder is unclear because of the varying question­
naires, criteria and thresholds employed, but it seems to be highest in Asian countries and 
in male adolescents 12-20 years of age. There is an abundance of reports from Asian coun­
tries, especially China and South Korea, but fewer from Europe and North America, from 
which prevalence estimates are highly variable. The point prevalence in adolescents (ages 
15-19 years) in one Asian study using a threshold of five criteria was 8.4% for males and 
4.5% for females.
Environmental. Computer availability with Internet connection allows access to the 
types of games with which Internet gaming disorder is most often associated.

Genetic and physiological. Adolescent males seem to be at greatest risk of developing 
Internet gaming disorder, and it has been speculated that Asian environmental and/or ge­
netic background is another risk factor, but this remains unclear.
Functional Consequences of Internet Gaming Disorder
Internet gaming disorder may lead to school failure, job loss, or marriage failure. The com­
pulsive gaming behavior tends to crowd out normal social, scholastic, and family activities. 
Students may show declining grades and eventually failure in school. Family responsibil­
ities may be neglected.
Excessive use of the Internet not involving playing of online games (e.g., excessive use of 
social media, such as Facebook; viewing pornography online) is not considered analogous

to Internet gaming disorder, and future research on other excessive uses of the Internet
would need to follow similar guidelines as suggested herein. Excessive gambling online
may qualify for a separate diagnosis of gambling disorder.
Health may be neglected due to compulsive gaming. Other diagnoses that may be associ­
ated with Internet gaming disorder include major depressive disorder, ADHD, and OCD.
Neurobehavioral Disorder Associated  
With Prenatal Alcohol Exposure
A. More than minimal exposure to alcohol during gestation, including prior to pregnancy  
recognition. Confirmation of gestational exposure to alcohol may be obtained from ma­
ternal self-report of alcohol use in  pregnancy, medical or other records, or clinical ob­
servation.
B. Impaired neurocognitive functioning as manifested by one or more of the following:
1. Impairment in global intellectual performance (i.e., IQ of 70 or below, or a standard

1. Impairment in global intellectual performance (i.e., IQ of 70 or below, or a standard  
score of 70 or below on a comprehensive developmental assessment).
2. Impairment in  executive functioning (e.g., poor planning and organization; inflexi­
bility: difficulty with behavioral inhibition).
3. Impairment in learning (e.g., lower academic achievement than expected for intel­
lectual level; specific learning disability).
4. Memory impairment (e.g., problems remembering information learned recently;  
repeatedly making the same mistakes; difficulty remembering lengthy verbal in­
structions).
5. Impairment in visual-spatial reasoning (e.g., disorganized or poorly planned draw­
ings or constructions; problems differentiating left from right).
C. Impaired self-regulation as manifested by one or more of the following:

1. Impairment in mood or behavioral regulation (e.g., mood lability; negative affect or  
irritability; frequent behavioral outbursts).
2. Attention deficit (e.g., difficulty shifting attention; difficulty sustaining mental effort).
3. Impairment in impulse control (e.g., difficulty waiting turn; difficulty complying with  
rules).
D. Impairment in  adaptive functioning as manifested by two or more of the following, one  
of which must be (1) or (2):
1. Communication deficit (e.g., delayed acquisition of language; difficulty understand­
ing spoken language).
2. Impainnent in social communication and interaction (e.g., overly friendly with strang­
ers; difficulty reading social cues; difficulty understanding social consequences).
3. Impairment in daily living skills (e.g., delayed toileting, feeding, or bathing; difficulty

3. Impairment in daily living skills (e.g., delayed toileting, feeding, or bathing; difficulty  
managing daily schedule).
4. Impairment in motor skills (e.g., poor fine motor development; delayed attainment  
of gross motor milestones or ongoing deficits in gross motor function; deficits in co­
ordination and balance).
E. Onset of the disorder (symptoms in  Criteria B, C, and D) occurs in childhood.

F. The disturbance causes clinically significant distress or impairment in social, aca­
G. The disorder is not better explained by the direct physiological effects associated with  
postnatal use of a substance (e.g., a medication, alcohol or other drugs), a general  
medical condition (e.g., traumatic brain injury, delirium, dementia), another known te­
ratogen (e.g., fetal hydantoin syndrome), a genetic condition (e.g., Williams syndrome,  
Down syndrome, Cornelia de Lange syndrome), or environmental neglect.
Alcohol is a neurobehavioral teratogen, and prenatal alcohol exposure has teratogenic 
effects oil central nervous system (CNS) development and subsequent fimction. Neurobe­
havioral disorder associated with prenatal alcohol exposure  (ND-PAE) is a new clarifying term, 
intended to encompass the full range of developmental disabilities associated with expo­

sure to alcohol in utero. The current diagnostic guidelines allow ND-PAE to be diagnosed 
both in the absence and in the presence of the physical effects of prenatal alcohol exposure 
(e.g., facial dysmorphology required for a diagnosis of fetal alcohol syndrome).
The essential features of ND-PAE are the manifestation of impairment in neurocognitive, 
behavioral, and adaptive functioning associated with prenatal alcohol exposure. Impair­
ment can be documented based on past diagnostic evaluations (e.g., psychological or ed­
ucational assessments) or medical records, reports by the individual or informants, and/ 
or observation by a clinician.
A clinical diagnosis of fetal alcohol syndrome, including specific prenatal alcohol-

A clinical diagnosis of fetal alcohol syndrome, including specific prenatal alcohol- 
related facial dysmorphology and growth retardation, can be used as evidence of signifi­
cant levels of prenatal alcohol exposure. Although both animal and human studies have 
documented adverse effects of lower levels of drinking, identifying how much prenatal 
exposure is needed to significantly impact neurodevelopmental outcome remains chal­
lenging. Data suggest that a history of more than minimal gestational exposure (e.g., more 
than light drinking) prior to pregnancy recognition and/or following pregnancy recogni­
tion may be required. Light drinking is defined as 1-13 drinks per month during preg­
nancy with no more than 2 of these drinks consumed on any 1  drinking occasion. Identifying 
a minimal threshold of drinking during pregnancy will require consideration of a variety

a minimal threshold of drinking during pregnancy will require consideration of a variety 
of factors known to affect exposure and/or interact to influence developmental outcomes, 
including stage of prenatal development, gestational smoking, maternal and fetal genet­
ics, and maternal physical status (i.e., age, health, and certain obstetric problems).
Symptoms of ND-PAE include marked impairment in global intellectual performance 
(IQ) or neurocognitive impairments in any of the following areas: executive functioning, 
learning, memory, and/or visual-spatial reasoning. Impairments in self-regulation are pres­
ent and may include impairment in mood or behavioral regulation, attention deficit, or 
impairment in impulse control. Finally, impairments in adaptive functioning include com­
munication deficits and impairment in social communication and interaction. Impairment

munication deficits and impairment in social communication and interaction. Impairment 
in daily living (self-help) skills and impairment in motor skills may be present. As it may be 
difficult to obtain an accurate assessment of the neurocognitive abilities of very young chil­
dren, it is appropriate to defer a diagnosis for children 3 years of age and younger.
Associated features vary depending on age, degree of alcohol exposure, and the individ­
ual's environment. An individual can be diagnosed with this disorder regardless of socio­
economic or cultural background. However, ongoing parental alcohol/substance misuse, 
parental mental illness, exposure to domestic or community violence, neglect or abuse, 
disrupted caregiving relationships, multiple out-of-home placements, and lack of conti­
nuity in medical or mental health care are often present.

The prevalence rates of ND-PAE are unknown. However, estimated prevalence rates of clini­
cal conditions associated with prenatal alcohol exposure are 2%-5% in the United States.
Among individuals with prenatal alcohol exposure, evidence of CNS dysfunction varies 
according to developmental stage. Although about one-half of young children prenatally 
exposed to alcohol show marked developmental delay in the first 3 years of life, other chil­
dren affected by prenatal alcohol exposure may not exhibit signs of CNS dysfunction until 
they are preschool- or school-age. Additionally, impairments in higher order cognitive 
processes (i.e., executive functioning), which are often associated with prenatal alcohol ex­
posure, may be more easily assessed in older children. When children reach school age, 
learning difficulties, impairment in executive function, and problems with integrative lan­

guage functions usually emerge more clearly, and both social skills deficits and challeng­
ing behavior may become more evident. In particular, as school and other requirements 
become more complex, greater deficits are noted. Because of this, the school years repre­
sent the ages at which a diagnosis of ND-PAE would be most likely.
Suicide is a high-risk outcome, with rates increasing significantly in late adolescence and 
early adulthood.
Functional Consequences of Neurobehavioral Disorder  
Associated With Prenatal Alcohol Exposure
The CNS dysfunction seen in individuals with ND-PAE often leads to decrements in adap­
tive behavior and to maladaptive behavior with lifelong consequences. Individuals 
affected by prenatal alcohol exposure have a higher prevalence of disrupted school expe­

riences, poor employment records, trouble with the law, confinement (legal or psychiat­
ric), and dependent living conditions.
Disorders that are attributable to the physiological effects associated with postnatal use  
of a substance, another medical condition, or environmental neglect. Other consid­
erations include the physiological effects of postnatal substance use, such as a medication, 
alcohol, or other substances; disorders due to another medical condition, such as traumatic 
brain injury or other neurocognitive disorders (e.g., delirium, major neurocognitive dis­
order [dementia]); or environmental neglect.
Genetic and teratogenic conditions. Genetic conditions such as Williams syndrome. 
Down syndrome, or Cornelia de Lange syndrome and other teratogenic conditions such as

Down syndrome, or Cornelia de Lange syndrome and other teratogenic conditions such as 
fetal hydantoin syndrome and maternal phenylketonuria may have similar physical and 
behavioral characteristics. A careful review of prenatal exposure history is needed to clar­
ify the teratogenic agent, and an evaluation by a clinical geneticist may be needed to dis­
tinguish physical characteristics associated with these and other genetic conditions.
Mental health problems have been identified in more than 90% of individuals with histo­
ries of significant prenatal alcohol exposure. The most common co-occurring diagnosis is 
attention-deficit/hyperactivity disorder, but research has shown that individuals with 
ND-PAE differ in neuropsychological characteristics and in their responsiveness to phar­

macological interventions. Other high- probability co-occurring disorders include oppo­
sitional defiant disorder and conduct disorder, but the appropriateness of these diagnoses 
should be weighed in the context of the significant impairments in general intellectual and 
executive functioning that are often associated with prenatal alcohol exposure. Mood 
symptoms, including symptoms of bipolar disorder and depressive disorders, have been 
described. History of prenatal alcohol exposure is associated with an increased risk for 
later tobacco, alcohol, and other substance use disorders.
Suicidal Behavior Disorder
A. Within the last 24 months, the individual has made a suicide attempt.
Note: A suicide attempt is a self-initiated sequence of behaviors by an individual who,  
at the time of initiation, expected that the set of actions would lead to his or her own  
death. The “ time of initiation”  is the time when a behavior took place that involved ap­

plying the method.)
B. The act does not meet criteria for nonsuicidal self-injury—that is, it does not involve  
self-injury directed to the surface of the body undertaken to induce relief from a nega­
tive feeling/cognitive state or to achieve a positive mood state.
C. The diagnosis is not applied to suicidal ideation or to preparatory acts.
D. The act was not initiated during a state of delirium or confusion.
E. The act was not undertaken solely for a political or religious objective.
Current: Not more than 12 months since the last attempt.
In early remission: 12-24 months since the last attempt.
Suicidal behavior is often categorized in terms of violence of the method. Generally, over­
doses with legal or illegal substances are considered nonviolent in method, whereas jump­

ing, gunshot wounds, and other methods are considered violent. Another dimension for 
classification is medical consequences of the behavior, with high-lethality attempts being 
defined as those requiring medical hospitalization beyond a visit to an emergency depart­
ment. An additional dimension considered includes the degree of planning versus impul­
siveness of the attempt, a characteristic that might have consequences for the medical 
outcome of a suicide attempt.
If the suicidal behavior occurred 12-24 months prior to evaluation, the condition is 
considered to be in early remission. Individuals remain at higher risk for further suicide at­
tempts and death in the 24 months after a suicide attempt, and the period 12-24 months af­

ter the behavior took place is specified as "early remission."
The essential manifestation of suicidal behavior disorder is a suicide attempt. A suicide at­
tempt  is a behavior that the individual has undertaken with at least some intent to die. The 
behavior might or might not lead to injury or serious medical consequences. Several fac­
tors can influence the medical consequences of the suicide attempt, including poor plan­
ning, lack of knowledge about the lethality of the method chosen, low intentionality or 
ambivalence, or chance intervention by others after the behavior has been initiated. These 
should not be considered in assigning the diagnosis.

Determining the degree of intent can be challenging. Individuals might not acknowl­
edge intent, especially in situations where doing so could result in hospitalization or cause 
distress to loved ones. Markers of risk include degree of planning, including selection of a 
time and place to minimize rescue or interruption; the individual's mental state at the time 
of the behavior, with acute agitation being especially concerning; recent discharge from 
inpatient care; or recent discontinuation of a mood stabilizer such as lithium or an anti­
psychotic such as clozapine in the case of schizophrenia. Examples of environmental ''trig­
gers" include recently learning of a potentially fatal medical diagnosis such as cancer, 
experiencing the sudden and unexpected loss of a close relative or partner, loss of employ­
ment, or displacement from housing. Conversely, features such as talking to others about

ment, or displacement from housing. Conversely, features such as talking to others about 
future events or preparedness to sign a contract for safety are less reliable indicators.
In order for the criteria to be met, the individual must have made at least one suicide at­
tempt. Suicide attempts can include behaviors in which, after initiating the suicide attempt, 
the individual changed his or her mind or someone intervened. For example, an individual 
might intend to ingest a given amount of medication or poison, but either stop or be stopped 
by another before ingesting the full amount. If the individual is dissuaded by another or 
changes his or her mind before initiating the behavior, the diagnosis should not be made. 
The act must not meet criteria for nonsuicidal self-injury—that is, it should not involve re­

peated (at least five times within the past 12 months) self-injurious episodes undertaken to 
induce relief from a negative feeling/cognitive state or to achieve a positive mood state. The 
act should not have been initiated during a state of delirium or confusion. If the individual 
deliberately became intoxicated before initiating the behavior, to reduce anticipatory anxi­
ety and to minimize interference with the intended behavior, the diagnosis should be made.
Suicidal behavior can occur at any time in the lifespan but is rarely seen in children under 
the age of 5. In prepubertal children, the behavior will often consist of a behavior (e.g., sit­
ting on a ledge) that a parent has forbidden because of the risk of accident. Approximately

ting on a ledge) that a parent has forbidden because of the risk of accident. Approximately 
25%-30% of persons who attempt suicide will go on to make more attempts.There is sig­
nificant variability in terms of frequency, method, and lethality of attempts. However, this 
is not different from what is observed in other illnesses, such as major depressive disorder, 
in which frequency of episode, subtype of episode, and impairment for a given episode can 
vary significantly.
Suicidal behavior varies in frequency and form across cultures. Cultural differences might 
be due to method availability (e.g., poisoning with pesticides in developing countries; 
gunshot wounds in the southwestern United States) or the presence of culturally specific 
syndromes (e.g., ataques de nervios,  which in some Latino groups might lead to behaviors

syndromes (e.g., ataques de nervios,  which in some Latino groups might lead to behaviors 
that closely resemble suicide attempts or might facilitate suicide attempts).
Laboratory abnormalities consequent to the suicidal attempt are often evident. Suicidal 
behavior that leads to blood loss can be accompanied by anemia, hypotension, or shock. 
Overdoses might lead to coma or obtundation and associated laboratory abnormalities 
such as electrolyte imbalances.
Functional Consequences of Suicidal Behavior Disorder
Medical conditions (e.g., lacerations or skeletal trauma, cardiopulmonary instability, in­
halation of vomit and suffocation, hepatic failure consequent to use of paracetamol) can 
occur as a consequence of suicidal behavior.

Suicidal behavior is seen in the context of a variety of mental disorders, most commonly bipo­
lar disorder, major depressive disorder, schizophrenia, schizoaffective disorder, anxiety dis­
orders (in particular, panic disorders associated with catastrophic content and PTSD 
flashbacks), substance use disorders (especially alcohol use disorders), borderline personality 
disorder, antisocial personality disorder, eating disorders, and adjustment disorders. It is 
rarely manifested by individuals with no discernible pathology, unless it is undertaken be­
cause of a painful medical condition with the intention of drawing attention to martyrdom for 
political or religious reasons, or in partners in a suicide pact, both of which are excluded from 
this diagnosis, or when third-party informants wish to conceal the nature of the behavior.
Nonsuicidal Self-lnjuiy
A. In the last year, the individual has, on 5 or more days, engaged in  intentional self-inflicted

A. In the last year, the individual has, on 5 or more days, engaged in  intentional self-inflicted  
damage to the surface of his or her body of a sort likely to induce bleeding, bruising, or pain  
(e.g., cutting, buming, stabbing, hitting, excessive rubbing), with the expectation that the  
injury w ill lead to only minor or moderate physical harm (i.e., there is no suicidal intent).  
Note: The absence of suicidal intent has either been stated by the individual or can be  
inferred by the individual’s repeated engagement in a behavior that the individual  
knows, or has learned, is not likely to result in  death.
B. The individual engages in the self-injurious behavior with one or more of the following  
expectations:
1. To obtain relief from a negative feeling or cognitive state.
2. To resolve an interpersonal difficulty.
3. To induce a positive feeling state.

Note: The desired relief or response is experienced during or shortly after the self­
injury, and the individual may display patterns of behavior suggesting a dependence  
on repeatedly engaging in it.
C. The intentional self-injury is associated with at least one of the following:
1. Interpersonal difficulties or negative feelings or thoughts, such as depression, anx­
iety, tension, anger, generalized distress, or self-criticism, occurring in the period  
immediately prior to the self-injurious act.
2. Prior to engaging in the act, a period of preoccupation with the intended behavior  
that is difficult to control.
3. Thinking about self-injury that occurs frequently, even when it is not acted upon.
D. The behavior is not socially sanctioned (e.g., body piercing, tattooing, part of a religious

D. The behavior is not socially sanctioned (e.g., body piercing, tattooing, part of a religious  
or cultural ritual) and is not restricted to picking a scab or nail biting.
E. The behavior or its consequences cause clinically significant distress or interference in  
interpersonal, academic, or other important areas of functioning.
F. The behavior does not occur exclusively during psychotic episodes, delirium, sub­
stance intoxication, or substance withdrawal. In individuals with a neurodevelopmental  
disorder, the behavior is not part of a pattern of repetitive stereotypies. The behavior  
is not better explained by another mental disorder or medical condition (e.g., psychotic  
disorder, autism spectrum disorder, intellectual disability, Lesch-Nyhan syndrome, ste­
reotypic movement disorder with self-injury, trichotillomania [hair-pulling disorder], ex­
coriation [skin-picking] disorder).

The essential feature of nonsuicidal self-injury is that the individual repeatedly inflicts 
shallow, yet painful injuries to the surface of his or her body. Most commonly, the purpose 
is to reduce negative emotions, such as tension, anxiety, and self-reproach, and/or to re­
solve an interpersonal difficulty. In some cases, the injury is conceived of as a deserved 
self-punishment. The individual will often report an immediate sensation of relief that oc­
curs during the process. When the behavior occurs frequently, it might be associated with 
a sense of urgency and craving, the resultant behavioral pattern resembling an addiction. 
The inflicted wounds can become deeper and more numerous.
The injury is most often inflicted with a knife, needle, razor, or other shaφ object. Com­
mon areas for injury include the frontal area of the thighs and the dorsal side of the forearm.

mon areas for injury include the frontal area of the thighs and the dorsal side of the forearm. 
A single session of injury might involve a series of superficial, parallel cuts—separated by 
1  or 2 centimeters—on a visible or accessible location. The resulting cuts will often bleed and 
will eventually leave a characteristic pattern of scars.
Other methods used include stabbing an area, most often the upper arm, with a needle 
or sharp, pointed knife; inflicting a superficial bum with a lit cigarette end; or burning the 
skin by repeated rubbing with an eraser. Engagement in nonsuicidal self-injury with mul­
tiple methods is associated with more severe psychopathology, including engagement in 
The great majority of individuals who engage in nonsuicidal self-injury do not seek 
clinical attention. It is not known if this reflects frequency of engagement in the disorder,

clinical attention. It is not known if this reflects frequency of engagement in the disorder, 
because accurate reporting is seen as stigmatizing, or because the behaviors are experi­
enced positively by the individual who engages in them, who is unmotivated to receive 
treatment. Young children might experiment with these behaviors but not experience re­
lief. In such cases, youths often report that the procedure is painful or distressing and 
might then discontinue the practice.
Nonsuicidal self-injury most often starts in the early teen years and can continue for many 
years. Admission to hospital for nonsuicidal self-injury reaches a peak at 20-29 years of 
age and then declines. However, research that has examined age at hospitalization did not 
provide information on age at onset of the behavior, and prospective research is needed to

provide information on age at onset of the behavior, and prospective research is needed to 
outline the natural history of nonsuicidal self-injury and the factors that promote or in­
hibit its course. Individuals often leam of the behavior on the recommendation or observa­
tion of another. Research has shown that when an individual who engages in nonsuicidal 
self-injury is admitted to an inpatient unit, other individuals may begin to engage in the 
behavior.
Male and female prevalence rates of nonsuicidal self-injury are closer to each other than in 
suicidal behavior disorder, in which the female-to-male ratio is about 3:1 or 4:1.
Two theories of psychopathology—^ based  on functional behavioral analyses—have been 
proposed: In the first, based on learning theory, either positive or negative reinforcement

proposed: In the first, based on learning theory, either positive or negative reinforcement 
sustains the behavior. Positive reinforcement might result from punishing oneself in a way 
that the individual feels is deserved, with the behavior inducing a pleasant and relaxed state 
or generating attention and help from a significant other, or as an expression of anger. Neg­
ative reinforcement results from affect regulation and the reduction of unpleasant emotions 
or avoiding distressing thoughts, including thinking about suicide. In the second theory, 
nonsuicidal self-injury is thought to be a form of self-punishment, in which self-punitive ac­
tions are engaged in to make up for acts that caused distress or harm to others.

Functional Consequences of Nonsuicidal Self-lnjuiy
The act of cutting\might be performed with shared implements, raisiiig the possibility of 
blood-borne disease transmission.
Borderline personality disorder. As indicated, nonsuicidal self-injury has long been re­
garded as a "symptom" of borderline personality disorder, even though comprehensive 
clinical evaluations have found that most individuals with nonsuicidal self-injury have 
symptoms that also meet criteria for other diagnoses, with eating disorders and substance 
use disorders being especially common. Historically, nonsuicidal self-injury was regarded 
as pathognomonic of borderline personality disorder. Both conditions are associated with 
several other diagnoses. Although frequently associated, borderline personality disorder 
is not invariably found in individuals with nonsuicidal self-injury. The two conditions dif­

fer in several ways. Individuals with borderline personality disorder often manifest dis­
turbed aggressive and hostile behaviors, whereas nonsuicidal self-injury is more often 
associated with phases of closeness, collaborative behaviors, and positive relationships. At 
a more fundamental level, there are differences in the involvement of different neurotrans­
mitter systems, but these will not be apparent on clinical examination.
Suicidal behavior disorder. The differentiation between nonsuicidal self-injury and sui­
cidal behavior disorder is based either on the stated goal of the behavior being a wish to 
die (suicidal behavior disorder) or, in nonsuicidal self-injury, to experience relief as de­
scribed in the criteria. Depending on the circumstances, individuals may provide reports

scribed in the criteria. Depending on the circumstances, individuals may provide reports 
of convenience, and several studies report high rates of false intent declaration. Individu­
als with a history of frequent nonsuicidal self-injury episodes have learned that a session 
of cutting, while painful, is, in the short-term, largely benign. Because individuals with 
nonsuicidal self-injury can and do attempt and commit suicide, it is important to check 
past history of suicidal behavior and to obtain information from a third party concerning 
any recent change in stress exposure and mood. Likelihood of suicide intent has been as­
sociated with the use of multiple previous methods of self-harm.
In a follow-up study of cases of "self-harm" in males treated at one of several multiple 
emergency centers in the United Kingdom, individuals with nonsuicidal self-injury were

emergency centers in the United Kingdom, individuals with nonsuicidal self-injury were 
significantly more likely to commit suicide than other teenage individuals drawn from the 
same cohort. Studies that have examined the relationship between nonsuicidal self-injury 
and suicidal behavior disorder are limited by being retrospective and failing to obtain ver­
ified accounts of the method used during previous "attempts." A significant proportion of 
those who engage in nonsuicidal self-injury have responded positively when asked if they 
have ever engaged in self-cutting (or their preferred means of self-injury) with an intention 
to die. It is reasonable to conclude that nonsuicidal self-injury, while not presenting a high 
risk for suicide when first manifested, is an especially dangerous form of self-injurious 
behavior.

behavior.
This conclusion is also supported by a multisite study of depressed adolescents who had 
previously failed to respond to antidepressant medication, which noted that those with pre­
vious nonsuicidal self-injury did not respond to cognitive-behavioral therapy, and by a study 
that found that nonsuicidal self-injury is a predictor of substance use/misuse.
Trichotillomania (hair-pulling disorder). Trichotillomania is an injurious behavior con­
fined to pulling out one's own hair, most commonly from the scalp, eyebrows, or eyelashes. 
The behavior occurs in "sessions" that can last for hours. It is most likely to occur during a 
period of relaxation or distraction.

Stereotypic self-injury. Stereotypic self-injury, which can include head banging, self- 
biting, or self-hitting, is usually associated with intense concentration or under conditions 
of low external stimulation and might be associated with developmental delay.
Excoriation (skin-picking) disorder. Excoriation disorder occurs mainly in females and 
is usually directed to picking at an area of the skin that the individual feels is unsightly or 
a blemish, usually on the face or the scalp. As in nonsuicidal self-injury, the picking is often 
preceded by an urge and is experienced as pleasurable, even though the individual real­
izes that he or she is harming himself or herself. It is not associated with the use of any im­
plement.

Highlights of Changes From DSIVI-IV to DSIVI-5 .................................... 809
Glossary of Technical Terms .................................................................. 817
Glossary of Cultural Concepts of Distress............................................ 833
Alphabetical Listing of DSM-5 Diagnoses and Codes
(ICD-9-CM and ICD-10-CM)................................................................ 839
Numerical Listing of DSM-5 Diagnoses and Codes (ICD-9-CM) .......... 863
Numerical Listing of DSM-5 Diagnoses and Codes (ICD-10-CM) ........ 877
DSM-5 Advisors and Other Contributors ................................................ 897

Highlights of Changes FiNiii 
DSiVi-IV to D Ü * i
ChsngGS msdG to DSM’5 diagnostic criteria and texts are outlined in this chapter 
in the same order in which they appear in the DSM-5 classification. This abbreviated descrip­
tion is intended to orient readers to only the most significant changes in each disorder cate­
gory. An expanded description of nearly all changes (e.g., except minor text or wording 
changes needed for clarity) is available online (www.psychiatry.org/dsm5). It should also be 
noted that Section I contains a description of changes pertaining to the chapter organization 
in DSM-5, the multiaxial system, and the introduction of dimensional assessments.
The term mental retardation  was used in DSM-IV. However, intellectual disability (intel­
lectual developmental disorder) is the term that has come into common use over the past 
two decades among medical, educational, and other professionals, and by the lay public

two decades among medical, educational, and other professionals, and by the lay public 
and advocacy groups. Diagnostic criteria emphasize the need for an assessment of both 
cognitive capacity (IQ) and adaptive functioning. Severity is determined by adaptive func­
tioning rather than IQ score.
The communication disorders, which are newly named from DSM-IV phonological dis­
order and stuttering, respectively, include language disorder (which combines the previous 
expressive and mixed receptive-expressive language disorders), speech sound disorder (pre­
viously phonological disorder), and childhood-onset fluency disorder (previously stutter­
ing). Also included is social (pragmatic) commimication disorder, a new condition involving 
persistent difficulties in the social uses of verbal and nonverbal communication.
Autism spectrum disorder is a new DSM-5 disorder encompassing the previous DSM-

Autism spectrum disorder is a new DSM-5 disorder encompassing the previous DSM- 
IV autistic disorder (autism), Asperger's disorder, childhood disintegrative disorder, 
Rett's disorder, and pervasive developmental disorder not otherwise specified. It is char­
acterized by deficits in two core domains: 1) deficits in social communication and social in­
teraction and 2) restricted repetitive patterns of behavior, interests, and activities.
Several changes have been made to the diagnostic criteria for attention-deficit/hyperactiv-  
ity disorder (ADHD). Examples have been added to the criterion items to facilitate application 
across the life span; the age at onset description has been changed (from "some hyperactive- 
impulsive or inattentive symptoms that caused impairment were present before age 7 years" 
to "Several inattentive or hyperactive-impulsive symptoms were present prior to age 12");

to "Several inattentive or hyperactive-impulsive symptoms were present prior to age 12"); 
subtypes have been replaced with presentation specifiers that map directly to the prior sub­
types; a comorbid diagnosis with autism spectrum disorder is now allowed; and a symptom 
tlu-eshold change has been made for adults, to reflect the substantial evidence of clinically sig­
nificant ADHD impairment, with the cutoff for ADHD of five symptoms, instead of six re­
quired for younger persons, both for inattention and for hyperactivity and impulsivity.
Specific learning disorder combines the DSM-IV diagnoses of reading disorder, math­
ematics disorder, disorder of written expression, and learning disorder not otherwise 
specified. Learning deficits in the areas of reading, written expression, and mathematics 
are coded as separate specifiers. Acknowledgment is made in the text that specific types of

are coded as separate specifiers. Acknowledgment is made in the text that specific types of 
reading deficits are described internationally in various ways as dyslexia  and specific types 
of mathematics deficits as dyscalculia.

The following motor disorders are included in DSM-5: developmental coordination disor­
der, stereotypic movement disorder, Tourette's disorder, persistent (chronic) motor or vocal 
tic disorder, provisional tic disorder, other specified tic disorder, and unspecified tic disorder. 
The tic criteria have been standardized across all of these disorders in this chapter.
Schizophrenia Spectrum and Other Psychotic Disorders
Two changes were made to Criterion A for schizophrenia: 1) the elimination of the special at­
tribution of bizarre delusions and Schneiderian first-rank auditory hallucinations (e.g., two or 
more voices conversing), leading to the requirement of at least two Criterion A symptoms for 
any diagnosis of schizophrenia, and 2) the addition of the requirement that at least one of the 
Criterion A symptoms must be delusions, hallucinations, or disorganized speech. The DSM-IV 
subtypes of schizophrenia were eliminated due to their limited diagnostic stability, low reli­

ability, and poor validity. Instead, a dimensional approach to rating severity for the core symp­
toms of schizophrenia is included in DSM-5 Section Π Ι to capture the important heterogeneity 
in symptom type and severity expressed across individuals with psychotic disorders. 
Schizoaffective disorder is reconceptualized as a longitudinal instead of a cross-sectional di­
agnosis—more comparable to schizophrenia, bipolar disorder, and major depressive disorder, 
which are bridged by this condition—and requires that a major mood episode be present for a 
majority of the total disorder's duration after Criterion A has been met. Criterion A for delu­
sional disorder no longer has the requirement that the delusions must be nonbizarre; a spec­

ifier is now included for bizarre type delusions to provide continuity with DSM-IV. Criteria for 
catatonia are described uniformly across DSM-5. Furthermore, catatonia may be diagnosed 
with a specifier (for depressive, bipolar, and psychotic disorders, including schizophrenia), in 
the context of a known medical condition, or as an other specified diagnosis.
Bipolar and Related Disorders
Diagnostic criteria for bipolar disorders now include both changes in mood and changes in 
activity or energy. The DSM-IV diagnosis of bipolar I disorder, mixed episodes—requiring 
that the individual simultaneously meet full criteria for both mania and major depressive ep­
isode—is replaced with a new specifier "with mixed features." Particular conditions can

isode—is replaced with a new specifier "with mixed features." Particular conditions can 
now be diagnosed under other specified bipolar and related disorder, including categori­
zation for individuals with a past history of a major depressive disorder whose symptoms 
meet all criteria for hypomania except the duration criterion is not met (i.e., the episode lasts 
only 2 or 3 days instead of the required 4 consecutive days or more). A second condition con­
stituting an other specified bipolar and related disorder variant is that too few symptoms of 
hypomania are present to meet criteria for the full bipolar II syndrome, although the dura­
tion, at least 4 consecutive days, is sufficient. Finally, in both this chapter and in the chapter 
"Depressive Disorders," an anxious distress specifier is delineated.
Depressive Disorders

To address concerns about potential overdiagnosis and overtreatment of bipolar disorder in 
children, a new diagnosis, disruptive mood dysregulation disorder, is included for children 
up to age 18 years who exhibit persistent irritability and frequent episodes of extreme behav­
ioral dyscontrol. Premenstrual dysphoric disorder is now promoted from Appendix B, "Cri­
teria Sets and Axes Provided for Further Study," in DSM-IV to the main body of DSM-5. What 
was referred to as dysthymia in DSM-IV now falls under the category of persistent depressive  
disorder, which includes both chronic major depressive disorder and the previous dysthymic 
disorder. The coexistence within a major depressive episode of at least three manic symp­

toms (insufficient to satisfy criteria for a manic episode) is now acknowledged by the specifier

"with mixed features." In DSM-IV, there was an exclusion criterion for a major depressive ep­
isode that was applied to depressive symptoms lasting less than 2 months following the death 
of a loved one (i.e., the bereavement exclusion). This exclusion is omitted in DSM-5 for several 
reasons, including the recognition that bereavement is a severe psychosocial stressor that can 
precipitate a major depressive episode in a vulnerable individual, generally beginning soon 
after the loss, and can add an additional risk for suffering, feelings of worthlessness, suicidal 
ideation, poorer medical health, and worse interpersonal and work functioning. It was critical 
to remove the implication that bereavement typically lasts only 2 months, when both physi­
cians and grief counselors recognize that the duration is more commonly 1-2 years. A detailed 
footnote has replaced the more simplistic DSM-IV exclusion to aid clinicians in making the

footnote has replaced the more simplistic DSM-IV exclusion to aid clinicians in making the 
critical distinction between the symptoms characteristic of bereavement and those of a major 
depressive disorder. Finally, a new specifier to indicate the presence of mixed symptoms has 
been added across both the bipolar and the depressive disorders.
Anxiety Disorders
The chapter on anxiety disorders no longer includes obsessive-compulsive disorder (which 
is in the new chapter "Obsessive-Compulsive and Related Disorders") or posttraumatic 
stress disorder (PTSD) and acute stress disorder (which are in the new chapter "Trauma- 
and Stressor-Related Disorders"). Changes in criteria for specific phobia and social anxiety  
disorder (social phobia) include deletion of the requirement that individuals over age 18

disorder (social phobia) include deletion of the requirement that individuals over age 18 
years recognize that their anxiety is excessive or unreasonable. Instead, the anxiety must be 
out of proportion to the actual danger or threat in the situation, after cultural contextual fac­
tors are taken into account. In addition, the 6-month duration is now extended to all ages. 
Panic attacks can now be listed as a specifier that is applicable to all DSM-5 disorders. Panic  
disorder and agoraphobia are unlinked in DSM-5. Thus, the former DSM-IV diagnoses of 
panic disorder with agoraphobia, panic disorder without agoraphobia, and agoraphobia 
without history of panic disorder are now replaced by two diagnoses, panic disorder and ag­
oraphobia, each with separate criteria. The "generalized" specifier for social anxiety disor­

der has been deleted and replaced with a "performance only" specifier. Separation anxiety  
disorder and selective mutism are now classified as anxiety disorders. The wording of the 
criteria is modified to more adequately represent the expression of separation anxiety symp­
toms in adulthood. Also, in contrast to DSM-IV, the diagnostic criteria no longer specify that 
onset must be before age 18 years, and a duration statement—"typically lasting for 6 months 
or more"—has been added for adults to miiumize overdiagnosis of transient fears.
Obsessive-Compulsive and Related Disorders
The chapter "Obsessive-Compulsive and Related Disorders" is new in DSM-5. New disor­
ders include hoarding disorder, excoriation (skin-picking) disorder, substance/medica­

tion-induced obsessive-compulsive and related disorder, and obsessive-compulsive and  
related disorder due to another medical condition. The DSM-IV diagnosis of trichotillo­
mania is now termed trichotillomania (hair-pulling disorder) and has been moved from a 
DSM-IV classification of impulse-control disorders not elsewhere classified to obsessive- 
compulsive and related disorders in DSM-5. The DSM-IV "with poor insight" specifier for 
obsessive-compulsive disorder has been refined to allow a distinction between individuals 
with good or fair insight, poor insight, and "absent insight/delusional" obsessive-compul­
sive disorder beliefs (i.e., complete conviction that obsessive-compulsive disorder beliefs 
are true). Analogous "insight" specifiers have been included for body dysmorphic disorder

are true). Analogous "insight" specifiers have been included for body dysmorphic disorder 
and hoarding disorder. A "tic-related" specifier for obsessive-compulsive disorder has also 
been added, because presence of a comorbid tic disorder may have important clinical im­
plications. A "muscle dysmoφhia" specifier for body dysmorphic disorder is added to re­
flect a growing literature on the diagnostic validity and clinical utility of making this

distinction in individuals with body dysmorphic disorder. The delusional variant of body 
dysmorphic disorder (which identifies individuals who are completely convinced that their 
perceived defects or flaws are truly abnormal appearing) is no longer coded as both delu­
sional disorder, somatic type, and body dysmorphic disorder; in DSM-5, this presentation is 
designated only as body dysmoφhic disorder with the absent insight/delusional specifier. 
Individuals can also be diagnosed with other specified obsessive-compulsive and related  
disorder, which can include conditions such as body-focused repetitive behavior disorder 
and obsessional jealousy, or unspecified obsessive-compulsive and related disorder.
Trauma- and Stressor-Related Disorders
For a diagnosis of acute stress disorder, qualifying traumatic events are now explicit as to 
whether they were experienced directly, witnessed, or experienced indirectly. Also, the

whether they were experienced directly, witnessed, or experienced indirectly. Also, the 
DSM-IV Criterion A2 regarding the subjective reaction to the traumatic event (e.g., expe­
riencing '"fear, helplessness, or horror") has been eliminated. Adjustment disorders are 
reconceptualized as a heterogeneous array of stress-response syndromes that occur after 
exposure to a distressing (traumatic or nontraumatic) event, rather than as a residual cat­
egory for individuals who exhibit clinically significant distress but whose symptoms do 
not meet criteria for a more discrete disorder (as in DSM-IV).
DSM-5 criteria for PTSD differ significantly from the DSM-IV criteria. The stressor cri­
terion (Criterion A) is more explicit with regard to events that qualify as "traumatic" ex­
periences. Also, DSM-IV Criterion A2 (subjective reaction) has been eliminated. Whereas

periences. Also, DSM-IV Criterion A2 (subjective reaction) has been eliminated. Whereas 
there were three major symptom clusters in DSM-IV—reexperiencing, avoidance/numb­
ing, and arousal—there are now four symptom clusters in DSM-5, because the avoidance/ 
numbing cluster is divided into two distinct clusters: avoidance and persistent negative al­
terations in cognitions and mood. This latter category, which retains most of the DSM-IV 
numbing symptoms, also includes new or reconceptualized symptoms, such as persistent 
negative emotional states. The final cluster—alterations in arousal and reactivity—retains 
most of the DSM-IV arousal symptoms. It also includes irritable behavior or angry out­
bursts and reckless or self-destructive behavior. PTSD is now developmentally sensitive in 
that diagnostic thresholds have been lowered for children and adolescents. Furthermore,

that diagnostic thresholds have been lowered for children and adolescents. Furthermore, 
separate criteria have been added for children age 6 years or younger with this disorder.
The DSM-IV childhood diagnosis reactive attachment disorder had two subtypes: 
emotionally withdrawn/inhibited and indiscriminately social/disinhibited. In DSM-5, 
these subtypes are defined as distinct disorders: reactive attachment disorder and disin-  
hibited social engagement disorder.
Dissociative Disorders
Major changes in dissociative disorders in DSM-5 include the following: 1) derealization is 
included in the name and symptom structure of what previously was called depersonali­
zation disorder (depersonalization/derealization disorder); 2) dissociative fugue is now a 
specifier of dissociative amnesia rather than a separate diagnosis, and 3) the criteria for

specifier of dissociative amnesia rather than a separate diagnosis, and 3) the criteria for 
dissociative identity disorder have been changed to indicate that symptoms of disruption 
of identity may be reported as well as observed, and that gaps in the recall of events may 
occur for everyday and not just traumatic events. Also, experiences of pathological pos­
session in some cultures are included in the description of identity disruption.
Somatic Symptom and Related Disorders
In DSM-5, somatoform disorders are now referred to as somatic symptom and related dis­
orders. The DSM-5 classification reduces the number of these disorders and subcategories to 
avoid problematic overlap. Diagnoses of somatization disorder, hypochondriasis, pain dis­
order, and undifferentiated somatoform disorder have been removed. Individuals previ­

ously diagnosed with somatization disorder will usually have symptoms that meet DSM-5 
criteria for somatic symptom disorder, but only if they have the maladaptive thoughts, feel­
ings, and behaviors that define the disorder, in addition to their somatic symptoms. Because 
the distinction between somatization disorder and undifferentiated somatoform disorder 
was arbitrary, they are merged in DSM-5 under somatic symptom disorder. Individuals pre­
viously diagnosed with hypochondriasis who have high health anxiety but no somatic symp­
toms would receive a DSM-5 diagnosis of illness anxiety disorder (unless their health 
anxiety was better explained by a primary anxiety disorder, such as generalized anxiety dis­
order). Some individuals with chronic pain would be appropriately diagnosed as having so­
matic symptom disorder, with predominant pain. For otiiers, psychological factors affecting 
other medical conditions or an adjustment disorder would be more appropriate.

Psychological factors affecting other medical conditions is a new mental disorder in 
DSM-5, having formerly been listed in the DSM-IV chapter "Other Conditions That May 
Be a Focus of Clinical Attention." This disorder and factitious disorder are placed among 
the somatic symptom and related disorders because somatic symptoms are predominant 
in both disorders, and both are most often encountered in medical settings. The variants of 
psychological factors affecting other medical conditions are removed in favor of the stem 
diagnosis. Criteria for conversion disorder (functional neurological symptom disorder)  
have been modified to emphasize the essential importance of the neurological examina­
tion, and in recognition that relevant psychological factors may not be demonstrable at the

tion, and in recognition that relevant psychological factors may not be demonstrable at the 
time of diagnosis. Other specified somatic symptom disorder, other specified illness anx­
iety disorder, and pseudocyesis are now the only exemplars of the other specified somatic  
symptom and related disorder classification.
Feeding and Eating Disorders
Because of the elimination of the DSM-IV-TR chapter "Disorders Usually First Diagnosed 
During Infancy, Childhood, or Adolescence," this chapter describes several disorders found in 
the DSM-IV section "Feeding and Eating Disorders of Infancy or Early Childhood," such as 
pica and rumination disorder. The DSM-IV category feeding disorder of infancy or early 
childhood has been renamed avoidant/restrictive food intake disorder, and the criteria are 
significantly expanded. The core diagnostic criteria for anorexia nervosa are conceptually un­

changed from E)SM-rV with one exception: the requirement for amenorrhea is eliminated. As 
in DSM-IV, individuals with this disorder are required by Criterion A to be at a significantly 
low body weight for their developmental stage. The wording of the criterion is changed for 
clarification, and guidance regarding how to judge whether an individual is at or below a sig­
nificantly low weight is provided in the text. In DSM-5, Criterion B is expanded to include not 
only overtly expressed fear of weight gain but also persistent behavior that interferes with 
weight gain. The only change in the DSM-IV criteria for bulimia nervosa is a reduction in the 
required minimum average frequency of binge eating and inappropriate compensatory be­

havior frequency from twice to once weekly. The extensive research that followed the prom­
ulgation of preliminary criteria for binge-eating disorder in Appendix B of DSM-IV 
documented the clinical utility and validity of binge-eating disorder. The only significant dif­
ference from the preliminary criteria is that the minimum average frequency of binge eating re­
quired for diagnosis is once weekly over the last 3 months, identical to the frequency criterion 
for bulimia nervosa (rather than at least 2 days a week for 6 months in DSM-IV).
Elimination Disorders
There have been no significant changes in this diagnostic class from DSM-IV to DSM-5. 
The disorders in this chapter were previously classified under disorders usually first di­

agnosed in infancy, childhood, or adolescence in DSM-IV and exist now as an independent 
classification in DSM-5.

In DSM-5, the DSM-IV diagnoses named sleep disorder related to another mental disorder 
and sleep disorder related to another medical condition have been removed, and instead 
greater specification of coexisting conditions is provided for each sleep-wake disorder. The 
diagnosis of primary insomnia has been renamed insomnia disorder to avoid the differen­
tiation between primary and secondary insomnia. DSM-5 also distinguishes narcolepsy—  
now known to be associated with hypocretin deficiency—from other forms of hypersomno­
lence (hypersomnolence disorder). Finally, throughout the DSM-5 classification of sleep- 
wake disorders, pediatric and developmental criteria and text are integrated where existing 
science and considerations of clinical utility support such integration. Breathing-related  
sleep disorders are divided into three relatively distinct disorders: obstructive sleep apnea

sleep disorders are divided into three relatively distinct disorders: obstructive sleep apnea 
hypopnea, central sleep apnea, and sleep-related hypoventilation. The subtypes of circadian  
rhythm sleep disorders are expanded to include advanced sleep phase type and irregular 
sleep-wake type, whereas the jet lag type has been removed. The use of the former "not oth­
erwise specified" diagnoses in DSM-IV have been reduced by elevating rapid eye move­
ment sleep behavior disorder and restless legs syndrome to independent disorders.
Sexual Dysfunctions
In DSM-5, some gender-specific sexual dysfunctions have been added, and, for females, 
sexual desire and arousal disorders have been combined into one disorder: female sexual  
interest/arousal disorder. All of the sexual dysfunctions (except substance/medication-in­

duced sexual dysfunction) now require a minimum duration of approximately 6 months and 
more precise severity criteria. Genito-pelvic pain/penetration disorder has been added to 
DSM-5 and represents a merging of vaginismus and dyspareunia, which were highly co- 
morbid and difficult to distinguish. The diagnosis of sexual aversion disorder has been re­
moved due to rare use and lack of supporting research.
There are now only two subtypes for sexual dysfunctions: lifelong versus acquired  
and generalized versus situational. To indicate the presence and degree of medical and 
other nonmedical correlates, the following associated features have been added to the text: 
partner factors, relationship factors, individual vulnerability factors, cultural or religious 
factors, and medical factors.

Gender Dysplioria
Gender dysphoria is a new diagnostic class in DSM-5 and reflects a change in conceptual­
ization of the disorder's defining features by emphasizing the phenomenon of "gender in­
congruence" rather than cross-gender identification per se, as was the case in DSM-IV gender 
identity disorder. Gender dysphoria includes separate sets of criteria: for children and for 
adults and adolescents. For the adolescents and adults criteria, the previous Criterion A 
(cross-gender identification) and Criterion B (aversion toward one's gender) are merged. In 
the wording of the criteria, "the other sex" is replaced by "the other gender" (or "some alter­
native gender")." Gender  instead of sex is used systematically because the concept "sex" is in­
adequate when referring to individuals with a disorder of sex development. In the child

adequate when referring to individuals with a disorder of sex development. In the child 
criteria, "strong desire to be of the other gender" replaces the previous "repeatedly stated de­
sire to be...the other sex" to capture the situation of some children who, in a coercive envi­
ronment, may not verbalize the desire to be of another gender. For children. Criterion A1 ("a 
strong desire to be of the other gender or an insistence that he or she is the other gender...)" 
is now necessary (but not sufficient), which makes the diagnosis more restrictive and conser­
vative. The subtyping on the basis of sexual orientation is removed because the distinction is 
no longer considered clinically useful. A posttransition specifier has been added to identify

individuals who have undergone at least one medical procedure or treatment to support the 
new gender assignment (e.g., cross-sex hormone treatment). Although the concept of post­
transition is modeled on the concept of full or partial remission, the term remission  has impli­
cations in terms of symptom reduction that do not apply directly to gender dysphoria.
Disruptive, Impulse-Control, and Conduct Disorders
The chapter "Disruptive, Impulse-Control, and Conduct Disorders" is new to DSM-5 and 
combines disorders that were previously included in the chapter "Disorders Usually First Di­
agnosed in Infancy, Childhood, or Adolescence" (i.e., oppositional defiant disorder; conduct 
disorder; and disruptive behavior disorder not otherwise specified, now categorized as other 
specified and unspecified disruptive, impulse-control, and conduct disorders) and the chap­
ter "Impulse-Control Disorders Not Elsewhere Classified" (i.e., intermittent explosive disor­

der, pyromania, and kleptomania). These disorders are all characterized by problems in 
emotional and behavioral self-control. Notably, ADHD is frequently comorbid with the dis­
orders in this chapter but is listed with the neurodevelopmental disorders. Because of its 
close association with conduct disorder, antisocial personality disorder is listed both in this 
chapter and in the chapter "Personality Disorders," where it is described in detail.
The criteria for oppositional defiant disorder are now grouped into three types: an­
gry/irritable mood, argumentative/defiant behavior, and vindictiveness. Additionally, 
the exclusionary criterion for conduct disorder has been removed. The criteria for conduct  
disorder include a descriptive features specifier for individuals who meet full criteria for

disorder include a descriptive features specifier for individuals who meet full criteria for 
the disorder but also present with limited prosocial emotions. The primary change in in­
termittent explosive disorder is in the type of aggressive outbursts that should be consid­
ered: DSM-IV required physical aggression, whereas in DSM-5 verbal aggression and 
nondestructive/noninjurious physical aggression also meet criteria. DSM-5 also provides 
more specific criteria defining frequency needed to meet the criteria and specifies that the 
aggressive outbursts are impulsive and/or anger based in nature, and must cause marked 
distress, cause impairment in occupational or interpersonal functioning, or be associated 
with negative financial or legal consequences. Furthermore, a minimum age of 6 years (or 
equivalent developmental level) is now required.
Substance-Related and Addictive Disorders

An important departure from past diagnostic manuals is that the chapter on substance-related 
disorders has been expanded to include gambling disorder. Another key change is that 
DSM-5 does not separate the diagnoses of substance abuse  and dependence  as in DSM-IV. Rather 
criteria are provided for substance use disorder, accompanied by criteria for intoxication, 
withdrawal, substance-induced disorders, and unspecified substance-related disorders, 
where relevant. Within substance use disorders, the DSM-IV recurrent substance-related legal 
problems criterion has been deleted from DSM-5, and a new criterion—craving, or a strong de­
sire or urge to use a substance—^ h a s  been added. In addition, the threshold for substance use

sire or urge to use a substance—^ h a s  been added. In addition, the threshold for substance use 
disorder diagnosis in DSM-5 is set at two or more criteria, in contrast to a threshold of one or 
more criteria for a diagnosis of DSM-IV substance abuse and three or more for DSM-IV depen­
dence. Cannabis withdrawal and caffeine withdrawal are new disorders (the latter was in 
DSM-IV Appendbc B, "Criteria Sets and Axes Provided for Further Study").
Severity of the DSM-5 substance use disorders is based on the number of criteria en­
dorsed. The DSM-IV specifier for a physiological subtype is eliminated in DSM-5, as is the 
DSM-IV diagnosis of polysubstance dependence. Early remission from a DSM-5 substance 
use disorder is defined as at least 3 but less than 12 months without meeting substance use 
disorder criteria (except craving), and sustained remission is defined as at least 12 months

disorder criteria (except craving), and sustained remission is defined as at least 12 months 
without meeting criteria (except craving). Additional new DSM-5 specifiers include "in a  
controlled environment" and "on maintenance therapy" as the situation warrants.

The DSM-IV diagnoses of dementia and amnestic disorder are subsumed under the newly 
named entity major neurocognitive disorder (NCD). The term dementia  is not precluded from 
use in the etiological subtypes where that term is standard. Furthermore, DSM-5 now recog­
nizes a less severe level of cognitive impairment, mild NCD, which is a new disorder that per­
mits the diagnosis of less disabling syndromes that may nonetheless be the focus of concern 
and treatment. Diagnostic criteria are provided for both of these disorders, followed by diag­
nostic criteria for different etiological subtypes. In DSM-IV, individual diagnoses were desig­
nated for dementia of the Alzheimer's type, vascular dementia, and substance-induced 
dementia, whereas the other neurodegenerative disorders were classified as dementia due to 
another medical condition, with HIV, head trauma, Parkinson's disease, Huntington's disease.

another medical condition, with HIV, head trauma, Parkinson's disease, Huntington's disease. 
Pick's disease, Creutzfeldt-Jakob disease, and other medical conditions specified. In DSM-5, 
major or mild NCD due to Alzheimer's disease and major or mild vascular NCD have been re­
tained, while new separate criteria are now presented for major or mild frontotemporal NCD, 
NCD with Lewy bodies, and NCDs due to traumatic brain injury, a substance/medication, 
HIV infection, prion disease, Parkinson's disease, Huntington's disease, another medical con­
dition, and multiple etiologies, respectively. Unspecified NCD is also included as a diagnosis.
Personality Disorders
The criteria for personality disorders in Section II of DSM-5 have not changed from those in 
DSM-IV. An alternative approach to the diagnosis of personality disorders was developed

DSM-IV. An alternative approach to the diagnosis of personality disorders was developed 
for DSM-5 for further study and can be found in Section III (see "Alternative DSM-5 Model 
for Personality Disorders"). For the general criteria for personality disorder, presented in 
Section III, a revised personality functioning criterion (Criterion A) has been developed 
based on a literature review of reliable clinical measures of core impairments central to per­
sonality pathology. A diagnosis of personality disorder—trait specified, based on moderate 
or greater impairment in personality functioning and the presence of pathological personal­
ity traits, replaces personality disorder not otherwise specified and provides a much more in­
formative diagnosis for individuals who are not optimally described as having a specific

formative diagnosis for individuals who are not optimally described as having a specific 
personality disorder. A greater emphasis on personality functioning and trait-based criteria 
increases the stability and empirical bases of the disorders. Personality functioning and per­
sonality traits also can be assessed whether or not the individual has a personality disor­
der—a feature that provides clinically useful information about all individuals.
Paraphilic Disorders
An overarching change from DSM-IV is the addition of the course specifiers "in a controlled  
environment" and "in remission" to the diagnostic criteria sets for all the paraphilic disor­
ders. These specifiers are added to indicate important changes in an individual's status. In 
DSM-5, paraphilias are not ipso facto  mental disorders. There is a distinction between paraphil­

ias and paraphilic disorders. A paraphilic disorder  is a paraphilia that is currently causing dis­
tress or impairment to the individual or a paraphilia whose satisfaction has entailed personal 
harm, or risk of harm, to others. A paraphilia is a necessary but not a sufficient condition for 
having a paraphilic disorder, and a paraphilia by itself does not automatically justify or require 
clinical intervention. The distinction between paraphilias and paraphilic disorders was im­
plemented without making any changes to the basic structure of the diagnostic criteria as they 
had existed since DSM-III-R. The change proposed for DSM-5 is that individuals who meet 
both Criterion A and Criterion B  would now be diagnosed as having a paraphilic disorder. A

both Criterion A and Criterion B  would now be diagnosed as having a paraphilic disorder. A 
diagnosis would not be given to individuals whose symptoms meet Criterion A but not Cri­
terion B—that is, to individuals who have a paraphilia but not a paraphilic disorder.

Glossa 
Technical Terms
affect A pattern of observable behaviors that is the expression of a subjectively experi­
enced feeling state (emotion). Examples of affect include sadness, elation, and anger. In 
contrast to mood,  which refers to a pervasive and sustained emotional "climate," ajfect  
refers to more fluctuating changes in emotional "weather." What is considered the nor­
mal range of the expression of affect varies considerably, both within and among dif­
ferent cultures. Disturbances in affect include
blunted Significant reduction in the intensity of emotional expression.
flat Absence or near absence of any sign of affective expression.
inappropriate Discordance between affective expression and the content of speech 
or ideation.
labile Abnormal variability in affect with repeated, rapid, and abrupt shifts in af­
fective expression.
restricted or constricted Mild reduction in the range and intensity of emotional ex­
pression.
affective blunting See AFFECT.

pression.
agitation (psychomotor) See PSYCHOMOTOR AGITATION.
agnosia Loss of ability to recognize objects, persons, sounds, shapes, or smells that occurs 
in the absence of either impairment of the specific sense or significant memory loss.
alogia An impoverishment in thinking that is inferred from observing speech and lan­
guage behavior. There may be brief and concrete replies to questions and restriction in 
the amount of spontaneous speech (termed poverty of speech).  Sometimes the speech is 
adequate in amoimt but conveys little information because it is overconcrete, overab­
stract, repetitive, or stereotyped (termed poverty of content).
amnesia An inability to recall important autobiographical information that is inconsis­
tent with ordinary forgetting.
anhedonia Lack of enjoyment from, engagement in, or energy for life's experiences; def­

icits in the capacity to feel pleasure and take interest in things. Anhedonia is a facet of 
the broad personality trait domain DETACHMENT.
anosognosia A condition in which a person with an illness seems unaware of the exis­
tence of his or her illness.
antagonism Behaviors that put an individual at odds with other people, such as an ex­
aggerated sense of self-importance with a concomitant expectation of special treat­
ment, as well as a callous antipathy toward others, encompassing both unawareness of 
others' needs and feelings, and a readiness to use others in the service of self-enhance­
ment. Antagonism is one of the five broad PERSONALITY TRAIT DOMAINS defined in Sec­
tion III "Alternative DSM-5 Model for Personality Disorders."
Small  caps  indicate term found elsewhere in this glossary. Glossary definitions were informed by

Small  caps  indicate term found elsewhere in this glossary. Glossary definitions were informed by  
DSM-5 Work Groups, publicly available Internet sources, and previously published glossaries for  
mental disorders (World Health Organization and American Psychiatric Association).

antidepressant discontinuation syndrome A set of symptoms that can occur after 
abrupt cessation, or marked reduction in dose, of an antidepressant medication that 
had been taken continuously for at least 1 month.
anxiety The apprehensive anticipation of future danger or misfortune accompanied by 
a feeling of worry, distress, and/or somatic symptoms of tension. The focus of antici­
pated danger may be internal or external.
anxiousness Feelings of nervousness or tenseness in reaction to diverse situations; frequent  
v^orry about the negative effects of past unpleasant experiences and future negative possi­
bilities; feeling fearful and apprehensive about uncertainty; expecting the worst to happen.  
Anxiousness is a facet of the broad personality trait domain N EG A T IV E AFFECnviTY.
arousal The physiological and psychological state of being awake or reactive to stimuli.
asociality A reduced initiative for interacting with other people.

attention The ability to focus in a sustained manner on a particular stimulus or activity. 
A disturbance in attention may be manifested by easy DISTRACTIBILITY or difficulty in 
finishing tasks or in concentrating on work.
attention seeking Engaging in behavior designed to attract notice and to make oneself 
the focus of others' attention and admiration. Attention seeking is a facet of the broad 
personality trait domain ANTAGONISM.
autogynephilia Sexual arousal of a natal male associated with the idea or image of being 
a woman.
avoidance The act of keeping away from stress-related circumstances; a tendency to cir­
cumvent cues, activities, and situations that remind the individual of a stressful event 
experienced.
avolition An inability to initiate and persist in goal-directed activities. When severe enough

avolition An inability to initiate and persist in goal-directed activities. When severe enough 
to be considered pathological, avolition is pervasive and prevents the person from com­
pleting many different types of activities (e.g., work, intellectual pursuits, self-care).
bereavement The state of having lost through death someone with whom one has had 
a close relationship. This state includes a range of grief and mourning responses.
biological rhythms See CIRCADIAN RHYTHMS.
callousness Lack of concern for the feelings or problems of others; lack of guilt or re­
morse about the negative or harmful effects of one's actions on others. Callousness is a 
facet of the broad personality trait domain ANTAGONISM.
catalepsy Passive induction of a posture held against gravity. Compare with WAXY FLEX­
IBILITY.

IBILITY.
cataplexy Episodes of sudden bilateral loss of muscle tone resulting in the individual 
collapsing, often occurring in association with intense emotions such as laughter, an­
ger, fear, or surprise.
circadian rhythms Cyclical variations in physiological and biochemical function, level 
of sleep-wake activity, and emotional state. Circadian rhythms have a cycle of about 24 
hours, ultradian  rhythms have a cycle that is shorter than 1 day, and infradian  rhythms 
have a cycle that may last weeks or months.
cognitive and perceptual dysregulation Odd or unusual thought processes and experi­
ences, including DEPERSONALIZAΉON, DEREALIZATON, and DISSOCIATON; mixed sleep- 
wake state experiences; and thought-control experiences. Cognitive and perceptual 
dysregulation is a facet of the broad personality trait domain PSYCHOTICISM.

coma State of complete loss of consciousness.

compulsion Repetitive behaviors (e.g., hand washing, ordering, checking) or mental 
acts (e.g., praying, counting, repeating words silently) that the individual feels driven 
to perform in response to an obsession, or according to rules that must be applied rig­
idly. The behaviors or mental acts are aimed at preventing or reducing anxiety or dis­
tress, or preventing some dreaded event or situation; however, these behaviors or 
mental acts are not connected in a realistic way with what they are designed to neutral­
ize or prevent or are clearly excessive.
conversion symptom A loss of, or alteration in, voluntary motor or sensory functioning, 
with or without apparent impairment of consciousness. The symptom is not fully ex­
plained by a neurological or another medical condition or the direct effects of a sub­
stance and is not intentionally produced or feigned.
deceitfulness Dishonesty and fraudulence; misrepresentation of self; embellishment or

deceitfulness Dishonesty and fraudulence; misrepresentation of self; embellishment or 
fabrication when relating events. Deceitfulness is a facet of the broad personality trait 
domain ANTAGONISM.
defense mechanism Mechanisms that mediate the individual's reaction to emotional 
conflicts and to external stressors. Some defense mechanisms (e.g., projection, splitting, 
acting out) are almost invariably maladaptive. Others (e.g., suppression, denial) may 
be either maladaptive or adaptive, depending on their severity, their inflexibility, and 
the context in which they occur.
delusion A false belief based on incorrect inference about external reality that is firmly 
held despite what almost everyone else believes and despite what constitutes incontro­
vertible and obvious proof or evidence to the contrary. The belief is not ordinarily ac­
cepted by other members of the person's culture or subculture (i.e., it is not an article of

cepted by other members of the person's culture or subculture (i.e., it is not an article of 
religious faith). When a false belief involves a value judgment, it is regarded as a delusion 
only when the judgment is so extreme as to defy credibility. Delusional conviction can 
sometimes be inferred from an overvalued idea (in which case the individual has an un­
reasonable belief or idea but does not hold it as firmly as is the case with a delusion). De­
lusions are subdivided according to their content. Common types are listed below:
bizarre A delusion that involves a phenomenon that the person's culture would re­
gard as physically impossible.
delusional jealousy A delusion that one's sexual partner is unfaithful.
érotomanie A delusion that another person, usually of higher status, is in love with 
the individual.
grandiose A delusion of inflated worth, power, knowledge, identity, or special re­

lationship to a deity or famous person.
mixed type Delusions of more than one type (e.g., EROTOMANIC, GRANDIOSE, PERSE­
CUTORY, SOMATIC) in which no one theme predominates.
mood-congruent See MOOD-CONGRUENT PSYCHOTIC FEATURES.
mood-incongruent See MOOD-INCONGRUENT PSYCHOΉC FEATURES.
of being controlled A delusion in which feelings, impulses, thoughts, or actions 
are experienced as being under the control of some external force rather than be­
ing under one's own control.
of reference A delusion in which events, objects, or other persons in one's immedi­
ate environment are seen as having a particular and unusual significance. These 
delusions are usually of a negative or pejorative nature but also may be grandiose 
in content. A delusion of reference differs from an idea of reference,  in which the

in content. A delusion of reference differs from an idea of reference,  in which the 
false belief is not as firmly held nor as fully organized into a true belief.
persecutory A delusion in which the central theme is that one (or someone to whom 
one is close) is being attacked, harassed, cheated, persecuted, or conspired against.

somatic A delusion whose main content pertains to the appearance or functioning 
of one's body.
thought broadcasting A delusion that one's thoughts are being broadcast out loud 
so that they can be perceived by others.
thought insertion A delusion that certain of one's thoughts are not one's own, but 
rather are inserted into one's mind.
depersonalization The experience of feeling detached from, and as if one is an outside 
observer of, one's mental processes, body, or actions (e.g., feeling like one is in a dream; 
a sense of unreality of self, perceptual alterations; emotional and/or physical numbing; 
temporal distortions; sense of unreality).
depressivity Feelings of being intensely sad, miserable, and/or hopeless. Some patients  
describe an absence of feelings and/or dysphoria; difficulty recovering from such  
moods; pessimism about the future; pervasive shame and/or guilt; feelings of inferior

moods; pessimism about the future; pervasive shame and/or guilt; feelings of inferior  
self-worth; and thoughts of suicide and suicidal behavior. Depressivity is a facet of the  
broad personality trait domain D ETA CH M EN T.
derealization The experience of feeling detached from, and as if one is an outside ob­
server of, one's surroundings (e.g., individuals or objects are experienced as unreal, 
dreamlike, foggy, lifeless, or visually distorted).
detachment Avoidance of socioemotional experience, including both W IT H D R A W A L  from 
interpersonal interactions (ranging from casual, daily interactions to friendships and inti­
mate relationships [i.e., IN T IM A C Y  A V O ID A N C E ]) and R E S T R IC T E D  A FFEC T W IT Y , particularly 
limited hedonic capacity. Detachment is one of the five pathological PER SO N A LIT Y  T R A IT

limited hedonic capacity. Detachment is one of the five pathological PER SO N A LIT Y  T R A IT  
D O M A IN S  defined in Section ΙΠ  "Alternative DSM-5 Model for Personality Disorders."
disinhibition Orientation toward immediate gratification, leading to impulsive behav­
ior driven by current thoughts, feelings, and external stimuli, without regard for past 
learning or consideration of future consequences. R IG ID  PER FEC T IO N ISM , the opposite 
pole of this domain, reflects excessive constraint of impulses, risk avoidance, hyper­
responsibility, hyperperfectionism, and rigid, rule-governed behavior. Disinhibition 
is one of the five pathological PER SO N A LIT Y  T R A IT  D O M A IN S defined in Section III "Al­
ternative DSM-5 Model for Personality Disorders."
disorder of sex development Condition of significant inborn somatic deviations of the 
reproductive tract from the norm and/or of discrepancies among the biological indica­
tors of male and female.

disorientation Confusion about the time of day, date, or season (time); where one is 
(place); or who one is (person).
dissociation The splitting off of clusters of mental contents from conscious awareness. 
Dissociation is a mechanism central to dissociative disorders. The term is also used to 
describe the separation of an idea from its emotional significance and affect, as seen in 
the inappropriate affect in schizophrenia. Often a result of psychic trauma, dissociation 
may allow the individual to maintain allegiance to two contradictory truths while re­
maining unconscious of the contradiction. An extreme manifestation of dissociation is 
dissociative identity disorder, in which a person may exhibit several independent per­
sonalities, each unaware of the others.

distractibility Difficulty concentrating and focusing on tasks; attention is easily divert­
ed by extraneous stimuli; difficulty maintaining goal-focused behavior, including both 
planning and completing tasks. Distractibility is a facet of the broad personality trait 
domain DiSlNHlBmON.
dysarthria A disorder of speech sound production due to structural or motor impair­
ment affecting the articulatory apparatus. Such disorders include cleft palate, muscle

disorders, cranial nerve disorders, and cerebral palsy affecting bulbar structures (i.e., 
lower and upper motor neuron disorders).
dyskinesia Distortion of voluntary movements with involuntary muscle activity.
dysphoria (dysphoric mood) A condition in which a person experiences intense feelings 
of depression, discontent, and in some cases indifference to the world around them.
dyssomnias Primary disorders of sleep or wakefulness characterized by IN SO M N IA  or 
H Y PER SO M N IA  as the major presenting symptom. Dyssomnias are disorders of the 
amount, quality, or timing of sleep. Compare with PA R A SO M N IA S.
dysthymia Presence, while depressed, of two or more of the following: 1) poor appetite 
or overeating, 2) insomnia or hypersonnnia, 3) low energy or fatigue, 4) low self-esteem, 
5) poor concentration or difficulty making decisions, or 6) feelings of hopelessness.
dystonia Disordered tonicity of muscles.

eccentricity Odd, unusual, or bizarre behavior, appearance, and/or speech having  
strange and unpredictable thoughts; saying unusual or inappropriate things. Eccentric­
ity is a facet of the broad personality trait domain PSY C H O T IC ISM .
echolalia The pathological, parrotlike, and apparently senseless repetition (echoing) of 
a word or phrase just spoken by another person.
echopraxia Mimicking the movements of another.
emotional lability Instability of emotional experiences and mood; emotions that are 
easily aroused, intense, and/or out of proportion to events and circumstances. Emo­
tional lability is a facet of the broad personality trait domain N EG A T IV E A FFEC T IV IT Y .
empathy Comprehension and appreciation of others' experiences and motivations; tol­
erance of differing perspectives; understanding the effects of own behavior on others.

episode (episodic) A specified duration of time during which the patient has developed or 
experienced symptoms that meet the diagnostic criteria for a given mental disorder. De­
pending on the type of mental disorder, episode  may denote a certain number of symptoms 
or a specified severity or frequency of symptoms. Episodes may be further differentiated 
as a single (first) episode or a recurrence or relapse of multiple episodes if appropriate.
euphoria A mental and emotional condition in which a person experiences intense feel­
ings of well-being, elation, happiness, excitement, and joy.
fatigability Tendency to become easily fatigued. See also  FA T IG U E.
fatigue A state (also called exhaustion, tiredness, lethargy, languidness, languor, lassi­

tude, and listlessness) usually associated with a weakening or depletion of one's phys­
ical and/or mental resources, ranging from a general state of lethargy to a specific, 
work-induced burning sensation within one's muscles. Physical fatigue leads to an in­
ability to continue functioning at one's normal level of activity. Although widespread 
in everyday life, this state usually becomes particularly noticeable during heavy exer­
cise. Mental fatigue, by contrast, most often manifests as SO M N O LEN C E (sleepiness).
fear An emotional response to perceived imminent threat or danger associated with 
urges to flee or fight.
flashback A dissociative state during which aspects of a traumatic event are reexperi­
enced as though they were occurring at that moment.

flight of ideas A nearly continuous flow of accelerated speech with abrupt changes 
from topic to topic that are usually based on understandable associations, distracting 
stimuli, or plays on words. When the condition is severe, speech may be disorganized 
and incoherent.

gender The public (and usually legally recognized) lived role as boy or girl, man or 
woman. Biological factors are seen as contributing in interaction with social and psy­
chological factors to gender development.
gender assignment The initial assignment as male or female, which usually occurs at 
birth and is subsequently referred to as the "natal gender."
gender dysphoria Distress that accompanies the incongruence between one's experi­
enced and expressed gender and one's assigned or natal gender.
gender experience The unique and personal ways in which individuals experience their 
gender in the context of the gender roles provided by their societies.
gender expression The specific ways in which individuals enact gender roles provided 
in their societies.
gender identity A category of social identity that refers to an individual's identification 
as male, female or, occasionally, some category other than male or female.

gender reassignment A change of gender that can be either medical (hormones, sur­
gery) or legal (government recognition), or both. In case of medical interventions, often 
referred to as sex reassignment.
geometric hallucination See H A LLU C IN A TIO N .
grandiosity Believing that one is superior to others and deserves special treatment; self- 
centeredness; feelings of entitlement; condescension toward others. Grandiosity is a 
facet of the broad personality trait domain A N T A G O N ISM .
grimace (grimacing) Odd and inappropriate facial expressions unrelated to situation 
(as seen in individuals with C A TA TO N IA ).
hallucination A perception-like experience with the clarity and impact of a true percep­
tion but without the external stimulation of the relevant sensory organ. Hallucinations

tion but without the external stimulation of the relevant sensory organ. Hallucinations 
should be distinguished from ILLU SIO N S, in which an actual external stimulus is 
misperceived or misinteφreted. The person may or may not have insight into the non- 
veridical nature of the hallucination. One hallucinating person may recognize the false 
sensory experience, whereas another may be convinced that the experience is grounded 
in reality. The term hallucination  is not ordinarily applied to the false perceptions that 
occur during dreaming, while falling asleep (hypnagogic),  or upon awakening (hypno-  
pompic).  Transient hallucinatory experiences may occur without a mental disorder.
auditory A hallucination involving the perception of sound, most commonly of 
voice.
geometric Visual hallucinations involving geometric shapes such as tunnels and 
funnels, spirals, lattices, or cobwebs.

voice.
gustatory A hallucination involving the perception of taste (usually unpleasant).
mood-congruent See M O O D -C O N G R U EN T P SY C H O T IC  FEA T U R ES.
mood-incongruent See M O O D -IN C O N G R U EN T PSY C H O T IC  FEA T U R ES.
olfactory A hallucination involving the perception of odor, such as of burning rub­
ber or decaying fish.
somatic A hallucination involving the perception of physical experience localized 
within the body (e.g., a feeling of electricity). A somatic hallucination is to be dis­
tinguished from physical sensations arising from an as-yet-undiagnosed general 
medical condition, from hypochondriacal preoccupation with normal physical 
sensations, or from a tactile hallucination.
tactile A hallucination involving the perception of being touched or of something

tactile A hallucination involving the perception of being touched or of something 
being under one's skin. The most common tactile hallucinations are the sensation

of electric shocks and formication (the sensation of something creeping or crawl­
ing on pr under the skin).
visual A hallucination involving sight, which may consist of formed images, such as of 
people, or of unformed images, such as flashes of light. Visual hallucinations should 
be distinguished from ILLU SIO N S, which are misperceptions of real external stimuli.
hostility Persistent or frequent angry feelings; anger or irritability in response to minor 
slights and insults; mean, nasty, or vengeful behavior. Hostility is a facet of the broad 
personality trait domain A N T A G O N ISM .
hyperacusis Increased auditory perception.
hyperorality A condition in which inappropriate objects are placed in the mouth.
hypersexuality A stronger than usual urge to have sexual activity.
hypersomnia Excessive sleepiness, as evidenced by prolonged nocturnal sleep, difficul­
ty maintaining an alert awake state during the day, or undesired daytime sleep epi­
sodes. See also SO M N O LEN C E.

hypervigilance An enhanced state of sensory sensitivity accompanied by an exaggerated 
intensity of behaviors whose purpose is to detect threats. Hypervigilance is also accompa­
nied by a state of increased anxiety which can cause exhaustion. Other symptoms include 
abnormally increased arousal, a high responsiveness to stimuli, and a continual scanning 
of the environment for threats. In hypervigilance, there is a perpetual scanning of the envi­
ronment to search for sights, sounds, people, behaviors, smells, or anything else that is rem­
iniscent of threat or trauma. The individual is placed on high alert in order to be certain 
danger is not near. Hypervigilance can lead to a variety of obsessive behavior patterns, as 
well as producing difficulties with social interaction and relationships.

hypomania An abnormality of mood resembling mania but of lesser intensity. See also  
M A N IA .
hypopnea Episodes of overly shallow breathing or an abnormally low respiratory rate.
ideas of reference The feeling that causal incidents and external events have a particu­
lar and unusual meaning that is specific to the person. An idea of reference is to be dis­
tinguished from a D EL U S IO N  O F REFEREN CE, in which there is a belief that is held with 
delusional conviction.
identity Experience of oneself as unique, with clear boundaries between self and others; 
stability of self-esteem and accuracy of self-appraisal; capacity for, and ability to regu­
late, a range of emotional experience.
illusion A misperception or misinterpretation of a real external stimulus, such as hear­

ing the rustling of leaves as the sound of voices. See also  H A LLU C IN A TIO N .
impulsivity Acting on the spur of the moment in response to immediate stimuli; acting 
on a momentary basis without a plan or consideration of outcomes; difficulty establish­
ing and following plans; a sense of urgency and self-harming behavior under emotion­
al distress. Impulsivity is a facet of the broad personality trait domain DiSlNHlBmON.
incoherence Speech or thinking that is essentially incomprehensible to others because 
word or phrases are joined together without a logical or meaningful connection. This 
disturbance occurs within  clauses, in contrast to derailment, in which the disturbance 
is between  clauses. This has sometimes been referred to a "word salad" to convey the 
degree of linguistic disorganization. Mildly ungrammatical constructions or idiomatic

degree of linguistic disorganization. Mildly ungrammatical constructions or idiomatic 
usages characteristic of a particular regional or cultural backgrounds, lack of educa­
tion, or low intelligence should not be considered incoherence. The term is generally 
not applied when there is evidence that the disturbance in speech is due to an aphasia.
insomnia A subjective complaint of difficulty falling or staying asleep or poor sleep quality.

intersex condition A condition in which individuals have conflicting or ambiguous bi­
ological indicators of sex.
intimacy Depth and duration of connection with others; desire and capacity for close­
ness; mutuality of regard reflected in interpersonal behavior.
intimacy avoidance Avoidance of close or romantic relationships, interpersonal attach­
ments, and intimate sexual relationships. Intimacy avoidance is a facet of the broad 
personality trait domain DETACHMENT.
irresponsibility Disregard for—and failure to honor—financial and other obligations or 
commitments; lack of respect for—and lack of follow-through on—agreements and 
promises; carelessness with others' property. Irresponsibility is a facet of the broad per­
sonality trait domain DiSINHIBmON.
language pragmatics The understanding and use of language in a given context. For 
example, the warning "Watch your hands" when issued to a child who is dirty is in­

tended not only to prompt the child to look at his or her hands but also to communicate 
the admonition "Don't get anything dirty."
lethargy A state of decreased mental activity, characterized by sluggishness, drowsi­
ness, inactivity, and reduced alertness.
macropsia The visual perception that objects are larger than they actually are. Compare 
with M IC R O P S IA .
magical thinking The erroneous belief that one's thoughts, words, or actions will cause 
or prevent a specific outcome in some way that defies commonly understood laws of 
cause and effect. Magical thinking may be a part of normal child development.
mania A mental state of elevated, expansive, or irritable mood and persistently in­
creased level of activity or energy. See also  H YPO M A N IA .

manipulativeness Use of subterfuge to influence or control others; use of seduction, 
charm, glibness, or ingratiation to achieve one's ends. Manipulativeness is a facet of the 
broad personality trait domain AN TAG O N ISM .
mannerism A peculiar and characteristic individual style of movement, action, thought, 
or speech.
melancholia (melancholic) A mental state characterized by very severe depression.
micropsia The visual perception that objects are smaller than they actually are. Com­
pare with M A C R O PSIA .
mixed symptoms The specifier "with mixed features" is applied to mood episodes during 
which subthreshold symptoms from the opposing pole are present. Whereas these con­
current "mixed" symptoms are relatively simultaneous, they may also occur closely

current "mixed" symptoms are relatively simultaneous, they may also occur closely 
juxtaposed in time as a waxing and waning of individual symptoms of the opposite 
pole (i.e., depressive symptoms during hypomanie or manic episodes, and vice versa).
mood A pervasive and sustained emotion that colors the perception of the world. Com­
mon examples of mood include depression, elation, anger, and anxiety. In contrast to 
affect,  which refers to more fluctuating changes in emotional "weather," mood refers to 
a pervasive and sustained emotional "climate." Types of mood include
dysphoric An unpleasant mood, such as sadness, anxiety, or irritability.
elevated An exaggerated feeling of well-being, or euphoria or elation. A person 
with elevated mood may describe feeling "high," "ecstatic," "on top of the world," 
or "up in the clouds."

euthymie Mood in the "normal" range, which implies the absence of depressed or 
elevated mood.

expansive Lack of restraint in expressing one's feelings, frequently with an over- 
valuatipn of one's significance or importance.
irritable Easily annoyed and provoked to anger.
mood-congruent psychotic features Delusions or hallucinations whose content is en­
tirely consistent with the typical themes of a depressed or manic mood. If the mood is 
depressed, the content of the delusions or hallucinations would involve themes of per­
sonal inadequacy, guilt, disease, death, nihilism, or deserved punishment. The content 
of the delusion may include themes of persecution if these are based on self-derogatory 
concepts such as deserved punishment. If the mood is manic, the content of the delusions 
or hallucinations would involve themes of inflated worth, power, knowledge, or iden­
tity, or a special relationship to a deity or a famous person. The content of the delusion 
may include themes of persecution if these are based on concepts such as inflated 
worth or deserved punishment.

mood-incongruent psychotic features Delusions or hallucinations whose content is not 
consistent with the typical themes of a depressed or manic mood. In the case of depres­
sion, the delusions or hallucinations would not involve themes of personal inadequacy, 
guilt, disease, death, nihilism, or deserved punishment. In the case of mania, the delu­
sions or hallucinations would not involve themes of inflated worth, power, knowledge, 
or identity, or a special relationship to a deity or a famous person.
multiple sleep latency test Polysomnographie assessment of the sleep-onset period, 
with several short sleep-wake cycles assessed during a single session. The test repeat­
edly measures the time to daytime sleep onset ("sleep latency") and occurrence of and 
time to onset of the rapid eye movement sleep phase.

mutism No, or very little, verbal response (in the absence of known aphasia).
narcolepsy Sleep disorder characterized by periods of extreme drowsiness and frequent 
daytime lapses into sleep (sleep attacks). These must have been occurring at least three 
times per week over the last 3 months (in the absence of treatment).
negative affectivity Frequent and intense experiences of high levels of a wide range of 
negative emotions (e.g., anxiety, depression, guilt/shame, worry, anger), and their be­
havioral (e.g., self-harm) and interpersonal (e.g., dependency) manifestations. Nega­
tive Affectivity is one of the five pathological PER SO N A LIT Y  T R A IT  D O M A IN S  defined in 
Section III "Alternative DSM-5 Model for Personality Disorders."
negativism Opposition to suggestion or advice; behavior opposite to that appropriate to

negativism Opposition to suggestion or advice; behavior opposite to that appropriate to 
a specific situation or against the wishes of others, including direct resistance to efforts 
to be moved.
night eating syndrome Recurrent episodes of night eating, as manifested by eating after 
awakening from sleep or excessive food consumption after the evening meal. There is 
awareness and recall of the eating. The night eating is not better accounted for by ex­
ternal influences such as changes in the individual's sleep-wake cycle or by local social 
norms.
nightmare disorder Repeated occurrences of extended, extremely dysphoric, and well- 
remembered dreams that usually involve efforts to avoid threats to survival, security 
or physical integrity and that generally occur during the second half of the major sleep 
episode. On awakening from the dysphoric dreams, the individual rapidly becomes 
oriented and alert.

nonsubstance addiction(s) Behavioral disorder (also called behavioral addiction)  not re­
lated to any substance of abuse that shares some features with substance-induced 
addiction.

obsession Recurrent and persistent thoughts, urges, or images that are experienced, at 
some time during the disturbance, as intrusive and unwanted and that in most individ­
uals cause marked anxiety or distress. The individual attempts to ignore or suppress 
such thoughts, urges, or images, or to neutralize them with some other thought or ac­
tion (i.e., by performing a compulsion).
overeating Eating too much food too quickly.
overvalued idea An unreasonable and sustained belief that is maintained with less than 
delusional intensity (i.e., the person is able to acknowledge the possibility that the be­
lief may not be true). The belief is not one that is ordinarily accepted by other members 
of the person's culture or subculture.
panic attacks Discrete periods of sudden onset of intense fear or terror, often associated 
with feelings of impending doom. During these attacks there are symptoms such as

with feelings of impending doom. During these attacks there are symptoms such as 
shortness of breath or smothering sensations; palpitations, pounding heart, or acceler­
ated heart rate; chest pain or discomfort; choking; and fear of going crazy or losing con­
trol. Panic attacks may be unexpected, in which the onset of the attack is not associated 
with an obvious trigger and instead occurs "out of the blue," or expected, in which the 
panic attack is associated with an obvious trigger, either internal or external.
paranoid ideation Ideation, of less than delusional proportions, involving suspicious­
ness or the belief that one is being harassed, persecuted, or unfairly treated.
parasomnias Disorders of sleep involving abnormal behaviors or physiological events 
occurring during sleep or sleep-wake transitions. Compare with D Y S S O M N IA S .

perseveration Persistence at tasks or in particular way of doing things long after the be­
havior has ceased to be functional or effective; continuance of the same behavior de­
spite repeated failures or clear reasons for stopping. Perseveration is a facet of the 
broad personality trait domain NEGATIVE A ffectivity .
personality Enduring patterns of perceiving, relating to, and thinking about the envi­
ronment and oneself. PERSO N A LITY T R A IT S  are prominent aspects of personality that are 
exhibited in relatively consistent ways across time and across situations. Personality 
traits influence self and interpersonal functioning. Depending on their severity, im­
pairments in personality functioning and personality trait expression may reflect the 
presence of a personality disorder.

personality disorder—trait specified In Section III "Alternative DSM-5 Model for Per­
sonality Disorders," a proposed diagnostic category for use when a personality disor­
der is considered present but the criteria for a specific disorder are not met. Personality 
disorder—trait specified (PD-TS) is defined by significant impairment in personality 
functioning, as measured by the Level of Personality Functioning Scale and one or 
more pathological PER SO N A LIT Y  T R A IT  D O M A IN S or PER SO N A LIT Y  T R A IT  FA C ET S. PD-TS is 
proposed in DSM-5 Section III for further study as a possible future replacement for 
other specified personality disorder and unspecified personality disorder.
personality functioning Cognitive models of self and others that shape patterns of emo­
tional and affiliative engagement.

personality trait A tendency to behave, feel, perceive, and think in relatively consistent 
ways across time and across situations in which the trait may be manifest.
personality trait facets Specific personality components that make up the five broad per­
sonality trait domains in the dimensional taxonomy of Section III "Alternative DSM-5 
Model for Personality Disorders." For example, the broad domain antagonism has the 
following component facets: M A N IPU LA Ή V EN ESS, D EC EIT FU LN ESS, G R A N D IO S IT Y , A TTEN -  
Ή Ο Ν  SE E K IN G , C A LLO U SN ESS, and H O S T IL IT Y .

personality trait domains In the dimensional taxonomy of Section III ''Alternative DSM- 
5 Model for Personality Disorders," personality traits are organized into five broad do­
mains: Negative  Affectivity , D etachment , A ntagonism , DisiNHiBmoN, and Psy- 
CHOTICISM. Within these five broad trait domains are 25 specific personality trait facets 
(e.g., IMPULSIVITY, RIG ID  PERFECTIONISM).
phobia A persistent fear of a specific object, activity, or situation (i.e., the phobic stimu­
lus) out of proportion to the actual danger posed by the specific object or situation that 
results in a compelling desire to avoid it. If it cannot be avoided, the phobic stimulus is 
endured with marked distress.
pica Persistent eating of nonnutritive nonfood substances over a period of at least 1  month. 
The eating of nonnutritive nonfood substances is inappropriate to the developmental 
level of the individual (a minimum age of 2 years is suggested for diagnosis). The eat­

ing behavior is not part of a culturally supported or socially normative practice.
polysomnography Polysomnography (PSG), also known as a sleep study, is a multipa- 
rametric test used in the study of sleep and as a diagnostic tool in sleep medicine. The 
test result is called a polysomnogram,  also abbreviated PSG. PSG monitors many body 
functions, including brain (electroencephalography), eye movements (electro-oculog­
raphy), muscle activity or skeletal muscle activation (electromyography), and heart 
rhythm (electrocardiography).
posturing Spontaneous and active maintenance of a posture against gravity (as seen in 
catatonia ). Abnormal posturing may also be a sign of certain injuries to the brain or 
spinal cord, including the following:

decerebrate posture The arms and legs are out straight and rigid, the toes point 
downward, and the head is arched backward.
decorticate posture The body is rigid, the arms are stiff and bent, the fists are tight, 
and the legs are straight out.
opisthotonus The back is rigid and arching, and the head is thrown backward.
An affected person may alternate between different postures as the condition changes.
pressured speech Speech that is increased in amount, accelerated, and difficult or impossi­
ble to interrupt. Usually it is also loud and emphatic. Frequently the person talks without 
any social stimulation and may continue to talk even though no one is listening.
prodrome An early or premonitory sign or symptom of a disorder.
pseudocyesis A false belief of being pregnant that is associated with objective signs and 
reported symptoms of pregnancy.

psychological distress A range of symptoms and experiences of a person's internal life 
that are commonly held to be troubling, confusing, or out of the ordinary.
psychometric measures Standardized instruments such as scales, questionnaires, tests, 
and assessments that are designed to measure human knowledge, abilities, attitudes, 
or personality traits.
psychomotor agitation Excessive motor activity associated with a feeling of inner tension. 
The activity is usuaUy nonproductive and repetitious and consists of behaviors such as pac­
ing, fidgeting, wringing of the hands, pulling of clothes, and inability to sit still.
psychomotor retardation Visible generalized slowing of movements and speech.
psychotic features Features characterized by delusions, hallucinations, and formal thought 
disorder.

disorder.
psychoticism Exhibiting a wide range of culturally incongruent odd, eccentric, or un­
usual behaviors and cognitions, including both process (e.g., perception, dissociation)

and content (e.g., beliefs). Psychoticism is one of the five broad PER SO N A LIT Y  T R A IT  D O ­
M A IN S defined in Section III "Alternative DSM-5 Model for Personality Disorders."
purging disorder Eating disorder characterized by recurrent purging behavior to influ­
ence weight or shape, such as self-induced vomiting, misuse of laxatives, diuretics, or 
other medications, in the absence of binge eating.
racing thoughts A state in which the mind uncontrollably brings up random thoughts 
and memories and switches between them very quickly. Sometimes the thoughts are 
related, with one thought leading to another; other times they are completely random. 
A person experiencing an episode of racing thoughts has no control over them and is 
unable to focus on a single topic or to sleep.
rapid cycling Term referring to bipolar disorder characterized by the presence of at least 
four mood episodes in the previous 12 months that meet the criteria for a manic, hypo-

four mood episodes in the previous 12 months that meet the criteria for a manic, hypo- 
manic, or major depressive episode. Episodes are demarcated either by partial or full 
remissions of at least 2 months or by a switch to an episode of the opposite polarity 
(e.g., major depressive episode to manic episode). The rapid cycling specifier can be ap­
plied to bipolar I or bipolar II disorder.
rapid eye movement (REM) A behavioral sign of the phase of sleep during which the 
sleeper is likely to be experiencing dreamlike mental activity.
repetitive speech Morphologically heterogeneous iterations of speech.
residual phase Period after an episode of schizophrenia that has partly or completed re­
mitted but in which some symptoms may remain, and symptoms such as listlessness, 
problems with concentrating, and withdrawal from social activities may predominate.

restless legs syndrome An urge to move the legs, usually accompanied or caused by 
uncomfortable and unpleasant sensations in the legs (for pediatric restless legs syn­
drome, the description of these symptoms should be in the child's own words). The 
symptoms begin or worsen during periods of rest or inactivity. Symptoms are partially 
or totally relieved by movement. Symptoms are worse in the evening or at night than 
during the day or occur only in the night/evening.
restricted affectivity Little reaction to emotionally arousing situations; constricted 
emotional experience and expression; indifference and aloofness in normatively engaging 
situations. Restricted affectivity is a facet of the broad personality trait domain DETACH­
M EN T.

M EN T.
rigid perfectionism Rigid insistence on everything being flawless, perfect, and without 
errors or faults, including one's own and others' performance; sacrificing of timeliness 
to ensure correctness in every detail; believing that there is only one right way to do 
things; difficulty changing ideas and/or viewpoint; preoccupation with details, orga­
nization, and order. Lack of rigid perfectionism is a facet of the broad personality trait 
domain DisiNHiBmON.
risk taking Engagement in dangerous, risky, and potentially self-damaging activities, un­
necessarily and without regard to consequences; lack of concern for one's limitations and  
denial of the reality of personal danger; reckless pursuit of goals regardless of the level of

denial of the reality of personal danger; reckless pursuit of goals regardless of the level of  
risk involved. Risk taking is a facet of the broad personality trait domain D iS lN H lB m O N .
rumination (rumination disorders) Repeated regurgitation of food over a period of at 
least 1 month. Regurgitated food may be re-chewed, re-swallowed, or spit out. In 
rumination disorders, there is no evidence that an associated gastrointestinal or an­
other medical condition (e.g., gastroesophageal reflux) is sufficient to account for the 
repeated regurgitation.

seasonal pattern A pattern of the occurrence of a specific mental disorder in selected 
seasons of thç year.
self-directedness, self-direction Pursuit of coherent and meaningful short-term and life 
goals; utilization of constructive and prosocial internal standards of behavior; ability to 
self-reflect productively.
separation insecurity Fears of being alone due to rejection by and/or separation from 
significant others, based in a lack of confidence in one's ability to care for oneself, both 
physically and emotionally. Separation insecurity is a facet of the broad personality 
trait domain NEGATIVE A ffectivity .
sex Biological indication of male and female (understood in the context of reproductive 
capacity), such as sex chromosomes, gonads, sex hormones, and nonambiguous inter­
nal and external genitalia.
sign An objective manifestation of a pathological condition. Signs are observed by the 
examiner rather than reported by the affected individual. Compare with S Y M PT O M .

sleep-onset REM Occurrence of the rapid eye movement (REM) phase of sleep within 
minutes after falling asleep. Usually assessed by a polysomnographic M U LTIPLE SLEEP  
LA TEN C Y T E S T .
sleep terrors Recurrent episodes of abrupt terror arousals from sleep, usually occurring 
during the first third of the major sleep episode and beginning with a panicky scream. 
There is intense fear and signs of autonomic arousal, such as mydriasis, tachycardia, 
rapid breathing, and sweating, during each episode.
sleepwalking Repeated episodes of rising from bed during sleep and walking about, 
usually occurring during the first third of the major sleep episode. While sleepwalking, 
the person has a blank, staring face, is relatively unresponsive to the efforts of others to

the person has a blank, staring face, is relatively unresponsive to the efforts of others to 
communicate with him or her, and can be awakened only with great difficulty.
somnolence (or "drowsiness") A state of near-sleep, a strong desire for sleep, or sleep­
ing for unusually long periods. It has two distinct meanings, referring both to the usual 
state preceding falling asleep and to the chronic condition that involves being in that 
state independent of a circadian rhythm. Compare with H Y PER SO M N IA .
specific food cravings Irresistible desire for special types of food.
startle response (or "startle reaction") An involuntary (reflexive) reaction to a sudden 
unexpected stimulus, such as a loud noise or sharp movement.
stereotypies, stereotyped behaviors/movements Repetitive, abnormally frequent, non­
goal-directed movements, seemingly driven, and nonfunctional motor behavior (e.g.,

goal-directed movements, seemingly driven, and nonfunctional motor behavior (e.g., 
hand shaking or waving, body rocking, head banging, self-biting).
stress The pattern of specific and nonspecific responses a person makes to stimulus 
events that disturb his or her equilibrium and tax or exceed his or her ability to cope.
stressor Any emotional, physical, social, economic, or other factor that disrupts the nor­
mal physiological, cognitive, emotional, or behavioral balance of an individual.
stressor, psychological Any life event or life change that may be associated temporally 
(and perhaps causally) with the onset, occurrence, or exacerbation of a mental disorder.
stupor Lack of psychomotor activity, which may range from not actively relating to the 
environment to complete immobility.
submissiveness Adaptation of one's behavior to the actual or perceived interests and

submissiveness Adaptation of one's behavior to the actual or perceived interests and 
desires of others even when doing so is antithetical to one's own interests, needs, or 
desires. Submissiveness is a facet of the broad personality trait domain NEGATIVE Af­
fectivity .

subsyndromal Below a specified level or threshold required to qualify for a particular 
condition. Subsyndromal conditions (formes frustes)  are medical conditions that do not 
meet full criteria for a diagnosis—for example, because the symptoms are fewer or less 
severe than a defined syndrome—but that nevertheless can be identified and related to 
the "'full-blown" syndrome.
suicidal ideas (suicidal ideation) Thoughts about self-harm, with deliberate consider­
ation or planning of possible techniques of causing one's own death.
suicide The act of intentionally causing one's own death.
suicide attempt An attempt to end one's own life, which may lead to one's death.
suspiciousness Expectations of—and sensitivity to—signs of interpersonal ill intent or 
harm; doubts about loyalty and fidelity of others; feelings of being mistreated, used, 
and/or persecuted by others. Suspiciousness is a facet of the broad personality trait do­
main Detachment .

symptom A subjective manifestation of a pathological condition. Symptoms are reported 
by the affected individual rather than observed by the examiner. Compare with S IG N .
syndrome A grouping of signs and symptoms, based on their frequent co-occurrence 
that may suggest a common underlying pathogenesis, course, familial pattern, or treat­
ment selection.
synesthesias A condition in which stimulation of one sensory or cognitive pathway 
leads to automatic, involuntary experiences in a second sensory or cognitive pathway.
temper outburst An emotional outburst (also called a "tantrum"), usually associated 
with children or those in emotional distress, and typically characterized by stubborn­
ness, crying, screaming, defiance, angry ranting, a resistance to attempts at pacifica­

tion, and in some cases hitting. Physical control may be lost, the person may be unable 
to remain still, and even if the "goal" of the person is met, he or she may not be calmed.
thought-action fusion The tendency to treat thoughts and actions as equivalent.
tic An involuntary, sudden, rapid, recurrent, nonrhythmic motor movement or vocal­
ization.
tolerance A situation that occurs with continued use of a drug in which an individual 
requires greater dosages to achieve the same effect.
transgender The broad spectrum of individuals who transiently or permanently identify 
with a gender different from their natal gender.
transsexual An individual who seeks, or has undergone, a social transition from male to 
female or female to male, which in many, but not all cases may also involve a somatic

female or female to male, which in many, but not all cases may also involve a somatic 
transition by cross-sex hormone treatment and genital surgery ("sex reassignment 
surgery").
traumatic stressor Any event (or events) that may cause or threaten death, serious injury, 
or sexual violence to an individual, a close family member, or a close friend.
unusual beliefs and experiences Belief that one has unusual abilities, such as mind 
reading, telekinesis, or TH O U G H T-A C TIO N  FU SIO N ; unusual experiences of reality, in­
cluding hallucinatory experiences. In general, the unusual beliefs are not held at the 
same level of conviction as D ELU SIO N S. Unusual beliefs and experiences are a facet of 
the personality trait domain PSY C H O T IC ISM .
waxy flexibility Slight, even resistance to positioning by examiner. Compare with CA T­
A LEPSY .

withdrawal, social Preference for being alone to being with others; reticence in social 
situations; AVpiD AN CE of social contacts and activity; lack of initiation of social contact. 
Social withdrawal is a facet of the broad personality trait domain D ETA CH M EN T.
worry Unpleasant or uncomfortable thoughts that cannot be consciously controlled by 
trying to turn the attention to other subjects. The worrying is often persistent, repeti­
tive, and out of proportion to the topic worried about (it can even be about a triviality).

Glossary of Culltai^l 
Concepts of Distréii
Ataque de nervios
Ataque de nervios  ("attack of nerves") is a syndrome among individuals of Latino descent, 
characterized by symptoms of intense emotional upset, including acute anxiety, anger, or 
grief; screaming and shouting uncontrollably; attach of crying; trembling; heat in the chest 
rising into the head; and becoming verbally and physically aggressive. Dissociative experi­
ences (e.g., depersonalization, derealization, amnesia), seizure-like or fainting episodes, and 
suicidal gestures are prominent in some ataques  but absent in others. A general feature of an 
ataque de nervios  is a sense of being out of control. Attacks frequently occur as a direct result 
of a stressful event relating to the family, such as news of the death of a close relative, con­
flicts with a spouse or children, or witnessing an accident involving a family member. For a

flicts with a spouse or children, or witnessing an accident involving a family member. For a 
minority of individuals, no particular social event triggers their ataques;  instead, their vul­
nerability to losing control comes from the accumulated experience of suffering.
No one-to-one relationship has been found between ataque  and any specific psychiatric dis­
order, although several disorders, including panic disorder, other specified or unspecified dis­
sociative disorder, and conversion disorder, have symptomatic overlap with ataque.
In community samples, ataque  is associated with suicidal ideation, disability, and out­
patient psychiatric utilization, after adjustment for psychiatric diagnoses, traumatic expo­
sure, and other covariates. However, some ataques  represent normative expressions of

sure, and other covariates. However, some ataques  represent normative expressions of 
acute distress (e.g., at a funeral) without clinical sequelae. The term ataque de nervios  may 
also refer to an idiom of distress that includes any "fit"-like paroxysm of emotionality (e.g., 
hysterical laughing) and may be used to indicate an episode of loss of control in response 
to an intense stressor.
Related conditions in other cultural contexts: Indisposition in Haiti, blacking out in 
the Southern United States, and falling out in the West Indies.
Related conditions in DSM-5: Panic attack, panic disorder, other specified or unspec­
ified dissociative disorder, conversion (functional neurologic symptom) disorder, inter­
mittent explosive disorder, other specified or unspecified anxiety disorder, other specified 
or unspecified trauma and stressor-related disorder.
Dhat syndrome

Dhat syndrome  is a term that was coined in South Asia little more than half a century ago to 
account for common clinical presentations of young male patients who attributed their 
various symptoms to semen loss. Despite the name, it is not a discrete syndrome but rather 
a cultural explanation of distress for patients who refer to diverse symptoms, such as anx­
iety, fatigue, weakness, weight loss, impotence, other multiple somatic complaints, and 
depressive mood. The cardinal feature is anxiety and distress about the loss of dhat in the 
absence of any identifiable physiological dysfunction. Dhat  was identified by patients as 
a white discharge that was noted on defecation or urination. Ideas about this substance 
are related to the concept of dhatu  (semen) described in the Hindu system of medicine,

are related to the concept of dhatu  (semen) described in the Hindu system of medicine, 
Ayurveda, as one of seven essential bodily fluids whose balance is necessary to maintain 
health.

Although dhat syndrome  was formulated as a cultural guide to local clinical practice, related 
ideas about the harmful effects of semen loss have been shown to be widespread in the general 
population, suggesting a cultural disposition for explaining health problems and symptoms 
with reference to dhat syndrome.  Research in health care settings has yielded diverse estimates 
of the syndrome's prevalence (e.g., 64% of men attending psychiatric clinics in India for sexual 
complaints; 30% of men attending general medical clinics in Pakistan). Although dhat syndrome  
is most commonly identified with young men from lower socioeconomic backgrounds, mid­
dle-aged men may also be affected. Comparable concerns about white vaginal discharge (leu- 
korrhea) have been associated with a variant of the concept for women.
Related conditions in other cultural contexts: koro in Southeast Asia, particularly Sin­
gapore and shen-k'uei  ("kidney deficiency") in China.

Related conditions in DSM-5: Major depressive disorder, persistent depressive disor­
der (dysthymia), generalized anxiety disorder, somatic symptom disorder, illness anxiety 
disorder, erectile disorder, early (premature) ejaculation, other specified or unspecified 
sexual dysfunction, academic problem.
Khyâl cap
"Khyal  attacks" (khyâl cap),  or "wind attacks," is a syndrome found among Cambodians in 
the United States and Cambodia. Common symptoms include those of panic attacks, such 
as dizziness, palpitations, shortness of breath, and cold extremities, as well as other symp­
toms of anxiety and autonomic arousal (e.g., tinnitus and neck soreness). Khyâl  attacks in­
clude catastrophic cognitions centered on the concern that khyâl  (a windlike substance) 
may rise in the body—along with blood—and cause a range of serious effects (e.g., com­

pressing the lungs to cause shortness of breath and asphyxia; entering the cranium to 
cause tinnitus, dizziness, blurry vision, and a fatal syncope). Khyâl  attacks may occur with­
out warning, but are frequently brought about by triggers such as worrisome thoughts, 
standing up (i.e., orthostasis), specific odors with negative associations, and agoraphobic- 
type cues like going to crowded spaces or riding in a car. Khyâl  attacks usually meet panic 
attack criteria and may shape the experience of other anxiety and trauma- and stressor- 
related disorders. Khyâl  attacks may be associated with considerable disability.
Related conditions in other cultural contexts: Laos (pen lom),  Tibet (srog rlunggi nad),  
Sri Lanka (vata),  and Korea (hwa byung).

Related conditions in DSM-5: Panic attack, panic disorder, generalized anxiety disor­
der, agoraphobia, posttraumatic stress disorder, illness anxiety disorder.
Kufungisisa
Kufungisisa  ("thinking too much" in Shona) is an idiom of distress and a cultural explana­
tion among the Shona of Zimbabwe. As an explanation, it is considered to be causative of 
anxiety, depression, and somatic problems (e.g., "my heart is painful because I think too 
much"). As an idiom of psychosocial distress, it is indicative of interpersonal and social 
difficulties (e.g., marital problems, having no money to take care of children). Kufungisisa  
involves ruminating on upsetting thoughts, particularly worries.
Kufungisisa  is associated with a range of psychopathology, including anxiety symp­

toms, excessive worry, panic attacks, depressive symptoms, and irritability. In a study of a 
random community sample, two-thirds of the cases identified by a general psychopathol­
ogy measure were of this complaint.
In many cultures, "thinking too much" is considered to be damaging to the mind and 
body and to cause specific symptoms like headache and dizziness. "Thinking too much" 
may also be a key component of cultural syndromes such as "brain fag" in Nigeria. In the 
case of brain fag, "thinking too much" is primarily attributed to excessive study, which is 
considered to damage the brain in particular, with symptoms including feelings of heat or 
crawling sensations in the head.

Related conditions in other cultural contexts: "'Thinking too much" is a common id­
iom of distress ^nd cultural explanation across many countries and ethnic groups. It has 
been described in Africa, the Caribbean and Latin America, and among East Asian and 
Native American groups.
Related conditions in DSM-5: Major depressive disorder, persistent depressive disorder 
(dysthymia), generalized anxiety disorder, posttraumatic stress disorder, obsessive-compul­
sive disorder, persistent complex bereavement disorder (see "Conditions for Further Study").
Maladi moun
Maladi moun  (literally "humanly caused illness," also referred to as "sent sickness") is a 
cultural explanation in Haitian communities for diverse medical and psychiatric disor­
ders. In this explanatory model, interpersonal envy and malice cause people to harm their 
enemies by sending illnesses such as psychosis, depression, social or academic failure, and

enemies by sending illnesses such as psychosis, depression, social or academic failure, and 
inability to perform activities of daily living. The etiological model assumes that illness 
may be caused by others' envy and hatred, provoked by the victim's economic success as 
evidenced by a new job or expensive purchase. One person's gain is assumed to produce 
another person's loss, so visible success makes one vulnerable to attack. Assigning the la­
bel of sent sickness depends on mode of onset and social status more than presenting 
symptoms. The acute onset of new symptoms or an abrupt behavioral change raises sus­
picions of a spiritual attack. Someone who is attractive, intelligent, or wealthy is perceived 
as especially vulnerable, and even young healthy children are at risk.
Related conditions in other cultural contexts: Concerns about illness (typically, phys­

ical illness) caused by envy or social conflict are common across cultures and often ex­
pressed in the form of "evil eye" (e.g. in Spanish, mal de ojo,  in Italian, mal'occhiu).
Related conditions in DSM-5: Delusional disorder, persecutory type; schizophrenia 
with paranoid features.
Nervios
Nervios  ("nerves") is a common idiom of distress among Latinos in the United States and 
Latin America. Nervios  refers to a general state of vulnerability to stressful life experiences 
and to difficult life circumstances. The term nervios  includes a wide range of symptoms of 
emotional distress, somatic disturbance, and inability to function. The most common 
symptoms attributed to nervios  include headaches and "brain aches" (occipital neck ten­

sion), irritability, stomach disturbances, sleep difficulties, nervousness, easy tearfulness, 
inability to concentrate, trembling, tingling sensations, and mareos  (dizziness with occa­
sional vertigo-like exacerbations). Nervios  is a broad idiom of distress that spans the range 
of severity from cases with no mental disorder to presentations resembling adjustment, 
anxiety, depressive, dissociative, somatic symptom, or psychotic disorders. "Being ner­
vous since childhood" appears to be more of a trait and may precede social anxiety disor­
der, while "being ill with nerves" is more related than other forms of nervios  to psychiatric 
problems, especially dissociation and depression.
Related conditions in other cultural contexts: Nevra  among Greeks in North America,

Related conditions in other cultural contexts: Nevra  among Greeks in North America, 
nierbi  among Sicilians in North America, and nerves  among whites in Appalachia and 
Newfoundland.
Related conditions in DSM-5: Major depressive disorder, peristent depressive disor­
der (dysthymia), generalized anxiety disorder, social anxiety disorder, other specified or 
unspecified dissociative disorder, somatic symptom disorder, schizophrenia.
Shenjing shuairuo
Shenjing shuairuo ("weakness of the nervous system" in Mandarin Chinese) is a cultural 
syndrome that integrates conceptual categories of traditional Chinese medicine with the

Western diagnosis of neurasthenia. In the second, revised edition of the Chinese Classifica­
tion of Mental Disorders  (CCMD-2-R), shenjing shuairuo  is defined as a syndrome composed 
of three out of five nonhierarchical symptom clusters: weakness (e.g., mental fatigue), 
emotions (e.g., feeling vexed), excitement (e.g., increased recollections), nervous pain (e.g., 
headache), and sleep (e.g., insomnia). Fan nao  (feeling vexed) is a form of irritability mixed 
with worry and distress over conflicting thoughts and unfulfilled desires. The third edi­
tion of the CCMD retains shenjing shuairuo  as a somatoform diagnosis of exclusion. Salient 
précipitants of shenjing shuairuo  include work- or family-related stressors, loss of face 
{mianzi, lianzi),  and an acute sense of failure (e.g., in academic performance). Shenjing sh­
uairuo  is related to traditional concepts of weakness (xu) and health imbalances related to

uairuo  is related to traditional concepts of weakness (xu) and health imbalances related to 
deficiencies of a vital essence (e.g., the depletion of qi [vital energy] following overstrain­
ing or stagnation of qi due to excessive worry). In the traditional interpretation, shenjing  
shuairuo  results when bodily channels (jing)  conveying vital forces (shen)  become dysreg­
ulated as a result of various social and interpersonal stressors, such as the inability to 
change a chronically frustrating and distressing situation. Various psychiatric disorders 
are associated with shenjing shuairuo,  notably mood, anxiety, and somatic symptom disor­
ders. In medical clinics in China, however, up to 45% of patients with shenjing shuairuo  do 
not meet criteria for any DSM-IV disorder.
Related conditions in other cultural contexts: Neurasthenia-spectrum idioms and

Related conditions in other cultural contexts: Neurasthenia-spectrum idioms and 
syndromes are present in India (ashaktapanna)  and Japan (shinkei-suijaku),  among other set­
tings. Other conditions, such as brain fag syndrome, burnout syndrome, and chronic fa­
tigue syndrome, are also closely related.
der (dysthymia), generalized anxiety disorder, somatic symptom disorder, social anxiety 
disorder, specific phobia, posttraumatic stress disorder.
Susto
Susto  ("fright") is a cultural explanation for distress and misfortune prevalent among 
some Latinos in the United States and among people in Mexico, Central America, and 
South America. It is not recognized as an illness category among Latinos from the Carib­
bean. Susto  is an illness attributed to a frightening event that causes the soul to leave the

bean. Susto  is an illness attributed to a frightening event that causes the soul to leave the 
body and results in unhappiness and sickness, as well as difficulties functioning in key 
social roles. Symptoms may appear any time from days to years after the fright is experi­
enced. In extreme cases, susto  may result in death. There are no specific defining symp­
toms for susto;  however, symptoms that are often reported by people with susto  include 
appetite disturbances, inadequate or excessive sleep, troubled sleep or dreams, feelings of 
sadness, low self-worth or dirtiness, interpersonal sensitivity, and lack of motivation to do 
anything. Somatic symptoms accompanying susto  may include muscle aches and pains, 
cold in the extremities, pallor, headache, stomachache, and diarrhea. Precipitating events 
are diverse, and include natural phenomena, animals, interpersonal situations, and super­

natural agents, among others.
Three syndromic types of susto  (referred to as cibih in the local Zapotec language) have 
been identified, each having different relationships with psychiatric diagnoses. An interper­
sonal susto  characterized by feelings of loss, abandonment, and not being loved by family, 
with accompanying symptoms of sadness, poor self-image, and suicidal ideation, seemed to 
be closely related to major depressive disorder. When susto  resulted from a traumatic event 
that played a major role in shaping symptoms and in emotional processing of the experience, 
the diagnosis of posttraumatic stress disorder appeared more appropriate. Susto  character­
ized by various recurrent somatic symptoms—for which the person sought health care from

ized by various recurrent somatic symptoms—for which the person sought health care from 
several practitioners—was thought to resemble a somatic symptom disorder.
Related conditions in other cultural contexts: Similar etiological concepts and symp­
tom configurations are found globally. In the Andean region, susto  is referred to as espanto.

Related conditions in DSM-5: Major depressive disorder, posttraumatic stress disor­
der, other specified or unspecified trauma and stressor-related disorder, somatic symp­
tom disorders.
Taijin kyofusho
Taijin kyofusho  ("interpersonal fear disorder" in Japanese) is a cultural syndrome charac­
terized by anxiety about and avoidance of interpersonal situations due to the thought, feel­
ing, or conviction that one's appearance and actions in social interactions are inadequate 
or offensive to others. In the United States, the variant involves having an offensive body 
odor and is termed olfactory reference syndrome.  Individuals with taijin kyofusho  tend to focus 
on the impact of their symptoms and behaviors on others. Variants include major concerns 
about facial blushing (erythrophobia), having an offensive body odor (olfactory reference 
syndrome), inappropriate gaze (too much or too little eye contact), stiff or awkward facial

syndrome), inappropriate gaze (too much or too little eye contact), stiff or awkward facial 
expression or bodily movements (e.g., stiffening, trembling), or body deformity.
Taijin kyofusho  is a broader construct than social anxiety disorder in DSM-5. In addition 
to performance anxiety, taijin kyofusho  includes two culture-related forms: a "sensitive type," 
with extreme social sensitivity and anxiety about interpersonal interactions, and an "of­
fensive type," in which the major concern is offending others. As a category, taijin kyofusho  
thus includes syndromes with features of body dysmorphic disorder as well as delusional 
disorder. Concerns may have a delusional quality, responding poorly to simple reassurance 
or counterexample.
The distinctive symptoms of taijin kyofusho  occur in specific cultural contexts and, to

The distinctive symptoms of taijin kyofusho  occur in specific cultural contexts and, to 
some extent, with more severe social anxiety across cultures. Similar syndromes are found 
in Korea and other societies that place a strong emphasis on the self-conscious mainte­
nance of appropriate social behavior in hierarchical interpersonal relationships. Taijin kyo-  
fushoAike  symptoms have also been described in other cultural contexts, including the 
United States, Australia, and New Zealand.
Related conditions in other cultural contexts: Taein kong po  in Korea.
Related conditions in DSM-5: Social anxiety disorder, body dysmorphic disorder, de­
lusional disorder, obsessive-compulsive disorder, olfactory reference syndrome (a type of 
other specified obsessive-compulsive and related disorder). Olfactory reference syndrome

other specified obsessive-compulsive and related disorder). Olfactory reference syndrome 
is related specifically to the jikoshu-kyofu  variant of taijin kyofusho,  whose core symptom is 
the concern that the person emits an offensive body odor. This presentation is seen in var­
ious cultures outside Japan.

Alphabetical Listing of 
DSIM-5 Diagnoses and Codes 
(iCD-9-CIVi and iCD-IO-CIM)
ICD-9-CM codes are to be used for coding purposes in the United States through 
September 30, 2014. ICD-IO-CM codes are to be used starting October 1,2014.
ICD-9-CM ICD-10-CM Disorder, condition, or problem
V62.3 Z55.9 Academic or educational problem
V62.4 Z60.3 Acculturation difficulty
308.3 F43.0 Acute stress disorder 
Adjustment disorders
309.24 F43.22 With anxiety
309.0 F43.21 With depressed mood
309.3 F43.24 With disturbance of conduct
309.28 F43.23 With mixed anxiety and depressed mood
309.4 F43.25 With mixed disturbance of emotions and conduct
309.9 F43.20 Unspecified
V71.01 Z72.811 Adult antisocial behavior
307.0 F98.5 Adult-onset fluency disorder
Adult physical abuse by nonspouse or nonpartner. Confirmed
995.81 T74.11XA Initial encounter
995.81 T74.11XD Subsequent encounter 
Adult physical abuse by nonspouse or nonpartner. Suspected
995.81 T76.11XA Initial encounter

995.81 T76.11XD Subsequent encounter 
Adult psychological abuse by nonspouse or nonpartner. 
Confirmed
995.82 T74.31XA Initial encounter
995.82 T74.31XD Subsequent encounter 
Adult psychological abuse by nonspouse or nonpartner. Suspected
995.82 T76.31XA Initial encounter
995.82 T76.31XD Subsequent encounter 
Adult sexual abuse by nonspouse or nonpartner. Confirmed
995.83 T74.21XA Initial encounter
995.83 T74.21XD Subsequent encounter 
Adult sexual abuse by nonspouse or nonpartner, Suspected
995.83 T76.21XA Initial encounter
995.83 T76.21XD Subsequent encounter

300.22
291.89
291.89
291.89
291.1
291.2
291.89
291.9
291.89
291.82
303.00F40.00
F10.180
F10.280
F10.980
F10.14
F10.24
F10.94
F10.14
F10.24
F10.94
F10.26
F10.96
F10.27
F10.97
F10.288
F10.988
F10.159
F10.259
F10.959
F10.181
F10.281
F10.981
F10.182
F10.282
F10.982
F10.129
F10.229
F10.929
F10.121
F10.221
F10.921Agoraphobia
Alcohol-induced anxiety disorder 
With mild use disorder 
With moderate or severe use disorder 
Alcohol-induced bipolar and related disorder 
Alcohol-induced depressive disorder 
Alcohol-induced major neurocognitive disorder. Amnestic 
confabulatory type
Alcohol-induced major neurocognitive disorder, Nonamnestic 

Alcohol-induced mild neurocognitive disorder 
Alcohol-induced psychotic disorder 
Alcohol-induced sexual dysfunction 
Alcohol-induced sleep disorder 
Alcohol intoxication 
Alcohol intoxication delirium 

Alcohol use disorder
305.00 FIO.IO Mild
303.90 F10.20 Moderate
303.90 F10.20 Severe
291.81 Alcohol withdrawal
F10.232 With perceptual disturbances
F10.239 Without perceptual disturbances
291.0 F10.231 Alcohol withdrawal delirium
292.89 Amphetamine (or other stimulant)-induced anxiety disorder 
F15.180 With mild use disorder
F15.280 With moderate or severe use disorder
F15.980 Without use disorder
292.84 Amphetamine (or other stimulant)-induced bipolar and related
disorder
F15.14 With mild use disorder
F15.24 With moderate or severe use disorder
F15.94 Without use disorder
F15.921 Amphetamine (or other stimulant)-induced delirium
292.84 Amphetamine (or other stimulant)-induced depressive disorder 
292.89 Amphetamine (or other stimulant)-induced obsessive-compulsive
and related disorder
F15.188 With mild use disorder
F15.288 With moderate or severe use disorder

F15.988 Without use disorder
292.9 Amphetamine (or other stimulant)-induced psychotic disorder
F15.159 With mild use disorder
F15.259 With moderate or severe use disorder
F15.959 Without use disorder
292.89 Amphetamine (or other stimulant)-induced sexual dysfunction 
F15.181 With mild use disorder
F15.281 With moderate or severe use disorder
F15.981 Without use disorder
292.85 Amphetamine (or other stimulant)-induced sleep disorder 
F15.182 With mild use disorder
F15.282 With moderate or severe use disorder
F15.982 Without use disorder
292.89 Amphetamine or other stimulant intoxication 
Amphetamine or other stimulant intoxication. With perceptual
disturbances
F15.122 With mild use disorder
FI5.222 With moderate or severe use disorder
F15.922 Without use disorder

F15.129Amphetamine or other stimulant intoxication. Without perceptual 
With mild use disorder
F15.229 With moderate or severe use disorder
F15.929 Without use disorder
292.81 Amphetamine (or other stimulant) intoxication delirium
F15.121 With mild use disorder
F15.221 With moderate or severe use disorder
F15.921 Without use disorder
292.0 F15.23 Amphetamine or other stimulant withdrawal
305.70 F15.10Amphetamine-type substance use disorder 
Mild
304.40 F15.20 Moderate
304.40 F15.20 Severe
307.1 Anorexia nervosa
F50.02 Binge-eating/purging type
F50.01 Restricting type
995.29 T43.205AAntidepressant discontinuation syndrome 
Initial encounter
995.29 T43.205S Sequelae
995.29 T43.205D Subsequent encounter
301.7 F60.2 Antisocial personality disorder
293.84 F06.4 Anxiety disorder due to another medical condition
314.01 F90.2Attention-deficit/  hyperactivity disorder 
Combined presentation

314.01 F90.1 Predominantly hyperactive/impulsive presentation
314.00 F90.0 Predominantly inattentive presentation
299.00 F84.0 Autism spectrum disorder
301.82 F60.6 Avoidant personality disorder
307.59 F50.8 Avoidant/restrictive food intake disorder
307.51 F50.8 Binge-eating disorder
296.56 F31.76Bipolar I disorder. Current or most recent episode depressed 
In full remission
296.55 F31.75 In partial remission
296.51 F31.31 Mild
296.52 F31.32 Moderate
296.53 F31.4 Severe
296.54 F31.5 With psychotic features
296.50 F31.9 Unspecified
296.40 F31.0 Bipolar I disorder. Current or most recent episode hypomanie
296.46 F31.74 In full remission
296.45 F31.73 In partial remission
296.40 F31.9 Unspecified

296.46 F31.74Bipolar I disorder. Current or most recent episode manic 
296.41 F31.il Mild
296.42 F31.12 Moderate
296.43 F31.13 Severe
296.44 F31.2 With psychotic features
296.7 F31.9 Bipolar I disorder. Current or most recent episode unspecified
296.89 F31.81 Bipolar II disorder
293.83 Bipolar and related disorder due to another medical condition
F06.33 With manic features
F06.33 With manic- or hypomanic-like episodes
F06.34 With mixed features
300.7 F45.22 Body dysmorphic disorder
V62.89 R41.83 Borderline intellectual functioning
301.83 F60.3 Borderline personality disorder
298.8 F23 Brief psychotic disorder
307.51 F50.2 Bulimia nervosa
292.89 Caffeine-induced anxiety disorder
292.85 Caffeine-induced sleep disorder

305.90 F15.929 Caffeine intoxication
292.0 F15.93 Caffeine withdrawal
292.89 Cannabis-induced anxiety disorder
F12.180 With mild use disorder
F12.280 With moderate or severe use disorder
F12.980 Without use disorder
292.9 Cannabis-induced psychotic disorder
F12.159 With mild use disorder
F12.259 With moderate or severe use disorder
F12.959 Without use disorder
292.85 Cannabis-induced sleep disorder
F12.188 With mild use disorder
F12.288 With moderate or severe use disorder
F12.988 Without use disorder

F12.122Cannabis intoxication. With perceptual disturbances 
F12.222 With moderate or severe use disorder
F12.922 Without use disorder
F12.129Carmabis intoxication. Without perceptual disturbances 
F12.229 With moderate or severe use disorder
F12.929 Without use disorder
292.81 Cannabis intoxication delirium
F12.121 With mild use disorder
F12.221 With moderate or severe use disorder
F12.921 Without use disorder
305.20 F12.10Cannabis use disorder 
Mild
304.30 F12.20 Moderate
304.30 F12.20 Severe
292.0 F12.288 Cannabis withdrawal
293.89 F06.1 Catatonia associated with another mental disorder (catatonia
293.89 F06.1specifier)
Catatonic disorder due to another medical condition
780.57 G47.37Central sleep apnea 
Central sleep apnea comorbid with opioid use
786.04 R06.3 Cheyne-Stokes breathing
327.21 G47.31 Idiopathic central sleep apnea

V61.29 Z62.898 Child affected by parental relationship distress
995.52 T74.02XAChild neglect. Confirmed 
995.52 T74.02XD Subsequent encounter
995.52 T76.02XAChild neglect. Suspected 
995.52 T76.02XD Subsequent encounter
V71.02 Z72.810 Child or adolescent antisocial behavior
995.54 T74.12XAChild physical abuse. Confirmed 
995.54 T74.12XD Subsequent encounter
995.54 T76.12XAChild physical abuse. Suspected 
995.54 T76.12XD Subsequent encounter
995.51 T74.32XAChild psychological abuse. Confirmed 
995.51 T74.32XD Subsequent encounter
995.51 T76.32XAChild psychological abuse. Suspected 
995.51 T76.32XD Subsequent encounter

995.53 T74.22XAChild sexual abuse. Confirmed 
995.53 T74.22XD Subsequent encounter
995.53 T76.22XAChild sexual abuse. Suspected 
995.53 T76.22XD Subsequent encounter
315.35 F80.81 Childhood-onset fluency disorder (stuttering)
307.45 G47.22Circadian rhythm sleep-wake disorders 
Advanced sleep phase type
307.45 G47.21 Delayed sleep phase type
307.45 G47.23 Irregular sleep-wake type
307.45 G47.24 Non-24-hour sleep-wake type
307.45 G47.26 Shift work type
307.45 G47.20 Unspecified type
292.89 Cocaine-induced anxiety disorder
F14.180 With mild use disorder
F14.280 With moderate or severe use disorder
F14.980 Without use disorder
292.84 Cocaine-induced bipolar and related disorder
F14.14 With mild use disorder
F14.24 With moderate or severe use disorder
F14.94 Without use disorder
292.84 Cocaine-induced depressive disorder

292.89 Cocaine-induced obsessive-compulsive and related disorder
F14.188 With mild use disorder
F14.288 With moderate or severe use disorder
F14.988 Without use disorder
292.9 Cocaine-induced psychotic disorder
F14.159 With mild use disorder
F14.259 With moderate or severe use disorder
F14.959 Without use disorder
292.89 Cocaine-induced sexual dysfunction
F14.181 With mild use disorder
F14.281 With moderate or severe use disorder
F14.981 Without use disorder
292.85 Cocaine-induced sleep disorder
F14.182 With mild use disorder
F14.282 With moderate or severe use disorder
F14.982 Without use disorder

292.89 Cocaine intoxication
Cocaine intoxication. With perceptual disturbances
F14.122 With mild use disorder
F14.222 With moderate or severe use disorder
F14.922 Without use disorder 
Cocaine intoxication. Without perceptual disturbances
F14.129 With mild use disorder
F14.229 With moderate or severe use disorder
F14.929 Without use disorder
292.81 Cocaine intoxication delirium
F14.121 With mild use disorder
F14.221 With moderate or severe use disorder
F14.921 Without use disorder 
Cocaine use disorder
305.60 F14.10 Mild
304.20 F14.20 Moderate
304.20 F14.20 Severe
292.0 F14.23 Cocaine withdrawal 
Conduct disorder
312.32 F91.2 Adolescent-onset type
312.81 F91.1 Childhood-onset type
312.89 F91.9 Unspecified onset
300.11 Conversion disorder (functional neurological symptom disorder)
F44.4 With abnormal movement
F44.6 With anesthesia or sensory loss
F44.5 With attacks or seizures
F44.7 With mixed symptoms

F44.6 With special sensory symptoms
F44.4 With speech symptoms
F44.4 With swallowing symptoms
F44.4 With weakness/paralysis
V62.5 Z65.0 Conviction in civil or criminal proceedings without imprisonment
301.13 F34.0 Cyclothymic disorder
302.74 F52.32 Delayed ejaculation 
Delirium
293.0 F05 Delirium due to another medical condition
293.0 F05 Delirium due to multiple etiologies
292.81 Medication-induced delirium (for ICD-IO-CM codes, see specific  
substances)
Substance intoxication delirium (see specific substances for codes)  
Substance withdrawal delirium (see specific substances for codes)
297.1 F22 Delusional disorder
301.6 F60.7 Dependent personality disorder

ICD-9-CM ICD-10-CM
\Disorder, condition, or problem
300.6 F48.1 Depersonalization/derealization disorder
293.83 Depressive disorder due to another medical condition
F06.31 With depressive features
F06.32 With major depressive-like episode
315.4 F82 Developmental coordination disorder
V60.89 Z59.2 Discord with neighbor, lodger, or landlord
V62.89 Z64.4 Discord with social service provider, including probation officer, 
case manager, or social services worker
313.89 F94.2 Disinhibited social engagement disorder
V61.03 Z63.5 Disruption of family by separation or divorce
296.99 F34.8 Disruptive mood dysregulation disorder
300.12 F44.0 Dissociative amnesia
300.13 F44.1 Dissociative amnesia, with dissociative fugue
300.14 F44.81 Dissociative identity disorder
307.7 F98.1 Encopresis
307.6 F98.0 Enuresis
302.72 F52.21 Erectile disorder
698.4 L98.1 Excoriation (skin-picking) disorder
302.4 F65.2 Exhibitionistic disorder

V62.22 Z65.5 Exposure to disaster, war, or other hostilities
V60.2 Z59.5 Extreme poverty
300.19 F68.10 Factitious disorder
302.73 F52.31 Female orgasmic disorder
302.72 F52.22 Female sexual interest/arousal disorder
302.81 F65.0 Fetishistic disorder
302.89 F65.81 Frotteuristic disorder
312.31 F63.0 Gambling disorder
302.85 F64.1 Gender dysphoria in adolescents and adults
302.6 F64.2 Gender dysphoria in children
300.02 F41.1 Generalized anxiety disorder
302.76 F52.6 Genito-pelvic pain/penetration disorder
315.8 F8 8 Global developmental delay
292.89 F16.983 Hallucinogen persisting perception disorder
V61.8 Z63.8 High expressed emotion level within family
301.50 F60.4 Histrionic personality disorder
300.3 F42 Hoarding disorder
V60.0 Z59.0 Homelessness
780.54 G47.10 Hypersomnolence disorder
300.7 F45.21 Illness anxiety disorder

V62.5 Z65.1 Imprisonment or other incarceration
V60.1 Z59.1 Inadequate housing

292.89 Inhalant-induced anxiety disorder
F18.180 With mild use disorder
F18.280 With moderate or severe use disorder
F18.980 Without use disorder
292.84 Inhalant-induced depressive disorder
F18.14 With mild use disorder
F18.24 With moderate or severe use disorder
F18.94 Without use disorder
292.82 Inhalant-induced major neurocognitive disorder
F18.17 With mild use disorder
F18.27 With moderate or severe use disorder
F18.97 Without use disorder
292.89 Inhalant-induced mild neurocognitive disorder
F18.188 With mild use disorder
F18.288 With moderate or severe use disorder
F18.988 Without use disorder
292.9 Inhalant-induced psychotic disorder
F18.159 With mild use disorder
F18.259 With moderate or severe use disorder
F18.959 Without use disorder
292.89 Inhalant intoxication
F18.129 With mild use disorder
F18.229 With moderate or severe use disorder
F18.929 Without use disorder
292.81 Inhalant intoxication delirium

F18.121 With mild use disorder
F18.221 With moderate or severe use disorder
F18.921 Without use disorder 
Inhalant use disorder
305.90 F18.10 Mild
304.60 F18.20 Moderate
304.60 F18.20 Severe
780.52 G47.00 Insomnia disorder
V60.2 Z59.7 Insufficient social insurance or welfare support
319 Intellectual disability (intellectual developmental disorder)
F70 Mild
F71 Moderate
F73 Profound
F72 Severe
312.34 F63.81 Intermittent explosive disorder
312.32 F63.3 Kleptomania
V60.2 Z59.4 Lack of adequate food or safe drinking water
315.39 F80.9 Language disorder
V60.2 Z59.6 Low income

296.36 F33.42Major depressive disorder. Recurrent episode 
296.35 F33.41 In partial remission
296.31 F33.0 Mild
296.32 F33.1 Moderate
296.33 F33.2 Severe
296.34 F33.3 With psychotic features
296.30 F33.9 Unspecified
296.26 F32.5Major depressive disorder. Single episode 
296.25 F32.4 In partial remission
296.21 F32.0 Mild
296.22 F32.1 Moderate
296.23 F32.2 Severe
296.24 F32.3 With psychotic features
296.20 F32.9 Unspecifed
331.9 G31.9 Major frontotemporal neurocognitive disorder. Possible
294.11 F02.81Major frontotemporal neurocognitive disorder. Probable (code first  
331.19 [G31.09] frontotemporal disease)
With behavioral disturbance
294.10 F02.80 Without behavioral disturbance
331.9 G31.9 Major neurocognitive disorder due to Alzheimer's disease. Possible
294.11 F02.81Major neurocognitive disorder due to Alzheimer's disease. 
Probable {code first  331.0 [G30.9] Alzheimer's disease)

Probable {code first  331.0 [G30.9] Alzheimer's disease) 
294.11 F02.81Major neurocognitive disorder due to another medical condition 
294.11 F02.81Major neurocognitive disorder due to H TV  infection (code first  042 
[B20] HIV infection)
294.11 F02.81Major neurocognitive disorder due to Huntington's disease (code  
first 333.4 [GIO] Huntington's disease)
331.9 G31.9 Major neurocognitive disorder with Lewy bodies. Possible
294.11 F02.81Major neurocognitive disorder with Lewy bodies. Probable (code  
first 331.82 [G31.83] Lewy body disease)

294.11 F02.81Major neurocognitive disorder due to multiple etiologies 

331.9 G31.9 Major neurocognitive disorder due to Parkinson's disease. Possible 
Major neurocognitive disorder due to Parkinson's disease. 
Probable (code first  332.0 [G20] Parkinson's disease)
294.11 F02.81 With behavioral disturbance
294.10 F02.80 Without behavioral disturbance 
Major neurocognitive disorder due to prion disease {code first  
046.79 [A81.9] prion disease)
Major neurocognitive disorder due to traumatic brain injury {code  
first 907.0 late effect of intracranial injury without skull fracture 
[S06.2X9S diffuse traumatic brain injury with loss of conscious­
ness of unspecified duration, sequela])
331.9 G31.9 Major vascular neurocognitive disorder. Possible 
Major vascular neurocognitive disorder. Probable
290.40 F01.51 With behavioral disturbance

290.40 F01.50 Without behavioral disturbance
302.71 F52.0 Male hypoactive sexual desire disorder
V65.2 Z76.5 Malingering
333.99 G25.71 Medication-induced acute akathisia
333.72 G24.02 Medication-induced acute dystonia
292.81 Medication-induced dehrium (for ICD-IO-CM codes, see specific  
333.1 G25.1 Medication-induced postural tremor
331.83 G31.84 Mild frontotemporal neurocognitive disorder
331.83 G31.84 Mild neurocognitive disorder due to Alzheimer's disease
331.83 G31.84 Mild neurocognitive disorder due to another medical condition
331.83 G31.84 Mild neurocognitive disorder due to HIV infection
331.83 G31.84 Mild neurocognitive disorder due to Huntington's disease
331.83 G31.84 Mild neurocognitive disorder due to multiple etiologies

331.83 G31.84 Mild neurocognitive disorder due to Parkinson's disease
331.83 G31.84 Mild neurocognitive disorder due to prion disease
331.83 G31.84 Mild neurocognitive disorder due to traumatic brain injury
331.83 G31.84 Mild neurocognitive disorder with Lewy bodies
331.83 G31.84 Mild vascular neurocognitive disorder
301.81 F60.81 Narcissistic personality disorder 
347.00 G47.419 Autosomal dominant cerebellar ataxia, deafness, and 
347.00 G47.419 Autosomal dominant narcolepsy, obesity, and type 2 diabetes
347.10 G47.429 Narcolepsy secondary to another medical condition
347.01 G47.411 Narcolepsy with cataplexy but without hypocretin deficiency
347.00 G47.419 Narcolepsy without cataplexy but with hypocretin deficiency
332.1 G21.il Neuroleptic-induced parkinsonism

ICD-9-CM ICD-10-CM\Disorder, condition, or problem
333.92 G21.0 Neuroleptic malignant syndrome
307.47 F51.5 Nightmare disorder
V15.81 Z91.19 Nonadherence to medical treatment 
Non-rapid eye movement sleep arousal disorders
307.46 F51.4 Sleep terror type
307.46 F51.3 Sleepwalking type
300.3 F42 Obsessive-compulsive disorder
301.4 F60.5 Obsessive-compulsive personality disorder
294.8 F06.8 Obsessive-compulsive and related disorder due to another 
medical condition
327.23 G47.33 Obstructive sleep apnea hypopnea
292.89 Opioid-induced anxiety disorder
F11.188 With mild use disorder
F11.288 With moderate or severe use disorder
F11.988 Without use disorder
F11.921 Opioid-induced delirium
292.84 Opioid-induced depressive disorder
F11.14 With mild use disorder
F11.24 With moderate or severe use disorder
FI 1.94 Without use disorder
292.89 Opioid-induced sexual dysfunction
F11.181 With mild use disorder
FI 1.281 With moderate or severe use disorder
F11.981 Without use disorder

292.85 Opioid-induced sleep disorder
F11.182 With mild use disorder
F11.282 With moderate or severe use disorder
FI 1.982 Without use disorder
292.89 Opioid intoxication
Opioid intoxication. With perceptual disturbances
F11.122 With mild use disorder
FI 1.222 With moderate or severe use disorder
F11.922 Without use disorder 
Opioid intoxication. Without perceptual disturbances
F11.129 With mild use disorder
FI 1.229 With moderate or severe use disorder
F11.929 Without use disorder
292.81 Opioid intoxication delirium
F11.121 With mild use disorder
FI 1.221 With moderate or severe use disorder
FI 1.921 Without use disorder 
Opioid use disorder
305.50 Fll.lO Mild
304.00 FI 1.20 Moderate
304.00 FI 1.20 Severe

292.0 FI 1.23 Opioid withdrawal
292.0 F11.23 Opioid withdrawal delirium
313.81 F91.3 Oppositional defiant disorder 
Other adverse effect of medication
995.20 T50.905A Initial encounter
995.20 T50.905S Sequelae
995.20 T50.905D Subsequent encounter 
Other circumstances related to adult abuse by nonspouse or nonpartner
V62.83 Z69.82 Encounter for mental health services for perpetrator of 
V65.49 Z69.81 Encounter for mental health services for victim of nonspousal 
adult abuse 
Other circumstances related to child neglect
V62.83 Z69.021 Encounter for mental health services for perpetrator of 
V61.22 Z69.011 Encounter for mental health services for peφetrator of parental 
V61.21 Z69.010 Encounter for mental health services for victim of child neglect by 
parent
V61.21 Z69.020 Encounter for mental health services for victim of nonparental 

parent
V15.42 Z62.812 Personal history (past history) of neglect in childhood 
Other circumstances related to child physical abuse
V61.22 Z69.011 Encounter for mental health services for perpetrator of parental 
V61.21 Z69.010 Encounter for mental health services for victim of child abuse by 
parent
V15.41 Z62.810 Personal history (past history) of physical abuse in childhood 
Other circumstances related to child psychological abuse

V61.21 Z69.010 Encounter for mental health services for victim of child 
psychological abuse by parent
V15.42 Z62.811 Personal history (past history) of psychological abuse in childhood 
Other circumstances related to child sexual abuse
V61.22 Z69.011 Encounter for mental health services for perpetrator of parental

V61.21 Z69.010 Encounter for mental health services for victim of child sexual 
V15.41 Z62.810 Personal history (past history) of sexual abuse in childhood 
Other circumstances related to spouse or partner abuse, Psychological
V61.12 Z69.12 Encounter for mental health services for perpetrator of spouse or 
V61.ll Z69.ll Encounter for mental health services for victim of spouse or 
V15.42 Z91.411 Personal history (past history) of spouse or partner 
psychological abuse 
Other circumstances related to spouse or partner neglect
V15.42 Z91.412 Personal history (past history) of spouse or partner neglect

V15.42 Z91.412 Personal history (past history) of spouse or partner neglect 
Other circumstances related to spouse or partner violence, Physical
partner violence. Physical
V15.41 Z91.410 Personal history (past history) of spouse or partner violence. 
Physical
Other circumstances related to spouse or partner violence, Sexual
V61.12 Z69.12 Encounter for mental health services for peφetrator of spouse or 
partner violence. Sexual
V61.ll Z69.81 Encounter for mental health services for victim of spouse or 
Sexual
V65.40 Z71.9 Other counseling or consultation

Sexual
292.89 Other hallucinogen-induced anxiety disorder
F16.180 With mild use disorder
F16.280 With moderate or severe use disorder
F16.980 Without use disorder
292.84 Other hallucinogen-induced bipolar and related disorder
F16.14 With mild use disorder
F16.24 With moderate or severe use disorder
F16.94 Without use disorder
292.84 Other hallucinogen-induced depressive disorder

292.9 Other hallucinogen-induced psychotic disorder
F16.159 With mild use disorder
F16.259 With moderate or severe use disorder
F16.959 Without use disorder
292.89 Other hallucinogen intoxication
F16.129 With mild use disorder
F16.229 With moderate or severe use disorder
F16.929 Without use disorder
292.81 Other hallucinogen intoxication delirium
F16.121 With mild use disorder
F16.221 With moderate or severe use disorder
F16.921 Without use disorder 
Other hallucinogen use disorder
305.30 F16.10 Mild
304.50 F16.20 Moderate
304.50 F16.20 Severe
333.99 G25.79 Other medication-induced movement disorder
332.1 G21.19 Other medication-induced parkinsonism
V15.49 Z91.49 Other personal history of psychological trauma
V15.89 Z91.89 Other personal risk factors
V62.29 Z56.9 Other problem related to employment
V62.89 Z65.8 Other problem related to psychosocial circumstances
300.09 F41.8 Other specified anxiety disorder

314.01 F90.8 Other specified attention-deficit/hyperactivity disorder
296.89 F31.89 Other specified bipolar and related disorder
780.09 R41.0 Other specified delirium
311 F32.8 Other specified depressive disorder
312.89 F91.8 Other specified disruptive, impulse-control, and conduct disorder
300.15 F44.89 Other specified dissociative disorder 
Other specified elimination disorder
787.60 R15.9 With fecal symptoms
788.39 N39.498 With urinary symptoms
307.59 F50.8 Other specified feeding or eating disorder
302.6 F64.8 Other specified gender dysphoria
780.54 G47.19 Other specified hypersomnolence disorder
780.52 G47.09 Other specified insomnia disorder
300.9 F99 Other specified mental disorder
294.8 F06.8 Other specified mental disorder due to another medical condition
315.8 F 8 8 Other specified neurodevelopmental disorder

300.3 F42 Other specified obsessive-compulsive and related disorder
302.89 F65.89 Other specified paraphilic disorder
301.89 F60.89 Other specified personality disorder
298.8 F28 Other specified schizophrenia spectrum and other psychotic disorder
302.79 F52.8 Other specified sexual dysfunction

780.59 G47.8 Other specified sleep-wake disorder
300.89 F45.8 Other specified somatic symptom and related disorder
307.20 F95.8 Other specified tic disorder
309.89 F43.8 Other specified trauma- and stressor-related disorder
292.89 Other (or unknown) substance-induced anxiety disorder
F19.180 With mild use disorder
F19.280 With moderate or severe use disorder
F19.980 Without use disorder
292.84 Other (or unknown) substance-induced bipolar and related disorder
F19.14 With mild use disorder
F19.24 With moderate or severe use disorder
F19.94 Without use disorder
F19.921 Other (or unknown) substance-induced delirium
292.84 Other (or unknown) substance-induced depressive disorder
292.82 Other (or unknown) substance-induced major neurocognitive 
disorder
F19.17 With mild use disorder
F19.27 With moderate or severe use disorder

disorder
F19.97 Without use disorder
292.89 Other (or unknown) substance-induced mild neurocognitive 
disorder
F19.188 With mild use disorder
F19.288 With moderate or severe use disorder
F19.988 Without use disorder
292.89 Other (or unknown) substance-induced obsessive-compulsive 
292.9 Other (or unknown) substance-induced psychotic disorder
F19.159 With mild use disorder
F19.259 With moderate or severe use disorder
F19.959 Without use disorder
292.89 Other (or unknown) substance-induced sexual dysfunction
F19.181 With mild use disorder
F19.281 With moderate or severe use disorder
F19.981 Without use disorder
292.85 Other (or unknown) substance-induced sleep disorder

F19.182 With mild use disorder
F19.282 With moderate or severe use disorder
F19.982 Without use disorder

292.89 Other (or unknown) substance intoxication
F19.129 With mild use disorder
F19.229 With moderate or severe use disorder
F19.929 Without use disorder
292.81 Other (or unknown) substance intoxication delirium
F19.121 With mild use disorder
F19.221 With moderate or severe use disorder
F19.921 Without use disorder 
Other (or unknown) substance use disorder
305.90 F19.10 Mild
304.90 F19.20 Moderate
304.90 F19.20 Severe
292.0 F19.239 Other (or unknown) substance withdrawal
292.0 F19.231 Other (or unknown) substance withdrawal delirium 
Other or unspecified stimulant use disorder
305.70 F15.10 Mild
278.00 E66.9 Overweight or obesity 
Panic attack specifier
300.01 F41.0 Panic disorder
301.0 F60.0 Paranoid personahty disorder
V61.20 Z62.820 Parent-child relational problem
302.2 F65.4 Pedophilic disorder
307.22 F95.1 Persistent (chronic) motor or vocal tic disorder

300.4 F34.1 Persistent depressive disorder (dysthymia)
V62.22 Z91.82 Personal history of military deployment
V15.59 Z91.5 Personal history of self-harm
310.1 F07.0 Personality change due to another medical condition
V62.89 Z60.0 Phase of life problem
292.89 Phencyclidine-induced anxiety disorder
292.84 Phencyclidine-induced bipolar and related disorder
292.84 Phencyclidine-induced depressive disorder

292.9 Phencyclidine-induced psychotic disorder
292.89 Phencyclidine intoxication
292.81 Phencyclidine intoxication delirium
Phencyclidine use disorder
305.90 F16.10 Mild
304.60 F16.20 Moderate
304.60 F16.20 Severe
307.52 Pica
F50.8 In adults
F98.3 In children
309.81 F43.10 Posttraumatic stress disorder
302.75 F52.4 Premature (early) ejaculation
625.4 N94.3 Premenstrual dysphoric disorder
V62.21 Z56.82 Problem related to current military deployment status
V69.9 Z72.9 Problem related to lifestyle
V60.3 Z60.2 Problem related to living alone
V60.6 Z59.3 Problem related to living in a residential institution

V61.5 Z64.1 Problems related to multiparity
V62.5 Z65.3 Problems related to other legal circumstances
V62.5 Z65.2 Problems related to release from prison
V61.7 Z64.0 Problems related to unwanted pregnancy
307.21 F95.0 Provisional tic disorder
316 F54 Psychological factors affecting other medical conditions 
Psychotic disorder due to another medical condition
293.81 F06.2 With delusions
293.82 F06.0 With hallucinations
312.33 F63.1 Pyromania
327.42 G47.52 Rapid eye movement sleep behavior disorder
313.89 F94.1 Reactive attachment disorder
V61.10 Z63.0 Relationship distress with spouse or intimate partner
V62.89 Z65.8 Religious or spiritual problem
333.94 G25.81 Restless legs syndrome
307.53 F98.21 Rumination disorder

Schizoaffective disorder
295.70 F25.0 Bipolar type
295.70 F25.1 Depressive type
301.20 F60.1 Schizoid personality disorder
295.90 F20.9 Schizophrenia
295.40 F20.81 Schizophreniform disorder
301.22 F21 Schizotypal personality disorder
292.89 Sedative-, hypnotic-, or anxiolytic-induced anxiety disorder 
F13.180 With mild use disorder
F13.280 With moderate or severe use disorder
F13.980 Without use disorder
292.84 Sedative-, hypnotic-, or anxiolytic-induced bipolar and related
disorder
F13.14 With mild use disorder
F13.24 With moderate or severe use disorder
F13.94 Without use disorder
F13.921 Sedative-, hypnotic-, or anxiolytic-induced delirium
292.84 Sedative-, hypnotic-, or anxiolytic-induced depressive disorder 
292.82 Sedative-, hypnotic-, or anxiolytic-induced major neurocognitive 
disorder
F13.27 With moderate or severe use disorder
F13.97 Without use disorder

disorder
292.89 Sedative-, hypnotic-, or anxiolytic-induced mild neurocognitive
disorder
F13.288 With moderate or severe use disorder
F13.988 Without use disorder
292.9 Sedative-, hypnotic-, or anxiolytic-induced psychotic disorder
F13.159 With mild use disorder
F13.259 With moderate or severe use disorder
F13.959 Without use disorder
292.89 Sedative-, hypnotic-, or anxiolytic-induced sexual dysfunction 
F13.181 With mild use disorder
F13.281 With moderate or severe use disorder
F13.981 Without use disorder
292.85 Sedative-, hypnotic-, or anxiolytic-induced sleep disorder 
F13.182 With mild use disorder
F13.282 With moderate or severe use disorder
F13.982 Without use disorder
292.89 Sedative, hypnotic, or anxiolytic intoxication 
F13.129 With mild use disorder
FI3.229 With moderate or severe use disorder

F13.929 Without use disorder

F13.121 With mild use disorder
F13.221 With moderate or severe use disorder
F13.921 Without use disorder 
Sedative, hypnotic, or anxiolyhc use disorder
305.40 F13.10 Mild
304.10 F13.20 Moderate
304.10 F13.20 Severe
292.0 Sedative, hypnotic, or anxiolytic withdrawal
F13.232 With perceptual disturbances
F13.239 Without perceptual disturbances
292.0 F13.231 Sedative, hypnotic, or anxiolytic withdrawal delirium
312.23 F94.0 Selective mutism
309.21 F93.0 Separation anxiety disorder
V65.49 Z70.9 Sex counseling
302.83 F65.51 Sexual masochism disorder
302.84 F65.52 Sexual sadism disorder
V61.8 Z62.891 Sibling relational problem 
Sleep-related hypoventilation
327.26 G47.36 Comorbid sleep-related hypoventilation
327.25 G47.35 Congenital central alveolar hypoventilation
327.24 G47.34 Idiopathic hypoventilation
300.23 F40.10 Social anxiety disorder (social phobia)
V62.4 Z60.4 Social exclusion or rejection
315.39 F80.89 Social (pragmatic) communication disorder

300.82 F45.1 Somatic symptom disorder 
Specific learning disorder
315.1 F81.2 With impairment in mathematics
315.00 F81.0 With impairment in reading
315.2 F81.81 With impairment in written expression 
Specific phobia
300.29 F40.218 Animal
300.29 Blood-injection-injury
F40.230 Fear of blood
F40.231 Fear of injections and transfusions
F40.233 Fear of injury
F40.232 Fear of other medical care
300.29 F40.228 Natural environment
300.29 F40.298 Other
300.29 F40.248 Situational
315.39 F80.0 Speech sound disorder
Spouse or partner abuse. Psychological, Confirmed
995.82 T74.31XD Subsequent encounter

995.82
995.82
995.85
995.85
995.85
995.85
995.81
995.81
995.81
995.81
995.83
995.83
995.83
995.83 
307.3T76.31XA
T76.31XD
T74.01XA
T74.01XD
T76.01XA
T76.01XD
T74.11XA
T74.11XD
T76.11XA
T76.11XD
T74.21XA
T74.21XD
T76.21XA
T76.21XD
F98.4Spouse or partner abuse. Psychological, Suspected 
Initial encounter 
Subsequent encounter 
Spouse or partner neglect. Confirmed 
Spouse or partner neglect. Suspected 
Spouse or partner violence. Physical, Confirmed 
Spouse or partner violence. Physical, Suspected 
Spouse or partner violence. Sexual, Confirmed 
Spouse or partner violence. Sexual, Suspected 
Stereotypic movement disorder
Stimulant intoxication (see amphetamine or cocaine intoxication for  
specific codes)

Stimulant use disorder (see amphetamine or cocaine use disorder for  
Stimulant withdrawal (see amphetamine or cocaine withdrawal for  
Substance withdrawal delirium (see specific substances for codes)  
Substance/medication-induced anxiety disorder (see specific  
substances for codes)
Substance/medication-induced bipolar and related disorder (see 
specific substances for codes)
Substance/medication-induced depressive disorder (see specific  
Substance/medication-induced major or mild neurocognitive 
disorder (see specific substances for codes)
Substance/medication-induced obsessive-compulsive and related 

Substance/medication-induced psychotic disorder (see specific  
Substance/medication-induced sexual dysfunction (see specific  
Substance/medication-induced sleep disorder (see specific  

333.99 G25.71 Tardive akathisia
333.85 G24.01 Tardive dyskinesia
333.72 G24.09 Tar dive dystonia
V62.4 Z60.5 Target of (perceived) adverse discrimination or persecution
292.85 Tobacco-induced sleep disorder
F17.208 With moderate or severe use disorder 
Tobacco use disorder
305.1 Z72.0 Mild
305.1 F17.200 Moderate
305.1 F17.200 Severe
292.0 F17.203 Tobacco withdrawal
307.23 F95.2 Tourette's disorder
302.3 F65.1 Transvestic disorder
312.39 F63.2 Trichotillomania (hair-pulling disorder)
V63.9 Z75.3 Unavailability or inaccessibility of health care facilities
V63.8 Z75.4 Unavailability or inaccessibility of other helping agencies
V62.82 Z63.4 Uncomplicated bereavement
291.9 F10.99 Unspecified alcohol-related disorder
300.00 F41.9 Unspecified anxiety disorder
314.01 F90.9 Unspecified attention-deficit/hyperactivity disorder
296.80 F31.9 Unspecified bipolar and related disorder
292.9 F15.99 Unspecified caffeine-related disorder

292.9 F12.99 Unspecified cannabis-related disorder
293.89 F06.1 Unspecified catatonia {code first  781.99 [R29.818] other symptoms 
involving nervous and musculoskeletal systems)
307.9 F80.9 Unspecified communication disorder
780.09 R41.0 Unspecified delirium
311 F32.9 Unspecified depressive disorder
312.9 F91.9 Unspecified disruptive, impulse-control, and conduct disorder
300.15 F44.9 Unspecified dissociative disorder 
Unspecified elimination disorder
788.30 R32 With urinary symptoms
307.50 F50.9 Unspecified feeding or eating disorder
302.6 F64.9 Unspecified gender dysphoria
292.9 F16.99 Unspecified hallucinogen-related disorder
V60.9 Z59.9 Unspecified housing or economic problem
780.54 G47.10 Unspecified hypersomnolence disorder
292.9 F18.99 Unspecified inhalant-related disorder

780.52 G47.00 Unspecified insomnia disorder
319 F79 Unspecified intellectual disability (intellectual developmental 
disorder)
300.9 F99 Unspecified mental disorder
294.9 F09 Unspecified mental disorder due to another medical condition
799.59 R41.9 Unspecified neurocognitive disorder

315.9 F89 Unspecified neurodevelopmental disorder
300.3 F42 Unspecified obsessive-compulsive and related disorder
292.9 FI 1.99 Unspecified opioid-related disorder
292.9 F19.99 Unspecified other (or unknown) substance-related disorder
302.9 F65.9 Unspecified paraphilic disorder
301.9 F60.9 Unspecified personality disorder
292.9 F16.99 Unspecified phencyclidine-related disorder
V62.9 Z60.9 Unspecified problem related to social environment
V62.9 Z65.9 Unspecified problem related to imspecified psychosocial 
circumstances
298.9 F29 Unspecified schizophrenia spectrum and other psychotic disorder
292.9 F13.99 Unspecified sedative-, hypnotic-, or anxiolytic-related disorder
302.70 F52.9 Unspecified sexual dysfunction
780.59 G47.9 Unspecified sleep-wake disorder
300.82 F45.9 Unspecified somatic symptom and related disorder
292.9 Unspecified stimulant-related disorder
F15.99 Unspecified amphetamine or other stimulant-related disorder

F14.99 Unspecified cocaine-related disorder
307.20 F95.9 Unspecified tic disorder
292.9 F17.209 Unspecified tobacco-related disorder
309.9 F43.9 Unspecified trauma- and stressor-related disorder
V61.8 Z62.29 Upbringing away from parents
V62.89 Z65.4 Victim of crime
V62.89 Z65.4 Victim of terrorism or torture
302.82 F65.3 Voyeuristic disorder
V40.31 Z91.83 Wandering associated with a mental disorder

Numerical Listing of 
DSIVi-5 Diagnoses and Codes 
(ICD-9-CM)
ICD-9-CM codes are to be used for coding purposes in the United States through
September 30,2014.
ICD-9-CM Disorder, condition, or problem
278.00 Overweight or obesity
290.40 Probable major vascular neurocognitive disorder. With behavioral disturbance
290.40 Probable major vascular neurocognitive disorder. Without behavioral
disturbance
291.0 Alcohol intoxication delirium
291.0 Alcohol withdrawal delirium
291.1 Alcohol-induced major neurocognitive disorder. Amnestic confabulatory type
291.2 Alcohol-induced major neurocognitive disorder, Nonamnestic confabulatory type
291.82 Alcohol-induced sleep disorder
291.89 Alcohol-induced anxiety disorder
291.89 Alcohol-induced bipolar and related disorder
291.89 Alcohol-induced depressive disorder
291.89 Alcohol-induced mild neurocognitive disorder
291.89 Alcohol-induced sexual dysfunction
291.9 Alcohol-induced psychotic disorder

291.9 Unspecified alcohol-related disorder
292.0 Amphetamine or other stimulant withdrawal
292.0 Caffeine withdrawal
292.0 Cannabis withdrawal
292.0 Cocaine withdrawal
292.0 Opioid withdrawal
292.0 Opioid withdrawal delirium
292.0 Other (or unknown) substance withdrawal
292.0 Other (or unknown) substance withdrawal delirium
292.0 Sedative, hypnotic, or anxiolytic withdrawal delirium
292.0 Tobacco withdrawal

292.81 Medication-induced delirium
292.81 Sedative, hypnotic, or anxiolytic intoxication delirium
292.82 Other (or unknown) substance-induced major neurocognitive disorder
292.82 Sedative-, hypnotic-, or anxiolytic-induced major neurocognitive disorder
292.84 Amphetamine (or other stimulant)-induced bipolar and related disorder
292.84 Amphetamine (or other stimulant)-induced depressive disorder

292.84 Sedative-, hypnotic-, or anxiolytic-induced bipolar and related disorder
292.84 Sedative-, hypnotic-, or anxiolytic-induced depressive disorder
292.85 Amphetamine (or other stimulant)-induced sleep disorder
292.85 Sedative-, hypnotic-, or anxiolytic-induced sleep disorder
292.89 Amphetamine (or other stimulant)-induced anxiety disorder

292.89 Amphetamine (or other stimulant)-induced obsessive-compulsive and related
disorder
292.89 Amphetamine (or other stimulant)-induced sexual dysfunction
292.89 Amphetamine or other stimulant intoxication
292.89 Cannabis intoxication
292.89 Hallucinogen persisting perception disorder

292.89 Other (or unknown) substance-induced mild neurocognitive disorder
292.89 Other (or unknown) substance-induced obsessive-compulsive and related disorder
292.89 Sedative-, hypnotic-, or anxiolytic-induced anxiety disorder
292.89 Sedative-, hypnotic-, or anxiolytic-induced mild neurocognitive disorder
292.89 Sedative-, hypnotic-, or anxiolytic-induced sexual dysfunction

292.89 Sedative, hypnotic, or anxiolytic intoxication
292.9 Other (or ui^cnown) substance-induced psychotic disorder
292.9 Unspecified caffeine-related disorder
292.9 Unspecified cannabis-related disorder
292.9 Unspecified hallucinogen-related disorder
292.9 Unspecified inhalant-related disorder
292.9 Unspecified opioid-related disorder
292.9 Unspecified other (or unknown) substance-related disorder
292.9 Unspecified phencyclidine-related disorder

292.9 Unspecified sedative-, hypnotic-, or anxiolytic-related disorder
292.9 Unspecified tobacco-related disorder
293.0 Delirium due to another medical condition
293.0 Delirium due to multiple etiologies
293.81 Psychotic disorder due to another medical condition. With delusions
293.82 Psychotic disorder due to another medical condition. With hallucinations
293.84 Anxiety disorder due to another medical condition
293.89 Catatonia associated with another mental disorder (catatonia specifier)

293.89 Catatonic disorder due to another medical condition
293.89 Unspecified catatonia (code first  781.99 other symptoms involving nervous and
musculoskeletal systems)
294.10 Major neurocognitive disorder due to another medical condition. Without
behavioral disturbance
294.10 Major neurocognitive disorder due to HIV infection. Without behavioral
disturbance (code first 042 HIV infection)
294.10 Major neurocognitive disorder due to Huntington's disease. Without
behavioral disturbance (code first 333.4 Huntington's disease)
294.10 Major neurocognitive disorder due to multiple etiologies. Without behavioral
294.10 Major neurocognitive disorder probably due to Parkinson's disease. Without
behavioral disturbance (code first 332.0 Parkinson's disease)
294.10 Major neurocognitive disorder due to prion disease. Without behavioral
disturbance (code first 046.79 prion disease)

294.10 Major neurocognitive disorder due to traumatic brain injury. Without
behavioral disturbance (code first 907.0 late effect of intracranial injury without 
skull fracture)
294.10 Probable major frontotemporal neurocognitive disorder. Without behavioral
disturbance (code first 331.19 frontotemporal disease)
294.10 Probable major neurocognitive disorder due to Alzheimer's disease. Without
behavioral disturbance (code first 331.0 Alzheimer's disease)
294.10 Probable major neurocognitive disorder with Lewy bodies. Without behavioral
disturbance (code first 331.82 Lewy body disease)
294.11 Major neurocognitive disorder due to another medical condition. With
294.11 Major neurocognitive disorder due to HIV infection. With behavioral

294.11 Major neurocognitive disorder due to Huntington's disease. With behavioral
disturbance (code first 333.4 Huntington's disease)
294.11 Major neurocognitive disorder due to multiple etiologies. With behavioral
294.11 Major neurocognitive disorder probably due to Parkinson's disease. With
294.11 Major neurocognitive disorder due to prion disease. With behavioral
294.11 Major neurocognitive disorder due to traumatic brain injury. With behavioral
disturbance (code first 907.0 late effect of intracranial injury without skull 
fracture)
294.11 Probable major frontotemporal neurocognitive disorder. With behavioral

fracture)
294.11 Probable major neurocognitive disorder due to Alzheimer's disease. With
294.11 Probable major neurocognitive disorder with Lewy bodies. With behavioral
294.8 Obsessive-compulsive and related disorder due to another medical condition
294.8 Other specified mental disorder due to another medical condition
294.9 Unspecified mental disorder due to another medical condition

295.40 Schizophreniform disorder
295.70 Schizoaffective disorder. Bipolar type
295.70 Schizoaffective disorder. Depressive type
295.90 Schizophrenia
296.20 Major depressive disorder. Single episode, Unspecifed
296.21 Major depressive disorder. Single episode. Mild
296.22 Major depressive disorder. Single episode. Moderate
296.23 Major depressive disorder. Single episode. Severe
296.24 Major depressive disorder. Single episode. With psychotic features
296.25 Major depressive disorder. Single episode. In partial remission
296.26 Major depressive disorder. Single episode. In full remission
296.30 Major depressive disorder. Recurrent episode. Unspecified
296.31 Major depressive disorder. Recurrent episode. Mild
296.32 Major depressive disorder. Recurrent episode. Moderate
296.33 Major depressive disorder. Recurrent episode. Severe
296.34 Major depressive disorder. Recurrent episode. With psychotic features
296.35 Major depressive disorder. Recurrent episode. In partial remission

296.36 Major depressive disorder. Recurrent episode. In full remission
296.40 Bipolar I disorder. Current or most recent episode hypomanie
296.40 Bipolar I disorder. Current or most recent episode hypomanie. Unspecified
296.40 Bipolar I disorder. Current or most recent episode manic. Unspecified
296.41 Bipolar I disorder. Current or most recent episode manic. Mild
296.42 Bipolar I disorder. Current or most recent episode manic. Moderate
296.43 Bipolar I disorder. Current or most recent episode manic. Severe
296.44 Bipolar I disorder. Current or most recent episode manic. With psychotic features
296.45 Bipolar I disorder. Current or most recent episode hypomanie. In partial remission
296.45 Bipolar I disorder. Current or most recent episode manic. In partial remission

296.46 Bipolar I disorder. Current or most recent episode hypomanie. In full remission
296.46 Bipolar I disorder. Current or most recent episode manic. In full remission
296.50 Bipolar I disorder. Current or most recent episode depressed. Unspecified
296.51 Bipolar I disorder. Current or most recent episode depressed. Mild
296.52 Bipolar I disorder. Current or most recent episode depressed. Moderate
296.53 Bipolar I disorder. Current or most recent episode depressed. Severe
296.54 Bipolar I disorder. Current or most recent episode depressed. With psychotic
features
296.55 Bipolar I disorder. Current or most recent episode depressed. In partial remission
296.56 Bipolar I disorder. Current or most recent episode depressed. In full remission
296.7 Bipolar I disorder. Current or most recent episode unspecified

296.80 Unspecified bipolar and related disorder
296.89 Bipolar II disorder
296.89 Other specified bipolar and related disorder
296.99 Disruptive mood dysregulation disorder
297.1 Delusional disorder
298.8 Brief psychotic disorder
298.8 Other specified schizophrenia spectrum and other psychotic disorder

298.9 Unspecified schizophrenia spectrum and other psychotic disorder
299.00 Autism spectrum disorder
300.00 Unspecified anxiety disorder
300.01 Panic disorder
300.02 Generalized anxiety disorder
300.09 Other specified anxiety disorder
300.12 Dissociative amnesia
300.13 Dissociative amnesia. With dissociative fugue
300.14 Dissociative identity disorder
300.15 Other specified dissociative disorder
300.15 Unspecified dissociative disorder
300.19 Factitious disorder
300.22 Agoraphobia
300.23 Social anxiety disorder (social phobia)
300.29 Specific phobia. Animal
300.29 Specific phobia, Blood-injection-injury
300.29 Specific phobia. Natural environment
300.29 Specific phobia. Other
300.29 Specific phobia. Situational
300.3 Hoarding disorder
300.3 Obsessive-compulsive disorder
300.3 Other specified obsessive-compulsive and related disorder
300.3 Unspecified obsessive-compulsive and related disorder

300.4 Persistent depressive disorder (dysthymia)
300.6 Depersonalization/derealization disorder
300.7 Body dysmorphic disorder
300.7 Illness anxiety disorder
300.82 Somatic symptom disorder
300.82 Unspecified somatic symptom and related disorder
300.89 Other specified somatic symptom and related disorder
300.9 Other specified mental disorder
300.9 Unspecified mental disorder
301.0 Paranoid personality disorder 
301.13 Cyclothymic disorder
301.20 Schizoid personality disorder
301.22 Schizotypal personality disorder
301.4 Obsessive-compulsive personality disorder
301.50 Histrionic personality disorder
301.6 Dependent personality disorder
301.7 Antisocial personality disorder
301.81 Narcissistic personality disorder
301.82 Avoidant personality disorder
301.83 Borderline personality disorder

301.89 Other specified personality disorder

301.9 Unspecified personality disorder
302.2 Pedophilic disorder
302.3 Transvestic disorder
302.4 Exhibitionistic disorder
302.6 Gender dysphoria in children
302.6 Other specified gender dysphoria
302.6 Unspecified gender dysphoria
302.70 Unspecified sexual dysfunction
302.71 Male hypoactive sexual desire disorder
302.72 Erectile disorder
302.72 Female sexual interest/arousal disorder
302.73 Female orgasmic disorder
302.74 Delayed ejaculation
302.75 Premature (early) ejaculation
302.76 Genito-pelvic pain/penetration disorder 
302.79 Other specified sexual dysfunction
302.81 Fetishistic disorder
302.82 Voyeuristic disorder
302.83 Sexual masochism disorder
302.84 Sexual sadism disorder
302.85 Gender dysphoria in adolescents and adults
302.89 Frotteuristic disorder
302.89 Other specified paraphilic disorder
302.9 Unspecified paraphilic disorder
303.00 Alcohol intoxication
303.90 Alcohol use disorder. Moderate
303.90 Alcohol use disorder. Severe
304.00 Opioid use disorder. Moderate

304.00 Opioid use disorder. Severe
304.10 Sedative, hypnotic, or anxiolytic use disorder. Moderate
304.10 Sedative, hypnotic, or anxiolytic use disorder. Severe
304.20 Cocaine use disorder. Moderate
304.20 Cocaine use disorder. Severe
304.30 Cannabis use disorder. Moderate
304.30 Cannabis use disorder. Severe
304.40 Amphetamine-type substance use disorder. Moderate
304.40 Amphetamine-type substance use disorder. Severe
304.40 Other or unspecified stimulant use disorder. Moderate
304.40 Other or unspecified stimulant use disorder. Severe
304.50 Other hallucinogen use disorder. Moderate
304.50 Other hallucinogen use disorder. Severe
304.60 Inhalant use disorder. Moderate
304.60 Inhalant use disorder. Severe
304.60 Phencyclidine use disorder. Moderate
304.60 Phencyclidine use disorder. Severe

304.90 Other (or unknown) substance use disorder. Moderate
304.90 Other (or unknown) substance use disorder. Severe
305.00 Alcohol use disorder. Mild
305.1 Tobacco use disorder. Mild
305.1 Tobacco use disorder. Moderate
305.1 Tobacco use disorder. Severe
305.20 Cannabis use disorder. Mild
305.30 Other hallucinogen use disorder. Mild
305.40 Sedative, hypnotic, or anxiolytic use disorder. Mild
305.50 Opioid use disorder. Mild
305.60 Cocaine use disorder. Mild
305.70 Amphetamine-type substance use disorder. Mild
305.70 Other or unspecified stimulant use disorder. Mild
305.90 Caffeine intoxication
305.90 Inhalant use disorder. Mild
305.90 Other (or unknown) substance use disorder. Mild
305.90 Phencyclidine use disorder. Mild
307.0 Adult-onset fluency disorder
307.20 Other specified tic disorder
307.20 Unspecified tic disorder
307.21 Provisional tic disorder
307.22 Persistent (chronic) motor or vocal tic disorder
307.23 Tourette's disorder

307.3 Stereotypic movement disorder
307.45 Circadian rhythm sleep-wake disorders. Advanced sleep phase type
307.45 Circadian rhythm sleep-wake disorders. Delayed sleep phase type
307.45 Circadian rhythm sleep-wake disorders. Irregular sleep-wake type
307.45 Circadian rhythm sleep-wake disorders, Non-24-hour sleep-wake type
307.45 Circadian rhythm sleep-wake disorders. Shift work type
307.45 Circadian rhythm sleep-wake disorders. Unspecified type
307.46 Non-rapid eye movement sleep arousal disorders. Sleep terror type
307.46 Non-rapid eye movement sleep arousal disorders. Sleepwalking type
307.47 Nightmare disorder
307.50 Unspecified feeding or eating disorder
307.51 Binge-eating disorder
307.51 Bulimia nervosa
307.53 Rumination disorder
307.59 Avoidant/restrictive food intake disorder

307.59 Other specified feeding or eating disorder
307.6 Enuresis
307.7 Encopresis
307.9 Unspecified communication disorder
308.3 Acute stress disorder

309.0 Adjustment disorders. With depressed mood
309.21 Separation anxiety disorder
309.24 Adjustment disorders. With anxiety
309.28 Adjustment disorders. With mixed anxiety and depressed mood
309.3 Adjustment disorders. With disturbance of conduct
309.4 Adjustment disorders. With mixed disturbance of emotions and conduct
309.81 Posttraumatic stress disorder
309.89 Other specified trauma- and stressor-related disorder
309.9 Adjustment disorders. Unspecified
309.9 Unspecified trauma- and stressor-related disorder
310.1 Personality change due to another medical condition 
311 Other specified depressive disorder
311 Unspecified depressive disorder
312.23 Selective mutism
312.31 Gambling disorder
312.32 Conduct disorder, Adolescent-onset type
312.32 Kleptomania
312.33 Pyromania
312.34 Intermittent explosive disorder
312.39 Trichotillomania (hair-pulling disorder)
312.81 Conduct disorder, Childhood-onset type
312.89 Conduct disorder. Unspecified onset

312.89 Other specified disruptive, impulse-control, and conduct disorder
312.9 Unspecified disruptive, impulse-control, and conduct disorder
313.81 Oppositional defiant disorder
313.89 Disinhibited social engagement disorder
313.89 Reactive attachment disorder
314.00 Attention-deficit/hyperactivity disorder. Predominantly inattentive presentation
314.01 Attention-deficit/hyperactivity disorder. Combined presentation
314.01 Attention-deficit/hyperactivity disorder. Predominantly hyperactive/
impulsive presentation
314.01 Other specified attention-deficit/hyperactivity disorder
314.01 Unspecified attention-deficit/hyperactivity disorder
315.00 Specific learning disorder. With impairment in reading
315.1 Specific learning disorder. With impairment in mathematics

315.2 Specific learning disorder. With impairment in written expression
315.35 Childhood-onset fluency disorder (stuttering)
315.39 Language disorder
315.39 Social (pragmatic) communication disorder
315.39 Speech sound disorder
315.4 Developmental coordination disorder
315.8 Global developmental delay
315.8 Other specified neurodevelopmental disorder
315.9 Unspecified neurodevelopmental disorder
316 Psychological factors affecting other medical conditions

319 Unspecified intellectual disability (intellectual developmental disorder)
327.21 Central sleep apnea. Idiopathic central sleep apnea
327.23 Obstructive sleep apnea hypopnea
327.24 Sleep-related hypoventilation. Idiopathic hypoventilation
327.25 Sleep-related hypoventilation. Congenital central alveolar hypoventilation
327.26 Sleep-related hypoventilation, Comorbid sleep-related hypoventilation
327.42 Rapid eye movement sleep behavior disorder
331.83 Mild frontotemporal neurocognitive disorder
331.83 Mild neurocognitive disorder due to Alzheimer's disease
331.83 Mild neurocognitive disorder due to another medical condition
331.83 Mild neurocognitive disorder due to HIV infection
331.83 Mild neurocognitive disorder due to Huntington's disease
331.83 Mild neurocognitive disorder with Lewy bodies
331.83 Mild neurocognitive disorder due to multiple etiologies
331.83 Mild neurocognitive disorder due to Parkinson's disease

331.83 Mild neurocognitive disorder due to prion disease
331.83 Mild neurocognitive disorder due to traumatic brain injury
331.83 Mild vascular neurocognitive disorder
331.9 Major neurocognitive disorder possibly due to Parkinson's disease
331.9 Possible major frontotemporal neurocognitive disorder
331.9 Possible major neurocognitive disorder due to Alzheimer's disease
331.9 Possible major neurocognihve disorder with Lewy bodies
331.9 Possible major vascular neurocognitive disorder
333.1 Medication-induced postural tremor
332.1 Neuroleptic-induced parkinsonism
332.1 Other medication-induced parkinsonism
333.72 Medication-induced acute dystonia
333.72 Tardive dystonia
333.85 Tardive dyskinesia
333.92 Neuroleptic malignant syndrome
333.94 Restless legs syndrome
333.99 Medication-induced acute akathisia

333.99 Other medication-induced movement disorder
333.99 Tardive akathisia
347.00 Autosomal dominant cerebellar ataxia, deafness, and narcolepsy
347.00 Autosomal dominant narcolepsy, obesity, and type 2 diabetes
347.00 Narcolepsy without cataplexy but with hypocretin deficiency
347.01 Narcolepsy with cataplexy but without hypocretin deficiency
347.10 Narcolepsy secondary to another medical condition
625.4 Premenstrual dysphoric disorder
698.4 Excoriation (skin-picking) disorder
780.09 Other specified delirium
780.09 Unspecified delirium
780.52 Insomnia disorder

780.52 Other specified insomnia disorder
780.52 Unspecified insomnia disorder
780.54 Hypersomnolence disorder
780.54 Other specified hypersomnolence disorder
780.54 Unspecified hypersomnolence disorder
780.57 Central sleep apnea. Central sleep apnea comorbid with opioid use
780.59 Other specified sleep-wake disorder
780.59 Unspecified sleep-wake disorder
786.04 Central sleep apnea, Cheyne-Stokes breathing
787.60 Other specified elimination disorder. With fecal symptoms
787.60 Unspecified elimination disorder. With fecal symptoms
788.30 Unspecified elimination disorder. With urinary symptoms
788.39 Other specified elimination disorder. With urinary symptoms
799.59 Unspecified neurocognitive disorder
995.20 Other adverse effect of medication. Initial encounter
995.20 Other adverse effect of medication. Sequelae
995.20 Other adverse effect of medication. Subsequent encounter
995.29 Antidepressant discontinuation syndrome. Initial encounter

995.29 Antidepressant discontinuation syndrome. Sequelae
995.29 Antidepressant discontinuation syndrome. Subsequent encounter
995.51 Child psychological abuse. Confirmed, Initial encounter
995.51 Child psychological abuse. Confirmed, Subsequent encounter
995.51 Child psychological abuse. Suspected, Initial encounter
995.51 Child psychological abuse. Suspected, Subsequent encounter
995.52 Child neglect. Confirmed, Initial encounter
995.52 Child neglect. Confirmed, Subsequent encounter
995.52 Child neglect. Suspected, Initial encounter
995.52 Child neglect. Suspected, Subsequent encounter
995.53 Child sexual abuse. Confirmed, Initial encounter
995.53 Child sexual abuse. Confirmed, Subsequent encounter
995.53 Child sexual abuse. Suspected, Initial encounter

995.53 Child sexual abuse. Suspected, Subsequent encounter
995.54 Child physical abuse. Confirmed, Initial encounter
995.54 Child physical abuse. Confirmed, Subsequent encounter
995.54 Child physical abuse. Suspected, Initial encounter
995.54 Child physical abuse. Suspected, Subsequent encounter
995.81 Adult physical abuse by nonspouse or nonpartner. Confirmed, Initial encounter
995.81 Adult physical abuse by nonspouse or nonpartner. Confirmed, Subsequent
encounter
995.81 Adult physical abuse by nonspouse or nonpartner. Suspected, Initial encounter
995.81 Adult physical abuse by nonspouse or nonpartner. Suspected, Subsequent
encounter
995.81 Spouse or partner violence. Physical, Confirmed, Initial encounter
995.81 Spouse or partner violence. Physical, Confirmed, Subsequent encounter

encounter
995.81 Spouse or partner violence. Physical, Suspected, Initial encounter

995.81 Spouse or partner violence. Physical, Suspected, Subsequent encounter
995.82 Adult psychological abuse by nonspouse or nonpartner. Confirmed, Initial
encounter
995.82 Adult psychological abuse by nonspouse or nonpartner. Confirmed,
Subsequent encounter
995.82 Adult psychological abuse by nonspouse or nonpartner, Suspected, Initial
encounter
995.82 Adult psychological abuse by nonspouse or nonpartner. Suspected,
995.82 Spouse or partner abuse. Psychological, Confirmed, Initial encounter
995.82 Spouse or partner abuse. Psychological, Confirmed, Subsequent encounter
995.82 Spouse or partner abuse. Psychological, Suspected, Initial encounter
995.82 Spouse or partner abuse. Psychological, Suspected, Subsequent encounter
995.83 Adult sexual abuse by nonspouse or nonpartner. Confirmed, Initial encounter
995.83 Adult sexual abuse by nonspouse or nonpartner. Confirmed, Subsequent
encounter

encounter
995.83 Adult sexual abuse by nonspouse or nonpartner. Suspected, Initial encounter
995.83 Adult sexual abuse by nonspouse or nonpartner. Suspected, Subsequent
encounter
995.83 Spouse or partner violence. Sexual, Confirmed, Initial encounter
995.83 Spouse or partner violence. Sexual, Confirmed, Subsequent encounter
995.83 Spouse or partner violence. Sexual, Suspected, Initial encounter
995.83 Spouse or partner violence. Sexual, Suspected, Subsequent encounter
995.85 Spouse or partner neglect. Confirmed, Initial encounter
995.85 Spouse or partner neglect. Confirmed, Subsequent encounter
995.85 Spouse or partner neglect. Suspected, Initial encounter
995.85 Spouse or partner neglect. Suspected, Subsequent encounter 
V15.41 Personal history (past history) of physical abuse in childhood

V15.41 Personal history (past history) of physical abuse in childhood 
V15.41 Personal history (past history) of sexual abuse in childhood
VI5.41 Personal history (past history) of spouse or partner violence. Physical
V15.41 Personal history (past history) of spouse or partner violence. Sexual
V15.42 Personal history (past history) of neglect in childhood
V15.42 Personal history (past history) of psychological abuse in childhood
V15.42 Personal history (past history) of spouse or partner neglect
V15.42 Personal history (past history) of spouse or partner psychological abuse
VI5.49 Other personal history of psychological trauma
V15.59 Personal history of self-harm
V15.81 Nonadherence to medical treatment
VI5.89 Other personal risk factors
V40.31 Wandering associated with a mental disorder
V60.0 Homelessness
V60.1 Inadequate housing
V60.2 Extreme poverty
V60.2 Insufficient social insurance or welfare support

V60.2 Lack of adequate food or safe drinking water
V60.2 Low income

V60.3 Problem related to living alone 
V60.6 Problem related to living in a residential institution
V60.89 Discord with neighbor, lodger, or landlord 
V60.9 Unspecified housing or economic problem 
V61.03 Disruption of family by separation or divorce 
V61.10 Relationship distress with spouse or intimate partner 
V61.ll Encounter for mental health services for victim of spouse or partner neglect 
V61.ll Encounter for mental health services for victim of spouse or partner 
V61.ll Encounter for mental health services for victim of spouse or partner violence. 
Physical
Sexual
V61.12 Encounter for mental health services for perpetrator of spouse or partner 
neglect
violence, Physical

violence. Sexual 
V61.20 Parent-child relational problem
V61.21 Encounter for mental health services for victim of child abuse by parent 
V61.21 Encounter for mental health services for victim of child neglect by parent 
V61.21 Encounter for mental health services for victim of child psychological abuse by 
parent
V61.21 Encounter for mental health services for victim of child sexual abuse by parent 
V61.21 Encounter for mental health services for victim of nonparental child abuse 
V61.21 Encounter for mental health services for victim of nonparental child neglect 
V61.21 Encounter for mental health services for victim of nonparental child 
V61.21 Encounter for mental health services for victim of nonparental child sexual 
abuse

abuse
V61.22 Encounter for mental health services for perpetrator of parental child abuse 
V61.22 Encounter for mental health services for perpetrator of parental child neglect 
V61.22 Encounter for mental health services for perpetrator of parental child 
V61.22 Encounter for mental health services for perpetrator of parental child sexual 
abuse
V61.29 Child affected by parental relationship distress
V61.5 Problems related to multiparity
V61.7 Problems related to unwanted pregnancy
V61.8 High expressed emotion level within family
V61.8 Sibling relational problem
V61.8 Upbringing away from parents
V62.21 Problem related to current military deployment status
V62.22 Exposure to disaster, war, or other hostilities

V62.22 Personal history of military deployment
V62.29 Other problem related to employment
V62.3 Academic or educational problem
V62.4 Acculturation difficulty
V62.4 Social exclusion or rejection
V62.4 Target of (perceived) adverse discrimination or persecution
V62.5 Conviction in civil or criminal proceedings without imprisonment
V62.5 Imprisonment or other incarceration
V62.5 Problems related to other legal circumstances
V62.5 Problems related to release from prison
V62.82 Uncomplicated bereavement
V62.83 Encounter for mental health services for perpetrator of nonparental child abuse
V62.83 Encounter for mental health services for perpetrator of nonparental child 
neglect
V62.83 Encounter for mental health services for perpetrator of nonspousal adult abuse

V62.89 Borderline intellectual functioning
V62.89 Discord with social service provider, including probation officer, case manager, 
or social services worker
V62.89 Other problem related to psychosocial circumstances
V62.89 Phase of life problem
V62.89 Religious or spiritual problem
V62.89 Victim of crime
V62.89 Victim of terrorism or torture
V62.9 Unspecified problem related to social environment
V62.9 Unspecified problem related to unspecified psychosocial circumstances
V63.8 Unavailability or inaccessibility of other helping agencies
V63.9 Unavailability or inaccessibility of health care facilities
V65.2 Malingering
V65.40 Other counseling or consultation
V65.49 Encounter for mental health services for victim of nonspousal adult abuse
V65.49 Sex counseling
V69.9 Problem related to lifestyle

V71.01 Adult antisocial behavior
V71.02 Child or adolescent antisocial behavior

(iCD-10-CIM)
ICD-IO-CM codes are to be used for coding purposes in the United States starting
October 1, 2014.
ICD-10-CM Disorder, condition, or problem
E66.9 Overweight or obesity
FOl .50 Probable major vascular neurocognitive disorder. Without behavioral disturbance
F01.51 Probable major vascular neurocognitive disorder. With behavioral disturbance
F02.80 Major neurocognitive disorder due to another medical condition. Without
behavioral disturbance 
F02.80 Major neurocognitive disorder due to HIV infection. Without behavioral
disturbance (code first  B20 HIV infection)
F02.80 Major neurocognitive disorder due to Huntington's disease. Without
behavioral disturbance (code first  GIO Huntington's disease)
F02.80 Major neurocognitive disorder due to multiple etiologies. Without behavioral
F02.80 Major neurocognitive disorder probably due to Parkinson's disease. Without

behavioral disturbance (code first  G20 Parkinson's disease)
F02.80 Major neurocognitive disorder due to prion disease. Without behavioral
disturbance (code first  A81.9 prion disease)
F02.80 Major neurocognitive disorder due to traumatic brain injury. Without
behavioral disturbance (code first  S06.2X9S diffuse traumatic brain injury 
with loss of consciousness of unspecified duration, sequela)
F02.80 Probable major frontotemporal neurocognitive disorder. Without behavioral
disturbance (code first  G31.09 frontotemporal disease)
F02.80 Probable major neurocognitive disorder due to Alzheimer's disease. Without
behavioral disturbance (code first  G30.9 Alzheimer's disease)
F02.80 Probable major neurocognitive disorder with Lewy bodies. Without
behavioral disturbance (code first  G31.83 Lewy body disease)

F02.81 Major neurocognitive disorder due to another medical condition. With
F02.81 Major neurocognitive disorder due to HIV infection. With behavioral
F02.81 Major neurocognitive disorder due to Huntington's disease. With behavioral
disturbance (code first  GIO Huntington's disease)
F02.81 Major neurocognitive disorder due to multiple etiologies. With behavioral

F02.81 Major neurocognitive disorder probably due to Parkinson's disease. With
F02.81 Major neurocognitive disorder due to prion disease. With behavioral
disturbance {code first  A81.9 prion disease)
F02.81 Major neurocognitive disorder due to traumatic brain injury. With behavioral
disturbance {code first  S06.2X9S diffuse traumatic brain injury with loss of 
consciousness of unspecified duration, sequela)
F02.81 Probable major frontotemporal neurocognitive disorder. With behavioral
disturbance {code first  G31.09 frontotemporal disease)
F02.81 Probable major neurocognitive disorder due to Alzheimer's disease. With
behavioral disturbance {code first  G30.9 Alzheimer's disease)
F02.81 Probable major neurocognitive disorder with Lewy bodies. With behavioral
disturbance {code first  G31.83 Lewy body disease)
F05 Delirium due to another medical condition
F05 Delirium due to multiple etiologies

F06.0 Psychotic disorder due to another medical condition. With hallucinations
F06.1 Catatonia associated with another mental disorder (catatonia specifier)
F06.1 Catatonic disorder due to another medical condition
F06.1 Unspecified catatonia {code first  R29.818 other symptoms involving nervous
and musculoskeletal systems)
F06.2 Psychotic disorder due to another medical condition. With delusions
F06.31 Depressive disorder due to another medical condition. With depressive features
F06.32 Depressive disorder due to another medical condition. With major
depressive-like episode 
F06.33 Bipolar and related disorder due to another medical condition. With manic features
F06.33 Bipolar and related disorder due to another medical condition. With manic- or
hypomanic-like episodes

hypomanic-like episodes 
F06.34 Bipolar and related disorder due to another medical condition. With mixed
features
F06.34 Depressive disorder due to another medical condition. With mixed features
F06.4 Anxiety disorder due to another medical condition
F06.8 Obsessive-compulsive and related disorder due to another medical condition
F06.8 Other specified mental disorder due to another medical condition
F07.0 Personality change due to another medical condition
F09 Unspecified mental disorder due to another medical condition
FIO.IO Alcohol use disorder. Mild
F10.121 Alcohol intoxication delirium. With mild use disorder 
F10.129 Alcohol intoxication. With mild use disorder
F10.14 Alcohol-induced bipolar and related disorder. With mild use disorder
F10.14 Alcohol-induced depressive disorder. With mild use disorder

FI0.159 Alcohol-induced psychotic disorder. With mild use disorder 
F10.180 Alcohol-induced anxiety disorder. With mild use disorder 
F10.181 Alcohol-induced sexual dysfunction. With mild use disorder 
F10.182 Alcohol-induced sleep disorder. With mild use disorder 
FI 0.20 Alcohol use disorder. Moderate
FI0.20 Alcohol use disorder. Severe
F10.221 Alcohol intoxication delirium. With moderate or severe use disorder

F10.229 Alcohol intoxication. With moderate or severe use disorder 
F10.231 Alcohol withdrawal delirium 
F10.232 Alcohol withdrawal. With perceptual disturbances 
FI0.239 Alcohol withdrawal. Without perceptual disturbances 
F10.24 Alcohol-induced bipolar and related disorder. With moderate or severe use
disorder
FI0.24 Alcohol-induced depressive disorder. With moderate or severe use disorder
F10.259 Alcohol-induced psychotic disorder. With moderate or severe use disorder 
F10.26 Alcohol-induced major neurocognitive disorder. Amnestic confabulatory
type. With moderate or severe use disorder 
F10.27 Alcohol-induced major neurocognitive disorder, Nonamnestic confabulatory
F10.280 Alcohol-induced anxiety disorder. With moderate or severe use disorder 
F10.281 Alcohol-induced sexual dysfunction. With moderate or severe use disorder 
FI0.282 Alcohol-induced sleep disorder. With moderate or severe use disorder

FI0.282 Alcohol-induced sleep disorder. With moderate or severe use disorder 
F10.288 Alcohol-induced mild neurocognitive disorder. With moderate or severe use 
disorder
F10.921 Alcohol intoxication delirium. Without use disorder 
F10.929 Alcohol intoxication. Without use disorder
F10.94 Alcohol-induced bipolar and related disorder. Without use disorder
FI0.94 Alcohol-induced depressive disorder. Without use disorder
F10.959 Alcohol-induced psychotic disorder. Without use disorder 
F10.96 Alcohol-induced major neurocognitive disorder. Amnestic confabulatory
type. Without use disorder 
F10.97 Alcohol-induced major neurocognitive disorder, Nonanmestic confabulatory
F10.980 Alcohol-induced anxiety disorder. Without use disorder 
F10.981 Alcohol-induced sexual dysfunction. Without use disorder 
FI0.982 Alcohol-induced sleep disorder. Without use disorder

FI0.982 Alcohol-induced sleep disorder. Without use disorder 
FI0.988 Alcohol-induced mild neurocognitive disorder. Without use disorder 
F10.99 Unspecified alcohol-related disorder
FI 1.10 Opioid use disorder. Mild
FI 1.121 Opioid intoxication delirium. With mild use disorder
FI 1.122 Opioid intoxication. With perceptual disturbances. With mild use disorder
FI 1.129 Opioid intoxication. Without perceptual disturbances. With mild use disorder
FI 1.14 Opioid-induced depressive disorder. With mild use disorder
F11.181 Opioid-induced sexual dysfunction. With mild use disorder
F11.182 Opioid-induced sleep disorder. With mild use disorder
FI 1.188 Opioid-induced anxiety disorder. With mild use disorder
FI 1.20 Opioid use disorder. Moderate
FI 1.20 Opioid use disorder. Severe
FI 1.221 Opioid intoxication delirium. With moderate or severe use disorder

FI 1.221 Opioid intoxication delirium. With moderate or severe use disorder 
FI 1.222 Opioid intoxication. With perceptual disturbances. With moderate or severe 
use disorder
FI 1.229 Opioid intoxication. Without perceptual disturbances. With moderate or 
severe use disorder 
FI 1.23 Opioid withdrawal

FI 1.23 Opioid withdrawal delirium
FI 1.24 Opioid-induced depressive disorder. With moderate or severe use disorder
FI 1.281 Opioid-induced sexual dysfunction. With moderate or severe use disorder
FI 1.282 Opioid-induced sleep disorder. With moderate or severe use disorder
FI 1.288 Opioid-induced anxiety disorder. With moderate or severe use disorder
FI 1.921 Opioid-induced delirium
FI 1.921 Opioid intoxication delirium. Without use disorder
FI 1.922 Opioid intoxication. With perceptual disturbances. Without use disorder
FI 1.929 Opioid intoxication. Without perceptual disturbances. Without use disorder
FI 1.94 Opioid-induced depressive disorder. Without use disorder
FI 1.981 Opioid-induced sexual dysfunction. Without use disorder
FI 1.982 Opioid-induced sleep disorder. Without use disorder
FI 1.988 Opioid-induced anxiety disorder. Without use disorder
FI 1.99 Unspecified opioid-related disorder
F12.10 Cannabis use disorder. Mild

F12.121 Cannabis intoxication delirium. With mild use disorder
F12.122 Cannabis intoxication. With perceptual disturbances. With mild use disorder
F12.129 Cannabis intoxication. Without perceptual disturbances. With mild use disorder
F12.159 Cannabis-induced psychotic disorder. With mild use disorder
F12.180 Cannabis-induced anxiety disorder. With mild use disorder
F12.188 Cannabis-induced sleep disorder. With mild use disorder
F12.20 Cannabis use disorder. Moderate
FI 2.20 Cannabis use disorder. Severe
F12.221 Cannabis intoxication delirium. With moderate or severe use disorder
F12.222 Cannabis intoxication. With perceptual disturbances. With moderate or severe 
F12.229 Cannabis intoxication. Without perceptual disturbances. With moderate or 
severe use disorder

F12.259 Cannabis-induced psychotic disorder. With moderate or severe use disorder
F12.280 Cannabis-induced anxiety disorder. With moderate or severe use disorder
F12.288 Cannabis-induced sleep disorder. With moderate or severe use disorder
F12.288 Cannabis withdrawal
FI2.921 Cannabis intoxication delirium. Without use disorder
F12.922 Cannabis intoxication. With perceptual disturbances. Without use disorder
F12.929 Cannabis intoxication. Without perceptual disturbances. Without use disorder
F12.959 Cannabis-induced psychotic disorder. Without use disorder
F12.980 Cannabis-induced anxiety disorder. Without use disorder
F12.988 Cannabis-induced sleep disorder. Without use disorder
F12.99 Unspecified cannabis-related disorder
FI3.10 Sedative, hypnotic, or anxiolytic use disorder. Mild
F13.121 Sedative, hypnotic, or anxiolytic intoxication delirium. With mild use disorder

F13.129 Sedative, hypnotic, or anxiolytic intoxication. With mild use disorder
F13.14 Sedative-, hypnotic-, or anxiolytic-induced bipolar and related disorder. With 
mild use disorder
F13.14 Sedative-, hypnotic-, or anxiolytic-induced depressive disorder. With mild use 
disorder

F13.159 Sedative-, hypnotic-, or anxiolytic-induced psychotic disorder. With mild use 
disorder
F13.180 Sedative-, hypnotic-, or anxiolytic-induced anxiety disorder. With mild use 
disorder
F13.181 Sedative-, hypnotic-, or anxiolytic-induced sexual dysfunction. With mild use 
disorder
F13.182 Sedative-, hypnotic-, or anxiolytic-induced sleep disorder. With mild use disorder 
FI3.20 Sedative, hypnotic, or anxiolytic use disorder. Moderate
F13.20 Sedative, hypnotic, or anxiolytic use disorder. Severe
F13.221 Sedative, hypnotic, or anxiolytic intoxication delirium. With moderate or 
FI3.229 Sedative, hypnotic, or aiOdolytic intoxication. With moderate or severe use disorder 
FI3.231 Sedative, hypnotic, or anxiolytic withdrawal delirium 
F13.232 Sedative, hypnotic, or anxiolytic withdrawal. With perceptual disturbances 
F13.239 Sedative, hypnotic, or anxiolytic withdrawal. Without perceptual disturbances

F13.239 Sedative, hypnotic, or anxiolytic withdrawal. Without perceptual disturbances 
F13.24 Sedative-, hypnotic-, or anxiolytic-induced bipolar and related disorder. With
moderate or severe use disorder 
F13.24 Sedative-, hypnotic-, or anxiolytic-induced depressive disorder. With
F13.259 Sedative-, hypnotic-, or anxiolytic-induced psychotic disorder. With moderate 
or severe use disorder
F13.27 Sedative-, hypnotic-, or anxiolytic-induced major neurocognitive disorder.
F13.280 Sedative-, hypnotic-, or anxiolytic-induced anxiety disorder. With moderate or 
F13.281 Sedative-, hypnotic-, or anxiolytic-induced sexual dysfunction. With moderate 
F13.282 Sedative-, hypnotic-, or anxiolytic-induced sleep disorder. With moderate or 

F13.288 Sedative-, hypnotic-, or anxiolytic-induced mild neurocognitive disorder.
F13.921 Sedative, hypnotic, or anxiolytic intoxication delirium. Without use disorder 
FI3.929 Sedative, hypnotic, or anxiolytic intoxication. Without use disorder 
F13.94 Sedative-, hypnotic-, or anxiolytic-induced bipolar and related disorder.
F13.94 Sedative-, hypnotic-, or anxiolytic-induced depressive disorder. Without use
disorder
F13.959 Sedative-, hypnotic-, or anxiolytic-induced psychotic disorder. Without use 
disorder
F13.97 Sedative-, hypnotic-, or anxiolytic-induced major neurocognitive disorder.
FI3.980 Sedative-, hypnotic-, or anxiolytic-induced anxiety disorder. Without use disorder

FI3.980 Sedative-, hypnotic-, or anxiolytic-induced anxiety disorder. Without use disorder 
F13.981 Sedative-, hypnotic-, or anxiolytic-induced sexual dysfunction. Without use 
disorder
F13.982 Sedative-, hypnotic-, or anxiolytic-induced sleep disorder. Without use disorder 
F13.988 Sedative-, hypnotic-, or anxiolytic-induced mild neurocognitive disorder. 

F13.99 Unspecified sedative-, hypnotic-, or anxiolytic-related disorder
F14.10 Cocaine use disorder. Mild
F14.121 Cocaine intoxication delirium. With mild use disorder
F14.122 Cocaine intoxication. With perceptual disturbances. With mild use disorder
F14.129 Cocaine intoxication. Without perceptual disturbances. With mild use disorder
F14.14 Cocaine-induced bipolar and related disorder. With mild use disorder
F14.14 Cocaine-induced depressive disorder. With mild use disorder
F14.159 Cocaine-induced psychotic disorder. With mild use disorder
F14.180 Cocaine-induced anxiety disorder. With mild use disorder
F14.181 Cocaine-induced sexual dysfunction. With mild use disorder
F14.182 Cocaine-induced sleep disorder. With mild use disorder
F14.188 Cocaine-induced obsessive-compulsive and related disorder. With mild use 
disorder
F14.20 Cocaine use disorder. Moderate
F14.20 Cocaine use disorder. Severe
FI4.221 Cocaine intoxication delirium. With moderate or severe use disorder

disorder
F14.222 Cocaine intoxication. With perceptual disturbances. With moderate or severe 
F14.229 Cocaine intoxication. Without perceptual disturbances. With moderate or 
F14.23 Cocaine withdrawal
F14.24 Cocaine-induced bipolar and related disorder. With moderate or severe use 
disorder
F14.24 Cocaine-induced depressive disorder. With moderate or severe use disorder
F14.259 Cocaine-induced psychotic disorder. With moderate or severe use disorder
F14.280 Cocaine-induced anxiety disorder. With moderate or severe use disorder
F14.281 Cocaine-induced sexual dysfunction. With moderate or severe use disorder
F14.282 Cocaine-induced sleep disorder. With moderate or severe use disorder
F14.288 Cocaine-induced obsessive-compulsive and related disorder. With moderate 

F14.921 Cocaine intoxication delirium. Without use disorder
F14.922 Cocaine intoxication. With perceptual disturbances. Without use disorder
F14.929 Cocaine intoxication. Without perceptual disturbances. Without use disorder
F14.94 Cocaine-induced bipolar and related disorder. Without use disorder
F14.94 Cocaine-induced depressive disorder. Without use disorder
F14.959 Cocaine-induced psychotic disorder. Without use disorder
F14.980 Cocaine-induced anxiety disorder. Without use disorder
F14.981 Cocaine-induced sexual dysfunction. Without use disorder
F14.982 Cocaine-induced sleep disorder. Without use disorder
F14.988 Cocaine-induced obsessive-compulsive and related disorder. Without use disorder
F14.99 Unspecified stimulant-related disorder. Unspecified Cocaine-related disorder

F15.10 Amphetamine-type substance use disorder. Mild
F15.10 Other or unspecified stimulant use disorder. Mild
F15.121 Amphetamine (or other stimulant) intoxication delirium. With mild use disorder
F15.122 Amphetamine or other stimulant intoxication. With perceptual disturbances. 

F15.129 Amphetamine or other stimulant intoxication. Without perceptual 
disturbances. With mild use disorder 
F15.14 Amphetamine (or other stimulant)-induced bipolar and related disorder.
F15.14 Amphetamine (or other stimulant)-induced depressive disorder. With mild
F15.159 Amphetamine (or other stimulant)-induced psychotic disorder. With mild use 
disorder
F15.180 Amphetamine (or other stimulant)-induced anxiety disorder. With mild use 
disorder
F15.180 Caffeine-induced anxiety disorder. With mild use disorder 
F15.181 Amphetamine (or other stimulant)-induced sexual dysfunction. With mild 
F15.182 Amphetamine (or other stimulant)-induced sleep disorder. With mild use disorder 
F15.182 Caffeine-induced sleep disorder. With mild use disorder 
F15.188 Amphetamine (or other stimulant)-induced obsessive-compulsive and related 
disorder. With mild use disorder 
F15.20 Amphetamine-type substance use disorder. Moderate

FI5.20 Amphetamine-type substance use disorder. Severe
F15.20 Other or unspecified stimulant use disorder. Moderate
F15.20 Other or unspecified stimulant use disorder. Severe
F15.221 Amphetamine (or other stimulant) intoxication delirium. With moderate or 
F15.222 Amphetamine or other stimulant intoxication. With perceptual disturbances. 
F15.229 Amphetamine or other stimulant intoxication. Without perceptual 
disturbances. With moderate or severe use disorder 
FI5.23 Amphetamine or other stimulant withdrawal
F15.24 Amphetamine (or other stimulant)-induced bipolar and related disorder.
F15.24 Amphetamine (or other stimulant)-induced depressive disorder. With
moderate or severe use disorder

F15.259 Amphetamine (or other stimulant)-induced psychotic disorder. With 
F15.280 Amphetamine (or other stimulant)-induced anxiety disorder. With moderate 
or severe use disorder 
F15.280 Caffeine-induced anxiety disorder. With moderate or severe use disorder 
F15.281 Amphetamine (or other stimulant)-induced sexual dysfunction. With 
F15.282 Amphetamine (or other stimulant)-induced sleep disorder. With moderate or 
F15.282 Caffeine-induced sleep disorder. With moderate or severe use disorder 
F15.288 Amphetamine (or other stimulant)-induced obsessive-compulsive and related 
disorder. With moderate or severe use disorder 

F15.921 Amphetamine (or other stimulant) intoxication delirium. Without use disorder 
F15.922 Amphetamine or other stimulant intoxication. With perceptual disturbances. 

FI5.929 Amphetamine or other stimulant intoxication. Without perceptual 
disturbances. Without use disorder 
F15.929 Caffeine intoxication 
FI5.93 Caffeine withdrawal
F15.94 Amphetamine (or other stimulant)-induced bipolar and related disorder.
FI5.94 Amphetamine (or other stimulant)-induced depressive disorder. Without use
disorder
FI5.959 Amphetamine (or other stimulant)-induced psychotic disorder. Without use 
disorder
F15.980 Amphetamine (or other stimulant)-induced anxiety disorder. Without use 
disorder
FI5.980 Caffeine-induced anxiety disorder. Without use disorder 
F15.981 Amphetamine (or other stimulant)-induced sexual dysfunction. Without use 
disorder
FI5.982 Amphetamine (or other stimulant)-induced sleep disorder. Without use disorder 
F15.982 Caffeine-induced sleep disorder. Without use disorder 
FI5.988 Amphetamine (or other stimulant)-induced obsessive-compulsive and related 
disorder. Without use disorder

disorder. Without use disorder 
FI5.99 Unspecified caffeine-related disorder
F16.10 Other hallucinogen use disorder. Mild
FI 6.10 Phencyclidine use disorder. Mild
F16.121 Other hallucinogen intoxication delirium. With mild use disorder 
F16.121 Phencyclidine intoxication delirium. With mild use disorder 
F16.129 Other hallucinogen intoxication. With mild use disorder 
F16.129 Phencyclidine intoxication. With mild use disorder
FI6.14 Other hallucinogen-induced bipolar and related disorder. With mild use disorder
F16.14 Other hallucinogen-induced depressive disorder. With mild use disorder
FI 6.14 Phencyclidine-induced bipolar and related disorder. With mild use disorder
F16.14 Phencychdine-induced depressive disorder. With mild use disorder

F16.159 Other hallucinogen-induced psychotic disorder. With mild use disorder 
F16.159 Phencyclidine-induced psychotic disorder. With mild use disorder 
F16.180 Other hallucinogen-induced anxiety disorder. With mild use disorder 
F16.180 Phencyclidine-induced anxiety disorder. With mild use disorder 
F16.20 Other hallucinogen use disorder. Moderate
FI6.20 Other hallucinogen use disorder. Severe
F16.20 Phencyclidine use disorder. Moderate
FI6.20 Phencyclidine use disorder. Severe
FI6.221 Other hallucinogen intoxication delirium. With moderate or severe use disorder 
F16.221 Phencyclidine intoxication delirium. With moderate or severe use disorder 
F16.229 Other hallucinogen intoxication. With moderate or severe use disorder 
FI6.229 Phencyclidine intoxication. With moderate or severe use disorder

FI6.229 Phencyclidine intoxication. With moderate or severe use disorder 
F16.24 Other hallucinogen-induced bipolar and related disorder. With moderate or

FI 6.24 Other hallucinogen-induced depressive disorder. With moderate or severe 
FI6.24 Phencyclidine-induced bipolar and related disorder. With moderate or severe 
FI6.24 Phencyclidine-induced depressive disorder. With moderate or severe use disorder
F16.259 Other hallucinogen-induced psychotic disorder. With moderate or severe use 
disorder
FI6.259 Phencyclidine-induced psychotic disorder. With moderate or severe use disorder
FI6.280 Other hallucinogen-induced anxiety disorder. With moderate or severe use 
disorder
FI6.280 Phencyclidine-induced anxiety disorder. With moderate or severe use disorder
F16.921 Other hallucinogen intoxication delirium. Without use disorder
F16.921 Phencyclidine intoxication delirium. Without use disorder
FI6.929 Other hallucinogen intoxication. Without use disorder
FI6.929 Phencyclidine intoxication. Without use disorder
FI6.94 Other hallucinogen-induced bipolar and related disorder. Without use disorder

FI 6.94 Other hallucinogen-induced depressive disorder. Without use disorder
F16.94 Phencyclidine-induced bipolar and related disorder. Without use disorder
FI 6.94 Phencyclidine-induced depressive disorder. Without use disorder
FI6.959 Other hallucinogen-induced psychotic disorder. Without use disorder
F16.959 Phencyclidine-induced psychotic disorder. Without use disorder
F16.980 Other hallucinogen-induced anxiety disorder. Without use disorder
F16.980 Phencyclidine-induced anxiety disorder. Without use disorder
FI6.983 Hallucinogen persisting perception disorder
FI 6.99 Unspecified hallucinogen-related disorder
FI6.99 Unspecified phencyclidine-related disorder
FI7.200 Tobacco use disorder, Moderate
F17.200 Tobacco use disorder. Severe
F17.203 Tobacco withdrawal
FI7.208 Tobacco-induced sleep disorder. With moderate or severe use disorder

FI7.209 Unspecified tobacco-related disorder
F18.10 Inhalant use disorder. Mild
F18.121 Inhalant intoxication delirium. With mild use disorder
F18.129 Inhalant intoxication. With mild use disorder
F18.14 Inhalant-induced depressive disorder. With mild use disorder
F18.159 Inhalant-induced psychotic disorder. With mild use disorder
F18.17 Inhalant-induced major neurocognitive disorder. With mild use disorder
FI8.180 Inhalant-induced anxiety disorder. With mild use disorder
F18.188 Inhalant-induced mild neurocognitive disorder. With mild use disorder
FI 8.20 Inhalant use disorder. Moderate
F18.20 Inhalant use disorder. Severe
F18.221 Inhalant intoxication delirium. With moderate or severe use disorder
F18.229 Inhalant intoxication. With moderate or severe use disorder

FI8.24 Inhalant-induced depressive disorder. With moderate or severe use disorder
FI8.259 Inhalant-induced psychotic disorder, With moderate or severe use disorder

FI8.27 Inhalant-induced major neurocognitive disorder. With moderate or severe use
disorder
F18.280 Inhalant-induced anxiety disorder. With moderate or severe use disorder 
F18.288 Inhalant-induced mild neurocognitive disorder. With moderate or severe use 
disorder
F18.921 Inhalant intoxicahon delirium. Without use disorder
FI8.929 Inhalant intoxication. Without use disorder
F18.94 Inhalant-induced depressive disorder. Without use disorder
F18.959 Inhalant-induced psychotic disorder. Without use disorder
FI8.97 Inhalant-induced major neurocognitive disorder. Without use disorder
F18.980 Inhalant-induced anxiety disorder. Without use disorder
FI8.988 Inhalant-induced mild neurocognitive disorder. Without use disorder
F18.99 Unspecified inhalant-related disorder
F19.10 Other (or unknown) substance use disorder. Mild
FI9.121 Other (or unknown) substance intoxication delirium. With mild use disorder 
FI9.129 Other (or unknown) substance intoxication. With mild use disorder

FI9.129 Other (or unknown) substance intoxication. With mild use disorder 
F19.14 Other (or unknown) substance-induced bipolar and related disorder. With
F19.14 Other (or unknown) substance-induced depressive disorder. With mild use
disorder
F19.159 Other (or unknown) substance-induced psychotic disorder. With mild use 
disorder
F19.17 Other (or unknown) substance-induced major neurocognitive disorder. With
F19.180 Other (or unknown) substance-induced anxiety disorder. With mild use disorder 
F19.181 Other (or unknown) substance-induced sexual dysfunction. With mild use 
disorder
F19.182 Other (or unknown) substance-induced sleep disorder. With mild use disorder 
F19.188 Other (or unknown) substance-induced mild neurocognitive disorder. With 
F19.188 Other (or unknown) substance-induced obsessive-compulsive and related

F19.188 Other (or unknown) substance-induced obsessive-compulsive and related 
F19.20 Other (or unknown) substance use disorder. Moderate
FI9.20 Other (or unknown) substance use disorder. Severe
F19.221 Other (or unknown) substance intoxication delirium. With moderate or severe 
F19.229 Other (or unknown) substance intoxication. With moderate or severe use disorder 
FI9.231 Other (or unknown) substance withdrawal delirium 
FI9.239 Other (or unknown) substance withdrawal
F19.24 Other (or unknown) substance-induced bipolar and related disorder. With
F19.24 Other (or unknown) substance-induced depressive disorder. With moderate
F19.259 Other (or unknown) substance-induced psychotic disorder. With moderate or 

F19.27 Other (or unknown) substance-induced major neurocognitive disorder. With

F19.280 Othei· (or unknown) substance-induced anxiety disorder. With moderate or 
F19.281 Other (or unknown) substance-induced sexual dysfunction. With moderate or 
F19.282 Other (or unknown) substance-induced sleep disorder. With moderate or 
F19.288 Other (or unknown) substance-induced mild neurocognitive disorder. With 
F19.288 Other (or unknown) substance-induced obsessive-compulsive and related 
FI9.921 Other (or unknown) substance-induced delirium
F19.921 Other (or unknown) substance intoxication delirium. Without use disorder 
F19.929 Other (or unknown) substance intoxication. Without use disorder 
F19.94 Other (or unknown) substance-induced bipolar and related disorder. Without
F19.94 Other (or unknown) substance-induced depressive disorder. Without use disorder

FI9.959 Other (or unknown) substance-induced psychotic disorder. Without use disorder 
FI9.97 Other (or unknown) substance-induced major neurocognitive disorder.
FI9.980 Other (or unknown) substance-induced anxiety disorder. Without use disorder 
F19.981 Other (or unknown) substance-induced sexual dysfunction. Without use disorder 
F19.982 Other (or unknown) substance-induced sleep disorder. Without use disorder 
FI9.988 Other (or unknown) substance-induced mild neurocognitive disorder. 
F19.988 Other (or unknown) substance-induced obsessive-compulsive and related 
F19.99 Unspecified other (or unknown) substance-related disorder
F20.81 Schizophreniform disorder
F20.9 Schizophrenia
F21 Schizotypal personality disorder

F22 Delusional disorder
F23 Brief psychotic disorder
F25.0 Schizoaffective disorder. Bipolar type
F25.1 Schizoaffective disorder. Depressive type
F28 Other specified schizophrenia spectrum and other psychotic disorder
F29 Unspecified schizophrenia spectrum and other psychotic disorder
F31.0 Bipolar I disorder. Current or most recent episode hypomanie
F31.il Bipolar I disorder. Current or most recent episode manic. Mild
F31.12 Bipolar I disorder, Current or most recent episode manic. Moderate
F31.13 Bipolar I disorder. Current or most recent episode manic. Severe
F31.2 Bipolar I disorder. Current or most recent episode manic. With psychotic features
F31.31 Bipolar I disorder. Current or most recent episode depressed. Mild
F31.32 Bipolar I disorder, Current or most recent episode depressed. Moderate

F31.4 Bipolar I disorder, Current or most recent episode depressed. Severe
F31.5 Bipolar I disorder. Current or most recent episode depressed. With psychotic
features

F31.73 Bipolar I disorder. Current or most recent episode hypomanie. In partial remission
F31.73 Bipolar I disorder. Current or most recent episode manic. In partial remission
F31.74 Bipolar I disorder. Current or most recent episode hypomanie. In full remission
F31.74 Bipolar I disorder. Current or most recent episode manic. In full remission
F31.75 Bipolar I disorder. Current or most recent episode depressed. In partial remission
F31.76 Bipolar I disorder. Current or most recent episode depressed. In full remission
F31.81 Bipolar II disorder
F31.89 Other specified bipolar and related disorder
F31.9 Bipolar I disorder. Current or most recent episode depressed. Unspecified
F31.9 Bipolar I disorder. Current or most recent episode hypomanie. Unspecified
F31.9 Bipolar I disorder. Current or most recent episode manic. Unspecified
F31.9 Bipolar I disorder. Current or most recent episode unspecified
F31.9 Unspecified bipolar and related disorder

F32.0 Major depressive disorder. Single episode. Mild
F32.1 Major depressive disorder. Single episode. Moderate
F32.2 Major depressive disorder. Single episode. Severe
F32.3 Major depressive disorder. Single episode. With psychotic features
F32.4 Major depressive disorder. Single episode. In partial remission
F32.5 Major depressive disorder. Single episode. In full remission
F32.8 Other specified depressive disorder
F32.9 Major depressive disorder. Single episode, Unspecifed
F32.9 Unspecified depressive disorder
F33.0 Major depressive disorder. Recurrent episode. Mild
F33.1 Major depressive disorder. Recurrent episode. Moderate
F33.2 Major depressive disorder. Recurrent episode. Severe
F33.3 Major depressive disorder. Recurrent episode. With psychotic features

F33.41 Major depressive disorder. Recurrent episode. In partial remission
F33.42 Major depressive disorder. Recurrent episode. In full remission
F33.9 Major depressive disorder. Recurrent episode. Unspecified
F34.0 Cyclothymic disorder
F34.1 Persistent depressive disorder (dysthymia)
F34.8 Disruptive mood dysregulation disorder
F40.00 Agoraphobia
F40.10 Social anxiety disorder (social phobia)
F40.218 Specific phobia. Animal
F40.228 Specific phobia. Natural environment
F40.230 Specific phobia. Fear of blood
F40.231 Specific phobia. Fear of injections and transfusions
F40.232 Specific phobia. Fear of other medical care
F40.233 Specific phobia. Fear of injury
F40.248 Specific phobia. Situational
F40.298 Specific phobia. Other
F41.0 Panic disorder
F41.1 Generalized anxiety disorder

F41.8 Other specified anxiety disorder

F41.9 Unspecified anxiety disorder
F42 Hoarding disorder
F42 Obsessive-compulsive disorder
F42 Other specified obsessive-compulsive and related disorder
F42 Unspecified obsessive-compulsive and related disorder
F43.0 Acute stress disorder
F43.10 Posttrauma tic stress disorder
F43.20 Adjustment disorders. Unspecified
F43.21 Adjustment disorders. With depressed mood
F43.22 Adjustment disorders. With anxiety
F43.23 Adjustment disorders. With mixed anxiety and depressed mood
F43.24 Adjustment disorders. With disturbance of conduct
F43.25 Adjustment disorders. With mixed disturbance of emotions and conduct
F43.8 Other specified trauma- and stressor-related disorder
F43.9 Unspecified trauma- and stressor-related disorder
F44.0 Dissociative amnesia
F44.1 Dissociative amnesia. With dissociative fugue
F44.4 Conversion disorder (functional neurological symptom disorder). With
abnormal movement
speech symptoms

swallowing symptoms 
weakness /  paralysis
F44.5 Conversion disorder (functional neurological symptom disorder). With
attacks or seizures
F44.6 Conversion disorder (functional neurological symptom disorder). With
anesthesia or sensory loss 
special sensory symptoms 
F44.7 Conversion disorder (functional neurological symptom disorder). With mixed
symptoms
F44.81 Dissociative identity disorder
F44.89 Other specified dissociative disorder
F44.9 Unspecified dissociative disorder
F45.1 Somatic symptom disorder
F45.21 Illness anxiety disorder
F45.22 Body dysmorphic disorder

F45.8 Other specified somatic symptom and related disorder
F45.9 Unspecified somatic symptom and related disorder
F48.1 Depersonalization/derealization disorder
F50.01 Anorexia nervosa. Restricting type
F50.02 Anorexia nervosa. Binge-eating/purging type
F50.2 Bulimia nervosa
F50.8 Avoidant/restrictive food intake disorder

F50.8 Binge-eating disorder
F50.8 Other specified feeding or eating disorder
F50.8 Pica, in adults
F50.9 Unspecified feeding or eating disorder
F51.3 Non-rapid eye movement sleep arousal disorders. Sleepwalking type
F51.4 Non-rapid eye movement sleep arousal disorders. Sleep terror type
¥51.5  Nightmare disorder
F52.0 Male hypoactive sexual desire disorder
F52.21 Erectile disorder
F52.22 Female sexual interest/arousal disorder
F52.31 Female orgasmic disorder
F52.32 Delayed ejaculation
F52.4 Premature (early) ejaculation
F52.6 Genito-pelvic pain/penetration disorder
F52.8 Other specified sexual dysfunction
F52.9 Unspecified sexual dysfunction
F54 Psychological factors affecting other medical conditions
F60.0 Paranoid personality disorder
F60.1 Schizoid personality disorder
F60.2 Antisocial personality disorder
F60.3 Borderline personality disorder
F60.4 Histrionic personality disorder
F60.5 Obsessive-compulsive personality disorder
F60.6 Avoidant personality disorder

F60.7 Dependent personality disorder
F60.81 Narcissistic personality disorder
F60.89 Other specified personality disorder
F60.9 Unspecified personality disorder
F63.0 Gambling disorder
F63.1 Pyromania
F63.2 Trichotillomania (hair-pulling disorder)
F63.3 Kleptomania
F63.81 Intermittent explosive disorder
F64.1 Gender dysphoria in adolescents and adults
F64.2 Gender dysphoria in children
F64.8 Other specified gender dysphoria
F64.9 Unspecified gender dysphoria
F65.0 Fetishistic disorder
F65.1 Transvestic disorder
F65.2 Exhibitionistic disorder
F65.3 Voyeurishc disorder
F65.4 Pedophilic disorder
F65.51 Sexual masochism disorder
F65.52 Sexual sadism disorder
F65.81 Frotteuristic disorder

F65.89 Other specified paraphilic disorder
F65.9 Unspecified paraphilic disorder
F68.10 Factitious disorder
F70 Intellectual disability (intellectual developmental disorder). Mild
F71 Intellectual disability (intellectual developmental disorder). Moderate
F72 Intellectual disability (intellectual developmental disorder). Severe
F73 Intellectual disability (intellectual developmental disorder). Profound
F79 Unspecified intellectual disability (intellectual developmental disorder)
F80.0 Speech sound disorder
F80.81 Childhood-onset fluency disorder (stuttering)
F80.89 Social (pragmatic) communication disorder
F80.9 Language disorder
F80.9 Unspecified communication disorder
F81.0 Specific learning disorder. With impairment in reading
F81.2 Specific learning disorder. With impairment in mathematics
F81.81 Specific learning disorder. With impairment in written expression
F82 Developmental coordination disorder
F84.0 Autism spectrum disorder
F88 Global developmental delay

F88 Other specified neurodevelopmental disorder
F89 Unspecified neurodevelopmental disorder
F90.0 Attention-deficit/hyperactivity disorder. Predominantly inattentive presentation
F90.1 Attention-deficit/hyperactivity disorder. Predominantly hyperactive/ 
F90.2 Attention-deficit/hyperactivity disorder. Combined presentation
F90.8 Other specified attention-deficit/hyperactivity disorder
F90.9 Unspecified attention-deficit/hyperactivity disorder
F91.1 Conduct disorder, Childhood-onset type
F91.2 Conduct disorder, Adolescent-onset type
F91.3 Oppositional defiant disorder
F91.8 Other specified disruptive, impulse-control, and conduct disorder
F91.9 Conduct disorder. Unspecified onset
F91.9 Unspecified disruptive, impulse-control, and conduct disorder
F93.0 Separation anxiety disorder

F94.0 Selective mutism
F94.1 Reactive attachment disorder
F94.2 Disinhibited social engagement disorder
F95.0 Provisional tic disorder
F95.1 Persistent (chronic) motor or vocal tic disorder
F95.2 Tourette's disorder
F95.8 Other specified tic disorder
F95.9 Unspecified tic disorder
F98.0 Enuresis
F98.1 Encopresis
F98.21 Rumination disorder

F98.3 Pica, in children
F98.4 Stereotypic movement disorder
F98.5 Adult-onset fluency disorder
F99 Other specified mental disorder
F99 Unspecified mental disorder
G21.0 Neuroleptic malignant syndrome
G21.il Neuroleptic-induced parkinsonism
G21.19 Other medication-induced parkinsonism
G24.01 Tardive dyskinesia
G24.02 Medication-induced acute dystonia
G24.09 Tardive dystonia
G25.1 Medication-induced postural tremor
G25.71 Medication-induced acute akathisia
G25.71 Tardive akathisia
G25.79 Other medication-induced movement disorder
G25.81 Restless legs syndrome
G31.84 Mild frontotemporal neurocognitive disorder
G31.84 Mild neurocognitive disorder due to Alzheimer's disease
G31.84 Mild neurocognitive disorder due to another medical condition
G31.84 Mild neurocognitive disorder due to HIV infection
G31.84 Mild neurocognitive disorder due to Huntington's disease
G31.84 Mild neurocognitive disorder with Lev^y bodies
G31.84 Mild neurocognitive disorder due to multiple etiologies

G31.84 Mild neurocognitive disorder due to Parkinson's disease
G31.84 Mild neurocognitive disorder due to prion disease
G31.84 Mild neurocognitive disorder due to traumatic brain injury
G31.84 Mild vascular neurocognitive disorder
G31.9 Major neurocognitive disorder possibly due to Parkinson's disease
G31.9 Possible major frontotemporal neurocognitive disorder
G31.9 Possible major neurocognitive disorder due to Alzheimer's disease
G31.9 Possible major neurocognitive disorder with Lewy bodies
G31.9 Possible major vascular neurocognitive disorder
G47.00 Insomnia disorder
G47.00 Unspecified insomnia disorder
G47.09 Other specified insomnia disorder
G47.10 Hypersonrmolence disorder
G47.10 Unspecified hypersomnolence disorder
G47.19 Other specified hypersomnolence disorder

G47.20 Circadian rhythm sleep-wake disorders. Unspecified type
G47.21 Circadian rhythm sleep-wake disorders. Delayed sleep phase type
G47.22 Circadian rhythm sleep-wake disorders. Advanced sleep phase type
G47.23 Circadian rhythm sleep-wake disorders, Irregular sleep-wake type
G47.24 Circadian rhythm sleep-wake disorders, Non-24-hour sleep-wake type
G47.26 Circadian rhythm sleep-wake disorders. Shift work type
G47.31 Central sleep apnea. Idiopathic central sleep apnea

G47.33 Ot^structive sleep apnea hypopnea
G47.34 Sleep-related hypoventilation. Idiopathic hypoventilation
G47.35 Sleep-related hypoventilation. Congenital central alveolar hypoventilation
G47.36 Sleep-related hypoventilation, Comorbid sleep-related hypoventilation
G47.37 Central sleep apnea comorbid with opioid use
G47.411 Narcolepsy with cataplexy but without hypocretin deficiency
G47.419 Autosomal dominant cerebellar ataxia, deafness, and narcolepsy
G47.419 Autosomal dominant narcolepsy, obesity, and type 2 diabetes
G47.419 Narcolepsy without cataplexy but with hypocretin deficiency
G47.429 Narcolepsy secondary to another medical condition
G47.52 Rapid eye movement sleep behavior disorder
G47.8 Other specified sleep-wake disorder
G47.9 Unspecified sleep-wake disorder
L98.1 Excoriation (skin-picking) disorder
N39.498 Other specified elimination disorder. With urinary symptoms
N94.3 Premenstrual dysphoric disorder
R06.3 Central sleep apnea, Cheyne-Stokes breathing

R15.9 Other specified elimination disorder. With fecal symptoms
R15.9 Unspecified elimination disorder. With fecal symptoms
R32 Unspecified elimination disorder, With urinary symptoms
R41.0 Other specified delirium
R41.0 Unspecified delirium
R41.83 Borderline intellectual functioning
R41.9 Unspecified neurocognitive disorder
T43.205A Antidepressant discontinuation syndrome. Initial encounter
T43.205D Antidepressant discontinuation syndrome. Subsequent encounter
T43.205S Antidepressant discontinuation syndrome. Sequelae
T50.905A Other adverse effect of medication. Initial encounter
T50.905D Other adverse effect of medication. Subsequent encounter
T50.905S Other adverse effect of medication. Sequelae
T74.01XA Spouse or partner neglect. Confirmed, Initial encounter

T74.01XD Spouse or partner neglect. Confirmed, Subsequent encounter
T74.02XA Child neglect. Confirmed, Initial encounter
T74.02XD Child neglect. Confirmed, Subsequent encounter
T74.11XA Adult physical abuse by nonspouse or nonpartner. Confirmed, Initial encounter
T74.11XA Spouse or partner violence. Physical, Confirmed, Initial encounter
T74.11XD Adult physical abuse by nonspouse or nonpartner. Confirmed, Subsequent  
encounter
T74.11XD Spouse or partner violence. Physical, Confirmed, Subsequent encounter
T74.12XA Child physical abuse. Confirmed, Initial encounter  
T74.12XD Child physical abuse. Confirmed, Subsequent encounter
T74.21XA Adult sexual abuse by nonspouse or nonpartner. Confirmed, Initial encounter
T74.21XA Spouse or partner violence. Sexual, Confirmed, Initial encounter

T74.21XA Spouse or partner violence. Sexual, Confirmed, Initial encounter  
T74.21XD Adult sexual abuse by nonspouse or nonpartner. Confirmed, Subsequent  
encounter

T74.21XD Spouse or partner violence. Sexual, Confirmed, Subsequent encounter
T74.22XA Child sexual abuse. Confirmed, Initial encounter
T74.22XD Child sexual abuse. Confirmed, Subsequent encounter
T74.31XA Adult psychological abuse by nonspouse or nonpartner. Confirmed, Initial  
encounter
T74.31XA Spouse or partner abuse. Psychological, Confirmed, Initial encounter
T74.31XD Adult psychological abuse by nonspouse or nonpartner. Confirmed,  
T74.31XD Spouse or partner abuse. Psychological, Confirmed, Subsequent encounter
T74.32XA Child psychological abuse. Confirmed, Initial encounter
T74.32XD Child psychological abuse. Confirmed, Subsequent encounter
T76.01XA Spouse or partner neglect. Suspected, Initial encounter
T76.01XD Spouse or partner neglect. Suspected, Subsequent encounter
T76.02XA Child neglect. Suspected, Initial encounter
T76.02XD Child neglect. Suspected, Subsequent encounter

T76.11XA Adult physical abuse by nonspouse or nonpartner. Suspected, Initial encounter
T76.11XA Spouse or partner violence. Physical, Suspected, Initial encounter
T76.11XD Adult physical abuse by nonspouse or nonpartner. Suspected, Subsequent  
encounter
T76.11XD Spouse or partner violence. Physical, Suspected, Subsequent encounter
T76.12XA Child physical abuse. Suspected, Initial encounter
T76.12XD Child physical abuse. Suspected, Subsequent encounter
T76.21XA Adult sexual abuse by nonspouse or nonpartner. Suspected, Initial encounter
T76.21XA Spouse or partner violence. Sexual, Suspected, Initial encounter
T76.21XD Adult sexual abuse by nonspouse or nonpartner. Suspected, Subsequent  
encounter
T76.21XD Spouse or partner violence. Sexual, Suspected, Subsequent encounter

encounter
T76.22XA Child sexual abuse. Suspected, Initial encounter
T76.22XD Child sexual abuse. Suspected, Subsequent encounter
T76.31XA Adult psychological abuse by nonspouse or nonpartner. Suspected, Initial  
encounter
T76.31XA Spouse or partner abuse. Psychological, Suspected, Initial encounter
T76.31XD Adult psychological abuse by nonspouse or nonpartner. Suspected,  
T76.31XD Spouse or partner abuse. Psychological, Suspected, Subsequent encounter
T76.32XA Child psychological abuse. Suspected, Initial encounter
T76.32XD Child psychological abuse. Suspected, Subsequent encounter
Z55.9 Academic or educational problem
Z56.82 Problem related to current military deployment status
Z56.9 Other problem related to employment
Z59.0 Homelessness
Z59.1 Inadequate housing

Z59.2 Discord with neighbor, lodger, or landlord
Z59.3 Problem related to living in a residential institution
Z59.4 Lack of adequate food or safe drinking water
Z59.5 Extreme poverty

Z59.6 Low income
Z59.7 Insufficient social insurance or welfare support
Z59.9 Unspecified housing or economic problem
Z60.0 Phase of life problem
Z60.2 Problem related to living alone
Z60.3 Acculturation difficulty
Z60.4 Social exclusion or rejection
Z60.5 Target of (perceived) adverse discrimination or persecution
Z60.9 Unspecified problem related to social environment
Z62.29 Upbringing away from parents
Z62.810 Personal history (past history) of physical abuse in childhood
Z62.810 Personal history (past history) of sexual abuse in childhood
Z62.811 Personal history (past history) of psychological abuse in childhood
Z62.812 Personal history (past history) of neglect in childhood
Z62.820 Parent-child relational problem
Z62.891 Sibling relational problem
Z62.898 Child affected by parental relationship distress
Z63.0 Relationship distress with spouse or intimate partner
Z63.4 Uncomplicated bereavement
Z63.5 Disruption of family by separation or divorce

Z63.8 High expressed emotion level within family
Z64.0 Problems related to unwanted pregnancy
Z64.1 Problems related to multiparity
Z64.4 Discord with social service provider, including probation officer, case  
manager, or social services worker
Z65.0 Conviction in civil or criminal proceedings without imprisonment
Z65.1 Imprisonment or other incarceration
Z65.2 Problems related to release from prison
Z65.3 Problems related to other legal circumstances
Z65.4 Victim of crime
Z65.4 Victim of terrorism or torture
Z65.5 Exposure to disaster, war, or other hostilities
Z65.8 Other problem related to psychosocial circumstances
Z65.8 Religious or spiritual problem
Z65.9 Unspecified problem related to unspecified psychosocial circumstances
Z69.010 Encounter for mental health services for victim of child abuse by parent

Z69.010 Encounter for mental health services for victim of child neglect by parent
Z69.010 Encounter for mental health services for victim of child psychological abuse by  
parent
Z69.010 Encounter for mental health services for victim of child sexual abuse by parent
Z69.011 Encounter for mental health services for perpetrator of parental child abuse
Z69.011 Encounter for mental health services for perpetrator of parental child neglect
Z69.011 Encounter for mental health services for perpetrator of parental child  
Z69.011 Encounter for mental health services for peφetrator of parental child sexual abuse
Z69.020 Encounter for mental health services for victim of nonparental child abuse

Z69.020 Encounter for mental health services for victim of nonparental child neglect  
Z69.020 Encounter for mental health services for victim of nonparental child psycho­
logical abuse
Z69.020 Encounter for mental health services for victim of nonparental child sexual abuse  
Z69.021 Encounter for mental health services for perpetrator of nonparental child abuse  
Z69.021 Encounter for mental health services for perpetrator of nonparental child neglect  
Z69.021 Encounter for mental health services for perpetrator of nonparental child  
Z69.ll Encounter for mental health services for victim of spouse or partner neglect
Z69.ll Encounter for mental health services for victim of spouse or partner
Z69.ll Encounter for mental health services for victim of spouse or partner violence.
Physical

Physical
Z69.12 Encounter for mental health services for peφetrator of spouse or partner neglect
Z69.12 Encounter for mental health services for perpetrator of spouse or partner
Z69.12 Encounter for mental health services for perpetrator of spouse or partner  
violence. Physical
violence. Sexual
Z69.81 Encounter for mental health services for victim of nonspousal adult abuse
Z69.81 Encounter for mental health services for victim of spouse or partner violence.
Sexual
Z69.82 Encounter for mental health services for peφetΓator of nonspousal adult abuse
Z70.9 Sex counseling
Z71.9 Other counseling or consultation
Z72.0 Tobacco use disorder, mild
Z72.810 Child or adolescent antisocial behavior

Z72.811 Adult antisocial behavior
Z72.9 Problem related to lifestyle
Z75.3 Unavailability or inaccessibility of health care facilities
Z75.4 Unavailability or inaccessibility of other helping agencies
Z76.5 Malingering
Z91.19 Nonadherence to medical treatment
Z91.410 Personal history (past history) of spouse or partner violence. Physical
Z91.410 Personal history (past history) of spouse or partner violence. Sexual
Z91.411 Personal history (past history) of spouse or partner psychological abuse
Z91.412 Personal history (past history) of spouse or partner neglect
Z91.49 Other personal history of psychological trauma
Z91.5 Personal history of self-harm
Z91.82 Personal history of military deployment
Z91.83 Wandering associated with a mental disorder
Z91.89 Other personal risk factors

IW I^ irav isö rö^ n ä  
Other Contributor
APA Board of Trustees DSM-5 Review Committees
Scientific Review Committee (SRC)
Kenneth S. Kendler, M.D. (Chair)
Robert Freedman, M.D. (Co-chair)
David Brent, M.D. (2011-)
Ellen Leibenluft, M.D.
Sir Michael Rutter, M.D. (-2011)
Paul S. Summergrad, M.D.
Robert J. Ursano, M.D. (-2011)
Myrna Weissman, Ph.D. (2011-)
Joel Yager, M.D.
Jill L. Opalesky M.S. (Administrative Support)
Clinical and Public Health Review  
Committee (CPHC)
John s. McIntyre, M.D. (Chair)
Joel Yager, M.D. (Co-chair)
Anita Everett M.D.
Cathryn A. Galanter, M.D.
Jeffrey M. Lyness, M.D.
James E. Nininger, M.D.
Victor I. Reus, M.D.
Michael J. Vergäre, M.D.
Ann Miller (Administrative Support)
Oversight Committee
Carolyn Robinowitz, M.D. (Chair)
Mary Badaracco, M.D.
Ronald Burd, M.D.
Robert Freedman, M.D.
Jeffrey A. Lieberman, M.D.
Kyla Pope, M.D.
Daniel K. Winstead, M.D.
APA Assembly DSM-5 Review  
Committee

Committee
Glenn A. Martin, M.D. (Chair)
R. Scott Benson, M.D. (Speaker of the  
Assembly)
William Cardasis, M.D.
John M. de Figueiredo, M.D.
Lawrence S. Gross, M.D.
Brian S. Hart, M.D.Stephen A. McLeod Bryant, M.D.  
Gregory A. Miller, M.D.
Charles S. Price, M.D.
Deepika Sastry, M.D.
John P.D. Shemo, M.D.
Eliot Sorel, M.D.
DSM-5 Summit Group
Dilip V. Jeste, M.D. (Chair)
R. Scott Benson, M.D.
Kenneth S. Kendler, M.D.
Glenn A. Martin, M.D.
John S. McIntyre, M.D.
John M. Oldham, M.D.
James H. Scully Jr., M.D.
Paul S. Appelbaum, M.D. (Consultant)  
Michael B. First, M.D. (Consultant)
DSM-5 Field Trials Review
Robert D. Gibbons, Ph.D.
Craig Nelson, M.D.

DSM-5 Forensic Review
Paul S. Appelbaum, M.D.
Lama Bazzi, M.D.
Alec W. Buchanan, M.D., Ph.D.
Carissa Caban Aleman, M.D.
Michael Champion, M.D.
Jeffrey C. Eisen, M.D.
Elizabeth Ford, M.D.
Daniel T. Hackman, M.D.
Mark Hauser, M.D.
Steven K. Hoge, M.D., M.B.A.
Debra A. Pinals, M.D.
Guillermo Portillo, M.D.
Patricia Recupero, M.D., J.D.
Robert Weinstock, M.D.
Cheryl Wills, M.D.
Howard V. Zonana, M.D.

Erin J. Dalder-Alpher  
Kristin Edwards  
Leah I. EngelPast DSM-5 APA Staff
Lenna Jawdat  
Elizabeth C. Martin  
Rocio J. Salvador
Work Group Advisors
ADHD and Disruptive Behavior  
Disorders
Emil F. Coccaro, M.D.
Deborah Dabrick, Ph.D.
Prudence W. Fisher, Ph.D.
Benjamin B. Lahey, Ph.D.
Salvatore Mannuzza, Ph.D.
Mary Solanto, Ph.D.
J. Blake Turner, Ph.D.
Eric Youngstrom, Ph.D.
Anxiety, Obsessive-Compulsive  
Spectrum, Posttraumatic, and  
Lynn E. Alden, Ph.D.
David B. Arciniegas, M.D.
David H. Barlow, Ph.D.
Katja Beesdo-Baum, Ph.D.
Chris R. Brewin, Ph.D.
Richard J. Brown, Ph.D.
Timothy A. Brown, Ph.D.
Richard A. Bryant, Ph.D.
Joan M. Cook, Ph.D.
Joop de Jong, M.D., Ph.D.
Paul F. Dell, Ph.D.
Damiaan Denys, M.D.
Bruce P. Dohrenwend, Ph.D.
Brian A. Fallon, M.D., M.P.H.
Edna B. Foa, Ph.D.
Martin E. Franklin, Ph.D.
Wayne K. Goodman, M.D.
Jon E. Grant, J.D., M.D.
Bonnie L. Green, Ph.D.
Richard G. Heimberg, Ph.D.
Judith L. Herman, M.D.
Devon E. Hinton, M.D., Ph.D.

Stefan G. Hofmann, Ph.D.
Charles W. Hoge, M.D.
Terence M. Keane, Ph.D.
Nancy J. Keuthen, Ph.D.
Dean G. Kilpatrick, Ph.D.
Katharina Kircanski, Ph.D.
Laurence J. Kirmayer, M.D.
Donald F. Klein, M.D., D.Sc.
Amaro J. Laria, Ph.D.
Richard T. LeBeau, M.A.
Richard J. Loewenstein, M.D.
David Mataix-Cols, Ph.D.
Thomas W. McAllister, M.D.Harrison G. Pope, M.D., M.P.H.  
Ronald M. Rapee, Ph.D.
Steven A. Rasmussen, M.D.
Patricia A. Resick, Ph.D.
Vedat Sar, M.D.
Sanjaya Saxena, M.D.
Paula P. Schnurr, Ph.D.
M. Katherine Shear, M.D.
Daphne Simeon, M.D.
Harvey S. Singer, M.D.
Melinda A. Stanley, Ph.D.
James J. Strain, M.D.
Kate Wolitzky Taylor, Ph.D.
Onno van der Hart, Ph.D.
Eric Vermetten, M.D., Ph.D.
John T. Walkup, M.D.
Sabine Wilhelm, Ph.D.
Douglas W. Woods, Ph.D.
Richard E. Zinbarg, Ph.D.

Joseph Zohar, M.D.
Childhood and Adolescent  
Disorders
Adrian Angold, Ph.D.
Deborah Beidel, Ph.D.
David Brent, M.D.
John Campo, M.D.
Gabrielle Carlson, M.D.
David Klonsky, Ph.D.
Matthew Nock, Ph.D.
Michael J. Devlin, M.D.
Denise E. Wilfley, Ph.D.
Susan Z. Yanovski, M.D.
Boris Birmaher, M.D.
Yeates Conwell, M.D.
Ellen B. Dennehy, Ph.D.
S. Ann Hartlage, Ph.D.
Jack M. Hettema, M.D., Ph.D.  
Michael C. Neale, Ph.D.
Gordon B. Parker, M.D., Ph.D., D.Sc.  
Roy H. Perlis, M.D. M.Sc.
Holly G. Prigerson, Ph.D.
Norman E. Rosenthal, M.D.
Peter J. Schmidt, M.D.

Mort M. Silverman, M.D.
Meir Steiner, M.D., Ph.D.
Mauricio Tohen, M,D., Dr.P.H., M.B.A.  
Sidney Zisook, M.D.
Jiska Cohen-Mansfield, Ph.D.
Vladimir Hachinski, M.D., C.M., D.Sc.  
Sharon Inouye, M.D., M.P.H.
Grant Iverson, Ph.D.
Laura Marsh, M.D.
Bruce Miller, M.D.
Jacobo Mintzer, M.D., M.B.A.
Bruce Pollock, M.D., Ph.D.
George Prigatano, Ph.D.
Ron Ruff, Ph.D.
Ingmar Skoog, M.D., Ph.D.
Robert Sweet, M.D.
Paula Trzepacz, M.D.
Ari Ne'eman  
Nickola Nelson, Ph.D.
Diane Paul, Ph.D.
Eva Petrova, Ph.D.
Andrew Pickles, Ph.D.
Jan Piek, Ph.D.
Helene Polatajko, Ph.D.
Alya Reeve, M.D.
Mabel Rice, Ph.D.
Joseph Sergeant, Ph.D.
Bennett Shaywitz, M.D.
Sally Shaywitz, M.D.
Audrey Thurm, Ph.D.
Keith Widaman, Ph.D.
Warren Zigman, Ph.D.
Personality and Personality  
Disorders
Eran Chemerinski, M.D.
Thomas N. Crawford, Ph.D.
Harold W. Koenigsberg, M.D.
Kristian E. Markon, Ph.D.
Rebecca L. Shiner, Ph.D.
Kenneth R. Silk, M.D.
Jennifer L. Tackett, Ph.D.

Disorders
David Watson, Ph.D.
Kamaldeep Bhui, M.D.
Manuel J. Cuesta, M.D., Ph.D.
Richard Douyon, M.D.
Paolo Fusar-Poli, Ph.D.
John H. Krystal, M.D.
Thomas H. McGlashan, M.D.
Victor Peralta, M.D., Ph.D.
Anita Riecher-Rössler, M.D.
Mary V. Seeman, M.D.Sexual and Gender Identity  
Disorders
Stan E. Althof, Ph.D.
Richard Balon, M.D.
John H.J. Bancroft, M.D., M.A., D.P.M.  
Howard E. Barbaree, Ph.D., M.A.  
Rosemary J. Basson, M.D.
Sophie Bergeron, Ph.D.
Anita L. Clayton, M.D.
David L. Delmonico, Ph.D.
Domenico Di Ceglie, M.D.
Esther Gomez-Gil, M.D.
Jamison Green, Ph.D.
Richard Green, M.D, J.D.
R. Karl Hanson, Ph.D.
Lawrence Hartmann, M.D.
Stephen J. Hucker, M.B.
Eric S. Janus, J.D.
Patrick M. Jem, Ph.D.
Megan S. Kaplan, Ph.D.
Raymond A. Knight, Ph.D.
Ellen T.M. Laan, Ph.D.

Stephen B. Levine, M.D.
Christopher G. McMahon, M.B.
Marta Meana, Ph.D.
Michael H. Miner, Ph.D., M.A.
William T. O'Donohue, Ph.D.
Michael A. Perelman, Ph.D.
Caroline F. Pukall, Ph.D.
Robert E. Pyke, M.D., Ph.D.
Vernon L. Quinsey, Ph.D. M.Sc.
David L. Rowland, Ph.D., M.A.  
Michael Sand, Ph.D., M.P.H.
Leslie R. Schover, Ph.D., M.A.
Paul Stem, B.S, J.D.
David Thomton, Ph.D.
Leonore Tiefer, Ph.D.
Douglas E. Tucker, M.D.
Jacques van Lankveld, Ph.D.
Marcel D. Waldinger, M.D., Ph.D.
Donald L. Bliwise, Ph.D.
Daniel J. Buysse, M.D.
Vishesh K. Kapur, M.D., M.P.H.  
Sanjeeve V. Kothare, M.D.
Kenneth L. Lichstein, Ph.D.
Mark W. Mahowald, M.D.
Rachel Manber, Ph.D.
Emmanuel Mignot, M.D., Ph.D.  
Timothy H. Monk, Ph.D., D.Sc.
Thomas C. Neylan, M.D.
Maurice M. Ohayon, M.D., D.Sc., Ph.D.

Maurice M. Ohayon, M.D., D.Sc., Ph.D.  
Judith Owens, M.D., M.P.H.
Daniel L. Picchietti, M.D.
Stuart F. Quan, M.D.
Thomas Roth, Ph.D.
Daniel Weintraub, M.D.

Theresa B. Young, Ph.D.
Phyllis C. Zee, M.D., Ph.D.
Brenda Bursch, Ph.D.
Kurt Kroenke, M.D.
W. Curt LaFrance, Jr., M.D., M.P.H.
Jon Stone, M.B., Ch.B., Ph.D.
Lynn M. Wegner, M.D.Substance-Related Disorders
Raymond F. Anton, Jr., M.D.
Deborah A. Dawson, Ph.D.
Roland R. Griffiths, Ph.D.
Dorothy K. Hatsukami, Ph.D.
John E. Heizer, M.D.
Marilyn A. Huestis, Ph.D.
John R. Hughes, M.D.
Thomas R. Kosten, M.D.
Nora D. Volkow, M.D.
DSM-5 Study Group and Other DSM-5 Group Advisors
Lifespan Developmental  
Approaches
Christina Bryant, Ph.D.
Amber Gum, Ph.D.
Thomas Meeks, M.D.
Jan Mohlman, Ph.D.
Steven Thorp, Ph.D.
Julie Wetherell, Ph.D.
Neil K. Aggarwal, M.D., M.B.A., M.A.
Sofie Bäämhielm, M.D., Ph.D.
José J. Bauermeister, Ph.D.
James Boehnlein, M.D., M.Sc.
Jaswant Guzder, M.D.
Alejandro Interian, Ph.D.
Sushrut S. Jadhav, M.B.B.S., M.D., Ph.D.  
Alex J. Kopelowicz, M.D.

Steven R. Lopez, Ph.D.
Kwame J. McKenzie, M.D.
John R. Peteet, M.D.Hans Q.G.B.M.) Rohlof, M.D.
Cecile Rousseau, M.D.
Mitchell G. Weiss, M.D., Ph.D.
Psychiatric/General Medical  
Interface
Daniel L. Coury, M.D.
Bernard P. Dreyer, M.D.
Danielle Laraque, M.D.
Lynn M. Wegner, M.D.
Martin Prince, M.D., M.Sc.
Michael R. Von Korff, Sc.D.
Diagnostic Assessment  
Instruments
Ruben Gur, Ph.D.
John Houston, M.D., Ph.D.
Other Contributors/Consultants
Disorders
Patrick E. Shrout, Ph.D.
Erik Willcutt, Ph.D.
Eric Hollander, M.D.
Charlie Marmar, M.D.

Disorders
Mark W. Miller, Ph.D.
Mark H. Pollack, M.D.
Heidi S. Resnick, Ph.D.Childhood and Adolescent  
Disorders
Grace T. Baranek, Ph.D.
Colleen Jacobson, Ph.D.
Maria Oquendo, M.D.
Sir Michael Rutter, M.D.
Nancy L. Zucker, Ph.D.
Keith Hawton, M.Sc.
David A. Jobes, Ph.D.
Maria A. Oquendo, M.D.

J. Eric Ahlskog, M.D, Ph.D.
Allen J. Aksamit, M.D.
Marilyn Albert, Ph.D.
Guy Mckhann, M.D.
Bradley Boeve, M.D.
Helena Chui, M.D.
Sureyya Dikmen, Ph.D.
Douglas Galasko, M.D.
Harvey Levin, Ph.D.
Mark Lovell, Ph.D.
Jeffery Max, M.B.B.Ch.
Ian McKeith, M.D.
Cynthia Munro, Ph.D.
Marlene Oscar-Berman, Ph.D.
Alexander Tröster, Ph.D.
Arma Barnett, Ph.D.
Martha Denckla, M.D.
Jack M. Fletcher, Ph.D.
Dido Green, Ph.D.
Stephen Greenspan, Ph.D.
Bruce Pennington, Ph.D.
Ruth Shalev, M.D.
Larry B. Silver, M.D.
Lauren Swineford, Ph.D.
Michael Von Aster, M.D.
Disorders
Patricia R. Cohen, Ph.D.
Jaime L. Derringer, Ph.D.
Lauren Helm, M.D.
Christopher J. Patrick, Ph.D.
Anthony Pinto, Ph.D.
Scott W. Woods, M.D.
Sexual and Gender Identity  
Disorders
Alan J. Riley, M.Sc.
Ray C. Rosen, Ph.D.
Jack D. Edinger, Ph.D.
David Gozal, M.D.
Hochang B. Lee, M.D.
Tore A. Nielsen, Ph.D.

Disorders
Michael J. Sateia, M.D.
Jamie M. Zeitzer, Ph.D.
Chuck V. Ford, M.D.
Patricia L Rosebush, M.Sc.N., M.D.Sally M. Anderson, Ph.D.
Julie A. Kable, Ph.D.
Christopher Martin, Ph.D.
Sarah N. Mattson, Ph.D.
Edward V. Nunes, Jr., M.D.
Mary J. O'Connor, Ph.D.
Heather Carmichael Olson, Ph.D.
Blair Paley, Ph.D.
Edward P. Riley, Ph.D.
Tulshi D. Saha, Ph.D.
Wim van den Brink, M.D., Ph.D.
George E. Woody, M.D.
Diagnostic Spectra and DSM/ICD  
Harmonization
Bruce Cuthbert, Ph.D.
Aartjan Beekman Ph.D.
Alistair Flint, M.B.
David Sultzer, M.D.
Ellen Whyte, M.D.
Sergio Aguilar-Gaxiola, M.D., Ph.D.
Kavoos G. Bassiri, M.S.
Venkataramana Bhat, M.D.
Marit Boiler, M.P.H.
Denise Canso, M.Sc.
Smita N. Deshpande, M.D., D.P.M.

Ravi DeSilva, M.D.
Esperanza Diaz, M.D.
Byron J. Good, Ph.D.
Simon Groen, M.A.
Ladson Hinton, M.D.
Lincoln L Khasakhala, Ph.D.
Francis G. Lu, M.D.
Athena Madan, M.A.
Arme W. Mbwayo, Ph.D.
Oanh Meyer, Ph.D.
Victoria N. Mutiso, Ph.D., D.Sc.
David M. Ndetei, M.D.
Andel V. Nicasio, M.S.Ed.
Vasudeo Paralikar, M.D., Ph.D.
Kanak Patil, M.A.
Filipa L Santos, H.B.Sc.
Sanjeev B. Sarmukaddam, Ph.D., M.Sc.  
Monica Z. Scalco, M.D., Ph.D.
Katie Thompson, M.A.
Hendry Ton, M.D., M.Sc.
Rob C.J. van Dijk, M.Sc.
Johann M. Vega-Dienstmaier, M.D.
Joseph Westermeyer, M.D., Ph.D.

Interface
Daniel J. Balog, M.D.
Charles C. Engel M.D., M.P.H.  
Charles D. Motsinger, M.D.
Cille Kennedy, Ph.D.
Paul J. Pikonis, Ph.D.Other Conditions That May Be  
a Focus of Clinical Attention
William E. Narrow, M.D., M.P.H., Chair  
Lawson R. Wulsin, M.D.
Charles H. Zeanah, M.D.
Prudence W. Fisher, Ph.D., Advisor  
Stanley N. Caroff, M.D., Contributor/Consultant  
James B. Lohr, M.D., Contributor/Consultant  
Marianne Wambolt, Ph.D., Contributor/Consultant
Allan Dormer, Ph.D.
CPHC Peer Reviewers
Kenneth Altshuler, M.D.
Pedro G. Alvarenga, M.D.  
Diana J. Antonacci, M.D.  
L. Jarrett Banihill, M.D.
Katja Beesdo-Baum, Ph.D.  
Marty Boman, Ed.D.
James Bourgeois, M.D.
David Braff, M.D.
Harry Brandt, M.D.
Kirk Brower, M.D.
Rachel Bryant-Waugh, Ph.D.  
Jack D. Burke Jr., M.D., M.P.H.  

Joseph Camilleri, M.D.
Patricia Casey, M.D.
F. Xavier Castellanos, M.D.  
Wai Chen, M.D.
Elie Cheniaux, M.D., D.Sc.  
Cheryl Chessick, M.D,
J. Richard Ciccone, M.D.
Anita H. Clayton, M.D.
Tihalia J. Coleman, Ph.D.
John Csemansky, M.D.  
Manuel J. Cuesta M.D., Ph.D.  
Joanne L. Davis, M.D.
David L. Delmonico, Ph.D.  
Ray J. DePaulo, M.D.
Dinnitris Dikeos, M.D.
Ina E. Djonlagic, M.D.
C. Neill Epperson, M.D.
Javier I. Escobar, M.D., M.Sc.  
Spencer Eth, M.D.
David Fassler, M.D.
Giovanni A. Fava, M.D.
Robert Feinstein, M.D.
Molly Finnerty, M.D.
Mark H. Fleisher, M.D.
Alessio Florentini, M.D.Laura Fochtmann, M.D.  
Marshal Forstein, M.D.
William French, M.D.  
MaximiUian Gahr, M.D.  
Cynthia Geppert, M.D.
Ann Germaine, Ph.D.
Marcia Goin, M.D.
David A. Gorelick, M.D., Ph.D.

David A. Gorelick, M.D., Ph.D.  
David Graeber, M.D.
Cynthia A. Graham, Ph.D.  
Andreas Hartmann, M.D.  
Victoria Hendrick, M.D.
Merrill Herman, M.D.
David Herzog, M.D.
Mardi Horowitz, M.D.
Ya-fen Huang, M.D.
Anthony Kales, M.D  
Niranjan S. Karnik, M.D., Ph.D.  
Jeffrey Katzman, M.D.
Bryan King, M.D.
Cecilia Kjellgren, M.D.
Harold W. Koenigsberg, M.D.  
Richard B. Krueger, M.D.  
Steven Lamberti, M.D.
Ruth A. Lanius, M.D.
John Lauriello, M.D.
Anthony Lehman, M.D.  
Michael Linden, M.D.
MarkW. Mahowald, M.D.  
Marsha D. Marcus, Ph.D.  
Stephen Marder, M.D.
Wendy Marsh, M.D.
Michael S. McCloskey, Ph.D.  
Jeffrey Metzner, M.D.
Robert Michels, M.D.
Laura Miller, M.D.
Michael C. Miller, M.D.  
Frederick Moeller, M.D.
Peter T. Morgan, M.D., Ph.D.  
Madhav Muppa, M.D.
Philip Muskin, M.D.

Joachim Nitschke, M.D.  
Abraham Nussbaum, M.D.
Ann Olincy, M.D. ^
Mark Onslow, Ph.D.
Sally Ozonoff, Ph.D.
John R. Peteet, M.D.
Ismene L. Petrakis, M.D.  
Christophe M. Pfeiffer, M.D.  
Karen Pierce, M.D.
Belinda Plattner, M.D.
Franklin Putnam, M.D.
John Racy, M.D.
Phillip Resnick, M.D.
Michele Riba, M.D.
Jerold Rosenbaum, M.D.  
Stephen Ross, M.D.
Lawrence Scahill, M.S.N., Ph.D.  
Daniel Schechter, M.D.
Mary V. Seeman, M.D.  
Alessandro Serretti, M.D.  
Jianhua Shen, M.D.Ravi Kumar R. Singareddy, M.D.  
Gary Small, M.D.
Paul Soloff, M.D.
Christina Stadler, M.D., Ph.D.  
Nada Stotland, M.D.
Neil Swerdlow, M.D.
Kim Tillery, Ph.D.
David Tolin, Ph.D.
Jayne Trachman, M.D.
Luke Tsai, M.D.
Ming T. Tsuang, M.D., Ph.D.  
Richard Tuch, M.D.
Johan Verhulst, M.D.
Michael Weissberg, M.D.  
Godehard Weniger, M.D.
Thomas Wise, M.D.
George E. Woods, M.D.
Kimberly A. Yonkers, M.D.  
Alexander Young, M.D.

DSM-5 Field Trials in Academic Clinical Centers—  
Adult Samples
David Geffen School of Medicine, University of California, Los Angeles
Investigator
Helen Lavretsky, M.D., Principal Investigator
Referring and Interviewing  
Clinicians
Jessica Brommelhoff, Ph.D.
Xavier Cagigas, Ph.D.
Paul Cemin, Ph.D.
Linda Ercoli, Ph.D.
Randall Espinoza, M.D.Helen Lavretsky, M.D.
Jeanne Kim, Ph.D.
David Merrill, M.D.
Karen Miller, Ph.D.
Christopher Nunez, Ph.D.
Research Coordinators
Natalie St. Cyr, M.A., Lead Research  
Nora Nazarian, B.A.
Colin Shinn, M.A.
Centre for Addiction and Mental Health, Toronto, Ontario, Canada
Investigators
Bruce G. Pollock, M.D., Ph.D., Lead Principal  
Investigator  
R. Michael Bagby, Ph.D., Principal Investigator  
Kwame J. McKenzie, M.D., Principal  

Tony P. George, M.D., Co-investigator  
Lena C. Quilty, Ph.D., Co-investigator  
Peter Voore, M.D., Co-investigator
Referring and Interviewing Clinicians
Donna E. Akman, Ph.D.
R. Michael Bagby, Ph.D.
Wayne C. V. Baici, M.D.
Crystal Baluyut, M.D.Eva W. C. Chow, M.D., J.D., M.P.H.
Z. J. Daskalakis, M.D., Ph.D.
Pablo Diaz-Hermosillo, M.D.
George Foussias, M.Sc., M.D.
Paul A. Frewen, Ph.D.
Ariel Graff-Guerrero, M.D., M.Sc., Ph.D.  
Margaret K. Hahn, M.D.
Lorena Hsu, Ph.D.
Justine Joseph, Ph.D.
Sean Kidd, Ph.D.
Mahesh Menon, Ph.D.
Romina Mizrahi, M.D., Ph.D.
Daniel J. Mueller, M.D., Ph.D.
Lena C. Quilty, Ph.D.
Anthony C. Ruocco, Ph.D.

Jorge Soni, M.D.
Aristotle N. Voineskos, M.D., Ph.D.  
George Voineskos, M.D.
Peter Voore, Ph.D.
Chris Watson, Ph.D.
Referring Clinicians
Ofer Agid, M.D.
Ash Bender, M.D.
Patricia Cavanagh, M.D.
Sarah Colman, M.D.
Vincenzo Deluca, M.D.
Justin Geagea, M.D.
David S. Goldbloom, M.D.
Daniel Greben, M.D.
Malati Gupta, M.D.
Ken Harrison, M.D.
Imraan Jeeva, M.D.
Joel Jeffries, M.B.
Judith Laposa, Ph.D.Jan Malat, M.D.
Shelley McMain, Ph.D.
Andriy V. Samokhvalov, M.D., Ph.D.
Martin Strassnig, M.D.
Albert H. C. Wong, M.D., Ph.D.
Gloria I. Leo, M.A., Lead Research Coordinator  
Anissa D. Bachan, B.A.
Bahar Haji-Khamneh, M.A.
Olga Likhodi, M.Sc.
Eleanor J. Liu, Ph.D.
Sarah A. McGee Ng, B.B.A.
other Research Staff
Susan E. Dickens, M.A., Clinical Research  
Manager
Sandy Richards, B.Sc.N., Schizophrenia  
Research Manager
Dallas VA Medical Center, Dallas, Texas
Carol S. North, M.D., M.P.E., Principal  

Manager
Alina Suris, Ph.D., A.B.P.P., Principal  
Barry Ardolf, Psy.D.
Abila Awan, M.D.
Joel Baskin, M.D.
John Black, Ph.D.
Jeffrey Dodds, Ph.D.
Gloria Emmett, Ph.D.
Karma Hudson, M.D.
Jamylah Jackson, Ph.D., A.B.P.P.
Lynda Kirkland-Culp, Ph.D., A.B.P.P.
Heidi Koehler, Ph.D., A.B.P.P.
Elizabeth Lewis, Psy.D.
Aashish Parikh, M.D.
Reed Robinson, Ph.D.
Jheel Shah, M.D.
Geetha Shivakumar, M.D.
Sarah Spain, Ph.D., A.B.P.P.Lisa Thoman, Ph.D.
Lia Thomas, M.D.
Jamie Zabukovec, Psy.D.
Mustafa Zaidi, M.D.
Andrea Zartman, Ph.D.
General Referral Sources
Robert Blake, L.M.S.W.
Evelyn Gibbs, L.M.S.W.
Michelle King-Thompson, L.M.S.W.
Jeannie B. Whitman, Ph.D., Lead Research  
Sunday Adewuyi, M.D.
Elizabeth Anderson, B.A.
Solaleh Azimipour, B.S.

Carissa Barney, B.S.
Kristie Cavazos, B.A.
Robert Devereaux, B.S.
Dana Downs, M.S., M.S.W.
Sharjeel Farooqui, M.D.
Julia Smith, Psy.D.
Kun-Ying H. Sung, B.S.
School of Medicine, The University of Texas San Antonio, 
San Antonio, Texas
Mauricio Tohen, M.D., Dr.P.H., M.B.A.,  
Principal Investigator
Suman Baddam, Psy.D.
Charles L. Bowden, M.D.Nancy Diazgranados, M.D., M.S.  
Craig A. Dike, Psy.D.
Dianne E. Dunn, Psy.D., M.P.H.  
Elena Gherman, M.D.
Jodi M. Gonzalez, Ph.D.
Pablo Gonzalez, M.D.
Phillip Lai, Psy.D.

Natalie Maples-Aguilar, M.A., L.P.A.  
Marlon P. Quinones, M.D.
Jeslina J. Raj, Psy.D.
David L. Roberts, Ph.D.
Nancy Sandusky, R.N., F.P.M.H.N.P.-B.C.,
D.N.P.-C.
Donna S. Stutes, M.S., L.P.C.
Mauricio Tohen, M.D., Dr.PH, M.B.A.  
Dawn I. Velligan, Ph.D.
Weiran Wu, M.D., Ph.D.
Albana Dassori, M.D.
Megan Frederick, M.A.Robert Gonzalez, M.D.
Uma Kasinath, M.D.
Camis Milam, M.D.
Vivek Singh, M.D.
Peter Thompson, M.D.
Melissa Hernandez, B.A., Lead Research  
Fermin Alejandro Carrizales, B.A.  
Martha Dahl, R.N., B.S.N.
Patrick M. Smith, B.A.
Nicole B. Watson, M.A.
Michael E . DeBakey VA Medical Center and the Menninger Clinic, 
Houston, Texas (Joint Study Site)
Michael E. DeBakey VA Medical Center
Laura Marsh, M.D., Principal Investigator
Shalini Aggarwal, M.D.
Su Bailey, Ph.D.
Minnete (Helen) Beckner, Ph.D.
Crystal Clark, M.D.
Charles Dejohn, M.D.
Robert Garza, M.D.

Aruna Gottumakkla, M.D.
Janet Hickey, M.D.
James Ireland, M.D.
Mary Lois Lacey, A.P.R.N.
Wendy Leopoulos, M.D.
Deleene Menefee, Ph.D.
Brian I. Miller, Ph.D.
Candy Smith, Ph.D.
Avila Steele, Ph.D.
Jill Wanner, Ph.D.
Rachel Wells, Ph.D.
Kaki York-Ward, Ph.D.Referring Clinicians
Sara Allison, M.D.
Leonard Denney, L.C.S.W.
Catherine Flores, L.C.S.W.
Nathalie Marie, M.D.
Christopher Martin, M.D.
Sanjay Mathev^, M.D.
Erica Montgomery, M.D.
Gregory Scholl, P.A.
Jocelyn Ulanday, M.D., M.P.H.
Sarah Neely Torres, B.S., Lead Research  
Kathleen Grout, M.A.
Lea Kiefer, M.P.H.
Jana Tran, M.A.
Volunteer Research Assistants
Catherine Clark  
Linh Hoang
Menninger Clinic
Efrain Bleiberg, M.D., Principal Investigator
Refening and Interviewing Clinicians

Linh Hoang
Jennifer Baumgardner, Ph.D.
Elizabeth Dodd Conaway, L.C.S.W., B.C.D.  
Warren Christianson, D.O.
Wesley Clayton, L.M.S.W.
J. Christopher Fowler, Ph.D.
Michael Groat, Ph.D.
Edythe Harvey, M.D.
Denise Kagan, Ph.D.
Hans Meyer, L.C.S.W.Segundo Robert-Ibarra, M.D.
Sandhya Trivedi, M.D.
Rebecca Wagner, Ph.D.
Harrell Woodson, Ph.D.
Amanda Yoder, L.C.S.W.
James Flack, M.D.
David Ness, M.D.
Steve Herrera, B.S., M.T., Lead Research  
Allison Kalpakci, B.A.

Mayo Clinic, Rochester, Minnesota
Mark A. Frye, M.D., Principal Iiwestigator  
Glenn E. Smith, Ph.D., Principal Investigator  
Jeffrey P. Staab M.D., M.S., Principal  
Osama Abulseoud, M.D.
Jane Cerhan, Ph.D.
Julie Fields, Ph.D.
Mark A. Frye, M.D.
Manuel Fuentes, M.D.
Yonas Geda, M.D.
Maria Harmandayan, M.D.
Reba King, M.D.
Simon Kung, M.D.
Mary Machuda, Ph.D.
Donald McAlpine, M.D.
Alastair McKean, M.D.
Juliana Moraes, M.D.
Teresa Rummans, M.D.James R. Rundell, M.D.
Richard Seime, Ph.D.
Glenn E. Smith, Ph.D.
Christopher Sola, D.O.
Jeffrey P. Staab M.D., M.S.
Marin Veldic, M.D.
Mark D. Williams, M.D.
Maya Yustis, Ph.D.
Lisa Seymour, B.S., Lead Research Coordinator  
Scott Feeder, M.S.
Lee Gunderson, B.S.
Sherrie Hanna, M.A., L.P.
Kelly Harper, B.A.
Katie Mingo, B.A.
Cynthia Stoppel, A.S.
other Study Staff
Anna Frye  
Andrea Hogan
Perelman School of Medicine, University of Pennsylvania,

Anna Frye  
Perelman School of Medicine, University of Pennsylvania, 
Philadelphia, Pennsylvania
Mahendra T. Bhati, M.D., Principal Investigator  
Mama S. Barrett, Ph.D., Co-investigator  
Michael E. Thase, M.D., Co-investigator
Peter B. Bloom, M.D.
Nicole K Chalmers L.C.S.W.
Torrey A. Creed, Ph.D.
Mario Cristancho, M.D.
Amy Cunningham, Psy.D.
John P. Dennis, Ph.D.
Josephine Elia, M.D.
Peter Gariti, Ph.D., L.C.S.W.
Philip Gehrman, Ph.D.
Laurie Gray, M.D.
Emily A.P. Haigh, Ph.D.
Nora J. Johnson, M.B.A., M.S., Psy.D.
Paulo Knapp, M.D.
Yong-Tong Li, M.D.
Bill Mace, Ph.D.
Kevin S. McCarthy, Ph.D.
Dimitri Perivoliotis, Ph.D.
Luke Schultz, Ph.D.
Tracy Steen, Ph.D.
Chris Tjoa, M.D.
Nancy A. Wintering, L.C.S.W.
Eleanor Ainslie, M.D.
Kelly C. Allison, Ph.D.Rebecca Aspden, M.D.  
Claudia F. Baldassano, M.D.

Claudia F. Baldassano, M.D.  
Vijayta Bansal, M.D.
Rachel A. Bennett, M.D.  
Richard Bollinger, Ph.D.  
Andrea Bowen, M.D.
Karla Campanella, M.D.  
Anthony Carlino, M.D.
Noah Carroll, M.S.S.
Alysia Cirona, M.D.
Samuel Collier, M.D.  
Andreea Crauciuc, L.C.S.W.  
Pilar Cristancho, M.D.
Traci D'Almeida, M.D.  
Kathleen Diller, M.D.
Benoit Dube, M.D.
Jon Dukes, M.S.W.
Lauren Elliott, M.D.
Mira Elwell, B.A.
Mia Everett, M.D.
Lucy F. Faulconbridge, Ph.D.  
Patricia Furlan, Ph.D.
Joanna Goldstein, L.C.S.W.  
Paul Grant, Ph.D.
Jillian Graves, L.C.S.W.  
Tamar Gur, M.D., Ph.D.
Alisa Gutman, M.D., Ph.D.  
Nora Hymowitz, M.D.
Sofia Jensen, M.D.
Tiffany King, M.S.W.  
Katherine Levine, M.D.

Alice Li, M.D.
Janet Light, L.C.S.W.
John Listerud, M .D y, Ph.D.  
Emily Malcoun, Ph.D.  
Donovan Maust, M.D.
Adam Meadows, M.D.  
Michelle Moyer, M.D.  
Rebecca Naugle, L.C.S.W.  
Cory Newman, Ph.D.
John Northrop, M.D., Ph.D.  
Elizabeth A. ElUs Ohr, Psy.D.  
John O'Reardon, M.D.  
Abraham Pachikara, M.D.  
Andrea Perelman, M.S.W.  
Diana Perez, M.S.W.
Bianca Previdi, M.D.
J. Russell Ramsay, Ph.D.  
Jorge Rivera-Colon, M.D.
Jan Smedley, L.C.S.W.
Katie Struble, M.S.W.
Aita Susi, M.D.
Yekaterina Tatarchuk, M.D.  
Ellen Tarves, M.A.
Allison Tweedie, M.D.
Holly Valerio, M.D.Thomas A. Wadden, Ph.D.
Joseph Wright, Ph.D.
Yan Xuan, M.D.
David Yusko, Psy.D.
Jordan A. Coello, B.A., Lead Research  
Eric Wang, B.S.E.
Volunteer Research Assistants/  
Interns
Jeannine Barker, M.A., A.T.R.
Jacqueline Baron  
Kelsey Bogue  
Alexandra Ciomek  
Martekuor Dodoo, B.A.
Julian Domanico  
Laura Heller, B.A.
Leah Hull-Rawson, B.A.
Jacquelyn Klehm, B.A.
Christina Lam

Christina Lam  
Dante Proetto, B.S.
Molly Roy  
Casey Shannon
Stanford University Scliool of Medicine, Stanford, California
Carl Feinstein, M.D., Principal Investigator  
Debra Safer, M.D., Principal Investigator
Kari Berquist, Ph.D.
Eric Clausell, Ph.D.
Danielle Colbom, Ph.D.
Whitney Daniels, M.D.
Ahson Darcy, Ph.D.
Krista Fielding, M.D.
Mina Fisher, M.D.
Kara Fitzpatrick, Ph.D.
Wendy Froehlich, M.D.
Grace Gengoux, Ph.D.
Anna Cassandra Golding, Ph.D.
Lisa Groesz, Ph.D.
Kyle Hinman, M.D.
Rob Holaway, Ph.D.
Matthew Holve, M.D.
Rex Huang, M.D.
Nina Kirz, M.D.
Megan Klabunde, Ph.D.
John Leckie, Ph.D.
Naomi Leslie, M.D.
Adrianne Lona, M.D.
Ranvinder Rai, M.D.
Rebecca Rialon, Ph.D.
Beverly Rodriguez, M.D., Ph.D.
Debra Safer, M.D.
Mary Sanders, Ph.D.Jamie Scaletta, Ph.D.

Norah Simpson, Ph.D.
Manpreet Singh, M.D.
Maria-Christina Stewart, Ph.D.
Melissa Valias, M.D.
Patrick Whalen, Ph.D.
Sanno Zack, Ph.D.
Robin Apple, Ph.D.
Victor Carrion, M.D.
Carl Feinstein, M.D.
Qhristine Gray, Ph.D.
Antonio Hardan, M.D.
Megan Jones, Psy.D.
Linda Lotspeich, M.D.
Lauren Mikula, Psy.D.
Brandyn Street, Ph.D.
Violeta Tan, M.D.
Heather Taylor, Ph.D.
Jacob Towery, M.D.
Sharon Williams, Ph.D.
Kate Amow, B.A., Lead Research Coordinator  
Nandini Datta, B.S.
Stephanie Manasse, B.A.
Interns
Arianna Martin, M .S.
Adriana Nevado, B.A.

Children’s Hospital Colorado, Aurora, Colorado
Marianne Wamboldt, M.D., Principal  
Galia Abadi, M.D.
Steven Behling, Ph.D.
Jamie Blume, Ph.D.
Adam Burstein, M.D.
Debbie Carter, M.D.
Kelly Caywood, Ph.D.
Meredith Chapman, M.D.
Paulette Christian, A.P.P.M.H.N.  
Mary Cook, M.D.
Anthony Cordaro, M.D.
Audrey Dumas, M.D.
Guido Frank, M.D.
Karen Frankel, Ph.D.
Darryl Graham, Ph.D.
Yael Granader, Ph.D.
Isabelle Guillemet, M.D.
Patrece Hairston, Ph.D.
Charles Harrison, Ph.D.
Tammy Herckner, L.C.S.W.
Cassie Karlsson, M.D.
Kimberly Kelsay, M.D.
David Kieval, Ph.D.
Jaimelyn Kost, L.C.S.W.
Harrison Levine, M.D.
Raven Lipmanson, M.D.
Susan Lurie, M.D.
Asa Marokus, M.D.
Idalia Massa, Ph.D.
Christine McDunn, Ph.D.
Scot McKay, M.D.
Marissa Murgolo, L.C.S.W.
Alyssa Oland, Ph.D.
Lina Patel, Ph.D.
Rheena Pineda, Ph.D.
Gautam Rajendran, M.D.
Diane Reichmuth, Ph.D  
Michael Rollin, M.D.Marlena Romero, L.C.S.W.

Michelle Roy, Ph.D.
Celeste St. John-Larkin, M.D.
Elise Sannar, Ph.D.
Daniel Savin, M.D.
Claire Dean Sinclair, Ph.D.
Ashley Smith, L.C.S.W.
Mindy Solomon, Ph.D.
Sally Tarbell, Ph.D.
Helen Thilly, L.C.S.W.
Sara Tlustos-Carter, Ph.D.
Holly Vause, A.P.P.M.H.N  
Mariarme Wamboldt, M.D.
Angela Ward, L.C.S.W.
Jason Williams, Ph.D.
Jason Willoughby, Ph.D.
Brennan Young, Ph.D.
Kelly Bhatnagar, Ph.D.
Jeffery Dolgan, Ph.D.
Jennifer Eichberg, L.C.S.W.
Jennifer Hagman, M.D.
James Masterson, L.C.S.W.
Hy Gia Park, M.D.
Tami Roblek, Ph.D.
Wendy Smith, Ph.D.
David Williams, M.D.
Laurie Burnside, M.S.M., C.C.R.C., Lead  
Research Coordinator  
Darci Anderson, B.A., C.C.R.C.
Heather Kennedy, M.P.H.
Amanda Millar, B.A.
Vanessa Waruinge, B.S.
Elizabeth Wallace, B.A.

Interns
Wisdom Amouzou  
Ashley Anderson  
Michael Richards  
Mateya Whyte
Baystate Medioal Center, Springfield, Massachusetts
Bruce Waslick, M.D., Principal Investigator  
Cheryl Bonica, Ph.D., Co-investigator  
John Fanton, M.D., Co-investigator  
Barry Sarvet, M.D., Co-investigatorReferring and Interviewing Clinicians
Julie Bermant, R.N., M.S.N., N.P.
Cheryl Bonica, Ph.D.
Jodi Devine, L.I.C.S.W.
William Fahey, Ph.D.
John Fanton, M.D.

Stephane Jacobus, Ph.D.
Barry Sarvet, M.D.
Peter Thunfors, Ph,.D .
Bruce Waslick, M.D.
Vicki Weld, L.I.C.S.W.
Sara Wiener, L.I.C.S.W.
Shadi Zaghloul, M.D.
Sarah Detenber, L.I.C.S.W.
Gordon Garrison, L.I.C.S.W.
Jacqueline Humpreys, L.I.C.S.W.
Noreen McGirr, L.I.C.S.W.
New York state Psychiatric Institute, New York, N.Y., Weill Cornell 
Medical College, Payne Whitney and Westchester Divisions, New York 
and White Plains, N.Y., and North Shore Child and Family Guidance 
Center, Roslyn Heights, N.Y. (Joint Study Site)Sarah Marcotte, L.C.S.W.
Patricia Rogowski, R.N., C.N.S.
Julie Kingsbury, C.C.R.P., Lead Research  
Brenda Martin, B.A.
Volunteer Research Assistant/  
Intern
Liza Detenber
Prudence W. Fisher, Ph.D., Principal  
Julia K. Carmody, B.A., Lead Research  
Zvi R. Shapiro, B.A., Lead ResearchVolunteers
Preeya Desai  
Samantha Keller  
Jeremy Litfin, M.A.

Jeremy Litfin, M.A.  
Sarah L. Pearlstein, B.A.  
Cedilla Sacher
Coordinator
New York State Psychiatric Institute
Michele Cohen, L.C.S.W.
Eduvigis Cruz-Arrieta, Ph.D.
Miriam Ehrensaft, Ph.D.
Laurence Greenhill, M.D.
Schuyler Henderson, M.D., M.P.H.
Sharlene Jackson, Ph.D.
Lindsay Moskowitz, M.D.
Sweene C. Oscar, Ph.D.
Xenia Protopopescu, M.D.
James Rodriguez, Ph.D.
Gregory Tau, M.D.
Melissa Tebbs, L.C.S.W.
Carolina Velez-Grau, L.C.S.W.
Khadijah Booth Watkins, M.D.
George Alvarado, M.D.
Alison Baker, M.D.
Elena Baron, Psy.D.
Lincoln Bickford, M.D., Ph.D.
Zachary Blumkin, Psy.D.
Colleen Cullen, L.C.S.W.
Chyristianne DeAlmeida, Ph.D.
Matthew Ehrlich, M.D.Eve Friedl, M.D.
Clare Gaskins, Ph.D.
Alice Greenfield, L.C.S.W.
Liora Hoffman, M.D.
Kathleen Jung, M.D.

Karimi Mailutha, M.D., M.P.H.  
Valentina Nikulina, Ph.D.
Tal Reis, Ph.D.
Moira Rynn, M.D.
Jasmine Sawhney, M.D.
Sarajbit Singh, M.D.
Katherine Stratigos, M.D.  
Oliver Stroeh, M.D.
Russell Tobe, M.D.
Meghan Tomb, Ph.D.
Michelle Tricamo, M.D.
Angel A. Caraballo, M.D.
Erica M. Chin, Ph.D.
Daniel T. Chrzanowski, M.D.  
Tess Dougherty, B.A.
Stephanie Hundt, M.A.
Moira A. Rynn, M.D.
Deborah Stedge, R.N.

Weill Cornell Medical College, Payne Whitney and Westchester Divisions
Archana Basu, Ph.D.
Shannon M. Bennett, M.D.
Maria De Pena-Nowak, M.D.
Jill Feldman, L.M.S.W.
Dennis Gee, M.D.
Jo R. Hariton, Ph.D.
Lakshmi P. Reddy, M.D.
Margaret Yoon, M.D.
Margo Benjamin, M.D.
Vanessa Bobb, M.D.
Elizabeth Bochtler, M.D.
Katie Cave, L.C.S.W.
Maalobeeka Gangopadhyay, M.D.Jodi Gold, M.D.
Tejal Kaur, M.D.
Aaron Krasner, M.D.
Amy Miranda, L.C.S.W.
Cynthia Pfeffer, M.D.
James Rebeta, Ph.D.
Sharon Skariah, M.D.
Jeremy Stone, Ph.D.
Dirk Winter, M.D.
Alex Eve Keller, B.S., Lead Research Coordinator  
Nomi Bodner (volunteer)
Barbara L. Flye, Ph.D.
Jamie S. Neiman (volunteer)
Rebecca L. Rendleman, M.D.
North Shore Child and Family Guidance Center
Casye Brachfeld-Launer, L.C.S.W.
Susan Klein Cohen, Ph.D.
Amy Gelb, L.C.S.W.-R.
Jodi Glasser, L.C.S.W.
Elizabeth Goulding-Tag, L.C.S.W.

Deborah B. Kassimir, L.C.S.W.
Margo Posillico Messina, L.C.S.W.
Andréa Moullin-Heddle, L.M.S.W.
Lisa Pineda, L.C.S.W.
Elissa Smilowitz, L.C.S.W.
Regina Barros-Rivera, L.C.S.W.-R. Assistant  
Executive Director  
Maria Christiansen, B.S.
Amy Davies-Hollander, L.M.S.W.
Eartha Hackett, M.S.Ed., M.Sc., B.Sc.Bruce Kaufstein, L.C.S.W.-R, Director of  
Clinical Services  
Kathy Knaust, L.C.S.W.
John Levinson, L.C.S.W.-R, B.C.D.  
Andrew Maleckoff, L.C.S.W., Executive  
Director/CEO  
Sarah Rosen, L.C.S.W.-R, A.C.S.W.  
Abigail Rothenberg, L.M.S.W.
Christine Scotten, A.C.S.W.
Michelle Spatano, L.C.S.W.-R.
Diane Straneri, M.S., R.N., C.S.
Rosara Torrisi, L.M.S.W.
Rob Vichnis, L.C.S.W.
Toni Kolb-Papetti, L.C.S.W.
Sheena M. Dauro (volunteer)
DSM-5 Field Trials Pilot Study,

DSM-5 Field Trials Pilot Study,  
Johns Hopkins Medical institution, Baltimore, Maryland
A d u lt S am ple
Community Psychiatry Outpatient Program, Department of Psychiatry 
and Behavioral Sciences Main Campus
Bernadette Cullen, M.B., B.Ch., B.A.O.,  
Principal Investigator  
Holly C. Wilcox, Ph.D., Principal Investigator
Bernadette Cullen, M.B., B.Ch., B.A.O.
Shane Grant, L.C.S.W.-C.
Charee Green, L.C.P.C.Emily Lorensen, L.C.S.W.-C.  
Kathleen Malloy, L.C.P.C.
Gary Pilarchik, L.C.S.W.-C  
Holly Slater, L.C.P.C.
Stanislav Spivak, M.D.
Tarcia Spencer Turner, L.C.P.C.  
Nicholas Seldes Windt, L.C.S.W.-C.
Mellisha McKitty, B.A.
Alison Newcomer, M.H.S.

P e d ia tric S a m ple
Child and Adölescent Outpatient Program, Department of Psycliiatry and 
Behavioral Sciences Bayview Medical Center
Joan P. Gerring, M.D., Principal Investigator  
Leslie Miller, M.D., Principal Investigator  
Holly C. Wilcox, Ph.D., Co-investigator
Shannon Barnett, M.D.
Gwen Condon, L.C.P.C.
Brijan Fellows, L.C.S.W.-C.
Heather Gamer, L.C.S.W.-C.
Joan P. Gerring, M.D.Anna Gonzaga, M.D.
Debra Jenkins, L.C.S.W.-C.  
Paige N. Johnston, L.C.P.C.  
Brenda Memel, D.N.P., R.N.  
Leslie Miller, M.D.
Ryan Moore, L.C.S.W.-C.  
Shauna Reinblatt, M.D.  
Monique Vardi, L.C.P.C.
DSM-5 Field Trials in Routine Clinical Practice Settings:  
Collaborating Investigators
Archil Abashidze, M.D.
Francis R. Abueg, Ph.D.
Jennifer Louise Accuardi, M.S.
Balkozar S. Adam, M.D.
Miriam E. Adams, Sc.D., M.S.W., L.I.C.S.W.  
Suzanna C. Adams, M.A.
Lawrence Adler, M.D.

Rownak Afroz, M.D.
Khalid I. Afzal, M.D.
Joseph Alimasuya, M.D.
Emily Allen, M.S.
Katherine A. Allen, L.M.F.T., M.A.
William D. Allen, M.S.
Jafar AlMashat, M.D.
Anthony T. Alonzo, D.M.F.T.
Guillermo Alvarez, B.A., M.A.
Angela Amoia-Lutz, L.M.F.T.
Krista A. Anderson, M.A., L.M.F.T.
Lisa R. Anderson, M.Ed., L.C.P.C.
Pamela M. Anderson, L.M.F.T.
Shannon N. Anderson, M.A., L.P.C., N.C.C.  
Eric S. Andrews, M.A.
Vicki Arbuckle, M.S., Nursing(N.P.)
Namita K. Arora, M.D.
Darryl Arrington, M.A.
Bearlyn Y. Ash, M.S.
Wylie J. Bagley, Ph.D.
Kumar D. Bahl, M.D.
Deborah C. Bailey, M.A., M.S., Ph.D.  
Carolyn Baird, D.N.P., M.B.A., R.N.-B.C.,  
C.A.R.N.-A.P., I.C.C.D.P.D.
Joelle Bangsund M.S.W.
Maria Baratta, M.S.W., Ph.D.
Stan Barnard, M.S.W.
Deborah Barnes, M.S.Margaret L. Barnes, Ph.D.
David Bamum, Ph.D.

Raymond M. Baum, M.D.
Edward Wescott Beal, M.D.
Michelle Beaudoin, M.A.
Ernest E. Beckham, Ph.D.
Lori L. Beckwith, M.Ed  
Emmet Bellville, M.A.
Randall E. Bennett, M.A.
Lynn Benson, Ph.D.
Robert Scott Benson, M.D.
Linda Benton, M.S.W.
Ditza D. Berger, Ph.D.
Louise I. Bertman, Ph.D.
Robin Bieber, M.S., L.M.F.T.
Diana M. Bigham, M.A.
David R. Blackburn, Ph.D.
Kelley Blackwell, L.M.F.T.
Lancia Blatchley, B.A., L.M.F.T.
Stacey L. Block, L.M.S.W., A.C.S.W.  
Karen J. Bloodworth, M.S., N.C.C., L.P.C.  
Lester Bloomenstiel, M.S.
Christine M. Blue, D.O.
Marina Bluvshtein, Ph.D.
Callie Gray Bobbitt, M.S.W., L.C.S.W.  
Moses L. Boone, Jr., L.M.S.W., B.C.D.  
Steffanie Boudreau-Thomas, M.A.-L.P.C.  
Jay L. Boulter, M.A.
Aaron Daniel Bourne, M.A.
Helen F. Bowden, Ph.D.
Aryn Bowley-Safranek, B.S., M.S.  
Elizabeth Boyajian, Ph.D.

Beth K. Boyarsky, M.D.
Gail M. Boyd, Ph.D.
Jeffrey M. Brandler, Ed.S., C.A.S., S.A.P.

Sandra L. Branton, Ed.D.
Karen J. Brocco-Kish, M.D.
Kristin Brooks, P.M.H.N.P.
Ann Marie Brown, M.S.W.
Philip Brown, M.S.W.
Kellie Buckner, Ed.S.
Richard Bunt, M.D.
Neil P. Buono, D.Min.
Janice Bureau, M.S.W., L.C.S.W.
Kimlee Butterfield, M.S.W.
Claudia Byrne, Ph.D.
Quinn Callicott, M.S.W., L.C.S.W.
Alvaro Camacho, M.D., M.P.H.
Sandra Cambra, Ph.D.
Heather Campbell, M.A.
Nancy Campbell, Ph.D., M.S.W.
Karen Ranee Canada, L.M.F.T.
Joseph P. Cannavo, M.D.
Catherine P. Caporale, Ph.D.
Frederick Capps, Ph.D., M.S.
Rebecca J. Carney, M.B.A., M.A., L.M.H.C.  
Kelly J. Carroll, M.S.W.
Richard W. Carroll, Ph.D., L.P.C., A.C.S.  
Sherry Casper, Ph.D.
Joseph A. Catania, L.I.S.W.S., L.C.D.C. Ill  
Manisha P. Cavendish, Ph.D.
Kenneth M. Certa, M.D.
Shambhavi Chandraiah, M.D.
Calvin Chatlos, M.D.
Daniel C. Chen, M.D.
Darlene Cheryl, M.S.W.
Matthew R. Chirman, M.S.
Carole A. Chisholm, M.S.W.
Shobha A. Chottera, M.D.
Joseph Logue Christenson, M.D.
Pamela Christy, Psy.D.

Sharon M. Freeman Clevenger, Ph.D.,  
P.M.H.C.N.S.-B.C.
Mary Ann Cohen, M.D.
Mitchell J. Cohen, M.D.
Diego L. Coira, M.D.
Melinda A. Lawless Coker, Psy.D.
Carol Cole, M.S.W., L.C.S.W.
Caron Collins, M.A., L.M.F.T.
Wanda Collins, M.S.N.
Linda Cook Cason, M.A.
Ayanna Cooke-Chen, M.D., Ph.D.
Heidi B. Cooperstein, D.O.
Ileana Corbelle, M.S.W.
Kimberly Corbett, Ph.D.
Angelina Cordova, M.A.Ed.
Jennifer Carol Cox, L.P.C.
Sheree Cox, M.A., R.N., N.C.C., D.C.C.,  
L.M.H.C.
William Frederick Cox, M.D.
Sally M. Cox, M.S.Ed.
Debbie Herman Crane, M.S.W.
Arthur Ray Crawford, III, Ph.D.Roula Creighton, M.D.
John R. Crossfield, L.M.H.C.
Sue Cutbirth, R.N., M.S.N, C.S., P.M.H.N.P.  
Marco Antonio Cuyar, M.S.
Rebecca Susan Daily, M.D.
Lori S. Danenberg, Ph.D.
Chan Dang-Vu, M.D.
Mary Hynes Danielak, Psy.D.

Cynthia A. Darby, M.Ed., Ed.S.
Douglas Darnall, Ph.D.
Christopher Davidson, M.D.
Doreen Davis, Ph.D., L.C.S.W.
Sandra Davis, Ph.D., L.M.H.C., N.C.C.
Walter Pitts Davis, M.Th.
Christian J. Dean, Ph.D.
Kent Dean, Ph.D.
Elizabeth Dear, M.A.
Shelby DeBause, M.A.
Rebecca B. DeLaney, M.S.S.W., L.C.S.W., B.C.D.  
John R. Delatorre, M.A.
Frank DeLaurentis, M.D.
Eric Denner, M.A., M.B.A.
Mary Dennihan, L.M.F.T.
Kenny Dennis, M.A.
Pamela L. Detrick, Ph.D., M.S., F.N.P.-B.C.,  
P.M.H.N.P.-B.C., R.N.-B.C., C.A.P.,
G.C.A.C.
Robert Detrinis, M.D.
Daniel A. Deutschman, M.D.
Tania Diaz, Psy.D.
Sharon Dobbs, M.S.W., L.C.S.W.
David Doreau, M.Ed.
Gayle L. Dosher, M.A.
D’Ann Downey, Ph.D., M.S.W.
Beth Doyle, M.A.
Amy J. Driskill, M.S., L.C.M.F.T.
James Drury, M.D.
Brenda-Lee Duarte, M.Ed.

Shane E. Dulemba, M.S.N.
Nancy R. G. Dunbar, M.D.
Cathy Duncan, M.A.
Rebecca S. Dunn, M.S.N., A.R.N.P.
Debbie Earnshaw, M.A.
Shawna Eddy-Kissell, M.A.
Momen El Nesr, M.D.
Jeffrey Bruce Elliott, Psy.D.
Leslie Ellis, Ph.D.
Donna M. Emfield, L.C.P.C.
Gretchen S. Enright, M.D.
John C. Espy, Ph.D.
Renuka Evani, M.B.B.S., M.D.
Heather Evans, M.S.Ed, L.P.C.N.C.C.
Cesar A. Fabiani, M.D.
Fahim Fahim, M.D.
Samuel Fam, M.D.
Edward H. Fankhanel, Ph.D., Ed.D.
Tamara Farmer, M.S.N, A.R.N.P.
Farida Farzana, M.D.

Philip Fast, M.S.
Patricia Feltrup-Exum, M.A.M.F.T.  
Hector J. Femandez-Barillas, Ph.D.
Julie Ferry, M.S.W., L.I.C.S.W.
Jane Fink, Ph.D., M.S.S.A.
Kathy Finkle, L.P.C.M.H.
Steven Finlay, Ph.D.
Rik Fire, M.S.W., L.C.S.W.
Ann Flood, Ph.D.
Jeanine Lee Foreman, M.S.
Thyra Fossum, Ph.D.
Karen S. Franklin, L.I.C.S.W.
Sherre K. Franklin, M.A.
Helen R. Frey, M.A., E.D.
Michael L. Freytag, B.S., M.A.
Beth Gagnon, M.S.W.
Patrice L.R. Gallagher, Ph.D.
Angela J. Gallien, M.A.
Robert Gallo, M.S.W.
Mario Galvarino, M.D.
Vladimir L Gasca, M.D.
Joshua Gates, Ph.D.
Anthony Gaudioso, Ph.D.
Michelle S. Gauthier, A.P.R.N., M.S.N,  
P.M.H.N.P.-B.C.
Rachel E. Gearhart, L.C.S.W.
Stephen D. Gelfond, M.D.
Nancy S. Gerow, M.S.
Michael J. Gerson, Ph.D.
Susan M. A. Geyer, L.M.S.W.
Lorrie Gfeller-Strouts, Ph.D.
Shubu Ghosh, M.D.
Richard Dorsey Gillespie, M.Div.
Stuart A. Gitlin, M.S.S.A.
Jeannette E. Given, Ph.D.
Frances Gizzi, L.C.S.W.
Stephen L Glicksman, Ph.D.
Martha Glisky, Ph.D.
Sonia Godbole, M.D.

Howard M. Goldfischer, Psy.D.
Mary Jane Gonzalez-Huss, Ph.D.  
Michael L Good, M.D.
Dawn Goodman-Martin, M.A.-L.M.H.C.  
Robert Gorkin, Ph.D., M.D.
JeffGorski, M.S.W.
Linda O. Graf, M.Ed., L.C.P.C.
Ona Graham, Psy.D.
Aubrie M. Graves, L.M.S.W., C.A.S.A.C.  
Howard S. Green, M.D.
Karen Torry Green, M.S.W.
Gary Greenberg, Ph.D.
Marjorie Greenhut, M.A.
James L. Greenstone, Ed.D., J.D.  
Raymond A. Griffin, Ph.D.
Joseph Grillo, Ph.D.
Janeane M. Grisez, A.A., B.A.
Robert J. Gross, M.D.Sally J. Grosscup, Ph.D.
Philip A. Grossi, M.D.
Gabrielle Guedet, Ph.D.
Nicholas Guenzel, B.A., B.S., M.S.N.
Mary G. Hales, M.A.
Tara C. Haley, M.S., L.M.F.T.
John D. Hall, M.D.
Amy Hammer, M.S.W.
Michael S. Hanau, M.D.
Linda K.W. Hansen, M.A., L.P.
Genevieve R. Hansler, M.S.W.

Mary T. Harrington, L.C.S.W.
Lois Hartman, Ph.D.
Steven Lee Hartsock, Ph.D., M.S.W.
Victoria Ann Harwood, M.S.W., L.C.S.W.  
Rossi A. Hassad, Ph.D., M.P.H.
Erin V. Hatcher, M.S.N.
Richard L. Hauger, M.D.
Kimberly M. Haverly, M.A.
Gale Eisner Heater, M.S., M.F.T.
Katlin Hecox, M.A.
Brenda Heideman, M.S.W.
Melinda Heinen, M.Sc.
Marie-Therese Heitkamp, M.S.
Melissa B. Held, M.A.
Jessica Hellings, M.D.
Bonnie Helmick-O'Brien, M.A., L.M.F.T.  
MaLinda T. Henderson, M.S.N, F.P.M.H.N.P.  
Gwenn Herman, M.S.W.
Martha W. Hernandez, M.S.N, A.P.R.N.,  
P.M.H.C.N.S.
Robin L. Hewitt, M.S.
Kenneth Hoffman, Ph.D.
Patricia E. Hogan, D.O.
Peggy Holcomb, Ph.D.
Garland H. Holloman, Jr., M.D.
Kimberly Huegel, M.S.W., L.C.S.W.
Jason Hughes, L.P.C.-S., N.C.C.
Jennifer C. Hughes, Ph.D., M.S.W., L.LS.W.-S.  
Michelle K. Humke, M.A.

Judith G. Hunt, L.M.F.T.
Tasneem Hussainee, M.D.
Sharlene J. Hutchinson, M.S.N.
Muhammad Ikram, M.D.
Sunday Ilechukwu, M.D., D.Psy. Cli.
Douglas H. Ingram, M.D.
Marilynn Irvine, Ph.D.
Marjorie Isaacs, Psy.D.
Raymond Isackila, Ed.S., P.C.C.-S., L.I.C.D.C.  
Mohammed A. Issa, M.D.
John L. Jankord, M.A.
Barbara P. Jannah, L.C.S.W.
C. Stuart Johnson, M.S.
Dawn M. Johnson, M.A.
Deanna V. Johnson, M.S., A^P.R.N., B.C.
Eric C. Johnson, M.F.T.
Joy Johnson, Ph.D., L.C.S.W.
Willard Johnson, Ph.D.

Xenia Johnson-Bhembe, M.D.
Vann S. Joines, Ph.D.
Margaret Jones, Psy.D.
Patricia Jorgenson, M.S.W.
Steven M. Joseph, M.D.
Taylere Joseph, M.A.
Jeanette M. Joyner-Craddock, M.S.S.W.
Melissa Kachapis, M.A.
Charles T. Kaelber, M.D.
Aimee C. Kaempf, M.D.
Peter Andrew Kahn, M.D.
Robert P. Kahn-Rose, M.D.
Maher Karam-Hage, M.D.
Todd H. Kasdan, Ph.D.
Karen Kaufman, M.S., L.M.F.T.
Rhesa Kaulia, M.A., M.F.T.
Debbie Lynn Kelly, M.S.N, P.M.H.N.P.-B.C.
W. Stephen Kelly, Ph.D.
Selena Kennedy, M.A.
Judith A. Kenney, M.S., L.P.C.
Mark Patrick Kerekes, M.D.
Alyse Kerr, M.S., N.C.C., N.A.D.D.-C.C., L.P.C.  
Karen L. Kerschmann, L.C.S.W.
Marcia Kesner, M.S.
Ashan Khan, Ph.D.
Shaukat Khan, M.D.
Audrey Khatchikian, Ph.D.
Laurie B. Kimmel, M.S.W.
Jason H. King, Ph.D.
Nancy Leigh King, M.S.W., L.C.S.W., L.C.A.S.  
Kyle Kinne, M.S.C  
Cassandra M. Klyman, M.D.
David R. Knapp, L.C.S.W.
Margaret Knerr, M.S.
Michael R. Knox, Ph.D.
Carolyn Koblin, M.S.
Valerie Kolbert, M.S., A.R.N.P.-B.C.
Heather Koontz, M.S.W.

Faye Koop, Ph.D., L.C.M.F.T.
Fern M. Kopakin, M.S.W., L.C.S.W.
Joel Kotin, M.D.
Sharlene K. Kraemer, M.S.E.
Marjorie Vego Krausz, M.A., Ed.D.
Nancy J. Krell, M.S.W.
Mindy E. Kronenberg, Ph.D.
EHvayne Kruse, M.S., M.F.T.
Ajay S. Kuchibhatla, M.D.
Shubha N. Kumar, M.D.
Helen H. Kyomen, M.D., M.S.
Rebecca M. Lachut, M.Ed., Ed.S.
Alexis Lake, M.S.S.
Ramaswamy Lakshmanan, M.D.
Brigitta Lalone, L.C.S.W.-R  
John W. Lancaster, Ph.D.
Patience R. Land, L.I.C.S.W., M.S.W., M.P.A.  
Amber Lange, M.A., Ph.D.
Jeff K. Larsen, M.A.
Nathan E. Lavid, M.D.Michelle Leader, Ph.D.
Stephen E. Lee, M.D.
Cathryn L. Leff, Ph.D., L.M.F.T.
Rachael Kollar Leombruno, L.M.F.T.  
Arlene I. Lev, M.S.W., L.C.S.W.-R  
Gregory K. Lewis, M.A.-L.M.F.T.
Jane Hart Lewis, M.S.
Melissa S. Lewis, M.S.W., L.I.C.S.W.

Melissa S. Lewis, M.S.W., L.I.C.S.W.  
Norman Gerald Lewis, F.R.A.N.Z.C.P.  
Robin Joy Lewis, Ph.D.
Ryan Michael Ley, M.D.
Tammy R. Lias, M.A.
Russell F. Lim, M.D.
Jana Lincoln, M.D.
Ted Lindberg, L.M.S.W., L.M.F.T., M.S.W.  
Peggy Solow Liss, M.S.W.
Andrea Loeb, Psy.D.
William David Lohr, M.D.
Mary L. Ludy, M.A., L.M.H.C., L.M.F.T.  
Nathan Lundin, M.A., L.P.C.
Veena Luthra, M.D.
Patti Lyerly, L.C.S.W.
Denise E. Maas, M.A.
Silvia MacAllister, L.M.F.T.
Nicola MacCallum, M.S., M.F.C. Therapy  
Colin N. MacKenzie, M.D.
Cynthia Mack-Emsdorff, Ph.D.
John R. Madsen-Bibeau, M.S., M.Div  
Christopher J. Maglio, Ph.D.
Deepak Mahajan, M.D.
Debra Majewski, M.A.
Harish Kumar Malhotra, M.D.
Pamela Marcus, R.N., M.S.
Mary P. Marshall, Ph.D.
Flora Lynne Martin, M.A., L.P.C., A.D.C.  
Robert S. Martin, M.D.
Jennifer L. Martinez, M.S.

Ninfa Martinez-Aguilar, M.A., M.F.T.  
Emily Martinsen, M.S.W.
Farhan A. Matin, M.D.
Janus Maybee, P.M.H.N.P.
Karen Mazarin-Stanek, M.A.
Eben L. McClenahan, M.D., M.S.
Jerlyn C. McCleod, M.D.
Susan E. McCue, M.S.W., L.C.S.W.
Kent D. McDonald, M.S.
Daniel McDonnell, M.S.N, P.M.H.-N.P.  
Robert McElhose, Ph.D.
Lisa D. McGrath, Ph.D.
Mark McGrosky, M.S.W.
Katherine M. McKay, Ph.D.
Darren D. McKinnis, M.S.W.
Mona McNelis-Broadley, M.S.W., L.C.S.W.  
Rick McQuistion, Ph.D.
Susan Joy Mendelsohn, Psy.D.
Barbara S. Menninga, M.Ed.
Hindi Mermelstein, M.D., F.A.P.M.
Rachel B. Michaelsen, M.S.W.

Thomas F. Micka, M.D.
Tonya Miles, Psy.D.
Matthew Miller, M.S.
Michael E. Miller, M.D.
Noel Miller, L.M.S.W., M.B.A., M.P.S.
Kalpana Miriyala, M.D.
Sandra Moenssens, M.S.
Erin Mokhtar, M.A.
Robert E. Montgomery, M.Ed.
Susan Moon, M.A.
Theresa K. Moon, M.D.
David B. Moore, B.A., M.Div., M.S.S.W., Ph.D.  
Joanne M. Moore, M.S.
Peter I. M. Moran, M.B.B.Ch.
Anna Moriarty, M.P.S., L.P.C., L.M.H.C.  
Richard Dean Morris, M.A.
Michael M. Morrison, M.A.
Carlton E. Munson, Ph.D.
Timothy A. Murphy, M.D.
Beth L. Murphy, Psy.D.
Melissa A. Myers, M.D.
Stefan Nawab, M.D.
Allyson Matney Neal, D.N.P.
Steven Nicholas, M.A.
Aurelian N. Niculescu, M.D.
Earl S. Nielsen, Ph.D.
Terry Oleson, Ph.D.
Julianne R. Oliver, B.S., M.S., Ph.D.
Robert O. Olsen, M.D.
Amy O’Neill, M.D.
Oscar H. Oo, Psy.D., A.B.P.P.
Laurie Orlando, J.D., M.A.
Jill Osborne, M.S., Ed.S.
Kimberly Overlie, M.S.
L. Kola Oyev^umi, Ph.D.
Zachary J. Pacha, M.S.W.
Suzette R. Papadakis, M.S.
Amanda C. Parsons, M.A., L.P.C.C.

Lee R. Pate, B.A., M.A.
Eric L. Patterson, L.P.C.
Sherri Paulson, M.Ed., L.S.C.W.
Peter Dennis Pautz, B.A., M.S.W.
Malinda J. Perkins, M.S.W., L.C.S.W.
Eleanor F. Perlman, M.S.W.
Deborah K. Perry, M.S.W.
Amanda Peterman, L.M.F.T.
Shawn Pflugardt, Psy.D.
Robert J. Dean Phillips, M.S.
Laura Pieper, M.S.W., L.C.S.W.
Lori D. Pink, M.S.W., B.C.D  
Michael G. Pipich, M.S., L.M.F.T.
Cynthia G. Pizzulli, M.S.W., Ph.D.
Kathy C. Points, M.A.
Marya E. Pollack, M.D., M.P.H.
Sanford E. Pomerantz, M.D.
Eva Ponder, M.S.W., Psy.D.
Ernest Poortinga, M.D.
David Post, M.D.Laura L. Post, M.D., Ph.D., J.D.
Patrick W. Powell, Ed.D.
Beth M. Prewett, Psy.D.
Robert Price, D.C.C., M.Ed.
John Pruett, M.D.
Aneita S. Radov, M.A.
Dawn M. Raffa, Ph.D.
Kavitha Raja, M.D.
Ranjit Ram, M.D.
Mohamed Ibrahim Ramadan, M.D., M.S.

Mohamed Ibrahim Ramadan, M.D., M.S.  
Christopher S. Randolph, M.D.
Nancy Rappaport, M.Ed.
John Moir Rauenhorst, M.D.
Laurel Jean Rebenstock, L.M.S.W.
Edwin Renaud, Ph.D.
Heather J. Rhodes, M.A.
Jennifer S. Ritchie-Goodline, Psy.D.
Daniel G. Roberts, M.A.
Brenda Rohren, M.A., M.F.S., L.LM.H.P.,  
L.A.D.C., M.A.C.
Donna G. Rolin-Kenny, Ph.D., A.P.R.N.,  
Sylvia E. Rosario, M.Ed.
Mindy S. Rosenbloom, M.D.
Harvey A. Rosenstock, M.D.
Thalia Ross, M.S.S.W.
Fernando Rosso, M.D.
Barry H. Roth, M.D.
Thomas S. Rue, M.A., L.M.H.C.
Elizabeth Ruegg, L.C.S.W.
Diane Rullo, Ph.D.
Angie Rumaldo, Ph.D.
Eric Rutberg, M.A., D.H.Ed.
Joseph A. Sabella, L.M.H.C.
Kemal Sagduyu, M.D.
Adam H. Saltz, M.S.W.
Jennifer A. Samardak, L.LS.W.-S.
George R. Samuels, M.A., M.S.W.
Carmen Sanjurjo, M.A.
John S. Saroyan, Ed.D.

Brigid Kathleen Sboto, M.A., M.F.T.
Lori Cluff Schade, M.S.
Joan E. Schaper, M.S.N.
Rae J. Schilling, Ph.D.
Larry Schor, Ph.D.
Donna J. Schwartz, M.S.W., L.I.C.S.W.
Amy J. Schwarzenbart, P.M.H.-C.N.S., B.C.,
A.P.N.P.
John V. Scialli, M.D.
Chad Scott, Ph.D., L.P.C.C.
Sabine Sell, M.F.T.
Minal Shah, N.S., N.C.C., L.P.C.
Lynn Shell, M.S.N.
Dharmesh Navin Sheth, M.D.
S. Christopher Shim, M.D.
Marta M. Shinn, Ph.D.
Andreas Sidiropoulos, M.D., Ph.D.
Michael Siegell, M.D.

Michael G. Simonds, Psy.D.
Gagandeep Singh, M.D.
Melissa Rae Skrzypchak, M.S.S.W., L.C.S.W.  
Paula Slater, M.D.
WiUiam Bill Slaughter, M.D., M.A.
Aki Smith, Ph.D.
Deborah L. Smith, Ed.M.
Diane E. Smith, M.A., L.M.F.T.
James S. Sommer, M.S.
J. Richard Spatafora, M.D.
Judy Splittgerber, M.S.N., C.S., N.P.  
Thiruneermalai T.G. Sriram, M.D.
Martha W. St. John, M.D.
Sybil Stafford, Ph.D.
Timothy Stambaugh, M.A.
Laura A. Stamboni, M.S.W.
Carol L. R. Stark, M.D.
Stephanie Steinman, M.S.
Claudia M. Stevens, M.S.W.
Jennifer Boyer Stevens, Psy.D.
Dominique Stevens-Young, M.S.W., L.C.S.W.  
Kenneth Stewart, Ph.D.
Daniel Storch, M.D.
Suzanne Straebler, A.P.R.N.
Dawn Stremel, M.A., L.M.F.T.
Emel Stroup, Psy.D.
John W. Stump, M.S., L.M.F.T.
Thomas G. Suk, M.A.
Elizabeth Sunzeri, M.S.
Linnea Swanson, M.A., Psy.D.
Patricia Swanson, M.A.
Fereidoon Taghizadeh, M.D.
Bonnie L. Tardif, L.M.H.C., N.C.C., B.C.P.C.C.  
Joan Tavares, M.S.W.
Ann Taylor, M.S.W.
Dawn O'Dwyer Taylor, Ph.D.

Chanel V. Tazza, L.M.H.C.
Martha H. Teater, M.A.
Clark D. Terrell, M.D.
Mark R. Thelen, Psy.D.
Norman E. Thibault, M.S., Ph.D.
Tojuana L. Thomason, Ph.D.
Paula Thomson, Psy.D.
D. Chadwick Thompson, M.A.
Susan Thome-Devin, A.M.
Jean Eva Thumm, M.A.P.C., M.A.T., L.M.F.T.,
B.C.C.
James E. Tille, Ph.D., D.Min.
Jacalyn G. Tippey, Ph.D.
Saraswathi Tirumalasetty, M.D.
Jacqueline A. Torrance, M.S.
Terrence Trobaugh, M.S.
Louisa V. Troemel, Psy.D., L.M.F.T.Susan Ullman, M.S.W.
Jennifer M. Underwood, M.S.W., L.C.S.W.  
Rodney Dale Veldhuizen, M.A.
Michelle Voegels, B.S.N., M.S.N., B.C.
Wess Vogt, M.D.
R. Christopher Votolato, Psy.D.
John W. Waid, Ph.D.
Christa A. Wallis, M.A.
Dominique Walmsley, M.A.
Bhupinder Singh Waraich, M.D.
Joseph Ward, N.C.C., L.P.C. M.Ed.
Robert Ward, M.S.W.

Marilee L. M. Wasell, Ph.D.
Gannon J. Watts, L.P.C.-S., L.A.C., N.C.C.,  
N.C.S.C., A.A.D.C., LC.A.A.D.C.
Sheila R. Webster, M.A., M.S.S.A.
Burton Weiss, M.D.
Dennis V. Weiss, M.D.
Jonathan S. Weiss, M.D.
Richard Wendel, Ph.D.
Paul L. West, Ed.D.
Kris Sandra Wheatley, M.A., L.P.C., N.C.C.  
Leneigh White, M.A.
Danny R. Whitehead, L.I.C.S.W.
Jean Whitinger, M.A.
Peter D. Wilk, M.D.
Vanessa Wilkinson, L.P.C.
Tim F. Willia, M.S., M.A.Ed., L.P.C.
Cathy E. Willis, M.A., L.M.F.T., C.A.D.C.  
Jeffery John Wilson, M.D.
Jacquie Wilson, M.Ed.
David D. Wines, M.S.W.
Barbara A. Wirebaugh, M.S.W.
Daniel L. Wise, Ph.D.
Christina Wong, M.S.W., L.C.S.W.
Susanna Wood, M.S.W., L.C.S.W.
Linda L. Woodall, M.D.
Leoneen Woodard-Faust, M.D.
Sheryl E. Woodhouse, L.M.F.T.
Gregory J. Worthington, Psy.D.
Tanya Wozniak, M.D.

Kimberly Isaac Wright, M.A.
Peter Yamamoto, M.D.
Maria Ruiza Ang Yee, M.D.
Michael B. Zafrani, M.D.
Jafet E. Gonzalez Zakarchenco, M.D.
John Zibert, Ph.D.
Karen Zilberstein, M.S.W.
Cathi Zillmann, C.P.N.P., N.P.P.
Gerald A. Zimmerman, Ph.D.
Michele Zimmerman, M.A., P.M.H.C.N.S.-B.C.  
Judith A. Zink, M.A.
Vanderbilt University REDCap Team
Paul Harris, Ph.D.  
Sudah Kashyap, B.E.  
Brenda MinorJon Scherdin, M.A.  
Rob Taylor, M.A.  
Janey Wang, M.S.

Page numbers printed in boldface type refer to tables.Index
Abuse and neglect, 22, 7V7-722
adult maltreatment and neglect problems, 
720-722
child maltreatment and neglect problems, 
717-719
Access to medical and other health care, problems 
related to, 726 
Acute dissociative reactions to stressful events, 
306-307
Acute stress disorder, 265,280-286
associated features supporting diagnosis of, 
283-284
culture-related diagnostic issues in, 285 
development and course of, 284 
diagnostic criteria for, 280-281 
diagnostic features of, 281-283 
differential diagnosis of, 285-286 
functional consequences of, 285 
gender-related diagnostic issues in, 285 
prevalence of, 284
risk and prognostic factors for, 284-285 
Addiction. See Substance-related and addictive 
disorders
ADHD. See Attention-deficit/hyperactivity 
disorder
Adjustment disorders, 265, 286-289 
comorbidity with, 289 
culture-related diagnostic issues in, 288 
development and course of, 287 
diagnostic criteria for, 286-287

disorder
diagnostic criteria for, 286-287 
diagnostic features of, 287 
differential diagnosis of, 288-289 
functional consequences of, 288 
prevalence of, 287 
risk and prognostic factors for, 288 
Adjustment-like disorders, 289 
Adult maltreatment and neglect problems, 720­
722
adult abuse by nonspouse or nonpartner, 722 
spouse or partner abuse, psychological, 721­
722
spouse or partner neglect, 721 
spouse or partner violence, physical, 720 
spouse or partner violence, sexual, 720Agoraphobia, 190,217-221
219
comorbidity with, 221 
development and course of, 219-220 
diagnostic criteria for, 217-218 
diagnostic features of, 218-219 
differential diagnosis of, 220-221 
functional consequences of, 220 
gender-related diagnostic issues in, 220 
prevalence of, 219 
risk and prognostic factors for, 220

risk and prognostic factors for, 220 
Akathisia, medication-induced, 22 
acute, 711 
tardive, 712 
Alcohol intoxication, 497-499
497-498 
comorbidity with, 499 
culture-related diagnostic issues in, 498 
development and course of, 498 
diagnostic criteria for, 497 
diagnostic features of, 497 
diagnostic markers for, 499 
differential diagnosis of, 499 
functional consequences of, 499 
gender-related diagnostic issues in, 498 
prevalence of, 498 
risk and prognostic factors for, 498 
Alcohol-related disorders, 481,490-503 
alcohol intoxication, 497-499 
alcohol use disorder, 490-497 
alcohol withdrawal, 484,499-501 
diagnoses associated with, 482 
other alcohol-induced disorders, 502-503 
development and course of, 502-503 
features of, 502 
unspecified alcohol-related disorder, 503

unspecified alcohol-related disorder, 503 
Alcohol use disorder, 490-497
492-193 
comorbidity with, 496-497 
culture-related diagnostic issues in, 494-495 
development and course of, 493-494

Alcohol use disorder (continued)  
diagnostic criteria for, 49CM91 
diagnostic features of, 492 
diagnostic markers for, 495-496 
differential diagnosis of, 496 
functional consequences of, 496 
prevalence of, 493 
risk and prognostic factors for, 494 
specifiers for, 492 
Alcohol withdrawal, 499-501
associated features supporting diagnosis of, 500 
comorbidity with, 501 
development and course of, 501 
diagnostic criteria for, 499-500 
diagnostic features of, 500 
diagnostic markers for, 501 
differential diagnosis of, 501 
functional consequences of, 501 
prevalence of, 501 
risk and prognostic factors for, 501 
specifiers for, 500 
Alzheimer's disease, major or mild
neurocognitive disorder due to, 591, 603, 
611-614
associated features supporting diagnosis of, 612 
comorbidity with, 614 
culture-related diagnostic issues in, 613 
development and course of, 612-613 
diagnostic criteria for, 611-612 
diagnostic features of, 612 
diagnostic markers for, 613

diagnostic markers for, 613 
differential diagnosis of, 614 
functional consequences of, 614 
prevalence of, 612 
risk and prognostic factors for, 613 
American Psychiatric Association (APA), 5-7 
Anorexia nervosa, 329,338-345
associated features supporting diagnosis of, 341 
atypical, 353
comorbidity with, 344-345 
culture-related diagnostic issues in, 342 
development and course of, 341-342 
diagnostic criteria for, 338-339 
diagnostic features of, 339-340 
diagnostic markers for, 342-343 
differential diagnosis of, 344 
functional consequences of, 343 
prevalence of, 341 
risk and prognostic factors for, 342 
subtypes of, 339 
suicide risk in, 343 
Antidepressant discontinuation syndrome, 22, 
712-714 
comorbidity with, 714 
course and development of, 713diagnostic features of, 713 
differential diagnosis of, 713-714

712-714 
differential diagnosis of, 713-714 
prevalence of, 713 
Antisocial personality disorder, 461,476, 645, 646, 
659-663
660-661
culture-related diagnostic issues in, 662 
development and course of, 661 
diagnostic criteria for, 659 
diagnostic features of, 659-660 
differential diagnosis of, 662-663 
features and criteria in alternative DSM-5 
model for personality disorders, 763,
764-765
gender-related diagnostic issues in, 662 
prevalence of, 661
risk and prognostic factors for, 661-662 
Aruciety disorder due to another medical 
condition, 190,230-232 
231
development and course of, 231 
diagnostic criteria for, 230 
diagnostic features of, 230-231 
diagnostic markers for, 231 
differential diagnosis of, 231-232 
prevalence of, 231

231
prevalence of, 231 
Anxiety disorders, 189-264 
agoraphobia, 190,217-221 
anxiety disorder due to another medical 
generalized anxiety disorder, 190, 222-226 
highlights of changes from DSM-IV to DSM-5,
811
other specified anxiety disorder, 233 
panic attack specifier, 214-217 
panic disorder, 190,208-214 
selective mutism, 189,195-197 
separation anxiety disorder, 189,190-195 
social anxiety disorder (social phobia), 190, 
202-208
specific phobia, 189-190,197-202 
substance/medication-induced anxiety 
disorder, 190, 226-230 
unspecified anxiety disorder, 233 
APA (American Psychiatric Association), 5-7 
Assessment measures, 23-24, 733-748
cross-cutting symptom measures, 733-741 
DSM-5 Level 1  Cross-Cutting Symptom 
Measure, 734-736, 738-741 
DSM-5 Level 2 Cross-Cutting Symptom

DSM-5 Level 2 Cross-Cutting Symptom 
Measures, 734, 735, 736, 737 
frequency of use of, 737 
severity measures, 733, 742

Clinician-Rated Dimensions of Psychosis 
Symptom Severity, 742-744 
frequency of use of, 742 
scoring and interpretation of, 742 
WHO Disability Assessment Schedule 
(WHODAS), 16,21, 734, 745-748 
Ataque de nervios,  14,211-212,233,833 
Attention-deficit /  hyperactivity disorder 
(ADHD), 11,32,59-66 
associated features supporting diagnosis of, 61 
comorbidity with, 65 
culture-related diagnostic issues in, 62 
development and course of, 61 
diagnostic criteria for, 59-61 
diagnostic features of, 61 
differential diagnosis of, 63-65 
functional consequences of, 63 
gender-related diagnostic issues in, 63 
medication-induced symptoms of, 65 
other specified attention-deficit/hyperactivity 
disorder, 65-66 
prevalence of, 61
risk and prognostic factors for, 62 
unspecified attention-deficit/hyperactivity 
disorder, 66 
Attenuated psychosis syndrome, 122, 783-786 
associated features supporting diagnosis of, 784 
comorbidity with, 786 
development and course of, 785

development and course of, 785 
diagnostic features of, 783-784 
differential diagnosis of, 785-786 
functional consequences of, 785 
prevalence of, 784-785 
proposed criteria for, 783 
risk and prognostic factors for, 785 
Autism spectrum disorder, 31-32,50-59
associated features supporting diagnosis of, 55 
comorbidity with, 58-59 
culture-related diagnostic issues in, 57 
development and course of, 55-56 
diagnostic criteria for, 50-51 
diagnostic features of, 53-55 
differential diagnosis of, 57-58 
functional consequences of, 57 
gender-related diagnostic issues in, 57 
prevalence of, 55 
recording procedures for, 51 
risk and prognostic factors for, 56-57 
specifiers for, 51-53, 52 
Avoidant personality disorder, 645,646, 672-675 
673-674
culture-related diagnostic issues in, 674

673-674
culture-related diagnostic issues in, 674 
development and course of, 674 
diagnostic criteria for, 672-673diagnostic features of, 673 
differential diagnosis of, 674-675 
765-766
gender-related diagnostic issues in, 674 
prevalence of, 674 
Avoidant/restrictive food intake disorder, 329, 
334-338
associated features supporting diagnosis of, 335 
comorbidity with, 338 
culture-related diagnostic issues in, 336 
development and course of, 335-336 
diagnostic criteria for, 334 
diagnostic features of, 334-335 
diagnostic markers for, 336 
differential diagnosis of, 336-338 
functional consequences of, 336 
gender-related diagnostic issues in, 336 
risk and prognostic factors for, 336
Bereavement, 125-126,134,155,161,194 
persistent complex, 289, 789-792

persistent complex, 289, 789-792 
Binge-eating disorder, 329, 350-353
associated features supporting diagnosis of, 351 
comorbidity with, 353 
culture-related diagnostic issues in, 352 
development and course of, 352 
diagnostic criteria for, 350 
diagnostic features of, 350-351 
differential diagnosis of, 352-353 
functional consequences of, 352 
of low frequency and/or limited duration, 353 
prevalence of, 351 
risk and prognostic factors for, 352 
Bipolar I disorder, 123-132
associated features supporting diagnosis of, 129 
comorbidity with, 132 
culture-related diagnostic issues in, 130 
development and course of, 130 
diagnostic criteria for, 123-127 
diagnostic features of, 127-129 
differential diagnosis of, 131-132 
functional consequences of, 131 
gender-related diagnostic issues in, 130 
prevalence of, 130

prevalence of, 130 
risk and prognostic factors for, 130 
suicide risk and, 131 
Bipolar II disorder, 123,132-139
associated features supporting diagnosis of, 136 
comorbidity with, 139 
development and course of, 136-137 
diagnostic criteria for, 132-135 
diagnostic features of, 135-136 
differential diagnosis of, 138-139

Bipolar II disorder (continued)  
functional consequences of, 138 
gender-related diagnostic issues in, 137 
prevalence of, 136 
risk and prognostic factors for, 137 
suicide risk in, 138 
Bipolar and related disorder due to another 
medical condition, 123,145-147 
associated features supporting diagnosis of, 146 
comorbidity with, 147 
culture-related diagnostic issues in, 147 
development and course of, 146-147 
diagnostic criteria for, 145-146 
diagnostic features of, 146 
diagnostic markers for, 147 
differential diagnosis of, 147 
functional consequences of, 147 
gender-related diagnostic issues in, 147 
Bipolar and related disorders, 123-154 
bipolar I disorder, 123-132 
bipolar II disorder, 123,132-139 
bipolar and related disorder due to another 
cyclothymic disorder, 123,139-141 
highlights of changes from DSM-IV to DSM-5, 
810
other specified bipolar and related disorder, 
123,148 
specifiers for, 149-154

810
123,148 
specifiers for, 149-154 
substance/medication-induced bipolar and 
related disorder, 123,142-145 
unspecified bipolar and related disorder, 149 
Body dysmorphic disorder, 235, 236, 242-247 
associated features supporting diagnosis of, 244 
comorbidity with, 247 
culture-related diagnostic issues in, 245 
development and course of, 244 
diagnostic criteria for, 242-243 
diagnostic features of, 243-244 
differential diagnosis of, 245-247 
functional consequences of, 245 
gender-related diagnostic issues in, 245 
prevalence of, 244 
risk and prognostic factors for, 245 
suicide risk and, 245 
Body dysmorphic-like disorder with actual flaws, 
263
Body dysmorphic-like disorder without repetitive 
behaviors, 263 
Body-focused repetitive behavior disorder, 235, 
263-264
Borderline personality disorder, 645, 646, 663-666

263
263-264
Borderline personality disorder, 645, 646, 663-666 
associated features supporting diagnosis of, 665 
culture-related diagnostic issues in, 665-666 
development and course of, 665diagnostic criteria for, 663 
diagnostic features of, 663-664 
differential diagnosis of, 666 
766-767
gender-related diagnostic issues in, 666 
prevalence of, 665 
risk and prognostic factors for, 665 
Breathing-related sleep disorders, 361,378-390 
central sleep apnea, 383-386 
obstructive sleep apnea hypopnea, 378-383 
sleep-related hypoventilation, 387-390 
Brief illness anxiety disorder, 327 
Brief psychotic disorder, 94-96
associated features supporting diagnosis of, 95
culture-related diagnostic issues in, 95
development and course of, 95
diagnostic criteria for, 94
diagnostic features of, 94-95

differential diagnosis of, 96
duration of, 89,94, 99
functional consequences of, 95
prevalence of, 95
risk and prognostic factors for, 95 
Brief somatic symptom disorder, 327 
Bulimia nervosa, 329, 345-350
associated features supporting diagnosis of, 347
comorbidity with, 349-350
culture-related diagnostic issues in, 348
development and course of, 347-348
diagnostic criteria for, 345
diagnostic features of, 345-347
diagnostic markers for, 348
differential diagnosis of, 349
functional consequences of, 349
gender-related diagnostic issues in, 348
of low frequency and/or limited duration, 353
prevalence of, 347
risk and prognostic factors for, 348
suicide risk in, 349
Caffeine intoxication, 503-506
associated features supporting diagnosis of, 504 
comorbidity with, 506 
development and course of, 505

development and course of, 505 
diagnostic criteria for, 503-504 
diagnostic features of, 504 
differential diagnosis of, 505 
functional consequences of, 505 
prevalence of, 505 
risk and prognostic factors for, 505 
Caffeine-related disorders, 481, 503-509 
caffeine intoxication, 503-506 
caffeine withdrawal, 506-508

other caffeine-induced disorders, 508 
unspecified caffeine-related disorder, 509 
Caffeine use disorder, 792-795 
comorbidity with, 795 
development and course of, 794 
diagnostic features of, 793-794 
differential diagnosis of, 795 
functional consequences of, 794-795 
prevalence of, 794 
proposed criteria for, 792-793 
risk and prognostic factors for, 794 
Caffeine withdrawal, 506-508
associated features supporting diagnosis of, 507 
comorbidity with, 508 
culture-related diagnostic issues in, 508 
development and course of, 507 
diagnostic criteria for, 506 
diagnostic features of, 506-507 
differential diagnosis of, 508 
functional consequences of, 508 
prevalence of, 507
risk and prognostic factors for, 507-508 
Cannabis intoxication, 516-517 
diagnostic criteria for, 516 
diagnostic features of, 516-517 
differential diagnosis of, 517 
functional consequences of, 517 
prevalence of, 517 
specifiers for, 516

specifiers for, 516 
Cannabis-related disorders, 481,509-519 
cannabis intoxication, 516-517 
cannabis use disorder, 509-516 
cannabis withdrawal, 484, 517-519 
other cannabis-induced disorders, 519 
unspecified cannabis-related disorder, 519 
Cannabis use disorder, 509-516
associated features supporting diagnosis of, 512 
comorbidity with, 515-516 
culture-related diagnostic issues in, 514 
development and course of, 513 
diagnostic criteria for, 509-510 
diagnostic features of, 510-512 
diagnostic markers for, 514 
functional consequences of, 514-515 
prevalence of, 512
risk and prognostic factors for, 513-514 
specifiers for, 510 
Cannabis withdrawal, 517-519 
development and course of, 518 
diagnostic criteria for, 517-518 
diagnostic features of, 518 
differential diagnosis of, 519

differential diagnosis of, 519 
risk and prognostic factors for, 519Case formulation, 19-20
cultural, 749-759 {See also  Cultural 
formulation)
Catatonia, 89,119-121
associated with another mental disorder 
(catatonia specifier), 119-120 
diagnostic criteria for, 119-120 
diagnostic features of, 120 
unspecified, 89,121 
Catatonic disorder due to another medical 
condition, 120-121 
associated features supporting diagnosis of, 121 
diagnostic criteria for, 120-121 
diagnostic features of, 121 
differential diagnosis of, 121 
Central sleep apnea, 383-386
associated features supporting diagnosis of, 385 
comorbidity with, 386 
development and course of, 385 
diagnostic criteria for, 383-384 
diagnostic features of, 384-385 
diagnostic markers for, 385 
differential diagnosis of, 386 
functional consequences of, 386 
prevalence of, 385

prevalence of, 385 
risk and prognostic factors for, 385 
specifiers for, 384 
subtypes of, 384 
CFI. See Cultural Formulation Interview 
Cheyne-Stokes breathing, 383-386. See also  Central 
sleep apnea
Childhood-onset fluency disorder (stuttering), 31, 
45^ 7
associated features supporting diagnosis of, 46 
development and course of, 46-47 
diagnostic criteria for, 45-46 
diagnostic features of, 46 
differential diagnosis of, 47 
functional consequences of, 47 
risk and prognostic factors for, 47 
Child maltreatment and neglect problems, 717-719 
child neglect, 718-719 
child physical abuse, 717-718 
child psychological abuse, 719 
child sexual abuse, 718 
Circadian rhythm sleep-wake disorders, 361, 
390-398
advanced sleep phase type, 393-394
associated features supporting diagnosis 
of, 393 
comorbidity with, 394

390-398
of, 393 
comorbidity with, 394 
culture-related diagnostic issues in, 394 
development and course of, 393 
diagnostic features of, 393 
diagnostic markers for, 394

Circadian rhythm sleep-wake disorders 
(continued)  
advanced sleep phase type (continued)  
differential diagnosis of, 394 
functional consequences of, 394 
prevalence of, 393 
risk and prognostic factors for, 394 
specifiers for, 393 
delayed sleep phase type, 391-392
of, 391 
comorbidity with, 392 
development and course of, 391 
diagnostic features of, 391 
diagnostic markers for, 392 
differential diagnosis of, 392 
functional consequences of, 392 
prevalence of, 391 
risk and prognostic factors for, 392 
diagnostic criteria for, 390-391 
irregular sleep-wake type, 394-396
of, 395 
comorbidity with, 396 
development and course of, 395 
diagnostic features of, 394-395 
diagnostic markers for, 395 
differential diagnosis of, 395 
functional consequences of, 395 
prevalence of, 395 
risk and prognostic factors for, 395 
non-24-hour sleep-wake type, 396-397 
associated features supporting diagnosis

of, 396 
comorbidity with, 397 
development and course of, 396 
diagnostic features of, 396 
diagnostic markers for, 397 
differential diagnosis of, 397 
functional consequences of, 397 
prevalence of, 396
risk and prognostic factors for, 396-397 
relationship to International Classification of  
Sleep Disorders,  398 
shift work type, 397-398 
comorbidity with, 398 
development and course of, 398 
diagnostic features of, 397 
diagnostic markers for, 398 
differential diagnosis of, 398 
functional consequences of, 398 
prevalence of, 397 
risk and prognostic factors for, 398 
Symptom Severity, 742-744Coding and reporting procedures, 12,16, 22, 23,
29
Cognitive disorders. See Neurocognitive disorders 
Communication disorders, 31, 41-49

29
childhood-onset fluency disorder (stuttering), 
45-47
language disorder, 42-44 
social (pragmatic) communication disorder, 
47-i9
speech sound disorder, 44 -45 
unspecified communication disorder, 49 
Comorbidity, 5
Compulsions, 235-236, 239. See also  Obsessive- 
compulsive and related disorders 
Conditions for further study, 7,11, 24, 783-806 
attenuated psychosis syndrome, 783-786 
caffeine use disorder, 792-795 
depressive episodes with short-duration 
hypomania, 786-789 
Internet gaming disorder, 795-798 
neurobehavioral disorder associated with 
prenatal alcohol exposure, 798-801 
nonsuicidal self-injury, 803-805 
persistent complex bereavement disorder, 
789-792
suicidal behavior disorder, 801-803 
Conduct disorder, 32, 461, 469-475
472-473 
comorbidity with, 475

789-792
472-473 
comorbidity with, 475 
culture-related diagnostic issues in, 474 
development and course of, 473 
diagnostic criteria for, 469-471 
diagnostic features of, 472 
differential diagnosis of, 474-^75 
functional consequences of, 474 
gender-related diagnostic issues in, 474 
prevalence of, 473
risk and prognostic factors for, 473-474 
specifiers for, 471^72 
subtypes of, 471 
Conversion disorder (functional neurological 
symptom disorder), 309, 310, 318-321 
319-320 
comorbidity with, 321 
culture-related diagnostic issues in, 320 
development and course of, 320 
diagnostic criteria for, 318-319 
diagnostic features of, 319 
differential diagnosis of, 321 
functional consequences of, 321 
gender-related diagnostic issues in, 320 
prevalence of, 320

prevalence of, 320 
risk and prognostic factors for, 320

Creutzfeldt-Jakob disease. See Prion disease,
major or mild neurocognitive disorder due to 
Crime or interactioh with the legal system, 
problems related to, 725 
Criterion for clinical significance, 21 
Cross-cutting symptom measures, 733-741 
Cultural concepts of distress, 750,758,759,833-837 
Cultural explanations or perceived causes, 14, 758 
Cultural formulation, 749-759 
definitions related to, 749 
diagnostic importance of, 758-759 
outline for, 749-750 
relationship to DSM-5 nosology, 758 
Cultural Formulation Interview (CFI), 17, 24, 749, 
750-757 
domains of assessment, 751 
indications for, 751 
Informant Version, 755-757 
supplementary modules of, 751 
Cultural idioms of distress, 14, 758 
Cultural issues, 14-15, 749-759 
in anxiety disorders
generalized anxiety disorder, 224 
panic attacks, 216

panic attacks, 216 
panic disorder, 211-212 
selective mutism, 196 
separation anxiety disorder, 193 
social anxiety disorder (social phobia), 
205-206 
specific phobia, 201 
in bipolar and related disorders 
bipolar I disorder, 130 
medical condition, 147 
in depressive disorders
major depressive disorder, 166 
premenstrual dysphoric disorder, 173 
in disruptive, impulse-control, and conduct 
disorders 
conduct disorder, 474 
intermittent explosive disorder, 468 
oppositional defiant disorder, 465 
in dissociative disorders
depersonalization/derealization disorder, 
304
dissociative amnesia, 300 
dissociative identity disorder, 295 
in enuresis, 357
in feeding and eating disorders 
anorexia nervosa, 342avoidant/restrictive food intake disorder, 
336
binge-eating disorder, 352

336
binge-eating disorder, 352 
bulimia nervosa, 348 
pica, 331 
in fetishistic disorder, 701 
in gender dysphoria, 457 
in neurocognitive disorders, 609 
due to Alzheimer's disease, 613 
in neurodevelopmental disorders
attention-deficit/hyperactivity disorder,
62
autism spectrum disorder, 57 
developmental coordination disorder, 76 
intellectual disability (intellectual 
developmental disorder), 39 
specific learning disorder, 72-73 
stereotypic movement disorder, 79 
tic disorders, 83 
in obsessive-compulsive and related disorders 
body dysmoφhic disorder, 245 
hoarding disorder, 250 
obsessive-compulsive disorder, 240 
trichotillomania (hair-pulling disorder), 
253
in personality disorders, 648
antisocial personality disorder, 662 
avoidant personality disorder, 674 
borderline personality disorder, 665-666

253
borderline personality disorder, 665-666 
dependent personality disorder, 677 
histrionic personality disorder, 668 
obsessive-compulsive personality disorder, 
681
paranoid personality disorder, 651 
schizoid personality disorder, 654 
schizotypal personality disorder, 657 
in schizophrenia spectrum and other psychotic 
disorders 
brief psychotic disorder, 95 
delusional disorder, 93 
schizoaffective disorder, 108-109 
schizophrenia, 103 
in sexual dysfunctions, 423 
delayed ejaculation, 425 
erectile disorder, 428 
female orgasmic disorder, 432 
female sexual interest/arousal disorder, 
435-436
genito-pelvic pain/penetration disorder, 
439
male hypoactive sexual desire disorder, 
442
premature (early) ejaculation, 445 
substance/medication-induced sexual 
dysfunction, 449

Cultural issues (continued)  
in sleep-wake disorders
central sleep apnea hypopnea, 381 
circadian rhythm sleep-wake disorders, 
advanced sleep phase type, 394 
narcolepsy, 376 
nightmare disorder, 406 
substance/medication-induced sleep 
disorder, 418 
in somatic symptoms and related disorders 
conversion disorder (functional
neurological symptom disorder), 320 
illness anxiety disorder, 317 
psychological factors affecting other 
medical conditions, 323 
somatic symptom disorder, 313 
in substance-related and addictive disorders 
alcohol intoxication, 498 
alcohol use disorder, 495 
caffeine withdrawal, 508 
cannabis use disorder, 514 
gambling disorder, 588 
inhalant use disorder, 536 
opioid use disorder, 544 
other hallucinogen use disorder, 526 
other (or unknown) substance use 
disorder, 580 
other (or unknown) substance withdrawal, 
580
phencyclidine use disorder, 522 
sedative, hypnotic, or anxiolytic use 
disorder, 554 
stimulant use disorder, 565 
tobacco use disorder, 574

580
tobacco use disorder, 574 
in suicidal behavior disorder, 802 
in trauma- and stressor-related disorders 
acute stress disorder, 285 
adjustment disorders, 288 
posttraumatic stress disorder, 278 
reactive attachment disorder, 267 
Cultural syndromes, 14, 758 
Culture-bound syndromes, 14, 758 
Cyclothymic disorder, 123,139-141 
comorbidity with, 141 
development and course of, 140-141 
diagnostic criteria for, 139-140 
diagnostic features of, 140 
differential diagnosis of, 141 
prevalence of, 140 
risk and prognostic factors for, 141
Definition of a mental disorder, 20 
Delayed ejaculation, 423,424-426
424-425comorbidity with, 426 
culture-related diagnostic issues in, 425 
development and course of, 425 
diagnostic criteria for, 424 
diagnostic features of, 424

diagnostic features of, 424 
differential diagnosis of, 425-426 
functional consequences of, 425 
prevalence of, 425 
risk and prognostic factors for, 425 
Delirium, 591, 596-602
due to another medical condition, 597
associated features supporting diagnosis of, 600
development and course of, 600-601
diagnostic criteria for, 596-598
diagnostic features of, 599-600
diagnostic markers for, 601
differential diagnosis of, 601
functional consequences of, 601
medication-induced, 597, 599
due to multiple etiologies, 597
other specified, 602
prevalence of, 600
recording procedures for, 598-599
risk and prognostic factors for, 601
specifiers for, 599
substance intoxication, 596-597,598 
substance withdrawal, 597, 598-599 
unspecified, 602 
Delusional disorder, 89, 90-93
associated features supporting diagnosis of, 92 
culture-related diagnostic issues in, 93

culture-related diagnostic issues in, 93 
delusional symptoms in partner of individual 
with, 122 
development and course of, 92-93 
diagnostic criteria for, 90-91 
diagnostic features of, 92 
functional consequences of, 93 
prevalence of, 92 
subtypes of, 91-92 
Delusions, 87, 89, 90-93 
bizarre, 87, 91 
of control, 87 
érotomanie, 87, 90 
grandiose, 87, 90 
jealous, 90, 91 
mixed type, 91 
nihilistic, 87 
nonbizarre, 87 
persecutory, 87, 90-91 
referential, 87
with significant overlapping mood episodes, 
122
somatic, 87,90, 92 
unspecified type, 91 
Dementia, 591. See also  Neurocognitive disorders

Dependent personality disorder, 645,646, 675-678 
associated features supporting diagnosis of, 677 
culture-related dia^iostic issues in, 677 
development and course of, 677 
diagnostic criteria for, 675 
diagnostic features of, 675-677 
differential diagnosis of, 677-678 
gender-related diagnostic issues in, 677 
prevalence of, 677 
Depersonalization/derealization disorder, 291, 
302-306
associated features supporting diagnosis of, 303 
comorbidity with, 306 
culture-related diagnostic issues in, 304 
development and course of, 303-304 
diagnostic criteria for, 302 
diagnostic features of, 302-303 
differential diagnosis of, 305-306 
functional consequences of, 304-305 
prevalence of, 303 
risk and prognostic factors for, 304 
Depressive disorder due to another medical 
condition, 155,180-183 
associated features supporting diagnosis of, 181 
comorbidity with, 183 
development and course of, 181-182 
diagnostic criteria for, 180-181 
diagnostic features of, 181

diagnostic features of, 181 
diagnostic markers for, 182 
differential diagnosis of, 182-183 
functional consequences of, 182 
gender-related diagnostic issues in, 182 
risk and prognostic factors for, 182 
suicide risk in, 182 
Depressive disorders, 155-188
depressive disorder due to another medical 
disruptive mood dysregulation disorder, 155, 
156-160
810-eil
major depressive disorder, 155,160-168 
other specified depressive disorder, 155, 
183-184
persistent depressive disorder (dysthymia), 
155,168-171 
premenstrual dysphoric disorder, 155,171-175 
specifiers for, 184-188 
substance /  medication-induced depressive 
disorder, 155,175-180 
unspecified depressive disorder, 155,184 
Depressive episode or symptoms in bipolar and 
related disorders

related disorders 
bipolar I disorder, 125-126,129 
bipolar II disorder, 133-134,135-136Depressive episodes with short-duration 
788
comorbidity with, 789 
diagnostic features of, 788 
differential diagnosis of, 788-789 
functional consequences of, 788 
prevalence of, 788 
proposed criteria for, 786-787 
risk and prognostic factors for, 788 
suicide risk in, 788 
Developmental coordination disorder, 32, 74-77 
associated features supporting diagnosis of, 75 
comorbidity with, 76 
culture-related diagnostic issues in, 76 
development and course of, 75-76 
diagnostic criteria for, 74 
diagnostic features of, 74-75 
differential diagnosis of, 76-77 
functional consequences of, 76 
prevalence of, 75 
risk and prognostic factors for, 76

risk and prognostic factors for, 76 
Dhat syndrome,  833-834 
Diagnosis, 5-6
assessment and monitoring measures for, 
23^24, 733-748 
categorical, 5,8,12,13,19,20 
clinical utility of, 20
coding and reporting procedures for, 12,16, 
22, 23, 29 
criterion for clinical significance, 21 
culture and, 14-15,749-759 
definition of a mental disorder, 20 
diagnostic criteria and descriptors, 21 
dimensional approach to, 5, 8,9,12-13,17 
elements of, 21-24 
in forensic settings, 25
of medication-induced movement disorders, 
20, 22, 29, 709-714 
of other conditions that may be a focus of 
clinical attention, 20, 22, 29, 715-727 
principal, 22-23 
provisional, 23 
Diagnostic criteria, 21, 29 
case formulation and, 19 
proposed criteria for conditions for further 
study, 11, 783 
revisions of, 6-10 
subtypes and specifiers for, 21-22

subtypes and specifiers for, 21-22 
validators for, 5, 9,11,12, 20 
Diagnostic spectra, 6,9,12

Disinhibited social engagement disorder, 265, 
268-270
269
development and course of, 269-270 
diagnostic criteria for, 268-269 
diagnostic features of, 269 
differential diagnosis of, 270 
functional consequences of, 270 
prevalence of, 269 
risk and prognostic factors for, 270 
Disorganized thinking (speech), 88 
Disruptive, impulse-control, and conduct 
disorders, 461^80 
antisocial personality disorder, 461,476, 645, 
646,659-663 
conduct disorder, 461,469-475 
815
intermittent explosive disorder, 461,466-469 
kleptomania, 461,478-479 
oppositional defiant disorder, 461, 462^66 
other specified disruptive, impulse-control, 
and conduct disorder, 461,479 
pyromania, 461,476-477 
unspecified disruptive, impulse-control, and 
conduct disorder, 480 
Disruptive mood dysregulation disorder, 155, 
156-160 
comorbidity with, 160 
development and course of, 157 
diagnostic criteria for, 156

156-160 
diagnostic criteria for, 156 
diagnostic features of, 156-157 
differential diagnosis of, 158-160 
functional consequences of, 158 
gender-related diagnostic issues in, 158 
prevalence of, 157
risk and prognostic factors for, 157-158 
suicide risk in, 158 
Dissociative amnesia, 291, 298-302
associated features supporting diagnosis of, 299 
comorbidity with, 302 
culture-related diagnostic issues in, 300 
development and course of, 299 
diagnostic criteria for, 298 
diagnostic features of, 298-299 
differential diagnosis of, 300-302 
functional consequences of, 300 
prevalence of, 299
risk and prognostic factors for, 299-300 
suicide risk in, 300 
Dissociative disorders, 291-307
depersonalization/derealization disorder, 291, 
302-306
dissociative amnesia, 291, 298-302dissociative identity disorder, 291-298 
812

302-306
812
other specified dissociative disorder, 292, 
306-307
unspecified dissociative disorder, 307 
Dissociative identity disorder, 291-298
294
comorbidity with, 297-298 
culture-related diagnostic issues in, 295 
development and course of, 294 
diagnostic criteria for, 292 
diagnostic features of, 292-294 
differential diagnosis of, 296-297 
functional consequences of, 295-296 
gender-related diagnostic issues in, 295 
prevalence of, 294
risk and prognostic factors for, 294r-295 
suicide risk in, 295 
Dissociative reactions to stressful events, acute, 
306-307
Dissociative stupor or coma, 292 
Dissociative trance, 292,307 
Down syndrome, 38,40,44,53 
DSM, history of, 5, 6 
DSM-5
cultural issues in, 14-15, 749-759 
developmental and lifespan considerations in, 
13

DSM-5
13
forensic use of, 25 
gender differences in, 15 
glossary of technical terms in, 817-831 
harmonization with ICD-11,11-12 
highlights of changes from DSM-IV to, 809-817 
anxiety disorders, 811 
bipolar and related disorders, 810 
depressive disorders, 810-811 
disruptive, impulse-control, and conduct 
disorders, 815 
dissociative disorders, 812 
elimination disorders, 813 
feeding and eating disorders, 813 
gender dysphoria, 814-815 
neurodevelopmental disorders, 809-810 
obsessive-compulsive and related 
disorders, 811-812 
paraphilic disorders, 816 
personality disorders, 816 
schizophrenia spectrum and other 
psychotic disorders, 810 
sexual dysfunctions, 814 
sleep-wake disorders, 814 
somatic symptom and related disorders, 
812-813

substance-related and addictive disorders, 
815-816 X  
trauma- and stressor-related disorders, 812 
multiaxial system and, 16 
online enhancements of, 17 
organizational structure of, 10-11,13 
other specified and unspecified mental 
disorders in, 15-16,19-20, 707-708 
revision process for, 5, 6-10 
expert review, 8-10 
field trials, 7-8 
proposals for revisions, 7 
public and professional review, 8 
use of, 19-24
assessment and monitoring tools, 23-24, 
733-748 
case formulation, 19-20 
coding and reporting procedures, 12,16,
22,23,29
definition of a mental disorder, 20-21 
elements of a diagnosis, 21-24 
DSM-5 Level 1  Cross-Cutting Symptom Measure, 
734-736
adult self-rated version, 734, 735, 738-739 
parent/guardian-rated version, 734, 736, 
740-741
scoring and interpretation of, 734-736 
Measures, 734,735, 736, 737 
Dysthymia. See Persistent depressive disorder 
(dysthymia)
Dystonia, medication-induced, 22 
acute, 711 
tardive, 712

acute, 711 
Eating disorders. See Feeding and eating disorders 
Economic problems, 724 
Educational problems, 723 
Ejaculation
delayed, 423,424-426 
premature (early), 423,443-446 
Elements of diagnosis, 21-24 
Elimination disorders, 355-360 
encopresis, 355,357-359 
enuresis, 355-357
813
other specified elimination disorder, 359 
unspecified elimination disorder, 360 
Encopresis, 355,357-359
associated features supporting diagnosis of, 358 
comorbidity with, 359 
development and course of, 359 
diagnostic criteria for, 357-358 
diagnostic features of, 358diagnostic markers for, 359 
differential diagnosis of, 359 
prevalence of, 359 
risk and prognostic factors for, 359 
subtypes of, 358 
Enuresis, 355-357
associated features supporting diagnosis of, 356

associated features supporting diagnosis of, 356 
comorbidity with, 356 
culture-related diagnostic issues in, 356 
development and course of, 356 
diagnostic criteria for, 355 
diagnostic features of, 355-356 
differential diagnosis of, 356 
functional consequences of, 356 
gender-related diagnostic issues in, 356 
prevalence of, 356 
risk and prognostic factors for, 356 
subtypes of, 355 
Erectile disorder, 423,426-429
associated features supporting diagnosis of, 427 
comorbidity with, 429 
culture-related diagnostic issues in, 428 
development and course of, 427-428 
diagnostic criteria for, 426-427 
diagnostic features of, 427 
diagnostic markers for, 428 
differential diagnosis of, 428-429 
functional consequences of, 428 
prevalence of, 427 
risk and prognostic factors for, 428 
Excoriation (skin-picking) disorder, 235,236, 
254-257

254-257
associated features supporting diagnosis of, 255 
comorbidity with, 257 
development and course of, 255 
diagnostic criteria for, 254 
diagnostic features of, 254-255 
diagnostic markers for, 255 
differential diagnosis of, 256 
functional consequences of, 256 
prevalence of, 255 
risk and prognostic factors for, 255 
Exhibitionistic disorder, 685,689-691 
comorbidity with, 691 
development and course of, 690 
diagnostic criteria for, 689 
diagnostic features of, 689-690 
differential diagnosis of, 691 
functional consequences of, 691 
gender-related diagnostic issues in, 691 
prevalence of, 690
risk and prognostic factors for, 690-691 
specifiers for, 689 
subtypes of, 689 
Externalizing disorders, 13

Factitious disorder, 309, 310, 324-326
325-326
development and course of, 326 
diagnostic criteria for, 324-325 
diagnostic features of, 325 
differential diagnosis of, 326 
imposed on another, 310, 325-325, 338 
prevalence of, 326 
recording procedures for, 325 
Family upbringing, problems related to, 715-716 
Feeding and eating disorders, 329-354 
anorexia nervosa, 329,338-345 
avoidant/restrictive food intake disorder, 329, 
334-338
binge-eating disorder, 329, 350-353 
bulimia nervosa, 329, 345-350 
813
other specified feeding or eating disorder, 
353-354 
pica, 329-331
rumination disorder, 329,332-333 
unspecified feeding or eating disorder, 354 
Female orgasmic disorder, 423, 429-432
430-431 
comorbidity with, 432 
culture-related diagnostic issues in, 432 
development and course of, 431 
diagnostic criteria for, 429-430

430-431 
diagnostic criteria for, 429-430 
diagnostic features of, 430 
diagnostic markers for, 432 
differential diagnosis of, 432 
functional consequences of, 432 
prevalence of, 431
risk and prognostic factors for, 431-432 
Female sexual interest/arousal disorder, 423, 
433-137
434-435 
comorbidity with, 436-437 
culture-related diagnostic issues in, 435^36 
development and course of, 435 
diagnostic criteria for, 433 
diagnostic features of, 433-434 
differential diagnosis of, 436 
functional consequences of, 436 
gender-related diagnostic issues in, 436 
prevalence of, 435 
risk and prognostic factors for, 435 
Fetishistic disorder, 685, 700-702
associated features supporting diagnosis of, 701
comorbidity with, 702
culture-related diagnostic issues in, 701development and course of, 701

culture-related diagnostic issues in, 701development and course of, 701 
diagnostic criteria for, 700 
diagnostic features of, 701 
differential diagnosis of, 702 
functional consequences of, 701-702 
gender-related diagnostic issues in, 701 
specifiers for, 701 
Forensic settings, 25 
Formal thought disorder, 88 
Frontotemporal neurocognitive disorder, major or 
mild, 591, 603, 614-618 
616
development and course of, 616 
diagnostic criteria for, 614-615 
diagnostic features of, 615-616 
diagnostic markers for, 616-617 
differential diagnosis of, 617-618 
functional consequences of, 617 
prevalence of, 616 
risk and prognostic factors for, 616 
Frotteuristic disorder, 685, 691-694 
comorbidity with, 693-694 
development and course of, 693 
diagnostic criteria for, 691-692 
diagnostic features of, 692 
differential diagnosis of, 693

differential diagnosis of, 693 
gender-related diagnostic issues in, 693 
prevalence of, 692-693 
risk and prognostic factors for, 693 
specifiers for, 692 
Functional neurological symptom disorder. See 
Conversion disorder
GAF (Global Assessment of Functioning) scale, 16 
Gambling disorder, 481, 585-589
587
comorbidity with, 589 
culture-related diagnostic issues in, 588 
development and course of, 587-588 
diagnostic criteria for, 585-586 
diagnostic features of, 586-587 
differential diagnosis of, 589 
functional consequences of, 589 
gender-related diagnostic issues in, 588 
prevalence of, 587 
risk and prognostic factors for, 588 
specifiers for, 586 
Gender differences, 15 
Gender dysphoria, 451-459
454
comorbidity with, 458-459

454
comorbidity with, 458-459 
culture-related diagnostic issues in, 457

development and course of, 454-456 
in association with a disorder of sex 
development, 456 
without a disorder of sex development, 
455-456 
diagnostic criteria for, 452-453 
diagnostic features of, 453-454 
diagnostic markers for, 457 
differential diagnosis of, 458 
functional consequences of, 457-458 
814-815 
other specified, 459 
prevalence of, 454
risk and prognostic factors for, 456-457 
specifiers for, 453 
unspecified, 459 
Generalized anxiety disorder, 190,222-226
associated features supporting diagnosis of, 223 
comorbidity with, 226 
culture-related diagnostic issues in, 224 
development and course of, 223-224 
diagnostic criteria for, 222 
diagnostic features of, 222-223 
differential diagnosis of, 225-226 
functional consequences of, 225 
gender-related diagnostic issues in, 224-225 
prevalence of, 223 
risk and prognostic factors for, 224 
Genito-pelvic pain/penetration disorder, 423, 
437-440

437-440
438
comorbidity with, 440 
culture-related diagnostic issues in, 439 
development and course of, 439 
diagnostic criteria for, 437 
diagnostic features of, 437-438 
differential diagnosis of, 440 
functional consequences of, 439 
gender-related diagnostic issues in, 439 
prevalence of, 438 
risk and prognostic factors for, 439 
Global Assessment of Functioning (GAF) scale, 16 
Global developmental delay, 31,41 
Glossary of technical terms, 817-831
Hair pulling. See Trichotillomania (hair-pulling 
disorder)
Hallucinations, 87-88
auditory, 87,103,116,122 
gustatory, 116 
hypnagogic, 87 
hypnopompic, 88 
olfactory, 116,118tactile, 116
visual, 102,103,104,116,118 
Hallucinogen persisting perception disorder, 
531-532

531-532
associated features supporting diagnosis of, 531 
comorbidity with, 532 
development and course of, 532 
diagnostic criteria for, 531 
diagnostic features of, 531 
differential diagnosis of, 532 
functional consequences of, 532 
prevalence of, 531 
risk and prognostic factors for, 532 
Hallucinogen-related disorders, 481, 520-533 
hallucinogen persisting perception disorder,
531-532
other hallucinogen-induced disorders,
532-533
other hallucinogen intoxication, 529-530 
other hallucinogen use disorder, 523-527 
other phencyclidine-induced disorders, 532 
phencyclidine intoxication, 527-529 
phencyclidine use disorder, 520-523 
unspecified hallucinogen-related disorder, 533 
unspecified phencyclidine-related disorder, 533

unspecified phencyclidine-related disorder, 533 
Histrionic personality disorder, 645,646,667-669 
associated features supporting diagnosis of,
668
culture-related diagnostic issues in, 668 
diagnostic criteria for, 667 
diagnostic features of, 667-668 
differential diagnosis of, 669 
gender-related diagnostic issues in, 668 
prevalence of, 668 
HIV infection, major or mild neurocognitive 
disorder due to, 591, 604, 632-634 
associated features supporting diagnosis of, 633 
comorbidity with, 634 
development and course of, 633 
diagnostic criteria for, 632 
diagnostic features of, 632 
diagnostic markers for, 634 
differential diagnosis of, 634 
functional consequences of, 634 
prevalence of, 633 
risk and prognostic factors for, 633 
Hoarding disorder, 235,236, 247-251
associated features supporting diagnosis of, 249
comorbidity with, 251

culture-related diagnostic issues in, 250
development and course of, 249
diagnostic criteria for, 247
diagnostic features of, 248-249
differential diagnosis of, 250-251

Hoarding disorder (continued)  
functional consequences of, 250 
gender-related diagnostic issues in, 250 
prevalence of, 249 
risk and prognostic factors for, 249 
specifiers for, 248 
Housing problems, 723-724 
Huntington's disease, 81,117,181,182
major or mild neurocognitive disorder due to, 
591, 604, 638-641 
of, 639
development and course of, 639-640 
diagnostic criteria for, 638-639 
diagnostic features of, 639 
diagnostic markers for, 640 
differential diagnosis of, 640-641 
functional consequences of, 640 
prevalence of, 639 
risk and prognostic factors for, 640 
Hypersomnolence disorder, 361,368-372
370
comorbidity with, 372 
development and course of, 370 
diagnostic criteria for, 368-369 
diagnostic features of, 369-370 
diagnostic markers for, 371 
differential diagnosis of, 371-372 
functional consequences of, 371 
other specified, 421 
prevalence of, 370

Sleep Disorders,  372 
risk and prognostic factors for, 370-371 
unspecified, 421 
Hypochondriasis, 310,315-316,318. See also  
Illness anxiety disorder 
Hypomanie episode or symptoms in bipolar and 
bipolar I disorder, 124-125,129 
bipolar II disorder, 132-133,135-136 
medical condition, 146 
cyclothymic disorder, 139,140 
148
ICD. See International Classification of Diseases  
ICF (International Classification of Functioning, 
Disability and Health), 21, 734 
ICSD-2. See International Classification of Sleep  
Disorders,  2nd EditionIdentity disturbance due to prolonged and intense

Disorders,  2nd EditionIdentity disturbance due to prolonged and intense 
coercive persuasion, 306 
Illness anxiety disorder, 309,310,315-318
associated features supporting diagnosis of, 316 
brief, 327
comorbidity with, 318 
culture-related diagnostic issues in, 317 
diagnostic criteria for, 315 
diagnostic features of, 315-316 
differential diagnosis of, 317-318 
functional consequences of, 317 
prevalence of, 316
risk and prognostic factors for, 316-317 
without excessive health-related behaviors, 
327
Inhalant intoxication, 538-540
539
diagnostic criteria for, 538 
diagnostic features of, 538 
differential diagnosis of, 539-540 
functional consequences of, 539 
gender-related diagnostic issues in, 539 
prevalence of, 539 
Inhalant-related disorders, 481,533-540 
inhalant intoxication, 538-540

inhalant intoxication, 538-540 
inhalant use disorder, 533-538 
other inhalant-induced disorders, 540 
unspecified inhalant-related disorder, 540 
Inhalant use disorder, 533-538
535
comorbidity with, 538 
culture-related diagnostic issues in, 536 
development and course of, 536 
diagnostic criteria for, 533-534 
diagnostic features of, 535 
diagnostic markers for, 536-537 
differential diagnosis of, 537 
functional consequences of, 537 
gender-related diagnostic issues in, 536 
prevalence of, 535-536 
risk and prognostic factors for, 536 
specifiers for, 535 
Insomnia disorder, 361,362-368
364 
brief, 420
comorbidity with, 368 
development and course of, 365 
diagnostic criteria for, 362-363 
diagnostic features of, 363-364

364 
brief, 420
diagnostic features of, 363-364 
diagnostic markers for, 366-367 
differential diagnosis of, 367-368

functional consequences of, 367 
gender-related c^iagnostic issues in, 366 
other specified, 420 
prevalence of, 364^365 
Sleep Disorders,  368 
restricted to nonrestorative sleep, 420 
risk and protective factors for, 366 
unspecified, 420-421 
Intellectual disability (intellectual developmental 
disorder), 31,33-41 
associated features supporting diagnosis of, 38 
coding and reporting for, 33 
comorbidity with, 40 
culture-related diagnostic issues in, 39 
development and course of, 38-39 
diagnostic criteria for, 33 
diagnostic features of, 37-38 
diagnostic markers for, 39 
differential diagnosis of, 39-40 
gender-related diagnostic issues in, 39 
global developmental delay, 31,41 
prevalence of, 38
relationship to other classifications, 40-41 
risk and prognostic factors for, 39 
specifiers for levels of severity of, 33,34-36 
unspecified intellectual disability, 41 
Intermittent explosive disorder, 461,466-469

Intermittent explosive disorder, 461,466-469 
467
comorbidity with, 469 
culture-related diagnostic issues in, 468 
development and course of, 467 
diagnostic criteria for, 466 
diagnostic features of, 466-467 
differential diagnosis of, 468-469 
functional consequences of, 468 
gender-related diagnostic issues in, 468 
prevalence of, 467
risk and prognostic factors for, 467-468 
Internalizing disorders, 13 
International Classification of Diseases  (ICD), 21 
revision process for ICD-11, 6,10,11-12 
use of ICD-9-CM and ICD-10 codes, 12,16,22,
23,29
International Classification of Functioning, 
Disability and Health (ICF), 21, 734 
International Classification of Sleep Disorders,  2nd 
Edition (ICSD-2), relationship of DSM-5 to, 
361-362
circadian rhythm sleep-wake disorders, 398 
hypersomnolence disorder, 372

361-362
hypersomnolence disorder, 372 
insomnia disorder, 368 
narcolepsy, 378 
nightmare disorder, 407obstructive sleep apnea hypopnea, 383 
rapid eye movement sleep behavior disorder,
410
restless legs syndrome, 413 
sleep-related hypoventilation, 390 
substance/medication-induced sleep disorder,
420
Internet gaming disorder, 795-798
797
comorbidity with, 798 
diagnostic features of, 796-797 
differential diagnosis of, 797-798 
functional consequences of, 797 
prevalence of, 797 
proposed criteria for, 795-796 
risk and prognostic factors for, 797 
subtypes of, 796 
Intoxication, 481,485-487 
alcohol, 497-499
associated with use of multiple substances, 486
caffeine, 503-506
cannabis, 516-517
delirium due to, 598
development and course of, 487
duration of effects and, 486
inhalant, 538-540

laboratory findings associated with, 486-487 
opioid, 546-547 
other hallucinogen, 529-530 
other (or unknown) substance, 581-582 
phencyclidine, 527-529 
recording procedures for, 487 
related to route of administration and speed of 
substance effects, 486 
sedative, hypnotic, or anxiolytic, 556-557 
stimulant, 567-569
Jealousy, obsessional, 264 
Jikoshu-kyofu,  264
Khyâl cap, 211,212,233, 834 
Kleptomania, 461,478-479
478
comorbidity with, 478 
development and course of, 478 
diagnostic criteria for, 478 
diagnostic features of, 478 
differential diagnosis of, 478 
functional consequences of, 478 
prevalence of, 478 
risk and prognostic factors for, 478 
Koro,  264
Kufungisisa,  14, 834-835

Language disorder, 31, 42-44
associated features supporting diagnosis of, 43 
comorbidity with, 44 
development and course of, 43 
diagnostic criteria for, 42 
diagnostic features of, 42 
differential diagnosis of, 43 
risk and prognostic factors for, 43 
Learning disorder. See Specific learning disorder 
Level of Personality Functioning Scale (LPFS),
772, 775-778 
Lewy bodies, major or mild neurocognitive 
disorder with, 591, 603, 618-621 
associated features supporting diagnosis of, 619 
comorbidity with, 621 
development and course of, 619-620 
diagnostic criteria for, 618-619 
diagnostic features of, 619 
diagnostic markers for, 620 
differential diagnosis of, 620 
functional consequences of, 620 
prevalence of, 619 
risk and prognostic factors for, 620 
LPFS (Level of Personality Functioning Scale),
772, 775-778
Major depressive disorder, 155,160-168
164-165 
comorbidity with, 168 
culture-related diagnostic issues in, 166

164-165 
culture-related diagnostic issues in, 166 
development and course of, 165-166 
diagnostic criteria for, 160-162 
diagnostic features of, 162-164 
differential diagnosis of, 167-168 
functional consequences of, 167 
gender-related diagnostic issues in, 167 
prevalence of, 165 
risk and prognostic factors for, 166 
suicide risk in, 164,167 
Major depressive episode in bipolar and related 
disorders 
bipolar II disorder, 133-134,135-136 
148
Maladi moun,  14,835
Male hypoactive sexual desire disorder, 423, 
440-443
441-^2  
comorbidity with, 443 
culture-related diagnostic issues in, 442 
development and course of, 442 
diagnostic criteria for, 440-441diagnostic features of, 441 
differential diagnosis of, 443

441-^2  
differential diagnosis of, 443 
gender-related diagnostic issues in, 4 4 2 ^ 3  
prevalence of, 442 
risk and prognostic factors for, 442 
Manic episode
in bipolar I disorder, 124,127-129 
in bipolar and related disorder due to another 
Medication-induced delirium, 597, 599 
Medication-induced movement disorders and 
other adverse effects of medication, 20, 22, 
29, 709-714
antidepressant discontinuation syndrome, 22, 
712-714
medication-induced acute akathisia, 22, 711 
medication-induced acute dystonia, 711 
medication-induced postural tremor, 712 
neuroleptic-induced parkinsonism, 709 
neuroleptic malignant syndrome, 22, 709-711 
other adverse effect of medication, 712-714 
other medication-induced movement 
disorder, 712 
other medication-induced parkinsonism, 709 
tardive akathisia, 712

tardive akathisia, 712 
tardive dyskinesia, 22, 712 
tardive dystonia, 712 
Mental disorder(s)
culture and, 14-15, 749-759 
definition of, 20
in forensic settings, 25 
gender and, 15 
Motor disorders, neurodevelopmental, 32, 74-85 
developmental coordination disorder, 74-77 
stereotypic movement disorder, 77-80 
tic disorders, 81-85 
Movement disorders, medication-induced. See 
Medication-induced movement disorders 
and other adverse effects of medication 
Muscle dysmorphia, 236, 243, 245
Narcissistic personality disorder, 645, 646, 
669-672
671
development and course of, 671 
diagnostic criteria for, 669-670 
diagnostic features of, 670-671 
differential diagnosis of, 671-672 

767-768
gender-related diagnostic issues in, 671 
prevalence of, 671

Narcolepsy, 361, 372-378
374-375 
comorbidity with, 377-378 
culture-related diagnostic issues in, 376 
development and course of, 375 
diagnostic criteria for, 372-373 
diagnostic features of, 374 
diagnostic markers for, 376 
differential diagnosis of, 376-377 
functional consequences of, 376 
prevalence of, 375
Sleep Disorders, 378 
risk and prognostic factors for, 375-376 
subtypes of, 373-374 
NCDs. See Neurocognitive disorders 
Neglect
child, 718-719 
spouse or partner, 721 
Nervios,  835
Neurobehavioral disorder associated with 
associated features supporting diagnosis of, 799 
comorbidity with, 800-801 
development and course of, 800 
diagnostic features of, 799 
differential diagnosis of, 800 
functional consequences of, 800 
prevalence of, 800 
proposed criteria for, 798-799 
suicide risk in, 800 
Neurocognitive disorders (NCDs), 591-643

Neurocognitive disorders (NCDs), 591-643 
delirium, 591, 596-602
other specified delirium, 602 
unspecified delirium, 602 
816
major and mild neurocognitive disorders, 591, 
602-611, 611-643 
of, 608
comorbidity with, 610-611 
culture-related diagnostic issues in, 609 
development and course of, 608-609 
diagnostic criteria for, 602-606 
diagnostic features of, 607-608 
diagnostic markers for, 609-610 
differential diagnosis of, 610 
functional consequences of, 610 
gender-related diagnostic issues in, 609 
prevalence of, 608 
risk and prognostic factors for, 609 
specifiers for, 606-607 
subtypes of, 591, 603-604,  606, 611-643major or mild frontotemporal neuro­
cognitive disorder, 591, 603,  614-618 
major or mild neurocognitive disorder

major or mild neurocognitive disorder 
due to Alzheimer's disease, 591, 603,  
611-614
due to another medical condition, 
591, 604,  641-642 
due to HIV infection, 591, 604,  632­
634
due to Huntington's disease, 591, 
604,  638-641 
with Lewy bodies, 591, 603,  618-621 
due to multiple etiologies, 591, 604,  
642-643
due to Parkinson's disease, 591, 604,  
636-638
due to prion disease, 591, 604,  634­
636
due to traumatic brain injury, 591, 
603,  624-627, 626 
major or mild substance/medication- 
induced neurocognitive disorder,

636
induced neurocognitive disorder, 
591, 603,627-632 
unspecified neurocognitive disorder, 
591, 604,643 
vascular neurocognitive disorder, 591, 
603,  621-624 
neurocognitive domains, 592, 593-595  
Neurodevelopmental disorders, 11,13, 31-86 
attention-deficit/hyperactivity disorder, 11, 
32, 59-66
autism spectrum disorders, 31-32, 50-59 
communication disorders, 31, 41^9 
809-810
intellectual disabilities, 31, 33-41 
motor disorders, 32, 74-85 
other specified neurodevelopmental disorder, 
86
specific learning disorder, 32, 66-74 
specifiers for, 32-33 
tic disorders, 32, 81-85
unspecified neurodevelopmental disorder, 86 
Neurodevelopmental motor disorders, 32, 74-85 
tic disorders, 81-85

Neuroleptic-induced parkinsonism, 709 
Neuroleptic malignant syndrome, 22, 709-711 
development and course of, 710 
diagnostic features of, 710 
differential diagnosis of, 711 
risk and prognostic factors for, 711 
Night eating syndrome, 354 
Nightmare disorder, 361,404-407
associated features supporting diagnosis of, 405 
comorbidity with, 407 
culture-related diagnostic issues in, 406 
development and course of, 405 
diagnostic criteria for, 404 
diagnostic features of, 404-405 
diagnostic markers for, 406 
differential diagnosis of, 406-407 
functional consequences of, 406 
gender-related diagnostic issues in, 406 
prevalence of, 405
Sleep Disorders,  407 
risk and prognostic factors for, 405 
Nonadherence to medical treatment, 22, 726-727 
Non-rapid eye movement sleep arousal 
disorders, 361,399-404 
400-401 
comorbidity with, 403 
development and course of, 401

400-401 
development and course of, 401 
diagnostic criteria for, 399 
diagnostic features of, 400 
diagnostic markers for, 402 
differential diagnosis of, 402^03 
functional consequences of, 402 
gender-related diagnostic issues in, 401 
prevalence of, 401
Sleep Disorders,  404 
risk and prognostic factors for, 401 
Nonsuicidal self-injury, 803-805 
development and course of, 804 
diagnostic features of, 804 
differential diagnosis of, 805-806 
functional consequences of, 805 
proposed criteria for, 803 
risk and prognostic factors for, 804
Obesity, 22
feeding and eating disorders and, 329, 344, 
348,351-353 
sleep-wake disorders and, 413
hypersomnia, 372, 373, 375,376, 377 
obstructive sleep apnea hypopnea, 
379-380, 382 
sleep-related hypoventilation, 387-388,389Obsessional jealousy, 264

sleep-related hypoventilation, 387-388,389Obsessional jealousy, 264 
Obsessive-compulsive disorder (OCD), 235-236, 
237-242
238-239 
comorbidity with, 243 
culture-related diagnostic issues in, 240 
development and course of, 239 
diagnostic criteria for, 237 
diagnostic features of, 238 
differential diagnosis of, 242-243 
functional consequences of, 241-242 
gender-related diagnostic issues in, 239,240 
prevalence of, 239
risk and prognostic factors for, 239-240 
specifiers for, 236,238 
suicide risk in, 240 
Obsessive-compulsive personality disorder, 645, 
646,678-682 
680^81
culture-related diagnostic issues in, 681 
diagnostic criteria for, 678-679 
diagnostic features of, 679-680 
differential diagnosis of, 681-682 
features and criteria in alternative DSM-5

680^81
model for personality disorders, 764,
768-769
gender-related diagnostic issues in, 681 
prevalence of, 681 
Obsessive-compulsive and related disorder due to 
another medical condition, 235, 236,260-263 
262
development and course of, 262 
diagnostic criteria for, 260-261 
diagnostic features of, 261-262 
diagnostic markers for, 262 
differential diagnosis of, 262-263 
Obsessive-compulsive and related disorders, 
235-264
body dysmorphic disorder, 235,236, 242-247 
excoriation (skin-picking) disorder, 235,236, 
254-257
highlights of changes from DSM-FV to DSM-5,
811-812
hoarding disorder, 235, 236,247-251 
obsessions and compulsions in, 235-236,239 
obsessive-compulsive disorder, 235-236, 
237-242
obsessive-compulsive and related disorder

811-812
237-242
obsessive-compulsive and related disorder 
235.236, 260-263 
other specified obsessive-compulsive and 
related disorder, 235,236, 263-264

substance /  medication-induced obsessive- 
compulsive and related disorder, 235,
236,257-260 ' 
trichotillomania (hair-pulling disorder), 235, 
236, 251-254 
unspecified obsessive-compulsive and related 
disorder, 235,236 
Obstructive sleep apnea hypopnea, 378-383 
379
comorbidity with, 383 
culture-related diagnostic issues in, 381 
development and course of, 379-380 
diagnostic criteria for, 378 
diagnostic features of, 379 
diagnostic markers for, 381 
differential diagnosis of, 381-383 
functional consequences of, 381 
gender-related diagnostic issues in, 381 
prevalence of, 379
Sleep Disorders,  383 
risk and prognostic factors for, 380-381 
specifiers for, 378-379 
Occupational problems, 723 
OCD. See Obsessive-compulsive disorder 
Olfactory reference syndrome, 246,264,837 
Online enhancements, 17 
Opioid intoxication, 546-547 
diagnostic criteria for, 546-547

diagnostic criteria for, 546-547 
diagnostic features of, 547 
differential diagnosis of, 547 
specifiers for, 547 
Opioid-related disorders, 481,540-550 
opioid intoxication, 546-547 
opioid use disorder, 541-546 
opioid withdrawal, 484, 547-549 
other opioid-induced disorders, 549 
unspecified opioid-related disorder, 550 
Opioid use disorder, 541-546
associated features supporting diagnosis of, 543 
comorbidity with, 546 
culture-related diagnostic issues in, 544 
development and course of, 543 
diagnostic criteria for, 541-542 
diagnostic features of, 542 
diagnostic markers for, 544 
differential diagnosis of, 545-546 
functional consequences of, 544-545 
gender-related diagnostic issues in, 544 
prevalence of, 543
risk and prognostic factors for, 543-544 
specifiers for, 542

specifiers for, 542 
suicide risk in, 544Opioid withdrawal, 484, 547-549
associated features supporting diagnosis of, 549 
development and course of, 549 
diagnostic criteria for, 547-548 
diagnostic features of, 548 
differential diagnosis of, 549 
prevalence of, 549 
Oppositional defiant disorder, 32,461,462-466 
464
comorbidity with, 466 
culture-related diagnostic issues in, 465 
development and course of, 464 
diagnostic criteria for, 462-463 
diagnostic features of, 463 
differential diagnosis of, 465 
functional consequences of, 465 
prevalence of, 464 
risk and prognostic factors for, 464 
specifiers for, 463 
Other circumstances of personal history, 726 
Other conditions that may be a focus of clinical 
attention, 20, 22, 29, 715-727

attention, 20, 22, 29, 715-727 
abuse and neglect, 717-722
720-722
717-719
educational and occupational problems, 723 
housing and economic problems, 723-724 
nonadherence to medical treatment, 726-727 
other circumstances of personal history, 726 
other health service encounters for counseling 
and medical advice, 725 
other problems related to the social 
environment, 724-725 
problems related to access to medical and 
other health care, 726 
problems related to crime or interaction with 
the legal system, 725 
problems related to other psychosocial, 
personal, and environmental 
circumstances, 725 
relational problems, 715-717
other problems related to primary support 
group, 716-717 
problems related to family upbringing,
715-716

715-716
Other hallucinogen intoxication, 529-530 
diagnostic criteria for, 529 
diagnostic features of, 529 
differential diagnosis of, 530 
functional consequences of, 530 
prevalence of, 530 
suicide risk in, 530

Other hallucinogen use disorder, 523-527 
525
comorbidity with, 527 
culture-related diagnostic issues in, 526 
development and course of, 525-526 
diagnostic criteria for, 523-524 
diagnostic features of, 524-525 
diagnostic markers for, 526 
differential diagnosis of, 527 
functional consequences of, 527 
gender-related diagnostic issues in, 526 
prevalence of, 525 
risk and prognostic factors for, 526 
specifiers for, 524 
Other health service encounters for counseling 
Other mental disorders, 707-708
other specified mental disorder, 15-16,19,
708
other specified mental disorder due to another 
medical condition, 707 
unspecified mental disorder, 15-16,19-20, 708 
unspecified mental disorder due to another 
medical condition, 708 
Other problems related to primary support group,
716-717
Other problems related to social environment, 
724-725
Other psychosocial, personal, and environmental

716-717
724-725
Other psychosocial, personal, and environmental 
circumstances, problems related to, 725 
Other specified mental disorder, 15-16,19, 708 
due to another medical condition, 707 
Other (or unknown) substance intoxication, 
581-582 
comorbidity with, 582 
development and course of, 581-582 
diagnostic criteria for, 581 
diagnostic features of, 581 
differential diagnosis of, 582 
functional consequences of, 582 
prevalence of, 581 
Other (or unknown) substance-related disorders, 
577-585 
other (or unknown) substance-induced 
disorders, 584-585 
other (or unknown) substance intoxication, 
581-582
other (or unknown) substance use disorder, 
577-580
583-584
unspecified other (or unknown) substance- 
related disorder, 585Other (or unknown) substance use disorder, 
577-580

577-580
583-584
577-580
associated features supporting diagnosis of, 579
comorbidity with, 580
culture-related diagnostic issues in, 580
development and course of, 580
diagnostic criteria for, 577-578
diagnostic features of, 579
diagnostic markers for, 580
differential diagnosis of, 580
prevalence of, 579
risk and prognostic factors for, 580
specifiers for, 578
Other (or unknown) substance withdrawal, 
583-584 
comorbidity with, 584 
culture-related diagnostic issues in, 583 
development and course of, 583 
diagnostic criteria for, 583 
diagnostic features of, 583 
differential diagnosis of, 584 
functional consequences of, 584 
prevalence of, 583
Panic attacks, 189,190,208-209, 214-217 
associated features with, 215 
comorbidity with, 217 
culture-related diagnostic issues in, 216 
development and course of, 215-216

development and course of, 215-216 
diagnostic markers for, 216 
differential diagnosis of, 217 
expected vs. unexpected, 215 
features of, 214-215 
functional consequences of, 217 
gender-related diagnostic issues in, 216 
nocturnal, 209, 215 
in older adults, 210-211, 215-216 
prevalence of, 215 
risk and prognostic factors for, 216 
specifier for, 214-217 
suicide risk and, 215 
symptoms of, 214
Panic disorder, 190, 208-214
associated features supporting diagnosis of, 210 
culture-related diagnostic issues in, 211-212 
development and course of, 210-211 
diagnostic criteria for, 208-209 
diagnostic features of, 209 
diagnostic markers for, 212 
differential diagnosis of, 212-213 
functional consequences of, 212 
gender-related diagnostic issues in, 210.212 
prevalence of, 210 
risk and prognostic factors for, 211

risk and prognostic factors for, 211 
suicide risk in, 212

Paranoid personality disorder, 645,646,649-652 
650-651 ^  
culture-related diagnostic issues in, 651 
development and course of, 651 
diagnostic criteria for, 649 
diagnostic features of, 649-650 
differential diagnosis of, 652 
prevalence of, 651 
risk and prognostic factors for, 651 
Paraphilic disorders, 685-705
exhibitionistic disorder, 685, 689-691 
fetishistic disorder, 685, 700-702 
frotteuristic disorder, 685,691-694 
816
other specified paraphilic disorder, 705 
pedophilic disorder, 685,697-700 
sexual masochism disorder, 685,694-695 
sexual sadism disorder, 685,695-697 
tansvestic disorder, 685, 702-704 
unspecified paraphilic disorder, 705 
voyeuristic disorder, 685,686-688 
Parasomnias, 361,399^10
nightmare disorder, 361,404^07 
non-rapid eye movement sleep arousal 
rapid eye movement sleep behavior disorder, 
361,407-410 
Parkinsonism

neuroleptic-induced, 709 
other medication-induced, 709 
Parkinson's disease
anxiety disorders and, 203,205,207,218,221 
depressive disorders and, 181,182 
591,604,636-638 
of, 637 
comorbidity with, 638 
development and course of, 637 
diagnostic criteria for, 636-637 
diagnostic features of, 637 
diagnostic markers for, 637-638 
differential diagnosis of, 638 
prevalence of, 637 
risk and prognostic factors for, 637 
sleep-wake disorders and, 372,383,395,413,
421
REM sleep behavior disorder, 361, 408,410 
Pedophilic disorder, 685, 697-700
associated features supporting diagnosis of, 698 
comorbidity with, 700 
development and course of, 699 
diagnostic criteria for, 697-698diagnostic features of, 698

diagnostic criteria for, 697-698diagnostic features of, 698 
diagnostic markers for, 699 
differential diagnosis of, 700 
gender-related diagnostic issues in, 699 
prevalence of, 698 
risk and prognostic factors for, 699 
Persistent complex bereavement disorder, 289, 
789-792
791
comorbidity with, 792 
culture-related diagnostic issues in, 791 
development and course of, 791 
diagnostic features of, 790-791 
differential diagnosis of, 792 
functional consequences of, 792 
prevalence of, 791 
proposed criteria for, 789-790 
risk and prognostic factors for, 791 
suicide risk in, 791 
Persistent depressive disorder (dysthymia), 155, 
168-171 
comorbidity with, 171 
development and course of, 170 
diagnostic criteria for, 168-169 
diagnostic features of, 169-170 
differential diagnosis of, 170-171

168-171 
differential diagnosis of, 170-171 
functional consequences of, 170 
prevalence of, 170 
risk and prognostic factors for, 170 
Personality change due to another medical 
condition, 645,682-684 
683
diagnostic criteria for, 682 
diagnostic features of, 683 
differential diagnosis of, 683-684 
subtypes of, 683 
Personality disorders, 645-684 
Cluster A, 646,649-659
paranoid personality disorder, 645,646, 
649-652
schizoid personality disorder, 645,646,
652-655
schizotypal personality disorder, 87,89,90, 
645,646, 655-659 
Cluster B, 646, 659-672
antisocial personality disorder, 461,476, 
645, 646, 659-663 
borderline personality disorder, 645, 646, 
663-666
histrionic personality disorder, 645,646, 
667-669
narcissistic personality disorder, 645,646, 
669-672

Personality disorders (continued)
Cluster C, 646, 672-682
avoidant personality disorder, 645, 646, 
672-675
dependent personality disorder, 645, 646, 
675-678
645, 646, 678-682 
general personality disorder, 646-649 
criteria for, 646-647
culture-related diagnostic issues in, 648 
development and course of, 647-648 
diagnostic features of, 647 
differential diagnosis of, 648-649 
gender-related diagnostic issues in, 648 
816
other specified personality disorder, 645-646,
684
personality change due to another medical 
condition, 645, 682-684 
unspecified personality disorder, 645-646, 684 
Personality disorders: alternative DSM-5 model, 
761-781 
diagnosis of, 771
general criteria for personality disorder, 
761-763
Criterion A: level of personality 
functioning, 762, 762 
Criterion B: pathological personality traits, 
762-763
Criteria C and D: pervasiveness and 
stability, 763

761-763
762-763
stability, 763 
Criteria E, F, and G: alternative 
explanations for personality 
pathology, 763 
level of personality functioning, 762, 762, 
771-772
Level of Personality Functioning Scale for 
rating of, 772, 775-778 
self- and interpersonal  functioning 
dimensional definition, 772 
personality traits, 772-774 
assessment of Personality Trait Model, 774 
clinical utility of multidimensional 
personality functioning and trait 
model, 774 
definition and description of, 772-773 
definitions of personality disorder trait 
domains and facets, 779-781 
dimensionality of, 772-773 
distinguishing traits, symptoms, and 
specific behaviors, 773-774 
hierarchical structure of personality, 773 
Personality Trait Model, 773scoring algorithms for, 771 
specific personality disorders, 763-771
antisocial personality disorder, 763, 764-765

antisocial personality disorder, 763, 764-765 
avoidant personality disorder, 763, 765-766 
borderline personality disorder, 763, 766­
767
narcissistic personality disorder, 763, 
767-768
764, 768-769 
personality disorder—trait specified, 761, 
770-771
schizotypal personality disorder, 764, 
769-770
Phencyclidine intoxication, 527-529 
diagnostic criteria for, 527-528 
diagnostic features of, 528 
diagnostic markers for, 528 
differential diagnosis of, 528-529 
functional consequences of, 528 
prevalence of, 528 
Phencyclidine-related disorders, 481 
diagnoses associated v^ith, 482 
Phencyclidine use disorder, 520-523

associated features supporting diagnosis of, 522 
culture-related diagnostic issues in, 522 
diagnostic criteria for, 520-521 
diagnostic features of, 521-522 
diagnostic markers for, 522 
differential diagnosis of, 523 
functional consequences of, 522 
gender-related diagnostic issues in, 522 
prevalence of, 522 
risk and prognostic factors for, 522 
specifiers for, 521 
Phobic disorders
agoraphobia, 190, 217-221 
202-208
Physical abuse 
child, 717-718
nonspouse or nonpartner, 722 
spouse or partner, 720 
Pica, 329-331
330
comorbidity with, 331 
culture-related diagnostic issues in, 331 
development and course of, 330 
diagnostic criteria for, 329-330

diagnostic features of, 330 
diagnostic markers for, 331 
differential diagnosis' of, 331 
functional consequences of, 331 
gender-related diagnostic issues in, 331 
prevalence of, 330 
risk and prognostic factors for, 330 
Posttraumatic stress disorder (PTSD), 265,271-280 
276
comorbidity with, 280 
culture-related diagnostic issues in, 278 
development and course of, 276-277 
diagnostic criteria for, 271-274 
diagnostic features of, 274-276 
differential diagnosis of, 279-280 
functional consequences of, 278-279 
gender-related diagnostic issues in, 278 
prevalence of, 276
risk and prognostic factors for, 277-278 
suicide risk in, 278 
Postural tremor, medication-induced, 712 
Premature (early) ejaculation, 423,443-446 
444
comorbidity with, 446 
culture-related diagnostic issues in, 445 
development and course of, 444-445 
diagnostic criteria for, 443-444 
diagnostic features of, 444

444
diagnostic features of, 444 
diagnostic markers for, 445 
differential diagnosis of, 445-446 
functional consequences of, 445 
gender-related diagnostic issues in, 445 
prevalence of, 444 
risk and prognostic factors for, 445 
Premenstrual dysphoric disorder, 155,171-175 
associated features supporting diagnosis of, 173 
comorbidity with, 175 
culture-related diagnostic issues in, 173 
development and course of, 173 
diagnostic criteria for, 171-172 
diagnostic features of, 172-173 
diagnostic markers for, 173-174 
differential diagnosis of, 174-175 
functional consequences of, 174 
prevalence of, 173 
recording procedures for, 172 
risk and prognostic factors for, 173 
Principal diagnosis, 22-23 
Prion disease, major or mild neurocognitive 
disorder due to, 591, 604,  634-636 
development and course of, 635 
diagnostic criteria for, 634-635

diagnostic criteria for, 634-635 
diagnostic features of, 635diagnostic markers for, 636 
differential diagnosis of, 636 
prevalence of, 635 
risk and prognostic factors for, 636 
Problems related to access to medical and other 
health care, 726 
Problems related to crime or interaction with the 
legal system, 725 
Problems related to family upbringing, 715-716 
Problems related to other psychosocial, personal, 
and environmental circumstances, 725 
Provisional diagnosis, 23 
Pseudocyesis, 310,327 
Psychological abuse 
child, 719
spouse or partner abuse, 721-722 
Psychological factors affecting other medical 
conditions, 309,310,322-324 
comorbidity with, 324 
culture-related diagnostic issues in, 323 
development and course of, 323 
diagnostic criteria for, 322 
diagnostic features of, 322-323

diagnostic features of, 322-323 
differential diagnosis of, 323-324 
functional consequences of, 323 
prevalence of, 323 
Psychotic disorder due to another medical 
condition, 89,115-118 
associated features supporting diagnosis of, 116 
comorbidity with, 118 
development and course of, 117 
diagnostic criteria for, 115-116 
diagnostic features of, 116 
diagnostic markers for, 117 
differential diagnosis of, 118 
functional consequences of, 118 
prevalence of, 116-117 
risk and prognostic factors for, 117 
specifiers for, 116 
suicide risk in, 118 
Psychotic disorders. See Schizophrenia spectrum 
and other psychotic disorders 
PTSD. See Posttraumatic stress disorder 
Purging disorder, 353 
Pyromania, 461, 476-A77
476^77 
comorbidity with, 477 
development and course of, 477

476^77 
development and course of, 477 
diagnostic criteria for, 476 
diagnostic features of, 476 
differential diagnosis of, 477 
gender-related diagnostic issues in, 477 
prevalence of, 477

Rapid eye movement (REM) sleep behavior 
disorder, 361,407-410 
associated features supporting diagnosis of, 408 
comorbidity with, 410 
development and course of, 408-409 
diagnostic criteria for, 407-408 
diagnostic features of, 408 
diagnostic markers for, 409 
differential diagnosis of, 409-410 
functional consequences of, 409 
prevalence of, 408
Sleep Disorders,  410 
risk and prognostic factors for, 409 
Reactive attachment disorder, 265-268
associated features supporting diagnosis of, 266 
comorbidity with, 268 
culture-related diagnostic issues in, 267 
development and course of, 266 
diagnostic criteria for, 265-266 
diagnostic features of, 266 
differential diagnosis of, 267-268 
functional consequences of, 267 
prevalence of, 266 
risk and prognostic factors for, 267 
Recurrent brief depression, 183 
Relational problems, 22, 715-717
group, 716-717

problems related to family upbringing, 715-716 
REM sleep behavior disorder. See Rapid eye 
movement sleep behavior disorder 
Restless legs syndrome (RLS), 361,410-413 
411
comorbidity with, 413 
development and course of, 411-412 
diagnostic criteria for, 410 
diagnostic features of, 411 
diagnostic markers for, 412 
differential diagnosis of, 413 
functional consequences of, 412-413 
gender-related diagnostic issues in, 412 
prevalence of, 411
Sleep Disorders,  413 
risk and prognostic factors for, 412 
Rett syndrome, 33, 38, 51, 53, 56, 57, 79, 80 
RLS. See Restless legs syndrome 
Rumination disorder, 329, 332-333
332-333 
comorbidity with, 333

332-333 
comorbidity with, 333 
development and course of, 333 
diagnostic criteria for, 332diagnostic features of, 332 
differential diagnosis of, 333 
functional consequences of, 333 
prevalence of, 333 
risk and prognostic factors for, 333
Schizoaffective disorder, 89-90,105-110
associated features supporting diagnosis of, 107 
comorbidity with, 110 
culture-related diagnostic issues in, 108-109 
development and course of, 108 
diagnostic criteria for, 105-106 
diagnostic features of, 106-107 
differential diagnosis of, 109-110 
functional consequences of, 109 
prevalence of, 107-108 
risk and prognostic factors for, 108 
suicide risk in, 109 
Schizoid personality disorder, 645, 646, 652-655 
653-654
culture-related diagnostic issues in, 654 
development and course of, 654

653-654
development and course of, 654 
diagnostic criteria for, 652-653 
diagnostic features of, 653 
differential diagnosis of, 654-655 
gender-related diagnostic issues in, 654 
prevalence of, 654 
risk and prognostic factors for, 654 
Schizophrenia, 87, 99-105
101-102 
with catatonia, 88,100 
comorbidity with, 105 
culture-related diagnostic issues in, 103 
development and course of, 102-103 
diagnostic features of, 87-88,100-101 
differential diagnosis of, 104-105 
functional consequences of, 104 
gender-related diagnostic issues in, 103-104 
prevalence of, 102 
risk and prognostic factors for, 103 
suicide risk in, 104 
Schizophrenia spectrum and other psychotic 
disorders, 87-122 
brief psychotic disorder, 89,94-96 
catatonia, 88, 89,119-121

catatonia, 88, 89,119-121 
clinician-rated assessment of symptoms and 
related clinical phenomena in, 89-90 
delusional disorder, 89,90-93 
810
key features of, 87-88 
delusions, 87
disorganized thinking (speech), 88

grossly disorganized or abnormal motor 
behavior (including catatonia), 88 
hallucinations, 87-88 
negative symptoms, 88 
other specified schizophrenia spectrum and 
other psychotic disorder, 122 
psychotic disorder due to another medical 
schizoaffective disorder, 89-90,105-110 
schizophrenia, 87,99-105 
schizophreniform disorder, 89, 96-99 
schizotypal (personality) disorder, 87, 89, 90 
substance /  medication-induced psychotic 
disorder, 89,110-115 
unspecified schizophrenia spectrum and other 
psychotic disorder, 122 
Schizophreniform disorder, 89, 96-99
associated features supporting diagnosis of, 98 
development and course of, 98 
diagnostic criteria for, 96-97 
diagnostic features of, 97-98 
differential diagnosis of, 98-99 
functional consequences of, 98 
prevalence of, 98 
provisional diagnosis of, 97 
risk and prognostic factors for, 98 
Schizotypal personality disorder, 87,89,90, 645, 
646,655-659 
657

657
culture-related diagnostic issues in, 657 
development and course of, 657 
diagnostic criteria for, 655-656 
diagnostic features of, 656-657 
differential diagnosis of, 658-659 
769-770
gender-related diagnostic issues in, 658 
prevalence of, 657 
risk and prognostic factors for, 657 
Sedative, hypnotic, or anxiolytic intoxication, 
556-557
associated features supporting diagnosis of, 557 
diagnostic criteria for, 556 
diagnostic features of, 556-557 
differential diagnosis of, 557 
prevalence of, 557 
Sedative-, hypnotic-, or anxiolytic-related 
disorders, 481, 550-560 
other sedative-, hypnotic-, or anxiolytic- 
induced disorders, 560

induced disorders, 560 
sedative, hypnotic, or anxiolytic intoxication,
556-557sedative, hypnotic, or anxiolytic use disorder, 
550-556
sedative, hypnotic, or anxiolytic withdrawal, 
484, 557-560 
unspecified sedative-, hypnotic-, or anxiolytic- 
related disorder, 560 
Sedative, hypnotic, or anxiolytic use disorder, 
550-556
553
comorbidity with, 555-556 
culture-related diagnostic issues in, 554 
development and course of, 553-554 
diagnostic criteria for, 550-552 
diagnostic features of, 552-553 
diagnostic markers for, 554-555 
differential diagnosis of, 555 
functional consequences of, 555 
gender-related diagnostic issues in, 554 
prevalence of, 553 
risk and prognostic factors for, 554 
specifiers for, 552 
Sedative, hypnotic, or anxiolytic withdrawal, 484,
557-560

557-560
associated features supporting diagnosis of, 559 
diagnostic criteria for, 557-558 
diagnostic features of, 558 
diagnostic markers for, 559 
differential diagnosis of, 559-560 
prevalence of, 559 
Selective mutism, 189,195-197
195-196 
comorbidity with, 197 
culture-related diagnostic issues in, 196 
development and course of, 196 
diagnostic criteria for, 195 
diagnostic features of, 195 
differential diagnosis of, 197 
functional consequences of, 196-197 
prevalence of, 196 
risk and prognostic factors for, 196 
Separation anxiety disorder, 189,190-195
associated features supporting diagnosis of, 192
comorbidity with, 195
culture-related diagnostic issues in, 193
development and course of, 192-193
diagnostic criteria for, 190-191

diagnostic features of, 191-192
differential diagnosis of, 194-195
functional consequences of, 193-194
gender-related diagnostic issues in, 193
prevalence of, 192
risk and prognostic factors for, 193
suicide risk in, 193

Severity measures, 733,742
scoring and inteφretation of, 742 
Sexual abuse 
child, 718
Sexual dysfunctions, 423-450
delayed ejaculation, 423,424-426 
erectile disorder, 423,426-429 
female orgasmic disorder, 423,429-432 
female sexual interest/arousal disorder, 423, 
433-437
genito-pelvic pain/penetration disorder, 423, 
437-440
814
male hypoactive sexual desire disorder, 423, 
440-443
other specified sexual dysfunction, 423,450 
premature (early) ejaculation, 423,443-446 
substance/  medication-induced sexual 
dysfunction, 423,446-450 
subtypes of, 423
unspecified sexual dysfunction, 423,450 
Sexual masochism disorder, 685, 694-695
associated features supporting diagnosis of, 694 
comorbidity with, 695 
development and course of, 695 
diagnostic criteria for, 694 
diagnostic features of, 694

diagnostic features of, 694 
differential diagnosis of, 695 
functional consequences of, 695 
prevalence of, 694 
Sexual sadism disorder, 685,695-697
associated features supporting diagnosis of, 696 
comorbidity with, 697 
development and course of, 697 
diagnostic criteria for, 695 
diagnostic features of, 696 
differential diagnosis of, 697 
prevalence of, 696 
Shenjing shuairuo,  835-836 
Shubo-kyofu,  264
Skin picking. See Excoriation (skin-picking) 
disorder
Sleep-related hypoventilation, 387-390
387-388 
comorbidity with, 389-390 
development and course of, 388 
diagnostic criteria for, 387 
diagnostic features, 387diagnostic markers for, 389 
differential diagnosis of, 389 
functional consequences of, 389 
gender-related diagnostic issues in, 389 
prevalence of, 388

Sleep Disorders,  390 
risk and prognostic factors for, 388 
subtypes of, 387 
Sleep terrors, 399-403. See also  Non-rapid eye 
movement sleep arousal disorders 
Sleep-wake disorders, 361^22
breathing-related sleep disorders, 361,378-390 
circadian rhythm sleep-wake disorders, 361, 
390-398
advanced sleep phase type, 393-394 
delayed sleep phase type, 391-392 
irregular sleep-wake type, 394-396 
814
hypersomnolence disorder, 361,368-372 
insomnia disorder, 361,362-368 
other specified, 420

814
narcolepsy, 361,372-378 
other specified sleep-wake disorder, 421 
parasomnias, 399-410
nightmare disorder, 361,404-407 
rapid eye movement sleep behavior 
Sleep Disorders,  361-362 (See also specific  
sleep-wake disorders)  
restless legs syndrome, 361,410-413 
substance/medication-induced sleep disorder, 
413-420
unspecified sleep-wake disorder, 422 
Sleepwalking, 399-403. See also  Non-rapid eye 
Smoking. See Tobacco-related disorders 
Social anxiety disorder (social phobia), 190, 
202-208
204
comorbidity with, 208
culture-related diagnostic issues in, 205-206

development and course of, 205 
diagnostic criteria for, 202-203 
diagnostic features oi, 203-204 
differential diagnosis of, 206-207 
functional consequences of, 206 
gender-related diagnostic issues in, 204, 206 
prevalence of, 204 
risk and prognostic factors for, 205 
specifiers for, 203 
Social (pragmatic) communication disorder, 31, 
47-49
associated features supporting diagnosis of, 48 
development and course of, 48 
diagnostic criteria for, 47-48 
diagnostic features of, 48 
differential diagnosis of, 49 
risk and prognostic factors for, 48 
Somatic symptom disorder, 309,310,311-315 
312
comorbidity with, 314-315 
culture-related diagnostic issues in, 313 
development and course of, 312-313 
diagnostic criteria for, 311 
diagnostic features of, 311-312 
differential diagnosis of, 314 
prevalence of, 312 
risk and prognostic factors for, 313 
Somatic symptoms and related disorders, 309-327

Somatic symptoms and related disorders, 309-327 
conversion disorder (functional neurological 
symptom disorder), 309,310,318-321 
factitious disorder, 309, 310, 324-326 
812-813
illness anxiety disorder, 309,310,315-318 
other specified somatic symptom and related 
disorder, 309,310,327 
psychological factors affecting other medical 
conditions, 309, 310, 322-324 
somatic symptom disorder, 309, 310, 311-315 
unspecified somatic symptom and related 
Specific learning disorder, 32, 66-74
associated features supporting diagnosis of, 70
comorbidity with, 72, 74
culture-related diagnostic issues in, 72-73
development and course of, 70-72
diagnostic criteria for, 66-68
diagnostic features of, 68-70
differential diagnosis of, 73-74
functional consequences of, 73
gender-related diagnostic issues in, 73

prevalence of, 70
recording procedures for, 68
risk and prognostic factors for, 72Specific phobia, 189-190,197-202
associated features supporting diagnosis of, 199 
comorbidity with, 202 
culture-related diagnostic issues in, 201 
development and course of, 199-200 
diagnostic criteria for, 197-198 
diagnostic features of, 198-199 
differential diagnosis of, 201-202 
functional consequences of, 201 
prevalence of, 199 
risk and prognostic factors for, 200 
specifiers for, 198 
suicide risk in, 201 
Specifiers, 21-22
Specifiers for bipolar and related disorders, 
149-154
Specifiers for depressive disorders, 184^188 
Speech sound disorder, 31,44r-45
associated features supporting diagnosis of, 44 
development and course of, 44-45 
diagnostic criteria for, 44 
diagnostic features of, 44

diagnostic features of, 44 
differential diagnosis of, 45 
Spouse or partner abuse, psychological, 721-722 
Spouse or partner neglect, 721 
Spouse or partner violence 
physical, 720 
sexual, 720 
Stereotypic movement disorder, 32, 77-80 
comorbidity with, 80 
culture-related diagnostic issues in, 79 
development and course of, 79 
diagnostic criteria for, 77-78 
diagnostic features of, 78-79 
differential diagnosis of, 79-80 
prevalence of, 79 
recording procedures for, 78 
risk and prognostic factors for, 79 
specifiers for, 78 
Stimulant intoxication, 567-569
associated features supporting diagnosis of, 568 
diagnostic criteria for, 567-568 
diagnostic features of, 568 
differential diagnosis of, 568-569 
Stimulant-related disorders, 481, 561-570 
other stimulant-induced disorders, 570

other stimulant-induced disorders, 570 
stimulant intoxication, 567-569 
stimulant use disorder, 561-567 
stimulant withdrawal, 484, 569-570 
unspecified stimulant-related disorder, 570 
Stimulant use disorder, 561-567
563-564 
comorbidity with, 566-567

Stimulant use disorder (continued)
culture-related diagnostic issues in, 565 
development and course of, 564-565 
diagnostic criteria for, 561-562 
diagnostic features of, 563 
diagnostic markers for, 565-566 
differential diagnosis of, 566 
functional consequences of, 566 
prevalence of, 564 
risk and prognostic factors for, 565 
specifiers for, 563 
Stimulant withdrawal, 484, 569-570
associated features supporting diagnosis of, 570 
diagnostic criteria for, 569 
differential diagnosis of, 570 
Stroke, 46, 73,117
bipolar disorder and, 146,147 
depressive disorders and, 164,167,181-182 
Stuttering. See Childhood-onset fluency disorder 
(stuttering)
Substance-induced disorders, 481,485^90. See 
also specific substances of abuse  
alcohol-related, 497-503 
caffeine-related, 503-508 
cannabis-related, 516-519 
hallucinogen-related, 527-533 
inhalant-related, 538-540 
opioid-related, 546-549 
other (or unknown) substance-related, 581-585 
sedative-, hypnotic-, or anxiolytic-related,

sedative-, hypnotic-, or anxiolytic-related, 
556-560
substance intoxication and withdrawal, 481, 
485-487 {See also  Intoxication;
Withdrawal from substance) 
associated with use of multiple substances, 
486
development and course of, 487 
duration of effects and, 486 
laboratory findings associated with, 
486-487 
related to route of administration and 
speed of substance effects, 486 
substance/medication-induced mental 
disorders, 481,487-490 
development and course of, 489 
features of, 488-489 
functional consequences of, 490 
recording procedures for, 490 
tobacco-related, 575-576 
Substance intoxication delirium, 596-597, 598 
Substance/medication-induced anxiety disorder, 
190,226-230 
228-229diagnostic criteria for, 226-227 
diagnostic features of, 228

diagnostic features of, 228 
diagnostic markers for, 229 
differential diagnosis of, 229-230 
prevalence of, 229 
recording procedures for, 227-228 
Substance/medication-induced bipolar and 
associated features supporting diagnosis of, 144 
comorbidity with, 146 
development and course of, 144-145 
diagnostic criteria for, 142-143 
diagnostic features of, 144 
diagnostic markers for, 145 
differential diagnosis of, 145 
prevalence of, 144 
recording procedures for, 143-144 
Substance/  medication-induced depressive 
comorbidity with, 180 
development and course of, 178 
diagnostic criteria for, 175-176 
diagnostic features of, 177-178 
diagnostic markers for, 179 
differential diagnosis of, 179-180 
prevalence of, 178 
recording procedures for, 176-177

recording procedures for, 176-177 
risk and prognostic factors for, 178-179 
suicide risk in, 179 
Substance /  medication-induced neurocognitive 
disorder, 591, 603, 627-632 
associated features supporting diagnosis of, 630 
comorbidity with, 632 
development and course of, 631 
diagnostic criteria for, 627-629 
diagnostic features of, 629-630 
diagnostic markers for, 631 
differential diagnosis of, 631 
functional consequences of, 631 
prevalence of, 630 
recording procedures for, 629 
risk and prognostic factors for, 631 
Substance /  medication-induced obsessive-
compulsive and related disorder, 235, 236, 
257-260
associated features supporting diagnosis of, 259 
diagnostic criteria for, 257-258 
diagnostic features of, 259 
differential diagnosis of, 259-260 
prevalence of, 259 
recording procedures for, 258-259

recording procedures for, 258-259 
Substance /  medication-induced psychotic 
associated features supporting diagnosis of, 113 
development and course of, 114

diagnostic criteria for, 110-111 
diagnostic features o(, 112-113 
diagnostic markers for, 114 
differential diagnosis of, 114-115 
functional consequences of, 114 
prevalence of, 113 
recording procedures for, 112 
Substance /  medication-induced sexual 
448-449
culture-related diagnostic issues in, 449 
development and course of, 449 
diagnostic criteria for, 446-447 
diagnostic features of, 448 
differential diagnosis of, 450 
functional consequences of, 450 
gender-related diagnostic issues in, 449 
prevalence of, 449 
recording procedures for, 447-448 
Substance/medication-induced sleep disorder, 
413-420
416-418 
comorbidity with, 420 
culture-related diagnostic issues in, 418 
development and course of, 418 
diagnostic criteria for, 413-415 
diagnostic features of, 416 
diagnostic markers for, 419 
differential diagnosis of, 419^20

differential diagnosis of, 419^20 
functional consequences of, 419 
gender-related diagnostic issues in, 418 
recording procedures for, 415^16 
Sleep Disorders,  420 
risk and prognostic factors for, 418 
Substance-related and addictive disorders, 
481-589
gambling disorder, 481, 585-589 
815
substance-related disorders, 481-585 {See also  
specific substances of abuse)  
alcohol-related disorders, 490-503 
caffeine-related disorders, 503-509 
cannabis-related disorders, 509-519 
diagnoses associated with substance class, 
482
drug classes in, 481
hallucinogen-related disorders, 520-533 
inhalant-related disorders, 533-540 
opioid-related disorders, 540-550 
other (or unknown) substance-related 
disorders, 577-585sedative-, hypnotic- or anxiolytic-related

disorders, 577-585sedative-, hypnotic- or anxiolytic-related 
disorders, 550-560 
stimulant-related disorders, 561-570 
substance-induced disorders, 481,485-490 
substance use disorders, 481, 483-485, 
490-585
tobacco-related disorders, 571-577 
Substance use disorders, 481,483-485 
features of, 483^84 
577-580
recording procedures for, 485 
sedative, hypnotic, or anxiolytic use disorder, 
550-556 
severity and specifiers for, 484 
tobacco use disorder, 571-574 
tolerance and withdrawal in, 484 
Substance withdrawal delirium, 597, 598-599

550-556 
Substance withdrawal delirium, 597, 598-599 
Suicidal behavior disorder, 801-803 
comorbidity with, 803 
culture-related diagnostic issues in, 802 
development and course of, 802 
diagnostic features of, 801-802 
diagnostic markers for, 802 
functional consequences of, 802 
proposed criteria for, 801 
specifiers for, 801 
Suicide risk
anorexia nervosa and, 343 
bipolar I disorder and, 131 
bipolar II disorder and, 138 
body dysmorphic disorder and, 245 
bulimia nervosa and, 349 
condition and, 182 
hypomania and, 788 
disruptive mood dysregulation disorder and, 
158
dissociative amnesia and, 300 
dissociative identity disorder and, 295 
major depressive disorder and, 164,167 
prenatal alcohol exposure and, 800

158
prenatal alcohol exposure and, 800 
obsessive-compulsive disorder and, 240 
opioid use disorder and, 544 
other hallucinogen intoxication and, 530

Suicide risk (continued)  
panic attacks and, 215 
panic disorder and, 212 
persistent complex bereavement disorder and, 
791
posttraumatic stress disorder and, 278 
condition and, 118 
schizoaffective disorder and, 109 
schizophrenia and, 104 
separation anxiety disorder and, 193 
specific phobia and, 201 
disorder and, 180 
Susto,  836-837
Taijin kyofiisho,  205, 837 
Tardive akathisia, 712 
Tardive dyskinesia, 22, 712 
Tardive dystonia, 712 
Technical terms, glossary of, 817-831 
Tic disorders, 32, 81-85 
comorbidity with, 83, 85 
culture-related diagnostic issues in, 83 
development and course of, 83 
diagnostic criteria for, 81 
diagnostic features of, 81-82 
differential diagnosis of, 84 
functional consequences of, 84 
gender-related diagnostic issues in, 83, 84 
other specified tic disorder, 85 
prevalence of, 83 
risk and prognostic factors for, 83 
specifiers for, 81

specifiers for, 81 
unspecified tic disorder, 85 
Tobacco-related disorders, 481, 571-577 
other tobacco-induced disorders, 576 
tobacco withdrawal, 484, 575-576 
unspecified tobacco-related disorder, 577 
Tobacco use disorder, 571-574
associated features supporting diagnosis of, 573
comorbidity with, 574
culture-related diagnostic issues in, 574
development and course of, 573
diagnostic criteria for, 571-572
diagnostic features of, 572-573
diagnostic markers for, 574
functional consequences of, 574
prevalence of, 573
risk and prognostic factors for, 573-574 
specifiers for, 572 
Tobacco withdrawal, 484,575-576
associated features supporting diagnosis of, 575development and course of, 576 
diagnostic criteria for, 575 
diagnostic features of, 575

diagnostic features of, 575 
diagnostic markers for, 576 
differential diagnosis of, 576 
functional consequences of, 576 
prevalence of, 576 
risk and prognostic factors for, 576 
Tolerance to substance effects, 484 
Tourette's disorder, 32. See also  Tic disorders 
prevalence of, 83
Transvestic disorder, 685, 702-704
703
comorbidity with, 704 
development and course bf, 703-704 
diagnostic criteria for, 702 
diagnostic features of, 703 
differential diagnosis of, 704 
functional consequences of, 704 
prevalence of, 703 
specifiers for, 703 
Trauma- and stressor-related disorders, 265-290 
acute stress disorder, 265, 280-286

acute stress disorder, 265, 280-286 
adjustment disorders, 265, 286-289 
disinhibited social engagement disorder, 265, 
268-270
812
other specified trauma- and stressor-related 
disorder, 289 
posttraumatic stress disorder, 265, 271-280 
reactive attachment disorder, 265-268 
unspecified trauma- and stressor-related 
disorder, 290 
Traumatic brain injury 
bipolar disorder and, 146 
depressive disorders and, 181 
dissociative amnesia and, 298,299, 301 
hoarding disorder and, 247, 250 
591, 603, 624-627, 626 
of, 625 
comorbidity with, 627 
development and course of, 625-626 
diagnostic criteria for, 624 
diagnostic features of, 625 
diagnostic markers for, 627 
differential diagnosis of, 627

of, 625 
differential diagnosis of, 627 
functional consequences of, 627

prevalence of, 625
risk and prognostic factors for, 626-627 
specifiers for, 62^ 
neurodevelopmental disorders and, 38,39,44, 
73
psychotic disorders and, 99,117 
severity ratings for, 625, 626 
trauma- and stressor-related disorders and, 
280, 281, 284, 286 
Tremor, medication-induced, 712 
Trichotillomania (hair-pulling disorder), 235, 236, 
251-254
252
comorbidity with, 254 
culture-related diagnostic issues in, 253 
development and course of, 253 
diagnostic criteria for, 251 
diagnostic features of, 251-252 
diagnostic markers for, 253 
differential diagnosis of, 253-254 
functional consequences of, 253 
prevalence of, 252 
risk and prognostic factors for, 253 
Trùnggiô,  211,212
Unspecified mental disorder, 15-16,19-20, 708 
due to another medical condition, 708
Vascular neurocognitive disorder, major or mild, 
591, 603, 621-624 
622
comorbidity with, 624 
development and course of, 623

622
development and course of, 623 
diagnostic criteria for, 621 
diagnostic features of, 621-622 
diagnostic markers for, 623 
differential diagnosis of, 623-624 
functional consequences of, 623 
prevalence of, 622-623 
risk and prognostic factors for, 623Voyeuristic disorder, 685,686-688 
comorbidity with, 688 
development and course of, 688 
diagnostic criteria for, 686-687 
diagnostic features of, 687 
differential diagnosis of, 688 
gender-related diagnostic issues in, 688 
prevalence of, 687-688 
risk and prognostic factors for, 688 
specifiers for, 687
Withdrawal from substance, 481,485-487 
alcohol, 499-501 
caffeine, 506-508 
cannabis, 517-519 
delirium due to, 598 
multiple substances, 486 
opioids, 484,547-549

opioids, 484,547-549 
other (or unknown) substance, 583-584 
sedative, hypnotic, or anxiolytic, 484, 557-560 
stimulant, 484,569-570 
tobacco, 484,575-576 
World Health Organization (WHO), 6,23
revision process for ICD-11,6,10,11-12 
use of ICD-9-CM and ICD-10 codes, 12,16, 
22, 23,29
World Health Organization Disability Assessment 
Schedule 2.0 (WHODAS), 16,21, 734, 
745-748
additional scoring and inteφretation guidance 
for DSM-5 users, 745-746 
frequency of use of, 746 
scoring instructions provided by WHO for, 745

nutrients
Review
What Is the Evidence for “Food Addiction?”
A Systematic Review
Eliza L. Gordon1,*ID, Aviva H. Ariel-Donges1, Viviana Bauman1and Lisa J. Merlo2
1Department of Clinical and Health Psychology, University of Florida, 1225 Center Drive, Gainesville,
FL 32603, USA; ahariel@uﬂ.edu (A.H.A.-D.); baumanv@uﬂ.edu (V .B.)
2Center for Addiction Research and Education, Department of Psychiatry, University of Florida,
1149 Newell Drive, Gainesville, FL 32610, USA; lmerlo@uﬂ.edu
*Correspondence: elwarren.22@uﬂ.edu; Tel.: +1-352-273-5234
Received: 10 March 2018; Accepted: 6 April 2018; Published: 12 April 2018
/gid00030/gid00035/gid00032/gid00030/gid00038/gid00001/gid00033/gid00042/gid00045 /gid00001
/gid00048/gid00043/gid00031/gid00028/gid00047/gid00032/gid00046
Abstract: The diagnostic construct of “food addiction” is a highly controversial subject. The current
systematic review is the ﬁrst to evaluate empirical studies examining the construct of “food addiction”

in humans and animals. Studies were included if they were quantitative, peer-reviewed, and in the
English language. The 52 identiﬁed studies (35 articles) were qualitatively assessed to determine the
extent to which their ﬁndings indicated the following addiction characteristics in relation to food:
brain reward dysfunction, preoccupation, risky use, impaired control, tolerance/withdrawal, social
impairment, chronicity, and relapse. Each pre-deﬁned criterion was supported by at least one study.
Brain reward dysfunction and impaired control were supported by the largest number of studies
(n= 21 and n= 12, respectively); whereas risky use was supported by the fewest ( n= 1). Overall,
ﬁndings support food addiction as a unique construct consistent with criteria for other substance
use disorder diagnoses. The evidence further suggests that certain foods, particularly processed

foods with added sweeteners and fats, demonstrate the greatest addictive potential. Though both
behavioral and substance-related factors are implicated in the addictive process, symptoms appear to
better ﬁt criteria for substance use disorder than behavioral addiction. Future research should explore
social/role impairment, preoccupation, and risky use associated with food addiction and evaluate
potential interventions for prevention and treatment.
Keywords: food addiction; eating behavior; process addiction; systematic review
1. Introduction
The term “addiction” is commonplace in present society, despite the lack of consensus on an
established clinical deﬁnition (see Table 1 for deﬁnitions set forth by various health-related professional

organizations). In clinical practice, there is no ofﬁcial diagnosis of “addiction.” Instead, the Diagnostic
and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) states that the term may be used to
describe severe substance use disorders [1].
Criteria for substance use disorder diagnoses include 11 biopsychosocial symptoms grouped into
four categories (see Table 2) [ 1]. Diagnostic criteria focus on the consequences (e.g., symptoms, distress,
and impairment in daily functioning) of addictive disorders, however, research has provided insight
into the actual process (e.g., the neurobiological correlates) of addiction. Some important ﬁndings
focus on neurological factors related to reward and motivation, including DeltaFosB ( ∆FosB; a gene

transcription factor), dopamine, and opioid expression [2–4].
Behavioral and biological indicators of addiction have also been observed in certain excessive
behaviors [ 1], and research highlighting these similarities has sparked interest in addictive behavior
more generally [ 5]. The proposed “behavioral addictions” reﬂect dependence on a behavior or feeling
Nutrients 2018 ,10, 477; doi:10.3390/nu10040477 www.mdpi.com/journal/nutrients

Nutrients 2018 ,10, 477 2 of 30
brought about by an action, as opposed to a substance [ 6]. Several studies have conﬁrmed similarities
between behavioral and substance addictions regarding ∆FosB, dopamine, and opioid expression;
impaired control over the behavior; neglect of relationships and role obligations; and continued
problematic behavior in the face of negative health outcomes [ 5,7]. As a result, the DSM-5 recently
introduced a new diagnostic category, Non-Substance-Related Disorders, within the newly-named
Substance-Related and Addictive Disorders section of the manual. This category currently includes
only gambling disorder, however, several other behaviors were considered, including compulsive
overeating [ 5,8], problematic sexual behavior [ 9], and excessive Internet gaming [ 5,9]. Although
overeating was ultimately excluded from this category due to insufﬁcient empirical evidence,

discussion regarding the addictive potential of food has continued. Indeed, organizations such as the
American Society of Addiction Medicine (ASAM) have chosen to include “food addiction” in their
list of possible addictive disorders [ 10], and a number of studies have observed clear biological and
behavioral similarities between drug use and overeating (i.e., altered dopamine expression, cravings,
relapse to highly palatable food) [ 11–13]. In a review of food addiction studies in humans, Meule
and Gearhardt [ 14] reported that four out of the 11 DSM-5 substance use disorder symptoms were
empirically supported by studies of highly palatable food, and that the remaining seven symptoms
were “plausible” based on the literature available at that time. Several additional studies on food

addiction have been published since that review.
Table 1. Deﬁnitions of addiction.
Source Deﬁnition
English Oxford Dictionary [15] “Physically and mentally dependent on a particular substance.”
American Psychological
Association [16]“A chronic disorder with biological, psychological, social and
environmental factors inﬂuencing its development and maintenance.
Genes affect the degree of reward that individuals experience when
initially using a substance (e.g., drugs) or engaging in certain behaviors
(e.g., gambling), as well as the way the body processes alcohol or other
drugs. Heightened desire to re-experience use of the substance or
behavior, potentially inﬂuenced by psychological (e.g., stress, history of
trauma), social (e.g., family or friends’ use of a substance),

and environmental factors (e.g., accessibility of a substance, low cost)
can lead to regular use/exposure, with chronic use/exposure leading to
brain changes.”
American Society of Addiction
Medicine [10]“A primary, chronic disease of brain reward, motivation, memory and
related circuitry. Dysfunction in these circuits leads to characteristic
biological, psychological, social and spiritual manifestations. This is
reﬂected in an individual pathologically pursuing reward and/or relief
by substance use and other behaviors. Addiction is characterized by
inability to consistently abstain, impairment in behavioral control,
craving, diminished recognition of signiﬁcant problems with one’s
behaviors and interpersonal relationships, and a dysfunctional
emotional response. Like other chronic diseases, addiction often

involves cycles of relapse and remission. Without treatment or
engagement in recovery activities, addiction is progressive and can
result in disability or premature death.”
[17]“A complex condition, a brain disease that is manifested by compulsive
substance use despite harmful consequence. People with addiction
(severe substance use disorder) have an intense focus on using a certain
substance(s), such as alcohol or drugs, to the point that it takes over their
life. They keep using alcohol or a drug even when they know it will
causes problems. Yet a number of effective treatments are available and
people can recover from addiction and lead normal, productive lives.”

Nutrients 2018 ,10, 477 3 of 30
Table 2. Substance Use Disorder criteria, adapted from the Diagnostic and Statistical Manual of Mental
Disorders, 5th Edition (DSM-5) [1].
Impaired Control
1. Consuming a substance in greater amounts or over longer periods of time than intended.
2. Having a persistent desire or unsuccessfully attempting to decrease or limit substance use.
3. Spending a signiﬁcant amount of time acquiring, using, or recovering from a substance.
4. Craving the substance or having a strong urge to use it.
Social Impairment
5. Being unable to fulﬁll obligations at work, school, or home due to use of a substance.
6. Continually using a substance despite its effects causing or exacerbating persistent or recurrent social or
interpersonal problems.
7. Giving up or reducing social, occupational, or recreational activities due to substance use.
Risky Use
8. Continually using a substance in situations in which it is physically dangerous (e.g., driving under the inﬂuence of

Risky Use
a substance).
9. Continually using a substance despite physical or psychological problems that are caused or made worse by the
substance use.
Pharmacological Criteria
10. Needing a substantially higher dose of the substance to achieve the desired effect; or experiencing a substantially
reduced effect of the substance when the usual dose is consumed (i.e., tolerance).
11. Experiencing negative physical and psychological symptoms when the substance is not consumed at the typical
dose or frequency (i.e., withdrawal).
Note. To meet DSM-5 criteria for a substance use disorder, clinical distress or impairment must be evidenced by two
or more of the above symptoms within a 12-month period. Severity is classiﬁed as mild (2–3 symptoms), moderate
(4–5 symptoms), or severe ( ≥6 symptoms).

Nonetheless, there have been inconsistencies regarding the deﬁnition of food addiction. A variety
of approaches have been used to measure it, such as self-report questionnaires [ 18]; patient
self-identiﬁcation [ 19]; and the Yale Food Addiction Scale (YFAS), which is currently the best
available measure for evaluating food addiction based upon modiﬁed DSM criteria for substance use
disorders [ 20,21]. Some have erroneously conceptualized food addiction as either obesity or binge
eating [ 22–25], yet mounting evidence indicates that these constructs are distinct [ 26,27]. Though some
individuals with obesity may display neurological and behavioral similarities to individuals addicted
to drugs [ 24], estimates suggest that only approximately 24.9% of overweight/obese individuals

report clinically-signiﬁcant symptoms of food addiction and 11.1% of healthy-weight individuals also
report these symptoms [ 28]. Similarly, while food addiction symptoms are associated with binge
eating behavior and account for 6–14.8% of the unique variance in binge eating disorder [ 28], current
estimates suggest that only approximately 56.8% of individuals with binge eating disorder report
clinically signiﬁcant food addiction symptoms [ 29]. Although there is substantial overlap between
food addiction and binge eating symptoms, the two constructs are not synonymous [26,27].
The concept of food addiction remains controversial [ 25,30,31]. Some researchers question whether
food or eating can be addictive if it is necessary to our survival [ 25], while others point out the common

biological (e.g., brain reward pathways, ∆FosB expression), behavioral (e.g., relapse, using more
than intended), and psychological (e.g., preoccupation, impaired control) similarities between the
compulsive consumption of highly palatable foods and use of addictive drugs [ 2,32,33]. Nevertheless,
critics and proponents alike agree that more research is needed to conﬁrm the validity of food
addiction [ 30,34]. A non-systematic review by Hone-Blanchet and Fecteau [ 31] comparing animal and
human models of food addiction to characteristics of substance use disorder concluded that there was
signiﬁcant overlap between the two conditions, but that more research was needed. Extant published
systematic reviews on the concept of food addiction have either conﬂated obesity with food addiction or

excluded animal studies [ 22,28,29]. As such, a more recent and inclusive systematic review was needed.
The present systematic review aimed to summarize the peer-reviewed empirical literature examining

Nutrients 2018 ,10, 477 4 of 30
the evidence for food addiction in both animal and human studies. The chosen method involved
assessing its association with key characteristics of addiction in relation to food: (a) neurobiological
changes, (b) preoccupation with the substance, (c) impaired control, (d) social impairments, (e) risky
use, (f) tolerance/withdrawal, (g) chronicity of the condition, and (h) relapse [1,10,17].
2. Materials and Methods
Data collection, review, reporting, and discussion were conducted according to the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement [ 35,36]. The literature
search was carried out in PubMed and PsychINFO databases using varying combinations of the
following keywords: food addiction, addiction, process addiction, binge eating, hedonic eating,
compulsive overeating, compulsive eating, eating behavior, food, eat, feeding behavior/psychology,

food preferences, food habits, hyperphagia, eating disorders, obesity, overeat*. Meshterms were used
in the PubMed search. Filters were used in both databases according to the study’s predetermined
inclusion and exclusion criteria. Given that the “study type” ﬁlters on PubMed only identiﬁed articles
in print, a second search was done using the same search terms without ﬁlters in order to identify
recent articles published online before print. Additional studies were identiﬁed through review of the
references listed in the identiﬁed articles. Due to the proliferative nature of research on food addiction,
two searches were done: the ﬁrst was completed on 29 June 2016, and the second was completed on 8

January 2018. Protocols were followed for both searches exactly as described above, with the exception
that the second search included only articles published since 30 June 2016.
Articles were included if their stated purpose was to test the validity of the food addiction
construct, and if they fulﬁlled the following modiﬁed PICOS (Participants, Interventions, Comparisons,
Outcomes, and Study Design) criteria [ 35,36]. Acceptable participants included humans or animals
of any age with no speciﬁc limitations on disease or diagnosis. Only quantitative, empirical,
peer-reviewed studies published in the English language were included. The American Psychological
Association’s deﬁnes “quantitative” studies as those which “provide numerical representation of
observations for the purpose of describing and explaining the phenomenon studied followed by

the application of . . .statistical methods” [ 37], (“Quantitative Study”). Therefore, studies using
self-report measures that produced a numerical outcome (e.g., Likert scale, yes/no, hunger ratings)
were considered quantitative. Empirical studies were deﬁned as those “based on . . .systematic
observation, or experiment, rather than theory or general philosophical principle” [ 37] (“Empirical
Study”). Studies examining any type of intervention or comparison (e.g., randomized control trial,
cross-sectional) within these constraints were included in order to accurately reﬂect the heterogeneous
nature of the existing literature. Studies could be published online or in print, and no limits were
set on date of publication. Finally, because not all overweight/obese individuals or individuals with

eating disorders report addiction-like symptoms related to food [29], studies deﬁning food addiction
solely by weight, BMI, or eating disorder diagnosis were excluded.
Articles selected from PubMed and PsychINFO were reviewed ﬁrst by title, then abstract,
and ﬁnally full article for relevancy and eligibility using the inclusion criteria described above. The ﬁrst
author independently assessed study eligibility, and articles whose eligibility was unclear were
reviewed by two experienced obesity researchers. The last included study was identiﬁed in January
2018. A ﬂowchart for study inclusion is depicted in Figure 1.
The data extraction form used for this study was modeled after forms used in similar systematic
reviews (e.g., [ 28]) and was modiﬁed for the current paper. The following data were extracted:

author/year of publication, study type, sample characteristics, number of subjects in treatment/control
groups, main independent variable(s), and main outcome variable(s). Two of the current authors
assessed risk of bias on the study level using a modiﬁed combined scoring system based on those
reported by Jamaty and colleagues [ 38] and Pursey and colleagues [ 28]. These scoring systems were
combined in order to include relevant criteria for both animal [ 38] and human [ 28] studies. Criteria
included questions about sample selection, study design, and reporting of ﬁndings. The authors

Nutrients 2018 ,10, 477 5 of 30
gave answers of “Yes”, “No”, or “Unclear” regarding each question for every article included in the
review. An answer of “non-applicable” was given for the question “Was there sufﬁcient description
of the groups?” if a study did not have multiple groups. Quality scores were obtained by summing
the number of “Yes”, “No”, and “Unclear” ratings, then calculating the ratio of “Yes” ratings to the
sum of the “No” and “Unclear” ratings combined. “Not applicable” ratings were not included in
the calculation of the overall quality rating. Disagreements between authors were discussed until a
resolution was agreed upon.
Figure 1. Study selection ﬂow diagram, presented according to the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA) statement [35,36].
3. Results
The original database search produced a total of 2421 articles, and the updated search produced

3. Results
577 articles. Three additional articles describing eight studies were identiﬁed from references in other
papers. After removing duplicate references and excluding articles that did not meet the predetermined
inclusion criteria, a total of 35 articles and 52 studies were identiﬁed (see Figure 1 and Appendix,
Table A1). Primary reasons for exclusion were study objective (i.e., did not aim to evaluate the validity
of the food addiction construct) and study type (i.e., not a quantitative empirical study). Publishing
dates of included articles ranged from 1999 to 2017. Twenty articles (comprising 22 studies) involved
human participants and 15 articles (comprising 30 studies) involved animal subjects (i.e., rats, mice,
and monkeys). Forty-nine studies focused on the addictive potential of certain foods, ﬁve studies

focused on the addictive potential of eating patterns, and two studies focused on the addictive potential
of both certain foods and eating patterns.
As seen in Appendix, Table A2, quality scores for included articles ranged from 0.8 (lowest ratio of
“Yes” ratings to “No” ratings plus “Unclear” ratings) [ 39] to a perfect score (all “Yes” ratings) [ 40–43].
Three articles disclosed competing ﬁnancial interests, including Coca-Cola [ 44], the International
Sweeteners Association [ 44], sugar industry relations [ 44], pharmaceutical companies [ 13,40] and
involvement in addiction/impulse disorder organizations [ 13]. Nineteen articles reported no
competing interests and 13 made no statement (see Table A2). As competing ﬁnancial interests
may bias study conclusions [45], data should be objectively considered with this context in mind.

Nutrients 2018 ,10, 477 6 of 30
Of the 35 articles (52 studies) included in this review, 31 articles (47 studies) reported results
supporting the criteria for addiction, two articles (two studies) were mixed, and two articles
(three studies) reported unsupportive ﬁndings (see Appendix, Table A3). Results examining support
for each pre-speciﬁed addiction characteristic were evaluated separately and are described below.
3.1. Neurobiological Correlates of Addiction
3.1.1. ∆FosB
Sharma, Fernandes, and Fulton [ 46] showed that rats placed on a 12-week high-fat diet of
primarily hydrogenated coconut oil, maltodextrin, sucrose, and casein had signiﬁcantly higher ∆FosB,
dopamine D2 receptor, and brain-derived neurotropic factor expression, and lower dopamine D1
receptor expression, in the NAc. These changes were observed before the onset of obesity and were
linked to behaviors suggestive of anhedonia. The authors concluded that the brain changes may have

put the animals at greater risk for addictive-like symptoms such as relapse. No human studies reported
ﬁndings related to ∆FosB.
3.1.2. Dopamine
Colantuoni and associates [ 47] compared brain chemistry changes in rats with intermittent,
excessive glucose intake to rats given a normal diet of chow. They found that exposure to the
highly palatable food in an intermittent eating pattern caused increased activation of dopamine
D1 ( p< 0.05) and µ-opioid-1 receptors ( p< 0.05), as well as decreased binding of dopamine D2
receptors, in the dorsal striatum ( p< 0.05). Adams and colleagues [ 41] found that rats given a
high-fat/low-sucrose diet (primarily lard) also had decreased D2 receptor expression in the NAc,

but those given a low-fat/high-sucrose diet did not (high fat diet: F= 11.1, p= 0.009; high sucrose
dietF= 3.8, p= 0.074). Reduced D2 receptor expression ( p< 0.01) in the striatum (along with other
indicators of down-regulation of reward functioning) was also observed in rats who volitionally
overate highly palatable foods (bacon, sausage, cheesecake, pound cake, frosting, chocolate) in a study
by Johnson and Kenny [ 48]. Authors of each study concluded that their results were consistent with
ﬁndings in substance use disorder literature.
In humans, Davis and associates [ 49] found that individuals who met the YFAS cutoff suggesting
clinically signiﬁcant food addiction symptoms had higher multi-locus genetic proﬁle (MLGP) scores

associated with increased dopamine signaling ( p= 0.023), and that the relationship between the
MLGP scores and food addiction was mediated by reward-driven eating (95% CI: 0.00–1.12). Davis,
Levitan, Kaplan, Kennedy, and Carter [ 50] showed that an appetite suppressant that blocked dopamine
functioning was not effective in adults who screened positive for food addiction on the YFAS compared
with controls, suggesting altered dopamine signaling strength in adults with more food addiction
symptoms similar to what is seen among adults with substance use disorders.
3.1.3. Opioid Expression
Opioid receptors were reported to play a role in food reward in rats. Le Merrer and Stephens [ 51]
found that rats conditioned on sugar sweetened pellets no longer responded to the conditioned reward

when given an opiate antagonist (naltrexone; dose effect: F2,32= 1.72, non-signiﬁcant). Newman,
Pascal, Sadeghian, and Baldo [ 52] showed that rats who were fed sweetened shortening daily ate
signiﬁcantly more standard chow than rats not fed the palatable food when given a µ-opioid receptor
agonist (DAMGO), suggesting that opioid receptor activity may be associated with overeating and
consumption of highly palatable foods.
As a measure of opioid function, Daubenmier and colleagues [ 53] analyzed the effects of an
acute opioid blockade drug (naltrexone) on cortisol and nausea in overweight/obese women. They
found that women who engaged in more emotional and restrained eating had greater levels of cortisol

(r= 0.37, p< 0.05), and women who engaged in binge eating had greater levels of nausea in response

Nutrients 2018 ,10, 477 7 of 30
to the drug ( p= 0.048), suggesting that these individuals “may have a down-regulated opioidergic
system” (p. 99). Cambridge and associates [ 40] similarly found a signiﬁcant role for the µ-opioid
receptor system in motivation for food reward; they observed that a µ-opioid receptor antagonist
reduced motivation for, but not liking of, high calorie foods (e.g., chocolate) in people with obesity and
moderate binge eating ( p< 0.05). Although the authors did not conclude that their results supported
food as an addictive substance, they did indicate a role for the µ-opioid system in food-related reward.
3.1.4. Other Neurobiological Changes
In a controlled study conducted on primates, Duarte and colleagues [ 54] found that chocolate
induced a persistent conditioned place preference response usually only seen in response to drug
rewards. Monkeys who received chocolate spent more time in environments where they had previously

received chocolate, whereas controls showed no place preference ( F1,13= 13.59, p= 0.003, η2p= 0.53).
Conditioning persisted even after a 15-day follow-up ( F1,13= 4.31, p= 0.06, η2p= 0.26), indicating that
chocolate, like drugs, can be used for this type of conditioning. In rats, Le Merrer and Stephens [ 51]
found that an AMPA receptor antagonist blocked the conditioned response to sweetened pellets
(F2,34= 3.02, non-signiﬁcant) in a manner comparable to drugs of abuse. Additionally, Newman and
colleagues [ 52] suggested that gamma-aminobutyric acid (GABA) receptor activity may be implicated
in food addiction; they found that rats given a daily dose of sweetened shortening ate signiﬁcantly
more standard chow than rats not fed the palatable food when given muscimol, a GABA agonist that

induces feeding ( ps < 0.01).
In a study comparing rats genetically prone to obesity against rats resistant to obesity, Mary
Brown and colleagues [ 55] reported a signiﬁcant role for the NAc glutamatergic system in driving
overeating ( ps < 0.05), similar to the glutamatergic mechanisms seen in animal models of relapse to drug
addictions. Additionally, P érez-Ortiz and associates [ 56] found that rats fed a high-fat diet (primarily
lard, casein, and sucrose), exhibited increases in potential biomarkers of addiction (fumarate hydratase,
ATP synthase subunit alpha, and transketolase) in the NAc ( p< 0.05). Adams and colleagues [ 41],
however, found that a high fat diet (primarily lard) reduced activity of cAMP response element-binding

protein (CREB; F1,10= 5.4, p= 0.042) and its activated form (pCREB; F1,10= 5.9, p= 0.036) in the NAc,
contrary to their prediction.
In an electroencephalographic (EEG) study by Imperatori and colleagues [ 57], participants with
three or more food addiction symptoms on the YFAS exhibited brain changes similar to those in people
with addictive disorders (e.g., increased functional connectivity in fronto-parietal areas; ps < 0.05).
A functional magnetic resonance imaging (FMRI) study by Gearhardt and colleagues [ 12] found that
YFAS symptom scores were correlated with increased activation in the amygdala, cingulate cortex,
and medial orbitofrontal cortex when participants were anticipating consumption of a chocolate
milkshake. When participants received the milkshake, those with higher YFAS scores had greater

activation in the dorsolateral prefrontal cortex ( p= 0.007) and caudate ( p= 0.004) and less activation in
the lateral orbitofrontal cortex ( p= 0.009) compared to those with lower YFAS scores. Gearhardt and
colleagues concluded that this pattern of increased activation in areas of the brain related to reward
and decreased activation in areas related to inhibition is similar to that seen in substance dependence.
De Ridder and colleagues [ 58] compared resting-state EEG brain activity between (1) adults with
obesity who endorsed more than three YFAS symptoms (“High YFAS”), (2) adults with obesity who
endorsed less than three YFAS symptoms (“Low YFAS”), (3) adults without obesity or food addiction
(“Lean controls”), and (4) adults without obesity but with alcohol use disorder (“Alcohol addiction”).

Positive correlations were found between YFAS symptoms and the rostral anterior cingulate cortex
(rACC) for theta ( r= 0.23, p= 0.041) and beta3 ( r= 0.22, p= 0.041) frequency bands. Increased gamma
activity in the rostral anterior cingulate cortex (rACC) extending to the dorsal medial prefrontal
cortex (dmPFC) was associated with increased hunger ratings in the High YFAS group only ( r= 0.72,
p= 0.002), and increased alcohol craving in the Alcohol addiction group ( r= 0.72, p= 0.002), while
the rACC was negatively correlated with hunger in the Low YFAS group. Conjunction analyses

Nutrients 2018 ,10, 477 8 of 30
further revealed similarities between the High YFAS group and the Alcohol addiction group in the
ACC/dmPFC and precuneus ( Z= 2.24, p= 0.013), sgACC, orbitofrontal cortex (OFC), and temporal
lobe (fusiform/parahippocampal area) ( Z= 2.78, p= 0.003). No correlations were found between
the Low YFAS and Alcohol addiction groups. The authors concluded that there were signiﬁcant
neurobiological similarities between persons with food addiction symptoms and alcohol dependence.
In a gustatory cue exposure trial among overweight/obese adolescents, Feldstein Ewing and
associates [ 59] found that consumption of high-calorie beverages (Sprite, Fanta, or Coca Cola) produced
brain responses (e.g., increased activation in the nucleus accumbens, cerebellum, bilateral OFC, etc.)
similar to those observed in response to addictive drugs. Unlike Gearhardt and colleagues, however,
they found no signiﬁcant relationship between YFAS symptoms and brain response.

Finally, Franken and colleagues [ 60] found that, similar to patterns seen in drug addiction,
individuals with more YFAS symptoms displayed more impairments in cognitive control and
performance monitoring on behavioral (Flanker task; r= 0.39, p= 0.001) and neurological (EEG;
p< 0.05) tests.
3.2. Preoccupation with Substance Use
Given obvious constraints, no animal studies assessed the characteristic of “preoccupation” as it
relates to food addiction. However, Tuomisto and colleagues [ 61] found that self-identiﬁed chocolate
addicts were signiﬁcantly more susceptible to hunger compared to controls, possibly indicating a
heightened preoccupation with food ( F1,26= 11.65, p< 0.005). Additionally, Merlo and colleagues [ 18]

found that in children, food addiction symptoms (measured by the Eating Behaviors Questionnaire)
were signiﬁcantly associated with greater preoccupation with food ( r= 0.58, p< 0.001; measured by
the Children’s Eating Attitude Test).
3.3. Impaired Control
3.3.1. Substance Used in Larger Amounts or over a Longer Period than Intended
Burmeister, Hinman, Koball, and Hoffmann [ 62] found that in a sample of treatment-seeking
adults with obesity, the number of addictive-like eating symptoms endorsed on the YFAS was
associated with greater self-reported difﬁculty controlling eating in certain situations (e.g., when
nervous or in social settings; r= 0.59, p< 0.01). In their pediatric sample, Merlo and colleagues [ 18]

found a signiﬁcant positive association between the uncontrolled eating subscale on the Three
Factor Eating Questionnaire and symptoms of food addiction ( r= 0.60, p< 0.001) on the Eating
Behaviors Questionnaire.
3.3.2. Persistent Desire or Unsuccessful Efforts to Cut Down or Control Substance Use
No studies speciﬁcally evaluated this sub-criterion.
3.3.3. Great Deal of Time Spent Obtaining, Using, or Recovering from the Effects of the Substance
Furlong and colleagues [ 42] randomly assigned rats to either restricted, continuous, or no access
to sweetened condensed milk for ﬁve weeks. They reported that, compared to the continuous access
and no access (control) conditions, rats given restricted access to sweetened condensed milk exhibited
more habitual behavior and time attempting to obtain the treat (i.e., continuing to press a lever, despite

the absence of its conditioned reward). Mary Brown and colleagues [ 55] reported that rats who became
obese due to overconsumption of highly palatable food (consisting mostly of lard, casein, and sucrose)
also exhibited more perseverative behaviors related to highly palatable foods by lever pressing in the
absence of a reward ( t= 3.76, p= 0.006), greater motivation for the palatable food ( t =3.755, p= 0.006),
and greater number of lever presses ( t= 2.87, p= 0.007) compared to rats on the same diet who did not
become obese.

Nutrients 2018 ,10, 477 9 of 30
3.3.4. Craving, or a Strong Urge to Use the Substance
Lenoir and associates [ 43] found that rats preferred saccharin over cocaine when given the choice
(ps < 0.05), and were more willing to work for saccharin in the face of increased cost ( ps < 0.05),
indicating a strong desire to consume the sweetener.
Davis and colleagues [ 39] found that adults with obesity who met YFAS criteria for food addiction
reported signiﬁcantly greater food cravings ( p< 0.001), hedonic eating ( p< 0.001), and snacking on
sweets ( p< 0.001). In a separate study, Davis and associates [ 49] reported that participants with
clinically signiﬁcant food addiction symptoms (based on the YFAS) had higher scores on a measure
of food cravings ( F= 55.07, p< 0.001) compared to those without, and found that craving mediated
the relationship between dopamine signaling and clinically signiﬁcant food addiction symptoms

(95% CI: 0.04–0.93), even after controlling for binge eating and emotional eating. Additionally, Davis
and colleagues [ 50] demonstrated that individuals who met the YFAS criteria for clinically signiﬁcant
food addiction symptoms reported greater food cravings and appetite following a taste of their favorite
palatable food (e.g., potato chips, chocolate, cookies; p< 0.001).
In a study of bariatric surgery candidates with binge eating disorder, Lent and Swencionis [ 63]
found that food cravings were associated with higher scores on a measure of addictive personality
(r= 0.31, p= 0.005) and that addictive personality scores explained a signiﬁcant amount of the variance
in cravings ( R2= 0.10, p= 0.005). Tuomisto and colleagues [ 61] found that self-identiﬁed “chocolate

addicts” were more subjectively aroused and reported experiencing greater cravings when presented
with chocolate related cues (e.g., sight, smell, taste) than controls ( p< 0.001). Finally, Feldstein Ewing
and associates [ 59] observed significant increases in adolescent boys’ self-reported urges to eat after
tasting a sweetened beverage (e.g., Sprite, Fanta, or Coca Cola) compared to water ( t(23) = 2.20, p= 0.04).
3.4. Social Impairment
3.4.1. Failure to Fulﬁll Major Role Obligations at Work, School, or Home due to Recurrent
Substance Use
3.4.2. Continued Use Despite Social or Interpersonal Problems Caused/Exacerbated by Substance
Adams and colleagues [ 41] found that rats fed a calorie-restricted high-fat/low-sucrose diet began
seeking sucrose rewards more impulsively, even when impulsive behavior was punished with time-out

from other rats ( F1,11= 6.4, p= 0.028). However, rats fed the low-fat/high-sucrose diet did not show
the same level of impulsive behavior ( F1,12= 1.2, p= 0.297). No human studies speciﬁcally evaluated
this sub-criterion.
3.4.3. Reduction of Important Social, Occupational, or Recreational Activities due to Substance Use
No animal studies evaluated this sub-criterion; however, Lent and Swencionis [ 63] found that 60%
of their sample of bariatric surgery candidates endorsed choosing to spend time eating over conducting
other activities, and that this subgroup also had higher addictive personality scores ( p< 0.01). In turn,
higher scores on their addictive personality measure explained a signiﬁcant amount of the variance in
social isolation ( R2= 0.28, p< 0.001).
3.5. Risky Substance Use

3.5.1. Recurrent Substance Use in Physically Hazardous Situations
Johnson and Kenny [ 48] observed that rats given unrestricted access to a diet consisting of bacon,
sausage, cheesecake, pound cake, frosting, and chocolate continued to compulsively consume these
foods despite the presence of an aversive conditioned stimulus (i.e., a cue light that had previously been
paired with foot shock; F1,26= 29.7, p< 0.001). In contrast, rats previously fed only regular chow and/or

Nutrients 2018 ,10, 477 10 of 30
given restricted access to the high-fat/high-sugar diet signiﬁcantly decreased their palatable food
consumption in the presence of the aversive conditioned stimulus ( F1,26= 44.9, p< 0.001). No human
studies evaluated this sub-criterion.
3.5.2. Continued Use Despite Knowledge of Physical or Psychological Problem Likely Caused or
Exacerbated by the Substance
3.6. Pharmacological Criteria
3.6.1. Tolerance
Johnson and Kenny [ 48] found that rats who volitionally overate highly palatable food exhibited
reward dysfunction (e.g., downregulated dopamine D2 receptors, elevated reward thresholds) that
worsened as the rats gained more weight ( F2,6= 5.2, p< 0.05).
Among bariatric surgery candidates in Lent and Swencionis’s study [ 63], 68.5% reported
increasing quantities of food to reach satiation, and those who endorsed this symptom also had

higher scores on the addictive personality measure. Additionally, Spring and associates [ 64] showed
that among women who reported craving carbohydrates, a 100% carbohydrate sweetened beverage
(including sucralose, maltodextrin, dextrose, high maltose rice syrup, etc.) signiﬁcantly dispelled
negative mood ( t(789) = 2.17, p= 0.03). However, this effect decreased over multiple exposures,
indicating signs of tolerance among this sample ( t(95) = −2.82, p= 0.01). Finally, Markus and
colleagues [ 44] reported that the most common foods associated with tolerance-like effects in their
study were high-fat sweet foods (3.2%) and high-fat savory foods (2.9%), and that the “intensity” of
tolerance was greater for these foods compared to low-fat sugary foods ( ps < 0.05). The authors did

not report how “intensity” was measured.
3.6.2. Withdrawal
Mangabeira, Garcia-Mijares, and Silva [ 65] found that rats who preferred a sugar solution had
impaired differential reinforcement of low rate performance (a measure of impulsivity) when forced
into abstinence ( p< 0.001), similar to animals in withdrawal from addictive drugs. Pickering, Alsiö,
Hulting, and Schiöth [ 66] found that when given a high-fat/high-sugar diet, obesity-prone rats
exhibited withdrawal symptoms, including spending less time in the center of an open-ﬁeld test
(an indicator of anxiety; p< 0.05) and eating signiﬁcantly less regular chow ( p< 0.05) upon removal of
the high-fat/high-sugar diet. Sharma and colleagues [ 46] reported that upon withdrawal from their
diet, mice fed high-fat food (primarily hydrogenated coconut oil, maltodextrin, sucrose, and casein)

showed more signs of anxiety and increased basal cortisone levels ( p< 0.01), and the rats were more
motivated for both sucrose and high-fat foods compared to rats fed a low-fat diet ( p< 0.01). However,
Yakovenko, Speidel, Chapman, and Dess [ 67] reported that spontaneous withdrawal symptoms of
rats reported in other studies (forepaw tremor, teeth chatter, and head shake) were rare in their study.
While they did observe elevated startle (a symptom of ethanol withdrawal seen in the same line of
rats) dependent upon the prior dose of glucose intake ( r= 0.63), it was not signiﬁcantly different from
controls ( p> 0.10).
Lent and Swencionis [ 63] found that, in their sample of bariatric surgery candidates, individuals

who scored signiﬁcantly higher on an addictive personality measure also reported feeling more anxious
when they were not near food ( p< 0.01). Finally, Markus and associates [ 44] reported that among 1414
participants who reported experiencing at least one YFAS symptom in the past year, 9.5% endorsed
“withdrawal-like” physiological effects in response to either high-fat savory foods (3.8%), high-fat
sweet foods (2.8%), low-fat sugary foods (1.6%), or low-fat savory foods (1.3%). The self-reported
“intensity” of withdrawal symptoms were signiﬁcantly greater for high-fat savory and high-fat sweet
foods compared to low-fat sugary foods ( ps < 0.05).

Nutrients 2018 ,10, 477 11 of 30
3.7. Chronicity
McGee, Amare, Bennett, and Duncan-Vaidya [ 68] found that three days of a binge/compensate
pattern of eating sweetened vegetable shortening still had a signiﬁcant impact on rats’ motivation for
sucrose over one month later ( F2,19= 7.72, p< 0.01), suggesting long-term effects of palatable food
consumption. Pickering and colleagues [ 66] reported that obesity-prone rats fed a high-fat/high-sugar
diet consumed signiﬁcantly less chow during a three-week withdrawal period from those foods
(p< 0.05), possibly suggesting long-term changes to the rats’ reward system analogous to the chronic
state of dependence seen in drug addictions.
Konkolÿ Thege, Woodin, Hodgins, and Williams [ 5] described a longitudinal study in which they
evaluated the prevalence of six potentially-addictive behaviors among 4121 Canadian adults. They
found that only 6.3% of participants reported problems with excessive overeating for four consecutive

years compared to 58% reporting problems for one year only. The authors concluded that excessive
overeating may be more transient than drug addictions.
3.8. Relapse
Two articles by Pickering and colleagues [ 66] and Sharma and colleagues [ 46] reported that rats
and mice withdrawn from a highly palatable food diet demonstrated increased motivation for sucrose,
suggesting risk for relapse ( F1,390 = 4.71, p= 0.0491 and ps < 0.01, respectively). No human studies
evaluated this criterion.
3.9. Additional Observations
3.9.1. Genetics
In a genome-wide investigation of food addiction, Cornelis and associates [ 69] observed that
food addiction scores on the modiﬁed YFAS were signiﬁcantly associated with signaling in the

mitogen-activated protein kinase pathway, which has been identiﬁed as a possible drug addiction
pathway ( p= 0.02); however, other addiction-related genetic underpinnings did not overlap (e.g., genes,
single-nucleotide polymorphisms) with food addiction ( ps > 0.05).
3.9.2. Substance Sensitization
Le Merrer and Stephens [ 51] observed that mice exposed to sweetened pellets paired with a
speciﬁc context displayed signs of behavioral sensitization by showing greater progressive activity in
that context compared to mice that did not have the same pairing ( p< 0.05). This activity persisted for
three weeks in the absence of the palatable food and was described as being similar to those seen in
models of drugs sensitization. These authors also reported that conditioned environments produced

greater food consumption.
In humans, Spring and colleagues [ 64] observed that participants who reported craving
carbohydrates endorsed increased “liking” for a pure carbohydrate beverage over time, compared
to a control high-protein beverage ( t(98) = 1.98, p= 0.05), which the authors concluded suggested
sensitization to carbohydrates in this sample.
3.9.3. Cross-Sensitization
Le Merrer and Stephens [ 51] reported that rats sensitized to palatable food had a signiﬁcantly
enhanced locomotor response when given cocaine and morphine ( F1,18= 6.18, p< 0.05), suggesting
a cross-sensitization effect. However, Yakovenko and colleagues [ 67] failed to ﬁnd evidence for a
cross-sensitization effect of cookie consumption on alcohol intake among rats.

In a study on weight-loss surgery patients, Fowler, Ivezaj, and Saules [ 70] observed that
those who reported more problems with high glycemic index and high-sugar/low-fat foods before

Nutrients 2018 ,10, 477 12 of 30
surgery were more likely to develop a new substance use disorder post-surgery ( ps < 0.05),
indicating cross-sensitization.
3.9.4. Impulsivity
Adams and colleagues [ 41] found that rats fed a high-fat diet showed increased impulsivity in
working for a sucrose reward compared to rats fed a high-sugar diet ( F1,11= 6.4, p= 0.02). In humans,
Davis and associates [ 39] reported greater impulsivity among adults with obesity who met YFAS
criteria for food addiction compared to controls who did not ( p< 0.001).
3.10. Overall Addiction
Four studies reported results relevant to an overall characterization of addiction. Tuomisto and
associates [ 61] compared self-identiﬁed “chocolate addicts” to “non-chocolate addicts” in two studies
and found that exposure to chocolate cues led to affective changes (e.g., anxiety, restlessness) similar to
those seen in substance addiction. Additionally, Schulte, Avena, and Gearhardt [ 13] evaluated whether

certain foods were more likely to be associated with addictive-like eating in undergraduates and in a
more diverse sample of adults recruited through Amazon MTurk, respectively. Participants in their
study completed the YFAS and then were asked to complete a forced-choice task of identifying which
foods were associated with addictive symptoms. The authors reported that the foods most likely
to be implicated in addictive-like eating patterns were processed foods high in fat and/or reﬁned
carbohydrates. These foods, the authors stated, parallel pharmacokinetic properties of addictive drugs
(e.g., highly concentrated, rapid absorption rate).
4. Discussion
The concept of food addiction has sparked much controversy among researchers. While some
have questioned the validity of this construct [ 25,30], an increasing number of studies have produced

evidence of biological and behavioral changes in response to highly palatable foods that parallel
addiction criteria. The current study reviewed existing food addiction research and organized the
ﬁndings into key diagnostic constructs: (a) neurobiological changes, (b) preoccupation with the
substance, (c) impaired control, (d) social impairments, (e) risky use, (f) tolerance/withdrawal,
(g) chronicity of the condition, and (h) relapse. We found signiﬁcant support for the construct of
food addiction in both animals and humans, with each primary criterion having support from at
least one study (see Appendix, Table A3), though some sub-criteria have not yet been studied. Of the
addiction characteristics assessed in this review, brain reward changes and impaired control had

the greatest number of supportive ﬁndings (21 and 12 studies, respectively). The current review
also found evidence for supplemental characteristics consistent with addiction, including genetic
susceptibility, substance sensitization and cross-sensitization, and impulsivity. More research is
needed to evaluate the diagnostic criteria with less empirical support, including risky use, chronicity,
relapse, preoccupation, and social impairment. Only four of the 35 eligible articles reported ﬁndings
contrary to the proposed criteria for addiction [ 5,41,59,67], yet two of these also included supportive
ﬁndings [ 41,59]. Overall, evidence supporting the validity of food addiction signiﬁcantly outweighed
evidence against it.

Some have proposed that food addiction should be classiﬁed as a behavioral disorder (i.e., “eating
addiction”) similar to a gambling disorder [ 71]. However, most research studies, including the vast
majority of studies identiﬁed for this review, have conceptualized food addiction as a substance use
disorder (i.e., “reﬁned food use disorder”, “highly palatable food use disorder”, or simply “food
use disorder” [ 14,19,72–75]. To address this question, Meule and Gearhart [ 14] compared diagnostic
criteria for gambling disorder—the only ofﬁcially recognized behavioral addiction in the DSM-5—to
symptoms of food addiction and found that despite several similarities (e.g., unsuccessful efforts to
cut down), food addiction symptoms more closely resembled those of a substance use disorder due to

Nutrients 2018 ,10, 477 13 of 30
the necessary consumption of a substance (food) and the inapplicability of certain behavioral criteria
(e.g., monetary loss: DSM-5 criteria 1, 6, and 5).
By deﬁnition, behavioral addictions involve dependence on a behavior, not a substance; however,
addictive-like consumption of highly palatable food involves both a behavior (eating) and substance
(food). Some classic substance addictions, such as tobacco use disorder, also appear to include
behavioral dependencies. For example, behavior modiﬁcation is typically required in treatment for
tobacco use disorder due to the strong connection between the effects of the substance (tobacco)
and the act of using it (e.g., smoking) [ 76]. Nevertheless, tobacco is the primary driver of the
addiction, and it is therefore classiﬁed as a substance use disorder. In the current review, symptoms
suggestive of “addiction” to highly palatable foods were often intertwined with speciﬁc eating patterns

(i.e., restriction, binge eating) [ 42,52,67]. However, these behavioral patterns are also frequently
observed among individuals with alcohol and other drug use disorders. In addition, characteristics of
food addiction were found in the absence of such eating patterns (e.g., [ 48]) and were preceded by
consumption of highly palatable foods, suggesting a proﬁle most similar to substance addiction. In light
of these ﬁndings, the results of the current review support Meule and Gearhardt’s [ 14] conclusion
that, while food addiction involves both behavioral and substance-related symptoms, it more closely
parallels criteria for substance use disorder.
Overall, the majority of the studies in the present systematic review evaluated foods with added
sweeteners (e.g., sugar, saccharine), and many experiments combined sweeteners with fats such as

hydrogenated oils or lard (see Appendix, Table A1). The current review found that the most common
foods associated with addictive symptoms were those high in added fats and/or reﬁned carbohydrates
such as sugar. These ﬁndings are consistent with prior literature. Avena, Rada, and Hoebel [ 77]
found that neural adaptations in response to sugar consumption could lead to dependence in rats,
and Iﬂand and colleagues [ 19] concluded that reﬁned foods (e.g., sodas, breakfast cereal, high-fructose
corn syrup) should be considered a “classic” addictive substance. Taking it one step further, Lustig
and colleagues [ 73] argued that sugar should be regulated as substance of abuse given the negative
health outcomes common to both sugar and alcohol at the individual and societal levels (e.g., liver

disease, associated medical costs). Schulte, Potenza, and Gearhardt [ 75] proposed that food addiction
more closely resembles a substance-based addiction as opposed to a behavioral addiction due to
the differential effects of certain foods types on eating behavior. Finally, Pursey and colleagues [ 34]
reviewed the literature on food addiction and concluded that the foods most commonly associated with
addictive-like symptoms in humans are those that are highly-processed, high on the glycemic index,
and contain large amounts of added fats and sugar. Although there is strong support for the addictive
potential of sugar in animal studies [ 77], data from human studies suggest that the combination of

sweet and fat is more commonly associated with addictive symptoms than sugar alone [34,44]. More
research is needed to identify the types and characteristics of food ingredients that may have addictive
effects in humans.
Few studies have evaluated whether food addiction can manifest in response to consumption of
unprocessed “whole foods.” Animal studies in the current review found no evidence for addictive-like
symptoms to rodent chow (e.g., [ 48]), and human studies reported increased addictive symptoms
toward reﬁned/processed foods compared to non-processed foods [ 13]. Nevertheless, in a study
by Schulte and colleagues [ 13] evaluating the addictive potential of speciﬁc foods, nuts (typically
considered a whole food, without added sugars) were rated more addictive on average than
granola bars (typically processed, with added sugars and fats). Furthermore, there was an isolated

report describing individuals who displayed addictive-like symptoms toward carrots [ 78]. While
highly palatable foods are associated with more addictive-like symptoms than non-processed foods,
the possibility of these symptoms occurring in response to “natural” food merits further exploration.
Future research should also examine potential biological and hormonal factors that play a role in
food addiction symptoms. Studies in this review found that rodents genetically prone to obesity had
greater risk for developing certain food addiction symptoms (i.e., craving, impaired control) compared

Nutrients 2018 ,10, 477 14 of 30
to obesity-resistant rodents [ 48,66]. In humans, symptoms of food addiction are more prevalent among
adults in the overweight and obese BMI categories (24.9%) compared to adults in the normal BMI
category (11.1%) [ 28]. However, a study comparing adults with overweight/obesity, found hormonal
differences (e.g., amylin, prolactin, thyroid stimulating hormone) between those who met criteria for
food addiction and those who did not [ 79]. These data indicate a need to further explore the biological
and hormonal factors associated with both weight and food addiction.
Finally, while multiple studies have shown that obesity, binge eating disorder, and food addiction
are separate constructs [ 26,27], their distinct etiologies leave much to be clariﬁed. Future research
should continue to examine the neurological correlates and differences between obesity, eating
disorders, and food addiction. Potential theoretical and clinical implications of these differences

should be explored.
To our knowledge, this is the ﬁrst systematic review on food addiction that was not limited to
deﬁnitions based on the YFAS or body weight status. Strengths include the use of human and animal
studies, rigorous methodology using PRISMA guidelines and inclusion of both animal and human
studies. Limitations include that our search was limited to two electronic databases and only included
studies published in English, and that animal studies limit generalizability to humans. In addition,
our risk of bias assessment may have resulted in lower scores for older studies, due to changes over
time in reporting standards (e.g., ﬁnancial support, conﬂicts of interest). The study question may

also have produced biased results, as researchers interested in evaluating the validity of the food
addiction construct may be more inclined (consciously or not) to observe and report conﬁrmatory
results. When combined with publication bias, this may have resulted in an underrepresentation of
studies producing contrary or null ﬁndings. Finally, our search criteria likely excluded evidence for
certain characteristics of addiction (e.g., social impairment, risky use, preoccupation) because these
constructs are relatively difﬁcult to measure quantitatively. However, these symptoms have been
reported in qualitative studies (e.g., [ 80]) and are plausible when considering, for example, individuals

who continue to overeat post-bariatric surgery or despite exacerbated chronic medical conditions such
as diabetes or heart disease [ 14,26]. As recommended by Burrows and colleagues [ 26], future reviews
on food addiction could beneﬁt from including both quantitative and qualitative studies.
5. Conclusions
The results of the current systematic review generally support the validity of food addiction
as a diagnostic construct, particularly as it relates to foods high in added sweeteners and reﬁned
ingredients. The majority of studies in the current review reported evidence for symptoms related to
neurological changes and impaired control, with fewer studies evaluating preoccupation, chronicity,
relapse, social impairment, and risky use. Behavioral and substance-related aspects of food addiction

appear to be intertwined, but we suggest that the substance (highly-palatable food) component may be
more salient to the diagnostic classiﬁcation of this phenomenon than the behavior (eating). We propose
that the food addiction construct merits serious attention in regard to its presentation, prevention,
and treatment in humans.
Acknowledgments: Publication of this article was funded in part by the University of Florida Open Access
Publishing Fund.
Author Contributions: The review protocol was developed by Eliza L. Gordon. Retrieval and screening of
articles for inclusion was undertaken by Eliza L. Gordon with assistance from Viviana Bauman. The risk of bias
assessment was undertaken by Eliza L. Gordon and Viviana Bauman. Signiﬁcant revisions were completed by
Lisa J. Merlo. Additional revisions were provided by Aviva H. Ariel-Donges and Viviana Bauman. All authors

contributed content to and approved the ﬁnal manuscript.
Conﬂicts of Interest: The authors declare no conﬂict of interest.

Nutrients 2018 ,10, 477 15 of 30
Appendix
Table A1. Characteristics of included studies.
First Author (Year) Study Type Sample Characteristicsn
(Experimental/Control)Independent Variable(s) Outcome(s)
Adams (2015) [41] Animal Male Long-Evans rats 16/8Restricted, equicaloric
high-fat/low-sugar vs.
low-fat/high-sugar dietsImpulsivity and attention,
measured by the ﬁve-choice serial
reaction time task; dopamine
signaling in the dorsal and ventral
striatum; insulin and leptin levels
in the plasma
Burmeister (2013) [62] Cross-sectionalAdults with obesity in a
behavioral weight-loss program
Female: 68.4%
Age: 47.4 years
BMI: 38.2 kg/m2
Caucasian: 84.2%57/0Food addiction symptoms
(YFAS continuous)7-week weight change; measures of
psychological distress, disordered
eating, weight bias,
and weight-focused attitudes
Cambridge (2013) [40]Double-blind,
placebo-controlled
parallel group studyAdults with obesity and
moderate binge eating
Female: 53.3%
Age: 40.2 years16/14Mu-opioid receptor

antagonist (GSK1521498) or
placeboBrain responses to food images
(FMRI and behavioral measures);
motivation to expend energy to
view comparable images
Colantuoni (2001) [47] Animal Female Sprague-Dawley rats 10/5“Intermittent excessive sugar
intake” (25% glucose solution
with chow for 12 h followed
by 12 h of food deprivation
each day)Receptor binding (e.g., dopamine,
opioid)
Cornelis (2016) [69]Genome-wide
association studyWomen of European ancestry
participating in the Nurses’
Health Study
Age: 25–55 years at start9314/0 Food addiction (mYFAS)Enrichment of SNPs, genes,
and pathways implicated in
drug addiction
Daubenmier (2014) [53] Cross-sectionalWomen in a waitlist control for
a randomized controlled trial of
a mindfulness intervention for
stress eating
Age: 40.9 years

BMI: 31.1 kg/m216/17Naltrexone-induced nausea
and cortisol levels (measure
of central opioidergic activity)Indices of hedonic-related eating
behaviors (binge, emotional,
external, or restrained eating);
intake of sweets/desserts,
carbohydrates; interoceptive
awareness; adiposity;
weight change

Nutrients 2018 ,10, 477 16 of 30
Table A1. Cont.
Davis (2011) [39] Cross-sectionalAdults with obesity
Female: 68.1%
Age: 33.6 years
BMI: 38.5 kg/m2
Caucasian: 81.4%18/54Food addiction (YFAS
dichotomous)Clinical co-morbidities (e.g., binge
eating disorder, attention deﬁcit
hyperactivity disorder),
psychological risk factors
(e.g., impulsivity), and abnormal
motivation for the addictive
substance
Davis (2013) [49] Case-controlAdults recruited for study on
overeating/overweight
Female: 68.3%
Age: 25–47 years21/99Composite index of elevated
dopamine signaling (a
multi-locus genetic proﬁle
score)Food addiction (YFAS
dichotomous); eating-related
sub-phenotypes of food addiction
(e.g., binging)
Davis (2014) [50]Three-way mixed model,
double-blind cross-overAdults, predominately
overweight/obese
Female: 67.7%
Age: 32.7 years
BMI: 33.9 kg/m223/113Food addiction (YFAS

dichotomous); psychomotor
stimulant (methylphenidate)
vs. placeboAppetite, cravings,
and consumption of favorite snack
De Ridder (2016) [58] Cross-sectionalAdults
Female: 79.3%
Age: 45.1 years
BMI: 33.2 kg/m238/34Weight category (normal vs.
obese BMI); food addiction
(YFAS continuous)EEG; hunger; behavioral inhibition;
eating style; binge eating; food
awareness
Duarte (2014) [54] AnimalMarmoset monkeys
Female: 50%6/815 min exposure to 50 g
chocolateConditioned-place-preference
Feldstein Ewing (2017)
[59]Cross-sectionalYouth, overweight/obese
Male: 83.3%
Age: 16.5 years
BMI: 33.1 kg/m2
Hispanic: 79%24/0Beverage type (sweetened
soft drink vs. water); food
addiction (YFAS continuous);
BMI; insulin resistanceUrge to eat; FMRI response
patterns (BOLD activation)

Fowler (2014) [70] Secondary data analysesAdults, 2.7 years post-bariatric
surgery
Female: 88.4%
Age: 48.7 years
BMI: 32.3 kg/m2
Caucasian: 94.2%154/0Pre-surgical problems with
high-sugar/low-fat foods and
foods with a high glycemic
indexRisk for new onset substance use
disorder post-surgery
Franken (2016) [60] Cross-sectionalStudents recruited for larger
YFAS study
Age: 20.4 years
BMI: 21.7 kg/m234/34Food addiction (YFAS
continuous)Cognitive control (error
monitoring) via Eriksen ﬂanker
task and EEG (ERN, Pe)

Nutrients 2018 ,10, 477 17 of 30
Furlong (2014) [42]
study 1Animal Male Long-Evans rats 24/12Continuous vs. restricted
access to sweetened
condensed milk (3:1 ratio of
Nestle to water)Goal-directed performance and
neuronal activity in corticostriatal
circuits
study 2Animal Male Long-Evans rats 8/10AMPA-receptor and
dopamine D1-receptor
antagonistsHabitual performance following
restricted access to a highly
palatable food
Gearhardt (2011) [12] Cross-sectionalYoung women
Age: 20.8 years
BMI: 28.0 kg/m239/0Food addiction symptoms
(YFAS continuous)FMRI patterns of neural activation
similar to substance dependence (in
response to actual and anticipated
receipt of chocolate milkshake)
Imperatori (2015) [57] Cross-sectionalAdults with overweight or
obesity admitted to a medical
center for obesity treatment
Female: 78.6%
Age: 43.6 years

BMI: 28.5 kg/m214/14Food addiction symptoms
(I-YFAS continuous and
dichotomous); taste of
chocolate milkshakeEEG modiﬁcations and
connectivity
Johnson (2010) [48]
study 1Animal Male Wistar rats 22/9Restricted vs. extended access
to “cafeteria style” diet (e.g.,
bacon, sausage, cheesecake,
frosting)Brain stimulation reward threshold;
body weight change; caloric intake;
type of food consumed (cafeteria
vs. chow)
study 2Animal Male Wistar rats Not reportedRestricted vs. extended access
to cafeteria style diet; body
weight; knockdown of striatal
dopamine D2 receptorReward hyposensitivity (measured
by striatal D2 receptor density);
brain stimulation reward threshold;
vs. chow)

vs. chow)
study 3Animal Male Wistar rats Not reportedRestricted vs. extended access
to cafeteria style diet followed
by intermittent access (30
min) to cafeteria food;
environmental stimulus
(light) predicting adversity
(foot shock)Brain stimulation reward threshold;
vs. chow); compulsive-like eating
behavior

Nutrients 2018 ,10, 477 18 of 30
study 4Animal Male Wistar rats Not reportedRestricted vs. extended access
to cafeteria style diet;
knockdown of striatal
dopamine D2 receptor;
(light) predicting foot shockBrain stimulation reward threshold;
caloric intake; type of food
consumed (cafeteria vs. chow);
compulsive-like eating behavior
Konkolÿ Thege (2015) [5] Longitudinal studyAdults
Female: 54.7%
Age: 46.1 years4121/0Over-involvement (causing
signiﬁcant problems) in one
of six excessive behaviors
(including eating)Prevalence, substance use
comorbidity, ﬁve-year trajectory
Le Merrer (2006) [51]
studies 1 & 2Animal Male mice 20/10Sweetened pellets while
hungry vs. while satiatedBehavioral sensitization (assessed
by locomotor activity in
sweetened-pellet-paired
environment)

study 3Animal Male mice 9-10/0Dopaminergic agonists
(SCH23390, sulpiride)Pellet-induced conditioned activity
study 4Animal Male mice 20/0Opiate (naltrexone) and
AMPA (GYKI 52466) receptor
antagonistsPellet-induced conditioned activity
study 5Animal Male mice 20/0Cocaine or morphine;
pretreatment of GYKI 52466,
naltrexone, or SCH23390Cross-sensitization (pellet-induced
conditioned activity following
cocaine or morphine injection)
study 6Animal Male mice 7–9/0Sweetened-pellet-conditioned
environmentConsumption of sweetened pellets;
locomotor activity
Lenoir (2007) [43] Animal Young male Wistar rats 132/0Mutually exclusive choice
between sweetened water
and intravenous cocaine;
history of cocaine preferencePreferred substance (saccharin,
sugar, or cocaine)

Lent (2012) [63] Cross-sectionalAdult bariatric surgery
candidates
Female: 85.6%
Age: 41.0 years
BMI: 45.2 kg/m2
Caucasian: 67.0%97/0Addictive personality
(Eysenck Personality
Questionnaire Addiction
Scale)Maladaptive eating behaviors
(Overeating Questionnaire;
binge-eating questions from
Questionnaire of Eating and
Weight Patterns; Eating Attitudes
and Behaviors Questionnaire)

Nutrients 2018 ,10, 477 19 of 30
Mangabeira (2015) [65] Animal Male Wistar rats 14/14Withdrawal from prolonged
sugar consumptionImpulsivity (assessed by differential
reinforcement of low rate
performance)
Markus (2017) [44] Cross-SectionalUndergraduates
Female: 69.9%
Age: 21.6 years1495/0Food addiction (YFAS
dichotomous, continuous}Depressive symptoms; BMI; YFAS;
“problem foods” (high-fat savory,
high-fat sweet, low-fat sugary,
low-fat savory)
Mary Brown (2015) [55] Animal Male Sprague-Dawley rats Not reportedPropensity to diet-induced
obesityAddictive-like behavior
(i.e., heightened motivation;
excessive intake; increased food
seeking); synaptic impairments in
NAc
McGee (2010) [68] Animal Male Long–Evans rats 16/8Withdrawal from intermittent
access to a sweet fat mixtureMotivation (operant performance for
sucrose on progressive ratio

NAc
schedule); craving (lever pressing for
palatable food); anxiety (elevated
plus maze)
Merlo (2009) [18] Cross-sectionalChildren
Female: 64%
Age: 13.8 years
BMI: 35.6 kg/m2
Caucasian: 60%
Parent/guardian
Female: 87%
Age: 43.2 years
BMI: 33.0 kg/m250/0 children and their
parent/guardianBMI; Food addiction
symptoms (Eating Behaviors
Questionnaire)Food- and eating-related attitudes
and behaviors
Newman (2013) [52] Animal Male Sprague-Dawley rats 10/11Bouts of sweetened-fat intake
(shortening with 10%
sucrose); predator stress;
intra-NAc shell infusions of
either d-amphetamine or
opioid agonist DAMGO;
GABA agonist, muscimolNeuroadaptations in NAc shell
GABA systems

Nutrients 2018 ,10, 477 20 of 30
Pérez-Ortiz (2016) [56] AnimalC57BL/6J male mice
Age: 4 weeks20/20High fat diet followed by 12 h
food deprivationPalatable food seeking; expression
of potential addiction biomarkers
in the NAc: fumarate hydratase
(FH), ATP synthase subunit alpha
(ATP5a1) and transketolase (TKT)
Pickering (2009) [66]
study 1Animal Male Wistar rats 12/0Sugar content of pellets
(50% vs. 95%)Sugar consumption
study 2Animal Male Wistar rats 9/3High-fat high-sugar diet
(lard, sucrose)Caloric intake; body weight change
study 3Animal Male Wistar rats 16/8High-fat high-sugar diet
(lard, sucrose); vulnerability
for weight gain; withdrawal
from lard and sucrose dietCaloric intake; body weight change;
motivation for sugar; anxiety-like
behavior (open-ﬁeld test)

Schulte (2015) [ 13] study 1 Cross-sectionalUndergraduates
Female: 67.5%
Age: 19.3 years
BMI: 23.0 kg/m2
Caucasian: 72.5%120/0Food items (e.g., chocolate,
broccoli) and types
(e.g., processed)Food addiction symptoms (YFAS)
Schulte (2015) [ 13] study 2 Cross-sectionalAdults
Male: 59.4%
Age: 31.1 years
BMI: 27.0 kg/m2
Caucasian: 76.8%384/0Food characteristics
(e.g., proportions of fats,
carbohydrates; level of
processing)Self-reported problematic eating
behavior
Sharma (2013) [ 46] study 1 AnimalMale mice
Age: 6–7 weeks12 (treated + control)High fat diet (58% kcal from
fat: including hydrogenated
coconut oil, maltodextrin,
sucrose, casein) vs.
ingredient-matched low fat
diet (10.5% kcal from fat);
withdrawal from dietMotivation for sucrose or high-fat
reward; caloric intake; body weight
change

change
Sharma (2013) [ 46] study 2 AnimalMale mice
Age: 6–7 weeks30 (treated + control)High fat diet vs. low fat diet
(10.5% kcal from fat);
withdrawal from dietAnxiety-like behavior (elevated
plus maze); plasma corticosterone

Nutrients 2018 ,10, 477 21 of 30
Sharma (2013) [ 46] study 3 AnimalMale mice
Age: 6–7 weeks48 (treated + control)High fat diet vs. low fat diet
withdrawal from dietBasal corticosterone; protein levels
for tyrosine hydroxylase,
corticosterone releasing factor type
1 receptor, BDNF, phospho-CREB
and∆FosB in amygdala, NAc and
ventral tegmental area via western
immunoblotting
Spring (2008) [64]Double-blind within and
between subjects
cross-overWomen who are overweight or
obese
Age: 28.0 years
BMI: 27.6 kg/m2
Caucasian: 50.8%61/0Negative mood; consumption
of carbohydrate-rich beverageMood; drink preference
(carbohydrate-rich vs.
macronutrient-balanced) during
negative mood state
Tuomisto (1999) [61]
study 1Case-controlWomen
Age: 35.4 years
BMI: 26.7 kg/m216/15Self-identiﬁed “chocolate
addiction”; type of exposure
to chocolate (look, smell, or

taste)Psychological symptoms
(e.g., depression, disinhibition,
disordered eating) measured by
questionnaires; self-reported
reactivity to cues (e.g., anxiety,
calmness); salivation, heart rate
study 2Case-controlWomen
to chocolate (look or smell)Amount of chocolate consumed;
psychological symptoms
Yakovenko (2011) [67]
study 1AnimalOccidental low- and
high-saccharin-consuming rats
(LoS and HiS, respectively)
Age: 60–90 days13–15/0Line of ingestive phenotype
(LoS vs. HiS); periodic access
to glucose solution followed

by 24 h food withdrawalWithdrawal symptoms (acoustic
startle); glucose consumption
study 2AnimalLoS and HiS rats
Age: 60–90 days8/0Line of ingestive phenotype
by 24 h food withdrawal;
naloxoneWithdrawal symptoms (e.g., startle
behavior); glucose consumption
study 3AnimalLoS and HiS rats
Age: 60–90 days8/0Binge-like feeding of cookies
and shorteningCookie, shortening, and ethanol
consumption

Nutrients 2018 ,10, 477 22 of 30
Table A2. Risk of bias assessment of included studies.Was a Random or Pseudo
Random Sample Used?
Was the Inclusion Criteria
Clearly Deﬁned?
Were Confounding Factors
Identiﬁed and Control
Strategies Stated?
Were Outcomes Assessed
Using Objective Criteria?
Was There Sufﬁcient
Description of the Groups?
Is There a Description of
Withdrawals and
Drop-Outs?
Are the Methods of
Statistical Analysis
Described?
Is the Source of Financial
Support Described?
Investigators and
Assessors, with Possible
Conﬂicts of Interest?
Quality Score [Y/(N + UC)]
Adams (2015) [41] Y Y Y Y Y Y Y Y Y All Ys
Burmeister (2013) [62] N Y UC Y N/A Y Y N N 1
Cambridge (2013) [40] Y Y Y Y Y Y Y Y Y All Ys
Colantuoni (2001) [47] Y Y Y Y Y Y Y Y N 8
Cornelis (2016) [69] N Y Y Y N/A Y Y Y Y 7
Daubenmier (2014) [53] Y Y Y Y UC Y Y Y N 3.5
Davis (2011) [39] N Y UC Y Y UC Y N N 0.8
Davis (2013) [49] N Y Y Y Y UC Y Y Y 3.5
Davis (2014) [50] Y Y Y Y Y N Y N Y 3.5

De Ridder (2016) [58] N Y Y Y Y UC Y N Y 2
Duarte (2014) [54] Y Y Y Y Y Y Y Y N 8
Feldstein Ewing (2017) [59] N Y Y Y N/A N Y Y Y 3
Fowler (2014) [70] UC Y Y Y UC N UC Y Y 1.25
Franken (2016) [60] N Y Y Y Y Y Y N Y 3.5
Furlong (2014) [42] Y Y Y Y Y Y Y Y Y All Ys
Gearhardt (2011) [12] UC Y Y Y N N Y Y Y 2
Imperatori (2015) [57] UC Y Y Y Y UC Y N Y 2
Johnson (2010) [48] Y Y Y Y Y UC Y Y Y 8
Konkolÿ Thege (2015) [5] N N UC Y Y Y Y Y Y 2
Le Merrer (2006) [51] Y Y Y Y Y N Y N N 2

Nutrients 2018 ,10, 477 23 of 30
Table A2. Cont.Was a Random or Pseudo
Lenoir (2007) [43] Y Y Y Y Y Y Y Y Y All Ys
Lent (2012) [63] N N Y Y N/A Y Y Y Y 3
Mangabeira (2015) [65] Y Y Y Y Y UC Y Y N 3.5
Markus (2017) [44] N N Y Y N UC Y Y Y 1.25
Mary Brown (2015) [55] Y Y Y Y Y UC Y Y Y 8
McGee (2010) [68] Y Y Y Y Y Y Y Y N 8
Merlo (2009) [18] N Y UC Y Y UC Y Y N 1.25
Newman (2013) [52] Y Y Y Y Y UC Y Y Y 8
Pérez-Ortiz (2016) [56] Y Y Y Y Y Y Y Y N 8
Pickering (2009) [66] N Y Y Y Y Y Y Y N 3.5

Schulte (2015) [13] N N Y Y N/A Y Y Y Y 3
Sharma (2013) [46] Y Y Y Y Y UC Y Y Y 8
Spring (2008) [64] N Y Y N N/A Y Y Y N 1.67
Tuomisto (1999) [61] Y UC Y Y Y Y Y N N 2
Yakovenko (2011) [67] Y Y Y Y Y UC Y Y N 3.5
N = No, Y = Yes, UC = Unclear, N/A = Non-Applicable.

Nutrients 2018 ,10, 477 24 of 30
Table A3. Evidence for and against addiction criteria.
Characteristic Supporting Evidence Null/Contrary Evidence
Brain changesAnimal studies:
1. Adams (2015) [41]
2. Colantuoni (2001) [47]
3. Duarte (2014) [54]
4. Furlong (2014) [42] study 2
5. Johnson (2010) [48] study 2
6. Johnson (2010) [48] study 4
7. Le Merrer (2006) [51] study 3
8. Le Merrer (2006) [51] study 4
9. Mary Brown (2015) [55]
10. Newman (2013) [52]
11. Pérez-Ortiz (2016) [56]
12. Sharma (2013) [46] study 3
Human studies:
13. Cambridge (2013) [40]
14. Daubenmier (2014) [53]
15. Davis (2013) [49]
16. Davis (2014) [50]
17. De Ridder (2016) [58]
18. Feldstein Ewing (2017) [59]
19. Franken (2016) [60]
20. Gearhardt (2011) [12]
21. Imperatori (2015) [57]Adams (2015) [41] (animal study)
Feldstein Ewing (2017) [59] (human study)
PreoccupationHuman studies:
1. Merlo (2009) [18].
2. Tuomisto (1999) [61] study 1.
3. Tuomisto (1999) [61] study 2.N/A

Nutrients 2018 ,10, 477 25 of 30
Table A3. Cont.
Impaired controlAnimal studies:
1. Furlong (2014) [ 42] study 1—Spending a signiﬁcant amount of time acquiring, using, or
recovering from a substance.
2. Lenoir (2007) [43]—Craving.
3. Mary Brown (2015) [55]—Spending a signiﬁcant amount of time acquiring, using, or
4. Burmeister (2013) [62]—Consuming a substance in greater amounts or over longer
periods of time than intended.
5. Davis (2011) [39]—Craving.
6. Davis (2013) [49]—Craving.
7. Davis (2014) [50]—Craving.
8. Feldstein Ewing (2017) [59]—Craving.
9. Lent (2012) [63]—Craving.
10. Merlo (2009) [18]—Consuming a substance in greater amounts or over longer periods
of time than intended.
11. Tuomisto (1999) [61] study 1—Craving.
12. Tuomisto (1999) [61] study 2—Craving.N/A
Social impairmentAnimal studies:
1. Adams (2015) [41]—Continually using a substance despite its effects causing or

exacerbating persistent or recurrent social or interpersonal problems.
2. Lent (2012) [63]—Giving up or reducing social, occupational, or recreational activities.N/A
Risky useAnimal studies:
1. Johnson (2010) [ 48] study 3—Continually using a substance in situations in which it is
physically dangerous.N/A

Nutrients 2018 ,10, 477 26 of 30
Tolerance/WithdrawalAnimal studies:
1. Johnson (2010) [48] study 1—Tolerance.
2. Mangabeira (2015) [65]—Withdrawal.
3. Pickering (2009) [66] study 3—Withdrawal.
4. Sharma (2013) [46] study 2—Withdrawal.
5. De Ridder (2016) [58]—Withdrawal.
6. Lent (2012) [63]—Tolerance; Withdrawal.
7. Markus (2017) [44]—Tolerance; Withdrawal.
8. Spring (2008) [64]—Tolerance.Yakovenko (2011) [67]
study 1
study 2 (animal studies)
ChronicityAnimal studies:
1. McGee (2010) [68].
2. Pickering (2009) [66] study 3.Konkolÿ Thege (2015) [5] (human study)
RelapseAnimal studies:
1. Pickering (2009) [66] study 3.
2. Sharma (2013) [46] study 1.N/A
OverallHuman studies:
1. Tuomisto (1999) [61] study 1.
2. Tuomisto (1999) [61] study 2.
3. Schulte (2015) [13] study 1.
4. Schulte (2015) [13] study 2.N/A

Nutrients 2018 ,10, 477 27 of 30
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A matter of changes in behavior rather than food addiction? Int. J. Obes. 2016 ,40, S12–S21. [CrossRef]
[PubMed]
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that evaluate health care interventions: Explanation and elaboration. J. Clin. Epidemiol. 2009 ,62, e1–e34.
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Review and Resource Manual
Psychiatric–
Mental 
Health Nurse 
Practitioner
4th Edition
CONTINUING E DUC ATION S OURCE
NURSING CERTIFIC ATION REVIEW MANUAL 
CLINICAL PRACTICE RESOURCE
Published by American Nurses Association
Kathryn Johnson, MSN, PMHNP -BC, PMHCNS-BC  
Dawn Vanderhoef, PhD, DNP, PMHNP -BC, PMHCNS-BC

Names: Johnson, Kathryn, 1947-, author. | Vanderhoef, Dawn, author. | 
   Nursing Knowledge Center, publisher.
Title: Psychiatric-mental health nurse practitioner review and resource 
   manual / Kathryn Johnson, Dawn Vanderhoe.
Other titles: Psychiatric-mental health nurse practitioner review manual
Description: 4th edition. | Silver Spring, MD : Nursing Knowledge Center, 
   American Nurses Association, 2016. | Preceded by Psychiatric-mental health 
   nurse practitioner review manual / by Kathryn Johnson and Dawn Vanderhoef. 
   3rd edition. 2013. | Includes bibliographical references and index.
Identifiers: LCCN 2016012871| ISBN 9781935213796 (pbk.) | ISBN 9781935213802 
   (ePub) | ISBN 9781935213819 (prc) | ISBN 9781935213826 (epdf)
Subjects: | MESH: Psychiatric Nursing--methods | Education, Nursing, 
   Continuing
Classification: LCC RC438 | NLM WY 18.5 | DDC 616.89/0231--dc23 LC record available at

Classification: LCC RC438 | NLM WY 18.5 | DDC 616.89/0231--dc23 LC record available at  
http://lccn.loc.gov/2016012871
The American Nurses Association (ANA) is the only full-service professional organization 
representing the interests of the nation’s 3.1 million registered nurses through its constituent/
state nurses associations and its organizational affiliates. The ANA advances the nursing 
profession by fostering high standards of nursing practice, promoting the rights of nurses in the 
workplace, projecting a positive and realistic view of nursing, and lobbying the Congress and 
regulatory agencies on healthcare issues affecting nurses and the public.
© 2016 American Nurses Association
8515 Georgia Ave., Suite 400
Silver Spring, MD 20910
All rights reserved. 
Third printing, August 2018

iii
CONTENTS
INSTRUCTIONS FOR OBTAINING CONTINUING EDUCATION 
CREDIT   . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XI
CHAPTER 1  . Taking The Certification Examination   . . . . . . . . . . . . . 1
General Suggestions for Preparing for the Exam 1
About the Certification Exams 8
Internet Resources 9
CHAPTER 2 . Psychiatric–Mental Health Nurse Practitioner Role, 
Scope of Practice, and Regulatory Process   . . . . . . . 11
Nurse Practitioner Advanced Practice Core Content 11
Nurse Practitioner Advanced Practice Specialized 
Content 12
History of the NP Role 13
Professional Role Responsibilities 16
Roles of the PMHNP 22
Culturally Competent Care and Special Populations 23
Case Study 1 29
Case Study 2 29
Answers to Case Study Discussion Questions 31
References and Resources 32
CHAPTER 3 . Theoretical Basis of Care   . . . . . . . . . . . . . . . . . . . . . . 37
Biopsychosocial Framework of Care 37

Classification of Psychiatric Disorders: DSM-5 38

iv 
CONTENTS
Therapeutic Relationship 38
Developmental Theories 40
Foundational Theories Supporting PMHNP Role 41
Nursing Theories 47
Case Study 1 48
Case Study 2 48
Answers to Case Study Discussion Questions 49
References and Resources 49
CHAPTER 4 . Psychiatric–Mental Health Nurse Practitioner 
Professional Role and Health Policy: Leadership, 
Quality Improvement and Safety, Practice Inquiry, 
and Health Policy   . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Leadership 51
Quality Improvement 55
Just Culture of Safety 55
Health Delivery Systems 56
Conflict of Interest 57
Rights of Clients 58
Health Policy Development 58
Case Study 59
Answers to Case Study Discussion Questions 60
References and Resources 60
CHAPTER 5 . Neuroanatomy, Neurophysiology, and Behavior   . .63
The Nervous System 63
Neuroanatomy and the Brain 64
Neurophysiology and the Brain 68
Neuroimaging Assessment and Diagnostic 
Procedures 71
Genomics 73

v
CONTENTS
Case Study 1 76
Case Study 2 76
Answers to Case Study Discussion Questions 77
References and Resources 77
CHAPTER 6 . Advanced Health and Physical Health Assessment   . .79
Physical Exam 79
Neurological Exam 80
Disease Prevention Activities 97
Gender-Based Medical Testing and Screening 
Recommendations for the General Public 99
Health Behavior Guidelines 101
Public Health Principles 103
Case Study 1 105
Case Study 2 105
Answers to Case Study Discussion Questions 107
References and Resources 107
CHAPTER 7  . Pharmacological Principles   . . . . . . . . . . . . . . . . . . . 111
Concepts in Pharmacological Management 111
PMHNP Pharmacological Management Role 114
Case Study 1 120
Case Study 2 120
Case Study 3 120
Answers to Case Study Discussion Questions 122
References and Resources 123
CHAPTER 8 . Nonpharmacological Treatment   . . . . . . . . . . . . . . . 125
Individual Therapy 125
Group Therapy 127

vi 
CONTENTS
Family Therapies 129
Complementary and Alternative Therapies (CATs) 132
Case Study 136
Answers to Case Study Discussion Questions 137
References and Resources 137
CHAPTER 9 . Depressive Disorders and Bipolar Disorders   . . . . . 139
Sadness as a Common Emotional State 139
Major Depressive Disorder (MDD) 140
Persistent Depressive Disorder (Dysthymia) 166
Grief and Bereavement 169
Premenstrual Dysphoric Disorder 173
Bipolar (BP) Disorder 173
Stevens Johnson Syndrome (SJS) 184
Cyclothymic Disorder 186
Case Study 189
Answers to Case Study Discussion Questions 191
References and Resources 191
CHAPTER 10 . Anxiety Disorders, Obsessive–Compulsive Disorder, 
and Trauma- and Stressor-Related Disorders   . . . . . 195
Anxiety Disorders 196
Panic Disorder 207
Agoraphobia 210
Specific Phobias (Simple Phobias) 211
Social Anxiety (Phobia) Disorder 214
Generalized Anxiety Disorder (GAD) 215
Separation Anxiety Disorder  218
Obsessive–Compulsive Disorder (OCD) 218

Posttraumatic Stress Disorder (PTSD) 222

vii
CONTENTS
Dissociative Disorders 225
Body Dysmorphic Disorder 226
Hoarding Disorder 226
Trichotillomania  226
Excoriation Disorder 226
Case Study 227
Answers to Case Study Discussion Questions 230
References and Resources 230
CHAPTER 11  . Schizophrenia Spectrum and Other Psychotic 
Disorders   . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
General Description of Psychotic Disorders 233
Schizophrenia 235
Schizophreniform Disorder 258
Schizoaffective Disorder 260
Delusional Disorder 262
Brief Psychotic Disorder 264
Shared Psychotic Disorder (Folie á Deux) 266
Case Study 268
Answers to Case Study Discussion Questions 269
References and Resources 269
CHAPTER 12 . Neurocognitive Disorders   . . . . . . . . . . . . . . . . . . . . 271
Cognitive Disorders 271
Delirium 271
Dementia 277
Major or Minor Neurocognitive Disorder Due to 
Traumatic Brain Injury  285
Case Study 291
Answers to Case Study Discussion Questions 292
References and Resources 292

viii 
CONTENTS
CHAPTER 13 . Substance-Related and Addictive Disorders   . . . . . 293
Substance-Related Disorders 293
Case Study 308
Answers to Case Study Discussion Questions 310
References and Resources 310
CHAPTER 14 . Personality Disorders   . . . . . . . . . . . . . . . . . . . . . . . . 313
Personality 313
Personality Disorders 314
Case Study 324
Answers to Case Study Discussion Questions 325
References and Resources 325
CHAPTER 15 . Disorders of Childhood and Adolescence   . . . . . . . 327
Assessment and Care Planning for Children and 
Adolescents 327
Oppositional Defiant Disorder (ODD) 329
Conduct Disorder 332
Attention-Deficit Hyperactivity Disorder (ADHD) 335
Autism Spectrum Disorder 340
Rett Syndrome 343
Eating Disorders 346
Intellectual Disability 351
Disruptive Mood dysRegulation Disorder 355
Case Study 357
Answers to Case Study Discussion Questions 358
References and Resources 358

CHAPTER 16 . Sleep   . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361
General Considerations 361
Insomnia 362

ix
CONTENTS
Case Study 1 369
Case Study 2 369
Case Study 3 369
Answers to Case Study Discussion Questions 370
References and Resources 371
CHAPTER 17  . Violence   . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373
Intimate Partner Violence (IPV) 373
Assessment 375
Sexual Assault and Abuse 376
Lethality Assessment 379
Violence in School 380
Suicide Assessment 380
Homicide: Early Warning Signs  381
Threats of Violence 381
Case Study 383
Answers to Case Study Discussion Questions 384
References and Resources 384
APPENDIX A . Review Questions   . . . . . . . . . . . . . . . . . . . . . . . . . . . 385
APPENDIX B  . Review Question Answers   . . . . . . . . . . . . . . . . . . . . 409
INDEX   . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417

xi
INSTRUCTIONS FOR OB TAINING CONTINUING EDUCATION 
CREDIT FOR STU DY OF THE PS YCHIATRIC–MENT AL HEAL TH NURSE 
PRACTITIONER REVIEW AND RESOURCE MANUAL, 4TH EDITION
The American Nurses Association offers continuing nursing education contact hours (CE) to 
those who review and study this manual and successfully complete an online module. To obtain 
CE credit you must purchase and review the manual, pay required fees to enroll in the online 
module, and complete all module components by the published CE expiration date.  To purchase 
the online module for this manual visit www.nursingworld.org Please contact online support with 
any questions about the CE or module.
Inquiries or Comments
If you have any questions about the content of the manual please e-mail publications@ana.org. 
You may also mail any comments to Editorial Project Manager at the address listed below. 
CE Provider Information

CE Provider Information 
ANA ’s Center for Continuing Education and Professional Development is accredited as a provider 
of continuing nursing education by the American Nurses Credentialing Center’s Commission on 
Accreditation. 
ANCC Provider Number 0023. 
ANA is approved by the California Board of Registered Nursing, Provider Number 
CEP6178.
Disclaimer
Review and study of this manual and successful completion of the online module do not guaran-tee success on a certification examination. Purchase of this manual and completion of the online 
module are not required to obtain certification.

CHAPTER 1TAKING THE CERTIFICATION EXAMINATION
When you sign up to take a national certification exam, you will be instructed to go on -
line and review the testing and review handbook ( http://www.nursecredentialing.org/
GeneralTestingRenewalHandbook ). Review it carefully and be sure to bookmark the site so you 
can refer to it frequently. It contains information on test content and sample questions. This is 
critical information; it will give you insight into the nature of the test. The agency will send you 
information about the test site; keep this in a safe place until needed.
GENERAL SUGGESTIONS FOR PREPARING FOR THE EXAM
Step One: Control Y our Anxiety
Everyone experiences anxiety when faced with taking the certification exam. 
 XRemember, your program was designed to prepare you to take this exam. 
 XYour instructors took a similar exam, and have probably talked to students who took 
exams more recently, so they know how to help you prepare.

XYour instructors took a similar exam, and have probably talked to students who took 
 XTaking a review course or setting up your own study plan will help you feel more 
confident about taking the exam. 
Step T wo: Do Not Listen to Gossip About the Exam
A large volume of information exists about the tests based on reports from people who have 
taken the exams in the past. Because information from the testing facilities is limited, it is hard 
to ignore this gossip. 
 XRemember that gossip about the exam that you hear from others is not verifiable. 
 XBecause this gossip is based on the imperfect memory of people in a stressful situa -
tion, it may not be very accurate. 
 XPeople tend to remember those items testing content with which they are less com -
fortable; for instance, those with a limited background in women’s health may say 
that the exam was “all women’s health. ” In fact, the exam blueprint ensures that the

that the exam was “all women’s health. ” In fact, the exam blueprint ensures that the 
exam covers multiple content areas without overemphasizing any one.

2 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
Step Three: Set Reasonable Expectations for Y ourself
 XDo not expect to know everything.
 XDo not try to know everything in great detail.
 XYou do not need a perfect score to pass the exam. 
 XThe exam is designed for a beginner level—it is testing readiness for entry-level  
practice. 
 XLearn the general rules, not the exceptions.
 XThe most likely diagnoses will be on the exam, not questions on rare diseases or 
atypical cases. 
 XThink about the most likely presentation and most common therapy.
Step Four: Prepare Mentally and Physically
 XWhile you are getting ready to take the exam, take good physical care of yourself. 
 XGet plenty of sleep and exercise, and eat well while preparing for the exam. 
 XThese things are especially important while you are studying and immediately before 
you take the exam. 
Step Five: Access Current Knowledge
General Content

XThese things are especially important while you are studying and immediately before 
You will be given a list of general topics that will be on the exam when you register to take the 
exam. In addition, examine the table of contents of this book and the test content outline, avail -
able at http://nursecredentialing.org/FamilyPsychMentalHealthNP .
 XWhat content do you need to know?
 XHow well do you know these subjects?
T ake a Review Course
 XTaking a review course is an excellent way to assess your knowledge of the content 
that will be included in the exam. 
 XIf you plan to take a review course, take it well before the exam so you will have 
plenty of time to master any areas of weakness the course uncovers. 
 XIf you are prepared for the exam, you will not hear anything new in the course. You 
will be familiar with everything that is taught.

XIf you are prepared for the exam, you will not hear anything new in the course. You 
will be familiar with everything that is taught. 
 XIf some topics in the review course are new to you, concentrate on these in your 
studies.
 XPeople have a tendency to study what they know; it is rewarding to study some -
thing and feel a mastery of it! Unfortunately, this will not help you master unfamiliar 
content. Be sure to use a review course to identify your areas of strength and weak -
ness, then concentrate on the weaknesses.

3 taking the certification exaMination
Depth of Knowledge
How much do you need to know about a subject? 
 XYou cannot know everything about a topic. 
 XRemember that the depth of knowledge required to pass the exam is for entry-level 
performance. 
 XStudy the information sent to you from the testing agency, what you were taught in 
school, what is covered in this text, and the general guidelines given in this chapter. 
 XLook at practice tests designed for the exam. Practice tests for other exams will not 
be helpful. 
 XConsult your class notes or clinical diagnosis and management textbook for the ma -
jor points about a disease. Additional reference books can be found online at http://
nursecredentialing.org/PsychNP-TestReferenceList .
 XFor example, with regard to medications, know the drug categories and the major 
medications in each. Assume all drugs in a category are generally alike, and then fo -
cus on the differences among common drugs. Know the most important indications,

cus on the differences among common drugs. Know the most important indications, 
contraindications, and side effects. Emphasize safety. The questions usually do not 
require you to know the exact dosage of a drug. 
Step Six: Institute a Systematic Study Plan
Develop Y our Study Plan 
 XWrite up a formal plan of study. 
 ZInclude topics for study, timetable, resources, and methods of study that work 
for you. 
 ZDecide whether you want to organize a study group or work alone. 
 ZSchedule regular times to study. 
 ZAvoid cramming; it is counterproductive. Try to schedule your study periods in 
1-hour increments.
 XIdentify resources to use for studying. To prepare for the examination, you should 
have the following materials on your shelf:
 ZA good pathophysiology text.
 ZThis review book.
 ZA physical assessment text.
 ZYour class notes.

 ZOther important sources, including: information from the testing facility, a 
clinical diagnosis textbook, favorite journal articles, notes from a review course, 
and practice tests. 
 ZKnow the important national standards of care for major illnesses. 
 ZConsult the bibliography on the test blueprint. When studying less familiar material, 
it is helpful to study using the same references that the testing center uses.
 XStudy the body systems from head to toe.

4 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XThe exams emphasize health promotion, assessment, differential diagnosis, and plan 
of care for common problems.
 XYou will need to know facts and be able to interpret and analyze this information 
utilizing critical thinking.
Personalize Y our Study Plan
 XHow do you learn best? 
 ZIf you learn best by listening or talking, attend a review course or discuss topics 
with a colleague. 
 XRead everything the test facility sends you as soon as you receive it and several 
times during your preparation period. It will give you valuable information to help 
guide your study. 
 XHave a specific place with good lighting set aside for studying. Find a quiet place 
with no distractions. Assemble your study materials.
Implement Y our Study Plan
You must have basic content knowledge. In addition, you must be able to use this information to 
think critically and make decisions based on facts.

think critically and make decisions based on facts. 
 XRefer to your study plan regularly. 
 XStick to your schedule. 
 XTake breaks when you get tired. 
 XIf you start procrastinating, get help from a friend or reorganize your study plan. 
 XIt is not necessary to follow your plan rigidly. Adjust as you learn where you need to 
spend more time.
 XMemorize the basics of the content areas you will be required to know. 
Focus on General Material
 XMost of what you need to know is basic material that does not require constant 
updating. 
 XYou do not need to worry about the latest information being published as you are 
studying for the exam. Remember, it can take 6 to 12 months for new information to 
be incorporated into test questions. 
Pace Y our Studying
 XStop studying for the examination when you are starting to feel overwhelmed and

 XStop studying for the examination when you are starting to feel overwhelmed and 
look at what is bothering you. Then make changes. 
 XBreak overwhelming tasks into smaller tasks that you know you can do. 
 XStop and take breaks while studying. 
Work With Others
 XTalk with classmates about your preparation for the exam.
 XKeep in touch with classmates, and help each other stick to your study plans.

5 taking the certification exaMination
 XIf your classmates become anxious, do not let their anxiety affect you. Walk away if 
you need to. 
 XDo not believe bad stories you hear about other people’s experiences with previous 
exams. 
 XRemember, you know as much as anyone about what will be on the next exam!
Consider a Study Group
 XStudy groups can provide practice in analyzing cases, interpreting questions, and 
critical thinking. 
 XYou can discuss a topic and take turns presenting cases for the group to analyze. 
 XStudy groups can also provide moral support and help you continue studying.
Step Seven:  Strategies Immediately Before the Exam
Final Preparation Suggestions
 XUse practice exams when studying to get accustomed to the exam format and time 
restrictions.
 ZMany books that are labeled as review books are simply a collection of 
examination questions. 
 ZIf you have test anxiety, such practice tests may help alleviate the anxiety.

 ZIf you have test anxiety, such practice tests may help alleviate the anxiety. 
 ZPractice tests can help you learn to judge the time it should take you to 
complete the exam.
 ZPractice tests are useful for gaining experience in analyzing questions. 
 ZBooks of questions may not uncover the gaps in your knowledge that a more 
systematic content review text will reveal.
 ZIf you feel that you don’t know enough about a topic, refer to a text to learn 
more. After you feel that you have learned the topic, practice questions are a 
wonderful tool to help improve your test-taking skill.
 XKnow your test-taking style. 
 ZDo you rush through the exam without reading the questions thoroughly? 
 ZDo you get stuck and dwell on a question for a long time? 
 ZYou should spend about 45 to 60 seconds per question and finish with time to 
review the questions you were not sure about.

ZDo you get stuck and dwell on a question for a long time? 
 ZBe sure to read the question completely, including all four answer choices. 
Choice “a” may be good, but “d” may be best.
The Night Before the Exam
 XBe prepared to get to the exam on time. 
 ZKnow the test site location and how long it takes to get there. 
 ZTake a “dry run” beforehand to make sure you know how to get to the testing 
site, if necessary.

6 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZGet a good night’s sleep. 
 ZEat sensibly. 
 ZAvoid alcohol the night before. 
 ZAssemble the required material—two forms of identification, admission card, 
pencil, and watch. Both IDs must match the name on the application, and one 
photo ID is preferred. 
 ZKnow the exam room rules. 
 XYou will be given scratch paper, which will be collected at the end of the 
exam. 
 XNothing else is allowed in the exam room. 
 XYou will be required to put papers, backpacks, etc., in a corner of the room 
or in a locker. 
 XNo water or food will be allowed. 
 XYou will be allowed to walk to a water fountain and go to the bathroom one 
at a time.
The Day of the Exam
 XGet there early. You must arrive to the test center at least 15 minutes before your 
scheduled appointment time. If you are late, you may not be admitted. 
 XThink positively. You have studied hard and are well-prepared.

 XRemember your anxiety reduction strategies. 
Specific Tips for Dealing With Anxiety
Test anxiety is a specific type of anxiety. Symptoms include upset stomach, sweaty palms, 
tachycardia, trouble concentrating, and a feeling of dread. But there are ways to cope with test 
anxiety.
 XThere is no substitute for being well-prepared. 
 XPractice relaxation techniques. 
 XAvoid alcohol, excess coffee, caffeine, and any new medications that might sedate 
you, dull your senses, or make you feel agitated.
 XTake a few deep breaths and concentrate on the task at hand.
Focus on Specific T est-T aking Skills
To do well on the exam, you need good test-taking skills in addition to knowledge of the content 
and ability to use critical thinking.
All Certification Exams Are Multiple Choice
 XMultiple-choice tests have specific rules for test construction.

 XMultiple-choice tests have specific rules for test construction. 
 XA multiple-choice question consists of three parts: the information (or stem), the 
question, and the four possible answers (one correct and three distracters).

7 taking the certification exaMination
 XCareful analysis of each part is necessary. Read the entire question before 
answering. 
 XPractice your test-taking skills by analyzing the practice questions in this book and on 
the ANCC website.
Analyze the Information Given
 XDo not assume you have more information than is given. 
 XDo not overanalyze. 
 XRemember, the writer of the question assumes this is all of the information needed 
to answer the question. 
 XIf information is not given, it is not relevant and will not affect the answer.
 XDo not make the question more complicated than it is.
What Kind of Question Is Asked? 
 XAre you supposed to recall a fact, apply facts to a situation, or understand and dif -
ferentiate between options? 
 ZRead the question thinking about what the writer is asking. 
 ZLook for key words or phrases that lead you (see Figure 1 –1). These help 
determine what kind of answer the question requires.
Read All of the Answers

ZLook for key words or phrases that lead you (see Figure 1 –1). These help 
 XIf you are absolutely certain that answer “a” is correct as you read it, mark it, but 
read the rest of the question so you do not trick yourself into missing a better 
answer.
 XIf you are absolutely sure answer “a” is wrong, cross it off or make a note on your 
scratch paper and continue reading the question. 
 XAfter reading the entire question, go back, analyze the question, and select the best 
answer. 
 XDo not jump ahead. 
 XIf the question asks you for an assessment, the best answer will be an assessment. 
Do not be distracted by an intervention that sounds appropriate.
 XIf the question asks you for an intervention, do not answer with an assessment.
avoid
best
except 
notinitial 
first
contributing to
appropriatemost
significant
likely
of the following
most consistent with
FIGURE 1–1  . 
EXAMPLES OF KEY WORDS AND PHRASES

8 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XWhen two answer choices sound very good, the best one is usually the least ex -
pensive, least invasive way to achieve the goal. For example, if your answer choices 
include a physical exam maneuver or imaging, the physical exam maneuver is prob -
ably the better choice provided it will give the information needed.
 XIf the answers include two options that are the opposite of each other, one of the 
two is probably the correct answer. 
 XWhen numeric answers cover a wide range, a number in the middle is more likely to 
be correct. 
 XWatch out for distracters that are correct but do not answer the question, combine 
true and false information, or contain a word or phrase that is similar to the correct 
answer. 
 XErr on the side of caution  .
Only One Answer Can Be Correct 
 XWhen more than one suggested answer is correct, you must identify the one that 
best answers the question asked.

answer. 
best answers the question asked. 
 XIf you cannot choose between two answers, you have a 50% chance of getting it 
right if you guess. 
Avoid Changing Answers 
 XChange an answer only if you have a compelling reason, such as you remembered 
something additional, or you understand the question better after rereading it. 
 XPeople change to a wrong answer more often than to a right answer. 
Time Y ourself to Complete the Whole Exam
 XDo not spend a large amount of time on one question. 
 XIf you cannot answer a question quickly, mark it and continue the exam. 
 XIf time is left at the end, return to the difficult questions. 
 XMake educated guesses by eliminating the obviously wrong answers and choosing a 
likely answer even if you are not certain. 
 XTrust your instinct.

XMake educated guesses by eliminating the obviously wrong answers and choosing a 
 XTrust your instinct. 
 XAnswer every question. There is no penalty for a wrong answer.
 XOccasionally a question will remind you of something that helps you with a question 
earlier in the test. Look back at that question to see if what you are remembering 
affects how you would answer that question. 
ABOUT THE CERTIFICATION EXAMS
The American Nurses Credentialing Center Computerized Exam
The ANCC examination is given only as a computer exam, and each exam is different.
The order of the questions is scrambled for every test, so even if two people are taking the 
same exam, the questions will be in a different order. The exam consists of 175 multiple-choice 
questions.

9 taking the certification exaMination
 X150 of the 175 questions are part of the test and how you answer will count toward 
your score; 25 are included to refine questions and will not be scored. You will not 
know which ones count, so treat all questions the same. 
 XYou will need to know how to use a mouse, scroll by either clicking arrows on the 
scroll bar or using the up and down arrow keys, and perform other basic computer 
tasks.
 XThe exam does not require computer expertise.
 XHowever, if you are not comfortable with using a computer, you should practice us -
ing a mouse and computer beforehand so you do not waste time on the mechanics 
of using the computer.
Know what to expect during the test.
 XEach ANCC test question is independent of the other questions. 
 ZFor each case study, there is only one question. This means that a correct 
answer on any question does not depend on the correct answer to any other 
question.

ZFor each case study, there is only one question. This means that a correct 
question. 
 ZEach question has four possible answers. There are no questions asking for 
combinations of correct answers (such as “a and c”) or multiple-multiples.
 XYou can skip a question and go back to it at the end of the exam. 
 XYou cannot mark key words in the question or right or wrong answers. If you want to 
do this, use the scratch paper.
 XYou will get your results immediately, and a grade report will be provided upon leav -
ing the testing site. 
INTERNET RESOURCES
 XANCC website: www.nursecredentialing.org  
 XANA bookstore: www.nursesbooks.org . Catalog of ANA nursing scope and stan -
dards publications and other titles that may be listed on your test content outline
 XNational Guideline Clearinghouse: www.ngc.gov

CHAPTER 2PSYCHIATRIC–MENTAL HEALTH NURSE 
PRACTITIONER ROLE, SCOPE OF PRACTICE, AND 
REGULATORY PROCESS
Starting in the 1950s with the seminal work of two psychiatric nurses, June Mellow (1968) and 
Hildegard Peplau (1952), psychiatric nursing has been a well-established, well-recognized sub -
specialty of nursing. The emergence of the psychiatric–mental health nurse practitioner (PMHNP) 
role reflects the growth of the advanced practice role, the acceptance of a brain-based etiology 
of psychiatric disorders, and an awareness of the need to provide holistic nursing care that does 
not artificially separate mind and body (Stuart, 2013).
The PMHNP role is built on fundamental, core advanced practice knowledge common to all 
nurse practitioners. This base of knowledge is expanded to include the very specific knowledge 
of the subspecialty of psychiatry. This chapter reviews the role of the PMHNP , the scope of prac -
tice, and the regulatory process.

Advanced practice nurses specializing in psychiatry are educationally prepared at the master’s 
or doctoral level, possess in-depth knowledge and skills in the specialty area, and provide pri -
mary psychiatric care to individuals or families at risk for or currently experiencing a psychiatric 
disorder.
NURSE PRACTITIONER ADVANCED PRACTICE CORE CONTENT
All nurse practitioners upon graduation are expected to meet a set of core competencies 
(National Organization of Nurse Practitioner Faculties [NONPF], 2014). Specialty competencies, 
such as the Psychiatric–Mental Health Nurse Practitioner Competencies , are then built upon 
these core competencies (NONPF , 2013).
Nurse Practitioner Core Competencies 
 XScientific Foundations
 XLeadership 
 XQuality

12 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XPractice Inquiry
 XTechnology and Information Literacy 
 XPolicy 
 XHealth Delivery System
 XEthics
 XIndependent Practice 
NURSE PRACTITIONER ADVANCED PRACTICE SPECIALIZED 
CONTENT
The specialty competencies are specifically designed for entry-level psychiatric–mental health 
nurse practitioners. These specialty competencies are to be used with the Nurse Practitioner 
(NP) Core Competencies. The specialty competencies address the life-span PMHNP focus, in -
cluding families and populations. As changes occur within the healthcare system, these compe -
tencies will also change (NONPF , 2013).
Leadership Competencies
 XParticipates in community and population-focused programs that evaluate programs 
and promote mental health and prevent or reduce risk of mental health problems
 XAdvocates for complex client and family medicolegal rights and issues

 XAdvocates for complex client and family medicolegal rights and issues 
 XCollaborates with interprofessional colleagues about advocacy, policy to reduce 
health disparities and improve outcomes for populations
Quality Competencies 
 XEvaluates the appropriate uses of seclusion and restraints in the care process 
Policy Competencies 
 XEmploys opportunities to influence health policy to reduce the impact of stigma on 
services for prevention and treatment of mental health problems and psychiatric 
disorders 
Independent Practice Competencies 
 XDevelops age-appropriate treatment plans
 XIncludes differential diagnosis
 XAssesses impact of acute and chronic medical problems on psychiatric treatment 
 XConducts individual and group psychotherapy 
 XApplies supportive psychodynamic, cognitive, behavioral, and other evidence-based 
psychotherapies to brief and long-term practice

XConducts individual and group psychotherapy 
psychotherapies to brief and long-term practice 
 XApplies recovery-oriented principles 
 XDemonstrates best practices of family care approaches 
 XPlans care to minimize the development of complications and promote function 
 XTreats acute and chronic psychiatric disorders and problems

13 Psychiatric–Mental health nurse Practitioner role, scoPe of Practice, and regulatory Process
 XSafely prescribes pharmacologic agents 
 XEnsures client safety through the appropriate prescription of pharmacologic and 
nonpharmacologic interventions 
 XExplains the risks and benefits of treatment to client and family 
 XIdentifies the role of PMHNP in risk mitigation strategies in areas of opiate use and 
substance abuse
 XSeeks consultation 
 XUses self-reflection to improve care 
 XProvides consultation to healthcare providers and others to enhance quality and cost
 XGuides the client in evaluating the appropriate use of complementary and alternative 
treatment
 XUses individualized outcome measure to evaluate psychiatric care
 XManages psychiatric emergencies 
 XRefers clients appropriately 
 XFacilitates the transition of clients across levels of care 
 XUses outcomes to evaluate care 
 XAttends to the client–NP relationship as a vehicle for change

XRefers clients appropriately 
 XAttends to the client–NP relationship as a vehicle for change 
 XMaintains a therapeutic relationship over time with individuals and groups
 XTherapeutically concludes the client–NP relationship 
 XDemonstrates ability to address sexual and physical abuse, substance abuse, sexual -
ity, and spiritual conflicts 
 XApplies therapeutic relationship strategies based on theory and research
 XApplies principles of self-efficacy, empowerment, and others to effect change
 XIdentifies and maintains professional boundaries 
 XTeaches clients, families, and groups 
 XProvides psychoeducation 
 XModifies the treatment approach based on client readiness
 XConsiders motivation and readiness to improve self-care 
 XDemonstrates knowledge of appropriate use of seclusion and restraint 
 XDocuments appropriate use of seclusion and restraint 
HISTORY OF THE NP ROLE

XDemonstrates knowledge of appropriate use of seclusion and restraint 
The NP role was introduced in 1965 by Loretta C. Ford, EdD, and Henry K. Silver, MD, at the 
University of Colorado (Mirr Jansen & Zwygart-Stauffacher, 2006). They identified new roles in 
which experienced registered nurses (RNs) with advanced education and skills were perform -
ing clinical duties traditionally reserved for physicians. Universities were slow to implement NP 
programs at the master’s level. However, RNs embraced the new role and rushed into continuing 
education programs of varying length, quality, and focus to accomplish the necessary educa -
tional preparation for this new role.

14 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
In 2008 the License, Accreditation, Certification, and Education (LACE) consensus model was 
finalized and adopted by many nursing organizations. The consensus model identified four 
Advanced Practice Registered Nurse roles: Certified Registered Nurse Anesthetist (CRNA), 
Certified Nurse Midwife (CNM), Clinical Nurse Specialist (CNS), and Certified Nurse Practitioner 
(CNP). As part of the LACE model, Psychiatric–Mental Health was identified as a population fo -
cus. The American Psychiatric Nurses Association (APNA) and International Society of Psychiatric 
Nurses (ISPN) recommendation was for psychiatric–mental health nurse practitioners (PMHNPs) 
to be prepared across the life span (APNA, 2011). As of 2015 APRNs in psychiatric–mental 
health nursing have one certification examination, PMHNP–Life Span, with the American Nurses

health nursing have one certification examination, PMHNP–Life Span, with the American Nurses 
Credentialing Center (ANCC, 2015). All previous psychiatric–mental health advanced practice 
certification examinations have been retired as of December 2015 (ANCC, 2015). 
Proven competence brought an acceptance of the NP role in the healthcare system, with ac -
ceptance and recognition of the title and role by consumers and other health professionals. NP 
programs are accredited by one of two organizations to achieve standardization and control over 
quality: the Commission on Collegiate Nursing Education (CCNE, 2016) and the Accreditation 
Commission for Education in Nursing (ACEN, 2016). NPs are recognized providers under many 
third-party insurance coverage plans (e.g., Medicare, Medicaid, CHAMPUS, federal programs 
funding school-based clinics, U.S. military, Veterans Administration).

Growth of the NP Role
 XFacilitating factors for growth
 ZConsumer demand for services
 ZAcceptance of the advanced practice nursing role
 ZEmergence of the PMHNP role
 ZDecreasing stigmatization
 ZEmphasis on integrated healthcare services
 XConstraining factors for growth
 ZGrowing competition in job market in general for NPs
 ZReimbursement struggles with Medicare and private insurance companies
 ZOverlapping scope of practice with other NPs
 ZIncreased concerns over reimbursement fraud and abuse (e.g., issues of coding 
and billing for services)
 ZScope of practice and need for formal supervisory or collaborative relationships 
with physicians
Regulatory and Statutory Dimensions of the NP Role
 XState legislative statutes
 ZGrant legal authority for NP practice
 ZThe Nurse Practice Act of every state

 XProvides title protection (who may be called a nurse practitioner)
 XDefines advanced practice

15 Psychiatric–Mental health nurse Practitioner role, scoPe of Practice, and regulatory Process
 XPrevailing state laws that define scope of practice (what NPs may do)
 XPlaces restrictions on practice
 XSets NP credentialing requirements (e.g., educational requirements, 
certification)
 XStates grounds for disciplinary action:
 ZPracticing without valid license
 ZFalsification of records
 ZMedicare fraud
 ZFailure to use appropriate nursing judgment
 ZFailure to follow accepted nursing standards
 ZFailure to complete accurate nursing documentation
 XMay specifically require that an NP develop a collaborative agreement with 
a physician
 ZCollaborative agreement: Also known as a protocol that describes what 
types of drugs might be prescribed and defines some form of oversight 
for NP practice
 XStatutory law
 ZRules and regulations differ for each state
 ZMay further define scope of practice and practice requirements
 ZMay provide restrictions in practice unique to specific state

XStatutory law
 XLicensure
 ZA process by which an agency of state government grants permission to 
persons to engage in the practice of that profession
 ZAlso prohibits all others from legally doing protected practice
 XCredentialing
 ZProcess used to protect the public by ensuring a minimum level of professional 
competence
 XCertification
 ZA credential that provides title protection
 ZDetermines scope of practice (i.e., whom NPs can see and what NPs can treat)
 ZThe process by which a professional organization or association certifies that 
a person licensed to practice as a professional has met certain predetermined 
standards specified by that profession for specialty practice
 ZAssures the public that a person has mastery of a specified body of knowledge

 ZAssures that the person has acquired the skills necessary to function in a 
particular specialty

16 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZThe American Nurses Credentialing Center (ANCC), which is a subsidiary of the 
American Nurses Association, is the only certifying body for advanced practice 
psychiatric nursing.
 XCertification offered as a Psychiatric–Mental Health Nurse Practitioner–Life 
Span (ANCC, 2015)
 XScope of practice
 ZDefines NP roles and actions
 ZIdentifies competencies assumed to be held by all NPs who function in a 
particular role
 ZVaries broadly from state to state
 ZAdvanced practice PMHNP standards are identified in Psychiatric-Mental Health 
Nursing: Scope and Standards of Practice  (ANA, 2014).
 XStandards of practice
 ZAuthoritative statements regarding the quality and type of practice that should 
be provided
 ZProvide a way to judge the nature of care provided
 ZReflect the expectation for the care that should be provided to clients with 
various illnesses

 ZReflect professional agreement focused on the minimum levels of acceptable 
performance
 ZCan be used to legally describe the standard of care that must be met by a 
provider
 ZMay be precise protocols that must be followed or more general guidelines that 
recommend actions
PROFESSIONAL ROLE RESPONSIBILITIES
 XConfidentiality
 ZThe client’s right to assume that information given to the healthcare provider will 
not be disclosed
 ZProtected under federal statute through the Medical Record Confidentiality Act 
of 1995 (S. 1360) 
 ZPertains to verbal and written client information
 ZRequires that the provider discuss confidentiality issues with clients, establish 
consent, and clarify any questions about disclosure of information
 ZRequires that provider obtain a signed medical authorization and consent form

 ZRequires that provider obtain a signed medical authorization and consent form 
to release medical records and information when requested by the client or 
another healthcare provider
 XHIPAA
 ZThe first national comprehensive privacy protection act
 ZGuarantees clients four fundamental rights:

17 Psychiatric–Mental health nurse Practitioner role, scoPe of Practice, and regulatory Process
1. To be educated about HIPAA privacy protection,
2. To have access to their own medical records,
3. To request amendment of their health information to which they object, and
4. To require their permission for disclosure of their personal information.
 XThe Health Information Technology for Economic and Clinical Health Act (HITECH) of 
2009 (Health Resources and Services Administration [HRSA], 2013)
 ZIncentive payments for sharing specific electronic health record (EHR) data
 ZMeaningful use incentives
 ZElectronic health records can improve both individual and population-based 
health outcomes (Friedman, Parrish, & Ross, 2013). 
 ZElectronic health records can improve quality, safety, efficiency, effectiveness, 
and outcomes (U.S. DHHS, Office for Civil Rights, 2013).
 XE-prescribing
 XComputerized physician order sets
 XTracking care and avoiding duplication of services
 XTelehealth

 ZThe use of telephone or videoconferencing tools to deliver mental health care 
to clients who reside in rural areas or who may otherwise not be able to access 
care 
 ZMust follow the same standards as care delivered in person
 ZMust be practiced in accordance with international, federal, and state regulatory 
agency standards
 ZMust include provisions for emergency care of the client
 ZThe PMHNP must assure that HIPAA regulations regarding confidentiality and 
maintenance of the health record are followed.
 XExceptions to guaranteed confidentiality
 ZWhen appropriate persons or organizations determine that the need for 
information outweighs the principle of confidentiality
 ZIf a client reveals an intent to harm self or others
 ZInformation given to attorneys involved in litigation

 ZReleasing records to insurance companies
 ZAnswering court orders, subpoenas, or summonses
 ZMeeting state requirements for mandatory reporting of diseases or conditions
 ZTarasoff principle (Tarasoff v. Regents at the University of California, 1976): Duty 
to warn potential victim of imminent danger of homicidal clients 
 ZIn cases of child or elder abuse
 XInformed consent
 ZThe communication process between the provider and the client that results in 
the client’s acceptance or rejection of the proposed treatment

18 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZAn explanation of relevant information that enables the client to make an 
appropriate and informed decision
 ZThe right of all competent adults or emancipated minors
 XEmancipated minors:  Persons younger than 18 years old who are married, 
parents, or self-sufficiently living away from the family domicile
 ZElements of informed consent
 XNature and purpose of proposed treatment or procedure
 XRisks or discomforts and benefits of treatment
 XRisks and benefits of not undergoing treatment
 XAlternative procedures or treatments
 XDiagnosis and prognosis
 ZProvider must document in the medical record that informed consent has been 
obtained from the client.
 ZPMHNP is responsible for ensuring that the client is cognitively capable of giving 
informed consent.
 XEthics
 ZImportant aspect of the NP role that deals with moral duties, obligations, and 
responsibilities

 XEthics
 ZWhat is right versus what is wrong
 ZEthical principles that provide foundation and direction for complex decisions:
 XJustice:  Doing what is fair; fairness in all aspects of care
 XBeneficence:  Promoting well-being and doing good
 XNonmaleficence:  Doing no harm
 XFidelity:  Being true and loyal
 XAutonomy:  Doing for self
 XVeracity:  Telling the truth
 XRespect:  Treating everyone with equal respect
 ZIn 2015 the American Nurses Association (ANA) published the Code of Ethics for 
Nurses with Interpretive Statements  (ANA, 2015). Its nine provisions are: 
1. The nurse practices with compassion and respect for the inherent dignity, 
worth, and unique attributes of everyone.
2. The nurse’s primary commitment is to the client, whether an individual, 
family, group, community, or population.

3. The nurse promotes, advocates for, and protects the rights, health, and 
safety of the client.
4. The nurse has the authority, accountability, and responsibility for nursing 
practice, makes decisions, and takes action consistent with the obligation 
to promote health and provide optimal care.

19 Psychiatric–Mental health nurse Practitioner role, scoPe of Practice, and regulatory Process
5. The nurse owes the same duties to self as to others, including the 
responsibility to promote health and safety, preserve wholeness of 
character and integrity, maintain competence, and continue personal and 
professional growth.
6. The nurse, through individual and collective effort, establishes, maintains, 
and improves the ethical environment of the work setting and conditions of 
employment that are conducive to safe, quality health care.
7. The nurse, in all roles and settings, advances the profession through 
research and scholarly inquiry, professional standards development, and the 
generation of both nursing and health policy.
8. The nurse collaborates with other health professionals and the public 
to protect human rights, promote health diplomacy, and reduce health 
disparities.
9. The profession of nursing, collectively through its professional organizations,

9. The profession of nursing, collectively through its professional organizations, 
must articulate nursing values, maintain the integrity of the profession, and 
integrate principles of social justice into nursing and health policy.
 ZImportant ethical principles in psychiatry
 XClients must be involved in decision-making to the full extent of their 
capacity (mutual decision-making).
 XClients have a right to treatment in the least restrictive setting.
 XClients have a right to refuse treatment unless a legal process resulting in a 
mandatory court order for treatment has been obtained.
 ZEthical dilemma
 XOccurs in a situation in which there are two or more justifiable alternatives
 XOccurs when the choice is made to promote good
 XWhich option sacrifices the fewest high-priority values (a harm reduction 
approach)?
 ZTheoretical approaches to ethical decision-making

XOccurs when the choice is made to promote good
 XDeontological Theory:  An action is judged as good or bad based on the act 
itself regardless of the consequences.
 XTeleological Theory:  An action is judged as good or bad based on the 
consequence or outcome.
 XVirtue Ethics:  Actions are chosen based on the moral virtues (e.g., honesty, 
courage, compassion, wisdom, gratitude, self-respect) or the character of 
the person making the decision. 
Ethics of Disclosure by Providers
 XClients have a right to know what is happening during the course of their treatment.
 XProviders have an ethical responsibility to disclose medical errors, accidents, injuries, 
and negative results to clients.
 XAs a result of the disclosure, a client may have legal right to compensation for harm 
suffered due to medical misadventures (Sadock, Sadock, & Ruiz, 2015).

20 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
Risk vs .  Benefits of Disclosure of Disability Regarding Employment
 XThe Americans with Disabilities Act (ADA) works to prevent discrimination by 
employers with 15 or more employees against qualified persons in hiring, firing, 
advancement, job training, compensation, and workplace conditions (Buppert, 2012).
 XThe ADA is federal legislation granting Americans who have disabilities, includ -
ing mental illness, the opportunity for employment on an equal basis with the 
nondisabled.
 XEmployers are required to make reasonable accommodations for qualified applicants 
or employees with a disability.
Risk of Disclosure
 XEmployers may find ways to avoid hiring persons known to have a disability.
 XCoworkers may harass or discriminate against persons with psychiatric illnesses.
 XAssumption that persons with psychiatric illnesses may be less productive

XCoworkers may harass or discriminate against persons with psychiatric illnesses.
 XMay limit an employee’s chance for advancement in career
 XFeedback for improvement may not be given to employee because others may at -
tribute the employee’s behavior to the psychiatric illness.
 XLabeling oneself as “disabled” may affect one’s beliefs or self-image.
Benefits of Disclosure
 XAble to request reasonable accommodations
 XOpportunity to have a job coach come to the worksite and communicate directly 
with employer
 XEmployee can involve an employment service provider, employee assistance pro -
gram, or other third party in the development of accommodations.
 XEasier for employee to come to work during an exacerbation of symptoms
 XMay help with the recovery process
 XAllows coworkers to offer personal support
 XMay empower another employee to disclose
Legal Considerations
 XMalpractice insurance

XMay help with the recovery process
 ZProvides financial protection against claims of malpractice
 XCoverage for negligent professional acts
 XCoverage for highly technical or professional skills required by health 
professionals, including NPs
 ZRecommended universally for all NPs
 ZDoes not protect NPs from charges of practicing outside their legal scope of 
practice

21 Psychiatric–Mental health nurse Practitioner role, scoPe of Practice, and regulatory Process
 ZProvides NPs their own legal representation to advocate for them even if their 
agency also carries malpractice liability insurance protection
 ZFour elements of negligence that must be established to prove malpractice:
1. Duty: The NP had a duty to exercise reasonable care when undertaking and 
providing treatment to the client.
2. Breach of duty:  The NP violated the applicable standard of care in treating 
the client’s condition.
3. Proximate cause:  There is a causal relationship between the breach in the 
standard of care and the client’s injuries.
4. Damages: The client experiences permanent and substantial damages as a 
result of the breach in the standard of care.
Competency
 XA legal, not a medical concept
 XA determination that a client can make reasonable judgments and decisions regard -
ing treatment and other health concerns

 XA person is considered competent until a court rules the person to be incompetent.
 XIf a person is deemed incompetent, a court-appointed guardian will make health-
related decisions for that person.
Commitment
 XProcess of forcing a person to receive involuntarily evaluation or treatment
 XProcess may differ from state to state
 XBasic criteria include
 ZPerson has a diagnosed psychiatric disorder,
 ZPerson is harmful to self or others as a consequence of the disorder,
 ZPerson is unaware or unwilling to accept the nature and severity of the disorder, 
and
 ZTreatment is likely to improve functioning.
 XInvoluntary admission
 ZAdmission to a hospital or other treatment facility against the person’s will
 ZClients maintain all civil liberties except the ability to come and go as they please

XInvoluntary admission
 ZAmount of time clients can be kept against their wishes varies by state
 XVoluntary admission
 ZAdmission to a hospital or other treatment facility that a person desires or 
agrees to
 ZClient maintains all civil liberties
 ZClient consents to potential confinement within the structure of a hospital setting

22 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
ROLES OF THE PMHNP
Scholarly Activities
 XIt is important for NPs to engage in the following scholarly activities:
 ZPublishing
 ZLecturing or presenting
 ZPreceptorship
 ZContinuing education
Mentoring
 XA process in which a more experienced NP agrees to guide and support a junior col -
league in the role, competencies, and skills
 XRequires mutual respect and an interactive process of learning
 XNeeds involvement by both the mentor and the mentee in the relationship
Client Advocacy
 XStand up for clients’ rights and empower them to become their own advocates
 XReduce the stigma of mental illness
 XHelp clients receive available services
 XPromote mental health by participating in one or more of these professional 
organizations:
 ZAmerican Nurses Association (ANA)
 ZAmerican Psychiatric Nurses Association (APNA)
 ZInternational Society of Psychiatric Nurses (ISPN)
Health Policy

 XAdvanced practice nurses have a legal and ethical responsibility to be a client 
advocate. 
 ZParticipation in local, state, national, and international health policy activities 
(Buppert, 2012)
 ZInvolvement: Testify at a public meeting, lobby, or work with the media to bring 
awareness to an issue
 ZPhases of policy-making: formulation, implementation, and evaluation (Abood, 
2007)
Case Management
 XA system of controlled oversight and authorization of services and benefits provided 
to clients

23 Psychiatric–Mental health nurse Practitioner role, scoPe of Practice, and regulatory Process
 XConsists of coordinating care, ensuring quality outcomes, monitoring plan of care, 
and doing advocacy
 XOverall goal is to promote quality, cost-effective outcomes
Risk Assessment 
 XContinuous monitoring for high-risk situations
 XAssessing persons for nonhealthy behaviors
Risk Management
 XActivities or systems designed to recognize and intervene to reduce the risk of injury 
to clients
 XAppropriate interventions implemented to reduce nonhealthy behaviors in clients 
and high-risk situations
 XRecognition and intervention to reduce subsequent claims against healthcare providers
Advance Directives
 XDurable power of attorney for health care. Also known as healthcare proxy
 ZLegally binding in all 50 states
 ZDesignates, in writing, an agent to act on behalf of a person should he or she 
become unable to make healthcare decisions

ZLegally binding in all 50 states
 ZNot limited to terminal illness; also covers other aspects of illness, such as 
making financial decisions during a person’s illness
 ZShould be considered as an aspect of relapse planning for clients with chronic 
psychiatric disorders
 XLiving will: Document prepared while client is mentally competent to designate 
preferences for care if client becomes incompetent or terminally ill
 ZNot legally binding in all states
CULTURALLY COMPETENT CARE AND SPECIAL POPULATIONS
 XTreating clients from diverse cultures, viewing each client as a unique person, and 
noting a potential relationship between clients’ cultural experiences and their symp -
tom presentation and perceptions
 XAssumes that if the NP becomes more sensitive to cultural issues influencing the

 XAssumes that if the NP becomes more sensitive to cultural issues influencing the 
client’s symptoms and treatment, more comprehensive health care can be provided
 XCulture: The learned beliefs and behaviors or the socially inherited characteristics 
that are common among all members of a group; may be a racial, social, ethnic, or 
religious grouping
 XCulture-bound syndromes: Specific behaviors related to a person’s culture and not 
linked to a psychiatric disorder
 ZBe cognizant of inaccurately judging a client’s behavior as psychopathology 
when it is really related to his or her culture.

24 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
Cultural Influences and Determinants of Health
 XFamily:  A group of adults and children who are usually related and whose adults 
participate in carrying out the essential functions of providing food, clothing, shelter, 
safety, and education of children
 ZConcept broadened beyond the traditional husband–wife–children pattern
 ZFamily initially teaches the belief patterns, religion, culture, and mores of a society.
 XEthnicity:  Self-identified race, tribe, or nation with which a person or group identifies 
and which greatly influences beliefs and behavior
 XCommunity:  A group of families, often sharing the same race, tribe, or culture, who 
have beliefs or behavior not shared by others
 XEnvironment:  Includes both physical and psychosocial factors; the general circum -
stances of a person’s life:
 ZSocial contacts
 ZHousing surroundings
 ZClimate
 ZAltitude
 ZTemperature

XEnvironment:  Includes both physical and psychosocial factors; the general circum -
 ZClimate
 ZAltitude
 ZAir pollution ZFluoride in water
 ZWater contamination
 ZCrime
 ZPoverty
 ZTransportation
Homelessness
Homelessness is an enormous problem affecting the United States and the world. It can have 
devastating effects on individuals’ and families’ emotional and physical health. Drugs, alco -
hol, violence, and behavioral problems are just a few major issues faced by persons who are 
homeless. The practitioner must be aware of the challenges faced by this vulnerable popula -
tion. Possessing appropriate communication skills and knowledge of available resources are 
invaluable. 
 XHomeless person
 ZSomeone who does not have stable or consistent nighttime housing or who 
maintains permanent residence at shelters, hotels, transitional housing, or

maintains permanent residence at shelters, hotels, transitional housing, or 
public places not appropriate for human beings to live in; someone intended to 
be institutionalized who is in an institution for transitory residence
 ZMen, women, and children make up the homeless population. The number of 
homeless families is on the rise. 
 XThe majority of homeless families are headed by a single parent, usually a 
woman.
 ZFemale-headed households are at high risk for becoming homeless 
if the head of household has limited education or employment skills, 
low-paying employment with little or no benefits, and limited access to 
affordable housing.
 ZTeen mothers are at high risk due to lack of education and incomes that 
older parents possess.

25 Psychiatric–Mental health nurse Practitioner role, scoPe of Practice, and regulatory Process
 ZReasons for homelessness:
 XMental illness 
 XAddictive disorders
 XPoverty
 XUnemployment
 XInadequate public assistance
 XDomestic violence
 XLifestyle choice
 XMental illness and addictive disorders in the homeless population:
 ZApproximately 50% of homeless people have co-occurring substance use 
disorders and serious mental illness, including bipolar disorder, schizophrenia, 
and depression.
 ZSchizophrenia accounts for 15% to 45% of the U.S. homeless population 
(Sadock, Sadock, & Ruiz, 2015).
 ZSymptoms are often active and untreated.
 ZUntreated serious mental illness results in symptoms such as paranoia, 
hallucinations, mania, anxiety, and depression, making it difficult for people to 
maintain employment, relationships, and other activities of daily living. 
 ZHomeless people with co-occurring disorders are at a greater risk for violence,

 ZHomeless people with co-occurring disorders are at a greater risk for violence, 
medication noncompliance, and treatment resistance.
Strategies for Reducing Homelessness
 XOutreach : Introducing services to homeless persons with serious mental illness 
in various settings, building an empathetic, consistent, and caring relationship to 
provide treatment
 XIntegrated care : Treatment combining mental health and medical care to improve 
overall functioning in the community; may also include access to dental care and 
pharmacy services
 ZColocation:  Providing mental health and primary care services at a single site
 XSupporting services to persons in housing : Effective in moving homeless persons 
with serious mental illness directly to independent housing with support and inten -
sive attention
 XPrevention : Beginning with discharge planning in inpatient settings, provide resourc -

es for mental health care, housing, transitioning service, and follow-up 
Migrant and Seasonal Farm Workers
 XMigrants : Persons who leave their permanent residences to take agricultural jobs in 
different locations
 XSeasonal : Workers who travel from their permanent residences seasonally for agri -
cultural employment
 XMen, women, and children of all cultures

26 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XIt is estimated that more than 3 million migrant and seasonal farm workers work in 
the United States (National Center for Farmworker Health, 2009). 
 ZHard to get an accurate census because families and workers move a great deal
 XWorking conditions, problems with the process of acculturation, isolation, discrimina -
tion, and impaired access to health care play a role in a high prevalence of mental 
illness among migrant and seasonal farm workers.
 XVery high incidence of depression, anxiety, and substance abuse
 XPhysical and emotional abuse of women is harder to address because of frequent 
changes of location.
 XMeeting the mental health needs of this vulnerable population can pose a challenge 
because of the ways specific cultures perceive mental illness. Displaying an em -
pathic, understanding, and culturally sensitive attitude is imperative when promoting 
care to this population.

care to this population. 
Sexual Orientation
Possessing a thorough understanding of sexuality is of great importance when communicating 
with clients of different sexual orientations. The practitioner must possess an open, supportive, 
sensitive, empathetic attitude toward the client. Understanding the client’s viewpoint and what 
he or she is seeking will help facilitate an effective psychiatric evaluation. In addition, an aware -
ness of the factors the client may have faced because of his or her sexuality is crucial. 
 XSexual identity:  How people identify psychologically on a continuum between female 
and male and to whom they are sexually or affectionately attracted (Sadock, Sadock, 
& Ruiz, 2015)
 XGender identity : A person’s identity along a continuum between normative con -

structs of masculinity and femininity
 ZInfluences of gender identity may consist of biological and social factors. 
 ZBiological factors may include pre- and postnatal hormone levels and gene 
expression.
 ZSocial factors may include gender messages from family, mass media, and 
cultural attitudes. 
 XGender dysphoria : The formal diagnosis to describe a marked incongruence between 
one’s experienced and expressed gender and the gender assigned at birth (American 
Psychiatric Association [APA], 2013)
 XSexual orientation : The direction of sexual attraction; preferred over “sexual prefer -
ence” or “lifestyle, ” which imply choice, whereas “orientation” does not; some prefer 
“sexual identity” because it allows people to determine their own identities. Sexual

“sexual identity” because it allows people to determine their own identities. Sexual 
orientation does not always relate to gender identity. 
 ZAsexual:  Not attracted to either sex
 ZBisexual: Attracted to both sexes
 ZHeterosexual : Attracted to the opposite sex
 ZHomosexual : Attracted to the same sex

27 Psychiatric–Mental health nurse Practitioner role, scoPe of Practice, and regulatory Process
 ZTransgender : Umbrella term describing persons whose gender identity does not 
conform to gender norms associated with the gender they were assigned at 
birth; does not imply a particular sexual orientation
 ZTranssexual : Persons who identify as the opposite gender from the one they 
were assigned at birth; some change their bodies hormonally and surgically to 
conform to their gender identity 
 ZLGBTQ : Lesbian, gay, bisexual, transgender, and queer or questioning
 ZMany clients seek treatment from a provider of the same orientation
 XSexual behavior : The manner in which humans experience and express their sexual -
ity; includes attracting partners, sexual interactions, and social interactions (Sadock, 
Sadock, & Ruiz, 2015)
Forensics and Corrections
In the 1970’s deinstitutionalization began, leaving many with a mental illness or intellectual dis -

ability in need of housing in the community. One of the places persons with a mental illness 
are overrepresented is in the criminal justice system (Kennedy-Hendricks, Huskamp, Rutkow & 
Berry, 2016, pg. 1077). Persons in the prison system have higher rates of serious mental illness -
es compared to those in the community (Prins, 2014). Prins found higher rates of post-traumatic 
stress disorder, major depression, generalized anxiety disorder, dysthymia, bipolar disorder, so -
cial anxiety, panic, and schizophrenia in prison populations compared to community populations. 
A large number of US prisoners need mental health care. A case study of inmates in Texas found 
that approximately 15% to 24% of inmates reported symptoms of a psychotic disorder, 43% to

that approximately 15% to 24% of inmates reported symptoms of a psychotic disorder, 43% to 
54% of inmates reported symptoms of mania, and 23% to 30% of inmates reported symptoms 
of major depression. Unfortunately, lack of synchronized care among criminal justice, mental, 
and public health systems results in repeat incarcerations (Baillargeon et al., 2010; Kushel, Hahn, 
Evans, Bangsberg, & Moss, 2005). It is essential to remain neutral, calm, and objective, and be 
skilled in self-reflective techniques as well as acknowledging one’s own emotional response and 
biases when providing care for imprisoned clients. Lyons (2009) recommends that the practitio -
ner compartmentalize emotional responses and biases temporarily then debrief afterward.
 XForensic : The application of scientific knowledge to legal problems and legal pro -

ceedings, for example, in forensic anthropology, forensic dentistry, forensic medicine 
(legal medicine), forensic pathology, and forensic science
 XForensic science : The application of a broad range of sciences to answer questions 
of interest to the legal system; a high-technology field using electron microscopes, 
lasers, ultraviolet and infrared light, advanced analytical techniques, and computer -
ized databanks to analyze and research evidence
 XForensic nursing : The practice of nursing when health and legal systems intersect; 
the forensic nurse provides direct services to individual clients; consultation services 
to nursing, medical, and legal agencies; and expert court testimony in areas dealing 
with trauma or investigations of questioned deaths, adequacy of services delivery,

with trauma or investigations of questioned deaths, adequacy of services delivery, 
and specialized diagnoses of specific conditions as related to nursing
Forensic Versus Correctional
 XForensic : Nurse–client relationship based on crime committed and investigational 
aspect of the interaction

28 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XCorrectional : Nurse–client relationship based on offender’s current mental health and 
medical conditions
 XLocations : Emergency departments, prisons (high-, medium-, and low-security units), 
courts, and police stations (Lyons, 2009)
Forensic Knowledge Base
 XRelies on evidence-based practice as well as past clinical experience
 XIncorporates both criminal justice and mental health systems
 XThe forensic PMHNP should possess theoretical and practical knowledge of the 
criminal justice and mental health systems
 ZFunction of the court
 ZLitigation procedures
 ZWorkings of the criminal justice system
 ZRelevant case law and health litigation 
 ZUnderstanding of mental health, distorted thinking patterns, and impaired 
cognition
 ZCompetence:  Safety, security, management, and assessment of risk; 
management of aggression and violence; therapeutic relationship; offending

cognition
management of aggression and violence; therapeutic relationship; offending 
behavior knowledge; prison culture; documentation; medical knowledge; 
psychopharmacology; and crisis de-escalation (Lyons, 2009)
Forensic Risk Assessment vs .  Risk Assessment
 XForensic risk assessment:  Protect the public from persons with known mental disor -
ders having dangerous, violent, and criminal histories
 XRisk assessment:  Psychiatric evaluation performed in emergency department after 
arrest and before person is confined to a correctional facility (Lyons, 2009)

29 Psychiatric–Mental health nurse Practitioner role, scoPe of Practice, and regulatory Process
CASE STUDY 1
Karen Harris is a newly graduated PMHNP . She worked as a psychiatric nurse for 5 years before 
going to graduate school. She is considering a job at the local community mental health center. 
The director of the center has told her that her role would consist of seeing mainly adult clients 
with serious, chronic, and persistent mental illness. 
On occasions when the psychiatrist is “busy, ” Ms. Harris is told she may be expected to see a 
few children in addition to adults. The director expects Ms. Harris to provide medication manage -
ment to well-known clients and occasionally to assist in diagnostic evaluations of new clients or 
clients in crisis. He also expects that she will “from time to time” meet the emergent medical 
needs of clients who have limited access to primary care providers, including the routine, ongo -

ing care of nonpsychiatric disorders such as diabetes, hypertension, and chronic pain. Ms. Harris 
has many issues to consider before deciding to take or not take the position.
1. Would Ms. Harris be legally authorized to treat both children and adults?
2. What regulation, rule, or standard should Ms. Harris consult to determine if she is 
legally allowed to treat both children and adults?
3. What regulation, rule, or standard should Ms. Harris consult to determine if she is 
legally allowed to treat both physical and psychiatric disorders?
4. What is the role of professional psychiatric nursing organizations in assisting Ms. 
Harris to determine the scope of practice that is appropriate for her as a new 
graduate?

graduate? 
Ms. Harris decides not to take that job and instead has been working for about a year as a 
PMHNP in a nurse-managed primary mental health clinic. One day she is asked to assess a 
client who is clearly psychotic, experiencing hallucinations and delusions, and expressing verbal 
threats against many persons at another clinical practice in town who had “malpracticed” them. 
The client is adamant that he does not wish any treatment and that he is not ill. To care for this 
client, Ms. Harris has many issues to consider.
5. Is Ms. Harris able to treat the client if he is not consenting to care?
6. What legal standards must be met if she is to treat this client without his consent?
About 5 weeks later the above-mentioned client returns to the clinic for follow-up care. He is

About 5 weeks later the above-mentioned client returns to the clinic for follow-up care. He is 
clinically stable, on medication, and showing no active symptoms. He is interested in developing 
a relapse prevention plan and asks Ms. Harris to assist him in this process. Ms. Harris has many 
issues to consider.
7. Is the inclusion of a durable power of attorney an appropriate strategy in relapse 
planning for this client?
8. What quality indicators should be considered in planning the client’s care with him?
9. What risk management and liability issues should Ms. Harris consider?
CASE STUDY 2
A PMHNP working in a rural mental health clinic is asked by a women’s clinic to evaluate Ms. M., 
a 35-year-old female. Ms. M. insists she is not depressed, but that she has been feeling under -
standably distressed because she was fired from her job for excessive absenteeism related to

standably distressed because she was fired from her job for excessive absenteeism related to 
“head, neck, and back pain. ” Ms. M. has difficulty falling and staying asleep, wakes up feel -
ing tearful, and doesn’t want to get out of bed. She has become socially isolative and spends

30 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
hours sitting in front of the television. She has been taking 50 mg of amitriptyline for the past 6 
months. The medication has been prescribed by a physician’s assistant at a women’s clinic. She 
was last seen at the women’s clinic 4 months ago. After evaluating Ms. M., the PMHNP de -
cides that she meets criteria for major depression. He decides to continue the amitriptyline but 
increases the dose. 
1. How should the PMHNP explain his rationale for increasing the dose of the amitrip -
tyline to the client?
2. Since amitriptyline is a tricyclic antidepressant, is it reasonable for the PMHNP to 
continue and even adjust the dose of this medication—in other words, is this treat -
ment within the scope of the PMHNP’s practice?

31 Psychiatric–Mental health nurse Practitioner role, scoPe of Practice, and regulatory Process
ANSWERS TO CASE STUDY DISCUSSION QUESTIONS
Case Study 1
1. The key word here is “legally. ” Professional standards and scope of practice docu -
ments suggest what is reasonable and prudent practice. Professional nursing 
organizations will provide information on what is seen as acceptable educational 
preparation for practice. However, the individual legislative regulations of each state 
determine what constitutes legal practice for each individual PMHNP .
2. The Nurse Practice Act and related legislation of the state in which she practices will 
delineate the legal boundaries of her practice.
3. Professional standards and scope-of-practice documents suggest what is reasonable 
and prudent practice. The individual legislative regulations of each state determine 
what constitutes legal practice for each individual PMHNP .

4. Professional nursing organizations provide information through a Scope and 
Standards document about what is seen as an acceptable practice role for PMHNPs, 
but the PMHNP’s practice is ultimately guided by the individual state’s Nurse 
Practice Act.
5. Any client, including a psychiatric client, has the right to refuse treatment. Ms. Harris 
is legally and ethically bound to honor the client’s rights.
6. Ms. Harris must meet the legal standard in the state where she practices to treat a 
client against his or her wishes. This usually entails performing the legal task of com -
mitting a client and in most states, ensuring that the following criteria are met:
 ZThe person has a diagnosed psychiatric disorder
 ZThe person is unaware or unwilling to accept the nature and severity of disorder

ZThe person has a diagnosed psychiatric disorder
 ZAs a result of a mental disorder, a person is harmful to self or others
 ZAs a result of a mental disorder, a person cannot take care of his or her basic 
needs of food, clothing, and shelter
7. A durable power of attorney allows a person in a state of health to choose another 
person to act on his or her behalf should he or she become unable to make his or 
her own healthcare decisions. Chronic mental illness has the potential to render a 
person unable to make healthcare decisions, and a durable power of attorney docu -
ment should be part of relapse planning.
8. Standardized client assessment and rating scales, evidence-based standards of 
care, and measures of quality, including client and family satisfaction, should be 
9. Ms. Harris should adhere to standards and scope of practice and identify factors

9. Ms. Harris should adhere to standards and scope of practice and identify factors 
specific to this client that increase liability exposure.
Case Study 2
1. The PMHNP must discuss the treatment plan in the context of the client’s psychi -
atric symptoms. Without trying to convince the client that she has major depres -
sion, the PMHNP can discuss how chronic pain may have led to the distress she is

32 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
currently experiencing and that the medication may address many of her distressing 
symptoms. He will also need to address the potential side effects from this tricyclic 
antidepressant, and the usual course of treatment in terms of dosing and timeline.
2. Yes, if the PMHNP is using the medication to target the client’s depressive symp -
toms and if he believes the benefit-to-risk ratio is reasonable in this instance, it is 
reasonable for the PMHNP to continue the medication and adjust the dose. The 
PMHNP must do all the relevant medical tests to prescribe this medication.
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http://www.acenursing.org/accreditation-manual/  
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Author.
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CHAPTER 3THEORETICAL BASIS OF CARE
Although the psychiatric–mental health nurse practitioner (PMHNP) role is relatively new, psy -
chiatric–mental health nursing has a long, well-established, and cherished tradition of advanced 
practice. As with all other specialty areas of nursing, advanced practice psychiatric nursing is 
theoretically grounded, and a wide array of theories form the basis of the PMHNP role. These 
theories help identify the foundational, core concepts of advanced-practice psychiatric nursing. 
The scope of practice for the PMHNP is based on an understanding of foundational core con -
cepts and theories (Alligood, 2014).
This chapter reviews the concepts of biopsychosocial theories that underpin PMHNP practice.
BIOPSYCHOSOCIAL FRAMEWORK OF CARE
Recovery
 XRecovery is the single most important goal in the transformation of mental health 
care of the past 2 decades. Four major dimensions of recovery include: health,

Recovery
care of the past 2 decades. Four major dimensions of recovery include: health, 
home, purpose, and community (U.S. Department of Health and Human Services 
[DHHS], Substance and Mental Health Services Administration, 2015).
 XPMHNP interventions follow evidence-based practice guidelines, are always client 
goal–directed, and take into account the client’s ethnicity and culture. 
 XPMHNPs help clients to recognize strengths, set attainable goals, and have hope for 
their future.
 XA key part of the PMHNP’s work is to use empirical evidence in educating their 
clients, clients’ families, and the community about mental health, psychiatric illness, 
and effective management of illness.
 XThe PMHNP oversees and guides the psychiatric–mental health nurse in design -
ing evidence-based health information and educational programs that are geared to

ing evidence-based health information and educational programs that are geared to 
consumer learning needs, ability, and readiness to learn.
 XPMHNPs care for people with co-occurring medical and psychiatric disorders.
 XPrinciples of mental health recovery are integrated into all levels of mental health 
care (American Psychiatric Nurses Association [APNA], 2012).

38 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
CLASSIFICATION OF PSYCHIATRIC DISORDERS: DSM-5
 XPrior to May of 2013, psychiatric disorders were classified using standard criteria of 
the Diagnostic and Statistical Manual of Mental Disorders  (DSM-IV-TR; American 
Psychiatric Association [APA], 2000).
 XUnlike previous editions, the DSM-5 does not use multiaxial classifications (APA, 
2013).
 XThe DSM-5 classifies mental illnesses on the basis of specific criteria that have been 
tested for reliability when used by mental health professionals.
 XEmphasizes dimensional assessments
THERAPEUTIC RELATIONSHIP
 XAssumes the client and nurse enter into a mutual, interactive, interpersonal relation -
ship specifically to focus on the identified needs of the client
 XTherapeutic relationships are focused on the client’s needs, and are goal-directed, 
theory-based, and open to supervision.

 XThe following are a few characteristics of a therapeutic relationship:
 ZGenuineness
 ZAcceptance
 ZNonjudgment
 ZAuthenticity
 ZEmpathy
 ZRespect
 ZProfessional boundaries
 XThe therapeutic relationship has specific and sequential phases (see Table 3–1).
 XTransference and countertransference are key concepts in the nurse–client 
relationship.
 ZTransference : Displacement of feelings for significant people in the client’s past 
onto the PMHNP in the present relationship
 ZCountertransference : The nurse’s emotional reaction to the client based on her 
or his past experiences
 XSigns indicating the presence of countertransference in the PMHNP include
 ZIntense emotional reactions, positive or negative, on first contact with 
client;

client;
 ZRecurrent anxiety or uneasiness while dealing with the client;
 ZUncharacteristic carelessness in interaction and follow-up with client;
 ZDifficulty empathizing;
 ZResistance to others treating or interacting with the client;
 ZPreoccupation with or dreaming about the client;

39 theoretical Basis of care
 ZFrequently running overtime or cutting time short with client;
 ZDepression or other strong emotions during or after interaction with 
client; and
 ZFeedback from others over involvement with client.
 XThe PMHNP is expected to monitor her or his reaction to clients to 
constantly assess for the presence of countertransference.
 XIf identified, countertransference is usually dealt with through the 
supervisory process and in talking to coworkers about the issues.
 ZProvided in peer–peer or peer–supervisor relationship
 ZExamines interpersonal dynamics inherent in the PMHNP’s relationship 
with clientsTABLE 3–1  .
PHASES OF A THERAPEUTIC NURSE–CLIENT RELATIONSHIP
PHASE NURSING ACTION COMMON CLIENT BEHAVIOR
(Orientation)Creating a trusting environment
Establishing professional 
boundaries
Establishing the length of 
anticipated interaction
Providing diagnostic evaluation
Setting mutually agreed-upon

Setting mutually agreed-upon 
treatment objectivesInitial hesitancy by the client to 
participate fully in assessment 
and treatment planning (approach 
avoidance) 
Working
(Identification and 
Exploitation)Clarifying client expectations and 
mutually set goals
Implementing treatment plan
Monitoring health
Undertaking preventative health 
care
Measuring outcomes of care
Evaluating outcomes of care
Reprioritizing plan and objectives as 
indicatedTransference—client 
(countertransference—nurse)
Client resistance to care 
practices
Client resistance to change
Termination
(Resolution)Reviewing client’s progress toward 
objectives
Establishing long-term plan of care
Focusing on self-management 
strategies
Disengaging from relationship
Referring client to other services as 
neededClient resistance to termination
Regression

Reemergence of symptoms or 
problems
Note.  Adapted from Keltner, N., Schwecke, L. H., & Bostrom, C. E. (2006). Psychiatric nursing  
(5th ed.). St. Louis, MO: Mosby.

40 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
DEVELOPMENTAL THEORIES
 XGrowth, change, and development are a part of the dynamic, constant life process of 
being human.
 XHumans develop uniquely from simple to complex.
 XThe health states of individuals and families can be viewed over a continuum of 
development.
 XDevelopmental stages and the milestones or tasks that accompany them give insight 
into age-appropriate behaviors, measure levels of comprehension for client teaching, 
and provide a context within which to evaluate assessment data (see Table 3–2).
TABLE 3–2 .
ERIK ERIKSON’S (1902–1994) STAGES OF HUMAN DEVELOPMENT
DEVELOPMENTAL 
STAGE AGEDEVELOPMENTAL 
TASKINDICATIONS OF 
MASTERYINDICATIONS OF 
FAILURE
Infancy Birth–1 
yearTrust vs. mistrust Ability to form 
meaningful 
relationships, hope 
about the future, 
trust in othersPoor relationships, lack of 
future hope, suspicious of 
others

FAILURE
others
Early childhood 1–3 
yearsAutonomy vs. 
shame and doubtSelf-control, self-
esteem, willpowerPoor self-control, low self-
esteem, self-doubt, lack 
of independence
Late childhood 3–6 
yearsInitiative vs. guilt Self-directed 
behavior, goal 
formation, sense of 
purposeLack of self-initiated 
behavior, lack of goal 
orientation
School-age 6–12 
yearsIndustry vs. 
inferiorityAbility to 
work; sense of 
competency and 
achievementSense of inferiority; 
difficulty with working, 
learning
Adolescence 12–20
yearsIdentity vs. role 
confusionPersonal sense of 
identityIdentity confusion, poor 
self-identification in group 
settings
Early adulthood 20–35 
yearsIntimacy vs. 
isolationCommitted 
relationships, 
capacity to loveEmotional isolation, 
egocentrism
Middle adulthood 35–65

settings
Middle adulthood 35–65 
yearsGenerativity vs. 
self-absorption or 
stagnationAbility to give 
time and talents 
to others, ability 
to care for othersSelf-absorption, inability 
to grow and change as a 
person, inability to care 
for others
Late adulthood >65 Integrity vs. 
despairFulfillment and 
comfort with life, 
willingness to 
face death, insight 
and balanced 
perspective on 
life’s eventsBitterness, sense of 
dissatisfaction with life, 
despair over impending 
death
Note . Adapted from Sadock, B. J., Sadock, V. A., & Ruiz, P . (2015). Kaplan and Sadock’s synopsis 
of psychiatry  (11th ed. ). Philadelphia, PA: Wolters Kluwer.

41 theoretical Basis of care
 ZExample: The mental status finding of concrete thinking in a 9-year-old client 
would be normal and expected; however, the same finding in a 29-year-old client 
is nonnormative and suggestive of psychopathology (see Table 3–3 for typical 
age of onset for psychiatric disorders).
FOUNDATIONAL THEORIES SUPPORTING PMHNP ROLE
 XPsychodynamic ( Psychoanalytic) Theory ( Sigmund Freud, 1856–1939)
 ZFocus is on concepts of intrapsychic conflict among the structures of the mind
 ZInitially designed to explain neurosis and conditions of high anxiety such as 
phobias and hysteria
 ZTheory later expanded to include normal and abnormal development and 
personality development
 ZBasic tenets of psychodynamic theory
 XPsychoanalytical theory assumes that all behavior is purposeful and 
meaningful. All behavior has meaning.
 XPrinciple of Psychic Determinism : Even apparently meaningless, random, or

XPsychoanalytical theory assumes that all behavior is purposeful and 
 XPrinciple of Psychic Determinism : Even apparently meaningless, random, or 
accidental behavior is actually motivated by underlying unconscious mental 
content.
 ZExample: A person forgets where he parked the car because he really 
does not wish to go wherever it was that he was headed.
 XMost mental activity is unconscious—urges, feelings, and fantasies that 
would be unacceptable to the person’s values if consciously experienced.
 XConscious behaviors and choices are affected by unconscious mental 
content.
 XChildhood experiences shape adult personality.
TABLE 3–3 .  
EXAMPLES OF  TYPICAL AGE OF ONSET FOR COMMON PSYCHIATRIC DISORDERS
DISORDER AGE OF ONSET
Intellectual Disability Infancy—usually evident at birth
Attention deficit hyperactivity disorder Early childhood (per DSM-5, by age 12)
Schizophrenia 18 to 25 years for men
25 to 35 years for women

Major depression Late adolescence to young adulthood
Dementia Most common after age 85
Note. Adapted from Sadock, B. J., Sadock, V. A., & Ruiz, P . (2015). Kaplan and Sadock’s 
synopsis of psychiatry  (11th ed.). Philadelphia, PA: Wolters Kluwer.

42 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XInstincts, urges, or fantasies function as drives that motivate thoughts, 
feelings, and behaviors.
 ZTwo types of normal drives: sexual drives (libido) and aggressive drives
 ZDrives affect behavior as an individual attempts to deal with the 
associated feelings and seeks gratification through release of the 
tension that the drives produce.
 ZNormally, different actions or behaviors are used at different ages to 
discharge tension from drives and seek gratification.
 ZPsychosexual stages of development have been identified to show 
the age-related behaviors commonly used for discharging drives and 
obtaining gratification (see Table 3–4).
 ZThree primary psychic structures make up the mind and personality and are 
responsible for mental functioning:
1. The Id
 ZContains primary drives or instincts, urges (hunger, sex, or aggression), 
or fantasies

1. The Id
 ZDrives are largely unconscious, sexual, or aggressive in content, and 
infantile in nature
 ZOperates on the pleasure principle; seeks immediate satisfaction
 ZIs present at birth and motivates early infantile actions
 ZThe id says, “I want”
TABLE 3–4 .
FREUD’S PSYCHOSEXUAL STAGES OF DEVELOPMENT
STAGE AGEPRIMARY MEANS OF 
DISCHARGING DRIVES AND 
ACHIEVING GRATIFICATIONPSYCHIATRIC 
DISORDER LINKED 
TO FAILURE OF 
STAGE
Oral stage 0–18 
monthsSucking, chewing, feeding, crying Schizophrenia
Substance abuse
Paranoia
Anal stage 18 months– 
3 yearsSphincter control, activities of 
expulsion and retentionDepressive disorders
Phallic stage 3–6 years Exhibitionism, masturbation with 
focus on Oedipal conflict, castration 
anxiety, and female fear of lost 
maternal loveSexual identity 
disorders
Latency stage 6 years–

disorders
Latency stage 6 years– 
pubertyPeer relationships, learning, motor-
skills development, socializationInability to form 
social relationships
Genital stage Puberty 
forwardIntegration and synthesis of 
behaviors from early stages, primary 
genital-based sexualitySexual perversion 
disorders
of psychiatry (11th ed.). Philadelphia, PA: Wolters Kluwer.

43 theoretical Basis of care
2. The Ego
 ZContains the concept of external  reality
 ZRational mind; responsible for logical and abstract thinking
 ZFunctions in adaptation
 ZMediates between the demands of drives and environmental realities
 ZOperates on the reality principle
 ZBegins to develop at birth as infant struggles to deal with environment
 ZResponsible for use of defense mechanisms
 ZThe ego says, “I think, I evaluate”
3. The Superego
 ZIs the ego-ideal
 ZContains sense of conscience or right versus wrong
 ZAlso contains aspirations, ideals, and moral values
 ZRegulated by guilt and shame
 ZBegins to fully develop around age six as a child comes into contact 
with external authority figures such as other parents, schoolteachers, 
coaches, or religious figures
 ZThe superego says “I should or ought”
 ZPsychic structures commonly come into conflict over what to do to achieve 
gratification.
 ZAlthough the exact nature of conflict is often unconscious, conflict is

ZPsychic structures commonly come into conflict over what to do to achieve 
 ZAlthough the exact nature of conflict is often unconscious, conflict is 
experienced consciously as anxiety.
 ZThe function of anxiety is to alert the conscious mind to the presence of 
conflict.
 ZConflict is normally dealt with through the use of defense mechanisms (see 
Table 3–5), which
 XAre a function of the ego,
 XAre unconsciously called into action,
 XAre used to reduce anxiety,
 XBecome part of the personality, 
 XMaintain a sense of safety,
 XPromote self-esteem and a sense of well-being,
 XMay be used episodically or habitually, and
 XMay be used constantly and become fixed, as seen in neurosis.
 XCognitive Theory ( Jean Piaget, 1896–1980)
 ZPiaget believed that human development evolves through cognition, learning, 
and comprehending.

44 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZHe believed that factors such as native endowment and biological and 
environmental factors set the course for a child’s development.
 ZHe described four stages of cognitive development:
1. Sensorimotor (Birth–2 years): The critical achievement of this stage is object 
permanence: the ability to understand that objects have an existence 
independent of the child’s involvement with them
2. Preoperational  (2–7 years): More extensive use of language and symbolism; 
magical thinking
3. Concrete Operations (7–12 years): Child begins to use logic; develops 
concepts of reversibility and conservation
 ZReversibility:  The realization that one thing can turn into another and 
back again (e.g., water and ice)
 ZConservation:  Ability to recognize that although the shape of an object 
may change, it will still maintain characteristics that enable it to be

may change, it will still maintain characteristics that enable it to be 
recognized as that object (e.g., clay)TABLE 3–5 .  
DEFENSE MECHANISMS
DEFENSE MECHANISM EXPLANATION
Denial Avoidance of unpleasant realities by unconsciously ignoring their 
existence
Projection Unconscious rejection of emotionally unacceptable personal 
attributes, beliefs, or actions by attributing them to other people, 
situations, or events
Regression Return to more comfortable thoughts, behaviors, or feelings used 
in earlier stages of development in response to current conflict, 
stress, or threat
Repression Unconscious exclusion of unwanted, disturbing emotions, 
thoughts, or impulses from conscious awareness
Reaction formation Often called overcompensation; unacceptable feelings, thoughts, 
or behaviors are pushed from conscious awareness by displaying

or behaviors are pushed from conscious awareness by displaying 
and acting on the opposite feeling, thought, or behavior
Rationalization Justification of illogical, unreasonable ideas, feelings, or actions by 
developing an acceptable explanation that satisfies the person
Undoing Behaviors that attempt to make up for or undo an unacceptable 
action, feeling, or impulse
Intellectualization Attempts to master current stressor or conflict by expansion of 
knowledge, explanation, or understanding
Suppression Conscious analog of repression; conscious denial of a disturbing 
situation, feeling, or event
Sublimation Unconscious process of substitution of socially acceptable, 
constructive activity for strong unacceptable impulse
Altruism Meeting the needs of others in order to discharge drives, conflicts, 
or stressors

Note . Adapted from Shea, C. A., Pelletier, L., Poster, E. C., Stuart, G. W., & Verhey, M. P . (1999). 
Advanced practice nursing in psychiatric and mental health care.  St. Louis, MO: Mosby.

45 theoretical Basis of care
4. Formal Operations  (12 years–adult): Ability to think abstractly; thinking 
operates in a formal, logical manner
 XInterpersonal Theory ( Harry Stack Sullivan, 1892–1949)
 ZBehavior occurs because of interpersonal dynamics.
 ZInterpersonal relationships and experiences influence one’s personality 
development, which is called the self-system  (the total components of 
personality traits).
 ZUnderstanding behavior requires understanding the relationships in the person’s 
life.
 ZTwo drives for behavior: the drive for satisfaction  (basic human drives such as 
sleep, sex, hunger) and the drive for security  (conforming to social norms of a 
person’s reference group).
 ZWhen the person’s need for satisfaction and security is interfered with by the 
self-system, mental illness occurs.
 ZHumans experience anxiety and behavior is directed toward relieving the 
anxiety, which then results in interpersonal security .

 ZSullivan also described stages of interpersonal development  (see Table 3–6).
 XHierarchy of Needs Theory ( Abraham Maslow, 1908–1970)
 ZHealth model rather than illness model
 ZA hierarchical organization of needs
 ZHypothesizes that certain needs are more important to than others
 ZStates that a person will attempt to meet more important needs first before 
satisfying other needs
 ZHierarchy of needs:
 XSurvival
 ZWater
 ZAir
 ZFood
 ZSleep
TABLE 3–6 .  
SULLIVAN’S STAGES OF INTERPERSONAL DEVELOPMENT
STAGE TIME PERIOD DEVELOPMENTAL TASK
Infancy Birth–18 months Oral gratification; anxiety occurs for the first time
Childhood 18 months–6 years Delayed gratification
Juvenile 6–9 years Forming of peer relationships
Preadolescence 9–12 years Same-sex relationships
Early adolescence 12–14 years Opposite-sex relationships

Late adolescence 14–21 years Self-identity developed
Note . Adapted from Sadock, B. J., Sadock, V. A., & Ruiz, P . (2015). Kaplan and Sadock’s 
synopsis of psychiatry (11th ed.). Philadelphia, PA: Wolters Kluwer.

46 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XSafety and security needs
 ZProtection from harm: emotional and physical
 XLove and belonging
 ZAffection, intimacy, and companionship
 XSelf-esteem
 ZSense of worth
 XSelf-actualization 
 ZAchieving one’s potential
 ZBeing all that one can be
 XHealth Belief Model ( Marshall Becker, 1940–1993)
 ZExplains that healthy people do not always take advantage of screening or 
preventative programs because of the following certain variables:
 XPerception of susceptibility
 XSeriousness of illness
 XPerceived benefits of treatment
 XPerceived barriers to change
 XExpectations of efficacy
 XTranstheoretical Model of Change
 ZStates that change such as in health behaviors occurs in six predictable stages 
(Prochaska, Norcross, & DiClemente, 1992):
1. Precontemplation:  The person has no intention to change.
2. Contemplation:  The person is thinking about changing; is aware that there is

2. Contemplation:  The person is thinking about changing; is aware that there is 
a problem but not committed to changing.
3. Preparation:  The person has made the decision to change; is ready for 
action.
4. Action: The person is engaging in specific, overt actions to change.
5. Maintenance:  The person is engaging in behaviors to prevent relapse.
 XMotivational Interviewing (Miller & Rollnick, 1991)
 ZFocused, goal-directive therapy
 ZBuilds on the Transtheoretical Model of Change
 ZMotivation is elicited from the client
 ZNonconfrontational, nonadversarial
 XSelf-Efficacy and Social Learning Theory ( Albert Bandura, born 1925)
 ZBehavior is the result of cognitive and environmental factors.
 ZPeople learn by observing others, relying on role-modeling.
 ZSelf-efficacy  is the perception of one’s ability to perform a certain task at a 
certain level of accomplishment.

47 theoretical Basis of care
 ZBehavioral change and maintenance are functions of outcome expectations and 
efficacy expectations.
NURSING THEORIES
 XTheory of Cultural Care ( Madeline Leininger, born 1925)
 ZRegardless of the culture, care is the unifying focus and the essence of nursing.
 ZHealth and well-being can be predicted through cultural care.
 XTheory of Self-Care ( Dorothy Orem, 1914–2007)
 ZSelf-care : Activities that maintain life, health, and well-being
 XTherapeutic Nurse–Client Relationship Theory or Interpersonal Theory ( Hildegard 
Peplau, 1909–1999)
 ZFirst significant psychiatric nursing theory
 ZBased in part on interpersonal theory (Sullivan, 1953)
 ZSees nursing as an interpersonal process in which all interventions occur within 
the context of the nurse–client relationship
 ZThe therapeutic nurse–client relationship is central to nursing
 ZIncludes phases of the nurse–client relationship (see Table 3–2 above):
 XOrientation phase

ZThe therapeutic nurse–client relationship is central to nursing
 XWorking phase (identification, exploitation)
 XTermination phase (resolution)
 ZPromoting adaptive responses is the goal of nursing
 ZBehavior represents the person trying to adapt to internal or environmental 
forces
 XCaring Theory ( Jean Watson, born 1940)
 ZCaring is an essential component of nursing.
 Z“Carative factors” guide the core of nursing and should be implemented in 
health care.
 ZCarative factors are those aspects of care that potentiate therapeutic healing 
and relationships.

48 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
Thomas is a 19-year-old college freshman. During the second week of classes, he presented to 
his college’s student health services clinic seeking help for “shyness. ” The PMHNP is responsible 
for assessment and care planning with this client.
As the PMHNP begins working with him, he gives a chief complaint of feeling uncomfortable 
meeting new people and desiring to return home and drop out of school. The PMHNP has sev -
eral issues to consider as he or she continues to work with Thomas.
1. Chronologically, what stage of development should Thomas be experiencing?
2. What are the tasks of this stage?
3. How would the PMHNP assess the actual developmental issues that he is 
experiencing?
4. What factors does the PMHNP need to consider to determine whether he is experi -
encing normative or nonnormative behaviors?

5. What characteristic does the PMHNP need to display to establish a therapeutic 
relationship with him?
Thomas reported that he has not been sleeping well, has experienced a decrease in appetite, 
and just wants to talk to someone about his problems in adjusting to school. In planning the 
follow-up care for Thomas, the PMHNP has many issues to consider.
6. What would be the goal of continued work with Thomas?
7. If the PMHNP were to start therapy with him, what kind of therapy would he or she 
consider?
8. According to DSM-5, does Thomas have a mental illness?
Jason is an 18-year-old, second-semester business major who presents to his university’s mental 
health clinic because “my parents said I have to come here or they will pull me out of school. I

health clinic because “my parents said I have to come here or they will pull me out of school. I 
don’t think I need to be here. ” Jason is on academic probation. The PMHNP learns that Jason’s 
parents grew alarmed when, while home on holiday, Jason was brought home by police after he 
and his friend were pulled over and friend was given a DUI. Jason allows that perhaps he “par -
tied too much” during his first semester at school, but insists he “doesn’t drink any more than 
anybody else. ” Jason reluctantly agrees to see the PMHNP for an evaluation and for 8 weekly 
psychotherapy sessions “to please my parents. ”
1. What defense mechanism(s) is Jason using?
2. How should the PMHNP approach working with this client?

49 theoretical Basis of care
1. Thomas’s chronologic age should align with the developmental stage of 
adolescence.
2. According to Erikson, the developmental task of adolescence is identity versus role 
confusion.
3. The PMHNP should assess the degree of development of his personal sense of 
identity.
4. The PMHNP must have an awareness of the normal milestones of development and 
the behaviors that indicate failure of developmental stages. The client’s history and 
behaviors are then matched to the known norm for comparison.
5. In order to develop a therapeutic relationship with Thomas, the PMHNP must display 
genuineness, acceptance, nonjudgmental attitude, authenticity, empathy, and re -
spect professional boundaries.
6. The goals of continued work with Thomas are assisting Thomas to establish insight 
into behaviors and to increase range and maturity of coping behaviors.

7. Options for psychotherapy depend on factors such as a client’s goals, motivation, 
past experiences with counseling, expectations for therapy, and resources.
8. Mental illness causes a disruption in the usual constitutions of mental health. Mental 
illness assumes an underlying psychopathology and can be defined as a clinically 
significant behavioral or psychological syndrome or pattern that occurs in a person 
that is associated with persistent distress or disability or with a significantly in -
creased risk of death, pain, or an important loss of freedom. Thomas appears to be 
experiencing mental health concerns but based on available data, does not meet the 
definition of mental illness.
1. Jason is using denial and rationalization.

2. The PMHNP needs to work with Jason to establish goals using the principles of the 
Transtheoretical Model of Change and motivational interviewing.
Alligood, M. R. (2014). Nursing theorists and their work (8th ed.). St. Louis, MO: Elsevier Mosby.
American Nurses Association, American Psychiatric Nurses Association, & International Society 
of Psychiatric-Mental Health Nurses. (2014). Psychiatric–mental health nursing: Scope and 
standards of practice  (2nd ed.). Silver Spring, MD: Nursesbooks.org.
American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders 
(4th ed., text rev.). Arlington, VA: American Psychiatric Publishing. 
American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders

American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders 
(5th ed.). Arlington, VA: American Psychiatric Publishing.
Erikson, E. H. (1963). Childhood and society.  New York, NY: Basic Books.

50 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
Freud, S. (1934). The ego and the id.  New York, NY: W. W. Norton.
Freud, S. (1936). The problem of anxiety.  New York, NY: Basic Books.
Haley, J. (1996). Learning and teaching therapy.  New York, NY: Guilford Press.
Keltner, N., Schwecke, L. H., & Bostrom, C. E. (2006). Psychiatric nursing  (5th ed.). St. Louis, 
MO: Mosby.
Kerr, M., & Bowen, M. (1989). Family evaluation: An approach based on Bowen theory.  New York, 
NY: W. W. Norton.
Marsh, D. (1998). Serious mental illness and the family: The practitioner’s guide. New York, NY: 
John Wiley. 
Miller, W. R., & Rollnick, S. (1991). Motivational interviewing: Preparing people for change. New 
York, NY: Guilford Press.
Minuchin, S., & Fishman, H. (1981). Family therapy techniques.  Cambridge, MA: Harvard 
University Press.
Mohr, W. (2000). Partnering with families. Journal of Psychosocial Nursing, 38 , 15–19.

National Institute of Mental Health. (1990). Decade of the brain.  Washington, DC: Author.
Peplau, H. (1952). Interpersonal relations in nursing.  New York, NY: Putnam.
Prochaska, J., & DiClemente, C. (1984). The transtheoretical approach: Crossing traditional 
boundaries therapy. Homewood, IL: Dow Jones Irwin.
Prochaska, J., Norcross, J., & DiClemente, C. (1992). In search of how people change: 
Applications to addictive behaviors. American Psychologist , 47(9), 1102–1112.
Sadock, B., Sadock, V., & Ruiz, P . (2015). Kaplan and Sadock’s synopsis of psychiatry  (11th ed.). 
New York, NY: Lippincott Williams & Wilkins.
nursing in psychiatric and mental health care.  St. Louis, MO: Mosby.

Sherman, C. (2000). Assessment is good opportunity to change family dynamics. Clinical 
Psychiatric News , 3, 25–29.
Stuart, G. W., & Laraia, M. (2004). Principles and practice of psychiatric nursing.  St. Louis, MO: 
Mosby.
Sullivan, H. S. (1953). Interpersonal theory of psychiatry.  New York, NY: Basic Books.
U.S. Department of Health and Human Services, Substance and Mental Health Services 
Administration. (2015). Recovery and recovery support. Retrieved from http://www.samhsa.
gov/recovery  
Yalom, I. (2005). The theory and practice of group psychotherapy  (5th ed.). New York, NY: Basic 
Books.

CHAPTER 4PSYCHIATRIC–MENTAL HEALTH NURSE 
PRACTITIONER PROFESSIONAL ROLE AND 
HEALTH POLICY: LEADERSHIP , QUALITY 
IMPROVEMENT AND SAFETY, PRACTICE INQUIRY, 
AND HEALTH POLICY
LEADERSHIP
Nurses should be leaders and engage with health professionals to transform and redesign health 
care (Institute of Medicine [IOM], 2010).
 XThe nurse practitioner is educated to lead interdisciplinary treatment teams
 ZActs as full partner in health care
 ZDesigns, implements, evaluates, and advocates to redesign the U.S. healthcare 
system
 ZTranslates research into practice
 XTeam leadership model
 ZDecision 1: Should the leader monitor the team or take action?
 XSeek out information to understand the team
 XAnalyze information 
 XInterpret the information and decide how to act
 ZDecision 2: Should the leader intervene to meet the task or relational need?
 XPerformance functions
 XTask functions
 ZDecision 3: Should the leader intervene internally or externally?

52 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XAssess for conflicts between group members—action to maintain group 
 ZAssess for unclear goals
 ZAssess for proper support (Northouse, 2007 , pp. 209–234)
Reflective Practice
 XReflection uses a model or framework to systematically “make sense of experience” 
(Sherwood & Horton-Deutsch, 2012, p. 4).
 XProcess to tell a story about self and others to gain insight into practice 
 XEnhances critical thinking to problem-solve and enhance clinical reasoning and 
decision-making
 XLink theory to practice 
Conflict Resolution, Negotiation, Mediation, and Professional 
Civility
 XConflict : occurs when a person believes his or her needs, interests, or values are 
incompatible with others’
 XConflict resolution : directed by a neutral third party who facilitates a “win-win” 
situation
 XNegotiation : discussion among two or more people with the goal of reaching an 
agreement

XConflict resolution : directed by a neutral third party who facilitates a “win-win” 
situation
agreement
 XMediation : voluntary and confidential process in which a third party facilitates discus -
sion to reach an agreement 
 XArbitration : process in which a third party reviews evidence from both sides and 
makes a decision to settle the case 
 XProfessional civility : behavior that shows respect toward another person
Critical Thinking
 XDefined as the acquisition of knowledge with an attitude of deliberate inquiry
 XMaking clinical decisions based on evidence-based practice
 ZDecreases the difficulty of choosing from conflicting or multiple 
recommendations when diagnosing and treating clients
 XDevelops self-awareness though a metacognitive process to gain new insights about 
self, and in relation to others
Research

Research
 XResearch utilization: Process of synthesizing, disseminating, and using research-gen -
erated knowledge to make a change in practices; a subset of the broader evidence-
based practice

53
PSYCHIATRIC–MENTAL HEALTH NURSE PRACTITIONER PROFESSIONAL ROLE AND HEALTH POLICY
 XEvidence-based practice:  The integration of best research evidence with clinical 
expertise and client values and needs. PMHNPs need to know the effectiveness of 
evidence-based interventions and select the intervention to meet the client need 
(Perese, 2012, p. 29).
 XResearch utilization and evidence-based practice are two models for reducing the 
gap between research findings and application to practice
 ZResearch utilization process
 XCritique research
 XSynthesize the findings
 XApply the findings
 XMeasure the outcomes
 XDevelop a clinical question using the PICO method 
P = patient, population of patients, problem
I = intervention
C = comparison (another treatment or therapy, placebo)
O = outcome
 XSystematically search for relevant research evidence
 ZCritique the research evidence
 XQuanitative hierarchy (Fineout-Overholt, Melnyk, & Schultz, 2005)

O = outcome
 ZRandomized controlled trials (RCT), meta-analysis, or systematic review
 ZEvidence-based guidelines based on systematic review 
 ZEvidence from RCT without randomization
 ZEvidence from systemic review of descriptive and qualitative studies
 ZEvidence from expert opinion or committee reports 
 XQualtitative hierarchy (Fineout-Overholt, Melnyk, & Schultz, 2005)
 ZEvidence from systematic reviews of descriptive and qualitative studies
 ZEvidence from a single descriptive or qualitative study
 ZEvidence from expert opinion or committee
 ZEvidence-based guideline based on systematic review of RCTs
 ZEvidence from well-designed controlled trials without randomization
 ZSystematic reviews or meta-analysis 
 ZEvidence from at least one well-designed RCT
 ZMake an evidence-based decision regarding implementation

ZSystematic reviews or meta-analysis 
 ZImplement the change, depending on the above decision
 ZEvaluate the change
 XDissemination
 ZPresent at local, regional, and national conferences

54 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZPublish in peer-reviewed journals
 ZPublish in professional newsletters (Melnyk, Fineout-Overholt, Stillwell, & 
Williamson, 2010)
 XConcepts in interpreting research findings
 ZInternal validity : The independent variable (the treatment) caused a change in the 
dependent variable (the outcome)
 ZExternal validity : The sample is representative of the population and the results 
can be generalized
 ZDescriptive statistics : Used to describe the basic features of the data in the 
study; numerical values that summarize, organize, and describe observations; 
can be generated by either quantitative or qualitative studies
 XExamples include
 ZMean : Average of scores
 ZStandard deviation : Indication of the possible deviations from the mean
 ZVariance : How the values are dispersed around the mean; the larger 
the variance, the larger the dispersion of scores

ZStandard deviation : Indication of the possible deviations from the mean
 ZInferential statistics : Numerical values that enable one to reach conclusions that 
extend beyond the immediate data alone; generated by quantitative research 
designs
 Zt test : Assesses whether the means of two groups are statistically 
different from each other
 ZAnalysis of variance (ANOVA) : Tests the differences among three or 
more groups
 ZPearson’s r correlation : Tests the relationship between two variables
 ZProbability : Likelihood of an event occurring; lies between 0 and 1; 
an impossible event has a probability of 0, and a certain event has a 
probability of 1
 ZP value : Also known as level of significance; describes the probability 
of a particular result occurring by chance alone (if P = .01, there is a 1%

of a particular result occurring by chance alone (if P = .01, there is a 1% 
probability of obtaining a result by chance alone)
 XEthical considerations in research
 ZInstitutional Review Boards  (IRBs) ensure that
 XRisks to participants are minimized,
 XParticipant selection is equitable,
 XAdverse events are reported and risks and benefits are reevaluated,
 XInformed consent is obtained and documented,
 XData and safety monitoring plans are implemented when indicated, and
 XOverall, that the rights and welfare of human research participants are 
protected, and has the authority to approve, require modifications, or 
disapprove of any research activities.

55
 XAll investigators or persons involved in research studies must take and pass a test on 
protection of human participants
QUALITY IMPROVEMENT
 XAgency-specific projects that aim to improve systems, decrease cost, and improve 
productivity
 XProvides standardized method to identify gaps in practice and systems to evaluate 
ways to improve structure, function, and resources in care delivery within complex 
health systems
 XInstitute of Medicine’s quality aims (IOM, 2001)
 ZSafe
 ZEffective 
 ZClient-centered
 ZTimely
 ZEfficient
 ZEquitable
 XExamine internal processes
 XNew knowledge is specific to an organization
 XDonabedian model
 ZStructure
 ZProcess
 ZOutcome
 XProcess of quality improvement can be PDSA  cycle:
 ZPlan: Plan the change
 ZDo: Carry out the plan
 ZStudy: Examine the results
 ZAct: Decide what actions will improve the process

ZOutcome
 XTranslation of research into practice using quality improvement efforts and clini -
cal inquiry leads to improved systems and process, which create improved health 
outcomes
JUST CULTURE OF SAFETY
 XAmerican Nurses Association Position Statement (ANA, 2010)
 ZSupports collaboration efforts among state boards of nursing, professional 
organizations, patient safety centers, and health systems to develop Just 
Culture initiatives
 ZHolds people accountable for their behaviors and investigates errors

56 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZGoal of creating open and fair learning environment to design safe systems and 
manage choices
 ZMindset that affects work environment to proactively look for system 
breakdowns and identify ways to improve systems
HEALTH DELIVERY SYSTEMS
 XHealth care is complex and fragmented; complexity science provides a framework to 
understand, design, and structure change.
 XFocus is on the interaction of the parts and relationships
 XNonlinear process
Access to Care
Access to care is a client-centered care model based on the principle that healthcare services 
should be coordinated and directed by a single physician or other provider. In this model, clients 
can access services from multiple entry points. Services can be located in the same facility, or 
an integrated care network of providers in different locations can be accessed when needed.
Quality of Care

The National Committee for Quality Assurance (NCQA) has developed Health Effectiveness Data 
Information Sets (HEDIS) to measure health outcomes. Currently, eleven HEDIS measures exist 
for behavioral health:
1. Antidepressant medication management
2. Follow-up care for children prescribed ADHD medication
3. Follow-up after hospitalization for mental illness
4. Diabetes screening for people with schizophrenia and bipolar disorder who are using 
antipsychotic medications
5. Diabetes monitoring for people with diabetes and schizophrenia
6. Cardiovascular monitoring for people with cardiovascular disease and schizophrenia
7. Adherence to antipsychotic medications for individuals with schizophrenia
8. Use of multiple concurrent antipsychotics in children and adolescents
9. Metabolic monitoring for children and adolescents on antipsychotic medication

10. Use of first-line psychosocial care for children and adolescents on antipsychotic 
medication
11. Mental health utilization
Organization of Practices
With the Affordable Care Act (ACA; 2010), practices are being reorganized and redesigned to pro -
vided integrated care, including medical and psychiatric care. The client-centered medical (health)

57
home has support of the Health Resources and Services Administration (HRSA) and initiatives to 
provide client-centered, evidenced-based, coordinated, and quality care are moving forward.
Patient-Centered Care Model (PCC)
 XWelcoming environment:  Provide a physical space and an initial personal interaction 
that is welcoming and familiar, not intimidating.
 XRespect for clients’ values and expressed needs:  Obtain information about the 
client’s care preferences and priorities; inform and involve the client and family or 
caregivers in decision-making; tailor care to the person; and promote a mutually 
respectful, consistent client–provider relationship.
 XClient empowerment or “activation”:  Educate and encourage the client to expand his 
or her role in decision-making, health-related behaviors, and self-management.
 XSociocultural competence:  Understand and consider culture, economic and educa -

tional status, health literacy level, family patterns and situation, and traditions (includ -
ing alternative and folk remedies); communicate in language and at a level that the 
client understands.
 XCoordination and integration of care:  Assess the client’s need for formal and informal 
services that may affect health or treatment; provide team-based care, care manage -
ment, and referrals as needed; advocate for the client and family; and ensure smooth 
transitions between different providers and phases of care.
 XComfort and support:  Emphasize physical comfort, privacy, emotional support, and 
involvement of family and friends.
 XAccess and navigation skills:  Provide what the patient can consider a “medical 
home”; keep waiting times to a minimum; provide convenient service hours; pro -

mote access and client flow; help client attain skills to better navigate the healthcare 
system.
 XCommunity outreach:  Make demonstrable, proactive efforts to understand and reach 
out to the local community (Silow-Carroll, Alteras, & Stepnick, 2006).
Health Care Home (Substance Abuse and Mental Health Services 
Administration [SAMHSA], 2015)
 XDefined in the Affordable Care Act (2010) as an approach to primary care that pro -
vides coordinated care to persons with multiple chronic health conditions, including 
mental health and substance use
 XOffers team-based care
 XBuilds on community supports
CONFLICT OF INTEREST
A conflict of interest (COI) is a situation in which a person’s financial, professional, or personal

XOffers team-based care
A conflict of interest (COI) is a situation in which a person’s financial, professional, or personal 
situation may affect or appear to affect the person’s judgment in his or her professional respon -
sibilities, including healthcare decisions, research, and other matters, with the potential for

58 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
personal or professional gain or advantage—or, conversely, loss or disadvantage—of any kind 
and the possibility of potential harm to clients.
 XDisclosure of potential COIs should be done at least annually and whenever new 
significant financial interests are received.
 XDisclosure must be reported to employers, boards, professional agencies, and wher -
ever there is potential for a COI.
 XAction should be carried out to resolve potential or actual COIs and reduce bias.
 XHealthcare agencies and educational and research institutions have policies to 
require the disclosure of any potential COI and to define the limits allowed in any 
relationship with external organizations and companies.
 XA COI form indicating any financial or other relationship with the products being dis -
cussed must be completed prior to any professional presentation. In addition, if any

XA COI form indicating any financial or other relationship with the products being dis -
cussed must be completed prior to any professional presentation. In addition, if any 
off-label uses of medications or medical devices will be discussed, this information 
must also be disclosed.
 XTypes of conflict of interest:
 ZRelationships with pharmaceutical, medical supply, or insurance companies
 ZMoney, gifts in kind
 ZReferrals
 ZFee splitting
RIGHTS OF CLIENTS
 XLeast restrictive treatment
 XGive consent for treatment and withdraw consent at any time
HEALTH POLICY DEVELOPMENT
Health policy is decisions, actions, and plans to achieve specific healthcare goals (World Health 
Organization [WHO], 2016).
 XFour components of health policy:
1. Process:  formulation, implementation, and evaluation
2. Policy reform:  changes in programs and practices
3. Policy environment:  arena the process takes place in (government, media, 
public)

public)
4. Policy makers:  key players and stakeholders
 XHealth policies are developed through law and regulations.
 ZBranches of law:  executive (implement law), legislative (initial formulation), and 
judicial (interpret law)

59
CASE STUDY
A PMHNP who is working at a federally qualified health center (FQHC) is asked to implement 
routine depression screening for all clients who present to the clinic. The PMHNP is excited 
about the project but has never implemented a system change and is not sure how to proceed. 
The PMHNP does have access to the quality improvement department and the clinical manager 
to get guidance.
1. What depression screening measures are in the public domain and have been found 
to be sensitive to and specific for depression screening?
2. What is the first step the PMHNP should complete to begin her system change 
process?
3. Who are key players that should be part of the PMHNP’s quality improvement team?
4. What model or framework can the PMHNP use to guide her quality improvement 
project?
5. When conducting a literature review on depression screening in an FQHC, the

project?
5. When conducting a literature review on depression screening in an FQHC, the 
PMHNP finds two RCT studies and two expert opinion articles. Which type has the 
highest level of evidence?

60 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
1. The screening measures in the public domain, sensitive to and specific for depres -
sion screening are: Patient Health Questionnaire–2 (PHQ2) and Patient Health 
Questionnaire–9 (PHQ9).
2. The first step in beginning a systems change project is to conduct a systemic needs 
assessment of the organization.
3. The key players that need to be part of the team include all members of the clinic 
who will be affected by implementation of the depression screening project.
4. The two models that can be used to conduct a quality improvement project include 
Donabedian model and Plan Do Study Act cycle.
5. The highest level of evidence in the literature when evaluating quantitative research 
studies is an RCT .
American Nurses Association. (2010). Just culture position statement . Retrieved from  
http://nursingworld.org/psjustculture

http://nursingworld.org/psjustculture  
Institute of Medicine. (2001). Crossing the quality chasm: A new health system for the 21st cen -
Institute of Medicine. (2010). The future of nursing: Leading change, advancing health . Available 
from http://www.nap.edu/catalog/12956/the-future-of-nursing-leading-change-advancing  
-health  
Northouse, P . G. (2007). Leadership theory and practice (4th ed.). London, Eng.: Sage

Northouse, P . G. (2007). Leadership theory and practice (4th ed.). London, Eng.: Sage 
Patient Protection and Affordable Care Act, Pub. L. No. 111–148 (2010). 
Perese, E. F . (2012). Psychiatric advanced practice nursing: A biopsychosoical foundation for prac -
tice. Philadelphia, PA: F . A. Davis. 
improving outcomes . Indianapolis, IN: Sigma Theta Tau International.
Silow-Carroll, S., Alteras, T ., & Stepnick, L. (2006). Patient-centered care for underserved popula -
tions: Definitions and best practices . Retrieved from http://hsc.unm.edu/community/toolkit/
docs8/Overview.pdf  
Substance Abuse and Mental Health Services Administration. (2014). Advancing behavioral 
health integration with NCQA recognized patient-centered medical homes . Retrieved from

health integration with NCQA recognized patient-centered medical homes . Retrieved from 
http://www.integration.samhsa.gov/integrated-care-models/Behavioral_Health_Integration_
and_the_Patient_Centered_Medical_Home_FINAL.pdf

61
Substance Abuse and Mental Health Services Administration. (2015). What is a health home? 
Retrieved from http://www.integration.samhsa.gov/integrated-care-models/Health_Homes_
Fact_Sheet_FINAL.pdf  
World Health Organization. (2016). Health policy. Retrieved from http://www.who.int/topics/
health_policy/en/

CHAPTER 5NEUROANATOMY, NEUROPHYSIOLOGY, AND 
BEHAVIOR
A tremendous expansion of knowledge about the brain has occurred in the past 2 decades. As 
more has been learned about the brain and its complex functioning, assessment and treatment 
for psychiatric disorders have been altered dramatically. Increasingly, the links among genetics, 
altered brain anatomy and physiology, and the symptoms of psychiatric disorders have been 
identified (Sadock, Sadock, & Ruiz, 2015).
This growing knowledge base will continue to alter the treatment of psychiatric disorders. As 
new knowledge is disseminated, it is helping diminish the stigma long associated with psychiat -
ric illness.
This chapter reviews the basics of neuroanatomy and physiology that provide the scientific 
rationale for many of the psychiatric–mental health nurse practitioner (PMHNP) care practices, in -
cluding psychopharmacological interventions described elsewhere in this review book. PMHNPs

cluding psychopharmacological interventions described elsewhere in this review book. PMHNPs 
need a solid grounding in neurobiology. Increasingly, the roles of the PMHNP require the applica -
tion of this knowledge to clinical practice.
THE NERVOUS SYSTEM
 XAll human thoughts, feelings, and actions are seated in and start with actions of the 
nervous system.
 XNecessary for the PMHNP’s role functioning is an understanding of the following 
basic neuroanatomy and physiology:
 ZNeurodeficits that underlie psychiatric disorders
 ZActions of and client responses to psychopharmacological treatment agents
 XThe nervous system’s primary function is to transfer and exchange information.
The Neuron (“Nerve Cells”)
 XThe basic cellular unit of the nervous system
 XThe microprocessor of the brain responsible for conducting impulses from one part 
of the body to another

64 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XComponents of the neuron:
 ZCell body : Also known as soma; made up of the nucleus and cytoplasm within 
cell membrane
 ZStem  or axon : Transmits signals away from the neuron’s cell body to connect 
with other neurons and cells
 ZDendrites : Collect incoming signals from other neurons and send the signal 
toward the neuron’s cell body
Nervous System
 XComposed of two separate, interconnected divisions:
 ZCentral nervous system (CNS)
 XComposed of the spinal cord and the brain
 ZPeripheral nervous system (PNS)
 XComposed of the peripheral nerves that connect the CNS to receptors, 
muscles, and glands
 XIncludes the cranial nerves just outside the brain stem
 XComprises the somatic nervous system and the autonomic nervous 
system:
 ZSomatic nervous system : Conveys information from the CNS to 
skeletal muscles; responsible for voluntary movement

XComprises the somatic nervous system and the autonomic nervous 
system:
 ZAutonomic nervous system : Regulates internal body functions to 
maintain homeostasis; conveys information from the CNS to smooth 
muscle, cardiac muscle, and glands; responsible for involuntary 
movement; divided into the sympathetic nervous system and the 
parasympathetic nervous system:
 XSympathetic nervous system : The excitatory division; prepares the 
body for stress (fight or flight); stimulates or increases activity of 
organs
 XParasympathetic nervous system : Maintains or restores energy; 
inhibits or decreases activity of organs
NEUROANATOMY AND THE BRAIN
 XBrain tissue is categorized as either white matter or gray matter.
 ZWhite matter  is the myelinated axons of neurons.
 ZGray matter  is composed of nerve cell bodies and dendrites; it is the working

ZWhite matter  is the myelinated axons of neurons.
 ZGray matter  is composed of nerve cell bodies and dendrites; it is the working 
area of the brain and contains the synapses, the area of neuronal connection.
 XOutermost surface of the brain: Structured to contain grooves and dips of corrugated 
wrinkles within the brain tissue that provide anatomical landmarks or reference 
points

65 neuroanatoMy, neuroPhysiology, and Behavior
 ZFunctions to increase brain’s surface area
 XIncreases working area and cell communication area
 ZGrooves and dips named by size and depth
 XSulci : Small shallow grooves
 XFissures : Deeper groves extending into the brain
 ZGyri are the raised tissue areas.
 XDistinct anatomical areas of brain
 ZThe brain is subdivided into the cerebrum and the brainstem.
Cerebrum
 XLargest part of the brain, which is divided into two halves, the right and left cerebral 
hemispheres
 ZLeft hemisphere:  Dominant in most people; controls most right-sided body 
functions
 ZRight hemisphere:  Controls most left-sided body functions
 ZNormal functioning requires effective coordination of two hemispheres.
 ZBoth hemispheres connected by a large bundle of white matter, the corpus 
callosum , an area of sensorimotor information exchange between the two 
 ZEach hemisphere is divided into four major lobes, which work in an interactive

 ZEach hemisphere is divided into four major lobes, which work in an interactive 
and integrated manner, and each with a distinct function:
 XFrontal lobe : Largest and most developed lobe. Functions include: 
 ZMotor function:  Responsible for controlling voluntary motor activity of 
specific muscles 
 ZPremotor area: Coordinates movement of multiple muscles
 ZAssociation cortex:  Allows for multimodal sensory input to trigger 
memory and lead to decision-making
 ZSeat of executive functions:  Working memory, reasoning, planning, 
prioritizing, sequencing behavior, insight, flexibility, judgment, impulse 
control, behavioral cueing, intelligence, abstraction
 ZLanguage (Broca’s area): Expressive speech
 ZPersonality variables: The most focal area for personality development
 ZProblems in the frontal lobe can lead to personality changes, emotional, 
and intellectual changes

ZPersonality variables: The most focal area for personality development
 XTemporal lobe ; functions include:
 ZLanguage (Wernicke’s area):  Receptive speech or language 
comprehension
 ZPrimary auditory area
 ZMemory

66 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZEmotion
 ZIntegration of vision with sensory information
 ZProblems in the temporal lobe can lead to visual or auditory 
hallucinations, aphasia, and amnesia
 XOccipital lobe ; functions include:
 ZPrimary visual cortex
 ZIntegration area: Integrates vision with other sensory information
 ZProblems in the occipital lobe can lead to visual field defects, blindness, 
and visual hallucinations
 XParietal lobe ; functions include:
 ZPrimary sensory area
 ZTaste
 ZReading and writing
 ZProblems in the parietal lobe can lead to sensory–perceptual 
disturbances and agnosia
 XCerebrum includes the cerebral cortex, limbic system, thalamus, hypothalamus, and 
basal ganglia.
 ZCerebral cortex
 XControls wide array of behaviors
 XControls the contralateral  (opposite) side of the body: The right hemisphere 
controls the left side of the body, and the left hemisphere controls the right 
side of the body.

XControls the contralateral  (opposite) side of the body: The right hemisphere 
 XSensory information is relayed from the thalamus and then processed and 
integrated in the cortex.
 XResponsible for much of the behavior that makes us human: speech, 
cognition, judgment, perception, and motor function
 ZLimbic system
 XEssential system for the regulation and modulation of emotions and 
memory
 XComposed of the hypothalamus, thalamus, hippocampus, and the amygdala
 ZHypothalamus:  Plays key roles in various regulatory functions such 
as appetite, sensations of hunger and thirst, water balance, circadian 
rhythms, body temperature, libido, and hormonal regulation
 ZThalamus : Sensory relay station except for smell; modulates flow of 
sensory information to prevent overwhelming the cortex; regulates 
emotions, memory, and related affective behaviors

ZThalamus : Sensory relay station except for smell; modulates flow of 
 ZHippocampus : Regulates memory and converts short-term memory 
into long-term memory
 ZAmygdala : Responsible for mediating mood, fear, emotion, and 
aggression; also responsible for connecting sensory smell information 
with emotions

67 neuroanatoMy, neuroPhysiology, and Behavior
 ZBasal ganglia : Also known as the corpus striatum
 XServes as a complex feedback system to modulate and stabilize somatic 
motor activity (information conveyed from the CNS to skeletal muscles)
 XPlays a role in movement initiation; complex motor functions with 
association connections
 XFunctions in learning and automatic actions such as walking or driving a car
 XContains extrapyramidal motor system or nerve tract
 XFunctions in involuntary motor activities (e.g., muscle tone, posture, 
coordination of muscle movement and common reflexes)
 XMany psychotropic medications can affect the extrapyramidal motor nerve 
track, causing involuntary movement side effects
 XContains both the caudate  and the putamen
 XProblems in the basal ganglia can lead to bradykinesia, hyperkinesias, and 
dystonia.
Brainstem
 XMade up of cells that produce neurotransmitters
 XIncludes the midbrain, pons, medulla, cerebellum, and reticular formation

dystonia.
Brainstem
 ZMidbrain : Houses the ventral tegmental area and the substantia nigra (areas of 
dopamine synthesis)
 ZPons : Houses the locus ceruleus (area of norepinephrine synthesis)
 ZMedulla : Together with the pons, contains autonomic control centers that 
regulate internal body functions
 ZCerebellum : Responsible for maintaining equilibrium; acts as a gross movement 
control center (e.g., control movement, balance, posture)
 XEach hemisphere of cerebellum has ipsolateral  control (same side of body).
 XProblems with the cerebellum can lead to ataxia (uncoordinated and 
inaccurate movements).
 XRomberg test is important for detecting deficiencies in cerebellar 
 ZReticular formation system: The primitive brain
 XReceives input from cortex; an integration area for input from postsensory 
pathways

pathways
 XInnervates thalamus, hypothalamus, and cortex
 XRegulation functions include:
 ZInvoluntary movement
 ZReflex
 ZMuscle tone
 ZVital sign control

68 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZBlood pressure
 ZRespiratory rate
 ZCritical to consciousness and ability to mentally focus, to be alert and 
pay attention to environmental stimuli
NEUROPHYSIOLOGY AND THE BRAIN
 XTwo classes of cells are in the nervous system: glia and neurons.
 ZGlia: Structures that form the myelin sheath around axons and provide 
protection and support
 ZNeurons : Nerve cells responsible for conducting impulses from one part of the 
body to another
 XComponents of a neuron include:
 ZCell body : Also known as soma ; made up of the nucleus and cytoplasm within 
the cell membrane
 ZDendrites : Receive information to conduct impulse toward  the cell body
 ZAxon : Sends or conducts information away  from cell body
 XSynapse  or synaptic cleft —The connection site and area of communication between 
neurons where neurotransmitters are released

ZAxon : Sends or conducts information away  from cell body
 ZThe synapse converts an electrical signal (action potential) from the presynaptic 
neuron into a chemical signal (neuron transmitter) that is transferred to the 
postsynaptic neuron.
 ZNeurotransmitters are released at the synaptic cleft as the result of an electrical 
activity (action potential).
 ZThe two phases of an action potential are:
 XDepolarization : The initial phase of the action potential (an excitatory 
response), when sodium and calcium ions flow into the cell; and
 XRepolarization : The restoration phase (an inhibitory response), when 
potassium leaves the cell or chloride enters the cell.
 ZProblems in either the structure or chemistry of the synapse interrupt normal 
flow of impulses and stimuli, which then contribute to symptoms commonly 
seen in psychiatric disorders.

ZProblems in either the structure or chemistry of the synapse interrupt normal 
 XNeurotransmitters:  Chemicals synthesized from dietary substrates that communi -
cate information from one cell to another.
 ZThe neurotransmitter will be released from the presynaptic neuron, cross the 
synapse, and then bind to a specific receptor on the postsynaptic neuron.
 ZSpecific criteria must be met for a molecule to be classified as a 
neurotransmitter (see Table 5–1).
 ZCategories of neurotransmitters: Monoamines, amino acids, cholinergics, 
neuropeptides

69 neuroanatoMy, neuroPhysiology, and Behavior
 XMonoamines : “Biogenic amines”—dopamine, norepinephrine, epinephrine, 
serotonin
 ZDopamine:  Known as a catecholamine ; produced in the substantia 
nigra and the ventral tegmental area; precursor is tyrosine; removed 
from the synaptic cleft by monoamine oxidase (MAO) enzymatic action
 XFour dopaminergic pathways: Mesocortical, mesolimbic, 
nigrostriatal, tuberoinfundibular (see Chapter 10)
 ZNorepinephrine : Also known as a catecholamine ; produced in the 
locus ceruleus of the pons; precursor is tyrosine; removed from the 
synaptic cleft and returned to storage via an active reuptake process; 
major neurotransmitter implicated in mood, anxiety, and concentration 
disorders
 ZEpinephrine : Also known as a catecholamine ; produced by the adrenal 
glands; epinephrine system also referred to as the adrenergic system
 ZSerotonin : Known as an indole ; produced in the raphe nuclei of the

 ZSerotonin : Known as an indole ; produced in the raphe nuclei of the 
brainstem; precursor is tryptophan; removed from the synaptic 
cleft and returned to storage via an active reuptake process; major 
neurotransmitter implicated in mood and anxiety disorders
 XAmino acids : Glutamate, aspartate, γ-aminobutyric acid (GABA), glycine
 ZGlutamate : Universal excitatory neurotransmitter; major 
neurotransmitter involved in process of kindling, which is implicated in 
seizure disorders and possibly bipolar disorder; imbalance implicated in 
mood disorders and schizophrenia
 ZAspartate : Another excitatory neurotransmitter; works with glutamate
 ZGABA : Universal inhibitory neurotransmitter; site of action of 
benzodiazepines, alcohol, barbiturates, and other CNS depressants 
 ZGlycine : Another inhibitory neurotransmitter; works with GABA
 XCholinergics : Acetylcholine

 ZAcetylcholine : Synthesized by the basal nucleus of Meynert; precursors 
are acetylcoenzyme A and cholineTABLE 5–1  .
 CLASSIFICATION REQUIREMENTS FOR NEUROTRANSMITTERS
Criteria 1. Neurotransmitter must be present in the nerve terminal.
2. Stimulation of neuron must cause release of neurotransmitter in sufficient 
quantities to cause an action to occur at postsynaptic membrane.
3. Effects of exogenous transmitter on postsynaptic membrane must be similar to 
those caused by stimulation of presynaptic neuron.
4. A mechanism for inactivation or metabolism of the neurotransmitter must exist 
in the area of the synapse.
5. Exogenous drugs should alter the dose–response curve of the neurotransmitter 
in a manner similar to the naturally occurring synaptic potential.

Note. Adapted from Sadock, B., Sadock, V., & Ruiz, P . (2015).  Kaplan and Sadock’s synopsis of 
psychiatry  (11th ed.). Philadelphia, PA: Wolters Kluwer

70 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XNeuropeptides : Nonopioid type (substance P , somatostatin); opioid type 
(endorphins, enkephalins, dynorphins)
 ZModulate pain; decreased amount of neuropeptides is thought to 
cause substance abuse
 ZSee Table 5–2 for identification of neurotransmitters’ role in symptom expression 
in common psychiatric disorders.
 ZRecovery and degradation of neurotransmitters
 XAfter the neurotransmitter reaches the postsynaptic neuron, it may then 
diffuse off its receptor to be destroyed by enzymes or to be transported 
back to the presynaptic neuron for reuse.
 XEnzymatic destruction  occurs either in the cytosol or in the synapse. The 
neurotransmitter can be destroyed by the enzymes monoamine oxidase 
(MAO) in the cytosol or catechol-O-methyl transferase (COMT) intracellularly 
or in the synapse.
TABLE 5–2 .  
COMMON PSYCHIATRIC DISORDERS AND NEUROTRANSMITTERS IMPLICATED IN THE

TABLE 5–2 .  
COMMON PSYCHIATRIC DISORDERS AND NEUROTRANSMITTERS IMPLICATED IN THE 
COMPLEX PATHOPHYSIOLOGY OF COMMON PSYCHIATRIC DISORDERS
NEUROTRANSMITTERSUSPECTED 
IMBALANCE PSYCHIATRIC PRESENTATION
Acetylcholine Decrease
 
IncreaseAlzheimer’s disease  
Impaired memory
Parkinsonian symptoms
Dopamine Increase
 
DecreaseSchizophrenia  
Psychosis
Substance abuse  
Anhedonia  
Parkinson’s disease
Norepinephrine Decrease
IncreaseDepression
Anxiety
Serotonin Decrease Depression 
Obsessive–compulsive disorder, anxiety 
disorders
γ-Aminobutyric acid ( GABA) Decrease Anxiety disorders
Glutamate Increase
 
DecreaseBipolar affective disorder  
Psychosis from ischemic neurotoxicity or 
excessive pruning
Memory and learning difficulty  
Negative symptoms of schizophrenia
Opioid neuropeptides Decrease Substance abuse

Note . Adapted from Thibodeau, G., & Patton, K. (2015). Anatomy and physiology  (9th ed.). St. 
Louis, MO: Mosby.

71 neuroanatoMy, neuroPhysiology, and Behavior
 XReuptake pumps  can remove the neurotransmitter from acting in the 
synapse. The neurotransmitter will be reloaded into the presynaptic neuron 
and will be recycled.
 ZFunction of neurotransmitters: see Table 5–3
TABLE 5–3 .
COMPARISON OF COMMON CNS NEUROTRANSMITTERS
NEURO-
TRANSMITTER RECEPTORSGENERAL 
FUNCTIONSYMPTOMS OF 
DEFICITSYMPTOMS OF 
EXCESS
Dopamine D1-like
D2-likeThinking
Decision-making
Reward-seeking 
behavior
Fine muscle action 
Integrated 
cognitionMild:
Poor impulse 
control
Poor spatiality
Lack of abstractive 
thought
Severe :
Endocrine 
alterations
Movement 
disordersMild:
Improved creativity
Improved ability for 
abstract thinking
Improved 
executive 
functioning
Improved spatiality
Severe :
Disorganized 
thinking
Loose association
Tics
Stereotypic 
behavior
Norepinephrine α1
α2Alertness
Focused attention
Orientation
Primes “fight or 
flight”
Learning
MemoryDullness
Low energy

Severe :
thinking
Tics
behavior
flight”
Learning
Low energy
Depressive affectAnxiety
Hyperalertness
Increased startle
Paranoia
Decreased 
appetite
Serotonin 5HT1a
5HT1d
5HT2
5HT2a
5HT3
5HT4Regulation of sleep
Pain perception
Mood states
Temperature 
Regulation of 
aggression
Libido
Precursor for 
melatoninIrritability
Hostility
Depression
Sleep 
dysregulation
Loss of appetite
Loss of libidoSedation
Increased 
Hallucinations 
(rare)
CONTINUED

72 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
NEUROIMAGING ASSESSMENT AND DIAGNOSTIC PROCEDURES
 XTechniques that permit observation of the brain can be divided into three categories: 
structural imaging, functional imaging, and combined structural and functional imaging.
 ZStructural imaging : Provides evidence of size and shape of anatomical structures
 XCommon structural imaging tests include:
 ZComputed tomography (CT) : Provides a three-dimensional view of the 
brain structures; differentiates structures based on density; provides 
suggestive evidence of brain-based problems but no specific testing for 
 XAdvantages : Widely available, relatively inexpensive
 XDisadvantages : Lack of sensitivity, cannot differentiate white 
matter from gray matter; cannot view structures close to the bone 
tissue; underestimation of brain atrophy; inability to image sagittal 
and coronal viewsNEURO-
TRANSMITTER RECEPTORSGENERAL

EXCESS
Acetylcholine Nicotinic
MuscarinicAttention
Memory
Thirst
Mood regulation
REM sleep
Sexual behavior
Muscle toneLack of inhibition
Decreased 
memory
Euphoria
Antisocial action
Speech decrease
Dry mouth, blurred 
vision, constipationOver-inhibition
Anxiety
Somatic 
complaints
Self-consciousness
Drooling
Extrapyramidal 
movements
GABA GABAa
GABAbReduces arousal
Reduces 
Reduces anxiety
Reduces excitationIrritability
Hostility
Tension and worry
Anxiety
Seizure activityReduced cellular 
excitability
Sedation
Glutamate AMPA
MNDAMemory
Sustained 
automatic 
functions Poor memory
Low energy
DistractibleKindling
Seizures
Anxiety or panic
Peptides: 
Opioid type μ (mu)
k (kappa)
ε (epsilon)
δ (delta)
σ (sigma)Modulate

Sustained 
automatic 
Low energy
Seizures
Peptides: 
k (kappa)
δ (delta)
σ (sigma)Modulate 
emotions
Reward-center 
function
Consolidation of 
memory
Modulate reactions 
to stressHypersensitivity to 
pain and stress
Decreased 
pleasure sensation
DysphoriaInsensitivity to pain
Catatonic-like 
movement 
Auditory 
hallucinations
Decreased 
memory
Note . Adapted from Sadock, B., Sadock, V., & Ruiz, P . (2015). Kaplan and Sadock’s synopsis of 
psychiatry  (11th ed.). Philadelphia, PA: Wolters Kluwer.

73 neuroanatoMy, neuroPhysiology, and Behavior
 ZMagnetic resonance imaging (MRI) : Provides a series of two-dimensional 
images that represent the brain
 XAdvantages : Can view brain structures close to the skull and can separate 
white matter from gray matter; readily available; resolution of brain tissue 
superior to CT scanning
 XDisadvantages : Expensive; many contraindications to its use (e.g., clients 
with pacemakers or any metallic implants such as orthopedic screws or 
plates, or on ventilators); clients with claustrophobia often are unable to 
complete study because of design of machinery (an enclosed tubelike 
structure with a confining environment)
 ZFunctional imaging : Technique that measures function of areas of the brain 
and bases the resulting assessment on blood flow; may use radioactive 
pharmaceuticals to cross the blood-brain barrier; mainly used for research
 XCommon functional imaging tests include

 ZEEG and evoked potentials testing : Least expensive tests that convey 
information on electrical functioning of the CNS
 ZMagnetoencephalography (MEG) : Similar to the EEG but detects 
different electrical activities; often used in a complementary fashion 
with EEG testing
 ZSingle photon emission computed tomography (SPECT) : Provides 
information on the cerebral blood flow; limited availability; expensive 
but less than positron emission tomography 
 ZPositron emission tomography (PET) : Provides images of the brain 
when positron-emitting radionuclei interact with an electron; expensive 
procedure that requires extensive resources and support team
 ZCombined structural and functional imaging : The newest imaging; attempts

 ZCombined structural and functional imaging : The newest imaging; attempts 
to examine structure in conjunction with function; currently mainly used for 
research
 XAvailable tests include
 ZFunctional MRI (fMRI)
 ZThree-dimensional, event-related functional MRI (3fEMRI)
 ZFluorine magnetic spectroscopy
 ZDopamine D2 receptor binding
GENOMICS
Family History, Family T ree, or Pedigree
 XTool in determining likelihood of genetic disorder in family, inheritance patterns, and 
risk of recurrence in family members
 XSurgeon General recommended that families know their family history (U.S. 
Department of Health and Human Services, n.d.)
 XPedigree symbols in drawing a family tree indicate male, female, marriage, divorce, 
adoption, twins, pregnancy, consanguinity (relatives having children), conditions

74 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XFamily history starts with current family and moves back to grandparents.
 XAutosomal-dominant conditions may be present in more than one generation and in 
up to 50% of offspring when one parent is affected (e.g., Marfan syndrome).
 XRecessive conditions appear only in one generation, affecting people who have two 
copies of a faulty gene, one from each (unaffected) parent (e.g., hemochromatosis, 
cystic fibrosis).
 XX-linked disorders are caused by faulty genes on an X chromosome (e.g., fragile X 
syndrome, color blindness).
 XRisk assessment is based on inheritance patterns and may be by percentage of risk.
Genetic Counseling
 XGenetic counseling is a communication process used when a client has a genetic 
risk and often involves offering a test that could provide information about the ge -
netic status of the person and possible implications for the family.

 XA genetic counselor is someone whose primary role is to offer information and sup -
port to people concerned about an illness that may have a genetic basis.
 XA referral to a genetic counselor may be needed when a client is anticipating a preg -
nancy and concerned for the health of the fetus.
Genetic T erms
 XChromosomes are structures of DNA (deoxyribonucleic acid) in the nucleus of cells; 
there are normally 46 total (23 pairs) in humans.
 XDNA is made up of two twisted, paired strands, composed of sugars linked by four 
nucleotide bases—adenine (A), thymine (T), cytosine (C), and guanine (G)—specify -
ing the amino acids that make proteins. A is always paired with T and G is always 
paired with C.
 XGenes  are a sequence of DNA that cause human characteristics to be passed to the

 XGenes  are a sequence of DNA that cause human characteristics to be passed to the 
next generation; genes direct the production of proteins.
 XMessenger RNA (mRNA) codes for an amino acid. 
 XThe Human Genome Project mapped the entire nucleotide sequence of the human 
genome in 2003. The genome is a complete set of DNA.
 XA phenotype  is the observable characteristic of a specific trait and is connected 
to the genetic contributions to that trait (e.g., fast metabolizer of CYP4502D6 
medications).
 XGene therapy involves replacing a faulty copy of a gene with a healthy copy of the 
same gene.
 XPersonalized medicine is health care based on genetic variability.

75 neuroanatoMy, neuroPhysiology, and Behavior
Studies of Population Genetics
 XFamily studies investigate the occurrence of disorders in first-degree relatives (par -
ents, siblings, and offspring) and second-degree relatives (grandparents, cousins, 
aunts, and uncles).
 XTwin studies survey the concordance rate (presence) of a disorder in monozygotic 
(identical) and dizygotic (fraternal) twins.
 XAdoption studies investigate the risk of a disorder developing in children raised in a 
different environment from the biological parent with a specific disorder.
 XStrong genetic contributions have been found for most psychiatric disorders, with a 
range of 40% to 90% heritability for some disorders (e.g., attention-deficit hyperac -
tivity disorder, bipolar disorder).
 XGenes are risk factors that make a person vulnerable to developing the illness when 
combined with certain environmental risk factors that increase susceptibility of 
developing the disorder.

XGenes are risk factors that make a person vulnerable to developing the illness when 
 XEnvironmental risk factors include prenatal insults, stress, infections, poor nutrition, 
exposure to toxins, catastrophic loss, and physical and sexual abuse.
 XMost diseases are multifactorial, caused by both environmental and genetic factors; 
single-gene disorders are rare.
Gene Expression and Disease
 XSingle nucleotide polymorphisms (SNP) detect single base changes in DNA 
sequence.
 XReduced penetrance of a gene decreases chances of disease in person at genetic 
risk. 
 XVariable expression of a gene for a disorder occurs at the cellular level.
Pharmacogenomics
 XGenes account for differences in the way enzymes metabolize drugs.
 XMedications may act differently based on how genes affect metabolism.
 XGenetic testing or profiling helps identify the presence of gene variants that may

XMedications may act differently based on how genes affect metabolism.
 XGenetic testing or profiling helps identify the presence of gene variants that may 
help determine dosing of medication (e.g., CYP450 test of CYP4502D6, CYP450 
2C19, and methylene tetrahydrofolate reductase [MTHFR] genes—see Chapter 7 for 
further information on pharmacokinetics).
 XTesting for presence of HLA-B*1502 allele, an inherited variant of HLA-B gene, is 
required by the FDA in people of Asian descent prior to prescribing the anticonvul -
sant carbamazepine due to risk of Stevens-Johnson syndrome and toxic epidermal 
necrolysis (TEN).

76 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
Ms. Franklin is a 24-year-old sales clerk. She has a strong family history of mental illness and is 
worried that she may experience some problems in her life because of her family history. She 
presents to her local primary care provider complaining of the following symptoms:  
 XHyperalertness
 XIncreased startle response
 XConcern that people are staring at her and watching what she eats
 XDecreased appetite
 XDifficulty falling asleep
Ms. Franklin is trying to determine if these experiences are the beginning of a mental illness. 
She wants to have a brain scan done to determine the answer. She also is getting married soon 
and wants to know what the risk is that her future children will experience mental illness, be -
cause she believes it runs in her family. In working with Ms. Franklin, the PMHNP must consider 
many issues.

1. Are the symptoms described by Ms. Franklin consistent with a psychiatric disorder?
2. Do psychiatric disorders run in families, as Ms. Franklin believes?
3. Do the symptoms as described by Ms. Franklin link with any known neuroanatomical 
or neurophysiologic deficit?
4. Is a brain scan warranted for Ms. Franklin?
5. Can the risk of Ms. Franklin’s children developing psychiatric disorders be 
determined?
Joel is an 18-year-old college freshman who developed psychotic symptoms necessitating a brief 
hospitalization at his university’s medical center. Joel is given haloperidol (Haldol) 5 mg IM with 
lorazepam (Ativan) 1 mg IM and diphenhydramine (Benadryl) 50 mg IM upon admission and is 
started on risperidone (Risperdal). One day after admission, Joel presents to the nurses’ station 
complaining of a painful “stiff neck” and “thick tongue. ”

complaining of a painful “stiff neck” and “thick tongue. ” 
1. What is the best description of Joel’s presentation?
2. What is the best explanation for Joel’s presentation?
3. Which neurotransmitters are involved in Joel’s presentation?
4. How should the PMHNP address this scenario?
5. In formulating diagnostic conclusions about Joel, what should the PMHNP consider?

77 neuroanatoMy, neuroPhysiology, and Behavior
1. More assessment would be needed to determine whether Ms. Franklin’s symptoms 
are consistent with a psychiatric disorder, but they may be consistent with an anxiety 
or mood disorder.
2. Most psychiatric illnesses have been shown to have, in part, a genetic link and there -
fore, do tend to run in families.
3. Ms. Franklin’s symptoms are consistent with excessive levels of norepinephrine.
4. No. There is insufficient data to warrant the cost of a brain scan at this time.
5. Yes, the risk of Ms. Franklin’s children developing psychiatric disorders can be deter -
mined but only if Ms. Franklin meets criteria for an actual psychiatric illness. Once 
this is determined, the genetic risk to her children can be identified through the use 
of such things as concordant rate tables.
1. Joel’s presentation is consistent with acute dystonia.

2. Both haloperidol and risperidone are high-potency D2 antagonists. Although Joel 
received prophylactic diphenhydramine, adding risperidone, particularly with aggres -
sive dosing, increases the risk of extrapyramidal side effects.
3. CNS dopamine (DA) and acetylcholine (ACH) have a reciprocal relationship. As DA 
receptors are antagonized by antipsychotic medication, acetylcholine levels increase, 
giving rise to extrapyramidal side effects. This is particularly true of first-generation 
antipsychotics, but also of high-potency second-generation agents.
4. Administer diphenhydramine or benztropine (Cogentin) IM immediately and hold 
subsequent doses of risperidone until dystonia completely resolves. Resume risperi -
done at a lower dose along with an oral anticholinergic medication. Adjust the dose

done at a lower dose along with an oral anticholinergic medication. Adjust the dose 
of the antipsychotic as indicated. If Joel continues to experience extrapyramidal side 
effects, switching to a lower-potency antipsychotic may be necessary.
5. Joel may have experienced a sentinel episode of schizophrenia. Joel’s symptoms 
may also have been substance-induced.
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CHAPTER 6ADVANCED HEALTH AND PHYSICAL HEALTH 
ASSESSMENT
This chapter reviews the role of psychiatric–mental health nurse practitioners  (PMHNPs) in 
physical health and advanced health assessment. In this chapter you will review information on 
the process of completing a physical exam and differential diagnosis, and the appropriate use 
of diagnostic and laboratory testing in providing competent nursing care for clients and families 
experiencing psychiatric disorders. The chapter specifically highlights the PMHNP role in the 
identification of physical health problems.
PHYSICAL EXAM
 XReasons to be familiar with the physical exam in psychiatry:
 ZTo be able to detect underlying medical problems
 ZTo be familiar with a screening neurological exam and to be able to rule out 
neurological problems that may manifest as symptoms of a psychiatric problem
 ZTo be able to differentiate normal and abnormal signs and symptoms
 ZTo know when to refer

 XDone by the PMHNP in the context of his or her primary psychiatric care role
 XGoals are identifying presence of psychiatric disorders, identifying general health 
status, and screening for other nonpsychiatric disorders
 XFocuses on physical assessment required to accomplish differential diagnoses to 
determine client health needs
 XSpecifically focuses on assessing for disorders or conditions that explain client 
presentation
 ZPsychiatric disorders
 ZNonpsychiatric disorders
 XNot intended to replace the role of primary healthcare provider for the client
 ZPMHNP should assist client to establish primary care provider if he or she does 
not already have one.

80 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XAvoids highly personal or intrusive procedures (e.g., Pap exam, male genital exam, 
rectal exam, breast exam) that may make the formation of a therapeutic alliance 
more difficult, but it is important to be familiar with these exams and be able to dif -
ferentiate normal from abnormal
 XRequires the PMHNP to have depth of knowledge regarding the common health 
disorders that can mimic symptoms of a psychiatric disorder
 ZDifferential diagnostic considerations
 XRequires the PMHNP to have depth of knowledge regarding the common psychiatric 
disorders that can mimic or produce symptoms of other disorders
 ZComorbid conditions and clinical management issues
 XGenerally, if client’s health issues are determined to be nonpsychiatric, client is 
referred to primary care providers other than the PMHNP .

ZComorbid conditions and clinical management issues
 XBecause of the brain-based nature of psychiatric disorders, the PMHNP role requires 
the ability to perform an in-depth neurological exam.
NEUROLOGICAL EXAM
 XReflexes (biceps, triceps, brachioradialis, patellar, Achilles, plantar) 
 ZGrade reflexes and note symmetry between right and left sides.
 ZCheck primitive reflexes in infants (head lag, flexion, rooting, grasping, Moro, 
glabellar, Babinski).
 ZA positive Babinski (fanning of toes and dorsiflexion of the great toe) is normal in 
infants up to age 2 years.
 XCranial nerves ( mnemonic italicized in parentheses )
 ZOlfactory : 1st ( On)
 XTest sense of smell and ensure patency of the nasal passages.
 XHave the client close eyes and test each nostril separately while other is 
occluded, asking the client to identify familiar odors.

XTest sense of smell and ensure patency of the nasal passages.
 ZOptic : 2nd ( Old)
 XTest vision using Snellen chart or other suitable chart depending on the 
client’s acuity and ability to cooperate.
 XExamine the inner aspect of the eyes with the ophthalmoscope.
 XTest peripheral vision using the confrontation test.
 ZOculomotor : 3rd ( Olympus ’)
 XThis is the motor nerve to the five extrinsic eye muscles. Test together with 
cranial nerve 4 (trochlear) and cranial nerve 6 (abducens; see below).
 XTest the extraocular movements (EOMs).
 XCheck the equality of pupils, their reaction to light, and their ability to 
accommodate.
 XTest the corneal light reflex (when shining a light at the bridge of the nose, 
the light should appear symmetrically in both eyes).

81 advanced health and Physical health a ssessMent
 ZTrochlear : 4th ( Towering )
 XUse the same process as cranial nerve 3 (oculomotor) and cranial nerve 6 
(abducens).
 ZTrigeminal : 5th (Motor division; Top)
 XPalpate the masseter muscles with the fingertips while the client clenches 
his or her teeth.
 XLook for disparity in tension between the two muscles, which can indicate 
paralysis on the weak side.
 XLook for tremor of the lips, involuntary chewing movements, and spasm of 
the masticatory muscles.
 ZTrigeminal : 5th (Sensory division)
 XTest tactile perception of the facial skin by touching with a wisp of cotton.
 XTest corneal reflex with wisp of cotton.
 XTest superficial pain of the skin and mucosa with pinpricks.
 XTest the sense of touch in the oral mucosa. 
 ZAbducens : 6th ( A)
 XUse the same process as for cranial nerves 3 (oculomotor) and 4 (trochlear).
 ZFacial : 7th (Motor division; Finn)
 XInspect the face in repose for evidence of flaccid paralysis.

XUse the same process as for cranial nerves 3 (oculomotor) and 4 (trochlear).
 XInspect the face in repose for evidence of flaccid paralysis. 
 XTest by asking the client to elevate eyebrows, wrinkle forehead, close eyes, 
frown, smile, and puff cheeks.
 ZFacial : 7th (Sensory division)
 XTest taste for sugar, vinegar, and salt.
 ZAcoustic : 8th ( And)
 XCheck hearing with the audiometer or by the whisper test.
 XCheck for hearing loss using the Weber and the Rinne tests.
 ZGlossopharyngeal : 9th ( German )
 XTest together with cranial nerve 10 (vagus; see below).
 ZVagus : 10th ( Viewed )
 XTest for elevation of the uvula by having the client open his or her mouth 
and say “ah. ”
 XTest the gag reflex by touching the back of throat with a tongue blade.
 ZAccessory spinal : 11th ( Some )
 XTest the strength of the sternocleidomastoid and trapezius muscles against 
resistance of your hands.
 ZHypoglossal : 12th ( Hops )

ZAccessory spinal : 11th ( Some )
 XLook for tremors and other involuntary movement when the client 
protrudes his or her tongue.

82 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XCoordination and fine-motor skills
 ZEquilibrium : Check by administering the Romberg test: have the client stand 
up straight with feet together, arms by sides, and eyes closed. Only slight 
swaying would be normal, and the client will be able to sustain this pose for 
approximately 5 seconds. More than slight swaying suggests cerebellar ataxia 
or vestibular dysfunction.
 ZDiadochokinesia : Ability to perform rapid alternating movements (such as patting 
knees alternating palm and back of hands, touching thumb to each finger); the client 
should be able to smoothly execute these movements and maintain the rhythm.
 ZDyssynergia : Finger-to-nose test, heel-to-knee test
 ZHandwriting
 ZGait: Observe client walking.
 XSensory functions
 ZPain: Check sensation to pain with pinprick, and compare on each side of body.
 ZTemperature : Check temperature if sensation to pain is abnormal.

XSensory functions
 ZSuperficial touch : Test with wisp of cotton.
 ZTwo-point discrimination:  Apply pins to skin simultaneously; ask the client if he 
or she feels one or two pinpricks.
 ZStereognosis: Tests the ability to distinguish forms by placing objects in the 
client’s hands while his or her eyes are closed.
 ZGraphesthesia:  Tests the ability to identify figures, letters, or words by tracing 
the figure on the skin of the palm of the hand.
 XMotor functions
 ZMuscle mass:  Measure muscle mass to check for atrophy or hypertrophy.
 ZMuscle tone:  Tension is present when the muscle is resting.
 ZMuscle strength:  Check muscular strength against resistance.
Be aware of abnormal muscle movements.
 XNeurological soft signs
 ZDysdiadochokinesia:  Inability to perform rapid alternating movements; result of a

 ZDysdiadochokinesia:  Inability to perform rapid alternating movements; result of a 
lesion to the posterior lobe of the cerebellum
 ZAstereognosis:  Inability to discriminate between objects based on touch alone; 
result of a lesion in the parietal lobe
 ZChoreiform movements
 ZTics
 ZAgraphesthesia : Inability to recognize letters or numbers “drawn” on the client’s 
hand with a pointed object
 ZFacial grimacing
 ZImpaired fine-motor skills
 ZAbnormal blinking
 ZAbnormal motor tone

83 advanced health and Physical health a ssessMent
Be alert for extrapyramidal symptoms (as in Parkinsonism, dystonia, akathisia) in the cli -
ent taking antipsychotics.
 XVital signs
 ZMeasure height, weight, blood pressure (on children ages two or older), pulse, 
respirations, temperature, and head circumference (during the first 2 years).
 ZUse growth charts for infants and children.
 XGreater than 85th percentile for body mass index (BMI) places a child at 
increased risk for being overweight.
 ZUse BMI charts
 XNormal: 20 to 25
 XOverweight: 26 to 29
 XObese: 30 to 35
 ZHigh BMI is a risk factor for diabetes, heart disease, stroke, hypertension, 
osteoarthritis, and some forms of cancer. 
Be alert for high BMI if the client also is being prescribed psychotropic meds with a pro -
pensity for weight gain, especially atypical antipsychotics. 
 ZIf a client is presenting with elevated temperature and also is taking

 ZIf a client is presenting with elevated temperature and also is taking 
psychotropic meds such as carbamazepine (Tegretol) or clozapine (Clozaril), be 
alert for agranulocytosis.
 XHead, skin, nails
 ZNote the color and integrity of the skin and whether lesions are present.
 ZNote if the skin is well-hydrated, dry, or scaly.
 ZAssess skin turgor.
 ZPalpate the skin’s temperature.
 ZNote any unusual moles or other lesions.
 ZLook at hair texture and distribution.
 ZDetermine the quality of the nails, noting splitting, clubbing, or onychomycosis.
 ZCheck capillary refill.
 ZExamine head, scalp, sutures, and fontanelles (if infant).
 ZCheck cranial nerve 7 (facial nerve) for symmetry (have client smile, frown, 
wrinkle forehead, puff cheeks).
Be alert for Stevens-Johnson syndrome (life-threatening rash), especially if the client is 
taking carbamazepine or lamotrigine (Lamictal).

 ZCancerous moles can be detected by using the acronym ABCDE —asymmetry, 
border irregularity, color variation, diameter greater than 6 millimeters, and 
elevation.
 XEyes
 ZCheck visual acuity using the Snellen chart (tests cranial nerve 2: optic nerve).
 ZTest peripheral vision using the confrontation test (tests cranial nerve 2: optic 
nerve).

84 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZNote the symmetry of eyes and the appearance of orbits, eyelids, and brows.
 ZInspect the sclera.
 ZAssess corneal sensation with wisp of cotton (tests cranial nerves 5 and 7).
 ZAssess papillary reaction to light and accommodation (tests cranial nerves 3, 4, 
and 6).
 ZAssess the six cardinal fields of gaze (extraocular movements; tests cranial 
nerves 3, 4, and 6). 
 ZAssess corneal light reflex. Light reflections should appear symmetrically in both 
pupils (tests cranial nerves 3, 4, and 6).
 ZExamine the inner aspect of the eyes with the ophthalmoscope (tests cranial 
nerve 2).
Be aware that many psychotropics can cause blurry vision (an anticholinergic side effect).
 ZQuetiapine (Seroquel) may cause cataracts.
 XEars
 ZCheck for configuration, position, and alignment of auricles.
 ZTest auditory acuity (cranial nerve 8) with the whisper test or audiometer.

ZQuetiapine (Seroquel) may cause cataracts.
 XEars
 ZInspect external auditory canals with otoscope for redness, swelling, or excess 
cerumen.
 ZTympanic membrane should be translucent pearly gray without retractions or 
bulges.
 XNose and sinuses
 ZNote the appearance of the external nose and whether it is smooth, intact, 
symmetric, midline, has discharge, or is flaring.
 ZAssess nasal patency.
 ZAssess sense of smell.
 ZInspect internal nasal cavity for patency and septal deviation.
 ZPalpate maxillary and frontal sinuses.
 XNeck 
 ZPalpate the lymph nodes (preauricular, postauricular, tonsillar, submandibular, 
submental, anterior cervical) for swelling or masses.
 ZPalpate thyroid (usually not palpable except in very thin people).
 ZPalpate and auscultate carotid pulse and note any bruits.
 XBack

 XBack
 ZInspect skin and respiratory pattern on posterior chest. 
 ZPalpate cervical, thoracic, lumbar, and sacral spine.
 ZPalpate thoracic expansion.
 ZPercuss posterior chest for tympany.
 ZAuscultate posterior chest for vesicular or bronchovesicular sounds and note any 
adventitious breath sounds.

85 advanced health and Physical health a ssessMent
 XThorax and lungs
 ZAssess respiratory rate and depth, regularity, and ease of respirations.
 ZNote anterior–posterior (AP) diameter, which should be less than the transverse 
diameter.
 ZPercuss anterior chest for resonance and note the quality and symmetry of 
percussion notes.
 ZAuscultate anterior chest for lung sounds; normal breath sounds include 
vesicular over peripheral lung, bronchovesicular over first and second intercostal 
spaces at the sternal border, and bronchial over the trachea.
 XBreasts
 ZInspect breasts in different positions: with client arms relaxed and by side, 
with arms elevated above head, and with hands on hips. Look for dimpling, 
retractions, and orange-peel appearance.
 ZPalpate breasts for lumps, including Tail of Spence.
 ZPalpate axillary and epitrochlear lymph nodes.
 ZPalpate supraclavicular lymph nodes (also known as sentinel or Virchow nodes).

ZPalpate breasts for lumps, including Tail of Spence.
Be aware that typical antipsychotics as well as atypical antipsychotics may cause 
galactorrhea.
 XHeart
 ZInspect, palpate, and auscultate the carotid pulse.
 ZPalpate peripheral pulses and check for symmetry (carotid, brachial, radial, 
femoral, popliteal, pedal, and posterior tibial).
 ZAssess heart rate, rhythm, amplitude, and contour.
 ZAssess anatomic location of the apical pulse.
 ZPalpate precordium for pulsations, thrills, heaves, and lifts.
 ZAuscultate heart sounds with bell and diaphragm and note characteristics of the 
first and second heart sounds.
 ZAssess for jugular venous distention (JVD).
Be alert for possible electrocardiogram (ECG) changes if the client is taking tricyclic anti -
depressants or antipsychotics.
Be aware that lithium and anorexia nervosa can cause peripheral edema.

 XAbdomen
 ZInspect the contour of the abdomen and check for scars, abdominal aortic 
pulsations, and the umbilical cord in the newborn.
 ZAuscultate for bowel sounds and the abdominal aorta for bruits.
 ZPercuss the abdomen, and note areas of tympany and dullness. It is normal to 
hear tympany over the small and large intestines and dullness over organs and a 
distended bladder.
 ZPercuss the size of liver and spleen.

86 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZPalpate the abdomen for masses and tenderness. Also palpate the liver and 
spleen, which are not normally palpable (sometimes the liver can be palpable in 
thin clients).
 XMusculoskeletal
 ZAssess client’s posture for alignment of extremities and spine and for symmetry 
of body parts.
 ZTest muscle strength of upper and lower extremities.
 ZNote symmetry of muscle mass, tone, and strength.
 ZAssess active range of motion in neck and upper and lower extremities, and 
note any presence of pain with movement.
 ZPalpate muscles and joints to elicit pain, deformities, crepitus, and passive range 
of motion.
 ZCheck for hip dysplasia in infants.
 ZCheck for scoliosis in children and adolescents.
 XCommon indicators of physical child abuse
 ZHistory of unexplained multiple fractures
 ZBurns, hand or bite marks
 ZInjuries at various stages of healing
 ZEvidence of neglect

XCommon indicators of physical child abuse
 ZBruising on padded parts of body
Diagnostic and Laboratory T esting
 XAssessment of diagnostic and laboratory testing is an essential element of the 
PMHNP role. It is important for the PMHNP to know when to order such tests, how 
to interpret the findings, and how to appropriately alter care based on the findings.
 XReasons to assess diagnostic and laboratory testing in psychiatry:
 ZTo assist in the establishment of a diagnosis; as knowledge of underlying 
pathophysiology grows, diagnostic and laboratory testing use will grow as well 
 ZUsed to rule out other disorders such as medical causes of psychiatric 
symptoms; helpful in differential diagnostic assessment
 ZUsed to determine whether a client’s symptoms are better explained by a 
nonpsychiatric disorder or by factors such as drug use or abuse

 ZFor routine ongoing monitoring such as general health screening, monitoring 
drug levels of certain psychiatric meds, and assessment and monitoring for 
complications of psychiatric disorders or adverse effects of drugs
 XThyroid function tests 
 ZFunction of thyroid gland is to take iodine from the circulating blood, combine 
it with the amino acid tyrosine, and convert it to the thyroid hormones T3 and T4.

87 advanced health and Physical health a ssessMent
 ZThe thyroid gland also stores T3 and T4 until they are released into the 
bloodstream under the influence of thyroid-stimulating hormone (TSH) released 
from the pituitary gland.
 ZOnly a small amount of T3 and T4 are bound to protein.
 ZThe free portion of the thyroid hormones is the true determinant of thyroid status.
 XFree thyroxine T4 (FT4; normal values 0.8 to 2.8 ng/dl)
 ZFT4 composes a small portion of the total thyroxine, is available to the tissues, 
and is the metabolically active form of this hormone.
 ZFT4 test is commonly done to determine thyroid status, to rule out hypo- and 
hyperthyroidism, and to evaluate thyroid therapy.
 XDiseases that have increased thyroid levels include: 
 ZGraves’ disease
 ZThyrotoxicosis due to T4
 ZHashimoto’s thyroiditis
 ZAcute thyroiditis
 XDiseases that have decreased thyroid levels include: 
 ZPrimary hypothyroidism
 ZSecondary hypothyroidism (pituitary insufficiency)

ZHashimoto’s thyroiditis
 ZTertiary hypothyroidism (hypothalamic failure)
 ZThyrotoxicosis due to T3
 ZRenal failure
 ZCushing’s syndrome
 ZCirrhosis
 XInterfering factors:
 ZValues can be increased during treatment with heparin, aspirin, and 
propranolol.
 ZValues can be decreased during treatment with furosemide (Lasix) or 
methadone.
 XThyroid-stimulating hormone (normal values 2–10 mU/l)
 ZStimulation of the thyroid gland by TSH causes release and distribution of stored 
thyroid hormones.
 XWhen T4 and T3 are high, TSH secretion decreases.
 XWhen T4 and T3 are low, TSH secretion increases.
 XIn primary hypothyroidism, TSH levels rise because of low levels of thyroid 
hormone.
 XIf the pituitary gland fails, TSH is not secreted and blood levels of TSH fall.

88 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZTSH testing is commonly performed to establish the diagnosis of primary 
hypothyroidism.
 XDiseases that have increased thyroid levels include:
 ZThyroiditis
 XDiseases that have decreased thyroid levels include:
 ZHyperthyroidism
 ZSecondary and tertiary hypothyroidism
 ZValues can be decreased during treatment with T3, acetylsalicylic acid, 
corticosteroids, and heparin.
 ZValues can be increased during drug therapy with lithium.
 XSystemic effects of hypothyroidism (decreased T4, increased TSH)
 ZMimics symptoms of unipolar mood disorders
 XConfusion
 XDecreased libido
 XImpotence
 XMemory loss
 XLethargy
 XConstipation
 XHeadaches
 XSlow or clumsy 
movements 
 XSyncope
 XWeight gain XFluid retention
 XMuscle aching and 
stiffness
 XSlowed reflexes
 XSomatic discomfort 
including aching and joint 
stiffness

XHeadaches
movements 
 XSyncope
stiffness
stiffness
 XSlowed speech and 
thinking
 XSensory disturbances, 
including hearing 
 XCerebellar ataxia
 XLoss of amplitude in ECG
 XSystemic effects of hyperthyroidism (increased T4, decreased TSH)
 ZMay mimic symptoms of bipolar affective disorders
 XMotor restlessness
 XEmotional lability 
 XShort attention span
 XCompulsive movement
 XFatigue
 XTremor
 XInsomnia
 XImpotence 
 XWeight loss XIncrease in appetite 
 XAbdominal pain
 XExcessive sweating
 XFlushing 
 XElevated upper eyelid 
leading to decreased 
blinking, staring, fine 
tremor of eyelid
 XTachycardia
 XDysrhythmias

89 advanced health and Physical health a ssessMent
 XElectrolytes
 ZCarried out as a part of routine screening in acute and critical illness or where 
there is a known or suspected disorder associated with fluid, electrolyte, or 
acid-base balance.
 XCalcium (Ca; normal values 8.8–10.5 mg/dl) 
 ZAbnormal values: 
 X<7 .0 mg/dl associated with tetany
 X>11 .0 mg/dl associated with hyperparathyroidism
 X>13.5 mg/dl associated with hypercalcemic coma and metastatic cancer. 
 ZMost Ca (99%) is located in bone and the remainder is in the plasma and body cells.
 ZOf the Ca in the plasma, 50% is bound to plasma proteins and 40% is in the 
free or ionized form. The remaining fraction circulates in the blood.
 ZCa is the major cation for the structure of bones and teeth.
 ZFunctions:
 XEnzymatic cofactor for blood clotting
 XRequired for hormone secretion
 XRequired for function of cell receptors
 XRequired for plasma membrane stability and permeability

ZFunctions:
 XRequired for plasma membrane stability and permeability 
 XRequired for transmission of nerve impulses and the contraction of muscles
 ZCa balance is mediated by interactions among three hormones: parathyroid 
hormone, vitamin D, and calcitonin.
 ZActing together, these substances determine the amount of dietary Ca 
absorbed and the renal reabsorption and excretion of Ca by the kidney.
 XIncreased levels of Ca can cause:
 ZAcidosis
 ZHyperparathyroidism
 ZCancers (for example, of bone, leukemia, myeloma)
 ZDrugs (such as thiazide diuretics, hormones, vitamin D, Ca)
 ZVitamin D intoxication
 ZAddison’s disease
 XDecreased levels of Ca can cause:
 ZAlkalosis
 ZHypoparathyroidism
 ZPancreatitis
 ZInadequate dietary intake of calcium, vitamin D
 ZDrugs, including barbiturates, anticonvulsants, acetazolamide,

ZAlkalosis
 ZDrugs, including barbiturates, anticonvulsants, acetazolamide, 
adrenocorticosteroids

90 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZValues are higher in children because of growth and active bone 
formation.
 ZValues can be increased by excessive ingestion of milk or during 
treatment with lithium, thiazide diuretics, alkaline antacids, or vitamin D.
 ZValues can be decreased during treatment with anticonvulsants, 
aspirin, calcitonin, corticosteroids, heparin, laxatives, diuretics, 
albuterol, and oral contraceptives.
 XSystemic effects of hypocalcemia (Ca <8.5 mg/dl):
 ZIncrease in 
neuromuscular 
 ZConfusion
 ZParesthesias around 
the mouth and in the 
digits
 ZMuscle spasms in the 
hands and feet
 ZHyperreflexia ZConvulsions
 ZTetany
 ZContinuous severe 
muscle spasm
 ZECG changes: 
prolonged QT interval
 ZIntestinal cramping
 ZHyperactive bowel 
sounds
 XSystemic effects of hypercalcemia (Ca >12.0 mg/dl):
 ZFatigue
 ZWeakness
 ZLethargy
 ZAnorexia
 ZNausea

ZECG changes: 
sounds
 ZFatigue
 ZWeakness
 ZLethargy
 ZAnorexia
 ZNausea
 ZConstipation ZBehavioral changes
 ZImpaired renal 
function
shortened QT 
interval, depressed 
T-waves
 ZBradycardia
 ZHeart block
 XSodium (Na; normal values 135–148 mEq/l)
 ZNa accounts for 90% of the extracellular fluid cations and is the most powerful 
cation in the extracellular fluid.
 ZNa regulates osmolality (interstitial and intravascular fluid volume).
 ZNa works with potassium and calcium to maintain neuromuscular irritability for 
conduction of nerve impulses.
 ZNa regulates acid-base balance.
 ZNa participates in cellular chemical reactions and membrane transport.
 ZNa regulates renal retention and excretion of water.

91 advanced health and Physical health a ssessMent
 ZNa maintains systemic blood pressure.
 XIncreased levels of Na can cause:
 ZHypovolemia
 ZDehydration
 ZDiabetes insipidus
 ZExcessive salt ingestion
 ZGastroenteritis
 ZDrugs such as adrenocorticosteroids, methyldopa, hydralazine, or 
cough medication
 XDecreased levels of Na can cause:
 ZRenal disorder
 ZGI fluid loss from vomiting, diarrhea, nasogastric suction, ileus
 ZDiuresis
 ZDrugs such as lithium, vasopressin, or diuretics
 ZSystemic effects of hyponatremia (Na <135 mEq/l):
 XLethargy
 XHeadache
 XApprehension
 XSeizures
 XComa
 XHypotension XTachycardia
 XDecreased urine output
 XWeight gain
 XEdema
 XAscites 
 XJugular vein distention
 ZSystemic effects of hypernatremia (Na >147 mEq/l):
 XConvulsions
 XPulmonary edema
 XThirst
 XFever
 XDry mucous membranes XHypotension
 XLow jugular venous 
pressure
 XRestlessness
 XMagnesium (Mg; normal values 1 .3–2.1 mEq/l)

XConvulsions
 XThirst
 XFever
pressure
 ZMg is a major intracellular cation; 40% to 60% is stored in bone and muscle, 
with 30% in cells.
 ZA small amount is in the serum, where one-third is bound to plasma proteins 
and the rest is in ionized form.
 ZRegulation of Mg metabolism is primarily by the kidney.
 ZLow serum levels cause renal conservation of Mg.

92 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZMg is a cofactor in intracellular enzymatic reactions. 
 ZMg is a cause of neuromuscular excitability.
 XIncreased levels:
 ZAdrenalectomy
 ZDiabetic ketoacidosis ZDehydration
 ZHypothyroidism
 XDecreased levels:
 ZHyperaldosteronism
 ZHypokalemia
 ZDiabetic ketoacidosis
 ZMalnutrition
 ZAlcoholism
 ZAcute pancreatitis ZGI loss from vomiting, 
diarrhea, nasogastric 
suction, and fistula
 ZMalabsorption 
syndrome
 ZPregnancy-induced 
hypertension
 ZHemolysis of a sample leads to falsely elevated levels.
 ZNumerous drugs can alter levels.
 ZValues can be increased by drugs such as antacids, laxatives containing 
Mg, salicylates, and lithium.
 ZValues can be decreased by drugs such as thiazide diuretics, calcium 
gluconate, insulin, amphotericin B, neomycin, aldosterone, and ethanol.

 ZSystemic effects of hypomagnesemia (Mg <1 .5 mEq/l):
 XDepression
 XIrritability
 XIncreased reflexes
 XMuscle weakness XAtaxia
 XNystagmus
 XTetany
 ZSystemic effects of hypermagnesemia (Mg >2.5 mEq/L):
 XNausea and vomiting
 XMuscle weakness
 XHypotension
 XBradycardia XRespiratory depression
 XDepressed skeletal 
muscle contraction and 
nerve function
 XChloride (normal values 98–106 mEq/L)
 ZChloride is the major anion in the extracellular fluid.
 ZIt provides electroneutrality in relation to sodium (see above).
 ZTransport of chloride is passive and follows the active transport of sodium so 
that increases or decreases in chloride are proportional to changes in sodium.

93 advanced health and Physical health a ssessMent
 ZAcidosis
 ZHyperkalemia, 
hypernatremia
 ZDehydration ZRenal failure
 ZHyperventilation
 ZAnemia
 ZHyponatremia
 ZGI loss from vomiting, 
suction, and fistula ZDiuresis
 ZOverhydration
 ZBurns
 ZElevated serum triglyceride levels and myeloma proteins may lead to 
falsely decreased levels.
 ZValues can be increased by potassium chloride, acetazolamide, 
methyldopa, diazoxide, and guanethidine.
 ZValues can be decreased by ethacrynic acid, furosemide, thiazide diuretics, and 
bicarbonate.
 ZNo specific symptoms are associated with chloride increase or decrease.
 XPotassium (K+; normal values 3.5–5.1 mEq/l)
 ZK+ is the major intracellular electrolyte.
 ZTotal body K+ is about 4,000 mEq, with most of it located in the cells.

XPotassium (K+; normal values 3.5–5.1 mEq/l)
 ZIntracellular concentration of K+ is 150 to 160 mEq/l; extracellular concentration 
is 3.5 to 4.5 mEq/l.
 ZAs the predominant intracellular ion, K+ regulates intracellular fluid osmolality 
and provides the balance for intracellular electrical neutrality.
 ZK+ is required for glycogen deposition in liver and skeletal muscle cells.
 ZK+ maintains resting membrane potential and assists in transmission and 
conduction of nerve impulses, maintenance of normal cardiac rhythms, and 
skeletal and smooth muscle contraction.
 ZK+ balance is regulated by the kidney, aldosterone levels, insulin secretion, and 
changes in pH.
 ZAcidosis
 ZInsulin deficiency
 ZAcute renal failure ZHypoaldosteronism
 ZInfection

94 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZExcessive insulin
 ZGI loss
 ZLaxative abuse
 ZBurns
 ZTrauma ZSurgery
 ZThyrotoxicosis
 ZAnorexia nervosa
 ZDiet deficient in meat 
and vegetables
 ZFalse elevations can occur with vigorous pumping of the hand during 
venipuncture, hemolysis of the sample, or high platelet counts during 
clotting.
 ZFalse decreases are seen in anticoagulated samples left at room 
temperature.
 ZValues can be decreased by drugs such as furosemide, ethacrynic acid, 
thiazide diuretics, insulin, aspirin, prednisone, cortisone, gentamycin, 
lithium, and laxatives.
 ZValues can be increased by drugs such as amphotericin B, tetracycline, 
heparin, epinephrine, potassium-sparing diuretics, and isoniazid.
 ZChronic marijuana use can elevate K+ level.
 ZSystemic effects of hyperkalemia (K+ >5.5 mEq/l):

 XParalysis
 XTingling of lips and fingers
 XIntestinal cramping
 XDiarrhea
 XECG changes: narrow and taller T -waves
 ZMild hyperkalemia: shortened QT interval
 ZSevere hyperkalemia: depressed ST segment, prolonged PR interval, 
widened QRS complex leading to cardiac arrest
 ZSystemic effects of hypokalemia (K+ <3.5 mEq/l):
 XImpaired carbohydrate metabolism
 XImpaired renal function
 XPolyuria
 XPolydipsia
 XSkeletal muscle weakness
 XSmooth muscle atony

95 advanced health and Physical health a ssessMent
 XCardiac dysrhythmias
 XParalysis and respiratory arrest
 XLiver function tests
 ZUsed to monitor liver disease or damage caused by hepatotoxic drugs, as 
confirmed by elevated levels
 XAlanine aminotransferase (ALT ; normal values 5–35 U/l)
 ZFormerly known as glutamic-pyruvic transaminase (SGPT), ALT is an enzyme 
produced by the liver that acts as a catalyst in the transamination reaction 
necessary for amino acid production.
 ZALT is found in liver cells in high concentrations and in moderate amounts in 
body fluids, heart, kidneys, and skeletal muscles.
 ZWhen liver damage occurs, serum levels of ALT rise to as much as 50 times 
normal.
 XPronounced elevated levels (>300 U/l):
 ZLiver disease or damage, such as hepatic cancer, hepatitis, or 
infectious mononucleosis
 XModerately elevated levels (100–300 U/l):
 ZBiliary tract obstruction
 ZRecent cerebrovascular accident

ZLiver disease or damage, such as hepatic cancer, hepatitis, or 
 ZMuscle injury from intramuscular injections, trauma, infection, and 
seizures
 ZMuscular dystrophy
 ZAcute pancreatitis
 ZIntestinal injury
 ZMyocardial infarction
 ZCongestive heart failure
 ZSevere burns
 ZUremia and hemodialysis can cause falsely decreased levels.
 ZValues can be increased with acetaminophen, allopurinol, aspirin, 
ampicillin, carbamazepine, cephalosporins, codeine, digitalis, 
indomethacin, heparin, isoniazid, methotrexate, methyldopa, oral 
contraceptives, phenothiazines, propranolol, tetracycline, and 
verapamil.
 XAspartate aminotransferase (AST ; normal values 5–40 U/l)
 ZPreviously known as serum glutamate oxaloacetate transaminase (SGOT), AST 
measures the level of the enzyme that catalyzes the reversible transfer of an

ZPreviously known as serum glutamate oxaloacetate transaminase (SGOT), AST 
measures the level of the enzyme that catalyzes the reversible transfer of an 
amino group between the amino acid, aspartate, and alphaketoglutamic acid.

96 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZAST exists in large amounts in both liver and myocardial cells and in smaller but 
significant amounts in skeletal muscles, kidneys, the pancreas, and the brain.
 ZSerum AST rises when there is cellular damage to the tissues in which the 
enzyme is found.
 XPronounced elevation (>5× normal):
 ZAcute hepatocellular damage
 ZShock
 ZInfectious mononucleosis
 XModerate elevation (3–5× normal):
 ZBiliary tract 
obstruction
 ZCardiac arrhythmias
 ZCongestive heart 
failure ZLiver tumors
 ZChronic hepatitis
 ZDermatomyositis
 XSlight elevation (2–3× normal):
 ZPericarditis
 ZCirrhosis, fatty liver
 ZPulmonary infarction
 ZDelirium tremens
 ZCerebrovascular accident
 ZHemolytic anemia
 ZNumerous drugs may elevate levels, including antihypertensives,

ZPulmonary infarction
 ZNumerous drugs may elevate levels, including antihypertensives, 
cholinergic agents, anticoagulants, digitalis, erythromycin, isoniazid, 
methyldopa, oral contraceptives, opiates, salicylates, hepatotoxic 
medications, and verapamil.
 ZExercise can cause increased levels.
 XGamma glutamyl transpeptidase (GGT ; normal values 10–38 IU/l)
 ZGGT is an isoenzyme of alkaline phosphatase and assists with the transfer of 
amino acids and peptides across cellular membranes.
 ZHepatobiliary tissues and renal tubular and pancreatic epithelium contain large 
amounts of GGT .
 ZOther sources of GGT include the prostate gland, brain, and heart.
 ZGGT is used to evaluate and monitor a client with known or suspected alcohol 
abuse, because levels rise even after ingestion of small amounts of alcohol.
 ZAlso used to evaluate elevated alkaline phosphatase of uncertain etiology.

 ZPronounced early increases in GGT are found in in hepatic disease.

97 advanced health and Physical health a ssessMent
 ZModest elevation in GGT occurs in cirrhosis and in pancreatic or renal disease.
 XElevated GGT :
 ZHepatobiliary tract disorders
 ZHepatocellular carcinoma
 ZHepatocellular degeneration such as cirrhosis
 ZHepatitis
 ZPancreatic or renal cell damage or neoplasm
 ZAcute myocardial infarction (after 4–10 days)
 ZHyperlipoproteinemia
 ZDiabetes mellitus with hypertension
 ZSeizure disorder
 ZSignificant alcohol ingestion
 ZAlcohol, barbiturates, and phenytoin can elevate GGT levels.
 ZLate pregnancy, oral contraceptives, and clofibrate can lower GGT levels.
DISEASE PREVENTION ACTIVITIES
Immunization
Immunizations are critical to preventing disease, according to the U.S. Centers for Disease 
Control and Prevention (CDC). Immunizations protect individual children and adults from develop -
ing potentially serious diseases while also protecting the community by reducing the spread of

ing potentially serious diseases while also protecting the community by reducing the spread of 
infectious disease.
 XSchedules for children and adults are available on the CDC website at www.cdc.gov/  
vaccines/schedules/index.html .
 XSeasonal influenza vaccination (as live attenuated influenza vaccine or as inactivated 
type).
 XAll persons age 6 months or older should receive annual influenza vaccination.
 ZChildren 6 months to 8 years of age require two doses of influenza vaccine (4 
weeks apart) during their first season of vaccinations. 
 ZLAIV should not be used in persons younger than 2 years of age or older than 
49 years of age.
 ZPersons with egg allergy should always receive the vaccination from a health 
care provider familiar with potential reaction and should be observed for at least 
30 minutes post injection for signs of reaction.

 ZImmunocompromised persons should not receive live vaccination.
 ZUse live vaccine or inactivated vaccine for healthy nonpregnant adults younger 
than 50 years of age with no high-risk medical conditions. All others should 
receive the inactivated vaccine only (Grohskopf et al., 2015).

98 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XHPV vaccination for girls is recommended at age 11 or 12 years with catch-up vacci -
nation at ages 13 through 26 years to prevent genital human papillomavirus infection, 
which can cause cervical cancer and genital warts.
 ZHPV4 may be administered to males age 9 through 26 years to prevent genital 
warts. 
 XMeasles, mumps, rubella (MMR; live vaccine)
 ZNot for pregnant women; people with cancer, weakened immune systems, or 
HIV or AIDS with T -cell counts below 200; or people currently being treated with 
high-dose steroids or who have received a blood transfusion within the previous 
2 weeks
 XDiphtheria, tetanus, acellular pertussis 
 ZTd (tetanus, diphtheria) vaccine should be given every 10 years beginning at age 
11 years, with Tdap (tetanus, diphtheria, acellular pertussis) substituted once for 
Td but no less than 5 years after the last DTaP dose was given. DTaP should not

Td but no less than 5 years after the last DTaP dose was given. DTaP should not 
be given to anyone 7 years of age or older.
 XShingles (also known as herpes zoster ) vaccine (CDC, 2015b)
 ZRecommended for anyone age 60 or older who has had chickenpox.
 ZDo not give shingles vaccine to persons with weakened immune systems or 
HIV or AIDS with T -cell counts below 200, or to persons being treated with high-
dose steroids.
 ZShingles is an inflammatory condition in which a virus produces painful vesicular 
eruptions along the distribution of the nerves from one or more dorsal root 
ganglia.
 XVaricella (chickenpox) vaccine
 ZNot for pregnant women; persons with weakened immune systems, HIV or 
AIDS with T -cell counts below 200, or cancer; or for people being treated with 
high-dose steroids or who received a blood transfusion within the previous 2 
weeks
Anticipatory Guidance

weeks
Anticipatory guidance is a framework for implementation of prevention strategies.
 XBased on the premise that information can be provided to people to help them cope 
more effectively with events that occur along the life span. Within the framework of 
anticipatory guidance, the practitioner seeks to determine the specific informational 
needs of the client in a systematic, standard way. 
 XPediatrics:  Soliciting information from parents about their concerns in parenting and 
providing information specific to their concerns. Teaching parents about health haz -
ards and strategies to prevent harm, such as car seat safety, water safety, wearing 
helmets, and so forth.
 XBright Futures  (www.brightfutures.org/ ) is a national health promotion initiative

 XBright Futures  (www.brightfutures.org/ ) is a national health promotion initiative 
(launched by the Health Resources and Services Administration in partnership with 
other agencies) dedicated to the principle that every child deserves to be healthy and 
that optimal health involves trusting relationships among the health professional, the

99 advanced health and Physical health a ssessMent
child, the family, and the community as partners in health practice. Expansion of the 
model includes screening, care management, and education about mental health 
problems and disorders in developmental context.
 XIn specific healthcare situations, anticipatory guidance can be used to assist people 
in meeting healthcare challenges across the life span. Some examples include
 ZCoping with terminal illness or death and dying (anticipatory grief)
 ZCoping with disease progression, such as with Alzheimer’s dementia, in a loved 
one
 ZCoping with change and limitations resulting from spinal cord injuries
 ZCan be implemented in each “well check” to identify information needs 
pertinent to the client’s current life situation. Some examples:
 XResponsible alcohol use for the adolescent going off to college
 XLife after the loss of a loved one (through divorce or death)
 XPlanning for retirement

XResponsible alcohol use for the adolescent going off to college
GENDER-BASED MEDICAL TESTING AND SCREENING 
RECOMMENDATIONS FOR THE GENERAL PUBLIC
T anner Stages Assessment
Defines physical measurements of development in children, adolescents, and adults. The de -
velopment of primary and secondary sex characteristics (breasts, genitalia, and pubic hair) are 
assessed by stages to describe the onset and progression of puberty in both males and females. 
Because of natural variability, males and females pass through the stages at different rates based 
on timing of puberty. 
Girls: Breast Development
Stage 1:  Prepubertal
Stage 2:  Breast bud stage with elevation of breast and papilla; enlargement of areola
Stage 3:  Further enlargement of breast and areola; no separation of their contour
Stage 4:  Areola and papilla from a secondary mound above level of breast

Stage 5:  Mature stage: projection of papilla only, related to recession of areola (Jarvis, 2011)
Boys: Development of External Genitalia
Stage 1:  Prepubertal 
Stage 2:  Enlargement of scrotum and testes; scrotum skin reddens and changes in 
texture
Stage 3: Enlargement of penis (length at first); further growth of testes
Stage 4: Increase in size of penis with growth in breadth and development of glans; 
testes and scrotum larger, scrotum skin darker
Stage 5: Adult genitalia (Jarvis, 2011)

100 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
Boys and Girls: Pubic Hair
Stage 1: Prepubertal (can see vellus hair similar to abdominal wall)
Stage 2: Sparse growth of long, slightly pigmented hair, straight or curled, at base of 
penis or along labia
Stage 3: Darker, coarser, and curlier hair, spreading sparsely over junctions of pubes
Stage 4: Adult-type hair, but covering smaller area than in adult, no spread to medial 
surface of thighs
Stage 5: Adult type and quantity, with horizontal distribution (Jarvis, 2011)
Women
Ages 18 through 39
 XMonthly: Skin and oral self-exams
 XYearly: Blood pressure; blood tests and urinalysis; physical exam; Pap smear (begin -
ning at age 21 or within 3 years of sexual activity, whichever comes first), pelvic 
exam, sexually transmitted infection (STI) detection
 XAll persons age 13 to 64 should be tested at least once for HIV (CDC, 2016)
Ages 40 through 49

 XYearly: Blood pressure; blood tests and urinalysis; physical exam; Pap smear (every 
2 or 3 years after three consecutive negative smears), pelvic exam, STI detection; 
electrocardiogram (ECG) every 4 years
Ages 50+
 XYearly: Blood pressure; blood tests (complete blood count, metabolic panel, thyroid-
stimulating hormone) and urinalysis; physical exam; Pap smear (65 and older not rec -
ommended if person had proper recent normal Pap smear and is not at high risk for 
cervical cancer), pelvic exam, STI detection; mammography every 2 years; routine 
bone density screening starting at age 65 and older (beginning at 60 if increased risk 
for osteoporotic fractures)
 XEvery 4 years: Electrocardiogram (ECG)

 XEvery 5 years through age 75: flexible sigmoidoscopy or double-contrast barium 
enema or CT colonography (if any of these tests are positive, a colonoscopy should 
be done), or colonoscopy every 10 years
 XConsult provider: Hearing, vision
Additional Colorectal Cancer Screening for High-Risk Women
The American Cancer Society recommends that some people be screened using a different 
schedule because of their personal or family history.
Men
 XMonthly: Self-exams (testicles, skin, and oral)

101 advanced health and Physical health a ssessMent
stimulating hormone) and urinalysis; physical exam
 XScreening at least once a year for syphilis, chlamydia, and gonorrhea for all sexually 
active gay, bisexual, and men who have sex with men up to age 64 (CDC, 2016)
 XMonthly: Testicles, skin, and oral self-exams
stimulating hormone) and urinalysis; physical exam; ECG every 4 years
Ages 50+
stimulating hormone) and urinalysis; physical exam; electrocardiogram (ECG) every 3 
years
 XEvery 5 years through age 75: Flexible sigmoidoscopy or double-contrast barium

years
 XEvery 5 years through age 75: Flexible sigmoidoscopy or double-contrast barium 
 XConsult provider: Testosterone blood test; hearing and vision screening
HEALTH BEHAVIOR GUIDELINES
Exercise
Exercise benefits both physical and mental health. Inactivity has a direct link to obesity, a major 
health problem in this country. In results of recent studies, exercise has demonstrated effects 
comparable to antidepressant therapy in the treatment of depression.
 XKey factor in staying healthy: strengthens bones, heart, and lungs, tones muscles, 
improves vitality, relieves depression, and helps to improve sleep. It is particularly 
beneficial to persons with comorbid medical conditions such as diabetes, obesity, 
and hypertension.

 XMind–body connection: improves cognition and enhances mood 
 XNeurobiological explanation: promotes increased concentrations of serotonin, norepi -
nephrine, and endorphins
 XIntegrative psychiatry includes strategies to improve lifestyle practices (diet, exer -
cise, smoking cessation, decrease or cease drug and alcohol use) and reduce stress 
to prevent illness.
 XClient teaching regarding exercise:
 ZCheck with provider before starting an exercise program. 
 ZBegin exercising gradually. Don’t expect results overnight. If you are consistent, 
you will see improvement within 3 months.
 ZWork hard enough to sweat, but not so hard that you cannot carry on a 
conversation.

102 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZPlan an exercise routine that lasts at least 30 minutes, and perform the workout 
at least 3 to 5 days a week. Warming up before exercise helps avoid injury. 
 ZInclude both aerobic and strengthening activities in exercise program. 
 ZExercise programs need to be modified for children, pregnant women, the 
elderly, clients who are obese or disabled, and heart attack survivors as well as 
modified for high altitudes and extreme hot or cold conditions.
 ZMonitor the intensity of exercise by measuring heart rate. The target heart rate 
during physical activity should be 60% to 90% of the maximum heart rate. Use 
the following formula to calculate target heart rate:
 X220 (beats per minute) minus age = maximum heart rate
 XMaximum heart rate multiplied by the intensity level = target heart rate
 XPhysical activity at 60% to 70% of the maximum heart rate is considered 
moderate-intensity exercise.

XMaximum heart rate multiplied by the intensity level = target heart rate
 ZCDC recommends 60 minutes (1 hour) or more of physical activity each day for 
children and adolescents.
 ZCDC recommends 150 minutes of moderate-intensity aerobic activity (such as 
brisk walking) every week and muscle-strengthening activities 2 or more days a 
week for adults, including healthy older adults (CDC, 2015a).
Self-Awareness
 XRequires reflection on one’s personal beliefs, thoughts, emotions, motives, biases, 
and limitations and being aware of how they influence behavior toward others 
 XA trusted person who can give open, honest feedback to self-examination is helpful.
 XPersonal experiences influence communication patterns and responses to clients. 
 XSocial biases, feelings, and beliefs projected onto the client may affect the nurse–
client relationship.

XPersonal experiences influence communication patterns and responses to clients. 
 XBeing nonjudgmental and objective cultivates trust in the relationship.
 XClinical supervision by colleague provides ongoing feedback for therapeutic develop -
ment of the helper, including supporting change as needed.
 XIf personal values and beliefs make it difficult to be therapeutic with a particular cli -
ent, refer the client to another provider.
Self-Disclosure
 XRevealing personal information to the client changes the focus away from the client. 
 XWhen asked personal questions, self-disclosure can be limited by redirecting, giv -
ing a vague answer, or reminding the client that you will not share your personal 
information. 
 XSelf-disclosure may be therapeutic only when it is purposeful and has an identified 
therapeutic outcome, such as role modeling.

103 advanced health and Physical health a ssessMent
Health Promotion and Disease Prevention Education
 XPreventative care and screening practices are essential aspects of the PMHNP role.
 XScreening for physical health problems in the psychiatric client
 XUsually guided by Healthy People 2020 (U.S. Department of Health and Human 
Services, 2016), which identifies national health objectives, including behavioral 
health
 XMental health promotion and education includes:
 ZTeaching about interventions and ways to cope with specific stressors
 ZValidating “normalcy” of feelings; ensuring clients that they are not “crazy”
 ZHelping clients recognize and identify their feelings or behaviors
 ZHelping clients identify resources in the community
PUBLIC HEALTH PRINCIPLES
 XPrimary prevention: Aimed at decreasing the incidence (number of new cases) of 
mental disorders
 ZHelping people avoid stressors or cope with them more adaptively

 XExample : Stress management classes for graduate students, smoking 
prevention classes, Drug Abuse Resistance Education (DARE) Keepin’ It 
REAL elementary and middle school curriculum (DARE, 2015) 
 XSecondary prevention:  Aimed at decreasing the prevalence (number of existing 
cases) of mental disorders
 ZEarly case finding
 ZScreening
 ZPrompt and effective treatment
 XExample:  Telephone hotlines, crisis intervention, disaster responses
 XTertiary prevention:  Aimed at decreasing the disability and severity of a mental 
disorder
 ZRehabilitative services
 ZAvoidance or postponement of complications
 XExample:  Day treatment programs; case management for physical, housing, 
or vocational needs; social skills training
Risk Factors

ZAvoidance or postponement of complications
 XPredisposing characteristics that make it more likely that a person will develop a 
disorder
 XBiological risk factors:  History of mental illness in family, poor nutritional status, poor 
general health

104 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XPsychological risk factors:  Poor self-concept, external locus of control, poor ego 
defenses
 XSocial risk factors:  Stressful occupation, low socioeconomic status, poor level of 
social integration
Preventative Factors
 XFactors that prevent or protect the person from the disorder
 XCoping mechanisms or resources that facilitate a healthy response to stress
 XBiological preventative factors:  No history of mental illness in the family, healthy 
nutritional status, good general health
 XPsychological preventative factors:  Good self-esteem or self-concept, internal locus 
of control, healthy ego defenses
 XSocial preventative factors:  Low-stress occupation, higher socioeconomic status, 
higher level of education

105 advanced health and Physical health a ssessMent
Mr. J. is a 79-year-old married man, being treated by the PMHNP for major depression. Mr. J. 
was started on citalopram 10 mg 4 weeks ago and has now been taking 20 mg p.o. q.a.m. for 
the past 3 weeks. 
Pertinent medical history includes hypertension, which is well controlled by benazepril and hydro -
chlorothiazide (Lotensin HCT). He also takes finasteride (Proscar) for benign prostatic hyperplasia.
1. How should the PMHNP think about what may be going on with Mr. J.? 
2. How should the PMHNP intervene? 
Mr. J. arrives at his follow-up appointment, accompanied by his spouse. He tells you his primary 
care provider checked his sodium level, which was low, and Mr. J. was instructed to stop the 
citalopram. He is not on any antidepressant treatment and reports he has been feeling progres -
sively more tired, his stomach has been upset, and he feels “a little foggy. ” These symptoms 
began “about a week ago. ”

began “about a week ago. ” 
3. How would this presentation change the PMHNP’s treatment plan?
4. What is the appropriate intervention for Mr. J.? 
Ms. Smith, a 27-year-old single woman who works in a retail store, has been referred by her 
primary care provider to the PMHNP for evaluation and treatment of “mood swings. ” Ms. Smith 
tells the PMHNP that she has been feeling “pretty good” for the past week after coming through 
a 3-week period of depression. Her PCP discontinued her fluoxetine 20 mg several days ago. 
She is mildly euphoric, but there is also evidence of irritability. Her speech is pressured and she 
is hyperverbal, but she is easily redirected. She reports she has been sleeping “about 4 to 5 
hours a night, ” and describes her energy as “pretty good!” There is no evidence of psychosis.

hours a night, ” and describes her energy as “pretty good!” There is no evidence of psychosis. 
Her insight and judgment are intact, and she tells the NP “I think I’m a little high. I’m worried it’s 
going to get me in trouble at work. ”
Past psychiatric history is significant for depressive episodes beginning in early teens, during 
which she experienced suicidal ideation. She has been treated with many selective serotonin 
reuptake inhibitors (SSRIs) over the years, all prescribed by her primary care provider and in 
each case, she noticed rapid improvement of her mood and discontinued the drug after several 
months. She denies a history of hypomania until the past year. 
Medical history is noncontributory. 
Family history is significant for bipolar I disorder in dad and possibly paternal grandmother. 
Mother has a long history of untreated “depression and anxiety. ”

Mother has a long history of untreated “depression and anxiety. ” 
The PMHNP and Ms. Smith discuss treatment options and decide to start lithium carbonate.
1. What client teaching should be included in preparation for beginning lithium?
2. What tests should be ordered before beginning this drug?
3. If Ms. Smith were an older adult, what additional test should be ordered before 
treating her with lithium?

106 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
Three months after beginning lithium, Ms. Smith presents with lethargy, constipation, and 
bradycardia. 
4. What should the PMHNP consider as etiology?
5. What labs tests should be ordered?
6. What adjustment should be made to the client’s medication?

107 advanced health and Physical health a ssessMent
1. All SSRIs and some other antidepressants have been implicated in hyponatremia. 
Owing to diminished renal functioning and frequent polypharmacy, hyponatremia is 
more common in the elderly. In addition to citalopram, Mr. J. is taking hydrochloro -
thiazide, which may also cause hyponatremia. 
2. The signs and symptoms of hyponatremia vary, depending on how quickly sodium 
levels drop. Slow decrease in sodium may lead to a subtle presentation such as 
feeling tired, and slightly “foggy. ” Clients experiencing a more precipitous drop will 
present with dramatic changes in level of consciousness and severe headache owing 
to cerebral edema. The PMHNP should assess for signs and symptoms of hypona -
tremia and order a sodium level. 
3. An assessment should be made if the client has had trials on another SSRI.

3. An assessment should be made if the client has had trials on another SSRI. 
Assessment of his depression needs to be completed and use of a depression 
scale, such as the PHQ-9 or GDS, are indicated. 
4. If the client has not had another trial on a SSRI it is indicated to place Mr. J. on a 
SSRI and follow his response. 
1. The client should be taught about the potential risks and benefits of taking lithium. 
Women of childbearing age should be educated about the risk of birth defects, 
including Ebstein’s anomaly. Consideration of lithium dose and maintenance blood 
levels should be included in discussing the relative risk. The client should be taught 
about the signs and symptoms of lithium toxicity. 
2. Baseline labs consisting of a metabolic panel, TSH, and complete blood count (CBC)

2. Baseline labs consisting of a metabolic panel, TSH, and complete blood count (CBC) 
should be done. Women of childbearing age should have a pregnancy test. 
3. Clients over the age of 65 or those who have a history of heart disease should have 
a baseline ECG.
4. Lethargy and constipation may be due to hypothyroidism or hypercalcemia, both of 
which may be caused by lithium. 
5. The client should have TSH, free T4, and electrolytes drawn. 
6. The lithium should be tapered off and an alternative medication used for mood 
stabilization. 
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Psychopharmacology, 14 (Suppl. 1), S5–S12.

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Gray.
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http://www.healthypeople.gov/

CHAPTER 7PHARMACOLOGICAL PRINCIPLES
Psychopharmacology , one of the most active and developing areas of psychiatric research, is 
the use of psychotropic medication to treat psychiatric disorders. Psychiatric–mental health 
nurse practitioners  (PMHNPs) must have a thorough understanding of the science and art of 
prescribing—of the pharmacokinetic and pharmacodynamic actions of a given drug, as well as 
the client’s motivation to take the drug. The basic pharmacological principles are discussed in this 
chapter. 
CONCEPTS IN PHARMACOLOGICAL MANAGEMENT
 XPharmacology:  Study of what drugs do and how they do it
 XPharmacokinetics:  Study of what the body does to drugs; includes absorption, distri -
bution, metabolism, and excretion
 XPharmacodynamics:  Study of what drugs do to the body; target sites for drug actions 
include receptors, ion channels, enzymes, and carrier proteins
Pharmacokinetics
 XAbsorption:  Method and rate at which drugs leave the site of administration

 ZWith oral medications, absorption normally occurs in the small intestine and 
then in the liver.
 XDistribution:  Occurs after the drug leaves the systemic circulation and enters the 
interstitium and cells
 ZDrugs are redistributed in organs according to their fat and protein content.
 ZMost psychotropic medications are lipophilic and highly protein-bound. Only the 
unbound (free) portion of the drug is active. Therefore, people with low protein 
(albumin) levels, such as in malnutrition, wasting, or aging, can potentially 
experience toxicity (see below) from an increased amount of free drug. People 
with high fat-to-lean body mass ratio (as in older adults) will have erratic 
amounts of active drug in their system.

112 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XMetabolism:  Process by which the drug becomes chemically altered in the body
 XFirst-pass metabolism:  Process by which the drug is metabolized by cytochrome 
P450 (P450) enzymes in the intestines and liver prior to going to the systemic 
circulation
 XElimination:  Process by which the drug is removed from the body
 XHalf-life (T ½):  Time needed to clear 50% of the drug from the plasma
 ZThe half-life also determines the dosing interval and the length of time to reach 
a steady state.
 XSteady state:  Point at which the amount of drug eliminated between doses is ap -
proximately equal to the dose administered.
 ZDrugs usually are administered once every half-life to achieve a steady state.
 ZIt takes approximately five half-lives to achieve a steady state and five half-lives 
to completely eliminate a drug.
 XAlterations in pharmacokinetics

ZIt takes approximately five half-lives to achieve a steady state and five half-lives 
 ZHepatic cytochrome P450 enzyme interactions can induce or inhibit the 
metabolism of certain drugs, thus changing their desired concentration levels 
(see Table 7–1).
 ZApproximately 10% of Caucasians are poor metabolizers of the P450 2D6 
enzyme.
 ZApproximately 20% of Asians may have reduced activity of the P450 2C19 
enzyme.
 ZFirst-pass metabolism activity of P450 enzymes 2C9, 2C19, 2D6, and 3A4 
in young children may exceed rates of adolescents and adults and give rise 
to underexposure to certain medications Conversely, the ontogeny of the 
1A2 pathway is delayed, possibly leading to toxic effects from drugs that are 
substrates of this pathway (e.g., some antipsychotics). 
 ZEnzyme inducers can decrease the serum level of other drugs that are 
substrates of that enzyme, thus possibly causing subtherapeutic drug levels.

ZEnzyme inducers can decrease the serum level of other drugs that are 
TABLE 7–1  . 
CYTOCHROME P450 INHIBITORS AND INDUCERS
INHIBITORS INDUCERS
Buproprion
Clomipramine
Cimetidine 
Clarithromycin
Fluoroquinolones
Grapefruit and grapefruit juice
Ketoconazole
Nefazodone
SSRIsCarbamazepine
Hypericum (St. John’s Wort)
Phenytoin
Phenobarbital
Tobacco

113 PharMacological PrinciPles
 ZEnzyme inhibitors can increase the serum level of other drugs that are 
substrates of that enzyme, thus possibly causing toxic levels.
 ZLiver disease will affect liver enzyme activity and first-pass metabolism, possibly 
resulting in toxic plasma drug levels.
 ZKidney disease or drugs that reduce renal clearance, such as nonsteroidal anti-
inflammatory drugs (NSAIDs), may increase serum concentration of drugs that 
are excreted by the kidneys (such as lithium). Older adults are more sensitive 
to psychotropics because of their decreased intracellular water, protein binding, 
low muscle mass, decreased metabolism, and increased body fat concentration. 
 XMost psychotropics are lipophilic and highly protein-bound. Thus, because 
older adults have more body fat and less protein, they are more likely to 
develop toxicity due to accumulation and erratic blood levels of drug.
Pharmacodynamics

 XTarget sites for drug actions include receptors. Several types of pharmacodynamics 
involve receptors:
 ZAgonist effect: Drug binds to receptors and activates a biological response
 ZInverse agonist effect: Drug causes the opposite effect of agonist; binds to 
same receptor
 ZPartial agonist effect:  Drug does not fully activate the receptors
 ZAntagonist effect:  Drug binds to the receptor but does not activate a biological 
response
 XAnother site for drug actions is ion channels, which exist for many ions such as 
sodium, potassium, chloride, and calcium and can be open at some times and closed 
at other times. Neurotransmitters or drugs may be excitatory or inhibitory depending 
on the type of ion channel they gate.
 ZExcitatory response:  Depolarization; involves the opening of sodium and calcium

 ZExcitatory response:  Depolarization; involves the opening of sodium and calcium 
channels so these ions go into the cell
 ZInhibitory response: Repolarization; involves the opening of chloride channels so 
chloride goes into the cell, potassium leaves, or both
 XAnother site for drug actions are enzymes, which are important for drug metabolism 
and play an important role in the chemical alteration of the drug. Some drugs (e.g., 
monoamine oxidase inhibitors [MAOIs]) inhibit the action of a particular enzyme, 
thus increasing the availability of the neurotransmitter. 
 XAnother site for drug actions is carrier proteins or reuptake pumps, which transport 
neurotransmitters out of the synapse and back into the presynaptic neuron to be 
recycled or reused. Some drugs, such as selective serotonin reuptake inhibitors 
(SSRIs), will inhibit reuptake pumps, thus increasing the synaptic availability of the 
neurotransmitter.
Other T erminology

 XPotency:  Relative dose required to achieve certain effects

114 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XTherapeutic index:  Relative measure of the toxicity or safety of a drug; ratio of the 
median toxic dose to the median effective dose
 ZDrugs with a high therapeutic index (e.g., divalproex, 50–125 mcg/ml) have a 
high margin of safety; that is, the therapeutic dose and the toxic dose are far 
apart.
 ZDrugs with a low therapeutic index (e.g., lithium, 0.5–1 .2 mEQ/L) have a low 
margin of safety; that is, the therapeutic dose and the toxic dose are close 
together.
 XTolerance: The process of becoming less responsive to a particular drug over time
 XTachyphylaxis:  An acute decrease in the therapeutic response
PMHNP PHARMACOLOGICAL MANAGEMENT ROLE
 XPharmacological management process:
 ZMake a diagnosis and identify the target symptoms.
 ZConsider the phase of illness (such as acute, relapse, recurrence).
 ZAssess prior personal and family history of response to certain medications.

ZConsider the phase of illness (such as acute, relapse, recurrence).
 ZAssess the client’s motivation for and any misgivings about treatment.
 ZIdentify potential interactions between the currently prescribed medications.
 ZIdentify cultural implications of certain drugs.
 ZDiscuss the risks and benefits of the treatment.
 ZDocument informed consent and the client’s understanding of target symptoms, 
benefits, risks, and alternatives to treatment.
 ZMonitor response and side effects.
 XFollow-up and role of the PMHNP
 ZUse of standards of care:
 XAssist in determining length of treatment.
 XDo relapse planning.
 ZIt is helpful and advised to use standardized clinical rating scales to establish 
the client’s baseline and to monitor progress or decompensation over time. 
Screening tests also will aid in making a diagnosis and ruling out other disorders.

Screening tests also will aid in making a diagnosis and ruling out other disorders. 
(See corresponding chapters for a list of relevant screening tools.)
 ZIt is important to recognize the large body of evidence-based data supporting 
the combined use of pharmacological and nonpharmacological treatments 
as offering psychiatric clients the best possibility for significant clinical 
improvement.
 ZNonadherence is a common problem with all chronic illness, including 
psychiatric disorders, and should be a continuous focus of concern for the 
PMHNP .

115 PharMacological PrinciPles
 ZCommon medications used in the clinical management of psychiatric disorders 
and usually prescribed by the PMHNP are identified in Table 7–2. See 
corresponding chapters for specific information on each medication. 
 ZA Drug Enforcement Administration (DEA) number is required for prescription of 
controlled substances.
 XSchedule of controlled substances 
 ZSchedule I
 XNonmedicinal substances
TABLE 7–2 .
MEDICATIONS COMMONLY USED IN THE CLINICAL MANAGEMENT OF PSYCHIATRIC 
DISORDERS
MEDICATIONS USED TO TREAT SCHIZOPHRENIA AND OTHER PSYCHOTIC DISORDERS
Typical Antipsychotics Haloperidol (Haldol), haloperidol decanoate (Haldol Decanoate)
Loxapine (Loxitane) 
Thioridazine (Mellaril)
Thiothixene (Navane)
Fluphenazine (Prolixin), fluphenazine decanoate (Prolixin Decanoate)
Mesoridazine (Serentil)
Trifluoperazine (Stelazine)
Chlorpromazine (Thorazine)
Perphenazine (Trilafon)
Second-Generation 
AntipsychoticsClozapine (Clozaril)
Ziprasidone (Geodon)

Risperidone (Risperdal)
Quetiapine (Seroquel)
Olanzapine (Zyprexa)
Aripiprazole (Abilify)
Paliperidone (Invega)
Iloperidone (Fanapt)
Asenapine (Saphris)
Lurasidone (Latuda)
MEDICATIONS USED TO TREAT MOOD DISORDERS AND BIPOLAR AFFECTIVE DISORDERS
Mood Stabilizers Valproic acid (Depakene)
Divalproex sodium (Depakote) 
Lithium carbonate (Eskalith, Lithobid, Lithonate, Lithotabs)
Lamotrigine (Lamictal)
Carbamazepine (Tegretol)
Carbamazepine ER (Equetro)
Oxcarbazepine (Trileptal; off-label)
CONTINUED

116 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
MEDICATIONS USED TO TREAT MOOD DISORDERS, UNIPOLAR AFFECTIVE DISORDERS, 
AND DEPRESSIVE DISORDERS
Tricyclics (TCAs) Clomipramine (Anafranil)
Amoxapine (Asendin)
Amitriptyline (Elavil)
Desipramine (Norpramin)
Nortriptyline (Pamelor)
Doxepin (Sinequan)
Trimipramine (Surmontil)
Imipramine (Tofranil)
Protriptyline (Vivactil)
Serotonin Selective 
Reuptake Inhibitors 
(SSRIs)Citalopram (Celexa)
Fluvoxamine (Luvox)
Paroxetine (Paxil)
Paroxetine mesylate (Pexeva)
Fluoxetine (Prozac)
Sertraline (Zoloft)
Escitalopram (Lexapro)
Monoamine Oxidase 
Inhibitors (MAOIs)Phenelzine (Nardil)
Tranylcypromine sulfate (Parnate)
Selegiline transdermal (EMSAM)
SNRIs and Other Agents Trazodone (Desyrel)
Venlafaxine (Effexor)
Desvenlafaxine (Pristiq)
Mirtazapine (Remeron)
Nefazodone (Serzone)
Bupropion (Wellbutrin, Forfivo, Aplenzin)
Duloxetine (Cymbalta)
Vilazodone (Viibryd)
Vortioxetine (Brintellix)

Levomilnacipran (Fetzima)
MEDICATIONS USED TO TREAT ANXIETY DISORDERS
Benzodiazepines (BNZs) Lorazepam (Ativan)
Clonazepam (Klonopin)
Chlordiazepoxide (Librium)
Oxazepam (Serax)
Clorazepate (Tranxene)
Alprazolam (Xanax)
Anxiolytics Buspirone (BuSpar)
Other Agents Propranolol (Inderal)
Atenolol (Tenormin)

117 PharMacological PrinciPles
 XHigh abuse potential
 XUsed for research purposes only
 XNot legally available by prescription
 XExamples include heroin and marijuana
 ZSchedule II
 XMedicinal drugs in current use
 XHigh potential for abuse and dependency
 XWritten prescription only
 XNo telephone orders allowed
 XNo refills allowed on prescription
 XExamples include morphine sulfate, codeine, fentanyl, 
methadone, hydromorphone (Dilaudid), oxycodone (OxyContin, 
Percocet), hydrocodone (Vicodin and others), amphetamine salts, 
methylphenidate
 ZSchedule III
 XMedicinal drugs with less abuse potential than Schedule II drugs
 XStill greater potential for abuse than Schedule IV drugs
 XTelephone orders if followed by written prescription
 XPrescription must be renewed every 6 months
 XRefills limited to five
 XExamples include appetite suppressants, butalbital, testosterone, 
buprenorphine/naloxone
 ZSchedule IV

XPrescription must be renewed every 6 months
 XMedicinal drugs with less abuse potential than Schedule III drugsMEDICATIONS USED TO TREAT ATTENTION DEFICIT DISORDER AND ATTENTION DEFICIT 
HYPERACTIVITY DISORDER
Stimulants Amphetamine/dextroamphetamine (Adderall)
Dexmethylphenidate (Focalin)
Dextroamphetamine (Dexedrine)
Methylphenidate (Ritalin)
Methylphenidate (Concerta)
Lisdexamfetamine dimesylate (Vyvanse)
Other Agents Guanfacine (Intuniv)
Clonidine (Kapvay)
Atomoxetine (Strattera)
Antidepressants such as desipramine (Norpramin), venlafaxine 
(Effexor), and bupropion (Wellbutrin) are also used in the clinical 
management of ADHD.

118 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XExamples include dextropropoxyphene (Darvon), pentazocine 
(Talwin), benzodiazepines (such as alprazolam [Xanax], 
chlordiazepoxide [Librium], clonazepam [Klonopin], diazepam 
[Valium], clorazepate [Tranxene], and lorazepam [Ativan]), modafinil 
(Provigil), phenobarbital, zolpidem (Ambien), eszopiclone (Lunesta), 
temazepam (Restoril), armodafinil (Nuvigil)
 ZSchedule V
 XMedicinal drugs with the lowest abuse potential
 XHandled in manner similar to noncontrolled drugs
 XExamples include buprenorphine (Buprenex), cheratussin 
(Robitussin) with codeine, promethazine (Phenergan) with codeine, 
diphenoxylate/atropine (Lomotil)
Other Pharmacological Considerations
 XIt is vital to be aware of the teratogenic nature of many psychotropic agents. It is 
important to discuss the risks versus the benefits of medications during pregnancy.

XIt is vital to be aware of the teratogenic nature of many psychotropic agents. It is 
 ZPossible risks of psychotropic medications during pregnancy include:
 XProblems with appetite 
 XTransient agitation or sedation
 XPremature labor
 XDrug discontinuation symptoms
 XTeratogenic effects of certain psychotropics
 ZPossible risks of not taking psychotropic medications during pregnancy include
 XRecurrence of symptoms
 XAdverse effects on mother–infant bonding
 XPoor maternal self-care
 XFederal Drug Administration (FDA) pregnancy ratings for medications
 ZA: Controlled studies show no risk
 ZB: No evidence of risk in humans
 ZC: Risk cannot be ruled out
 ZD: Positive evidence of risk
 ZX: Absolutely contraindicated in pregnancy
 XTeratogenic risks of common psychiatric medications
 ZBenzodiazepines: Floppy baby syndrome, cleft palate
 ZCarbamazepine (Tegretol): Neural tube defects

XTeratogenic risks of common psychiatric medications
 ZLithium (Eskalith): Epstein anomaly
 ZDivalproex sodium (Depakote): Neural tube defects, specifically spina bifida, 
atrial septal defect, cleft palate, and possible long-term developmental deficits

119 PharMacological PrinciPles
 XSome common medications can induce depression or mania (see Table 7–3).
 XRemember that some medications can possibly  cause a false urinary drug screen 
result (see Table 7–4).
TABLE 7–3 .  
MEDICATIONS THAT INDUCE DEPRESSION OR MANIA
MEDICATIONS THAT INDUCE 
DEPRESSION MEDICATIONS THAT INDUCE MANIA
• Beta blockers
• Steroids
• Interferon
• Isotretinoin (Accutane)
• Some retroviral drugs
• Antineoplastic drugs
• Benzodiazepines
• Progesterone• Steroids
• Disulfiram (Antabuse)
• Isoniazid (INH)
• Antidepressants in persons with bipolar 
disorder
TABLE 7–4 .  
MEDICATIONS THAT CAN CAUSE DRUG SCREEN FALSE POSITIVE RESULTS
FALSE POSITIVE 
FOR DRUG RESPONSIBLE
Amphetamines • Stimulants (i.e., amphetamine/dextroamphetamine [Adderall], methyl -
phenidate [Ritalin])
• Bupropion (Wellbutrin)
• Fluoxetine (Prozac)
• Trazodone
• Ranitidine
• Nefazodone (Serzone) 
• Nasal decongestants
• Pseudoephedrine
Alcohol • Valium
Benzodiazepines • Sertraline (Zoloft)

Cocaine • Amoxicillin
• Most antibiotics
• NSAIDs
Heroin or 
morphine• Quinolones
• Rifampin
• Codeine
• Poppy seeds
Methadone or 
PCP• Over-the-counter cough medicine (such as Nyquil) Dextromethorphan

120 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
Ms. J., a 74-year-old client whom the PHMNP has been seeing for depression, presented at her 
appointment with complaints of tremors, diaphoresis, headache, and nausea over the past week. 
She is currently being prescribed amitriptyline (50 mg q.h.s.), which was increased at her last 
visit, and sertraline (100 mg q.d.). She denies depression but admits to increased confusion and 
memory problems. 
1. What is the biggest pharmacological concern with the combination of medication the 
client is being prescribed?
2. What would be the PHMNP’s plan of action?
3. What pharmacokinetics should the PHMNP keep in mind when treating older adults?
Ms. M. is a 30-year-old married Chinese woman who is in the midst of a first major depres -
sive episode. Ms. M. is employed as a grade school teacher but is currently on summer break.

sive episode. Ms. M. is employed as a grade school teacher but is currently on summer break. 
Despite participating in 6 months of cognitive behavioral therapy with an experienced therapist, 
her symptoms have not improved. Ms. M describes feeling sad and cries easily. She feels anx -
ious and has trouble shutting her thoughts off, particularly when trying to fall asleep at night. She 
feels tired upon awakening, despite getting 7 to 8 hours of sleep, and she has trouble getting out 
of bed. Her energy remains low throughout the day. She notes a worsening in her motivation as 
well. Her weight and appetite are unchanged. She denies suicidal ideation. After careful evalua -
tion, the PMHNP suggests a trial of fluoxetine and prescribes 20 mg p.o. q.a.m. with food. 
Ms. M. calls the PMHNP before her scheduled follow-up appointment, requesting to come in

Ms. M. calls the PMHNP before her scheduled follow-up appointment, requesting to come in 
sooner because she feels “worse. ” She describes more difficulty falling asleep, feels “revved 
up” much of the time, and is having mild nausea and headaches.
1. What are possible reasons for Ms. M. feeling “worse”?
2. What should the PMHNP suggest as the next intervention for Ms. M.?
CASE STUDY 3
Ms. S. is a 22-year-old woman who presents to the PMHNP with signs and symptoms of major 
depression. Ms. S. has a strong family history of major depression and both her mother and 
older sister have been treated with an antidepressant. Ms. S. herself has never been treated for 
depression before, and she says she is nervous about taking medication because she “gets side 
effects from everything. ” 
1. How should the PMHNP respond to Ms. S. ’s concerns about taking medication?

2. How should the PMHNP begin to think about medication management for Ms. S.?

121 PharMacological PrinciPles
Ms. S. is started on sertraline 50 mg. She calls within a few days of starting the drug and says 
that she is experiencing an upset stomach, headache, difficulty sleeping, and an overall feeling of 
being “edgy. ” 
3. What is the most likely reason for Ms. S. ’s reported side effects?
4. What is the most reasonable intervention by the PMHNP?
5. Other than potential side effects, what information should the PMHNP include in 
client teaching when starting a person on a new medication?

122 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
1. The SSRI is potentially increasing the concentration of the TCA to toxic levels.
2. Check the blood level of amitriptyline and decrease the dose; consider tapering Ms. 
J. off the TCA.
3. Higher body fat content, decreased gastric acid secretion, and decreased hepatic 
and renal functioning all predispose an older adult to the potential toxic effects of 
medications. Anticholinergic effects and orthostasis are particularly common and 
1. Fluoxetine may cause uncomfortable activation in some clients. In addition, Ms. M. 
appears to be having multiple side effects. Fluoxetine is metabolized primarily by cy -
tochrome P450 2D6. People who are deficient in 2D6 are considered “slow metabo -
lizers, ” and may need significantly lower doses of medications that are substrates

lizers, ” and may need significantly lower doses of medications that are substrates 
of 2D6. Finally, all clients started on antidepressants must be monitored closely for 
a switch from depression to hypomania or mixed mania. While Ms. M. ’s increase in 
insomnia and feeling “revved up” and “worse” are likely side effects from fluoxetine, 
this could signal beginning symptoms of a shift into a bipolar spectrum mood state.
2. Unless agitation is prominent, the first prudent intervention would be to lower the 
dose of the fluoxetine. If this is not helpful in diminishing side effects, prescribing a 
low dose of lorazepam or other benzodiazepine used as a “bridge” medication until 
the SSRI is effective may be prudent. If neither of these interventions proves helpful, 
the medication should be changed.
Case Study 3
1. The PMHNP should ask Ms. S. to tell her more about being anxious about taking

1. The PMHNP should ask Ms. S. to tell her more about being anxious about taking 
medicine, and ask about the medications her immediate family members are taking, 
whether or not the family members have had problems with side effects, and finally, 
whether any medication has been particularly helpful to her family members.
2. A genetic polymorphism screening test to determine gene variants may be reason -
able. Because mood and anxiety disorders have a genetic component, beginning 
with a medication that has been beneficial in the treatment of similar symptoms in a 
first-degree relative is a reasonable starting point of treatment.
3. The sertraline was started at too high a dose.
4. Lower the dose to 25 mg. Make sure Ms. S. is taking the medication with food. If 
not already doing so, switch the time of dosing to after breakfast.
5. During client teaching, the PMHNP should cover the usual course of treatment: typi -

cal time until benefit, typical therapeutic dosing, and expected length of treatment. 
The PMHNP should also emphasize that most side effects are transient and can 
usually be managed, such as by adjusting the dose.

123 PharMacological PrinciPles
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Boyd, M. A. (2002). Psychiatric nursing: Contemporary practice (2nd ed.).  Philadelphia, PA: 
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CHAPTER 8NONPHARMACOLOGICAL TREATMENT 
This chapter discusses nonpharmacological interventions such as individual psychotherapies, 
group therapy, family therapies, and complementary and alternative therapies. Because medi -
cations alone do not treat a person’s environmental or interpersonal stressors and his or her 
responses to these stressors, an integrated approach is the most beneficial in treating mental 
illnesses. Although some people seek counseling for self-discovery, the most common issues 
for individual therapy are:
 XLosses
 XInterpersonal conflicts
 XSymptomatic presentations such as panic, phobias, and negativity
 XUnfulfilled expectations at life transitions
 XCharacterological issues such as narcissism or aggressiveness
Confidentiality may be broken when there is increased potential for self-harm or harm to others; 
abuse of a child, older adult, or person with disabilities; when the therapist determines that the

abuse of a child, older adult, or person with disabilities; when the therapist determines that the 
person needs hospitalization; and when clients request that their information be released to a 
third party.
INDIVIDUAL THERAPY
 XPsychoanalytic Therapy 
 ZOriginated by Sigmund Freud (1856–1939), who believed that behavior is 
determined by unconscious motivations and instinctual drives (see also 
Chapter 3)
 ZPromotes change by the development of greater insight and awareness of 
maladaptive defenses
 ZAttends to past developmental and psychodynamic factors, which shape present 
behaviors
 XCognitive Therapy
 ZOriginated by Aaron Beck (born 1921)

126 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZPurports that external events do not cause anxiety or maladaptive responses
 ZStates that a person’s expectations, perceptions, and interpretations of events 
cause anxiety
 ZAllows clients to view reality more clearly through an examination of their 
central distorted cognitions
 ZGoal is to change clients’ irrational beliefs, faulty conceptions, and negative 
cognitive distortions
 XBehavioral Therapy
 ZOriginated by Arnold Lazarus (born 1932)
 ZFocuses on changing maladaptive behaviors by participating in active behavioral 
techniques such as exposure, relaxation, problem-solving, and role-playing
 XDialectical Behavioral Therapy
 ZOriginated by Marsha Linehan (born 1943)
 ZCommonly used with people with borderline personality disorder
 ZFocuses on emotional regulation, tolerance for distress, self-management skills, 
interpersonal effectiveness, and mindfulness, with an emphasis on treating

ZFocuses on emotional regulation, tolerance for distress, self-management skills, 
interpersonal effectiveness, and mindfulness, with an emphasis on treating 
therapy-interfering behaviors
 ZGoals
 XDecrease suicidal behaviors
 XDecrease therapy-interfering behaviors
 XDecrease emotional reactivity
 XDecrease self-invalidation
 XDecrease crisis-generating behaviors
 XDecrease passivity
 XIncrease realistic decision-making
 XIncrease accurate communication of emotions and competencies
 XExistential Therapy
 ZOriginated by Viktor Frankl (1905–1997)
 ZA philosophical approach in which reflection on life and self-confrontation is 
encouraged
 ZEmphasizes accepting freedom and making responsible choices
 ZStates that a basic dimension of humans includes finding meaning and purpose 
in life—“Why am I here? What is my purpose?”
 ZGoals are to live authentically and to focus on the present and on personal 
responsibility
 XHumanistic Therapy
 ZOriginated by Carl Rogers (1902–1987)

 ZAlso known as person-centered therapy

127 nonPharMacological treatMent 
 ZConcepts include self-directed growth and self-actualization; people are born 
with the capacity to direct themselves toward self-actualization
 ZEach person has the potential to actualize and find meaning.
 XInterpersonal Therapy 
 ZOriginated by Gerald L. Klerman (1928–1992) and Myrna M. Weissman (born 
1940)
 ZEvidence-based therapy with focus on interpersonal issues that are creating 
distress
 ZTime-limited, active, focused on the present and on interpersonal distress 
 ZDeveloped to treat aspects of depression and is effective for adults and 
adolescents
 ZHas been applied to treat interpersonal distress related to other disorders, 
including bipolar, substance use, and eating disorders
 XEye Movement Desensitization and Reprocessing (EMDR)
 ZOriginated by Francine Shapiro (born 1948)
 ZA form of behavioral and exposure therapy
 ZInvolves the use of bilateral stimulation—moving the eyes back and forth,

ZOriginated by Francine Shapiro (born 1948)
 ZInvolves the use of bilateral stimulation—moving the eyes back and forth, 
alternating tapping on hand or knee, or sounds in ears
 ZMost commonly used in post-traumatic stress disorder
 ZGoal is to achieve adaptive resolution
 ZDesensitization phase:  The client visualizes the trauma, verbalizes the negative 
thoughts or maladaptive beliefs, and remains attentive to physical sensations. 
This process occurs for a limited time while the client maintains rhythmic eye 
movements. He or she is then instructed to block out negative thoughts; to 
breathe deeply; and then to verbalize what he or she is thinking, feeling, or 
imagining.
 ZInstallation phase:  The client installs and increases the strength of the positive 
thought that he or she has declared as a replacement of the original negative 
thought.
 ZBody scan:  The client visualizes the trauma along with the positive thought and

thought.
 ZBody scan:  The client visualizes the trauma along with the positive thought and 
then scans his or her body mentally to identify any tension within. 
GROUP THERAPY
 XBenefits
 ZIncreases insight about oneself
 ZIncreases social skills
 ZIs cost-effective
 ZDevelops sense of community

128 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XIrvin Yalom (born 1931) was the first person to put a theoretical perspective on group 
work and identified 10 therapeutic factors that differentiate group therapy from indi -
vidual therapy.
1. Instillation of hope: Participants develop hope for creating a different life. 
Members are at different levels of growth; thus, they gain hope from others that 
change is possible.
2. Universality: Participants discover that others have similar problems, thoughts, 
or feelings and that they are not alone.
3. Altruism: This results from sharing oneself with another and helping another.
4. Increased development of socialization skills: New social skills are learned, and 
maladaptive social behaviors are corrected. The group can provide a “natural 
laboratory. ”
5. Imitative behaviors: Participants are able to increase their skills by imitating the 
behaviors of others.

6. Interpersonal learning: Interacting with others increases adaptive interpersonal 
relationships.
7. Group cohesiveness: Participants develop an attraction to the group and other 
members as well as a sense of belonging.
8. Catharsis: Participants experience catharsis as they openly express their 
feelings, which were previously suppressed.
9. Existential factors: Groups enable participants to deal with the meaning of their 
own existence.
10. Corrective refocusing: Participants reexperience family conflicts in the group, 
which allows them to recognize and change behaviors that may be problematic.
 XGroup phases (Tuckman, 1965)
 ZPregroup phase : The leader considers the direction and framework of the group. 
 XPurpose
 XGoals
 XMembership criteria
 XMembership size
 XPregroup interview

ZPregroup phase : The leader considers the direction and framework of the group. 
 XPurpose
 XGoals
 ZForming phase : Members are concerned about self-disclosure and being 
rejected. Goals and expectations are identified, and boundaries are established. 
The development of trust and rapport is very important.
 ZStorming phase : Members are resistant and may begin to use testing behaviors. 
Issues related to inclusion, control, and affection begin to surface. Leaders’ 
tasks are to allow expression of both positive and negative feelings, assist the 
group in understanding the underlying conflict, and examine nonproductive 

129 nonPharMacological treatMent 
 ZNorming phase : Resistance to the group is overcome by members. A 
strong attraction to the group and others emerges. Open and spontaneous 
communication occurs, and the group norms are established.
 ZPerforming phase: The group’s work becomes more focused. Creative problem-
solving and solutions begin to emerge. Experiential learning takes place. Group 
energy is directed toward completion of goals. 
 ZAdjourning phase: Preparation is made to end the group. (Remember that the 
work of termination begins during the first stage of the group.) Both members 
and leaders express their feelings about each other and termination. A 
discussion and overview of what has been learned, as well as what issues still 
need to be worked on, takes place. 
 XReminiscence Therapy 
 ZCharacterized by a progressive return of memories of past experiences
 ZUsed with older adults
 ZEnables participants to search for meaning in their lives and strive for some

ZCharacterized by a progressive return of memories of past experiences
 ZEnables participants to search for meaning in their lives and strive for some 
resolution of past interpersonal and intrapsychic conflicts
FAMILY THERAPIES
 XFamily system concepts
 ZA system is any unit structured on feedback—such as the family.
 ZThe process by which all family members operate together is referred to as the 
family system.
 ZFamily systems theory is based on the idea that one could not understand any 
family member (part) without understanding how all family members operate 
together (system).
 ZThe family system operates based on a set of rules that may be overt or covert.
 ZBoundaries: Barriers that protect and enhance the functional integrity of 
families, individuals, and subsystems. System boundaries can be physical or 
psychological.
 ZTypes of boundaries
 XClearly defined boundaries: Maintain person’s separateness while 
emphasizing belongingness

 XRigid or inflexible boundaries: May lead to distant relationships and to 
disengagement
 XDiffuse boundaries: Blurred and indistinct boundaries; lead to enmeshment
 ZCircular causality: An ongoing feedback loop; a series of actions and 
reactions that maintain a problem. Individuals and emotional problems are 
best understood within the context of relationships and through assessing 
interactions within an entire family.
 ZFamily homeostasis: Tendency of families to resist change and to maintain a 
steady state

130 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZMorphogenesis: A family’s tendency to adapt to change when changes are 
necessary
 ZMorphostasis: A family’s tendency to remain stable in the midst of change
 XFamily Systems Therapy
 ZOriginated by Murray Bowen (1913–1990), who believed that a person’s 
problematic behavior may serve a function or purpose for the family or be a 
symptom of dysfunctional patterns
 ZFocus is on chronic anxiety within families
 ZTreatment goals are to increase the family’s awareness of each member’s 
function within the family and to increase levels of self-differentiation  (the level 
at which one’s sense of self-worth is not dependent on external relationships, 
circumstances, or occurrences).
 XTriangles: Dyads that form triads to decrease stress; the lower the level of 
family adaptation, the more likely a triangle will develop
 XNuclear family emotional system: Level of differentiation of the parents is

 XNuclear family emotional system: Level of differentiation of the parents is 
usually equal to the level of differentiation for the entire family
 XMultigenerational transmission process: Dysfunction present over several 
generations
 XFamily projection process: Parents transmitting their own level of 
differentiation on the most susceptible child
 XEmotional cutoffs: Attempting to break contact with the family of origin
 XSibling position: Influences interactions and personality characteristics
 XStructural Family Therapy
 ZOriginated by Salvador Minuchin (1913–1990), who placed emphasis on how, 
when, and to whom family members relate in order to understand and then 
change the family’s structure
 ZA person’s symptoms are rooted in the context of family transaction patterns. 
The symptom is a function of the health of the whole family and is maintained 
by structural problems in the system.

ZA person’s symptoms are rooted in the context of family transaction patterns. 
 ZThe main treatment goal is to produce a structural change in the family 
organization to more effectively manage problems—changing transactional 
patterns and family structure.
 XFamily structure: An invisible set of functional demands that organize the 
way members interact with each other, made up of subsystems (e.g., 
marital, parental, sibling), coalitions (e.g., two members joining forces 
against a third member), and boundaries
 XStructural mapping  (genogram): Mapping relationships using symbols to 
represent overinvolvement, conflict, coalitions, and so forth
 XHierarchies: Distribution of power
 XExperiential Therapy
 ZOriginated by Virginia Satir (1916–1988) 
 ZBehavior is determined by personal experience and not by external reality.

131 nonPharMacological treatMent 
 ZFocus is on being authentic, on freedom of choice, on human validation, and on 
experiencing the moment
 ZTreatment goals are to develop authentic, nurturing communication and 
increased self-worth of each family member; overall goal is growth rather than 
symptom reduction alone.
 ZIt does not focus on particular techniques.
 XStrategic Therapy
 ZOriginated by Jay Haley (1923–2007)
 ZSymptoms are viewed as metaphors and reflect problems in the hierarchal 
structure. Symptoms are a way to communicate metaphorically within a family.
 ZTreatment goal is to help family members behave in ways that will not 
perpetuate the problem behavior.
 ZInterventions are problem-focused. Strategic therapy is more symptom-focused 
than structural therapy. 
 ZStrategic family therapists are concerned mainly with those techniques that 
change the sequence of interactions that is maintaining the problem.

 ZTechniques are straightforward directives, paradoxical directives, and reframing 
belief systems.
 XStraightforward directives: Tasks that are designed in expectation of the 
family member’s compliance
 XParadoxical directives: A negative task that is assigned when family 
members are resistant to change and the member is expected to be 
noncompliant (use this technique with caution)
 XReframing belief systems: Problematic behaviors are relabeled to have 
more positive meaning (e.g., jealousy  reframed to caring )
 XSolution-Focused Therapy
 ZOriginated by Steve deShazer (1940–2005), Bill O’Hanlon (born 1952), and Insoo 
Berg (1934–2007)
 ZFocus is to rework for the present situation solutions that have worked 
previously
 ZTreatment goal is effective resolution of problems through cognitive problem-

solving and use of personal resources and strengths.
 ZTechniques include the use of miracle questions, exception-finding questions, 
and scaling questions.
 XMiracle questions: “If a miracle were to happen tonight while you were 
asleep, and tomorrow morning you awoke to find that the problem no 
longer existed, what would be different?” “How would you know the 
miracle took place?” “How would others know?”
 XException-finding questions: Directing clients to a time in their lives when 
the problem did not exist, which helps them move toward solutions by 
assisting them in searching for any exceptions to the pattern. “Was there a 
time when the problem did not occur?”

132 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XScaling questions: “On a scale of 1–10, with 10 being very anxious and 
depressed, how would you rate how you are feeling now?” This is useful 
for highlighting small increments of change.
COMPLEMENTARY AND ALTERNATIVE THERAPIES (CATS)
 XCATs deal with the connection between the mind and the body and are viewed as 
holistic health care (dealing with the biopsychosocial and spiritual components of the 
person). 
 ZComplementary therapies: Used in addition to traditional medical practices
 ZAlternative therapies: Used in place of traditional medical practices
 ZIntegrative therapies: Recent term used to describe the use of traditional 
complementary therapies
 XWhy people use CATs
 ZDesire for more control over decision-making
 ZDecreased insurance coverage for traditional medical therapies, therefore 
making the use of CATs cheaper
 ZPreference for natural rather than synthetic medications

ZDecreased insurance coverage for traditional medical therapies, therefore 
 ZIncreased costs of prescriptions and services
 ZFailure of conventional medications
 XMind–body interventions 
 ZGuided imagery 
 ZMeditation 
 ZYoga
 ZBiofeedback
 XBiologically based therapies 
 ZHerbal products
 ZVitamins
 ZSupplements 
 ZAromatherapy 
 XManipulative and body-based therapies 
 ZAcupressure and acupuncture
 ZMassage
 ZReflexology
 XAcupressure and Acupuncture
 ZBased on the basic tenet of Chinese medicine that vital energy ( chi) flows 
along specific pathways that have many points of access and that manipulating 
these points, by either hands or needles, corrects imbalances by stimulating or 
removing blockages to energy flow

133 nonPharMacological treatMent 
 ZThought to produce effects by regulating the nervous system and aiding the 
activity of endorphins and immune system cells at different sites in the body
 ZAlso thought to alter brain chemistry by changing the release of neurohormones 
and neurotransmitters
 XBiofeedback
 ZA process providing a person with visual or auditory information about the 
autonomic physiologic functions of his or her body, such as blood pressure, 
muscle tension, and brain wave activity
 ZThe person learns to consciously control these processes, which were 
previously regarded as involuntary.
 ZUses
 XStress-related symptoms (e.g., anxiety)
 XPain
 XInsomnia
 XNeuromuscular problems (e.g., migraines, muscular tension, tension 
headaches, Raynaud’s disease, urinary incontinence)
 XNeurobehavioral disorders
 XEnhancement of healing
 XAthletic and work performance
 ZDesired outcome
 XPositive change in baseline measures
 XDemonstrated skill at self-regulation

XNeurobehavioral disorders
 XImprovement in symptoms
 XImproved use of skills in daily life
 XReduction of muscle bracing
 XIncreased sense of self-efficacy
 XAromatherapy
 ZTherapeutic use of plants or oils to obtain many therapeutic effects, such as 
analgesic, psychological, and antimicrobial benefits
 ZIn psychiatry, olfactory stimulation used to elicit feelings or memories during 
psychotherapy
 XHerbal Products and Supplements
 ZPractice of herbal medicine originated in China and is the oldest system of 
medicine
 ZRelies on plants to cure illnesses and maintain health
 ZSimilar to prescription medications, many plants contain active compounds that 
produce physiological effects
 ZFood and Drug Administration (FDA) approval is not required; thus no uniform 
standards ensure quality control or potency

134 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZCommon supplements and interactions include:
 XOmega-3 fatty acids
 ZUsed for attention deficit hyperactivity disorder, dyslexia, cognitive 
impairment, dementia, cardiovascular disease, asthma, lupus, and 
rheumatoid arthritis
 ZInteracts with warfarin (Coumadin), increasing anticoagulant effect 
(people cautioned to stop using before surgery) 
 XSam-e
 ZUsed for depression, osteoarthritis, and liver disease
 ZMay cause hypomania, hyperactive muscle movements, and possible 
serotonin syndrome
 XTryptophan
 ZUsed for depression, obesity, insomnia, headaches, and fibromyalgia
 ZFound in high concentrations in turkey
 ZIncreased risk of serotonin syndrome with use of selective serotonin 
reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), 
and St. John’s wort
 XVitamin E
 ZUsed for enhancing the immune system and protecting cells against 
effects of free radicals

 XVitamin E
 ZUsed for neurological disorders, diabetes, and premenstrual syndrome
 ZInteracts with warfarin, increasing anticoagulant effect; antiplatelet 
drugs; and statins, increasing additive effect and risk of rhabdomyolysis 
 XMelatonin
 ZUsed for insomnia, jet lag, shift work, and cancer
 ZSets timing of circadian rhythms and regulates seasonal responses
 ZInteracts with aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), 
beta blockers, corticosteroids, valerian, kava kava, and alcohol
 ZCan inhibit ovulation in large doses
 XFish oil
 ZUsed for bipolar disorder, hypertension, lowering triglycerides, and 
decreasing blood clotting
 ZInteracts with warfarin, aspirin, NSAIDs, garlic, and ginkgo 
 ZMay alter glucose regulation

ZUsed for bipolar disorder, hypertension, lowering triglycerides, and 
 ZMost herbals are contraindicated during pregnancy and, because they are 
secreted in breast milk, during lactation.
 ZCommon herbals with psychoactive effects include:
 XBlack cohosh: Menopausal symptoms, premenstrual syndrome, 
dysmenorrhea

135 nonPharMacological treatMent 
 XBelladonna: Anxiety
 XCatnip: Sedation
 XChamomile: Sedation, anxiety
 XGinkgo: Delirium, dementia, sexual dysfunction caused by SSRIs
 XGinseng: Depression, fatigue
 XValerian: Sedation
 XMassage
 ZBelieved to increase blood circulation, improve lymph flow, improve 
musculoskeletal tone, and have a relaxing effect on the mind
 XMeditation
 ZConsciously directing one’s attention to alter one’s state of consciousness
 ZProduces physiological effects such as decreased heart rate, blood pressure, 
and respiratory rate; decreased anxiety; and increased alpha brain waves
 XReflexology
 ZStimulates the body’s natural healing power through massaging the feet, hands, 
and ears
 ZAlleviates tension by cleaning crystalline deposits under the skin that may 
interfere with the natural flow of the body’s energy
 ZBased on the mapping of body parts on the soles and sides of the feet, hands, 
and ears

and ears 
 ZTreats disorders related to the represented body parts by application of pressure
 ZUsed for back pain, migraines, infertility, sleep disorders, digestive disorders, 
and stress-related conditions
 XMacrobiotics
 ZFoods classified as yin (cold and wet) and yang (hot and dry)
 ZGoal is to keep the dietary yin and yang in balance in attempt to live in harmony 
with nature
 XYoga
 ZOriginated in Indian religious practices
 ZCombines mind and body connection 
 ZUses breathing, physical movements, and meditation

136 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
CASE STUDY
You are a psychiatric–mental health nurse practitioner working with Jill, who has depression. In 
session Jill states, “Nothing good ever happens to me. I’m just a failure and should accept that 
people at work think I’m inadequate to do my job. ”
1. What therapeutic approach would be most helpful in working with Jill? 
2. Specifically, what cognitive and behavioral techniques would be helpful for Jill?
3. Which scales would be helpful to use in assessing her depression and negative 
thoughts? 
4. If you chose a CBT approach to work with Jill, what is the three-question technique? 
5. What types of distortions does Jill have and, as her therapist, how would you begin 
to address her distortions?

137 nonPharMacological treatMent 
1. The therapy that would be most helpful for Jill is cognitive behavioral therapy.
2. In working with Jill, having her complete a thought record to identify situations that 
lead to automatic thoughts, emotions, and her responses would be helpful.
3. Scales that would be useful to track Jill’s progress in therapy include: PHQ-9, Beck 
Depression Scale, and Schema questionnaire.
4. The three-question technique when using CBT involves Socratic questioning. For 
example, asking the following: (1) Evidence for her negative belief; (2) How else can 
she interpret the situation?; (3) If it is true, what are the implications?
5. The types of distortions Jill has are all-or-nothing thinking and overgeneralization. A 
technique that would be helpful to address Jill’s distortion are using a scale will help 
her put the distortions on a continuum to help her respond differently to low scale 
items.

items.
Corey, M., Corey, G., & Corey, C. (2010). Groups: Process and practice  (8th ed.). Pacific Grove, 
CA: Brooks/Cole.
Goldenberg, I., & Goldenberg, H. (2013). Family therapy: An overview (8th ed.). Boston, MA: 
Brooks/Cole Cengage Learning. 
Scharf, R. (2013). Theories of psychotherapy and counseling (5th ed.). Boston, MA: Brooks/Cole 
Cengage Learning. 
Snyder, M., & Lindquist, R. (Eds.). (2010). Complementary & alternative therapies in nursing (6th 
ed.). New York, NY: Springer. 
Tusaie, K., & Fitzpatrick, J. (2013). Advanced practice psychiatric nursing integrating psychother -

apy, psychopharmacology, and complementary and alternative approaches. New York, NY: 
Springer Publishing Company. 
Weisz, J. & Kazdin, A. (2010). Evidence-based psychotherapies for children and adolescents (2nd 
ed.). New York, NY: Guilford Press.
Wheeler, K. (2014). Psychotherapy for the advanced practice psychiatric nurse (2nd ed.). New 
York, NY: Springer Publishing Company. 
Yalom, I. (2005). Theory and practice of group psychotherapy  (5th ed.). New York, NY: Basic 
Books.

CHAPTER 9DEPRESSIVE DISORDERS AND BIPOLAR 
DISORDERS
This chapter reviews the mood disorders and evidence-based practice guidelines that  
psychiaric–mental health nurse practitioners (PMHNPs) use in treating clients who have these 
disorders. As a childhood disorder, Disruptive Mood Dysregulation Disorder will be discussed in 
Chapter 15. 
Mood disorders are the most common of all psychiatric illnesses. 
It has become increasingly common for mood disorders to be treated in primary care settings, 
and often clients first present in such settings because of the high degree of somatic symptom -
atology that accompanies these disorders. 
Sadness is a common, normal human emotion. PMHNPs caring for clients who present for 
evaluation of depression must distinguish between normal levels of sadness and pathological 
levels that are symptomatic of an underlying brain-based illness called major depression. Major

levels that are symptomatic of an underlying brain-based illness called major depression. Major 
depression requires treatment and generally will not fully abate without therapeutic intervention. 
Untreated, major depression predisposes people to other serious health problems, so pathologi -
cal levels of depression should not go untreated.
SADNESS AS A COMMON EMOTIONAL STATE
 XSadness, one of the most common human emotions, exists on a continuum ranging 
from the absence of depression at one end to pathological levels that produce sig -
nificant symptoms of a psychiatric disorder called major depression at the other.
 XCultural differences affect behavioral manifestations of depression.
 XMild depression can be a healthy reaction to life stressors that motivates a person to 
deal with events and emotions 
 ZSadness can be pathological if:

XMild depression can be a healthy reaction to life stressors that motivates a person to 
 XIt is disproportionate to events and sustained over a significant time period;
 XIt significantly impairs normal social functioning (e.g., occupational, social, 
school, relational functioning);

140  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XIt significantly impairs normal somatic functioning (e.g., loss of appetite, 
altered sleep, altered self-care activities, altered sexual functioning); or
 XIt is apparently unrelated to any identifiable event or situation in a person’s 
life.
MAJOR DEPRESSIVE DISORDER (MDD)
Description
 XOne of the most common psychiatric disorders; the primary unipolar affective 
disorder
 XA complex brain-based illness with a primary characteristic of a persistent distur -
bance in mood
 XAn excessive or distorted degree of sadness that manifests with behavioral, affec -
tive, cognitive, and somatic symptoms
 XMay have a known precipitating event, situation, or concern but often occurs without 
any precipitating stressor identified
 XSignificantly interferes with daily functioning and goal attainment
 XHas complex genetic, biochemical, and environmental etiological factors
Etiology

Etiology
 XMultiple theories of the etiology of depression fall into two categories: psychological 
and neurobiological.
 XPsychodynamic theories
 ZObject Loss Theory (Ronald Fairbairn, D. W. Winnicott, Harry Guntrip; Gilbert, 
2006)
 XThis theory assumes that early psychological developmental issues lay the 
foundation for depressive responses in later life; that the accomplishment 
of the first stage of development in which the child is able to form 
relationships is normal; and that, during second stage of development, 
the child experiences traumatic separation from significant objects of 
attachment (usually a maternal object).
 XLoss may be related to maternal death, illness, or emotional lack of 
availability and is unexpected and overwhelming.

 XDepth of loss produces constellation of responses dominated by separation 
anxiety, grief, mourning, and despair.
 XThis critical object loss event predisposes the child to respond in similar 
ways to any future losses or significant separation.
 ZAggression-Turned-Inward Theory ( Sigmund Freud)
of the first stage of development in which the child is able to form

141 dePressive disorders and BiPolar disorders
relationships is normal; and that, during second stage of development, the 
child experiences the loss of the significant mothering person.
 XThe loss can be a real or imagined and is unexpected and overwhelming.
 XThe loss may be related to maternal death, illness, or emotional lack of 
availability or to the birth of a new sibling and the child’s perception of 
losing undivided, individualized attention from the mother. The child’s initial 
reaction is anger; however, the child feels unsafe to express this anger 
openly and directly. This may relate to the child’s fearing further loss if he or 
she responds with anger or his or her subjective perception that anger is 
unacceptable.
 XThe child uses defense mechanisms to deal with conflict created by desire 
for the love object but co-occurring with anger for the love object.
 XInstead of anger being expressed outward at the maternal figure, it turns

 XInstead of anger being expressed outward at the maternal figure, it turns 
inward because it is more acceptable and safer to be angry at oneself than 
at the mother.
 XAnger at oneself is rationalized as the child assumes that loss of the 
mother was related to something bad that he or she did rather than to the 
caregiver’s actions.
 XExcessive guilt becomes a manifestation of the process of dealing with 
aggression experienced with the loss of the mother’s attention.
 XA similar emotional reaction (such as low self-esteem, excessive guilt, 
inability to cope with anger, self-destructive impulses) occurs as an adult 
whenever a loss is experienced.
 ZCognitive Theory ( Aaron Beck, 1979)
 XThis theory represents a cognitive diathesis–stress model in which 
developmental experiences sensitize a person to respond to stressful life 
events in a depressed manner.

XThis theory represents a cognitive diathesis–stress model in which 
events in a depressed manner. 
 XCognitive theory assumes that people with a tendency to be depressed 
think about the world differently than nondepressed people and that 
depressed people are more negative and believe that bad things are going 
to happen to them because of their own personal shortcomings and 
inadequacies.
 XThis thinking promotes low self-esteem and beliefs that the person 
deserves to have bad things happen to him or her and promotes 
pessimistic perceptions about the world at large and about his or her future, 
as well as globalizes the negativity to all events, situations, and people in 
his or her life.
 XWhen confronted by stressful events, these people tend to appraise 
them and the potential consequences in a negative, hopeless manner and 
therefore are more depressed than people with different cognitive styles.

 ZLearned Helplessness-Hopelessness Theory ( Martin Seligman)
 XThis theory is a modified aspect of cognitive theory, which assumes that 
a person becomes depressed due to perceptions of lack of control over

142  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
life events and experiences. These perceptions are learned over time, 
especially as the person perceives others seeing him or her as inadequate.
 XPerceptions of lack of control lead to the person not adapting or coping. 
 XThe person’s behavior becomes passive and nonreactive because of self-
perceptions of personal characteristics of being helpless, hopeless, and 
powerless. 
 XBiological theories
 ZGenetic predisposition
 XThere is a clear genetic predisposition to depressive disorders; one 
assumption is a polygenic s ingle nucleotide polymorphism (SNP)  disorder.
 XHaving a depressed parent is the single strongest predictor of depression. 
Children of depressed parents are three times more likely to experience 
MDD in their lifetimes than the general population and have a 40% chance 
of having a depressive episode before age 18 years.

 XThe earlier the age of onset for MDD and the more severe the symptoms, 
the more likely it is that a person has a strong genetic predisposition for 
depression.
 ZEndocrine dysfunction
 XMDD has symptoms that suggest endocrine abnormalities as part of the 
etiologic picture.
 XNeurovegetative symptoms commonly seen in MDD (e.g., sleep 
disturbances, appetite disturbances, libido disturbances, lethargy, 
anhedonia) are related to functions of the hypothalamus and pituitary and 
the hormones they secrete. 
 XA high incidence of postpartum mood disturbances is suggestive of 
endocrine dysfunction.
 XDysphoria is often triggered by changes in levels of sex steroids that occur 
during the menstrual cycle. 
 XDeregulation of the hypothalamic–pituitary–adrenal axis  (HPA, which

XDysphoria is often triggered by changes in levels of sex steroids that occur 
 XDeregulation of the hypothalamic–pituitary–adrenal axis  (HPA, which 
controls the physiological response to stress and consists of interconnected 
feedback pathways between the hypothalamus, pituitary gland, and adrenal 
glands) is another theory of an endocrine basis for MDD. In this theory, 
MDD is presumed to be, at least in part, a result of an abnormal stress 
response related to HPA dysregulation.
 ZIn response to stress, the hypothalamus releases corticotropin-
releasing hormone (CRH), which then stimulates the pituitary to 
release adrenocorticotropic hormone (ACTH). This then stimulates the 
adrenals to release cortisol.
 ZHyperactivity of the HPA has been shown to be present in people with 
MDD, as have possible elevated cortisol levels.
 ZOver time, elevated cortisol levels damage the central nervous system

ZHyperactivity of the HPA has been shown to be present in people with 
 ZOver time, elevated cortisol levels damage the central nervous system 
(CNS) by altering neurotransmission and electrical signal conduction.

143 dePressive disorders and BiPolar disorders
 ZEvidence supports that cortisol over time can cause changes in size 
and function of brain tissue. 
 ZEvidence supports that major depression may be associated with 
proinflammatory cytokine activation
 XHPA dysregulation is the rationale and scientific basis for the 
dexamethasone suppression test (DST), a screening test for depression, 
which has proved to be too nonspecific and is not commonly used in clinical 
practice. 
 ZAbnormalities of neurotransmitter function
 XAll of the following are possible neurotransmitter function abnormalities 
causing depression:
 ZDysregulation of one or more biogenic amine neurotransmitters: 
dopamine, serotonin, norepinephrine
 ZLow levels of endogenous catecholamines in specific areas of the brain
 ZSerotonin levels were shown to be low in postmortem studies on 
people who commit suicide and in people with MDD.
 ZLow level of precursor tryptophan
 ZLow levels of serotonin metabolite 5HTIAA

ZSerotonin levels were shown to be low in postmortem studies on 
 ZReceptor sensitivity for neurotransmitters set unusually high in specific 
areas of the brain
 XA stronger neurotransmitter receptor cascade is required to induce 
neuronal activity.
 ZLow density of receptor sites in specific areas of the brain
 ZHypometabolism in specific areas of the brain regulating mood, 
appetite, and cognition 
 ZComplexity of brain functions implies that the etiology of complex 
disorders such as MDD involves the relative balance of available 
neurotransmitters and not just a low level of one neurotransmitter.
 ZStructural brain changes
 XNeuroimaging has shown consistent abnormalities in certain structures of 
the brain in people with chronic and severe depression.
 ZHypovolemic hippocampus
 ZHypovolemic prefrontal cortex–limbic striatal regions

 XMDD is a common comorbidity in people who have experienced brain 
damage, including damage from stroke and trauma.
 ZChronobiological theory
 XDesynchronization of circadian rhythms produces the symptom 
constellation collectively called MDD.
 XCircadian rhythms control biological processes that are frequent problems 
in depressed persons.
 ZInterrupted sleep–rest cycle

144  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZREM abnormalities
 ZFrequent waking
 ZIntensified dreaming
 ZDiurnal variations to circadian-related behaviors
 ZDecreased arousal and energy levels
 ZDecreased activity patterns
 ZIncreased cortisol secretion
 ZIncreased emotional reactivity
Incidence and Demographics
 XMDD is a common illness, with approximately 5% of the U.S. population ages 18 
and older in a given year, or 15 million U.S. adults, having the disorder.
 XMDD is the leading cause of disability in the United States and is the most common 
psychiatric illness seen in primary care practices; however, only 50% of people with 
MDD ever receive treatment.
 XMDD can occur at any age; however, the average age of onset is mid-20s.
 XDuring reproductive years, the lifetime risk for MDD varies with gender—25% for 
women, 12% for men; the risk is equal for the genders before puberty and after 
menopause.

XDuring reproductive years, the lifetime risk for MDD varies with gender—25% for 
 XMDD is a greater source of morbidity for women than any other illness.
 XMDD is associated with high mortality; 15% of people with MDD will die by suicide. 
People with MDD have a 4-times-greater risk of premature death than the normal 
control population.
 XThe disease course is variable and can involve isolated episodes separated by many 
years, clusters of episodes, or a severe episode with some remission of symptoms 
but with chronic symptoms persisting over time.
 XIf left untreated, an episode of MDD usually lasts four months or longer.
 XMDD tends to be a chronic, recurrent illness.
 XOne year after initial diagnosis of MDD, symptoms often persist.
 Z40% of clients have significant enough symptoms to meet full Diagnostic 
and Statistical Manual of Mental Disorders (DSM-5; American Psychiatric

Z40% of clients have significant enough symptoms to meet full Diagnostic 
and Statistical Manual of Mental Disorders (DSM-5; American Psychiatric 
Association, 2013) criteria for MDD.
 Z20% of clients do not meet full DSM-5  criteria but still have a significant 
symptom level that impairs functioning.
 Z40% have no symptoms.
 XThe number of prior episodes predict the likelihood of future episodes (Judd et. al., 
2000).
 XPeople with first episode of major depression have approximately a 60% risk of a 
second episode.

145 dePressive disorders and BiPolar disorders
 ZPeople who experience a second episode have approximately a 70% risk of a 
third episode.
 ZPeople who experience a third episode have approximately a 90% risk of a 
fourth episode.
 XGenetic loading
 ZFamily history, especially a first-degree relative
 XPrior episode of MDD
 XFemale gender
 XPostpartum period
 XMedical comorbidity
 XSingle marital status
 XSignificant environmental stressors, especially multiple losses
Prevention and Screening
 XProvide at-risk family education.
 XProvide community education to help reduce stigma, to convey signs and symptoms 
of illness, and to emphasize the treatment potential for control of symptoms.
 XProvide significant screening efforts to help recognize, intervene, and initiate treat -
ment early.
 XProvide healthcare provider education to facilitate early recognition and effective 
 XSignificant and protracted prodromal symptom period usually noted before full onset

 XSignificant and protracted prodromal symptom period usually noted before full onset 
of illness.
Assessment
Conduct baseline screening with a tool such as the Patient Health Questionnaire 9 (PHQ-9) or 
Edinburgh Postnatal Depression Scale (EPDS) (Siu & U.S. Preventive Task Force, 2016). Or the 
Beck Depression Inventory (BDI), or Hamilton Depression Rating Scale (HAM-D),and repeat 
throughout the course of treatment to evaluate initial symptoms and response to treatment. 
History
 XDetailed history of present illness, including time frame, progression, and any associ -
ated symptoms
 XSocial history, including present living situation, marital status, occupation, spiritual -
ity; education, alcohol, tobacco, and illicit drug use
 XMedication use, including prescription, over-the-counter, alternative, supplements, 
and home remedies

146  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XRecent medical illness or surgery
 XInitial and periodic functional history and assessment
 XValidation of history with family member
 ZInitial presentation: often manifests as vague somatic complaints
 XBodily aches, pains
 XMuscle pains
 XLack of energy
 XGastrointestinal problems
 XWhen mood is the presenting complaint, often client word choice may be vague or 
indirect.
 ZThe person may describe mood as depressed, discouraged, sad, “blue, ” “blah, ” 
or “down in the dumps. ”
 ZIrritable mood is a frequent subjective state validated by a significant person in 
the client’s life.
 XCharacteristic low energy is seen, so assess for individual activity intolerance with -
out other apparent cause.
 XAnhedonia is almost always present to some degree.
 XSleep disturbance is almost always present.
 ZTypically problems occur with middle or terminal insomnia. 
 ZHypersomnia can be present.

XAnhedonia is almost always present to some degree.
 ZDiurnal variations can be present.
 XA prodromal episode consisting of a high level of subjective anxiety and mild depres -
sive symptoms often develops over days to weeks before onset of a full episode.
 XWomen often report symptoms occurring in fixed pattern around several days before 
onset of menses, so assess menstrual history.
 XPsychotic features can be present, so always assess for their presence.
 XAssess for client’s symptoms according to diagnostic criteria for MDD:
 ZAnhedonia or a depressed mood, or both
 ZDepressed mood most of the day, nearly every day, as indicated by subjective 
reports or observations of others
 XIn children, irritable mood
 ZMarked anhedonia in all or almost all activities of daily living

 ZAt least three or more significant symptoms present during the same 2-week 
period that represent a change in previous functioning
 ZSignificant, unintentional weight loss or gain of more than 5% of body weight; 
with increased appetite and usually a concurrent craving for specific foods, such 
as carbohydrates or sweets
 ZHypersomnia or insomnia nearly every day

147 dePressive disorders and BiPolar disorders
 ZPsychomotor agitation or retardation
 ZFatigue or loss of energy
 ZSelf-deprecating comments or thoughts
 ZFeelings of worthlessness or excessive or inappropriate guilt nearly every day
 ZDecreased concentration and memory
 ZRecurrent morbid thoughts or suicidal ideation
 ZSymptoms that begin within 2 months of significant loss such as death of 
a loved one and do not persist beyond 2 months are generally considered 
bereavement and not MDD.
Physical Exam Findings
 XThere are no specific physical findings.
 XPeople with certain other disorders (such as diabetes, myocardial infarction, carcino -
mas, stroke) have a statistically significant increased risk for MDD. 
 ZPrognosis for treatment of other disorders is poor if MDD is not recognized and 
effectively treated.
 XClients with MDD may have trouble participating in assessments related to the cog -
nitive problems of the disorder.

 ZImpaired ability to report chronological timeline of illness
 ZPoor decision-making
 ZSlowed thought processes
 ZPoor concentration
 XClients with MDD often have psychomotor findings.
 ZAgitation
 ZRetardation
Mental Status Exam Findings
 XAppearance
 ZUnkempt
 ZTired-looking
 ZClothing showing little attention or care about how the person looks
 ZDark-colored, loose-fitting clothing
 ZSignificant weight change from baseline
 XMood 
 ZSad
 Z“Depressed”
 ZAnxious
 ZIrritable

148  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XAffect
 ZConstricted or blunted
 ZSad, tearful
 ZAnxious
 XSpeech
 ZUnderproductive
 ZSlowed response times
 ZMonotonal intonation
 XThought process
 ZUsually organized but may be disorganized if psychosis present
 ZSlowing
 ZDistractible
 ZRuminative
 XThought content
 ZMorbid preoccupation
 ZSuicidal ideation exists on continuum of severity:
 XGuilt for not being able to overcome the depression or for what they are 
“putting loved ones through”
 XThoughts that others would be better off if the person was “gone”
 XTransient recurrent thoughts of suicide
 XNonspecific thoughts of active action to commit suicide
 XSpecific plan for committing suicide
 XSpecific plan with timeline for completion
 XSpecific plan with acquisition of the means to carry out plan (suicidal 
motivation differs for different clients)
 XDesire to give up struggle
 XAttempt to end significant emotional pain

XSpecific plan with acquisition of the means to carry out plan (suicidal 
 XLack of any visible options for dealing with stressors, hopeless, helpless
 XAnger and frustration with poor impulse control 
 ZResearch evidence supports that it is not possible to predict accurately whether 
or when a person will attempt suicide (see Table 9–1 for review of suicide 
assessment).
 ZSuicide risk especially high for persons with certain symptoms or history:
 XPresence of psychotic symptoms
 XHistory of past attempts
 XHistory of first-degree relative who committed suicide

149 dePressive disorders and BiPolar disorders
 XConcurrent substance abuse or dependency
 XCurrent serious health problem (see below for clinical management of 
suicidality)
 XOrientation
 ZClient is usually oriented to person, place, and time unless psychosis is present.
 XMemory
 ZUsually impaired recent and short-term memory
 XConcentration
 ZUsually significantly impaired
 XAbstraction
 ZAbstract ability on proverb testing usually intact
 ZIf concrete, assess for other psychotic findings
 XInsight 
 ZMay be intact or impaired
 XJudgment
 ZMay be impaired for self-welfare
Diagnostic and Laboratory Findings
 XNo lab findings specific to MDD exist
 XComplete blood count (CBC), chemistry profile, thyroid function tests, or B12 and folate 
levels to rule out metabolic causes or unidentified conditions; consider referral for 
sleep study if snoring, apnea, or suspicion of other sleep disorder
 XDrug toxicity screening, if indicated by history

 XDepression related to a differential diagnosisTABLE 9–1  . 
ASSESSING FOR SUICIDAL BEHAVIOR
Past history for suicide attempts or completed suicide in client or family
Negativity and morbidity
Suicidal ideation currently
Plan and intent for suicide action
Means and access to commit suicide
Perceived social supports
Lethality of intended suicide action:
High lethality:  Jumping from significant height, gun, hanging
Moderate lethality: Overdose of toxic agents (such as aspirin, sleeping pills)
Low lethality:  Superficial wrist-cutting, breath-holding
Substance abuse or dependence
History of psychiatric disorder

150  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZEndocrine disorders
 XHypothyroidism
 XDiabetes
 XHyperaldosteronism
 XCushing’s or Addison’s disease
 ZNeurological disorders
 XStroke
 XEpilepsy
 XDementia
 XHuntington’s disease
 XSleep apnea
 XWilson’s disease
 XNeoplasms
 XHead trauma
 XMultiple sclerosis 
 XParkinson’s disease
 ZCardiac disorders
 XMyocardial infarction
 XCongestive heart failure
 XHypertension
 ZInfectious and inflammatory states
 XMononucleosis
 XAIDS
 XPneumonia: viral and bacterial
 XSystemic lupus erythematous
 XTemporal arteritis
 XTuberculosis
 ZNutritional disorders
 XPernicious anemia
 XPellagra
 ZOther disorders
 XFibromyalgia
 XChronic fatigue syndrome
 XBereavement or grief reaction
 XElectrolyte imbalance
 XUremia and other renal conditions

151 dePressive disorders and BiPolar disorders
 XAnxiety disorders
 XEating disorders
 XBipolar affective disorder
 XSubstance dependence–related disorders
 ZMedications that can cause altered mood states as side effects
 XSteroids
 XEstrogen compounds
 XAntihypertensive agents
 XAnti-Parkinson’s agents
 XAntineoplastic agents
 XAntibacterial and antifungal agents
 XAnalgesics
 XIsotretinoin (Accutane)
 XBenzodiazepines
Clinical Management
 XThe top goal in the acute phase of MDD is ensuring client safety.
 XA general consideration is to rule out or treat any conditions that may contribute to 
depression and cognitive impairment.
 XAssess for the acuity level of client presentation.
 ZReasons for brief hospitalization during acute episodes of MDD:
 XEnsure client safety
 XInitiate medication change, when doing so as an outpatient poses undue risk
 XRestabilize on medication
 XMonitor suicidality
 XEnsure client compliance with treatment to reach stabilization.

XInitiate medication change, when doing so as an outpatient poses undue risk
 ZClinical management during nonacute episodes occurs most often in community 
settings. 
 XObtain baseline labs as indicated before initiation of treatment.
 ZPharmacological management
 ZNonpharmacological management (psychotherapy)
Pharmacological Management
 XInform client that therapeutic effect may take at least 4 to 6 weeks. 
 XOnce started, continue antidepressants for a minimum of 6 to 12 months.
 ZIf client has more than two prior episodes of MDD, consider continuing 
antidepressants indefinitely.

152  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XNot all symptoms of MDD will respond to pharmacological interventions.
 ZIdentify clear, measurable target symptoms and educate the client about these 
symptoms (see Table 9–2).
 XResearch has found that the most effective intervention is a combination of medica -
tion and psychotherapy.
 XAntidepressant rebound is common when stopping antidepressants abruptly, particu -
larly when drugs with short half-lives are involved.
 XAntidepressants may induce mania or mixed mania in susceptible persons.
 XAll antidepressants have “black box” warnings regarding suicidality for children, 
adolescents, and young adults.
 XClasses of antidepressants
 ZSelective serotonin reuptake inhibitors (SSRIs)
 XAct primarily to increase serotonin levels in central nervous system (CNS) 
by inhibiting their presynaptic reuptake
 XSee Table 9–3 for examples
 ZTricyclic antidepressants (TCAs)

XAct primarily to increase serotonin levels in central nervous system (CNS) 
 XElevate serotonin and norepinephrine levels primarily by inhibiting their 
presynaptic reuptake
 XSee Table 9–4 for examples.
 ZMonoamine oxidase inhibitors (MAOIs)
 XElevate serotonin and norepinephrine levels primarily by inhibiting MAO, the 
enzyme that breaks down monoamine neurotransmitters
 XSee Table 9–5 for examples. 
 ZSerotonin norepinephrine reuptake inhibitors (SNRIs)
 XInhibit dual reuptake of norepinephrine and serotonin
 XAction very selective on neurotransmitters
TABLE 9–2 .
TARGET SYMPTOMS OF ANTIDEPRESSANT TREATMENT
Depressed mood
Sleep–rest disturbances
Anxiety
Irritability
Impaired concentration
Appetite disturbance
Agitation
Anhedonia
Impaired energy and motivation

153 dePressive disorders and BiPolar disorders
 XElevate serotonin and norepinephrine levels by inhibiting their presynaptic 
reuptake
 XSee Table 9–7 for examples.TABLE 9–3 .  
DRUGS FOR MOOD DISORDERS: ANTIDEPRESSANTS—SELECTIVE SEROTONIN REUPTAKE 
INHIBITORS
AGENTBRAND 
NAMEDOSAGE 
FORMS DAILY 
DOSAGE SIDE EFFECTS COMMENTS
Citalopram Celexa Tablet
20–40 mg/daySedation
Sexual dysfunction
Agitation
Yawning
GI disturbances
Weight gainPregnancy Category C 
Lactation Category L2
2011 warning about 
prolonged QTc interval in 
doses above 40 mg (20 
mg in older adults) and 
in those susceptible to 
prolonged QTc 
Escitalopram Lexapro Tablet
10–20 mg/day Somnolence
Headache
GI disturbancesPregnancy Category C
Fluoxetine Prozac Capsule, 
tablet, or liquid
20–80 mg/dayInsomnia
Headache
Sexual dysfunctionLong half-life
Pregnancy Category C
Lactation Catagory L2
Discontinuation syndrome 
unlikely
Fluvoxamine Luvox Tablet
100–300 mg/

Headache
unlikely
daySedation 
Agitation
GI disturbancesDoses above 150 mg 
should generally be given 
b.i.d.
Paroxetine Paxil 
CR, 
PexevaTablet or liquid
20–60 mg/dayHeadache
Somnolence
Sexual dysfunctionPregnancy Category D
very common
Sertraline Zoloft Tablet
50–200 mg/
daySexual dysfunction 
HeadachePregnancy Category C
Serotonin partial agonist reuptake inhibitor (SPARI)
Vilazodone Viibryd Tablet
20–40 mg Diarrhea
Nausea
Dry mouth
(lower risk of sexual 
side effects) Pregenancy Category C
Lactation Category: 
Unknown, is excreted in 
breast milk

154  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XNorepinephrine dopamine reuptake inhibitors (NDRIs)
 ZInhibit dual reuptake of norepinephrine and dopamine
 ZAction very selective on neurotransmitters
 ZElevate dopamine and norepinephrine levels by inhibiting their 
 ZSee Table 9–6 for examples.
 XSerotonin agonist and reuptake inhibitors (SARIs)
 ZDual action
 ZAgonist of serotonin 5HT -2 receptors
 ZElevate serotonin levels by inhibiting serotonin reuptakeTABLE 9–4 .  
TRICYCLIC ANTIDEPRESSANTS
NAMEDOSAGE FORMS 
DAILY DOSAGE COMMENTS
Amitriptyline Elavil Tablet or IM 
50–300 mg/dayAlso used for chronic pain (particularly 
neuropathic), insomnia
Clomipramine Anafranil Capsule
100–250 mg/dayApproved for obsessive–compulsive disorder; 
250 mg/day maximum because of increased 
seizure risk

Desipramine Norpramin Tablet or capsule
100–300 mg/dayAlso used for attention-deficit hyperactivity 
disorder (off-label for pediatric clients and for 
ADHD)
Doxepin Sinequan Capsule or liquid
100–300 mg/dayAlso used for insomnia
Lactation Category L5 Avoid
Imipramine Tofranil Tablet, capsule, 
or IM
100–300 mg/dayAlso used for enuresis and separation anxiety
Pregnancy Category D
Nortriptyline Pamelor Capsule or liquid
50–150 mg/dayAlso used for enuresis and attention deficit 
hyperactivity disorder
Protriptyline Vivactil Tablet
15–60 mg/dayPregnancy Category C
Lactation Category: Inadequate data
Trimipramine Surmontil Capsule

100–300 mg/dayPregnancy Category C

155 dePressive disorders and BiPolar disorders
 XThe various antidepressants differ markedly in characteristics such as
 ZCost
 ZSide-effect profile
 ZSafety in overdose
 ZSafety in clients with other disorders
 ZDrug–drug interactions
 ZCytochrome P450 liver effects
 XTo achieve best control of symptoms, match client’s symptom profile 
to the pharmacodynamic and pharmacokinetic properties of specific 
antidepressant agents.TABLE 9–5 .  
MONOAMINE OXIDASE INHIBITORS
DRUGBRAND 
NAMEDOSAGE FORMS
Isocarboxazid Marplan Tablet
20–60 mg/dayAlso used for panic disorder, phobic 
disorders, selective mutism
Caution:  High-tyramine diet; 
sympathomimetic agents
Divided dosing: b.i.d. and q.i.d.
All Pregnancy Category C
Lactation Category: Inadequate 
InformationPhenelzine Nardil Tablet
45–90 mg/day
Tranylcypromine Parnate Tablet
30–60 mg/day
Selegiline EMSAM Transdermal patch
6–12 mgNo dietary restrictions with 6 mg

6–12 mgNo dietary restrictions with 6 mg 
dosage; may need higher dose to see 
antidepressant effect
Lactation Catagory L4 Avoid
TABLE 9–6 .  
TYRAMINE-FREE DIETARY CONSIDERATIONS 
CATEGORY OF FOOD SPECIFIC FOODS TO AVOID
Cheeses Aged cheeses, such as blue, brie, Camembert, and Roquefort
Meat Smoked, aged, and cured meats such as sausages, pastrami, and 
salami
Fish Smoked, aged, and cured fish such as pickled herring and salted 
fish
Beverages Any aged and fermented beverages such as red wine, aged liquors, 
whiskey (gin and vodka permissible), beer (bottled and pasteurized 
permissible)
Other Bean curd (tofu), soy products, sauerkraut, miso, yeast extract, 
MSG, ripe bananas, avocado

156  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
SSRIs
 XFirst-line treatment for first episode of major depression with mild to moderate 
symptoms
 XSerious side effects are rare
 XMuch safer in overdose than TCAs 
 XAlso effective for panic disorder, obsessive–compulsive disorder, bulimia, general -
ized anxiety disorder, social phobia, posttraumatic stress disorder, and premenstrual 
dysphoric disorder
TCAs
 XConsidered second-line drugs for treating MDD (see Table 9–4).
 XAffect many neurotransmitters, leading to more side effects and possibly poor 
adherence.
 ZAnticholinergic:  Dry mouth, blurred vision, constipation, memory problems 
(from muscarinic receptor blockade)
 ZAntiadrenergic:  Orthostatic hypotension (from alpha 1 receptor blockade)
 ZAntihistaminergic:  Sedation and weight gain (from histamine receptor blockade)
 ZElectrocardiogram (EKG) changes and cardiac dysrhythmias possible; avoid in

ZAntihistaminergic:  Sedation and weight gain (from histamine receptor blockade)
 ZElectrocardiogram (EKG) changes and cardiac dysrhythmias possible; avoid in 
clients known to have susceptibility (personal or family history). Monitor EKG 
before treatment and annually in older adults.
 ZUnsafe in many co-occurring disorders (such as cardiac disease)
 ZKnown to induce hypomania in susceptible clients
 XWell-identified serum blood levels guide dosing (particularly nortriptyline) and predict 
toxicity.
 XInexpensive and available in generic forms.
 XAnticholinergic properties may be highly problematic but may also be useful in those 
who have significant bowel irritability.
 XAvoid abrupt withdrawal because of significant discontinuation syndrome.
 XAvoid prescribing to people who are at high risk for suicide; lethal dose is 1,000 mg 
or more (a week’s supply of an average dose). Combination of TCAs with MAOIs

XAvoid prescribing to people who are at high risk for suicide; lethal dose is 1,000 mg 
or more (a week’s supply of an average dose). Combination of TCAs with MAOIs 
can cause lethal serotonin syndrome, hypertensive crisis, or both; adhere to 2-week 
washout period (5 weeks for fluoxetine) before switching between the two classes 
of medications.
 XUse caution if the person is taking both a TCA and an SSRI, because the SSRI can 
elevate TCA concentrations because of pharmacodynamic or pharmacokinetic inter -
actions. Monitor TCA levels.
MAOIs
 XNot first or second-line agents for MDD because of dangerous food and drug interac -
tions (see Tables 9–5 and 9–6).

157 dePressive disorders and BiPolar disorders
 ZHypertensive crisis  occurs when MAOIs are taken in conjunction with foods 
containing tyramine , a dietary precursor to norepinephrine.
 ZWhen MAO is inhibited, tyramine exerts a strong vasopressor effect, stimulating 
the release of catecholamines, epinephrine, and norepinephrine, which can 
increase blood pressure and heart rate.
 ZHypertensive crisis is life-threatening and cannot be reversed unless more MAO 
is produced by the body. 
 XHypertensive crisis  and death also can occur when MAOIs are taken in 
conjunction with certain medications: 
 ZMeperidine
 ZDecongestants
 ZTCAs
 ZAtypical antipsychotics
 ZSt. John’s wort
 ZL -tryptophan
 ZStimulants and other sympathomimetics
 ZAsthma medications
 XSymptoms of hypertensive crisis:
 ZSudden, explosive-like headache, usually in occipital region
 ZElevated blood pressure
 ZFacial flushing
 ZPalpitations
 ZPupillary dilation
 ZDiaphoresis
 ZFever
 XTreatment of hypertensive crisis:

ZElevated blood pressure
 ZFever
 ZDiscontinue the MAOI.
 ZGive phentolamine (binds with norepinephrine receptor sites, blocks 
norepinephrine).
 ZStabilize fever.
 ZReevaluate the person’s diet and adherence, and reiterate medication 
guidelines as necessary.
 ZPeople on MAOIs must follow a tyramine-free diet and must avoid many 
medications, including most over-the-counter cold and allergy preparations.
 ZCombining an MAOI with a serotonergic agent is contraindicated, because this 
may cause serotonin syndrome.
 XSymptoms of serotonin syndrome
 ZAgitation, restlessness
 ZRapid heart rate and elevation in blood pressure

158  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZHeadache
 ZSweating, shivering, and goose bumps
 ZMyoclonic jerking and loss of coordination
 ZConfusion, fever, seizures, unconsciousness
 XTreatment of serotonin syndrome includes discontinuing the offending 
agents and supportive treatment of symptoms. Mild symptoms such 
as restlessness may respond to removal of the offending agent, close 
monitoring, and judicious use of a benzodiazepine. More severe symptoms 
constitute a medical emergency necessitating hospitalization and treatment 
such as cyproheptadine, anticonvulsants, and autonomic support.
 XCan be fatal in overdose.
 XSide-effect profile and stringent dietary restrictions often lead to poor client 
 XClients who are on MAOIs must be taught to recognized the signs and symptoms 
of hypertensive crisis and serotonin syndrome and understand that they must seek

of hypertensive crisis and serotonin syndrome and understand that they must seek 
immediate medical attention should they suspect either one of occurring.
 XClinically significant side effects of MAOIs include  
 ZInsomnia
 ZHypertensive crisis
 ZWeight gain
 ZAnticholinergic side effects
 ZLightheadedness and dizziness
 ZSexual dysfunction
 XMAOIs are unsafe in many co-occurring disorders. 
Other Antidepressants
 XOther antidepressants used in the treatment of MDD may be classified as SNRIs, 
NDRIs, and SARIs. See Table 9–7 and Table 9–8.
 XPsychotic features can be present with MDD and Bipolar I Disorder.
 ZRoutinely assess for the presence of psychotic symptoms during periods of 
symptom exacerbation
 ZFeatures are usually mood-congruent.
 ZCan be managed with short-term use of antipsychotic medications (see 
Chapter 11)

 XComorbidities are common and include various medical conditions (as noted 
earlier in the chapter) as well as psychiatric comorbidities such as panic disorder, 
obsessive–compulsive disorder, and substance abuse or dependence.
 XAltered appetite and sleep–rest patterns predispose clients with MDD to decreased 
overall health status.
 XIncreased mortality exists in people with MDD.

159 dePressive disorders and BiPolar disorders
Nonpharmacological Management
 XElectroconvulsive therapy (ECT)
 ZGrand mal seizure induced in anesthetized person
 ZUsual course is 6 to 12 treatments
 ZMechanism of action:
 XNeurotransmitter theory: Increases dopamine, serotonin, and 
norepinephrineTABLE 9–7  . 
SNRIS
DRUG  
(CLASS)BRAND 
DAILY DOSAGE SIDE EFFECTS COMMENTS
Venlafaxine
(SNRI)Effexor, 
Effexor 
XRCapsule (XR), or 
tablet
75–375 mg/day
XR 75–225 mg/dDiaphoresis
Headache
Dizziness
GI disturbancesCan raise BP
QD for XR capsules
b.i.d.–t.i.d. dosing for 
tablets
Full SNRI effect at doses 
at or above 150 mg
Safer in overdose than 
TCAs
Has significant  
discontinuation syndrome 
if stopped abruptly
Lactation Category L3
Duloxetine
(SNRI)Cymbalta Capsule
30–120 mgDizziness
Headache
GI disturbancesOnce-daily dosing
Can elevate BP
Can elevate liver function 
tests

Headache
tests
Vortioxetine 
(5HT -3 and 5HT7 
antagonist,  
5HT 1A agonist)Brintellix Tablet (5, 10, 
20mg)
20 mg q.d.Nausea
Diarrhea
DizzinessPregnancy Category C
Inadequate Information
Levomilnacipran
(SNRI)Fetzima Tablet 
(20,40,80,120mg)
40-120 mg q.d.Nausea and vomiting
Constipation
Sweating
Palpitations
Urinary hesitancy
Hypertension
Hypotension
Decreased appetitePregnancy Category C

160  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
TABLE 9–8 .  
OTHER ANTIDEPRESSANT AGENTS
DRUG  
(CLASS)BRAND  
Bupropion
(NDRI)Wellbutrin Tablet
150–450 mg/dayHeadache
Nervousness
Tremors
Tachycardia
Insomnia
Decreased 
appetiteContraindicated if client 
has seizures, eating 
disorder
SR offers b.i.d. dosing; XL 
offers once-daily dosing
Can increase energy level
Also used for attention-
deficit hyperactivity 
disorder and smoking 
cessation
Bupropion 
SR/XLWellbutrin SR Sustained release
150–400 mg/day
Extended release
150–450 mg/dayCaution with caffeine 
and in people with panic 
disorder
Mirtazapine 
(alpha2/5HT2 
antagonist)Remeron Tablet
15–45 mg/daySedation
Weight gain
Increased 
cholesterolInverse relationship 
between dosage and 
sedation
Nefazodone 
(SARI)Serzone Tablet
300–600 mg/dayHeadache

Increased 
sedation
Drowsiness
GI disturbancesMust  monitor LFTs
Can cause liver failure 
TCAs
q.h.s. or b.i.d. dosing
Potent P450 3A4 inhibitor
Pregnancy Cateogory C
Lactation Category L4 
Avoid
Trazodone
(SARI)Desyrel Tablet
200–600 mg/daySedation
Nausea
Headache
HypotensionSafer in overdose than 
TCAs
Priapism possible
Not well tolerated at 
antidepressant dosage 
because of sedation
Most commonly used 
as hypnotic at 50–200 
mg/h.s.
May prolong QTc interval
Pregnancy Category B

161 dePressive disorders and BiPolar disorders
 XNeuroendocrine theory: Releases hormones such as prolactin, 
thyroid-stimulating hormone, pituitary hormones, endorphins, and 
adrenocorticotropic hormone
 XAnticonvulsant theory: Exerts an anticonvulsant effect, which then produces 
an antidepressant effect
 ZSituations in which ECT is used:
 XClient preference
 XNeed for rapid response because of severity of illness 
 XMDD with psychotic features
 XRisk of other treatment outweighs risk of ECT
 XTreatment resistance
 ZPossible contraindications:
 XCardiac disease
 XCompromised pulmonary status
 XHistory of brain injury or brain tumor
 XAnesthesia medical complications
 ZAdverse effects:
 XPossible cardiovascular effects
 XSystemic effects (e.g., headaches, muscle aches, drowsiness)
 XCognitive effects (e.g., memory disturbance and confusion)
 XTranscranial magnetic stimulation (TMS)
 ZOption for clients who have not had adequate response to medications and

XCognitive effects (e.g., memory disturbance and confusion)
 ZOption for clients who have not had adequate response to medications and 
psychotherapy (treatment-resistant depression)
 ZInvolves placement of small wire coil on scalp to conduct electrical current, 
creating a magnetic field through the tissues of the head
 ZPerformed in office setting, without anesthesia
 ZSessions typically last 40 minutes and typical course is 5 sessions per week for 
6 weeks.
 ZSide effects are minimal but may include headache, scalp discomfort, tingling 
or twitches to facial muscles, lightheadedness, and hearing discomfort from 
procedure noise.
 ZSeizures, although rare, have been reported.
 XVagal nerve stimulation (VNS)
 ZPacemaker-like device implanted in left side of chest to stimulate left branch of

 ZPacemaker-like device implanted in left side of chest to stimulate left branch of 
nerve; transcutaneous devices being tested
 ZGenerally done as outpatient procedure, but anesthesia is required

162  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZSide effects generally occur as the pulse generator stimulates the vagal nerve 
and include voice changes, hoarseness, cough, throat or neck pain, chest 
spasms, dyspnea on exertion, tingling of skin, dysphagia
 ZIntended for use along with traditional treatments
 XPhototherapy
 Z2,500 to 10,000 lux light for 30 minutes up to 2 hours, 1 to 2 times daily 
(Sadock, Sadock, & Ruiz, 2015)
 XIndividual therapy (See Chapter 8. Nonpharmacological Treatment)
 ZPsychodynamic psychotherapy
 ZCognitive behavioral therapy (CBT)
 XModify perceptions
 XDecrease negativity
 XIncrease sense of internal control
 XEnhance coping skills
 XModify environmental factors contributing to illness
 ZBrief therapy (solution-focused therapy)
 XFocus on precipitant stressor
 XCope with immediate impact of MDD on personal life
 XModify contributory environmental factors
 ZGroup therapy
 XImprove decision-making

XFocus on precipitant stressor
 XImprove socialization skills
 XImprove assessment of individual strengths
 XGain new coping skills
 ZFamily therapy
 XEnhance family coping
 XImprove knowledge base
 XPlan for relapse
 XGain insight into effects of MDD on family unit
 XUndertake psychoeducation for family members about the illness state of 
MDD
Clinical Management of Suicidality
 XPay significant attention to positive assessments for suicidality.
 XAlways assume client is serious when he or she vocalizes suicidal thoughts.
 XIdentify current stressors that may be contributing to crisis. 
 XGenerally do not manage in community setting during acute suicidal ideation periods 
unless client is able to make “no harm” agreement.

163 dePressive disorders and BiPolar disorders
 XConsider hospitalization.
 XConsider mobilizing available social resources.
 ZRisk factors for suicide:
 XAges 45 or older if male
 XAges 55 or older if female
 XDivorced, single, or separated
 XWhite
 XLiving alone
 XPsychiatric disorder
 XPhysical illness
 XSubstance abuse
 XPrevious suicide attempt
 XFamily history of suicide
 XRecent loss
 XMale gender
Life Span Considerations: Children
 XCore symptoms of MDD are the same for children. However, some symptoms are 
more pronounced in children.
 ZIrritability
 ZSomatic complaints
 ZSocial withdrawal
 XSome core symptoms are less common  in children before onset of puberty:
 ZPsychosis
 ZMotor retardation
 ZHypersomnia
 ZIncreased appetite
 XMDD often has a strong separation anxiety component in children.
 XChildren usually do not respond well to tricyclics; however, they do respond well to 
SSRIs.
 XAll antidepressants indicated for children, adolescents, and young adults carry a

XChildren usually do not respond well to tricyclics; however, they do respond well to 
SSRIs.
 XAll antidepressants indicated for children, adolescents, and young adults carry a 
black box warning about an increase in suicidal thoughts; monitor closely for suicidal 
thoughts, behavior, agitation, and aggression in children taking antidepressants.
Life Span Considerations: Older Adults
 XPersons with MDD admitted to a long-term-care facility have significantly shorter life 
spans than control population.

164  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 X65% are more likely to die within the first year in a long-term-care facility.
 XCognition and memory symptoms of MDD in the older adult population often are 
confused with dementia-related symptoms (pseudodementia).
 ZClients with dementia usually have a premorbid history of slowly declining 
cognition.
 ZIn MDD, cognitive changes have a relatively acute onset and are significant 
when compared to premorbid functioning.
 XIt is important to complete a functional assessment  for older adults.
 ZDetermines the degree to which the person’s abilities and performance match 
the demands of his or her life
 ZDetermines the impact of illness on overall functioning
 ZSkill deficit : Inability to perform a functional skill despite the physical ability, as in 
dementia
 ZPerformance deficit : Ability to perform a functional skill but lacks the motivation 
to do so, as in depression

dementia
 XReasons for performing functional assessment:
 ZTo correctly diagnose (for example, to differentiate depression from dementia)
 ZTo track client improvement or decompensation
 ZTo help families set realistic expectations
 XComponents of functional assessment:
 ZActivities of daily living (ADLs): Basic self-care skills, such as bathing, dressing, 
eating, and toileting
 ZInstrumental activities of daily living (IADLs): Complex activities needed for 
independent functioning, such as shopping, cooking, driving, and housekeeping
 ZExecutive functioning: Judgment and planning; ability to maintain calendar, 
manage money and appointments, and prioritize activities
 XThe degree of change over time and the speed of change are better observed with 
objective recording and when the assessment is measured at intervals such as every 
6 months.
Follow-up

XThe degree of change over time and the speed of change are better observed with 
6 months.
Follow-up
 XFollow-up care practices for the PMHNP to consider
 ZInclude teaching client the goals, risks, benefits, and potential side effects of 
medication treatment
 ZContinuously monitor client’s response to medication; the treatment goal is 
complete remission of symptoms. 
 ZUtilize screening tool such as PHQ-9 in follow-up appointments.
 ZTeach clients the symptoms of depression and that it is a chronic illness; establish 
a relapse plan for all clients.
 ZAssess for suicidality during every client contact.

165 dePressive disorders and BiPolar disorders
 ZAssess for the presence of psychotic symptoms during every client contact.
 ZAssess and manage client for side effects of treatment, including sexual side 
effects, in an attempt to increase medication compliance.
 ZObserve all clients treated with antidepressants for development of serotonin 
syndrome  (overstimulation of serotonin receptors usually caused by drug–drug 
interactions).
 XDrug combinations that can cause serotonin syndrome:
 ZSSRIs and MAOIs
 ZDrug and herbal interactions
 ZSSRIs and St. John’s wort
 XSymptoms of serotonin syndrome:
 ZAutonomic instability
 ZAltered sensorium
 ZRestlessness
 ZMyoclonus
 ZHyperreflexia
 ZHyperthermia
 ZTremor
 ZChills
 ZDiarrhea and cramps
 ZAtaxia
 ZHeadache
 ZInsomnia
 ZMonitor for adverse effects over time.
 ZSome SSRIs are known to increase blood glucose and contribute to 
hyperlipidemia, and others may elevate liver function tests.

ZHeadache
 ZInsomnia
 ZDiscontinue SSRIs slowly to prevent discontinuation syndrome.
 XSymptoms of discontinuation syndrome:
 ZFlu-like symptoms (due to cholinergic rebound; particularly problematic 
with TCAs)
 ZFatigue and lethargy
 ZMyalgia
 ZDecreased concentration
 ZNausea and vomiting
 ZImpaired memory

166  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZParesthesias, including “shock-like” sensations
 ZAnxiety
 ZInsomnia
 ZCrying without provocation
 ZDizziness and vertigo
 XRisk factors for discontinuation syndrome:
 ZMedications with short half-life
 ZAbrupt discontinuation
 ZNoncompliant, irregular use pattern
 ZHigh dose range
 ZLong-term treatment
 ZPrior history of discontinuation syndrome
 XExpected course of MDD
 ZEvidence indicates the best treatment outcomes if medications are used in 
conjunction with appropriate therapy.
 ZEvidence indicates that clients should take an antidepressant agent for at least 
12 months after remission of symptoms.
 ZClients who have had 3 or more episodes of MDD usually require lifelong 
medication.
PERSISTENT DEPRESSIVE DISORDER (DYSTHYMIA)
 XA disorder similar to MDD but with less acute symptoms; with a more protracted,

 XA disorder similar to MDD but with less acute symptoms; with a more protracted, 
chronic disease course; and without any manifestations of psychotic symptoms
 XLess discrete episodes of illness than MDD
 XSymptoms often go undetected and therefore untreated for years
 XVegetative symptoms (e.g., sleep, appetite, weight changes) much less common in 
dysthymic disorder than in MDD
Etiology
 XSimilar to MDD
 XAffects 5.4% of the U.S. population ages 18 or older, or 10.9 million Americans.
 XPeople with dysthymia have an increased risk for developing MDD; 15% to 25% of 
people diagnosed with dysthymic disorder will have a lifetime episode of MDD.

167 dePressive disorders and BiPolar disorders
 XPeople with onset of symptoms before age 21 have a 75% likelihood of a lifetime 
episode of MDD.
 XWomen are 2 to 3 times more likely to develop dysthymic disorder than men.
 XGenetic predisposition 
 XA first-degree relative with MDD
 XA first-degree relative with dysthymic disorder
 XAt-risk family education
 XCommunity education
 XStigma reduction
 XSigns and symptoms of illness
 XTreatment potential for control of symptoms
 XEarly recognition, intervention, and initiation of treatment
 XBecause of chronic nature of disorder, symptoms become a part of clients’ day-to-
day existence and often go unreported unless solicited by direct questioning
 XAggressive screening procedure required
History
 XAssess for the following:
 ZChronically depressed mood that occurs for most of the day, more days than 
not, for at least 2 years

XAggressive screening procedure required
History
 ZProminent presence of low self-esteem, self-criticism, and a perception of 
general incompetence compared to others
 ZOther common symptoms:
 XLow energy and fatigue
 XPoor concentration 
 XDifficulty with decision-making
 XFeelings of hopelessness
 XFeelings of inadequacy
 XMild anhedonia 
 XSocial withdrawal

168  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XBrooding about past issues
 XSubjective irritability or anger
 XDecreased productivity and activity
 ZLess common symptoms:
 XAlteration in appetite
 XAlteration in sleep–rest patterns
 XUsually no vegetative findings
 XMood described as sad, “down for all of my life”
 XNonspecific
Polysomnographic Findings
 XSimilar to those found in MDD
 XBecause of increased risk for development of MDD, dysthymia is often treated with 
antidepressant medications in a manner similar to MDD.
 XOften good clinical outcomes with nonpharmacological management if client is 
willing
Common comorbidities
 XMDD is often superimposed on dysthymia (“ double depression”)

XSimilar to MDD
willing
 XThe subjective worsening of symptoms or onset of new symptoms such as vegeta -
tive ones often brings the person into treatment.
 XWhen dysthymia precedes MDD, clinical management is more complex and out -
comes can be less positive.

169 dePressive disorders and BiPolar disorders
 XDysthymic disorder is associated with personality disorders.
 ZBorderline
 ZHistrionic
 ZNarcissistic
 ZAvoidant
 ZDependent
Life Span Considerations
 XIn children, prevalence rates of dysthymia are equal for boys and girls.
 XAssociated with several childhood disorders:
 ZAttention-deficit hyperactivity disorder
 ZConduct disorder
 ZAnxiety disorders
 ZLearning disorders
 XPeriod of symptoms required for diagnosis is only 1 year, compared with 2 years for 
adults.
 XIn children, the mood usually described as irritable  rather than sad but may report 
both irritability and sadness
 XLow self-esteem, poor social skills, and pessimism
Follow-up
GRIEF AND BEREAVEMENT
 XInvolve a wide range of normal responses that can become abnormal and excessive
 XInvolve normative emotional, cognitive, and behavioral reactions to death or loss of a 
significant person or object

XInvolve normative emotional, cognitive, and behavioral reactions to death or loss of a 
 XUnlike in major depression, self-esteem is usually preserved in the grieving person
 XInvolve nonnormative psychological responses to an identifiable stressor that can 
result in the development of clinically significant emotional or behavioral symptoms
 ZStressor encompassing elements of perceived loss
 ZDevelops within 3 months  of stressor
 XSingle event
 ZEnd of relationship
 ZDeath of relative or partner

170  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XRecurring event
 ZLiving with person with terminal illness
 XDevelopmental event
 ZLeaving home to go away to school
 ZGetting married
 ZBecoming a parent
 ZRetiring from work
 XPMHNP assessment is needed to separate normal, healthy grieving from pathologi -
cal grieving, which may represent an adjustment disorder or major depression. The 
PMHNP must consider:
 ZSeverity of response
 ZDuration of response
 ZEffects of response on normal daily functioning
 ZPerson’s perception of impact of stressor
 XWhen severity or duration is excessive, the grieving may be abnormal.
 XIn the absence of other significant clinical symptoms, grief usually is classified as 
adjustment disorder:
 ZAdjustment disorder with depressed mood
 ZAdjustment disorder with anxiety
 ZAdjustment disorder with mixed anxiety and depression
 ZAdjustment disorder with disturbed conduct
Etiology
 XSignificant loss

ZAdjustment disorder with anxiety
Etiology
 XLimited coping skills
 XLimited social supports
 XNormal grief is universally experienced.
 XGrief is common in older adults as their social sphere begins to decrease.
 X20% of older adults who lose a spouse experience depression within the first year 
of that loss.
 XLifetime prevalence for adjustment disorder is 2% to 8% in the U.S. population. 
 XGrief occurs in 12% of general hospital clients.
 XGrief occurs in 50% of clients after cardiac surgery.

171 dePressive disorders and BiPolar disorders
 XLimited social network
 XPoor physical health
 XAsk about losses.
 XIdentify at-risk persons.
 XDo preventative counseling.
 XBegin early recognition, intervention, and initiation of treatment.
 ZRoutine screening at all healthcare settings.
 XOften clients will not disclose grieving or bereavement issues unless directly asked.
History
 ZRecent losses
 ZAnniversary dates of past losses
 ZReaction to loss
 ZFunctional impairment
 ZSocial and family support systems
 ZInsomnia
 ZAnorexia
 ZPresence of dysfunctional coping
 XSuicidal thoughts
 XDenial
 XDepressed mood
 XAnxious affect
 XCrying uncontrollably

172  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XCBC, chemistry profile, thyroid function tests, and B12 level to rule out metabolic 
causes or unidentified conditions
 XNormal grieving
 XMajor depressive disorder (MDD)
 XAnxiety disorders (see Chapter 10)
 XSubstance-related disorders (see Chapter 13)
 XIf needed
 ZShort-term use of anti-anxiety agents
 XBNZs
 ZShort-term use of sleep-induction agents
 XBNZs
 XNonbenzodiazepine hypnotic such as zolpidem
 XTricyclic or other sedating antidepressants
 XAntihistamines
 XEncourage expression of grief and loss.
 XUse support groups.
 XOffer community resources.
 XOffer psychoeducation on grief reactions and responses.
 XWith significant functional impairment, consider psychotherapy (e.g., crisis therapy,

XUse support groups.
 XWith significant functional impairment, consider psychotherapy (e.g., crisis therapy, 
brief solution-focused therapy, CBT).
 XCan occur at any age
 XOlder adults are at greater risk because of higher numbers of losses that may be -
come cumulative in their impact.

173 dePressive disorders and BiPolar disorders
Follow-up
 XFollow up weekly during acute period.
 XMonitor for development of MDD.
 XMonitor for impact on general health state.
 XMaintain supportive follow-up over time.
 XBe sensitive to nontraditional losses that may be significant to the person:
 ZLoss of a pet
 ZLoss of status in work or school setting
PREMENSTRUAL DYSPHORIC DISORDER
 XDysphoric symptoms that occur in response to changing sex steroid hormones 
which occur during the ovulatory menstrual cycle.
 XSymptoms generally begin during the luteal phase, approximately 1 week before 
onset of menses, and generally lift within a day or two after menses has begun.
 XCommon symptoms include:
 ZMarked lability 
 ZIrritability 
 ZDepressed mood
 ZAnxiety
 ZLow energy
 ZSleep disturbances
 XSymptoms occur repeatedly during each menstrual cycle and there must be a 
symptom-free period in the follicular phase, after menses has occurred.

ZAnxiety
 XSymptoms may worsen as the woman becomes perimenopausal.
 XSymptoms cause marked impairment in functioning and sense of well-being.
 XA careful evaluation must be completed to rule out other mood disorder.
 XTreatment may consist of hormonal contraceptives, SSRI antidepressants, or both.
BIPOLAR (BP) DISORDER
 XComplex brain-based illness with a primary characteristic of disturbance in mood 
 XMood disturbance often of both polarities:
 ZDepressive
 ZExpansive or manic

174  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XSeveral patterns:
 ZSingle-polarity symptoms only (mania)
 ZDistinct symptom patterns of alternating polarity—manic symptoms alternating 
with depressive symptoms
 ZMixed, co-occurring symptoms
 XPresents with excessive or distorted degree of sadness or elation, or both
 XManifests with behavioral, affective, cognitive, and somatic symptoms
 XMay have precipitating event, situation, or concern but often occurs without any 
precipitating stressor identified
Etiology
 XMultiple theories ranging from psychological to neurobiological
 XProbable multifactorial etiological profile
 ZBiological theories
 XGABA deregulation
 XIncreased noradrenergic activity
 XVoltage-gated ion channel abnormalities
 XAbnormalities lead to abnormal balances of intracellular and extracellular

ZBiological theories
 XAbnormalities lead to abnormal balances of intracellular and extracellular 
levels of neurotransmitters, which then cause subsequent disruption of 
electric signal transmission in brain regions.
 XKindling: Process of neuronal membrane threshold sensitivity dysfunction
 ZLong-lasting, epileptogenic changes induced by daily subthreshold 
brain stimulation
 ZBrain becomes overly sensitive to electrical stimuli
 ZNeuronal misfiring occurs
 ZProcess becomes automatic; neuronal firing occurs even without 
stimuli.
 XLess common than MDD
 X0.7% of general population at risk
 XAffects 2.3 million American adults; 1 .2% of the U.S. adult population older than age 
18
 XMean age of onset is early 20s
 XMay present in childhood (rare) or adolescent years
 XPrevalence for males and females is the same.

175 dePressive disorders and BiPolar disorders
 XFamily history of first-order relative having MDD or BP disorder
 X24% increased risk if relative has BP disorder Type I (see below)
 X5% increased risk if relative has BP disorder Type II (see below)
 X25% increased risk if relative has MDD
 XFor BP disorder Type II, similar to MDD
 ZStigma reduction
 ZSigns and symptoms of illness
 ZTreatment potential for control of symptoms
 ZSignificant and protracted prodromal symptom period usually noted before full 
onset of illness
 ZUsually mild manifestations of criteria symptoms before full clinical syndrome is 
apparent
 ZThe longer time between onset of symptoms and diagnosis, the more difficult 
to interrupt cyclicity of illness.
 ZDepressive episodes predominate, making misdiagnosis common.
History

ZThe longer time between onset of symptoms and diagnosis, the more difficult 
History
 ZDetailed history of present illness, including time frame, progression, and any 
associated symptoms
 ZSocial history, including present living situation; marital status; occupation; 
education; and alcohol, tobacco, and illicit drug use
 ZMedication use, including prescription, over-the-counter, alternative, 
supplements, and home remedies
 ZInitial and periodic functional history and assessment
 ZCorroborative information from family member when possible
 XDiagnostic criteria
 ZPeriod of abnormally or persistently elevated, expansive, or irritable mood, 
lasting for at least 1 week

176  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZMood episode has rapid development and escalation of symptoms over a few 
days
 ZOften precipitated by significant environmental stressor
 ZMood disturbance may result in brief psychotic symptoms
 ZManic episodes last days to several months
 ZBriefer duration and ending more abruptly than major depressive episodes
 ZIn 60% of people, a major depressive episode immediately precedes or follows 
the manic episode
 ZPersistence of other suggestive symptoms:
 XDecreased need for sleep
 XFeels rested after 3 hours sleep on average
 XUsually a marked difference from normal baseline sleep pattern
 XInflated self-esteem
 XGrandiosity
 XIncreased goal-directed activities
 XExcessive involvement in pleasurable activities with a high potential for 
painful consequences
 XUnrestrained buying sprees
 XSexual indiscretions
 XUnsound business ventures
 XExcessive substance use or abuse

 XHighly recurrent depressive episodes
 ZRecurrent shifts in polarity 
 XMajor depressive episode shifting to a manic episode 
 XManic episode shifting to a major depressive episode 
 XMajor depressive episode shifting to a mixed episode.
 ZExpansive or elated mood symptoms
 XManic 
 ZSymptoms as described above
 XHypomanic
 ZSimilar to mania
 ZMore brief in duration
 ZEpisode not as severe as mania
 ZDoes not require hospitalization
 ZDoes not cause significant functional impairment

177 dePressive disorders and BiPolar disorders
 XTwo common types
 ZType I
 XClinical history characterized by occurrence of one or more manic or mixed 
episodes 
 ZType II
 XClinical history characterized by occurrence of one or more major 
depressive episodes accompanied by at least one manic or hypomanic 
episode
 XIn a small subset of people with BP disorder, the recurrent shifts in polarity 
can occur more frequently— rapid cycling.
 ZOccurrence of 4 or more mood episodes during the previous 12 
months
 ZMood episodes are either major depressive or manic
 ZOther than occurring more frequently, mood episodes are same as 
nonrapid-cycling episodes
 Z20% of people with BP disorder have rapid cycling
 ZMost rapid cyclers are women (90%).
 XIdentifying rapid cycling is important.
 XAntidepressants may accelerate the cycling.
 XPersons with rapid cycling have a poorer prognosis.
 XClinical findings consistent with thyroid dysfunction

XAntidepressants may accelerate the cycling.
Mental Status Exam Findings in Mania or Hypomania
 ZPsychomotor restlessness or agitation
 ZFrequent change of dress
 ZProne to bright-colored, often sexualized dress
 ZDramatic or flamboyant dress usually out of character for person when 
compared to nonsymptomatic periods
 XSpeech
 ZRapid
 ZLoud
 ZPressured
 ZDifficult to interrupt
 ZJoking, irrelevant, amusing
 ZWord clanging in severely ill clients

178  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XAffect
 ZLabile
 ZOverly theatrical and dramatic
 XMood
 ZEuphoric
 ZCheerful
 ZHigh
 ZExpansive
 ZThoughts racing
 ZFlight of ideas
 ZThoughts disorganized and incoherent in severely ill clients
 ZInflated self-esteem
 ZIndiscriminate enthusiasm
 ZInflated sense of abilities bordering on delusional 
 ZIncreased sexual content
 ZFully oriented
 XMemory
 ZImpaired short-term
 ZImpaired recall
 ZHighly distractible
 ZGenerally abstractive
 ZCan be concrete on proverb testing during psychotic episodes
 XJudgment
 ZPoor
 ZProne to imprudent behavioral choices with potential for negative consequences
 XInsight
 ZThe person usually does not recognize that he or she is ill
 ZResists treatment options

179 dePressive disorders and BiPolar disorders
 XDrug toxicity screening if indicated by history
 XIf first onset of manic symptoms occurs after age 40, most likely symptoms are 
caused by another medical condition.
 XMany medical conditions mimic manic symptoms: 
 ZIntoxication or withdrawal from illicit drug use:
 XAmphetamines
 XCocaine
 XHallucinogens
 XOpiates
 XMedications:
 ZCaptopril
 ZCimetidine
 ZCorticosteroids
 ZCyclosporine
 ZDisulfiram
 ZHydralazine
 ZIsoniazid
 XMania can be precipitated by treatment of MDD or other unipolar mood disorders in 
susceptible persons.
 ZAntidepressants
 ZECT
 ZLight therapy
 XRule out or treat any conditions that may contribute to current symptom 
manifestation.

 ZECT
 XAssess and identify client’s level of acuity. 
 XDetermine severity of illness.
 XDetermine duration of illness.
 XAscertain history of response to treatment.

180  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XDuring acute manic episodes or significant depressive episodes, client may require 
brief hospitalization
 ZTo ensure client safety,
 ZTo ensure client adherence with treatment to reach stabilization, or
 ZTo rapidly stabilize on medication.
 XClinical management during nonacute episodes occurs most often in community 
settings. 
Pharmacological T reatment
 XPharmacological management should generally not entail the use of an antidepres -
sant agent if a mood-stabilizing agent is not in place.
 ZEspecially important in clients who are rapid-cycling
 ZMay precipitate shift from depression to hypomania, mania, or dysphoric 
hypomania (mixed state)
 XMood-stabilizing agents
 ZCommonly used pharmacological agents
 XLithium
 ZGold standard for treating manic episodes
 ZEvidence of antisuicidal effects
 ZAction largely unknown
 ZLong history of use; drug profile well established

XLithium
 ZEvidence exists showing some effectiveness on depressive symptoms 
as well as on manic symptoms
 ZHas many clinically significant side effects; clients on this drug require 
careful monitoring (see Table 9–10)
 ZNarrow therapeutic window
 ZTherapeutic effect and potential for adverse side effects monitored by 
use of serum lithium level
 XDrawn at trough level
 X12 hours post-dose
 XTherapeutic serum range 0.5 to 1 .2 mEq/l
 XLevel greater than 1 .2 mEq/l increases risk for toxic side effects.
 ZBaseline labs before initiation of lithium to ensure safety and efficacy:
 XThyroid panel
 XSerum creatinine
 XBlood urea nitrogen (BUN)
 XPregnancy test 
 XECG for clients older than age 50

181 dePressive disorders and BiPolar disorders
 ZRapid-cycling clients seldom respond to lithium monotherapy
 ZMust educate client (and significant others) about side effects and 
signs and symptoms of lithium toxicity
 XAnticonvulsant medication 
 ZCarbamazepine
 XBlack box warning for carbamazepine: agranulocytosis and aplastic 
anemia
 XValproic acid/divalproex sodium
 XBlack box warning for valproic acid/divalproex sodium: 
hepatotoxicity and pancreatitis
 ZLamotrigine
 XBlack box warning for lamotrigine: serious rash
 ZBaseline labs before carbamazepine or valproic acid/divalproex sodium
 XCBC
 XLiver function tests (LFTs)TABLE 9–9 .  
CLINICALLY SIGNIFICANT SIDE EFFECTS OF LITHIUM
ORGAN SYSTEM AFFECTED CLINICAL FINDING
Endocrine Weight gain
Impaired thyroid functioning
Central nervous system Fine hand tremors
Fatigue 
Mental cloudiness
Headaches
Coarse hand tremors with toxicity
Nystagmus
Dermatological Maculopapular rash
Pruritus
Acne
Gastrointestinal GI upset
Diarrhea
Vomiting

Fatigue 
Headaches
Nystagmus
Pruritus
Acne
Diarrhea
Vomiting
Cramps
Anorexia
Renal Polyuria with related polydipsia
Diabetes insipidus
Edema
Microscopic tubular changes
Cardiac T -wave inversions
Dysrhythmias
Hematological Leukocytosis

182  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th editionTABLE 9–10 .
DRUGS FOR MOOD DISORDERS: ANTICONVULSANTS
NAMEDAILY  
DOSSAGETHERAPEUTIC 
PLASMA 
LEVEL SIDE EFFECTS COMMENTS
Lithium 
carbonateEskalith
Lithobid1,200–2,400 
mg/day (acute)
900–1,200 
mg/day 
(maintenance)0.8–1 .2 mEq/l
0.6–1 .2 mEq/lCommon : Nausea, fine-hand tremors, 
increased urination and thirst
Toxicity : Slurred speech, confusion, 
severe GI effectEstablished standard treatment for bipolar 
disorder
Risk of hypothyroidism
Avoid in pregnancy, especially 1st trimester
Monitoring kidney functioning is essential 
Concurrent use of NSAIDs and angiotensin-
converting enzyme inhibitors (ACEIs) may 
double lithium level
Carbamazepine Tegretol 10–20 mg/kg/
day6–12 mcg/ml Common : Nausea, dizziness, 
sedation, headache, dry mouth, 
constipation, skin rash
Rare: Agranulocytos/aplastic anemia,
Stevens-Johnson syndrome,

Stevens-Johnson syndrome, 
particularly in Asians (screen for 
HLA-B 1502 allele before initiating) Hepatic enzyme inducer
Monitor LFTs
Alternative to lithium or valproic acid
Valproic acid, 
divalproex 
sodiumDepakene, 
Depakote15–40 mg/kg/
day50–125 mcg/ml Common : Nausea, diarrhea, 
abdominal cramps, sedation, tremor
Rare: Increased liver enzymes,
Stevens-Johnson syndrome (unlike 
carbamazepinedivalproex does not 
carry screening directive for HLA-B 
1502 antigen at this time) Depakote minimizes GI effects
More effective than lithium for rapid cycling 
and mixed bipolar
Loading dose: 20 mg/kg

183 dePressive disorders and BiPolar disordersLamotrigine Lamictal 25–600 mg/
dayBlood 
monitoring not 
necessaryCommon : Dizziness, ataxia, 
somnolence, diplopia, nausea, 
headache, hepatotoxicity 
Rare: Life-threatening rashes, 
including Stevens-Johnson syndrome 
(unlike carbamazepine, lamotrigine 
does not carry directive to screen 
for HLA-B 1502 antigen at this time), 
leukopeniaIndication for maintenance only
Helps in depressive phase of bipolar affective 
disorder
Titrate slowly: 25 mg p.o, q.d.x 2 weeks, then 
50 mg p.o. q.d. x 2 weeks, etc. Concomitant 
use with divalproex may double lamotrigine 
level and should be factored into dosing
Concomitant use with carbamazepine may 
increase metabolism and should be factored 
into dosing
Often used in combination with lithium, 
second-generation antipsychotics, and 
antidepressants

184  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZLabs drawn 1 week after start of carbamazepine, valproic acid/
divalproex sodium
 X12-hour trough serum drug level
 XCBC
 XLFTs
 ZResponse to treatment with lithium or anticonvulsant medications is 1 to 2 weeks.
STEVENS JOHNSON SYNDROME (SJS)
SJS is a rare, potentially life-threatening immune reaction to a foreign antigen that can occur with 
exposure to any anticonvulsant drug. Treatment includes stopping the offending agent with sup -
portive measures, often in a hospital burn unit. Signs and symptoms of SJS include: 
 Xfacial swelling
 Xtongue swelling
 Xmacules, papules, and “burning, ” confluent erythematic rash
 Xskin sloughing 
 Xprodromal headache, malaise, arthralgia, and painful mucous membranes may occur 
before rash occurs
Clinical Managment
 XSomatic treatments
 ZTreatment as previously discussed for MDD episodes
 XTherapies

 XDuring acute phase of manic episode:
 ZMonitor and help client meet nutritional needs.
 ZHelp client meet sleep–rest needs.
 ZMonitor for safety.
 XDuring less acute periods:
 ZCBT
 ZBehavioral therapies
 ZInterpersonal therapies
 ZSupportive groups
 ZMilieu therapy
 XProvides for structure and safety needs
 XProvides socialization and interpersonal support
 XEncourages independence

185 dePressive disorders and BiPolar disorders
 XClient and family education
 ZExplain underlying pathology of illness.
 ZDiscuss signs and symptoms.
 ZHelp identify strategies for living with illness.
 XHelp understand and make decisions regarding care options
 XRelapse prevention plan
 XOverall health promotion
Common Comorbidities
General Health Considerations
 XHigh-risk activities from manic behavior
 ZSexual
 XClient education for sexually transmitted infections (STIs)
 XAssessment and monitoring for STIs
 ZFinancial and legal
 XClient access to community resources
 XNutritional counseling
 XClient health education
 XAdolescent manic episodes present differently from adult episodes.
 ZMore psychotic features
 ZOften associated with antisocial behavior
 ZOften associated with substance abuse
 ZProdromal period of significant behavioral problems
 XSchool truancy
 XFailing grades
Follow-up

ZOften associated with antisocial behavior
Follow-up
 XClients initially should be seen weekly to titrate medications and monitor serum 
blood levels of pharmacological agents.
 XTreatment duration and success rates vary with individual characteristics and motivation.

186  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XClients and significant others should be taught symptoms of mania and depression 
and that the disorders are chronic illnesses. 
 XRelapse is common and occurs frequently.
 XRelapse plans need to be developed.
 XClient teaching should include risks, benefits, potential side effects, and signs and 
symptoms of medication toxicity. 
 XEducate about potential dietary and fluid intake effects on lithium level
 XLithium and divalproex sodium are teratogenic.
 ZWomen of child-bearing years need effective contraceptive care while on BP 
disorder treatment medication.
 XRoutine use of lab tests to monitor for therapeutic serum levels of anticonvulsants 
and lithium is needed.
 ZRoutine evaluation of CBC, renal function, and thyroid and parathyroid function 
(thyroid-stimulating hormone and calcium levels) is needed for clients taking 
lithium long-term.

ZRoutine evaluation of CBC, renal function, and thyroid and parathyroid function 
 XAssessment for suicidality should occur during every client contact.
 XAll clients should be observed for development of adverse effects of pharmacologi -
cal management.
 XStandardized rating scales help to monitor clinical status, establish baseline function -
ing, and monitor disorder course over time:
 ZYoung Mania Rating Scale (YMRS; Young, Biggs, Ziegler, & Meyer, 1978)
 ZA daily mood chart that tracks mood, energy, and specific information about 
sleep is helpful in informing both diagnosis and treatment
CYCLOTHYMIC DISORDER
 XChronic, fluctuating mood disorder with symptoms similar to but less severe than BP 
disorder
 XNumerous periods of hypomanic and dysthymic symptoms.
Etiology
 XSimilar to BP disorder
 XLifetime prevalence 0.4% to 1%
 XInsidious onset

disorder
Etiology
 XChronic course
 XBegins early in life

187 dePressive disorders and BiPolar disorders
 X15% to 50% of persons with cyclothymic disorder subsequently develop BP 
disorder.
 XFamily history 
 XBP disorder Type I
 ZThe longer the time period between onset of symptoms and diagnosis, the 
more difficult to interrupt cyclicity of illness.
History
 ZFluctuating mood episodes
 ZAffected people can function well during hypomanic episodes
 ZMay experience clinically significant distress or impaired function related to cyclicity
 ZUnpredictable mood changes

ZAffected people can function well during hypomanic episodes
 ZOften regarded by others as temperamental, moody, unpredictable, 
inconsistent,  and unreliable
 ZNo psychotic episodes
 XSimilar to MDD and BP disorder
 XSimilar to MDD and BP disorder but with less severity of symptoms

188  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XNonpsychiatric
 ZSimilar to MDD and BP disorder
 XPsychiatric
 ZBP disorder
 ZDysthymia
 ZSubstance abuse
 XBecause of increased risk for development of BP disorder, commonly treated with 
 XUsually begins in adolescence
 XOnset in later life usually suggests general medical condition such as multiple 
sclerosis.
Follow-up 

189 dePressive disorders and BiPolar disorders
CASE STUDY
Ms. M., a 35-year-old homemaker and mother of two children, presents to the PMHNP on refer -
ral from her primary care provider. Accompanied by her husband, Mary describes worsening 
insomnia and poor energy. The symptoms are affecting her ability to take care of her children and 
the household. Husband reports that Ms. M. often has crying spells, is not eating, and cannot 
seem to concentrate. When questioned further, husband reports that Ms. M. has mentioned not 
wanting to live, but he thought that she was just having a bad day. 
Past Psychiatric History
 XReports depression off and on since late adolescence
 XNo history of treatment
 XHusband adds that Ms. M. had “the baby blues” for several months after the births 
of both of their children
Past Medical History
 XSeasonal allergies and stress-induced asthma
 XNo significant surgical history, except for a tonsillectomy when she was a child

 XNo significant surgical history, except for a tonsillectomy when she was a child 
 XNormal pregnancies and deliveries
 XNo chronic health problems identified
Family History
 XSignificant for grandmother and father, who had “breakdowns. ”
 XFather had alcoholism.
Social History
Ms. M. is a homemaker and has two children, ages 8 and 10. She and her husband moved to the 
area 6 months ago. She does not smoke or use drugs but drinks socially. She has an MA degree 
in English and had planned to go back to school to get her teaching certificate when her children 
began high school. 
Mental Status Exam
Client appears disheveled. Hair is not combed. She appears very tired. She avoids eye contact, 
talks very softly, and is slow to respond to questions. She hardly moves during the interview. 
Affect is constricted and sad. She says she has no energy, and her mood is “very sad. ” She does

Affect is constricted and sad. She says she has no energy, and her mood is “very sad. ” She does 
not hear voices or have hallucinations. Her thoughts are appropriate and organized. She does 
admit to having episodic thoughts of suicide and has a vague plan to ingest an overdose of aspi -
rin, acetaminophen, and alcohol when the children are with their father but has no clear timeline 
or planned intent. She is unable to do serial number testing and shows impaired short-term 
memory. She exhibits a few problems with immediate recall. She has difficulty concentrating but

190  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
no difficulty with abstractions. She is oriented times 3, and shows good judgment and insight. 
She has above-average intelligence. 
Current Medications
Ms. M. takes cetirizine for allergies and is now on ethinyl estradiol/norgestimate contraceptive 
pills. 
Labs
 XPlatelets 230/mm3 
 XWBC 6,000/mm3 
 XHematocrit 40%, hemoglobin 13.0 
 XNA 140, K 4.0, Cl 101, CO2 26, BUN 15, creatinine 0.9, glucose 102
 XTSH 1 .1, T3 179, T4 1 .3
There are several issues to consider in planning care for Ms .  M .
1. What is the most probable diagnosis?
2. What further assessment is needed? 
3. What target symptoms does the client display that are consistent with the probable 
diagnosis?
4. What medications would be considered? 
5. If client had psychotic features with her depression, how would this change the 
treatment plan?
6. What nonmedication treatment would be indicated for a client with MDD with psy -

chotic features?
7. How would the plan differ if client had a heart condition and was taking no other 
medications?
8. Assume Ms. M. has started an antidepressant and returns after 2 weeks on the 
medication. Her speech has normalized and is now more spontaneous. If Ms. 
M now tells you that she feels “better” and that her energy and motivation have 
improved, but that she is still having difficulty falling and staying asleep, would your 
diagnosis change?
9. What further assessment should be done?
10. How would you change the treatment plan?
11. If Ms. M. returns for her follow-up appointment reporting irritable mood, racing 
thoughts, rapid speech and inability to sleep, should your diagnosis and treatment 
plan change?

191 dePressive disorders and BiPolar disorders
1. The client’s most probable diagnosis is consistent with major depressive disorder.
2. Further assessment needed is to ensure that the client meets the DSM-5 criteria for 
major depression. Complete physical assessment and use common symptom rating 
scale such as Beck’s Depression Inventory or PHQ-9. Complete assessment for any 
other physical health states. The PMHNP should explore what “inability to sleep” 
means in specific detail.
3. The target symptoms for this client include: depressed mood most of the day nearly 
every day, lack of energy, suicidal ideation, MSE findings consistent with MDD.
4. The medications to be considered for this client are SSRIs as this class of antide -
pressant medication is often considered the first-line agent for treatment of MDD.
5. If the client had psychotic symptoms, clinical management would include the short-

term use of an antipsychotic agent to control psychotic symptoms. If used, an atypi -
cal antipsychotic is usually best tolerated.
6. For clients with severe MDD, with psychosis ECT might be considered. 
7. If the client had cardiovascular disease, the PMHNP must look at compatibility 
issues to ensure that the medication choice for treatment of MDD does not have 
significant risk for adverse cardiac side effects. TCAs are contraindicated. 
8. If the client presented for a follow-up appointment stating that she is feeling better, 
but still has residual symptoms of sleep problems your diagnosis would not change 
because the symptoms Ms. M. reports are consistent with a depressive episode 
that is beginning to resolve.
9. Further assessment of this client should include an assessment for mood, anhedo -

nia, suicidal ideation, and activities over the past 2 weeks and for any indication that 
the antidepressant may be fueling a switch from depression to hypomania or mixed 
state.
10. In this client, if the treatment plan changes, monitor for further improvements. Teach 
Ms. M about sleep hygiene measures. Discuss expected outcomes and the impor -
tance of monitoring for any significant increase in goal-directed activities, decreased 
need for sleep, racing thoughts, and shift in mood to euphoria or irritability. Begin 
psychotherapy.
11. If Ms. M. returns for a follow-up appointment reporting irritable mood, racing 
thoughts, rapid speech and inability to sleep, yes, your treatment plan should 
change. Rule out unspecified bipolar disorder, bipolar II disorder, and bipolar I disor -

der. The antidepressant dose should be lowered and a medication with mood stabiliz -
ing properties should be added. The client should be monitored closely and reevalu -
ated within several days.
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CHAPTER 10ANXIETY DISORDERS, OBSESSIVE–COMPULSIVE 
DISORDER, AND TRAUMA- AND STRESSOR-
RELATED DISORDERS
This chapter reviews the psychiatric–mental health nurse practitioner’s (PMHNP’s) evaluation 
of and treatment of people who have anxiety-related disorders. Anxiety disorders are among 
the most common of all psychiatric illnesses, and can initially manifest as a number of physical 
illness states. Often only after extensive, unnecessary assessment and diagnostic evaluation 
is a client’s problem correctly identified as an anxiety disorder. Because of the high degree of 
somatic symptomatology, it is common for clients to present to a primary care setting and thus 
receive initial care from a primary care provider. 
Anxiety is a very common and normal human emotion. PMHNPs caring for clients who pres -
ent for evaluation of anxiety must be able to distinguish between normal levels of anxiety and

ent for evaluation of anxiety must be able to distinguish between normal levels of anxiety and 
pathological levels that are symptomatic of an underlying brain-based illness. Pathological levels 
of anxiety require treatment and generally will not fully abate without therapeutic intervention. 
Untreated high levels of anxiety predispose people to other serious health problems; therefore, 
pathological levels of anxiety should not go untreated (Narrow, Rae, & Regier, 1998). 
 XNormal emotion of anxiety
 ZAnxiety is one of the most common human emotions.
 ZAnxiety exists on a continuum ranging from the absence of anxiety at one end 
to pathological levels that produce significant symptoms of psychiatric disorder 
at the other (see Table 10–1).
 ZAnxiety can be a normal, healthy reaction to life stressors that motivates a 
person to deal with events and emotions.

 ZAnxiety can be pathological if it is disproportionate to events, if it is sustained 
over a significant time frame, if it significantly impairs functioning, or if it is 
apparently unrelated to any identifiable event or situation in a person’s life.
 ZHigh pathological levels of anxiety interfere with perceptions, memory, 
judgment, and motor responses.

196  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZCultural differences can affect behavioral manifestations of anxiety. 
 X“ Ataques de nervios” is a Latino cultural syndrome usually provoked by 
disruptions in family bonds and may be manifested by trembling, crying, 
and screaming. The attacks are usually experienced in the presence of 
others and the person often feels relief afterward.
 X“Khyal” (wind) attacks are a common manifestation among Cambodian and 
other Asian cultures, and commonly manifest in neck soreness and tinnitus.
 ZOlder adults often express anxiety as somatic concerns and anxiety disorders 
may overlap with medical conditions.
 ZPsychotherapy is the first-line treatment for children and adolescents who are 
diagnosed with an anxiety disorder.
 ZThe role of the PMHNP in assessing anxiety is to separate normal versus 
pathological levels of anxiety, to intervene to lower the level of anxiety, and to

pathological levels of anxiety, to intervene to lower the level of anxiety, and to 
improve overall functioning.
ANXIETY DISORDERS
 XAnxiety disorders are the most common group of psychiatric disorders and are 
characterized by the degree of anxiety experienced by the client, by the duration TABLE 10–1  . 
ASSESSING LEVELS OF ANXIETY
LEVEL OF 
ANXIETY DEFINITIONPHYSIOLOGICAL SIGNS 
AND SYMPTOMSPSYCHOLOGICAL SIGNS 
AND SYMPTOMS
Level I: 
MildNormative level 
experienced by all, 
which functions to 
motivateVital signs normal, pupils 
constricted, minimal increase 
in muscle tonePerceptual field broadened, 
heightened awareness of 
environment 
Level II: 
ModerateNormative level 
experienced by 
most in response 
to significant 
stressorsVital signs normal, mild 
increased heart rate, 
moderate increase in muscle 
toneSubjective feeling of

Level II: 
toneSubjective feeling of 
tension or worry, narrowed 
perceptions 
Level III: 
SeverePathological level Autonomic nervous system 
triggered, fight-or-flight 
response, pupils dilated, vital 
signs increased, diaphoresis, 
muscles rigid, hearing 
decreased, pain threshold 
increased, urinary frequency, 
diarrheaPerceptual field greatly 
narrowed, difficulty with 
problem-solving, distorted 
perception of time, selective 
inattention, dissociative 
sensations, automatic 
behavior
Level IV: 
PanicPathological level Severe symptoms markedly 
increased: client is pale, 
hypotensive, has poor eye–
hand coordination, muscle 
pains, marked decrease in 
hearing, dizziness, shortness 
of breathScattered perceptions, unable 
to attend to environmental 
stimuli, illogical thinking, 
may exhibit hallucinations or 
delusions

197 anxiety disorders, oBsessive–c oMPulsive disorder, and trauMa- and s tressor-related disorders
and severity of the anxiety, and by the typical behavioral manifestation of anxiety 
observed in the client. Anxiety ranges from acute states to chronic disorders and is 
accompanied by multiple somatic symptoms.
 XPeople most often present first in primary care settings with nonspecific physical 
concerns.
 ZPanic attacks are often confused with cardiac and respiratory disorders, so 
careful differential diagnostic assessment is essential.
 XFrequent comorbidity exists with substance abuse, depression, and eating disorders.
 XSymptoms significantly impair functioning and occur more days than not for a period 
of at least 6 months, with the person reporting little or no volitional control over the 
symptoms.
 XNine specific anxiety disorders are identified in the Diagnostic and Statistical Manual 
of Mental Disorders  (DSM-5; American Psychiatric Association, 2015) and are de -

symptoms.
scribed in more detail in this chapter.
Etiology
 XMultiple theories range from psychological to neurobiological; however, most likely 
there is a multifactorial etiological profile.
 ZPsychodynamic Theory
 XThis theory is based on work of Sigmund Freud (1856–1939), who believed 
that anxiety initially occurs in response to the stimulation of birth and need 
of the infant to adapt to the changed environment.
 XSubsequent anxiety results from intrapsychic conflict. TABLE  10–2 .  
DSM-5 ANXIETY, OBSESSIVE–COMPULSIVE DISORDER (OCD), AND TRAUMA- AND 
STRESSOR-RELATED DISORDERS
ANXIETY DISORDERSOBSESSIVE–COMPULSIVE 
AND RELATED DISORDERSTRAUMA AND STRESSOR-
• Panic Disorder
• Agoraphobia
• Specific Phobia
• Social Anxiety (Social 
Phobia)
• Selective Mutism
• Generalized Anxiety

Phobia)
• Generalized Anxiety 
Disorder• Obsessive–Compulsive 
Disorder
• Body Dysmorphic 
Disorder
• Hoarding Disorder
• Trichotillomania (Hair-
Pulling Disorder)
• Excoriation (Skin-Picking 
Disorder)
• Substance- or 
Medication-Induced 
Obsessive–Compulsive 
and Related Disorder• Reactive Attachment 
Disorder
• Disinhibited Social 
Engagement Disorder
• Posttraumatic Stress 
Disorder
• Acute Stress Disorder
• Dissociative Identity 
Disorder
• Dissociative Amnesia
• Depersonalization or 
Derealization Disorder

198  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XThe process of unconscious repression of sexual drive is at the core of 
much of the conflict.
 XConflict exists between instinctual needs of the id and the superego  
(conscience);  anxiety signals the person of the need to deal with the id–
superego conflict.
 XConflict is unconscious, but anxiety is consciously perceived.
 XConflict entails fear of punishment and of doing wrong. 
 XDefense mechanisms are unconsciously used by the person to deal with 
the conflict.
 XThe behavioral manifestations of anxiety disorders stem from the 
pathological overuse of defense mechanisms.
 ZInterpersonal Theory
 XThis theory is based on work of Harry Stack Sullivan (1892–1949), who 
believed that humans are goal-directed toward attainment of satisfaction 
and security needs.
 XSatisfaction and security needs are normally met in interpersonal 
interactions.
 XAnxiety arises when a person’s needs are unmet.

 XAnxiety is first experienced in an infant’s interactions with his or her mother.
 XSubsequent anxiety arises because of interpersonal conflict. 
 XConflict occurs when a person perceives his or her needs will not be met 
because of rejection, feelings of inferiority, or inability to engage with 
significant others.
 XSense of self becomes based on the person’s perception of how others 
view him or her.
 ZNeurobiological Theory  
 XPathological levels of anxiety result from neurobiological deficits in normal 
brain functioning.
 XDeficits are genetically mediated by and involve predominantly the limbic 
system, midline brainstem area, and sections of the cortex.
 XDeficits predispose the person to abnormal stress responses, with 
hyperactivity of autonomic nervous system causing symptoms such as

hyperactivity of autonomic nervous system causing symptoms such as 
increased heart rate and blood pressure, diaphoresis, papillary dilation, 
tremors, and increased respiratory rate. 
 XProblems with the hypothalamic pituitary adrenal (HPA) axis:
 ZThreat is perceived, and amygdala signals the hypothalamus to secrete 
corticotrophin-releasing hormone (CRH).
 ZThe amygdala also activates the sympathetic nervous system to start 
the fight-or-flight response.
 ZThe pituitary is stimulated to release adrenocorticotropic hormone 
(ACTH).

199 anxiety disorders, oBsessive–c oMPulsive disorder, and trauMa- and s tressor-related disorders
 ZThe adrenal glands are then stimulated to release cortisol, which shuts 
off the alarm system and restores the body to homeostasis.
 XIn anxiety disorders, the amygdala may not be able to shut off the response 
(overactive amygdala), or there may not be enough cortisol to stop the fight-
or-flight response.
 XNeurobiological deficits result in low levels of the neurotransmitter gamma-
aminobutyric acid (GABA), the chemical responsible for inhibitory responses 
of neurons, and in high levels of norepinephrine, the chemical associated 
with the fight-or-flight response
 XNeurotransmitters involved in suppressing the HPA axis are serotonin and 
GABA.
 XAnxiety disorders are common, with a lifetime prevalence of 28.8% among the 
general U.S. population.
 XExcept for obsessive–compulsive disorder (OCD) and social phobia, anxiety disorders

XAnxiety disorders are common, with a lifetime prevalence of 28.8% among the 
 XExcept for obsessive–compulsive disorder (OCD) and social phobia, anxiety disorders 
are more common in girls and women than in boys and men.
 XMost anxiety disorders manifest in adolescence and early adulthood (Narrow, Rae, & 
Regier, 1998).
 XMedian age at onset is 11 years of age.
 XGenetic loading (National Institute of Mental Health, Genetics Workgroup, 1998)
 ZA first-degree relative of a person with panic disorder is up to 8 times more 
likely than general population to develop panic disorder.
 ZIf a first-degree relative of a person developed panic disorder before age 20, that 
person is up to 20 times more likely than general population to develop panic 
disorder.
 XLimited range of coping skills.
 XHistory of trauma
 XHigh levels of parental distress affect a child’s ability to cope with traumatic events

XLimited range of coping skills.

200  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZTeach at-risk persons to recognize and manage anxiety levels.
 ZHelp at-risk persons reduce anxiety through improved coping activities. 
History
 ZDetailed history of present illness, including time frame and progression, any 
education level
 ZClients initially may be more troubled by, and complain more often of, physical 
symptoms and may not identify anxiety as a concern.
 ZExplore the client’s subjective sensations of being nervous, tense, worried, 
anxious, or stressed out.
 ZIdentify current environmental stressors as experienced by the client.

ZExplore the client’s subjective sensations of being nervous, tense, worried, 
 ZDetermine if anxiety is normative or pathological. 
 ZPathological  levels of anxiety indicative of underlying anxiety disorder:
 XAnxiety is perceived of as distressing and out of the control of the person..
 XAnxiety is unlinked and not seen as caused by life events.
 XAnxiety is accompanied by somatic complaints, which is more uncommon 
in normal anxiety levels.
 XAnxiety interferes with social, occupational, and recreation activities and 
with activities of daily living.
 ZDetermine the level of the client’s anxiety using the 4-point scale of mild to 
panic levels (1 = mild to 4 = panic; see Table 9–1).
 ZUse standardized rating scales such as the Hamilton Rating Scale for Anxiety 
(HAM-A; Hamilton, 1959) for establishing and monitoring the client’s anxiety 
level over time.

ZUse standardized rating scales such as the Hamilton Rating Scale for Anxiety 
 ZAssess general level of health and presence of concomitant illnesses.
 ZAssess for dysfunctional coping:
 XAlcohol use or abuse
 XIllicit substance use or abuse
 XCaffeine use
 XIncreased nicotine use
 XMisuse of anti-anxiety medications

201 anxiety disorders, oBsessive–c oMPulsive disorder, and trauMa- and s tressor-related disorders
 ZAssess for specific psychological symptoms of anxiety: 
 XFear of dying, losing one’s mind, or a sense of unreality
 XBelief that he or she is very ill, with no findings to support this belief
 XNarrowed perceptions 
 XLimited eye contact
 XPossible physical manifestations:
 ZHeadaches
 ZDizziness and lightheadedness
 ZMissing hair on scalp, eyebrows, or eye lashes (for trichotillomania or excoriation 
disorders)
 ZIncreased muscle tone
 ZPalpitations, often with tightness in chest
 ZTachycardia
 ZHypertension
 ZGI problems such as nausea, diarrhea, or abdominal discomfort
 ZPsychomotor restlessness
 ZTremors
 ZHand wringing
 XSpeech
 ZOverproductive
 ZRapid
 ZDistractible speech patterns
 ZThought blocking
 XMood 
 ZNervous
 ZWorried
 XAffect 
 ZAnxious
 ZWorried
 ZTearful

202  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZOverall organized
 ZGoal-directed
 ZRedirectable
 ZThematic for worry
 ZMild perseveration on topics of concern
 ZUsually fully oriented
 XMemory 
 ZImpaired short-term and immediate memory
 ZForgetful
 XConcentration 
 ZInattentive
 ZAbstract on proverbs and similarities
 XJudgment
 ZIntact
 XInsight
 ZIntact or limited insight
 XObtain baseline labs such as complete blood count (CBC), chemistry profile, thyroid 
function tests, and B12 level to rule out metabolic causes or unidentified conditions.
 XObtain drug toxicity screening if indicated by history.
 XIn some cases, clients may have labs reflecting compensated respiratory alkalosis:
 ZDecreased carbon dioxide levels
 ZDecreased bicarbonate levels
 ZNormal pH

XIn some cases, clients may have labs reflecting compensated respiratory alkalosis:
 ZNormal pH
 XMany medical conditions can cause worry, fear, and normal levels of anxiety (see 
Table 10–3). 
 XEnsure that client symptoms meet criteria for anxiety disorders.
General Clinical Management
 XRule out or treat any conditions that may contribute to pathological levels of anxiety.

203 anxiety disorders, oBsessive–c oMPulsive disorder, and trauMa- and s tressor-related disorders
 XMost of the medications known to improve symptoms of anxiety act directly or 
indirectly on the GABA system.
 XConsidered first-line agents  for chronic anxiety disorders
 XAction on serotonin system and indirectly on GABA system
 XCarry no risk of dependency
 XCannot be used p.r.n.
 XGenerally well tolerated 
 XTakes time to reach symptom control (usually 3–4 weeks)
 XBest when combined with psychotherapy
 XBlack box warning for increased suicidality in children, adolescents, and 
young adultsTABLE 10–3 .  
MEDICAL CONDITIONS THAT MAY MIMIC ANXIETY DISORDERS
GENERAL CATEGORY OF DISORDER SPECIFIC ILLNESS
Cardiovascular Congestive heart failure
Mitral valve prolapse
Myocardial infarct
Arrhythmias, especially tachycardic arrhythmias
Pulmonary embolism
Coronary artery disease
Respiratory Asthma

Chronic obstructive pulmonary disorder
Pneumonia
Endocrine Hyperthyroidism
Hyperparathyroidism
Cushing’s disease
Neurological Seizure disorders
Transient ischemic attacks
Cerebral vascular accident
Encephalitis
Central nervous system (CNS) neoplasms
Metabolic Hypoglycemia
Vitamin B deficiency
Porphyria
Substance abuse or dependency Intoxication with CNS stimulants (e.g., cocaine, 
amphetamines, caffeine)
Withdrawal from CNS depressants (e.g., alcohol, 
marijuana)

204  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZBenzodiazepines (BNZs) 
 XPotentiate the effect of GABA
 XRapid onset of action 
 XCan be used p.r.n.
 XLimit to lowest possible dose and short-term use if possible, because long-
term use may lead to tolerance, dependence, memory impairment, and 
 XUse should be limited to period of excessive symptoms, period of high 
stress, or in unremitting symptoms.
 XUse with extreme caution in clients with history of substance dependence.
 ZEffective but carry risk for addiction, especially in persons who have a 
history of substance abuse.
 XThe use of benzodiazepines has been associated with Alzheimer’s disease.
 XBNZs with longer half-lives  require less frequent dosing, have less severe 
withdrawal, and have less rebound anxiety.
 XBNZs with longer half-lives are more useful for continuous, moderate to 
severe anxiety or as bridge medications while waiting for efficacy of SSRI:

severe anxiety or as bridge medications while waiting for efficacy of SSRI: 
 ZClonazepam (Klonopin)
 ZDiazepam (Valium)
 XBNZs with shorter half-lives  require more frequent dosing, have more 
severe withdrawal, and have more rebound anxiety:
 ZAlprazolam (Xanax)
 ZLorazepam (Ativan)
 XAdvantages of BNZs with short half-lives
 ZBNZs with short half-lives are often useful for intermittent or infrequent 
moderate to severe anxiety
 XLess daytime sedation
 XLess drug accumulation
 XQuick onset of action
 XUseful for treatment of insomnia
 XDisadvantages of BNZs with short half-lives:
 ZIncreased risk of addiction
 ZTricyclics (TCAs)
 XEffective but affect multiple receptors and have problematic side-effect 
profiles
 XSide effects often affect compliance

205 anxiety disorders, oBsessive–c oMPulsive disorder, and trauMa- and s tressor-related disorders
 ZNon-BNZ anxiolytics (see Table 10–4)
 XBuspirone (BuSpar) 
 ZMust be taken regularly, not as p.r.n.
 XTiagabine (Gabitril)—off-label use
 XGabapentin (Neurontin)—off-label use
 XBeta blockers (propranolol, atenolol)—off-label use 
 ZUsually adjunctive use with other pharmacological agent
 XIn children, alpha-agonists are often used for anxiety.
 ZClonidine (Catapres), .003–.01 mg/kg/d, off-label use
 ZGuanfacine (Tenex), .015–.05 mg/kg/d), off-label use
 XBehavioral therapy
 ZSystematic desensitization
 ZExposure therapy
 ZRelaxation therapies 
 XCognitive behavioral therapy (CBT)
 XInterpersonal therapies
 XCommunity self-help groups
 XAlternative therapies as adjunctive treatmentsTABLE 10–4 .  
NON-BENZODIAZEPINE ANXIOLYTICS FOR ADULTS 
GENERIC BRANDDOSAGE 
RANGE SIDE EFFECTS COMMENTS
Buspirone Buspar 20–60 mg

XAlternative therapies as adjunctive treatmentsTABLE 10–4 .  
Buspirone Buspar 20–60 mg 
dailyDizziness, insomnia, 
tremors, akathisia, stomach 
upset, dry mouthHelpful adjunct for anxiety
Tiagabine Gabitril 4–56 mg 
dailyDizziness, somnolence, 
stomach upset, tremors, 
dry mouthHelpful adjunct for anxiety
Off-label use
Gabapentin Neurontin 300–
3,600 mg 
dailyAtaxia, decreased 
coordination, sedation, 
disequilibriumUsed for anxiety, 
neuropathic pain, 
fibromyalgia, and as an 
anti-craving medication
Propranolol Inderal 10–20 mg 
daily p.r.n. Bradycardia, hypotension Performance anxiety

206  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
Comorbidities
 XAnemia
 XCardiac disorders, especially in clients with dysrhythmias
 XEndocrine disorders 
 ZCushing’s disease
 ZHypoglycemia
 XPulmonary conditions
 ZChronic obstructive pulmonary disorder
 ZAsthma
 ZPulmonary embolism
 ZPneumothorax
 XAdverse medication reactions
 ZCaffeine
 ZNicotine
 ZAnticholinergics
 ZAntihistamines
 ZAntipsychotics
 ZSteroids
 ZBronchodilators
 ZAnesthetics
 XMood disorders
 XSubstance abuse–related disorders
 XChronic anxiety is wearing on the body; therefore, assess for effects on the cardio -
vascular system.
 XPerform a general assessment for a healthy lifestyle.
Follow-up
 XGeneral considerations
 ZClients should initially be seen weekly or biweekly to titrate medications.
 ZClient teaching should include risks, benefits, and potential side effects of 
medication treatment.

ZClients should initially be seen weekly or biweekly to titrate medications.
 XIf the client is taking BNZs, monitor for appropriate use and potential 
dependence.
 XIf the client is taking SSRIs, monitor for common side effects and adverse 
effects.

207 anxiety disorders, oBsessive–c oMPulsive disorder, and trauMa- and s tressor-related disorders
 ZClients should be taught symptoms of anxiety and the fact that disorders are 
chronic illnesses; a relapse plan should be established for all clients.
 ZAssessment for suicidality should occur during symptom exacerbation periods. 
 ZBecause of frequent comorbidity with major depressive disorder, assess 
frequently for depression levels using standardized rating scales (see below).
 ZMedication should be combined with therapy to reach maximum control of 
symptoms.
 ZClients may need encouragement to continue treatment, especially after initial 
symptom relief occurs.
 XStandardized rating scales for anxiety disorders 
 ZZung’s Self-Rating Anxiety Scale (Zung, 1971)
 ZHamilton Rating Scale for Anxiety (HAM–A; Hamilton, 1959)
 ZYale-Brown Obsessive Compulsive Scale (Y -BOCS; Goodman et al., 1989).
PANIC DISORDER

ZHamilton Rating Scale for Anxiety (HAM–A; Hamilton, 1959)
 XPanic disorder is experienced as discrete episodes or attacks with sudden onset of 
intense apprehension, fearfulness, or terror, often associated with sense of impend -
ing doom.
 XAttacks occur without warning and in the absence of any real danger.
 XAttacks build to a peak of intensity within a short, self-limiting time, usually within 10 
minutes of onset.
 XPanic disorder is more common in women than in men.
History
 ZDiagnostic criteria  of panic disorder:
 XDiscrete episode in which client experiences 4 or more of the following 
symptoms having a sudden onset and peaking within 10 minute of onset:
 ZParesthesias
 ZChills or hot flushing
 ZFear of losing control or of going crazy
 ZFear of dying
 ZShortness of breath or smothering sensation

ZParesthesias
 ZPalpitations, pounding, or accelerated heart rate 
 ZChest pain, tightness, or discomfort

208  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZSweating
 ZTrembling or shaking
 ZNausea or abdominal distress
 XAfter first attack, persistent concern over having another attack, worry over 
the consequences of initial attack, or a significant behavioral change related 
to attack
 XWith high somatic sensations, clients are often sensitive to new somatic 
experiences or perceptions.
 XOften intolerant of or concerned with common side effects of medication 
treatments
 ZDiscouraged or ashamed about “failure” to control emotions and over concern 
about dying when no other pathology identified
 XIn two-thirds of cases, major depression occurs first, followed by panic 
disorder symptoms.
 XIn one-third of cases, panic disorder symptoms precede major depression 
symptoms.
 XNonspecific, especially when client not experiencing panic attack
 XNonspecific cardiac-related complaints during panic episodes often bring client into

symptoms.
 XNonspecific cardiac-related complaints during panic episodes often bring client into 
treatment: 
 ZChest pain
 ZNumbness and paresthesia
 ZShortness of breath
Mental Status Exam Findings 
 XGeneral findings of anxiety as described earlier
 XFindings very pronounced during panic episodes and less pronounced during non -
panic periods
 XHigh level of anticipatory anxiety between panic episodes
 XNone specific
 XRule out general medical conditions known to produce similar symptoms, including
 ZPheochromocytosis
 ZVestibular dysfunction

209 anxiety disorders, oBsessive–c oMPulsive disorder, and trauMa- and s tressor-related disorders
 ZSeizure disorders
 ZCardiac arrhythmias such as supraventricular tachycardia (SVT)
 ZUse of CNS stimulants, including
 XCocaine
 XCaffeine
 ZAnother anxiety disorder such as posttraumatic stress disorder (PTSD) or 
phobias
 ZSeparation anxiety disorder
 ZConsider general medical disorder if
 XFirst episode of panic attack symptoms occurs after age 45
 XPanic symptoms are atypical, such as
 ZVertigo
 ZLoss of consciousness
 ZIncontinence
 ZHeadache
 ZSlurred speech
 ZAmnesic pattern after attacks
 XDifferentiated from other anxiety conditions by
 ZSudden onset of attack
 ZDiscrete, self-limiting nature of symptoms
 ZParoxysmal symptom profile
 ZLevel 3–4 anxiety symptoms with somatic symptoms that are experienced as 
distressing and severe by the client
 XFollow guidelines of general clinical management of anxiety disorders.

 XSSRIs 
 XBNZs, usually used for short-term symptom control or “bridge” medication when 
starting an SSRI or other antidepressant
 ZBuspar effective as an adjunct to an antidepressant
 ZOther non-benzodiazepine anxiolytic meds used as adjuncts
 XCBT
 XIndividual or group therapy

210  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XExposure therapy
 XRelaxation therapies
 XFrequent with major depressive disorder 
 XEstimated between 10% and 65%, depending on source:
 ZSocial phobia
 ZOCD
AGORAPHOBIA
 XAgoraphobia is characterized by avoidance of places or situations from which escape 
may be difficult or embarrassing or in which help may not be available in the event 
of perceived need, such as a panic attack. Up to 50% of people meeting criteria for 
agoraphobia report panic attacks or panic disorder preceded onset of agoraphobia.
 XThe anxiety usually leads to avoidant behavior that impairs a person’s ability to travel, 
to work, or to carry out responsibilities of daily living.
 XDifferential diagnosis is assisted by the awareness that people with agoraphobia 
feel better and report less significant concerns with anxiety when accompanied by a 
trusted companion.

XDifferential diagnosis is assisted by the awareness that people with agoraphobia 
 XWhen people meet criteria for agoraphobia and panic or other anxiety disorder, both 
diagnoses should be assigned.
History
 ZClinical presentation meets diagnostic criteria  for agoraphobia:
 XPresence of agoraphobic anxiety related to fear of developing panic-like 
symptoms
 XNever met criteria for panic disorder
 XAvoidant behavior as a result of the agoraphobic anxiety
 XNonspecific for agoraphobia
 XConsistent with finding for anxiety
 XThought content consistent with criteria for agoraphobia

211 anxiety disorders, oBsessive–c oMPulsive disorder, and trauMa- and s tressor-related disorders
 XFollow guidelines of general clinical management of anxiety disorders
Pharmacological Management 
 XSSRIs 
 XBNZs for short-term use
 XBeta blockers (off-label use) used for discrete episodes of social anxiety
 XCBT
 XSupportive group therapy
 XDesensitization therapy
 XPanic disorder
SPECIFIC PHOBIAS (SIMPLE PHOBIAS)
 XIn specific phobias is a clinically significant level of marked and persistent fear that 
is clearly observable and is, by client perception, clearly related to specific objects or 
 XIn adults, but not in children, exists the conscious recognition that the fear is exces -
sive or unreasonable.
 XIn children, the degree of insight to the unreasonable nature of the fear increases as 
age increases.

 XTraumatic past exposure
 ZHaving been bitten by dog, having choked on food, and so forth.
 XObservation of another’s trauma
 ZSeeing others be bitten by dog, seeing others choking on food, and so forth.
 XExcessive informational transmission
 ZRepeated graphic parental warnings of dangers of certain events or situations.
 ZHaving family member with specific phobia

212  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZBlood-injection-injury type is most familial
 ZSubtype aggregation patterns noted within families; for example, if a person’s 
first-degree relative has animal subtype, the risk is highest for him or her to 
develop animal subtype
History
 ZThe content of phobias, which can vary with culture, ethnicity, and age
 ZPhobic diagnosis should occur only when accompanied by significant functional 
impairment, such as full avoidance of school related to fear of encountering a spider.
 ZExposure to the specific feared object or situation immediately provokes the 
onset of clinically significant levels of anxiety
 XThis anxiety may fit the criteria for cued panic attack.
 XThe level of anxiety is directly related to how physically close the object or 
situation is to the person and the degree to which escape from the object 
or situation is possible.

XThe level of anxiety is directly related to how physically close the object or 
 XChildren manifest fear and anxiety as crying, freezing, tantrums, or 
excessive clinging behavior.
 XChildren normatively express a transient fear of animals and other natural 
objects.
 ZPerson engages in avoidant behavior to prevent reaction to object or situation or 
endures object or situation with dread. 
 XAvoidant behavior is distressful and has implications for social, recreational, 
and occupational or school functioning.
 XAssess for subtypes:
 ZThere are five common subtypes: situational, natural environment, blood 
injection injury, animal, and other.
 XA person can experience more than one subtype at a time.
 XA phobia to one object or situation in a subclass predisposes a person to 
another phobia within the same subclass (e.g., fear of rats increases the 
risk for fear of spiders).

XA phobia to one object or situation in a subclass predisposes a person to 
1. Situational Type:  Cued by specific situations; examples include driving, 
enclosed spaces, tunnels or bridges, or flying
 ZMost common adult form
 ZIn older adults, fear of closed-in situations most common
 ZBimodal peak of onset
 XFirst peak, childhood
 XSecond peak, mid-20s

213 anxiety disorders, oBsessive–c oMPulsive disorder, and trauMa- and s tressor-related disorders
2. Natural Environment Type:  Fear cued by objects in the natural environment; 
examples include storms, lightning, water, or heights
 ZSecond most common adult form
 ZOnset usually during childhood
3. Blood-Injection-Injury Type:  Cued by seeing blood or an injury or by receiving 
an injection or other invasive medical procedure
 ZThird most common adult form
 ZStrong vasovagal component that can produce other somatic 
sensations
 XMay exacerbate underlying cardiac or respiratory disorders
 XPerson often presents with fainting as chief complaint
 XExperiences paroxysmal tachycardia and hypertension followed by 
deceleration of heart rate and drop in blood pressure
 XClinical presentation and disease natural history similar to panic 
disorder with agoraphobia
4. Animal Type:  Fear cued by animals or insects; examples include rats, 
snakes, or spiders
 ZFourth most common adult form

5. Other Type: Fear cued by range of other stimuli; examples include fear of 
choking, vomiting, or fear of a specific illness
 ZIn children, often manifests as fear of loud sounds or costumed 
characters
 XNonspecific 
 XThought content consistent with criteria for phobia
 XAvoidance behavior in PTSD, OCD, separation anxiety disorder, or psychotic 
disorders

214  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XSSRIs
 XTCAs
 XShort term use of BNZs
 XCBT
SOCIAL ANXIETY (PHOBIA) DISORDER
 XSocial anxiety disorder is a marked and persistent fear of social or performance situa -
tions in which embarrassment may occur.
 XAnxiety levels often are sufficient to fit criteria for a situationally bound panic attack.
 XThe disorder has an estimated 3% to 13% prevalence rate among the U.S. 
population.
 XRates are equal for the genders.
History
 ZSome degree of social anxiety is common and normative in adolescence.
 ZSocial phobia should be diagnosed only if symptoms persist for longer than 6 
months.
 ZOnset is in the mid-teens, often following stressful or humiliating experience, 
and tends to remit with age.

ZSocial phobia should be diagnosed only if symptoms persist for longer than 6 
months.
 XDifferential diagnosis is assisted by awareness that people with social phobia do 
not feel better or experience decreased anxiety when accompanied by a trusted 
companion.
 ZCommon descriptive features:
 XHypersensitivity to criticism
 XNegative self-evaluations
 XSensitivity to rejection
 XLow self-esteem
 XInferiority feelings
 XLack of assertiveness

215 anxiety disorders, oBsessive–c oMPulsive disorder, and trauMa- and s tressor-related disorders
 ZProtracted anticipatory anxiety may occur days or weeks before the feared 
social situation.
 ZLevels of subjective distress and impaired functioning can be significant and 
have been associated with suicidal ideation.
Physical Exam Findings for a Person Who Is Acutely Anxious
 XSweating
 XTremors
 XPalpitations
 XMuscle tension
 XDiarrhea 
 XBlushing 
 XConsistent for anxiety
 XThought content consistent with criteria for social anxiety
Diagnostic and laboratory findings
 XSSRIs
 XBNZs, for short-term use
 XBeta blockers
 ZUsed for discrete episode relief
 ZFor example, before having to attend a scheduled social function
 XCBT
 XRelaxation therapy

XBeta blockers
 XCBT
GENERALIZED ANXIETY DISORDER (GAD)
 XIn GAD, excessive worry, apprehension, or anxiety about events or activities occurs 
more days than not for a period of at least 6 months.
 ZThe person finds it hard to control the anxiety.

216  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZNo clear link exists to life events or stressors.
 ZWorry and anxiety interfere with activities of daily living.
 ZThe nature and focus of worry shift frequently.
 ZA pattern of waxing and waning of symptoms exists.
 XSymptoms worsen as life events stress the person.
History
 ZIn GAD, anxiety and worry are out of proportion to the actual likelihood or effect 
of the feared event.
 ZPeople report subjective distress caused by the constant worry but do not 
always describe the worry as excessive.
 ZExcessive anxiety and worry last for more days than not for at least 6 months.
 ZThe person finds it difficult to control anxiety.
 XDifferential diagnosis
 ZPTSD
 ZObsessions in OCD
 ZAnxiety associated with another disorder such as hypochondriasis or social 
phobia

ZPTSD
phobia
 XAssociated with other health states
 ZIrritable bowel syndrome
 ZMigraine and other headache disorders
 XPhysical signs of anxiety 
 ZMuscle tension
 ZGeneralized muscle ache and soreness
 ZTremors
 ZTwitching
 ZSubjective complaints of shakiness
 ZAutonomic hyperarousal signs

217 anxiety disorders, oBsessive–c oMPulsive disorder, and trauMa- and s tressor-related disorders
 ZIncreased respiratory rates
 ZDizziness
 ZNumbness
 ZEasily fatigued, often experienced as activity intolerance
 ZMuscle tension and increased tone
 ZSleep disturbance
 XMood 
 ZAnxious
 ZFeeling keyed up or on edge 
 ZDifficulty concentrating
 ZThematic for the anxiety and worry
 ZDescriptive of the significant distress and impairment in daily functioning caused 
by GAD
 XSSRIs 
 XBuspar
 XBNZs as p.r.n. agents
 XGood candidates for therapy as single treatment modality
 XCBT
 XStress management
 XSupportive counseling

218  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XOther anxiety disorders
 XSubstance-related disorders
 XChildren
 ZAnxiety is common in children, but it is important to assess normal versus 
pathological levels.
 ZAnxiety is manifested in excessive worry over competence or quality of 
performance in school, work, sports, or other activities.
 ZCommon worry often manifests as anxiety over punctuality or catastrophes 
such as earthquakes or war.
 ZOften accompanied by
 XOverly conforming behavior
 XPerfectionist self-expectations
 XExcessive seeking of approval of others
 XNeed for frequent reassurance about performance
SEPARATION ANXIETY DISORDER
 XDevelopmentally inappropriate and excessive distress occurring after the age of 4 
when faced with separation from a major attachment figure. 
 XRefer to Chapter 15: Disorders of Childhood and Adolescence

 XMay persist into adulthood and in the DSM-5 it can be diagnosed in adulthood
OBSESSIVE–COMPULSIVE DISORDER (OCD)
 XOCD is the presence of anxiety-provoking obsessions or compulsions that function 
to reduce the person’s subjective anxiety level.
 ZObsession
 XDefined as recurrent and persistent thoughts, impulses, or images that are 
experienced and cause anxiety and distress
 XExperienced as intrusive and inappropriate 
 XEgo-dystonic experience in which a person feels the content of obsession 
is alien to his or her belief structure and not the kind of common thought, 
impulse, or image he or she usually experiences
 ZCompulsion 
 XDefined as repetitive behaviors or mental actions that a person feels driven 
to perform in response to an obsession.

219 anxiety disorders, oBsessive–c oMPulsive disorder, and trauMa- and s tressor-related disorders
 XGenetic predisposition
 ZFamilial transmission pattern
 XDisease rates higher in people with a first-degree relative who has OCD 
than in the general population.
 XRates are also higher in people with a first-degree relative who has 
Tourette’s syndrome than in the general population.
 XPANDAS (pediatric autoimmune neuropsychiatric disorders associated with 
streptococcal infections) should be considered in all children with sudden-
onset OCD symptoms
History
 ZDiagnostic criteria:
 XPresence of either  obsessions or compulsions
 XThe person recognizing that the obsession or compulsion is excessive or 
unreasonable
 XThe obsession or compulsion is causing marked distress, is time-
consuming, or interferes with normal daily activity.
 ZCommon obsessions include: 
 XRepeated thoughts about contamination, dirt, or germs

 XRepeated doubts, such as having hit someone with a car or having left an 
oven on, without evidence
 XNeed to have things in a specific order, with marked distress when that 
order is disturbed
 XAggressive or horrific thoughts
 XMay occur in pregnancy and postpartum periods and manifest as intrusive 
thoughts about something happening to their baby or doing something to 
their baby; the thoughts are highly ego-dystonic 
 XSexual imagery
 ZObsessions usually do not involve real-world worries such as concern over 
finances.
 ZThe person recognizes that the thoughts, impulses, or images are a product of 
his or her own mind.
 ZThe person attempts to ignore or suppress thoughts, impulses, or images or to 
override them with other thoughts or actions.
 ZPeople often avoid situations in which the content of obsession may be

 ZPeople often avoid situations in which the content of obsession may be 
encountered (e.g., avoiding public restrooms to avoid contamination)

220  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZCommon compulsions include 
 XRepetitive actions, usually behavioral, and often called rituals
 ZHandwashing
 ZExcessive cleaning
 ZChecking to see, for example, if the lights are turned off, the stove is 
turned off, or the doors are locked
 ZNeeding to place objects in certain order
 XCommon mental actions include
 ZCounting
 ZSilently repeating words
 ZPraying
 XBehaviors or mental acts are not experienced as pleasurable and are 
intended to prevent or reduce distress and subjective anxiety.
 ZIf the person resists the compulsion, anxiety and subjective tension 
usually increase. 
 ZSome people believe the compulsion can prevent some dreaded event 
or situation that is experienced as an obsession, such as sexual or 
horrific images.
 XDermatitis may be present related to excessive handwashing or overuse of caustic 
cleaning agents.

 XHypochondriasis and somatic fixation common
 XThought content dominated by obsessions
 XBehavioral manifestations of rituals may be noted
 XBody dysmorphic disorder
 XTrichotillomania
 XHypochondriasis

221 anxiety disorders, oBsessive–c oMPulsive disorder, and trauMa- and s tressor-related disorders
 XObsessive–compulsive personality disorder
 XTic or stereotypic movement disorder
 XSSRIs (clients often need higher dosing range for adequate symptom control)
 XTCAs (clomipramine)
 XSecond-generation antipsychotics such as risperidone are off-label but have data sup -
porting their adjunctive use with SSRI medication
 XCBT
 XMajor depression
 XChildren
 ZCommon in childhood, usually with prepubertal onset 
 ZMore common in boys than in girls
 ZWashing, checking, and ordering are the most common behavioral 
manifestations.
 ZCommon comorbidities in children:
 XLearning disorders
 XDisruptive behavioral disorders

ZWashing, checking, and ordering are the most common behavioral 
 XTourette’s syndrome
 ZAssociated in children with Group A beta-hemolytic streptococcal infections 
(e.g., scarlet fever, strep throat)
 XOlder adults
 ZMore obsessions than compulsions usually present
 ZObsessive content characteristically about dying
 ZCompulsions characteristically about washing and cleaning

222  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
POSTTRAUMATIC STRESS DISORDER (PTSD)
 XPTSD is the reexperiencing of an extremely traumatic event accompanied by symp -
toms of increased arousal and avoidance of stimuli associated with the trauma.
 XThe traumatic event can be experienced directly or witnessed.
 ZCommon experienced  trauma includes
 XMilitary combat
 XViolent personal assault such as robbery or rape
 XKidnapping or hostage situation
 XTerrorist attack
 XTorture
 XProlonged sexual abuse
 XNatural or human-made disasters
 ZCommon witnessed  trauma includes
 XObserving the death of or significant injury to another
 XUnexpectedly witnessing of any of the above traumas
 XLearning of the sudden or unexpected death of or significant injury to family 
member or close friend
 XA relationship exists between the person’s physical proximity to the traumatic event 
and the likelihood of symptom onset.

 XExperienced or witnessed trauma
 ZAssumed to have strong genetic etiological component and tends to run in families
 ZHistory of major depression in first-degree relative related to increased risk of 
developing PTSD
Assessment 
History
 ZSymptoms cannot predate exposure to trauma.
 ZPresenting symptoms and history can be delineated as one of three subtypes:
 XAcute : Duration of symptoms less than 3 months
 XChronic: Symptoms lasting 3 months or longer
 XDelayed onset: At least 6 months between traumatic event and the onset 
of symptoms

223 anxiety disorders, oBsessive–c oMPulsive disorder, and trauMa- and s tressor-related disorders
 XIncreased rates of somatic complaints
 XInsomnia frequently chief complaint on presentation for evaluation
 XDistractibility in motor tasks
 XMeasurable increased autonomic symptoms
 ZIncreased startle response
 XThought content consistent with criteria for PTSD and often dominated by traumatic 
experience
 XMay demonstrate some psychotic findings during flashback episodes.
 XDiagnostic criteria (symptoms for 1 month or longer):
 ZExposure to a traumatic event 
 XThe person experienced, witnessed, or was confronted with an event 
involving the actual or threatened death or serious injury, and the person’s 
response involved intense fear, helplessness, or horror.

 ZThe traumatic event is persistently reexperienced in one or more of the 
 XRecurrent and intrusive, distressing recollection of the event, including 
images, thoughts, and perceptions
 XMay be experienced as flashbacks
 XRare cases involve dissociative states lasting hours to days
 XRecurrent distressing dreams about the event
 XActing or feeling as if the traumatic event were reoccurring
 XIntense psychological distress at exposure to cues that symbolize or 
resemble aspects of the traumatic event
 XPhysiological reactivity on exposure to cues that symbolize or resemble 
aspects of the traumatic event
 ZThree or more avoidance symptoms
 XPersistent avoidance of stimuli associated with the traumatic event and 
numbing of responsiveness
 XEfforts to avoid talking about or thinking about traumatic event

224  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XAvoidance of activities, places, or people that arouse recollections of 
traumatic event
 XInability to recall important aspects of event
 XMarked decreased interest or participation in activities
 XFeelings of detachment or estrangement from others
 XRestricted range of affect
 XSense of foreboding and of shortened future, premature death, or no 
expectation for success or happiness
 ZTwo or more increased arousal symptoms
 XPersistent symptoms of increased arousal
 ZDifficulty falling asleep
 ZIrritability or outburst of anger
 ZHypervigilance
 ZExaggerated startle response
 ZSymptoms causing significant distress or impairment in activities of daily 
 ZSymptoms usually occur within 3 months of trauma
 ZDuration of symptoms highly variable
 XSymptoms remit within 3 months in one-half of cases

 XCommon waxing and waning of symptoms related to internal and external 
cues that resemble the trauma
 XAdjustment disorder
 XBrief psychotic disorder
 XAcute stress disorder
 XIntrusive thoughts in OCD
 XSSRIs
 XTCAs

225 anxiety disorders, oBsessive–c oMPulsive disorder, and trauMa- and s tressor-related disorders
 XBNZs are not recommended in the treatment of PTSD
 XAntipsychotics may be useful during episodes of flashbacks.
 XAlpha antagonists (e.g., Prazosin) may be used for treating nightmares (off-label use).
 XCBT
 XExposure Therapy with Response Prevention (ERP)
 XEye movement desensitization and reprocessing
 XDysthymia
 XSubstance abuse or dependence
 XCan occur at any age, including childhood
 ZChildren
 XExpression of fear and horror occurs in disorganized or agitated behavior.
 XRepetitive play behaviors show themes or aspects of trauma.
 XFrightening dreams, but without recognized content, are common.
 XIn young children, learning that a traumatic event occurred to a parent or a 
caregiver may be the precipitating factor.

XFrightening dreams, but without recognized content, are common.
DISSOCIATIVE DISORDERS
 XDissociative amnesia, depersonalization or derealization, and dissociative identity 
disorder (DID)
 XDissociation  is a defense mechanism that protects a person from overwhelming 
anxiety by emotionally separating.
 ZDissociation causes gaps or interruption in the person’s memory
 XDepersonalization or derealization: A persistent feeling of oneself not being real, or 
the environment not being real; reality testing remains intact
 ZDepersonalization and derealization are generally perceived as uncomfortable.
 ZEtiology of depersonalization and derealization can be physical or psychological.
 ZPhysical causes are seizures, migraine headaches, psychedelic drugs, and 
alcohol.
 ZPsychological causes are severe anxiety and traumatic stress.

226  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XDID is characterized by two or more distinct personality states (“alters”).
 ZPersonality states are generally split off from one another, leading to gaps in 
recall of everyday events.
 ZSymptoms cause significant distress and impaired functioning.
 ZComorbid with PTSD.
 ZEtiology is a history of severe physical or sexual trauma, or both, in childhood.
BODY DYSMORPHIC DISORDER
 XPreoccupation with one or more perceived defects or flaws in physical appearance
 XEngages in repetitive behaviors (checking mirror, reassurance-seeking, etc.) in re -
sponse to appearance concerns
 XPreoccupation causes considerable distress
 XInsight ranges from good to poor to absent (fixed delusion)
HOARDING DISORDER
 XPersistent difficulty discarding possessions, regardless of actual value
 XExperiences marked distress in response to pressure to discard

 XResults in accumulation of possessions that compromise living space or ability to 
function, including maintaining a safe environment for self or others
TRICHOTILLOMANIA 
 XRecurrent pulling out of one’s hair despite repeated attempts to stop
 XCauses significant distress or impairment in functioning
 XHair-pulling is not an attempt to improve a perceived defect or flaw
EXCORIATION DISORDER
 XRecurrent skin picking that results in lesions despite attempts to stop
 XResults in significant distress or impairment
 XBehavior not better explained by physiologic response to substance (e.g., metham -
phetamine use) or intentional attempt at self-harm

227 anxiety disorders, oBsessive–c oMPulsive disorder, and trauMa- and s tressor-related disorders
CASE STUDY
Mr. J. is a 47-year-old school custodian with a long history of GAD. He reports he had been doing 
well until about 4 weeks ago, when he was traveling overseas with his church group for a car -
ing mission in South America. Mr. J. noted that he began feeling “depressed by seeing all the 
poverty and despair in those places. ” He began to have difficulty falling and staying asleep. He 
experienced disturbing dreams about what he was seeing during the day. The sleep disturbances 
persisted upon his return home, and he started feeling anxious and could not concentrate during 
his work day.
One week ago, Mr. J. began to feel overwhelmed by anxiety. He was unable to go to work. He 
experienced discreet “attacks” of rapid heart rate, sweating, and difficulty breathing. He went 
to a local emergency department several times, was evaluated, and each time was given “a

to a local emergency department several times, was evaluated, and each time was given “a 
shot” and sent home. The emergency department doctor also suggested he contact a therapist. 
He was not convinced that his distress was due to anxiety. On the third visit to the emergency 
department, the doctor gave Mr. J. a prescription for alprazolam 0.5 mg #30 with the directions 
“take as needed for anxiety” and referred him back to his primary care provider. Although Mr. 
J. initially felt the medication was helping, he has continued to have difficulty falling and staying 
asleep and has continued to have “bad dreams. ” He needed 4 tablets of alprazolam yesterday 
before finally falling asleep until this morning. He now believes “the medicine isn’t working. 
There is something really wrong with me and nobody believes me. My wife and the people

There is something really wrong with me and nobody believes me. My wife and the people 
at the hospital think it’s all in my head. I know I’m anxious, but what if there’s also something 
wrong with my heart? Doctors miss things all the time…. ” Mr. J. now presents to the PMHNP at 
the hospital-based outpatient psychiatry department. 
 XAppearance: Well-nourished, well-dressed
 XMotor: Some motor restlessness
 XSpeech: Some pressure
 XAffect: Anxious
 XMood: Depressed
 XThought process and content: Thematic for fear of serious cardiac etiology not being 
adequately assessed or treated. There is no evidence of an overt delusional process.
 XAbstractive on proverbs
 XMemory: Impaired
 XConcentration: Impaired
 XMarried and has 3 children 
 XWorks as high school custodian
 XOverweight at 280 lbs., with sedentary lifestyle
 XSmokes 2 packs a day

XMemory: Impaired
 XDoes not drink alcohol for religious reasons
 XWife very concerned and supportive

228  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XHospitalized in 1998 for “nerves”
 XAt that time started on paroxetine (Paxil) 20 mg/d 
 XAfter 3 months, dose was raised to 40 mg q.d. and he remained on that dose for 
the next 18 months, when he tapered off the drug under his primary care provider’s 
 XHas had no significant exacerbation of symptoms since initial treatment
 XHistory of seizure disorder since childhood; well-controlled with levetiracetam 
(Keppra)
 XAlprazolam 0.5 mg p.o. p.r.n. q 4 hrs.
Labs
 XElectrocardiogram (EKG), CBC, thyroid function tests, and chemistry panel done in 
emergency department and all within normal limits
Screening T ools
 XCurrent level of anxiety: moderate–severe 
In planning care for this client, the PMHNP has many issues to 
consider:
1. What is the most likely diagnosis?

consider:
2. How will the PMHNP separate comorbidity from complications of current diagnosis?
3. What medication adjustments would the PMHNP make?
4. How will the PMHNP address the family issues?
5. How often will the PMHNP plan to see the client?
Given the level of Mr. J. ’s initial distress, you decide to restart paroxetine and continue using al -
prazolam as a bridge medication while waiting for a therapeutic response to the antidepressant. 
6. What considerations should be given to using a benzodiazepine in a client with panic 
disorder?
Mr. J. has now been taking paroxetine 20 mg for the past 2 weeks. He has not had a panic attack 
since beginning treatment with the scheduled dose of benzodiazepine that was started when 
he started the paroxetine. He no longer worries that he has a heart condition. He falls asleep

he started the paroxetine. He no longer worries that he has a heart condition. He falls asleep 
quickly, but continues to have some mild middle-phase insomnia that lasts up to one hour. He

229 anxiety disorders, oBsessive–c oMPulsive disorder, and trauMa- and s tressor-related disorders
eventually falls back to sleep, but wakes up feeling anxious. He is tearful at times during the day, 
and worries that the panic attacks will recur if he stops taking the benzodiazepine. 
7. How should the PMHNP adjust the treatment plan?
8. Mr. J. has been taking paroxetine 40 mg q.d. for the past month. He is now taking 
clonazepam 0.5 mg q.a.m. and q.h.s. for the past 2 weeks after he experienced 
sedation while taking 0.5 mg q.a.m. and 1 .0 mg q.h.s. He continues to experience 
mild–moderate anxiety periodically most days. How should the PMHNP alter the 
9. At what point should the PMHNP begin to taper the client off the clonazepam?

230  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
1. Mr. J meets criteria for panic disorder. It is not unusual for people who have panic 
attacks to misinterpret the symptoms as cardiac or other etiology. The PMHNP must 
also assess for a mood disorder as symptoms anxiety and mood symptoms often 
overlap. 
2. The PMHNP should perform a complete assessment which includes a physical 
examination, mental status examination, and lab studies. The client’s current medica -
tions should be evaluated and the chronology of symptoms should be compared to 
any changes in his health status.
3. After assessing the efficacy of Mr. J’s treatment history, the PMHNP should con -
sider restarting paroxetine.
4. Several approaches might be appropriate, including using psychoeducation for the 
family, providing supportive counseling, or involving the family in family therapy.

5. Mr. J. should be seen frequently until symptoms are stable. Weekly appointments 
during the initial phase of treatment would be ideal.
6. Before starting a benzodiazepine, the PMHNP should assess the client’s history of 
recent and remote substance use or abuse. Potential risks versus benefits of short-
term use must also be discussed along with the expectation that the medication will 
be tapered once the antidepressant is therapeutic. The PMHNP should discuss the 
expected therapeutic outcome of using an SSRI or other antidepressant. When using 
a benzodiazepine, consider using scheduled dosing to prevent onset of panic symp -
toms. Clients who have severe anxiety often underdose or overdose medications

toms. Clients who have severe anxiety often underdose or overdose medications 
to address their symptoms. Discuss expectations that the client will not adjust his 
dose of medication without direction. Short-acting benzodiazepines require dosing 
more frequently than long-acting benzodiazepines and may contribute to the client 
connecting the feeling of being anxious with taking a pill.
7. The PMHNP should consider switching to a long-acting benzodiazepine that may be 
scheduled in the a.m. and h.s. to provide better nighttime and early morning cover -
age. The NP should discuss the expected outcome of each medication with the cli -
ent. The PMHNP should increase the paroxetine dose in increments back to the dose 
that was previously therapeutic (40 mg).
8. As long as he is not having considerable side effects, increase the paroxetine to 50 
mg q.d. Continue weekly psychotherapy. Continue clonazepam.

9. Although benzodiazepines should be used for as brief a period as possible, discon -
tinuing the medication too quickly may result in relapse. Unless otherwise indicated 
by side effects, benzodiazepine taper should begin after the client is at an adequate 
dose of antidepressant and he is no longer having significant anxiety symptoms
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CHAPTER 11SCHIZOPHRENIA SPECTRUM AND OTHER 
PSYCHOTIC DISORDERS
This chapter describes a category of severe mental illnesses that have a researched biological 
basis to the disorders. Schizophrenia, the prototypic disorder of this category of illnesses, is mul -
tifaceted and affects a person’s ability to function in many spheres of daily life. Of the psychotic 
disorders, schizophrenia is the illness that has been heavily researched and the one we know the 
most about.
The other disorders that compose this category of illnesses will be presented after the in-depth 
discussion of schizophrenia. Almost all of the information provided for schizophrenia and for the 
clinical management of this disorder will pertain to the other psychotic disorders presented in 
this chapter. 
GENERAL DESCRIPTION OF PSYCHOTIC DISORDERS
 XThese brain-based psychiatric disorders are grouped together because of similarity in 
frequent psychotic symptoms. Each disorder has a different etiology.

XThese brain-based psychiatric disorders are grouped together because of similarity in 
frequent psychotic symptoms. Each disorder has a different etiology. 
 XPsychotic disorders are some of the most debilitating classes of psychiatric disor -
ders, as determined by the degree of functional impairment and financial burden of 
severe mental illness.
 XPsychotic implies inability to test reality.
 ZManifests in symptoms (see Table 11–1) such as 
 XHallucinations
 XDelusions
 XDisorganized thinking and speech
 XReferential thinking
 XAbnormal motor behavior 
 XNegative symptoms 
 XPsychotic disorders are generally known to have a strong genetic component.

234 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
TABLE 11–1  .
SYMPTOMS OF PSYCHOSIS
CLINICAL 
MANIFESTATION DEFINITION TYPE
Hallucinations False sensory 
experience without 
stimuli being present(Arranged in order of commonality)
Auditory
Visual
Tactile
Olfactory
Gustatory
Note: Hypnogogic* and hypnopompic* 
experiences are considered normative 
and do not fall under the true definition of 
hallucinations.
Delusions A false belief firmly 
maintained despite 
evidence to the 
contraryPersecutory
Religious
Grandiose
Somatic
Jealous
Erotomanic
thinking (often 
referred to as 
formal thought 
disturbance  or 
disorder)Problems with 
information organization 
and interpretation that 
is best assessed in 
the speech patterns of 
clients Loose association
Derailment
Speaks tangentially
Word salad
behaviorUnusual behavior 
ranging from childlike 
silliness to anger Silliness
Unpredictable anger

Word salad
Difficulties with activities of daily living
Disheveled
Odd or unusual dress
Inappropriate sexual activity
Stereotypic motor activities
Referential thinking 
and delusions of 
controlBelief that events, 
actions, or situations in 
the environment hold 
special significance or 
meaningThought insertion
Thought withdrawal
Thought control
Thought broadcasting
Illusional Misperception of actual 
environmental stimuliAuditory
Visual
Tactile
Olfactory
Gustatory
*Hypnopompic hallucination = a false perception that occurs when one is waking up; 
hypnogogic hallucination = a false perception that occurs when one is falling asleep; both are 
not considered pathological hallucinations.

235 schizoPhrenia sPectruM and o ther Psychotic disorders
SCHIZOPHRENIA
 XSchizophrenia causes significant disturbance in many areas of functioning:
 ZCognition
 ZPerception
 ZEmotion
 ZBehavior
 ZEye movement
 ZSocialization
Etiology
 XMultiple theories exist, ranging from psychological to neurobiological.
 XThe etiological profile is probably multifactorial.
 XNeurobiological theory
 ZImplicates three areas of neurobiological functioning: genetics, 
neurodevelopment, and neurobiological defects
 XGenetics
 ZStudies of twins have identified schizophrenia as having a strong 
genetic component. 
 ZIncidence increases from 1% risk of illness in general population to 
50% risk in monozygotic twin of a person with schizophrenia.
 Z15% risk in dizygotic twin of a person with schizophrenia.
 Z40% risk in children if both parents have schizophrenia.
 ZNo one specific gene has yet been identified.
 ZA polygenic SNIP defect is believed to exist.

Z40% risk in children if both parents have schizophrenia.
 ZChromosomes 6p24–22 have been implicated (Sadock, Sadock, & Ruiz, 
2015). 
 XNeurodevelopment
 ZGenetic defects are believed to cause abnormal neuronal cell 
development, connection, organization, and migration.
 XThese include inadequate synapse formation, excessive pruning of 
synapses, and excitotoxic death of neurons.
 ZIntrauterine insults may contribute to etiological picture:
 XPrenatal exposure to toxins, including viral agents
 XOxygen deprivation
 XMaternal malnutrition, substance use, or other illness

236 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XNeurobiological defect
 ZSeveral abnormal brain structures have been identified in people with 
schizophrenia:
 XEnlarged ventricles
 XSmaller frontal and temporal lobes
 ZReduced symmetry in temporal, frontal and occipital lobes 
 XCortical atrophy
 XDecreased cerebral blood flow
 XHippocampal and amygdala reduction (Sadock, Sadock, & Ruiz, 
2015).
 ZAbnormalities lead to suspected impaired neuronal communication:
 XSuspected alterations in chemical neuronal signal transmission
 ZExcess dopamine in mesolimbic pathway
 ZDecreased dopamine in the mesocortical pathway
 ZExcess glutamate
 ZDecreased gamma-aminobutyric acid (GABA)
 ZDecreased serotonin
 XGeographic and historical variations in incidence give insight into etiological factors; 
higher rates seen in:
 ZUrban-born
 ZFirst-born
 ZLower socioeconomic status
 ZBorn in winter and early spring

 XSchizophrenia tends to occur less often in women than in men.
 ZMen: Onset ages 18–25 years
 XTend to have more negative symptoms than women
 XTend to have poorer prognosis, more hospitalizations, and less 
responsiveness to medications than women
 ZWomen: Onset ages 25–35 years
 XUsually have less premorbid dysfunction than men
 XUsually experience more dysphoria than men
 XTend to have paranoid delusions and more hallucinations than men
 XAge of onset has pathophysiological and prognostic significance.
 ZEarlier age of onset
 XTend to be men

237 schizoPhrenia sPectruM and o ther Psychotic disorders
 XHave poorer premorbid functioning
 XHave more evidence of structural brain abnormalities
 XHave more prominent negative symptoms
 XHave more cognitive impairment
 XHave poorer prognosis
 ZLater age of onset
 XTend to be women
 XHave less evidence of structural abnormalities
 XHave less cognitive impairment
 XHave better prognosis
Possible Risk Factors
 ZFirst-order relative with schizophrenia
 XPrenatal exposure to flu or virus
 XPrenatal malnutrition
 XObstetrical complications
 XCentral nervous system (CNS) infection in early childhood

XEarly recognition, intervention, and initiation of treatment
 ZUsually mild manifestations of criteria symptoms:
 XOdd or unusual beliefs but not to delusional proportion
 XFeel unliked or picked on but not to delusional proportion
 XOdd speech patterns but not illogical
 ZDigressions
 ZTangentiality
 XOverly concrete or abstractive

238 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XOdd behavior but not disorganized
 ZCollects odd or worthless items
 ZMumbles to self
 ZIsolates self and avoids interaction with others
History
 ZThere exists no single pathognomonic symptom of schizophrenia, but rather a 
constellation of symptoms.
 ZSchizophrenia is a disease of information processing.
 ZThe symptoms are behavioral and cognitive.
 ZThe illness is associated with marked social or occupational functioning.
 ZProminent dysfunctions exist in many spheres of daily living.
 XInterpersonal relationships
 Z60% to 70% of clients do not marry
 XSocial or occupational functioning
 Z“Downdrift” functionality is noted over time.
 XLower academic achievement compared to unaffected siblings
 XDifficulty holding a job
 XUnderemployed relative to intellectual capacity
 XSelf-care deficits
 ZPoor hygiene
 ZDifficulty with financial management

XDifficulty holding a job
 ZLimited independent living skills
 ZCharacteristic symptom clusters for the illness (see Table 11–2) include
 XPositive symptom cluster
 XNegative symptom cluster
 XAssociated symptoms
 XDSM-5 (American Psychiatric Association, 2013) diagnostic criteria for schizophrenia:
 ZTwo or more of the following frequently are present during a 1-month period and 
at least one must be delusions, hallucinations, or disorganized speech:
 XDelusions: Bizarre and unorganized type; examples include delusions that 
manifest as loss of control over mind or body:
 ZThought withdrawal
 ZThought insertion

239 schizoPhrenia sPectruM and o ther Psychotic disorders
 XHallucinations: Bizarre and unorganized type; examples include 
hallucinations that are improbable or readily apparent as not likely to have 
occurred
 XDisorganized speech
 XGrossly disorganized behavior
 XNegative symptoms
 XSignificant impairment usually is evident by social or occupational 
dysfunction.
 XDuration of symptoms lasts for at least 6 months.
 ZThe course of illness is variable.
 XMany clients have a fairly stable illness course.
 XSome clients have clear episodic remissions and exacerbation periods.
 XNegative symptoms tend to appear first as the illness develops.
 XPositive symptoms appear to decrease over time, but negative symptoms 
persist.
 XNegative symptoms are more debilitating.TABLE 11–2 .  
POSITIVE AND NEGATIVE SYMPTOM CLUSTERS OF SCHIZOPHRENIA
SYMPTOM 
CLUSTER EXPLANATION CLINICAL MANIFESTATIONS
Positive symptoms Symptoms that respond positively 
to and that can be controlled by

SYMPTOM 
to and that can be controlled by 
Reflect excesses or distortions of 
normal brain functioning
Caused by increased dopamine in 
the mesolimbic pathwayHallucinations
Delusions
Referential thinking
Disorganized behavior
Hostility
Mania
Suspiciousness
Negative 
symptomsSymptoms less responsive 
to antipsychotic medications 
but respond better to atypical 
Represent a decrease or loss of 
normal functioning
Caused by decreased dopamine in 
the mesocortical pathwayAffective flattening 
Alogia or poverty of speech
Avolition
Apathy
Abstract-thinking problems
Anhedonia
Attention deficits
Associated 
symptomsSymptoms not required to be 
present to diagnose the disorder 
but often are present and a focus of 
treatmentInappropriate affect
Dysphoric mood
Depersonalization

Derealization
High anxiety

240  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XFactors predictive of good prognosis:
 ZHigh level of premorbid functioning
 ZAcute onset
 ZClear precipitating event
 ZMarried or partnered
 ZGood support system
 ZPositive symptoms
 ZShort interval between treatment and onset of first symptoms
 XThe sooner the client is treated, the better the prognosis.
 XLonger untreated premorbid period is associated with a poorer 
prognosis.
 ZAbsence of structural brain abnormalities
 ZFamily history of mood disorders
 ZNo family history of schizophrenia
 XSubtype identification is of limited clinical value, because illness course, 
response to treatment, and prognosis appear unrelated to subtype (see 
Table 11–3).
 XAbnormal smooth pursuit eye movements
 XAbnormal saccadic eye movement
 XPoor eye–hand coordination
 ZClient identified as “clumsy” or “awkward”
TABLE 11–3 .  
SUBTYPES OF SCHIZOPHRENIA*

XAbnormal smooth pursuit eye movements
SUBTYPE CHARACTERISTIC
Paranoid Prominent delusions or auditory hallucinations
Lack of prominence of disorganized speech or behavior
Disorganized Prominence of disorganized speech, behavior, and flat or inappropriate affect
Catatonic Prominence of motor symptoms, including immobility as evidenced by 
catalepsy or stupor, excessive motor movement that is purposeless and not 
influenced by environmental stimuli, extreme negativity, mutism, oddities of 
posturing, echolalia,* and echopraxia*
Undifferentiated Presence of symptoms consistent with schizophrenia but not a prominence 
of symptoms consistent with any of the other subtypes
Residual Absence of prominent delusions, hallucinations, disorganized speech, 
and disorganized or catatonic behavior, and the continued presence of

and disorganized or catatonic behavior, and the continued presence of 
disturbance as indicated by presence of negative symptoms
*Subtypes are no longer diagnosed in the DSM-5. Echolalia  = repetition of the last-heard words 
of other people; e chopraxia  = imitation of observed behavior or movements.

241 schizoPhrenia sPectruM and o ther Psychotic disorders
 XPresence of neurological nonlocalizing “soft signs”:
 ZAstereognosis : Loss of ability to judge the form of an object by touch
 ZTwitches, tics, or rapid eye blinking
 ZDysdiadochokinesia : Impairment of the ability to perform rapidly alternating 
movements
 ZImpaired fine-motor movement
 ZLeft–right confusion
 ZMirroring
 XPresence of neurological localizing “hard signs”:
 ZWeakness
 ZDecreased reflexes
 XOther abnormalities that may be noted:
 ZHighly arched palate
 ZNarrow or wide-set eyes
 ZSubtle malformations of the ears
 ZOdd
 ZUnusual
 ZPeculiar
 XSpeech
 ZBizarre content
 ZDisorganized
 ZTangential
 ZLoose association
 XAffect
 ZBlunted
 ZFlat
 ZInappropriate
 XMood
 ZBlandness
 ZImpoverished
 ZPsychotic
 XHallucination
 XDelusion

242 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XReferential
 XThought control, insertion, or withdrawal
 XThematically matched to psychotic content
 XMay be impoverished
 XCognition
 ZIllogical
 ZUsually intact
 XMemory
 ZMay have impaired short-term
 ZImpaired during acute episodes
 ZConcrete on formal testing
 XJudgment
 ZImpaired for self-welfare
 XNo specific diagnostic lab findings exist.
 XAbnormalities noted in structural studies 
 ZEnlargement of lateral ventricles
 ZWidened cortical sulci
 ZDiffuse decrease in volume of white and gray matter
 ZDecreased volume of temporal lobe
 ZDecreased volume in hippocampus, amygdala, and thalamus (Sadock, Sadock, & 
Ruiz, 2015)
 XAbnormalities noted in functional studies 
 ZHypofrontality
 ZDecreased cerebral blood flow and metabolism

ZDecreased volume in hippocampus, amygdala, and thalamus (Sadock, Sadock, & 
 ZDiffuse hypometabolic action in cortical–subcortical circuitry
 XNonpsychiatric disorders
 ZEpilepsy
 ZCNS neoplasm

243 schizoPhrenia sPectruM and o ther Psychotic disorders
 ZAIDS
 ZAcute intermittent porphyria
 ZB12 deficiency
 ZHeavy-metal poisoning
 ZHuntington’s disease
 ZNeurosyphilis
 ZSystemic lupus erythematosus
 ZWernicke-Korsakoff syndrome
 ZWilson’s disease
 XPsychiatric disorders
 ZBipolar affective disorder
 ZSubstance-induced psychotic disorder
 XAlcoholic hallucinosis
 XBarbiturate withdrawal
 XCocaine
 XPCP (phencyclidine or angel dust)
 ZMood disorders with psychotic features (see Chapter 9)
 ZSchizoaffective disorder (see below)
 ZSchizophreniform disorder (see below)
 ZBrief psychotic disorder (see below)
 ZDelusional disorder (see below)
 ZSchizotypal personality disorder (see Chapter 14)
 ZSchizoid personality disorder (see Chapter 14)
 ZParanoid personality disorder (see Chapter 14)
 XAssess for acuity level
 ZDuring acute psychotic episodes, client may require brief hospitalization to
 XEnsure client safety,

ZParanoid personality disorder (see Chapter 14)
 XRapidly stabilize client’s symptom level in a controlled environment, and/or
 XMonitor treatment adherence with the goal of stabilization and recovery.
settings.

244  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th editionTABLE 11–4 .  
ATYPICAL ANTIPSYCHOTICS
FORMS; 
DAILY 
Clozapine Clozaril Tablet or oral 
disintegrated 
tablet; 25–900 
mg/dCommon:  
Tachycardia, 
drowsiness, 
dizziness, 
hypersalivation 
(sialorrhea), weight 
gain, hyperlipidemia 
Rare:  
Agranulocytosis, 
myocarditis, 
neuroleptic 
malignant 
syndromeOnly drug for treatment-resistant schizophrenia
Must be enrolled in a clozapine risk evaluation and management strategy program 
(clozapine REMS program) 
Risk for neutropenia is monitored by the absolute neutrophil count (ANC) only ,not 
in conjunction with the white blood cell count
During first 6 months: weekly; during second 6 months: every 2 weeks; then 
monthly if ANC normal
ANC levels less than 500/μl suspend drug
Clients can be rechallenged if the prescriber determines benefits outweigh the risks 
Monitor for myocarditis

Dose-related seizure risk
Significant weight gain and risk of diabetes
Rare hyperprolactinemia 
Monitor weight, body mass index (BMI), waist circumference
Monitor serum lipids and glucose
Assess family and personal history of cardiovascular disease 
Quetiapine Seroquel 
and 
Seroquel 
XRTablet;  
50–800 mg/dCommon:  Sedation 
and hypotension 
(orthostatic 
hypotension), 
weight gain
Rare:  Cataract 
formationTransient and asymptomatic elevated liver function tests (LFTs)
Monitor for cataract development
Divided doses: b.i.d. or t.i.d.
No prolactin elevation
Monitor weight, BMI, waist circumference
Assess family and personal history of cardiovascular disease

245 schizoPhrenia sPectruM and o ther Psychotic disordersOlanzapine Zyprexa, 
Zyprexa 
Zydis, 
Zyprexa 
RelprevvTablet and 
intramuscular 
injection 
(acute);  
5–20 mg/d
Injection; 
150–405 mg 
every 2–4 
weeks Sedation, 
weight gain, 
hyperlipidemia, 
elevated glucose, 
elevated LFTs, mild 
prolactin elevation
Long-acting 
preparation 
(Zyprexa Relprevv) 
requires that clients 
be monitored for 3 
hours postinjection 
due to risk of 
postinjection 
delirium sedation 
syndrome Significant weight gain
Risperidone Risperdal, 
Risperdal 
ConstaTablet, liquid, 
and orally 
tablets; 2–8 
mg
Injectable; 
25–50 mg IM 
every 2 weeksHypotension, 
galactorrhea, 
nausea, insomniaDoses >6 mg associated with a higher incidence of extrapyramidal symptoms
Less weight gain than with clozapine or olanzapine

25–50 mg IM 
Greatest prolactin elevation among atypical psychotics
Ziprasidone Geodon Tablets; 
40–200 mg/d
10–20 mg 
IM (acute 
treatment) Hypotension, 
sedation,
dizziness
Rare:  Prolongation 
of QTc interval, 
skin reaction, 
drug reaction with 
eosinophilia and 
systemic symptoms 
(DRESS)Requires QTc monitoring
Avoid coadministration with other drugs known to prolong QTc
Taking with food increases absorption twofold
Use caution when administering with clients at risk for hypokalemia, 
hypomagnesemia, after myocardial infarction, or with congestive heart failure

CONTINUED

246 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
FORMS; 
DAILY 
Paliperidone Invega, 
Invega 
Sustenna 
(monthly 
injection) 
Invega 
Trinza 
(3-month 
injection)Tablets; 3–12 
mg/d
Injection; 39 
mg–234 IM 
Injection every 
three months; 
273 mg, 410 
mg, 546 mg, 
or 819 mg IM 
 Orthostatic 
hypotension, 
hyperprolactinemia, 
GI upset, dizziness, 
headacheExtended-release risperidone
Aripiprizole Abilify Tablets; 5–30 
mg/d
Injection 
(acute 
agitation); 
5.25–15 mg 
IM, (long-
acting) or 
200–400 mg 
IM monthly Headache, agitation, 
anxiety, insomnia, 
somnolence, 
akathisia, 
gastrointestinal (GI) 
problemsIs a partial agonist of D2 receptors
Iloperidone Fanapt 12–24 mg/
day in divided 
doses Orthostatic 
hypotension,

sedation, dizzinessTitrate slowly due to the alpha 1 antagonist properties 
Might be helpful for posttraumatic stress disorder hyperarousal symptoms due to 
alpha 1 blocking 

247 schizoPhrenia sPectruM and o ther Psychotic disordersAsenapine Saphris 5–10 mg 
p.o. b.i.d. 
sublingualAkathisia, 
somnolence Monitor weight, BMI, waist circumference
Lurasidone Latuda 40–160 mg 
daily Akathisia, sedation, 
and nausea Should be taken with food to increase absorption 
Use with caution at lower doses in clients with renal and hepatic impairment 
Brexpiprazole Rexulti 2–4 mg p.o. 
once dailyAkathisia, weight 
gain Monitor serum lipids and glucose
Assess family and personal history of cardiovascular disease (July 2015 approval)
Cariprazine Vraylar 1 .5– 6 mg p.o. 
daily EPSE, akathesia, 
gI upset, 
restlessness, 
somnolence Monitor serum lipids and glucose
Assess family and personal history of cardiovascular disease (September 2015 
approval)

gI upset, 
approval)
Aripiprazole 
lauroxilAristada Once a month 
IM injection; 
441 mg, 662 
mg, or 882 
mg Akathisia Monitor serum lipids and glucose
Assess family and personal history of cardiovascular disease (October 2015 
approval) 
Note. All atypical antipsychotic medications have a warning: increase in mortality in older adults with dementia-related psychosis

248 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XPharmacological therapy is the primary treatment modality, augmented by nonphar -
macological treatments.
 XMost clients will require lifelong medication.
 XClient and family education is important for treatment adherence. 
 XAdjunctive medications may be used to achieve full symptom control:
 ZAnxiolytics
 ZAnticonvulsants
 XAtypical antipsychotics  (see Table 11–4)
 ZPrimary first-line treatment agents
 ZFirst introduced in the 1990s
 ZHave fewer significant neurological side effects compared to typical 
antipsychotic medication 
 ZEffectively treat positive and negative symptoms
 ZFunction as serotonin-dopamine antagonists (SDAs)
 XD2 and 5HT2a blockade
 ZExpensive (some generics now available)
 ZFewer clinically significant side effects related to EPS and TD compared to 
typical antipsychotics

XD2 and 5HT2a blockade
typical antipsychotics 
 XCan cause extrapyramidal side effects (EPSE; see five common types in 
Table 11–5) but with lower risk compared to typical antipsychotics 
 XLower incidence of tardive dyskinesia (TD; see below).
 ZImproved compliance 
 ZMode of action: 
 XIn addition to the dopaminergic blockade found in first-generation 
antipsychotics, second-generation drugs capitalize on the interplay between 
dopamine and serotonin. Serotonin binds to 5HT2a heteroreceptors 
on dopamine (DA) neurons, thus further shutting off release of DA. By 
antagonizing (blocking) the 5HT2a heteroreceptors on DA neurons, DA 
release in the nigrostriatal, tuberoinfundibular, and mesocortical pathways is 
enhanced.
 XDopamine pathways:  These explain both the therapeutic effects and the 
side effects of the atypical antipsychotics.

enhanced.
 ZMesolimbic pathway: SDAs block dopamine in this pathway, causing 
decreased positive symptoms.
 ZMesocortical pathway: SDAs increase dopamine in this pathway, 
causing decreased negative symptoms.

249 schizoPhrenia sPectruM and o ther Psychotic disorders
 ZNigrostriatal pathway: Dopamine has a reciprocal relationship with 
acetylcholine (ACh). When serotonin is blocked by the SDA, dopamine 
increases; therefore, ACh decreases, which causes decreased EPSE. 
(EPSE is caused by increased ACh.)
 ZTuberoinfundibular pathway: Dopamine inhibits prolactin. The blockade 
of dopamine by SDAs cause prolactin to increase, causing galactorrhea 
and gynecomastia.
 XHyperprolactinemia associated with the antipsychotics may cause 
sexual problems, galactorrhea, amenorrhea, gynecomastia, and 
bone demineralization in postmenopausal women not on estrogen.
 XTypical antipsychotics  (first-generation; see Table 11–6)
 ZCross-classified as neuroleptics because of significant side effects
 ZFirst introduced in the 1950s
 ZUseful for treating positive symptoms by blocking dopamine in the mesolimbic 
pathway
 ZCan make negative symptoms worse by blocking dopamine in the mesocortical 
pathway

ZUseful for treating positive symptoms by blocking dopamine in the mesolimbic 
pathway
pathway
 ZTherapeutic effect related primarily to D2 receptor blockade
 ZGeneric (inexpensive) 
 ZCan be used as sustained-released injectable agents TABLE 11–5 .  
EXTRAPYRAMIDAL SIDE EFFECTS (EPSE)
SIDE EFFECT DEFINITION
Akathisia Motor restlessness; inability to remain still; rocking, pacing, or constant 
motion of unilateral limb; also can manifest as a subjective sense of 
restlessness without objective finding
Note:  Often mistaken for increasing anxiety
Akinesia Absence of movement, difficulty initiating motion, subjective feeling of 
lack of motivation to move
Note:  Often mistaken for laziness or lack of interest
Dystonia Muscle spasm; spasticity of muscle group, especially back or neck 
muscles; subjectively painful 
Note:  Often mistaken for agitation or unusual, stereotypic movements

Note:  Often mistaken for agitation or unusual, stereotypic movements 
characteristic of schizophrenia
Pseudo-Parkinson’s Presence of symptoms of Parkinson’s disease produced by D2 blockade; 
includes shuffling gait, motor slowing, mask-like facial expression, pill-
rolling, tremors, and muscle rigidity
Note:  Mask-like facial expression often confused as affective blunting or 
flattening
Tardive dyskinesia Involuntary abnormal muscle movement of the mouth, tongue, face, 
and jaw that may progress to limbs; can be irreversible; can occur as an 
acute process at initiation of medications or as a chronic condition at any 
point in treatment

250  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XDecanoate long-acting injectable dose forms of typical antipsychotics:
 ZProlixin-D (limited availability due to low production)
 ZHaldol-D
TABLE 11–6 .  
TYPICAL ANTIPSYCHOTICS
NAMEDOSAGE FORMS; 
Chlorpromazine Thorazine Tablet, SR, liquid; 
50–2,000 mg/dHigh:  Sedation, 
hypotension
Moderate:  EPSE, 
anticholinergicAllergic dermatitis
Photosensitivity
ECG changes—QTc 
monitoring 
Mesoridazine Serentil Tablet, liquid, 
injection; 100–400 
mg/dHigh:  Anticholinergic, 
sedation, hypotension
Low:  EPSEECG changes—QTc 
Thioridazine Mellaril Tablet, liquid; 50–800 
sedation, 
Low:  EPSECG changes—QTc 
monitoring
Irreversible retinal 
pigmentation at 
doses >800 mg/d
Decreased libido
Retrograde 
ejaculation
Fluphenazine Permitil
ProlixinTablet, liquid, 
injection; 2–40 mg/d,

injection; 2–40 mg/d, 
12.5–75 mg/IM every 
2 weeks (decanoate)Very high:  EPSE
Low:  Anticholinergic, 
Perphenazine Trilafon Tablet, liquid, 
injection; 8–64 mg/dHigh:  EPSE
Trifluoperazine Stelazine Tablet, injection; 5–80 
mg/dHigh:  EPSE
Haloperidol Haldol Tablet, liquid, 
50–300 mg IM, every 
month
(decanoate)Very high:  EPSE
High:  Anticholinergic, 
sedation
Low:  HypotensionIn older adults, 
monitor for oculogyric 
crisis and pneumonia
Loxapine Loxitane Capsule, liquid; 
20–250/dHigh:  EPSE
Moderate:  Sedation, 
Low:  Anticholinergic
Molindone Moban Tablet, liquid; 50–225 
Very low:  sedationLittle or no weight 
gain

gain
Thiothixene Navane Capsule, liquid, 
injection ; 5–60 mg/dHigh:  EPSE

251 schizoPhrenia sPectruM and o ther Psychotic disorders
 ZHigh potency : Have a greater risk of EPSE but less risk of sedation and 
anticholinergic symptoms
 ZLow potency: Have a greater risk of sedation and anticholinergic side effects but 
less risk of EPSE
 ZCaffeine and nicotine cause diminished antipsychotic effect; dose may need to 
be higher
TABLE 11–7  . 
MEDICATIONS USED TO TREAT EPSE
EFFECTIVE DRUG; 
CROSS-CLASSIFICATION AKINESIA AKATHISIA DYSTONIAPSEUDO-
PARKINSON’STARDIVE 
DYSKINESIA
Cogentin
(benztropine) 0.5 mg–2 mg 
p.o. t.i.d.;
AnticholinergicX X X X
Best 
treatment 
strategy is 
prevention 
through 
careful 
monitoring.
If present, 
treat by 
reducing 
current dose, 
or change 
client to 
atypical 
agent.Kemadrin
(procyclidine) 2.5 mg–5 mg 
p.o. b.i.d.–q.i.d.;
Artane
(trihexyphenidyl) 2–5 mg 
Benadryl
(diphenhydramine) 25 mg 
p.o. q.i.d.;
AntihistamineX X X
Symmetrel
(amantadine) 100–200 mg 
p.o. b.i.d.;

Artane
Benadryl
Symmetrel
Dopamine agonistX X
Inderal
(propranolol) 20–40 mg p.o. 
t.i.d.;
Beta blockerX
Catapres
(clonidine) 0.1 mg p.o. t.i.d.;
Alpha 2 agonistX
Klonopin
(clonazepam) 1 mg p.o. 
b.i.d.;
BenzodiazepineX X
Ativan
(lorazepam) 1 mg p.o. t.i.d.;

252 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZBecause of multiple clinically significant side effects, are not considered first-line 
treatment agents
 XSide effects leading to poor adherence 
 XHigh client teaching needs
 XEPSE most common side effect (see Table 11–6)
 ZCaused by D2 receptor antagonism (when dopamine receptors are 
blocked, ACh increases, which causes EPSE; a reciprocal relationship 
exists between ACh and dopamine)
 ZTreated by use of anti-Parkinson drugs (cross-classified; see Table 11–7)
 XAnticholinergics
 XDopamine agonists
 XBenzodiazepines (BNZs)
 ZTardive dyskinesia (TD)
 XTD is a potentially irreversible movement disorder that may 
occur in people who are treated for more than 1 year with typical 
antipsychotics.
 XSymptoms consist of abnormal, involuntary movements such as 
lip smacking, chewing, tongue protrusion, or twisting movements 
of the trunk or limbs.
 XPerioral movements are most common.

XSymptoms consist of abnormal, involuntary movements such as 
 XTreatment involves discontinuation of the offending agent and 
often starting an atypical antipsychotic.
 ZClients on typical antipsychotics should have routine abnormal involuntary 
muscle movement screening (see below) every 6 months.
 XClient and family education on the detection of early signs and symptoms 
of abnormal movements
 XIf abnormal movements are noted, consider reducing the dosage or 
switching to an atypical antipsychotic.
 XRisk factors include
 ZLong-term treatment with neuroleptics
 ZOlder age
 ZFemale gender
 ZPresence of mood or cognitive disorder
 XAssessment of abnormal movement rating scales 
 ZAbnormal Involuntary Movement Scale (AIMS)
 ZDyskinesia Identification System Condensed User Scale (DISCUS)
 ZSimpson-Angus Rating Scale (SAS)

253 schizoPhrenia sPectruM and o ther Psychotic disorders
 XNeuroleptic malignant syndrome (NMS)
 ZRare but potentially life-threatening
 ZCan occur at any point during treatment
 ZMost common with typical but has been reported with atypical 
antipsychotics
 ZRisk factors  include
 XRapid dose escalation
 XUse of high-potency typical antipsychotic
 XParenteral administration of antipsychotics
 ZAssess for the following abnormal labs:
 XElevated CPK (creatine phosphokinase)
 XElevated WBCs (white blood cell count)
 XElevated LFTs (liver function tests)
 ZAssess for symptoms known to occur first:
 XAltered sensorium
 XHyperthermia
 XHyperreflexia
 ZAssess for symptoms of autonomic instability:
 XExtreme muscular rigidity
 XDiaphoresis
 XTachypnea
 XComa and potentially death
 XTreatment
 ZSeek immediate medical care for treatment 
 ZDiscontinue antipsychotic medication(s)
 ZAdministration of Dantrium (dantrolene) or Parlodel (bromocriptine) for

XTreatment
 ZAdministration of Dantrium (dantrolene) or Parlodel (bromocriptine) for 
antipsychotic inducted dopamine receptor blockade
 ZAntipyretic (Acetaminophen) and cooling blanket for hyperthermia 
 ZIntravenous hydration 
 ZBenzodiazepine for muscular rigidity (catatonic symptoms) 
 ZOther common side effects related to effects on receptors other than dopamine:
 XAlpha adrenergic blockade 
 ZCardiovascular side effects
 ZOrthostatic hypotension

254 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XMuscarinic cholinergic blockade 
 ZDry mouth
 ZBlurred vision
 ZConstipation
 ZUrinary retention
 XEndocrine side effects
 ZIncreased prolactin levels
 XNeurological side effects
 ZLowering of seizure threshold
 XOther side effects
 ZPhotosensitivity
 ZAgranulocytosis
 XIndividual therapy
 ZUsually supportive rather than insight-oriented
 XFocuses on establishing reality testing
 XBuilds daily-life skills
 XAssists client in establishing and meeting life goals
 ZCognitive behavioral therapy (CBT) for management of hallucinations and delusions. 
 XGroup therapy
 ZFocuses on problem-solving
 ZFocuses on education
 XMedication groups
 XLife skills groups
 XProactive crisis management planning to deal with potential relapse needs
 ZIdentify symptom triggers.
 ZIdentify symptoms that indicate relapse.

XMedication groups
 ZIdentify past pattern of relapse to help predict future relapses.
 ZIdentify self-care interventions.
 ZIdentify point at which professional intervention is required.
 ZIdentify support network of family and friends.
 ZIdentify other resources to be mobilized when symptom level increases.
 XAssertive community treatment (ACT)
 ZEvidence-based case management program 
 ZMultidisciplinary treatment team

255 schizoPhrenia sPectruM and o ther Psychotic disorders
 XIllness management recovery (IMR)
 ZEvidence-based recovery program 
 XEducation modules
 ZRecovery strategies, information on mental illness, building supports, using 
medication, drugs and alcohol, coping, reducing relapse, mental health system, 
advocacy, and stress-vulnerability model (Whitley, Gingerick, Lutz, & Mueser, 2009).
 XMilieu therapy
 ZProvides for structure and safety needs
 ZProvides socialization and interpersonal support
 ZEncourages independency
 ZAssist in identifying strategies for living with illness.
 ZAssist in understanding and making decisions about care options.
 ZDevelop relapse prevention plan.
 ZPromote overall health.
Common Comorbidities 
 XRates of substance abuse and dependency are high.
 Z20% to 40% comorbidity
 XNicotine dependence is especially high.
 Z80% to 90% comorbidity

ZPromote overall health.
 ZTend to use cigarettes with highest nicotine content
 XDrug interaction with antipsychotic medications 
 ZMay need to reduce doses when client quits or cuts back.
 XOther common psychiatric comorbidities are anxiety disorders (see Chapter 10), 
especially panic disorder and obsessive–compulsive disorder.
 XSchizophrenia is significantly associated with shorter-than-expected life span when 
compared to the general population. 
 XPersons with a severe mental illness (SMI) prematurely lose 10 to 25 years of life 
compared to the general population.
 ZReasons are unclear but may include overall general lack of routine health care 
and high levels of comorbidity (see below)
 XSuicide
 ZSuicide rates are high; assess for suicidal ideations at every visit.

 XSuicide
 Z10% commit suicide.

256 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 Z20% to 40% attempt suicide.
 ZKnown risk factors for suicide include
 XAges 45 or younger
 XPresence of depressive symptoms
 XHopelessness
 XUnemployed
 XNoncompliance
 XRecent hospitalization
 XPostpsychotic period
 XComorbid substance abuse
 XGeneral medical illnesses
 ZClients need access to ongoing primary care.
 ZHigh rates of cardiometabolic illnesses 
 ZMonitor client for development of metabolic syndrome, diabetes, hypertension, 
hyperlipidemia, respiratory illnesses, and cardiac illnesses.
 XMonitor weight gain, lipids, and blood glucose.
 XProvide weight management and nutritional assistance.
 XUse the body mass index (BMI) as the accepted standard for determining if a 
client’s weight places him or her at risk of developing serious health problems.
 XBMI categories
 ZUnderweight: BMI 18.5 or less
 ZNormal weight: BMI 18.5–24.9
 ZOverweight : BMI 25.0–29.9

 ZObese: BMI 30.0–39.9
 ZSeverely obese: BMI 40 and higher.
 XRisks related to BMI
 ZClients who are overweight to obese as determined by BMI have 
 X2.9 times increased risk for diabetes
 X2.9 times increased risk for hypertension
 X2.1 times increased risk of coronary artery disease
 X3.0 times increased risk for endometrial cancer
 X2.7 times increased risk for colon cancer
 XChildren
 ZHallucinatory and delusional content less rich, elaborate, and bizarre
 ZVisual hallucinations more common than auditory

257 schizoPhrenia sPectruM and o ther Psychotic disorders
 ZMore women than men with rare late onset
 ZAlthough exhibiting prodromal social isolation, are more often married
 ZPrognosis usually better; more responsive to medications due to dominance of 
positive symptom cluster (see below)
 ZBlack box warning on all atypical antipsychotic medications: increase in mortality 
in older adults with dementia-related psychosis
 ZRisk factors
 XPostmenopausal states
 XPresence of human leukocyte antigen
 XPositive family history
 ZSymptoms 
 XPredominance of positive symptoms
 XHigh levels of persecutory delusions and hallucinations
 XLower levels of disorganized behavior
 XPreservation of social and occupational interest
 XFewer negative symptoms
Follow-up
 XChronic illness
 ZUsually requires lifelong treatment
 ZCase management necessary to coordinate aspects of care.
 XRelapse periods
 ZDevelop relapse plan with client and family.
 XMultiple health needs

ZUsually requires lifelong treatment
 ZPerform frequent assessment of general health status.
 ZAddress comorbid nicotine addiction.
 XPreventative care
 ZMonitor routine labs to screen for complications of treatment:
 XSerum glucose and lipid panels 
 XWeight, BMI, and waist-to-hip ratio 
 XLiver and kidney function (based on medication)
 XComplete blood count
 XAmerican Diabetes Association, American Psychiatric Association, American 
Association of Clinical Endocrinologists, & North American Association for 
the Study of Obesity ADA APA SGA Guidelines (2004) 
 XPerform annual eye exam if on typical antipsychotic agent or Seroquel 
(quetiapine)

258 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZClinical outcome measures
 XStandardized rating scales include: 
 ZPositive and Negative Syndrome Scale (PANNS) 
 ZBrief Psychiatric Rating Scale (BPRS)
 ZScale for Assessment of Positive Symptoms (SAPS) 
 ZScale for Assessment of Negative Symptoms (SANS)
SCHIZOPHRENIFORM DISORDER
 XClosely resembles schizophrenia
 XTwo differences from schizophrenia:
 ZTotal duration of the illness is at least 1 month but less than 6 months, including 
prodrome, active illness period, and residual symptom phase
 ZDoes not require impaired social or occupational functioning for diagnosis, 
although these may be present
Etiology
 XSimilar to schizophrenia
Demographics
 XLittle is known 
 XFivefold increase in men than women 
 XLifetime prevalence rate of 0.11 percent 
 XIdentification of individuals at high risk and monitoring

XLifetime prevalence rate of 0.11 percent 
 XIdentification of individuals at high risk and monitoring 
 XRelative with Schizophrenia and Bipolar Disorder 
History

259 schizoPhrenia sPectruM and o ther Psychotic disorders
 ZTwo or more of the following frequently present during a 1-month period
 XPresence of negative symptoms
 ZDuration of symptoms for at least 1 month and for no longer than 6 months
 ZAlmost all information provided for schizophrenia pertains to this disorder, 
except:
 XOccurs much less often than schizophrenia; incidence is 0.03% of general 
U.S. population.
 XApproximately one-third recover completely within 6 months.
 XRemaining two-thirds develop schizophrenia or schizoaffective disorder (see 
below).
 ZSimilar to schizophrenia
 XAssess for acuity level.
 XDuring acute psychotic or affective episodes, client may require brief hospitalization 
to

ZSimilar to schizophrenia
to
 ZEnsure client safety.
 ZRapidly stabilize client’s symptom level in a controlled environment.
 ZEnsure client compliance with treatment to reach stabilization.
settings. 

260  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
Follow-up 
SCHIZOAFFECTIVE DISORDER
 XAn uninterrupted period of illness in which the person experiences psychotic symp -
toms similar to those seen in schizophrenia as well as mood symptoms similar to 
major depressive disorder (MDD) or bipolar (BP) disorder (see Chapter 9).
Etiology
 XCause is unknown
 XThe disorder may be a psychotic spectrum disorder, mood spectrum disorder, or both
Prevalence and Demographics
 XLess than 1%. 
 XEqual number males and females.
 XDepressed type of the disorder is more common in older persons.
 XMen with the disorder tend to exhibit more antisocial behaviors. 
 XFamily history of schizophrenia or bipolar disorder 
 XScreening persons with a positive family history 
History

History
 XSymptoms of schizophrenia—two or more of the following frequently present during 
a 1-month period:
 ZDelusions
 ZHallucinations
 ZDisorganized speech

261 schizoPhrenia sPectruM and o ther Psychotic disorders
 ZGrossly disorganized behavior
 ZPresence of negative symptoms but usually less severe than those in 
schizophrenia
 XSymptoms of one or more of mood disorders (see Chapter 9): 
 ZMajor depressive episode
 ZManic episode
 ZMixed-mood episode
 XPresence of delusions or hallucinations for at least 2 weeks in the absence of promi -
nent mood symptoms
 XSubtypes
 ZTwo subtypes differentiated by type of mood-related symptoms:
 XDepressive : When prominent mood symptoms are of the depressive type 
only
 XBipolar : When predominant mood symptoms are manic or mixed type
 XSimilar to MDD or BP disorder (see Chapter 9)

Follow-up

262 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
DELUSIONAL DISORDER
 XPresence of one or more nonbizarre delusions lasting for at least 1 month
 XPsychosocial functioning and daily behavior not at all impaired except as they sur -
round content of delusion
 XSeldom any other symptoms; in rare cases may have hallucinations or mood 
Etiology
 X0.2% to 0.3% of population in the United States 
 XMean onset is about 40 years of age 
 XMen are more likely to have paranoid delusions 
 XWomen are more likely to have delusions of erotomania 
 XPerson with disorders of the limbic system and basal ganglia
 XUnknown
History
 ZPresence of delusions
 XWell-organized and potentially believable
 XAny unusual behavior is explainable if content of delusion understood

XUnknown
History
 ZSubtypes (categorized by thematic content of delusion)
 XErotomanic
 ZDelusional content focused on false belief that another person is in 
love with the client
 ZUsually focused on idealized or spiritual love and only infrequently has 
strong sexual content

263 schizoPhrenia sPectruM and o ther Psychotic disorders
 ZFocus of love usually a famous or powerful person who does not 
usually know the client
 XIn rare cases, person may know client
 ZLeads to obsessive behaviors such as surveillance or stalking
 XGrandiose
 ZDelusional content focuses on the client having some great talent, skill, 
or knowledge
 ZMay have strong religious component, such as prophecy or deity 
connections (special connection to God)
 XJealous
 ZDelusional content focuses on false belief that client’s spouse or 
partner is being unfaithful with someone else.
 ZBelief has no connection with realistic evidence.
 ZUsually seen in men.
 ZClient may try to control behavior of spouse or partner in an attempt to 
prevent imagined infidelities.
 XPersecutory
 ZDelusional content focuses on clients’ belief that others are out to 
harm them, spy on them, or otherwise do them harm
 ZOften angry and hostile at perceived persecution
 XSomatic

XPersecutory
 XSomatic
 ZDelusional content focuses on bodily functions and sensations
 ZOften belief that a body part is infected, absent, emits a strange odor, 
or is misshapen or malformed.
 XMixed
 ZNo clear predominant theme for the delusional content
 ZRelated symptoms that can be present but are not required for diagnosis include
 XMay become depressed over protracted problems with thematic content
 XMay become involved in legal difficulties related to behaviors based on 
delusional content
 XMay be subjected to or request unnecessary medical tests and procedures
 XNormal except for delusions
 ZAbstraction
 XMay be concrete on proverbs during delusional episodes

264  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZThought process
 XPresence of delusions
 XPerseveration on topics related to delusion
 ZThought content
 XThematic for type of delusion
BRIEF PSYCHOTIC DISORDER
 XDisorder with sudden onset of psychotic symptoms lasting at least 1 day but less 
than a month
Etiology
 XUnknown cause 
 XUnknown incidence 
 XOccurs more in younger clients (20 to 30 years of age)
 XFamily history of psychotic disorder 
 XUnknown

265 schizoPhrenia sPectruM and o ther Psychotic disorders
History
 ZAge of onset in adolescence or early adulthood
 ZPositive-type psychotic symptoms:
 ZCan occur with or without identified stressor
 ZPerson always returns to premorbid level of functioning
 XAcute episode requires frequent monitoring for safety needs because of the 
 ZRapid shifting in emotions
 ZImpaired judgment
 ZInability to meet nutritional and hygiene needs
SHARED PSYCHOTIC DISORDER (FOLIE Á DEUX)
 XCharacterized by development of a delusion in a client who has a close relationship

ZInability to meet nutritional and hygiene needs
 XCharacterized by development of a delusion in a client who has a close relationship 
with another person who already has a psychotic disorder with a prominent delusion

266 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
Etiology
 XCause is unknown 
 XUnknown 
 XUnknown 
 XUnknown
History
 ZClient in close contact with a person who already has a delusion and
 XThat person usually has schizophrenia. 
 XThat person usually is the dominant person in the relationship. 
 XThat person gradually imposes his or her delusion on the client. 
 XUsually the relationship is long-term and very close.
 ZAside from the delusional content, the client’s behavior is otherwise normal.

267 schizoPhrenia sPectruM and o ther Psychotic disorders
 XChronic disease course
 XPoor prognosis if relationship continues, especially if person with delusion goes 
untreated
 XGood prognosis if the client can be separated from person with the delusion

268 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
CASE STUDY
Casey is a 23-year-old client who has been recently diagnosed with schizophrenia. He experi -
enced his first psychotic break at age 22 while serving in the military. Casey lives at home with 
his parents and is reluctant to accept his diagnosis, stating “I got bad weed” in the service and 
“will be fine once the weed leaves my body. ” He has been adherent with appointments but only 
intermittently takes his Risperdal (3 mg p.o.) twice a day. His parents are threatening to kick him 
out of the house if he does not start accepting treatment. 
Casey has a history of juvenile-onset diabetes and has struggled to maintain a diabetic diet and 
to control his weight. When asked to identify his current goals, Casey wishes to find a good wife, 
have children, and settle down to a normal life. There are many issues to consider in planning 
care with this client.

care with this client. 
1. What is the top priority for the psychiatric–mental health nurse practitioner 
(PMHNP)? 
2. What medications changes would the PMHNP consider for Casey? 
3. What is the relationship between his diabetes and schizophrenia? 
4. How will his comorbid illness affect the PMHNP’s care planning? 
5. What routine ongoing monitoring will he require?

269 schizoPhrenia sPectruM and o ther Psychotic disorders
1. The top priority for the PMHNP is to build a therapeutic alliance with Casey 
2. Medication changes appropriate for Casey include switching to an alternative atypical 
antipsychotic medication that has a lower risk for weight gain and elevated glucose 
levels
3. The relationship between diabetes and schizophrenia is that individuals with schizo -
phrenia have a twofold increase of developing diabetes which is considered an 
independent risk factor.
4. Because clients with schizophrenia are at high risk for developing cardiometabolic 
illness as comorbidities, the care plan must address both his physical health, specifi -
cally his diabetes management, and his mental health.
5. The routine monitoring required for Casey includes ongoing monitoring for atypi -
cal antipsychotic medication should include serum glucose or A1c, lipid profile, and

cal antipsychotic medication should include serum glucose or A1c, lipid profile, and 
complete blood count, weight, height, body mass index.
American Diabetes Association, American Psychiatric Association, American Association of 
Clinical Endocrinologists, & North American Association for the Study of Obesity. (2004). 
Consensus development conference on antipsychotic drugs and obesity and diabetes. 
Diabetes Care, 27 (2), 596–601 . 
Rector, N. A., & Beck, A. (2002). A clinical review of cognitive therapy for schizophrenia. Current 
Psychiatric Reports, 4,  284–292.
Richardson, C., Faulkner, G., McDevitt, J., Skrinar, G., Hutchinson, D., & Piette, J. (2005).

Richardson, C., Faulkner, G., McDevitt, J., Skrinar, G., Hutchinson, D., & Piette, J. (2005). 
Integrating physical activity into mental health services for persons with serious mental ill -
ness.  Psychiatric Services, 56 (3), 324–331 .
Sable, J. A. (2002). Antipsychotic treatment for late-life schizophrenia. Current Psychiatric 
Reports, 4, 299–306.
Sadock, B. J., Sadock, V. A., & Ruiz, P . (2015). Kaplan & Sadock’s synopsis of psychiatry: 
Behavioral sciences/clinical psychiatry  (11th ed.). New York, NY: Wolters Kluwer. 
Staal, W. G., Hulshoff Pol, H., Schnack, G., van Haren, N. E., Seifert, N., & Kahn, R. (2001). 
Structural brain abnormalities in chronic schizophrenia at the extremes of the outcome spec -
trum. American Journal of Psychiatry, 158,  1140–1142.
Stahl, S. M. (2014). The prescriber’s guide Stahl’s essential psychopharmacology (5th ed.). New 
York, NY: Cambridge University Press.

York, NY: Cambridge University Press. 
Tamminga, C. (2001). Treating schizophrenia now and developing strategies for the next decade. 
CNS Spectrums, 6,  987–991 .
Tandon, R., & Jibson, M. D. (2001). Pharmacologic treatment of schizophrenia: What the future 
holds. CNS Spectrums, 6,  980–986.

270 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
U.S. Food and Drug Administration/Protecting and Promoting Your Health. (2013). FDA Drug 
Safety Communication: FDA is investigating two deaths following injection of long-acting 
antipsychotic Zyprexa Relprevv (olanzapine pamoate). Retrieved from www.fda.gov/Drugs/
DrugSafety/ucm356971 .htm
Whitley, R., Gingerich, S., Lutz, W., & Mueser, K. (2009). Implementing the illness manage -
ment and recovery program in community mental health settings: Facilitators and barriers. 
Psychiatric Services, 60 (2), 202–209.

CHAPTER 12NEUROCOGNITIVE DISORDERS
Cognitive disorders often are thought of as disorders of older adults. Although most common 
in this population, cognitive disorders can occur at any age. Very young or very old people with 
cognitive disorders have multiple health needs. Older adult clients usually have more than one 
chronic illness, and psychiatric disorders can be accompanied by other comorbidities.
Psychiatric–mental health nurse practitioners (PMHNPs) must approach clients with cognitive 
disorders by conducting a multisystem assessment. 
COGNITIVE DISORDERS
 XCognitive disorders cause a clinically significant deficit in cognition that represents a 
major change from the person’s previous baseline level of functioning.
 XTwo common disorders are
 ZDelirium
 ZDementia 
Etiology
 XCognitive disorders are a complex general medical condition resulting in changes 
in multiple domains including memory, interpersonal relationships, and behavior.

ZDelirium
 ZDementia 
Etiology
in multiple domains including memory, interpersonal relationships, and behavior. 
Cognitive disorders can result from injury, medical condition, substance use or 
abuse, a reaction to medications or other ingested agents, or a combination of some 
or all of these factors.
DELIRIUM
 XDelirium is a syndrome and not a disease, with an acute onset that causes short-
term changes in cognition.

272  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XThe hallmark symptom is a disturbance of consciousness accompanied by changes 
in cognition.
 XSubtypes of delirium 
 ZHyperactive: Agitated, restless, hyperalert
 ZHypoactive: Lethargic, slowed, apathetic 
 ZMixed: Cycles between hyperactive and hypoactive 
Etiology
 XDue to changes in one of the following:
 ZGeneral medical condition 
 ZSubstance induced
 ZMultiple physical health problems 
 ZMedication, sleep deprivation, or other causes 
 XCommon, especially in older adults 
 XOften overlooked and mistaken for other medical conditions or dementia 
 XIn persons with psychiatric disorders, often mistaken for worsening of psychotic 
symptoms instead of a distinct condition
 XPrevalence varies based on age, client setting, and sample
 ZHighest in hospitalized older adults 
 Z0.4% in general U.S. population ages 18 years or older
 Z1% to 2% in those ages 65 or older

XPrevalence varies based on age, client setting, and sample
 Z6% to 56% of hospitalized clients 
 Z15% to 53% in postoperative older adults 
 Z70% to 87% of older adults in the intensive care unit 
 Z60% in nursing home patients 
 Z25% in clients with cancer
 Z80% in terminal clients nearing death
 XPoor prognosis 
 Z1 year mortality rate of clients with delirium is up to 40%
 XAdvancing age 
 XMultisystem medical illness
 ZThe more physically ill the client, the higher the risk.

273 neurocognitive disorders
 XVisual or hearing impairment 
 XPast episode of delirium or preexisting brain disorder or cognitive impairment
 XUse of the Confusion Assessment Method (CAM) instrument 
 ZWhenever a client’s clinical presentation changes rapidly from baseline, consider 
delirium as one possible differential diagnosis.
History
 ZKey findings
 XDisturbance of consciousness develops over a short time, usually hours to 
days.
 XThis disturbance tends to fluctuate during the day.
 ZSleep–rest cycle disturbances
 XReversal of the sleep–wake cycle is common: clients are awake at night and 
sleep during the day.
 ZImpaired recent and intermediate memory 
 ZPsychomotor agitation

ZSleep–rest cycle disturbances
 XThe client exhibits purposeless, random actions.
 ZCourse of illness may resolve within hours to days
 XThe more quickly the underlying physiological disturbance is recognized and 
treated, the more rapidly the delirium will resolve.
 XSymptoms, when unrecognized, may persist for months.
 XMost symptoms resolve within 3 to 6 months.
 XEvidence that significant clinical symptoms are a consequence of direct physiological 
processes, substance use or abuse, or general medical condition

274  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XUsually nonspecific neurological abnormalities
 ZTremors
 ZIncoordination
 ZUrinary incontinence
 ZNystagmus
 ZAsterixis—a flapping motion of the wrists
 ZIncreased muscle tone and reflex
 XGeneral appearance
 ZUnconcerned with appearance
 ZDisheveled
 ZHighly inattentive
 XSpeech
 ZImpaired
 ZRambling
 ZIncoherent
 ZSlurred
 XAffect
 ZRapid, unpredictable shifts in affective state without known precipitation
 XLethargic
 XAgitated
 XMood
 ZDifficult to elicit from client
 ZPerceptual disturbances
 XIllusions most common
 XHallucinations are typically visual and accompanied by illusions 
 ZDisorganized, distorted thought 
 ZDelusions and hallucinations are common.
 ZDisorientation is usually the first symptom to appear

275 neurocognitive disorders
 ZClient usually disoriented to time and place
 XMemory
 ZImpaired recent and immediate memory
 ZGrossly impaired
 XJudgment
 XFindings consistent with underlying physiological etiology
 XWorkup includes standard tests 
 ZBlood chemistry
 ZComplete blood count (CBC)
 ZThyroid function tests
 ZSyphilis 
 ZHuman immunodeficiency virus (HIV) antibody test
 ZUrinalysis 
 ZChest radiograph 
 ZSerum or urine drug screen
 XElectroencephalogram (EEG) abnormalities
 ZGeneralized slowing
 ZGeneralized increased activity if delirium is related to alcohol withdrawal
 XDementia (see below)
 XSubstance intoxication or withdrawal (see Chapter 13)
 XSchizophrenia (see Chapter 11)
 XSchizophreniform disorder (see Chapter 11)
 XMood disorders with psychotic features (see Chapter 9)

XSchizophrenia (see Chapter 11)
 XUndertake treatment of underlying condition or disorder.
 XAvoid the use of new medications whenever possible, because using them can 
cloud the diagnostic picture.

276  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XSymptomatic treatment 
 XAgitation and psychotic symptoms
 ZAntipsychotic agents 
 XHaloperidol (Haldol)
 XAtypical antipsychotic agents
 XAnxiolytic agents for insomnia 
 XMonitor for safety needs.
 XDetermine reality orientation frequently.
 XPay attention to basic needs: 
 ZHydration
 ZNutrition
 XClient should be neither sensory-deprived nor overstimulated.
 XIt is helpful to have in the client’s room familiar people; familiar pictures or decora -
tions; a clock or calendar; and regular orientation to person, place, or time.
 XDelirium is associated with high morbidity and mortality.
 XHigh morbidity results from injury or its associated problems related to inactivity:
 ZPneumonia
 ZHydration and nutritional deficits
 XSafety concerns exist.
 XMnemonic: DELIRIUM (Dick & Morency, 2011)
 ZDrugs

ZPneumonia
 ZDrugs
 ZElectrolyte abnormality 
 ZLow oxygen saturation 
 ZInfection 
 ZReduced sensory input 
 ZIntracranial
 ZUrinary or renal retention 
 ZMyocardial 
 XChildren
 ZEspecially susceptible
 ZRelated to immature brain development

277 neurocognitive disorders
 ZOften mistaken for uncooperative behavior
 XIf a child is not soothed by common methods (e.g., parental presence), 
delirium is suspected.
 ZMost common in febrile states
 ZMedications known to affect cognition
 XEspecially common with anticholinergic medications
 ZSusceptibility related to physiological changes of aging
 ZOlder men more prone than older women for unknown reasons
DEMENTIA
 XDementia is a group of disorders characterized by gradual development of multiple 
cognitive deficits: 
 ZImpaired executive functioning
 ZImpaired global intellect with preservation of level of consciousness
 ZImpaired problem-solving
 ZImpaired organizational skills
 ZAltered memory
 XVarious forms of dementia share common symptoms but have different underlying 
pathology.
 ZDementia of Alzheimer’s type (DAT)
 XMost common type
 XGradual onset and progressive decline without focal neurological deficits

 XHallmark amyloid deposits and neurofibrillary tangles
 ZVascular dementia (VD) 
 XSecond most common type
 XFormerly called multi-infarct dementia  
 XPrimarily caused by cardiovascular disease and characterized by step-type 
declines
 XMost common in men with preexisting high blood pressure and 
cardiovascular risk factors
 XHallmarks: carotid bruits, fundoscopic abnormalities, and enlarged cardiac 
chambers
 ZDementia due to HIV disease
 XClassified as a subcortical dementia.
 XParenchymal abnormalities visualized on magnetic resonance imaging (MRI) 
scan.

278  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XHIV-associated neurocognitive disorder or HIV encephalopathy are less 
severe forms.
 XHIV can cause many psychiatric symptoms.
 XManifests by progressive cognitive decline, motor abnormalities, and 
behavioral abnormalities.
 XCo-occurs with obsessive–compulsive disorder, posttraumatic stress 
disorder, generalized anxiety disorder, depression, and mania.
 XDevelopment of dementia in client with HIV is an indicator of poor 
prognosis; death usually occurs within 6 months.
 XPsychotic symptoms usually occur in late-stage infection.
 XClinical signs of late-stage HIV-related dementia include cognitive, motor, 
behavioral, and affective impairment:
 ZGlobal cognitive impairment
 ZMutism
 ZSeizures
 ZApathy
 ZMania
 XAntiretrovirals and protease inhibitors can interact with psychotropic medications,

ZGlobal cognitive impairment
 ZMutism
 ZSeizures
 ZApathy
 ZMania
 XAntiretrovirals and protease inhibitors can interact with psychotropic medications, 
because many are metabolized by the P450 system or are CYP3A4 inhibitors. 
Therefore, prescribing psychotropic medications in this client population should 
be done with caution while monitoring for drug interactions.
 ZPick’s  disease
 XAlso known as frontotemporal dementia
 XNeuronal loss, gliosis, and Pick’s bodies present
 XMore common in men
 XPersonality and behavioral changes in early stage
 XCognitive changes in later stages
 XKluver-Bucy syndrome: hypersexuality, hyperorality, and placidity
 ZCreutzfeldt-Jakob disease
 XFatal and rapidly progressive disorder
 XOccurs mainly in adults in middle age or older
 XInitially manifests with fatigue, flulike symptoms, and cognitive impairment
 XLater manifests with aphasia, apraxia, emotional lability, depression, mania,

XInitially manifests with fatigue, flulike symptoms, and cognitive impairment
 XLater manifests with aphasia, apraxia, emotional lability, depression, mania, 
psychosis, marked personality changes, and dementia
 XDeath usually occurs within 6 months.
 XSubcortical type of dementia

279 neurocognitive disorders
 XCharacterized mostly by motor abnormalities (e.g., choreoathetoid movements)
 XPsychomotor slowing and difficulty with complex tasks
 XMemory, language, and insight usually intact until late stages
 XHigh incidence of depression and psychosis
 ZLewy body disease
 XCaused by Lewy inclusion bodies in the cortex
 XPresents with recurrent visual hallucinations
 XParkinson features (bradykinesia, cogwheel rigidity, tremor) 
 XAdversely react to antipsychotics
Etiology
 ZProbable multifactorial etiological profile
 XPrimary cause mostly unknown 
 XGeneral medical condition, result of substance use or abuse, reaction to medications 
or other ingested agents, or combination of some or all of these factors
 XDiffuse cerebral atrophy and enlarged ventricles in DAT
 XDecreased acetylcholine (ACh) and norepinephrine in DAT

XDiffuse cerebral atrophy and enlarged ventricles in DAT
 ZGenes on chromosomes 1, 14, and 21 have been identified in families with a 
history of DAT .
 ZAutosomal dominant trait.
 ZInherited alleles for apolipoprotein E4 (APOE4) on chromosome 19 are 
suspected to be related to late-onset dementia.
 XOften misdiagnosed or unrecognized, especially in early stages and in young clients
 XPrevalence of 1 .6% for people in the United States ages 65 or older
 Z16% to 25% in people ages 85 or older
 XDAT the most common
 ZAffects an estimated 4 million in the United States
 ZDuration of illness averages 8 to 10 years
 XAge 
 XMultisystem medical illnesses

280  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZFamily history of dementia in first-order relative
 XHistory of substance use or abuse
 ZAllows for ruling out age-related memory changes or unidentified conditions
 ZCognitive and functional evaluation at least every 3 years for people ages 65 or older
 ZBaseline and regular cognitive evaluation to monitor cognitive decline and 
treatment response to medications in persons diagnosed with dementia
 XThe U.S. Preventive Services Task Force concluded that there is insufficient evi -
dence to determine if the benefits of routine screening outweigh the harms (U.S. 
Preventive Services Task Force, 2014).
History

History
 ZDetailed history of present illness, including time frame, progression, and 
associated symptoms 
 ZPast medical history of hypertension, strokes, head trauma, and psychiatric illness
 ZPsychiatric history of depression, anxiety, and schizophrenia
education; and alcohol, tobacco, or illicit drug use
 ZMedications, including prescription, over-the-counter, herbals, supplements, and 
home remedies
 ZValidate history with family or caregiver. 
 ZMemory impairment—immediate and intermediate 
 XMost prominent feature of disorder
 XUsually earliest symptom
 XProduces multiple deficits in daily functioning
 ZUnable to learn new information

281 neurocognitive disorders
 ZForgets past information
 ZLoses valuables
 ZForgets daily activities such as eating and dressing
 ZBecomes easily lost
 ZHas other cognitive deficits such as impaired executive functioning
 ZInstruments for assessing level of impairment
 XNot in public domain
 ZMini-Mental State Examination (MMSE)
 XIn public domain 
 ZMontreal Cognitive Assessment (MoCA) 
 ZMini-Cog
 ZSt Louis University Mental Status Examination (SLUMS)
 XRemember to always consider visual, sensory, language, and physical 
disabilities as well as education when administering mental status tests. 
 XAmaurosis fugax : Unilateral transient vision loss, described as “curtain over eye” 
 XUnilateral focal–motor weakness
 XAsymmetrical reflexes
 ZApraxia
 ZDecreased self-care activities of daily living
 XSpeech
 ZDeterioration of language skills
 ZAphasia
 ZCircumlocutory phrases

 ZApraxia
 XSpeech
 ZAphasia
 ZIndefinite object recognition (such as calling items “things” and being unable to 
find discrete name)
 ZIn advanced stages are
 XMutism
 XEcholalia
 XAffect
 ZLability
 XMood
 ZDepressed 
 ZOften difficult to elicit from client

282  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZAgnosia
 ZDisoriented to time and place
 ZDisoriented to person in late stages of disorder
 XMemory
 ZImpaired in many dimensions of memory:
 XWord registration
 XRecall
 XRetention
 XRecognition
 ZConcrete on proverb testing
 XJudgment
 ZGrossly impaired for self- and social judgment
 XCBC, chemistry profile, thyroid function tests, B12 level, and folate level to rule out 
metabolic causes or unidentified conditions 
 XSyphilis drug toxicity screening if indicated by history
 XAlcohol and illicit drug screen if suspected or indicated
 XUrinalysis if urinary tract infection suspected 
 XArterial oxygen or pulse oximetry if hypoxemia suspected
 XComputed tomography (CT) or magnetic resonance imaging (MRI) not routinely used

XUrinalysis if urinary tract infection suspected 
 XComputed tomography (CT) or magnetic resonance imaging (MRI) not routinely used 
 XEEG not useful
 XNeuropsychological testing recommended to complete diagnostic assessment
Differential diagnosis
 ZParkinson’s disease
 ZHearing loss
 ZB12 and folate deficiencies
 ZTrauma, especially with history of falls

283 neurocognitive disorders
 ZPolypharmacy
 ZAlcohol intoxication
 ZMood disorders (see Chapter 9)
 ZDelirium (see above)
 ZAnxiety disorders (see Chapter 10)
General Considerations
 XRule out or treat any conditions that may contribute to cognitive impairment. 
 XDiscontinue unnecessary medications, especially sedatives and hypnotics.
 XCognitive symptoms
 ZN-methyl D-aspartate glutamate receptor antagonists
 XPrevent overexcitation of glutamate receptors and stabilize the 
neurodegenerative process
 XMemantine (Namenda; 10 to 20 mg b.i.d.)
 ZModerate to severe Alzheimer’s Dementia 
 ZMay slow the degenerative process
 ZPromotes synaptic plasticity
 ZMay be used in combination with cholinesterase inhibitors.
 ZMemantine/Donepezil (Namzric) combination medication) 
 ZCholinesterase inhibitors
 XMay be initiated for mild to moderate Alzheimer’s disease

ZMemantine/Donepezil (Namzric) combination medication) 
 XCan lead to modest clinical improvement in some clients, with studies 
showing 2- to 3-point improvement in mental state exam (MSE) testing
 XTreat only symptoms, slow loss of function, and may improve agitated behaviors
 XDo not prevent pathological progression of disease
 XNot effective in severe, end-stage disease
 XShould stop if side effects, usually nausea and vomiting, develop
 XCommonly used agents:
 ZDonepezil (Aricept; 5 to 10 mg/day; Stahl, 2014)
 XApproved for mild, moderate, and severe Alzheimer’s disease

284  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XNausea, diarrhea, vomiting, appetite and weight loss, abnormal 
dreams, insomnia, dizziness common
 ZRivastigmine tartrate (Exelon; 1 .5 to 6 mg twice a day; increase 
gradually to avoid nausea) 
 XIndicated for mild to moderate Alzheimer’s disease and Parkinson’s 
disease dementia (Stahl, 2014)
 XTransdermal: 4.5, 9.5, or 13.3 mg / 24 hours 
 XRetitrate if a lapse in treatment occurs 
 XPsychosis and agitation
 ZTry nonpharmacological therapies first.
 ZUse antipsychotic agents for agitation or psychotic symptoms regularly.
 ZUse lowest effective dose and attempt to wean periodically.
 ZAntipsychotics may cause many side effects of significance in the older adult:
 XExtrapyramidal symptoms
 XSedation
 XPostural hypotension
 XAnticholinergic side effects
 ZBenzodiazepines may be used for treating anxiety or infrequent agitation.
 ZTreat clients with depressive symptoms:

XSedation
 ZTreat clients with depressive symptoms: 
 XInsomnia
 XFatigue
 XAppetite loss
 ZUse lowest effective dose.
 ZTreat for 6 to 12 months, then attempt to taper; depression may reoccur and 
need to be treated as a chronic condition.
 ZClients may have less depression as the dementia progresses and they become 
less aware of their circumstances.
 XEducate client and family about the illness, treatment, and community resources.
 XAssist with long-term planning, including financial, legal, and advanced directives.
 XAssess home and driving safety.
 XUse behavioral therapy to identify causes of problem behaviors and changes to the 
environment to reduce the behavior.
 XUse recreational therapy, art, and pet therapy to reduce agitation and promote nor -
malized behavior.

285 neurocognitive disorders
 XUse reminiscence therapy or life review to process through any unresolved issues 
and recollect the past.
 XMaintain a simple daily routine for bathing, dressing, eating, toileting, and bedtime.
 XIntegrate cultural beliefs into the management of all clients with dementia.
 XPsychotherapeutic approaches for HIV-related dementia
 ZMajor psychodynamic themes for people with HIV-related dementia  are issues 
of guilt, self-esteem, and fear of dying. 
 ZBecause the client may not be able to give a complete and accurate history, 
family or friends should be questioned about any unusual behavior or mental 
status changes.
 ZChanges in the level of activity, in interest in other people, or in personality are 
clues to an acute central nervous system disturbance. 
 ZSome changes are directly due to brain dysfunction, while other changes are 
due to psychological distress of a systemic problem—anxiety that the person is 
dying.

ZSome changes are directly due to brain dysfunction, while other changes are 
dying.
 ZThe spectrum of neuropsychiatric and neurological manifestations depends on 
the severity of immunosuppression.
 ZPsychiatric disorders may preexist or result from HIV.
 ZEven subtle neurocognitive impairment can affect psychological coping.
 ZNeuropsychiatric disorders are much more prevalent in late-stage illness.
 XPrimarily a disease of older adults but can occur in children
 ZDiagnosis based on impaired cognition; diagnoses not applicable until ages 4 to 
6 years, when cognition can be fully assessed
 ZDementia in children usually presents as deterioration in functioning, such as 
school performance or delay in normal development.
MAJOR OR MINOR NEUROCOGNITIVE DISORDER DUE TO 
TRAUMATIC BRAIN INJURY 

 XDSM-5 diagnostic criteria are not met for a major or minor neurocognitive disorder.
 XEvidence of a traumatic brain injury—an impact to the head or other mechanism of 
rapid movement or displacement of the brain within the skull—with one or more of 
the following: 
 ZPosttraumatic amnesia
 ZDisorientation and confusion 
 ZNeurological signs (neuroimaging demonstrating an injury; new onset of 
seizures; worsening seizure disorder; visual field cuts; hemiparesis; anosmia)

286  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XThe neurocognitive disorder presents immediately after the occurrence of the trau -
matic brain injury or immediately after recovery of consciousness and persists past 
the acute postinjury period.
Etiology
 XBrain injury resulting when the head is hit or violently shaken, such as from a blast or 
explosion.
 XAbout 2% of the population and estimated 30% of returning soldiers 
 XCombat duty exposing personnel to improvised explosive devices (IEDs) used by 
opposing factions
Prevention and Screening for Military Personnel 
 XMandatory postdeployment screening for all veterans returning from combat 
assignment
 XTraumatic brain injury screening
 ZExposure to events (such as blasts, vehicle accidents, falls) that may have 
caused brain injury
 ZImmediate symptoms (such as loss of consciousness, feeling dazed, head 
injury, amnesia of event)

ZExposure to events (such as blasts, vehicle accidents, falls) that may have 
 ZOnset or worsening of problems (such as with memory, balance, headaches, 
dizziness, irritability, sensitivity to bright light, sleep problems) that may indicate 
brain injury
 ZPresence of symptoms in past week
 XFour factors complicate recovery from combat-related concussions compared with 
mild TBI acquired in civilian settings.
1. The physically and emotionally traumatic environment in which they occur
2. The potentially repetitive and cumulative nature of concussions sustained over a 
tour (or multiple tours) of combat duty
3. The high incidence of comorbid mental health conditions
4. The difficulty in following typical recommendations for postconcussion care, 
such as rest (U.S. Department of Veteran Affairs, 2015)

287 neurocognitive disorders
Physical Findings and Mental Status
 XSymptoms of TBI (see Table 12–1)
 XRisk for suicide
 ZFactors increasing risk for suicide attempt with TBI:
 XMales
 XAges 18 and 19
 XAggressive behavior
 XSubstance use
 XNo current diagnostic test can retrospectively diagnose mild TBI or determine that 
current symptoms or problems are due to a past mild TBI. Conventional structural 
neuroimaging studies are typically normal in mild TBI.TABLE 12–1  . 
SYMPTOMS OF TRAUMATIC BRAIN INJURY
MILD TBI MODERATE TO SEVERE TBI
Mental status changes:
Poor concentration
Memory difficulty
Intellectual impairment
Anxiety
Physical findings:
Dizziness
Balance problems
Headaches 
Tinnitus (ringing in the ears)
Numbness and tingling
Vision changes
Sensitivity to light
Sensitivity to sound
Extreme fatigue
Sleep problems
Acute symptoms: 
Dazed and confusedSymptoms in first column plus:

Chronic, worsening headaches
Repeated nausea and vomiting
Seizures
Difficult to arouse from sleep
Slurred speech
Unequal pupils
Confusion
Restlessness and agitation
Extreme weakness or numbness
Loss of coordination

288  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XPosttraumatic stress disorder (PTSD)
 XAnxiety
 XOther mental health diagnosis
 XNo specific medications for TBI.
 XTreat related symptoms according to current evidence-based standards.
 XIncreased sensitivity to side effects of medication (secondary to head injury).
 ZSedation
 ZAnticholinergic side effects (decrease memory)
 ZSeizures with tricyclic antidepressants (TCAs), buproprion, and amantadine 
(lower seizure threshold)
 ZExtrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia
 ZNeuroleptics: decrease neuronal recovery
 ZBenzodiazepines: decrease memory, increase confusion, decrease coordination, 
abuse potential 
 XCognitive disorders recommendations:
 ZMethylphenidate: increase attention, processing speed, general cognitive 
function, learning, and memory

function, learning, and memory 
 ZDextroamphetamine: increase attention, processing speed 
 ZBromocriptine (off label, possibly helpful): increase executive function
 ZAmantadine (off label, possibly helpful): increase general cognitive function, 
attention, concentration 
 XWhen using medications, start low and go slow.
 XTreat comorbidities (military personnel with TBI frequently have posttraumatic stress 
disorder [PTSD], which makes treatment of TBI more difficult).
 XSafety plan for suicide risk; limit availability of means.
 XTeach family to identify signs of risk for suicide.
 XFollow up for 1 year after anyone with TBI makes a suicide attempt. 
 XTreat vestibular dysfunction with physical therapy to reduce dizziness.
 XTreat traumatic vision syndrome with occupational therapy; scanning and accommo -

XTreat vestibular dysfunction with physical therapy to reduce dizziness.
dation difficulties lead to headaches, irritability, and fatigue.

289 neurocognitive disorders
 XTreat memory impairment with occupational therapy to teach memory improvement 
skills.
 XTeach about symptoms and implications for relationships, employment, etc.
 XAvoid alcohol.
 XNeuropsychological testing.
 XPsychotherapy
 ZSupportive
 XIncrease understanding of relationships between cognition and emotion
 XTarget adjustment or development of new beliefs and assumptions (see 
Table 12–2)
 ZBehavioral therapy
 XBehavioral, affective, and personality changes are most difficult for families 
to adjust to
 XTips for families:
 ZIf concentration is an issue, ask the TBI survivor for one thing at a time. 
Use of white noise machines may reduce distractions. May take longer 
to complete tasks.
 ZIf memory is an issue, keep note pads near the phone for messages 
and in other places throughout the house. Keep a “memory book. ” 
Make a calendar and keep in a central location.

ZIf memory is an issue, keep note pads near the phone for messages 
 ZIf anger or irritability is an issue, leave the situation if possible and 
wait for TBI survivor to calm down. Use a soft, calm voice. Keep your 
distance and give the TBI survivor space.
 ZResources
 XDefense and Veterans Brain Injury Center: http://www.DVBIC.org
 XBrain Injury Association of America: http://www.biausa.org
 XU.S. Department of Veterans Affairs: www.VA.gov
TABLE 12–2 .  
COGNITIVE IMPAIRMENT AND ASSOCIATED CORE FEATURES OF COGNITIVE BEHAVIORAL 
THERAPY
COGNITIVE IMPAIRMENT CORE FEATURE OF CBT
Impulsivity “Stop–think–reflect”
Decreased awareness, encoding, and recall Monitoring problems and successes
Memory Use of audiotapes of sessions
Executive impairment Develop independent problem-solving for 
every day difficulties

290  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XTips for the PMHNP for therapy with the client with TBI:
 ZDetermine what having a TBI means to the client.
 ZFocus on “real life” difficulties in the here-and-now.
 ZMonitor speed and complexity of comments.
 ZAdjust session length according to level of attention and fatigue.
 ZReestablish an acceptable sense of self.
 ZInstill hope without making predictions of a successful rehabilitation outcome.
 XMild TBI
 ZMost clients achieve full recovery within 3 months; if residual symptoms 
continue, 80% to 85% will clear within 6 months
Follow-up
 XSymptoms may occur immediately but may also appear much later, which under -
scores the importance of screening for TBI
 XResource for guidelines, conditions and concerns: Deployment Health Clinical Center 
http://www.pdhealth.mil/main.asp

291 neurocognitive disorders
CASE STUDY
Mrs. Dean, a 59-year-old homemaker with a positive family history for Alzheimer’s disease, has 
been very worried lately because she believes that she is losing her memory. She has hesitated 
to go for an evaluation because of her concern and is very upset as she shares her beliefs with 
the PMHNP . She gives a social history of being happily married for the past 35 years and of hav -
ing several children and two new grandchildren. She has had no recent stressors and has felt 
a slow decline in her memory for the past 2 years. She believes no one else has noticed, but 
recently it is harder to hide her deficit from her family. 
She has been employed as a nurse for the past 25 years at the local hospital but has begun to no -
tice a decline in her ability to keep track of all of the information needed to do her job well. She has 
a history of asthma and periodically uses a rescue inhaler and steroids to manage her asthma. She

a history of asthma and periodically uses a rescue inhaler and steroids to manage her asthma. She 
routinely takes one aspirin a day and uses over-the-counter kava kava when she feels stressed. She 
has been taking pravastatin (Pravachol) 20 mg/day for her cholesterol level for the past 2 years. She 
has no significant physical findings but does show mild impairment in short-term memory testing 
during the MSE. There are many issues to consider in planning care with this client:
1. What is the probable diagnosis at this time? 
3. What does the PMHNP need to take into account when considering medication for 
this client? 
4. Would the PMHNP include the family in care planning at this time? 
5. Are medications indicated at this time?

292  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
1. The correct diagnosis in this case is unspecified neurocognitive disorder.
2. Additional assessment information needed is to refer client for a complete medical 
examination.
3. Before starting the client on medication the PMHNP needs to understand the cor -
rect diagnosis for the client’s symptoms and the stage of their illness, and discuss 
the client’s preference for treatment.
4. In this case, yes, family should be involved as early as possible.
5. For this client, medication is not indicated at this time.
American Geriatric Society. (1999). Geriatric review syllabus.  New York, NY: Kendall/Hunt.
Bickley, L. S. (2007). Bates’ guide to physical examination and history taking  (9th ed.).

Philadelphia, PA: Lippincott Williams & Wilkins.
Borson, S., Scanlan, J., Brush, M., Vitaliano, P ., & Dokmak A. (2000). The mini-cog: A cognitive 
‘vital signs’ measure for dementia screening in multilingual elderly. International Journal of 
Geriatric Psychiatry, 15,  1021–1027 . 
Burke, M., & Laramie, J. A. (2003). Primary care of older adults  (2nd ed.). St. Louis, MO: Mosby.
Dick, K., & Morency, C. R. (2011). Delirium. In K. Devereaux & S. Crock (Eds.), Geropsychiatric 
and mental health nursing  (2nd ed., pp. 255–272). Sudbury, MA: Jones & Bartlett Learning. 
Doornbos, M. M. (2002). Family caregivers and the mental health care system: Reality and 
dreams. Archives of Psychiatric Nursing, 15 (4), 39–46.
de Lange, E., Verhaak, P . F ., & van der Meer, K. (2013). Prevalence, presentation and progno -

sis of delirium in older people in the population, at home and in long term care: A review . 
International Journal of Geriatric Psychiatry, 28 (2), 127–134. 
Jacobson, S. (2014). Clinical manual of geriatric psychopharmacology  (2nd ed.) Arlington, VA: 
American Psychiatric Publication. 
Melillo Devereaux, K., & Houde Crocker, S. (2011). Geropsychiatric and mental health nursing  
(2nd ed.). Sudbury, MA: Jones & Bartlett Learning. 
Pfeiffer, E. (1975). A short portable mental status questionnaire for the assessment of organic 
brain deficit in elderly patients. Journal of American Geriatric Society, 23, 433–441 .

Stahl, S. (2014). Essential psychopharmacology prescribers guide (5th ed.). New York, NY: 
Cambridge University Press. 
Steffens, D., Blazer, D., & Thakur, M. (2015). The American Psychiatric Publishing textbook of 
geriatric psychiatry  (5th ed.). Arlington, VA: American Psychiatric Publishing.
U.S. Department of Veterans Affairs. (2015). Polytrauma/TBI system of care. Retrieved from 
http://www.polytrauma.va.gov/understanding-tbi/
U.S. Preventive Services Task Force. (2014). Screening for dementia: Recommendations and 
rationale. Retrieved from http://www.uspreventiveservicestaskforce.org/Page/Document/
UpdateSummaryFinal/cognitive-impairment-in-older-adults-screening?ds=1&s=dementia

CHAPTER 13SUBSTANCE-RELATED AND ADDICTIVE 
DISORDERS
One of the most common but least well-addressed classes of disorders is substance use 
disorders. Psychiatric–mental health nurse practitioners (PMHNPs) who work in primary psychi -
atric settings or integrated primary care settings commonly treat clients with substance-related 
disorders. These disorders can stand alone or be part of complex co-occuring illness with either 
general medical conditions or psychiatric disorders. 
Many substances can be used and abused. No matter what the substance, the continuum of 
use can range from mild to severe. Although the specific substances of abuse will determine 
many of the physical, behavioral, and cognitive symptoms exhibited by the client, some com -
monalities exist for all drugs. New to the fifth edition of the Diagnostic and Statistical Manual of 
Mental Disorders  (DSM-5; American Psychiatric Association, 2013) is the inclusion of gambling 
as a behavioral addiction.

as a behavioral addiction. 
This chapter focuses on the PMHNP role in determining the severity of substance use and the 
available clinical management and treatments. It also emphasizes alcohol use disorders as a 
primary example. Alcohol is discussed because it is the most commonly abused substance, it 
is well researched, and PMHNPs will most often encounter people in clinical settings with an 
alcohol use disorder. Much of what is known about disorders of alcohol use is believed to be 
transferable to other substances. 
SUBSTANCE-RELATED DISORDERS
 XSubstance use disorders  are a cluster of disorders in which cognitive, behavioral, and 
physiological symptoms indicate that a person continues using a substance despite 
significant substance-related problems (American Psychiatric Association, 2013).

 XPsychiatric symptom clusters may be related to substance use, discontinuation of 
substance use, or withdrawal from habitual substance use.
 XSubstance use disorders lead to changes in brain circuits and physiological functions 
that lead to a need for detoxification and a possible need for long-term treatment.

294  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XThe word substance  can describe a drug of abuse, a medication, or a toxin that pro -
duces psychoactivation and alters cognitive, behavioral, and affective perceptions. 
 XDependence:  repeated use of a substance with or without physical dependence 
 XAbuse:  use that is inconsistent with sociality use patterns 
 XMisuse:  usually applies to a prescribed substance 
 XIntoxication:  reversible syndrome caus ed by a specific substance affecting memory, 
judgment, behavior, or social or occupational functioning
 XWithdrawal:  substance-specific symptoms that occur after stopping or reducing use 
 XTolerance:  needing more of the substance to get the desired effect 
Etiology
 XTwo common types of theories: psychodynamic and biological
 ZPsychodynamic theory

XMultiple theories ranging from psychological to neurobiological
 XBehaviors of abuse are seated in oral-stage fixation.
 XA person seeks gratification through oral behaviors.
 XMaladaptive regressive behaviors can become overlearned, fixed, and 
reinforced through dysfunctional family patterns.
 XSociocultural factors attempt to explain population-based differences in 
substance abuse rates.
 ZBiological theory
 ZPeople with a strong genetic vulnerability to addiction are thought to 
have defects in the working of the reward center of the brain, which 
predisposes them to stronger-than-normal positive rewards that draw 
them to substance use.
 ZGender differences
 ZEthnic differences
 ZA person is predisposed to stronger-than-normal negative rewards, 
making it more difficult to stop abuse once it has begun.

 XInvolves two neurobiological processes:
1. Reinforcement
 XBrain-based changes in structure and function can lead to addictive 
behavior.
 XThe process of positive and negative rewards is physiologically 
linked to memory function.
 XChanges appear to occur with any drug of abuse.

295 suBstance-related and addictive disorders
 XReinforcement results in “feel good” sensations when a drug of 
abuse is used and in “feel bad” sensations when the drug exits 
the body.
 XPositive rewards of reinforcement result in the social rewards 
commonly associated with drug use, such as disinhibition, 
euphoric mood, and anxiety reduction.
 ZMediated by dopamine (DA) pathways
 XNegative rewards are aversive, such as increased anxiety and 
 ZMediated by the gamma amino butyric acid (GABA) pathways
 XReinforcement occurs in the ventral tegmental area and the 
nucleus accumbens of the brain, collectively called the reward 
center.
 XDA release within the reward center is enhanced further by 
the release of natural morphine-like neurotransmitters called 
neuropeptides  (enkephalins, beta-endorphins).
 XNeuropeptides further enhance the reinforcing pleasure 
experienced by the person.
 XWith repeated drug use, the DA system becomes increasingly 
sensitized.

XNeuropeptides further enhance the reinforcing pleasure 
 XEventually, associated drug use stimuli (e.g., pictures of drug 
paraphernalia) can cause DA release, leading to reinforcement of 
use and often to increased drug use.
2. Neuroadaptation 
 XBrain-based changes in structure and function can lead to 
tolerance  and withdrawal.
 XDrug-specific alterations in the normal level and function of 
neurotransmitters occur as the body adapts to the chronic 
presence of the substance of abuse. 
 XNeuroadaptive processes become very significant when the 
person stops substance use.
 XThese processes become the basis for withdrawal symptoms, 
because adaptive responses are unopposed when the substance 
is no longer present. 
 XNeuroadaptive changes may be more enduring in some persons, 
possibly lasting for years, thus increasing their potential for 
relapse.

relapse. 
 XThis concept helps to explain why, after a long period of sobriety, 
a person who returns to substance abuse often picks up at the 
same level of tolerance and physical impact as experienced before 
sobriety.

296 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XPersons age 18 to 24 years of age have high prevalence rates for using most 
substances. 
 XThe United States has higher rates of substance use than any other developed 
country.
 XMore than 50% of U.S. clients with a psychiatric disorder have a comorbid sub -
stance use disorder.
 ZPersons with schizophrenia are 4 times more likely to have a substance use 
comorbidity than the general population.
 ZPersons with bipolar affective disorder are 5 times more likely to have a 
substance use comorbidity than the general population.
 XMore than 2 million admissions annually are made to inpatient substance use treat -
ment facilities.
 ZThough now legal in some states, marijuana is the most commonly abused 
illegal substance.
 XAlcohol is the most commonly abused legal substance.
 ZRates are higher in men than in women.
 X90% of men have used alcohol.

 X70% of women have used alcohol.
 XRates are highest in African Americans, Hispanic Americans, and Native 
Americans; rates are lowest in Asian Americans.
 Z55% of fatal driving accidents in the United States occur with a driver 
under the influence of alcohol.
 Z50% of crimes in the United Stated are committed under the influence 
of alcohol.
 ZThe lifetime risk for alcohol use disorder is 15% in the general U.S. 
 XGenetic loading 
 ZFamily history of substance abuse or major depressive disorder (MDD)
 XAssociation with peer structure with heavy substance use 
 XCo-occurring psychiatric disorder
 XAge and gender (younger, males)
 XExistence of chronic pain
 XUntreated chronic pathological-level anxiety

297 suBstance-related and addictive disorders
 XEarly recognition, intervention, and initiation of treatment to prevent disease devel -
opment of complications of disorder
 XImplications of alcohol and other drugs of abuse during pregnancy:
 ZFetal alcohol syndrome (FAS)
 XPrevalence : one third of all infants born to females with alcohol use disorder 
 XSigns : low birth weight and height, microphthalmia, short palpebral fissure, 
midface hypoplasia, smooth or short philtrum, thin upper lip
 ZBirth defects
 XAcute alcohol intoxication in nontolerant persons such as teenagers:
 ZComa
 ZRespiratory depression
 ZDeath
 ZAdministered by asking the client four questions
 ZEach positive answer scored as 1 point; negative answers receive no score
 ZThe more positive answers, the greater the likelihood of an alcohol abuse disorder.

ZEach positive answer scored as 1 point; negative answers receive no score
 ZThe more positive answers, the greater the likelihood of an alcohol abuse disorder. 
 ZClients scoring 2 or greater are at mild to moderate risk for alcohol dependency, 
and the score is considered clinically significant 
 ZClients scoring 3 to 4 are considered at high risk for alcohol dependency
 XOther screening 
 ZAUDIT :  Alcohol Use Disorders Identification Test 
 ZS-MAST : Short Michigan Alcoholism Screening Test (or Geriatric Version)
 ZCRAFFT : Children and adolescents under 21 years of age 
 ZCOWS: The Clinical Opiate Withdrawal Scale 
CAGE SCREENING TEST IS THE MOST COMMONLY USED SCREENING TOOL FOR 
ALCOHOL ABUSE (SAMHSA, 2016)
C: Have you ever felt the need to cut down on your drinking? 
A: Have people annoyed you by mentioning your drinking? 
G: Have you ever felt bad or guilty about your drinking? 
E: Have you ever had a drink the first thing in the morning to steady your nerves or

E: Have you ever had a drink the first thing in the morning to steady your nerves or 
get rid of a hangover (eye-opener)?

298 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
History
 ZValidate history with a family member
 ZIdentify the category of drug abused by the client
 XKnowing category allows for anticipation of physical impact of drug and to 
predict potential symptoms of withdrawal 
 XClients often abuse drugs from categories with similar pharmacological 
properties.
 XCategories of abused agents: 
 ZAlcohol
 ZAmphetamines or similar sympathomimetics
 ZCaffeine
 ZCannabis
 ZCocaine
 ZHallucinogens
 ZInhalants
 ZNicotine
 ZOpioids

 ZAlcohol
 ZCaffeine
 ZCannabis
 ZCocaine
 ZNicotine
 ZOpioids
 ZPhencyclidine (PCP) or similar arylcyclohexylamines
 ZSedatives
 ZHypnotics
 ZAssess for presence of substance abuse 
 XMaladaptive pattern of substance use manifested by recurrent and 
significant adverse consequences related to repeated use of a substance
 XIs not synonymous with use, misuse,  or hazardous use
 XSpecific criteria needed to identify substance use as abuse:
 ZMaladaptive pattern of use occurring for at least a 12-month period of 
sustained use

299 suBstance-related and addictive disorders
 ZMust be accompanied by repeated failure to fulfill major role obligation
 ZMust be accompanied by use in situation that presents as physically 
hazardous, such as drinking and driving
 ZAbuse continues despite multiple problems related to substance use 
patterns, such as legal, interpersonal, or social problems
 ZAssess for presence of substance use disorder
 XCluster of cognitive, behavioral, and physiological symptoms indicating that 
the person continues use of a substance despite significant substance-
related problems
 XSynonymous with addiction
 XPattern of repeated use that leads to clinically significant impairment or 
distress with three or more of the following symptoms within a 12-month 
period:
 ZTolerance
 ZWithdrawal
 ZUsing larger amounts than intended
 ZPersistent craving or unsuccessful attempts to cut down
 ZLarge amount of time spent obtaining substance, using substance, or 
recovering from its effects

ZUsing larger amounts than intended
 ZActivities decreased or given up because of use
 ZUsing despite consequences
 XPhysiological dependence implies tolerance and withdrawal
 XDegree of tolerance and withdrawal symptoms are substance-specific.
 ZCan be physical, psychological, or both, depending on the substance
 ZWithdrawal symptoms are almost always the opposite of the acute 
action of the substance.
 ZCategories of abused substances with pronounced, obvious withdrawal 
symptoms :
 XAlcohol
 XOpioids
 XSedatives
 XHypnotics
 XAnxiolytics
 ZCategories of abused substances with less pronounced, less obvious 
withdrawal symptoms :
 XStimulants
 XNicotine
 XCannabis

300  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZCategories of abused substances with little to no pronounced, obvious 
withdrawal  symptoms:
 XPCP
 ZAssess for the presence of substance withdrawal or intoxication
 XClients abusing substances present for assessment either under the 
influence of the drug (intoxication) or experiencing problems related to 
cessation of substance use (withdrawal)
 ZIntoxication: Reversible substance-specific syndrome caused by recent 
ingestion of a psychoactivating substance
 ZWithdrawal: Potentially nonreversible substance-specific syndrome 
caused by cessation or significant reduction in heavy, prolonged use of 
a substance
 XBlood alcohol levels determine presence of alcohol in the body
 ZTolerant persons often have higher blood levels with less impairment 
than nontolerant persons
 ZMust interpret blood alcohol levels of a client based on his or her 
degree of tolerance

ZTolerant persons often have higher blood levels with less impairment 
 XDiagnostic criteria for substance withdrawal:
 ZCessation or reduction in substance use that has been heavy or 
prolonged
 ZTwo or more of the following symptoms within several hours or days of 
reduction or cessation of the substance:
 XHand tremor
 XInsomnia
 XAutonomic hyperactivity (sweating, increased heart rate, and 
increased blood pressure)
 XNausea or vomiting
 XHallucinations or illusions
 XPsychomotor agitation
 XAnxiety
 XSeizures
 XStructured interview allows for assessment of the use patterns and 
consequences of a person’s substance use
 ZAssess for all dimensions of the impact of substance abuse or 
dependence in the person.
 XCurrent use
 XPattern of use
 XConsequences (interpersonal, occupational, legal) 
 XPhysical health consequences

301 suBstance-related and addictive disorders
 XSubstance abuse or dependence produces many physical symptoms.
 ZUsually a result of sequelae of use or abuse rather than findings specific to 
abuse or dependence
 XGenerally nonspecific when viewed in isolation
 XMust be considered as a cluster of symptoms that raise an index of suspicion of 
addiction potential
 ZAbdominal pain and tenderness
 ZNausea
 ZWeight loss
 ZGastrointestinal bleeding
 ZAnxiety
 ZFirst-episode seizure in adult
 XPhysical findings related to alcohol use disorders (Domino, Baldor, Golding, & 
Stephens, 2015; NIAAA, 2016). 
 ZBrain : mood changes, behavior changes
 ZHEENT : poor oral health
 ZCardiovascular : hypertension, cardiomyopathy, tachycardia 
 ZGastrointestinal : liver disease, cirrhosis, peptic ulcer, esophageal malignancies
 ZNeurologic : tremor, cognitive deficits, peripheral neuropathy, Wernicke-Korsakoff 
syndrome
 ZMetabolic : hyperlipidemia

ZNeurologic : tremor, cognitive deficits, peripheral neuropathy, Wernicke-Korsakoff 
syndrome
Mental Status Exam (MSE) Findings
 XNature of findings depends heavily on whether the client is experiencing substance 
intoxication or withdrawal, or is substance-free at the time of assessment.
 ZIndex of suspicion for substance-related disorder should be raised if client 
presents differently during different periods of assessment (Sadock, Sadock, & 
Ruiz, 2015).
 XStimulants : agitation, anxiety, irritability, mood swings, elevated mood
 XOpioids : mood swings, aggression, disinhibition, impaired cognition, slurred 
speech, psychomotor slowing 
 XHallucinogens : mood swings, hallucinations, paranoia, flashbacks, panic, 
impaired judgement 
 XCannabis : confusion, paranoia, panic 
 XInhalants : agitation, irritability, confusion, hallucinations

302 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XComplete blood count (CBC), chemistry profile, thyroid function tests, and B12 level 
to rule out metabolic causes or unidentified conditions
 XAlcohol dependence and abuse produce characteristic laboratory findings. 
 ZBlood alcohol level >100 mg/dL outpatient; >150 mg/dL anytime with sx; >300 
mg/dL anytime
 ZAspartate transaminase (AST)/Alanine transaminase (ALT) ration >2.0 
 ZElevated: glutamyltransferase, mean corpuscular volume, prothrombin time, uric 
acid, total cholesterol, and triglycerides 
 ZDecreased: magnesium, calcium, potassium, blood urea nitrogen, hemoglobin, 
hematocrit, platelet count and albumin (Domino et al., 2015).
 XEndocrine disorders
 XNeurological disorders
 XCardiovascular disorders

 ZMDD
 ZBipolar (BP) disorder
 XPersonality disorders
 XDifferential diagnostic consideration for acute alcohol withdrawal:
 ZMany acute general health conditions can mimic symptoms of alcohol 
 XRule out or treat any conditions that may contribute to clinical findings.
 XNote:  80% to 90% of people who require alcohol treatment do not get it. 
 ZCommon reasons for failure to receive needed treatment:
 XLack of diagnosis
 XLack of referral
 XLack of access to services
 XResistance to treatment

303 suBstance-related and addictive disorders
 XThe genetics of addiction vulnerability are becoming better known, which allows for 
preventative and early intervention treatments.
 XThe knowledge base of the pathophysiology of dependence has promoted new 
somatic interventions.
 ZPsychopharmacology offers the promise of a new era in the treatment of 
addictions.
 XClinical management differs depending on the substance-related syndrome exhibited 
by the person.
 ZAcute withdrawal
 ZAcute intoxication
 ZLong-term sobriety maintenance
 ZRelapse prevention
 XAlcohol withdrawal carries a high risk of mortality. 
 XClinical management of alcohol withdrawal is a specialized treatment that requires 
specific experience in this type of care.
 XSome clinical findings may assist in identification of clients at risk for severe alcohol 
withdrawal: 
 ZDecreased short-term memory
 ZDisorientation
 ZIrregular pulse
 ZOphthalmoplegia

 XClinical Institute Withdrawal Assessment for Alcohol 
 ZUsed to determine likelihood of withdrawal and delirium tremens (DTs), which 
usually occur within the first 24 to 72 hours after cessation of alcohol.
 ZAssesses 10 common withdrawal symptoms:
 XTremors
 XParoxysmal sweats
 XAnxiety
 XAgitation
 XTactile disturbances
 XAuditory disturbances
 XVisual disturbances

304  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZEach symptom is graded on a 0- to 7-point scale with the exception of 
orientation and sensorium, which are graded on a 0- to 4-point scale. The higher 
the total score (maximum = 67), the more likely the person will experience 
severe withdrawal and DTs: 0–9 = absent or very mild withdrawal, 10–15 = mild 
withdrawal, 16–20 = moderate withdrawal, and 21–67 = severe withdrawal and 
possible DTs.
 XPharmacological treatments are symptom-specific
 XClinical management of acute withdrawal
 ZDetoxification (detox) agents replace uncontrolled use of substance with slow 
tapering of controlled substance to minimize neuroadaptive rebound.
 XMultiple daily doses of benzodiazepines are used according to a fixed 
schedule and gradually tapered down over several days.
 XExamples include:
 ZLorazepam (Ativan) 
 ZChlordiazepoxide (Librium)
 ZOxazepam (Serax)

 XPolytherapy is a newer approach that matches drugs required for safe and 
effective withdrawal with neurotransmitter deficits created by substance 
use.
 ZSelective serotonin reuptake inhibitors
 ZOpioid antagonists nalmefene hydrochloride (Revex), naltrexone (Revia), 
or naltrexone for extended-release injectable suspension (Vivitrol) 
 ZN-methyl-D-aspartate (NMDA) agonists
 XAntiseizure medications such as carbamazepine (Tegretol) and valproic acid 
(Depakene) are sometimes used to decrease the potential for seizures.
 XAdrenergic medications are sometimes used to decrease blood pressure 
and pulse rate associated with withdrawal.
 ZClinical management of craving (see Table 13–1) 
 XUse anticraving medication such as naltrexone (Revia), acamprosate 
(Campral), ondansetron (Zofran), or buprenorphine (Buprenex).

ZClinical management of craving (see Table 13–1) 
 XUse behavior treatment to help client learn substitute behaviors.
 ZClinical management and maintenance of sobriety (see Table 13–1)
 XPerson may require ongoing treatment for comorbid psychiatric disorder.
 XMay use aversion treatment  to avoid alcohol in persons with alcohol 
 ZDisulfiram (Antabuse)
 XDo not administer until the person has been alcohol-free for at 
least 12 hours.

305 suBstance-related and addictive disorders
 XAdvise client to refrain from using anything that contains alcohol 
(e.g., vinegar, aftershave lotion, perfumes, mouthwash, cough 
medication) while taking disulfiram and up to 2 weeks after 
discontinuing disulfiram.
 XDisulfiram can elevate liver function tests, so monitor.
 XAntabuse may potentially induce mania in people with BP disorder.
 ZGeneral health maintenance medication to treat vitamin deficiencies in persons 
with alcohol dependence include thiamine, folic acid, and B-complex vitamins.
 XMultimodality treatment needed.
 XLifetime treatment often required.
 XInpatient treatment usually needed for safe and effective withdrawal from alcohol.
 XIndications for inpatient alcohol detoxification include history of severe withdrawal 
symptoms, seizures, or delirium tremens; multiple past detoxifications; additional

XIndications for inpatient alcohol detoxification include history of severe withdrawal 
symptoms, seizures, or delirium tremens; multiple past detoxifications; additional 
medical or psychiatric illness; recent significant alcohol consumption; lack of reliable 
support system; and pregnancy.
 XReduce central nervous system stimulation by maintaining a quiet environment; 
put client in room close to the nurses’ station to facilitate frequent observation 
and monitoring; minimize abrupt changes in environment; decrease bright light and 
sharp, sudden noises; decrease room clutter; and do not restrain.
 XMaintain hydration by monitoring intake and anticholinergic effects of benzodiaz -
epines. Frequently offer fluids.
 XBefore discharge from acute-care setting, have a definite plan for follow-up treatment.TABLE 13–1  .
PHARMACOLOGICAL AGENTS USEFUL IN TREATING CRAVING AND MAINTAINING (STAHL, 
2014)
PHARMACOLOGICAL 
AGENT CHEMICAL CATEGORY ACTION EFFECT

2014)
Citalopram (Celexa) Selective serotonin reuptake 
inhibitorDecrease desire
Disulfiram (Antabuse) Aldehyde dehydrogenase 
inhibitorAversion therapy
Naloxone( Narcan) Opioid antagonist, antidote Blocks effects of opioids
Buprenorphine (buprenex) Opioid partial agonist, opioid 
antagonistAgonist and antagonist, 
decrease cravings
Buprenorphine and
naloxone (Suboxone)Narcotic analgesic Opioid agonist/antagonist
Methadone (Dolophine) Narcotic analgesic Suppresses withdrawal
Nalmefene (Revex) Opioid antagonist Increases abstinence
IM (Revia; Vivitrol) Opioid antagonist Increases abstinence
Acamprosate (Campral) Homotaurine Decreases craving

306  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XConnect client and family with support groups.
 Z12-step groups in community
 ZConcrete plan for first week of support group attendance (may need daily)
 XConnect client with counseling or psychotherapy. 
 XIdentify a primary healthcare provider.
 XNote medical problems that will require further evaluation and potential treatment:
 ZNeurological sequelae of chronic alcohol consumption
 ZNutritional deficiencies
 ZCardiomyopathy, hypertension, arrhythmias, ischemic heart disease
 ZBlood dyscrasias
 ZGastrointestinal inflammations
 ZEsophageal, liver, nasopharyngeal, and laryngeal cancers
 XClient care needs:
 ZSubstance abuse education classes
 ZSubstance abuse counseling program
 ZContinued 12-step program involvement (e.g., Alcoholics Anonymous, Narcotics 
Anonymous)
 ZHalfway housing
 ZCognitive behavioral therapy
 XFamily care needs:

ZSubstance abuse counseling program
 ZCurrent and understandable information about condition, progress, and 
treatment plan
 ZConnect family to community support groups such as Al-Anon and Alateen
 ZManagement of feelings such as guilt and anger
 ZReferrals to community resources 
 ZSpecific considerations: relationship with treatment team; role strain; financial 
stresses; social isolation and “code of silence”; family support systems; family 
violence; marital and family strife; family members’ work and school functioning; 
history of mental disorders, including substance-related disorders
 ZAssist family in coping with difficulties incorporating drinking member back into 
routines; encourage further counseling to resolve these difficulties
 ZRefer for further treatment if family members report symptom clusters from

 ZRefer for further treatment if family members report symptom clusters from 
anxiety and mood disorders, eating disorders, and addiction
 XChildren and adolescents
 ZMost common period for starting drug use
 ZSignificant impact of peer pressure on substance use patterns
 Z30% to 40% of adolescents report drinking frequently

307 suBstance-related and addictive disorders
 Z15% report binge-drinking patterns
 ZApproximately 50% of high school–age students report at least a one-time use 
of illicit drugs
 ZReferral to specialized treatment program that emphasizes interventions to deal 
with losses
 ZLarge-print psychoeducation materials
 ZTransportation to service locations
 ZTreatment with same-age peer group
 ZAdaptations to home environment to cope with physical disabilities
 ZClose collaboration with primary-care physician for follow-up

308  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
CASE STUDY
Mrs. Day is a 61-year-old widow who has multiple health problems. She had been diagnosed 
with essential hypertension and chronic bronchitis and has non-insulin-dependent diabetes. 
She has been coming to your primary care clinic for 6 months, and before that she had been 
receiving her care from multiple other providers in the community. She receives Social Security 
Disability Insurance.
Mrs. Day’s chief complaint for the past few months has been stasis ulcers on her lower left leg, 
which have not healed well despite multiple approaches to care. She also complains of problems 
with her “nerves. ” She currently is taking
 Xmultivitamin daily
 Xranitidine (Zantac) 150 mg q 12 hrs
 Xalprazolam (Xanax) 1 mg b.i.d.
 Xglipizide (Glucotrol) 20 mg b.i.d.
Mrs. Day is in today, and this is the first time you see her. On initial approach, she is hostile and

Xalprazolam (Xanax) 1 mg b.i.d.
Mrs. Day is in today, and this is the first time you see her. On initial approach, she is hostile and 
difficult to get information from, stating, “You should know all this; you have my chart right there 
in your hand. ” She states that today she wants a refill of all of her prescriptions, and she wants 
you to write a letter to her landlord to “stop harassing me. ” She reports that her landlord is insist -
ing that she place her garbage in the containers in the parking lot of the complex. She feels that 
is too far for her to walk, and she wants a letter supporting her current practice of leaving her 
garbage bags in the hallway outside her apartment door.
She also is reporting that her nerves are worse, and the pain in her legs is worse as well. She 
also believes that she has had a return of “chronic bronchitis, ” and she is requesting an antibiotic.

also believes that she has had a return of “chronic bronchitis, ” and she is requesting an antibiotic. 
She is requesting that you increase her alprazolam and add codeine or morphine or “any other 
thing like that” for her “constant pain. ” She states, “Just do this and get me out of here. I know 
what I need. ” 
 XAppearance:  moderately obese, well-dressed with appropriate hygiene, poor eye 
contact
 XMotor:  mild psychomotor restlessness, slightly ataxic gait, tremulous
 XSpeech:  loud and pressured 
 XAffect:  angry 
 XMood:  self-described as “cranky”; assessed as irritable 
 XThought processes:  goal-directed and organized without evidence of psychotic pro -
cessing but does show some mild thought-blocking and tangentiality
 XThought content:  thematic for mistrust of health providers and for fear of pain 
continuing 
 XMemory:  one-third of objects after 15 minutes
 XConcentration:  refuses to do numbers testing, stating “I was never good with book

 XConcentration:  refuses to do numbers testing, stating “I was never good with book 
work or numbers”
 XAbstraction:  is abstract on proverbs; asks, “You got any more dumb questions?”

309 suBstance-related and addictive disorders
 XJudgment:  intact for self-welfare
 XEducation:  completed 12th grade and went to 2-year secretarial business school
 XEmployment history:  was a medical claims clerk for 32 years at the VA Medical 
Center
 XSocial history:  no children; lives by herself; history of 2-pack-a-day smoker and “I 
drink a six-pack or so at night to relax myself—wouldn’t you?”
Her physical exam is overall unremarkable. Her vital signs are within her documented baseline, 
with BP 132/88, P 96, RR 26, Temp 98.5° F , Weight 209 lbs. Her lungs are overall clear. On her 
left leg she has a stasis ulcer, which is circular and approximately 6 cm in circumference. It is 
open and oozing white–yellow liquid drainage, with redness around the borders. She reports it 
is painful to touch and increasingly painful when weight-bearing. She was ordered silver sulfa -
diazine treatments with cling wrap and hot soaks q 6 hours. She refuses to cover it because

diazine treatments with cling wrap and hot soaks q 6 hours. She refuses to cover it because 
“it hurts when I remove the bandage” and is not very clear about whether or not she is doing 
the hot soaks. Recent labs are all within normal limits, including thyroid-stimulating hormone, 
electrolytes, and CBC.
1. What is the primary healthcare concern of this client? 
2. What method of interviewing would be useful for Mrs. Day? 
3. What further laboratory testing should be considered? 
4. If the client is unwilling to participate in further assessment, how will you deal with 
her health needs?

310 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
1. Given her laboratory values are within normal limits and she has no physical signs of 
a respiratory infection, the main concern is current or risk for addiction.
2. The method of interviewing Mrs. Day would be using the SBIRT technique.
3. Additional laboratory assessments should be obtained, which include liver function 
tests, including ALT , AST , GGT , albumin, and possibly uric acid level.
4. If Mrs. Day is unwilling to engage in a further assessment, the use of motivational 
interviewing techniques, building rapport, and keeping the client engaged would be 
indicated.
Barbosa, C., Cowell, A., Bray, J., & Aldridge, A. (2015). The cost effectiveness of alcohol screen -

ing, brief intervention, and referral to treatment (SBIRT) in emergency and outpatient medi -
cal settings. Journal of Substance Abuse Treatment, 53 , 1–8. 
DiClemente, C., Bellino, L., & Neavins, T . (1999). Motivation for change and alcoholism treatment. 
Alcohol Research and Health, 23 (2), 86–92.
Domino, F . J., Baldor, R. A., Golding, J., & Stephens, M. B. (2015). The 5-minute clinical consult 
standard (24th ed.). Philadelphia, PA: Wolters Kluwer. 
Dunn, K., Saulsgiver, K., Miller, M., Nuzzo, P ., & Sigmon, S. (2015). Characterizing opioid with -
drawal during double blind buprenorphine detoxification. Drug and Alcohol Dependence, 
151(1), 47–55. 
Graham, A. W., & Schultz, T . K. (2007). Principles of addiction medicine  (3rd ed.). Baltimore, MD: 
American Society of Addiction Medicine.

American Society of Addiction Medicine. 
Mayfield, D., McLeod, G., & Hall, P . (1974). The CAGE questionnaire: Validation of a new alcohol -
ism instrument. American Journal of Psychiatry, 131, 1121–1123.
Miller, N., Gold, M., & Smith, D. (1997). Manual of therapeutics for addictions.  New York, NY: 
Wiley-Liss.
National Institute on Alcohol Abuse and Alcoholism. (1997). Alcohol and health  (DHHS Publication 
No. 97-4017). Rockville, MD: Author.
National Institute on Alcohol Abuse and Alcoholism. (2016). Alcohol’s Effects on the body.  http://
www.niaaa.nih.gov/alcohol-health/alcohols-effects-body 
National Institute on Drug Abuse.  (2012). Medical consequences of drug abuse: Mental health 
effects. Bethesda, MD: National Institutes of Health. Retrieved from http://www.drugabuse.
gov/publications/medical-consequences-drug-abuse/mental-health-effects

Sadock, B., Sadock, V. A., & Ruiz, P . (2015). Kaplan and Sadock’s synopsis of psychiatry: 

311 suBstance-related and addictive disorders
Stahl, S. (2014). Essential psychopharmacology prescribers guide  (5th ed.). New York, NY: 
Substance Abuse and Mental Health Services Administration (SAMHSA). (2016). Screening tools. 
http://www.integration.samhsa.gov/clinical-practice/screening-tools#drugs
York, NY: Springer Publishing Company.

CHAPTER 14PERSONALITY DISORDERS
This chapter reviews a category of illnesses called personality disorders, common disorders that 
can affect the quality of the general health care that a person receives. Although these disorders 
can create great difficulty for the given person, he or she remains able to perform routine daily 
functions. Often the person does not recognize a problem or seek treatment.
This chapter briefly reviews the concept of personality  and then its disorders. Assessment and 
clinical management features of personality disorders are discussed. 
PERSONALITY
 XPersonality  is the sum total of all emotional, cognitive, and behavioral attributes of a 
person.
 XPersonality involves an enduring pattern of perceiving, relating to, and thinking about 
the environment and one’s self that are exhibited in a wide array of social and per -
sonal contexts. 
 XWhen healthy, personality structures allow for realistic, happy, and satisfying self-

perceptions and interpersonal interactions.
 XCharacteristics
 ZPersonality is organized early in life and is dynamic and deeply ingrained; 
however, it can be altered.
 ZPatterns of behavior based on personality can be perceived by the person as 
comfortable ( ego-syntonic ) or uncomfortable ( ego-dystonic ):
 XEgo-syntonic
 ZBehavior consistent with personality
 ZCauses little concern to the person
 ZPerson generally fails to recognize problem
 ZPerson does not seek treatment

314  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XEgo-dystonic
 ZBehavior inconsistent with personality
 ZCauses discomfort and concern to the person
 ZPerson generally recognizes problem
 ZPerson often seeks treatment
 ZPersonality is reflected in behavioral traits habitually displayed by the person:
 XCoping
 ZInterpersonal or interactive style
 ZPerceptions
 ZCognitive beliefs about events, people, and situations
PERSONALITY DISORDERS
 XPersonality disorders are chronically maladaptive patterns of behavior that cause 
functional impairment in work, school, or relationships.
 XThese disorders manifest as maladaptive patterns in four areas of functionality:
 ZMaladaptive affective  traits, such as overly affectual patterns of response
 ZMaladaptive behavioral  traits, such as poor impulse control patterns of response
 ZMaladaptive cognitive  traits, such as unrealistic perceptual patterns of response

ZMaladaptive behavioral  traits, such as poor impulse control patterns of response
 ZMaladaptive social  traits, such as maladaptive unsatisfying interpersonal patterns 
of response
 XThese disorders can cause subjective distress.
 ZA person is unlikely to recognize the problem or seek help if maladaptive 
patterns of behavior are ego-syntonic.
 ZA person is more likely to recognize problem and seek help if maladaptive 
patterns of behavior are ego-dystonic.
 ZMaladaptive patterns are inflexible  and pervasive  across most personal and 
 ZThese disorders are coded in the DSM-5 (see Table 14–1).
 ZClients seldom fit neatly into one personality disorder diagnosis; rather, they 
often exhibit features of several similar disorders.
 ZFor this reason, personality disorders often are referred to by the category of 
commonly manifesting symptom clusters (A, B, or C).
Etiology

Etiology

315 Personality disorders
 XLess empirical data available on neurobiological etiological factors
 XBorderline personality disorder is the most well researched.
 XTwo common types of theories of personality disorders:
1. Psychodynamic theory (primarily borderline personality disorder)—based on two 
etiological factors:
 XEarly separation problems
 ZObject relations theory
 XInternalized intrapsychic experiences of interpersonal relationships
 XMental representation of the self in relation to others
 XStability and depth of a person’s relationships
 XDuring development, child must accomplish two tasks: separation  
and individuation.
 ZSeparation : Develop intrapsychic self-representation distinct 
and separate from mother
 ZIndividuation: Form distinct identity with characteristics unique 
to the person.
 ZFailure in separation–individuation is etiologically linked to development 
of personality disorders.
 ZDifferent personality disorders linked to problems with different stages

 ZDifferent personality disorders linked to problems with different stages 
of the separation–individuation process.
 XDisturbed parental interaction
 XFamily background assumed to be dysfunctional:
 ZEnmeshed family patterns
 ZRole-reversal patterns of child–parent interaction
 ZRestricted involvement of family with the rest of the 
environmentTABLE 14–1  . 
CATEGORIES OF PERSONALITY DISORDERS
CATEGORY CHARACTERISTIC BEHAVIOR DISORDERS
Cluster A Odd, unusual, eccentric, asocial Paranoid personality disorder
Schizoid personality disorder 
Schizotypal personality disorder
Cluster B Dramatic, affective instability Antisocial personality disorder 
Borderline personality disorder 
Histrionic personality disorder 
Narcissistic personality disorder
Cluster C Anxious Avoidant personality disorder 
Dependent personality disorder 
Obsessive–compulsive personality 
disorder

316  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZSocial isolation
 ZConfusion of parental authority and nurturing roles
 ZBlurred family boundaries
 XDysfunctional family patterns block separation–individuation 
processes; family rejection occurs if person attempts individuation. 
2. Biological theory
 XGenetic factors 
 ZFamilial tendency
 ZGenetic overlap between loading for some Axis I disorders and 
personality disorders
 XStructural abnormalities
 ZReduced gray-matter volume in prefrontal cortex
 ZLimbic system deregulation
 XNeurotransmitter dysfunction
 ZDecreased levels of serotonin
 ZElevated levels of norepinephrine
 ZDysregulation of dopamine receptors
 XNeurobiological impact of trauma
 ZMost studied in borderline personality disorder
 ZAssumes early childhood trauma alters basic brain patterns of response
 ZIn genetically susceptible people, may function as the environmental 
vulnerability that causes expression of genetic load

ZAssumes early childhood trauma alters basic brain patterns of response
 XDifficult to estimate, because people with personality disorders are rarely hospital -
ized and often receive no treatment
 XIncidence varies with disorder
 XGenerally assumed to be 0.5% to 5.4% in the general U.S. population
 XDysfunctional family of origin

317 Personality disorders
 XPreventative work with young children in identified dysfunctional family 
settings
 XSymptoms of personality disorder are enduring maladaptive patterns of behavior, 
generally seen as problems with living.
 XOften several interviews are needed to clarify the diagnostic picture.
History
education; and alcohol, tobacco, and illicit drug use 
 ZValidate history with family member
 XLong-term patterns of functioning

 ZStability of traits over time and across situations
 XCultural issues versus maladaptive personality traits
 ZIssues of acculturation in new immigrants
 ZCultural expression of habitual behavior 
 ZCustom or religious practices
Assessment for Cluster A Disorders
 XPatterns of pervasive distrust and suspiciousness, with odd and unusual behavior
 ZPresent in a variety of contexts, even without supportive evidence
 XDistrust usually not at psychotic level but can display brief psychotic episodes under 
stress
 XSignificant history includes the following:
 ZLimited social network 
 ZPoor interpersonal relationships
 ZLimited disclosure or revealing of self to others, often refusing to answer 
personal questions
 ZCompliments often misinterpreted

318  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZPathological jealousy common
 ZDifficult to get along with
 ZAppearing cold and lacking in feelings
 ZHigh control needs
 ZRigid and critical of others
 ZOften highly litigious
 ZNegatively perceive others; often biased and prone to stereotypes
 XDifferences in Cluster A disorders are in degree of suspiciousness and mistrust and 
in behavioral manifestations of those traits (see Table 14–2).
Assessment for Cluster B Disorders
 XPatterns of pervasive affective and interpersonal disruption 
 XDisturbance usually not at psychotic level but can display brief psychotic episodes 
under stress
 XOf all clusters, disorders of Cluster B type may require hospitalization during period of 
active symptom expression and when client is under significant levels of stress

 ZFluctuating emotional states
 ZDramatic qualities to how the person lives his or her life
TABLE 14–2 .  
CHARACTERISTICS OF CLUSTER A PERSONALITY DISORDERS
DISORDER CHARACTERISTIC
Schizoid personality disorder Neither desires nor enjoys close relationships
Chooses solitary activities
Shows little to no interest in sexual activity with another 
person
Derives no pleasure in social activities
Lacks close friends or social supports
Is indifferent of opinion of others
Appears cold and detached
Exhibits affective flattening
Schizotypal personality disorder Ideas of reference
Odd beliefs
Magical thinking
Unusual perceptual experiences
Paranoid ideation
Inappropriate or constricted affect
Behavior overtly odd, eccentric, or peculiar
Few or no close friends
Excessive social anxiety

319 Personality disorders
 XAntisocial personality disorder
 ZUsually diagnosed by age 18
 ZMore common in men
 ZHigh substance abuse comorbidity
 ZHigh impulsivity
 ZOften diagnosed with conduct disorder as children
 XBorderline personality disorder 
 ZPredominantly in women
 ZOften with positive history of significant childhood physical abuse, sexual abuse, 
neglect, or early parental separation or loss
 XDifferences in Cluster B disorders are in degree of affective instability, type of inter -
personal disruption, and behavioral manifestations of those traits (see Table 14–3).
Assessment for Cluster C Disorders
 XPatterns of pervasive anxiety and fear 
 ZAvoidant behavior
 ZProcrastination
 ZDifficulty in following through
 ZFearful of rejection and criticism

 ZDifficulty relaxing
 XAvoidant personality disorder
 ZMust consider cultural variable when looking at avoidant behavior
 ZDisorder equal for both genders
 XDependent personality disorder
 ZMost frequently diagnosed personality disorder
 ZRates higher in women than in men
 ZCommonly diagnosed in people with history of chronic physical illnesses
 ZPredominantly in men
 ZSymptoms similar to but less severe than obsessive–compulsive disorder 
 XDifferences in Cluster C disorders are in the degree of anxiety and fear and in behav -
ioral manifestations of those traits (see Table 14–4).

320  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XComplete blood count (CBC), chemistry profile, and thyroid function tests to rule out 
metabolic causes or unidentified conditions
 XDrug toxicity screening if indicated by historyTABLE 14–3 .  
CHARACTERISTICS OF CLUSTER B PERSONALITY DISORDERS
Antisocial personality 
disorderFailure to conform to social norms
Repeated acts that are grounds for arrest
Deceitfulness, lying, and use of aliases for profit or pleasure
Impulsivity and failure of future planning
Reckless disregard for the welfare of others
Consistent irresponsibility
Lack of remorse; indifference to the feelings of others
Borderline personality 
disorderFrantic efforts to avoid real or imagined abandonment
Pattern of unstable, intense interpersonal relationships
Identity disturbances
Impulsivity, often with self-damaging behavior
Recurrent suicidal behavior

Chronic feelings of emptiness
Inappropriate, intensified affective anger responses
Transient psychotic symptoms of paranoia and dissociation
Histrionic personality 
disorderUncomfortable in situations in which he or she is not center of 
attention
Interactions with others characterized by inappropriate 
seductive or sexualized or provocative behavior, rapid shifting, 
and shallow emotional responses
Consistent use of physical appearance to draw attention to self
Speech excessively impressionistic and lacking in detail
Suggestible and easily influenced
Relationships considered more intimate than they are
Narcissistic personality 
disorderGrandiose sense of self-importance
Preoccupation with fantasies of power, success, brilliance, and 
beauty
Belief of self-importance and being special and unique
Excessive admiration required

beauty
Unreasonable expectations or sense of entitlement
Interpersonally exploitative
Empathy lacking
Envy of others and belief that others envy him or her
Arrogant and haughty behaviors

321 Personality disorders
 XComorbidity is common
 XMood disorders (see Chapter 9)
 ZAffective instability of borderline personality disorder often mistaken for bipolar 
affective disorder
 XSubstance-induced disorders (see Chapter 13)
 XRule out or treat any conditions that may contribute to cognitive impairment.
 XPersonality disorders are generally managed in a community setting.
 XIn some cases, hospitalization may be required. TABLE 14–4 .
 CHARACTERISTICS OF CLUSTER C PERSONALITY DISORDERS
Avoidant personality 
disorderAvoidance of activities involving significant interpersonal contact
Fear of criticism, disapproval, or rejection
Unwillingness to be involved with people unless sure of being 
liked
Restraint in intimate relationships for fear of being shamed
Preoccupation with being criticized or rejected in social settings
View of self as socially inept, personally unappealing, or inferior

Unusual reluctance to take personal risks or engage in new 
activities
Dependent personality 
disorderDifficulty making everyday decisions without excessive advice
Needing others to assume responsibility for most areas of life
Difficulty expressing disagreement
Difficulty initiating projects by himself or herself
Going to excessive lengths to obtain nurturing and support from 
others
Urgent seeking of another relationship if a close relationship 
ends
Unrealistic preoccupation with fears of being left alone
Obsessive–compulsive 
personality disorderPreoccupation with details, rules, order, and organization
Perfectionism that interferes with task completion
Excessive devotion to work and productivity
Overly conscientious, scrupulous, and inflexible on issues of 
morality

morality 
Inability to discard worn-out or worthless objects
Reluctance to delegate tasks or work with others
Adoption of a miserly spending style toward self and others
Rigidity and stubbornness

322  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XNo specific class of pharmacological agents used to treat personality disorders
 XIndividualized symptom control
 ZImpulsivity
 XSelective serotonin reuptake inhibitors (SSRIs)
 XAnticonvulsant mood stabilizers
 ZAffective instability
 XSSRIs
 ZAnxiety
 XNon-benzodiazepine anxiolytics
 XSSRIs
 XBenzodiazepines are used with extreme caution 
 XMost common form of treatment for personality disorders
 XFocus on issues of limit-setting, protection from self-harm, improved coping, and 
enhanced interpersonal functioning
 XMultiple therapeutic interventions may be used, such as
 ZCase management
 ZPsychotherapy
 XFocus on the person gaining control
 XImprovement of interpersonal skill level
 XEnhanced coping
 XAlteration of problematic patterns of behavior
 XForms of therapy:
 ZDialectical behavioral therapy

XImprovement of interpersonal skill level
 ZPsychodynamic therapy 
 ZInterpersonal therapy
 XAssist with realistic expectation formation
 XStructure environment
 XImprove realistic self-appraisal ability

323 Personality disorders
 XChildren
 ZBefore diagnosis is determined, sufficient life experiences must occur so that 
chronicity of maladaptive patterns can be observed.
 ZFeatures of personality disorder usually become apparent during adolescence to 
 ZIt is unusual for someone to be given personality disorder diagnosis before 
ages 16 to 18 (an exception is antisocial personality disorder, which often is 
observable by onset of puberty; however, diagnosis of antisocial personality 
disorder is not made until age 18).
 ZSeparation anxiety and chronic physical illness often precede and predict onset 
of dependent personality disorder.
Follow-up
 XThese are chronic disorders, and clients may be resistant to change.
 XRelapse is common and frequent.
 XHow long to treat and success rates vary with client characteristics and motivation.
 XPrognosis is poor without treatment.

XRelapse is common and frequent.
 XPrognosis improves if treatment is started as early in life as possible.

324  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
CASE STUDY
Mr. Jevers is 42-year-old new client who seeks health care for a general physical exam. The fam -
ily nurse practitioner who examines Mr. Jevers asks the psychiatric–mental health nurse prac -
titioner (PMHNP) to speak with him because of his odd presentation. The client discusses with 
the PMHNP an unusual, recurrent experience he has been having.
Mr. Jevers lives in an apartment building downtown and works as a bartender in the late eve -
ning. He tells the PMHNP that every night as he walks home from work he watches to see if 
the wind “blows north to south or south to north. ” He relates that, on the occasions that wind 
goes north to south, he takes that as a sign that a woman will visit him. He tells of a woman 
who rides a bicycle down the road and, as she passes him, he receives a blessing from her that

who rides a bicycle down the road and, as she passes him, he receives a blessing from her that 
protects him from those who wish him harm. He believes the woman is a “spirit from the other 
side” and that no one but he can see the woman. 
As Mr. Jevers tells his story, his affect is inappropriate, his mood pleasant and happy, and he 
exhibits some paranoid ideation as he worries that others will try to take away the spirit. His 
mental status examination (MSE) shows ideas of reference and some magical thinking as he 
shares his “blessing” with customers in the bar, and he describes odd, eccentric, and peculiar 
behaviors. Mr. Jevers is not at all bothered by his unusual experience and seems to enjoy telling 
it to others. He considers himself lucky to have “special powers” and to see and understand

it to others. He considers himself lucky to have “special powers” and to see and understand 
things that other do not. Mr. Jevers denies the presence of any typical manifestations of halluci -
nations or delusions, any mood disturbance or anxiety, and alcohol or other drug use. He reports 
having several close friends, a strong support network, and is in general good health but does 
experience significant social anxiety. He does not believe his unusual experience is a symptom 
of an illness and wishes no intervention or assistance at this time.
1. What is the most probable diagnosis for this client? 
2. What further assessment should occur? 
3. If the client desires no treatment, should the PMHNP attempt to follow up with him?
4. What treatment should be suggested at this time?

325 Personality disorders
1. The most likely diagnosis for this client is schizotypal personality disorder.
2. Medical work-up including drug screen is indicated to complete a thorough 
3. If the client is unwilling to engage in treatment, the PMHNP should try to follow up 
with the client at regular intervals and continue to build a therapeutic alliance.
4. If the client is willing to engage in treatment, treatment indicated is using a CBT ap -
proach would be helpful for the client to find “evidence” for his unusual thoughts and 
beliefs.
Linehan, M., … Lindenboim, N. (2006). Two-year randomized controlled trial and follow-up of dia -
lectical behavior therapy vs therapy by experts for suicidal behaviors and borderline personal -
ity disorder. JAMA, 63 (7), 757–766.

Neacsiu, A., Lungu, A., Harned, M., Rizvi, S., & Linehan, M. (2014). Impact of dialectical behav -
ioral therapy versus community treatment by experts on emotional experience, expression, 
and acceptance in borderline personality disorder. Behaviour Research and Therapy, 53, 
47–54.  
Nelson, K., Zagoloff, A., Quinn, S., Swanson, H., Garber, C., & Schulz, C. (2014). Borderline per -
sonality disorder: Treatment approaches and perspectives. Clinical Practice, 11 (3), 341–349. 
Rees, C., & Prichard, R. (2015). Brief cognitive therapy for avoidant personality disorder. 
Psychotherapy, 52 (1), 45–55. 
Reichborn-Kjennerud, T ., Czajkowski, N., Ystrom, E., Orstavik, R., Aggen, S., & Kendler, K. (2015)

Reichborn-Kjennerud, T ., Czajkowski, N., Ystrom, E., Orstavik, R., Aggen, S., & Kendler, K. (2015) 
A longitudinal twin study of borderline and antisocial disorder traits in early to middle adult -
hood. Psychological Medicine , 45(14), 3121–1331 . 
Schmahl, C. G., McGlashan, T ., & Bremner, J. D. (2002). Neurobiological correlates of borderline 
personality disorder. Psychopharmacology Bulletin, 36 (2), 69–78.
apy, psychopharmacology, and complementary and alternative approached. New York, NY: 

CHAPTER 15DISORDERS OF CHILDHOOD AND ADOLESCENCE
Disorders first diagnosed in infancy, childhood, or adolescence, such as conduct disorder, oppo -
sitional defiant disorder, attention-deficit hyperactivity disorder, Rett syndrome, autism spectrum 
disorder, eating disorders, and intellectual disabilities, are considered brain-based illnesses and 
have many similarities to disorders diagnosed more commonly in adulthood. In addition, these 
disorders often are missed during childhood and adolescent years and are therefore not identi -
fied until early adulthood.
The disorders diagnosed during childhood or in adolescent differ in presentation based on de -
velopmental context of the person, age of onset, and gender. Assessment, treatment planning, 
and therapeutic interventions for these disorders must always occur within the context of the 
family and assume a multimodal, systems-oriented approach to care. In addition, assessment of

family and assume a multimodal, systems-oriented approach to care. In addition, assessment of 
children is different from assessment of adults. Prior to making a psychiatric diagnosis, all pos -
sible medical causes of the symptoms must be ruled out. Therefore, psychiatric–mental health 
nurse practitioners (PMHNPs) must apply principles of child assessment to care and have a good 
understanding of normal growth and development to detect what is disordered. Effective as -
sessment, diagnosis, and treatment is completed in the context of the family system, however 
family is defined for the client. 
ASSESSMENT AND CARE PLANNING FOR CHILDREN AND 
ADOLESCENTS
 XRequires alteration in assessment process
 ZGenerally takes more time.
 ZPMHNP must develop trusting relationship with the child to put him or her at 
ease.
 ZInterview the child and parent separately: child can provide information on

ZGenerally takes more time.
ease.
 ZInterview the child and parent separately: child can provide information on 
internal symptoms and family or care providers on external signs (Hamrin & 
Gray Deering, 2012).
 ZMust attend to developmental needs and interests of the child.
 ZMust attend to the cognitive and language abilities of the child.

328 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XMental status examination (Sadock, Sadock, & Ruiz, 2015).
 ZModified to reflect developmental and other age-related issues in children
 ZOften requires establishment of a play environment to open communication 
with the child
 ZAppearance
 XConclusions must consider age and developmental processes (e.g., 
physical appearance and dress for weather and age group).
 XGait and motor skills are assessed on expected normative behaviors for 
age.
 XParent–child interaction
 ZObserve interaction in waiting room
 ZExamine way parent and child talk with one another and emotional overtones 
 Z Separation and reunion
 XExamine how child reacts to separation and reunion with parent 
 XSpeech and language 
 ZAssessed on expected normative and appropriate language use for age 
 ZComprehension, word selection, and range of vocabulary
 ZRate, rhythm, latency, intonation, spontaneity
 XMood and affect

ZAssessed on expected normative and appropriate language use for age 
 XMood and affect 
 ZMood : Verbal admission of feelings or assessment based on themes, play, and 
fantasy 
 ZAffect : Range of emotions expressed, appropriateness of affect to thought 
content
 XThought process and content 
 ZThought process : Looseness of associations, magical thinking, preservation, 
echolalia, ability to distinguish fantasy from reality (by age 4 children have some 
understanding of what is real or made up), flight of ideas
 ZThought content : Suicidal or homicidal ideation, perceptual disturbances 
(hallucinations) 
 XSocial relatedness
 ZChild’s response to interviewer
 XMotor behavior
 ZCoordination, activity level, involuntary movements, tremors, tics, unusual 
asymmetries 
 ZIntellectual functioning and problem-solving abilities 
 XMemory

329 disorders of childhood and adolescence
 ZTest recall after 5 minutes (school-age children should be able to remember 
three objects after 5 minutes) 
 ZAssessed on expected normative behaviors for age
 ZChildren ages 12 or younger not expected to have abstractive thought abilities 
(young children have concrete thinking) 
 ZProverb testing and similarity testing require prior exposure to concept, word 
choices, and ability to think abstractly
 XJudgement and insight
 ZChild’s view of problem
 ZChild’s understanding of what he or she can do to help the problem 
 XTherapeutic care planning
 ZVariety of effective treatments commonly used with children and adolescents:
 XPlay therapy
 XArt therapy
 XBibliotherapy
 XOrative therapy (such as storytelling, family narrative therapy)
 XInterpersonal therapy 
 XCognitive therapy 
 XPharmacotherapy
OPPOSITIONAL DEFIANT DISORDER (ODD)

XBehavioral therapy
 XOppositional defiant disorder (ODD)  is an enduring pattern of angry or irritable mood 
and argumentative, defiant, or vindictive behavior lasting at least 6 months with at 
least four of the associated symptoms:
 Z Loses temper
 ZTouchy or easily annoyed
 ZAngry or resentful
 ZArgues with authority
 ZActively defies or refuses to comply with request or rules from authority figures
 ZBlames others
 ZDeliberately annoys others
 ZSpiteful or vindictive

330  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
Etiology
 XTemperament
 XParents who model extreme ways of expressing emotions 
 XTrauma
 XUnresolved conflicts 
 XODD is more common in children of parents with a history of ODD, conduct disor -
der, attention-deficit hyperactivity disorder (ADHD), antisocial personality disorder, 
mood disorders, or substance abuse disorder.
 XIt affects 1% to 11% of the general U.S. population, with an average of 3.3%.
 XMore common in males (1 .4:1).
 XAbout 30% of children with ODD develop conduct disorder.
 XGenetic and physiological
 XTemperamental
 XEnvironmental 
 XWell-child visit mental health screening 

ZSigns and symptoms of illness
 ZSecondary prevention important in younger clients
History
 ZSocial history, including present living situation; education; and alcohol, tobacco, 
or illicit drug use

331 disorders of childhood and adolescence
 ZSubstance or alcohol use 
 XMood
 ZLability:  Low frustration tolerance, angry, argue and lose temper
 ZImpaired
 ZOften blame others for mistakes
 XNo specific laboratory tests
 ZLead toxicity
 ZToxicology screen to rule out a substance abuse disorder
 XADHD (see below)
 XSubstance abuse disorders (see Chapter 13)
 XIntellectual disability (see below)

 XIntellectual disability (see below) 
 XConduct disorder (see below)
 XPsychotic disorders (see Chapter 11)
 XRule out or treat any conditions that may contribute to current symptom manifestation.
 XNonspecific: not first-line treatment
 XTarget symptoms: mood or aggression

332 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XTherapy is mainstay:
 ZIndividual therapy
 ZFamily therapy, with emphasis on child management skills
 ZEvidence-based treatment: child and parent problem-solving skills training 
(American Academy of Child and Adolescent Psychiatry [AACAP], 2007b).
 XIncredible Years (group intervention)
 XParent–child interactional therapy (individual or family intervention)
 XAdolescent Transitions Program (ATP; individual or family and group 
intervention)
CONDUCT DISORDER
 XConduct disorder  is a repetitive and persistent pattern of behavior in which the rights 
of others or societal norms or rules are violated. The presence of at least three of 
the following criteria must be present in the past 12 months, with one in the past 6 
months: 
 ZAggression toward people or animals—bullies, threatens, intimidates, initiates

months: 
 ZAggression toward people or animals—bullies, threatens, intimidates, initiates 
physical fights, uses a weapon to cause physical harm to others, physically cruel 
to people or animals, stealing while confronting a victim, forced sexual activity 
on someone
 ZDestruction of property—engaged in fire-setting, destroyed others’ property
 ZDeceit or theft—broke into house, building, or car; lies, steals items
 ZSerious violation of rules—stays out late before age 13, runs away from home, 
truant before age 13
 ZChild onset before age 10 or adolescent onset after age 10
Etiology
 XNo single factor accounts for presentation.
 XEtiology is largely unknown.
 XMany biopsychosocial factors contribute to the development.
 XConduct disorder is more common in children of parents with antisocial personality 
disorder, alcohol dependence, mood disorders, or schizophrenia than in the general

disorder, alcohol dependence, mood disorders, or schizophrenia than in the general 

333 disorders of childhood and adolescence
 XAffects 2% to 10% of general U.S. population, 6% to 16% of boys and 2% to 9% of girls
 XOnset is earlier for boys (10 to 12 years) than for girls (16 years)
 XTemperamental: Lower than average IQ 
 XEnvironmental: Family rejection and neglect, unsupervised, physical or sexual abuse, 
substance use
 ZSecondary prevention is important in younger clients
History

 ZDevelopmental history

334 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XAffect
 ZAngry
 ZUncooperative
 XMood
 ZAnger
 ZLack of empathy or concern for others
 XInsight
 ZPoor
 XDrug screening to rule out possible substance abuse
 XAttention-deficit hyperactivity disorder (ADHD; see below)
 XOppositional defiant disorder (ODD; see above)
 XPosttraumatic stress disorder (see Chapter 10)
 XSubstance abuse disorders (see Chapter 11)
 XDevelopmental disorders (see below)

XDevelopmental disorders (see below)
 XNo specific pharmacological interventions 
 XAggression and agitation treated with antipsychotics, mood stabilizers, selective 
serotonin reuptake inhibitors (SSRIs), and alpha agonists

335 disorders of childhood and adolescence
 XMultimodality treatment programs that use all available family and community 
resources
 XBehavioral therapy is mainstay:
 XMay be diagnosed in clients ages 18 years or older if criteria for antisocial personality 
disorder are not met. 
ATTENTION-DEFICIT HYPERACTIVITY DISORDER (ADHD)
 XAttention-deficit hyperactivity disorder (ADHD)  is a persistent pattern of inattention or 
hyperactivity, impulsivity, or both, that interferes with functioning and development. 
 ZInattention, six or more of the following:
 XFails to give attention to details
 XDifficulty sustaining attention
 XDoes not listen when spoken to
 XDoes not follow through on instructions
 XDisorganized
 XAvoids or dislikes tasks requiring sustained mental effort
 XLoses things
 XDistracted
 XForgetful
 ZHyperactive and impulsive, six or more of the following:
 XFidgets

XDisorganized
 XFidgets
 XLeaves seat
 XRuns or climbs
 XUnable to engage in quiet activities
 X“On the go”
 XTalks excessively
 XBlurts out information
 XDifficulty waiting turn
 XInterrupts others

336 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XSeveral symptoms were present prior to age 12 
 ZSubtypes:
 XADHD, inattentive type
 ZInattentive symptoms dominate
 ZLack of criterion symptoms for hyperactivity or impulsivity
 XADHD, hyperactive type
 ZHyperactivity or impulsivity symptoms dominate
 ZLack of criterion symptoms for inattention
 XADHD, combined type
 ZCriterion symptoms met for inattention and hyperactivity or impulsivity
Etiology
 XMany biopsychosocial factors contribute to the development of ADHD.
 XPolygenic neurobiological deficits are associated with ADHD.
 ZProblems with executive functioning
 ZAbnormalities of fronto–subcortical pathways
 XFrontal cortex
 XBasal ganglia
 ZAbnormalities of reticular activating system
 ZStructural abnormalities producing neurotransmitter abnormalities
 XDopamine dysfunction
 XNorepinephrine dysfunction

ZAbnormalities of reticular activating system
Incidence and Demographics 
 X5% of children and 2.5% of adults in the United States have ADHD.
 XBoys are more likely to be diagnosed (13.2%) than girls (5.6%; CDC, 2010).
 XAverage age of onset is 3 years; mean age of diagnosis is 9 years.
 XApproximately 60% of clients have symptoms persisting into adulthood.
 ZInattention symptoms are more persistent than hyperactivity and impulsivity 
symptoms.
 ZPregnancy and perinatal complications
 ZFamily conflict

337 disorders of childhood and adolescence
 ZLow birth weight
 ZNeglect, foster placement 
 ZAlcohol exposure in utero 
 XTemperamental 
 ZReduced behavioral inhibition 
 ZSecondary prevention is important in young clients.
 XMinor physical anomalies at higher rates in people with ADHD than in general 
population:
 ZHypertelorism
 ZLow-set ears
 XHigher-than-average accidental injury rates
 XInattention
 XDistractible speech patterns
 XOverproductive speech patterns
 XAffective lability
 XPoor memory
 XPoor concentration

338 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XUnderstimulated home environment
 XBipolar (BP) disorder
 XStereotypic movement disorder
 XMost commonly used agents (see Table 15–1) are stimulants (Schedule II)—
controlled substances that carry risk for abuse.
 ZMonitor for side effects and adverse effects of stimulants:
 XGastrointestinal (GI) upset
 XCramps
 XAnorexia
TABLE 15–1  . 
MOST COMMONLY USED AGENTS FOR ADHD
DRUG DOSAGE
Ritalin (methylphenidate hydrochloride), Schedule II 5–40 mg/day
Ritalin LA/Ritalin SR (methylphenidate hydrochloride), Schedule II 10–60 mg/day
Metadate CD (methylphenidate hydrochloride), Schedule II 10–60 mg/day
Metadate ER (methylphenidate hydrochloride), Schedule II 10–60 mg/day
Concerta (methylphenidate hydrochloride), Schedule II 18–72 mg/day

Methylin (methylphenidate hydrochloride), Schedule II 5–60 mg/day
Methylin ER (methylphenidate hydrochloride), Schedule II 10–60 mg/day
Daytrana (methylphenidate transdermal patch), Schedule II 10 mg–30 mg/day  
(9 hours)
Dexedrine (dextroamphetamine), Schedule II 2.5–20 mg/day
Adderall (amphetamine, dextroamphetamine), Schedule II 5–40 mg/day
Adderall XR (amphetamine, dextroamphetamine), Schedule II 5–60 mg/day
Focalin/Focalin XR (dexmethylphenidate), Schedule II 2.5–20 mg/day
Vyvanse (lisdexamfetamine dimesylate), Schedule II 30–70 mg/day
Strattera (atomoxetine hydrochloride), not a controlled substance 10–100 mg/day
Intuniv (guanfacine), alpha agonist; not a controlled substance; FDA-
approved for ages 6–17 1–4 mg/day
Catapres (clonidine), alpha agonist; not a controlled substance; not FDA-
approved 0.1–0.4 mg/day

Wellbutrin SR/XL (bupropion), norepinephrine dopamine reuptake 
inhibitor; not FDA-approved 100–450 mg/day

339 disorders of childhood and adolescence
 XWeight loss
 XBlood pressure changes 
 XIncreased pulse rate 
 XGrowth suppression (rare)
 XHeadache, dizziness
 XPsychosis (rare)
 XPatient and parent cognitive behavioral training program
 XPsychoeducation
 XTreatment of learning disorders
 XFamily therapy and education
 ZParents of children with ADHD have many difficult emotions:
 XStress
 XSelf-blame
 XSocial isolation
 XEmbarrassment
 XDepressive reaction 
 XMarital discord
 ZTypical family concerns:
 XStigma
 XAnger
 XConcerns over treatment options
 XPresence of controversial information in media
 ZClaims of dietary causes of disorder
 ZBelief in family etiological factors
 ZFamily educational needs:
 XEnvironmental structuring
 XPsychiatric comorbidities
 XSchool issues and concerns
 XPeer relationship-building
 XSmoking and substance abuse rates
 XCommon comorbidities

XEnvironmental structuring
 ZMajor depressive disorder (see Chapter 9)

340  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZBipolar disorder (see Chapter 9)
 ZOppositional defiant disorder (see above)
 ZSubstance abuse disorders (see Chapter 13)
 ZTic disorder
Follow-up
 XMonitor clinical progress over time.
 XUse standardized rating scales such as:
 ZConners’ Parent and Teacher Rating Scales (copyrighted)
 ZVanderbilt ADHD Diagnostic Parent and Teacher Rating Scales (public domain) 
 XMonitor attainment of growth and development milestones.
 XSymptoms may persist into adulthood.
 ZPlan for long-term needs.
AUTISM SPECTRUM DISORDER
 XPersistent deficits in social communication and social interaction across multiple set -
tings associated with deficits in: 
 ZSocial reciprocity
 ZNonverbal communication
 ZDeveloping, maintaining, and understanding relationships. 
 XRestricted repetitive behavior: 
 ZStereotyped or repetitive motor movements

ZSocial reciprocity
 ZInsistence on sameness
 ZHighly restricted with fixed interests
 ZHyper- or hyposensory input
 Etiology
 XNo single factor can account for presentation.

341 disorders of childhood and adolescence
 XThe disorder appears to be more common in families in which other members have  
autism spectrum disorder (ASD).
 XAffects about 1% of U.S population, but the disorder is more common in boys.
 XImbalances of glutamate, serotonin, and gamma-aminobutyric acid (GABA) are 
thought to be implicated in causation.
 XBrain imaging studies of children with autism revealed microscopic and macroscopic 
abnormalities of the amygdala, hippocampus, and cerebellum.
 XDecreased numbers of Purkinje cells in the cerebellum are thought to play a role in 
the development.
 XASD is more common in children with a family history of pervasive developmental 
 XThe concordant rate for an identical twin with autism is 60%.
 XThe incidence is 2 to 5 cases per 10,000 in the United States.
 XThe male-to-female ratio is 4:1 . 
 XOnset of symptoms is before age 3 years.

XThe incidence is 2 to 5 cases per 10,000 in the United States.
 XAbout 10% of people with autism also have a genetic or chromosomal condition 
such as Down syndrome or fragile X syndrome (CDC, 2015).
 XMale
 XIntellectual disability 

342 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
History
 ZImpairment with social interaction, communications, and behavior
 XImpaired social interactions such as abnormal gaze, posture, and expression 
in social interactions
 ZLack of peer relationships, emotional reciprocity, and spontaneous seeking of 
enjoyment
 ZImpaired communication, such as a delay or lack in the development of spoken 
language, impaired ability to initiate and sustain conversations, repetitive and 
stereotyped use of language, and inability to play with others
 ZRestricted repetitive and stereotyped patterns of behavior, interests, and activities, 
such as inflexible adherence to specific nonfunctional routines and repetitive, 
stereotyped motor mannerisms (e.g., hand or finger flapping, rocking, swaying)
 ZParents may report any of the following symptoms:
 XNo cooing by age 1 year, no single words by age 16 months, no two-word

ZParents may report any of the following symptoms:
 XNo cooing by age 1 year, no single words by age 16 months, no two-word 
phrases by age 24 months
 XLoss of language skills at any time
 XNo imaginary play
 XLittle interest in playing with other children
 XExtremely short attention span
 XNo response when called by name
 XLittle or no eye contact
 XIntense tantrums
 XFixations on single objects
 XUnusually strong resistance to changes in routines
 XOversensitivity to certain sounds, textures, or smells
 XAppetite or sleep–rest disturbance, or both
 XSelf-injurious behavior
 XFlat or blunted affect
 XLack of emotional reciprocity
 XStereotyped or repetitive motor mannerisms
 ZExpressive- and receptive-language impairment

343 disorders of childhood and adolescence
Screening 
 XScreened for developmental delays at well-child visit (CDC, 2015).
 ZModified Checklist for Autism in Toddlers (M-CHAT)
 ZAutism Diagnostic Observation Schedule–Generic (ADOS-G)
 ZAges and Stages Questionnaires (ASQ)
 XRett syndrome (see below)
 XAsperger syndrome
 XChildhood disintegrative disorder
 XHearing impairment
 XDevelopmental language and speech disorders
 XTic disorders
 XCluster A personality disorders (see Chapter 14)
 XNo specific pharmacological interventions
 XAntipsychotics effective for symptoms such as tantrums; aggressive behavior; self-
injurious behavior; hyperactivity; and repetitive, stereotyped behaviors

XAntipsychotics effective for symptoms such as tantrums; aggressive behavior; self-
 XAntidepressants, naltrexone, clonidine, and stimulants to diminish self-injurious and 
hyperactive and obsessive behaviors
 XBehavioral therapy to improve cognitive functioning and reduce inappropriate 
behavior
 XOccupational therapy to improve sensory integration and motor skills
 XSpeech therapy to address communication and language barriers
 XPivotal response training 
 XAppropriate school placement with a highly structured approach

344  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
RETT SYNDROME
 XRett syndrome  is the development of specific deficits following a period of normal 
functioning after birth.
Etiology
 XEtiology is unknown.
 XThere is a known, progressive, and deteriorating course after an initial period without 
apparent disability.
 XIt is compatible with probable metabolic disorder.
 XGenetic mutation is suspected.
 XThe disorder occurs primarily in girls.
 XIt is usually associated with an intellectual disability (see below).
 XSeizure disorder
 ZSecondary prevention is important in young clients

ZTreatment potential for control of symptoms
 XDetailed history of present illness, including time frame, progression, and associated 
symptoms
 XSocial history, including present living situation and education
 XValidate all physical health findings with a family member.

345 disorders of childhood and adolescence
History
 ZNormal prenatal and perinatal development
 ZNormal psychomotor development through the first 5 months after birth
 ZNormal head circumference at birth
 ZOnset of all of the following after the period of normal development:
 XDeceleration of head growth between the ages 5 to 48 months
 XLoss of previously acquired purposeful hand skills between ages 5 to 
30 months, with the subsequent development of stereotyped hand 
movements
 XEarly loss of social engagement
 XAppearance of poorly coordinated gait or trunk movements
 XSeverely impaired expressive- and receptive-language development with 
severe psychomotor retardation.
 XAssociated features:
 ZSeizures
 ZIrregular respirations
 ZScoliosis
 ZLoss of purposeful hand skills
 ZStereotypic hand movements
 XSpeech

ZLoss of purposeful hand skills
 XSpeech
 XAffect
 ZFlat or blunted affect
 ZDiagnostic and laboratory findings
 ZNo specific laboratory or diagnostic findings
 ZCBC, chemistry profile, thyroid function tests, and B12 level to rule out metabolic 
 ZDrug toxicity screening, if indicated by history
 ZElectroencephalogram (EEG) and nonspecific abnormalities on brain imaging

346  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XAutism spectrum disorder (see above).
 XMultimodality treatment
 XTreatment aimed at symptomatic intervention
EATING DISORDERS
 XEating disorders  are characterized by disordered patterns of eating, accompanied by 
distress, disparagement, preoccupation, and a distorted perception of one’s body 
shape.
 XCommon forms of eating disorders:
 XClients refuse to maintain a normal body weight.
 XInvolves restricted caloric intake.
 XClients have an intense fear of gaining weight because of a distorted body image.
 ZBulimia nervosa
 XClients engage in binge eating, combined with inappropriate ways of 
stopping weight gain

XClients have an intense fear of gaining weight because of a distorted body image.
 XAssociated with efforts made to lose weight
 XUsually normal or slightly overweight 
 ZBinge eating disorder
 XRecurrent episodes of binge eating with lack of control
 XBingeing occurs at least 2 days weekly for 6 months
 XNot regularly associated with compensatory behaviors
Etiology
 XEtiology is multifactorial, with biological, social, and psychological factors implicated 
in causation.

347 disorders of childhood and adolescence
 XNeurobiological factors include decreased hypothalamic norepinephrine activation, 
dysfunction of lateral hypothalamus, and decreased serotonin.
 XIncidence is more common in girls, with 85% to 95% of occurrences.
 XAnorexia nervosa affects approximately 0.28% of the general U.S. population.
 XBulimia nervosa affects approximately 1 .0% of the general U.S. population.
 XOnset is typically between ages 14 and 18 years.
 XIncreased risk of eating disorders among first-degree biological relatives of people 
with certain other psychiatric disorders:
 ZEating disorders
 ZMood disorders
 ZSubstance abuse disorders

XCommunity education
symptoms
 XSocial history, including present living situation; marital status; occupation; education; 
and alcohol, tobacco, or illicit drug use
 XValidate history with a family member.

348 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
History
 XRefusal to maintain a minimally normal body weight
 XWeight less than 85% of expected weight
 XFear of gaining weight or becoming fat
 XDistorted body image
 ZRestricting type: During the current episode, the person has not 
regularly engaged in binge eating or purging behavior.
 ZBinge eating or purging type: During the current episode, the person 
has regularly engaged in binge eating or purging behavior.
 XRecurrent, episodic binge eating
 XBoth binge eating and inappropriate compensatory behaviors occur at least 
twice weekly for 3 months 
 XRecurrent, inappropriate compensatory behaviors to prevent weight gain:
 ZSelf-induced vomiting
 ZLaxatives
 ZEnemas
 ZDiuretics
 ZStimulants
 ZAbuse of diet pills
 ZFasting
 ZExcessive exercise
 XSelf-evaluation unduly influenced by body shape and weight

ZSelf-induced vomiting
 ZEnemas
 ZFasting
 ZPurging type: During the current episode, the person regularly has 
engaged in purging or the misuse of laxatives, enemas, or diuretics.
 ZNonpurging type: During the current episode, the person has used 
other inappropriate compensatory behaviors, such as fasting or 
excessive exercise, but has not regularly engaged in purging or misuse 
of laxatives, enemas, or diuretics.
 XAnorexia nervosa:
 ZLow body mass index
 ZAmenorrhea
 ZEmaciation
 ZHypotension

349 disorders of childhood and adolescence
 ZElectrocardiogram (ECG) changes
 XInversion of T -waves
 XST segment depression
 XProlonged QT interval
 ZHypothermia
 ZYellow skin secondary to carotenemia
 ZDry skin
 ZBrittle hair and nails
 ZLanugo growth on face, extremities, and trunk
 ZPeripheral edema
 ZHypertrophy of the salivary glands
 ZErosion of dental enamel
 ZRussell’s sign—scarring or calluses on the dorsum of the hand, secondary to 
self-induced vomiting
 XBulimia nervosa:
 ZWeight usually within normal range
 ZRussell’s sign
 ZHypertrophy of salivary glands
 ZRectal prolapse
 ZEmaciated appearance with anorexia nervosa
 XAffect
 ZLability
 ZAnxiety
 ZConstricted and sad
 XMood
 ZDysphoric mood
 ZPreoccupation with food and body weight
 ZSuicidal ideation
 ZLow self-esteem

350  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XJudgment
 XInsight
 ZImpaired
 XAnorexia nervosa
 ZNo definitive laboratory test for diagnosis 
 ZLaboratory changes:
 XNormochromic, normocytic anemia
 XLeukopenia
 XNeutropenia
 XAnemia
 XThrombocytopenia
 XHypokalemia
 XHypomagnesemia
 XHypoglycemia
 XDecreased LH and FSH
 XBulimia nervosa
 ZNo definitive laboratory tests
 XBradycardia
 XHyponatremia
 XHypochloremia
 XMetabolic acidosis or alkalosis
 XElevated serum amylase
 XGeneral medical condition
 XCluster B personality disorders (see Chapter 14)

351 disorders of childhood and adolescence
 XObsessive–compulsive disorder (OCD; see Chapter 10)
 XMedication management as adjunctive therapy to psychotherapy
 XNo specific medication therapy for anorexia nervosa
 XFluoxetine is FDA-approved for bulimia nervosa.
 XSSRIs and tricyclic antidepressants (TCAs) effective in reducing the frequency of 
bingeing and purging
 XTreat associated symptoms, such as depression and anxiety, with appropriate phar -
macological therapy.
 XMultimodal treatment
 ZMedical and nutritional stabilization
 XWeight restoration
 XCorrection of electrolyte disturbance
 XVitamin supplementation
 XNutrition counseling
 ZDental care
 ZPsychotherapeutic interventions
 XIndividual psychotherapy
 XCognitive behavioral therapy
 XFamily therapy

XVitamin supplementation
 ZCommunity resources
 XEating disorder support groups
 X12-step programs
Follow-up
 XRegular follow up with a multidisciplinary team is necessary

352 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
INTELLECTUAL DISABILITY
 XIntellectual disability has an onset during the developmental period and includes low 
intellect and adaptive functioning. 
 XOnset must occur before age 18 years.
 XMild, moderate, severe, or profound.
 ZBased on adaptive functioning and not IQ scores 
 ZIQ scores are less valid on the lower end of IQ range
Etiology
 XHeredity accounts for 5% of cases:
 ZInborn errors of metabolism (e.g., Tay-Sachs disease)
 ZSingle-gene abnormalities (e.g., tuberous sclerosis)
 ZChromosomal aberrations (e.g., translocation of chromosome 21 [Down 
syndrome] and X-linked gene of FMR-1 [fragile X syndrome]).
 XEarly alterations of embryonic development account for 30% of cases.
 ZPrenatal exposure to toxins (e.g., maternal alcohol consumption, infections)
 XPregnancy and perinatal problems account for 10% of cases.
 ZFetal malnutrition
 ZPremature birth
 ZFetal hypoxia

ZPrenatal exposure to toxins (e.g., maternal alcohol consumption, infections)
 ZBirth trauma
 XGeneral medical conditions acquired during infancy or childhood contribute to ap -
proximately 5% of cases.
 ZInfections
 ZBrain trauma
 ZExposure to toxins (e.g., lead poisoning)
 XNo clear etiology can be found in 30% to 50% of cases.
 XThe most preventable cause of intellectual disability is fetal alcohol syndrome.
 ZCharacteristics of fetal alcohol syndrome include:
 XEpicanthal skin folds
 XLow nasal bridge
 XShort nose
 XIndistinct philtrum
 XSmall head circumference
 XSmall eye openings

353 disorders of childhood and adolescence
 XWide-set eyes
 XThin upper lip
Prevalence 
 X1% of the general population
 XHighest rates are reported in school-age children (10–14 years of age). 
 X1 .5 percent more males than females 
 XAdverse birth events
 XAt well-baby examinations 
 XSchool screenings 
Physical Exam Findings 
 XOblique eye folds
 XSmall, flattened skull
 XLarge tongue
 XBroad hands with stumpy fingers
 XSingle transverse palm crease
 XHigh cheekbones
 XSmall height
 XBrushfield spots on iris
 XAbnormal finger and toe prints
 XCryptorchidism
 XCongenital cardiac defects
 XEarly dementia

354 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XCommunication deficits
 XDependency
 XPassivity
 XPoor self-esteem
 XLow frustration tolerance
 XAggressiveness
 XStereotyped, repetitive motor movement 
 XNo specific laboratory findings
 XSome laboratory findings associated with a variety of causes of intellectual disability 
(e.g., metabolic disturbances)
 XBorderline intellectual functioning
 XLearning and communication disorders
 XPervasive developmental disorder (PDD)
 Z75% of people with a PDD have comorbid intellectual disability.
 XADHD (see above)
 XPharmacological treatment is symptom-specific.
 ZTreat concomitant psychopathology (e.g., ADHD, depressive disorder, anxiety 
disorder, schizophrenia).

 ZAggressive or self-injurious behavior may be controlled with antipsychotics and 
mood stabilizers.
 XTherapy

355 disorders of childhood and adolescence
 XCommunity resources
 ZDay care settings
 ZSheltered workshops
 ZGroup homes
Separation Anxiety Disorder (refer to Chapter 10)
DISRUPTIVE MOOD DYSREGULATION DISORDER
 XChildhood depressive disorder that is diagnosed in children older than age 6 but 
younger than age 18. 
 XThe features of this disorder are
 Zchronic dysregulated mood, 
 Zfrequent temper outbursts, and 
 Zsevere irritability. 
Etiology
 XAffects about 2% to 5% of children and adolescents 
 XHigher incidence in boys and school-age children than girls and adolescents 
 XComplicated psychiatric history including comorbid ADD and ADHD. 
 XChildren and adolescents should be screened for a personal and family history of bi -
polar disorder as symptoms of disruptive mood dysregulation disorder can be similar 
to bipolar disorder. 
 XAssess for comorbid conditions such as:

 ZBipolar disorder
 ZODD
 ZADHD

356 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZDepressive and anxiety disorders 
 ZAutism spectrum disorder
Pharmacologic Management
 XMedications can be used to treat the target symptoms of the disorder. 
 XSelective serotonin reuptake inhibitors, mood stabilizers, and atypical antipsychotics 
can be helpful.
Nonpharmacologic Management
 XIndividual, group, and family therapy are helpful.
Follow-Up
 XRegular follow-up is necessary, as is ongoing assessment for comorbid conditions

357 disorders of childhood and adolescence
CASE STUDY
The parents of a 14-year-old with attention-deficit hyperactivity disorder (ADHD) ask to speak to 
you privately after you complete your assessment of their child. They tell you they have several 
questions that they want answered, and they want to ask you to keep the answers to yourself 
and not tell their son what they ask. Their first question is about diet. They have read that ADHD 
can be managed by dietary therapy instead of medications, and they want your opinion about 
trying this strategy with their child. They also want to know how likely it is that he will “outgrow” 
the disorder. You have many issues to consider before answering the parents’ questions.
1. What is the most accepted theory of etiology regarding ADHD? 
2. What is the empirical database for dietary treatment in ADHD clients? 
3. What is the natural course of this illness? Is it likely that the son’s symptoms will 
improve as he ages?

improve as he ages? 
4. What are the other issues to consider regarding the parents’ request to keep confi -
dential the concerns that they are expressing?

358 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
1. The accepted theory is that ADHD is a neurobiological disorder 
2. The best-studied treatment for ADHD is stimulant medication. Elimination of food 
allergens, sugar, and aspartame can be helpful to decrease hyperactivity. Limited 
evidence exists about the use of herbal remedies; however, it is always best to 
meet the client and parents where they are and if nonpharmacological treatments or 
dietary alterations are requested, the PMHNP should provide evidence for treatment 
of ADHD so the family can make an informed decision. 
3. ADHD is a lifespan disorder; however, as children progress into adulthood, symp -
toms of inattention usually remain with a decrease in impulsive and hyperactive 
symptoms. 
4. Other issues of concern in a child with ADHD include a lack of involvement of the

symptoms. 
4. Other issues of concern in a child with ADHD include a lack of involvement of the 
child in treatment might lead to nonadherence by the child. Working in family therapy 
would be beneficial. 
American Academy of Child and Adolescent Psychiatry. (1997). Practice parameter for the treat -
ment of children and adolescents with conduct disorder. Journal of the American Academy 
of Child and Adolescent Psychiatry, 36 (10), 122S–139S.
American Academy of Child and Adolescent Psychiatry. (2007a). Practice parameter for the as -
sessment and treatment of children and adolescents with attention-deficit/hyperactivity dis -
order. Journal of the American Academy of Child and Adolescent Psychiatry, 46 (7), 894–921 .
American Academy of Child and Adolescent Psychiatry. (2007b). Practice parameter for the

American Academy of Child and Adolescent Psychiatry. (2007b). Practice parameter for the 
assessment and treatment of children and adolescents with oppositional defiant disorder. 
Journal of the American Academy of Child and Adolescent Psychiatry, 46 (1), 126–141 .
American Psychiatric Association. (2001). Practice parameters for the assessment and treatment 
of children and adolescents with suicidal behavior. Journal of the American Academy of 
Child and Adolescent Psychiatry, 4 (Suppl. 7), 245–478.
American Psychiatric Association. (2009). Practice parameters on the use of psychotropic 
medication in children and adolescents. Journal of the American Academy of Child and 
Adolescent Psychiatry, 4 8(9), 961–973.
(5th ed.).Washington, DC: Author.

(5th ed.).Washington, DC: Author. 
Centers for Disease Control and Prevention. (2010). Morbidity and mortality weekly report: 
Increasing prevalence of parent reported attention-deficit/hyperactivity disorder among chil -
dren – United States, 2003 and 2007 . Morbidity and Mortality Weekly Report,  59(44), 1–40.
Centers for Disease Control and Prevention. (2015). Facts about ASD.  Retrieved from http://www.
cdc.gov/ncbddd/autism/facts.html
Hamrin, V., & Gray Deering, C. (2012). Mental health assessment of children and adoles -
cents. In M. Boyd (Ed.), Psychiatric nursing contemporary practice (5th ed., pp. 661–678). 
Philadelphia, PA: Lippincott Williams & Wilkins. 
Lock, J., LaVia, M., & The American Academy of Child and Adolescent Psychiatry Committee 
on Quality Issues. (2015). Practice parameter for the assessment and treatment of children

359 disorders of childhood and adolescence
and adolescents with eating disorders. Journal of the American Academy of Child and 
Adolescent Psychiatry, 54 (5), 412–425.
Murphy, T ., Lewin, A., Storch, E., Stock, S., & The American Academy of Child and Adolescent 
Psychiatry Committee on Quality Issues. (2013). Practice parameter for the assessment and 
treatment of children and adolescents with tic disorders. Journal of the American Academy 
of Child and Adolescent Psychiatry, 52 (12), 1341–1359.
Nolan, E., Gadow, K., & Sprafkin, J. (2001). Teacher reports of DSM-IV ADHD, ODD, and CD 
symptoms in school children. Journal of the American Academy of Child and Adolescent 
Psychiatry, 40,  241–249.
Sadock, B. J., Sadock, A. V., & Ruiz, P . (2015). Kaplan & Sadock’s synopsis of psychiatry: 
Behavioral sciences/clinical psychiatry  (11th ed.). Baltimore, MD: Wolters Kluwer. 
U. S. Department of Health and Human Services. (2000). Mental health: A report of the Surgeon

U. S. Department of Health and Human Services. (2000). Mental health: A report of the Surgeon 
General. Washington, DC: Author.
Volkmar, F ., Siegel, M., Woodbury-Smith, M., King, B., McCracken, J., & The American Academy 
of Child and Adolescent Psychiatry Committee on Quality Issues. (2014). Practice parameter 
for the assessment and treatment of children and adolescents with autism spectrum disor -
der. Journal of the American Academy of Child and Adolescent Psychiatry, 53 (2), 237–257 .

CHAPTER 16SLEEP
This chapter addresses sleep issues and disorders commonly encountered by the psychiatric–
mental health nurse practitioner (PMHNP). These conditions and clinical problems may co-occur 
with the disorders already discussed or may present in clients with no other identifiable psychiat -
ric or mental health problems. They also may be frequent findings in primary care settings while 
working with clients with general medical conditions.
GENERAL CONSIDERATIONS
 XMust be systematically assessed
 XComparison of present level of sleep to historical baseline
 XCan be measured by polysomnography
 XRapid eye movement (REM) alternating with four distinct nonrapid eye movement 
stages (NREM).
 ZStage I
 X NREM
 XTransitional stage from wakefulness to sleep
 X5% of total normal sleep cycle
 ZStage II
 XNREM
 XSpecific electroencephalogram (EEG) waveforms
 X50% of total sleep cycle
 ZStages III and IV
 XNREM
 XSlow-wave sleep period
 XDeepest level of sleep

ZStage II
 XNREM
 XNREM
 X20% to 25% of total sleep cycle

362 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZSleep stages are organized and sequential during sleep period.
 XStages III and IV tend to occur in first one-third to one-half of sleep period
 XREM occurs cyclically throughout the night, alternating with NREM on 
average every 80 to 100 minutes.
 XREM increases in duration toward morning.
 ZSleep patterns vary with age.
 XChildren and adolescents have large amounts of slow-wave sleep.
 XSleep continuity and depth decrease with age.
 XConsider age when assessing for sleep–rest problems.
 ZSleep patterns vary with medication use.
 XMany medications and agents of abuse affect sleep cycle.
 XAssess recent changes in medication or drug use in a person presenting 
with sleep pattern disturbances.
INSOMNIA
 XInsomnia is the inability to get the amount of sleep needed to function efficiently 
during the day.
 XSituational or acute insomnia lasts from days to weeks.

INSOMNIA
 XInsomnia disorder is characterized by a significant inability to initiate or maintain sleep, 
or early morning awakening with inability to return to sleep and. Occurs at least 3 
nights per week and is present for at least 1 month (episodic insomnia disorder) and 
may persist for greater than 3 months (persistent insomnia disorder).
 XInsomnia disorder is associated with increased mortality, poor career performance, 
overeating, and increased hospitalization.
 XInsomnia disorder is not better explained by or occurring exclusively during the course 
of another sleep disorder, and is not attributable to the effects of a substance.
Etiology
 XDysfunction in sleep–wake circuits of the brainstem
 XNeurochemical imbalances impinging on these circuits
 XMay be stress-related in brief episodic insomnia

Etiology
 X33% of Americans have difficulty sleeping.
 XUp to 10% meet criteria for insomnia disorder.
 XInsomnia is highly comorbid with other psychiatric disorders.

363 sleeP
 XFemale gender and advancing age
 XPast history of insomnia
 XSignificant stress
 XForced pattern changes
 ZWorking alternating shifts
 ZSwing-shift work patterns
 ZTravel across time zones
 ZGenetic (obstructive sleep apnea)
 XHigh-use patterns of medications, drugs, or substances known to affect sleep cycles
 ZCaffeine, other stimulants
 ZAlcohol
 ZBenzodiazepines (BNZs)
 XAt-risk family education for children and adolescents
 XLimits on shift work
 XAvoidance of medications known to affect sleep patterns
 XGood sleep hygiene patterns
 XAvoidance of stimulants late in the day
 ZRoutine screening at all healthcare settings
 XDetailed history of present insomnia, including time frame, progression, and associ -
 XSocial history, including present living situation; marital status; occupation; educa -
tion; and alcohol, tobacco, or illicit drug use

 XNumber of hours in usual sleep pattern
 XInitial- or middle-phase insomnia; early morning awakening
 XUse of sleep aids
 XBed position, use of pillows
 XEnvironment: temperature, sound, light

364  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XSelf-reported excessive sleepiness despite adequate main sleep period
 XDifficulty being fully awake—“groggy” after abrupt awakening
 XOccurs at least 3 times per week and lasts for several months
 XCauses significant distress or impairment
 XNot better explained by another sleep disorder, viral infection, or physiologic affect of 
 XMay occur within 18 months of experiencing a head trauma
 XComorbidity includes various depressive disorders (e.g., major depression with atypi -
cal features, seasonal affective disorder [SAD], bipolar disorder depressed state)
Obstructive Sleep Apnea (OSA)
 XHallmark of disorder is snoring and repeated apnea during sleep
 XDaytime sleepiness or sense of feeling unrefreshed despite adequate sleep period is 
prominent.
 XHeadache upon awakening is common.

XDaytime sleepiness or sense of feeling unrefreshed despite adequate sleep period is 
 XConsequences include panic attacks (waking up “gasping”), attention-deficit hyperac -
tivity disorder, depression, hypertension, and motor vehicle and workplace accidents
 XAffects up to 2% of children, up to 15% to 20% of adults
 XEtiology due to abnormally small nasopharynx, tonsillar tissue in children; obesity 
Polysomnography to Make Definitive Diagnosis
 XSleep disturbance often a manifestation of an underlying disorder
 XClients in whom a sleep disorder is suspected should have full exam
 XMay have preoccupation or excessive worry about “not getting enough sleep”
 XDepending on duration of sleep deprivation, many areas of mental status exam 
(MSE) may be affected

XDepending on duration of sleep deprivation, many areas of mental status exam 
 XComplete blood count (CBC), chemistry profile, thyroid function tests, ferritin level (if 
restless legs), and B12 level to rule out metabolic causes or unidentified conditions

365 sleeP
Differential Diagnosis 
 XMore than 50% of insomnia cases are related to primary psychiatric disorder.
 ZSubstance-related disorders (see Chapter 13).
 ZAttention-deficit hyperactivity disorder (ADHD; see Chapter 15)
 ZEarly-morning wakefulness a possible sign of depression
 ZSudden, dramatic decrease in sleep a sign of possible mania or schizophrenia
 ZPoor sleep a sign of possible obsessive–compulsive disorder (see Chapter 10)
 ZPanic and anxiety episodes during sleep a sign of possible panic disorder 
 ZAlcohol may cause numerous awakenings during the night
 ZCardiac illnesses
 ZParasomnias
 ZGastrointestinal disorders
 ZChronic obstructive pulmonary disease
 ZMedication side effects
 ZSleep apnea
 ZRestless leg syndrome
 ZChronic pain
 ZStress reaction
 ZActive substance abuse
 ZDrug use
 XCaffeine

ZMedication side effects
 ZDrug use
 XCaffeine
 XWeight loss and avoiding supine sleep position may alleviate sleep apnea
 XPositive airway pressure, continuous( CPAP) or bilevel (BPAP) for OSA
 XMelatonin is particularly useful to correct sleep onset issues and may be helpful for 
the person with ADHD.
 XBenzodiazepine (BNZ) or hypnotics (should not be used in OSA)
 XFlurazepam (Dalmane)
 ZLong-lasting agent

366 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZMay cause excess drowsiness
 ZAvoid in older adults
 XTemazepam (Restoril)
 ZIntermediate acting agent
 XTriazolam (Halcion)
 ZShort-acting agent
 ZLittle to no excess sedation
 ZCommon side effects:
 XImpaired memory 
 XEfficacy decreases over time
 XShould not be used on a long-term basis
 XNonbenzodiazepine hypnotics
 ZZaleplon (Sonata)
 XUltra-short half-life makes this drug particularly useful for initial or middle-
phase insomnia
 ZZolpidem (Ambien, Ambien CR)
 XShort half-life drugs, but may affect person the next morning; must allow for 
8 hours before planned awakening
 XGive on empty stomach
 ZEszopiclone (Lunesta) 
 XIntermediate-acting agent
 ZRozerem
 XMelatonin receptor agonist
 ZSuvorexant (Belsomra)
 ZOrexin antagonist, suppresses wakefulness
 XMust consider long half-life
 XAntidepressants 
 ZUsed for sedating properties

ZRozerem
 ZAmitriptyline (Elavil), doxepin (Sinequan, Silenor); generally avoid use in older 
adults
 ZMirtazapine (Remeron)
 ZTrazadone
 XWake-promoting drugs
 ZArmodafinil (Nuvigil) indicated for daytime sleepiness associated with OSA
 XSleep hygiene practices
 ZEstablish a bedtime routine.

367 sleeP
 ZHave a regular time to sleep and wake.
 ZAvoid computer and other electronic device use 1 hour before bedtime.
 ZNever lie in bed for more than 15 minutes if not able to sleep.
 ZReduce stress.
 ZDo stress reduction activities before bedtime.
 ZAvoid late-in-the-day exercise intensive.
 ZAvoid late-in-the-day stimulant use, such as caffeine.
 ZUse bed/bedroom for sleep or sex only.
 ZConsider moving phone and other devices away from sleeping area; restrict 
phone and computer use to 1 or more hours before bed time.
 ZPsychotherapy.
 ZCognitive therapy for insomnia.
 XRelaxation and other therapies
 ZAbdominal breathing
 ZProgressive muscle relaxation
 ZMeditation
 ZImaging
 ZHypnosis
 ZStimulus control
 ZSleep curtailment
 ZLight therapy 
 XSomatic and other therapies
 ZExercise (during the day)
 ZWarm bath
 ZWarm milk
 ZChange bedroom environment
 ZInsomnia in children 
 XMost commonly related to stress

XSomatic and other therapies
 ZWarm bath
 ZWarm milk
 XChildren with insomnia often have been poor sleepers since birth. 
 XPharmacological treatment is not recommended for most children.
 ZInsomnia in older adults 
 XIf first presentation is in older years, insomnia often is the result of changes 
in chronobiological rhythms. Older adults often become sleepier early in the 
evening and wake up early.

368 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XSleep latency, decreased REM sleep, and increased sleep fragmentation 
are common.
 XInsomnia may be related to underlying psychiatric disorders:
 ZAlzheimer’s disease
 XOlder adults often manifest confusion and restlessness as aspects of 
insomnia.
 XA careful, complete assessment is necessary when pharmacological 
interventions are planned.

369 sleeP
Ms. Jones, a 43-year-old receptionist, presents at the PMHNP’s clinic with a primary complaint 
of insomnia. She reports lifelong problems with sleeping that “comes and goes” depending on 
her stress level and general health. She has been experiencing a 4- to 5-day period of poor sleep -
ing, reporting only 3 to 4 hours of sleep and early morning awakening. She has tried over-the-
counter medication and has received no relief. She reports that her health is generally good but 
states that she is a 2-pack-a-day smoker and has increased her recreational use of alcohol to 1 
to 2 drinks a night in the past few weeks in order to get to sleep. Her insomnia is now beginning 
to impair her daily functioning and her interest in social activities. She reports an irritable mood 
since her sleep has been difficult and problems with memory and concentration in the morning 
after she has slept poorly. She denies depression or any other mood problem and currently is

after she has slept poorly. She denies depression or any other mood problem and currently is 
taking no routine medication. Her physical exam is unremarkable, and routine lab studies, includ -
ing thyroid-stimulating hormone (TSH), CBC, and electrolytes, are all normal. 
1. What is the most likely diagnosis for this client at this time?
2. What further assessment should the PMHNP make?
3. What treatment should the PMHNP consider?
4. Is medication warranted at this time to induce sleep?
Mr. Smith is a 40-year-old married man who presents to the PMHNP with a chief complaint of “I 
can’t fall asleep. I’ve tried everything. Nothing works! That medicine the doctor gave me made 
me feel worse. It made me feel really anxious. I’m exhausted! I can’t function. I’m going to lose 
my job. ” Mr. Smith states his primary care provider has prescribed various sleeping medications,

my job. ” Mr. Smith states his primary care provider has prescribed various sleeping medications, 
“ Ambien, Lunesta, and Ativan, ” which have all caused a worsening of his insomnia. His physical 
exam and routine labs performed by his primary care provider have all been within normal limits.
1. What further assessment should the PMHNP make at this time?
2. What treatment should the PMHNP consider?
3. Why might a person report feeling more anxious and have more trouble sleeping in 
response to a hypnotic or anxiolytic medication?
4. Mr. Smith begins psychotherapy with the PMHNP and he begins to discuss growing 
up in an alcoholic family in which his parents fought at night after the children went 
to bed. In addition to continuing psychotherapy, should medication be considered? 
Ms. Johnson, a 39-year-old single, obese woman is self-referred to the PMHNP for assess -

ment and treatment of “depression and exhaustion. ” Ms. Johnson states “I sleep just fine, but 
I’m always tired. My doctor did some blood work and said that everything was normal. I can’t 
concentrate. I’m dragging at work. The other day I had to go out to my car and take a nap. I can’t 
take this any more! This is really getting me down. Do you think an antidepressant would help?” 
Ms. Johnson has had a CBC, comprehensive metabolic panel, serum iron, B12, folate levels, and 
thyroid function tests which were all within normal limits. 
1. What further assessment should be completed?
2. Should Ms. Johnson be started on medication?

370 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
1. Ms. Jones is suffering from transient insomnia.
2. The PMHNP should identify life stressors, complete a full psychiatric assessment, 
and identify any other mental health needs.
3. The PMHNP should assist Ms. Jones in managing her sleep by using effective sleep 
hygiene strategies, encouraging diet changes, reducing smoking, and omitting the 
use of alcohol for sleep induction.
4. Short-term use of sleep induction medications such as a low-dose sedating antide -
pressant would provide relief with little risk to this client and may help her reduce 
current reliance on alcohol.
1. The PMHNP should complete a comprehensive psychiatric evaluation exploring for 
signs and symptoms of a mood or anxiety disorder. The history should include a 
thorough evaluation of past sleep patterns and issues with insomnia. The PMHNP

thorough evaluation of past sleep patterns and issues with insomnia. The PMHNP 
should carefully assess for issues such as childhood or more recent trauma, alcohol, 
or other related violence exposure. Clients who have experienced significant trauma 
directed at them, or who have been raised in an environment of violence, may have 
fear related to falling asleep.
2. The PMHNP should consider psychotherapy, which should include psychoeducation 
about insomnia, the impact of anxiety on sleep, and sleep hygiene measures.
3. Children raised in traumatic environments commonly have difficulty falling and 
staying asleep. Many children become hypervigilant. These patterns can persist into 
adulthood. Adults may not be cognizant of the connection between current sleep 
issues and childhood trauma. Any medication that prevents a person from being

issues and childhood trauma. Any medication that prevents a person from being 
hypervigilant could be experienced as a lack of control, thus causing an increase in 
anxiety and insomnia.
4. The PMHNP should discuss the possibility of using a selective serotonin reuptake 
inhibitor (SSRI) or perhaps another sedating antidepressant to address Mr. Smith’s 
heightened arousal and insomnia.
1. The PMHNP should complete a comprehensive psychiatric evaluation to rule out 
a mood, anxiety, or substance abuse disorder. A careful sleep and energy history 
should be taken and the PMHNP should screen for evidence of snoring or apnea. 
Further assessment should be done by a sleep specialist to rule out obstructive 
sleep apnea (OSA) or other sleep disorder. 
2. The PMHNP should consider that medications may be indicated. If Ms. Johnson

2. The PMHNP should consider that medications may be indicated. If Ms. Johnson 
does have OSA, she will be treated with a continuous or bilevel airway pressure 
device (CPAP or BPAP). Wake-promoting medication such as armodafinil may also be 
helpful in reducing Ms. Johnson’s excessive daytime sleepiness.

371 sleeP
(5th ed., text rev.). Washington, DC: Author.
Buysse, D. (2013). Insomnia. The Journal of the American Medical Association,  309 (7), 706-716.
Redeker, N., & McEnany, G. P . (2011). Sleep disorders and sleep promotion in nursing practice.  
New York, NY: Springer Publishing.
Rajput, V., & Johnson, R. (1999). Chronic insomnia: A practical review. American Family Practice, 
11, 1–6.
Stahl, S. M. (2013). Stahl’s essential psychopharmacology (4th ed.) . New York, NY:  Cambridge 

CHAPTER 17VIOLENCE
This chapter deals with the psychiatric–mental health nurse practitioner’s (PMHNP’s) role in iden -
tifying and treating clients who are impacted by intimate partner violence (IPV), sexual assault, 
homicide, and suicide. Assessment of lethality will also be reviewed. These issues may co-occur 
INTIMATE PARTNER VIOLENCE (IPV)
 XIPV is physical, emotional, economic, or sexual pain and injury that is intentionally 
inflicted by a person’s intimate partner.
 XThe goal of the abuser is to:
 ZEstablish power
 ZManipulate the other person
 ZIntimidate the other person
 ZControl the other person
Etiology
 XCharacteristics of abusers :
 ZPersonality disorders

ZManipulate the other person
Etiology
 XNarcissistic personality disorder
 XBorderline personality disorder

374 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 ZEnvironmental stressors
 XFinancial difficulties
 XEnding of a relationship
 XIPV occurs among heterosexual and homosexual couples.
 XIPV is the leading cause of injury to women ages 15–44. 
 XIt is the leading cause of death among African-American women between the ages 
of 15 and 24.
 X1 in 10 female high school students in the United States have reported violence from 
their dating partners.
 X15% to 25% of pregnant women are physically abused.
 X22% to 35% of all women seen in emergency rooms experienced injuries as a result 
of IPV.
 X1 in 3 women and 1 in 4 men are victims of IPV.
 X50% of homeless women experience IPV.
 X63% of men incarcerated for murder between the ages of 11 and 20 have murdered 
their mother’s abuser.
 X33% of male abusers are well educated and include men in professional jobs.

X63% of men incarcerated for murder between the ages of 11 and 20 have murdered 
 X33% of male abusers are well educated and include men in professional jobs. 
(National Coalition Against Domestic Violence, 2015)
 XFor abusers:
 ZExposure to violence at an early developmental age
 ZLow self-esteem 
 ZLack of support
 ZCognitive impairment
 ZPhysical or financial dependency
 XPublic education and awareness beginning in high school
 XSocial programs
 ZStigma reduction to allow victims to come forward

375 violence
 ZSigns and symptoms of being the victim of abuse
 ZPrevention programs 
 ZEarly recognition, intervention, and initiation of treatment for victims
 ZRoutine screening for victimization at all healthcare settings
 XInterview the person who has experienced the violence alone. 
 XDetermine primary caregivers, living arrangements, legal custodian
History
 ZDetermine recurrent history of medical treatment consistent with abuse:
 XAccidents
 XSuspicious or repeated fractures
 XPhysical injuries
 XTraumas
 XRefusal of ongoing treatment or follow-up 
 XMissed medical appointments
 ZDetermine environmental, psychosocial, and financial stressors
 XMonitor nutritional status for dehydration and malnutrition.
 XLook for lacerations, bruises, wounds, burns, or fractures.
 XLook for poor skin and personal hygiene.
 XFindings of traits and behaviors suggestive of experiencing abuse:
 ZFearful

XLook for poor skin and personal hygiene.
 ZFearful
 ZEvasive
 ZGuarded
 ZDepressed
 ZPassive
 XNone specific to abuse
 XDetermine general health and nutritional status

376 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XAccidental injuries
 XSubstance use disorders (see Chapter 13)
 XMost state laws mandate reporting of suspected abuse and neglect of vulnerable populations:
 ZOlder adults
 ZPeople with disabilities
 ZChildren
 XNone specific to condition
 XThe safety and medical well-being of the person experiencing the abuse is most 
important.
 XRefer the person to a domestic abuse shelter when feasible.
 XHelp the person develop a safety plan.
 ZAssist client in developing a “code word” for family or other support system as 
an attempt to inform them that the person is in need of help.
 ZAdvise client to tell one person in his or her support system about the situation.

 ZAdvise client to pack an “emergency bag” and hide it in case of need to leave 
quickly.
 ZAdvise client to keep the IPV hotline and other telephone numbers (e.g., police 
department, counselor, shelter) in a secure place. 
 ZMonitor medical status as symptomology presents.
 ZMonitor nutritional status and vital signs.
 ZSuggest psychotherapy to assist in gaining insight and in developing new coping 
skills.
 ZSuggest hospitalization when in the best interest of the client.
SEXUAL ASSAULT AND ABUSE
 XSexual assault or abuse  is any sexual act or penetration committed through coercion 
or physical force.
 ZThis includes rape, incest, sodomy, oral and anal acts, and use of a foreign 
object.

377 violence
 ZIt is an act of violence and humiliation expressed through sexual means. 
 ZIt is used to express power or anger.
Etiology
 ZCharacter disorders
 ZBehavioral act of violence is reinforcing
 XOnce done, likely to repeat
 ZSocial exposure to violence in culture, media, and home
 XWomen have a greater incidence of being assaulted than men. 
 XSexual assault is the most common form of abuse.
 XPerpetrators are more frequently men than women. 
 ZSexual assaults are often committed by fathers and stepfathers, uncles, older 
siblings, other family members, and men that women are dating.
 XAlcohol is involved in 34% of all rapes.
 XOnly 1 in 4 rapes is reported.
Factors that Increase Incidence of Abusing
 XSubstance abuse disorders 
 XDivorce
 XFamily or personal history of physical or sexual abuse
 XLong-term exposure to violence
 XSocial isolation and lack of support systems

XSubstance abuse disorders 
 XDivorce
 XEnvironmental stressors such as unwanted pregnancy in an intimate partner, unem -
ployment, or financial difficulty
Prevention and Screening of Victims
 XPublic education and awareness campaigns
 XCommunity resources and support
 XCommunity emergency shelters, help lines, and safe houses
 XAssertiveness training and self-defense
 XEarly recognition, intervention, and initiation of treatment 

378 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
 XInterview persons who have experienced the assault alone when possible.
 XEstablish a safe, trusting relationship to promote sharing.
 ZRoutine inclusion of questions concerning sexual assault in medical history. 
 ZInterview alone and not in presence of family, friend, or partner.
 ZInterview for social history, including history of living arrangements and 
 XPresentation of traits and behaviors consistent with potential for having suffered 
sexual assault or other abuse:
 ZWithdrawn
 ZFrightened appearance
 ZHyperreactive to touch
 XAssociated findings:
 ZUnexplained bruises, abrasions, cuts, laceration, burns, soft-tissue swellings, 
and hematomas
 ZSexually transmitted diseases
 ZGenital rash or discharge
 ZRectal tissue swelling or discharge
 ZPhysical signs that are strongly suggestive of sexual abuse in children:

 XLacerations, ecchymosis, and newly healed scars of the hymen or posterior 
fourchette
 XNo hymenal tissue in 3- to 9-o’clock area
 XHealed hymenal transactions, especially in the above area
 XPerianal lacerations
Remember that any child presenting with concerning physical signs should be evaluated 
by a sexual abuse expert. A complete history and a sexual abuse examination need to 
take place. 
 XWithdrawn
 XFrightened 
 XAnxious
 XScattered appearance
 XHyperreactive to touch
 XDissociative

379 violence
 XAssessment and documentation labs
 ZForensic specimens
 ZPregnancy tests
 ZRectal, throat, and vaginal cultures
 ZScreening for sexually transmitted diseases: Syphilis, HIV, hepatitis B, herpes 
simplex, human papillomavirus, trichomonas vaginalis
 XConsensual sexual activity
 XLichen sclerosis
 XPosttraumatic stress disorder
 XAnxiety disorder (see Chapter 10)
 XUse sensitivity and respectful care.
 XBe aware of legal reporting requirements.
 XUse available community resources.
 XEnsure safety and well-being.
 XEnsure confidentiality.
 XComplete accurate documentation.
 XAssess for potential suicidal ideation if the person is showing any depressive symptoms.
 XSuggest cognitive behavioral therapy (CBT).
 XOffer support groups and community resources.
 XAssist with access to criminal and legal supports. 
LETHALITY ASSESSMENT

XSuggest cognitive behavioral therapy (CBT).
 XLethality assessment : evaluation, screening, or testing.
 XLethality  refers to the likelihood that a person will commit suicide or homicide—  
focused violence at the extreme.
 XViolence:  the behavioral expression of anger, rage, and hostility that is demonstrated 
by the use of physical force directed toward persons (in case of suicide, toward self) 
or property.

380  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
VIOLENCE IN SCHOOL
 XSerious physical fighting with peers or family members
 XSevere destruction of property
 XSevere rage for seemingly minor reasons 
 XDetailed threats of lethal violence 
 XPossession, use, or both of firearms or other weapons
 XSelf-injurious behaviors or threats of suicide 
 XBullying or being bullied
 XWhen warning signs indicate that danger is imminent, safety must always be the 
first and foremost consideration. Action must be taken immediately. Immediate 
intervention by school authorities and possibly law enforcement officers is needed 
when a child:
 ZHas presented a detailed plan (time, place, method) to harm or kill others, 
particularly if the child has a history of aggression or has attempted to carry out 
threats in the past
 ZIs carrying a weapon, particularly a firearm, and has threatened to use it
SUICIDE ASSESSMENT

 XAll antidepressants have black box warnings about increased risk of suicide in chil -
dren, adolescents, and young adults under the age of 24.
 XPrior suicide attempt
 XFamily history of mental disorder or substance abuse
 XFamily violence
 XFirearms in the home
 XIncarceration
 XMales are 5 times more likely than females to commit suicide
 XWhite males over age 85 have highest rate of suicide
Signs of Imminent Danger
 XThreatening to hurt or kill oneself 
 XLooking for ways to kill oneself (weapons, pills, or other means) 
 XTalking or writing about death, dying, or suicide 
 XPlans or preparations for a potentially serious attempt
 XAlcohol use increases the risk of suicide attempts in persons with ideation

381 violence
HOMICIDE: EARLY WARNING SIGNS
 XPrior history of threatening or violent behavior 
 XParanoia or easily panicked behavior 
 XA fascination or preoccupation with weapons, particularly weapons or explosives that 
could be used for mass destruction, such as semi-automatic guns 
 XExtreme stress from personal problems or a life crisis 
 XIdentifying with incidents of workplace violence reported in the media and either 
condoning or sympathizing with the actions of the persons committing violence 
 XBeing a loner with little or no involvement with other employees 
 XEngaging in frequent disputes with supervisors or coworkers 
 XPersistent violation of company policy 
 XObsessive involvement with one’s job, particularly where it occurs with no apparent 
outside interests 
 XVolatile or violent home or other personal situation that has the potential to bring 
violence into the workplace 
THREATS OF VIOLENCE
 XThrowing objects

 XMaking a verbal threat to harm another person or destroy property
 XMaking menacing gestures or physical posturing without actually touching the 
person
 XDisplaying an intense or obsessive romantic interest that exceeds the normal 
bounds of interpersonal interest
 XAttempting to intimidate or harass other persons
 XBehavior indicating that the person is significantly out of touch with reality and that 
he or she may pose a danger to himself or herself or to others
 XVolatile or violent personal situations such as found in some custody battles
 XAlcohol use increases the risk for violence
Safety is the number one priority and any threatening behavior must be taken seriously.

382 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
CASE STUDY
Ms. Smith, a 24-year-old single Caucasian female is referred to the PMHNP for persistent in -
somnia and depression after being treated in the emergency department of her local hospital for 
headaches, stomach pain, and various other physical complaints five times in the past 6 months. 
The PMHNP suspects that Ms. Smith is a victim of IPV.
1. What should the PMHNP’s assessment include?
2. How should the PMHNP approach suspicions of IPV with Ms. Smith?
3. Should anyone beside Ms. Smith be interviewed?
4. If the PMHNP concludes that Ms. Smith meets criteria for major depression, should 
medication be included as part of the treatment plan?
Assume Ms. Smith is an immigrant.
5. What other considerations must be included in the assessment?
6. How should the PMHNP approach the client with her suspicions of IPV? 
7. What other considerations must be included in this woman’s treatment plan?

Assume Ms. Smith is an 80-year-old widowed woman.
8. What other considerations must be included in the assessment?
9. Who should be included in the assessment findings?
10. What other considerations must be included in the treatment plan for any person 
suspected of being the victim of IPV?

383 violence
1. Ms. Smith should undergo a complete physical assessment, labs as indicated (likely 
working in conjunction with primary care providers) and a comprehensive psychiatric 
evaluation. The PMHNP should also inquire about sexual partner(s), sexual behaviors, 
birth control, and possibility of sexually transmitted infection.
2. The PMHNP should approach Ms. Smith privately (1:1). Questions should be posed 
in a matter-of-fact manner, using language that is not stigmatizing, such as “Has 
___________ ever threatened you or made you feel afraid?” or “Does _________’s 
temper ever make you feel scared?”
3. Generally no one else besides the victim should be interviewed. Women often feel 
reluctant to discuss being abused because they think if their partner finds out, things 
will get worse. Women may feel embarrassed or judged if anyone else were to know 
what is going on.

4. Possibly. Treating significant depression will allow Ms. Smith to be in a better posi -
tion to make decisions and take action. 
5. The PMHNP must make sure the interview is done in the woman’s native language. 
Interpreters must not be a family member or friend. 
6. The PMHNP must consider that different cultures may have different perceptions 
of IPV. The PMHNP must use culturally sensitive language. The PMHNP will need to 
consider the woman’s concerns about legal issues related to immigration status.
7. The availability of culturally sensitive and relevant resources for therapy and medica -
tion management.
8. The client’s living situation and her ability to care for her own needs. Whether or not 
she has caregivers, and whether or not her family member or other caregiver is pos -

sibly abusing her.
9. All states have mandatory reporting for suspected elder abuse.
10. A safety plan should be first and foremost. The victim should know where and how 
to get help. Resources should include 24-hour hotlines, shelters, support groups, 
and the like. The victim should have an escape plan that includes having some cloth -
ing and money packed and ready, in case she decides to leave.
of Psychiatric-Mental Health Nurses. (2014).  Psychiatric–mental health nursing: Scope and 
Davidson, J. R. (2000). Trauma: The impact of post-traumatic stress disorder. Journal of

Blunt, E., & Reinisch, C. (2013) The family nurse practitioner review manual  (4th ed). Washington, 
DC: American Nurses Credentialing Center. 
National Coalition Against Domestic Violence. (2015). National statistics. Retrieved from http://
www.ncadv.org/learn/statistics

384 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
Behavioral sciences/clinical psychiatry  (11th ed.). Philadelphia, PA: Walters Kluwer.
Tusaie, K., & Fitzpatrick, J. (2013). Advanced practice psychiatric nursing: integrating psychother -
apy, psychopharmacology and complementary and alternative approaches. New York, NY: 
Springer.
General.  Washington, DC: Author.

386 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
1. The purpose of the American Nurses Association’s Psychiatric–Mental Health Nursing: 
Scope and Standards of Practice is to
a. Define the role and actions for the NP 
b. Establish the legal authority for the prescription of psychotropic medications 
c. Define the legal statutes of the role of the PMHNP
d. Define the differences between the physician role and the NP role
2. Primary prevention care practices are an essential aspect of the PMHNP role. Which of the 
following is the best example of a primary prevention care strategy for community behav -
ioral health?
a. Aftercare program for chronically mentally ill clients recently discharged from the 
hospital
b. Court-ordered counseling for abusive parents
c. 24-hour crisis hotlines
d. Parenting skills classes for pregnant adolescents 
3. The trend in legal rulings on cases involving mental illness over the past 25 years has 
been to

been to
a. Encourage juries to find defendants not guilty by reason of insanity
b. Protect the person’s freedoms or rights when he or she is committed to a mental 
hospital 
c. Place increasing trust in mental health professionals to make good and ethical decisions
d. Decrease the “red tape” associated with commitments so that commitments are faster 
and easier
4. Mr. Smithers, an involuntarily hospitalized patient experiencing psychotic symptoms, refuses 
to take any of his ordered medication because he believes “Jesus Christ told me I am the 
prophet and must fast for a year. ” Your actions should be based on your knowledge of which 
of the following? 
a. Psychiatric clients cannot refuse treatment
b. Psychiatric clients do not always know what is good for them
c. Psychiatric clients can refuse treatment

d. Psychiatric clients cannot be trusted to make good healthcare decisions and, therefore, 
the nurse’s best clinical judgment should guide actions
5. Which of the following statements best reflects the difference between the nurse–client 
(N–C) relationship and a social relationship? 
a. In the N–C relationship, the primary focus is on the client and the client’s needs.
b. Goals in the N–C relationship are deliberately left vague and unspoken so that the client 
can work on any issue.
c. In the N–C relationship, the nurse is solely responsible for making the relationship work.
d. In the N–C relationship, there is no place for social interaction.

387 review Questions
6. A community has an unusually high incidence of depression and drug use among the teen -
age population. The public health nurses decide to address this problem, in part, by modify -
ing the environment and strengthening the capacities of families to prevent the develop -
ment of new cases of depression and drug use. What is this is an example of? 
a. Primary prevention 
b. Secondary prevention
c. Tertiary prevention 
d. Protective factorial prevention 
7. Mrs. Kemp is voluntarily admitted to the hospital. After 24 hours, she states she wishes to 
leave because “this place can’t help me. ” The best nursing action that reflects the legal right 
of this client is
a. Discharge the client
b. Explain that the client cannot leave until you can complete further assessment 
c. Allow the client to leave but have her sign forms stating she is leaving against medical 
advice
d. Immediately start the paperwork to commit the client and to allow you to treat her

advice
d. Immediately start the paperwork to commit the client and to allow you to treat her 
against her wishes 
8. In forming a therapeutic relationship with clients, the PMHNP must consider developing 
many characteristics that are known to be helpful in relationship-building. Which of the fol -
lowing is an essential part of building a therapeutic relationship?
a. Collecting a family history
b. Like-mindedness
c. Authenticity
d. Accuracy in assessment 
9. According to the DSM-5, which of the following is true? (Ch. 3)
a. A mental disorder is equivalent to the need for treatment.
b. Diagnostic criteria are used to inform clinical judgment.
c. Socially deviant behavior is considered a mental disorder.
d. A culturally expected response to a stressor is not a mental disorder.
10. Mrs. French has been in individual therapy for 3 months. She has shown much growth and

10. Mrs. French has been in individual therapy for 3 months. She has shown much growth and 
improvement in her functioning and insight and is to discontinue services within the next 
few weeks. In the next session, after you discuss service termination, she suddenly begins 
to demonstrate the original symptoms that had brought her to treatment initially. She is now 
hesitant to discharge, wants to continue services, and is displaying an increase in regressive 
defense mechanisms. What is the best explanation for Ms. French’s behavior? 
a. An exacerbation of her symptoms related to stress
b. The normal cyclic nature of chronic mental health symptoms
c. A sign of normal resistance to termination seen in the termination phase of therapy
d. A sign of pathological attachment to the therapist that must be addressed

388 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
11. A client is displaying low self-esteem, poor self-control, self-doubt, and a high level of de -
pendency. These behaviors indicate developmental failure of which of the following stages 
of development:
a. Infancy
b. Early childhood 
c. Late childhood
d. School age
12. Mr. Thompson has been forgetful lately, for example, forgetting where he has placed his 
keys or what time appointments are scheduled, and he has stated that he thinks these are 
just random behaviors that have no particular meaning. Which Freudian-based psychodynam -
ic principle assumes that all behavior and actions are purposeful?
a. Pleasure principle
b. Psychic determinism principle 
c. Reality principle
d. Unconsciousness principle
13. An example of a mature, healthy defense mechanism is
a. Denial
b. Rationalization
c. Repression
d. Suppression

a. Denial
d. Suppression 
14. Mr. Johnson is a 54-year-old client you have been seeing for several weeks in therapy. While 
discussing his current concerns of marital stress, he lies on the floor and assumes the fetal 
position. This is most likely an example of
a. Immature regressive defense mechanism 
b. Denial of reality
c. Immature fantasy defense mechanism
d. Repressive behavior
15. Defense mechanisms are best viewed as a function of the ego
a. To alert us to harm and danger
b. To alert us to problems
c. Used to resolve a conflict 
d. Used to protect the id
16. One of the health care changes that has occurred as a result of the affordable care act (ACA) 
is that doctors/hospitals/clinic groups or health systems are coming together and assum -

ing the responsibility for quality care to large groups of individuals insured by Medicare. The

389 review Questions
health care clinics/systems doctors or hospitals that join together are called which of the 
following? 
a. Health Maintenance Organization (HMO)
b. Preferred Provider Network (PPO)
c. Accountable Care Organization (ACO)
d. Individual Health Plan (IHP)
1 7. Health care economics is concerned with making decisions so the benefits outweigh the 
cost of resource utilization. What are two concepts that healthcare economics is concerned 
with in regard to fair distribution of resources and allocation? 
a. Equity and efficiency
b. Cost and benefits
c. Opportunity and waste 
d. Affordable and quality
18. What four elements need to be present for a malpractice lawsuit to be filed? 
a. Beneficence, Non-Maleficence, Truthfulness, and Justice 
b. Duty of care, Breach of standard of care, Injury, and Injury must be related to breach of 
the standard of care 
c. Abandonment, Breach of care, Violation of ethics, and Reimbursement for poor care

c. Abandonment, Breach of care, Violation of ethics, and Reimbursement for poor care 
d. Breach of standard of care, Injury, Deceit, and Malpractice
19. Mary is a Psychiatric–Mental Health Nurse Practitioner (PMHNP) who is working in a 
hospitalist role. Mary has encountered over five incidences in which attending psychiatrists 
and medical residents have been demeaning to nursing staff and not answering calls in the 
middle of the night or telling the nursing staff to write orders and the MD would sign off 
in the a.m. Mary is concerned about errors and wants to improve quality, reduce errors to 
promote safety. What concept is Mary employing? 
a. Bullying 
b. Abuse 
c. Civil Disobedience 
d. Just Culture 
20. The role of neurotransmitters in the central nervous system is to function as
a. A communication medium 
b. A gatekeeper for transmissions
c. A building block for amino acids
d. An agent to break down enzymes

21 . Serotonin is produced in which of the following locations:
a. Locus ceruleus
b. Nucleus basalis

390  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
c. Raphe nuclei 
d. Substantia nigra
22. Dopamine is produced in which of the following locations:
c. Raphe nuclei
d. Substantia nigra 
23. A client presents with complaints of changes in appetite, feeling fatigued, problems with 
sleep–rest cycle, and changes in libido. What is the neuroanatomical area of the brain that is 
responsible for the normal regulation of these functions?
a. Thalamus
b. Hypothalamus
c. Limbic system
d. Hippocampus
24. In considering whether to order an MRI of the head for a client, which of the following 
would be a contraindication to this diagnostic test?
a. Prosthetic limb
b. History of head trauma
c. Pacemaker 
d. Pregnancy
25. The primary excitatory neurotransmitter is
a. GABA
b. Serotonin
c. Dopamine
d. Glutamate 
26. A client who is experiencing difficulties with working memory, planning and prioritizing,

a. GABA
26. A client who is experiencing difficulties with working memory, planning and prioritizing, 
insight into his problems, and impulse control presents for assessment. In planning his care, 
the PMHNP should apply his or her knowledge that these symptoms represent problems 
with the
a. Frontal lobe 
b. Temporal lobe
c. Parietal lobe
d. Occipital lobe

391 review Questions
27 . The concept of target symptom identification is best explained as
a. Identification of the major clinical presentation of the client
b. Identification of specific, precise, and individualized symptoms reasonably expected to 
improve with medication 
c. Identification of the secondary messenger system syndrome
d. Intentional modulation of synaptic pathways
28. The goal of the psychiatric assessment process performed by the PMHNP is to
a. Gain an understanding of the life experiences of the client
b. Correctly diagnose the client
c. Identify the mental health needs of the client 
d. Be able to communicate with other staff about the client’s health needs
29. Mr. Johnson is a client newly admitted to an inpatient psychiatric hospital. The PMHNP on 
call at the facility plans to perform the initial intake assessment and diagnostic process. 
Mr. Johnson asks to please talk in his room because, he says, “People make me nervous. ”

Mr. Johnson asks to please talk in his room because, he says, “People make me nervous. ” 
His room is at the end of the hallway and is the farthest away from the nursing station. 
The PMHNP’s action should be based on awareness that the best location to do the 
assessment is
a. In Mr. Johnson’s room, because it is least noisy and most comfortable for him, thus 
facilitating data collection
b. In the dayroom, which is full of people, to observe his interactions with other people
c. In a quiet place, but public enough to get assistance with client care should it be re -
quired during the assessment 
d. In the treatment room with the door closed, a neutral location
30. Which communication technique is the PMHNP using in the following situation? Client: 
“Sorry I was late. I didn’t realize what time it was. ” PMHNP : “This is the third time now that

“Sorry I was late. I didn’t realize what time it was. ” PMHNP : “This is the third time now that 
you have been late for our sessions. I am wondering how committed you are to our working 
on your problems. ”
a. Theming
b. Recognizing
c. Validating
d. Sequencing
31 . In assessing a client, you ask him the meaning of the proverb “People who live in glass 
houses shouldn’t throw stones. ” He replies, “Because it will break the windows. ” The cor -
rect interpretation of this findings is 
a. Client has a probable mood disorder
b. Client has a probable anxiety disorder
c. Client has limited intellectual ability
d. Unable to interpret the finding without knowing the client’s age

392 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
32. The PMHNP is planning to work with a client using an individual therapy model of care. 
During the first session, the client makes the following statement: “This is the third time my 
son has run away. I’ve grounded him, taken away his bike, even tried cutting off his allow -
ance and confining him to his room. What should I do now?” The most therapeutic response 
for the PMHNP to make is
a. “I wonder if confining him to his room was abusive?”
b. “Maybe that depends on what you are trying to accomplish. ” 
c. “Perhaps talking to his friends and teachers would help. ”
d. Remain silent
33. A client says to the PMHNP , “Some days life is just not worth it. All my wife and I ever do is 
fight and scream. Things at home would be calmer and simpler if I just wasn’t there any -
more. ” The most therapeutic response for the PMHNP to make is

a. “Do you mean that you are thinking about leaving your wife and moving out?”
b. “Tell me what you mean by ‘it would be simpler if you just weren’t there anymore. ’” 
c. “So you are thinking suicide might be an option for you?”
34. Mrs. Shea has come to the mental health center seeking treatment for depression. She has 
a history of a suicide attempt by overdose 1 month ago. She was started on imipramine (tri -
cyclic antidepressant [TCA]) after that event but stopped taking the medication 1 week later 
because it “did no good. ” The PMHNP meets with Mrs. Shea to plan care with her. Which of 
the following is the most appropriate initial action?
a. Asking Mrs. Shea how to help her
b. Providing client teaching about the long time frame for TCAs to work

c. Contracting with Mrs. Shea for 6 sessions of individual therapy 
d. Providing Mrs. Shea with feedback about how suicide might affect her family
35. In completing the PMHNP assessment for the Mrs. Shea, the most appropriate lab test for 
the PMHNP to order at this time is
a. CBC
b. TSH
c. Liver function tests 
d. Electrolyte panel
36. A client comes into the clinic with a longstanding history of depression and chronic renal fail -
ure. He is on an antidepressant and a diuretic and complains of increased depression, mild 
confusion, irritability, and overall apathy from being too tired to do anything. The best initial 
PMHNP action to take at this time is
a. Increase his dose of antidepressant medication to better capture symptoms
b. Change him to another antidepressant for better symptom control

c. Augment his antidepressant with an atypical antipsychotic medication
d. Order a comprehensive metabolic panel

393 review Questions
37 . Sarah presents for her initial intake appointment with complaints of depression. She is be -
ing treated for hypertension and asthma by her primary care provider. Knowing that certain 
medications can cause or exacerbate depression, you obtain a complete medication history. 
Which of the following medications is known to exacerbate or cause depression? 
a. Omeprazole
b. Propranolol
c. Levothyroxine
d. Clarithromycin
38. When treating older adults, you should keep in mind that they are more sensitive to issues 
of drug toxicity because of which of the following reasons?
a. Decreased body fat
b. Increased liver capacity
c. Decreased protein binding
d. Increased muscle concentration
39. Which known teratogenic effects can be caused by the common psychotropic medications 
divalproex and lithium? 
a. Divalproex—Epstein anomaly; lithium—cleft palate
b. Divalproex—spina bifida; lithium—Epstein anomaly 
c. Divalproex—limb malformations; lithium—seizure disorder

d. Divalproex—mental retardation; lithium—spina bifida
40. The study of what the body does to drugs is called
a. Pharmacodynamics
b. Pharmacology
c. Pharmacokinetics
d. Distribution
41 . Your client Sam is being treated for panic disorder with agoraphobia. He currently is being 
prescribed paroxetine (Paxil CR, 37 .5 mg q.d.) and clonazepam (Klonopin, 0.5 mg q.d., p.r.n.). 
He has been on clonazepam for 2 years and admits to needing 4 pills to achieve the same 
effect that 1 pill initially produced. This is possibly an example of which process? 
a. Kindling 
b. Addiction
c. Tolerance
d. Potency
42. Why is group therapy beneficial?
a. It assists the client to focus on self
b. It lacks theoretical frameworks

394  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
c. It enables participants to acquire therapeutic factors
d. It is always time limited 
43. Which of the following is the best rationale for using cognitive behavioral therapy?
a. Recognize and change his or her automatic thoughts 
b. See reality as you see it
c. Change his or her reality by changing his or her environment
d. Recognize and accept that automatic thoughts suggest delusional thinking
44. When working with a dysfunctional family, you find that the father, Jim, worries excessively 
and is resistant to change. You give Jim a paradoxical directive to worry extremely well for 1 
hour per day, knowing that he will likely be noncompliant, and thus change will occur. With 
this technique, you are using which type of therapy?
a. Experiential therapy
b. Structural therapy
c. Strategic therapy 
d. Solution-focused therapy
45. Which of the following best describes homeostasis in a family system?

a. Choices a family makes to keep the peace
b. Balance or stability that the family returns to despite its dysfunction 
c. Need for change and balance in a family
d. Calm in a family that returns after a crisis
46. In an attempt to bring the client toward the goal he or she is working on, you ask the client, 
“If a miracle were to happen tonight while you slept, and you awoke in the morning and 
the problem no longer existed, how would you know, and what would be different?” This 
technique is used in which type of therapy?
a. Behavioral therapy
b. Solution-focused therapy 
c. Adlerian therapy
d. Existential therapy
47 . Ms. Thomas has been diagnosed with major depressive disorder (MDD) and is placed on 
fluoxetine 20 mg for her depression. For the PMHNP to effectively monitor her use of the

fluoxetine 20 mg for her depression. For the PMHNP to effectively monitor her use of the 
medication, which of the following actions should be part of ongoing care? 
a. Use of a standardized rating scale of depression
b. Monitoring for potential abuse of the medication
c. Monitoring of labs for renal functioning
d. Monitoring for potential cardiac side effects

395 review Questions
48. Which of the following is the best reason for considering the SSRI among the first-line drug 
choices for treating major depression?
a. Need to stair-step initial dosages
b. Sedating and calming effect of the medication
c. Safe use in suicidal overdose clients 
d. Ability to obtain therapeutic serum drug levels
49. A 23-year-old woman is brought into the ER after attempting suicide by cutting her wrists. 
Which nursing action by the PMHNP would be of highest priority initially?
a. Assess her coping behaviors
b. Assess her current level of suicidality
c. Take her vital signs 
d. Assess her health history
50. Which of the following interventions by the PMHNP for a person experiencing ataque de 
nervios  demonstrates culturally informed care? 
a. Offering brief supportive psychotherapy
b. Offering a brief hospitalization 
c. Requesting a family member act as an interpreter
d. Offering low-dose, short-term anxiolytic medication

51 . The PMHNP working at a student mental health clinic has now been working with a fresh -
man student for several weeks. The PMHNP learns that the student considers himself shy. 
He tells the NP that he has always felt uncomfortable in social situations or when he has 
to do oral presentations in class. He had few friends up until his senior year of high school 
when he discovered he could enjoy himself if he “had a couple of drinks before going out. ” 
He has continued this pattern in college and now occasionally drinks “2 to 3 beers” on 
weekends as well. According to the DSM-5, does the student have a mental disorder?
a. Yes, alcohol use disorder, mild
b. Yes, generalized anxiety disorder
c. No, at this point, the student does not meet criteria for a mental disorder.

d. Yes, adjustment disorder with mixed features
52. Jason misses several appointments. The PMHNP notes she feels resentful toward Jason 
and is struggling with how to respond to Jason when he finally comes in for his appoint -
ment. Which of the following demonstrates a therapeutic response?
a. “Jason, since you have missed several appointments, we are closing your case. ” 
b. “Jason, it’s pretty clear to me that you don’t want to be here. ” 
c. “Jason, you are ambivalent about seeking treatment. ”
d. “Jason, help me understand what’s going on so we can figure out how to proceed. ”

396 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
53. Which is true about pharmacologic treatment of anxiety in older adults? 
a. Course of treatment is generally shorter than for younger adults.
b. Drugs that are highly oxidized are more unpredictable than drugs that are mostly 
conjugated.
c. The therapeutic dose of SSRIs is generally lower than for young adults.
d. Highly lipophilic drugs have a more linear elimination in older adults.
54. A client returns for a follow-up appointment 3 weeks after starting on fluoxetine 20 mg. 
During this appointment you notice that her speech is a little rapid, in marked contrast to 
the psychomotor retardation and paucity of spontaneous speech she displayed on her first 
visit. Instead of looking at the floor, she now makes normal eye contact. Her affect has gone 
from constricted to expansive. She continues to have difficulty sleeping, but her energy has

from constricted to expansive. She continues to have difficulty sleeping, but her energy has 
improved and she states she feels “so much better!” What should you conclude about the 
shift in the client’s presentation? 
a. She is experiencing the activating side effects of fluoxetine.
b. She is becoming euthymic.
c. She is becoming hypomanic.
d. She is in a mixed state. 
55. Mr. D. is a 35-year-old, married, high-tech industry executive who is referred to the PMHNP 
for “insomnia. ” Mr. D. reports that he falls asleep quickly, but has difficulty staying asleep. 
He wakes up several times during the night, and believes he tosses and turns even when he 
is sleeping. He wakes up feeling exhausted and drinks “a pot of coffee” to stay awake and 
concentrate during his long work day. He drinks 1 glass of wine most evenings. He denies

concentrate during his long work day. He drinks 1 glass of wine most evenings. He denies 
any illicit substance use. He denies any symptoms of a mood or anxiety disorder, but is feel -
ing increasingly frustrated and concerned about his sleep. Which of the following is the most 
likely contributing factor to Mr. D. ’s ongoing middle insomnia?
a. Obstructive sleep apnea (OSA)
b. Caffeine dependence
c. Alcohol withdrawal
d. Attention-deficit hyperactivity disorder (ADHD)
56. Tina is a 54-year-old single white woman who has been a Psychiatric–Mental Health Nurse 
Practitioner for over 20 years. She is considering making application to a Doctor of Nursing 
Practice (DNP) program but states “if a DNP is required to practice I’ll get grandfathered 
in, no need for me to go back to school. ” Following the 2008 License, Accreditation,

in, no need for me to go back to school. ” Following the 2008 License, Accreditation, 
Certification, and Education (LACE) Consensus Model for Advanced Practice Registered 
Nurse Regulation, which statement is correct? 
a. Tina is correct: if the DNP becomes a requirement, she will be grandfathered in and 
obtain a DNP degree.
b. The DNP is an academic terminal degree and there will not be an opportunity for Tina to 
be grandfathered in a DNP .

397 review Questions
c. Tina will be grandfathered in and obtain a DNP only if her state requires a DNP to prac -
tice as an APRN.
d. The DNP is a certification and Tina will have to take an examination to be grandfathered 
in to obtain a DNP .
57 . Tim is a board-certified Psychiatric–Mental Health Nurse Practitioner (PMHNP) working in 
a busy community mental health center (CMHC). He is currently seeing a client diagnosed 
with bipolar I disorder who has comorbid hypertension and diabetes. During the visit, Tim 
takes the client’s blood pressure and her reading is 160/94 mm Hg. The client denies any 
headaches, nausea, chest pain, or shortness of breath. The client states “I can’t afford all 
these medications so I haven’t seen my doctor in 7 months and I am out of all my blood 
pressure and sugar medications, can you give me some?” What is Tim’s most appropriate 
action? 
a. Call the pharmacy to find out what medications the client is taking and refill for 1 month

action? 
a. Call the pharmacy to find out what medications the client is taking and refill for 1 month 
to cover until she can get in to see his primary care provider. 
b. Tell the client he cannot refill her medications and inform her to go to the emergency 
room should she develop any signs or symptoms of an elevated blood pressure or 
hyperglycemia. 
c. Call the client’s primary care provider, explain the situation, and coordinate the client 
getting an appointment and medication refills. 
d. Send the client to an urgent care clinic to get refills today.
58. The chief nursing officer of a large behavioral health system approached the PMHNP to dis -
cuss the new Healthcare Effectiveness Data and Information Set (HEDIS) behavioral health 
measures and specifications. The PMHNP is asked to do a retrospective chart review of all

measures and specifications. The PMHNP is asked to do a retrospective chart review of all 
hospital discharge clients who received a follow-up visit within 7 days of discharge and with -
in 30 days of discharge. The PMHNP has been asked to engage in which of the following? 
a. Needs assessment project
b. Plan, do, study, act project 
c. A task that is outside of the PMHNP’s scope of practice 
d. Quality improvement initiative
59. A PMHNP who is working on the consult liaison service is referred to a patient in the medi -
cal intensive care unit by the attending hospitalist. The consult note read “Evaluate the 
patient for competency to make independent medical decisions and consent for a surgical 
procedure. ” Based on the scope of practice of a PMHNP , which response would be most 
appropriate? 
a. Complete the patient assessment and write up the findings in the patient’s medical 
record.

record. 
b. Complete a patient assessment, including the mini mental status examination and fam -
ily collateral data to determine competency. 
c. Call the hospitalist and provide education that competency is a legal concept and ex -
plain that you can assess the patient for the capacity to make medical decisions.
d. Refuse the consult and inform the hospitalist that this is outside your scope of practice.

398 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
60. You are asked by a church organization to work with members within your health system to 
develop a flu vaccination program. According to public health principles, this is an example 
of what level of prevention? 
a. Secondary
b. Preventative 
c. Tertiary 
d. Primary
61 . A client with bipolar I disorder presents to your PMHNP office for a follow-up visit. During 
the visit the client informs you that he no longer wants to be treated with medication, 
and he does not have bipolar disorder, that was a misdiagnosis. He further informs you he 
stopped all his medication 2 months ago and is here to thank you for your care and tell you 
that he no longer needs follow-up appointments. Understanding the ethical conflict, you use 
which of the following ethical principles in working with this client? 
a. Autonomy
b. Nonmaleficence 
c. Justice 
d. Beneficence

c. Justice 
d. Beneficence 
62. A new client reveals to the PMHNP that her boyfriend screams at her and has repeatedly 
slapped and pushed her in front of her 3-year-old son. She goes on to say that the boyfriend 
has thrown things at her and on one occasion threw a glass of water at her that hit her son 
in the back. Should the PMHNP report this to child protective services (CPS)?
a. Yes, the client is issuing a cry for help for her son.
b. Yes, the PMHNP has a duty to report.
c. No, this does not constitute a reportable offense.
d. No, a report to CPS will escalate the violence.
63. Which of the following is a function of the psychiatric interview?
a. Understand the client’s psychosocial needs and communicate them to the treatment 
team
b. Identify the mental health needs of the client
c. Review previous medical records
d. Evaluate a treatment plan

team
64. A 74-year-old married white woman was referred to you by her primary care provider for a 
psychiatric evaluation. She had a normal medical and neurological examination in the last 2 
months. The client presents with her husband of 45 years who states, “My wife is just not 
the same anymore, she is irritable and asks the same question several times, even though 
I’ve answered it many times. ” The client responds, “Oh, Henry, you do the same thing, it’s 
just a normal part of getting older, and the kids think everything is fine. ” During the assess -
ment you compete the mini mental status examination (MMSE) and the client scores 18. As

399 review Questions
the PMHNP treating the client, you know the results of her MMSE indicate which level of 
cognitive impairment? 
a. No cognitive impairment 
b. Mild cognitive impairment 
c. Moderate cognitive impairment 
d. Severe cognitive impairment 
65. You are the PMHNP treating Tim, a 10-year-old child, for ADHD and social anxiety disorder. 
His mother presents with Tim for his scheduled individual therapy session. At the end of the 
session his mother says, “I need to take Tim to see his pediatrician and at the last visit I was 
told he needed some HPV shot. I don’t know, he’s a boy, why would he need that? What do 
you think?” What is the PMHNP’s best response to her question? 
a. “The Centers for Disease Control and Prevention (CDC) recommends the human papil -
lomavirus (HPV) vaccine for all boys and girls at age 10. HPV can cause cancer in both 
men and women, and the vaccine is effective in protecting against the virus. Can you

men and women, and the vaccine is effective in protecting against the virus. Can you 
tell me your concerns about Tim getting this vaccine?” 
b. “While the Centers for Disease Control and Prevention (CDC) recommends the vaccine, 
every parent has the right to choose and if you do not think Tim needs this vaccine, as 
his parent you have the right to refuse. ” 
c. “The Centers for Disease Control and Prevention (CDC) recommends the human papil -
lomavirus (HPV) vaccine for older teenagers, starting at age 18, so you have time to 
research and think about your decision. ”
d. “My daughters received the vaccine, and I’m like you, I did not let my sons receive 
the vaccine. They don’t need it. I agree, vaccines can be scary, can you tell me your 
concerns?” 
66. As a PMHNP working in a crisis evaluation center, you are aware that the initial focus of a 
crisis assessment is on which of the following?

crisis assessment is on which of the following? 
a. Client’s past diagnosis and medication trials 
b. Psychosocial history and supports 
c. Safety of the client and others 
d. Current living situation and coping skills 
67 . When conducting a neurological examination on a client, the PMHNP asks the client to hold 
out her arms and stick out her tongue while assessing for tremors. Which cranial nerve is 
being assessed? 
a. Glossopharyngeal
b. Vagus 
c. Trigeminal 
d. Hypoglossal 
68. A 20-year-old Asian man who was recently diagnosed with schizophrenia comes to your 
office for a follow-up appointment. During the assessment, he talks about his experience

400  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
in the group home, thinking that the television is sending him messages through news 
anchors during the 10 p.m. evening news. What symptom is the client describing? 
a. Paranoia 
b. Illusions 
c. Ideas of reference
d. Neologisms 
69. You are working with a family: mother, father, and two biological children. Sam, the father, 
is very rigid and controlling, which seems to be out of fear that something might happen to 
his family. He worries daily and it affects his family relationships. You give Sam a paradoxical 
directive and instruct him to intensely worry about everything he can think of for 1 hour a 
day. Using a paradoxical directive is part of which therapy? 
a. Experimental 
b. Structural
c. Strategic
d. Cognitive 
70. As a PMHNP working in an outpatient addiction clinic, you often refer your clients to com -

munity AA and NA meetings. Using Yalom’s therapeutic factors, you are aware that peer-
led groups can inspire and encourage other group participants. Which therapeutic factor is 
instilled in AA and NA group members? 
a. Hope
b. Altruism
c. Catharsis 
d. Existential factors 
71 . Which of the following client statements best describes imitative behavior as a therapeutic 
factor in group therapy? 
a. Group members talk over one another so the loudest person is heard 
b. Group members begin to model aspects of other members of the group and group 
leaders 
c. Group members discuss past situations when they were bullied and felt ashamed 
d. Group leaders take charge of the group and redirect members when they monopolize 
the group 
72. Dialectical behavioral therapy (DBT) draws on cognitive theory and behavioral theory, along

the group 
72. Dialectical behavioral therapy (DBT) draws on cognitive theory and behavioral theory, along 
with other theories. Elements of behavioral theory in DBT include which of the following?
a. Skills training and exposure
b. Examination of feelings and relating feelings to visceral sensations
c. Working through the transference with the therapist
d. Cognitive interpretation of past traumatic experiences

401 review Questions
73. Dialectical behavioral therapy (DBT) affirms dialectical thinking, which involves examining 
and discussing opposing ideas to find the truth. This philosophy is a supportive principle 
of DBT training. The central dialectical pattern emphasized in DBT involves the tension 
between:
a. Radical acceptance and change
b. Cue exposure and block avoidance
c. Problem avoidance and problem-solving
d. Crisis survival and acceptance
74. Samantha is a 26-year-old partnered woman who works full time as a teacher. She is in a 
long-term relationship with Mary and they are getting along well, and doing well financially. 
They have two children, ages 2 and 6. Samantha is seeing the PMHNP to address her 
concerns that she is feeling down and sad for no reason and states, “I know my life is going 
well but I just don’t feel happy. I have always worried a lot and have been sad most of my 
life. ” As a PMHNP trained in transactional analysis (TA), you understand that personality

life. ” As a PMHNP trained in transactional analysis (TA), you understand that personality 
is multifaceted and wonder if which of the following is affecting her ability to experience 
happiness: 
a. She had long periods of separation from her primary caregiver as a child and now has a 
difficult time accepting and receiving love and experiencing happiness
b. She likely had a traumatic event in her childhood and her thoughts and feelings related 
to the event are locked together in her brain and cannot be accessed
c. Her unhappiness is likely related to distorted thoughts and feelings about her 
relationship 
d. As an adolescent she experienced an event that was processed in an ego state as an 
older sibling
75. You have been working with a 54-year-old man who has been treated for schizophrenia since 
age 19. He has limited social interactions, likes to be alone, and has never dated nor had a

age 19. He has limited social interactions, likes to be alone, and has never dated nor had a 
desire to date. His symptoms are best explained by which of the following? 
a. Antisocial personality disorder 
b. Lack of personal hygiene 
c. Negative symptoms 
d. Positive symptoms 
76. Following evidence-based (EB) practice, which laboratory screening tests and assessments 
should be completed prior to placing a person on a second-generation (“atypical”) antipsy -
chotic medication? 
a. Serum glucose, lipid profile, weight, blood pressure, waist circumference, and family 
history of cardiovascular disease
b. Comprehensive metabolic panel, body mass index, complete blood count, and thyroid 
panel

402  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
c. Serum glucose or hemoglobin A1c, lipid profile, weight, body mass index, blood pres -
sure, waist circumference, and family history of cardiovascular disease 
d. Serum glucose, complete blood count, assessment of family history of cardiovascular 
disease and cancer 
77 . Which type of hallucination is rare in persons with psychotic illnesses and is often associ -
ated with an organic etiology? 
a. Auditory hallucinations
b. Gustatory hallucinations
c. Visual hallucinations
d. Combination hallucinations 
78. What differentiates atypical antipsychotic medications from first-generation or typical anti -
psychotic medications? 
a. 5HT2a receptor antagonist properties 
b. 5HT2a receptor agonist properties 
c. Specific dopamine receptor 3 and 5HT2a blockade
d. Dopamine receptor 2 antagonist properties 
79. You are treating a client with schizophrenia who takes clozapine. What laboratory values will

79. You are treating a client with schizophrenia who takes clozapine. What laboratory values will 
indicate the client needs to discontinue treatment? 
a. White blood cell count of less than 1,800/mm3 and absolute neutrophil count of less 
than 1,200/mm3
b. Absolute neutrophil count of less than 1,000/uL
c. White blood cell count of less than 1,200/mm3
d. Absolute neutrophil count of less than 2,000/uL 
80. Sean is a 47-year-old Gulf War veteran who was in combat during Operation Desert Storm. 
Sean has been treated by the PMHNP for major depressive disorder and associated anxiety 
symptoms. During the most recent visit, the PMHNP learns that Sean sustained a traumatic 
brain injury during his service, which was recently diagnosed at the TBI clinic in the Veterans 
Affairs clinic. What is the rationale for the PMHNP to taper Sean off clonazepam?

Affairs clinic. What is the rationale for the PMHNP to taper Sean off clonazepam? 
a. Benzodiazepines causes memory problems and confusion in clients with a history of a 
TBI.
b. Benzodiazepines lower the seizure threshold in clients with a history of a TBI. 
c. Veterans Affairs has banned benzodiazepines from the medication formulary. 
d. Benzodiazepines place clients with a TBI at risk for a second head injury.
81 . Alice is a 68-year-old woman who presents to you with concerns about her memory. She 
explains that her mother and grandmother both experienced dementia and she wants to do 
what she can to prevent this terrible disease. Alice is treated for hypertension, which is well 
controlled; other than that she is in good health. She is socially and physically active and 
participates in a monthly cooking class, volunteers at her church, and plays bridge twice a

403 review Questions
week at the senior center. She says, “I understand that I am losing brain cells at my age, but 
I would still like to keep my mind and body active. ” Which is the best response to Alice? 
a. “You are correct that you cannot form new brain cells at your age but you should 
continue with your activities because they offer excellent physical and mental health 
benefits and in turn will lower your risk for dementia. ”
b. “ Although most brain development occurs early in life, we still form some new brain 
cells in a couple of areas of the brain during adulthood. You should continue with your 
activities because they offer excellent physical and mental health benefits and are 
neuroprotective. ”
c. “Scientists now know that we do continue to form new brain cells throughout the 
entire brain during adulthood. Continue with your activities because you are producing 
new brain cells in the frontal lobe and this will decrease your risk of dementia. ”

d. “You should continue the social activities such as bridge, volunteering, and the book 
club but should consider the risks and benefits of physical activities such as dancing. 
If you were to fall and break a hip, this could lead to prolonged hospitalization, loss of 
independence, and ultimately increase your risk of dementia. ”
82. What is the best treatment for AIDS dementia complex? 
a. Acetylcholinesterase inhibitors 
b. Symptom-targeted pharmacologic treatments 
c. Nonpharmacologic supportive care 
d. Antiretroviral therapy
83. As a PMHNP working on the consult liaison team, you know the importance of preventing 
delirium due to which of the following? 
a. Risk of 1-year mortality rate
b. Risk of harm to the client and staff
c. Risk of unremitting psychosis
d. Risk of aspiration

d. Risk of aspiration 
84. When working with a 26-year-old, Mike, who presents for treatment of cannabis use and 
gambling, you use motivational interviewing techniques. As a PMHNP , you are familiar with 
the core counseling skills used in motivational interviewing. Mike made the following state -
ment: “I don’t know why I came here in the first place but I thought maybe some medica -
tion would help me. ” You respond by saying, “You’re feeling confused about the process” 
and Mike replies, “I never thought I’d need to come to a place like this. ” You respond, “You 
kept your appointment today and I appreciate the courage it took for you to come here. ” 
What two motivational interviewing techniques are used in this interaction? 
a. Interrupting and reassurance 
b. Affirming and reflecting
c. Open-ended questions and summarizing

d. Clarification and data collection

404  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
85. You are a PMHNP working in a hospitalist role on an acute inpatient psychiatric unit at a lo -
cal hospital. As you make rounds, the registered nurse informs you that a 32-year-old client 
who was admitted for alcohol detox has a score of 17 on the Clinical Institute Withdrawal 
Assessment for Alcohol. What phase of withdrawal is this client in? 
a. Mild withdrawal
b. Moderate withdrawal
c. Severe withdrawal
d. Delirium tremens
86. A client who has been addicted to opioids has not used in 15 days. During your medication 
management visit, the client states, “I’m going to die from not having my Opanas. You need 
to give me something now. ” The PMHNP’s best response is: 
a. “I know you are feeling very uncomfortable and we need to get you to the emergency 
room immediately to prevent a seizure. ” 
b.  “I know you are feeling very uncomfortable, let’s take your vital signs and talk about a

b.  “I know you are feeling very uncomfortable, let’s take your vital signs and talk about a 
trial on Catapres to treat your withdrawal symptoms. ”
c. “You have been using Opana for a long time and it is going to take several months for 
the withdrawal to end. In the meantime, I will see you weekly. ”
d. “There is no treatment for opioid withdrawal; you will have to wait it out. ”
87 . Signs and symptoms of cannabis intoxication include: 
a. Increase sensitivity to external stimuli
b. Enhanced motor skills 
c. Fast passage of time 
d. Lower heart rate
88. Which defense mechanisms are commonly used by persons with obsessive–compulsive 
personality disorder? 
a. Rationalization, isolation, and intellectualization
b. Projection, distortion, and hypochondriasis
c. Regression, somatization, and dissociation 
d. Sexualization, displacement, and reaction formation

89. You have been working with Cody, a 30-year-old single man, in weekly individual psychother -
apy for 3 weeks. At the start of session 4 he says, “I noticed when I came in that your usual 
parking spot has a new car in it with temporary tags, and it’s a BMW. Nice car. ” What is the 
best response from the PMHNP psychotherapist to Cody? 
a. “Thanks for noticing, it is a nice car. ”
b. “How do you know what spot I park in?”
c. “I noticed you drive a BMW as well, how do you like your car?”
d. “Sounds like having expensive things is important to you. ”

405 review Questions
90. When working in individual psychotherapy with a client who has a personality disorder, what 
are the primary treatment goals? 
a. Change the client’s personality structure and make him or her more adaptable in every -
day life.
b. Reparent the client, following Bowlby’s theoretical framework. 
c. Allow the client to reprocess his or her childhood trauma because all clients with per -
sonality disorders have a history of severe abuse.
d. Assist the client in changing dysfunctional interpersonal relationships and use of imma -
ture defense mechanisms.
91 . For a client who has paranoid personality disorder, what are the best treatment strategies? 
a. Confront negative and misinterpreted thoughts and feelings. 
b. Deflate grandiose thoughts. 
c. Engage the client in detailed and emotional responses and dialog. 
d. Do not challenge negative views or recollections of events.

92. John, a client with paranoid personality disorder, states the following: “I noticed there is a 
red light in the upper corner of your door and it has been going on and off during our ses -
sions. Are you recording me?” What is the PMHNP best response? 
a. “No, it would be illegal for me to record you, and that is not a camera it’s just a red 
light. ”
b. “John, thank you for asking the question. The light you see in the upper corner of my 
door tells me when a client has arrived and is in the waiting room. The client turns on 
the light, as you do, when they arrive in the waiting room, alerting me their arrival, and I 
turn off the light when we get into the office using the switch by my desk. ”
c. “Come on John, do you think I would record your sessions? You are not that interesting.

c. “Come on John, do you think I would record your sessions? You are not that interesting. 
I’m just kidding, no John, it is not a recorder or camera. ” 
d. “John, it takes courage to ask me the question. Tell me a time in your life when you had 
a similar experience. ”
93. As a PMHNP , you understand the genetic factors that contribute to psychiatric and personal -
ity disorders. Persons who develop antisocial personality disorder often are raised in families 
with high rates of which of the following? 
a. Psychotic disorders 
b. Alcohol use disorders
c. Anxiety disorders 
d. Mood disorders 
94. Persons with obsessive–compulsive personality disorder often use isolation as a de -
fense mechanism. Which of the following examples best describes isolation as a defense 
mechanism? 
a. Staying in the house for days or weeks to clean
b. Declining invites by friends or family to attend social gatherings

406  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
c. Describing information with very little affect variation
d. Being an introvert in the work setting to prevent talking with coworkers
95. In the Diagnostic and Statistical Manual of Mental Disorders,  5th Edition (DSM-5), how 
should a personality disorder be coded? 
a. Coded with the major psychiatric disorder 
b. Coded on Axis II
c. Coded on Axis III
d. Coded on Axis IV 
96. When prescribing a selective serotonin reuptake inhibitor (SSRI) for a child or young adult up 
to age 24, what education must be included? 
a. Black box warning about increased suicidality in this population 
b. Black box warning about increased risk of mania in this population 
c. Risk of sexual side effects on this class of medication 
d. Risk of stomach upset and headaches, to prevent unnecessary primary care visits
97 . Tommy is an 8 year-old who presents to the PMHNP for evaluation of attention-deficit hyper -

activity disorder. His mother completed the Vanderbilt ADHD rating scale and brought in the 
Vanderbilt teaching rating scale. Both your clinical interview and the rating scales indicate 
Tommy has ADHD. What assessment indicator(s) need to be completed prior to starting a 
stimulant mediation? 
a. Get a copy of the rating scale completed by his grandparents. 
b. Assess for family history of cardiovascular disease and, if positive for conduction prob -
lems, order an electrocardiogram before prescribing medication.
c. Obtain blood pressure, and pulse, and begin the stimulant medication.
d. Assess for a family history of bipolar disorder. 
98. A mother brings in her 7-year-old son for a psychiatric follow-up visit with the PMHNP . This

98. A mother brings in her 7-year-old son for a psychiatric follow-up visit with the PMHNP . This 
is the fourth visit the PMHNP has had with the client, his mother, and his younger sister, 
Renee, now 7 months old. You notice that she has a decrease in head growth, along with 
stereotypic motions of the hands, often licking and slapping. Renee has also lost her lan -
guage skills. What medical condition do you suspect Renee has developed? 
a. Autism spectrum disorder 
b. Rett syndrome 
c. Selective mutism 
d. Childhood onset diabetes 
99. You are treating Timothy, a 16-year-old boy, for an eating disorder. Timothy is of normal 
weight and socially extroverted, at times appearing to seek attention when in a peer group 
or class. Timothy’s symptoms are most consistent with which eating disorder? 
a. Anorexia nervosa
b. Bulimia nervosa

407 review Questions
c. Binge eating disorder 
d. Anxiety-induced eating disorder 
100. You are treating a 14-year-old female for attention-deficit hyperactivity disorder (ADHD) who 
has a family history of bipolar disorder. As a PMHNP familiar with symptoms of both ADHD 
and pediatric bipolar disorder, you know the following are overlapping symptoms of both 
disorders: 
a. Excessive talking, increased activity, and distractibility
b. Irritability, sleep problems, and mood swings 
c. Excessive talking, irritability, and sleep problems 
d. Sleep problems, mood swings, and distractibility

410 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
1. Correct Answer: A. The ANA ’s Psychiatric–Mental Health Nursing: Scope and 
Standards of Practice  defines the role and actions of the nurse practitioner.
2. Correct Answer: D. Information reduces incidence of disease.
3. Correct Answer: B. Identifies the trend of ensuring the protection of individual civil 
liberties for psychiatric clients.
4. Correct Answer: C. As with any client, psychiatric clients can refuse treatment un -
less a legal process resulting in involuntary commitment or mandatory court order 
for treatment has been obtained.
5. Correct Answer: A. Social relationships are mutual interpersonal relationships in 
which the needs of both parties are addressed. The N–C relationship is most con -
cerned with meeting the needs of the client.
6. Correct Answer: A. This action focuses on interventions designed to reduce the 
incidence of new cases of disease.

7. Correct Answer: B. Almost every state allows for a brief period of detainment to as -
sess a client for dangerousness to self or others before allowing the client to leave a 
hospital setting, even if the admission was voluntary.
8. Correct Answer: C. Authenticity. Being genuine, honest, and respectful are essential 
elements in establishing a working relationship with any client.  Like-mindedness 
is not a part of the therapeutic relationship. Although an important aspect of the 
PMHNP role, collecting a family history and accuracy in assessment does not in and 
of itself facilitate relationship-building.
9. Correct Answer: D. All DSM-5 disorders need to be made taking a person’s culture 
into account. A cultural expression of a response to grief, loss, or stress is not con -
sidered a DSM-5 diagnosis.

10. Correct Answer: C. Clients frequently display resistance and regression at the termi -
nation of a meaningful therapeutic process. The PMHNP is responsible for planning 
an effective termination and monitoring clients during the termination period.
11. Correct Answer: B. These signs indicate developmental failure of early childhood.
12. Correct Answer: B. The psychic determinism principle states that all behavior has 
purpose and meaning, often unconscious in nature, and that no behaviors occur 
randomly or by coincidence.
13. Correct Answer: D. Suppression is the only defense mechanism listed in which the 
client channels conflicting energies into growth-promoting activities.
14. Correct Answer: A. Immature regressive defense mechanism is a return to a behav -
ior common to an earlier stage of development.

15. Correct Answer: C. Defense mechanisms are a function of the ego used to resolve a 
conflict.
16. Correct Answer: C. ACO’s are groups of doctors or other health care providers who 
voluntarily come together and assume the care provided to Medicare patients. 
1 7. Correct Answer: A. Health care efficiency is making risk and benefit decision about 
how care resources are allocated and equity is ensuring that there is a fair distribu -
tion of the resources.

411 review Question answers
18. Correct Answer: B. The four elements that must be satisfied for malpractice to have 
occurred are a duty of care between clinician and patient, breach of standard of care, 
an injury to the patient, and the patient’s injury must be related to the clinician’s 
breach of care. 
19. Correct Answer: D. The ANA has a position statement that nurses are responsible for 
developing health care settings that include just culture initiatives understanding that 
human error can cause error and harm by creating an open and fair environment. 
20. Correct Answer: A. Neurotransmitters in the central nervous system function as a 
communication medium.
21 . Correct Answer: C. Serotonin is produced in the raphe nuclei.
22. Correct Answer: D. Dopamine is produced in the substantia nigra.
23. Correct Answer: B. Appetite, sleep, and libido are regulated by the hypothalamus.
24. Correct Answer: C. A client with a pacemaker should not receive an MRI of the 
head.

head.
25. Correct Answer: D. Glutamate is the primary excitatory neurotransmitter.
26. Correct Answer: A. Problems with working memory, planning and prioritizing, insight 
into problems, and impulse control indicate a problem in the frontal lobe.
27 . Correct Answer: B. Target symptom identification is the identification of specific, 
precise, and individualized symptoms reasonably expected to improve with a given 
medication. 
28. Correct Answer: C. Although diagnosis is an important aspect of the assessment 
process, the assessment ultimately should identify the needs of the client.
29. Correct Answer: C. One PMHNP role is to control the milieu as an aspect of as -
sessment, so the PMHNP should choose a quiet place that is public enough to get 
assistance with client care should it be required during the assessment.

30. Correct Answer: B. This exchange is an illustration of the technique of recognizing.
31 . Correct Answer: D. The answer demonstrates concrete thought processes, which 
are normal in persons younger than age 12 but are abnormal after age 12. To inter -
pret the finding, the PMHNP must know the age of the client.
32. Correct Answer: B. This response will be the most therapeutic in moving forward 
with the client.
33. Correct Answer: B. This response is the most therapeutic, allowing the client to 
further clarify and express feelings.
34. Correct Answer: A. Asking the client how to help is an aspect of assessment—all 
other answers are aspects of interventions, which are not initial actions of the 
PMHNP .
35. Correct Answer: C. Client overdosed and then was placed on a medication that af -

PMHNP .
fects the liver. The PMHNP needs to assess the client’s liver function as an aspect of 
care planning for her.
36. Correct Answer: D. Client symptoms are consistent with electrolyte imbalance and a 
physical cause of his symptoms must be ruled out first.
37 . Correct Answer: B. Beta blockers can cause or exacerbate depression.

412 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
38. Correct Answer: C. Older adults usually have decreased protein levels. Most psycho -
tropic medications are highly protein-bound. It is the unbound (free) concentration 
of the drug that is active; the bound concentration of the drug is inert. Thus, with 
decreased protein available for binding, more free (active) drug remains in the body, 
which then predisposes older adults to toxicity.
39. Correct Answer: B. Divalproex can cause spina bifida and lithium can cause Epstein’s 
anomaly.
40. Correct Answer: C. Pharmacokinetics is the study of what the body does to drugs.
41 . Correct Answer: C. Tolerance means needing more to achieve the same effect.
42. Correct Answer: D. Group therapy is beneficial because it increases social skills, is 
cost-effective, and enables participants to acquire the curative factors.

43. Correct Answer: A. Cognitive behavioral therapy helps clients recognize and change 
their automatic thoughts.
44. Correct Answer: C. Paradoxical directives are used in strategic therapy.
45. Correct Answer: B. Homeostasis is balance or stability that the family returns to 
despite its dysfunction.
46. Correct Answer: B. Miracle questions are used in solution-focused therapy.
47 . Correct Answer: A. The use of a standardized rating scale will allow the PMHNP to 
monitor the level of client symptoms and to evaluate the efficacy of the medication.
48. Correct Answer: C. SSRIs are considered among the first-line medications used to 
treat depression because of safety  in suicidal overdose clients.
49. Correct Answer: C. The PMHNP needs to ensure that her suicide attempt has not led 
to medical instability.

50. Correct Answer: A. The literature suggests that although short-term anxiolytic 
medication may be offered in an emergency room setting, ataque de nervios is best 
treated by brief supportive therapy by a Spanish-speaking Latino therapist. 
51 . Correct Answer: C. The student does not meet criteria for alcohol use or other 
disorder at this point, but if he does not learn alternative coping skills to deal with his 
shyness, he is at risk of developing an alcohol use disorder. 
52. Correct Answer: D. Although the PMHNP’s resentment is in response to actual 
behavior by Jason (his missing several appointments), clarifiying what is going on for 
him, his expectations for treatment and the PMHNP’s (and the clinic’s) expectations 
in a non-judgemental manner will help to develop a therapeutic alliance.

in a non-judgemental manner will help to develop a therapeutic alliance. 
53. Correct Answer: B. Liver enzyme functioning (among other things) diminishes as we 
age. All of the other statements are false. 
54. Correct Answer: C. In this case, you see a shifting set of symptoms, the most impor -
tant being her expansive mood and statement “so much better” that indicates she 
has gone beyond euthymia.
55. Correct Answer: A. OSA is the only plausible possibility if the rest of the information 
given by the client is accurate. OSA causes clients to have frequent awakenings and 
a sense that they are not sleeping deeply (“tossing and turning”) that is caused by 
apnea. The client should be assessed further for snoring and awareness of apnea. 
Although the client states he drinks a lot of coffee, this is driven by his sleep issues.

413 review Question answers
Drinking 1 glass of wine in the evening would not cause the degree of sleep pathol -
ogy he is exhibiting. Other than diminishing concentration that is consistent with 
sleep deprivation, there are no other signs and symptoms of ADHD.
56. Correct Answer: B. APRNs are not grandfathered into an academic degree; degrees 
must be earned from accredited academic institutions. 
57 . Correct Answer: C. It is not within the scope of practice of a PMHNP to treat hyper -
tension. Coordination of care to ensure the client does not run out of medication is 
the appropriate course of action. 
58. Correct Answer: D. Engaging in a project to assess whether a standard of care was 
met is a quality improvement project. 
59. Correct Answer: C. The legal system makes determination whether a person is com -
petent; practitioners can assess and make a determination about a person’s capacity 
to make medical decisions.

to make medical decisions. 
60. Correct Answer: D. Prevention of illness is primary prevention and administration of 
flu vaccinations in a community is intended to prevent a flu outbreak. 
61 . Correct Answer: A. Clients who are legally competent have the ability to make medi -
cal decisions and maintain individual autonomy. 
62. Correct Answer: B. PMHNPs are mandated reporters of child abuse. The 3-year-old 
is being exposed to violence and although not the target, could have been injured 
when the boyfriend threw the glass of water. 
63. Correct Answer: B. During a psychiatric interview, the PMHNP is responsible to iden -
tify symptoms and needs of a client to develop an appropriate treatment plan. 
64. Correct Answer: C. Cut points on the MMSE are as follows: total score 30, 25–30

64. Correct Answer: C. Cut points on the MMSE are as follows: total score 30, 25–30 
questionable significance, 20–25 mild impairment, 10–20 moderate impairment, and 
10 or lower severe impairment. 
65. Correct Answer: A. When family members or clients ask questions about illnesses 
and treatment, it is the PMHNP’s responsibility to provide data and then assess 
understanding and meaning. 
66. Correct Answer: C. In a crisis, the first assessment should be safety of the client and 
those near the client. 
67 . Correct Answer: D. The tongue is controlled by the hypoglossal cranial nerve. 
68. Correct Answer: C. Ideas of reference are misinterpretations of incidents and events 
that one believes have a direct personal reference to oneself. 
69. Correct Answer: C. Paradoxical directives may be used in strategic family therapy.

69. Correct Answer: C. Paradoxical directives may be used in strategic family therapy. 
70. Correct Answer: A. Working in support groups such as AA and NA, hearing stories of 
others who had similar struggles, instills hope. 
71 . Correct Answer: B. As group progresses the leader is less active and the members 
of the group take over and begin to model other members and the leaders. 
72. Correct Answer: A. DBT focuses on cognitive and behavioral techniques, mindful -
ness including meditation, and emotional regulation. 
73. Correct Answer: A. DBT emphasis acceptance of the current reality of what is and 
the ability to engage in personal change.

414 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
74. Correct Answer: B. According to TA, when a person is traumatized the thoughts and 
feelings get tied together and the process of therapy is to unlock the two. 
75. Correct Answer: C. Negative symptoms include flat affect, alogia, avolition, poor 
attention, and anhedonia. In the case study, the symptoms are avolition and 
anhedonia. 
76. Correct Answer: C. EB practice guidelines indicate that all clients should have the fol -
lowing prior to starting antipsychotic medication: fasting glucose or A1c, lipid profile, 
weight, body mass index, blood pressure, waist circumference, and family history of 
cardiovascular disease. 
77 . Correct Answer: B. The most common type of hallucinations in persons with psy -
chotic illnesses are auditory and visual. Tactile and gustatory hallucinations are less 
common and more likely related to an organic illness.

common and more likely related to an organic illness. 
78. Correct Answer: A. Typical antipsychotic medications block D2 receptors; atypical 
antipsychotic medications block D2 receptors and have 5HT2a antagonist properties. 
79. Correct Answer: B. The recent change in monitoring clozapine clients using the risk 
evaluation and mitigation strategy (REMS) indicates persons treated on clozapine 
need to have absolute neutrophil count monitored and, if it drops below 1,000/uL, 
treatment must be interrupted and can be resumed once the absolute neutrophil 
count normalizes above 1,000/uL. 
80. Correct Answer: A. Benzodiazepines are contraindicated in clients with a TBI due to 
increase rates of confusion and memory problems. 
81 . Correct Answer: B. While it was once thought that brain neurons did not regenerate, 
we now known that while most brain development occurs early in life, we continue

we now known that while most brain development occurs early in life, we continue 
to form some new brain cells throughout life. As we age, we need to engage in 
activities that keep our brains healthy by encouraging this growth. Examples are diet, 
exercise, socialization, and cognitive stimulation. 
82. Correct Answer: D. All persons with AIDS should be treated with antiretroviral 
therapy. Those who develop dementia complex should have those symptoms treated 
with appropriate pharmacological or nonpharmacological interventions. 
83. Correct Answer: A. Studies have identified high rates of mortality post hospitalization 
for delirium so the best treatment is prevention. 
84. Correct Answer: B. When a person is in contemplation stage, interventions should 
be affirming and reflecting. 
85. Correct Answer: B. CIWA cut off scores are as follows: 0–9, absent or very mild

85. Correct Answer: B. CIWA cut off scores are as follows: 0–9, absent or very mild 
withdrawal; 10–15, mild withdrawal; 16–20, moderate withdrawal; and 21–67 , severe 
86. Correct Answer: B. Opioid withdrawal symptoms can be treated with central alpha 
agonists. 
87 . Correct Answer: A. Persons intoxicated on cannabis exhibit distorted perceptions, 
increase relaxation and sensitivity, and loss of coordination. 
88. Correct Answer: A. Persons with obsessive–compulsive personality disorder use 
defense mechanisms of rationalization, isolation of affect, and intellectualization to 
make sense of their behavior.

415 review Question answers
89. Correct Answer: D. In a therapy relationship, the therapist should try to understand 
the meaning of a client’s statement rather than engage in social conversations. 
90. Correct Answer: D. Persons with personality disorders have a pervasive maladaptive 
pattern of behavior and the goal of therapy is to slowly shift how they relate in the 
world and begin to use higher-order defenses. 
91 . Correct Answer: D. Persons with fixed false beliefs should not be challenged.
92. Correct Answer: B. When working with a paranoid client, help the person find proof 
of meaning and explain any questions in a matter-of-fact manner. 
93. Correct Answer: B. Being raised in an alcoholic family increases the likelihood of 
chaos, unpredictability, and lack of rules and order, leading to higher rates of develop -
ing antisocial personality disorder. 
94. Correct Answer: C. Isolation is a defense mechanism often used by people with

94. Correct Answer: C. Isolation is a defense mechanism often used by people with 
obsessive–compulsive personality disorder and has to do with affect and emotion 
rather than getting out and being social.
95. Correct Answer: A. DSM-5 no longer uses the axial system.
96. Correct Answer: A. The SSRIs all carry a black box warning for increased suicidal 
ideation for this age group. 
97 . Correct Answer: B. American Academy of Child and Adolescent Psychiatry practice 
parameters require physical exam, pulse, weight, height, and blood pressure workup 
prior to the start of stimulant medication. Because his grandfather had a cardiac 
conduction problem, an electrocardiogram (ECG) should also be obtained prior to the 
start of medication. 
98. Correct Answer: B. Girls with Rett’s syndrome develop normally and around the 7th 
month regress, with a decrease in head size and language loss.

month regress, with a decrease in head size and language loss. 
99. Correct Answer: B. Clients with bulimia are often of normal weight or overweight 
and are outgoing. 
100. Correct Answer: A. Clients with ADHD and bipolar disorder often have excessive 
talking, increased activity, and distractibility.

418 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
A
Abdomen 85–86
Absorption 111
of drugs 111
Abuse  294
Access to care 56
Acetylcholine
explanation of 69
function of 72
psychiactric disorders and 70
Acupressure 132–133
Acupuncture 132–133
Addiction. See Substance-related disorders
Addictive disorders. See Substance-related 
disorders
Adolescent Transitions Program (ATP) 332
Advance directives 23
Affect  328
Affordable Care Act (2010) 57
Aggression-turned-inward theory 140–141
Agonist effect 113
Agoraphobia  210–211. See also  Anxiety 
disorders
assessment of 210–211
clinical management of 211
comorbidities of 211
description of 210
diagnostic and laboratory findings and 211
history of 210
mental status exams for 210
nonpharmacological management of 211
pharmacological management of 211
physical exams for 210
Alanine aminotransferase 95
Alcohol use disorders identification test 
(AUDIT) 297
Alzheimer’s dementia 283
Amaurosis fugax 281

Amino acids 69
Amygdala 66
Anal stage  42
Analysis of variance (ANOV A) 54
Anhedonia 146
Anorexia nervosa 348
Antagonist effect 113
Antiadrenergic 156
Anticholinergic 156
Anticipatory guidance 98–99
Anticonvulsants 182–183Antidepressants 158–159, 161
classes of 152–154
target symptons of treatment 152
tricyclic 154
Antihistaminergic 156
Antipsychotics 115
atypical 244–247
typical 249–250, 250
Anxiety
certification examination and 1
description of 195–196
levels of 195, 196
pathological levels of 200
tips for dealing with 6
Anxiety disorders 196–207, 197
agoraphobia as 210–211
assessment of 200–202
clinical management of 202
comorbidities of 206
demographics for 199
description of 196–197
diagnostic and laboratory findings 202
differential diagnosis of 202, 203
etiology for 197–199
follow-up for 206–207

generalized anxiety disorder as 215–218
health considerations for 206
history of 200–201
incidence of 199
life span considerations for 205
mental status exams for 201–202
nonpharmacological management of 205
obsessive–compulsive disorder as 218–221
panic disorder as 207–210
pharmacological management of 203–205, 
205
physical exams for 201
posttraumatic stress disorder as 222–225
prevention of 199–200
risk factors for 199
screening for 199–200
separation anxiety disorder as 218
social anxiety disorder as 214–215
specific phobias as 211–214
Anxiolytics 116, 205
Arbitration 52
Aromatherapy 132, 133
Aspartate  69
aminotransferase 95–96

419
INDEX
gender-based 99–101
health behavior guidelines and 101–103
Assessment components
abdomen as 85–86
back as 84–85
breasts as 85
coordination and fine-motor skills as 82
ears as 84
eyes as 83
head, skin, and nails as 83
heart as 85
indicators of child abuse as 86
motor functions as 82
musculoskeletal system as 86
neck as 84
neurological exam as 80–86
neurological soft signs as 82–83
nose and sinuses as 84
physical exam as 79–86
sensory functions as 82
thorax and lungs as 85
vital signs as 83
Attention deficit disorder 117
Attention-deficit hyperactivity disorder 
(ADHD) 117, 335–340
agents for treatment of 338
assessment of 337
clinical management of 338–339
comorbidities of 339–340
demographics of 336
description of 335–336
diagnostic and laboratory findings 337–338
differential diagnosis of 338
etiology of 336
follow-up for 340
incidence of 336
mental status exams for 337
nonpharmacological management 
of 339–340
pharmacological management of 338–339

of 339–340
physical exams for 337
prevention of 337
risk factors for 336–337
screening for 337
Autism spectrum disorder 340–343
assessment of 342
clinical management of 343–344
demographics of 341description of 340
diagnostic and laboratory findings 343
differential diagnosis of 343
etiology of 340
history of 342
incidence of 341
mental status exams for 342
of 343–344
pharmacological management of 343
physical exams for 342
prevalence 341
prevention of 341
risk factors for 341
screening for 341, 343
symptons of 342
Autonomic nervous system 64
Aversion treatment 304
Axon  64, 68
B
Back 84–85
Bandura, Albert 46
Basal Ganglia 67
Beck, Aaron 125, 141
Beck depression inventory (BDI) 145
Becker, Marshall 46
Behavioral therapy 289
explanation of 126
Belladonna 135

Axon  64, 68
B
Back 84–85
Benzodiazepines (BNZs) 116, 204
Bereavement. See Grief and bereavement
Berg, Insoo 131
Binge eating  348
Biofeedback 132, 133
Biological
based therapies 132
preventative factors 104
risk factors 103
theories of personality disorders 316
theories of substance-related 
disorders 294–296
Biopsychosocial framework of care, recovery 
and 37
Bipolar (BP) disorder 173–184
anticonvulsants and 182–183
assessment of 175–177
clinical management of 179–180
demographics of 174

420  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
Bipolar (BP) disorder (continued)
description of 173–174
diagnostic and laboratory findings for 179
differential diagnosis of 179
drugs for 182–183
etiology of 174
history of 175–177
incidence of 174
lithium for treatment of 180
medications for 179
mental status exam for 177–178
pharmacological management of 180–182
phycial exam for 177
prevention of 175
rapid cycling and 177
risk factors for 175
screening for 175
symptoms of 176, 179
types of 177
Black cohosh 134
Body dysmorphic disorder 226
Body mass index (BMI) 83
Bowen, Murray 130
Brain/brain function
brainstem and 67–68
cerebrum and 65–67
depression and 143
gray matter and 64
neuroanatomy and 64–68
neurophysiology and 68–70
outermost surface of 64–65
white matter and 64
Brainstem 67–68
Breasts 85
Brief psychotic disorder 264–265
assessment of 265
clinical management of 265
demographics of 264
description of 264

Breasts 85
diagnostic and laboratory findings 265
etiology of 264
history of 265
incidence of 264
mental status exams for 265
nonpharmacological management of 265
pharmacological management of 265
physical exams for 265
prevention of 264
risk factors for 264screening for 264
Brief therapy 162
Bright Futures 98–99
Bulimia nervosa 348
C
CAGE alcohol screening test 297
Calcium 89–90
Cardiac disorders 150
Caring theory 47
Carrier proteins 113
Case management 22
Catecholamine. See Dopamine (DA)
Catnip 135
Cell body and neurons 64, 68
Central nervous system (CNS) 64
Cerebellum 67
Cerebral cortex 66
Cerebrum
basal ganglia in 67
cerebral cortex in 66
function of 65
limbic system in 66
lobes in 65–66
Certification 15–16
Certification examination 1–10
anxiety 1
current knowledge about 2

anxiety 1
depth of knowledge required 3
expectations for 2
facts about 8–9
general content 2
instituting a study plan for 3–5
internet resources for 9
mentally preparing for 2
physically preparing for 2
preparing for 1–8
review courses for 2
strategies prior to 5–6
test-taking strategies for 6–8
Chamomile 135
Child abuse 86
Childhood and adolescence 
disorders 327–360
assessment and care planning for 327–329
attention-deficit hyperactivity disorder 
(ADHD) 335–340
autism spectrum disorder 340–342

421
INDEX
conduct disorder 332–334
disruptive mood dysregulation 
disorder 355–356
eating disorders 346–351
intellectual disability 352–355
oppositional defiant disorder 
(ODD) 329–332
Rett syndrome 344–346
Children and adolescents under 21 years of 
age test (CRAFT) 297
Chloride 92–93
Cholinergics 69
Chronic fatigue syndrome 150
Chronobiological theory 143–144
Circadian rhythms 143
Circular causality 129
Client advocacy 22
Clinical Opiate Withdrawal Scale 
(COWS) 297
Cluster A personality disorders 317–318
characteristics of 318
Cluster B personality disorders 318–319
characteristics of 320
Cluster C personality disorders 319
characteristics of 321
Cognitive behavioral therapy (CBT) 162, 289, 
379
Cognitive disorders 271
description 271
etiology 271
Cognitive theory 43–45, 141
Cognitive therapy 125–126
Combined structural and functional 
imaging 73
Commitment, involuntary 21
Competency, elements of 21
Complementary and alternative therapies 
(CATs)
origins of 132
types of 132–135

imaging 73
(CATs)
Complete blood count (CBC) 149
Computed tomography (CT) 72
Concrete operations stage 44
Conduct disorder 332–335
assessment of 333
clinical management of 334
demographics of 333
description of 332
diagnostic and laboratory findings 334differential diagnosis of 334
etiology of 332
history of 333
incidence of 333
life span considerations for 335
mental status exams for 334
nonpharmacological management of 335
pharmacological management of 334
physical exams for 333
prevalence of 332
prevention of 333
risk factors for 333
screening for 333
Confidentiality 16
exceptions to guaranteed 17
Conflict 52
defense mechanisms and 43
of interest (COI) 57–58
resolution  52
Confusion Assessment Method (CAM) 273
Conservation 44
Coordination 82
Corpus striatum 67
Corticotropin-releasing hormone (CRH) 142

Countertransference 38–39
Cranial nerves 80–82
Credentialing 15
Creutzfeldt-Jakob disease 278
Critical thinking 52
Cultural differences and health influences and 
determinants 24
Culturally competent care 23–24
forensics and corrections and 27–28
homeless individuals and 24–25
migrant and seasonal farm workers and 25
sexual orientation and 26–27
Culture 23
Culture-bound syndromes 23
Cyclothymic disorder 186–187
assessment of 187–188
clinical management of 188
demographics of 186–187
description of 186–187
diagnostic and laboratory findings 188
differential diagnosis of 188
etiology of 186–187
follow-up for 188
history of 187
indicence of 186–187

422 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
Cyclothymic disorder (continued)
life span considerations for 188
mental status exams for 187–188
nonpharmacological management of 188
pharmacological management of 188
physical exams for 187
prevention of 187
risk factors for 187
screening for 187
Cytochrome P450
inhibitors and inducers 112
D
Defense mechanisms 43, 44
Delirium 271–277
assessment of 273
clinical management of 275
demographics of 272
description of 271
diagnostic and laboratory findings 275
differential diagnosis of 275
etiology of 272
health considerations for 276
history of 273
incidence of 272
life span considerations for 276–277
mental status exams for 274
nonpharmacological management of 276
pharmacological management of 276
physical exam for 273
prevention of 273
risk factors for 272–273
screening for 273
subtypes of 272
Delusional disorder 262–265
assessment of 262–263
clinical management of 264
demographics of 262

description of 262
diagnostic and laboratory findings 264
erotomanic 262–263
etiology of 262
grandiose 263
history of 262–263
jealous 263
mental status exam for 263–264
nonpharmacological management of 264
persecutory  263
pharmacological management of 264physical exam for 263
prevalence of 262
prevention of 262
risk factors for 262
screening for 262
somatic 263
subtypes 262–263
Dementia 277–285
assessment of 280–281
clinical management of 283
demographics of 279
description of 277–279
diagnostic and laboratory findings 282
differential diagnosis of 282–283
etiology of 279
history of 280–281
incidence of 279
life span considerations for 285
mental status exams for 281
nonpharmacological management of 284
pharmacological management of 283–284
physical exams for 281
prevention of 280

risk factors for 279
Dendrites 64, 68
Deontological theory 19
Dependence 294
Depolarization 68
Depression. See also  Cyclothymic disorder; 
See also  Persistent depressive disorder 
(Dysthymia); See also  Premenstrual 
dysphoric disorder; See also  Stevens 
Johnson syndrome (SJS)
aggression-turned-inward theory 140–141
anhedonia during 146
biological theories of 142–144
chronobiological theory of 143–144
circadian rhythms and 143
cognitive theory 141
corticotropin-releasing hormone (CRH) 
and 142
diagnostic and laboratory findings 149
dysphoria and 142
endocrine dysfunction and 142–143
etiology of 140–146
genetic predisposition to 142
hypothalamic–pituitary–adrenal axis deregu -
lation and 142

423
INDEX
learned helplessness-hopelessness 
theory  141–142
major depressive disorder (MDD) 140–166
medications that induce 119
menses and 146
mental status exams for 147
mood and  146
neurotransmitter abnormalities and 143
object loss theory 140
physical exams for 147
psychodynamic theories of 140–142
versus sadness 139
sex steroid hormones and 173
sleep disruption and 146
structural brain changes causing 143
weight loss from 146
Descriptive statistics 54
deShazer, Steve 131
Developmental stages 99–101
Developmental theories 40–41
Dexamethasone suppression test (DST) 143
Diagnostic and laboratory testing 86–97
Diagnostic and Statistical Manual of Mental 
Disorders 293
Dialectical behavioral therapy 126
anxiety disorders and 202, 203
obsessive–compulsive disorder and 220–221
panic disorder and 208–209
posttraumatic stress disorder and 224
specific phobias and 213
Disclosure
benefits of 20
of disability 20
ethics of provider 19–20
risk of 20

risk of 20
Discontinuation syndrome 165
symptoms of 165–166
Disease prevention strategies
immunization and 97–98
implementation of 98–99
Disruptive mood dysregulation 
assessment of 355–356
clinical management of 356
demographics of 355
description of 355
etiology of 355
follow-up for 356nonpharmacological management of 356
pharmacological management of 356
prevalence of 355
prevention of 355
risk factors for 355
screening for 355
Dissociative disorders 225–226
body dysmorphic disorder as 226
excoriation disorder as 226
hoarding disorder as 226
trichotillomania as 226
Distribution 111
DNA  74
Donabedian model 55
Dopamine (DA) 295
function of 71
pathways 248–249
psychiatric disorders and 70
Double depression 168
Drug Enforcement Administration (DEA) 115

DNA  74
Drug screening and false positives 119
Dysphoria 142
Dysthymia. See Persistent depressive disorder 
(Dysthymia)
E
Ears  84
Eating disorders 346–351
assessment of 347
clinical management of 351
description of 346
diagnostic and laboratory findings 350
differential diagnosis of 350–351
etiology of 346–347
follow-up for 351
history of 348
incidence of 347
mental status exams for 349–350
nonpharmacological management of 351
pharmacological management of 351
physical exams for 348–349
prevention of 347
risk factors for 347
screening for 347
Edinburgh Postnatal Depression Scale 
(EPDS) 145
EEG 73

424  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
Ego 43
Electrocardiogram (EKG) 156
Electroconvulsive therapy (ECT) 159
Electrolytes 89
Electronic health records, function of 17
Elimination 112
of drugs 112
Emancipated minors 18
Endocrine
disorders 150
dysfunction 142–143
Enzymatic destruction 70
Epinephrine 69
Erikson, Erik 40
Ethical issues
in decision-making 19
disclosure by providers as 19–20
for nurse practitioners 18–19
in research 54–55
Evidence-based practice 53
Evoked potentials testing 73
Excitatory response 113
Excoriation disorder 226
Exercise
benefits of 101
client teaching regarding 101–102
monitoring intenstity of 102
recommendations for 102
Existential therapy 126
Experiential therapy 130–131
External validity 54
Extrapyramidal side effects (EPSE) 249
medications used to treat 251
side effects of 252
Eye movement desensitization and reprocess -
ing (EMDR) 127
Eyes 80, 83
F
Family history, explanation of 73–74

Eyes 80, 83
F
Family homeostasis 129
Family structure 130
Family systems theory 129–130
Family systems therapy 130
Family therapy 162, 289
family system concepts in 129–130
types of 130–132
Federal Drug Administration (FDA)
pregnancy ratings for medications from 118Fetal alcohol syndrome (FAS) 297, 352–353
Fibromyalgia 150
Fine-motor skills 82
First-pass metabolism 112
Fish oil 134
Fissures in the brain 65
Folie á Deux. See Shared psychotic disorder
Forensics
corrections and 27–28
knowledge base of 28
Formal operations stage 45
Frankl, Viktor 126
Free thyroxine T4 87
Freud, Sigmund 41, 42, 125, 140–141, 197
Frontal lobe 65
Functional imaging 73
G
GABA
Gamma amino butyric acid (GABA) 295
Gamma glutamyl transpeptidase 96–97
Gender

G
GABA
Gender
based screening 99–101
dysphoria  26
identity 26
Generalized anxiety disorder (GAD) 215–218
assessment of 216–217
comorbidities of 218
description of 215–216
history of 216
life span considerations for 218
mental status exams for 217
nonpharmacological management of 217
pharmacological management of 217
physical exams for 216–217
Genes 74–75
Gene therapy 74
Genetic
counseling 74
loading 294
predisposition to depression 142
terms 74
testing 75
Genital stage 42
Genomics 73–75
Ginkgo 135

425
INDEX
Ginseng  135
Glia 68
Glutamate
Glycine 69
Gray matter 64
Grief and bereavement 150, 169–173
assessment of 171
clinical management of 172
demographics of 170
description of 169–170
diagnostic and laboratory findings 172
differential diagnosis of 172
etiology of 170
follow-up for 173
history of 171
indidence of 170
life span considerations for 172
mental status exams for 171
nonpharamacological management of 172
pharamacological management of 172
physical exams for 171
prevention of 171
psychotherapy and 172
risk factors for 171
screening for 171
Group therapy 162
explanation of 127–128
phases in 128–129
Gyri  65
H
Haley, Jay 131
Half-life 112
Hamilton Depression Rating Scale 
(HAM-D) 145
Health
behavior guidelines 101–103
belief model 46
cultural influences on 24
delivery systems 56
policy and nurse practitioners 22–23
policy development 58
promotion  103

Health
Health care home 57Health Information Technology for Economic 
and Clinical Health Act (HITECH) of 
2009 17
Heart  85
Herbal products/supplements 132, 133–135
Hierarchy of needs theory 45–46
HIPAA, privacy protections under 16–17
Hippocampus  66
Hoarding disorder 226
Homelessness 24–25
strategies for reducing 25
Homicide 381
early warning signs of 381
Human Genome Project 74
Humanistic therapy 126–127
Huntington’s disease 278
Hypercalcemia 90
Hyperkalemia 94
Hypermagnesemia 92
Hypernatremia 91
Hypersomnia. See Sleep disorders
Hypersomnolence disorder 364
Hypertensive crisis 157
Hyperthyroidism 88
Hypocalcemia 90
Hypokalemia 94
Hypomagnesemia 92
Hypomania 177
Hyponatremia 91
Hypothalamic–pituitary–adrenal axis 142
Hypothalamus  66
Hypothyroidism 88
Hypovolemic hippocampus 143

Hypovolemic prefrontal cortex 143
I
Id 42
Illness management recovery (IMR) 255
Immunization 97–98
Improvised explosive devices (IEDs) 286
Incredible years 332
Individual therapy 162
Indole. See Serotonin
Infectious and inflammatory states 150
Inferential statistics 54
Informed consent 17–18
Inhibitory response  113
Insomnia 362–367. See also  Sleep disorders
assessment of 363–364

426  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
Insomnia (continued)
in children 367
clinical management of 365
demographics of 362
diagnostic and laboratory findings 364
differential diagnosis of 365
etiology of 362
hypersomnolence disorder and 364
incidence of 362
life span considerations for 367–368
mental status exams for 364
of 366–367
obstructive sleep apnea (OSA) and 364
in older adults 367–368
pharmacological management of 365–366
physical exams for 364
polysomnography and diagnosis of 364
prevention of 363
risk factors for 363
screening for 363
Institutional review boards (IRBs) 54–55
Intellectual disability 352–354
assessment of 353–354
clinical management of 354
demographics of 353
description of 352
diagnostic and laboratory findings 354
differential diagnosis of 354
etiology of 352–353
and fetal alcohol syndrome 352–353
mental status exams for 354
of 354–355

of 354–355
pharmacological management of 354
physical exams for 353–354
prevalence of 353
prevention of 353
risk factors for 353
screening for 353
Internal validity 54
Interpersonal theory 45, 47, 198
Interpersonal therapy 127
Intimate partner violence (IPV) 373–376
assessment of 375
clinical management of 376
demographics of 374
description of 373
diagnostic and laboratory findings 375differential diagnosis of 376
etiology of 373–374
history of 375
incidence of 374
mental status exams for 375
nonpharmacological management of 376
pharmacological management of 376
physical exams for 375
prevention of 374–375
risk factors for 374
screening for 374–375
Intoxication 294, 300
Inverse agonist effect 113
Involuntary admission 21
Involuntary commitment 21
J
Just culture of safety 55–56
K
Kidney disease 113

J
K
Kindling 174
Klerman, Gerald L. 127
L
Laboratory testing, diagnostic and 86–97
Latency stage 42
Lazarus, Arnold 126
Leadership, nurse practitioners and 51
Learned helplessness-hopelessness 
Left hemisphere (of brain) 65
Leininger, Madeline 47
Lethality assessment 379
Lewy body disease 279
Licensure 15
Limbic system 66
Linehan, Marsha 126
Lithium 180
side effects of 181
Stevens Johnson syndrome (SJS) and 186
Liver disease 113
Liver function tests (LFTs) 95, 181
Living wills 23
Lungs 85
M
Macrobiotics 135
Magnesium 91–92

427
INDEX
Magnetic resonance imaging (MRI) 73–74
Magnetoencephalography (MEG) 73
Major depressive disorder (MDD) 140–166. 
See also  Depression
adults and 163–164
age and 142
assessment of 145
brain damage and 143
children and 163
clinical management of 151
demographics of 144–145
description of 140
diagnostic and laboratory findings 
for 149–151
electroconvulsive therapy (ECT) treatment 
for 159
expected course of 166
follow-up for 164–166
history of 145–146
hospitalization for 151
HPA dysregulation causing 142
incidence of 144–145
individual therapy 162
life span considerations for 163–164
mental status exams for 147–149
of 159–162
pharmacological management of 151–155
phototherapy 162
prevention of 145
risk factors for 145
screening for 145
transcranial magnetic stimulation (TMS) 
treatment for 160
vagal nerve stimulation (VNS) treatment 
for 160
Malpractice
insurance 20–21
negligence as proof of 21
Mania 177

for 160
Mania 177
medications inducing 119
Manipulative and body-based therapies 132
Maslow, Abraham 45
Massage  132, 135
Mean  54
Mediation 52
Medications
absorption of 111antipsychotics 115
for anxiety disorders 116
anxiolytics 116
for attention deficit disorder 117
for attention deficit hyperactivity 
disorder 117
benzodiazepines (BNZs) 116
for bipolar affective disorders 115
for bipolar (BP) disorder 179, 182–183
depression inducing 119
for depressive disorders 116
distribution in organs 111
and drug screening results 119
enzyme inducers and 112
enzyme inhibitors and 113
FDA pregnancy ratings for 118
first-pass metabolism and 112
half-life of 112
kidney disease from 113
liver disease from 113
mania inducing 119
median effective dose 114
median toxic dose 114
metabolism and 112
monoamine oxidase inhibitors

monoamine oxidase inhibitors 
(MAOIs) 113, 116, 152, 156
mood altered states as side effects 151
for mood disorders 115, 153
mood stabilizers 115
norepinephrine dopamine reuptake inhibi -
tors (NDRIs) 154
pharmacodynamics and 113
pharmacokinetics and 111–113
potency of 113
for psychiatric disorders 115
for psychotic disorders 115
schedules for controlled substances 118
for schizophrenia 115
selective serotonin reuptake inhibitors 
(SSRIs) 113, 116, 152, 156
serotonin agonist and reuptake inhibitors 
(SARIs) 154
serotonin norepinephrine reuptake inhibi -
tors (SNRIs) 152–153, 159
steady state of 112
stimulants 117
tachyphylaxis 114
teratogenic nature of 118–119
therapeutic index for 114

428 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
Medications (continued)
tolerance to 114
tricyclic antidepressants (TCAs) 152, 156
for unipolar affective disorders 116
Meditation 132, 135
Medulla  67
Melatonin 134
Mental state exam (MSE) 283
Mental status exams
for agoraphobia  210
for anxiety disorders 201
for attention-deficit hyperactivity disorder 
(ADHD) 337
for autism spectrum disorder 342
for bipolar (BP) disorder 177–178
for brief psychotic disorder 265
for conduct disorder 334
for cyclothymic disorder 187–188
for delirium 274
for delusional disorder 263–264
for dementia 281
for depression 147
for eating disorders 349–350
for generalized anxiety disorder (GAD) 217
for grief and bereavement 171
for insomnia 364
for intellectual disability 354
for intimate partner violence (IPV) 375
for major depressive disorder 
(MDD) 147–149
for obsessive–compulsive disorder 
(OCD) 220
for oppositional defiant disorder (ODD) 331
for panic disorder 208

(OCD) 220
for persistent depressive disorder 
(Dysthymia) 168
for phobias  213
for posttraumatic stress disorder 
(PTSD) 223
for Rett syndrome 345
for schizoaffective disorder 261
for schizophrenia 241–242
for schizophreniform disorder 259
for sexual assault and abuse 378
for shared psychotic disorder 266
for social anxiety disorder 215
for substance-related disorders 301
Mentoring 22
Messenger RNA (mRNA) 74Metabolism 112
Midbrain 67
Migrant workers 25
Mind–body interventions 132
Mini-cog 281
Mini-Mental State Examination (MMSE) 281
Minuchin, Salvador 130
Misuse (of substances) 294
Monoamine oxidase inhibitors (MAOIs) 69, 
113, 116, 152, 155, 156
hypertensive crisis from 157
side effects of 158
Montreal Cognitive Assessment (MoCA) 281
Mood  328
depression and 146
stabilizers 115

Mood  328
Morphogenesis 130
Morphostasis 130
Motivational interviewing 46
Motor functions 82
Musculoskeletal system 86
N
Neck  84
Negotiation 52
Nervous system
central 64
components of 64
function of 63
peripheral 64
Neuroadaptation 295
Neuroanatomy 64–68
Neurobiological theory 198–199
of schizophrenia 235
Neurocognitive disorders 271–292
cognitive disorders 271
delirium 271–277
dementia 277–285
traumatic brain injuries and 285–290
Neuroimaging 72–74
Neuroleptic malignant syndrome (NMS) 253
Neurological
examinations 80–86
soft signs 82–83
Neurons 63–64, 68
Neuropeptides 70, 70–71
Neurophysiology 68–70

429
INDEX
Neurotransmitters 113
abnormalities of 143
categories of 68–70
classification requirements for 69
function of 68, 71–72
recovery and degradation of 70
Nonpharmacological management
of agoraphobia  211
of anxiety disorders 205
of generalized anxiety disorder 217
of obsessive–compulsive disorder 221
of panic disorder 209–210
of personality disorders 322
of posttraumatic stress disorder 225
of social anxiety disorder 215
of specific phobias 214
Nonpharmacological treatment
complementary and alternative therapies 
as 132–135
family therapy as 129–132
group therapy as 127–129
individual therapy as 125–127
issues related to 125
Nonrapid eye movement stages (NREM) 361
Norepinephrine
Norepinephrine dopamine reuptake inhibitors 
(NDRIs) 154
Nose 84
Nurse practitioners. See also  Psychiatric–
mental health nurse practitioners 
(PMHNPs)
admissions criteria and 21
client advocacy and 22

Nose 84
(PMHNPs)
commitment process and criteria and 21–22
competency issues and 21
core competencies of 11–12
disclosure issues and 19–20
ethical behavior for 18–19
growth of 14
health policy and 22–23
historical background of 13–14
leadership and 51
legal considerations for 20–21
mentoring of 22
public health principles and 103–104regulatory dimensions of 14–16
research utilization and 52–53
role responsibilities of 16–19
scholarly activities of 22
specialty competencies of 12–13
statutory dimensions of 14–16
Nursing theories 47
Nutritional disorders 150
O
Object loss theory 140
Obsessive–compulsive disorder 
(OCD) 218–221
assessment of 219–220
clinical management of 221
comorbidities of 221
description of 218
differential diagnosis of 220–221
history of 219–220
life span considerations for 221
mental status exams for 220

nonpharmacological management of 221
pharmacological management of 221
physical exams for 220
risk factors for 219
Obstructive sleep apnea (OSA) 364
Occipital lobe 66
O’Hanlon, Bill 131
Omega-3 fatty acids 134
Opioid neuropeptides 70, 72
Oppositional defiant disorder 
assessment of 330–331
clinical management of 331
demographics of 330
description of 329–330
diagnostic and laboratory findings 331
differential diagnosis of 331
etiology of 330
history of 330–331
mental status exams for 331
nonpharmacological management of 332
pharmacological management of 331–332
physical exams for 331
prevalence of 330
prevention of 330
risk factors for 330
screening for 330
Oral stage 42

430  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
Orem, Dorothy 47
Organization of practices 56
P
Panic disorder 207–210. See also  Anxiety 
disorders
assessment of 207–208
clinical management of 209
comorbidities of 210
description of 207
diagnostic and laboratory findings 208
differential diagnosis of 208–209
history of 207–208
mental status exams for 208
of 209–210
pharmacological management of 209
physical exams for 208
Parasympathetic nervous system 64
Parietal lobe 66
Partial agonist effect 113
Pathways
mesocortical 248
mesolimbic 248
nigrostriatal 249
tuberoinfundbular 249
Patient-centered care model (PCC) 56
Patient Health Questionnaire 9 (PHQ-9) 145
Pearson’s r correlation 54
Peplau, Hildegard 47
Peptides 72. See also  Opioid neuropeptides
Peripheral nervous system (PNS) 64
Persistent depressive disorder 
(Dysthymia) 166–194
assessment of 167–168
clinical management of 168–169
comorbities of 168–169

demographics of 166–167
description of 166
diagnostic and laboratory findings for 168
differential diagnosis of 168
double depression and 168–169
etiology of 166
follow-up for 169
history of 167–168
indicence of 166–167
life span considerations for 169
and major depressive disorder 
(MDD) 168–169mental status exams for 168
nonpharmacological management of 168
personality disorders and 169
pharmacological management of 168
physical exams for 168
polysomnographic findings for 168
prevention of 167
risk factors for 167
screening for 167
symptoms of 167–168
Personality 313–314
Personality disorders 314–323. See 
also Cluster A, B, and C personality 
disorders
assessment of 317–320
categories of 315
client history and 317
clinical management of 321
demographics of 316
description of 314
diagnostic and laboratory findings 320

disorders
differential diagnosis of 321
etiology of 314–316
follow-up for 323
history of 317
incidence of 316
life span considerations for 323
nonpharmacological management of 322
pharmacological management of 322
physical exams for 319–320
prevention of 316–317
risk factors for 316
screening for 316–317
Person-centered therapy. See Humanistic 
therapy
Phallic stage 42
Pharmacodynamics 111, 113
agonist effect 113
antagonist effect 113
excitatory response 113
inhibitory response 113
inverse agonist effect 113
monoamine oxidase inhibitors (MAOIs) 113
neurotransmitters and 113
partial agonist effect 113
(SSRIs) 113
target sites and 113
Pharmacogenomics 75

431
INDEX
Pharmacokinetics 111–113
absorption of 111
alterations in 112–113
distribution of 111
elements of 111–113
elimination and 112
explanation of 111
half-life of medications 112
steady state 112
Pharmacological management
concepts in 111–114
of anxiety disorders 203–205, 205
of panic disorder 209
of posttraumatic stress disorder 224–225
psychiatric–mental health nurse practitio -
ners (PMHNPs) role in 114–120
Pharmacology 111. See 
also Psychopharmacology
considerations related to 118–119
Phenotype 74
Phototherapy 162
Physical exams 79–86
(ADHD) 337
for bipolar (BP) disorder 177

(ADHD) 337
for conduct disorder 333
for delirium 273
for delusional disorder 263
for eating disorders 348–349
for intellectual disability 353–354for intimate partner violence (IPV) 375
for major depressive disorder (MDD) 147
(OCD) 220
for personality disorders 319–320
(PTSD) 223
for schizophrenia 240–241

(PTSD) 223
Piaget, Jean 43
Pick’s disease 278
PICO method 53
Polygenic single nucleotide polymorphism 
(SNP) disorder 142
Polysomnography 364
Pons (of brainstem) 67
Population genetics 75–76
Positron emission tomography (PET) 73
Posttraumatic stress disorder (PTSD) 222–225
assessment of 222–224
clinical management of 224
comorbidities of 225
description of 222
diagnostic and laboratory findings 223–224
differential diagnosis of 224
history of 222
life span considerations for 225
mental status exams for 223
nonpharmacological management of 225
pharmacological management of 224–225
physical exams for 223
risk factors for 222
Potassium 93–94
Potency 113
Premenstrual dysphoric disorder 173
description of 173

symptoms of 173
Preoperational stage 44

432 Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
Preventative factors 104
Primary prevention of mental disorders 103
Probability  54
Professional civility 52
Psychiatric
nursing 11
research in psychotropic medications 111
Psychiatric disorders 151
age of onset for 41
among incarcerated individuals 27–28
classification of 38
neurotransmitters and 70
schizophreniform 258–260
Psychiatric–mental health nurse practi -
tioners (PMHNPs). See also  Nurse 
practitioners
assessment of childhood and adolescent 
disorders 327–329
bipolar disorders treatment of and 139–194
and childhood disorders 327–360
culturally competent care and 23–24
depressive disorders treatment of 
and 139–194
foundational theories supporting role 
of 41–47
and grief and bereavement 170
health policy of 22–23
major depressive disorder (MDD) follow-up 
care practices from 164
nursing theories and 47
origins of 11
pharmacological management role 
of 114–120

of 114–120
psychopharmacology and 111–124
research utilization by 52–53
roles of 22
specialized content for 12–13
Psychiatry 19
Psychic determinism 41
Psychoanalytic
theory  41
therapy 125
Psychodynamic theories
anxiety disorders and 197–198
explanation of 41–43
of personality disorders 315–316
of substance-related disorders 294
psychotherapy 162
Psychological preventative factors 104Psychological risk factors 104
Psychopharmacology 111–124
management concepts 111–112
pharmacological considerations in 118–119
principles of 111
Psychosexual stages of development 42
Psychosis, symtoms of 234
Psychotic 233
Psychotic disorders 233–270
delusional disorder 262–265
schizoaffective disorder 260–261
schizophrenia 235–257
schizophreniform disorder 258–260
shared psychotic disorder 265–267
Psychotropic medications
older adults and 113

pregnancy and 118
risks of 118–119
weight gain and 83
Public health principles 103–104
Purging 348
p value 54
Q
Qualitative hierarchy 53
Quality improvement 55
Quality of care 56
Quantitative hierarchy 53
R
Rapid cycling 177
Rapid eye movement (REM) 361
Reflective practice 52
Reflexes 80
Reflexology 132, 135
Reminiscence therapy 129
Repolarization 68
Research
dissemination of 53–54
donabedian model 55
ethical considerations in 54–55
interpretation of 54
quality improvement 55
utilization of 52–53
Reticular formation system (of brain) 67–68
assessment of 344
clinical management of 346

433
INDEX
demographics of 344
description of 344
differential diagnosis of 346
etiology of 344
history of 345
incidence of 344
mental status exams for 345
nonpharmacological management of 346
pharmacological management of 346
physical exams for 345
prevention of 344
risk factors for 344
screening for 344
Reuptake pumps 71, 113
Reversibility 44
Right hemisphere (of brain) 65
Rights of clients 58
Risk assessment 23, 28
Risk factors 103–104
Risk management 23
Rogers, Carl 126
S
Sadness 139–140. See also  Depression
Sam-e 134
Satir, Virginia 130
Schedules for controlled substances 118
Schizoaffective disorder 260–261
assessment of 260–261
clinical management of 261
demographics of 260
description of 260
diagnostic and laboratory findings 261
etiology of 260
follow-up for 261
mental status exams for 261
nonpharmacological management of 261
pharmacological management of 261
physical exams for 261
prevalence of 260
prevention of 260
risk factors for 260
screening for 260
symptoms of 261

Schizophrenia 233, 235–257
abnormalities and 236
assertive community treatment (ACT) 
for 254–255
assessment of 238–240atypical antipsychotics for 248–249
clinical management of 243
comorbidities of 255
delusions and 238
demographics of 236–237
description of 235
diagnostic and laboratory findings 242
differential diagnosis of 242–243
dopamine pathways and 248–249
downdrift and 238
DSM-5 diagnostic criteria for 238–240
etiology of 235–236
extrapyramidal side effects (EPSE) of 249
follow-up for 257–258
genetics and 235
group therapy for 254–255
hallucinations and 239
health considerations of 255–256
history of 238–240
illness management recovery (IMR) for 255
incidence of 236–237
individual therapy for 254–255
life span considerations for 256–257
mental status exams for 241–242
milieu therapy for 255

neurobiological defect and 236
neurobiological theory of 235
neurodevelopment and 235–236
of 254–255
pharmacological management of 248–254
physical exams for 240–241
prevention of 237–238
proactice crisis management planning 
risk factors for 237
screening for 237–238
subtypes of 240
suicide and 255–256
symptom of 239
typical antipsychotics for 249–250
Schizophreniform disorder 258–260
assessment of 258–259
clinical management of 259
demographics for 258
description of 258
diagnostic and laboratory findings 259
etiology of 258
follow-up for 260

434  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
Schizophreniform disorder (continued)
history of 258–259
mental status exams for 259
nonpharmacological management of 259
pharmacological management of 259
physical exams for 259
prevention of 258
risk factors for 258
screening for 258
Scholarly activities 22
Scope of practice 16
Seasonal farm workers 25
Secondary prevention of mental disorders 103
Selective serotonin reuptake inhibitors 
(SSRIs) 113, 116, 152, 156, 203
discontinuation syndrome 165–166
Self
awareness 102
disclosure 102
efficacy and social learning theory 46–47
system 45
Seligman, Martin 141
Sensorimotor stage 44
Sensory functions 82
Separation anxiety disorder 218
Serotonin
Serotonin agonist and reuptake inhibitors 
Serotonin norepinephrine reuptake inhibitors 
(SNRIs) 152–153, 159
Serotonin syndrome 165
symptoms of 165
Sex steroid hormones 173
Sexual

Sexual
behavior 27
orientation 26–27
Sexual assault and abuse
assessment of 378
clinical management of 379
demographics of 377
description of 376–377
diagnostic and laboratory findings 379
differential diagnosis of 379
etiology 377
factors of 377incidence of 377
mental status exams for 378
of 379–380
pharmacological management of 379
physical exams for 378
prevention of 377–378
screening for 377–378
Sexually transmitted infections (STIs) 185
Shapiro, Francine 127
Shared psychotic disorder
assessment of 266
clinical management of 266
demographics of 266
description of 265
diagnostic and laboratory findings 266
etiology 266
history of 266
incidence of 266
mental status exams for 266
nonpharmacological management of 266, 
266–267
pharmacological management of 266

266–267
physical exams for 266
prevention of 266
risk factors for 266
screening for 266
Short Michigan alcoholism screening test 
(S-MAST) 297
Single nucleotide polymorphism (SNP) 
disorder 142
Single photon emission computed tomography 
(SPECT) 73
Sinuses 84
Sleep disorders 361–368
considerations of 361–362
disturbances 146
insomnia 362–367
Social anxiety disorder 214–215
assessment of 214–215
clinical management of 215
description of 214–215
history of 214–215
mental status exams for 215
nonpharmacological management of 215
pharmacological management of 215
physical exams for 215
Social preventative factors 104
Social risk factors 104

435
INDEX
Sodium 90–91
Solution-focused therapy 131–132
Somatic nervous system 64
Special populations, culturally competent care 
and. See Culturally competent care
Specific phobias 211–214
assessment of 212–213
client history and 212–213
clinical management of 213
description of 211
diagnostic and laboratory findings 213
differential diagnosis of 213
mental status exams for 213
nonpharmacological management of 214
pharmacological management of 214
physical exams for 213
risk factors for 211–212
Stages of human development (Erikson) 40
Stages of interpersonal development 
(Sullivan) 45
Standard deviation 54
Standards of practice 16
State legislative statutes 14–15
Statistics
descriptive 54
inferential 54
Statutory law  15
Steady state 112
Stem (of neuron) 64
Stevens Johnson syndrome (SJS) 83, 
184–186
clinical management of 184–185
comorbidities of 185
description of 184
follow-up for 185–186
health considerations for 185
life span considerations for 185
lithium and 186

184–186
of 184–185
symptoms of 184
Stimulants 117
St Louis University Mental Status Examination 
(SLUMS) 281
Strategic therapy 131
Structural family therapy 130
Structural imaging 72–73
Structural mapping (genogram) 130
Substance 294Substance-related disorders 293–312
abused agents list 298
assessment of 298–300
biological theories of 294–296
clinical management of 302–304
demographics of 296
description of 293–294
diagnostic and laboratory findings 302
differential diagnosis of 302
etiology of 294–296
history of 298–300
incidence of 296
intoxication 300
life span considerations for 306–307
mental status exams for 301–302
of 305–306
pharmacological management of 304–305
physical exams for 301
prevention of 297–298
psychodynamic theory of 294

of 305–306
risk factors for 296
screening for 297–298
withdrawal 300
Substance use disorders. See Substance-related 
disorders
Suicide 143, 148–149
assessing for 149, 379–381
clinical management of 162
risk factors for 163, 380–381
schizophrenia and 255–256
signs of imminent danger 380
traumatic brain injury and 287–288
Sulci 65
Sullivan, Harry Stack 45, 198
Superego 43
Sympathetic nervous system 64
Synapse 68, 70
Synaptic cleft 68, 69
T
Tachyphylaxis 114
Tardive dyskinesia (TD) 248, 252
Target sites 113
Team leadership model 51–52
Telehealth  17
Teleological theory 19
Temporal lobe 65–66
Tertiary prevention of mental disorders 103

436  Psychiatric-Mental health nurse Practitioner review and resource Manual, 4th edition
Tests
alcohol use disorders identification test 
children and adolescents under 21 years of 
clinical opiate withdrawal scale (COWS) 297
dexamethasone suppression test (DST) 143
liver function tests (LFTs) 181
short Michigan alcoholism screening test 
Thalamus  66
Theory of cultural care 47
Theory of self-care 47
Therapeutic index 114
Therapeutic nurse–client relationship 38–39, 
39
theory or interpersonal theory 47
Therapies
behavioral 126
cognitive 125–126
complementary and alternative 132–135
dialectical behavioral 126
existential 126
eye movement desensitization and reprocess -
family 129–132
group  127–129
humanistic 126–127
individual 125–127
interpersonal 127
psychoanalytic 125
reminiscence 129
Thorax 85
Thought content 328
Thought process 328
Thyroid function tests 86

Thorax 85
Thyroid-stimulating hormone 87–88
Tolerance 294
to drugs 114
Transcranial magnetic stimulation (TMS) 160
Transference 38
Transtheoretical model of change 46
Traumatic brain injury
assessment of 287
clinical management of 288
demographics of 286
description of 285
diagnostic and laboratory findings 287–288
differential diagnosis of 288etiology of 286
follow-up for 290
incidence of 286
life span considerations for 290
mental status of 287
military personnel and 286
of 288–289
pharmacological management of 288
physical findings for 287
prevention of 286
psychotherapies for 289
risk factors for 286
screening for 286
suicide and 287–288
symptoms of 287
Trichotillomania 226
Tricyclic antidepressants (TCAs) 116, 152, 
156, 204
Tryptophan  134
t test 54
V

156, 204
t test 54
V
Vagal nerve stimulation (VNS) 160
Valerian 135
Variance  54
Violence 382–384
homicide 381
intimate partner violence (IPV) 373–376
and lethality assessment 380
in school 380
sexual assault and abuse 376–379
suicide assessment 380–381
threats of 381
Virtue ethics 19
Vital signs 83
Vitamin E 134
Voluntary admission 21–22
W
Watson, Jean 47
Weight loss 146
Weissman, Myrna M. 127
White matter 64
Withdrawal 294, 300
Y
Y alom, Irvin 128
Y oga 132, 135
Y oung Mania Rating Scale (YMRS) 186

CHAPTER #
Addendum to 
Psychiatric–Mental Health Nurse Practitioner
CONTINUING EDUCATION SOURCE
NURSING CERTIFICATION REVIEW MANUAL
CLINICAL PRACTICE RESOURCE4th Edition
Nancy Magrath, PGC-N P, ANP , CNS-BC, PMHNP-BC

representing the interests of the nation’s 3.1 million registered nurses through its 
constituent/state nurses associations and its organizational affiliates. The ANA advances 
the nursing profession by fostering high standards of nursing practice, promoting the rights 
of nurses in the workplace, projecting a positive and realistic view of nursing, and lobbying 
the Congress and regulatory agencies on healthcare issues affecting nurses and the public.
ISBN
© 2019 American Nurses Association
All rights reserved.

3
TABLE OF CONTENTS
INTRODUCTION TO THE PSYCHIATRIC–MENTAL HEALTH NURSE 
PRACTITIONER REVIEW AND RESOURCE MANUAL, 4TH EDITION 
ADDENDUM
CHAPTER 2.  Psychiatric–Mental Health Nurse Practitioner Role, 
Scope of Practice, and Regulatory Process
 Culturally Competent Care and Special Populations
 References
CHAPTER 4.  Psychiatric–Mental Health Nurse Practitioner 
and Health Policy
 Health Policy Development
CHAPTER 10.  Anxiety Disorders, Obsessive–Compulsive Disorder, 
and Trauma- and Stressor-Related Disorders
 Trauma Informed Care (TIC)
CHAPTER 11.  Schizophrenia Spectrum and Other Psychotic 
Disorders
 Treatment of EPS Symptoms with Antipsychotic Use
CHAPTER 13. Substance-Related and Addictive Disorders
 Substance-Related Disorders

5
ADDENDUM
The requirements for Psychiatric–Mental Health Nurse Practitioners and the needs of patients 
are constantly evolving alongside new research, techniques, policies, and technologies. The 
American Nurses Credentialing Center and American Nurses Association both recognize the 
importance of staying abreast of these changes. This addendum is based on ANCC’s revised 
2019 test content outline to ensure that the Psychiatric–Mental Health Nurse Practitioner 
Review and Resource Manual is up to date. This additional information will assist you with 
successful completion of the certification exam and may be used as a guideline for your 
practice. While this addendum highlights these content areas, it is not meant to be all-inclusive. 
For detailed information, we encourage you to explore the topics, using the Psychiatric–Mental

For detailed information, we encourage you to explore the topics, using the Psychiatric–Mental 
Health Nurse Practitioner reference list. We hope you will find this content useful as a study 
guide and a source of information for your practice.
Questions regarding this addendum should be sent to publications@ana.org.

PSYCHIATRIC–MENTAL HEALTH NURSE 
PRACTITIONER ROLE, SCOPE OF PRACTICE, 
AND REGULATORY PROCESS
CULTURALLY COMPETENT CARE AND SPECIAL POPULATIONS 
(p. 23)
Caring for Clients in the LGBTQ Population
People with gender identity and sexual orientation outside of the perceived societal norms:
 ▶Have increased mental illness
 ▶Have high risk behaviors
 ▶Have suicide attempts
 ▶Lack of stable housing, especially with youth
 ▶Have less access to care because of provider/clinic bias
Because of the above, this population is often medically and psychiatrically underserved.
Mental Health Statistics for the LGBTQ population (NAMI, 2019):
 ▶LGBTQ adults are more than twice as likely as heterosexual adults to experience a 
mental health condition.
 ▶LGBTQ people are at a higher risk than the general population for suicidal thoughts and 
 ▶High school students who identify as lesbian, gay, or bisexual are almost five times as

▶LGBTQ people are at a higher risk than the general population for suicidal thoughts and 
 ▶High school students who identify as lesbian, gay, or bisexual are almost five times as 
likely to attempt suicide compared to their heterosexual peers.
 ▶48% of all transgender adults report that they have considered suicide in the past 
12 months, compared to 4% of the overall U.S. population.CHAPTER 2

2 Psychiatric–Mental health nurse Practitioner review and resource Manual, 4th edition
Best practices:
 ▶Use requested names and pronouns—ask patient for preferences,
 ▶Accept “parents” as outside the mother–father dyad (i.e., two mothers cannot come into 
ICU),
 ▶Be respectful, and
 ▶Ask about their lives and what is important in their care—accept the answers.
Documentation and legal issues:
 ▶Have a way to document in the MR the preferred name and gender, if it does not match 
official documentation.
 ▶Documented names and genders are only needed for legal items such as consents or 
prescriptions.
 ▶It is acceptable to use preferred name and gender in notes if there is notation of this 
elsewhere in the chart.
Unique Medical Needs of T ransgendered Clients
There is no standard stage of physical transition. It is highly variable due to time since transition, 
various ages when transition starts, ability to have surgery/hormones, and patient preference.

various ages when transition starts, ability to have surgery/hormones, and patient preference. 
It is impossible to tell by visual exam.
Document medications and hormones the patient is taking, plus a list of surgical procedures and 
an “organ list” that the patient has presented. This will inform what preventative care and routine 
screenings are needed.
Examples, trans men with breasts, female genitals and sexual organs; trans women with 
prostates, testicles.
Guidelines for medical/surgical transitioning (Wylie, et al., 2017):
 ▶The diagnosis of gender dysphoria/gender incongruence is made by a mental health 
professional prior to surgical or medical treatment by an endocrinologist.
 ▶A mental health professional needs to be involved in the diagnosis and treatment of 
gender dysphoria/gender incongruence in adolescents.

▶A mental health professional needs to be involved in the diagnosis and treatment of 
 ▶For adolescents who have entered puberty but not completed, pubertal blockers are 
prescribed.
 ▶Surgery is considered after the person has successfully made the gender change and is 
at least age 16.
 ▶Mental health care is recommended due to the risk of side effects from the medications 
used and the stresses of transitioning.
Gender-Affirming Medical T reatment—Hormone Therapy  
(Lexicomp, 2019)
Testosterone (“T”) Used as monotherapy—FDA off label use
	ZProvided as IM<SubQ, and topical formulations;

3 Psychiatric–Mental health nurse Practitioner role, scoPe of Practice, and regulatory Process
	ZRisk of cardiovascular events, hyperlidemia, increased blood pressure when 
using testosterone—increased monitoring required;
	ZRisk of increased depression and/or suicidal ideation; and
	ZCan interact with oral hypoglycemic agents with increased lowering of blood 
sugar.
Leuprolide (Lupron)
	ZHormonal suppression for male to female transgender in combination with 
estrogen—off label use;
	ZGiven as a depot shot, 1-month and 3-month formulations;
	ZIncreased risk of hyperglycemia and cardiac events when used with trans 
women; and
	ZPossible psychiatric side effects—emotional lability, irritability, anger, and/or 
aggression.
Estrogen
	ZUsed to reduce the male secondary sexual characteristics
	ZFormulations transdermal or oral
	ZConcern with prolonged use—breast cancer and decrease in bone density
Spironolactone

Estrogen
	ZA potassium-sparing diuretic; is also a mineralocorticoid receptor antagonist;
	ZGiven orally;
	ZCommonly used in the United States as aldosterone blocker in combination 
with estrogen due to higher cost and IM dosing of Lupron; and
	ZPotassium levels need to be monitored.
REFERENCES
Institute of Medicine, Board on the Health of Special Populations. (2011). The Health of Lesbian, 
Gay, Bisexual, and Transgender People: Building a Foundation for Better Understanding. 
Washington DC: National Academies Press. Retrieved from http://www.nationalacademies.
org/HMD/Reports/2011/The-Health-of-Lesbian-Gay-Bisexual-and-Transgender-People.aspx  on 
Aug 13, 2019.
King, M. et al. (2008). A systematic review of mental disorder, suicide, and deliberate self-harm

King, M. et al. (2008). A systematic review of mental disorder, suicide, and deliberate self-harm 
in lesbian, gay and bisexual people. BMC Psychiatry:70 . Downloaded from: https://
bmcpsychiatry.biomedcentral.com/articles/10.1186/1471-244X-8-70  on August 13, 2019.
Kruks, G. (2010). Gay and lesbian homeless/street youth: Special issues and concerns. J Adolesc 
Health. 2010;12(7): 515–8.
National Alliance on Mental Illness [Internet]. (2019). LGBTQ (Internet) https://www.nami.org/
Find-Support/LGBTQ  Retrieved on Aug 10, 2019.
New York City Health and Hospitals. (2011). To Treat Me You Have To Know Who I Am. [Training 
video]. Retrieved from https://www.youtube.com/watch?v=NUhvJgxgAac  on Sept 6, 2019.

4 Psychiatric–Mental health nurse Practitioner review and resource Manual, 4th edition
US Department of Health and Human Services [Internet]. (2019). Healthy People 2020: Lesbian, 
Gay, Bisexual and Transgender Health. Available from: https://www.healthypeople.gov/2020/
topics-objectives/topic/lesbian-gay-bisexual-and-transgender-health . Retrieved on Aug 1, 
2019.
Ward, B.W., Dahlhamer, J.M., Galinsky, A.M., Joesti, S.S. [PDF]. (2014). Sexual orientation and 
health among U.S. adults: National Health Interview Survey, 2013. Hyattsville (MD): National 
Center for Health Statistics; 2014 [cited 2018 Apr 12]. 12 p. Available from: https://www.cdc.
gov/nchs/data/nhsr/nhsr077 .pdf
Wylie, C., Hembree, P .T ., Cohen-Kettenis, L.G., Hannema, S.E., Meyer, W.J., Hassan Murad, 
M., … T’Sjoen, G.G. (2017). Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent 
Persons: An Endocrine Society Clinical Practice Guideline, The Journal of Clinical

Persons: An Endocrine Society Clinical Practice Guideline, The Journal of Clinical 
Endocrinology & Metabolism , Volume 102, Issue 11 , 1 November 2017 , Pages 3869–3903, 
https://doi.org/10.1210/jc.2017-01658

CHAPTER 4
IMPROVEMENT AND SAFETY, PRACTICE 
INQUIRY, AND HEALTH POLICY
(Current manual text in italics )
HEALTH POLICY DEVELOPMENT ( p58)
 ▶ Four components of health policy:
1. Process: formulation, implementation, and evaluation
2. Policy reform: changes in programs and practices
3. Policy environment: arena the process takes place in (government, media, public)
4. Policy makers: key players and stakeholders
 ▶ Health policies are developed through law and regulations.
 ▶ Branches of law: executive (implement law), legislative (initial formulation), and judicial 
(interpret law)
The Role of the NP in Health Policy Development
Advanced practice nurses are key stakeholders in health policy and have a professional

Advanced practice nurses are key stakeholders in health policy and have a professional 
responsibility to be involved in influencing policy as they are able. The NP has information on 
the effects of current policy from the clients and their experiences, their personal healthcare 
experiences, and their professional dealing with the healthcare system. This includes:

2 PSYCHIATRIC–MENTAL  HEALTH  NURSE  PRACTITIONER  REVIEW  AND  RESOURCE  MANUAL , 4TH EDITION
 ▶ Access to care and insurance coverage for care;
 ▶ Cost of care to the patient and to the system;
 ▶ Ability of NP to prescribe best medication for patient’s condition and have that still be 
affordable; and
 ▶ Availability of healthcare resources, especially in rural or underserved areas.
The PMHNP has three specific issues that are across the board—the cost of psychiatric 
medication under patent, the availability of providers both psychiatric and therapists, and the 
local statutes related to mental health care.
How to be involved in influencing health care policy:
 ▶ Know your local and federal statutes and policy related to:
	Z Mental health care—especially involuntary care and patient rights
	Z Medicaid coverage—state level—for individuals and services
	Z Medicare coverage—federal level—for individuals and services
This information is available online.

Z Medicaid coverage—state level—for individuals and services
 ▶ Know your state and federal representatives and senators:
	Z Their stance on issues and their legislative committee responsibilities
	Z Upcoming legislation that affects healthcare policy
 ▶ Keep in contact with your representatives, and let them know your stance and reasons 
for such. As a constituent, you have access to them through phone or email. Information 
is online. Take advantage of any ability to meet them and talk face to face—town 
meetings, constituent events. In some local areas, it is possible to go to the legislative 
offices and make appointments to meet with them.
 ▶ VOTE at every opportunity—understand the issues.
Burke, S. (2016). Influence through policy: Nurses have a unique role. In Reflections on Nursing

▶ VOTE at every opportunity—understand the issues.
Burke, S. (2016). Influence through policy: Nurses have a unique role. In Reflections on Nursing 
Leadership [Webpage] 6.2.2016. Retrieved from https://www.reflectionsonnursingleadership.
org/commentary/more-commentary/Vol42_2_nurses-have-a-unique-role  on October 5, 2019.
Institute of Medicine. (2010). The future of nursing: Leading change, advancing health 
[Consensus report]. Retrieved from http://www.nationalacademies.org/hmd/Reports/2010/
The-Future-of-Nursing-Leading-Change-Advancing-Health.aspx  on October 5, 2019.

CHAPTER 10
ANXIETY DISORDERS, OBSESSIVE–
COMPULSIVE DISORDER, AND TRAUMA- 
AND STRESSOR-RELATED DISORDERS
TRAUMA INFORMED CARE (TIC)
TIC is a concept arising in the literature after the CDC/Kaiser ACE study in 1998 (Felitti, et al., 
1998). Adverse Childhood Experience Study (1995–1997) is a joint retrospective study between 
CDC and Kaiser Permanente with over 15,000 adult subjects who were questioned about their 
childhood experiences, and this was correlated with their long-term mental, emotional, and 
physical health.
The tool was a questionnaire of 17 questions in 7 categories of adverse experience (A positive 
score was one positive answer in a category—could score from 0 to 7).
Abuse by category:
 ▶Sexual
 ▶Physical
 ▶Psychological
Household dysfunction by category:
 ▶Lived with a person who was an alcoholic or other substance user;
 ▶Lived with a person who had mental illness issues or committed suicide;

▶Psychological
 ▶Mother or stepmother was threatened by violence or experienced violence; and
 ▶Household member in prison.
Findings:
 ▶Common 52% of responders had at least one, 6.2% 4 or greater;
 ▶Correlated with 10 health risk behaviors and diagnosed illnesses; and

 ▶Strong dose–response relationship between experiences and health risk, pathology, and 
early death.
These results have been replicated in numerous studies, reviews, and meta-analyses.
What Is T rauma Informed Care?
“ A program, organization, or system that is trauma-informed realizes the widespread impact 
of trauma; and understands and experiences were identified potential paths for recovery; 
recognizes the signs and symptoms of trauma in clients, families, staff, and others involved with 
the system; and responds by fully integrating knowledge about trauma into policies, procedures, 
and practices, and seeks to actively resist re-traumatization. ” (SAMSHA, 2015)
Pathology of Chronic Stress
Chronic sustained stress in the lack of a supportive environment is toxic (Oral, 2016).
Stress response—engagement of the hypothalamus–pituitary–adrenal (HPA) axis and the

Stress response—engagement of the hypothalamus–pituitary–adrenal (HPA) axis and the 
sympathetic nervous system (SNS). Activation leads to cortisol secretion by the adrenals. 
Normally, there is a feedback loop that turns the cortisol off, but in chronic toxic stress, the 
cortisol levels remain high with too little cortisol over time as the HPA axis is dysregulated. This 
causes immune problems with increased risk of infection, chronic inflammation, decreased 
wound healing, and greater risk of autoimmune diseases.TABLE 10-1.  
ACES STUDY—QUESTIONNAIRE CATEGORIES
ADVERSE EXPERIENCE 
CATEGORIES HIGH-RISK BEHAVIORSDIAGNOSES AND 
ILLNESSES
Psychological abuse Smoking Ischemic cardiac disease
Physical abuse Severe obesity (BMI over 35) Cancer
Sexual abuse Physical inactivity Stroke
Living with drug abuse Depressed mood Chronic bronchitis
Living with mental illness Suicide attempt(s) Emphysema/COPD

Mother threatened by violence Alcoholism Diabetes
Household member in prison Drug abuse Hepatitis
Parenteral drug abuse History of skeletal fractures 
(unintentional injury)
Over 50 lifetime sexual 
partners
History of STI

3 anxiety disorders, obsessive–c oMPulsive disorder, and trauMa- and s tressor-related disorders
The T rauma Informed Care Pyramid (Raja, 2015)
“Traumatic events (including sexual abuse, domestic violence, elder abuse, and combat trauma) 
are associated with long-term physical and psychological effects. These events may influence 
patients’ health care experiences and engagement in preventative care. Although the term 
trauma-informed care (TIC) is widely used, it is not well understood how to apply this concept 
in daily health care practice. On the basis of a synthesis of a review of the literature, the TIC 
pyramid is a conceptual and operational framework that can help physicians translate TIC 
principles into interactions with patients. ”
Trauma Informed interventions can work at the three levels of preventative care:
 ▶Primary preventions : Interventions aimed at families at risk.
 ▶Secondary prevention : Interventions for children and families following an adverse event

▶Primary preventions : Interventions aimed at families at risk.
 ▶Secondary prevention : Interventions for children and families following an adverse event 
to mitigate the impact of the event and work toward prevention.
 ▶Tertiary prevention : Treat and reduce long-term consequences of ACEs.
The strength of TIC is the lens that the provider uses in assessments and interventions with 
clients.
SAMSHA gives six principles that support TIC (Harris & Fallot, 2001):
 ▶Safety : Organizations promote a sense of safety involving a conscious effort to ensure 
that all members and clients of an organization are physically and emotionally safe.
 ▶Trustworthiness and transparency : Organizations must approach decisions with 
transparency and engender trust of staff and their clientele.
 ▶Peer support : Peers, which include family of traumatized children as well as individuals 
who have lived with histories of trauma, can be critical resources for support.

▶Peer support : Peers, which include family of traumatized children as well as individuals 
 ▶Collaboration and mutuality : All members of an organization can equally contribute to the 
healing of children impacted by adverse experiences.BirthDeat h
Early 
Deat h
Disease, 
Disability,  and 
Social Problem s
Adop/g415on of Health-Risk 
Beha viors
Social, Emo/g415onal, and Cogni/g415ve  
Impairmen t
Adve rse Childhood Experiences

 ▶Empowerment, voice, and choice : Developing plans of action for clients require patient-
centered approaches that empower clients.
 ▶Cultural, historical, and gender issues : Efforts must be culturally sensitive and free of 
prejudices based on biases and stereotypes.
Trauma—informed interventions:
 ▶Cognitive Behavioral Therapy—address cognitive distortions, self-defeating behaviors;
 ▶Peer support;
 ▶Appropriate referrals for further care;
 ▶Dealing with behaviors using a trauma informed lens;
	ZThe behavior is the result of learned reactions, not bad training or habits
	ZAddress as a symptom, not as a “behavior problem”
 ▶Harm reduction approaches to high-risk behaviors.
Cohen, J.A. & Mannarino, A.P . (2015). Trauma-focused cognitive behavior therapy for traumatized 
children and families. Child Adolesc Psychiatr Clin N Am 2015;24 :557–70.

Felitti, Vincent J et al. (1998). Relationship of childhood abuse and household dysfunction to 
many of the leading causes of death in adults: The Adverse Childhood Experience (ACE) 
Study. Am J Prev Med. 14(4): 245–58 .
Harris, M. & Fallot, R.D. (2001). Envisioning a Trauma-Informed Service System: A Vital Paradigm 
Shift: New Directions for Mental Health Services . San Francisco, CA: Jossey-Bass.
Oral, R. et al. (2016). Adverse childhood experiences and trauma-informed care: The future of 
healthcare (review). Pediatric Research, 79(1): 227–233. Retrieved from https://www.nature.
com/articles/pr2015197 .pdf on August 15 2019.
Raja, S., Hasnain, M., Hoersch, M., Gove-Yin, S., Rajagopalan, C. (2015). Trauma informed care

Raja, S., Hasnain, M., Hoersch, M., Gove-Yin, S., Rajagopalan, C. (2015). Trauma informed care 
in medicine: current knowledge and future research directions. Family Community Health, 
2015 Jul–Sep;38(3 ):216–26.
Substance Abuse and Mental Health Services Administration [Web Page]. (2015). Trauma-
Informed Approach and Trauma-Specific Interventions. Retrieved from (http:// www.samhsa.
gov/nctic/trauma-interventions  on Aug 17 , 2019.
Substance Abuse and Mental Health Services Administration [Web page]. (2017). Trauma-
informed approach and trauma-specific interventions. http://www.samhsa.gov/nctic/trauma-
interventions . Retrieved July 30, 2019.

CHAPTER 11
SCHIZOPHRENIA SPECTRUM AND OTHER 
TREATMENT OF EPS SYMPTOMS WITH ANTIPSYCHOTIC USE 
(p. 252)
Since this manual was written, evidence has come forward about increased death rate with 
use of benzodiazepines in schizophrenia. Therefore, the 2019 recommendation is to use anti-
EPS meds in the following order:
1. First line—Propranolol—beta blocker
2. Second line—Benzotropine—anticholinergic
3. Third line and use with care—clonazepam.
See Table 11-7 for drug information.
Fontanella, C.A. et al. (2016). Benzodiazepine use and risk of mortality among patients with 
schizophrenia: a retrospective longitudinal study. J Clin Psychiatry. 2016;77(5) :661.
Marder, S. & Stroup, T.S. (2018). Pharmacotherapy for schizophrenia: Side effect management. 
In UpToDateTM.
Tiihonen, J., Mittendorfer-Rutz, E., Torniainen, M., Alexanderson, K., & Tanskanen, A. 
(2015). Mortality and cumulative exposure to antipsychotics, antidepressants, and

(2015). Mortality and cumulative exposure to antipsychotics, antidepressants, and 
benzodiazepines in patients with schizophrenia: An observational follow-up study. 
Am J Psychiatry. 2016;173(6): 600. Epub 2015 Dec 7.

CHAPTER 13
SUBSTANCE-RELATED AND ADDICTIVE 
DISORDERS
SUBSTANCE-RELATED DISORDERS (p. 293)
Opioid Use Disorder (OUD)
Overdoses Statistics
In 2017, among 70,237 drug overdose deaths, 47,600 (67.8%) involved opioids, with increases 
across age groups, racial/ethnic groups, county urbanization levels, and in multiple states.
From 2016 to 2017, synthetic opioid-involved overdose death rates increased by 45.2% 
(MMWR, 2018).
DSM-5 Diagnostic Criteria for OUD
A problematic pattern of opioid use leading to clinically significant impairment or distress is 
manifested by two or more of the following within a 12-month period:
 ▶ Opioids are often taken in larger amounts or over a longer period than was intended;
 ▶ A persistent desire or unsuccessful efforts to cut down or control opioid use;
 ▶ A great deal of time is spent in activities necessary to obtain the opioid, use the opioid, 
or recover from its effects;
 ▶ Craving or a strong desire or urge to use opioids;

▶ A great deal of time is spent in activities necessary to obtain the opioid, use the opioid, 
 ▶ Recurrent opioid use resulting in a failure to fulfill major role obligations at work, 
school, or home;
 ▶ Continued opioid use despite having persistent or recurrent social or interpersonal 
problems caused or exacerbated by the effects of opioids;
 ▶ Important social, occupational, or recreational activities are given up or reduced 
because of opioid use;

2 PSy CHIATRIC–MENTAL  HEALTH  NURSE  PRACTITIONER  REVIEW  AND  RESOURCE  MANUAL , 4TH EDITION
 ▶ Recurrent opioid use in situations in which it is physically hazardous;
 ▶ Continued opioid use despite knowledge of having a persistent or recurrent physical 
or psychological problem that is likely to have been caused or exacerbated by the 
substance;
 ▶ Tolerance*; and
 ▶ Withdrawal*.
*Experiencing these symptoms while taking opioids solely under appropriate medical 
supervision is an exception to (does not meet) these criteria for OUD.
Clinical Signs
Intoxication
 ▶ Altered mental status—from euphoria to lethargy to coma
 ▶ Miotic pupils (pinpoint)
 ▶ Slowed bowel sounds
 ▶ Normal to low HR and BP
 ▶ Hypoventilation/respiratory depression
The signs and symptoms of unmedicated opioid withdrawal include:
 ▶ Gastrointestinal distress—abdominal cramps, diarrhea, nausea, and/or vomiting;
 ▶ Flu-like symptoms—lacrimation, rhinorrhea, diaphoresis, shivering, and piloerection

▶ Gastrointestinal distress—abdominal cramps, diarrhea, nausea, and/or vomiting;
 ▶ Flu-like symptoms—lacrimation, rhinorrhea, diaphoresis, shivering, and piloerection 
(goosebumps);
 ▶ Sympathetic nerve and central nervous system arousal—mydriatic pupils (dilated), mild 
hypertension and tachycardia, anxiety and irritability, insomnia, agitation, restless leg 
syndrome, general restlessness, tremor, and, less frequently, low-grade temperature and 
tactile sensitivity; and
 ▶ yawning, sneezing, anorexia, dizziness, myalgias/arthralgias, and leg cramps (Farrell, 
1994).
Emergency Treatment of Overdose—Naloxone (Narcan) and Respiratory 
Support
Naloxone (Narcan) (Lexicomp, 2019)—a pure opioid antagonist that replaces opioids at the 
receptor sites:
 ▶ Available IV, IM, intranasal. Intranasal response is slower and a larger dose is required;
 ▶ Kits and cartridges are available in some states without a prescription;
 ▶ Dosing depends on clinical presentation—usually 0.4 up to 5–10 mg;

▶ Kits and cartridges are available in some states without a prescription;
 ▶ Larger doses will push person into profound withdrawal;
 ▶ Goal of naloxone is adequate ventilation, not mental status normalization; and
 ▶ Depending on the opioid half-life, the drug may outlast the Narcan; be aware of a return 
to hypoventilation.

3 SUBSTANCE-RELATED  AND  ADDICTIVE  DISORDERS
Management of Withdrawal Symptoms
Symptoms last in relation to the half-life of the ingested opiate.
Withdrawal precipitated by medication (i.e., naloxone, naltrexone) is more abrupt and severe, and 
reports of life-threatening autonomic instability and delirium have been reported in the literature.
Use of a validated tool to quantify symptoms.
COWS (Clinical Opiate Withdrawal Scale) (Wesson & Ling, 2003)
A scale of 11 items that quantifies symptoms of withdrawal:
 ▶ Resting pulse rate
 ▶ Sweating
 ▶ Restlessness
 ▶ Pupil size
 ▶ Bone or joint aches
 ▶ Runny nose or tearing
 ▶ GI upset
 ▶ Tremor
 ▶ yawning
 ▶ Anxiety, irritability
 ▶ Gooseflesh
Withdrawal may be inadvertent (given Narcan, ran out of opioid, person hospitalized with an 
undisclosed heroin habit), required by setting (i.e., incarceration), or supervised withdrawal 
(detoxification) as part of a treatment program.

Medially assisted detoxification as a bridge to medically assisted treatment is the best treatment 
for pregnant women during pregnancy, as withdrawal and use of cycles can result to preterm 
labor, fetal distress, or placental abruption. An infant born to a mother taking opioids for medical 
or illicit purposes, or who are being treated with buprenorphine or methadone, will go through 
withdrawal after birth. Neonatal abstinence syndrome is treated to reduce the withdrawal 
symptoms, and the infant is monitored and assisted through withdrawal (ACOG, 2012).
Opioid medications for treatment of withdrawal  (these medications are also used in 
supervised medication-assisted treatment (MAT) programs and require an addendum to DEA 
license to be prescribed)

The goal is to bridge the patient through withdrawal and continue the opioid treatment in a 
treatment program:
 ▶ Buprenorphine (Subutex, Suboxone (with naltrexone)) : A partial mu-opioid agonist 
and Kappa-receptor antagonist with a long half-life. Naltrexone is added to sublingual 
formulation as a deterrent to diversion and IV use; the naltrexone is not absorbed through 
the buccal membranes.
	Z Buprenorphine has the advantage that it can be prescribed and administered 
through an outpatient program.
	Z Because of the mechanism of action, the person needs to be in moderate 
withdrawal before the buprenorphine is started, to allow for a successful transition.

4 PSy CHIATRIC–MENTAL  HEALTH  NURSE  PRACTITIONER  REVIEW  AND  RESOURCE  MANUAL , 4TH EDITION
 ▶ Methadone : Long-acting full mu-receptor agonist. Lethal in overdose related to cardiac 
arrhythmia, therefore only given in supervised settings. In the United States, methadone-
supervised withdrawal to treatment must be in a designated opioid treatment program 
or in an inpatient hospital (only if the person is hospitalized for another reason than opioid 
withdrawal).
	Z The literature shows both methadone and buprenorphine are effective for 
treatment of withdrawal symptoms, and are superior to clonidine (alpha 
agonist) in keeping patients off illicit opioids. However, use of these drugs 
means that the person remains opioid dependent.
Clonidine  (alpha-2 adrenergic receptor agonist).
This medication can be used in combination with an opioid treatment, as a primary agent with 
or without other adjunct medication. It is most effective with opioid treatments; however, it is

or without other adjunct medication. It is most effective with opioid treatments; however, it is 
used where opioid treatments are undesirable (i.e., prison) or unavailable (they require a specific 
program and DEA license).
Clonidine is most effective against the autonomic symptoms of sweating, diarrhea, intestinal 
cramps, nausea, anxiety, and irritability. IT is less effective against myalgias, restlessness, 
insomnia, and craving.
Other Adjunct Medications Targeting Withdrawal Symptoms
Anxiety
Anxiety, irritability, restlessness
Diphenhydramine  50 to 100 mg orally every 4 to 6 h as needed (maximum 300 mg daily)
	Z May also treat nausea
	Z Use reduced dose in hepatic impairment
	Z IV and IM administration available
Hydroxyzine  25 to 100 mg orally every 6 to 8 h as needed (maximum 400 mg daily)
	Z May also treat lacrimation and rhinorrhea

Z IV and IM administration available
	Z Use reduced dose (50%) in renal or hepatic impairment
	Z IM administration available
Benzodiazepines
While Benzodiazepines are effective medications for anxiety, they are also controlled substances 
with a high potential for abuse and may not be allowed in some settings.
	Z Clonazepam  0.5 to 1.5 mg orally every 6 to 8 h as needed (maximum 6 mg 
daily). Use with caution and reduce dose in mild hepatic or renal impairment; 
active metabolites can accumulate
	▶ Avoid in moderate to severe hepatic impairment or hepatic 
encephalopathy.
	Z Lorazepam  1 mg orally every 4 to 6 h as needed (maximum 6 mg daily)
	▶ Relatively safe in mild to moderate hepatic impairment; use of reduced 
dose may be needed.
	▶ Avoid in severe hepatic impairment or hepatic encephalopathy

5 SUBSTANCE-RELATED  AND  ADDICTIVE  DISORDERS
	▶ IV and IM administration available; use with caution in renal impairment 
due to propylene glycol diluent. Parenteral and oral dosing the same.
	Z Alprazolam —not suggested due to short half-life and highly reinforcing nature.
Gastrointestinal Symptoms
Abdominal cramping
Dicyclomine 10 to 20 mg orally every 6 to 8 h as needed (maximum 160 mg daily)
IM administration available (lower doses are used)
Use with caution and reduce dose in renal or hepatic impairment
Diarrhea
Bismuth 524 mg orally every 30 to 60 min as needed (up to 4200 mg daily)
Monitor for dehydration and maintain fluid levels with oral and/or IV hydration
Loperamide 4 mg orally followed by 2 mg after each loose stool (maximum 16 mg daily)
Nausea/vomiting
Ondansetron 4 to 8 mg orally or IV every 12 h as needed (maximum 16 mg/day)
Dose-dependent QT interval prolongation

Use with caution and reduce dose (50%) in severe hepatic impairment
Prochlorperazine 5 to 10 mg orally three times daily before meals or every 6 h as needed 
(maximum 40 mg/day)
Use with caution in mild to moderate hepatic impairment; avoid in severe hepatic impairment
IV and rectal administration available
Promethazine 25 mg orally every 4 to 6 h as needed (maximum 50 mg/day)
Use with caution in mild to moderate hepatic impairment; avoid in severe hepatic impairment 
IM and rectal administration available
Insomnia
Trazodone 25 to 100 mg orally at bedtime; may titrate nightly up to 300 mg at bedtime if needed

Insomnia
Use with caution in severe hepatic or renal impairment
Watch with other serotonergic medications
May induce priapism in younger men
Doxepin 6 to 50 mg orally at bedtime
Use with caution and reduce dose in severe hepatic impairment

6 PSy CHIATRIC–MENTAL  HEALTH  NURSE  PRACTITIONER  REVIEW  AND  RESOURCE  MANUAL , 4TH EDITION
Mirtazapine 7.5 to 15 mg orally at bedtime
May need to use lower dose in moderate to severe hepatic or renal impairment
Quetiapine 50 to 100 mg orally at bedtime
Use lower initial dose (25 mg) in hepatic impairment and adjust based on response 
Zolpidem 5 to 10 mg orally at bedtime
 A dose of 5 mg is usually appropriate for female patients, and those with mild or moderate 
hepatic impairment 
Avoid in severe hepatic impairment or hepatic encephalopathy
A controlled substance with some addiction risk
Muscle aches, joint pain, headache
Ibuprofen 400 mg orally every 4 to 6 h as needed (maximum 2400 mg daily)
Patient should be well hydrated and without significant kidney disease
Use with caution in mild to moderate hepatic or renal impairment
Avoid all NSAIDs in severe renal or hepatic impairment or cirrhosis
May increase gastric irritation

Acetaminophen 650 to 1000 mg orally every 4 to 6 h as needed (maximum 4000 mg daily)
Appropriate analgesic for most patients
Use reduced dose (i.e., 2000 mg daily) or avoid in hepatic impairment or if malnourished
Naproxen 500 mg orally twice daily with meals
Muscle spasm, restless legs
Cyclobenzaprine 5 to 10 mg orally every 8 h as needed (maximum 30 mg daily)
Use reduced dose in mild hepatic impairment
Avoid in moderate to severe haptic impairment
Baclofen 5 to 10 mg orally every 8 h as needed (maximum 60 mg daily)
Use reduced dose in renal impairment

Diazepam 5 to 10 mg orally every 6 to 12 h as needed (maximum 40 mg daily)
Use with caution in hepatic or renal impairment

7 SUBSTANCE-RELATED  AND  ADDICTIVE  DISORDERS
IM and IV administration available—dosing less than oral
A long-acting benzodiazepine—controlled substance
Methocarbamol 750 to 1500 mg orally every 8 h as needed (maximum 6 g daily)
 IM and IV administration available (lower doses are used); avoid parenteral formulation in renal 
impairment (propylene glycol additive)
Non-Pharmacological Care Issues in Opioid Withdrawal Management
A calm quiet environment with supportive and reassuring staff can be instrumental in helping 
patients overcome most symptoms of acute opioid withdrawal and decrease the need for 
pharmacologic interventions.
Patients who have diarrhea, vomiting, or sweating should be monitored for dehydration and fluid 
levels maintained with oral and/or intravenous fluids.
Treatment of OUD and other Addictions
The most effective treatment is medically assisted treatment plus a therapeutic program.

Program alone is less likely to keep a person off illicit opioids.
Psychotherapeutic Treatments
 ▶ CBT—including psychoeducation, functional analysis of use, identifying triggers, 
enhancing overall functioning, building healthy coping skills;
 ▶ Contingency management—behavior modification through use of incentives (and less often 
punishment) to assist patient in staying in treatment and progressing through program;
 ▶ 12-step facilitation—has the advantage of a group setting and social support;
 ▶ Addiction counseling; and
 ▶ Family therapy.
Motivational Interviewing
A method of assessing a person’s willingness to engage in treatment, and a tool to help the 
person to make decisions about treatment.
It is not meant to convince or coerce the person into accepting treatment—the core concept in

It is not meant to convince or coerce the person into accepting treatment—the core concept in 
MI is meeting the person where they are at.
Guiding the person to help them look toward “change thinking” can help to increase motivation 
and consider positive changes.
Relapse Prevention (Melemis, 2015)
Relapse prevention is key to staying sober and achieving recovery.
There are four key concepts:
1. Relapse is a gradual process with distinct stages; people can learn to recognize the early 
warning signs.
2. Recovery is a process of personal growth with stages that each have their own risk of relapse.

8 PSy CHIATRIC–MENTAL  HEALTH  NURSE  PRACTITIONER  REVIEW  AND  RESOURCE  MANUAL , 4TH EDITION
3. The main tools of relapse prevention are cognitive therapy and mind–body relaxation, 
which change negative thinking and develop healthy coping skills.
4. Most relapses can be explained in terms of a few basic rules. Educating clients in these 
few rules can help them focus on what is important.
These concepts can be integrated into group or individual therapy and skill building.
Dual Diagnosis
There is a strong correlation between addiction and psychiatric illness. While psychiatric 
symptoms are often obscured when a person is using, it is important to treat both psychiatric 
and addiction simultaneously to obtain the best result.
ACOG Committee on Health Care for Underserved Women; American Society of Addiction 
Medicine. (2012). ACOG Committee Opinion No. 524: Opioid abuse, dependence, 
and addiction in pregnancy. Obstet Gynecol. 2012 May;119(5) : 1070-6. doi: 10.1097/

AOG.0b013e318256496e.
American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders. 
Fifth Edition (DSM-5).  Arlington, Virginia: American Psychiatric Association.
Farrell, M. (1994). Opioid withdrawal. Addiction, 89(11) . November 1994: pp 1471–1475. 
Retrieved from https://doi.org/10.1111/j.1360-0443.1994.tb03745.x  on August 24, 2019
Food and Drug Administration [Web page] (2019). FDA Safety Announcement: FDA identifies 
harm reported from sudden discontinuation of opioid pain medicines and requires label 
changes to guide prescribers on gradual, individualized tapering. On Sept 1, 2019, retrieved 
from https://www.fda.gov/drugs/drug-safety-and-availability/fda-identifies-harm-reported-
sudden-discontinuation-opioid-pain-medicines-and-requires-label-change

Galanter, M. (1993). Network Therapy for Alcohol and Drug Abuse , New york: Basic Books.
Hanna, J. & Swetter, S. (2017). A Case of Delirium and Rhabdomyolysis in Severe Iatrogenic 
Opioid Withdrawal. Psychosomatics. 2018;59(4) :405. Epub 2017 Dec 14.
Ling, W., Amass, L., Shoptaw, S., Annon, J.J., Hillhouse, M., Babcock D.,…, Ziedonis, D. 
Buprenorphine Study Protocol Group. (2005). A multi-center randomized trial of 
buprenorphine-naloxone versus clonidine for opioid detoxification: findings from the National 
Institute on Drug Abuse Clinical Trials Network.  Addiction. 2005 Aug;100(8): 1090–1100.
Melemis, S.M. (2015). Relapse prevention and the five rules of recovery.  The yale Journal of 
Biology and Medicine, 88(3),  325–332.
Prendergast, M., Podus, D., Finney, J., et al. Contingency management for treatment of

Prendergast, M., Podus, D., Finney, J., et al. Contingency management for treatment of 
substance use disorders: a meta-analysis. Addiction 2006; 101 :1546.
Sevarino, K.A. (2019). Up to DateTM: Medically supervised opioid withdrawal during treatment for 
addiction. Last updated Feb 13, 2019.
Scholl, L., Seth, P ., Kariisa, M., Wilson, N., Baldwin, G. (2019). Drug and Opioid-Involved Overdose 
Deaths—United States, 2013–2017. MMWR Morb Mortal Wkly Rep 2019;67 :1419–1427. DOI: 
http://dx.doi.org/10.15585/mmwr.mm675152e1
Wesson, D.R., & Ling, W. (2003). The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive 
Drugs, 35(2), 253–9.

PSYCHIATRIC-
MENTAL HEALTH  
NURSE PRACTITIONER
Nursing Certification Review Manual
Continuing Education ResourceClinical Practice Resource
Kathryn Johnson, MSN, PMHNP-BC, PMHCNS-BC
Dawn Vanderhoef, PhD, DNP, PMHNP-BC, PMHCNS-BCReview and Resource Manual
Psychiatric-Mental Health  
Nurse Practitioner  Review and Resource Manual4TH  
EDITION
PSYCHIATRIC-MENTAL HEALTH 
Review and Resource Manual, 4th Edition
Are you looking into how to advance your professional development through 
certification? Need a reliable and credible reference resource? No matter where you are in the process, make sure you have the most valuable review and resource tool at your disposal. 
The Nursing Knowledge Center’s Psychiatric-Mental Health Nurse Practitioner 
Review and Resource Manual is a must-have tool for nurses planning to take the American Nurses Credentialing Center’s (ANCC’s) Psychiatric-Mental Health  Nurse Practitioner certification exam.

Review and Resource Manual is a must-have tool for nurses planning to take the American Nurses Credentialing Center’s (ANCC’s) Psychiatric-Mental Health  Nurse Practitioner certification exam. 
Based on the official ANCC certification exam test content outline, this  
review and resource manual will help you:
n     Study and analyze comprehensive material and concepts written by  
nursing experts. 
n     Develop a recommended seven-step plan to equip you for the exam  
and map out what to do on the day of the exam. 
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standards of practice. 
n     And much more ...
Make the Psychiatric-Mental Health Nurse Practitioner Review  
and Resource Manual a key resource in your certification preparation.  
AMERICAN NURSES ASSOCIATION
8515 GEORGIA AVE., SUITE 400SILVER SPRING, MD 20910-34921.800.284.2378   |   301.628.5000
©2016 American Nurses Association. All rights reserved.

Nursing Knowledge Center is part of the American Nurses Association.Completion of this or any other course(s)/material(s) does not imply eligibility for certification or successful performance on any certification examination, nor is 
it a requirement to qualify for certification. The American Nurses Credentialing Center (ANCC) does not endorse any products or services.www.nursingknowledgecenter.org

Bioidentical Hormone Therapy: Custom Compounded 
versus Government Approved 
 
Many types of hormone therapy are  available for you to use for your menopause symptoms. These 
include hormones that are manufactured to be chemically identic al to the naturally occurring hormones 
produced by your ovaries during the reproductive years, princip ally estradiol, progesterone, and 
testosterone. Many of these products are derived from natural s ources, including yams or soy. Although 
the term bioidentical hormones  often is used to refer to these identical copies of natural ho rmones 
(typically prescribed as custom mixes or compounds for an indiv idual woman), bioidentical hormones  is a 
term invented by marketers and has no clear scientific meaning.  
 
Although natural hormones are not necessarily safer or more eff ective than other forms of estrogen and 
progestogen, some women prefer to use hormones after menopause that are identical to those their

progestogen, some women prefer to use hormones after menopause that are identical to those their 
ovaries produced when they were younger.  
 
If you prefer to treat your bothersome menopause symptoms with hormones that are chemically identical 
to those you produced naturally before menopause, ask your heal thcare provider to prescribe estradiol 
and progesterone products that are scientifically tested and go vernment approved. Estradiol is available 
as an oral tablet, skin patch, topical gel, topical spray, and vaginal ring. Low doses of estradiol used in 
the vagina (to treat vaginal dryness and painful intercourse bu t not hot flashes) are available as a vaginal 
tablet, cream, and ring. Progesterone is available as an oral c apsule (see table below for product 
names).  
 
Bioidentical custom-compounded hormones  
Some healthcare providers prescribe custom-mixed ( custom-compounded ) bioidentical hormones

names).  
 
Some healthcare providers prescribe custom-mixed ( custom-compounded ) bioidentical hormones 
containing one or more natural hormones mixed in differing amou nts. These products not only contain 
the active hormone(s) but also other ingredients to create a cr eam, gel, lozenge, tablet, spray, or skin 
pellet. Healthcare providers who prescribe bioidentical hormone s often claim that these products are 
more safe and effective than clinically tested and government-a pproved hormones produced by large 
pharmaceutical companies. They also may assert that bioidentica l hormones slow the aging process. 
There is no scientific evidence to support any of these claims.  
 
Government-approved hormone products are required by law to com e with a package insert that 
describes possible risks and side effects. Custom-compounded ho rmones are not required to come with

describes possible risks and side effects. Custom-compounded ho rmones are not required to come with 
this information, but this does not mean they are safer. They c ontain the same active hormones (such as 
estradiol and progesterone), so they share the same risks.  
 
Custom-compounded hormones allow for individualized doses and m ixtures; however, this may result in 
reduced efficacy or greater risk. These compounds do not have g overnment approval because 
individually mixed recipes are not tested to verify that the ri ght amount of hormone is absorbed to provide 
predictable hormone levels in blood and tissue. If you have a u terus, there are no studies showing that 
the amount of progesterone in these custom-mixed hormones is en ough to protect you from developing 
uterine cancer.

There is a long history of pharmacies providing a wide range of  compounded products, typically when an 
equivalent government-approved product is not available. Becaus e preparation methods vary from one 
pharmacist to another and between pharmacies, you may receive d ifferent amounts of active medication 
every time you fill the prescription. Inactive ingredients may vary from batch to batch as well. Sterile 
production technique and freedom from undesired contaminants ar e additional concerns. Expense is 
another issue, because most custom-compounded preparations are viewed as experimental drugs and 
are not covered by insurance plans.  
Determining the right dose 
The right dose of hormones for you is the lowest dose of estrog en that treats your menopause symptoms 
combined with enough progestogen to protect your uterus from ca ncer. It is not necessary to check 
blood, urine, or saliva hormone levels to find the right dose. During reproductive life, estrogen levels vary

blood, urine, or saliva hormone levels to find the right dose. During reproductive life, estrogen levels vary 
throughout the menstrual cycle and during each day, so there is  no perfect hormone level for any 
woman.  
 
Recommendations for natural hormone therapy options  
If you prefer to use hormones for your menopause symptoms that are identical to the hormones you 
produced naturally before menopause, ask your healthcare provid er for government-approved products 
containing estradiol and progesterone. There is no benefit to u sing custom-compounded hormones, and 
there may be additional risks. 
 
 Government-Approved Natural Hormone Therapy Products 
 
Systemic doses of estradiol/progesterone for treatment of hot flashes 
 Estradiol oral tablet:  Estrace, generics 
 Estradiol skin patch: Alora, C limara, Esclim, Menostar, Vivell e (Dot), Estraderm, generics 
 Estradiol skin gel/cream: EstroGel, Elestrin, Divigel, Estraso rb 
 Estradiol skin spray: Evamist

 Estradiol skin spray: Evamist 
 Estradiol vaginal ring: Femring 
 Progesterone oral tablet: Prometrium, generics 
 Estradiol plus progesterone combined oral capsule: Bijuva 
 
Low doses of vaginal estradiol for treatment of vaginal dryness and pain with intercourse 
 Vaginal cream: Estrace vaginal cream 
 Vaginal ring: Estring 
 Vaginal tablet: Vagifem 
 Vaginal insert: Imvexxy 
This MenoNote , developed by The North Americ an Menopause Society, provides c urrent general information but not 
specific medical advice. It is not intended to substitute for t he judgment of a person’s healthcare provider. Additional 
information can be found at www.menopause.org . 
Copyright © 2020 The North American Menopause Society. All righ ts reserved. NAMS grants permission to

Copyright © 2020 The North American Menopause Society. All righ ts reserved. NAMS grants permission to 
healthcare providers to reproduce this  MenoNote  for distribution to women in their quest for good health. 
Made possible by donations to the NAMS Education and Research Fund.

62 American Family Physician www.aafp.org/afp  Volume 94, Number 1  ◆ July 1, 2016
APA Updates Guidelines on Psychiatric Evaluation  
in Adults
Coverage of guidelines 
from other organizations 
does not imply endorse -
ment by AFP or the AAFP.
This series is coordinated 
by Sumi Sexton, MD, 
Associate Deputy Editor.
A collection of Practice 
Guidelines published in 
AFP is available at http://
www.aafp.org /afp/
practguide.
CME This clinical content 
conforms to AAFP criteria 
for continuing medical 
education (CME). See 
CME Quiz Questions on 
page 18.The American Psychiatric Association (APA) 
recently released the third edition of its guide -
lines on psychiatric evaluation of adults. The 
nine-part  guideline has been updated based 
on new evidence identified since the previ -
ous edition was released in 2006. Although 
the strength of the evidence supporting the 
recommendations in the updated guidelines 
is low, there is consensus that their benefits

is low, there is consensus that their benefits 
clearly outweigh the harms. In cases where the 
balance of benefits and harms is difficult to 
judge, or the benefits or harms are unclear, the 
APA made suggestions for care instead of rec -
ommendations. For more information about 
these guidelines, including tips for implemen -
tation, see the full report from the APA.
Guideline 1: Review Symptoms, 
Trauma History, and Treatment History
The APA recommends that the initial psy -
chiatric evaluation include a review of the 
patient’s mood, anxiety level, thought con -
tent and process, perception, and cognition. 
The clinician should review the patient’s 
trauma history and his or her psychiat -
ric history, including psychiatric diagnoses, 
treatments (type, duration, and medication 
dosages), adherence and response to treat -

ments, and history of psychiatric hospitaliza -
tion and emergency department visits for psychiatric issues. The goal of this guideline 
is to improve the quality of the clinician-
patient  relationship, the accuracy of psy -
chiatric diagnoses, and the appropriateness 
of treatment selection. Knowledge of prior 
psychiatric diagnoses can inform the current 
diagnosis because a patient may be presenting 
with a continuation of a previously diagnosed 
disorder, or may now have a different disor -
der that commonly co-occurs  with the first. 
Past treatments are relevant because lack of 
effectiveness may suggest a need to reconsider 
the accuracy of the diagnosis. Symptoms that 
emerge during treatment (e.g., hypomania or 
mania in a patient with depression) may also 
require reassessment of the diagnosis.

Guideline 2: Evaluate Substance Use 
To identify patients with substance use disor -
der and to facilitate treatment planning, the 
APA recommends that clinicians assess the 
patient’s use of tobacco, alcohol, and other 
substances (e.g., marijuana, cocaine, heroin, 
hallucinogens), as well as misuse of pre -
scribed or over-the -counter medications or 
supplements. Ensuring that initial psychiatric 
evaluations include assessment of substance 
use may improve the differential diagnosis 
because substance use disorders, other psychi -
atric disorders, and other medical conditions 
may share similar presenting symptoms, such 
as anxiety, depression, mania, and psychosis.
Guideline 3: Assess Risk of Suicide
The APA recommends that clinicians evaluate 
the patient’s current suicidal ideas, plans, and

the patient’s current suicidal ideas, plans, and 
intent, including active or passive thoughts of 
suicide or death; prior suicidal ideas, plans, 
and attempts, including attempts that were 
aborted or interrupted; prior intentional self-
injury  in which there was no suicide intent; 
anxiety symptoms, including panic attacks; 
hopelessness; impulsivity; current or recent Practice Guidelines
Key Points for Practice
•  The initial psychiatric evaluation should include a review of the patient’s 
mood, anxiety level, thought content and process, perception, and 
cognition, and history of trauma and psychiatric history.
•  In the setting of current suicidal ideas, identify the intended course of 
action, access to suicide methods, motivations for suicide and reasons 
for living, quality of the therapeutic alliance, and history of suicidal

for living, quality of the therapeutic alliance, and history of suicidal 
behaviors of biologic relatives.
•  Quantitative measures of symptoms, level of functioning, and quality 
of life should be obtained to improve clinical decision making and 
treatment outcomes.
From the AFP Editors
Downloaded from the American Family Physician website at www.aafp.org/afp. Copyright © 2016 American Academy of Family Physicians. For the private, noncom -
mercial use of one individual user of the website. All other rights reserved. Contact copyrights@aafp.org for copyright questions and/or permission requests.

Practice GuidelinesJuly 1, 2016  ◆ Volume 94, Number 1  www.aafp.org/afp  American Family Physician  63substance use disorder or change in use of alcohol or 
other substances; presence of psychosocial stressors (e.g., 
financial, housing, legal, school/occupational, or inter -
personal/relationship problems; lack of social support; 
painful, disfiguring, or terminal illness); and aggressive or 
psychotic ideas, including thoughts of physical or sexual 
aggression or homicide. The clinician who conducts 
the initial psychiatric evaluation should document an 
estimation of the patient’s suicide risk, including factors 
influencing risk.
If the patient reports having current suicidal ideas, the 
APA recommends that clinicians identify the intended 
course of action if symptoms worsen; determine the 
patient’s access to suicide methods, including firearms; 
identify possible motivations for suicide (e.g., attention 
or reaction from others, revenge, shame, humiliation,

or reaction from others, revenge, shame, humiliation, 
delusional guilt, command hallucinations) and reasons 
for living (e.g., sense of responsibility to children or 
others, religious beliefs); assess the quality and strength 
of the therapeutic alliance; and ask about the history of 
suicidal behaviors in the patient’s biological relatives. If 
the patient has attempted suicide in the past, the clini -
cian should ask about details of each attempt (e.g., con -
text, method, damage, potential lethality, intent). 
Guideline 4: Assess Risk of Aggressive Behaviors
To identify patients at risk of aggressive behaviors, the 
APA recommends that the initial psychiatric evaluation 
of a patient include assessment of current or past aggres -
sive or psychotic ideas, including thoughts of physical or 
sexual aggression or homicide; past aggressive ideas or

sexual aggression or homicide; past aggressive ideas or 
behaviors (e.g., homicide, domestic or workplace vio -
lence, other physically or sexually aggressive threats or 
acts); legal or disciplinary consequences of past aggressive 
behaviors; exposure to violence or aggressive behavior, 
including combat exposure or childhood abuse; and 
current or past neurologic or neurocognitive disorders 
or symptoms. The clinician who conducts the initial psy -
chiatric evaluation should document an estimation of the 
patient’s risk of aggressive behavior, including homicide, 
and factors influencing risk.
If the patient reports having aggressive ideas, the APA 
recommends that clinicians assess the patient’s impul -
sivity, including anger management issues; determine 
the patient’s access to firearms; identify specific persons

the patient’s access to firearms; identify specific persons 
toward whom homicidal or aggressive ideas or behaviors 
have been directed; and ask about the history of violent 
behaviors in the patient’s biological relatives.
There is no evidence that risk of aggression is increased 
by asking about past experiences, symptoms such as 
impulsivity, or current aggressive and homicidal ideas 
or plans. However, assessment could identify persons 
as being at risk when they are not, which could result in unneeded hospitalization or other consequences. 
Just as it is not possible to predict which persons will 
exhibit aggressive behaviors, there is no way to predict 
which ones would be incorrectly identified as being at 
risk, and no way to estimate the potential magnitude of 
this harm.
Guideline 5: Evaluate Cultural Factors

this harm.
To identify cultural factors that could influence the thera -
peutic alliance, promote diagnostic accuracy, and enable 
treatment planning, the APA recommends determining 
the patient’s need for an interpreter—even if the patient 
speaks the same language as the clinician—and assessing 
cultural factors related to the patient’s social environment. 
Persons from different backgrounds may have different 
explanations of illness, views of mental illness, and pref -
erences for psychiatric treatment, particularly given the 
cross-cultural  differences in the stigma of psychiatric dis -
orders. For this reason, the APA also suggests assessing the 
patient’s personal and cultural beliefs, and cultural expla -
nations of psychiatric illness. For example, an individual’s 
self concept, response to stressors, or current symptoms

self concept, response to stressors, or current symptoms 
may be shaped by racism, sexism, or discrimination; by 
traumatic experiences during or after migration from 
other countries; or by challenges of acculturation, includ -
ing intergenerational family conflict. Cultural factors can 
also influence the patient’s style of relating with authority 
figures, such as health care professionals.
Guideline 6: Assess Medical Health
The APA recommends that clinicians determine whether 
the patient has an ongoing relationship with a primary 
care health professional. Persons with psychiatric dis -
orders can have medical conditions that influence their 
functioning, quality of life, and life span. Compared with 
the general population, mortality rates are increased 
in persons with mental illness, particularly those with

in persons with mental illness, particularly those with 
psychotic disorders, depressive disorders, alcohol or sub -
stance use disorders, personality disorders, and delirium. 
To identify nonpsychiatric medical conditions that could 
affect the accuracy of a psychiatric diagnosis and the safety 
of the treatment plan, the APA recommends that the initial 
psychiatric evaluation include assessment of the patient’s 
general appearance and nutritional status; involuntary 
movements or abnormal motor tone; coordination and 
gait; speech, including fluency and articulation; sight and 
hearing; physical trauma, including head injuries; past 
or current medical illnesses and related hospitalizations; 
relevant past or current treatments, including surgeries, 
other procedures, or complementary and alternative 
treatments; allergies or drug sensitivities; sexual and

treatments; allergies or drug sensitivities; sexual and 
reproductive history; and past or current sleep abnor -
malities, including sleep apnea. It also recommends that

Practice Guidelines64 American Family Physician www.aafp.org/afp  Volume 94, Number 1  ◆ July 1, 2016clinicians document all current and recent medications  
(prescribed and nonprescribed, including herbal and 
nutritional supplements and vitamins) and adverse 
effects of these medications.
In addition, the APA suggests that the initial psychiat -
ric evaluation include assessment of the patient’s height, 
weight, and body mass index; vital signs; skin, including 
any stigmata of trauma, self-injury , or drug use; cardio -
pulmonary status; past or current endocrine disease; 
past or current infectious disease, including sexually 
transmitted diseases, human immunodeficiency virus 
infection, tuberculosis, hepatitis C, and locally endemic 
infectious diseases (e.g., Lyme disease); past or current 
neurologic or neurocognitive disorders or symptoms; 
and past or current symptoms or conditions associated 
with significant pain and discomfort. The APA also sug -

gests that clinicians review the patient’s constitutional 
symptoms (e.g., fever, weight loss), eyes, ears, nose, 
mouth, throat; and cardiovascular, respiratory, gastroin -
testinal, genitourinary, musculoskeletal, integumentary, 
neurologic, endocrine, hematologic, lymphatic, and 
allergic/immunologic symptoms.
Guideline 7: Use Quantitative Tools
To improve clinical decision making and treatment out -
comes, the APA suggests that the initial psychiatric evalu -
ation include quantitative measures of symptoms, level of 
functioning, and quality of life (e.g., rating scales, patient 
questionnaires). Clinical decision making, including diag -
nosis and treatment planning, requires a careful and sys -
tematic assessment of the type, frequency, and magnitude 
of psychiatric symptoms, as well as an assessment of the

of psychiatric symptoms, as well as an assessment of the 
effect of those symptoms on the patient’s day-to -day 
functioning and quality of life. There are several potential 
benefits to obtaining this information as part of the initial 
psychiatric evaluation through the use of quantitative 
measures. Compared with a clinical interview, these tools 
may help the clinician conduct a more consistent and comprehensive review of the patient’s symptoms, which 
may prevent potentially relevant symptoms from being 
overlooked.
Guideline 8: Involve the Patient in Decision 
Making
To improve patient engagement and knowledge about 
his or her diagnosis and treatment options, the APA rec -
ommends that during the initial psychiatric evaluation, 
the clinician should explain the differential diagnosis, 
risks of untreated illness, treatment options, and benefits

risks of untreated illness, treatment options, and benefits 
and risks of treatment. The clinician should also ask 
about the patient’s treatment preferences and collaborate 
on decisions about treatment. Such collaboration may 
improve the therapeutic alliance, satisfaction with care, 
and adherence with treatment.
Guideline 9: Document the Psychiatric Evaluation
When a patient’s care is being provided by multiple health 
care professionals using a shared treatment or treatment 
team approach, collaboration and coordination of care 
are crucial. To improve clinical decision making and 
increase coordination of psychiatric treatment with other 
clinicians, the APA recommends documenting the ratio -
nale for treatment selection, including the specific factors 
that influenced the treatment choice. It suggests that clini -

cians also document the rationale for clinical tests. 
Guideline source:  American Psychiatric Association
Evidence rating system used?  Yes
Literature search described?  Yes
Guideline developed by participants without relevant financial 
ties to industry?  Yes
Published source:  PsychiatryOnline.  November 2015.
Available at:  http://psychiatryonline.org/doi/full/10.1176/appi.
books.9780890426760.pe 02
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the Board of Trustees of Kent State University,
upon the recommendation of the Faculty, has conferred upon
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Psychiatric Mental Health Nurse Practitioner
Presented this fourteenth day of May
two thousand and twenty-two.
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 Dean, College of NursingPrinted from certified digital credential

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Nicotinic Acetylcholine Receptor Agonists for the Treatment of Alzheimer’s Dementia: An Update
Justin L Hoskin, MD,1 Yazan Al-Hasan, MD, PhD,1 and Marwan Noel Sabbagh, MD, FAAN1,2
Author information Article notes Copyright and License information PMC Disclaimer
Abstract

/content/PDF1_DB/Nicotinic Acetylcholine Receptor Agonists for the Treatment of Alzheimer’s Dementia An Update.txt

A significant portion of the clinical phenotype observed in Alzheimer’s disease (AD) occurs through nicotinic acetylcholine receptors (nAChRs). Degeneration of cholinergic neurons, combined with aberrant nAChR expression and activation partially through amyloid-beta peptide (Aβ)–nAChR leads to upregulation of pro-inflammatory pathways and subsequently the progressive cognitive decline of AD. Interestingly, the cholinergic anti-inflammatory pathway is also mediated through nAChR particularly α7 nAChR. Thus, agonists of these receptors will likely exert pro-cognitive benefits through multiple mechanisms including stimulating the cholinergic pathway, modulating inflammation, and buffering the effects of amyloid. Despite this promising theoretical use, trials thus far have been complicated by adverse effects or minimal improvement. This review will provide an update on several pharmacological nAChR agonists tested in clinical trials and reasons that further investigation of nAChR agonists

adverse effects or minimal improvement. This review will provide an update on several pharmacological nAChR agonists tested in clinical trials and reasons that further investigation of nAChR agonists is merited.

Implications
nAChRs have consistently presented a promising theoretical use in the treatment of AD; however, trials thus far have been complicated by adverse effects or minimal improvement. This review will provide an update on several pharmacological nAChR agonists trialed and reasons that further investigation of nAChR agonists is merited.

The significance of cholinergic systems cannot be overstated in understanding the pathology and progression of Alzheimer’s dementia.1 Neurons in the basal forebrain, including the neurons that form the nucleus basalis of Meynert, hippocampus, and cerebral neocortex are lost in the disease and contribute to the symptomatic development of dementia. Two of the main histopathological markers of Alzheimer disease are the accumulation of amyloid-beta peptide (Aβ) and misfolded hyperphosphorylated tau forming neurofibrillary tangles.2 Alzheimer’s disease (AD) is also accompanied by cholinergic dysfunction as evidenced by the reduction of choline acetyltransferase, vesicular acetylcholine (ACh) transporter,3,4 release of ACh, and nicotinic receptors.5 The loss of cholinergic innervation in early AD is most prominent in the cortex and hippocampus, and the mainstay of AD symptomatic control relies on acetylcholinesterase inhibitors (AChEIs; donepezil and galantamine), which exert positive

AD is most prominent in the cortex and hippocampus, and the mainstay of AD symptomatic control relies on acetylcholinesterase inhibitors (AChEIs; donepezil and galantamine), which exert positive cholinergic effects mediated by indirectly increasing activity at nicotinic acetylcholine receptors (nAChRs).6,7 The importance of the cholinergic system in progression of AD is summarized in the cholinergic hypothesis proposed by Perry et al. in 1999, which is strengthened by the phenocopying of cognitive deficits in rodent models with antagonism of acetylcholine receptors (AChRs).1,8,9 More specifically, animal lesion studies that target cholinergic input to the neocortex or hippocampus from the basal forebrain and incidental human disruptions via arterial aneurysms, arterial venous malformations, and resections can reproduce similar cognitive deficits observed in AD.10,11 Thus, the basal forebrain and rostral forebrain cholinergic pathways including projections to the thalamus are critical

and resections can reproduce similar cognitive deficits observed in AD.10,11 Thus, the basal forebrain and rostral forebrain cholinergic pathways including projections to the thalamus are critical for awareness, attention, and working memory.12,13

Degeneration of these pathways results in the development of cognitive decline.14 Accordingly, AChRs (nicotine and muscarinic) have been posited to play a central role in mediating AD pathology, which might offer potential treatment targets. They are cys-loop ligand-gated ion channels composed of five heteromeric or homomeric subunits that form an ionic pore.15,16 These channels have been implicated in the development of memory, locomotion, attention, and anxiety.4 In the mammalian brain, 11 different subunits are known to exist, alpha (α2–α7, α9, and α10) and beta (β2–β4), that pentamerize to form a multimeric ligand-gated ion channel. The α and β distinction is based on the presence of adjacent cysteine groups in the extracellular domain found only in the α subunits. The unique anatomical distribution of each nAChR subtype within the structures involved in cognition (the basal forebrain, hippocampus, and cerebral cortex) implicates receptors composed of α7, α4, and β2 subunits as

distribution of each nAChR subtype within the structures involved in cognition (the basal forebrain, hippocampus, and cerebral cortex) implicates receptors composed of α7, α4, and β2 subunits as important potential targets of pharmacological intervention (Figure 1).17–20 As discussed by Wu and Lukas21 and numerous others,22–31 the receptor subunit composition confers different functional and pharmacological properties governed by subunit composition. Despite the greater than 50 000 permutations that can be achieved with 11 subunits forming a pentameric channel, the α7 nAChR and α4β2 nAChR are predominant with differing functional properties.3,16,32 As described by Dineley et al., the α7 homomeric receptor when compared to the α4β2 nAChR has rapid activation and desensitization as well as high calcium permeability.4

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Figure 1.
Cholinergic circuitry of the nucleus basalis with relative expression of α7 and α4β2. (Based on data presented in Mesulam18 and Paterson and Nordberg.40)

The α4β2 nAChR and α7 nAChR localize presynaptically and somatodendritically on hippocampal principal glutamatergic neurons, and GABAergic interneurons that modulate principal cell activity. This modulation is thought to occur through several mechanisms, including direct large Ca2+ conductance through α7 nAChRs, by depolarization with subsequent activation of voltage-gated Ca2+ channels, and Ca2+-mediated release from intracellular stores.33 Furthermore, in vivo studies demonstrated that activation of α7 nAChRs potentiated hippocampal-prefrontal cortex synapses.34,35 Interestingly, the gene encoding the α7 subunit harbors a high degree of variability and polymorphism.36 A study conducted by Carson et al. identified a single nucleotide polymorphism affecting the α7 nAChR promoter and 5ʹUTR as protective against AD. This finding led to the conclusion that this haplotype may result in increased α7 nAChR expression with improved cholinergic neurotransmission and ultimately decreased

5ʹUTR as protective against AD. This finding led to the conclusion that this haplotype may result in increased α7 nAChR expression with improved cholinergic neurotransmission and ultimately decreased susceptibility to AD.37

The nAChRs are widely distributed throughout the central nervous system (CNS) and are expressed in both neurons and glia.38–40 Neuroinflammation mediated by the neuroimmune system, mainly microglia, is hypothesized to play a central and complex role in the progression of AD.41 On the one hand, microglia clear Aβ, likely to serve a protective role during early stages of AD.42–47 However, in aged brains and later stages of AD, microglia lose their protective ability and become overactive resulting in uncontrolled inflammation.48–51 A role of the α7 nAChR as a potent mediator of anti-inflammatory pathways was reviewed by Campbell52 and Egea et al.53 who described the engagement of the Jak2/STAT3 pathway to potentiate subsequent inhibition of nuclear factor-κB nuclear translocation and activation of the master regulator of oxidative stress, Nrf2/HO-1, following α7 nAChR activation. They concluded that α7 nAChR activation may be a potential therapeutic target for AD treatment because

of the master regulator of oxidative stress, Nrf2/HO-1, following α7 nAChR activation. They concluded that α7 nAChR activation may be a potential therapeutic target for AD treatment because oxidative stress and neuroinflammation are currently thought to be the most important pathological mechanisms in neurodegenerative diseases such as AD.

Physiology of nAChR and Aβ in AD
The discovery of a direct Aβ–nAChR interaction led to a significant expansion in the molecular understanding of their role in AD.54 This interaction has been observed in rodent experimental models, as well as postmortem AD brains.54,55 Interestingly, Aβ enriches in regions abundant in α4β2 and α7 nAChRs; this observation may provide important insight into the selectivity of hippocampal and neocortical toxicity in AD.56–58 Under normal conditions, low levels of the α7 nAChRs–Aβ complex are thought to play a physiological role by enhancing learning and memory.59,60 However, at elevated levels, the α7 nAChRs–Aβ complex leads to disruption of the cholinergic phenotype, synaptic plasticity, and ultimately cognitive dysfunction.60–62

It has been shown that nAChRs play a central role in the cholinergic anti-inflammatory pathway, demonstrated in blood-borne macrophages.63 In non-neuronal cells of the nervous system, an important observation regarding the role of nicotine-mediated anti-inflammatory effects is demonstrated by the reduction of lipopolysaccharide-induced tumor necrosis factor-α release by microglia. In these studies, activation of the α7 nAChR is thought to reduce inflammation by an increase of cyclooxygenase 2 expression and the synthesis of prostaglandin E2.32 Furthermore, blockade of ionic flux through the receptor did not alter tumor necrosis factor-α release, suggesting an alternate metabotropic mechanism. This mechanism has been shown to be crucial for neuroprotection in both in vitro and in vivo models of lipopolysaccharide-mediated neuronal death; in particular, nicotine has been demonstrated to prevent neuronal death in the substantia nigra after the injection of lipopolysaccharide.64 Nicotine

of lipopolysaccharide-mediated neuronal death; in particular, nicotine has been demonstrated to prevent neuronal death in the substantia nigra after the injection of lipopolysaccharide.64 Nicotine induces the expression of a wide plethora of genes in human microglia such as TGF-β1, IL4, CX3CL1, CCR2, CXCR6, and has potent anti-inflammatory effects by reducing tumor necrosis factor-α and interleukin-1β release.

nAChR agonists are being developed as symptomatic treatments for Alzheimer’s dementia (summarized in Table 1).

Table 1.
Summary of Investigational Drugs Targeting Nicotinic Acetylcholine Receptors (nAChRs) in AD

Compound/Clinicaltrials.gov ID	Mechanism of action	Participant’s characteristic	Status
Encenicline	Partial agonist of the α7 nAChR, with long half-life	Mild-to-moderate AD	Some improvement from baseline; suspended after phase 3 trial due to serious complications
Pozanicline (ABT-089)	Partial agonist with high affinity for α4β2, and low affinity for α6β2, not α7, and α3β4	Mild-to-moderate AD	No improvement, futility criteria met
ABT-418	Bioisostere of nicotine; agonist binding with high affinity to the α4β2, α7/5-HT3, and α2β2	Moderate AD (small sample size)	Robust improvement in verbal learning and recall
WAY-317538/SEN-12333	α7 agonist	Rodent model	Improved cognition in experimental model
RG3487	α7 agonist and 5-HT3 antagonist	Mild-to-moderate AD	Press release with cognitive improvements, drug has been discontinued, reason unknown
Nelonicline (ABT-126)	α7 allosteric modulator	Mild-to-moderate AD	No significant improvement

AZD-3480 (TC-1734, ispronicline)	α4β2 partial agonist	Mild-to-moderate AD	Similar to donepezil, development halted
Varenicline	Α4β2, α3β4, α7, 5-HT3 partial agonist	Mild-to-moderate AD	No improvement in cognition, psychiatric, and gastrointestinal side effects
Cholinergic dysfunction is a key feature in the pathology of AD. The degeneration of cholinergic neurons, a decrease in ACh-mediated signaling via reduction in choline acetyltransferase, and loss of cholinergic receptors form the cornerstone of our current understanding of AD and therapy. The role of the nAChRs has been evaluated extensively in human AD as well as numerous animal models of the disease. Here we discuss the role of nAChR in AD as well as the potential pharmacological interventions that may serve in the ameliorating and possibly reversing AD progression.

The history of AChEIs, including physostigmine,65 tacrine,66,67 tetrahydroaminoacridine,68 donepezil,69,70 metrifonate,71 and others, showed some promise in improving memory and cognitive deficits seen with AD. Xanomeline, an orthosteric muscarinic agonist, has also been investigated.72 However, there is less research available on nAChR agonists. In the past two decades, there have been nAChR agonists developed for symptomatic AD dementia, including encenicline, pozanicline, ABT-418, and WAY-317538.

The selective partial agonist of the α7 nAChR, encenicline, a member of the quinuclidines with high specificity for α7 nAChR, demonstrated procognitive effects at low nanomolar concentration in animal and human subjects. Pharmacokinetic analysis demonstrated linear kinetics with increasing doses, with a long plasma half-life of approximately 60 hours and a high volume of distribution. Thus, it can be given in once-daily dosing. Encenicline was also found to improve neuropsychological test performance in a U-shaped dose–response manner and increased relative power of α waves (8–12 Hz) on electroencephalogram, a bandwidth known to be affected in AD and mild cognitive impairment.73,74 Thus, a clear pharmacodynamic effect was demonstrated on the CNS in favor of a potential treatment of cognitive impairment. However, a phase 3 study at doses of 3 mg/day versus 2 mg/day was started in 2014 that resulted in suspension of further studies of encenicline in the fall of 2015 due to a rare but

impairment. However, a phase 3 study at doses of 3 mg/day versus 2 mg/day was started in 2014 that resulted in suspension of further studies of encenicline in the fall of 2015 due to a rare but serious gastrointestinal issue in elderly patients. No further details regarding the gastrointestinal presentation were made available.75

Pozanicline (ABT-089) is a partial agonist that binds with high affinity to the α4β2 nAChR and has partial agonism to the α6β2 subtype, but not the α7 and α3β4 subtypes. A phase 2 double-blind adaptive study evaluating safety and efficacy for pozanicline when combined with AChEIs was conducted. The study (which included randomization of 337 patients) was stopped when futility criteria were met. There were no clinically meaningful differences among the treatment groups for any of the demographics or baseline characteristics in regard to AD when administered as adjunctive therapy to AChEIs.76,77

ABT-418 acts as an agonist binding with high affinity to the α4β2, α7/5-HT3, and α2β2 receptors. It has been studied in both attention deficit hyperactivity disorder and AD. One study found that the most robust effects after ABT-418 administration were seen in verbal learning and recall. This initial study was published in 1999, and no follow-up studies regarding AD are currently available. There are mixed results regarding adverse effects, though some studies noted patients experienced nausea.78–80

WAY-317538/SEN-12333 is a potent, selective, small α7 nAChR agonist that has also been investigated for use in AD. It was shown to have excellent brain penetration and oral bioavailability with a favorable pharmacokinetic profile. Initial results in a structure–activity relationship study and biological evaluation showed procognitive efficacy in multiple behavioral cognition assays.81 Despite these initial results, there are currently no trials to further investigate this agonist as a therapeutic medication.

RG3487 is a novel α7 nAChR selective partial agonist having 5-HT3 receptor antagonist properties. Initially tested in age-impaired rats, RG3487 improved object recognition memory and reversed spatial learning deficit and impairments in executive function tasks.82,83 Initially, RG3487 was tested in cognitive symptoms of schizophrenia. When further assessed in 2014 in patients with schizophrenia, cognitive symptoms did not improve, though negative symptoms associated with schizophrenia did improve.84 In 2006, Memory Pharmaceuticals announced positive preliminary data from a phase 1 trial.85 In 2007, they announced positive phase 2a results from a proof-of-concept trial in 80 patients with AD that ran over 8 weeks. The primary endpoint of the trial looked at change from baseline in the Quality of Episodic Secondary Memory factor score of the Cognitive Drug Research battery. Results for the trial noted that subjects receiving 5 and 15 mg of RG3487 demonstrated a statistically significant

of Episodic Secondary Memory factor score of the Cognitive Drug Research battery. Results for the trial noted that subjects receiving 5 and 15 mg of RG3487 demonstrated a statistically significant effect on the Quality of Episodic Secondary Memory compared to placebo.86 In 2009 and 2010, a phase 2 dose ranging study in 389 people with mild-to-moderate AD compared 1, 5, or 15 mg/day of RG3487 to placebo. Results of this phase 2 study have not been announced to the public. Development of this drug has been discontinued.85

Nelonicline (ABT-126) is an α7 nAChR allosteric modulator developed to treat cognitive deficits in schizophrenia and AD. For AD, a phase 2 study in 2009 in 274 subjects with mild-to-moderate AD compared 5–25 mg of ABT-126 to placebo and to donepezil. Results showed good tolerability for ABT-126 with side effects similar to donepezil.87 In 2012, AbbVie started two 24-week phase 2b trials with 400 patients each, comparing doses from 25 to 75 mg. The first of the two trials compared ABT-126 combined with an AChEI to placebo. The second trial compared ABT-126 as a monotherapy to placebo. The studies found no efficacy at these higher doses was insufficient to continue further development.88,89 Each trial offered a 28-week, open-label extension to participants who completed the blinded portion of the study. These studies were terminated with formal results showing insufficient efficacy to continue development.87,90

AZD-3480 (TC-1734, ispronicline) is an α4β2 nAChR partial agonist. It showed memory-enhancing properties in rodents. Two phase 1 studies were performed evaluating pharmacokinetics, safety profile, and bioavailability. The first study was a double-blind, placebo-controlled crossover design with a rising single-dose scheme, whereas the second used a double-blind, placebo-controlled, parallel group design with a rising multiple-dose scheme.91 Adverse events were generally mild with dizziness and headache being reported most frequently.91–93 A phase 2b monotherapy trial was performed on 293 patients with mild-to-moderate AD. However, the trial failed to show superiority when compared to donepezil at 52 weeks and development as a pharmaceutical drug was halted.94

Varenicline (Chantix) is a partial α4β2 nAChR agonist that also acts on α3β4 and α7 nAChRs. It is most commonly prescribed to aid smoking cessation. It also acts as an agonist at 5-HT3 serotonin receptors, which may explain its effects on mood. In 2009 and 2010, a phase 2 trial comparing varenicline to placebo was performed.95 This 6-week trial involving 66 patients with mild-to-moderate AD measured for improvement in cognition. The results showed that varenicline did not improve cognition and patients developed worsening neuropsychiatric state and gastrointestinal side effects. Development of varenicline for AD was discontinued.96

Discussion
The nAChRs are widely dispersed throughout the CNS, making them a reasonable target when treating degenerative diseases. This is particularly true in patients with AD as targeted treatment would be both disease and target specific. AD is well documented to result from cholinergic deficit, with loss of production of ACh and loss of cholinergic neurons, specifically the α4β2 nAChR subtype. Despite this increasing understanding of the pathophysiology behind AD, there has been limited success with nAChR agonists in clinical trials as outlined earlier. Although this may create some hesitation to continue to pursue nAChR agonists as a potential treatment option, we contend that there are several reasons that this endeavor should not be abandoned.

There is evidence that the cholinergic pathway can alter the course of AD. This has been demonstrated by two decades of AChEIs use. As nAChR agonists develop, there should be further investigation exploring the synergy between AChEIs and nAChR agonists. This would need to be evaluated cautiously to avoid any potentiating side effects, particularly gastrointestinal, that can arise from increased ACh in the body.

There is a growing consensus among experts that clinical trials with AD must enroll patients during the earliest stages of disease. A central issue to date in studies evaluating nAChR agonists is that patient selection often involves subjects with moderate-to-severe disease. As advances in reliable diagnostic tools become available (biomarkers, brain imaging, and cognitive testing), patients can be treated earlier and potentially alter the course of their disease.97,98 There are many ongoing trials regarding early diagnosis including identifying mild cognitive impairment due to AD prodrome. These patients, if willing, must be identified and enrolled in these studies. Along a similar theme, as there is early loss of the α4β2 receptor subtype, there have been advances to attempt to detect early loss of these receptors. This includes single photon emission computed tomography and positron emission tomography radioligands as potential diagnostic tools and biomarkers. As this early

early loss of these receptors. This includes single photon emission computed tomography and positron emission tomography radioligands as potential diagnostic tools and biomarkers. As this early identification improves, so too may the disease-modifying potential of these medications.

Although researchers continue to develop nAChR agonists, it is possible that a more specific pharmaceutical that targets the α4β2 or α7 nAChRs would minimize non-CNS effects and have a safer side effect profile.16

Future drug development might continue to explore targeting the α7 nAChR with the aim of mitigating inflammation and amyloid toxicity due the well-described α7 nAChR–Aβ interaction as well as the modulation of inflammatory pathways.

In addition to being widely distributed throughout the peripheral nervous system and CNS, the nAChRs are also found within the immune system. The inflammatory response mediated by the immune system within the CNS leads to the classical maladaptive features of stroke, neurodegenerative disease, spinal cord injury, and autoimmune-mediated disease such as multiple sclerosis. Activation of inflammatory pathways serves many important functions in the human body such as tissue remodeling, repair, and metabolic adaptations.99 The neuroimmune system, represented by microglia, a type of macrophage that drives neuroinflammation, has a beneficial effect on scavenging cellular debris, tissue healing, and repair. However, chronic activation of microglia leads to the noxious effect on neurons and thus contributing to the pathophysiology of neurodegenerative diseases. Thus, continuing to pursue the cholinergic pathway as a potential therapeutic target in AD will likely be efficacious if implemented

contributing to the pathophysiology of neurodegenerative diseases. Thus, continuing to pursue the cholinergic pathway as a potential therapeutic target in AD will likely be efficacious if implemented during the early prodromal stage prior to symptom onset.

Funding
This work was supported by NIA P30 AG091610, the Barrow Neurological Foundation, and the Keep Memory Alive Foundation. JLH and YA-H received no funding.

Declaration of Interests
JLH and YA-H declare no conflict of interest.

Acknowledgments
Justin L. Hoskin and Yazan Al-Hasan contributed equally to the study.

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Contents
List of icons
1 acamprosate
2 agomelatine
3 alprazolam
4 amisulpride
5 amitriptyline
6 amoxapine
7 amphetamine (d)
8 amphetamine (d,l)
9 aripiprazole
10 armodafinil
1 1 asenapine
12 atomoxetine
13 benztropine
14 blonanserin
15 bremelanotide
16 brexanolone
17 brexpiprazole
18 buprenorphine
19 bupropion
20 buspirone
21 caprylidene
22 carbamazepine
23 cariprazine
24 chlordiazepoxide
25 chlorpromazine

26 citalopram
27 clomipramine
28 clonazepam
29 clonidine
30 clorazepate
31 clozapine
32 cyamemazine
33 desipramine
34 desvenlafaxine
35 deutetrabenazine
36 dextromethorphan
37 diazepam
38 diphenhydramine
39 disulfiram
40 donepezil
41 dothiepin
42 doxepin
43 duloxetine
44 escitalopram
45 esketamine
46 estazolam
47 eszopiclone
48 flibanserin
49 flumazenil
50 flunitrazepam
51 fluoxetine
52 flupenthixol
53 fluphenazine

54 flurazepam
55 fluvoxamine
56 gabapentin
57 galantamine
58 guanfacine
59 haloperidol
60 hydroxyzine
61 iloperidone
62 imipramine
63 isocarboxazid
64 ketamine
65 lamotrigine
66 lemborexant
67 levetiracetam
68 levomilnacipran
69 lisdexamfetamine
70 lithium
71 lofepramine
72 lofexidine
73 loflazepate
74 lorazepam
75 loxapine
76 lumateperone
77 lurasidone
78 maprotiline
79 memantine
80 methylfolate (l)
81 methylphenidate (d)

82 methylphenidate (d,l)
83 mianserin
84 midazolam
85 milnacipran
86 mirtazapine
87 moclobemide
88 modafinil
89 molindone
90 nalmefene
91 naltrexone
92 naltrexone/bupropion
93 nefazodone
94 nortriptyline
95 olanzapine
96 oxazepam
97 oxcarbazepine
98 paliperidone
99 paroxetine
100 perospirone
101 perphenazine
102 phenelzine
103 phentermine/topiramate
104 pimavanserin
105 pimozide
106 pipothiazine
107 pitolisant
108 prazosin
109 pregabalin

1 10 propranolol
1 1 1 protriptyline
1 12 quazepam
1 13 quetiapine
1 14 ramelteon
1 15 reboxetine
1 16 risperidone
1 17 rivastigmine
1 18 selegiline
1 19 sertindole
120 sertraline
121 sildenafil
122 sodium oxybate
123 solriamfetol
124 sulpiride
125 suvorexant
126 tasimelteon
127 temazepam
128 thioridazine
129 thiothixene
130 tiagabine
131 tianeptine
132 topiramate
133 tranylcypromine
134 trazodone
135 triazolam
136 trifluoperazine
137 trihexyphenidyl

138 triiodothyronine
139 trimipramine
140 valbenazine
141 valproate
142 varenicline
143 venlafaxine
144 vilazodone
145 vortioxetine
146 zaleplon
147 ziprasidone
148 zolpidem
149 zonisamide
150 zopiclone
151 zotepine
152 zuclopenthixol
Index by Drug Name
Index by Use
Index by Class
Abbr eviations

This Guide  is intended to complement Stahl ’s Essential
Psychopharmacology  . Stahl ’s Essential Psychopharmacology  emphasizes
mechanisms of action and how psychotropic drugs work upon receptors and
enzymes in the brain. This Guide  gives practical information on how to use
these drugs in clinical practice.
It would  be impossible to inclu de all available information about any
drug in a single work, and no attempt is made here to be comprehensive.
The purpose of this Guide  is instead to integrate the art of clinical practice
with the science of psycho-pharmacology . That means including only
essential facts in order to keep  things short. Unfortunately it also means
excluding less critical facts as well as extraneous information,  which may
nevertheless be useful to the reader but would make the book too long and
dilute the most important inform ation. In deciding what to inclu de and what
to omit, the author has drawn upon common sense and 30 years of clinical

experience with patients. He has also consulted with many experienced
clinicians and analyzed the evidence from controlled clinical trials and
regulatory filings with government agencies.
In order to meet the needs of the clinician and to facilitate  future
updates of this Guide  , the opinions of readers are sincerely solicited.
Feedback can be emailed to customerservice@neiglobal.com. Specifically ,
are the best and most essential psychotropic drugs included here? Do you
find any factual errors? Are there agreements or disagreements with any of
the opinions expressed here? Are there suggestions for any additional tips
or pearls for future editions? Any and all suggestions and comments are
welcomed.

All of the select ed drugs are presented in the same format in order to
facilitate rapid access to infor mation. Specifically , each drug is broken
down into five sections, each designated by a unique color background:
Therapeutics, Side Effects, Dosing and Use, Special Populatio ns, and The
Art of Psychopharmacology , followed by key references.
Therapeutics  covers the brand names in majo r countries; the class of
drug; what it is commonly prescribed and approved for by the United States
Food and Drug Administration (FDA); how the drug works; how long it
takes to work; what to do if it works or if it doesn ’t work; the best
augmenting combinations for partial response or treatment resistance; and
the tests (if any) that are required.
Side Effects  explains how the drug causes side effects; gives a list of
notable, life-thre atening, or dangerous side effects; gives a specific rating
for weig ht gain or sedation; and gives advice about how to handle side

effects, including best augmenting agents for side ef fects.
Dosing and Use gives the usual dosing range; dosage forms; how to
dose and dosing tips; symptoms of overdose; long-term use; if habit
forming, how to stop; pharmacokinetics; drug interactions; when not to use;
and other warnings or precautions.
Special Populations  gives specific information about any possible
renal, hepatic, and cardiac impairments, and any precautions to be taken for
treating the elderly , children, adolescents, and pregnant and breast-feeding
women.
The Art of Psychopharmacology  gives the author ’s opinions on
issues such as the potential advantages and disadvantages of any one drug,
the prim ary target symptoms, and clinical pearls to get the best out of a
drug.

In addition, drugs for which switching between medications can be
complicated have a special section called The Art of Switching, which
includes clinical pearls and graphical representations to help guide the
switching process.
There is a list of icons used in this Guide  following this Introduction
and at the back of the Guide  are several indices. The first is an index by
drug name, giving both generic names (uncapitalized) and trade names
(capitalized and followed by the generic name in parentheses). The second
is an index of common uses for the generic drugs included in the Guide  and
is organized by disorder/symptom. Agents that are approved by the FDA for
a particular use are shown in bold. The third index is organized by drug
class and lists all the agents that fall within each particular class. In addition
to these indices there is a list of abbreviations.
Readers are encouraged to consult standard references  1 and

comprehensive psychiatry and pharmacology textbooks for more in-depth
information. They are also reminded that the Art of Psychopharmacology
section is the author ’s opinion.
It is strongly advised that readers familiarize themselves with the
standard use of these drugs before attempting any of the more exotic uses
discussed, such as unusual drug combinations and doses. Reading about
both drugs before augmentin g one with the other is also strongly
recommended. Today ’s psychopharma cologist should also regularly track
blood pressure, weight, and body mass index for most of his or her patients.
The dutiful clinician will also check out the drug interactions of non-central
nervous system (CNS) drugs with those that act in the CNS, including any
prescribed by other clinicians.

Certain drugs may be for experts only, and these might include
clozapine, thior idazine, pimozi de, nefazodone, and monoam ine oxidase
(MAO) inhibitors, among other s. Off-label uses not approved by the FDA
and inadequately studied doses or combinations of drugs may also be for
the expert only, who can weigh risks and benefits in the presence of
sometimes vagu e and conflicting evidence. Pregnant or nursing women, or
people with two or more psychiatric illnesses, substance abuse, and/or a
concomitant medical illness may be suitable patients for the expert only.
Controlled substances also require expertise. Use your best judgment as to
your level of expertise and realize that we are all learning in this rapidly
advancing field.  The practice of medicine is often not so much a science as
it is an art. It is important to stay within the standards of medical care for
the field, and also within your personal comfort zone, while trying to help

extremely ill and often difficult patients with medicines that can relieve
their suf fering and sometimes transform their lives.
Finally , this book is intended to be genuinely helpful for practitioners
of psychopharm acology by providing them with the mixture of facts and
opinions selected by the author . Ultimately , prescribing choices are the
reader ’s responsibility . Every effort has been made in preparing this book to
provide accurate and up-to-date information in accord with accepted
standards and practice at the time of publication. Nevertheless, the
psychopharmacology field is evolving rapidly and the author and publisher
make no warranties that the information contained herein is totally free
from error , not least because clinical standards are constantl y changing

through research and regulation. Furthermore, the author and publisher
disclaim any responsibility for the continued currency of this information
and disclaim all liability for any and all damages, including direct or

consequential damages, resulting from the use of information contained in
this book. Doctors recommending and patients using these  drugs are
strongly advised to pay careful attention to, and consult information
provided by , the manufacturer .
1 For example, Physician ’s Desk Refer ence and Martindale: The
Complete Drug Refer ence .

agomelatine
alcohol dependence treatment
alpha adrener gic blocker
alpha 2 agonist
anticonvulsant
antiparkinson/anticholiner gic
benzodiazepine
benzodiazepine receptor antagonist
beta blocker
cholinesterase inhibitor
dopamine 2 antagonist

dopamine 2 partial agonist
dual orexin receptor antagonist
flibanserin
histaminic
lithium
medical food
melanocortin receptor agonist
l-methylfolate
modafinil (wake-promoter)
monoamine oxidase inhibitor
naltrexone/bupropion

nefazodone (serotonin antagonist/reuptake inhibitor)
neuroactive steroid
nicotinic partial agonist
N-methyl-D-aspartate antagonist
noradrener gic and specific serotoner gic antidepressant
norepinephrine and dopamine reuptake inhibitor
phentermine/topiramate
phosphodiesterase inhibitor
pimavanserin
sedative-hypnotic
selective norepinephrine reuptake inhibitor
selective serotonin reuptake inhibitor

serotonin-dopamine antagonist
serotonin and norepinephrine reuptake inhibitor
serotonin 1A partial agonist
serotonin partial agonist reuptake inhibitor
sodium oxybate
stimulant
thyroid hormone
trazodone (serotonin antagonist/reuptake inhibitor)
tricyclic/tetracyclic antidepressant
vesicular monoamine transporter 2 inhibitor
vortioxetine

How the drug works, mechanism of action
Best augmenting agents to add for partial response or treatment
resistance
Life-threatening or dangerous side ef fects
Weight Gain  : Degrees of weight gain associated with the drug, with
unusual signifying that weight gain has been reported but is not expected;
not unusual signifying that weight gain occurs in a significant minority;
common signifying that many experience weight gain and/or it can be
significant in amount; and problematic signifying that weight gain occurs
frequently , can be significant in amount, and may be a health problem in
some patients
Sedation  : Degrees of sedation associated with the drug, with unusual
signifying that sedation has been reported but is not expected; not
unusual signifying that sedation occurs in a significant minority; common
signifying that many experience sedation and/or it can be significant in
amount; and problematic signifying that sedation occurs frequently , can

be significant in amount, and may be a health problem in some patients
Tips for dosing based on the clinical expertise of the author
Drug interactions that may occur

Warnings and precautions regarding use of the drug
Dosing and other information specific to children and adolescents
Information regarding use of the drug during pregnancy
Clinical pearls of information based on the clinical expertise of the author
The art of switching
Suggested reading

Acamprosate
Therapeutics
Brands
Generic?
Not in USA
 Class
Commonly Pr escribed for
(bold for FDA appr oved)
 How the Drug W orksCampral
see index for additional brand names
Neuroscience-based Nomenclature: glutamate multimodal (Glu-
MM)
Alcohol dependence treatment
Maintenance of alcohol abstinence
Theoretically reduces excitatory glutamate neurotransmission and
increases inhibitory gamma-aminobutyric acid (GABA)
neurotransmission

How Long Until It W orks
If It W orks
If It Doesn ’t Work
 Best Augmenting Combos for Partial Response or T reatment
ResistanceBinds to and blocks certain glutamate receptors, including
metabotropic glutamate receptors
Because withdrawal of alcohol following chronic administration can
lead to excessive glutamate activity and deficient GABA activity ,
acamprosate can act as “artificial alcohol ” to mitigate these ef fects
Has demonstrated ef ficacy in trials lasting between 13 and 52 weeks
Increases abstinence from alcohol
Evaluate for and address contributing factors
Consider switching to another agent
Consider augmenting with naltrexone
Naltrexone
Augmentation therapy may be more ef fective than monotherapy
Augmentation with behavioral, educational, and/or supportive
therapy in groups or as an individual is probably key to successful
treatment

Tests
Side Effects
How Drug Causes Side Effects
Notable Side Effects
 Life-Thr eatening or Danger ous Side Effects
Weight Gain
None for healthy individuals
Theoretically , behavioral side ef fects due to changes in
neurotransmitter concentrations at receptors in parts of the brain and
body other than those that cause therapeutic actions
Gastrointestinal side ef fects may be related to lar ge doses of a drug
that is an amino acid derivative, increasing osmotic absorption in the
gastrointestinal tract
Diarrhea, nausea
Anxiety , depression
Suicidal ideation and behavior (suicidality)
Reported but not expected

Sedation
What to Do About Side Effects
Best Augmenting Agents for Side Effects
Dosing and Use
Usual Dosage Range
Dosage Forms
How to DoseReported but not expected
Wait
Adjust dose
If side ef fects persist, discontinue use
Dose reduction or switching to another agent may be more ef fective
since most side ef fects cannot be improved with an augmenting
agent
666 mg three times daily (>60 kg)
666 mg two times daily (<60 kg)
Tablet 333 mg

Dosing T ips
Overdose
Long-T erm Use
Habit FormingPatient should begin treatment as soon as possible after achieving
abstinence
Recommended dose is 666 mg three times daily; titration is not
required
Providing educational materials and counseling in combination with
acamprosate treatment can increase the chances of success
Patients should be advised to continue treatment even if relapse
occurs, and to disclose any renewed drinking
Although absorption of acamprosate is not af fected by food, it may
aid adherence if patients who regularly eat three meals per day take
each dose with a meal
Adherence with three times daily dosing can be a problem; having
patient focus on frequent oral dosing of drug rather than frequent
drinking may be helpful in some patients
Limited available data; diarrhea
Has been studied in trials up to 1 year

How to Stop
 Drug Interactions
 Other W arnings/Pr ecautions
Do Not UseNo
Taper not necessary
Terminal half-life 20 –33 hours
Excreted unchanged via the kidneys
Does not inhibit hepatic enzymes, and thus is unlikely to af fect
plasma concentrations of drugs metabolized by those enzymes
Is not hepatically metabolized and thus is unlikely to be af fected by
drugs that induce or inhibit hepatic enzymes
Concomitant administration with naltrexone may increase plasma
levels of acamprosate, but this does not appear to be clinically
significant and dose adjustment is not recommended
Monitor patients for emer gence of depressed mood or suicidal
ideation and behavior (suicidality)
Use cautiously in individuals with known psychiatric illness

Special Populations
Renal Impairment
Hepatic Impairment
Cardiac Impairment
Elderly
 Childr en and AdolescentsIf patient has severe renal impairment
If there is a proven aller gy to acamprosate
For moderate impairment, recommended dose is 333 mg three times
daily
Contraindicated in severe impairment
Dose adjustment not generally necessary
Limited data available
Some patients may tolerate lower doses better
Consider monitoring renal function
Safety and ef ficacy have not been established

Pregnancy
Breast Feeding
The Art of Psychopharmacology
Potential AdvantagesEffective June 30, 2015, the US FDA requires changes to the
content and format of pregnancy and lactation information in
prescription drug labels, including the elimination of the pregnancy
letter categories; the Pregnancy and Lactation Labeling Rule (PLLR
or final rule) applies only to prescription drugs and will be phased in
gradually for drugs approved on or after June 30, 2001
Controlled studies have not been conducted in pregnant women
In animal studies, acamprosate demonstrated teratogenicity in doses
approximately equal to the human dose (rat studies) and in doses
approximately 3 times the human dose (rabbit studies)
Pregnant women needing to stop drinking may consider behavioral
therapy before pharmacotherapy
Not generally recommended for use during pregnancy , especially
during first trimester
Unknown if acamprosate is secreted in human breast milk, but all

psychotropics are assumed to be secreted in breast milk
Recommended either to discontinue drug or bottle feed

Potential Disadvantages
Primary T arget Symptoms
 Pearls
 Suggested Reading
Anton  RF , O’Malley  SS , Ciraulo  DA , et al. Combined pharmacotherapies
and behavioral interventions for alcohol dependence: the COMBINE study:
a randomized controlled trial  . JAMA  2006  ;295 (17 ): 2003  –17.Individuals who have recently abstained from alcohol
For the chronic daily drinker
Individuals who are not abstinent at time of treatment initiation
For binge drinkers
Alcohol dependence
Because acamprosate serves as “artificial alcohol, ” it may be less
effective in situations in which the individual has not yet abstained
from alcohol or suf fers a relapse
Thus acamprosate may be a preferred treatment if the goal is
complete abstinence, but may not be preferred if the goal is reduced-
risk drinking

Kranzler  HR , Gage  A . Acamprosate ef ficacy in alcohol-dependent
patients: summary of results from three pivotal trials  . Am J Addictions
2008  ; 17 :70 –6.
Rosner  S , Leucht  P , Soyka  M . Acamprosate supports abstinence,
naltrexone prevents excessive drinking: evidence from a met-analysis with
unreported outcomes  . J Psychopharmacol  2008  ;22 :11 –23 .

Agomelatine
Brands
Generic?
No
 Class
 How the Drug W orksValdoxan
Neuroscience-based Nomenclature: melatonin multimodal (Mel-
MM)
Agonist at melatoner gic 1 and melatoner gic 2 receptors
Antagonist at 5HT2C receptors
Generalized anxiety disorder

If It W orksActions at both melatoner gic and 5HT2C receptors may be
syner gistic and increase norepinephrine and dopamine
neurotransmission in the prefrontal cortex; may resynchronize
circadian rhythms that are disturbed in depression
No influence on extracellular levels of serotonin
Daytime functioning, anhedonia, and sleep can improve from the
first week of treatment
Onset of full therapeutic actions in depression is usually not
immediate, but often delayed 2 –4 weeks
May continue to work for many years to prevent relapse of
symptoms
The goal of treatment is complete remission of current symptoms as
well as prevention of future relapses
Treatment most often reduces or even eliminates symptoms, but not
a cure since symptoms can recur after medicine is stopped
Continue treatment until all symptoms are gone (remission)
Once symptoms are gone, continue treating for 1 year for the first
episode of depression

For second and subsequent episodes of depression, treatment may
need to be indefinite

ResistanceMany patients have only a partial response where some symptoms
are improved but others persist (especially insomnia, fatigue, and
problems concentrating)
Other patients may be nonresponders, sometimes called treatment-
resistant or treatment-refractory
Consider increasing dose as early as 2 weeks after initiating
treatment if response is insuf ficient (decision on dose increase has to
be balanced with a higher risk of transaminase elevation; any dose
increase should be made on an individual patient benefit/risk basis
and with strict respect of liver function tests monitoring)
Consider switching to another agent or adding an appropriate
augmenting agent
Consider psychotherapy
Consider evaluation for another diagnosis or for a comorbid
condition (e.g., medical illness, substance abuse, etc.)
Some patients may experience apparent lack of consistent ef ficacy

due to activation of latent or underlying bipolar disorder , and require
antidepressant discontinuation and a switch to a mood stabilizer
SSRIs (excluding fluvoxamine), SNRIs, bupropion, reboxetine,
atomoxetine (use combinations of antidepressant with caution as

Tests
How Drug Causes Side Effectsthis may activate bipolar disorder and suicidal ideation)
Modafinil, especially for fatigue, sleepiness, and lack of
concentration
Mood stabilizers or atypical antipsychotics for bipolar depression,
psychotic depression, or treatment-resistant depression
Liver function tests before initiation of treatment and then at 3
weeks, 6 weeks, 12 weeks, 24 weeks, and thereafter when clinically
indicated
When increasing the dose, liver function tests should be performed
at the same frequency as when initiating treatment
Liver function tests should be repeated within 48 hours in any
patient who develops raised transaminases
Adverse reactions usually mild to moderate and occur within the
first 2 weeks of treatment
Actions at melatoner gic receptors and at 5HT2C receptors could
contibute to the side ef fects described below

✽ Rare hepatitis, hepatic failure
 Weight Gain
 Sedation (Somnolence)Nausea and dizziness are most common
Other adverse reactions are somnolence, fatigue, insomnia,
headache, anxiety , diarrhea, constipation, upper abdominal pain,
vomiting, hyperhidrosis
Increase of transaminase levels
Theoretically rare induction of mania (class warning)
Rare activation of suicidal ideation and behavior (suicidality) (short-
term studies did not show an increase in the risk of suicidality with
antidepressants compared to placebo beyond age 24) (class warning)
Occurs in significant minority
In clinical studies, weight changes were similar to those in placebo
Cases of weight decrease have been reported
Generally transient
May be more likely to cause fatigue than sedation

Dosage FormsWait
Wait
Stop if transaminase levels reach 3 times the upper limit of normal
Switch to another drug
Often best to try another antidepressant monotherapy prior to
resorting to augmentation strategies to treat side ef fects
Many side ef fects are time-dependent (i.e., they start immediately
upon dosing and upon each dose increase, but go away with time)
Many side ef fects cannot be improved with an augmenting agent
Therotically activation and agitation may represent the induction of
a bipolar state, especially a mixed dysphoric bipolar II condition
sometimes associated with suicidal ideation, and require the addition
of lithium, a mood stabilizer or an atypical antipsychotic, and/or
discontinuation of agomelatine (class warning)
25–50 mg/day at bedtime

How to Dose
 Dosing T ips
Overdose
Habit Forming
How to StopTablet 25 mg
Initial 25 mg/day at bedtime; after 2 weeks can increase to 50
mg/day at bedtime
If intolerable anxiety , insomnia, agitation, akathisia, or activation
occur upon either dosing initiation or discontinuation, consider the
possibility of activated bipolar disorder and switch to a mood
stabilizer or an atypical antipsychotic
Drowsiness and epigastralgia; fatigue, agitation, anxiety , tension,
dizziness, cyanosis, or malaise have also been reported
Treatment up to 12 months has been found to decrease rate of
relapse
No

 Other W arnings/Pr ecautionsNo need to taper dose
Half-life 1 –2 hours
Metabolized primarily by CYP450 1A2
Use of agomelatine with potent CYP450 1A2 inhibitors (e.g.,
fluvoxamine) is contraindicated
Tramadol increases the risk of seizures in patients taking an
antidepressant (class warning)
Use with caution in patients with hepatic injury risk factors, such as
obesity/overweight/non-alcoholic fatty liver disease, diabetes,
patients who drink lar ge quantities of alcohol and/or have alcohol
use disorder , or who take medication associated with risk of hepatic
injury . Doctors should ask their patients if they have ever had liver
problems
If symptoms or signs of potential liver injury (dark urine, light-
colored stools, yellow skin/eyes, pain in upper right belly , sustained
new-onset and unexplained fatigue) are present, agomelatine should
be discontinued immediately

Do Not UseUse caution in patients with pretreatment elevated transaminases (>
the upper limit of the normal range and <3 times the upper limit of
the normal range)
Discontinue treatment if serum transaminases increase to 3 times the
upper limit of normal; liver function tests should be performed
regularly until serum transaminases return to normal
Agomelatine should be administered at bedtime
Use with caution in patients with bipolar disorder unless treated
with concomitant mood-stabilizing agent
When treating children of f label (an unapproved use), carefully
weigh the risks and benefits of pharmacological treatment against
the risks and benefits of nontreatment with antidepressants and
make sure to document this in the patient ’s chart
Whenever possible, warn patients and their caregivers about the
possibility of activating side ef fects, and advise them to report such
symptoms immediately
Monitor patients for activation of suicidal ideation, especially
children and adolescents

If patient has hepatic impairment
If patient has transaminase levels >3 times the upper limit of normal
If patient is taking a potent CYP450 1A2 inhibitor (e.g.,
fluvoxamine, ciprofloxacin)

Elderly
 Childr en and AdolescentsIf patient is taking an MAO inhibitor (MAOI)
If patient has galactose intolerance, Lapp lactase deficiency , or
glucose-galactose malabsorption
If there is a proven aller gy to agomelatine
Drug should be used with caution
Contraindicated
Dose adjustment not necessary
Efficacy and safety have been established (< 75 years old)
Should not be used in patients age 75 years and older
Should not be used in elderly patients with dementia

Pregnancy
Breast FeedingCarefully weigh the risks and benefits of pharmacological treatment
against the risks and benefits of nontreatment with antidepressants
and make sure to document this in the patient ’s chart
Monitor patients face-to-face regularly , particularly during the first
several weeks of treatment
Safety and ef ficacy have not been established and it is not
recommended
Must weigh the risk of treatment (first trimester fetal development,
third trimester newborn delivery) to the child against the risk of no
treatment (recurrence of depression, maternal health, infant
bonding) to the mother and child
For many patients this may mean continuing treatment during
pregnancy
Unknown if agomelatine is secreted in human breast milk, but all

pregnancy
Therefore, breast feeding or drug needs to be discontinued

Potential Advantages
 PearlsImmediate postpartum period is a high-risk time for depression,
especially in women who have had prior depressive episodes, so
drug may need to be reinstituted late in the third trimester or shortly
after childbirth to prevent a recurrence during the postpartum period
Patients with lack of ener gy, anhedonia, anxious comorbidity , and
sleep-wake disturbances
Patients particularly concerned about sexual side ef fects or weight
gain
Patients with hepatic impairment
Depressed mood, anhedonia
Functioning
Anxiety within depression
Agomelatine represents a novel approach to depression through a
novel pharmacologic profile, agonist at melatoner gic MT1 / MT2

Suggested Reading
DeBodinat  C , Guardiola-Lemaitre  B , Mocaer  E , et al. Agomelatine, the
first melatoner gic antidepressant: discovery , characterization, and
development  . Nat Rev Drug Discov  2010  ;9 :628–42 .
Goodwin  GM , Emsley  R , Rembry  S , Rouillon  F. Agomelatine prevents
relapse in patients with major depressive disorder without evidence of areceptors and antagonist at 5HT2C receptors acting syner gistically
This syner gy provides agomelatine with a distinctive ef ficacy
profile, dif ferent from conventional antidepressants with potentially
an early and continuous improvement over time
Agomelatine improves anhedonia early in treatment
Improves anxiety in major depressive disorder
May be fewer withdrawals/discontinuations for adverse events than
with other antidepressants
No significant ef fect on cardiac parameters such as blood pressure
and heart rate
Some data suggest that agomelatine may be specially ef ficacious in
achieving functional remission

Agomelatine may improve sleep quality by promoting proper
maintenance of circadian rhythms underlying a normal sleep-wake
cycle

discontinuation syndrome: a 24-week randomized, double-blind, placebo-
controlled trial  . J Clin Psychiatry  2009  ;70 :1128 –37.
Kennedy  SH , Avedisova  A , BelaÃ¯di  C , Picarel-Blanchot  F , de Bodinat
C. Sustained ef ficacy of agomelatine 10 mg, 25 mg, and 25 –50 mg on
depressive symptoms and functional outcomes in patients with major
depressive disorder  . A placebo-controlled study over 6 months.
Neur opsychopharmacol  2016  ;26 (2 ):378–89 .
Khoo  AL , Zhou  HJ , Teng M , et al. Network meta-analysis and cost-
effectiveness analysis of new generation antidepressants  . CNS Drugs  2015
;29 (8 ):695 –712 .
Martinotti  G , Sepede  G , Gambi  F , et al. Agomelatine versus venlafaxine
XR in the treatment of anhedonia in major depressive disorder: a pilot study
. J Clin Psychopharmacol  2012  ;32 (4 ):487–91 .
Racagni  G , Riva  MA , Molteni  R , et al. Mode of action of agomelatine:
syner gy between melatoner gic and 5-HT2C receptors  . World J Biol

Psychiatry  2011 ;12 (8 ):574–87 .
Stahl  SM . Mechanism of action of agomelatine: a novel antidepressant
exploiting syner gy between monoaminer gic and melatoner gic properties  .
CNS Spectr  2014  ;19 :207–12
Stahl  SM , Fava  M , Trivedi  M , et al. Agomelatine in the treatment of
major depressive disorder . An 8 week, multicenter , randomized, placebo-
controlled trial  . J Clin Psychiatry  2010  ;71 (5 ):616–26 .

Stein  DJ , Picarel-Blanchot  F , Kennedy  SH . Efficacy of the novel
antidepressant agomelatine on anxiety symptoms in major depression  . Hum
Psychopharmacol  2013  ;28 (2 ):151–9 .
Taylor  D , Sparshatt  A , Varma  S , Olofinjana  O . Antidepressant ef ficacy of
agomelatine: meta-analysis of published and unpublished studies  . BMJ
2014  ;348 :g2496.

Alprazolam
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)XanaxXanax XR
Neuroscience-based Nomenclature: GABA positive allosteric
modulator (GABA-P AM)
Benzodiazepine (anxiolytic)
Generalized anxiety disorder (IR)
Panic disorder (IR and XR)
Other anxiety disorders
Anxiety associated with depression
Premenstrual dysphoric disorder

How the Drug W orks
If It W orksIrritable bowel syndrome and other somatic symptoms associated
with anxiety disorders
Insomnia
Acute mania (adjunctive)
Acute psychosis (adjunctive)
Catatonia
Binds to benzodiazepine receptors at the GABA-A ligand-gated
chloride channel complex
Enhances the inhibitory ef fects of GABA
Boosts chloride conductance through GABA-regulated channels
Inhibits neuronal activity presumably in amygdala-centered fear
circuits to provide therapeutic benefits in anxiety disorders
Some immediate relief with first dosing is common; can take several
weeks with daily dosing for maximal therapeutic benefit
For short-term symptoms of anxiety –after a few weeks, discontinue
use or use on an “as-needed ” basis

If It Doesn ’t WorkFor chronic anxiety disorders, the goal of treatment is complete
remission of symptoms as well as prevention of future relapses
For chronic anxiety disorders, treatment most often reduces or even
eliminates symptoms, but not a cure since symptoms can recur after
medicine stopped
For long-term symptoms of anxiety , consider switching to an SSRI
or SNRI for long-term maintenance
If long-term maintenance with a benzodiazepine is necessary ,
continue treatment for 6 months after symptoms resolve, and then
taper dose slowly
If symptoms reemer ge, consider treatment with an SSRI or SNRI, or
consider restarting the benzodiazepine; sometimes benzodiazepines
have to be used in combination with SSRIs or SNRIs for best results
Consider psychotherapy , especially cognitive behavioral
Consider presence of concomitant substance abuse
Consider presence of alprazolam abuse

Consider another diagnosis, such as a comorbid medical condition

Best Augmenting Combos for Partial Response or T reatment
Resistance
Tests
How Drug Causes Side EffectsBenzodiazepines are frequently used as augmenting agents for
antipsychotics and mood stabilizers in the treatment of psychotic
and bipolar disorders
Benzodiazepines are frequently used as augmenting agents for
SSRIs and SNRIs in the treatment of anxiety disorders
Not generally rational to combine with other benzodiazepines
Caution if using as an anxiolytic concomitantly with other sedative
hypnotics for sleep
Could consider augmenting alprazolam with either gabapentin or
pregabalin for treatment of anxiety disorders
In patients with seizure disorders, concomitant medical illness,
and/or those with multiple concomitant long-term medications,
periodic liver tests and blood counts may be prudent
Same mechanism for side ef fects as for therapeutic ef fects –namely
due to excessive actions at benzodiazepine receptors

✽ Sedation, fatigue, depression
✽ Dizziness, ataxia, slurred speech, weakness
✽ Forgetfulness, confusion
✽ Hyperexcitability , nervousness
Long-term adaptations in benzodiazepine receptors may explain the
development of dependence, tolerance, and withdrawal
Side ef fects are generally immediate, but immediate side ef fects
often disappear in time
Rare hallucinations, mania
Rare hypotension
Hypersalivation, dry mouth
Respiratory depression, especially when taken with CNS
depressants in overdose
Rare hepatic dysfunction, renal dysfunction, blood dyscrasias

Sedation
Usual Dosage RangeOccurs in significant minority
Especially at initiation of treatment or when dose increases
Tolerance often develops over time
Wait
Wait
Wait
Lower the dose
Switch to alprazolam XR
Take lar gest dose at bedtime to avoid sedative ef fects during the day
Switch to another agent
Administer flumazenil if side ef fects are severe or life-threatening
Anxiety: alprazolam IR: 1 –4 mg/day

How to Dose
 Dosing T ipsPanic: alprazolam IR: 5 –6 mg/day
Panic: alprazolam XR: 3 –6 mg/day
Alprazolam IR tablet 0.25 mg scored, 0.4 mg (Japan), 0.5 mg
scored, 0.8 mg (Japan), 1 mg scored, 2 mg multiscored
Alprazolam IR solution, concentrate 1 mg/mL
Alprazolam XR (extended-release) tablet 0.5 mg, 1 mg, 2 mg, 3 mg
For anxiety , alprazolam IR should be started at 0.75 –1.5 mg/day
divided into 3 doses; increase dose every 3 –4 days until desired
efficacy is reached; maximum dose generally 4 mg/day
For panic, alprazolam IR should be started at 1.5 mg/day divided
into 3 doses; increase 1 mg or less every 3 –4 days until desired
efficacy is reached, increasing by smaller amounts for dosage over 4
mg/day; may require as much as 10 mg/day for desired ef ficacy in
difficult cases
For panic, alprazolam XR should be started at 0.5 –1 mg/day once
daily in the morning; dose may be increased by 1 mg/day every 3 –4
days until desired ef ficacy is reached; maximum dose generally 10

mg/day

Use lowest possible ef fective dose for the shortest possible period of
time (a benzodiazepine-sparing strategy)
Assess need for continued treatment regularly
Risk of dependence may increase with dose and duration of
treatment
For interdose symptoms of anxiety , can either increase dose or
maintain same total daily dose but divide into more frequent doses,
or give as extended-release formulation
Can also use an as-needed occasional “top-up ” dose for interdose
anxiety
Because panic disorder can require doses higher than 4 mg/day , the
risk of dependence may be greater in these patients
Some severely ill patients may require 8 mg/day or more
Extended-release formulation only needs to be taken once or twice
daily
Do not break or chew XR tablets as this will alter controlled-release
properties
Frequency of dosing in practice is often greater than predicted from
half-life, as duration of biological activity is often shorter than
pharmacokinetic terminal half-life

Alprazolam and alprazolam XR generally dosed about one-tenth the
dosage of diazepam

✽ Alprazolam and alprazolam XR generally dosed about twice the
dosage of clonazepam
Overdose
How to StopFatalities have been reported both in monotherapy and in
conjunction with alcohol; sedation, confusion, poor coordination,
diminished reflexes, coma
Risk of dependence, particularly for treatment periods longer than
12 weeks and especially in patients with past or current
polysubstance abuse
Alprazolam is a Schedule IV drug
Patients may develop dependence and/or tolerance with long-term
use
Seizures may rarely occur on withdrawal, especially if withdrawal is
abrupt; greater risk for doses above 4 mg and in those with
additional risks for seizures, including those with a history of
seizures

PharmacokineticsTaper by 0.5 mg every 3 days to reduce chances of withdrawal
effects
For dif ficult-to-taper cases, consider reducing dose much more
slowly after reaching 3 mg/day , perhaps by as little as 0.25 mg per
week or less (not for XR)
For other patients with severe problems discontinuing a
benzodiazepine, dosing may need to be tapered over many months
(i.e., reduce dose by 1% every 3 days by crushing tablet and
suspending or dissolving in 100 mL of fruit juice and then disposing
of 1 mL and drinking the rest; 3 –7 days later , dispose of 2 mL, and
so on). This is both a form of very slow biological tapering and a
form of behavioral desensitization. Not for XR
Be sure to dif ferentiate reemer gence of symptoms requiring
reinstitution of treatment from withdrawal symptoms
Benzodiazepine-dependent anxiety patients and insulin-dependent
diabetics are not addicted to their medications. When
benzodiazepine-dependent patients stop their medication, disease

symptoms can reemer ge, disease symptoms can worsen (rebound),
and/or withdrawal symptoms can emer ge
Metabolized by CYP450 3A4
Inactive metabolites
Elimination half-life 12 –15 hours

Drug Interactions
 Other W arnings/Pr ecautionsFood does not af fect absorption
Increased depressive ef fects when taken with other CNS depressants
(see W arnings below)
Inhibitors of CYP450 3A, such as nefazodone, fluvoxamine,
fluoxetine, and even grapefruit juice, may decrease clearance of
alprazolam and thereby raise alprazolam plasma levels and enhance
sedative side ef fects; alprazolam dose may need to be lowered
Thus, azole antifungal agents (such as ketoconazole and
itraconazole), macrolide antibiotics, and protease inhibitors may
also raise alprazolam plasma levels
Inducers of CYP450 3A, such as carbamazepine, may increase
clearance of alprazolam and lower alprazolam plasma levels and
possibly reduce therapeutic ef fects
Boxed warning regarding the increased risk of CNS depressant
effects when benzodiazepines and opioid medications are used
together , including specifically the risk of slowed or dif ficulty
breathing and death

If alternatives to the combined use of benzodiazepines and opioids
are not available, clinicians should limit the dosage and duration of
each drug to the minimum possible while still achieving therapeutic
efficacy

Do Not UsePatients and their caregivers should be warned to seek medical
attention if unusual dizziness, lightheadedness, sedation, slowed or
difficulty breathing, or unresponsiveness occur
Dosage changes should be made in collaboration with prescriber
Use with caution in patients with pulmonary disease; rare reports of
death after initiation of benzodiazepines in patients with severe
pulmonary impairment
History of drug or alcohol abuse often creates greater risk for
dependency
Hypomania and mania have occurred in depressed patients taking
alprazolam
Use only with extreme caution if patient has obstructive sleep apnea
Some depressed patients may experience a worsening of suicidal
ideation
Some patients may exhibit abnormal thinking or behavioral changes
similar to those caused by other CNS depressants (i.e., either
depressant actions or disinhibiting actions)
If patient has angle-closure glaucoma
If patient is taking ketoconazole or itraconazole (azole antifungal
agents)

agents)
If there is a proven aller gy to alprazolam or any benzodiazepine

Elderly
 Childr en and AdolescentsDrug should be used with caution
Should begin with lower starting dose (0.5 –0.75 mg/day in 2 or 3
divided doses)
Benzodiazepines have been used to treat anxiety associated with
acute myocardial infarction
divided doses) and be monitored closely
Safety and ef ficacy not established but often used, especially short-
term and at the lower end of the dosing scale
Long-term ef fects of alprazolam in children/adolescents are
unknown
Should generally receive lower doses and be more closely
monitored

Pregnancy
✽ Recommended either to discontinue drug or bottle feedEffective June 30, 2015, the US FDA requires changes to the
Possible increased risk of birth defects when benzodiazepines are
taken during pregnancy
Because of the potential risks, alprazolam is not generally
recommended as treatment for anxiety during pregnancy , especially
Drug should be tapered if discontinued
Infants whose mothers received a benzodiazepine late in pregnancy
may experience withdrawal ef fects
Neonatal flaccidity has been reported in infants whose mothers took
a benzodiazepine during pregnancy

Seizures, even mild seizures, may cause harm to the embryo/fetus
Some drug is found in mother ’s breast milk
Effects on infant have been observed and include feeding
difficulties, sedation, and weight loss

 Pearls
✽ One of the most popular benzodiazepines for anxiety , especially
among primary care physicians and psychiatristsRapid onset of action
Less sedation than some other benzodiazepines
Availability of an XR formulation with longer duration of action
Euphoria may lead to abuse
Abuse especially risky in past or present substance abusers
Panic attacks
Anxiety
Is a very useful adjunct to SSRIs and SNRIs in the treatment of
numerous anxiety disorders
Not ef fective for treating psychosis as a monotherapy , but can be
used as an adjunct to antipsychotics

✽ Alprazolam XR may be less sedating than immediate-release
✽ Alprazolam XR may be dosed less frequently than immediate-
release alprazolam, and lead to less interdose breakthrough symptoms
and less “clock-watching ” in anxious patientsNot ef fective for treating bipolar disorder as a monotherapy , but can
be used as an adjunct to mood stabilizers and antipsychotics
May both cause depression and treat depression in dif ferent patients
Risk of seizure is greatest during the first 3 days after
discontinuation of alprazolam, especially in those with prior
seizures, head injuries, or withdrawal from drugs of abuse
Clinical duration of action may be shorter than plasma half-life,
leading to dosing more frequently than 2 –3 times daily in some
patients, especially for immediate-release alprazolam
Adding fluvoxamine, fluoxetine, or nefazodone can increase
alprazolam levels and make the patient very sleepy unless the
alprazolam dose is lowered by half or more

When using to treat insomnia, remember that insomnia may be a
symptom of some other primary disorder itself, and thus warrant
evaluation for comorbid psychiatric and/or medical conditions
Slower rises in plasma drug levels for alprazolam XR have the
potential to reduce euphoria/abuse liability , but this has not been
proven

✽ Alprozolam XR generally has longer biological duration of action
than clonazepam
✽ If clonazepam can be considered a “long-acting alprazolam-like
anxiolytic, ” then alprazolam XR can be considered “an even longer -
acting clonazepam-like anxiolytic ” with the potential of improved
tolerability features in terms of less euphoria, abuse, dependence, and
withdrawal problems, but this has not been proven
DeVane CL , Ware MR , Lydiard  RB . Pharmacokinetics,
pharmacodynamics, and treatment issues of benzodiazepines: alprazolam,
adinazolam, and clonazepam  . Psychopharmacol Bull  1991  ;27 :463–73 .
Greenblatt  DJ , Wright  CE . Clinical pharmacokinetics of alprazolam.
Therapeutic implications  . Clin Pharmacokinet  1993  ; 24 :453–71 .
Jonas  JM , Cohon  MS . A comparison of the safety and ef ficacy of
alprazolam versus other agents in the treatment of anxiety , panic, andSlower falls in plasma drug levels for alprazolam XR have the

potential to facilitate drug discontinuation by reducing withdrawal
symptoms, but this has not been proven
Though not systematically studied, benzodiazepines have been used
effectively to treat catatonia and are the initial recommended
treatment

depression: a review of the literature  . J Clin Psychiatry  1993  ;54
(Suppl):S 25 –45.
Klein  E . The role of extended-release benzodiazepines in the treatment of
anxiety: a risk-benefit evaluation with a focus on extended-release
alprazolam  . J Clin Psychiatry  2002  ;63 (Suppl 14):S 27 –33 .
Speigel  DA . Efficacy studies of alprazolam in panic disorder  .
Psychopharmacol Bull  1998  ; 34 :191–5 .
van Marwijk  H , Allick  G , Wegman  F , Bax A , Riphagen  II . Alprazolam
for depression  . Cochrane Database Syst Rev  2012  ; (7) :CD007139.

Amisulpride
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Solian
Barhemsys
Neuroscience-based Nomenclature: dopamine receptor antagonist
(D-RAn)
Atypical antipsychotic (benzamide; possibly a dopamine stabilizer
and dopamine partial agonist)
Prevention of postoperative nausea and vomiting (PONV)
(monotherapy or with antiemetic of a differ ent class)
(Barhemsys injection)

✽ May be a partial agonist at dopamine 2 receptors, which would
theoretically reduce dopamine output when dopamine concentrations
are high and increase dopamine output when dopamine concentrations
are low
✽ Unlike other atypical antipsychotics, amisulpride does not have
potent actions at serotonin 2A or serotonin 1A receptors
✽ Does have antagonist actions at serotonin 7 receptors and serotonin
2B receptors, which may contribute to antidepressant ef fects
How Long Until It W orksTreatment of PONV in patients who have r eceived antiemetic
prophylaxis with an agent of a differ ent class or have not
received pr ophylaxis (Barhemsys injection)
Schizophrenia, acute and chronic (outside of USA, especially
Europe)
Dysthymia
Theoretically blocks presynaptic dopamine 2 receptors at low doses
Theoretically blocks postsynaptic dopamine 2 receptors at higher
doses
Blocks dopamine 3 receptors, which may contribute to its clinical
actions

If It W orksPsychotic symptoms can improve within 1 week, but it may take
several weeks for full ef fect on behavior as well as on cognition and
affective stabilization
Classically recommended to wait at least 4 –6 weeks to determine
efficacy of drug, but in practice some patients require up to 16 –20
weeks to show a good response, especially on negative or cognitive
symptoms
Most often reduces positive symptoms in schizophrenia but does not
eliminate them
Can improve negative symptoms, as well as aggressive, cognitive,
and af fective symptoms in schizophrenia
Most schizophrenic patients do not have a total remission of
symptoms but rather a reduction of symptoms by about a third
Perhaps 5 –15% of schizophrenic patients can experience an overall
improvement of greater than 50 –60%, especially when receiving
stable treatment for more than a year
Such patients are considered super -responders or “awakeners ” since
they may be well enough to be employed, live independently , and

sustain long-term relationships
Continue treatment until reaching a plateau of improvement
After reaching a satisfactory plateau, continue treatment for at least
a year after first episode of psychosis

ResistanceFor second and subsequent episodes of psychosis, treatment may
Even for first episodes of psychosis, it may be preferable to continue
treatment indefinitely to avoid subsequent episodes
Try one of the other first-line atypical antipsychotics
If two or more antipsychotic monotherapies do not work, consider
clozapine
Some patients may require treatment with a conventional
antipsychotic
If no atypical antipsychotic is ef fective, consider higher doses or
augmentation with valproate or lamotrigine
Consider noncompliance and switch to another antipsychotic with
fewer side ef fects or to an antipsychotic that can be given by depot
injection
Consider initiating rehabilitation and psychotherapy such as
cognitive remediation
Consider presence of concomitant drug abuse
Valproic acid (valproate, divalproex, divalproex ER)

Tests
✽ Although risk of diabetes and dyslipidemia with amisulpride has
not been systematically studied, monitoring as for all other atypical
antipsychotics is suggested
Befor e starting an atypical antipsychotic
✽ Weigh all patients and track BMI during treatmentAugmentation of amisulpride has not been systematically studied
Other mood-stabilizing anticonvulsants (carbamazepine,
oxcarbazepine, lamotrigine)
Lithium
Get baseline personal and family history of diabetes, obesity ,
dyslipidemia, hypertension, and cardiovascular disease
Get waistline circumference (at umbilicus), blood pressure, fasting
plasma glucose, and fasting lipid profile
Determine if the patient
is overweight (BMI 25.0 –29.9)
is obese (BMI >30)
has pre-diabetes (fasting plasma glucose 100 –125 mg/dL)
has diabetes (fasting plasma glucose >126 mg/dL)

Monitoring after starting an atypical antipsychotic
✽ BMI monthly for 3 months, then quarterly
✽ Even in patients without known diabetes, be vigilant for the rare but
life-threatening onset of diabetic ketoacidosis, which always requires
immediate treatment by monitoring for the rapid onset of polyuria,
polydipsia, weight loss, nausea, vomiting, dehydration, rapid
respiration, weakness and clouding of sensorium, even comahas hypertension (BP >140/90 mmHg)
has dyslipidemia (increased total cholesterol, LDL cholesterol,
and triglycerides; decreased HDL cholesterol)
Treat or refer such patients for treatment, including nutrition and
weight management, physical activity counseling, smoking
cessation, and medical management
Consider monitoring fasting triglycerides monthly for several
months in patients at high risk for metabolic complications and
when initiating or switching antipsychotics
Blood pressure, fasting plasma glucose, fasting lipids within 3

months and then annually , but earlier and more frequently for
patients with diabetes or who have gained >5% initial weight
Treat or refer for treatment and consider switching to another
atypical antipsychotic for patients who become overweight, obese,
pre-diabetic, diabetic, hypertensive, or dyslipidemic while receiving
an atypical antipsychotic

How Drug Causes Side EffectsECGs may be useful for selected patients (e.g., those with personal
or family history of QT c prolongation; cardiac arrhythmia; recent
myocardial infarction; uncompensated heart failure; or taking agents
that prolong QT c interval such as pimozide, thioridazine, selected
antiarrhythmics, moxifloxacin, sparfloxacin, etc.)
Patients at risk for electrolyte disturbances (e.g., patients on diuretic
therapy) should have baseline and periodic serum potassium and
magnesium measurements
Patients with low white blood cell count (WBC) or history of drug-
induced leukopenia/neutropenia should have complete blood count
(CBC) monitored frequently during the first few months and
amisulpride should be discontinued at the first sign of decline of
WBC in the absence of other causative factors
Patients should be monitored periodically for the development of
abnormal movements of tardive dyskinesia, using neurological

exam and the AIMS (Abnormal Involuntary Movement Scale)
Acute blockade of dopamine 2 receptors in the striatum can cause
drug-induced parkinsonism, dystonia, or akathisia
Chronic blockade of dopamine 2 receptors in the striatum can cause
tardive dyskinesia

✽ Drug-induced parkinsonism
✽ Galactorrhea, amenorrhea
✽ Atypical antipsychotics may increase the risk for diabetes and
dyslipidemia, although the specific risks associated with amisulpride
are unknown
 Life-Thr eatening or Danger ous Side EffectsBy blocking dopamine 2 receptors in the pituitary , it can cause
elevations in prolactin
Mechanism of weight gain and increased incidence of diabetes and
dyslipidemia with atypical antipsychotics is unknown, and risks
vary based on the particular agent
Insomnia, sedation, agitation, anxiety
Constipation, weight gain
Tardive dyskinesia
Risk of potentially irreversible involuntary dyskinetic movements
may increase with cumulative dose and treatment duration
Rare neuroleptic malignant syndrome (NMS) may cause
hyperpyrexia, muscle rigidity , delirium, and autonomic instability
with elevated creatine phosphokinase, myoglobinuria
(rhabdomyolysis), and acute renal failure

 Sedation
What to Do About Side EffectsRare seizures
Dose-dependent QT c prolongation
As a class, antipsychotics are associated with an increased risk of
death and cerebrovascular events in elderly patients with dementia;
not approved for treatment of dementia-related psychosis
Many experience and/or can be significant in amount, especially at
high doses
Wait
Wait
Wait
For drug-induced parkinsonism, add an anticholiner gic agent
Beta blockers, benzodiazepines, or 5HT2A antagonists (e.g.,
mirtazapine, cyproheptadine) may reduce akathisia
Take more of the dose at bedtime to help reduce daytime sedation

Dosing And Use
Dosage FormsWeight loss, exercise programs, and medical management for high
BMIs, diabetes, dyslipidemia
Metformin may help prevent or reverse antipsychotic-induced
Switch to another atypical antipsychotic
Benztropine, trihexyphenidyl, or amantadine for drug-induced
parkinsonism
mirtazapine, cyproheptadine) for akathisia
Valbenazine or deutetrabenazine for tardive dyskinesia
Schizophrenia: 400 –800 mg/day in 2 doses
Negative symptoms only: 50 –300 mg/day
Dysthymia: 50 mg/day
Different formulations may be available in dif ferent markets

How to Dose
✽ Efficacy for negative symptoms in schizophrenia may be achieved
at lower doses, while ef ficacy for positive symptoms may require
higher doses
✽ For dysthymia and depression, use only low doses
✽ Dose-dependent QT c prolongation, so use with caution, especially
at higher doses (>800 mg/day)
✽ Amisulpride may accumulate in patients with renal insuf ficiency ,
requiring lower dosing or switching to another antipsychotic to avoid
QTc prolongation in these patientsTablet 50 mg, 100 mg, 200 mg, 400 mg
Oral solution 100 mg/mL
Initial 400 –800 mg/day in 2 doses; daily doses above 400 mg should
be divided in 2; maximum generally 1200 mg/day
See also the Switching section below , after Pearls
Patients receiving low doses may only need to take the drug once
daily
Rather than raise the dose above normal dosing in acutely agitated
patients requiring acute antipsychotic actions, consider short-term
(one dose or more) augmentation with a benzodiazepine or another

antipsychotic, especially intramuscularly

Overdose
How to StopRather than raise the dose above normal dosing in partial
responders, consider augmentation with a mood-stabilizing
anticonvulsant, such as valproate, topiramate, or lamotrigine
Children and elderly should generally be dosed at the lower end of
the dosage spectrum
Treatment should be suspended if absolute neutrophil count falls
below 1000/mm3
Sedation, coma, hypotension, drug-induced parkinsonism
Amisulpride is used for both acute and chronic schizophrenia
treatment
Should periodically reevaluate long-term usefulness in individual
patients, but treatment may need to continue for many years
No
See Switching section of individual agents for how to stop
amisulpride

 Other W arnings/Pr ecautionsRapid discontinuation may lead to rebound psychosis and worsening
Elimination half-life approximately 12 hours
Excreted lar gely unchanged
Can decrease the ef fects of levodopa, dopamine agonists
Can increase the ef fects of antihypertensive drugs
CNS ef fects may be increased if used with a CNS depressant
May enhance QT c prolongation of other drugs capable of
prolonging QT c interval
Since amisulpride is only weakly metabolized, few drug interactions
that could raise amisulpride plasma levels are expected
Use cautiously in patients with alcohol withdrawal or convulsive
disorders because of possible lowering of seizure threshold
If signs of neuroleptic malignant syndrome develop, treatment
should be immediately discontinued
Because amisulpride may dose-dependently prolong QT c interval,
use with caution in patients who have bradycardia or who are taking

Do Not Usedrugs that can induce bradycardia (e.g., beta blockers, calcium
channel blockers, clonidine, digitalis)
use with caution in patients who have hypokalemia and/or
hypomagnesemia or who are taking drugs that can induce
hypokalemia and/or magnesemia (e.g., diuretics, stimulant laxatives,
intravenous amphotericin B, glucocorticoids, tetracosactide)
Use only with caution if at all in Parkinson ’s disease or Lewy body
dementia, especially at high doses
Atypical antipsychotics have the potential for cognitive and motor
impairment, especially related to sedation
Atypical antipsychotics can cause body temperature dysregulation;
use caution in patients who may experience conditions that increase
body temperature (e.g., strenuous exercise, saunas, extreme heat,
dehydration, or concomitant anticholiner gic medication)
Antipsychotics may cause somnolence, postural hypotension, motor

and sensory instability , which may lead to falls; for patients with
diseases, conditions, or medications that could exacerbate these
effects, complete fall risk assessments when initiating antipsychotic
treatment, and recurrently for patients on long-term antipsychotic
therapy
As with any antipsychotic, use with caution in patients with history
of seizures

Renal ImpairmentIf patient has pheochromocytoma
If patient has prolactin-dependent tumor
If patient is pregnant or nursing
If patient is taking agents capable of significantly prolonging QT c
interval (e.g., pimozide; thioridazine; selected antiarrhythmics such
as quinidine, disopyramide, amiodarone, and sotalol; selected
antibiotics such as moxifloxacin and sparfloxacin)
If there is a history of QT c prolongation or cardiac arrhythmia,
recent acute myocardial infarction, uncompensated heart failure
If patient is taking cisapride, intravenous erythromycin, or
pentamidine
In children
If there is a proven aller gy to amisulpride
Use with caution; drug may accumulate
Amisulpride is eliminated by the renal route; in cases of severe renal
insuf ficiency , the dose should be decreased and intermittent
treatment or switching to another antipsychotic should be
considered

ElderlyUse with caution, but dose adjustment not generally necessary
Amisulpride produces a dose-dependent prolongation of QT c
interval, which may be enhanced by the existence of bradycardia,
hypokalemia, congenital or acquired long QT c interval, which
should be evaluated prior to administering amisulpride
Use with caution if treating concomitantly with a medication likely
to produce prolonged bradycardia, hypokalemia, slowing of
intracardiac conduction, or prolongation of the QT c interval
Avoid amisulpride in patients with a known history of QT c
prolongation, recent acute myocardial infarction, and
uncompensated heart failure
Some patients may be more susceptible to sedative and hypotensive
effects
Although atypical antipsychotics are commonly used for behavioral
disturbances in dementia, no agent has been approved for treatment
of elderly patients with behavioral symptoms of dementia such as
agitation

agitation
Elderly patients with dementia-related psychosis treated with
atypical antipsychotics are at an increased risk of death compared to

Childr en and Adolescents
 Pregnancy
✽ Recommended either to discontinue drug or bottle feed
Potential Advantagesplacebo, and also have an increased risk of cerebrovascular events
Efficacy and safety not established under age 18
Although animal studies have not shown teratogenic ef fect,
amisulpride is not recommended for use during pregnancy
There is a risk of abnormal muscle movements and withdrawal
symptoms in newborns whose mothers took an antipsychotic during
the third trimester; symptoms may include agitation, abnormally
increased or decreased muscle tone, tremor , sleepiness, severe
difficulty breathing, and dif ficulty feeding
Psychotic symptoms may worsen during pregnancy and some form
of treatment may be necessary
Unknown if amisulpride is secreted in human breast milk, but all

 Pearls
✽ Efficacy has been particularly well demonstrated in patients with
predominantly negative symptoms
✽ The increase in prolactin caused by amisulpride may cause
menstruation to stopNot as clearly associated with weight gain as some other atypical
For patients who are responsive to low-dose activation ef fects that
reduce negative symptoms and depression
Patients who have dif ficulty being compliant with twice daily
dosing
Patients for whom elevated prolactin may not be desired (e.g.,
possibly pregnant patients; pubescent girls with amenorrhea;
postmenopausal women with low estrogen who do not take estrogen
replacement therapy)
Patients with severe renal impairment
Positive symptoms of psychosis
Negative symptoms of psychosis
Depressive symptoms

For treatment-resistant patients with inadequate responses to
clozapine, amisulpride may be a preferred augmentation option
Risks of diabetes and dyslipidemia not well studied, but does not
seem to cause as much weight gain as some other atypical
Has atypical antipsychotic properties (i.e., antipsychotic action
without a high incidence of drug-induced parkinsonism), especially
at low doses, but not a serotonin dopamine antagonist
Mediates its atypical antipsychotic properties via novel actions on
dopamine receptors, perhaps dopamine stabilizing partial agonist
actions on dopamine 2 receptors
May be more of a dopamine 2 antagonist than aripiprazole, but less
of a dopamine 2 antagonist than other atypical or conventional
Low-dose activating actions may be beneficial for negative
symptoms in schizophrenia
Very low doses may be useful in dysthymia
Compared to sulpiride, amisulpride has better oral bioavailability

and more potency , thus allowing lower dosing, less weight gain, and
a lower risk of drug-induced parkinsonism
Compared to other atypical antipsychotics with potent serotonin 2A
antagonism, amisulpride may have more drug-induced parkinsonism
and prolactin elevation, but may still be classified as an atypical
antipsychotic, particularly at low doses

Patients have very similar antipsychotic responses to any
conventional antipsychotic, which is dif ferent from atypical
antipsychotics where antipsychotic responses of individual patients
can occasionally vary greatly from one atypical antipsychotic to
another
Patients with inadequate responses to atypical antipsychotics may
benefit from determination of plasma drug levels and, if low , a
dosage increase even beyond the usual prescribing limits
also benefit from a trial of augmentation with a conventional
antipsychotic or switching to a conventional antipsychotic
However , long-term polypharmacy with a combination of a
conventional antipsychotic with an atypical antipsychotic may
combine their side ef fects without clearly augmenting the ef ficacy
of either
For treatment-resistant patients, especially those with impulsivity ,
aggression, violence, and self-harm, long-term polypharmacy with 2

of either
atypical antipsychotics or with 1 atypical antipsychotic and 1
conventional antipsychotic may be useful or even necessary while
closely monitoring
In such cases, it may be beneficial to combine 1 depot antipsychotic
with 1 oral antipsychotic
Although a frequent practice by some prescribers, adding two
conventional antipsychotics together has little rationale and may
reduce tolerability without clearly enhancing ef ficacy

The Art of Switching
 Switching fr om Oral Antipsychotics to Amisulpride
* Benzodiazepine or anticholiner gic medication can be administered
during cross-titration to help alleviate side ef fects such as insomnia,
agitation, and/or psychosis
It is advisable to begin amisulpride at an intermediate dose and build
the dose rapidly over 3 –7 days
Clinical experience has shown that asenapine, quetiapine, and
olanzapine should be tapered of f slowly over a period of 3 –4 weeks,
to allow patients to readapt to the withdrawal of blocking
choliner gic, histaminer gic, and alpha 1 receptors
Clozapine should always be tapered of f slowly , over a period of 4
weeks or more

Huhn  M , Nikolakopoulou  A , Schneider -Thoma  J , et al. Comparative
efficacy and tolerability of 32 oral antipsychotics for the acute treatment of
adults with multi-episode schizophrenia: a systematic review and network
meta-analysis  . Lancet  2019  ;394: 939–51 .
Komossa  K , Rummel-Kluge  C , Hunder  H , et al. Amisulpride versus other
atypical antipsychotics for schizophrenia  . Cochrane Database Syst Rev
2010  ;(1):CD006624.
Leucht  S , Pitschel-W alz G , Engel  RR , Kissling  W . Amisulpride, an
unusual “atypical ” antipsychotic: a meta-analysis of randomized controlled
trials  . Am J Psychiatry  2002  ;159 (2 ):180–90 .

Amitriptyline
Brands
Generic?
Yes
 Class
✽ Neuropathic pain/chronic pain
✽ FibromyalgiaElavil
Neuroscience-based Nomenclature: serotonin, norepinephrine
multimodal (SN-MM)
Tricyclic antidepressant (TCA)
Serotonin and norepinephrine/noradrenaline reuptake inhibitor
Depr ession
Endogenous depr ession

✽ Headache
✽ Low back pain/neck pain
 How the Drug W orks
How Long Until It W orksAnxiety
Insomnia
Treatment-resistant depression
Boosts neurotransmitters serotonin and
norepinephrine/noradrenaline
Blocks serotonin reuptake pump (serotonin transporter), presumably
increasing serotoner gic neurotransmission
Blocks norepinephrine reuptake pump (norepinephrine transporter),
presumably increasing noradrener gic neurotransmission
Presumably desensitizes both serotonin 1A receptors and beta
adrener gic receptors
Since dopamine is inactivated by norepinephrine reuptake in frontal
cortex, which lar gely lacks dopamine transporters, amitriptyline can
increase dopamine neurotransmission in this part of the brain
May have immediate ef fects in treating insomnia or anxiety
Onset of therapeutic actions usually not immediate, but often
delayed 2 –4 weeks

If It W orksIf it is not working within 6 –8 weeks for depression, it may require
a dosage increase or it may not work at all
symptoms
The goal of treatment of depression is complete remission of current
symptoms as well as prevention of future relapses
The goal of treatment of chronic pain conditions such as neuropathic
pain, fibromyalgia, headaches, low back pain, and neck pain is to
reduce symptoms as much as possible, especially in combination
with other treatments
Treatment of depression most often reduces or even eliminates
symptoms, but not a cure since symptoms can recur after medicine
stopped
Treatment of chronic pain conditions such as neuropathic pain,
fibromyalgia, headache, low back pain, and neck pain may reduce
symptoms, but rarely eliminates them completely , and is not a cure
since symptoms can recur after medicine is stopped
Continue treatment of depression until all symptoms are gone
(remission)

Once symptoms of depression are gone, continue treating for 1 year
for the first episode of depression

ResistanceFor second and subsequent episodes of depression, treatment may
Use in anxiety disorders and chronic pain conditions such as
neuropathic pain, fibromyalgia, headache, low back pain, and neck
pain may also need to be indefinite, but long-term treatment is not
well studied in these conditions
Many depressed patients have only a partial response where some
symptoms are improved but others persist (especially insomnia,
fatigue, and problems concentrating)
Other depressed patients may be nonresponders, sometimes called
treatment-resistant or treatment-refractory
Consider increasing dose, switching to another agent, or adding an
appropriate augmenting agent

Tests
✽ Since tricyclic and tetracyclic antidepressants are frequently
associated with weight gain, before starting treatment, weigh all
patients and determine if the patient is already overweight (BMI 25.0 –
29.9) or obese (BMI >30)
✽ Monitor weight and BMI during treatment
✽ While giving a drug to a patient who has gained >5% of initial
weight, consider evaluating for the presence of pre-diabetes, diabetes,
or dyslipidemia, or consider switching to a dif ferent antidepressantLithium, buspirone, thyroid hormone (for depression)
Gabapentin, tiagabine, other anticonvulsants, even opiates if done
by experts while monitoring carefully in dif ficult cases (for chronic
pain)
Baseline ECG is recommended for patients over age 50
Before giving a drug that can cause weight gain to an overweight or
obese patient, consider determining whether the patient already has
pre-diabetes (fasting plasma glucose 100 –125 mg/dL), diabetes
(fasting plasma glucose >126 mg/dL), or dyslipidemia (increased

total cholesterol, LDL cholesterol, and triglycerides; decreased HDL
cholesterol), and treat or refer such patients for treatment, including
nutrition and weight management, physical activity counseling,
smoking cessation, and medical management

Notable Side EffectsECGs may be useful for selected patients (e.g., those with personal
Anticholiner gic activity may explain sedative ef fects, dry mouth,
constipation, and blurred vision
Sedative ef fects and weight gain may be due to antihistamine
Blockade of alpha adrener gic 1 receptors may explain dizziness,
sedation, and hypotension
Cardiac arrhythmias and seizures, especially in overdose, may be
caused by blockade of ion channels
Blurred vision, constipation, urinary retention, increased appetite,

dry mouth, nausea, diarrhea, heartburn, unusual taste in mouth,

Life-Thr eatening or Danger ous Side Effects
 Weight Gainweight gain
Fatigue, weakness, dizziness, sedation, headache, anxiety ,
nervousness, restlessness
Sexual dysfunction (impotence, change in libido)
Sweating, rash, itching
Paralytic ileus, hyperthermia (TCAs + anticholiner gic agents)
Lowered seizure threshold and rare seizures
Orthostatic hypotension, sudden death, arrhythmias, tachycardia
QTc prolongation
Hepatic failure, drug-induced parkinsonism
Increased intraocular pressure
Rare induction of mania
antidepressants compared to placebo beyond age 24)
Many experience and/or can be significant in amount
Can increase appetite and carbohydrate craving

Sedation
Dosage FormsMany experience and/or can be significant in amount
Tolerance to sedative ef fects may develop with long-term use
Wait
Wait
Wait
Switch to an SSRI or newer antidepressant
50–150 mg/day
Tablet 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg

How to Dose
Overdose
Long-T erm UseInitial 25 mg/day at bedtime; increase by 25 mg every 3 –7 days
75 mg/day in divided doses; increase to 150 mg/day; maximum 300
mg/day
If given in a single dose, should generally be administered at
bedtime because of its sedative properties
If given in split doses, lar gest dose should generally be given at
If patients experience nightmares, split dose and do not give lar ge
dose at bedtime
Patients treated for chronic pain may only require lower doses
possibility of activated bipolar disorder , and switch to a mood
Death may occur; CNS depression, convulsions, cardiac
dysrhythmias, severe hypotension, ECG changes, coma
Safe

How to Stop
 Drug InteractionsNo
Taper to avoid withdrawal ef fects
Even with gradual dose reduction, some withdrawal symptoms may
appear within the first 2 weeks
Many patients tolerate 50% dose reduction for 3 days, then another
50% reduction for 3 days, then discontinuation
If withdrawal symptoms emer ge during discontinuation, raise dose
to stop symptoms and then restart withdrawal much more slowly
Substrate for CYP450 2D6 and 1A2
Plasma half-life 10 –28 hours
Metabolized to an active metabolite, nortriptyline, which is
predominantly a norepinephrine reuptake inhibitor , by
demethylation via CYP450 1A2
Food does not af fect absorption
Tramadol increases the risk of seizures in patients taking TCAs

Other W arnings/Pr ecautionsUse of TCAs with anticholiner gic drugs may result in paralytic ileus
or hyperthermia
Fluoxetine, paroxetine, bupropion, duloxetine, and other CYP450
2D6 inhibitors may increase TCA concentrations
Fluvoxamine, a CYP450 1A2 inhibitor , can decrease the conversion
of amitriptyline to nortriptyline and increase amitriptyline plasma
concentrations
Cimetidine may increase plasma concentrations of TCAs and cause
anticholiner gic symptoms
Phenothiazines or haloperidol may raise TCA blood concentrations
May alter ef fects of antihypertensive drugs; may inhibit hypotensive
effects of clonidine
Use of TCAs with sympathomimetic agents may increase
sympathetic activity
Methylphenidate may inhibit metabolism of TCAs
Activation and agitation, especially following switching or adding
antidepressants, may represent the induction of a bipolar state,
especially a mixed dysphoric bipolar II condition sometimes

associated with suicidal ideation, and require the addition of lithium,
a mood stabilizer or an atypical antipsychotic, and/or
discontinuation of amitriptyline

Add or initiate other antidepressants with caution for up to 2 weeks
after discontinuing amitriptyline
Generally , do not use with MAOIs, including 14 days after MAOIs
are stopped; do not start an MAOI for at least 5 half-lives (5 to 7
days for most drugs) after discontinuing amitriptyline, but see Pearls
Use with caution in patients with history of seizures, urinary
retention, angle-closure glaucoma, hyperthyroidism
TCAs can increase QT c interval, especially at toxic doses, which
can be attained not only by overdose but also by combining with
drugs that inhibit TCA metabolism via CYP450 2D6, potentially
causing torsade de pointes-type arrhythmia or sudden death
Because TCAs can prolong QT c interval, use with caution in
patients who have bradycardia or who are taking drugs that can
induce bradycardia (e.g., beta blockers, calcium channel blockers,
clonidine, digitalis)

patients who have hypokalemia and/or hypomagnesemia, or who are
taking drugs that can induce hypokalemia and/or magnesemia (e.g.,
diuretics, stimulant laxatives, intravenous amphotericin B,
glucocorticoids, tetracosactide)
When treating children, carefully weigh the risks and benefits of
pharmacological treatment against the risks and benefits of
nontreatment with antidepressants and make sure to document this
in the patient ’s chart

Do Not Use
Renal ImpairmentDistribute the brochures provided by the FDA and the drug
companies
If patient is recovering from myocardial infarction
interval (e.g., pimozide, thioridazine, selected antiarrhythmics,
moxifloxacin, sparfloxacin)
If patient is taking drugs that inhibit TCA metabolism, including
CYP450 2D6 inhibitors, except by an expert
If there is reduced CYP450 2D6 function, such as patients who are
poor 2D6 metabolizers, except by an expert and at low doses

If there is a proven aller gy to amitriptyline or nortriptyline

Cardiac ImpairmentUse with caution; may need to lower dose
Use with caution; may need to lower dose
Baseline ECG is recommended
TCAs have been reported to cause arrhythmias, prolongation of
conduction time, orthostatic hypotension, sinus tachycardia, and
heart failure, especially in the diseased heart
Myocardial infarction and stroke have been reported with TCAs
TCAs produce QT c prolongation, which may be enhanced by the
existence of bradycardia, hypokalemia, congenital or acquired long
QTc interval, which should be evaluated prior to administering
amitriptyline
Avoid TCAs in patients with a known history of QT c prolongation,
recent acute myocardial infarction, and uncompensated heart failure
TCAs may cause a sustained increase in heart rate in patients with

ischemic heart disease and may worsen (decrease) heart rate
variability , an independent risk of mortality in cardiac populations

✽ Risk/benefit ratio may not justify use of TCAs in cardiac
impairment
Elderly
 Childr en and AdolescentsSince SSRIs may improve (increase) heart rate variability in patients
following a myocardial infarct and may improve survival as well as
mood in patients with acute angina or following a myocardial
infarction, these are more appropriate agents for cardiac population
than tricyclic/tetracyclic antidepressants
May be more sensitive to anticholiner gic, cardiovascular ,
hypotensive, and sedative ef fects
Initial dose 50 mg/day; increase gradually up to 100 mg/day
Reduction in the risk of suicidality with antidepressants compared to
placebo in adults age 65 and older
Carefully weigh the risks and benefits of pharmacological treatment
Use with caution, observing for activation of known or unknown

bipolar disorder and/or suicidal ideation, and inform parents or
guardians of this risk so they can help observe child or adolescent
patients

PregnancyMonitor patients face-to-face regularly , particularly during the first
Not generally recommended for use under age 12
Several studies show lack of ef ficacy of TCAs for depression
May be used to treat enuresis or hyperactive/impulsive behaviors
Some cases of sudden death have occurred in children taking TCAs
Adolescents: initial dose 50 mg/day; increase gradually up to 100
mg/day
Effective June 30, 2015, the US FDA requires changes to the
Crosses the placenta
Adverse ef fects have been reported in infants whose mothers took a

TCA (lethar gy, withdrawal symptoms, fetal malformations)

Potential Advantagestreatment (recurrence of depression, maternal health, infant
pregnancy
National Pregnancy Registry for Antidepressants: 1-866-961-2388,
https://womensmentalhealth.or g/research/pregnancyregistry/antidepr
essants
Immediate postpartum period is a high-risk time for depression,
Must weigh benefits of breast feeding with risks and benefits of
antidepressant treatment versus nontreatment to both the infant and
the mother
For many patients this may mean continuing treatment during breast
feeding

 PearlsPatients with insomnia
Severe or treatment-resistant depression
Patients with a wide variety of chronic pain syndromes
Pediatric and geriatric patients
Patients concerned with weight gain
Cardiac patients
Symptoms of anxiety
Somatic symptoms
Chronic pain
Insomnia
Was once one of the most widely prescribed agents for depression
Remains one of the most favored TCAs for treating headache and a
wide variety of chronic pain syndromes, including neuropathic pain,
fibromyalgia, migraine, neck pain, and low back pain

✽ Preference of some prescribers for amitriptyline over other
tricyclic/tetracyclic antidepressants for the treatment of chronic pain
syndromes is based more upon art and anecdote rather than controlled
clinical trials, since many TCAs/tetracylics may be ef fective for
chronic pain syndromes
✽ Amitriptyline has been shown to be ef fective in primary insomniaTCAs are no longer generally considered a first-line treatment
option for depression because of their side ef fect profile
TCAs may aggravate psychotic symptoms
Alcohol should be avoided because of additive CNS ef fects
Underweight patients may be more susceptible to adverse
cardiovascular ef fects
Children, patients with inadequate hydration, and patients with
cardiac disease may be more susceptible to TCA-induced
cardiotoxicity than healthy adults
For the expert only: although generally prohibited, a heroic but
potentially dangerous treatment for severely treatment-resistant

patients is to give a tricyclic/tetracyclic antidepressant other than
clomipramine simultaneously with an MAOI for patients who fail to
respond to numerous other antidepressants
If this option is elected, start the MAOI with the tricyclic/tetracyclic
antidepressant simultaneously at low doses after appropriate drug
washout, then alternately increase doses of these agents every few
days to a week as tolerated

Suggested ReadingAlthough very strict dietary and concomitant drug restrictions must
be observed to prevent hypertensive crises and serotonin syndrome,
the most common side ef fects of MAOI/tricyclic or tetracyclic
combinations may be weight gain and orthostatic hypotension
Patients on TCAs should be aware that they may experience
symptoms such as photosensitivity or blue-green urine
SSRIs may be more ef fective than TCAs in women, and TCAs may
be more ef fective than SSRIs in men
Since tricyclic/tetracyclic antidepressants are substrates for CYP450
2D6, and 7% of the population (especially Caucasians) may have a
genetic variant leading to reduced activity of 2D6, such patients may
not safely tolerate normal doses of tricyclic/tetracyclic
antidepressants and may require dose reduction
Phenotypic testing may be necessary to detect this genetic variant
prior to dosing with a tricyclic/tetracyclic antidepressant, especially
in vulnerable populations such as children, elderly , cardiac

populations, and those on concomitant medications
Patients who seem to have extraordinarily severe side ef fects at
normal or low doses may have this phenotypic CYP450 2D6 variant
and require low doses or switching to another antidepressant not
metabolized by 2D6

Guaiana  G , Barbui  C , Hotopf  M. Amitriptyline for depression  . Cochrane
Database Syst Rev  2007  ;(3):CD004186  .
Hauser  W , Petzke  F , Uceyler  N , Sommer  C. Comparative ef ficacy and
acceptability of amitriptyline, duloxetine and milnacipran in fibromyalgia
syndrome: a systematic review with meta-analysis  . Rheumatology (Oxfor d)
2011 ;50 (3 ):532–43 .
Torrente Castells  E , Vazquez Delgado  E , Gay Escoda  C. Use of
amitriptyline for the treatment of chronic tension-type headache. Review of
the literature  . Med Oral Patol Oral Cir Bucal  2008  ;13 (9 ):E567  –72.

Amoxapine
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Asendin
Neuroscience-based Nomenclature: norepinephrine, serotonin
reuptake inhibitor (SN-RI)
Tricyclic antidepressant (TCA), sometimes classified as a tetracyclic
antidepressant
Norepinephrine/noradrenaline reuptake inhibitor
Serotonin 2A antagonist
Parent drug and especially an active metabolite are dopamine 2
antagonists

How the Drug W orksNeur otic or r eactive depr essive disorder
Endogenous and psychotic depr essions
Depr ession accompanied by anxiety or agitation
Depressive phase of bipolar disorder
Anxiety
Insomnia
Neuropathic pain/chronic pain
Boosts neurotransmitter norepinephrine/noradrenaline
cortex, which lar gely lacks dopamine transporters, amoxapine can
thus increase dopamine neurotransmission in this part of the brain
A more potent inhibitor of norepinephrine reuptake pump than
serotonin reuptake pump (serotonin transporter)
At high doses may also boost neurotransmitter serotonin and
presumably increase serotoner gic neurotransmission
Blocks dopamine 2 receptors, reducing positive symptoms of
psychosis

If It W orks
If It Doesn ’t WorkOnset of therapeutic actions usually not immediate, but often
If it is not working within 6 –8 weeks for depression, it may require
symptoms
a cure since symptoms can recur after medicine stopped
Use in anxiety disorders may also need to be indefinite
Many patients have only a partial response where some symptoms

Tests
29.9) or obese (BMI >30)problems concentrating)
Lithium, buspirone, thyroid hormone

or dyslipidemia, or consider switching to a dif ferent antidepressant
How Drug Causes Side Effectspre-diabetes (fasting plasma glucose 100 –125 mg/dL), diabetes
ECGs may be useful for selected patients (e.g., those with personal

✽ Can cause drug-induced parkinsonism, akathisia, and theoretically ,
 Life-Thr eatening or Danger ous Side EffectsSedative ef fects and weight gain may be due to antihistamine
Sexual dysfunction, sweating
Paralytic ileus, hyperthermia (TCAs/tetracyclics + anticholiner gic
agents)

Sedation
What to Do About Side EffectsHepatic failure, drug-induced parkinsonism
Tolerance to sedative ef fect may develop with long-term use
Wait
Wait
Wait

How to Dose
 Dosing T ipsMany side ef fects cannot be improved with an augmenting agent
May use anticholiner gics for drug-induced parkinsonism, or switch
to another antidepressant
200–300 mg/day
Tablet 25 mg, 50 mg, 100 mg, 150 mg
Initial 25 mg 2 –3 times/day; increase gradually to 100 mg 2 –3
times/day or a single dose at bedtime; maximum 400 mg/day (may
dose up to 600 mg/day in inpatients)

Overdose
How to StopIf patients experience nightmares, split dose and do not give lar ge
Death may occur; convulsions, cardiac dysrhythmias, severe
hypotension, CNS depression, coma, changes in ECG
Generally safe
Some patients may develop withdrawal dyskinesias when
discontinuing amoxapine after long-term use
Some patients may develop tolerance
Even with gradual dose reduction some withdrawal symptoms may

✽ 7- and 8-hydroxymetabolites are active and possess serotonin 2A
and dopamine 2 antagonist properties, similar to atypical
✽ Amoxapine is the N-desmethyl metabolite of the conventional
antipsychotic loxapine
 Drug InteractionsMany patients tolerate 50% dose reduction for 3 days, then another
Substrate for CYP450 2D6
Half-life of parent drug approximately 8 hours
Half-life of the active metabolites approximately 24 hours
Use of TCAs/tetracyclics with anticholiner gic drugs may result in
paralytic ileus or hyperthermia
2D6 inhibitors may increase TCA/tetracyclic concentrations
Cimetidine may increase plasma concentrations of

TCAs/tetracyclics and cause anticholiner gic symptoms

Other W arnings/Pr ecautionsPhenothiazines or haloperidol may raise TCA/tetracyclic blood
Use of TCAs/tetracyclics with sympathomimetic agents may
increase sympathetic activity
Methylphenidate may inhibit metabolism of TCAs/tetracyclics
discontinuation of amoxapine
after discontinuing amoxapine
days for most drugs) after discontinuing amoxapine, but see Pearls

Use with caution in patients with history of seizure, urinary
TCAs/tetracyclics can increase QT c interval, especially at toxic
doses, which can be attained not only by overdose but also by

Do Not Usecombining with drugs that inhibit its metabolism via CYP450 2D6,
potentially causing torsade de pointes-type arrhythmia or sudden
death
Because TCAs/tetracyclics can prolong QT c interval, use with
caution in patients who have bradycardia or who are taking drugs
that can induce bradycardia (e.g., beta blockers, calcium channel
blockers, clonidine, digitalis)
caution in patients who have hypokalemia and/or hypomagnesemia,
or who are taking drugs that can induce hypokalemia and/or
magnesemia (e.g., diuretics, stimulant laxatives, intravenous
amphotericin B, glucocorticoids, tetracosactide)
Distribute the brochures provided by the FDA and the drug
companies

companies

Cardiac ImpairmentIf patient is recovering from myocardial infarction
If patient is taking drugs that inhibit TCA/tetracyclic metabolism,
including CYP450 2D6 inhibitors, except by an expert
If there is a proven aller gy to amoxapine or loxapine
Use with caution –may require lower than usual adult dose

TCAs/tetracyclics have been reported to cause arrhythmias,
prolongation of conduction time, orthostatic hypotension, sinus
tachycardia, and heart failure, especially in the diseased heart
Myocardial infarction and stroke have been reported with
TCAs/tetracyclics
TCAs/tetracyclics produce QT c prolongation, which may be
enhanced by the existence of bradycardia, hypokalemia, congenital
or acquired long QT c interval, which should be evaluated prior to
administering amoxapine
Avoid TCAs/tetracyclics in patients with a known history of QT c
TCAs/tetracyclics may cause a sustained increase in heart rate in
patients with ischemic heart disease and may worsen (decrease)

heart rate variability , an independent risk of mortality in cardiac
populations
Since SSRIs may improve (increase) heart rate variability in patients

✽ Risk/benefit ratio may not justify use of TCAs/tetracyclics in
cardiac impairment
Elderly
 Childr en and AdolescentsBaseline ECG is recommended for patients over age 50
Initial dose 25 mg/day at bedtime; increase by 25 mg/day each
week; maximum dose 300 mg/day
patients
Not generally recommended for use under age 16
Several studies show lack of ef ficacy of TCAs/tetracyclics for
depression

Pregnancy
✽ Recommended either to discontinue drug or bottle feedSome cases of sudden death have occurred in children taking
Adolescents: initial 25 –50 mg/day; increase gradually to 100
mg/day in divided doses or single dose at bedtime
Some animal studies show adverse ef fects
Amoxapine crosses the placenta
Evaluate for treatment with an antidepressant with a better
risk/benefit ratio
essants

 Pearlsdrug may need to be reinstituted late in the third trimester or shortly
Treatment-resistant psychotic depression
Patients with Parkinson ’s disease or tardive dyskinesia
Tricyclic/tetracyclic antidepressants are no longer generally
considered a first-line treatment option for depression because of

✽ Because of potential drug-induced parkinsonism, akathisia, and
theoretical risk of tardive dyskinesia, first consider other
TCAs/tetracyclics for long-term use in general and for treatment of
chronic patientstheir side ef fect profile
Tricyclic/tetracyclic antidepressants continue to be useful for severe
or treatment-resistant depression

Use of MAOIs with clomipramine is always prohibited because of
the risk of serotonin syndrome and death
Amoxapine may be the preferred trycyclic/tetracyclic antidepressant
to combine with an MAOI in heroic cases due to its theoretically
protective 5HT2A antagonist properties

✽ May cause some motor ef fects, possibly due to ef fects on dopamine
receptors
✽ Amoxapine may have a faster onset of action than some other
✽ May be pharmacologically similar to an atypical antipsychotic in
✽ At high doses, patients who form high concentrations of active
metabolites may have akathisia or drug-induced parkinsonism, and
possibly develop tardive dyskinesia
✽ Structurally and pharmacologically related to the antipsychotic
loxapineIf this option is elected, start the MAOI with the tricyclic/tetracyclic
Although very strict dietary and concomitant drug restrictions must

Patients on TCAs/tetracyclics should be aware that they may
experience symptoms such as photosensitivity or blue-green urine
SSRIs may be more ef fective than TCAs/tetracyclics in women, and
TCAs/tetracyclics may be more ef fective than SSRIs in men

Anderson  IM . Meta-analytical studies on new antidepressants  . Br Med
Bull 2001  ; 57 :161–78 .
Anderson  IM . Selective serotonin reuptake inhibitors versus tricyclic
antidepressants: a meta-analysis of ef ficacy and tolerability  . J Aff Disor ders
2000  ;58 :19 –36 .
Hayes  PE , Kristof f CA . Adverse reactions to five new antidepressants  .
Clin Pharm  1986  ; 5 :471–80 .Since tricyclic/tetracyclic antidepressants are substrates for CYP450

Jue SG , Dawson  GW , Brogden  RN . Amoxapine: a review of its
pharmacology and ef ficacy in depressed states  . Drugs  1982  ;24 :1 –23 .

Amphetamine (D)
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Dexedrine
Dexedrine Spansules
Zenzedi
ProCentra
Neuroscience-based Nomenclature: dopamine, norepinephrine
reuptake inhibitor and releaser (DN-RIRe)
Stimulant
Attention deficit hyperactivity disorder (ADHD) (ages 6 and
older or 3 and older depending on formulation)

✽ Increases norepinephrine and especially dopamine actions by
blocking their reuptake and facilitating their release
If It W orks (for ADHD)Narcolepsy (ages 6 and older)
Enhancement of dopamine and norepinephrine actions in certain
brain regions may improve attention, concentration, executive
function, and wakefulness (e.g., dorsolateral prefrontal cortex)
Enhancement of dopamine actions in other brain regions (e.g., basal
ganglia) may improve hyperactivity
Enhancement of dopamine and norepinephrine in yet other brain
regions (e.g., medial prefrontal cortex, hypothalamus) may improve
depression, fatigue, and sleepiness
Some immediate ef fects can be seen with first dosing
Can take several weeks to attain maximum therapeutic benefit
The goal of treatment of ADHD is reduction of symptoms of
inattentiveness, motor hyperactivity , and/or impulsiveness that
disrupt social, school, and/or occupational functioning

If It Doesn ’t Work (for ADHD)
✽ Some ADHD patients and some depressed patients may experience
lack of consistent ef ficacy due to activation of latent or underlying
bipolar disorder , and require either augmenting with a mood stabilizer
or switching to a mood stabilizer
✽ Best to attempt other monotherapies prior to augmentingContinue treatment until all symptoms are under control or
improvement is stable and then continue treatment indefinitely as
long as improvement persists
Reevaluate the need for treatment periodically
Treatment for ADHD begun in childhood may need to be continued
into adolescence and adulthood if continued benefit is documented
Consider adjusting dose or switching to another formulation of d-
amphetamine or to another agent
Consider behavioral therapy
Consider the presence of noncompliance and counsel patient and
parents

parents
condition (e.g., bipolar disorder , substance abuse, medical illness,
etc.)

Tests
How Drug Causes Side EffectsFor the expert, can combine immediate-release formulation with a
sustained-release formulation of d-amphetamine for ADHD
For the expert, can combine with modafinil or atomoxetine for
ADHD
For the expert, can occasionally combine with atypical
antipsychotics in highly treatment-resistant cases of bipolar disorder
or ADHD
For the expert, can combine with antidepressants to boost
antidepressant ef ficacy in highly treatment-resistant cases of
depression while carefully monitoring patient
Before treatment, assess for presence of cardiac disease (history ,
family history , physical exam)
Blood pressure should be monitored regularly
In children, monitor weight and height
Increases in norepinephrine peripherally can cause autonomic side
effects, including tremor , tachycardia, hypertension, and cardiac
arrhythmias

✽ Insomnia, headache, exacerbation of tics, nervousness, irritability ,
overstimulation, tremor , dizziness
Increases in norepinephrine and dopamine centrally can cause CNS
side ef fects such as insomnia, agitation, psychosis, and substance
abuse
Anorexia, nausea, dry mouth, constipation, diarrhea, weight loss
Can temporarily slow normal growth in children (controversial)
Sexual dysfunction long-term (impotence, libido changes) but can
also improve sexual dysfunction short-term
Psychotic episodes, especially with parenteral abuse
Seizures
Palpitations, tachycardia, hypertension
Rare activation of hypomania, mania, or suicidal ideation
(controversial)
Cardiovascular adverse ef fects, sudden death in patients with
preexisting cardiac structural abnormalities

Sedation
Dosing and UseReported but not expected
Some patients may experience weight loss
Activation much more common than sedation
Wait
Switch to a long-acting stimulant
For insomnia, avoid dosing in afternoon/evening
Beta blockers for peripheral autonomic side ef fects
agent

How to Dose
 Dosing T ipsNarcolepsy: 5 –60 mg/day (divided doses for tablet, once daily
morning dose for Spansule capsule)
ADHD: 5 –40 mg/day (divided doses for tablet, once daily morning
dose for Spansule capsule)
Immediate-release tablet 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20
mg, 30 mg
Extended-release capsule 5 mg, 10 mg, 15 mg
Immediate-release oral solution 5 mg/5 mL
Narcolepsy , ages 12 and older (Spansule capsule or tablet): initial 10
mg/day; can increase by 10 mg each week; give first dose on
waking; tablet is administered in divided doses
Narcolepsy , ages 6 to 12 (tablet IR): initial 5 mg/day; can increase
by 5 mg each week; administered in divided doses
ADHD, ages 6 and older (Spansule capsule or tablet): initial 5
mg/day; can increase by 5 mg each week; give first dose on waking
ADHD, ages 3 to 5 (tablet IR): initial 2.5 mg/day; can increase by
2.5 mg each week; administered in divided doses

✽ Immediate-release dextroamphetamine has 3 –6 hour duration of
clinical action
✽ Sustained-release dextroamphetamine (Dexedrine Spansule) has up
to 8-hour duration of clinical action
✽ Controlled-release delivery of dextroamphetamine may be
sufficiently long in duration to allow elimination of lunchtime dosing
in many but not all patients
✽ This innovation can be an important practical element in stimulant
utilization, eliminating the hassle and pragmatic dif ficulties of
lunchtime dosing at school, including storage problems, potential
diversion, and the need for a medical professional to supervise dosing
away from home
✽ May be possible to dose only during the school week for some
ADHD patientsClinical duration of action often dif fers from pharmacokinetic half-
life
Tablets contain tartrazine, which may cause aller gic reactions,
particularly in patients aller gic to aspirin
Dexedrine Spansules are controlled-release and should therefore not

life
be chewed but rather should only be swallowed whole
Avoid dosing late in the day because of the risk of insomnia
Off-label uses are dosed the same as for ADHD

✽ May be able to give drug holidays over the summer in order to
reassess therapeutic utility and ef fects on growth and to allow catch-up
from any growth suppression as well as to assess any other side ef fects
and the need to reinstitute stimulant treatment for the next school term
However , most studies show that parental height is what determines a
patient ’s final height, and that most children/adolescents taking
stimulants reach their expected height, just more slowly than
children/adolescents not exposed to stimulants
Overdose
Long-T erm UseSide ef fects are generally dose-related
Taking with food may delay peak actions for 2 –3 hours
Rarely fatal; panic, hyperreflexia, rhabdomyolysis, rapid respiration,
confusion, coma, hallucination, convulsion, arrhythmia, change in
blood pressure, circulatory collapse
Often used long-term for ADHD when ongoing monitoring
documents continued ef ficacy
Dependence and/or abuse may develop

Tolerance to therapeutic ef fects may develop in some patients
Long-term stimulant use may be associated with growth suppression
in children (controversial)

How to Stop
 Drug InteractionsPeriodic monitoring of weight, blood pressure, CBC, platelet counts,
and liver function may be prudent
High abuse potential, Schedule II drug
Patients may develop tolerance, psychological dependence
Withdrawal following chronic therapeutic use may unmask
symptoms of the underlying disorder and may require follow-up and
reinstitution of treatment
Careful supervision is required during withdrawal from abusive use
since severe depression may occur
Half-life approximately 10 –12 hours
May af fect blood pressure and should be used cautiously with agents
used to control blood pressure
Gastrointestinal acidifying agents (guanethidine, reserpine, glutamic
acid, ascorbic acid, fruit juices, etc.) and urinary acidifying agents
(ammonium chloride, sodium phosphate, etc.) lower  amphetamine

plasma levels, so such agents can be useful to administer after an
overdose but may also lower therapeutic ef ficacy of amphetamines
Gastrointestinal alkalinizing agents (sodium bicarbonate, etc.) and
urinary alkalinizing agents (acetazolamide, some thiazides) increase
amphetamine plasma levels and potentiate amphetamine ’s actions
Desipramine and protryptiline can cause striking and sustained
increases in brain concentrations of d-amphetamine and may also
add to d-amphetamine ’s cardiovascular ef fects
Theoretically , other agents with norepinephrine reuptake blocking
properties, such as venlafaxine, duloxetine, atomoxetine,
milnacipran, and reboxetine, could also add to amphetamine ’s CNS
and cardiovascular ef fects
Amphetamines may counteract the sedative ef fects of antihistamines
Haloperidol, chlorpromazine, and lithium may inhibit stimulatory
effects of amphetamines
Theoretically , atypical antipsychotics should also inhibit stimulatory

Theoretically , amphetamines could inhibit the antipsychotic actions
of antipsychotics
Theoretically , amphetamines could inhibit the mood-stabilizing
actions of atypical antipsychotics in some patients
Combinations of amphetamines with mood stabilizers (lithium,
anticonvulsants, atypical antipsychotics) is generally something for

Other W arnings/Pr ecautionsexperts only , when monitoring patients closely and when other
options fail
Absorption of phenobarbital, phenytoin, and ethosuximide is
delayed by amphetamines
Amphetamines inhibit adrener gic blockers and enhance adrener gic
effects of norepinephrine
Amphetamines may antagonize hypotensive ef fects of veratrum
alkaloids and other antihypertensives
Amphetamines increase the analgesic ef fects of meperidine
Amphetamines contribute to excessive CNS stimulation if used with
large doses of propoxyphene
Amphetamines can raise plasma corticosteroid levels
MAOIs slow absorption of amphetamines and thus potentiate their
actions, which can cause headache, hypertension, and rarely
hypertensive crisis and malignant hyperthermia, sometimes with
fatal results
Use with MAOIs, including within 14 days of MAOI use, is not
advised, but this can sometimes be considered by experts who
monitor depressed patients closely when other treatment options for
depression fail

Use with caution in patients with any degree of hypertension,
hyperthyroidism, or history of drug abuse

Children who are not growing or gaining weight should stop
treatment, at least temporarily
May worsen motor and phonic tics
May worsen symptoms of thought disorder and behavioral
disturbance in psychotic patients
Stimulants have a high potential for abuse and must be used with
caution in anyone with a current or past history of substance abuse
or alcoholism or in emotionally unstable patients
Administration of stimulants for prolonged periods of time should
be avoided whenever possible or done only with close monitoring,
as it may lead to marked tolerance and drug dependence, including
psychological dependence with varying degrees of abnormal
behavior
Particular attention should be paid to the possibility of subjects
obtaining stimulants for nontherapeutic use or distribution to others
and the drugs should in general be prescribed sparingly with
documentation of appropriate use
Usual dosing has been associated with sudden death in children with
structural cardiac abnormalities

Not an appropriate first-line treatment for depression or for normal
fatigue
May lower the seizure threshold
Emer gence or worsening of activation and agitation may represent
the induction of a bipolar state, especially a mixed dysphoric bipolar

Do Not Use
Renal ImpairmentII condition sometimes associated with suicidal ideation, and require
the addition of a mood stabilizer and/or discontinuation of d-
amphetamine
If patient has extreme anxiety or agitation
If patient has motor tics or T ourette ’s syndrome or if there is a
family history of T ourette ’s, unless administered by an expert in
cases when the potential benefits for ADHD outweigh the risks of
worsening tics
Should generally not be administered with an MAOI, including
within 14 days of MAOI use, except in heroic circumstances and by
an expert
If patient has arteriosclerosis, cardiovascular disease, or severe
If patient has glaucoma
If patient has structural cardiac abnormalities
If there is a proven aller gy to any sympathomimetic agent
No dose adjustment necessary

Elderly
 Childr en and AdolescentsUse with caution
Use with caution, particularly in patients with recent myocardial
infarction or other conditions that could be negatively af fected by
increased blood pressure
Do not use in patients with structural cardiac abnormalities
Safety and ef ficacy not established in children under age 3
Use in young children should be reserved for the expert
d-amphetamine may worsen symptoms of behavioral disturbance
and thought disorder in psychotic children
Half-life and duration of clinical action tend to be shorter in younger
children
d-amphetamine has acute ef fects on growth hormone; long-term
effects are unknown but weight and height should be monitored
during long-term treatment

PregnancyNarcolepsy: ages 6 –12: initial 5 mg/day; increase by 5 mg each
week
ADHD: ages 3 –5: initial 2.5 mg/day; increase by 2.5 mg each week
American Heart Association recommends ECG prior to initiating
stimulant treatment in children, although not all experts agree
There is a greater risk of premature birth and low birth weight in
infants whose mothers take d-amphetamine during pregnancy

Infants whose mothers take d-amphetamine during pregnancy may
experience withdrawal symptoms
In animal studies, d-amphetamine caused delayed skeletal
ossification and decreased post-weaning weight gain in rats; no
major malformations occurred in rat or rabbit studies

✽ For ADHD patients, d-amphetamine should generally be
discontinued before anticipated pregnancies
Potential DisadvantagesUse in women of childbearing potential requires weighing potential
benefits to the mother against potential risks to the fetus
If infant shows signs of irritability , drug may need to be
discontinued
May work in ADHD patients unresponsive to other stimulants
Established long-term ef ficacy of immediate-release and Spansule
formulations
Patients with current or past substance abuse
Patients with current or past bipolar disorder or psychosis
Patients with anorexia
Patients with insomnia

 Pearls
✽ May be useful for treatment of depressive symptoms in medically
ill elderly patients
✽ May be useful for treatment of post-stroke depression
✽ A classical augmentation strategy for treatment-refractory
✽ Specifically , may be useful for treatment of cognitive dysfunction
and fatigue as residual symptoms of major depressive disorder
unresponsive to multiple prior treatments
✽ May also be useful for the treatment of cognitive impairment,
depressive symptoms, and severe fatigue in patients with HIV
infection and in cancer patientsConcentration, attention span
Motor hyperactivity
Impulsiveness
Physical and mental fatigue
Daytime sleepiness
Can be used to potentiate opioid analgesia and reduce sedation,
particularly in end-of-life management

✽ Despite warnings, can be a useful adjunct to MAOIs for heroic
treatment of highly refractory mood disorders when monitored with
vigilance
✽ Can reverse sexual dysfunction caused by psychiatric illness and by
some drugs such as SSRIs, including decreased libido, erectile
dysfunction, delayed ejaculation, and anor gasmia
Fry JM . Treatment modalities for narcolepsy  . Neur ology  1998  ;50 (2
Suppl 1  ):S43 –8.
Greenhill  LL , Pliszka  S , Dulcan  MK , et al. Practice parameter for the use
of stimulant medications in the treatment of children, adolescents, and
adults  . J Am Acad Child Adolesc Psychiatry  2002  ;41 (2 ):S26 –49 .Some patients respond to or tolerate d-amphetamin better than
methylphenidate and vice versa
Some patients may benefit from an occasional addition of 5 –10 mg
of immediate-release d-amphetamine to their daily base of
sustained-release Dexedrine Spansules
Atypical antipsychotics may be useful in treating stimulant or

psychotic consequences of overdose
Drug abuse may actually be lower in ADHD adolescents treated
with stimulants than in ADHD adolescents who are not treated

Jadad  AR , Boyle  M , Cunningham  C , Kim M , Schachar  R . Treatment of
attention-deficit/hyperactivity disorder  . Evid Rep T echnol Assess (Summ)
1999  ;11 :i –viii , 1 –341 .
Stiefel  G , Besag  FM . Cardiovascular ef fects of methylphenidate,
amphetamines, and atomoxetine in the treatment of attention-deficit
hyperactivity disorder  . Drug Saf  2010  ;33 (10 ):821–42 .
Vinson  DC . Therapy for attention-deficit hyperactivity disorder  . Arch Fam
Med 1994  ;3 :445–51 .
Wender  PH , Wolf LE , Wasserstein  J . Adults with ADHD. An overview  .
Ann NY Acad Sci  2001  ;931 :1 –16 .

Amphetamine (D,L)
Brands
Generic?
Yes
 Class
Commonly Pr escribed forAdderall
Adderall XR
Evekeo
Adzenys-XR-ODT
Dyanavel XR
Mydayis
Adzenys ER
Stimulant

blocking their reuptake and facilitating their releaseAttention deficit hyperactivity disorder (ADHD) in patients ages
3 and older (Adderall, Evekeo)
ADHD in childr en ages 6 –17 (Dyanavel XR)
ADHD in patients ages 6 and older (Adderall XR, Evekeo,
Adzenys XR-ODT , Adzenys ER)
ADHD in patients ages 13 and older (Mydayis)
Narcolepsy in patients ages 6 and older (Adderall, Evekeo)
Exogenous obesity in patients ages 12 and older (Evekeo)
brain regions (e.g., dorsolateral prefrontal cortex) may improve
attention, concentration, executive function, and wakefulness

If It W orks (for ADHD)
If It Doesn ’t Work (for ADHD)Some immediate ef fects can be seen with first dosing
Continue treatment until all symptoms are under control or
Consider adjusting dose or switching to another formulation of d,l-
parents

parents

Testsetc.)
Best to attempt other monotherapies prior to augmenting
For the expert, can combine immediate-release formulation with a
sustained-release formulation of d,l-amphetamine for ADHD
ADHD
or ADHD

 Life-Thr eatening or Danger ous Side EffectsIn children, monitor weight and height
abuse
Seizures

Sedation
What to Do About Side EffectsPalpitations, tachycardia, hypertension
Wait

Dosage FormsBeta blockers for peripheral autonomic side ef fects
agent
Narcolepsy: 5 –60 mg/day in divided doses
ADHD: varies by formulation; see How to Dose section
Exogenous obesity: 30 mg/day in divided doses
Immediate-release Adderall tablet 5 mg double-scored, 7.5 mg
double-scored, 10 mg double-scored, 12.5 mg double-scored, 15 mg
double-scored, 20 mg double-scored, 30 mg double-scored
Immediate-release Evekeo tablet 5 mg scored, 10 mg double-scored
Extended-release orally disintegrating tablet (Adzenys XR-ODT)
3.1 mg, 6.3 mg, 9.4 mg, 12.5 mg, 15.7 mg, 18.8 mg
Extended-release tablet (Adderal XR) 5 mg, 10 mg, 15 mg, 20 mg,
25 mg, 30 mg

How to DoseExtended-release capsule (Mydayis) 12.5 mg, 25 mg, 37.5 mg, 50
mg
Extended-release oral suspension (Dynavel XR) 2.5 mg/mL
Extended-release oral suspension (Adzenys ER) 1.25 mg/mL
Immediate-release Adderall or Evekeo in ADHD (ages 6 and older):
initial 5 mg once or twice per day; can increase by 5 mg each week;
maximum dose generally 40 mg/day; split daily dose with first dose
on waking and every 4 –6 hours thereafter
Immediate-release Evekeo in ADHD (ages 3 to 5): initial 2.5
mg/day; can increase by 2.5 mg each week; administered in divided
doses
Immediate-release Adderall or Evekeo in narcolepsy (ages 12 and
older): initial 10 mg/day; can increase by 10 mg each week; split
daily dose with first dose on waking and every 4 –6 hours thereafter
Immediate-release Evekeo in narcolepsy (ages 6 to 12): initial 5
mg/day; can increase by 5 mg each week; administered in divided
doses
Extended-release tablet in ADHD: initial 10 mg/day in the morning;

doses
can increase by 5 –10 mg/day at weekly intervals; maximum dose
generally 30 mg/day
Extended-release oral suspension in ADHD (Dynavel XR): initial
2.5 mg or 5 mg once in the morning; can increase by 2.5 –10 mg/day

Dosing T ipsevery 4 –7 days; maximum recommended dose 20 mg/day
Extended-release oral suspension in pediatric ADHD (Adzenys ER):
initial 6.3 mg once in the morning; maximum dose 18.8 mg/day for
patients ages 6 to 12 years and 12.5 mg/day for patients ages 13 to
17 years
Extended-release oral suspension in adult ADHD (Adzenys ER):
12.5 mg once daily in the morning
Extended-release orally disintegrating tablet in ADHD: initial 6.3
mg once in the morning; maximum dose 18.8 mg/day for patients
ages 6 –12 or 12.5 mg/day for patients ages 13 and older
Extended-release capsule in adult ADHD: initial dose 12.5 mg
immediately upon waking; can increase daily dose weekly by 12.5
mg; maximum recommended daily dose 50 mg
Extended-release capsule in ADHD (ages 13 to 17): initial dose 12.5
mg immediately upon waking; can increase daily dose weekly by
12.5 mg; maximum recommended daily dose 25 mg
Immediate-release Evekeo in exogenous obesity (ages 12 and

older): usual daily dose 30 mg; taken in divided doses of 5 –10 mg,
30–60 minutes before meals
Clinical duration of action often dif fers from pharmacokinetic half-
life

✽ Immediate-release d,l-amphetamine has 3 –6 hour duration of
✽ Extended-release d,l-amphetamine has up to 8-hour duration of
✽ Controlled-release delivery of d,l-amphetamine is suf ficiently long
in duration to allow elimination of lunchtime dosing
reassess therapeutic utility and ef fects on growth and to allow catch-upAdderall XR is controlled-release and should therefore not be
chewed but rather should only be swallowed whole
Extended-release oral suspension (Dyanavel XR) and extended-
release orally disintegrating tablet (Adzenys XR-ODT) should not

be substituted for other amphetamine products on a mg-per -mg basis
due to dif fering amphetamine base compositions and
pharmacokinetic profiles
May be possible to dose only during the school week for some
ADHD patients

Overdose
Long-T erm UseHowever , most studies show that parental height is what determines
a patient ’s final height, and that most children/adolescents taking
Side ef fects are generally dose-related
confusion, coma, hallucinations, convulsions, arrhythmia, change in

Periodic monitoring of weight, blood pressure, CBC, platelet counts,

How to Stop
PharmacokineticsHigh abuse potential, Schedule II drug
Adderall and Adderall XR are a mixture of d-amphetamine and l-
amphetamine salts in the ratio of 3:1
A single dose of Adderall XR 20 mg gives drug levels of both d-
amphetamine and l-amphetamine comparable to Adderall
immediate-release 20 mg administered in 2 divided doses 4 hours
apart
In adults, half-life for d-amphetamine is 10 hours and for l-
amphetamine is 13 hours
For children ages 6 –12, half-life for d-amphetamine is 9 hours and
for l-amphetamine is 1 1 hours

Drug InteractionsSubstrate for CYP450 2D6
increases in brain concentrations of amphetamine and may also add
to amphetamine ’s cardiovascular ef fects

experts only , when monitoring patients closely and when other

Other W arnings/Pr ecautionshypertensive crisis and malignant hyperthermia, sometimes with

behavior

Do Not UseParticular attention should be paid to the possibility of subjects
fatigue
II condition sometimes associated with suicidal ideation, and require
the addition of a mood stabilizer and/or discontinuation of d,l-
children

children

ElderlyShould generally not be administered with an MAOI, including
an expert

 PregnancySome patients may tolerate lower doses better
Safety and ef ficacy not established under age 3
d,l-amphetamine may worsen symptoms of behavioral disturbance
children
d,l-amphetamine has acute ef fects on growth hormone; long-term
ADHD: ages 3 –5: initial 2.5 mg/day; can increase by 2.5 mg each
week
Narcolepsy: ages 6 –12: initial 5 mg/day; increase by 5 mg each
week

✽ For ADHD patients, d,l-amphetamine should generally be
Infants whose mothers take d,l-amphetamine during pregnancy may
In rat and rabbit studies, amphetamine d,l did not af fect embryofetal
development or survival throughout or ganogenesis at doses of
approximately one and a half and eight times the maximum
recommended human dose of 30 mg/day (child)

Use in women of childbearing potential requires weighing potential

Primary T arget SymptomsIf infant shows signs of irritability , drug may need to be
May work in ADHD patients unresponsive to other stimulants,
including pure d-amphetamine sulfate
Multiple formulation options
Concentration, attention span

Pearls
infection and in cancer patients
vigilance
dysfunction, delayed ejaculation, and anor gasmiaDepression

✽ Adderall and Adderall XR are a mixture of d-amphetamine and l-
✽ Specifically , Adderall and Adderall XR combine 1 part
dextroamphetamine saccharate, 1 part dextroamphetamine sulfate, 1
part d,l-amphetamine aspartate, and 1 part d,l-amphetamine sulfate
✽ This mixture of salts may have a dif ferent pharmacologic profile,
including mechanism of therapeutic action and duration of action,
compared to pure dextroamphetamine, which is given as the sulfate
salt
✽ Specifically , d-amphetamine may have more profound action on
dopamine than norepinephrine whereas l-amphetamine may have a
more balanced action on both dopamine and norepinephrine
✽ Theoretically , this could lead to relatively more noradrener gic
actions of the Adderall mixture of amphetamine salts than that of pure
dextroamphetamine sulfate, but this is unproven and of no clear
clinical significanceDrug abuse may actually be lower in ADHD adolescents treated

Some patients respond to or tolerate d,l-amphetamine better than
Nevertheless, some patients may respond to or tolerate
Adderall/Adderall XR dif ferently than they do pure dextro-
amphetamine sulfate

Suppl 1): S43–8 .
adults  . J Am Acad Child Adolesc Psychiatry  2002  ;41 (2 Suppl):S 26 –49 .
1999  ;11:i –viii,1 –341 .
Stiefel  G , Besag  FM. Cardiovascular ef fects of methylphenidate,
Ann NY Acad Sci  2001  ;931 :1 –16 .Adderall XR capsules also contain 2 types of drug-containing beads

designed to give a double-pulsed delivery of amphetamines to
prolong their release

Aripiprazole
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Abilify
Abilify Maintena
Aristada
Neuroscience-based Nomenclature: dopamine, serotonin receptor
partial agonist (DS-RP A)
Dopamine partial agonist (dopamine-serotonin partial agonist,
dopamine stabilizer , atypical antipsychotic, third-generation
antipsychotic; sometimes included as a second-generation
antipsychotic; also a mood stabilizer)

How the Drug W orksSchizophr enia (adults) (Abilify , Abilify Maintena, Aristada,
Aristada Initio)
Schizophr enia (ages 13 to 17) (Abilify)
Maintaining stability in schizophr enia (Abilify)
Acute mania/mixed mania (ages 10 and older; monotherapy and
adjunct) (Abilify)
Bipolar maintenance [monotherapy (Abilify , Abilify Maintena)
and adjunct (Abilify)]
Depr ession (adjunct) (Abilify)
Autism-r elated irritability in childr en ages 6 to 17 (Abilify)
Tourette’s disorder in childr en ages 6 to 18 (Abilify)
Acute agitation associated with schizophr enia or bipolar
disorder (IM Abilify)
Bipolar depression
Other psychotic disorders
Behavioral disturbances in dementias
Behavioral disturbances in children and adolescents
Disorders associated with problems with impulse control
Posttraumatic stress disorder (PTSD)
Obsessive-compulsive disorder (adjunct to SSRIs)

✽ Partial agonism at dopamine 2 receptors
How Long Until It W orksTheoretically reduces dopamine output when dopamine
concentrations are high, thus improving positive symptoms and
mediating antipsychotic actions
Theoretically increases dopamine output when dopamine
concentrations are low , thus improving cognitive, negative, and
mood symptoms
Interactions at a myriad of other neurotransmitter receptors may
contribute to aripiprazole ’s efficacy
Actions at dopamine 3 receptors could theoretically contribute to
aripiprazole ’s efficacy
Partial agonism at 5HT1A receptors may be relevant at clinical
doses
Blocks serotonin 2A receptors, causing enhancement of dopamine
release in certain brain regions and thus reducing motor side ef fects
and possibly improving cognitive and af fective symptoms
Blockade of serotonin type 2C and 7 receptors as well as partial
agonist actions at 5HT1A receptors may contribute to antidepressant
actions

actions
Psychotic and manic symptoms can improve within 1 week, but it
may take several weeks for full ef fect on behavior as well as on
cognition and af fective stabilization

If It W orksClassically recommended to wait at least 4 –6 weeks to determine
symptoms
Many bipolar patients may experience a reduction of symptoms by
half or more

Treatment may not only reduce mania but also prevent recurrences
of mania in bipolar disorder

ResistanceAfter reaching a satisfactory plateau, continue treatment for at least
For second and subsequent episodes of psychosis, treatment may
Try one of the other atypical antipsychotics
clozapine
If no first-line atypical antipsychotic is ef fective, consider higher
doses or augmentation with valproate or lamotrigine
injection

Tests
✽ Weigh all patients and track BMI during treatment
✽ Get waist circumference (at umbilicus), blood pressure, fasting
plasma glucose, and fasting lipid profileValproic acid (valproate, divalproex, divalproex ER)
Topiramate
Lithium
has hypertension (BP >140/90 mmHg)

✽ Consider monitoring fasting triglycerides monthly for several
months in patients at high risk for metabolic complications and when
initiating or switching antipsychotics
✽ Blood pressure, fasting plasma glucose, fasting lipids within 3
months and then annually , but earlier and more frequently for patients
with diabetes or who have gained >5% of initial weight
immediate treatment, by monitoring for the rapid onset of polyuria,
respiration, weakness and clouding of sensorium, even comahas dyslipidemia (increased total cholesterol, LDL cholesterol,

✽ Dizziness, insomnia, akathisia, activationPatients with low white blood cell count (WBC) or history of drug-
aripiprazole should be discontinued at the first sign of decline of
Blocking alpha 1 adrener gic receptors can cause dizziness,
hypotension, and syncope
Partial agonist actions at dopamine 2 receptors in the striatum can
cause akathisia and drug-induced parkinsonism
Partial agonist actions at dopamine 2 receptors can also cause
nausea, occasional vomiting, and activating side ef fects

✽ Nausea, vomiting
Weight GainOrthostatic hypotension, occasionally during initial dosing
Headache, asthenia, sedation
Tardive dyskinesia (reduced risk compared to conventional
antipsychotics)
Rare impulse control problems
Rare seizures
As a class, antidepressants have been reported to increase the risk of
suicidal thoughts and behaviors in children and young adults

Sedation
What to Do About Side EffectsReported in a few patients, especially those with low BMIs, but not
expected
Less frequent and less severe than for most other antipsychotics
May be more risk of weight gain in children than in adults
Reported in a few patients but not expected
May be less than for some other antipsychotics, but never say never
Can be activating
Wait
Wait
Wait
Reduce the dose
Anticholiner gics may reduce drug-induced parkinsonism when
present
Weight loss, exercise programs, and medical management for high

Usual Dosage RangeMetformin may help prevent or reverse antipsychotic-induced
15–30 mg/day for schizophrenia and mania
2–10 mg/day for augmenting SSRIs/SNRIs in depression
5–15 mg/day for autism
5–20 mg/day for T ourette ’s disorder
300–400 mg/4 weeks (LAI Maintena; see Aripiprazole Depot
Formulations after Pearls for dosing and use)
441 mg, 662 mg, or 882 mg administered monthly; 882 mg
administered every 6 weeks; or 1064 mg administered every 2

How to Dose –Oral and Acute IMmonths (LAI Aristada; see Aripiprazole Depot Formulations after
Pearls for dosing and use)
Aristada Initio: single 675 mg injection combined with a 30 mg oral
dose (on the same day as the first maintenance-dose injection or up
to 10 days later)
Tablet 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg
Orally disintegrating tablet 10 mg, 15 mg
Oral solution 1 mg/mL
Injection 9.75 mg/1.3 mL
Depot (Maintena) 300 mg, 400 mg
Depot (Aristada) 441 mg, 662 mg, 882 mg, 1064 mg
Single-dose injection (Initio) 675 mg
Schizophrenia, mania: initial approved recommendation is 10 –15
mg/day; maximum approved dose 30 mg/day
Depression (adjunct): initial dose 2 –5 mg/day; can increase by 5
mg/day at intervals of no less than 1 week; maximum dose 15
mg/day
Autism: initial dose 2 mg/day; can increase by 5 mg/day at intervals
of no less than 1 week; maximum dose 15 mg/day

Dosing T ips –Oral
✽ For some, less may be mor e: frequently , patients not acutely
psychotic may need to be dosed lower (e.g., 2.5 –10 mg/day) in order
to avoid akathisia and activation and for maximum tolerability
✽ Although studies suggest patients switching to aripiprazole from
another antipsychotic can do well with rapid switch or with cross-
titration, clinical experience suggests many patients may do best by
adding either an intermediate or full dose of aripiprazole to theTourette ’s disorder (patients weighing less than 50 kg): initial dose 2
mg/day; after 2 days increase to 5 mg/day; after 1 additional week
can increase to 10 mg/day if needed
Tourette ’s disorder (patients weighing more than 50 kg): initial dose
2 mg/day; after 2 days increase to 5 mg/day; after 5 additional days
can increase to 10 mg/day; can increase by 5 mg/day at intervals of
no less than 1 week; maximum dose 20 mg/day
Agitation: 9.75 mg/1.3 mL; maximum 30 mg/day

Oral solution: solution doses can be substituted for tablet doses on a
mg-per -mg basis up to 25 mg; patients receiving 30 mg tablet
should receive 25 mg solution
For others, mor e may be mor e: rarely , patients may need to be
dosed higher than 30 mg/day for optimum ef ficacy
Consider administering 1 –5 mg as the oral solution for children and
adolescents, as well as for adults very sensitive to side ef fects

maintenance dose of the first antipsychotic for at least several days and
possibly as long as 3 or 4 weeks prior to slow down-titration of the
first antipsychotic. See also the Switching section below , after Pearls
Overdose
Long-T erm UseRather than raise the dose above normal dosing in acutely agitated
Rather than raise the dose above normal dosing in partial
Due to its very long half-life, aripiprazole will take longer to reach
steady state when initiating dosing, and longer to wash out when
stopping dosing, than other atypical antipsychotics

No fatalities have been reported; sedation, vomiting
Approved to delay relapse in long-term treatment of schizophrenia
Approved for long-term maintenance in bipolar disorder

How to Stop
 Drug InteractionsOften used for long-term maintenance in various behavioral
disorders
No
aripiprazole
Rapid discontinuation could theoretically lead to rebound psychosis
and worsening of symptoms, but less likely with aripiprazole due to
its long half-life
Metabolized primarily by CYP450 2D6 and CYP450 3A4
Mean elimination half-life 75 hours (aripiprazole) and 94 hours
(major metabolite dehydro-aripiprazole)
Ketaconazole and possibly other CYP450 3A4 inhibitors such as
nefazodone, fluvoxamine, and fluoxetine may increase plasma

Other W arnings/Pr ecautionslevels of aripiprazole
Carbamazepine and possibly other inducers of CYP450 3A4 may
decrease plasma levels of aripiprazole
Quinidine and possibly other inhibitors of CYP450 2D6 such as
paroxetine, fluoxetine, and duloxetine may increase plasma levels of
Aripiprazole may enhance the ef fects of antihypertensive drugs
Aripiprazole may antagonize levodopa, dopamine agonists
There have been reports of problems with impulse control in
patients taking aripiprazole, including compulsive gambling,
shopping, binge eating, and sexual activity; use caution when
prescribing to patients at high risk for impulse-control problems
(e.g., patients with bipolar disorder , impulsive personality ,
obsessive-compulsive disorder , substance use disorders) and
monitor all patients for emer gence of these symptoms; dose should
be lowered or discontinued if impulse-control problems manifest
Use with caution in patients with conditions that predispose to

hypotension (dehydration, overheating)

Do Not Use
Renal Impairmentbody temperature (e.g., strenuous exercise, saunas, extreme heat,
Dysphagia has been associated with antipsychotic use, and
aripiprazole should be used cautiously in patients at risk for
aspiration pneumonia
therapy
If there is a proven aller gy to aripiprazole

Elderly
 Childr en and AdolescentsDose adjustment not necessary
Use in patients with cardiac impairment has not been studied, so use
with caution because of risk of orthostatic hypotension
Use with caution if patient is taking concomitant antihypertensive or
alpha 1 antagonist
Dose adjustment generally not necessary , but some elderly patients
may tolerate lower doses better
agitation
placebo, and also have an increased risk of cerebrovascular events
Consider pimavanserin for dementia-related psychosis or
Parkinson's disease psychosis instead of an atypical antipsychotic

PregnancyApproved for use in schizophrenia (ages 13 and older), manic/mixed
episodes (ages 10 and older), irritability associated with autism
(ages 6 –17), and treatment of T ourette ’s disorder (ages 6 –18)
Clinical experience and early data suggest aripiprazole may be safe
and ef fective for behavioral disturbances in children and
adolescents, especially at lower doses
Children and adolescents using aripiprazole may need to be
monitored more often than adults and may tolerate lower doses
better

Potential AdvantagesIn animal studies, aripiprazole demonstrated developmental toxicity ,
including possible teratogenic ef fects, at doses higher than the
maximum recommended human dose
Aripiprazole may be preferable to anticonvulsant mood stabilizers if
treatment is required during pregnancy
National Pregnancy Registry for Atypical Antipsychotics: 1-866-
961-2388,
https://womensmentalhealth.or g/research/pregnancyregistry/atypical
Infants of women who choose to breast feed while on aripiprazole
should be monitored for possible adverse ef fects
Some cases of psychosis and bipolar disorder refractory to treatment
with other antipsychotics

✽ Patients concerned about gaining weight and patients who are
already obese or overweight
✽ Patients with diabetes
✽ Patients with dyslipidemia (especially elevated triglycerides)
✽ Patients who wish to avoid sedation
 Pearls
✽ Approved as an adjunct treatment for depression (e.g., to SSRIs,
SNRIs)Patients requiring rapid onset of antipsychotic action without dosage
titration
Patients in whom sedation is desired
May be more dif ficult to dose for children, elderly , or “off-label ”
uses
Cognitive symptoms
Unstable mood (both depression and mania)
Aggressive symptoms

✽ Well accepted in clinical practice when wanting to avoid weight
gain because less weight gain than most other antipsychotics
✽ Well accepted in clinical practice when wanting to avoid sedation
because less sedation than most other antipsychotics at all doses
✽ Can even be activating, which can be reduced by lowering the dose
or starting at a lower dose
✽ May not have diabetes or dyslipidemia risk, but monitoring is still
indicatedMay work better in 2 –10 mg/day range than at higher doses for
augmenting SSRIs/SNRIs in treatment-resistant unipolar depression
Frequently used for bipolar depression as augmenting agent to
lithium, valproate. and/or lamotrigine
If sedation is desired, a benzodiazepine can be added short-term at
the initiation of treatment until symptoms of agitation and insomnia
are stabilized or intermittently as needed
Anecdotal reports of utility in treatment-resistant cases of psychosis
Has a very favorable tolerability profile in clinical practice

Favorable tolerability profile leading to “off-label ” uses for many
indications other than schizophrenia (e.g., bipolar II disorder ,
including hypomanic, mixed, rapid cycling, and depressed phases;
treatment-resistant depression; anxiety disorders)
A short-acting intramuscular formulation is available as well as
long-acting depot

Depot FormulationsLacks D1 antagonist, anticholiner gic, and antihistamine properties,
which may explain relative lack of sedation or cognitive side ef fects
in most patients
High af finity of aripiprazole for D2 receptors means that combining
with other D2 antagonist antipsychotics could reverse their actions
and thus often makes sense not to combine with other antipsychotics
An exception to this is in case of hyperprolactinemia or
galactorrhea, when administration of even low dose (1 –5 mg) can
reverse the hyperprolactinemia/galactorrhea of other antipsychotics,
also proving that aripiprazole interferes with the D2 actions of other
Abilify Maintena (depot) may be particularly well suited to early-
onset psychosis/first-episode psychosis to reduce rehospitalizations
and to enhance adherence with relatively low side ef fect burden
Aristada can be initiated in one day using two injections and one pill
(Aristada formulation plus Initio single-dose injection plus a 30 mg

oral pill); this avoids the need for any further oral medication or for
a follow-up injection for another 4, 6, or 8 weeks
Aristada might be the formulation of choice for patients on the last
day of hospitalization or incarceration, obviating the need for further
treatment or follow-up until the next LAI injection of Aristada is
due

Monohydrate
(Maintena)Laur oxil (Aristada) Monohydrate
(Maintena)Laur oxil (Aristada)
Vehicle Water Water
Tmax 6.5–7.1 days 44.1–50.0 days
T1/2 with multiple
dosing29.9–46.5 days 29.2–34.9 days
Time to reach steady
state4 monthly injections
Able to be loaded No Yes, with Initio
formulation
Dosing schedule
(maintenance)4 weeks 4–6 weeks
Injection site Intramuscular
glutealIntramuscular injection
in deltoid (441 mg dose
only) or gluteal (441,
662, or 882 mg)
Needle gauge 21 20 or 21
Dosage forms 300 mg, 400 mg 441 mg, 662 mg, 882
mg, 1064 mg
Injection volume 200 mg/mL; range
0.8 mL (160 mg) –2
mL (400 mg)441 mg/1.6 mL; 662
mg/2.4 mL; 882 mg/3.2
mL, 1064 mg/3.9 mL

How to Dose300–400 mg/4 weeks (monohydrate Maintena)
months
Not recommended for patients who have not first demonstrated
tolerability to oral aripiprazole (in clinical trials, 2 oral or short-
acting IM doses are generally used to establish tolerability)
Maintena: loading is not possible, necessitating oral coverage for 14
days
Conversion from oral to Maintena: administer initial 400 mg
injection along with an overlapping 14-day dosing of oral
Aristada: loading is not possible, necessitating either oral coverage
for 21 days or use of the single-dose injection
Conversion from oral to Aristada with oral supplementation:
administer initial injection (441 mg, 662 mg, 882 mg, or 1064 mg)

along with an overlapping 21-day dosing of oral aripiprazole
Conversion from oral to Aristada with the single-dose injection
(Initio): administer the 675 mg single-dose injection in combination

Dosing T ipswith a 30 mg oral dose; the first maintenance aripiprazole lauroxil
injection can be administered on the same day as the single-dose
injection or up to 10 days later; avoid injecting both the single-dose
injection and maintenance-dose injection into the same deltoid or
gluteal muscle
With LAIs, the absorption rate constant is slower than the
elimination rate constant, thus resulting in “flip-flop ” kinetics –i.e.,
time to steady state is a function of absorption rate, while
concentration at steady state is a function of elimination rate
The rate-limiting step for plasma drug levels for LAIs is not drug
metabolism, but rather slow absorption from the injection site
In general, 5 half-lives of any medication are needed to achieve 97%
of steady-state levels
The long half-lives of depot antipsychotics mean that one must
either adequately load the dose (if possible) or provide oral
supplementation
The failure to adequately load the dose leads either to prolonged

cross-titration from oral antipsychotic or to sub-therapeutic
antipsychotic plasma levels for weeks or months in patients who are
not receiving (or adhering to) oral supplementation
Because plasma antipsychotic levels increase gradually over time,
dose requirements may ultimately decrease from initial; obtaining

Maintena: CYP450 Dose Adjustment
Adjusted dose for
patients taking 300
mgAdjusted dose for
patients taking 400
mg
Poor 2D6 metabolizers N/A 300 mg
Patients taking strong
2D6 OR 3A4 inhibitors200 mg 300 mg
Poor 2D6 metabolizers
taking concomitant 3A4
inhibitorsN/A 200 mg
Patients taking 2D6
AND 3A4 inhibitors160 mg 200 mgperiodic plasma levels can be beneficial to prevent unnecessary
plasma level creep
The time to get a blood level for patients receiving LAI is the
morning of the day they will receive their next injection
Advantages: refrigeration not required; option of 6-week injections
with Aristada
Disadvantages: both formulations require oral coverage
Downward dose adjustment is needed for poor CYP450 2D6
metabolizers and patients taking strong CYP450 2D6 or 3A4
inhibitors; avoid use with strong CYP450 3A4 inducers, as this can
lead to sub-therapeutic plasma levels

mg
Patients taking 3A4
inducersAvoid Avoid
Aristada: CYP450 Dose Adjustment
Adjusted
dose for
patients
taking 441
mgAdjusted
dose for
patients
taking 662
dose for
patients
taking 882
dose for
patients
taking 1064
mg
Poor 2D6
metabolizersN/A N/A N/A N/A
Patients
taking
strong 2D6
OR 3A4
inhibitorsN/A 441 mg 662 mg 882 mg
Poor 2D6
metabolizers
taking
concomitant
3A4
inhibitorsN/A 441 mg 441 mg 441 mg

Adjusted
dose for
patients
taking 441
dose for
patients
taking 662
dose for
patients
taking 882
dose for
patients
mg
Patients
taking 2D6
AND 3A4
inhibitorsN/A Avoid Avoid Avoid
Patients
taking 3A4
inducers662 mg N/A N/A N/A
Switching fr om Oral Antipsychotics to Aripiprazole Depot
Formulations

Discontinuation of oral antipsychotic can begin following oral
coverage of 14 days (Maintena) or 21 days (Aristada)
How to discontinue oral formulations
Down-titration is not required for: amisulpride, aripiprazole,
brexpiprazole, cariprazine, paliperidone ER
1-week down-titration is required for: iloperidone, lurasidone,
risperidone, ziprasidone
3–4-week down-titration is required for: asenapine, olanzapine,
quetiapine
4+-week down-titration is required for: clozapine

 Switching fr om Oral Antipsychotics to Aripiprazole
agitation, and/or psychosisFor patients taking benzodiazepine or anticholiner gic
medication, this can be continued during cross-titration to help
alleviate side ef fects such as insomnia, agitation, and/or
psychosis. Once the patient is stable on LAI, these can be
tapered one at a time as appropriate
It is advisable to begin aripiprazole at an intermediate dose and
build the dose rapidly over 3 –7 days

El-Sayeh  HG , Morganti  C. Aripiprazole for schizophrenia  . Cochrane
Database Syst Rev  2006  ;(2) :CD004578  .
meta-analysis  . Lancet  2019  ;394 :939–51 .
Kane  JM , Sanchez  R , Perry  PP , et al. Aripiprazole intramuscular depot as
maintenance treatment in patients with schizophrenia: a 52-week,
multicenter , randomized, double-blind, placebo-controlled study  . J Clin
Psychiatry  2012  ;73 (5 ):617–24 .

Marcus  RN , McQuade  RD , Carson  WH , et al. The ef ficacy and safety of
aripiprazole as adjunctive therapy in major depressive disorder: a second
Psychopharmacol  2008  ;28 (2 ):156–65 .
Montastruc  F , Nie R , Loo S , et al. Association of aripiprazole with the
risk for psychiatric hospitalization, self-harm, or suicide  . JAMA Psychiatry
2019  ;76 (4 ):409–17 .
Nasrallah  HA . Atypical antipsychotic-induced metabolic side ef fects:
insights from receptor -binding profiles  . Mol Psychiatry  2008  ;13 (1 ):27 –
35 .

Armodafinil
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Nuvigil
Neuroscience-based Nomenclature: dopamine reuptake inhibitor (D-
RI)
Wake-promoting
Reducing excessive sleepiness in patients with nar colepsy and
shift work sleep disorder
Reducing excessive sleepiness in patients with obstructive sleep
apnea/hypopnea syndr ome (OSAHS) (adjunct to standard
treatment for underlying airway obstruction)

✽ Presumably enhances activity in hypothalamic wakefulness center
(TMN, tuberomammillary nucleus) within the hypothalamic sleep-
wake switch by an unknown mechanism
✽ Activates tuberomammillary nucleus neurons that release histamine
✽ Activates other hypothalamic neurons that release
orexin/hypocretin
How Long Until It W orksAttention deficit hyperactivity disorder (ADHD)
Fatigue and sleepiness in depression
Fatigue in multiple sclerosis
Unknown, but clearly dif ferent from classical stimulants such as
methylphenidate and amphetamine
Binds to and requires the presence of the dopamine transporter; also
requires the presence of alpha adrener gic receptors
Hypothetically acts as an inhibitor of the dopamine transporter
Increases neuronal activity selectively in the hypothalamus
Can immediately reduce daytime sleepiness and improve cognitive
task performance within 2 hours of first dosing

Can take several days to optimize dosing and clinical improvement

If It W orks
✽ Improves daytime sleepiness and may improve attention as well as
fatigue
✽ Does not generally prevent one from falling asleep when needed
✽ Change dose; some patients may do better with an increased dose
but some may actually do better with a decreased dose
✽ Armodafinil is itself an adjunct to standard treatments for OSAHS;
if continuous positive airway pressure (CP AP) is the treatment of
choice, a maximal ef fort to treat first with CP AP should be made prior
to initiating armodafinil and CP AP should be continued after initiation
of armodafinil
✽ Armodafinil is itself an augmenting therapy to antidepressants for
residual sleepiness and fatigue in major depressive disorderMay not completely normalize wakefulness
Treat until improvement stabilizes and then continue treatment
indefinitely as long as improvement persists (studies support at least
12 weeks of treatment)

Augment or consider an alternative treatment for daytime
sleepiness, fatigue, or ADHD

✽ Armodafinil is itself an augmenting therapy to mood stabilizers for
bipolar depression
Tests
✽ HeadacheBest to attempt another monotherapy prior to augmenting with other
drugs in the treatment of sleepiness associated with sleep disorders
or problems concentrating in ADHD
Combination of armodafinil with stimulants such as
methylphenidate or amphetamine or with atomoxetine for ADHD
has not been systematically studied
However , such combinations may be useful options for experts, with
close monitoring, when numerous monotherapies for sleepiness or
ADHD have failed
Unknown
CNS side ef fects presumably due to excessive CNS actions on
various neurotransmitter systems

Sedation
What to Do About Side EffectsAnxiety , dizziness, insomnia
Dry mouth, diarrhea, nausea
Transient ECG ischemic changes in patients with mitral valve
prolapse or left ventricular hypertrophy have been reported (rare)
Rare activation of (hypo)mania, anxiety , hallucinations, or suicidal
ideation
Rare severe dermatologic reactions (Stevens-Johnson syndrome and
others)
Angioedema, anaphylactoid reactions, and multi-or gan
hypersensitivity reactions have been reported
Patients are usually awakened and some may be activated
Wait

How to DoseLower the dose
For activation or insomnia, do not give in the evening
If unacceptable side ef fects persist, discontinue use
For life-threatening or dangerous side ef fects, discountinue
immediately (e.g., at first sign of a drug-related rash)
150–250 mg/day
Tablet 50 mg, 100 mg, 150 mg, 200 mg, 250 mg
Titration up or down only necessary if not optimally ef ficacious at
the standard starting dose of 150 mg once a day
For OSA and narcolepsy , give as a single dose in the morning
For shift work sleep disorder , give as a single dose 1 hour prior to
the start of the work shift

✽ For sleepiness, more may be more: higher doses may be better than
lower doses in patients with daytime sleepiness in sleep disorders
✽ For problems concentrating and fatigue, less may be more: lower
doses may be paradoxically better than higher in some patients
Overdose
Long-T erm UseAt high doses, may slightly induce its own metabolism, possibly by
actions of inducing CYP450 3A4
Dose may creep upward in some patients with long-term treatment
due to autoinduction; drug holiday may restore ef ficacy at original
dose
Pharmacokinetics and clinical experience suggest armodafinil has
longer duration of action than racemic modafinil, generally
requiring only once daily administration
Agitation, insomnia, increase in hemodynamic parameters
Postmarketing experience includes CNS symptoms, such as
restlessness, disorientation, confusion, excitation, and
hallucinations; digestive changes, such as nausea and diarrhea; and
cardiovascular changes, such as tachycardia, bradycardia,

hypertension, and chest pain
The need for continued treatment should be reevaluated periodically

How to Stop
 Drug InteractionsSchedule IV ; may have some potential for abuse but unusual in
clinical practice
Taper not necessary; patients may have sleepiness on
discontinuation
Metabolized by the liver
Elimination half-life approximately 15 hours
Inhibits CYP450 2C19
Induces CYP450 3A4 (and slightly 1A2)
May increase plasma levels of drugs metabolized by CYP450 2C19
(e.g., diazepam, phenytoin, propranolol)
May decrease plasma levels of CYP450 3A4 substrates such as
ethinyl estradiol and triazolam
Due to induction of CYP450 3A4, ef fectiveness of steroidal
contraceptives may be reduced by armodafinil, including 1 month
after discontinuation

✽ However , coadministration with methylphenidate or
dextroamphetamine does not significantly change the
pharmacokinetics of armodafinil or either stimulant
 Other W arnings/Pr ecautionsInducers or inhibitors of CYP450 3A4 may af fect levels of
armodafinil (e.g., carbamazepine may lower modafinil plasma
levels; fluvoxamine and fluoxetine may raise armodafinil plasma
levels)
Armodafinil may slightly reduce its own levels by autoinduction of
CYP450 3A4
Patients on armodafinil and warfarin should have prothrombin times
monitored
Methylphenidate and dextroamphetamine may delay absorption of
armodafinil by an hour
Interaction studies with MAOIs have not been performed, but
MAOIs can be given with armodafinil by experts with cautious
Patients with history of drug abuse should be monitored closely
Armodafinil may cause CNS ef fects similar to those caused by other
CNS agents (e.g., changes in mood and, theoretically , activation of
psychosis, mania, or suicidal ideation)

Armodafinil should be used in patients with sleep disorders that
have been completely evaluated for narcolepsy , OSAHS, and shift

Do Not Use
Cardiac Impairmentwork sleep disorder
In OSAHS patients for whom CP AP is the treatment of choice, a
maximal ef fort to treat first with CP AP should be made prior to
initiating armodafinil, and then CP AP should be continued after
initiating armodafinil
The ef fectiveness of hormonal contraceptives may be reduced when
used with armodafinil and for 1 month after discontinuation of
armodafinil
Armodafinil is not a replacement for sleep
If there is a proven aller gy to armodafinil or modafinil
Use with caution
Reduce dose in severely impaired patients

Elderly
 Childr en and Adolescents
 PregnancyNot recommended for use in patients with a history of left
ventricular hypertrophy , ischemic ECG changes, chest pain,
arrhythmias, or recent myocardial infarction
Limited experience in patients over 65
Clearance of armodafinil may be reduced in elderly patients
Can be used cautiously by experts for children and adolescents
Intrauterine growth restriction and spontaneous abortion have been
reported with armodafinil and modafinil

In animal studies, developmental toxicity was observed at clinically
relevant plasma exposures

✽ Generally , armodafinil should be discontinued prior to anticipated
pregnancies
Primary T arget SymptomsUse in women of childbearing potential requires weighing potential
Unknown if armodafinil is secreted in human breast milk, but all
Selective for areas of brain involved in sleep/wake promotion
Less activating and less abuse potential than stimulants
May not work as well as stimulants in some patients
Sleepiness
Concentration

Pearls
✽ Armodafinil is not a replacement for sleep
✽ The treatment for sleep deprivation is sleep, not armodafinil
✽ May be useful to treat fatigue in patients with depression as well as
other disorders, such as multiple sclerosis, myotonic dystrophy ,
HIV/AIDS
✽ Compared to traditional stimulants, armodafinil has a novel
mechanism of action, novel therapeutic uses, and less abuse potentialArmodafinil is the longer -lasting R enantiomer of racemic modafinil
Armodafinil maintains high plasma concentrations later in the day
than does modafinil on a mg-to-mg basis, which could theoretically
result in improved wakefulness throughout the day with armodafinil
compared to modafinil
Controlled studies suggest armodafinil improves attention in
OSAHS and shift work sleep disorder , but controlled studies of
attention have not been performed in ADHD or major depressive
disorder
Controlled studies of racemic modafinil in ADHD suggest
improvement in attention

disorder
May be useful in treating sleepiness associated with opioid
analgesia, particularly in end-of-life management
Subjective sensation associated with armodafinil is usually one of
normal wakefulness, not of stimulation, although jitteriness can
rarely occur

Darwish  M , Kirby  M , Hellriegel  ET , Robertson P  Jr . Interaction profile
of armodafinil with medications metabolized by cytochrome P450 enzymes
1A2, 3A4, and 2C19 in healthy subjects  . Clin Pharmacokinet  2008  ;47 (1
):61 –74 .
Darwish  M , Kirby  M , Hellriegel  ET , Robertson  P Jr. Armodafinil and
modafinil have substantially dif ferent pharmacokinetic profiles despite
having the same terminal half-lives: analysis of data from three randomized,
single-dose, pharmacokinetic studies  . Clin Drug Investig  2009  ;29 (9
):613–23 .
Garnock-Jones  KP , Dhillon  S , Scott  LJ . Armodafinil  . CNS Drugs  2009
;23 (9 ):793 –803 .Alpha 1 antagonists such as prazosin may block the therapeutic
actions of armodafinil
Some controlled trials suggest ef ficacy in bipolar depression as an
adjunct to atypical antipsychotics

Asenapine
Brands
Generic?
No
 Class
(bold for FDA appr oved)SaphrisSecuado (transdermal)
Neuroscience-based Nomenclature: dopamine, serotonin,
norepinephrine receptor antagonist (DSN-RAn)
Atypical antipsychotic (serotonin-dopamine antagonist; second-
generation antipsychotics; also a mood stabilizer)
Schizophr enia, adults (Saphris, Secuado)
Acute mania/mixed mania, monotherapy , ages 10 to 17 and in
adults (Saphris)

How the Drug W orksAcute mania/mixed mania, adjunct to lithium or valpr oate,
Bipolar maintenance, adults (Saphris)
Bipolar maintenance
Behavioral disturbances in dementia
Posttraumatic stress disorder
psychosis and stabilizing af fective symptoms
contribute to asenapine ’s efficacy
Partial agonist at 5HT1A receptors, which may be beneficial for
mood, anxiety , and cognition in a number of disorders

✽ Serotonin 2C, serotonin 7, and alpha 2 antagonist properties may
contribute to antidepressant actions
several weeks for full ef fect on behavior as well as on cognition
efficacy of drug, but in practice some patients may require up to 16 –
20 weeks to show a good response, especially on negative or
cognitive symptoms
Most often reduces positive symptoms but does not eliminate them
Most schizophrenia patients do not have a total remission of
Perhaps 5 –15% of schizophrenia patients can experience an overall

If It Doesn ’t WorkMany bipolar patients may experience a reduction of symptoms by
If 2 or more antipsychotic monotherapies do not work, consider
clozapine

injection

Tests
plasma glucose, and fasting lipid profileConsider initiating rehabilitation and psychotherapy such as
Lithium

with diabetes or who have gained >5% of initial weightis obese (BMI >30)

respiration, weakness and clouding of sensorium, even coma
How Drug Causes Side EffectsPatients with low white blood cell count (WBC) or history of drug-
asenapine should be discontinued at the first sign of decline in WBC
in the absence of other causative factors

By blocking dopamine 2 receptors in the pituitary , it can cause

✽ Sedation, dizziness
✽ Drug-induced parkinsonism, akathisia
✽ May increase risk for diabetes and dyslipidemia
 Life-Thr eatening or Danger ous Side EffectsBlocking alpha 1 adrener gic receptors can cause dizziness,
Oral hypoesthesia
Application site reactions (oral ulcers, blisters, peeling/sloughing,
inflammation for sublingual; irritation, burning for transdermal)
Orthostatic hypotension
Type 1 hypersensitivity reactions (anaphylaxis, angioedema, low
blood pressure, rapid heart rate, swollen tongue, dif ficulty breathing,
wheezing, rash)

Sedation
What to Do About Side EffectsHyper glycemia, in some cases extreme and associated with
ketoacidosis or hyperosmolar coma or death, has been reported in
patients taking atypical antipsychotics
Occurs in a significant minority
May be less than for some antipsychotics, more than for others
Wait
Wait

Usual Dosage RangeWait
present

How to Dose –SublingualSchizophrenia and bipolar mania (sublingual): 10 –20 mg/day in 2
divided doses
Schizophrenia (transdermal): 3.8 mg/24 hours
Sublingual tablet 2.5 mg, 5 mg, 10 mg
Transdermal system 3.8 mg/24 hours, 5.7 mg/24 hours, 7.6 mg/24
hours
Must be administered sublingually; patients may not eat or drink for
10 minutes following administration
Schizophrenia: initial 10 mg/day in 2 divided doses; maximum dose
generally 20 mg/day in 2 divided doses; limited experience with
once daily administration
Bipolar mania (adults, monotherapy): initial 20 mg/day in 2 divided
doses; can reduce dose to 10 mg/day in 2 divided doses if there are
adverse ef fects
Bipolar mania (adults, adjunct): initial 10 mg/day in 2 divided
doses; can increase to 20 mg/day in 2 divided doses
Bipolar mania (children, monotherapy): initial 5 mg/day in 2
divided doses; after 3 days can increase to 10 mg/day in 2 divided
doses; after 3 more days can increase to 20 mg/day in 2 divided
doses

How to Dose –Transdermal
 Dosing T ips –SublingualPediatric patients may be more sensitive to dystonia with initial
dosing if the recommended titration schedule is not followed
Apply one Secuado transdermal system every 24 hours to one of the
following sites: hip, abdomen, upper arm, or lower back area
Recommended starting dose: 3.8 mg/24 hours
After 1 week, may increase to 5.7 mg/24 hours or 7.6 mg/24 hours
Asenapine is not absorbed after swallowing (less than 2%
bioavailable orally) and thus must be administered sublingually
(35% bioavailable), as swallowing would render asenapine inactive
Patients should be instructed to place the tablet under the tongue and
allow it to dissolve completely , which will occur in seconds; tablet
should not be divided, crushed, chewed, or swallowed
Patients may not eat or drink for 10 minutes following sublingual
administration so that the drug in the oral cavity can be absorbed
locally and not washed into the stomach (where it would not be
absorbed)

absorbed)
Once daily use seems theoretically possible because the half-life of
asenapine is 13 –39 hours, but this has not been extensively studied
and may be limited by the need to expose the limited sublingual
surface area to a limited amount of sublingual drug dosage

Dosing T ips –TransdermalSome patients may respond to doses greater than 20 mg/day but no
single administration should be greater than 10 mg, thus
necessitating 3 or 4 separate daily doses
Due to rapid onset of action, can be used as a rapid acting “prn” or
“as needed ” dose for agitation or transient worsening of psychosis
or mania instead of an injection

Based on the average exposure (AUC) of asenapine, Secuado 3.8
mg/24 hours corresponds to 5 mg twice daily of sublingual
asenapine, and Secuado 7.6 mg/24 hours corresponds to 10 mg
twice daily of sublingual asenapine

Overdose
Habit FormingInstruct patient to select a dif ferent transdermal system application
site each day to limit the occurrence of skin reactions
Do not cut Secuado; the whole transdermal system should be
applied
Discard Secuado by folding the used transdermal system so that the
adhesive side sticks to itself, and dispose of safely
If irritation or a burning sensation occurs while wearing Secuado,
remove the system and apply a new transdermal system to a new
application site
Showering is permitted, but the use of Secuado during swimming or
taking a bath has not been evaluated
Agitation, confusion
No

How to Stop
 Drug InteractionsDown-titration, over 2 –4 weeks when possible, especially when
simultaneously beginning a new antipsychotic while switching (i.e.,
cross-titration)
and worsening of symptoms
Half-life 13 –39 hours
Inhibits CYP450 2D6
Substrate for CYP450 1A2
Optimal bioavailability is with sublingual administration (~35%); if
food or liquid is consumed within 10 minutes of administration
bioavailability decreases to 28%; bioavailability decreases to 2% if
swallowed
Transdermal: maximum asenapine concentrations are typically
reached between 12 and 24 hours, with sustained concentrations
during wear time (24 hours); following removal, elimination half-
life is approximately 30 hours
May increase ef fects of antihypertensive agents
May antagonize levodopa, dopamine agonists

Other W arnings/Pr ecautionsCYP450 1A2 inhibitors (e.g., fluvoxamine) can raise asenapine
levels
Via CYP450 2D6 inhibition, asenapine could theoretically interfere
with the analgesic ef fects of codeine, and increase the plasma levels
of some beta blockers and of atomoxetine
Via CYP450 2D6 inhibition, asenapine could theoretically increase
concentrations of thioridazine and cause dangerous cardiac

asenapine should be used cautiously in patients at risk for aspiration
pneumonia

Do Not Use
Hepatic ImpairmentAntipsychotics may cause somnolence, postural hypotension, motor
therapy
Avoid exposing transdermal system to external heat sources during
wear , because both the rate and extent of absorption are increased
During wear time or immediately after removal of transdermal
system, local skin reactions may occur
Severe hepatic impairment (Child-Pugh C)
If there is a proven aller gy to asenapine or any components in the
transdermal system
No dose adjustment necessary for mild to moderate impairment
Contraindicated in patients with severe hepatic impairment

Elderly
 Childr en and AdolescentsUse in patients with cardiac impairment has not been studied, so use
agitation
Transdermal asenapine is approved only in adults
Sublingual asenapine is approved to treat acute manic/mixed

episodes of bipolar I disorder in children ages 10 and older
Efficacy of sublingual asenapine for schizophrenia was not
demonstrated in an 8-week, placebo-controlled, double-blind trial in

Pregnancyadolescent patients ages 12 to 17 years
Children and adolescents using asenapine may need to be monitored
more often than adults and may tolerate lower doses better
In animal studies, asenapine increased post-implantation loss and

decreased pup weight and survival at doses similar to or less than
recommended clinical doses; there was no increase in the incidence
of structural abnormalities

Potential DisadvantagesNational Pregnancy Registry for Atypical Antipsychotics: 1-866-
961-2388,
antipsychotic/
Unknown if asenapine is secreted in human breast milk, but all
Infants of women who choose to breast feed while on asenapine
Patients requiring rapid onset of antipsychotic action without dosage
titration
Patients who are less likely to be adherent
Efficacy for schizophrenia was not demonstrated in an 8-week,
placebo-controlled, double-blind trial in adolescent patients ages 12
to 17 years

 PearlsPositive symptoms of psychosis
Asenapine ’s chemical structure is related to the antidepressant
mirtazapine and it shares many of the same pharmacologic binding
properties of mirtazapine plus many others
Not approved for depression, but binding properties suggest
potential use in treatment-resistant and bipolar depression
Sublingual administration may require prescribing asenapine to
reliable, adherent patients, or those who have someone who can
supervise drug administration
Asenapine has a more rapid onset of action (Cmax) when given
sublingually than most atypical antipsychotics do when given orally ,
and thus may be suitable for use as a prn (as needed) agent to treat
acute agitation in patients with schizophrenia when an injection is
not possible

 Switching fr om Oral Antipsychotics to AsenapinePatients with inadequate responses to atypical antipsychotics may
of either
Although a frequent practice by some prescribers, adding 2

With amisulpride, aripiprazole, brexpiprazole, cariprazine,
lumateperone, and paliperidone ER, immediate stop is possible;
begin asenapine at middle dose

* May need to taper clozapine slowly over 4 weeks or longer
Citrome  L . Asenapine for schizophrenia and bipolar disorder: a review of
the ef ficacy and safety profile for this newly approved sublingually
absorbed second-generation antipsychotic  . Int J Clin Pract  2009  ;63 (12
):1762 –84 .
meta-analysis  . Lancet  2019  ;394 :939–51 .With risperidone, ziprasidone, iloperidone, and luasidone, begin
asenapine gradually , titrating over at least 2 weeks to allow patients
to become tolerant to the sedating ef fect

Shahid  M , Walker  GB , Zorn  SH , Wong EH . Asenapine: a novel
psychopharmacologic agent with a unique human receptor signature  . J
Psychopharmacol  2009  ;23 (1 ):65 –73 .
Tarazi  F , Stahl  SM . Iloperidone, asenapine and lurasidone: a primer on
their current status  . Exp Opin Pharmacother  2012  ;13 (13 ):1911–22 .

Atomoxetine
Brands
Generic?
Yes
 Class
 How the Drug W orksStrattera
Neuroscience-based Nomenclature: norepinephrine reuptake
inhibitor (N-RI)
Selective norepinephrine reuptake inhibitor (NRI)
Attention deficit hyperactivity disorder (ADHD) in adults and
childr en over 6

✽ Onset of therapeutic actions in ADHD can be seen as early as the
first day of dosing
If It W orksBoosts neurotransmitter norepinephrine/noradrenaline and may also
increase dopamine in prefrontal cortex
Blocks norepinephrine reuptake pumps, also known as
norepinephrine transporters
Presumably this increases noradrener gic neurotransmission
cortex, which lar gely lacks dopamine transporters, atomoxetine can
also increase dopamine neurotransmission in this part of the brain
Therapeutic actions may continue to improve for 8 –12 weeks
If it is not working within 6 –8 weeks, it may not work at all

✽ Best to attempt other monotherapies prior to augmentingTreatment for ADHD begun in childhood may need to be continued
Consider adjusting dose or switching to another agent
parents
etc.)
atomoxetine discontinuation and a switch to a mood stabilizer
SSRIs, SNRIs, or mirtazapine for treatment-resistant depression (use
combinations of antidepressants with atomoxetine with caution as
this may theoretically activate bipolar disorder and suicidal ideation)

Mood stabilizers or atypical antipsychotics for comorbid bipolar
disorder

Tests
✽ Sedation, fatigue (particularly in children)
✽ Decreased appetite
✽ Rare priapismFor the expert, can combine with modafinil, methylphenidate, or
amphetamine for ADHD
None recommended for healthy patients
May be prudent to monitor blood pressure and pulse when initiating
treatment and until dosage increments have stabilized
Norepinephrine increases in parts of the brain and body and at
receptors other than those that cause therapeutic actions (e.g.,
unwanted actions of norepinephrine on acetylcholine release causing
decreased appetite, increased heart rate and blood pressure, dry
mouth, urinary retention, etc.)
Most side ef fects are immediate but often go away with time
Lack of enhancing dopamine activity in limbic areas theoretically
explains atomoxetine ’s lack of abuse potential

Increased heart rate (6 –9 beats/min)
Increased blood pressure (2 –4 mmHg)
Insomnia, dizziness, anxiety , agitation, aggression, irritability
Dry mouth, constipation, nausea, vomiting, abdominal pain,
dyspepsia
Urinary hesitancy , urinary retention (older men)
Dysmenorrhea, sweating
Sexual dysfunction (men: decreased libido, erectile disturbance,
impotence, ejaculatory dysfunction, abnormal or gasm; women:
decreased libido, abnormal or gasm)
Increased heart rate and hypertension
Severe liver damage (rare)
Hypomania and, theoretically , rare induction of mania

Sedation
Best Augmenting Agents for Side EffectsPatients may experience weight loss
Occurs in significant minority , particularly in children
Wait
Wait
Wait
If giving once daily , can change to split dose twice daily
If atomoxetine is sedating, take at night to reduce daytime
drowsiness
In a few weeks, switch or add other drugs
For urinary hesitancy , give an alpha 1 blocker such as tamsulosin
Often best to try another monotherapy prior to resorting to
augmentation strategies to treat side ef fects
Many side ef fects are dose-dependent (i.e., they increase as dose
increases, or they reemer ge until tolerance redevelops)

How to DoseMany side ef fects are time-dependent (i.e., they start immediately
Activation and agitation may represent the induction of a bipolar
state, especially a mixed dysphoric bipolar II condition sometimes
discontinuation of atomoxetine
0.5–1.2 mg/kg/day in children up to 70 kg; 40 –100 mg/day in adults
Capsule 10 mg, 18 mg, 25 mg, 40 mg, 60 mg, 80 mg, 100 mg
For children 70 kg or less: initial dose 0.5 mg/kg per day; after 7
days can increase to 1.2 mg/kg per day either once in the morning or
divided; maximum dose 1.4 mg/kg per day or 100 mg/day ,
whichever is less
For adults and children over 70 kg: initial dose 40 mg/day; after 7
days can increase to 80 mg/day once in the morning or divided; after

2–4 weeks can increase to 100 mg/day if necessary; maximum daily
dose 100 mg

✽ Efficacy with once daily dosing despite a half-life of 5 hours
suggests therapeutic ef fects persist beyond direct pharmacologic
effects, unlike stimulants whose ef fects are generally closely correlated
with plasma drug levels
Overdose
Long-T erm UseCan be given once a day in the morning
Once daily dosing may increase gastrointestinal side ef fects
Lower starting dose allows detection of those patients who may be
especially sensitive to side ef fects such as tachycardia and increased
blood pressure
Patients especially sensitive to the side ef fects of atomoxetine may
include those individuals deficient in the enzyme that metabolizes
atomoxetine, CYP450 2D6 (i.e., 7% of Caucasians and 2% of
African Americans)
In such individuals, drug should be titrated slowly to tolerability and
effectiveness
Other individuals may require up to 1.8 mg/kg total daily dose
No fatalities have been reported as monotherapy; sedation, agitation,

hyperactivity , abnormal behavior , gastrointestinal symptoms
Safe

How to Stop
Metabolized by CYP450 2D6
Half-life approximately 5 hours
Plasma concentrations of atomoxetine may be increased by drugs
that inhibit CYP450 2D6 (e.g., paroxetine, fluoxetine), so
atomoxetine dose may need to be reduced if coadministered
Coadministration of atomoxetine and oral or IV albuterol may lead
to increases in heart rate and blood pressure
Coadministration with methylphenidate does not increase
cardiovascular side ef fects beyond those seen with methylphenidate
alone

Other W arnings/Pr ecautionsUse with caution with MAOIs, including 14 days after MAOIs are
stopped (for the expert)
Growth (height and weight) should be monitored during treatment
with atomoxetine; for patients who are not growing or gaining
weight satisfactorily , interruption of treatment should be considered
Use with caution in patients with hypertension, tachycardia,
cardiovascular disease, or cerebrovascular disease
Use with caution in patients with bipolar disorder
Use with caution in patients with urinary retention, benign prostatic
hypertrophy
Rare reports of hepatotoxicity; although causality has not been
established, atomoxetine should be discontinued in patients who
develop jaundice or other evidence of significant liver dysfunction
Use with caution with antihypertensive drugs
Increased risk of sudden death has been reported in children with
structural cardiac abnormalities or other serious heart conditions

nontreatment and make sure to document this in the patient ’s chart
companies

Do Not Use
Hepatic ImpairmentWhenever possible, warn patients and their caregivers about the
If patient is taking an MAOI (except as noted under Drug
Interactions)
If patient has pheochromocytoma or history of pheochromocytoma
If patient has a severe cardiovascular disorder that might deteriorate
with clinically important increases in heart rate and blood pressure
If there is a proven aller gy to atomoxetine
For patients with moderate liver impairment, dose should be
reduced to 50% of normal dose

Elderly
 Childr en and AdolescentsFor patients with severe liver impairment, dose should be reduced to
25% of normal dose
Use with caution because atomoxetine can increase heart rate and
Approved to treat ADHD in children over age 6
Recommended tar get dose is 1.2 mg/kg per day
Do not use in children with structural cardiac abnormalities or other
serious cardiac problems
against the risks and benefits of nontreatment and make sure to
document this in the patient ’s chart

Pregnancy
✽ For women of childbearing potential, atomoxetine should generally
be discontinued before anticipated pregnancies
✽ Recommend either to discontinue drug or bottle feedUse with caution, observing for activation of known or unknown
patients
Some animal studies have shown adverse ef fects

Unknown if atomoxetine is secreted in human breast milk, but all

 Pearls
✽ Unlike stimulants approved for ADHD, atomoxetine does not have
abuse potential and is not a scheduled substance
✽ Despite its name as a selective norepinephrine reuptake inhibitor ,
atomoxetine enhances both dopamine and norepinephrine in frontal
cortex, presumably accounting for its therapeutic actions on attention
and concentrationNo known abuse potential
May not act as rapidly as stimulants when initiating treatment in

increase dopamine as well as norepinephrine in this part of the
brain, presumably causing therapeutic actions in ADHD
Since dopamine is inactivated by dopamine reuptake in nucleus
accumbens, which lar gely lacks norepinephrine transporters,
atomoxetine does not increase dopamine in this part of the brain,
presumably explaining why atomoxetine lacks abuse potential
Atomoxetine ’s known mechanism of action as a selective
norepinephrine reuptake inhibitor suggests its ef ficacy as an
Pro-noradrener gic actions may be theoretically useful for the
treatment of chronic pain
Atomoxetine ’s mechanism of action and its potential antidepressant
actions suggest it has the potential to destabilize latent or
undiagnosed bipolar disorder , similar to the known actions of
proven antidepressants
Thus, administer with caution to ADHD patients who may also have
bipolar disorder
Unlike stimulants, atomoxetine may not exacerbate tics in T ourette ’s
syndrome patients with comorbid ADHD

Urinary retention in men over 50 with borderline urine flow has
been observed with other agents with potent norepinephrine
reuptake blocking properties (e.g., reboxetine, milnacipran), so
administer atomoxetine with caution to these patients

Garnock-Jones  KP , Keating  GM . Atomoxetine: a review of its use in
attention-deficit hyperactivity disorder in children and adolescents  .
Paediatr Drugs  2009  ;11 (3 ):203–26 .
Kelsey  D , Sumner  C , Casat  C , et al. Once daily atomoxetine treatment for
children with attention deficit hyperactivity behavior including an
assessment of evening and morning behavior: a double-blind, placebo-
controlled trial  . Pediatrics  2004  ;114 :el –8.
Michelson  D , Adler  L L , Spencer  T , et al. Atomoxetine in adults with
ADHD: two randomized, placebo-controlled studies  . Biol Psychiatry  2003
;53 (2 ):112–20 .
Michelson  D , Buitelaar  JK , Danckaerts  M , et al. Relapse prevention in
pediatric patients with ADHD treated with atomoxetine: a randomized,
double-blind, placebo-controlled study  . J Am Acad Child Adolesc
Psychiatry  2004  ;43 (7 ):896 –904 .

hyperactivity disorder  . Drug Saf  2010  ;33 (10 ):821–42 .Atomoxetine was originally called tomoxetine but the name was
changed to avoid potential confusion with tamoxifen, which might
lead to errors in drug dispensing

Benztropine
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Cogentin
Antiparkinson agent; anticholiner gic
Extrapyramidal disorders (drug-induced parkinsonism)
Acute dystonic reactions
Idiopathic generalized dystonia
Focal dystonias
Dopa-responsive dystonia

If It W orks
ResistanceDiminishes the excess acetylcholine activity caused by removal of
dopamine inhibition when dopamine receptors are blocked
May also inhibit the reuptake and storage of dopamine at central
dopamine receptors, prolonging dopamine action
For drug-induced parkinsonism and in Parkinson ’s disease, onset of
action can be within minutes or hours
Reduces motor side ef fects
Does not lessen the ability of antipsychotics to cause tardive
dyskinesia
Consider switching to trihexyphenidyl, diphenhydramine, or a
Disorders that develop after prolonged antipsychotic use may not
respond to treatment
Consider discontinuing the agent that precipitated the parkinsonism

Tests
 Life-Thr eatening or Danger ous Side EffectsIf inef fective, switch to another agent rather than augment
Benztropine is itself an augmenting agent to antipsychotics
Prevents the action of acetylcholine on muscarinic receptors
Dry mouth, blurred vision, diplopia
Confusion, hallucinations
Constipation, nausea, vomiting
Dilation of colon/paralytic ileus/bowel obstruction
Erectile dysfunction
Angle-closure glaucoma
Heat stroke, especially in elderly patients
Tachycardia, cardiac arrhythmias, hypotension

Sedation
Dosing and UseUrinary retention
Anticholiner gic agents such as benztropine can exacerbate or
unmask tardive dyskinesia
For confusion or hallucinations, discontinue use
For sedation, lower the dose and/or take the entire dose at night
For dry mouth, chew gum or drink water
For urinary retention, obtain a urological evaluation; may need to
discontinue use

How to Dose
 Dosing T ipsDrug-induced parkinsonism: 2 –8 mg/day
Parkinsonism: 0.5 –6 mg/day
Tablet 0.5 mg, 1 mg, 2 mg
Injection 1 mg/mL
Drug-induced parkinsonism: 1 –4 mg once or twice daily; can be
given orally or parenterally
Parkinsonism (oral): initial 0.5 mg once daily; increase by 0.5 mg at
5–6 day intervals until desired ef ficacy is reached
If drug-induced parkinsonism occurs soon after initiation of a
neuroleptic drug, it is likely to be transient; thus, attempt to
withdraw benztropine after 1 –2 weeks to determine if still needed
Patients may take benztropine once daily at night to improve sleep
and allow for earlier rising in the morning
Taking benztropine with meals can reduce side ef fects
Intramuscular and intravenous dosing are equally ef fective and fast-
acting

Overdose
How to Stop
 Drug InteractionsCirculatory collapse, cardiac arrest, respiratory depression or arrest,
psychosis, shock, coma, seizure, ataxia, combativeness, anhidrosis
and hyperthermia, fever , dysphagia, decreased bowel sounds,
sluggish pupils
Safe
Effectiveness may decrease over time (years), and side ef fects such
as sedation and cognitive impairment may worsen
No
Half-life 36 hours, although greatest ef fect lasts about 6 –8 hours
Metabolism is not well understood
Use with amantadine may increase side ef fects

Other W arnings/Pr ecautions
Do Not Use
Renal ImpairmentBenztropine and all other anticholiner gic agents may increase serum
levels and ef fects of digoxin
Can lower concentration of haloperidol and other phenothiazines,
causing worsening of schizophrenia symptoms
Can decrease gastric motility , resulting in increased gastric
deactivation of levodopa and reduction in ef ficacy
Use with caution in hot weather , as benztropine may increase
susceptibility to heat stroke
Anticholiner gic agents have additive ef fects when used with drugs
of abuse such as cannabinoids, barbiturates, opioids, and alcohol
In patients with glaucoma, particularly angle-closure glaucoma
In patients with pyloric or duodenal obstruction, stenosing peptic
ulcers, prostate hypertrophy or bladder neck obstructions, achalasia,
or megacolon
If there is a proven aller gy to benztropine
No known ef fects, but use with caution

Elderly
 PregnancyNo known ef fects, but use with caution
Use with caution in patients with known arrhythmias, especially
tachycardia
Elderly patients may be more susceptible to side ef fects
Do not use in children ages 3 and younger
Generalized dystonias may respond to anticholiner gic treatment, and
young patients usually tolerate the medication better than the elderly
Usual dose is 0.05 mg/kg once or twice daily

✽ Recommended either to discontinue drug or bottle feed unless the
potential benefit to the mother justifies the potential risk to the child
Primary T arget SymptomsControlled studies have not been conducted in pregnant women
Unknown if benztropine is secreted in human breast milk, but all
Infants of women who choose to breast feed while on benztropine
Drug-induced parkinsonism, particularly in acute setting
Patients with long-standing drug-induced parkinsonism may not
Generalized dystonias (less established as treatment than
trihexyphenidyl)
Tremor , akinesia, rigidity , drooling

Pearls
First-line agent for drug-induced parkinsonism related to
antipsychotic use
Useful adjunct in younger Parkinson ’s patients with tremor , but
trihexyphenidyl is more commonly used
Useful in the treatment of post-encephalitic Parkinson ’s disease and
for drug-induced parkinsonism, but not for tardive dyskinesias
Post-encephalitic Parkinson ’s patients usually tolerate higher doses
better than idiopathic Parkinson ’s patients
Generalized dystonias are more likely to benefit from
anticholiner gic therapy than focal dystonias; trihexyphenidyl is used
more commonly than benztropine
Sedation limits use, especially in older patients
Patients with cognitive impairment may do poorly
Can cause cognitive side ef fects with chronic use, so periodic trials
of discontinuation may be useful to justify continuous use,
especially in institutional settings when used as an adjunct to
Can be abused in institutional or correctional settings

Commonly used in an oral or intramuscular formulation as needed
with concomitant antipsychotics to reduce or prevent drug-induced

Brocks  DR . Anticholiner gic drugs used in Parkinson ’s disease: an
overlooked class of drugs from a pharmacokinetic perspective  . J Pharm
Pharm Sci  1999  ;2 (2 ):39 –46 .
Colosimo  C , Gori MC , Inghilleri  M . Postencephalitic tremor and delayed-
onset parkinsonism  . Parkinsonism Relat Disor d 1999  ;5 (3 ):123–4 .
Costa  J , EspÃrito-Santo  C , Borges A , et al. Botulinum toxin type A
versus anticholiner gics for cervical dystonia  . Cochrane Database Syst Rev
2005  ;(1):CD004312  .
Hai NT , Kim J , Park ES , Chi SC . Formulation and biopharmaceutical
evaluation of transdermal patch containing benztropine  . Int J Pharm  2008
;357 (1–2 ):55 –60 .

Blonanserin
Brands
Generic?
No
 Class
(bold for FDA appr oved)Lonasen
Atypical antipsychotic (serotonin dopamine antagonist; second-
generation antipsychotic; also a potential mood stabilizer)
Acute mania/mixed mania

If It W orksBehavioral disturbances in dementia
and possibly improving cognition and af fective symptoms
blonanserin ’s efficacy
Psychotic symptoms can improve within 1 week, but it may take

If It Doesn ’t WorkCan improve negative symptoms, as well as aggressive, cognitive,
treatment

treatment
clozapine

Tests
Befor e starting any atypical antipsychoticSome patients may require treatment with a conventional
injection
Mood-stabilizing anticonvulsants (carbamazepine, oxcarbazepine,
lamotrigine)
Lithium

Monitoring after starting any atypical antipsychotic
initiating or switching antipsychoticsGet baseline personal and family history of diabetes, obesity ,

How Drug Causes Side EffectsTreat or refer for treatment and consider switching to another
(CBC) monitored frequently during the first few months, and

blonanserin should be discontinued at the first sign of decline in

 Life-Thr eatening or Danger ous Side EffectsAcute blockade of dopamine 2 receptors in the striatum can cause
Akathisia, drug-induced parkinsonism
Insomnia, anxiety , sedation
Urinary retention
Tardive dyskinesia (TD) (reduced risk compared to conventional
Hyper glycemia, in some cases extreme and associated with

Sedation
What to Do About Side EffectsAs a class, antipsychotics are associated with an increased risk of
Wait
Wait
Wait
present

Dosage FormsBeta blockers, benzodiazepines, or 5HT2A antagonists (e.g.,
8–16 mg/day divided in 2 doses
Tablet 2 mg, 4 mg, 8 mg

How to Dose
 Dosing T ipsPowder 20 mg per 1 g powder
Initial 8 mg/day divided in 2 doses; maintenance dose 8 –16 mg/day
divided in 2 doses; maximum dose 24 mg/day
Blonanserin should be taken after a meal, as maximum
concentrations are increased in the fed state; however , because the
increase in systemic exposure continues until at least 4 hours after
food intake, blonanserin can be taken before bedtime
Start with twice daily dosing; once stabilized, some patients do well
with 1 dose given at night

Overdose
How to Stop
 Drug InteractionsLimited data
Not extensively studied past 56 weeks, but long-term maintenance
treatment is often necessary for schizophrenia
No
Down-titration, especially when simultaneously beginning a new
antipsychotic while switching (i.e., cross-titration)
Elimination half-life 10 –16 hours after single dose

Other W arnings/Pr ecautionsCYP450 3A4 inducers, such as carbamazepine, can lower the
plasma levels of blonanserin
CYP450 3A4 inhibitors, such as ketoconazole, nefazodone,
fluvoxamine, and fluoxetine, can increase plasma levels of
blonanserin
blonanserin should be used cautiously in patients at risk for

Do Not Use
Elderlytreatment, and recurrently for patients on long-term antipsychotic
therapy
In conjunction with adrenaline/epinephrine
If patient is taking ketoconazole
If there is a proven aller gy to blonanserin
Not studied
with caution

 Pregnancy
potential benefit to the mother justifies the potential risk to the childAlthough atypical antipsychotics are commonly used for behavioral
agitation
placebo and also have an increased risk of cerebrovascular events
Children and adolescents using blonanserin may need to be
better
Psychotic symptoms may worsen during pregnancy , and some form
Unknown if blonanserin is secreted in human breast milk, but all

 PearlsInfants of women who choose to breast feed while on blonanserin
May be useful when other antipsychotics have failed to provide
adequate response or have not been tolerated
Patients who require once daily dosing from the initiation of
treatment
Patients who require intramuscular administration
Relatively selective binding profile

Deeks  ED , Keating  GM . Blonanserin. A review of its use in the
management of schizophrenia  . CNS Drugs  2010  ;24 (1 ):65 –84 .
Hida  H , Mouri  A , Mori  K , et al. Blonanserin ameliorates phencyclidine-
induced visual-recognition memory deficits: the complex mechanism of
blonanserin action involving D3-5-HT2A and D1-NMDA receptors in the
mPFC  . Neur opsychopharmacology  2015  ;40 (3 ):601–13 .
Kishi  T , Matsuda  Y , Nakamura  H , Iwata  N. Blonanserin for
schizophrenia: a systematic review and meta-analysis of double-blind,
randomized, controlled trials  . J Psychiatr Res  2013  ;47 (2 ):149–54 .Not approved for mania, but almost all atypical antipsychotics
approved for acute treatment of schizophrenia have proven ef fective
in the acute treatment of mania as well
Blonanserin ’s binding af finity for D2 dopamine receptors (0.14 nM)
is greater than for D3 receptors (0.49 nM); however , it is one of the

very few antipsychotics in which the binding af finity for D3
receptors is greater than dopamine ’s binding af finity for D3
receptors (~60 nM)
D3 antagonist actions have been hypothetically associated with
improvement in negative, cognitive, and af fective symptoms

Yang J , Bahk  WM , Cho HS , et al. Efficacy and tolerability of blonanserin
in the patients with schizophrenia: a randomized, double-blind, risperidone-
compared trial  . Clin Neur opharmacol  2010  ;33 (4 ):169–75 .

Bremelanotide
Brands
Generic?
No
 Class
Acquir ed, generalized hypoactive sexual desir e disorder (HSDD)
in pr emenopausal women
 How the Drug W orksVyleesi
Nonselective melanocortin receptor agonist
Bremelanotide is a nonselective melanocortin receptor agonist; at
therapeutic doses, bremelanotide binding to melanocortin 1 and 4
receptors is most relevant

If It W orks
If there is no improvement after 8 weeks, discontinue use
ResistanceSexual dysfunction is theoretically linked to an imbalance in central
excitatory and inhibitory sexual signals
HSDD hypothetically results from excessive inhibitory signals,
inadequate excitatory signals, or a combination of the two
Melanocortin receptors are located in the medial preoptic area of the
hypothalamus, which is implicated in the sexual behavior of both
sexes; stimulation of those receptors leads to dopamine release
Should be used at least 45 minutes before anticipated sexual
activity; duration of ef ficacy after each dose is unknown and optimal
window for bremelanotide administration has not been established
Increases ratings on sexual desire scores
Reduces distress related to sexual dysfunction
None known

Tests
Blood pressure and risk for cardiovascular disease should be evaluated
before initiation and periodically during treatment
Binding at melanocortin 1 receptors on melanocytes leads to
melanin expression and increased pigmentation
Nausea
Flushing
Injection site reactions
Headache
Vomiting
Hyperpigmentation (higher risk with daily dosing)
Transient increase in blood pressure and decrease in heart rate

Sedation
Dosage FormsNone
Wait
In most cases nausea improves after the first dose; for persistent or
severe nausea, consider discontinuation or initiating antiemetic
therapy
For hyperpigmentation, consider discontinuation
Switch to another treatment option
Antiemetic medication
1.75 mg as needed, at least 45 minutes before anticipated sexual
activity

How to Dose
Overdose
Long-T erm UseSubcutaneous injection 1.75 mg/0.3 mL in a single-dose
autoinjector
Patient should self-inject 1.75 mg subcutaneously in the abdomen or
thigh using the autoinjector , as needed, at least 45 minutes before
anticipated sexual activity
Do not administer more than one dose in 24 hours
Not recommended to administer more than 8 doses per month
Duration of ef ficacy after each dose is unknown and the optimal
Patient should be advised to visually inspect the drug product prior
to administration, and to discard if the solution is cloudy or
discolored or if visible particles are observed
Limited data; nausea, focal hyperpigmentation, and more
pronounced blood pressure increases are more likely with higher
doses

How to Stop
 Other W arnings/Pr ecautionsSafe and ef fective in controlled trials (24 weeks) and open-label
extension studies lasting an additional 52 weeks
No
Bremelanotide is administered as needed
Tmax is approximately 1 hour
Mean terminal half-life approximately 2.7 hours
Absorption is not af fected by injection site (thigh or abdomen)
Bremelanotide may slow gastric emptying, which could impact the
rate and extent of absorption of concomitantly administered oral
medications
Bremelanotide may significantly decrease exposure to oral
naltrexone, so avoid use with orally administered naltrexone-
containing products

Do Not Use
Renal ImpairmentBremelanotide can cause transient increase in blood pressure and
decrease in heart rate, which occurs after each dose and usually
resolves within 12 hours; patients should be evaluated for
cardiovascular risk before and periodically during treatment;
treatment should not be initiated in those at high risk for
cardiovascular disease
Focal hyperpigmentation can occur , with greater risk in patients
with darker skin and with daily dosing; resolution was not
confirmed in some patients; consider discontinuation if
hyperpigmentation develops
Nausea can be severe enough to require antiemetic therapy or
treatment discontinuation; for most patients in clinical trials it
improved with the second dose; for persistent nausea, consider
discontinuation or initiation of antiemetic therapy
In patients with uncontrolled hypertension or known cardiovascular
disease
If there is a proven aller gy to bremelanotide

disease
Dose adjustment not necessary for mild to moderate impairment

Elderly
 PregnancyUse with caution in patients with severe impairment
Use with caution in patients with severe impairment
Not approved for use in postmenopausal women, and safety and
efficacy have not been established

Potential AdvantagesIn clinical trials of up to 12 months, 7 pregnancies were reported;
among these 7 pregnancies, no major congenital anomalies were
reported; there was one spontaneous abortion (miscarriage), five
full-term live births, and one outcome unknown as it was lost to
follow-up
When administered to pregnant dogs during or ganogenesis,
embryofetal toxicity occurred at doses approximately 16 times the
maximum recommended human dose (MRHD)
When administered to pregnant mice during pregnancy and
lactation, developmental ef fects occurred at doses approximately
125 times the MRHD
Advise patients to discontinue bremelanotide if pregnancy is
suspected
Pregnancy registry for bremelanotide: 1-877-41 1-2510
Unknown if bremelanotide is secreted in human breast milk, but all
Bremelanotide is dosed episodically (average 2 –3 times per month)
and has a half-life of 2.7 hours

 PearlsCan be taken as needed
For patients who do not respond to flibanserin
Patients with cardiovascular disease
Patients taking oral medications for which gastric absorption is
relevant (e.g., antibiotics)
Patients who do not like injections
Reduced sexual desire
Bremelanotide is not approved for treatment in postmenopausal
women or in men and is not indicated to enhance sexual
If not ef fective for HSDD, consider avoiding any concomitant use of
agents that either enhance serotonin activity (such as SSRIs or
SNRIs) or diminish dopamine activity (such as antipsychotics)
In women of childbearing potential who are or are likely to become
sexually active, should inform about risk of harm to the fetus and
monitor contraceptive status
Patients should be counseled that bremelanotide of fers no protection
against sexually transmitted diseases

Kingsber g SA , Clayton  AH , Portman  D , et al. Bremelanotide for the
treatment of hypoactive sexual desire disorder: two randomized phase 3
trials  . Obstet Gynecol  2019  ;134 (5 ):899 –908 .
Simon  JA , Kingsber g SA , Portman  D , et al. Long-term safety and ef ficacy
of bremelanotide for hypoactive sexual desire disorder  . Obstet Gynecol
2019  ;134 (5 ):909–17 .
Weinber ger JM , Houman  J , Caron  AT , et al. Female sexual dysfunction
and the placebo ef fect: a meta-analysis  . Obstet Gynecol  2018  ;132 (2
):453–8 .No studies, but theoretically possible to combine with flibanserin for
partial responders to either drug

Brexanolone
Brands
Generic?
No
 Class
 How the Drug W orksZulresso
Neuroactive steroid
Postpartum depr ession
Positive allosteric modulator at neuroactive steroid sites on both
gamma-aminobutyric acid (GABA) A benzodiazepine-sensitive and
benzodiazepine-insensitive ligand-gated ion channels
Benzodiazepine-insensitive GABA-A receptor subtypes (with Î´
subunits and Î± 4 or Î± 6 subunits) are located extrasynaptically ,

If It W orks
If It Doesn ’t Workwhere they capture not only GABA that dif fuses away from the
synapse, but also neuroactive steroids synthesized and released by
glia
GABA binding at these receptors hypothetically regulates tonic
inhibition
Brexanolone binds to the neuroactive steroid site, acting as a
positive allosteric modulator to enhance the ef fects of GABA
binding, i.e., to increase tonic GABAer gic tone
Only known therapeutic agent for depression with positive allosteric
modulation of the benzodiazepine-insensitive GABA-A receptor
Clinical improvement may be evident as early as 12 –24 hours into
the infusion
Improvement may continue over the 60-hour infusion regimen
In clinical trials, antidepressant ef fect was sustained at 30 days post-
infusion
Consider psychotherapy and/or initiating treatment with an oral

Tests
Weight GainBrexanolone is a short-term treatment
Some patients may require initiation of a longer -term oral
due to excessive actions at GABA-A receptors
Sedation, dizziness, dry mouth, flushing/hot flush
Excessive sedation or sudden loss of consciousness
Syncope, presyncope
Theoretical activation or emer gence of suicidal ideation

Sedation
Usual Dosage RangeNone
Excessive sedation with sudden loss of consciousness can occur
If excessive sedation occurs at any time during the infusion, stop the
infusion until the symptoms resolve; the infusion may be resumed at
the same or lower dose as clinically appropriate
If hypoxia occurs at any time during the infusion, immediately stop
the infusion; after hypoxia, the infusion should not be resumed
For other side ef fects, consider a maximum dose of 60 Î¼ g/kg/hour
(hours 24 to 52)
None

How to Dose
 Dosing T ipsAdministered as a continuous intravenous infusion over 60 hours,
titrated from 30 Î¼ g/kg/hour up to 90 Î¼ g/kg/hour and back down
to 30 Î¼ g/kg/hour on a set schedule (see How to Dose)
Injection 100 mg/20 mL (5 mg/mL) single-dose vial
Healthcare provider must be available on site for the duration of the
infusion in order to continuously monitor the patient and intervene
as necessary
0 to 4 hours: initial dose 30 Î¼ g/kg/hour
4 to 24 hours: increase dosage to 60 Î¼ g/kg/hour
24 to 52 hours: increase dosage to 90 Î¼ g/kg/hour; alternatively
consider 60 Î¼ g/kg/hour for those who do not tolerate 90 Î¼
g/kg/hour
52 to 56 hours: decrease dosage to 60 Î¼ g/kg/hour
56 to 60 hours: decrease dosage to 30 Î¼ g/kg/hour
Dilution is required prior to administration
Because of the risk of excessive sedation and loss of consciousness,
patients must be monitored continuously for the duration of the
infusion

Overdose
How to StopMonitor patients for hypoxia using continuous pulse oximetry
equipped with an alarm
Monitor for excessive sedation every 2 hours during planned, non-
sleep periods
Initiate brexanolone early enough during the day to allow for
recognition of excessive sedation
Patients must be accompanied during interactions with their children
Brexanolone is supplied as a concentrated solution that must be
diluted prior to administration; after dilution the product can be
stored in infusion bags under refrigerated conditions for up to 96
hours; however , because the diluted product can be used for only 12
hours at room temperature, each 60-hour infusion will require
preparation of at least 5 infusion bags
Limited data
Not intended for long-term use
Schedule IV

Do Not Use
Special PopulationsDown-titrate per the standard dosing regimen (see How to Dose)
Terminal half-life approximately 9 hours
Extensively metabolized by non-CYP-based pathways; metabolites
are inactive
Brexanolone can cause excessive sedation and sudden loss of
consciousness; for that reason, brexanolone is available only
through a Risk Evaluation and Mitigation Strategy (REMS); the
patient must be enrolled in the program prior to administration of
brexanolone
Brexanolone can cause hypoxia; monitor patients using pulse
oximetry and stop the infusion if hypoxia occurs
If there is a proven aller gy to brexanolone

Elderly
 PregnancyDose adjustment not necessary for mild, moderate, or severe renal
Avoid use in patients with end-stage renal disease, due to the
potential accumulation of the stabilizing agent, betadex sulfobutyl
ether sodium

Breast Feedingletter categories; the Pregnancy and Lactation Labeling Rule (PLLR
In animal studies, malformations were not seen in rats or rabbits at
levels up to 5 and 6 times the maximum recommended human dose
(MRHD), respectively
Developmental toxicities were seen in rats and rabbits at 5 and >3
times the MRHD, respectively , and reproductive toxicities were
seen in rabbits at >3 the MRHD
When administered during pregnancy and lactation in rats, lower
pup survival occurred at doses >2 times the MRHD and a
neurobehavioral deficit in female of fspring occurred at doses 5
times the MRHD
In published animal studies, administration of other drugs that
enhance GABAer gic inhibition to neonatal rats caused widespread
apoptotic neurodegeneration during the period of brain development

that corresponds to the third trimester of pregnancy in humans
essants

 PearlsIn a study of 12 healthy adult lactating women treated with
intravenous brexanolone according to the recommended 60-hour
regimen, concentrations of brexanolone in breast milk were low
(<10 ng/mL) in >95% of women; the calculated maximum relative
infant dose during infusion was 1 –2%
Rapid response
Can only be administered in a Zulresso REMS-certified healthcare
setting
Brexanolone is the first medication approved for the treatment of
postpartum depression
Brexanolone is first-in-class as an antidepressant with a GABAer gic
mechanism

Cooper  MC , Kilvert  HS , Hodgkins  P , Roskell  NS , Eldar -Lissai  A . Using
matching-adjusted indirect comparisons and network meta-analyses to
compare ef ficacy of brexanolone injection with selective serotonin reuptake
inhibitors for treating postpartum depression  . CNS Drugs  2019  ;33 (10
):1039 –52 .
Meltzer -Brody  S , Colquhoun  H , Riesenber g R , et al. Brexanolone
injection in post-partum depression: two multicentre, double-blind,
randomised, placebo-controlled, phase 3 trials  . Lancet  2018  ;392 (10152
):1058 –70 .
Zheng  W , Cai DB , Zheng  W , et al. Brexanolone for postpartum
depression: a meta-analysis of randomized controlled studies  . Psychiatry
Res 2019  ;279 :83–9 .
Zorumski  CF , Paul SM , Covey  DF , Mennerick  S . Neurosteroids as novel
antidepressants and anxiolytics: GABA-A receptors and beyond  . Neur obiol
Stress 2019  ;11 :100196  .A related neuroactive steroid is currently being studied in an oral

formulation for the treatment of postpartum depression and unipolar

Brexpiprazole
Brands
Generic?
No
 Class
(bold for FDA appr oved)Rexulti
antipsychotic; also a potential mood stabilizer)
Schizophr enia
Treatment-r esistant depr ession (adjunct)

✽ Partial agonism at dopamine 2 receptorsBipolar maintenance
Theoretically reduces dopamine output when dopamine
contribute to brexpiprazole ’s efficacy

If It W orks –for Schizophr eniaBlockade of alpha 1B receptors may reduce arousal symptoms in
posttraumatic stress disorder and in agitation associated with
dementia as well as motor side ef fects such as akathisia
Blockade of alpha 2C receptors may contribute to antidepressant
actions
brexpiprazole ’s efficacy
Blocks serotonin 7 receptors, which may be beneficial for mood,
cognitive impairment, and negative symptoms in schizophrenia, and
also in bipolar disorder and major depressive disorder
For psychosis, classically recommended to wait at least 4 –6 weeks
to determine ef ficacy of drug, but in practice some patients may
require up to 16 –20 weeks to show a good response, especially on
negative or cognitive symptoms

For depression, onset of therapeutic actions usually not immediate,
but often delayed 2 –4 weeks

If It W orks –for Depr essionCan improve negative symptoms, as well as aggressive, cognitive,
treatment

treatment

If It Doesn ’t Work –for Schizophr enia
If It Doesn ’t Work –for Depr essionContinue treatment until all symptoms are gone (remission) or
significantly reduced
clozapine
injection
Consider initiating rehabilitation and psychotherapy

Tests
Befor e starting any atypical antipsychoticSome patients may be nonresponders, sometimes called treatment-
Some patients who have an initial response may relapse even though
they continue treatment, sometimes called “poop-out ”
due to activation of latent or underlying bipolar disorder
For depression, brexpiprazole is itself an augmenting agent
Lithium

months in patients at high risk for metabolic complications and whenGet baseline personal and family history of diabetes, obesity ,
and
triglycerides; decreased HDL cholesterol)

brexpiprazole should be discontinued at the first sign of decline in

Partial agonist actions at dopamine 2 receptors and 5HT1A
receptors can also cause nausea, occasional vomiting, and activating
side ef fects
Akathisia (dose-dependent), restlessness (dose-dependent), anxiety
Sedation, headache

 Sedation
Wait
Wait
Wait

Usual Dosage RangeAnticholiner gics may reduce drug-induced parkinsonism when
present
Schizophrenia: 2 –4 mg once daily
Depression: 2 mg once daily

How to Dose
OverdoseTablet 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg
Schizophrenia: Initial 1 mg once daily for days 1 –4; increase to 2
mg once daily for days 5 –7; increase to 4 mg once daily on day 8;
maximum dose 4 mg once daily
Depression: initial 0.5 –1 mg once daily; increase in weekly intervals
up to 1 mg once daily and then up to 2 mg once daily; maximum
dose 3 mg once daily
Can be taken with or without foodRather than raise the dose above
normal dosing in acutely agitated patients requiring acute
antipsychotic actions, consider short-term (one dose or more)
augmentation with a benzodiazepine or another antipsychotic,
especially intramuscularlyRather than raise the dose above normal
dosing in partial responders, consider augmentation with a mood-
stabilizing anticonvulsant, such as valproate, topiramate, or
lamotrigine Children and elderly should generally be dosed at the
lower end of the dosage spectrumT reatment should be suspended if

absolute neutrophil count falls below 1000/mm3
Limited experience

How to Stop
PharmacokineticsSafety and ef ficacy demonstrated in schizophrenia in a maintenance
study lasting over 1 year
No
Because clinical experience is lacking, down-titration may be
prudent, especially when simultaneously beginning a new
However , the long half-life suggests that it may be possible to stop
brexpiprazole abruptly
brexpiprazole
and worsening of symptoms, but less likely with brexpiprazole due
to its long half-life
Mean half-life 91 hours (brexpiprazole) and 86 hours (major
metabolite DM-341 1)

Drug InteractionsMetabolized primarily by CYP450 2D6 and CYP450 3A4
In patients receiving a strong/moderate CYP450 3A4 inhibitor (e.g.,
ketaconazole), brexpiprazole should be administered at half the
usual dose
In patients receiving a strong CYP450 3A4 inducer (e.g.,
carbamazepine), brexpiprazole should be administered at double the
usual dose
In patients with schizophrenia who are receiving a strong/moderate
CYP450 2D6 inhibitor (e.g., quinidine) or who are known CYP450
2D6 poor metabolizers, brexpiprazole should be administered at half
the usual dose
However , clinical trials in major depressive disorder took into
account the potential concomitant administration of strong CYP450
2D6 inhibitors (e.g., paroxetine, fluoxetine), so the dose of
brexpiprazole does not need to be adjusted in these cases
In patients receiving both a strong/moderate CYP450 3A4 inhibitor
and a strong/moderate CYP450 2D6 inhibitor , brexpiprazole should
be administered at one-quarter the usual dose

In patients receiving a strong/moderate CYP450 3A4 inhibitor who
are known CYP450 2D6 poor metabolizers, brexpiprazole should be
administered at one-quarter the usual dose

Other W arnings/Pr ecautionsMay antagonize levodopa, dopamine agonists

brexpiprazole should be used cautiously in patients at risk for

Do Not Use
Cardiac ImpairmentAs with any antipsychotic, use with caution in patients with history
therapy
If there is a proven aller gy to brexpiprazole
Moderate, severe, or end-stage: maximum recommended dose for
depression is 2 mg once daily and for schizophrenia is 3 mg once
daily
Moderate to severe: maximum recommended dose for depression is
2 mg once daily and for schizophrenia is 3 mg once daily

Elderly
 PregnancyUse in patients with cardiac impairment has not been studied, so use
Some elderly patients may tolerate lower doses better
agitation
Parkinson ’s disease psychosis instead of an atypical antipsychotic
Children and adolescents using brexpiprazole may need to be

better

Breast FeedingEffective June 30, 2015, the US FDA requires changes to the
In animal studies, brexpiprazole did not demonstrate teratogenicity
Brexpiprazole may be preferable to anticonvulsant mood stabilizers

if treatment is required during pregnancy
961-2388,
http://womensmentalhealth.or g/research/pregnancyregistry/atypicala
ntipsychotic/

 PearlsUnknown if brexpiprazole is secreted in human breast milk, but all
Infants of women who choose to breast feed while on brexpiprazole
For patients who do not tolerate aripiprazole or cariprazine
Expensive

 Switching fr om Oral Antipsychotics to Br expiprazoleApproved as an adjunct treatment for depression
Animal data suggest that brexpiprazole may improve cognitive
impairment in schizophrenia
Brexpiprazole is in late-stage clinical testing for agitation associated
with Alzheimer dementia
Brexpiprazole has shown evidence of ef ficacy especially in
combination with sertraline for posttraumatic stress disorder
Not approved for mania, but almost all atypical antipsychotics
Pharmacological dif ferences from aripiprazole suggest less akathisia
with brexpiprazole, but no head-to-head trials
Compared to aripiprazole, brexpiprazole has more potent binding of
several receptor sites relative to dopamine 2 receptor binding,
namely 5HT1A, 5HT2A, and alpha 1 receptors; however , the
clinical significance of these dif ferences is still under investigation

It is advisable to begin brexpiprazole at an intermediate dose and

* Benzo diazepine or anticholiner gic medication can be admin istered
during cross-titration to help alleviate side effects such as insomnia,
meta-analysis  . Lancet  2019  ;394 :939–51 .to allow patients to readapt to the withdrawal of blocking

Kane  JM , Skuban  A , Ouyang  J , et al. A multicenter , randomized, double-
blind, controlled phase 3 trial of fixed-dose brexpiprazole for the treatment
of adults with acute schizophrenia  . Schizophr Res  2015  ;164 (1 –3):127–35
.
Kishi  T , Sakuma  K , Nomura  I , et al. Brexpiprazole as adjunctive
treatment for major depressive disorder following treatment failure with at
least one antidepressant in the current episode: a systematic review and
meta-analysis  . Int J Neur opsychopharmacol  2019  ;22 (11 ):698 –709 .
Ward K , Citrome  L . Brexpiprazole for the maintenance treatment of adults
with schizophrenia: an evidence-based review and place in therapy  .
Neur opsychiatr Dis T reat 2019  ;15 :247–57 .

Buprenorphine
Brands
Generic?
Yes (not for implant or injection)
 Class
(bold for FDA appr oved)Suboxone (with naloxone)
Probuphine (implant)
Sublocade (subcutaneous injection)
mu opioid receptor partial agonist
Induction of tr eatment for opioid dependence (Bunavail only)
Maintenance tr eatment of opioid dependence (sublingual)
Maintenance tr eatment of opioid dependence in patients who
have achieved and sustained pr olonged clinical stability on low-

How the Drug W orksto-moderate doses (no mor e than 8 mg) of a transmucosal
bupr enorphine-containing pr oduct (implant)
Moderate to sever e opioid use disorder in patients who have
initiated tr eatment with a transmucosal bupr enorphine-
containing pr oduct, followed by dose adjustment for a minimum
of 7 days (injection)
Binds with strong af finity to the mu opioid receptor , preventing
exogenous opioids from binding there and thus preventing the
pleasurable ef fects of opioid consumption
Because buprenorphine is a partial agonist, it can cause immediate
withdrawal in a patient currently taking opioids (i.e., reduces
receptor stimulation in the presence of a full agonist) but can relieve
withdrawal if a patient is already experiencing it (i.e., increases
receptor stimulation in the absence of a full agonist)
Buprenorphine is also an antagonist at the kappa opioid receptor
In combination with naloxone: naloxone is a mu opioid receptor

antagonist and can therefore block the ef fects of buprenorphine;
however , because naloxone has poor sublingual bioavailability , it
does not interfere with buprenorphine ’s effects when used properly .
Naloxone does have good parenteral bioavailability; thus, if one
tries to administer the buprenorphine/naloxone formulation
intravenously , naloxone will prevent any rewarding ef fects from
buprenorphine

If It W orks
ResistanceEffects on withdrawal can be immediate
Effects on reducing opioid use disorder/dependence can take many
months of treatment
Reduces cravings, decreases opioid consumption
Reduces ef fects of opioid withdrawal
Diminishes rewarding ef fects of opioid consumption
If patients receiving the implant feel a need for supplemental dosing,
they should be evaluated and transmucosal buprenorphine should be
treatment
Buprenorphine can be prescribed in combination with naloxone
(Suboxone) to decrease the potential for abuse or diversion

Tests
Sedation
Liver function tests at baseline and during treatment
Binding at mu opioid receptors
Headache, constipation, nausea
Oral hypoesthesia, glossodynia
Implant specific: insertion site pain, pruritis, erythema
Respiratory depression
Hepatotoxicity

Wait
Reduce dose
agent
Sublingual: 8 –32 mg/day
Implant: 4 implants intended to be in place for 6 months
Injection: maintenance dose is 100 –300 mg monthly
Sublingual tablet 2 mg, 8 mg
Sublingual tablet (with naloxone) 2 mg/ 0.5 mg, 8 mg/ 2 mg

How to Dose –SublingualSublingual film (with naloxone) 2 mg/0.5 mg, 4 mg/1 mg, 8 mg/2
mg, 12 mg/3 mg
Each implant is 26 mm in length and 2.5 mm diameter and contains
74.2 mg of buprenorphine (equivalent to 80 mg of buprenorphine
hydrochloride)
Injection 100 mg/0.5 mL, 300 mg/1.5 mL
Patients must be in a mild withdrawal state prior to starting bupre
Initiation (7 days)
Day 1 Day 2 Days 3 –7
Buprenorphine 8 mg 12 or 16
mgIncrease in
increments
of 4 mg;
maximum
32 mg
Buprenorphine/naloxone 8 mg/2
mg12 mg/3
mg or 16
mg/4 mgIncrease in
of 4 mg/1
mg;
maximum
32 mg/8 mg
norphine

Dosing T ips –SublingualObserve patient for at least 2 hours with initial dose, then have 1 –2
visits in first week
Achieve the lowest dose that eliminates withdrawal symptoms and
illicit opioid use
Stabilization (up to 2 months) and maintenance dose is generally 8 –
24 mg (8 mg/2 mg up to 24 mg/6 mg for buprenorphine/naloxone)
During stabilization patients should be seen once per week
During maintenance patients should be seen biweekly or monthly
Buprenorphine must be administered sublingually , as swallowing
reduces its bioavailability
Patients should be instructed to place the sublingual formulation
under the tongue and allow it to dissolve completely; the
formulation should not be divided, crushed, chewed, or swallowed
Can be dosed less often than once daily; one should double the dose
for each additional 24-hour interval
Buprenorphine alone is often used to initiate treatment, while
buprenorphine/naloxone is preferred for stabilization and
maintenance treatment

Only buprenorphine with naloxone should be used for unsupervised
administration, unless the patient has a proven aller gy to naloxone

How to Dose –Implant
 Dosing T ips –ImplantCan be distributed through clinicians ’offices by those who obtain a
DEA DA TA 2000 waiver
Patients being switched between the 2 sublingual formulations
(tablet and film) should be started on the same dose as the
previously administered product; however , because the sublingual
film has greater bioavailability than the sublingual tablet, patients
must be monitored for over -medication (when switching from tablet
to film) or under -medication (when switching from film to tablet);
dose adjustment may be necessary
Patient must have achieved and sustained prolonged clinical
stability on transmucosal buprenorphine
Four implants are inserted subdermally in the inner side of the upper
arm for 6 months of treatment and are removed by the end of the
sixth month
Implants must be inserted and removed by trained healthcare
providers who are certified in the Probuphine REMS program;
information is available at www .probuphinerems.com  or 1-844-859-
6341

6341
Patients must currently be on a maintenance dose of 8 mg/day or
less of transmucosal buprenorphine and should not be transitioned to
a lower dose for the sole purpose of transitioning to the implant

How to Dose –InjectionPatients should be on a stable transmucosal buprenorphine dose (8
mg/day or less) for 3 months or longer without any need for
supplemental dosing or adjustments
Examine the insertion site 1 week after implant insertion for signs of
infection or other problems
Patients should not receive prescriptions for transmucosal
buprenorphine for as-needed use; patients who feel a need for
supplemental dosing should be evaluated and alternative treatment
should be considered
For continued treatment, new implants may be inserted subdermally
in an area of the inner side of either upper arm that has not been
previously used at the time of removal
If new implants are not inserted on the same day as removal, then
patients should be maintained on their previous dosage of
transmucosal buprenorphine
After one insertion in each arm, most patients should be transitioned
back to transmucosal buprenorphine if continued treatment is

desired, as there is no experience with re-insertion into previously
used administration sites or insertion into sites other than the upper
arm
Two monthly initial doses of 300 mg, followed by 100 mg monthly
maintenance dose; can increase monthly maintenance dose to 300
mg if benefits outweigh risks

Dosing T ips –Injection
Overdose
How to StopShould be administered subcutaneously in the abdominal region;
should not be administered intravenously or intramuscularly
There should be a minimum of 26 days between doses
Occasional delays in dosing of up to 2 weeks are not expected to
have clinically significant impact on treatment ef fects
Can be fatal (less common than with methadone); respiratory
depression, sedation, constricted pupils, bradycardia, hypotension,
coma
Maintenance treatment may be required; typical maintenance period
is up to 2 years but may need to be indefinite
Buprenorphine is a Schedule III drug
Can cause physical dependence
Patients may experience a mild withdrawal syndrome if
buprenorphine is stopped abruptly

 Drug InteractionsTaper to avoid withdrawal ef fects
Elimination half-life of sublingual buprenorphine is 24 –42 hours
Elimination half-life of naloxone is 2 –12 hours
Implant: Tmax is 12 hours; time to steady state is 4 weeks
Increased depressive ef fects, particularly respiratory depression,
have occurred when taken with benzodiazepines or other CNS
depressants; prescribe the lowest ef fective dose and shortest
duration if taken concomitantly
Plasma concentrations of buprenorphine may be increased by drugs
that inhibit CYP450 3A4, so buprenorphine dose may need to be
reduced if coadministered
Patients taking a CYP450 3A4 inhibitor who transfer to the implant
should be monitored to ensure that plasma buprenorphine levels are
adequate
If a CYP450 3A4 inhibitor is initiated in a patient with the implant,
the patient should be monitored for signs of over -medication
If a CYP450 3A4 inhibitor is discontinued in a patient with the

implant, the patient should be monitored for signs of withdrawal

Other W arnings/Pr ecautionsPlasma concentrations of buprenorphine may be reduced by drugs
that induce CYP450 3A4, so buprenorphine dose may need to be
increased if coadministered
Patients taking a CYP450 3A4 inducer who transfer to the implant
not excessive
If a CYP450 3A4 inducer is initiated in a patient with the implant,
the patient should be monitored for signs of withdrawal
If a CYP450 3A4 inducer is discontinued in a patient with the
implant, the patient should be monitored for signs of over -
Increased risk of CNS depressant ef fects when benzodiazepines and
opioid medications are used together , including specifically the risk
of slowed or dif ficult breathing and death
efficacy

efficacy
Although the risk is lower , buprenorphine can be abused in a
manner similar to other opioids
Parenteral misuse of buprenorphine/naloxone may result in marked
opioid withdrawal syndrome

To prevent withdrawal in patients dependent on opioids, patients
must be in a mild withdrawal state prior to initiating treatment
Attempts by patients to overcome blockade of opioid receptors by
taking lar ge amounts of exogenous opioids could lead to opioid
intoxication or even fatal overdose
Use with caution in patients with compromised respiratory function
Risk of respiratory depression is increased with concomitant use of
CNS depressants, particularly with parenteral administration
Can cause severe, possibly fatal respiratory depression in children
who are accidentally exposed to it
Withdrawal symptoms can occur when switching from methadone
to buprenorphine
Buprenorphine may elevate cerebrospinal fluid pressure and should
be used with caution in patients with head injury , intracranial
lesions, and other circumstances when cerebrospinal pressure may
be increased
Buprenorphine may increase intracholedochal pressure and should

be administered with caution to patients with dysfunction of the
biliary tract
Use with caution in debilitated patients and those with myxedema or
hypothyroidism, adrenal cortical insuf ficiency (e.g., Addison ’s
disease); CNS depression or coma; toxic psychoses; prostatic
hypertrophy or urethral stricture; acute alcoholism; delirium
tremens; or kyphoscoliosis

Do Not UseUse the implant with caution in patients with a history of keloid
formation, connective tissue disease, or history of recurrent
recurrent methicillin-resistant Staphylococens aur eus (MRSA)
infections
Rare nerve damage and migration resulting in embolism and death
may occur due to improper insertion of the implant in the upper
arm; local migration, protrusion, and expulsion can also occur as a
result of improper or incomplete insertion; protrusion and expulsion
may occur as a result of infection
In the event that an implant is expelled, the patient should store it in
a plastic bag out of reach of children and bring it to their healthcare
provider to ensure that the entire implant was expelled
The prescribing healthcare provider will need to monitor the patient
until the implant is replaced
As an analgesic
If the patient is naive to opioid use
If there is a proven aller gy to buprenorphine
If patient has severe hepatic impairment (buprenorphine/naloxone
combinations only)

If there is a proven aller gy to naloxone (buprenorphine/naloxone

ElderlyDose adjustment not necessary
In patients with moderate to severe impairment, plasma levels of
buprenorphine can be higher and half-life can be longer; thus, these
patients should be monitored for signs and symptoms of toxicity or
overdose
For severe impairment, the dose should be reduced
Because dose adjustment is not possible with the implant, it is not
recommended for use in patients with moderate to severe hepatic
Hepatic impairment results in reduced clearance of naloxone, so
patients with severe impairment should not take
buprenorphine/naloxone combinations; caution is warranted for
patients with moderate impairment

Buprenorphine may be preferable to methadone in pregnant women
Neonatal withdrawal has been reported following use of
buprenorphine during pregnancy
In animal studies, adverse events have been observed at clinically
relevant doses; no clear teratogenic ef fects were seen, but increases
in skeletal abnormalities were observed in rats and rabbits given
daily buprenorphine at doses 5.4 and 10.8 times the maximum

human recommended dose

 Pearls
 Suggested ReadingSome drug is found in mother ’s breast milk
Patients with mild to moderate physical dependence
Patients unable to tolerate mild withdrawal symptoms
Opioid dependence
Considered a “take home ” medication that generally has less stigma
and better adherence than methadone
Relatively convenient to administer , with flexible dosing and ease of

Bonhomme  J , Shim  RS , Gooden  R , Tyus D , Rust G. Opioid addiction
and abuse in primary care practice: a comparison of methadone and
buprenorphine as treatment options  . J Natl Med Assoc  2012  ;104 (7–
8):342–50 .
Jones  HE , Finnegan  LP , Kaltenbach  K. Methadone and buprenorphine for
the management of opioid dependence in pregnancy  . Drugs  2012  ;72 (6
):747–57 .
Kraus  ML , Alford  DP , Kotz  MM , et al. Statement of the American
Society of Addiction Medicine Consensus Panel on the use of
buprenorphine in of fice-based treatment of opioid addiction  . J Addict Med
2011 ;5 (4 ):254–63 .
Yokell  MA , Zaller  ND , Green  TC , Rich  JD. Buprenorphine and
buprenorphine/naloxone diversion, misuse, and illicit use: an international
review  . Curr Drug Abuse Rev  2011 ;4 (1 ):28 –41 .

Bupropion
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)WellbutrinW ellbutrin SR Wellbutrin XL
Zyban
Aplenzin
Neuroscience-based Nomenclature: dopamine reuptake inhibitor and
releaser (D-RIRe)
NDRI (norepinephrine and dopamine reuptake inhibitor);
antidepressant; smoking cessation treatment
Major depr essive disorder (bupr opion, bupr opion SR, and
bupr opion XL)

How Long Until It W orksSeasonal affective disorder (bupr opion XL)
Nicotine addiction (bupr opion SR)
Attention deficit hyperactivity disorder (ADHD)
Boosts neurotransmitters norepinephrine/noradrenaline and
dopamine
presumably increasing norepinephrine neurotransmission
cortex, which lar gely lacks dopamine transporters, bupropion can
Blocks dopamine reuptake pump (dopamine transporter),
presumably increasing dopaminer gic neurotransmission

If It W orks
If It Doesn ’t WorkMay continue to work for many years to prevent relapse of
symptoms
symptoms, but is not a cure since symptoms can recur after
Treatment for nicotine addiction should consist of a single treatment
for 6 weeks

✽ Can be added to SSRIs to reverse SSRI-induced sexual dysfunction,
SSRI-induced apathy (use combinations of antidepressants with
caution as this may activate bipolar disorder and suicidal ideation)
✽ Can be added to SSRIs to treat partial responders
✽ Often used as an augmenting agent to mood stabilizers and/or
atypical antipsychotics in bipolar depressionSome patients who have an initial response may relapse even though
antidepressant discontinuation and a switch to a mood stabilizer ,

although this may be a less frequent problem with bupropion than
Trazodone for residual insomnia
Benzodiazepines for residual anxiety

Tests
How Drug Causes Side EffectsMood stabilizers or atypical antipsychotics can also be added to
bupropion for psychotic depression or treatment-resistant depression
Hypnotics for insomnia
Mirtazapine, modafinil, atomoxetine (add with caution and at lower
doses since bupropion could theoretically raise atomoxetine levels)
both for residual symptoms of depression and attention deficit
disorder
Recommended to assess blood pressure at baseline and periodically
during treatment
Side ef fects are probably caused in part by actions of norepinephrine
and dopamine in brain areas with undesired ef fects (e.g., insomnia,
tremor , agitation, headache, dizziness)
Side ef fects are probably also caused in part by actions of
norepinephrine in the periphery with undesired ef fects (e.g.,
sympathetic and parasympathetic ef fects such as dry mouth,
constipation, nausea, anorexia, sweating)

Dry mouth, constipation, nausea, weight loss, anorexia, myalgia
Insomnia, dizziness, headache, agitation, anxiety , tremor , abdominal
pain, tinnitus
Sweating, rash
Rare seizures (higher incidence for immediate-release than for
sustained-release; risk increases with doses above the recommended
maximums; risk increases for patients with predisposing factors)
Anaphylactoid/anaphylactic reactions and Stevens-Johnson
syndrome have been reported
Hypomania (more likely in bipolar patients but perhaps less
common than with some other antidepressants)

✽ Patients may experience weight loss
Sedation
Best Augmenting Agents for Side EffectsReported but not expected
Wait
Wait
Wait
Keep dose as low as possible
Take no later than mid-afternoon to avoid insomnia
Trazodone or a hypnotic for drug-induced insomnia
Mirtazapine for insomnia, agitation, and gastrointestinal side ef fects
Benzodiazepines or buspirone for drug-induced anxiety , agitation

Dosage FormsMany side ef fects are time-dependent (i.e., they start immediately
discontinuation of bupropion
Bupropion: 225 –450 mg in 3 divided doses (maximum single dose
150 mg)
Bupropion SR: 200 –450 mg in 2 divided doses (maximum single
dose 200 mg)
Bupropion XL: 150 –450 mg once daily (maximum single dose 450
mg)
Bupropion hydrobromide: 174 –522 mg once daily (maximum single
dose 522 mg)
Bupropion: tablet 75 mg, 100 mg
Bupropion SR (sustained-release): tablet 100 mg, 150 mg, 200 mg
Bupropion XL (extended-release): tablet 150 mg, 300 mg, 450 mg

How to Dose
 Dosing T ipsBupropion hydrobromide (extended-release): tablet 174 mg, 378
mg, 522 mg
Depression: for bupropion immediate-release, dosing should be in
divided doses, starting at 75 mg twice daily , increasing to 100 mg
twice daily , then to 100 mg 3 times daily; maximum dose 450 mg
per day
Depression: for bupropion SR, initial dose 100 mg twice a day ,
increase to 150 mg twice a day after at least 3 days; wait 4 weeks or
longer to ensure drug ef fects before increasing dose; maximum dose
400 mg total per day
Depression: for bupropion XL, initial dose 150 mg once daily in the
morning; can increase to 300 mg once daily after 4 days; maximum
single dose 450 mg once daily
Depression: for bupropion hydrobromide, initial dose 174 mg once
daily in the morning; can increase to 522 mg administered as a
single dose
Nicotine addiction (for bupropion SR): initial dose 150 mg/day once
a day , increase to 150 mg twice a day after at least 3 days; maximum

dose 300 mg/day; bupropion treatment should begin 1 –2 weeks
before smoking is discontinued

XL formulation has replaced immediate-release and SR
formulations as the preferred option
XL is best dosed once a day , whereas SR is best dosed twice daily ,
and immediate-release is best dosed 3 times daily
Dosing higher than 450 mg/day (400 mg/day SR) increases seizure
risk
Patients who do not respond to 450 mg/day should discontinue use
or get blood levels of bupropion and its major active metabolite 6-
hydroxy-bupropion
If levels of parent drug and active metabolite are low despite dosing
at 450 mg/day , experts can prudently increase dosing beyond the
therapeutic range while monitoring closely , informing the patient of
the potential risk of seizures and weighing risk/benefit ratios in
difficult-to-treat patients
When used for bipolar depression, it is usually as an augmenting
agent to mood stabilizers, lithium, and/or atypical antipsychotics
For smoking cessation, may be used in conjunction with nicotine
replacement therapy

Do not break or chew SR or XL tablets as this will alter controlled-
release properties
The more anxious and agitated the patient, the lower the starting
dose, the slower the titration, and the more likely the need for a
concomitant agent such as trazodone or a benzodiazepine

Overdose
How to Stop
PharmacokineticsIf intolerable anxiety , insomnia, agitation, akathisia, or activation
Rarely lethal; seizures, cardiac disturbances, hallucinations, loss of
consciousness
For smoking cessation, treatment for up to 6 months has been found
to be ef fective
For depression, treatment up to 1 year has been found to decrease
rate of relapse
No
Can be abused by individuals who crush and then snort or inject it
Tapering is prudent to avoid withdrawal ef fects, but no well-
documented tolerance, dependence, or withdrawal reactions

Drug InteractionsInhibits CYP450 2D6
Parent half-life 10 –14 hours
Metabolite half-life 20 –27 hours
Can increase TCA levels; use with caution with TCAs or when
switching from a TCA to bupropion
Use with caution with MAOIs, including 14 days after MAOIs are
There is increased risk of hypertensive reaction if bupropion is used
in conjunction with MAOIs or other drugs that increase
norepinephrine
There may be an increased risk of hypertension if bupropion is
combined with nicotine replacement therapy
Via CYP450 2D6 inhibition, bupropion could theoretically interfere
with the analgesic actions of codeine, and increase the plasma levels
Via CYP450 2D6 inhibition, bupropion could theoretically increase

Do Not UseUse cautiously with other drugs that increase seizure risk (TCAs,
lithium, phenothiazines, thioxanthenes, some antipsychotics)
Bupropion should be used with caution in patients taking levodopa
or amantadine, as these agents can potentially enhance dopamine
neurotransmission and be activating
Do not use if patient has severe insomnia
companies

Discontinuing smoking may lead to pharmacokinetic or
pharmacodynamic changes in other drugs the patient is taking,
which could potentially require dose adjustment

Hepatic ImpairmentZyban or Aplenzin in combination with each other or with any
formulation of W ellbutrin
If patient has history of seizures
If patient is anorexic or bulimic, either currently or in the past, but
see Pearls
If patient is abruptly discontinuing alcohol, sedative use, or
anticonvulsant medication
If patient has had recent head injury
If patient has a nervous system tumor
If patient is taking thioridazine
If there is a proven aller gy to bupropion
Lower initial dose, perhaps give less frequently
Drug concentration may be increased
Patient should be monitored closely

Elderly
 Childr en and AdolescentsLower initial dose, perhaps give less frequently
In severe hepatic cirrhosis, bupropion XL should be administered at
no more than 150 mg every other day
Limited available data
Evidence of rise in supine blood pressure

Pregnancyguardians of this risk so they can help observe child or adolescent
patients
May be used for ADHD in children or adolescents
May be used for smoking cessation in adolescents
Preliminary research suggests ef ficacy in comorbid depression and
ADHD
Dosage may follow adult pattern for adolescents
Children may require lower doses initially , with a maximum dose of
300 mg/day
Epidemiological studies do not indicate increased risk of congenital
malformations overall or of cardiovascular malformations

In animal studies, no clear evidence of teratogenicity has been
observed; however , slightly increased incidences of fetal

Breast Feedingmalformations and skeletal variations were observed in rabbit
studies at doses approximately equal to and greater than the
maximum recommended human doses, and greater and decreased
fetal weights were observed in rat studies at doses greater than the
maximum recommended human doses
Pregnant women wishing to stop smoking may consider behavioral
pregnancy
essants

pregnancy
essants
If child becomes irritable or sedated, breast feeding or drug may
need to be discontinued

Potential DisadvantagesImmediate postpartum period is a high-risk time for depression,
the mother
For many patients, this may mean continuing treatment during
breast feeding
Retarded depression
Atypical depression
Patients concerned about sexual dysfunction
Patients concerned about weight gain
Patients experiencing weight loss associated with their depression
Patients who are excessively activated

 Pearls
✽ May be ef fective if SSRIs have failed or for SSRI “poop-out ”
✽ May improve cognitive slowing/pseudodementia
✽ Reduces hypersomnia and fatigueDepressed mood
Sleep disturbance, especially hypersomnia
Cravings associated with nicotine withdrawal
Cognitive functioning
Less likely to produce hypomania than some other antidepressants
Approved to help reduce craving during smoking cessation
Anecdotal use in attention deficit disorder
May cause sexual dysfunction only infrequently
May exacerbate tics
Bupropion may not be as ef fective in anxiety disorders as many
other antidepressants
Prohibition for use in eating disorders due to increased risk of
seizures is related to past observations when bupropion immediate-
release was dosed at especially high levels to low body weight
patients with active anorexia nervosa

Current practice suggests that patients of normal BMI without
additional risk factors for seizures can benefit from bupropion,
especially if given prudent doses of the XL formulation; such
treatment should be administered by experts, and patients should be
monitored closely and informed of the potential risks
Recently approved hydrobromide salt formulation of bupropion may
facilitate high dosing for dif ficult-to-treat patients, as it allows
administration of single-pill doses up to 450 mg equivalency to
bupropion hydrochloride salt (522 mg tablet), unlike bupropion
hydrochloride controlled-release formulations for which the biggest
dose in a single pill is 300 mg
As bromide salts have anticonvulsant properties, hydrobromide salts
of bupropion could theoretically reduce risk of seizures, but this has
not been proven
The active enantiomer of the principal active metabolite [(+)-6-
hydroxy-bupropion] is in clinical development as a novel

The combination of bupropion and naltrexone has demonstrated
efficacy as a treatment for obesity and is currently being evaluated
in a long-term study to assess the cardiovascular health outcomes of
this treatment
Phase 2 trials of the combination of bupropion and zonisamide for
the treatment of obesity have been completed

Clayton  AH . Extended-release bupropion: an antidepressant with a broad
spectrum of therapeutic activity?  Expert Opin Pharmacother  2007  ;8 (4
):457–66 .
Ferry  L , Johnston  JA . Efficacy and safety of bupropion SR for smoking
cessation: data from clinical trials and five years of postmarketing
experience  . Int J Clin Pract  2003  ;57 (3 ):224–30 .
Foley  KF , DeSanty  KP , Kast RE . Bupropion: pharmacology and
therapeutic applications  . Expert Rev Neur other  2006  ;6 (9 ):1249 –65 .
Jefferson  JW , Pradko  JF . Muir KT . Bupropion for major depressive
disorder: pharmacokinetic and formulation considerations  . Clin Ther  2005
;27 (11 ):1685 –95 .
Papakostas  GI , Nutt DJ , Hallett  LA , et al. Resolution of sleepiness and
fatigue in major depressive disorder: a comparison of bupropion and the
selective serotonin reuptake inhibitors  . Biol Psychiatry  2006  ;60 (12
):1350 –5 .

Buspirone
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)BuSpar
Neuroscience-based Nomenclature: serotonin receptor partial
agonist (S-RP A)
Anxiolytic (azapirone; serotonin 1A partial agonist; serotonin
stabilizer)
Management of anxiety disorders
Short-term tr eatment of symptoms of anxiety
Mixed anxiety and depression
Treatment-resistant depression (adjunctive)

If It W orks
If It Doesn ’t WorkBinds to serotonin type 1A receptors
Partial agonist actions postsynaptically may theoretically diminish
serotoner gic activity and contribute to anxiolytic actions
Partial agonist actions at presynaptic somatodendritic serotonin
autoreceptors may theoretically enhance serotoner gic activity and
Generally takes within 2 –4 weeks to achieve ef ficacy
If it is not working within 6 –8 weeks, it may require a dosage
increase or it may not work at all
The goal of treatment is complete remission of symptoms as well as
prevention of future relapses
Chronic anxiety disorders may require long-term maintenance with
buspirone to control symptoms
Consider switching to another agent (a benzodiazepine or
antidepressant)

Tests
✽ Dizziness, headache, nervousness, sedation, excitement
Sedative hypnotic for insomnia
Buspirone is often given as an augmenting agent to SSRIs or SNRIs
Serotonin partial agonist actions in parts of the brain and body and
at receptors other than those that cause therapeutic actions
Nausea
Restlessness
Rare cardiac symptoms

Sedation
Dosage FormsReported but not expected
Wait
Wait
Wait
Give total daily dose divided into 3, 4, or more doses
20–30 mg/day

How to Dose
Overdose
How to StopTablet 5 mg scored, 10 mg scored, 15 mg multiscored, 30 mg
multiscored
Initial 15 mg twice a day; increase in 5 mg/day increments every 2 –
3 days until desired ef ficacy is reached; maximum dose generally 60
mg/day
Requires dosing 2 –3 times a day for full ef fect
Absorption is af fected by food, so administration with or without
food should be consistent
No deaths reported in monotherapy; sedation, dizziness, small
pupils, nausea, vomiting
Limited data suggest that it is safe
No

 Other W arnings/Pr ecautionsTaper generally not necessary
Metabolized primarily by CYP450 3A4
Elimination half-life approximately 2 –3 hours
Absorption is af fected by food
CYP450 3A4 inhibitors (e.g., fluxotine, fluvoxamine, nefazodone)
may reduce clearance of buspirone and raise its plasma levels, so the
dose of buspirone may need to be lowered when given
concomitantly with these agents
CYP450 3A4 inducers (e.g., carbamazepine) may increase clearance
of buspirone, so the dose of buspirone may need to be raised
Buspirone may increase plasma concentrations of haloperidol
Buspirone may raise levels of nordiazepam, the active metabolite of
diazepam, which may result in increased symptoms of dizziness,
headache, or nausea
None

Do Not Use
Elderly
 Childr en and AdolescentsIf patient is taking an MAOI (except as noted under Drug
If there is a proven aller gy to buspirone
Not recommended for patients with severe renal impairment
Not recommended for patients with severe hepatic impairment
Buspirone has been used to treat hostility in patients with cardiac

Pregnancy
Breast FeedingStudies in children age 6 –17 do not show significant reduction in
anxiety symptoms in generalized anxiety disorder (GAD)
Safety profile in children encourages use
Animal studies have not shown adverse ef fects
Not generally recommended in pregnancy , but may be safer than
some other options
Trace amounts may be present in nursing children whose mothers
are on buspirone

 Pearls
✽ Buspirone does not appear to cause dependence and shows virtually
no withdrawal symptoms
✽ Generally lack of sexual dysfunctionSafety profile
Lack of dependence, withdrawal
Lack of sexual dysfunction or weight gain
Takes 4 weeks for results, whereas benzodiazepines have immediate
effects
Anxiety
May have less severe side ef fects than benzodiazepines
Buspirone may reduce sexual dysfunction associated with GAD and
with serotoner gic antidepressants
Sedative ef fects may be more likely at doses above 20 mg/day

Apter  JT , Allen  LA . Buspirone: future directions  . J Clin
Psychopharmacol  1999  ;19 :86 –93 .
Mahmood  I , Sahaiwalla  C . Clinical pharmacokinetics and
pharmacodynamics of buspirone, an anxiolytic drug  . Clin Pharmacokinet
1999  ;36 :277–87 .
Pecknold  JC . A risk-benefit assessment of buspirone in the treatment of
anxiety disorders  . Drug Saf  1997  ;16 :118–32 .
Sramek  JJ , Hong  WW  , Hamid  S , Nape  B , Cutler  NR . Meta-analysis of
the safety and tolerability of two dose regimens of buspirone in patients
with persistent anxiety  . Depr ess Anxiety  1999  ;9 :131–4 .May have less anxiolytic ef ficacy than benzodiazepines for some
patients
Buspirone is generally reserved as an augmenting agent to treat
anxiety

Caprylidene
Brands
Generic?
No
 Class
 How the Drug W orksAxona
Medical food
Cognitive enhancer
Dietary management of metabolic pr ocesses associated with
Alzheimer disease (mild to moderate)
Mild cognitive impairment

If It W orks
ResistanceInduces hyperketonemia and provides an alternative ener gy
substrate to glucose in the brain
Caprylidene is processed in the gut, resulting in medium-chain fatty
acids that pass to the liver and under go obligate oxidation,
ultimately being formed into ketone bodies (acetoacetate and beta-
hydroxybutyric acid (BHB))
Ketone bodies cross the blood –brain barrier and are taken up by
neurons and enter the mitochondria, where they increase
mitochondrial ef ficiency
Ketone bodies also generate A TP and increase pools of acetyl-CoA
and acetylcholine
May begin working immediately
May improve or stabilize memory and cognitive function, but does
not reverse the degenerative process
Consider a cholinesterase inhibitor or memantine

Tests
Cholinesterase inhibitors or memantine
Triglyceride levels should be monitored periodically for individuals
who meet multiple criteria for metabolic syndrome (i.e., elevated
waist circumference, elevated triglycerides, high blood pressure,
reduced fasting HDL, and/or elevated fasting glucose)
Caprylidene is processed in the gut, which may contribute to
gastrointestinal side ef fects
Diarrhea, flatulence, dyspepsia
Nausea, headache
None reported

Sedation
Take it with food
Sip it slowly over approximately 30 minutes
Consider lowering the dose
Over -the-counter simethicone, antacids, or antidiarrheals
40 g/day
Powder 40 g/packet

How to Dose
Overdose
Habit FormingOne 40 g packet of caprylidene should be fully mixed with 4 –8 oz
of liquid; dosing should occur shortly after a meal (preferably
breakfast or lunch)
Each 40 g packet of caprylidene powder contains 20 g of medium-
chain triglycerides (MCT s)
Gastrointestinal side ef fects are reduced if caprylidene is taken with
food and/or sipped slowly over approximately 30 minutes
Some patients may require a lower starting dose in order to improve
tolerability
No fatalities have been reported; diarrhea, sometimes severe
Drug may lose ef fectiveness as the course of Alzheimer disease
progresses
No

How to Stop
Do Not Use
Renal ImpairmentTaper not necessary
Absorbed in the gut; metabolized in the liver
Crosses the blood –brain barrier
Use with caution in patients with known hypersensitivity to palm or
coconut oil
Use with caution in patients at risk for ketoacidosis (e.g., alcoholics,
patients with poorly controlled diabetes)
Use with caution in patients with a history of gastrointestinal
inflammatory conditions
If there is a proven aller gy to caprylidene, milk, or soy

Elderly
 Pregnancy
Potential AdvantagesNot studied
Animal studies have not shown teratogenic ef fects
Unknown if caprylidene is secreted in human breast milk

 Pearls
✽ Perhaps only 50% of Alzheimer patients are diagnosed, and only
50% of those diagnosed are treated, and then only for 200 days in a
disease that lasts 7 –10 yearsPatients with residual memory problems on Alzheimer treatment
Patients with gastrointestinal disorders
Memory loss in Alzheimer disease
Memory loss in mild cognitive impairment
Dramatic reversal of symptoms of Alzheimer disease is not
generally seen with caprylidene
Must evaluate lack of ef ficacy and loss of ef ficacy over months, not
weeks
Patients who complain themselves of memory problems may have
depression, whereas patients whose spouses or children complain of
the patient ’s memory problems may have Alzheimer disease
Treat the patient but ask the caregiver about ef ficacy
What you see may depend upon how early you treat

Henderson  ST . Ketone bodies as therapeutic for Alzheimer ’s disease  .
Neur otherapeutics  2008  ;5 (3 ):470–80 .
Traul KA , Driedger  A , Ingle  DL , Nakhasi  D. Review of the toxicoogic
properties of medium-chain triglycerides  . Food Chem T oxicol  2000  ;38 :79
–98 .The first symptoms of Alzheimer disease are generally mood
changes; thus, Alzheimer disease may initially be diagnosed as
Women may experience cognitive symptoms in perimenopause as a
result of hormonal changes that are not a sign of dementia or
Alzheimer disease
If treatment with antidepressants fails to improve apathy and
depressed mood in the elderly , it is possible that this represents early
Delay in progression in Alzheimer disease is not evidence of
disease-modifying actions of caprylidene
The most prominent side ef fects of caprylidene are gastrointestinal
effects, which are usually mild and transient

Weight loss can be a problem in Alzheimer patients with debilitation
and muscle wasting

Carbamazepine
Brands
Generic?
Yes (not for extended-release formulation)
 Class
(bold for FDA appr oved)Tegretol
Carbatrol
Equetro
Neuroscience-based Nomenclature: glutamate, voltage-gated
sodium and calcium channel blocker (Glu-CB)
Anticonvulsant, antineuralgic for chronic pain, voltage-sensitive
sodium channel antagonist
Partial seizur es with complex symptomatology
Generalized tonic –clonic seizur es (grand mal)

✽ Acts as a use-dependent blocker of voltage-sensitive sodium
channels
✽ Interacts with the open channel conformation of voltage-sensitive
sodium channels
✽ Interacts at a specific site of the alpha pore-forming subunit of
voltage-sensitive sodium channels
How Long Until It W orksMixed seizur e patterns
Pain associated with true trigeminal neuralgia
Acute mania/mixed mania (Equetr o)
Glossopharyngeal neuralgia
Psychosis, schizophrenia (adjunctive)
Inhibits release of glutamate
For acute mania, ef fects should occur within a few weeks
May take several weeks to months to optimize an ef fect on mood
stabilization
Should reduce seizures by 2 weeks

If It W orks
If It Doesn ’t Work (for Bipolar Disorder)
✽ Many patients have only a partial response where some symptoms
are improved but others persist or continue to wax and wane without
stabilization of moodThe goal of treatment is complete remission of symptoms (e.g.,
seizures, mania, pain)
Continue treatment until all symptoms are gone or until
improvement is stable and then continue treating indefinitely as long
as improvement persists
Continue treatment indefinitely to avoid recurrence of mania and
seizures
Treatment of chronic neuropathic pain most often reduces but does
not eliminate pain and is not a cure since symptoms usually recur
after medicine stopped
Consider adding psychotherapy
Consider biofeedback or hypnosis for pain

For bipolar disorder , consider the presence of noncompliance and
counsel patient

✽ Antidepressants (with caution because antidepressants can
destabilize mood in some patients, including induction of rapid cycling
or suicidal ideation; in particular consider bupropion; also SSRIs,
SNRIs, others; generally avoid TCAs, MAOIs)
Tests
✽ Before starting: blood count, liver , kidney , and thyroid function
testsSwitch to another mood stabilizer with fewer side ef fects or to
extended-release carbamazepine
Lithium
Atypical antipsychotics (especially risperidone, olanzapine,
quetiapine, ziprasidone, and aripiprazole)
Valproate (carbamazepine can decrease valproate levels)
Lamotrigine (carbamazepine can decrease lamotrigine levels)
During treatment: blood count every 2 –4 weeks for 2 months, then
every 3 –6 months throughout treatment

During treatment: liver , kidney , and thyroid function tests every 6 –
12 months

✽ Before starting: individuals with ancestry across broad areas of
Asia should consider screening for the presence of the HLA-B* 1502
allele; those with HLA-B*1502 should not be treated with
carbamazepine
✽ Sedation, dizziness, confusion, unsteadiness, headache
✽ Nausea, vomiting, diarrhea
✽ Benign leukopenia (transient; in up to 10%)
✽ RashConsider monitoring sodium levels because of possibility of
hyponatremia
CNS side ef fects theoretically due to excessive actions at voltage-
sensitive sodium channels
Major metabolite (carbamazepine-10, 1 1 epoxide) may be the cause
of many side ef fects
Mild anticholiner gic ef fects may contribute to sedation, blurred
vision
Blurred vision

✽ Rare aplastic anemia, agranulocytosis (unusual bleeding or
bruising, mouth sores, infections, fever , sore throat)
✽ Rare severe dermatologic reactions (purpura, Stevens-Johnson
syndrome)
✽ SIADH (syndrome of inappropriate antidiuretic hormone secretion)
with hyponatremia
Sedation
Rare anaphylaxis and angioedema
Rare cardiac problems
Rare induction of psychosis or mania
Increased frequency of generalized convulsions (in patients with
atypical absence seizures)
Rare activation of suicidal ideation and behavior (suicidality)
Frequent and can be significant in amount
Some patients may not tolerate it
Dose-related

Usual Dosage RangeCan wear of f with time, but commonly does not wear of f at high
doses
CNS side ef fects significantly lower with controlled-release
formulation (e.g., Equetro, Carbatrol)
Wait
Wait
Wait
Take with food or split dose to avoid gastrointestinal ef fects
Extended-release carbamazepine can be sprinkled on soft food
Take at night to reduce daytime sedation
Switch to another agent or to extended-release carbamazepine
400–1200 mg/day
Under age 6: 10 –20 mg/kg per day

How to DoseTablet 100 mg, 200 mg
Tablet 100 mg chewable, 200 mg chewable
Extended-release tablet 100 mg, 200 mg, 400 mg
Extended-release capsule 100 mg, 200 mg, 300 mg
Oral suspension 100 mg/5mL (450 mL)
For bipolar disorder and seizures (ages 13 and older): initial 200 mg
twice daily (tablet) or 1 teaspoon (100 mg) 4 times a day
(suspension); each week increase by up to 200 mg/day in divided
doses (2 doses for extended-release formulation, 3 –4 doses for other
tablets); maximum dose generally 1200 mg/day for adults and 1000
mg/day for children under age 15; maintenance dose generally 800 –
1200 mg/day for adults; some patients may require up to 1600
mg/day
Seizures (under age 13): see Children and Adolescents
Trigeminal neuralgia: initial 100 mg twice daily (tablet) or 0.5
teaspoon (50 mg) 4 times a day; each week increase by up to 200
mg/day in divided doses (100 mg every 12 hours for tablet
formulations, 50 mg 4 times a day for suspension formulation);

maximum dose generally 1200 mg/day
Lower initial dose and slower titration should be used for
carbamazepine suspension

✽ Slow dose titration may delay onset of therapeutic action but
enhance tolerability to sedating side ef fects
✽ Can sometimes minimize the impact of carbamazepine upon the
bone marrow by dosing slowly and monitoring closely when initiating
treatment; initial trend to leukopenia/neutropenia may reverse with
continued conservative dosing over time and allow subsequent dosage
increases with careful monitoring
✽ Carbamazepine often requires a dosage adjustment upward with
time, as the drug induces its own metabolism, thus lowering its own
plasma levels over the first several weeks to months of treatment
OverdoseHigher peak levels occur with the suspension formulation than with
the same dose of the tablet formulation, so suspension should
generally be started at a lower dose and titrated slowly
Take carbamazepine with food to avoid gastrointestinal ef fects
Controlled-release formulations (e.g., Equetro, Carbatrol) can
significantly reduce sedation and other CNS side ef fects

Should titrate slowly in the presence of other sedating agents, such
as other anticonvulsants, in order to best tolerate additive sedative
Do not break or chew carbamazepine extended-release tablets as this
will alter controlled-release properties

How to Stop
✽ Rapid discontinuation may increase the risk of relapse in bipolar
disorder
PharmacokineticsCan be fatal (lowest known fatal dose in adults is 3.2 g, in
adolescents is 4 g, and in children is 1.6 g); nausea, vomiting,
involuntary movements, irregular heartbeat, urinary retention,
trouble breathing, sedation, coma
May lower sex drive
Monitoring of liver , kidney , thyroid functions, blood counts, and
sodium may be required
No
Taper; may need to adjust dosage of concurrent medications as
carbamazepine is being discontinued
Epilepsy patients may seize upon withdrawal, especially if
withdrawal is abrupt
Discontinuation symptoms uncommon
Metabolized in the liver , primarily by CYP450 3A4

✽ Is not only a substrate for CYP450 3A4, but also an inducer of
CYP450 3A4
✽ Thus, carbamazepine induces its own metabolism, often requiring
an upward dosage adjustment
 Drug InteractionsRenally excreted
Active metabolite (carbamazepine-10,1 1 epoxide)
Initial half-life 26 –65 hours (35 –40 hours for extended-release
formulation); half-life 12 –17 hours with repeated doses
Half-life of active metabolite is approximately 34 hours
Is also an inducer of CYP450 2C9 and weakly of 1A2 and 2C19
Enzyme-inducing antiepileptic drugs (carbamazepine itself as well
as phenobarbital, phenytoin, and primidone) may increase the
clearance of carbamazepine and lower  its plasma levels
CYP450 3A4 inducers, such as carbamazepine itself, can lower  the
plasma levels of carbamazepine
CYP450 3A4 inhibitors, such as nefazodone, fluvoxamine, and
fluoxetine, can increase plasma levels of carbamazepine
Carbamazepine can increase plasma levels of clomipramine,

phenytoin, primidone

✽ Patients should be monitored carefully for signs of unusual
bleeding or bruising, mouth sores, infections, fever , or sore throat, as
the risk of aplastic anemia and agranulocytosis with carbamazepine
use is 5 –8 times greater than in the general population (risk in theCarbamazepine can decrease plasma levels of acetaminophen,
clozapine, benzodiazepines, dicumarol, doxycycline, theophylline,
warfarin, rivaroxaban, apixaban, dabigatran, edoxaban, and
haloperidol as well as other anticonvulsants such as phensuximide,
methsuximide, ethosuximide, phenytoin, tiagabine, topiramate,
lamotrigine, and valproate
Carbamazepine can decrease plasma levels of hormonal
contraceptives and adversely af fect their ef ficacy
Combined use of carbamazepine with other anticonvulsants may
lead to altered thyroid function
Combined use of carbamazepine and lithium may increase risk of
neurotoxic ef fects
Depressive ef fects are increased by other CNS depressants (alcohol,

MAOIs, other anticonvulsants, etc.)
Combined use of carbamazepine suspension with liquid
formulations of chlorpromazine has been shown to result in
excretion of an orange rubbery precipitate; because of this,
combined use of carbamazepine suspension with any liquid
medicine is not recommended

untreated general population is 6 patients per 1 million per year for
agranulocytosis and 2 patients per 1 million per year for aplastic
anemia)
Do Not UseBecause carbamazepine has a tricyclic chemical structure, use with
caution with MAOIs, including 14 days after MAOIs are stopped
(for the expert)
May exacerbate angle-closure glaucoma
Because carbamazepine can lower plasma levels of hormonal
contraceptives, it may also reduce their ef fectiveness
May need to restrict fluid intake because of risk of developing
syndrome of inappropriate antidiuretic hormone secretion,
hyponatremia and its complications
Use with caution in patients with mixed seizure disorders that
include atypical absence seizures because carbamazepine has been
associated with increased frequency of generalized convulsions in
such patients
Individuals with the HLA-B*1502 allele are at increased risk of
developing Stevens-Johnson syndrome and toxic epidermal
necrolysis

side ef fects immediately

ElderlyIf patient has history of bone marrow suppression
If patient tests positive for the HLA-B*1502 allele
If there is a proven aller gy to any tricyclic compound
If there is a proven aller gy to carbamazepine
Suspension: in patients with hereditary problems with fructose
intolerance
Carbamazepine is renally secreted, so the dose may need to be
lowered
Rare cases of hepatic failure have occurred
Elderly patients may be more susceptible to adverse ef fects

 Pregnancy
✽ Use during first trimester may raise risk of neural tube defects (e.g.,
spina bifida) or other congenital anomaliesApproved use for epilepsy; therapeutic range of total carbamazepine
in plasma is considered the same for children and adults
Ages 6 –12: initial dose 100 mg twice daily (tablets) or 0.5 teaspoon
(50 mg) 4 times a day (suspension); each week increase by up to
100 mg/day in divided doses (2 doses for extended-release
formulation, 3 –4 doses for all other formulations); maximum dose
generally 1000 mg/day; maintenance dose generally 400 –800
mg/day
Ages 5 and younger: initial 10 –20 mg/kg per day in divided doses
(2–3 doses for tablet formulations, 4 doses for suspension); increase
weekly as needed; maximum dose generally 35 mg/kg/day

benefits to the mother against the risks to the fetus

✽ If drug is continued, perform tests to detect birth defects
✽ If drug is continued, start on folate 1 mg/day early in pregnancy to
reduce risk of neural tube defects
✽ For bipolar patients, carbamazepine should generally be
✽ Atypical antipsychotics may be preferable to lithium or
anticonvulsants such as carbamazepine if treatment of bipolar disorder
is required during pregnancy
Breast FeedingAntiepileptic Drug Pregnancy Registry: 1-888-233-2334,
www .aedpregnancyregistry .org
Use of anticonvulsants in combination may cause a higher
prevalence of teratogenic ef fects than anticonvulsant monotherapy
Taper drug if discontinuing
Recurrent bipolar illness during pregnancy can be quite disruptive
For bipolar patients, given the risk of relapse in the postpartum
period, some form of mood stabilizer treatment may need to be

restarted immediately after delivery if patient is unmedicated during
pregnancy
Bipolar symptoms may recur or worsen during pregnancy and some
form of treatment may be necessary

✽ Bipolar disorder may recur during the postpartum period,
particularly if there is a history of prior postpartum episodes of either
depression or psychosis
Potential DisadvantagesSome drug is found in mother ’s breast milk
If drug is continued while breast feeding, infant should be monitored
for possible adverse ef fects, including hematological ef fects
If infant shows signs of irritability or sedation, drug may need to be
Some cases of neonatal seizures, respiratory depression, vomiting,
and diarrhea have been reported in infants whose mothers received
carbamazepine during pregnancy
Relapse rates may be lower in women who receive prophylactic
treatment for postpartum episodes of bipolar disorder
Atypical antipsychotics and anticonvulsants such as valproate may
be safer than carbamazepine during the postpartum period when

Treatment-resistant bipolar and psychotic disorders

 Pearls
✽ An extended-release formulation has better evidence of ef ficacy
and improved tolerability in bipolar disorder than does immediate-
release carbamazepinePatients who do not wish to or cannot comply with blood testing and
close monitoring
Patients who cannot tolerate sedation
Pregnant patients
Incidence of seizures
Unstable mood, especially mania
Pain
Carbamazepine was the first anticonvulsant widely used for the
treatment of bipolar disorder and is now formally approved for acute
mania and mixed mania
Dosage frequency as well as sedation, diplopia, confusion, and
ataxia may be reduced with extended-release carbamazepine
Risk of serious side ef fects is greatest in the first few months of
treatment
Common side ef fects such as sedation often abate after a few
months

✽ May be ef fective in patients who fail to respond to lithium or other
mood stabilizers
Leucht  S , McGrath  J , White  P , Kissling  W . Carbamazepine for
schizophrenia and schizoaf fective psychoses  . Cochrane Database Syst Rev
2002  ;(3 ):CD001258  .
Marson  AG , Williamson  PR , Hutton  JL , Clough  HE , Chadwick  DW .
Carbamazepine versus valproate monotherapy for epilepsy  . Cochrane
Database Syst Rev  2000  ;(3 ):CD001030  .
Smith  LA , Cornelius  V , Warnock  A , Tacchi  MJ , Taylor  D .
Pharmacological interventions for acute bipolar mania: a systematic review
of randomized placebo-controlled trials  . Bipolar Disor d 2007  ;9 (6 ):551–
60 .
Weisler  RH , Kalali  AH , Ketter  TA . A multicenter , randomized, double-
blind, placebo-controlled trial of extended-release carbamazepine capsules
as monotherapy for bipolar disorder patients with manic or mixed episodes  .

J Clin Psychiatry  2004  ;65 :478–84 .May be ef fective for the depressed phase of bipolar disorder and for
maintenance in bipolar disorder
Can be complicated to use with concomitant medications

Cariprazine
Brands
Generic?
No
 Class
(bold for FDA appr oved)Vraylar
norepinephrine receptor partial agonist
dopamine stabilizer , atypical antipsychotic, third- generation
Schizophr enia, acute and maintenance

✽ Partial agonism at dopamine 2 receptorsBipolar depr ession (bipolar I disorder)
Bipolar depressive episodes with mixed features (subsyndromal
manic symptoms)
Major depressive episodes (unipolar) with mixed features
(subsyndromal manic symptoms)
Manic episodes with mixed features (subsyndromal depressive
symptoms)
Augmentation of other antidepressants in (unipolar) major
depressive disorder

How Long Until It W orksmediating antipsychotic actions
Preferentially binds to dopamine 3 over dopamine 2 receptors at low
doses; the clinical significance is unknown but could theoretically
contribute to cariprazine ’s efficacy for negative symptoms. D3
partial agonism could theoretically be useful for treating cognition,
mood, emotions, and reward/substance use
contribute to cariprazine ’s efficacy
Cariprazine also has high af finity for the serotonin 1A (partial
agonist) and 2B (antagonist) receptors
Psychotic, and manic and depressive symptoms can improve within

1 week, but it may take several weeks for full ef fect on behavior as
well as on cognition
full antipsychotic and antidepressant ef ficacy of drug, but in practice

If It W orkssome patients require up to 16 –20 weeks to show a good response,
especially on negative or cognitive symptoms
May reduce and eliminate acute manic symptoms and depressive
symptoms

If It W orks –for Bipolar Depr ession
If It Doesn ’t WorkEven for first episodes of psychosis, it may be preferable to continue
treatment
Continue treatment until all symptoms are gone (remission) or
clozapine
If no first-line atypical antipsychotic is ef fective for schizophrenia,
consider higher doses or augmentation with valproate or lamotrigine

If It Doesn ’t Work –for Bipolar Depr ession
ResistanceConsider lithium and anticonvulsant mood stabilizers for mania
injection
Some patients may be nonresponders, sometimes called treatment-
Lamotrigine
Lithium

Tests
Befor e starting any atypical antipsychotic
✽ BMI monthly for 3 months, then quarterlyGet baseline personal and family history of diabetes, obesity ,

respiration, weakness and clouding of sensorium, even comaTreat or refer for treatment and consider switching to another

cariprazine should be discontinued at the first sign of decline in

 Life-Thr eatening or Danger ous Side EffectsPartial agonist actions at dopamine 2 receptors in the striatum can
Akathisia, drug-induced parkinsonism, restlessness
Gastrointestinal distress
Sedation
Side ef fects may theoretically appear several weeks after initiating
cariprazine, because plasma levels and major active metabolites
accumulate over time

 Sedation
Wait
Wait

present
Schizophrenia: 1.5 –6 mg once daily

How to Dose
 Dosing T ipsBipolar mania: 3 –6 mg once daily
Bipolar depression: 1.5 –3 mg once daily
Capsule 1.5 mg, 3 mg, 4.5 mg, 6 mg
Schizophrenia: initial 1.5 mg once daily; can increase to 3 mg once
daily on day 2; should increase in 1.5 –3 mg increments to reach
therapeutic dose (recommended dose 1.5 –6 mg once daily)
Bipolar mania: initial 1.5 mg once daily; can increase to 3 mg once
daily on day 2; can increase in 1.5 –3 mg increments to reach
therapeutic dose (recommended dose 3 –6 mg once daily)
Bipolar depression: initial 1.5 mg once daily; can increase to 3 mg
once daily on day 15 if clinically warranted (recommended dose
1.5–3 mg once daily)
Because of its long half-life, and the especially long half-life of one
of its active metabolites, monitor for adverse ef fects and response
for several weeks after starting cariprazine and with each dosage
change; also washout of active drug will take several weeks

Because of its long half-life, missing a few doses may not be as
detrimental compared to other antipsychotics

Dosing for bipolar depression is generally lower than for
schizophrenia or bipolar mania
For bipolar depression without mixed features, 1.5 mg/day dose may
be adequate for many patients
For bipolar depression with mixed features, 3.0 mg/day may be a
better dose for some patients
In general, the more manic features, the higher the dose in bipolar
disorder , and dose can be adjusted according to this principle as the
patient waxes and wanes symptoms of mania and depression
Some patients with schizophrenia or acute bipolar mania may
benefit from doses higher than 6.0 mg/day , as cariprazine has been
studied up to 12 mg/day , but it is not approved for this use and side
effects are definitely dose-related and in general therapeutic ef fects
for the majority of patients do not justify dosing over 6.0 mg/day
Slow titration from 1.5 mg/day to 3.0 mg/day in bipolar depression
produced much less akathisia compared to rapid dose increases in
studies of mania and schizophrenia

Can be taken with or without food

Overdose
How to Stopanticonvulsant, such as valproate, topiramate, or lamotrigine
Approved for maintenance treatment of schizophrenia in adults
No
However , the long half-lives of cariprazine and its two active
metabolites suggest that it may be possible to stop cariprazine
abruptly

 Drug InteractionsSee Switching section of individual agents for how to stop
cariprazine
and worsening of symptoms, but less likely with cariprazine due to
Metabolized by CYP450 3A4 into two long-lasting active
metabolites
Based on time to reach steady state, half-life for cariprazine is 2 –4
days and for one of its active metabolites, didesmethyl cariprazine
(DDCAR), is 1 –3 weeks
Initiating a strong CYP450 3A4 inhibitor in patients on a stable dose
of cariprazine: reduce the current dose of cariprazine by half (for
patients taking 4.5 mg, reduce to either 1.5 mg or 3 mg once daily;
for patients taking 1.5 mg once daily , reduce to 1.5 mg every other
day)
Initiating cariprazine in patients taking a strong CYP450 3A4
inhibitor: administer 1.5 mg on day 1; do not dose on day 2;
administer 1.5 mg on day 3 and on day 4; maximum dose 3 mg once
daily

day)
daily
Concomitant use of cariprazine and a CYP450 3A4 inducer is not

Other W arnings/Pr ecautionsMay increase ef fects of antihypertensive agents
cariprazine should be used cautiously in patients at risk for

therapy

Do Not Use
If there is a proven aller gy to cariprazine
Mild to moderate impairment (creatinine clearance <30 mL/minute):
no dose adjustment necessary
Severe or end-stage: not recommended
Mild to moderate impairment (Child-Pugh score between 5 and 9):
Severe: not recommended

Elderly
 PregnancySome elderly patients may tolerate lower doses better
disturbances in dementia, no atypical antipsychotic has been
approved for treatment of elderly patients with behavioral symptoms
of dementia such as agitation
Children and adolescents using cariprazine may need to be
better

better

Breast Feedingor final rule) applies only to prescription drugs and will be phased in
In rats, administration of cariprazine during or ganogenesis caused
malformations, lower pup survival, and developmental delays at
exposures less than the human exposure at maximum recommended
human dose (6 mg/day); cariprazine was not teratogenic in rabbits at
doses up to 4.6 times the maximum recommended human dose
961-2388,

961-2388,
Unknown if cariprazine is secreted in human breast milk, but all

Primary T arget SymptomsInfants of women who choose to breast feed while on cariprazine
For patients who do not tolerate aripiprazole or brexpiprazole for
For patients who do not tolerate quetiapine, lurasidone, or
olanzapine for bipolar depression
Possibly negative symptoms in schizophrenia
Possibly mixed mood states such as depression or mania with mixed
features
Expensive
Symptoms of acute mania/mixed mania

PearlsCognitive symptoms
Mixtures of manic and depressive symptoms in bipolar disorder
Cariprazine is metabolized into a very long-lasting active
metabolite; it is therefore possible that adverse events could appear
several weeks after initiation of cariprazine due to accumulation of
cariprazine and major metabolites over time
It is also possible that cariprazine or its very long-lasting active
metabolites could be developed as an “oral depot, ” namely a very
long-lasting oral formulation for weekly or even monthly oral
administration
Based on short-term clinical trials, cariprazine appears to have a
favorable metabolic profile, with changes in triglycerides, fasting
glucose, and cholesterol similar to placebo; little or no weight gain
in bipolar depression, and a small amount of weight gain in bipolar
mania and schizophrenia studies especially at higher doses

Approved as a monotherapy for bipolar depression, with post hoc
analyses showing ef ficacy in bipolar depression with mixed features
Approved as a monotherapy for acute bipolar mania, with post hoc
analyses showing ef ficacy in bipolar mania with mixed features

May be one of the best choices for treatment across the spectrum of
bipolar disorder , from bipolar depression, to mixed states of bipolar
depression and mania, to acute bipolar mania
Cariprazine is in late-stage testing for augmentation of SSRIs/SNRIs
in unipolar major depression
Approved in Europe for the negative symptoms of schizophrenia
D3-preferring (over D2) actions represent a novel pharmacologic
profile among antipsychotics, especially at lower doses; clinical
advantages of this profile remain to be determined but animal
models suggest that tar geting D3 receptors may have advantages for
mood, cognition, negative symptoms, and substance abuse
All antipsychotics bind to the D3 receptor in vitro, but cariprazine
has af finity for the D3 receptor much greater than dopamine itself
has for the D3 receptor . Cariprazine is the most potent antipsychotic
and one of the only antipsychotics with functional D3 partial
agonism in vivo in the living human brain. This means that at

therapeutic dosing, cariprazine may have a unique action as a partial
agonist at the D3 receptor
Cariprazine may exert its ef ficacy across the bipolar spectrum by
partial agonist actions at D2 receptors, mostly blocking them in
limbic areas, to treat mania and psychosis while having
simultaneous partial agonist actions at D3 receptors, especially in
the substantia nigra/ventral tegmental area, leading to enhanced
dopamine release in prefrontal cortex to treat mood, cognition, and

 Switching fr om Oral Antipsychotics to Cariprazine
* Benzodiazepine or anticholiner gic medication can be administered during
cross-titration to help alleviate side effects such as insomnia, agitation,
and/or psychosisnegative symptoms in both schizophrenia and across the mood
disorder spectrum
It is advisable to begin cariprazine at an intermediate dose and build

therapeutic dosing, cariprazine may have a unique action as partial

Choi  YK , Adham  N , Kiss B , GyertyÃ¡n  I , Tarazi  FI. Long-term ef fects
of cariprazine exposure on dopamine receptor subtypes  . CNS Spectr  2014
;19 (3 ):268–77 .
Citrome  L. Cariprazine in schizophrenia: clinical ef ficacy , tolerability , and
place in therapy  . Adv Ther  2013  ;30 (2 ):114–26 .
Earley  WR , Burgess MV , Khan  B , et al. Ef ficacy and safety of
cariprazine in bipolar I depression: a double-blind, placebo-controlled phase
3 study . Bipolar Disord 2020  ;22(4):372 –84. doi: 10.1111/bdi.12852  .

McIntyre  RS , Suppes  T , Earley  W , Patel  M , Stahl  SM. Cariprazine
efficacy in bipolar I depression with and without concurrent manic
symptoms: post hoc analysis of 3 randomized, placebo-controlled studies.
CNS Spectr 2019  ;1–9. doi: 10.1017/S1092852919001287  .
Stahl  SM , Drugs for psychosis and mood: unique actions at D3, D2, and
D1 dopamine receptor subtypes, CNS Spectr 2017  ;22:375 –84.
Stahl  SM , Laredo  S , Morrissette  DA . Cariprazine as a treatment across
the bipolar I spectrum from depression to mania: mechanism of action and
review of clinical data  . Ther Adv Psychopharmacol  2020  ;10
:2045125320905752  . doi: 10.1177/2045125320905752  . eCollection 2020.
Vieta E , Durgam S , Lu K , et al. Effect of cariprazine across the symptoms
of mania in bipolar I disorder: analyses of pooled data from phase II/III
trials  . Eur Neur opsychopharmacol  2015  ;25 (11 ):1882  –91.
Vieta E , Earley  WR , Burgess MV , et al. Longterm safety and tolerability

of cariprazine as adjunctive therapy in major depressive disorder . Int Clin
Psychopharmacol 2019  ;34(2):76 –83.

Chlordiazepoxide
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Limbitrol
Librium
Librax
Anxiety disorders
Preoperative appr ehension and anxiety

If It W orksWithdrawal symptoms of acute alcoholism
Catatonia
For chronic anxiety disorders, the goal of treatment is complete

ResistanceFor long-term symptoms of anxiety , consider switching to an SSRI
Consider presence of chlordiazepoxide abuse

Tests
✽ Dizziness, ataxia, slurred speech, weaknessBenzodiazepines are frequently used as augmenting agents for

Sedation
What to Do About Side EffectsRare hallucinations, mania
Wait

How to DoseWait
Wait
Mild to moderate anxiety: 15 –40 mg/day in 3 –4 doses
Severe anxiety: 60 –100 mg/day in 3 –4 doses
Capsule 2.5 mg, 5 mg, 10 mg, 25 mg

Risk of dependence may increase with dose and duration of treatment
maintain same total daily dose but divide into more frequent doses
anxiety
Because anxiety disorders can require higher doses, the risk of
dependence may be greater in these patients
Some severely ill patients may require doses higher than the generally
recommended maximum dose
Overdose
Long-T erm UseFatalities can occur; hypotension, tiredness, ataxia, confusion, coma
Evidence of ef ficacy for up to 16 weeks

How to StopRisk of dependence, particularly for treatment periods longer than
12 weeks, and especially in patients with past or current
Chlordiazepoxide is a Schedule IV drug
use
Patients with history of seizure may seize upon withdrawal,
especially if withdrawal is abrupt
Taper by 10 mg every 3 days to reduce chances of withdrawal
effects
For dif ficult-to-taper patients, consider reducing dose much more
slowly after reaching 20 mg/day , perhaps by as little as 5 mg per
week or less

form of behavioral desensitization

 Other W arnings/Pr ecautionsBe sure to dif ferentiate reemer gence of symptoms requiring
Elimination half-life 24 –48 hours

efficacy

Do Not Use
Renal ImpairmentPatients and their caregivers should be warned to seek medical
ideation
If there is a proven aller gy to chlordiazepoxide or any
Initial 10 –20 mg/day in 2 –4 doses; increase as needed

Elderly
 PregnancyInitial 10 –20 mg/day in 2 –4 doses; increase as needed
Elderly patients may be more sensitive to sedative ef fects
Not recommended for use in children under age 6
Initial 10 –20 mg/day in 2 –4 doses; may increase to 20 –30 mg/day in
2–3 doses if inef fective
Hyperactive children should be monitored for paradoxical ef fects
Long-term ef fects of chlordiazepoxide in children/adolescents are
unknown
monitored

Because of the potential risks, chlordiazepoxide is not generally

Unknown if chlordiazepoxide is secreted in human breast milk, but
all psychotropics are assumed to be secreted in breast milk
Effects of benzodiazepines on nursing infants have been reported
and include feeding dif ficulties, sedation, and weight loss

 PearlsRapid onset of action
Anxiety
Can be a useful adjunct to SSRIs and SNRIs in the treatment of
numerous anxiety disorders, but not used as frequently as some
other benzodiazepines
Not ef fective for treating bipolar disorder as a monotherapy , but can
Can both cause depression and treat depression in dif ferent patients

✽ Remains a viable treatment option for alcohol withdrawal
Baskin  SI , Esdale  A. Is chlordiazepoxide the rational choice among
benzodiazepines  ? Pharmacotherapy  1982  ;2 :110–19 .
Erstad  BL , Cotugno  CL. Management of alcohol withdrawal  . Am J Health
Syst Pharm  1995  ;52 :697 –709 .
Fraser  AD. Use and abuse of the benzodiazepines  . Ther Drug Monit  1998
;20 :481–9 .
Murray  JB. Effects of valium and librium on human psychomotor and
cognitive functions  . Genet Psychol Monogr  1984  ;109 (2D Half): 167–97 .evaluation for comorbid psychiatric and/or medical conditions
treatment

Chlorpromazine
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Thorazine
Neuroscience-based Nomenclature: dopamine and serotonin
receptor antagonist (DS-RAn)
Conventional antipsychotic (neuroleptic, phenothiazine, dopamine 2
antagonist, antiemetic)
Schizophr enia (oral)
Sever e behavioral pr oblems associated with oppositional defiant
disorder or other disruptive behavioral disorders, or for
attention deficit hyperactivity disorder (ADHD) in pediatric
patients who show excessive motor activity with accompanying

How Long Until It W orksconduct disorders (oral, intramuscular for acute, sever e
agitation in hospitalized patients)
Acute psychosis (intramuscular)
Nausea, vomiting (oral, r ectal, intramuscular , intravenous)
Acute intermittent porphyria (oral, intramuscular)
Tetanus (intramuscular , adjunct)
Intractable hiccups (oral, intramuscular , intravenous)
Bipolar disorder
Restlessness and apprehension before sur gery
psychosis and improving other behaviors
Combination of dopamine D2, histamine H1, and choliner gic M1
blockade in the vomiting center may reduce nausea and vomiting
several weeks for full ef fect on behavior
Immediate and short-term (a few hours) relief of severe behavioral
problems if given during an acute exacerbation on an “as needed ”
prn basis (most common use in children)
Actions on nausea and vomiting are immediate

If It W orks
If It Doesn ’t WorkMost often reduces positive symptoms in schizophrenia but does not
Continue treatment in schizophrenia until reaching a plateau of
improvement
a year after first episode of psychosis in schizophrenia
For second and subsequent episodes of psychosis in schizophrenia,
treatment may need to be indefinite
Reduces symptoms of acute psychotic mania but not proven as a
mood stabilizer or as an ef fective maintenance treatment in bipolar
disorder
After reducing acute psychotic symptoms in mania, switch to a
mood stabilizer and/or an atypical antipsychotic for mood
stabilization and maintenance
Consider trying one of the first-line atypical antipsychotics
Consider trying another conventional antipsychotic

clozapine

Tests
✽ Since conventional antipsychotics are frequently associated with
weight gain, before starting treatment, weigh all patients and determine
if the patient is already overweight (BMI 25.0 –29.9) or obese (BMI
>30)
✽ Monitor weight and BMI during treatmentAugmentation of conventional antipsychotics has not been
systematically studied
Addition of a mood-stabilizing anticonvulsant such as valproate,
carbamazepine, or lamotrigine may be helpful in both schizophrenia
and bipolar mania
Augmentation with lithium in bipolar mania may be helpful
Addition of a benzodiazepine, especially short-term for agitation

or dyslipidemia, or consider switching to a dif ferent antipsychotic
How Drug Causes Side EffectsShould check blood pressure in the elderly before starting and for
the first few weeks of treatment
Monitoring elevated prolactin levels of dubious clinical benefit
Phenothiazines may cause false-positive phenylketonuria results
chlorpromazine should be discontinued at the first sign of decline of

✽ Neuroleptic-induced deficit syndrome
✽ Akathisia
✽ Priapism
✽ Galactorrhea, amenorrheaChronic blockade of dopamine 2 receptors in the striatum can cause
By blocking dopamine 2 receptors excessively in the mesocortical
and mesolimbic dopamine pathways, especially at high doses, it can
cause worsening of negative and cognitive symptoms (neuroleptic-
induced deficit syndrome)
Blocking muscarinic choliner gic receptors can cause dry mouth,
blurred vision, urinary retention, constipation, and paralytic ileus
Antihistaminic actions may cause sedation, weight gain
Mechanism of weight gain and any possible increased incidence of
diabetes or dyslipidemia with conventional antipsychotics is
unknown
Dizziness, sedation, impaired memory
Dry mouth, constipation, urinary retention, blurred vision

Decreased sweating
Hypotension, tachycardia, syncope
Rare jaundice, agranulocytosis

Sedation
Best Augmenting Agents for Side EffectsTolerance to sedation can develop over time
Wait
Wait
Wait
For sedation, give at night
Switch to an atypical antipsychotic
BMIs, diabetes dyslipidemia

How to DoseBeta blockers, benzodiazepines, or 5HT2A antagonists (e.g.,
200–800 mg/day
Tablet 10 mg, 25 mg, 50 mg, 100 mg, 200 mg
Capsule 30 mg, 75 mg, 150 mg (not in USA)
Ampoule 25 mg/mL; 1 mL, 2 mL
Liquid 10 mg/5 mL (discontinued in USA)
Suppository 25 mg, 100 mg (discontinued in USA)
Psychosis: increase dose until symptoms are controlled; after 2
weeks reduce to lowest ef fective dose
Psychosis (intramuscular): varies by severity of symptoms and
inpatient/outpatient status

Low doses may have more sedative actions than antipsychotic
actions
Low doses have been used to provide short-term relief of daytime
agitation and anxiety and to enhance sedative hypnotic actions in
nonpsychotic patients, but other treatment options such as atypical
antipsychotics are now preferred
Higher doses may induce or worsen negative symptoms of
Ampoules contain sulfites that may cause aller gic reactions,
particularly in patients with asthma
One of the few antipsychotics available as a suppository

Overdose
How to Stop
 Drug InteractionsDrug-induced parkinsonism, sedation, hypotension, coma,
respiratory depression
No
Slow down-titration of oral formulation (over 6 –8 weeks),
especially when simultaneously beginning a new antipsychotic
while switching (i.e., cross-titration)
Rapid oral discontinuation may lead to rebound psychosis and
worsening of symptoms
If antiparkinson agents are being used, they should be continued for
a few weeks after chlorpromazine is discontinued
Half-life approximately 8 –33 hours

Other W arnings/Pr ecautionsMay decrease the ef fects of levodopa, dopamine agonists
May increase the ef fects of antihypertensive drugs except for
guanethidine, whose antihypertensive actions chlorpromazine may
antagonize
Additive ef fects may occur if used with CNS depressants
Some pressor agents (e.g., epinephrine) may interact with
chlorpromazine to lower blood pressure
Alcohol and diuretics may increase the risk of hypotension
Reduces ef fects of anticoagulants
May reduce phenytoin metabolism and increase phenytoin levels
Plasma levels of chlorpromazine and propranolol may increase if
used concomitantly
Some patients taking a neuroleptic and lithium have developed an
encephalopathic syndrome similar to neuroleptic malignant
syndrome

Use with caution in patients with respiratory disorders, glaucoma, or
urinary retention

Do Not UseUse with caution in patients with hematological disease
Avoid extreme heat exposure
Avoid undue exposure to sunlight
Antiemetic ef fect of chlorpromazine may mask signs of other
disorders or overdose; suppression of cough reflex may cause
asphyxia
dementia
therapy
If patient is in a comatose state
If patient is taking metrizamide or lar ge doses of CNS depressants
If patient shows signs of Reye ’s syndrome
If patient has a sulfite hypersensitivity (injectable preparations)

If there is a proven aller gy to chlorpromazine

ElderlyIf there is a known sensitivity to any phenothiazine
Cardiovascular toxicity can occur , especially orthostatic hypotension
Lower doses should be used and patient should be monitored closely
Often do not tolerate sedating actions of chlorpromazine
Although conventional antipsychotics are commonly used for
behavioral disturbances in dementia, no agent has been approved for
treatment of elderly patients with behavioral symptoms of dementia
such as agitation
antipsychotics are at an increased risk of death compared to placebo,
and also have an increased risk of cerebrovascular events

 PregnancyCan be used cautiously in children or adolescents over age 1 with
severe behavioral problems
Oral –0.25 mg/lb every 4 –6 hours as needed; rectal –0.5 mg/lb every
6–8 hours as needed; IM –0.25 mg/lb every 6 –8 hours as needed;
maximum 40 mg/day (under 5), 75 mg/day (5 –12)
Do not use if patient shows signs of Reye ’s syndrome
Generally consider second-line after atypical antipsychotics

Reports of drug-induced parkinsonism, jaundice, hyperreflexia,
hyporeflexia in infants whose mothers took a phenothiazine during

Potential Advantagespregnancy
Chlorpromazine should generally not be used during the first
trimester
Chlorpromazine should be used during pregnancy only if clearly
needed
Atypical antipsychotics may be preferable to conventional
antipsychotics or anticonvulsant mood stabilizers if treatment is
required during pregnancy
Effects on infant have been observed (dystonia, tardive dyskinesia,
sedation)
Intramuscular formulation for emer gency use
Patients who require sedation for behavioral control

 PearlsPatients with tardive dyskinesia
Children
Elderly
Patients who wish to avoid sedation
Patients who wish to avoid anticholiner gic side ef fects, especially
patients on clozapine
Motor and autonomic hyperactivity
Violent or aggressive behavior
Chlorpromazine is one of the earliest classical conventional
Chlorpromazine has a broad spectrum of ef ficacy , but risk of tardive
dyskinesia and the availability of alternative treatments make its
utilization outside of psychosis a short-term and second-line
treatment option
Adding chlorpromazine as the choice for patients who require
sedation or behavioral control, either as a daily or as a prn (as
needed) treatment, should be avoided in order to reduce the chances

of potentially fatal paralytic ileus in patients on concomitant
anticholiner gics, including antipsychotic drugs with anticholiner gic
properties such as clozapine
Chlorpromazine is a low-potency phenothiazine
Sedative actions of low-potency phenothiazines are an important
aspect of their therapeutic actions in some patients and side ef fect
profile in others
Low-potency phenothiazines like chlorpromazine have a greater risk
of cardiovascular side ef fects
another
benefit from a trial of augmentation with a conventional
antipsychotic such as chlorpromazine or from switching to a
conventional antipsychotic such as chlorpromazine

conventional antipsychotic such as chlorpromazine with an atypical
antipsychotic may combine their side ef fects without clearly
augmenting the ef ficacy of either

Adams  CE , Awad G , Rathbone  J , Thornley  B. Chlorpromazine versus
placebo for schizophrenia  . Cochrane Database Syst Rev  2007  ;18 (2
):CD000284  .
Ahmed  U , Jones  H , Adams  CE. Chlorpromazine for psychosis induced
aggression or agitation  . Cochrane Database Syst Rev  2010  ;14 (4
):CD007445  .
Leucht  C , Kitzmantel  M , Chua  L , Kane  J , Leucht  S. Haloperidol versus
chlorpromazine for schizophrenia  . Cochrane Database Syst Rev  2008  ;23
(1 ):CD004278  .
Liu X , De Haan  S. Chlorpromazine dose for people with schizophrenia  .
Cochrane Database Syst Rev  2009  ;15 (2 ):CD007778  .atypical antipsychotics or with 1 atypical antipsychotic and 1

Citalopram
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Celexa
Neuroscience-based Nomenclature: serotonin reuptake inhibitor (S-
RI)
SSRI (selective serotonin reuptake inhibitor); often classified as an
antidepressant, but it is not just an antidepressant
Premenstrual dysphoric disorder (PMDD)
Obsessive-compulsive disorder (OCD)
Panic disorder

✽ Citalopram also has mild antagonist actions at H1 histamine
receptors
✽ Citalopram ’s inactive R enantiomer may interfere with the
therapeutic actions of the active S enantiomer at serotonin reuptake
pumps
How Long Until It W orksGeneralized anxiety disorder (GAD)
Social anxiety disorder (social phobia)
Boosts neurotransmitter serotonin
Blocks serotonin reuptake pump (serotonin transporter)
Desensitizes serotonin receptors, especially serotonin 1A
autoreceptors
Presumably increases serotoner gic neurotransmission
symptoms

If It W orks
If It Doesn ’t WorkThe goal of treatment is complete remission of current symptoms as
significantly reduced (e.g., OCD, PTSD)
problems concentrating in depression)

ResistanceConsider psychotherapy
Trazodone, especially for insomnia
Bupropion, mirtazapine, reboxetine, or atomoxetine (add with
caution and at lower doses since citalopram could theoretically raise
atomoxetine levels); use combinations of antidepressants with
caution as this may activate bipolar disorder and suicidal ideation
psychotic depression, treatment-resistant depression, or treatment-
resistant anxiety disorders

If all else fails for anxiety disorders, consider gabapentin or
tiagabine
Classically , lithium, buspirone, or thyroid hormone

Tests
✽ Citalopram ’s unique mild antihistamine properties may contribute
to sedation and fatigue in some patients
Notable Side EffectsNone for healthy individuals
Theoretically due to increases in serotonin concentrations at
serotonin receptors in parts of the brain and body other than those
that cause therapeutic actions (e.g., unwanted actions of serotonin in
sleep centers causing insomnia, unwanted actions of serotonin in the
gut causing diarrhea, etc.)
Increasing serotonin can cause diminished dopamine release and
might contribute to emotional flattening, cognitive slowing, and
apathy in some patients
Most side ef fects are immediate but often go away with time, in
contrast to most therapeutic ef fects which are delayed and are
enhanced over time
Sexual dysfunction (dose-dependent; men: delayed ejaculation,
erectile dysfunction; men and women: decreased sexual desire,
anorgasmia)

Gastrointestinal (decreased appetite, nausea, diarrhea, constipation,
dry mouth)
Mostly CNS (dose-dependent insomnia but also sedation, agitation,
tremors, headache, dizziness)
Activation (short-term; patients with diagnosed or undiagnosed
bipolar or psychotic disorders may be more vulnerable to CNS-
activating actions of SSRIs)
Sweating (dose-dependent)
Bruising and rare bleeding
Rare hyponatremia (mostly in elderly patients and generally
reversible on discontinuation of citalopram)
SIADH (syndrome of inappropriate antidiuretic hormone secretion)

Sedation
Best Augmenting Agents for Side EffectsCitalopram has been associated with both weight gain and weight
loss in various studies, but is relatively weight neutral overall
Wait
Wait
Wait
Take in the morning if nighttime insomnia
Take at night if daytime sedation
In a few weeks, switch to another agent or add other drugs
Often best to try another SSRI or another antidepressant
monotherapy prior to resorting to augmentation strategies to treat
Trazodone or a hypnotic for insomnia
Bupropion, sildenafil, vardenafil, or tadalafil for sexual dysfunction
Bupropion for emotional flattening, cognitive slowing, or apathy

How to DoseBenzodiazepines for jitteriness and anxiety , especially at initiation
of treatment and especially for anxious patients
discontinuation of citalopram
20–40 mg/day
Tablet 10 mg, 20 mg scored, 40 mg scored
Solution 10 mg/5 mL
Initial 20 mg/day; increase by 20 mg/day after 1 or more weeks;
maximum 40 mg/day; single-dose administration, morning or

Overdoseevening
Citalopram should no longer be prescribed at doses greater than 40
mg/day because if can cause abnormal changes in the electrical
activity of the heart
Some controversy with FDA dosage limit of 40 mg/day , and higher
doses may be prescribed by experts
Tablets are scored, so to save costs, give 10 mg as half of 20 mg
tablet or 20 mg as half of 40 mg tablet, since the tablets cost about
the same in many markets
Many patients respond better to 40 mg than to 20 mg
Given once daily , any time of day when best tolerated by the
individual
Rare fatalities have been reported with citalopram overdose, both
alone and in combination with other drugs
Vomiting, sedation, heart rhythm disturbances, dizziness, sweating,

nausea, tremor

How to Stop
 Drug InteractionsRarely amnesia, confusion, coma, convulsions
Safe
No
Taper not usually necessary
However , tapering to avoid potential withdrawal reactions generally
prudent
Parent drug has 23 –45 hour half-life
Weak inhibitor of CYP450 2D6
Metabolized by CYP450 3A4 and 2C19

Can increase TCA levels; use with caution with TCAs
Can cause a fatal “serotonin syndrome ” when combined with
MAOIs, so do not use with MAOIs or at least for 14 days after
MAOIs are stopped
Do not start an MAOI for at least 5 half-lives (5 to 7 days for most
drugs) after discontinuing citalopram
May displace highly protein-bound drugs (e.g., warfarin)
Can rarely cause weakness, hyperreflexia, and incoordination when
combined with sumatriptan or possibly other triptans, requiring
careful monitoring of patient
Possible increased risk of bleeding especially when combined with
anticoagulants (e.g., warfarin, NSAIDs)
NSAIDs may impair ef fectiveness of SSRIs
Should not be dosed above 20 mg/day in patients taking a CYP450
2C19 inhibitor (e.g., cimetidine) due to risk of QT prolongation
Via CYP450 2D6 inhibition, citalopram could theoretically interfere

Via CYP450 2D6 inhibition, citalopram could theoretically increase

Do Not Use
Renal ImpairmentUse with caution in patients with history of seizures
companies
If patient is taking an MAOI
If patient is taking thioridazine or pimozide
If there is a proven aller gy to citalopram or escitalopram

ElderlyNo dose adjustment for mild to moderate impairment
Use cautiously in patients with severe impairment
Should not be used at doses greater than 20 mg/day
May need to dose cautiously at the lower end of the dose range in
some patients for maximal tolerability
May cause abnormal changes in the electrical activity of the heart at
doses greater than 40 mg/day
Treating depression with SSRIs in patients with acute angina or
following myocardial infarction may reduce cardiac events and
improve survival as well as mood
Doses greater than 20 mg/day should not be used in patients over
age 60 years
May need to dose at the lower end of the dose range in some
patients for maximal tolerability
Risk of SIADH with SSRIs is higher in the elderly
Citalopram may be an especially well-tolerated SSRI in the elderly

 PregnancyReduction in the risk of suicidality with antidepressants compared to
patients
Not specifically approved, but preliminary data suggest citalopram
is safe and ef fective in children and adolescents with OCD and with

Nonetheless, continuous treatment during pregnancy may be
necessary and has not been proven to be harmful to the fetus
At delivery there may be more bleeding in the mother and transient
irritability or sedation in the newborn
pregnancy
Exposure to SSRIs early in pregnancy may be associated with
increased risk of septal heart defects (absolute risk is small)
SSRI use beyond the 20th week of pregnancy may be associated
with increased risk of pulmonary hypertension in newborns,
although this is not proven
Exposure to SSRIs late in pregnancy may be associated with

increased risk of gestational hypertension and preeclampsia
Neonates exposed to SSRIs or SNRIs late in the third trimester have
developed complications requiring prolonged hospitalization,
respiratory support, and tube feeding; reported symptoms are
consistent with either a direct toxic ef fect of SSRIs and SNRIs or ,
possibly , a drug discontinuation syndrome, and include respiratory

Breast Feedingdistress, cyanosis, apnea, seizures, temperature instability , feeding
difficulty , vomiting, hypoglycemia, hypotonia, hypertonia,
hyperreflexia, tremor , jitteriness, irritability , and constant crying
essants
are on citalopram
the mother

the mother

 Pearls
✽ May be more tolerable than some other antidepressants
✽ May be less well tolerated than escitalopramElderly patients
Patients excessively activated or sedated by other SSRIs
May require dosage titration to attain optimal ef ficacy
Can be sedating in some patients
Anxiety
Panic attacks, avoidant behavior , reexperiencing, hyperarousal
Sleep disturbance, both insomnia and hypersomnia
May have less sexual dysfunction than some other SSRIs
May be especially well tolerated in the elderly
Documentation of ef ficacy in anxiety disorders is less
comprehensive than for escitalopram and other SSRIs

Cipriani  A , Purgato M , Furukawa  TA , et al. Citalopram versus other anti-
depressive agents for depression  . Cochrane Database Syst Rev  2012  ;11 (7
):CD006534  .
Rush  AJ , Trivedi  MH , Wisniewski  SR . Acute and longer -term outcomes
in depressed outpatients requiring one or several treatment steps: a
STAR*D report  . Am J Psychiatry  2006  ;163 (11 ):1905  –17.
Vieweg  WV , Hasnain  M , Howland  RH , et al. Citalopram, QT c interval
prolongation, and torsade de pointes. How should we apply the recent FDA
ruling?  Am J Med  2012  ;125 (9 ):859–68 .Can cause cognitive and af fective “flattening ”
Some evidence suggests that citalopram treatment during only the
luteal phase may be more ef fective than continuous treatment for
patients with PMDD
SSRIs may be less ef fective in women over 50, especially if they are
not taking estrogen
SSRIs may be useful for hot flushes in perimenopausal women
Nonresponse to citalopram in elderly may require consideration of

mild cognitive impairment or Alzheimer disease

Brands
Generic?
Yes
 Class
✽ Obsessive-compulsive disorderAnafranil
Neuroscience-based Nomenclature: serotonin reuptake inhibitor
(SRI)
Parent drug is a potent serotonin reuptake inhibitor
Active metabolite is a potent norepinephrine/noradrenaline reuptake
inhibitor

✽ Severe and treatment-resistant depression
✽ Cataplexy syndrome
Insomnia
cortex, which lar gely lacks dopamine transporters, clomipramine
can increase dopamine neurotransmission in this part of the brain
Onset of therapeutic actions in depression usually not immediate,
but often delayed 2 to 4 weeks

If It W orksOnset of therapeutic action in OCD can be delayed 6 to 12 weeks
If it is not working for depression within 6 to 8 weeks, it may
require a dosage increase or it may not work at all
If it is not working for OCD within 12 weeks, it may not work at all
symptoms
Although the goal of treatment of OCD is also complete remission
of symptoms, this may be less likely than in depression
The goal of treatment of chronic neuropathic pain is to reduce
symptoms as much as possible, especially in combination with other

ResistanceUse in OCD may also need to be indefinite, starting from the time of
initial treatment
Use in other anxiety disorders and chronic pain may also need to be
indefinite, but long-term treatment is not well studied in these
conditions
Consider psychotherapy , especially behavioral therapy in OCD

Lithium, buspirone, hormone (for depression and OCD)

Tests
✽ Monitoring of plasma drug levels is potentially available at
specialty laboratories for the expert
✽ Weight and BMI during treatment
weight, consider evaluating for the presence of pre-diabetes, diabetes,For the expert: consider cautious addition of fluvoxamine for
treatment-resistant OCD
Thyroid hormone (for depression)
Atypical antipsychotics (for OCD)

Weight GainBlurred vision, constipation, urinary retention, increased appetite,

Sedation
Wait
Wait
Wait
100–200 mg/day
Capsule 25 mg, 50 mg, 75 mg

How to Dose
✽ Patients treated for OCD may often require doses at the high end of
the range (e.g., 200 –250 mg/day)
✽ Dose of 300 mg may be associated with up to 7/1000 incidence of
seizures, a generally unacceptable risk
OverdoseInitial 25 mg/day; increase over 2 weeks to 100 mg/day; maximum
dose generally 250 mg/day
Risk of seizure increases with dose, especially with clomipramine at
doses above 250 mg/day

How to Stop
PharmacokineticsDeath may occur; convulsions, cardiac dysrhythmias, severe
Limited data but appears to be ef ficacious and safe long-term
No
Metabolized to an active metabolite, desmethyl-clomipramine, a
predominantly norepinephrine reuptake inhibitor , by demethylation
via CYP450 1A2

Half-life approximately 17 –28 hours
drugs) after discontinuing clomipramine
Use of TCAs with anticholiner gic drugs may result in paralytic ileus
of clomipramine to desmethyl-clomipramine, and increase
clomipramine plasma concentrations
May alter ef fects of antihypertensive drugs

Other W arnings/Pr ecautionsUse of TCAs with sympathomimetic agents may increase
TCAs may inhibit hypotensive ef fects of clonidine
discontinuation of clomipramine
after discontinuing clomipramine

Do Not UseBecause TCAs can prolong QT c interval, use with caution in
patients who have hypokalemia and/or hypomagnesemia or who are
companies

Cardiac ImpairmentIf there is a history of QT c prolongation or cardiac arrhythmia,
If there is a proven aller gy to clomipramine

ElderlyTCAs produce QT c prolongation, which may be enhanced by the
clomipramine

Childr en and AdolescentsDose may need to be lower than usual adult dose, at least initially
patients
Not recommended for use in children under age 10
Effective for OCD in children

Dose in children/adolescents should be titrated to a maximum of
100 mg/day or 3 mg/kg per day after 2 weeks, after which dose can
then be titrated up to a maximum of 200 mg/day or 3 mg/kg per day

Pregnancy
Clomipramine crosses the placenta
treatment (recurrence of depression, worsening of OCD, maternal
health, infant bonding) to the mother and child

pregnancy
essants

Potential DisadvantagesImmediate postpartum period is a high-risk time for depression and
worsening of OCD, especially in women who have had prior
depressive episodes or OCD symptoms, so drug may need to be
reinstituted late in the third trimester or shortly after childbirth to
prevent a recurrence or exacerbation during the postpartum period
the mother
feeding
Patients with comorbid OCD and depression
Patients with cataplexy

 Pearls
✽ The only TCA with proven ef ficacy in OCDPatients with seizure disorders
Obsessive thoughts
Compulsive behaviors
Normally , clomipramine (CMI), a potent serotonin reuptake blocker ,
at steady state is metabolized extensively to its active metabolite
desmethyl-clomipramine (de-CMI), a potent nonadrenaline reuptake
blocker , by the enzyme CYP450 1A2
Thus, at steady state, plasma drug activity is generally more
noradrener gic (with higher de-CMI levels) than serotoner gic (with
lower parent CMI levels)
Addition of the SSRI and CYP450 1A2 inhibitor fluvoxamine
blocks this conversion and results in higher CMI levels than de-CMI
levels
For the expert only: addition of the SSRI fluvoxamine to CMI in
treatment-resistant OCD can powerfully enhance serotoner gic
activity , not only due to the inherent additive pharmacodynamic
serotoner gic activity of fluvoxamine added to CMI, but also due to a

favorable pharmacokinetic interaction inhibiting CYP450 1A2 and

✽ One of the most favored TCAs for treating severe depression
✽ Unique among TCAs, clomipramine has a potentially fatal
interaction with MAOIs in addition to the danger of hypertension
characteristic of all MAOI-TCA combinations
✽ A potentially fatal serotonin syndrome with high fever , seizures,
and coma, analogous to that caused by SSRIs and MAOIs, can occur
with clomipramine and SSRIs, presumably due to clomipramine ’s
potent serotonin reuptake blocking propertiesthus converting CMI ’s metabolism to a more powerful serotoner gic
portfolio of parent drug
TCAs are no longer generally considered a first-line treatment
TCAs continue to be useful for severe or treatment-resistant
TCAs are often a first-line treatment option for chronic pain

2000  ;58 :19 –36 .Patients on TCAs should be aware that they may experience

Bull 2001  ;57 :161–78 .
Cox BJ , Swinson  RP , Morrison  B , Lee PS . Clomipramine, fluoxetine,
and behavior therapy in the treatment of obsessive-compulsive disorder: a
meta-analysis  . J Behav Ther Exp Psychiatry  1993  ;24 :149–53 .
Feinber g M . Clomipramine for obsessive-compulsive disorder  . Am Fam
Physician  1991  ; 43 :1735 –8 .

Clonazepam
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Klonopin
Benzodiazepine (anxiolytic, anticonvulsant)
Panic disorder , with or without agoraphobia
Lennox-Gastaut syndr ome (petit mal variant)
Akinetic seizur e
Myoclonic seizur e
Absence seizur e (petit mal)

If It W orksAtonic seizures
Other seizure disorders
Insomnia
Catatonia
Inhibitory actions in cerebral cortex may provide therapeutic
benefits in seizure disorders

If It Doesn ’t WorkFor short-term symptoms of anxiety –after a few weeks, discontinue
For long-term treatment of seizure disorders, development of
tolerance dose escalation and loss of ef ficacy necessitating adding or

switching to other anticonvulsants is not uncommon

Tests
Side EffectsConsider presence of concomitant substance abuse
Consider presence of clonazepam abuse
Consider another diagnosis such as a comorbid medical condition
Clonazepam is commonly combined with other anticonvulsants for
the treatment of seizure disorders

 Life-Thr eatening or Danger ous Side EffectsSame mechanism for side ef fects as for therapeutic ef fects –namely
Grand mal seizures

Sedation
Wait
Wait
Wait

How to Dose
 Dosing T ipsSeizures: dependent on individual response of patient, up to 20
mg/day
Panic: 0.5 –2 mg/day either as divided doses or once at bedtime
Tablet 0.5 mg scored, 1 mg, 2 mg
Disintegrating (wafer) 0.125 mg, 0.25 mg, 0.5 mg, 1 mg, 2 mg
Seizures –1.5 mg divided into 3 doses, raise by 0.5 mg every 3 days
until desired ef fect is reached; divide into 3 even doses or else give
largest dose at bedtime; maximum dose generally 20 mg/day
Panic –1 mg/day; start at 0.25 mg divided into 2 doses, raise to 1 mg
after 3 days; dose either twice daily or once at bedtime; maximum
dose generally 4 mg/day
For anxiety disorders, use lowest possible ef fective dose for the
shortest possible period of time (a benzodiazepine-sparing strategy)
Assess need for continuous treatment regularly

✽ Clonazepam is generally dosed half the dosage of alprazolam
✽ Available as an oral disintegrating waferRisk of dependence may increase with dose and duration of
treatment
maintain same daily dose but divide into more frequent doses
anxiety
Because seizure disorder can require doses much higher than 2
mg/day , the risk of dependence may be greater in these patients
Because panic disorder can require doses somewhat higher than 2
mg/day , the risk of dependence may be greater in these patients than
in anxiety patients maintained at lower doses
Some severely ill seizure patients may require more than 20 mg/day
Some severely ill panic patients may require 4 mg/day or more

Escalation of dose may be necessary if tolerance develops in seizure
disorders
Escalation of dose usually not necessary in anxiety disorders, as
tolerance to clonazepam does not generally develop in the treatment
of anxiety disorders

Overdose
How to StopRarely fatal in monotherapy; sedation, confusion, coma, diminished
reflexes
May lose ef ficacy for seizures; dose increase may restore ef ficacy
Clonazepam is a Schedule IV drug
use
Patients with history of seizures may seize upon withdrawal,
Taper by 0.25 mg every 3 days to reduce chances of withdrawal
effects
slowly after reaching 1.5 mg/day , perhaps by as little as 0.125 mg
per week or less

 Drug InteractionsFor other patients with severe problems discontinuing a
Long half-life compared to other benzodiazepine anxiolytics
(elimination half-life approximately 30 –40 hours)
Substrate for CYP450 3A4

Other W arnings/Pr ecautionsInhibitors of CYP450 3A4 may af fect the clearance of clonazepam,
but dosage adjustment usually not necessary
Flumazenil (used to reverse the ef fects of benzodiazepines) may
precipitate seizures and should not be used in patients treated for
seizure disorders with clonazepam
Use of clonazepam with valproate may cause absence status
efficacy
Patients and their caregivers should be warned to seek medical

efficacy

Do Not Use
Hepatic ImpairmentHistory of drug or alcohol abuse often creates greater risk for
Clonazepam may induce grand mal seizures in patients with
multiple seizure disorders
ideation
If patient has severe liver disease
If there is a proven aller gy to clonazepam or any benzodiazepine
Dose should be reduced

Elderly
 PregnancyBenzodiazepines have been used to treat anxiety associated with
Should receive lower doses and be monitored
Seizures –up to 10 years or 30 kg –0.01–0.03 mg/kg per day divided
into 2 –3 doses; maximum dose 0.05 mg/kg per day
Safety and ef ficacy not established in panic disorder
For anxiety , children and adolescents should generally receive lower
doses and be more closely monitored
Long-term ef fects of clonazepam in children/adolescents are
unknown

Potential AdvantagesPossible increased risk of birth defects when benzodiazepines are
Because of the potential risks, clonazepam is not generally
Rapid onset of action

 Pearls
among psychiatristsLonger duration of action than some other benzodiazepines
Availability of oral disintegrating wafer
Development of tolerance may require dose increases, especially in
seizure disorders
Frequency and duration of seizures
Spike and wave dischar ges in absence seizures (petit mal)
Anxiety

✽ Easier to taper than some other benzodiazepines because of long
half-life
✽ May have less abuse potential than some other benzodiazepines
✽ May cause less depression, euphoria, or dependence than some
✽ Clonazepam is often considered a “longer -acting alprazolam-like
anxiolytic ” with improved tolerability features in terms of less
euphoria, abuse, dependence, and withdrawal problems, but this has
 Suggested ReadingGenerally used as second-line treatment for petit mal seizures if
succinimides are inef fective
Can be used as an adjunct or as monotherapy for seizure disorders
Clonazepam is the only benzodiazepine that is used as a solo
maintenance treatment for seizure disorders

treatment

Davidson  JR , Moroz  G. Pivotal studies of clonazepam in panic disorder  .
Psychopharmacol Bull  1998  ;34 :169–74 .
DeVane CL , Ware MR , Lydiard  RB. Pharmacokinetics,
Iqbal  MM , Sobhan  T , Ryals T. Effects of commonly used benzodiazepines
on the fetus, the neonate, and the nursing infant  . Psychiatr Serv  2002  ;53
:39 –49 .
Panayiotopoulos  CP. Treatment of typical absence seizures and related
epileptic syndromes  . Paediatr Drugs  2001  ;3 :379 –403 .

Clonidine
Brands
Generic?
Yes (not for transdermal)
 Class
(bold for FDA appr oved)Duraclon (injection)
Catapres
Kapvay
Neuroscience-based Nomenclature: norepinephrine receptor agonist
(N-RA)
Antihypertensive; centrally acting alpha 2 agonist hypotensive
agent, nonstimulant for ADHD

How Long Until It W orksAttention deficit hyperactivity disorder (ADHD) (Kapvay , ages
6 to 17)
Tourette ’s syndrome
Substance withdrawal, including opiates and alcohol
Anxiety disorders, including posttraumatic stress disorder (PTSD)
and social anxiety disorder
Clozapine-induced hypersalivation
Menopausal flushing
Severe pain in cancer patients that is not adequately relieved by
opioid analgesics alone (combination with opiates)
For ADHD, theoretically has central actions on postsynaptic alpha 2
receptors in the prefrontal cortex
For hypertension, stimulates alpha 2 adrener gic receptors in the
brain stem, reducing sympathetic outflow from the CNS and
decreasing peripheral resistance, renal vascular resistance, heart
rate, and blood pressure
An imidazoline, so also interacts at imidazoline receptors

If It W orks
If It Doesn ’t WorkFor ADHD, can take a few weeks to see maximum therapeutic
benefits
Blood pressure may be lowered 30 –60 minutes after first dose;
greatest reduction seen after 2 –4 hours
May take several weeks to control blood pressure adequately
For hypertension, continue treatment indefinitely and check blood
pressure regularly

Tests
How Drug Causes Side EffectsConsider the presence of noncompliance and counsel patient and
parents
etc.)
Best to attempt another monotherapy prior to augmenting for
ADHD
Possibly combination with stimulants (with caution as benefits of
combination poorly documented and there are some reports of
serious adverse events)
Combinations for ADHD should be for the expert, while monitoring
the patient closely , and when other treatment options have failed
Chlorthalidone, thiazide-type diuretics, and furosemide for
Blood pressure should be checked regularly during treatment

✽ Dry mouth
✽ Dizziness, constipation, sedation
Excessive actions on alpha 2 receptors and/or on imidazoline
receptors
Weakness, fatigue, impotence, loss of libido, insomnia, headache
Major depression
Dermatologic reactions (especially with transdermal clonidine)
Hypotension, occasional syncope
Nervousness, agitation
Nausea, vomiting
Sinus bradycardia, atrioventricular block
During withdrawal, hypertensive encephalopathy , cerebrovascular
accidents, and death (rare)

Sedation
✽ For withdrawal and discontinuation reactions, may need to reinstate
clonidine and taper very slowly when stabilized
Usual Dosage RangeMany experience and/or can be significant in amount
Can abate with time
Wait
Take lar ger dose at bedtime to avoid daytime sedation
Switch to another medication with better evidence of ef ficacy
agent
Extended-release for ADHD: 0.1 –0.4 mg/day in divided doses

How to DoseImmediate-release for hypertension: 0.2 –0.6 mg/day in divided
doses
Opioid withdrawal: 0.1 mg 3 times daily (can be higher in inpatient
setting)
Extended-release tablet 0.1 mg, 0.2 mg
Immediate-release tablet 0.1 mg scored, 0.2 mg scored, 0.3 mg
scored
Topical (7 day administration) 0.1 mg/24 hours, 0.2 mg/24 hours,
0.3 mg/24 hours
Injection 0.1 mg/mL, 0.5 mg/mL
Oral (for ADHD): initial 0.1 mg at bedtime; can increase by 0.1
mg/day each week with dosing divided and lar ger dose at bedtime;
maximum dose generally 0.4 mg/day in divided doses
For opioid withdrawal: 0.1 mg 3 times daily; next dose should be
withheld if blood pressure falls below 90/60 mmHg; outpatients
should not be given more than a 3-day supply , detoxification can
usually be achieved in 4 –6 days for short-acting opioids
Oral (for hypertension): initial 0.1 mg in 2 divided doses, morning
and night; can increase by 0.1 mg/day each week; maximum dose
generally 2.4 mg/day

Dosing T ipsTopical (for hypertension): apply once every 7 days in hairless area;
change location with each application
Injection (for hypertension): initial 30 Î¼ g/hour; maximum 40 Î¼
g/hour; 500 mg/mL must be diluted
Extended-release tablet should not be chewed, crushed, or broken
before swallowing, as this could alter controlled-release properties
Do not substitute dif ferent clonidine products for each other on a
mg-per -mg basis, because they have dif ferent pharmacokinetic
profiles
Adverse ef fects are dose-related and usually transient
The last dose of the day should occur at bedtime so that blood
pressure is controlled overnight
If clonidine is terminated abruptly , rebound hypertension may occur
within 2 –4 days, so taper dose in decrements of no more than 0.1
mg every 3 to 7 days when discontinuing
Using clonidine in combination with another antihypertensive agent
may attenuate the development of tolerance to clonidine ’s
antihypertensive ef fects

The likelihood of severe discontinuation reactions with CNS and
cardiovascular symptoms may be greater after administration of
high doses of clonidine

✽ In patients who have developed localized contact sensitization to
transdermal clonidine, continuing transdermal dosing on other skin
areas or substituting with oral clonidine may be associated with the
development of a generalized skin rash, urticaria, or angioedema
✽ If administered with a beta blocker , stop the beta blocker first for
several days before the gradual discontinuation of clonidine in cases of
planned discontinuation
Overdose
✽ Studies have not established the utility of clonidine for long-term
CNS uses
✽ Be aware that for getting to take clonidine or running out of
medication can lead to abrupt discontinuation and associated
withdrawal reactions and complications
Habit FormingHypotension, hypertension, miosis, respiratory depression, seizures,
bradycardia, hypothermia, coma, sedation, decreased reflexes,
weakness, irritability , dysrhythmia
Patients may develop tolerance to the antihypertensive ef fects
Reports of some abuse by opiate addicts

Reports of some abuse by non-opioid-dependent patients

How to Stop
✽ Discontinuation reactions are common and sometimes severe
 Drug InteractionsSudden discontinuation can result in nervousness, agitation,
headache, and tremor , with rapid rise in blood pressure
Rare instances of hypertensive encephalopathy , cerebrovascular
accident, and death have been reported after clonidine withdrawal
Taper over 2 –4 days or longer to avoid rebound  effects
(nervousness, increased blood pressure)
If administered with a beta blocker , stop the beta blocker first for
several days before the gradual discontinuation of clonidine
Half-life 12 –16 hours
Excreted renally
cardiovascular symptoms may be greater when clonidine is
combined with beta blocker treatment
Increased depressive  and sedative ef fects when taken with other
CNS depressants
TCAs may reduce the hypotensive ef fects of clonidine

Other W arnings/Pr ecautionsCorneal lesions in rats increased by use of clonidine with
Use of clonidine with agents that af fect sinus node function or A V
nodal function (e.g., digitalis, calcium channel blockers, beta
blockers) may result in bradycardia or A V block
There have been cases of hypertensive encephalopathy ,
cerebrovascular accidents, and death after abrupt discontinuation
If used with a beta blocker , the beta blocker should be stopped
several days before tapering clonidine
In patients who have developed localized contact sensitization to
Use with caution in patients at risk for hypotension, heart block, and
bradycardia
Be aware that for getting to take clonidine or running out of

Injection is not recommended for use in managing obstetrical,
postpartum, or peri-operative pain
Certain transdermal patches containing even small traces of
aluminum or other metals in the adhesive backing can cause skin

Do Not Use
Elderly
 Childr en and Adolescentsburns if worn during MRI, so warn patients taking the transdermal
formulation about this possibility and advise them to disclose this
information if they need an MRI
If there is a proven aller gy to clonidine
Use with caution and possibly reduce dose
Use with caution in patients with recent myocardial infarction,
severe coronary insuf ficiency , cerebrovascular disease
Elderly patients may tolerate a lower initial dose better

✽ Because children commonly have gastrointestinal illnesses that lead
to vomiting, they may be more likely to abruptly discontinue clonidine
and therefore be more susceptible to hypertensive episodes resulting
from abrupt inability to take medication
 PregnancySafety and ef ficacy not established for children under age 6
Children may be more sensitive to hypertensive ef fects of
withdrawing treatment
Children may be more likely to experience CNS depression with
overdose and may even exhibit signs of toxicity with 0.1 mg of
clonidine
Injection may be used in pediatric cancer patients with severe pain
unresponsive to other medications

✽ For ADHD patients, clonidine should generally be discontinued
before anticipated pregnancies
Primary T arget SymptomsSome drug is found in mother ’s breast milk
No adverse ef fects have been reported in nursing infants
If irritability or sedation develop in nursing infant, may need to
discontinue drug or bottle feed
Not a controlled substance
Not well studied in adults with ADHD
Withdrawal reactions
Noncompliant patients
Patients on concomitant CNS medications

Pearls
✽ Clonidine extended-release is approved for ADHD in children ages
6–17
✽ Clonidine may also be ef fective for treatment of tic disorders,
including T ourette ’s syndromeOppositional and impulsive behavior
High blood pressure
As monotherapy or in combination with methylphenidate for ADHD
with conduct disorder or oppositional defiant disorder , may improve
aggression, oppositional, and conduct disorder symptoms
Clonidine is sometimes used in combination with stimulants to
reduce side ef fects and enhance therapeutic ef fects on motor
hyperactivity
Doses of 0.1 mg in 3 divided doses have been reported to reduce
stimulant-induced insomnia as well as impulsivity
May suppress tics especially in severe T ourette ’s syndrome, and
may be even better at reducing explosive violent behaviors in
Sedation is often unacceptable in various patients despite
improvement in CNS symptoms and leads to discontinuation of
treatment, especially for ADHD and T ourette ’s syndrome

Considered an investigational treatment for most other CNS
applications

May block the autonomic symptoms in anxiety and panic disorders
(e.g., palpitations, sweating) and improve subjective anxiety as well
May be useful in decreasing the autonomic arousal of PTSD
May be useful as an as-needed medication for stage fright or other
predictable socially phobic situations
May also be useful when added to SSRIs for reducing arousal and
dissociative symptoms in PTSD
May block autonomic symptoms of opioid withdrawal (e.g.,
palpitations, sweating) especially in inpatients, but muscle aches,
irritability , and insomnia may not be well suppressed by clonidine
Often prescribed with naltrexone to suppress symptoms of opioid
withdrawal; this requires monitoring of the patient for 8 hours on the
first day due to the potential severity of naltrexone-induced
withdrawal and the potential blood pressure ef fects of clonidine
May be useful in decreasing the hypertension, tachycardia, and
tremulousness associated with alcohol withdrawal, but not the

seizures or delirium tremens in complicated alcohol withdrawal
Clonidine may improve social relationships, af fectual responses, and
sensory responses in autistic disorder
Clonidine may reduce the incidence of menopausal flushing
Growth hormone response to clonidine may be reduced during
menses

✽ Guanfacine is a related centrally active alpha 2 agonist hypotensive
agent that has been used for similar CNS applications but has not been
as widely investigated or used as clonidine
✽ Guanfacine may be tolerated better than clonidine in some patients
(e.g., sedation) or it may work better in some patients for CNS
applications than clonidine, but no head-to-head trials
American Psychiatric Association  . Practice guideline for the treatment of
patients with substance use disorders, second edition  . Am J Psychiatry
2007  ;164 (4 ):1 –86 .
Burris  JF . The USA experience with the clonidine transdermal therapeutic
system  . Clin Auton Res  1993  ;3 :391–6 .
Croxtall  JD. Clonidine extended-release: in attention-deficit hyperactivity
disorder  . Paediatr Drugs  2011 ;13 (5 ):329–36 .
Gavras  I , Manolis  AJ , Gayras  H . The alpha2-adrener gic receptors in
hypertension and heart failure: experimental and clinical studies  . J

Hypertens  2001  ;19 :2115–24 .Clonidine stimulates growth hormone secretion (no chronic ef fects
have been observed)
Alcohol may reduce the ef fects of clonidine on growth hormone

Neil MJ. Clonidine: clinical pharmacology and therapeutic use in pain
management  . Curr Clin Pharmacol  2011 ;6 (4 ):280–7 .

Clorazepate
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Azene
Tranxene
Anxiety disorder
Acute alcohol withdrawal
Partial seizures (adjunct)

If It W orksCatatonia

ResistanceIf long-term maintenance with a benzodiazepine is necessary ,
Consider presence of clorazepate abuse

Tests
 Sedation, fatigue, depression
 Dizziness, ataxia, slurred speech, weakness
 Forgetfulness, confusion
 NervousnessCaution if using as an anxiolytic concomitantly with other sedative

Sedation
What to Do About Side EffectsRare hypotension
Wait
Wait
Wait

How to DoseTake lar gest dose at bedtime to avoid sedative ef fects during the day
Anxiety: 15 –60 mg/day in divided doses
Alcohol withdrawal: 30 –60 mg/day in divided doses
Tablet 3.75 mg scored, 7.5 mg scored, 15 mg scored
Anxiety: initial 15 mg/day in divided doses; adjust dose as needed
on subsequent days; single-dose tablet may be given once daily at
bedtime after patient is stable; maximum generally 90 mg/day
Alcohol withdrawal: initial 30 mg, then 30 –60 mg in divided doses;
second day 45 –90 mg in divided doses; third day 22.5 –45 mg in
divided doses; fourth day 15 –30 mg in divided doses; after fourth

Overdoseday decrease dose gradually and discontinue when patient is stable;
maximum generally 90 mg/day
Epilepsy: initial 7.5 mg 3 times/day; increase by 7.5 mg weekly;
treatment
anxiety
Fatalities can occur; hypotension, tiredness, ataxia, confusion, coma

How to StopEvidence of ef ficacy for up to 16 weeks
Risk of dependence, particularly for periods longer than 12 weeks
and especially in patients with past or current polysubstance abuse
Clorazepate is a Schedule IV drug
use
Taper by 7.5 mg every 3 days to reduce chances of withdrawal
effects
slowly after reaching 30 mg/day , perhaps by as little as 3.75 mg per

 Other W arnings/Pr ecautionsso on). This is both a form of very slow biological tapering and a
Elimination half-life 40 –50 hours

Do Not Use
Renal Impairmenteach drug to the minimum possible while still achieving therapeutic
efficacy
ideation
If there is a proven aller gy to clorazepate or any benzodiazepine

Elderly
 PregnancyInitial 7.5 –15 mg/day in divided doses or in 1 dose at bedtime
Initial 7.5 –15 mg/day in divided doses or in 1 dose at bedtime
Not recommended for use in children under age 9
Recommended initial dose: 7.5 mg twice a day

Because of the potential risks, clorazepate is not generally
 Recommended either to discontinue drug or bottle feed

 PearlsEuphoria may lead to abuse
Anxiety
Incidence of seizures (adjunct)
Can be very useful as an adjunct to SSRIs and SNRIs in the
treatment of numerous anxiety disorders
 More commonly used than some other benzodiazepines for
treating alcohol withdrawal

Griffith JL , Murray  GB . Clorazepate in the treatment of complex partial
seizures with psychic symptomatology  . J Nerv Ment Dis  1985  ;173 :185 –6
.
Kiejna  A , Kantorska-Janiec  M , Malyszczak  K . [The use of chlorazepate
dipotassium (T ranxene) in the states of restlessness and agitation]  .
Psychiatr Pol  1997  ;31 :753 –60 .
Mielke  L , Breinbauer  B , Schubert  M , et al. [Comparison of the
effectiveness of orally administered clorazepate dipotassium and
nordiazepam on preoperative anxiety]  . Anaesthesiol Reanim  1995  ;20 :144
–8 .
Rickels  K , Schweizer  E , Csanalosi  I , Case  WG , Chung  H . Long-term
treatment of anxiety and risk of withdrawal. Prospective comparison of
clorazepate and buspirone  . Arch Gen Psychiatry  1988  ;45 :444 –50 .Though not systematically studied, benzodiazepines have been used
treatment

Clozapine
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Clozaril
Leponex
Versacloz (oral suspension)
Fazaclo ODT (oral disintegrating tablet)
generation antipsychotic; also a mood stabilizer)
Treatment-r esistant schizophr enia

✽ Specifically , interactions at 5HT2C and 5HT1A receptors may
contribute to ef ficacy for cognitive and af fective symptoms in some
patients
How Long Until It W orksReduction in risk of r ecurr ent suicidal behavior in patients with
schizophr enia or schizoaffective disorder
Treatment-resistant bipolar disorder
Violent aggressive patients with psychosis and other brain disorders
not responsive to other treatments
contribute to clozapine ’s efficacy
Mechanism of ef ficacy for psychotic patients who do not respond to
other antipsychotics is unknown but is presumed to be a mechanism
other than D2 antagonism

Likelihood of response depends on achieving trough plasma levels
of at least 350 ng/mL

If It W orks
✽ Such patients are considered super -responders or “awakeners ” since
sustain long-term relationships; superresponders are anecdotallyMedian time to response after achieving therapeutic plasma levels
(350 ng/mL) is approximately 3 weeks
If there is no response after 3 weeks of therapeutic plasma levels,
recheck plasma levels and continue titration
In strictly defined refractory schizophrenia, 50 –60% of patients will
respond to clozapine
The response rate to other atypical antipsychotic in the refractory
patient population ranges from 0 –9%
Many patients with bipolar disorder and other disorders with
psychotic, aggressive, violent, impulsive, and other types of

behavioral disturbances may respond to clozapine when other agents
have failed

reported more often with clozapine than with some other
✽ Consider augmentation with valproate, lamotrigine, or topiramate,
but use caution with valproate as it can also cause bone marrow
suppression and be sedatingMany bipolar patients may experience a reduction of symptoms by
Obtain clozapine plasma levels and continue titration
Levels greater than 700 ng/mL are often not well tolerated
No evidence to support dosing that results in plasma levels greater
than 1000 ng/mL
Some patients may require augmentation with a conventional
antipsychotic or with an atypical antipsychotic (especially
risperidone or amisulpride), but these are the most refractory of all
psychotic patients and such treatment can be expensive

injection

TestsConsider initiating rehabilitation and psychotherapy such as
Conventional antipsychotics
Lithium
Evaluate bowel function before starting a patient on clozapine
Lower ANC threshold for starting clozapine:
General population: >1500/µL
Benign ethnic neutropenia (BEN): >1000/µL
Testing for myocarditis:
Myocarditis is rare and only occurs in the first 6 weeks of
treatment
Baseline: check troponin I/T , C-reactive protein (CRP)

plasma glucose, and fasting lipid profileWeekly troponin I/T and CRP for the first month
Fever is usually benign and self-limited; suspicion of
myocarditis should only be raised based on elevated troponin
and other features of myocarditis
Clozapine should be stopped if troponin >2× upper limits of
normal or CRP >100 mg/L
Cardiomyopathy is a late complication; consider annual ECG

respiration, weakness and clouding of sensorium, even comaTreat or refer such patients for treatment, including nutrition and

Liver function testing, ECG, general physical exam, and assessment
of baseline cardiac status before starting treatment

Side effects
Notable Side EffectsLiver tests may be necessary during treatment in patients who
develop nausea, vomiting, or anorexia
By blocking histamine 1 receptors in the brain, it can cause sedation
and possibly weight gain
Insulin regulation may be impaired by blocking pancreatic M3
muscarinic receptors
Orthostasis
Sialorrhea

Life-Thr eatening or Danger ous Side EffectsConstipation
Sedation
Dyslipidemia and hyper glycemia
Benign fever (~20%)
Tardive dyskinesia (reduced risk compared to other antipsychotics)
Severe neutropenia
Myocarditis (only in first 6 weeks of treatment)
Paralytic ileus
Seizures (risk increases with dose)
Pulmonary embolism (may include deep vein thrombosis or
respiratory symptoms)
Dilated cardiomyopathy

Sedation
(rhabdomyolysis), and acute renal failure (more likely when
clozapine is used with another agent)
May increase risk for aspiration events
Should be managed aggressively
Can become a health problem in some
More than for some other antipsychotics, but never say always as
not a problem in everyone

What to Do About Side EffectsCan wear of f over time
Can reemer ge as dose increases and then wear of f again over time
Slow titration to minimize orthostasis and sedation
Minimize use of other alpha 1 antagonists
If orthostasis remains a problem, Florines 0.1 –0.3 mg qd for
volume expansion (contraindicated in congestive heart failure)
Take at bedtime to help reduce daytime sedation
Sialorrhea management
Atropine 1% drops, 1 –3 drops sublingually at bedtime; can use
up to 3 times per day if needed
Ipratropium bromide 0.06% spray , 1–3 sprays intra-orally at
bedtime; can use up to 3 times per day if needed
Avoid use of systemic anticholiner gic agents, which increase
risk of ileus (benztropine, glycopyrrolate, etc.)
Consider novel use of botulinum toxin injections for severe
cases
Constipation management
Avoid psyllium as it may worsen symptoms
All patients should receive docusate 250 mg when starting
clozapine

If needed, add Miralax 17 g
If docusate + Miralax are inef fective, add either bisacodyl or
sennosides
If constipation still remains a problem, prescribe lubiprostone
8–24 Î¼ g twice per day
Advise patients to contact a healthcare professional right away
if they have dif ficulty having a bowel movement, do not have a
bowel movement at least three times a week or less than their
normal frequency , or are unable to pass gas
Weight gain and metabolic ef fects
Consider prophylactic metformin; start at 500 mg for 1 week,
then increase dose
All patients should be referred for lifestyle management and
exercise
Atenolol 12.5 mg qd, increase to keep resting HR <100 bpm
Chest pain during the first 6 weeks
Obtain workup for myocarditis Fever
In the absence of elevated troponin and myocarditis symptoms,
fever is usually self-limited and there is no need to stop
clozapine
Seizures

Dosing and use
How to DoseValproate for myoclonic or generalized seizures
Avoid phenytoin and carbamazepine because of kinetic
interactions
Depends on plasma levels; threshold for response is trough plasma
level of 350 ng/mL
Tablet 12.5 mg, 25 mg scored, 50 mg, 100 mg scored, 200 mg
Orally disintegrating tablet 12.5 mg, 25 mg, 100 mg, 150 mg, 200
mg
Oral suspension 50 mg/mL

Dosing T ipsInitial 25 mg at night; increase by 25 –50 mg/day every 48 –72 hours
as tolerated
Obtain trough plasma level on 200 mg at bedtime
Threshold for response is 350 ng/mL
Doses greater than 500 mg per day may require a split dose
See also The Art of Switching, after Pearls
Because of the monitoring schedule, prescriptions are generally
given 1 week at a time for the first 6 months, then every 2 weeks for
months 6 –12, and then monthly after 12 months
Plasma half-life suggests twice daily administration, but in practice
it may be given once a day at night
Prior to initiating treatment with clozapine, a baseline ANC must be
at least 1500/µL for the general population and at least 1000/µL for
patients with documented benign ethnic neutropenia (BEN)
Recommended ANC Monitoring for the General Population
ANC Level Recommendation ANC Monitoring

Continue treatmentRecommended ANC Monitoring for the General Population
Normal range
(at least 1500/
µL)
Initiate treatment
If treatment is interrupted for <30 days, continue monitoring as
before
If treatment is interrupted for 30 days or more, monitor as if new
patient
First 6 months: weekly
Second 6 months: every 2 weeks
After 1 year: every month
Mild neutropenia
(1000 –1499/µL)
Confirm all initial reports of ANC <1500/ Î¼ L with a repeat ANC
measurement within 24 hours
Monitor 3 times/week until ANC >1500/µL

Once ANC >1500/µL, return to patient ’s last “normal range ” ANC
monitoring interval
Moderate neutropenia
(500–999/µL)
Interrupt treatment for suspected clozapine-induced neutropenia
Recommend hematology consultation
Monitor ANC daily until >1000/µL THEN
Once ANC >1500/µL, check ANC weekly for 4 weeks, then return
to patient ’s last “normal range ” ANC monitoring interval
(<500/µL)
Do not rechallenge unless prescriber determines benefits outweigh
risks

Recommended ANC Monitoring for BEN Patients
ANC Level Recommendation ANC MonitoringIf patient is rechallenged, resume treatment as a new patient under
“normal range ” monitoring once ANC >1500/µL
Normal BEN
range
(established
ANC baseline
>1000/µL)Obtain at
least 2
baseline
ANC levels
before
initiating
treatment
If treatment
is
interrupted
for <30
days,
continue
as before
is
for 30 days
or more,
monitor as if
new patientFirst 6 months:
weekly
Second 6
months: every 2
weeks
After 1 year:
every month

BEN
neutropenia
(500–999/µL)Continue
treatment
Recommend
hematology
consultationConfirm all
initial reports of
ANC <1500/ Î¼
L with a repeat
ANC
measurement
within 24 hours
Monitor 3
times/week until
ANC >1000/µL
or >patient ’s
known baseline
Once ANC
>1000/µL or
above patient ’s
known baseline,
check ANC
weekly for 4
weeks, then
return to
patient ’s last
“normal BEN
range ” ANC
interval

BEN severe
(<500/µL)Interrupt
treatment
for
suspected
clozapine-
induced
Recommend
consultation
Do not
rechallenge
unless
prescriber
determines
benefits
outweigh
risksConfirm all
ANC
Monitor ANC
daily until
>500/µL THEN
Monitor 3
ANC >patient ’s
baseline
If patient is
rechallenged,
resume
treatment as a
new patient
under “normal
BEN range ”
monitoring once
or at patient ’s

If treatment is discontinued for more than 2 days, reinitiate with 12.5
mg once or twice daily; if that dose is tolerated, the dose may be increased
to the previously therapeutic dose more quickly than recommended for
If abrup t discontinuation of clozapine is necessary , the patient must be
covered for choliner gic rebound; those with higher clozapine plasma levels
may need extremely high doses  of anticholiner gic medications to prevent
delirium and other rebound symptoms
Slow off-titration is preferred if possible to avoid choliner gic rebound
and rebound psychosis
patients requiring acute antipsychotic actions, consider short-term (one dose
or more) augmentation with a benzodiazepine or another antipsychotic,
especially intramuscularly
Rather than raise the dose abov e normal dosing in partial responders,
consider augme ntation with a mood-stabilizing anticonvulsa nt, such as

valproate, topiramate, or lamotrigine
For treatment resistance, consider obtaining plasma drug levels to
guide dosing above recommended levels
Overdose
Long-T erm UseSometimes lethal; changes in heart rhythm, excess salivation,
respiratory depression, altered state of consciousness

How to Stop
✽ Rapid discontinuation may lead to rebound psychosis and
 Drug InteractionsTreatment to reduce risk of suicidal behavior should be continued
for at least 2 years
Medication of choice for treatment-refractory schizophrenia
No
See The Art of Switching section of individual agents for how to
stop clozapine, generally over at least 4 weeks
See T ables for guidance on stopping due to neutropenia
Half-life 5 –16 hours
Metabolized primarily by CYP450 1A2 and to a lesser extent by
CYP450 2D6 and 3A4
Use clozapine plasma levels to guide treatment due to propensity for
drug interactions

Other W arnings/Pr ecautionsIn the presence of a strong CYP450 1A2 inhibitor (e.g.,
fluvoxamine, ciprofloxacin): use 1/3 the dose of clozapine
In the presence of a strong CYP450 1A2 inducer (e.g., cigarette
smoke), clozapine plasma levels are decreased
May need to decrease clozapine dose by up to 50% during periods
of extended smoking cessation (>1 week)
Strong CYP450 2D6 inhibitors (e.g., bupropion, duloxetine,
paroxetine, fluoxetine) can raise clozapine levels; dose adjustment
may be necessary
Strong CYP450 3A4 inhibitors (e.g., ketoconazole) can raise
clozapine levels; dose adjustment may be necessary
Clozapine may enhance ef fects of antihypertensive drugs
Use with caution in patients on other anticholiner gic agents
(benztropine, trihexyphenidyl, olanzapine, quetiapine,
chlorpromazine, oxybutynin, and other antimuscarinics)
Constipation caused by clozapine can uncommonly lead to serious

bowel complications, so advise patients of the risk and the need to
stay hydrated, question patients about their bowel movements
throughout treatment, and advise them to contact a healthcare
professional right away if they have dif ficulty having a bowel

movement, do not have a bowel movement at least three times a
week or less than their normal frequency , or are unable to pass gas
Should not be used in conjunction with agents that are known to
cause neutropenia
Myocarditis is rare and only occurs in the first 6 weeks of treatment
Cardiomyopathy is a late complication (consider annual ECG)
Use with caution in patients with glaucoma
Use with caution in patients with enlar ged prostate

clozapine should be used cautiously in patients at risk for aspiration
pneumonia

Do Not Use
Special populations
Cardiac Impairmenttreatment, and recurrently for patients on long-term antipsychotic
therapy
In patients with myeloproliferative disorder
In patients with uncontrolled epilepsy
In patients with paralytic ileus
In patients with CNS depression
If there is a proven aller gy to clozapine
Should be used with caution

Elderly
 PregnancyUse with caution if patient is taking concomitant antihypertensive or
agitation
Preliminary research has suggested ef ficacy in early-onset
treatment-resistant schizophrenia
Children and adolescents using clozapine may need to be monitored

Clozapine should be used only when the potential benefits outweigh
potential risks to the fetus

961-2388,

The art of psychopharmacology
✽ Treatment-resistant schizophrenia
✽ Violent, aggressive patients
✽ Patients with tardive dyskinesia
✽ Patients with suicidal behavior
✽ Patients with diabetes, obesity , and/or dyslipidemia
Primary T arget SymptomsUnknown if clozapine is secreted in human breast milk, but all
Infants of women who choose to breast feed while on clozapine
Sialorrhea, sedation, and orthostatis may be intolerable for some

Pearls
✽ Clozapine is the gold standard treatment for refractory
✽ Clozapine is not used first-line due to side ef fects and monitoring
burden
✽ However , some studies have shown that clozapine was associated
with the lowest risk of mortality among the antipsychotics, causing the
study authors to question if its use should continue to be restricted to
resistant cases
✽ Reduces suicide in schizophreniaUnstable mood (both depression and mania)
Suicidal behavior
May reduce violence and aggression in dif ficult cases, including
forensic cases
May reduce substance abuse
May improve tardive dyskinesia
Little or no prolactin elevation, motor side ef fects, or tardive
Clinical improvements often continue slowly over several years
Cigarette smoke can decrease clozapine levels and patients may be
at risk for relapse if they begin or increase smoking

More weight gain than many other antipsychotics –does not mean
every patient gains weight
Patients can have much better responses to clozapine than to any
other agent, but not always
To treat constipation and reduce risk of paralytic ileus and bowel
obstruction, taper of f other anticholiner gic agents and start all
patients routinely on docusate
The US FDA has changed the requirements for monitoring,
prescribing, dispensing, and receiving clozapine in order to address
concerns related to neutropenia; in addition to updating the
prescribing information for clozapine, the FDA has approved a new ,

shared Risk Evaluation and Mitigation Strategy (REMS)
The Clozapine REMS program replaces the six existing clozapine
registries, which are maintained by individual clozapine
manufacturers. Prescribers, pharmacies, and patients will now be
required to enroll in a single centralized program; patients already
treated with clozapine will be automatically transferred. In order to
prescribe and dispense clozapine, prescribers and pharmacies will be

 Switching fr om Oral Antipsychotics to Clozapine
agitation, and/or psychosis. However , use with caution in combination
with clozapine as this can increase the risk of circulatory collapse
required to be certified in the Clozapine REMS program. V isit the
Clozapine REMS program homepage for more information.
begin clozapine at middle dose
With risperidone, ziprasidone, iloperidone, and lurasidone, begin
clozapine gradually , titrating over at least 2 weeks to allow patients

meta-analysis  . Lancet  2019  ;394 :939 -51 .
Masuda  T , Misawa  F , Takase  M , Kane  JM , Correll  CU . Association with
hospitalization and all-cause discontinuation among patients with
schizophrenia on clozapine vs other oral second-generation antipsychotics:
a systematic review and meta-analysis of cohort studies  . JAMA Psychiatry
2019  ;76 :1052  –62 . doi: 10.1001/jamapsychiatry .2019.1702  .
Meyer  JM , Stahl  SM . Stahl's handbooks: the clozapine handbook  . New
York, NY  : Cambridge University Press  ; 2019  .
Ronaldson  KJ , Fitzgerald  PD , McNeil  JJ . Clozapine-induced myocarditis,
a widely overlooked adverse reaction  . Acta Psychiatr Scand  2015  ;132
:231–40 .
Rosenheck  RA , Davis  S , Covell  N , et al. Does switching to a new

:231–40 .
antipsychotic improve outcomes? Data from the CA TIE T rial . Schizophr
Res 2009  ;170 (1 ):22 –9.
Schulte  P . What is an adequate trial with clozapine?: therapeutic drug
monitoring and time to response in treatment-refractory schizophrenia  .
Clin Pharmacokinet  2003  ;42 :607–18 .
Tiihonen  J , Lonnqvist  J , Wahlbeck  K , et al. 11-year follow-up of mortality
in patients with schizophrenia: a population-based cohort study (FIN1 1

Cyamemazine
Brands
Generic?
Not in USA
 Class
✽ Anxiety associated with psychosis (short-term)Tercian
antagonist, serotonin dopamine antagonist)
Anxiety associated with nonpsychotic disorders, including mood
disorders and personality disorders (short-term)
Severe depression

✽ Although classified as a conventional antipsychotic, cyamemazine
is a potent serotonin 2A antagonist
✽ Specifically , antagonist actions at 5HT2C receptors may contribute
to notable anxiolytic ef fects in many patients
If It W orksOther psychotic disorders
Acute agitation/aggression (injection)
Benzodiazepine withdrawal
psychosis
Affinity at a myriad of other neurotransmitter receptors may
contribute to cyamemazine ’s efficacy
5HT2C antagonist actions may also contribute to antidepressant
actions in severe depression and to improvement of cognitive and
negative symptoms of schizophrenia in some patients
Psychotic symptoms can improve with high doses within 1 week,
but it may take several weeks for full ef fect on behavior
Anxiolytic actions can improve with low doses within 1 week, but it
may take several days to weeks for full ef fect on behavior

If It Doesn ’t WorkHigh doses most often reduce positive symptoms in schizophrenia
but do not eliminate them
Low doses most often reduce anxiety symptoms in psychotic and
nonpsychotic disorders
a year , after first episode of psychosis in schizophrenia
For symptomatic treatment of anxiety in psychotic and nonpsychotic
disorders, treatment may also need to be indefinite while monitoring
the risks versus the benefits of long-term treatment
disorder

disorder
After reducing acute psychotic symptoms in mania, consider
switching to a mood stabilizer and/or an atypical antipsychotic for
long-term mood stabilization and maintenance

TestsFor treatment of psychotic symptoms, consider trying one of the
first-line atypical antipsychotics (risperidone, olanzapine,
quetiapine, ziprasidone, aripiprazole, paliperidone, amisulpiride)
clozapine
For treatment of anxiety symptoms, consider adding a
benzodiazepine or switching to a benzodiazepine
Generally , best to switch to another agent
Augmentation of conventional antipsychotics has not been
Addition of a benzodiazepine, especially for short-term agitation
Addition of antidepressants for severe depression

if the patient is already overweight (BMI 25.0 –29.9) or obese BMI
>30)
or dyslipidemia, or consider switching to a dif ferent antipsychoticBefore giving a drug that can cause weight gain to an overweight or
pre-diabetes (fasting glucose 100 –125 mg/dL), diabetes (fasting
plasma glucose >126 mg/dL), or dyslipidemia (increased total
cholesterol, LDL cholesterol, and triglycerides; decreased HDL

Should check blood pressure in the elderly before starting and for

How Drug Causes Side Effects(CBC) monitored frequently during the first few months and
cyamemazine should be discontinued at the first sign of decline of
By blocking dopamine 2 receptors in the striatum, it can cause
motor side ef fects at antipsychotic (high) doses
Much lower propensity to cause motor side ef fects at low doses used
to treat anxiety
elevations in prolactin, but unlike other conventional antipsychotics,
prolactin elevations at low doses of cyamemazine are uncommon or
transient
Anticholiner gic actions, especially at high doses, may cause
sedation, blurred vision, constipation, dry mouth

Antihistamine actions may contribute to anxiolytic actions at low
doses and to sedation and weight gain at high doses

✽ Neuroleptic-induced deficit syndrome (unusual at low doses)
 Life-Thr eatening or Danger ous Side EffectsBy blocking alpha 1 adrener gic receptors, cyamemazine can cause
dizziness, sedation, and hypotension especially at high doses
diabetes and dyslipidemia with conventional antipsychotics is
unknown
Akathisia
Drug-induced parkinsonism, tardive dyskinesia (unusual at low
doses)
Galactorrhea, amenorrhea (unusual at low doses)
Hypotension, tachycardia (unusual at low doses)
Dry mouth, constipation, vision disturbance, urinary retention
Sedation
Weight gain (may be unusual at low doses)
Metabolic ef fects, glucose tolerance
Rare neuroleptic malignant syndrome

Sedation
Increased risk of death and cerebrovascular events in elderly
patients with dementia-related psychosis
Reported but not expected especially at low doses
high doses
Sedation is usually dose-dependent and may not be experienced as
sedation but as anxiolytic actions on anxiety and aggression at low
doses where cyamemazine may function as an atypical antipsychotic
(e.g., <300 mg/day; especially 25 –100 mg/day)
Wait
Wait
Wait
For motor symptoms, add an anticholiner gic agent

Dosage FormsReduce the dose
Benztropine or trihexyphenidyl for motor side ef fects
Benzodiazepines may be helpful for akathisia
50–300 mg at bedtime for treatment of psychosis
25–100 mg for anxiety; duration of treatment 4 weeks
Children (ages 6 and older): 1 –4 mg/kg per day
Injection: 25 –100 mg/day
Tablet 25 mg, 100 mg
Oral solution 40 mg/mL

How to Dose
✽ Binding studies, PET studies, and clinical observations suggest that
cyamemazine may be “atypical ” with low motor side ef fects or
prolactin elevations at low doses (below 300 mg/day)
✽ Clinical evidence suggests substantial anxiolytic benefits at 25 –100
mg/day in many patients
✽ Clinical evidence suggests low risk of drug-induced parkinsonism,
little prolactin elevation yet demonstrable anxiolytic, anti-aggression,
and antidepressant actions at doses below 300 mg/dayInjection 50 mg/5 mL
Psychosis: usual maintenance dose 50 –300 mg at bedtime;
maximum dose 600 mg/day divided into 2 or 3 doses; after 2 weeks
consider reducing to lowest ef fective dose
Anxiety (adults): usual dose 25 –100 mg/day; reduce dose if
unacceptable sedation; maximum duration of treatment 4 weeks
Anxiety (children): usual dose 1 –4 mg/kg per day
Has conventional antipsychotic properties at originally
recommended high doses (300 –600 mg/day)

Robust antipsychotic actions on positive symptoms may require
dosing above 300 mg/day

Overdose
How to StopLow doses up to 100 mg/day may be used to augment partial
responders to other conventional or atypical antipsychotics,
especially for anxiolytic actions
Drug-induced parkinsonism, sedation, hypotension, coma,
Some side ef fects may be irreversible (e.g., tardive dyskinesia)
No
Slow down-titration (over 6 –8 weeks), especially when
Rapid oral discontinuation of high doses of phenothiazines in
psychotic patients may lead to rebound psychosis and worsening of
symptoms

 Drug InteractionsIf antiparkinsonian agents are being used, they should generally be
continued for a few weeks after high-dose cyamemazine is
Half-life 10 hours
May decrease the ef fects of levodopa; contraindicated for use with
dopamine agonists other than levodopa
guanethidine, whose antihypertensive actions phenothiazines may
Anticholiner gic ef fects may occur if used with atropine or related
compounds
syndrome
Epinephrine may lower blood pressure; diuretics and alcohol may
increase risk of hypotension when administered with a
phenothiazine

Use cautiously in patients with respiratory disorders
disorders because phenothiazines can lower seizure threshold
Do not use epinephrine in event of overdose as interaction with
some pressor agents may lower blood pressure
Antiemetic ef fects of phenothiazines may mask signs of other
asphyxia
Observe for signs of ocular toxicity (corneal and lenticular deposits)
as for other phenothiazines
Use only with caution or at low doses, if at all, in Parkinson ’s
disease or Lewy body dementia
Because cyamemazine may dose-dependently prolong QT c interval,

drugs that can induce bradycardia (e.g., beta blockers, calcium

Do Not Use
✽ If QT c interval greater than 450 msec or if taking an agent capable
of prolonging the QT c intervalBecause cyamemazine may dose-dependently prolong QT c interval,
use with caution in patients who have hyperkalemia and/or
intravenous amphotericin B, glucocorticoids, tetracosaclides)
Cyamemazine can increase the QT c interval, potentially causing
torsade de pointes-type arrhythmia or sudden death
If patient is taking sultopride
If patient is in a comatose state or has CNS depression
If there is the presence of blood dyscrasias, bone marrow
depression, or liver disease
If there is subcortical brain damage
If patient has sensitivity to or intolerance of gluten (tablets contain
gluten)

gluten)
If patient has congenital galactosemy , does not adequately absorb
glucose/galactose, or has lactase deficit (tablets contain lactose)

ElderlyIf patient is intolerant of fructose, does not adequately absorb
glucose/galactose, or has sugar -isomaltase deficit (oral solution
only; oral solution contains saccharose)
If there is a proven aller gy to cyamemazine
If there is a known sensitivity to any phenothiazine
Cardiovacular toxicity can occur , especially orthostatic hypotension
Generally , doses above 100 mg/day are not recommended

 Pregnancyand also have an increased risk of cerebrovascular events
Sometimes used for severe behavioral disturbances in children ages
6 and older
Oral solution is preferable to the other formulations
pregnancy
Phenothiazines should only be used during pregnancy if clearly
needed
Atypical antipsychotics may be preferable to phenothiazines or
anticonvulsant mood stabilizers if treatment is required during
pregnancy

Primary T arget SymptomsUnknown if cyamemazine is secreted in human breast milk, but all
For anxiety in patients with psychotic illnesses
For anxiety in patients with nonpsychotic illnesses
For severe depression
Patients with tardive dyskinesia
Children
Elderly
Anxiety associated with psychosis
Anxiety
Aggression
Agitation

Pearls
✽ Appears to have unique anxiolytic actions at low doses without
rebound anxiety following discontinuation
✽ Low doses rarely associated with motor side ef fects or with
✽ Recently discovered to be a serotonin dopamine antagonist with
more potent binding of 5HT2A and 5HT2C receptors than D2
receptors (binding studies and PET scans)
 Suggested ReadingPositive symptoms of psychosis
One of the most frequently prescribed antipsychotics in France,
especially as a low-dose anxiolytic for psychotic patients
Low doses appear to saturate 5HT2A receptors in frontal cortex
while not saturating D2 receptors in the striatum, accounting for
apparent atypical antipsychotic and anxiolytic properties at low
doses
May be useful second-line therapy in facilitating benzodiazepine
withdrawal for those patients in whom substitution with another
benzodiazepine is not ef fective or is not appropriate

Hameg  A , Bayle  F , Nuss  P , Dupuis  P , et al. Affinity of cyamemazine, an
anxiolytic antipsychotic drug, for human recombinant dopamine vs.
serotonin receptor subtypes  . Biochem Pharmacol  2003  ;65 (3 ):435–40 .
Hode  Y , Reimold  M , Demazieres  A , et al. A positron emission
tomography (PET) study of cerebral dopamine D2 and serotonine 5-HT2A
receptor occupancy in patients treated with cyamemazine (T ercian)  .
Psychopharmacology (Berl)  2005  ;180 (2 ):377–84 .
Lemoine  P , Kermadi  I , Garcia-Acosta  S , Garay  RP , Dib M . Double-
blind, comparative study of cyamemazine vs. bromazepam in the
benzodiazepine withdrawal syndrome  . Prog Neur opsychopharmacol Biol
Psychiatry  2006  ;30 (1 ):131 –7 .

Desipramine
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Norpramin
Predominantly a norepinephrine/noradrenaline reuptake inhibitor
Anxiety
Insomnia

If It W orksTreatment-resistant depression
cortex, which lar gely lacks dopamine transporters, desipramine can

symptoms

If It Doesn ’t WorkThe goal of treatment of depression is complete remission of current
stopped
Treatment of chronic neuropathic pain may reduce symptoms, but
rarely eliminates them completely , and is not a cure since symptoms
can recur after medicine is stopped
Use in anxiety disorders and chronic pain may also need to be

Tests
✽ Monitoring of plasma drug levels is availablefatigue, and problems concentrating)
Lithium, buspirone, thyroid hormone (for depression)
pain)

or dyslipidemia, or consider switching to a dif ferent antidepressantBefore giving a drug that can cause weight gain to an overweight or

✽ Anticholiner gic activity for desipramine may be somewhat less than
for some other TCAs, yet can still explain the presence, if lower
incidence, of sedative ef fects, dry mouth, constipation, and blurred
vision

Sedation
What to Do About Side EffectsLowered seizure threshold and rare seizures
Blood dyscrasias
Wait

How to Dose
 Dosing T ipsWait
Wait
100–200 mg/day (for depression)
50–150 mg/day (for chronic pain)
Initial 25 mg/day at bedtime; increase by 25 mg every 3 –7 days
75 mg/day once daily or in divided doses; gradually increase dose to
achieve desired therapeutic ef fect; maximum dose 300 mg/day

✽ Monitoring plasma levels of desipramine is recommended in
patients who do not respond to the usual dose or whose treatment is
regarded as ur gent
Overdose
Long-T erm UseIf given in a single dose, should generally be administered at
Patients treated for chronic pain may only require lower doses (e.g.,
50–75 mg/day)
Risk of seizure increases with dose
Death may occur , and may be more likely than with other TCAs;
convulsions, cardiac dysrhythmias, severe hypotension, CNS
depression, coma, changes in ECG
Safe

How to Stop
Is the active metabolite of imipramine, formed by demethylation via
CYP450 1A2
Half-life approximately 24 hours

Other W arnings/Pr ecautionsFluoxetine, paroxetine, bupropion, duloxetine, and other CYP450
discontinuation of desipramine
after discontinuing desipramine

days for most drugs) after discontinuing desipramine, but see Pearls

Use caution when prescibing in patients with a family history of
sudden death, cardiac dysrhythmias, and cardiac conduction
Some patients may have seizures before cardiac dysrhythmias and
death

Do Not Use
Special populationsDistribute the brochures provided by the FDA and the drug
companies
If there is a proven aller gy to desipramine, imipramine, or
lofepramine

May need to monitor plasma levels
desipramine

Elderly
 Childr en and AdolescentsTCAs may cause a sustained increase in heart rate in patients with
Initial dose 25 –50 mg/day , raise to 100 mg/day; maximum 150
mg/day
May be useful to monitor plasma levels in elderly patients

mg/day

Pregnancyand make sure to document this in the patient ’s chart
patients
Not recommended for use in children under age 12
May reduce tic symptoms
Adolescents: initial dose 25 –50 mg/day , increase to 100 mg/day;
maximum dose 150 mg/day
May be useful to monitor plasma levels in children and adolescents

✽ Recommended either to discontinue drug or bottle feedControlled studies have not been conducted in pregnant women
pregnancy
essants

the mother

 PearlsFor many patients this may mean continuing treatment during breast
feeding
Patients for whom therapeutic drug monitoring is desirable
TCAs are no longer generally considered a first-line option for
depression because of their side ef fect profile

Noradrener gic reuptake inhibitors such as desipramine can be used
as a second-line treatment for smoking cessation, cocaine
dependence, and attention deficit disorder

✽ Desipramine is one of the few TCAs where monitoring of plasma
drug levels has been well studied
✽ Fewer anticholiner gic side ef fects than some other TCAsthe most common side ef fects of MAOI/tricyclic or tetracyclic
Not recommended for first-line use in children with ADHD because
of the availability of safer treatments with better documented
efficacy and because of desipramine ’s potential for sudden death in
children

Janowsky  DS , Byerley  B . Desipramine: an overview  . J Clin Psychiatry
1984  ;45 :3 –9.
Levin  FR , Lehman  AF . Meta-analysis of desipramine as an adjunct in the
treatment of cocaine addiction  . J Clin Psychopharmacol  1991  ;11 :374 –8 .and require low doses or switching to another antidepressant not

Desvenlafaxine
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Pristiq
Neuroscience-based Nomenclature: serotonin norepinephrine
SNRI (dual serotonin and norepinephrine reuptake inhibitor); often
classified as an antidepressant, but it is not just an antidepressant
Major depr essive disorder
Vasomotor symptoms
Fibromyalgia
Generalized anxiety disorder (GAD)

How Long Until It W orksSocial anxiety disorder (social phobia)
Boosts neurotransmitters serotonin, norepinephrine/noradrenaline,
and dopamine
Desensitizes both serotonin 1A receptors and beta adrener gic
receptors
cortex, which lar gely lacks dopamine transporters, desvenlafaxine
If it is not working within 6 or 8 weeks for depression, it may

If It W orks
depressive symptoms
Vasomotor symptoms in perimenopausal women with or without
depression may improve within 1 week

ResistanceSome patients who have an initial response may relapse even though
antidepressant discontinuation and switch to a mood stabilizer
Mirtazapine ( “California rocket fuel ” ; a potentially powerful dual
serotonin and norepinephrine combination, but observe for
activation of bipolar disorder and suicidal ideation)
Bupropion, reboxetine, nortriptyline, desipramine, maprotiline,
atomoxetine (all potentially powerful enhancers of noradrener gic

action, but observe for activation of bipolar disorder and suicidal
ideation)

Tests
Notable Side EffectsBenzodiazepines
tiagabine
Hypnotics or trazodone for insomnia
Check blood pressure before initiating treatment and regularly
Theoretically due to increases in serotonin and norepinephrine
concentrations at receptors in parts of the brain and body other than
those that cause therapeutic actions (e.g., unwanted actions of
serotonin in sleep centers causing insomnia, unwanted actions of
norepinephrine on acetylcholine release causing constipation and
dry mouth, etc.)
Most side ef fects increase with higher doses, at least transiently
Insomnia, sedation, anxiety , dizziness

Sedation
Nausea, vomiting, constipation, decreased appetite
Sexual dysfunction (abnormal ejaculation/or gasm, impotence)
Sweating
Hyponatremia
Increase in blood pressure
Rare induction of hypomania
May also be activating in some patients

Best Augmenting Agents for Side EffectsWait
Wait
Wait
Benzodiazepines for jitteriness and anxiety , especially at initiation

How to Dose
 Dosing T ipsa mood stabilizer or an atypical antipsychotic, and/or
discontinuation of desvenlafaxine
Depression: 50 mg once daily
Tablet (extended-release) 25 mg, 50 mg, 100 mg
Initial dose 50 mg once daily; maximum recommended dose
generally 100 mg once daily; doses up to 400 mg once daily have
been shown to be ef fective but higher doses are associated with
increased side ef fects
Desvenlafaxine is the active metabolite O-desmethylvenlafaxine
(ODV) of venlafaxine, and is formed as the result of CYP450 2D6
More potent at the serotonin transporter (SER T) than at the
norepinephrine transporter (NET), but has greater inhibition of NET
relative to SER T compared to venlafaxine

OverdoseNonresponders at lower doses may try higher doses to be assured of
the benefits of dual SNRI action
For vasomotor symptoms, current data suggest that a dose of 100
mg/day is ef fective
Do not break or chew tablets, as this will alter controlled-release
For some patients with severe problems discontinuing
desvenlafaxine, it may be useful to add an SSRI with a long half-
life, especially fluoxetine, prior to taper of desvenlafaxine. While
maintaining fluoxetine dosing, first slowly taper desvenlafaxine and
then taper fluoxetine
Be sure to dif ferentiate between reemer gence of symptoms requiring
reinstitution of treatment and withdrawal symptoms
May dose up to 400 mg/day in patients who do not respond to lower
doses, if tolerated
No fatalities have been reported as monotherapy; headache,
vomiting, agitation, dizziness, nausea, constipation, diarrhea, dry
mouth, paresthesia, tachycardia
Desvenlafaxine is the active metabolite of venlafaxine; fatal toxicity

index data from the UK suggest a higher rate of deaths from
overdose with venlafaxine than with SSRIs; it is unknown whether

How to Stop
Pharmacokineticsthis is related to dif ferences in patients who receive venlafaxine or
to potential cardiovascular toxicity of venlafaxine
See doctor regularly to monitor blood pressure
No
Taper to avoid withdrawal ef fects (dizziness, nausea, diarrhea,
sweating, anxiety , irritability)
Recommended taper schedule is to give a fully daily dose (50 mg)
less frequently
Active metabolite of venlafaxine
Half-life 9 –13 hours
Minimally metabolized by CYP450 3A4

 Other W arnings/Pr ecautionsTramadol increases the risk of seizures in patients taking an
MAOIs, so do not use with MAOIs or for at least 14 days after
drugs) after discontinuing desvenlafaxine
Possible increased risk of bleeding, especially when combined with
Potent inhibitors of CYP450 3A4 may increase plasma levels of
desvenlafaxine, but the clinical significance of this is unknown
Few known adverse drug interactions
False-positive urine immunoassay screening tests for phencyclidine
(PCP) and amphetamine have been reported in patients taking

desvenlafaxine, due to a lack of specificity of the screening tests.
False-positive test results may be expected for several days
following discontinuation of desvenlafaxine

Do Not Use
Special populationsUse with caution in patients with history of seizure
Use with caution in patients with heart disease
companies
If patient has uncontrolled angle-closure glaucoma
If there is a proven aller gy to desvenlafaxine or venlafaxine

ElderlyFor moderate impairment, recommended dose is 50 mg/day
For severe impairment, recommended dose is 50 mg every other day
Patients on dialysis should not receive subsequent dose until dialysis
is completed
Doses greater than 100 mg/day not recommended
Hypertension should be controlled prior to initiation of
desvenlafaxine and should be monitored regularly during treatment
Desvenlafaxine has a dose-dependent ef fect on increasing blood
pressure
Desvenlafaxine is the active metabolite of venlafaxine, which is
contraindicated in patients with heart disease in the UK
Venlafaxine can block cardiac ion channels in vitro and worsens
(i.e., reduces) heart rate variability in depression, perhaps due to
norepinephrine reuptake inhibition

 PregnancyRisk of SIADH with SSRIs is higher in the elderly
patients

In animal studies, there was no evidence of teratogenicity at plasma
exposure up to 19 times (rat) and 0.5 times (rabbit) the exposure at a
usual adult dose; however , fetotoxicity and pup deaths occurred in
rats at 4.5 times the exposure at a usual adult dose
pregnancy

pregnancy
distress, cyanosis, apnea, seizures, temperature instability , feeding

Potential AdvantagesNational Pregnancy Registry for Antidepressants: 1-866-961-2388,
essants
are on desvenlafaxine
the mother
Patients with retarded depression

 PearlsPatients with atypical depression
Patients with depression may have higher remission rates on SNRIs
than on SSRIs
Depressed patients with somatic symptoms, fatigue, and pain
Depressed patients with vasomotor symptoms
Patients who do not respond or remit on treatment with SSRIs
Patients sensitive to nausea
Patients with borderline or uncontrolled hypertension
Patients with cardiac disease
Energy, motivation, and interest
Sleep disturbance
Physical symptoms
Pain
Because desvenlafaxine is only minimally metabolized by CYP450
3A4 and is not metabolized at all by CYP450 2D6, as venlafaxine

is, it should have more consistent plasma levels than venlafaxine
In addition, although desvenlafaxine, like venlafaxine, is more
potent at the serotonin transporter (SER T) than the norepinephrine
transporter (NET), it has relatively greater actions on NET versus
SERT than venlafaxine does at comparable doses
The greater potency for NET may make it a preferable agent for
conditions theoretically associated with tar geting norepinephrine
actions, such as vasomotor symptoms and fibromyalgia
May be particularly helpful for hot flushes in perimenopausal
women
May be ef fective in patients who fail to respond to SSRIs
May be used in combination with other antidepressants for
treatment-refractory cases
May be ef fective in a broad array of anxiety disorders and possibly
adult ADHD, although it has not been studied in these conditions
May be associated with higher depression remission rates than
SSRIs
Because of recent studies from the UK that suggest a higher rate of

SSRIs
deaths from overdose with venlafaxine than with SSRIs, and
because of its potential to af fect heart function, venlafaxine can only
be prescribed in the UK by specialist doctors and is contraindicated
there in patients with heart disease
Overdose data are from fatal toxicity index studies, which do not
take into account patient characteristics or whether drug use was

Deecher  DC , Beyer  CE , Johnston  G , et al. Desvenlafaxine succinate: a
new serotonin and norepinephrine reuptake inhibitor  . J Pharmacol Exp
Ther  2006  ;318 (2 ):657–65 .
Lieberman  DZ , Montgomery  SA , Tourian  KA , et al. A pooled analysis of
two placebo-controlled trials of desvenlafaxine in major depressive disorder
. Int Clin Psychopharmacol  2008  ;23 (4 ):188–97 .
Sperof f L , Gass  M , Constantine  G . Efficacy and tolerability of
desvenlafaxine succinate treatment for menopausal vasomotor symptoms: a
randomized controlled trial  . Obstet Gynecol  2008  ;111 (1 ):77 –87 .first- or second-line
Venlafaxine ’s toxicity in overdose is less than that for TCAs

Deutetrabenazine
Brands
Generic?
No
 Class
 How the Drug W orksAustedo
Vesicular monoamine transporter 2 (VMA T2) inhibitor
Tardive dyskinesia in adults
Chor ea associated with Huntington ’s disease
Deutetrabenazine is a selective and reversible inhibitor of the
vesicular monoamine transporter 2 (VMA T2), which packages
monoamines, including dopamine, into synaptic vesicles of
presynaptic neurons in the central nervous system

If It W orks
If tardive dyskinesia does not reverse with deutetrabenazine, then other
management options include valbenazine, tetrabenazine, reserpine,
clonazepam, amantadine, botulinum toxin injections for focal dystonia
symptoms, or ginkgo biloba
Some patients may require suppressive therapy , in which the of fending
antipsychotic is reinstituted or its dose raised; this should only be
considered if the symptoms are very severe and cause marked
functional impact (e.g., inability to eat; mouth sores from rubbing);
this can make tardive dyskinesia worse in the long run, but the short-
term benefits may justify the risk for certain  patients
ResistanceIn clinical trials deutetrabenazine separated from placebo as early as
weeks 2 –4
Patients should experience a significant reduction in the total
Abnormal Involuntary Movement Scale (AIMS) score

weeks 2 –4
Deutetrabenazine is itself an augmenting agent to treat a side ef fect
of antipsychotic drugs

Tests
No need for CYP450 2D6 testing
For patients at risk for QT prolongation: assess the QT interval before
and after increasing the total dosage above 24 mg/day
Sedation, fatigue, dizziness, insomnia, nasopharyngitis
Diarrhea, dry mouth
 Life-Thr eatening or Danger ous Side EffectsTheoretically due to increases in monoamine concentrations at
receptors in parts of the brain and body other than those that cause
therapeutic actions
Depletion of dopamine due to long-term inhibition of VMA T2 may
also be responsible for some side ef fects
QT prolongation, although the degree of QT prolongation is not
clinically significant at concentrations expected with recommended
dosing

Sedation
Deutetrabenazine is itself an augmenting agent to treat a side ef fect of
antipsychotic drugsNeuroleptic malignant syndrome (NMS) (has not been observed in
patients taking deutetrabenazine, but has been observed in patients
taking tetrabenazine)
Risk of depression and suicidal thoughts and behavior in patients
with Huntington ’s disease
Wait
Wait
Wait
Reduce dose or discontinue if agitation, akathisia, restlessness, or
parkinsonism occurs

How to Dose
Should be taken with food because that is how clinical trials were
conducted; however , food has no ef fect on the AUC of
deutetrabenazine ’s active metabolites, but increased Cmax by 50%
Tablet should be swallowed whole and should not be chewed or
crushedTardive dyskinesia: 12 –48 mg/day in two divided doses
Chorea associated with Huntington ’s disease: 6 –48 mg/day (in two
divided doses for total daily dosages of 12 mg or more)
Tablet 6 mg, 9 mg, 12 mg
Tardive dyskinesia: initial dose 12 mg in two divided doses; titrate
by 6 mg/day in weekly intervals; maximum recommended dose is
48 mg/day in two divided doses
Chorea associated with Huntington ’s disease: initial dose 6 mg once
daily; titrate by 6 mg/day in weekly intervals; doses above 12
mg/day should be administered in two divided doses; maximum
recommended dose is 48 mg/day in two divided doses

If switching from tetrabenazine: discontinue tetrabenazine and initiate
deutetrabenazine the next day:
Current tetrabenazine daily dose Initial deutetrabenazine dose
12.5 mg 6 mg once daily
25 mg 6 mg twice daily
37.5 mg 9 mg twice daily
50 mg 12 mg twice daily
62.5 mg 15 mg twice daily
75 mg 18 mg twice daily
87.5 mg 21 mg twice daily
100 mg 24 mg twice daily
If switching from reserpine: at least 20 days should elapse after
stopping reserpine before starting deutetrabenazine
Overdose
Long-T erm UseLimited experience
Overdose with tetrabenazine: acute dystonia, oculogyric crisis,
nausea and vomiting, sweating, sedation, hypotension, confusion,
diarrhea, hallucinations, rubor , and tremor have been reported

How to Stop
PharmacokineticsLong-term clinical trials have not been conducted
No
Deutetrabenazine is a deuterated from of tetrabenazine
Deuteration is a process in which the stable isotope deuterium
replaces selected hydrogen atoms, resulting in a compound with
similar pharmacodynamic ef fects but dif ferent pharmacokinetic
profiles, because the carbon –deuterium covalent bond requires 8
times more ener gy to break than a carbon –hydrogen bond
Substitution of deuterium for hydrogen slows the breakdown of
metabolites; thus, the active metabolites of deutetrabenazine have
longer half-lives and greater absorption than those of tetrabenazine
Deutetrabenazine is broken down into 4 metabolites
Half-life of total (a+b)-HTBZ from deutetrabenazine is
approximately 9 to 10 hours
Metabolized by CYP450 2D6, but deuteration means that, unlike
tetrabenazine, CYP450 2D6 genotyping is not necessary

Strong CYP450 2D6 inhibitors (e.g., paroxetine, fluoxetine) may
increase exposure to deutetrabenazine; maximum recommended dose
in patients taking strong CYP450 2D6 inhibitors or who are known
CYP2D6 poor metabolizers is 36 mg/day
May be additive sedative ef fects if deutetrabenazine is given
concomitantly with alcohol or other sedating drugs
May cause an increase in QT interval, although the degree of QT
prolongation is not clinically significant at concentrations expected
with recommended dosing
Avoid use in patients with congenital long QT syndrome or with
arrhythmias associated with a prolonged QT interval
For patients at increased risk of prolonged QT interval, assess the QT
interval before and after increasing the total dose above 24 mg/day
Due to the increased risk of depression and suicidality in patients with
Huntington ’s disease who take deutetrabenazine, one should monitor

for the emer gence or worsening of depression, suicidality , or unusual
changes in behavior; patients and caregivers should be informed of the
risk of depression and suicidality and told to report behaviors of
concern promptly
Do Not Use

ElderlyIn patients with Huntington ’s disease who are suicidal or have
untreated/inadequately treated depression
In patients with hepatic impairment
If patient is taking a monoamine oxidase inhibitor (MAOI)
If patient is taking reserpine, tetrabenazine, or valbenazine
If there is a proven aller gy to deutetrabenazine
Not evaluated
May cause an increase in QT interval; avoid use in patients with
congenital long QT syndrome or with arrhythmias associated with a
For patients at risk for QT prolongation: assess the QT interval
before and after increasing the total dosage above 24 mg/day

 Pregnancy
Breast FeedingSome patients may tolerate lower doses better
In rat studies, no malformations were observed when
deutetrabenazine was administered during the period of
organogenesis at doses up to 6 times the maximum recommended
human dose
In rat studies, administration of tetrabenazine during or ganogenesis
through lactation produced an increase in the number of stillborn
pups and postnatal pup mortalities

human dose
Unknown if deutetrabenazine is secreted in human breast milk, but

 Pearls
In clinical trials, deutetrabenazine was well tolerated, with low rates of
psychiatric adverse events, including anxiety
Unlike with tetrabenazine, clinical trials with deutetrabenazine did not
result in reports of depression or suicidal ideationMultiple doses for flexible dosing
No CYP450 3A4 drug interactions
Expensive
Requires twice daily dosing (12 mg/day and above)
Carries a black box warning for depression and suicidality in
patients with Huntington ’s disease
Repetitive involuntary movements of tardive dyskinesia (usually
associated with lower facial and distal extremity musculature, e.g.,
tongue protrusion, writhing of tongue, lip smacking, chewing,
blinking, and grimacing)

The safety profile of deutetrabenazine appears similar regardless of
whether a concomitant antipsychotic drug is administered
At therapeutic doses, deutetrabenazine ’s active metabolites bind
predominantly to VMA T2, with low D2 dopamine receptor blockade
Deutetrabenazine ’s active metabolites have moderate blockade of
5HT7; the clinical significance of this is unknown, although 5HT7
antagonism has been associated with antidepressant and pro-cognitive
actions in animal models
Can rarely cause akathisia
Anderson  KE , Stamler  D , Davis  MD , et al. Deutetrabenazine for
treatment of involuntary movements in patients with tardive dyskinesia
(AIM-TD): a double-blind, randomised, placebo-controlled, phase 3 trial  .
Lancet Psychiatry  2017  ;4 (8 ):595 –604 .
Fernandez  HH , Factor  SA , Hauser  RA , et al. Randomized controlled trial
of deutetrabenazine for tardive dyskinesia: the ARM-TD study  . Neur ology
2017  ;88 (21 ):2003  –10 .

Frank  S , Stamler  D , Kayson  E , et al. Safety of converting from
tetrabenazine to deutetrabenazine for the treatment of chorea  . JAMA Neur ol
2017  ;74 (8 ):977 –82 .

Huntington Study Group, Frank  S , Testa CM , et al. Effect of
deutetrabenazine on chorea among patients with Huntington disease: a
randomized clinical trial.  JAMA  2016  ;316 (1 ):40 –50 .
Meyer  JM . Forgotten but not gone: new developments in the understanding
and treatment of tardive dyskinesia  . CNS Spectr  2016  ;21 (S1 ):13 –24 .

Dextromethorphan
Brands
Generic?
No
 Class
 How the Drug W orksNuedexta (in combination with quinidine)
Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist
and sigma 1 agonist
Pseudobulbar affect (PBA)
Diabetic peripheral neuropathic pain
Unstable mood and af fect in PTSD and mild traumatic brain injury
Third-line for treatment-resistant depression

If It W orks
TestsDextromethorphan reduces glutamate neurotransmission through
blocking NMDA receptors and by acting as an agonist at sigma 1
receptors
Dextromethorphan also has af finity for the serotonin transporter and
may therefore modulate serotonin levels
Quinidine increases availability of dextromethorphan by inhibiting
its metabolism via CYP450 2D6
In clinical trials the rate of pseudobulbar af fect episodes was
significantly decreased beginning at day 15
Reduces the frequency and severity of episodes of uncontrollable
laughing and/or crying
Consider switching to a TCA or an SSRI
Often best to attempt another monotherapy prior to resorting to
augmentation strategies

Presumably mechanism-related, including central actions at sigma
and NMDA receptors causing dissociative symptoms, euphoria, or
sedation
Dizziness, asthenia
Diarrhea, vomiting
Cough, peripheral edema
Urinary tract infection
Euphoria
Immune-mediated thrombocytopenia
Dose-dependent QT prolongation

Sedation
Usual Dosage RangeReported but not expected
Wait
Wait
Wait
Often best to try another agent prior to resorting to augmentation
strategies to treat side ef fects

How to Dose
Overdose
Habit Forming20 mg/10 mg twice per day
Capsule 20 mg/10 mg (dextromethorphan/quinidine)
Initial 20 mg/10 mg once per day; after 7 days increase to 20 mg/10
mg twice per day
Some patients may tolerate and respond to doses higher than the
approved doses, but few controlled studies of high doses
Nausea, dizziness, headache, ventricular arrhythmias, hypotension,
coma, respiratory depression, seizures, tachycardia,
hyperexcitability , toxic psychosis
No

How to Stop
 Drug InteractionsTaper not necessary
Elimination half-life of dextromethorphan is approximately 13 hours
Elimination half-life of quinidine is approximately 7 hours
Dextromethorphan is metabolized by CYP450 2D6, while quinidine
inhibits CYP450 2D6
Quinidine is metabolized by CYP450 3A4
Via CYP450 2D6 inhibition, dextromethorphan/quinidine could
increase plasma concentrations of drugs metabolized by CYP450
2D6 (e.g., desipramine), potentially requiring dose reduction of the
substrate
drugs) after discontinuing dextromethorphan/quinidine
Via P-glycoprotein inhibition, quinidine could increase plasma
concentrations of P-glycoprotein substrates such as digoxin,
potentially requiring dose reduction of the substrate

Do Not UseCan theoretically cause serotonin syndrome when combined with
serotonin reuptake inhibitors, but not well studied
Quinidine can cause immune-mediated thrombocytopenia that can
be severe or fatal; dextromethorphan/quinidine should be
discontinued immediately if thrombocytopenia occurs unless it is
clearly not drug-related, and should not be restarted in sensitized
patients
Quinidine has been associated with a lupus-like syndrome involving
polyarthritis
ECG should be monitored if patient must take an agent that prolongs
QT interval or that inhibits CYP450 3A4
Anticholiner gic ef fects of quinidine may lead to worsening in
myasthenia gravis and other sensitive conditions
If patient is taking another medication containing quinidine, quinine,
or mefloquine
If patient has a history of quinidine, quinine, or mefloquine-induced
thrombocytopenia, hepatitis, or other hypersensitivity reaction

If patient has prolonged QT interval, congenital long QT syndrome,
history suggestive of torsade de pointes, or heart failure

ElderlyIf patient has complete atrioventricular (A V) block without
implanted pacemaker , or patients at high risk of complete A V block
If patient is taking a drug that prolongs QT interval and is
metabolized by CYP450 2D6 (e.g., thioridazine, pimozide)
If there is a proven aller gy to dextromethorphan or quinidine
Dose adjustment not necessary in patients with mild to moderate
Contraindicated in patients with prolonged QT interval, congenital
long QT syndrome, history suggestive of torsade de pointes, and
heart failure
Monitor ECG in patients with left ventricular hypertrophy or left
ventricular dysfunction

 Pregnancy
bipolar disorder and/or suicidal ideation, and strongly consider
informing parents or guardian of this risk so they can help observe
child or adolescent patients
Unknown if dextromethorphan/quinidine is secreted in human breast
milk, but all psychotropics are assumed to be secreted in breast milk

 PearlsMust weigh benefits of breast feeding with risks and benefits of
the mother
No other approved agent for PBA
CYP450 2D6 poor metabolizers may require dose reduction
In patients with past substance abuse, especially of
dextromethorphan, ketamine, or PCP
Uncontrollable crying
Uncontrollable laughter
Quinidine is intended to increase the actions of dextromethorphan
by inhibiting its metabolism by CYP450 2D6; therefore, poor
metabolizers of CYP450 2D6 may not benefit as much from this
treatment while still experiencing adverse ef fects associated with
quinidine

Brooks  BR , Thisted  RA , Appel  SH , et al. Treatment of pseudobulbar
affect in ALS with dextromethorphan/quinidine: a randomized trial  .
Neur ology  2004  ;63 (8 ):1364  –70.
Garnock-Jones  KP . Dextromethorphan/quinidine in pseudobulbar af fect .
CNS Drugs  2011 ;25 (5 ):435–45 .
The Medical Letter Inc  . Dextromethorphan/quinidine (neudexta) for
pseudobulbar af fect . Med Lett Drugs Ther  2011 ;53 (1366  ):46 –7.
Pioro  EP , Brooks  BR , Cummings  J , et al. Dextromethorphan plus ultra
low-dose quinidine reduces pseudobulbar af fect . Ann Neur ol 2010  ;68 (5
):693–702 .Affective instability in Alzheimer disease may be treatable with this
agent, including agitation, allowing antipsychotics to be avoided in
this population
Some men express emotional lability as laughter and anger rather
than laughter and crying
Affective instability in PTSD and in mild traumatic brain injury may
be improved by dextromethorphan/quinidine

Similar binding properties to ketamine suggest possible ef ficacy in
both treatment-resistant depression and chronic pain

Diazepam
Brands
Generic?
Yes (not Diastat)
 Class
(bold for FDA appr oved)Valium
Diastat
Benzodiazepine (anxiolytic, muscle relaxant, anticonvulsant)
Symptoms of anxiety (short-term)
Acute agitation, tr emor , impending or acute delirium tr emens
and hallucinosis in acute alcohol withdrawal

How the Drug W orksSkeletal muscle spasm due to r eflex spasm to local pathology
Spasticity caused by upper motor neur on disorder
Athetosis
Stiff-person syndr ome
Convulsive disorder (adjunctive)
Anxiety during endoscopic pr ocedur es (adjunctive) (injection
only)
Preoperative anxiety (injection only)
Anxiety r elief prior to cardioversion (intravenous)
Initial tr eatment of status epilepticus (injection only)
Insomnia
Catatonia
Inhibiting actions in cerebral cortex may provide therapeutic

If It W orksInhibitory actions in spinal cord may provide therapeutic benefits
for muscle spasms
For short-term symptoms of anxiety or muscle spasms –after a few
weeks, discontinue use or use on an “as-needed ” basis
Chronic muscle spasms may require chronic diazepam treatment

TestsConsider switching to another agent or adding an appropriate
Consider presence of diazepam abuse

✽ Pain at injection site

Sedation
Best Augmenting Agents for Side EffectsRare hepatic dysfunction, renal dysfunction, blood dyscrasias
Wait
Wait
Wait

How to DoseOral: 4 –40 mg/day in divided doses
Intravenous (adults): 5 mg/minute
Intravenous (children): 0.25 mg/kg every 3 minutes
Tablet 2 mg, 5 mg, 10 mg
Nasal 5 mg/spray , 7.5 mg/spray , 20 mg/spray
Concentrate 5 mg/mL
Solution 5 mg/5 mL
Injection vial 5 mg/mL, 10 mg/2 mL, 50 mg/10 mL
Rectal gel 2.5 mg/0.5 mL, 10 mg/2 mL, 20 mg/4 mL
Oral (anxiety , muscle spasm, seizure): 2 –10 mg, 2 –4 times/day
Oral (alcohol withdrawal): initial 10 mg, 3 –4 times/day for 1 day;
reduce to 5 mg, 3 –4 times/day; continue treatment as needed
Liquid formulation should be mixed with water or fruit juice,
applesauce, or pudding
Because of risk of respiratory depression, rectal diazepam treatment
should not be given more than once in 5 days or more than twice

✽ Only benzodiazepine with a formulation specifically for rectal
✽ One of the few benzodiazepines available in an oral liquid
✽ One of the few benzodiazepines available in an injectable
formulationduring a treatment course, especially for alcohol withdrawal or
status epilepticus
Diazepam injection is intended for acute use; patients who require
long-term treatment should be switched to the oral formulation
treatment
anxiety
Because some anxiety disorder patients and muscle spasm patients

anxiety
can require doses higher than 40 mg/day or more, the risk of

Overdose
How to Stopdependence may be greater in these patients
Evidence of ef ficacy up to 16 weeks
Not recommended for long-term treatment of seizure disorders
Diazepam is a Schedule IV drug
use

PharmacokineticsTaper by 2 mg every 3 days to reduce chances of withdrawal ef fects
slowly after reaching 20 mg/day , perhaps by as little as 0.5 –1 mg
every week or less

Elimination half-life 20 –50 hours
Substrate for CYP450 2C19 and 3A4

 Other W arnings/Pr ecautionsIncreased depressive ef fects when taken with other CNS depressants
Cimetidine may reduce the clearance and raise the levels of
diazepam
seizure disorders with diazepam
efficacy

efficacy

Do Not Use
Cardiac Impairmentpulmonary impairment
ideation
If angle-closure glaucoma
If there is a proven aller gy to diazepam or any benzodiazepine
Initial 2 –2.5 mg, 1 –2 times/day; increase gradually as needed

Elderly
 PregnancyDiazepam may be used as an adjunct during cardiovascular
emer gencies
6 months and up: initial 1 –2.5 mg, 3 –4 times/day; increase gradually
as needed
Parenteral: 30 days or older
Rectal: 2 years or older
Long-term ef fects of diazepam in children/adolescents are unknown
monitored

Potential AdvantagesBecause of the potential risks, diazepam is not generally
Unknown if diazepam is secreted in human breast milk, but all
Availability of oral liquid, rectal, and injectable dosage formulations

 Pearls
✽ Diazepam is often the first-choice benzodiazepine to treat status
epilepticus, and is administered either intravenously or rectallyEuphoria may lead to abuse
Can be sedating at doses necessary to treat moderately severe
anxiety disorders
Anxiety
Muscle spasms
numerous anxiety disorders, but not used as frequently as other
benzodiazepines for this purpose

✽ Remains a popular benzodiazepine for treating muscle spasms
✽ Remains a popular benzodiazepine to treat acute alcohol
withdrawal
✽ Multiple dosage formulations (oral tablet, oral liquid, rectal gel,
injectable) allow more flexibility of administration compared to most
 Suggested ReadingBecause diazepam suppresses stage 4 sleep, it may prevent night
terrors in adults
Was once one of the most commonly prescribed drugs in the world
and the most commonly prescribed benzodiazepine
A commonly used benzodiazepine to treat sleep disorders
Not especially useful as an oral anticonvulsant

treatment

Ashton  H . Guidelines for the rational use of benzodiazepines. When and
what to use  . Drugs  1994  ;48 :25 –40 .
De Negri  M , Baglietto  MG . Treatment of status epilepticus in children  .
Paediatr Drugs  2001  ;3 :411–20 .
Mandelli  M , Tognoni  G , Garattini  S . Clinical pharmacokinetics of
diazepam  . Clin Pharmacokinet  1978  ;3 :72 –91 .
Rey E , Treluver  JM , Pons  G . Pharmacokinetic optimization of
benzodiazepine therapy for acute seizures. Focus on delivery routes  . Clin
Pharmacokinet  1999  ;36 :409–24 .

Diphenhydramine
Brands
Generic?
Yes
 Class
 How the Drug W orks (for drug-induced parkinsonism)BenadrylSominex
Antihistamine; anticholiner gic agent
Allergy symptoms
Motion sickness
Occasional sleeplessness
Antiparkinsonism
Drug-induced parkinsonism

If It W orks (for drug-induced parkinsonism)
If It Doesn ’t Work (for drug-induced parkinsonism)
Also has potent histamine 1 antagonist properties
Consider switching to trihexyphenidyl, benztropine, or a
If inef fective, switch to another agent rather than augment
Diphenhydramine itself is an augmenting agent to antipsychotics

Tests
 Life-Thr eatening or Danger ous Side EffectsNone for healthy individuals
Blocking histamine 1 receptors can cause sedation
Preventing the action of acetylcholine on muscarinic receptors can
cause anticholiner gic ef fects such as dry mouth, blurred vision,
constipation
Sedation, dizziness
Constipation, nausea
Dry mouth, blurred vision
Rare convulsions (at high doses)
Tachycardia, cardiac arrhythmias
Confusion
Paralytic ileus/bowel obstruction

Sedation
Usual Dosage RangeFrequent and can be significant in amount
Oral: 50 mg/day
Injection: 10 –50 mg

How to Dose
OverdoseInjection 50 mg/mL
Capsule 50 mg
Elixir 12.5 mg/5 mL
Also available in formulations in combination with other
Injection: 10 –50 mg intravenously at a rate not exceeding 25
mg/min or deep intramuscularly; can dose at 100 mg if required;
maximum daily dose 400 mg
withdraw diphenhydramine after 1 –2 weeks to determine if still
needed
The injection should be used for parkinsonism only if oral therapy is
impossible or contraindicated
CNS depression, CNS stimulation (more likely in pediatric
patients), dry mouth, dilated pupils, flushing, gastrointestinal
symptoms

How to Stop
 Other W arnings/Pr ecautionsSafe
Effectiveness may decrease over time, even after a few doses, but
side ef fects such as cognitive impairment and sedation may persist
No
Tapering generally not necessary
Plasma half-life approximately 8 hours; may be longer in children
and in the elderly
May potentiate the ef fects of other CNS depressants
If anticholiner gic agents are used with diphenhydramine, the
anticholiner gic ef fects may be enhanced
Use with caution in patients with a history of bronchial asthma,
lower respiratory disease, increased intraocular pressure,
hyperthyroidism, cardiovascular disease, or hypertension

Do Not Use
ElderlyMay have additive ef fects if taken with anticholiner gic agents
If patient is breast feeding
In neonates or premature infants
ulcers, prostate hypertrophy , or bladder neck obstructions
If there is a proven aller gy to diphenhydramine
Not systematically evaluated in patients with cardiac impairment

 Pregnancy
Diphenhydramine injection is preferred for parkinsonism in the
elderly who are unable to tolerate more potent agents
Not recommended for children under age 12
Injection: 5 mg/kg/24 hours or 150 mg/m2 /24 hours; maximum
daily dose 300 mg; divide into 4 doses; can be given intravenously
at a rate not exceeding 25 mg/min, or deep intramuscularly
Contraindicated in neonates and premature infants

 Pearls
 Suggested ReadingMild cases of parkinsonism
Can be too sedating for some patients
Can cause confusion in elderly patients and in patients with
dementia
Can be useful for occasional insomnia

Gonzalez  F. Diphenhydramine may be useful as a palliative treatment for
patients dying with Parkinson ’s disease and tremors: a case report and
discussion  . Am J Hosp Palliat Car e 2010  ;26 (6 ):474 –5 .

Disulfiram
Brands
Generic?
Yes
 Class
 How the Drug W orksAntabuse
Irreversibly inhibits aldehyde dehydrogenase, the enzyme involved
in second-stage metabolism of alcohol
Alcohol is metabolized to acetaldehyde, which in turn is
metabolized by aldehyde dehydrogenase; thus, disulfiram blocks
this second-stage metabolism

If It W orks
ResistanceIf alcohol is consumed by a patient taking disulfiram, toxic levels of
acetaldehyde build up, causing unpleasant side ef fects
This aversive experience ideally leads to negative conditioning, in
which patients abstain from alcohol in order to avoid the unpleasant
effects
Disulfiram ’s effects are immediate; patients should not take
disulfiram until at least 12 hours after drinking
Patients who drink alcohol while taking disulfiram can experience
side ef fects, including alcohol toxicity
treatment

Tests
Baseline and follow-up liver function tests
When alcohol is consumed by a patient taking disulfiram, levels of
acetaldehyde build up, causing side ef fects of alcohol toxicity
One of disulfiram ’s metabolites is carbon disulfide, which may be
excreted through the lungs; this could account for the side ef fect of
metallic taste
Metallic taste, dermatitis, sedation
Flushing, headache, tachycardia, nausea, vomiting (if alcohol is
consumed)
Myocardial infarction, congestive heart failure, respiratory
depression, other signs of alcohol toxicity (if alcohol is consumed)

Sedation
Wait
Take at night to reduce sedation
agent
250–500 mg/day; 1-year duration
Tablet 250 mg, 500 mg scored

How to Dose
Overdose
Long-T erm UseThe patient should not take disulfiram until at least 12 hours after
drinking
Initial 250 –500 mg/day for 1 –2 weeks
Usually dosed in the morning but can be dosed at night if sedation is
a problem
Maintenance dose usually 250 mg/day; maximum dose 500 mg/day
The patient must be fully informed of the disulfiram-alcohol
reaction
The patient should be advised not to consume any food or beverages
containing alcohol or to use any alcohol-containing preparations
(e.g., cough syrup)
The patient should be warned that reactions may occur up to 2
weeks after disulfiram is stopped
The patient should carry an emer gency card stating that he or she is
taking disulfiram
Unknown

How to Stop
 Drug InteractionsMaintenance treatment should be continued until the patient is
recovered
No
A disulfiram-alcohol reaction may occur for up to 2 weeks after
disulfiram is stopped
Half-life of parent drug is 60 –120 hours
Half-life of metabolites is 13.9 hours (diethyldithiocarbamate) and
8.9 hours (carbon disulfide)
Disulfiram may increase blood levels of phenytoin; baseline and
follow-up levels of phenytoin should be taken
Disulfiram may prolong prothrombin time, requiring dose
adjustment of oral anticoagulants
Use with isoniazid may lead to unsteady gait or change in mental
status

Do Not UseDisulfiram should not be given to a patient in a state of alcohol
intoxication or without the patient ’s full knowledge
Not recommended for patients older than age 60 or for those with
severe pulmonary disease, chronic renal failure, diabetes, peripheral
neuropathy , seizures, cirrhosis, or portal hypertension
Use with extreme caution in patients with hypothyroidism, epilepsy ,
cerebral damage
Patients taking disulfiram should not be exposed to ethylene
dibromide or its vapors, as this has resulted in a higher incidence of
tumors in rats
If the patient is in a state of alcohol intoxication
Without the patient ’s full knowledge
For at least 12 hours after the patient last drank
If patient is taking metronidazole, amprenavir , ritonavir , or sertraline
If patient has psychosis
If patient has cardiovascular disease
If there is a proven aller gy to disulfiram
If there is a proven aller gy to thiuram derivatives

Elderly
 PregnancyNot recommended for patients with chronic renal failure
Not recommended
Not generally recommended for patients older than age 60

 PearlsControlled studies have not been conducted in pregnant women
Unknown if disulfiram is secreted in human breast milk, but all
Individuals who are motivated to abstain from alcohol
Adherence rates can be low

Barth  KS , Malcolm  RJ . Disulfiram: an old therapeutic with new
applications  . CNS Neur ol Disor d Drug T argets 2010  ;9 (1 ):5 –12.
Jorgensen  CH , Pedersen  B , Tonnesen  H. The ef ficacy of disulfiram for the
treatment of alcohol use disorder  . Alcohol Clin Exp Res  2011 ;35 (10
):1749  –58.
Pani PP , Troqu E , Vacca R , et al. Disulfiram for the treatment of cocaine
dependence  . Cochrane Database Syst Rev  2010  ;20 (1 ):CD007024  .Some evidence of ef ficacy in comorbid alcohol use disorder and
PTSD
Preliminary evidence of ef ficacy for use in cocaine dependence,
both alone and comorbid with alcohol use disorder

Donepezil
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Aricept
Memac
Neuroscience-based Nomenclature: acetylcholine enzyme inhibitor
(ACh-EI)
Cholinesterase inhibitor (selective acetylcholinesterase inhibitor);
cognitive enhancer
Alzheimer disease (mild, moderate, and sever e)
Memory disorders in other conditions

✽ Reversibly but noncompetitively inhibits centrally active
acetylcholinesterase (AChE), making more acetylcholine available
If It W orks
If It Doesn ’t WorkIncreased availability of acetylcholine compensates in part for
degenerating choliner gic neurons in neocortex that regulate memory
Does not inhibit butyrylcholinesterase
May release growth factors or interfere with amyloid deposition
May take up to 6 weeks before any improvement in baseline
memory or behavior is evident
May take months before any stabilization in degenerative course is
evident
May improve symptoms and slow progression of disease, but does
Consider adjusting dose, switching to a dif ferent cholinesterase
inhibitor , or adding an appropriate augmenting agent
Reconsider diagnosis and rule out other conditions such as
depression or a dementia other than Alzheimer disease

✽ Atypical antipsychotics to reduce behavioral disturbances
✽ Antidepressants if concomitant depression, apathy , or lack of
interest
✽ Memantine for moderate to severe Alzheimer disease
Tests
✽ Nausea, diarrhea, vomiting, appetite loss, increased gastric acid
secretion, weight lossDivalproex, carbamazepine, or oxcarbazepine for behavioral
Not rational to combine with another cholinesterase inhibitor
Peripheral inhibition of acetylcholinesterase can cause
Central inhibition of acetylcholinesterase may contribute to nausea,
vomiting, weight loss, and sleep disturbances

Sedation
What to Do About Side EffectsInsomnia, dizziness
Muscle cramps, fatigue, depression, abnormal dreams
Rare syncope
Wait
Wait
Wait
Take in daytime to reduce insomnia
Use slower dose titration

How to DoseConsider lowering dose, switching to a dif ferent agent, or adding an
Hypnotics or trazodone may improve insomnia
5–10 mg at night
Tablet 5 mg, 10 mg, 23 mg
Orally disintegrating tablet 5 mg, 10 mg
Namzaric extended-release (combination memantine/donepezil) 7
mg/10 mg, 14 mg/10 mg, 21 mg/10 mg, 28 mg/10 mg
Initial 5 mg/day; may increase to 10 mg/day after 4 –6 weeks
Namzaric, for patients already on donepezil 10 mg once daily: initial
dose 7 mg/10 mg once daily in the evening; increase weekly in 7 mg
increments; maximum dose 28 mg/10 mg

✽ When switching to another cholinesterase inhibitor , probably best
to cross-titrate from one to the other to prevent precipitous decline in
function if the patient washes out of one drug entirely
OverdoseNamzaric, for patients already on memantine (10 mg twice per day
or 28 mg extended-release once per day) and donepezil 10 mg once
daily: can switch to 28 mg/10 mg once daily in the evening
Side ef fects occur more frequently at higher doses than at lower
doses
Slower titration (e.g., 6 weeks to 10 mg/day) may reduce the risk of
Food does not af fect the absorption of donepezil
Probably best to utilize highest tolerated dose within the usual
dosage range
Some of f-label uses for cognitive disturbances other than Alzheimer
disease have anecdotally utilized doses higher than 10 mg/day
Namzaric can be taken with or without food, whole or sprinkled on
applesauce; do not divide, chew , or crush
Can be lethal; nausea, vomiting, excess salivation, sweating,

hypotension, bradycardia, collapse, convulsions, muscle weakness
(weakness of respiratory muscles can lead to death)

How to Stop
 Drug InteractionsDrug may lose ef fectiveness in slowing degenerative course of
Alzheimer disease after 6 months
Can be ef fective in some patients for several years
No
Discontinuation may lead to notable deterioration in memory and
behavior , which may not be restored when drug is restarted or
another cholinesterase inhibitor is initiated
Metabolized by CYP450 2D6 and CYP450 3A4
Elimination half-life approximately 70 hours
Donepezil may increase the ef fects of anesthetics and should be
discontinued prior to sur gery
Inhibitors of CYP450 2D6 and CYP450 3A4 may inhibit donepezil
metabolism and increase its plasma levels

Do Not Use
Renal ImpairmentInducers of CYP450 2D6 and CYP450 3A4 may increase clearance
of donepezil and decrease its plasma levels
Donepezil may interact with anticholiner gic agents and the
combination may decrease the ef ficacy of both
May have syner gistic ef fect if administered with cholinomimetics
(e.g., bethanechol)
Bradycardia may occur if combined with beta blockers
Theoretically , could reduce the ef ficacy of levodopa in Parkinson ’s
disease
May exacerbate asthma or other pulmonary disease
Increased gastric acid secretion may increase the risk of ulcers
Bradycardia or heart block may occur in patients with or without
If there is a proven aller gy to donepezil

Elderly
 PregnancyFew data available but dose adjustment is most likely unnecessary
Severe renal impairment: the recommended maintenance dose for
Namzaric is 14 mg/10 mg once daily in the evening
Few data available; may need to lower dose
Syncopal episodes have been reported with the use of donepezil
Use of cholinesterase inhibitors may be associated with increased
rates of syncope, bradycardia, pacemaker insertion, and hip fracture
in older adults with dementia
Preliminary reports of ef ficacy as an adjunct in attention deficit
hyperactivity disorder (ADHD) (ages 8 –17)

✽ Not recommended for use in pregnant women or women of
childbearing potential
Unknown if donepezil is secreted in human breast milk, but all
Donepezil is not recommended for use in nursing women
Once a day dosing
May be used in vascular dementia
May work in some patients who do not respond to other
cholinesterase inhibitors

 Pearls
50% of those diagnosed are treated, and only 50% of those treated are
given a cholinesterase inhibitor , and then only for 200 days in a disease
that lasts 7 –10 yearsMay work in some patients who do not tolerate other cholinesterase
inhibitors
Behavioral symptoms in Alzheimer disease
Memory loss in other dementias
A fixed-dose combination of memantine extended-release and
donepezil (Namzaric) has been approved for the treatment of
moderate to severe Alzheimer dementia in patients stabilized on
memantine and donepezil
generally seen with cholinesterase inhibitors
Can lead to therapeutic nihilism among prescribers and lack of an
appropriate trial of a cholinesterase inhibitor

✽ Treats behavioral and psychological symptoms of Alzheimer
dementia as well as cognitive symptoms (i.e., especially apathy ,
disinhibition, delusions, anxiety , cooperation, pacing)Must evaluate lack of ef ficacy and loss of ef ficacy over months, not
weeks
The first symptoms of Alzheimer disease are generally mood
Aggressively treat concomitant symptoms with augmentation (e.g.,
atypical antipsychotics for agitation, antidepressants for depression)

Alzheimer disease and a cholinesterase inhibitor like donepezil may
be helpful
What to expect from a cholinesterase inhibitor:

✽ May cause more sleep disturbances than some other cholinesterase
inhibitorsPatients do not generally improve dramatically although this
can be observed in a significant minority of patients
Onset of behavioral problems and nursing home placement can
be delayed
Functional outcomes, including activities of daily living, can be
preserved
Caregiver burden and stress can be reduced
disease-modifying actions of cholinesterase inhibition
Cholinesterase inhibitors like donepezil depend upon the presence
of intact tar gets for acetylcholine for maximum ef fectiveness and
thus may be most ef fective in the early stages of Alzheimer disease
The most prominent side ef fects of donepezil are gastrointestinal
For patients with intolerable side ef fects, generally allow a washout
period with resolution of side ef fects prior to switching to another

Women over 85, particularly with low body weights, may
experience more adverse ef fects

✽ Donepezil may slow the progression of mild cognitive impairment
to Alzheimer disease
✽ May be useful for dementia with Lewy bodies (DLB, constituted by
early loss of attentiveness and visual perception with possible
hallucinations, Parkinson-like movement problems, fluctuating
cognition such as daytime drowsiness and lethar gy, staring into space
for long periods, episodes of disor ganized speech)
✽ May be useful for vascular dementia (e.g., acute onset with slow
stepwise progression that has plateaus, often with gait abnormalities,
focal signs, imbalance, and urinary incontinence)Use with caution in underweight or frail patients
Cognitive improvement may be linked to substantial (>65%)
inhibition of acetylcholinesterase
Donepezil has greater action on CNS acetylcholinesterase than on
peripheral acetylcholinesterase
Some Alzheimer patients who fail to respond to donepezil may
respond to another cholinesterase inhibitor
Some Alzheimer patients who fail to respond to another

cholinesterase inhibitor may respond when switched to donepezil
To prevent potential clinical deterioration, generally switch from
long-term treatment with one cholinesterase inhibitor to another
without a washout period
May decrease delusions, apathy , agitation, and hallucinations in
dementia with Lewy bodies

Bentue-Ferrer  D , Tribut  O , Polard  E , Allain  H . Clinically significant drug
interactions with cholinesterase inhibitors: a guide for neurologists  . CNS
Drugs  2003  ;17 :947–63 .
Birks  JS , Harvey  R . Donepezil for dementia due to Alzheimer ’s disease  .
Cochrane Database Syst Rev  2003  ;(1):CD001 190 .
Bonner  LT , Peskind  ER . Pharmacologic treatments of dementia  . Med Clin
North Am  2002  ;86 :657–74 .
Jones  RW . Have choliner gic therapies reached their clinical boundary in
Alzheimer ’s disease  ? Int J Geriatr Psychiatry  2003  ;18 (Suppl 1): S7 –13.
Seltzer  B . Donepezil: an update  . Expert Opin Pharmacother  2007  ;8 (7
):1011 –23.May be helpful for dementia in Down ’s syndrome
Suggestions of utility in some cases of treatment-resistant bipolar
disorder
Theoretically , may be useful for ADHD, but not yet proven
Theoretically , could be useful in any memory condition
characterized by choliner gic deficiency (e.g., some cases of brain

disorder
injury , cancer chemotherapy-induced cognitive changes, etc.)

Dothiepin
Brands
Generic?
In UK
 Class
(bold for FDA appr oved)Prothiaden
Major depressive disorder
Anxiety
Insomnia

How Long Until It W orksTreatment-resistant depression
cortex, which lar gely lacks dopamine transporters, dothiepin can
symptoms

If It W orks
stopped

TestsMany depressed patients have only a partial response where some
pain)

pain)

cholesterol), and treat or refer such patients for treatment including

 Life-Thr eatening or Danger ous Side EffectsAnticholiner gic activity may explain sedative ef fects, dry mouth,

Sedation
What to Do About Side EffectsQTc prolongation
Wait
Wait
Wait

How to Dose
 Dosing T ipsSwitch to an SSRI or newer antidepressant
75–150 mg/day
Capsule 25 mg
Tablet 75 mg

Overdose
Safe
No

Half-life approximately 14 –40 hours

Other W arnings/Pr ecautionsActivation and agitation, especially following switching or adding
discontinuation of dothiepin
after discontinuing dothiepin
days for most drugs) after discontinuing dothiepin, but see Pearls
retention, angle-closure glaucoma, hyperthyroidism, and in patients
recovering from myocardial infarction

companies

Cardiac ImpairmentIf patient is taking drugs that inhibit TCA metabolism, including
If there is a proven aller gy to dothiepin
dothiepin

Elderly
 Childr en and AdolescentsUse with caution if treating concomitantly with a medication likely

PregnancyCarefully weigh the risks and benefits of pharmacological treatment
patients
Not recommended for use in children under age 18

pregnancy
essants
the mother
feeding

 Pearls
✽ Close structural similarity to amitriptylinePatients with insomnia
Anxious depression

For the expert only: a heroic treatment (but potentially dangerous)
for severely treatment-resistant patients is to give simultaneously
with MAOIs for patients who fail to respond to numerous other
antidepressants, but generally recommend a dif ferent TCA than
dothiepin for this use
the most common side ef fects of MAOI and tricyclic/tetracyclic

antidepressant combinations may be weight gain and orthostatic

Donovan  S , Dearden  L , Richardson  L . The tolerability of dothiepin: a
review of clinical studies between 1963 and 1990 in over 13,000 depressedSince tricyclic/tetracyclic antidepressants are substrates for CYP450

patients  . Prog Neur opsychopharmacol Biol Psychiatry  1994  ; 18 :1143 –
62.
Lancaster  SG , Gonzalez  JP . Dothiepin. A review of its pharmacodynamic
and pharmacokinetic properties, and therapeutic ef ficacy in depressive
illness  . Drugs  1989  ;38 :123–47 .

Doxepin
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)SinequanSilenor
Antihistamine
Psychoneur otic patient with depr ession and/or anxiety
Depr ession and/or anxiety associated with alcoholism
Depr ession and/or anxiety associated with organic disease

✽ Pruritus/itching (topical)
At antidepressant doses:Psychotic depr essive disorders with associated anxiety
Involutional depr ession
Manic-depr essive disorder
Insomnia (difficulty with sleep maintenance) (Silenor only)
Dermatitis, atopic (topical)
Lichen simplex chronicus (topical)
Anxiety
Blocks serotonin reuptake pump (serotonin transporter),
presumably increasing serotoner gic neurotransmission
Blocks norepinephrine reuptake pump (norepinephrine
transporter), presumably increasing noradrener gic

At hypnotic doses (3 –6 mg/day):
If It W orksSince dopamine is inactivated by norepinephrine reuptake in
frontal cortex, which lar gely lacks dopamine transporters,
doxepin can thus increase dopamine neurotransmission in this
part of the brain
May be ef fective in treating skin conditions because of its strong
antihistamine properties
Selectively and potently blocks histamine 1 receptors, presumably
decreasing wakefulness and thus promoting sleep
Onset of therapeutic actions in depression is usually not immediate,
May also work long-term for insomnia (studied for up to 12 weeks)

If It Doesn ’t WorkThe goal of treatment of insomnia is to improve quality of sleep,
including ef fects on total wake-time and number of nighttime
awakenings
stopped
Use in anxiety disorders, chronic pain, and skin conditions may also

need to be indefinite, but long-term treatment is not well studied in
these conditions

ResistanceMany depressed patients have only a partial response where some
If insomnia does not improve after 7 –10 days, it may be a
manifestation of a primary psychiatric or physical illness such as
obstructive sleep apnea or restless leg syndrome, which requires
independent evaluation

Trazodone, GABA-er gic sedative hypnotics (for insomnia)

Tests
or dyslipidemia, or consider switching to a dif ferent antidepressantpain)
Baseline ECG is recommended for patients over age 50 (not for
Silenor)

Antidepr essant Dosesthat prolong QT c interval such as pimozide, thioridazine, selected
At antidepressant doses, anticholiner gic activity may explain
sedative ef fects, dry mouth, constipation, and blurred vision
At antidepressant doses, blockade of alpha adrener gic 1 receptors
may explain dizziness, sedation, and hypotension

Hypnotic Doses
Topical: burning, stinging, itching, or swelling at application site
Few side ef fects at low doses (3 –6 mg/day), the most common being
somnolence/sedation
Increased intraocular pressure, increased psychotic symptoms

Sedation
Best Augmenting Agents for Side EffectsMany experience and/or can be significant in amount
(antidepressant doses)
Weight gain is unusual at hypnotic doses
Sedation is not unusual at hypnotic doses
Wait
Wait
Wait
Switch to another hypnotic

How to Dose
 Dosing T ips75–150 mg/day for depression
3–6 mg at bedtime for insomnia
Capsule 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg
Solution 10 mg/mL
Topical 5%
Tablet 3 mg, 6 mg
75 mg/day; increase gradually until desired ef ficacy is achieved; can
be dosed once a day at bedtime or in divided doses; maximum dose
300 mg/day
Topical: apply thin film 4 times a day (or every 3 –4 hours while
awake)
Insomnia: 6 mg once daily , 30 minutes before bedtime; should not
be taken within 3 hours of a meal; maximum dose 6 mg/day

✽ Topical administration is absorbed systematically and can cause the
same systematic side ef fects as oral administration
OverdoseIf given in a single antidepressant dose, should generally be
administered at bedtime because of its sedative properties
If given in split antidepressant doses, lar gest dose should generally
be given at bedtime because of its sedative properties
If patients experience nightmares, split antidepressant dose and do
not give lar ge dose at bedtime
Patients treated for insomnia may benefit from doses of 3 –6 mg at
bedtime
Liquid formulation should be diluted with water or juice, excluding
grape juice
150 mg capsule available only for maintenance use, not initial
therapy

How to Stop
 Drug InteractionsSafe
No
At antidepressant doses, taper to avoid withdrawal ef fects
Taper not necessary for low doses (3 –6 mg/day); withdrawal ef fects
generally not observed
Half-life approximately 8 –24 hours

Use with sympathomimetic agents may increase sympathetic
activity
Most drug interactions may be less likely at low doses (1 –6 mg/day)
due to the lack of ef fects on receptors other than the histamine 1
receptors

discontinuation of doxepin

after discontinuing doxepin
days for most drugs) after discontinuing doxepin, but see Pearls

Do Not Use
companies
If patient has angle-closure glaucoma or severe urinary retention

If there is a proven aller gy to doxepin

Cardiac ImpairmentUse with caution
Use with caution –may need lower than usual adult dose
Baseline ECG is recommended (not for Silenor)
doxepin

Elderly
Silenor)
Low-dose doxepin (3 –6 mg/day) has been studied and found
effective for insomnia in elderly patients; recommended dose is 3
mg/day

patients
Initial dose 25 –50 mg/day; maximum 100 mg/day

✽ Recommended either to discontinue drug or bottle feedNot generally recommended for use during pregnancy , especially
pregnancy for depression
essants
Significant drug levels have been detected in some nursing infants

the mother

feeding
Patients with neurodermatitis and itching
Anxiety
Disturbed sleep, ener gy
Itching skin

✽ Only TCA available in topical formulation
✽ Topical administration may reduce symptoms in patients with
various neuro-dermatitis syndromes, especially itching
Although low doses are specifically approved for sleep maintenance
in insomnia they may also work for sleep onset in insomnia
At low doses, one of the few hypnotics that is not a controlled
substance, because it has no risk of dependence, withdrawal, or
abuse
At low doses, there is no tolerance to hypnotic actions seen
At low doses, there is little or no weight gain
At low doses doxepin is selective for the histamine 1 receptor and
thus can improve sleep without causing side ef fects associated with
other neurotransmitter systems
In particular , low-dose doxepin does not appear to cause
anticholiner gic symptoms, memory impairment, or weight gain, nor
is there evidence of tolerance, rebound insomnia, or withdrawal
effects

effects

Godfrey  RG . A guide to the understanding and use of tricyclic
antidepressants in the overall management of fibromyalgia and other
chronic pain syndromes  . Arch Intern Med  1996  ;156 :1047  –52.Since tricyclic/tetracyclic antidepressants are substrates for CYP450

Roth  T , Rogowski  R , Hull S , et al. Efficacy and safety of doxepin 1 mg, 3
mg, and 6 mg in adults with primary insomnia  . Sleep  2007  ;30 (11 ):1555  –
61.
Singh  H , Becker  PM . Novel therapeutic usage of low-dose doxepin
hydrochloride  . Expert Opin Investig Drugs  2007  ;16 (8 ):1295  –305.
Stahl  SM . Selective histamine 1 antagonism: novel hypnotic and
pharmacologic actions challenge classical notions of antihistamines  . CNS
Spectr  2008  ;13 (12 ):855–65 .

Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Cymbalta
SNRI (dual serotonin and norepinephrine reuptake inhibitor); may
be classified as an antidepressant, but it is not just an antidepressant
Diabetic peripheral neur opathic pain (DPNP)
Generalized anxiety disorder , acute and maintenance

How Long Until It W orksChronic musculoskeletal pain
Stress urinary incontinence
cortex, which lar gely lacks dopamine transporters, duloxetine can
Weakly blocks dopamine reuptake pump (dopamine transporter),
and may increase dopamine neurotransmission
delayed 2 –4 weeks for depression

Can reduce neuropathic pain within a week, but onset can take
longer
depressive symptoms or prevent worsening of painful symptoms
The goal of treatment of depression and anxiety disorders is
complete remission of current symptoms as well as prevention of
future relapses
The goal of treatment of diabetic peripheral neuropathic pain and
fibromyalgia and chronic neuropathic pain is to reduce symptoms as
much as possible, especially in combination with other treatments
Treatment of diabetic peripheral neuropathic pain, fibromyalgia, and

chronic neuropathic pain may reduce symptoms, but rarely
eliminates them completely , and is not a cure since symptoms can
recur after medicine is stopped

If It Doesn ’t WorkContinue treatment of depression and anxiety disorders until all
symptoms are gone (remission)
Use in diabetic peripheral neuropathic pain, fibromyalgia, and
chronic neuropathic pain may also need to be indefinite, but long-
term treatment is not well studied in these conditions
Some depressed patients who have an initial response may relapse
even though they continue treatment, sometimes called “poop-out ”

Consider psychotherapy for depression or biofeedback or hypnosis
for pain

ResistanceConsider evaluation for another diagnosis or for a comorbid
Consider the presence of noncompliance and counsel the patient
 Augmentation experience is limited compared to other
antidepressants and treatments for neuropathic pain
 Adding other agents to duloxetine for treating depression could
follow the same practice for augmenting SSRIs or other SNRIs if
done by experts while monitoring carefully in dif ficult cases
Although no controlled studies and little clinical experience, adding
other agents for treating diabetic peripheral neuropathic pain and
fibromyalgia and neuropathic pain could theoretically include

gabapentin, pregabalin, and tiagabine, if done by experts while
monitoring carefully in dif ficult cases
Mirtazapine ( “California rocket fuel ” for depression; a potentially
powerful dual serotonin and norepinephrine combination, but
observe for activation of bipolar disorder and suicidal ideation)

Tests
How Drug Causes Side Effectsaction for depression, but observe for activation of bipolar disorder
and suicidal ideation)
If all else fails for anxiety disorders, consider gabapentin,
pregabalin, or tiagabine
Classically , lithium, buspirone, or thyroid hormone for depression

Weight Gainnorepinephrine on acetylcholine release causing decreased appetite,
increased blood pressure, urinary retention, etc.)
Nausea, diarrhea, decreased appetite, dry mouth, constipation (dose-
dependent)
Insomnia, sedation, dizziness
Sexual dysfunction (men: abnormal ejaculation/or gasm, impotence,
decreased libido; women: abnormal or gasm)
Sweating
Increase in blood pressure (up to 2 mmHg)
Rare activation of suicidal ideation, suicide attempts, and completed
suicide
Short-term studies did not show an increase in the risk of suicidality
with antidepressants compared to placebo beyond age 24

Sedation
Wait
Wait
Wait

How to DoseMirtazapine for insomnia, agitation, and gastrointestinal side ef fects
discontinuation of duloxetine
40–60 mg/day in 1 –2 doses for depression
60 mg once daily for diabetic peripheral neuropathic pain and
fibromyalgia
60 mg once daily for generalized anxiety disorder
40 mg twice daily for stress urinary incontinence
Capsule 20 mg, 30 mg, 40 mg, 60 mg

Dosing T ipsFor depression, initial 40 mg/day in 2 doses; can increase to 60
mg/day in 1 –2 doses if necessary; maximum dose generally 120
mg/day
For neuropathic pain and fibromyalgia initial 30 mg once daily;
increase to 60 mg once daily after 1 week; maximum dose generally
60 mg/day
For generalized anxiety , initial 60 mg once daily; maximum dose
generally 120 mg/day
Studies have not demonstrated increased ef ficacy beyond 60 mg/day
 Some patients may require up to or more than 120 mg/day , but
clinical experience is quite limited with high dosing
In relapse prevention studies in depression, a significant percentage
of patients who relapsed on 60 mg/day responded and remitted
when the dose was increased to 120 mg/day
In neuropathic pain and fibromyalgia doses above 60 mg/day have
been associated with increased side ef fects without an increase in
efficacy
Some studies suggest that both serotonin and norepinephrine
reuptake blockade are present at 40 –60 mg/day

efficacy
Do not chew or crush and do not sprinkle on food or mix with food,
but rather always swallow whole to avoid af fecting enteric coating

Overdose
How to Stop
PharmacokineticsSome patients may require dosing above 120 mg/day in 2 divided
doses, but this should be done with caution and by experts
Rare fatalities have been reported; serotonin syndrome, sedation,
vomiting, seizures, coma, change in blood pressure
No
Taper to avoid withdrawal ef fects (dizziness, nausea, vomiting,
headache, paresthesias, irritability)
 If withdrawal symptoms emer ge during discontinuation, raise
dose to stop symptoms and then restart withdrawal much more
slowly

Drug InteractionsMetabolized mainly by CYP450 2D6 and CYP450 1A2
Inhibitor of CYP450 2D6 (probably clinically significant) and
CYP450 1A2 (probably not clinically significant)
Absorption may be delayed by up to 3 hours and clearance may be
increased by one-third after an evening dose as compared to a
morning dose
switching from a TCA to duloxetine
drugs) after discontinuing duloxetine
Inhibitors of CYP450 1A2, such as fluvoxamine, increase plasma
levels of duloxetine and may require a dosage reduction of
duloxetine
Cigarette smoking induces CYP450 1A2 and may reduce plasma

levels of duloxetine, but dosage modifications are not recommended
for smokers

 Inhibitors of CYP450 2D6, such as paroxetine, fluoxetine, and
quinidine, may increase plasma levels of duloxetine and require a
dosage reduction of duloxetine
Via CYP450 1A2 inhibition, duloxetine could theoretically reduce
clearance of theophylline and clozapine; however , studies of
coadministration with theophylline did not demonstrate significant
effects of duloxetine on theophylline pharmacokinetics
Via CYP450 2D6 inhibition, duloxetine could theoretically interfere
Via CYP450 2D6 inhibition, duloxetine could theoretically increase
Use with caution in patients with history of seizures

established, duloxetine should be discontinued in patients who

Do Not Use
Renal Impairmentnontreatment with antidepressants and make sure to document this
companies
Duloxetine may increase blood pressure, so blood pressure should
be monitored during treatment
If patient has substantial alcohol use
If there is a proven aller gy to duloxetine

Elderly
 Childr en and AdolescentsDose adjustment generally not necessary for mild to moderate
Not recommended for use in patients with end-stage renal disease
(requiring dialysis) or severe renal impairment
Not to be administered to patients with any hepatic insuf ficiency
Not recommended for use in patients with substantial alcohol use
Increased risk of elevation of serum transaminase levels
Duloxetine may raise blood pressure

patients
Not studied, but can be used by experts

Breast FeedingFor many patients this may mean continuing treatment during
pregnancy

the mother

Primary T arget SymptomsFor many patients, this may mean continuing treatment during
Patients with physical symptoms of depression
Patients with atypical depression
Patients with comorbid anxiety
Patients who do not respond or do not remit on treatment with
SSRIs
Patients with urologic disorders, prostate disorders (e.g., older men)

PearlsSleep disturbance
Anxiety
Pain
 Duloxetine has well-documented ef ficacy for the painful
physical symptoms of depression
Duloxetine has only somewhat greater potency for serotonin
reuptake blockade than for norepinephrine reuptake blockade, but
this is of unclear clinical significance as a dif ferentiator from other
SNRIs
No head-to-head studies, but may have less hypertension than
venlafaxine XR
Powerful pro-noradrener gic actions may occur at doses greater than
60 mg/day
Not well studied in ADHD, but may be ef fective
 Approved in many countries for stress urinary incontinence
Patients may have higher remission rate for depression on SNRIs
Add or switch to or from pro-noradrener gic agents (e.g.,
atomoxetine, reboxetine, other SNRIs, mirtazapine, maprotiline,
nortriptyline, desipramine, bupropion) with caution

Arnold  LM , Pritchett  YL , D’Souza  DN , et al. Duloxetine for the
treatment of fibromyalgia in women: pooled results from two randomized,
placebo-controlled trials  . J Womens Health (Lar chmt)  2007  ;16 (8 ):1145 –
56.
Bymaster  FP , Dreshfield-Ahmad  LJ , Threlkeld  PG , et al. Comparative
affinity of duloxetine and venlafaxine for serotonin and norepinephrine
transporters in vitro and in vivo, human serotonin receptor subtypes, and
other neuronal receptors  . Neur opsychopharmacology  2001  ;25 (6 ):871–80
.
Hartford  J , Kornstein  S , Liebowitz  M , et al. Duloxetine as an SNRI
treatment for generalized anxiety disorder: results from placebo and active-
controlled trial  . Int Clin Psychopharmacol  2007  ;22 (3 ):167–74 .
Muller  N , Schennach  R , Riedel  M , Moller  HJ . Duloxetine in the
treatment of major psychiatric and neuropathic disorders  . Expert Rev

Neur other  2008  ;8 (4 ):527–36 .Add or switch to or from CYP450 2D6 substrates with caution (e.g.,
atomoxetine, maprotiline, nortriptyline, desipramine)
Mechanism of action as SNRI suggests it may be ef fective in some
patients who fail to respond to SSRIs

Zinner  NR . Duloxetine: a serotonin-noradrenaline re-uptake inhibitor for
the treatment of stress urinary incontinence  . Expert Opin Investig Drugs
2003  ;12 (9 ):1559  –66.

Escitalopram
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Lexapro
RI)
Major depr essive disorder (ages 12 and older)

If It W orksPosttraumatic stress disorder (PTSD)
symptoms

If It Doesn ’t WorkTreatment most often reduces or even eliminates symptoms, but not

TestsSome patients may experience apparent lack of consistent ef ficacy
Bupropion, mirtazapine, reboxetine, or atomoxetine (use
combinations of antidepressants with caution as this may activate
bipolar disorder and suicidal ideation)
tiagabine

✽ As escitalopram has no known important secondary pharmacologic
properties, its side ef fects are presumably all mediated by its serotonin
reuptake blockade
Notable Side EffectsTheoretically due to increases in serotonin concentrations at
Sexual dysfunction (men: delayed ejaculation, erectile dysfunction;
men and women: decreased sexual desire, anor gasmia)

dry mouth)
Mostly central nervous system (insomnia but also sedation,
agitation, tremors, headache, dizziness)

Sedation
Note: patients with diagnosed or undiagnosed bipolar or psychotic
disorders may be more vulnerable to CNS-activating actions of
SSRIs
Autonomic (sweating)
reversible on discontinuation of escitalopram

Wait
Wait

How to Dose
✽ 10 mg of escitalopram may be comparable in ef ficacy to 40 mg of
citalopram with fewer side ef fectsa mood stabilizer or an atypical antipsychotic, and/or
discontinuation of escitalopram
10–20 mg/day
Tablet 5 mg, 10 mg (scored), 20 mg (scored)
Oral solution 5 mg/5 mL
Initial 10 mg/day; increase to 20 mg/day if necessary; single-dose
administration, morning or evening
Given once daily , any time of day tolerated
Thus, give an adequate trial of 10 mg prior to giving 20 mg
Some patients require dosing with 30 or 40 mg

Overdose
How to StopIf intolerable anxiety , insomnia, agitation, akathisia, or activation
Rare fatalities have been reported; symptoms include convulsions,
coma, dizziness, hypotension, insomnia, nausea, vomiting, sinus
tachycardia, somnolence, and ECG changes
Safe
No
prudent

 Drug InteractionsMean terminal half-life 27 –32 hours
Steady-state plasma concentrations achieved within 1 week
No significant actions on CYP450 enzymes
drugs) after discontinuing escitalopram
Could theoretically cause weakness, hyperreflexia, and
incoordination when combined with sumatriptan or possibly other
triptans, requiring careful monitoring of patient

Do Not Use
companies
If patient is taking pimozide
If there is a proven aller gy to escitalopram or citalopram

Elderly
 Childr en and AdolescentsNo dose adjustment for mild to moderate impairment
Recommended dose 10 mg/day
Preliminary data suggest that citalopram is safe in patients with
cardiac impairment, suggesting that escitalopram is also safe
Approved for depression in adolescents ages 12 –17

patients

pregnancy

essants

are on escitalopram
the mother
Patients taking concomitant medications (few drug interactions and
fewer even than with citalopram)
Patients requiring faster onset of action

 Pearls
✽ May be among the best-tolerated antidepressants
✽ R-citalopram may interfere with the binding of S-citalopram at the
serotonin transporter
✽ For this reason, S-citalopram may be more than twice as potent as
R,S-citalopram (i.e., citalopram)More expensive than citalopram in markets where citalopram is
generic
Anxiety
May be better tolerated than citalopram
Can cause cognitive and af fective “flattening ”
Thus, 10 mg starting dose of S-citalopram may have the therapeutic
efficacy of 40 mg of R,S-citalopram
Thus, escitalopram may have faster onset and better ef ficacy with
reduced side ef fects compared to R,S-citalopram

✽ Escitalopram is commonly used with augmenting agents, as it is the
SSRI with the least interaction at either CYP450 2D6 or 3A4,
therefore causing fewer pharmacokinetically mediated drug
interactions with augmenting agents than other SSRIs
Baldwin  DS , Reines  EH , Guiton  C , Weiller  E. Escitalopram therapy for
major depression and anxiety disorders  . Ann Pharmacother  2007  ;41 (10
):1583  –92.
Bareggi  SR , Mundo  E , Dell’Osso  B , Altamura  AC . The use of
escitalopram beyond major depression: pharmacological aspects, ef ficacy
and tolerability in anxiety disorders  . Expert Opin Drug Metab T oxicol  2007
;3 (5 ):741–53 .Some data may actually suggest remission rates comparable to
SNRIs, but this is not proven
Some postmenopausal women ’s depression will respond better to

escitalopram plus estrogen augmentation than to escitalopram alone
Nonresponse to escitalopram in elderly may require consideration of

Burke  WJ . Escitalopram  . Expert Opin Investig Drugs  2002  ;11 (10 ):1477
–86.

Esketamine
Brands
Generic?
No
 Class
 How the Drug W orksSpravato
N-methyl-D-aspartate (NMDA) receptor antagonist
Treatment-r esistant depr ession in adults (adjunct)
Depr essive symptoms in adults with major depr essive disorder
(MDD) with acute suicidal ideation or behavior (adjunct)
Esketamine is a nonselective, noncompetitive open channel inhibitor
of the NMDA receptor; specifically , it binds to the phencyclidine
site of the NMDA receptor

If It W orks
Try a traditional antidepressant or stimulation therapy
Tests
Assess blood pressure prior to dosing: if baseline blood pressure is
elevated (e.g., >140 mmHg systolic, >90 mmHg diastolic), consider
the risks of short-term increases in blood pressure and benefit ofThis leads to downstream glutamate release and consequent
stimulation of other glutamate receptors, including AMP A receptors
Theoretically , esketamine may have antidepressant ef fects because
activation of AMP A receptors leads to activation of signal
transduction cascades, including mT ORC1, and an increase in
growth factors such as BDNF that cause the expression of synaptic
proteins and an increase in the density of dendritic spines
Antidepressant ef fects can occur within 24 hours
Can immediately alleviate depressed mood and suicidal ideation
Esketamine itself is an augmenting agent

esketamine treatment in patients with treatment-resistant depression,
and do not administer esketamine if an increase in blood pressure or
intracranial pressure poses a serious risk
Given its potential to induce dissociative ef fects, carefully assess
patients with psychosis before administering esketamine
Dissociation, dizziness, sedation, vertigo, anxiety , lethar gy, feeling
drunk, numbness, hypoesthesia
Lower urinary tract symptoms, including increased frequency of
urination (pollakiuria)
 Life-Thr eatening or Danger ous Side EffectsDirect ef fect on NMDA receptors
Dissociation, sedation (requires monitoring for at least 2 hours at
each treatment session)
Increased blood pressure (peak at approximately 40 minutes post-
administration and lasts approximately 4 hours)

Sedation
Best Augmenting Agents for Side EffectsShort-term cognitive impairment (generally resolves by 2 hours
post-dose)
Use lower dose (56 mg rather than 84 mg)
For CNS side ef fects, discontinuation of nonessential centrally
acting medications may help
If blood pressure remains high, promptly seek assistance from
practitioners experienced in blood pressure management
Refer patients experiencing symptoms of a hypertensive crisis (e.g.,
chest pain, shortness of breath) or hypertensive encephalopathy
(e.g., sudden severe headache, visual disturbances, seizures,
diminished consciousness, or focal neurological deficits)
immediately for emer gency care

How to DoseInduction phase (weeks 1 –4): administer twice per week; day 1
starting dose 56 mg; subsequent doses 56 mg or 84 mg
Maintenance phase (weeks 5 –8): administer once weekly; 56 mg or
84 mg
Maintenance phase (weeks 9 and after): administer every 2 weeks or
once weekly (use least frequent dosing to maintain
remission/response); 56 mg or 84 mg
56 mg dose kit: unit-dose carton containing two 28 mg nasal spray
devices
84 mg dose kit: unit-dose carton containing three 28 mg nasal spray
devices
Given in conjunction with an oral antidepressant
Administered intranasally under the supervision of a healthcare
provider

Each nasal spray device delivers 2 sprays containing a total of 28
mg of esketamine
To prevent loss of medication, do not prime the device before use
Patient should recline head at about 45 degrees during
administration to keep medication inside the nose
Patient should blow nose before first device only
After patient self-administers both sprays (one in each nostril),
check that the indicator shows no green dots; if there is a green dot,
have patient spray again into the second nostril
Use 2 devices (for a 56 mg dose) or 3 devices (for a 84 mg dose)
with a 5-minute rest period between each device
Blood pressure must be assessed before administration; if blood
pressure is elevated, weigh the risks vs. benefits of esketamine
Reassess blood pressure 40 minutes post-administration and
thereafter as clinically warranted
Patients must be monitored for at least 2 hours at each treatment
session, followed by an assessment to determine when the patient is

clinically stable and ready to leave the healthcare facility; this is due
to the risks of sedation, dissociation, and hypertension
If blood pressure is decreasing and patient is clinically stable for at
least 2 hours, the patient may be dischar ged; if not, continue to
monitor

Nausea and vomiting are potential side ef fects, so advise patients to
avoid food for at least 2 hours before administration and liquids for at
least 30 minutes before administration
Nasal corticosteroid or nasal decongestant should not be used within
an hour prior to administration of esketamine
If a patient misses treatment sessions and there is a worsening of
symptoms, consider returning to the previous dosing schedule (i.e.,
every 2 weeks to once weekly , weekly to twice weekly)
Evidence of therapeutic benefit should be evaluated at the end of the
induction phase to determine the need for continued treatment
Overdose
Long-T erm UseAdvise the patient not to engage in potentially hazardous activities,
such as driving or operating machinery , until the next day after a
restful sleep; patients will need to arrange transportation home
With racemic ketamine, symptoms of overdose include restlessness,
psychosis, hallucinations, stupor , respiratory depression

Long-term cognitive ef fects of esketamine have not been evaluated
beyond 1 year

How to Stop
Little potential to af fect metabolism of drugs cleared by CYP450
enzymesLong-term cognitive and memory impairment have been reported
with repeated ketamine misuse or abuse
Esketamine is a Schedule III drug and is available only through a
restricted program under a Risk Evaluation and Mitigation Strategy
(REMS)
Time to maximum plasma concentration is approximately 20 –40
minutes after the last administered nasal spray
Mean terminal half-life 7 –12 hours
Metabolized primarily by CYP450 2B6 and CYP450 3A4, and to a
lesser extent by CYP450 2C9 and 2C19
No significant actions on CYP450 enzymes, although esketamine
has modest induction ef fects on CYP450 2B6 and 3A4 in human
hepatocytes

Use with caution with other drugs that are NMDA antagonists
(amantadine, memantine, dextromethorphan)
Esketamine may increase the ef fects of other sedatives, including
benzodiazepines, barbiturates, opioids, anesthetics, and alcohol
Concomitant use with stimulants or monoamine oxidase inhibitors
may increase blood pressure
Because of the risks of sedation and dissociation and of abuse and
misuse, esketamine is only available through a restricted program
under a REMS; healthcare settings and pharmacies must be certified in
the REMS program, and pharmacies must only dispense esketamine to
healthcare settings that are certified in the program
Esketamine can raise blood pressure; patients with cardiovascular and
cerebrovascular conditions and risk factors may be at an increased risk
of associated adverse ef fects
Blood pressure should be monitored for at least 2 hours post-
administration of esketamine, and prompt medical care should be

sought if blood pressure remains high; refer patients experiencing
symptoms of a hypertensive crisis or hypertensive encephalopathy for
immediate emer gency care
In patients with a history of hypertensive encephalopathy , more
intensive monitoring, including more frequent blood pressure and
symptom assessment, is warranted because these patients are at higher

risk for developing encephalopathy with even small increases in blood
pressure
Because of the risks of delayed or prolonged sedation and dissociation,
patients must be monitored for at least 2 hours at each treatment
clinically stable and ready to leave the healthcare facility
Because of the risk of dissociation, carefully assess patients with
psychosis before administering esketamine and only initiate treatment
if the potential benefits outweigh the risks
Monitor patients for activation of suicidal ideation
Esketamine may impair attention, judgment, thinking, reaction speed,
and motor skills
Esketamine may impair ability to drive and operate machinery;
patients should not drive or operate machinery until the next day after
a restful sleep

nontreatment with antidepressants and make sure to document this in
the patient ’s chart
Distribute the brochures provided by the FDA and the drug companies

Monitor patients for activation of suicidal ideation, especially children
and adolescents
Do Not Use
Cardiac ImpairmentIf patient has aneurysmal vascular disease (including thoracic and
abdominal aorta, intracranial and peripheral arterial vessels) or
arteriovenous malformation
If patient has intracerebral hemorrhage
If there is a proven aller gy to esketamine or ketamine
Patients with moderate impairment may need to be monitored for
adverse reactions for a longer period of time
Not recommended for use in patients with severe impairment
Contraindicated in patients with aneurysmal vascular disease
(including thoracic and abdominal aorta, intracranial and peripheral
arterial vessels) or arteriovenous malformation

Elderly
 PregnancyPatients with cardiovascular and cerebrovascular conditions and risk
factors may be at an increased risk of associated adverse ef fects
In clinical trials, no dif ferences were observed in safety profile
between patients aged 65 years and older and patients younger than
65 years
In clinical trials, Cmax and AUC values were higher in patients
aged 65 years and older than in patients younger than 65 years
Not recommended for use during pregnancy

In pregnant primates, use of NMDA receptor antagonists during the
period of peak brain development increased neuronal apoptosis in

The art of psychopharmacologythe developing brain of the fetuses
In rabbits, skeletal malformations were observed when ketamine
was administered intranasally at estimated esketamine exposures of
0.3 times the maximum recommended human dose
In rats, delay in sensorimotor development in pups was observed
when esketamine was administered intranasally at exposures similar
to the maximum recommended human dose
Because of the risk for fetal harm, consider pregnancy planning and
prevention in females of reproductive potential
essants
Animal studies have shown neurotoxicity in juvenile animals when
NMDA antagonists were administered during a window of
vulnerability that correlates with exposures in the third trimester
through the first several months of life, but this window may extend

out to approximately 3 years of age in humans

 Pearls
Esketamine is the “s” enantiomer of ketamine
Esketamine is not approved as an anesthetic, and its safety or ef ficacy
as an anesthetic has not been established
In clinical trials, treatment-resistant depression was defined as a DSM-
5 diagnosis for major depressive disorder (MDD) in patients who have
not responded adequately to at least two dif ferent antidepressants of
adequate dose and duration in the current depressive episode
Several studies suggest rapid reduction of depressive symptoms in
patients with MDD who have active suicidal ideation with intent
Studies of esketamine or IV ketamine administered during
psychotherapy sessions suggest potential improvement of substanceSeverely treatment-resistant depression, suicidal ideation
Only available through a restricted program under a REMS
Must be administered in the presence of a healthcare professional

Requires monitoring for at least 2 hours post-administration

and alcohol abuse
Canuso CM  Canuso CM  , Singh JB  Singh JB  , Fedgchin M  Fedgchin M  , et
al. Efficacy and safety of esketamine for the rapid reduction of symptoms of
depression and suicidality in patients at imminent risk for suicide: results of
a double-blind, randomized, placebo-controlled study  . Am J Psychiatry
2018  ;175 (7 ):620 –30 .
Daly EJ  Daly EJ  , Trivedi MH  Trivedi MH  , Janik A  Janik A  , et al.
Efficacy of esketamine nasal spray plus oral antidepressant treatment for
relapse prevention in patients with treatment-resistant depression: a
randomized clinical trial  . JAMA Psychiatry  2019  ;76 :893 –903 . doi:
10.1001/jamapsychiatry .2019.1 189 .
Fedgchin M  Fedgchin M  , Trivedi M  Trivedi M  , Daly E  Daly E  , et al.
Efficacy and safety of fixed-dose esketamine nasal spray combined with a
new oral antidepressant in treatment-resistant depression: results of a
randomized, double-blind, active-controlled study (TRANSFORM-1)  . Int J

Neur opsychopharmacol  2019  ;22 (10 ):616 –30 .
Ochs-Ross R  Ochs-Ross R  , Daly EJ  Daly EJ  , Zhang Y  Zhang Y  , et al.
Efficacy and safety of esketamine nasal spray plus an oral antidepressant in
elderly patients with treatment-resistant depression –TRANSFORM-3  . Am
J Geriatr Psychiatry  2019  ;28 (2 ):121 –41 .

Popova V  Popova V  , Daly EJ  Daly EJ  , Trivedi M  Trivedi M  , et al.
Efficacy and safety of flexibly dose esketamine nasal spray combined with
a newly initiated oral antidepressant in treatment-resistant depression: a
randomized double-blind active-controlled study  . Am J Psychiatry  2019
;176 (6 ):428 –38 .

Estazolam
Brands
Generic?
Yes
 Class
 How the Drug W orksProSom
Benzodiazepine (hypnotic)
Insomnia characterized by difficulty in falling asleep, fr equent
nocturnal awakenings, and/or early morning awakenings
Catatonia

If It W orks
If It Doesn ’t WorkBinds to benzodiazepine receptors at the GABA-A ligand-gated
Inhibitory actions in sleep centers may provide sedative hypnotic
effects
Generally takes ef fect in less than an hour
Improves quality of sleep
Effects on total wake-time and number of nighttime awakenings
may be decreased over time
Increase the dose
Improve sleep hygiene

Tests
✽ Dizziness, ataxia, slurred speech, weaknessGenerally , best to switch to another agent
Trazodone
Agents with antihistamine actions (e.g., diphenhydramine, TCAs)
Actions at benzodiazepine receptors that carry over to the next day
can cause daytime sedation, amnesia, and ataxia

Sedation
Rebound insomnia when withdrawing from long-term treatment
Wait

How to Dose
 Dosing T ipsTo avoid problems with memory , take estazolam only if planning to
have a full night ’s sleep
Switch to a shorter -acting sedative hypnotic
Switch to a non-benzodiazepine hypnotic
1–2 mg/day at bedtime
Tablet 1 mg scored, 2 mg scored
Initial 1 mg/day at bedtime; increase to 2 mg/day at bedtime if
ineffective

Overdose
How to StopUse lowest possible ef fective dose and assess need for continued
treatment regularly
Estazolam should generally not be prescribed in quantities greater
than a 1-month supply
Patients with lower body weights may require lower doses
treatment
No death reported in monotherapy; sedation, slurred speech, poor
coordination, confusion, coma, respiratory depression
Not generally intended for long-term use
Evidence of ef ficacy up to 12 weeks
Estazolam is a Schedule IV drug
Some patients may develop dependence and/or tolerance; risk may
be greater with higher doses
History of drug addiction may increase risk of dependence

 Other W arnings/Pr ecautionsIf taken for more than a few weeks, taper to reduce chances of
withdrawal ef fects
Patients with seizure history may seize upon sudden withdrawal
Rebound insomnia may occur the first 1 –2 nights after stopping
For patients with severe problems discontinuing a benzodiazepine,
dosing may need to be tapered over many months (i.e., reduce dose
by 1% every 3 days by crushing tablet and suspending or dissolving
in 100 mL of fruit juice and then disposing of 1 mL and drinking the
rest; 3 –7 days later , dispose of 2 mL, and so on). This is both a form
of very slow biological tapering and a form of behavioral
desensitization
Half-life 10 –24 hours
Increased clearance and thus decreased estazolam levels in smokers

Do Not Usetogether , including specifically the risk of slowed or dif ficulty
efficacy
Insomnia may be a symptom of a primary disorder , rather than a
primary disorder itself
ideation
Use only with extreme caution in patients with impaired respiratory
function or obstructive sleep apnea
Estazolam should be administered only at bedtime

ideation
If patient is pregnant

Elderly
 Childr en and AdolescentsIf there is a proven aller gy to estazolam or any benzodiazepine
Benzodiazepines have been used to treat insomnia associated with
No dose adjustment in healthy patients
Debilitated patients: recommended initial dose of 0.5 mg/day
Long-term ef fects of estazolam in children/adolescents are unknown
monitored

Pregnancy
Potential AdvantagesContraindicated for use in pregnancy
Unknown if estazolam is secreted in human breast milk, but all
Transient insomnia

 Pearls
Pierce  MW , Shu VS . Efficacy of estazolam. The United States clinical
experience  . Am J Med  1990  ;88 :S6 –11.Smokers (may need higher dose)
Time to sleep onset
Total sleep time
Nighttime awakenings
If tolerance develops, it may result in increased anxiety during the
day and/or increased wakefulness during the latter part of the night
Best short-term use is for less than 10 consecutive days, and for less
than half of the nights in a month
Drug holidays may restore drug ef fectiveness if tolerance develops
treatment

Pierce  MW , Shu VS , Groves  LJ . Safety of estazolam. The United States
clinical experience  . Am J Med  1990  ;88 :S12 –17.
Vogel GW , Morris  D . The ef fects of estazolam on sleep, performance, and
memory: a long-term sleep laboratory study of elderly insomniacs  . J Clin
Pharmacol  1992  ;32 :647–51 .

Eszopiclone
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Lunesta
Non-benzodiazepine hypnotic; alpha 1 isoform selective agonist of
GABA-A/benzodiazepine receptors
Insomnia
Primary insomnia
Chronic insomnia

If It W orks
If It Doesn ’t WorkInsomnia secondary to psychiatric or medical conditions
Residual insomnia following treatment with antidepressants
May bind selectively to a subtype of the benzodiazepine receptor ,
the alpha 1 isoform
May enhance GABA inhibitory actions that provide sedative
hypnotic ef fects more selectively than other actions of GABA
effects

Tests
✽ Chronic studies of eszopiclone suggest lack of notable tolerance or
dependence developing over timeobstructive sleep apnea or restless leg syndrome, which requires
Trazodone

✽ Unpleasant taste
Sedation
What to Do About Side EffectsSedation
Dizziness
Dose-dependent amnesia
Dry mouth, headache
Respiratory depression, especially when taken with other CNS
Rare angioedema
Next-day carryover sedation following nighttime dosing uncommon

How to Dose
To avoid problems with memory , take eszopiclone only if planning
to have a full night ’s sleep
2–3 mg at bedtime
Tablet 1 mg, 2 mg, 3 mg
No titration, take dose at bedtime
Not restricted to short-term use

OverdoseNo notable development of tolerance or dependence seen in studies
up to 6 months
Recent study adding eszopiclone to patients with major depression
and only a partial response to fluoxetine showed improvement not
only in residual insomnia, but in other residual symptoms of
depression as well
Most studies were done with 3 mg dose or less at night, but some
patients with insomnia associated with psychiatric disorders may
require higher dosing
However , doses higher than 3 mg may be associated with carryover
effects, hallucinations, or other CNS adverse ef fects
To avoid problems with memory or carryover sedation, only take
eszopiclone if planning to have a full night ’s sleep
Most notable side ef fect may be unpleasant taste
Other side ef fects can include sedation, dizziness, dose-dependent
amnesia, nervousness, dry mouth, and headache
Few reports of eszopiclone overdose, but probably similar to
zopiclone overdose
Rare fatalities have been reported in zopiclone overdose

Symptoms associated with zopiclone overdose include clumsiness,
mood changes, sedation, weakness, breathing trouble,
unconsciousness

How to Stop
 Drug InteractionsNo development of tolerance was seen in studies up to 6 months
Eszopiclone is a Schedule IV drug
Some patients could develop dependence and/or tolerance with
drugs of this class; risk may be theoretically greater with higher
doses
History of drug addiction may theoretically increase risk of
dependence
Rebound insomnia may occur the first night after stopping
If taken for more than a few weeks, taper to reduce chances of
Metabolized by CYP450 3A4 and 2E1
Terminal elimination half-life approximately 6 hours
Heavy high-fat meal slows absorption, which could reduce ef fect on
sleep latency

Other W arnings/Pr ecautionsIncreased depressive ef fects when taken with other CNS depressants
Inhibitors of CYP450 3A4, such as nefazodone and fluvoxamine,
could increase plasma levels of eszopiclone
Inducers of CYP450 3A4, such as rifampicin, could decrease plasma
levels of eszopiclone
ideation
Use only with caution in patients with impaired respiratory function
or obstructive sleep apnea
Eszopiclone should only be administered at bedtime
Rare angioedema has occurred with sedative hypnotic use and could
potentially cause fatal airway obstruction if it involves the throat,
glottis, or larynx; thus if angioedema occurs treatment should be

Sleep driving and other complex behaviors, such as eating and
preparing food and making phone calls, have been reported in
patients taking sedative hypnotics; in some cases these behaviors

Do Not Use
Elderlyhave resulted in serious injury or death, prompting the FDA to
require a black box warning
If the patient has experienced an episode of complex sleep behaviors
after taking a sleep medication
If there is a proven aller gy to eszopiclone or zopiclone
Dose adjustment not generally recommended for mild-to-moderate
hepatic impairment
For severe impairment, recommended initial dose 1 mg at bedtime;
maximum dose 2 mg at bedtime
Dosage adjustment may not be necessary
May be more susceptible to adverse ef fects

 Pregnancy
Breast FeedingInitial dose 1 mg at bedtime; maximum dose generally 2 mg at
bedtime
Long-term ef fects of eszopiclone in children/adolescents are
unknown
monitored
Infants whose mothers took sedative hypnotics during pregnancy
may experience some withdrawal symptoms
sedative hypnotics during pregnancy

 PearlsUnknown if eszopiclone is secreted in human breast milk, but all
Those who require long-term treatment
Those with depression whose insomnia does not resolve with
antidepressant treatment
More expensive than some other sedative hypnotics

✽ May be preferred over benzodiazepines because of its rapid onset of
action, short duration of ef fect, and safety profile
Eszopiclone: esopiclone, estorra, S-zopiclone, zopiclone –Sepracor  . Drugs
R D 2005  ;6 (2 ):111–15 .
Krystal  AD , Walsh JK , Laska  E , et al. Sustained ef ficacy of eszopiclone
over 6 months of nightly treatment: results of a randomized, double-blind,
placebo-controlled study in adults with chronic insomnia  . Sleep  2003  ;26
(7 ):793 –9 .Eszopiclone is the best documented agent to be safe for long-term
use, with little or no suggestion of tolerance, dependence, or abuse
May even be safe to consider in patients with a past history of
substance abuse who require treatment with a hypnotic
May be preferred over benzodiazepine hypnotics, which all cause
tolerance, dependence, and abuse as a class
Not a benzodiazepine itself but binds to the benzodiazepine receptor
May be a preferred agent in primary insomnia

Targeting insomnia may prevent the onset of depression and
maintain remission after recovery from depression
Rebound insomnia does not appear to be common

Zammit  GK , McNabb  LJ , Caron  J , Amato  DA , Roth  T . Efficacy and
safety of eszopiclone across 6-weeks of treatment for primary insomnia  .
Curr Med Res Opin  2004  ;20 (12 ):1979  –91.

Flibanserin
Brands
Generic?
No
 Class
 How the Drug W orksAddyi
Serotonin 1A agonist and serotonin 2A antagonist
Sexual dysfunction is theoretically linked to an imbalance in central

If It W orks
ResistanceFlibanserin hypothetically counteracts this imbalance in HSDD
through its ability to both reduce inhibitory signals and enhance
excitatory signals
Specifically , flibanserin increases the release of dopamine and
norepinephrine, which are excitatory sexual signals, and reduces the
release of serotonin, an inhibitory sexual signal
In clinical trials, improvement was seen at 4 weeks
Increases number of satisfying sexual events and ratings on sexual
desire scores
None known
Theoretically , bupropion augmentation could be considered, but no
published trials

Tests
Most common side ef fects (e.g., notable side ef fects below) likely
caused by 5HT1A agonism and/or 5HT2A antagonism
Hypotension, dizziness, and syncope of flibanserin as a
monotherapy is theoretically related to its 5HT1A agonist actions
Weak alpha 1 antagonist actions may also contribute to hypotension
and dizziness of flibanserin, especially when given in combination
with alcohol, which is contraindicated
Nausea
Fatigue
Insomnia
Dry mouth

 Sedation
Usual Dosage RangeDizziness, syncope, especially when combined with alcohol
(contraindicated)
Wait
Wait
Wait
Review any concomitant medications and consider reducing the
dose or discontinuing agents that may be interacting with flibanserin

How to Dose
Overdose
How to Stop
Pharmacokinetics100 mg once daily at bedtime
Tablet 100 mg
Flibanserin is dosed at bedtime to reduce the risk of hypotension,
syncope, and somnolence
However , flibanserin is recommended for long-term use with close
No
Taper not necessary but may be better tolerated in some patients

Drug InteractionsMetabolized primarily by CYP450 3A4 and to a lesser extent by
CYP450 2C19
Mean terminal half-life approximately 1 1 hours
The risk of hypotension, syncope, and CNS depression with
flibanserin is increased in the presence of alcohol; therefore, the
concomitant use of alcohol and flibanserin is contraindicated
flibanserin is increased in the presence of moderate or strong
CYP450 3A4 inhibitors; therefore, the concomitant use of
moderate/strong CYP450 3A4 inhibitors and flibanserin is
contraindicated
If the patient requires a moderate or strong CYP450 3A4 inhibitor ,
flibanserin should be discontinued at least 2 days prior to starting
the CYP450 3A4 inhibitor
If the patient is taking a moderate or strong CYP450 3A4 inhibitor ,
it should be discontinued 2 weeks prior to starting flibanserin
Concomitant use of flibanserin and weak CYP450 3A4 inhibitors

may increase flibanserin exposure, potentially increasing risk of
Concomitant use of flibanserin and CNS depressants may increase
the risk of adverse ef fects such as somnolence

Do Not UseConcomitant use of flibanserin and CYP450 3A4 inducers may
decrease exposure to flibanserin and is not recommended
Concomitant use of flibanserin and CYP450 2C19 inhibitors may
increase flibanserin exposure, potentially increasing risk of adverse
effects
Use of flibanserin in patients who are poor CYP450 2C19
metabolizers may increase flibanserin exposure, potentially
increasing risk of adverse ef fects
Concomitant use of flibanserin and P-glycoprotein substrates (e.g.,
digoxin) may increase concentrations of the P-glycoprotein
substrate; monitoring is required for P-glycoprotein substrates that
have narrow therapeutic index (e.g., digoxin)
Flibanserin can cause severe hypotension and loss of consciousness,
with increased risk in the presence of alcohol or CYP450 3A4
inhibitors; for that reason, flibanserin is available only through a
Risk Evaluation and Mitigation Strategy (REMS), which includes
elements to assure safe use (ET ASU)

In the presence of alcohol
With moderate/strong CYP450 3A4 inhibitors

Elderly
 PregnancyIf there is a proven aller gy to flibanserin
Exposure may be increased
Contraindicated; flibanserin exposure increases 4.5-fold in patients
with hepatic impairment
Use in patients with cardiac impairment has not been studied
Not approved for use in postmenopausal women
Some elderly patients may theoretically tolerate lower doses better
but this has not been formally studied

In animal studies, fetal toxicity occurred only in the presence of
significant maternal toxicity including reductions in weight gain and
sedation
In animal studies, decreased fetal weight, structural anomalies, and
increases in fetal loss occurred with flibanserin at exposures greater
than 15 times those achieved with recommended human doses
Unknown if flibanserin is secreted in human breast milk, but all

Breast feeding is not recommended during treatment with

 Pearls
 Suggested ReadingPatients who drink alcohol
Patients who take concomitant medications that may interact with
flibanserin ’s pharmacokinetic and pharmacodynamic properties
Flibanserin is not approved for treatment in postmenopausal women
or in men and is not indicated to enhance sexual performance
May act on reward circuits in the CNS to enhance motivation and
interest
Theoretically , may wish to avoid concomitant use with agents that
have potent alpha 1 antagonist actions that may enhance the
possibility of hypotension

Simon  JA , Thorp  J , Millheiser  L . Flibanserin for premenopausal
hypoactive sexual desire disorder: pooled analysis of clinical trials  . J
Womens Health (Lar chmt)  2019  ;28 (6 ):769–77 .
Stahl  SM . Mechanism of action of flibanserin, a multifunctional serotonin
agonist and antagonist (MSAA), in hypoactive sexual desire disorder  . CNS
Spectr  2015  ;20 (1 ):1 –6 .
Stahl  SM , Sommer  B , Allers  KA . Multifunctional pharmacology of
flibanserin: possible mechanism of therapeutic action in Hypoactive Sexual
Desire Disorder  . J Sex Med  2011 ;8 :15 –27 .
):453–8 .

Flumazenil
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Romazicon
Anexate
Lanexat
Benzodiazepine receptor antagonist
Reversal of sedative effects of benzodiazepines after general
anesthesia has been induced and/or maintained with
benzodiazepines
Reversal of sedative effects of benzodiazepines after sedation
has been pr oduced with benzodiazepines for diagnostic and

If It W orks
✽ Reverses sedation and psychomotor retardation rapidly , but may not
restore memory completely
✽ Patients treated for benzodiazepine overdose may experience CNS
excitation
✽ Patients who receive flumazenil to reverse benzodiazepine ef fects
should be monitored for up to 2 hours for resedation, respiratory
depression, or other lingering benzodiazepine ef fects
If It Doesn ’t Worktherapeutic pr ocedur es
Management of benzodiazepine overdose
Reversal of conscious sedation induced with benzodiazepines
(pediatric patients)
Blocks benzodiazepine receptors at GABA-A ligand-gated chloride
channel complex, preventing benzodiazepines from binding there
Onset of action 1 –2 minutes; peak ef fect 6 –10 minutes
Flumazenil has not been shown to treat hypoventilation due to
benzodiazepine treatment

Tests
 Life-Thr eatening or Danger ous Side EffectsSedation is most likely not due to a benzodiazepine, and treatment
with flumazenil should be discontinued and other causes of sedation
investigated
None –flumazenil is basically used as a monotherapy antidote to
reverse the actions of benzodiazepines
May precipitate benzodiazepine withdrawal in patients dependent
upon or tolerant to benzodiazepines
Dizziness, injection site pain, sweating, headache, blurred vision

Sedation
Best Augmenting Agents for Side EffectsSeizures
Death (majority occurred in patients with severe underlying disease
or who overdosed with non-benzodiazepines)
Cardiac dysrhythmia
Patients may experience resedation if the ef fects of flumazenil wear
off before the ef fects of the benzodiazepine
Monitor patient
Restrict ambulation because of dizziness, blurred vision, and
possibility of resedation
None –augmenting agents are not appropriate to treat side ef fects
associated with flumazenil use

How to Dose
Overdose0.4–1 mg generally causes complete antagonism of therapeutic
doses of benzodiazepines
1–3 mg generally reverses benzodiazepine overdose
Intravenous 0.1 mg/mL –5 mL multiple-use vial, 10 mL multiple-use
vial
Conscious sedation, general anesthesia: 0.2 mg (2 mL) over 15
seconds; can administer 0.2 mg again after 45 seconds; can
administer 0.2 mg each additional 60 seconds; maximum 1 mg
Benzodiazepine overdose: 0.2 mg over 30 seconds; can administer
0.3 mg over next 30 seconds; can administer 0.5 mg over 30
seconds after 1 minute; maximum 5 mg
May need to administer follow-up doses to reverse actions of
benzodiazepines that have a longer half-life than flumazenil (i.e.,
longer than 1 hour)

How to Stop
 Other W arnings/Pr ecautionsAnxiety , agitation, increased muscle tone, hyperesthesia,
convulsions
Not a long-term treatment
No
N/A
Terminal half-life 41 –79 minutes
Food increases its clearance
Flumazenil may induce seizures, particularly in patients tolerant to
or dependent on benzodiazepines, or who have overdosed on cyclic
antidepressants, received recent/repeated doses of parenteral
benzodiazepines, or have jerking or convulsion during overdose

Do Not Use
Special populationsPatients dependent on benzodiazepines or receiving
benzodiazepines to suppress seizures in cyclic antidepressant
overdose should receive the minimally ef fective dose of flumazenil
Use with caution in patients with head injury
Greater risk of resedation if administered to a patient who took a
long-acting benzodiazepine or a lar ge dose of a short-acting
Flumazenil may induce panic attacks in patients with panic disorder
Use with caution in cases of mixed overdose because toxic ef fects of
other drugs used in overdose (e.g., convulsions) may appear when
the ef fects of the benzodiazepine are reversed
Should not be used until after ef fects of neuromuscular blockers
have been reversed
If benzodiazepine was prescribed to control a life-threatening
condition (e.g., status epilepticus, intracranial pressure)
If there is a high risk of seizure
If patient exhibits signs of serious cyclic antidepressant overdose

If there is a proven aller gy to flumazenil or benzodiazepines

Elderly
 Childr en and AdolescentsDosage adjustment may not be necessary
Prolongation of half-life
Moderate: clearance reduced by half
Severe: clearance reduced by three-quarters
More variability of pharmacokinetics than in adults
Safety and ef ficacy established for reversal of conscious sedation for
children over age 1
Initial 0.01 mg/kg (up to 0.2 mg) over 15 seconds; same dosing
pattern as adults; maximum 0.05 mg/kg or 1 mg
Safety and ef ficacy for reversal of benzodiazepine overdose, general
anesthesia induction or resuscitation of a newborn have not been

Pregnancy
Potential Advantagesestablished, but anecdotal data suggest similar safety and ef ficacy as
for conscious sedation
Not recommended to treat the ef fects of benzodiazepines during
labor and delivery because the ef fects on the infant have not been
studied
Unknown if flumazenil is secreted in human breast milk, but all
If treatment with flumazenil is necessary , it should be administered

 Pearls
✽ Can wear of f before the benzodiazepine it is reversing
✽ Can precipitate anxiety or panic in conscious patients with anxiety
disorders
Malizia  AL , Nutt DJ . The ef fects of flumazenil in neuropsychiatric
disorders  . Clin Neur opharmacol  1995  ;18 :215–32 .To reverse a low dose of a short-acting benzodiazepine
May be too short-acting
Effects of benzodiazepines
Sedative ef fects
Recall and psychomotor impairments
Ventilatory depression
Can precipitate benzodiazepine withdrawal seizures

McCloy  RF . Reversal of conscious sedation by flumazenil: current status
and future prospects  . Acta Anaesthesiol Scand Suppl  1995  ;108 :35 –42 .
Weinbroum  AA , Flaishon  R , Sorkine  P , Szold  O , Rudick  V . A risk-
benefit assessment of flumazenil in the management of benzodiazepine
overdose  . Drug Saf  1997  ;17 :181–96 .
Whitwam  JG . Flumazenil and midazolam in anaesthesia  . Acta
Anaesthesiol Scand Suppl  1995  ;108 :15 –22 .
Whitwam  JG , Amrein  R . Pharmacology of flumazenil  . Acta Anaesthesiol
Scand Suppl  1995  ;108 :3 –14.

Flunitrazepam
Brands
Generic?
No
 Class
 How the Drug W orksRohypnol
Short-term treatment of insomnia (severe, disabling)
Catatonia

Tests
Trazodone

How to Dose
 Dosing T ipsTo avoid problems with memory , only take flunitrazepam if
planning to have a full night ’s sleep
0.5–1 mg/day at bedtime
Tablet 0.5 mg, 1 mg, 2 mg, 4 mg
Initial 0.5 –1 mg/day at bedtime; maximum generally 2 mg/day at
bedtime

Overdose
Habit FormingUse lowest possible ef fective dose and assess need for continued
Flunitrazepam should generally not be prescribed in quantities
greater than a 1-month supply
treatment
Use doses over 1 mg only in exceptional circumstances
Patients who request or who require doses over 1 mg may be more
likely to have present or past substance abuse
Flunitrazepam is 10 times more potent than diazepam
Sedation, slurred speech, poor coordination, confusion, coma,
Use is not recommended to exceed 4 weeks

How to Stop
 Drug InteractionsHistory of drug addiction may increase risk of dependence
Currently classified as Schedule III by the W orld Health
Organization
Currently classified as a Schedule IV drug in the USA, but not
legally available in the USA
Elimination half-life 16 –35 hours
Half-life of active metabolite 23 –33 hours

Cisapride may hasten the absorption of flunitrazepam and thus cause
a temporary increase in the sedative ef fects of flunitrazepam
efficacy

ideation

Do Not Use
Hepatic ImpairmentUse only with extreme caution in patients with impaired respiratory
Flunitrazepam should be administered only at bedtime
If patient has severe chronic hypercapnia, myasthenia gravis, severe
respiratory insuf ficiency , sleep apnea, or severe hepatic
insuf ficiency
If there is a proven aller gy to flunitrazepam or any benzodiazepine
Dose should be lowered
Should not be used in patients with severe hepatic insuf ficiency , as it
may precipitate encephalopathy

Elderly
 PregnancyBenzodiazepines have been used to treat insomnia associated with
Initial starting dose 0.5 mg at bedtime; maximum generally 1
Paradoxical reactions with restlessness and agitation are more likely
to occur in the elderly
Not recommended for use in children or adolescents
to occur in children
Positive evidence of risk to human fetus; contraindicated for use in
pregnancy

 PearlsUnknown if flunitrazepam is secreted in human breast milk, but all
For severe, disabling insomnia unresponsive to other sedative
hypnotics
For those who need treatment for longer than a few weeks
For those with current or past substance abuse

✽ Psychiatric symptoms and “paradoxical ” reactions may be quite
severe with flunitrazepam and may be more frequent than with other
✽ “Paradoxical ” reactions include symptoms such as restlessness,
agitation, irritability , aggressiveness, delusions, rage, nightmares,
hallucinations, psychosis, inappropriate behavior , and other adverse
behavioral ef fects
✽ Has earned a reputation as a “date rape drug ” in which sexual
predators have allegedly slipped flunitrazepam into women ’s drinks to
induce sexual relations
✽ Flunitrazepam, especially in combination with alcohol, is claimed
to reduce the woman ’s judgment, inhibitions, or physical ability to
resist sexual advances, as well as to reduce or eliminate her recall of
the events
✽ Until 1999 was colorless, but a colorimetric compound is now
added that turns the drug blue when added to a liquid, making it
obvious that a drink was tampered withAlthough legally available in Europe, Mexico, South America, and

many other countries, it is not legally available in the USA
Although currently classified as a Schedule IV drug, the US Drug
Enforcement Administration is considering reclassifying it as
Schedule I
Illicit use since 1999 has fallen in part due to this additive

Simmons  MM , Cupp  MJ . Use and abuse of flunitrazepam  . Ann
Pharmacother  1998  ;32 (1 ):117–19 .Illicit use has also fallen in the USA due to the Drug-Induced Rape
Prevention and Punishment Act of 1996, making it punishable to
commit a violent crime using a controlled substance such as
flunitrazepam
Street names for flunitrazepam, based in part upon its trade name of
Rohypnol, manufacturer Roche, and the presence of RO-2 on the
surface of the tablets, include “roofies, ” “ruffies,” “roapies, ” “la
roacha, ” “roach-2, ” “Mexican valium, ” “rope, ” “roache vitamins, ”
and others

treatment

Woods  JH , Winger  G . Abuse liability of flunitrazepam  . J Clin
Psychopharmacol  1997  ;17 (3 Suppl 2): S1 –57.

Fluoxetine
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Prozac
Prozac weekly
Sarafem
RI)
Major depr essive disorder (ages 8 and older)
Obsessive-compulsive disorder (OCD) (ages 7 and older)

✽ Fluoxetine also has antagonist properties at 5HT2C receptors,
which could increase norepinephrine and dopamine neurotransmission
✽ Some patients may experience increased ener gy or activation early
after initiation of treatmentPremenstrual dysphoric disorder (PMDD)
Bulimia nervosa
Bipolar depr ession [in combination with olanzapine (Symbyax)]
Treatment-r esistant depr ession [in combination with olanzapine
(Symbyax)]
Desensitizes serotonin receptors, especially serotonin 1A receptors

If It W orks
If It Doesn ’t WorkIf it is not working within 6 –8 weeks, it may require a dosage
symptoms
For anxiety disorders and bulimia, treatment may also need to be
indefinite

ResistanceOther patients may be nonresponders, sometimes called treatment-
caution and at lower doses since fluoxetine could theoretically raise

✽ Fluoxetine has been specifically studied in combination with
olanzapine (olanzapine/fluoxetine combination) with excellent results
for bipolar depression, treatment-resistant unipolar depression, and
psychotic depression
Tests
How Drug Causes Side Effectsresistant anxiety disorders
tiagabine

✽ Fluoxetine ’s unique 5HT2C antagonist properties could contribute
to agitation, anxiety , and undesirable activation, especially early in
dosing
 Life-Thr eatening or Danger ous Side Effectsapathy in some patients
dry mouth)
Mostly CNS (insomnia but also sedation, agitation, tremors,
headache, dizziness)
SSRIs

Sedation
Possible weight loss, especially short-term
Wait
Wait
Wait
If fluoxetine is activating, take in the morning to help reduce
insomnia
Reduce dose to 10 mg, and either stay at this dose if tolerated and
effective, or consider increasing again to 20 mg or more if tolerated

Best Augmenting Agents for Side Effectsbut not ef fective at 10 mg

discontinuation of fluoxetine

How to Dose
 Dosing T ips20–80 mg for depression and anxiety disorders
60–80 mg for bulimia
Capsule 10 mg, 20 mg, 40 mg
Tablet 10 mg, 15 mg, 20 mg, 60 mg
Liquid 20 mg/5 mL –120 mL bottles
Weekly capsule 90 mg
Olanzapine/fluoxetine combination capsule (mg equivalent
olanzapine/mg equivalent fluoxetine) 3 mg/25 mg, 6 mg/25 mg, 6
mg/50 mg, 12 mg/25 mg, 12 mg/50 mg
Depression and OCD: initial dose 20 mg/day in morning, usually
wait a few weeks to assess drug ef fects before increasing dose;
maximum dose generally 80 mg/day
Bulimia: initial dose 60 mg/day in morning; some patients may need
to begin at lower dose and titrate over several days

✽ For some patients, weekly dosing with the weekly formulation may
enhance compliance
OverdoseThe long half-lives of fluoxetine and its active metabolites mean
that dose changes will not be fully reflected in plasma for several
weeks, lengthening titration to final dose and extending withdrawal
from treatment
Give once daily , often in the mornings, but at any time of day
tolerated
Often available in capsules, not tablets, so unable to break capsules
in half
Occasional patients are dosed above 80 mg
Liquid formulation easiest for doses below 10 mg when used for
cases that are very intolerant to fluoxetine or for very slow up-and
down-titration needs

How to Stop
 Drug InteractionsRarely lethal in monotherapy overdose; respiratory depression
especially with alcohol, ataxia, sedation, possible seizures
Safe
No
Taper rarely necessary since fluoxetine tapers itself after immediate
discontinuation, due to the long half-life of fluoxetine and its active
Active metabolite (norfluoxetine) has 2 week half-life
Parent drug has 2 –3 day half-life
Inhibits CYP450 3A4

switching from a TCA to fluoxetine
Do not start an MAOI for at least 5 weeks after discontinuing
fluoxetine
combined with sumatriptan, or possibly with other triptans,
requiring careful monitoring of patient
anticoagulants (e.g.,warfarin, NSAIDs)
Via CYP450 2D6 inhibition, could theoretically interfere with the
analgesic actions of codeine, and increase the plasma levels of some
beta blockers and of atomoxetine
Via CYP450 2D6 inhibition, fluoxetine could theoretically increase

May reduce the clearance of diazepam or trazodone, thus increasing
their levels

✽ Add or initiate other antidepressants with caution for up to 5 weeks
after discontinuing fluoxetineVia CYP450 3A4 inhibition, may increase the levels of alprazolam,
buspirone, and triazolam
Via CYP450 3A4 inhibition, fluoxetine could theoretically increase
concentrations of certain cholesterol-lowering HMG CoA reductase
inhibitors, especially simvastatin, atorvastatin, and lovastatin, but
not pravastatin or fluvastatin, which would increase the risk of
rhabdomyolysis; thus, coadministration of fluoxetine with certain
HMG CoA reductase inhibitors should proceed with caution
the concentrations of pimozide, and cause QT c prolongation and
dangerous cardiac arrhythmias
Use with caution in patients with history of seizure

companies

Do Not Use
Cardiac ImpairmentWhenever possible, warn patients and their caregivers about the
If patient is taking tamoxifen
If there is a proven aller gy to fluoxetine
No dose adjustment
Not removed by hemodialysis
Lower dose or give less frequently , perhaps by half

Elderly
 Childr en and AdolescentsPreliminary research suggests that fluoxetine is safe in these patients
patients
Approved for OCD and depression

patients
Adolescents often receive adult dose, but doses slightly lower for
children

PregnancyChildren taking fluoxetine may have slower growth; long-term
effects are unknown
Current patient registries of children whose mothers took fluoxetine
during pregnancy do not show adverse consequences

pregnancy

essants

The art of Psychopharmacology
Potential AdvantagesTrace amounts may be present in nursing children whose mothers
are on fluoxetine
the mother
feeding
Patients with atypical depression (hypersomnia, increased appetite)
Patients with fatigue and low ener gy
Patients with comorbid eating and af fective disorders
Generic is less expensive than brand name where available
Patients for whom weekly administration is desired

Children with OCD or depression

 Pearls
✽ May be a first-line choice for atypical depression (e.g.,
hypersomnia, hyperphagia, low ener gy, mood reactivity)
✽ Actions at 5HT2C receptors may explain its activating propertiesPatients with anorexia
Initiating treatment in anxious, agitated patients
Initiating treatment in severe insomnia
Anxiety (eventually , but can actually increase anxiety , especially
short-term)
Sleep disturbance, both insomnia and hypersomnia (eventually , but
may actually cause insomnia, especially short-term)
Consider avoiding in agitated insomniacs
Not as well tolerated as some other SSRIs for panic disorder and
other anxiety disorders, especially when dosing is initiated, unless
given with co-therapies such as benzodiazepines or trazodone
Long half-life; even longer -lasting active metabolite

✽ Actions at 5HT2C receptors may explain in part fluoxetine ’s
efficacy in combination with olanzapine for bipolar depression and
treatment-resistant depression, since both agents have this property
 Suggested ReadingFor sexual dysfunction, can augment with bupropion, sildenafil,
vardenafil, or tadalafil, or switch to a non-SSRI such as bupropion
or mirtazapine
Mood disorders can be associated with eating disorders (especially
in adolescent females) and be treated successfully with fluoxetine
fluoxetine plus estrogen augmentation than to fluoxetine alone
Nonresponse to fluoxetine in elderly may require consideration of
SSRIs may not cause as many patients to attain remission of

depression as some other classes of antidepressants (e.g., SNRIs)
A single pill containing both fluoxetine and olanzapine is available
for combination treatment of bipolar depression, psychotic
depression, and treatment-resistant unipolar depression

antidepressants: a meta-analysis of ef ficacy and tolerability  . J Affect Disor d
Beasley  CM Jr, Ball SG , Nilsson  ME , et al. Fluoxetine and adult
suicidality revisited: an updated meta-analysis using expanded data sources
from placebo-controlled trials  . J Clin Psychopharmacol  2007  ;27 (6 ):682
–6 .
March  JS , Silva  S , Petrycki  S , et al. The treatment for adolescents with
depression study (T ADS): long-term ef fectiveness and safety outcomes  .
Arch Gen Psychiatry  2007  ;64 (10 ):1132 –43.
Wagstaf f AJ , Goa KL . Once-weekly fluoxetine  . Drugs  2001  ;61 :2221  –8.

Flupenthixol
Brands
Generic?
No
 Class
(bold for FDA appr oved)Depixol
(D-RAn)
Conventional antipsychotic (neuroleptic, thioxanthene, dopamine 2
antagonist)
Depression (low dose)

If It W orksBlocks dopamine 2 receptors, reducing positive symptoms of
psychosis
With injection, psychotic symptoms can improve within a few days,
but it may take 1 –2 weeks for notable improvement
With oral formulation, psychotic symptoms can improve within 1
week, but it may take several weeks for full ef fect on behavior

disorder

Tests
weight gain, before starting treatment, weigh all patients and determineAfter reducing acute psychotic symptoms in mania, switch to a
clozapine

>30)

flupenthixol should be discontinued at the first sign of decline of

How Drug Causes Side EffectsPatients should be monitored periodically for the development of

✽ Insomnia, restlessness, agitation, sedation
✽ Tardive dyskinesia (risk increases with duration of treatment and
with dose)
✽ Risk of potentially irreversible involuntary dyskinetic movements
 Life-Thr eatening or Danger ous Side Effectsunknown
Hypomania
Rare eosinophilia

Sedation
What to Do About Side EffectsRare jaundice, leukopenia
Wait
Wait
Wait

Oral 3 –6 mg/day in divided doses
Intramuscular 40 –120 mg every 1 –4 weeks
Tablet 0.5 mg, 3 mg
Injection 20 mg/mL, 100 mg/mL

How to Dose
 Dosing T ipsOral: initial 1 mg 3 times a day; increase by 1 mg every 2 –3 days;
maximum generally 18 mg/day
Intramuscular: initial dose 20 mg for patients who have not been
exposed to long-acting depot antipsychotics, 40 mg for patients who
have previously demonstrated tolerance to long-acting depot
antipsychotics; after 4 –10 days can give additional 20 mg dose;
maximum 200 mg every 1 –4 weeks
The peak of action for the decanoate is usually 7 –10 days, and doses
generally have to be administered every 2 –3 weeks
May have more activating ef fects at low doses, which can
sometimes be useful as a second-line, short-term treatment of
Some evidence that flupenthixol may improve anxiety and
depression at low doses

Overdose
How to StopChildren and elderly should generally be dosed at the lower end of
Agitation, confusion, sedation, drug-induced parkinsonism,
respiratory collapse, circulatory collapse
No
a few weeks after flupenthixol is discontinued

 Other W arnings/Pr ecautionsOral: maximum plasma concentrations within 3 –8 hours
Intramuscular: rate-limiting half-life approximately 8 days with
single dose, approximately 17 days with multiple doses
May decrease the ef fects of levodopa, dopamine agonists
guanethidine, whose antihypertensive actions flupenthixol may
CNS ef fects may be increased if used with other CNS depressants
Combined use with epinephrine may lower blood pressure
Ritonavir may increase plasma levels of flupenthixol
May increase carbamazepine plasma levels
syndrome

Do Not UseIn epilepsy patients, dose 10 –20 mg every 15 days for intramuscular
Use with caution if at all in patients with Parkinson ’s disease, severe
arteriosclerosis, or Lewy body dementia
Possible antiemetic ef fect of flupenthixol may mask signs of other
asphyxia
therapy
If patient is taking a lar ge concomitant dose of a sedative hypnotic

therapy
If patient has CNS depression
If patient is comatose or if there is brain damage

Cardiac ImpairmentIf there is blood dyscrasia
If patient has pheochromocytoma
If patient has liver damage
If patient has a severe cardiovascular disorder
If patient has renal insuf ficiency
If patient has cerebrovascular insuf ficiency
If there is a proven aller gy to flupenthixol
Oral: recommended to take half or less of usual adult dose
Intramuscular: recommended dose schedule generally 10 –20 mg
every 15 days

Elderly
 PregnancyIntramuscular: recommended initial dose generally 5 mg;
recommended dose schedule generally 10 –20 mg every 15 days
antipsychotics are at increased risk of death compared to placebo,
Not recommended for use in children

hyporeflexia in infants whose mothers took a conventional

The Art Of Psychopharmacology
Primary T arget Symptomsantipsychotic during pregnancy
Children
Elderly

PearlsNegative symptoms of psychosis
Less sedation and orthostatic hypotension but more drug-induced
parkinsonism than some other conventional antipsychotics
another
antipsychotic such as flupenthixol or from switching to a
conventional antipsychotic such as flupenthixol
conventional antipsychotic such as flupenthixol with an atypical

Gerlach  J . Depot neuroleptics in relapse prevention: advantages and
disadvantages  . Int Clin Psychopharmacol  1995  ;(9 Suppl 5): S17 –20.
Quraishi  S , David  A . Depot flupenthixol decanoate for schizophrenia or
other similar psychotic disorders  . Cochrane Database Syst Rev  2000  ;
(2):CD001470  .
Soyka  M , De V ry J . Flupenthixol as a potential pharmacotreatment of
alcohol and cocaine abuse/dependence  . Eur Neur opsychopharmacol  2000
;10 (5 ):325–32 .In such cases, it may be beneficial to combine 1 depot antipsychotic

Fluphenazine
Brands
Generic?
Yes
 Class
 How the Drug W orksProlixin
Psychotic disorders
psychosis

If It W orks
If It Doesn ’t WorkPsychotic symptoms can improve within 1 week, but it may take
disorder

disorder

Tests
>30)Consider trying another conventional antipsychotic
clozapine

initiating or switching anitpsychotics
or dyslipidemia, or consider switching to a dif ferent antipsychoticcholesterol), and treat or refer such patients for treatment, including

fluphenazine should be discontinued at the first sign of decline of

✽ Neuroleptic-induced deficit syndromeAcute blockade of dopamine 2 receptors in the striatum can cause

unknown

✽ Priapism
✽ Tardive dyskinesia, tardive dystonia
 Life-Thr eatening or Danger ous Side EffectsDizziness, sedation
Decreased sweating, depression

Sedation
Wait
Wait
Wait
For sedation, take at night

Oral: 1 –20 mg/day maintenance
Intramuscular: generally 1/3 to 1/2 the oral dose
Decanoate for intramuscular or subcutaneous administration:12.5 –
100 mg/2 weeks maintenance (see Fluphenazine Decanoate section
after Pearls for dosing and use)

How to Dose
 Dosing T ips –OralTablet 1 mg, 2.5 mg scored, 5 mg scored, 10 mg scored
Decanoate for long-acting intramuscular or subcutaneous
administration 25 mg/mL
Injection for acute intramuscular administration 2.5 mg/mL
Elixir 2.5 mg/5 mL
Oral: initial 0.5 –10 mg/day in divided doses; maximum 40 mg/day
Intramuscular (short-acting): initial 1.25 mg; 2.5 –10 mg/day can be
given in divided doses every 6 –8 hours; maximum dose generally
10 mg/day
Patients receiving atypical antipsychotics may occasionally require a
“top-up ” of a conventional antipsychotic to control aggression or
violent behavior
Fluphenazine tablets 2.5 mg, 5 mg, and 10 mg contain tartrazine,
which can cause aller gic reactions, especially in patients sensitive to
aspirin
Oral solution should not be mixed with drinks containing caf feine,
tannic acid (tea), or pectinates (apple juice)

Overdose
Habit FormingRather than raise the dose above normal dosing in acutely agitated
Drug-induced parkinsonism, coma, hypotension, sedation, seizures,
No

How to Stop
 Drug InteractionsSlow down-titration of oral formulation (over 6 to 8 weeks),
a few weeks after fluphenazine is discontinued
Mean half-life of oral formulation approximately 15 hours
Mean half-life of intramuscular formulation approximately 6.8 –9.6
days
guanethidine, whose antihypertensive actions fluphenazine may
Additive anticholiner gic ef fects may occur if used with atropine or
related compounds

Other W arnings/Pr ecautionsSome patients taking a neuroleptic and lithium have developed an
syndrome
Antiemetic ef fect can mask signs of other disorders or overdose
dementia

dementia

Do Not Use
therapy
If patient is taking caber goline, per golide, or metrizamide
If there is a proven aller gy to fluphenazine
Decanoate and enanthate injectable formulations are contraindicated
in children under age 12
Use with caution; titration should be slower

Elderly
 PregnancyTitration should be slower; lower initial dose (1 –2.5 mg/day)
Safety and ef ficacy not established

The Art Of PsychopharmacologyThere is a risk of abnormal muscle movements and withdrawal
pregnancy
Fluphenazine should only be used during pregnancy if clearly
indicated
sedation)

 PearlsIntramuscular formulation for emer gency use
Relatively rapid onset of LAI (but see fluphenazine decanoate after
Pearls section)
Children
Elderly
Fluphenazine is a high-potency phenothiazine
Less risk of sedation and orthostatic hypotension but greater risk of
drug-induced parkinsonism than with low-potency phenothiazines
Not shown to be ef fective for behavioral problems in mental
retardation

Fluphenazine Decanoate
Vehicle Sesame Oilantipsychotics where antipsychotic responses of individual patients
another
antipsychotic such as fluphenazine or from switching to a
conventional antipsychotic such as fluphenazine
conventional antipsychotic such as fluphenazine with an atypical

Tmax 0.3–1.5 days
T1/2 with multiple dosing 14 days
Able to be loaded Yes
Time to reach steady state 4–6 weeks with loading
Dosing schedule (maintenance) 2 weeks
Injection site Intramuscular or subcutaneous
Needle gauge 21
Dosage forms 25 mg
Injection volume 25 mg/mL
How to Dose
Dosing T ips12.5–100 mg/2 weeks maintenance
Conversion from oral: can either supplement with oral formulation
at half-dose for at least 2 weeks OR use weekly loading injections of
1.6 times the oral daily dose (mg/day) for 4 –6 weeks

periodic plasma levels can be beneficial to prevent unnecessary

Advantages: early peak (see following graph) may be beneficial in
the management of acute patients
Disadvantages: early peak also carries risk of drug-induced
parkinsonism or akathisia in first 48 hours; 2-week injection
schedule; higher incidence of local site reactions (due to sesame oil
vehicle)

The Art Of Switching
 Switching from Oral Antipsychotics to Fluphenazine Decanoate
Response threshold is 0.81 ng/mL; plasma levels greater than 2 –3
ng/mL are generally not well tolerated, although treatment-resistant
cases might tolerate and respond to plasma levels up to 4 ng/mL,
which is the point of futility if no response and even if tolerated
Discontinuation of oral antipsychotic can begin immediately if
adequate loading is pursued; otherwise, supplement with oral
formulation at half-dose for at least 2 weeks

David  A , Adams  CE , Eisenbruch  M , Quraishi  S , Rathbone  J. Depot
fluphenazine decanoate and enanthate for schizophrenia  . Cochrane
Database Syst Rev  2005  ;25 (1 ):CD000307  .
Ereshefsky  L , Saklad  SR , Jann MW . Future of depot neuroleptic therapy:
pharmacokinetic and pharmacodynamic approaches  . J Clin Psychiatry
1984  ;45 (Suppl): 50 –9.
Matar  HE , Almerie  MQ. Oral fluphenazine versus placebo for
schizophrenia  . Cochrane Database Syst Rev  2007  ;24 (1 ):CD006352  .3–4-week down-titration is required for: asenapine, olanzapine,
For patients taking benzodiazepine or anticholiner gic medication,

this can be continued during cross-titration to help alleviate side
effects such as insomnia, agitation, and/or psychosis. Once the
patient is stable on LAI, these can be tapered one at a time as
appropriate.

Meyer  JM . Converting oral to long-acting injectable antipsychotics: a
guide for the perplexed  . CNS Spectr  2017  ;22 (S1): 14 –28 .
Milton  GV , Jann MW . Emer gency treatment of psychotic symptoms.
Pharmacokinetic considerations for antipsychotic drugs  . Clin
Pharmacokinet  1995  ;28 (6 ):494–504 .

Flurazepam
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Dalmane
nocturnal awakenings, and/or early morning awakening
Recurring insomnia or poor sleeping habits
Acute or chr onic medical situations r equiring r estful sleep
Catatonia

If It W orks
effects

Tests
Notable Side EffectsSwitch to another agent
Trazodone

Sedation

To avoid problems with memory , only take flurazepam if planning
15–30 mg/day at bedtime for 7 –10 days
Capsule 15 mg, 30 mg
15 mg/day at bedtime; may increase to 30 mg/day at bedtime if

✽ Because flurazepam tends to accumulate over time, perhaps not the
best hypnotic for chronic nightly use
Overdose
✽ Because of its relatively longer half-life, flurazepam may cause
some daytime sedation and/or impaired motor/cognitive function, and
may do so progressively over time
Flurazepam should generally not be prescribed in quantities greater
treatment
Flurazepam is a Schedule IV drug

How to Stop
 Drug InteractionsSome patients may develop dependence and/or tolerance; risk may
Elimination half-life approximately 24 –100 hours
Active metabolites
Cimetidine may decrease flurazepam clearance and thus raise
flurazepam levels

Other W arnings/Pr ecautionsFlurazepam and kava combined use may af fect clearance of either
drug
efficacy

ideation

Do Not Use
ElderlyUse only with extreme caution in patients with impaired respiratory
Flurazepam should be administered only at bedtime
If there is a proven aller gy to flurazepam or any benzodiazepine
Recommended dose: 15 mg/day

 Pregnancy
✽ Recommended either to discontinue drug or bottle feedSafety and ef ficacy have not been established
Long-term ef fects of flurazepam in children/adolescents are
unknown
monitored
Contraindicated for use in pregnancy
Unknown if flurazepam is secreted in human breast milk, but all

 Pearls
✽ Flurazepam has a longer half-life than some other sedative
hypnotics, so it may be less likely to cause rebound insomnia on
discontinuationEffects on infant have been observed and include feeding
Chronic nightly insomnia
Flurazepam may not be as ef fective on the first night as it is on
subsequent nights
Was once one of the most widely used hypnotics

✽ Long-term accumulation of flurazepam and its active metabolites
may cause insidious onset of confusion or falls, especially in the
elderly
Greenblatt  DJ . Pharmacology of benzodiazepine hypnotics  . J Clin
Psychiatry  1992  ;53 (Suppl): S7 –13.
Hilbert  JM , Battista  D . Quazepam and flurazepam: dif ferential
pharmacokinetic and pharmacodynamic characteristics  . J Clin Psychiatry
1991  ;52 (Suppl): S21 –6.
Johnson  LC , Chernik  DA , Sateia  MJ . Sleep, performance, and plasma
levels in chronic insomniacs during 14-day use of flurazepam and
midazolam: an introduction  . J Clin Psychopharmacol  1990  ;10 (4
Suppl): S5 –9.
Roth  T , Roehrs  TA . A review of the safety profiles of benzodiazepine
hypnotics  . J Clin Psychiatry  1991  ;52 (Suppl): S38 –41.Though not systematically studied, benzodiazepines have been used
treatment

Fluvoxamine
Brands
Generic?
Yes (not for fluvoxamine CR)
 Class
(bold for FDA appr oved)Luvox
Luvox CR
RI)
Obsessive-compulsive disorder (OCD)(fluvoxamine and
fluvoxamine CR)
Social anxiety disorder (fluvoxamine CR)

✽ Fluvoxamine also binds at sigma 1 receptors
✽ Some patients may experience relief of insomnia or anxiety early
after initiation of treatment
If It W orksDepression
symptoms

significantly reduced (e.g., OCD)

For the expert, consider cautious addition of clomipramine for

tiagabine

Tests
How Drug Causes Side EffectsIn Europe and Japan, augmentation is more commonly administered
for the treatment of depression and anxiety disorders, especially
with benzodiazepines and lithium
In the USA, augmentation is more commonly administered for the
treatment of OCD, especially with atypical antipsychotics,
buspirone, or even clomipramine; clomipramine should be added
with caution and at low doses as fluvoxamine can alter
clomipramine metabolism and raise its levels

✽ Fluvoxamine ’s sigma 1 agonist properties may contribute to
sedation and fatigue in some patients
 Life-Thr eatening or Danger ous Side Effectsenhanced over time
dry mouth)
SSRIs
Rare hyponatremia

Sedation
Best Augmenting Agents for Side Effectsantidepressants compared to placebo beyond age 24)
Patients may actually experience weight loss
Wait
Wait
Wait
If fluvoxamine is sedating, take at night to reduce drowsiness

Usual Dosage RangeTrazodone or a hypnotic for insomnia
discontinuation of fluvoxamine
100–300 mg/day for OCD
100–200 mg/day for depression

100–300 mg/day for social anxiety disorder

How to Dose
 Dosing T ipsTablet 25 mg, 50 mg scored, 100 mg scored
Controlled-release capsule 100 mg, 150 mg
For immediate-release, initial 50 mg/day; increase by 50 mg/day in
4–7 days; usually wait a few weeks to assess drug ef fects before
increasing dose further , but can increase by 50 mg/day every 4 –7
days until desired ef ficacy is reached; maximum 300 mg/day
For immediate-release, doses below 100 mg/day usually given as a
single dose at bedtime; doses above 100 mg/day can be divided into
two doses to enhance tolerability , with the lar ger dose administered
at night, but can also be given as a single dose at bedtime
For controlled-release, initial 100 mg/day; increase by 50 mg/day
each week until desired ef ficacy is reached; maximum generally 300
mg/day
50 mg and 100 mg tablets are scored, so to save costs, give 25 mg as
half of 50 mg tablet, and give 50 mg as half of 100 mg tablet
To improve tolerability of immediate-release formulation, dosing

can either be given once a day , usually all at night, or split either
symmetrically or asymmetrically , usually with more of the dose
given at night

Overdose
How to StopSome patients take more than 300 mg/day
Controlled-release capsules should not be chewed or crushed
Rare fatalities have been reported, both in combination with other
drugs and alone; sedation, dizziness, vomiting, diarrhea, irregular
heartbeat, seizures, coma, breathing dif ficulty
Safe
No
Taper to avoid withdrawal ef fects (dizziness, nausea, stomach
cramps, sweating, tingling, dysesthesias)

 Drug InteractionsIf withdrawal symptoms emer ge during discontinuation, raise dose
Parent drug has 9 –28 hour half-life
Inhibits CYP450 1A2
Inhibits CYP450 2C9/2C19
Can increase tricyclic antidepressant levels; use with caution with
TCAs
Can cause a fatal “serotonin syndrome ” when combined with MAO
inhibitors (MAOIs), so do not use with MAOIs or for at least 14
days after MAOIs are stopped
drugs) after discontinuing fluvoxamine
combined with sumatriptan or possibly with other triptans, requiring

Via CYP450 1A2 inhibition, fluvoxamine may reduce clearance of
theophylline and clozapine, thus raising their levels and requiring
their dosing to be lowered
Fluvoxamine administered with either caf feine or theophylline can
thus cause jitteriness, excessive stimulation, or rarely seizures, so
concomitant use should proceed cautiously
Metabolism of fluvoxamine may be enhanced in smokers and thus
its levels lowered, requiring higher dosing
Via CYP450 3A4 inhibition, fluvoxamine may reduce clearance of
carbamazepine and benzodiazepines such as alprazolam and
triazolam, and thus require dosage reduction
Via CYP450 3A4 inhibition, fluvoxamine could theoretically
increase concentrations of certain cholesterol-lowering HMG CoA
reductase inhibitors, especially simvastatin, atorvastatin, and

lovastatin, but not pravastatin or fluvastatin, which would increase
the risk of rhabdomyolysis; thus, coadministration of fluvoxamine
with certain HMG CoA reductase inhibitors should proceed with
caution
increase the concentrations of pimozide, and cause QT c
prolongation and dangerous cardiac arrhythmias

Do Not UseAdd or initiate other antidepressants with caution for up to 2 weeks
after discontinuing fluvoxamine
May cause photosensitivity
companies
If patient is taking thioridazine, pimozide, tizanidine, alosetron, or
ramelteon

Elderly
 Childr en and AdolescentsIf there is a proven aller gy to fluvoxamine
Consider lower initial dose
Lower dose or give less frequently , perhaps by half; use slower
titration
Preliminary research suggests that fluvoxamine is safe in these
patients
May require lower initial dose and slower titration

PregnancyImmediate-release approved for ages 8 –17 for OCD
8–17: initial 25 mg/day at bedtime; increase by 25 mg/day every 4 –
7 days; maximum 200 mg/day; doses above 50 mg/day should be
divided into 2 doses with the lar ger dose administered at bedtime
Preliminary evidence suggests ef ficacy for other anxiety disorders
and depression in children and adolescents
patients

patients

pregnancy

essants
are on fluvoxamine
the mother

the mother
feeding

 Pearls
✽ Often a preferred treatment of anxious depression as well as major
depressive disorder comorbid with anxiety disordersPatients with mixed anxiety/depression
Patients with irritable bowel or multiple gastrointestinal complaints
Can require dose titration and twice daily dosing
Anxiety
Some withdrawal ef fects, especially gastrointestinal ef fects
May have lower incidence of sexual dysfunction than other SSRIs
Preliminary research suggests that fluvoxamine is ef ficacious in
obsessive-compulsive symptoms in schizophrenia when combined
with antipsychotics

✽ Actions at sigma 1 receptors may explain in part fluvoxamine ’s
sometimes rapid onset ef fects in anxiety disorders and insomnia
✽ Actions at sigma 1 receptors may explain potential advantages of
fluvoxamine for psychotic depression and delusional depression
✽ For treatment-resistant OCD, consider cautious combination of
fluvoxamine and clomipramine by an expertNot FDA approved for depression, but used widely for depression in
many countries
CR formulation may be better tolerated than immediate-release
formulation, particularly with less sedation
desmethyl-clomipramine (de-CMI), a potent noradrener gic reuptake
blocker

blocker
Addition of a CYP450 1A2 inhibitor , fluvoxamine, blocks this
conversion and results in higher CMI levels than de-CMI levels

Cheer  SM , Figgitt  DP . Spotlight on fluvoxamine in anxiety disorders in
children and adolescents  . CNS Drugs  2002  ;16 :139–44 .
Edwards  JG , Anderson  I . Systematic review and guide to selection of
selective serotonin reuptake inhibitors  . Drugs  1999  ;57 :507–33 .
Figgitt  DP , McClellan  KJ . Fluvoxamine. An updated review of its use in
the management of adults with anxiety disorders  . Drugs  2000  ;60 :925–54 .
Omori  M , Watanabe  N , Nakagawa  A , et al. Fluvoxamine versus other
anti-depressive agents for depression  . Cochrane Database Syst Rev  2010
;17 (3 ):CD0061 14 .
Pigott  TA , Seay  SM . A review of the ef ficacy of selective serotonin
reuptake inhibitors in obsessive-compulsive disorder  . J Clin Psychiatry
1999  ;60 :101–6 .Thus, addition of the SSRI fluvoxamine to CMI in treatment-
resistant OCD can powerfully enhance serotoner gic activity , not
only due to the inherent serotoner gic activity of fluvoxamine, but

also due to a favorable pharmacokinetic interaction inhibiting
CYP450 1A2 and thus converting CMI ’s metabolism to a more
powerful serotoner gic portfolio of parent drug

Gabapentin
Brands
Generic?
Yes (not for extended-release)
 Class
(bold for FDA appr oved)Neurontin
Horizant
calcium channel blocker (Glu-CB)
Anticonvulsant, antineuralgic for chronic pain, alpha 2 delta ligand
at voltage-sensitive calcium channels
Partial seizur es with or without secondary generalization
(adjunctive)
Postherpetic neuralgia

✽ Binds to the alpha 2 delta subunit of voltage-sensitive calcium
channels
How Long Until It W orksRestless leg syndr ome (extended-r elease)
Anxiety (adjunctive)
Bipolar disorder (adjunctive)
Gabapentin is a leucine analog and is transported both into the blood
from the gut and also across the blood –brain barrier into the brain
from the blood by the system L transport system
This closes N and P/Q presynaptic calcium channels, diminishing
excessive neuronal activity and neurotransmitter release
Although structurally related to gamma-aminobutyric acid (GABA),
no known direct actions on GABA or its receptors
Should also reduce pain in postherpetic neuralgia by 2 weeks; some
patients respond earlier
May reduce pain in other neuropathic pain syndromes within a few
weeks

If It W orks
If It Doesn ’t Work (for Neur opathic Pain or Bipolar Disorder)If it is not reducing pain within 6 –8 weeks, it may require a dosage
May reduce anxiety in a variety of disorders within a few weeks
Not yet clear if it has mood-stabilizing ef fects in bipolar disorder or
antineuralgic actions in chronic neuropathic pain, but some patients
may respond and if so, would be expected to show clinical ef fects
starting by 2 weeks although it may take several weeks to months to
optimize
The goal of treatment is complete remission of symptoms (e.g.,
seizures)
not eliminate symptoms and is not a cure since symptoms usually
recur after medicine stopped

✽ May only be ef fective in a subset of bipolar patients, in some
patients who fail to respond to other mood stabilizers, or it may not
work at all
✽ Gabapentin is itself an augmenting agent to numerous other
anticonvulsants in treating epilepsy; and to lithium, atypical
antipsychotics, and other anticonvulsants in the treatment of bipolar
disorderMany patients have only a partial response where some symptoms
stabilization of pain or mood
Consider the presence of noncompliance and counsel patient
Switch to another agent with fewer side ef fects

For postherpetic neuralgia, gabapentin can decrease concomitant
opiate use

✽ For neuropathic pain, gabapentin can augment TCAs and SNRIs as
well as tiagabine, other anticonvulsants and even opiates if done by
experts while carefully monitoring in dif ficult cases
Tests
✽ Sedation (dose-dependent), dizziness
✽ Ataxia (dose-dependent), fatigue, nystagmus, tremorFor anxiety , gabapentin is a second-line treatment to augment
SSRIs, SNRIs, or benzodiazepines
False-positive readings with the Ames N-Multistix SG® dipstick test
for urinary protein have been reported when gabapentin was
administered with other anticonvulsants
CNS side ef fects may be due to excessive blockade of voltage-
sensitive calcium channels
Peripheral edema

Sedation
What to Do About Side EffectsVomiting, dyspepsia, diarrhea, dry mouth, constipation, weight gain
Additional ef fects in children under age 12: hostility , emotional
lability , hyperkinesia, thought disorder , weight gain
Anaphylaxis and angioedema
Sudden unexplained deaths have occurred in epilepsy (unknown if
related to gabapentin use)
Dose-related; can be problematic at high doses
Can wear of f with time, but may not wear of f at high doses
Wait
Wait

Take more of the dose at night to reduce daytime sedation
900–1800 mg/day in 3 divided doses (immediate-release)
Capsule 100 mg, 300 mg, 400 mg
Tablet 100 mg, 300 mg, 400 mg, 600 mg, 800 mg
Tablet extended-release 300 mg, 600 mg
Liquid 250 mg/5 mL –470 mL bottle
Postherpetic neuralgia (immediate-release): 300 mg on day 1; on
day 2 increase to 600 mg in 2 doses; on day 3 increase to 900 mg in
3 doses; maximum dose generally 1800 mg/day in 3 doses

Dosing T ipsPostherpetic neuralgia (extended-release): 600 mg in the morning on
day 1; on day 4 increase to 600 mg twice daily
Restless leg syndrome (extended-release): 600 mg once daily at
about 5 pm
Seizures (ages 12 and older): initial 900 mg/day in 3 doses;
recommended dose generally 1800 mg/day in 3 doses; maximum
dose generally 3600 mg/day; time between any 2 doses should
usually not exceed 12 hours
Gabapentin should not be taken until 2 hours after administration of
an antacid
If gabapentin is added to a second anticonvulsant, the titration
period should be at least a week to improve tolerance to sedation
Some patients need to take immediate-release gabapentin only twice
daily in order to experience adequate symptomatic relief for pain or
anxiety
At the high end of the dosing range, tolerability may be enhanced by
splitting immediate-release dose into more than 3 divided doses

anxiety
Half-tablets not used within several days of breaking the scored
tablet should be discarded
Do not break or chew extended-release tablets, as this could alter
controlled-release properties

Overdose
How to Stop
disorderExtended-release tablets should be taken with food
For intolerable sedation, can give most of the dose at night and less
during the day
To improve slow-wave sleep, may need to take gabapentin only at
bedtime
No fatalities; slurred speech, sedation, double vision, diarrhea
Safe
No
Taper over a minimum of 1 week

 Other W arnings/Pr ecautionsGabapentin is not metabolized but excreted intact renally
Not protein bound
Elimination half-life approximately 5 –7 hours
Antacids may reduce  the bioavailability of gabapentin, so
gabapentin should be administered approximately 2 hours before
antacid medication
Naproxen may increase  absorption of gabapentin
Morphine and hydrocodone may increase  plasma AUC (area under
the curve) values of gabapentin and thus gabapentin plasma levels
over time
Depressive ef fects, including respiratory depression, may be
increased by other CNS depressants (opioids, benzodiazepines,
alcohol, MAOIs, other anticonvulsants, etc.)
Use lowest possible dose of gabapentin and monitor for symptoms
of respiratory depression if patient is taking concomitant CNS
depressant, has underlying respiratory disease, or is elderly
Dizziness and sedation could increase the chances of accidental
injury (falls) in the elderly

Do Not Use
Renal ImpairmentPancreatic acinar adenocarcinomas have developed in male rats that
were given gabapentin, but clinical significance is unknown
Development of new tumors or worsening of tumors has occurred in
humans taking gabapentin; it is unknown whether gabapentin
affected the development or worsening of tumors
If there is a proven aller gy to gabapentin or pregabalin
Gabapentin is renally excreted, so the dose may need to be lowered
Immediate-Release
Creatinine Clearance
(mL/min)Dosing
30–59 400–1400 mg/day in 2 doses
16–29 200–700 mg/day in 1 dose
<16 100–300 mg/day in 1 dose

<16 on hemodialysis May need supplemental doses
following dialysis
Extended-Release for Restless Leg Syndr ome
30–59 Initial 300 mg/day; increase to
600 mg/day if needed
15–29 300 mg/day
<15 300 mg every other day
<15 on hemodialysis Not recommended
30–59 Initial 300 mg in the morning;
on day 4 increase to 300 mg
twice daily; increase to 600 mg
twice daily if needed

Cardiac ImpairmentExtended-Release for Restless Leg Syndr ome
15–29 Initial 300 mg in the morning
on days 1 and 3; on day 4
increase to 300 mg in the
morning; increase to 300 mg
<15 300 mg every other day in the
morning; increase to 300
mg/day in the morning if
needed
<15 on hemodialysis 300 mg following dialysis;
increase to 600 mg following
dialysis if needed
Can be removed by hemodialysis; patients receiving hemodialysis
may require supplemental doses of gabapentin
Use in renal impairment has not been studied in children under age
12
No available data but not metabolized by the liver and clinical
experience suggests normal dosing

Elderly
 PregnancyNo specific recommendations
Elderly patients may be more susceptible to adverse ef fects,
including peripheral edema and ataxia
Approved for use starting at age 3 as adjunct treatment for partial
seizures
Ages 5 –12: initial 10 –15 mg/kg per day in 3 doses; titrate over 3
days to 25 –35 mg/kg per day given in 3 doses; maximum dose
generally 50 mg/kg per day; time between any 2 doses should
Ages 3 –4: initial 10 –15 mg/kg per day in 3 doses; titrate over 3 days
to 40 mg/kg per day; maximum dose generally 50 mg/kg per day;
time between any 2 doses should usually not exceed 12 hours

✽ Lack of convincing ef ficacy for treatment of bipolar disorder or
psychosis suggests risk/benefit ratio is in favor of discontinuing
gabapentin during pregnancy for these indications
✽ For bipolar patients, given the risk of relapse in the postpartum
period, mood-stabilizer treatment, especially with agents with better
evidence of ef ficacy than gabapentin, should generally be restarted
immediately after delivery if patient is unmedicated during pregnancy
✽ Atypical antipsychotics may be preferable to gabapentin if
treatment of bipolar disorder is required during pregnancyor final rule) applies only to prescription drugs and will be phased in
In animal studies, gabapentin was developmentally toxic (increased
fetal skeletal and visceral abnormalities, and increased embryofetal
mortality) when administered to pregnant animals at doses similar to

or lower than those used clinically
Antiepileptic Drug Pregnancy Registry: 1-888-233-2334,

✽ Relapse rates may be lower in women who receive prophylactic
Potential AdvantagesBipolar symptoms may recur or worsen during pregnancy and some
for possible adverse ef fects
If infant becomes irritable or sedated, breast feeding or drug may
be safer and more ef fective than gabapentin during the postpartum
period when treating a nursing mother with bipolar disorder
Chronic neuropathic pain

 Pearls
✽ Most use is of f label
✽ Off-label use for first-line treatment of neuropathic pain may be
justified
✽ Off-label use for second-line treatment of anxiety may be justifiedHas relatively mild side ef fect profile
Has few pharmacokinetic drug interactions
Usually requires 3 times a day dosing
Poor documentation of ef ficacy for many of f-label uses, especially
Seizures
Pain
Anxiety
Gabapentin is generally well tolerated, with only mild adverse
effects
Well studied and approved in epilepsy and postherpetic neuralgia

✽ Off-label use as an adjunct for bipolar disorder may not be justified
✽ Misperceptions about gabapentin ’s efficacy in bipolar disorder have
led to its use in more patients than other agents with proven ef ficacy ,
such as lamotrigine
✽ Off-label use as an adjunct for schizophrenia may not be justified
✽ One of the few agents that enhances slow-wave delta sleep, which
may be helpful in chronic neuropathic pain syndromes
✽ May be a useful adjunct for fibromyalgia
MacDonald  KJ , Young  LT . Newer antiepileptic drugs in bipolar disorder  .
CNS Drugs  2002  ;16 :549–62 .
Marson  AG , Kadir  ZA , Hutton  JL , Chadwick  DW . Gabapentin for drug-
resistant partial epilepsy  . Cochrane Database Syst Rev  2000  ;
(2):CD001415  .
Moore  RA , Wiffen PJ , Derry  S , McQuay  HJ. Gabapentin for chronic
neuropathic pain and fibromyalgia in adults  . Cochrane Database Syst Rev
2011 ;16 (3 ):CD007938  .May be useful for some patients in alcohol withdrawal

Drug absorption and clinical ef ficacy may not necessarily be
proportionately increased at high doses, and thus response to high
doses may not be consistent

Stahl  SM . Anticonvulsants and the relief of chronic pain: pregabalin and
gabapentin as alpha(2)delta ligands at voltage-gated calcium channels  . J
Clin Psychiatry  2004  ;65 :596 –7 .
Stahl  SM . Anticonvulsants as anxiolytics, part 2: pregabalin and
Clin Psychiatry  2004  ;65 :460 –1 .

Galantamine
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Razadyne
Razadyne ER
Neuroscience-based Nomenclature: acetylcholine multimodal;
enzyme inhibitor; receptor P AM (ACh-MM)
Cholinesterase inhibitor (acetylcholinesterase inhibitor); also an
allosteric nicotinic choliner gic modulator; cognitive enhancer
Memory disturbances in other dementias
Memory disturbances in other conditions

✽ Reversibly and competitively inhibits centrally active
✽ Modulates nicotinic receptors, which enhances actions of
acetylcholine
If It W orksMild cognitive impairment
Increased availability of acetylcholine compensates in part for
Nicotinic modulation may also enhance the actions of other
neurotransmitters by increasing the release of dopamine,
norepinephrine, serotonin, GABA, and glutamate
evident

interest
Tests
How Drug Causes Side EffectsConsider adjusting dose, switching to a dif ferent cholinesterase
inhibitor or adding an appropriate augmenting agent
Divalproex, carbamazepine, or oxcarbazepine for behavioral

secretion, weight loss
Sedation
What to Do About Side EffectsCentral inhibition of acetylcholinesterase may contribute to nausea,
Headache, dizziness
Fatigue, depression
Wait

Wait
Consider lowering dose, switching to a dif ferent agent, or adding an
16–24 mg/day
Tablet 4 mg, 8 mg, 12 mg
Extended-release capsule 8 mg, 16 mg, 24 mg
Liquid 4 mg/mL –100 mL bottle
Immediate-release: initial 4 mg twice daily; after 4 weeks may
increase dose to 8 mg twice daily; after 4 more weeks may increase
to 12 mg twice daily

Overdose
Long-T erm UseExtended-release: same titration schedule as immediate-release but
dosed once a day in the morning, preferably with food
Gastrointestinal side ef fects may be reduced if drug is administered
with food
Gastrointestinal side ef fects may also be reduced if dose is titrated
slowly
dosing range
Drug may lose ef fectiveness in slowing degenerative course of

How to Stop
Terminal elimination half-life approximately 7 hours
Metabolized by CYP450 2D6 and 3A4
Galantamine may increase the ef fects of anesthetics and should be
Inhibitors of CYP450 2D6 and CYP450 3A4 may inhibit
galantamine metabolism and raise galantamine plasma levels
Galantamine may interact with anticholiner gic agents and the
Cimetidine may increase bioavailability of galantamine

Do Not Use
Hepatic ImpairmentBradycardia may occur if combined with beta blockers
disease
If there is a proven aller gy to galantamine
Not recommended for use in patients with severe renal impairment

Elderly
 PregnancyReduction of clearance may increase with the degree of hepatic
Not recommended for use in patients with severe hepatic
Syncopal episodes have been reported with the use of galantamine
Clearance is reduced in elderly patients

✽ Not recommended for use in pregnant women or in women of
Potential Disadvantagesor final rule) applies only to prescription drugs and will be phased in
Animal studies do not show adverse ef fects
Unknown if galantamine is secreted in human breast milk, but all
Galantamine is not recommended for use in nursing women
Alzheimer disease with cerebrovascular disease
Theoretically , nicotinic modulation may provide added therapeutic
benefits for memory and behavior in some Alzheimer patients
Theoretically , nicotinic modulation may also provide ef ficacy for
cognitive disorders other than Alzheimer disease

 Pearls
that lasts 7 –10 years
disinhibition, delusions, anxiety , cooperation, pacing)Patients who have dif ficulty taking a medication twice daily
weeks

weeks

Alzheimer disease and a cholinesterase inhibitor like galantamine
may be helpful
Patients do not generally improve dramatically although this
be delayed

be delayed
preserved

✽ Galantamine is a natural product present in daf fodils and snowdrops
✽ Novel dual action uniquely combines acetylcholinesterase
inhibition with allosteric nicotine modulation
✽ Novel dual action should theoretically enhance choliner gic actions
but incremental clinical benefits have been dif ficult to demonstrateDelay in progression in Alzheimer disease is not evidence of
Cholinesterase inhibitors like galantamine depend upon the presence
The most prominent side ef fects of galantamine are gastrointestinal

Use with caution in underweight or frail patients
New extended-release formulation allows for once daily dosing

✽ Actions at nicotinic receptors enhance not only the release of
acetylcholine but also that of other neurotransmitters, which may boost
attention and improve behaviors caused by deficiencies in those
neurotransmitters in Alzheimer disease
✽ Galantamine may slow the progression of mild cognitive
impairment to Alzheimer disease
focal signs, imbalance, and urinary incontinence)Some Alzheimer patients who fail to respond to another
cholinesterase inhibitor may respond when switched to galantamine

Some Alzheimer patients who fail to respond to galantamine may
May be helpful for dementia in Down ’s syndrome

Coyle  J , Kershaw  P . Galantamine, a cholinesterase inhibitor that
allosterically modulates nicotinic receptors: ef fects on the course of
Alzheimer ’s disease  . Biol Psychiatry  2001  ;49 :289–99 .
Olin J , Schneider  L . Galantamine for Alzheimer ’s disease  . Cochrane
Database Syst Rev  2002  ;(3):CD001747  .Suggestions of utility in some cases of treatment-resistant bipolar
disorder

Stahl  SM . Cholinesterase inhibitors for Alzheimer ’s disease  . Hosp Pract
(Off Ed)  1998  ;33 :131 –6 .
Stahl  SM . The new cholinesterase inhibitors for Alzheimer ’s disease, part 1
. J Clin Psychiatry  2000  ;61 :710–11 .
Stahl  SM . The new cholinesterase inhibitors for Alzheimer ’s disease, part 2
. J Clin Psychiatry  2000  ;61 :813–14 .

Guanfacine
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Intuniv
Tenex
(N-RA)
Centrally acting alpha 2A agonist; antihypertensive; nonstimulant
for ADHD
Attention deficit hyperactivity disorder (ADHD) in childr en
ages 6 –17 (Intuniv , adjunct and monotherapy)

How Long Until It W orksOppositional defiant disorder
Pervasive developmental disorders
Motor tics
For ADHD, theoretically has central actions on postsynaptic alpha
2A receptors in the prefrontal cortex
Guanfacine is 15 –20 times more selective for alpha 2A receptors
than for alpha 2B or alpha 2C receptors
The prefrontal cortex is thought to be responsible for modulation of
working memory , attention, impulse, control, and planning
For hypertension, stimulates alpha 2A adrener gic receptors in the
For ADHD, can take a few weeks to see maximum therapeutic
benefits

If It W orks
If It Doesn ’t WorkMay take several weeks to control blood pressure adequately
Some studies of up to 2 years
parents
etc.)

Tests
Notable Side EffectsBest to attempt another monotherapy prior to augmenting for
ADHD
Possibly combination with stimulants (with caution)
Chlorthalidone, thyazide-type diuretics, and furosemide for
Excessive actions on alpha 2A receptors, nonselective actions on
alpha 2B and alpha 2C receptors
Dry mouth, constipation, abdominal pain
Fatigue, weakness

 Sedation
Best Augmenting Agents for Side EffectsHypotension
Sinus bradycardia, hypotension (dose-related)
May be less sedation with extended-release formulation
Wait
agent

How to Dose
 Dosing T ipsImmediate-release: 1 –2 mg/day
Extended-release: 1 –4 mg/day
Immediate-release tablet 1 mg, 2 mg, 3 mg
Extended-release: 1 mg, 2 mg, 3 mg, 4 mg
Immediate-release: initial 1 mg/day at bedtime; after 3 –4 weeks can
increase to 2 mg/day
Extended-release: initial 1 mg/day; can increase by 1 mg/week;
maximum dose 4 mg/day
Doses greater than 2 mg/day are associated with increased side
effects
If guanfacine is terminated abruptly , rebound hypertension may
occur within 2 –4 days
For hypertension, dose can be raised to 2 mg/day if 1 mg/day is
ineffective, but 2 mg may have no more ef ficacy than 1 mg

Overdose
How to Stop
PharmacokineticsFor extended-release formulation, do not administer with high-fat
meals because this increases exposure
Extended-release tablets should not be crushed, chewed, or broken
Extended-release and immediate-release tablets have dif ferent
pharmacokinetic properties, so do not substitute on a mg-per -mg
basis
Consider dosing extended-release on a mg/kg basis (0.05 mg/kg to
0.12 mg/kg)
Drowsiness, lethar gy, bradycardia, hypotension
Shown to be safe and ef fective for treatment of hypertension
Studies of up to 2 years in ADHD
No
Taper to avoid rebound ef fects (nervousness, increased blood
pressure)

 Other W arnings/Pr ecautionsPharmacokinetic properties dif fer for immediate- and extended-
release fomulations
CYP450 3A inhibitors, such as nefazodone, fluoxetine,
fluvoxamine, and ketoconazole, may decrease clearance of
guanfacine and raise guanfacine levels significantly
CYP450 3A inducers may increase clearance of guanfacine and
lower guanfacine levels significantly
Do not administer extended-release with high-fat meals, because
this increases exposure
Combined use with valproate may increase plasma concentrations of
valproate
Phenobarbital and phenytoin may reduce plasma concentrations of
guanfacine
Excessive heat (e.g., saunas) may exacerbate some of the side
effects, such as dizziness and drowsiness
Titrate slowly and monitor vital signs frequently in patients at risk
for hypotension, heart block, bradycardia, syncope, cardiovascular

Do Not Use
Elderlydisease, vascular disease, cerebrovascular disease, or chronic renal
failure
If there is a proven aller gy to guanfacine
Patients should receive lower doses
Use with caution in patients at risk for hypotension, bradycardia,
heart block, or syncope
Elimination half-life may be longer in elderly patients

 Pregnancy
The Art Of PsychopharmacologySafety and ef ficacy not established in children under age 6
Some reports of mania and aggressive behavior in ADHD patients
taking guanfacine
Unknown if guanfacine is secreted in human breast milk, but all

 PearlsNo known abuse potential; not a controlled substance
Not a stimulant
For oppositional behavior associated with ADHD
Less sedation than clonidine
Oppositional and impulsive behavior
The extended-release formulation often is much more tolerable than
the immediate-release formulation, especially for patients sensitive
to peak dose sedation of the immediate-release formulation
Guanfacine has been shown to be ef fective in both children and
adults, and guanfacine extended-release is approved for ADHD in
children ages 6 –17

Arnsten  AF , Scahill  L , Findling  RL . alpha2-Adrener gic receptor agonists
for the treatment of attention-deficit/hyperactivity disorder: emer ging
concepts from new data  . J Child Adolesc Psychopharmacol  2007  ;17 (4
):393 –406 .
Biederman  J , Melmed  RD , Patel  A , et al. Long-term, open-label extension
study of guanfacine extended-release in children and adolescents with
ADHD  . CNS Spectr  2008  ;13 (12 ):1047  –55.
Posey  DJ , McDougal  CJ . Guanfacine and guanfacine extended-release:
treatment for ADHD and related disorders  . CNS Drug Rev  2007  ;13 (4
):465–74 .Guanfacine can also be used to treat tic disorders, including
Although both guanfacine and clonidine are alpha 2 adrener gic
agonists, guanfacine is relatively selective for alpha 2A receptors,
whereas clonidine binds not only alpha 2A, 2B, and 2C receptors
but also imidazoline receptors, causing more sedation, hypotension,
and side ef fects than guanfacine

May be used as monotherapy or in combination with stimulants for
the treatment of oppositional behavior in children with or without
ADHD

Sallee  FR , Lyne A , Wigal T , McGough  J . Long-term safety and ef ficacy
of guanfacine extended-release in children and adolescents with attention-
deficit/hyperactivity disorder  . J Child Adolesc Psychopharmacol  2009  ;19
(3 ):215–26 .
Sallee  FR , McGough  J , Wigal T , et al. Guanfacine extended-release in
children and adolescents with attention-deficit/hyperactivity disorder: a
placebo-controlled trial  . J Am Acad Child Adolesc Psychiatry  2009  ;48 (2
):155–65 .
Spencer  TJ , Greenbaum  M , Ginsber g LD , Murphy  WR . Safety and
effectiveness of coadministration of guanfacine extended-release and
psychostimulants in children and adolescents with attention-
(5 ):501–10 .

Haloperidol
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Haldol
(D-RAn)
Conventional antipsychotic (neuroleptic, butyrophenone, dopamine
2 antagonist)
Manifestations of psychotic disorders (oral, immediate-r elease
injection)
Tics and vocal utterances in T ourette’s syndr ome (oral,
immediate-r elease injection)

If It W orksSecond-line tr eatment of sever e behavior pr oblems in childr en
of combative, explosive hyper excitability (oral)
Second-line short-term tr eatment of hyperactive childr en (oral)
Treatment of schizophr enic patients who r equir e prolonged
parenteral antipsychotic therapy (depot intramuscular
decanoate)
Delirium (with lorazepam)
psychosis and possibly combative, explosive, and hyperactive
behaviors
Blocks dopamine 2 receptors in the nigrostriatal pathway , improving
tics and other symptoms in T ourette ’s syndrome

ResistanceMost schizophrenic patients do not have a total remission of
disorder
clozapine

Tests
>30)
months in patients at high risk for metabolic complications and whenAugmentation of conventional antipsychotics has not been

haloperidol should be discontinued at the first sign of decline of

✽ Galactorrhea, amenorrheaBy blocking dopamine 2 receptors in the pituitary , it can cause
unknown
Dizziness, sedation

 Sedation
What to Do About Side EffectsHypotension, tachycardia, hypertension
Rare jaundice, agranulocytosis, leukopenia
Sedation is usually transient
Wait
Wait

How to Dose
 Dosing T ips –Oral1–40 mg/day orally
Immediate-release injection 2 –5 mg each dose
Decanoate injection 10 –20 times the previous daily dose of oral
antipsychotic (see Haloperidol Decanoate section after Pearls for
dosing and use)
Tablet 0.5 mg scored, 1 mg scored, 2 mg scored, 5 mg scored, 10
mg scored, 20 mg scored
Concentrate 2 mg/mL
Injection 5 mg/mL (immediate-release)
Decanoate injection 50 mg/mL, 100 mg/mL
Oral: initial 1 –15 mg/day; can give once daily or in divided doses at
the beginning of treatment during rapid dose escalation; increase as
needed; can be dosed up to 100 mg/day; safety not established for
doses over 100 mg/day
Immediate-release injection: initial dose 2 –5 mg; subsequent doses
may be given as often as every hour; patient should be switched to
oral administration as soon as possible
Haloperidol is frequently dosed too high

OverdoseSome studies suggest that patients who respond well to low doses of
haloperidol (e.g., approximately 2 mg/day) may have ef ficacy
similar to atypical antipsychotics for both positive and negative
symptoms of schizophrenia
Higher doses may actually induce or worsen negative symptoms of
Low doses, however , may not have beneficial actions for treatment-
resistant cases or violence

How to Stop
PharmacokineticsFatalities have been reported; drug-induced parkinsonism,
hypotension, sedation, respiratory depression, shock-like state
Often used for long-term maintenance
No
a few weeks after haloperidol is discontinued
Decanoate half-life approximately 3 weeks
Oral half-life approximately 12 –38 hours

 Other W arnings/Pr ecautionsMay decrease the ef fects of levodopa, dopamine agonists
guanethidine, whose antihypertensive actions haloperidol may
Additive ef fects may occur if used with CNS depressants; dose of
other agent should be reduced
haloperidol to lower blood pressure
Haloperidol and anticholiner gic agents together may increase
intraocular pressure
Plasma levels of haloperidol may be lowered by rifampin
Some patients taking haloperidol and lithium have developed an
syndrome
May enhance ef fects of antihypertensive drugs
Use with caution in patients with respiratory disorders

Do Not UseIf haloperidol is used to treat mania, patients may experience a rapid
switch to depression
Patients with thyrotoxicosis may experience neurotoxicity
Use only with caution if at all in Parkison ’s disease or Lewy body
dementia
Higher doses and IV administration may be associated with
increased risk of QT prolongation and torsade de pointes; use
particular caution if patient has a QT -prolonging condition,
underlying cardiac abnormalities, hypothyroidism, familial long-QT
syndrome, or is taking a drug known to prolong QT interval
therapy

therapy
If patient has Parkinson ’s disease
If there is a proven aller gy to haloperidol

ElderlyUse with caution
Use with caution because of risk of orthostatic hypertension
Possible increased risk of QT prolongation or torsade de pointes at
higher doses or with IV administration
Elderly patients may be more susceptible to respiratory side ef fects
and hypotension

 PregnancySafety and ef ficacy have not been established; not intended for use
under age 3
Oral: initial 0.5 mg/day; tar get dose 0.05 –0.15 mg/kg per day for
psychotic disorders; 0.05 –0.075 mg/kg per day for nonpsychotic
disorders

antipsychotic during pregnancy

Potential AdvantagesReports of limb deformity in infants whose mothers took
haloperidol during pregnancy
Haloperidol should generally not be used during the first trimester
Haloperidol should only be used during pregnancy if clearly needed
4-week depot formulation for noncompliance
Low-dose responders may have comparable positive and negative
symptom ef ficacy to atypical antipsychotics
Low-cost, ef fective treatment

 PearlsFor treatment-resistant cases with uncontrolled positive symptoms,
aggression, and/or violence (at high doses, guided by plasma drug
levels and tolerability)
Patients with tardive dyskinesia or who wish to avoid tardive
dyskinesia and drug-induced parkinsonism
Vulnerable populations such as children or elderly
Patients with notable cognitive or mood symptoms
Prior to the introduction of atypical antipsychotics, haloperidol was
one of the most preferred antipsychotics
Haloperidol may still be a useful antipsychotic, especially at low
doses for those patients who require management with a
conventional antipsychotic or who cannot af ford an atypical
Low doses may not induce negative symptoms, but high doses may
Not clearly ef fective for improving cognitive or af fective symptoms
of schizophrenia

May be ef fective for bipolar maintenance, but there may be more
tardive dyskinesia when af fective disorders are treated with a
conventional antipsychotic long-term
Less sedating than many other conventional antipsychotics,
especially “low-potency ” phenothiazines
Haloperidol is often used to treat delirium, generally in combination
with lorazepam, with the haloperidol dose 2 times the lorazepam
dose
Haloperidol ’s long-acting intramuscular formulation lasts up to 4
weeks, whereas some other long-acting intramuscular antipsychotics
may last only up to 2 weeks
Decanoate administration is intended for patients with chronic
schizophrenia who have been stabilized on oral antipsychotic
another

another
“top-up ” of a conventional antipsychotic such as haloperidol to
control aggression or violent behavior

Haloperidol Decanoate
Haloperidol Decanoate Pr operties
Vehicle Sesame oil
Tmax 3–9 days
T1/2 with multiple dosing 21 days
Time to reach steady state 4 weeks with loading
Dosing schedule (maintenance) 4 weeksantipsychotic such as haloperidol or from switching to a
conventional antipsychotic such as haloperidol
conventional antipsychotic such as haloperidol with an atypical

Dosage forms 50 mg, 100 mg
Injection volume 50 or 100 mg/mL; not to exceed 3
mL
How to Dose
Dosing T ips10–20 times the previous oral dose
Conversion from oral: loading with 20 times the oral daily dose
(mg/day) for the first month, divided into 2 biweekly injections;
weekly loading is an alternate option; may require oral coverage for
the first week

Advantages: reliable conversion formula from oral dosing,
established loading regimens
Disadvantages: higher incidence of local site reactions (due to

sesame oil vehicle); even with loading, may require oral coverage
for at least a week
Minimum therapeutic level for plasma drug level is 5 ng/mL and
point of futility is 30 ng/mL; many with treatment resistance will
improve if they can tolerate dosing that attains plasma drug levels
between 15 and 30 ng/mL

 Switching fr om Oral Antipsychotics to Haloperidol Decanoate
Single injection volumes greater than 300 (3 mL) are not tolerated,
so patients who require higher doses typically receive the monthly
dose as split injections every 2 weeks
A loading strategy advocated by some is to give 300 mg LAI every
1–2 weeks for 2 doses and then measure plasma drug concentrations
just prior to a third loading dose to see if a third dose is necessary
adequate loading is pursued; however , oral coverage may still be
necessary for the first week

Cipriani  A , Rendell  JM , Geddes  JR. Haloperidol alone or in combination
for acute mania  . Cochrane Database Syst Rev  2006  ;19 (3 ):CD004362  .
Huf G , Alexander  J , Allen  MH , Raveendran  NS. Haloperidol plus
promethazine for psychosis-induced aggression  . Cochrane Database Syst
Rev 2009  ;8 (3 ):CD005146  .
meta-analysis  . Lancet  2019  ;394 :939–51 .1-week down-titration is required for: iloperidone, lurasidone,
For patients taking benzodiazepine or anticholiner gic

tapered one at a time as appropriate.

Joy CB , Adams  CE , Lawrie  SM. Haloperidol versus placebo for
schizophrenia  . Cochrane Database Syst Rev  2006  ;18 (4 ):CD003082  .

Hydroxyzine
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Atarax
Marax
Vistaril
Neuroscience-based Nomenclature: histamine receptor antagonist
(H-RAn)
Antihistamine (anxiolytic, hypnotic, antiemetic)
Anxiety and tension associated with psychoneur osis
Adjunct in organic disease states in which anxiety is manifested
Pruritus due to allergic conditions

If It W orksHistamine-mediated pruritus
Premedication sedation
Sedation following general anesthesia
Acute disturbance/hysteria (injection)
Anxiety withdrawal symptoms in alcoholics or patients with
delirium tr emens (injection)
Adjunct in pr e/postoperative and pr e/postpartum patients to
allay anxiety , contr ol emesis, and r educe nar cotic dose
(injection)
Nausea and vomiting (injection)
Insomnia
Blocks histamine 1 receptors
15–20 minutes (oral administration)
weeks with daily dosing for maximal therapeutic benefit in chronic

TestsFor short-term symptoms of anxiety –after a few weeks, discontinue
If long-term maintenance is necessary , continue treatment for 6
months after symptoms resolve, and then taper dose slowly
consider restarting hydroxyzine
Hydroxyzine can be used as an adjunct to SSRIs or SNRIs in
treating anxiety disorders

 SedationNone for healthy individuals
Hydroxyzine may cause falsely elevated urinary concentrations of
17-hydroxycorticosteroids in certain lab tests (e.g., Porter -Silber
reaction, Glenn-Nelson method)
Dry mouth, sedation, tremor
Rare convulsions (generally at high doses)
Rare cardiac arrest, death (intramuscular formulation combined with
CNS depressants)
Bronchodilation

Wait
Wait
Wait
Anxiety: 50 –100 mg 4 times a day
Sedative: 50 –100 mg oral, 25 –100 mg intramuscular injection
Pruritus: 75 mg/day divided into 3 –4 doses
Tablet 10 mg, 25 mg, 50 mg
Capsule 25 mg, 50 mg, 100 mg

How to Dose
Overdose
Long-T erm UseOral liquid 10 mg/5 mL
Intramuscular 25 mg/mL, 50 mg/mL
Oral dosing does not require titration
Emer gency intramuscular injection: initial 50 –100 mg, repeat every
4–6 hours as needed
Hydroxyzine intramuscular injection should not be given in the
lower or mid-third of the arm and should only be given in the
deltoid area if it is well developed
In adults, hydroxyzine intramuscular injections may be given in the
upper outer quadrant of the buttock or in the mid-lateral thigh
Hydroxyzine may be administered intramuscularly initially , but
should be changed to oral administration as soon as possible
Tolerance usually develops to sedation, allowing higher dosing over
time
Sedation, hypotension, possible QT c prolongation

How to Stop
 Other W arnings/Pr ecautionsEvidence of ef ficacy for up to 16 weeks
No
Taper generally not necessary
Rapidly absorbed from gastrointestinal tract
Mean elimination half-life approximately 20 hours
If hydroxyzine is taken in conjunction with another CNS depressant,
the dose of the CNS depressant should be reduced by half
If hydroxyzine is used pre- or post-operatively , the dose of narcotic
can be reduced
If anticholiner gic agents are used with hydroxyzine, the
Hydroxyzine may reverse the vasopressor ef fect of epinephrine;
patients requiring a vasopressor agent should use norepinephrine or
metaraminol instead

Do Not Use
ElderlyHydroxyzine should not be administered subcutaneously , intra-
arterially , or intravenously
If patient is in early stages of pregnancy
If there is a proven aller gy to hydroxyzine
Hydroxyzine may be used to treat anxiety associated with cardiac
Elderly patients may be more sensitive to sedative and
anticholiner gic ef fects
Should be avoided in elderly patients with dementia

 Pregnancy
✽ Hydroxyzine is contraindicated in early pregnancy
Breast FeedingAnxiety , pruritus (6 and older): 50 –100 mg/day in divided doses
Anxiety , pruritus (under 6): 50 mg/day in divided doses
Sedative: 0.6 mg/kg oral, 0.5 mg/lb intramuscular injection
Small children should not receive hydroxyzine by intramuscular
injection in the periphery of the upper quadrant of the buttock unless
absolutely necessary because of risk of damage to the sciatic nerve
Hydroxyzine intramuscular injection can be used prepartum,

reducing narcotic requirements by up to 50%
Unknown if hydroxyzine is secreted in human breast milk, but all

 Pearls
✽ A preferred anxiolytic for patients with dermatitis or skin
symptoms such as pruritisHas multiple formulations, including oral capsules, tablets, and
liquid, as well as injectable
No abuse liability , dependence, or withdrawal
Patients with severe anxiety disorders
Elderly patients
Dementia patients
Anxiety
Skeletal muscle tension
Itching

Diehn  F , Tefferi A . Pruritus in polycythaemia vera: prevalence, laboratory
correlates and management  . Br J Haematol  2001  ;115 :619–21 .
Ferreri  M , Hantouche  EG . Recent clinical trials of hydroxyzine in
generalized anxiety disorder  . Acta Psychiatr Scand Suppl  1998  ;393 :102–8
.
Guaiana  G , Barbui  C , Cipriani  A. Hydroxyzine for generalised anxiety
disorder  . Cochrane Database Syst Rev  2010  ;8 (12 ):CD006815  .
Paton  DM , Webster  DR . Clinical pharmacokinetics of H1-receptor
antagonists (the antihistamines)  . Clin Pharmacokinet  1985  ;10 :477–97 .Anxiolytic actions may be proportional to sedating actions
Hydroxyzine tablets are made with 1,1,1- trichloroethane, which
destroys ozone
Hydroxyzine by intramuscular injection may be used to treat
agitation during alcohol withdrawal
Hydroxyzine may not be as ef fective as benzodiazepines or newer
agents in the management of anxiety

Iloperidone
Brands
Generic?
No
 Class
(bold for FDA appr oved)Fanapt
Schizophr enia maintenance

How Long Until It W orksBipolar maintenance
Blockade of central alpha 1 adrener gic receptors may contribute to
low potential for drug-induced parkinsonism
Slow titration may delay antipsychotic ef fects during the first 1 to 2
weeks compared to some other antipsychotic drugs that do not
require similar titration

ResistanceMany bipolar patients may experience a reduction of symptoms by
clozapine
injection (a depot formulation of iloperidone is in clinical testing)

Tests
Befor e Starting an Atypical Antipsychotic
plasma glucose, and fasting lipid profileOther mood-stabilizing anticonvulsants (carbamazepine,
Lithium

Monitoring After Starting an Atypical Antipsychotic
respiration, weakness, and clouding of sensorium, even comaTreat or refer such patients for treatment, including nutrition and

How Drug Causes Side Effectsiloperidone should be discontinued at the first sign of decline in

✽ Orthostatic hypotension
 Life-Thr eatening or Danger ous Side EffectsSedation, dose-dependent dizziness, fatigue
Dry mouth, nasal congestion
Dose-dependent weight gain
Dose-dependent tachycardia

 Sedation
Wait
Wait
Wait
present

How to Dose
 Dosing T ipsBenztropine, trihexyphenidyl, or amantadine for drug-induced
12–24 mg/day in 2 divided doses
Tablet 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg
Initial 2 mg in 2 divided doses on day 1; 4 mg in 2 divided doses on
day 2; 8 mg in 2 divided doses on day 3; 12 mg in 2 divided doses
on day 4; 16 mg in 2 divided doses on day 5; 20 mg in 2 divided
doses on day 6; 24 mg in 2 divided doses on day 7
Maximum dose studied is 32 mg/day

May titrate even slower in patients who develop side ef fects,
especially orthostasis, or when adding or switching from another
drug with alpha 1 antagonist properties
Patients most vulnerable to side ef fects during titration would be
those sensitive to orthostasis (e.g., the young, the elderly , those with
cardiovascular problems, those taking concomitant vasoactive
drugs)
Slow dosing could lead to delayed onset of antipsychotic ef fects
iloperidone is 18 –33 hours
Some patients may respond to doses greater than 24 mg/day if
tolerated

Overdose
How to Stop
PharmacokineticsIf treatment is discontinued for more than 3 days, it may need to be
restarted following the initial titration schedule in order to maximize
Iloperidone should be discontinued in patients with persistent QT c
measurements of more than 500 msec
Sedation, tachycardia, hypotension
No
Half-life 18 –33 hours

 Other W arnings/Pr ecautionsMetabolized by CYP450 2D6 and 3A4
Inhibitors of CYP450 2D6 (e.g., paroxetine, fluoxetine, duloxetine,
quinidine) may increase plasma levels of iloperidone and require a
dosage reduction by one-half of iloperidone
Inhibitors of CYP450 3A4 (e.g., nefazodone, fluvoxamine,
fluoxetine, ketoconazole) may increase plasma levels of iloperidone
and require a dosage reduction by one-half of iloperidone

Do Not UseDysphagia has been associated with antipsychotic use, and
iloperidone should be used cautiously in patients at risk for
Iloperidone prolongs QT c interval more than some other
antipsychotics, an ef fect that is augmented by concomitant use of
drugs that inhibit iloperidone metabolism
Priapism has been reported with iloperidone
therapy

If there is a proven aller gy to iloperidone

ElderlyDose adjustment not generally necessary
Not recommended for patients with hepatic impairment
Not recommended for patients with significant cardiovascular
illness
agitation

 Pregnancyplacebo, and also have an increased risk of cerebrovascular events
Children and adolescents using iloperidone may need to be
better

✽ Recommended either to discontinue drug or bottle feedWhen administered to pregnant rats during or ganogenesis,
iloperidone was not teratogenic at doses up to 26 times the
maximum recommended human dose (MRHD); however , at the
highest dose it prolonged the duration of pregnancy and parturition;
increased stillbirths, early intrauterine deaths, and incidence of
developmental delays; and decreased postpartum pup survival
When administered to pregnant rabbits during or ganogenesis,
iloperidone was not teratogenic at doses up to 20 times the MRHD;
however , at the highest dose, which was also a maternally toxic
dose, it increased early intrauterine deaths and decreased fetal
viability at term
Iloperidone may be preferable to anticonvulsant mood stabilizers if
961-2388,

961-2388,
Unknown if iloperidone is secreted in human breast milk, but all

Primary T arget SymptomsInfants of women who choose to breast feed while on iloperidone
Patients wishing to avoid drug-induced parkinsonism
titration
Patients noncompliant with twice daily dosing

PearlsAggressive symptoms
Not approved for mania, but all atypical antipsychotics approved for
acute treatment of schizophrenia have proven ef fective in the acute
treatment of mania as well
Seems to have placebo-level drug-induced parkinsonism, including
little or no akathisia
Potent alpha 1 blocking properties suggest potential utility in PTSD
(e.g., nightmares, as for prazosin)
Binding properties suggest theoretical ef ficacy in depression, but
studies and clinical experience are required to confirm this
QTc warning similar to that for ziprasidone, where this has not
materialized into a significant clinical problem
A 4-week depot preparation is in clinical testing
Early studies indicate iloperidone ’s efficacy may be linked to
pharmacogenomic markers such as ciliary neurotrophic factor
(CNTF), and others

 Switching fr om Oral Antipsychotics to Iloperidone
agitation, and/or psychosisconventional antipsychotic may be useful or even necessary while
lumateperone, and paliperidone ER, immediate stop is possible
Clinical experience has shown that quetiapine, olanzapine, and
asenapine should be tapered of f slowly over a period of 3 –4 weeks,

Dargani NV , Malhotra  AK . Safety profile of iloperidone in the treatment
of schizophrenia  . Expert Opin Drug Saf  2014  ;13 (2 ):241–6 .
Kane  JM , Lauriello  J , Laska  E , Di Marino  M , Wolfgang  CD . Long-term
efficacy and safety of iloperidone: results from 3 clinical trials for the
treatment of schizophrenia  . J Clin Psychopharmacol  2008  ;28 (2 Suppl 1
):S29 –35 .

Volpi S , Potkin  SG , Malhotra  AK , Licamele  L , Lavedan  C . Applicability
of a genetic signature for enhanced iloperidone ef ficacy in the treatment of
schizophrenia  . J Clin Psychiatry  2009  ;70 :801–9 .

Imipramine
Brands
Generic?
Yes
 Class
✽ EnuresisTofranil
Anxiety
Insomnia

How Long Until It W orksNeuropathic pain/chronic pain
Cataplexy syndrome
cortex, which lar gely lacks dopamine transporters, imipramine can
May be ef fective in treating enuresis because of its anticholiner gic

symptoms
stopped

ResistanceUse in anxiety disorders and chronic pain may also need to be
Consider increasing dose, switching to another agent or adding an

Tests

Notable Side EffectsPatients at risk for electrolyte disturbances (e.g., patients on diuretic

 Sedation
What to Do About Side EffectsParalytic ileus, hyperthermia (TCAs + anticholiner gic agents)
Wait

Wait
Capsule 75 mg, 100 mg, 125 mg, 150 mg
75–100 mg/day once daily or in divided doses; gradually increase
daily dose to achieve desired therapeutic ef fects; dose at bedtime for
daytime sedation and in morning for insomnia; maximum dose 300
mg/day

Overdose
Tofranil-PM(r) (imipramine pamoate) 100 and 125 mg capsules
contain the dye tartrazine (FD&C yellow No. 5), which may cause
allergic reactions in some patients; this reaction is more likely in
patients with sensitivity to aspirin
Safe

How to Stop
Metabolized to an active metabolite, desipramine, a predominantly
norepinephrine reuptake inhibitor , by demethylation via CYP450
1A2

of imipramine to desmethylimipramine (desipramine) and increase
imipramine plasma concentrations
activity

discontinuation of imipramine
after discontinuing imipramine

Generally , do not use with MAO inhibitors, including 14 days after
MAOIs are stopped; do not start an MAOI for at least 5 half-lives (5
to 7 days for most drugs) after discontinuing imipramine, but see
Pearls
drugs that inhibit its metabolism via CYP450 2D6, potentially

companies

Do Not Use
Renal ImpairmentWhenever possible, warn patients and their caregivers about the
If there is a proven aller gy to imipramine, desipramine, or
Cautious use; may need lower dose

Cardiac ImpairmentCautious use; may need lower dose
imipramine

Elderly
 Childr en and Adolescentsinfarction, these are more appropriate agents for cardiac population
Initial 30 –40 mg/day; maximum dose 100 mg/day

patients

PregnancyUsed age 6 and older for enuresis; age 12 and older for other
disorders
May be used to treat hyperactive/impulsive behaviors
Adolescents: initial 30 –40 mg/day; maximum 100 mg/day
Children: initial 1.5 mg/kg per day; maximum 5 mg/kg per day
Functional enuresis: 50 mg/day (age 6 –12) or 75 mg/day (over 12)
Should be used only if potential benefits outweigh potential risks

essants
the mother
feeding
Patients with enuresis

 Pearls
✽ Probably the most preferred TCA for treating enuresis in children
✽ Preference of some prescribers for imipramine over other TCAs for
the treatment of enuresis is based more upon art and anecdote and
empiric clinical experience than comparative clinical trials with other
TCAsPediatric and geriatric patients

Preskorn  SH . Comparison of the tolerability of bupropion, fluoxetine,
imipramine, nefazodone, paroxetine, sertraline, and venlafaxine  . J Clin
Psychiatry  1995  ;56 (Suppl 6): S12 –21.
Workman  EA , Short  DD . Atypical antidepressants versus imipramine in
the treatment of major depression: a meta-analysis  . J Clin Psychiatry  1993
;54 :5 –12.Phenotypic testing may be necessary to detect this genetic variant

Isocarboxazid
Brands
Generic?
Not in USA
 Class
If It W orksMarplan
Neuroscience-based Nomenclature: serotonin, norepinephrine, dopamine enzyme inhibitor (SN-EI)
Monoamine oxidase inhibitor (MAOI)
Treatment-resistant panic disorder
Treatment-resistant social anxiety disorder
Irreversibly blocks monoamine oxidase (MAO) from breaking down norepinephrine, serotonin, and
dopamine
This boosts noradrener gic, serotoner gic, and dopaminer gic neurotransmission
Onset of therapeutic actions usually not immediate, but often delayed 2 –4 weeks following adequate dosing
If it is not working within 6 –8 weeks, it may require a dosage increase or it may not work at all
May continue to work for many years to prevent relapse of symptoms

The goal of treatment is complete remission of current symptoms as well as prevention of future relapses

 Best Augmenting Combos for Partial Response or T reatment Resistance
✽ Augmentation of MAOIs has not been systematically studied, and this is something for the expert, to be
done with caution and with careful monitoring
✽ A stimulant such as d-amphetamine or methylphenidate (with caution; may activate bipolar disorder and
suicidal ideation; may elevate blood pressure)
TestsTreatment most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after
Once symptoms are gone, continue treating for 1 year for the first episode of depression
For second and subsequent episodes of depression, treatment may need to be indefinite
Many patients have only a partial response where some symptoms are improved but others persist
(especially insomnia, fatigue, and problems concentrating)

Other patients may be nonresponders, sometimes called treatment-resistant or treatment-refractory
Some patients who have an initial response may relapse even though they continue treatment, sometimes
called “poop-out ”
Consider increasing dose, switching to another agent, or adding an appropriate augmenting agent
Consider evaluation for another diagnosis or for a comorbid condition (e.g., medical illness, substance
abuse, etc.)
Some patients may experience apparent lack of consistent ef ficacy due to activation of latent or underlying
bipolar disorder , and require antidepressant discontinuation and a switch to a mood stabilizer
Lithium
Mood-stabilizing anticonvulsants
Atypical antipsychotics (with special caution for those agents with monoamine reuptake blocking

Lithium
properties, such as lumateperone, ziprasidone, and zotepine)
Patients should be monitored for changes in blood pressure; check before and 45–60 minutes after dosing
until stable
For patients receiving high doses or long-term treatment, consider periodic evaluation of hepatic function

✽ Since MAOIs are frequently associated with weight gain, before starting treatment, weigh all patients and
determine if the patient is already overweight (BMI 25.0 –29.9) or obese (BMI >30)
✽ While giving a drug to a patient who has gained >5% of initial weight, consider evaluating for the
presence of pre-diabetes, diabetes, or dyslipidemia, or consider switching to a dif ferent antidepressant
 Weight GainBefore giving a drug that can cause weight gain to an overweight or obese patient, consider determining
whether the patient already has pre-diabetes (fasting plasma glucose 100 –125 mg/dL), diabetes (fasting
plasma glucose >126 mg/dL), or dyslipidemia (increased total cholesterol, LDL cholesterol, and
triglycerides; decreased HDL cholesterol), and treat or refer such patients for treatment, including nutrition

and weight management, physical activity counseling, smoking cessation, and medical management
Theoretically due to increases in monoamines in parts of the brain and body and at receptors other than
those that cause therapeutic actions (e.g., unwanted actions of serotonin in sleep centers causing insomnia,
unwanted actions of norepinephrine on vascular smooth muscle causing hypotension, etc.)
Side ef fects are generally immediate, but immediate side ef fects often disappear in time
Dizziness, sedation, headache, sleep disturbances, fatigue, tremor
Change in appetite, weight gain
Orthostatic hypotension (dose-related); syncope may develop at high doses
Hypertensive crisis (especially when MAOIs are used with certain tyramine-containing foods or prohibited
drugs)
Induction of mania in patients with bipolar disorder
Rare hepatotoxicity

drugs)

Sedation
How to Dose
OverdoseMany experience and/or can be significant in amount
Can also cause activation
Wait
Wait
Wait
Switch after appropriate washout to an SSRI or newer antidepressant
Trazodone (with caution) for insomnia
Benzodiazepines for insomnia
40–60 mg/day
Tablet 10 mg
Initial 10 mg twice a day; increase by 10 mg/day every 2 –4 days; dosed 2 –4 times/day; maximum dose 60
mg/day
Orthostatic hypotension, especially at higher doses, may require splitting into 3 or 4 daily doses
Patients receiving high doses may need to be evaluated periodically for ef fects on the liver
Little evidence to support ef ficacy of isocarboxazid at doses below 30 mg/day

How to Stop
 Other W arnings/Pr ecautionsDizziness, sedation, ataxia, headache, insomnia, restlessness, anxiety , irritability; cardiovascular ef fects,
confusion, respiratory depression, or coma may also occur
Consider periodic evaluation of hepatic function
MAOIs may lose some ef ficacy long-term
Dependence to MAOIs reported but rare
Generally no need to taper , as drug wears of f slowly over 2 –3 weeks
Clinical duration of action may be up to 14 days due to irreversible enzyme inhibition
Tramadol (serotonin reuptake inhibitor) may increase the risk of seizures in patients taking an MAOI
Can cause a fatal “serotonin syndrome ” when combined with drugs that block serotonin reuptake, so do not
use with a serotonin reuptake inhibitor or for 5 half-lives after stopping the serotonin reuptake inhibitor
(see Table 1  after Pearls)

Hypertensive crisis with headache, intracranial bleeding, and death may result from combining MAOIs
with sympathomimetic drugs (e.g., amphetamines, methylphenidate, cocaine, dopamine, epinephrine,
norepinephrine)
Do not combine with another MAOI, alcohol, or guanethidine
Adverse drug reactions can result from combining MAOIs with tricyclic/tetracyclic antidepressants and
related compounds, including carbamazepine, cyclobenzaprine, and mirtazapine, and should be avoided
except by experts
MAOIs in combination with spinal anesthesia may cause combined hypotensive ef fects
Combination of MAOIs and CNS depressants may enhance sedation and hypotension
Use requires strict adherence to low-tyramine diet (see Table 2  after Pearls)
Patient and prescriber must be vigilant to potential interactions with any drug, including antihypertensives

and over -the-counter cough/cold preparations

Do Not Use
Cardiac ImpairmentOver -the-counter medications to avoid include cough and cold preparations, including those containing
dextromethorphan (serotonin reuptake inhibitor), nasal decongestants (tablets, drops, or spray), hay-fever
medications, sinus medications, asthma inhalant medications, anti-appetite medications, weight reducing
preparations, “pep” pills (see Table 3  after Pearls)
Hypoglycemia may occur in diabetic patients receiving insulin or oral antidiabetic agents (hydrazine ef fect)
Binds and inactivates vitamin B6 (hydrazine ef fect); reversible with high-dose B6 administration
Use cautiously in patients receiving reserpine, anesthetics, disulfiram, metrizamide, anticholiner gic agents
Isocarboxazid is not recommended for use in patients who cannot be monitored closely
If patient is taking meperidine (pethidine) (serotonin reuptake inhibitor)
If patient is taking a sympathomimetic agent or taking guanethidine

If patient is taking another MAOI
If patient is taking any agent that can inhibit serotonin reuptake (e.g., SSRIs, tramadol, milnacipran,
duloxetine, venlafaxine, clomipramine, imipramine, etc.)
If patient is taking dextromethorphan, a serotonin reuptake inhibitor
If patient is taking diuretics or other antihypertensives without careful monitoring of blood pressure
If patient has cardiovascular or cerebrovascular disease, until cleared by the patient ’s medical doctor
If patient is taking a prohibited drug
If patient is not compliant with a low-tyramine diet
If there is a proven aller gy to isocarboxazid
Use with caution –drug may accumulate in plasma
May require lower than usual adult dose
Use cautiously in hepatic impairment

Elderly
 Pregnancy
Breast FeedingContraindicated in patients with congestive heart failure or hypertension, unless cleared by the patient ’s
medical doctor
Initial dose lower than usual adult dose
Elderly patients may have greater sensitivity to adverse ef fects, but many tolerate MAOIs
Reduction in the risk of suicidality with antidepressants compared to placebo in adults age 65 and older
Not recommended for use in children under age 16
Carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of
nontreatment with antidepressants and make sure to document this in the patient ’s chart
Whenever possible, warn patients and their caregivers about the possibility of activating side ef fects, and
advise them to report such symptoms immediately
Use with caution, observing for activation of known or unknown bipolar disorder and/or suicidal ideation,

and inform parents or guardians of this risk so they can help observe child or adolescent patients
Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation
information in prescription drug labels, including the elimination of the pregnancy letter categories; the
Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be
phased in gradually for drugs approved on or after June 30, 2001
Not generally recommended for use during pregnancy , especially during first trimester
Should evaluate patient for treatment with an antidepressant with a better risk/benefit ratio

https://womensmentalhealth.or g/research/pregnancyregistry/antidepressants
Immediate postpartum period is a high-risk time for depression, especially in women who have had prior
depressive episodes, so drug may need to be reinstituted late in the third trimester or shortly after childbirth
to prevent a recurrence during the postpartum period

 Pearls
✽ Myths about the danger of dietary tyramine can be exaggerated, but prohibitions against concomitant
drugs often not followed closely enoughAtypical depression
Treatment-resistant depression or anxiety disorders
Requires compliance to dietary restrictions, concomitant drug restrictions
Patients with cardiac problems or hypertension, unless cleared by the patient ’s medical doctor
Multiple daily doses, although many patients can be dosed once a day
Sleep and eating disturbances
Psychomotor retardation
Morbid preoccupation
MAOIs are generally reserved for third- or fourth-line use after SSRIs, SNRIs, and combinations of newer
antidepressants have failed
Despite little utilization, some patients respond to isocarboxazid who do not respond to other
antidepressants including other MAOIs

Patient should be advised not to take any prescription or over -the-counter drugs without consulting their
doctor because of possible drug interactions with the MAOI
Headache is often the first symptom of hypertensive crisis
The rigid dietary restrictions may reduce compliance (see Table 2  after Pearls)
Mood disorders can be associated with eating disorders (especially in adolescent females), and
isocarboxazid can be used to treat both depression and bulimia
Orthostatic hypotension, insomnia, and sexual dysfunction are often the most troublesome common side
effects

✽ MAOIs should be for the expert, especially if combining with agents of potential risk (e.g., stimulants,
trazodone, TCAs)
✽ MAOIs should not be neglected as therapeutic agents for the treatment-resistant
Table 1.  Drugs contraindicated due to risk of serotonin syndrome/toxicity
Do Not Use:
Antidepr essants Drugs of Abuse Opioids Other
SSRIs MDMA (ecstasy) Meperidine Non-subcutaneous sumatriptan
SNRIs Cocaine Tramadol Chlorpheniramine
Clomipramine Methamphetamine Methadone Brompheniramine
Imipramine St. John ’s wort High-dose or
injected
amphetamineDextromethorphanLumateperoneZiprasidone
Table 2.  Dietary guidelines for patients taking MAOIs*
Foods to avoid ** Foods allowed
Dried, aged, smoked, fermented, spoiled, or
improperly stored meat, poultry , and fishFresh or processed meat, poultry , and fish; properly
stored pickled or smoked fish
Broad bean pods All other vegetables
Aged cheeses Processed cheese slices, cottage cheese, ricotta cheese,

yogurt, cream cheeseFor treatment-resistant patients, experts can give a tricyclic/tetracyclic antidepressant other than
clomipramine or imipramine simultaneously with an MAOI for patients who fail to respond to numerous
Use of MAOIs with clomipramine is always prohibited because of the risk of serotonin syndrome and
death due to serotonin reuptake inhibition
Amoxapine may be the preferred trycyclic/tetracyclic antidepressant to combine with an MAOI in heroic
cases due to its theoretically protective 5HT2A antagonist properties
If this option is elected, start the MAOI with the tricyclic/tetracyclic antidepressant simultaneously at low
doses after appropriate drug washout, then alternately increase doses of these agents every few days to a
week as tolerated

Although very strict dietary and concomitant drug restrictions must be observed to prevent hypertensive
crises and serotonin syndrome, the most common side ef fects of MAOI and tricyclic/tetracyclic

Tap and unpasteurized beer Canned or bottled beer and alcohol
Marmite Brewer ’s and baker ’s yeast
Banana peel Bananas, avocados, raspberries
Sauerkraut, kimchee Peanuts
Soy products/tofu
Tyramine-containing nutritional supplement
* Consult up-to-date listing of tyramine content, as most foods now have low tyramine amounts**Not
necessary for 6 mg transdermal or low-dose oral selegiline
Table 3.  Drugs that boost norepinephrine: should only be used with caution with MAOIs
Use W ith Caution:
Decongestants Stimulants Antidepr essants
with
reuptake
inhibitionOther
Phenylephrine Amphetamines Most tricyclics Phente
Pseudoephedrine MethylphenidateCocaineMethamphetamineModafinilArmodafinil NRIsNDRIs Local a
contain
vasoco
Gillman K. PsychoT ropical Research (PTR). https://psychotropical.com  .
Gillman PK. A reassessment of the safety profile of monoamine oxidase inhibitors: elucidating tired old tyramine

myths. J Neural T ransm (V ienna) 2018  ;125(1 1):1707 –17.
Kennedy  SH . Continuation and maintenance treatments in major depression: the neglected role of monoamine
oxidase inhibitors  . J Psychiatry Neur osci 1997  ;22 :127–31 .
Kim T , Xu C, Amsterdam JD. Relative ef fectiveness of tricyclic antidepressant versus monoamine oxidase
inhibitor monotherapy for treatment-resistant depression. J Af fect Disord 2019  ;250:199 –203.

Ketamine
Brands
Generic?
Yes
 Class
 How the Drug W orksKetalar
Induction and maintenance of general anesthesia
Pain/neuropathic pain
Sedation
Treatment-resistant depression (experimental)

If It W orksKetamine is a noncompetitive open channel inhibitor of the NMDA
receptor; specifically , it binds to the phencyclidine site of the
NMDA receptor
This leads to downstream glutamate release and consequent
Theoretically , ketamine may have antidepressant ef fects at low
(subanesthetic) doses because activation of AMP A receptors leads to
activation of signal transduction cascades that cause the expression
of synaptic proteins and an increase in the density of dendritic
spines
Low (subanesthetic) doses also produce analgesia and modulate
central sensitization, hyperalgesia, and opioid tolerance
For treatment-resistant depression, antidepressant ef fects can occur
within hours
For neuropathic pain, ef fects can occur within hours but may take
weeks for full ef fect
For treatment-resistant depression, can immediately alleviate

depressed mood and suicidal ideation, but antidepressant ef fects last
only a few days
For neuropathic pain, can continue to use as long as it is beneficial

Tests
Notable Side EffectsTry a traditional antidepressant or electro-convulsive therapy (ECT)
for treatment-resistant depression
Try traditional analgesics and treatments for neuropathic pain
For neuropathic pain, may use cautiously with opioids
For treatment-resistant depression, combinations have not been
Direct ef fect on NMDA receptors
When used as an anesthesia induction/maintenance agent (generally
at doses >2 mg/kg IV), it may produce emer gent psychosis,
including auditory and visual hallucinations, restlessness,
disorientation, vivid dreams, and irrational behavior . Spontaneous

Life-Thr eatening or Danger ous Side Effectsinvoluntary movements, nystagmus, hypertonus, and vocalizations
are also common. These adverse ef fects are uncommon with very
low-dose therapy
CSF pressure increased, erythema (transient), morbilliform rash
(transient), anorexia, pain/erythema at the injection site, exanthema
at the injection site, skeletal muscle tone enhanced, intraocular
pressure increased, bronchial secretions increased, potential for
dependence with prolonged use, emer gence reactions (includes
confusion, dreamlike state, excitement, irrational behavior , vivid
imagery)
Psychotomimetic phenomena (euphoria, dysphasia, blunted af fect,
psychomotor retardation, vivid dreams, nightmares, impaired
attention, memory and judgment, illusions, hallucinations, altered
body image), delirium, dizziness, diplopia, blurred vision,
nystagmus, altered hearing, hypertension, tachycardia,
hypersalivation, nausea and vomiting, erythema and pain at
injection site
Urinary tract toxicity

When used at higher doses in anesthesia, tonic –clonic movements
are very common (>10%); however , these have not been reported
after oral use or with the lower parenteral doses used for analgesia
Syncope or cardiac arrhythmias
Hypertension/hypotension

Sedation
Dosing and UseAnaphylaxis
CNS depression
Respiratory depression/apnea
Airway obstruction/laryngospasm
Pretreatment with a benzodiazepine reduces incidence of psychosis
by >50%

How to Dose
 Dosing T ipsOral: 10 –50 mg
IV infusion: 1 –10 µg/kg per minute
Oral solution: 50 mg/mL
Injection: 50 mg/mL, 100 mg/mL
For pain (oral): initial 10 mg; titrate up as appropriate
For pain (IM): 2 –4 mg/kg
For pain (IV): 0.2 –0.075 mg/kg
For pain (continuous IV infusion): 2 –7 µg/kg per minute
Slow titration can reduce side ef fects
For oral use: to prepare 100 mL of 50 mg/5 mL ketamine oral
solution
2 x 10 mL vials of generic ketamine 50 mg/mL for injection
(cheapest concentration)
80 mL purified water

Overdose
Long-T erm UseStore in a refrigerator with an expiry date of 1 week from
manufacture
Patients can add their own flavoring, e.g., fruit cordial, just
before use to disguise the bitter taste
For sublingual use:
Place under the tongue and ask patient not to swallow for 2
minutes
Use a high concentration to minimize dose volume; retaining
>2 mL is dif ficult
Start with 10 mg
Incompatibility
Ketamine forms precipitates with barbiturates and diazepam
(manufacturer ’s data on file); do not mix
Mixing lorazepam with ketamine is also not recommended;
compatibility data are lacking, and there is a risk of adsorption
of lorazepam to the tubing
Restlessness, psychosis, hallucinations, stupor , respiratory

How to Stop
 Drug InteractionsLong-term cognitive and memory impairment have been reported
No
Plasma half-life: alpha: 10 –15 minutes; beta: 2.5 hours; 1 –3 hours
IM; 2.5 –3 hours orally; 12 hours norketamine
Metabolized by CYP450 2B6, 2C9, and 3A4
Ketamine may increase the ef fects of other sedatives, including
CYP450 3A4 inhibitors (e.g., clarithromycin, ketoconazole) can
increase plasma concentrations of ketamine and reduce those of
norketamine, but the clinical relevance of this is unclear
Plasma concentrations of ketamine are increased by diazepam

Do Not Use
Hepatic ImpairmentBarbiturates and hydroxyzine may increase the ef fects of ketamine;
avoid combination
Use with caution in patients with current or past history of
psychiatric disorder; epilepsy , glaucoma, hypertension, heart failure,
ischemic heart disease, and a history of cerebrovascular accidents
If patient has a condition in which an increase in blood pressure
would be hazardous
If patient has schizophrenia or another psychotic disorder
If patient has a condition in which an increase in intraocular
pressure would be hazardous
If there is a proven aller gy to ketamine
Reduce dose for moderate impairment
Should not be used in severe impairment
Dose reduction not necessary

Elderly
 Pregnancy
Breast FeedingUse with caution
Use only if potential benefits outweigh the potential risks to the
fetus
essants

 PearlsUnknown if ketamine is secreted in human breast milk, but all
For pain, may be especially useful when used in conjunction with
opioids
Severely treatment-resistant depression, suicidal ideation
May produce dysphoria, nightmares, excitement (uncommon with
very low-dose therapy)
Antidepressant ef fects are short-lived
Pain
Actions in treatment-resistant depression are transient, lasting only a
few days following infusion

The use of ketamine can cause urinary tract symptoms (e.g.,
frequency , urgency , urge incontinence, dysuria, and hematuria); the
causal agent has not been determined, but direct irritation by
ketamine and/or its metabolites is a possibility . (Investigations have
revealed interstitial cystitis, detrusor overactivity , decreased bladder
capacity; symptoms generally settle several weeks after stopping
ketamine.)
May be used in combination with anticholiner gic agents to decrease
hypersalivation
Do not mix with barbiturates or diazepam (precipitation may occur)
Bronchodilation is beneficial in asthmatic or chronic obstructive
pulmonary disease (COPD) patients. Laryngeal reflexes may remain
intact or may be obtunded
The direct myocardial depressant action of ketamine can be seen in
stressed, catecholamine-deficient patients
Ketamine releases endogenous catecholamines (epinephrine,
norepinephrine), which maintain blood pressure and heart rate, and
increase myocardial oxygen demand

Ketamine increases cerebral metabolism and cerebral blood flow
while producing a noncompetitive block of the neuronal
postsynaptic NMDA receptor
Lowers seizure threshold
Recent laboratory/clinical studies support the use of low-dose
ketamine to improve postoperative analgesia/outcome

Cohen  SP , Liao W , Gupta  A , Plunkett  A . Ketamine in pain management  .
Adv Psychosom Med  2011 ;30 :139–61 .
Duman  RS , Voleti B. Signaling pathways underlying the pathophysiology
and treatment of depression: novel mechanisms for rapid-acting agents  .
Trends Neur osci 2012  ;35 (1 ):47 –56 .
Schwartzman  RJ , Alexander  GM , Grothusen  JR . The use of ketamine in
complex regional pain syndrome: possible mechanisms  . Expert Rev
Neur other  2011 ;11 (5 ):719–34 .
Stahl  SM . Mechanism of action of ketamine  . CNS Spectr  2013  ;18 (4
):171–4 .May be especially beneficial for refractory neuropathic
pain/complex regional pain syndrome
May be especially beneficial when used in conjunction with opioids
(S)-ketamine is available in a preservative-free solution in Europe;
however , it currently is not approved by the FDA. S(+)-ketamine
may be more potent and have fewer side ef fects when used
intravenously than the racemate. Although not rigorously tested and

not available in the USA; some European investigators have utilized
the preservation-free solution for intrathecal/epidural use –this is not

Zarate  CA Jr, Singh  JB , Carlson  PH , et al. A randomized trial of an N-
methyl-D-aspartate antagonist in treatment-resistant major depression  .
Arch Gen Psychiatry  2006  ;63 (8 ):856–64 .

Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Lamictal
Labileno
Lamictin
sodium channel blocker (Glu-CB)
Anticonvulsant, mood stabilizer , voltage-sensitive sodium channel
antagonist
Maintenance tr eatment of bipolar I disorder

channels
voltage-sensitive sodium channelsPartial seizur es (adjunctive; adults and childr en ages 2 and
older)
Generalized seizur es of Lennox-Gastaut syndr ome (adjunctive;
adults and childr en ages 2 and older)
Primary generalized tonic –clonic seizur es (adjunctive; adults
and childr en ages 2 and older)
Conversion to monotherapy in adults (16 and older) with partial
seizur es who ar e receiving tr eatment with carbamazepine,
phenytoin, phenobarbital, primidone, or valpr oate
Bipolar mania (adjunctive and second-line)
Major depressive disorder (adjunctive)
Other seizure types and as initial monotherapy for epilepsy

If It W orks
are improved but others persist or continue to wax and wane withoutInhibits release of glutamate and asparate
May take several weeks to improve bipolar depression
Can reduce seizures by 2 weeks, but may take several weeks to
months to reduce seizures
seizures, depression, pain)
Continue treatment indefinitely to avoid recurrence of mania,
depression, and/or seizures
Treatment of chronic neuropathic pain may reduce but does not
eliminate pain symptoms and is not a cure since pain usually recurs

stabilization of mood
Resistance (for Bipolar Disorder)
✽ Valproate (with caution and at half-dose of lamotrigine in the
presence of valproate, because valproate can double lamotrigine
levels)
destabilize mood in some patients, including induction of rapid cyclingOther patients may be nonresponders, sometimes called treatment-
Switch to another mood stabilizer with fewer side ef fects
Lithium

Tests
✽ Benign rash (approximately 10%)None required
The value of monitoring plasma concentrations of lamotrigine has
not been established
Because lamotrigine binds to melanin-containing tissues,
opthalmological checks may be considered
Rash hypothetically an aller gic reaction
Dose-dependent: blurred or double vision, dizziness, ataxia
Sedation, headache, tremor , insomnia, poor coordination, fatigue
Nausea (dose-dependent), vomiting, dyspepsia, rhinitis

✽ Rare serious rash (risk may be greater in pediatric patients but still
rare)
Sedation
Additional ef fects in pediatric patients with epilepsy: infection,
pharyngitis, asthenia
Rare multi-or gan failure associated with Stevens-Johnson syndrome,
toxic epidermal necrolysis, or drug hypersensitivity syndrome
Rare blood dyscrasias
Rare aseptic meningitis
Rare hemophagocytic lymphohistiocytosis (HLH)
Rare sudden unexplained deaths have occurred in epilepsy
(unknown if related to lamotrigine use)
Withdrawal seizures upon abrupt withdrawal

✽ If patient develops signs of a rash with benign characteristics (i.e., a
rash that peaks within days, settles in 10 –14 days, is spotty ,
nonconfluent, nontender , has no systemic features, and laboratory tests
are normal):
✽ If patient develops signs of a rash with serious characteristics (i.e., a
rash that is confluent and widespread, or purpuric or tender; with any
prominent involvement of neck or upper trunk; any involvement of
eyes, lips, mouth, etc.; any associated fever , malaise, pharyngitis,
anorexia, or lymphadenopathy; abnormal laboratory tests for complete
blood count, liver function, urea, creatinine):Dose-related
Can wear of f with time
Wait
Divide dosing to twice daily
Reduce lamotrigine dose or stop dosage increase
Warn patient to stop drug and contact physician if rash worsens or
new symptoms emer ge
Prescribe antihistamine and/or topical corticosteroid for pruritis
Monitor patient closely

Stop lamotrigine (and valproate if administered)

Usual Dosage RangeMonitor and investigate or gan involvement (hepatic, renal,
hematologic)
Patient may require hospitalization
Monitor patient very closely
Antihistamines and/or topical corticosteroid for rash, pruritis
Monotherapy for bipolar disorder: 100 –200 mg/day
Adjunctive treatment for bipolar disorder: 100 mg/day in
combination with valproate; 400 mg/day in combination with
enzyme-inducing antiepileptic drugs such as carbamazepine,
phenobarbital, phenytoin, and primidone
Monotherapy for seizures in patients over age 12: 300 –500 mg/day
in 2 doses
Adjunctive treatment for seizures in patients over age 12: 100 –400
mg/day for regimens containing valproate; 100 –200 mg/day for
valproate alone; 300 –500 mg/day in 2 doses for regimens not
containing valproate

How to Dose
✽ Bipolar disorder (monotherapy , see chart): for the first 2 weeks
administer 25 mg/day; at week 3 increase to 50 mg/day; at week 5
increase to 100 mg/day; at week 6 increase to 200 mg/day; maximum
dose generally 200 mg/day
✽ Bipolar disorder (adjunct to valproate): for the first 2 weeks
administer 25 mg every other day; at week 3 increase to 25 mg/day; at
week 5 increase to 50 mg/day; at week 6 increase to 100 mg/day;
maximum dose generally 100 mg/dayPatients ages 2 –12 with epilepsy are dosed based on body weight
and concomitant medications
Tablet 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg
Chewable tablet 2 mg, 5 mg, 25 mg
Orally disintegrating tablet 25 mg, 50 mg, 100 mg, 200 mg
Extended-release tablet 25 mg, 50 mg, 100 mg, 200 mg, 250 mg,
300 mg
Bipolar disorder (adjunct to enzyme-inducing antiepileptic drugs):
for the first 2 weeks administer 50 mg/day; at week 3 increase to
100 mg/day in divided doses; starting at week 5 increase by 100

mg/day each week; maximum dose generally 400 mg/day in divided
doses

When lamotrigine is added to epilepsy treatment that includes
valproate (ages 12 and older): for the first 2 weeks administer 25 mg
every other day; at week 3 increase to 25 mg/day; every 1 –2 weeks
can increase by 25 –50 mg/day; usual maintenance dose 100 –400
mg/day in 1 –2 doses or 100 –200 mg/day if lamotrigine is added to
valproate alone
carbamazepine, phenytoin, phenobarbital, or primidone (without
valproate) (ages 12 and older): for the first 2 weeks administer 50
mg/day; at week 3 increase to 100 mg/day in 2 doses; every 1 –2
weeks can increase by 100 mg/day; usual maintenance dose 300 –
500 mg/day in 2 doses
When converting from a single enzyme-inducing antiepileptic drug
to lamotrigine monotherapy for epilepsy: titrate as described above
to 500 mg/day in 2 doses while maintaining dose of previous
medication; decrease first drug in 20% decrements each week over
the next 4 weeks

When converting from valproate to lamotrigine monotherapy for
epilepsy: titrate as described above to 200 mg/day while maintaining

✽ Very slow dose titration may reduce the incidence of skin rash
✽ If lamotrigine is added to patients taking valproate, remember that
valproate inhibits lamotrigine metabolism and therefore titration rate
and ultimate dose of lamotrigine should be reduced by 50% to reduce
the risk of rash
✽ Thus, if concomitant valproate is discontinued after lamotrigine
dose is stabilized, then the lamotrigine dose should be cautiously
doubled over at least 2 weeks in equal increments each week following
discontinuation of valproatedose of valproate, then gradually increase lamotrigine up to 500
mg/day while gradually discontinuing valproate
Seizures (under age 12): see Children and Adolescents
Therefore, dose should not be titrated faster than recommended
because of possible risk of increased side ef fects, including rash
If patient stops taking lamotrigine for 5 days or more it may be
necessary to restart the drug with the initial dose titration, as rashes

have been reported on reexposure
Advise patient to avoid new medications, foods, or products during
the first 3 months of lamotrigine treatment in order to decrease the
risk of unrelated rash; patient should also not start lamotrigine
within 2 weeks of a viral infection, rash, or vaccination

OverdoseAlso, if concomitant enzyme-inducing antiepileptic drugs such as
carbamazepine, phenobarbital, phenytoin, and primidone are
discontinued after lamotrigine dose is stabilized, then the
lamotrigine dose should be maintained for 1 week following
discontinuation of the other drug and then reduced by half over 2
weeks in equal decrements each week
Since oral contraceptives and pregnancy can decrease lamotrigine
levels, adjustments to the maintenance dose of lamotrigine are
recommended in women taking, starting, or stopping oral
contraceptives, becoming pregnant, or after delivery
Chewable dispersible tablets should only be administered as whole
tablets; dose should be rounded down to the nearest whole tablet
Chewable dispersible tablets can be dispersed by adding the tablet to
liquid (enough to cover the drug); after approximately 1 minute the
solution should be stirred and then consumed immediately in its
entirety
Orally disintegrating tablet should be placed onto the tongue and

entirety
moved around in the mouth; the tablet will disintegrate rapidly and
can be swallowed with or without food or water
Some fatalities have occurred; ataxia, nystagmus, seizures, coma,
intraventricular conduction delay

How to Stop
✽ Rapid discontinuation can increase the risk of relapse in bipolar
disorder
PharmacokineticsSafe
No
Taper over at least 2 weeks
Patients with epilepsy may seize upon withdrawal, especially if
Elimination half-life in healthy volunteers approximately 33 hours
after a single dose of lamotrigine
Elimination half-life in patients receiving concomitant valproate
treatment approximately 59 hours after a single dose of lamotrigine
Elimination half-life in patients receiving concomitant enzyme-
inducing antiepileptic drugs (such as carbamazepine, phenobarbital,
phenytoin, and primidone) approximately 14 hours after a single
dose of lamotrigine

✽ Valproate increases plasma concentrations and half-life of
lamotrigine, requiring lower doses of lamotrigine (half or less)
✽ Use of lamotrigine with valproate may be associated with an
increased incidence of rashMetabolized in the liver through glucorunidation but not through the
CYP450 enzyme system
Inactive metabolite
Renally excreted
Lamotrigine inhibits dihydrofolate reductase and may therefore
reduce folate concentrations
Rapidly and completely absorbed; bioavailability not af fected by
food
Enzyme-inducing antiepileptic drugs (e.g., carbamazepine,
phenobarbital, phenytoin, primidone) may increase the clearance of
lamotrigine and lower its plasma levels
Oral contraceptives may decrease plasma levels of lamotrigine
No likely pharmacokinetic interactions of lamotrigine with lithium,
oxcarbazepine, atypical antipsychotics, or antidepressants

(PCP) have been reported in patients taking lamotrigine due to a
lack of specificity of the screening tests

✽ Life-threatening rashes have developed in association with
lamotrigine use; lamotrigine should generally be discontinued at the
first sign of serious rash
✽ Risk of rash may be increased with higher doses, faster dose
escalation, concomitant use of valproate, or in children under age 12
Patient should be instructed to report any symptoms of
hypersensitivity immediately (fever; flu-like symptoms; rash;
blisters on skin or in eyes, mouth, ears, nose, or genital areas;
swelling of eyelids, conjunctivitis, lymphadenopathy)
Aseptic meningitis has been reported rarely in association with
lamotrigine use
Patients should be advised to report any symptoms of aseptic
meningitis immediately; these include headache, chills, fever ,
vomiting and nausea, a stif f neck, and sensitivity to light
Lamotrigine may cause a rare but serious immune system reaction
called hemophagocytic lymphohistiocytosis (HLH), which causes an
uncontrolled immune system response

Patients should be instructed to report any symptoms of HLH
immediately (fever; rash; pain, swelling, or tenderness over the liver
area; swollen lymph nodes; yellow skin or eyes; unusual bleeding;
nervous system problems such as seizures, visual disturbance, or
trouble walking)

Do Not Use
Hepatic ImpairmentDepressive ef fects may be increased by other CNS depressants
(alcohol, MAOIs, other anticonvulsants, etc.)
A small number of people may experience a worsening of seizures
Lamotrigine binds to tissue that contains melanin, so for long-term
treatment ophthalmological checks may be considered
If there is a proven aller gy to lamotrigine
Lamotrigine is renally excreted, so the maintenance dose may need
to be lowered
may require supplemental doses of lamotrigine
Dose adjustment not necessary in mild impairment

Elderly
✽ Risk of rash is increased in pediatric patients, especially in children
under 12 and in children taking valproateInitial, escalation, and maintenance doses should be reduced by 25%
in patients with moderate and severe liver impairment without
ascites and 50% in patients with severe liver impairment with
ascites
Clinical experience is limited
Ages 2 and older: approved as add-on for Lennox-Gastaut syndrome
Ages 2 and older: approved as add-on for partial seizures
No other use of lamotrigine is approved for patients under 16 years
of age
When lamotrigine is added to treatment that includes valproate (ages
2–12): for the first 2 weeks administer 0.15 mg/kg per day in 1 –2
doses rounded down to the nearest whole tablet; at week 3 increase

to 0.3 mg/kg per day in 1 –2 doses rounded down to the nearest

Pregnancywhole tablet; every 1 –2 weeks can increase by 0.3 mg/kg per day
rounded down to the nearest whole tablet; usual maintenance dose
1–5 mg/kg per day in 1 –2 doses (maximum generally 200 mg/day)
or 1–3 mg/kg per day in 1 –2 doses if lamotrigine is added to
When lamotrigine is added to treatment with carbamazepine,
phenytoin, phenobarbital, or primidone (without valproate) (ages 2 –
12): for the first 2 weeks administer 0.6 mg/kg per day in 2 doses
rounded down to the nearest whole tablet; at week 3 increase to 1.2
mg/kg per day in 2 doses rounded down to the nearest whole tablet;
every 1 –2 weeks can increase by 1.2 mg/kg per day rounded down
to the nearest whole tablet; usual maintenance dose 5 –15 mg/kg per
day in 2 doses (maximum dose generally 400 mg per day)
Clearance of lamotrigine may be influenced by weight, such that
patients weighing less than 30 kg may require an increase of up to
50% for maintenance doses

✽ If treatment with lamotrigine is continued, plasma concentrations of
lamotrigine may be reduced during pregnancy , possibly requiring
increased doses with dose reduction following delivery
✽ For bipolar patients, lamotrigine should generally be discontinued
✽ For bipolar patients in whom treatment is discontinued, given the
risk of relapse in the postpartum period, lamotrigine should generally
be restarted immediately after delivery
anticonvulsants such as lamotrigine if treatment of bipolar disorder is
required during pregnancy , but lamotrigine may be preferable to other
anticonvulsants such as valproate if anticonvulsant treatment is
required during pregnancyUse in women of childbearing potential requires weighing potential
Pregnancy registry data show increased risk of isolated cleft palate

or cleft lip deformity with first trimester exposure
Pregnancy exposure registry for lamotrigine: 1-800-336-2176

✽ Generally recommended either to discontinue drug or bottle feed
be preferable to lithium or lamotrigine during the postpartum period
when breast feeding
Depressive stages of bipolar disorder (bipolar depression)
To prevent recurrences of both depression and mania in bipolar
disorder

 Pearls
✽ Lamotrigine is a first-line treatment option that may be best for
patients with bipolar depression
✽ Seems to be more ef fective in treating depressive episodes than
manic episodes in bipolar disorder (treats from below better than it
treats from above)
✽ Seems to be ef fective in preventing both manic relapses as well as
depressive relapses (stabilizes both from above and from below)
although it may be even better for preventing depressive relapses than
for preventing manic relapses
✽ Despite convincing evidence of ef ficacy in bipolar disorder , is often
used less frequently than anticonvulsants without convincing evidence
of efficacy in bipolar disorder (e.g., gabapentin or topiramate)
✽ Low levels of use may be based upon exaggerated fears of skin
rashes or lack of knowledge about how to manage skin rashes if they
occurMay not be as ef fective in the manic stage of bipolar disorder

Unstable mood, especially depression, in bipolar disorder
Pain

✽ May actually be one of the best tolerated mood stabilizers with little
weight gain or sedation
✽ To manage rashes in bipolar patients receiving lamotrigine, realize
that rashes that occur within the first 5 days or after 8 –12 weeks of
treatment are rarely drug-related, and learn the clinical distinctions
between a benign rash and a serious rash (see What to Do About Side
Effects section)Actual risk of serious skin rash may be comparable to agents
erroneously considered “safer ” including carbamazepine, phenytoin,
phenobarbital, and zonisamide
Rashes are common even in placebo-treated patients in clinical trials
of bipolar patients (5 –10%) due to non-drug-related causes
including eczema, irritant, and aller gic contact dermatitis, such as
poison ivy and insect bite reactions
Rash, including serious rash, appears riskiest in younger children, in
those who are receiving concomitant valproate, and/or in those
receiving rapid lamotrigine titration and/or high dosing

Risk of serious rash is less than 1% and has been declining since
slower titration, lower dosing, adjustments to use of concomitant
valproate administration, and limitations on use in children under 12
have been implemented
Incidence of serious rash is very low (approaching zero) in recent
studies of bipolar patients

✽ Given the limited treatment options for bipolar depression, patients
with benign rashes can even be rechallenged with lamotrigine 5 –12
mg/day with very slow titration after risk/benefit analysis if they are
informed, reliable, closely monitored, and warned to stop lamotrigine
and contact their physician if signs of hypersensitivity occurBenign rashes related to lamotrigine may af fect up to 10% of
patients and resolve rapidly with drug discontinuation
Only a third of bipolar patients experience adequate relief with a
monotherapy , so most patients need multiple medications for best
control
Lamotrigine is useful in combination with atypical antipsychotics
and/or lithium for acute mania
Usefulness for bipolar disorder in combination with anticonvulsants
other than valproate is not well demonstrated; such combinations
can be expensive and are possibly inef fective or even irrational
May be useful as an adjunct to atypical antipsychotics for rapid
onset of action in schizophrenia

May be useful as an adjunct to antidepressants in major depressive
disorder
Early studies suggest possible utility for patients with neuropathic
pain such as diabetic peripheral neuropathy , HIV -associated
neuropathy , and other pain conditions including migraine

Calabrese  JR , Bowden  CL , Sachs  GS , et al. A double-blind placebo-
controlled study of lamotrigine monotherapy in outpatients with bipolar I
depression  . J Clin Psych  1999  ;60 :79 –88 .
Calabrese  JR , Sullivan  JR , Bowden  CL , et al. Rash in multicenter trials of
lamotrigine in mood disorders: clinical relevance and management  . J Clin
Psychiatry  2002  ;63 :1012  –19.
Culy  CR , Goa KL . Lamotrigine. A review of its use in childhood epilepsy
. Paediatr Drugs  2000  ;2 :299 –330 .
Cunningham  M , Tennis  P , and the International Lamotrigine Pregnancy
Registry Scientific Advisory Committee. Lamotrigine and the risk of
malformations in pregnancy  . Neur ology  2005  ;64 :955–60 .
Goodwin  GM , Bowden  CL , Calabrese  JR , et al. A pooled analysis of 2
placebo-controlled 18-month trials of lamotrigine and lithium maintenance
treatment in bipolar I disorder  . J Clin Psychiatry  2004  ;65 :432–41 .

Green  B . Lamotrigine in mood disorders  . Curr Med Res Opin  2003  ;19
:272–7 .

Lemborexant
Brands
Generic?
No
 Class
How Long Until It W orksDayvigo
Dual orexin receptor antagonist (DORA); hypnotic
Insomnia (pr oblems with sleep onset and/or maintenance)
Orexin serves to stabilize and promote wakefulness; lemborexant
binds to orexin 1 and orexin 2 receptors, blocking orexin from
binding there and thus preventing it from promoting wakefulness

If It W orks
TestsGenerally takes ef fect in less than an hour
could theoretically be decreased over time
No controlled trials of combinations with other hypnotics or
psychotropic drugs

Sedation
What to Do About Side EffectsTheoretically due to downstream ef fects of blocking orexin
receptors
Sedation, headache, abnormal dreams
Sleep paralysis, hypnagogic/hypnopompic hallucinations, and
cataplexy-like symptoms (rare)
Wait
To avoid problems with memory , take lemborexant only if planning

How to Dose
 Dosing T ipsLower the dose
Switch to a dif ferent hypnotic
5 mg/night
Tablet 5 mg, 10 mg
Starting dose is 5 mg, no more than once per night immediately
before going to bed
Should not take unless there are at least 7 hours remaining of sleep
time
Patients who tolerate but do not respond to 5 mg may receive the 10
mg dose; 10 mg is the maximum recommended dose
Use the lowest ef fective dose for the patient

Overdose
How to Stop
PharmacokineticsTaking lemborexant with or soon after a meal can delay the time to
sleep onset
Limited data; sedation
Has been evaluated and found ef fective in trials up to 1 year
Lemborexant is under review by the DEA for scheduling
No evidence of physiological dependence or withdrawal symptoms
in clinical trials
Terminal elimination half-life 52.8 hours; ef fective half-life 17 –29
hours
Metabolized primarily by CYP450 3A4 and to a lesser extent by
CYP450 3A5

 Other W arnings/Pr ecautionsAbsorption is delayed in the presence of food
Not recommended in patients taking concomitant strong or
moderate CYP450 3A4 inhibitors
Patients taking mild CYP450 3A4 inhibitors should receive a
maximum dose of 5 mg/night
moderate CYP450 3A4 inducers
Lemborexant decreases the AUC of drugs that are CYP450 2B6
substrates (e.g., bupropion, methadone), potentially reducing their
ideation

Do Not Use
Hepatic ImpairmentLemborexant should only be administered at bedtime
Label contains warning for risk of next-day impaired alertness and
motor coordination
patients taking sedative hypnotics; if complex sleep behaviors occur ,
If patient has narcolepsy
If there is a proven aller gy to lemborexant
Somnolence may be increased in patients with severe renal
Dose adjustment not necessary for mild hepatic impairment
Initial and maximum recommended dose 5 mg/night for moderate

Elderly
 PregnancyNot recommended for patients with severe hepatic impairment
Not studied in patients with cardiac impairment
When administered during or ganogenesis, the no observed adverse
effect levels (NOAELs) for fetal toxicity are approximately >100
and 23 times the maximum recommended human dose (MRHD)
based on AUC in rats and rabbits, respectively

Primary T arget SymptomsWhen administered during pregnancy and lactation, the NOAEL for
toxicity is 93 times the MRHD based on AUC in rats
Pregnancy registry for lemborexant: 1-888-274-2378
Unknown if lemborexant is secreted in human breast milk, but all

PearlsNighttime awakenings
DORAs are reversible inhibitors of orexin, so their action can
theoretically be reversed as endogenous orexin is released upon
awakening, and even to a certain extent in the middle of the night
This is unlike Z-drug and benzodiazepine hypnotics, which do not
reverse upon wakening
DORAs hypothetically switch of f alertness-related circuits,
countering inappropriate wakefulness associated with insomnia,
whereas Z-drug and benzodiazepine hypnotics and melatonin
hypothetically switch on sleep-related circuits
Curbing alertness-related factors in patients with insomnia may have
some theoretical ef ficacy and tolerability advantages over enhancing
sleep drives, sedation, and somnolence
Targeting insomnia may prevent the onset of major depressive
disorder (MDD) or generalized anxiety disorder (GAD) and help
maintain remission after recovery from MDD or GAD
Rebound insomnia was not observed in clinical trials

May be ef fective in patients with insomnia unresponsive to
medications with other mechanisms of action (e.g., Z-drug
hypnotics, benzodiazepines)

Murphy  P , Moline  M , Mayleben  D , et al. Lemborexant, a dual orexin
receptor antagonist (DORA) for the treatment of insomnia disorder: results
from a Bayesian, adaptive, randomized, double-blind, placebo-controlled
study  . J Clin Sleep Med  2017  ;13 (11 ):1289 –99 .
Rosenber g R , Murphy  P , Zammit  G , et al. Comparison of lemborexant
with placebo and zolpidem tartrate extended release for the treatment of
older adults with insomnia disorder: a phase 3 randomized clinical trial  .
JAMA Netw Open  2019  ;2 (12 ):e1918254  . doi:
10.1001/jamanetworkopen.2019.18254  .
Vermeeren  A , Jongen  S , Murphy  M , et al. On-the-road driving
performance the morning after bedtime administration of lemborexant in
healthy adult and elderly volunteers  . Sleep  2019  ;42 (4 ). pii: zsy260. doi:
10.1093/sleep/zsy260  .

Levetiracetam
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Keppra
Keppra XR
Anticonvulsant, synaptic vesicle protein SV2A modulator
Adjunct therapy for partial seizur es in patients with epilepsy
(>16 years of age for extended-r elease, >4 years of age for
immediate-r elease)
Adjunct therapy for myoclonic seizur es in juvenile myoclonic
epilepsy (ages 12 and older)

✽ Binds to synaptic vesicle protein SV2A, which is involved in
synaptic vesicle exocytosis
If It W orksAdjunct therapy for primary generalized tonic –clonic seizur es
in idiopathic generalized epilepsy (ages 6 and older)
Mania
Opposes the activity of negative modulators of GABA- and glycine-
gated currents and partially inhibits N-type calcium currents in
neuronal cells
optimize clinical ef fects

If It Doesn ’t Work (for Bipolar Disorder or Neur opathic Pain)
✽ May be ef fective only in a subset of bipolar patients, in some
work at allThe goal of treatment of chronic neuropathic pain is to reduce
Continue treatment until all symptoms are gone or until mood is
stable and then continue treating indefinitely as long as
improvement persists
Continue treatment indefinitely to avoid recurrence of seizures,
mania, and pain

Consider increasing dose or switching to another agent with better
demonstrated ef ficacy in bipolar disorder or neuropathic pain

Tests
✽ Sedation, dizziness, ataxia, asthenia
 Life-Thr eatening or Danger ous Side EffectsLevetiracetam is itself a second-line augmenting agent to numerous
other anticonvulsants, lithium, and atypical antipsychotics for
bipolar disorder and to gabapentin, tiagabine, other anticonvulsants,
SNRIs, and TCAs for neuropathic pain
CNS side ef fects may be due to excessive actions on SV2A synaptic
vesicle proteins or to actions on various voltage-sensitive ion
channels
Hematologic abnormalities (decrease in red blood cell count and
hemoglobin)
Rare severe dermatologic reactions [Stevens-Johnson syndrome
(SJS), toxic epidermal necrolysis (TEN)]

Sedation
Best Augmenting Agents for Side EffectsActivation of suicidal ideation and acts (rare)
Changes in behavior (aggression, agitation, anxiety , hostility)
Wait
Wait
Wait

How to Dose
 Dosing T ips1000 –3000 mg/day in 2 doses
Tablet 250 mg, 500 mg, 750 mg, 1000 mg
Extended-release tablet 500 mg, 750 mg, 1000 mg, 1500 mg
Tablet for suspension 250 mg, 500 mg, 750 mg, 1000 mg
Intravenous injection 500 mg/5 mL
Intravenous injection (levetiracetam in sodium chloride) 500
mg/100 mL, 1000 mg/100 mL, 1500 mg/100 mL
Initial 1000 mg/day in 1 (extended-release) or 2 (immediate-release)
doses; after 2 weeks can increase by 1000 mg/day every 2 weeks;
maximum dose generally 3000 mg/day
Some patients may tolerate and respond to doses greater than 3000
mg/day

Overdose
How to Stop
disorder
PharmacokineticsNo fatalities; sedation, agitation, aggression, respiratory depression,
coma
Safe
No
Taper
Elimination half-life approximately 6 –8 hours
Not metabolized by CYP450 enzymes
Does not inhibit/induce CYP450 enzymes

Do Not Use
Renal ImpairmentRenally excreted
Because levetiracetam is not metabolized by CYP450 enzymes and
does not inhibit or induce CYP450 enzymes, it is unlikely to have
significant pharmacokinetic drug interactions
Depressive ef fects may be increased by other CNS depressants
Monitor patients for behavioral symptoms (aggression, agitation,
anger , anxiety , apathy , depression, hostility , irritability) as well as
for possible psychotic symptoms or suicidality
If there is a proven aller gy to levetiracetam

Elderly
 Childr en and AdolescentsRecommended dose for patients with mild impairment may be
between 500 mg and 1500 mg twice a day
Recommended dose for patients with moderate impairment may be
between 250 mg and 750 mg twice a day
Recommended dose for patients with severe impairment may be
between 250 mg and 500 mg twice a day
Patients on dialysis may require doses between 500 mg and 1000
mg once a day , with a supplemental dose of 250 –500 mg following
dialysis
Dose adjustment usually not necessary
No specific recommendations
Safety and ef ficacy not established under age 16

Pregnancy
evidence of ef ficacy than levetiracetam, should generally be restarted
immediately after delivery if patient is unmedicated during pregnancyChildren may require higher doses than adults; dosing should be
adjusted according to weight

Lack of convincing ef ficacy for treatment of bipolar disorder or
chronic neuropathic pain suggests risk/benefit ratio is in favor of
discontinuing levetiracetam during pregnancy for these indications

✽ For bipolar patients, levetiracetam should generally be discontinued
✽ Atypical antipsychotics may be preferable to levetiracetam if
treatment of bipolar disorder is required during pregnancy
treatment for postpartum episodes of bipolar disorderBipolar symptoms may recur or worsen during pregnancy and some

be safer than levetiracetam during the postpartum period when

 Pearls
✽ Off-label use second-line and as an augmenting agent may be
justified for bipolar disorder and neuropathic pain unresponsive to
other treatmentsPatients on concomitant drugs (lack of drug interactions)
Treatment-refractory bipolar disorder
Treatment-refractory neuropathic pain
Efficacy for bipolar disorder or neuropathic pain not well
documented
Seizures
Pain
Mania
Well studied in epilepsy

✽ Unique mechanism of action suggests utility where other
anticonvulsants fail to work
✽ Unique mechanism of action as modulator of synaptic vesicle
release suggests theoretical utility for clinical conditions that are
hypothetically linked to excessively activated neuronal circuits, such
as anxiety disorders and neuropathic pain as well as epilepsy
Ben-Menachem  E . Levetiracetam: treatment in epilepsy  . Expert Opin
Pharmacother  2003  ;4 (11 ):2079  –88.
French  J . Use of levetiracetam in special populations  . Epilepsia  2001  ;42
(Suppl 4): S40 –3.
Leppik  IE . Three new drugs for epilepsy: levetiracetam, oxcarbazepine,
and zonisamide  . J Child Neur ol 2002  ;17 (Suppl 1): S53 –7.
Lynch  BA , Lambeng  N , Nocka  K , et al. The synaptic vesicle protein
SV2A is the binding site for the antiepileptic drug levetiracetam  . Proc Natl
Acad Sci USA  2004  ;101 :9861  –6.
Pinto  A , Sander  JW . Levetiracetam: a new therapeutic option for

refractory epilepsy  . Int J Clin Pract  2003  ;57 (7 ):616–21 .

Brands
Generic?
No
 Class
(bold for FDA appr oved)Fetzima
SNRI (dual serotonin and norepinephrine reuptake inhibitor);

If It W orksBoosts neurotransmitters serotonin, norepinephrine/noradrenaline,
cortex, which lar gely lacks dopamine transporters, levomilnacipran
Onset of therapeutic actions is usually not immediate, but often
If it is not working within 6 or 8 weeks, it may require a dosage
increase (of f label), or it may not work at all
symptoms

symptoms

If It Doesn ’t WorkTreatment of depression most often reduces or even eliminates
stopped
(remission) or significantly reduced
Many depressed patients only have a partial response where some

Augmentation experience is limited compared to other
Benzodiazepines can reduce insomnia and anxiety
Check heart rate and blood pressure before initiating treatment and
regularly during treatment

 Life-Thr eatening or Danger ous Side EffectsTheoretically due to increases in serotonin and norepinephrine
norepinephrine on acetylcholine release causing urinary retention or
constipation)
contrast to most therapeutic ef fects, which are delayed and are
Nausea, vomiting, constipation
Hyperhidrosis
Tachycardia, heart rate increase, palpitations
Urinary hesitancy or retention
Rare induction of mania and activation of suicidal ideation

Sedation
✽ For urinary hesitancy , give an alpha 1 blocker such as tamsulosin or
naftopidilReported but not expected
Wait
Wait
Wait
Benzodiazepines for anxiety , agitation

How to Dose
 Dosing T ipsMirtazapine for insomnia, agitation, and gastrointestinal side ef fects
discontinuation of levomilnacipran
40–120 mg once daily
Extended-release capsule 20 mg, 40 mg, 80 mg, 120 mg
Initial dose 20 mg once daily for 2 days, then increase to 40 mg
once daily; can increase by 40 mg/day every 2 or more days;
maximum recommended dose 120 mg once daily

Overdose
How to Stop
PharmacokineticsDo not break or chew levomilnacipran capsules, as this will alter
possibility of activating a bipolar disorder and switch to a mood
No fatalities have been reported; experience is limited
Has not been evaluated in controlled studies, but long-term
treatment of major depressive disorder is generally necessary
No
Taper is prudent, but usually not necessary
Metabolized by CYP450 3A4; renally excreted
Terminal elimination half-life approximately 12 hours

drugs) after discontinuing levomilnacipran
Strong CYP450 3A4 inhibitors, such as ketoconazole, can increase
plasma levels of levomilnacipran; do not exceed 80 mg once daily
of levomilnacipran if used with a strong CYP450 3A4 inhibitor
Alcohol may interact with the extended-release properties of
levomilnacipran, causing a pronounced accelerated drug release
(“drug dumping ” ); thus, taking levomilnacipran with alcohol is not
Switching from or addition of other norepinephrine reuptake
inhibitors should be done with caution, as the additive pro-

noradrener gic ef fects may enhance therapeutic actions in depression,
but also enhance noradrener gically mediated side ef fects

Do Not Use
Renal ImpairmentUse with caution in patients with bipolar disorder unless treated
Use with caution in patients with controlled angle-closure glaucoma
Not approved in children, so when treating children of f label,
carefully weigh the risks and benefits of pharmacological treatment
against the risks and benefits of non-treatment with antidepressants
companies
If there is a proven aller gy to levomilnacipran or milnacipran

Elderly
 Childr en and AdolescentsMaximum dose 80 mg once daily for moderate impairment
Maximum dose 40 mg once daily for severe impairment
Reduction in risk of suicidality with antidepressants compared to

PregnancyUse with caution, observing for activation of known or unknown

Breast FeedingFor many patients, this may mean continuing treatment during
pregnancy
Exposure to serotonin reuptake inhibitors early in pregnancy may be
associated with increased risk of septal heart defects (absolute risk is
small)
Use of serotonin reuptake inhibitors beyond the 20th week of
pregnancy may be associated with increased risk of pulmonary
hypertension in newborns, although this is not proven
Exposure to serotonin reuptake inhibitors late in pregnancy may be
associated with increased risk of gestational hypertension and
preeclampsia

essants

Potential DisadvantagesUnknown if levomilnacipran is secreted in human breast milk, but
the mother
Cost
Patients with urologic disorders, prostate disorders

 Pearls
✽ Has greater potency for norepinephrine reuptake blockade than for
serotonin reuptake blockade, but this is of unclear clinical significance
as a dif ferentiating feature from other SNRIs, although it might
contribute to theoretical ef fects in fibromyalgia and chronic pain
✽ Potent noradrener gic actions may account for possibly higher
incidence of sweating and urinary hesitancy than some other SNRIsPatients with borderline or uncontrolled hypertension
Patients with agitation and anxiety (short-term)
Urinary hesitancy more common in men than women and in older
men than in younger men
Alpha 1 antagonists such as tamsulosin or naftopidil can reverse
urinary hesitancy or retention
Alpha 1 antagonists given prophylactically may prevent urinary
hesitancy or retention in patients at higher risk, such as elderly men
with borderline urine flow
Nonresponse to levomilnacipran in elderly may require

consideration of mild cognitive impairment or Alzheimer disease

Auclair  AL , Martel  JC , AssiÃ©  MB , et al. Levomilnacipran (F2695), a
norepinephrine-preferring SNRI: profile in vitro and in models of
depression and anxiety  . Neur opharmacology  2013  ;70 :338–47 .
Citrome  L. Levomilnacipran for major depressive disorder: a systematic
review of the ef ficacy and safety profile for this newly approved
antidepressant –what is the number needed to treat, number needed to harm
and likelihood to be helped or harmed?  Int J Clin Pract  2013  ;67 :1089  –
104.
Mago  R , Forero  G , Greenber g WM , Gommoll  C , Chen  C. Safety and
tolerability of levomilnacipran ER in major depressive disorder: results
from an open-label, 48-week extension study  . Clin Drug Investig  2013  ;33
:761–71 .

Lisdexamfetamine
Brands
Generic?
No
 Class
(bold for FDA appr oved)Vyvanse
Neuroscience-based Nomenclature: dopamine and norepinephrine
Stimulant
older)
Binge eating disorder

✽ Lisdexamfetamine is a prodrug of dextroamphetamine and is thus
not active until after it has been absorbed by the intestinal tract and
converted to dextroamphetamine (active component) and l-lysine
✽ Once converted to dextroamphetamine, it increases norepinephrine
and especially dopamine actions by blocking their reuptake and
facilitating their release
If It W orks (for ADHD)Enhancement of dopamine and norepinephrine in certain brain
regions (e.g., dorsolateral prefrontal cortex) may improve attention,
concentration, executive dysfunction, and wakefulness

Consider the presence of noncompliance and counsel patients and
parents

parents
etc.)

Tests
How Drug Causes Side EffectsFor the expert, can combine with modafinil or atomoxetine for
ADHD
or ADHD
Increases in norepinephrine especially peripherally can cause
autonomic side ef fects, including tremor , tachycardia, hypertension,
and cardiac arrhythmias
abuse

✽ Anorexia, nausea, dry mouth, constipation, diarrhea, weight loss
SedationCan temporarily slow normal growth in children (controversial)
Sexual dysfunction long-term (impotence, libido changes), but can
Psychotic episodes
Seizures

Wait
Switch to another long-acting stimulant
agent
ADHD: 30 –70 mg/day
Binge eating disorder: 50 –70 mg/day

How to Dose
 Dosing T ipsCapsule 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg
Chewable tablet 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg
Initial 30 mg/day in the morning; can increase by 10 –20 mg each
week; maximum dose generally 70 mg/day
Binge eating disorder: initial 30 mg/day in the morning; can
increase by 20 mg each week; maximum dose generally 70 mg/day
10–12 hour duration of clinical action
Capsules can either be taken whole or they can be opened and the
contents dissolved in water
When taken in water , the entire solution should be consumed
immediately
Dose of a single capsule should not be divided
Once daily dosing can be an important practical element in
stimulant utilization, eliminating the hassle and pragmatic
difficulties of lunchtime dosing at school, including storage
problems, potential diversion, and the need for a medical
professional to supervise dosing away from home
Avoid dosing after the morning because of the risk of insomnia

✽ May be able to give drug holidays for patients with ADHD over the
summer in order to reassess therapeutic utility and ef fects on growth
suppression as well as to assess any other side ef fects and the need to
reinstitute stimulant treatment for the next school term
Overdose
Can be used long-term for ADHD when ongoing monitoring

How to Stop
Schedule II drug
Theoretically less abuse potential than other stimulants when taken
as directed because it is inactive until it reaches the gut and thus has
delayed time to onset as well as long duration of action
Careful supervision is required during withdrawal from abuse use
1 hour to maximum concentration of lisdexamfetamine, 3.5 hours to
maximum concentration of dextroamphetamine
Duration of clinical action 10 –12 hours

(ammonium chloride, sodium phosphate, etc.) lower amphetamine

effects of amphetamine

Amphetamines may antagonize hypotensive ef fects of V eratrum

May worsen symptoms of thought disorder and behavior
behavior

fatigue

Do Not UseMay lower the seizure threshold
the addition of a mood stabilizer and/or discontinuation of
lisdexamfetamine
an expert
If patient has hyperthyroidism

Elderly
 Childr en and AdolescentsSevere impairment: maximum dose 50 mg/day
End-stage renal disease: maximum dose 30 mg/day
Do not use in patients with structural cardiac abnormalities, cardiac
myopathy , serious heart arrhythmia, or coronary artery disease
Safety and ef ficacy not established in children under age 6

PregnancyHalf-life and duration of clinical action tend to be shorter in younger
children

Potential Disadvantagesmajor malformations occurred in rat or rabbit studies
For ADHD patients, lisdexamfetamine should generally be
Only approved treatment for binge eating disorder
Although restricted as a Schedule II controlled substance like other
stimulants, as a prodrug lisdexamfetamine may have less propensity
for abuse, intoxication, or dependence than other stimulants
May be particularly useful in adult patients without prior diagnosis
and treatment of ADHD as a child to prevent abuse and diversion
since lisdexamfetamine may be less abusable than other stimulants

 PearlsPatients with current or past substance abuse
Binge eating
First medication approved for the treatment of binge eating disorder
Theoretically , efficacy in binge eating disorder is due to controlled-
release of a stimulant enhancing tonic over phasic dopamine
neuronal firing
Theoretically , binge eating in binge eating disorder could be due to a
shift from reward-related eating to habit, and from impulsivity to

vigilance
dysfunction, delayed ejaculation, and anor gasmiacompulsivity due to a shift of control of dopamine from dorsal to
ventral striatum, which can be reversed by lisdexamfetamine
May be useful for treatment of depressive symptoms in medically ill
elderly patients
May be useful for treatment of post-stroke depression
A classical augmentation strategy for treatment-refractory
Specifically , may be useful for treatment of cognitive dysfunction
May also be useful for the treatment of cognitive impairment,

Some patients respond to or tolerate lisdexamfetamine better than
methylphenidate or amphetamine and vice versa

Biederman  J , Boellner  SW , Childress  A , et al. Lisdexamfetamine
dimesylate and mixed amphetamine salts extended-release in children with
ADHD: a double-blind, placebo-controlled, crossover analog classroom
study  . Biol Psychiatry  2007  ;62 (9 ):970–6 .
Biederman  J , Krishnan  S , Zhang  Y , McGough  JJ , Findling  RL . Efficacy
and tolerability of lisdexamfetamine dimesylate (NRP-104) in children with
attention-deficit/hyperactivity disorder: a phase III, multicenter ,
randomized, double-blind, forced dose, parallel-group study  . Clin Ther
2007  ;29 (3 ):450–63 .Atypical antipsychotics may be useful in treating stimulant or

Lithium
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Eskalith
Eskalith CR
Lithobid slow-release tablets
Lithostat tablets
Lithium carbonate tablets
Lithium citrate syrup
Neuroscience-based Nomenclature: lithium enzyme interactions (Li-
Eint)
Mood stabilizer

✽ May alter intracellular signaling through actions on second
messenger systemsManic episodes of manic-depressive illness (adults)
Acute mania/mixed mania (ages 7 and older , monotherapy)
Maintenance tr eatment for manic-depr essive patients with a
history of mania
Bipolar maintenance (ages 7 and older , monotherapy)
Bipolar depression (adults)
Major depressive disorder (adults, adjunctive)
Vascular headache (adults)
Neutropenia (adults)
Unknown and complex
Alters sodium transport across cell membranes in nerve and muscle
cells
Alters metabolism of neurotransmitters including catecholamines
and serotonin
Specifically , inhibits inositol monophosphatase, possibly af fecting
neurotransmission via phosphatidyl inositol second messenger
system

If It W orks
stabilization of moodAlso reduces protein kinase C activity , possibly af fecting genomic
expression associated with neurotransmission
Increases cytoprotective proteins, activates signaling cascade
utilized by endogenous growth factors, and increases gray matter
content, possibly by activating neurogenesis and enhancing trophic
actions that maintain synapses
1–3 weeks
The goal of treatment is complete remission of symptoms (i.e.,
mania and/or depression)
Continue treatment indefinitely to avoid recurrence of mania or

TestsOther patients may be nonresponders, sometimes called treatment-
Consider checking plasma drug level, increasing dose, switching to
another agent, or adding an appropriate augmenting agent
Valproate

✽ Before initiating treatment, kidney function tests (including
creatinine and urine specific gravity) and thyroid function tests;
electrocardiogram for patients over 50
✽ Frequent tests to monitor trough lithium plasma levels (about 12
hours after last dose; should generally be between 1.0 and 1.5 mEq/L
for acute treatment, 0.6 and 1.2 mEq/L for chronic treatment)
✽ Initial monitoring: every 1 –2 weeks until desired serum
concentration is achieved, then every 2 –3 months for the first 6 months
✽ Stable monitoring: every 6 –12 months
✽ One-of f monitoring after dose change, other medication change,
illness change (not before 1 week)
✽ Since lithium is frequently associated with weight gain, before
starting treatment, weigh all patients and determine if the patient is
already overweight (BMI 25.0 –29.9) or obese (BMI >30)
✽ Monitor weight and BMI during treatmentRepeat kidney function tests 1 –2 times/year

or dyslipidemia, or consider switching to a dif ferent agent
✽ Ataxia, dysarthria, delirium, tremor , memory problems
✽ Polyuria, polydipsia (nephrogenic diabetes insipidus)
✽ Diarrhea, nausea
✽ Weight gainUnknown and complex
CNS side ef fects theoretically due to excessive actions at the same
or similar sites that mediate its therapeutic actions
Some renal side ef fects theoretically due to lithium ’s actions on ion
transport
Euthyroid goiter or hypothyroid goiter , possibly with increased TSH
and reduced thyroxine levels
Acne, rash, alopecia
Leukocytosis
Side ef fects are typically dose-related

Sedation
What to Do About Side EffectsLithium toxicity
Renal impairment (interstitial nephritis)
Nephrogenic diabetes insipidus
Arrhythmia, cardiovascular changes, sick sinus syndrome,
bradycardia, hypotension
T-wave flattening and inversion
Rare pseudotumor cerebri
May be associated with increased appetite
May wear of f with time
Wait

✽ Take entire dose at night as long as ef ficacy persists all day long
with this administration
✽ Change to a dif ferent lithium preparation (e.g., controlled-release)
✽ Reduce dosing from 3 times/day to 2 times/day
✽ Propranolol 20 –30 mg 2 –3 times/day may reduce tremor
Dosing and UseWait
Wait
If signs of lithium toxicity occur , discontinue immediately
For stomach upset, take with food
For tremor , avoid caf feine
For the expert, cautious addition of a diuretic (e.g., chlorothiazide
50 mg/day) while reducing lithium dose by 50% and monitoring
plasma lithium levels may reduce polydipsia and polyuria that does
not go away with time alone

How to Dose
✽ Sustained-release formulation may reduce gastric irritation, lower
peak lithium plasma levels, and diminish peak dose side ef fects (i.e.,
side ef fects occurring 1 –2 hours after each dose of standard lithium
carbonate may be improved by sustained-release formulation)Mania: recommended 1.0 –1.5 mEq/L
Depression: recommended 0.6 –1.0 mEq/L
Maintenance: recommended 0.7 –1.0 mEq/L
Liquid: 10 mL three times/day (acute mania); 5 mL 3 –4 times/day
(long-term)
Tablet 300 mg (slow-release), 450 mg (controlled-release)
Capsule 150 mg, 300 mg, 600 mg
Liquid 8 mEq/5 mL
Start 300 mg 2 –3 times/day and adjust dosage upward as indicated
by plasma lithium levels
Lithium sulfate and other dosage strengths for lithium are available
in Europe

✽ Some patients apparently respond to doses as low as 300 mg twice
a day , even with plasma lithium levels below 0.5 mEq/L
✽ Rapid discontinuation increases the risk of relapse and possibly
suicide, so lithium may need to be tapered slowly over 3 months if it is
to be discontinued after long-term maintenance
Overdose
Long-T erm UseCheck therapeutic blood levels as “trough ” levels about 12 hours
after the last dose
After stabilization, some patients may do best with a once daily dose
at night
Responses in acute mania may take 7 –14 days even with adequate
plasma lithium levels
Use the lowest dose of lithium associated with adequate therapeutic
response
Lower doses and lower plasma lithium levels (<0.6 mEq/L) are
often adequate and advisable in the elderly
Fatalities have occurred; tremor , dysarthria, delirium, coma,
seizures, autonomic instability
Indicated for long-term prevention of relapse
May cause reduced kidney function

How to Stop
✽ Nonsteroidal anti-inflammatory agents, including ibuprofen and
selective COX-2 inhibitors (cyclooxygenase 2), can increase plasma
lithium concentrations; add with caution to patients stabilized on
lithium
✽ Diuretics, especially thiazides, can increase plasma lithium
concentrations; add with caution to patients stabilized on lithiumRequires regular therapeutic monitoring of lithium levels as well as
of kidney function and thyroid function
No
Taper gradually over 3 months to avoid relapse
Rapid discontinuation increases the risk of relapse, and possibly
suicide
Half life 18 –30 hours
Lower absorption on empty stomach

✽ Toxic levels are near therapeutic levels; signs of toxicity include
tremor , ataxia, diarrhea, vomiting, sedationAngiotensin-converting enzyme inhibitors can increase plasma
lithium
Metronidazole can lead to lithium toxicity through decreased renal
clearance
Acetazolamide, alkalizing agents, xanthine preparations, and urea
may lower lithium plasma concentrations
Methyldopa, carbamazepine, and phenytoin may interact with
lithium to increase its toxicity
Use lithium cautiously with calcium channel blockers, which may
also increase lithium toxicity
Use of lithium with an SSRI may raise risk of dizziness, confusion,
diarrhea, agitation, tremor
syndrome
Lithium may prolong ef fects of neuromuscular blocking agents
No likely pharmacokinetic interactions of lithium with mood-

syndrome
stabilizing anticonvulsants or atypical antipsychotics

Do Not Use
Hepatic ImpairmentMonitor for dehydration; lower dose if patient exhibits signs of
infection, excessive sweating, diarrhea
Closely monitor patients with thyroid disorders
Lithium may cause unmasking of Brugada syndrome; consultation
with a cardiologist is recommended if patients develop unexplained
syncope or palpitations after starting lithium
If patient has severe kidney disease
If patient has severe cardiovascular disease
If patient has Brugada syndrome
If patient has severe dehydration
If patient has sodium depletion
If there is a proven aller gy to lithium
Some experts recommend no dosing modification for glomerular
filtration rate (GFR)>50 mL/min

Elderly
✽ Neurotoxicity , including delirium and other mental status changes,
may occur even at therapeutic doses in elderly and or ganically
compromised patients
 Childr en and AdolescentsNo special indications
Lithium can cause reversible T -wave changes, sinus bradycardia,
sick sinus syndrome, or heart block
Likely that elderly patients will require lower doses to achieve
therapeutic serum levels
Elderly patients may be more sensitive to adverse ef fects
Lower doses and lower plasma lithium levels (<0.6 mEg/L) are
Safety and ef ficacy not established in children under age 7
Use only with caution
Younger children tend to have more frequent and severe side ef fects
Children should be monitored more frequently

Pregnancy
✽ Evidence of increased risk of major birth defects (perhaps 2 –3
times the general population), but probably lower than with some other
mood stabilizers (e.g., valproate)Effective June 30, 2015, the US FDA requires changes to the
Evidence of increase in cardiac anomalies (especially Ebstein ’s
anomaly) in infants whose mothers took lithium during pregnancy
No long-term neurobehavioral ef fects of late-term neonatal lithium
exposure have been observed
If lithium is continued, monitor serum lithium levels every 4 weeks,
then every week beginning at 36 weeks
Dehydration due to morning sickness may cause rapid increases in
lithium levels

Lithium administration during delivery may be associated with
hypotonia in the infant; most recommend withholding lithium for
24–48 hours before delivery
Monitoring during delivery should include fluid balance
After delivery , monitor for 48 hours for “floppy baby syndrome ”

anticonvulsants if treatment of bipolar disorder is required during
pregnancy
treatment for postpartum episodes of bipolar disorderUse in women of childbearing potential requires weighing potential
Given the risk of bipolar relapse in the postpartum period, lithium
should generally be restarted immediately after delivery
This may mean no breast feeding, since lithium can be found in
breast milk, possibly at full therapeutic levels

Some drug is found in mother ’s breast milk, possibly at full
therapeutic levels since lithium is soluble in breast milk

Primary T arget SymptomsAtypical antipsychotics and anticonvulsants such as valproate may
be safer than lithium during the postpartum period when breast
feeding
Euphoric mania
Reduces suicide risk
Works well in combination with atypical antipsychotics and/or
mood-stabilizing anticonvulsants such as valproate
Dysphoric mania
Mixed mania, rapid-cycling mania
Depressed phase of bipolar disorder
Patients unable to tolerate weight gain, sedation, gastrointestinal
effects, renal ef fects, and other side ef fects
Requires blood monitoring
Unstable mood

Pearls
✽ Lithium was the original mood stabilizer and is still a first-line
treatment option but may be underutilized since it is an older agent and
is less promoted for use in bipolar disorder than newer agents
✽ May be best for euphoric mania; patients with rapid-cycling and
mixed state types of bipolar disorder generally do less well on lithium
✽ Seems to be more ef fective in treating manic episodes than
depressive episodes in bipolar disorder (treats from above better than it
treats from below)
✽ May also be more ef fective in preventing manic relapses than in
preventing depressive episodes (stabilizes from above better than it
stabilizes from below)
✽ May decrease suicide and suicide attempts not only in bipolar I
disorder but also in bipolar II disorder and in unipolar depression
✽ Due to its narrow therapeutic index, lithium ’s toxic side ef fects
occur at doses close to its therapeutic ef fectsMania
Close therapeutic monitoring of plasma drug levels is required

during lithium treatment; lithium is the first psychiatric drug that
required blood level monitoring
Probably less ef fective than atypical antipsychotics for severe,
excited, disturbed, hyperactive, or psychotic patients with mania

Due to delayed onset of action, lithium monotherapy may not be the
first choice in acute mania, but rather may be used as an adjunct to
atypical antipsychotics, benzodiazepines, and/or valproate loading
After acute symptoms of mania are controlled, some patients can be
maintained on lithium monotherapy
However , only a third of bipolar patients experience adequate relief
with a monotherapy , so most patients need multiple medications for
best control
Lithium is not a convincing augmentation agent to atypical
antipsychotics for the treatment of schizophrenia
Lithium is one of the most useful adjunctive agents to augment
antidepressants for treatment-resistant unipolar depression
Lithium may be useful for a number of patients with episodic,
recurrent symptoms with or without af fective illness, including
episodic rage, anger or violence, and self-destructive behavior; such
symptoms may be associated with psychotic or nonpsychotic

illnesses, personality disorders, or ganic disorders, or mental
Lithium is better tolerated during acute manic phases than when
manic symptoms have abated
Adverse ef fects generally increase in incidence and severity as
lithium serum levels increase
Although not recommended for use in patients with severe renal or
cardiovascular disease, dehydration, or sodium depletion, lithium

Baldessarini  RJ , Tondo  L , Davis  P , et al. Decreased risk of suicides and
attempts during long-term lithium treatment: a meta-analytic review  .
Bipolar Disor d 2006  ;8 (5 Pt 2): 625–39 .
Goodwin  FK . Rationale for using lithium in combination with other mood
stabilizers in the management of bipolar disorder  . J Clin Psychiatry  2003
;64 (Suppl 5): S18 –24.
Malhi  GS , Tanious  M. Optimal frequency of lithium administration in the
treatment of bipolar disorder: clinical and dosing considerations  . CNS
Drugs  2011 ;25 (4 ):289–98 .
Tueth MJ , Murphy  TK , Evans  DL . Special considerations: use of lithium
in children, adolescents, and elderly populations  . J Clin Psychiatry  1998

;59 (Suppl 6): S66 –73.can be administered cautiously in a hospital setting to such patients,
with lithium serum levels determined daily
Lithium-induced weight gain may be more common in women than
in men

Lofepramine
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Deprimyl
Gamanil
Anxiety
Insomnia

cortex, which lar gely lacks dopamine transporters, lofepramine can

symptoms

How to Dose
140–210 mg/day
Tablet 70 mg multiscored
Liquid 70 mg/5mL
Initial 70 mg/day once daily or in divided doses; gradually increase
daytime sedation and in morning for insomnia; maximum dose 280
mg/day for inpatients, 210 mg/day for outpatients

Overdose
How to StopIf given in split doses, lar gest dose should generally be given at
Unusual dose compared to most TCAs
Safe
No

✽ Major metabolite is the antidepressant desipramine, with a half-life
of approximately 24 hours
 Drug InteractionsEven with gradual dose reduction some withdrawal symptoms may
Half-life of parent compound approximately 1.5 –6 hours

Other W arnings/Pr ecautionsMay alter ef fects of antihypertensive drugs; may inhibit hypotensive
activity
discontinuation of lofepramine
after discontinuing lofepramine
days for most drugs) after discontinuing lofepramine, but see Pearls

companies

companies

Cardiac ImpairmentIf patient is taking agents capable of significantly prolonging QT c
If there is a proven aller gy to lofepramine, desipramine, or

Elderlyheart failure, especially in the diseased heart

 PregnancyMay be more sensitive to anticholiner gic, cardiovascular ,
patients
Not recommended for use under age 18

✽ Recommended either to discontinue drug or bottle feedletter categories; the Pregnancy and Lactation Labeling Rule (PLLR
pregnancy

pregnancy

 Pearlsthe mother
feeding

✽ Lofepramine is a short-acting prodrug of the TCA desipramine
✽ Fewer anticholiner gic side ef fects, particularly sedation, than some
other tricyclicsTCAs continue to be useful for severe or treatment-resistant
Noradrener gic reuptake inhibitors such as lofepramine can be used
Once a popular TCA in the UK but not widely marketed throughout
the world
For the expert only: although generally prohibited, a heroic
treatment (but potentially dangerous) for severely treatment-
resistant patients is to give a tricyclic/tetracyclic antidepressant

other than clomipramine simultaneously with an MAOI for patients
who fail to respond to numerous other antidepressants

Kerihuel  JC , Dreyfus  JF . Meta-analyses of the ef ficacy and tolerability of
the tricyclic antidepressant lofepramine  . J Int Med Res  1991  ;19 :183 –201
.
Lancaster  SG , Gonzales  JP . Lofepramine. A review of its
pharmacodynamic and pharmacokinetic properties, and therapeutic ef ficacy
in depressive illness  . Drugs  1989  ;37 :123–40 .

Lofexidine
Brands
Generic?
No
 Class
 How the Drug W orksLucemyra
Centrally acting alpha 2 agonist
Mitigation of opioid withdrawal symptoms to facilitate abrupt
opioid discontinuation
Stimulates alpha 2 adrener gic receptors in the brain stem, reducing
sympathetic outflow from the CNS, which in turn results in
improvement in withdrawal symptoms

If It W orks
Tests
How Drug Causes Side EffectsCan begin relieving withdrawal symptoms within the first day of
dosing
Increases completion of opioid detoxification
Support medications for withdrawal symptoms (e.g., guaifenesin,
antacids, dioctyl sodium sulfosuccinate, psyllium hydrocolloid
suspension, bismuth sulfate, acetaminophen, zolpidem)

Sedation
Best Augmenting Agents for Side EffectsExcessive actions on alpha 2 receptors
Orthostatic hypotension, hypotension, dizziness, sedation, dry
mouth
Bradycardia
None
Reduce dose; in particular , lower doses may be appropriate as
withdrawal symptoms wane
Dose reduction or switching to another agent may be more ef fective,

How to Dose
 Dosing T ipsagent
0.54 mg 4 times daily at 5- to 6-hour intervals
Tablet 0.18 mg
Usual dose is three 0.18 mg tablets (0.54 mg) taken 4 times daily at
5- to 6-hour intervals
Lofexidine is taken during the time of peak withdrawal for up to 14
days
Total daily dose should not exceed 2.88 mg
Total single dose should not exceed 0.72 mg
Maximum dose should coincide with the most severe withdrawal
symptoms (about 5 –7 days after opioid discontinuation), after which
down-titration may be appropriate as withdrawal symptoms wane

Overdose
How to Stop
 Drug InteractionsHypotension, bradycardia, sedation
No
Sudden discontinuation can result in nervousness, agitation,
Down-titrate over 2 –4 days (e.g., reduce by 1 tablet per dose every 1
to 2 days) to avoid rebound ef fects (nervousness, increased blood
pressure)
Metabolized by CYP450 2D6 and to a lesser extent by CYP450 1A2
and CYP450 2C19

Other W arnings/Pr ecautionsBecause lofexidine and methadone both prolong the QT interval,
ECG monitoring is recommended when they are used concomitantly
Concomitant use of lofexidine and oral naltrexone alters the steady-
state pharmacokinetics of naltrexone, and it is possible that
naltrexone ef ficacy may be reduced
Plasma concentrations of lofexidine may be increased by drugs that
inhibit CYP450 2D6 (e.g., paroxetine, fluoxetine), so lofexidine
dose may need to be reduced if coadministered, and patients should
be monitored for orthostatic hypotension and bradycardia
Monitor vital signs before dosing and monitor patients for
symptoms related to bradycardia and orthostasis; for outpatient use,
ensure that patients are capable of self-monitoring signs and
symptoms
Avoid use in patients with severe coronary insuf ficiency , recent
myocardial infarction, cerebrovascular disease, marked bradycardia,
or chronic renal failure

symptoms
Lofexidine prolongs the QT interval; its use should be avoided in
patients with known QT prolongation, and ECG should be
monitored in patients with electrolyte abnormalities, congestive
heart failure, bradyarrhythmias, hepatic or renal impairment, or in
patients taking agents capable of causing QT prolongation
Patients who complete opioid discontinuation are at increased risk
of fatal overdose should they resume opioid use

Do Not Use
Cardiac ImpairmentIf there is a proven aller gy to lofexidine
Dose adjustment not necessary for mild impairment
For moderate impairment, the recommended dose is 0.36 mg 4
times daily
For severe impairment, the recommended dose is 0.18 mg 4 times
daily
For mild impairment, the recommended dose is 0.54 mg 4 times
daily
daily

Elderly
In rats and rabbits, administration of lofexidine during
organogenesis caused a reduction in fetal weights, increases in fetal
resorption, and litter loss at exposures below the maximum
recommended human dose (MRHD)
organogenesis through lactation resulted in increased stillbirths and
litter loss, and of fspring exhibited delays in sexual maturation,

auditory startle, and surface righting, at exposures below the MRHD
In rats, administration of lofexidine during or ganogenesis resulted in
maternal toxicity , including death, at exposures below the MRHD

 Pearls
 Suggested ReadingUnknown if lofexidine is secreted in human breast milk, but all
No known abuse potential; not a controlled substance
Less experience in the USA with lofexidine than with clonidine
Opioid withdrawal symptoms
Although not approved for use in the USA until 2018, lofexidine has
been available as an approved option in Europe since 1992
In the limited head-to-head comparisons available, lofexidine
appears comparable to clonidine in ef ficacy , with fewer adverse
effects

Alam  D , Tirado  C , Pirner  M , Clinch  T . Efficacy of lofexidine for
mitigating opioid withdrawal symptoms: results from two randomized,
placebo-controlled trials  . J Drug Assess  2020  ;9 (1 ):13 –19 .
Kuszmaul  AK , Palmer  EC , Frederick  EK . Lofexidine versus clonidine for
mitigation of opioid withdrawal symptoms: a systematic review  . J Am
Pharm Assoc  2003  ;60 (1 ):145–52 .
Patel  B , Kosten  TR . Keeping up with clinical advances: opioid use
disorder  . CNS Spectr  2019  ;24 (S1 ):14 –24 .

Loflazepate
Brands
Generic?
No
 Class
 How the Drug W orksMeilax
Anxiety , tension, depression, or sleep disorder in patients with
neurosis
psychosomatic disease
Catatonia

If It W orksBinds to benzodiazepine receptors at the GABA-A ligand-gated

ResistanceIf symptoms reemer ge, consider treatment with an SSRI or SNRI, or
Consider presence of loflazepate abuse

Tests
✽ Hyperexcitability , nervousnessIn patients with seizure disorders, concomitant medical illness,

Sedation
What to Do About Side EffectsRespiratory depression, especially when taken with CNS
Wait
Wait
Wait

How to Dose
✽ Because of its long half-life, patients who require chronic treatment
may need dose reduction after a few weeks due to drug accumulation
✽ Because of its long half-life, once daily dosing is the most frequent
dosing generally necessary
✽ Because of its long half-life, some patients may have sustained
benefits even if dosing is intermittently skipped on some daysMany side ef fects cannot be improved with an augmenting agent
1 mg once or twice a day
Tablet 1 mg, 2 mg
Start at 1 mg, increase to 1 mg twice/day or 2 mg once a day in a
few days if necessary

Overdose
Habit FormingAssess need for continued treatment regularly
treatment
anxiety
Because panic disorder can require doses higher than 2 mg/day , the
Some severely ill patients may require more than 2 mg/day
pharmacokinetic terminal half-life, which is why once daily dosing
is usually the favored option despite the long half-life
Sedation, confusion, poor coordination, diminished reflexes, coma

How to StopPatients may develop dependence and/or tolerance with long-term
use
Taper by 0.5 mg every 3 –7 days to reduce chances of withdrawal
effects
slowly after reaching 3 mg/day , perhaps by as little as 0.25 mg every
7–10 days or slower

 Other W arnings/Pr ecautionsElimination half-life approximately 122 hours (ultra-long half-life)
Cimetidine raises loflazepate plasma levels
Rapid dose reduction or discontinuation of loflazepate during
concomitant use with tetracyclic antidepressants such as maprotiline
may result in convulsive seizures, possibly due to the loss of
anticonvulsant actions that suppress the proconvulsant actions of
tetracyclic antidepressants
efficacy

efficacy

Do Not Use
Special Populationsdifficulty breathing, or unresponsiveness occur
loflazepate
ideation
If patient has myasthenia gravis
If there is a proven aller gy to loflazepate or any benzodiazepine

Elderly
 PregnancyDrug should be used with caution
Should begin with lower starting dose
Benzodiazepines are often used in children and adolescents,
especially short-term and at the lower end of the dosing scale
Long-term ef fects of loflazepate in children/adolescents are
unknown
monitored

Because of the potential risks, loflazepate is not generally
Patients who have interdose anxiety on shorter -acting

 Pearls
✽ Is the only “ultra-long half-life ” benzodiazepine with a half-life
much longer than 24 hours
✽ Less interdose anxiety than other benzodiazepines
✽ Long half-life could theoretically reduce abuse and withdrawal
symptomsPatients who wish to take drug only once daily
Patients who occasionally for get to take their dose
Drug may accumulate in long-term users and require dosage
reduction
Anxiety
Tension

Ba BB , Iliadis  A , Cano  JP . Pharmacokinetic modeling of ethyl loflazepate
(Victan) and its main active metabolites  . Ann Biomed Eng  1989  ;17 (6
):633–46 .
Chambon  JP , Perio  A , Demarne  H , et al. Ethyl loflazepate: a prodrug
from the benzodiazepine series designed to dissociate anxiolytic and
sedative activities  . Arzneimittelforschung  1985  ;35 (10 ):1573  –7.May both cause depression and treat depression in dif ferent patients
discontinuation of loflazepate, especially in those with prior
patients

patients
treatment

Murasaki  M , Mori  A , Noguchi  T , et al. Comparison of therapeutic
efficacy of neuroses between CM6912 (ethyl loflazepate) and diazepam in a
double-blind trial  . Prog Neur opsychopharmacol Biol Psychiatry  1989  ;13
(1–2):145–54 .

Lorazepam
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Ativan
Anxiety disorder (oral)
Anxiety associated with depr essive symptoms (oral)
Initial tr eatment of status epilepticus (injection)
Preanesthetic (injection)
Insomnia

How Long Until It W orksMuscle spasm
Alcohol withdrawal psychosis
Headache
Delirium (with haloperidol)
Catatonia
weeks for maximal therapeutic benefit with daily dosing

If It W orks

Consider presence of lorazepam abuse

Tests
How Drug Causes Side EffectsConsider another diagnosis such as a comorbid medical condition

Sedation
Wait
Wait
Wait
Oral: 2 –6 mg/day in divided doses, lar gest dose at bedtime

How to Dose
formulationInjection: 4 mg administered slowly
Catatonia: 1 –2 mg per dose
Liquid 2 mg/mL
Injection 2 mg/mL, 4 mg/mL
Oral: initial 2 –3 mg/day in 2 –3 doses; increase as needed, starting
with evening dose; maximum generally 10 mg/day
Injection: initial 4 mg administered slowly; after 10 –15 minutes may
administer again
Take liquid formulation with water , soda, applesauce, or pudding
Catatonia: initial 1 –2 mg; can repeat in 3 hours and then again in
another 3 hours if necessary

Overdose
Long-T erm UseLorazepam injection is intended for acute use; patients who require
treatment
anxiety
Because panic disorder can require doses higher than 6 mg/day , the
Some severely ill patients may require 10 mg/day or more

Lorazepam is a Schedule IV drug
use
Taper by 0.5 mg every 3 days to reduce chances of withdrawal
effects
slowly once reaching 3 mg/day , perhaps by as little as 0.25 mg per

 Drug InteractionsBe sure to dif ferentiate reemer gence of symptoms requiring
Elimination half-life 10 –20 hours
No active metabolites
Valproate and probenecid may reduce clearance and raise plasma
concentrations of lorazepam
Oral contraceptives may increase clearance and lower plasma
seizure disorders with lorazepam

efficacy
Use oral formulation only with extreme caution if patient has

obstructive sleep apnea; injection is contraindicated in patients with
ideation

Do Not Use
Cardiac ImpairmentSome patients may exhibit abnormal thinking or behavioral changes
If patient has sleep apnea (injection)
Must not be given intra-arterially because it may cause arteriospasm
and result in gangrene
If there is a proven aller gy to lorazepam or any benzodiazepine
1–2 mg/day in 2 –3 doses
Because of its short half-life and inactive metabolites, lorazepam
may be a preferred benzodiazepine in some patients with liver
disease

Elderly
Rare reports of QT c prolongation in patients with underlying
arrhythmia
Lorazepam may be used as an adjunct to control drug-induced
cardiovascular emer gencies
May be more sensitive to sedative or respiratory ef fects
Oral: safety and ef ficacy not established in children under age 12
Injection: safety and ef ficacy not established in children under age
18
Long-term ef fects of lorazepam in children/adolescents are
unknown
monitored

The Art of Psychopharmacologyletter categories; the Pregnancy and Lactation Labeling Rule (PLLR
Because of the potential risks, lorazepam is not generally

 Pearls
✽ One of the most popular and useful benzodiazepines for treatment
of agitation associated with psychosis, bipolar disorder , and other
disorders, especially in the inpatient setting; this is due in part to useful
sedative properties and flexibility of administration with oral tablets,
oral liquid, or injectable formulations, which is often useful in treating
uncooperative patientsRapid onset of action
Availability of oral liquid as well as injectable dosage formulations
Possibly more sedation than some other benzodiazepines commonly
used to treat anxiety
Anxiety

✽ Lorazepam may be preferred over other benzodiazepines for the
treatment of delirium
✽ Lorazepam is often used to induce pre-operative anterograde
amnesia to assist in anesthesiologyIs a very useful adjunct to SSRIs and SNRIs in the treatment of
Though not systematically studied, benzodiazepines, and lorazepam
in particular , have been used ef fectively to treat catatonia and are the
initial recommended treatment
may be preferred over some benzodiazepines for patients with liver
disease
When treating delirium, lorazepam is often combined with
haloperidol, with the haloperidol dose 2 times the lorazepam dose

disease
patients

Bonnet  MH , Arand  DL . The use of lorazepam TID for chronic insomnia  .
Int Clin Psychopharmacol  1999  ;14 :81 –9.
Greenblatt  DJ . Clinical pharmacokinetics of oxazepam and lorazepam  .
Clin Pharmacokinet  1981  ;6 :89 –105.
Starreveld  E , Starreveld  AA . Status epilepticus. Current concepts and
management  . Can Fam Physician  2000  ;46 :1817  –23.
Wagner  BK , O’Hara  DA , Hammond  JS . Drugs for amnesia in the ICU  .
Am J Crit Car e 1997  ;6 :192 –201 .When using to treat insomnia, remember that insomnia may be a

Loxapine
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Loxitane
Adasuve (Staccato loxapine, inhaled loxapine)
Conventional antipsychotic (neuroleptic, dopamine 2 antagonist,
serotonin dopamine antagonist)
Acute tr eatment of agitation associated with schizophr enia or

✽ Although classified as a conventional antipsychotic, loxapine is a
potent serotonin 2A antagonist
psychosis
Serotonin 2A antagonist properties might be relevant at low doses,
but generally are overwhelmed by high dosing

ResistanceFor second and subsequent episodes of psychosis in schizophrenia,
disorder
clozapine

Tests
>30)

loxapine should be discontinued at the first sign of decline of WBC

✽ Rare tachycardia
 Life-Thr eatening or Danger ous Side EffectsAntihistaminic actions may cause sedation, weight gain
unknown
Sedation
Dry mouth, constipation, vision disturbance, urninary retention
Hypotension, tachycardia

Sedation
What to Do About Side Effectswith elevated creatine phosphokinase, myoglobinuria
Rare agranulocytosis
Rare hepatocellular injury
Bronchospasm, with the potential to lead to respiratory distress and
respiratory arrest (inhalant)
Sedation is usually dose-dependent and may not be experienced at
low doses where loxapine may function as an atypical antipsychotic
(e.g., <50 mg/day; especially 5 –25 mg/day)

Wait
Wait

How to Dose60–100 mg/day in divided doses
Capsule 6.8 mg loxapine succinate equivalent to 5 mg loxapine,
13.6 mg loxapine succinate equivalent to 10 mg loxapine, 34.0 mg
loxapine succinate equivalent to 25 mg loxapine, 68.1 mg loxapine
succinate equivalent to 50 mg loxapine
Oral liquid 25 mg/mL (discontinued in USA)
Injection 50 mg/mL (discontinued in USA)
Inhalant 10 mg unit in a single-use inhaler
Initial 20 mg/day in 2 doses; titrate over 7 –10 days to 60 –100
mg/day in 2 –4 doses; maximum generally 250 mg/day
Take liquid formulation in orange or grapefruit juice
Inhalation powder: 10 mg by oral inhalation using an inhaler; only 1
dose per 24 hours; must be administered by a healthcare
professional in a setting with immediate onsite access to equipment
and personnel trained to manage acute bronchospasm, including
advanced airway management

✽ Binding studies, PET studies, and anecdotal clinical observations
suggest that loxapine may be atypical at lower doses (perhaps 5 –30
mg/day) but further studies neededHas conventional antipsychotic properties at originally
recommended doses (i.e., starting at 10 mg twice a day , maintenance
60–100 mg/day , maximum 250 mg/day given in 2 divided doses)
Anecdotal evidence that many patients can be maintained at 20 –60
mg/day as monotherapy
To augment partial responders to an atypical antipsychotic, consider
doses of loxapine as low as 5 –60 mg/day , but use full doses if
necessary
No formal studies, but some patients may do well on once daily
dosing, especially at night, rather than twice daily dosing
Available as 5 mg and 10 mg capsules for low-dose use and as 25
mg and 50 mg capsules for routine use
Available as a liquid dosage formulation
Available for acute inhalation administration
Prior to administering inhalation powder , screen all patients for a

history of pulmonary disease, and examine patients (including chest
auscultation) for respiratory abnormalities (e.g., wheezing)
After administering inhalation powder , monitor patients for signs
and symptoms of bronchospasm at least every 15 minutes for at
least an hour

OverdoseAvailable for acute intramuscular administration (50 mg/mL)
Intramuscular loxapine may have faster onset of action and superior
efficacy for agitated/excited and aggressive behavior in some
patients than intramuscular haloperidol
In the acute situation, give 25 –50 mg intramuscularly (0.5 –1.0 mL
of 50 mg/mL solution) with onset of action within 60 minutes
When initiating therapy with an atypical antipsychotic in an acute
situation, consider short-term intramuscular loxapine to “lead in ” to
orally administered atypical; e.g., initiate oral dosing of an atypical
antipsychotic with 25 –50 mg loxapine 2 –3 times a day
intramuscularly to achieve antipsychotic ef fects without drug-
induced parkinsonism and sedation
When using loxapine to “top up ” previously stabilized patients now
decompensating, may use loxapine as single 25 –50 mg doses as
needed intramuscularly or as oral liquid or tablets

Deaths have occurred; drug-induced parkinsonism, CNS depression,
cardiovascular ef fects, hypotension, seizures, respiratory depression,

How to Stop
✽ N -desmethyl loxapine is amoxapine, an antidepressantrenal failure, coma
No
Slow down-titration of oral formulation (at least 4 weeks when
possible), especially when simultaneously beginning a new
a few weeks after loxapine is discontinued
Half-life approximately 4 hours for oral formulation
Half-life approximately 12 hours for intramuscular formulation
Multiple active metabolites with longer half-lives than parent drug

 Other W arnings/Pr ecautions8-hydroxyloxapine and 7-hydroxyloxapine are also serotonin-
dopamine antagonists
8-hydroxyamoxapine and 7-hydroxyamoxapine are also serotonin-
Respiratory depression may occur when loxapine is combined with
lorazepam
syndrome
guanethidine, whose antihypertensive actions loxapine may

Do Not UseAntiemetic ef fect can mask signs of other disorders or overdose
Do not use epinephrine in event of overdose, as interaction with
Use cautiously in patients with glaucoma, urinary retention
Observe for signs of ocular toxicity (pigmentary retinopathy ,
lenticular pigmentation)
dementia
therapy
If patient has asthma or history of asthma, COPD, other lung disease

associated with bronchospasm, acute respiratory signs/symptoms,
current use of medications to treat airways, history of bronchospasm
following treatment with loxapine inhalation powder (inhalant only)

ElderlyIf there is a proven aller gy to loxapine
If there is a known sensitivity to any dibenzoxazepine

 PregnancySafety and ef ficacy not established
Generally , consider second-line after atypical antipsychotics
Renal papillary abnormalities have been seen in rats during
pregnancy

pregnancy

 Pearls
✽ Recently discovered to be a serotonin dopamine antagonist (binding
studies and PET scans)
✽ Active metabolites are also serotonin dopamine antagonists with
longer half-lives than parent drug, thus possibly allowing once dailyUnknown if loxapine is secreted in human breast milk, but all

treatment
✽ One active metabolite is an antidepressant (amoxapine, also known
as N -desmethyl-loxapine)
✽ Causes less weight gain than other antipsychotics, both atypical and
conventional, and may even be associated with weight loss
✽ Enhances ef ficacy in clozapine partial responders when given
concomitantly with clozapineTheoretically , loxapine should have antidepressant actions,
especially at high doses, but no controlled studies
Theoretically , loxapine may have advantages for short-term use in
some patients with psychotic depression
Developed as a conventional antipsychotic; i.e., reduces positive
symptoms, but causes drug-induced parkinsonism and prolactin
elevations
Lower risk of drug-induced parkinsonism than haloperidol in some
studies, but not fixed-dose studies and no low-dose studies
No formal studies of negative symptoms, but some studies show
superiority to conventional antipsychotics for emotional withdrawal
and social competence

Best use may be as low-cost augmentation agent to atypical
For previously stabilized patients with “breakthrough ” agitation or
incipient decompensation, “top up ” the atypical antipsychotic with

as-needed intramuscular or oral single doses of loxapine
An inhalation powder for acute agitation is available only through a
(REMS) called the ADASUVE REMS
Due to the risk of bronchospasm, loxapine inhalation powder should
be administered only in an enrolled healthcare facility that has
immediate onsite access to equipment and personnel trained to
manage acute bronchospasm, including advanced airway
management (intubation and mechanical ventilation)
another
benefit from determination of plasma levels and, if low , a dosage
increase even beyond the usual prescribing limits

another
antipsychotic such as loxapine or from switching to a conventional
antipsychotic such as loxapine
conventional antipsychotic such as loxapine with an atypical

Chakrabarti  A , Bagnall  A , Chue  P , et al. Loxapine for schizophrenia  .
Cochrane Database Syst Rev  2007  ;17 (4 ):CD001943  .
Fenton  M , Murphy  B , Wood J , et al. Loxapine for schizophrenia  .
Cochrane Database Syst Rev  2000  ;(2):CD001943  .
Heel  RC , Brogden  RN , Speight  TM , Avery GS . Loxapine: a review of its
pharmacological properties and therapeutic ef ficacy as an antipsychotic
agent  . Drugs  1978  ;15 (3 ):198 –217 .
meta-analysis  . Lancet  2019  ;394 :939-51  .For treatment-resistant patients, especially those with impulsivity ,

closely monitoring. In such cases, it may be beneficial to combine 1
depot antipsychotic with 1 oral antipsychotic

Zisook  S , Click  MA Jr . Evaluations of loxapine succinate in the
ambulatory treatment of acute schizophrenic episodes  . Int
Pharmacopsychiatry  1980  ;15 (6 ):365–78 .

Lumateperone
Brands
Generic?
 Class
Commonly Pr escribed forCaplyta
No

How Long Until It W orksBehavioral disturbances in dementias
Blocks postsynaptic dopamine 2 receptors, reducing positive
symptoms of psychosis and stabilizing af fective symptoms
Binds as a partial agonist at presynaptic D2 receptors
contribute to lumateperone ’s efficacy
Binds to D1 receptors, with preclinical data showing D1-dependent
activation of AMP A receptors leading to activation of the mT OR
pathway , a mechanism that has been associated with antidepressant
effects
Also has af finity for the serotonin reuptake pump (SER T, serotonin
transporter)

If It W orksPsychotic and manic symptoms can improve within 1 week, but it
symptoms

If It Doesn ’t WorkFor second and subsequent episodes of psychosis, treatment may
clozapine
If no first-line atypical antipsychotic is ef fective, generally do not
consider higher doses of lumateperone, as higher doses do not have
established ef ficacy
May consider augmentation with lamotrigine; do not consider
augmentation with valproate as this increases lumateperone levels

fewer side ef fects, or to an antipsychotic that can be given by depot
injection

Tests
Befor e starting any atypical antipsychoticConsider initiating rehabilitation and psychotherapy such as
Lithium
Weigh all patients and track BMI during treatment
Get waist circumference (at umbilicus), blood pressure, fasting

Monitoring after starting an atypical antipsychotichas diabetes (fasting plasma glucose >126 mg/dL)
BMI monthly for 3 months, then quarterly
patients with diabetes or who have gained >5% of initial weight

Even in patients without known diabetes, be vigilant for the rare but
life-threatening onset of diabetic ketoacidosis, which always
requires immediate treatment, by monitoring for the rapid onset of
polyuria, polydipsia, weight loss, nausea, vomiting, dehydration,
rapid respiration, weakness, clouding of sensorium, even coma

lumateperone should be discontinued at the first sign of decline of
By blocking serotonin 2A receptors, it can cause sedation

Sedation, dry mouth, nausea

Sedation
Occurs less frequently with evening administration
Wait
Wait
Wait
Take in the evening to help reduce daytime sedation
present

How to Dose
 Dosing T ipsBeta blockers, benzodiazepines, or 5HT2A antagonists (e.g.,
42 mg once daily
Capsule 42 mg
Initial dose 42 mg once daily; titration is not required
Recommended to be taken with food because this is how clinical
trials were performed; however , food increases the AUC by only 9%

Overdose
anticonvulsant, such as topiramate or lamotrigine
Take in the evening to avoid daytime sedation
Studied in clinical trials for up to 1 year
No
lumateperone

 Other W arnings/Pr ecautionsTerminal half-life approximately 18 hours after intravenous
Metabolized by multiple enzymes, including CYP450 3A4 and
CYP450 1A2
Absorption is delayed in the presence of food; ingestion of a high-
fat meal reduces Cmax by 33% and increases mean AUC by 9%
Avoid concomitant use with moderate or strong CYP450 3A4
inhibitors (e.g., fluvoxamine, nefazodone, foods such as grapefruit
juice)
Avoid concomitant use with CYP450 3A4 inducers (e.g.,
carbamazepine, phenytoin, St. John ’s wort)
Avoid concomitant use with UGT (uridine 5 ’-diphospho-
glucuronosyltransferase) inhibitors (e.g., valproate)
enzymes
May enhance the ef fects of antihypertensive drugs

Do Not Use
Special PopulationsUse with caution in patients with conditions that predispose to
lumateperone should be used cautiously in patients at risk for
therapy

therapy
If there is a proven aller gy to lumateperone

Mild impairment (Child-Pugh score between 5 and 6): no dose
adjustment necessary
Not recommended for use in patients with moderate to severe
agitation

 PregnancyConsider pimavanserin for dementia-related psychosis or
Children and adolescents using lumateperone may need to be
monitored more often than adults
In rats and rabbits, administration of lumateperone during
organogenesis did not result in malformations at doses 2.4 and 9.7
times, respectively , the maximum recommended human dose
(MRHD) of 42 mg

In rats, administration of lumateperone during or ganogenesis
through lactation resulted in lower pup survival at 4.9 times the
MRHD, but not at 2.4 times the MRHD

Potential AdvantagesThere is a risk of abnormal muscle movements and withdrawal
961-2388,
Unknown if lumateperone is secreted in human breast milk, but all
Infants of women who choose to breast feed while on lumateperone
For patients who do not tolerate other antipsychotics

 PearlsPatients requiring rapid onset of antipsychotic action without dosage
titration
Patients wishing to avoid drug-induced parkinsonism and akathisia
Patients wishing to avoid weight gain and metabolic dysfunction
such as dyslipidemia
Dose adjustment not possible
Expensive
Positive findings in two clinical trials in bipolar depression with
approval pending for bipolar depression in patients with Bipolar I or
II disorder as monotherapy and adjunctive therapy
A phase 3 trial for treatment of agitation in patients with probable
Alzheimer disease was discontinued after a pre-specified interim

Correll  CU , Davis  RE , Weingart  M , et al. Efficacy and safety of
lumateperone for treatment of schizophrenia: a randomized clinical trial  .
JAMA Psychiatry  2020  ;77 :349–58  .
doi:10.1001/jamapsychiatry .2019.4379  .
Kumar  B , Kuhad  A , Kuhad  A . Lumateperone: a new treatment approach
for neuropsychiatric disorders  . Drugs T oday (Bar c) 2018  ;54 (12 ):713–19 .
Lieberman  JA , Davis  RE , Correll  CU et al. ITI-007 for the treatment of
schizophrenia: a 4-week randomized, double-blind, controlled trial  . Biolanalysis indicated that the study was not likely to meet its primary
endpoint; the decision was not related to safety
Impressions from clinical experience include observations of
notable pro-social ef fects in many patients
Pro-social ef fects include improved interpersonal relations; less
isolation; more shopping, errands, cooking, walking; better
organized in activities
Neutral for weight gain in long-term studies and in clinical practice

Favorable metabolic profile with changes in triglycerides, fasting
glucose, and cholesterol similar to placebo in clinical trials and in
Neutral or placebo level of drug-induced parkinsonism and akathisia

Psychiatry  2016  ;79 (12 ):952–61 .
Snyder  GL , Vanover  KE , Zhu H . Functional profile of a novel modulator
of serotonin, dopamine, and glutamate neurotransmission  .
Psychopharmacology (Berl)  2015  ;232 (3 ):605–21 .
Vanover  KE , Davis  RE , Zhou  Y . Dopamine D2 receptor occupancy of
lumateperone (ITI-007): a positron emission tomography study in patients
with schizophrenia  . Neur opsychopharmacology  2019  ;44 (3 ):598 –605 .

Lurasidone
Brands
Generic?
No
 Class
(bold for FDA appr oved)Latuda
antagonist (DS-RAn)
Schizophr enia (ages 13 and older)
Bipolar depr ession (monotherapy , ages 10 and older)
Bipolar depr ession (adjunct, adults)

How the Drug W orksOther psychotic disorders
contribute to lurasidone ’s efficacy
Potently blocks serotonin 7 receptors, which may be beneficial for
mood, sleep, cognitive impairment, and negative symptoms in
schizophrenia, and also in bipolar disorder and major depressive
disorder
Partial agonist at 5HT1A receptors, and antagonist actions at
serotonin 7 and alpha 2A and alpha 2C receptors, which may be

disorder
beneficial for mood, anxiety , and cognition in a number of disorders

If It W orks –for Schizophr eniaLacks potent actions at dopamine D1, muscarinic M1, and histamine
H1 receptors, theoretically suggesting less propensity for inducing
cognitive impairment, weight gain, or sedation compared to other
agents with these properties
to determine ef ficacy of drug, but in practice some patients require
up to 16 –20 weeks to show a good response, especially on negative
or cognitive symptoms
For bipolar depression, onset of therapeutic actions usually not

If It Doesn ’t Work –for Schizophr eniaSuch patients are considered super -responders or “awakeners ” since

If It Doesn ’t Work –for Bipolar Depr essionTry one of the other atypical antipsychotics
clozapine
injection

Tests
Before starting any atypical antipsychotic
Mood-stabilizing anticonvulsants (see drug interactions  )
Lithium

with diabetes or who have gained >5% of initial weighty
respiration, weakness, and clouding of sensorium, even comahas dyslipidemia (increased total cholesterol, LDL cholesterol,

Notable Side EffectsPatients with low white blood cell count (WBC) or history of drug-
lurasidone should be discontinued at the first sign of decline in
WBC in the absence of other causative factors (class warning)

Dose-dependent sedation

Life-Thr eatening or Danger ous Side EffectsAkathisia
Nausea
Dose-dependent hyperprolactinemia
May increase risk for diabetes and dyslipidemia
Tachycardia, first-degree A V block
patients taking atypical antipsychotics (class warning)

Sedation
What to Do About Side EffectsMany experience about one- to two-pound weight gain greater than
placebo in short-term 6-week trials
Patients in long-term 52-week trials actually lost 1.5 pounds on
average
Clinical experience, however , is still limited
Appears to be less weight gain than observed with some
Many patients lost weight in long-term trials when switching from
olanzapine to lurasidone
May be higher in short-term trials than in long-term use
Wait
Wait
Wait
present
Dose reduction may reduce akathisia when present

Usual Dosage RangeBeta blockers, benzodiazepines, or 5HT2A antagonists (e.g.,
Consider changing to nighttime dosing (with evening meal)
40–80 mg/day for schizophrenia
Some patients with schizophrenia may benefit from doses up to 160
mg/day

How to Dose
 Dosing T ips20–60 mg/day for bipolar depression
Some patients with bipolar depression may benefit from doses up to
120 mg/day
Tablet 20 mg, 40 mg, 60 mg, 80 mg, 120 mg
Initial 40 –80 mg once daily with food for schizophrenia
Dose titration to initial dose of 40 mg/day is not required for
Consider dose increases from 40 mg/day up to 160 mg/day as
necessary and as tolerated for schizophrenia
Initial 20 mg once daily with food for bipolar depression
Can titrate to 120 mg/day in bipolar depression if necessary and
tolerated
Lurasidone should be taken with food (i.e., at least a small meal of a
minimum of 350 calories)
Lurasidone absorption can be decreased by up to 50% on an empty
stomach and more consistent ef ficacy will be seen if dosing is done
regularly withfood

Once daily dosing
Giving lurasidone at bedtime can greatly reduce daytime sedation,
akathisia, and drug-induced parkinsonism
Starting dose for schizophrenia is 40 mg/day , which may be an
adequate dose for early-onset psychosis cases
40–80 mg per day was suggested by controlled clinical trials as
adequate for many patients with schizophrenia
Some patients with schizophrenia benefit from higher dosing, with
controlled clinical trials up to 160 mg/day
Higher doses than 160 mg/day may benefit more dif ficult patients
with schizophrenia with treatment nonresponsiveness to other agents
Higher dosing, however , may cause more side ef fects

Dosing for bipolar depression or major depressive episodes with
mixed features is generally lower than for schizophrenia, with a 20
mg starting dose; 20 mg/day may be an adequate dose for some
patients

Overdose
How to StopDoses between 20 and 60 mg/day are generally as ef ficacious as
doses between 60 and 120 mg/day for bipolar depression or major
depressive episodes with mixed features
Some patients with bipolar depression or major depressive episodes
with mixed features may require higher doses
Not extensively studied past 52 weeks, but long-term maintenance
No

 Drug InteractionsDown-titration, especially when simultaneously beginning a new
Half-life 18 –31 hours (shorter half-life better documented at the 40
mg dose)
Cmax and bioavailability are reduced if taken without food
fluoxetine, ketoconazole) may increase plasma levels of lurasidone
Coadministration of lurasidone with a strong CYP450 3A4 inhibitor
(e.g., ketoconazole) or with a strong CYP450 3A4 inducer (e.g.,
rifampin) is contraindicated
Coadministration of lurasidone with moderate CYP450 3A4
inhibitors can be considered; recommended starting dose is 20
mg/day; recommended maximum dose is 80 mg/day
Moderate inducers of CYP450 3A4 may decrease plasma levels of
lurasidone

lurasidone should be used cautiously in patients at risk for aspiration
pneumonia

therapy

Do Not Use
Cardiac ImpairmentIf patient is taking a strong CYP 3A4 inhibitor (e.g., ketoconazole)
or inducer (e.g., rifampin)
In patients with a history of angioedema
If there is a proven aller gy to lurasidone
Moderate and severe impairment: initial 20 mg/day; maximum dose
80 mg/day
Moderate impairment: initial 20 mg/day; maximum dose 80 mg/day
Severe impairment: initial 20 mg/day; maximum dose 40 mg/day
with caution because of risk of orthostatic hypotension, although
low potency at alpha 1 receptors suggests this risk may be less than
for some other antipsychotics
Lurasidone does not have a warning for QT c prolongation

Elderly
 Childr en and AdolescentsIn general, no dose adjustment is necessary for elderly patients
However , some elderly patients may tolerate lower doses better
agitation
Approved for schizophrenia in adolescents ages 13 and older
Although lurasidone can be initiated at 40 mg/day , often a good idea
to initiate at 20 mg to test for tolerability before raising dose to 40
mg, especially in children and in small body weight adolescents

Approved for bipolar depression in bipolar I disorder in adolescents
ages 10 and older
Little or no weight gain documented in long-term studies up to 2
years
Children and adolescents using lurasidone may need to be

Pregnancybetter
Animal studies do not show adverse ef fects; not teratogenic in rats
and rabbits at doses up to 1.5 –6 times the maximum recommended
human dose

Lurasidone may be preferable to anticonvulsant mood stabilizers if
961-2388,

Potential Disadvantageshttps://womensmentalhealth.or g/research/pregnancyregistry/atypical
Unknown if lurasidone is secreted in human breast milk, but all
Infants of women who choose to breast feed while on lurasidone
titration
Patients who wish to take an antipsychotic once a day
Patients experiencing weight gain from other antipsychotics or who
wish to avoid weight gain
Children with schizophrenia or bipolar disorder , as excellent
tolerability in long-term studies documented
Patients who cannot take a medication consistently with food

Clinical trials suggest that lurasidone is well tolerated with a
favorable balance of ef ficacy and safety
One of the few “metabolically friendly ” antipsychotics
Neutral for weight gain (1 –2 pounds weight gain in short-term
studies, with 1 –2 pounds weight loss in long-term studies)
Neutral for lipids (triglycerides and cholesterol)
Neutral for glucose
Only atypical antipsychotic documented not to cause QT c
prolongation, and one of the few atypical antipsychotics without a
QTc warning
Seems to have low-level drug-induced parkinsonism, especially
when dosed at bedtime
Somnolence and akathisia are the most common side ef fects in
short-term clinical trials of schizophrenia that dosed lurasidone in

the daytime, but these adverse ef fects were reduced in a controlled
study of lurasidone administered at night with food
Nausea and occasional vomiting occurred in bipolar depression
studies especially at higher doses
Nausea and vomiting generally rapidly abates within a few days or
can be avoided by slow dose titration and giving lower doses
Prolactin elevations low and generally transient
Agitation experienced by some patients
Receptor binding profile suggests favorable potential as an
5HT7 antagonism is antidepressant in animal models and has
pro-cognitive actions in animal models
5HT7 antagonism and 5HT1A partial agonism enhance
serotonin levels in animals treated with SSRIs/SNRIs,
suggesting use for lurasidone as an augmenting agent to
SSRIs/SNRIs in depression
5HT7 antagonism plus the absence of D1, H1, and M1
antagonism suggest potential for cognitive improvement
Lack of D1 antagonist, anticholiner gic, and antihistamine

properties may explain relative lack of cognitive side ef fects in
most patients
One of the best studied agents for depression with mixed
features, showing ef ficacy in a lar ge randomized controlled

The Art of Switchingtrial
of either

Switching fr om Oral Antipsychotics to Lurasidone
begin lurasidone at an intermediate dose

Arango  C , Ng-Mak  D , Finn E , Byrne  A , Loebel  A . Lurasidone
compared to other atypical antipsychotic monotherapies for adolescent
schizophrenia: a systematic literature review and network meta-analysis.
Eur Child Adolesc Psychiatry 2019  . doi: 10.1007/s00787-019-01425-2  .
Ostacher  M , Ng-Mak  D , Patel  P , et al. Lurasidone compared to other
atypical antipsychotic monotherapies for bipolar depression: a systematic
review and network meta-analysis  . World J Biol Psychiatry  2018  ;19 (8
):586 –601 .
Suppes  T , Silva  R , Cucchiaro  J , et al. Lurasidone for the treatment of
major depressive disorder with mixed features: a randomized, double-blind,

placebo-controlled study  . Am J Psychiatry  2016  ;173 (4 ):400–7 .
Wang H , Xiao  L , Wang HL , Wang GH . Efficacy and safety of lurasidone
versus placebo as adjunctive to mood stabilizers in bipolar I depression: a
meta-analysis  . J Affect Disor d 2020  ;264 :227–33 .

Maprotiline
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Ludiomil
antidepressant (tetra)
Anxiety
Insomnia

If It W orksNeuropathic pain/chronic pain
cortex, which lar gely lacks dopamine transporters, maprotiline can
symptoms

is stopped

Tests
associated with weight gain, before starting treatment, weigh allfatigue, and problems concentrating)
pain)

Side EffectsBefore giving a drug that can cause weight gain to an overweight or

Paralytic ileus, hyperthermia (TCAs/tetracylics + anticholiner gic
agents)

Sedation
What to Do About Side EffectsOrthostatic hypotension, sudden death, arrhythmias, tachycardia
Wait
Wait
Wait

How to Dose
75–150 mg/day (for depression)
Tablet 25 mg, 50 mg, 75 mg
75 mg/day; after 2 weeks increase dose gradually by 25 mg/day;
maximum dose generally 225 mg/day

✽ Risk of seizures increases with dose, especially with maprotiline
above 200 mg/day
Overdose
Safe
No

Mean half-life approximately 51 hours
Peak plasma concentration 8 –24 hours
Phenothiazines or haloperidol may raise TCA/tetracyclic blood

activity
discontinuation of maprotiline
after discontinuing maprotiline
days for most drugs) after discontinuing maprotiline, but see Pearls

combining with drugs that inhibit TCA/tetracyclic metabolism via

Do Not UseCYP450 2D6, potentially causing torsade de pointes-type
arrhythmia or sudden death
caution in patients who have hypokalemia and/or hypomagnesemia
companies

companies

If there is a proven aller gy to maprotiline

administering maprotiline

Elderly
Usual dose generally 50 –75 mg/day
patients

patients

PregnancyMay be used to treat enuresis or hyperactive/impulsive behaviors
Some cases of sudden death have occurred in children taking
Maximum dose for children and adolescents is 75 mg/day
TCA/tetracyclic (lethar gy, withdrawal symptoms, fetal
malformations)

pregnancy

Potential DisadvantagesNational Pregnancy Registry for Antidepressants: 1-866-961-2388,
essants
the mother
feeding

 Pearls
✽ May have somewhat increased risk of seizures compared to some
other TCAs, especially at higher dosesPediatric and geriatric patients
Patients with seizure disorders
Tricyclic/tetracyclic antidepressants are often a first-line treatment
option for chronic pain
their side ef fect profile
TCAs/tetracyclics may aggravate psychotic symptoms

✽ May have a more rapid onset of action than some other
TCAs/tetracyclicsChildren, patients with inadequate hydration, and patients with
cardiac disease may be more susceptible to TCA/tetracyclic-induced

Patients on tricyclics/tetracyclics should be aware that they may

Kane  JM , Lieberman  J . The ef ficacy of amoxapine, maprotiline, and
trazodone in comparison to imipramine and amitriptyline: a review of the
literature  . Psychopharmacol Bull  1984  ;20 :240–9 .not safely tolerate normal doses of tricyclic/tetracyclic

Memantine
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Namenda
Namenda XR
Neuroscience-based Nomenclature: glutamate receptor antagonist
(Glu-RAn)
N-methyl-D-aspartate (NMDA) receptor antagonist; NMDA
subtype of glutamate receptor antagonist; cognitive enhancer
Alzheimer disease (moderate to sever e)

✽ Is a low to moderate af finity noncompetitive (open-channel)
NMDA receptor antagonist, which binds preferentially to the NMDA
receptor -operated cation channels
If It W orks
If It Doesn ’t WorkMild cognitive impairment
Presumably interferes with the postulated persistent activation of
NMDA receptors by excessive glutamate release in Alzheimer
disease
Memory improvement is not expected and it may take months
before any stabilization in degenerative course is evident
May slow progression of disease, but does not reverse the
degenerative process
Consider adjusting dose, switching to a cholinesterase inhibitor or
adding a cholinesterase inhibitor

interest
✽ May be combined with cholinesterase inhibitors
Tests
 Life-Thr eatening or Danger ous Side EffectsDivalproex, carbamazepine, or oxcarbazepine for behavioral
Presumably due to excessive actions at NMDA receptors
Dizziness, headache
Seizures (rare)

Sedation
Fatigue may occur
Wait
Wait
Wait
Consider lowering dose or switching to a dif ferent agent
10 mg twice daily
28 mg once daily (extended-release)

How to Dose
✽ Despite very long half-life, is generally dosed twice daily , although
some data suggest once daily is safe and tolerableNamzaric extended-release (combination memantine/donepezil) 7
Oral solution 2 mg/mL
Extended-release capsule 7 mg, 14 mg, 21 mg, 28 mg
Initial 5 mg/day; can increase by 5 mg each week; doses over 5 mg
should be divided; maximum dose 10 mg twice daily
Extended-release: initial 7 mg once daily; can increase by 7 mg each
week; maximum dose 28 mg once daily
Namzaric, for patients already on memantine (10 mg twice per day

✽ Memantine is unlikely to af fect pharmacokinetics of
acetylcholinesterase inhibitors
Overdose
How to StopBoth the patient and the patient ’s caregiver should be instructed on
how to dose memantine since patients themselves have moderate to
severe dementia and may require assistance
Absorption not af fected by food
No fatalities have been reported; restlessness, psychosis, visual
hallucinations, sedation, stupor , loss of consciousness
No
No known withdrawal symptoms
Theoretically , discontinuation could lead to notable deterioration in
memory and behavior which may not be restored when drug is

✽ No interactions with cholinesterase inhibitors
✽ Use cautiously if coadministering with other NMDA antagonists
such as amantadine, ketamine, and dextromethorphan
Do Not Use
Renal Impairmentrestarted or a cholinesterase inhibitor is initiated
Little metabolism; mostly excreted unchanged in the urine
Terminal elimination half-life approximately 60 –80 hours
Minimal inhibition of CYP450 enzymes
No interactions with drugs metabolized by CYP450 enzymes
Drugs that raise the urine pH (e.g., carbonic anhydrase inhibitors,
sodium bicarbonate) may reduce elimination of memantine and raise
plasma levels of memantine
If there is a proven aller gy to memantine

Elderly
 PregnancyNo dose adjustment in mild or moderate impairment
Reduce dose in severe impairment
Not likely to require dosage adjustment
Pharmacokinetics similar to younger adults
Memantine use has not been studied in children or adolescents

Unknown if memantine is secreted in human breast milk, but all
Memantine is not recommended for use in nursing women
In patients with more advanced Alzheimer disease
Unproven to be ef fective in mild to moderate Alzheimer disease
Patients who have dif ficulty taking a medication twice daily

Pearls
✽ Memantine ’s actions are somewhat like the natural inhibition of
NMDA receptors by magnesium, and thus memantine is a sort of
“artificial magnesium ”
✽ Memantine is well tolerated with a low incidence of adverse ef fectsMemory loss in other dementias
Theoretically , NMDA antagonism of memantine is strong enough to
block chronic low-level overexcitation of glutamate receptors
associated with Alzheimer disease, but not strong enough to
interfere with periodic high level utilization of glutamate for
plasticity , learning, and memory
Structurally related to the antiparkinsonian and anti-influenza agent
amantadine, which is also a weak NMDA antagonist
Antagonist actions at 5HT3 receptors have unknown clinical
consequences but may contribute to low incidence of
donepezil has been approved for the treatment of moderate to severe
Alzheimer dementia in patients stabilized on memantine and

donepezil
Delay in progression of Alzheimer disease is not evidence of
disease-modifying actions of NMDA antagonism

✽ Theoretically , could be useful for any condition characterized by
moderate overactivation of NMDA glutamate receptors (possibly
neurodegenerative conditions or even bipolar disorder , anxiety
disorders, or chronic neuropathic pain), but this is not proven
Areosa  SA , Sherrif f F . Memantine for dementia  . Cochrane Database Syst
Rev 2003  ;(3):CD003154  .
Doggrell  S . Is memantine a breakthrough in the treatment of moderate-to-
severe Alzheimer ’s disease?  Expert Opin Pharmacother  2003  ;4 :1857  –60.
Mobius  HJ . Memantine: update on the current evidence  . Int J Geriatr
Psychiatry  2003  ;18 (Suppl 1): S47 –54.
Sani G , Serra  G , Kotzalidis  GD , et al. The role of memantine in the
treatment of psychiatric disorders other than the dementias: a review of
current preclinical and clinical evidence  . CNS Drugs  2012  ;26 (8 ):663–90
.
Tariot PN , Federof f HJ . Current treatment for Alzheimer disease and

.
future prospects  . Alzheimer Dis Assoc Disor d 2003  ;17 (Suppl 4): S105  –
13.May or may not be ef fective in vascular dementia
Under investigation for dementia associated with HIV/AIDS
May or may not be ef fective in chronic neuropathic pain

Methylfolate (L)
Brands
Generic?
No
 Class
(bold for FDA appr oved as medical food indications)Deplin
Medical food (bioavailable form of folate)
Trimonoamine modulator
Suboptimal folate levels in depr essed patients (adjunct to
antidepr essant)
Hyperhomocysteinemia in schizophr enia patients (adjunct to
antipsychotic)
Enhancement of antidepressant response at the initiation of
treatment

If It W orksCognitive or mood symptoms in patients with MTHFR (methylene
tetrahydrofolate) deficiency
Folate is a water -soluble B vitamin (B9) that is essential for cell
growth/reproduction, breakdown/utilization of proteins, formation
of nucleic acids, and other functions
L-methylfolate, or 6-(S)-5-methyl-tetrahydrofolate, is derived from
folate and is the form that enters the brain and works directly as a
methyl donor and monoamine synthesis modulator
That is, it regulates tetrahydrobiopterin (BH4), a critical enzyme
cofactor for trimonoamine neurotransmitter synthesis
Methyl donor for DNA methylation and thus an epigenetic regulator
symptoms

If It Doesn ’t WorkThe goal of treatment for depression is complete remission of
current symptoms as well as prevention of future relapses
Many patients with depression have only a partial response where
some symptoms are improved but others persist (especially
insomnia, fatigue, and problems concentrating)

Tests
How Drug Causes Side Effectsantidepressant discontinuation and a switch to a mood stabilizer
L-methylfolate is itself an adjunct to standard treatments for
depression or schizophrenia at the initiation of treatment or to
augment a partial response
Baseline folate levels (serum levels for recent folate intake; red
blood cell or CSF levels for long-term folate levels)
Baseline homocysteine levels (reciprocal relationship with folate
levels; high homocysteine levels may be more sensitive in detected
folate deficiency than folate levels themselves in some patients)
May monitor folate levels for patients taking an agent capable of
affecting folate metabolism, absorption, or degradation
May consider genotyping for deficient folate synthesis via MTHFR
T alleles or MTHFD1 A alleles
L-methylfolate does not typically cause side ef fects

Sedation
Best Augmenting Agents for Side EffectsL-methylfolate does not typically cause side ef fects
Theoretically , rare induction of mania or suicidal ideation and
behavior (suicidality)
Wait
Lower the dose or administer in divided doses

How to Dose
 Dosing T ipsassociated with suicidal ideation, and require the addition of lithium,
discontinuation of l-methylfolate or the primary antidepressant
7.5–15 mg/day
Tablet 7.5 mg, 15 mg
Initial 7.5 –15 mg/day
Doses above 15 mg/day should be administered in divided doses
L-methyltetrahydrofolate was shown to be 7 times more
bioavailable than folic acid
That means 7.5 mg of the active l enantiomer of methylfolate may
be equivalent to 52 mg of folate (usual dose of folate is 100 ug to
1.0 mg)

Overdose
How to Stop
Doses up to 90 mg/day of methylfolate (45 mg l-methylfolate) have
been studied without any additional adverse events
L-methylfolate is generally regarded as safe
A toxic dose of l-methylfolate is not known at this time
Safe
No
Mean elimination half-life approximately 3 hours for d,l-
methylfolate

 Other W arnings/Pr ecautionsL-methylfolate is naturally stored in most cells and used by the body
when needed; therefore, l-methylfolate may not follow typical drug
pharmacokinetic patterns
L-methylfolate may reduce plasma levels of certain anticonvulsants,
including phenytoin, carbamazepine, fosphenytoin, phenobarbital,
primidone, or valproate
L-methylfolate may reduce plasma levels of pyrimethamine
Patients taking folate-lowering drugs (e.g., anticonvulsants,
cholestyramine, colestipol, cycloserine, aminopterin, methotrexate,
sulfasalazine, pyrimethamine, triamterene, trimethoprim,
isotretinoin, fluoxetine, nonsteroidal anti-inflammatory drugs
(NSAIDs), methylprednisolone, pentamidine, or who smoke or
drink heavily may require higher doses of l-methylfolate
Folic acid may mask symptoms of B12 deficiency (e.g., pernicious
anemia), although this may be less likely with l-methylfolate

Do Not Use
Elderly
 Childr en and AdolescentsFolic acid, when administered in doses above 800 Î¼ g, may
increase the amount of unmetabolized folic acid, which has been
linked to accelerated growth of existing neoplasms in the colon; l-
methylfolate may be less likely than folic acid to accelerate the
growth of existing neoplasms
If there is a proven aller gy to folate or folic acid

Pregnancy
Potential AdvantagesUse with caution, observing for activation of known or unknown
patients
No controlled studies in humans or animals
Controlled studies of folic acid at recommended doses have failed to
demonstrate risk to the fetus
There are no studies of folic acid at high doses
Because pregnant women are advised to take folic acid or prenatal
vitamins that contain folic acid, it is important to ask the patient
about any supplements or vitamins she may be taking and consider
this when deciding whether to prescribe l-methylfolate
Patients who need ef ficacy greater than an antidepressant alone at
the initiation of treatment

 PearlsPatients with partial or inadequate response to antidepressants
Patients who cannot tolerate other antidepressants
Patients with adequate folate levels
Numerous studies suggest that low plasma, red blood cell, and/or
CSF levels of folate may be associated with depression in some
patients
Treatment with l-methylfolate seems to be safe, has few if any side
effects, and is generally less expensive than augmenting with a
second branded antidepressant or atypical antipsychotic
L-methylfolate is able to cross the blood –brain barrier and support
the synthesis of monoamines
Early studies suggest that those with obesity may be better
responders
Early studies suggest that those with genetic polymorphisms
reducing the formation of l-methylfolate may be better responders

Bottiglieri  T . Homocysteine and folate metabolism in depression  . Prog
Neur opsychopharmacology Biol Psychiatry  2005  ;29 :1103 –12.
Fava  M , Mischoulon  D . Folate in depression: ef ficacy , safety , differences
in formulations, and clinical issues  . J Clin Psychiatry  2009  ;70 (Suppl
5):S12 –17.
Miller  AL . The methylation, neurotransmitter , and antioxidant connections
between folate and depression  . Altern Med Rev  2008  ;13 (3 ):216–26 .
Stahl  SM . L-methylfolate: a vitamin for your monoamines  . J Clin
Psychiatry  2008  ;69 (9 ):1352  –3.

Methylphenidate (D)
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Focalin
Focalin XR
Stimulant
ages 6 –17 (Focalin, Focalin XR) and in adults (Focalin XR)

blocking their reuptake
If It W orks (for ADHD)Enhancement of dopamine and norepinephrine actions in certain
Onset of action can occur 30 minutes post-administration

Consider adjusting dose or switching to a formulation of d,l-
methylphenidate or to another agent
parents
etc.)
For the expert, can combine immediate-release formulation of d-
methylphenidate with a sustained-release formulation of d-

etc.)
methylphenidate for ADHD

Tests
ADHD
or ADHD
Periodic complete blood cell and platelet counts may be considered
during prolonged therapy (rare leukopenia and/or anemia)

✽ Rare priapism
Weight GainIncreases in norepinephrine and dopamine centrally can cause CNS
abuse
Anorexia, nausea, abdominal pain, weight loss
Seizures

Sedation
Wait
Switch to a formulation of d,l-methylphenidate
agent

How to Dose2.5–10 mg twice per day
Immediate-release tablet 2.5 mg, 5 mg, 10 mg
Extended-release capsule 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30
mg, 35 mg, 40 mg
Immediate-release: for patients who are not taking racemic d,l-
methylphenidate, initial 2.5 mg twice per day in 4-hour intervals;
may adjust dose in weekly intervals by 2.5 –5 mg/day; maximum
dose generally 10 mg twice per day
Immediate-release: for patients currently taking racemic d,l-
methylphenidate, initial dose should be half the current dose of
racemic d,l-methylphenidate; maximum dose generally 10 mg twice
per day
Extended-release: for children, same titration schedule as
immediate-release but dosed once in the morning; maximum dose
30 mg/day
Extended-release: for adults not taking racemic d,l-methylphenidate,
initial 10 mg/day in the morning; may adjust dose in weekly
intervals by 10 mg/day; maximum dose generally 40 mg/day

✽ Immediate-release d-methylphenidate has the same onset of action
and duration of action as immediate-release racemic d,l-
methylphenidate (i.e., 2 –4 hours) but at half the dose
and the need to reinstitute stimulant treatment for the next school termExtended-release d-methylphenidate contains half the dose as
immediate-release beads and half as delayed-release beads, so the
dose is released in 2 pulses
Although d-methylphenidate is generally considered to be twice as
potent as racemic d,l-methylphenidate, some studies suggest that the
d-isomer is actually more than twice as ef fective as racemic d,l-

However , most studies show that parental height is what determines

Overdose
How to StopTaking with food may delay peak actions for 2 –3 hours
Vomiting, tremor , coma, convulsion, hyperreflexia, euphoria,
confusion, hallucination, tachycardia, flushing, palpitations,
sweating, hyperpyrexia, hypertension, arrhythmia, mydriasis,
agitation, delirium, headache

d-threo -enantiomer of racemic d,l-methylphenidate
Mean plasma elimination half-life approximately 2.2 hours (same as
d,l-methylphenidate)
Does not inhibit CYP450 enzymes
May inhibit metabolism of SSRIs, anticonvulsants (phenobarbital,
phenytoin, primidone), TCAs, and coumarin anticoagulants,
requiring downward  dosage adjustments of these drugs
Serious adverse ef fects may occur if combined with clonidine

Other W arnings/Pr ecautionsmonitor depressed patients closely when other treatment options for
CNS and cardiovascular actions of d-methylphenidate could
theoretically be enhanced by combination with agents that block
norepinephrine reuptake, such as the TCAs desipramine or
protriptyline, venlafaxine, duloxetine, atomoxetine, milnacipran,
and reboxetine
Theoretically , antipsychotics should inhibit the stimulatory ef fects of
d-methylphenidate
Theoretically , d-methylphenidate could inhibit the antipsychotic
actions of antipsychotics
Theoretically , d-methylphenidate could inhibit the mood-stabilizing
Combinations of d-methylphenidate with mood stabilizers (lithium,
Antacids or acid suppressants could alter the release of extended-
release formulation

Do Not Use
Hepatic ImpairmentII condition sometimes associated with suicidal ideation, and require
an expert
If patient has angioedema or anaphylaxis
If there is a proven aller gy to methylphenidate

Elderly
 Childr en and AdolescentsNo dose adjustment necessary
Methylphenidate has acute ef fects on growth hormone; long-term
children

Pregnancy
✽ For ADHD patients, methylphenidate should generally be
Infants whose mothers took methylphenidate during pregnancy may
Racemic methylphenidate has been shown to have teratogenic
effects in rabbits when given in doses of 200 mg/kg/day throughout
organogenesis

Unknown if methylphenidate is secreted in human breast milk, but

 PearlsThe active d enantiomer of methylphenidate may be slightly more
than twice as ef ficacious as racemic d,l-methylphenidate
Patients with current or past substance abuse, bipolar disorder , or
psychosis

particularly in end-of- life management
Some patients respond to or tolerate methylphenidate better than
amphetamine, and vice versa
New extended-release formulation is truly a once daily dose
Extended-release capsule can be sprinkled over applesauce for
patients unable to swallow the capsule

Some patients may benefit from an occasional addition of an
immediate-release dose of d-methylphenidate to the daily base dose
of extended-release d-methylphenidate

Dexmethylphenidate –Novartis/Celgene. Focalin, D-MPH, D-
methylphenidate hydrochloride, D-methylphenidate, dexmethylphenidate,
dexmethylphenidate hydrochloride  . Drugs R D  2002  ;3 (4 ):279–82 .
Keating  GM , Figgitt  DP . Dexmethylphenidate  . Drugs  2002  ;62 (13 ):1899
–904.

Methylphenidate (D,L)
Brands
Generic?
YesConcerta
Metadate CD
Ritalin
Ritalin LA
Methylin
QuilliChew ER
Quillivant XR
Aptensio XR
Daytrana
Jornay PM
Adhansia XR
Cotempla XR-ODT

Class
blocking their reuptakeNeuroscience-based Nomenclature: dopamine, norepinephrine
Stimulant
Attention deficit hyperactivity disorder (ADHD) in childr en and
adults (appr oved ages vary based on formulation)
Narcolepsy (Metadate ER, Methylin ER, Ritalin, Ritalin SR)

parents

parents

✽ Best to attempt other monotherapies prior to augmenting
sustained-release formulation of d,l-methylphenidate for ADHD
ADHD
or ADHD

overstimulation, tremor , dizzinessIn children, monitor weight and height
abuse
Transdermal: application site reactions, including contact
sensitization (erythema, edema, papules, vesicles) and chemical
leukoderma

Sedation
What to Do About Side EffectsPsychotic episodes, especially with parenteral abuse
Seizures
Wait

Dosage FormsAdjust dose
Switch to another formulation of d,l-methylphenidate
agent
ADHD (oral): varies by formulation; see How to Dose section
ADHD (transdermal): 10 –30 mg/9 hours
Narcolepsy: 20 –60 mg/day in 2 –3 divided doses
Immediate-release tablet 5 mg, 10 mg, 20 mg (Ritalin, generic
methylphenidate)
Oral solution 5 mg/mL, 10 mg/5 mL (Methylin)

✽ Newer sustained-release capsule 10 mg, 20 mg, 30 mg, 40 mg, 60
mg (Ritalin LA); 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg
(Metadate CD)
✽ Newer sustained-release tablet 18 mg, 27 mg, 36 mg, 54 mg
(Concerta)
How to DoseOlder sustained-release tablet 10 mg, 20 mg (Methylin ER); 20 mg
(Ritalin SR, Metadate ER)
Sustained-release chewable tablet 20 mg scored, 30 mg, 40 mg
(QuilliChew ER)
Extended-release capsule, multi-layer release 10 mg, 15 mg, 20 mg,
30 mg, 40 mg, 50 mg, 60 mg (Aptensio XR)
Orally disintegrating tablet 8.6 mg, 17.3 mg, 25.9 mg (Cotempla
XR-ODT)
Extended-release capsule 20 mg, 40 mg, 60 mg, 80 mg, 100 mg
(Jornay PM)
Extended-release capsule 25 mg, 35 mg, 45 mg, 55 mg, 70 mg, 85
mg (Adhansia XR)
Extended-release oral suspension 5 mg/mL (Quillivant XR)
Transdermal patch 27 mg/12.5 cm2 (10 mg/9 hours; 1.1 mg/hour),
41.3 mg/18.75 cm2 (15 mg/9 hours; 1.6 mg/hour), 55 mg/25 cm2 (20
mg/9 hours; 2.2 mg/hour), 82.5 mg/37.5 cm2 (30 mg/9 hours; 3.3
mg/hour)

✽ Newer sustained-release formulations for ADHDImmediate-release Ritalin, generic methylphenidate (2 –4 hour
duration of action)
ADHD: initial 5 mg in morning, 5 mg at lunch; can increase by
5–10 mg each week; maximum dose generally 60 mg/day
Narcolepsy: give each dose 30 –45 minutes before meals;
maximum dose generally 60 mg/day
Older extended-release Ritalin SR, Methylin SR, and Metadate ER
These formulations have a duration of action of approximately
4–6 hours; therefore, these formulations may be used in place
of immediate-release formulations when the 4 –6 hour dosage
of these sustained-release formulations corresponds to the
titrated 4 –6 hour dosage of the immediate-release formulation
Average dose is 20 –30 mg/day , usually in 2 divided doses
Concerta (up to 12 hours duration of action): initial 18 mg/day in
morning; can increase by 18 mg each week; maximum dose
generally 72 mg/day
Ritalin LA, Metadate CD, QuilliChew ER (up to 8 hours duration

of action): initial 20 mg once daily; dosage may be adjusted in
weekly increments of 10 mg or 20 mg (QuilliChew ER only) to a
maximum of 60 mg/day taken in the morning
Quillivant XR (up to 12-hour duration): initial 20 mg once daily;
dosage may be adjusted in weekly increments of 10 –20 mg to a

✽ Transdermal formulation for ADHDAptensio XR (up to 12-hour duration): initial 10 mg once daily;
dosage may be adjusted in weekly increments of 10 mg to a
Cotempla XR-ODT (up to 12-hour duration): initial dose 17.3 mg
once daily in the morning; can increase weekly in increments of
8.6 mg to 17.3 mg per day; maximum recommended dose 51.8
mg; should be taken consistently either with or without food
Jornay PM (nighttime dosing): initial dose 20 mg in the evening
at 8 pm; can increase in weekly increments of 20 mg per day;
maximum daily dose 100 mg; can adjust administration time
between 6:30 to 9:30, depending on optimal ef ficacy and
tolerability; once optimal administration time is set it should
remain consistent
Adhansia XR: initial dose 25 mg once in the morning; can
increase every 5 days in increments of 10 –15 mg per day;
maximum daily dose 85 mg in adults and 70 mg in pediatric
patients; doses above 85 mg in adults and 70 mg in pediatric

patients are associated with increased risk of adverse ef fects
Initial 10 mg/9 hours; can increase by 5 mg/9 hours every week;
maximum dose generally 30 mg/9 hours
Patch should be applied 2 hours before ef fect is needed and
should be worn for 9 hours

✽ Immediate-release formulations (Ritalin, Methylin, generic
methylphenidate) have 2 –4 hour durations of clinical action
✽ Sustained-release formulations such as Methylin ER, Ritalin SR,
Metadate ER, and generic methylphenidate sustained-release all have
approximately 4 –6 hour durations of clinical action, which for most
patients is generally not long enough for once daily dosing in the
morning and thus generally requires lunchtime dosing at school
✽ Sustained-release Metadate CD has an early peak and an 8-hour
duration of action
✽ Sustained-release Ritalin LA also has an early peak and an 8-hour
duration of action, with 2 pulses (immediate and after 4 hours)Patients should follow the same titration schedule when they are
naive to methylphenidate or are switching from another
life
Taking oral formulations with food may delay peak actions for 2 –3
hours

life
hours
Do not substitute methylphenidate products on a mg-per -mg basis
due to dif fering methylphenidate base compositions and

✽ Sustained-release Concerta trilayer tablet, orally disintegrating
tablet Cotempla XRODT , Quillivant XR, and Aptensio XR have 12-
hour durations of action
Orally disintegrating tablet Cotempla-XR-ODT has a 12-hour
Most sustained-release formulations (especially Concerta, Metadate
CD, and Ritalin LA) should not be chewed but rather should only be
swallowed whole
QuilliChew ER is a chewable tablet and can be taken with or
without food
Jornay PM can be taken with or without food, but should be
consistent; the capsule can be opened and the contents sprinkled
onto applesauce
Jornay PM: if the evening dose is missed and not remembered until
the next morning, then the patient should wait until their next
scheduled evening dose
Adhansia XR can be taken with or without food; the capsule can be
opened and the contents sprinkled onto applesauce or yogurt; if
mixture is not consumed within 10 minutes it should be discarded;

45 mg capsule contains tartrazine, which may cause aller gic
reactions, particularly in patients aller gic to aspirin
Adhansia XR: if the morning dose is missed, then the patient should
wait until their next scheduled morning dose

✽ Newer sustained-release formulations have a suf ficiently long
duration of clinical action to eliminate the need for a lunchtime dosing
if taken in the morning
and the need to reinstitute stimulant treatment for the next school termOff-label uses are dosed the same as for ADHD

Concerta tablet does not change shape in the gastrointestinal tract
and generally should not be used in patients with gastrointestinal
narrowing because of the risk of intestinal obstruction

Overdose
Long-T erm UseTransdermal patch should be applied to dry , intact skin on the hip
New application site should be selected for each day; only one patch
should be applied at a time; patches should not be cut
Avoid touching the exposed (sticky) side of the patch, and after
application, wash hands with soap and water; do not touch eyes until
after hands have been washed
Heat can increase the amount of methylphenidate absorbed from the
transdermal patch, so patients should avoid exposing the application
site to external source of direct heat (e.g., heating pads, prolonged
direct sunlight)
If a patch comes of f a new patch may be applied at a dif ferent site;
total daily wear time should remain 9 hours regardless of number of
patches used
Early removal of transdermal patch can be useful to terminate drug
action when desired

sweating, hyperprexia, hypertension, arrhythmia, mydriasis

How to Stop
PharmacokineticsDependence and/or abuse may develop
Average half-life in adults is 3.5 hours (1.3 –7.7 hours)
Average half-life in children is 2.5 hours (1.5 –5 hours)

Drug InteractionsFirst-pass metabolism is not extensive with transdermal dosing, thus
resulting in notably higher exposure to methylphenidate and lower
exposure to metabolites as compared to oral dosing
phenytoin, primidone), TCA, and coumarin anticoagulants,
requiring downward dosage adjustments of these drugs
CNS and cardiovascular actions of d,l-methylphenidate could

d,l-methylphenidate

Other W arnings/Pr ecautionsTheoretically , d,l-methylphenidate could inhibit the antipsychotic
Theoretically , d,l-methylphenidate could inhibit the mood-
stabilizing actions of atypical antipsychotics in some patients
Combination of d,l-methylphenidate with mood stabilizers (lithium,

behavior
fatigue
Permanent skin color loss, known as chemical leukoderma, may
occur with use of the transdermal Daytrana patch; patients should be
advised to watch for signs of skin color changes and if they occur

alternative treatment options should be considered
burns if worn during MRI, so warn patients taking the transdermal

Do Not Use
Hepatic Impairmentformulation about this possibility and advise them to disclose this
an expert

Elderly
 PregnancyUse with caution, particularly in patients with recent myocardial
children

 PearlsEstablished long-term ef ficacy as a first-line treatment for ADHD
Multiple options for drug delivery , peak actions, and duration of
action

amphetamine and vice versa

Older sustained-release technologies for methylphenidate were not
significant advances over immediate-release methylphenidate
because they did not eliminate the need for lunchtime dosing or
allow once daily administration

✽ Newer sustained-release technologies are truly once a day dosing
systems
✽ Metadate CD and Ritalin LA are somewhat similar to each other ,
both with an early peak and duration of action of about 8 hours
✽ Concerta has less of an early peak but a longer duration of action
(up to 12 hours)
✽ Concerta trilayer tablet consists of 3 compartments (2 containing
drug, 1 a “push ” compartment) and an orifice at the head of the first
drug compartment; water fills the push compartment and gradually
pushes drug up and out of the tablet through the orifice
✽ Concerta may be preferable for those ADHD patients who work in
the evening or do homework up to 12 hours after morning dosing
✽ Metadate CD and Ritalin LA may be preferable for those ADHD
patients who lose their appetite for dinner or have insomnia with
Concerta
of immediate-release methylphenidate to their daily base of
sustained-release methylphenidate

Concerta
Transdermal formulation may confer lower abuse potential than oral
Transdermal formulation may enhance adherence to treatment
compared to some oral formulations because it allows once daily
application with all day ef ficacy , has a smoother absorption curve,

Challman  TD , Lipsky  JJ . Methylphenidate: its pharmacology and uses  .
Mayo Clin Pr oc 2000  ;75 :711–21 .
Kimko  HC , Cross  JT , Abemethy  DR . Pharmacokinetics and clinical
effectiveness of methylphenidate  . Clin Pharmacokinet  1999  ;37 :457–70 .
Wolraich  ML , Greenhill  LL , Pelham  W , et al. Randomized, controlled
trial of oros methylphenidate once a day in children with attention-
deficit/hyperactivity disorder  . Pediatrics  2001  ;108 :883–92 .and allows for daily customization of treatment (i.e., it can be
removed early if desired)
On the other hand, transdermal formulation has slower onset than
oral formulations, requires a specific removal time, can cause skin
sensitization, can be lar ge depending on dose, and may lead to
reduced ef ficacy if removed prematurely

Mianserin
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Lerivon
Neuroscience-based Nomenclature: norepinephrine multimodal (N-
MM)
Tetracyclic antidepressant
Noradrener gic agent
Anxiety
Insomnia

✽ Actions on insomnia and anxiety can start shortly after initiation of
dosing
If It W orksBlocks alpha 2 adrener gic presynaptic receptor , thereby increasing
norepinephrine neurotransmission
This is a novel mechanism independent of norepinephrine reuptake
blockade
Blocks alpha 2 adrener gic presynaptic receptors but also alpha 1
adrener gic receptors on serotonin neurons, thereby causing little
increase in serotonin neurotransmission
Blocks 5HT2A, 5HT2C, and 5HT3 serotonin receptors
Blocks H1 histamine receptors
Onset of therapeutic actions in depression, however , is usually not
symptoms

Once symptoms gone, continue treating for 1 year for the first

SSRIs, SNRIs, bupropion, reboxetine, atomoxetine (use
combinations of antidepressant with caution as this may activate
May need to monitor blood count during treatment for those with
blood dyscrasias, leukopenia, or granylocytopenia
Since some antidepressants such as mianserin can be associated with
weight gain, before starting treatment, weigh all patients and

determine if the patient is already overweight (BMI 25.0 –29.9) or
obese (BMI >30)

✽ Histamine 1 receptor antagonism may explain sedative ef fects
✽ Histamine 1 receptor antagonism plus 5HT2C antagonism may
explain some aspects of weight gain
Notable Side EffectsBefore giving a drug that can cause weight gain to an overweight or

Sedation
Increased appetite, weight gain

Sedation
Wait
Wait
Wait

How to DoseOften best to try another antidepressant monotherapy prior to
discontinuation of mianserin
Tablet 10 mg, 30 mg, 60 mg
Initial 30 mg/day; maximum usually 90 mg/day

Overdose
How to Stop
 Drug InteractionsCan be dosed once or twice daily
Relatively safe in overdose; sedation, hypertension, or hypotension
Safe
Not expected
Taper is prudent to avoid withdrawal ef fects, but tolerance,
dependence, and withdrawal ef fects not reliably reported
Half-life 12 –29 hours

Other W arnings/Pr ecautiosTramadol increases the risk of seizures in patients taking an
Carbamazepine and phenytoin may reduce mianserin levels
Theoretically could cause a fatal “serotonin syndrome ” when
combined with MAOIs, so do not use with MAOIs or for at least 14
days after MAOIs are stopped unless you are an expert and only for
treatment-resistant cases that may justify the risk
drugs) after discontinuing mianserin
Drug may lower white blood cell count (rare; may not be increased
compared to other antidepressants but controlled studies lacking)
Avoid alcohol, which may increase sedation and cognitive and
motor ef fects

Do Not Use
Elderlysymptoms immediately
If there is a proven aller gy to mianserin

 PregnancyBlood dyscrasias, though still rare, may be more common in the
elderly
patients

Potential AdvantagesFor many patients this may mean continuing treatment during
pregnancy
the mother
Patients particularly concerned about sexual side ef fects
Patients with symptoms of anxiety
As an augmenting agent to boost the ef ficacy of other

 Pearls
✽ Adding alpha 2 antagonism to agents that block serotonin and/or
norepinephrine reuptake may be syner gistic for severe depression
✽ Only causes sexual dysfunction infrequentlyPatients with cardiovascular disease
Patients particularly concerned about gaining weight
Patients with low ener gy
Anxiety
Adding mianserin to venlafaxine or SSRIs may reverse drug-
induced anxiety and insomnia
Efficacy of mianserin for depression in cancer patients has been
shown in small controlled studies
Generally better tolerated than TCAs, including safer in overdose
General lack of cardiovascular toxicity

Brogden  RN , Heel  RC , Speight  TM , Avery GS . Mianserin: a review of
its pharmacological properties and therapeutic ef ficacy in depressive illness
. Drugs  1978  ;16 (4 ):273 –301 .
De Ridder  JJ . Mianserin: result of a decade of antidepressant research  .
Pharm W eekbl Sci  1982  ;4 (5 ):139–45 .
Leinonen  E , Koponen  H , Lepola  U . Serum mianserin and ageing  . Prog
Neur opsychopharmacol Biol Psychiatry  1994  ;18 (5 ):833–45 .
Rotzinger  S , Bourin  M , Akimoto  Y , Coutts  RT , Baker  GB . Metabolism
of some “second- ” and “fourth- ” generation antidepressants: iprindole,
viloxazine, bupropion, mianserin, maprotiline, trazodone, nefazodone, and
venlafaxine  . Cell Mol Neur obiol  1999  ;19 (4 ):427–42 .
Wakeling  A . Efficacy and side ef fects of mianserin, a tetracyclic
antidepressant  . Postgrad Med J  1983  ;59 (690 ):229–31 .

Midazolam
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Versed
Sedation in pediatric patients
Sedation (adjunct to anesthesia)
Preoperative anxiolytic
Drug-induced amnesia
Catatonia

If It W orks
ResistanceBinds to benzodiazepine receptors at the GABA-A ligand-gated
effects
Intravenous injection: onset 3 –5 minutes
Intramuscular injection: onset 15 minutes, peak 30 –60 minutes
Patients generally recover 2 –6 hours after awakening
Augmenting agents have not been adequately studied

Tests
Oversedation, impaired recall, agitation, involuntary movements,
headache
Hiccups, fluctuation in vital signs, irritation/pain at site of injection
Respiratory depression, apnea, respiratory arrest
Cardiac arrest

Sedation
Wait
Intravenous (adults): 1 –2.5 mg
Liquid (age 16 and under): 0.25 –1.0 mg/kg
Syrup 2 mg/mL
Nasal 5 mg/spray
Intravenous 1 mg/mL, 5 mg/mL
Intramuscular solution 50 mg/10 mL (5 mg/mL)

How to Dose
Overdose
Habit FormingLiquid single dose: 0.25 –1.0 mg/kg; maximum dose generally 20
mg
Intravenous (adults): administer over 2 minutes; monitor patient
over the next 2 or more minutes to determine ef fects; allow 3 –5
minutes between administrations; maximum 2.5 mg within 2
minutes
Better to underdose, observe for ef fects, and then prudently raise
dose while monitoring carefully
Sedation, confusion, poor coordination, respiratory depression,
coma

How to Stop
 Other W arnings/Pr ecautionsIf administration was prolonged, do not stop abruptly
Elimination half-life 1.8 –6.4 hours
Active metabolite
If CNS depressants are used concomitantly , midazolam dose should
be reduced by half or more
Drugs that inhibit CYP450 3A4, such as nefazodone and
fluvoxamine, may reduce midazolam clearance and thus raise
midazolam levels
Midazolam decreases the minimum alveolar concentration of
halothane needed for general anesthesia

Do Not Use
ElderlyMidazolam should be used only in an environment in which the
patient can be closely monitored (e.g., hospital) because of the risk
of respiratory depression and respiratory arrest
Sedated pediatric patients should be monitored throughout the
procedure
Patients with COPD should receive lower doses
Use with caution in patients with impaired respiratory function
If there is a proven aller gy to midazolam or any benzodiazepine
May have longer elimination half-life, prolonging time to recovery
Longer elimination half-life; clearance is reduced

 PregnancyLonger elimination half-life; clearance is reduced
Intravenous: 1 –3.5 mg; maximum 1.5 mg within 2 minutes
In most pediatric populations, pharmacokinetic properties are
similar to those in adults
Seriously ill neonates have reduced clearance and longer elimination
half-life
Hypotension has occurred in neonates given midazolam and
fentanyl
Intravenous dose: dependent on age, weight, route, procedure
Midazolam crosses the placenta
Neonatal flaccidity has been reported in infants whose mother took

 PearlsSome drug is found in mother ’s breast milk
Midazolam can be used to relieve postoperative pain after cesarean
section
Fast onset
Parenteral dosage forms
Can be oversedating
Anxiety
Recovery (e.g., ability to stand/walk) generally takes from 2 –6
hours after wakening
Half-life may be longer in obese patients

Blumer  JL . Clinical pharmacology of midazolam in infants and children  .
Clin Pharmacokinet  1998  ;35 :37 –47 .
Fountain  NB , Adams  RE . Midazolam treatment of acute and refractory
status epilepticus  . Clin Neur opharmacol  1999  ;22 :261–7 .
Shafer  A . Complications of sedation with midazolam in the intensive care
unit and a comparison with other sedative regimens  . Crit Car e Med  1998
;26 :947–56 .
Yuan R , Flockhart  DA , Balian  JD . Pharmacokinetic and
pharmacodynamic consequences of metabolism-based drug interactions
with alprazolam, midazolam, and triazolam  . J Clin Pharmacol  1999  ;39
:1109 –25.Patients with premenstrual syndrome may be less sensitive to
midazolam than healthy women throughout the cycle
Midazolam clearance may be reduced in postmenopausal women
compared to premenopausal women
treatment

Milnacipran
Brands
Generic?
No
 Class
(bold for FDA appr oved)Toledomin
Ixel
Savella
antidepressant; chronic pain treatment

✽ Weak noncompetitive NMDA receptor antagonist (high doses),
which may contribute to actions in chronic pain
cortex, which lar gely lacks dopamine transporters, milnacipran can

symptoms in depression

If It W orks
The goal of treatment of fibromyalgia and chronic neuropathic pain
is to reduce symptoms as much as possible, especially in
combination with other treatments
Treatment of fibromyalgia and chronic neuropathic pain may reduce
Use in fibromyalgia and chronic neuropathic pain may also need to

be indefinite, but long-term treatment is not well studied in these

Adding other agents to milnacipran for treating depression could

Tests
How Drug Causes Side EffectsAlthough no controlled studies and little clinical experience, adding
other agents for treating fibromyalgia and chronic neuropathic pain
could theoretically include gabapentin, tiagabine, other
anticonvulsants, or even opiates if done by experts while monitoring
carefully in dif ficult cases
Mirtazapine, bupropion, reboxetine, atomoxetine (use combinations
of antidepressants with caution as this may activate bipolar disorder

 Life-Thr eatening or Danger ous Side Effectsthose that cause therapeutic actions (e.g., unwanted actions of
Headache, nervousness, insomnia, sedation
Nausea, diarrhea, decreased appetite
Asthenia, sweating
Dose-dependent increased blood pressure
Dry mouth, constipation
Dysuria, urological complaints, urinary hesitancy , urinary retention
Increase in heart rate

Sedation
naftopidilRare activation of suicidal ideation and behavior (suicidality) (short-
Wait
Wait
Wait

Dosage FormsOften best to try another antidepressant monotherapy prior to
discontinuation of milnacipran
30–200 mg/day in 2 doses

How to Dose
✽ Once daily dosing has far less consistent ef ficacy , so only give as
twice dailyCapsule 25 mg, 50 mg (France, other European countries, and
worldwide markets)
Capsule 15 mg, 25 mg, 50 mg (Japan)
Tablet 12.5 mg, 25 mg, 50 mg, 100 mg
Should be administered in 2 divided doses
Initial 12.5 mg once daily; increase to 25 mg/day in 2 divided doses
on day 2; increase to 50 mg/day in 2 divided doses on day 4;
increase to 100 mg/day in 2 divided doses on day 7; maximum dose
generally 200 mg/day
Preferred dose for fibromyalgia may be 100 mg twice daily
Higher doses usually well tolerated in fibromyalgia patients
Higher doses (>200 mg/day) not consistently ef fective in all studies
of depression
Nevertheless, some patients respond better to higher doses (200 –300
mg/day) than to lower doses
Different doses in dif ferent countries
Different doses in dif ferent indications and dif ferent populations

✽ Thus, clinicians must be aware that titration of twice daily dosing
across a 10-fold range (30 mg –300 mg total daily dose) can optimize
milnacipran ’s efficacy in broad clinical use
OverdosePreferred dose for depression may be 50 mg twice daily to 100 mg
twice daily in France
Preferred dose for depression in the elderly may be 15 mg twice
daily to 25 mg twice daily in Japan
Preferred dosing for depression in other adults may be 25 mg twice
daily to 50 mg twice daily in Japan
Patients with agitation or anxiety may require slower titration to
optimize tolerability
No pharmacokinetic drug interactions (not an inhibitor of CYP450
2D6 or 3A4)
As milnacipran is a more potent norepinephrine reuptake inhibitor
than a serotonin reuptake inhibitor , some patients may require
dosing at the higher end of the dosing range to obtain robust dual
SNRI actions
At high doses, NMDA glutamate antagonist actions may be a factor
Vomiting, hypertension, sedation, tachycardia

The emetic ef fect of high doses of milnacipran may reduce the risk
of serious adverse ef fects

How to Stop
No
Half-life 8 hours
No active metabolite
drugs) after discontinuing milnacipran

Other W arnings/Pr ecautionsSwitching from or addition of other norepinephrine reuptake
Few known adverse pharmacokinetic drug interactions
Can cause mild elevations in AL T/AST , so avoid use with alcohol or
in cases of chronic liver disease
companies

Do Not Use
ElderlyIf patient has uncontrolled angle-closure glaucoma
If there is a proven aller gy to milnacipran
Use caution for moderate impairment
For severe impairment, 50 mg/day; can increase to 100 mg/day if
needed
Not recommended for patients with end-stage renal disease
Not recommended for use in chronic liver disease

patients
Not well studied

Breast FeedingNot generally recommended for use during pregnancy , especially
pregnancy

Primary T arget SymptomsMust weigh benefits of breast feeding with risks and benefits of
the mother
Fibromyalgia, chronic pain syndrome
Patients with hypersomnia

Pearls
contribute to its therapeutic activity in fibromyalgia and chronic pain
✽ Onset of action in fibromyalgia may be somewhat faster than
depression (i.e., 2 weeks rather than 2 –8 weeks)
incidence of sweating and urinary hesitancy than other SNRIsPain
Approved in the USA for use in pain and fibromyalgia
Not studied in stress urinary incontinence
Not well studied in ADHD or anxiety disorders, but may be
effective
Therapeutic actions in fibromyalgia are partial, with symptom
reduction but not necessarily remission of painful symptoms in
many patients

Bisserbe  JC . Clinical utility of milnacipran in comparison with other
antidepressants  . Int Clin Psychopharmacol  2002  ;17 (Suppl 1): S43 –50.
Derry  S , Gill D , Phillips  T , Moore  RA . Milnacipran for neuropathic pain
and fibromyalgia in adults  . Cochrane Database Syst Rev  2012  ;14 (3
):CD008244  .
Leo RJ , Brooks  VL . Clinical potential of milnacipran, a serotonin and
norepinephrine reuptake inhibitor in pain  . Curr Opin Investig Drugs  2006
;7 (7 ):637–42 .Urinary hesitancy more common in men than women and in older
May be better tolerated than tricyclic or tetracyclic antidepressants
in the treatment of fibromyalgia or other chronic pain syndromes

No pharmacokinetic interactions or elevations in plasma drug levels
of tricyclic or tetracyclic antidepressants when adding or switching
to or from milnacipran

Puozzo  C , Panconi  E , Deprez  D . Pharmacology and pharmacokinetics of
milnacipran  . Int Clin Psychopharmacol  2002  ;17 (Suppl 1): S25 –35.

Mirtazapine
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Remeron
receptor antagonist (SN-RAn)
Alpha 2 antagonist; NaSSA (noradrenaline and specific serotoner gic
agent); dual serotonin and norepinephrine agent; antidepressant

dosing
If It W orksBoosts neurotransmitters serotonin and
Blocks alpha 2 adrener gic presynaptic receptor , thereby increasing
Blocks alpha 2 adrener gic presynaptic receptor on serotonin neurons
(heteroreceptors), thereby increasing serotonin neurotransmission
This is a novel mechanism independent of norepinephrine and
serotonin reuptake blockade
symptoms

✽ Venlafaxine ( “California rocket fuel ” ; a potentially powerful dual
serotonin and norepinephrine combination, but observe for activation
of bipolar disorder and suicidal ideation)
SSRIs, bupropion, reboxetine, atomoxetine (use combinations of
antidepressants with caution as this may activate bipolar disorder
May need liver function tests for those with hepatic abnormalities
before initiating treatment

✽ Histamine 1 receptor antagonism may explain sedative ef fectsMay need to monitor blood count during treatment for those with
blood dyscrasias, leukopenia, or granulocytopenia
Since some antidepressants such as mirtazapine can be associated
with significant weight gain, before starting treatment, weigh all
patients and determine if the patient is already overweight (BMI
>25.0 –29.9) or obese (BMI >30)

Sedation
Dry mouth, constipation, increased appetite, weight gain
Sedation, dizziness, abnormal dreams, confusion
Flu-like symptoms (may indicate low white blood cell or
granulocyte count)
Change in urinary function

Wait
Wait
Wait
discontinuation of mirtazapine

How to Dose
✽ Breaking a 15 mg tablet in half and administering 7.5 mg dose may
actually increase sedation15–45 mg at night
Tablet 7.5 mg, 15 mg scored, 30 mg scored, 45 mg
SolTab disintegrating tablet 15 mg, 30 mg, 45 mg
Initial 15 mg/day in the evening; increase every 1 –2 weeks until
desired ef ficacy is reached; maximum generally 45 mg/day
Sedation may not worsen as dose increases
Some patients require more than 45 mg daily , including up to 90 mg
in dif ficult patients who tolerate these doses

Overdose
How to Stop
 Drug InteractionsRarely lethal; all fatalities have involved other medications;
symptoms include sedation, disorientation, memory impairment,
rapid heartbeat
Safe
Half-life 20 –40 hours
Substrate for CYP450 2D6, 3A4, and possibly also CYP450 1A2
No significant pharmacokinetic drug interactions

Other W arnings/Pr ecautionsCan cause a fatal “serotonin syndrome ” when combined with
drugs) after discontinuing mirtazapine
compared to other antidepressants but controlled studies lacking; not
a common problem reported in postmarketing surveillance)
Drug may increase cholesterol

companies

Do Not Use
ElderlyWhenever possible, warn patients and their caregivers about the
If there is a proven aller gy to mirtazapine
May require lower dose
The potential risk of hypotension should be considered

patients

pregnancy
essants
Unknown if mirtazapine is secreted in human breast milk, but all

 PearlsFor many patients, this may mean continuing treatment during
Patients on concomitant medications
Anxiety

✽ Does not af fect the CYP450 system, and so may be preferable in
patients requiring concomitant medications
✽ May cause sexual dysfunction only infrequentlyAdding mirtazapine to venlafaxine or SSRIs may reverse drug-
Adding mirtazapine ’s 5HT3 antagonism to venlafaxine or SSRIs
may reverse drug-induced nausea, diarrhea, stomach cramps, and
SSRIs, venlafaxine, bupropion, phentermine, or stimulants may
mitigate mirtazapine-induced weight gain
If weight gain has not occurred by week 6 of treatment, it is less
likely for there to be significant weight gain
Has been demonstrated to have an earlier onset of action than SSRIs
Preliminary evidence suggests ef ficacy as an augmenting agent to
haloperidol in treating negative symptoms of schizophrenia

Anecdotal reports of ef ficacy in recurrent brief depression
Weight gain as a result of mirtazapine treatment is more likely in
women than in men, and before menopause rather than after
Patients can have carryover sedation and intoxicated-like feeling if
particularly sensitive to sedative side ef fects when initiating dosing

Anttila  SA , Leinonen  EV . A review of the pharmacological and clinical
profile of mirtazapine  . CNS Drug Rev  2001  ;7 (3 ):249–64 .
Benkert  O , Muller  M , Szegedi  A . An overview of the clinical ef ficacy of
mirtazapine  . Hum Psychopharmacol  2002  ;17 (Suppl 1): S23 –6.
Falkai  P . Mirtazapine: other indications  . J Clin Psychiatry  1999  ;60 (Suppl
17):S36 –40.
Fawcett  J , Barkin  RL . A meta-analysis of eight randomized, double-blind,
controlled clinical trials of mirtazapine for the treatment of patients with
major depression and symptoms of anxiety  . J Clin Psychiatry  1998  ;59
:123–7 .
Masand  PS , Gupta  S . Long-term side ef fects of newer -generation
antidepressants: SSRIS, venlafaxine, nefazodone, bupropion, and
mirtazapine  . Ann Clin Psychiatry  2002  ;14 :175–82 .
Watanabe  N , Omori  IM , Nakagawa  A , et al. Mirtazapine versus other
antidepressive agents for depression  . Cochrane Database Syst Rev  2011 ;7

(12 ):CD006528  .Rarely , patients may complain of visual “trails ” or after -images on
mirtazapine

Moclobemide
Brands
Generic?
No
 Class
If It W orksAurorix
Arima
Manerix
Neuroscience-based Nomenclature: serotonin, norepinephrine, dopamine reversible enzyme inhibitor (SN-
RevEI)
Reversible inhibitor of monoamine oxidase A (MAO-A) (RIMA)
Social anxiety disorder
Reversibly blocks MAO-A from breaking down norepinephrine, dopamine, and serotonin
This boosts noradrener gic and serotoner gic neurotransmission
MAO-A inhibition predominates unless significant concentrations of monoamines build up (e.g., due to
dietary tyramine), in which case MAO-A inhibition is theoretically reversed

done with caution and with careful monitoring, but may be somewhat less risky with moclobemide than with
other MAOIs
suicidal ideation)
Tests
Side EffectsThe goal of treatment is complete remission of current symptoms as well as prevention of future relapses
Treatment most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after

Lithium

Lithium
Patients should be monitored for changes in blood pressure

Sedation
Best Augmenting Agents for Side EffectsTheoretically due to increases in monoamines in parts of the brain and body and at receptors other than
unwanted actions of norepinephrine on vascular smooth muscle causing hypotension)
Insomnia, dizziness, agitation, anxiety , restlessness
Galactorrhea
Rare hypertension
Hypertensive crisis (especially when MAOIs are used with certain tyramine containing foods –much
reduced risk compared to irreversible MAOIs)
Wait
Wait
Wait

Wait
Wait
Wait

How to Dose
✽ At higher doses, moclobemide also inhibits MAO-B and thereby loses its selectivity for MAO-A, with
uncertain clinical consequences
✽ Taking moclobemide after meals as opposed to before may minimize the chances of interactions with
tyramine
Overdose
How to Stop
Pharmacokinetics300–600 mg/day
Tablet 100 mg scored, 150 mg scored
Initial 300 mg/day in 3 divided doses after a meal; increase dose gradually; maximum dose generally 600
mg/day; minimum dose generally 150 mg/day
May be less toxic in overdose than TCAs and older MAOIs
Clinical duration of action may be longer than biological half-life and allow twice daily dosing in some
patients, or even once daily dosing, especially at lower doses
Agitation, aggression, behavioral disturbances, gastrointestinal irritation
MAOIs may lose ef ficacy long-term
Taper not generally necessary

Partially metabolized by CYP450 2C19 and 2D6

Do Not Use:
SSRIs MDMA (ecstasy) Meperidine Non-subcutaneous
sumatriptan
Imipramine St. John ’s wort High-dose or injected
.amphetamineDextromethorphan
Ziprasidone
 Other W arnings/Pr ecautionsElimination half-life approximately 1 –4 hours
Clinical duration of action at least 24 hours

Cimetidine may increase plasma concentrations of moclobemide
Moclobemide may enhance the ef fects of NSAIDs such as ibuprofen
Risk of hypertensive crisis may be increased if moclobemide is used concurrently with levodopa or other
dopaminer gic agents

Table 2.  Dietary guidelines for patients taking MAOIs *
yogurt, cream cheese
* Consult up-to-date listing of tyramine content, as most foods now have low tyramine amounts
** Not necessary for 6 mg transdermal or low-dose oral selegiline
Use W ith Caution:Use still requires a low-tyramine diet, although more tyramine may be tolerated with moclobemide than

with other MAOIs before eliciting a hypertensive reaction (see Table 2  after Pearls)
Over -the-counter medications to avoid include cough and cold preparations, including those containing
Use cautiously in hypertensive patients
Moclobemide is not recommended for use in patients who cannot be monitored closely

with
reuptake
contain
vasoco
Do Not Use
ElderlyIf patient is taking meperidine (pethidine) (serotonin reuptake inhibitor)
If patient is in an acute confusional state
If patient has pheochromocytoma or thyrotoxicosis
If there is a proven aller gy to moclobemide
Plasma concentrations are increased
May require one-half to one-third of usual adult dose
Cardiac impairment may require lower than usual adult dose

Patients with angina pectoris or coronary artery disease should limit their exertion

 Pregnancy
Primary T arget SymptomsReduction in the risk of suicidality with antidepressants compared to placebo in adults age 65 and older
Monitor patients face-to-face regularly , particularly during the first several weeks of treatment

Effects on infant are unknown
Patients noncompliant with dietary restrictions, concomitant drug restrictions, and twice daily dosing after
meals

Pearls
✽ May be a safer alternative to classical irreversible nonselective MAO-A and MAO-B inhibitors with less
propensity for tyramine and drug interactions and hepatotoxicity (although not entirely free of interactions)
drugs often not followed closely enough
✽ MAOIs should not be neglected as therapeutic agents for the treatment-resistantMAOIs are generally reserved for third- or fourth-line use after SSRIs, SNRIs, and combinations of newer
Patient should be advised not to take any prescription or over -the-counter drugs without consulting his/her

Moclobemide has a much reduced risk of interactions with tyramine than nonselective MAOIs
Especially at higher doses of moclobemide, foods with high tyramine need to be avoided (see Table 2  )
The rigid dietary restrictions may reduce compliance
May not be as ef fective at low doses, and may have more side ef fects at higher doses
Moclobemide ’s profile at higher doses may be more similar to classical MAOIs
effects
For treatment-resistant patients, experts can give a tricyclic/tetracyclic antidepressant other than

Amoxapine may be a preferred trycyclic/tetracyclic antidepressant to combine with an MAOI in heroic

Gillman  K. PsychoT ropical Research (PTR). https://psychotropical.com  .
Gillman  PK . A reassessment of the safety profile of monoamine oxidase inhibitors: elucidating tired old tyramine
myths  . J Neural T ransm (V ienna)  2018  ;125 (11 ):1707 –17 .

Modafinil
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Provigil
Alertec
Modiodal
RI)

✽ Activates TMN that release histamine
How Long Until It W orksReducing excessive sleepiness in patients with obstructive sleep

If It W orks
fatigue
✽ Change dose; some patients do better with an increased dose but
some actually do better with a decreased dose
✽ Modafinil is itself an adjunct to standard treatments for obstructive
sleep apnea/hypopnea syndrome (OSAHS); if continuous positive
airway pressure (CP AP) is the treatment of choice, a maximal ef fort toCan immediately reduce daytime sleepiness and improve cognitive
May not completely normalize wakefulness

treat first with CP AP should be made prior to initiating modafinil and
CPAP should be continued after initiation of modafinil
✽ Modafinil is itself an augmenting therapy to antidepressants for
residual sleepiness and fatigue in major depressive disorder
Tests
How Drug Causes Side EffectsBest to attempt another monotherapy prior to augmenting with other
Combination of modafinil with stimulants such as methylphenidate
or amphetamine or with atomoxetine for ADHD has not been
Unknown

✽ Headache (dose-dependent)
SedationAnxiety , nervousness, insomnia
Dry mouth, diarrhea, nausea, anorexia
Pharyngitis, rhinitis, infection
ideation
others)

Wait
Give only once daily
Give smaller split doses 2 or more times daily
For life-threatening or dangerous side ef fects, discontinue
200 mg/day in the morning

How to Dose
✽ For sleepiness, more may be more: higher doses (200 –800 mg/day)
may be better than lower doses (50 –200 mg/day) in patients with
daytime sleepiness in sleep disorders
doses (50 –200 mg/day) may be paradoxically better than higher doses
(200–800 mg/day) in some patients
OverdoseTablet 100 mg, 200 mg (scored)
the standard starting dose of 200 mg once a day in the morning
At high doses, may slightly induce its own metabolism, possibly by
dose
No fatalities; agitation, insomnia, increase in hemodynamic
parameters

How to Stop
Pharmacokineticshallucinations; digestive changes, such as nausea and diarrhea; and
Efficacy in reducing excessive sleepiness in sleep disorders has been
demonstrated in 9- to 12-week trials
Unpublished data show safety for up to 136 weeks
Schedule IV ; may have some potential for abuse but unusual in
Elimination half-life 10 –12 hours
Inhibits CYP450 2C19 (and perhaps 2C9)

Drug InteractionsInduces CYP450 3A4 (and slightly 1A2 and 2B6)
Modafinil may increase plasma levels of CYP450 2D6 substrates
such as TCAs and SSRIs, perhaps requiring downward dose
adjustments of these agents
Modafinil may decrease plasma levels of CYP450 3A4 substrates
such as ethinyl estradiol and triazolam
Due to induction of CYP450 3A4, ef fectiveness of hormonal
contraceptives may be reduced by modafinil, including 1 month
Inducers or inhibitors of CYP450 3A4 may af fect levels of
modafinil (e.g., carbamazepine may lower modafinil plasma levels;
fluvoxamine and fluoxetine may raise modafinil plasma levels)
Modafinil may slightly reduce its own levels by autoinduction of
CYP450 3A4
Modafinil may increase clearance of drugs dependent on CYP450
1A2 and reduce their plasma levels
Patients on modafinil and warfarin should have prothrombin times
monitored

CYP450 3A4
monitored
Methylphenidate may delay absorption of modafinil by an hour

✽ However , coadministration with methylphenidate does not
significantly change the pharmacokinetics of either modafinil or
✽ Coadministration with dextroamphetamine also does not
dextroamphetamine
 Other W arnings/Pr ecautionsInteraction studies with MAOIs have not been performed, but
MAOIs can be given with modafinil by experts with cautious
Modafinil may cause CNS ef fects similar to those caused by other
Modafinil should be used in patients with sleep disorders that have
been completely evaluated for narcolepsy , obstructive sleep
apnea/hypopnea syndrome (OSAHS), and shift work sleep disorder
In OSAHS patients for whom continuous positive airway pressure

(CPAP) is the treatment of choice, a maximal ef fort to treat first with
CPAP should be made prior to initiating modafinil, and then CP AP
should be continued after initiating modafinil
used with modafinil and for 1 month after discontinuation of

Do Not Use
Elderlymodafinil
Modafinil is not a replacement for sleep
If patient has severe hypertension
If patient has cardiac arrhythmias
If there is a proven aller gy to modafinil
Use with caution; dose reduction is recommended
Reduce dose by half in severely impaired patients
Not recommended for use in patients with a history of left

 Pregnancy
✽ Generally , modafinil should be discontinued prior to anticipated
pregnanciesLimited experience in patients over 65
Clearance of modafinil may be reduced in elderly patients

relevant plasma exposures of armodafinil and modafinil

 Pearls
✽ Anecdotal usefulness for jet lag short-term (of f label)
✽ Modafinil is not a replacement for sleep
✽ The treatment for sleep deprivation is sleep, not modafinilUnknown if modafinil is secreted in human breast milk, but all

HIV/AIDSControlled studies suggest modafinil improves attention in OSAHS,
shift work sleep disorder , and ADHD (both children and adults), but
controlled studies of attention have not been performed in major
In depression, modafinil ’s actions on fatigue appear to be
independent of actions (if any) on mood
In depression, modafinil ’s actions on sleepiness also appear to be
independent of actions (if any) on mood but may be linked to
actions on fatigue or on global functioning
Several controlled studies in depression show improvement in
sleepiness or global functioning, especially for depressed patients
with sleepiness and fatigue
May be useful adjunct to mood stabilizers for bipolar depression

Subjective sensation associated with modafinil is usually one of
Anecdotally , some patients may experience wearing of f of ef ficacy
over time, especially for of f-label uses, with restoration of ef ficacy

✽ Compared to stimulants, modafinil has a novel mechanism of
action, novel therapeutic uses, and less abuse potential, but is often
inaccurately classified as a stimulant
Batejat  DM , Lagarde  DP . Naps and modafinil as countermeasures for the
effects of sleep deprivation on cognitive performance  . Aviat Space Envir on
Med 1999  ;70 :493–8 .
Bourdon  L , Jacobs  I , Bateman  WA , Vallerand  AL . Effect of modafinil on
heat production and regulation of body temperatures in cold-exposed
humans  . Aviat Space Envir on Med  1994  ;65 :999 –1004  .
Cox JM , Pappagallo  M . Modafinil: a gift to portmanteau  . Am J Hosp
Palliat Car e 2001  ;18 :408–10 .
Jasinski  DR , Koyacevic-Ristanovic. Evaluation of the abuse liability of
modafinil and other drugs for excessive daytime sleepiness associated with
narcolepsy  . Clin Neur opharmacol  2000  ;23 :149–56 .after a drug holiday; such wearing of f is less likely with intermittent
dosing

dosing
Alpha 1 antagonists such as prazosin may block the therapeutic
actions of modafinil
The active R enantiomer of modafinil, called armodafinil, is also
available

Kumar  R. Approved and investigational uses of modafinil: an evidence-
based review  . Drugs  2008  ;68 (13 ):1803  –39.
Wesensten  NJ , Belenky  G , Kautz  MA , et al. Maintaining alertness and
performance during sleep deprivation: modafinil versus caf feine  .
Psychopharmacology (Berl)  2002  ;159 :238–47 .

Molindone
Brands
Generic?
Yes
 Class
 How the Drug W orksMoban
Conventional antipsychotic (neuroleptic, dopamine 2 antagonist)
Schizophr enia (no longer available in the USA)
psychosis

Side Effectscholesterol), and treat or refer such patients for treatment, including

molindone should be discontinued at the first sign of decline of

✽ AkathisiaAcute blockade of dopamine 2 receptors in the striatum can cause

✽ Tardive dyskinesia
Sedation
(rhabdomyolysis), and acuterenal failure
Rare leukopenia

Sedation
Wait
Wait
Wait
present

How to Dose
40–100 mg/day in divided doses
Tablet 5 mg, 10 mg, 25 mg scored, 50 mg scored, 100 mg scored
Liquid 20 mg/mL
Initial 50 –75 mg/day; increase to 100 mg/day after 3 –4 days;
maximum 225 mg/day
Very short half-life, but some patients may only require once daily
dosing

Overdose
Long-T erm UseOther patients may do better with 3 or 4 divided doses daily
Deaths have occurred; drug-induced parkinsonism, sedation,
hypotension, respiratory depression, coma

How to Stop
Rapid discontinuation may lead to rebound psychosis and worsening
a few weeks after molindone is discontinued
Half-life approximately 1.5 hours
syndrome
Molindone tablets contain calcium sulfate, which may interfere with
absorption of phenytoin sodium or tetracyclines

Other W arnings/Pr ecautionsMay increase the ef fects of antihypertensive drugs
Liquid molindone contains sodium metabisulfite, which may cause
allergic reactions in some people, especially in asthmatic people
dementia

dementia
therapy

Do Not Use
ElderlyAs with any antipsychotic, use with caution in patients with history
If there is a proven aller gy to molindone
Should receive initial lower dose

 Pregnancy
Breast FeedingElderly patients with dementia-related psychosis treated with
Safety and ef ficacy not well established

 Pearls
✽ May cause less weight gain than some other antipsychoticsUnknown if molindone is secreted in human breast milk, but all
Some patients benefit from molindone ’s sedative properties
After having been produced and subsequently discontinued by Core
Pharma in 2015 –2017, molindone is available again from Epic
Pharma ef fective December , 2018

Bagnall  A , Fenton  M , Kleijnen  J , Lewis  R. Molindone for schizophrenia
and severe mental illness  . Cochrane Database Syst Rev  2007  ;24 (1
):CD002083  .Not shown to be ef fective for behavioral problems in mental
another
antipsychotic such as molindone or from switching to a
conventional antipsychotic such as molindone
conventional antipsychotic such as molindone with an atypical

Owen  RR Jr , Cole  JO . Molindone hydrochloride: a review of laboratory
and clinical findings  . J Clin Psychopharmacol  1989  ;9 (4 ):268–76 .

Nalmefene
Brands
Generic?
Yes (not for oral)
 Class
 How the Drug W orksSelincro
Neuroscience-based Nomenclature: opioid receptor antagonist (O-
RAn)
Alcohol dependence treatment; mu and delta opioid receptor
antagonist and kappa opioid receptor partial agonist
Reduction of alcohol consumption in patients with alcohol
dependence who have a high drinking risk level

If It W orks
TestsReduces alcohol consumption through modulation of opioid
systems, thereby reducing the reinforcing ef fects of alcohol
Blockade of mu opioid receptors prevents the pleasurable ef fects of
alcohol, whereas modulation of the kappa opioid receptors may
reduce dysphoria associated with alcohol withdrawal
Can begin working immediately and can be used as needed
Reduces alcohol consumption by diminishing reinforcing properties
of alcohol (rewarding ef fects, cravings)
therapy in groups or as an individual is key to successful treatment

Sedation
None for healthy individuals, although baseline liver function
testing, usually obtained anyway for managing alcohol dependence,
may be useful
Blockade of mu opioid receptors
Dizziness, insomnia, headache
Confusion, rare hallucinations
May cause weight loss

Switching to another agent may be more ef fective since most side
effects cannot be improved with an augmenting agent
18 mg/day as needed
Tablet 18 mg
After an initial visit, patient should keep a record of alcohol
consumption for 2 weeks; patients who continue to have a high
drinking risk level during those 2 weeks can be initiated on
nalmefene
Nalmefene is taken as needed: on each day the patient perceives a
risk of drinking alcohol, 18 mg should be taken 1 –2 hours before the
anticipated time of drinking

Overdose
How to StopIf the patient has already begun drinking, 18 mg should be taken as
soon as possible
Maximum dose is 18 mg/day
Patient should be opioid-free for 7 –10 days prior to initiating
treatment
nalmefene treatment can increase the chances of success
Nalmefene tablet should not be chewed or crushed, as nalmefene
may cause skin sensitization when in direct contact with skin
Has been evaluated in trials for up to 1 year
No

 Other W arnings/Pr ecautionsTaper not necessary
Extensively metabolized by the liver
Terminal half-life is 12.5 hours
have occurred when taken with other CNS depressants; consider
dose reduction of either or both when taken concomitantly
UGT2B7 inhibitors (e.g., diclofenac, fluconazole,
medroxyprogesterone acetate, meclofenamic acid) may increase
nalmefene levels
UGT2B7 inducers (e.g., dexamethasone, phenobarbital, rifampicin,
omeprazole) may decrease nalmefene levels
must be opioid-free for at least 7 –10 days prior to initiating
treatment
Individuals receiving nalmefene who require pain management with
opioid analgesia may need a higher dose than usual and may
experience deeper and more prolonged respiratory depression; pain

Do Not Use
Renal Impairmentmanagement with non-opioid or rapid-acting opioid analgesics is
recommended if possible
Nalmefene should be temporarily discontinued 1 week prior to
anticipated use of opioids (e.g., opioid analgesia during elective
surgery)
Use caution when using products containing opioids (e.g., cough
medicines)
If patient is taking opioid analgesics
If patient is currently dependent on opioids or is in acute opiate
If patient has severe renal or hepatic impairment
If patient has a recent history of acute alcohol withdrawal syndrome
If there is a proven aller gy to nalmefene

Elderly
 PregnancyDose adjustment not necessary for mild to moderate impairment
Not recommended for use in severe impairment

 PearlsUnknown if nalmefene is secreted in human breast milk, but all
Individuals who are not ready to abstain completely from alcohol
Individuals whose goal is immediate abstinence
Nalmefene was originally used as a parenteral agent to reverse the
opioid agonist ef fects of opioid anesthesia or in opioid overdose
In Europe, nalmefene is approved for reduction of alcohol
consumption without previous detoxification
Nalmefene is intended for patients with the goal of reduced-risk
drinking (i.e., 3 –4 drinks per day in men, maximum 16 drinks per
week; 2 –3 drinks per day in women, maximum 12 drinks per week);

Gual  A , He Y , Torup L , et al. A randomized, double-blind, placebo-
controlled, ef ficacy study of nalmefene, as-needed use, in patients with
alcohol dependence  . Eur Neur opsychopharmacol  2013  ;23 :1432  –42.
Keating  GM . Nalmefene: a review of its use in the treatment of alcohol
dependence  . CNS Drugs  2013  ;27 :761–72 .
Mann  K , Bladstrom  A , Torup L , Gual  A , van den Brink  W. Extending the
treatment options in alcohol dependence: a randomized controlled study of
as-needed nalmefene  . Biol Psychiatry  2013  ;73 (8 ):706–13 .it has been shown to reduce alcohol consumption on average by
60%
Reduction in alcohol consumption has been shown to be maintained
for 12 years
There is no clinically reported dose-dependent hepatotoxicity
Like naltrexone, nalmefene is a mu opioid receptor antagonist;
however , nalmefene is also a partial agonist at kappa opioid
receptors, which are thought to contribute to the dysphoria and

anxiety experienced during alcohol withdrawal
Nalmefene is unique in that it is taken as needed when the patient
perceives a risk of drinking alcohol

Rosner  S , Hackl-Herrwerth  A , Leucht  S , et al. Opioid antagonists for
alcohol dependence  . Cochrane Database Syst Rev  2010  Dec; 8 (12
):CD001867  .
van den Brink  W , Aubin  HJ , Bladstrom  A , et al. Efficacy of as-needed
nalmefene in alcohol-dependent patients with at least a high drinking risk
level: results from a subgroup analysis of two randomized controlled 6-
month studies  . Alcohol Alcohol  2013  ;48 (5 ):570–8 .

Brands
Generic?
Yes (not injection or solution)
 Class
(bold for FDA appr oved)Revia (oral)
Vivitrol (injection)
RAn)
Alcohol dependence treatment; mu opioid receptor antagonist
Blockade of effects of exogenously administer ed opioids (oral)
Prevention of r elapse to opioid dependence (injection)

If It W orks
ResistanceBlocks mu opioid receptors, preventing exogenous opioids from
binding there and thus preventing the pleasurable ef fects of opioid
Reduces alcohol consumption through modulation of opioid
Can begin working within a few days but maximum ef fects may not
be seen for a few weeks
Reduces alcohol and opioid consumption by diminishing their
reinforcing properties (rewarding ef fects, cravings)
Consider augmenting with acamprosate

Tests
 Life-Thr eatening or Danger ous Side EffectsAugmentation with behavioral, education, and/or supportive therapy
in groups or as an individual is probably key to successful treatment
Urine screen for opioids and/or naloxone challenge test prior to
initiating treatment for opioid use
None for use in treating alcohol dependence, although baseline liver
function testing, usually obtained anyway for managing alcohol
dependence, may be useful
Nausea, vomiting, decreased appetite
Dizziness, dysphoria, anxiety
Injection site reactions (pain, tenderness, pruritis, induration,
swelling, erythema, or bruising); in some cases injection site
reactions may be very severe
Eosinophilic pneumonia

Sedation
Usual Dosage RangeHepatocellular injury (at excessive doses)
Severe injection site reactions requiring sur gery
Wait
agent

How to DoseOral: 50 mg/day or 100 mg on Mon and W ed and 150 mg on Fri
Injection: 380 mg every 4 weeks
Tablet 25 mg, 50 mg, 100 mg
Methylnaltrexone bromide tablet 150 mg
Solution (subcutaneous) 8 mg/0.4 mL, 12 mg/0.6 mL
Intramuscular formulation 380 mg/vial
treatment with naltrexone, as confirmed by negative urine screen
and/or naloxone challenge test
For treating alcohol dependence (oral): recommended dose is 50
mg/day; titration is not required
For treating alcohol dependence (injection): 380 mg delivered
intramuscularly in the gluteal region every 4 weeks; alternate
buttocks; must be administered by health-care professional
For treating opioid dependence (oral): initial 25 mg/day; day 2 can
increase to 50 mg/day
For treating opioid dependence (injection): 380 mg delivered
intramuscularly in the gluteal region every 4 weeks or once a month;
alternate buttocks; must be administered by healthcare professional

Overdose
Long-T erm UseProviding educational materials and counseling in combination with
naltrexone treatment can increase the chances of success
Individuals who abstain from alcohol for several days prior to
initiating treatment with naltrexone may have greater reductions in
the number of drinking days as well as number of heavy drinking
days, and may also be more likely to abstain completely throughout
treatment
Long-acting naltrexone (injection) must be kept refrigerated
For long-acting naltrexone (injection), the suspension should be
administered immediately after mixing
Adherence greatly enhanced and assured for 30 days at a time when
administering by once monthly depot injection; oral treatment
requires 30 decisions to comply in 30 days whereas long-acting
injection requires only one decision every 30 days to comply
Patients must be completely withdrawn and abstinent from opioids
for 5 days (short-acting opioids) to 7 days (long-acting opioids)

before starting naltrexone
Nausea, abdominal pain, sedation, dizziness, injection site reactions

How to Stop
 Other W arnings/Pr ecautionsNo
Elimination half-life of oral naltrexone is approximately 13 hours
Elimination half-life of naltrexone via injection is 5 –10 days
Is hepatically metabolized by dihydrodiol dehydrogenase and not by
the CYP450 enzyme system, and thus is unlikely to be af fected by
drugs that induce or inhibit CYP450 enzymes
Can block the ef fects of opioid-containing medications (e.g., some
cough and cold remedies, antidiarrheal preparations, opioid
analgesics)
Concomitant administration with acamprosate may increase plasma
Can cause hepatocellular injury when given in excessive doses

Do Not UseTo prevent withdrawal in patients dependent on opioids, patients
treatment
Individuals who have been previously treated with naltrexone
should be warned that they may respond to lower doses of opioids
than previously used, and thus previous doses may also lead to
opioid intoxication
Individuals receiving naltrexone who require pain management with
management with non-opioid or rapid-acting opioid analgesics is
Monitor patients for emer gence of depressed mood or suicidality
Injection should be used cautiously in individuals with

thrombocytopenia or any coagulation disorder

Cardiac ImpairmentIf patient has failed the naloxone challenge test or has a positive
urine screen for opioids
If patient has acute hepatitis or liver failure
If there is a proven aller gy to naltrexone
If there is a proven aller gy to polylactideco-glycolide (PLG),
arboxymethylcellulose, or any other components of the diluent
Dose adjustment not generally necessary for mild impairment
Not studied in moderate to severe renal impairment
Has the potential to cause hepatocellular injury when given in
excessive doses
Not studied in severe hepatic impairment
Contraindicated in acute hepatitis or liver failure

Elderly
 Pregnancy
Breast FeedingSafety and ef ficacy have not been established

 PearlsIndividuals who are not ready to abstain completely from alcohol
Patients who “drink over ” their treatment, including their long-
acting injection
Less ef fective in patients who are not abstinent at the time of
treatment initation
Not only increases total abstinence, but also can reduce days of
heavy drinking
May be a preferred treatment if the goal is reduced-risk drinking
(i.e., 3 –4 drinks per day in men, maximum 16 drinks per week; 2 –3
drinks per day in women, maximum 12 drinks per week)
treatment initiation

a randomized controlled trial  . JAMA  2006  ;295 (17 ):2003  –17.
Johansson  BA , Berglund  M , Lindregn  A . Efficacy of maintenance
treatment with naltrexone for opioid dependence: a meta-analytical review  .
Addiction  2006  ;101 (4 ):491 –503 .
Mannelli  P , Peindl  K , Masand  PS , Patkar  SS . Long-acting injectable
naltrexone for the treatment of alcohol dependence  . Expert Rev Neur other
2007  ;7 (10 ):1265  –77.
Rosner  S , Leucht  S , Lehert  P , Soyka  M . Acamprosate supports
abstinence, naltrexone prevents excessive drinking: evidence from a meta-
analysis with unreported outcomes  . J Psychopharmacol  2008  ;22 :11 –23 .Some patients complain of apathy or loss of pleasure with chronic
treatment
The combination of naltrexone and bupropion has demonstrated

treatment
efficacy as treatment for obesity and is currently being evaluated in
a long-term study to assess the cardiovascular health outcomes of

Naltrexone/Bupropion
Brands
Generic?
No
 Class
(bold for FDA appr oved)Contrave
Neuroscience-based Nomenclature: opioid receptor antagonist
(naltrexone, O-RAn) and dopamine reuptake inhibitor and releaser
(bupropion, D-RIRe)
Opioid antagonist (naltrexone) combined with a norepinephrine
dopamine reuptake inhibitor (bupropion); weight management
Chronic weight management (adjunct to r educed-calorie diet
and incr eased physical activity) in adults with an initial BMI of

If It W orksat least 30 kg/m2 (obese) or at least 27 kg/m2 (overweight) in the
presence of at least 1 weight-r elated comorbid condition
Bupropion increases dopamine and norepinephrine by blocking both
the dopamine and the norepinephrine transporters. In the
hypothalamus, these 2 neurotransmitters activate POMC neurons,
causing the release of proopiomelanocortin (POMC). POMC is then
broken down into alpha-melanocyte stimulating hormone, which
binds to melanocortin 4 receptors to suppress appetite. However ,
stimulation of POMC neurons also activates an endogenous opioid-
mediated negative feedback loop, which mitigates the appetite-
suppressing ef fects.
Naltrexone can block mu opioid receptors, thus preventing opioid-
mediated negative feedback. Such an action would syner gize with
simultaneous activation of the appetite-suppressing pathway by
bupropion. This results in more robust and long-lasting appetite

suppression than with either drug alone
At least 5% weight loss is generally achieved after 12 weeks on
maximum daily dose
Patients may achieve 5 –10% reduction from baseline in body weight

Tests
Notable Side EffectsDiscontinue if 5% weight loss is not achieved after 12 weeks on
Naltrexone/bupropion itself should be administered in conjunction
with reduced-calorie diet and increased physical activity
Often best to try another strategy prior to resorting to augmentation
Measurement of blood glucose levels before and during treatment is
recommended for patients with type 2 diabetes
Measurement of blood pressure and heart rate prior to starting
naltrexone/bupropion and during treatment is recommended,
particularly in patients with cardiac or cerebrovascular disease
CNS side ef fects theoretically due to excessive actions at mu opioid
receptors or excessive actions on norepinephrine and dopamine

 Sedation
What to Do About Side EffectsNausea, constipation, vomiting, diarrhea, dry mouth
Headache, dizziness, insomnia
Increased blood pressure or heart rate
Rare seizures (risk increases with doses above the recommended
Hepatocellular injury (at excessive doses)
Wait
In a few weeks, switch to another agent

How to DoseOften best to try another treatment prior to resorting to
associated with suicidal ideation, and require discontinuation of
bupropion
16 mg naltrexone/180 mg bupropion twice per day
Extended-release tablet (naltrexone/bupropion) 8 mg/90 mg
Week 1: 8 mg/90 mg in the morning; week 2: increase to 8 mg/90
mg twice per day; week 3: increase to 16 mg/180 mg in the morning
and 8 mg/90 mg in the evening; week 4: increase to 16 mg/180 mg
twice per day (maximum recommended dose)
Discontinue if at least 5% weight loss is not achieved after 12 weeks
on 16 mg/180 mg twice per day

Overdose
Long-T erm UseDo not break or chew tablets as this will alter controlled-release
Can be taken with food, but should not be taken with a high-fat meal
because this may increase bupropion and naltrexone systemic
exposure
before starting naltrexone-bupropion; if patients require intermittent
opioid treatment, naltrexone/bupropion should be temporarily
discontinued and lower doses of opioids may be needed
Naltrexone: nausea, abdominal pain, sedation, dizziness
Bupropion: rarely lethal; seizures, cardiac disturbances,
hallucinations, loss of consciousness

Has been evaluated in controlled studies up to 56 weeks

How to Stop
Tapering is prudent
Mean elimination half-life following a single dose of
naltrexone/bupropion to healthy subjects was approximately 5 hours
for naltrexone and 21 hours for bupropion
Bupropion inhibits CYP450 2D6
Do not use with MAOIs, including 14 days after MAOIs are stopped
Via CYP450 2D6 inhibition, naltrexone/bupropion could increase
concentrations of drugs metabolized by CYP450 2D6 (e.g., TCAs,
thioridazine); this may require lower doses of the concomitant
Bupropion is metabolized by CYP450 2B6; the maximum dose of
naltrexone-bupropion in patients receiving a concomitant CYP450
2B6 inhibitor (ticlopidine, clopidogrel) is 8 mg/90 mg twice per day;

Other W arnings/Pr ecautionscoadministration of naltrexone/bupropion with CYP450 2B6
inducers (e.g., ritonavir , lopinavir , efavirenz) is not recommended
False-positive urine immunoassay screening tests for amphetamines
have been reported in patients taking bupropion due to a lack of
specificity of the screening tests
False-positive results may be expected even following
Naltrexone is hepatically metabolized by dihydrodiol
dehydrogenase and not by the CYP450 enzyme system, and thus is
unlikely to be af fected by drugs that induce or inhibit CYP450
enzymes
Naltrexone/bupropion can increase blood pressure or heart rate,

enzymes
particularly during the first 3 months of treatment
Use cautiously with other drugs that increase seizure risk (TCAs,
lithium, phenothiazines, thioxanthenes, some antipsychotics) or in

Do Not Usepatients with predisposing factors that may increase the risk of
seizures (e.g., history of head trauma)
must be opioid-free (including tramadol) for at least 7 –10 days prior
to initiating treatment
Individuals who have previously been treated with naltrexone
Weight loss may increase the risk of hypoglycemia in patients with
type 2 diabetes mellitus treated with insulin and/or insulin
secretagogues, and medication adjustments may be necessary

Warn patients about the possibility of activation of suicidal ideation
and advise them to report such side ef fects immediately
If patient has uncontrolled hypertension

Hepatic ImpairmentIf patient is anorexic or bulimic, either currently or in the past
If patient is abruptly discontinuing alcohol or sedative use
If patient is taking opioid analgesics, is currently dependent on
opioids, or is in acute opiate withdrawal
If patient is taking W ellbutrin, Zyban, Aplenzin, or any other
formulation that contains bupropion
If patient is taking Revia, V ivitrol, or any other formulation that
contains naltrexone
If there is a proven aller gy to naltrexone or bupropion
Maximum dose is 8 mg/90 mg twice per day in patients with
moderate to severe impairment
Not studied or recommended for use in patients with end-stage renal
disease
Maximum dose is 8 mg/90 mg once per day in the morning

Elderly
 Pregnancy
Breast FeedingNot systematically evaluated in patients with cardiac impairment
Measure blood pressure and heart rate before and during treatment
Recommended to discontinue drug or bottle feed

 PearlsPatients who have had past weight loss on either active compound
alone may experience a more robust weight loss ef fect and better
tolerability on the combination of naltrexone with bupropion than
with administration of either drug alone
Women who are pregnant or wish to become pregnant
Excess weight
No head-to-head studies with other drugs approved for weight
management, so comparative ef ficacy to these agents is unknown;
however , some patients who do not respond to these other agents
may respond to Contrave
Unlike phentermine/topiramate, naltrexone/bupropion does not have
abuse potential
Could theoretically be ef fective in binge eating disorder
May be useful in antipsychotic-induced weight gain, especially for
nonpsychotic patients taking antipsychotic agents for depression

Caixas  A , Albert  L , Capel  I , Rigla  M. Naltrexone sustained-
release/bupropion sustained-release for the management of obesity: review
of the data to date  . Drug Des Devel Ther  2014  ;8 :1419  –27.
Verpeut  JL , Bello  NT . Drug safety evaluation of naltrexone/bupropion for
the treatment of obesity  . Expert Opin Drug Saf  2014  ;13 (6 ):831–41 .
Wang GJ , Tomasi  D , Volkow  ND , et al. Effect of combined naltrexone
and bupropion therapy on the brain ’s reactivity to food cues  . Int J Obes
(Lond)  2014  ;38 (5 ):682–8 .Contrave could theoretically exacerbate psychosis in patients with a
psychotic disorder; however , no controlled studies of this use yet

Brands
Generic?
Yes
 Class
 How the Drug W orksDutonin
Neuroscience-based Nomenclature: serotonin receptor antagonist
SARI (serotonin 2 antagonist/reuptake inhibitor); antidepressant
Relapse pr evention in major depr essive disorder

If It W orksBlocks serotonin 2A receptors potently
Blocks serotonin reuptake pump (serotonin transporter) and
norepinephrine reuptake pump (norepinephrine transporter) less
potently
Can improve insomnia and anxiety early after initiating dosing
symptoms

If It Doesn ’t WorkFor second and subsequent episodes of depression, treatment may
Consider psychotherapy , especially cognitive-behavioral
psychotherapies, which have been specifically shown to enhance
nefazodone ’s antidepressant actions

✽ Venlafaxine and escitalopram may be the best tolerated when
switching or augmenting with a serotonin reuptake inhibitor , as neither
is a potent CYP450 2D6 inhibitor (use combinations of antidepressants
with caution as this may activate bipolar disorder and suicidal
ideation)
Tests
✽ Liver function testing is not required but is often prudent given the
small but finite risk of serious hepatoxicity
✽ However , to date no clinical strategy , including routine liver
function tests, has been identified to reduce the risk of irreversible
liver failure
Side EffectsModafinil, especially for fatigue, sleepiness, and lack of
Benzodiazepines for anxiety , but give alprazolam cautiously with
nefazodone as alprazolam levels can be much higher in the presence
of nefazodone

✽ If CYP450 2D6 is absent (7% of Caucasians lack CYP450 2D6) or
inhibited (concomitant treatment with CYP450 2D6 inhibitors such as
fluoxetine or paroxetine), increased levels of mCPP can form, leading
to stimulation of 5HT2C receptors and causing dizziness, insomnia,
and agitation
 Life-Thr eatening or Danger ous Side EffectsBlockade of alpha adrener gic 1 receptors may explain dizziness,
A metabolite of nefazodone, mCPP (meta-chloro-phenyl-
piperazine), can cause side ef fects if its levels rise significantly
Nausea, dry mouth, constipation, dyspepsia, increased appetite
Headache, dizziness, vision changes, sedation, insomnia, agitation,
confusion, memory impairment
Ataxia, paresthesia, asthenia
Cough increased
Rare postural hypotension

Sedation
Best Augmenting Agents for Side EffectsRare activation of suicidal ideation and behavior (suicidality) (short-
Rare priapism (no causal relationship established)
Hepatic failure requiring liver transplant and/or fatal
Wait
Wait
Wait
Take once daily at night to reduce daytime sedation
Lower the dose and try titrating again more slowly as tolerated

discontinuation of nefazodone
300–600 mg/day
Tablet 50 mg, 100 mg scored, 150 mg scored, 200 mg, 250 mg
Initial dose 100 mg twice a day; increase by 100 –200 mg/day each
week until desired ef ficacy is reached; maximum dose 300 mg twice

Overdose
How to Stopa day
Take care switching from or adding to SSRIs (especially fluoxetine
or paroxetine) because of side ef fects due to the drug interaction
Do not underdose the elderly
Normally twice daily dosing, especially when initiating treatment
Patients may tolerate all dosing once daily at night once titrated
Often much more ef fective at 400 –600 mg/day than at lower doses
if tolerated
Slow titration can enhance tolerability when initiating dosing
Rarely lethal; sedation, nausea, vomiting, low blood pressure
Safe
No

✽ Since a metabolite of nefazodone, mCPP , is a substrate of CYP450
2D6, combination of 2D6 inhibitors with nefazodone will raise mCPP
levels, leading to stimulation of 5HT2C receptors and causing
dizziness and agitationTaper is prudent to avoid withdrawal ef fects, but problems in
withdrawal not common
Half-life of parent compound is 2 –4 hours
Half-life of active mebatolites up to 12 hours
May interact with SSRIs such as paroxetine, fluoxetine, and others
that inhibit CYP450 2D6
drugs) after discontinuing nefazodone
Via CYP450 3A4 inhibition, nefazodone may increase the half-life
of alprazolam and triazolam, so their dosing may need to be reduced

✽ Hepatotoxicity , sometimes requiring liver transplant and/or fatal,
has occurred with nefazodone use. Risk may be one in every 250,000
to 300,000 patient years. Patients should be advised to report
symptoms such as jaundice, dark urine, loss of appetite, nausea, and
abdominal pain to prescriber immediately . If patient develops signs ofby half or more
Via CYP450 3A4, nefazodone may increase plasma concentrations
of buspirone, so buspirone dose may need to be reduced
Via CYP450 3A4 inhibition, nefazodone could theoretically
increase concentrations of certain cholesterol lowering HMG CoA
the risk of rhabdomyolysis; thus, coadministration of nefazodone
caution

caution
Nefazodone may reduce clearance of haloperidol, so haloperidol
dose may need to be reduced
It is recommended to discontinue nefazodone prior to elective
surgery because of the potential for interaction with general
anesthetics

hepatocellular injury , such as increased serum AST or serum ALPT
levels >3 times the upper limit of normal, nefazodone treatment should
be discontinued
✽ No risk factor yet predicts who will develop irreversible liver
failure with nefazodone and no clinical strategy , including routine
monitoring of liver function tests, is known to reduce the risk of liver
failure
Do Not UseUse with caution in patients with history of seizures
companies

companies

Cardiac ImpairmentIf patient has acute hepatic impairment or elevated baseline serum
transaminases
If patient was previously withdrawn from nefazodone treatment due
to hepatic injury
If patient is taking pimozide, as nefazodone could raise pimozide
levels and increase QT c interval, perhaps causing dangerous
If patient is taking carbamazepine, as this agent can dramatically
reduce nefazodone levels and thus interfere with its antidepressant
actions
If there is a proven aller gy to nefazodone
Contraindicated in patients with known hepatic impairment

Elderly
 PregnancyRecommended to initiate treatment at half the usual adult dose, but
to follow the same titration schedule as with younger patients,
including same ultimate dose
patients
Preliminary research indicates ef ficacy and tolerability of
nefazodone in children and adolescents with depression

patients

Breast Feedingprescription drug labels, including the elimination of the pregnancy
pregnancy
essants
Unknown if nefazodone is secreted in human breast milk, but all

essants
are on nefazodone

Primary T arget SymptomsImmediate postpartum period is a high-risk time for depression,
the mother
Depressed patients with anxiety or insomnia who do not respond to
Patients with SSRI-induced sexual dysfunction
Patients who have dif ficulty with a long titration period or twice
daily dosing

Pearls
✽ Studies suggest that cognitive behavioral psychotherapy enhances
the ef ficacy of nefazodone in chronic depression
✽ Risk of hepatotoxicity makes this agent a second-line choice and
has led to its withdrawal from some markets, including the withdrawal
of Serzone from the US market
 Suggested ReadingSleep disturbance
Anxiety
Preliminary data for ef ficacy in panic disorder and PTSD
Fluoxetine and paroxetine may not be tolerated when switching or
augmenting
For elderly patients with early dementia and agitated depression,
consider nefazodone in the morning and additional trazodone at
night
Anecdotal reports suggest that nefazodone may be ef fective in
treating PMDD
Rarely , patients may complain of visual “trails ” or after -images on
nefazodone

DeVane CL , Grothe  DR , Smith  SL . Pharmacology of antidepressants:
focus on nefazodone  . J Clin Psychiatry  2002  ;63 (1 ):10 –17 .
Dunner  DL , Laird  LK , Zajecka  J , et al. Six-year perspectives on the safety
and tolerability of nefazodone  . J Clin Psychiatry  2002  ;63 (1 ):32 –41 .
Khouzam  HR . The antidepressant nefazodone. A review of its
pharmacology , clinical ef ficacy , adverse ef fects, dosage, and administration
. J Psychosocial Nursing Ment Health Serv  2000  ;38 :20 –5.
antidepressants: SSRIs, venlafaxine, nefazodone, bupropion, and
Schatzber g AF , Prather  MR , Keller  MB , et al. Clinical use of nefazodone
in major depression: a 6-year perspective  . J Clin Psychiatry  2002  ;63 (1
):18 –31 .

Nortriptyline
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Pamelor
Anxiety
Insomnia

cortex, which lar gely lacks dopamine transporters, nortriptyline can
delayed 2 to 4 weeks
If it is not working within 6 to 8 weeks for depression, it may

symptoms

75–150 mg/day once daily or in up to 4 divided doses (for
depression)
Capsule 10 mg, 25 mg, 50 mg, 75 mg
Liquid 10 mg/5mL
Initial 10 –25 mg/day at bedtime; increase by 25 mg every 3 –7 days;
can be dosed once daily or in divided doses
When treating nicotine dependence, nortriptyline should be initiated
10–28 days before cessation of smoking to achieve steady drug
states

✽ Monitoring plasma levels of nortriptyline is recommended in
OverdoseIf given in a single dose, should generally be administered at
Patients treated for chronic pain may require only lower doses
Some formulations of nortriptyline contain sodium bisulphate,
which may cause aller gic reactions in some patients, perhaps more
frequently in asthmatics

How to Stop
No
Substrate for CYP450 2D6 and 3A4
Nortriptyline is the active metabolite of amitriptyline, formed by
Half-life approximately 36 hours

Other W arnings/Pr ecautionsTramadol increases the risk of seizures in patients taking TCAs
2D6 inhibitors may increase TCA concentrations and cause side
effects including dangerous arrhythmias
Nortriptyline may raise plasma levels of dicumarol

discontinuation of nortriptyline

after discontinuing nortriptyline
days for most drugs) after discontinuing nortriptyline, but see Pearls

If there is a proven aller gy to nortriptyline or amitriptyline

May require a lower dose with slower titration
nortriptyline

Elderly
May require lower dose; it may be useful to monitor plasma levels
in elderly patients

patients
Not intended for use in children under age 6
Plasma levels may need to be monitored
Dose in children generally less than 50 mg/day

The Art of PsychopharmacologyShould be used only if potential benefits outweigh potential risks
essants
the mother

Noradrener gic reuptake inhibitors such as nortriptyline can be used

patients is for an expert to give a tricyclic/tetracyclic antidepressant

✽ Nortriptyline is one of the few TCAs where monitoring of plasma
drug levels has been well studiedSSRIs may be more ef fective than TCAs in women, and TCAs may
efficacy and because of nortriptyline ’s potential for sudden death in
children
Most individuals have optimal response with plasma levels of 50 –
150 ng/mL
Risk of toxicity with nortriptyline levels greater than 500 ng/mL

Hughes  JR , Stead  LF , Lancaster  T . Antidepressants for smoking cessation
. Cochrane Database Syst Rev  2000  ;(4) :CD000031  .
Wilens  TE , Biederman  J , Baldessarini  RJ , et al. Cardiovascular ef fects of
therapeutic doses of tricyclic antidepressants in children and adolescents  . J
Am Acad Child Adolesc Psychiatry  1996  ;35 (11 ):1491  –501.

Olanzapine
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Zyprexa
Symbyax (olanzapine/fluoxetine combination)
Relprevv
Maintaining r esponse in schizophr enia (long-acting injectable)

How the Drug W orksAcute agitation associated with schizophr enia (intramuscular)
Acute mania/mixed mania (monotherapy , ages 13 and older)
and adjunct to lithium or valpr oate (adults)
Acute agitation associated with bipolar I mania (intramuscular)
Bipolar depr ession [in combination with fluoxetine (Symbyax),
ages 10 and older]
Treatment-r esistant depr ession [in combination with fluoxetine
Borderline personality disorder

to efficacy for cognitive and af fective symptoms in some patients
✽ 5HT2C antagonist actions plus serotonin reuptake blockade of
fluoxetine add to the actions of olanzapine when given as Symbyax
(olanzapine/fluoxetine combination)
If It W orksInteractions at a myriad of other neurotransmitter receptors may
contribute to olanzapine ’s efficacy
symptoms
IM formulation can reduce agitation in 15 –30 minutes

symptoms

If It Doesn ’t WorkMost schizophrenic patients do not have a total remission of

ResistanceIf 2 or more antipsychotic monotherapies do not work, consider
clozapine
injection
Lithium
Fluoxetine and other antidepressants may be ef fective augmenting
agents to olanzapine for bipolar depression, psychotic depression,

Tests
plasma glucose, and fasting lipid profileand for unipolar depression not responsive to antidepressants alone
(e.g., olanzapine/fluoxetine combination)

respiration, weakness, and clouding of sensorium, even comaTreat or refer for treatment and consider switching to another

Patients with liver disease should have blood tests a few times a
year
olanzapine should be discontinued at the first sign of decline of

✽ Probably increases risk for diabetes mellitus and dyslipidemia
Dry mouth, constipation, dyspepsia, weight gain
Joint pain, back pain, chest pain, extremity pain, abnormal gait,
ecchymosis
Orthostatic hypotension, usually during initial dose titration
Rare rash on exposure to sunlight
Rare but serious skin condition known as drug reaction with
eosinophilia and systemic symptoms (DRESS)

Sedation
Usually transient

Wait
Wait
present

How to Dose10–20 mg/day (oral or intramuscular)
6–12 mg olanzapine/25 –50 mg fluoxetine (olanzapine/fluoxetine
combination)
150–300 mg/2 weeks or 300 –405 mg/4 weeks (see Olanzapine
Pamoate after Pearls for dosing and use)
Tablet 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg
Orally disintegrating tablet 5 mg, 10 mg, 15 mg, 20 mg
Intramuscular formulation 5 mg/mL, each vial contains 10 mg
(available in some countries)
Depot 210 mg, 300 mg, 405 mg
Initial 5 –10 mg once daily orally; increase by 5 mg/day once a week
until desired ef ficacy is reached; maximum approved dose is 20
mg/day

✽ More may be mor e: raising usual dose above 15 mg/day can be
useful for acutely ill and agitated patients and some treatment-resistant
patients, gaining ef ficacy without many more side ef fects
✽ Some heroic uses for patients who do not respond to other
antipsychotics can occasionally justify dosing over 30 mg/day and
short-term up to 90 mg/dayFor intramuscular formulation, recommended initial dose 10 mg;
second injection of 5 –10 mg may be administered 2 hours after first
injection; maximum daily dose of olanzapine is 20 mg, with no
more than 3 injections per 24 hours
For olanzapine/fluoxetine combination, recommended initial dose 6
mg/25 mg once daily in evening; increase dose based on ef ficacy
and tolerability; maximum generally 18 mg/75 mg
For high doses in treatment-resistant or violent patients, monitor
therapeutic drug levels and tar get generally higher than the usual
range of 5 –75 mg/mL (i.e., greater than 125 mg/mL), but keep

below the toxic range associated with QT c prolongation (700 –800
mg/mL)
See also the Switching section, after Pearls, for initiating both oral
and long-acting injectable

✽ Olanzapine intramuscularly can be given short-term, both to initiate
dosing with oral olanzapine or another oral antipsychotic and to treat
breakthrough agitation in patients maintained on oral antipsychotics
Overdose
Long-T erm Use(one dose or more) augmentation with a benzodiazepine or another
Clearance of olanzapine is slightly reduced in women compared to
men, so women may need lower doses than men
Rarely lethal in monotherapy overdose; sedation, slurred speech

Approved to maintain response in long-term treatment of

How to Stop
disorders
No
olanzapine
Metabolites are inactive
Parent drug has 21 –54 hour half-life
Substrate for CYP450 1A2 and 2D6
May increase ef fect of antihypertensive agents

Other W arnings/Pr ecautionsDose may need to be lowered if given with CYP450 1A2 inhibitors
(e.g., fluvoxamine); raised if given in conjunction with CYP450
1A2 inducers (e.g., cigarette smoke, carbamazepine)
Olanzapine is associated with a rare but serious skin condition
known as drug reaction with eosinophilia and systemic symptoms
(DRESS). DRESS may begin as a rash but can progress to others
parts of the body and can include symptoms such as fever , swollen
lymph nodes, swollen face, inflammation of or gans, and an increase
in white blood cells known as eosinophilia. In some cases, DRESS
can lead to death. Clinicians prescribing olanzapine should inform
patients about the risk of DRESS; patients who develop a fever with
rash and swollen lymph nodes or swollen face should seek medical
care. Patients are not advised to stop their medication without
consulting their prescribing clinician

Use with caution in patients with prostatic hypertrophy , angle-
closure glaucoma, paralytic ileus
Patients receiving the intramuscular formulation of olanzapine
should be observed closely for hypotension

Do Not UseIntramuscular formulation is not generally recommended to be
administered with parenteral benzodiazepines; if patient requires a
parenteral benzodiazepine it should be given at least 1 hour after
intramuscular olanzapine
olanzapine should be used cautiously in patients at risk for

therapy
If there is a known risk of angle-closure glaucoma (intramuscular

Cardiac ImpairmentIf patient has unstable medical condition (e.g., acute myocardial
infarction, unstable angina pectoris, severe hypotension and/or
bradycardia, sick sinus syndrome, recent heart sur gery)
(intramuscular formulation)
If there is a proven aller gy to olanzapine
No dose adjustment required for oral formulation
For intramuscular formulation, consider lower starting dose (5 mg)
May need to lower dose
Patients with liver disease should have liver function tests a few
times a year
For moderate to severe hepatic impairment, starting oral dose 5 mg;
increase with caution
For intramuscuar formulation, consider lower starting dose (5 mg)

Elderly
Increased incidence of stroke
For intramuscular formulation, recommended starting dose is 2.5 –5
mg; a second injection of 2.5 –5 mg may be administered 2 hours
after first injection; no more than 3 injections should be
administered within 24 hours
agitation

PregnancyApproved for use in schizophrenia and manic/mixed episodes (ages
13 and older for both)
Clinical experience and early data suggest olanzapine is probably
safe and ef fective for behavioral disturbances in children and
Children and adolescents using olanzapine may need to be
better
Intramuscular formulation has not been studied in patients under 18
and is not recommended for use in this population

Potential AdvantagesPsychotic symptoms may worsen during pregnancy , and some form
Early findings of infants exposed to olanzapine in utero currently do
not show adverse consequences
When administered to pregnant rats and rabbits, olanzapine was not
teratogenic at doses 9 and 30 times the maximum recommended
human dose; some fetal toxicities were observed at these doses
Olanzapine may be preferable to anticonvulsant mood stabilizers if
961-2388,
Unknown if olanzapine is secreted in human breast milk, but all
Infants of women who choose to breast feed while on olanzapine

✽ Some cases of psychosis and bipolar disorder refractory to
treatment with other antipsychotics
✽ Often a preferred augmenting agent in bipolar depression or
treatment-resistant unipolar depression
✽ Patients needing rapid onset of antipsychotic action without drug
titration
✽ Patients with diabetes mellitus, obesity , and/or dyslipidemia
 PearlsPatients switching from intramuscular olanzapine to an oral
preparation
Patients concerned about gaining weight
Unstable mood (both depressed mood and mania)
Head-to-head study in schizophrenia suggests greater ef fectiveness
(i.e., lower dropouts of all causes) at moderately high doses

✽ Documented utility in treatment-refractory cases, especially at
✽ Documented ef ficacy as augmenting agent to SSRIs (fluoxetine) in
nonpsychotic treatment-resistant major depressive disorder
✽ Documented ef ficacy in bipolar depression, especially in
combination with fluoxetinecompared to some other atypical and conventional antipsychotics at
moderate doses
Same head-to-head study in schizophrenia suggests greater ef ficacy
but greater metabolic side ef fects compared to some other atypical
and conventional antipsychotics
Well accepted for use in schizophrenia and bipolar disorder ,
including dif ficult cases
Combination of olanzapine with the opioid antagonist samidorphan
in late-stage clinical development to mitigate weight gain
For treatment-refractory cases, consider dosing guided by plasma
drug levels and tolerability , with minimum therapeutic level of 40
ng/mL and point of futility of 200 ng/mL; many who don ’t respond

to lower levels have a clinical response at plasma drug levels above
125 ng/mL (may require oral dosing at or above 40 mg/day to attain
these plasma drug levels)
Motor side ef fects unusual at low to mid-doses

✽ Controversial as to whether olanzapine has more risk of diabetes
and dyslipidemia than other antipsychotics
✽ A short-acting intramuscular dosage formulation is availableLess sedation than for some other antipsychotics, more than for
others
Cigarette smoke can decrease olanzapine levels and patients may
require a dose increase if they begin or increase smoking
Long-acting intramuscular dosage formulation is also approved
of either

of either

Olanzapine Pamoate
Vehicle Water
Tmax 3–4 days
T1/2 with multiple dosing 30 days
Time to reach steady state 3 months
Dosing schedule (maintenance) 2 weeks or 4 weeks
Injection site Intramuscular gluteal
Needle gauge 19
Dosage forms 210 mg, 300 mg, 405 mg
Injection volume 150 mg/mL (range 1.0 –2.7 mL)
Usual Dosage RangeIn such cases, it may be beneficial to combine 1 depot antipsychotic
150–300 mg/2 weeks or 300 –405 mg/4 weeks

How to Dose
Daily oral
doseLAI dose: first 8 weeks LAI dose: after
8 weeks
10 mg 210 mg/2 weeks OR 405 mg/4
weeks150 mg/2 weeks
OR 300 mg/4
weeks
15 mg 300 mg/2 weeks 210 mg/2 weeks
OR 405 mg/4
weeks
20 mg 300 mg/2 weeks 300 mg/2 weeks
Dosing T ipsConversion from oral: dose should be loaded during the initial 8
weeks based on the prior stable oral dose of olanzapine
Oral supplementation may be needed if adequate loading is not used
Maximum dose 300 mg/2 weeks
elimination rate constant, thus resulting in “flip-flop ” kinetic –i.e.,

Switching fr om Oral Antipsychotics to Olanzapine PamoateIn general, 5 half-lives of any medication are needed to achieve 97%
Advantages: ef ficacy advantage of oral olanzapine
Disadvantages: 3-hour post-injection monitoring required due to risk

(0.2%) of post-injection delirium from vascular breach
Response threshold is generally 21 ng/mL; plasma levels greater
than 176 ng/mL are generally not well tolerated

 Switching fr om Oral Antipsychotics to Oral OlanzapineDiscontinuation of oral antipsychotic can begin immediately if
adequate loading is pursued
brexpiprazole, cariprazine, olanzapine, paliperidone ER
risperidone, ziprasidone, asenapine, quetiapine
4+-week down-titration may be required for: clozapine
begin olanzapine at middle dose

Citrome  L. Adjunctive aripiprazole, olanzapine, or quetiapine for major
depressive disorder: an analysis of number needed to treat, number needed
to harm, and likelihood to be helped or harmed  . Postgrad Med  2010  ;122
(4 ):39 –48 .
Detke  HC , Zhao  F , Garhyan  P , Carlson  J , McDonnell  D . Dose
correspondence between olanzapine long-acting injection and oral
olanzapine: recommendations for switching  . Int Clin Psychopharmacol
2011 ;26 :35 –42 .
efficacy and tolerability of 32 oral antipsychotics for the acute treatment ofWith risperidone, ziprasidone, iloperidone, and luasidone, begin
olanzapine gradually , titrating over at least 2 weeks to allow patients
*May need to taper clozapine slowly over 4 weeks or longer

Komossa  K , Rummel-Kluge  C , Hunger  H , et al. Olanzapine versus other
2010  ;17 (3 ):CD006654  .
35 .
60 .

Oxazepam
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Serax
Anxiety
Anxiety associated with depr ession
Alcohol withdrawal
Catatonia

Consider presence of oxazepam abuse

Tests
✽ Hyperexcitability , nervousnessCaution if using as an anxiolytic concomitantly with other sedative

Sedation
Wait
Wait
Wait

How to Dose
Mild to moderate anxiety: 30 –60 mg/day in 3 –4 divided doses
Severe anxiety , anxiety associated with alcohol withdrawal: 45 –120
mg/day in 3 –4 divided doses
Capsule 10 mg, 15 mg, 30 mg
Tablet 15 mg
Titration generally not necessary

Overdose
Long-T erm UseUse lowest possible ef fective dose for the shortest possible period of
15 mg tablet contains tartrazine, which may cause aller gic reactions
in certain patients, particularly those who are sensitive to aspirin
anxiety
Some severely ill patients may require doses higher than the
generally recommended maximum dose

How to StopOxazepam is a Schedule IV drug
use
Taper by 15 mg every 3 days to reduce chances of withdrawal
effects
slowly once reaching 45 mg/day , perhaps by as little as 10 mg per

 Other W arnings/Pr ecautionsbenzodiazepine-dependent patients stop their medication, disease
Elimination half-life 3 –21 hours
efficacy

Do Not Use
Hepatic ImpairmentDosage changes should be made in collaboration with prescriber
ideation
If there is a proven aller gy to oxazepam or any benzodiazepine
Use with caution; oxazepam levels may be increased

Elderly
 PregnancyBecause of its short half-life and inactive metabolites, oxazepam
disease
Initial 30 mg in 3 divided doses; can be increased to 30 –60 mg/day
in 3–4 divided doses
Safety and ef ficacy not established under age 6
No clear dosing guidelines for children ages 6 –12
Long-term ef fects of oxazepam in children/adolescents are unknown
monitored

Potential Advantagesor final rule) applies only to prescription drugs and will be phased in
Because of the potential risks, oxazepam is not generally

 Pearls
✽ Because of its short half-life and inactive metabolites, oxazepam
diseaseRapid onset of action
Anxiety
Agitation
Can be a very useful adjunct to SSRIs and SNRIs in the treatment of
Oxazepam may be preferred over some other benzodiazepines for
the treatment of delirium

Ayd FJ Jr . Oxazepam: update 1989  . Int Clin Psychopharmacol  1990  ;5 :1
–15.
Garattini  S . Biochemical and pharmacological properties of oxazepam  .
Acta Psychiatr Scand Suppl  1978  ;274 :9 –18.
Clin Pharmacokinet  1981  ;6 :89 –105.Can both cause and treat depression in dif ferent patients
treatment

Oxcarbazepine
Brands
Generic?
Yes
 Class
 How the Drug W orksTrileptal
Anticonvulsant, voltage-sensitive sodium channel antagonist
Partial seizur es in adults with epilepsy (monotherapy or
adjunctive)
Partial seizur es in childr en ages 4 –16 with epilepsy
(monotherapy or adjunctive)

channels
If It W orks
If It Doesn ’t Work (for Bipolar Disorder)Inhibits release of glutamate
seizures, mania)
seizures

Oxcarbazepine is itself a second-line augmenting agent for
numerous other anticonvulsants, lithium, and atypical antipsychotics
in treating bipolar disorder , although its use in bipolar disorder is not
yet well studied
Oxcarbazepine may be a second- or third-line augmenting agent for

antipsychotics in treating schizophrenia, although its use in
schizophrenia is also not yet well studied

Tests
✽ Sedation (dose-dependent), dizziness (dose-dependent), headache,
ataxia (dose-dependent), nystagmus, abnormal gait, confusion,
nervousness, fatigue
✽ Nausea (dose-dependent), vomiting, abdominal pain, dyspepsia
✽ Rash
Consider monitoring sodium levels because of possibility of
hyponatremia, especially during the first 3 months
Diplopia (dose-dependent), vertigo, abnormal vision

Sedation
Some patients experience increased appetite
Less than carbamazepine
More when combined with other anticonvulsants
Wait
Wait
Wait

How to Dose
 Dosing T ips1200 –2400 mg/day
Tablet 150 mg, 300 mg, 600 mg
Extended-release tablet 150 mg, 300 mg, 600 mg
Liquid 300 mg/5 mL
Monotherapy for seizures or bipolar disorder: initial 600 mg/day in
2 doses; increase every 3 days by 300 mg/day; maximum dose
generally 2400 mg/day
Adjunctive: initial 600 mg/day in 2 doses; each week can increase
by 600 mg/day; recommended dose 1200 mg/day; maximum dose
When converting from adjunctive to monotherapy in the treatment
of epilepsy , titrate concomitant drug down over 3 –6 weeks while
titrating oxcarbazepine up over 2 –4 weeks, with an initial daily
oxcarbazepine dose of 600 mg divided in 2 doses
Extended-release: initial 600 mg once per day; increase weekly by
600 mg once per day; recommended maintenance dose 1200 –2400
mg once per day

✽ Doses of oxcarbazepine need to be about one-third higher than
those of carbamazepine for similar results
Overdose
Long-T erm UseUsually administered as adjunctive medication to other
anticonvulsants, lithium, or atypical antipsychotics for bipolar
disorder
Side ef fects may increase with dose
Although increased ef ficacy for seizures is seen at 2400 mg/day
compared to 1200 mg/day , CNS side ef fects may be intolerable at
the higher dose
Liquid formulation can be administered mixed in a glass of water or
directly from the oral dosing syringe supplied
Slow dose titration may delay onset of therapeutic action but
When converting from immediate-release to extended-release,
higher doses may be necessary
No fatalities reported
Safe

How to Stop
disorder
✽ Oxcarbazepine is a prodrug for 10-hydroxy carbazepine
✽ This main active metabolite is sometimes called the monohydroxy
derivative or MHD, and is also known as licarbazepine
✽ Half-life of parent drug is approximately 2 hours; half-life of MHD
is approximately 9 hours; thus oxcarbazepine is essentially a prodrugMonitoring of sodium may be required, especially during the first 3
months
No
Taper
Metabolized in the liver

rapidly converted to its MHD, licarbazepine
 Other W arnings/Pr ecautionsA mild inducer of CYP450 3A4
Strong inducers of CYP450 cytochromes (e.g., carbamazepine,
phenobarbital, phenytoin, and primidone) can decrease  plasma
levels of the active metabolite MHD
Verapamil may decrease  plasma levels of the active metabolite
MHD
Oxcarbazepine can decrease  plasma levels of hormonal
contraceptives and dihydropyridine calcium antagonists
Oxcarbazepine at doses greater than 1200 mg/day may increase
plasma levels of phenytoin, possibly requiring dose reduction of
phenytoin
Because oxcarbazepine has a tricyclic chemical structure, it is not
recommended to be taken with MAOIs, including 14 days after
MAOIs are stopped; do not start an MAOI until 2 weeks after
discontinuing oxcarbazepine

Do Not Use
Renal ImpairmentBecause oxcarbazepine can lower plasma levels of hormonal
May need to restrict fluids and/or monitor sodium because of risk of
Use cautiously in patients who have demonstrated hypersensitivity
to carbamazepine
If there is a proven aller gy to oxcarbazepine
Oxcarbazepine is renally excreted
Elimination half-life of active metabolite MHD is increased
Reduce initial dose by half; may need to use slower titration

Elderly
 Childr en and AdolescentsNo dose adjustment recommended for mild to moderate hepatic
No dose adjustment recommended
Older patients may have reduced creatinine clearance and require
reduced dosing
Approved as adjunctive therapy or monotherapy for partial seizures
in children ages 4 and older
Ages 4 –16 (adjunctive): initial 8 –10 mg/kg per day or less than 600
mg/day in 2 doses; increase over 2 weeks to 900 mg/day (20 –29 kg),
1200 mg/day (29.1 –39 kg), or 1800 mg/day (>39 kg)
When converting from adjunctive to monotherapy , titrate
concomitant drug down over 3 –6 weeks while titrating
oxcarbazepine up by no more than 10 mg/kg per day each week,

Pregnancywith an initial daily oxcarbazepine dose of 8 –10 mg/kg per day
divided in 2 doses
Monotherapy: initial 8 –10 mg/kg per day in 2 doses (immediate-
release) or 1 dose (extended-release); increase every 3 days by 5
mg/kg per day; recommended maintenance dose dependent on
weight
0–20 kg (600 –900 mg/day)
21–30 kg (900 –1200 mg/day)
31–40 kg (900 –1500 mg/day)
41–45 kg (1200 –1500 mg/day)
46–55 kg (1200 –1800 mg/day)
56–65 kg (1200 –2100 mg/day)
over 65 kg (1500 –2100 mg)
Children below age 8 may have increased clearance compared to
adults

✽ Oxcarbazepine is structurally similar to carbamazepine, which is
thought to be teratogenic in humans
spina bifida) or other congenital anomalies
✽ If drug is continued, start on folate 1 mg/day to reduce risk of
neural tube defects
✽ For bipolar patients, oxcarbazepine should generally be
pregnancy
anticonvulsants such as oxcarbazepine if treatment of bipolar disorderControlled studies have not been conducted in pregnant women

✽ Relapse rates may be lower  in women who receive prophylactic
Bipolar disorder may recur during the postpartum period,
particularly if there is a history of prior postpartum episodes of
either depression or psychosis
be safer than oxcarbazepine during the postpartum period when

 Pearls
✽ Some evidence of ef fectiveness in treating acute mania; included in
American Psychiatric Association ’s bipolar treatment guidelines as an
option for acute treatment and maintenance treatment of bipolar
disorderTreatment-resistant bipolar and psychotic disorders
Those unable to tolerate carbamazepine but who respond to
Patients at risk for hyponatremia
Severity of seizures
Some evidence of ef fectiveness as adjunctive treatment in
schizophrenia and schizoaf fective disorders
Oxcarbazepine is the 10-keto analog of carbamazepine, but not a
metabolite of carbamazepine
Less well investigated in bipolar disorder than carbamazepine

✽ Oxcarbazepine seems to have the same mechanism of therapeutic
action as carbamazepine but with fewer side ef fects
✽ Specifically , risk of leukopenia, aplastic anemia, agranulocytosis,
elevated liver enzymes, or Stevens-Johnson syndrome and serious rash
associated with carbamazepine does not seem to be associated with
oxcarbazepine
Skin rash reactions to carbamazepine may resolve in 75% of
patients with epilepsy when switched to oxcarbazepine; thus, 25%
of patients who experience rash with carbamazepine may also
experience it with oxcarbazepine
Oxcarbazepine has much less prominent actions on CYP 450
enzyme systems than carbamazepine, and thus fewer drug-drug
Specifically , oxcarbazepine and its active metabolite, the
monohydroxy derivative (MHD), cause less enzyme induction of
CYP450 3A4 than the structurally related carbamazepine
The active metabolite MHD, also called licarbazepine, is a racemic
mixture of 80% S-MHD (active) and 20% R-MHD (inactive)

A related compound, APTIOM, is a dibenz[b,f]azepine-5-
carboxamide derivative of eslicarbazepine and is also extensively
converted to eslicarbazepine
APTIOM is now approved as an anticonvulsant, but adequate
studies have not been conducted on its potential use as a mood
stabilizer

✽ Most significant risk of oxcarbazepine may be clinically significant
hyponatremia (sodium level <125 m mol/L), most likely occurring
within the first 3 months of treatment, and occurring in 2 –3% of
patients
✽ Since SSRIs can sometimes also reduce sodium due to SIADH
(syndrome of inappropriate antidiuretic hormone production), patients
treated with combinations of oxcarbazepine and SSRIs should be
carefully monitored, especially in the early stages of treatment
Beydoun  A . Safety and ef ficacy of oxcarbazepine: results of randomized,
double-blind trials  . Pharmacotherapy  2000  ;20 (8 Pt 2): 152S  –158S.
Centorrino  F , Albert  MJ , Berry  JM , et al. Oxcarbazepine: clinical
experience with hospitalized psychiatric patients  . Bipolar Disor d 2003  ;5
:370 –4 .
Dietrich  DE , Kropp  S , Emrich  HM . Oxcarbazepine in af fective and
schizoaf fective disorders  . Pharmacopsychiatry  2001  ;34 :242–50 .

:370 –4 .
Glauser  TA . Oxcarbazepine in the treatment of epilepsy  . Pharmacotherapy
2001  ;21 :904–19 .Unknown if this risk is higher than for carbamazepine
By analogy with carbamazepine, could theoretically be useful in
chronic neuropathic pain

Vasudev  A , Macritchie  K , Vasudev  K , et al. Oxcarbazepine for acute
affective episodes in bipolar disorder  . Cochrane Database Syst Rev  2011 ;7
(12 ):CD004857  .

Paliperidone
Brands
Generic?
No
 Class
(bold for FDA appr oved)Invega
Invega Sustenna
Invega T rinza
Schizophr enia (ages 12 and older)
Maintaining r esponse in schizophr enia

✽ Serotonin 7 antagonist properties may contribute to antidepressant
actions
How Long Until It W orksSchizoaffective disorder
contribute to paliperidone ’s efficacy

Such patients are considered superresponders or “awakeners ” since

ResistanceEven for first episodes of psychosis, it may be preferable to continue
clozapine
fewer side ef fects

paliperidone should be discontinued at the first sign of decline of

✽ Dose-dependent drug-induced parkinsonism
✽ Hyperprolactinemia
 Life-Thr eatening or Danger ous Side EffectsMechanism of weight gain and increased incidence of diabetes and
Rare tardive dyskinesia (much reduced risk compared to
conventional antipsychotics)
Sedation, hypersalivation
Dose-dependent orthostatic hypotension

Sedation
What to Do About Side EffectsRare neuroleptic malignant syndrome (NMS) may cause
May be dose-dependent
Wait

Wait
present

How to Dose
 Dosing T ips –Oral6 mg/day (oral)
39–234 mg/month (Sustenna; see Paliperidone Palmitate section
273–819 mg/3 months (T rinza; see Paliperidone Palmitate section
Tablet (extended-release) 1.5 mg, 3 mg, 6 mg, 9 mg
1-month injection 39 mg, 78 mg, 1 17 mg, 156 mg, 234 mg
3-month injection 273 mg, 410 mg, 546 mg, 819 mg
Initial dose 6 mg/day taken in the morning
Can increase by 3 mg/day every 5 days; maximum dose generally
12 mg/day
LAI paliperidone is not recommended for patients who have not
first demonstrated tolerability to oral paliperidone or risperidone
See also the Switching section, after Pearls
Tablet should not be divided or chewed, but rather should only be

Tablet does not change shape in the gastrointestinal tract and
generally should not be used in patients with gastrointestinal
Some patients may benefit from doses above 6 mg/day;
alternatively , for some patients 3 mg/day may be suf ficient
A common dosage error is to assume the paliperidone ER oral dose
is the same as the risperidone oral dose in mg, and that paliperidone
should be titrated. However , many patients do well initiating a dose
of 6 mg orally of paliperidone ER without titration
There is a dose-dependent increase in some side ef fects, including
drug-induced parkinsonism and weight gain, above 6 mg/day

Overdose
How to Stop
PharmacokineticsOral doses correspond to injection doses as follows: 3 mg oral to
39–78 mg injection, 6 mg oral to 1 17 mg injection, 12 mg oral to
234 mg injection
Drug-induced parkinsonism, gait unsteadiness, sedation,
tachycardia, hypotension, QT prolongation
Approved for maintenance in schizophrenia
No
paliperidone ER and LAI
Active metabolite of risperidone

 Other W arnings/Pr ecautionsHalf-life approximately 23 hours
Absorption is reduced if taken on an empty stomach
paliperidone should be used cautiously in patients at risk for
Paliperidone prolongs QT c interval more than some other

Do Not Use
Renal ImpairmentPriapism has been reported with other antipsychotics, including
risperidone
therapy
If patient has a preexisting severe gastrointestinal narrowing
If there is a proven aller gy to paliperidone or risperidone

For mild impairment, maximum recommended dose 6 mg/day

ElderlyFor moderate impairment, initial and maximum recommended dose
3 mg/day
For severe impairment, initial dose 1.5 mg/day; maximum
recommended dose 3 mg/day
Use in individuals with severe hepatic impairment has not been
studied
agitation

Safety and ef ficacy have not been established under age 12
Adolescents <51 kg: initial 3 mg/day; recommended 3 –6 mg/day;
maximum 6 mg/day
Adolescents >51 kg: initial 3 mg/day; recommended 3 –12 mg/day;
maximum 12 mg/day
Children and adolescents using paliperidone may need to be
better

Breast Feedingthe third trimester; symptoms may include agitation, abnormally
When administered to rats during the period of or ganogenesis, there
were no treatment-related ef fects at doses up to 10 times the
Paliperidone may be preferable to anticonvulsant mood stabilizers if
Effects of hyperprolactinemia on the fetus are unknown
961-2388,
Infants of women who choose to breast feed while on paliperidone

should be monitored for possible adverse ef fects; sedation, failure to
thrive, jitteriness, and drug-induced parkinsonism (tremor and
abnormal muscle movements) have been reported

 PearlsSome cases of psychosis and bipolar disorder refractory to treatment
titration
Some patients respond to paliperidone or tolerate paliperidone better
than the parent drug risperidone

Hyperprolactinemia in women with low estrogen may accelerate
osteoporosis
Less weight gain than some antipsychotics, more than others
May cause more motor side ef fects than some other atypical
antipsychotics, especially when administered to patients with
Parkinson ’s disease or Lewy body dementia
Trilayer tablet consists of 3 compartments (2 containing drug, 1 a
“push ” compartment) and an orifice at the head of the first drug
compartment; water fills the push compartment and gradually
LAI does not require simultaneous oral medication
LAI may work better and better after a few weeks of treatment in
LAI may be very well tolerated
LAI may be combined with a second antipsychotic administered
orally for dif ficult cases
A 6-month long-acting injectable formulation is in development

dosage increase even beyond the usual prescribing limits if
tolerated; minimum therapeutic level is 28 ng/mL with point of
futility of 1 12 ng/mL if ef fective and tolerated

Paliperidone Palmitate
1-month
(Sustenna)3-month (T rinza)
Tmax 13 days 30–33 daysFor treatment-resistant patients, especially those with impulsivity ,
of either

of either

1-month
dosing25–49 days 84–95 days (deltoid)
118–139 days (gluteal)
Time to reach
steady state1 week
Able to be loaded Yes N/A
(maintenance)4 weeks 12 weeks
(deltoid at
initiation, then
either deltoid or
gluteal)Intramuscular (deltoid or
gluteal)
Needle gauge 22 or 23 22
Dosage forms 39 mg, 78 mg, 1 17
mg, 156 mg, 234
mg273 mg, 410 mg, 546 mg,
819 mg
Injection volume 156 mg/mL; range
0.25–1.5 mL0.875 –2.625 mL
1-month injectable maintenance dose: 1 17 mg/month (range 39 –234
mg/month)

How to Dose –1-month Injectable
Oral Equivalence (Appr oximate)
Oral paliperidone 1-month Sustenna
3 mg 39–78 mg
6 mg 117 mg
9 mg 156 mg
12 mg 234 mg
How to Dose –3-month Injectable3-month injectable maintenance dose: 273 –819 mg/3 months
tolerability to oral paliperidone or risperidone (in clinical trials, 2
oral or short-acting IM doses are generally used to establish
tolerability)
Conversion from oral: 234 mg delivered intramuscularly in the
deltoid on day 1; 156 mg delivered intramuscularly in the deltoid on
day 8; maintenance dose should start 4 weeks after the 2nd loading
injection
Only for patients who have received adequate treatment with
paliperidone Sustenna for at least 4 months

1-month Sustenna 3-month T rinza
78 mg 273 mg
117 mg 410 mg
156 mg 546 mg
234 mg 819 mg
Last T rinza
DoseDay 1 Day 8 1 Month After
Day 8The last 2 doses of paliperidone Sustenna should ideally be the same
dosage strength, so that a consistent maintenance dose is established
prior to starting paliperidone T rinza
Conversion from 1-month injectable: initiate 3-month LAI when the
next 1-month LAI injection is scheduled; dosing is based on the
previous 1-month injection dose
Dose adjustments can be made every 3 months if needed; the long-
acting nature of paliperidone T rinza means that a patient ’s response
to an adjusted dose may not be apparent for multiple months
Injection can be given up to 2 weeks before or after the 3-month
time point
If dose has been missed for 4 –9 months, the following reinitiation
schedule must be followed:

Day 8
273 mg78 mg Sustenna
(deltoid)78 mg Sustenna
(deltoid)273 mg T rinza
(deltoid or
gluteal)
410 mg117 mg
Sustenna
(deltoid)117 mg
Sustenna
(deltoid)410 mg T rinza
gluteal)
546 mg156 mg
Sustenna
(deltoid)156 mg
Sustenna
(deltoid)546 mg T rinza
gluteal)
819 mg156 mg
Sustenna
Sustenna
(deltoid)819 mg T rinza
gluteal)
Dosing T ipsIf dose has been missed for more than 9 months, reinitiate treatment
with paliperidone Sustenna according to its prescribing information;
paliperidone T rinza can be used after the patient has been
adequately treated with paliperidone Sustenna for at least 4 months

Kinetics for paliperidone palmitate are determined by particle size:
smaller particles (1-month) vs. lar ger particles (3-month)
Advantages: no need for oral coverage; 3-month injection schedule
with T rinza
Disadvantages: plasma levels have limited value in guiding
treatment

 Switching fr om Oral Antipsychotics to Paliperidone Palmitate
(1-Month)
brexpiprazole, cariprazine, lumateperone, or paliperidone ER

  Switching fr om Oral Antipsychotics to
Paliperidone ER
during cross-titration to help alleviate side ef fects such as insomnia,For patients taking benzodiazepine or anticholiner gic
Due to OROS technology , paliperidone ER can be initiated at full
desired dose; however , titration over 1 –2 weeks may be appropriate
for some patients
With amisulpride, aripiprazole, brexpiprazole, cariprazine, and
lumateperone, immediate stop is possible; begin paliperidone ER at
an intermediate, or if needed, ef fective dose
Risperidone, ziprasidone, iloperidone, and lurasidone can be tapered
off over a period of 1 week due to the risk of withdrawal symptoms
such as insomnia

Harrington  CA , English  C . Tolerability of paliperidone: a meta-analysis of
randomized, controlled trials  . Int Clin Psychopharmacol  2010  ;25 (6
):334–41 .
Nussbaum  A , Stroup  TS . Paliperidone for schizophrenia  . Cochrane
Database Syst Rev  2008  ;16 (2 ):CD006369  .

Nussbaum  AM , Stroup  TS . Paliperidone palmitate for schizophrenia  .
Cochrane Database Syst Rev  . 2012  ;(6):CD008296  .
Patel  C , Emond  B , Lafeuille  MH , et al. Real-world analysis of switching
patients with schizophrenia from oral risperidone or oral paliperidone to
once-monthly paliperidone palmitate  . Drugs Real W orld Outcomes  2020  ;7
(1 ):19 –29 . doi: 10.1007/s40801-019-00172-9  .

Paroxetine
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Paxil
Paxil CR
RI)
Major depr essive disorder (par oxetine and par oxetine CR)
Panic disorder (par oxetine and par oxetine CR)

after initiation of treatmentSocial anxiety disorder (social phobia) (par oxetine and
paroxetine CR)
Posttraumatic str ess disorder (PTSD)
Premenstrual dysphoric disorder (PMDD) (par oxetine CR)
Vasomotor symptoms (Brisdelle)
Paroxetine also has mild anticholiner gic actions
Paroxetine may have mild norepinephrine reuptake blocking actions

If It W orks
If It Doesn ’t WorkIf it is not working within 6 –8 weeks for depression, it may require
By contrast, for generalized anxiety , onset of response and increases
in remission rates may still occur after 8 weeks of treatment and for
up to 6 months after initiating dosing
symptoms

Resistanceproblems concentrating in depression)
caution and at lower doses since paroxetine could theoretically raise

Tests
How Drug Causes Side EffectsMood stabilizers or atypical antipsychotics for bipolar depression,
tiagabine

✽ Paroxetine ’s weak antimuscarinic properties can cause constipation,
dry mouth, sedation
 Life-Thr eatening or Danger ous Side EffectsMost side ef fects are immediate but often go away with time, in
dry mouth)
Mostly CNS (insomnia but also sedation, agitation, dose-dependent
activating actions of SSRIs
Autonomic (dose-dependent sweating)

Sedation
Wait
Wait
Wait
If paroxetine is sedating, take at night to reduce daytime drowsiness
Reduce dose to 5 –10 mg (12.5 mg for CR) until side ef fects abate,
then increase as tolerated, usually to at least 20 mg (25 mg CR)

Usual Dosage RangeOften best to try another SSRI or another antidepressant

discontinuation of paroxetine

How to DoseDepression: 20 –50 mg (25 –62.5 mg CR)
Vasomotor symptoms: 7.5 mg at bedtime
Anxiety disorders and OCD: 10 –60 mg/day (12.5 –75 mg CR)
Tablet 10 mg scored, 20 mg scored, 30 mg, 40 mg
Controlled-release tablet 12.5 mg, 25 mg, 37.5 mg
Capsule 7.5 mg
Liquid 10 mg/5mL –250 mL bottle
Depression: initial 20 mg (25 mg CR); usually wait a few weeks to
assess drug ef fects before increasing dose, but can increase by 10
mg/day (12.5 mg/day CR) once a week; maximum generally 50
mg/day (62.5 mg/day CR); single dose
Panic disorder: initial 10 mg/day (12.5 mg/day CR); usually wait a
few weeks to assess drug ef fects before increasing dose, but can
increase by 10 mg/day (12.5 mg/day CR) once a week; maximum
generally 60 mg/day (75 mg/day CR); single dose
Social anxiety disorder: initial 20 mg/day (25 mg/day CR); usually
wait a few weeks to assess drug ef fects before increasing dose, but
can increase by 10 mg/day (12.5 mg/day CR) once a week;

maximum 60 mg/day (75 mg/day CR); single dose

Dosing T ipsOther anxiety disorders: initial 20 mg/day (25 mg/day CR); usually
Premenstrual dysphoric disorder: initial dose 12.5 mg/day CR;
should be administered as a single dose in the morning, with or
without food; can be administered either daily or only during the
luteal phase of the menstrual cycle
20 mg tablet is scored, so to save costs, give 10 mg as half of 20 mg
tablet, since 10 mg and 20 mg tablets cost about the same in many
markets
Given once daily , often at bedtime, but any time of day tolerated
20 mg/day (25 mg/day CR) is often suf ficient for patients with
social anxiety disorder and depression
Other anxiety disorders, as well as dif ficult cases in general, may
Occasional patients are dosed above 60 mg/day (75 mg/day CR), but
this is for experts and requires caution

✽ Main advantage of CR is reduced side ef fects, especially nausea
and perhaps sedation, sexual dysfunction, and withdrawal
✽ For patients with severe problems discontinuing paroxetine, dosing
may need to be tapered over many months (i.e., reduce dose by 1%
every 3 days by crushing tablet and suspending or dissolving in 100
mL of fruit juice and then disposing of 1 mL and drinking the rest; 3 –7
days later , dispose of 2 mL, and so on). This is both a form of very
slow biological tapering and a form of behavioral desensitization (not
for CR)Liquid formulation easiest for doses below 10 mg when used for
cases that are very intolerant to paroxetine or especially for very
slow down-titration during discontinuation for patients with
withdrawal symptoms
Paroxetine CR tablets not scored, so chewing or cutting in half can
destroy controlled-release properties
Unlike other SSRIs and antidepressants where dosage increments
can be double and triple the starting dose, paroxetine ’s dosing

increments are in 50% increments (i.e., 20, 30, 40; or 25, 37.5, 50
CR)
Paroxetine inhibits its own metabolism and thus plasma
concentrations can double when oral doses increase by 50%; plasma
concentrations can increase 2 –7-fold when oral doses are doubled
For some patients with severe problems discontinuing paroxetine, it
may be useful to add an SSRI with a long half-life, especially

Overdose
How to Stop
✽ Withdrawal ef fects can be more common or more severe with
paroxetine than with some other SSRIsfluoxetine, prior to taper of paroxetine; while maintaining fluoxetine
dosing, first slowly taper paroxetine and then taper fluoxetine
Rarely lethal in monotherapy overdose; vomiting, sedation, heart
rhythm disturbances, dilated pupils, dry mouth
Safe
No

 Drug InteractionsParoxetine ’s withdrawal ef fects may be related in part to the fact
that it inhibits its own metabolism
Thus, when paroxetine is withdrawn, the rate of its decline can be
faster as it stops inhibiting its metabolism
Controlled-release paroxetine may slow the rate of decline and thus
reduce withdrawal reactions in some patients
Readaptation of choliner gic receptors after prolonged blockade may
contribute to withdrawal ef fects of paroxetine
switching from a TCA to paroxetine

drugs) after discontinuing paroxetine
There are reports of elevated theophylline levels associated with
paroxetine treatment, so it is recommended that theophylline levels
be monitored when these drugs are administered together
May increase anticholiner gic ef fects of procyclidine and other drugs
with anticholiner gic properties
Via CYP450 2D6 inhibition, paroxetine could theoretically interfere

Via CYP450 2D6 inhibition, paroxetine could theoretically increase
Paroxetine increases pimozide levels, and pimozide prolongs QT
interval, so concomitant use of pimozide and paroxetine is

after discontinuing paroxetine
companies

ElderlyIf there is a proven aller gy to paroxetine
Lower dose [initial 10 mg/day (12.5 mg CR), maximum 40 mg/day
(50 mg/day CR)]
Preliminary research suggests that paroxetine is safe in these
patients

patients
Not specifically approved, but preliminary evidence suggests
possible ef ficacy in children and adolescents with OCD or social
phobia

phobia

Epidemiological data have shown an increased risk of
cardiovascular malformations (primarily ventricular and atrial septal
defects) in infants born to women who took paroxetine during the
first trimester (absolute risk is small)
Unless the benefits of paroxetine to the mother justify continuing
treatment, consider discontinuing paroxetine or switching to another
Paroxetine use late in pregnancy may be associated with higher risk
of neonatal complications, including respiratory distress

pregnancy

Breast FeedingNeonates exposed to SSRIs or SNRIs late in the third trimester have
essants
are on paroxetine

the mother

Patients with anxiety disorders and insomnia
Patients with mixed anxiety/depression
Alzheimer/cognitive disorders
Patients with psychomotor retardation, fatigue, and low ener gy
Anxiety
Sleep disturbance, especially insomnia
Obsessions, compulsions
Panic attacks, avoidant behavior , re-experiencing, hyperarousal

depressive disorder comorbid with anxiety disorders
✽ Withdrawal ef fects may be more likely than for some other SSRIs
when discontinued (especially akathisia, restlessness, gastrointestinal
symptoms, dizziness, tingling, dysesthesias, nausea, stomach cramps,
restlessness)
✽ Paroxetine has mild anticholiner gic actions that can enhance the
rapid onset of anxiolytic and hypnotic ef ficacy but also cause mild
anticholiner gic side ef fectsInhibits own metabolism, so dosing is not linear
May be less activating than other SSRIs
Paroxetine is a potent CYP450 2D6 inhibitor
Some anecdotal reports suggest greater weight gain and sexual
dysfunction than some other SSRIs, but the clinical significance of
this is unknown

For sexual dysfunction, can augment with bupropion, sildenafil,
tadalafil, or switch to a non-SSRI such as bupropion or mirtazapine
paroxetine plus estrogen augmentation than to paroxetine alone

Bourin  M , Chue  P , Guillon  Y . Paroxetine: a review  . CNS Drug Rev  2001
;7 :25 –47 .
Gibiino  S , Serretti  A. Paroxetine for the treatment of depression: a critical
update  . Expert Opin Pharmacother  2012  ;13 (3 ):421–31 .
Green  B . Focus on paroxetine  . Curr Med Res Opin  2003  ;19 :13 –21 .
Wagstaf f AJ , Cheer  SM , Matheson  AJ , Ormrod  D , Goa KL . Paroxetine:
an update of its use in psychiatric disorders in adults  . Drugs  2002  ;62 :655
–703 .Nonresponse to paroxetine in elderly may require consideration of
CR formulation may enhance tolerability , especially for nausea
Can be better tolerated than some SSRIs for patients with anxiety
and insomnia and can reduce these symptoms early in dosing

Perospirone
Brands
Generic?
No
 Class
 How the Drug W orksLullan
Atypical antipsychotic (serotonin-dopamine antagonist, second-
generation antipsychotic)
Schizophrenia (Japan)
psychosis

✽ Interactions at 5HT1A receptors may contribute to ef ficacy for
cognitive and af fective symptoms in some patients
If It W orksBlocks serotonin 2A receptors, causing enhancement of dopamine
weeks to show a good response, especially on cognitive symptoms

If It Doesn ’t WorkSuch patients are considered super -responders or “awakeners ” since
treatment
clozapine
injection

Tests
✽ Potential of weight gain, diabetes, and dyslipidemia associated with
perospirone has not been systematically studied, but patients should be
monitored the same as for other atypical antipsychotics
Augmentation of perospirone has not been systematically studied
carbamazepine, or lamotrigine may theoretically be helpful in both
schizophrenia and bipolar mania

with diabetes or who have gained >5% of initial weightDetermine if the patient

respiration, weakness, and clouding of sensorium, even coma
How Drug Causes Side Effectspre-diabetic, diabetic, hypertensive, or dyslipidemic while receiving
perospirone should be discontinued at the first sign of decline of

✽ Insomnia
 Life-Thr eatening or Danger ous Side EffectsChronic blockade of dopamine 2 receptors in the striatum can cause
Receptor binding portfolio of perospirone is not well characterized
Sedation, anxiety , weakness, headache, anorexia, constipation
Elevated creatine phosphokinase levels

✽ Not well characterized
Sedation
Wait
Wait
Wait
present

How to DoseMetformin may help prevent or reverse antipsychotic-induced
8–48 mg/day in 3 divided doses
Tablet 4 mg, 8 mg

OverdoseBegin at 4 mg 3 times a day , increasing as tolerated up to 16 mg 3
times a day
Some patients have been treated with up to 96 mg/day in 3 divided
doses
Unknown whether dosing frequency can be reduced to once or twice
daily , but by analogy with other agents in this class with half-lives
shorter than 24 hours, this may be possible
Not reported

How to Stop
 Drug InteractionsShould periodically reevaluate long-term usefulness in individual
No
a few weeks after perospirone is discontinued
levels of perospirone

Do Not UseCarbamazepine and possibly other inducers of CYP450 3A4 may
decrease plasma levels of perospirone
perospirone should be used cautiously in patients at risk for

ElderlyIf there is a proven aller gy to perospirone
agitation

 Pregnancy
Unknown if perospirone is secreted in human breast milk, but all
Infants of women who choose to breast feed should be monitored

 Pearls
 Suggested ReadingIn Japan, studies suggest ef ficacy for negative symptoms of
Patients who have dif ficulty complying with three times daily
Affective symptoms (depression, anxiety)
Drug-induced parkinsonism may be more frequent than with some
other atypical antipsychotics
Potent 5HT1A binding properties may be helpful for improving
cognitive symptoms of schizophrenia in long-term treatment
Theoretically , should be ef fective in acute bipolar mania

Ohno  Y . Pharmacological characteristics of perospirone hydrochloride, a
novel antipsychotic agent  . Nippon Y akurigaku Zasshi  2000  ;116 (4 ):225–
31 .

Perphenazine
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Trilafon
(D-RAn)

psychosis
Psychotic symptoms can improve within 1 week, but may take
Injection: initial ef fect after 10 minutes, peak after 1 –2 hours

TestsReduces symptoms of acute psychotic mania but not proven as a
disorder
clozapine

>30)

perphenazine should be discontinued at the first sign of decline of

✽ Galactorrhea, amenorrheaAntihistaminic actions may cause sedation, weight gain
unknown

Sedation
Wait
Wait
Wait

Usual Dosage RangeFor drug-induced parkinsonism, add an anticholiner gic agent

How to Dose
 Dosing T ipsPsychosis: oral: 12 –24 mg/day; 16 –64 mg/day in hospitalized
patients
Nausea/vomiting: 8 –16 mg/day oral, 5 mg intramuscularly
Tablet 2 mg, 4 mg, 8 mg, 16 mg
Injection 5 mg/mL (discontinued in USA)
Oral: psychosis: 4 –8 mg 3 times a day; 8 –16 mg 2 times a day to 4
times a day in hospitalized patients; maximum 64 mg/day
Oral: nausea/vomiting: 8 –16 mg/day in divided doses; maximum 24
mg/day
Intramuscular: psychosis: initial 5 mg; can repeat every 6 hours;
maximum 15 mg/day (30 mg/day in hospitalized patients)
Injection contains sulfites that may cause aller gic reactions,
Oral perphenazine is less potent than the injection, so patients
should receive equal or higher dosage when switched from injection
to tablet

Overdose
How to Stop(one dose or more) augmentation with a benzodiazepine or another
No

 Other W arnings/Pr ecautionswhile switching (i.e., cross-titration)
a few weeks after perphenazine is discontinued
Half-life approximately 9.5 hours
guanethidine, whose antihypertensive actions perphenazine may
compounds
syndrome
increase risk of hypotension

Antiemetic ef fect of perphenazine may mask signs of other
asphyxia
dementia

Do Not Use
If there is the presence of blood dyscrasias, subcortical brain
damage, bone marrow depression, or liver disease
If there is a proven aller gy to perphenazine
Use with caution; may not be recommended as long-term treatment
because perphenazine may increase risk of further liver damage

 PregnancyAlthough conventional antipsychotics are commonly used for
Over age 12: if given intramuscularly , should receive lowest adult
dose

Potential Advantagesthe third trimester; symptoms may include agitation, abnormally
pregnancy
Perphenazine should only be used during pregnancy if clearly
needed
Unknown if perphenazine is secreted in human breast milk, but all

Children
Elderly
Some studies suggest comparable ef fectiveness with atypical
Perphenazine is a higher potency phenothiazine
another

efficacy and tolerability of 32 oral antipsychotics for the acute treatment ofantipsychotic such as perphenazine or from switching to a
conventional antipsychotic such as perphenazine
conventional antipsychotic such as perphenazine with an atypical

Availability of alternative treatments and risk of tardive dyskinesia
make utilization of perphenazine for nausea and vomiting a short-
term and second-line treatment option

Lieberman  JA , Stroup  TS , McEvoy  JP , et al. Effectiveness of
antipsychotic drugs in patients with chronic schizophrenia  . N Engl J Med
2005  ;353 (12 ):1209  –23.
Quraishi  S , David  A . Depot perphenazine decanoate and enanthate for
schizophrenia  . Cochrane Database Syst Rev  2000  ;(2):CD001717  .

Phenelzine
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Nardil
Nardelzine
Neuroscience-based Nomenclature: serotonin, norepinephrine,
dopamine enzyme inhibitor (SN-EI)
Depr essed patients characterized as “atypical, ” “nonendogenous, ”
or “neur otic”

If It W orksIrreversibly blocks monoamine oxidase (MAO) from breaking down
norepinephrine, serotonin, and dopamine
This boosts noradrener gic, serotoner gic, and dopaminer gic
Onset of therapeutic actions usually not immediate, but often delayed
2–4 weeks following adequate dosing
If it is not working within 6 –8 weeks, it may require a dosage increase
or it may not work at all
Treatment most often reduces or even eliminates symptoms, but not a
cure since symptoms can recur after medicine stopped

✽ Augmentation of MAOIs has not been systematically studied, and this
is something for the expert, to be done with caution and with careful
✽ A stimulant such as d-amphetamine or methylphenidate (with caution;
may activate bipolar disorder and suicidal ideation; may elevate blood
pressure)Many patients have only a partial response where some symptoms are
improved but others persist (especially insomnia, fatigue, and
Consider evaluation for another diagnosis or for a comorbid condition
(e.g., medical illness, substance abuse, etc.)

Some patients may experience apparent lack of consistent ef ficacy due
to activation of latent or underlying bipolar disorder , and require

Tests
✽ Since some MAOIs are frequently associated with weight gain, before
weight, consider evaluating for the presence of pre-diabetes, diabetes, orLithium
Atypical antipsychotics (with special caution for those agents with
monoamine reuptake blocking properties, such as lumateperone,
ziprasidone, and zotepine)
Patients should be monitored for changes in blood pressure; check
before and 45–60 minutes after dosing until stable
For patients receiving high doses or long-term treatment, consider
periodically evaluating hepatic function

(fasting plasma glucose >126 mg/dL), or dyslipidemia (increased total

dyslipidemia, or consider switching to a dif ferent antidepressant
 Life-Thr eatening or Danger ous Side EffectsTheoretically due to increases in monoamines in parts of the brain and
body and at receptors other than those that cause therapeutic actions
(e.g., unwanted actions of serotonin in sleep centers causing insomnia,
unwanted actions of norepinephrine on vascular smooth muscle
causing hypotension, etc.)
Side ef fects are generally immediate, but immediate side ef fects often
disappear in time
Constipation, dry mouth, nausea, change in appetite, weight gain
Sexual dysfunction (may be highest of any MAOI)
Orthostatic hypotension (dose-related); syncope may develop at high
doses
Hypertensive crisis (especially when MAOIs are used with certain
tyramine-containing foods or prohibited drugs)

Sedation
Best Augmenting Agents for Side EffectsInduction of mania in patients with bipolar disorder
Problematic; may be most of any MAOI
Wait
Wait
Wait

How to Dose
OverdoseBenzodiazepines for insomnia
45–75 mg/day
Initial 45 mg/day in 3 divided doses; increase to 60 –90 mg/day; after
desired therapeutic ef fect is achieved lower dose as far as possible
Once dosing is stabilized, some patients may tolerate once or twice
daily dosing rather than 3 times a day dosing
Orthostatic hypotension, especially at higher doses, may require
splitting into 4 daily doses, or tincture of time (waiting)
Patients receiving high doses may need to be evaluated periodically
for ef fects on the liver
Little evidence to support ef ficacy of phenelzine below doses of 45
mg/day

How to Stop
 Drug InteractionsDeath may occur; dizziness, ataxia, sedation, headache, insomnia,
restlessness, anxiety , irritability , cardiovascular ef fects, confusion,
respiratory depression, coma
Generally no need to taper , as the drug wears of f slowly over 2 –3
weeks
Clinical duration of action may be up to 14 days due to irreversible
enzyme inhibition
Tramadol (serotonin reuptake inhibitor) may increase the risk of
seizures in patients taking an MAOI
Can cause a fatal “serotonin syndrome ” when combined with drugs
that block serotonin reuptake, so do not use with a serotonin reuptake

Do Not Use:
Clomipramine Methamphetamine Methadone Brompheniramineinhibitor or for 5 half-lives after stopping the serotonin reuptake
inhibitor (see Table 1  after Pearls)
Hypertensive crisis with headache, intracranial bleeding, and death
may result from combining MAOIs with sympathomimetic drugs (e.g.,
amphetamines, methylphenidate, cocaine, dopamine, epinephrine,
Adverse drug reactions can result from combining MAOI with
tricyclic/tetracyclic antidepressants and related compounds, including
carbamazepine, cyclobenzaprine, and mirtazapine, and should be
avoided except by experts
MAOIs in combination with spinal anesthesia may cause combined
hypotensive ef fects

Combination of MAOIs and CNS depressants may enhance sedation

Do Not Use:
Imipramine High-dose or
injected
amphetamineDextromethorphan
St. John ’s wort Lumateperone
Use requires strict adherence to low-tyramine diet (see Table 2  after
Pearls)
Patient and prescriber must be vigilant to potential interactions with
any drug, including antihypertensives and over -the-counter cough/cold
preparations
Over -the-counter medications to avoid include cough and cold
preparations, including those containing dextromethorphan (serotonin
reuptake inhibitor), nasal decongestants (tablets, drops, or spray), hay-
fever medications, sinus medications, asthma inhalant medications,
anti-appetite medications, weight reducing preparations, “pep” pills
(see Table 3  after Pearls)
Hypoglycemia may occur in diabetic patients receiving insulin or oral
antidiabetic agents (hydrazine ef fect)
Binds and inactivates vitamin B6 (hydrazine ef fect); reversible with

high-dose B6 administration

Dried, aged, smoked, fermented,
spoiled, or improperly stored meat,
poultry , and fishFresh or processed meat, poultry ,
and fish; properly stored pickled or
smoked fish
Aged cheeses Processed cheese slices, cottage
cheese, ricotta cheese, yogurt, cream
cheese
Tyramine-containing nutritional
supplement
* Consult up-to-date listing of tyramine content, as most foods now have
low tyramine amountsUse cautiously in patients receiving reserpine, anesthetics, disulfiram,
metrizamide, anticholiner gic agents
Phenelzine is not recommended for use in patients who cannot be
monitored closely

Table 3.  Drugs that boost norepinephrine: should only be used with caution
with MAOIs
with
reuptake
Phenylephrine Amphetamines Most tricyclics Phentermine
Pseudoephedrine Methylphenidate
Cocaine
Methamphetamine
Modafinil
ArmodafinilNRIs NDRIs Local
containing
vasoconstrictors
Tapentadol
Do Not Use
If patient is taking meperidine (pethidine) (serotonin reuptake
inhibitor)
If patient is taking any agent that can inhibit serotonin reuptake (e.g.,
SSRIs, tramadol, milnacipran, duloxetine, venlafaxine, clomipramine,
imipramine, etc.)

ElderlyIf patient is taking dextromethorphan (serotonin reuptake inhibitor)
If patient is taking diuretics or other antihypertensives without careful
monitoring of blood pressure
If patient has cardiovascular or cerebrovascular disease, unless cleared
by the patient ’s medical doctor
If there is a proven aller gy to phenelzine
Phenelzine should be used cautiously
Contraindicated in patients with congestive heart failure or
hypertension, unless cleared by the patient ’s medical doctor

 PregnancyInitial dose 7.5 mg/day; increase every few days by 7.5 –15 mg/day
Elderly patients may have greater sensitivity to adverse ef fects, but
many tolerate MAOIs
Not recommended for use under age 16
against the risks and benefits of nontreatment with antidepressants and
patients
Effective June 30, 2015, the US FDA requires changes to the content
and format of pregnancy and lactation information in prescription drug

patients
labels, including the elimination of the pregnancy letter categories; the
Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies
only to prescription drugs and will be phased in gradually for drugs
approved on or after June 30, 2001

The Art of PsychopharmacologyControlled studies have not been conducted in pregnant women
Possible increased incidence of fetal malformations if phenelzine is
taken during the first trimester
Should evaluate patient for treatment with an antidepressant with a
better risk/benefit ratio
https://womensmentalhealth.or g/research/pregnancyregistry/antidepres
sants
If child becomes irritable or sedated, breast feeding or drug may need
to be discontinued
especially in women who have had prior depressive episodes, so drug
may need to be reinstituted late in the third trimester or shortly after
childbirth to prevent a recurrence during the postpartum period

 PearlsAtypical depression
Requires compliance to dietary restrictions, concomitant drug
restrictions
Patients with cardiac problems or hypertension, unless cleared by the
patient ’s medical doctor
Multiple daily doses, although many patients can be dosed more than
once a day
Anxiety
Excellent anxiolytic ef fects often observed

✽ Myths about the danger of dietary tyramine can be exaggerated, but
prohibitions against concomitant drugs often not followed closely
enough
✽ MAOIs should be for the expert, especially if combining with agents
of potential risk (e.g., stimulants, trazodone, TCAs)
✽ MAOIs should not be neglected as therapeutic agents for the
treatment-resistantGenerally more weight gain and sexual dysfunction than with
tranylcypromine
MAOIs are generally reserved for third- or fourth-line use after SSRIs,
SNRIs, and combinations of newer antidepressants have failed
Patient should be advised not to take any prescription or over -the-
counter drugs without consulting their doctor because of possible drug
interactions with the MAOI
The rigid dietary restrictions may reduce compliance (see Table 2  after
Pearls)
Mood disorders can be associated with eating disorders (especially in
adolescent females), and phenelzine can be used to treat both

Pearls)
depression and bulimia
Orthostatic hypotension, insomnia, and sexual dysfunction are often
the most troublesome common side ef fects
For treatment-resistant patients, experts can give a tricyclic/tetracyclic
antidepressant other than clomipramine or imipramine simultaneously

Gillman  K . PsychoT ropical Research (PTR). https://psychotropical.com  .
Gillman  PK . A reassessment of the safety profile of monoamine oxidase
inhibitors: elucidating tired old tyramine myths  . J Neural T ransm (V ienna)
2018  ;125 (11 ):1707 –17 .with an MAOI for patients who fail to respond to numerous other
Use of MAOIs with clomipramine is always prohibited because of the
risk of serotonin syndrome and death due to serotonin reuptake
Amoxapine may be the preferred trycyclic/tetracyclic antidepressant to
combine with an MAOI in heroic cases due to its theoretically
Although very strict dietary and concomitant drug restrictions must be

observed to prevent hypertensive crises and serotonin syndrome, the
most common side ef fects of MAOI and tricyclic/tetracyclic

Kennedy  SH . Continuation and maintenance treatments in major depression:
the neglected role of monoamine oxidase inhibitors  . J Psychiatry Neur osci
1997  ;22 :127–31 .

Phentermine/topiramate
Brands
Generic?
No
 Class
 How the Drug W orksQsymia
Norepinephrine and dopamine reuptake inhibitor (phentermine)
combined with a voltage-sensitive sodium channel modulator
(topiramate); weight management medication
at least 30 kg/m  2 (obese) or at least 27 kg/m  2 (overweight) in the

If It W orks
If It Doesn ’t WorkPhentermine increases dopamine and norepinephrine by blocking
both the dopamine and the norepinephrine transporters. In the
causing the release of POMC. POMC is then broken down into Î± -
melanocyte-stimulating hormone, which binds to melanocortin 4
receptors to suppress appetite. However , stimulation of POMC
neurons also activates an endogenous opioid-mediated negative
feedback loop, which mitigates the appetite-suppressing ef fects
Theoretically , through modulation of voltage-sensitive sodium
channels topiramate may reduce glutamater gic stimulation and
increase GABAer gic inhibition in the appetite-stimulating pathway ,
resulting in net inhibition of this pathway . Such an action would
syner gize with simultaneous activation of the appetite-suppressing
pathway by phentermine. This results in more robust and long-

lasting appetite suppression than with either drug alone
At least 3% weight loss is generally achieved after 14 weeks; at
least 5% weight loss is generally achieved after an additional 12
weeks on maximum daily dose

Tests
Side EffectsDiscontinue if 5% weight loss is not achieved after 12 weeks on
Phentermine/topiramate itself should be administered in conjunction
Women of childbearing potential should have a negative pregnancy
test before starting phentermine/topiramate and monthly during
treatment
Regular measurement of resting heart rate, especially for patients
with cardiac or cerebrovascular disease or when initiating or
increasing the dose of phentermine/topiramate
Obtain a blood chemistry profile that includes bicarbonate,
creatinine, potassium, and glucose at baseline and periodically
Measurement of blood pressure prior to starting
phentermine/topiramate and during phentermine/topiramate
treatment is recommended in patients being treated for hypertension

 Life-Thr eatening or Danger ous Side EffectsCNS side ef fects theoretically due to excessive actions at voltage-
sensitive sodium channels or excessive actions on norepinephrine
Weak inhibition of carbonic anhydrase may lead to kidney stones
and paresthesias
Inhibition of carbonic anhydrase may also lead to metabolic acidosis
Constipation, dry mouth
Paresthesia, dizziness, dysgeusia, insomnia
Cognitive impairment (may be more likely with rapid titration or
high initial doses)
Hypoglycemia
Increased heart rate
Metabolic acidosis
Kidney stones
Secondary angle-closure glaucoma
Oligohidrosis and hyperthermia (more common in children)
related to topiramate use)

Sedation
Usual Dosage RangeRare activation of suicidal ideation and behavior (suicidality)
Wait
Avoid dosing in evening due to the possibility of insomnia
Often best to try another treatment prior to resorting to
7.5 mg/46 mg per day up to 15 mg/92 mg per day

How to Dose
OverdoseCapsule (phentermine mg/topiramate mg extended-release) 3.75
mg/23 mg, 7.5 mg/46 mg, 1 1.25 mg/69 mg, 15 mg/92 mg
Initial 3.75 mg/23 mg per day; after 14 days increase to 7.5 mg/46
mg per day
If at least 3% weight loss is not achieved after 12 weeks on 7.5
mg/46 mg per day , can increase to 1 1.25 mg/69 mg per day; after 14
days increase to 15 mg/92 mg per day
on 15 mg/92 mg per day
Side ef fects tend to abate with time but may recur again briefly with
dose increases
Phentermine: restlessness, tremor , hyperreflexia, rapid respiration,
confusion, aggression, hallucinations, panic
Topiramate: severe metabolic acidosis, convulsions, sedation,
speech disturbance, blurred or double vision, impaired coordination,
hypotension, abdominal pain, agitation, dizziness

How to Stop
 Drug InteractionsHas been evaluated in controlled studies up to 1 year
Phentermine is a Schedule IV drug
Topiramate is not controlled in the Controlled Substances Act
For patients taking 15 mg/92 mg per day , take a dose every other
day for at least 1 week prior to discontinuing treatment, due to the
possibility of precipitating a seizure
Phentermine mean terminal half-life approximately 20 hours
Topiramate mean terminal half-life approximately 65 hours
Neither phentermine nor topiramate is extensively metabolized
May cause irregular bleeding in patients taking oral contraceptives,
but does not increase risk of pregnancy; patients should be advised
not to discontinue oral contraceptives if spotting occurs
May increase ef fects of CNS depressants

May potentiate hypokalemia in patients taking non-potassium-
sparing diuretic agents
Weight loss associated with phentermine/topiramate may increase
the risk of hypotension in patients taking antihypertensive
Carbamazepine, phenytoin, and valproate may increase the
clearance of topiramate, and thus decrease topiramate levels,
possibly requiring a higher dose of topiramate
Topiramate may increase the clearance of phenytoin and thus
decrease phenytoin levels, possibly requiring a higher dose of
phenytoin
Topiramate may increase the clearance of valproate and thus
decrease valproate levels, possibly requiring a higher dose of
valproate
Topiramate may increase plasma levels of metformin; also,
metformin may reduce clearance of topiramate and increase
topiramate levels
Topiramate may interact with carbonic anhydrase inhibitors to
increase the risk of kidney stones
Reports of hyperammonemia with or without encephalopthay in

patients taking topiramate combined with valproate, though this is
not due to a pharmacokinetic interaction; in patients who develop
unexplained lethar gy, vomiting, or change in mental status, an
ammonia level should be measured

Do Not UsePhentermine is contraindicated with MAOIs due to risk of
hypertensive crisis
Phentermine/topiramate can cause fetal toxicity; women of
childbearing potential should obtain a negative pregnancy test
before treatment and monthly thereafter and use ef fective
contraception
If a patient develops a sustained increase in resting heart rate while
taking phentermine/topiramate, the dose should be reduced or the
medication should be discontinued
May cause an increase in serum creatinine; if persistent elevations in
creatinine occur during phentermine/topiramate treatment, the dose
should be reduced or the medication should be discontinued
Phentermine/topiramate has not been studied in combination with
insulin; weight loss may increase the risk of hypoglycemia in
patients with type 2 diabetes mellitus treated with insulin and/or
insulin secretagogues, and medication adjustments may be
necessary

necessary

Cardiac ImpairmentIf patient has glaucoma
If there is a proven aller gy to phentermine or topiramate
Maximum dose is 7.5 mg/46 mg per day in patients with moderate
to severe impairment
disease
Not recommended for patients with recent or unstable cardiac or
cerebrovascular disease

Elderly
 Pregnancy
Potential AdvantagesSome patients may tolerate lower doses better
There is an increased risk of cleft lip/palate with topiramate

 Pearls
 Suggested ReadingPatients who have had past weight loss on either active compound
tolerability on the combination of phentermine with topiramate than
Patients with a history of kidney stones or risks for metabolic
acidosis
Patients with a history of past stimulant abuse
Has perhaps the lar gest ef fect size on weight loss of drugs available
for the treatment of obesity
Because of the teratogenic risk with phentermine/topiramate, it is
available only through a Risk Management and Mitigation Strategy
(REMS) program; only certified pharmacies may distribute it

Colman  E , Golden  J , Roberts  M , et al. The FDA ’s assessment of two
drugs for chronic weight management  . N Engl J Med  2012  ;367 (17
):1577 –9 .
Cosentino  G , Conrad  AO , Uwaifo  GI . Phentermine and topiramate for the
management of obesity: a review  . Drug Des Devel Ther  2011 ;7 :267–87 .
Holes-Lewis  KA , Malcolm  R , O’Neil PM . Pharmacotherapy of obesity:
clinical treatments and considerations  . Am J Med Sci  2013  ;345 (4 ):284–8
.
Shin JH , Gadde  KM . Clinical utility of phentermine/topiramate
(QsymiaTM) combination for the treatment of obesity  . Diabetes Metab
Syndr Obes  2013  ;6 :1319  .

Pimavanserin
Brands
Generic?
No
 Class
✽ Antagonism/inverse agonism at 5HT2A receptorsNuplazid
Atypical antipsychotic; serotonin 2A/2C antagonist/inverse agonist
Hallucinations and delusions associated with Parkinson ’s
disease psychosis
Dementia-related psychosis

If It W orks
ResistancePimavanserin is also an antagonist/inverse agonist at 5HT2C
receptors (activity is very low compared to that at 5HT2A receptors)
In a clinical trial, psychotic symptom improvement reached
significance within 1 month
Most often reduces hallucinations and delusions without worsening
Try reducing the dose of antiparkinsonian dopaminer gic therapies
Try low-dose quetiapine
Try low-dose clozapine
Do not try any other atypical or conventional antipsychotic
None known
Theoretically , might be possible to combine with low-dose
quetiapine, especially during prolonged cross-titration when
switching from one to the other

Tests
 SedationNone
Mechanism of peripheral edema, confusional state, and nausea
unknown
Confusional state
Nausea
patients with dementia-related psychosis has occurred with

Wait
Wait
Wait
Discontinue if side ef fects are intolerable
34 mg once daily
Capsule 34 mg
34 mg/day taken once daily; no titration required

Overdose
How to Stop
PharmacokineticsCan be taken with or without food
No dose adjustment of carbidopa/levodopa is required
Not studied, but long-term maintenance treatment is often necessary
for Parkinson ’s disease psychosis
No
The long half-life suggests that it may be possible to stop
pimavanserin abruptly
and worsening of symptoms, but less likely with pimavanserin due
Mean half-life 57 hours (pimavanserin) and 200 hours (active
metabolite N-desmethylated metabolite)

Do Not Use
Renal ImpairmentMetabolized primarily by CYP450 3A4 and CYP450 3A5
In the presence of strong/moderate CYP450 3A4 inhibitors (e.g.,
ketaconazole), recommended dose of pimavanserin is 10 mg once
daily
inducers (e.g., carbamazepine)
Pimavanserin can cause prolongation of the QT c interval
If there is a proven aller gy to pimavanserin
Use with caution in patients with severe impairment or end-stage
renal disease

Elderly
However , pimavanserin is not contraindicated for patient s with
dementia RELA TED to Parkinson ’s disease who have hallucinations and
delusions of Parkinson ’s disease psychosis
Pimavanserin can cause QT c prolongation and should be avoided in
patients with known QT prolongation or in combination with drugs
that are known to prolong QT interval
Pimavanserin should be avoided in patients with a history of cardiac
arrhythmias, symptomatic bradycardia, hypokalemia, or
hypomagnesemia, or presence of congenital prolongation of the QT
interval
Pimavanserin is not approved for the treatment of dementia-related
psychosis UNRELA TED to the hallucinations and delusions
associated with Parkinson ’s disease psychosis, such as the
behavioral symptoms of comorbid Alzheimer dementia

Pregnancy
✽ Recommended to either discontinue drug or bottle feed unless the
potential benefit to the mother justifies the potential risk to the childEffective June 30, 2015, the US FDA requires changes to the
In rat and rabbit studies, pimavanserin did not demonstrate
teratogenicity at doses up to 10 or 12 times the maximum
recommended human dose
In rat studies, doses 2 times the maximum recommended daily dose
in humans based on area under the curve (AUC) resulted in maternal
toxicity , including mortality and reduced body weight and food

consumption, with corresponding decreases in pup survival, reduced
litter size, and reduced pup body weight
Unknown if pimavanserin is secreted in human breast milk, but all
Infants of women who choose to breast feed while on pimavanserin

 PearlsDoes not worsen motor symptoms of Parkinson ’s disease
Not associated with the metabolic side ef fects of quetiapine and
clozapine, including weight gain, dyslipidemia, and diabetes
mellitus
Not associated with the sedation sometimes caused by quetiapine
and clozapine
Does not require dose reduction of antiparkinsonian dopaminer gic
therapy given concomitantly
Expensive
Hallucinations and delusions associated with Parkinson ’s disease
Hallucinations and delusions associated with all causes of dementia
Improvement in negative symptoms of schizophrenia when
augmenting atypical antipsychotics has been reported; now in phase
3 trials for negative symptoms of schizophrenia

Cummings  J , Isaacson  S , Mills  R , et al. Pimavanserin for patients with
Parkinson ’s disease psychosis: a randomized, placebo-controlled phase 3
trial . Lancet  2014  ;383 (9916  ):533–40 .
Hacksell  U , Burstein  ES , McFarland  K , Mills  RG , Williams  H. On the
discovery and development of pimavanserin: a novel drug candidate for
Parkinson ’s psychosis  . Neur ochem Res  2014  Oct;39 (10 ):2008 –17 .
Hermanowicz  S , Hermanowicz  N. The safety , tolerability and ef ficacy of
pimavanserin tartrate in the treatment of psychosis in Parkinson ’s disease  .
Expert Rev Neur other  2016  ;16 (6 ):625–33 .
Howland  RJ . Pimavanserin: an inverse agonist antipsychotic drug  . J
Psychosoc Nurs Ment Health Serv  2016  ;54 (6 ):21–4 .
Stahl  SM . Mechanism of action of pimavanserin in Parkinson ’s disease
psychosis: tar geting serotonin 5HT2A and 5HT2C receptors  . CNS Spectr
2016  ;21 (4 ):271–5 .Some indications of improvement in depression when augmenting

antidepressants, with further trials in progress
Theoretically should be ef fective for the hallucinations associated
with Lewy body psychosis
Enhances slow-wave sleep and may have hypnotic properties

Pimozide
Brands
Generic?
Not in USA
 Class
(bold for FDA appr oved)Orap
(D-RAn)
Tourette ’s syndrome/tic suppressant; conventional antipsychotic
(neuroleptic, dopamine 2 antagonist)
Suppr ession of motor and phonic tics in patients with T ourette’s
syndr ome who have failed to r espond satisfactorily to standard
treatment
Psychotic disorders in patients who have failed to respond
satisfactorily to standard treatment

If It W orks
✽ Is a second-line treatment option for T ourette ’s syndrome
✽ Is a secondary or tertiary treatment option for psychosis or other
behavioral disorders
If It Doesn ’t WorkBlocks dopamine 2 receptors in the nigrostriatal dopamine pathway ,
reducing tics in T ourette ’s syndrome
When used for psychosis, can block dopamine 2 receptors in the
mesolimbic dopamine pathway , reducing positive symptoms of
psychosis
Relief from tics may occur more rapidly than antipsychotic actions
Should evaluate for switching to an antipsychotic with a better/risk
benefit ratio

✽ Augmentation of pimozide has not been systematically studied and
can be dangerous, especially with drugs that can either prolong QT c
interval or raise pimozide plasma levels
Tests
✽ Baseline ECG and serum potassium levels should be determined
✽ Periodic evaluation of ECG and serum potassium levels, especially
during dose titration
>30)If 2 or more antipsychotic monotherapies do not work, consider
clozapine
Serum magnesium levels may also need to be monitored

How Drug Causes Side Effectsnutrition and weight management, physical activity counseling,
pimozide should be discontinued at the first sign of decline of WBC

✽ Drug-induced parkinsonismAcute blockade of dopamine 2 receptors in the striatum can cause

✽ Hypotension
✽ Weight gain
✽ Dose-dependent QT c prolongation
Weight GainSedation, akinesia
Galactorrhea, amenorrhea
Dry mouth, constipation, blurred vision
Ventricular arrhythmias and sudden death

Sedation
interval or raise pimozide plasma levelsOccurs in significant minority
Wait
Wait
Wait
present

How to Dose
✽ The ef fects of pimozide on the QT c interval are dose-dependent, so
start low and go slow while carefully monitoring QT c interval
✽ Sudden, unexpected deaths have occurred in patients taking high
doses of pimozide for conditions other than T ourette ’s disorder;
therefore, patients should be instructed not to exceed the prescribed
dose of pimozideLess than 10 mg/day
Initial 1 –2 mg/day in divided doses; can increase dose every other
day; maximum 10 mg/day or 0.2 mg/kg per day
Children: initial 0.05 mg/kg per day at night; can increase every 3
days; maximum 10 mg/day or 0.2 mg/kg per day

Overdose
Deaths have occurred; drug-induced parkinsonism, ECG changes,
No
Slow down-titration (over 6 to 8 weeks), especially when

✽ Use with CYP450 3A4 inhibitors (e.g., drugs such as fluoxetine,
sertraline, fluvoxamine, and nefazodone; foods such as grapefruit
juice) can raise pimozide levels and increase the risks of dangerous
arrhythmiasRapid discontinuation may lead to rebound psychosis and worsening
a few weeks after pimozide is discontinued
Metabolized by CYP450 3A and to a lesser extent by CYP450 1A2
Mean elimination half-life approximately 55 hours
May increase the ef fects of antihypertensive drugs
Use of pimozide and fluoxetine may lead to bradycardia
syndrome

✽ Pimozide can increase the QT c interval and potentially cause
arrhythmia or sudden death, especially in combination with drugs thatCombined use with epinephrine may lower blood pressure
dementia
Because pimozide may dose-dependently prolong QT c interval, use
with caution in patients who have bradycardia or who are taking

with caution in patients who have hypokalemia and/or
Pimozide can increase tumors in mice (dose-related ef fect)

raise its levels
Do Not Use
✽ If patient is taking an agent capable of significanty prolonging QT c
interval (e.g., thioridazine, selected antiarrhythmics, moxifoxacin, and
sparfloxacin)
✽ If there is a history of QT c prolongation or cardiac arrhythmia,
✽ If patient is taking drugs that inhibit pimozide metabolism, such as
macrolide antibiotics, azole antifungal agents (ketoconazole,
itraconazole), protease inhibitors, nefazodone, fluvoxamine,
fluoxetine, sertaline, etc.Antipsychotics may cause somnolence, postural hypotension, motor
therapy

therapy
If patient is taking drugs that can cause tics
If there is a proven aller gy to pimozide
If there is a known sensitivity to other antipsychotics

Pimozide produces a dose-dependent prolongation of QT c interval,
which may be enhanced by the existence of bradycardia,
should be evaluated prior to administering pimozide
Avoid pimozide in patients with a known history of QT c

 Pregnancytreatment of elderly patients with behavioral symptoms of dementia
Safety and ef ficacy established for patients over age 12
Preliminary data show similar safety for patients ages 2 –12 as for
patients over 12
Generally use second-line after atypical antipsychotics and other
conventional antipsychotics

pregnancy

Should evaluate for an antipsychotic with a better risk/benefit ratio
if treatment required during pregnancy
Unknown if pimozide is secreted in human breast milk, but all
Not recommended for use because of potential for tumorigenicity or
cardiovascular ef fects on infant

 Pearls
✽ In the past, pimozide was a first-line choice for T ourette ’s
syndrome and for certain behavioral disorders, including
monosymptomatic hypochondriasis; however , it is now recognized that
the benefits of pimozide generally do not outweigh its risks in most
patients
✽ Because of its ef fects on the QT c interval, pimozide is not intended
for use unless other options for tic disorders (or psychotic disorders)
 Suggested ReadingOnly for patients who respond to this agent and not to other
Vulnerable populations such as children and elderly
Patients on other drugs
Vocal and motor tics in patients who fail to respond to treatment
Psychotic symptoms in patients who fail to respond to treatment

Pringsheim  T , Marras  C . Pimozide for tics in T ourette ’s syndrome  .
Cochrane Database Syst Rev  2009  ;15 (2 ):CD006996  .
Rathbone  J , McMonagle  T . Pimozide for schizophrenia or related
psychoses  . Cochrane Database Syst Rev  2007  ;18 (3 ):CD001949  .

Pipothiazine
Brands
Generic?
No
 Class
(bold for FDA appr oved)Piportil
(D-RAn)
Maintenance treatment of schizophrenia

psychosis
disorder

disorder

Tests
weight gain, before starting treatment, weigh all patients and determinestabilization and maintenance
(risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole,
paliperidone, amisulpride, asenapine, iloperidone, lurasidone)
clozapine

the first few weeks

How Drug Causes Side Effectspipothiazine should be discontinued at the first sign of decline of

✽ Excitement, insomnia, restlessness
with dose)
 Life-Thr eatening or Danger ous Side EffectsMechanism of weight gain and any possible increased incidence of
unknown
Dry mouth, nausea, blurred vision, sweating, appetite change
Sexual dysfunction (impotence)
Hypotension, arrhythmia, tachycardia
Rare rash
Jaundice, leukopenia

Sedation
Wait
Wait
Wait

How to DoseWeight loss, exercise programs, and medical management for high
50–100 mg once a month
Injection 50 mg/mL
Initial 25 mg; can be increased by 25 –50 mg; maximum 200 mg
once a month

✽ Only available as long-acting intramuscular formulation and not as
oral formulation
Overdose
Habit FormingDrug should be administerd intramuscularly in the gluteal region
The peak of action generally occurs after 9 –10 days
May need to treat with an oral antipsychotic for 1 –2 weeks when
initiating treatment
One of the few conventional antipsychotics available in a depot
formulation lasting for up to a month
Sedation, tachycardia, drug-induced parkinsonism, arrhythmia,
hypothermia, ECG changes, hypotension
No

How to Stop
 Other W arnings/Pr ecautionsIf antiparkinson agents are being used, they should be continued for
a few weeks after pipothiazine is discontinued
Onset of action of palmitic ester formulation within 2 –3 days
Duration of action of palmitic ester formulation 3 –6 weeks
Use with TCAs may increase risk of cardiac symptoms
May increase the ef fects of antihypertensive agents
May decrease the ef fects of amphetamines, levodopa, dopamine
agonists, clonidine, guanethidine, adrenaline
Effects may be reduced by anticholiner gic agents
Antacids, antiparkinson drugs, and lithium may reduce pipothiazine
absorption
syndrome

Do Not UsePatients may be more sensitive to extreme temperatures
Use with caution in patients with Parkinson ’s disease, Lewy body
dementia, or drug-induced parkinsonism with previous treatments
Use with caution in patients with respiratory disease, Lewy body
dementia, angle-closure glaucoma (including family history),
alcohol withdrawal syndrome, brain damage, epilepsy ,
hypothyroidism, myaesthenia gravis, prostatic hypertrophy ,
thyrotoxicosis
Contact with skin can cause rash
If patient is comatose
If there is cerebral atherosclerosis
If patient has phaeochromocytoma
If patient has renal or liver failure, blood dyscrasias
If patient has severe cardiac impairment
If patient has subcortical brain damage
If there is a proven aller gy to pipothiazine

Elderly patients do not metabolize the drug as quickly
Recommended starting dose 5 –10 mg

 Pregnancy
✽ Recommended either to discontinue drug or bottle feedNot recommended for use in children
pregnancy
Not recommended unless absolutely necessary
Unknown if pipothiazine is secreted in human breast milk, but all

 Pearls
✽ Only available in long-acting parenteral formulationNoncompliant patients
Patients who need immediate onset of antipsychotic actions
Pipothiazine is a higher potency phenothiazine
Generally , patients must be stabilized on an oral antipsychotic prior
to switching to parenteral long-acting pipothiazine

Suggested Readingcan occasionally vary greatly from one atypical antipsychotic to
another
antipsychotic such as pipothiazine or from switching to a
conventional antipsychotic such as pipothiazine
conventional antipsychotic with an atypical antipsychotic such as
pipothiazine may combine their side ef fects without clearly

Leong  OK , Wong KE , Tay WK , Gill RC . A comparative study of
pipothiazine palmitate and fluphenazine decanoate in the maintenance of
remission of schizophrenia  . Singapor e Med J  1989  ;30 (5 ):436–40 .
Quraishi  S , David  A . Depot pipothiazine palmitate and undecylenate for
schizophrenia  . Cochrane Database Syst Rev  2001  ;(3 ):CD001720  .
Schmidt  K . Pipothiazine palmitate: a versatile, sustained-action neuroleptic
in psychiatric practice  . Curr Med Res Opin  1986  ;10 (5 ):326–9 .

Pitolisant
Brands
Generic?
No
 Class
 How the Drug W orksWakix
Histamine 3 antagonist/inverse agonist
Reducing excessive daytime sleepiness in patients with
Cataplexy
Histamine is a wake-promoting neurotransmitter released from the
tuberomammillary nucleus in the hypothalamus

If It W orks
ResistanceHistamine 3 receptors are presynaptic autoreceptors; thus, when
histamine binds to these receptors it shuts down further histamine
release
Antagonism/inverse agonism of histamine 3 receptors by pitolisant
therefore disinhibits histamine release, boosting histamine levels in
the brain and enhancing wakefulness
Can take up to 8 weeks for some patients to achieve a clinical
response
Improves daytime sleepiness and may improve fatigue
May improve cataplexy
indefinitely as long as improvement persists
Augment or consider an alternative treatment
Stimulants
Modafinil or armodafinil

Tests
SedationBest to attempt another monotherapy prior to augmenting with other
Increased histamine in the brain can lead to insomnia or anxiety ,
decreased appetite, and nausea
Insomnia, anxiety , nausea, decreased appetite
Increased heart rate, tachycardia
Visual hallucinations, hypnagogic hallucinations

Wait
17.8–35.6 mg once daily upon wakening
Tablet 4.45 mg, 17.8 mg
Initial dose 8.9 mg once daily; after 1 week increase to 17.8 mg
once daily; after 2 weeks can increase to 35.6 mg once daily if
needed; maximum dose 35.6 mg once daily

Overdose
How to Stop
Pharmacokinetics4.45 mg tablet contains 5 mg of pitolisant hydrochloride equivalent
to 4.45 mg of pitolisant; 17.8 mg tablet contains 20 mg of pitolisant
hydrochloride equivalent to 17.8 mg of pitolisant
Has been evaluated and found safe and ef fective in trials up to 1
year
No
Taper may be prudent
Extensively metabolized by CYP450 2D6 and to a lesser extent by
CYP450 3A4
Median half-life approximately 20 hours

Drug InteractionsFood does not af fect absorption
In patients taking strong CYP450 2D6 inhibitors the maximum dose
is 17.8 mg once daily
For patients on a stable dose of pitolisant, reduce the pitolisant dose
by half upon initiating a strong CYP450 2D6 inhibitor
In patients who are poor metabolizers of CYP450 2D6 the
maximum dose is 17.8 mg once daily
Strong CYP450 3A4 inducers may reduce exposure of pitolisant
For patients on a stable dose of pitolisant, assess for loss of ef ficacy
after initiating a strong CYP450 3A4 inducer and consider dose
adjustment
If concomitant use of a strong CYP450 3A4 inducer is discontinued,
decrease pitolisant dose by half
Due to weak induction of CYP450 3A4, pitolisant may reduce the
effectiveness of sensitive CYP450 3A4 substrates, including
hormonal contraceptives; patients should use an alternative
nonhormonal contraceptive method during treatment with pitolisant
and for at least 21 days after discontinuation of treatment

Histamine 1 receptor antagonists may reduce ef fectiveness of
pitolisant

Do Not Use
Renal ImpairmentPitolisant prolongs the QT interval; its use should be avoided in
patients with known QT prolongation, in combination with other
drugs known to prolong QT interval, in patients with a history of
cardiac arrhythmnias, and in patients with symptomatic bradycardia,
hypokalemia, or hypomagnesemia
Risk of QT prolongation may be greater in patients with hepatic or
renal impairment due to higher concentrations of pitolisant; such
patients should be monitored for increased QT c
used with pitolisant and for 21 days after discontinuation of
Pitolisant is not a replacement for sleep
If patient has severe hepatic impairment
If there is a proven aller gy to pitolisant
Pitolisant prolongs the QT interval, so monitor patients with renal
impairment for increased QT c

Elderly
 Childr en and AdolescentsModerate to severe renal impairment: initial dose 8.9 mg once daily;
titrate to a maximum dose of 17.8 mg once daily after 7 days
Not recommended for use in end-stage renal disease
Dose adjustment not necessary in patients with mild hepatic
Moderate hepatic impairment: initial dose 8.9 mg once daily; titrate
to a maximum dose of 17.8 mg once daily after 14 days
Pitolisant prolongs the QT interval, so monitor patients with hepatic
Severe hepatic impairment: contraindicated
Pitolisant prolongs the QT interval, so its use should be avoided in
patients with a history of cardiac arrhythmias, symptomatic
bradycardia, hypokalemia, hypomagnesemia, or congenital
prolongation of the QT interval

PregnancySafety and ef ficacy have not been established
Case reports have not determined a drug-associated risk of major
birth defects, miscarriage, or adverse maternal or fetal outcomes
When administered to pregnant rats during or ganogenesis, the no
observed adverse ef fect level (NOAEL) for embryofetal toxicity is
27 times the maximum recommended human dose (MRHD) based
on mg/m2 body surface area
When administered to pregnant rabbits during or ganogenesis, the
NOAELs for maternal toxicity and embryofetal development are 2

and 4 times the MRHD based on mg/m2 body surface
When administered to pregnant rats from gestation day 7 through
lactation, maternal toxicity , including death, occurred at 22 times the
MRHD based on mg/m2 body surface area; at the maternally toxic
dose, fetal toxicity and major malformations occurred
Pregnancy registry for pitolisant: 1-800-833-7460

 PearlsUnknown if pitolisant is secreted in human breast milk, but all
Minimal abuse potential
Did not demonstrate non-inferiority to modafinil in clinical trials
Pitolisant has been approved in the EU since 2016 for the treatment
of narcolepsy with or without cataplexy in adults
Pitolisant is the only anti-narcoleptic drug that is not scheduled as a
controlled substance in the USA
Pitolisant was formerly known as tiprolisant

Dauvilliers  Y , Arnulf  I , Szakacs  Z , et al. Long-term use of pitolisant to
treat patients with narcolepsy: Harmony III Study  . Sleep  2019  ;42 (11 ).
pii: zsz174  . doi: 10.1093/sleep/zsz174  .
Dauvilliers  Y , Verbraecken  J , Partinen  M , et al. Pitolisant for daytime
sleepiness in obstructive sleep apnea patients refusing CP AP: a randomized
trial . Am J Respir Crit Car e Med  2020  ;201 (9 ):1135–45 . doi:
10.1164/rccm.201907-1284OC  .
Kollb-Sielecka  M , Demolis  P , Emmerich  J , et al. The European
Medicines Agency review of pitolisant for treatment of narcolepsy:
summary of the scientific assessment by the Committee for Medicinal
Products for Human Use  . Sleep Med  2017  ;33 :125–9 .
Lamb  YN . Pitolisant: a review in narcolepsy with or without cataplexy  .
CNS Drugs  2020  ;34 (2 ):207–18 . doi: 10.1007/s40263-020-00703-x  .
Setnik  M , McDonnell  M , Mills  C , et al. Evaluation of the abuse potential

of pitolisant, a selective H3-receptor antagonist/inverse agonist, for the
treatment of adult patients with narcolepsy with or without cataplexy  . Sleep
2020  ;43 (4 ):zsz252  . doi: 10.1093/sleep/zsz252  .Preliminary controlled data have shown that pitolisant may reduce
daytime sleepiness in obstructive sleep apnea

Szakacs  Z , Dauvilliers  Y , Mikhaylov  V , et al. Safety and ef ficacy of
pitolisant on cataplexy in patients with narcolepsy: a randomised, double-
blind, placebo-controlled trial  . Lancet Neur ol 2017  ;16 (3 ):200–7 .

Prazosin
Brands
Generic?
Yes
 Class
 How the Drug W orksMinipress
Alpha 1 adrener gic blocker
Nightmares associated with PTSD
Blood circulation disorders
Problems urinating due to enlar ged prostate
Passing of kidney stones

If It W orks
TestsBlocks alpha 1 adrener gic receptors to reduce noradrener gic
hyperactivation
Stimulation of central noradrener gic receptors during sleep may
activate traumatic memories, so blocking this activation may reduce
nightmares
Within a few days to a few weeks
Reduces the severity and frequency of nightmares associated with
PTSD
Increase dose
Prazosin is itself an adjunct agent for the treatment of nightmares
associated with PTSD

Sedation
False-positive results may occur in screening tests for
pheochromocytoma in patients who are being treated with prazosin;
if an elevated urinary VMA is found, prazosin should be
discontinued and the patient retested after a month
Excessive blockade of alpha 1 peripheral noradrener gic receptors
Dizziness, lightheadedness, headache, fatigue, blurred vision
Nausea
Syncope with sudden loss of consciousness

Wait
Wait
Wait
1–16 mg/day , generally in divided doses
Capsule 1 mg, 2 mg, 5 mg
Formal dosing recommendations for treating nightmares have not
been established

Overdose
Habit FormingInitial 1 mg at bedtime; increase dose (divided) until the nightmares
resolve or an intolerable side ef fect occurs
Dosing may be extremely individualized, with as little as 2 mg/day
helpful for some patients and as much as 40 mg/day necessary for
other patients
Therapeutic dose does not correlate with blood levels
Divided dosing may be preferable; in particular , giving a smaller
dose during the day may be beneficial if the patient has persistent
hyperarousal and re-experiencing symptoms during the day
Risk of syncope can be decreased by limiting the initial dose to 1
mg and using slow dose titration
No fatalities have been reported; sedation, depressive reflexes,
Has not been evaluated in controlled studies
Nightmares may return if prazosin is stopped
No

How to Stop
 Other W arnings/Pr ecautionsTaper to avoid hypertension
Elimination half-life 2 –3 hours
Concomitant use with a phosphodiesterase-5 (PDE-5) inhibitor can
have additive ef fects on blood pressure, potentially leading to
hypotension; thus, a PDE-5 inhibitor should be initiated at the
lowest possible dose
Concomitant use with a beta blocker (e.g., propranolol) can have
additive ef fects on blood pressure
Concomitant use with other alpha 1 blockers, which include many
psychotropic agents, can have additive ef fects leading to
Prazosin can cause syncope with sudden loss of consciousness, most
often in association with rapid dose increases or the introduction of
another antihypertensive drug
Intraoperative floppy iris syndrome (IFIS) has been observed during
cataract sur gery in some patients treated with alpha 1 adrener gic
blockers, which may require modifications to the sur gical technique;

Do Not Use
Elderlyhowever , there does not appear to be a benefit of stopping the alpha
1 adrener gic blocker prior to cataract sur gery
Avoid situations that can cause orthostatic hypotension, such as
extensive periods of standing, prolonged or intense exercise, and
exposure to heat
If there is a proven aller gy to quinazolines or prazosin
Use with caution in patients who are predisposed to hypotensive or
syncopal episodes

 Pregnancy
Breast FeedingHigher risk of orthostatic hypotension and syncope
Prazosin has been used alone or in combination with other
hypotensive agents in severe hypertension of pregnancy , with no
fetal or neonatal abnormalities reported
Prazosin should be used during pregnancy only if the potential
benefits justify the potential risks to the mother and fetus
Some drug is present in breast milk

treatment versus nontreatment to both the infant and the mother
For patients with PTSD who do not respond to SSRIs/SNRIs or
exposure therapy
Specifically for nightmares and other symptoms of autonomic
arousal
Patients taking concomitant psychotropic drugs with alpha 1
antagonist properties
Nightmares
The evidence base for using prazosin to treat nightmares associated
with PTSD is limited but positive, and prazosin is recommended by
the Department of V eterans Af fairs as an adjunct treatment for this
purpose

Kung  S , Espinel  Z , Lapid  MI . Treatment of nightmares with prazosin: a
systematic review  . Mayo Clin Pr oc 2012  ;87 (9 ):890 –900 .
Schoenfeld  FB , Deviva  JC , Manber  R . Treatment of sleep disturbances in
posttraumatic stress disorder: a review  . J Rehabil Res Dev  2012  ;49 (5
):729–52 .
Van Berkel  VM , Bevelander  SE , Mommersteeg  PM . Placebo-controlled
comparison of prazosin and cognitive-behavioral treatments for sleep
disturbances in US Military V eterans  . J Psychosom Res  2012  ;73 (2 ):153 .Initiate treatment early in the onset of nightmares following
exposure to trauma
May also be useful for nightmares and symptoms of autonomic
arousal in other trauma and stress-related disorders in addition to
PTSD

Pregabalin
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Lyrica
Lyrica CR
Neuroscience-based Nomenclature: glutamate voltage-gated
Diabetic peripheral neur opathy (IR and CR)
Postherpetic neuralgia (IR and CR)
Fibromyalgia (IR)

channels
How Long Until It W orksNeur opathic pain associated with spinal cord injury (IR)
Partial onset seizur es in adults and pediatric patients ages 1
month and older (IR, adjunctive)
Peripheral neuropathic pain
Pregabalin is a leucine analog and is transported both into the blood
by the system L transport system (a sodium-independent
transporter) as well as by additional sodium-dependent amino acid
transporter systems
Can reduce neuropathic pain and anxiety within a week

If It W orks
If It Doesn ’t Work (for Neur opathic Pain)Should reduce seizures by 2 weeks
If it is not producing clinical benefits within 6 –8 weeks, it may
The goal of treatment of neuropathic pain, seizures, and anxiety
disorders is to reduce symptoms as much as possible, and if
necessary in combination with other treatments
Treatment of neuropathic pain most often reduces but does not
eliminate all symptoms and is not a cure since symptoms usually
are improved but others persist

Consider psychotherapy for anxiety

✽ In addition to being a first-line treatment for neuropathic pain and
anxiety disorders, pregabalin is itself an augmenting agent to
numerous other anticonvulsants in treating epilepsy
✽ For neuropathic pain, TCAs and SNRIs as well as tiagabine, other
anticonvulsants, and even opiates can augment pregabalin if done by
Tests
How Drug Causes Side EffectsConsider the presence of noncompliance and counsel patient
For postherpetic neuralgia, pregabalin can decrease concomitant
opiate use
For anxiety , SSRIs, SNRIs, or benzodiazepines can augment
pregabalin

Sedation
Ataxia, fatigue, tremor , dysarthria, paresthesia, memory impairment,
coordination abnormal, impaired attention, confusion, euphoric
mood, irritability
Vomiting, dry mouth, constipation, weight gain, increased appetite,
flatulence
Blurred vision, diplopia
Libido decreased, erectile dysfunction

Dosage FormsDose-related
Wait
Wait
Wait
IR: 150 –600 mg/day in 2 –3 doses
CR: 330 mg once per day
Capsule 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg,
300 mg

How to Dose
✽ Generally given in one-third to one-sixth the dose of gabapentinOral solution 20 mg/mL
Extended-release tablet 82.5 mg, 165 mg, 330 mg
Neuropathic pain (IR): initial 150 mg/day in 2 –3 doses; can increase
to 300 mg/day in 2 –3 doses after 7 days; can increase to 600 mg/day
in 2–3 doses after 7 more days; maximum dose generally 600
mg/day (may be lower for diabetic peripheral neuropathy and
fibromyalgia)
Neuropathic pain (CR): 165 mg once per day; can increase to 330
mg once per day within a week; maximum dose 660 mg once per
day for postherpetic neuralgia
Seizures (adults): initial 150 mg/day in 2 –3 doses; can increase to
300 mg/day in 2 –3 doses after 7 days; can increase to 600 mg/day in
2–3 doses after 7 more days; maximum dose generally 600 mg/day
If pregabalin is added to a second sedating agent, such as another
anticonvulsant, a benzodiazepine, or an opiate, the titration period
should be at least a week to improve tolerance to sedation

Most patients need to take pregabalin IR only twice daily
splitting IR dose into 3 or more divided doses

Overdose
How to StopExtended-release formulation of pregabalin allows for once daily
dosing
Extended-release tablet should be swallowed whole and should not
be split, crushed, or chewed
For intolerable sedation with the immediate-release formulation, can
give most of the dose at night and less during the day or switch to
extended-release
To improve slow-wave sleep, may only need to take pregabalin at
bedtime
May be taken with or without food
No fatalities
Safe
No

 Other W arnings/Pr ecautionsEpilepsy patients may seize upon withdrawal, especially if
Pregabalin is not metabolized but excreted intact renally
Pregabalin has not been shown to have significant pharmacokinetic
Because pregabalin is excreted unchanged, it is unlikely to have
May add to or potentiate the sedative ef fects of oxycodone,
lorazepam, and alcohol
Use lowest possible dose of pregabalin and monitor for symptoms

Do Not Use
Renal ImpairmentDizziness and sedation could increase the chances of accidental
Increased incidence of hemangiosarcoma at high doses in mice
involves platelet changes and associated endothelial cell
proliferation not present in rats or humans; no evidence to suggest
an associated risk for humans
If there is a proven aller gy to pregabalin or gabapentin
If patient has a problem of galactose intolerance, the Lapp lactase
deficiency , or glucose-galactose malabsorption
Pregabalin is renally excreted, so the dose may need to be lowered
Dosing can be adjusted according to creatinine clearance, such that
patients with clearance below 15 mL/min should receive 25 –75
mg/day in 1 dose, patients with clearance between 15 –29 mL/min

should receive 25 –150 mg/day in 1 –2 doses, and patients with

Elderly
 Childr en and Adolescentsclearance between 30 –59 mL/min should receive 75 –300 mg/day in
2–3 doses
Starting dose should be at the bottom of the range; titrate as usual up
to maximum dose
may require a supplemental dose of pregabalin following
hemodialysis (25 –100 mg)
Approved for partial onset seizures in children ages 1 month and
older
Safety and ef ficacy have not been established in mental illness
indications

Pregnancy
Breast FeedingUse should be reserved for the expert
In animal studies, developmental toxicity (including fetal structural
abnormalities, skeletal malformations, retarded ossification, and
decreased fetal body weight) was observed when pregabalin was
administered to pregnant animals at doses greater than or equal to 16
times the maximum recommended human dose (MRHD)

Potential DisadvantagesUnknown if pregabalin is secreted in human breast milk, but all
First-line for diabetic peripheral neuropathy
Sleep
Has relatively mild side ef fect profile
More potent and probably better tolerated than gabapentin
Requires 2 –3 times a day dosing
Not approved for anxiety disorders in the USA

 Pearls
✽ First treatment approved for fibromyalgia
✽ One of the first treatments approved for neuropathic pain associated
with diabetic peripheral neuropathy
✽ Off-label use for GAD, panic disorder , and social anxiety disorder
may be justified in the USA
✽ Off-label use as an adjunct for bipolar disorder may not be justifiedNot approved for fibromyalgia in Europe
Seizures
Pain
Anxiety
Also approved in postherpetic neuralgia
Improves sleep disruption as well as pain in patients with painful
diabetic peripheral neuropathy or postherpetic neuralgia
Improves sleep disruption as well as pain associated with
Well studied in epilepsy , peripheral neuropathic pain, and GAD, and
actually approved for GAD in Europe
May have uniquely robust therapeutic actions for both the somatic
and the psychic symptoms of GAD

✽ Although no head-to-head studies, appears to be better tolerated and
more consistently ef ficacious at high doses than gabapentin
✽ Drug absorption and clinical ef ficacy may be more consistent at
high doses for pregabalin compared to gabapentin because of the
higher potency of pregabalin and the fact that, unlike gabapentin, it is
transported by more than one transport system
Lauria-Horner  BA , Pohl RB . Pregabalin: a new anxiolytic  . Expert Opin
Investig Drugs  2003  ;12 :663–72 .
Moore  RA , Straube  S , Wiffen PJ , Derry  S , McQuay  HJ . Pregabalin for
acute and chronic pain in adults  . Cochrane Database Syst Rev  2009  ;8 (3
):CD007076  .
Clin Psychiatry  2004  ;65 :596–7 .

Clin Psychiatry  2004  ;65 :460–1 .Pregabalin is generally well tolerated, with only mild adverse ef fects

Stahl  SM , Eisenach  JC , Taylor  CP , et al. The diverse therapeutic actions
of pregabalin: is a single mechanism responsible for several pharmacologic
activities  . Trends Pharmacological Sci  2013  ;34 (6 ):332–9 .

Propranolol
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Inderal
Inderal LA
InnoPran XL
Beta blocker , antihypertensive
Migraine pr ophylaxis
Essential tr emor
Angina pectoris due to cor onary ather oscler osis

How the Drug W orksCardiac arrhythmias (including supraventricular arrhythmias,
ventricular tachycardia, digitalis intoxication)
Myocardial infar ction
Hypertr ophic subaortic stenosis
Pheochr omocytoma
Akathisia (antipsychotic induced)
Parkinsonian tremor
Violence, aggression
PTSD, prophylactic
Prevention of variceal bleeding
Congestive heart failure
Tetralogy of Fallot
Hyperthyroidism (adjunctive)
For migraine, proposed mechanisms include inhibition of the
adrener gic pathway , interaction with the serotonin system and
receptors, inhibition of nitric oxide synthesis, and normalization of
contingent negative variation
For tremor , antagonism of peripheral beta 2 receptors is the
proposed mechanism

If It W orks
If It Doesn ’t WorkFor PTSD, blockade of beta 1 adrener gic receptors may theoretically
prevent fear conditioning and reconsolidation of fear
For violence/aggression, the mechanism is poorly established;
presumed to be related to central actions at beta adrener gic and
serotonin receptors
For migraine, can begin to work within 2 weeks, but may take up to
3 months on a stable dose to see full ef fect
For tremor , can begin to work within days
For migraine, the goal is a 50% or greater decrease in migraine
frequency or severity; consider tapering or stopping if headaches
remit for more than 6 months
For tremor , can cause reduction in the severity of tremor , allowing
greater functioning with daily activities and clearer speech
For PTSD, may theoretically block the ef fects of stress from prior
traumatic experiences
For aggression, may reduce aggression, agitation, or
uncooperativeness
Increase to highest tolerated dose

ResistanceFor migraine, address other issues such as medication overuse or
other coexisting medical disorders; consider changing to another
drug or adding a second drug
For tremor , coadministration with primidone up to 250 mg/day can
augment response; second-line medications include
benzodiazepines, gabapentin, topiramate, methazolamide, nadolol,
and botulinum toxin (useful for voice and hand tremor); alternative
treatments include caf feine and hand weights
For patients with truly refractory tremor , thalamotomy or deep brain
stimulation of the ventral intermediate nucleus of the thalamus is an
option
For PTSD, consider initiating first-line pharmacotherapy (SSRI,
SNRI) and psychotherapy
For violence/aggression, switch to another agent, e.g., valproate or
an antipsychotic
Migraine: for some patients, low-dose polytherapy with 2 or more
drugs may be better tolerated and more ef fective than high-dose

monotherapy; may use propranolol in combination with
anticonvulsants, antidepressants, natural products, and non-
pharmacologic treatments, such as biofeedback, to improve
headache control
For tremor , can combine with primidone or second-line medications

Tests
 Life-Thr eatening or Danger ous Side EffectsFor aggression and violence, can combine with valproate and/or
By blocking beta adrener gic receptors, it can cause dizziness,
bradycardia, and hypotension
Bradycardia, hypotension, hyper - or hypoglycemia, weight gain
Bronchospasm, cold/flu symptoms, sinusitis, pneumonias
Dizziness, vertigo, fatigue/tiredness, depression, sleep disturbances
Sexual dysfunction, decreased libido, dysuria, urinary retention,
joint pain
Exacerbation of symptoms in peripheral vascular disease and
Raynaud ’s syndrome
In acute congestive heart failure, may further depress myocardial
contractility

Sedation
Best Augmenting Agents for Side EffectsCan blunt premonitory symptoms of hypoglycemia in diabetes and
mask clinical signs of hyperthyroidism
Nonselective beta blockers such as propranolol can inhibit
bronchodilation, making them contraindicated in asthma, severe
COPD
Do not use in pheochromocytoma unless alpha blockers are already
being used
Risk of excessive myocardial depression in general anesthesia
Lower dose, change to an extended-release formulation, or switch to
another agent
When patients have significant benefit from beta blocker therapy but
hypotension limits treatment, consider alpha agonists (midodrine) or

How to Dosevolume expanders (fludrocortisones) for symptomatic relief
40–400 mg/day
Tablet 10 mg, 20 mg, 40 mg, 60 mg, 80 mg, 90 mg
Extended-release capsule 60 mg, 80 mg, 120 mg, 160 mg
Oral solution 4 mg/mL, 8 mg/mL
Migraine: initial dose 40 mg/day in divided doses or once daily in
extended-release preparations; gradually increase over days to
weeks until ef fective dose is reached; maximum dose 400 mg/day
Tremor: initial dose 40 mg twice per day; dosage may be gradually
increased as needed to 120 –320 mg/day in 2 to 3 divided doses
PTSD: ef fective dose varies greatly; up to 240 mg/day has been
used

Overdose
How to StopAggression: same as migraine; up to 400 mg/day if tolerated and
effective
For extended-release capsules, give once daily at bedtime
consistently , with or without food
Doses above 120 mg had no additional antihypertensive ef fect in
clinical trials
High doses may be ef fective in some patients with tremor , migraine,
or aggression/violence
Bradycardia, hypotension, low-output heart failure, shock, seizures,
coma, hypoglycemia, apnea, cyanosis, respiratory depression, and
broncospasm
Safe
No

 Drug InteractionsShould not be discontinued abruptly; instead gradually reduce
dosage over 1 –2 weeks
May exacerbate angina, and there are reports of tachyarrhythmias or
myocardial infarction with rapid discontinuation in patients with
cardiac disease
Half-life 3 –5 hours (immediate-release) or 8 –11 hours (extended-
release)
Cimetidine, oral contraceptives, ciprofloxacin, hydralazine,
hydroxychloroquine, loop diuretics, certain SSRIs (with CYP 2D6
metabolism), and phenothiazines can increase levels and/or ef fects
of propranolol
Use with calcium channel blockers can be syner gistic or additive,
use with caution
Barbiturates, penicillins, rifampin, calcium and aluminum salts,
thyroid hormones, and cholestyramine can decrease ef fects of beta
blockers
NSAIDs, sulfinpyrazone, and salicyclates inhibit prostaglandin
synthesis and may inhibit the antihypertensive activity of beta
blockers

Do Not UsePropranolol can increase adverse ef fects of gabapentin and
benzodiazapines
Propranolol can increase levels of lidocaine, resulting in toxicity ,
and increase the anticoagulant ef fect of warfarin
Increased postural hypotension with prazosin and peripheral
ischemia with er got alkaloids
Sudden discontinuation of clonidine while on beta blockers or when
stopping together can cause life-threatening increases in blood
pressure
May elevate blood urea, serum transaminases, alkaline phosphatase,
and lactate dehydrogenase (LDH)
Rare development of antinuclear antibodies (ANAs)
May worsen symptoms of myasthenia gravis
Can lower intraocular pressure, interfering with glaucoma screening
test
If patient has bradycardia, greater than first-degree heart block, or
cardiogenic shock
If patient has bronchial asthma or severe COPD
If there is a proven aller gy to propranolol

Elderly
 PregnancyNo dose adjustment necessary
Use with caution with severe impairment; dose reduction may be
necessary
Do not use in acute shock, myocardial infarction, hypotension, and
greater than first-degree heart block, but indicated in clinically
stable patients post-myocardial infarction to reduce risk of re-
infarction starting 1 –4 weeks after event
May increase risk of stroke
Usual dose in children is 2 –4 mg/kg in 2 divided doses; maximum
16 mg/kg/day
Clinical trials for migraine prophylaxis did not include children

May reduce perfusion of the placenta
fetus
Due to high lipid solubility , propranolol is found in breast milk more
than many other beta blockers
Patients who do not respond to or tolerate other options

Patients with autonomic hyperactivity

 Pearls
 Suggested ReadingMultiple potential undesirable adverse ef fects, including
bradycardia, hypotension, and fatigue
Migraine frequency and severity
Tremor
Effects of stress from prior traumatic experience
Aggression, agitation
Often used in combination with other drugs in migraine, which may
allow patients to better tolerate medications that cause tremor , such
as valproate
May worsen depression, but helpful for anxiety
50–70% of patients with essential tremor receive some relief,
usually with about 50% improvement or greater
Propranolol may theoretically block the ef fects of stress from prior
traumatic experiences, but this is unproven and data thus far are
mixed

Brunet  A , Poundja  J , Tremblay  J , et al. Trauma reactivation under the
influence of propranolol decreases posttraumatic stress symptoms and
disorders: 3 open-label trials  . J Clin Psychopharmacol  2011 ;31 (4 ):547–
50 .
Cohen  H , Kaplan  Z , Koresh  O , et al. Early post-stressor intervention with
propranolol is inef fective in preventing posttraumatic stress responses in an
animal model for PTSD  . Eur Neur opsychopharmacol  2011 ;21 (3 ):230–40
.
Fleminger  S , Greenwood  RJ , Oliver  DL . Pharmacological management
for agitation and aggression in people with acquired brain injury  . Cochrane
Database Syst Rev  2003  ;(1 ):CD003299  .
Lyons  KE , Pahwa  R . Pharmacotherapy of essential tremor: an overview of
existing and upcoming agents  . CNS Drugs  2008  ;22 (12 ):1037 –45 .
Silberstein  SD . Preventive migraine treatment  . Neur ol Clin  2009  ;27 (2
):429–43 .

Protriptyline
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Triptil
Vivactil
reuptake inhibitor
Mental depr ession

✽ Some evidence it may have an early onset of action with
improvement in activity and ener gy as early as 1 week
If It W orksBoosts neurotransmitter norepinephrine/noradrenaline
cortex, which lar gely lacks dopamine transporters, protriptyline can

symptoms

Tests
weight, consider evaluating for the presence of pre-diabetes, diabetes,Some patients may experience apparent lack of consistent ef ficacy

✽ Anticholiner gic activity for protriptyline may be more potent than
for some other TCAs and may explain sedative ef fects, dry mouth,
constipation, blurred vision, tachycardia, and hypotension
Blockade of alpha 1 adrener gic receptors may explain dizziness,

Cardiac arrhythmias, especially in overdose, may be caused by
blockade of ion channels

Rare activation of suicidal ideation and behavior (suidicality) (short-

Sedation
✽ Not as sedating as other TCAs; more likely to be activating than
other TCAs
Usual Dosage RangeCan increase appetite and carbohydrate craving
Wait
Wait
Wait
Benzodiazepines for agitation and anxiety

How to Dose
✽ Be aware that among this class of agents (tricyclic/tetracyclic
antidepressants), protriptyline has uniquely low dosing (15 –40 mg/day
for protriptyline compared to 75 –300 mg/day for most other
tricyclic/tetracyclic antidepressants)
antidepressants), protriptyline has uniquely frequent dosing (3 –4 times
a day compared to once daily for most other tricyclic/tetracyclic
antidepressants)
Overdose15–40 mg/day in 3 –4 divided doses
Initial 15 mg/day in divided doses; increase morning dose as
needed; maximum dose 60 mg/day

How to Stop
 Drug InteractionsDeath may occur; CNS depression, convulsions, cardiac
Safe
No
Half-life approximately 74 hours

Fluoxetine, paroxetine, bupropion, duloxetine, and other 2D6
inhibitors may increase TCA concentrations
anti-choliner gic symptoms
activity
discontinuation of protriptyline

after discontinuing protriptyline

days for most drugs) after discontinuing protriptyline

Do Not Use
If there is a proven aller gy to protriptyline

Cardiac ImpairmentPatient may need to be monitored closely
Patient may need to be monitored closely
protriptyline

Elderly
Recommended dose is between 15 –20 mg/day; doses >20 mg/day
require close monitoring of patient

patients
Not recommended for use under age 12
Not intended for use under age 6
Recommended dose: 15 –20 mg/day

 Pearls
✽ Has some potential advantages for withdrawn, aner gic patients
✽ May have a more rapid onset of action than some other TCAs
✽ May aggravate agitation and anxiety more than some other TCAs
✽ May have more anticholiner gic side ef fects, hypotension, and
tachycardia than some other TCAsSevere or treatment-resistant depression
Withdrawn, aner gic patients
Pediatric, geriatric, and cardiac patients
Patients noncompliant with 3 –4 times daily dosing
Noradrener gic reuptake inhibitors such as protriptyline can be used

protriptyline for this use

Bull 2001  ;57 :161–78 .SSRIs may be more ef fective than TCAs in women, and TCAs may

Rudorfer  MV , Potter  WZ . Metabolism of tricyclic antidepressants  . Cell
Mol Neur obiol  1999  ;19 (3 ):373 –409 .

Quazepam
Brands
Generic?
No
 Class
 How the Drug W orksDoral
Short-term tr eatment of insomnia
Catatonia

Sedation
Wait
To avoid problems with memory , only take quazepam if planning to

How to Dose
15 mg/day at bedtime
15 mg/day at bedtime; increase to 30 mg/day if inef fective;
maximum dose 30 mg/day
Use lowest possible ef fective dose and assess need for continued

Overdose
✽ Because of its relatively longer half-life, quazepam may cause some
daytime sedation and/or impaired motor/cognitive function, and may
do so progressively over time
How to StopQuazepam should generally not be prescribed in quantities greater
treatment
No death reported in monotherapy; sedation, respiratory depression,
poor coordination, confusion, coma
Not generally intended for use beyond 4 weeks
Quazepam is a Schedule IV drug

Half-life 25 –41 hours
Metabolized in part by CYP450 3A4
Effects of quazepam may be increased by CYP450 3A4 inhibitors
such as nefazodone or fluvoxamine

Do Not UseBoxed warning regarding the increased risk of CNS depressant
efficacy
ideation

ideation
Quazepam should be administered only at bedtime

Elderly
 Childr en and AdolescentsIf patient has angle-closure glaucoma
If there is a proven aller gy to quazepam or any benzodiazepine
Recommended dose: 7.5 mg/day
If 15 mg/day is given initially , try to reduce the dose to 7.5 mg/day
after the first 1 –2 nights
Long-term ef fects of quazepam in children/adolescents are unknown

Pregnancy
The Art of PsychopharmacologyShould generally receive lower doses and be more closely
monitored

 Pearls
✽ Because quazepam tends to accumulate over time, perhaps not the
✽ Long-term accumulation of quazepam and its active metabolites
elderlyTransient insomnia
Total night sleep
Nighttime awakening
Quazepam has a longer half-life than some other sedative hypnotics,
so it may be less likely to cause rebound insomnia on

Ankier  SI , Goa KL . Quazepam. A preliminary review of its
in insomnia  . Drugs  1988  ;35 :42 –62 .
1991  ;52 (Suppl  ):S21–6 .
Kales  A . Quazepam: hypnotic ef ficacy and side ef fects  . Pharmacotherapy
1990  ;10 :1 –10 .
Kirkwood  CK . Management of insomnia  . J Am Pharm Assoc (W ash) 1999
;39 :688–96 .
hypnotics  . J Clin Psychiatry  1991  ;52 (Suppl  ):S38 –41 .Though not systematically studied, benzodiazepines have been used
treatment

Quetiapine
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Seroquel
Seroquel XR
Neuroscience-based Nomenclature: dopamine, serotonin multimodal
(DS-MM)
Acute schizophr enia in adults (quetiapine, quetiapine XR) and
ages 13 –17 (quetiapine)
Schizophr enia maintenance (quetiapine XR)

How the Drug W orksAcute mania in adults (quetiapine and quetiapine XR,
monotherapy and adjunct to lithium or valpr oate) and ages 10 –
17 (quetiapine, monotherapy and adjunct to lithium or
valpr oate)
Bipolar maintenance (quetiapine, quetiapine XR)
Bipolar depr ession (quetiapine, quetiapine XR)
Depr ession (quetiapine XR, adjunct)
Mixed mania
Behavioral disturbances in Parkinson ’s disease and Lewy body
dementia
Psychosis associated with levodopa treatment in Parkinson ’s disease
Severe treatment-resistant anxiety

✽ Interactions at a myriad of other neurotransmitter receptors may
contribute to quetiapine ’s efficacy in treatment-resistant depression or
bipolar depression, especially 5HT1A partial agonist action,
norepinephrine reuptake blockade and 5HT2C antagonist and 5HT7
✽ Specifically , actions at 5HT1A receptors may contribute to ef ficacy
for cognitive and af fective symptoms in some patients, especially at
moderate to high doses
If It W orks –for Schizophr enia and Bipolar DisorderBlocks serotonin 2A receptors, causing enhancement of dopamine

symptoms

If It Doesn ’t Work –for Schizophr enia and Bipolar DisorderThe goal of treatment is complete remission of current symptoms as
clozapine
injection

If It Doesn ’t Work –for Depr ession
coginitive remediation
Lithium

Side EffectsTreat or refer for treatment and consider switching to another
Although US manufacturer recommends 6-month eye checks for
cataracts, clinical experience suggests this may be unnecessary

quetiapine should be discontinued at the first sign of decline of

✽ Dizziness, sedationBy blocking histamine 1 receptors in the brain, it can cause sedation
Dyspepsia, abdominal pain

Sedation
Many experience and/or can be significant in amount at ef fective
antipsychotic doses

What to Do About Side EffectsFrequent and can be significant in amount
Can wear of f over time
Not necessarily increased as dose is raised
Wait
Wait
Wait
Usually dosed twice daily , so take more of the total daily dose at
bedtime to help reduce daytime sedation
Start dosing low and increase slowly as side ef fects wear of f at each
dosing increment

How to DoseSwitch to another atypical antipsychotic
400–800 mg/day in 1 (quetiapine XR) or 2 (quetiapine) doses for
bipolar mania
300 mg once daily for bipolar depression
Tablet 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg
Extended-release tablet 50 mg, 150 mg, 200 mg, 300 mg, 400 mg

✽ More may be much mor e: clinical practice suggests quetiapine
often underdosed, then switched prior to adequate trials(According to manufacturer for quetiapine in schizophrenia): initial
25 mg/day twice a day; increase by 25 –50 mg twice a day each day
until desired ef ficacy is reached; maximum approved dose 800
mg/day
In practice, can start adults with schizophrenia under age 65 with
same doses as recommended for acute bipolar mania
(According to manufacturer for quetiapine in acute bipolar mania):
initiate in twice daily doses, totaling 100 mg/day on day 1,
increasing to 400 mg/day on day 4 in increments of up to 100
mg/day; further dosage adjustments up to 800 mg/day by day 6
should be in increments of no greater than 200 mg/day
Bipolar depression for quetiapine and quetiapine XR: once daily at
bedtime; titrate as needed to reach 300 mg/day by day 4
Quetiapine XR in schizophrenia and acute mania: initial 300 mg

once daily , preferably in the evening; can increase by 300 mg/day
each day until desired ef ficacy is reached; maximum approved dose
800 mg/day
See also The Art of Switching section, after Pearls
Clinical practice suggests that at low doses it may be a sedative
hypnotic, possibly due to potent H1 antihistamine actions, but this

✽ Initial tar get dose of 400 –800 mg/day should be reached in most
cases to optimize the chances of success in treating acute psychosis
and acute mania, but many patients are not adequately dosed in clinical
practice
✽ Higher doses generally achieve greater response for manic or
psychotic symptoms
✽ Occasional patients may require more than 800 –1200 mg/day for
psychosis or maniacan risk numerous antipsychotic-related side ef fects and there are
many other options
Many patients do well with immediate-release as a single daily oral
dose, usually at bedtime
Recommended titration to 400 mg/day by the fourth day can often
be achieved when necessary to control acute symptoms
Rapid dose escalation in manic or psychotic patients may lessen
sedative side ef fects
In contrast, some patients with bipolar depression may respond well
to doses less than 300 mg/day and as little as 25 mg/day
Dosing in major depression may be even lower than in bipolar

depression, and dosing may be even lower still in GAD

Overdose
Long-T erm UseRather than raise the dose above normal dosing in partial
Quetiapine XR is controlled-release and therefore should not be
chewed or crushed but rather should be swallowed whole
Quetiapine XL may theoretically generate increased concentrations
of active metabolite norquetiapine, with theoretically improved
profile for af fective and anxiety disorders
Rarely lethal in monotherapy overdose; sedation, slurred speech,
Approved for long-term maintenance in schizophrenia and bipolar
disorder , and often used for long-term maintenance in various

How to Stop
See also the Switching section of individual agents for how to stop
Parent drug has 6 –7 hour half-life
Food may slightly increase absorption
CYP450 3A inhibitors and CYP450 2D6 inhibitors may reduce
clearance of quetiapine and thus raise quetiapine plasma levels, but
dosage reduction of quetiapine usually not necessary
There are case reports of increased international normalized ratio
(INR) (used to monitor the degree of anticoagulation) when

Other W arnings/Pr ecautionsquetiapine is coadministered with warfarin, which is also a substrate
of CYP450 3A4
In the USA, manufacturer recommends examination for cataracts
before and every 6 months after initiating quetiapine, but this does
not seem to be necessary in clinical practice
Quetiapine should be used cautiously in patients at risk for
aspiration pneumonia, as dysphagia has been reported
Priapism has been reported
Use with caution in patients with known cardiovascular disease,
Avoid use with drugs that increase the QT interval and in patients
with risk factors for prolonged QT interval

Do Not Use
Cardiac ImpairmentDysphagia has been associated with antipsychotic use, and
quetiapine should be used cautiously in patients at risk for aspiration
pneumonia
therapy
If there is a proven aller gy to quetiapine
No dose adjustment required
Downward dose adjustment may be necessary

Elderly
Lower dose is generally used (e.g., 25 –100 mg twice a day),
although higher doses may be used if tolerated
agitation
Approved for use in schizophrenia (ages 13 and older) and
manic/mixed episodes (ages 10 and older)

Clinical experience and early data suggest quetiapine may be safe
and ef fective for behavioral disturbances in children and adolescents

PregnancyChildren and adolescents using quetiapine may need to be
better
Use with caution, observing for activation of suicidal ideation, and
inform parents or guardians of this risk so they can help observe

When administered to pregnant rats and rabbits, embryofetal
toxicity occurred at doses 1 and 2 times the maximum
recommended human dose (MRHD), and maternal toxicity occurred
at 2 times the MRHD in rats and 1 –2 times the MRHD in rabbits

✽ Patients with Parkinson ’s disease who need an antipsychotic or
mood stabilizer
✽ Patients with Lewy body dementia who need an antipsychotic or
mood stabilizerPsychotic symptoms may worsen during pregnancy and some form
961-2388,
Unknown if quetiapine is secreted in human breast milk, but all
Infants of women who choose to breast feed while on quetiapine

 Pearls
✽ May be the preferred antipsychotic for psychosis in Parkinson ’s
disease and Lewy body dementia
✽ Efficacy may be underestimated for psychosis and mania since
quetiapine is often underdosed in clinical practice
✽ Approved in bipolar depressionPatients requiring rapid onset of action
Patients who have dif ficulty tolerating sedation
Insomnia and anxiety
Anecdotal reports of ef ficacy in treatment-refractory cases and
positive symptoms of psychoses other than schizophrenia
The active metabolite of quetiapine, norquetiapine, has the
additional properties of norepinephrine reuptake inhibition and

✽ Essentially no motor side ef fects or prolactin elevation
✽ Controversial as to whether quetiapine has more or less risk of
diabetes and dyslipidemia than some other antipsychoticsantagonism of 5HT2C receptors, which may contribute to
therapeutic ef fects for mood and cognition
Dosing dif fers depending on the indication, with high-dose
mechanisms including robust blockade of D2 receptors above 60%
occupancy and equal or greater 5HT2A blockade; medium-dose
mechanisms including moderate amounts of NET inhibition
combined with 5HT2C antagonism and 5HT1A partial agonism; and
low-dose mechanisms including H1 antagonism and 5HT1A partial
agonism and, to a lesser extent, NET inhibition and 5HT2C
antagonism
More sedation than some other antipsychotics, which may be of
benefit in acutely manic or psychotic patients but not for stabilized
patients in long-term maintenance
May have less weight gain than some antipsychotics, more than
others
Commonly used at low doses to augment other atypical

others
antipsychotics, but such antipsychotic polypharmacy has not been
systematically studied and can be quite expensive
Anecdotal reports of ef ficacy in PTSD, including symptoms of sleep
disturbance and anxiety

 Switching fr om Oral Antipsychotics to QuetiapinePatients with inadequate responses to atypical antipsychotics may
begin quetiapine at middle dose
With risperidone, ziprasidone, iloperidone, and lurasidone, it is
generally advisable to begin quetiapine gradually , titrating over at
least 2 weeks to allow patients to become tolerant to the sedating

effect
For more convenient dosing, patients who are currently being
treated with divided doses of immediate-release tablets may be
switched to extended-release quetiapine at the equivalent total daily
dose taken once daily

>
35 .

Suttajit  S , Srisurapanont  M , Xia J , et al. Quetiapine versus typical
antipsychotic medications for schizophrenia  . Cochrane Database Syst Rev
2013  ;(5 ):CD007815  .
Suttajit  S , Srisurapanont  M , Maneeton  N , Maneeton  B . Quetiapine for
acute bipolar depression: a systematic review and meta-analysis  . Drug Des
Devel Ther  2014  ;8 :827–38 .

Ramelteon
Brands
Generic?
No
 Class
(bold for FDA appr oved)Rozerem
Neuroscience-based Nomenclature: melatonin receptor agonist
(Mel-RA)
Melatonin 1 and 2 receptor agonist
Insomnia (difficulty with sleep onset)

If It W orks
If It Doesn ’t WorkInsomnia associated with shift work, jet lag, or circadian rhythm
Binds selectively to melatonin 1 and melatonin 2 receptors as a full
agonist
Reduces time to sleep onset
Increases total sleep time
May improve quality of sleep

Tests
✽ Sedation
✽ DizzinessGenerally , best to switch to another agent
Eszopiclone, zolpidem
Trazodone
For patients presenting with unexplained amenorrhea, galactorrhea,
decreased libido, or problems with fertility , could consider
measuring prolactin and testosterone levels
Actions at melatonin receptors that carry over to the next day could
theoretically cause daytime sedation, fatigue, and sluggishness, but
this is not common

✽ Fatigue
✽ Headache
Sedation
What to Do About Side EffectsRespiratory depression, especially when taken with other CNS
May experience sedation or sleepiness immediately after dosing, but
not commonly after awakening from a night ’s sleep
Wait
To avoid problems with memory , only take ramelteon if planning to

How to Dose
 Dosing T ipsSwitch to a non-benzodiazepine sedative hypnotic
8 mg at bedtime
Tablet 8 mg
Unusual lack of apparent dose response curve
Doses between 4 mg and 64 mg may have similar ef fects on sleep
and similar side ef fects
Doses up to 160 mg were studied without apparent abuse liability
Suggests therapeutic ef fects may be mediated by an “on-of f” type of
therapeutic ef fect on a sleep switch that works at any dose over a
certain threshold

Overdose
How to StopSince ramelteon has very low oral bioavailability and thus highly
variable absorption, a substantial dose range may be required to
generate suf ficient absorption in various patients
Thus, “one size does not fit all ” despite approval at only one dose
without titration (i.e., 8 mg)
Suggest increasing dose before concluding lack of ef ficacy
Do not administer with or immediately after a high-fat meal as this
may delay its onset of action or diminish its ef ficacy
No reports of ramelteon overdose
No safety or tolerability concerns in studies up to 160 mg
No reports of dependence, tolerance, or abuse liability
Not restricted to short-term use but few long-term studies
No
No evidence of rebound insomnia the first night after stopping
No need to taper dose

 Other W arnings/Pr ecautionsMetabolized predominantly by CYP450 1A2
CYP450 3A4 and 2C are also involved in metabolism of ramelteon
Mean elimination half-life of parent drug 1 –2.6 hours
Mean elimination half-life of major metabolite, M-II, is 2 –5 hours
Inhibitors of CYP450 1A2, such as fluvoxamine, could increase
plasma levels of ramelteon
Inducers of CYP450, such as rifampin, could decrease plasma levels
of ramelteon
Inhibitors of CYP450 3A4, such as ketoconazole, could increase
Inhibitors of CYP450 2C9, such as fluconazole, could increase
Exercise caution if combining with alcohol
No interaction with fluoxetine (CYP450 2D6 inhibitor)

Do Not Use
Cardiac ImpairmentRamelteon should only be administered at bedtime
May decrease testosterone levels or increase prolactin levels, but the
clinical significance of this is unknown
Patients who develop angioedema after treatment with ramelteon
should not be rechallenged
With fluvoxamine
In patients with severe hepatic impairment
If there is a proven aller gy to ramelteon
Use with caution in patients with moderate hepatic impairment

Elderly
 Pregnancy
The Art of PsychopharmacologyNo adjustment necessary
Greater absorption and higher plasma drug concentrations but no
increase in side ef fects
Unknown if ramelteon is secreted in human breast milk, but all

 PearlsThose who require long-term treatment
Those who need a hypnotic but have a past history of substance
abuse
Possibly for circadian rhythm disturbances
More expensive than some other hypnotics
For patients who require sedation
First in a new class of agents, chronohypnotics, that act upon
circadian rhythms by stimulating melatonin receptors in the brain ’s
“pacemaker ,” namely the suprachiasmatic nucleus
Theoretically , stimulation of melatonin 1 receptors mediates the
suppressive ef fects of melatonin on the suprachiasmatic nucleus
Theoretically , stimulation of melatonin 2 receptors mediates the
phase shifting ef fect of melatonin
Ramelteon may act by promoting the proper maintenance of
circadian rhythms underlying a normal sleep-wake cycle

Erman  M , Seiden  D , Zammit  G , Sainati  S , Zhang  J . An ef ficacy , safety ,
and dose-response study of ramelteon in patients with chronic primary
insomnia  . Sleep Med  2006  ;7 (1 ):17 –24 .
Kato  K , Hirai  K , Nishiyama  K , et al. Neurochemical properties of
ramelteon (T AK-375), a selective MT1/MT2 receptor agonist  .
Neur opharmacology  2005  ;48 (2 ):301–10 .Thus, ramelteon may also prove ef fective for treatment of circadian
rhythm disturbances such as shift work sleep disorder and jet lag
Lack of actions on GABA systems, which may be related to lack of
apparent abuse liability
Only approved hypnotic agent that is not scheduled and is
considered to have no abuse liability
No evidence that ramelteon worsens apnea/hypopnea index in
COPD or in obstructive sleep apnea, but not recommended in severe
cases

cases
May have fewer carryover side ef fects than some other sedative
hypnotics

McGechan  A , Wellington  K . Ramelteon  . CNS Drugs  2005  ;19 (12
):1057 –65 .
Pandi-Perumal  SR , Zisapel  N , Srinivasan  V , Cardinali  DP . Melatonin
and sleep in aging population  . Exp Ger ontol  2005  ;40 (12 ):911–25 .

Reboxetine
Brands
Generic?
No
 Class
(bold for FDA appr oved)Norebox
Edronax
Selective norepinephrine reuptake inhibitor (NRI); antidepressant
Dysthymia

Blocks norepinephrine reuptake pump (norepinephrine transporter)
Presumably , this increases noradrener gic neurotransmission
cortex which lar gely lacks dopamine transporters, reboxetine can
symptoms

ResistanceOnce symptoms are gone, continue treating for 1 year for the first

Tests
Notable Side EffectsSSRIs, SNRIs, mirtazapine (use combinations of antidepressants
ideation)
Benzodiazepines for anxiety
constipation and dry mouth, etc.)

Sedation
What to Do About Side EffectsInsomnia, dizziness, anxiety , agitation
Urinary hesitancy , urinary retention
Dose-dependent hypotension
Wait

Wait
Benzodiazepines for drug-induced anxiety and activation
Mirtazapine for drug-induced insomnia or anxiety
discontinuation of reboxetine

How to Dose
 Dosing T ips8 mg/day in 2 doses (10 mg usual maximum daily dose)
Tablet 2 mg, 4 mg scored
Initial 2 mg/day twice a day for 1 week, 4 mg/day twice a day for
second week
When switching from another antidepressant or adding to another
antidepressant, dosing may need to be lower and titration slower to
prevent activating side ef fects (e.g., 2 mg in the daytime for 2 –3
days, then 2 mg bid for 1 –2 weeks)
Give second daily dose in late afternoon rather than at bedtime to
avoid undesired activation or insomnia in the evening
May not need full dose of 8 mg/day when given in conjunction with
another antidepressant
Some patients may need 10 mg/day or more if well tolerated without
orthostatic hypotension and if additional ef ficacy is seen at high
doses in dif ficult cases

Overdose
How to Stop
 Drug InteractionsEarly dosing in patients with panic and anxiety may need to be
lower and titration slower , perhaps with the use of concomitant
short-term benzodiazepines to increase tolerability
Postural hypotension, anxiety , hypertension
Safe
No
Inhibits CYP450 2D6 and 3A4 at high doses
Elimination half-life approximately 13 hours

May need to reduce reboxetine dose or avoid concomitant use with
inhibitors of CYP450 3A4, such as azole and antifungals, macrolide
antibiotics, fluvoxamine, nefazodone, fluoxetine, sertraline, etc.
Via CYP450 2D6 inhibition, reboxetine could theoretically interfere
of some beta blockers and of atomoxetine and TCAs
Via CYP450 2D6 inhibition, reboxetine could theoretically increase
Via CYP450 3A4 inhibition, reboxetine may increase the levels of
alprazolam, buspirone, and triazolam
Via CYP450 3A4 inhibition, reboxetine could theoretically increase
concentrations of certain cholesterol lowering HMG CoA reductase
rhabdomyolysis; thus, coadministration of reboxetine with certain

Use with er gotamine may increase blood pressure
Hypokalemia may occur if reboxetine is used with diuretics
Use with caution with MAO inhibitors, including 14 days after

Do Not UseUse with caution in patients with bipolar disorder unless treated
hyperplasia, glaucoma, epilepsy
Use with caution with drugs that lower blood pressure
companies
If patient is taking an MAOI (except as noted under drug
interactions)
If patient is taking pimozide or thioridazine

Elderly
 Childr en and AdolescentsIf there is a proven aller gy to reboxetine
Lower dose is recommended (4 –6 mg/day)

Pregnancy
Breast FeedingMonitor patients face-to-face regularly , particularly during the first
patients
No guidelines for children; safety and ef ficacy have not been
established
No controlled studies in humans
pregnancy

Primary T arget Symptomsdrug may need to be reinstituted late in the third trimester or shortly
the mother
Tired, unmotivated patients
Patients with cognitive disturbances
Patients with psychomotor retardation
Patients unable to comply with twice daily dosing
Patients unable to tolerate activation
Suicidal ideation

Pearls
✽ May be more likely than SSRIs to improve social and work
✽ Side ef fects may appear “anticholiner gic,” but reboxetine does not
directly block muscarinic receptors
✽ Thus, antidotes for these side ef fects can be alpha 1 antagonists
such as tamsulosin, especially for urinary retention in men over 50
with borderline urine flowCognitive disturbance
May be ef fective if SSRIs have failed or for SSRI “poop-out ”
Reboxetine is a mixture of an active and an inactive enantiomer , and
the active enantiomer may be developed in future clinical testing
Constipation, dry mouth, and urinary retention are noradrener gic,
due in part to peripheral alpha 1 receptor stimulation causing
decreased acetylcholine release
Novel use of reboxetine may be for attention deficit disorder ,
analogous to the actions of another norepinephrine selective
reuptake inhibitor , atomoxetine, but few controlled studies
Another novel use may be for neuropathic pain, alone or in

combination with other antidepressants, but few controlled studies
Some studies suggest ef ficacy in panic disorder

Eyding  D , Lelgemann  M , Grouven  U , et al. Reboxetine for acute
treatment of major depression: systematic review and meta-analysis of
published and unpublished placebo and selective serotonin reuptake
inhibitor controlled trials  . BMJ  2010  ;341 :c4737  .
Fleishaker  JC . Clinical pharmacokinetics of reboxetine, a selective
norepinephrine reuptake inhibitor for the treatment of patients with
depression  . Clin Pharmacokinet  2000  ;39 (6 ):413–27 .
Kasper  S , el Giamal  N , Hilger  E . Reboxetine: the first selective
noradrenaline re-uptake inhibitor  . Expert Opin Pharmacother  2000  ;1 (4
):771–82 .
Keller  M . Role of serotonin and noradrenaline in social dysfunction: a
review of data on reboxetine and the Social Adaptation Self-evaluation
Scale (SASS)  . Gen Hosp Psychiatry  2001  ;23 (1 ):15 –19 .
Tanum  L . Reboxetine: tolerability and safety profile in patients with major
depression  . Acta Psychiatr Scand Suppl  2000  ;402 :37 –40 .

Risperidone
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Risperdal
Consta
Perseris
Schizophr enia, ages 13 –17 (oral) and adults (oral, Consta,
Perseris)

How the Drug W orksDelaying r elapse in schizophr enia (oral)
Other psychotic disorders (oral)
Acute mania/mixed mania, ages 10 and older (oral,
monotherapy and adjunct to lithium or valpr oate)
Autism-r elated irritability in childr en ages 5 –16 (oral)
Bipolar maintenance (oral, Consta, monotherapy and adjunct to
lithium or valpr oate)
contribute to risperidone ’s efficacy

✽ Specifically , 5HT7 antagonist properties may contribute to
antidepressant actions
symptoms

If It Doesn ’t Worksustain long-term relationships
clozapine

Tests
plasma glucose, and fasting lipid profileinjection
Lithium

with diabetes or who have gained >5% of initial weightis overweight (BMI 25.0 –29.9)

risperidone should be discontinued at the first sign of decline of

drug-induced parkinsonism, dystonia, or akathisia, especially at high

✽ Dose-related hyperprolactinemia
✽ Dose-dependent dizziness, insomnia, anxiety , sedation
 Life-Thr eatening or Danger ous Side Effectsdoses
Nausea, constipation, abdominal pain, weight gain
Tachycardia, dose-dependent sexual dysfunction
Rare orthostatic hypotension, usually during initial dose titration

Sedation

Wait
Wait
present

How to Dose –OralOral: 2 –8 mg/day for acute psychosis and bipolar disorder
Oral: 0.5 –2.0 mg/day for children and elderly
Consta: 12.5 –50 mg every 2 weeks (deep intramuscular) (see
section after Pearls for dosing and use)
Perseris: 90 or 120 mg every month (subcutaneous) (see section
Tablet 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 6 mg
Orally disintegrating tablet 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg
Liquid 1 mg/mL –30 mL bottle
Risperidone long-acting depot microspheres formulation for deep
intramuscular administration 12.5 mg vial/kit, 25 mg vial/kit, 37.5
mg vial/kit, 50 mg vial/kit
Long-acting monthly formulation 90 mg, 120 mg
In adults with psychosis in nonemer gent settings, initial dosage
recommendation is 1 mg/day orally in 2 divided doses

✽ Less may be mor e: lowering the dose in some patients with stable
efficacy but side ef fects may reduce side ef fects without loss of
efficacy , especially for doses over 6 mg/day orally
✽ Target doses for best ef ficacy/best tolerability in many adults with
psychosis or bipolar disorder may be 2 –6 mg/day (average 4.5 mg/day)
orallyIncrease each day by 1 mg/day orally until desired ef ficacy is
reached
Maximum generally 16 mg/day orally
Typically maximum ef fect is seen at 4 –8 mg/day orally
Can be administered on a once daily schedule as well as twice daily
orally
Low doses may not be adequate in dif ficult patients

Overdose
Long-T erm UseApproved for use up to 16 mg/day orally , but data suggest that risk
of drug-induced parkinsonism is increased above 6 mg/day
Risperidone oral solution is not compatible with cola or tea
Children and elderly may need to have oral twice daily dosing
during initiation and titration of drug dosing and then can switch to
oral once daily when maintenance dose is reached
Rarely lethal in monotherapy overdose; sedation, rapid heartbeat,
convulsions, low blood pressure, dif ficulty breathing
Often used for long-term maintenance in bipolar disorder and
various behavioral disorders

How to Stop
See Switching sections of individual agents for how to stop
Metabolites are active
Parent drug of oral formulation has 20 –24 hour half-life
Consta (long-acting intramuscular) has 3 –6 day half-life and
elimination phase of approximately 7 –8 weeks after last injection
Clearance of risperidone may be reduced and thus plasma levels
increased by clozapine; dosing adjustment usually not necessary

Other W arnings/Pr ecautionsCoadministration with carbamazepine may decrease plasma levels
of risperidone
Coadministration with fluoxetine and paroxetine may increase
plasma levels of risperidone
Since risperidone is metabolized by CYP450 2D6, any agent that
inhibits this enzyme could theoretically raise risperidone plasma
levels; however , dose reduction of risperidone is usually not
necessary when such combinations are used
Perseris: if a strong CYP450 2D6 inhibitor is to be initiated, patients
may be placed on the lowest dose (90 mg) 2 –4 weeks before the
start of the 2D6 inhibitor , to adjust for the expected increase in
risperidone plasma concentrations
Perseris: if a strong CYP450 3A4 inducer is to be initiated, patient
should be closely monitored during the first 4 –8 weeks; upward
dose adjustment (for patients taking 90 mg) or oral supplementation
(for patients taking 120 mg) may be necessary

Risperidone should be used cautiously in patients at risk for

Do Not Use
Renal ImpairmentAtypical antipsychotics can cause body temperature dysregulation;
risperidone should be used cautiously in patients at risk for
therapy
If there is a proven aller gy to risperidone or paliperidone

Cardiac ImpairmentOral: initial 0.5 mg twice a day for first week; increase to 1 mg
twice a day during second week; dosage increases above 1.5 mg
twice a day should occur at least 1 week apart
Consta: patient should demonstrate tolerability of at least 2 mg/day
orally prior to initiation; should be dosed at 25 mg every 2 weeks;
oral administration should be continued for 3 weeks after the first
injection
Perseris: has not been studied in this population; recommended to
titrate patients to at least 3 mg/day of oral risperidone and establish
efficacy/tolerability prior to initiating the monthly injection
Oral: initial 0.5 mg twice a day for first week; increase to 1 mg
twice a day during second week
injection

injection

✽ When administered to elderly patients with atrial fibrillation, may
increase the chances of stroke
Elderly
 Childr en and AdolescentsUse with caution if patient is taking concomitant antihypertensive or
Initial 0.5 mg orally twice a day; increase by 0.5 mg twice a day;
titrate once a week for doses above 1.5 mg twice a day
Consta: recommended dose is 25 mg every 2 weeks; oral
administration should be continued for 3 weeks after the first
injection
Perseris: not studied in this population
agitation

✽ Oral risperidone is approved for use in schizophrenia (ages 13 and
older), mania/mixed episodes (ages 10 and older), and irritability
associated with autism (ages 5 –16)
✽ Risperidone is the most frequently used atypical antipsychotic in
 PregnancyClinical experience and early data suggest risperidone is safe and
effective for behavioral disturbances in children and adolescents
Children and adolescents using risperidone may need to be
better

✽ Recommended either to discontinue drug or bottle feedPsychotic symptoms may worsen during pregnancy and some form
Early findings of infants exposed to risperidone in utero do not show
adverse consequences
When administered to pregnant rats and rabbits, risperidone was not
teratogenic at doses up to 6 times the maximum recommended
human dose (MRHD); increased stillbirths and decreased birth
weight occurred at 1.5 times the MRHD when administered to
pregnant rats
Risperidone may be preferable to anticonvulsant mood stabilizers if
961-2388,
Infants of women who choose to breast feed while on risperidone

961-2388,

✽ Often a preferred treatment for dementia with aggressive features
✽ Often a preferred atypical antipsychotic for children with
behavioral disturbances of multiple causations
✽ Noncompliant patients (LAI risperidone)
✽ Long-term outcomes may be enhanced when compliance is
enhanced (LAI risperidone)
Primary T arget SymptomsSome cases of psychosis and bipolar disorder refractory to treatment

Pearls
✽ Well accepted for treatment of behavioral symptoms in children and
adolescents, but may have more sedation and weight gain in pediatric
populations than in adult populationsAggressive symptoms
Well accepted for treatment of agitation and aggression in elderly
demented patients; however , numerous treatments are in late-stage
clinical development for agitation and psychosis in dementia and
will likely become first-line treatments rather than risperidone if
approved
Many anecdotal reports of utility in treatment-refractory cases and
for positive symptoms of psychosis in disorders other than
Less sedation than some antipsychotics, more than others
Increased risk of stroke may be most relevant in the elderly with
atrial fibrillation

Long-Acting InjectablesPatients with inadequate responses to atypical antipsychotics may
Minimum therapeutic level is 28 ng/mL, with point of futility of 1 12
ng/mL (of active moiety , i.e., risperidone plus paliperidone)
of either

ConstaConsta
Tmax 21 days
T1/2 with multiple dosing 3–6 days
Time to reach steady state 6 weeks (4 injections)
Able to be loaded No
Needle gauge 20 or 21
Dosage forms 12.5 mg, 25 mg, 37.5 mg, 50 mg
Injection volume 2 mL
Perseris
Tmax 2 peaks: first at 4 –6 hours and
second at 10 –14 days
Time to reach steady state 2 months (2 injections)
Able to be loaded No (oral supplementation not
needed)
Dosing schedule 1 month
Injection site Abdomen (subcutaneous)

Perseris
Needle gauge 18
Dosage forms 90 mg, 120 mg
How to Dose
Dosing T ips –DepotConsta: 12.5 –50 mg every 2 weeks (deep intramuscular)
Perseris: 90 or 120 mg every month (subcutaneous)
tolerability to oral risperidone (in clinical trials, 2 oral or short-
Conversion from oral to Consta: oral coverage is required for 3 –4
weeks; 2 mg oral risperidone is approximately 25 mg LAI every 2
weeks
Conversion from oral to Perseris: no loading or oral
supplementation; dose may be initiated at 90 mg (corresponding to 3
mg oral) or 120 mg (corresponding to 4 mg oral); administered once
a month by subcutaneous injection in the abdomen
elimination rate constant, thus resulting in “flip-flop ” kinetics; i.e.,

Dosing T ips –Constatime to steady state is a function of absorption rate, while
cross-titration from oral antipsychotic or to subtherapeutic
not receiving (or adhering to) oral supplementation; the exception is
Perseris, which does not require loading or oral supplementation

Advantages: also indicated for bipolar I maintenance (adjunct);
pharmacokinetics are linear and stable over time

Dosing T ips –PerserisDisadvantages: Tmax is long (21 days) and loading is not possible,
thus necessitating oral coverage for 3 –4 weeks; split doses are not
possible since drug is not in a solution (i.e., half a syringe is not
necessarily half the drug dose); vials require refrigeration storage
Response threshold is generally 20 ng/mL; the tolerability threshold
is poorly defined
Changes in blood levels due to dosage changes (or missed dose) are
not apparent for 3 –4 weeks, so titration should occur at intervals of
no less than 4 weeks
Two dif ferent dosage strengths of LAI risperidone should not be
combined in a single administration
Missed dose: if dose is 2 or more weeks late, oral coverage for 3
weeks while reinitiating injections may be necessary
Steady-state plasma concentrations are maintained for 4 –6 weeks
after the last injection
Does not require loading or oral supplementation
The delivery system hardens upon contact with bodily fluids,

subsequently releasing the active drug at a controlled rate and for an
extended period of time
There are two absorption peaks: the first occurs 4 –6 hours after
injection due to an initial release of the active drug during the depot
formation process; the second occurs 10 –14 days days after the

Switching fr om Oral Antipsychotics to Risperidone Micr ospher es
injection, with similar magnitude and at levels that approach steady
state; thus, no oral supplementation or loading is necessary
90 mg and 120 mg doses correspond to 3 and 4 mg doses of oral
risperidone, respectively
Discontinuation of oral antipsychotic can begin following a 3 –4
week oral coverage period

 Switching fr om Oral Antipsychotics to Risperidone
begin risperidone at an intermediate dose
Concomitant use with paliperidone ER is not recommended;
paliperidone ER is the active metabolite of risperidone, and the
combination of the 2 may lead to additive active antipsychotic
fraction exposure

Citrome  L . Sustained-release risperidone via subcutaneous injection: a
systematic review of RBP-7000 (PERSERIS ™) for the treatment of
schizophrenia  . Clin Schizophr Relat Psychoses  2018  ;12 (3 ):130–41 .
Moller  HJ . Long-acting injectable risperidone for the treatment of
schizophrenia: clinical perspectives  . Drugs  2007  ;67 (11 ):1541 –66 .

35 .
Scott  LJ , Dhillon  S . Risperidone: a review of its use in the treatment of
irritability associated with autistic disorder in children and adolescents  .
Paediatr Drs  2007  ;9 (5 ):343–54 .
60 .
Wilson  WH . A visual guide to expected blood levels of long-acting
injectable risperidone in clinical practice  . J Psychiatr Pract  2004  ;10 :393
–401 .

Rivastigmine
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Exelon
(ACh-EI)
Cholinesterase inhibitor (acetylcholinesterase inhibitor and
butyrylcholinesterase inhibitor); cognitive enhancer
Parkinson ’s disease dementia (mild to moderate)

✽ Pseudoirreversibly inhibits centrally active acetylcholinesterase
(AChE), making more acetylcholine available
✽ Inhibits butyrylcholinesterase (BuChE)
If It W orks
evident

interest
Tests
Notable Side EffectsDivalproex, carbamazepine, or oxcarbazepine for behavioral
Peripheral inhibition of butyrylcholinesterase can cause

✽ Nausea, diarrhea, vomiting, appetite loss, weight loss, dyspepsia,
increased gastric acid secretion
Sedation
What to Do About Side EffectsHeadache, dizziness
Fatigue, asthenia, sweating
Wait
Wait
Wait

How to Dose
 Dosing T ipsConsider lowering dose, switching to a dif ferent agent or adding an
Oral: 6 –12 mg/day in 2 doses
Transdermal: 9.5 mg/24 hours once daily
Transdermal 9 mg/5 cm2 (4.6 mg/24 hours), 18 mg/10 cm2 (9.5
mg/24 hours), 27 mg/15 cm2 (13.3 mg/24 hours)
Oral: initial 1.5 mg twice daily; increase by 3 mg every 2 weeks;
titrate to tolerability; maximum dose generally 6 mg twice daily
Transdermal: initial 4.6 mg/24 hours; after 4 weeks increase to 9.5
mg/24 hours; maximum recommended dose 13.3 mg/24 hours

✽ If restarting treatment after a lapse of several days or more, dose
titration should occur as when starting drug for the first timeIncidence of nausea is generally higher during the titration phase
than during maintenance treatment
Oral doses between 6 –12 mg/day have been shown to be more
effective than doses between 1 –4 mg/day
Recommended to take oral rivastigmine with food
Rapid dose titration increases the incidence of gastrointestinal side
effects
For transdermal formulation, dose increases should occur after a
minimum of 4 weeks at the previous dose and only if the previous
dose was well tolerated
Transdermal patch should only be applied to dry , intact skin on the
upper torso or another area unlikely to rub against tight clothing
Plasma exposure with transdermal rivastigmine is 20 –30% lower
when applied to the abdomen or thigh as compared to the upper
back, chest, or upper arm
New application site should be selected for each day; patch should

be applied at approximately the same time every day; only one patch
should be applied at a time; patches should not be cut; new patch
should not be applied to the same spot for at least 14 days

Overdose
Habit FormingSwitching from oral formulation to transdermal formulation:
patients receiving oral rivastigmine <6 mg/day can switch to 4.6
mg/24 hours transdermal; patients receiving oral rivastigmine 6 –12
mg/day can switch to 9.5 mg/24 hours transdermal; apply the first
patch on the day following the last oral dose
Can be ef fective in many patients for several years
No

How to Stop
Elimination half-life 1 –2 hours
Not hepatically metabolized; no CYP450-mediated pharmacokinetic
Rivastigmine may increase the ef fects of anesthetics and should be
Rivastigmine may interact with anticholiner gic agents and the
Clearance of rivastigmine may be increased by nicotine
disease

✽ Severe vomiting with esophageal rupture may occur if rivastigmine
therapy is resumed without retitrating the drug to full dosing
Do Not Use
Special PopulationsNot recommended in combination with metoclopramide due to risk
of drug-induced parkinsonism
Individuals with low body weight may be at greater risk for adverse
effects
If there is a proven aller gy to rivastigmine or other carbamates

Elderly
 PregnancyDose adjustment not necessary; titrate to point of tolerability
Dose adjustment not necessary; titrate to point of tolerability
Syncopal episodes have been reported with the use of rivastigmine

Unknown if rivastigmine is secreted in human breast milk, but all
Rivastigmine is not recommended for use in nursing women
Theoretically , butyrylcholinesterase inhibition centrally could
enhance therapeutic ef ficacy
May be useful in some patients who do not respond to or do not
tolerate other cholinesterase inhibitors
Later stages or rapidly progressive Alzheimer disease

 Pearls
disinhibition, delusions, anxiety , lack of cooperation, pacing)Theoretically , butyrylcholinesterase inhibition peripherally could
enhance side ef fects
weeks

weeks

Alzheimer disease and a cholinesterase inhibitor like rivastigmine

be delayed
preserved

✽ May cause more gastrointestinal side ef fects than some other
cholinesterase inhibitors, especially if not slowly titratedDelay in progression in Alzheimer disease is not evidence of
Cholinesterase inhibitors like rivastigmine depend upon the
presence of intact tar gets for acetylcholine for maximum
effectiveness and thus may be most ef fective in the early stages of
The most prominent side ef fects of rivastigmine are gastrointestinal
At recommended doses, transdermal formulation may have lower
incidence of gastrointestinal side ef fects than oral formulation

✽ More potent inhibitor of the G1 form of acetylcholinesterase
enzyme, found in high concentrations in Alzheimer patient ’s brains,
than the G4 form of the enzyme
✽ May be more useful for later stages or for more rapidly progressive
forms of Alzheimer disease, when gliosis increases
butyrylcholinesterase
✽ Butyrylcholinesterase actively could interfere with amyloid plaque
formation, which contains this enzymeRivastigmine may be more selective for the form of
acetylcholinesterase in hippocampus (G1)
Butyrylcholinesterase action in the brain may not be relevant in
individuals without Alzheimer disease or in early Alzheimer
disease; in the later stages of the disease, enzyme actively increases
as gliosis occurs
Rivastigmine ’s effects on butyrylcholinesterase may be more
relevant in later stages of Alzheimer disease, when gliosis is
occurring
cholinesterase inhibitor may respond when switched to rivastigmine

occurring
Some Alzheimer patients who fail to respond to rivastigmine may

✽ May slow the progression of mild cognitive impairment to
focal signs, imbalance, and urinary incontinence)
 Suggested ReadingMay decrease delusion, apathy , agitation, and hallucinations in
disorder

Birks  J , Grimley Evans  J , Iakovidou  V , Tsolaki  M , Holt FE.
Rivastigmine for Alzheimer ’s disease  . Cochrane Database Syst Rev  2009
;15 (2 ):CD001 191 .
Dhillon  S . Rivastigmine transdermal patch: a review of its use in the
management of dementia of the Alzheimer ’s type  . Drugs  2011 ;71 (9
):1209 –31 .
Alzheimer ’s disease  ? Int J Geriatr Psychiatry  2003  ;18 (Suppl 1  ):S7 –13 .

Selegiline
Brands
Generic?
Yes (oral only)
 Class
(bold for FDA appr oved)Emsam
Eldepryl
norepinephrine enzyme inhibitor
Transdermal: tissue selective monoamine oxidase (MAO) inhibitor
(MAO-A and MAO-B inhibitor in brain and relatively selective MAO-
B inhibitor in gut)
Oral: selective MAO-B inhibitor
Major depr essive disorder (transdermal)

How the Drug W orksOral: Parkinson ’s disease or symptomatic parkinsonism
Panic disorder (transdermal)
Social anxiety disorder (transdermal)
Treatment-resistant anxiety disorders (transdermal)
Alzheimer disease and other dementias (oral)
Transdermal selegiline (recommended doses): in the brain  ,
irreversibly inhibits both MAO-A and MAO-B from breaking down
norepinephrine, serotonin, and dopamine, which boosts noradrener gic,
serotoner gic, and dopaminer gic neurotransmission
Transdermal selegiline (recommended doses): in the gut , is a
relatively selective irreversible inhibitor of MAO-B (intestine and
liver), reducing the chances of dietary interactions
Oral: at recommended doses, selectively and irreversibly blocks
MAO-B, which presumably boosts dopaminer gic neurotransmission
Oral: above recommended doses, irreversibly blocks both MAO-A and
MAO-B from breaking down norepinephrine, serotonin, and dopamine

while simultaneously blocking metabolism of tyramine in the gut
Thus, high-dose oral administration is not tissue selective and is not
MAO-A sparing in the gut, and may interact with tyramine-containing
foods to cause hypertension

If It W orksOnset of therapeutic actions in depression with transdermal
administration is usually not immediate, but often delayed 2 –4 weeks
or longer following adequate dosing
If it is not working for depression within 6 –8 weeks, it may require a
dosage increase or it may not work at all
May continue to work in depression for many years to prevent relapse
Can enhance the actions of levodopa in Parkinson ’s disease within a
few weeks of initiating oral dosing
Theoretical slowing of functional loss in both Parkinson ’s disease and
Alzheimer disease is a provocative possibility under investigation and
would take many months or more than a year to observe
The goal of treatment in depression is complete remission of current
stopped

stopped
Continue treatment of depression until all symptoms of depression are
gone (remission)

Continue use in Parkinson ’s disease as long as there is evidence that
selegiline is favorably enhancing the actions of levodopa
Use of selegiline to slow functional loss in Parkinson ’s disease or
Alzheimer disease would be long-term if proven ef fective for this use
For depression, consider increasing dose, switching to another agent,
or adding an appropriate augmenting agent, psychotherapy , and
evaluation for another diagnosis or for a comorbid condition (e.g.,

medical illness, substance abuse, etc.)
Use alternate treatments for Parkinson ’s disease or Alzheimer disease

✽ Augmentation of selegiline has not been systematically studied in
depression, and this is something for the expert, to be done with caution
and with careful monitoring
Tests
How Drug Causes Side EffectsA stimulant such as d-amphetamine or methylphenidate (with caution
and by experts only as use of stimulants with selegiline is listed as a
warning; may activate bipolar disorder and suicidal ideation; may
elevate blood pressure)
Lithium
Carbidopa-levodopa (for Parkinson ’s disease)
Although preliminary evidence from clinical trials suggests little or no
weight gain, nonselective MAOIs are frequently associated with

 Life-Thr eatening or Danger ous Side EffectsAt recommended transdermal doses, norepinephrine, serotonin, and
dopamine increase in parts of the brain and at receptors other than
those that cause therapeutic actions
At high transdermal doses, loss of tissue selectivity and loss of MAO-
A sparing actions in the gut may enhance the possibility of dietary
tyramine interactions if MAO-B inhibition occurs in the gut
At recommended oral doses, dopamine increases in parts of the brain
and body and at receptors other than those that cause therapeutic
actions
Transdermal: application site reactions, headache, insomnia, diarrhea,
dry mouth
Oral: exacerbation of levodopa side ef fects, especially nausea,
dizziness, abdominal pain, dry mouth, headache, dyskinesia,
confusion, hallucinations, vivid dreams
Transdermal: hypertensive crisis was not observed with preliminary

experience in clinical trials, even in patients who were not following a
low-tyramine diet
Oral: hypertensive crisis (especially when MAOIs are used with
certain tryamine-containing foods or prohibited drugs) –reduced risk

Sedation
What to Do About Side Effectsat low oral doses compared to nonselective MAOIs
Theoretically , when used at high doses may induce seizures and mania
as do nonselective MAOIs
Transdermal: reported but not expected; some patients may experience
weight loss
Oral: occurs in significant minority
Can be activating in some patients
Wait
Wait
Wait
(depression)
Switch to other antiparkinsonian therapies (Parkinson ’s disease)

How to DoseTrazodone (with caution) for insomnia in depression
Benzodiazepines for insomnia in depression
Depression (transdermal): 6 mg/24 hours –12 mg/24 hours
Depression (oral): 30 –60 mg/day
Parkinson ’s disease/Alzheimer disease: 5 –10 mg/day
Transdermal patch 20 mg/20 cm2 (6 mg/24 hours), 30 mg/30 cm2 (9
mg/24 hours), 40 mg/40cm2 (12 mg/24 hours)
Capsule 5 mg
Tablet 5 mg scored
Orally disintegrating tablet 1.25 mg
Depression (transdermal): initial 6 mg/24 hours; can increase by 3
mg/24 hours every 2 weeks; maximum dose generally 12 mg/24 hours
Parkinson ’s disease: initial 2.5 mg/day twice daily; increase to 5 mg
twice daily; reduce dose of levodopa after 2 –3 days

Transdermal patch contains 1 mg of selegiline per 1 cm2 and delivers
approximately 0.3 mg of selegiline per cm2 over 24 hours
Patch is available in three sizes –20 mg/20 cm2 , 30 mg/30 cm2 , and
40 mg/40 cm2 –that deliver doses of approximately 6 mg, 9 mg, and
12 mg, respectively , over 24 hours
At 6 mg/24 hours (transdermal) dietary adjustments are not generally
required
Dietary modifications to restrict tyramine intake from foods are
recommended for doses above 6 mg/24 hours (transdermal)
upper torso, upper thigh, or outer surface of the upper arm
New application site should be selected for each day; patch should be
applied at approximately the same time every day; only one patch
In cases of topical aller gic reaction, it is likely due to adhesive, so
consider cutting of f adhesive and use nonaller gic tape to hold patch on

application, wash  hands  with soap and water; do not touch eyes until
Heat could theoretically increase the amount of selegiline absorbed
from the transdermal patch, so patients should avoid exposing the
application site to external sources of direct heat (e.g., heating pads,
prolonged direct sunlight)

OverdoseAlthough there is theoretically a 3-day reservoir of drug in each patch,
multiday administration from a single patch is generally not
recommended and has not been tested; because of residual drug in the
patch after 24 hours of administration, discard used patches in a
manner that prevents accidental application or ingestion by children,
pets, or others
For Parkinson ’s disease, oral dosage above 10 mg/day generally not
Dosage of carbidopa-levodopa can at times be reduced by 10 –30%
after 2 –3 days of administering oral selegiline 5 –10 mg/day in
Parkinson ’s disease
At doses above 10 mg/day (oral), selegiline may become nonselective
and inhibit both MAO-A and MAO-B
At doses above 30 mg/day (oral), selegiline may have antidepressant
Patients receiving high oral doses may need to be evaluated
periodically for ef fects on the liver
Doses above 10 mg/day (oral) may increase the risk of hypertensive

crisis, tyramine interactions, and drug interactions similar to those of
phenelzine and tranylcypromine
Overdose with the transdermal formulation is likely to produce
substantial amounts of MAO-A inhibition as well as MAO-B

How to Stop
Pharmacokineticsinhibition, and should be treated the same as overdose with a
nonselective oral MAOI
Dizziness, anxiety , ataxia, insomnia, sedation, irritability , headache;
cardiovascular ef fects, confusion, respiratory depression, coma
Long-term use has not been systematically studied although generally
recommended for chronic use as for other antidepressants
Lack of evidence for abuse potential with transdermal selegiline
despite its metabolism to l-amphetamine and l-methamphetamine
Dependence to other MAOIs reported but rare
Transdermal: MAOI slowly recovers over 2 –3 weeks after patch
removed
Oral: generally no need to taper , as the drug wears of f slowly over 2 –3
weeks
Major metabolite of selegiline is desmethylselegiline; other
metabolites are l-methamphetamine and l-amphetamine

Drug InteractionsBecause first-pass metabolism is not extensive with transdermal
dosing, this results in notably higher exposure to selegiline and lower
With transdermal selegiline, 25 –30% of selegiline content is delivered
systemically over 24 hours from each patch
Mean half-life of transdermal selegiline is approximately 18 –25 hours
Steady-state mean elimination half-life of oral selegiline is
approximately 10 hours
Many misunderstandings about what drugs can be combined with
MAOIs
Theoretically and especially at high doses, selegiline could cause a
fatal “serotonin syndrome ” when combined with drugs that block
serotonin reuptake, so do not use with a serotonin reuptake inhibitor
for up to 5 half-lives after stopping the serotonin reuptake inhibitor
(i.e., “wash-in ” of selegiline should be about 1 week after
discontinuing most agents [except 5 weeks or more after discontinuing

fluoxetine because of its long half-life and that of its active
metabolite]) (see Table 1  after Pearls)
When discontinuing selegiline ( “wash-out ” period), wait 2 weeks
before starting another antidepressant in order to allow enough time
for the body to regenerate MAO enzyme
Transdermal: no pharmacokinetic drug interactions present in studies
with alprazolam, ibuprofen, levothyroxine, olanzapine, risperidone,

Do Not Use:
SNRIs Cocaine Tramadol Chlorpheniramineand warfarin
Tramadol (a serotonin reuptake inhibitor) may increase the risk of
may result from combining nonselective MAOIs with
sympathomimetic drugs (e.g., amphetamines, methylphenidate,
cocaine, dopamine, epinephrine, norepinephrine)
Adverse drug reactions can result from combining MAOIs with
Carbamazepine increases plasma levels of selegiline

Do Not Use:
injected
Ingestion of a “high-tyramine meal ” is generally defined as 40 mg or
more of tyramine in the fasted state
Studies show that 200 –400 mg of tyramine in the fasted state (and
even more ingestion of tyramine in the fed state) may be required for a
hypertensive response with administration of the low-dose transdermal
patch (6 mg/24 hours); thus, no dietary precautions are required at this
dose
Tyramine sensitivity of the low-dose transdermal patch (6 mg/24
hours) may be comparable to that of low-dose oral selegiline (10 mg)
with neither causing a hypertensive reaction to high-tyramine meals
Tyramine sensitivity and hypertensive responses to the high-dose
transdermal patch (12 mg/24 hours) may occur with administration of

70–100 mg of tyramine in the fasted state, so dietary restrictions may

also not be necessary at 9 mg/24 hours or 12 mg/24 hours of
transdermal administration of selegiline
However , insuf ficient studies have been performed to be sure of the
safety of transdermal administration at 9 mg/24 hours or 12 mg/24
hours
Oral administration of nonselective irreversible MAOIs generally
requires adherence to a low-tyramine diet (see Table 2  after Pearls)
Ingestion of a “high-tyramine meal, ” defined as 40 mg or more of
tyramine in the fasted state or as little as ingestion of 10 mg of
tyramine in the fasted state, can cause hypertensive reactions in
patients taking a nonselective irreversible MAOI orally
Food restrictions (see Table 2  after Pearls) are generally recommended
for patients taking the higher doses of transdermal selegiline (9 mg/24
hours or 12 mg/24 hours) but not for the lower doses of transdermal
selegiline (6 mg/24 hours) or for the low dose orally (10 mg)
Transdermal: studies of low-dose transdermal administration of

selegiline (6 mg/24 hours) failed to show changes in systolic or
diastolic blood pressure or pulse when administered to normal
volunteers taking either pseudoephedrine 60 mg three times a day for
2 days or 25 mg of phenylpropanolamine (no longer commercially
available in the USA) every 4 hours for 1 day
However , sufficient safety information is not available to recommend
administration of pseudoephedrine without a precaution; blood
pressure should be monitored if low-dose transdermal selegiline is
given at all with pseudoephedrine

Pseudoephedrine may need to be avoided when administering
transdermal selegiline, particularly at higher doses of selegiline or in
vulnerable patients with hypertension
Although risk may be reduced with transdermal administration of
selegiline, patient and prescriber must be vigilant to potential
interactions with any drug, including antihypertensives and over -the-
counter cough/cold preparations
Over -the-counter medications to avoid or use with caution under the
care of an expert include cough and cold preparations, including those
containing dextromethorphan (a serotonin reuptake inhibitor), nasal
decongestants (tablets, drops, or spray), hay-fever medications, sinus
medications, asthma inhalant medications, anti-appetite medications,
weight reducing preparations, “pep” pills (see Table 3  after Pearls)
Certain transdermal patches containing even small traces of aluminum
or other metals in the adhesive backing can cause skin burns if worn

during MRI, so warn patients taking the transdermal formulation about
this possibility and advise them to disclose this information if they
need an MRI
antidiabetic agents (more so with hydrazine MAOIs)
Use cautiously in patients receiving reserpine, anesthetics, disulfiram,
Selegiline is not recommended for use in patients who cannot be

cheese
low tyramine amounts
** Not necessary for 6 mg transdermal or low-dose oral selegilineOnly use sympathomimetic agents or guanethidine with oral doses of
selegiline below 10 mg/day

with MAOIs
with
reuptake
Cocaine
Modafinil
Do Not Use
If patient is taking meperidine (pethidine) (a serotonin reuptake
If patient is taking dextromethorphan (a serotonin reuptake inhibitor)

Cardiac ImpairmentIf patient is taking diuretics or other antihypertensives without careful
If patient is taking St. John ’s wort, cyclobenzaprine, methadone,
propoxyphene
If patient is under going elective sur gery and requires general
anesthesia
If there is a proven aller gy to selegiline
No dose adjustment necessary for transdermal administration in
patients with mild to moderate renal impairment
Use oral administration with caution –drug may accumulate in plasma
in patients with renal impairment
Oral administration may require lower than usual adult dose
patients with mild to moderate hepatic impairment

Elderly
 PregnancyMay require lower than usual adult dose
Observe closely for orthostatic hypotension
Recommended dose for patients over 65 years old is 20 mg oral and 6
mg/day transdermal
Dose increases in the elderly should be made with caution and patients
should be observed for postural changes in blood pressure throughout
treatment
Not recommended for use in children under 18
patients

Breast FeedingEffective June 30, 2015, the US FDA requires changes to the content
sants

sants

 PearlsTreatment-resistant depression
Patients with atypical depression (hypersomnia, hyperphagia)
Patients who wish to avoid weight gain and sexual dysfunction
Parkinson ’s patients inadequately responsive to levodopa
Patients with motor complications and fluctuations on levodopa
treatment
Depressed mood (depression)
Somatic symptoms (depression)
Sleep and eating disturbances (depression)
Psychomotor disturbances (depression)
Motor symptoms (Parkinson ’s disease)
Transdermal administration may allow freedom from dietary

✽ Enhancement of levodopa action can occur for Parkinson ’s patients at
low oral doses, but antidepressant actions probably require high oral
doses that do not have the potential tissue selectivity and lack of dietary
restrictions of the low-dose transdermal formulation
✽ High doses may lose safety featuresTransdermal selegiline theoretically appealing as a triple action agent
(serotonin, norepinephrine, and dopamine) for treatment-refractory
and dif ficult cases of depression
Transdermal selegiline may have low risk of weight gain and sexual
dysfunction, and may be useful for cognitive dysfunction in attention
deficit disorder and other cognitive disorders, as it increases dopamine
and is metabolized to l-amphetamine and l-methamphetamine
Low-dose oral administration generally used as an adjunctive
treatment for Parkinson ’s disease after other drugs have lost ef ficacy
At oral doses used for Parkinson ’s disease, virtually no risk of
interactions with food

Neuroprotective ef fects are possible but unproved

✽ Combining multiple psychotropic agents with MAOIs should be for
the expert, especially if combining with agents of potential risk (e.g.,
stimulants, trazodone, TCAs)
treatment-resistant
Bodkin  JA , Amsterdam  JD . Transdermal selegiline in major depression: a
double-blind, placebo-controlled, parallel-group study in outpatients  . Am J
Psychiatry  2002  ;159 (11 ):1869 –75 .
2018  ;125 (11 ):1707 –17 .
1997  ;22 :127–31 .Myths about the danger of dietary tyramine can be exaggerated, but

enough

Sertindole
Brands
Generic?
No
 Class
(bold for FDA appr oved)Serdolect
Schizophrenia (for patients intolerant to at least one other

✽ Serotonin 2C properties may contribute to antidepressant actions
If It W orksBipolar maintenance

If It Doesn ’t WorkMost schizophrenia patients do not have a total remission of
treatment
clozapine

TestsIf no first-line atypical antipsychotic is ef fective, consider higher
injection
Lithium
Baseline ECG, serum potassium, and serum magnesium
measurements
ECG should be repeated upon reaching steady state about 3 weeks
after treatment initiation or upon reaching 16 mg/day , at 3 months,

plasma glucose, and fasting lipid profileand then every 3 months for the duration of treatment
ECG is recommended prior to and after any dose increase as well as
after addition of any drug that can change sertindole concentration
(e.g., CYP450 2D6 or 3A4 inhibitors)

Should check blood pressure during titration and early maintenance
treatment

✽ May increase risk for diabetes and dyslipidemiaBlocking alpha 1 adrener gic receptors can cause dizziness,
Dizziness, dry mouth, nasal congestion
Weight gain, peripheral edema, decreased ejaculatory volume

Sedation
Wait

How to Dose
Overdose
Habit Forming12–20 mg/day
Tablet 4 mg, 12 mg, 16 mg, 20 mg
Initial 4 mg/day; increase by 4 mg every 4 –5 days; maximum dose
generally 24 mg/day
A starting dose of 8 mg or a rapid increase in dose significantly
increase risk of orthostatic hypotension
Sertindole should be discontinued if QT c interval of more than 500
msec is observed during treatment
Fatalities have been reported; sedation, slurred speech, tachycardia,
hypotension, transient QT c prolongation; torsade de pointes

How to Stop
Terminal half-life approximately 3 days
Extensively metabolized by CYP450 2D6 and 3A
quinidine) may significantly increase plasma levels of sertindole and
require a dosage reduction of sertindole
Inhibitors of CYP450 3A (e.g., nefazodone, fluvoxamine,
fluoxetine, ketoconazole) can increase plasma levels of sertindole
and concomitant use of these agents with sertindole is

Do Not UseUse with caution in patients with conditions that predispose to
sertindole should be used cautiously in patients at risk for aspiration
pneumonia
Sertindole prolongs QT c interval more than some other

therapy

Hepatic ImpairmentIf patient is taking agents capable of significantly prolonging QT c
If there is a personal or family history of QT c prolongation
If there is a history of significant cardiovascular illness, including
congestive heart failure, cardiac hypertrophy , arrhythmia,
bradycardia, or congential prolonged QT syndrome
If patient has hypokalemia, hypomagnesemia, or QT c greater than
450 msec (males) or 470 msec (females)
If patient is taking a CYP450 3A inhibitor
If there is a proven aller gy to sertindole
For mild to moderate impairment, use slower titration and lower
maintenance dose

Elderly
 Childr en and AdolescentsContraindicated in patients with severe hepatic impairment
Drug should be used with caution because of risk of orthostatic
illness, including congestive heart failure, cardiac hypertrophy ,
arrhythmia, bradycardia, or congential prolonged QT syndrome
Use cautiously and only after thorough cardiovascular examination
agitation

Children and adolescents using sertindole may need to be monitored

Pregnancy
Potential AdvantagesSome animal studies show adverse ef fects; no controlled studies in
humans
Unknown if sertindole is secreted in human breast milk, but all
Infants of women who choose to breast feed while on sertindole

 Pearls
 Suggested ReadingPatients requiring rapid onset of antipsychotic action without dosage
titration
Aimed at patients intolerant to at least one other antipsychotic and
when potential benefits outweigh potential risks
acute schizophrenia are generally also useful for acute bipolar mania
potential use in treatment-resistant and bipolar depression, though
probably not as a first- or second-line agent given the need to
accumulate more real-world clinical experience of any actual risks
of sertindole

Komossa  K , Rummel-Kluge  C , Hunger  H , et al. Sertindole versus other
2009  ;(2) :CD006752  .
Lindstrom  E , Farde  L , Eberhard  L , Haverkamp  W . QTc interval
prolongation and antipsychotic drug treatments: focus on sertindole  . Int J
Neur opsychopharmacol  2005  ;8 :615–29 .
Spina  E , Zoccali  R . Sertindole: pharmacological and clinical profile and
role in the treatment of schizophrenia  . Expert Opin Drug Metab T oxicol
2008  ;4 :629–38 .

Sertraline
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Zoloft
RI)

✽ Sertraline also has some ability to block dopamine reuptake pump
(dopamine transporter), which could increase dopamine
neurotransmission and contribute to its therapeutic actions
after initiation of treatmentSocial anxiety disorder (social phobia)
Sertraline also binds at sigma 1 receptors
symptoms

In the USA, sertraline (Zoloft) is commonly augmented with
bupropion (W ellbutrin) with good results in a combination
anecdotally called “Well-loft ” (use combinations of antidepressants
ideation)
Mirtazapine, reboxetine, or atomoxetine (add with caution and at
lower doses since sertraline could theoretically raise atomoxetine
levels); use combinations of antidepressants with caution as this
may activate bipolar disorder and suicidal ideation

Tests
✽ Increasing serotonin can cause diminished dopamine release and
might contribute to emotional flattening, cognitive slowing, and apathy
in some patients, although this could theoretically be diminished in
some patients by sertraline ’s dopamine reuptake blocking propertiesBenzodiazepines
tiagabine

 Life-Thr eatening or Danger ous Side EffectsSertraline ’s possible dopamine reuptake blocking properties could
contribute to agitation, anxiety , and undesirable activation,
especially early in dosing
dry mouth)
SSRIs
reversible on discontinuation of sertraline)

Sedation
Some patients may actually experience weight loss
Possibly activating in some patients
Wait
Wait
Wait
If sertraline is activating, take in the morning to help reduce
insomnia

Best Augmenting Agents for Side EffectsReduce dose to 25 mg or even 12.5 mg until side ef fects abate, then
increase dose as tolerated, usually to at least 50 mg/day

discontinuation of sertraline

How to Dose
 Dosing T ips50–200 mg/day
Tablet 25 mg scored, 50 mg scored, 100 mg
Oral solution 20 mg/mL
Depression and OCD: initial 50 mg/day; usually wait a few weeks to
assess drug ef fects before increasing dose, but can increase once a
week by 50 mg/day; maximum generally 200 mg/day; single dose
Panic, PTSD, and social anxiety: initial 25 mg/day; increase to 50
mg/day after 1 week thereafter , usually wait a few weeks to assess
drug ef fects before increasing dose, but can increase once a week by
25–50 mg/day; maximum generally 200 mg/day in a single dose
PMDD: initial 50 mg/day; can dose daily through the menstrual
cycle (up to 150 mg/day) or limit to the luteal phase (up to 100
mg/day)
Oral solution: mix with 4 oz of water , ginger ale, lemon/lime soda,
lemonade, or orange juice only; drink immediately after mixing

OverdoseAll tablets are scored, so to save costs, give 50 mg as half of 100 mg
tablet, since 100 mg and 50 mg tablets cost about the same in many
markets
Give once daily , often in the mornings to reduce chances of
insomnia
Many patients ultimately require more than 50 mg dose per day
Some patients are dosed above 200 mg
Evidence that some treatment-resistant OCD patients may respond
safely to doses up to 400 mg/day , but this is for experts and use with
caution
stabilizer or atypical antipsychotic
Utilize half a 25 mg tablet (12.5 mg) when initiating treatment in

patients with a history of intolerance to previous antidepressants
rhythm disturbances, dilated pupils, agitation; fatalities have been
reported in sertraline overdose combined with other drugs or alcohol

How to Stop
No
Parent drug has 22 –36 hour half-life
Metabolite half-life 62 –104 hours
Inhibits CYP450 2D6 (weakly at low doses)
Inhibits CYP450 3A4 (weakly at low doses)

switching from a TCA to sertraline
drugs) after discontinuing sertraline
Via CYP450 2D6 inhibition, sertraline could theoretically interfere
Via CYP450 2D6 inhibition sertraline could theoretically increase

Via CYP450 3A4 inhibition, sertraline may increase the levels of

Other W arnings/Pr ecautionsVia CYP450 3A4 inhibition, sertraline could theoretically increase
rhabdomyolysis; thus, coadministration of sertraline with certain
Via CYP450 3A4 inhibition, sertraline could theoretically increase
False-positive urine immunoassay screening tests for
benzodiazepine have been reported in patients taking sertraline due
to a lack of specificity of the screening tests. False-positive results
may be expected for several days following discontinuation of

sertraline
after discontinuing sertraline

Do Not Use
Renal ImpairmentWhen treating children, carefully weigh the risks and benefits of
companies
Use of sertraline oral concentrate is contraindicated with disulfiram
due to the alcohol content of the concentrate
If there is a proven aller gy to sertraline

Elderly
 Childr en and AdolescentsNo dose adjustment
Proven cardiovascular safety in depressed patients with recent
myocardial infarction or angina
Should be used with caution in patients with risk factors for QT c
prolongation
Some patients may tolerate lower doses and/or slower titration better

patients
Approved for use in OCD
Ages 6 –12: initial dose 25 mg/day
Ages 13 and up: adult dosing
Long-term ef fects, particularly on growth, have not been studied

pregnancy

Breast Feedingdifficulty , vomiting, hypoglycemia, hypotonia, hypertonia,
essants
are on sertraline
Sertraline has shown ef ficacy in treating postpartum depression
the mother

Primary T arget SymptomsPatients with atypical depression (hypersomnia, increased appetite)
Patients who wish to avoid hyperprolactinemia (e.g., pubescent
children, girls and women with galactorrhea, girls and women with
unexplained amenorrhea, postmenopausal women who are not
taking estrogen replacement therapy)
Patients who are sensitive to the prolactin-elevating properties of
other SSRIs (sertraline is the one SSRI that generally does not
elevate prolactin)
Initiating treatment in anxious patients with some insomnia
Patients with comorbid irritable bowel syndrome
Can require dosage titration
Anxiety

Pearls
✽ May be a type of “dual action ” agent with both potent serotonin
reuptake inhibition and less potent dopamine reuptake inhibition, but
the clinical significance of this is unknown
hypersomnia, hyperphagia, low ener gy, mood reactivity)Sleep disturbance, both insomnia and hypersomnia (eventually , but
Cognitive and af fective “flattening ” may theoretically be diminished
in some patients by sertraline ’s dopamine reuptake blocking
Best documented cardiovascular safety of any antidepressant,
proven safe for depressed patients with recent myocardial infarction
or angina
May bind to sigma 1 receptors, enhancing sertraline ’s anxiolytic
actions
Can have more gastrointestinal ef fects, particularly diarrhea, than
some other antidepressants
May be more ef fective treatment for women with PTSD or

actions
depression than for men with PTSD or depression, but the clinical
significance of this is unknown

Cipriani  A , La Ferla  T , Furukawa  TA , et al. Sertraline versus other
antidepressive agents for depression  . Cochrane Database Syst Rev  2010SSRIs may be less ef fective in women over 50, especially if they are
vardenafil, tadalafil, or switch to a non-SSRI such as bupropion or
sertraline plus estrogen augmentation than to sertraline alone
Nonresponse to sertraline in elderly may require consideration of
Not as well tolerated as some SSRIs for panic, especially when
dosing is initiated, unless given with co-therapies such as
benzodiazepines or trazodone
Relative lack of ef fect on prolactin may make it a preferred agent for
some children, adolescents, and women

Some evidence suggests that sertraline treatment during only the

;14 (4 ):CD0061 17 .
DeVane CL , Liston  HL , Markowitz  JS . Clinical pharmacokinetics of
sertraline  . Clin Pharmacokinet  2002  ;41 :1247 –66 .
Flament  MF , Lane  RM , Zhu R , Ying Z . Predictors of an acute
antidepressant response to fluoxetine and sertraline  . Int Clin
Psychopharmacol  1999  ;14 :259–75 .
Khouzam  HR , Emes  R , Gill T , Raroque  R . The antidepressant sertraline:
a review of its uses in a range of psychiatric and medical conditions  .
Compr Ther  2003  ;29 :47 –53 .
McRae  AL , Brady  KT . Review of sertraline and its clinical applications in
psychiatric disorders  . Expert Opin Pharmacother  2001  ;2 :883–92 .

Sildenafil
Brands
Generic?
Yes
 Class
 How the Drug W orksViagraRevatio
Phosphodiesterase-5 (PDE-5) inhibitor
Erectile dysfunction (V iagra)
Pulmonary arterial hypertension (Revatio)
PDE-5 is responsible for degradation of cyclic guanosine
monophosphate (cGMP); cGMP produces smooth muscle relaxation
in the corpus cavernosum and allows inflow of blood

If It W orks
Can increase dose to 100 mg if not already tried
If there is no improvement, discontinue use
TestsInhibition of PDE-5 causes increased levels of cGMP in the corpus
cavernosum, resulting in smooth muscle relaxation and inflow of
blood to the corpus cavernosum
Sildenafil has no direct relaxant ef fects on isolated human corpus
carvernosum, and at recommended doses has no ef fect in the
absence of sexual stimulation
Maximum observed plasma concentrations are reached within 30 –
120 minutes (median 60 minutes) of oral dosing
Increases ability to achieve and sustain an erection suf ficient for
satisfactory sexual activity
None known

Headache
Flushing
Dyspepsia (indigestion, diarrhea)
Sedation
Inhibition of PDE-5 in tissues not associated with erectile
dysfunction
Sudden severe loss of vision and/or blurred vision
Sudden decrease or loss of hearing, ringing in ears
Erection that is painful or lasts longer than 4 hours

Over -the-counter medications for headache or dyspepsia
Sildenafil itself is used to treat erectile dysfunction as a side ef fect of
medications, notably paroxetine
Reduce dose to 25 mg
Erectile dysfunction: 25 –100 mg as needed, approximately 1 hour
before sexual activity (V iagra)
Pulmonary arterial hypertension (tablet and oral suspension): 5 mg
or 20 mg three times a day , 4–6 hours apart
Tablet 25 mg, 50 mg, 100 mg (V iagra)
Tablet 5 mg, 20 mg (Revatio)
Injectable solution 10 mg/12.5 mL (Revatio)
Oral suspension 10 mg/mL (Revatio)

How to Dose
Maximum recommended dosing frequency is once per day
Can adjust dose to a maximum of 100 mg or decrease to 25 mg
depending on ef ficacy and tolerability
Overdose
How to Stop50 mg as needed, recommended approximately 1 hour before sexual
activity; however , may be taken anywhere from 30 minutes to 4
hours before sexual activity
Similar symptoms as at usual doses, but incidence rates and severity
are increased
Safe
No
When used for erectile dysfunction, sildenafil is administered as
needed

CYP450 3A4 inhibitors (e.g., ritonavir , ketoconazole, itraconazole,
erythromycin, fluvoxamine, fluoxetine) can increase plasma levels of
sildenafil
In patients taking ritonavir , maximum single dose is 25 mg in a 48-
hour period
In patients taking erythromycin or strong CYP450 3A4 inhibitors,
consider a starting dose of 25 mg
Additive blood pressure lowering ef fects may occur with concomitant
use of nitrates, alpha blockers, and antihypertensives
If coadministered with an alpha blocker , the patient should be stable on
the alpha blocker prior to initiating sildenafil; starting dose of
sildenafil should be 25 mg
 Other W arnings/Pr ecautionsMaximum observed plasma concentrations are reached within 30 –
Metabolized to an active metabolite, primarily by CYP450 3A4
(major route) and CYP450 2C9 (minor route)
Parent drug and its active metabolite have approximately 4-hour
terminal half-lives

Absorption is delayed if taken with a high-fat meal

Patients should not use sildenafil if sexual activity is inadvisable due to
cardiovascular status
Patients should seek emer gency treatment if an erection lasts more
than 4 hours
Use with caution in patients who are predisposed to priapism or who
have anatomical deformation of the penis
Patients should stop taking sildenafil and seek medical attention if
sudden loss of vision occurs in one or both eyes; sildenafil should be
used only with caution in patients with a history of non-arteritic
anterior ischemic optic neuropathy (NAION)
Use with caution in patients with retinitis pigmentosa
there is a sudden decrease or loss of hearing
Use cautiously with alpha blockers or antihypertensives, as it may lead
to hypotension
Decreased blood pressure, syncope, and prolonged erection may occur
at higher sildenafil exposures
Not recommended for use in combination with other PDE-5 inhibitors
Do Not Use

Do Not Use
If patient is using or ganic nitrates in any form
If patient is taking a guanylate cyclase inhibitor
If there is a proven aller gy to sildenafil

Cardiac ImpairmentNo adjustment for mild to moderate impairment
For patients with severe impairment, consider a starting dose of 25
mg
Consider a starting dose of 25 mg
Elicits vasodilatory properties, resulting in mild and transient
decreases in blood pressure
Treatment for erectile dysfunction generally should not be instituted
in men for whom sexual activity is inadvisable because of their
underlying cardiovascular status
There are no controlled clinical data on the safety or ef ficacy of
sildenafil in patients who have suf fered a myocardial infarction,
stroke, or life-threatening arrhythmia within the last 6 months; have
resting hypotension (BP <90/50 mmHg) or hypertension (BP
>170/1 10 mmHg); or have cardiac failure or coronary artery disease
causing unstable angina; use only with caution in these patients
Use with caution in patients with left ventricular outflow obstruction

(e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) and
those with severely impaired autonomic control of blood pressure

Elderly
 Pregnancy
Not recommended for use in pediatric patients
Viagra is not indicated for use in women
Animal studies did not show teratogenicity or adverse
developmental outcomes when administered during or ganogenesis
at doses up to 16 and 32 times the maximum recommended human
dose

 Pearls
Patients should be counseled that sildenafil of fers no protection against
sexually transmitted diseases
Andersson KE.  Andersson KE.  PDE5 inhibitors –pharmacology and
clinical applications 20 years after sildenafil discovery  . Br J Pharmacol
2018  ;175 (13 ):2554  –65 .
Carson CC  Carson CC  . Long-term use of sildenafil  . Expert Opin
Pharmacother  2003  ;4 (3 ):397 –405 .Can be taken as needed
sildenafil ’s pharmacokinetic and pharmacodynamic properties

Sodium oxybate
Brands
Generic?
No
 Class
(bold for FDA appr oved)Xyrem
Neuroscience-based Nomenclature: GABA receptor agonist
CNS depressant; GABA-B receptor partial agonist
Reducing excessive sleepiness in patients with nar colepsy (ages 7
and older)
Cataplexy in patients with nar colepsy (ages 7 and older)
Chronic pain/neuropathic pain

If It W orks
If It Doesn ’t WorkGamma hydroxybutyrate (GHB) is an endogenous putative
neurotransmitter synthesized from its parent compound, GABA;
sodium oxybate is the sodium salt of GHB and is administered
exogenously
Has agonist actions at GHB receptors and partial agonist actions at
GABA-B receptors
Improves slow-wave sleep at night, presumably leaving patients
better rested and more alert during the day
Can immediately reduce daytime sleepiness
Improves daytime sleepiness and may improve fatigue in patients
with narcolepsy
Reduces frequency of cataplexy attacks
May improve sleep physiology and subjective experience of pain
and fatigue in patients with fibromyalgia and other chronic pain

✽ Sodium oxybate is itself often used as an augmenting therapy to
stimulants, modafinil, or armodafinil for excessive sleepiness in
✽ The majority of patients taking sodium oxybate in clinical trials for
narcolepsy and cataplexy were taking a concomitant stimulant
Tests
How Drug Causes Side EffectsConsider an alternative treatment
Often used as an augmenting agent for fibromyalgia with SNRIs
(e.g., duloxetine, milnacipran) and alpha 2 delta ligands (e.g.,
gabapentin, pregabalin), but has not been well studied in
combination with these agents
Unknown

Sedation
What to Do About Side EffectsHeadache, dizziness, sedation
Enuresis
Respiratory depression, especially when taken in overdose
Neuropsychiatric events (psychosis, depression, paranoia, agitation)
Confusion and wandering at night (unclear if this is true
somnambulism)
Wait

How to Dose
✽ Both nightly doses of sodium oxybate should be prepared prior to
bedtime, and the prepared second dose should be placed in closeIf unacceptable side ef fects persist, discontinue use
Discontinue concomitant medications that might be contributing to
sedation
6–9 g/night in 2 doses, 2.5 –4 hours apart
Oral solution 500 mg/mL
Initial 2.25 g at bedtime and while seated in bed; second dose of
2.25 g should be taken 2.5 –4 hours later , also while seated in bed;
dosing can be increased by 1.5 g/night every 1 –2 weeks; maximum
recommended dose 9 g/night

proximity to the patient ’s bed before the first dose is ingested
Overdose
Long-T erm UseEach dose must be diluted with 2 oz of water in a child-resistant cup
that is supplied by the pharmacist
The patient will probably need to set an alarm clock in order to
wake up for the second dose
Once prepared, the solution containing sodium oxybate should be
consumed within 24 hours in order to minimize bacterial growth and
contamination
Food significantly reduces the bioavailability of sodium oxybate, so
the patient should wait at least 2 hours after eating before taking the
first dose of sodium oxybate
It is best to minimize variability in the timing of dosing in relation to
meals
Once-nightly dosing has been studied and found ef fective in
Fatalities have been reported; headache, psychomotor impairment,
diaphoresis, vomiting (even when obtunded), confusion, agitation,
aggression, ataxia, seizures, coma, death
Long-term use has not been studied

How to Stop
 Other W arnings/Pr ecautionsMedical use of sodium oxybate is classified under Schedule III
Non-medical use of sodium oxybate is classified under Schedule I
Taper may not be necessary when used at therapeutic doses;
however , it is possible that some patients could develop withdrawal
syndrome
Elimination half-life approximately 30 –60 minutes
Absorption is delayed and decreased by high-fat meals
Should not be used in combination with CNS depressants or
sedative hypnotics

✽ Because of the rapid onset of CNS depressant ef fects, sodium
oxybate should only be ingested at bedtime and while in bed
Do Not Use
Renal ImpairmentSodium oxybate should not be used with alcohol or other CNS
depressants, including opiates
Sodium oxybate may cause CNS ef fects similar to those caused by
other CNS agents (e.g., confusion, psychosis, paranoia, agitation,
depression, and suicidality)
In patients taking sedative hypnotics
In patients with succinic semialdehyde dehydrogenase deficiency
If there is a proven aller gy to sodium oxybate (gamma
hydroxybutyrate)
Dose adjustment is not necessary
Not excreted renally

Elderly
 PregnancyBecause sodium oxybate has sodium content, this may need to be
considered in patients with renal impairment
Reduce dose by one-half and monitor patients closely
Because sodium oxybate has sodium content, this may need to be
considered in patients with hypertension or heart failure
Patients should be monitored closely
Approved for treatment of cataplexy or excessive daytime
sleepiness in pediatric patients 7 years of age and older with

✽ Generally , sodium oxybate should be discontinued prior to
anticipated pregnancies
Potential Advantagesletter categories; the Pregnancy and Lactation Labeling Rule (PLLR
Placental transfer is rapid; gamma hydroxybutyrate (GHB) has been
detected in newborns at delivery following intravenous
administration to mothers
Some drug is present in human breast milk
Less activating than stimulants
For narcolepsy , may help patients insuf ficiently responsive to
stimulants

 PearlsHas the biggest ef fect size on pain, fatigue, and sleep in
Has abuse potential
Requires a second dose in the middle of the night
Potentially more dangerous than other treatments, especially for
fibromyalgia or chronic pain, and especially if taken with sedative
hypnotics and/or opiates
Sleepiness, fatigue
Cataplexy
Painful physical symptoms
Lack of nonrestorative sleep in fibromyalgia and chronic pain
Sodium oxybate increases slow-wave sleep, thereby improving
sleep quality at night and allowing individuals to feel more rested
Sodium oxybate also increases growth hormone, which is one of the
reasons that it has been abused by athletes

✽ There are positive trials for ef ficacy in fibromyalgia, with
improvement in sleep, pain, and fatigue, but an FDA advisory
committee voted it down because of safety concerns and the drug is
not of ficially approved for this indication
Carter  LP , Pardi  D , Gorsline  J , Griffiths RR . Illicit gamma-
hydroxybutyrate (GHB) and pharmaceutical sodium oxybate (Xyrem):
differences in characteristics and misuse  . Drug Alcohol Depend  2009  ;104
(1–2):1 –10.
Moldofsky  H , Inhaber  NH , Guinta  DR , Alvarez-Horine  SB . Effects of
sodium oxybate on sleep physiology and sleep/wake-related symptoms in
patients with fibromyalgia syndrome: a double-blind, randomized, placebo-
controlled study  . J Rheumatol  2010  ;37 (10 ):2156  –66.
Owen  RT . Sodium oxybate: ef ficacy , safety and tolerability in the
treatment of narcolepsy with or without cataplexy  . Drugs T oday (Bar c)
2008  ;44 (3 ):197–204 .

Russell  IJ , Perkins  AT , Michalek  JE , et al. Sodium oxybate relieves pain
and improves function in fibromyalgia syndrome: a randomized, double-
blind, placebo-controlled, multicenter clinical trial  . Arthritis Rheum  2009
;60 (1 ):299 –309 .
Wang YG , Swich  TJ , Carter  LP , Thorpy  MJ , Benowitz  NL . Safety
overview of postmarketing and clinical experience of sodium oxybate

(Xyrem): abuse, misuse, dependence, and diversion  . J Clin Sleep Med  2009
;15 (4 ):365 –71 .

solriamfetol
Brands
Generic?
No
 Class
 How the Drug W orksSunosi
Dopamine and norepinephrine reuptake inhibitor
Excessive daytime sleepiness in patients with nar colepsy or
obstructive sleep apnea (OSA)
Boosts neurotransmitters dopamine and
presumably increasing dopaminer gic neurotransmission in brain

If It W orks
Consider an alternative treatment
Could augment with another wake-promoting agent other than
stimulantsregions where the dopamine transporter is present (e.g., striatum)
presumably increasing norepinephrine neurotransmission in the
prefrontal cortex and throughout the brain
cortex, which lar gely lacks dopamine transporters, solriamfetol can
increase dopamine neurotransmission in this part of the brain via its
actions on the norepinephrine transporter
Clinical ef fects can be seen as early as 1 week
Can take several weeks for some patients to achieve a clinical
response
Improves daytime sleepiness

Tests
Assess blood pressure and heart rate at baseline and periodically
If choosing to augment, consider modafinil, armodafinil, or
anxiety , headache, increased blood pressure, nausea)
norepinephrine in the periphery with undesired ef fects (e.g., nausea,
increased blood pressure, increased heart rate)

Headache, insomnia, anxiety
Nausea, decreased appetite
Dose-dependent increase in blood pressure, heart rate
Sedation
Best Augmenting Agents for Side EffectsTheoretical activation of (hypo)mania, anxiety , hallucinations, or
suicidal ideation
Wait

How to Dose
Avoid administering within 9 hours of bedtime so that it does not
interfere with sleep
In OSA, ensure that the underlying airway obstruction is treated for at
least 1 month prior to initiating solriamfetol; modalities to treat the
underlying airway obstruction should be continued during treatment
with solriamfetolNarcolepsy: 75 –150 mg once daily upon wakening
OSA: 75 –150 mg once daily upon wakening
Tablet 75 mg (scored), 150 mg
Narcolepsy: initial dose 75 mg once daily; can increase every 3 days
as needed; maximum dose 150 mg once daily
OSA: initial dose 37.5 mg once daily; can double dose every 3 days

Overdose
How to Stop
year
There was no evidence of physiological dependence or withdrawal
symptoms in clinical trials
Mean elimination half-life approximately 7.1 hours
Minimally metabolized; primarily cleared through the kidneys

Contraindicated with MAO inhibitors, including 14 days after MAOIs
are stopped
that increase blood pressure and/or heart rate as wellas with agents
Should be used cautiously with dopaminer gic agents
Use with caution in patients with bipolar disorder or psychosis
Solriamfetol should be used with caution in patients taking levodopa
Do Not Use
Renal ImpairmentIf patient is taking an MAO inhibitor
If there is a proven aller gy to solriamfetol
Dose adjustment not necessary in patients with mild renal
Moderate impairment: initial dose 37.5 mg once daily; can increase
to 75 mg once daily after 7 days

Elderly
 PregnancySevere impairment: initial and maximum dose 37.5 mg once daily
Avoid use in patients with unstable cardiovascular disease, serious
heart arrhythmias, or other serious heart problems

The art of psychopharmacologyWhen administered to pregnant rats during or ganogenesis, the no
observed adverse ef fect level (NOAEL) for malformations is 4 times
and for maternal and embryofetal toxicity is approximately 1 times
the maximum recommended human dose (MRHD) based on mg/m2
body surface area
NOAEL for malformations and fetal toxicity is approximately 2
times and for maternal toxicity is approximately 5 times the
maximum recommended human dose (MRHD) based on mg/m2
lactation, maternal toxicity occurred at 7 times the MRHD based on
mg/m2 body surface area; at the maternally toxic dose, fetal toxicity
occurred; the NOAEL for maternal and developmental toxicity is
approximately 2 times the MRHD based on mg/m2 body surface
area
Pregnancy registry for solfriamfetol: 1-877-283-6220

area
Unknown if solriamfetol is secreted in human breast milk, but all

 Pearls
Mechanism of action suggests possible utility in depression, binge
eating disorder , ADHD, and smoking cessation, but there are studies
only in depression
Monitor blood pressure and heart rate during treatment
Monitor activating side ef fects (e.g., anxiety , insomnia)
Carter LP  Carter LP  , Henningfield JE  Henningfield JE  , Wang YG  Wang
YG , et al. A randomized, double-blind, placebo-controlled, crossover study
to evaluate the human abuse liability of solriamfetol, a selective dopamine
and norepinephrine reuptake inhibitor  . J Psychopharmacol  2018  ;32 (12
):1351  –61 .Less abuse potential than stimulants
Not available generically

Emsellem HA  Emsellem HA  , Thorpy MJ  Thorpy MJ  , Lammers GJ
Lammers GJ  , et al. Measures of functional outcomes, work productivity ,
and quality of life from a randomized, phase 3 study of solriamfetol in
participants with narcolepsy  . Sleep Med  2019  ;67 :128 –36 .
Malhotra A  Malhotra A  , Shapiro C  Shapiro C  , Pepin JL  Pepin JL  , et al.
Long-term study of the safety and maintenance of ef ficacy of solriamfetol
(JZP-1 10) in the treatment of excessive sleepiness in participants with
narcolepsy or obstructive sleep apnea  . Sleep  2020  ;43 (2 ):zsz220  . doi:
10.1093/sleep/zsz220  .
Schweitzer PK  Schweitzer PK  , Rosenber g R Rosenber g R , Zammit GK
Zammit GK  , et al. Solriamfetol for excessive sleepiness in obstructive
sleep apnea (T ONES 3). A randomized controlled trial  . Am J Respir Crit
Care Med  2019  ;199 (11 ):1421  –31 .
Thorpy MJ  Thorpy MJ  , Shapiro C  Shapiro C  , Mayer G  Mayer G  , et al. A

randomized study of solriamfetol for excessive sleepiness in narcolepsy  .
Ann Neur ol 2019  ;85 (3 ):359 –70 .

Sulpiride
Brands
Generic?
Yes
 Class
 How the Drug W orksDolmatil
(D-RAn)
Conventional antipsychotic (neuroleptic, benzamide, dopamine 2

✽ Possibly blocks presynaptic dopamine 2 autoreceptors more
potently at low doses, which could theoretically contribute to
improving negative symptoms of schizophrenia as well as depression
psychosis
Blocks dopamine 3 and 4 receptors, which may contribute to
sulpiride ’s actions

Tests
>30)Consider trying one of the first-line atypical antipsychotics
clozapine

Side Effects(fasting plasma glucose >126 mg/dL), or dyslipidemia (increased

sulpiride should be discontinued at the first sign of decline of WBC

✽ Prolactin elevation, galactorrhea, amenorrheaAcute blockade of dopamine 2 receptors in the striatum can cause

Sedation, dizziness, sleep disturbance, headache, impaired
Dry mouth, nausea, vomiting, constipation, anorexia
Impotence
Rare hypomania
Palpitations, hypertension

Sedation
high doses
Wait
Wait
Wait

How to DoseBenztropine, trihexyphenidyl, or amantadine for drug-induced
Schizophrenia: 400 –800 mg/day in 2 doses (oral)
Predominantly negative symptoms: 50 –300 mg/day (oral)
Intramuscular injection: 600 –800 mg/day
Depression: 150 –300 mg/day (oral)
Tablet 200 mg, 400 mg, 500 mg
Intramuscular injection 50 mg/mL, 100 mg/mL
Initial 400 –800 mg/day in 1 –2 doses; may need to increase dose to
control positive symptoms; maximum generally 2400 mg/day

✽ Low doses of sulpiride may be more ef fective at reducing negative
symptoms than positive symptoms in schizophrenia; high doses may
be equally ef fective at reducing both symptom dimensions
✽ Lower doses are more likely to be activating; higher doses are more
likely to be sedating
OverdoseSome patients receive more than 2400 mg/day

Can be fatal; vomiting, agitation, hypotension, hallucinations, CNS
depression, sinus tachycardia, arrhythmia, dystonia, dysarthria,
hyperreflexia

How to Stop
No
Recommended to reduce dose over a week
a few weeks after sulpiride is discontinued
Sulpiride may increase the ef fects of antihypertensive drugs

Other W arnings/Pr ecautionsCNS ef fects may be increased if sulpiride is used with other CNS
depressants
Antacids or sucralfate may reduce the absorption of sulpiride
Antiemetic ef fect of sulpiride may mask signs of other disorders or
overdose; suppression of cough reflex may cause asphyxia
Use with caution in patients with hypertension, cardiovascular
disease, pulmonary disease, hyperthyroidism, urinary retention,
glaucoma
May exacerbate symptoms of mania or hypomania
dementia

Do Not Use
ElderlyIf patient has pheochromocytoma
In children under age 15
If there is a proven aller gy to sulpiride
Sulpiride is eliminated by the renal route; in cases of severe renal

Not recommended for use in children under age 15
14 and older: recommended 3 –5 mg/kg per day
Potential risks should be weighed against the potential benefits, and
sulpiride should be used only if deemed necessary

Primary T arget SymptomsAtypical antipsychotics may be preferable to conventional
Immediate postpartum period is a high-risk time for relapse of
psychosis
For negative symptoms in some patients
Patients who cannot tolerate sedation at high doses

Pearls
✽ There is some controversy over whether sulpiride is more ef fective
than older conventionals at treating negative symptoms
✽ Some patients with inadequate response to clozapine may benefit
from augmentation with sulpirideDepressive symptoms
Sulpiride has been used to treat migraine associated with hormonal
changes
Sulpiride is poorly absorbed from the gastrointestinal tract and
penetrates the blood –brain barrier poorly , which can lead to highly
variable clinical responses, especially at lower doses
Small studies and clinical anecdotes suggest ef ficacy in depression
and anxiety disorders ( “neuroses ” ) at low doses
another

another
antipsychotic such as sulpiride or from switching to a conventional
antipsychotic such as sulpiride

Caley  CF , Weber SS . Sulpiride: an antipsychotic with selective
dopaminer gic antagonist properties  . Ann Pharmacother  1995  ;29 (2 ):152–
60 .
efficacy and tolerabilityof 32 oral antipsychotics for the acute treatment of
meta-analysis  . Lancet  2019  ;394 :939–51 .However , long-term polypharmacy with a combination of a
of either

Omori  IM , Wang J. Sulpiride versus placebo for schizophrenia  . Cochrane
Database Syst Rev  2009  ;15 (2 ):CD00781 1 .
Wang J , Omori  IM , Fenton  M , Soares  B. Sulpiride augmentation for
schizophrenia  . Cochrane Database Syst Rev  2010  ;20 (1 ):CD008125  .

Suvorexant
Brands
Generic?
No
 Class
How Long Until It W orksBelsomra
Insomnia (pr oblems with sleep onset and/or sleep maintenance)
Orexin serves to stabilize and promote wakefulness; suvorexant

If It W orks
TestsImproves quality of sleep

 Sedation
receptors
Sedation, headache, dizziness, abnormal dreams
Sleep paralysis and hypnagogic/hypnopompic hallucinations (rare)
Dose-dependent symptoms similar to mild cataplexy (rare)
Wait
To avoid problems with memory , take suvorexant only if planning to

How to Dose
 Dosing T ipsSwitch to a dif ferent hypnotic
10 mg/night
Tablet 5 mg, 10 mg, 15 mg, 20 mg
Starting dose is 10 mg, no more than once per night and within 30
minutes of bedtime
time
Patients who tolerate but do not respond to 10 mg may receive 15
mg or 20 mg doses; 20 mg is the maximum recommended dose
Use the lowest dose ef fective for the patient

Overdose
How to Stop
Drug InteractionsTaking suvorexant with or soon after a meal can delay the time to
effect
Suvorexant is a Schedule IV drug
symptoms with prolonged use of suvorexant
Mean terminal half-life approximately 12 hours

Other W arnings/Pr ecautionsNot recommended in patients taking concomitant strong CYP450
3A4 inhibitors
Patients taking moderate CYP3A4 inhibitors should receive a 5 mg
dose; dose can be increased to 10 mg if needed
Patients taking CYP3A4 inducers may experience reduced ef ficacy
of suvorexant
Monitor digoxin levels if coadministered with suvorexant
ideation
Suvorexant should only be administered at bedtime

Do Not Use
ElderlySleep driving and other complex behaviors, such as eating and
If patient is taking strong CYP450 3A4 inhibitors
If there is a proven aller gy to suvorexant
Dose adjustment not necessary in mild to moderate hepatic
Not recommended in patients with severe hepatic impairment

 Pregnancy
effect levels (NOAELs) for fetal toxicity are 25 and 28 times the
maximum recommended human dose (MRHD) based on AUC in
rats and rabbits, respectively
When administered during pregnancy and lactation, the NOAEL for
developmental toxicity is 25 times the MRHD based on AUC in rats
Unknown if suvorexant is secreted in human breast milk, but all

Recommended to either discontinue drug or bottle feed

 PearlsPrimary insomnia

Citrome  L. Suvorexant for insomnia: a systematic review of the ef ficacy
and safety profile for this newly approved hypnotic –what is the numberDORAs hypothetically switch of f alertness-related circuits,
Suvorexant may be safe for long-term use, with little or no
suggestion of tolerance, dependence, or abuse

needed to treat, number needed to harm and likelihood to be helped or
harmed?  Int J Clin Pract  2014  ;68 (12 ):1429  –41.
Michelson  D , Snyder  E , Paradis  E , et al. Safety and ef ficacy of
suvorexant during 1-year treatment of insomnia with subsequent abrupt
treatment discontinuation: a phase 3 randomised, double-blind, placebo-
controlled trial  . Lancet Neur ol 2014  ;13 (5 ):461–71 .

Tasimelteon
Brands
Generic?
No
 Class
How Long Until It W orksHetlioz
Non-24-Hour Sleep-W ake Disorder (Non-24)
Insomnia associated with shift work, jet lag, or circadian rhythm
agonist, with greater af finity for melatonin 2 receptors than for
melatonin 1 receptors
Because of individual dif ferences in circadian rhythms, daily use for
several weeks or months may be necessary before ef ficacy is

If It W orks
Tests
How Drug Causes Side Effectsobserved
Causes circadian entrainment
Increases nighttime sleep time
Reduces daytime nap time

 Sedation
Best Augmenting Agents for Side EffectsHeadache, nightmares, or unusual dreams
Increased alanine aminotransferase
Upper respiratory infection, urinary infection
Wait
To avoid problems with memory , take tasimelteon only if planning
Over -the-counter pain medication for headache

How to Dose
Overdose
Long-T erm Use20 mg at bedtime
Capsule 20 mg
Should be taken at the same time every night
Should be taken without food
If tasimelteon cannot be taken at its usual time on a given night, the
dose for that night should be skipped
Capsule should be swallowed whole
Continued use is necessary to maintain circadian entrainment

How to Stop
 Drug InteractionsHas been studied and found safe in a small number of patients for up
to 1 year
No
Mean elimination half-life 1.3 hours
Metabolized by CYP450 1A2 and CYP 450 3A4
plasma levels of tasimelteon, so combination of tasimelteon with
fluvoxamine or other strong CYP450 1A2 inhibitors should be
avoided
Inducers of CYP450 3A4, such as rifampin, could decrease plasma
levels of tasimelteon, so combination of tasimelteon with CYP450
3A4 inducers should be avoided
Efficacy may be reduced if given in conjunction with CYP450 1A2
inducers (e.g., cigarette smoke)

Do Not Use
ElderlyInhibitors of CYP450 3A4, such as ketoconazole, could increase
plasma levels of tasimelteon
Tasimelteon should only be administered at bedtime
If there is a proven aller gy to tasimelteon
Not recommended for patients with severe impairment

 Pregnancy
The art of psychopharmacologyExposure to tasimelteon is increased by approximately 2-fold
In animal studies, administration of tasimelteon during pregnancy
resulted in developmental toxicity (embryofetal mortality ,
neurobehavioral impairment, decreased growth and development in
offspring)
Unknown if tasimelteon is secreted in human breast milk, but all
Use caution if patient is breast feeding

Circadian rhythm disorders
Expensive
Total nighttime sleep time
Tasimelteon acts upon circadian rhythms by stimulating melatonin
receptors in the brain ’s “pacemaker ,” namely the suprachiasmatic
nucleus
Tasimelteon may act by promoting the proper entrainment of
circadian rhythms underlying a normal sleep-wake cycle; this is
supported by biomarker data involving both melatonin and cortisol
Thus, tasimelteon may also prove ef fective for treatment of
circadian rhythm disturbances such as shift work sleep disorder and

Leger  D , Quera-Salva  MA , Vecchierini  MF , et al. Safety profile of
tasimelteon, a melatonin MT1 and MT2 receptor agonist: pooled safety
analyses from six clinical studies  . Expert Opin Drug Saf  2015  ;14
(11):1673  –85.
Lockley  SW , Dressman  MA , Licamele  L , et al. Tasimelteon for non-24-
hour sleep-wake disorder in totally blind people (SET and RESET): two
multicentre, randomised, double-masked, placebo-controlled phase 3 trials  .
Lancet  2015  ;386 (10005): 1754  –64.
Stahl  SM . Mechanism of action of tasimelteon in non-24 sleep-wake
syndrome: treatment for a circadian rhythm disorder in blind patients  . CNS
Spectr  2014  ;19 (6):475 –8 .jet lag, and studies in jet lag are currently under way; however , this
would be an expensive alternative
Theoretically could boost the ef fects of an antidepressant in blind
individuals with depression or anxiety , but this has not been
properly studied and augmentation studies in depression are not
positive

positive

Temazepam
Brands
Generic?
Yes
 Class
 How the Drug W orksRestoril
Catatonia

If It W orks
effects
Generally takes ef fect in less than an hour , but can take longer in

Tests
Trazodone

To avoid problems with memory , only take temazepam if planning
Capsule 7.5 mg, 15 mg, 22 mg, 30 mg

✽ Because temazepam is slowly absorbed, administering the dose 1 –2
hours before bedtime may improve onset of action and shorter sleep
latency
Overdose
Temazepam should generally not be prescribed in quantities greater
treatment
Can be fatal in monotherapy; slurred speech, poor coordination,
respiratory depression, sedation, confusion, coma
Temazepam is a Schedule IV drug

How to Stop
Patients with history of seizure may seize upon sudden withdrawal
Half-life approximately 8 –15 hours
If temazepam is used with kava, clearance of either drug may be
affected

efficacy
ideation

ideation
Temazepam should only be administered at bedtime

Elderly
 Childr en and AdolescentsIf patient is pregnant
If there is a proven aller gy to temazepam or any benzodiazepine

Pregnancy
✽ Recommended either to discontinue drug or bottle feedLong-term ef fects of temazepam in children/adolescents are
unknown
monitored
Unknown if temazepam is secreted in human breast milk, but all

 Pearls
✽ Slow gastrointestinal absorption compared to other sedative
benzodiazepines, so may be more ef fective for nocturnal awakening
than for initial insomnia unless dosed 1 –2 hours prior to bedtime
✽ Notable for delayed onset of action compared to some other
sedative hypnoticsPatients with middle insomnia (nocturnal awakening)
Patients with early insomnia (problems falling asleep)
treatment

Ashton  H . Guidelines for the rational use of benzodiazepines  . When and
what to use. Drugs  1994  ;48 :25 –40 .
Fraschini  F , Stankov  B . Temazepam: pharmacological profile of a
benzodiazepine and new trends in its clinical application  . Pharmacol Res
1993  ;27 :97 –113.
Heel  RC , Brogden  RN , Speight  TM , Avery GS . Temazepam: a review of
its pharmacological properties and therapeutic ef ficacy as an hypnotic  .
Drugs  1981  ;21 :321–40 .
McElnay  JC , Jones  ME , Alexander  B . Temazepam (Restoril, Sandoz
Pharmaceuticals)  . Drug Intell Clin Pharm  1982  ;16 :650 –6 .

Thioridazine
Brands
Generic?
Yes
 Class
 How the Drug W orksMellaril
Schizophr enic patients who fail to r espond to tr eatment with
other antipsychotic drugs

If It W orks
✽ Should evaluate for switching to an antipsychotic with a better
✽ Augmentation of thioridazine has not been systematically studied
and can be dangerous, especially with drugs that can either prolong
QTc interval or raise thioridazine plasma levelsBlocks dopamine 2 receptors, reducing positive symptoms of
psychosis
Is a second-line treatment option
clozapine

Tests
✽ Periodic evaluation of ECG and serum potassium levels
>30)
or dyslipidemia, or consider switching to a dif ferent antipsychoticSerum magnesium levels may also need to be monitored

thioridazine should be discontinued at the first sign of decline of

✽ Mechanism of potentially dangerous QT c prolongation may be
related to actions at ion channels
✽ Priapism
✽ Galactorrhea, amenorrheacause worsening of negative and cognitive symptoms (neuroleptic-
unknown

✽ Pigmentary retinopathy at high doses

Sedation
and can be dangerousMany experience and/or can be significant in amount
Wait
Wait
Wait

How to Dose
✽ Prolongation of the QT c interval is dose-dependent, so start low and
go slow while carefully monitoring QT c interval200–800 mg/day in divided doses
Tablet 10 mg, 15 mg, 25 mg, 50 mg, 100 mg
Liquid 30 mg/mL, 100 mg/mL (discontinued in USA)
Suspension 5 mg/mL, 20 mg/mL (discontinued in USA)
50–100 mg 3 times a day; increase gradually; maximum 800 mg/day
in divided doses
Pigmentary retinopathy has been reported in patients taking doses
exceeding the recommended range

Overdose
Sedation, confusion, respiratory depression, cardiac disturbance,
hypotension, seizure, coma
No

✽ CYP450 2D6 inhibitors including paroxetine, fluoxetine,
duloxetine, bupropion, sertraline, citalopram, and others can raise
thioridazine to dangerous levels
✽ Fluvoxamine, propranolol, and pindolol also inhibit thioridazine
metabolism and can raise thioridazine to dangerous levelsRapid discontinuation may lead to rebound psychosis and worsening
a few weeks after thioridazine is discontinued
Respiratory depression/arrest may occur if used with a barbiturate
Alcohol and diuretics may increase the risk of hypotension;
epinephrine may lower blood pressure

✽ Thioridazine can increase the QT c interval and potentially cause
torsade de pointes-type arrhythmia or sudden death, especially in
combination with drugs that raise its levelsSome patients taking a neuroleptic and lithium have developed an
syndrome
Use cautiously in patients with respiratory disorders, glaucoma, or
dementia
Observe for signs of pigmentary retinopathy , especially at higher

dementia
doses

Do Not Use
of significantly prolonging QT c interval (e.g., pimozide, selected
antiarrhythmics, moxifoxacin, and sparfloxacin)Because thioridazine may dose-dependently prolong QT c interval,
Because thioridazine may dose-dependently prolong QT c interval,

therapy
If patient suf fers from extreme hypertension/hypotension

✽ If patient is taking drugs that inhibit thioridazine metabolism,
including CYP450 inhibitors
✽ If there is reduced CYP450 2D6 function, such as in patients who
are 2D6 poor metabolizers
Cardiac ImpairmentIf there is a proven aller gy to thioridazine
Thioridazine produces a dose-dependent prolongation of QT c
should be evaluated prior to administering thioridazine
to produce prolonged bradycardia, hypokalemia slowing of

✽ Risk/benefit ratio may not justify use in cardiac impairment
Elderly
 Childr en and Adolescentsintracardiac conduction, or prolongation of the QT c interval
Avoid thioridazine in patients with a known history of QT c
Elderly patients may be more sensitive to adverse ef fects, including
agranulocytosis and leukopenia
Safety and ef ficacy not established in children under age 2
Dose: initial 0.5 mg/kg per day in divided doses; increase gradually;

maximum 3 mg/kg per day
Risk/benefit ratio may not justify use in children or adolescents

Pregnancy
pregnancy

pregnancy
Atypical antipsychotic may be preferable to conventional

Primary T arget SymptomsUnknown if thioridazine is secreted in human breast milk, but all
Only for patients who respond to this agent and not other
Children
Elderly
Those with low CYP450 2D6 metabolism
Positive symptoms of psychosis in patients who fail to respond to
Motor and autonomic hyperactivity in patients who fail to respond
to treatment with other antipsychotics

Pearls
✽ Generally , the benefits of thioridazine do not outweigh its risks for
✽ Because of its ef fects on the QT c interval, thioridazine is not
intended for use unless other options (at least 2 antipsychotics) have
failed
✽ Phenotypic testing may be necessary in order to detect the 7% of
the Caucasian population for whom thioridazine is contraindicated due
to a genetic variant leading to reduced activity of CYP450 2D6
✽ Was once a preferred antipsychotic for children and the elderly , and
for those whose symptoms benefited from a sedating low-potency
phenothiazine with a lower incidence of drug-induced parkinsonism
✽ However , now it is recognized that the dangers of cardiac
arrhythmias and drug interactions outweigh the benefits ofViolent or aggressive behavior in patients who fail to respond to
Thioridazine has not been systematically studied in treatment-
refractory schizophrenia

Conventional antipsychotics are much less expensive than atypical
Thioridazine causes less drug-induced parkinsonism than some
other conventional antipsychotics

thioridazine, and it is now considered a second-line treatment if it is
considered at all
Fenton  M , Rathbone  J , Reilly  J , Sultana  A. Thioridazine for schizophrenia
. Cochrane Database Syst Rev  2007  ;18 (3):CD001944  .
Frankenbur g FR . Choices in antipsychotic therapy in schizophrenia  . Harv
Rev Psychiatry  1999  ;6 :241 –9 .
Gardos  G , Tecce JJ , Hartmann  E , Bowers  P , Cole  JO . Treatment with
mesoridazine and thioridazine in chronic schizophrenia: II. Potential
predictors of drug response  . Compr Psychiatry  1978  ;19 :527–32 .
Leucht  S , Wahlbeck  K , Hamann  J , Kissling  W . New generation
antipsychotics versus low-potency conventional antipsychotics: a

systematic review and meta-analysis  . Lancet  2003  ;361 :1581  –9.

Thiothixene
Brands
Generic?
Yes
 Class
 How the Drug W orksNavane

psychosis
disorder

disorder

Side effects(fasting plasma glucose >126 mg/dL), or dyslipidemia (increased

thiothixene should be discontinued at the first sign of decline of

Weight GainSedation
Rare fine lenticular pigmentation
Rare hepatic toxicity

Sedation
Wait
Wait
Wait
For drug-induced parkinsonism, add an anticholiner gic agentBeta
blockers, benzodiazepines, or 5HT2A antagonists (e.g., mirtazapine,
cyproheptadine) may reduce akathisia

How T o Dose
15–30 mg/day
Capsule 2 mg, 5 mg, 10 mg
Initial 5 –10 mg/day; maximum dose generally 60 mg/day; higher
doses may be given in divided doses
When thiothixene is dosed too high, it can induce or worsen
negative symptoms of schizophrenia
Lower doses may provide the best benefit with fewest side ef fects in
patients who respond to low doses

Overdose
How to StopRather than raise the dose above normal dosing in acutely agitated
Muscle twitching, sedation, dizziness, CNS depression, rigidity ,
weakness, torticollis, dysphagia, hypotension, coma
No

 Drug InteractionsSlow down-titration (over 6 –8 weeks), especially when
a few weeks after thiothixene is discontinued
Initial elimination half-life approximately 3.4 hours
Terminal elimination half-life approximately 34 hours
Respiratory depression may occur when thiothixene is combined
with lorazepam
syndrome
guanethidine, whose antihypertensive actions thiothixene may

Other W arnings/Pr ecautionsantagonize
dementia

therapy

Do Not Use
If patient has CNS depression, is in a comatose state, has circulatory
collapse, or there is presence of blood dyscrasias
If there is a proven aller gy to thiothixene
Thiothixene may cause or aggravate ECG changes

Safety and ef ficacy have not been established in children under age
12

pregnancy

Potential DisadvantagesPsychotic symptoms may worsen during pregnancy and some form
Thiothixene should generally not be used during the first trimester
Thiothixene should be used during pregnancy only if clearly needed
Unknown if thiothixene is secreted in human breast milk, but all
For patients who do not respond to other antipsychotics
Children
Elderly

 Pearls
✽ Although not systematically studied, may cause less weight gain
than other antipsychoticsPositive symptoms of psychosis
Conventional antipsychotics are less expensive than atypical
another
antipsychotic such as thiothixene or from switching to a
conventional antipsychotic such as thiothixene
conventional antipsychotic such as thiothixene with an atypical

Huang  CC , Gerhardstein  RP , Kim DY , Hollister  L . Treatment-resistant
schizophrenia: controlled study of moderate- and high-dose thiothixene  . Int
Clin Psychopharmacol  1987  ;2 :69 –75 .
Sterlin  C , Ban TA , Jarrold  L . The place of thiothixene among the
thioxanthenes  . Curr Ther Res Clin Exp  1972  ;14 :205–14 .atypical antipsychotics or with 1 atypical antipsychotic and 1

Tiagabine
Brands
Generic?
Yes
 Class
 How the Drug W orksGabitril
Anticonvulsant; selective GABA reuptake inhibitor (SGRI)
Partial seizur es (adjunctive; adults and childr en 12 years and
older)

If It W orks
If It Doesn ’t Work (for Neur opathic Pain or Anxiety Disorders)Selectively blocks reuptake of gamma-aminobutyric acid (GABA)
by presynaptic and glial GABA transporters
Not clear that it works in anxiety disorders or chronic pain but some
patients may respond, and if they do, therapeutic actions can be seen
by 2 weeks
seizures, anxiety)

✽ For neuropathic pain, tiagabine can augment TCAs and SNRIs as
well as gabapentin, other anticonvulsants, and even opiates if done by
experts while carefully monitoring in dif ficult casesMany patients have only a partial response where some symptoms
May only be ef fective in a subset of patients with neuropathic pain
or anxiety disorders, in some patients who fail to respond to other
treatments, or it may not work at all
Tiagabine is itself an augmenting agent for numerous other

anticonvulsants in treating epilepsy
For anxiety , tiagabine is a second-line treatment to augment SSRIs,
SNRIs, or benzodiazepines

Tests
✽ Sedation, dizziness, asthenia, nervousness, dif ficulty concentrating,
speech/language problems, confusion, tremor
Tiagabine may bind to tissue that contains melanin, so for long-term
treatment opthalmological checks may be considered
CNS side ef fects may be due to excessive actions of GABA
Diarrhea, vomiting, nausea
Ecchymosis, depression
Exacerbation of EEG abnormalities in epilepsy
Status epilepticus in epilepsy (unknown if associated with tiagabine
use)
related to tiagabine use)

Sedation
Best Augmenting Agents for Side EffectsNew onset seizures and status epilepticus have been reported in
patients without epilepsy
Wait
Wait
Wait
Take more of the dose at night or all of the dose at night to reduce
daytime sedation

How T o Dose
32–56 mg/day in 2 –4 divided doses for adjunctive treatment of
epilepsy
2–12 mg/day for adjunctive treatment of chronic pain and anxiety
disorders
Tablet 2 mg, 4 mg, 12 mg, 16 mg, 20 mg
Adjunct to enzyme-inducing antiepileptic drugs: initial 4 mg once
daily; after 1 week can increase dose by 4 –8 mg/day each week;
maximum dose generally 56 mg/day in 2 –4 divided doses
Dosing for chronic pain or anxiety disorders not well established,
but start as low as 2 mg at night, increasing by 2 mg increments
every few days as tolerated to 8 –12 mg/day
Exercise particular caution when prescribing in uninduced patients

✽ Dosing recommendations are based on studies of adjunctive use
with enzyme-inducing antiepileptic drugs, which lower plasma levels
of tiagabine by half; thus, when tiagabine is used without enzyme-
inducing antiepileptic drugs the dose may need to be significantly
reduced and may require a much slower titration rate
✽ Also administered as adjunctive medication to benzodiazepines,
SSRIs, and/or SNRIs in the treatment of anxiety disorders; and to
SNRIs, gabapentin, other anticonvulsants, and even opiates in the
✽ Dosing varies considerably among individual patients but is
definitely at the lower end of the dosing spectrum for patients with
chronic neuropathic pain or anxiety disorders (i.e., 2 –12 mg either as a
split dose or all at night)
✽ Patients with chronic neuropathic pain and anxiety disorders are far
less tolerant of CNS side ef fects, so they require a much slower dosage
titration as well as a lower maintenance dose

✽ Thus, for improved tolerability and consistent clinical actions,
instruct patients to always take with foodUsually administered as adjunctive medication to other
anticonvulsants in the treatment of epilepsy
Gastrointestinal absorption is markedly slowed by the concomitant
intake of food, which also lessens the peak plasma concentrations

Overdose
How to Stop
PharmacokineticsNo fatalities have been reported; sedation, agitation, confusion,
speech dif ficulty , hostility , depression, weakness, myoclonus,
seizures, status epilepticus
Safe
No
Taper
Primarily metabolized by CYP450 3A4
Steady-state concentrations tend to be lower in the evening than in
the morning
Half-life approximately 7 –9 hours

 Other W arnings/Pr ecautionsClearance of tiagabine may be reduced and thus plasma levels
increased  if taken with a non-enzyme-inducing antiepileptic drug
(e.g., valproate, gabapentin, lamotrigine), so tiagabine dose may
need to be reduced
CYP450 3A4 inducers such as carbamazepine can lower  the plasma
levels of tiagabine
CYP450 3A4 inhibitors such as nefazodone, fluvoxamine, and
fluoxetine could theoretically increase  the plasma levels of tiagabine
Clearance of tiagabine is increased if taken with an enzyme-
inducing antiepileptic drug (e.g., carbamazepine, phenobarbital,
phenytoin, primidone) and thus plasma levels are reduced  ; however ,
no dose adjustments are necessary for treatment of epilepsy as the
dosing recommendations for epilepsy are based on adjunctive
treatment with an enzyme-inducing antiepileptic drug
Despite common actions upon GABA, no pharmacodynamic or
pharmacokinetic interactions have been shown when tiagabine is

combined with the benzodiazepine triazolam or with alcohol
However , sedating actions of any two sedative drugs given in
combination can be additive
Seizures have occurred in individuals without epilepsy who took
tiagabine

Do Not Use
Hepatic ImpairmentRisk of seizure may be dose-related; when tiagabine is used in the
absence of enzyme-inducing antiepileptic drugs, which lower
plasma levels of tiagabine, the dose may need to be reduced
Tiagabine may bind to melanin, raising the possibility of long-term
ophthalmologic ef fects
If there is a proven aller gy to tiagabine
Although tiagabine is renally excreted, the pharmacokinetics of
tiagabine in healthy patients and in those with impaired renal
function are similar and no dose adjustment is recommended
Clearance is decreased

Elderly
 PregnancyNo dose adjustment recommended
Safety and ef ficacy not established in children under age 12
Maximum recommended dose generally 32 mg/day in 2 –4 divided
doses

✽ Lack of definitive evidence of ef ficacy for chronic neuropathic pain
or anxiety disorders suggests risk/benefit ratio is in favor of
discontinuing tiagabine during pregnancy for those indications
Potential DisadvantagesSeizures, even mild seizures, may cause harm to the embryo/fetus
Treatment-resistant chronic neuropathic pain
Treatment-resistant anxiety disorders
May require 2 –4 times a day dosing
Needs to be taken with food

 Pearls
justified for treatment-resistant anxiety disorders and neuropathic pain
and also for fibromyalgia
✽ Off-label use for bipolar disorder may not be justified
 Suggested ReadingIncidence of seizures
Pain
Anxiety
Much use is of f label
Can be dif ficult to dose in patients who are not taking enzyme-
inducing anticonvulsant drugs as the doses in uninduced patients
have not been well studied, are generally much lower , and titration
is much slower than in induced patients
Can cause seizures even in patients without epilepsy , especially in
patients taking other agents (antidepressants, antipsychotics,
stimulants, narcotics) that are thought to lower the seizure threshold

Backonja  NM . Use of anticonvulsants for treatment of neuropathic pain  .
Neur ology  2002  ;59 (5 Suppl 2  ):S14 –17 .
Carta  MG , Hardoy  MC , Grunze  H , Carpiniello  B . The use of tiagabine in
affective disorders  . Pharmacopsychiatry  2002  ;35 :33–4 .
Evans  EA . Efficacy of newer anticonvulsant medications in bipolar
spectrum mood disorders  . J Clin Psychiatry  2003  ;64 (Suppl 8  ):S9 –14 .
Lydiard  RB . The role of GABA in anxiety disorders  . J Clin Psychiatry
2003  ;64 (Suppl 3  ):S21 –7.
Schmidt  D , Gram  L , Brodie  M , et al. Tiagabine in the treatment of
epilepsy –a clinical review with a guide for the prescribing physician  .
Epilepsy Res  2000  ;41 :245–51 .
Stahl  SM . Anticonvulsants as anxiolytics, part 1: tiagabine and other
anticonvulsants with actions on GABA  . J Clin Psychiatry  2004  ;65 :291–2
.
Stahl  SM . Psychopharmacology of anticonvulsants: do all anticonvulsants
have the same mechanism of action?  J Clin Psychiatry  2004  ;65 :149–50 .

Tianeptine
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Coaxil
Stablon
Tatinol
Neuroscience-based Nomenclature: glutamate; yet to be determined
(Glu)
Glutamater gic modulator
Often classified as a tricyclic antidepressant, but pharmacologically
distinct

✽ Modulates glutamater gic neurotransmission, perhaps through
potentiation of AMP A (alpha-amino-3- hydroxy-5-methyl-4-
isoxazolepropionic acid) receptor function
If It W orksDysthymia
Full agonist at mu opioid receptors; animal studies suggest that this
may contribute to its antidepressant ef fects
symptoms

TestsOnce symptoms are gone, continue treating for 1 year for the first
Augmentation has not been systematically studied with tianeptine
None recommended for healthy individuals

✽ Mild anticholiner gic activity (less than some TCAs) could possibly
lead to sedative ef fects, dry mouth, constipation, and blurred vision
✽ Pharmacologic studies do not indicate tianeptine to be a potent
alpha 1 antagonist or H1 antihistamine
 Life-Thr eatening or Danger ous Side EffectsMost side ef fects are immediate but often go away with time
Headache, dizziness, insomnia, sedation
Nausea, constipation, abdominal pain, dry mouth
Abnormal dreams
Increased transaminases
Theoretically , rare induction of mania and activation of suicidal
ideation or behavior
Cases of activation of suicidal ideation and behavior (suicidality)
(short-term did not show an increase in the risk of suicidality with
Hepatitis that can, in exceptional cases, be severe

Sedation
Dosing and UseDermatitis bulbous in exceptional cases
Wait
Wait
Wait
For skin reactions, stop treatment
Augmentation for side ef fects of tianeptine has not been

How to Dose
✽ Short half-life means multiple daily doses
Overdose
Habit Forming37.5 mg/day
Tablet 12.5 mg
12.5 mg 3 times/day
Tianeptine ’s rapid elimination necessitates strict adherence to the
dosing schedule
Effects are generally mild and nonfatal; unlikely to cause
Safe
Abuse and dependence may occur , in particular in patients under 50
years of age with a history of drug or alcohol dependence

How to Stop
 Other W arnings/Pr ecautionsMany patients tolerate 50% dose reduction for 3 days, then another
Not primarily metabolized by CYP 450 enzyme system
Tianeptine is rapidly eliminated
Half-life approximately 2.5 hours
discontinuation of tianeptine
Other drug interactions not well studied
For elective sur gery, tianeptine should be stopped 24 –48 hours
before general anesthesia is administered

Do Not Use
Hepatic ImpairmentGenerally , use only with extreme caution with MAOIs; do not use
until 14 days after MAOIs are stopped; do not start an MAOI for at
least 5 half-lives (5 to 7 days for most drugs) after discontinuing
tianeptine
Warn doctors to pay attention to patients with history of drug
dependencies
If there is a proven aller gy to tianeptine
Dose should be reduced for severe impairment to 25 mg/day

Elderly
 Childr en and AdolescentsIn patients with severe cirrhosis (class C, Child Plugh ’s Scale), the
dosage should be restricted to 25mg/day
Dose should be reduced to 25 mg/day
Tianeptine is not recommended for use in children or adolescents
under 18
patients

Pregnancy
✽ Not recommended for use during pregnancy
Potential DisadvantagesNot recommended for use during pregnancy
the mother
Patients who have dif ficulty being compliant with multiple daily
dosing

 Pearls
✽ Possibly a unique mechanism of action as a glutamater gic
Kasper  S , McEwen  BS . Neurobiological and clinical ef fects of the
antidepressant tianeptine  . CNS Drugs  2008  ;22 (1 ):15 –26 .
Kasper  S , Olie JP . A meta-analysis of randomized controlled trials of
tianeptine versus SSRI in the short-term treatment of depression  . Eur
Psychiatry  2002  ;17 (Suppl 3  ):331–40 .
McEwen  BS , Chattarji  S , Diamond  DM , et al. The neuribiological
properties of tianeptine (Stablon): from monoamine hypothesis to
glutamater gic modulation  . Mol Psychiatry  2010  ;15 :237–49 .
Samuels  BA , Nautiyal  KM , Kruegel  AC , et al. The behavioral ef fects of
the antidepressant tianeptine require the mu-opioid receptor  .
Neur opsychopharmacology  2017  ;42 (10 ):2052 –63 .Depressed mood
Is not metabolized by CYP450; therefore, the risk of
pharmacokinetic drug-drug interactions is minimized

Svenningsson  P , Bateup  H , Qi H , et al. Involvement of AMP A receptor
phosphorylation in antidepressant actions with special reference to
tianeptine  . Eur J Neuorsci  2007  ;26 :3509 –17 .
Wagstaf f AJ , Ormrod  D , Spencer  CM . Tianeptine: a review of its use in
depressive disorders  . CNS Drugs  2001  ;15 (3 ):231–59 .

Brands
Generic?
Yes (not for Qsymia)
 Class
(bold for FDA appr oved)Topamax
Epitomax
Topamac
Topimax
Trokendi XR
Qsymia
Anticonvulsant, voltage-sensitive sodium channel modulator
Partial onset seizur es (for immediate-r elease: adjunct for adults
and pediatric patients 2 –16 years of age; for extended-r elease:

✽ Blocks voltage-sensitive sodium channels by an unknown
mechanismmonotherapy or adjunct for patients 2 years and older)
Primary generalized tonic –clonic seizur es (adjunct and
monotherapy; adults and pediatric patients 2 years of age and
older)
Seizur es associated with Lennox-Gastaut syndr ome (adjunct; 2
years of age and older)
Migraine pr ophylaxis (ages 12 and older)
Chronic weight management (adjunct to r educed calorie diet
and incr eased physical activity) in adults with an initial body
mass index (BMI) of at least 30 kg/m2 (obese) or at least 27
kg/m2 (overweight) in the pr esence of at least one weight-r elated
comorbid condition [in combination with phentermine
(Qsymia)]
Bipolar disorder (adjunctive; no longer in development)
Psychotropic drug-induced weight gain
Potentiates activity of gamma-aminobutyric acid (GABA)
Carbonic anhydrase inhibitor

If It W orks
work at all
✽ Consider increasing dose or switching to another agent with better
demonstrated ef ficacy in bipolar disorder
ResistanceShould reduce seizures by 2 weeks
Not clear that it has mood-stabilizing properties, but some bipolar
patients may respond and if so, it may take several weeks to months
to optimize an ef fect on mood stabilization
mania, seizures, migraine)
seizures, and headaches

Tests
✽ Baseline and periodic serum bicarbonate levels to monitor for
hyperchloremic, non-anion gap metabolic acidosis (i.e., decreased
serum bicarbonate below the normal reference range in the absence of
chronic respiratory alkalosis)
✽ Sedation, asthenia, dizziness, ataxia, parasthesia, nervousness,
nystagmus, tremor
✽ Nausea, appetite loss, weight lossTopiramate is itself a second-line augmenting agent for numerous
other anticonvulsants, lithium, and antipsychotics in treating bipolar
disorder

✽ Metabolic acidosis
✽ Kidney stones
Sedation
Blurred or double vision, mood problems, problems concentrating,
confusion, memory problems, psychomotor retardation, language
problems, speech problems, fatigue, taste perversion
Hyperammonemia with or without encephalopathy has been
reported (may be dose-related; may be more likely with concomitant
valproate use)
Rare activation of suicidal ideation and behavior(suicidality)

Wait
Wait
Wait
Increase fluid intake to reduce the risk of kidney stones
Adults, immediate-release: 200 –400 mg/day in 2 divided doses for
epilepsy; 50 –300 mg/day for adjunctive treatment of bipolar
disorder
Adults, extended-release: 200 –400 mg/day as adjunct for partial
onset seizures; 400 mg/day as adjunct for primary generalized
tonic –clonic seizures; 400 mg/day as monotherapy for seizures

How to Dose
 Dosing T ipsMigraine: initial 25 mg/night for the first week; increase weekly in
25 mg increments; approved dose 100 mg/day in two divided doses
Tablet 25 mg, 50 mg, 100 mg, 200 mg
Sprinkle capsule 15 mg, 25 mg
Extended-release capsule 25 mg, 50 mg, 100 mg, 200 mg
Adults (immediate-release): initial 25 –50 mg/day; increase each
week by 50 mg/day; administer in 2 divided doses; maximum dose
generally 1600 mg/day
Adults (extended-release, adjunct for seizures): initial 25 –50 mg
once daily; increase weekly by 25 –50 mg
Seizures (extended-release, monotherapy , patients ages 10 and
older): initial 50 mg once daily; increase by 50 mg weekly for 4
weeks, increase by 100 mg weekly for weeks 5 and 6; recommended
dose 400 mg/day
Seizures (immediate-release, ages 2 –16): see Children and
Adolescents
For migraine, the individual dose may vary widely . Some patients
benefit from doses as low as 25 mg/day but others may require

✽ Weight loss is dose-related but most patients treated for weight gain
receive doses at the lower end of the dosing range
Overdosemuch higher doses than the 100 mg/day approved for migraine
prophylaxis
Headaches may return within days to months of stopping, but
patients often continue to do well for 6 or more months after
stopping
Adverse ef fects may increase as dose increases
Topiramate is available in a sprinkle capsule formulation, which can
be swallowed whole or sprinkled over approximately a teaspoon of
soft food (e.g., applesauce); the mixture should be consumed
Bipolar patients are generally administered doses at the lower end of
the dosing range
Slow upward titration from doses as low as 25 mg/day can reduce
the incidence of unacceptable sedation
Many bipolar patients do not tolerate more than 200 mg/day
No fatalities have been reported in monotherapy; convulsions,
sedation, speech disturbance, blurred or double vision, metabolic

acidosis, impaired coordination, hypotension, abdominal pain,
agitation, dizziness

How to Stop
patients
✽ Discontinuation symptoms uncommon
 Drug InteractionsProbably safe
Periodic monitoring of serum bicarbonate levels may be required
No
Taper
Elimination half-life approximately 21 hours
Inhibits CYP450 2C19 and induces CYP450 3A4

clearance of topiramate, and thus decrease  topiramate levels,
decrease  phenytoin levels, possibly requiring a higher dose of
phenytoin
decrease  valproate levels, possibly requiring a higher dose of
valproate
Topiramate may increase  plasma levels of metformin; also,
Topiramate may reduce the ef fectiveness of oral contraceptives
Topiramate levels may increase in the presence of
hydrochlorothiazide (HCTZ), possibly requiring a dose decrease of
topiramate
Topiramate may decrease the exposure of pioglitazone and its active
metabolites; patients taking both medications should be carefully

monitored for adequate control of their diabetic disease state
At high doses, topiramate may increase systemic exposure of
lithium

✽ If symptoms of metabolic acidosis develop (hyperventilation,
fatigue, anorexia, cardiac arrhythmias, stupor), then dose may need to
be reduced or treatment may need to be discontinued
Do Not UseReports of hypothermia and hyperammonemia with or without
encephalopthay in patients taking topiramate combined with
valproate, though this is not due to a pharmacokinetic interaction; in
patients who develop unexplained lethar gy, vomiting, or change in
mental status, an ammonia level should be measured
Use with caution when combining with other drugs that predispose
patients to heat-related disorders, including carbonic anhydrase
inhibitors and anticholiner gics

Within 6 hours prior to and 6 hours after alcohol use (extended-
release)
In patients with metabolic acidosis who are taking metformin
(extended-release)

Elderly
 Childr en and AdolescentsIf there is a proven aller gy to topiramate
Topiramate is renally excreted, so the dose should be lowered by
half
may require supplemental doses of topiramate
Approved for use in children age 2 and older (immediate-release)
for treatment of seizures
Clearance is increased in pediatric patients

PregnancySeizures (immediate-release, ages 2 –16): initial 1 –3 mg/kg per day
at night; after 1 week increase by 1 –3 mg/kg per day every 1 –2
weeks with total daily dose administered in 2 divided doses;
recommended dose generally 5 –9 mg/kg per day in 2 divided doses
Effectiveness was not demonstrated in infants/toddlers 1 to 24
months of age with refractory partial onset seizures; some adverse
effects/toxicities not observed in older patients did occur
Seizures (extended-release, adjunct): initial 25 mg once nightly (1 –3
mg/kg/night) for first week; increase at 1- or 2-week intervals by
increments of 1 –3 mg/kg/night; recommended dose 5 –9 mg/kg/night

Increased risk of cleft lip/palate
Increased risk of being small for gestational age
Hypospadia has occurred in some male infants whose mothers took
topiramate during pregnancy

✽ Lack of convincing ef ficacy for treatment of bipolar disorder
suggests risk/benefit ratio is in favor of discontinuing topiramate in
bipolar patients during pregnancy
✽ For bipolar patients, topiramate should generally be discontinued
period, mood stabilizer treatment, especially with agents with better
evidence of ef ficacy than topiramate, should generally be restarted
✽ Atypical antipsychotics may be preferable to topiramate if
✽ Recommended either to discontinue drug or bottle feedAntiepileptic Drug Pregnancy Registry: 1-888-233-2334,
https://www .aedpregnancyregistry .org

Primary T arget SymptomsIf infant shows signs of irritability or sedation, drug may need to be
be safer and more ef fective than topiramate during the postpartum
period when treating nursing mother with bipolar disorder
Patients who wish to avoid weight gain
Efficacy in bipolar disorder uncertain
acidosis
Migraine prophylaxis

Pearls
✽ However , randomized clinical trials do not suggest ef ficacy in
bipolar disorder; unfortunately these important studies have not been
published by the manufacturer , who has dropped topiramate from
further development as a mood stabilizer , though this is not widely
known
✽ Misperceptions about topiramate ’s efficacy in bipolar disorder have
such as lamotrigineIncidence of seizures
Side ef fects may actually occur less often in pediatric patients
Has been studied in a wide range of psychiatric disorders, including
bipolar disorder , PTSD, binge eating disorder , obesity , and others
Some anecdotes, case series, and open-label studies have been
published and are widely known suggesting ef ficacy in bipolar
disorder
Migraines may decrease in as little as 2 weeks, but can take up to 3
months on a stable dose to see full ef fect
The goal when using topiramate for migraine prophylaxis is a 50%

disorder
or greater reduction in migraine frequency or severity; consider
tapering or stopping if headaches remit for more than 6 months or if
considering pregnancy

✽ Due to reported weight loss in some patients in trials with epilepsy ,
topiramate is commonly used to treat weight gain, especially in
patients with psychotropic drug-induced weight gain
✽ Weight loss in epilepsy patients is dose-related with more weight
loss at high doses (mean 6.5 kg or 7.3% decline) and less weight loss
at lower doses (mean 1.6 kg or 2.2% decline)
✽ Changes in weight were greatest in epilepsy patients who weighed
the most at baseline (>100 kg), with mean loss of 9.6 kg or 8.4%
decline, while those weighing <60 kg had only a mean loss of 1.3 kg
or 2.5% decline
✽ Long-term studies demonstrate that weight losses in epilepsy
patients were seen within the first 3 months of treatment and peaked at
a mean of 6 kg after 12 –18 months of treatment; however , weight
tended to return to pretreatment levels after 18 months
✽ Some patients with psychotropic drug-induced weight gain may
experience significant weight loss (>7% of body weight) with

topiramate up to 200 mg/day for 3 months, but this is not typical, is not
often sustained, and has not been systemically studiedAugmenting options for migraine include beta blockers,
antidepressants, natural products, other anticonvulsants, and
nonmedication treatments such as biofeedback to improve headache
control
Early studies suggest potential ef ficacy in binge eating disorder

Johnson  BA , Ait-Daoud  N . Topiramate in the new generation of drugs:
efficacy in the treatment of alcoholic patients  . Curr Pharm Des  2010  ;16
(19 ):2103 –12 .
Kramer  CK , Leitao  CB , Pinto  LC , et al. Efficacy and safety of topiramate
on weight loss: a meta-analysis of randomized controlled trials  . Obes Rev
2011 ;12 (5 ):e338  –47.
Ormrod  D , McClellan  K . Topiramate: a review of its use in childhood
epilepsy  . Paediatr Drugs  2001  ;3 :293 –319 .
Shank  RP , Gardocki  JF , Streeter  AJ , Maryanof f BE . An overview of the
preclinical aspects of topiramate: pharmacology , pharmacokinetics, and
mechanism of action  . Epilepsia  2000  ;41 (Suppl 1  ):S3 –9 .
Suppes  T . Review of the use of topiramate for treatment of bipolar
disorders  . J Clin Psychopharmacol  2002  ;22 :599 –609 .The combination of topiramate and phentermine is approved as a
treatment for obesity (see phentermine/topiramate); the combination

is also being studied in diabetes and sleep apnea

Tranylcypromine
Brands
Generic?
Yes
 Class
 How the Drug W orksParnate
dopamine multimodal enzyme inhibitor (SN-MM)
Major depr essive episode without melancholia

✽ As the drug is structurally related to amphetamine, it may have some
stimulant-like actions due to monoamine release and reuptake inhibition
Some patients may experience stimulant-like actions early in dosing

is something for the expert, to be done with caution and with carefulFor second and subsequent episodes of depression, treatment may
Many patients have only a partial response where some symptoms are

pressure)
Tests
How Drug Causes Side EffectsLithium
Theoretically due to increases in monoamines in parts of the brain and

Sedation
Agitation, anxiety , insomnia, weakness, sedation, dizziness
Sexual dysfunction (less than with other MAOIs such as phenelzine)
doses
Hypertensive crisis (when MAOIs are used with certain tyramine-
containing foods or prohibited drugs)

Dosage FormsMany experience and/or can be significant in amount, especially
daytime somnolence from nighttime insomnia
Wait
Wait
Wait
Take at night if daytime sedation; take in daytime if overstimulated at
night
30–50 mg/day in divided doses

How to Dose
Overdose
Habit FormingTablet 10 mg
Initial 30 mg/day in divided doses; after 2 weeks increase by 10
mg/day each 1 –3 weeks; maximum 60 mg/day , rarely up to 120
mg/day
splitting into 3 –4 daily doses
Check blood pressure before and 45–60 minutes after an individual
dose >30 mg until stable
Patients receiving high doses (up to 120 mg/day if tolerated) may need
to be evaluated periodically for ef fects on the liver
Dizziness, sedation, ataxia, headache, insomnia, restlessness, anxiety ,
irritability; cardiovascular ef fects, confusion, respiratory depression,
or coma may also occur

How to Stop
 Drug InteractionsDependence to MAOIs reported but rare
weeks
Clinical duration of action may be 14–30 days due to irreversible
inhibitor or for 5 half-lives after stopping the serotonin reuptake
Do not combine with another MAOI inhibitor , alcohol, or
guanethidine

Do Not Use:
injected
 Other W arnings/Pr ecautionscarbamazepine, cyclobenzaprine, and mirtazapine, and should be
Pearls)

Broad bean pods All other vegetablesPatient and prescriber must be vigilant to potential interactions with
antidiabetic agents, although more so with hydrazine MAOIs than
with tranylcypromine

Tranylcypromine is not recommended for use in patients who cannot
be monitored closely

cheese
with MAOIs
with
reuptake

with
reuptake
Cocaine
Modafinil
Do Not Use
If patient is taking dextromethorphan (serotonin reuptake inhibitior)

ElderlyIf patient has cardiovascular or cerebrovascular disease until cleared
If there is a proven aller gy to tranylcypromine
Tranylcypromine should be used cautiously in patients with history of
hepatic impairment or in patients with abnormal liver function tests
Contraindicated in patients with cardiac impairment unless cleared by
the patient ’s medical doctor
Initial dose often lower than usual adult dose

Not generally recommended for use in children under age 18
patients

Potential AdvantagesShould evaluate patient for treatment with an antidepressant with a
sants
Effects on infant unknown
Melancholia

 PearlsRequires strict adherence to dietary restrictions, concomitant drug
Patients with cardiac problems or hypertension unless cleared by their
Multiple daily doses unless drug can be converted to once a day
Anxiety
Generally less weight gain or sexual dysfunction than with phenelzine

enough
treatment-resistantThe rigid dietary restrictions may reduce compliance (see Table 2  after
Pearls)
adolescent females), and tranylcypromine can be used to treat both
with an MAOI for patients who fail to respond to numerous other

Gillman  K. PsychoT ropical Research (PTR). http://psychotropical.com  .
2018  ;125 (11 ):1707  –17 .
Ricken  R , Ulrich  S , Schlattmann  P , Adli M . Tranylcypromine in mind (part
II): review of clinical pharmacology and meta-analysis of controlled studies in
depression  . Eur Neur opsychopharmacol  2017  ;27 (8 ):714 –31
Ulrich  S , Ricken  R , Adli M . Tranylcypromine in mind (part I): review of
pharmacology  . Eur Neur opsychopharmacol  2017  ;27 (8 ):697 –13 .
Ulrich  S , Ricken  R , Buspavanich  P , Schlattmann  P , Adli M . Efficacy and
adverse ef fects of tranylcypromine and tricyclic antidepressants in the
treatment of depression: a systematic review and comprehensive meta-
analysis  . J Clin Psychopharmacol  2020  ;40 (1 ):63 –74 .If this option is elected, start the MAOI with the tricyclic/tetracyclic

Trazodone
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Desyrel
Oleptro
(S-MM)
SARI (serotonin 2 antagonist/reuptake inhibitor); antidepressant;
hypnotic
Insomnia (primary and secondary)
Anxiety

✽ Onset of therapeutic actions in insomnia are immediate if dosing is
correct
If It W orks
✽ For insomnia, use possibly can be indefinite as there is no reliable
evidence of tolerance, dependence, or withdrawal, but few long-term
studiesBlocks serotonin 2A receptors potently
Blocks serotonin reuptake pump (serotonin transporter) less potently
but often delayed 2 –4 weeks whether given as an adjunct to another
antidepressant or as a monotherapy
symptoms in depression and to reduce symptoms of chronic
insomnia
For secondary insomnia, if underlying condition (e.g., depression,
anxiety disorder) is in remission, trazodone treatment may be
discontinued if insomnia does not reemer ge

current symptoms of depression as well as prevention of future
relapses
Treatment most often reduces or even eliminates symptoms of
depression, but is not a cure since symptoms can recur after
Continue treatment until all symptoms of depression are gone
For insomnia, try escalating doses or switch to another agent
Many patients have only a partial antidepressant response where

appropriate augmenting agent for treatment of depression

TestsConsider evaluation for another diagnosis or for a comorbid
Trazodone is not frequently used as a monotherapy for insomnia,
but can be combined with sedative hypnotic benzodiazepines in
Trazodone is most frequently used in depression as an augmenting
agent to numerous psychotropic drugs
Trazodone can not only improve insomnia in depressed patients
treated with antidepressants, but can also be an ef fective booster of
antidepressant actions of other antidepressants (use combinations of
Trazodone can also improve insomnia in numerous other psychiatric

conditions (e.g., bipolar disorder , schizophrenia, alcohol
withdrawal) and be added to numerous other psychotropic drugs
(e.g., lithium, mood stabilizers, antipsychotics)

 Life-Thr eatening or Danger ous Side EffectsSedative ef fects may be due to antihistamine properties
Nausea, vomiting, edema, blurred vision, constipation, dry mouth
Dizziness, sedation, fatigue, headache, incoordination, tremor
Hypotension, syncope
Occasional sinus bradycardia (long-term)
Rare rash
Rare priapism

Sedation
Wait
Wait
Wait
Take lar ger dose at night to prevent daytime sedation
Most side ef fects cannot be improved with an augmenting agent
discontinuation of trazodone

How to Dose
✽ Patients can have carryover sedation, ataxia, and intoxicated-like
feeling if dosed too aggressively , particularly when initiating dosing150–600 mg/day
Tablet 50 mg scored, 100 mg scored, 150 mg, 150 mg with
povidone scored, 300 mg with povidone scored
Depression as a monotherapy: initial 150 mg/day in divided doses;
can increase every 3 –4 days by 50 mg/day as needed; maximum 400
mg/day (outpatient) or 600 mg/day (inpatient), split into 2 daily
doses
Insomnia: initial 25 –50 mg at bedtime; increase as tolerated, usually
to 50 –100 mg/day , but some patients may require up to full
antidepressant dose range
Augmentation of other antidepressants in the treatment of
depression: dose as recommended for insomnia
Start low and go slow

✽ Do not discontinue trials if inef fective at low doses (<50 mg) as
many patients with dif ficult cases may respond to higher doses (150 –
300 mg, even up to 600 mg in some cases)
Overdose
How to StopFor relief of daytime anxiety , can give part of the dose in the
daytime if not too sedating
Although use as a monotherapy for depression is usually in divided
doses due to its short half-life, use as an adjunct is often ef fective
and best tolerated once daily at bedtime
Rarely lethal; sedation, vomiting, priapism, respiratory arrest,
seizure, ECG changes
Safe
No
dependence, and withdrawal ef fects have not been reliably
demonstrated

 Other W arnings/Pr ecautionsMetabolized by CYP450 3A4
Half-life is biphasic; first phase is approximately 3 –6 hours; second
phase is approximately 5 –9 hours
Fluoxetine and other SSRIs may raise trazodone plasma levels
Trazodone may block the hypotensive ef fects of some
antihypertensive drugs
Trazodone may increase digoxin or phenytoin concentrations
Trazodone may interfere with the antihypertensive ef fects of
clonidine
Reports of increased and decreased prothrombin time in patients
taking warfarin and trazodone
Possibility of additive ef fects if trazodone is used with other CNS

Do Not UseTreatment should be discontinued if prolonged penile erection
occurs because of the risk of permanent erectile dysfunction
Advise patients to seek medical attention immediately if painful
erections occur lasting more than 1 hour
Generally , priapism reverses spontaneously , while penile blood flow
and other signs are being monitored, but in ur gent cases, local
phenylephrine injections or even sur gery may be indicated
companies

companies
If patient is taking an MAOI, but see Pearls

Elderly
 Childr en and AdolescentsIf there is a proven aller gy to trazodone
Trazodone may be arrhythmogenic
Monitor patients closely
Not recommended for use during recovery from myocardial
infarction
Elderly patients may be more sensitive to adverse ef fects and may
require lower doses

patients
Safety and ef ficacy have not been established, but trazodone has
been used for behavioral disturbances, depression, and night terrors
Children require lower initial dose and slow titration
Boys may be even more sensitive to having prolonged erections
than adult men

Avoid use during first trimester

Breast FeedingMust weigh the risk of treatment (first trimester fetal development,
pregnancy
essants

 PearlsFor insomnia when it is preferred to avoid the use of dependence-
forming agents
As an adjunct to the treatment of residual anxiety and insomnia with
Depressed patients with anxiety
Patients concerned about sexual side ef fects or weight gain
For patients with fatigue, hypersomnia
For patients intolerant to sedating ef fects
Anxiety
Sleep disturbances
May be less likely than some antidepressants to precipitate
hypomania or mania

✽ May cause sexual dysfunction only infrequently
✽ For the expert psychopharmacologist, trazodone can be used
cautiously for insomnia associated with MAOIs, despite the warning –
must be attempted only if patients closely monitored and by experts
experienced in the use of MAOIsPreliminary data suggest that trazodone may be ef fective treatment
for drug-induced dyskinesias, perhaps in part because it reduces
accompanying anxiety
Trazodone may have some ef ficacy in treating agitation and
aggression associated with dementia
Can cause carryover sedation, sometimes severe, if dosed too high
Often not tolerated as a monotherapy for moderate to severe cases of
depression, as many patients cannot tolerate high doses (>150 mg)
Do not for get to try at high doses, up to 600 mg/day , if lower doses
well tolerated but inef fective
Priapism may occur in 1 in 8000 men
Early indications of impending priapism may be slow penile
detumescence when awakening from REM sleep

symptom of some other primary disorder , and not a primary disorder
itself, and thus warrant evaluation for comorbid psychiatric and/or

DeVane CL . Differential pharmacology of newer antidepressants  . J Clin
Psychiatry  1998  ;59 (Suppl 20): S85 –93.
Haria  M , Fitton  A , McTavish  D . Trazodone. A review of its
pharmacology , therapeutic use in depression and therapeutic potential in
other disorders  . Drugs Aging  1994  ;4 :331 –55 .
of some “second ” - and “fourth ” -generation antidepressants: iprindole,
venlafaxine  . Cell Mol Neur obiol  1999  ;19 :427 –42 .
Stahl  SM. Mechanism of action of trazodone: a multifunctional drug  . CNS
Spectr  2009  ;14 (10): 536 –46 .Rarely , patients may complain of visual “trails ” or after -images on
trazodone

Triazolam
Brands
Generic?
Yes
 Class
 How the Drug W orksHalcion
Catatonia

✽ Anterograde amnesia
Sedation
Wait

How to Dose
 Dosing T ipsTo avoid problems with memory , take triazolam only if planning to
0.125 –0.25 mg/day at bedtime for 7 –10 days
Tablet 0.125 mg, 0.25 mg
Initial 0.125 or 0.25 mg/day at bedtime; may increase cautiously to
0.5 mg/day if inef fective; maximum dose generally 0.5 mg/day

✽ Many patients cannot tolerate 0.5 mg dose (e.g., developing
anterograde amnesia)
✽ Higher doses associated with more behavioral problems and
anterograde amnesia
Overdose
Long-T erm UseUse lowest possible ef fective dose and assess need for continued
Triazolam should generally not be prescribed in quantities greater
Some side ef fects (sedation, dizziness, lightheadedness, amnesia)
seem to increase with dose
Patients with lower weights may require only a 0.125 mg dose
treatment
Can be fatal in monotherapy; poor coordination, confusion, seizure,
slurred speech, sedation, coma, respiratory depression
Increased wakefulness during the latter part of the night (wearing
off) or an increase in daytime anxiety (rebound) may occur because
of short half-life

How to Stop
 Drug InteractionsTriazolam is a Schedule IV drug
Half-life 1.5 –5.5 hours

Other W arnings/Pr ecautionsCYP450 3A inhibitors such as nefazodone, fluoxetine, and
fluvoxamine may decrease clearance of triazolam and raise
triazolam levels significantly
Ranitidine may increase plasma concentrations of triazolam
efficacy

Do Not Use
Cardiac ImpairmentSome depressed patients may experience a worsening of suicidal
ideation
Triazolam should be administered only at bedtime
Grapefruit juice could increase triazolam levels
If patient is taking ketoconazole, itraconazole, nefazodone, or other
potent CYP450 3A4 inhibitors
If there is a proven aller gy to triazolam or any benzodiazepine

Elderly
Recommended initial dose: 0.125 mg
May be more sensitive to adverse ef fects
Long-term ef fects of triazolam in children/adolescents are unknown
monitored

Primary T arget SymptomsNeonatal flaccidity has been reported in infants whose mothers took
Unknown if triazolam is secreted in human breast milk, but all
Short-acting
Patients on concomitant CYP450 3A4 inhibitors
Patients with terminal insomnia (early morning awakenings)

Pearls
✽ The shorter half-life should prevent impairments in cognitive and
motor performance during the day as well as daytime sedation
✽ If tolerance develops, the short half-life of elimination may result in
increased anxiety during the day and/or increased wakefulness during
the latter part of the night
✽ However , the risk of drug interactions with alcohol taken at night
may be greater than for some other sedative hypnotics, especially for
✽ Anterograde amnesia may be more likely with triazolam than with
other sedative benzodiazepines
✽ The risk of unusual behaviors or hallucinations may be greater with
triazolam than with other sedative benzodiazepinesThe short half-life may minimize the risk of drug interactions with
agents taken during the day (e.g., alcohol)
Because of its short half-life and inactive metabolites, triazolam
disease

disease
Clearance of triazolam may be slightly faster in women than in men
Women taking oral progesterone may be more sensitive to the
effects of triazolam
treatment

Jonas  JM , Coleman  BS , Sheridan  AQ , Kalinske  RW . Comparative
clinical profiles of triazolam versus other shorter -acting hypnotics  . J Clin
Psychiatry  1992  ;53 (Suppl): S19 –31.
Lobo  BL , Greene  WL . Zolpidem: distinct from triazolam?  Ann
Pharmacother  1997  ;31 :625–32 .
Rothschild  AJ . Disinhibition, amnestic reactions, and other adverse
reactions secondary to triazolam: a review of the literature  . J Clin
Psychiatry  1992  ;53 (Suppl): S69 –79.
:1109 –25.

Trifluoperazine
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Stelazine
(D-RAn)
Schizophr enia (oral, intramuscular)
Nonpsychotic anxiety (short-term, second-line)

Tests
>30)stabilization and maintenance
clozapine

trifluoperazine should be discontinued at the first sign of decline of
WBC in the absence of other causative factorsPatients should be

How Drug Causes Side Effectsmonitored periodically for the development of abnormal movements
of tardive dyskinesia, using neurological exam and the AIMS
(Abnormal Involuntary Movement Scale)

✽ Rash
✽ Priapism
Dry mouth, constipation, blurred vision, urinary retention

 Sedation
Wait
Wait
Wait

Dosage FormsFor sedation, give at night
Oral: psychosis: 15 –20 mg/day
Tablet 1 mg, 2 mg, 5 mg, 10 mg
Vial 2 mg/mL (discontinued in USA)

How to Dose
✽ Use only low doses and short-term for anxiety because
trifluoperazine is now a second-line treatment and has the risk of
tardive dyskinesiaConcentrate 10 mg/mL (discontinued in USA)
Psychosis: oral: initial 2 –5 mg twice a day; increase gradually over
2–3 weeks
Psychosis: intramuscular: 1 –2 mg every 4 –6 hours; generally do not
exceed 6 mg/day
Anxiety: initial 1 –2 mg/day; maximum 6 mg/day
Concentrate contains sulfites that may cause aller gic reactions,
Many patients can be dosed once a day

Overdose
Drug-induced parkinsonism, sedation, seizures, coma, hypotension,
Not intended to treat anxiety long-term (i.e., longer than 12 weeks)
No

a few weeks after trifluoperazine is discontinued
Mean elimination half-life approximately 12.5 hours
guanethidine, whose antihypertensive actions trifluoperazine may
Phenothiazines may reduce ef fects of anticoagulants
syndrome
If used with propranolol, plasma levels of both drugs may rise

Do Not UseUse cautiously in patients with alcohol withdrawal or convulsive
Antiemetic ef fect may mask signs of other disorders or overdose;
suppression of cough reflex may cause asphyxia
dementia
therapy

therapy

ElderlyIf there is the presence of blood dyscrasias, bone marrow
If there is a proven aller gy to trifluoperazine
Not recommended for use
Do not use parenteral administration unless necessary

 PregnancyElderly patients with dementia-related psychosis treated with
Children should be closely monitored when taking trifluoperazine
Oral: initial 1 mg; increase gradually; maximum 15 mg/day except
in older children with severe symptoms
Intramuscular: 1 mg once or twice a day

Potential Disadvantagesincreased or decreased muscle tone, tremor , sleepiness, severe
pregnancy
Trifluoperazine should only be used during pregnancy if clearly
needed

 Pearls
than other antipsychoticsChildren
Elderly
Trifluoperazine is a higher potency phenothiazine
drug-induced parkinsonism than with low-potency
another
antipsychotic such as trifluoperazine or from switching to a
conventional antipsychotic such as trifluoperazine

Doongaji  DR , Satoskar  RS , Sheth  AS , et al. Centbutindole vs
trifluoperazine: a double-blind controlled clinical study in acute
schizophrenia  . J Postgrad Med  1989  ;35 :3 –8.
efficacy and tolerability of 32 oral antipsychotics for the acute treatment ofHowever , long-term polypharmacy with a combination of a
conventional antipsychotic such as trifluoperazine with an atypical

Kiloh  LG , Williams  SE , Grant  DA , Whetton  PS . A double-blind
comparative trial of loxapine and trifluoperazine in acute and chronic
schizophrenic patients  . J Int Med Res  1976  ;4 :441 –8 .
Marques  LO , Lima  MS , Soares  BG. Trifluoperazine for schizophrenia  .
Cochrane Database Syst Rev  2004  ;(1):CD003545  .

Trihexyphenidyl
Brands
Generic?
Yes
 Class
 How the Drug W orksArtane

If It W orks
For drug-induced parkinsonism, increase to highest tolerated dose
Consider switching to benztropine, diphenhydramine, or a

Tests
Trihexyphenidyl itself is an augmenting agent to antipsychotics
Dilation of colon

Sedation
Dosing And UseUrinary retention
Anticholiner gic agents such as trihexyphenidyl can exacerbate or

How to Dose
 Dosing T ipsDrug-induced parkinsonism: 5 –15 mg/day
Parkinsonism: 6 –15 mg/day
Tablet 2 mg, 5 mg
Injection 2 mg/5 mL
Drug-induced parkinsonism: 5 –15 mg/day; assess ef fect and
increase dose empirically as tolerated; total daily dose varies from
patient to patient
Parkinsonism (oral): initial 1 mg/day; after 3 days can increase the
dose in 2 mg increments every 3 –5 days as tolerated until clinical
effect is reached; total daily dose should be divided into 3 doses and
given with meals
withdraw trihexyphenidyl after 1 –2 weeks to determine if still
needed
To achieve more rapid relief, temporarily lower the dose of the
offending agent (phenothiazine, thioxanthene, or butyrophenone)

Overdose
How to Stop
Pharmacokineticswhen starting trihexyphenidyl
Taking trihexyphenidyl with meals can reduce side ef fects
In Parkinson ’s disease, the usual dose is 6 –10 mg/day (divided into
3 doses) for idiopathic Parkinson ’s disease and 12 –15 mg/day
(divided into 3 or 4 doses) for post-encephalitic Parkinson ’s disease
Circulatory collapse, cardiac arrest, respiratory depression or arrest,
CNS depression or stimulation, psychosis, shock, coma, seizure,
ataxia, combativeness, anhidrosis and hyperthermia, fever ,
dysphagia, decreased bowel sounds, sluggish pupils
Safe
Effectiveness may decrease over time (years) and side ef fects such
No

Do Not UseHalf-life 6 –10 hours; time to peak ef fect is 1 –1.3 hours
Trihexyphenidyl and all other anticholiner gic agents may increase
serum levels and ef fects of digoxin
Use with caution in hot weather , as trihexyphenidyl may increase

Elderly
 Childr en and AdolescentsIf there is a proven aller gy to trihexyphenidyl

Pregnancy
Potential DisadvantagesEffective June 30, 2015, the US FDA requires changes to the
Unknown if trihexyphenidyl is secreted in human breast milk, but
Infants of women who choose to breast feed while on
trihexyphenidyl should be monitored for possible adverse ef fects

Generalized dystonias (well tolerated in younger age groups)

 PearlsPatients with long-standing drug-induced parkinsonism may not
Multiple dose-dependent side ef fects may limit use
Tremor , akinesia, rigidity , drooling, dystonia
Often abused in correctional settings for its euphoric and
sedative/hypnotic action, especially at high doses
Although any anticholiner gic agent is potentially abusable,
especially in a correctional setting, trihexyphenidyl may be more
abusable than others, presumably due to its dopamine-enhancing
actions
Useful adjunct in younger Parkinson ’s patients with tremor

Brocks  DR. Anticholiner gic drugs used in Parkinson ’s disease: an
Pharm Sci  1999  ;2 (2):39 –46 .
Colosimo  C , Gori MC , Inghilleri  M. Postencephalitic tremor and delayed-
onset parkinsonism  . Parkinsonism Relat Disor d 1999  ;5 (3):123 –4 .
2005  ;(1):CD004312  .Patients with mental impairment do poorly
Dystonias related to cerebral palsy , head injuries, and stroke may
improve with trihexyphenidyl, especially in younger , cognitively
normal patients
Schizophrenia patients may abuse trihexyphenidyl and other
anticholiner gic medications to relieve negative symptoms, for a
stimulant ef fect, or to improve symptoms of drug-induced

especially in institutional settings as adjunct to antipsychotics

Sanger  TD , Bastian  A , Brunstrom  J , et al. Prospective open-label clinical
trial of trihexyphenidyl in children with secondary dystonia due to cerebral
palsy  . J Child Neur ol 2007  ;22 (5):530–7 .
Zemishlany  Z , Aizenber g D , Weiner  Z , Weizman  A. Trihexyphenidyl
(Artane) abuse in schizophrenic patients  . Int Clin Psychopharmacol  1996
;11 (3):199 –202 .

Triiodothyronine
Brands
Generic?
Yes
 Class
 How the Drug W orksCytomel
Synthetic hormone; antidepressant adjunct
Replacement or supplemental therapy in patients with
hypothyr oidism (except transient hypothyr oidism during the
recovery phase of subacute thyr oiditis)
Pituitary thyr oid-stimulating hormone (TSH) suppr essant in the
treatment or pr evention of various types of euthyr oid goiters
Major depressive disorder (adjunct)

How Long Until It W orks (for Depr ession)
If It W orks (for Depr ession)
If It Doesn ’t Work (for Depr ession)Hypothetically boosts monoamine actions in the CNS
May work syner gistically with traditional antidepressants
Can work within days, but therapeutic ef fects may be delayed for up
to 8 weeks
Many patients only have a partial response where some symptoms

Consider switching to another antidepressant or adding a dif ferent
Triiodothyronine is itself an augmenting agent for partial response
in depression
Periodic assessment of thyroid status
Administration of triiodothyronine may lead to mild
hyperthyroidism with reduced levels of TSH

Sedation
Increases in thyroid hormone concentrations
Hyperthyroidism (headache, irritability , nervousness, sweating,
arrhythmia, increased bowel motility , menstrual irregularities)
Possible acceleration of bone demineralization, especially in
postmenopausal women (controversial)
Angina pectoris, congestive heart failure
Shock

How to Dose
Wait
Wait
25–50 Î¼ g/day
Tablet 5 Î¼ g, 25 Î¼ g, 50 Î¼ g
Initial 25 Î¼ g/day; if no response can increase to 50 Î¼ g/day after
2–4 weeks

Overdose
How to Stop
PharmacokineticsMonitor TSH levels to determine ef ficacy or thyroid actions in the
periphery and to guide dosing
If no ef fects on depressed mood, may want to discontinue in 8 –12
weeks
To assess ef ficacy in stabilizing mood in combination with other
mood stabilizers, may need to monitor for a few months
Chest pain, increased pulse rate, palpitations, excessive sweating,
heat intolerance, nervousness
No
Half-life approximately 2.5 days

Thyroid hormones appear to increase catabolism of vitamin K-
dependent clotting factors; patients stabilized on oral anticoagulants
who are treated with triiodothyronine should be watched very
closely when triiodothyronine is started and may require dose
reduction of the oral anticoagulant
Initiating thyroid replacement therapy may cause increases in
insulin or oral hypoglycemic requirements; patients receiving
insulin or oral hypoglycemics should be closely watched during
initiation of triiodothyronine
Cholestyramine binds both T4 and T3 in the intestine, thus
impairing absorption of these thyroid hormones; therefore, 4 to 5
hours should elapse between administration of cholestyramine and
thyroid hormones
Use of thyroid products with imipramine and other TCAs may
increase receptor sensitivity and enhance antidepressant activity;
transient cardiac arrhythmias have been observed; thyroid hormone
activity may also be enhanced

Thyroid preparations may potentiate the toxic ef fects of digitalis
Use with caution with ketamine; may cause hypertension and
Use with catecholamines may increase their adrener gic ef fects;
careful observation is required

Do Not Use
Renal ImpairmentUse of thyroid hormones in the therapy of obesity , alone or in
combination, is not effective at doses within the range of daily
hormonal requirements; lar ger doses may produce serious or even
life-threatening manifestations of toxicity , particularly when given
in association with sympathomimetic amines
Use of thyroid hormones is not justified for the treatment of male or
female infertility unless accompanied by hypothyroidism
Use with caution in patients in whom the integrity of the
cardiovascular system is suspected, including elderly patients or
those with angina pectoris
Thyroid hormone therapy in patients with concomitant diabetes
mellitus or insipidus or adrenal cortical insuf ficiency aggravates the
intensity of their symptoms
If patient has uncorrected adrenal cortical insuf ficiency
If patient has untreated thyrotoxicosis
If there is a proven aller gy to triiodothyronine

Elderly
Requires dose reduction: initial 5 Î¼ g; increase by no more than 5
Î¼ g at 2-week intervals; reduce dose if cardiovascular disease is
aggravated
Thyroid hormone is used safely in infants, children, and adolescents
for hypothyroidism
Not studied for use as adjunct in depression

Potential DisadvantagesAdequate, well-controlled studies in pregnant women have failed to
Thyroid hormones do not readily cross the placental barrier , and the
clinical experience to date does not indicate any adverse ef fect on
fetuses when thyroid hormones are administered to pregnant women
No known adverse ef fects but use should be cautious
Patients with lethar gy and fatigue
Patients with unstable or rapidly fluctuating mood
Patients with osteoporosis
Patients already taking thyroid replacement

 Pearls
Aronson  R , Offman  HJ , Joffe RT , et al. Triiodothyronine augmentation in
the treatment of refractory depression: a meta-analysis  . Arch Gen
Psychiatry  1996  ;53 :842 –8 .
Connolly  KR , Thase  ME. If at first you don ’t succeed: a review of the
evidence for antidepressant augmentation, combination and switching
strategies  . Drugs  2011 ;71 (1):43 –64 .
Garlow  SJ , Dunlop  BW , Ninan  PT , Nemerof f CB. The combination of
triiodothyronine (T3) and sertraline is not superior to sertraline
monotherapy in the treatment of major depressive disorder  . J Psychiatr Res
2012  ;46 (11):1406  –13 .Depressed mood
Have periodic monitoring by primary care physician, including neck
examination and thyroid palpation
Generally well tolerated, especially compared to other augmentation
options for depression
May be useful in stabilizing fluctuating mood states as well as
improving depressed mood

Hage  MP , Azar  ST. The link between thyroid function and depression  . J
Thyroid Res  2012  ;2012  :590648  .
Nierenber g AA , Fava  M , Trivedi  MH , et al. A comparison of lithium and
T(3) augmentation following two failed medication treatments for
depression: a ST AR*D report  . Am J Psychiatry  2006  ;163 :1519  –30 .

Trimipramine
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Surmontil
Anxiety
Insomnia

cortex, which lar gely lacks dopamine transporters, trimipramine can
May have immediate ef fects in treating insomnia, agitation, or
anxiety

If It W orksMay continue to work for many years to prevent relapse of
symptoms
stopped

Sedation
Wait
Wait
Wait

How to Dose
Initial 25 mg/day at bedtime; increase by 75 mg every 3 –7 days
75 mg/day in divided doses; increase to 150 mg/day; maximum 200
mg/day; hospitalized patients may receive doses up to 300 mg/day

Overdose
Safe
No

Substrate for CYP450 2D6, 2C19, and 2C9
Half-life approximately 7 –23 hours
activity

Other W arnings/Pr ecautionsespecially a mixed dysphoric bipolar II condition sometimes
discontinuation of trimipramine
after discontinuing trimipramine
days for most drugs) after discontinuing trimipramine, but see Pearls

Do Not Usediuretics, stimulant laxatives, intravenous amphotericin B,
companies

Cardiac ImpairmentIf there is reduced CYP450 2D6 function, such as patients who are
If there is a proven aller gy to trimipramine
trimipramine

Elderly

patients
mg/day

mg/day

✽ Recommended either to discontinue drug or bottle feedCrosses the placenta
pregnancy
essants

 Pearls
✽ May be more useful than some other TCAs for patients with
anxiety , sleep disturbance, and depression with physical illness
✽ May be more sedating than some other TCAsFor many patients this may mean continuing treatment during breast
feeding
Patients with insomnia, anxiety
Patients concerned with weight gain and sedation

antidepressants: a meta-analysis of ef ficacy and tolerability  . J Aff Disor dersantidepressant combinations may be weight gain and orthostatic
Patients on tricyclics should be aware that they may experience

Berger M , Gastpar  M . Trimipramine: a challenge to current concepts on
antidepressives  . Eur Ar ch Psychiatry Clin Neur osci 1996  ;246 :235–9 .
Lapierre  YD . A review of trimipramine. 30 years of clinical use  . Drugs
1989  ;38 (Suppl 1): S17 –24; discussion S49 –50.

Valbenazine
Brands
Generic?
No
 Class
 How the Drug W orksIngrezza
Valbenazine is a selective and reversible inhibitor of the vesicular
monoamine transporter 2 (VMA T2), which packages monoamines,
including dopamine, into synaptic vesicles of presynaptic neurons in
the central nervous system

If It W orks
If tardive dyskinesia does not reverse with valbenazine, then other
management options include deutetrabenazine, tetrabenazine,
reserpine, clonazepam, amantadine, botulinum toxin injections for
focal dystonia symptoms, or ginkgo biloba
ResistanceIn clinical trials valbenazine separated from placebo as early as
week 2

week 2
Valbenazine is itself an augmenting agent to treat a side ef fect of
antipsychotic drugs

Tests
None for healthy individuals; no need for CYP450 2D6 testing
Sedation
Theoretically due to increases in monoamine concentrations at
dosing

Sedation
How to DoseMany experience and/or can be significant in amount
Wait
Wait
Wait
40–80 mg once daily
Capsule 40 mg
Initial dose 40 mg once daily; after 1 week increase to 80 mg once
daily

Pharmacokinetics permit once daily dosing
Consider taking at night to reduce daytime sedation
If improvements in movements wear of f before the end of the day with
nighttime dosing, consider taking in the morning
Overdose
How to Stop
PharmacokineticsLimited experience
Clinical trials have shown continued improvement through 48
weeks
No
Tapering not necessary
In clinical trials, tardive dyskinesia symptoms returned during the 4-
week period following discontinuation of valbenazine

Strong CYP450 3A4 inducers (e.g., carbamazepine) may reduce
exposure to valbenazine; use with strong CYP3A4 inducers is not
Strong CYP450 3A4 inhibitors (e.g., ketoconazole) may increase
exposure to valbenazine; reduce dose to 40 mg in patients taking a
strong CYP3A4 inhibitor
increase exposure to valbenazine ’s active metabolite; consider
reducing dose based on tolerability in patients taking a strong CYP450
2D6 inhibitor or who are known CYP2D6 poor metabolizers
Not recommended for use with monoamine oxidase inhibitors
(MAOIs)
Valbenazine may increase concentrations of digoxin, so monitor
digoxin concentrations in patients taking concomitant digoxin; doseValbenazine is extensively metabolized by hydrolysis of the valine
ester to form the active metabolite ([+]- Î± -HTBZ) and by oxidative
metabolism, primarily by CYP450 3A4/5, to form monooxidized
valbenazine and other minor metabolites

[+]-Î± -HTBZ is further metabolized in part by CYP450 2D6
Valbenazine and [+]- Î± -HTBZ have half-lives of 15 –22 hours
Very little of the parent drug, valbenazine, is present in the blood
due to rapid conversion to its metabolites

adjustment may not be necessary
interval before increasing the dose
Do Not Use
Specia Populations
Cardiac ImpairmentIf there is a proven aller gy to valbenazine
Mild to moderate impairment: dose adjustment not necessary
Severe impairment: not recommended for use
Moderate to severe impairment: 40 mg once daily

Elderly
 PregnancyMay cause an increase in QT interval; avoid use in patients with
In animal studies, no malformations were observed when
valbenazine was administered during the period of or ganogenesis at
doses up to 1.8 (rat) or 24 (rabbit) times the maximum
In rat studies, administration during or ganogenesis through lactation

produced an increase in the number of stillborn pups and postnatal

Primary T arget Symptomspup mortalities at doses less than the maximum recommended
human dose
Unknown if valbenazine is secreted in human breast milk, but all
Breast feeding is not recommended, including for 5 days after the
final dose
Once-a-day administration
Expensive
Few dosing options for titration or individualizing dosing

Pearls
In clinical trials, valbenazine was well tolerated, with the frequency of
adverse events similar in all treatment groups
Valbenazine improved tardive dyskinesia regardless of the therapeutic
use or type of antipsychotic drug concomitantly administered
80 mg is generally associated with better ef ficacy than 40 mg
Valbenazine and its active metabolites bind predominantly only to
VMA T2, so there are no significant of f-target pharmacologic actions
such as blocking the D2 dopamine receptor or the 5HT7 receptor , as is
the case with tetrabenazine ’s and deutetrabenazine ’s active metabolites
Can rarely cause akathisia and dry mouth
Grigoriadis DE, Smith E, Hoare SR, Madan A, Bozigian H. Pharmacologic
characterization of valbenazine (NBI-98854) and its metabolites. J
Pharmacol Exp Ther 2017  ;361(3):454 –61. doi: 10.1124/jpet.1 16.239160  .
Hauser RA, Factor SA, Marder SR, et al. KINECT 3: a phase 3

randomized, double-blind, placebo-controlled trial of valbenazine for
tardive dyskinesia. Am J Psychiatry 2017  ;174(5):476 –84.
Meyer JM. For gotten but not gone: new developments in the understanding
and treatment of tardive dyskinesia. CNS Spectr 2016  ;21(S1):13 –24.

Valproate
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Depakene
Depacon
Depakote, Depakote ER
Stavzor
Neuroscience-based Nomenclature: glutamate (Glu); yet to be
determined
Anticonvulsant, mood stabilizer , migraine prophylaxis, voltage-
sensitive sodium channel modulator

mechanism
How Long Until It W orksAcute mania (divalpr oex) and mixed episodes (divalpr oex,
divalpr oex ER, valpr oic acid delayed-r elease)
Complex partial seizur es that occur either in isolation or in
association with other types of seizur es (monotherapy and
Simple and complex absence seizur es (monotherapy and
Multiple seizur e types, which include absence seizur es
Migraine pr ophylaxis (divalpr oex, divalpr oex ER, valpr oic acid
delayed-r elease)
Maintenance treatment of bipolar disorder
Increases brain concentrations of gamma-aminobutyric acid
(GABA) by an unknown mechanism

If It W orks
stabilization of moodFor acute mania, ef fects should occur within a few days depending
on the formulation of the drug
Should also reduce seizures and improve migraine within a few
weeks
depression, seizures, and headaches

✽ Lamotrigine (with caution and at half the dose in the presence of
valproate because valproate can double lamotrigine levels)
Tests
✽ Before starting treatment, complete blood counts, coagulation tests,
and liver function testsConsider adding psychotherapy
Lithium

Lithium
Consider coagulation tests prior to planned sur gery or if there is a
history of bleeding

✽ Since valproate is frequently associated with weight gain, before
How Drug Causes Side EffectsDuring the first few months of treatment, regular liver function tests
and platelet counts; this can be shifted to once or twice a year for the
remainder of treatment
Plasma drug levels can assist monitoring of ef ficacy , side ef fects,
and compliance

✽ Sedation, dose-dependent tremor , dizziness, ataxia, asthenia,
headache
✽ Abdominal pain, nausea, vomiting, diarrhea, reduced appetite,
constipation, dyspepsia, weight gain
✽ Alopecia (unusual)
Polycystic ovaries (controversial)
Hyperandrogenism, hyperinsulinemia, lipid dysregulation
Decreased bone mineral density (controversial)
Can cause tachycardia or bradycardia
Rare hepatotoxicity with liver failure sometimes severe and fatal,
particularly in children under 2 years old
Rare pancreatitis, sometimes fatal

Sedation
✽ Propranolol 20 –30 mg 2 –3 times/day may reduce tremorMany experience and/or can be significant in amount
Wait
Wait
Wait
Take at night to reduce daytime sedation, especially with divalproex
ER

✽ Multivitamins fortified with zinc and selenium may help reduce
alopecia
Dosage FormsMany side ef fects cannot be improved with an augmenting agent
Mania: 1200 –1500 mg/day
Migraine: 500 –1000 mg/day
Epilepsy: 10 –60 mg/kg per day
Tablet [delayed-release, as divalproex sodium (Depakote)] 125 mg,
250 mg, 500 mg
Tablet [extended-release, as divalproex sodium (Depakote ER)] 250
mg, 500 mg
Capsule [sprinkle, as divalproex sodium (Depakote Sprinkle)] 125
mg
Capsule [as valproic acid (Depakene)] 250 mg
Capsule [delayed-release, as valproic acid (Stavzor)] 125 mg, 250
mg, 500 mg
Injection [as sodium valproate (Depacon)] 100 mg/mL (5 mL)

How to Dose
✽ Oral loading with 20 –30 mg/kg per day may reduce onset of action
to 5 days or less and may be especially useful for treatment of acute
mania in inpatient settingsUsual starting dose for mania or epilepsy is 15 mg/kg in 2 divided
doses (once daily for extended-release valproate)
Acute mania (adults): initial 1000 mg/day; increase dose rapidly;
maximum dose generally 60 mg/kg per day
For less acute mania, may begin at 250 –500 mg the first day , and
then titrate upward as tolerated
Migraine (adults): initial 500 mg/day; maximum recommended dose
1000 mg/day
Epilepsy (adults): initial 10 –15 mg/kg per day; increase by 5 –10
mg/kg per week; maximum dose generally 60 mg/kg per day
Given the half-life of immediate-release valproate (e.g., Depakene,
Depakote), twice daily dosing is probably ideal
Extended-release valproate (e.g., Depakote ER) can be given once
daily
However , extended-release valproate is only about 80% as

daily
bioavailable as immediate-release valproate, producing plasma drug
levels 10 –20% lower than with immediate-release valproate

✽ Thus, extended-release valproate is dosed approximately 8 –20%
higher when converting patients to the ER formulation
✽ Divalproex immediate-release formulation reduces gastrointestinal
side ef fects compared to generic valproate
✽ Divalproex ER improves gastrointestinal side ef fects and alopecia
compared to immediate-release divalproex or generic valproate
Overdose
Long-T erm UseDepakote (divalproex sodium) is an enteric-coated stable compound
containing both valproic acid and sodium valproate
The amide of valproic acid is available in Europe [valpromide
(Depamide)]
Trough plasma drug levels >45 µg/mL may be required for either
antimanic ef fects or anticonvulsant actions
Trough plasma drug levels up to 100 µg/mL are generally well
tolerated
Trough plasma drug levels up to 125 µg/mL may be required in
some acutely manic patients
Dosages to achieve therapeutic plasma levels vary widely , often
between 750 –3000 mg/day
Fatalities have been reported; coma, restlessness, hallucinations,

sedation, heart block

How to Stop
✽ Rapid discontinuation increases the risk of relapse in bipolar
disorder
 Drug InteractionsRequires regular liver function tests and platelet counts
No
valproate is being discontinued
Patients may seize upon withdrawal, especially if withdrawal is
abrupt
Mean terminal half-life 9 –16 hours
Metabolized primarily by the liver , approximately 25% dependent
upon CYP450 system (CYP450 2C9 and 2C19)
Inhibits CYP450 2C9
Food slows rate but not extent of absorption

✽ Lamotrigine dose should be reduced by perhaps 50%  if used with
valproate, as valproate inhibits metabolism of lamotrigine and raises
lamotrigine plasma levels, theoretically increasing the risk of rash
✽ Be alert to the following symptoms of hepatotoxicity that require
immediate attention: malaise, weakness, lethar gy, facial edema,Plasma levels of valproate may be lowered  by carbamazepine,
phenytoin, ethosuximide, phenobarbital, rifampin
Aspirin may inhibit metabolism of valproate and increase  valproate
plasma levels
Plasma levels of valproate may also be increased  by felbamate,
chlorpromazine, fluoxetine, fluvoxamine, topiramate, cimetidine,
erythromycin, and ibuprofen
Valproate inhibits metabolism of ethosuximide, phenobarbital, and
phenytoin, and can thus increase  their plasma levels
No likely pharmacokinetic interactions of valproate with lithium or
atypical antipsychotics
Use of valproate with clonazepam may cause absence status

Reports of hypothermia and hyperammonemia with or without

anorexia, vomiting, yellowing of the skin and eyes
✽ Be alert to the following symptoms of pancreatitis that require
immediate attention: abdominal pain, nausea, vomiting, anorexia
✽ Teratogenic ef fects in developing fetuses such as neural tube
defects may occur with valproate use
✽ Somnolence may be more common in the elderly and may be
associated with dehydration, reduced nutritional intake, and weight
loss, requiring slower dosage increases, lower doses, and monitoring
of fluid and nutritional intake
Use in patients with thrombocytopenia is not recommended; patients
should report easy bruising or bleeding
Evaluate for urea cycle disorders, as hyperammonemic
encephalopathy , sometimes fatal, has been associated with valproate
administration in these uncommon disorders; urea cycle disorders,
such as ormithine transcarbamylase deficiency , are associated with
unexplained encephalopathy , mental retardation, elevated plasma
ammonia, cyclical vomiting, and lethar gy

Valproate is associated with a rare but serious skin condition known
as drug reaction with eosinophilia and systemic symptoms
lymph nodes, inflammation of or gans, and an increase in white
blood cells known as eosinophilia. In some cases, DRESS can lead
to death

Do Not Use
If patient has pancreatitis
If patient has serious liver disease
If patient has urea cycle disorder
If there is a proven aller gy to valproic acid, valproate, or divalproex
Reduce starting dose and titrate slowly; dosing is generally lower
than in healthy adults

✽ Sedation in the elderly may be more common and associated with
dehydration, reduced nutritional intake, and weight loss
✽ Not generally recommended for use in children under age 10 for
bipolar disorder except by experts and when other options have been
 Pregnancy
spina bifida) or other congenital anomaliesMonitor fluid and nutritional intake
1 in 3 elderly patients in long-term care who receive valproate may
ultimately develop thrombocytopenia
Children under age 2 have significantly increased risk of
hepatotoxicity , as they have a markedly decreased ability to
eliminate valproate compared to older children and adults
Use requires close medical supervision

✽ If drug is continued, monitor clotting parameters and perform tests
to detect birth defects
✽ If drug is continued, consider vitamin K during the last 6 weeks of
pregnancy to reduce risks of bleeding
✽ For bipolar patients, valproate should generally be discontinued
period, mood stabilizer treatment such as valproate should generally be
pregnancyCases of developmental delay in the absence of teratogenicity
associated with fetal exposure have been identified
Increased risk of lower cognitive test scores in children whose
mothers took valproate during pregnancy

anticonvulsants such as valproate if treatment of bipolar disorder is
✽ Generally considered safe to breast feed while taking valproate
The Art Of PsychopharmacologyBipolar symptoms may recur or worsen during pregnancy and some
feeding

 Pearls (for bipolar disorder)
✽ Valproate is a first-line treatment option that may be best for
patients with mixed states of bipolar disorder or for patients with
rapid-cycling bipolar disorderManic phase of bipolar disorder
Works well in combination with lithium and/or atypical
Patients unable to tolerate sedation or weight gain
Multiple drug interactions
Multiple side ef fect risks
Incidence of migraine
Incidence of partial complex seizures

✽ May also be useful for bipolar disorder in combination with
lamotrigine, but must reduce lamotrigine dose by half when combined
with valproate
✽ May be useful as an adjunct to atypical antipsychotics for rapid
✽ Used to treat aggression, agitation, and impulsivity not only in
bipolar disorder and schizophrenia but also in many other disorders,
including dementia, personality disorders, and brain injuryOnly a third of bipolar patients experience adequate relief with a
control
Useful in combination with atypical antipsychotics and/or lithium
for acute mania

control
other than lamotrigine is not well demonstrated; such combinations
Patients with acute mania tend to tolerate side ef fects better than
patients with hypomania or depression

✽ In women of childbearing potential who are or are likely to become
monitor contraceptive statusMultivitamins fortified with zinc and selenium may help reduce
alopecia
Association of valproate with polycystic ovaries is controversial and
may be related to weight gain, obesity , or epilepsy
Nevertheless, may wish to be cautious in administering valproate to
women of childbearing potential, especially adolescent female
bipolar patients, and carefully monitor weight, endocrine status, and
ovarian size and function
Association of valproate with decreased bone mass is controversial
and may be related to activity levels, exposure to sunlight, and
epilepsy , and might be prevented by supplemental vitamin D 2000
IU/day and calcium 600 –1000 mg/day
New delayed-release capsule of valproic acid (Stavzor) may be
easier to swallow than other formulations
A prodrug of valproic acid, valpromide, is available in several

European countries
Although valpromide is rapidly transformed to valproic acid, it has
some unique characteristics that can af fect drug interactions
In particular , valpromide is a potent inhibitor of liver microsomal
epoxide hydrolase and thus causes clinically significant increases in

Bowden  CL . Valproate  . Bipolar Disor ders 2003  ;5 :189–202 .
Gill D , Derry  S , Wiffen PJ , Moore  RA . Valproic acid and sodium
valproate for neuropathic pain and fibromyalgia in adults  . Cochrane
Database Syst Rev  2011 ;(10 ):CD009183.
Landy  SH , McGinnis  J . Divalproex sodium –review of prophylactic
migraine ef ficacy , safety and dosage, with recommendations  . Tenn Med
1999  ;92 :135–6 .
Macritchie  KA , Geddes  JR , Scott  J , Haslam  DR , Goodwin  GM . Valproic
acid, valproate and divalproex in the maintenance treatment of bipolar
disorder  . Cochrane Database Syst Rev  2001  ;(3 ):CD003196  .
60 .the plasma levels of carbamazepine-10,1 1-epoxide (the active
metabolite of carbamazepine)

Varenicline
Brands
Generic?
No
 Class
 How the Drug W orksChantix
Champix
Neuroscience-based Nomenclature: acetylcholine receptor partial
agonist (ACh-RP A)
Smoking cessation treatment; alpha 4 beta 2 partial agonist at
nicotinic acetylcholine receptors
Nicotine addiction/dependence

If It W orks
ResistanceCauses sustained but small amounts of dopamine release (less than
with nicotine)
Specifically , as a partial agonist at alpha 4 beta 2 nicotinic
acetylcholine receptors, varenicline activates these receptors to a
lesser extent than the full agonist nicotine and also prevents nicotine
from binding to these receptors
Most prominent actions are on mesolimbic dopaminer gic neurons in
the ventral tegmental area
Recommended initial treatment trial is 12 weeks; an additional 12-
week trial in individuals who stop smoking after 12 weeks may
increase likelihood of long-term abstinence
Reduces withdrawal symptoms and the ur ge to smoke; increases
Evaluate for and address contributing factors, then reattempt
treatment

Tests
Best to attempt other monotherapies
Theoretically due to increases in dopamine concentrations at
Dose-dependent nausea, vomiting, constipation, flatulence
Insomnia, headache, abnormal dreams
Rare activation of agitation, depressed mood, suicidal ideation,
suicidal behavior

Sedation
Dosage FormsSome patients report weight loss
Some patients report activation and insomnia
Wait
agent
1 mg twice daily
Tablet 0.5 mg, 1 mg

How to Dose
OverdosePatient should either set a quit date and then begin taking
varenicline 1 week before the quit date or start varenicline and then
quit smoking between days 8 and 35 of treatment
Initial 0.5 mg/day; after 3 days increase to 1 mg/day in two divided
doses; after 4 days can increase to 2 mg/day in two divided doses
Varenicline should be taken following a meal and with a full glass of
water
varenicline treatment can increase the chances of success
Initial recommended treatment duration is 12 weeks; for individuals
who have stopped smoking after 12 weeks continued treatment for
an additional 12 weeks can increase the likelihood of long-term
For patients who are unsuccessful in their attempt to quit following
12 weeks of treatment or those who relapse following treatment, it is
best to attempt to address factors contributing to the failed attempt
and then reintroduce treatment

How to Stop
 Drug InteractionsTreatment for up to 24 weeks has been found ef fective
No
Taper to avoid withdrawal ef fects, but no well-documented
tolerance, dependence, or withdrawal reactions
Elimination half-life 24 hours
Does not inhibit hepatic enzymes or renal transport proteins, and
thus is unlikely to af fect plasma concentrations of other drugs
other drugs
Side ef fects may be increased if varenicline is taken with nicotine
Varenicline may alter one ’s reaction to alcohol, with case reports
showing decreased tolerance to alcohol, increased drunkenness,
unusual or aggressive behavior , or no memory of things that
happened

Do Not Use
Hepatic ImpairmentMonitor patients for changes in behavior , agitation, depressed mood,
worsening of preexisting psychiatric illness, and suicidality
Use cautiously in patients with a history of seizures or other factors
that can lower the seizure threshold
If there is a proven aller gy to varenicline
Severe impairment: initial dose 0.5 mg once daily; maximum
recommended dose 0.5 mg twice daily
End-stage renal disease under going hemodialysis: maximum
recommended dose is 0.5 mg once daily if tolerated
Removed by hemodialysis

Elderly
 Pregnancy
Breast FeedingEffective in patients with cardiovascular disease; small increased
risk of certain cardiovascular adverse ef fects in these patients
Not shown to be ef fective for patients 16 years and younger

 PearlsUnknown if varenicline is secreted in human breast milk, but all
More ef fective than other pharmacotherapies for smoking cessation
Not well studied in patients with comorbid psychiatric disorders
More ef fective than nicotine or bupropion
Unlike nicotine or bupropion, the patient cannot “smoke over ”
varenicline since varenicline, but not the others, will block the
effects of additional smoked nicotine if the patient decides to smoke
Although tested in the general population excluding psychiatric
patients, where smoking rates in the USA are about 20 –25%, there
is great unmet need for smoking cessation treatments in patients

Anthenelli  RM , Benowitz  N , West R , et al. Neuropsychiatric safety and
efficacy of varenicline, bupropion, and nicotine patch in smokers with and
without psychiatric disorders (EAGLES): a double-blind, randomised,
placebo-controlled clinical trial  . Lancet  2016  ;387 (10037): 2507  –20.
Cerimele  JM , Durango  A. Does varenicline worsen psychiatric symptoms
in patients with schizophrenia or schizoaf fective disorder? A review ofwith psychiatric disorders, especially attention deficit hyperactivity
disorder and schizophrenia, which have smoking rates in the USA as
high as 50 –75%
Smoking cessation treatment in patients with comorbid psychiatric
disorders is not well studied
Preliminary results suggest that varenicline is not associated with
worsening of psychiatric symptoms in stable patients with
schizophrenia, schizoaf fective disorder , or depression
Patients with comorbid psychiatric disorders should be closely

monitored in terms of their psychiatric symptoms, especially
suicidality
In a lar ge multinational study requested by the FDA, there was no
significant increase in moderate-to-severe neuropsychiatric adverse
events with varenicline relative to nicotine patch or placebo in
participants with or without history of psychiatric disorder

published studies  . J Clin Psychiatry  2012  ;73 (8):e1039  –47.
Jorenby  DE , Hays  JT , Rigotti  NA . Efficacy of varenicline, an alpha4beta2
nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-
release bupropion for smoking cessation: a randomized controlled trial  .
JAMA  2006  ;296 (1):56 –63 .
Meszaros  ZS , Abdul-Malak  Y , Dimmock  JA , et al. Varenicline treatment
of concurrent alcohol and nicotine dependence in schizophrenia: a
randomized, placebo-controlled pilot trial  . J Clin Psychopharmacol  2013
;33 (2 ):243–7 .
Rollema  H , Coe JW , Chambers  LK , et al. Rationale, pharmacology and
clinical ef ficacy of partial agonists of alpha4beta2 nACh receptors for
smoking cessation  . Trends Pharmacol Sci  2007  ;28 (7):316–25 .
Wu P , Wilson  K , Dimoulas  P , Mills  EJ . Effectiveness of smoking
cessation therapies: a systematic review and meta-analysis  . BMC Public
Health  2006  ;6 :300 .

Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Effexor
Effexor XR
Neuroscience-based Nomenclature: serotonin and norepinephrine

How Long Until It W orksPanic disorder
cortex, which lar gely lacks dopamine transporters, venlafaxine can

If It W orks
in remission rates may still occur after 8 weeks, and for up to 6
months after initiating dosing
symptoms
Continue treatment until all symptoms are gone (remission),
especially in depression and whenever possible in anxiety disorders

✽ Mirtazapine ( “California rocket fuel ” ; a potentially powerful dual
of bipolar disorder and suicidal ideation)problems concentrating)

ideation)

Tests
How Drug Causes Side EffectsModafinil, especially for fatigue, sleepiness, and lack of
tiagabine

SedationMost side ef fects increase with higher doses, at least transiently
Dose-dependent increase in blood pressure

Best Augmenting Agents for Side EffectsOccurs in significant minority
Wait
Wait
Wait

discontinuation of venlafaxine
Depression: 75 –225 mg/day , once daily (extended-release) or
divided into 2 –3 doses (immediate-release)
GAD: 150 –225 mg/day
Capsule (extended-release) 37.5 mg, 75 mg, 150 mg
Tablet (extended-release) 37.5 mg, 75 mg, 150 mg, 225 mg
Tablet 25 mg scored, 37.5 mg scored, 50 mg scored, 75 mg scored,
100 mg scored
Initial dose 37.5 mg once daily (extended-release) or 25 –50 mg
divided into 2 –3 doses (immediate-release) for a week, if tolerated;

✽ Thus, nonresponders at lower doses should try higher doses to be
assured of the benefits of dual SNRI action
✽ Consider checking plasma levels of ODV and venlafaxine in
nonresponders who tolerate high doses, and if plasma levels are low ,increase daily dose generally no faster than 75 mg every 4 days until
desired ef ficacy is reached; maximum dose generally 375 mg/day
Usually try doses at 75 mg increments for a few weeks prior to
incrementing by an additional 75 mg
At all doses, potent serotonin reuptake blockade
75–225 mg/day may be predominantly serotoner gic in some
patients, and dual serotonin and norepinephrine acting in other
patients
225–375 mg/day is dual serotonin and norepinephrine acting in most
patients
At very high doses (e.g., >375 mg/day), dopamine reuptake blocked
as well in some patients
Up to 600 mg/day has been given for heroic cases
Venlafaxine has an active metabolite O-desmethylvenlafaxine
(ODV), which is formed as the result of CYP450 2D6

Thus, CYP450 2D6 inhibition reduces the formation of ODV , but
this is of uncertain clinical significance

experts can prudently prescribe doses above 375 mg/day while
monitoring closely
✽ For patients with severe problems discontinuing venlafaxine,
dosing may need to be tapered over many months (i.e., reduce dose by
1% every 3 days by crushing tablet and suspending or dissolving in
100 mL of fruit juice, and then disposing of 1 mL and drinking the
rest; 3 –7 days later , dispose of 2 mL, and so on). This is both a form of
very slow biological tapering and a form of behavioral desensitization
(not for XR)
OverdoseDo not break or chew venlafaxine XR capsules, as this will alter
For some patients with severe problems discontinuing venlafaxine,
it may be useful to add an SSRI with a long half-life, especially
fluoxetine, prior to taper of venlafaxine; while maintaining
fluoxetine dosing, first slowly taper venlafaxine and then taper

Can be lethal; may cause no symptoms; possible symptoms include
sedation, convulsions, rapid heartbeat
Fatal toxicity index data from the UK suggest a higher rate of deaths
from overdose with venlafaxine than with SSRIs

How to Stop
venlafaxine than with some other antidepressants
PharmacokineticsUnknown whether this is related to dif ferences in patients who
receive venlafaxine or to potential cardiovascular toxicity of
venlafaxine
See doctor regularly to monitor blood pressure, especially at doses
>225 mg/day
No
Parent drug has 3 –7 hour half-life
Active metabolite has 9 –13 hour half-life

MAOIs, so do not use with MAOI or for at least 14 days after
drugs) after discontinuing venlafaxine
Concomitant use with cimetidine may reduce clearance of
venlafaxine and raise venlafaxine levels
Could theoretically interfere with the analgesic actions of codeine or
possibly with other triptans

Do Not Use
companies
If there is a proven aller gy to venlafaxine
Lower dose by 25 –50%

Elderly
 Childr en and AdolescentsLower dose by 50%
Hypertension should be controlled prior to initiation of venlafaxine
and should be monitored regularly during treatment
Venlafaxine has a dose-dependent ef fect on increasing blood
pressure
Venlafaxine is contraindicated in patients with heart disease in the
UK
Venlafaxine can block cardiac ion channels in vitro
Venlafaxine worsens (i.e., reduces) heart rate variability in
depression, perhaps due to norepinephrine reuptake inhibition

patients
Not specifically approved, but preliminary data suggest that
venlafaxine is ef fective in children and adolescents with depression,
anxiety disorders, and ADHD

Breast FeedingNonetheless, continuous treatment during pregnancy may be
pregnancy

essants
are on venlafaxine

Potential AdvantagesIf child becomes irritable or sedated, breast feeding or drug may
the mother

 Pearls
✽ May be ef fective in patients who fail to respond to SSRIs, and may
be one of the preferred treatments for treatment-resistant depression
✽ May be used in combination with other antidepressants for
treatment-refractory casesPatients sensitive to nausea
Anxiety
XR formulation improves tolerability , reduces nausea, and requires
only once daily dosing
May be ef fective in a broad array of anxiety disorders
May be ef fective in adult ADHD

✽ Has greater potency for serotonin reuptake blockade than for
norepinephrine reuptake blockade, but this is of unclear clinical
significance as a dif ferentiating feature from other SNRIs
✽ In vitro binding studies tend to underestimate in vivo potency for
reuptake blockade, as they do not factor in the presence of high
concentrations of an active metabolite, higher oral mg dosing, or the
lower protein binding which can increase functional drug levels at
receptor sites
✽ Preliminary studies in neuropathic pain and fibromyalgia suggest
potential ef ficacy
✽ Because of recent studies from the UK that suggest a higher rate of
deaths from overdose with venlafaxine than with SSRIs, and because
of its potential to af fect heart function, venlafaxine can only beEffective dose range is broad (i.e., 75 –375 mg in many dif ficult
cases, and up to 600 mg or more in heroic cases)
Efficacy as well as side ef fects (especially nausea and increased
blood pressure) are dose-dependent

Blood pressure increases rare for XR formulation in doses up to 225
mg
More withdrawal reactions reported upon discontinuation than for
May be helpful for hot flushes in perimenopausal women
SSRIs

prescribed in the UK by specialist doctors and is contraindicated there
in patients with heart disease
Buckley  NA , McManus  PR . Fatal toxicity of serotoner gic and other
antidepressant drugs: analysis of United Kingdom mortality data  . BMJ
2002  ;325 :1332  –3.
Cheeta  S , Schifano  F , Oyefeso  A , Webb L , Ghodse  AH . Antidepressant-
related deaths and antidepressant prescriptions in England and W ales,
1998 –2000  . Br J Psychiatry  2004  ;184 :41 –7.
Davidson  J , Watkins  L , Owens  M , et al. Effects of paroxetine and
venlafaxine XR on heart rate variability in depression  . J Clin
Psychopharmacol  2005  ;25 :480 –4 .
Hackett  D . Venlafaxine XR in the treatment of anxiety  . Acta Psychiatrica
Scand  2000  ;406 (Suppl):S30 –5.
Sheehan  DV . Attaining remission in generalized anxiety disorder:
venlafaxine extended-release comparative data  . J Clin Psychiatry  2001  ;62
(Suppl 19): S26 –31.Overdose data are from fatal toxicity index studies, which do not

first- or second-line

Smith  D , Dempster  C , Glanville  J , Freemantle  N , Anderson  I . Efficacy
and tolerability of venlafaxine compared with selective serotonin reuptake
inhibitors and other antidepressants: a meta-analysis  . Br J Psychiatry  2002
;180 :396 –404 .
Wellington  K , Perry  CM . Venlafaxine extended-release: a review of its use
in the management of major depression  . CNS Drugs  2001  ;15 :643–9 .

Vilazodone
Brands
Generic?
Yes
 Class
 How the Drug W orksViibryd
Neuroscience-based Nomenclature: serotonin multimodal (S-MM)
SPARI (serotonin partial agonist reuptake inhibitor)
Dual-acting serotonin reuptake inhibitor plus 5HT1A partial agonist
Anxiety
Obsessive-compulsive disorder

If It W orksBoosts neurotransmitter serotonin
Partial agonist actions at presynaptic somatodendritic serotonin 1A
Partial agonist actions at postsynaptic serotonin 1A receptors may
theoretically diminish sexual dysfunction caused by serotonin
reuptake inhibition
Onset of therapeutic actions may be sooner than with other SSRIs
due to vilazodone ’s actions at serotonin 1A receptors, with current
data suggesting onset of ef ficacy as early as week 1, despite the fact
that standard titration does not arrive at full therapeutic dose of 40
mg until the third week
increase (of f label) or it may not work at all

symptoms

Consider increasing dose to 50 –80 mg/day “off label ” over several
weeks if tolerated

ResistanceConsider switching to another agent or adding an appropriate

Tests
Notable Side EffectsClassically , lithium, buspirone, or thyroid hormone
Nausea, diarrhea, vomiting
Insomnia, dizziness

Sedation
serotoner gic antidepressants
reversible on discontinuation of vilazodone)
Sexual dysfunction (men: delayed ejaculation; men and women:
decreased sexual desire, anor gasmia) slightly greater than placebo
and generally less than for SSRIs/SNRIs, but no head-to-head
studies

Wait
Wait

How T o Dose
discontinuation of vilazodone
Tablet 10 mg, 20 mg, 40 mg
Initial 10 mg/day; increase to 20 mg/day after one week; can
increase to 40 mg/day after one more week; should be taken with
food
Given once daily , any time of day tolerated but must be
administered with food, because taking on an empty stomach may
reduce absorption of vilazodone by 50%

Overdose
How to StopNo minimally ef fective dose has been established, so theoretically
possible that doses lower than 40 mg daily may be ef fective in some
patients
Doses higher than 40 mg daily have not been well studied, but
theoretically possible that slow titration to doses higher than 40 mg
may be ef fective in some patients, particularly those with treatment-
resistant depression who fail to respond adequately to 40 mg daily
Few reports of vilazodone overdose
No fatalities; serotonin syndrome, lethar gy, restlessness,
hallucinations, disorientation
No
Tapering to avoid potential withdrawal reactions generally prudent

Mean terminal half-life 25 hours
Absorption and bioavailability are reduced by half when taken on an
empty stomach
drugs) after discontinuing vilazodone
Inhibitors of CYP450 3A4, such as nefazodone, fluoxetine,
fluvoxamine, and even grapefruit juice, may decrease the clearance
of vilazodone and thereby raise its plasma levels, so dose should be
reduced to 20 mg when coadminstered with strong CYP3A4
Inducers of CYP450 3A4, such as carbamazepine, may increase

clearance of vilazodone and thus lower its plasma levels and

Do Not Usepossibly reduce therapeutic ef fects
companies

companies

ElderlyIf patient is taking an MAOI
If there is a proven aller gy to vilazodone
Has not been studied in patients with severe hepatic impairment
Vilazodone has not shown any significant ef fect on blood pressure,
heart rate, or QT interval in placebo-controlled trials

informing parents or guardians of this risk so they can help observe

pregnancy
small)
Serotonin reuptake inhibitor use beyond the 20th week of pregnancy
may be associated with increased risk of pulmonary hypertension in
newborns, although this is not proven

essants
Unknown if vilazodone is secreted in human breast milk, but all
are on vilazodone
the mother

 PearlsPatients with sexual dysfunction on an SSRI/SNRI or who wish to
avoid sexual dysfunction on an antidepressant
Patients with weight gain on another antidepressant or who wish to
avoid weight gain on an antidepressant
Patients with mixed anxiety and depression
Patients who cannot take medication reliably with food
Patients sensitive to gastrointestinal side ef fects such as diarrhea and
nausea
Anxiety
Serotonin 1A partial agonist property is a relatively unique
mechanism of action among approved antidepressants (also
vortioxetine and atypical antipsychotic augmenting agents such as
quetiapine, aripiprazole, brexpiprazole, and others)
First member of a new antidepressant class, SP ARIs, or serotonin
partial agonist reuptake inhibitors
Relative lack of sexual dysfunction and weight gain compared to
many other antidepressants that block serotonin reuptake may be

Citrome  L. Vilazodone for major depressive disorder: a systematic review
of the ef ficacy and safety profile for this newly approved antidepressant –
what is the number needed to treat, number needed to harm and likelihood
to be helped or harmed?  Int J Clin Pract  2012  ;66 (4):356–68 .
Dawson  LA , Watson  JM. Vilazodone: a 5HT1A receptor agonist/serotonin
transporter inhibitor for the treatment of af fective disorders  . CNS Neur osci
Therapeutics  2009  ;15 :107–17 .
Laughren  TP , Gobburu  J , Temple  RJ , et al. Vilazodone: clinical basis for
the US Food and Drug Administration ’s approval of a new antidepressant  .due to the serotonin 1A partial agonist properties of vilazodone
High doses would theoretically raise brain serotonin levels more
robustly than the standard dose, and may improve ef ficacy in some
patients but reduce tolerability in some patients
Consider doses of 50 –80 mg daily if ef fective and well tolerated for

patients with treatment-resistant depression or treatment-resistant
OCD and other anxiety disorders
Consider for patients with comorbid anxiety disorders plus
Nonresponse to vilazodone in elderly may require consideration of

J Clin Psychiatry  2011 ;72 (9):1166 –73.
Rickels  K , Athanasiou  M , Robinson  D , et al. Evidence for ef ficacy and
tolerability of vilazodone in the treatment of major depressive disorder: a
randomized, double-blind, placebo-controlled trial  . J Clin Psychiatry  2009
;e1 –e8.

Vortioxetine
Brands
Generic?
No
 Class
 How the Drug W orksTrintellix (formerly Brintellix)
Multimodal antidepressant
Cognitive symptoms associated with depression
Geriatric depression

Increases release of several dif ferent neurotransmitters (serotonin,
norepinephrine, dopamine, glutamate, acetylcholine, and histamine)
and reduces the release of GABA through 3 dif ferent modes of
action
Mode 1: blocks serotonin reuptake pump (serotonin transporter)
Mode 2: binds to G protein-linked receptors (full agonist at
serotonin 1A receptors, partial agonist at serotonin 1B receptors,
antagonist at serotonin 1D and serotonin 7 receptors)
Mode 3: binds to ion channel-linked receptors (antagonist at
serotonin 3 receptors)
Full agonist actions at presynaptic somatodendritic serotonin 1A
Full agonist actions at postsynaptic serotonin 1A receptors may
Antagonist actions at serotonin 3 receptors may theoretically
enhance noradrener gic, acetylcholiner gic, and glutamater gic activity

and contribute to antidepressant and pro-cognitive actions
Antagonist actions at serotonin 3 receptors may theoretically reduce
nausea and vomiting caused by serotonin reuptake inhibition
Antagonist actions at serotonin 7 receptors may theoretically
contribute to antidepressant and pro-cognitive actions as well as
reduce insomnia caused by serotonin reuptake inhibition

If It W orksPartial agonist actions at serotonin 1B receptors may enhance not
only serotonin release, but also acetylcholine and histamine release
Antagonist actions at serotonin 1D receptors may enhance serotonin
release and may also theoretically enhance the release of pro-
cognitive neurotransmitters and thereby enhance pro-cognitive
actions
symptoms

TestsAugmentation experience is limited compared to other
Use with caution with antidepressants that are CYP450 2D6
inhibitors (e.g., bupropion, duloxetine, fluoxetine, paroxetine), as
these agents will increase vortioxetine levels and may require a dose
reduction of vortioxetine

SedationTheoretically due to increases in serotonin concentrations at
that cause therapeutic actions (e.g., unwanted actions of serotonin at
central serotonin 1A receptors causing nausea, unwanted actions of
serotonin in the CNS causing sexual dysfunction, etc.)

Wait
Wait
Wait
Sildenafil, vardenafil, or tadalafil for sexual dysfunction
Bupropion for emotional flattening, cognitive slowing, apathy , or
sexual dysfunction (with caution, as bupropion can raise
vortioxetine levels via CYP450 2D6 inhibition)

How to Dose
 Dosing T ipsMany side ef fects are time-dependent (i.e., they start immediately
discontinuation of vortioxetine
5–20 mg/day
Initial 10 mg once daily; can decrease to 5 mg once daily or increase
to 20 mg once daily depending on patient response; maximum
recommended dose generally 20 mg once daily
Tablet should not be divided, crushed, or dissolved

Overdose
How to Stop
No fatalities have been reported; nausea, dizziness, diarrhea,
abdominal discomfort, generalized pruritus, somnolence, flushing
Long-term treatment of major depressive disorder is generally
necessary
No
Taper not necessary with recommended doses
Metabolized by CYP450 2D6, 3A4/5, 2C19, 2C9, 2A6, 2C8, and
2B6
Mean terminal half-life approximately 66 hours

MAOIs, so do not use with MAOIs or for at least 14 –21 days after
Do not start an MAOI for at least 5 half-lives (about 14 days for
vortioxetine with a half-life of 66 hours) after discontinuing
Strong CYP450 2D6 inhibitors can increase plasma levels of
vortioxetine, possibly requiring its dose to be decreased
Broad CYP450 2D6 inducers can decrease plasma levels of
vortioxetine, possibly requiring its dose to be increased

Do Not Use
Renal ImpairmentPossible risk of hyponatremia related to SIADH (syndrome of
inappropriate antidiuretic hormone secretion) with serotoner gic
drugs
companies
If there is a proven aller gy to vortioxetine

Elderly
 Childr en and AdolescentsNo dose adjustment necessary for mild to moderate impairment
improve survival as well as mood; not known for vortioxetine

pregnancy
small)

essants

Potential AdvantagesUnknown if vortioxetine is secreted in human breast milk, but all
the mother
Patients with sexual dysfunction
Patients with cognitive symptoms of depression
Patients with residual cognitive symptoms after treatment with

 PearlsPatients who have not responded to other antidepressants
Patients who do not want weight gain
Cost
Anxiety
In May 2016 the US FDA approved a brand name change from
Brintellix to T rintellix in order to decrease prescribing and
dispensing errors due to name confusion with the anti-platelet
medication Brilinta (ticagrelor)
May have less sexual dysfunction than SSRIs
Multiple studies show pro-cognitive ef fects greater than a
comparator antidepressant in patients with major depressive
episodes
Patients who do not respond to antidepressants with other
mechanisms of action may respond to vortioxetine

Bang-Anderson  B , Ruhland  T , Jorgensen  M , et al. Discovery of 1-[2-(2,4-
dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel
multimodal compound for the treatment of major depressive disorder  . J
Med Chem  2011 ;54 (9):3206  –21.Shown ef fective specifically in elderly patients with depression,
with a positive trial in geriatric depression with improvement of
cognition as well as mood
Has a unique claim of preventing recurrences in major depression
No weight gain in clinical trials
Long half-life means vortioxetine can generally be abruptly
discontinued, although some caution may be necessary when
stopping higher doses (i.e., 15 or 20 mg/day)
Despite serotonin 3 antagonist actions, nausea is common,
presumably due to full agonist actions at serotonin 1A receptors
Dose response for ef ficacy in depression: higher doses are more
effective
Vortioxetine has a unique multimodal mechanism of action

effective
Nonresponse to vortioxetine in elderly may require consideration of

Mork  A , Montezinho  LP , Miller  S , et al. Vortioxetine (LU AA21004), a
novel multimodal antidepressant, enhanced memory in rats  . Pharmacol
Biochem Behav  2013  ;105 :41 –50 .
Stahl  SM , Lee-Zimmerman  C , Cartwright  S , Morrissette  DA .
Serotoner gic drugs for depression and beyond  . Curr Drug T argets 2013  ;14
(5):578–85 .
Westrich  I , Pehrson  A , Zhong  H , et al. In vitro and in vivo ef fects of the
multimodal antidepressant vortioxetine (Lu AA21004) at human and rat
targets . Int J Psychiatry Clin Pract  2012  ;5 (Suppl 1): S47 .

Zaleplon
Brands
Generic?
Yes
 Class
 How the Drug W orksSonata
Non-benzodiazepine hypnotic; alpha 1 isoform agonist of GABA-
A/benzodiazepine receptors
Binds selectively to a subtype of the benzodiazepine receptor , the
alpha 1 isoform

If It W orks
If It Doesn ’t WorkMay enhance GABA inhibitory actions that provide sedative
effects

Tests
✽ Sedation
✽ Dizziness, ataxia
✽ Dose-dependent amnesiaGenerally , best to switch to another agent
Trazodone
Long-term adaptations of zaleplon not well studied, but chronic
studies of other alpha 1 selective non-benzodiazepine hypnotics
suggest lack of notable tolerance or dependence developing over
time

Sedation
What to Do About Side EffectsRare hallucinations
Headache
Decreased appetite
Wait
To avoid problems with memory , do not take zaleplon if planning to
sleep for less than 4 hours

How to Dose
 Dosing T ipsAdminister flumazenil if side ef fects are severe or life-threatening
10 mg/day at bedtime for 7 –10 days
Capsule 5 mg, 10 mg
Initial 10 mg/day at bedtime; may increase to 20 mg/day at bedtime
if inef fective; maximum dose generally 20 mg/day
Patients with lower body weights may require only a 5 mg dose
Zaleplon should generally not be prescribed in quantities greater
treatment

✽ However , treatment with alpha 1 selective non-benzodiazepine
hypnotics may cause less tolerance or dependence than benzodiazepine
hypnotics
Overdose
How to StopNo fatalities reported with zaleplon; fatalities have occurred with
other sedative hypnotics; sedation, confusion, ataxia, hypotension,
Zaleplon is a Schedule IV drug

Terminal phase elimination half-life approximately 1 hour (ultra-
short half-life)
Cimetidine may increase plasma concentrations of zaleplon,
requiring a lower initial dose of zaleplon (5 mg/day)
CYP450 3A4 inducers such as carbamazepine may reduce the
effectiveness of zaleplon
ideation

Do Not Use
Hepatic ImpairmentZaleplon should be administered only at bedtime
have resulted in serious injury or death, prompting the FDA to
If there is a proven aller gy to zaleplon
Mild to moderate impairment: recommended dose 5 mg

Elderly
 PregnancyNot recommended for use in patients with severe impairment
Zaleplon has not been studied in patients with cardiac impairment,
but dose adjustment may not be necessary
Recommended dose: 5 mg
Long-term ef fects of zaleplon in children/adolescents are unknown
monitored

Potential AdvantagesIn animal studies, administration during or ganogenesis was not
teratogenic at doses up to 49 (rats) and 48 (rabbits) times the
maximum recommended human dose (MRHD); in rats, pre- and
postnatal growth was reduced and maternal toxicity occurred
In a pre- and postnatal development study in rats, increased stillbirth
and postnatal mortality , and decreased growth and physical
development, were observed when zaleplon was administered at
doses of 7 mg/kg/day during the latter part of gestation and during
lactation; the no-ef fect dose for of fspring development was 1
mg/kg/day (0.5 times the MRHD of 20 mg on a mg/m2 basis)

Those needing short duration of action

 Pearls
✽ Popular for uses requiring short half-life (e.g., dosing in the middle
of the night, sleeping on airplanes, jet lag)
✽ May not be ideal for patients who desire immediate hypnotic onset
and eat just prior to bedtimeThose needing longer duration of action
Zaleplon has not been shown to increase the total time asleep or to
decrease the number of awakenings
Not a benzodiazepine itself, but binds to benzodiazepine receptors
hypnotics
May not have suf ficient ef ficacy in patients with severe chronic
insomnia resistant to some other sedative hypnotics

✽ Zaleplon is not absorbed as quickly if taken with high-fat foods,
which may reduce onset of action
Dooley  M , Plosker  GL . Zaleplon: a review of its use in the treatment of
insomnia  . Drugs  2000  ;60 :413–45 .
Heydorn  WE . Zaleplon –a review of a novel sedative hypnotic used in the
treatment of insomnia  . Expert Opin Invest Drugs  2000  ;9 :841–58 .
Mangano  RM . Efficacy and safety of zaleplon at peak plasma levels  . Int J
Clin Pract Suppl  2001  ;116 :9 –13.
Weitzel  KW , Wickman  JM , Augustin  SG , Strom  JG . Zaleplon: a
pyrazolopyrimidine sedative-hypnotic agent for the treatment of insomnia  .
Clin Ther  2000  ;22 :1254  –67.May cause less dependence than some other sedative hypnotics,
especially in those without a history of substance abuse

Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Geodon
Delaying r elapse in schizophr enia
Acute agitation in schizophr enia (intramuscular)

patients
✽ Specifically , interactions at 5HT1D and 5HT7 receptors and at
serotonin and norepinephrine transporters (especially at high doses)
may contribute to ef ficacy for af fective symptoms in some patientsBipolar maintenance

contribute to ziprasidone ’s efficacy

symptoms
IM formulation can reduce agitation in 15 minutes

Tests
Lithium

Side EffectsRoutine ECGs for screening or monitoring of dubious clinical value
myocardial infarction; uncompensated heart failure; or those taking
agents that prolong QT c interval such as pimozide, thioridazine,
selected antiarrhythmics, moxifloxacin, sparfloxacin, etc.)

ziprasidone should be discontinued at the first sign of decline of

✽ Activation (at very low to low doses)Blocking alpha 1 adrener gic receptors can cause dizziness,
hypotension, and syncope, especially at high doses
Dizziness, drug-induced parkinsonism, sedation (dose-dependent),
dystonia at high doses
Nausea, dry mouth (dose-dependent)
Asthenia, skin rash
Orthostatic hypotension (dose-dependent)

Sedation
Reported in a few patients, especially those with low BMIs, but not
expected
Some patients experience, especially at high doses

✽ For activating side ef fects at low doses, raise the dose
✽ For sedating side ef fects at high doses, lower the doseMay be less than for some antipsychotics, more than for others
Usually transient and at higher doses
Can be activating at low doses
Wait
Wait
Wait
present

Schizophrenia: 40 –200 mg/day (in divided doses) orally
Bipolar disorder: 80 –160 mg/day (in divided doses) orally
10–20 mg intramuscularly
Capsule 20 mg, 40 mg, 60 mg, 80 mg
Injection 20 mg/mL
Schizophrenia (according to manufacturer): initial oral dose 20 mg
twice a day; however , 40 mg twice a day or 60 mg twice a day may

✽ More may be much mor e: clinical practice suggests ziprasidone
often under -dosed, then switched prior to adequate trials, perhaps due
to unjustified fears of QT c prolongation
✽ Dosing many patients at 20 –40 mg twice a day is too low and in
fact activating, perhaps due to potent 5HT2C antagonist properties
✽ Paradoxically , such activation is often reduced by increasing the
dose to 60 –80 mg twice a day , perhaps due to increasing amounts of
dopamine 2 receptor antagonism
✽ Best ef ficacy in schizophrenia and bipolar disorder is at doses >120
mg/day , but only a minority of patients are adequately dosed in clinical
practicebe better tolerated in many patients (less activation); maximum
approved dose 100 mg twice a day
Bipolar disorder (according to manufacturer): initial oral dose 40 mg
twice a day; on day 2 increase to 60 or 80 mg twice a day
For intramuscular formulation, recommended dose is 10 –20 mg
given as required; doses of 10 mg may be administered every 2

hours; doses of 20 mg may be administered every 4 hours;
maximum daily dose 40 mg intramuscularly; should not be
administered for more than 3 consecutive days

✽ Recommended to be taken with food because food can double
bioavailability by increasing absorption and thus increasing plasma
drug levels
Meals of a few hundred calories (e.g., turkey sandwich and a piece
of fruit) or more are necessary to enhance the absorption of
ziprasidone
Some patients respond better to doses >160 mg/day and up to 320
mg/day in 2 divided doses (i.e., 80 –160 mg twice a day)
Many patients do well with a single daily oral dose, usually at
bedtime
QTc prolongation at 320 mg/day not significantly greater than at 160
mg/day

Ziprasidone intramuscular can be given short-term, both to initiate
dosing with oral ziprasidone or another oral antipsychotic and to

Overdose
How to Stoptreat breakthrough agitation in patients maintained on oral
QTc prolongation of intramuscular ziprasidone is the same or less
than with intramuscular haloperidol
transitory hypertension
No

 Other W arnings/Pr ecautionsRapid oral discontinuation may lead to rebound psychosis and
Mean half-life 6.6 hours
Protein binding >99%
Absorption is approximately doubled if taken with food
Neither CYP450 3A4 nor CYP450 2D6 inhibitors significantly
affect ziprasidone plasma levels
enzymes
Ziprasidone prolongs QT c interval more than some other

Ziprasidone is associated with a rare but serious skin condition
(DRESS). DRESS may begin as a rash but can progress to other
can lead to death. Clinicians prescribing ziprasidone should inform

ziprasidone should be used cautiously in patients at risk for

Do Not Use
Hepatic Impairmentdiseases, conditions, or medications that could exacerbate these
therapy
If there is a proven aller gy to ziprasidone
Intramuscular formulation should be used with caution

Elderly
 Childr en and AdolescentsZiprasidone is contraindicated in patients with a known history of
QTc prolongation, recent acute myocardial infarction, and
Should be used with caution in other cases of cardiac impairment
because of risk of orthostatic hypotension
agitation
Not of ficially recommended for patients under age 18

Clinical experience and early data suggest ziprasidone may be safe

PregnancyChildren and adolescents using ziprasidone may need to be
better

Ziprasidone may be preferable to anticonvulsant mood stabilizers if
961-2388,

✽ Patients noncompliant with dosing with foodUnknown if ziprasidone is secreted in human breast milk, but all
Infants of women who choose to breast feed while on ziprasidone
Patients requiring rapid relief of symptoms (intramuscular injection)
Patients switching from intramuscular ziprasidone to an oral

 Pearls
✽ When given to patients with obesity and dyslipidemia associated
with prior treatment with another atypical antipsychotic, many
experience weight loss and decrease in fasting triglycerides
✽ QTc prolongation fears are often exaggerated and not justified since
QTc prolongation with ziprasidone is not dose-related and few drugs
have any potential to increase ziprasidone ’s plasma levels
✽ Efficacy may be underestimated since ziprasidone is mostly
underdosed (<120 mg/day) in clinical practice
gain because less weight gain than most other atypical antipsychotics
indicatedPositive symptoms of psychosis
Head-to-head study in schizophrenia suggests lower metabolic side

effects and comparable ef ficacy compared to some other atypical

✽ More activating than some other antipsychotics at low doses
✽ A short-acting intramuscular dosage formulation is available
 Switching fr om Oral Antipsychotics to ZiprasidoneLess sedation than some antipsychotics, more than others (at
moderate to high doses)
Anecdotal reports of utility in treatment-resistant cases, especially
when adequately dosed
Approved for mania in children ages 10 –17

begin ziprasidone at an intermediate dose

efficacy and tolerability of 32 oral antipsychotics for the acute treatment ofClinical experience has shown that quetiapine, olanzapine, and

Komossa  K , Rummel-Kluge  C , Hunger  H , et al. Ziprasidone versus other
2009  ;7 (4):CD006627  .
Nasrallah  HA Jr . Atypical antipsychotic-induced metabolic side ef fects:
insights from receptor -binding profiles  . Mol Psychiatry  2008  ;13 (1):27 –
35 .
Taylor  D . Ziprasidone in the management of schizophrenia: the QT interval
issue in context  . CNS Drugs  2003  ;17 :423–30 .

Zolpidem
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Ambien
Ambien CR
Intermezzo
Short-term tr eatment of insomnia (contr olled-r elease indication
is not r estricted to short-term)

If It W orksAs needed for the tr eatment of insomnia when a middle-of-the-
night awakening is followed by difficulty r eturning to sleep and
there are at least 4 hours of bedtime r emaining befor e the
planned time of wakening (Intermezzo)
effects
CR formulation may allow suf ficient drug to persist at receptors to
improve total sleep time and to prevent early morning awakenings
that can be associated with the immediate-release formulation of
zolpidem

Tests
How Drug Causes Side EffectsEffects on total wake-time and number of nighttime awakenings
Trazodone

✽ Sedation
✽ Dose-dependent amnesia
Long-term adaptations of zolpidem immediate-release not well
studied, but chronic studies of zolpidem CR and other alpha 1
selective non-benzodiazepine hypnotics suggest lack of notable
tolerance or dependence developing over time
Rare hallucinations
Headache

Sedation
Wait
To avoid problems with memory , only take zolpidem or zolpidem
CR if planning to have a full night ’s sleep
10 mg/day at bedtime for 7 –10 days (immediate-release)
12.5 mg/day at bedtime (controlled-release)

How to Dose
✽ Zolpidem is not absorbed as quickly if taken with food, which
could reduce onset of actionImmediate-release tablet 5 mg, 10 mg
Controlled-release tablet 6.25 mg, 12.5 mg
Sublingual tablet 1.75 mg, 3.5 mg, 5 mg, 10 mg
Oral spray 5 mg
Men: 10 mg at bedtime for 7 –10 days (immediate-release); 12.5 mg
at bedtime for 7 –10 days (controlled-release); 3.5 mg sublingually
in the middle of the night if more than 4 hours of bedtime remain
(Intermezzo)
Women: 5 mg at bedtime for 7 –10 days (immediate-release); 6.25
mg at bedtime for 7 –10 days (controlled-release); 1.75 mg
sublingually in the middle of the night if more than 4 hours of
bedtime remain (Intermezzo)
Intermezzo formulation is administered sublingually in the middle
of the night; it should be placed under the tongue and allowed to
dissolve completely before swallowing
Intermezzo formulation should not be taken more than once per
night

hypnotics
Overdose
Long-T erm UsePatients with lower body weights may require only a 5 mg dose
immediate-release or 6.25 mg controlled-release
Zolpidem should generally not be prescribed in quantities greater
than a 1-month supply; however , zolpidem CR is not restricted to
short-term use
treatment
Controlled-release tablets should be swallowed whole and should
not be divided, crushed, or chewed
No fatalities reported with zolpidem monotherapy; sedation, ataxia,
confusion, hypotension, respiratory depression, coma
Original studies with zolpidem immediate-release did not assess
long-term use
Zolpidem CR is not restricted to short-term use
off) or an increase in daytime anxiety (rebound) may occur with

immediate-release and be less common with controlled-release

How to Stop
 Drug InteractionsZolpidem is a Schedule IV drug
Although rebound insomnia could occur , this ef fect has not
generally been seen with therapeutic doses of zolpidem or zolpidem
CR
Short elimination half-life (approximately 2.5 hours)
Sertraline may increase plasma levels of zolpidem
Rifampin may decrease plasma levels of zolpidem
Ketoconazole may increase plasma levels of zolpidem
Use with imipramine or chlorpromazine may be associated with
decreased alertness

Do Not UseInsomnia may be a symptom of a primary disorder , rather than a
ideation
Zolpidem and zolpidem CR should only be administered at bedtime
Temporary memory loss may occur at doses above 10 mg/night

ElderlyIf the patient has experienced an episode of complex sleep behaviors
If there is a proven aller gy to zolpidem
For Intermezzo, if the patient has fewer than 4 hours of bedtime
remaining before the planned time of waking
Patients should be monitored
Recommended dose 5 mg (immediate-release), 6.25 mg (controlled-
release), 1.75 mg (Intermezzo)
No available data
Recommended initial dose: 5 mg (immediate-release), 6.25 mg
(controlled-release), 1.75 mg (Intermezzo)

 PregnancyElderly may have increased risk for falls, confusion
Long-term ef fects of zolpidem or zolpidem CR in
children/adolescents are unknown
monitored
Hallucinations in children ages 6 –17 have been reported
In animal studies, oral administration of zolpidem did not indicate a
risk for adverse ef fects on fetal development at clinically relevant
doses

doses

 Pearls
✽ One of the most popular sedative hypnotic agents in
psychopharmacologyNeonatal flaccidity has been reported in infants whose mothers took
Patients who require long-term treatment, especially CR formulation

action, short duration of ef fect, and safety profileZolpidem has been shown to increase the total time asleep and to
reduce the amount of nighttime awakenings
Zolpidem CR may be even more ef fective on these sleep parameters
than immediate-release zolpidem due to prolonged drug delivery
In some patients, zolpidem blood levels may be high enough the
morning after use to impair activities that require alertness,
including driving; this has prompted the US FDA to issue new
dosing requirements
Specifically , because clearance of zolpidem is slightly slower in
women than in men, the FDA has required that the recommended
dose be lowered for women
The FDA also recommends that healthcare professionals consider
prescribing lower doses for men as well
A low-dose zolpidem product is approved for middle-of-the-night
awakenings by sublingual administration
May not be ideal for patients who desire immediate hypnotic onset

and eat just prior to bedtime
hypnotics

Daley  C , McNiel  DE , Binder  RL. “I did what? ” Zolpidem and the courts  .
J Am Acad Psychiatry Law  2011 ;39 (4):535–42 .
Greenblatt  DJ , Roth  T. Zolpidem for insomnia  . Expert Opin Pharmacother
2012  ;13 (6):879–93 .
Rush  CR . Behavioral pharmacology of zolpidem relative to
benzodiazepines: a review  . Pharmacol Biochem Behav  1998  ;61 :253–69 .
Soyka  M , Bottlender  R , Moller  HJ . Epidemiological evidence for a low
abuse potential of zolpidem  . Pharmacopsychiatry  2000  ;33 :138–41 .
Toner LC , Tsambiras  BM , Catalano  G , Catalano  MC , Cooper  DS .
Central nervous system side ef fects associated with zolpidem treatment  .
Clin Neur opharmacol  2000  ;23 :54 –8.May cause less dependence than some other sedative hypnotics,

Zonisamide
Brands
Generic?
Yes
 Class
(bold for FDA appr oved)Zonegran
Excegran
Anticonvulsant, voltage-sensitive sodium channel modulator; T -type
calcium channel modulator; structurally a sulfonamide
Adjunct therapy for partial seizur es in adults with epilepsy
Migraine

If It W orksPsychotropic drug-induced weight gain
Unknown
Modulates voltage-sensitive sodium channels by an unknown
mechanism
Also modulates T -type calcium channels
Facilitates dopamine and serotonin release
Inhibits carbonic anhydrase
Onset of action as well as convincing therapeutic ef ficacy have not
been demonstrated for uses other than adjunctive treatment of partial
seizures
seizures, pain, mania, migraine)
Would currently only be expected to work in a subset of patients for
conditions other than epilepsy as an adjunctive treatment to agents
with better demonstration of ef ficacy

If It Doesn ’t Work (for Conditions Other Than Epilepsy)
Tests
Notable Side EffectsMay be ef fective only in patients who fail to respond to agents with
proven ef ficacy , or it may not work at all
demonstrated ef ficacy
Zonisamide is itself a second-line augmenting agent to numerous
other agents in treating conditions other than epilepsy , such as
bipolar disorder , chronic neuropathic pain, and migraine
Consider baseline and periodic monitoring of renal function
sensitive ion channels
Serious rash theoretically an aller gic reaction

✽ Sedation, depression, dif ficulty concentrating, agitation, irritability ,
psychomotor slowing, dizziness, ataxia
SedationHeadache
Nausea, anorexia, abdominal pain, vomiting
Elevated serum creatinine and blood urea nitrogen
Rare serious rash (Stevens-Johnson syndrome, toxic epidermal
necrolysis) (sulfonamide)
Rare oligohidrosis and hyperthermia (pediatric patients)
Rare blood dyscrasias (aplastic anemia; agranulocytosis)
Sudden hepatic necrosis
Sudden unexplained deaths have occurred (unknown if related to
zonisamide use)

Can wear of f with time but may not wear of f at high doses
Wait
Wait
Wait
100–600 mg/day in 1 –2 doses

How to Dose
✽ Most clinical experience is at doses up to 400 mg/day
Overdose
Long-T erm UseInitial 100 mg/day; after 2 weeks can increase to 200 mg/day; dose
can be increased by 100 mg/day every 2 weeks if necessary and
tolerated; maximum dose generally 600 mg/day; maintain stable
dose for at least 2 weeks before increasing dose
No evidence from controlled trials of increasing response over 400
mg/day
However , some patients may tolerate and respond to doses up to 600
mg/day
Little experience with doses greater than 600 mg/day
Side ef fects may increase notably at doses greater than 300 mg/day
Can cause bradycardia, hypotension, respiratory depression
Safe
Consider periodic monitoring of blood urea nitrogen and creatinine

How to Stop
Taper
Rapid discontinuation may increase the risk of relapse in bipolar
patients
Plasma elimination half-life approximately 63 hours
Partially eliminated renally
Agents that inhibit CYP450 3A4 (such as nefazodone, fluvoxamine,
and fluoxetine) may decrease the clearance of zonisamide, and
increase  plasma zonisamide levels, possibly requiring lower doses
of zonisamide
Agents that induce CYP450 3A4 (such as carbamazepine) may
increase the clearance of zonisamide and decrease  plasma

zonisamide use; zonisamide should generally be discontinued at the
first sign of serious rashzonisamide levels, possibly requiring higher doses of zonisamide
Enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin,
phenobarbital, and primidone) may decrease  plasma levels of
zonisamide
Theoretically , zonisamide may interact with carbonic anhydrase
inhibitors to increase the risk of kidney stones

Patients should be monitored for signs of unusual bleeding or
bruising, mouth sores, infections, fever , and sore throat, as there
may be an increased risk of aplastic anemia and agranulocytosis
with zonisamide

Do Not Use
If there is a proven aller gy to zonisamide or sulfonamides
Zonisamide is primarily renally excreted
May require slower titration

 PregnancyElderly patients may be more susceptible to adverse ef fects
Cases of oligohidrosis and hyperthermia have been reported
Not approved for use in children under age 16
Use in children for the expert only , with close monitoring, after
other options have failed

Primary T arget SymptomsLack of convincing ef ficacy for treatment of conditions other than
epilepsy suggests risk/benefit ratio is in favor of discontinuing
zonisamide during pregnancy for these indications
Unknown if zonisamide is secreted in human breast milk, but all
Treatment-resistant conditions
Poor documentation of ef ficacy for of f-label uses

Pearls
✽ Much of f-label use is based upon theoretical considerations rather
than clinical experience or compelling ef ficacy studies
some patients with psychotropic-induced weight gain are treated with
zonisamideSeizures
Numerous other symptoms for of f-label uses
Patients with a history of kidney stones
Early studies suggest ef ficacy in binge eating disorder
Early studies suggest possible ef ficacy in migraine
Early studies suggest possible utility in Parkinson ’s disease
Early studies suggest possible utility in neuropathic pain
Early studies suggest some therapeutic potential for mood-
stabilizing
Chronic intake of caf feine may lower brain zonisamide
concentrations and attenuate its anticonvulsant ef fects (based on
animal studies)
Utility for this indication is not clear nor has it been systematically
studied

Chadwick  DW , Marson  AG . Zonisamide add-on for drug-resistant partial
epilepsy  . Cochrane Database Syst Rev  2002  ;(2):CD001416  .
Glauser  TA , Pellock  JM . Zonisamide in pediatric epilepsy: review of the
Japanese experience  . J Child Neur ol 2002  ;17 :87 –96 .
Jain KK . An assessment of zonisamide as an anti-epileptic drug  . Expert
Opin Pharmacother  2000  ;1 :1245  –60.
and zonisamide  . J Child Neur ol 2002  ;17 (Suppl 1): S53 –7.Phase 2 trials for the combination of zonisamide and bupropion as a
treatment for obesity have been completed

Zopiclone
Brands
Generic?
No
 Class
 How the Drug W orksImovane
Short-term treatment of insomnia

Tests
✽ Long-term adaptations of zopiclone, a mixture of an active S
enantiomer and an inactive R enantiomer , have not been well studied,
but chronic studies of the active isomer eszopiclone suggest lack of
notable tolerance or dependence developing over time
✽ Sedation
Trazodone

Sedation
What to Do About Side EffectsDry mouth, loss of appetite, constipation, bitter taste
Impaired vision
Wait
To avoid problems with memory , only take zopiclone if planning to

How to Dose
7.5 mg at bedtime
Tablet 5 mg, 7.5 mg scored
Zopiclone should generally not be prescribed in quantities greater
treatment
However , chronic treatment with alpha 1 selective non-
benzodiazepine hypnotics may cause less tolerance or dependence
than benzodiazepine hypnotics

Overdose
How to Stop
 Drug InteractionsCan be fatal; clumsiness, mood changes, sedation, weakness,
breathing trouble, unconsciousness
Not generally intended for use past 4 weeks
Terminal elimination half-life approximately 3.5 –6.5 hours

Do Not UseTheoretically , inhibitors of CYP450 3A4, such as nefazodone and
fluvoxamine, could increase plasma levels of zopiclone
ideation
Zopiclone should be administered only at bedtime

patients taking sedative hypnotics

ElderlyIf patient has severe respiratory impairment
If patient has had a stroke
If patient has severe hepatic insuf ficiency
If there is a proven aller gy to zopiclone
Increased plasma levels
Recommended dose 3.75 mg
Initial dose 3.75 mg at bedtime; can increase to usual adult dose if
necessary and tolerated

 Pregnancy
Potential AdvantagesSafety and ef ficacy have not been established
Long-term ef fects of zopiclone in children/adolescents are unknown
monitored

 Pearls
 Suggested ReadingMore expensive than some other sedative hypnotics
Zopiclone does not appear to be a highly dependence-causing drug,
at least not in patients with no history of drug abuse
hypnotics
The active enantiomer of zopiclone, eszopiclone, has received an
approvable letter from the US FDA

Fernandez  C , Martin  C , Gimenez  F , Farinotti  R . Clinical
pharmacokinetics of zopiclone  . Clin Pharmacokinet  1995  ;29 :431–41 .
Hajak  G . A comparative assessment of the risks and benefits of zopiclone:
a review of 15 years ’clinical experience  . Drug Saf  1999  ;21 :457–69 .
Noble  S , Langtry  HD , Lamb  HM . Zopiclone. An update of its
pharmacology , clinical ef ficacy and tolerability in the treatment of insomnia
. Drugs  1998  ;55 :277 –302 .

Zotepine
Brands
Generic?
No
 Class
(bold for FDA appr oved)Lodopin
Zoleptil
Atypical antipsychotic (serotonin-dopamine antagonist)
Mania

✽ Specifically inhibits norepinephrine uptake
psychosis
contribute to zotepine ’s efficacy

TestsIf 2 or more antipsychotic monotherapies do not work, consider
clozapine
injection
Augmentation of zotepine has not been systematically studied
Lithium

✽ Although risk of diabetes and dyslipidemia with zotepine has not
been systematically studied, monitoring as for all other atypical
Monitoring after starting an atypical antipsychoticGet baseline personal and family history of diabetes, obesity ,

How Drug Causes Side EffectsPatients with suspected hematologic abnormalities may require a
white blood cell count before initiating treatment
Monitor liver function tests in patients with established liver disease
zotepine should be discontinued at the first sign of decline of WBC
and weight gain

Atypical antipsychotics may increase the risk for diabetes and
dyslipidemia, although the specific risks associated with zotepine
Agitation, anxiety , depression, asthenia, headache, insomnia,
sedation, hypo/hyperthermia
Constipation, dry mouth, dyspepsia, weight gain
Tachycardia, hypotension, sweating, blurred vision
Dose-related hyperprolactinemia

Sedation
Rare seizures (risk increases with dose, especially over 300 mg/day)
Wait
Wait
Wait

Switch to a first-line atypical antipsychotic
75–300 mg/day in 3 divided doses

How to Dose
✽ Dose-related QT c prolongation, so use with caution, especially at
high dosesTablet 25 mg, 50 mg, 100 mg
Initial 75 mg/day in 3 doses; can increase every 4 days; maximum
300 mg/day in 3 doses
Slow initial titration can minimize hypotension
No formal studies, but some patients may do well on twice daily
dosing rather than 3 times daily dosing

Overdose
How to Stop
PharmacokineticsCan be fatal, especially in mixed overdoses; seizures, coma
Can be used to delay relapse in long-term treatment of
No
a few weeks after zotepine is discontinued
Metabolized by CYP450 3A4 and CYP450 1A2
Active metabolite norzotepine

 Other W arnings/Pr ecautionsCombined use with phenothiazines may increase risk of seizures
Epinephrine may lower blood pressure
May interact with hypotensive agents due to alpha 1 adrener gic
blockade
Plasma concentrations increased by diazepam, fluoxetine
Zotepine may increase plasma levels of phenytoin
May increase risk of bleeding if used with anticoagulants
Theoretically , dose may need to be raised if given in conjunction
with CYP450 1A2 inducers (e.g., cigarette smoke)
Theoretically , dose may need to be lowered if given in conjunction
with CYP450 1A2 inhibitors (e.g., fluvoxamine) in order to prevent
dangers of dose-dependent QT c prolongation
with CYP450 3A4 inhibitors (e.g., fluvoxamine, nefazodone,

fluoxetine) in order to prevent dangers of dose-dependent QT c
Not recommended for use with sibutramine

Because zotepine may dose-dependently prolong QT c interval, use
hypomagnesemia or who are taking drugs than can induce
Because zotepine dose-dependently prolongs QT c interval, use with
caution in patients taking any agent capable of increasing zotepine
plasma levels (e.g., diazepam, CYP450 1A2 inhibitors, and CYP450
3A4 inhibitors)

therapy

Do Not Use
Hepatic ImpairmentIf patient has epilepsy or family history of epilepsy
If patient has gout or history of nephrolithiasis
If patient is taking other CNS depressants
If patient is taking high doses of other antipsychotics
If patient is pregnant or breast feeding
If there is a proven aller gy to zotepine
Recommended starting dose 25 mg twice a day; recommended
maximum dose generally 75 mg twice a day

ElderlyMay require weekly monitoring of liver function during the first few
Zotepine produces a dose-dependent prolongation of QT c interval,
should be evaluated prior to administering zotepine
Avoid zotepine in patients with a known history of QT c
prolongation, recent acute myocardial infraction, and

agitation

 Pregnancy
Potential AdvantagesElderly patients with dementia-related psychosis treated with
Insuf ficient data in humans to determine risk
Zotepine is not recommended during pregnancy
Zotepine is not recommended during breast feeding
psychosis, so may consider treatment with another antipsychotic

 Pearls
✽ Zotepine inhibits norepinephrine reuptake, which may have
implications for treatment of depression, as well as for cognitive
symptoms of schizophreniaNorepinephrine reuptake blocking actions have theoretical benefits
for cognition (attention) and for depression
Patients not compliant with 3 times daily dosing
Patients requiring rapid onset of antipsychotic action
Patients with uncontrolled seizures
Risks of diabetes and dyslipidemia not well studied for zotepine, but
known significant weight gain suggests the need for careful
monitoring during zotepine treatment
Not as well investigated in bipolar disorder , but its mechanism of
action suggests ef ficacy in acute bipolar mania

Ackenheil  M . [The biochemical ef fect profile of zotepine in comparison
with other neuroleptics]  . Fortschr Neur ol Psychiatr  1991  ;59 (Suppl 1): S2
–9.
Fenton  M , Morris  S , De-Silva  P , et al. Zotepine for schizophrenia  .
Cochrane Database Syst Rev  2000  ;(2):CD001948  .
Stanniland  C , Taylor  D . Tolerability of atypical antipsychotics  . Drug Saf
2000  ;22 (3):195–214 .

Zuclopenthixol
Brands
Generic?
No
 Class
(bold for FDA appr oved)Clopixol
Clopixol-Acuphase
(D-RAn)
Acute schizophrenia (oral, acetate injection)
Maintenance treatment of schizophrenia (oral, decanoate injection)

If It W orksAggression
psychosis
For injection, psychotic symptoms can improve within a few days,
For oral formulation, psychotic symptoms can improve within 1
week, but may take several weeks for full ef fect on behavior

zuclopenthixol should be discontinued at the first sign of decline of

with dose)
✽ Priapism
unknown
Rare lens opacity
Dry mouth, constipation, vision problems

Sedation
Rare neutropenia
Rare respiratory depression
Some people may lose weight
Acetate formulation may be associated with an initial sedative
response
Wait

Dosing And UseWait
Wait

How to DoseOral 20 –60 mg/day
Acetate 50 –150 mg every 2 –3 days
Decanoate 150 –300 mg every 2 –4 weeks
Tablet 10 mg, 25 mg, 40 mg
Acetate 50 mg/mL (equivalent to zuclopenthixol 45.25 mg/mL), 100
mg/2 mL (equivalent to zuclopenthixol 45.25 mg/mL)
Decanoate 200 mg/mL (equivalent to zuclopenthixol 144.4 mg/mL),
500 mg/mL (equivalent to zuclopenthixol 361.1 mg/mL)
Oral: initial 10 –15 mg/day in divided doses; can increase by 10 –20
mg/day every 2 –3 days; maintenance dose can be administered as a
single nighttime dose; maximum dose generally 100 mg/day
Injection should be administered intramuscularly in the gluteal
region in the morning
Acetate generally should be administered every 2 –3 days; some
patients may require a second dose 24 –48 hours after the first
injection; duration of treatment should not exceed 2 weeks;
maximum cumulative dosage should not exceed 400 mg; maximum
number of injections should not exceed 4

OverdoseDecanoate: initial dose 100 mg; after 1 –4 weeks administer a second
injection of 100 –200 mg; maintenance treatment is generally 100 –
600 mg every 1 –4 weeks
Onset of action of the intramuscular acetate formulation following a
single injection is generally 2 –4 hours; duration of action is
generally 2 –3 days
Zuclopenthixol acetate is not intended for long-term use, and should
not generally be used for longer than 2 weeks; patients requiring
treatment longer than 2 weeks should be switched to a depot or oral
formulation of zuclopenthixol or another antipsychotic
When changing from zuclopenthixol acetate to maintenance
treatment with zuclopenthixol decanoate, administer the last
injection of acetate concomitantly with the initial injection of
decanoate
The peak of action for the decanoate is usually 4 –9 days, and doses

Sedation, convulsions, drug-induced parkinsonism, coma,
hypotension, shock, hypo/hyperthermia

How to Stop
PharmacokineticsZuclopenthixol decanoate is intended for maintenance treatment
No
a few weeks after zuclopenthixol is discontinued
For oral formulation, elimination half-life approximately 20 hours
For acetate, rate-limiting half-life approximately 32 hours
For decanoate, rate-limiting half-life approximately 17 –21 days with
multiple doses

 Other W arnings/Pr ecautionsTheoretically , concomitant use with CYP450 2D6 inhibitors (such
as paroxetine and fluoxetine) or with CYP450 3A4 inhibitors (such
as fluoxetine and ketoconazole) could raise zuclopenthixol plasma
levels and require dosage reduction
Theoretically , concomitant use with CYP450 3A4 inducers (such as
carbamazepine) could lower zuclopenthixol plasma levels and
require dosage increase
If used with anticholiner gic agents, may potentiate their ef fects
Zuclopenthixol may block the antihypertensive ef fects of drugs such
as guanethidine, but may enhance the actions of other
Using zuclopenthixol with metoclopramide or piperazine may
increase the risk of drug-induced parkinsonism
Zuclopenthixol may antagonize the ef fects of levodopa and
dopamine agonists

syndrome

Use with caution in patients with epilepsy , glaucoma, urinary
retention
Decanoate should not be used with clozapine because it cannot be
withdrawn quickly in the event of serious adverse ef fects such as
Possible antiemetic ef fect of zuclopenthixol may mask signs of
other disorders or overdose; suppression of cough reflex may cause
asphyxia
Use only with great caution if at all in Parkinson ’s disease or Lewy
body dementia
Observe for signs of ocular toxicity (pigmentary retinopathy and
lenticular and corneal deposits)

therapy

Do Not Use
Hepatic ImpairmentAs with any antipsychotic, use with caution in patients with history
If patient is taking guanethidine or a similar acting compound
If patient has CNS depression, is comatose, or has subcortical brain
damage
If patient has acute alcohol, barbiturate, or opiate intoxication
If patient has pheochromocytoma, circulatory collapse, or blood
dyscrasias
In case of pregnancy
If there is a proven aller gy to zuclopenthixol

Elderly
 PregnancyUse with caution
Maximum acetate dose 100 mg
18
Preliminary open-label data show that oral zuclopenthixol may be
effective in reducing aggression in mentally impaired children

Potential Disadvantagesthe third trimester; symptoms may include agitation, abnormally
Noncompliant patients (decanoate)
Emer gency use (acute injection)
Children

 PearlsElderly
Zuclopenthixol depot may reduce risk of relapse more than some
other depot conventional antipsychotics, but it may also be
associated with more adverse ef fects
Can combine acute injection with depot injection in the same
syringe for rapid onset and long duration ef fects when initiating
treatment
Zuclopenthixol may have serotonin 2A antagonist properties, but
these have never been systematically investigated for atypical
antipsychotic properties at low doses
another

Coutinho  E , Fenton  M , Quraishi  S . Zuclopenthixol decanoate for
schizophrenia and other serious mental illnesses  . Cochrane Database Syst
Rev 2000  ;(2):CD001 164 .Patients with inadequate responses to atypical antipsychotics may
antipsychotic such as zuclopenthixol or from switching to a
conventional antipsychotic such as zuclopenthixol
conventional antipsychotic such as zuclopenthixol with an atypical

Davies  S , Westin  A , Castber g I , et al. Characterisation of zuclopenthixol
metabolism by in vitro and therapeutic drug monitoring studies  . Acta
Psychiatr Scand  2010  ;122 (6 ):444–53 .
Fenton  M , Coutinho  ES , Campbell  C . Zuclopenthixol acetate in the
treatment of acute schizophrenia and similar serious mental illnesses  .
Cochrane Database Syst Rev  2000  ;(2):CD000525  .
Stahl  SM . How to dose a psychotropic drug: beyond therapeutic drug
monitoring to genotyping the patient  . Acta Psychiatr Scand  2010  ;122 (6
):440–1 .

(trade names and generic names)
Abilify (aripiprazole) , 53
Abilify Discmelt (aripiprazole) , 53
Abilify Maintena (aripiprazole) , 53
Abilify MyCite (aripiprazole) , 53
Absenor (valproate) , 829
acamprosate , 1
Aclonium (gabapentin) , 331
ACT Zopiclone (zopiclone) , 879
Acuilix (moclobemide) , 515
Adapin (doxepin) , 255
Adasuve (loxapine) , 443
Adderrall (d,l-amphetamine) , 45
Adderrall XR (d,l-amphetamine) , 45
Addyi (flibanserin) , 289
Adepil (amitriptyline) , 25
Adhansia XR (d, l-methylphenidate) , 487
Adipress (clonidine) , 179
Adofen (fluoxetine) , 301
Adumbran (oxazepam) , 569
Aduvanz (lisdexamfetamine) , 409

Adzenys ER (amphetamine d,l) , 45
Adzenys XR-ODT (amphetamine d,l) , 45
agomelatine , 5
AH3 N (hydroxyzine) , 355
Aiglonyl (sulpiride) , 741
Alased (haloperidol) , 347
Albium (lorazepam) , 437
Aldazine (thioridazine) , 759
Alemoxan (clozapine) , 191
Alepam (oxazepam) , 569
Alertec (modafinil) , 521
Aleviatin (zonisamide) , 875
Alimoral (sulpiride) , 741
Aliseum (diazepam) , 229
Allegron (nortriptyline) , 551
allopregnanolone (brexanolone) , 99
Almazine (lorazepam) , 437
Aloperidin (haloperidol) , 347
Aloperidin Decanoate (haloperidol) , 347
Alpralid (alprazolam) , 11
Alpraz (alprazolam) , 11
alprazolam , 11
alprazolam XR , 11
Alprox (alprazolam) , 11
Alti-Alprazolam (alprazolam) , 11
Alti-Clonazepam (clonazepam) , 173
Alti-Desipramine (desipramine) , 207
Alti-Doxepin (doxepin) , 255

Alti-T razodone (trazodone) , 793
Alti-T riazolam (triazolam) , 799
Alti-V alproic (valproate) , 829
Alupram (diazepam) , 229
Alzam (alprazolam) , 11
Alzon (alprazolam) , 11
Ambien (zolpidem) , 871
Ambien CR (zolpidem) , 871
Amboneural (selegiline) , 705
Ambo-neural (selegiline) , 705
Amilin (amitriptyline) , 25
Amilit (amitriptyline) , 25
Aminazins (chlorpromazine) , 153
Amindan (selegiline) , 705
Amineurin (amitriptyline) , 25
Aminuerin Retard (amitriptyline) , 25
Amioxid (amitriptyline) , 25
amisulpride , 17
Amitrip (amitriptyline) , 25
Amitriptilin (amitriptyline) , 25
Amitriptylin (amitriptyline) , 25
amitriptyline , 25
Amitriptylinum (amitriptyline) , 25
Amitrol (amitriptyline) , 25
Amizepin (carbamazepine) , 131
Amizol (amitriptyline) , 25
amoxapine , 33

amphetamine (d) , 39
amphetamine (d,l) , 45
Anafranil (clomipramine) , 165
Anafranil 75 (clomipramine) , 165
Anafranil Retard (clomipramine) , 165
Anatensoi Decanoaat (fluphenazine) , 313
Anatensol (fluphenazine) , 313
Anatensol Concentraat (fluphenazine) , 313
Anatensol Decanoate (fluphenazine) , 313
Ancholactil (chlorpromazine) , 153
Aneural (maprotiline) , 465
Aneurol (diazepam) , 229
Anexate (flumazenil) , 293
Ansilor (lorazepam) , 437
Ansiolin (diazepam) , 229
Ansised (buspirone) , 123
Ansium (diazepam) , 229
Ansium (sulpiride) , 741
Antabuse (disulfiram) , 239
Antalon (pimozide) , 627
Antelepsin (clonazepam) , 173
Anten (doxepin) , 255
Antenex (diazepam) , 229
Antideprin (imipramine) , 367
Antiparkin (selegiline) , 705
Antitussive (diphenhydramine) , 235
Antoderin (oxazepam) , 569
Anxial (buspirone) , 123

Anxidin (clorazepate) , 185
Anxiolit (oxazepam) , 569
Anxiolit Plus (oxazepam) , 569
Anxiron (buspirone) , 123
Apaurin (diazepam) , 229
Apilepsin (valproate) , 829
Aplenzin (bupropion) , 117
Apo-Alprax (alprazolam) , 11
Apo-Amitriptyline (amitriptyline) , 25
Apo-Buspirone (buspirone) , 123
Apo-Carbamazepine (carbamazepine) , 131
Apo-Clomipramine (clomipramine) , 165
Apo-Clonazepam (clonazepam) , 173
Apo-Clonidine (clonidine) , 179
Apo-Clorazepate (clorazepate) , 185
Apo-Desipramine (desipramine) , 207
Apo-Diazepam (diazepam) , 229
Apo-Doxepin (doxepin) , 255
Apo-Fluoxetine (fluoxetine) , 301
Apo-Fluphenazine (fluphenazine) , 313
Apo-Haloperidol (haloperidol) , 347
Apoh-Hydroxyzine (hydroxyzine) , 355
Apo-Imipramine (imipramine) , 367
Apollonset (diazepam) , 229
Apo-Lorazem (lorazepam) , 437
Aponal (doxepin) , 255
Apo-Oxepam (oxazepam) , 569
Apo-Perphenazine (perphenazine) , 607

Apo-Selegiline (selegiline) , 705
Apo-Thioridazine (thioridazine) , 759
Apo-T razodone (trazodone) , 793
Apo-T riazo (triazolam) , 799
Apo-T rifluoperazine (trifluoperazine) , 803
Apo-T rimip (trimipramine) , 817
Apozepam (diazepam) , 229
Apo-Zopiclone (zopiclone) , 879
Aptensio XR (methylphenidate d,l) , 487
Aremis (sertraline) , 721
Aricept (donepezil) , 243
Arima (moclobemide) , 515
Aripax (lorazepam) , 437
aripiprazole , 53
Aristada (aripiprazole) , 53
Aristada Initio (aripiprazole injection) , 53
Arminol (sulpiride) , 741
armodafinil , 65
Arol (moclobemide) , 515
Aropax (paroxetine) , 593
Artane (trihexyphenidyl) , 809
asenapine , 71
Asendin (amoxapine) , 33
Asendis (amoxapine) , 33
Asepin (triazolam) , 799
Aspam (diazepam) , 229
Atarax (hydroxyzine) , 355
Atarviton (diazepam) , 229

Atensine (diazepam) , 229
Aterax (hydroxyzine) , 355
Athymil (mianserin) , 495
Ativan (lorazepam) , 437
atomoxetine , 79
Atretol (carbamazepine) , 131
Audilex (clorazepate) , 185
Audium (diazepam) , 229
Aurorix (moclobemide) , 515
Austedo (deutetrabenazine) , 221
Autal (acamprosate) , 1
Avant (haloperidol) , 347
Aventyl (nortriptyline) , 551
Avoxin (fluvoxamine) , 325
Axona (caprylidene) , 127
Axoren (buspirone) , 123
Azene (clorazepate) , 185
Azepa (carbamazepine) , 131
Azepal (carbamazepine) , 131
Azona (trazodone) , 793
Azor (alprazolam) , 11
Azutranquil (oxazepam) , 569
Barclyd (clonidine) , 179
Barhemsys (amisulpride) , 17
Beconerv neu (flurazepam) , 321
Belbuca (buprenorphine) , 111
Beldin (diphenhydramine) , 235
Belivon (risperidone) , 687

Belix (diphenhydramine) , 235
Belpax (amitriptyline) , 25
Belseren (clorazepate) , 185
Belsomra (suvorexant) , 747
Benadryl (diphenhydramine) , 235
Benpon (nortriptyline) , 551
Bentapam (diazepam) , 229
Benylin (diphenhydramine) , 235
Benzopin (diazepam) , 229
Benzotran (oxazepam) , 569
benztropine , 85
Berk-Dothiepin (dothiepin) , 249
Besitran (sertraline) , 721
Bespar (buspirone) , 123
Betamaks (sulpiride) , 741
Betamed (diazepam) , 229
Betapam (diazepam) , 229
Bialzepam (diazepam) , 229
Bikalm (zolpidem) , 871
Bioperidolo (haloperidol) , 347
Bioxetin (fluoxetine) , 301
Biron (buspirone) , 123
Biscasil (chlorpromazine) , 153
Biston (carbamazepine) , 131
blonanserin , 89
Bolvidon (mianserin) , 495
Bortalium (diazepam) , 229
bremelanotide , 95

brexanolone , 99
brexpiprazole , 103
Brisdelle (paroxetine) , 593
Brintellix (vortioxetine) , 853
BritLofex (lofexidine) , 427
Buprenex (buprenorphine) , 111
buprenorphine , 111
buprenorphine with naloxone , 111
bupropion , 117
bupropion SR , 117
bupropion XL , 117
Buscalm (buspirone) , 123
Buspar (buspirone) , 123
BuSpar (buspirone) , 123
Buspimen (buspirone) , 123
buspirone , 123
Buspisal (buspirone) , 123
Buteridol (haloperidol) , 347
Butrans (buprenorphine) , 111
Calmoflorine (sulpiride) , 741
Camcolit (lithium) , 415
Campral (acamprosate) , 1
Caplyta (lumateperone) , 451
caprylidene , 127
Caprysin (clonidine) , 179
Carbabeta (carbamazepine) , 131
Carbagamma (carbamazepine) , 131
carbamazepine , 131

Carbapin (carbamazepine) , 131
Carbatrol (carbamazepine) , 131
Carbium (carbamazepine) , 131
Carbolith (lithium) , 415
Carbolithium (lithium) , 415
Carbymal (carbamazepine) , 131
Cardilac (fluphenazine) , 313
cariprazine , 137
Carpaz (carbamazepine) , 131
Cassadan (alprazolam) , 11
Cassipa (buprenorphine with naloxone) , 111
Catanidin (clonidine) , 179
Catapres (clonidine) , 179
Catapres-TTS (clonidine) , 179
Cedrol (zolpidem) , 871
Celexa (citalopram) , 159
Cenilene (fluphenazine) , 313
Centedrin (d,l-methylphenidate) , 487
Cereen (haloperidol) , 347
Championyl (sulpiride) , 741
Champix (varenicline) , 837
Chantix (varenicline) , 837
Chemmart (escitalopram) , 269
Chlorazin (chlorpromazine) , 153
chlordiazepoxide , 147
Chlorpromazin (chlorpromazine) , 153
Chlorpromazina HCl (chlorpromazine) , 153
chlorpromazine , 153

Cibalith S-Lithonate (lithium) , 415
Cidoxepin (doxepin) , 255
Cipram (citalopram) , 159
Cipramil (citalopram) , 159
Ciprilex (escitalopram) , 269
Ciproxidine (pitolisant) , 639
Cisordinol (zuclopenthixol) , 889
citalopram , 159
clomipramine , 165
clonazepam , 173
Clonazepamum (clonazepam) , 173
clonidine , 179
Clonisin (clonidine) , 179
Clonistada (clonidine) , 179
Clopixol (zuclopenthixol) , 889
Clopixol Acuphase (zuclopenthixol) , 889
Clopixol Conc (zuclopenthixol) , 889
Clopress (clomipramine) , 165
clorazepate , 185
Clordezalin (chlorpromazine) , 153
Clorpres (clonidine) , 179
clozapine , 191
Clozaril (clozapine) , 191
Coaxil (tianeptine) , 777
Cogentin (benztropine) , 85
Cognitiv (selegiline) , 705
Combipres (clonidine) , 179
Complutine (diazepam) , 229

Concerta (d,l-methylphenidate) , 487
Concordin (protriptyline) , 657
Concordine (protriptyline) , 657
Consta (risperidone) , 687
Contemnol (lithium) , 415
Contrave (naltrexone/bupropion) , 541
Control (lorazepam) , 437
Convulex (valproate) , 829
Convulsofin (valproate) , 829
Cosmopril (selegiline) , 705
Cotempla XR-ODT (d, l-methylphenidate) , 487
cyamemazine , 201
Cymbalta (duloxetine) , 263
Cytomel (triiodothyronine) , 813
Dalcipran (milnacipran) , 503
Dalmadorm (flurazepam) , 321
Dalmane (flurazepam) , 321
Dalparan (zolpidem) , 871
Dapotum (fluphenazine) , 313
Dapotum Acutum (fluphenazine) , 313
Dapotum D (fluphenazine) , 313
Dapotum Depot (fluphenazine) , 313
Daprimen (amitriptyline) , 25
Darkene (flunitrazepam) , 297
Darleton (sulpiride) , 741
Daytrana (d, l-methylphenidate) , 487
Dayvigo (lemborexant) , 395
Decafen (fluphenazine) , 313

Decanoate (haloperidol) , 347
Decazate (fluphenazine) , 313
Decentan (fluphenazine) , 313
Decentan (perphenazine) , 607
Decentan-Depot (perphenazine) , 607
Defanyl (amoxapine) , 33
Defobin (chlordiazepoxide) , 147
Deftan (lofepramine) , 421
Degranol (carbamazepine) , 131
Delepsine (valproate) , 829
Delgian (maprotiline) , 465
Delsym (dextromethorphan) , 225
Demolox (amoxapine) , 33
Deniban (amisulpride) , 17
Denion (diazepam) , 229
Depacon (valproate) , 829
Depakene (valproate) , 829
Depakine (LA) (valproate) , 829
Depakine Chrono (valproate) , 829
Depakine Zuur (valproate) , 829
Depakote (valproate) , 829
Depakote ER (valproate) , 829
Depakote sprinkle (valproate) , 829
Depamide (valproate) , 829
Deparkin (valproate) , 829
Depex (sulpiride) , 741
Depixol (flupenthixol) , 307
Depixol-Conc (flupenthixol) , 307

Deplin (l-methylfolate) , 477
Deprakine (valproate) , 829
Depral (sulpiride) , 741
Depramine (imipramine) , 367
Deprax (trazodone) , 793
Deprenon (fluoxetine) , 301
Deprenyl (selegiline) , 705
Depressase (maprotiline) , 465
Deprex (fluoxetine) , 301
Deprilan (selegiline) , 705
Deprilept (maprotiline) , 465
Deprimyl (lofepramine) , 421
Deprinocte (estazolam) , 281
Deprinol (imipramine) , 367
Depsin (mianserin) , 495
Deptran (doxepin) , 255
Deroxat (paroxetine) , 593
Desconex (loxapine) , 443
Desfax (desvenlafaxine) , 215
Desidox (doxepin) , 255
desipramine , 207
Desisulpid (sulpiride) , 741
Desitriptylin (amitriptyline) , 25
desvenlafaxine , 215
Desyrel (trazodone) , 793
deutetrabenazine , 221
Devidon (trazodone) , 793
DexAlone (dextromethorphan) , 225

Dexamphetamine (d-amphetamine) , 39
Dexamphetamine sulfate (d-amphetamine) , 39
Dexedrine (d-amphetamine) , 39
Dexedrine Spansules (d-amphetamine) , 39
Dexmethylphenidate (d-methylphenidate) , 481
dextromethorphan , 221
Dextro Stat (d-amphetamine) , 39
Diaceplex (diazepam) , 229
Diaceplex simple (diazepam) , 229
Diapam (diazepam) , 229
Diaquel (diazepam) , 229
Diastat (diazepam) , 229
Diazemuls (diazepam) , 229
diazepam , 229
Dibenil (diphenhydramine) , 235
Dicepin B6 (diazepam) , 229
Digton (sulpiride) , 741
Diligan (hydroxyzine) , 355
Dinalexin (fluoxetine) , 301
Diphen (diphenhydramine) , 235
diphenhydramine , 235
Dipromal (valproate) , 829
Discimer (trifluoperazine) , 803
Distedon (diazepam) , 229
disulfiram , 239
divalproex (valproate) , 829
Divial (lorazepam) , 437
Dixarit (clonidine) , 179

Dixibon (sulpiride) , 741
Dizac (diazepam) , 229
DM (dextromethorphan) , 225
d-methylphenidate , 481
Dobren (sulpiride) , 741
Dobupal (venlafaxine) , 841
Dogmatil (sulpiride) , 741
Dogmatyl (sulpiride) , 741
Dolmatil (sulpiride) , 741
Domical (amitriptyline) , 25
Dominans (nortriptyline) , 551
Domnamid (estazolam) , 281
DOM-trazodone (trazodone) , 793
donepezil , 243
donepezil/memantine combination , 243 , 473
Doneurin (doxepin) , 255
Donix (lorazepam) , 437
Dopress (dothiepin) , 249
Doral (quazepam) , 663
Dorken (clorazepate) , 185
Dorm (lorazepam) , 437
Dormalin (quazepam) , 663
Dormapam (temazepam) , 755
Dorme (quazepam) , 663
Dormicum (midazolam) , 499
Dormodor (flurazepam) , 321
Dothep (dothiepin) , 249
dothiepin , 249

Doxal (doxepin) , 255
Doxedyn (doxepin) , 255
doxepin , 255
Dozic (haloperidol) , 347
D-Pam (diazepam) , 229
Drenian (diazepam) , 229
Dresent (sulpiride) , 741
Ducene (diazepam) , 229
duloxetine , 263
Dumirox (fluvoxamine) , 325
Dumozolam (triazolam) , 799
Dumyrox (fluvoxamine) , 325
Duraclon (clonidine) , 179
Duract (dextromethorphan) , 225
Duradiazepam (diazepam) , 229
Duralith (lithium) , 415
Duraperidol (haloperidol) , 347
Durazepam (oxazepam) , 569
Durazolam (lorazepam) , 437
Dutonin (nefazodone) , 545
Dyanavel XR (amphetamine d,l) , 45
Eclorion (sulpiride) , 741
Edluar (zolpidem) , 871
Edronax (reboxetine) , 681
Efectin (venlafaxine) , 841
Efexir (venlafaxine) , 841
Efexor (venlafaxine) , 841
Efexor XL (venlafaxine) , 841

Effexor (venlafaxine) , 841
Effexor XR (venlafaxine) , 841
Effiplen (buspirone) , 123
Egibren (selegiline) , 705
Eglonyl (sulpiride) , 741
Elavil (amitriptyline) , 25
Elavil Plus (amitriptyline) , 25
Eldepryl (selegiline) , 705
Elenium (chlordiazepoxide) , 147
Elepsia XR (levetiracetam) , 399
Eliwel (amitriptyline) , 25
Ellefore (desvenlafaxine) , 215
Elmendos (lamotrigine) , 387
Elopram (citalopram) , 159
Elperil (thioridazine) , 759
Elroquil N (hydroxyzine) , 355
Elvanse (lisdexamfetamine) , 409
Emdalen (lofepramine) , 421
Emsam (selegiline) , 705
EnBrace HR (l-methylfolate) , 477
Endep (amitriptyline) , 25
Enimon (sulpiride) , 741
Enlyte (l-methylfolate) , 477
Epial (carbamazepine) , 131
Epilim (valproate) , 829
Epitol (carbamazepine) , 131
Epitomax (topiramate) , 781
Equetro (carbamazepine) , 131

Equilid (sulpiride) , 741
Equitam (lorazepam) , 437
Er Ding (lofexidine) , 427
Ergenyl (valproate) , 829
Ergocalm (lorazepam) , 437
Eridan (diazepam) , 229
Erocap (fluoxetine) , 301
escitalopram , 269
Esculid (diazepam) , 229
Esilgan (estazolam) , 281
Esipride (sulpiride) , 741
Eskalith (lithium) , 415
Eskalith CR (lithium) , 415
Eskazine (trifluoperazine) , 803
esketamine , 275
Esparon (alprazolam) , 11
estazolam , 281
Estorra (eszopiclone) , 285
eszopiclone , 285
Ethipam (diazepam) , 229
Ethipramine (imipramine) , 367
Euhypnos (temazepam) , 755
Euipnos (temazepam) , 755
Eurosan (diazepam) , 229
Eutimil (paroxetine) , 593
Eutimox (fluphenazine) , 313
Evacalm (diazepam) , 229
Evekeo (amphetamine d,l) , 45

Everiden (valproate) , 829
Exan (buspirone) , 123
Excegran (zonisamide) , 875
Exelon (rivastigmine) , 699
Exogran (zonisamide) , 875
Exostrept (fluoxetine) , 301
Fanapt (iloperidone) , 359
Fardalan (sulpiride) , 741
Fargenor (chlordiazepoxide) , 147
Faustan (diazepam) , 229
Faverin (fluvoxamine) , 325
Fazaclo ODT (clozapine) , 191
Felicium (fluoxetine) , 301
Felison (flurazepam) , 321
Fenactil (chlorpromazine) , 153
Fentazin (perphenazine) , 607
Fetzima (levomilnacipran) , 403
Fevarin (fluvoxamine) , 325
Fidelan (sulpiride) , 741
Finlepsin (carbamazepine) , 131
Flaracantyl (thioridazine) , 759
flibanserin , 289
Flonital (fluoxetine) , 301
Floxyfral (fluvoxamine) , 325
Fluanxol (flupenthixol) , 307
Fluanxol Depot (flupenthixol) , 307
Fluanxol Depot 10% (flupenthixol) , 307
Fluanxol Depot 2% (flupenthixol) , 307

Fluanxol LP 100 mg/mL (flupenthixol) , 307
Fluanxol LP 20 mg/mL (flupenthixol) , 307
Fluanxol Retard (flupenthixol) , 307
Fluctin (fluoxetine) , 301
Fluctine (fluoxetine) , 301
Fludecate (fluphenazine) , 313
Flufenazin (fluphenazine) , 313
Flufenazin dekanoat (fluphenazine) , 313
Flufenazin Enantat (fluphenazine) , 313
flumazenil , 293
Fluni OPT (flunitrazepam) , 297
Flunimerck (flunitrazepam) , 297
Fluninoc (flunitrazepam) , 297
Flunipam (flunitrazepam) , 297
Flunitrax (flunitrazepam) , 297
flunitrazepam , 297
Flunox (flurazepam) , 321
Fluocim (fluoxetine) , 301
Fluoxeren (fluoxetine) , 301
fluoxetine , 301
fluoxetine/olanzapine combination , 301 , 559
Fluoxifar (fluoxetine) , 301
Fluoxin (fluoxetine) , 301
Flupam (flunitrazepam) , 297
flupenthixol , 307
fluphenazine , 313
flurazepam , 321
Fluscand (flunitrazepam) , 297

Flutepam (flurazepam) , 321
Flutin (fluoxetine) , 301
Flutraz (flunitrazepam) , 297
Fluval (fluoxetine) , 301
fluvoxamine , 325
Fluxadir (fluoxetine) , 301
Fluxonil (fluoxetine) , 301
Focalin (d-methylphenidate) , 481
Focalin XR (d-methylphenidate) , 481
Foille (trifluoperazine) , 803
Fokalepsin (carbamazepine) , 131
Fondur (fluoxetine) , 301
Fontex (fluoxetine) , 301
Fonzac (fluoxetine) , 301
Forfivo (bupropion) , 117
Fortunan (haloperidol) , 347
Frontal (alprazolam) , 11
Frosinor (paroxetine) , 593
Frosnor (paroxetine) , 593
gabapentin , 331
Gabitril (tiagabine) , 771
galantamine , 337
Gamanil (lofepramine) , 421
Gamibetal Plus (diazepam) , 229
Gamonil (lofepramine) , 421
Gen-Alprazolam (alprazolam) , 11
Gen-Clomipramine (clomipramine) , 165
Gen-T riazolam (triazolam) , 799

Gen-V alproic (valproate) , 829
Geodon (ziprasidone) , 863
Gewakalm (diazepam) , 229
Gladem (sertraline) , 721
Gnostorid (oxazepam) , 569
Gobanal (diazepam) , 229
guanfacine , 343
Haemiton (clonidine) , 179
Halcion (triazolam) , 799
Haldol (haloperidol) , 347
Haldol decanoas (haloperidol) , 347
Haldol Decanoat (haloperidol) , 347
Haldol Decanoate (haloperidol) , 347
Haldol Decanoato (haloperidol) , 347
Haldol Depot (haloperidol) , 347
Haldol L.A. (haloperidol) , 347
Haloneural (haloperidol) , 347
Haloper (haloperidol) , 347
haloperidol , 347
Haloperidol Decanoat (haloperidol) , 347
Haloperidol Decanoato (haloperidol) , 347
Haloperin (haloperidol) , 347
Haloperin depotinjektio (haloperidol) , 347
Harmomed (dothiepin) , 249
Harmoned (diazepam) , 229
Helex (alprazolam) , 11
Helogaphen (chlordiazepoxide) , 147
Hermolepsin (carbamazepine) , 131

Herphonal (trimipramine) , 817
Hetlioz (tasimelteon) , 751
Hexafene (hydroxyzine) , 355
Hexalid (diazepam) , 229
Hibanil (chlorpromazine) , 153
Hibernal (chlorpromazine) , 153
Hipnodane (quazepam) , 663
Hipnosedon (flunitrazepam) , 297
Histilos (hydroxyzine) , 355
Hopacem (mianserin) , 495
Horizant (gabapentin) , 331
Huberplex (chlordiazepoxide) , 147
Hydoic acid (valproate) , 829
Hydophen (clomipramine) , 165
Hydramine (diphenhydramine) , 235
Hydroxyzin (hydroxyzine) , 355
hydroxyzine , 355
Hydroxyzinum (hydroxyzine) , 355
Hypam (triazolam) , 799
Hypnocalm (flunitrazepam) , 297
Hypnodorm (flunitrazepam) , 297
Hypnor (flunitrazepam) , 297
Hypnorex Retard (lithium) , 415
Hypnovel (midazolam) , 499
Idom (dothiepin) , 249
Iktoviril (clonazepam) , 173
Ilman (flunitrazepam) , 297
iloperidone , 359

Imavate (imipramine) , 367
Imipramiin (imipramine) , 367
Imipramin (imipramine) , 367
imipramine , 367
Imovane (zopiclone) , 879
Inadalprem (lorazepam) , 437
Inderal (propranolol) , 653
Inderal LA (propranolol) , 653
Ingrezza (valbenazine) , 825
InnoPran XL (propranolol) , 653
Insom (flunitrazepam) , 297
Intermezzo (zolpidem) , 871
Intuniv (guanfacine) , 343
Invega (paliperidone) , 581
Invega Sustenna (paliperidone injectable) , 581
Invega T rinza (paliperidone) , 581
Ipnovel (midazolam) , 499
Iremo Sedofren (trifluoperazine) , 803
Iremofar (hydroxyzine) , 355
isocarboxazid , 375
Ivadal (zolpidem) , 871
Ixel (milnacipran) , 503
Janimine (imipramine) , 367
Januar (oxazepam) , 569
Jardin (dothiepin) , 249
Jatroneural (trifluoperazine) , 803
Jatrosom (tranylcypromine) , 787
Jatrosom N (tranylcypromine) , 787

Jatrosom N (trifluoperazine) , 803
Jornay PM (d, l-methylphenidate) , 487
Julap (selegiline) , 705
Jumex (selegiline) , 705
Jumexal (selegiline) , 705
Kai (lofexidine) , 427
Kainever (estazolam) , 281
Kalma (alprazolam) , 11
Kanopan 75 (maprotiline) , 465
Kapvay (clonidine) , 179
Karbazin (carbamazepine) , 131
Kataved (esketamine) , 275
Keppra (levetiracetam) , 399
Ketalar (ketamine) , 383
ketamine , 383
Ketanest (esketamine) , 275
Ketanest S (esketamine) , 275
Kinabide (selegiline) , 705
Klarium (diazepam) , 229
Klofelins (clonidine) , 179
Klonopin (clonazepam) , 173
Klopoxid (chlordiazepoxide) , 147
Kloproman (chlorpromazine) , 153
Klorproman (chlorpromazine) , 153
Klotriptyl (chlordiazepoxide) , 147
Klozapol (clozapine) , 191
Labileno (lamotrigine) , 387

Ladose (fluoxetine) , 301
Lambipol (lamotrigine) , 387
Lamictal (lamotrigine) , 387
Lamictin (lamotrigine) , 387
lamotrigine , 387
Lamra (diazepam) , 229
Lanexat (flumazenil) , 293
Lantanon (mianserin) , 495
Largactil (chlorpromazine) , 153
Largatrex (chlorpromazine) , 153
Laroxyl (amitriptyline) , 25
Latuda (lurasidone) , 457
Laubeel (lorazepam) , 437
Lauracalm (lorazepam) , 437
Lebopride (sulpiride) , 741
Lelptilan (valproate) , 829
Lelptilanil (valproate) , 829
lemborexant , 395
Lentizol (amitriptyline) , 25
Lentolith (lithium) , 415
Lentotran (chlordiazepoxide) , 147
Leponex (clozapine) , 191
Leptilin (valproate) , 829
Lerivon (mianserin) , 495
Leukominerase (lithium) , 415
Levanxol (temazepam) , 755
levetiracetam , 399
levomilnacipran , 403

Lexapro (escitalopram) , 269
Li-450 (lithium) , 415
Librax (chlordiazepoxide) , 147
Libraxin (chlordiazepoxide) , 147
Librium (chlordiazepoxide) , 147
Lidone (molindone) , 527
Li-Liquid (lithium) , 415
Lilly Fluoxetine (fluoxetine) , 301
Limbatril (chlordiazepoxide) , 147
Limbatril F (chlordiazepoxide) , 147
Limbitrol (chlordiazepoxide) , 147
Limbitrol F (chlordiazepoxide) , 147
Limbitryl (chlordiazepoxide) , 147
Limbitryl Plus (chlordiazepoxide) , 147
lisdexamfetamine , 409
Liskonum (lithium) , 415
Litarex (lithium) , 415
Lithane (lithium) , 415
Lithiofor (lithium) , 415
Lithionit (lithium) , 415
Lithiucarb (lithium) , 415
lithium , 415
Lithium-aspartat (lithium) , 415
Lithium carbonate tablets (lithium) , 415
Lithium carbonicum (lithium) , 415
Lithium citrate syrup (lithium) , 415
Lithium-Duriles (lithium) , 415
Lithiumkarbonat (lithium) , 415

Lithiumorotat (lithium) , 415
Lithizine (lithium) , 415
Lithobid (lithium) , 415
Lithonate (lithium) , 415
Lithostat (lithium) , 415
Lito (lithium) , 415
Litoduron (lithium) , 415
L-ketamine (esketamine) , 275
l-methylfolate , 477
Lodopin (zotepine) , 883
lofepramine , 421
lofexidine , 427
loflazepate , 431
Lomesta (lorazepam) , 437
Lonasen (blonanserin) , 89
Lonseren (pipothiazine) , 633
Lorabenz (lorazepam) , 437
Lorafen (lorazepam) , 437
Loram (lorazepam) , 437
Lorans (lorazepam) , 437
Lorapam (lorazepam) , 437
lorazepam , 437
Lorenin (lorazepam) , 437
Loridem (lorazepam) , 437
Lorien (fluoxetine) , 301
Lorivan (lorazepam) , 437
Lorsedal (lorazepam) , 437
Lorsifar (lorazepam) , 437

Lorsilan (lorazepam) , 437
Lorzem (lorazepam) , 437
Lovan (fluoxetine) , 301
Loxapac (loxapine) , 443
loxapine , 443
Loxitane (loxapine) , 443
Lucemyra (lofexidine) , 427
Ludiomil (maprotiline) , 465
Lullan (perospirone) , 601
lumateperone , 451
Lumin (mianserin) , 495
Lunesta (eszopiclone) , 285
lurasidone , 457
Lustral (sertraline) , 721
Luvox (fluvoxamine) , 325
Luvox SR (fluvoxamine) , 325
Lyogen (fluphenazine) , 313
Lyogen Depot (fluphenazine) , 313
Lyoridin Depot (fluphenazine) , 313
Lyorodin (fluphenazine) , 313
Lyrica (pregabalin) , 647
Lyrica CR (pregabalin) , 647

Majorpin (zotepine) , 883
Mallorol (thioridazine) , 759
Maludil (maprotiline) , 465
Mandro-Zep (diazepam) , 229
Manerix (moclobemide) , 515
Maniprex (lithium) , 415
Mapro Gry (maprotiline) , 465
Mapro T ablinen (maprotiline) , 465
Maprolu (maprotiline) , 465
Maprolu-50 (maprotiline) , 465
Maprostad (maprotiline) , 465
Maprotibene (maprotiline) , 465
Maprotilin (maprotiline) , 465
maprotiline , 465
Marax (hyroxyzine) , 355
Mareen 50 (doxepin) , 255
Mariastel (sulpiride) , 741
Marplan (isocarboxazid) , 375
Martimil (nortriptyline) , 551
Masmoran (hydroxyzine) , 355
Maveral (fluvoxamine) , 325
Maximed (protriptyline) , 657
Maxivalet (amitriptyline) , 25
Mazepine (carbamazepine) , 131
Medipam (diazepam) , 229
Medopam (oxazepam) , 569
Mefurine (thioridazine) , 759
Megaphen (chlorpromazine) , 153

Meilax (loflazepate) , 431
Meleril (thioridazine) , 759
Melipramin (imipramine) , 367
Melipramine (imipramine) , 367
Mellaril (thioridazine) , 759
Melleretten (thioridazine) , 759
Melleril (thioridazine) , 759
Melzine (thioridazine) , 759
Memac (donepezil) , 243
memantine , 473
memantine/donepezil combination , 243 , 473
memantine XR , 473
Menfazona (nefazodone) , 545
Menrium (chlordiazepoxide) , 147
Mepizin (oxazepam) , 569
Meresa (sulpiride) , 741
Merlit (lorazepam) , 437
Metadate CD (d,l-methylphenidate) , 487
Metadate ER (d,l-methylphenidate) , 487
Metafolin (l-methylfolate) , 477
Metamidol (diazepam) , 229
methyfolate (l) , 477
Methylin (d,l-methylphenidate) , 487
Methylin ER (d,l-methylphenidate) , 487
methylphenidate (d) , 481
methylphenidate (d,l) , 487
Metylyl (desipramine) , 207
Miabene (mianserin) , 495

Mialin (alprazolam) , 11
Mianeurin (mianserin) , 495
Miansan (mianserin) , 495
mianserin , 495
Miansin (mianserin) , 495
Miaxan (mianserin) , 495
midazolam , 499
Milithin (lithium) , 415
milnacipran , 503
Minipress (prazosin) , 643
Minizide (prazosin) , 643
Mipralin (imipramine) , 367
Mirbanil (sulpiride) , 741
Mirenil (fluphenazine) , 313
Mirenil Prolongatum (fluphenazine) , 313
Mirfat (clonidine) , 179
Mirfudorm (oxazepam) , 569
Mirpan (maprotiline) , 465
mirtazapine , 509
Moban (molindone) , 527
Mocloamine (moclobemide) , 515
moclobemide , 515
modafinil , 521
Modalina (trifluoperazine) , 803
Modecate (fluphenazine) , 313
Modiodal (modafinil) , 521
Moditen (fluphenazine) , 313
Moditen Action Prolongee (fluphenazine) , 313

Moditen Depot (fluphenazine) , 313
Moditen Enanthate (fluphenazine) , 313
Modium (lorazepam) , 437
molindone , 527
Molipaxin (trazodone) , 793
Motipress (nortriptyline) , 551
Motival (nortriptyline) , 551
Motivan (paroxetine) , 593
Mover gan (selegiline) , 705
Moverin (selegiline) , 705
Moxadil (amoxapine) , 33
Multipax (hydroxyzine) , 355
Multum (chlordiazepoxide) , 147
Murelax (oxazepam) , 569
Mutan (fluoxetine) , 301
Mydayis (amphetamine d, l) , 45
Mylproin (valproate) , 829
Mysimba (naltrexone/bupropion) , 541
Nailin (nortriptyline) , 551
Nalin (nortriptyline) , 551
nalmefene , 533
naloxone with buprenorphine , 111
naltrexone , 537
naltrexone/bupropion , 541
Namenda (memantine) , 473
Namenda XR (memantine XR) , 473
Namzaric (memantine/donepezil combination) , 243 , 473
Nansius (clorazepate) , 185

Napoton (chlordiazepoxide) , 147
Narcozep (flunitrazepam) , 297
Nardelzine (phenelzine) , 613
Nardil (phenelzine) , 613
Narol (buspirone) , 123
Navane (thiothixene) , 765
Navicalm (hydroxyzine) , 355
Nefadar (nefazodone) , 545
nefazodone , 545
Nefirel (nefazodone) , 545
Neo Gnostoride (chlordiazepoxide) , 147
Neodorm SP (temazepam) , 755
Neoride (sulpiride) , 741
Neurol (alprazolam) , 11
Neurolepsin (lithium) , 415
Neurolithium (lithium) , 415
Neurolytril (diazepam) , 229
Neurontin (gabapentin) , 331
Neurotol (carbamazepine) , 131
Neurotop (carbamazepine) , 131
Nevropromazine (chlorpromazine) , 153
Nicoflox (fluoxetine) , 301
Nifalin (lorazepam) , 437
Nilium (flunitrazepam) , 297
Niotal (zolpidem) , 871
Nipolept (zotepine) , 883
Nivalin (galantamine) , 337
Noam (diazepam) , 229

Noan-Gap (lorazepam) , 437
Noctazepam (oxazepam) , 569
Noctran (clorazepate) , 185
Nocturne (temazepam) , 755
Nomapam (temazepam) , 755
Noneston (sulpiride) , 741
Nopress (nortriptyline) , 551
Nordotol (carbamazepine) , 131
Norebox (reboxetine) , 681
Norestran (sulpiride) , 741
Norfenazin (nortriptyline) , 551
Noriel (flunitrazepam) , 297
Noriline (nortriptyline) , 551
Noripam (oxazepam) , 569
Noritren (nortriptyline) , 551
Norkotral N (oxazepam) , 569
Norkotral T ema (temazepam) , 755
Normison (temazepam) , 755
Normum (sulpiride) , 741
Norpramin (desipramine) , 207
Northiaden (dothiepin) , 249
Nortimil (desipramine) , 207
Nortix (nortriptyline) , 551
Nortrilen (nortriptyline) , 551
Nortriptilin (nortriptyline) , 551
nortriptyline , 551
Norval (mianserin) , 495
Nova-Pam (chlordiazepoxide) , 147

Novazam (diazepam) , 229
Novhepar (lorazepam) , 437
Novo-Alprazol (alprazolam) , 11
Novo-Carbamaz (carbamazepine) , 131
Novo-Clonidine (clonodine) , 179
Novo-Clopamine (clomipramine) , 165
Novo-Clopate (clorazepate) , 185
Novodorm (triazolam) , 799
Novo-Doxepin (doxepin) , 255
Novo-fluoxetine (fluoxetine) , 301
Novo-Hydroxyzine (hydroxyzine) , 355
Novo-Lorazem (lorazepam) , 437
Novo-Maprotiline (maprotiline) , 465
Novo-Peridol (haloperidol) , 347
Novoprotect (amitriptyline) , 25
Novo-Selegine (selegiline) , 705
Novo-T razodone (trazodone) , 793
Novo-T rimipramine (trimipramine) , 817
Novo-T riolam (triazolam) , 799
Novo-V alproic (valproate) , 829
Nozepams (oxazepam) , 569
Nu-Alpraz (alprazolam) , 11
Nu-Carbamazepine (carbamazepine) , 131
Nu-Clonidine (clonidine) , 179
Nuctalon (estazolam) , 281
Nuedexta (dextromethorphan with quinidine) , 225
Nufarol (sulpiride) , 741
Nulans (lorazepam) , 437

Nu-Loraz (lorazepam) , 437
Nuplazid (pimavanserin) , 623
Nu-T razodone (trazodone) , 793
Nu-T rimipramine (trimipramine) , 817
Nuvigil (armodafinil) , 65
Nycoflox (fluoxetine) , 301
Nylipark (sulpiride) , 741
Oasil (chlordiazepoxide) , 147
olanzapine , 559
olanzapine/fluoxetine combination , 301 , 559
Olasek (olanzapine) , 559
Oleptro (trazodone XR) , 793
Omaha (sulpiride) , 741
Omca (fluphenazine) , 313
Omiryl (sulpiride) , 741
Omnali Esteve (chlordiazepoxide) , 147
Omnipress (amoxapine) , 33
Oniria (quazepam) , 663
Opamin (oxazepam) , 569
Opamox (oxazepam) , 569
Opiran (pimozide) , 627
Orap (pimozide) , 627
Orfidal (lorazepam) , 437
Orfilept (valproate) , 829
Orfiril (valproate) , 829
Orfiril Retard (valproate) , 829
Ormodon (temazepam) , 755
Orsanil (thioridazine) , 759

Orthon (fluoxetine) , 301
Oxabenz (oxazepam) , 569
Oxahexal (oxazepam) , 569
Oxaline (oxazepam) , 569
Oxanid (oxazepam) , 569
Oxapam (oxazepam) , 569
Oxapax (oxazepam) , 569
Oxaphar (oxazepam) , 569
Oxa-Puren (oxazepam) , 569
Oxascand (oxazepam) , 569
oxazepam , 569
oxcarbazepine , 575
Oxepam (oxazepam) , 569
Oxepam Expidet (oxazepam) , 569
Ox-Pam (oxazepam) , 569
Oxtellar XR (oxcarbazepine) , 575
Oxyperazine (trifluoperazine) , 803
Ozodeprin (sulpiride) , 741
Paceum (diazepam) , 229
Pacinol (fluphenazine) , 313
Pacium (diazepam) , 229
paliperidone , 581
Pamelor (nortriptyline) , 551
Panix (alprazolam) , 11
Pantrop Retard (chlordiazepoxide) , 147
Paracefan (clonidine) , 179
Paratil (sulpiride) , 741
Parkinyl (selegiline) , 705

Parmodalin (tranylcypromine) , 787
Parmodalin (trifluoperazine) , 803
Parnate (tranylcypromine) , 787
paroxetine , 593
paroxetine CR , 593
Parstelin (tranylcypromine) , 787
Parstelin (trifluoperazine) , 803
Pasrin (buspirone) , 123
Pax (diazepam) , 229
Paxal (alprazolam) , 11
Paxam (clonazepam) , 173
Paxil (paroxetine) , 593
Paxil CR (paroxetine CR) , 593
Paxium (chlordiazepoxide) , 147
Paxtibi (nortriptyline) , 551
Pazolan (alprazolam) , 11
Pefanium/Pefanic (chlordiazepoxide) , 147
Peratsin (perphenazine) , 607
Peratsin Dekanoaatti (perphenazine) , 607
Peratsin Enantaati (perphenazine) , 607
Perfenazin (perphenazine) , 607
Peridol (haloperidol) , 347
Permitil (fluphenazine) , 313
perospirone , 601
perphenazine , 607
Perseris (risperidone injection) , 687
Pertofrane (desipramine) , 207
Pertofrin (desipramine) , 207

Phasal (lithium) , 415
phenelzine , 613
phentermine/topiramate , 619
Piefol (trifluoperazine) , 803
pimavanserin , 623
pimozide , 627
Piportil (pipothiazine) , 633
Piportil Depot (pipothiazine) , 633
Piportil L4 (pipothiazine) , 633
Piportil Longum-4 (pipothiazine) , 633
Piportil palmitate (pipothiazine) , 633
Piportyl palmitat (pipothiazine) , 633
pipothiazine , 633
Pipotiazine (pipothiazine) , 633
Pirium (pimozide) , 627
pitolisant , 639
Placidia (lorazepam) , 437
Placil (clomipramine) , 165
Placinoral (lorazepam) , 437
Planum (temazepam) , 755
Plegomazin (chlorpromazine) , 153
Plenur (lithium) , 415
Plurimen (selegiline) , 705
PMS-carbamazepine (carbamazepine) , 131
PMS-Clonazepam (clonazepam) , 173
PMS-Desipramine (desipramine) , 207
PMS-Fluoxetine (fluoxetine) , 301
PMS-Fluphenazine (fluphenazine) , 313

PMS-Fluphenazine Decanoate (fluphenazine) , 313
PMS-Haloperidol (haloperidol) , 347
PMS-Hydroxyzine (hydroxyzine) , 355
PMS-Lithium (lithium) , 415
PMS-Methylphenidate (d,l-methylphenidate) , 487
PMS-T razodone (trazodone) , 793
Podium (diazepam) , 229
Poldoxin (doxepin) , 255
Polysal (amitriptyline) , 25
Portal (fluoxetine) , 301
Pragmarel (trazodone) , 793
Praxiten (oxazepam) , 569
prazosin , 643
pregabalin , 647
Priadel (lithium) , 415
Prisdal (citalopram) , 159
Prisma (mianserin) , 495
Pristiq (desvenlafaxine) , 215
Probuphine (buprenorphine) , 111
ProCentra (amphetamine d) , 39
Pro Dorm (lorazepam) , 437
Procythol (selegiline) , 705
Prolixin (fluphenazine) , 313
Prolixin Decanoate (fluphenazine) , 313
Prolixin Enanthate (fluphenazine) , 313
Prolongatum (fluphenazine) , 313
Pronervon T (temazepam) , 755
Propam (diazepam) , 229

Propaphenin (chlorpromazine) , 153
propranolol , 653
Propymal (valproate) , 829
Prosedar (quazepam) , 663
ProSom (estazolam) , 281
Prosulpin (sulpiride) , 741
Prothiaden (dothiepin) , 249
Protiaden (dothiepin) , 249
protriptyline , 657
Provigil (modafinil) , 521
Proxam (oxazepam) , 569
Prozac (fluoxetine) , 301
Prozil (chlorpromazine) , 153
Prozin (chlorpromazine) , 153
Prozyn (fluoxetine) , 301
Pryleugan (imipramine) , 367
Psicocen (sulpiride) , 741
Psicofar (chlordiazepoxide) , 147
Psiquiwas (oxazepam) , 569
Psychopax (diazepam) , 229
Psymoin (maprotiline) , 465
PT-141 (bremelanotide) , 95
Punktyl (lorazepam) , 437
Purata (oxazepam) , 569
Q-Med Hydroxyzine (hydroxyzine) , 355
Qsymia (phentermine/topiramate) , 619
Quait (lorazepam) , 437
Quastil (sulpiride) , 741

quazepam , 663
Quazium (quazepam) , 663
Qudexy (topiramate) , 781
Qudexy SR (topiramate) , 781
quetiapine , 667
Quiedorm (quazepam) , 663
Quilibrex (oxazepam) , 569
QuilliChew ER (methylphenidate d,l) , 487
Quillivant XR (methylphenidate d,l) , 487
Quilonum (lithium) , 415
Quilonum Retard (lithium) , 415
Quinolorm (lithium) , 415
Quinolorm Retard (lithium) , 415
Quiridil (sulpiride) , 741
Quitaxon (doxepin) , 255
Radepur (chlordiazepoxide) , 147
ramelteon , 677
Razadyne (galantamine) , 337
Razadyne ER (galantamine) , 337
Razolam (alprazolam) , 11
Reagila (cariprazine) , 137
reboxetine , 681
Redomex (amitriptyline) , 25
Redomex Dif fucaps (amitriptyline) , 25
Regepar (selegiline) , 705
Rekynda (bremelanotide) , 95
Relanium (diazepam) , 229
Relax Sedans (chlordiazepoxide) , 147

Relaxedans (chlordiazepoxide) , 147
Reliberan (chlordiazepoxide) , 147
Relistor (naltrexone) , 537
Relprevv (olanzapine) , 559
Remdue (flurazepam) , 321
Remer gil (mirtazapine) , 509
Remeron (mirtazapine) , 509
Remestan (temazepam) , 755
Reminyl (galantamine) , 337
Reneuron (fluoxetine) , 301
Repazine (chlorpromazine) , 153
Reposium (temazepam) , 755
Reseril (nefazodone) , 545
Restful (sulpiride) , 741
Restoril (temazepam) , 755
Retinyl (maprotiline) , 465
Reval (diazepam) , 229
Revatio (sildenafil) , 729
Revia (naltrexone) , 537
Rexer (mirtazapine) , 509
Rexulti (brexpiprazole) , 103
Rho-Doxepin (doxepin) , 255
Rho-Fluphenazine Decanoate (fluphenazine) , 313
Rho-Haloperidol (haloperidol) , 347
Rho-T rimine (trimipramine) , 817
Ridazine (thioridazine) , 759
Rilamir (triazolam) , 799
Rimarix (moclobemide) , 515

Riminyl (galantamine) , 337
Risolid (chlordiazepoxide) , 147
Risperdal (risperidone) , 687
Risperdal Consta (risperidone injectable) , 687
risperidone , 687
Risperin (risperidone) , 687
Rispolept (risperidone) , 687
Rispolin (risperidone) , 687
Ritalin (d,l-methylphenidate) , 487
Ritalin LA (d, l-methylphenidate) , 487
Ritalin SR (d,l-methylphenidate) , 487
Ritaline (d,l-methylphenidate) , 487
rivastigmine , 699
Rivatril (clonazepam) , 173
Rivotril (clonazepam) , 173
Robitussin (dextromethorphan) , 225
Rocam (midazolam) , 499
Rohipnol (flunitrazepam) , 297
Rohypnol (flunitrazepam) , 297
Roipnol (flunitrazepam) , 297
Romazicon (flumazenil) , 293
Ronal (flunitrazepam) , 297
Ropan (flunitrazepam) , 297
Rozerem (ramelteon) , 677
Rubifen (d,l-methylphenidate) , 487
Rulivan (nefazodone) , 545
Sanval (zolpidem) , 871
Sanzur (fluoxetine) , 301

Saphris (asenapine) , 71
Sapilent (trimipramine) , 817
Sarafem (fluoxetine) , 301
Saroten (amitriptyline) , 25
Saroten Retard (amitriptyline) , 25
Sarotex (amitriptyline) , 25
Sartuzin (fluoxetine) , 301
Savella (milnacipran) , 503
Sebor (lorazepam) , 437
Secuado (asenapine) , 71
Securit (lorazepam) , 437
Sedacoroxen (imipramine) , 367
Sedans (chlordiazepoxide) , 147
Sedapon (lorazepam) , 437
Sedazin (lorazepam) , 437
Sedex (flunitrazepam) , 297
Sedizepan (lorazepam) , 437
Seduxen (chlordiazepoxide) , 147
Seduxen (diazepam) , 229
Seledat (selegiline) , 705
Selegam (selegiline) , 705
selegiline , 705
Selepam (quazepam) , 663
Selepar (selegiline) , 705
Selepark (selegiline) , 705
Seletop 5 (selegiline) , 705
Selgene (selegiline) , 705
Selincro (nalmefene) , 533

Selpar (selegiline) , 705
Sensaval (nortriptyline) , 551
Sensival (nortriptyline) , 551
Sepatrem (selegiline) , 705
Serad (sertraline) , 721
Seralgan (citalopram) , 159
Serax (oxazepam) , 569
Serdolect (sertindole) , 715
Serelan (mianserin) , 495
Seren (chlordiazepoxide) , 147
Serenace (haloperidol) , 347
Serenase (haloperidol) , 347
Serenase (lorazepam) , 437
Serenase Decanoat (haloperidol) , 347
Serenase Depot (haloperidol) , 347
Serenelfi (haloperidol) , 347
Serepax (oxazepam) , 569
Seresta (oxazepam) , 569
Sereupin (paroxetine) , 593
Serlain (sertraline) , 721
Serlect (sertindole) , 715
Serol (fluoxetine) , 301
Seronil (fluoxetine) , 301
Seropram (citalopram) , 159
Seroquel (quetiapine) , 667
Seroquel XR (quetiapine) , 667
Seroxal (paroxetine) , 593
Seroxat (paroxetine) , 593

Serpax (oxazepam) , 569
sertindole , 715
Sertofren (desipramine) , 207
sertraline , 721
Serzone (nefazodone) , 545
Setous (zotepine) , 883
Sevinol (fluphenazine) , 313
Sevium (haloperidol) , 347
Sibason (diazepam) , 229
Sicorelax (diazepam) , 229
Sigacalm (oxazepam) , 569
Sigaperidol (haloperidol) , 347
Signopam (temazepam) , 755
sildenafil , 729
Silenor (doxepin) , 255
Silphen (diphenhydramine) , 235
Sinequan (doxepin) , 255
Sinquan (doxepin) , 255
Sinquane (doxepin) , 255
Siqualone (fluphenazine) , 313
Siqualone Decanoat (fluphenazine) , 313
Siqualone Enantat (fluphenazine) , 313
Sirtal (carbamazepine) , 131
S-ketamine (esketamine) , 275
SK-Pramine (imipramine) , 367
Sobile (oxazepam) , 569
Sobril (oxazepam) , 569
Socian (amisulpride) , 17

sodium oxybate , 733
Softramal (clorazepate) , 185
Solarix (moclobemide) , 515
Solian (amisulpride) , 17
Solidon (chlorpromazine) , 153
Solis (diazepam) , 229
solriamfetol , 737
Somagerol (lorazepam) , 437
Somapam (temazepam) , 755
Somatarax (hydroxyzine) , 355
Sominex (diphenhydramine) , 235
Somniton (triazolam) , 799
Somnium (lorazepam) , 437
Somnol (flurazepam) , 321
Somnubene (flunitrazepam) , 297
Sonata (zaleplon) , 859
Songar (triazolam) , 799
Sovigen (zolpidem) , 871
Spasmilan (buspirone) , 123
Spasmo Praxiten (oxazepam) , 569
Sporalon (trifluoperazine) , 803
Spravato (esketamine) , 275
Spritam (levetiracetam) , 399
Stablon (tianeptine) , 777
Stalleril (thioridazine) , 759
Stamoneurol (sulpiride) , 741
Staurodorm (flurazepam) , 321
Staurodorm Neu (flurazepam) , 321

Stavzor (valproate) , 829
Stazepine (carbamazepine) , 131
Stedon (diazepam) , 229
Stelabid (trifluoperazine) , 803
Stelabid forte (trifluoperazine) , 803
Stelabid mite (trifluoperazine) , 803
Stelazine (trifluoperazine) , 803
Stelbid (trifluoperazine) , 803
Stelbid forte (trifluoperazine) , 803
Stelium (trifluoperazine) , 803
Stelminal (amitriptyline) , 25
Stephadilat (fluoxetine) , 301
Stesolid (diazepam) , 229
Stilnoct (zolpidem) , 871
Stilnox (zolpidem) , 871
Strattera (atomoxetine) , 79
Stressigal (buspirone) , 123
Sublocade (buprenorphine injection) , 111
Suboxone (buprenorphine with naloxone) , 111
Subutex (buprenorphine) , 111
Sulamid (amisulpride) , 17
Sulp (sulpiride) , 741
Sulparex (sulpiride) , 741
Sulpiphar (sulpiride) , 741
Sulpirid (sulpiride) , 741
sulpiride , 741
Sulpiryd (sulpiride) , 741
Sulpitil (sulpiride) , 741

Sulpivert (sulpiride) , 741
Sulpril (sulpiride) , 741
Sunosi (solriamfetol) , 737
Suprium (sulpiride) , 741
Surmontil (trimipramine) , 817
suvorexant , 747
Suxidina (oxazepam) , 569
Sylador (haloperidol) , 347
Symbyax (olanzapine/fluoxetine combination) , 301 , 559
Synedil (sulpiride) , 741
Synedil Fort (sulpiride) , 741
Syneudon 50 (amitriptyline) , 25
Tafil (alprazolam) , 11
Tagonis (paroxetine) , 593
Tardotol (carbamazepine) , 131
Taro-Carbamazepine (carbamazepine) , 131
tasimelteon , 751
Tatanka (alprazolam) , 11
Tatig (sertraline) , 721
Tatinol (tianeptine) , 777
Tavor (lorazepam) , 437
Tazepam (oxazepam) , 569
Tegretal (carbamazepine) , 131
Tegretol (carbamazepine) , 131
Tegretol LP (carbamazepine) , 131
Teledomin (milnacipran) , 503
Temador (temazepam) , 755
Temaze (temazepam) , 755

temazepam , 755
Temesta (lorazepam) , 437
Temodal (quazepam) , 663
Temporal Slow (carbamazepine) , 131
Temporol (carbamazepine) , 131
Temtabs (temazepam) , 755
Tenex (guanfacine) , 343
Tenox (temazepam) , 755
Tensispes (buspirone) , 123
Tensium (diazepam) , 229
Tensopam (diazepam) , 229
Tenso-T imelets (clonidine) , 179
Tepavil (sulpiride) , 741
Tepazepam (diazepam) , 229
Tepazepam (sulpiride) , 741
Teperin (amitriptyline) , 25
Teralithe (lithium) , 415
Tercian (cyamemazine) , 201
Terfluoperazine (perphenazine) , 607
Terflurazine (trifluoperazine) , 803
Terfluzin (trifluoperazine) , 803
Teril (carbamazepine) , 131
Tetrabenazine D6 (deutetrabenazine) , 221
Texapam (temazepam) , 755
Thaden (dothiepin) , 249
thioridazine , 759
thiothixene , 765
Thombran (trazodone) , 793

Thorazine (chlorpromazine) , 153
Thymal (lorazepam) , 437
tiagabine , 771
tianeptine , 777
Timelit (lofepramine) , 421
Timonil (carbamazepine) , 131
Tingus (fluoxetine) , 301
Tiprolisant (pitolisant) , 639
Tirodil (thioridazine) , 759
Titus (lorazepam) , 437
Tofranil (imipramine) , 367
Tofranil pamoata (imipramine) , 367
Tofranil-PM (imipramine) , 367
Tolid (lorazepam) , 437
Tolmin (mianserin) , 495
Tolvin (mianserin) , 495
Tolvon (mianserin) , 495
Tonirem (temazepam) , 755
Topamac (topiramate) , 781
Topamax (topiramate) , 781
Topimax (topiramate) , 781
topiramate , 781
T-Pam (temazepam) , 755
Tramensan (trazodone) , 793
Trankilium (lorazepam) , 437
Trankimazin (alprazolam) , 11
Tranquase (diazepam) , 229
Tran-Quil (lorazepam) , 437

Tranquipam (lorazepam) , 437
Tranquirit (diazepam) , 229
Tranquo (oxazepam) , 569
Tranquo/T ablinen (diazepam) , 229
Transene (clorazepate) , 185
Tranxene (clorazepate) , 185
Tranxilen (clorazepate) , 185
Tranxilium (clorazepate) , 185
tranylcypromine , 787
Tranzen (clorazepate) , 185
Travin (buspirone) , 123
Trazepam (oxazepam) , 569
trazodone , 793
trazodone XR , 793
Trazolan (trazodone) , 793
Tremorex (selegiline) , 705
Trepiline (amitriptyline) , 25
Tresleen (sertraline) , 721
Trevicta (paliperidone) , 581
Trevilor (venlafaxine) , 841
Trewilor (venlafaxine) , 841
triazolam , 799
Triazoral (triazolam) , 799
Trifluo perazin (trifluoperazine) , 803
trifluoperazine , 803
trihexyphenidyl , 809
triiodothyronine , 813
Trilafon (perphenazine) , 607

Trilafon decanoaat (perphenazine) , 607
Trilafon dekanoat (perphenazine) , 607
Trilafon Depot (perphenazine) , 607
Trilafon enantat(e) (perphenazine) , 607
Trilafon enantato (perphenazine) , 607
Trilafon enenthaat (perphenazine) , 607
Trileptal (oxcarbazepine) , 575
Trilifan (perphenazine) , 607
Trilifan Retard (perphenazine) , 607
Trimen (trihexyphenidyl) , 809
trimipramine , 817
Trimonil (carbamazepine) , 131
Trimonil Retard (carbamazepine) , 131
Trintellix (vortioxetine) , 853
Trion (triazolam) , 799
Tripamine Surmontil (trimipramine) , 817
Triptafen (perphenazine) , 607
Triptil (protriptyline) , 657
Triptyl (amitriptyline) , 25
Triptyl Depot (amitriptyline) , 25
Trisedyl (trifluoperazine) , 803
Trittico (trazodone) , 793
Trokendi XR (topiramate) , 781
Tropar gal (nortriptyline) , 551
Tropium (chlordiazepoxide) , 147
Trycam (triazolam) , 799
Tryptanol (amitriptyline) , 25
Tryptine (amitriptyline) , 25

Tryptizol (amitriptyline) , 25
Tydamine (trimipramine) , 817
Tymelyt (lofepramine) , 421
Ucerax (hydroxyzine) , 355
Umbrium (diazepam) , 229
Unilan (alprazolam) , 11
Unisedil (diazepam) , 229
Unitranxene (clorazepate) , 185
U-Pan (lorazepam) , 437
Uskan (oxazepam) , 569
Valaxona (diazepam) , 229
Valclair (chlordiazepoxide) , 147
valbenazine , 825
Valclair (diazepam) , 229
Valcote 250 (valproate) , 829
Valdorm (flurazepam) , 321
Valdoxan (agomelatine) , 5
Valeans (alprazolam) , 11
Valinil (diazepam) , 229
Valiquid (diazepam) , 229
Valiquid 0.3 (diazepam) , 229
Valirem (sulpiride) , 741
Valium (diazepam) , 229
Valocordin Diazepam (diazepam) , 229
Valparine (valproate) , 829
Valpro (valproate) , 829
valproate , 829

valproic acid (valproate) , 829
valpromide (valproate) , 829
Valsera (flunitrazepam) , 297
Vandral (venlafaxine) , 841
varenicline , 837
Vatran (diazepam) , 229
Venefon (imipramine) , 367
venlafaxine , 841
venlafaxine XR , 841
Versacloz (clozapine) , 191
Versed (midazolam) , 499
Vertigo (sulpiride) , 741
Vesadol (haloperidol) , 347
Vesalium (haloperidol) , 347
Vesparax (hydroxyzine) , 355
Vesparax mite (hydroxyzine) , 355
Vesparax Novum (hydroxyzine) , 355
Viagra (sildenafil) , 729
Vicks Formula 44 (diphenhydramine) , 235
Vigiten (lorazepam) , 437
Viibryd (vilazodone) , 847
vilazodone , 847
Vincosedan (diazepam) , 229
Visergil (thioridazine) , 759
Vistaril (hydroxyzine) , 355
Vivactil (protriptyline) , 657
Vival (diazepam) , 229
Vivapryl (selegiline) , 705

Vividyl (nortriptyline) , 551
Vivitrol (naltrexone) , 537
Vivol (diazepam) , 229
vortioxetine , 853
Vraylar (cariprazine) , 137
Vulbegal (flunitrazepam) , 297
Vulpral (valproate) , 829
Vyleesi (bremelanotide) , 95
Vyvanse (lisdexamfetamine) , 409
Wakix (pitolisant) , 639
Wellbatrin (bupropion) , 117
Wellbutrin (bupropion) , 117
Wellbutrin SR (bupropion SR) , 117
Wellbutrin XL (bupropion XL) , 117
Xanax (alprazolam) , 11
Xanax XR (alprazolam XR) , 11
Xanor (alprazolam) , 11
Xepin (doxepin) , 255
Xeplion (paliperidone) , 581
Xyrem (sodium oxybate) , 733
Zactin (fluoxetine) , 301
Zafrionil (haloperidol) , 347
zaleplon , 859
Zelapon (selegiline) , 705
Zemorcon (sulpiride) , 741
Zentiva (aripiprazole) , 53

Zenzedi (amphetamine d) , 39
Zeptol (carbamazepine) , 131
Zerenal (dothiepin) , 249
ziprasidone , 863
Ziprexa (olanzapine) , 559
Zispin (mirtazapine) , 509
Zoleptil (zotepine) , 883
Zoloft (sertraline) , 721
zolpidem , 871
Zolpimist (zolpidem) , 871
Zonalon (doxepin) , 255
Zonegran (zonisamide) , 875
zonisamide , 875
Zopax (alprazolam) , 11
zopiclone , 879
Zopite (zotepine) , 883
zotepine , 883
Z-Pam (temazepam) , 755
Zubsolv (buprenorphine with naloxone) , 111
zuclopenthixol , 889
Zuledin (chlorpromazine) , 153
Zulex (acamprosate) , 1
Zulresso (brexanolone) , 99
Zyban (bupropion) , 117
Zymocomb (sulpiride) , 741
Zyprexa (olanzapine) , 559
Zyprexa Relprevv (olanzapine) , 559
Zyprexa Zydis (olanzapine) , 559

Commonly Prescribed For (bold for FDA approved)
Alcohol abstinence
acampr osate  , 1
disulfiram  , 239
Alcohol dependence , 255
naltr exone  , 537
chlordiazepoxide  , 11
clorazepate  , 185
diazepam  , 229
oxazepam  , 569

caprylidene  , 127
donepezil  , 243
galantamine  , 337
memantine  , 473
rivastigmine  , 699
Amnesia, Drug-induced
midazolam  , 499
Anxiety
buspir one , 123
chlordiazepoxide  , 147
doxepin  , 255

gabapentin (adjunct) , 331
hydr oxyzine  , 355
lorazepam  , 437

trifluoperazine  , 803
Attention deficit hyperactivity disorder
amphetamine (d)  , 39
amphetamine (d,l)  , 45
atomoxetine  , 79
chlorpr omazine (hyperactivity)  , 153
clonidine  , 179
guanfacine  , 343
haloperidol (hyperactivity)  , 347
lisdexamfetamine  , 409
methylphenidate (d)  , 481
methylphenidate (d,l)  , 487
Autism-related irritability
aripiprazole  , 53
risperidone  , 687
Behavioral problems

chlorpr omazine  , 153
haloperidol  , 347
Benzodiazepine reversal
flumazenil  , 293

cariprazine  , 137
lurasidone  , 457
olanzapine/fluoxetine combination  , 301 , 559
quetiapine  , 667
valproate (divalproex) , 829
clonazepam (adjunct) , 173

lorazepam (adjunct) , 437
topiramate (adjunct) , 781

asenapine  , 71
lamotrigine  , 387
olanzapine  , 559
ziprasidone  , 863
Bulimia nervosa/binge eating
fluoxetine  , 301

pitolisant  , 639
sodium  oxybate  , 733
Catatonia
Chorea, Huntington ’s disease
deutetrabenazine  , 221

Delirium
haloperidol (adjunct) , 347
Dementia
amitriptyline  , 25
amoxapine  , 33
aripiprazole (adjunct)  , 53
brexanolone  , 99
brexpiprazole (adjunct)  , 103
bupr opion  , 117
buspirone (adjunct) , 123

citalopram  , 159
desipramine  , 207
desvenlafaxine  , 215
dextromethorphan (with quinidine) , 225
duloxetine  , 263
escitalopram  , 269
esketamine  , 275
fluoxetine/olanzapine combination  , 301 , 559
imipramine  , 367
isocarboxazid  , 375
lamotrigine (adjunct) , 387
levomilnacipran  , 403
lithium (adjunct) , 415
l-methylfolate (adjunct)  , 477

mapr otiline  , 465
mirtazapine  , 509
modafinil (adjunct) , 521
nefazodone  , 545
nortriptyline  , 551
paroxetine  , 593
phenelzine  , 613
protriptyline  , 657
quetiapine (adjunct)  , 667
selegiline  , 705
sertraline  , 721
tranylcypr omine  , 787
trazodone  , 793
trimipramine  , 817
venlafaxine  , 841

vilazodone  , 847
vortioxetine  , 853
benztr opine  , 85
trihexyphenidyl  , 809
sildenafil  , 729
Excessive sleepiness
armodafinil  , 65
modafinil  , 521
sodium oxybate  , 733
solriamfetol  , 737
Fatigue
milnacipran  , 503
pregabalin  , 647

alprazolam  , 11
paroxetine  , 509
tiagabine (adjunct) , 771
Hiccups, intractable
Hypersalivation

prazosin  , 643
propranolol  , 653
Hypoactive sexual desire disorder
bremelanotide  , 95
flibanserin  , 289
Insomnia
diphenhydramine  , 235
estazolam  , 281
eszopiclone  , 285
flurazepam  , 321
lembor exant  , 395

quazepam  , 663
ramelteon  , 677
suvor exant  , 747
temazepam  , 755
triazolam  , 799
zaleplon  , 859
zolpidem  , 871
Mania
alprazolam (adjunct) , 11
carbamazepine  , 131
lithium  , 415

valpr oate (divalpr oex) , 829
Migraine
topiramate  , 781
Muscle spasm

sodium oxybate , 853
perphenazine  , 607
clonidine (adjunct) , 179

Nicotine addiction
varenicline  , 837
Non-24-hour sleep-wake disorder
tasimelteon  , 751
aripiprazole (adjunct) , 53
clomipramine  , 165
fluvoxamine  , 325
bupr enorphine  , 111

lofexidine  , 427
clonazepam  , 173
Parkinson ’s disease dementia

Parkinson ’s disease psychosis
pimavanserin  , 623
Porphyria
gabapentin  , 331
Postpartum depression

olanzapine , 558
paliperidone , 580
prazosin (nightmares)  643
propranolol (prophylactic)  653
Preoperative anxiety

Pruritus
Pseudobulbar af fect
dextr omethorphan (with  quinidine)  , 225
Psychosis
carbamazepine (adjunct) , 131
fluphenazine  , 313

valproate (divalproex) (adjunct) , 829
Restless leg syndrome
gabapentin ER  , 331
Schizoaf fective disorder

clozapine  , 191
l-methylfolate (adjunct) , 477
paliperidone  , 581

brexpiprazole  , 103
iloperidone  , 359
loxapine  , 443
lumateper one , 451
molindone  , 527
olanzapine  , 558

thioridazine  , 759
thiothixene  , 765
Seasonal af fective disorder
Sedation-induction
Seizure disorders
clorazepate (adjunct) , 185

gabapentin (adjunct)  , 331
levetiracetam  , 399
oxcarbazepine  , 575
pregabalin (adjunct)  , 647
tiagabine (adjunct)  , 771
zonisamide  , 875
Sleepiness, excessive

valbenazine  , 825
Tetanus
Tourette ’s syndrome/tic disorders
pimozide  , 627

Tremor
Trigeminal neuralgia
Weight management
naltr exone/bupr opion  , 541
phentermine/topiramate  , 619

Anticholiner gics
Anticonvulsants
zonisamide (adjunct) , 875
Antidepressants

Antipsychotics

Anxiolytics

Attention deficit hyperactivity disorder treatments

Benzodiazepine antagonist
Cognitive enhancers
Dementia treatments

Libido enhancers
Mood stabilizers

levetiracetam (adjunct) , 399
pregabalin (adjunct) , 647

Movement disorder treatments
Neuropathic/chronic pain treatments

NMDA antagonists
dextromethorphan , 225
Sedative hypnotics

Substance use disorder treatments

Tic suppressants
Wake-promoting agents

Abbreviations
5HT
serotonin
ACh
AChE
acetylcholinesterase
ADHD
attention deficit hyperactivity disorder
AE
adverse ef fect
AIMS
Abnormal Involuntary Movement Scale
ALPT
total serum alkaline phosphatase
ALT

alanine aminotransferase
AMP A
alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
ANA
antinuclear antibody
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUC
area under the curve
AV
atroventricular
BDNF
brain-derived neurotrophic factor
BEN
benign ethnic neutropenia
BHB
beta-hydroxybutyric acid
bid

twice a day
BMI
body mass index
BP
BuChE
CBC
complete blood count
Cmax
maximum concentration
CR
controlled-release
CRP
C-reactive protein
CSF
cerebrospinal fluid
CMI
CNS

central nervous system
COPD
chronic obstructive pulmonary disease
CPAP
continuous positive airway pressure
CYP450
cytochrome P450
DA
dopamine
DEA
Drug Enforcement Administration
De-CMI
desmethyl-clomipramine
dL
deciliter
DLB
DORA
DRESS

drug reaction with eosinophilia and systemic symptoms
DSM-5
Diagnostic and Statistical Manual of Mental Disor ders , 5th edition
ECG
electrocardiogram
EEG
electroencephalogram
ER
FDA
Food and Drug Administration
GABA
gamma-aminobutyric acid
GAD
generalized anxiety disorder
GFR
glomerular filtration rate
HDL
high-density lipoprotein
HLH

hemophagocytic lymphohistiocytosis
HMG CoA
beta-hydroxy-beta-methylglutaryl coenzyme A
HSDD
hypoactive sexual desire disorder
IM
intramuscular
IR
immediate-release
IV
intravenous
LAI
long-acting injectable
lb
pound
LDH
lactate dehydrogenase
LDL
low-density lipoprotein
MAO

monoamine oxidase
MAOI
mCPP
meta-chloro-phenyl-piperazine
MDD
major depressive disorder
MDMA
3,4-methylenedioxymethamphetamine (ecstasy)
mg
milligram
Î¼ g
microgram
MHD
monohydroxy derivative
mL
milliliter
mmHg
millimeters of mercury
MRHD

MRI
magnetic resonance imaging
MRSA
methicillin-resistant Staphylococcus aur eus
mTORC1
mammalian tar get of rapamycin complex 1
NE
NET
norepinephrine transporter
NMDA
N-methyl-D-aspartate
NMS
neuroleptic malignant syndrome
NOAEL
no observed adverse ef fect level
NSAID
nonsteroidal anti-inflammatory drug
OCD

obsessive-compulsive disorder
ODT
oral disintegrating tablet
ODV
O-desmethylvenlafaxine
OSAHS
obstructive sleep apnea/hypopnea syndrome
PBA
pseudobulbar af fect
PCP
phencyclidine
PDE
phosphodiesterase
PET
positron emission tomography
PLLR
Pregnancy and Lactation Labeling Rule
PMDD
premenstrual dysphoric disorder
prn

as needed
PTSD
posttraumatic stress disorder
qd
once a day
qhs
once a day at bedtime
qid
4 times a day
REMS
Risk Evaluation and Mitigation Strategy
RIMA
reversible inhibitor of monoamine oxidase A
SER T
SGRI
selective GABA reuptake inhibitor
SIADH
syndrome of inappropriate antidiuretic hormone secretion
SNRI

dual serotonin and norepinephrine reuptake inhibitor
SPARI
serotonin partial antagonist reuptake inhibitor
SR
sustained-release
SSRI
TCA
tricyclic antidepressant
TD
tid
3 times a day
Tmax
time to reach maximum concentration
TSH
thyroid-stimulating hormone
VMA
vanillylmandelic acid
VMA T

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/content/docs/Bipolar Disorders - Basic Mechanisms and Therapeutic Implications 2nd ed - J Soares A Young Informa 2007 WW - PDF Room.pdf

BIPOLAR
DISORDERS
Basic Mechanisms 
and Therapeutic Implications
Second Edition
Edited by
Jair C. Soares
University of North Carolina School of Medicine
Chapel Hill, North Carolina, USA
Allan H. Young
University of British Columbia
Vancouver , British Columbia, Canada

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Bipolar disorders : basic mechanisms and therapeutic implications—2nded./edited
by Jair C. Soares, Allan H. Young.
p. ; cm. -- (Medical psychiatry ; 35)
Includes bibliographical references and index.
ISBN-13: 978-0-8493-9897-1 (hardcover : alk. paper)
ISBN-10: 0-8493-9897-5 (hardcover : alk. paper)
1. Manic-depressive illness. I. Soares, Jair C. II. Young, A. H. (Allan H.) III. Series.
[DNLM: 1. Bipolar Disorder--diagnosis. 2. Bipolar Disorder--therapy. W1
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BPreface
Since the ﬁrst edition of our book was published, increasing progress has been
seen in the understanding of the basic mechanisms involved in the pathophysiol-
ogy of bipolar mood disorders. When our ﬁrst edition was prepared, there was
comparatively little research being conducted on the mechanisms involved in
this disorder. Recent years have seen an increasing interest in this ﬁeld and an
increasing amount of activity. Important research initiatives have begun to eluci-
date the pathophysiology of this disorder. These research initiatives are beginning
to lead to breakthroughs in the understanding of the causation of bipolar mood dis-
orders and the development of novel treatments. Some of these new advances have
recently translated into newer treatments available for these disorders.
Of particular importance is the development of newer tools from neuro-
psychopharmacology, which have provided new ways to study various brain

systems, including post-receptor and transcriptional mechanisms. Developments
in neuroimaging have made possible the in vivo study of brain anatomy, neuro-
transmission, and metabolic processes. Important tools from genetics are becoming
available and are being applied to further the understanding of mechanisms
involved in bipolar disorders. Cognitive neuropsychology has also provided
improved tools for the more reﬁned study of brain functions in these disorders.
These novel research avenues have provided new dimensions in exploring the bio-
logical mechanisms involved. New therapeutic developments have already become
available in the past few years. These advances are expected to gradually continue
to translate into new approaches for the treatment of bipolar disorder over the next
few to several years.

The updated ﬁndings from this research have not been comprehensively sum-
marized in a book focused speciﬁcally on the biological underpinnings of bipolar
mood disorders. There are some excellent books available on the subject of
bipolar disorders, but their focus is primarily on diagnostic issues, course of
illness, and treatment. To ﬁll this gap, we are proud to present the second edition
of our book, Bipolar Disorders: Basic Mechanisms and Therapeutic Implications . This
volume presents outstanding manuscripts by the leaders in the particular areas
of biological research pertinent to bipolar disorders. Among other very important
topics, we have included chapters on genetics, neuroimaging, neuropsychology,
investigations of post-receptor and transcriptional abnormalities, potential inter-

actions between biology and psychosocial factors, childhood onset and late-life
bipolar disorder, and several other important topics. A chapter on the implications
of these research areas for ongoing therapeutic developments in this ﬁeld is also
included. The potential therapeutic implications of new research, as in the ﬁrst
edition, are emphasized throughout the book.
We are very happy to have had the collaboration of some of the leading scien-
tists in their respective ﬁelds of research, and believe this volume will be a valuable
resource for researchers in this ﬁeld and in related areas. It is presented as a
iii

complete and accessible reference to the most updated information on the biologi-
cal basis and therapeutics of bipolar mood disorders. It should be useful as sup-
plemental reading for graduate and postgraduate courses on the neurobiology of
mental illness. Mental health practitioners will ﬁnd it extremely useful as an
updated source with the most recent research progress in this ﬁeld. We hope you
will share our excitement with these new developments.
Allan H. Youngiv Preface

BContents
Preface . . . . iii
Contributors . . . . vii
1.Classiﬁcation of Bipolar Disorders—Implications for Clinical Research 1
Ralph W. Kupka and Willem A. Nolen
2.Prospects for the Development of Animal Models for the Study
of Bipolar Disorder 19
Haim Einat, Alona Shaldubina, Yuly Bersudsky, and R. H. Belmaker
3.Abnormalities in Catecholamines and the Pathophysiology
of Bipolar Disorder 33
Amir Garakani, Dennis S. Charney, and Amit Anand
4.Cholinergic-Muscarinic Dysfunction in Mood Disorders 67
David S. Janowsky and David H. Overstreet
5.Serotonergic Dysfunction in Mood Disorders 89
J. John Mann and Dianne Currier
6.Cell Membrane and Signal Transduction Pathways—Implications for the
Pathophysiology of Bipolar Disorders 109
Guang Chen and Husseini K. Manji
7.Searching for a Cellular Endophenotype for Bipolar Disorder 131
Francine M. Benes
8.The Hypothalamic–Pituitary–Adrenal Axis in Bipolar Disorder 145
David J. Bond and Allan H. Young
9.Brain Imaging Studies in Bipolar Disorder 161

E. Serap Monkul, Paolo Brambilla, Fabiano G. Nery,
John P. Hatch, and Jair C. Soares
10.Sleep and Biological Rhythms Abnormalities in the
Pathophysiology of Bipolar Disorders 189
Stephany Jones and Ruth M. Benca
11.Hypothesis of an Infectious Etiology in Bipolar Disorder 209
Robert H. Yolken and E. Fuller Torrey
v

12.EEGs and ERPs in Bipolar Disorders 221
R. Hamish McAllister-Williams
13.Genetics of Bipolar Disorder 233
Nick Craddock
14.Neurocognitive Findings in Bipolar Disorder 251
David C. Glahn and Carrie E. Bearden
15.Biology vs. Environment: Stressors in the Pathophysiology
of Bipolar Disorder 275
Morgen A. R. Kelly, Stefanie A. Hlastala, and Ellen Frank
16.The Kindling /Sensitization Model: Implications for the Pathophysiology of
Bipolar Disorder 297
Robert M. Post
17.Biologic Factors in Different Bipolar Disorder Subtypes 325
Michael A. Cerullo and Stephen M. Strakowski
18.Biological Factors in Bipolar Disorder in Childhood and Adolescence 343
Melissa A. Brotman, Daniel P. Dickstein,
Brendan A. Rich, and Ellen Leibenluft
19.Biological Factors in Bipolar Disorders in Late Life 361
R. C. Young, J. M. deAsis, and G. S. Alexopoulos
20.Perspectives for New Pharmacological Interventions 377
Charles L. Bowden
21.Physical Comorbidity in Bipolar Disorder 387
Paul Mackin and Sylvia Ruttledge

22.Toward a Pathophysiology of Bipolar Disorders 401
John F. Neumaier and David L. Dunner
Index . . . . 409vi Contents

BContributors
G. S. Alexopoulos Institute for Geriatric Psychiatry, Weill Medical College
of Cornell University, and New York Presbyterian Hospital, White Plains,
New York, U.S.A.
Amit Anand Department of Psychiatry, Indiana University School of Medicine,
Indianapolis, Indiana, U.S.A.
Carrie E. Bearden Semel Institute for Neuroscience and Human Behavior,
University of California, Los Angeles, California, U.S.A.
R. H. Belmaker Division of Psychiatry, Faculty of Health Sciences, Ben-Gurion
University of the Negev, Beer Sheba, Israel
Ruth M. Benca Department of Psychiatry, University of Wisconsin–Madison,
Madison, Wisconsin, U.S.A.
Francine M. Benes Department of Psychiatry, Harvard Medical School, Boston,
Massachusetts, U.S.A.
Yuly Bersudsky Division of Psychiatry, Faculty of Health Sciences, Ben-Gurion
David J. Bond Mood Disorders Centre of Excellence, University of British
Columbia, Vancouver, British Columbia, Canada

Charles L. Bowden University of Texas Health Science Center at San Antonio,
San Antonio, Texas, U.S.A.
Paolo Brambilla Department of Pathology and Experimental and Clinical
Medicine, Section of Psychiatry, University of Udine, Udine, and Scientiﬁc
Institute IRCCS E. Medea, Bosisio Parini, Italy
Melissa A. Brotman Mood and Anxiety Disorders Program, National Institute
of Mental Health, Department of Health and Human Services, National Institutes
of Health, Bethesda, Maryland, U.S.A.
Michael A. Cerullo Division of Bipolar Disorders Research, Department
of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio,
U.S.A.
Dennis S. Charney Department of Psychiatry, Mount Sinai School of Medicine,
New York, New York, U.S.A.
vii

Guang Chen Laboratory of Molecular Pathophysiology, Mood and Anxiety
Disorders Research Program, National Institute of Mental Health, Bethesda,
Maryland, U.S.A.
Nick Craddock Department of Psychological Medicine, Wales School of
Medicine, Cardiff University, Cardiff, U.K.
Dianne Currier Department of Psychiatry, Columbia University, New York,
J. M. deAsis Institute for Geriatric Psychiatry, Weill Medical College of Cornell
University, and New York Presbyterian Hospital, White Plains, New York, U.S.A.
Daniel P. Dickstein Mood and Anxiety Disorders Program, National Institute of
Mental Health, Department of Health and Human Services, National Institutes of
Health, Bethesda, Maryland, U.S.A.
David L. Dunner Department of Psychiatry and Behavioral Sciences, University
of Washington, Seattle, Washington, U.S.A.
Haim Einat College of Pharmacy, University of Minnesota, Duluth,
Minnesota, U.S.A.
Ellen Frank Western Psychiatric Institute and Clinic, University of Pittsburgh

School of Medicine, Pittsburgh, Pennsylvania, U.S.A.
Amir Garakani Department of Psychiatry, Mount Sinai School of Medicine,
David C. Glahn Department of Psychiatry and Research Imaging Center,
University of Texas Health Science Center at San Antonio, San Antonio,
Texas, U.S.A.
John P. Hatch Mood Disorders Clinical Neurosciences Program, Department of
Psychiatry, and Department of Orthodontics, University of Texas Health Science
Center at San Antonio, San Antonio, Texas, U.S.A.
Stefanie A. Hlastala Children’s Hospital and Regional Medical Center, Seattle,
Washington, U.S.A.
David S. Janowsky Department of Psychiatry, University of North Carolina,
Chapel Hill, North Carolina, U.S.A.
Stephany Jones Department of Psychiatry, University of Wisconsin–Madison,

Morgen A. R. Kelly Western Psychiatric Institute and Clinic, University
of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A.
Ralph W. Kupka Bipolar Disorders Program, Altrecht Institute for Mental Health
Care, Utrecht, The Netherlands
Ellen Leibenluft Mood and Anxiety Disorders Program, National Institute of
Health, Bethesda, Maryland, U.S.A.viii Contributors

Paul Mackin School of Neurology, Neurobiology, and Psychiatry, University of
Newcastle upon Tyne, Newcastle upon Tyne, U.K.
Husseini K. Manji Laboratory of Molecular Pathophysiology, Mood and Anxiety
J. John Mann Department of Psychiatry, Columbia University, New York, New
York, U.S.A.
R. Hamish McAllister-Williams School of Neurology, Neurobiology, and
Psychiatry, University of Newcastle upon Tyne, Newcastle upon Tyne, U.K.
E. Serap Monkul Mood Disorders Clinical Neurosciences Program, Department
of Psychiatry, University of Texas Health Science Center at San Antonio, San
Antonio, Texas, U.S.A., and Department of Psychiatry, Dokuz Eylu ¨l University
School of Medicine, Izmir, Turkey
Fabiano G. Nery Mood Disorders Clinical Neurosciences Program, Department
of Psychiatry, University of Texas Health Science Center at San Antonio,

and Audie L. Murphy Division, South Texas Veterans Health Care System,
San Antonio, Texas, U.S.A., and Institute of Psychiatry, University of Sa ˜o Paulo
School of Medicine, Sa ˜o Paulo, Brazil
John F. Neumaier Department of Psychiatry and Behavioral Sciences, University
Willem A. Nolen Department of Psychiatry, University Medical Center
Groningen, Groningen, The Netherlands
David H. Overstreet Center for Alcohol Studies, Department of Psychiatry,
University of North Carolina, Chapel Hill, North Carolina, U.S.A.
Robert M. Post Mood and Anxiety Disorders Program, National Institute of
Mental Health, Department of Health and Human Services, National Institutes

Brendan A. Rich Mood and Anxiety Disorders Program, National Institute of
Sylvia Ruttledge School of Neurology, Neurobiology, and Psychiatry, University
of Newcastle upon Tyne, Newcastle upon Tyne, U.K.
Alona Shaldubina Division of Psychiatry, Faculty of Health Sciences, Ben-Gurion
Jair C. Soares Center of Excellence for Research and Treatment of Bipolar
Disorders, Department of Psychiatry, University of North Carolina School of
Medicine, Chapel Hill, North Carolina, U.S.A.
Stephen M. Strakowski Division of Bipolar Disorders Research, Department of
Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio, U.S.A.Contributors ix

E. Fuller Torrey Stanley Medical Research Institute, Chevy Chase, Maryland,
U.S.A.
Robert H. Yolken Stanley Division of Developmental Neurovirology, Johns
Hopkins University School of Medicine, Baltimore, Maryland, U.S.A.
Allan H. Young Mood Disorders Centre of Excellence, University of British
R. C. Young Institute for Geriatric Psychiatry, Weill Medical College of Cornell
University, and New York Presbyterian Hospital, White Plains, New York, U.S.A.x Contributors

B1 Classiﬁcation of Bipolar Disorders—
Implications for Clinical Research
Ralph W. Kupka
Bipolar Disorders Program, Altrecht Institute for Mental Health Care,
Utrecht, The Netherlands
Willem A. Nolen
Department of Psychiatry, University Medical Center Groningen,
Groningen, The Netherlands
INTRODUCTION
The classiﬁcation of mood disorders has been a subject of scientiﬁc debate for more
than 2500 years (1,2), and a precise delineation of these illnesses and its various
clinical manifestations has yet to emerge. Many aspects of this discussion have
recently been reviewed by Akiskal (2) and supplemented by commentaries from
authoritative researchers. In this chapter we will give an overview of the current
classiﬁcation, the boundaries of bipolar disorder with other major psychiatric
illnesses, the validity and reliability of diagnosis, and the implications for neurop-
sychiatric research. As all classiﬁcations that are based on clinical description rather

than on etiology and pathophysiology are deemed to be temporary, we will begin
with a brief historical overview and end with some areas that need further
clariﬁcation.
A BRIEF HISTORY OF MOOD DISORDER
Mania and melancholia, already described by Hippocrates (460–377 BC), were
linked as manifestations of one illness by Aretaeus of Cappadocia (c. 150 AD). His
conception of mania being a consequence of melancholia was adopted throughout
the Middle Ages and Renaissance by writers such as Vesalius, Burton, Willis, and
Boerhaave (1). It was not until the 19th century that longitudinal clinical course
was taken into account in the description of psychopathology. In 1854, Falret and
Baillarger simultaneously but independently described a pattern of illness in

which mania, depression, and a symptom-free interval appeared in more or less
regular cycles over time (1). In addition to these severe forms of circular and peri-
odic insanity, in 1882, Kahlbaum described cyclothymia and dysthymia with milder
degrees of excitement and depression (1). It was Kraepelin who in 1899 brought all
affective syndromes together under the name of manic-depressive insanity: circular
and periodic forms, unipolar mania, recurrent depression, milder manifestations,
and even subclinical forms that were considered part of personal predisposition
or temperament (3). From his longitudinal descriptions of many cases he could
not delineate clear boundaries between these clinical pictures and hypothesized
that they were all manifestations of the same disease process. These observations

from the pre-pharmacological era are of great importance for the understanding
1

of the natural course of bipolar disorder, since most patients in later longitudinal
studies have received both acute and prophylactic treatment, which may have
modiﬁed the course of illness for the better or the worse (4).
In 1957, Leonhard (5) proposed the distinction between unipolar depression
and bipolar illness, which was supported by Angst (6) and by Perris in 1966 (7),
and by Winokur, Clayton, and Reich in 1969 (8). Subsequently, the unipolar–
bipolar distinction was adopted by the American classiﬁcation diagnostic and
statistical manual of mental disorders-III (DSM-III) in 1980 (9), and the revised
edition (DSM-III-R) in 1987 (10). At the same time the WHO classiﬁcation Inter-
national Classiﬁcation of Diseases-9 (ICD) (1978) (11) still described all types of
depressive and other forms of affective disorders under the category of manic-
depressive psychosis. However, in the current ICD-10 (1992) (12), bipolar affective

disorder is classiﬁed next to recurrent depressive disorder.
CURRENT CLASSIFICATION: DSM-IV AND ICD-10
DSM-IV (13) describes mood disorders in three parts: mood episodes, mood
disorders, and speciﬁers, that is, characteristics of the most recent episode or the
longitudinal course of recurrent illness. Mood episodes (manic, hypomanic,
depressive, or mixed) are building blocks of mood disorders, and cannot be diag-
nosed as separate illnesses. Mood disorders are subdivided in depressive disorders
and bipolar disorders, and two disorders based on etiology: somatic illness and
substance abuse (Table 1). Speciﬁers describing the most recent episode refer to
severity, whether or not it is in remission, and the presence of psychotic features
or other clinical characteristics (Table 2). Longitudinal course speciﬁers refer to

the degree of interepisodic recovery, seasonal pattern, and rapid cycling. These
elements of classiﬁcation aim at identifying relatively homogeneous subgroups,
and are further enhanced by providing more or less detailed diagnostic criteria
for every category described (see next section).
Compared to the DSM-IV, the text revision published in 2000 (DSM-IV-TR)
(14) did not change the mood disorders section, nor the section on schizoaffective
disorders. Therefore, we further refer to DSM-IV.
Unlike previous editions of DSM and ICD, DSM-IV and ICD-10 agree
on major aspects of the classiﬁcation of mood disorders, although there are
several differences, as outlined in Table 1. One major difference is that ICD-10
allows for classifying a single manic /hypomanic or a single depressive episode

next to bipolar affective disorder and recurrent depressive disorder, whereas
in DSM-IV a single manic episode is always considered as being part of bipolar
disorder, and likewise a single depressive episode is classiﬁed as major depressive
disorder. Both classiﬁcation systems agree that the relatively rare condition
of repeated mania without a history of depressive episodes should be classiﬁed
as bipolar disorder. A recent study from the Zurich group suggested that
patients with a history of only mania(s) (M), or of mania(s) with only mild
depression(s) (Md), have a lower morbidity risk in ﬁrst degree relatives and a
better prognosis than bipolar I patients with both mania(s) and full depression(s)
(MD) (15).
DSM-IV gives a detailed deﬁnition of bipolar II disorder, characterized by one

(MD) (15).
or more major depressive episodes accompanied by at least one hypomanic episode
in the absence of a history of manic or mixed episodes (16,17). In contrast, in ICD-10,
bipolar I and II disorders are not classiﬁed separately, but the latter is included in2 Kupka and Nolen

the category of “other bipolar affective disorders,” without further description.
However, in ICD-10 “bipolar affective disorder, current episode hypomanic”
could also include those patients who have never experienced a full manic
episode, that is, those with bipolar II disorder.
The problem of distinguishing hypomania from normal mood swings on the
one hand and from mania on the other, which may occur in any classiﬁcation, will
be discussed in the next section.TABLE 1 DSM-IV Classiﬁcation of Mood Disorders with Corresponding ICD-10 Classiﬁcation
DSM-IV /DSM-IV-TRaCodebICD-10cCode
Depressive disorders
Single episode 296.2x Depressive episode F32.0–9
Recurrent 296.3x Recurrent depressive disorder F33.0–9
Dysthymic disorder 300.4 Dysthymia F34.1
Depressive disorder NOS 311 Other depressive episode F32.9
Other recurrent depressive
disorderF33.9
Bipolar disorders
Bipolar I disorder
Single manic episode 296.0x Manic (including hypomanic)
episodeF30.x

Hypomanicd296.40 Bipolar disorder, hypomaniceF31.0
Manicd296.4x Bipolar disorder, maniceF31.1–2
Mixedd296.6x Bipolar disorder, mixedeF31.6
Depressedd296.5x Bipolar disorder, depressedeF31.3–5
Unspeciﬁedd296.7 Bipolar disorder, unspeciﬁedeF31.9
Bipolar II disorder 286.89 Other bipolar affective disorder F31.8
Hypomanicd
Depressedd
Cyclothymic disorder 303.13 Cyclothymia F34.0
Bipolar disorder NOS 296.80 Other bipolar affective disorder F31.8
Mood disorder due to
General medical condition
(depressive /manic /
mixed)293.83 Organic mood disorders (manic /
bipolar /depressive /mixed)F06.30–33
Substance induced mood
disorder (depressive /
manic /mixed)292.84 Psychotic disorder due to
Psychoactive
(depressive /manic /mixed)F1x.54
F1x.55
F1x.56
Mood disorder NOS 296.90 Other mood disorders F38
Unspeciﬁed mood disorders F39

F1x.55
F1x.56
Schizoaffective disorderf295.70 Schizoaffective disordersfF25
Bipolar type Manic type F25.0
Depressive type Depressive type F25.1
Mixed type F25.2
aDSM-IV-TR is unchanged from DSM-IV with regard to mood disorders.
bFor ﬁfth digit see Table 2.
cNot all ICD-10 subcategories are listed.
dMost recent episode.
eCurrent episode.
fIncluded in the section: schizophrenia and other psychotic disorders.
Abbreviations : DSM, Diagnostic and Statistical Manual of Medical Disorders; ICD, International Classiﬁcation of
Diseases; NOS, not otherwise speciﬁed.Classiﬁcation of Bipolar Disorders 3

MANIA AND HYPOMANIA
At the core of the manic syndrome is a persistently elevated, expansive and /or irri-
table mood during at least seven days (or any duration when hospitalized),
accompanied by symptoms such as increased self-esteem, over-optimism or even
grandiosity, pressure of speech, racing thoughts, distractibility, increased energy,
increased sexual drive, overactivity or agitation, and loss of inhibitions leading to
reckless involvement in pleasurable, hazardous, or embarrassing activities that
may have serious marital, social, ﬁnancial, or judicial consequences. Finally,
symptoms cause marked impairment in social or occupational functioning. Error
of judgment and lack of insight, which are often seen in manic patients, are
not speciﬁcally included in DSM-IV diagnostic criteria. Even patients who did
previously acknowledge having bipolar disorder may lose insight during a next
manic episode. Highly characteristic of the manic syndrome is a decreased

need for sleep combined with an increased feeling of energy, which is quite
distinct from insomnia in depression or other psychiatric disorders where the
diminished sleep coincides with feeling tired. In severe mania, psychotic symptoms
may occur, either mood-congruent such as delusions of grandiosity, or mood-
incongruent, such as persecutory delusions.
Diagnosing “classic” mania should not be too difﬁcult a task for any clinician
with some experience. However, during an initial interview, an intelligent patient
may temporarily mislead the clinician by dissimulating the presence or the severity
of his symptoms and by ﬁnding apparently meaningful explanations for his
behaviors. In such cases, information from nurses and especially from close rela-
tives should conﬁrm the diagnosis of mania. The latter may be even truer in case

of hypomania.
In DSM-IV, a hypomanic episode has essentially the same clinical features as a
manic episode, but lasts a shorter period. In hypomania, there is an unequivocalTABLE 2 Diagnostic and Statistical Manual of Mental Disorders-IV Speciﬁers for Mood Disorders
Speciﬁers for most recent episodeaCode Longitudinal course speciﬁersa
Severity
Mild xxx.x1
Moderate xxx.x2
Severe xxx.x3
Severe with psychotic features xxx.x4
Mood-congruent psychotic features
Mood-incongruent psychotic features
Course
In partial remission xxx.x5 With /without interepisode
recovery
In full remission xxx.x6 Seasonal patternb
ChronicbRapid cyclingc
Postpartum onset
Associated features
Catatonic features
Melancholic featuresb
Atypical featuresb
bSpeciﬁer only for depressive episodes.

cSpeciﬁer only for bipolar I and II disorders.4 Kupka and Nolen

change from normal functioning, which is observable by others, lasting at least four
days. This separates hypomania from normal elevations of mood or the very mild
mood elevations that occur in cyclothymic disorder. On the other hand, the
symptoms are not severe enough to cause “marked impairment in social or
occupational functioning” as in mania. In the ICD-10 clinical descriptions and diag-
nostic guidelines (12) hypomania does not lead to “severe or complete disruption of
work or result in social rejection,” although “considerable interference with work or
social activity is consistent with a diagnosis of hypomania.” Thus, ICD-10 hypoma-
nia includes conditions that would justify a diagnosis of (mild) mania according to
DSM-IV criteria. Interestingly, the ICD-10 diagnostic criteria for research (18) are
more in accordance with DSM-IV, stating that hypomania leads to “some inter-
ference with personal functioning in daily living.” The problems that arise when

deﬁning the boundary between hypomania and (mild) mania are discussed by
Goodwin, who points out that this boundary depends entirely upon the meaning
of ill-deﬁned qualifying words like “some,” “considerable,” “marked,” “severe,”
or “complete” functional impairment (19). He also notes a tendency to avoid the
somewhat pejorative diagnosis of “mania” in favor of “hypomania” in clinical
settings.
The validity of a minimum duration of four days for a hypomanic episode
has been tested by the Zurich group that found that patients with brief hypomania
of one to three days duration did not signiﬁcantly differ from those whose
hypomanic episodes lasted at least four days (20).
In patients presenting with a current depressive episode, a history of prior
hypomanic episodes is easily missed, especially since depression is the prevailing

condition in bipolar II disorder (21). Thus, many of these patients will be misdiag-
nosed as suffering from (recurrent) unipolar depression. Revealing past hypomanic
episodes may beneﬁt from systematic inquiry in all aspects of the syndrome,
especially the behavioral symptoms rather than elevation of mood. Patients and
relatives will remember the short nights and the energetic overactivity more
sharply than a period of cheerfulness or irritability.
In a recent survey among U.S. citizens using the Mood Disorders Question-
naire (22), which systematically checks (hypo)manic symptoms, 3.7% screened
positive for bipolar I or II disorder. Of these, only 19.8% had previously received
a diagnosis of bipolar disorder, 31.2% had received a diagnosis of unipolar
depression, and 49.0% had received neither of these diagnoses (23).

Hypomanic or manic episodes may appear relatively late in the course of
bipolar disorder, inevitably leading to an initial diagnosis of unipolar depression.
The rate of spontaneous conversion from unipolar to bipolar mood disorder has
been estimated at median 9.7%, with a reported maximum of up to 37.5% (24).
Over the course of 11 years, hypomanic or manic episodes occurred in 12.5% of
559 prospectively followed unipolar patients (25). This phenomenon may in
part explain the long delay between the occurrence of ﬁrst mood symptoms and
the diagnosis of bipolar disorder, which was on average 10 years in a survey
among DMDA members (26) and also among clinical populations (27).
DEPRESSION
Depression is the main burden of bipolar illness. Longitudinal follow-up data from

the Collaborative Depression Study showed that patients with bipolar I disorder,
despite adequate treatment, on average reported depressive symptoms in 31.9%,Classiﬁcation of Bipolar Disorders 5

manic /hypomanic symptoms in 8.9%, and cycling /mixed symptoms in 5.9% of
weeks (28). In bipolar II disorder these percentages were even 50.3%, 1.3%, and
2.3% of weeks, respectively (28). The Stanley Foundation Bipolar Network reported
similar outcomes in treated bipolar I patients using daily prospective life chart data:
on average they were depressed 35.6% of the time, manic /hypomanic 12.6%, and
ultradian cycling 3.3% (29). Another research group using prospective life chart
data also found a depression-to-mania rating of 5.9 in bipolar I and 13.7 in
bipolar II patients (30).
Although a depressive episode in the course of bipolar disorder in general
has the same clinical features as unipolar depression, and both conditions have
identical diagnostic criteria in DSM-IV and ICD-10, cross-sectional as well as longi-
tudinal studies have revealed some features that may distinguish bipolar from
unipolar depression (31–37). These features are summarized in Table 3.

In patients with depression, a family history of bipolar disorder may point
to a bipolar course. The occurrence of brief episodes is also associated with
bipolar depression. DSM-IV requires for a major depressive episode a minimum
duration of at least two weeks. This may be appropriate in most cases of unipolar
depression and many cases of bipolar disorder, but patients with bipolar disorder
often also have brief episodes with rapid onset and remission, which may have
the full range of severities (32). Prospective life chart data from the Stanley Foun-
dation Bipolar Network showed that even patients with a nonrapid cycling
course have on average twice as many brief depressive episodes, that is, of less
than two weeks duration, than full-duration episodes (29). This was similar with
regard to brief manic and hypomanic episodes.

MIXED STATES
In mixed states the complexity of bipolar disorder reaches its maximum. Pure
depression and pure mania are the prototypical endpoints on a continuum of beha-
vioral and emotional disturbances. Mixed states have originally been described by
Kraepelin and his contemporary Weygandt as various admixtures of three dimen-
sions: mood, thinking, and psychomotor activity (38). They distinguished six
subtypes: depression with ﬂight of ideas, excited depression, depressive-anxious
mania, mania with thought poverty, inhibited mania, and manic stupor.
In DSM-IV, a patient with a mixed episode meets both criteria for a manic
episode and a major depressive episode during at least one week, and may experi-
ence rapidly alternating moods of sadness, irritability, and dysphoria. It is thusTABLE 3 Clues of Bipolarity in Patients with Major Depressive Episodes

Episode features Longitudinal illness history
Rapid onset and end of episode Family history of bipolar disorder
Brief episodes ( ,2 weeks) First episode at younger age ( ,25)
Psychotic features Frequent episodes
Atypical features History of brief major depressive episodes
Psychomotor retardation and anergia History of mania or hypomania
Hypersomnia History of antidepressant-induced hypomania
Mood lability History of postpartum depression
Nonresponse to antidepressants Cyclothymic or hyperthymic temperament
Response to lithium6 Kupka and Nolen

essentially a type of manic episode that also contains full syndromal depression
(“mixed mania”), which may be uncommon in clinical settings (39). This narrow
deﬁnition excludes many patients with combinations of syndromal and subsyndro-
mal symptoms of either polarity, for example, those with isolated depressive symp-
toms during a manic episode (“mixed mania”) or with some manic symptoms
during a major depressive episode (“mixed depression”). The prevalence of such
more broadly deﬁned mixed states in clinical practice is probably much higher
than DSM-IV mixed episodes. It is estimated that mixed states occur in about
30% to 40% of acutely manic patients (32,40). Dysphoric mania, deﬁned as a full
manic syndrome with the simultaneous presence of some depressive symptoms,
was present in 37% of manic patients in a clinical setting (41). In a recent study
among 908 treated bipolar outpatients mixed hypomania, that is, the co-occurrence

of depressive symptoms in patients with a hypomanic episode, was found in 57%
of visits for hypomanic episodes (42). Mixed hypomania was equally prevalent in
patients with bipolar I and II disorder, but more prevalent in women.
The concept and the terminology of mixed states are prone to confusion.
ICD-10 takes a somewhat broader view than DSM-IV on mixed states, deﬁned
as either a mixture or a rapid alternation (usually within a few hours) of manic,
hypomanic, and depressive symptoms; the minimum duration of mixed episodes
is two weeks. The term “dysphoric mania,” originally meant to indicate a mixed
state, may be wrongly used to indicate “classic” mania with predominantly irritable
rather than euphoric mood. Moreover, the distinction between these two conditions

may be difﬁcult and it is unclear whether this is clinically relevant since the
evidence that mixed states should be regarded as separate clinical entities is
controversial (40).
It is of clinical importance that mixed mania is less responsive to treatment, in
particular with lithium, than “classic” euphoric mania (43).
ANTIDEPRESSANT-INDUCED MANIA AND HYPOMANIA
According to DSM-IV, patients with unipolar major depression who become hypo-
manic or manic when treated with antidepressants receive an additional diagnosis
of substance-induced mood disorder with manic features. In these cases, it is
assumed that the manic syndrome is a direct physiological effect of antidepressant
medication, and such an episode should not lead to a diagnosis of bipolar disorder.

This also applies for mood episodes induced by other medications, alcohol, or drugs
of abuse. The concept that antidepressant-induced (hypo)mania in (unipolar) major
depression is not indicative of bipolar disorder has been strongly debated, and
evidence for an opposite point of view was recently reviewed by Chun and
Dunner (24). They found that cases of treatment-induced hypomania in 121
studies of antidepressants in major depressive disorder patients were relatively
rare, and within the rate of spontaneous conversion from unipolar to bipolar
disorder. They conclude that these patients should be recognized as having
bipolar disorder, and propose a revision of this category in DSM-V. Another argu-
ment for this position is that according to most guidelines, patients with a bipolar

depression should not be treated with an antidepressant alone, but only in combi-
nation with antimanic agents, that is lithium, an anticonvulsant, or, according to
some guidelines, an atypical antipsychotic. It appears logical to apply the same
approach for depressed patients with a history of an antidepressant-induced
hypomanic or manic episode, since when treated with antidepressant monotherapyClassiﬁcation of Bipolar Disorders 7

there is a signiﬁcant risk of another switch. Finally, it is also of interest that with-
drawal of antidepressants can induce mania (44). It is likely that for this condition
the same diagnostic considerations are relevant.
DIFFERENTIAL DIAGNOSIS: THE BOUNDARIES OF BIPOLAR DISORDER
External Boundaries
Cyclothymic disorder can be seen as the borderland between bipolar disorder
and normal mood ﬂuctuations. Patients with cyclothymia exhibit mood instability,
that is (often numerous) periods with hypomanic symptoms that never meet cri-
teria for a manic episode and with depressive symptoms that never meet criteria
for major depressive episodes over the course of at least two years. A family
history of mood disorders is more common in cyclothymic patients in whom the
disorder proceeds to a full-blown bipolar disorder in the course of their life.
Borderline personality disorder is another disorder with affective instability.

Therefore, it may be difﬁcult to distinguish borderline personality disorder from
cyclothymia and also from bipolar I or bipolar II disorder with rapid cycling
(i.e., at least four episodes per year) and especially ultrarapid cycling (i.e., mood
switches within a week of at least four episodes per month) or ultradian cycling
(i.e., mood switches within a single day) (45). Moreover, both conditions may
coexist. A controversial point of view is whether borderline personality disorder
in fact is part of the bipolar spectrum (2,46–48).
Schizoaffective disorder, bipolar type, ﬁlls the gap between mania with mood-
incongruent psychotic features and schizophrenia. A considerable number of
severely ill patients admitted to psychiatric hospitals have manic or depressive

episodes co-occurring with symptoms characteristic of schizophrenia, including
mood-incongruent delusions or hallucinations. In addition, patients have delusions
or hallucinations in the absence of prominent mood symptoms. The deﬁnition of
schizoaffective disorders has varied over the years among classiﬁcation systems
and is still diffuse and uncertain (49). According to DSM-IV, such patients are classi-
ﬁed as schizoaffective disorder when the co-occurrence of mood and psychotic
symptoms as described occurs during the same period of illness, which may last
for years. Nevertheless this deﬁnition is difﬁcult to use in clinical practice, as
shown by the small interrater reliability when diagnosing patients with these
problems (50). It challenges the classic Kraepelinian dichotomy between manic-

depressive illness and schizophrenia, and may be an indication of a considerable
genetic overlap between these two groups of major psychiatric disorders (51).
Another diagnostic category that ﬁts in the grey zone between bipolar
disorder and schizophrenia but has been omitted in DSM-IV and ICD-10 is
cycloid psychosis, as described by Leonhard (4). These conditions combine poly-
morphous psychotic symptoms with an episodic course and a generally favorable
prognosis (52).
The boundary between recurrent unipolar depression and bipolar disorder
has already been discussed, and will be further addressed in the section on the
bipolar spectrum. If one accepts the unipolar–bipolar dichotomy then the question
arises at which point these disorders split. This depends on the deﬁnition of

hypomania and its lower limit towards normality, being the mildest manifestation
of bipolarity. Current debate concentrates on the number of hypomanic symptoms
needed, and the minimum duration of a hypomanic episode. DSM-IV requires four
days, although at that time no data were present to determine whether three days8 Kupka and Nolen

would have been better (53). Recent studies by Angst et al. in Zurich (20) showed
that hypomanic episodes of one to three days were of comparable clinical
signiﬁcance. Including brief hypomanic episodes into the deﬁnition of bipolar II
disorder changes the rate of all major and minor forms of unipolar versus bipolar
disorder (see later) (20).
Another area of potential diagnostic confusion lies in the distinction between
agitated unipolar depression and bipolar mixed states, especially the “mixed
depression” described earlier. There is some research evidence that agitated
unipolar depression is part of the bipolar spectrum (54).
Internal Boundaries
Separating bipolar II from bipolar I disorder depends on the deﬁnition of hypomania
and its upper limits towards mania (see earlier). In the longitudinal Collaborative
Depression Study, patients with bipolar I disorder had more severe episodes
whereas those with bipolar II disorder had a substantially more chronic course

with signiﬁcantly more major and minor depressive episodes and shorter inter-
episodic well intervals (55). The authors conclude that these differences justify
classiﬁcation as two separate subtypes, although the overall clinical similarities of
these subtypes suggest that they exist in a disease spectrum (55).
Rapid cycling, deﬁned as the occurrence of at least four distinct mood
episodes in one year, has been introduced as a course speciﬁer of bipolar I and II
disorder in DSM-IV (53,56). Rapid cycling is not mentioned at all in ICD-10.
Taking a conventional categorical approach, a meta-analysis of 20 studies compar-
ing rapid cyclers and nonrapid cyclers revealed some signiﬁcant differences apart
from episode frequency, in particular a slight overrepresentation of women and of

bipolar II subtype among rapid cyclers (57). Associated with rapid cycling there
was also a trend for depressive episode at onset of illness, a history of serious
suicide attempts, a family history of affective disorder, and nonresponse to
lithium prophylaxis. However, recent large studies (29,58,59) have shed doubt
over the higher prevalence of rapid cycling among bipolar II patients. Moreover,
if one takes a dimensional approach, differences occur gradually with increasing
episode frequency and never reveal a cut-off point at four episodes per year or at
any other episode frequency, suggesting that rapid cycling is not a distinct
subtype but merely an extreme on a continuum of cycle frequency (29).
Finally, the boundary between mania and depression is blurred in patients

with mixed states. There is also a potential overlap between mixed states with
rapid mood shifts on the one hand, and ultra-rapid or ultradian cycling (45,47)
on the other. The latter conditions are not deﬁned in DSM-IV but can be classiﬁed
as mixed episodes or alternatively in the residual category Bipolar Disorder Not
Otherwise Speciﬁed. A summary of key criteria deﬁning the major boundaries of
bipolar disorder is given in Table 4.
THE BIPOLAR SPECTRUM CONCEPT
A broad deﬁnition of manic-depressive illness was originally proposed by Kraepe-
lin (3), and reintroduced by Akiskal (2,60,61), Goodwin and Jamison (32), Cassano
(63), and Angst (64), amongst others. This so-called bipolar spectrum includes syn-
dromal and subsyndromal clinical conditions beyond the more narrowly deﬁned

DSM-IV and ICD-10 classiﬁcations of bipolar disorder. In recent years, differentClassiﬁcation of Bipolar Disorders 9

variants of a bipolar spectrum have been presented; an example as proposed by
Akiskal is given in Table 5.
The bipolar spectrum concept puts emphasis on validators other than polarity
(i.e., the occurrence of mania), such as a recurrent (“cycling”) course of illness, posi-
tive family history of mood disorder, and unfavorable outcome of antidepressant
treatment (62). In such a broad deﬁnition, recurrent brief depressions (“cycling
within the depressive pole”) that do not respond to or even get worse with
antidepressants may be part of the spectrum. Lifetime prevalence rates of bipolar
spectrum disorders range from 2.8% to 6.6% of the population (65).
One major rationale for a bipolar spectrum is that the application of narrow
diagnostic criteria may result in misdiagnosis of many cases that would beneﬁt
from other treatments: mood stabilizing drugs rather than antidepressants.
A major objection towards the concept of a bipolar spectrum is that it shows

an expansive trend, incorporating subsyndromal conditions and conditions that
are only in part characterized by affective instability, such as borderline personality
disorder (66). This may weaken the core concept of bipolar disorder, which appears
to be a circumscript clinical entity suitable for genetic, biological, and treatment
studies (66). Reanalyzing the data of the epidemiologic catchment area (ECA)
study by taking into account all subsyndromal manic symptoms resulted in a
lifetime prevalence rate of 5.1% on top of the 0.8% for manic episodes (bipolar I)
and 0.5% for hypomanic episodes (bipolar II), yielding a total of 6.4% for bipolar
spectrum disorders (67). The prevalence of bipolar (and unipolar) mood disordersTABLE 4 Key Boundaries of Bipolar Disorders in DSM-IV
Boundary Criteria deﬁning boundary

Normal mood ﬂuctuations versus dys /
hyper /cyclothymic temperament
versus mood disorderOccurrence and severity of depressive and
hypomanic symptoms
Unipolar depression versus bipolar II
disorderNumber and duration of hypomanic symptoms
Bipolar II versus bipolar I disorder Impairment and duration of manic symptoms
Bipolar I versus schizoaffective disorder Timing of psychotic symptoms
Schizoaffective disorder versus
schizophreniaBalance of psychotic and affective symptoms
Rapid cycling versus nonrapid cycling
courseOccurrence of 4 distinct mood episodes /year
Source : From Ref. 73.
TABLE 5 A Bipolar Spectrum as Proposed by Akiskal
Bipolar1
2Schizobipolar disorder
Bipolar I Manic-depressive illness
Bipolar I1
2Depression with protracted hypomania
Bipolar II Depression with spontaneous hypomanic episodes
Bipolar II1

Bipolar1
Bipolar I1
2Depression superimposed on cyclothymic temperament
Bipolar III Recurrent depression with antidepressant-induced hypomania
Bipolar III1
2Recurrent depression with alcohol /substance-induced hypomania
Bipolar IV Depression superimposed on hyperthymic temperament
Bipolar V Recurrent depression ( /C215 episodes)
Source : From Ref. 61.10 Kupka and Nolen

is further exploded when thresholds are set even lower, such as in the Zurich
studies (20). Relaxing duration and severity criteria for hypomania resulted in an
almost equal lifetime prevalence of 24.6% for the depressive spectrum (including
major depression, dysthymia, minor depression, and brief recurrent depression)
and 23.7% for “soft” bipolar spectrum (including bipolar I and broadly deﬁned
bipolar II, minor bipolar disorder, cyclothymia, and pure hypomania) (20). These
authors state that 11% constitutes the spectrum of bipolar disorders proper, and
another 13% “probably represent the softest expression of bipolarity intermediate
between bipolar disorder and normality.” If almost a quarter of the population is
included, it is questionable whether such broad deﬁnitions are still meaningful
indicators of psychopathology, given the lifetime prevalence of core bipolar I dis-
order of 0.5% in the same cohort, which is consistent with other epidemiological
studies (19).

ASSESSMENT OF BIPOLAR DISORDER
Diagnostic assessment of bipolar disorders has several aspects: a lifetime diagnosis
according to DSM-IV of ICD-10, a diagnosis of the current mood episode or a state
of interepisodic remission, rating the severity of the current mood disturbance, and
depicting the longitudinal course of the illness.
A diagnosis of bipolar disorder in clinical research settings is commonly
obtained by applying one of the semi-structured interviews for axis I diagnoses
by trained clinicians, such as the Structured Clinical Interview for DSM-IV axis I
disorders, Research Version, Patient Edition (SCID-I /P) (68), the related Mini
International Neuropsychiatric Interview (MINI) (69), or the Schedules for
Clinical Assessment in Neuropsychiatry (SCAN) (70). In epidemiological studies,

fully structured interviews are used, often by trained lay interviewers, such as
the Composite International Diagnostic Interview (CIDI) (71) (REF WHO). All
these instruments arrive at current or lifetime DSM-IV (SCID) or DSM-IV and
ICD-10 (SCAN, CIDI) diagnoses. Since each diagnostic criterion of each mood
episode as well as every psychotic symptom is rated separately, these instruments
are suitable for assessing symptom proﬁles beyond the diagnostic boundaries
described earlier. Semistructured interviews by trained clinicians may be somewhat
more speciﬁc in diagnosing bipolar disorder than structured interviews by lay
interviewers (72).
An self-rated instrument for screening for bipolar disorder is the Mood
Disorders Questionnaire (MDQ) (22), which has been applied in a large U.S.

population sample (23) and various European countries, and actually checks the
previous presence of manic symptoms according to DSM-IV criteria. If rated
positive it should be followed by a clinical interview.
A dimensional scale that was designed to serve as an adjunct to conventional
categorical diagnosis is the Bipolar Affective Disorder Dimension Scale (BADDS)
(73). It provides a description of some of the basic features of an individual’s
lifetime experience of psychopathology relevant to the bipolar spectrum. The
scale is mainly based on the ICD-10 criteria and has four dimensions: ( i) mania:
the presence and severity of manic syndromes; ( ii) depression: the presence and
severity of depressive syndromes; ( iii) psychosis: the presence of psychotic symp-

toms and the balance of mood and psychotic symptomatology; and ( iv) incon-
gruence: the mood congruence of psychotic symptoms and the temporal
relationships between affective and psychotic symptomatology. Using multipleClassiﬁcation of Bipolar Disorders 11

data sources, every subject is scored in the range 1–100 on each of the four
dimensions. The instrument was developed within the context of family studies,
and incorporates the boundaries between unipolar, bipolar, schizoaffective,
and schizophrenic disorders (Table 4). It retains a measure of severity and also
includes mild or subclinical cases, and avoids hierarchical loss of information
inherent to classiﬁcation systems. BADDS appears to be especially suitable to
assess bipolar spectrum disorders next to or beyond the strict DSM-IV or ICD-10
categories.
There are various symptom rating scales for measurement of severity of
mania and depression, such as the Young Mania Rating Scale (YMRS) (74), the
Bech Rafaelsen Mania Scale (BR-MAS) (75), the Hamilton Rating Scale for
Depression (HAMD) (76), the Montgomery A ˚sberg Depression Rating Scale
(MADRS) (77), and the Inventory of Depressive Symptomatology (IDS) (78). The

latter includes many “atypical” symptoms, which frequently occur in bipolar
depression, and is thus particularly suitable for this condition.
A problem typical for the assessment of change in bipolar disorder is that
improvement of a depressive episode may go hand in hand with emerging
mania, and vice versa, and that rapid changes of polarity may add to the overall
illness burden beyond depressive and manic symptoms per se. To address this
problem, the Clinical Global Impressions scale, Bipolar Version (CGI-BP), was
designed (79). This is a modiﬁcation of the original CGI scale, providing global
severity ratings of both depression and mania, as well as a global severity rating
of overall bipolar disorder. A similar set of CGI scales was designed for the assess-
ment of change in clinical trials (79).

These scales all make a cross-sectional assessment of the manic or depressive
episode with a time span ranging from two days to two weeks. Given the waxing
and waning course of bipolar disorder, repeated cross-sectional assessments will
not reveal the frequently occurring mood episodes in between. For continuous
longitudinal assessments, either retrospective or prospective, a graphic method
such as the NIMH-Life Chart Methodology (NIMH-LCM) is more suitable
(Fig. 1) (80,81). This instrument has been validated in recent years (82,83), and is
available in a clinician-rated and a self-rated version. A similar instrument
for longitudinal assessment is the prospectively self-rated computerized ChronoR-
ecord (84).
FIGURE 1 One-year prospective daily life chart showing prototypical bipolar I disorder with a

continuous “rapid cycling” course in a man aged 67 with an illness history of over 50 years. Mania
above and depression below baseline. Source : From Ref. 29.12 Kupka and Nolen

DIAGNOSTIC VALIDITY AND IMPLICATIONS FOR
NEUROPSYCHIATRIC RESEARCH
Although our current diagnostic categories have limited validity and are provi-
sional until external validators are identiﬁed, the availability of clear diagnostic
categories with its criteria has nevertheless greatly improved the reliability of
diagnosis in clinical and research settings. In most neurobiological, genetic, and
treatment studies of bipolar disorder, subjects will have received a diagnosis of
(DSM-IV) bipolar disorder. Also, further distinctions are often made between
subjects with bipolar I or bipolar II disorder and subjects with a rapid cycling
course versus with slower cycle frequencies of less than four mood episodes per
year (often indicated as nonrapid cyclers). As discussed earlier, the boundaries
between these categories are arbitrary, and it is unlikely that these boundaries,
which are entirely based on clinical descriptive criteria, exactly point out the

potential boundaries between distinct disorders with a different etiologic or patho-
physiological background (73,85).
Dimensional diagnoses tend to be impractical and difﬁcult to communicate
(85). However, the concurrent use of categorical and dimensional diagnostic
instruments as proposed by Craddock et al. (73) may be particularly appropriate
in bipolar spectrum disorders. The bipolar spectrum concept provides a compro-
mise, since its prototypical categories lie along a unipolar–bipolar continuum
and on continuums with other diagnoses such as psychotic disorders. It is also
useful for clinical practice, alerting clinicians to search for clues for bipolar disorder
in patients with mood disorders and treat them according to the best available evi-

dence. However, for neurobiological research, a broadly deﬁned bipolar spectrum
as a whole may be over inclusive. Investigating relatively homogeneous subgroups
delineated by relatively narrow diagnostic categories that are now widely accepted
(major unipolar depression, bipolar I and bipolar II disorder) within the entire
bipolar spectrum could help to identify biological markers and the genetics for
core syndromes. Comparing shared and unshared neurobiological and genetic
features may eventually lead to subgroups that are more ﬁrmly based on etiology
and pathophysiology. This may also shed light on the true nature of overlapping
areas between prototypical phenotypes, such as “pseudo-unipolar” and schizoaf-
fective disorders.
The longitudinal evolution of bipolar disorder makes every diagnostic

assessment in a given individual temporary, since apparent unipolar depression
can turn out to be bipolar disorder, bipolar II disorder can progress to bipolar
I disorder, and bipolar disorder can deteriorate to schizoaffective disorder.
This may be particularly problematic in studies of unipolar depression. Patients
who have only had depressive episodes at the time of their participation in
such a study, but at a later point show features of bipolar disorder, may
compromise the identiﬁcation of potential differences between unipolar and
bipolar disorder.
TOWARDS DSM-V
Despite the limitations and pitfalls of categorical diagnostic classiﬁcations (85),
DSM-IV and ICD-10 have greatly improved the reliability of the different mood
disorder diagnoses. For the sake of continuity in epidemiologic, neurobiologic,

and genetic research, we should be reluctant to change diagnostic criteria forClassiﬁcation of Bipolar Disorders 13

mood episodes and mood disorders as long as there is no compelling evidence to do
so. Still, there are certain areas that are open for change.
First, the very restrictive deﬁnition of mixed episodes, in particular the
requirement of full syndromal criteria for mania and depression, could be
relaxed, as outlined earlier. Given all the possible variants of mixed states, it is
obvious that they can occur not only in bipolar I but also in bipolar II disorder.
Second, there is now enough evidence to include antidepressant-induced
(hypo)mania in the diagnostic category of bipolar disorder. Psychoactive substance-
or treatment-induced (hypo)mania could be a separate subcategory (bipolar III
disorder), or an episode speciﬁer of bipolar I and II disorder.
Third, a better-operationalized and more consistent deﬁnition of the hypoma-
nia–mania boundary would improve the delineation of bipolar II versus bipolar I
disorder, even if it remains uncertain whether these subtypes are fundamentally

different.
Fourth, the concept of rapid cycling, which represents a dimension rather
than a subtype, could be deﬁned along a continuum as proposed either by counting
episodes over a certain time period (e.g., a year) or at least by dividing it into
more subcategories (nonrapid, rapid, ultra-rapid, and ultradian cycling) as
suggested by Kramlinger and Post (45) which allows for the inclusion of briefer
but still signiﬁcant episodes (29).
Finally, a speciﬁer for depressive episodes indicating bipolarity in up till then
unipolar patients, including features as summarized in Table 3, could alert
clinicians and researchers for latent bipolar disorder, without prematurely crossing
the boundaries of the current diagnostic classiﬁcations.
CONCLUSION
Polarity and cyclicity have been described as core dimensions of manic-depressive

illness (Fig. 1) (32), which, despite its heterogeneity, can still be regarded as one of
the most consistently described disorders in psychiatry (2,12). From these dimen-
sions, a bipolar spectrum can be constructed, and within this bipolar spectrum,
various subtypes have been deﬁned. In this chapter we have highlighted the
main areas of uncertainty and controversy about the internal and external bound-
aries of this spectrum, which rely exclusively on clinical description and still
lack external validators. It may well be that the most speciﬁc validators for
bipolar disorder will be revealed by studying patients with the core bipolar I syn-
drome (66). Eventually, neurobiological and genetic studies must not only provide
such validators for accurate and valid diagnoses, but above all direct towards a

more targeted treatment for the individual patient with a variant of bipolar
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B2 Prospects for the Development of Animal
Models for the Study of Bipolar Disorder
Haim Einat
College of Pharmacy, University of Minnesota, Duluth, Minnesota, U.S.A.
Alona Shaldubina, Yuly Bersudsky, and R. H. Belmaker
Division of Psychiatry, Faculty of Health Sciences, Ben-Gurion University of the Negev,
Beer Sheba, Israel
Attitudes towards the study of lithium on behavior in animals and humans have
often been inﬂuenced by preconceived notions of the nature of psychiatry and
psychopharmacologic treatment. Many psychiatrists would like to see psychophar-
macological agents as “magic bullets” in a sense similar to antibiotics. Antibiotics
are not expected to have effects on organisms that are not infected with bacteria;
effects that do occur are seen as side effects unrelated to the mode of action. Thus
neuroleptic dopamine-blocking drugs are believed by many psychiatrists to have
no effects on persons who are not psychotic; antidepressants are seen as distin-

guished from stimulants of abuse as not having mood-elevating effects in the
absence of depression. The study of lithium’s effects has often been carried out in
a similar tradition. Moreover, lithium is seen as a difﬁcult drug to give to normal
volunteers for the period of three weeks or a month that would approximate the
amount of time necessary for signiﬁcant effect on a manic episode.
PSYCHOSTIMULANT-INDUCED MODELS
Animal studies have been a mainstay of the study of lithium effects on behavior
other than clinical studies of psychophathology. These animal studies were
reviewed in 1991 (1) and again in 2003 (2). The overriding majority of studies in
this ﬁeld has used the concept of pharmacologically induced mania and depression
and has attempted to show lithium prevention. The usual agent for pharmacologi-

cal induction of mania has been amphetamine, although more speciﬁc and direct
dopamine agonists such as quinpirole have also been used (3). Using reserpine
or tetrabenazine to induce depression has also been studied (4,5). A background
concept has been the fact that low dose amphetamine has effects primarily on
open ﬁeld activity whereas higher dose amphetamine causes stereotypy (6,7).
Dopamine blockers are well known to block both the low dose hyperactivity and
the high dose stereotypy of amphetamine, and this nicely ﬁts their usefulness in
both mania and schizophrenia (8). Further support for the amphetamine-induced
hyperactivity model comes from the association of psychostimulants with the
onset of mania in susceptible individuals (9,10) and from some clinical studies

that support an effect of lithium in preventing the behavioral effects of stimulants
in people (11,12). To delineate the differences between the dissimilar responses to
19

doses of amphetamine, attempts have been made to differentially look at the
effect of lithium pretreatment on low dose amphetamine effects versus high dose
amphetamine effects, the hypothesis being that lithium as an antimanic agent
will prevent the effects of low-dose amphetamine but because it is devoid of true
antipsychotic properties it will not be able to affect amphetamine-induced stereo-
typy. Often an underlying biochemical hypothesis was that low-dose amphetamine
released mostly serotonin and noradrenaline whereas high dose amphetamine
released more dopamine. All of these assumptions, hypotheses, and preconcep-
tions are today viewed skeptically. They were heuristic as hypotheses that
generated much good research; however, the yield of robust replicable data has
been poor. Given the fact that modern studies of psychopharmacologic agents
often require hundreds of patients to show statistically signiﬁcant effects, it may

not be surprising that animal studies with 10 to 15 rats in each group often come
up with conﬂicting results. The heterogeneity of the amphetamine response is
well known (13), and lithium response may also be heterogeneous in outbred rat
strains (14,15). We shall discuss later the possibility of using this heterogeneity in
responses to advance research.
The effect of lithium to block hyperactivity in rats has also been given new
impetus by a paper from Caron’s group (16). They injected dopamine transporter
knockout mice with lithium (50, 100, or 200 mg /kg) a half hour after they were
placed in an open ﬁeld and found signiﬁcant reduction in horizontal activity in
mice injected with 100 and 200 mg lithium. This paradigm had previously been
used by Nixon et al. (17) and positive results had also been found. However, in

humans even very high doses of lithium do not have immediate effects in mania
but clearly do have side effects such as nausea and muscle weakness. Therefore,
it is difﬁcult to evaluate these acute effects reported by Caron’s group (16),
especially in the light of the long history of contradictory results in this ﬁeld.
Several reports demonstrate inhibition of amphetamine-induced hyperactivity by
acute and chronic lithium pretreatment in rats and mice (7,15,18–23). However,
other publications show absence of lithium effect in this model (8,24–27).
New data coming from Manji’s laboratory (28) also indicate that lithium’s effects
on amphetamine hyperactivity may be related to genetic background. A compre-
hensive study of 12 strains of mice (three outbred and nine inbred strains) shows

that acute lithium injection at 100 mg /kg attenuated amphetamine-induced
hyperactivity in four strains, had no effect in four strains, and augmented the
effects of amphetamine in one strain (other strains did not respond to amphetamine
treatment at the dose used). Moreover, chronic oral lithium treatment at concen-
trations that had been previously demonstrated to result in therapeutic blood
levels (four weeks, 2.4 g /kg in food), resulted in similar effects with acute admin-
istration in some strains but not in all (28). All in all, these results suggest that
the effects of lithium on amphetamine hyperactivity may be strain (genetically)
dependent and that there may be different mechanisms that are involved in
the short term (acute) and long term (chronic) effects of lithium in this model.

An additional level of complexity in evaluation of lithium’s effects on the
response to amphetamine is added by the fact that behavioral responses to
psychostimulants are strongly affected by the testing environment and pro-
cedure. These variations are more prominent during chronic psychostimulant
treatment but are also apparent after acute administration (29). For example,
hyperactivity measures had been shown to increase more in large open ﬁeld
arena compared to smaller activity monitors (30) and an environment that is20 Einat et al.

similar to the home cage had been demonstrated to hinder the development of
ambulatory activity (31).
It is possible to give amphetamine or methylphenidate to humans on chronic
lithium and this was done in many studies (11,14,21,32,33). While some have
claimed marked effects of lithium to attenuate the amphetamine-induced response,
others have found no effect at all (32). The numbers on subjects in these studies
are smaller than the large numbers of patients required to show a lithium effect
in a clinical situation and human heterogeneity may be the answer to the con-
tradictory results. We await a clear paradigm that will give robust ﬁndings in the
amphetamine hyperactivity model of mania in humans as in rodents. Perhaps
the issue is blood lithium levels since these have varied greatly between studies
and usually levels of 0.7 mM have been considered sufﬁciently similar to human
treatment to be an acceptable model. It is unclear why behavioral effects are so

difﬁcult to demonstrate, whereas biochemical effects of lithium in normal subjects
are marked and highly replicable (34).
Interestingly, the notion of endophenotypes that had recently been strongly
emphasized in the research of bipolar disorder had renewed the interest of
scientists in the strength of amphetamine-induced behaviors and underlying
brain changes as important modeling tools.
Endophenotypes are quantiﬁable components in the genes-to-behaviors
pathways, distinct from psychiatric symptoms that make genetic and biological
studies of etiologies for disease categories more manageable (35). In the context
of modeling, endophenotypes approach can be helpful as it reduces the complexity
of symptoms and multifaceted behaviors, resulting in units of analysis that are
simpler to model in animals (36).

One of the tentative endophenotypes that had been repeatedly suggested
for bipolar disorder is dysregulation of dopaminergic function and hypersensi-
tivity to psychostimulants. This possible endophenotype was suggested based on
signiﬁcant data in both human and animal studies. Impaired brain reward path-
ways, enhanced rewarding effects of psychostimulants in patients with affective
illness, possible relationship between dopamine release in the ventral striatum,
euphoric responses, and some evidence for genetic variance that may explain the
individual differences in brain response to psychostimulants all suggest that beha-
vioral changes observed after exposure to amphetamine may be useful as marker
for bipolar disorder (37). However, this new line of study, exploring amphetamine

responses not as a model of mania but as a model of an endophenotype of
bipolar disorder, must include additional experimentation that will look beyond
hyperactivity into different facets of amphetamine-induced behavior, the possible
relationship between such behaviors, the effects of mood stabilizers, and the
genetic predisposition related to individual variability in responses to amphet-
amine as well as to lithium effects on amphetamine-induced behavior. Some
suggestions along these lines are detailed later in this chapter.
LITHIUM AS AN ANTIDEPRESSANT
Beyond the amphetamine-related models, a very exciting advance in this ﬁeld has
occurred recently, in a paper by O’Brien et al. (38) who used a speciﬁc regimen of
lithium administration to mice: mice received 0.2% lithium chloride in food for a

period of ﬁve days followed by 0.4% for 10 additional days and reported robust
effects in the Porsolt forced swim test. Previous studies of lithium in PorsoltProspects for the Development of Animal Models 21

forced swim test were equivocal, although Bourin’s group (39,40) showed that
lithium could reliably potentiate the effects of other antidepressants. The study of
Bourin et al. (39,40) used an acute lithium dose but it ﬁt the preconceived notion
that in the clinic lithium is an augmenter of antidepressant response and not a
powerful antidepressant itself. However, the paradigm of O’Brien et al. (38)
suggests a powerful effect of lithium in the Porsolt forced swim test. This is unlikely
to be an artifact, since activity in the Porsolt forced swim test requires an increase in
struggling behavior. Previous concerns about lithium artifacts have usually pointed
out that lithium patients experience some sense of malaise and muscle weakness
and nausea. These would be unlikely to cause the reported effects in the Porsolt
forced swim test.
We (41) have been able to replicate the O’Brien et al. (38) ﬁnding and have
shown that it is dependent on blood levels. Blood levels greater than 1 mM are

necessary for the robust effect that O’Brien et al. (38) ﬁnds, whereas blood levels
of 0.7 mM show no effect in the Porsolt forced swim test at all. Many studies of
chronic lithium in the past were quite satisﬁed with levels of 0.7 mM on the
average and even studies with higher blood levels had a signiﬁcant portion of
the animals with blood levels below 0.7 mM. This robust effect of lithium on the
Porsolt forced swim test provides an opening for behavioral pharmacological
analysis in the future. For instance, questions can be asked such as whether pre-
treatment with PCPA, a serotonin synthesis inhibitor, will prevent the effect of
lithium in the Porsolt forced swim test or whether presynaptic 5HT 1a/1bor postsyn-
aptic 5HT 2or˙b-adrenergic receptors agonists /antagonists will modulate this effect.

A recent hypothesis of antidepressant action is induction of neurogenesis in the
hippocampus. It could be an interesting question, whether TrkB (BDNF) receptor
agonists /antagonists will affect the lithium’s antidepressant effect in the Porsolt
forced swim test. Interestingly, inhibition of the Erk-MAP kinase pathway was
demonstrated to decrease immobility time in the forced swim test (42). However,
the same treatment also increased activity in an open ﬁeld and this effect was
ameliorated by chronic lithium treatment. Hence, suggesting that the effects of
Erk inhibition is less likely to be antidepressant-like and more likely to be pro-
manic (42), a notion that is further supported by other studies on the behavioral
effects of manipulating the Erk pathway (43,44). A key question would be

whether other mood stabilizers such as valproate have a similar effect in the
Porsolt swim test. Another key question will be whether the weight loss due to
reduced appetite in chronically lithium-treated rats might cause increased activity
in the Porsolt swim test. This needs to be done by “yoking” mice to others who are
eating lithium and let them eat only the exact same amount a day as the lithium-
treated animals eat. It is also possible to add a nontoxic bitter taste to the control
food to reduce the food intake and to see if this affects Porsolt results. Our
ﬁnding that lithium effects in the Porsolt swim test require a blood level greater
than 1 mM is actually congruent with clinical reports that the antidepressant
effects of lithium require higher blood levels than the prophylactic effect.

CURRENT PROBLEMS AND POSSIBLE SOLUTIONS
Although there were some advances in modeling bipolar disorders, it appears that
the ﬁeld had been quite limited for many years compared with model development
for other psychiatric disorders. It is possible that, at least in part, the nature of the
disease that includes oscillating between depression and mania episodes hindered22 Einat et al.

scientists from making serious attempts to model it. Just a few attempts were done
over the years to model the entire scope of bipolar disorder with manipulations
such as sleep deprivation (45) or intermittent cocaine administration (46), but for
a variety of reasons, these tentative models did not become a central tool to
explore the biology of bipolar disorder or to screen new drugs for it (2,47).
Bioassays
Attempts had also been made over the years to develop models that are more
a bioassay than a comprehensive behavioral model. An example of such incomplete
model is the study of Bersudsky et al. (48) showing lithium inhibition of
forskolin-induced hypoactivity. This study is based on the fact that lithium bio-
chemically inhibits forskolin induced rises in cyclic AMP. The behavioral ﬁnding
is therefore a bioassay of the chemical ﬁnding. However, to become a model it
would need to be corroborated by a ﬁnding that forskolin induces hypoactivity

or a depressive-like syndrome in humans. Another example is lithium augmenta-
tion of pilocarpine-induced seizures. This phenomenon had been repeatedly
demonstrated and can be used to explore lithium-mimetic drugs. Furthermore,
the increase in seizure susceptibility after lithium treatment was demonstrated to
be dependant on inositol depletion as it is blocked by inositol administration (49)
and augmented by inositol reuptake inhibition (50). Since the inositol depletion
theory (51) is one of the leading hypotheses regarding the therapeutic effects of
lithium, the use of pilocarpine-induced seizures as a rudimentary screening
model can be justiﬁed. However, the behavioral phenomenon is unrelated to the
features of the disease and therefore the utility of this paradigm as a real model
is questionable.

Whereas the models mentioned above did contribute to the research efforts on
bipolar disorder and its treatment, there is clearly a lack of better and more appro-
priate animal models for the disease. This deﬁciency is repeatedly emphasized as
one of the major problems hindering bipolar disorder research (52). Some new
approaches recently suggested in the literature are summarized below.
Modeling Facets of the Disease
One relatively simple approach stays within the realm of modeling based on face
validity, that is, the similarity in behavior observed in the disease and in the
model (53), and looking at components of the behavior rather than the entire
disease (54). However, in contrast to present work that is based mainly on very
few behavioral components of bipolar disorder (e.g., hyperactivity as a model

for manic behavior), this approach suggests a more comprehensive battery of
tests and models that will explore a broader range of the behavioral facets of the
disease. Accordingly, it may be possible to develop separate models for facets of
mania such as activity or restlessness; extreme irritability; reduced sleep; provoca-
tive, intrusive, or aggressive behavior; increased sexual drive; abuse of drugs; dis-
tractibility or reduced ability to concentrate; and poor judgment. Furthermore,
many such models were already developed in the context of research of other
disorders but they must be validated for bipolar disorder (54). If some of these
models can be validated, it may be possible to develop a battery of models that
will be appropriate for the screening of possible new mood stabilizers or to test

new hypotheses regarding the underlying biology of the disorder. One example
of such an initial validation attempt was recently demonstrated with a model forProspects for the Development of Animal Models 23

aggression (55). Since intrusive and aggressive behaviors are one of the facets of
mania, this study tested the validity of a commonly used test for aggression, the
resident intruder paradigm in mice, as a tentative model for this facet of mania.
The results of the study demonstrate that chronic administration of lithium or
valproate, at therapeutically relevant doses, ameliorates the aggressive behavior
in the resident intruder paradigm without affecting other aspects of social behavior.
Accordingly, this study suggests that the paradigm has predictive validity and can
be used as part of a battery of models for the study of new mood stabilizers (54).
Additional new models emphasized aggression in a competition for food task
(56) and irritability measured as resistance to capture (57,58).
Interestingly, even within this relatively simple approach, a number of candi-
date manipulations were identiﬁed that had been previously demonstrated

to result in a number of behavioral changes that are similar to facets of mania.
Therefore, if all these speciﬁc models will be validated, the resulting battery will
represent a group of bipolar-like behaviors (54). For example, psychostimulant
administration does not result only in hyperactivity (as discussed above) but was
also reported to induce reduced sleep, distractibility, risk taking behavior, and
increased responses to reward—all facets of mania (54).
From Molecules to Behavior
Although the approach described above may be conducive to further research,
modeling methods that concentrate on face validity of one component of the
disorder have been repeatedly criticized (59). Recent developments in basic
studies of the etiology of bipolar disorder coming from research using modern

techniques of brain imaging and novel methods of molecular biology may now
assist in the search for more comprehensive models that can be based more on
construct validity than on face validity, that is, models that will be developed
based on a possible mechanism rather than on behavioral similarities. One possible
strategy that can be employed was recently alluded to in a paper from the Soares
group (59). These authors suggest that genetic models can now be developed
for the disease and show that appropriate and relevant genes can be identiﬁed
by comparing genetic changes in available animal models to changes in patients.
For example, Machado-Vieira et al. (59) summarize ﬁndings regarding the genes
encoding GRK proteins and show they are related to defects in dopamine trans-

mission, to behavioral sensitization to psychostimulants in animals, and to a
more severe form of bipolar disorder in patients. Furthermore, postmortem
studies have shown changes in GRK genes in the prefrontal cortex of patients
who suffered from severe mood disorders (59). Altogether, the authors suggest
that modiﬁcations of the GRK genes (using transgenic techniques in mice for
example) may result in a better model for the disease that will be hypothesis-driven.
Other genes and intracellular pathways had been implicated during the last
decade in bipolar disorder and indeed some of these ideas can be used to create
hypothesis-driven models with strong construct validity.
Manipulations of many of these tentative genes proteins and intracellular
pathways in animals do indeed result in behaviors that resemble bipolar disorder

and were recently summarized in a review paper (44). Data regarding a variety of
manipulations, pharmacological and genetic, were summarized, and the conclusion
of the authors was that there is strong evidence for the involvement of PKC, GSK3,
and the Erk-pathway in bipolar-like changes with some evidence supporting24 Einat et al.

additional mechanisms including AMPA receptors, inositol, glucocorticoid recep-
tors, and Bcl-2 (44). Much of the behavioral information presented in that review
was collected while studying other disorders or the functions of normal brain beha-
vior and studies in the context of bipolar disorder are now needed to further explore
the role of these molecules and pathways in bipolar-like behavior in animals. Yet,
the data support the notion that bipolar-like behavioral changes correspond with
manipulations of bipolar-related molecules and this now may be a reasonable
approach to develop more speciﬁc, hypothesis-driven models for the disease.
Individual Variability
Further exploration of the relationship between speciﬁc genes, molecules, path-
ways, and behavioral models, may be enhanced by looking at individual variability
of responses. The issue of individual differences in behavioral modeling has been
grossly neglected for many practical reasons, but this neglect may represent one

of our major failures. It is apparent that the etiology of bipolar disorder (as
of other psychiatric and nonpsychiatric diseases) is based on an interaction
between the underlying genetics and the environmental effects on the biology
where susceptible individuals that are exposed to environmental precipitating
factors will express the disease phenotype (60–62). However, in most of our
attempts to model bipolar disorder we expose a group of “normal” animals to a
speciﬁc manipulation (whether it is a lesion, a drug, or an environmental stimulus),
and we expect them to become “sick” and allow us to explore possible new thera-
pies or the underlying biology of the “sickness.” Alternatively, with the develop-
ments in transgenic technology, we manipulate a mouse gene that is implicated

in bipolar disorder or its treatment and expect the entire population of mutant
mice to behave differently than the wild type controls. These approaches to
modeling can be helpful when there is an expectancy that a single gene mutation
may be responsible for a major part of a disease or its treatment, but this is probably
not the case for bipolar disorder, and accordingly, this approach may be limited to
demonstrating involvement of speciﬁc genes in the disease.
Any scientist who has been studying behavior knows the wide range of indi-
vidual variability within groups. Usually we try to overcome this variability by
increasing group size, but further attention to individual responses may in fact
be conducive to our research. If indeed subgroups of animals within a group

exposed to a speciﬁc manipulation can be identiﬁed as responders versus non-
responders (higher vs. lower behavioral change), it will enable us to ( i) use the
responders as a better model for the disease and ( ii) explore the biological differ-
ences between the subgroups. Some work using such methods has been done in
the context of other psychiatric disorders with interesting results demonstrating a
relationship between the extent of a behavioral response and biological changes
(63–66). For example, Cohen and her colleagues (67–69) exposed outbred rats to
a traumatic experience (inescapable cat odor) and tested them for anxiety-like
measures immediately and 10 days after the exposure. Whereas all rats showed
anxiety-like responses immediately after exposure, only about 30% of animals

remained anxious at the later testing. Interestingly, the animals that had a long-
term effect on behavior also had long lasting changes in physiological measures
(heart rate variability) and biochemical measures (higher plasma corticosterone
and ACTH levels, increased sympathetic activity, diminished vagal tone, and
increased sympathovagal balance) suggesting that these animals may be anProspects for the Development of Animal Models 25

excellent model for post-traumatic stress disorder (66). It may now be interesting to
explore the underlying genetic differences that may account for the differential
responding in these subgroups of outbred rats. A number of attempts to look at
individual variability have also been done in the context of depression and
bipolar disorder (65,70,71), but for most of it, scientists who identiﬁed differential
responses tried to amplify them by breeding the different subgroups to create
different lines of responders versus nonresponders (72,73). This approach may
clarify some of the genetics by making an extreme “caricature” of the initial
strain. However, the process of inbreeding may also mask the variability of the
normal population since other biological changes that evolve during inbreeding
may overshadow the speciﬁc differences that were responsible for the initial differ-
ential responses.
Research that emphasizes diversity in responding presents two main pro-

blems. First, a technical issue: if we want to identify subgroups in a general popu-
lation, we must start with a much larger number of animals. In light of constraints
such as money, space, and constant ethical concerns about animal research, this
may not always be easy. The second problem is more conceptual. Looking at
individual variability demands that we ﬁrst identify subgroups within a population
and then test them in the context of our study. For example, if one hypothesizes
that animals that show a higher response to psychostimulants may model the
susceptibility of manic patients to these drugs and wants to test the effects of a
new mood stabilizer in this model, the ﬁrst stage would be to treat a large group
of animals with a psychostimulant, identify the high- versus low-responding

subgroups, then treat with the new mood stabilizer, and see if indeed it has an
effect in the susceptible group but not in the resilient animals (as we may expect
from a good mood stabilizer). However, in testing for the effects of the new drug,
the behavior is not only inﬂuenced by the new treatment or the initial differences
between the subgroups, but also by the experience the animals had during the
screening procedure. Yet, if we can identify screening procedures that are mini-
mally intrusive or invasive, further attention to individual variability may open
many new avenues for our research and may result in signiﬁcantly better models.
Modeling Endophenotypes
An additional approach that in a way combines many of the tentative methods
described above is modeling endophenotypes of disease. As mentioned earlier,

endophenotypes are quantiﬁable components in the genes-to-behaviors pathways,
distinct from psychiatric symptoms. Endophenotypes are heritable; they are
associated with illness in the population; they are state-independent (manifest in
an individual whether or not illness is active) and may need to be elicited by a
challenge (36). In the context of animal models, it is important to emphasize that
endophenotypes are not synonymous with symptoms. As such, an animal model
of an endophenotype of bipolar disorder may not have face validity for any facet
of the disease but will have strong construct validity for the endophenotype [for
in-depth discussion of the validity of models in psychiatry see (2,47,74)]. Animal
models based on the endophenotypes approach may not be ideal for drug screening

purposes but may have great importance in the attempts to explore genes and
validate neurobiological mechanisms in model organisms (36).
Current theories regarding tentative endophenotypes for bipolar disorder
based on genetic and biological studies of patients and families include attention26 Einat et al.

deﬁcits, circadian rhythm instability, irregularities in motivation and reward, brain
structural changes, increased sensitivity to stress and psychostimulants, and
limbic-hypothalamo-pituitary-adrenocortical (LHPA) axis malfunction (36,37).
Animal models that will represent any of these tentative endophenotypes will be
helpful to decipher the biological basis of these speciﬁc endophenotypes and the
relationship between a speciﬁc endophenotype and susceptibility to the disease.
Models for endophenotypes can be developed genetically, by modulation of
speciﬁc genes that are implicated in the endophenotype, but can also be developed
based on individual variability within groups of “normal” animals as described
above. For example, it was recently demonstrated that the aggression displayed
in the resident-intruder test is ameliorated by chronic mood stabilizers treatment
(55). This behavior had been previously shown to be LHPA-axis dependent

(56,75) and it would be interesting to see now if variability in this behavior may
be related to other behavioral measures related to the LHPA axis and to any speciﬁc
genetic features (55).
CONCLUSIONS
There are several directions in which this ﬁeld can go heuristically:
1. Development of an entirely novel model. For instance, dogs are more difﬁcult to
study than rats, involving more expense and greater ethical concerns. However,
male dogs exposed to the scent of vaginal secretions of a female dog in heat
become hyperactive, aggressive, hypersexual, and will not sleep or eat for
days while under the inﬂuence of this scent. Since hypersexuality and hyper-
activity are clearly parts of mania and since a new love affair is a frequent
stimulus for the onset of a manic episode, this model could have face validity.

The effects of lithium and other mood stabilizers on this model could be an
important direction. The biochemical effects of the pheromones of female
canines in heat on the brain of the male dog might also elicit important
information.
Recent papers (16,38) suggest that the classic ﬁeld of study of lithium effects on
amphetamine hyperactivity or on the forced swim test might actually have been
a correct direction and that the contradictory results might have been due to
inadequate lithium dosing. A major effort is now underway to resolve
whether this is the case. If so, studies of other mood stabilizers and the bio-
chemical effects of higher dose lithium in these models could lead to rapid
new information.
2. Validation of additional facets of the disease may provide researchers with a

larger and broader arsenal of tools to explore the different components of
mania and depressive behavior, especially in the context of drug and mutant
animals screening (54).
3. Further attention to individual variability in behavioral response may be critical
for the development of more clinically relevant models and can forward the
understanding of genetic differences that may account for behavioral diversity.
Individual variability can also be of great importance in the exploration of
models for the endophenotypes of disease.
4. The notion of endophenotypes in bipolar disorder, suggesting an intermediate
level of exploration between symptoms and disease that may be genetically and
biologically relevant, poses a set of new challenges in modeling (36). Each of theProspects for the Development of Animal Models 27

tentative endophenotypes of bipolar disorder includes a set of biological and
behavioral components that may be possible to model using either genetic tech-
niques or other manipulations. Appropriate models for endophenotypes will
have a major impact on further research into this rejuvenated hypothesis.
Animal models for bipolar disorder have been used for many decades with
signiﬁcant success in studies related to both the development of new drugs and
the exploration of the biological basis of the disorder. Yet, it is now clear that
with the recent major developments in molecular and genetic methodologies and
brain imaging techniques, the available models cannot adequately respond to the
new challenges (52,76). It is now the time for behavioral scientists to make a
major effort, possibly combining all the approaches discussed above, to detect,
create, and validate new models that may provide better and more adequate
tools to further the research of bipolar disorder.

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B3 Abnormalities in Catecholamines and the
Pathophysiology of Bipolar Disorder
Amir Garakani and Dennis S. Charney
Department of Psychiatry, Mount Sinai School of Medicine, New York,
Amit Anand
Department of Psychiatry, Indiana University School of Medicine, Indianapolis,
Indiana, U.S.A.
The catecholamine (CA) hypothesis of bipolar disorder (BD)—a deﬁciency of CA in
depression and excess in mania—was proposed nearly three decades ago. CA
abnormalities remain the most replicated ﬁnding in the pathophysiology of BD.
However, the role of CA abnormalities in the pathophysiology of BD still
remains unclear. For example, it is unclear whether changes in CAs seen in
manic and depressed states are secondary to the mood state or primary, and it
remains to be clariﬁed whether abnormalities in the CA system are presynaptic
or postsynaptic. Rapid advances in the ﬁeld of neuroscience in the last three

decades have increased our knowledge of the role of CAs in the working of the
nervous system and provided new tools to explore CA abnormalities. Clinical
research in CA abnormalities in BD has evolved from measurement of changes in
CAs in bodily ﬂuids and peripheral tissue to neuroendocrine challenge studies to
molecular analysis of postmortem tissue and direct visualization of CA system
with brain imaging methods such as single photon emission computed tomography
(SPECT) and positron emission tomography (PET).
Preclinical and clinical literature on the role of CAs in depression and
psychiatric illnesses and mode of action of psychotropic drugs is fairly extensive.
In this review, the main focus is on studies that have speciﬁcally investigated the
role of CAs in BD. There are only a few preclinical studies regarding pathophysiol-

ogy of BD because of a lack of suitable animal models for bipolar illness. However,
there is an extensive preclinical literature regarding pathophysiology of depression
using animal models of depression. In this review, ﬁndings from depression
research are reviewed where they are relevant to understanding of pathophysiol-
ogy of BD.
This chapter ﬁrst reviews the role of CAs in physiology of mood and mood
regulation. Next, studies that have investigated CA abnormalities in BD, using
different methodological paradigms, are reviewed. The interaction of CAs with
other neuromodulators is discussed, and a model for the role of CAs in mood
regulation is presented. Finally, methodological difﬁculties in conducting research
in the pathophysiology of BD and future directions of research in this area are
discussed.
33

NEUROCHEMISTRY AND NEUROPHYSIOLOGY OF
CATECHOLAMINE
Neurochemistry and Neurophysiology of the Dopaminergic System
Dopaminergic cell bodies located in the ventral mesencephalon form most dopamine
(DA) cell bodies and project widely throughout the central nervous system (CNS).
These cell bodies give rise to the nigrostriatal, mesocortical, and mesolimbic DA pro-
jections. A separate set of dopaminergic cell bodies projecting to the hypothalamus
and pituitary arise from a different brain region—the arcuate nucleus—and are
referred to as the tuberoinfundibular (TIDA) and tuberohypophysial neurons (2).
The arcuate nucleus receives input from cortical regions and is involved in
production of hormones such as growth hormone (GH) and prolactin in response to
different mood states.
Dopamine receptors have traditionally been divided into D1 and D2 types
based on the presence and absence of a positive coupling between receptors and

adenylate cyclase activity. D1 receptors mediate the dopamine-stimulated increase
in adenylate cyclase activity. D2 receptors are thought to mediate effects that are
independent of D1-mediated effects and also to exert an opposing inﬂuence on
adenylate cyclase activity (3). Recently, a number of subtypes of these receptors
have been discovered that are of particular importance to the study of psychiatric
disorders. D3 receptors, a subtype of D2 receptors, and D5 receptors, a subtype
of D1 receptors, are present in high levels in the limbic brain structures. The D4
receptor, a subtype of D2 receptor that has high levels in the frontal cortex,
midbrain, amygdala, medulla, and lower levels in the basal ganglia, has been
implicated in the action of clozapine, which reverses both the negative and positive

symptoms of schizophrenia (4). Self et al. (5) have described opposite modulation of
reward behavior by D1 and D2 receptors agonists. D1 receptor agonists decrease
the reinforcement of reward-seeking behavior, whereas D2 receptor agonists
increase reinforcement of reward-seeking behavior (5). It can be postulated that
the state of anhedonia seen in depression could be a manifestation of either increase
in activity of the D1 receptors and /or a decrease in activity at the D2 receptor site
and opposite changes could lead to mania.
Role of Dopamine in Reward Mechanisms
Dopamine has been implicated in the neurochemical mechanisms involved in
reward behavior. Schultz (6) has reported that DA neurons in the ventral tegmen-
tal area (VTA) and substantia nigra are preferentially activated in response to a

novel rewarding stimulus and encode for reward predictability. Wainer (7), in a
series of studies, reported that anhedonia seen in an animal model of depression
is related to dopamine receptor subsensitivity that is reversed by a variety of
antidepressant drugs. Furthermore, the reward potential of a number of addict-
ing drugs such as cocaine and opiates seem to be mediated via the mesolimbic
dopamine pathways involving the nucleus accumbens (3). Alteration in
reward-related behavior has been thought to be central to the pathophysiology
of BD (8,9). Mesocortical and mesolimbic dopaminergic pathways have been
shown to be involved in reward-related behavior. Manic behavior is frequently
associated with reward-seeking behavior and depression with withdrawal and

inability to derive pleasure from a rewarding stimulus (anhedonia). Therefore,
it is likely that abnormalities of mesocorticolimbic dopamine system may be
present in BD.34 Garakani et al.

NEUROCHEMISTRY OF THE NORADRENERGIC SYSTEM
The major noradrenergic (NA) nucleus in the brain is the locus coeruleus (LC),
which is located on the ﬂoor of the fourth ventricle in the rostra /pons (10). NA
neurons give rise to diffuse axonal projections and innervate virtually all areas of
the brain and spinal cord. The mammalian brain also contains smaller collections
of additional NA neurons and adrenergic neurons that are located in discrete
regions of the pons and medulla. These neurons show more restricted patterns of
axonal projections. The NA cell bodies exert inﬂuence on the brain and the body.
Therefore, they are involved in both modulating brain function and producing
the body’s response to emotions.
The NA cell bodies projecting to other brain regions seem to exert a modula-
tory effect on the target site. Not all NA-containing nerve terminals in the cortex
make synaptic contact with the local cortical neurons; rather, some of these

neurons release NA in a manner similar to that through which hormones are
secreted and thus have generalized effects on the CNS regions (11). The LC is
also very sensitive to both external environmental stimuli and also changes in the
body’s internal homeostasis. The LC output is involved in ﬂight-and-ﬁght
responses and regulates level of arousal, the responses of the sympathetic
nervous system including pulse rate and blood pressure, and the signaling of the
danger signal of the organism.
LC neurons receive a number of inputs that provide information about
the state of the body’s external and internal environment. These inputs include
other neurotransmitter systems, for example, the serotonin [5-hydroxytryptamine
(5-HT)], opioid, gamma aminobutyric acid (GABA), acetylcholine (ACh),

dopamine, and glutamate systems. A number of peptides inﬂuence the ﬁring
rate of the LC neurons, most notable bein g the corticotropin-releasing hormone
(CRH). Finally, the NA system itself provides negative feedback to the LC
neurons (10,12). The synthetic pathway for CA involves a series of enzymatic
reactions. Tyrosine hydroxylase is the rate-limiting enzyme for the synthesis of
both norepinephrine (NE) and DA. Dopamine 3-hydroxylase, which converts
DA to NE, is present only in NA neurons. In adrenergic neurons, the enzyme
phenylethanolamine-N methyl transferase converts NE to epinephrine.
Adrenergic receptors have been classiﬁed as being either a-o rb-adrenergic
subtype. Each of these subtypes has two secondary subtypes, ( aland a2;b1and
b2). Each of these receptors has been cloned (4). Variant forms of these receptors

may exist with different regional distributions and functional properties.
Activation of the b-adrenergic receptors leads to physiological responses by stimu-
lating adenylate cyclase via coupling with G sprotein (13). Activation of the
al-adrenergic receptors leads to physiological responses through activation of G x
proteins (13). Activation of a2-adrenergic receptors leads to physiological responses
via coupling with G iand or G oproteins, which leads to activation of speciﬁc Kþ
channel and /or inhibition of adenylate cyclase (13). There are also a2-adrenorecep-
tors present on 5HT neuron terminals in the hippocampus, and electrophysiological
studies suggest that they exert a tonic inhibitory inﬂuence on the ﬁring of 5HT
neurons (14).
Role of Norepinephrine in Reward Mechanisms

As noted earlier, abnormalities in reward mechanisms are likely to be present in BD.
DA function has been implicated in maintenance of reinforcing properties of aAbnormalities in Catecholamines 35

rewarding stimulus. The role of NE in reward mechanisms is less clearly
understood. However, considering its role in attention and arousal, NE may be
involved in the initial phase of learning by increasing attention on the rewarding
stimulus (15), Increased LC ﬁring has been reported with exposure to a rewarding
stimulus (15). Furthermore, LC ﬁring has been shown to modulate the ﬁring of DA
neurons (16). In mania, increased NE neurotransmission may be responsible for
increased attention to rewarding stimuli, and in depression a decrease in NE
may lead to lack of attention or interest in rewarding stimuli (8,9).
CATECHOLAMINE AND MOOD
Mood and Mood Regulation
Our understanding of what constitutes emotion or mood has changed with
changing sociocultural views about emotions and with scientiﬁc progress in the
investigation of neural substrate of emotions. A century ago, William James (17)
postulated that emotions arose from bodily reactions to stimuli, such as changes

in the autonomic and motor system led to changes in heart rate, blood pressure,
increased or decreased bodily secretions, and changes in motor activity, which
was then perceived as an emotion. Selye’s (18) discovery of the stress response
highlighted the role of hormones, particularly stress hormones such as cortisol, in
the regulation of emotion. Until recently, the neural substrate of mood and
emotion was thought to be conﬁned to the older part of the brain, the so-called
emotional brain or the limbic circuit (19,20). Papez (20) described a circuit in the
brain, which he called the emotional brain, and postulated that changes in this
primitive part of the brain were responsible for changes in emotions. Recent
advances in neuroimaging and neurophysiology have brought to our attention

the role of cognition and neocortical function in the formulation and regulation
of mood. Damasio (21) postulated that emotions, instead of just a function of
primitive aspects of the brain, are more accurately conceptualized as arising from
interactive effects of the functioning of neocortex, limbic system, basal ganglia,
brain-stem autonomic nuclei, and bodily responses such as changes in blood
pressure and pulse rate.
Reciprocal links between the corpus striatum and the cerebral cortex have
been shown to be involved in the production of movements and more recently
have been implicated in the production of normal thought processes (22,23). The
basal ganglia plays a central role in regulation of the motor and cognitive
circuits. Recently, it has been proposed that a parallel medial prefrontal cortex–

striatum–palladium–thalamic circuit is responsible for mood regulation (24–29).
Such a hypothetical mood-regulating circuit (MRC) (30) is depicted in Figure 1.
Within this circuit the principal neurotransmitters for fast conductance ( ,1 msec)
(31) are glutamate (e.g., cortical–subcortical connections) (32) and GABA
(e.g., striatopallidial and pallidothalamic) (29,32). The double inhibition mediated
through GABA between the striatopallidial and pallidothalamic links can confer
an oscillating property to the activity of this circuit (29). The different states that
this circuit oscillates through can be conceptualized as varying mood states. The
fast-conductance feedback loops within this circuit can stabilize mood within
certain limits and prevent extreme changes in mood. However, feedback loop

circuits of this type have the disadvantage of uncontrollable oscillations when
any part of the circuit is damaged (33). Similarly, abnormalities in external
modulators could change the oscillatory properties of the circuit.36 Garakani et al.

Catecholamines as Modulators of the Mood-Regulating Circuit
A number of modulatory neurotransmitters modulate the fast-conductance neuro-
transmission mediated via glutamate and GABA (30,34) by acting on signal
transduction factors and change in neuronal excitability. The striatum plays an inte-
gral role in modulation of cortical outputs in the motor system and is postulated to
do the same for thought and emotions (22,23,29). The principal modulatory
neurotransmitter within the striatum is dopamine, which may act directly via G
protein-coupled receptors or indirectly via control of neuropeptide expression
(35). Mesostriatal dopamine projections from the midbrain provide the dopamin-
ergic modulation of the MRC in response to external rewards (6).
Diffuse projections from the LC also modulate the activity of the MRC.
NE neurons project more diffusely to the brain. NE has been shown to decrease
the signal-to-noise ratio for ﬁring of neurons (7). Adrenergic input can modulate

neuronal excitability through its actions on such signal transduction mechanisms
as the cAMP system or G proteins (34,36).
Additional modulation is provided by other neurotransmitters such as 5HT,
ACh, neuropeptides, and hormones. The activity of the MRC may also be regulated
by intracellular factors such as internal variations in signal transduction factors and
genomic factors. The central role of CAs in mood regulation is illustrated by mood
changes seen in a number of neuropsychiatric illnesses involving CA dysfunction.
Parkinson’s disease, which involves degeneration of DA neurons, is frequently
associated with depression. Patients with both BD and Parkinson’s disease have
been noted to have increased motor symptoms when depressed and decreased
symptoms during manic states, suggesting increased DA neurotransmission

during mania and decreased transmission in depression. Folstein et al. noted that
FIGURE 1 Relationship of catecholamine tracts originating from the midbrain to the MRS.
Abbreviations : DA, dopamine; GABA, gamma aminobatyric acid; NE, norepinephrine.Abnormalities in Catecholamines 37

Huntington’s disease, an autosomal dominant illness associated with DA neuronal
atrophy in the caudate and putamen region, is frequently accompanied by
depression (40% comorbidity) and mania (10% comorbidity). Familial calciﬁcation
of basal ganglia (Fahr’s disease) and striatal infarcts are also accompanied by
depression and mania (37). Together, these observations suggest that dopamine
abnormalities that are central to the motor abnormalities seen in these neuro-
psychiatric illnesses may also lead to dysregulation of the MRC. For example,
Swerdlow and Koob (29) have drawn a parallel between dyskinesias seen in
movement disorder associated with DA abnormalities and mood dysregulation
seen in BD.
The kindling and sensitization model proposed by Post and Weiss (38) draws
an analogy between seemingly increased incidence of mood episodes seen during
the natural course of BD and the increasing ability of a repeatedly administered

electrical or chemical stimulus to induce a seizure or changes in motor behavior.
There are some indications that CAs may be involved in this phenomenon
because kindled seizures are abolished by monoamine depletion with reserpine
(39) and administration of haloperidol. As discussed earlier, the neuromodulatory
properties of CAs can alter excitability of neurons; therefore, repeated release of
CAs may contribute to the kindling phenomena by altering signal transduction
mechanisms. Phasically applied DA has been shown to potentiate corticostriatal
neurotransmission and alter striatal neuronal plasticity (6,40). Recently, Antelman
et al. (1) reported a cycling animal model for BD. Repeated exposures to cocaine
led to cyclicity of amphetamine-induced efﬂux of dopamine from slices of rat

nucleus accumbens that was prevented by lithium treatment.
Catecholamines as Translators of Activity of MRC into the Body’s
Emotional Response
Changes in activity of the MRC are translated into bodily changes by the output of
the MRC directed at the hypothalamus, leading to neuroendocrinological changes
(e.g., through TIDA DA projections), actions on the parasympathetic and sympath-
etic (mediated through NE) nuclei in the brainstem, and actions on the motor circuit
(DA mediated). Activity of the sympathetic nervous system is mediated by
production of NE and epinephrine from the adrenal gland and nerve endings.
Increase in CM and their metabolites in serum, urine, and cerebrospinal ﬂuid
(CSF) frequently accompany increased arousal and activity. Therefore, besides reg-

ulating mood, CAs are also the product of any changes in mood arising from dys-
function of the MRC. Biochemical changes in the CA system, particularly in the
periphery, are therefore dependent on the mood state and are not necessarily
indicative of etiology of the change in mood state. A review of abnormalities of
CAs in BD is best done keeping in mind these two separate components of the
CA system.
ABNORMALITIES OF THE CATECHOLAMINE SYSTEM IN
BIPOLAR DISORDER
“This hypothesis, which has been designated the ‘catecholamine hypothesis of
affective disorders,’ proposes that some, if not all, depressions are associated with
an absolute or relative deﬁciency of catecholamines, particularly norepinephrine,38 Garakani et al.

at functionally important receptor sites in the brain. Elation conversely may be
associated with an excess of such amines” (41).
The biogenic amine, or catecholamine, hypothesis was ﬁrst described in the
literature, concurrently by Schildkraut (41) and Bunney and Davis (42). It was
noted that depletion in levels of norepinephrine and its metabolites, which could
be induced by antihypertensive agents such as reserpine, caused a depressive
state. Likewise, monoamine oxidase inhibitors, such as the antituberculosis
agent iproniazid, which blocked the enzyme responsible for the deactivation of
norepinephrine, were shown to have antidepressant properties. Imipramine,
initially developed for the treatment of schizophrenia, was also found to have
antidepressant properties, by blocking the reuptake of norepinephrine.
Shortly after, researchers focused on the contribution of other neurotransmit-
ters on the pathophysiology of BD. Mania was conceptualized as a state in which

there is an excess of the catecholamines while in depression there is a decrease in
CAs (43)—the so-called second generation CA hypothesis. Another hypothesis
incorporated the role of serotonin in CA dysfunctions—the permissive hypothesis
that stated that both mania and depression may be associated with decreased
serotonin function. Both Coppen (44) and Lapin (45) proposed an indoleamine
hypothesis, stating that decreased levels of serotonin contribute to depressive
illness. Prange and others (46) expounded on this idea by proposing the permissive
hypothesis of biogenic amines, which states that catecholamine activity is mediated
by a deﬁciency of serotonin transmission. Thus, in the context of decreased seroto-
nin, an increase in CA produces a manic state, while decrease in CA produces a
depressive state.

Abnormalities in Serum, Urine, and CSF Levels of Catecholamines
and Their Tetabolites
The original CA hypothesis of depression (41,42) postulated that depression was
caused by a decrease in the amount of CA production and mania was due to
a compensatory increase in CA production. Consequently, much of the earlier
studies of the pathophysiology of BD were directed toward measuring CAs and
their metabolites in bodily ﬂuids. The results of these studies shed only limited
light on the pathophysiology of BD because many of these studies did not give con-
sistent results and because it is difﬁcult to determine the relative contribution of
peripheral versus central origin of plasma and urinary CA metabolites homo-
vanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) levels. CSF

HVA levels are also considerably inﬂuenced by plasma levels and the brain (47),
and many studies did not make a correction for plasma levels while reporting
CSF levels of CAs and their metabolites. Furthermore, most CSF dopamine
metabolites are derived from the nigrostriatal pathways and do not necessarily
reﬂect the function of the mesocorticolimbic (MCL) system (7). Finally, it is difﬁcult
to completely tease out state-related confounds. As peripheral MHPG, HVA, NE,
and epinephrine levels are considerably inﬂuenced by motor activity and degree
of arousal, changes in these measures in mania and depression are more likely to
be a state-related rather than a trait abnormality.
Abnormalities in Norepinephrine and Its Metabolites
No consistent relationship has been found in levels of MHPG in the CSF, serum, or

urine in studies of depressed patients (48). Schatzberg et al. (49) reported thatAbnormalities in Catecholamines 39

bipolar depressed patients had signiﬁcantly lower urinary MHPG levels than
unipolar nonendogenous depressed patients. Similar results were obtained for
plasma NE and MHPG levels. Some recent studies have supported this ﬁnding,
whereas others have not. Negative ﬁndings were reported from the Depression
Collaborative studies (50) and in a Swedish study (51). According to Schatzberg
and Schildkraut (52), the negative ﬁndings of these studies could be due to the
inclusion of more bipolar II patients than bipolar I patients. Other studies have
used more complex measures of CA levels in an effort to ﬁnd a relationship with
the state of depression or to differentiate between different types of depression.
Ratio of NE and epinephrine to their metabolites, total body CA turnover, ratio
of NE to NE plus metabolites, and epinephrine to epinephrine plus metabolites
and discriminant functional analysis of 24-hour urinary CAs and metabolites

[depression (D)-type scores] have been studied. These studies showed that unipolar
depressed subjects have a higher excretion of CA than bipolar depressed subjects
and control subjects (53). These measures may be useful in differentiating
unipolar from bipolar depression; however, the signiﬁcance of these ﬁndings for
the pathophysiology of BD is not clear.
Dopamine Abnormalities
A number of studies of turnover of dopamine (analogous to studies of NE and its
metabolites) and its metabolites have been carried out. CSF levels of the major
dopamine metabolite HVA have been consistently found to be decreased in
depression associated with psychomotor retardation but not in agitated depression
and are increased in mania (54). Therefore, reduced CSF HVA is thought to be
related more to the symptom of psychomotor retardation than to depressed

mood (7). A decrease in prolactin levels in seasonal affective disorder has been
reported and was seen in both unipolar and bipolar patients throughout the year
irrespective of depressive symptoms (9,55). The decreased prolactin level has
been proposed as a trait abnormality that could be secondary to increased DA
receptor sensitivity secondary to decreases in DA levels in bipolar depression.
CHALLENGE STUDIES
Depletion Studies
Effects of acute depletion of CA using alphamethylparatyrosine (AMPT), a tyrosine
hydroxylase inhibitor, have been studied in patients with depression and in healthy
subjects. In healthy subjects, chronic administration of AMPT does not cause depress-
ive symptoms (56). In bipolar depressed patients, AMPT has been noted to increase
depression and in manic subjects it can decrease the severity of mania (57). Berman

et al. (58) reported an increase in depressive symptoms after AMPT-induced CA
depletion in euthymic subjects with a remote history of unipolar depression.
Anand et al. (59) reported on the effects of CA depletion in euthymic bipolar
subjects stable on lithium therapy. AMPT administration in these subjects did not
lead to relapse of depressive symptoms. However, 36 to 48 hours after depletion
was completed and the subjects were recovering from the depletion with return
of plasma MA and MHPG levels back to baseline, subjects had a transient
relapse of hypomanic symptoms. This relapse of hypomanic symptoms was not
accompanied by increase in plasma HVA and MHPG levels from baseline. It was
hypothesized that the relapse of hypomanic symptoms could have been due to

either an increase in receptor sensitivity or increased central production or
release of CAs that was not detected in plasma.40 Garakani et al.

Stimulation Studies
CA-releasing agents such as amphetamine have been used to increase CA levels in
the brain. Though several studies have shown increased arousal and activation
after amphetamine injection in bipolar subjects and even nonbipolar subjects,
sustained mania has not been consistently recorded (60,61,62). The psycho-
stimulant effect of amphetamines is blocked by dopamine antagonists (63,64).
McTavish et al. (65) used a methamphetamine challenge in acutely manic and
healthy control subjects who four hours earlier had received a tyrosine-free
amino acid mixture, in a double-blind crossover with a control mixture. The
tyrosine depletion caused a lowering of the physiological and psychological
responses to methamphetamine.
The observation that of all pharmacological challenges, L-dopa is most likely
to induce mania lends support to the CA hypothesis for mania. Similarly, direct DA
agonists such as bromocriptine and piribedil can relieve bipolar depression and

even precipitate mania (66), and the antidepressant response to piribedil has
been associated with low pretreatment levels of HVA in the CSF (67). Cocaine, a
potent inhibitor of dopamine transporter (DAT), can cause mania-like symptoms
in healthy control subjects and precipitate mania in bipolar subjects. There has
been one report of precipitation of manic symptoms with administration of
yohimbine, an a2-adrenergic presynaptic autoreceptor antagonist (68). There are
also two case reports of secondary mania caused by caffeine (69,70).
Neuroendocrine Challenge Studies of Catecholamine Receptor
Function in Bipolar Disorder
Neuroendocrine challenge studies measure plasma levels of hormones after a chal-
lenge with a drug that acts on a particular receptor. Most of these studies have been

done in depression, but no consistent abnormalities have emerged. Similarly, in BD
no consistent results have been found in DA systems using this method. The neuro-
endocrine challenge paradigm has a number of limitations: it is difﬁcult to ﬁnd
agents that are speciﬁc to only a particular receptor subtype because in many
cases the challenge paradigm cannot differentiate between pre- and postsynaptic
effects of the challenging agent (71), and the evidence for receptor sensitivity is
indirect and is inﬂuenced by a number of intervening variables. Some of these limit-
ations can be circumvented by using agents that are more speciﬁc and by combining
challenge studies with brain imaging studies in which the changes in brain events
can be measured directly.
Dopamine Receptor Abnormalities

Meltzer et al. (72) and Hirschowitz et al. (73) did not ﬁnd an increased GH response to
apomorphine (a postsynaptic D2 receptor stimulator) in manic subjects. McPherson
et al. (74) also failed to show a GH or prolactin change in response to apomorphine in
bipolar or unipolar depression. Linkowski et al. (75) and Nurnberger et al. (64) were
unable to differentiate manic subjects from other diagnostic groups on hormonal
responses to L-dopa and amphetamine.
Neuroendocrine Receptor Abnormalities
The GH response to clonidine that has been shown to be mediated through postsyn-
aptic a2receptors (76) has been used in a number of studies. A blunted
GH response to clonidine was shown to be present in depression (77), and a numberAbnormalities in Catecholamines 41

of studies have replicated this ﬁnding. However, Ansseau et al. (78) did not ﬁnd any
differences between manic and depressed subjects on GH response to clonidine. More-
over, GH response to the dopamine antagonist apomorphine (79), amphetamines
blockade of NA and DA uptake (80), and the serotonin agonist m-Chlorophenylpiper-
azine ( mCPP) (81) has also been found to be reduced. GH release is also mediated
by somatomedins and somatostatin, which have been reported to be altered in
depressed patients (61,82). Therefore, it is possible that an abnormality intrinsic to
GH release may be present in affective disorders. More studies in drug-free bipolar
depressed subjects are needed to elucidate the cause of the blunted response in
depressed subjects (76).
In summary, no consistent change in a particular CA receptor type is seen
in BD. Methodological issues, particularly the lack of ideal animal models of BD
and the limitations of the neuroendocrine challenge paradigm, make it difﬁcult to

draw ﬁrm conclusions from studies done so far. Brain imaging studies offer some
promise in the measurement of the DA and the 5T system. However, radioligands
for the adrenergic system have not been used often in clinical studies.
MECHANISM OF ACTION OF PHARMACOLOGICAL AGENTS USED
IN THE TREATMENT OF BIPOLAR DISORDER
The biochemical effects of medication used in the treatment of BD have been used
to elucidate the role of CAs in the pathophysiology of BD.
Medication Effects on the Dopamine System
A number of effective antimanic agents act on the dopamine system. Neuroleptics
such as haloperidol, which are D2 receptor antagonists, are one of the most effective
antimanic agents, lending support to the hypothesis of increased DA neurotrans-
mission in mania. Lithium and sodium valproate have both been shown to decrease

postsynaptic D2 receptor sensitivity. Waldmeier (83) reviewed the mechanism of
action of drugs useful in the treatment of BD and concluded that downregulation
of DA neurotransmission seemed to be a common property of medications useful
in the treatment of BD.
Willner (7) recently proposed the hypothesis that even selective serotonin
reuptake inhibitors (SSRIs) and tricyclic antidepressants improve depression by
increasing the sensitization of D2 /D3 receptors in the MCL dopamine system.
The MCL dopamine system is primarily responsible for reward reinforcement
and experience of pleasure. Using the paradigm of locomotor response to
amphetamine or apomorphine as a measure of DA receptor function, Willner (7)
showed that most antidepressants increase the psychomotor stimulant response

to dopamine agonists. This response is primarily mediated through the MCL DA
system, and behavioral stereotypes mediated through the mesostriatal system
and neuroendocrine responses mediated through the TIDA DA system are not
affected. The effects of chronically administered tricyclic antidepressants are
reversed by administration of the DA antagonist sulpiride in the nucleus
accumbens but not in the dorsal striatum (84).
Medication Effects on the Neuroendocrine System
O¨zerdem et al. (85) demonstrated lithium administration (after 5 days and 4 weeks)
in healthy volunteers produces increased plasma NE and increased response to42 Garakani et al.

idazoxan, an a2-adrenoreceptor antagonist. Antimanic effects of lithium have been
shown to be accompanied by decreases in plasma and urinary MHPG levels (86).
Clonidine, an a2-agonist that decreases presynaptic NE release, has been reported
to have some antimanic activity (87,88). Nearly all antidepressants have been impli-
cated in precipitation of mania when used for the treatment of bipolar depression.
However, tricyclic antidepressants that predominantly decrease NE reuptake
have been identiﬁed as most likely to precipitate mania or increase cycling (89).
Paradoxically, bupropion, a dopamine reuptake inhibitor, is thought to be an anti-
depressant least likely to precipitate mania.
Catecholamine Studies in Peripheral Tissue
Due to the inaccessibility of the brain cells themselves, investigators have studied
biochemistry in blood cells for general abnormalities that may be common
to both blood cells and to neurons. In this regard, platelet studies have been con-

ducted because platelets have a number of important similarities with neurons.
However, the relationship of biochemical abnormalities in peripheral tissue to
that in the CNS is not clear.
Enzyme Studies
Enzymes responsible for production and degradation of CA are also present in
platelets. Platelet dopamine b-hydroxylase (DBH), the enzyme that converts DA
and NE, has been found to be lower in bipolar depressed subjects compared with
unipolar subjects (90–93). The lower levels of DBH in bipolar subjects compared
with unipolar subjects have been found most in subjects with a family history of
affective illness (94). Ikeda et al. (95) reported higher DBH levels in the manic
phase compared with the depressed phase. The value of platelet DBH levels
for the diagnosis of BD is limited by a large variation between individuals that

precludes accurate statistical evaluation.
Monoamine oxidase (MAO) deaminates both DA and NE to their inactive
metabolites. MAO is of two types: MAO-A is found predominantly in neurons
and metabolizes both DA and NE, whereas MAO-B is found in platelets and metab-
olizes DA. Therefore, the interpretation of changes in platelets for changes in
neurons is questionable. MAO levels have been found to be lower than controls
in bipolar I depressed subjects, but this difference is not found in bipolar II
depressed subjects and unipolar depressed subjects (96).
Catechol-o-methyltransferase (COMT) is an extraneuronal enzyme that
degrades NE. It is also found in red blood cell membranes and is under genetic
control. In one study, this enzyme was found to be lower in bipolar depressed sub-

jects compared with unipolar subjects (97), but this ﬁnding has not been replicated
(98). Two interesting studies of velo-cardio-facial syndrome (22q11.2 deletion syn-
drome or DiGeorge syndrome) show that patients have a deletion of an allele
that results in low activity of COMT, and causes a rapid cycling BD (99). Graf
and colleagues (100) treated three of four patients with metyrosine, which
was given to reduce CA levels, and did in fact lower the baseline levels of CSF
HVA, and improve their aggression and behavioral symptoms. A larger study of
COMT is needed to clarify these ﬁndings.
Receptor Studies
Platelets and leukocytes have been most frequently used for peripheral
tissue receptor studies. Decreased prostaglandin E stimulation of platelet a2Abnormalities in Catecholamines 43

receptor-mediated cAMP production has been reported in unipolar depression
(101). Garcia-Sevilla et al. (102) investigated the a2-adrenergic receptor-mediated
inhibition of platelet adenylate cyclase and induction of platelet aggregation.
They found a hypersensitivity to a2-adrenergic receptor agonists in drug-free
depressed patients that was decreased after long-term antidepressant treatment
(102). Platelet a2receptor number measurement has revealed an increase in
some studies, but no change has been found in other studies (103). Results of
studies of peripheral a2-adrenergic receptors have also been contradictory (104).
a2-Adrenergic receptor studies for bipolar depression patients need to be
conducted.
b-Adrenergic receptors have been studied on human leukocytes. Though no
studies have investigated the bipolar group separately, a decreased cAMP response
tob-adrenergic receptors seems to be predominantly found in unipolar depressed

subjects (105). Wright et al. (106) reported decreased b-adrenergic receptors in
bipolar subjects and their ill relatives, a ﬁnding that has not been replicated
(107,108).
Signal Transduction Mechanisms
Manji and Lenox (109) reported an increase in leukocyte membranes of immuno-
labeling of the 45-kDa form of G a,s, in bipolar affective disorder group considered
as a whole (lithium-treated or untreated) compared with control subjects. It has
been shown that lithium competitively inhibits the phosphatidylinositol second
messenger signal transduction pathway (110–112). Manji et al. (113) reported
effects of lithium and sodium valproate on the protein kinase C (third messenger)
pathway, and the protein kinase C inhibitor tamoxifen has been shown to have
some antimanic efﬁcacy. Both lithium and sodium valproate also seem to have

genomic effects (113,114). Freidman et al. (115) reported altered protein kinase C
activity during the manic phase of BD. Recently, Kaya and colleagues found that
in bipolar patients, lithium, thought to inhibit inositol monophosphatase (IMPase),
does in fact increase erythrocyte IMPase activity with prolonged use (116).
POSTMORTEM STUDIES IN BIPOLAR DISORDER
Postmortem studies can directly assess brain neurotransmitters and their receptor
systems. Though numerous postmortem studies have investigated the role of
DA receptors in schizophrenia, few or none have examined DA receptors
in autopsy specimens from patients with BD. A more detailed discussion of
postmortem studies can be found in Chapter 8. Young et al. (117–120) in a series
of studies reported abnormalities in CA and signal transduction mechanisms in

BD. Young et al. (117) reported an elevation of G sasubunit in prefrontal cortex in
BD subjects; increased forskolin-stimulated cyclic AMP production in prefrontal,
occipital, and temporal cortex; but no increase in GTP-induced CAMP production
(118). Young et al. (119) did not ﬁnd any differences between bipolar subjects and
control subjects on basal levels of NE or DA but did ﬁnd an increased MHPG /
NE ratio in BD subjects. Young et al. (120) did not report any differences in brecep-
tor binding in any part of the brain in BD subjects and did not ﬁnd any change in
Gsasubunit. Rahman et al. (121) reported a decrease in cytosolic cAMP-dependent
phosphokinase levels that could be secondary to increased AMP signaling in BD
subjects. Freidman and Wang (122) reported that in bipolar brain membrane44 Garakani et al.

there is enhanced receptor–G protein coupling and an increase in the trimeric state
of the G proteins and concluded that these changes may contribute to produce exag-
gerated transmembrane signaling and to the alterations in affect that characterize
bipolar affective disorder. Wang and Freidman (123) also reported an increase in
phosphokinase C activity in postmortem brains of bipolar subjects. Recently,
Dean and others (124) measured zolpidem-insensitive and zolpidem-sensitive
(3H) ﬂumazenil binding in the hippocampus of postmortem patients with schizo-
phrenia and BD. They found an increase in zolpidem-insensitive binding,
suggesting an increase in GABA receptors containing the a5 subunit, which may
be related to cognitive symptoms seen in BD.
Postmortem studies point to a possible increased CA turnover and abnormal
postsynaptic signal transduction mechanisms. However, postmortem studies have
several limitations: dynamic changes in CA cannot be measured, the affective state

of the subject at the time of death cannot be controlled, frequently the medication
status of the subjects is also not known, and cause of death can affect results.
Obtaining a more homogenous sample of postmortem brains in regard to cause of
death, documentation of medication status before death, and clinical diagnosis at
the time of death can circumvent these difﬁculties. Setting up brain banks and con-
sortiums (e.g., the Stanley Foundation Brain Consortium) can help researchers
with access to a larger number of brain samples.
BRAIN IMAGING OF CATECHOLAMINE SYSTEM IN
Recent advances in brain imaging have opened new ways to directly measure
neurotransmitter receptor function in vivo. Compared with the number of
studies done in schizophrenia and depression, fewer brain-imaging studies have

been conducted in BD. Brain imaging studies are reviewed in detail in Chapter 9.
A short discussion is presented here of brain imaging studies that have direct
relevance to the role of CAs in BD.
Structural Brain Imaging Studies
These studies in BD have suggested the following abnormalities may be present:
increased rates of subcortical white matter and periventricular hyperintensities in
elderly and nonelderly patients (125,126), increased third and lateral ventricular
measures (127,128), and smaller cerebellar measures (129,130). There is also equiv-
ocal evidence of temporal lobe abnormalities (131). Several studies support the
ﬁnding of enlargement of the amygdala (132,133). Some studies have shown an
increased hippocampus volume (134) and increased caudate volumes in bipolar

subjects (126), a ﬁnding different from unipolar depression in which a decreased
hippocampal volume and decreased size of the caudate have been reported
(135,136). Drevets et al. (28) reported a structural defect in the subgenual prefrontal
cortex in subjects with familial depression (unipolar and bipolar depressed), a
ﬁnding that has been replicated (137).
Blood Flow Studies
Cerebral blood ﬂow studies have provided evidence for functional abnormalities in
structures in the MRC in BD. Work by Al Mousawi et al. (138) reported lower blood
ﬂow in the frontal lobe compared with the occipital lobe in BD. Gyulai et al. (139)Abnormalities in Catecholamines 45

reported asymmetries in anterior temporal lobes in both bipolar mania and
depression. Migliorelli et al. (140) reported reduced blood ﬂow in right basotemporal
cortex, whereas O’Connell et al. (141) reported increased activity in the temporal
lobes in manic subjects. Drevets et al. (28) reported decreased blood ﬂow in the pre-
frontal subgenual cortex in depressed BD subjects and increased ﬂow in mania.
Together the structural and functional studies of BD tend to point to abnorm-
alities in the prefrontal-striatal-thalamic-hippocampal area that may be abnormal in
BD. As discussed earlier, CAs, and in particular DA, are principal modulators of
this circuit.
Neurochemical Studies
PET, SPECT, and magnetic resonance spectroscopy studies explore the neurochemical
abnormalities that may underlie the structural and blood ﬂow abnormalities in BD.
Again, compared with a number of studies done in schizophrenia and depression,

very few neurochemical studies have been done in BD. PET studies of DA receptors
have shown an elevation of striatal D2 receptor numbers in psychotic mania but not
in nonpsychotic mania (142–145). In these studies, psychotic manic subjects were
more similar to schizophrenic subjects and non-psychotic manic subjects were more
similar to healthy control subjects on measures of D2 receptor binding. In another
study that did not make a distinction between unipolar and bipolardepressed subjects,
D’haenen and Bossuyt (146) reported bilateral increase in D2 receptors in the basal
ganglia. It is difﬁcult to reconcile the ﬁndings of these studies unless increased D2
receptor numbers is a trait marker for BP; however, euthymic bipolar subjects were
not studied using these methods.

Anand et al. (147) using single photon emission tomography investigated the
presysnaptic dopamine release in response to an amphetamine challenge in euthy-
mic bipolar patients. Baseline postsynaptic receptor concentration as measured
using the D2 speciﬁc radioligand iodobenzamide [(123I)IBZM] was not different
from healthy subjects. Moreover, presynaptic dopamine released in response to
an amphetamine challenge measured indirectly by the degrees of displacement
of IBZM from baseline was also not different in euthymic bipolar patients and
healthy subjects. However, BD patients had a greater euphoric response to amphet-
amine challenge than healthy subjects. Together, these ﬁndings were consistent
with postsynaptic intracellular signal transduction abnormalities in the CA neuro-
transmission in BD.
A more recent PET study compared [(18)F]6-ﬂuro-L-dopa uptake in manic

patients and healthy controls before and after treatment with divalproex (148).
Before treatment, there is no difference between the two groups, but post-treatment,
[(18)F]DOPA rate constants were signiﬁcantly reduced compared to controls,
indicating that the bipolar patients had lower presynaptic dopamine activity.
Genetic Studies
BD is a psychiatric illness with a strong genetic basis. However, the exact genetic
abnormality is still not known. Chapter 13 details the role of genetic factors in BD,
and here a brief review of genetic studies pertaining to CA abnormalities is pre-
sented. Potential phenotypic abnormalities of the CA system from CA synthesis to
CA signal transduction have been reviewed above. A number of investigators
have tried to ﬁnd a genetic association for these phenotypic abnormalities.

However, no consistent results have emerged.46 Garakani et al.

A number of studies have investigated the association between the tyrosine
hydroxylase (TH, the rate-limiting enzyme in CA synthesis) gene and BD. Though
some investigators have found a possible linkage between the M gene and BD
(149–150), most studies have found no such linkage (151–154). Turecki et al.
(153) conducted a meta-analysis of studies and concluded that there was no
overall association between BD and the TH gene. No linkage has been found
between BD and the DBH or dopa decaxboxylase gene. Some studies show
there is evidence of no genetic or allelic association between BD and the COMT
gene (155), although one study found a link between low-activity COMT and a
female bipolar I proband (156), and Kirov et al. (157) showed that the low activity
allele is common in rapid cycling patients. Lim et al. (158) and Rubinsztein et al.
(159) reported a possible allelic association between BD and the MAO-A enzyme,

whereas Parsian and Todd (160) did not ﬁnd allelic association of BD with either
the MAO-A or MAO-B enzyme. Some investigators reported a possible linkage
between BD and the DAT gene (161,162), whereas others have been unable to
ﬁnd this association (152,163). No association between any of the DA type 2, 3,
or 4 receptor genes and BD has been found (152,163,164), though Parsian and
Todd (160) reported a weak association. There has also been no link found
between the norepinephrine transporter (NET) and BD (165). Furthermore,
ongoing research has suggested a correlation between BD and the GABA-A recep-
torasubunit genes (GABRA), such as GABRA-1 (166), GABRA-3 (167), GABRA-5
(168), although some studies contradict these ﬁndings (169,170). Finally, Ram et al.

(171) did not ﬁnd genetic linkage between BD and the gene coding for the G s,a
subunit protein.
In summary, no convincing linkage between a gene encoding for a particular
aspect of CA function and BD has been found. However, with rapid progress in
genetic molecular biology, more evidence may become available.
MODULATION OF CATECHOLAMINE NEUROTRANSMISSION AND
IMPLICATIONS FOR THE PATHOPHYSIOLOGY
OF BIPOLAR DISORDER
Modulation by Other Neurotransmitters
As discussed earlier, mood regulation can be conceptualized as stable oscillatory
activity of the MRC maintained by fast feedback mechanisms within the circuit
and external modulation by other neuromodulators such as DA, NE, 5HT, ACh,
and neuropeptides. Fluctuations of mood seen in BD can be conceptualized as
breakdown of these feedback and modulatory mechanisms. CAs modulate the

MRC system directly by their effects on MRC fast conductance pathways (mediated
via GABA and glutamate) and in turn are modulated by other neurotransmitters
themselves (e.g., 5HT, ACh, neuropeptides, etc.). Therefore, abnormal modulation
of the CA system by other modulators can lead to abnormalities in MRC. The role of
each of these modulators is described in more detail in other chapters of this book
and here a brief summary of interactions with the CA system is presented.
NE Modulation of DA Neurotransmission
There is a close relationship between NE and DA neurotransmission, NE being
involved in the attention and arousal of the organism and DA involved in the
motivational /reward aspects of a task (6,172). There has been a more detailed

investigation of the effect of NE on the DA system and less so of the effect of DAAbnormalities in Catecholamines 47

on the NE system. It has been suggested that, teleologically speaking, because DA is
the precursor of NE, it seems reasonable that the latter would have evolved as the
more developed system, modulating its antecedent, the more primitive one (54).
However, considering the complementary role of these neurotransmitters, both
have signiﬁcant effect on the other’s function.
Earlier investigations of NE modulation of DA function revealed contradic-
tory ﬁndings. Antelman and Caggiula (173) reported that NE inhibits DA neuro-
transmission, whereas Archer et al. (174) suggested a facilitatory role of NE on
DA-mediated function. More recent evidence points to an excitatory role of NE
on the mesocortical DA system and inhibitory effect of noradrenergic system on
the prefrontal cortical DI receptor-mediated neurotransmission that is accompanied
by an increase in subcortical DA neurotransmission (175). Depletion of both NE and

DA results in greater blunting of GH response to clonidine in rats than depletion
alone (176). Therefore, overall the evidence points to a facilitatory role of NE on
the DA system within the MRC.
5HT Modulation of Catecholamine Neurotransmission
5HT neurons in the raphe nucleus in the brainstem have direct projections to the
striatum, frontal cortex, and the limbic system. Lesions of the 5HT system increase
low-afﬁnity b-adrenergic receptor density (177), and 5HT has been shown to have
an inhibitory effect on the NE system through the presynaptic heteroreceptors (14).
However, other investigators have reported a synergistic role of 5HT and NE
neurotransmissions. Stimulation of postsynaptic 5HT 2receptor has been reported
to increase the response of midbrain NE neurons to sensory stimuli (178). A

number of different types of 5HT and DA receptors have been discovered, and
therefore the interactions between the two systems are likely to be complex.
However, most studies indicate that the 5HT system has an inhibitory effect on
the DA neurotransmission (179–182). The so-called permissive hypothesis of the
role of 5HT in BD postulates that both mania and depression are due to low
levels of 5HT. However, increase in 5HT, for example by treatment with SSRIs,
has been shown to induce mania. Lithium, which has been shown to facilitate
5HT neurotransmission (183), has both antimanic and antidepressant properties.
The mechanism of the differential effect of 5HT on mood is not known at present
and needs to be further investigated. CAs also have a modulatory effect on the

5HT system, but this has been less well investigated. For example, it has been
shown that NA denervation prevents tricyclic antidepressants from causing
sensitization of forebrain neurons to 5HT in laboratory animals (184).
Excitatory Amino Acids Modulation of Catecholamine Neurotransmission
Excitatory amino acids such as glutamate and aspartate act through the N-methyl-
D-aspartate (NMDA) and non-NMDA receptors. They inﬂuence monoamine trans-
mission, including dopamine and NE, and are in turn inﬂuenced by these
catecholamines (185). Chronic, but not acute, administration of noncompetitive
NMDA antagonists is associated with decreased density of b-adrenergic receptors
in mouse cortex (186). Chronic desipramine binding has been shown to increase
total NMDA receptor binding (187).

Most neurotransmission is thought to involve the glutamate system, CAs
modulate glutamate neurotransmission, and DA has a predominantly inhibitory
modulatory effect on glutamate transmission (4,35). However, the glutamate
system itself has been shown to have a modulatory effect on the CA system.48 Garakani et al.

NMDA receptors such as ketamine, phencyclidine, and MK-801 are known to
cause increased subcortical DA neurotransmission (188). This effect is frequently
associated with increased motor activity, mood elevations, and cognitive
dysfunction—symptoms similar to those seen in mania. Furthermore, medications
such as lamotrigine, which decrease glutamate release, have been shown to have a
mood-elevating effect (189,190). Cortical glutamate projections to the subcortical
regions have a net inhibitory effect on the subcortical system activity. One mechan-
ism of this inhibitory effect has been postulated by Grace et al. (191), who proposed
that the inhibition occurs by increased tonic DA release that then has an inhibitory
effect on the subcortical system neurons (including DA neurons) by a negative
feedback mechanism. Inhibition of this cortical glutamate projection to the subcor-
tical MRC could lead to increased ﬁring of DA neurons and elevation in mood and

increased inhibition could lead to a depressed state. Anand et al. (189) reported
that decreasing glutamate neurotransmission by administration of the glutamate
release inhibitor lamotrigine leads to increased mood-elevating effects of the
NMDA receptor antagonist ketamine in healthy subjects.
In recent studies, Dager and colleagues (192) found that unmedicated patients
with BD, as compared to healthy controls, had increased levels of Glx (glutamate þ
glutamine þGABA) and lactate in the gray matter, as measured on proton echo-
planar spectroscopic imaging (PEPSI). This may represent a shift in redox states,
from oxidation to glycolysis. Their group also demonstrated that longitudinal
treatment of BD patients, versus controls, with lithium caused a decrease in Glx
concentrations, but not in lactate levels (193).

GABA Modulation of Catecholamine Neurotransmission
GABA is the most prevalent inhibitory neurotransmitter. However, GABA neuro-
transmission can be facilitatory in a circuit with two sequential GABA linkages.
This is the case in the MRC as depicted in Figure 1 in the linkages of the ventral
striatum to the palladium and the connection of the palladium to the thalamus.
Therefore, GABA neurotransmission could either facilitate or inhibit neurotrans-
mission in the MRC. Serum GABA levels have been found to be low in both
depression and mania and euthymic BD. Moreover, many of the mood-stabilizing
agents increase GABA neurotransmission in vitro and also have been shown to
increase CSF and plasma GABA levels (194–196).
Neuropeptide Modulation of Catecholamine Neurotransmission
Neuropeptides such as somatostatin, CRH, substance P, and neuropeptide Y can

alter neurotransmission function by direct action on noradrenergic or DA
neurons. CRH has been shown to acutely increase LC ﬁring rate. However,
effects of chronically elevated CRH as seen in depression (197) on norepinephrine
neurons have not been delineated. Chronic desipramine treatment attenuates the
stress-induced activation of LC neurons mediated by CRH neurotransmission
(195). Desipramine treatment has been shown to reduce CSF–CRH concentration
(198). Neuropeptide Y (NPY) is another peptide that is colocalized with NE (199).
Treatment with norepinephrine uptake inhibitors such as desipramine results in
decreased NPY receptor density that could possibly be a clue to increased NPY
levels (200). Somatostatin, a tetradecapeptide, is rich in the hypothalamus, amyg-

dala, and nucleus accumbens. It is found to be involved in NE and DA neurotrans-
mission (201). Chronic desipramine dosing in rats results in increased binding to
somatostatin receptors in the nucleus accumbens (202). In the striatum, DA andAbnormalities in Catecholamines 49

various neuropeptides interact together to inﬂuence neurotransmission via GABA
and glutamate pathways (32). Depressed patients show decreased CSF concen-
trations of somatostatin (201,203), a nonspeciﬁc ﬁnding because it is also decreased
in a variety of other neuropsychiatric illnesses (201). However, Berrettini et al. (204)
did not ﬁnd any abnormality in a number of neuropeptide levels in the CSF of
euthymic bipolar subjects compared with healthy control subjects.
ACh Modulation of Dopamine Neurotransmission
ACh is a major neurotransmitter with a predominant modulatory action on
synaptic neurotransmission. Its affect on the DA system has been well studied in
relation to the motor system where ACh has been shown to have an inhibitory
effect on DA-mediated function (32). Symptoms of Parkinson’s disease are
thought to arise from an imbalance between the ACh and the DA system. Similarly,
a decreased cholinergic tone is thought to remove the inhibitory effect on the CA

system, leading to mania, and an increased cholinergic tone could lead to
depression. The hypothesis that ACh could be involved in modulation of the CA
system and lead to changes in mood is supported by the observation that
physostigmine (a central cholinesterase inhibitor /cholinergic agonist) can lead to
a switch from mania to depression (205). The ability of lithium to prevent supersen-
sitivity of peripheral and central ACh receptors (as induced by denervation of
atropine) (206) may contribute to its mood-stabilizing properties. Thus, ACh by
its action on the CA system may play a critical role in mood stabilization, an area
that has been understudied and merits further investigation.
Hormonal Modulation of Catecholamines
Hormonal changes frequently accompany emotional changes. CAs themselves

directly regulate the production of a number of hormones such as GH and
prolactin, and these hormones have an inhibitory feedback effect on CA neurotrans-
mission at the level of the hypothalamus. Other hormones can also regulate CA
neurotransmission and thereby modulate mood. Thyroid hormone has a signiﬁcant
effect on the adrenergic system, and alterations in thyroid function have been
implicated in rapid cycling BD and refractory RD. Whybrow and Prange (207) pro-
posed that the ability of thyroid hormone to increase P-adrenergic receptor
sensitivity to norepinephrine may underlie its ability to modulate mood. Steroids
can modulate CA function. Cortisol can lead to increased production of CM in
the periphery and the brain.
Modulation of CA Neurotransmission by Intracellular Factors

In addition to changes at the circuit and synaptic levels, CA neurotransmission may
be altered by changes in intracellular factors such as signal transduction, neuro-
trophic factors, and genetic factors. These effects may alter information processing
or neurotransmitter release by the target neurons in a fashion that alters neural
circuit behavior, and eventually depressive symptoms are alleviated (208). Phasic
intracellular changes in the neurons of the MRC can lead to changes in the activity
of these circuits that can then manifest as changes in mood. These intracellular
changes are described in detail in other sections of this book and here a brief
review of their role in CA neurotransmission is presented.
Wachtel (209) postulated that a dysregulation of neuronal second messen-

ger function is involved in depression. This hypothesis suggests that, in50 Garakani et al.

depression, there is an imbalance of the major second messenger systems in
the CNS resulting from diminished adenylate cyclase pathway activity and
increased phospholipase C pathway activity, and in mania, the reverse occurs.
Since it was discovered that lithium may work by inhibiting signal transduction
mechanisms such as the G proteins and phosphatidylinositol pathways,
extensive research has been done in this area. Lachman and Papolos (210,211)
presented a hypothesis of cyclical changes in G proteins that could lead to cycli-
cal changes in mood. More recently, investigators have started to look at protein
kinase abnormalities (113) that could change CA receptor sensitivity such as DA
receptor sensitivity in BD.
Other intracellular factors have been recently discovered that may have a role
in the pathophysiology of BD and the mechanism of action of antidepressants and
mood stabilizers. In preclinical studies, brain-derived neurotrophic factor (BDNF)

and its receptor trkB have been shown to be increased with electroconvulsive
therapy and BDNF mRNA is increased with chronic administration of several
different classes of antidepressant drugs but not with acute administration of
these drugs and not by administration of nonantidepressant psychotropic drugs
(212). Local infusion of BDNF in the brain has been shown to have antidepressant
effects in two behavioral models of depression, the forced-swim and learned
helplessness paradigms (213,214). Neurotrophins such as BDNF and neurotro-
phin-3 (NT-3) may therefore be targets of long-term antidepressant drugs. Their
putative antidepressant effects may be a result of the ability of neurotrophins to
increase monoaminergic neurotransmission and to increase the survival of

monoamine neurons. In this regard, NT-3 has been shown to be protective to
norepinephrine (NE) neurons (215). Glial cell line-derived neurotrophic factor
(GDNF) has been shown to increase sprouting of adult midbrain DA neurons (216).
Finally, a new area of study is clock genes, genes that encode for biological
rhythms through production of certain proteins at a certain cycle length
(217,218). Keeping in mind the close relationship of BD to biological rhythms,
further study of the relationship of these genes to CA activity may provide clues
to the pathophysiology of BD.
Bipolar and Unipolar Depression
A distinction between bipolar and unipolar depression (depression without history
of hypomania or mania) is often made, and efforts have been made to investigate

biological differences between unipolar and bipolar depression. At the same
time, many studies of neurobiology of depression have not reported results
separately for bipolar and unipolar depression. Though a number of research
studies have looked at this issue, it is not clear whether a distinction between
the two groups can be made in terms of CA abnormalities. Many studies have
reported a decreased excretion of NE and its metabolites in bipolar depression
compared with unipolar depression (52). Other ﬁndings are less well-replicated
[e.g., lower DBH activity (91,92) and reduced platelet MAO activity (96) in
bipolar depression compared with unipolar depression]. Clinical experience
indicates that some depressed subjects have never had hypomania or mania and

do not have a family history of BD. Therefore, investigation of the unipolar
versus bipolar group has the potentia1 for uncovering the nature of abnormality
that makes the bipolar group vulnerable to manic episodes. This area needs
further study.Abnormalities in Catecholamines 51

Bipolar Disorder and Psychotic Illness
BD has a close relationship with psychotic disorder in that both bipolar depression
and mania can be associated with psychotic illness and BD can coexist with schizo-
phrenia-like symptoms (schizoaffective disorder). A common link with CA
abnormality may exist, as CA abnormalities (particularly DA abnormalities) are
present in both disorders. Patients with delusional depression show an increase
in peripheral HVA excretion as opposed to nondelusional patients who show
decreased HVA secretion (219). Hyperactivity of the CA system is also suggested
by an increase in peripheral MHPG excretion in patients with delusional depression
(220). Agren (51) reported increased CSF HVA in psychotic depression and that
increased CSF HVA levels correlate with the degree of psychosis. Other studies
have not reported an increase in plasma HVA in psychotic depression (221).
DBH, the enzyme that converts DA to NE, has been found to be lower in psychotic

depression than in nonpsychotic depression. Hyperactivity of the DA system is one
of the prominent hypotheses for positive psychotic symptoms (222) as it is for
mania. Therefore, questions regarding the speciﬁcity of CA abnormality for BD
are raised (e.g., why are acutely psychotic subjects not manic or how can
acutely psychotic subjects be often depressed) (223). These contradictions can be
reconciled by conceptualizing that the effect of CA abnormalities on different
parallel cortical–subcortical circuits may lead to different illnesses (8,26,29)
depending to what extent the mood, motor, or cognitive circuit is affected.
For example, the same CA abnormality leading to dysregulation of the cortical–
subcortical circuit may lead to mainly movement disorder if it affects predomi-

nantly the motor circuit, thought disorder if it affects the cognitive circuit, and
mood disorder if it predominantly affects the mood circuit. Keeping in mind the
close proximity and distributed nature of these circuits (27), CA abnormality
would be expected to lead to a dysregulation in all three aspects of behavior but
lead to a different clinical picture depending on the extent of involvement of the
motor-, cognitive-, or mood-regulating part of the circuit (25,29). This is the case
for most neuropsychiatric disorders that usually present as a combination of
motor, mood, and cognitive abnormalities. In BD, the predominant dysfunction is
mood; however, involvement of the motor circuit in the form of increased or
decreased motor activity is frequently seen, and thought disorder in the form of

ﬂight of ideas and frank psychosis is not uncommon.
PERSPECTIVE
A review of the role of CAs in the pathophysiology of BD presents a complex
picture (Table l). On one hand, CA abnormalities seem to be deﬁnitely present
during manic and depressed states but on the other the nature of the abnormality
remains elusive. The increase in CAs during mania and decrease in depression in
serum, urine, and CSF seems to be largely derived from changes in CAs in the per-
iphery, and therefore is likely to be, to a large extent, secondary to the manic or
depressed states themselves. If state-related CA changes are discounted, then
what kind of CA abnormality is likely to lie underneath in mania or depression?
The fact that drugs that increase CAs (e.g., amphetamine, cocaine, tricyclics, and

yohimbine) can induce mania suggests that an increase in CAs could underlie
the pathophysiology of mania. However, investigators have questioned whether
the transient euphoric state induced by CA-increasing drugs is a good model
of mania that involves a sustained change in mood over a period of time (43,61).52 Garakani et al.

TABLE 1 Role of Catecholamines in the Etiology of Depression and Mechanism of Action of
Site of Action Findings Replicability
Synthesis AMPT inhibition of TH leads to improvement in mania and
worsening of bipolar depressionþ
Withdrawal from AMPT leads to improvement in mood in
healthy subjects and emergence of hypomanic
symptoms in euthymic bipolar disorder subjects.þþ
Storage Reserpine can improve mania. þþ
Turnover #MHPG in serum and urine in bipolar depression þþ
#HVA in bipolar depression associated with psychomotor
retardationþþ
Lithium decreases CA turnover þþ
Clonidine, an a2 receptor agonist, decreases manic
symptomsþ
Autoreceptor
functionYohimbine, an a2 autoreceptor antagonist, can induce
maniaþ
D2 autoreceptor antagonists have antidepressant
propertiesþ
D2 autoreceptor stimulation in the striatum is associated
with decreased ﬁring of DA neuronsþ
Postsynaptic
receptor
functionGH response to clonidine blunted in both mania and
depressionþþ

receptor
D2 receptor increased in psychotic mania þ
D2 receptor unchanged in euthymic bipolar disorder þ
D2 receptor down regulation may be a common mode of
action in antimanic drugsþþ
Reuptake
inhibitionCA reuptake inhibitors are effective in bipolar depression þþþ
Amphetamine and cocaine inhibit CA uptake mechanisms
and can lead to mania-like statesþþþ
Second and third
messengersLithium mechanism of action linked with inhibition of PIP þþ
Antiphosphokinase drugs such as tamoxifen may be useful
in maniaþ
G protein abnormalities seen in euthymic bipolar disorder þþ
Neurotrophic
factorsNeurotrophic factor 3 increases NE transmission and
increases survival of NE neuronsþ
Transplantation of NE neurons in the frontal cortex
reverses depression in animal modelsþ
Modulatory

factorsNMDA receptor stimulation by excitatory amino acids
causes increased subcortical CA transmissionþþ
NMDA antagonism leads to mood elevation þ
Glutamate release inhibition can lead to mood elevation þ
Somatomedins and neuropeptide Y inﬂuence NE
transmissionþ
5HT has inhibitory effects on the CA system through
heteroreceptorsþþ
Thyroid hormone increases CA receptor sensitivity þþ
Steroids can lead to increase DA release þ
Abbreviations :þ, one or few studies; þþseveral studies; þþþ , highly replicated by several research groups; þ/2,
mixed or inconsistent results; 5-HT, 5-hydroxytryptamine (serotonin); AMPT, alphamethylparatyrosine; CA,
catecholamine, DA, dopamine; GH, growth hormone; HVA, homovanillic acid; MHPG, methoxyhydroxyphenylglycol;

NE, norephinephrine; NMDA, N-methyl- D-aspartate; PIP, phosphatidylinositolphosphate; TH, tyrosine hydroxylase.Abnormalities in Catecholamines 53

If not a presynaptic increase in CA production, then an abnormality in postsynaptic
receptor sensitivity is suggested by ﬁndings such as decreased prolactin levels in
bipolar depressed subjects (55) and by emergence of hypomania during recovery
from CA depletion with AMPT (43,59). However, extensive research using the neu-
roendocrinological challenge paradigm has been unable to uncover a speciﬁc
abnormality in receptor sensitivity in bipolar depression or mania (76). Nonetheless,
change in postsynaptic receptor sensitivity, either due to change in the receptors
themselves or due to changes in second or third messenger systems, is suggested
by the effects of medications useful in the treatment of BD (e.g., neuroleptics, anti-
depressants, lithium, and valproate). Current understanding of mode of action of
these medications, the action of which is usually delayed and prolonged, suggests
effects on signal transduction mechanisms, genetic effects, and changes in neuro-

trophic factors. However, more research needs to be done in this area to ascertain
whether systems implicated in mode of action of medications are also found to be
abnormal in BD. Brain imaging studies promise state-of-the-art technology to
study brain structure and function in vivo. However, there is a paucity of brain
imaging studies of the CA system in BD. The studies that have been conducted
point to possible changes in postsynaptic CA receptors in BD (142,146).
The role of CA abnormalities is best understood in the context of the
role of CAs in emotions and mood. In this regard, variations of the cortico–
striatopallidial–thalamic circuit (depending on which areas of the brain are
included) can be conceptualized as circuits involved in motor, thought, and

mood production (8,25,26,29). Just as abnormalities of regulatory factors in the
motor circuit can lead to motor abnormalities such as dyskinesias, tremors, or rigid-
ity, abnormalities in cognitive circuit could lead to disruption of thought processes
(22), and abnormalities of the MRC could lead to disruption in mood regulation,
leading to ﬂuctuations of mood between mania and depression (29). Therefore,
BD can be conceptualized as an abnormality of regulation of activity of the MRC.
As reviewed above, regulation of activity of the MRC is a function of a number
of different but interacting systems. Intracellular signal transduction mechanisms
and genetic mechanisms, some of which may be regulated by clock genes, regulate
intrinsic rhythmicity and sensitivity of neurons. Within the circuits themselves,

tight feedback control mediated by fast conductance via GABA and excitatory
amino acids (EAAs) maintains the oscillating activity of the system within a
certain range (33). Further regulatory control is provided by extrinsic neuro-
modulators such as CAs, 5HT, ACh, neuropeptides, and hormones. Among
these, the CAs are likely to have a primary role as is suggested by their prominent
role in reward mechanisms (6), widespread effects on the CNS, and as predominant
neuromodulators in the striatum (32), which has an important function in regulat-
ing cortical output (224). Furthermore, both DA and NE have been shown to have a
prominent role in arousal mechanisms, initiation and maintenance of motor
activity, diurnal rhythms, and sleep and cognitive functions that are frequently

abnormal in BD. Some investigators have suggested that the effect of other
neuromodulators (e.g., 5HT) on mood may ultimately be through effect on the
CA system, particularly the DA system (7). Therefore, the CA system may act as
a bridge between the MRC and other external neuromodulators and therefore
play a central role in mood regulation.
To further understand the factors involved in pathophysiology of BD, new
models of interactions of mood-regulating factors need to be developed. Some of
the models proposed for the role of CA in BD have been discussed above:54 Garakani et al.

Bunney and Garland’s (43) model of phasic changes in postsynaptic receptor sen-
sitivity, Post and Weiss’s (38) kindling hypothesis, Antelman et al.’s (1) sensitiz-
ation-induced cycling model, the permissive hypothesis regarding 5HT
modulation of DA function, Grace et al.’s (191) model of cortical–subcortical inter-
action, Lachman and Papolos’ (210) model of cyclic changes in signal transduction
mechanism, and the more recent but still developing model of modiﬁcation of beha-
vior by clock genes (217). New models need to be developed that can integrate the
role of all known neuromodulators. Such models will probably emerge with greater
understanding of mood regulation both at the molecular and the circuit levels.
The results of the studies reviewed earlier suggest an increase of CAs in
mania and a decrease in depression (though there is an increase of CAs
in bipolar depression associated with psychotic features). One major difﬁculty in

ascertaining the role of CA in BD is that CAs, besides modulating the activity of
the MRC, are also part of the output of the MRC. There is a close relationship
between CAs and neurophysiological mechanisms involved in arousal, neuroendo-
crine response, sympathetic and parasympathetic nervous system activity, and
motor activity and reward-related behavior. Therefore, it is difﬁcult, if not imposs-
ible, to tease out whether CA abnormalities are secondary to the depressed or manic
state or whether they have a more primary role in the induction of these states. It
follows that a study of the manic or depressed state is unlikely to reveal the
central abnormality in BD, particularly regarding CA abnormalities. Strategies
that may be more successful are investigation of euthymic or well state, investi-

gation of early or prodromal stages of BD before a full-blown manic or depressed
episode have occurred, and investigation of well relatives of BD subjects. Studies
of variables that are state independent (e.g., genetic studies that are not affected
by these state-related constraints) need to be more intensively investigated.
Brain imaging studies have the greatest potential to unravel the role of CAs in
the pathophysiology of BD. Future studies that are able to measure different aspects
of the CA system at the same time (i.e., CA release, uptake, pre- and postsynaptic
receptors) will be able to provide a more dynamic picture of CA abnormalities in
BD. Measurement of different neurotransmitters and investigation of the inter-
actions of other neurotransmitters with the CA system will provide a better under-

standing of abnormalities of modulation of the MRC in BD. Moreover, these brain
imaging studies need to be conducted in all three states of the illness, preferably in
the same subjects. Finally, the mechanism of action of medications useful to treat-
ment of BD on the CA system needs to be further investigated.
Beside the methodological problems enumerated above, other difﬁculties in
conducting research into the pathophysiology of BD are multiple: constantly chan-
ging phases of the illness (i.e., depression, mania, mixed states, and euthymia), con-
founding effects of medication or substance abuse, and difﬁculty in recruitment of
subjects. Nevertheless, study of CA abnormalities in BD remains an exciting area of
investigation. Rapid developments in our ability to directly observe brain events

and study molecular and intracellular processes promise to reveal CA abnormal-
ities that may be central to the pathophysiology of BD.
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B4 Cholinergic-Muscarinic Dysfunction in
David S. Janowsky
Department of Psychiatry, University of North Carolina, Chapel Hill,
North Carolina, U.S.A.
David H. Overstreet
Center for Alcohol Studies, Department of Psychiatry, University of North
Carolina, Chapel Hill, North Carolina, U.S.A.
HISTORICAL OVERVIEW AND HIGHLIGHTS
For more than a century, acetylcholine has been postulated to be a factor in the regu-
lation and etiology of affect. In 1889, Willoughby (1) reported a case in which pilo-
carpine, now known to be a muscarinic cholinergic agonist, was used to alleviate
acute mania. Subsequently, in the late 1940s, 1950s, and early 1960s, a number of
authors observed the anergic, inhibitory, anxiety-enhancing and mood-depressing
effects of centrally acting cholinesterase inhibitors, compounds that inhibit the
breakdown of acetylcholine. The mood altering effects of these compounds, used
as insecticides in the agriculture industry and as nerve agents by the military,

were described naturalistically and as tested in experimental settings. The obser-
vations by Grob et al. (2), Gershon et al. (3,4), Bowers et al. (5), and Rowntree
et al. (6) led to a series of reports suggesting that increases in central acetylcholine
led to depression, anxiety, and anergia.
In the early 1970s, based on the above studies and on animal data reported by
Domino and Olds (7), Stark and Boyd (8), and Carlton (9), Janowsky et al. (10)
developed an adrenergic-cholinergic balance hypothesis of manic depression.
This hypothesis proposed that depression represents an overabundance of
central acetylcholine, relative to central adrenergic neurochemicals, and that
mania represents the converse. Part of the work of Janowsky et al. (10,11) involved

infusing the short acting reversible central cholinesterase inhibitor physostigmine
on one occasion and the noncentrally acting cholinesterase inhibitor, neostigmine
on another. Comparing behavioral effects, Janowsky and colleagues used this
paradigm in manics, depressives, schizophrenics, and normals and observed
decreased manic and increased depressive symptoms only in their physostigmine
treated subjects (11,12). This work was replicated during the 1970s and early 1980s
by a variety of investigators. In the late 1970s Sitaram et al. (13) observed that short-
ening of the cholinergic-sensitive sleep parameter, rapid eye movement (REM)
latency, by cholinomimetic drugs was exaggerated in affective disorder patients,
suggesting cholinergic supersensitivity in these patients, a ﬁnding subsequently

replicated in a number of studies.
In the late 1970s and early 1980s, Davis and Davis (14) and Risch et al. (15)
began a series of experiments in which they evaluated the effect of cholinergic
inﬂuences on stress-sensitive neurohormones including ACTH, beta-endorphin,
67

cortisol, epinephrine, vasopressin, and prolactin in depressed patients, normals,
and patient controls. These authors discovered that the above neurohormones
were increased by cholinergic stimulation and antagonized by centrally acting
antimuscarinic agents such as atropine and scopolamine. Risch, Janowsky, and
colleagues (15,16) also observed that exaggerated increases in serum ACTH and
beta-endorphin levels occurred in depressed patients following cholinomimetic
administration, compared to the changes that occurred in patient controls who
did not have an affective disorder.
In the 1990s, peripheral cholinergic supersensitivity in affective disorder
patients was observed following administration of the muscarinic agonist pilocar-
pine, given to induce pupillary constriction (17), and following administration of
non-centrally acting cholinesterase inhibitor, pyridostigmine, given to stimulate
growth hormone release. In addition, in the mid- and late 1990s, Charles et al.

(18), Renshaw et al. (19) and others, using proton magnet resonance spectroscopy
techniques, found that the acetylcholine precursor choline and its related metab-
olites were increased in the brains of affective disorder patients. Furthermore,
the acetylcholine precursors lecithin and choline and the cholinesterase inhibitor
donepezil were reported to be useful in the treatment of mania and related
bipolar conditions (20,21). Finally, in the 2000s, the latest ﬁndings supporting a
role for acetylcholine in the etiology and phenomenology of the affective disorders
has involved discovering muscarinic receptor gene variants linked to major
BEHAVIORAL FINDINGS
Cholinomimetic Effects on Manic Symptoms
As noted above, some of the most direct and graphic evidence of a role for acetyl-

choline in the etiology and phenomenology of affective disorders is derived from
studies of manic patients who have been administered centrally acting cholinester-
ase inhibitors or directly acting muscarinic cholinergic agonists. As noted above,
the ﬁrst report of this phenomenon was published by Willoughby (1), who reported
alleviation of mania by pilocarpine in 1889. Later, in the 1950s, Rowntree et al. (6)
gave DFP, an irreversible centrally acting cholinesterase inhibitor, to a group of
nine bipolar disorder patients and ten normal controls. Normal subjects developed
depression, apathy, lassitude, irritability, and slowness of thoughts and some
became depressed. These phenomena occurred before the onset of peripheral
cholinergic symptoms such as nausea, cramping, and diarrhea, suggesting a

central mechanism. Two of the bipolar patients who were tested while in remission
showed mental changes like those observed in the normals, showing anergia and
nausea without serious affective symptoms. Two hypomanic patients’ symptoms
improved with DFP administration, and these patients continued to be euthymic
after DFP administration had ceased. One hypomanic patient became less manic,
becoming slightly depressed after each of two courses of DFP, and this patient
became manic again after DFP withdrawal. One nearly remitted hypomanic
patient became ﬂoridly manic once DFP had been withdrawn, and one depressed
bipolar patient showed a considerable increase in depression.
Beginning in 1972, Janowsky et al. (10,11) noted that the centrally active chol-
inesterase inhibitor physostigmine caused a short lived and very obvious reduction

in hypomanic and /or manic symptoms in eight bipolar patients with manic or
mixed manic and depressive symptoms. Saline placebo and the non-centrally68 Janowsky and Overstreet

acting cholinesterase inhibitor neostigmine, which does not enter the brain, pro-
duced no changes in mood or behavior. Furthermore, physostigmine’s antimanic
effects were reversed by the centrally acting antimuscarinic drug, atropine,
suggesting that the antimanic effects of physostigmine were caused by a central
muscarinic mechanism. After the patients received physostigmine, the average
Beigel-Murphy mania “Elation-Grandiosity” subscale score was reduced by 78%
and the “manic intensity” scale score was reduced by 48% (10,11). Physostigmine
caused a decrease in speciﬁc manic symptoms including “is talking,” “is active,”
“jumps from one subject to another,” and “looks happy and cheerful.” “Grandios-
ity” was signiﬁcantly decreased in the three patients in whom it was present during
the baseline period. “Irritability” was decreased in three patients and was increased
in ﬁve. Following physostigmine administration, depression, as measured by the

Bunney-Hamburg Depression Scale, showed an overall two-fold increase, with
ﬁve of the eight manic patients studied developing a depressed mood. Physostig-
mine’s effects lasted for a period of 20 to 90 minutes and were observed to begin
a few minutes after infusion occurred. The total amount of physostigmine given
varied from 0.25 mg to 3.0 mg. Physostigmine did not cause sedation as such,
and the patients were not obtunded. They showed no slurred speech or ataxia
and did not fall asleep. In addition to antimanic and mood depressing effects,
nausea and vomiting were also a common concomitant of physostigmine adminis-
tration (11,12,22), as had been noted occur in earlier studies (5,6).
Other studies subsequently replicated the antimanic effects of physostigmine.

In 1973, Modestin et al. (23,24) reported a lessening of manic symptoms following
the infusion of physostigmine in two of four manic patients. This effect did not
occur when neostigmine was administered. Davis et al. (25) reported that physos-
tigmine caused signiﬁcant antimanic effects, especially in patients who were not
hostile and /or irritable. In addition, Carroll et al. (26) studied a manic patient
who had a corticosteroid-induced mania and noted that physostigmine caused a
decrease in euphoria and mobility. Similarly, Krieg and Berger (27) reported data
suggesting that the relatively speciﬁc muscarinic (M1) cholinergic agonist RS86
had signiﬁcant antimanic effects.
However, several authors have wondered whether centrally active cholinomi-
metic agents were only effecting the affective and motoric components of mania,

and not effecting the cognitive aspects of mania. Thus, Carroll et al. (26) and
Shopsin et al. (28) brought up the question of whether cholinomimetics actually
effect what they considered “core” aspects of mania, such as manic grandiosity
and expansive thinking.
Manic Symptom Rebound Following Cholinomimetic Administration
There is some evidence that a late occurring effect of physostigmine administration
is the enhanced activation of manic symptoms and an increase in its animal ana-
logue, hyperactivity. Fibiger et al. (29) demonstrated in rats that increased central
cholinergic activity, caused by the administration of physostigmine, led ﬁrst to
motor inhibition, and later to an increase over baseline in locomotion. This hyper-

activity was presumed to be due to compensatory increases in adrenergic neuro-
transmitter activity. Hyperactivity became apparent as the cholinergic behavioral
inhibition induced by the physostigmine wore off. The hyperactivity was exagger-
ated if a centrally acting antimuscarinic drug (i.e., scopolamine) was given at the
beginning of the hyperactivity phase. The rebound hyperactivity was completelyCholinergic-Muscarinic Dysfunction in Mood Disorders 69

prevented if the centrally active antimuscarinic drug was given prior to initial
physostigmine administration (29).
In parallel with the above preclinical study, an infrequent occurring
exaggeration of baseline manic symptoms following cholinesterase inhibitor
administration has also been found to occur in bipolar patients (10,11,23,24). Rown-
tree et al. (6) observed that one of the manics to whom he had administered DFP
subsequently became more manic than at baseline. Later, Shopsin et al. (28)
studied three highly manic patients given physostigmine up to 6 mg intravenously
and observed rebounding. All three initially experienced varying degrees of seda-
tion, drowsiness, a desire but inability to sleep, some dysthymia, and mild slurring
of speech. A reduction in spontaneous speech and activity were apparent during
this time. During this initial phase, the patients’ ﬂight of ideas, rambling speech,
tangentiality, irritability, and cheerfulness were also attenuated. In this study,

all three patients spontaneously stated, that after receiving physostigmine, they
were “talked out” and did not want to be bothered. No vomiting occurred.
Apathy and anergia were apparent, yet no patient actually became depressed.
The most striking feature of this study was the late appearance in two patients of
a “rebound,” taking place approximately two hours after the physostigmine infu-
sion. A marked exacerbation of the manic state over baseline levels occurred,
lasting three to four hours, with a return to baseline at approximately six hours
following the last physostigmine injection.
Mood Effects of Centrally Active Anticholinergic Drugs
Whereas cholinomimetic agents appear to cause depression, there is evidence
that anticholinergic and anti-Parkinsonian medications have mood-elevating

properties. Jellinec et al. (30) and Smith (31) summarized data showing that anti-
Parkinsonian drugs, given to patients with Parkinsonian symptoms, caused
positive feelings and a reversal of depressed mood. Also, schizophrenics who
used or abused anti-Parkinsonian drugs have reported experiencing euphoria,
being “buzzed or high,” having a reduction in anxiety, having a sense of well
being, and feeling more sociable and more conﬁdent, cheerful, and energetic.
Coid and Strang (32) reported a case in which the anticholinergic agent procyclidine
appeared to cause mania in a bipolar patient. Furthermore, there are several reports
indicating that high doses of atropine and other centrally acting anticholinergics,
such as ditran and scopolamine, can cause euphoria and alleviate depression

(33,34,35,36). Similarly, Kasper et al. (33) observed antidepressant effects with the
anticholinergic anti-Parkinsonian drug biperiden, and this most often occurred in
patients with endogenous depression who had a non-suppressing dexamethasone
suppression test.
In a promising recent report, Furey and Drevets (37), using a placebo-
controlled double-blind crossover design in currently depressed patients, reported
that scopolamine four mcg /kg caused a signiﬁcant and relatively dramatic
reduction in depression, as measured by the MADRAS depression scale and the
Montgomery Asberg Depression Rating Scale. Scopolamine relieved depression
both when compared to baseline and as compared to placebo. The dose utilized
was relatively high compared to previous trials evaluating the effects of scopola-
mine in alleviating depression.

In contrast, some studies have been less promising with respect to the ability
of centrally acting anticholinergic drugs to alleviate depression. Fritze et al. (38,39)70 Janowsky and Overstreet

added centrally acting anticholinergic agents to a treatment regime consisting of
standard antidepressant drugs and did not show increased efﬁcacy. Similarly,
Gillin et al. (40) were unable to demonstrate that treatment of depressed patients
with biperiden led to alleviation of depression.
Marijuana-Physostigmine Interactions
Marijuana often induces a sense of well-being, euphoria, hilarity, increased
verbalizations, and ﬂight of ideas not unlike some of the symptoms of hypomania
(41). El-Yousef et al. (42) reported that small doses of physostigmine antagonized
the intoxicating effects of marijuana in two normal volunteers. In addition, both
volunteers became very severely depressed following physostigmine adminis-
tration. Thus, marijuana was able to induce wittiness, creativeness, and hilarity
in the subjects who smoked it; following physostigmine administration, a lethargic,
drained, sad, extremely depressed state manifested by utterances of hopelessness,

uselessness, and worthlessness, sobbing and crying, and extreme psychomotor
retardation occurred (42). This state was much more extreme than that noted
after physostigmine was given alone. This observation was inadvertently replicated
by Davis et al. (43) in normal volunteers who had covertly smoked marijuana before
receiving physostigmine. Thus, it appears that marijuana augments and ampliﬁes
the effects of physostigmine.
The above clinical observations concerning a marijuana-physostigmine inter-
action were paralleled in a preclinical study performed by Rosenblatt et al. (44).
This study demonstrated that the active ingredient in marijuana, D-9 tetrahydro-
cannabinol, signiﬁcantly increased physostigmine-induced lethality in rats. This
effect was prevented by the centrally and peripherally acting anticholinergic

agents, atropine and methylscopolamine respectively. Subsequently, cholinergic
behavioral effects were also found by Duncan and Dagirmanjian to be augmented
in rats by D-9 tetrahydrocannabinol (45).
Cholinomimetic-Catecholaminergic Interactions
A pharmacological model of naturally occurring adrenergic-cholinergic balance is
found in the interactions and reciprocal effects of psychostimulants, which increase
dopaminergic /noradrenergic activity, and cholinomimetics, which increase acetyl-
choline activity. Psychostimulant-induced increases in locomotor activity, self-
stimulation, and gnawing behavior in rats, which have been considered to be
animal models of mania, are rapidly antagonized by physostigmine, but not by
neostigmine (7,8,10,46). Conversely, physostigmine’s inhibitory effects in rats can

be reversed by methylphenidate (46).
In a study performed in the early 1970s by Janowsky et al. (47), manic and
schizophrenic patients were given intravenous physostigmine ﬁrst, followed by
methylphenidate and vice versa. Physostigmine alone decreased average mania
ratings of talkativeness, happiness, activity, ﬂight of ideas, and the overall Manic
Intensity Scale scores and Elation /Grandiosity scores on the Bunney-Hamburg
Mania Rating Scale. It also decreased activation and increased inhibition on the
Janowsky-Davis Activation-Inhibition Scale (47). When methylphenidate alone
was administered, six of the eight manics who received it rapidly and signiﬁcantly
increased their talkativeness, activity, ﬂight of ideas, manic intensity, and Janowsky-
Davis Activation Scale scores. The increase in the Janowsky-Davis Activation Scale

scores which methylphenidate induced was partially reversed by physostigmine,Cholinergic-Muscarinic Dysfunction in Mood Disorders 71

but not neostigmine. Conversely, physostigmine-induced increases in the Beha-
vioral Inhibition Scale scores were partially reversed by methylphenidate (46).
There is evidence that central cholinergic and catecholaminergic mechanisms
not only balance each other, but are interactive. One human study by Ostrow
et al. (48) demonstrated that physostigmine caused a rapid and dramatic drop
in the urinary norepinephrine metabolite, serum 3-methyoxy-4-hydroxphenylglcol
(MHPG) in a manic patient, presumably reﬂecting a drop in CNS noradrenergic
activity. This phenomenon was associated with the induction of a tearful depressed
state and improvement in the patients’ manic symptoms (48).
Also, a negative correlation was noted between amphetamine-induced beha-
vioral excitation and the ability of the muscarinic agonist arecoline, given on
another occasion to decrease REM latency, an acetylcholine-sensitive sleep parameter

(49). Likewise, Siever et al. (50) demonstrated that those individuals who showed the
most extreme physostigmine and arecoline-induced anergy and negative affect had a
blunted growth hormone response to the noradrenergic agonist clonidine, a sign of
decreased noradrenergic responsiveness. Similarly, Schittecatte et al. (51) demon-
strated that human depressives are subsensitive to the REM sleep-suppressing
effects of the noradrenergic agonist, clonidine. However, it is not clear whether this
subsensivity to clonidine reﬂects subsensitivity of the a-noradrenergic system as
such, or represents the consequences of cholinergic overactivity.
As with the above described behavioral and phenomenological studies, there
is a growing body of preclinical evidence suggesting that such monoamines as

dopamine, norepinephrine, and serotonin on the one hand, and acetylcholine on
the other, are reciprocally interactive. For example, Hasey and Hanin (52)
showed that the immobility-promoting effects of physostigmine could be modiﬁed
by manipulating the b-noradrenergic system. Ikarashi et al. (53) found that dopa-
mine 2 (D2) receptor stimulation in striatum led to a decrease in striatal acetyl-
choline release, suggesting a decrease in acetylcholine availability. Downs et al.
(54) demonstrated that brain dopamine depletion caused an exaggerated ACTH
response following physostigmine administration in rats, suggesting that the dopa-
mine depletion led to unantagonized acetylcholine activity. Similarly, imipramine, a
noradrenergic antidepressant, has been found to decrease acetylcholinesterase

activity in the hippocampus by Camarini and Benedito (55), who suggest that
this decreased acetylcholinesterase activity is a reﬂection of decreased acetylcholine
release.
With respect to serotonin, although the selective serotonin reuptake inhibitors
do not appear to directly block muscarinic receptors, Saito et al. (56) demonstrated
that acetylcholine release appears decreased by inhibitory serotonin (5HT) 1B
hetero-receptors found on cholinergic nerve terminals, and Crespi et al. (57)
found that 5HT3 receptor agonists decrease acetylcholine release by effecting
5HT3 heteroreceptors. Consistent with the above, the 5HT1A agonist 8-OH-DPAT
turned off cholinergic REM—on neurons, which normally activate REM sleep.
Inconsistent with the above antagonistic effects, however, 8-OH-DPAT also

enhanced acetylcholine release from rat hippocampus and cerebral cortex (58),
and the 5HT1A agonist MKC-242 increased extracellular acetylcholine activity (59).
Depressive Effects of Cholinomimetic Agents
Along with the antimanic effects of cholinomimetic agents, some of the most convin-
cing evidence that acetycholine is involved in the regulation of affect is the72 Janowsky and Overstreet

observation that centrally active cholinomimetic drugs can rapidly induce a
depressed mood. Cholinomimetic insecticides, as reported by Gershon et al. (3,4)
and experimental nerve agents, as reported by Bowers et al. (5) and Rowntree et
al. (6), cause depression in normals. A signiﬁcant proportion of the manic patients
who receive centrally acting cholinomimetics develop depressive symptoms, and
this appears true for some normal volunteers and depressed patients as well
(10,11,12). For example, Janowsky et al. (10,11) reported that six of the eight
manics and two depressives studied showed increased depressed mood following
physostigmine infusion (12). In addition, ﬁve of six schizoaffective patients (four
excited, two depressed types) showed depressed mood and sadness after physostig-
mine infusion. Similarly, Davis et al. (25) and Modestin et al. (23,24) reported an
increase in depression, following physostigmine administration in some of the

manic patients they studied, as did Risch et al. (15) when giving arecoline to
depressed patients.
Furthermore, Risch et al. (60) found a statistically signiﬁcant mean increase
in self and observer rated negative affect, including depression, in normals receiv-
ing intravenous physostigmine. Risch et al. (60) also found that normal volunteers
given the directly acting muscarinic cholinergic agonist arecoline developed
depression and other forms of negative affect including hostility and anxiety. Like-
wise, Mohs et al. (61) reported severe depression occurring in some Alzheimer’s
patients receiving the cholinergic agonist oxotremorine.
Consistent with the above information, acetylcholine precursors including
deanol, choline, and lecithin have been reported to cause depression. Thus,

Tamminga et al. (62) observed that a depressed mood was precipitated in some
schizophrenic patients treated with choline. Casey (63) observed that depressed
mood occurred in a subset of deanol-treated patients who had tardive dyskinesia.
Similarly, Bajada observed that depressed mood was a side effect of choline and
lecithin treatments employed to try to reverse the memory deﬁcits of Alzheimer’s
disease (64).
Increasing central cholinergic activity also induces an anergic-inhibitory syn-
drome which appears very similar to the psychomotor retardation component of
endogenous depression. This “inhibitory syndrome” has been operationalized in
the Janowsky-Davis Activation-Inhibition Scale (11,12) and has been observed by
a number of authors who have administered or observed the effects of centrally

acting cholinomimetic drugs (6,11,15,25). The “Inhibition” part of the Janowsky-
Davis scale consists of a composite of items rating for having lethargy, having
slow thoughts, wanting to say nothing, being withdrawn, being apathetic,
lacking energy, being drained, being hypoactive, lacking thoughts, being motor
retarded, and being emotionally withdrawn.
Although a consistent effect of the administration of centrally acting
cholinomimetic drugs is the induction of depressed mood and behavioral
inhibition, a separate question is whether or not affective disorder patients show
a differential sensitivity to these agents. There is a growing body of evidence
that while non-affective disorder patients show the psychomotor retarding and
inhibitory effects after receiving centrally acting cholinomimetics, they less often

show the depressive effects of these agents when compared to patients with an
affective disorder. Thus, Janowsky et al. (11) showed that of eight schizophrenics
without an affective component to their illness, only one showed increased depress-
ive symptoms following physostigmine infusion. Oppenheimer et al. (65) found no
increases in depressed mood in his normal subject cohort when they were givenCholinergic-Muscarinic Dysfunction in Mood Disorders 73

physostigmine, although behavioral inhibition did occur. Similarly, Silva et al.
(unpublished data) showed no increase in depressed mood after giving physostig-
mine to her carefully screened normal controls, although behavioral inhibition and
nausea occurred in most of her subjects. Conversely, as described above, most
studies in which cholinomimetic agents are given to affective disorder patients
report depressive symptoms in the majority of subjects (11,12,65). Thus, in the
studies by Janowsky et al. (11,12), approximately 25% of normals and nonaffective
disorder patients were found to have increases in negative mood following physos-
tigmine administration, in contrast to approximately 75% of the affective disorder
patients studied. In addition, Edelstein et al. (66) reported that schizophrenic
patients who responded to physostigmine with a clearing of psychotic symptoms
were signiﬁcantly more likely to respond with symptomatic improvement when

given lithium, presumably because their illness represented a variant of affective
disorder. Furthermore, Steinberg et al. (67) has found that increases in negative
affect after physostigmine administration occurred selectively in those borderline
personality disorder patients who had pre-existing affectively unstable personal-
ities. Patients with personality disorders who were affectively stable (i.e., borderline
patients who were primarily impulsive) did not show negative affect after physos-
tigmine infusion.
In addition to evidence demonstrating that affective disorder patients are
more likely to become depressed while receiving physostigmine and other centrally
active cholinomimetic drugs than are controls or nonaffective disorder patients,
affective disorder patients may also be relatively more sensitive to the general beha-

vioral effects of centrally acting cholinomimetic agents. Rater and patient evaluated
increases in the Janowsky-Davis Inhibition Scale Score and on the self-rated anxiety,
hostility, and confusion subscales of the Proﬁle of Mood States Scale showed signiﬁ-
cantly greater increases in the depressed patients than in non-affective disorder
patients or normals after arecoline (15,16) or physostigmine infusion (16).
Whether or not behavioral supersensitivity to cholinomimetic drugs is a state
or trait marker of affective disorders is uncertain. Oppenheimer et al. (65) found
that most of the euthymic lithium-treated bipolar patients he studied developed
a depressed mood after receiving physostigmine. Similarly, Casey (63) noted that
tardive dyskinesia patients having a signiﬁcant past history of affective disorder

were more likely to show increased affective symptoms when administered the
probable acetylcholine precursor, deanol, than were those without an affective dis-
order history. However, in contrast, Nurnberger (49,68,69) observed no difference in
behavior or mood sensitivity when euthymic affective disorder patients and
normals were compared after receiving arecoline. Thus, whether behavioral super-
sensitivity to centrally active cholinomimetic drugs in affective disorder patients is
a state- or trait-linked phenomenon is uncertain, although much evidence favors it
being a trait.
In spite of evidence suggesting that selective behavioral supersensitivity to
central cholinomimetic agents in affective disorder patients exists, it is alternatively

possible that cholinomimetic agents are actually affecting those underlying person-
ality characteristics which are risk factors for mood disorders. Thus, as noted above,
Steinberg et al. (67) found that increases in negative affect after physostigmine
administration occurred selectively in those personality disorder patients with
pre-existing affectively unstable personalities, as compared to those who were
affectively stable or had primarily impulsive traits. This differential effect was rela-
tively neurotransmitter-speciﬁc, since affectively unstable patients reacting to74 Janowsky and Overstreet

physostigmine with negative affect did not show mood changes following nor-
adrenergic, serotonergic, or placebo challenges. In work complementary to the
above study, Fritze et al. (38,39) noted that behavioral sensitivity to physostigmine
(i.e., increased inhibition) correlated with baseline irritability and emotional lability,
and with habitually passive stress coping strategies. These authors proposed that
cholinergic sensitivity may be predominantly related to stress supersensitivity
and coping proﬁles, rather than to speciﬁc affective disorder diagnoses.
BIOLOGICAL FINDINGS
Choline in Bipolar Patients
While there is considerable evidence suggesting that centrally acting muscarinic
agonists and cholinesterase inhibitors can effectively decrease manic symptoms
and/or precipitate depression, nonbehavioral biological markers also exist,
suggesting a role for acetylcholine in the affective disorders. One potential

marker of cholinergic changes in the affective disorders is erythrocyte choline
activity, and one function of choline is to be a precursor of acetylcholine. Slight
elevations in erythrocyte choline have been noted in patients with bipolar disorders
by Bidzinski et al. (70), and have also been observed in unipolar depressives and
schizophrenics. Furthermore, Stoll et al. (71) found that relatively increased levels
of red blood cell choline existed in a subgroup of manic patients, and it was
these manic patients who had relatively more symptoms at admission and a poor
outcome at discharge. In addition, bipolar patients having relatively low levels of
red blood cell choline had a history of having four times as many prior episodes
of mania compared to episodes of depression. In contrast, patients with high eryth-

rocyte choline levels had a history of similar numbers of manic and depressive
episodes (71).
SPECTROSCOPIC STUDIES IN AFFECTIVE DISORDER PATIENTS
In vivo proton magnetic resonance spectroscopy provides a means for more directly
assessing human brain choline activity in vivo, and possibly for indirectly assessing
central acetylcholine function, since choline is a major precursor of acetylcholine, as
well as many other compounds. Charles et al. (18) observed that there is a state-
dependent increase in choline in the brains of patients with major depression
when compared to controls. This increase in choline was noted to revert to
normal after successful antidepressant treatment of the depression. More recently,
Renshaw et al. (19) studied the basal ganglia of depressed and control subjects,

and noted an alteration in the metabolism of cytosolic choline compounds in the
depressives, particularly those who subsequently were responsive to ﬂuoxetine.
In addition, Hankura et al. (72) found that depressed bipolar disorder patients
had higher absolute subcortical choline-containing compounds than did normals.
Thus, it would appear that depression is associated with increased central choline
activity, a probable marker of increased central acetylcholine activity.
Cholinomimetic Induced Changes in REM Sleep in Affective Disorder Patients
Depression is generally associated with characteristic sleep changes. Among these
is a decrease in the time until rapid eye movement (REM) sleep occurs (REM
latency), increased REM duration, and increased REM density (13). Signiﬁcantly,

as with naturally occurring depression, centrally acting cholinergic agonists suchCholinergic-Muscarinic Dysfunction in Mood Disorders 75

as arecoline, pilocarpine, the muscarinic 1 (M1) agonist, RS86, and cholinesterase
inhibitors such as physostigmine have been shown to cause a shortening of REM
latency and an increase in REM density. Conversely, centrally acting anticholiner-
gic, dopaminergic, noradrenergic, and serotonergic agents cause an increase in
REM latency and a decrease in REM density and REM duration (73).
Signiﬁcantly, in the vast majority of studies performed to date, after central
cholinomimetic drug administration, REM latency is supershortened and REM
density relatively increased in affective disorder patients. Thus, in a groundbreak-
ing study utilizing affective disorder patients, Sitaram et al. (13) found that
following arecoline infusion, mean REM latency was signiﬁcantly more shortened
in euthymic bipolar patients and in a unipolar patient, compared to the shortening
that occurred in normal volunteers. Sitaram et al. (13) also found similar results in

six bipolar and two unipolar euthymic patients who had been kept off all medi-
cations for at least four months, thus, suggesting a trait phenomenon. Gillin et al.
(74) also demonstrated cholinergically supershortened REM latency in a group of
predominantly nonbipolar symptomatic depressives after infusion of arecoline,
compared to controls. Similarly, Berger et al. (75) demonstrated a super-shortening
of REM latency in nonbipolar depressives when compared to normals and to eating
disorder patients following administration of the cholinergic-muscarinic agonist
RS86. Berger also found that cholinomimetic-induced arousal and awakening
from sleep occurred more frequently in acutely symptomatic affective disorder
patients than in normals (75).
Gann et al. (76) investigated sleep EEG proﬁles following administration of

RS86 to patients with major depression and anxiety disorders and to normal con-
trols. RS86 caused supershortening of REM latency and an increase in REM
density and REM duration in patients with major depression. Patients with
anxiety disorders having secondary depression did not show enhanced REM
abnormalities following RS86 administration, and anxiety disorder patients
showed actually decreased REM density compared to controls. Similar results
with respect to REM sleep responses to RS86 were noted by Riemann et al. in
1994 (77). Likewise, Dube and coworkers (78) showed that the REM sleep response
to cholinergic stimulation with arecoline was signiﬁcantly more pronounced in
primary depressives than in patients with manic disorders, or those with mixed

anxious /depressive symptoms, and Dahl et al. (79) noted similar results in children.
Using a converse approach, Poland et al. (80) demonstrated that the anticho-
linergic agent scopolamine caused a differential effect on REM density, reducing
REM activity in a way consistent with a cholinergic abnormality in depression.
Rao et al. (81) observed that scopolamine 1.5 mcg /kg IM, administered using a ran-
domized double-blind crossover design, suppressed REM sleep and nocturnal cor-
tisol levels. Importantly, and not supportive of cholinergic supersensitivity, both in
the depressed patient group and in the controls, scopolamine suppressed REM
sleep and cortisol levels equally. Likewise, Gillin et al. (82) noted that depressives,
withdrawn from chronically administered scopolamine, did not show expected

exaggerated cholinergic rebound effects, as measured by sleep EEGs. Similarly,
the muscarinic receptor blocker biperiden was not capable of reversing the
relapse back into depression following napping, which occurred in patients
whose depression had been alleviated by sleep deprivation (83).
Studies demonstrating cholinergic supersensitivity of REM variables in
symptomatic affective disorder patients are remarkably consistent in their results.
What is less certain is whether or not this REM linked supersensitivity is a trait76 Janowsky and Overstreet

or a state phenomenon. The work of Sitaram et al. (13) and Nurnberger et al. (68,69)
suggest that the changes are a trait phenomena. Remitted bipolar patients, pre-
viously untreated by drugs or off medications for months, were shown to have
exaggerated REM latency shortening after receiving arecoline (68,69). Furthermore,
Schreiber et al. (84) observed exaggerated shortening of REM latency and increased
spontaneous sleep onset REM periods following RS86 administration in healthy
nondepressed ﬁrst degree relatives of nonbipolar patients with a DSM III diagnosis
of major depression. However, in contrast, Berger et al. (75,85) noted exaggerated
REM latency shortening following administration of RS86 only in actively
depressed major depressive disorder patients and not in remitted ones. Similarly,
Lauriello et al. (86) did not ﬁnd an overall supersensitive REM latency shortening
response to pilocarpine in mildly depressed patients, although these authors did

note a greater cholinomimetic induced shortening of REM latency in their most
highly symptomatic depressed patients, again suggesting a state phenomena.
The presumed hypersensitivity of REM sleep parameters to cholinomimetic
agents in affective disorder patients appears to have a genetic component. A signiﬁ-
cant concordance of REM sleep parameter changes in monozygotic twins to whom
arecoline was administered (69) was noted. Also, as observed in the work of
Sitaram et al. (87,88), affectively ill members of the same families showed exagger-
ated shortening of REM latency after an arecoline infusion. Furthermore, as
described above, the work of Schreiber et al. (84) suggests a genetic relationship
to RS86-induced REM shortening. In an early data analysis, it was shown that

those nondepressed ﬁrst degree relatives who initially showed the greatest
degree of REM shortening following RS86 administration were eventually found
more likely to become clinically depressed upon later follow-up (Holsboer et al.,
personal communication).
Supersensitive Pupillary Responses to Pilocarpine
Sokolski and DeMet (17) have recently reported that the pupillary constriction
response to pilocarpine is exaggerated in patients with major depression. They
suggest that this supersensitivity is trait dependent. These authors note that the
pupillary response to pilocarpine is probably mediated by muscarinic 3 (M3) recep-
tors, possibly exerting their inﬂuence through G protein-phosphoinositol mechan-
isms. Similarly, Sokolski and DeMet have found that lithium and valproate acid-

induced improvements in manic patients were correlated with increases in pupil-
lary sensitivity to pilocarpine (89). Conversely, these authors also found that
manic patients showed decreasing pupillary sensitivity to pilocarpine as the inten-
sity of mania increased (90). These authors also demonstrated that individuals with
more severe mania required higher concentrations of the muscarinic agonist pilo-
carpine to elicit a 50% reduction in pupil size (90). Thus the more symptomatic
the manic patient was, the less sensitive he /she was to a cholinergic agonist, a
ﬁnding consistent with an adrenergic-cholinergic balance hypothesis of mania
Cardiovascular Effects of Cholinomimetic Drugs
There is evidence that patients having major depressive disorder have increased

mean urinary epinephrine excretion, and to a lesser extent, norepinephrine
excretion. Depressed patients also have elevated pulse rates and blood pressure
levels (91,92). Physostigmine, administered to normal and affective disorderCholinergic-Muscarinic Dysfunction in Mood Disorders 77

patients causes profound increases in serum epinephrine levels, and slight increases
in serum norepinephrine levels (91). Interestingly, the release of epinephrine is
blunted, rather than exaggerated, in affective disorder patients (94). Furthermore,
physostigmine and arecoline have both been shown to increase pulse rates and
blood pressure in subjects pretreated with peripherally acting anticholinergic
drugs, an effect which occurs to a similar extent in affective disorder patients and
controls (90,91). These changes parallel preclinical observations in animals (93),
and provide one more parallel between the phenomenology of naturally occurring
depression and central cholinomimetic drug effects.
Growth Hormone Supersensitivity
Acetylcholine causes the release of growth hormone from the pituitary (95,96). Thus,
pilocarpine, acetylcholine, and physostigmine all increase growth hormone release
in vivo in rats and in vitro in rat pituitaries, and this increase is prevented and /or

reversed by administration of centrally and noncentrally acting anticholinergic
drugs (97). With respect to growth hormone release by cholinomimetics in
humans, Janowsky et al. (96) found no increase in serum growth hormone levels fol-
lowing physostigmine infusion. However, their subjects had been pretreated with
methscopolamine or propantheline (probanthene), both peripherally acting anticho-
linergic agents that block peripheral cholinergic effects including nocturnal
hormone secretion (97). O’Keane et al. (98) reported growth hormone release follow-
ing administration of the peripherally acting cholinomimetic agent pyridostigmine
to depressed patients who had not been treated with a peripheral anticholinergic
drug. These depressed patients showed exaggerated release of growth hormone

as compared to controls, a ﬁnding also noted in manic patients (99). This exagger-
ated growth hormone response was most predominant in males with high baseline
cortisol levels (99). Possibly suggesting some nonspeciﬁcity to the growth hormone
response, Lucey et al. (100) reported exaggerated pyridostigmine induced growth
hormone release in obsessive-compulsive disorder patients and O’Keane et al.
(101) noted an enhanced growth hormone response to pyridostigmine in schizo-
phrenics. However, Cooney et al. (102) noted that patients with schizophrenia and
those with panic disorder who had low depression scores did not differ from a
control group with respect to pyridostigmine-induced growth hormone release.
Rubin et al. (103) found that low dose physostigmine (8 mcg /kg, IV) caused exagger-

ated growth hormone levels in depressed women, as compared with depressed men
and controls. In a related study, Coplan et al. (104) in 2000 reviewed evidence that
early sleep is associated with an increased secretion of growth hormone, and that
this increase is due to muscarinic inhibition of somatostatin, a growth hormone sup-
pressant. In a decade long follow-up study of depressed subjects and controls
Coplan et al. (104) noted that initially “normal” subjects who subsequently devel-
oped depression /dysthymia or suicidality over the next decade on average had a
more rapid increase in nocturnal growth hormone secretion and greater growth
hormone secretion over the next four hours of sleep, respectively (104). This was
most likely due to continuingly increased muscarinic activity.

Hypothalamic-Pituitary-Adrenal Axis Supersensitivity
A major characteristic of clinical depression is the activation of the hypothalamic-
pituitary-adrenal (HPA) axis, and the associated ﬁnding that some depressed
patients fail to have suppression of cortisol secretion after the administration of78 Janowsky and Overstreet

dexamethasone (105). Cholinomimetic drugs can release corticotropin (ACTH)
releasing factor (CRF) and elevate serum ACTH and cortisol levels in animals and
in humans (97). Physostigmine has also been shown by Doerr and Berger (106) to
reverse dexamethasone-induced suppression of cortisol in normals and in depress-
ives. Signiﬁcantly, physostigmine-induced serum ACTH increases (but not cortisol
increases) are exaggerated in affective disorder patients (15), again suggesting
cholinergic supersensitivity. Thus, it appears that cholinomimetic-induced increases
in the HPA axis occur, and that these parallel hormonal phenomena noted in
endogenous depression, such as increased cortisol secretion, cortisol resistance to
suppression by dexamethasone, and elevated ACTH levels.
Beta-endorphin secretion, also regulated by CRF, like ACTH appears
naturalistically elevated in depressives and, like ACTH and cortisol, serum

b-endorphin levels are signiﬁcantly increased by physostigmine and other cholino-
mimetics (15,16). Furthermore, affective disorder patients have been shown to have
signiﬁcantly greater increases in b-endorphin levels after physostigmine infusion,
when compared to normal controls and to nonaffective disorder patients (16),
suggesting cholinergic supersensitivity.
A controversy has existed as to the interpretation of the above neuroendocrine
results. Davis and Davis (14) observed that serum prolactin, cortisol, and growth
hormone levels did not increase after physostigmine infusion unless other unplea-
sant symptoms occurred, such as dizziness, nausea, vomiting. They postulated that
cholinomimetic-induced increases in HPA axis hormone levels and in other hor-

mones may be due to a nonspeciﬁc stress effect, such as feeling nauseated or vomit-
ing, rather than to direct cholinergic mediation of the release of hormones.
Janowsky et al. (107) reviewed evidence suggesting that motion sickness, which
includes nausea, dizziness, and vomiting, almost certainly involves a central
cholinergic mechanism, and motion sickness is a potent stimulator of growth
hormone, prolactin, and cortisol secretion.
However, there is much evidence available to indicate that the increase in
HPA axis and other stress sensitive hormones occurring after cholinomimetic infu-
sion is not due to nonspeciﬁc stress as such. Hasey and Hanin (52) demonstrated
that centrally acting physostigmine caused signiﬁcantly greater increases in cortisol

release in rats than did noncentrally acting neostigmine. This ﬁnding occurred even
though the peripheral toxicity of both drugs was recorded to be severe and equal to
one another. Risch et al. (15,108,109) have observed that in arecoline-treated subjects
in whom serum beta-endorphin, ACTH, and cortisol levels signiﬁcantly increased,
a sizable proportion of the subjects could not tell when active drug and when
placebo had been administered.
Furthermore, Janowsky et al. (97) has noted that physostigmine’s anergic
effects precede its nauseating effects, and Raskind et al. (110) noted that increases
in serum ACTH, epinephrine, and cortisol occurred following administration of
physostigmine in aged controls and in Alzheimer’s patients, whether or not
nausea had occurred. Steinberg et al. (67) noted no correlations between the

mood response to physostigmine and changes in cortisol, prolactin, growth
hormone, or nausea. In addition, Janowsky and Risch (97) reported increases in
serum prolactin and cortisol in physostigmine-treated patients and normals that
concurrently manifested no nausea, emesis, or dizziness. Most recently, Rubin et
al. (111) observed that very low doses of physostigmine, causing elevation of
ACTH levels, caused only minimal or no subjective distress or nausea (111).
Rubin et al. (112) furthermore noted that a heightened sensitivity to low doses ofCholinergic-Muscarinic Dysfunction in Mood Disorders 79

physostigmine occurred in female depressives not associated with increased side
effects, with this group showing increased ACTH and cortisol levels when com-
pared to male depressives and controls. Thus, it is likely that the stress-like
effects of centrally acting cholinomimetic agents occurs via a direct mechanism,
rather than working by causing a nonspeciﬁc stress.
Acetycholine as a Regulator of Stress
As implied above, it is possible that acetylcholine as such actually has a major role
in moderating the body’s various stress responses. Stress, being multidimensional,
includes gastrointestinal, cardiovascular, behavioral, analgesic, immunological,
endocrinological, and psychopathological changes. Consistent with the stress-acti-
vating effects of central acetylcholine, centrally active cholinomimetic drugs cause
many, even most, of the same effects in man as do naturally occurring stressors. This
includes development of negative affect, including depression; irritability; and

anxiety; increases in stress sensitive neuroendocrines including ACTH, cortisol,
beta-endorphin, growth hormone, prolactin, epinephrine, and possibly norepi-
nephrine; increases in blood pressure and pulse rate; and increases in analgesia
and serum glucose levels (35,36,93). Furthermore, information from preclinical
studies suggests that many of the manifestations of stress may be mediated by
acetylcholine, acting alone and interacting with other depression-relevant neuro-
transmitters such as norepinephrine, dopamine, serotonin, and gamma aminobuty-
ric acid (GABA) (97).
Conversely, stress as such can cause signiﬁcant changes in central acetylcholine
activity (97). Gilad et al. (113) demonstrated that stress causes an increase in central
acetylcholine release and a compensatory downregulation of muscarinic receptors.

Gilad et al. (113) also demonstrated that acetylcholine release is differentially exagger-
ated in stress sensitive rats. Other investigators have noted that hypothalamic acetyl-
choline turnover increases after continuing stress, and that central acetylcholine
receptor sites are increased during uncontrollable stress (114).
A more recent study by Mizuno and Kimura found that hippocampal acetyl-
choline release, as well as cortisol release, is increased following stress in young but
not aged rats (115). Mark et al. (116), using microdialysis techniques, have demon-
strated that inescapable stress selectively enhances acetylcholine release in rat hip-
pocampus and prefrontal cortex, a phenomenon that they found increased further
when the stress was lifted. Consistent with the above results, Day et al. (118,119)

observed that prenatally stressed rats, when they became adults, showed a
greater release of hippocampal acetylcholine when exposed to a mild stress, or
after being given corticotropin-releasing factor. In addition, Kaufer et al. (117) has
observed that stress and cholinesterase inhibitors alter the expression of genes
that ultimately alter acetylcholine receptor function.
CENTRAL MUSCARINIC REGULATION OF
CHOLINOMIMETIC EFFECTS
It would appear that cholinomimetic-induced changes in mood and behavior,
increases in cortisol, ACTH, prolactin, beta-endorphin, and epinephrine as well as
increases in blood pressure and pulse are due to a central rather than a peripheral
muscarinic effect. Janowsky et al. (95) and Modestin et al. (23,24) noted that in contrast

to physostigmine, the peripherally acting cholinesterase inhibitor neostigmine did not80 Janowsky and Overstreet

exert behavioral effects. Janowsky et al. (96) also noted that increases in serum ACTH,
cortisol, prolactin, and serum epinephrine levels, as well as increases in blood
pressure and pulse rate, nausea, and negative affect caused by physostigmine did
not occur following neostigmine administration, suggesting a central mechanism
for physostigmine’s effects. In addition, physostigmine-induced effects, as described
above, can be blocked by administration of the centrally acting anticholinergic drug,
scopolamine, but not by the noncentrally acting anticholinergic drugs, methscopola-
mine and propantheline, suggesting a central muscarinic mechanism. Conversely, it
would appear that some aspects of peripheral cholinergic supersensivity also exist
in affective disorder patients. Exaggerated release of growth hormone and increased
pupillary sensitivity to pilocarpine, both peripheral manifestations of cholinergic

supersensitivity, exist in affective disorder patients and can be blocked by peripherally
acting anticholinergic agents.
MUSCARINIC RECEPTOR GENE AND BINDING ALTERATIONS
IN MAJOR DEPRESSION
Since the year 2000, several studies have suggested that aspects of the muscarinic
cholinergic 2 receptor (CHRM2) gene are selectively associated with major
depression. In 2002, Comings et al. (120) observed that there was a signiﬁcant
increase in the frequency of 11 homozygotes of the CHRM2 receptor gene in 126
women with major depression, as compared to 304 women without major
depression. This ﬁnding did not occur in men with major depression. Subsequently,
Wang et al. in 2004 (121) reported that variation in the CHRM2 gene predisposed to
alcohol dependence and major depressive syndrome. These authors assert that

their results provide strong evidence that variance within or close to the CHRM2
gene locus inﬂuenced the risk for Major Depressive Syndrome and alcohol depen-
dence. Subsequently, Luo et al. (122) concluded that variation in the CHRM2 gene
differentially predisposed to affective disorders, alcohol dependence, and drug
However, with respect to muscarinic binding, the evidence for an alteration in
binding in mood disorder patients is essentially negative. For example, there is little
evidence of alterations in binding to M2 and M4 receptors in anterior cingulate
cortex between major depressives, bipolars, schizophrenics, and controls (123).
Similarly, Katerina et al. (124), again using quantitative autoradiography to
measure [(3)H] pirenzepine binding to M1 and M4 receptors found no difference

in any laminae of the anterior cingulate cortex between bipolar and major depress-
ive patients and controls, although a trend toward decreased binding in major
depressives compared to controls was found. A signiﬁcant effect in those who
had suicided was also noted (124).
THERAPEUTIC IMPLICATIONS
Application of the adrenergic (monoaminergic)-cholinergic balance hypothesis of
affective disorders to the treatment of depression and mania have sporadically
been attempted. As described above, centrally acting anticholinergic drugs such
as biperiden only equivocally have antidepressant efﬁcacy, although results with
relatively high doses of scopolamine are promising (37). The treatment of mania
with centrally acting cholinomimetic agents has been more consistently rewarding.

The choline precursor lecithin was used by Cohen in the early 1980s to treat mania,Cholinergic-Muscarinic Dysfunction in Mood Disorders 81

with promising results (125). Stoll et al. (20) reported that choline augmentation of
lithium therapy in rapidly cycling bipolar disorder patients caused a substantial
reduction in mania in ﬁve, and a marked reduction of all symptoms in four patients
studied. Related to the above, Leiva (126) reported that phosphotidal choline was
effective in the treatment of mania. More recently, Burt et al. (21) observed that
the cholinesterase inhibitor donepezil (Aricept) 5.0 mg each day was useful in alle-
viating manic symptoms in six of eleven treatment resistant manic patients. Thus,
the use of cholinomimetic agents to treat mania appears to have therapeutic poten-
tial, although the widespread use of cholinomimetic agents to treat mania has not
occurred.
PERSPECTIVES
As reviewed above, there is considerable physiological and phenomenological data
indicating that muscarinic cholinergic mechanisms play an important part in the

occurred.
etiology and modulation of affective disorders. However, it is very possible that
pharmacologically or naturally induced changes in acetylcholine can cause relevant
perturbations in downstream neurochemical modulators and neurotransmitters
(i.e., serotonin, dopamine, norepinephrine, GABA, etc.) or in second messengers
(127,128), or the converse, since most neurotransmitters and neuromodulators con-
sidered important in causing affective changes interact with acetylcholine, and all
these neurochemicals exert important regulatory inﬂuence on downstream
phenomena such as second messengers and G proteins. Evaluation of these
complex interactions will likely yield promising results with respect to understand-
ing the pathophysiology of affective disorders.

Signiﬁcantly, exploration of the role of acetylcholine as it relates to bipolar
disorders and other mood disorders such as major depressive disorder has
remained a relatively under-explored area, in spite of much evidence supporting
an adrenergic-cholinergic balance hypothesis of mood disorders. Other neurotrans-
mitters and neurochemicals such as GABA, serotonin, norepinephrine, NMDA, and
dopamine continue to be more popular targets of psychobiological and psycho-
pharmacological research. However, applying 21st century technology such as
advances in molecular genetics or brain imaging to the understanding of the
relationship between acetylcholine and the affective disorders will help clarify
the role of this neurotransmitter. Studying the effects on the central cholinergic
nervous system of conventional and newer antidepressant and mood stabilizer

medications (129,130,131), and utilizing genetically determined animal models of
depression such as the hypercholinergic Flinders sensitive line rats (132,133),
should also yield especially promising leads. Such techniques have much potential
for supporting the possibility that acetylcholine is directly or indirectly involved in
the etiology and the expression of affective disorders, acting alone or through other
relevant neurotransmitters and /or second messengers.
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B5 Serotonergic Dysfunction in Mood Disorders
Department of Psychiatry, Columbia University, New York,
First puriﬁed from blood and named in 1948 (1), serotonin (5-hydroxytryptamine)
has a wide range of effects including cardiovascular regulation and intestinal
motility outside the brain, and within the brain it modulates: respiration, thermo-
regulation, circadian rhythm entrainment, sleep-wake cycle, appetite, aggression,
mood, sexual behavior, sensorimotor reactivity, pain sensitivity, and learning (2).
Dysfunction of the serotonergic system is thought to play a role in a variety of
psychiatric disorders including mood disorders, generalized anxiety disorder,
panic disorder, obsessive-compulsive disorder, social phobia, schizophrenia, anor-
exia nervosa, and Alzheimer’s dementia (2). This chapter outlines research ﬁndings
that provide the basis for our current understandings of the role of serotonin in

HISTORICAL VIEW
Serotonergic dysfunction has long been implicated in the etiology of depressive dis-
orders. In 1955 it was observed that reserpine, an antihypertensive drug that preci-
pitated depression, depleted serotonin in the brain (3). In 1958, demonstration of the
antidepressant properties of imipramine and iproniazid was subsequently linked to
their actions as a serotonin reuptake inhibitor and monoamine oxidase inhibitor
respectively, and further suggested a role of serotonin in the pathophysiology of
depressive disorders. These ﬁndings contributed to the formulation, by Coppen
(4) and Lapin and Oxenkrug (5) of the indoleamine hypothesis of depression,
wherein the vulnerability to major depression was related to low serotonergic

activity, attributable to either less serotonin release, fewer serotonin receptors, or
impaired serotonin receptor-mediated signal transduction. In 1974 Prange et al.
(6) extended this hypothesis from major depression by proposing a permissive
hypothesis of serotonin function in bipolar disorder in which both the manic and
depressive phases of bipolar disorder are characterized by a deﬁcit in central sero-
tonergic neurotransmission.
Over the ensuing 30 years a variety of research strategies have been pursued
to elucidate the role of serotonin in mania and depression, including studies of:
serotonin uptake and transporter binding in platelets; 5-hydroxyindole-acetic
acid (5-HIAA) the main serotonin metabolite in cerebrospinal ﬂuid (CSF); neuro-
endocrine challenge tests that provoke release of serotonin or activate serotonin

receptors or block reuptake; postmortem studies of serotonin and its metabolites;
serotonergic receptor density; and signal transduction in the brain. More recently
molecular genetic studies and in vivo brain imaging studies of neuroreceptors
have been utilized to study the serotonin system.
89

SEROTONERGIC FUNCTION IN MAJOR DEPRESSION
Most studies of serotonergic function in depression are conducted in major depress-
ive disorder (MDD), also known as unipolar depression, or in mixed groups of
MDD and bipolar depressed patients. This section considers studies of depressed
groups of any composition and a later section reviews studies of bipolar depression
speciﬁcally.
Cerebrospinal Fluid Studies
Levels of the major metabolite of serotonin, 5-hydroxyindoleacetic acid (5-HIAA),
in cerebrospinal ﬂuid (CSF) have been studied as an index of central serotonin turn-
over in depressive and other psychiatric disorders. Such an approach assumes that
CSF 5-HIAA is related to brain serotonin activity. This premise is supported by the
rostral-caudal concentration gradient of CSF 5-HIAA and the observation in post-
mortem studies that CSF 5-HIAA correlates with levels of 5-HIAA in the prefrontal
cortex (7). Those ﬁndings are supplemented by the observation of a positive corre-

lation with the prolactin response to fenﬂuramine, indicating that CSF 5-HIAA is a
reasonable index of prefrontal serotonin turnover (8), although methodological
factors and differences in study population may underlie the disparate ﬁndings
of studies of CSF 5-HIAA and depression. Some report lower CSF 5-HIAA in
depressed patients compared with healthy volunteers (9–14) but others do not
(15–18). The level of CSF 5-HIAA generally does not correlate with severity of
depression. In contrast to studies of CSF 5-HIAA in depression, the evidence of a
relationship is more robust for suicidality. The ﬁnding of lower brainstem serotonin
and/or 5-HIAA in depressed suicides and lower CSF 5-HIAA in depressed suicide
attempters has been consistently replicated (19). The suicide-related ﬁnding may

reﬂect a deﬁcit in serotonin input to the ventromedial prefrontal cortex considered
to underlie a predisposition to act on powerful feelings (20,21). Consistent with this
model, correlations are also reported between severity of lifetime externally
directed aggressive /impulsive behavior and low CSF 5-HIAA (22,23). This is a
biochemical trait that can predict future suicide risk (24).
Platelet Studies
Platelets have been used as a peripheral model for serotonin neurons in studies of
serotonin function in mood disorders. Platelets are more accessible for study than
obtaining CSF, and share many properties with central serotonin neurons, includ-
ing uptake, storage, and release of serotonin, some serotonin receptors, and seroto-
nin transporter binding sites (25,26). Lower serotonin uptake, due mainly to fewer

uptake sites (V max), in unmedicated depressed patients has been consistently
reported (27–31).
The ligands [3H]imipramine and [3H]paroxetine have been used to assay
serotonin transporter binding in platelets and postmortem brain. In the brain,
[3H]imipramine binds to at least two classes of sites: high- and low-afﬁnity. The
high-afﬁnity, sodium-dependent binding was found to be associated with the sero-
tonin transporter complex (32). Depressed unmedicated subjects have fewer transpor-
ter sites as measured by lower [3H]imipramine binding (31,33–38), though not all
studies agree (39–42). Meta-analysis of over 70 studies of [3H] imipramine compris-
ing more than 1900 depressed patients and slightly fewer controls found fewer

binding sites in depressed patients compared with controls (43). Studies using90 Mann and Currier

the ligand [3H]paroxetine, which is thought to be more selective, have also reported
lower binding (35,44,45) or no differences (38,46–48).
The 5-HT 2Areceptor has also been assayed in platelets with mixed results.
Many studies (49–54) but not all (55,56) report more 5-HT 2Abinding sites in
depressed patients compared with healthy controls. During treatment with anti-
depressants normalization of receptor density has been observed with symptomatic
improvement (57,58) but not always (59,60).
Neuroendocrine Challenge and Depletion Studies
Another indicator of central serotonin system function is a hormonal response to
the serotonin releasing agent /uptake inhibitor fenﬂuramine, and other related
direct and indirect serotonin agonists. Release of serotonin from raphe nuclei
projections to the hypothalamus causes the release of prolactin, cortisol, and adre-
nocorticotropic hormone (ACTH) from the pituitary. Thus, prolactin response is an

index of central serotonin responsivity (61). Fenﬂuramine challenge can measure
net serotonin transmission, including elements of presynaptic and postsynaptic ser-
otonergic functioning, which is not possible in cerebrospinal ﬂuid and platelet
studies (62).
Fenﬂuramine causes the release of serotonin and inhibits serotonin reuptake,
thus the prolactin response to fenﬂuramine is an index of serotonin responsivity. A
blunted prolactin response to fenﬂuramine, indicating less serotonin release and /or
serotonin 5-HT 1Aor 5-HT 2Areceptor signal transduction, in depressed patients, has
been reported by many (63–69) but not all studies (70–72). Remitted patients still
have blunted response, the same as severely depressed patients (73). Tryptophan
is a precursor of serotonin and intravenous administration increases prolactin

secretion. Blunted prolactin response to tryptophan challenge has been reported
in major depression (74–76).
Other methods of studying serotonergic function are through the depletion of
serotonin by inhibition of tryptophan hydroxylase (TPH), the rate-limiting biosyn-
thetic enzyme for serotonin, with parachlorophenylalanine (PCPA) (77), or via
acute tryptophan depletion combined with competitive inhibition of brain uptake
by ﬂooding with a bolus of large neutral amine acids (78,79). In long-term remitted,
medication-free depressed patients, depression recurs in hours after acute seroto-
nin or tryptophan depletion (80,81). In remitted patients taking serotonin-related
antidepressant medication, tryptophan depletion induces a transient and rapid
return of depression symptoms, while in untreated depressed patients or those

on noradrenergic antidepressants, there is no clear worsening (82).
Postmortem Studies
Postmortem studies have examined a variety of serotonergic indices. Most
postmortem studies are of depressed suicide victims and, given the evidence that
serotonergic anomalies characterize suicide across diagnostic categories, it can be
difﬁcult to ascertain if abnormalities observed are related speciﬁcally to depression
or to suicide.
SEROTONIN AND 5-HIAA
Postmortem studies found no differences between depressed suicide victims and
control subjects in levels of serotonin in the hippocampus (83,84), occipital cortexSerotonergic Dysfunction in Mood Disorders 91

(83), frontal cortex (84,85), temporal cortex (84,85), caudate (84), striatum (85), or
hypothalamus (85).
Postmortem studies of 5-HIAA have produced varied ﬁndings. In a study of
depressed nonsuicide deaths, 5-HIAA in frontal cortex tended to be lower than
in controls (86). Moreover, it was lower in patients who had not been on anti-
depressants in the month before death. In suicides Crow et al. (87) observed no
signiﬁcant differences in 5-HIAA levels in the frontal cortex, occipital cortex, and
hippocampus of depressed compared with nondepressed suicide victims. Owen
et al. (83) reported no difference in 5-HIAA in the hippocampus when comparing
depressed suicide victims to nondepressed subjects but modestly higher 5-HIAA
compared with normal control subjects. Likewise Cheetham (84) found depressed
suicides did not differ from controls in levels of 5-HIAA in cortical regions, hippo-
campus, amygdala, and caudate; however, 5-HIAA levels were higher in the amyg-

dala but not the hippocampus in drug-free depressed suicides.
Serotonin Transporter
Stanley et al. (1982) were the ﬁrst to report lower [3H]imipramine binding in the
prefrontal cortex of suicides compared with nonsuicides and this was soon con-
ﬁrmed in suicides with and without depression (88) compared with nonsuicides,
although others found no difference (83). It was not clear whether this ﬁnding
was associated with suicide or major depression. Depressed nonsuicides were
reported to have less serotonin transporter binding in the hippocampus and the
occipital cortex compared with normal controls (89). Others found no differences
(86,90). This question was resolved when a large study examining transporter
binding using [3H]cyanoimipramine found lower postmortem binding throughout

the prefrontal cortex of a group with a major depression (20) whereas in suicide
lower transporter binding appeared localized to the ventromedial prefrontal
cortex (20,21).
5-HT 1AReceptor
Several postmortem studies have examined the role of 5-HT 1Areceptors in MDD
and suicide. In the main, controls are compared with suicide victims with major
depression. The only study of depressed individuals who died by means other
than suicide reported a trend for higher 5-HT 1Abinding compared with controls
(86). Several studies reported no differences between depressed suicides and
controls in the prefrontal cortex (91–93), cortex (92,94,95), occipital cortex (95), tem-
poral cortex (94), hippocampus (92,93,95), and amygdala (95). Others report higher
binding in prefrontal cortex (21), and more rostral segments of raphe nuclei (96) and

lower binding in more caudal raphe nuclei (97), hippocampus (98), prefrontal
cortex, and temporal cortex. Arango et al. also report less gene expression in the
dorsal raphe (97).
5-HT 2AReceptor
Postmortem studies of 5-HT 2Areceptors in the prefrontal cortex have likewise
produced conﬂicting results. The ﬁrst study reported higher 5-HT 2Abinding in pre-
frontal cortex of suicides compared with nonsuicides (99). Other studies replicated
these ﬁndings (100–102). Pandey et al. subsequently showed that protein levels
were elevated and so was gene expression (102). A number of studies, using92 Mann and Currier

[3H]ketanserin, did not ﬁnd 5-HT 2Areceptors signiﬁcantly different in the prefron-
tal cortex in depressed suicides compared with controls (83,87,91,93,103–106).
Cheetham et al. (104) found that antidepressant-free depressed suicides had
lower 5-HT 2Abinding in the hippocampus than normal controls. Still other
studies ﬁnd higher binding. One study of the prefrontal cortex found more
5-HT 2Areceptors (107) while another reported a trend in that direction (108). A
study of the prefrontal cortex and the amygdala in depressed suicides also reported
more 5-HT 2Areceptors (109). Ferrier et al. (86), in a nonsuicide postmortem sample,
noted a trend for 5-HT 2Areceptors to be elevated in the frontal cortex of patients
with major depression compared with dysthymia and nondepressed controls
with the trend more pronounced in subjects who had been depressed immediately
prior to death. Depressed non-suicides on antidepressants at the time of death did

not show differences in [3H]ketanserin binding in the frontal cortex compared with
controls (107), suggesting that antidepressant treatment may reduce 5-HT 2Arecep-
tors density in major depressives (107).
Imaging Studies
Positron emission tomography (PET) studies of 5-HT 1Areceptor binding potential
in depressed subjects with primary, recurrent, familial mood disorders report lower
mean 5-HT 1Areceptor binding potential in the midbrain raphe, limbic, and neocor-
tical areas in the frontal, mesiotemporal, occipital, and parietal cortices compared
with healthy controls (110,111). In the Drevets et al. (110) studies, the effect was
mainly seen in bipolar subjects or unipolar with bipolar ﬁrst degree relatives.
Parsey et al. (2006) found depressed subjects who were antidepressant naı ¨ve had

greater binding potential than controls. Moreover, higher 5HT 1Abinding was
associated with the higher expressing G allele of the functional 5HT 1AG(-1019) pro-
moter polymorphism, and that allele was more common in the depressed group
(112). Imaging studies of 5-HT 2Areceptor binding in depressed subjects have
reported conﬂicting results. Some studies observe higher 5-HT 2Areceptor
binding in the prefrontal cortex; others report lower binding in the cingulate,
insula, and inferior frontal cortex; and still others observe no alterations (113). Vari-
ation in results may be related to the use of different ligands, patient heterogeneity,
or downregulation of 5-HT 2Areceptor binding by antidepressants (114,115). Lower
5-HT 2Areceptor binding in the hippocampus has also been reported in medication-

free depressed patients (116), supporting the ﬁndings of some postmortem studies
(104,106). A SPECT study using [2-123I]ketanserin to label 5-HT 2Areceptors found
higher uptake of the tracer in the parietal cortex of the patients, and a right
greater than left asymmetry in the infero-frontal region of the depressed subjects
compared with control subjects (117).
Other imaging studies report decreased uptake of 1-11C-hydroxytryptophan
across the blood-brain barrier in depressed subjects compared with normal subjects
(118). This ﬁnding suggests decreased serotonergic functioning secondary to
reduced availability of serotonin precursors such as 5-hydroxytryptophan. In a
FDG PET study of medication free major depression and healthy controls under-
going fenﬂuramine challenge, depressed patients had blunted regional brain

glucose utilization in response to serotonin release by fenﬂuramine compared
with controls (119). Finally, imaging studies of transporter binding report signiﬁ-
cantly lower serotonin transporter binding in the brainstem and other brain
regions of medication-free unipolar depressed patients compared with healthySerotonergic Dysfunction in Mood Disorders 93

volunteers (112,120), although one study found higher binding in the hypothala-
mus /midbrain in depressed children and adolescents (121).
SEROTONERGIC FUNCTION IN MANIA
There is evidence for the contribution of serotonin dysfunction to mania, and invol-
vement of the serotonin system in the mechanism of action of mood stabilizers
(122); however, it is much less extensive than for depression. Moreover, altered
functioning of other neurotransmitters in mania such as norepinephrine, dopa-
mine, acetylcholine, and GABA and their interaction with serotonin are involved
in the pathogenesis of bipolar disorder. Differences in these neurotransmitter
systems possibly underlie differences in the pathogenesis of depressive and
manic episodes.
Manic patients are variously reported to have lower CSF 5-HIAA levels
(9,10,123,124), no difference (125–132), or higher CSF 5-HIAA compared with
healthy controls (133). The majority of studies (10,17,123,127,129, 132,134,135),

though not all (126), also found no difference in CSF 5-HIAA levels in mania
compared with depression, consistent with the permissive hypothesis for bipolar
disorders (6). This hypothesis states that low serotonin function has a role in epi-
sodes of both depression and mania.
Probenecid blocks the active transport of 5-HIAA out of the CSF and was used
in older studies to boost levels of 5-HIAA when assays lacked the sensitivity of
current methods. It is potentially a more dynamic measure of central serotonergic
activity than basal level when CSF 5-HIAA is measured before and after
probenecid administration because by blocking egress of 5-HIAA, the rise in
5-HIAA reﬂects the rate of production and transport into CSF of 5-HIAA.
However, studies almost uniformly did not use probenecid in this way and just

made one measurement after it was administered. Such studies of CSF 5-HIAA
after probenecid administration in manics, depressives, and controls have
yielded mixed ﬁndings. Two studies found low CSF 5-HIAA in both manic and
depressed patients compared with controls (136,137), one reported lower CSF
5-HIAA accumulation in mania than depression and controls (127), and another,
with no control group, found similar levels in mania and depression (129).
Overall CSF studies suggest both mania and depression are associated with
impaired central serotonin function.
Studies of platelet serotonin uptake in mania have reported mixed results with two
studies ﬁnding no differences from healthy controls (28,138), one study reporting
greater serotonin uptake (139), and another less serotonin uptake compared with

controls (140). In the latter two studies not all manic patients were medication-
free, potentially confounding the ﬁndings. Two studies of transporter binding in
mania compared with depression found higher binding (141,142) and two others
found no difference (42,143). In all four studies binding in mania was not different
from healthy controls, which is inconsistent with the robust reports of lower
binding in major depression. Velayudhan et al. (144) used [125I]-ketanserin to94 Mann and Currier

examine platelet 5-HT 2Areceptor binding sites in drug-free manic patients and
found no differences compared with healthy controls.
Serotonin-induced platelet calcium mobilization is a measure of 5-HT 2A
receptor signal transduction (145,146) and more robust responses are reported in
untreated mania compared with healthy controls and euthymic lithium-treated
bipolar patients (147) and in both manic and depressive phases of bipolar disorder
compared with normal controls and euthymic bipolar patients (148). Together these
two studies suggest an increase in sensitivity of 5-HT 2Areceptors in both mania and
bipolar depression.
Challenge Studies
Thakore et al. (149) found a blunted prolactin response to D-fenﬂuramine in medi-
cated manic subjects compared with healthy controls. That may indicate a deﬁcit in
serotonin release because direct receptor agonists report enhanced 5-HT 1Areceptor-
mediated responses. Yatham (150,151) found no differences in prolactin response to

the 5-HT 1Aagonist buspirone or D,L-fenﬂuramine in mania compared with healthy
controls; however, using the more selective 5-HT 1Aagonist ipsapirone indicated
enhanced ACTH and cortisol responses in mania compared with controls (152).
ACTH and cortisol responses are mediated by postsynaptic 5-HT 1Areceptors
(153–155), thus suggesting an increase in postsynaptic 5-HT 1Areceptor sensitivity
in mania. Enhanced cortisol response has also been reported in mania in response
to 5-hydroxytryptophan (156), perhaps because the precursor corrects a deﬁcit in
serotonin, and reﬂects the receptor supersensitivity. Consistent with this hypoth-
esis, both medicated and medication- free mania show enhanced plasma GH and
cortisol response to oral 5-hydroxytryptophan administration compared with
MDD (156–158).

Challenge studies provide information about the hypothalamic serotonin
activity only and not limbic or other cortical areas. Taken together, they suggest
central presynaptic serotonin activity is decreased and postsynaptic serotonin
receptor sensitivity is increased in mania.
A PET study of 5-HT 2Areceptors using [18F]-setoperone in manic patients before
and after treatment with valproate found that although all patients experienced
remission of manic symptoms after treatment, there was no difference in 5-HT 2A
binding after treatment (159). This suggests that changes in brain 5-HT 2Areceptors
are not involved in the antimanic effects of this mood stabilizer. Given the efﬁcacy of
atypical antipsychotics in mania, it may be that the role of 5-HT 2Areceptors in
mania is via down-stream signaling pathways.

Medication Studies
Medication studies offer insight into serotonergic functioning in bipolar disorder or
at least its role in the therapeutic action of these treatments. Lithium is effective in
bipolar disorder for mania and depression and as a mood stabilizer. Lithium
increases CSF 5-HIAA in mania (122,160–162) and in euthymic bipolar patients
(163). Lithium’s short-term effect on platelet serotonin uptake in mania is less
clear (138,164), but longer-term lithium treatment increases serotonin uptake in
mania (164). Lithium treatment increases cortisol response to 5 hydroxytryptophanSerotonergic Dysfunction in Mood Disorders 95

in mania (156). There is no effect of lithium administration on 5-HT 1Areceptor-
mediated prolactin response to buspirone in manic patients but perhaps ACTH
or cortisol would be better indices for future studies (150). Tryptophan depletion
in recently remitted mania induces relapse of mania (165) but not in bipolar patients
that have been stable on lithium for a longer period of time (166–168).
FOCUS ON STUDIES OF BIPOLAR DISORDER PATIENTS
Most studies of serotonergic function do not separate results for bipolar depression
and MDD. As studies of bipolar mania have already been considered, this section
reviews ﬁndings in bipolar depression and euthymic bipolar patients.
Some studies of CSF 5-HIAA and bipolar depression ﬁnd lower CSF 5-HIAA levels
compared with normal controls, but no difference compared to MDD (13,169). Low
CSF 5-HIAA is reported in bipolar depression, mania, and MDD compared with

controls, and little changed with clinical recovery (10). Others ﬁnd no difference
between MDD, bipolar depressed, bipolar manic, and controls (17); euthymic bipo-
lars and controls (163); and MDD depressed, bipolar depressed, and controls (125).
In a study comparing depressed bipolar I and depressed bipolar II patients, platelet
serotonin content was higher in both groups compared with normal controls;
however, there was no difference between the two groups (170). Comparing seroto-
nin platelet uptake in different phases of bipolar disorder, two studies found that
medication-free bipolar subjects had higher platelet serotonin content than controls
in both depressed and hypomanic phases (171,172), while another study found
greater serotonin uptake in platelets only in depressed bipolar patients, with

manic and euthymic patients not different from healthy controls (173). Others
report low serotonin uptake in platelets in depressed bipolar patients, similar to
depressed MDD patients (28).
While3H-imipramine studies of platelet serotonin transporters in depression
consistently ﬁnd lower binding, and are mixed in mania, other studies in bipolar
disorder suggest that altered transporter function may be a trait characteristic of
the disorder. Lower binding is reported in depression, mania, and euthymia in
bipolar disorder compared with normal controls (174) and in euthymic bipolar
patients who had between 3–15 years of lithium treatment (175). However, not
all studies agree: Lewis and McChesney report lower binding in bipolar depression
compared with controls and mania (141), and Muscettola in 1986 found binding in

bipolar depression and hypomania no different from controls (42). Recent evidence
suggests genetic involvement, ﬁnding that both bipolar patients and their unaf-
fected relatives have fewer transporter binding sites compared with normal con-
trols (176). These studies did not report on suicidal behavior, which appears to be
associated with lower platelet paroxetine binding in bipolar suicide attempters
compared with bipolar nonattempters, who were all on mood stabilizers, and
healthy controls (177).
5-HT 2Areceptor binding in platelets, assessed with lysergic acid diethylamide
(LSD), was the same in manic and depressed bipolar subjects, and higher binding96 Mann and Currier

compared with normal controls (178). Moreover, binding was higher still in suicidal
compared with nonsuicidal bipolar patients, as reported by others in MDD (178).
Medication-free bipolar depression has a blunted prolactin response to fenﬂura-
mine, similar to MDD, when compared with healthy controls (66,179), although
others ﬁnd no difference in prolactin response (180). Tryptophan challenge
produced blunted cortisol and ACTH responses in bipolar depressed (181), but
prolactin response was not different compared with depressed MDD or healthy
controls (182). Depressed bipolar disorder has an enhanced cortisol response to
hydroxytryptophan compared with depressed MDD (156,158), but not to ipsapir-
one, a selective partial agonist of pre- and postsynaptic 5-HT 1Areceptors, in
bipolar depression compared with healthy controls (183). In a tryptophan deletion
study, a mood-lowering effect was observed in euthymic bipolar subjects and their

unaffected ﬁrst degree relatives compared with controls (176). Precursor challenges
are not in agreement in bipolar depression as to whether serotonin function is
impaired. Studies are lacking to determine whether 5-HT 1Aand 5-HT 2Aresponses
are supersensitive in bipolar depression, as has been reported in mania.
There have been few studies examining serotonergic indices in postmortem bipolar
depressed subjects. Lower 5-HIAA levels in the frontal and parietal cortex and
lower 5-HT /5-HIAA ratios in temporal cortex are reported compared with post-
mortem control brains (184). Bipolar subjects, on various medications including
antipsychotics, had lower serotonin transporter afﬁnity in the stratum lacuno-
sum-moleculare region of the hippocampus and no change in 5-HT 1Aor 5-HT 2A

receptor binding compared with controls (185). Wiste et al. found less postmortem
tryptophan hydroxylase (TPH) immunoreactivity, the rate-limiting biosynthetic
enzyme for serotonin, in serotonin nerve terminals in the locus coeruleus of
depressed bipolar suicides compared with depressed unipolar suicides and nonsui-
cide, nonpsychiatric controls (186). The same study found less tyrosine hydroxylase
immunoreactivity in depression, and one manic case had the highest level of any
case. These results are consistent with the serotonin-permissive hypothesis and
suggest that noradrenergic activity may be dependent on mood state.
Genetic factors are estimated to account for 60% to 85% of the liability for bipolar
disorder (187,188) and in recent years genetic studies have investigated association

between bipolar disorder and a number of serotonin-related genes including the
serotonin transporter, various serotonin receptors, and tryptophan hydroxylase 1,
reporting variable results.
In bipolar disorder, three meta-analyses report an association between bipolar
and the serotonin gene promotor 5-HTTLPR genotype (189–191), one ﬁnds a non-
signiﬁcant trend for an association (192), and one ﬁnds no association (193). There
have been conﬂicting reports of association with bipolar disorder for a second
variant in the same gene, namely, a variable number of tandem repeat (194,190).
Meta-analyses ﬁnd no evidence of an association of bipolar disorder with the
5-HT 2Areceptor T102C polymorphism (193,190). Recent large European multicentreSerotonergic Dysfunction in Mood Disorders 97

studies also found no association between the 5-HT 2A1438G /A and the His452Tyr
polymorphisms and bipolar disorders (195). Associations have been reported
between bipolar disorder and the 5-HT 3Avariant C178T in 156 patients, but not
C195T (196), and with 5-HT 4Ain a small Japanese sample (197). A 5-HT 5Areceptor
allelic association was reported between the -19G /C polymorphism and bipolar
disorder (198), although others found no association between 12A /T and bipolar
disorder (199). Vogt and associates reported an association between a 5-HT 6(267C)
polymorphism and bipolar disorder in a small European sample (200), however
no association between 5-HT 6polymorphism (C267T) was observed in a Taiwanese
group (201). Vincent et al. found no association between a 5-HT 7variant and bipolar
disorder (202).
The tryptophan hydroxylase 1 A218C polymorphism was associated with a
small increase in susceptibly to bipolar disorder in a European sample (203) that

is not replicated in other studies (202,204–207) and in a large multi-center
European study of bipolar and MDD (208).
CONTRAST WITH FINDINGS IN MAJOR DEPRESSIVE DISORDER
Bipolar depression and major depressive disorder differ modestly in terms of the
clinical picture of depression. With respect to the serotonergic system there is
considerable evidence indicating serotonergic dysfunction in both disorders. The
biochemical differences that may exist are likely to relate to the predisposition to
mania in bipolar disorders.
The observations of serotonergic abnormalities in manic, depressed, and euthymic
bipolar patients, and the unaffected relatives of bipolar patients suggest that seroto-
nergic dysfunction is a trait-related characteristic of bipolar disorder rather than a

mood state-dependent characteristic. Further studies in well-deﬁned bipolar
cohorts, in different phases of the disorder that include comparisons with MDD as
well as healthy controls, are required to determine the neurobiologic correlates
that are related to mood state. Such studies must include a consideration of the inter-
action of the serotonergic system with other neurotransmitters and the HPA axis.
Moreover, the role of genetic factors and their interaction with environment in the
development of this disorder requires investigation.
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B6 Cell Membrane and Signal Transduction
Pathways—Implications for the
Pathophysiology of Bipolar Disorders
Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Research
Program, National Institute of Mental Health, Bethesda, Maryland, U.S.A.
OVERVIEW AND HISTORICAL BACKGROUND
Although genetic factors play a major, unquestionable role in the etiology of bipolar
disorder, the biochemical abnormalities underlying the predisposition to and the
pathophysiology of this complex and intriguing neuropsychiatric disorder
remain to be fully elucidated. The brain systems that have heretofore received
the greatest attention in neurobiologic studies of these illnesses have been the
monoaminergic neurotransmitter systems, which were implicated by the following
observations:
1. Effective antidepressant drugs exert their primary biochemical effects by regu-
lating intrasynaptic concentrations of serotonin and norepinephrine

2. Antihypertensives that deplete these monoamines sometimes precipitate
depressive episodes in susceptible individuals.
3. Psychostimulants and dopamine agonists have been shown to be capable of
triggering manic episodes in susceptible individuals.
Furthermore, the monoaminergic systems are extensively distributed
throughout the network of limbic, striatal, and prefrontal cortical neuronal circuits
thought to support the behavioral and visceral manifestations of mood disorders
(1). Clinical studies over the past 40 years have attempted to uncover the biological
factors mediating the pathophysiology of bipolar disorder utilizing a variety of bio-
chemical and neuroendocrine strategies. Indeed, assessments of cerebrospinal ﬂuid
(CSF) chemistry, neuroendocrine responses to pharmacological challenge, and neu-

roreceptor and transporter binding have, in fact, demonstrated a number of
abnormalities of the serotonergic, noradrenergic, and other neurotransmitter and
neuropeptide systems in mood disorders.
While such investigations have been heuristic over the years, they have been
of limited value in elucidating the unique biology of this affective disorder that
must include an understanding of the underlying basis for the predilection to epi-
sodic and often profound mood disturbance that can become progressive over time.
Thus, bipolar disorder likely arises from the complex interaction of multiple sus-
ceptibility (and protective) genes and environmental factors, and the phenotypic
expression of the disease includes not only episodic and often profound mood dis-

turbance, but also a constellation of cognitive, motoric, autonomic, endocrine, and
sleep /wake abnormalities. Furthermore, while most antidepressants exert their
109

initial effects by increasing the intrasynaptic levels of serotonin and /or norepi-
nephrine, their clinical antidepressant effects are only observed after chronic
(days to weeks) administration, suggesting that a cascade of downstream effects
are ultimately responsible for their therapeutic effects. These observations have
led to the appreciation that while dysfunction within the monoaminergic neuro-
transmitter systems is likely to play important roles in mediating some facets of
the pathophysiology of bipolar disorder, they likely represent the downstream
effects of other, more primary abnormalities (2).
The subsequent challenge for the basic and clinical neuroscientist will be the
integration of these molecular /cellular changes to the systems and ultimately to the
behavioral level wherein the clinical expression of bipolar disorder becomes fully
elaborated.
Despite these formidable obstacles, there has been considerable progress in

our understanding of the underlying molecular and cellular basis of this unique
affective disorder in recent years. In particular, recent evidence demonstrating
that impairments of signaling pathways may play a role in the pathophysiology
of bipolar disorder, and that mood stabilizers exert major effects on signaling path-
ways which regulate neuroplasticity and cell survival, have generated consider-
able excitement among the clinical neuroscience community, and are reshaping
views about the neurobiological underpinnings of these disorders (3–5). In this
chapter, we critically review and appraise these data and discuss their impli-
cations not only for changing existing conceptualizations regarding the pathophy-
siology of mood disorders, but also for the strategic development of improved
therapeutics.

Signaling Networks: The Cellular Machinery Underlying Information
Processing and Long-Term Neuroplastic Events
It is hardly surprising that abnormalities in multiple neurotransmitter systems
and physiological processes have been found in a disorder as complex as
bipolar disorder. Signal transduction pathways are in a pivotal position in the
central nervous system (CNS), able to affect the functional balance between mul-
tiple neurotransmitter systems and may therefore play a role in mediating the
more “downstream” abnormalities that likely underlie the pathophysiology of
affective disorders. Moreover, as we discuss below, recent research has clearly
identiﬁed signaling pathways as therapeutically relevant targets for our most
effective pharmacological treatments. Indeed, the molecular and cellular targets

underlying lithium and valproate’s abilities to stabilize a dysregulation of the
limbic system and limbic associated function strongly suggest that abnormalities
in signaling pathways may also play a critical role in the pathophysiology of
Signal transduction pathways serve the critical roles of ﬁrst amplifying and
“weighting” numerous extracellularly generated neuronal signals and then trans-
mitting these integrated signals to effectors, thereby forming the basis for a
complex information processing network (6). The high degree of complexity gener-
ated by these signaling networks may be one mechanism by which neurons acquire
the ﬂexibility for generating the wide range of responses observed in the nervous
system. These pathways are thus undoubtedly involved in regulating such

diverse vegetative functions such as mood, appetite, and wakefulness and are
therefore likely to be involved in the pathophysiology of bipolar disorder.110 Chen and Manji

G-Proteins
Mammalian guanine nucleotide binding proteins (G proteins) can be categorized
into two major groups: heterotrimeric G proteins and small G proteins.
Heterotrimeric G proteins convey signaling from G-protein-coupled-receptors
(GPCRs) to their effectors, which include adenylyl and guanylyl cyclases (AC
and GC), phosphodiesterases (PDE), phopholipases A2 (PLA2), phospholipase C
(PLC), phosphoinositide 3-kinases (PI3Ks), ion channels, and Rho-GEF (Table 1).
These G proteins are composed of three distinct subunits, a,b, and g. These
trimeric complexes are loosely associated with the GPCRs. Upon receptor stimu-
lation, receptors and G proteins undergo conformational changes that lead to the
exchange of guanosine diphosphate (GDP) for guanosine triphosphate (GTP) at
Gasubunit and dissociation of G aand G bgsubunits. Consequently, G aand G bg
stimulate effector molecules. G asubunits process intrinsic GTPase activities,

thereby hydrolyzing GTP to GDT, resulting in G ainactivation and reassociation
of Gawith G bg. There are four G afamilies expressed in the brains: G as( Gas1–
4 and G aolf), Gi (G ai1–3, G ao1–2, G at1–2, G agust, and G az), G aq( G aq, and
Ga11, 14–16), and G a12 (G a12–13) (Table 1).
Small G proteins are monomeric G proteins with molecular weight of 20 to
40 kDa. Like heterotrimeric G proteins, small G proteins bind to guanine nucleo-
tides, process intrinsic GTPase activity, and cycle through GDP- and GTP-bond
forms. Exchange of GDP for GTP causes major conformational changes of
these G proteins and their afﬁnities for effector molecules. More than 150 small G
proteins have been identiﬁed. Small G proteins are classiﬁed into ﬁve families:
Ras, Rho, Rab, Ran, and Arf (Table 1). These G proteins have higher afﬁnities for

GDP and GTP and lower intrinsic GTPase activity, and GDP to GTP exchange
activities. The functioning of these G proteins is modulated by regulator proteins:
guanine nucleotide exchange factors (GEFs), which promote exchange between
GDP and GTP, and GTPase-activating proteins, (GAPs) which stimulate hydrolysis
of the bound GTP. Rho and Rab proteins are regulated by a third class of proteins,
TABLE 1 Major Signaling GTPase G Proteins
Groups Types Effectors and effects
Gaproteins G as ACs, increase in cAMP
Gai AC, inhibits cAMP production
Ion channel
Phosphodiesterase
Phospholipase
Gaq Phospholipase C- b, increase DAG and IPs, in turn
release Ca2þand activate PKC
Ga12 RhoGEFs, activates Rho
Small G
proteinsRas Regulate diverse signaling cascades involving gene expression
and cell proliferation, differentiation and survival

Small G
Rho Regulate diverse signaling cascades involving actin
organization, cell cycle progression and gene expression
Rab Regulate intracellular vesicular transport and trafﬁcking of
protein between different organelles of the endocytic and
secretory pathways
Ran Function in nucleocytoplasmic transport of RNA and proteins
Arf Regulate vesicular transport
Abbreviations : AC, adenylyl cyclase; cAMP, cyclic AMP; DAG, diacylglycerol; IP, inositol phosphotase; PKC, protein
kinase C.Cell Membrane and Signal Transduction Pathways 111

guanine nucleotide dissociation inhibitors (GDIs). The GAPs for heterotrimeric G
proteins are termed as the intracellular regulator of G protein signaling (RGS) pro-
teins. RGS protein activities are regulated by a complex web of intracellular factors.
G Protein Abnormalities in Bipolar Disorder
Likely due to the fact that lithium affects G proteins (discussed below), several inde-
pendent laboratories have investigated the potential role of G protein abnormalities
in the pathophysiology of bipolar disorder. Potential G protein dysfunction in
bipolar etiology has been investigated. Young and associates reported increases
in protein levels of G as, but not G ai, Gao, and G b1/2, in the frontal and occipital
cortex of bipolar patients (7). Follow-up work from the same laboratory suggested
that these increases in G as protein levels are likely due to changes in post-transla-
tional enzymatic modiﬁcation such as endogenous ADP-ribosylation (8), rather

than being due to change in G as gene transcription (9). Consistent with these ﬁnd-
ings, Wang and Friedman reported elevated levels of G as, but not G ai, Gao, Gaq,
Gaz, and G b1/2, in frontal cortical membrane preparations of bipolar patients (10).
In a recent study, Gonzalez-Maeso et al. found that the frontal cortical membrane
levels of G as, Gai1/2, Gai3, and G ao are not different between control subjects
and suicide victims with mood disorders. To investigate the functional coupling
of receptors to G proteins, Friedman and Wang utilized agonist-induced GTP gS.
They found increases in basal GTP gS binding, and increased GTP gS binding to
Gas induced by isoprenaline, G ai, Gao, and G aq induced by carbachol, and G as,
Gai, Gao, and G aq induced by serotonin in postmortem frontal cortical samples

of bipolar patients (11). Gonzalez-Maeso et al. found selective increases in GTP gS
binding sensitivity in response to stimulation of a-adrenoceptor 2A, but not
5-HT1a, y-opioid, GABA-B, and muscarinic receptors in frontal cortical membrane
samples of suicide victims with mood disorders (12). Despite the increases in G as
protein, Young and associates’ follow-up studies did not reveal any signiﬁcant
increase in cAMP production induced by GTP gS, although there was an increase
in cAMP production induced by forskolin which stimulates AC directly (13).
Jope and associates found signiﬁcant reductions in GTP gS, NaF, GTP gS plus
carbachol, and GTP gS plus serotonin-induced phosphatidylinositol hydrolysis in
occipital, but not temporal and frontal, cortical samples of bipolar subjects (14).

By contrast, Mathews and associates reported an increase in protein level of
Gaq11 in occipital, but not frontal or temporal, cortex of bipolar patients (15).
Finally, several studies have also found elevated G as protein levels and mRNA
levels in peripheral circulating cells in bipolar disorder, although the dependency
on clinical state remains unclear (16–19).
Lithium and G Proteins
There are two proposed magnesium sites on G proteins: high afﬁnity sites (nM) essen-
tial for GTPase activity, and low afﬁnity (mM) sites required for exchange GDP for GTP
(20). In 1988, Avissar and associates reported that lithium at 0.6 mM concentration
completely blocked isoprenaline ( b-adrenoceptor agonist), and carbachol (muscarinic
receptor agonist) induced [H3]GTP bindings in rat cerebral cortical membrane prep-

arations, in vitro and in cerebral cortical membrane preparations, from rats chronically
treated with lithium (21). However, while there is some additional data in support of a
direct effect of lithium on G proteins (22), this has not been consistently found.
Moreover, the inhibitory effects of chronic lithium treatment on rat brain ade-
nylyl cyclase AC are not reversed by Mg2þ, and still persist after washing of the112 Chen and Manji

membranes, but are reversed by increasing concentrations of GTP (23–27). These
results suggest that the effects of chronic lithium (those which are more likely to
be therapeutically relevant) may be exerted at the level of signal-transducing G pro-
teins at a GTP responsive step (discussed below). These two distinct actions of
lithium on the AC system may explain the differing results which have been
obtained by investigators using rat membrane preparations from those using
slice preparations (2). Overall, for both Gs and Gi, lithium’s major effects in both
humans and rodents are most compatible with a stabilization of the heterotrimeric,
undissociated, inactive ( abg) conformation of the G protein (16–18,28).
cAMP Signaling Cascade and PKA
Cyclic AMP (cAMP) is a second messenger generated by adenylyl cyclase (AC) upon
extracellular stimulation (Fig. 1). There are at least nine isoforms of membrane-
bound ACs, most of them expressed in the brain (Table 2). All membrane-bound

ACs can be activated by forskolin and G as proteins. In addition, Group I ACs can
be stimulated by calmodulin in Ca2þ-dependent manner. Group II ACs can be con-
ditionally activated by G bg. Group III ACs are highly sensitive to G ai inhibition and
also inhibited by Ca2þand protein kinase A (PKA). Group IVAC is less responsive to
FSK. Protein kinase C (PKC) markedly activates AC2, AC5, and AC7 and inactivates
AC4 and AC9. There is also a soluble (cytosol) AC. This AC does not respond to FSK
and G as, but becomes activated in presence of bicarbonate.
cAMP-dependent protein kinase A (PKA) in an inactivated state is a tetramer,
containing two of each regulatory and catalytic subunits. There are four regulatory
subunit isoforms (RI a,R Ib, RIIa, and RII b) and two catalytic subunit isoforms (C a

and C b). All isoforms are expressed in the brain (29). When intracellular cAMP
level rises, cAMP binds to the regulatory subunit of protein kinase A (PKA), and
this causes dissociation of the tetramer into its component monomers—two regulat-
ory subunits with cAMP attached, and two active catalytic subunit. The freed cata-
lytic subunits phosphorylate its cellular or nuclear substrates such as transcription
factor cAMP responding element binding protein (CREB). cAMP is converted to
FIGURE 1 Some signaling pathways being investigated in bipolar disorder studies. Abbreviations :
cAMP, cyclic AMP; DAG, diacyl glycerol; ERK, extracellular signal-regulated kinase; MEK, MAPK /
ERK kinase; PLC, phospholipase C; PKC, protein kinase C; RSK, ribosomal S6 kinase.Cell Membrane and Signal Transduction Pathways 113

AMP by cyclic nucleotide phosphodiesterases (PDE); this event turns off the cAMP
signaling at the second messenger level.
The cAMP /PKA Signaling Cascade in Bipolar Disorder
A limited number of postmortem brain studies suggest brain regional dysfunction
of cAMP signaling at PKA, but not at AC, may play a role in bipolar disorder.
Studies did not reveal any evidence for changes of basal and GTP gS-stimulated
AC activities in a variety of brain regions including prefrontal, temporal, and occi-
pital cortices, hippocampus, thalamus, and cerebellum in bipolar subjects
(13,30,31). An initial report showed that forskolin-stimulated cAMP production
was selectively increased in temporal and occipital cortexes of bipolar subjects
(13), and later studies conﬁrmed this ﬁnding, at least in temporal cortex (30,31).
No differences were found between control and bipolar subjects in temporal cortex
protein levels of AC1, AC4, and AC5 /6. (30). The initial PKA postmortem brain

study from the Warsh lab revealed widespread reductions in cytosolic, but not particu-
late, cAMP binding sites in bipolar subjects (32). In follow-up studies, the researchers
found increases in PKA activities basal and cAMP-stimulated cytosolic PKA activities
in temporal cortical samples. This higher PKA function seems due to reduction of
regulatory subunit proteins (33), rather than due to changes in mRNA levels of PKA
RIa, PKA RII b,a n dP K AC a(34).
The data obtained from behavioral studies using transgenic and knockout
mice indicate that selective components of cAMP-signaling cascade are required
for regulation of behavior relevant to mood disorders. Mice lacking AC8 show
reduced anxiety-like (or increased explorative) behaviors, which are more

obvious after restraint stress (35). AC5 null mice exhibited enhanced sensitivity
to D1 receptor agonist-induced locomotion and inverted locomotion response to
D2 receptor antagonists (36). AC1 and AC8 double knockout mice showed
signs of behavioral allodynia (37). Deletion of PKA RII bin mice resulted in
lean body size (38), markedly increased home-cage activity (39,40), supersensitiv-
ity to amphetamine-induced locomotion (41), and more alcohol consumption and
insensitivity to alcohol-induced sedation (42). Mice lacking RIb were indistin-
guishable from wild-type mice on indices of anxiety, exploration, and memory
(43). Mice lacking PKA Cb also appear indistinguishable from wild-type mice
in a variety of behavioral tests or tasks (43,44). PDE1B knockout mice possess

baseline hyperlocomotion, enhanced locomotor response to psychostimulants,TABLE 2 Membrane-Bound Adenylyl Cyclases
Group Type Distribution FSK G asG ai/oG bg Ca2þPKA PKC
I AC1 Brain ""# ai#" CaM "w
AC3 Olfactory,
pancreas""# w "CaM "w
AC8 Brain, pancreas ""# w "CaM
II AC2 Lung, brain "" " c "
AC4 Widespread "" " c #
AC7 Widespread "" " c "
III AC5 Heart, striatum ""# # # "
AC6 Widespread ""# # # # and"c
III AC9 Widespread "w"# w #
Calcineurin#
Note :", stimulation; #, inhibition; c, conditional action; w, weak action.114 Chen and Manji

and spatial memory deﬁciencies (45). PDE4D, but not PDE4A and PDE4B, null
mice showed antidepressant-like behavioral change in the forced swim and tail
suspension tests (46).
Lithium and the cAMP /PKA Signaling Cascade
The effects of lithium on the cAMP system have been extensively studied, and
reveal a complex, region-speciﬁc effect, likely due to lithium’s effects at multiple
levels of this signaling cascade. Studies in the early 70s showed that lithium inhibits
membrane AC activities induced by GPCR and G protein stimulations (47–49),
perhaps due to direct competition with magnesium required for AC catalytic
activity. However, the clear inhibitory effects of lithium on AC are observed at con-
centrations above its therapeutic range. Lithium has been demonstrated to exert
complex effects on the activity of AC, with the preponderance of the data demon-
strating an elevation of basal AC activity, while attenuating a variety of receptor-

mediated responses (16,50). Lithium in vitro inhibits the stimulation of AC by the
poorly hydrolyzable analog of GTP, Gpp(NH)p, and also by Ca2þ/calmodulin,
suggesting that lithium in vitro is directly able to inhibit the catalytic unit of AC
(23–27). Since these inhibitory effects of lithium in vitro can be overcome by
Mg2þ, they have been postulated to be mediated (at least in part) by a direct com-
petition with magnesium (whose hydrated ionic radius is similar to that of lithium)
for a binding site on the catalytic unit of AC (23–27). However, the inhibitory effects
ofchronic lithium treatment on rat brain AC are not reversed by Mg2þ, and still
persist after washing of the membranes, but are reversed by increasing concen-
trations of GTP (23–27). This has led to an investigation of lithium’s effects on

the AC system in vivo, using microdialysis. These studies found that chronic
lithium treatment produced a signiﬁcant increase in basal and post-
receptor stimulated (cholera toxin or forskolin) AC activity, while attenuating the
b-adrenergic mediated effect (51,52). Interestingly, chronic lithium treatment
resulted in an almost absent cAMP response to pertussis toxin, suggesting a
lithium-induced attenuation of Gi function. It should be noted, however, that
chronic lithium has also been found to increase not only cAMP levels (53), but
also the levels of AC Type I and Type II mRNA and protein levels in frontal
cortex (54,55), suggesting that lithium’s complex effects on the system may rep-
resent the net effects of direct inhibition of AC, upregulation of AC subtypes, and

effects on the stimulatory and inhibitory G proteins. Most recently, lithium’s
effects on the phosphorylation and activity of CREB have been examined in
rodent brain and generally demonstrate a lithium-induced increase (56,57).
A series of studies have also examined lithium’s effects on AC in humans. In a
longitudinal study of healthy volunteers, two weeks of lithium administration was
found to signiﬁcantly increase platelet basal and postreceptor stimulated AC
activity (58), effects which are strikingly similar to those observed in rodent
brain. Consistent with a lithium-induced increase in basal cAMP and AC levels,
a more recent study found that platelets obtained from lithium-treated euthymic
bipolar enhanced basal and the cAMP-stimulated phosphorylation of Rap1 (a

PKA substrate), as well as of a 38-kDa phosphoprotein (59). Somewhat surprisingly,
these investigators did not ﬁnd similar effects of lithium in healthy subjects.
Carbamazepine and the cAMP /PKA Signaling Cascade
Carbamazepine appears to dampen cAMP signaling. An earlier study showed
that carbamazepine reduced cAMP levels in rabbit CSF (60), and attenuatedCell Membrane and Signal Transduction Pathways 115

basal- and stimulated-cAMP accumulation in cerebral tissue and cortical slices
(61,62). Post and associates showed that carbamazepine reduced CSF cAMP
levels in patients with mood disorders (63). In the follow-up studies, it was
found that carbamazepine inhibits receptor- and forskolin-stimulated cAMP pro-
duction in cultured cells and in membrane preparation made from cell and brain,
and phosphorylation of CREB in cells, perhaps through direct interaction with ade-
nylyl cyclase or proteins tightly associated with adenylyl cyclases (64).
Phosphoinositide Signaling Cascades and Protein Kinase C (PKC)
Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2] is a minor membrane phospholi-
pid. In response to extracellular stimulation, phosphoinositide-speciﬁc phospho-
lipase C (PLC) catalyzes hydrolysis of PI(4,5)P 2and results in the generation of
two intracellular messengers, diacylglycerol (DAG) and inositol 1,4,5-trisphosphate

(I(1,4,5)P 3) (Fig. 1) (65). PLC isozymes are divided into four types: PLC b, PLC g,
PLCd, and a new type of PLC, termed PLC-?. An isoform of PLC originally
known as PLC- ais a proteolytic fragment of PLC- d1. Gq family G aproteins and
Gbgdimers activate PLC b. Receptor protein tyrosine kinases and nonreceptor
protein tyrosine kinases phosphorylate and activate PLC g. GPCR stimulations
can also activate PLC gthrough nonreceptor protein tyrosine kinases. The molecular
mechanisms underlying activations of PLC dand PLC-? are not well established.
Once DAG is generated in response to extracellular signals, it activates
protein kinase C (PKC). PKC is a large family of proteins divided into three sub-
groups: classic PKC (cPKC including a,bI,bII, and gisoforms), new PKC (nPKC

including 1,h,d,uisoform), and atypical PKC (aPKC including z,i/lisoform).
cPKC isoforms, but not nPKC and aPKC isoforms, are also sensitive to Ca2þiono-
phore. aPKC isoform does not respond to DAG, but are activated by other lipid
mediators such as FFA, PS, and PIP3. PKC gand1are the isoforms more selectively
expressed in the brain. Myristoylated alanine-rich C kinase substrate (MARCKS) is
an acidic protein and the most prominent substrate for PKC in the brain.
IP3, another signal generated through PIP2 hydrolysis catalyzed by PLC,
binds to the IP3 receptor, which functions as a calcium channel in the cell;
binding IP3 to its receptor releases intracellular calcium reservoirs from the endo-
plasmic reticulum. IP3 binding sets forth downstream effects such as activation

of calmodulins and calmodulin-dependent protein kinases and is then recycled
back to PIP2 by the enzymes inositol monophosphatase phosphatase (IMPase,
the rate limiting enzyme) and inositol polyphosphatase phosphatase (IPPase).
Lithium, at therapeutic concentration, directly inhibits IMPase and IPPase,
therefore blocking conversion of IPs to inositols and consequently dampening
PIP2 recycling and intracellular signaling requiring PIP2. The “inositol depletion
hypothesis” posited that lithium, as an uncompetitive inhibitor IMPase, produced
its therapeutic effects via a depletion of neuronal myo-inositol levels. Although this
hypothesis has been of great heuristic value, numerous studies examined the effects
of lithium on receptor-mediated PI responses, and although some report a

reduction in agonist stimulated PIP2 hydrolysis in rat brain slices following acute
or chronic lithium, these ﬁndings have often been small and inconsistent, and
subject to numerous methodological differences (66,67). Most recently, a magnetic
resonance spectroscopy study demonstrated that lithium-induced myo-inositol
reductions are observed in the frontal cortex of BD patients after only ﬁve days
of lithium administration, a time when the patients’ clinical state is completely
unchanged (68). Recent data suggest that valproate induces inositol depletion by116 Chen and Manji

blocking de novo inositol synthesis in yeast and cultured mammalian cells. These
data provide additional support for the role of inositol depletion in the initiation
of mood stabilizing effects. However, there is a lack of clear evidence for valpro-
ate-induced blockage of de novo inositol synthesis in the brain.
Given the predictable effects of inositol depletion on intracellular
PIP2-dependent signaling, it has been argued that reducing myo-inositol levels
per se is not associated with therapeutic response. This led to the working hypoth-
esis that some of the initial actions of lithium may occur with a relative reduction of
myo-inositol—that this reduction of myo-inositol initiates a cascade of secondary
changes in the PKC signaling pathway and gene expression in the CNS, effects
that are ultimately responsible for lithium’s therapeutic efﬁcacy.
Indeed, evidence accumulating from various laboratories clearly demon-

strates that lithium, at therapeutically relevant concentrations, exerts major
effects on the PKC-signaling cascade (2,67,69,70). The preponderance of the cur-
rently available data suggest that acute lithium may activate PKC, whereas
chronic lithium exposure results in an attenuation of phorbol ester mediated
responses, accompanied by a downregulation of PKC isozymes in the brain.
Using quantitative autoradiographic techniques, it has also been demonstrated
that chronic (ﬁve weeks) lithium administration results in a signiﬁcant decrease
in membrane-associated PKC in several hippocampal structures, most notably
the subiculum and CA1 region, in the absence of any signiﬁcant changes in the
various other cortical and subcortical structures examined (71,72). Furthermore,
immunoblotting using monoclonal anti-PKC antibodies revealed isozyme-speciﬁc

decreases in PKC aand 1(which have been particularly implicated in facilitating
neurotransmitter release), in the absence of signiﬁcant alterations in PKC b,
PKC g, PKC d,o rP K C z. It is also noteworthy that exposure of immortalized hippo-
campal cells (67), neuroblastoma cells or PC12 cells (73) to lithium (1.0 mM) in vitro
produces isozyme-selective decreases in PKC a, and (in the case of PC12 cells) PKC.
In view of lithium’s signiﬁcant effects on PKC as outlined above, the effects of
valproate on various aspects of PKC functioning have also been investigated. It has
been found that the structurally highly dissimilar agent, valproate, produces effects
strikingly similar to lithium on the PKC signaling pathway (67,74). Interestingly,
chronic lithium and valproate appear to regulate PKC isozymes by distinct mech-

anisms, with valproate’s effects appearing to be largely independent of myo-
inositol.
A major strategy used to investigate the downstream consequences of
mood stabilizer-induced alteration in PKC isozymes is the examination of the
effects of chronic lithium on endogenous PKC substrates in brain. The most promi-
nent substrate for PKC in brain is an acidic protein, MARCKS (myristoylated
alanine rich C kinase substrate), which is implicated in regulating long term neuro-
plastic events. Lenox and associates (1992) demonstrated that chronic lithium
administration dramatically reduced MARCKS expression in hippocampus,
effects that were not immediately reversed following lithium discontinuation
(75). Subsequent studies carried out in immortalized hippocampal cells demon-

strate that this action of chronic lithium on MARCKS regulation is dependent
upon both the inositol concentration and the level of receptor-mediated activation
of phosphoinositide hydrolysis (76). Recent studies provide evidence for regulation
of transcription as a major site for the action of chronic lithium on MARCKS
expression in brain (77). Since MARCKS may offer a speciﬁc target for pharmaco-
logic agents targeting mood stabilizing drugs, the effects of the anticonvulsantCell Membrane and Signal Transduction Pathways 117

valproate as well as lithium were studied in immortalized hippocampal cells,
showing a time- and concentration-dependent reduction in MARCKS protein
expression. The activity of valproate was observed within a concentration range
and time course considered consistent with clinical studies of patients with
bipolar disorder. Additionally, therapeutic concentrations of combined lithium
and valproate induced an additive reduction in MARCKS also consistent with
experimental ﬁndings that the two drugs work through different mechanisms on
the PKC system, plus consistent with the clinical observation of the additivity of
the two drugs in treatment responses (78).
Given that PKC signaling is a common target of lithium and valproate, and
that this signaling pathway plays a pivotal role in the regulation of neuronal excit-
ability, neurotransmitter release, and long term synaptic events, Manji and his
associates postulated that the attenuation of PKC activity may mediate the antima-

nic effects of lithium and valproate. In a pilot study it was found that tamoxifen
(a nonsteroidal antiestrogen known to be a PKC inhibitor at higher concentrations)
may indeed possess antimanic efﬁcacy (79). These data further support the poten-
tial role of the PKC pathway in mediating the pathophysiology of BD.
Phosphatidylinositol-3-Kinase (PI3K) Signaling Pathway
PI(4,5)P 2is also an essential substrate for PI(3,4,5)P 3production in the phosphatidyl-
inositol-3-kinase (PI3K) signaling pathway (Fig. 1) (80). Activated receptor protein
tyrosine kinases phosphorylate and activate phosphatidylinositol-3-kinase (PI3K).
Class 1A PI3Ks, which are composed of heterodimers of an inhibitory adaptor /
regulatory (p85 a/p85b/p85g) and a catalytic (p110 a/p110 b/p110 d) subunit, are

initially puriﬁed from the brain tissue. PI3K catalyzes phosphorylation of
PI(4,5)P 2. PI(3,4,5)P 3facilitate the recruitment of AKTs (AKT1 /AKT2 /AKT3) [also
known as protein kinase B (PKB)] to cell membrane. Akt is then phosphorylated
by constitutively active phosphoinositide-dependent kinase 1 (PDK1) (at threonine
308 in AKT1) to stabilize the activation loop, and by PDK2 in the hydrophobic
C-terminal domain (serine 473 in AKT1) for full activation. The downstream
target AKT is glycogen synthase kinase-3 (GSK-3), which is phosphorylated by
Akt at serine 21 of GSK-3 aand serine 9 of GSK-3 b, resulting in inactivation of its
catalytic activity. PTEN dephosphorylates the 3 position of PtdIns(3,4,5)P 3[and
PtdIns(3,4)P 2] to reverse the action by PI3K (81).
Mood Stabilizers and PI3K Pathway

Although the inositol depletion theory predicts diminished PIP2-related intracellu-
lar signaling, recent data suggest an enhanced function of PI3K /AKT pathway by
lithium and valproate treatments. Lithium is known to protect neurons against a
variety of insults in cultured cells and in intact animals (82,83). The PI3K /AKT
pathway is one of the signaling cascades that regulate cell survival. In search for
the molecular mechanism by which lithium protects cerebellum granular cells
against glutamate toxicity, Chuang and associates discovered that lithium activated
the PI3K /AKT pathway. They revealed that lithium rapidly increases PI3K activity,
phosphorylation of AKT1 at serine 473, and phosphorylation of GSK-3 aat serine 21
(84). Soon after the initial lithium ﬁndings, Jope and associates reported that valpro-

ate also activates the PI3K /AKT pathway in cultured cells supported by coherent
increases in phosphorylations of ATK1 at serine 473 and GSK-3 bat serine 9 (85).
Acute treatment with lithium increases phosphorylations of AKT-1 at threonin
308, but not serine 473, and of GSK-3 aand bat AKT sites (86). Studies also118 Chen and Manji

showed that chronic treatment with lithium and valproate increased GSK-3 bserine
9 phosphorylations in frontal cortex and hippocampus (85,87), effects that are
consistent with activation of the PI3K /AKT pathway by mood stabilizers. Other
signaling cascades may also be involved (see below).
The PI3K /AKT pathway is also affected by antipsychotics, psychostimulants,
and antidepressants; however, the behavioral and clinical relevance of these effects
are unclear. It is reported that acute and chronic treatment with haloperidol
increased phosphorylations of AKT1 at serine 473 and threonin 308 in whole
brains of mice, and chronic treatment also increased phosphorylations of GSK-3 b
at serine 9 (88). Since chronic treatment with haloperidol is reported to decrease
GSK-3 bserine 9 phosphorylation (87), it appears these whole brain effects are not
due to the changes in frontal cortex. In the same study, the investigators found

that clozapine treatment increased GSK-3 bserine 9 phosphorylation. Effects of
psychostimulants on the AKT pathway are not consistent across studies.
However, cocaine increased striatal levels of phosphorylated AKT1 at threonin
308 and seronine 485 (89), while amphetamine decreased striatal levels of phos-
phorylated AKT1 at threonine 308, GSK-3 aat serine 21, and GSK-3 bat seronine
9 (86). Imipramine treatment increased GSK-3 aat serine 21 and GSK-3 bat seronine
9 (90,91,92). Mice lacking functional AKT1 carry defects in both fetal and postnatal
growth (93) and greater sensitivity to the sensorimotor gating-disruptive effects of
amphetamine (88). However, mice with one copy of functional GSK-3 bshowed
attenuated locomotor response to amphetamine (86). The genetic data on the

AKT1 association with bipolar disorder is inconclusive (94).
The Extracellular Signal-Regulated Kinase Pathway
The extracellular signal-regulated kinase (ERK) pathway is one of the key signaling
cascades mediating neurotrophic action and synaptic plasticity (Fig. 1). Neurotro-
phins such as nerve growth factor (NGF), brain-derived nerve growth factor
(BDNF), and NT-3 /4 bind to speciﬁc Trks. This binding triggers a cascade of
events: Trk autophosphorylation and activation, recruitment of adaptor protein to
activation site on the cell membrane, guanine nucleotide exchange and activation
of small G protein Ras, Ras-facilitated dephosphorylation and phosphorylation
reactions leading to Raf activation, and a chain of sequential phosphorylation-
induced activations of MEK by Raf and ERK by MEK. ERK phosphorylates and

activates RSK. ERK and RSK phosphorylate and thereby modulate activity of pro-
teins with diverse functions including transcription factors, enzymes, ion channels,
structure proteins, and receptors. In addition to Trk, NMDA receptors, PLC-
coupled receptors, and adenylyl cyclase-coupled receptors also regulate the ERK
pathway, exerting their actions on synaptic plasticity in the CNS.
The ERK pathway is activated by mood stabilizers in brain regions involved
in mood regulation. Earlier works from several research groups showed that
lithium and valproate induce function of transcription factors such as AP-1 and
CREB and enhance expression of genes such as bcl-2 (95). These projects were
led by Chen and associates who suspected that the ERK might be targeted by the

mood stabilizers. They found that valproate activated the ERK pathway in cultured
human neuroblastoma cells and promoted neuronal differentiation and survival of
these cells (95). Later, they demonstrated that chronic treatments of rats with
lithium and valproate activated the ERK pathway in prefrontal cortex and hippo-
campus (57,96). They showed that lithium and valproate promote neurogenesis
in dentate gyrus of adult hippocampus, an effect mediated at least in partCell Membrane and Signal Transduction Pathways 119

through their ERK pathway activating action (96,97). Lithium- and valproate-
induced activation of the ERK pathway is also observed in other laboratories
(98). ERK pathway-activating effects of carbamazepine (99), but not lamotrigine,
have been reported from some studies using cells.
Studies on the effects of antidepressants on the ERK pathway have thus far
yielded inconsistent results. Chronic treatment of rats with venlafaxine, a dual ser-
otonin and norepinephrine reuptake inhibitor, did not induce signiﬁcant changes
on immunostaining of phosphorylated RSK in frontal cortex and hippocampus
(100). Chronic treatment of rats with ﬂuoxetine and reboxetine, a selective norepi-
nephrine reuptake inhibitor, signiﬁcantly reduced levels of phosphorylated ERK1,
but not those of phosphorylated ERK2 in nuclear fraction of hippocampal tissue
(101). The same treatments did not signiﬁcantly alter levels of phosphorylated
ERK1 and phosphorylated ERK2 in prefrontal cortex. Chronic treatment of rats

with desipramine signiﬁcantly elevated levels of phosphorylated ERK2 in
nuclear fraction of hippocampal tissue, but decreased levels of phosphorylated
ERK1 in nuclear fraction of prefrontal cortical tissue, without signiﬁcant effects
on levels of phosphorylated ERK1 in nuclear fraction of hippocampal tissue and
levels of phospho-ERK2 in nuclear fraction of prefrontal cortical tissue (101). A
recent study found that chronic treatment of rats with ﬂuoxetine signiﬁcantly
reduced levels of phosphorylated ERK1 and phosphorylated ERK2 in nuclear frac-
tions of hippocampal and frontal cortical tissues and reduced levels of phosphory-
lated ERK1 in hippocampal synaptosomes (102). However, chronic treatment with
imipramine did not produce similar effects (102).
Studies conducted in cultured cells, and animals, show typical and atypical

antipsychotics stimulate the ERK pathway. These effects, as suggested in some
studies, are mediated through D2 and /or 5HT1A receptors and require pertussis
toxin-sensitive Gi and Go proteins. Given that antipsychotics are highly effective
in treatment of mania, it is reasonable to postulate that the ERK pathway activation
may represent a convergent point of action of antimanic agents with varied chemi-
cal structures (98).
Inactivation of ERK pathway in CNS induces animal behavioral alterations
reminiscent of manic symptoms; these complex behaviors likely depend on
ERK’s effects on discrete brain regions and the presence of other interacting mol-
ecules. U327 is a MEK inhibitor that can penetrate blood-brain barrier and attenu-
ated ERK pathway activity. Chen and associates reported that systematic

administration of U327 induced increases in locomotion and travel distance in
the large open ﬁeld test (57). The injection also reduced immobility and increased
swimming time in the forced swim test. However, injection of its parent compound
U0126, which cannot penetrate the blood-brain barrier, did not induce any signiﬁ-
cant effects on the outcomes of both tests, indicating the effects of U327 are due to
inhibition of MEK in the CNS (57). Mice lacking one of two ERK subtypes are indis-
tinguishable from wild-type mice in appearance and a variety of neurological and
behavioral tests. However, these mice are hyperactive in novel environments;
resistant to forced-swim induced immobility; supersensitive to rewarding property
of morphine; over-engaged in wheel running, a naturally hedonic activity of

rodents; and supersensitive to psychostimulant-induced locomotion (98). Direct
infusion of a MEK inhibitor, or direct expression of functional null mutant ERK1
in left anterior cingulate cortex produce similar behavior types (98). Abnormal
left anterior cingulate cortex in bipolar patients is a consistent ﬁnding from
human brain imaging studies. The left anterior cingulate cortex is one of the120 Chen and Manji

brain regions repeatedly found altered in bipolar disorder in brain imaging and
postmortem studies (98). These converging animal and human data support a criti-
cal role of the ERK pathway in therapeutic action of mood stabilizers. The roles of
the ERK pathway in the susceptibility and pathophysiology of bipolar disorders are
largely unknown.
Glycogen Synthase Kinase-3 (GSK-3)
Although it was originally identiﬁed as a key modulator of glycogen catabolism,
GSK-3 plays critical roles in a variety of neuronal processes such as progenitor
cell fate determination, neuronal survival and apoptosis, and synaptic plasticity
(103–107). It has a wide substrate range and is a converging point of several
signaling pathways described above (Fig. 1). Two GSK-3 subtypes have been ident-
iﬁed, namely aand b, which share 97% sequence homology in their catalytic
domains. Both subtypes are expressed in the brain and generally (but not

always) have similar biological effects, while encoded by two separate genes.
Both kinases are constitutively active. The constitutive activity arises from phospor-
ylation of tyrosines 279 or 216 ( aand b, respectively), although there is some evi-
dence of active regulation of these sites in the brain (108). RSK, Akt, PKA, and
PKC phosphorylate N-terminal serine residue of GSK-3 aandb(21 and 9, respect-
ively) and the phosphorylation results in GSK-3 inhibition. Protein phosphatase 1
(PP1) and protein phosphatase 2A dephosphorylate GSK-3 (109–111). In addition,
GSK-3 activity is regulated by binding proteins; for instance, in the Wnt signaling
pathway, GSK-3-catalyzed phosphorylation of b-catenin is regulated by proteins
adenomatous polyposis coli (APC), the scaffold protein Axin, and frequently

rearranged in advanced T-cell lymphomas 1 (FRAT1) (106,107).
Seminal work by Klein and Melton (1996) led to the critical discovery that
lithium inhibits GSK-3 activity through direct and indirect mechanisms. The
initial in vitro data showed the IC50 of lithium to inhibit GSK-3 in test tube is
about 1–2 or 2 mM (112,113), suggesting marginal direct inhibition of GSK-3 by
lithium at therapeutically relevant serum levels of 0.6–1.2 mM. This direct inhi-
bition is later identiﬁed to be through competition for magnesium (103,114).
The proposed indirect inhibition mechanisms include: ( i) induction of GSK-3
phosphorylation-inactivation and ( ii) inhibition of GSK-3 dephosphorylation-
reactivation by mood stabilizers. The original work by Chuang and co-workers
demonstrated that lithium activates the PI3K pathway and phosphorylations of

GSK-3 aat serine 21, the phosphorylations-inactivation site, in cultured cells (84).
Jope et al. later demonstrated that lithium induced phosphorylation of GSK-3 bat
serine 9 in mouse brain after chronic treatment with lithium. In addition to the
PI3K pathway, the effects of lithium on the ERK /RSK pathway and on PKC signal-
ing could also contribute to phosphorylation-inactivation of GSK-3 (85).
Phosphatase inhibitor-2 (I-2) is an inhibitory component of PP1 complex.
GSK-3 phosphorylates I-2 at threonine 72 (115), the phosphorylation alters inter-
action between I-2 and PP1 catalytic unit (116), resulting in increases in PP1 activity
(116), and therefore PP1-induced dephosphorylation-reactivation of GSK-3
(111,117). According to this loop, an initial break on GSK-3 activity may cause

further ampliﬁcation of GSK-3 inhibitory signal. Although it is plausible, convin-
cing direct evidence for ampliﬁcation of GSK-3 inhibition through this feedback
loop in the brain is lacking.
Chen and associates report that valproate, at therapeutic relevant concen-
trations, also inhibits GSK-3 activity in vitro (118). This ﬁnding has now beenCell Membrane and Signal Transduction Pathways 121

replicated by several, but not all, laboratories. Similar to the effects of lithium,
studies also found valproate increased phosphorylation of GSK-3 at the inactivation
sites (85), perhaps through its effects on PI3K (84,85) and ERK /RSK pathways
(98,119). Taken together, these data suggest a therapeutic relevancy of GSK-3 inhi-
bition in mood stabilization.
To further examine the therapeutic relevancy of mood stabilizer-induced
GSK-3 inhibition, researchers evaluated the effects of GSK-3 blockage on rodent
behavior. Reducing immobility in the forced swim test is one of the behavioral
effects induced by acute administration of antidepressants. A recent study
showed that lithium, similar to antidepressants, reduces the immobility in mice
(120). GSK-3 bdeﬁcient mice (120) and GSK-3 inhibitor-treated mice (121) and
rats (122) exhibit similar reduction in immobility in the forced swim test, indicat-
ing GSK-3 inhibition mediates this behavioral effect of lithium. In support of such

a contention, recent studies showed that antidepressant (90) and atypical antipsy-
chotic (123), both agents known to reduce the immobility of animals in the forced
swim test, increase GSK-3 phosphorylations at the inactivation site in several
brain regions implicated in mood regulation. Lithium reduces holeboard explora-
tion and amphetamine-induced locomotion in rodents (120). These phenomena
are viewed as lithium-sensitive behavior related to antimanic action of this
agent. GSK-3 heterozygous knockout mice showed reduced holeboard explora-
tion (120) and rats that received GSK-3 inhibitor injection showed blunted
response to amphetamine challenge (122). It appears that GSK-3 inhibition
mediates antidepressant-like and antimanic agent-like behavioral effects (or

mood stabilizing effect). However, it remains to be elucidated how the similar
effects of mood stabilizers and antidepressants, two types of drugs with clearly
different clinical proﬁles, especially for manic episodes of bipolar disorder, on
brain GSK-3 phosphorylation at inactivation site result in different behavioral
outcomes.
PROSPECTS AND FUTURE DIRECTIONS
Overall, it should be clear from the information reviewed in this chapter
that bipolar disorder likely arises from abnormalities in cellular plasticity
cascades, leading to aberrant information processing in synapses and circuits
mediating affective, cognitive, motoric, and neurovegetative function. As we
have discussed, there is a considerable body of evidence in support of abnorm-
alities in the regulation of signaling as integral to the underlying neurobiology

of bipolar disorder. Indeed, the role of cellular signaling cascades offers much
explanatory power for understanding the complex neurobiology of manic-
depressive illness:
BSignaling cascades regulate the multiple neurotransmitter and neuropeptide
systems implicated in bipolar disorder.
BAbnormalities in cellular signaling cascades that regulate diverse physiologic
functions likely explains the tremendous comorbidity with a variety of
medical conditions (notably cardiovascular disease, diabetes mellitus, obesity,
and migraine) and substance abuse.
BSignaling pathways are clearly major targets for hormones that have been
implicated in the pathophysiology of manic-depressive illness, including
gonadal steroids, thyroid hormones, and glucocorticoids.122 Chen and Manji

BCellular signal transduction cascades are clearly the targets for our most effec-
tive treatments for manic-depressive illness.
BAbnormalities in cellular plasticity cascades likely also represent the underpin-
nings of the impairments of structural plasticity seen in morphometric studies
of bipolar disorder.
In conclusion, there have truly been tremendous advances in our understand-
ing of the molecular and cellular underpinnings of bipolar disorder. Moreover,
studies of cellular plasticity cascades in bipolar disorder are leading to a reconcep-
tualization about the pathophysiology, course, and optimal long-term treatment of
the illness. This data suggests that, while bipolar disorder is clearly not a classical
neurodegenerative disease, it is in fact associated with impairments of cellular plas-
ticity and resilience. As a consequence, there is a growing appreciation that optimal
long-term treatment will likely be achieved by attempting to prevent the underlying

disease progression and its attendant cellular dysfunction, rather than exclusively
focusing on the treatment of signs and symptoms. There has, unfortunately, been
little progress in developing truly novel drugs speciﬁcally for the treatment of
manic-depressive illness, and most recent additions to the pharmacopeia are
brain-penetrant drugs developed for the treatment of epilepsy or schizophrenia.
This era may now be over as there are a number of pharmacologic “plasticity enhan-
cing” strategies which may be of considerable utility in the treatment of bipolar
disorder. This progress holds much promise for the development of novel thera-
peutics for the long term treatment of severe, refractory mood disorders, and for
improving the lives of millions.

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2006:1–13.Cell Membrane and Signal Transduction Pathways 129

B7 Searching for a Cellular Endophenotype for
Bipolar Disorder
Department of Psychiatry, Harvard Medical School, Boston,
A critical question regarding the etiopathogenesis of bipolar disorder is whether
there is a cellular endophenotype that can explain abnormalities at the level of
dysfunctional neurons and circuits. A recent study has suggested that apoptosis
could play a role in the pathophysiology of bipolar disorder. Is it possible that
this abnormality is related to an endophenotype for this disorder? Fundamental
differences in the genetic regulation of the apoptotic cascade, electron transport
chain, and antioxidation enzymes are present and uniquely different from those
seen in schizophrenia. These differences may reﬂect the cellular endophenotype
for bipolar disorder and are revieved below.
Postmortem evidence gathered over the past 20 years has suggested that

bipolar disorder and, to a lesser extent, schizophrenia may involve apoptotic cell
death (1,2). Several cell counting studies demonstrated a reduction of interneurons
in the anterior cingulate cortex of schizophrenics, although this change has consist-
ently shown a stronger covariation with affective disorder (3,4,5). Subjects with
bipolar disorder, like those with schizophrenia, show decreases in the expression
of mRNA for GAD65 (6,7) and GAD67 (7,8). Additionally, presynaptic axon
terminals containing GAD65 have also been found to be signiﬁcantly reduced in
the anterior cingulate cortex of patients with bipolar disorder (9), suggesting that
neuronal cell death may be a feature of this disorder. The idea that bipolar disorder

involves cell death to a greater degree than schizophrenia is counterintuitive,
because the latter disorder involves a characteristic deterioration in function
that is not generally seen in affective disorder. This contrasts strikingly with the epi-
sodic nature of bipolar disorder and the characteristic return to normal baseline
functioning following a manic or depressive episode.
Based on postmortem evidence, a reduction of GABAergic interneurons
appears to be a more striking feature of bipolar disorder than schizophrenia (5).
On this basis, it was postulated that apoptotic cell death may play a role in the
pathophysiology of bipolar disorder to a greater extent than in schizophrenia
(1,2). Interestingly, schizophrenics show a marked reduction of single-stranded

DNA breaks, a marker for apoptosis, in the anterior cingulate cortex, whereas
bipolars do not show this change (10). This pattern is potentially explained by
the activation of a DNA “repair” mechanism that can offset the effects of the apop-
totic cascade (11).
Research aimed at elucidating the underlying neurobiology and genetics of
bipolar disorder, and factors associated with treatment response, have been
limited by a heterogeneous clinical phenotype and lack of knowledge about its
131

underlying diathesis (12). An important concept regarding the etiopathogenesis of
bipolar disorder and schizophrenia that must be factored into this discussion
involves the concept of the endophenotype, deﬁned as the “measurable components
unseen by the unaided eye along the pathway between disease and distal genotype”
(13). Endophenotypes are quantiﬁable components in the genes-to-behaviors
pathways, distinct from psychiatric symptoms, which make genetic and biological
studies of etiologies for disease categories more manageable (14). It is no surprise
then that the endophenotype concept has emerged as a strategic tool in neuropsy-
chiatric research. The question that is explored in the discussion that follows
is whether unique endophenotypes can be identiﬁed in bipolar disorder and schizo-
phrenia using gene expression proﬁling data. The potential strength of this approach
is the fact that databases obtained for these studies typically contain information

for as many as 20,000–30,000 different genes that can be organized according to
functionally relevant biopathways and /or clusters.
To explore this and other questions regarding the presence of a cellular endo-
phenotype for bipolar disorder, gene expression proﬁling (GEP) has been used as a
powerful screening tool, for the broad evaluation of molecular functions in subjects
with bipolar disorder.
THE STUDY OF APOPTOSIS IN HUMAN HIPPOCAMPUS
Brieﬂy, the cohort used in this study consisted of normal controls, schizophrenics,
and bipolars that were matched for age and postmortem interval and have been
previously described in detail (15). The normal control, schizophrenic, and
bipolar subjects were reasonably well-matched for age, postmortem interval,

gender, and hemisphere. All of the schizophrenic subjects were treated with
neuroleptic agents and all of the bipolar subjects were treated with lithium carbonate
and/or other mood stabilizing agents, including lithium carbonate, valproic acid,
carbamazepine, and clonazepam, during the year prior to death.
In analyzing the data, initial tests of signiﬁcance did not show appreciable
changes in the apoptosis cascade in either group (16). Since the human hippo-
campus is composed of many different subregions, sublaminae, and cellular
subtypes, it is relatively difﬁcult to detect subtle changes in the expression of
genes when whole extracts are analyzed, as they were in this study. To avoid
Type II statistical errors, that is, suggesting that there were no signiﬁcant

changes, when in fact they might exist within discrete subregions, layers, or
cellular subtypes within the hippocampus, we developed a post hoc method for
analyzing gene expression proﬁling data that would minimize the risk of such
errors. It is becoming broadly recognized that gene expression proﬁling and
other genomics technology in the hunt for disease genes requires that we
develop methods for evaluating associations between multiple and complicated
factors (17) and assessing the reliability of microarray data (18,19). To overcome
these limitations, we used a post hoc analysis (20) of the microarray data from
bipolars and schizophrenics that evaluated functional clusters of genes using a
low stringency approach (21).
An ad hoc metric was developed based on a combination of probability

theory and two separate corrections for multiple comparisons. A requirement for
such an analysis is that changes in the hybridization of any particular gene to its
probe sets must occur independently of probe sets for other genes. If the probe
sets for all of the genes in one particular biopathway were all clustered within a132 Benes

discrete sector of a microarray, then the hybridization of the respective mRNAs
to their appropriate probe sets could not be assumed to be independent of one
another and probability theory could not be used for the analysis.
To analyze the data, it was also important to examine changes in gene
expression at the functional cellular level, so that a coherent understanding of the
data could be obtained. In order to identify biologically relevant clusters
of interrelated genes, GenMapp algorithms (www.genmapp.org) were used to
relate the dChip ﬁndings to several different biochemical pathways and /or
biologically related clusters of genes. The ﬁrst stage of the analysis involved select-
ing genes according to high and low stringency criteria for inclusion in the
GenMapp biopathways analysis. The inclusionary criterion was initially set at
p¼0.05 and this was progressively increased to 0.1, 0.15, 0.2, and 0.25, respectively.

When the inclusionary criterion was increased in a stepwise manner to p ¼0.25,
further increases in the number of genes entered into the GenMapp pathways
were observed. Beyond this p-value, some of the GenMapp pathways that
previously had not shown any activation began to show a random scatter of a
small number of genes. This suggested that further increases of the inclusionary
p-value would likely increase the background and compromise the signal-to-
noise ratio of the post hoc analysis. When the post hoc composite probability (Pc)
was calculated for the apoptotic cascade, it was 3 /C210227for bipolars and
4/C21029for schizophrenics (Fig. 1).
As shown in Figure 1, there were striking differences in the changes in the
expression of genes associated with apoptosis in schizophrenics versus bipolars.

Some genes showed changes in the same direction in both groups, while most
others occurred in opposite directions. For example, while caspase 2 was upregulated
in both groups, the antiapoptotic factor, Bcl-2, showed decreased expression in
bipolars, but increased expression in the schizophrenic group. The remainder of the
apoptosis genes showed fundamental differences in regulation in the two disorders.
For the bipolars, 24 out of a total of 44 genes in the apoptosis pathways satisﬁed
the low stringency criterion for inclusion in the analysis. As depicted in Figure 1,
there were several upregulated proapoptotic genes, including FAS ligand, FAS
receptor (22,23) perforin (24), TNF a(23,25), c-Jun (26), c-myc (27), BAK (28),

APAF-1 and caspases 2 (29) and 8 (23,30). Other genes that are thought to inhibit
apoptosis, such as TRAF1, IKK, IAP3, NF-kB (31), and Bcl-2 (32) also showed
increased expression in the bipolar group, but these changes would tend to counter-
act the inﬂuence of the 10 upregulated proapoptotic genes, particularly when
other key proapoptotic factors, such as JNKK and JNK (33) were found to be down-
regulated. The DNA repair enzyme, poly(adenosine diphosphate-ribosyl) polymer-
ase, [PARP (11)], also showed a decrease in regulation and this would tend to
increase the apoptotic potential of hippocampal cells in the bipolar group.
When the bipolars were broken down according to neuroleptic exposure
(Table 1), mRNA expression for the proapoptotic factors, FAS ligand, RIP, BID,

TRAF1, FADD, MDM-2, caspase 2, p53, and c-myc, as well as the antiapoptotic
factors, NIK, IKK, IAP3, were all increased in the drug naı ¨ve bipolars, while the
proapoptotic factors JNKK and JNK, as well as the antiapoptotic factors, IAP2,
NF-kB-p105, and PARP, all showed decreased expression. The neuroleptic-free
bipolar subjects also showed a decreased expression of PARP (34). For the neuro-
leptic-treated bipolars, proapoptotic factors, such as perforin, TNF- a, caspase 6,
c-Jun, BAX, APAF-1, and caspase 2, all showed increased expression. Conversely,
antiapoptotic factors, such as IKK, NF-kB-p105, NF-kB-p65, MCL-1, Bcl-2, andSearching for a Cellular Endophenotype 133

FIGURE 1 A set of diagrams showing the apoptosis pathways, schizophrenics versus normal controls ( upper ) and bipolar disorder versus normal controls ( lower ).
The genes show either an upregulation ( dark gray ) or downregulation ( light gray ) and the intensity of the color varies according to whether the inclusion criterion for a
particular gene was p ¼0.05 (high stringency) or p ¼0.25 (low stringency). The p-values are shown to the right for each gene. Using low stringency criteria, the
apoptosis pathways for the bipolar subjects show 19 out of 44 genes with changes in expression. Of these 14 are upregulated and only ﬁve are downregulat ed.
For the schizophrenics, eight genes were upregulated and ﬁve were downregulated. In both cases, pivotal genes at the beginning of the apoptosis casca de show
changes in regulation. Overall, the bipolars show an increase of proapoptotic changes not seen in the schizophrenics.Searching for a Cellular Endophenotype 135

Bcl-x, were all upregulated in the bipolars receiving neuroleptic. As shown in
Table 1, there was an overall increase of antiapoptotic changes in gene expression
in the bipolars, suggesting that neuroleptics may suppress apoptotic cell death in
this disorder. The potential effect of mood-stabilizers on changes in apoptosis
gene expression was also considered; however, all of the bipolar subjects were
actively treated with these agents at the time of death.
In the schizophrenic group, signiﬁcant changes in the expression of genes
associated with apoptosis were also observed (post hoc Pc ¼4.3/C21029), but there
were differences with respect to the speciﬁc genes affected and the direction of the
changes (Fig. 1). Four proapoptotic genes (RIP, BID, JNK, and caspase 2), and two
prosurvival genes (Bcl-x and Bcl-2) showed an overall increase of expression.
Other proapoptotic genes, such as granzyme B (24,35), caspase 8 (30,36), MEKK1

(27,37), and c-myc (27), showed decreased expression in the schizophrenic group.
These latter changes would tend to suppress the apoptotic potential of hippocampal
cells, as these four factors are believed to play a critical role in facilitating the pro-
gression of apoptosis. When the schizophrenic group was broken down according
to “low” (CPZ-equivalent dose ,500 mg /day; average ¼189+173 mg /day) and
“high” (CPZ-equivalent dose .500 mg /day; average ¼816+290 mg /day) dose
neuroleptic exposure, the proapoptotic factors Fas ligand, perforin, TRAIL,
caspase 8, MEKK1, p53, c-myc, BAX, and BAK showed decreased expression in
schizophrenics receiving low dose neuroleptic (Table 1). Some prosurvival genes,
such as TRAF1 and MDM-2, showed decreased expression, whereas others, such

as BCL-2, showed increased expression. In the “high” dose subgroup, the pattern
observed was quite different. Several proapoptotic genes, including perforin,
TRAIL, RIP , TNF a, caspase 2, and BAK, were upregulated, whereas anti-apoptotic
genes, such as IAP3, MCL-1, and PARP , were downregulated. Unlike the subjects
with bipolar disorder, the subjects with schizophrenia showed no difference in the
number of genes showing proapoptotic changes in expression. On the other hand,
the number of genes showing antiapoptotic changes in expression was markedly
reduced, suggesting that neuroleptics might have some ability to increase apoptotic
potential in hippocampal cells of schizophrenics. The DNA repair enzyme, PARP ,
showed a decrease of expression in the schizophrenics treated with high dose neuro-

leptic and this change could potentially increase the amount of DNA fragmentation
present in these subjects (10). This observation further supports the view that the
decrease of DNA damage in schizophrenic is probably not due to a neuroleptic
effect (10).TABLE 1 Proapoptotic and Prosurvival Changes in Gene Expression in Schizophrenics and
Bipolars with and Without Neuroleptic Exposure
Proapoptotic Antiapoptotic Total
Bipolars
Neuroleptic-free 12 (66.7%) 6 (33.3%) 18
Neuroleptic-treated 14 (56.0%) 11 (44.0%) 25
Schizophrenics
Low neuroleptic 9 (47.4%) 10 (52.6%) 19
High neuroleptic 10 (76.9%) 3 (23.1%) 13
Data represent the number of genes showing changes in expression in relation to neuroleptic drug exposure.
Proapoptotic refers to genes associated with facilitation of the apoptosis cascade and cell death (e.g., BAX and

APAF-1) that showed an increase of expression, or genes associated with an inhibition of apoptosis (e.g., Bcl-2
and MDM-2) that showed a decrease of expression. Antiapoptotic refers to an increased expression of genes that
inhibit apoptosis and a decreased expression of genes that facilitate apoptosis.136 Benes

As shown in Figure 2, the microarray data for several apoptotic genes, includ-
ing FAS ligand, granzyme B, c-myc, PARP, BAK, Bcl-2, and APAF-1, were validated
using qRT-PCR. In each case, the direction of change in expression for the control,
schizophrenic, and bipolar groups were consistent with that seen using the micro-
array approach, except that the magnitude of these differences were generally
much greater. For example, in the case of c-myc, the fold changes were 25.2 and
þ5.4, respectively, in the schizophrenics and bipolars. Although there was no
change in PARP expression in the schizophrenics when neuroleptic effects were
not considered, the bipolars showed a 28.2 fold decrease when compared to
either the schizophrenic or control groups. Overall, the magnitude of the differences
between the groups that were detected with qRT-PCR was much larger than those
obtained with the microarrays and provided an important validation of the microar-
ray results.

Numerous earlier studies from this laboratory had suggested that oxidative
stress might occur in bipolar disorder and schizophrenia (38). Excessive amounts
FIGURE 2 FRET-based quantitative RT-PCR validation of microarray analyses of apoptosis genes
in normal controls, schizophrenics, and bipolars. Standard curves for log concentration versus
threshold cycle, like that shown for G3PDH, were established for each of the genes evaluated with
qRT-PCR. In addition, mRNA for glyceraldehyde-3-phosphate dehydrogenase (G3PDH), a
“housekeeping” gene, was similar for the three groups ( upper right hand ) and this gene was used
to normalize the data for the target genes ( lower tier ). As predicted from the microarray data,
mRNA for c-MYC was markedly decreased in schizophrenics, but increased in bipolars. In

contrast, PARP was strikingly reduced in the bipolars, while schizophrenics showed no differences.Searching for a Cellular Endophenotype 137

of glutamatergic activity acting upon GABAergic interneurons in both disorders (8)
could potentially cause oxidative stress to these and other neuronal cells (9). In this
setting, the antioxidation system, consisting of several different enzymes (Table 2)
that are capable of clearing reactive oxygen species (ROS), could potentially be
activated. If this occurs, it would tend to offset the effects of the apoptotic
cascade that is driven by the accumulation of ROS intracellularly. As shown in
Table 2, it is notable that several such genes were signiﬁcantly downregulated in
the bipolars, while the schizophrenics showed very little change in this system.
Together with a highly signiﬁcant reduction in the expression of the mitochondrial
electron transport chain (39) that results in a decline of energy production, the
reduced ability to clear ROS from cells in the hippocampus of bipolars could
contribute to the activation of the apoptosis pathway in these subjects (40).

This study reports the results of a novel post hoc analysis of an extant microarray
database, together with GenMapp biopathways and clusters, to obtain a more
inclusive understanding of how complex aspects of transduction, signaling, and
metabolism may be altered in schizophrenia and bipolar disorder. Indeed, with
this new methodology, it has been possible to detect marked changes in theTABLE 2 Comparison of Expression Proﬁling Results for Genes Associated with Antioxidant
Reactions in Normal Controls vs. Bipolars and Schizophrenics
Lactoperoxidase U39573 1.09 0.064
Heme oxygenease 1 Z82244 1.14 0.131
Superoxide dismutase 1 X02317 21.21 0.081
Catalase AL030579 21.17 0.124
Glutathione peroxidase 2 (gastrointestinal) X53463 1.11 0.041
Glutathione peroxidase 4 (phospholipid

hydroperoxidase)X71973 21.23 0.014
Glutathione peroxidase 1 X13710 21.14 0.134
Glyoxalase 1 NM006708 21.32 0.014
Microsomal glutathione S-transferase 3 AF026977 21.39 0.002
Hydroxyacyl glutathione hydrolase X90999 21.36 0.028
Glutathione S-transferase A4 AF025887 21.24 0.046
Glutathione S-transferase M3 (brain) AF043105 21.19 0.198
Esterase D /formylglutathione hydrolase AF112219 21.31 0.044
Glutathione synthetase U34683 21.23 0.015
Glutathione S-transferase A2 M16594 1.16 0.045
Glutathione S-transferase M5 L02321 1.14 0.032
Glutathione-S-transferase like; glutathione
transferase omegaU90313 21.25 0.021
C-terminal PDZ domain ligand of neuronal
nitric oxide synthaseAB007933 21.12 0.090
Human neuronal nitric oxide synthase
(NOS1 ) gene, exon 29, and complete cdsU17326 1.17 0.030

Human inducible nitric oxide synthase gene,
promoter and exon 1D29675 1.13 0.083
Nitric oxide synthase 3 (endothelial cell) M93718 1.23 0.059
Glutathione synthetase U34683 21.18 0.050138 Benes

regulation of genes associated with the apoptosic cascade and would not have been
detected, given the relative insensitivity of the standard approaches that employ an
alpha level of p ¼0.05 (39). The more sensitive analysis described above has
revealed robust changes in the expression of apoptosis genes in hippocampal
cells in both schizophrenic and bipolar subjects. Although there is some overlap
in the genes showing differences in expression when compared to normal controls,
the preponderance of such changes has been found to be remarkably different in
schizophrenics when compared to bipolars. The hypothesis that apoptosis may
play a role in the pathophysiology of schizophrenia and bipolar disorder can be
traced to earlier microscopic studies in the anterior cingulate cortex (41,42) and
hippocampus (43) that suggested a loss of interneurons occurs in both disorders.
These changes were found to be far more striking in bipolars (30–35% reduction)

when compared to schizophrenics (12–15% reduction) and it was postulated that
there may be a more marked activation of apoptosis in affective disorder than in
schizophrenia. A subsequent study demonstrated that there was a paradoxical
reduction in the amount of DNA damage present in the anterior cingulate cortex
of schizophrenic subjects (10). Indeed, the ﬁndings reported here are consistent
with this latter observation, as there was a downregulation of several proapoptotic
genes, such as granzyme B, caspase 8, c-myc, and BAX. Based on the results
reported here, it seems more likely that GABA cell pathology in schizophrenia
(4) may by related to an disturbance of intracellular signaling pathways, rather
than to overt cell loss, as appears to be the case in bipolar disorder (34,44).

A noteworthy aspect of these ﬁndings is the observation that neuroleptic
exposure was associated with a decrease of apoptotic potential in bipolars, but an
increase in schizophrenics. Both typical (45) and atypical (46) antipsychotic drugs
have been found to promote cell survival, although the atypical agents may be
more effective in this regard (47). Indeed, several atypical antipsychotic drugs
appear to protect against DNA damage (47). To date, only one neuroleptic, the
typical agent perphenazine, has been associated with increased DNA fragmenta-
tion (48), although one study has reported that clozapine may act as a hapten
and increase inﬂammatory potential (49). Contrary to the latter report, clozapine
has also been found to activate Akt (50), a prosurvival factor that, in turn, inhibits

glycogen synthase kinase-3 b(GSK-3 b), a protein that drives intracellular signaling
toward cell death via the Wnt pathway. Lithium carbonate, a standard mood-
stabilizing agent, is also believed to inhibit GSK-3 b(51). Both lithium and valproate
have also been found to be associated with increased expression of Bcl-2 (52,53) and
ultimately inﬂuence both signal transduction (51,54,55) and intracellular signaling
cascades that are fundamental to cell survival. Accordingly, the upregulation of
antiapoptotic genes in neuroleptic-treated bipolar subjects may reﬂect the fact that
all of these subjects were treated with mood-stabilizing agents during the year prior
to death.
IS THERE A CELLULAR ENDOPHENOTYPE IN THE HIPPOCAMPUS
OF BIPOLAR BRAIN?

to death.
Overall, the data reported here do support the hypothesis that there are fundamen-
tally different patterns of gene expression in subjects with bipolar disorder when
contrasted with those with schizophrenia (Fig. 3). These ﬁndings point to
the possibility that the activity of the apoptotic cascade and L-type calcium
channels are increased, while that for the electron transport chain and theSearching for a Cellular Endophenotype 139

anti-oxidation system are decreased in subjects with bipolar disorder. This dis-
tinctly proapoptotic pattern is in contradistinction to that seen in schizophrenics
that is antiapoptotic in nature. It is important to emphasize that the interpretation
of simultaneous changes in the expression of many genes that comprise a
FIGURE 3 Schematic diagrams depicting genes associated with the apoptosis cascade that show
changes in expression in bipolar disorder ( upper ) and schizophrenia ( lower ). In schizophrenia, as
postulated in an earlier study (10), there is an overall downregulation of the apoptosis cascade,
including granzyme B and caspase 8, in the cell periphery and the mitochondrial-associated
antiapoptotic factor, Bcl-2. In bipolars, proapoptotic factors, including two death ligands, FAS and
TNFa, as well as the FAS receptor, perforin, c-myc, and BAK are proapoptotic factors that are
upregulated. NF- kBp65 and p105 are also upregulated, but they may play a role in stimulating

the activity of the DNA repair enzyme, PARP-1, that is downregulated. Overall, the changes in
bipolars would promote apoptotic injury or death, while those in schizophrenics would promote cell
survival. Preliminary evidence has suggested that a voltage gated L-type calcium channel is
downregulated in schizophrenics and upregulated in bipolars, a pattern consistent with the idea
that oxidative stress may be contributing to the changes seen in the respective disorders.140 Benes

complex signaling pathway, such as apoptosis, is probably not straightforward, as it
is quite possible that such changes may not be additive in nature, as the post-
translational modiﬁcation of their respective proteins may not result in
corresponding changes.
Given this caveat, however, the detection of differences in the regulation of
proapoptosis changes in gene expression in bipolar disorder and detection of the
opposite changes in schizophrenia may provide some insight into the differential
nature of cellular endophenotypes in the respective two disorders. What is cur-
rently lacking is a detailed understanding of how these changes in gene expression
are determined at the cellular level. Are there genetic or epigenetic mechanisms
involved in the control of apoptosis that are mutated? Is it possible that the
neuronal activity mediated by these neurons contained within the hippocampus
plays a role in determining the expression of apoptotic genes? Can environmental

factors mediated via central mechanisms within the brain contribute to the abnor-
mal regulation of apoptosis genes in bipolar subjects (56)? What is clear is that
the answers to these questions, by their very nature, will bring us closer to under-
standing the nature of a cellular endophenotype in bipolar patients.
ACKNOWLEDGMENTS
This work was supported by grants from the National Institutes of Health
(MH42261, MH62822, MH /NS31862) and the generosity of Menachem and
Carmella Abraham, John and Virginia Taplin, and Anne Allen.
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B8 The Hypothalamic–Pituitary–Adrenal Axis in
Mood Disorders Centre of Excellence, University of British Columbia,
Vancouver, British Columbia, Canada
One of the most consistent ﬁndings in biological psychiatry is derangement of
the hypothalamic-pituitary-adrenal (HPA) axis in patients with severe mood
disorders. The HPA axis consists of the hypothalamus, pituitary, and adrenal
glands, various hormones and releasing factors, and regulatory neural inputs (1).
It regulates the body’s acute response to stress, and its actions in this regard
include mobilizing energy reserves through increased gluconeogenesis, lipolysis,
and protein degradation (2). It also plays a role in long-term adaptive changes to
physiological functions, for example, by modulating immune responses, facilitating
learning, and activating the sympathetic nervous system (1). The purpose of this

review is to examine the physiology of the HPA axis; outline the evidence for its
implication in the pathogenesis of depression and bipolar disorder; summarize
treatment options that may be efﬁcacious in restoring normal HPA axis functioning,
and thereby effective in treating mood disorders; and to suggest avenues for further
research.
PHYSIOLOGY OF THE HPA AXIS
The hypothalamus receives input from afferent catecholaminergic nerve ﬁbers,
including noradrenergic ﬁbers originating in the nucleus of the solitary tract
and the locus coeruleus (3), as well as from limbic structures, including the amyg-
dala, the hippocampus, and the stria terminalis. The medial parvicellular division
of the paraventricular nucleus of the hypothalamus produces corticotropin-

releasing hormone (CRH), a 41-amino acid peptide, and arginine vasopressin
(AVP), a nonapeptide, which are released into the portal circulation. CRH
interacts with the CRH1 receptor on the anterior surface of the pituitary gland,
stimulating the release of adrenocortcotropic hormone (ACTH) from the cortico-
tropes of the anterior pituitary. There is some evidence that AVP plays a role as
well, such that CRH and AVP act synergistically in regulating ACTH release
(3). ACTH enters the systemic circulation and binds to receptors on the adrenal
cortex, inducing the synthesis and release of the steroid hormone cortisol (4).
Once released into the serum, approximately 80% of cortisol molecules are
bound to cortisol-binding globulin (5). Cortisol itself plays a vital role in regulat-

ing the HPA axis, through a negative feedback loop in which it interacts with
receptors in the pituitary and hypothalamus to inhibit the synthesis and release
of CRH and ACTH.
145

The actions of cortisol, including negative feedback, are mediated through
two distinct cytoplasmic corticosteroid receptors, referred to as the type I or miner-
alocorticoid receptor (MR), and the type II or glucocorticoid receptor (GR) (1). The
mineralocorticoid receptor has a high afﬁnity for endogenous corticosteroids, and
regulates cortisol levels during normal physiological conditions, such as normal cir-
cadian ﬂuctuations in hormone levels. The glucocorticoid receptor has a high afﬁ-
nity for synthetic corticosteroids such as dexamethasone, but its afﬁnity for
cortisol is approximately one-tenth that of the MR (6). It is believed to mediate cor-
tisol activity during periods when high concentrations are present, such as during
the stress response (2).
The glucocorticoid receptor is present in almost all somatic cells, though the
relative number of receptors varies between cell types. The receptor resides in the

cytoplasm in an inactive form, as part of a complex with numerous other peptides,
including heat shock proteins, phosphatase PP5, and immunophilins FKBP5 and
Cyp40. When a substrate, such as cortisol or dexamethasone, binds to the ligand-
binding domain at the carboxy-terminal end of the glucocorticoid receptor, the
receptor complex is activated, and is translocated into the cell nucleus (2). Two pro-
jections at the centre of the receptor molecule allow the complex to bind to DNA. On
binding, the receptor complex undergoes an allosteric change, permitting a second
receptor complex to bind and dimerization of the complexes to occur. Once dimer-
ization is complete, the cortisol-receptor complex induces transcriptional trans-

activation or repression of selected genes, via interaction of two domains, an
N-terminal glucocorticoid-independent domain and a C-terminal glucocorticoid-
dependent domain, with glucocorticoid receptor elements in promoter regions (2).
The functional integrity of the HPA axis may be assessed by challenging it
with synthetic or natural hormones or glucocorticoids. The dexamethasone sup-
pression test (DST) measures serum cortisol levels following administration of
the synthetic glucocorticoid dexamethasone. In subjects with an intact HPA axis,
dexamethasone acts through the negative feedback loop outlined above to inhibit
the release of CRH, ACTH, and cortisol. Escape from cortisol suppression is indica-
tive of an abnormally functioning HPA axis. Recently, a reﬁned version of this test,

the combined dexamethasone /CRH test (7) has become widely utilized. The Dex /
CRH test involves administering a dose of human CRH following pretreatment
with dexamethasone. In patients with mood disorders, dexamethasone fails to
prevent a substantial release of ACTH and cortisol following CRH administration.
The Dex /CRH test has greater sensitivity in detecting abnormalities in the HPA axis
in patients with mood disorders compared to the DST (8).
HPA FUNCTION IN PATIENTS WITH MAJOR DEPRESSION
Most studies investigating alterations in HPA functioning in patients with mood
disorders have been carried out in patients with major depressive disorder. As
they have been important in guiding subsequent studies in bipolar patients, and
in understanding possible biological mechanisms of action, they are reviewed

brieﬂy here. Abnormalities in the HPA axis were reported in depressed patients
more than 50 years ago (9). The most widely reported ﬁnding, that a signiﬁcant per-
centage of patients with mood disorders hypersecrete cortisol, and do not suppress
cortisol production in response to administration of dexamethasone, a state akin to
a chronic sustained stress response, was ﬁrst described 30 years ago (10).146 Bond and Young

Since this initial work, numerous studies have demonstrated other abnormal-
ities in HPA axis functions. CRH levels have been reported as elevated in patients
with major depression (11,12). The Dex /CRH test has revealed that depressed
patients do not inhibit ACTH production to exogenous administration of CRH
stimulus following pre-treatment with dexamethasone (11,13). There is less consist-
ency in ﬁndings from studies of baseline levels of ACTH in depressed patients, with
some reporting elevated levels of ACTH (14–18), and others describing normal or
low ACTH levels (19–25). Enlarged pituitary and adrenal glands have been
reported in studies of depressed patients (26–29), though these may be a state
phenomenon, as adrenal gland volume has been reported to return to normal fol-
lowing remission of depression (30). Evidence for increased cortisol production
includes elevated levels in serum, urine, and cerebrospinal ﬂuid.

One theory to explain the discrepant ﬁndings regarding ACTH levels in
depressed patients suggests that the physiology of hypercortisolism changes over
the course of depressive illness (4,31). According to this hypothesis, elevated
CRH levels lead to increased production of ACTH early in the course of depression.
Over time, however, the sensitivity of the pituitary gland to CRH attenuates, and
ACTH production decreases. As ACTH release drops, elevated levels of cortisol
are maintained due to increased adrenal cortical sensitivity to ACTH. Supporting
evidence for this theory includes the observations that depressed patients with
hypercortisolemia display attenuated release of ACTH when administered exogen-
ous CRF (30,32–34) and that the greatest attenuation of ACTH release occurs in the

most severely depressed patients (23). As well, it has been demonstrated that
administration of exogenous ACTH leads to a long-lasting hyper-responsiveness
to ACTH in healthy individuals (35,36).
Successful treatment of depression is generally, though not invariably, associ-
ated with normalization of HPA axis functioning. Lack of resolution of HPA axis
abnormalities in successfully treated patients has been shown to be predictive of
a poor prognosis (37–39). Such patients in one study had a six-fold greater risk
of relapse in the ﬁrst six months after discharge from hospital (39). Recurrence of
HPA abnormalities during remission from depression is similarly predictive of
relapse (37), although whether this indicates a causal link, or simply that HPA
axis abnormalities are one of the ﬁrst signs of relapse, is not clear.

HPA FUNCTION IN PATIENTS WITH BIPOLAR DISORDER
Evidence of hypercortisolemia and other HPA axis abnormalities have been repeat-
edly demonstrated in all phases of bipolar illness. A review of 17 studies of the DST
in manic patients reported an average nonsuppression rate of 39% across studies
(40). Elevated baseline serum cortisol levels (41), nonsuppression of cortisol on
the DST (42–45) and elevated cortisol release during the Dex /CRH test (46) have
been frequently reported in bipolar depression. Rybakowski and Twardowska
(46) also described a positive correlation between cortisol levels following CRH
administration and severity of depression. While the relative rates of HPA axis
hyperactivity in the manic and depressive phases of bipolar disorder have not
been systematically investigated, one small study utilizing the DST in rapid

cycling patients (47) detected higher levels of urinary free cortisol during
depression than mania.
Elevated cortisol levels (48,49) and nonsuppression of cortisol in response to
dexamethasone (41,50,51) have also been reported in patients experiencing mixedHypothalamic–Pituitary–Adrenal Axis 147

manic episodes. Studies that have compared patients with mixed mania to “pure”
manic patients (40,48,50) have consistently reported greater HPA axis abnormalities
in patients with mixed episodes, though possibly due to small sample sizes, the
differences were generally not statistically signiﬁcant. One study (48) did report sig-
niﬁcantly greater morning plasma cortisol, post-dexamethasone plasma cortisol,
and CSF cortisol in patients with mixed mania compared to those with pure mania.
Two small studies (total N¼11) have reported on HPA axis functioning in
bipolar patients with a rapid cycling course, with conﬂicting results. Watson et al.
(52) found that cortisol response to the Dex /CRH was stable over two visits in
their sample, and was independent of mood state. Tomitaka et al. (47) found
greater cortisol levels during the DST in the depressed than the manic phase
The debate over whether HPA axis abnormalities in bipolar patients are

dependent on illness state, or are trait features and so indicative of underlying
pathophysiologic processes, has received some attention in the literature. A
recent report on 53 bipolar subjects (8) found that remitted subjects and those
with ongoing depressive symptoms had similarly enhanced cortisol response to
the Dex /CRH test compared to normal controls. Another study (53) reported
only partial normalization of cortisol response to the Dex /CRH test following
remission from a manic episode. Cortisol levels during remission in this sample
were still greater than those in normal controls. Interestingly, during serial
testing of euthymic bipolar patients over four years (54), most patients displayed
intermittently positive DSTs. This ﬁnding could be consistent with either the inﬂu-

ence of state factors, or an inherently oscillating biological process. Other studies
have reported elevated cortisol responses to the Dex /CRH test (55) and elevated
salivary cortisol levels (56) in ﬁrst degree relatives of bipolar patients. Finally,
expression of glucocorticoid receptor alpha mRNA was noted to be reduced in
affectively ill and remitted bipolar patients, as well as their ﬁrst degree relatives,
compared to a control group with no personal or family history of psychiatric
illness (57). Thus, while some of the results are preliminary, the preponderance of
evidence appears to suggest that HPA axis abnormalities in bipolar patients
persist into euthymia, and are present to some extent in unaffected family
members of bipolar probands.
Some evidence points toward distinct patterns of HPA axis abnormalities in

major depressive disorder and bipolar disorder. For example, while a number of
studies report a decreased density of brain GR receptors in both conditions, the
affected brain regions appear to be unique to the illnesses (see subsequently). As
well, reductions in GR receptors may be more pronounced in patients with major
depression. A direct comparison of lymphocyte GR numbers between patients
with major depressive disorder and bipolar manic patients described signiﬁcantly
lower mean GR numbers in the depressed patients (58). Depressed or euthymic
bipolar patients were not studied, so the possibility that the difference was
related to mood state in the bipolar patients cannot be ruled out. Interestingly, non-
suppression of cortisol during the DST appears to be more common in bipolar

illness than in major depressive disorder (46,53). Finally, pituitary gland volume,
which has been demonstrated to be increased in patients with major depression
(27), was reported in one study to be reduced in bipolar patients compared to
both depressed patients and healthy controls (59).
As DST nonsuppression has been described in many axis I psychiatric dis-
orders, including major depressive disorder, schizophrenia, and eating disorders148 Bond and Young

(60), its usefulness as a diagnostic instrument for bipolar illness is limited. Nonethe-
less, as in patients with major depressive disorder, persistence of HPA axis abnorm-
alities into remission in bipolar patients may have prognostic signiﬁcance. In one
study, Vieta et al. (61) administered 100 micrograms of CRH to 42 lithium-treated
bipolar I patients in remission, and 21 healthy controls. The bipolar patients dis-
played higher baseline and peak ACTH concentrations than the control subjects.
A higher area under the ACTH concentration curve in bipolar subjects predicted
relapse at both 6 and 12 months. When bipolar subjects who subsequently relapsed
were removed from the analysis, the difference between bipolar subjects and con-
trols with respect to ACTH levels disappeared.
POSSIBLE MECHANISMS OF HPA AXIS ABNORMALITIES
IN PATIENTS WITH MOOD DISORDERS
Research on the mechanism of HPA axis abnormalities in patients with major

depressive disorder has focused on alterations in GR number or functioning (2).
Research investigating whether the number of CNS or peripheral GR receptors is
decreased in depressed patients has been contradictory (62), with some studies
suggesting a decreased number of receptors (58,63–66), while others have not
found differences between depressed patients and normal controls, or patients
with other psychiatric illnesses (67–74). Studies in patients with bipolar disorder
have also produced inconsistent results. One study of lymphocyte GR numbers
(75) actually reported an increase in bipolar patients compared to healthy controls.
Most other studies have used mRNA as a surrogate marker for receptors, and have
reported decreased GR mRNA in lymphocytes (51) and postmortem brain samples

(66,76). GR mRNA appears to be decreased in characteristic brain regions in speciﬁc
mental illnesses. For example, Webster et al. (77) reported reduced GR mRNA in the
entorhinal cortex, subiculum, and CA3 and CA4 of the hippocampus in bipolar
patients, a pattern different from that seen in patients with major depression or
schizophrenia. Perlman et al. (76) described decreased GR mRNA in the basolat-
eral/lateral nuclei of the amygdala in patients with bipolar disorder and schizo-
phrenia, but not patients with major depressive disorder.
The common clinical observation that depressed patients do not display
the physical signs of hypercortisolism typical of Cushing’s Syndrome suggests
hypofunctionality of GRs (78). Many studies have demonstrated decreased
GR functioning in patients with major depressive disorder, such as decreased

translocation into the cell nucleus following ligand binding (69,79,80), or dimin-
ished inhibition of lymphocyte proliferation (71,80–83). Fewer studies have
been carried out in patients with bipolar illness. One paper (84) reported that
GR binding to DNA was decreased in depressed bipolar patients compared to
healthy controls, and was at an intermediate level in euthymic bipolar patients.
This was despite the fact that the number of nuclear GR receptors was increased
in patients, suggesting normal or increased translocation into the nucleus.
Moutsatsou et al. (85) were unable to detect any mutations in GR DNA in 15
bipolar patients, using agarose gel electrophoresis, heteroduplex analysis, and
DNA sequencing. This highlights the fact that physiologic derangements other

than those directly involving GR structure could also contribute to the HPA axis
abnormalities that have been observed in patients with mood disorders. These
include changes in cortisol-binding globulin levels which alter bioavailability of
cortisol (86); decreased entry or increased removal of glucocorticoids from cellsHypothalamic–Pituitary–Adrenal Axis 149

(87); alterations in intracellular metabolism of glucocorticoids (88); post-transla-
tional modiﬁcations such as phosphorylation (89); and expression or functioning
of other transcription factors (75), or components of the receptor complex other
than the GR (90,91). For example, Binder et al. (90) reported that overexpression
of the receptor complex component FKBP5 was associated with decreased GR func-
tion in squirrel monkeys. Also, depressed patients exhibit reduced activity of cyclic-
AMP-dependent protein kinase A (92), which normally plays a signiﬁcant role in
increasing GR activity.
There is evidence that AVP activity is increased in patients with mood dis-
orders, and may play a role in maintaining ACTH release despite downregulation
of CRH1 receptors and likely CRH activity. AVP has been demonstrated to have
ACTH-releasing properties when administered to human subjects (93), through
interaction with the V3 (also known as the V1b) receptor on the anterior surface

of the pituitary gland (3). Studies employing stress paradigms in rats have demon-
strated elevated AVP synthesis (94). Also, while CRH mRNA and CRH1-receptor
mRNA levels are reduced by elevated glucocorticoid levels (95), V3 receptor
mRNA levels are increased. Studies in patients with mood disorders are highly sug-
gestive of increased AVP activity. A mixed sample of patients with major depressive
disorder or bipolar disorder, depressed phase, exhibited a greater cortisol response
when administered AVP than did control subjects (96). Watson et al. (52) reported
that AVP levels after pre-treatment with dexamethasone were higher in bipolar
patients and patients with major depressive disorder than in controls, suggesting
a lack of negative feedback from glucocorticoids on AVP release.

The role of limbic structures, such as the amygdala and hippocampus, and
brainstem regions such as the locus coeruleus, in mediating HPA axis abnormal-
ities in patients with mood disorders has received surprisingly little attention.
Several lines of evidence are suggestive in this regard. Electrical stimulation of
the hippocampus has been demonstrated to decrease plasma corticosteroid
levels in several species, including primates (97), and lesions of the hippocampus
result in glucocorticoid hypersecretion during activation of the HPA through
stress (98). Electrical stimulation of the amygdala in rats has been correlated
with decreased release of CRH into the hypophyseal portal bloodstream (99).
As well, depletion of biogenic amines in rats by reserpine is associated with

decreased density of GRs in the hippocampus, frontal cortex, pituitary, and lym-
phoid tissues (100). A recent report in euthymic bipolar patients described
increased amygdala volume with HPA axis abnormalities (101). A corticotropin-
releasing hormone receptor, CHR2, is primarily expressed in the limbic brain,
suggesting a bidirectional relationship between this region and the HPA axis
(102). Studies in this area are clearly hindered by the complex interrelationships
between limbic system structures, neurotransmitter systems, and the HPA axis
(103), though electrical stimulation or neurotransmitter depletion studies such as
those described above may prove to be fruitful areas of research.
CONSEQUENCES OF HYPERCORTISOLEMIA
Glucocorticoid and mineralocorticoid receptors are distributed differentially

throughout the central nervous system. MRs are localized exclusively in the
limbic system, particularly the hippocampus, parahippocampal gyrus, and the
entorhinal and insular cortices. GRs have a wider distribution, and are found in
limbic system structures, various nuclei of the hypothalamus, including the150 Bond and Young

paraventricular nucleus, and particularly in the frontal cortex (6). The hippocampus
plays an important role in the formation of episodic or declarative memories, while
the frontal cortex mediates executive functioning and working memory.
Hypercortisolemia has been investigated in animal models, healthy human
volunteers, patients with endocrine diseases that cause hypercortisolism, such as
Cushing’s Syndrome, and in psychiatric patients. Investigations in rodents indicate
that chronic exposure to high levels of glucocorticoids is associated with cognitive
impairment. Young rats so exposed develop memory loss and hippocampal atrophy
similar to that seen in aged rats (104,105). Conversely, young rats that undergo
adrenalectomy, and are kept alive with low levels of exogenous glucocorticoids,
do not experience these changes as they age (105). Hippocampal changes appear
to be a result of dendritic atrophy of CA3 pyramidal cells (106). Further studies

have suggested that the ratio of MRs to GRs is important in mediating structural
and cognitive changes associated with hypercortisolism (6), and that excitatory
amino acids, serotonin, and NMDA also play roles in the development of cognitive
impairment and structural brain changes related to hypercortisolism (107).
Impairments in both declarative and working memory have also been
observed after glucocorticoid administration in healthy volunteers (108–110).
For instance, in a placebo-controlled crossover trial involving 20 healthy male
subjects, hydrocortisone 20 mg twice daily administered for 10 days was associated
with impairments on tests of cognitive functioning sensitive to frontal lobe
dysfunction. These deﬁcits were reversible after discontinuation of hydrocortisone
administration.

A relationship between chronically elevated levels of endogenous corticoster-
oids and cognitive impairment has also been unambiguously demonstrated. Stark-
man et al. (111) detected a signiﬁcant relationship between memory impairment,
high cortisol levels, and decreased hippocampal formation volume in a sample of
patients with Cushing’s syndrome. Lupien et al. (6) reported that long-term
elevation of endogenous corticosteroids in elderly human subjects was associated
with signiﬁcantly impaired declarative memory, but not with changes in non-
declarative memory. Furthermore, MRI scans revealed that subjects with chronically
elevated cortisol levels had a 14% smaller hippocampal volume when compared to
subjects with normal cortisol levels over time. Whether such cognitive impairment

is reversible is not clear. Interestingly, however, loss of brain volume in 38 patients
with Cushing’s syndrome was reversed after hypercortisolemia was corrected (112).
Many studies document the existence of cognitive deﬁcits in patients with
bipolar disorder. The data from these reports suggest that this impairment is a
trait phenomenon that persists even during euthymic intervals (113,114). One
report has correlated neuropsychological impairments in bipolar patients with glu-
cocorticoid receptor function, as measured by the DST (115). In this study, 17 euthy-
mic bipolar patients and 16 controls participated in tests of verbal declarative and
working memory. The patients made signiﬁcantly more errors of omission and
commission on tests of working memory, and also displayed impaired verbal rec-

ognition memory. Commission errors on tests of working memory were highly cor-
related with nonsuppression of cortisol on the DST ( r¼0.64, P,0.0006).
In addition to its effects on the central nervous system, cortisol is also known
to antagonize the effects of insulin and to raise blood pressure, thereby increasing
the risk of diabetes, hypertension, and coronary artery disease (6). This is particu-
larly noteworthy, given the known increase in early mortality in patients suffering
from bipolar disorder, particularly related to cardiovascular causes.Hypothalamic–Pituitary–Adrenal Axis 151

In summary, then, sustained hypercortisolism is associated with structural
changes in the hippocampus, as well as deﬁcits in working memory and declarative
memory, functions known to be mediated by the hippocampus and the frontal
lobes, areas of the brain which are rich in glucocorticoid receptors. The effects of
hypercortisolism may also increase the risk of cardiovascular disease and diabetes.
EFFECTS OF SOMATIC TREATMENTS
Research suggests that antidepressant treatment leading to the resolution of
depressive symptoms generally normalizes HPA axis functioning in patients with
major depression (116–119). HPA axis abnormalities frequently persist, however,
following unsuccessful antidepressant treatment (120). In contrast, there is evidence
that lithium therapy actually accentuates abnormalities on the DST and Dex /CRH
test, at least in patients with major depressive disorder. Bschor et al. studied
depressed patients who were refractory to at least four weeks of adequate anti-

depressant therapy. Signiﬁcant increases in serum cortisol and ACTH were noted
with both the DST (121) and the Dex /CRH test (122) after lithium was added as
an augmenting agent. Similar results were observed in both responders and non-
responders, and were in fact more pronounced in responders, suggesting that res-
titution of normal HPA axis functioning is not a prerequisite for treatment response.
The mechanism by which lithium exerts this effect is not clear. Serotoninergic axons
are known to project to both the hippocampus and the paraventricular nucleus of
the hypothalamus (123), and it has been speculated that enhanced serotonin-
mediated release of CRH as a result of lithium treatment may underlie the HPA
effects of lithium (122).
Investigations on the effect of lithium on the HPA axis in bipolar patients are

relatively lacking. One recent study reported that response to the Dex /CRH test in
bipolar patients taking lithium was no different than that observed in patients
receiving other medications, providing preliminary evidence that lithium may
not potentiate HPA axis abnormalities in bipolar patients (8). Few other investi-
gations on the effects of mood stabilizing medications have been reported in
mood disorders patients. Studies utilizing the Dex /CRH test in euthymic patients
with major depressive disorder (39) and bipolar disorder (8) reported that patients
treated with carbamazepine experienced a greater rise in serum cortisol levels
following CRH administration than did patients receiving other medications.
However, this is likely related to a pharmacokinetic drug interaction rather than

a speciﬁc effect on the HPA axis, as carbamazepine is known to induce CYP3A4,
the primary enzyme responsible for dexamethasone metabolism. Given the result-
ing decrement in dexamethasone suppression of cortisol, CRH acts relatively
unopposed in elevating ACTH and cortisol levels. Conﬁrming this hypothesis,
Watson et al. (8) found that patients taking carbamazepine had lower dexametha-
sone levels ( P,0.0005) than patients receiving other medications.
Research regarding the effects of lithium on the HPA axis has been carried out
in animals and healthy human subjects. Many (124–126) but not all (127) studies
indicate that rats receiving lithium over two to four weeks display increased GR
numbers in regions of the brain such as the hippocampus and the paraventricular

nucleus of the hypothalamus. A report on the effect of lithium on GR numbers in
mouse lymphoma cells, however, was negative. Two studies (128,129) suggest
that lithium diminishes GR functioning in rodents, possibly by way of interactions
with the GR receptor complex, particularly BAG-1, a protein constituent of the152 Bond and Young

complex (129). A study involving human subjects (130), however, reported that
lithium, in contrast to antidepressant medications, did not induce translocation of
the GR into the lymphocyte nucleus. If lithium does indeed inhibit GR functioning,
this may explain its effect on accentuating HPA hyperactivity, a ﬁnding that has
been replicated in animals receiving lithium (131–133).
The effects of sodium valproate and carbamazepine on the HPA axis have
been studied in rodents and human volunteers. Valproate treatment for one
week led to decreased CRH concentrations in several brain regions, including
the amygdala and the paraventricular nucleus of the hypothalamus (134).
However, neither acute (135) nor chronic (136) treatment with valproate decreased
ACTH or cortisol levels induced by hypoglycemia in human subjects, nor did acute
treatment lead to decreased release of ACTH stimulated by naloxone (137). Both
valproate and carbamazepine, like lithium, were reported to impair GR function-

ing in rodents (128). Valproate, unlike the other two mood stabilizers, was also
associated with decreased nuclear and cytoplasmic GR numbers. In a study in
healthy human subjects, carbamazepine was associated with HPA axis hyperactiv-
ity, including robust ACTH response to CRH infusion, despite the presence of
hypercortisolemia (138).
DIRECTIONS FOR FUTURE RESEARCH
Based on the currently available data, it is not possible to conclude with certainty
that HPA axis abnormalities observed in patients with mood disorders have
etiological signiﬁcance, or whether they are a consequence of other pathophysiolo-
gic processes. Recently, researchers have begun to focus on modulating HPA axis
functioning in patients with mood disorders as a possible treatment strategy.

If these investigations bear fruit, not only will they broaden the armamentarium
of available treatment options for major depression and bipolar illness, but they
will also provide evidence of a primary pathophysiologic basis for HPA axis
Preliminary evidence exists for a number of different approaches, including the
use of the adrenal steroid dehydroepiandrosterone (139), which is known to have
antiglucocorticoid properties, and steroid synthesis inhibitors such as ketokonazone,
aminoglutethimide, and metyrapone (140,141). Interestingly, both glucocorticoid
receptor agonists such as dexamethasone (142,143) and antagonists such as mifepris-
tone (144) may have some efﬁcacy in the treatment of mood disorders. Activation of
GRs leading to enhanced negative feedback at the level of the pituitary is hypoth-

esized to underlie the efﬁcacy of GR agonists, while GR antagonists are believed to
have acute antiglucocorticoid activity, as well as leading to upregulation in GR
number and consequently improved negative feedback. A recent small double-
blind placebo-controlled crossover trial of mifepristone versus placebo in patients
with bipolar disorder (144) provides preliminary evidence that this treatment
yields beneﬁts in both mood and cognition. Additional studies are needed to ade-
quately assess the efﬁcacy of these treatment approaches.
Further research is also needed to clarify other aspects of HPA axis function-
ing in patients with mood disorders. The roles of AVP, as well as neuroregulatory
input from higher brain centers, such as limbic structures, in HPA axis dysfunction

have yet to be fully elucidated. Little research has focused on the role of the miner-
alocorticoid receptor in mediating HPA axis abnormalities, although one recent
study demonstrated deﬁcits in mineralocorticoid receptor mRNA in the frontalHypothalamic–Pituitary–Adrenal Axis 153

cortex of patients with bipolar disorder and schizophrenia (143). Finally, most
investigations of HPA axis function have focused on patients with Bipolar I Dis-
order, and there is little or no information speciﬁcally regarding Bipolar II patients.
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B9 Brain Imaging Studies in Bipolar Disorder
E. Serap Monkul
Mood Disorders Clinical Neurosciences Program, Department of Psychiatry,
University of Texas Health Science Center at San Antonio, San Antonio, Texas, U.S.A.,
and Department of Psychiatry, Dokuz Eylu ¨l University School of Medicine,
Izmir, Turkey
Paolo Brambilla
Department of Pathology and Experimental and Clinical Medicine, Section of
Psychiatry, University of Udine, Udine, and Scientiﬁc Institute IRCCS E. Medea,
Bosisio Parini, Italy
Fabiano G. Nery
University of Texas Health Science Center at San Antonio, and Audie
L. Murphy Division, South Texas Veterans Health Care System, San Antonio, Texas,
U.S.A., and Institute of Psychiatry, University of Sa ˜o Paulo School of Medicine,
Sa˜o Paulo, Brazil
John P. Hatch
Mood Disorders Clinical Neurosciences Program, Department of Psychiatry, and

Department of Orthodontics, University of Texas Health Science Center at
San Antonio, San Antonio, Texas, U.S.A.
Center of Excellence for Research and Treatment of Bipolar Disorders, Department of
Psychiatry, University of North Carolina School of Medicine, Chapel Hill,
HISTORICAL BACKGROUND
The research on neurobiological markers of bipolar disorder has progressed rapidly
over the past two decades. The rapid progress started with the early computed tom-
ography studies in the 1980s, followed by studies with newer brain imaging tech-
niques, in particular magnetic resonance imaging (MRI). These studies have
focused mainly on brain structures that form a limbic–thalamic–cortical circuit

and a limbic–striatal–pallidal–thalamic circuit, which are thought to play a role
in the pathophysiology of mood disorders (1–4) (Fig. 1). The prefrontal cortex,
amygdala-hippocampus complex, thalamus, basal ganglia, and connections
among these areas comprise neuroanatomic brain circuits involved in mood regu-
lation (1). Other areas, not spatially related to this fronto-limbic circuit, including
the cerebellum, with its vermal connections to limbic structures, also participate
in the regulation of mood (3). Functional, neurochemical and anatomical
abnormalities in these brain regions have been examined with several imaging
161

tools including structural MRI, functional MRI (fMRI), magnetic resonance spec-
troscopy (MRS), single photon emission computerized tomography (SPECT), and
positron emission tomography (PET). These studies provide evidence of abnormal-
ities in the prefrontal cortex, medial temporal lobe structures, striatum, and cerebel-
lum of patients with bipolar disorder. Some of the suggested abnormalities include
the following: ( i) Decreased N-acetyl-aspartate levels, which is possibly an early
marker of neuronal impairment and that could possibly be abnormal even before
detectable anatomical MRI changes take place. ( ii) Cerebellar vermis size decreases
with repeated illness episodes, suggesting a neurodegenerative change. ( iii) Amyg-
dala volumes are directly correlated with age in adolescent bipolar patients,
suggesting abnormal neurodevelopmental processes affecting the medial temporal
lobe structures during adolescence. ( iv) Callosal white matter density seems to be

reduced in bipolar disorder, which may affect inter-hemispheric connections (5).
It is not known whether such abnormalities have a neurodevelopmental
origin or if they result from neurodegenerative or compensatory mechanisms.
In this chapter, we review existing neuroimaging literature on bipolar disorder,
speculate about their possible origins vis-a `-vis a neurodevelopmental versus
neurodegenerative hypothesis, and assess emerging new ﬁndings that suggest
future directions for this research.
STRUCTURAL NEUROIMAGING
Total Brain Volume
Studies evaluating the total brain volume of bipolar patients have produced inter-
esting ﬁndings. A meta-analysis by McDonald and colleagues (6) including 404
OFC
(VLPFC)SGPFC
(anterior cingulate)DLPFC
AmygdalaHippocampus
Hypothalamus

OFC
Striatum Thalamus Cerebellar vermisBehavior Emotion Cognition
Vegetative
symptoms
FIGURE 1 Neural circuitry related to the regulation of mood. Abbreviations : DLPFC, dorsolateral
prefrontal cortex; OFC, orbitofrontal cortex; SGPFC, subgenual prefrontal cortex; VLPFC,
ventrolateral prefrontal cortex. Source : modiﬁed from Ref. 99.162 Monkul et al.

bipolar patients from 26 studies showed that global cerebral volume was preserved
in bipolar disorder with the right lateral ventricular enlargement as the only signiﬁ-
cant abnormality, although the authors noted high levels of heterogeneity among
studies. A recent MRI study, using voxel-based morphometry to assess abnormal-
ities of total gray and white matter volumes throughout the entire brain, showed no
signiﬁcant differences in gray matter volume between patients with bipolar I dis-
order (n ¼37, 31 on mood stabilizers, one on olanzapine, ﬁve untreated, eight on
mood stabilizers plus antipsychotics) and healthy controls. In contrast, bipolar sub-
jects showed frontal and parietal white matter deﬁcits that overlapped anatomically
with ﬁndings for schizophrenic patients (7). This ﬁnding was conﬁrmed and
extended in a longitudinal study by Farrow and colleagues (8), who followed
ﬁrst-episode psychosis patients (25 with schizophrenia and 8 with bipolar disorder)

for 2.5 years after the initial scan. The authors noted that at the initial assessment,
bipolar patients had gray matter deﬁcits in regions differing from schizophrenic
patients, localized to bilateral inferior temporal gyri. Also, at follow-up, bipolar
patients showed progressive gray matter reduction in the anterior cingulate
gyrus, which was not an area that initially differentiated them from healthy con-
trols, pointing to the need for longitudinal anatomical MRI studies in bipolar dis-
order in order to clarify a possible neurodegenerative component. Three other
studies also showed that bipolar patients have smaller cortical gray matter
volumes and a more-pronounced age-related decline in total brain gray matter
compared to healthy controls (9–11) suggesting some degree of neurodegeneration

involved in the pathophysiology of bipolar disorder.
Interestingly, chronic lithium use may be protective against this gray matter loss.
One longitudinal (12) study showed a 3% increase in total brain gray matter in eight
out of ten bipolar patients treated with four weeks of lithium, while there were no
changes in the white matter. Another study, although cross-sectional, showed that
bipolar patients treated with lithium had greater total gray matter volumes than
untreated bipolar patients and healthy controls, while there were no signiﬁcant differ-
ences in total white matter volumes across three groups (13). These ﬁndings are
thought to reﬂect neurotrophic effects of lithium, possibly with resulting neuropil
increase. The possibility of mood stabilizers (particularly lithium) preventing or rever-

sing gray matter changes should be kept in mind when interpreting anatomical
MRI ﬁndings with medicated bipolar patients [i.e. 22 out of 37 bipolar patients
in the McDonald et al. (7) study were on lithium]. Further support for the neural
plasticity effects of lithium comes from Beyer and colleagues (14), showing enlarged
left hippocampus volumes in older (n ¼36, mean age ¼58 years) bipolar patients
compared to healthy controls. The authors thought this increase in hippocampal
volume might be associated with lithium use. Future larger longitudinal studies
may shed a light on the putative neurotrophic /neuroprotective effects of lithium
and valproate in bipolar patients with ﬁrst- and multiple-episodes, and the relation-
ship of the brain changes with treatment response.
Prefrontal Cortex

The prefrontal cortex, including subgenual prefrontal cortex, anterior cingulate and
dorsolateral prefrontal cortex (DLPFC), is a key region in the neuroanatomic model
of mood regulation. The subgenual prefrontal cortex is the part of the anterior cin-
gulate situated ventral to the genu of corpus callosum, corresponding to Brodmann
area 24. Two studies (15,16) showed smaller left subgenual prefrontal cortexBrain Imaging Studies in Bipolar Disorder 163

volumes in bipolar patients with a familial form of the disorder and one study (17)
noted smaller right subgenual prefrontal cortex gray matter volumes in a combined
sample of familial and non-familial bipolar patients. Drevets and colleagues also
conducted a postmortem study and showed that the anatomical reduction of sub-
genual prefrontal cortex gray matter was associated with a selective and signiﬁcant
reduction in glial cell number and density, but not neuronal density or number, in a
small group of familial unipolar (n ¼6) and bipolar (n ¼4) patients compared with
healthy controls (n ¼11) (18). In contrast, Brambilla and colleagues (19) did not
show any volumetric abnormality in this brain region in familial or non-familial
bipolar patients. Also, no abnormalities in the subgenual prefrontal cortex
volume were found in a study of children and adolescents with bipolar disorder
(n¼15) (20). These varying results could be due to different study samples, that

is, including patients with bipolar disorder I and II, with ﬁrst-episode versus mul-
tiple-episodes, and especially having a familial affective disorder history (Table 1).
Moreover, the neurotropic effects of mood stabilizers should also be considered as a
potential confounder in these results, as only the Drevets et al. (15) study had a
mostly unmedicated sample.
Another region of the prefrontal cortex that has received much attention lately
is the anterior cingulate (Brodmann’s areas 24, 25, and 33). An early study (21) using
relatively thick MRI slices (6 mm) did not demonstrate any cingulate abnormality in
17 unmedicated patients with bipolar disorder with ﬁrst-episode mania. However,
recent studies using thinner MRI slices show that left anterior cingulate gray matter

volume is smaller in adult (22) and juvenile (23) bipolar patients compared to
healthy controls. Complementary to the region-of-interest (ROI) volumetric
studies, research employing a statistical parametric mapping approach revealed
reduced gray matter density in the fronto-limbic cortex, particularly in the cingulate
(24,25) (Table 2). In Lyoo et al.’s study (25), the greater number of prior manic
episodes was correlated with a greater decrease in the gray matter density in left
medial frontal and right inferior frontal gyri, suggesting a neurodegenerative
effect over repeated episodes. As noted above, one of these studies showed a poss-
ible preventive or reversing effect of lithium on gray matter content, as the cingulate
volumes of lithium-treated bipolar patients did not differ from those of healthy

comparison subjects, while the untreated bipolar patients had smaller left anterior
cingulate volumes compared to healthy controls (22).
DLPFC (Brodmann’s areas 9 and 46) is a region with a main role in executive
functions, working memory, and regulation of emotion. One study showed signiﬁ-
cantly smaller gray matter volumes in the left middle and superior, and the right
middle and inferior prefrontal regions in 17 bipolar patients hospitalized for a
manic episode and receiving various psychotropic medications (9). Patients in
this study also presented a smaller left inferior prefrontal gray matter with increas-
ing illness duration and smaller right inferior prefrontal gray matter related to
antidepressant exposure. Although based on a cross-sectional design and in a

small sample, the authors underline the need to further explore this possible
antidepressant-related volume reduction as a possible way to understand the
cycle acceleration induced by antidepressants in bipolar disorder. Consistent with
the ﬁnding of reduced gray matter volume in prefrontal cortex in adult patients
with bipolar disorder, a recent study using voxel-based morphometry demon-
strated decreased gray matter volume in the left DLPFC in pediatric bipolar
patients (n ¼20, mean age 13.4 +2.5 years, bipolar I and II disorder, 19 of the
patients on psychotropic medications) (26).164 Monkul et al.

TABLE 1 Studies Measuring the Subgenual Prefrontal Cortex in Bipolar Disorder
AuthorsPatients with bipolar
disorder (age)Healthy
comparisons (age) Field strength Findings
Drevets et al., 1997 21 BP (35 +8.2) 6 medicated and
15 drug-free
All with familial BD21 (34 +8.2) 1.5 T Left subgenual prefrontal cortex gray
matter volume 39% smaller in
patients
Hirayasu et al., 1999 24 patients with ﬁrst-episode
affective psychosis (23.7 +5.1)
21 manic, 3 depressive episode
14 with familial BD
on various antipsychotics20 (24.0 +4.3) 1.5 T Left subgenual prefrontal cortex gray
matter volume smaller in patients
with a familial form of the disorder
Brambilla et al., 2002 27 BP (35 +11)
21 BP I, 6 BP II
12 with familial BD
11 unmedicated
16 on lithium monotherapy38 (37 +10) 1.5 T No signiﬁcant differences in
subgenual prefrontal cortex
volumes
Sharma et al., 2003 12 BP I (38.3 +6.2), 6 with familial
BD
on various mood stabilizers8 (38.3 +6.9) 4.0 T Right subgenual prefrontal cortex
volume reduction

volumes
BD
Sanches et al., 2005 15 BP (15.5 +3.5)
11 BP I
3B PI I
1B PN O S
all with familial BD
13 on mood stabilizers21 (16.9 +3.8) 1.5 T No signiﬁcant differences in
volumes
Abbreviations : BD, Bipolar disorder; BP, Bipolar patients; NOS, Not otherwise speciﬁed.Brain Imaging Studies in Bipolar Disorder 165

TABLE 2 Studies Measuring the Cingulate in Bipolar Disorder
disorder (age)Healthy comparisons
(age)Field
strength Findings
Strakowski et al., 1993 17 BP I (28.4 +6.8) ﬁrst-episode
mania Unmedicated16 (30.9 +7.3) 1.5 T No signiﬁcant differences in the
cingulate volume
Sassi et al., 2004 27 BP (35.1 +10)
11 untreated
16 on lithium monotherapy
14 with familial BD39 (37 +10) 1.5 T Untreated BP had decreased left
anterior cingulate volumes
compared with HC and lithium-
treated BP, lithium-treated BP not
signiﬁcantly different from HC
Doris et al., 2004 11 BP I (40.5 +11.6), on various
medications15 (39.1 +10.8) 2.0 T Decreased gray matter density in
fronto-limbic regions, mainly the
cingulate (more common in the right
hemisphere)
Lyoo et al., 2004 39 BP I (38.3 +11.6)
15 unmedicated, 24 on mood
stabilizers
11 drug-naı ¨ve43 (35.7 +10.1) 1.5 T Decreased left anterior cingulate and
left medial frontal gyrus gray matter
density

density
Kaur et al., 2005 15 BP (15.5 +3.5)
11 BP I, 3 BP II, 1 BP NOS
13 on mood stabilizers21 (16.9 +3.8) 1.5 T Left anterior and posterior, and right
posterior cingulate smaller in BP
Abbreviations : BD, Bipolar disorder; BP, Bipolar patients; NOS, Not otherwise speciﬁed.166 Monkul et al.

Available studies report smaller cingulate and subgenual prefrontal cortex
volumes in bipolar patients. DLPFC is an understudied region in MRI studies, poss-
ibly due to the lack of a sound manual ROI tracing method delineating Brodmann’s
areas 9 and 46. But with the availability of automated methods like voxel-based
morphometry, future MRI studies can be directed to further clarify the anatomical
changes in the DLPFC in bipolar patients.
White Matter and Corpus Callosum
One important aspect of the pathophysiology of bipolar disorder may be the loss of
effective connectivity between prefrontal areas and limbic regions, as evidenced by
white matter changes. One of the most consistently reported anatomical ﬁnding in
bipolar disorder is the “white matter hyperintensities” (27,28). These lesions rep-
resent a change in the water content in the brain, and their etiology is unknown,
although some associations with age, vascular pathology, and inﬂammatory

response in the anterior cingulate have been described (29,30). White matter hyper-
intensities have been associated with some clinical characteristics of the disease,
such as poor long-term outcome, female gender, multiple psychiatric admissions,
and better response to lithium treatment (27,31,32) and are present even in
bipolar adolescents (29).
The relationship between white matter hyperintensities, elements of one-
carbon cycle metabolism (including serum folate, vitamin B 12, and homocysteine
levels), and the outcome of antidepressant treatment was investigated in a rela-
tively young sample of outpatients (mean age 40.6 +10.3 years) with major depres-
sive disorder (33,34). It was shown that hypofolatemic and hypertensive patients
had more severe white matter hyperintensities than normal controls. Also, the

severity of subcortical white matter hyperintensities and the presence of hypofola-
temia independently predicted lack of clinical response to antidepressant treat-
ment. The authors concluded that hypofolatemia and hypertension might
represent modiﬁable risk factors to prevent the occurrence of white matter
hyperintensities.
Structural brain imaging studies also have revealed various other white
matter abnormalities in bipolar patients. White matter density reductions in the
anterior limb of internal capsule, connecting anterior thalamic nucleus to the
frontal lobe, were found in patients with familial bipolar I disorder, suggesting a
fronto-thalamic connection abnormality, common to both schizophrenia and
bipolar disorder (35). Studies have also shown white matter volume deﬁcits in

bipolar I patients and their unaffected co-twins (in the left hemisphere) (36), familial
male bipolar I patients (37), ﬁrst-episode bipolar patients (21), and children and
adolescents with bipolar disorder (in left superior temporal gyrus) (38). Presence
of white matter and axonal disorganization in frontal and prefrontal regions was
also shown in adult (39) and young ﬁrst-episode (40) bipolar patients, by diffusion
tensor imaging studies.
The corpus callosum is the major white matter commissure connecting
the cerebral hemispheres. It plays a crucial role in inter-hemispheric communi-
cation (41) and higher cognitive processes, such as sensory-motor integration,
attention, arousal, language, and memory (42,43). Corpus callosum is also an
important structure for the development of structural brain asymmetry, resulting

in cerebral functional lateralization in humans. Anatomical asymmetry is believed
to be the substrate of the functional lateralization, and corpus callosum size reﬂectsBrain Imaging Studies in Bipolar Disorder 167

inter-hemispheric connectivity, suggesting that cerebral asymmetry occurs with
decreased callosal connectivity (44). Inter-hemispheric information exchange
decreases with increasing cerebral asymmetry, leading to hemispheric indepen-
dence /dominance. Therefore, corpus callosum abnormalities may also play a
major role in affecting the development of structural and functional lateralization
in bipolar disorder, ultimately resulting in abnormal inter-hemispheric
Corpus callosum area is reduced in adult bipolar patients (45,46). Abnormally
reduced corpus callosum signal intensity was found in adult bipolar patients (47),
and lower circularity of the splenium was observed in young (mean age 16) patients
with bipolar disorder (48), suggesting abnormalities in corpus callosum white
matter in bipolar patients, possibly due to altered myelination, which may lead
to impaired inter-hemispheric communication.

In conclusion, it is likely that white matter hyperintensities are involved in the
pathophysiology of bipolar disorder by interrupting essential neural pathways in
the brain that are involved in mood regulation, as put forth by Soares and Mann
(1). Researchers also suggested that left hemisphere white matter changes may
reﬂect genetic factors predisposing to bipolar disorder (36), and that glial loss
might underlie both the white matter hyperintensities and volume reductions
observed in bipolar patients (49). Evidence from brain imaging studies point to
the importance of examining white matter changes in bipolar disorders.
Medial Temporal Structures
Three different research groups (50–52) reported amygdala enlargement in adult
bipolar patients, suggesting that hypertrophy of this region might reﬂect dysfunc-

tion underlying the mood lability of bipolar disorder. In contrast, two studies
(53,54) found smaller amygdala sizes in adult bipolar patients. In children and
adolescents with bipolar disorder, there is more consistent evidence of smaller
amygdala volumes (54–59). In Chen and colleagues’ (55) cross-sectional study,
pediatric bipolar outpatients (n ¼16, 14 on mood stabilizers, 11 with comorbid
Axis I disorders) showed a direct correlation between left amygdala volume and
age, in contrast to healthy comparisons, who showed the expected inverse relation-
ship. The tendency for larger amygdala volumes to occur in the older bipolar
children may be the result of some compensatory mechanisms of developmental
abnormalities. One recent longitudinal study (59) rescanned the same 10 bipolar I

outpatients (7 with various Axis I comorbidities, all exposed to various psychotro-
pics between ﬁrst and second scans) after an average of 2.5 +0.4 years. The authors
reported the persistence of decreased amygdala volumes in adolescents and young
adults with bipolar disorder, with healthy controls having an increase in the left
amygdala volume and bipolar patients having a decrease in the right amygdala
volume, although both small and nonsigniﬁcant (59). Preliminary evidence
suggests that lithium and valproate treatment is associated with increased amyg-
dala volume in pediatric bipolar patients (58). In Chang et al.’s study (58),
bipolar patients with past lithium or valproate exposure tended to have greater
amygdala gray matter volumes than bipolar patients without such exposure, and

the authors concluded that prolonged medication exposure to lithium or valproate
may account for ﬁndings of increased amygdala volumes relative to healthy con-
trols in adults with bipolar disorder. Further support for this possible neurotropic
effect of mood stabilizers comes from a neuropathological study (60) reporting168 Monkul et al.

higher glial numbers in the amygdala of 10 bipolar patients who were chronically
treated with either lithium and valproate compared with 2 bipolar patients who did
not receive lithium and /or valproate and 10 healthy subjects, although this needs to
be replicated.
Hippocampus is another temporal lobe structure with important mood-
regulating functions. One study, using 0.5 T ﬁeld strength and 10 mm image
slices, found smaller right hippocampus in 48 bipolar patients (more pronounced
in males) (61), but this ﬁnding was not replicated in several other studies with mod-
erate sample sizes ( /C2425) (50,51,62–65). Only in one study (65) did the authors
compare drug-free (n ¼9) and lithium-treated bipolar patients (n ¼15), and they
did not ﬁnd any signiﬁcant differences of hippocampal measurements between
the two groups. One recent study (66) reported a trend toward smaller left hippo-
campal volumes in psychotic bipolar patients (n ¼38, 23 with psychosis) compared

to healthy subjects, suggesting that future anatomical studies measuring hippo-
campus in bipolar disorder should also take into account psychosis. Moderate to
severe forms of hippocampal shape anomaly (characterized by a rounded hippo-
campus) were observed in patients with familial schizophrenia, whereas patients
with familial bipolar disorder did not have such anomaly (67). The ﬁndings in chil-
dren and adolescents are different from the adults, as two studies found smaller
hippocampal volumes in children and adolescents with bipolar disorder relative
to healthy subjects (54,68). Two possible explanations for this discrepancy
between adult and pediatric ﬁndings are that age at onset may differentially
affect brain structure, or that childhood- or adolescent-onset bipolar disorder

may be a distinct disorder from adult-onset illness with a different set of neuroana-
tomic correlates, as put forth by Frazier and colleagues (68).
In conclusion, there is very credible evidence for smaller amygdala volumes
in pediatric bipolar disorder (69), and there is also some evidence from adult
studies to suggest enlargement of this structure. Brambilla and colleagues (5)
suggested that abnormal pruning mechanisms in childhood and adolescence
or, alternatively, compensatory mechanisms might lead to enlargement of the
amygdala in adulthood. An alternative explanation for a larger amygdala in adult-
hood, as put forth by Chang and colleagues (58), is prolonged exposure to lithium
or valproate. Longitudinal studies, in children and adolescents with bipolar dis-

order, in high-risk populations, and also with controlled medication treatment,
are needed to deﬁne the nature of amygdala abnormalities in bipolar disorder.
The hippocampal volume changes in bipolar disorder are not well established.
Also, antidepressant and antipsychotic treatments, as well as mood stabilizers,
may affect hippocampal volume, and so far no study has examined the hippo-
campus in a sizable sample of untreated bipolar individuals.
Thalamus
The thalamus is another key structure in brain anatomic circuits involved in the
pathophysiology of mood disorders. ROI-based MRI studies yielded conﬂicting
results concerning the thalamus in bipolar patients. Two studies with sizable
samples (i.e., /C2124) found larger thalamic volumes in bipolar patients (51,70). None-

theless, six other studies, with two conducted in young bipolar patients (68,71),
failed to replicate these ﬁndings (21,72–74). Also, no signiﬁcant difference was
found in the thalamic volumes of ﬁrst- versus multiple-episode adult bipolar
patients (73) and healthy controls. Young and colleagues (75) reported thatBrain Imaging Studies in Bipolar Disorder 169

neuron numbers and volumes in limbic thalamic nuclei were normal in patients
with schizophrenia and bipolar disorder. However, a recent study utilizing voxel-
based morphometry in patients with schizophrenia and bipolar disorder and
their unaffected relatives demonstrated gray matter reductions in the anterior thal-
amic nucleus (receiving major input from the hippocampus and mamillary bodies)
in all groups compared to healthy controls, suggesting that this abnormality might
be a marker of liability for both disorders (76) and especially for psychosis, but this
ﬁnding needs to be replicated.
In conclusion, there are no consistent ﬁndings about thalamic anatomical
changes in bipolar disorder. Again, the distinction between psychotic and non-psy-
chotic bipolar disorder may be playing a role here, and needs to be further investi-
gated, preferably with more advanced techniques that can measure speciﬁc
thalamic nuclei.
Basal Ganglia

The basal ganlia are part of the neural networks underlying mood regulation, with
extensive connections to prefrontal areas. The earlier anatomical studies about
the basal ganglia in bipolar disorder did not ﬁnd any signiﬁcant abnormalities
(21,61,70,77). However, a more recent study by Brambilla and colleagues (78)
reported that age and length of illness may have signiﬁcant effects on basal
ganglia structures in bipolar patients (more pronounced among bipolar I patients).
In this study, the length of illness predicted smaller left putamen volumes, and
older patients ( .36 years) had a signiﬁcantly larger left globus pallidus than
younger ones ( /C2036 years). Also, two studies in adult (51,79) and one in adolescent
(57) bipolar patients reported enlargement of basal ganglia structures. Recently,

caudate size was also shown to be decreased in older (mean age 58) bipolar patients
(14). The age-related decline in some basal ganglia structures is also documented
in children and adolescents with bipolar disorder by Sanches and colleagues (80).
They found a signiﬁcant inverse correlation between age and the volumes of
left caudate, right caudate, and left putamen in bipolar patients, not present
in healthy controls. These ﬁndings suggest that bipolar patients may have
more pronounced age-related changes in basal ganglia structures than healthy
individuals (81).
Cerebellum
The cerebellar hemispheres do not seem to be affected in bipolar disorder, as shown
by several MRI reports (82–85). However, there may be anatomical changes in the
cerebellar vermis that originate from neurodegenerative processes during the

course of the illness. Vermis area V3 (the inferior posterior and ﬂocculonodular
lobes, lobules VIII-X) seems to be smaller in patients with multiple episodes than
in ﬁrst-episode bipolar patients and healthy volunteers (82,83,85). Another recently
conducted volumetric study showed that patients with multiple episodes had
smaller V2 volumes compared to ﬁrst-episode patients and healthy controls (84).
In bipolar children and adolescents with familial mood disorder, smaller vermis
V2 area (superior posterior vermis, neocerebellar vermal lobules VI-VII) was
reported (85). Taken together, these ﬁndings suggest that cerebellar vermal abnorm-
alities occur in bipolar disorder, and that these are likely neurodegenerative and
progressive.170 Monkul et al.

FUNCTIONAL NEUROIMAGING
Blood Flow and Metabolism Studies
Earlier positron emission tomography (PET) studies (86–90) showed that bipolar
patients had decreased cerebral blood ﬂow (i.e., hypofrontality) in prefrontal cor-
tices in the resting state. Martinot and colleagues also reported that successful
medication treatment with tricyclic antidepressants could reduce the left-right pre-
frontal asymmetry, but not the hypofrontality and whole-cortex hypometabolism
that was found in the patients in the depressed state (90), suggesting that this
was more a trait-like abnormality. Patients with bipolar affective illness (n ¼16)
also had signiﬁcantly lower metabolic rates in their basal ganglia in comparison
to normal controls, by PET using [18F]2-deoxyglucose as a tracer (88).
These earlier SPECT and PET studies were followed by newer studies using
more sophisticated techniques to examine the effect of mood state and drug

treatment. Gyulai and colleagues (91) examined the same patients (n ¼12) in
depressed /dysphoric, manic /hypomanic, and euthymic states and concluded
that there may be a state-dependent dysfunction in the temporal lobe, as evidenced
by an asymmetric distribution of I-123 iofetamine in depression but not in euthy-
mia, in bipolar patients with rapid cycling. One SPECT study with n-isopropilio-
doamphetamine showed increased blood ﬂow in the temporal lobe and basal
ganglia in manic state (n ¼11) (92). Recently, mood state-dependent alterations in
blood ﬂow and metabolism in other brain regions were also reported. Blumberg
and colleagues reported greater manic versus euthymic state-related activity in
the anterior cingulate and caudate (93), and decreased activity in the orbitofrontal

cortex (94), although the sample sizes were small (5 manic and 6 euthymic patients
in both studies, on various psychotropics). The ﬁndings of Blumberg and col-
leagues’ studies also converge with Drevets and colleagues’ (15) report that
bipolar patients in the manic phase (n ¼4) have a higher metabolism in the subgen-
ual prefrontal cortex, compared to healthy subjects and bipolar depressed patients.
Goodwin and colleagues (95) reported decreased anterior cingulate and right
caudate blood ﬂow after lithium withdrawal, whereas development of mania on
lithium withdrawal was associated with increased anterior cingulate blood ﬂow.
One explanation put forth by Blumberg and colleagues (93) for the heightened
anterior cingulate and caudate activity was a compensatory mechanism for the

increased demand to limit “manic-type distractibility and maladaptive excessive
behaviors” under scan conditions. Cingulate hypermetabolism as an adaptive
response to depression, and its failure underlying a poor outcome to antidepressant
treatment, were also reported by Mayberg and colleagues (96). Also, an fMRI study
by Caligiuri and colleagues (97) showed that affective state in bipolar disorder
might be related to a disturbance of inhibitory regulation within the basal
ganglia and that antipsychotics and /or mood stabilizers might normalize cortical
and subcortical (basal ganglia and thalamus) hyperactivity.
Recently, Drevets and colleagues (98), using higher-resolution glucose metab-
olism images and MRI-based ROI analysis, showed that the amygdala metabolism in

remitted bipolar patients (n ¼8) was intermediate between that of healthy controls
(n¼12) and depressed bipolar subjects (n ¼7), although not signiﬁcantly different
from either. The left and right amygdala metabolism was increased in the remitted
bipolar patients who were not taking mood stabilizers relative to the patients who
were taking one of these agents and healthy comparisons. The authors concluded
that chronic mood stabilizer treatment might normalize the increased amygdala
metabolism, and thus reduce and prevent pathological mood episodes (98).Brain Imaging Studies in Bipolar Disorder 171

In conclusion, there may be an elevated limbic activity with deﬁcient frontal
modulation, underlying the illness recurrence in mood disorders (98,99).
Activation Studies
Functional imaging studies coupled with cognitive testing provide a helpful tool to
understand the neurophysiology of bipolar disorder. Bipolar patients have atten-
tion, memory, and executive deﬁcits that are apparent during affective episodes
(72), but also persist in euthymia (100). Results from studies (100–103) indicate
that euthymic bipolar patients have poorer performance than healthy comparisons
on working memory tasks, and they exhibit increasing impairment as the task
becomes more difﬁcult, and suggest that memory impairments might be more a
trait marker than state in bipolar disorder (104). One recent study examined
verbal learning in eight euthymic, remitted bipolar I patients (7 of them unmedi-
cated) with15O PET scanning while doing a verbal learning paradigm. Bipolar

patients had more difﬁculties learning the lists of words compared with the
control subjects, and they had a blunted regional cerebral blood ﬂow increase in
the left DLPFC during encoding the words (104).
The cognitive deﬁcits that persist during euthymia were hypothesized to arise
from an over-reactive anterior limbic network (including prefrontal regions, thala-
mus, striatum, amygdala, and the cerebellar vermis), which affects the functioning
of the cognitive network through reciprocal connections. Strakowski and colleagues
reported evidence of anterior limbic overactivation during a simple attentional task
in euthymic, unmedicated bipolar patients (101). In this study, bipolar patients’
performance on the task was similar to that of healthy subjects, but they exhibited

activation in different cortical regions, and the authors interpreted this as a compen-
sation for interference from emotional brain networks in order to maintain task per-
formance. As a next step, they incorporated a more challenging attention task in
which compensatory mechanisms would be overwhelmed in patients, thereby
further differentiating brain activation patterns between the groups (105). Acti-
vation of the anterior cingulate (Brodmann’s area 24 /32) and DLPFC (Brodmann’s
area 9) while performing the Stroop task were not signiﬁcantly different between
groups, but patients demonstrated a pattern of lower activation in temporal
regions, midline cerebellum, ventrolateral prefrontal cortex, and putamen. Failure
to activate secondary brain regions involved in this task may have contributed

to impaired task performance in bipolar patients, as put forth by Strakowski and
colleagues (105).
Results of a recent SPECT study exploring the possible correlation of
neuropsychological functioning and cerebral blood ﬂow in patients with bipolar
disorder (n ¼30, all unmedicated, 7 manic, 8 hypomanic, 12 depressed, and 3
euthymic) showed that worse performance on memory, executive, and attention
tasks was related to a greater perfusion in the striatum (106). In this study, patients
with poor performance on tests of executive functions also showed low perfusion in
the frontal region and cerebellum and high perfusion in the cingulate. In another
study, bipolar patients showed activation in the thalamus and amygdala in addition
to cortical activation in regions implicated in the cognitive processing of affective

stimuli (107). The authors concluded that the bipolar brain manifested a different
perfusion pattern than the healthy brain, and perhaps an abnormal cognitive
emotional processing through ventral prefrontal cortex dysfunction (103,107). A
recent18F-ﬂuorodeoxyglucose-PET study, conducted in a small group (n ¼8) of172 Monkul et al.

unmedicated depressed bipolar patients using the continuous performance test to
assess sustained attention and vigilance, provided additional evidence that
decreased prefrontal activity may represent failure to activate some areas of inhibi-
tory control (108). This study showed that decreased subgenual prefrontal cortex
metabolism was related to decreased attention, and decreased DLPFC metabolism
was related to decreased inhibitory control.
Kru¨ger and colleagues (109) assessed bipolar risk and resilience in a very
small group of lithium-responsive bipolar patients (n ¼9) and their healthy sib-
lings (n ¼9) using an emotional challenge test. They reported that both patients
and their siblings had rCBF increases in the anterior cingulate and decreases in
the orbitofrontal and inferior temporal cortices. In addition, the siblings had
an increased metabolism in the medial frontal cortex, a ﬁnding that was not
observed in the patients, which the authors commented as being a compensatory

response, and possibly conferring resilience to these high-risk individuals.
However, the lack of a healthy control group in this study limits the interpretation
of these ﬁndings. The authors also compared lithium-responsive patients to valpro-
ate-responsive bipolar patients from an earlier study by their group, and concluded
that changes speciﬁc to the DLPFC and rostral anterior cingulate distinguished
these patient groups from each other.
In conclusion, both resting blood ﬂow and glucose metabolism studies using
SPECT and PET and studies using cognitive tasks during functional imaging comp-
lement results from other imaging modalities showing that limbic dysregulation by
prefrontal regions is a key element in the pathophysiology of bipolar disorder.
Neurochemical Brain Imaging
PET and SPECT Neuroreceptor Studies

Dopaminergic System
Dopaminergic system abnormalities are thought to underlie mania and depression,
and especially the psychosis associated with these conditions. Two PET studies
measuring dopamine D 2receptor density, as measured by D 2binding potential
with [11C]raclopride (110), and [11C]N-methylspiperone as a ligand (111) showed
that D 2receptors were unaltered in acute non-psychotic mania. Also, presynaptic
dopamine function as reﬂected by [18F]DOPA uptake does not seem to be altered
in medication-naı ¨ve ﬁrst-episode bipolar patients with non-psychotic mania
(112). In contrast, patients with psychotic mania have a higher D 2receptor
density compared with healthy comparisons, and the authors concluded that the
higher density of D 2receptors might be related to psychosis and not to manic symp-

toms (111). Yatham and colleagues (110) also showed that although divalproex
sodium treatment did not seem to affect D 2receptor availability, presynaptic dopa-
mine function in manic patients was lower after treatment with divalproex sodium
as measured by the [18F]6-ﬂuoro-L-dopa ([18F]DOPA) uptake in the striatum (112).
The authors concluded that divalproex sodium might exert its antimanic effects via
reducing the rate of dopamine synthesis (110,112).
In vivo brain intrasynaptic release of dopamine after amphetamine release
can be quantiﬁed by currently available neuroimaging methods. A SPECT study
investigating the differences in amphetamine-induced dopamine release in euthy-
mic bipolar disorder patients and healthy comparison subjects found no differences

in baseline D 2receptor binding between the two groups (113). Although there was a
greater behavioral response to an amphetamine challenge in euthymic bipolarBrain Imaging Studies in Bipolar Disorder 173

disorder patients, this was not accompanied by a signiﬁcant difference in decrease
in [123I]IBZM binding between the two groups. As a decrease in [123I]IBZM binding
is related to the amount of striatal dopamine release, the authors concluded that
mania-like symptoms induced by amphetamine may not be related to increased
dopamine release.
Suhara and colleagues (114) studied D 1binding potential in 10 bipolar
patients in various mood states, and found that the binding potentials for the
frontal cortex were signiﬁcantly lower in patients than healthy controls, whereas
those for striatum were not signiﬁcantly different, suggesting that D 1dopamine
receptors in the frontal cortex may be in a different state in patients with bipolar dis-
order, but this ﬁnding needs to be replicated.
In conclusion, very few in vivo brain-imaging studies examined dopamine
receptors in bipolar patients, and they suggested that D 2receptor abnormalities

might be related to psychosis in bipolar patients, and dopamine receptor blockade
might contribute to the anti-manic property of medications. The levels of dopamine
receptors in brain regions other than striatum should be assessed in future studies.
Also, future research should be directed to examining dopamine transporters in
medication-free bipolar individuals.
Serotonergic System
Involvement of the serotonergic system in the pathophysiology of mood disorders
is suggested by PET studies conducted mostly in patients with unipolar depression.
One study showed decreased mid-brain serotonin transporter (5-HTT) density
(115) in drug-free unipolar depressed patients. Another study conducted with 13
drug-free male patients with mood disorders (seven with major depressive dis-

order and six with bipolar disorder) showed no signiﬁcant change in 5-HTT
binding in the midbrain, but there was elevated thalamic binding in unipolar
patients compared to bipolar patients and healthy controls (116).
5HT 1Areceptor binding potential was also studied in vivo, and found to be
reduced in the raphe and mesiotemporal cortex, most prominently in bipolar
depressive patients (n ¼4) and unipolar depressive patients with bipolar relatives
(n¼4) (117). Sargent and colleagues (118) reported widespread reduction in corti-
cal postsynaptic 5-HT 1Areceptor binding potential measured by positron emission
tomography (PET) with [11C]WAY-1006357 in unmedicated depressed patients,
with a similar reduction in binding of [11C]WAY-100635 to 5-HT 1Aautoreceptors

in the raphe nuclei in the midbrain. These reductions persisted in patients who
responded clinically to treatment with selective serotonin reuptake inhibitors,
and the authors hypothesized that lowered post-synaptic 5-HT 1Areceptor
binding availability might be a trait abnormality and a vulnerability factor in recur-
rent unipolar depression. They tested this hypothesis recently with 14 male euthy-
mic unipolar patients, who had been free of psychotropic medications for at least
six months, and reported a persistent dysfunction in cortical 5-HT 1Abinding poten-
tial (119), supporting their hypothesis. Further studies are clearly needed to deter-
mine the origin of this reduction in cortical 5-HT 1Areceptor availability in bipolar
and unipolar patients.
Brain 5-HT 2receptors have also been examined in vivo in unipolar disorder

patients. A PET study (120) reported a decrease in uptake of [18F]altanserin in the
right anterior part of insular cortex and right posterolateral orbitofrontal cortex in
untreated unipolar depressed patients, consistent with 5-HT-2A receptor levels.
Three other PET studies, that used [18F]setoperone as a tracer, reported a signiﬁcant174 Monkul et al.

decrease in [18F]setoperone binding in the frontal cortex (121) and frontal, temporal,
parietal, and occipital cortical regions (122) of depressed patients compared with
control subjects, or no difference between the two groups (123). Another recent
PET study using (18F)-setoperone and conducted in seven bipolar patients in a
manic episode (drug naı ¨ve or psychotropic medication free for at least one week)
and treated with valproate (n ¼7) and lithium (n ¼1) for 3 to 5 weeks, showed
that treatment with valproate alone or in combination with lithium had no signiﬁ-
cant effect on brain 5-HT2A receptor binding (124). 5-HT 2Areceptors seem to be
altered in major depression, and some researchers suggested that the reduction
in brain 5-HT 2Areceptor density might be the result of a homeostatic mechanism
by the brain to compensate for depression (122). Studying 5-HT 2receptors in
bipolar patients is an intriguing area of research, as atypical antipsychotics that

are effective in the treatment of acute mania and as mood-stabilizers have greater
afﬁnity for 5-HT 2Areceptors than dopamine receptors (125).
Biochemical Findings
Magnetic resonance spectroscopy (MRS) is unique among in vivo brain imaging
modalities as being a noninvasive way to measure levels of different chemicals in
the brain.1H-MRS can be used to quantitate neurochemicals such as N-acetyl-
aspartate (NAA), choline, myo-inositol, creatine, glutamate, glutamine, and
GABA.31P-MRS provides information about phosphorus-based membrane pro-
cesses and metabolism, by estimation of brain levels of phosphomonoesters, phos-
phodiesters, and pH.
NAA is an amino acid found in high concentrations in mature neurons and
considered to be a marker of neuronal integrity, the formation and maintenance

of myelin and mitochondrial energy production (126,127). Lower dorsolateral
prefrontal cortex NAA levels were reported in adult (n ¼20, euthymic, unmedi-
cated) (128) and pediatric (129) bipolar patients, and also in both treatment-naı ¨ve
(130) and medicated (131) adolescent patients with bipolar disorder. Decreased
NAA levels were reported in other brain regions including orbital frontal gray
matter (132) and hippocampus (133,134) in adult patients with bipolar disorder.
This decrease in NAA may be the result of neurodegenerative changes of long-
standing illness duration, as a recent study by Gallelli and colleagues (135) in 60
children of parents with bipolar I or II disorder (32 with bipolar disorder and 28
with subsyndromal symptoms of bipolar disorder) did not reveal any signiﬁcant

changes in dorsolateral prefrontal NAA levels. Two other studies did not ﬁnd sig-
niﬁcant differences of dorsolateral prefrontal cortical NAA between mostly medi-
cated adult bipolar patients and healthy volunteers (133,136). There are other
negative studies where no abnormalities of NAA were found in other brain
regions such as the basal ganglia (133,137–139), cingulate (133), and thalamus
(133). However, these studies included mostly medicated subjects, and it is possible
that any regional abnormalities in NAA levels that were present and related to the
illness were altered by neurotrophic /neuroprotective effects of mood stabilizers.
Chronic lithium treatment was shown to increase NAA concentrations in total
brain (140), temporal lobe (141), and basal ganglia (139), providing indirect evi-

dence of its proposed neurotrophic /neuroprotective effects (142). Also, Brambilla
and colleagues (136) reported signiﬁcantly higher NAA /PCrþCr ratios in
lithium-treated bipolar patients compared to unmedicated ones and healthy con-
trols. This NAA increase has not been demonstrated with sodium valproate (141).Brain Imaging Studies in Bipolar Disorder 175

Choline is another neurochemical that can be measured via1H-MRS; it is a
membrane component and considered a potential biomarker for the status of mem-
brane phospholipid metabolism. Choline levels (measured as a ratio to creatine) in
the basal ganglia were elevated in euthymic (138,139) and depressive (137) bipolar
patients. Lithium and valproate treatment do not alter basal ganglia choline reson-
ance in bipolar patients (143–145) or healthy volunteers (146). Thus, the increased
choline in basal ganglia may not be related to medication exposure, and may rep-
resent an important aspect of the pathophysiology of bipolar disorder, although
future studies with drug-free patients and technologies that would allow the
measurement of free choline are warranted.
Glutamate, glutamine, and GABA (Glx peak) are also of interest, as antigluta-
matergic and GABAergic anticonvulsants are useful in treating bipolar disorder

and glutamatergic abnormalities may be involved in neurotoxicity that is poten-
tially responsible for speciﬁc brain insults present in bipolar disorder. In a group
of depressed bipolar adolescents, Castillo and colleagues (147) reported a bilateral
increase in Glx in frontal cortex and basal ganglia. Another study that examined
medication-free patients with bipolar disorder found elevated gray matter Glx
and lactate concentrations, which were postulated to reﬂect bioenergetic alterations
(148). In an extension of the previous study, the authors showed that the gray
matter Glx elevation was reduced with lithium treatment, but not with valproate
treatment (145).
Myo-inositol (mI) is another important metabolite in proton spectroscopy

that is a substrate for phosphoinositide cycle and a marker for glia, as it is actively
transported into astrocytes (149). Lithium inhibits inositol monophosphatase and
polyphosphate-1-phosphatase that are involved in recycling inositol mono- and
poly-phosphates to myo-inositol. Sodium valproate also decreases myo-inositol
concentration and increases the concentration of inositol monophosphates in rat
brain (150). In unmedicated euthymic bipolar patients, myo-inositol levels appear
unchanged in the frontal lobe (128). Moore and colleagues (151) found decreased
myo-inositol in the right frontal lobe of depressed bipolar subjects following
acute (5–7 days) lithium administration, which persisted through one month of
treatment. However, the patients’ clinical state was clearly unchanged at this

time, supporting the hypothesis that the initial actions of lithium may occur with
a reduction of myo-inositol, and that this reduction initiates a cascade of secondary
changes that are ultimately responsible for the therapeutic efﬁcacy of lithium.
Another study did not ﬁnd any differences in myo-inositol levels in the cingulate
cortex of depressed bipolar patients and healthy controls (152). However,
Davanzo and colleagues (153) observed a signiﬁcant decrease in anterior cingulate
mI/Cr ratios following seven days of lithium therapy in children and adolescents
with early-onset bipolar disorder, and children in the manic phase of bipolar
disorder had elevated mI /Cr levels within the anterior cingulate cortex.
Another metabolite that is closely related to myo-inositol and the phospha-

tidylinositol cycle is phosphomonoester (PME) level. PME can be quantiﬁed
using31P-MRS and it represents precursors of membrane phospholipid metab-
olism. In a comprehensive series of studies, a group of investigators (154–156)
demonstrated that frontal lobe PME levels vary with mood state in bipolar patients.
Deicken and colleagues (157) also reported signiﬁcantly reduced PME in both the
right and left temporal lobes in unmedicated, euthymic bipolar patients compared
with healthy controls. An increase in PME concentration with 7 and 14 days of
lithium administration in the human brain in vivo was observed (158), and as176 Monkul et al.

patients in the above-mentioned studies were mostly on lithium or off lithium for
short periods of time, increased levels of PME could reﬂect medication effects.
This is signiﬁcant as lithium inhibits inositol monophosphatase, producing
increased levels of PME, which would be consistent with increased membrane
anabolism.
1H-MRS studies have been using the creatine þphosphocreatine peak as an
unchanging internal standard, an application that has recently been challenged
by several studies showing that both creatine and phosphocreatine peaks change
in bipolar disorder. Hamakawa and colleagues (159) showed that creatine concen-
trations were reduced in the frontal lobe of patients with bipolar depression,
whereas in another study euthymic male bipolar I patients had higher creatine con-
centrations in the thalamus (160). Medication treatment also may modify creatine
levels, as O’Donnell and colleagues (161) showed that both lithium and valproate

changed creatine concentrations. Thus, with higher ﬁeld strength magnets becom-
ing more available, researchers are now more inclined to quantify absolute meta-
bolite concentrations or brain water concentration as the reference peak.
In conclusion, MRS studies have identiﬁed changes in cerebral concentrations
of NAA, glutamate /glutamine, choline, myo-inositol, lactate, phosphocreatine,
phosphomonoesters, and intracellular pH in bipolar patients. A recent review of
MRS studies in bipolar disorder, focusing on the dysfunction of cellular energy
metabolism, proposed a hypothesis of mitochondrial dysfunction in bipolar dis-
order that involves impaired oxidative phosphorylation, a resultant shift toward
glycolytic energy production, a decrease in total energy production and /or sub-

strate availability, and altered phospholipid metabolism (127).
The MRS studies carried out in bipolar patients generally have used lower
ﬁeld strength magnets, which did not allow optimal resolution of many metabolites
of interest, a problem that has recently been targeted by improved MRS methods.
Also, longitudinal MRS investigations with larger samples of untreated patients
are needed to further explore the putative neuroprotective effects of lithium and
their relationship to treatment response in bipolar disorder.
Contrast with Findings in Unipolar Disorder
Strakowski et al. (162) reviewed magnetic resonance imaging studies of mood dis-
orders and concluded that bipolar and unipolar disorders may share the pathology
of reduced volumes of prefrontal structures, causing loss of cortical modulation

over limbic structures. In regards to subcortical brain regions, the most striking
difference between unipolar and bipolar disorders seems to be in medial temporal
lobe structures, when the hippocampus and amygdala are measured as discrete
structures. Magnetic resonance imaging studies demonstrate that hippocampal
volume is decreased in patients with recurrent depression, whereas hippocampal
volume is preserved in bipolar disorder (6,163). The cellular basis for this observed
reduction in hippocampal volume in unipolar depression may be a signiﬁcant
reduction in neuropil (the lattice of glial cells and their processes, dendrites, and
proximal axons surrounding neuron cell bodies), as detected in a recent post-
mortem study by Stockmeier and colleagues (164).

The volumes of the basal ganglia are also different in unipolar and bipolar dis-
orders. In contrast to most of the studies of bipolar disorder, decreased volumes of
basal ganglia have been reported in unipolar depression, although it is not clear
whether medication effects are ruled out (81). Future studies comparing unmedi-
cated bipolar and unipolar patients for this speciﬁc brain region are needed.Brain Imaging Studies in Bipolar Disorder 177

Bipolar disorder and unipolar depression also differ regarding the corpus cal-
losum abnormalities. In contrast to bipolar disorder, in unipolar depression the
anterior and posterior quarters of the corpus callosum were larger in depressed
patients than in controls in an earlier study (165). Consistent with this study,
Lacerda and colleagues (166) also found signiﬁcantly increased anterior (middle
genu) and posterior (anterior and middle splenium) callosal sub-divisions in
patients with familial major depression. Although the functional signiﬁcance of
the observed callosal changes and their roles in the pathophysiology of mood dis-
orders remain unclear, future neuroimaging and neuropsychological studies with
larger patient samples will possibly clarify the difference between bipolar and uni-
polar disorders regarding this brain structure.
As for the results of postmortem studies, there may be regional “disease-

speciﬁc” differences in glial pathology between unipolar and bipolar mood dis-
orders. These differences are more apparent ventrally in the orbitofrontal cortex
and subgenual anterior cingulate, and less pronounced in dorsal regions such as
the dorsolateral prefrontal cortex and the supracallosal part of the anterior cingu-
late (167). Rajkowska and colleagues (167) suggested that these disease-speciﬁc
changes might be a reﬂection of different circuits involved in the neuropathology
of these two disorders and /or a consequence of different medication treatments.
When abnormal prefrontal cortical markers of neural plasticity, neurotransmission
(dopaminergic D2 receptor RNA, glutamate receptor dysfunction), signal transduc-
tion, glial cells, and GABA containing interneuron function were analyzed in

schizophrenia, bipolar disorder and non-psychotic depression, bipolar disorder
was found to be more similar to schizophrenia than depression (168).
There also are differences between unipolar and bipolar disorders regarding
MRS ﬁndings. Decreased GABA levels were reported in occipital cortex in nonme-
dicated depressed unipolar patients (169), and occipital cortex GABA concen-
trations after SSRI treatment were signiﬁcantly higher than the pretreatment
concentrations (170). Bipolar patients do not have such reductions in GABA
levels (171).
SUMMARY OF MAIN FINDINGS
Available ﬁndings from anatomical MRI studies implicate key regions involved in
mood regulation, such as anterior cingulate, subgenual prefrontal cortex, amyg-
dala, basal ganglia, and corpus callosum in adult and pediatric bipolar patients.

Both adult and pediatric bipolar patients seem to lose more brain gray matter by
aging than healthy controls, and this “cortical thinning” may be related to impair-
ment of emotional, cognitive, and sensory processing in bipolar disorder (11). There
seem to be regionally-speciﬁc brain abnormalities before the onset of disease, and
illness-speciﬁc, possibly neurodegenerative, changes taking place with repeated
episodes during the illness course. It is, however, not an easy task to differentiate
illness-related changes from medication treatment-related changes. Also, whether
these volume changes are related to changes in neuropil, neuronal size, or dendritic
or axonal consolidation and /or pruning, is not yet very clear, although ﬁndings
point to glial changes taking place in the early phases of the disease. The active epi-

sodes seem to have a neurotoxic effect, and those patients who show progressive
changes with recurring episodes may also be suffering from a more severe, recur-
rent form of bipolar disorder, whereas mood stabilizer treatment seems to
prevent and /or reverse some of the illness-associated changes (172). Psychotropic178 Monkul et al.

medications affect volumes of certain brain structures that are thought to play a role
in mood disorders (58,173,174), and some of the volumetric and neurochemical
changes seem to be reversed by mood-stabilizer treatment, such as lithium and
valproate. This points to the importance of keeping in mind the previous and
present exposure to psychotropic medications when interpreting the volumetric
and neurochemical ﬁndings.
Volume reduction in various brain regions is also corroborated by decreased
levels of N-acetyl-aspartate in DLPFC, which is the most consistently reported
ﬁnding in MRS studies, in adults as well as children and adolescents with
bipolar disorder, possibly developing only after the onset of bipolar disorder. In
addition, phosphomonoesther concentrations seem to be altered in different
mood states, reduced /unchanged in euthymic bipolar patients, and increased in
manic and hypomanic patients, suggesting that changes in phosphoinositol activity

occur in frontal and temporal regions.
PET and SPECT studies characterizing receptor changes in the brain show ser-
otonin receptors may be involved in disease vulnerability and prevention or relief
from mood disorder symptoms. These studies also provide insight that increased
dopamine levels may be important in psychosis associated with mood disorders,
and reduction of dopamine synthesis may play a role in anti-manic efﬁcacy.
Future longitudinal studies that prospectively examine the effects of
medication exposure and other factors associated with illness chronicity are
needed. Additionally, examining bipolar patients at the onset of illness would
help control for treatment effects and other variables associated with illness chroni-
city, and also confounding variables, such as medication history, electroconvulsive

therapy, and substance abuse. For future research, some of the above-mentioned
structural changes may qualify as putative brain structure endophenotypes, as
suggested by Hasler and colleagues (175), and to understand the potential rel-
evance of these brain changes to genetic susceptibility to the disorder.
This work was partly supported by grants MH 068662, MH 068766, MH069774,
RR020571, UTHSCSA GCRC (M01-RR-01346), NARSAD, the Krus Endowed
Chair in Psychiatry (UTHSCSA), and the Veterans Administration (VA Merit
Review).
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B10 Sleep and Biological Rhythms Abnormalities
in the Pathophysiology of Bipolar Disorders
Department of Psychiatry, University of Wisconsin–Madison, Madison,
Wisconsin, U.S.A.
Bipolar illness is, by deﬁnition, a cycling disorder. The longitudinal course is
characterized by recurrent episodes of depression and mania or hypomania, with
intervening periods of euthymia (1). The fact that cyclicity is a salient feature of
the clinical phenotype has led many investigators to speculate that abnormalities
in biological rhythms might prove etiologically or pathophysiologically signiﬁcant
in the disease process, and several lines of evidence support a relationship between
biological rhythm disturbances in the onset and maintenance of bipolar episodes.
Notably, physiological and behavioral timekeeping processes are often altered in
bipolar patients, and there is evidence to suggest that a susceptibility to biological

rhythm instability may be a factor in the onset and maintenance of affective
episodes. For some patients, interventions that serve to stabilize or resynchronize
sleep and biological rhythms prove therapeutically effective. Furthermore, sleep
propensity is markedly altered during different phases of the disorder, and sleep
disturbance is perhaps the most potent predictor of mood deterioration. Lastly,
although quite preliminary, several recent studies have attempted to identify
mutations in genes involved in circadian clock regulation that might inﬂuence
the disease process in a subgroup of patients. The prevalence of biological
rhythm dysfunction in bipolar disorder, the cyclical presentation of symptoms,
and the strong link between sleep disturbance and episodes of mania and

depression suggest that these features are pathophysiologically important in the
disease process and might inform treatment development for this illness. This
chapter will review these areas of research in bipolar illness.
BIOLOGICAL RHYTHM DYSFUNCTION
Irregularities in the Timing of Activity–Rest
A number of studies have used actigraphy to record the onset and amplitude of
activity rhythms in bipolar patients across periods of clinical illness and euthymia.
Given that increased energy and activity, combined with decrements in perceived
need for sleep, are hallmarks of a manic episode, it is perhaps not surprising that
several studies have reported an overall increase in motor activity during the
manic phase of bipolar illness relative to either the euthymic or depressed phases

(2,3). In contrast, both diminished activity and a delay in the timing of normal
activity onset is reported in the depressed phase of bipolar disorder relative to
the activity level of patients with a purely unipolar course (4–6). In addition to
providing evidence of activity irregularities during periods of clinical illness, beha-
vioral rhythm alterations also serve as prognosticators of an approaching clinical
189

episode, particularly an episode of mania. Patients who experienced relapse into
mania during lithium discontinuation were reported to have higher baseline
levels of daytime motor activity preceding the onset of mania. In contrast, those
patients who managed to remain euthymic showed no such increases in levels of
daily activity (7). Changes in the duration of sleep also provide an index of chan-
ging clinical state. Using actigraphy to longitudinally record sleep and activity
over 18 months in 11 bipolar patients, Leibenluft reported that reduced sleep dur-
ation and earlier awakening time were reliably prognostic for the onset of mania or
hypomania the following day (8). Similarly, in a recent meta-analysis of bipolar
prodromes, Lam and Wong reported that early predictors of an emerging
episode of mania were recognized by 97% of patients and of these, 77% reported
sleep disturbance, particularly sleep reduction and fragmentation, as the most
prominent early symptom of mania (9).

Although it is not entirely clear if rhythm and sleep disruption are causally
related to mood pathology, both clinical and experimental evidence support the
idea that disruptions of daily routine and activity patterns can lead to an episode
of clinical illness (10). Stressful life events, in particular, are often associated with
mood deterioration, and this effect is particularly marked when those stressful
life events result in abrupt changes in daily patterns of sleep timing and duration
(11–14). Malkoff-Schwartz et al. analyzed the association between stressful life
events and the onset of an affective episode in 39 bipolar patients and found that
life events characterized as subjectively stressful, which consequently led to a

disruption in normal social routines, were signiﬁcantly predictive of the onset of
mania (15). Moreover, although clinicians have long recognized that reductions
in sleep duration are correlated with the onset of mania, the importance of sleep
loss as a trigger for mania is empirically supported by studies employing sleep
deprivation as a therapeutic intervention for depression. In a meta-analysis based
on 10 studies of sleep deprivation effects, Wu and Bunney found a 30% switch
rate into the manic or hypomanic state following one night of enforced sleep
deprivation as a treatment for depression (16). Although estimates of state switch-
ing following sleep deprivation vary, the clear relationship between mania and
sleep loss has led some to speculate that sleep loss is “a ﬁnal common pathway

in the genesis of mania” (17). This data suggests that at least a subset of patients suf-
fering from bipolar disorder may have a particular sensitivity to biological rhythm
disruption. A closer analysis of the subset of patients who are susceptible to the
effects of rhythm disruption may offer insight into whether they show genetic
abnormalities in the circadian pacemaker.
Evidence of Circadian Abnormalities: Endocrine Variables
Based on the alterations in behavioral rhythms demonstrated by many patients,
Goodwin and Wirz-Justice hypothesized that patients with mood disorders,
including bipolar disorder, may have an endogenous circadian period that is sig-
niﬁcantly shorter or longer than 24 hours. The alteration in the period of the cir-
cadian clock is thought to lead to an abnormal phase relationship between the

individual and the environment, and this lack of synchrony is thought to contrib-
ute to the onset and maintenance of affective episodes (18,19). The notion that
desynchrony between the internal and external environment might somehow con-
tribute to affective deterioration is intuitively appealing given that a synchronous
relationship between the endogenous rhythm of the clock and the external
environment is critical to well-being; the adverse affects on mood, cognition,190 Jones and Benca

and physiology that result from jet-lag, shift work, or other conditions that
produce desynchrony are pronounced (20). A number of empirical studies have
sought to substantiate this hypothesis by attempting to characterize endogenous
circadian pacemaker abnormalities in bipolar patients. These attempts, however,
have produced largely contradictory and inconclusive ﬁndings due, in part, to
the methodological difﬁculties inherent in accurately measuring human clock
function.
Mammalian circadian rhythms are governed by a master oscillator in the
suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN regulates a
number of physiological variables in humans, including temperature, certain
elements of the sleep–wake cycle such as rapid-eye movement sleep propensity,
as well as the secretion of a variety of hormones. Measurements of these variables
can, theoretically, be used to assess the period and amplitude of the endogenous cir-

cadian rhythm. The oscillation and amplitude of most output rhythms, however, is
masked by both behavior and environment (21). Protocols specialized for disentan-
gling the true period of the endogenous pacemaker from the environment can be
used to measure the period and phase of the endogenous clock accurately, but
unfortunately, few studies have used such rigorous experimental control in
studies of bipolar patients. As a result, most studies published to date have been
confounded by the masking effects of activity and light exposure on the rhythms
studied. In addition to these methodological difﬁculties, other factors such as
small sample size, psychotropic medication use by patients, and diagnostic incon-
sistency conspire to limit the ability of a given study to detect statistically signiﬁcant

differences between groups.
Dysregulation of the hypothalamic pituitary axis (HPA) is a highly replicated
ﬁnding in at least a subset of patients with mood disorders. Frequently reported
ﬁndings include elevated levels of cortisol and corticotropin-releasing hormone
(CRH), nonsuppression of cortisol on the dexamethasone suppression test, and /
or a blunted adrenocorticotropic hormone (ACTH) response to CRH (22). Given
that the proﬁle of cortisol secretion is regulated in large measure by the circadian
system, substantial research has focused on identifying abnormalities in the circa-
dian regulation of the HPA axis in depression, but support for abnormalities in
either phase or amplitude of circadian rhythms have been mixed. Linkowski, for
example, reported a signiﬁcant phase advance of the serum cortisol and ACTH

rhythms in unipolar depressed patients, but although several of the patients with
a bipolar course also showed this phase advance, the effect did not reach signiﬁ-
cance at the group level. A later study by this same group characterized sleep
and 24-hour proﬁles of cortisol in 14 patients during the manic state and reported
an elevation of nocturnal cortisol levels and an earlier occurrence of the nadir of the
circadian secretory proﬁle relative to controls (23,24). In contrast, Cervantes and col-
leagues analyzed the amplitude and phase of the cortisol proﬁle in 18 bipolar
patients in either the depressed, hypomanic, or euthymic phase relative to a
control group, and although they did report hypersecretion of serum cortisol in
the depressed and hypomanic phase, they found no evidence for a circadian

phase shift in either phase of the illness relative to controls (25). Sleep loss and
changes in sleep timing, both of which invariably accompany depression and
mania, are known to alter both the timing and amplitude of the cortisol secretory
proﬁle and could thus easily account for the conﬂicting ﬁndings. In general,
mania-associated phase or amplitude abnormalities in the cortisol rhythm have
not been reported consistently.Sleep and Biological Rhythms Abnormalities 191

Attempts to characterize the phase and period of the endogenous clock in
patients with affective disorders have also been based on peripheral measurements
of the hormone melatonin. The pineal gland, which is responsible for the pro-
duction and secretion of melatonin, is directly controlled by the SCN. Since melato-
nin production is inhibited by light exposure, serial measurement under dim light
conditions has historically been thought to provide a valid estimate of circadian
phase. As a result, melatonin output has been widely used to assess the period of
the internal clock. Potential confounds to this measurement have been suggested
by more recent data, however; for instance, melatonin production is likely affected
by even dim light as well as postural position. In addition, the timing of the mela-
tonin secretory proﬁle is further altered by sleep loss and hypercortisolemia, both of
which invariably accompany clinical illness (26). These confounds ultimately com-

plicate the interpretation of the many early studies that used melatonin output to
assess clock function.
A recent longitudinal analysis comparing the melatonin secretory proﬁle of
bipolar patients in all phases (depressed, manic, and euthymic) of the disorder rela-
tive to controls reported no evidence for circadian phase differences during any
illness period, although the amplitude of melatonin secretion was diminished in
bipolar patients during all phases relative to controls. The authors speculated
that this diminished amplitude in melatonin production might result from an
abnormal response to light in bipolar patients, and suggested that this might
provide the mechanism for an abnormal coupling of the endogenous pacemaker
and the environment (27).

As a consequence, a number of recent analyses of melatonin abnormalities
have focused on the effects of light on melatonin suppression in bipolar patients.
Some, but not all studies support an increased sensitivity to light-induced suppres-
sion of melatonin in a subgroup of bipolar patients, and it has been hypothesized
that this sensitivity might result in circadian phase instability (28–30). Lewy et al.
compared the effects of light exposure on melatonin secretion between the hours
of 2 and 4 am in euthymic bipolar patients who were age and gender-matched
with controls. Bipolar patients were reported to have a 61.5% suppression of mela-
tonin after light exposure relative to a 28% suppression of melatonin in controls
(31). Similarly, in a recent comparison of euthymic bipolar, unipolar, and control

subjects, Nurnberger and colleagues reported enhanced melatonin suppression
by light in bipolar I patients relative to controls (32). This same group also reported
evidence of a hypersensitivity to light-induced melatonin suppression in the
offspring of bipolar disorder patients (33). The data do raise the possibility that
any circadian phase instability seen in bipolar patients may not be a dysfunction
in the clock itself, but may instead be a consequence of a more peripheral abnorm-
ality, which consequently results in an improper alignment between the clock and
the environment.
Seasonality in Bipolar Disorder
Most epidemiological studies support a seasonal component for bipolar disorder,
although there is some disagreement regarding the peak incidence for various

types of episodes, likely due in part to clinical heterogeneity. Nevertheless, there
is evidence for a signiﬁcant peak of episodes of mania in the spring, with
some studies reporting a minor or major peak in the late summer or fall as well
(34–37). If all episode types are included, there is a more clear spring-fall pattern,
probably related to a fall increase in depressive or mixed episodes (38,39).192 Jones and Benca

Seasonality of mood disorders is also evident in seasonal affective disorder
(SAD), a condition originally described by Rosenthal to characterize a bipolar
patient who developed seasonally recurrent depressions (40). Although SAD has
since been reconceptualized as primarily a disorder in which patients are afﬂicted
by winter-onset depression, there are those patients who present with seasonally
induced mania in addition to winter depressions. Although the shorter photo-
period during winter is thought to be etiologically responsible for SAD, studies
attempting to show an increased prevalence at more northern latitudes have not
been conclusive; some have been equivocal (41,42), whereas others suggest
increased prevalence in regions with reduced winter light (43). Although the
results of epidemiological studies have been inconsistent, SAD patients have
been reported to demonstrate unusual responses to seasonal lighting changes.

The duration of the melatonin signal is directly related to the length of the
dark period, and in this way melatonin secretion serves as the signal of photoperiod
length for many mammals. Wehr et al. have recently helped to characterize the
nature of circadian and circannual abnormalities in SAD. They reported that SAD
patients generate a seasonal change in the duration of the dim-light melatonin
secretion proﬁle, speciﬁcally that they produced a longer duration of nocturnal
melatonin secretion in winter relative to summer, whereas control subjects fail to
show such seasonal alteration in melatonin secretion (44). These data suggest that
SAD patients, in contrast to normal subjects, exhibit a change-of-season signal
similar to that used by mammals that show signiﬁcant seasonal changes in behavior

and physiology. Although this ﬁnding does not explain how abnormal responses
to the changing photoperiod lead to affective deterioration, it provides further
support for the idea that patients with bipolar disorder may have particular
sensitivities to biological rhythm disruption.
Cyclicity in bipolar illness not related to seasonality has primarily been
described in terms of rapid cycling over the course of hours or days (2); it is
likely that many bipolar patients may have underlying cycling with periods
ranging from days to weeks to months. In summary, mood disorders, in particular
bipolar disorder and SAD, are characterized by cycling that is often seasonally
related, suggesting a role for circadian and /or seasonal pacemakers in the onset
and maintenance of these disorders.
SLEEP ABNORMALITIES IN BIPOLAR DISORDER

Psychiatrists have been interested in the relationship between sleep and mental
illness since the time of Sigmund Freud when dream analysis was a major com-
ponent of the treatment for mental illness. After the discovery of rapid eye move-
ment (REM) sleep in 1953, psychiatrists, spurred on by the seeming similarities
between the hallucinations associated with psychosis and the hallucinogenic
quality of dreams, began to speculate that schizophrenia might represent a disorder
of REM sleep. Although this speculation did not prove accurate, an interest in the
relationship between speciﬁc sleep abnormalities and psychiatric disorders has per-
sisted. Sleep in depression has been studied more thoroughly that any other dis-
order, and as early as the 1950s abnormalities in both slow wave sleep (SWS) and

REM sleep were reported in depressed patients. Coincident with technological
advances in sleep science, a deeper understanding of the neural control of sleep was
developing. Given the widespread and robust changes in sleep architecture demon-
strated by patients with affective disorders, it was hoped that an understanding ofSleep and Biological Rhythms Abnormalities 193

the neural control of sleep might offer insight into the neurochemical abnormalities of
patients with mood disorders.
Overview of Sleep Regulation
Sleep is modulated by the endogenous circadian clock as well as by the accumulation
of sleep need over the course of wakefulness. The daily temporal modulation of sleep
and wakefulness is described by the two-process mathematical model of sleep regu-
lation, ﬁrst articulated by Borbely, where the circadian pacemaker (process C) inter-
acts with a sleep dependent homeostatic process (process S) to regulate sleep onset
and offset. The homeostatically regulated process S reﬂects an increasing sleep
drive, estimated from slow-wave analysis of the electroencephalogram (EEG), and
increases as duration of wakefulness increases. Process C is thought to be largely
governed by the circadian clock, and is subjectively measured by self-report assess-
ments of sleepiness during sleep-deprivation studies. REM sleep onset and offset is

governed largely, but not completely, by the circadian clock (45,46).
The transition from wakefulness to sleep is regulated by a complex interaction
between circadian and homeostatic processes and by myriad neurochemical
changes. The idea that the rostral brainstem reticular formation plays a central
role in arousal has not changed in over 50 years, but our understanding of the
complex neural circuits and multiple neuromodulatory systems involved in
sleep–wakefulness has grown considerably. Arousal is mediated by two cholin-
ergic nuclei of the laterodorsal tegmental (LDT) and pedunculopontine tegmental
(PPT) nuclei of the brainstem reticular formation. The dorsal pathway to the thala-
mus, which sends a broad glutamatergic inﬂuence to the cortex, is the classical

substrate of cortical arousal. A ventral pathway projects to both the hypothalamus,
which, in turn, sends a diffuse histaminergic projection to the cortex as well as to the
basal forebrain. Cells of the basal forebrain synthesize both acetylcholine and
GABA and project broadly to the cortex. Sleep is produced by structures distributed
throughout the brain that exert inhibitory inﬂuences upon this arousal system.
Neurons from the lower brainstem exert an inhibitory inﬂuence on the rostral reti-
cular formation, and GABAergic neurons of the ventrolateral preoptic area of the
hypothalamus and adjacent regions of the basal forebrain send inhibitory signals
to both the histaminergic nucleus of the hypothalamus, as well as to the cholinergic
nuclei of the reticular formation, dampening cortical and behavioral arousal (47,48).

The neural control of REM sleep, initially proposed by McCarley and Hobson,
outlined a reciprocal relationship between so-called REM-off and REM-on neurons in
the regulation of REM sleep (49). Experimental evidence identiﬁed brainstem cholin-
ergic neurons of the LDT and PPT nuclei as the cells that control the onset of REM
sleep. Noradrenergic cells of the locus coeruleus and serotonergic cells of the dorsal
raphe nucleus project to the PPT and LDT and normally have an inhibitory inﬂuence
on these cholinergic cells. Just prior to the onset of REM sleep, these aminergic
cells (referred to as REM-on neurons) decrease ﬁring, thus lifting their inhibitory inﬂu-
ence on PPT and LDT cholinergic neurons. The ﬁring of these neurons supports an

increase in acetylcholine release and, ultimately, the cerebral arousal evidenced by
the activated EEG of REM sleep (49).
Sleep Abnormalities in Bipolar Depression
Some of the best-documented clinical ﬁndings in depressed patients involve sleep
disruption. Disturbed sleep, including prolonged sleep latency, early morning awa-
kenings, and reduced sleep efﬁciency, is characteristic of depressive episodes.194 Jones and Benca

Consistent changes in polysomnographic sleep characteristics of depressed patients
have also been widely and consistently reported. Depressed patients show a rela-
tive loss of slow-wave sleep (SWS), including a reduction in the absolute number
of EEG delta waves during the ﬁrst nonrapid eye movement (NREM) period.
Changes in REM sleep are perhaps the most speciﬁc to mood disorders. In
healthy subjects, REM sleep propensity normally reaches its maximum in the
latter portion of the sleep period. In contrast, depressed patients often exhibit
abnormally early REM sleep onset (reduced REM latency), a larger proportion of
REM sleep during the ﬁrst third of the night, and increased eye movements
during the REM sleep period (50). Although most of the studies on depression to
date have likely included a mixture of unipolar and bipolar patients, a few
studies have focused exclusively on the question of whether the sleep of bipolar

depressed patients differs from that of unipolar depressed patients.
Riemann et al. analyzed the EEG of 27 bipolar and unipolar depressed
patients age- and gender-matched with controls. Although, as expected, both the
unipolar and bipolar depressed patients showed increased REM density, increased
percentage of REM sleep throughout the night, and a loss of SWS, differences
between the two patient groups were subtle. The authors reported a trend
toward increased REM density in the ﬁrst REM period in bipolar patients, but
this effect did not reach signiﬁcance (51). Similarly, Fossion et al., comparing EEG
data of unipolar and bipolar depressed patients during an episode of major
depression, reported a trend toward a longer REM sleep latency in the bipolar

patients relative to the depressed patients, but this trend was only evident in the
more severely afﬂicted bipolar patients. A total of ﬁve studies, in addition to the
two reviewed, have directly compared the sleep EEG of bipolar and unipolar
depressed patients (52). Although there have been some subtle differences
between the sleep of unipolar and bipolar depressed patients, overall these
studies have failed to demonstrate compelling differences between the two (53–58).
Sleep Abnormalities in Bipolar Mania
A subjectively reported decrease in the need for sleep is one of the most remarkable
correlates of a manic episode. As mentioned early in the chapter, it is regularly
reported in the clinical literature that sleep disruption not only often predicts but

may also precipitate the onset of a manic episode. These striking clinical observations
have naturally led to an interest in analyzing the sleep EEG in acutely manic patients,
but studying sleep in mania beyond behavioral observation is challenging. As a result,
only a few controlled EEG studies have been performed during bipolar mania.
Hudson et al., studying nine bipolar manic patients and nine age-matched
healthy controls, reported an overall decrease in time spent asleep, reduced REM
latency, and increased REM density in the manic patients relative to controls. In a
later study, the same group performed a comparison between the sleep EEG in
19 bipolar manic patients, 19 age- and gender-matched depressed patients, and
19 healthy controls. As expected, both patient groups exhibited behavioral and

EEG abnormalities relative to healthy controls, but although manic patients were
reported to have a decreased total sleep time relative to the depressed patients,
EEG recordings failed to distinguish manic from depressed patients on measures
of REM latency and density (59). Similarly, Linkowski et al. found that EEG record-
ings did not distinguish bipolar manic patients from depressed patients or healthy
controls, with the exception of longer sleep latencies and diminished total sleep
time in the manic group (60).Sleep and Biological Rhythms Abnormalities 195

Longitudinal Studies of Sleep in Bipolar Patients
Longitudinal studies have the potential to provide information that cannot be
achieved through cross-sectional analyses. These studies, however, are difﬁcult to
conduct and the extant studies have produced conﬂicting data. Bunney et al. ana-
lyzing the EEG of one patient during three switches into mania and one switch out
of mania, reported that REM sleep was uniformly decreased as patients entered into
the manic state (61). The authors suggested that since noradrenergic cells of the
locus coeruleus and serotonergic cells of the dorsal raphe nucleus are thought to
inhibit REM sleep by suppressing cholinergic ﬁring, the decrease in REM sleep pre-
ceding mania onset suggests the possibility of a decreasing cholinergic tone in
mania. The authors claimed that the data was supported by an early hypothesis
of mood disorders articulated by Janowsky, which argued for the pathophysiologi-

cal importance of increased cholinergic activity in depression and increased ami-
nergic activity in mania (62). In contrast to the Bunney data, however, Kupfer et
al. reported a higher REM density directly preceding the onset of a manic
episode in a rapid-cycling patient with a 48-hour cycle (63). Although longitudinal
designs have the potential to provide informative clinical data across behavioral
states, to date, these studies have proved inconsistent.
Sleep in Bipolar Remission
There is controversy over whether or not sleep abnormalities in bipolar patients
normalize with remission, or if these alterations reﬂect enduring trait or vulner-
ability markers. State-dependent abnormalities, which resolve when symptoms of
the affective disorder resolve, reﬂect alterations in neurobiological processes under-

lying an acute episode. Trait markers, in contrast, do not resolve with symptom
remission and suggest an increased risk for occurrence of the disorder, presumably
linked to genetic transmission. Several authors contend that some sleep alterations,
in particular REM abnormalities, normalize in unipolar and bipolar patients during
periods of euthymia, and may therefore be characterized as state-dependent.
Buysse et al. reported a decrease in REM density and a decrease in REM latency
during remission in depressed patients, and similar results have been reported in
several longitudinal studies, supporting the hypothesis that some REM abnormal-
ities may be episode-related biological features (64–67). A variety of other ﬁndings,
however, do not support this view. Giles et al. reported a persistence of shortened

REM latencies and enhanced REM density during remission in bipolar and uni-
polar patients, and longitudinal studies have further shown REM latency to be
stable during depressive episodes and periods of euthymia (Rush, 68–70). Familial
analyses provide further support for REM abnormalities, including increased REM
density and decreased REM latency as stable traits in patients with mood disorders.
(69,71). Lauer, investigating 54 high-risk probands by polysomnography, found that
the EEG patterns of subjects without a personal history of depression, but with a
strong familial history, showed reduced SWS and increased REM density in the
ﬁrst sleep cycle compared to control subjects with no personal or family history
of affective disorders (72). A recent study, attempting to identify risk factors for

the development of affective disorders similarly reported increased REM density
in the ﬁrst REM period in 82 subjects with a familial history of affective disorders
(73). This group failed to ﬁnd evidence of distinct differences between relatives of
unipolar and bipolar patients. EEG abnormalities, particularly increased REM
density, were similarly expressed in both ﬁrst degree relatives of bipolar and196 Jones and Benca

unipolar patients, causing the authors to conclude that REM abnormalities might
represent vulnerability markers for mood disorders in general (74).
In summary, sleep disturbances are an integral feature of bipolar disorder.
Like the disorder itself, the associated sleep disturbances are heterogenous,
ranging from hypersomnia to difﬁculty initiating or maintaining sleep (75).
Although there is controversy over whether sleep abnormalities represent stable,
trait-like features of depressive and bipolar disorders, most studies appear to
support the notion that reduced REM latency and increased REM density, at
least, are stable features. The persistence of these abnormalities during periods of
euthymia does call into question whether or not these abnormalities are pathophy-
siologically signiﬁcant or simply reﬂect a trait generally correlated with, but not
integral to, the pathophysiology of bipolar disorder. However, a major goal of

metal health research is to identify speciﬁc quantiﬁable, heritable markers of psy-
chiatric research, and particular sleep abnormalities may represent such markers.
Identifying discrete physiological features of bipolar disorder promises to not
only improve diagnostic reliability and consistency, but this strategy offers hope
for elucidating the genetic underpinnings of the disorder.
TREATMENTS FOR BIPOLAR DISORDER
Perhaps the most compelling demonstration for a signiﬁcant role for sleep and
rhythm disturbances in bipolar disorder comes from treatment studies. Manipula-
tions of the sleep–wake cycle, including total sleep deprivation as well as phase
advances in the timing of sleep onset, have been demonstrated to produce mood
improvement in bipolar depressed patients and also to induce mania in susceptible

patients. In addition, fostering sleep and stabilizing its timing has been shown to be
helpful in decreasing the duration of a manic episode. The most widely prescribed
mood stabilizer, lithium, has demonstrated effects on both sleep and circadian
rhythmicity, as do most of the antidepressant medications prescribed for bipolar
depression, although it is not known if their therapeutic efﬁcacy is related to
effects on circadian rhythms. How sleep and rhythm manipulations achieve thera-
peutic efﬁcacy, or how, in some cases, these manipulations lead to mood symptoms,
is unclear. An understanding of the mechanism(s) through which these interven-
tions lead to mood deterioration or improvement may ultimately lead to the devel-
opment of pharmaceutical agents that produce more rapid symptom alleviation

than currently available pharmaceutical agents are able to do.
Manipulations of the Sleep–Wake Cycle: Sleep Deprivation
Total sleep deprivation for one night has been convincingly demonstrated to
produce rapid improvement in mood, as well as in cognitive and motor functions,
in approximately 60% of patients with unipolar depression. Late night sleep depri-
vation, where a patient is kept awake for the latter half of the nocturnal sleep
period, has also been shown to produce signiﬁcant symptom alleviation. Selective
REM deprivation, a process in which the patient is awakened whenever he or she
shows polysomnographic evidence of REM sleep, has also been shown to have
some antidepressant effect, although there is a considerable latency between
initiation of the REM deprivation protocol and mood improvement (76). Although

the data supporting the therapeutic effect of sleep deprivation speciﬁcally in bipolar
disorder patients is not as extensive as that in unipolar depressed patients, there isSleep and Biological Rhythms Abnormalities 197

evidence to both support and contraindicate this therapeutic sleep intervention in
bipolar patients. In terms of efﬁcacy, the response of bipolar depressed patients
to sleep deprivation appears to be comparable to that seen in unipolar depressed
patients, with some studies suggesting a slightly better response in bipolar patients
(77). Early studies indicated that up to 30% of bipolar patients were at risk for enter-
ing a manic or hypomanic episode following a night of sleep deprivation. More
recent evidence, however, suggests that a switch into mania following a night of
sleep loss may be more characteristic of bipolar patients with a rapid cycling
course (78,79). A recent analysis of a large population of bipolar depressed patients
revealed a rate of switch into mania of approximately 5% following one night of
sleep deprivation, a rate comparable to that seen following initiation of antidepress-
ant treatment (79,80). The precise estimate of the rate of switch from depression to

mania is still controversial, and caution is warranted when sleep deprivation is
employed as a treatment for bipolar depression.
Sleep Deprivation: Potential Mechanisms
Although the effect of sleep deprivation therapy is transient, with relapse typically
occurring immediately following recovery sleep, it provides rapid symptom
improvement. This rapid effect is in contrast to antidepressant medications,
which typically require anywhere from several days to a week before symptom
relief occurs. Elucidating the biological mechanisms through which this rapid
therapeutic effect is achieved could thus aid in the development of antidepress-
ants that are superior to existing agents, and, to that end, many investigators
have attempted to characterize the mechanism of the therapeutic efﬁcacy of

sleep deprivation. Although the neurobiological mechanisms of depression and
mania are complex, theoretical conceptualizations of depression have implicated
monoaminergic signaling as a signiﬁcant factor in mood pathology.
The role of serotonin in modulating sleep and arousal, and the clinical efﬁcacy
of antidepressant medications that enhance monoaminergic transmission in the
central nervous system, provides an overt link between the systems regulating
both mood and sleep. Selective serotonin uptake inhibitors (SSRIs) represent the
most widely prescribed class of antidepressant medication and the most consistent
effect of the SSRIs on sleep is a reduction of REM sleep. It has long been suggested
that the antidepressant effect of SSRIs might be tied to this reduction of REM sleep;

however, recently developed antidepressant drugs with therapeutic efﬁcacy similar
to that of the SSRIs are not REM-suppressive, casting doubt on the importance of
REM reduction for mood elevation (81). Nevertheless, the serotonin system is
still thought be involved in the response to sleep deprivation. The SSRI drug ﬂuox-
etine, the mixed serotonergic-noradrenergic drug amitriptyline, and the 5HT1-A-
beta adrenoreceptor blocker drug pindolol have been demonstrated to enhance
and sustain the response to sleep deprivation in depressed patients (82–84). In
further support of a role for the serotonin system, a recent study reported that a
polymorphism in the transcriptional control region of the serotonin transporter
(5-HTT), a polymorphism which ultimately increases central serotonin production,

is associated with a better response to sleep deprivation in bipolar patients relative
to those patients homozygous for the short variant of this allele. Another group,
however, failed to replicate this effect (85,86). Altered serotonin signaling clearly
does not explain all of the therapeutic effects of sleep deprivation, however, since
experimental depletion of tryptophan, which rapidly lowers brain serotonin
levels and produces relapse in medicated depressed patients, does not reverse
the antidepressant effects of sleep deprivation in unmedicated patients (87).198 Jones and Benca

Dopamine has also received attention as a possible mediator of the effects of
sleep derivation (88). Patients who show symptom improvement in response to
sleep deprivation have been shown to have lower levels of cerebral spinal ﬂuid
homovanillic acid—a dopamine metabolite—before sleep deprivation and an
increase in this metabolite following sleep deprivation, when compared to those
patients who do not respond (88–90). Ebert et al., using SPECT to study receptor
occupancy of the dopamine D2 receptor, reported that sleep deprivation responders
had decreased occupancy of the D2 receptor following the sleep deprivation while
nonresponders showed an increase in D2 binding, and the authors interpreted
this result as an indication that sleep deprivation enhanced dopamine release in
responders to sleep deprivation. Later studies, however, failed to replicate this
ﬁnding and one group reported enhanced D2 binding in sleep deprivation respon-

ders (91,92). An additional piece of indirect evidence supporting the importance of
dopaminergic signaling in the effects of sleep deprivation comes from studies
of patients afﬂicted with Parkinson’s disease. Interestingly, following one night of
sleep deprivation, Parkinson’s patients show marked improvement in both
tremor and rigidity, suggesting a transient normalization of dopamine (93,94).
Although dopamine signaling may be increased following sleep deprivation, its
role in mood improvement is unclear.
Interestingly, recent data in animal models indicates that both antidepressant
medication and sleep deprivation lead to increased expression of genes involved
in synaptic potentiation and plasticity, suggesting a common mechanism for
their effects on depression. The time course of these changes in gene expression

parallels the time course of the antidepressant effect. Sleep deprivation results in
immediate increases in plasticity-related genes in rats (95) and an immediate anti-
depressant effect in humans, while chronic (but not acute) administration of
antidepressant medication results in increased expression of these same genes in
rodents (96). It has been suggested that the antidepressant effect of sleep depri-
vation may be directly related to synaptic potentiation and the induction of
such genes (97) and that “sleep deprivation may bring about its rapid antidepress-
ant effects by activation of the robust expression of plasticity genes, such as CREB
(cyclic AMP response element binding protein), BDNF (brain-derived neuro-
trophic factor) and TkrB (tyrosine kinase receptor beta), and consequently a
rapid antidepressant response” (98).

Despite these intriguing data, the mechanism of the antidepressant action of
sleep deprivation has not yet been identiﬁed. Nevertheless, a more complete under-
standing of the effects of sleep deprivation has the potential to lead to both a better
understanding of the neurobiology of mood disorders as well as the development
of improved pharmaceutical interventions.
Manipulations of the Sleep–Wake Cycle: Circadian Phase Advances
As described above, depressed patients often demonstrate a marked phase advance
in the ﬁrst REM sleep period of the night. Given that REM sleep timing is regulated
largely by the circadian system, the appearance of REM sleep earlier in the night in
depressed patients has been hypothesized to reﬂect abnormally advanced circadian

rhythms relative to the sleep–wake cycle. Several investigators have therefore
argued that depressed patients may thus sleep at the wrong circadian time, and
have advocated shifting the sleep–wake period to earlier in the evening in an
effort to synchronize out-of-phase rhythms with hopes of inducing mood improve-
ment. Several studies employing sleep phase advance, in which a patient’s sleep
onset and offset time is moved to an earlier clock time, have been reported toSleep and Biological Rhythms Abnormalities 199

alleviate depressive symptoms, although the time to improvement is considerably
longer than that seen following one night of total sleep deprivation (99,100).
Additionally, sleep phase advances have also been shown to successfully preserve
the antidepressant effects of total sleep deprivation (101,102).
Although these data suggest that an abnormal phase relationship between
sleep and the endogenous circadian rhythm or abnormal circadian control of sleep
might be of pathophysiological signiﬁcance, there is currently no evidence that
these sleep–wake manipulations alter REM sleep latency or distribution (103).
Reimann et al. recently examined REM sleep distribution of depressed patients fol-
lowing total sleep deprivation with a subsequent sleep phase advance. Even in those
patients who responded positively to the therapeutic regimen, shortened REM
latencies persisted (104). The failure to correct the purported circadian abnormality

calls into question whether these REM sleep abnormalities are pathophysiologically
signiﬁcant or whether they are merely epiphenomena of the depressed state.
Nevertheless, the efﬁcacy of sleep phase advance has been shown to be superior to
sleep phase delays in the treatment of depression, providing support for the idea
that the timing of sleep and its interaction with other biological variables may
be an essential element in symptom relief. Moreover, a recent study provided
evidence for an interactive effect between sleep and the circadian system on mood
regulation in normal subjects, further highlighting the importance of proper
alignment of endogenous circadian phase and sleep–wakefulness timing for
mood regulation (105).
Treating and Preventing Mania: Rhythm Stabilization

Although much of the emphasis on treating and preventing mania in bipolar
patients is on pharmacotherapy, there is some evidence that rhythm stabilization
might be effective in both shortening the duration of an acute episode of mania
as well as in preventing episode recurrence. Several case studies have demon-
strated that enforced sleep and extended darkness successfully reduces the dur-
ation of acute episodes of mania in rapid-cycling bipolar patients (106,107). Wehr
and colleagues employed a protocol of 14 hours of enforced bed rest in complete
darkness for a bipolar disorder patient with a long history of rapid cycling. This
enforced sleep and darkness protocol effectively reduced the duration of an acute
manic episode, and additionally served to dramatically stabilize the patient’s

rapid-cycling course (108). Similarly, behavioral interventions aimed at normalizing
and structuring a regular pattern of sleep and daytime activity also appear to have
some efﬁcacy in both reducing the duration of a manic episode, as well as extending
the time between episodes of clinical illness (109). As a result, Frank and Kupfer
developed social rhythm therapy and they advocate its use as an adjuvant to medi-
cation treatment for bipolar patients. This form of psychotherapy, which augments
the more conventional interpersonal therapy, employs behavioral strategies to
stabilize daily routines and rhythms (110,111). Currently, results are anticipated
from an ongoing large-scale clinical trial of social rhythm therapy at the University
of Pittsburgh.
Medication for Mania: Effects on Sleep and Circadian Rhythms

Lithium carbonate is the ﬁrst line of treatment for bipolar patients. It has established
effects on both sleep and circadian rhythmicity, and these effects have been pro-
posed to at least partially explain its clinical effect (112,113). Several early studies
demonstrated that lithium remediated sleep abnormalities associated with200 Jones and Benca

depression in bipolar patients. A 150-night analysis of sleep in ﬁve bipolar patients
reported that chronic lithium administration produced a signiﬁcant decrease in
both REM density as well as an increase in the latency to REM sleep (114).
In addition to conﬁrming this ﬁnding, a follow-up study by Mendels et al. reported
that lithium administration also signiﬁcantly increased stage 1, 3, and 4 sleep in
bipolar patients. Similarly, Hudson et al., studying nine bipolar manic patients,
reported evidence of both REM suppression and an increase in REM latency
following initiation of lithium carbonate therapy (59).
Lithium also has demonstrated effects on measures of circadian physiology
beyond REM sleep regulation in both healthy subjects and patients; it has been
demonstrated to delay the sleep–wake rhythm by approximately 15 minutes in
healthy human subjects (115). Campbell et al. examined the effects of lithium on

the circadian rhythms of body temperature and REM sleep in a single patient
with bipolar depression, and reported a phase delay of the body temperature
rhythm of 74 minutes after one week of lithium treatment. The authors also
reported a markedly increased REM sleep latency following lithium adminis-
tration as well as a signiﬁcant decrease in REM density (115). The data are consist-
ent with the hypothesized phase-delaying properties of lithium, although it is not
clear if these properties are related to therapeutic effect. Interestingly, however,
recent data have demonstrated that both lithium and valproic acid, another
widely prescribed mood stabilizer, are capable of reducing melatonin suppression
by light in healthy controls. As discussed above, sensitivity of the pineal hormone

melatonin to bright light suppression has been posited as a putative marker of
affective disorders. Hallam et al. recently demonstrated that both lithium and
valproic acid signiﬁcantly reduce the sensitivity of nocturnal melatonin secretion
to light in healthy volunteers (116). Both sets of data are in accord with a trend
for unmediated bipolar patients to demonstrate greater sensitivity to the melato-
nin-suppressing effects of light relative to lithium-treated patients (32). The clinical
relevance of this ﬁnding is not entirely clear, however.
GENES AND BIPOLAR DISORDER
Evidence from family, twin and adoption studies indicate that bipolar disorder has
a genetic basis with heritability estimates as high as 80% (117). To date, however,
neither genes of large or small effect have been identiﬁed. The search for genes

conveying risk for bipolar illness is complicated by the fact that the disorder is
both phenotypically and genetically heterogeneous (118). A number of genes inter-
acting with each other, as well as with environmental factors, likely conspire to
modulate susceptibility to the disease phenotype. Despite these complexities, a
substantial research effort is underway to identify genetic factors that contribute
to the bipolar disorder phenotype. In particular, several recent studies have
attempted to link particular genes involved in the regulation of the circadian
clock with a general susceptibility to bipolar disorder or with some speciﬁc
feature of the disease process.
The last decade has witnessed a phenomenal growth in our understanding
of the molecular basis of the circadian clock. In the 1980s, induced mutations in

fruit ﬂies led to the identiﬁcation of the ﬁrst circadian clock mutants period
(Per) and frequency (Frq), and in the 1990s a similar mutagenesis approach in
mice isolated the ﬁrst mammalian circadian mutation CLOCK (119,120). Although
most of our understanding of the molecular regulation of the circadian clockSleep and Biological Rhythms Abnormalities 201

comes from animal studies, genes dedicated to the generation and regulation
of circadian rhythms have also been identiﬁed in humans. Patients afﬂicted by
Familial Advanced Sleep Phase Syndrome (ASPS) have a short circadian period
with a four-hour advance of the daily sleep–wake cycle, and this trait has been
linked to a missense mutation that replaces a serine for a glycine in the human
Per2 gene (121), proving that, as is the case in lower animals, mutations in
circadian clock regulatory genes have demonstrable effects on the circadian phe-
notype. Researchers have therefore begun to consider the role of circadian genes
involved in other putative rhythmic disorders, including bipolar disorder.
Although the results of these studies have thus far failed to identify deﬁnitively
any gene or genes involved in susceptibility to bipolar disorder, our increasing
understanding of the molecular regulation of the circadian system has the poten-

tial to identify circadian genes that might contribute to some element of the
bipolar phenotype.
As noted above, lithium treatment is known to lengthen the period of circa-
dian rhythms in mammals (122). Although the mechanism through which this
effect is achieved is not entirely clear, lithium has been shown to directly inhibit
the activity of glycogen synthase kinase-3 beta (GSK3-B), a serine /threonine
kinase essential in a number of signaling pathways, which has recently been ident-
iﬁed as a fundamental regulator of the mammalian circadian clock (123,124). The
inhibition of GSK3-B is speculated to be the mechanism through which lithium
lengthens the circadian period, an effect that has been linked to its therapeutic
efﬁcacy, making GSK3-B a plausible candidate gene for bipolar disorder (125).

Three studies have attempted to link a particular allelic variant in the promoter
of the gene encoding the GSK3-B protein with particular features of bipolar dis-
order. Benedetti et al. analyzed 185 bipolar disorder patients and reported that
homozygotes for the wild-type variant (T /T) of the promoter had an earlier age
of onset than the carriers of the mutant (T /C) allele. These authors further evaluated
the association of GSK3-B with the response to both total sleep deprivation and to
lithium treatment in bipolar patients. In both cases, a moderate association was
made between the mutant allele (T /C) and an enhanced response to both thera-
peutic interventions relative to the (C /C) or (T /T) variants (126–128). Although
these associations are intriguing, sample sizes were small and differences in

allele frequency in different populations may introduce a bias. Importantly, there
is currently no experimental evidence that the particular allelic variant in the
GSK3-B promoter has any functional effect on GSK3-B gene expression or on the
expression of any constituent of the circadian clock in humans. Both larger
sample sizes as well as basic research on the functional role of GSK3-B variant
are necessary before any ﬁrm conclusions can be drawn.
Although not all patients with bipolar illness show evidence of sensitivities to bio-
logical rhythm or sleep disruption, nor do all patients respond to treatments that
normalize these rhythms, there is evidence that these abnormalities are important
in the disease process for at least a subset of bipolar patients. Given the increasing

recognition of etiological heterogeneity in bipolar illness, a critical next step is to
identify particular groups of patients who present with these abnormalities and
determine whether the abnormalities are merely epiphenomena of the disorder,
or, rather, are causally related. Advances in basic science and technology, including202 Jones and Benca

the sequencing of the human genome and reﬁnements in neuroimaging technology,
will help to expand and reﬁne our understanding of the central nervous system
mechanisms disrupted in bipolar disorder.
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B11 Hypothesis of an Infectious Etiology
in Bipolar Disorder
Robert H. Yolken
Stanley Division of Developmental Neurovirology, Johns Hopkins University
School of Medicine, Baltimore, Maryland, U.S.A.
E. Fuller Torrey
Stanley Medical Research Institute, Chevy Chase, Maryland, U.S.A.
Until recently, the possibility of viruses or other infectious agents being involved
in the etiology of bipolar disorder had not been seriously considered. For
example, in their 782 page Manic-Depressive Illness , published in 1990, Goodwin
and Jamison (1) covered viral factors in two pages, almost all of which was
devoted to viral factors in unipolar depression, not bipolar disorder. A major
reason for the neglect of a possible viral etiology of bipolar disorder has been the
widespread assumption that it is predominantly or exclusively genetic in origin.
Findings suggest that viruses and other infectious agents should be

considered as part of a multifactorial etiological pathway for at least some cases
of bipolar disorder: viral infections are strongly inﬂuenced by genetic factors, and
thus viral and genetic etiologies are not incompatible; viral central nervous
system (CNS) infections may mimic bipolar disorder; and season-of-birth, urban
birth, and perinatal studies all point toward an environmental risk factor in
bipolar disorder that may be a virus. This chapter summarizes these three factors
and then discusses recent ﬁndings of speciﬁc infectious agents and bipolar disorder.
Immunological research, which is also consistent with an infectious etiology, is
discussed elsewhere in this volume.
GENETIC FACTORS IN MICROBIAL INFECTION
At ﬁrst glance, the postulate that infections and other environmental factors may

play a role in the etiopathogenesis of bipolar disorder seems to contradict the
large body of evidence presented elsewhere in this volume indicating that
genetic factors are important predictors of disease susceptibility. However, it is
becoming increasingly clear that host factors under genetic control are major deter-
minants of host susceptibility to infectious agents and to the response to infection
after it has occurred (Table 1).
The human genes with the clearest association with susceptibility to infection
are those that encode components of the immune system. There are many single-
gene disorders associated with a complete ablation of a major component of
the immune system, such as major defects in T cells, B cells, macrophages, or
complement cascade (2). These rare defects are generally associated with serious,

often life-threatening, infection and are associated with a substantial rate of
209

morbidity and mortality (3). However, there are also more subtle genetic alterations
that are often speciﬁc for susceptibility or resistance to infection with deﬁned patho-
genic agents. These polymorphisms are generally more common in human popu-
lations than single-gene defects leading to complete immunodeﬁciency (4).
The human infectious agents that have been studied in most detail in terms of
genetic patterns of susceptibility and resistance are the plasmodia that cause
malaria. Interest in genetic interactions between malaria parasites and host
genes was initiated by Haldane (5), who noted in 1948 that sickle cell disease,
thalassemia, and other homoglobinopathies were most prevalent in areas of the
world where malaria is endemic. Since this original observation, more than
120 mutations in the hemoglobin molecule have been identiﬁed that are associated
with protection against malaria. The mechanism by which altered hemoglobin

provides against malaria is not known with certainty but may be related to the
increased clearance of parasites in altered erythrocytes or by decreased parasitic
growth under conditions of lowered oxygen concentrations. Susceptibility to
malaria has also been associated with genetic polymorphisms in other molecules,
including HLA class I, HLA class II, and tumor necrosis factor alpha (TNF- a).
Epidemiological studies have indicated additional, as yet unrecognized, factors
that contribute to susceptibility to malaria. The large number of polymorphisms
associated with susceptibility to malaria is a testimony to both the pervasiveness
of malaria as a human pathogen and the diversity by which genetic mechanisms
may determine susceptibility and resistance to an infectious agent (6).

The association between genes and susceptibility to malaria has led to the
search for genes that confer susceptibility to other parasitic agents. For example,
investigators have identiﬁed a region on chromosome 5 (5q31-33) that is associated
with susceptibility to Schistosoma mansoni . Known genes in this region include a
gene cluster that encodes a number of immunologically active molecules, including
granulocyte-macrophage colony stimulating factor, immune regulatory factor 1,
and interleukins 3, 4, 5, and 13 (7). An analysis of parasitic infections in Brazil
identiﬁed additional regions that may determine susceptibility to leishmaniasis,
including HLA II and HLA III, and a region on chromosome 17q that encodes a
number of inducible cytokine molecules. Susceptibility to leishmaniasis may also

be determined by polymorphisms in the gene encoding the promoter region ofTABLE 1 Genetic Determinants of Infection
Immunological activity
T cells—cell-mediated immunity
B cells—antibody generation
Macrophages
Complement
Cytokines
Interferons
Microbial receptors
Monokines
Lectins
Fusin
Mannose-binding proteins
Miscellaneous
Hemoglobin variants
Blood groups
Determinants of mucosal integrity210 Yolken and Torrey

TNF- a(8). Finally, a study of hookworm in Gambia concluded that approximately
37% of the susceptibility to this infection was related to genetic factors; however,
the speciﬁc genetic factors have not yet been determined (9).
Genetic factors have also been recognized as important factors in sus-
ceptibility to bacterial infections. Although such factors have been recognized in
terms of the response to pyogenic bacteria such as Haemophilus inﬂuenzae (10),
most information in this area had been directed at slow-growing intracellular bac-
teria, particularly those of the family mycobacteraciae. For example, susceptibility
toMycobacteria tuberculosis has been linked to the Nramp locus on human chromo-
some 2. This locus appears to control the functioning of bactericidal activity within
cells of the macrophage lineage and is thus central in determining the intracellular
survival of mycobacteria after phagocytosis (11). This gene locus may also be a

major determinant of disease response to other mycobacteria, including those
that cause leprosy. The response to lower pathogenicity mycobacteria, such as
bacillus C-G, is determined by another gene that encodes the receptor for TNF- a.
Individuals with defects in this gene have deﬁcient upregulation of TNF- a
after infection with mycobacteria and subsequent deﬁciencies in bacterial clearance
(12). The response to mycobacteria may also be determined by other genes such
as the 5q31-33 and 17q loci described above. Genetic factors may also play a
role in the response to other slowly growing bacteria. For example, susceptibility
toHelicobacter pylori , the organism that causes intestinal ulcers, is determined,
to a great extent, by DQA genes that are components of the human major histocom-
patibility system (13).

The response to viral infection is also determined, in part, by genetic factors.
For example, infection with Epstein-Barr virus results in asymptomatic or mild
infection in most individuals. However, some infected individuals will develop
overwhelming infections or malignant tumors due to mutations involved in the
immune response to infection (14). The response to other viral agents, such as
those causing hepatitis, is also under the control of a number of genes, including
those that encode the TNF- apromoter, mannose-binding proteins, and components
of the histocompatibility locus (15). A striking example of genetically encoded
protection against viral infection is provided by analyses of infection with
human immunodeﬁciency virus type 1 (HIV-1). In this case, individuals with

homozygous mutations in the viral coreceptor CCR5 are protected against
infection despite exposure to high levels of infecting virus (16,17). Heterozygosity,
although not associated with protection, may result in a slower course of disease
progression in infected individuals (18). Interestingly, these mutations, which
occur in 1% to 3% of individuals of European extraction, do not appear to have a
deleterious effect on the host (19). The discovery of these protective genes has led
to research directed at providing similar protective mechanisms to individuals
who are not genetically endowed with this inherent mechanism of disease
protection.
It can be seen from the above discussion that many genes determine the sus-
ceptibility to human infectious diseases. Furthermore, the clinical manifestations of

these genes depend, to a great extent, on individual environmental exposures; most
genes do not have any effect on individuals who are not exposed to the infectious
agents. Genes of a similar nature could be operant in psychiatric diseases such as
bipolar disorder in that they may confer susceptibility to infectious agents in the
absence of other clinical manifestations. This concept is consistent with the fact
that most studies of the genetics of bipolar disorder have identiﬁed multipleHypothesis of an Infectious Etiology in Bipolar Disorder 211

genomic regions of weak effect, none of which appear to be completely determinant
for disease acquisition (20). It is of note in this regard that many regions associated
with the acquisition of human psychiatric disease, such as 6p, contain several
genes involved in the immune response to infectious agents (21). Further studies
of the genetics of bipolar disorder are likely to identify additional regions
involved in the immune response to infectious agents. However, the role of these
genes in the pathogenesis of bipolar disorder is unlikely to be accurately evaluated
without corresponding data related to exposure to infectious agents and other
environmental stimuli of the immune response.
VIRAL INFECTIONS OF THE CNS AND BIPOLAR DISORDER
The epidemic of HIV infection has served as a reminder that many viruses can
infect the central nervous system (CNS) and cause symptoms that are clinically
identical to the symptoms of bipolar disorder. For example, Harris et al. (22)

described 31 cases of new-onset psychosis in HIV-infected individuals. Of these,
25 had “mood and /or affective disturbance,” including nine with depressions,
three with euphoria or irritability, and two with both depression and euphoria.
Many of these individuals responded to antipsychotic medication. The Epstein-
Barr virus, which causes mononucleosis, can also cause bipolar-like symptoms.
For example, Weinstein et al. (23) described a 22-year-old woman who developed
“auditory hallucinations, pressure of speech and ﬂight of ideas” one week after
having been diagnosed with mononucleosis. Similarly, Goldney and Temme (24)
described a 23-year-old woman with the onset of ﬂight of ideas and mania six
weeks after mononucleosis; her psychiatric symptoms were controlled with
lithium but recurred when the lithium was stopped.

Koehler and Guth (25) described a 41-year-old man who had severe depres-
sion lasting three weeks and then abruptly switched to having classic mania
with pressure of speech, ﬂight of ideas, psychomotor agitation, and grandiosity.
Symptoms of depression or mania lasted intermittently for six months, with a
good response to antipsychotic medication. Because he had a headache and stiff
neck at the onset of his illness, a lumbar puncture was done and revealed a
diagnosis of underlying herpes simplex encephalitis.
A similar case, suspected of being caused by Coxsackie virus, was reported by
Myers and Dunner (26). A 28-year-old woman developed increased energy,
decreased need for sleep, elation, pressure of speech, hypersexuality, and
disorganized behavior and was diagnosed as having bipolar disorder, manic

type. She was treated with antipsychotic medication and lithium, with improve-
ment of her symptoms. She then developed a fever, headache, and stiff neck; a
lumbar puncture and electroencephalograph were therefore done and suggested
a diagnosis of viral encephalitis. Her symptoms abated on medication, and she
was maintained on lithium for six months, at which time it was discontinued.
Six months later, she relapsed and had a second episode of mania.
There is, of course, no way to conclusively prove a cause-and-effect relation-
ship in such cases and rule out a coincidental but unrelated onset of bipolar
disorders and encephalitis. However, the co-occurrence of bipolar disorder symp-
toms with encephalitis has been repeatedly noted since the early 1900s and such
descriptions were especially prominent after the inﬂuenza pandemic (27) and

during the epidemic of encephalitis in the 1920s (28,29).212 Yolken and Torrey

ENVIRONMENTAL RISK FACTORS FOR BIPOLAR DISORDER
Despite the fact that genes are known to play a prominent role in the etiology of
bipolar disorder, it is also known that nongenetic environmental factors are also
operant. The pairwise concordance rate for bipolar disorder among monozygotic
twins was 56% (44 /79 pairs) in ﬁve European studies (30), suggesting that environ-
mental factors also play a signiﬁcant role. Recent studies of these environmental
factors are consistent with an etiological role for viruses.
One environmental factor is the season of birth of individuals who later
develop bipolar disorder. Torrey et al. (31), using time series analysis in a study
of 18,021 individuals in four states who were diagnosed with Diagnostic and
Statistical Method, 3rd edition serial (DSM-III-R) bipolar disorder, reported a
5.8% excess of births in December through March compared with 27.3 million
general births in the same states for the same years. Especially noteworthy were

the results in North Carolina, which had an 18% excess of bipolar disorder births
for February and a 22% excess for March. In this study, the 5.8% bipolar disorder
winter birth excess was slightly greater than the 5.0% excess for undifferentiated
schizophrenia for the same months. Individuals with severe depression showed a
different birth pattern, with a 5.4% excess for March, April, and May. The results
of this study of bipolar disorder births are consistent with four other studies of
bipolar disorder with much smaller numbers and are also consistent with previous
seasonal birth studies of manic-depressive psychosis and mania (32).
Urban birth is now a well-described risk factor for the development of later
schizophrenia, but far fewer studies have been done on bipolar disorder. A study

in The Netherlands reported some support for regarding urban birth as a risk
factor for “affective psychosis” (33), but studies from Denmark, using the Danish
Case Register, did not ﬁnd an association for either affective psychosis or bipolar
disorder (34).
Another environmental factor that predisposes individuals to the later devel-
opment of bipolar disorder is having complications of pregnancy or delivery. Lewis
and Murray (35), using retrospective maternal histories, rated deﬁnite obstetrical
complications in individuals with one of eight different psychiatric diagnosis,
including 110 with bipolar disorder. Individuals with schizophrenia (17%) and
anorexia nervosa (16%) had the highest percentage of deﬁnite obstetrical compli-
cations, followed by bipolar disorder (11%), unipolar depression (10%), other

psychosis (7%), personality disorder (6%), neurosis (5%), and alcoholism and
drug dependence (3%).
Kinney et al. (36) compared obstetrical complications in 16 individuals with
DSM-III-R bipolar disorder and 20 of their unaffected siblings by blindly rating
their obstetrical records. The weighted-sum score for the affected individuals was
3.56 compared with 1.95 for their siblings (Wilcoxon test, p¼0.01). According to
the authors, “the higher obstetrical complications (OC) scores in bipolar probands
were due to moderate elevations in the rates of a variety of different OCs.”
Viral Etiology in Bipolar Disorder
Using prospectively collected data from the 1958 British Perinatal Morality Survey,
Sacker et al. (37) compared 44 individuals with affective psychosis as diagnosed by

the Catego system with 16,812 control subjects. Among the 44 individuals, 15 had
mania, nine had depressive psychosis, and 20 had retarded depression. Compared
with control subjects, the group of individuals with affective psychosis had moreHypothesis of an Infectious Etiology in Bipolar Disorder 213

mothers over age 34 at the time of delivery ( p,0.05) and more cesarean sections
and forceps deliveries ( p,0.05), had been lighter at birth ( ,2500 g; p,0.01),
had been more premature (gestation ,37 weeks; p,0.01), and had been given
vitamin K at birth more often because of a risk of bleeding ( p,0.01).
Recent research, however, has cast doubt on the importance of perinatal
complications in bipolar disorder. Klaning et al. (38), using the Danish case register,
compared the incidence of bipolar disorder among twins, which are known to have
more perinatal complications, and singleton births; the incidence was found to be
the same. Scott et al. (39) examined all the relevant studies in a meta-analysis and
concluded that “there is no robust evidence that exposure to [obstetrical
complications] increases the risk of later development of BP [bipolar disorder].”
Findings for Speciﬁc Infectious Agents
In the modern era, the ﬁrst infectious agent to be tentatively linked to the etiology of

bipolar disorder was the borna disease virus (BDV). Two studies in the 1980s
reported increased BDV antibodies in patients with unipolar and bipolar
depression (40,41). Interest in BDV increased in the 1990s when Salvatore et al.
(42) reported ﬁnding BDV in two out of ﬁve postmortem brain samples from
patients with bipolar disorder and Bode et al. (43) described a BDV-positive
patient with chronic bipolar disorder whose symptoms improved dramatically
when treated with amantadine, an antiviral medication.
Since that time, interest in BDVas a possible etiologic factor in bipolar disorder
has waned. Studies of BDV antibody in the sera of bipolar patients by Fu et al. (44),
Sauder et al. (45), Kim et al. (46), and Terayama et al. (47) have yielded negative ﬁnd-
ings; additional unpublished studies in our laboratory have been uniformly nega-

tive. Studies of BDV in patients with unipolar depression have been modestly
more promising, and additional research may be warranted for that condition.
An infectious agent that has been intensively studied in relationship to its
possible role in causing schizophrenia is the inﬂuenza virus. For bipolar disorder,
there are fewer studies, and most of those combine bipolar disorder with unipolar
depression, with or without psychotic features, thus making any deﬁnitive view
of bipolar disorder problematic. In the study of Sacker et al. cited above (37),
there was a weak trend ( p,0.1) for the mothers of the individuals with affective
psychosis to have had more inﬂuenza during pregnancy. Macho ´n et al. (48) in
Finland reported a signiﬁcant ( p,0.002) increase in the births of individuals

with “unipolar forms of major affective disorder” and a trend ( p,0.05) for an
increase of individuals with “bipolar forms of major affective disorder.” Cannon
et al. (49) in Ireland also reported a signiﬁcantly ( p¼0.003) increased risk of
depressive disorder in the offspring of mothers exposed to inﬂuenza but no increase
in bipolar disorder. Three other studies in England (50), Queensland (51), Western
Australia (52) that examined the risk of affective disorders in offspring after
maternal exposure to inﬂuenza during pregnancy reported negative results.
The most interesting infectious agent to emerge from recent research on
bipolar disorder has been the herpes simplex virus, type 1 (HSV-1). This virus
has long been of interest to psychiatric researchers because of its known propensity

for neurotropism in general and its afﬁnity for limbic tissue in particular, as well as
for its ability to remain latent in the brain and periodically recur. Cases of known,
HSV-2 encephalitis with clinical features of bipolar disorder have been well
described.214 Yolken and Torrey

In a series of studies Dickerson et al. (53,54) have shown that individuals
with schizophrenia and those with bipolar disorder who also have past exposure
to HSV-1, as demonstrated by antibodies, are signiﬁcantly more likely to have
greater cognitive dysfunction, especially recent memory deﬁcits, as measured
by the Repeatable Battery for the Assessment of Neuropsychological Status
(RBANS) test. In the bipolar study 49 patients who had HSV-1 antibodies had an
RBANS score of 77.5, compared with 68 patients who did not have antibodies
who had an RBANS score of 90.3 ( p,0.00002). Among the patients who had the
lowest RBANS scores (lowest quartile), 65 percent had HSV-1 antibodies; among
patients who had the highest scores (highest quartile), only 14 percent had HSV-1
antibodies. Treatment with lithium, other mood stabilizers, or antidepressants and
other possible confounding variables did not account for the association. There was

also no signiﬁcant association between RBANS-measured cognitive dysfunction and
antibodies to other herpes family viruses, speciﬁcally HSV-2, Cytomegalo virus
(CMV), Epstein-Barr virus (EBV), Varicella-Zoster virus (VZV), or human herpes
virus-6 (HHV-6). The association between cognitive dysfunction and HSV-1 antibodies
was found only in the patient population and did not exist among the normal controls,
suggesting an interaction between the infectious agent and the disease.
Since it is known that genes play a signiﬁcant role in the etiology of bipolar
disorder, Dickerson and her colleagues, using the same patients as in the above
study, examined a polymorphism on the catechol-O-methyltransferase gene at
amino acid 158 (COMT Val 158 Met polymorphism) to ascertain whether it might

explain the association of cognitive dysfunction and HSV-1 antibodies. They
found that the polymorphism and HSV-1 antibodies were both independent risk
factors for the cognitive dysfunction but that individuals with bipolar disorder
who had both “were more than 85 times more likely to be in the lowest quintile
of cognitive functioning as compared with the highest quintile when controlling
for potential confounding variables such as symptom severity and education”
(55). This strongly suggests an interaction between a genetic predisposition and
an environmental (speciﬁcally, infectious) factor.
Finally, there is a preliminary study linking Toxoplasma gondii to bipolar disorder.
T. gondii is a coccidian protozoa whose deﬁnitive host is felines. It is known to cause a

congenital syndrome when transmitted from the mother to the fetus early in preg-
nancy, but later perinatal infection or postnatal infection have been thought to be rela-
tively benign. In recent years, however, several research groups have reported
signiﬁcantly increased antibodies to T. gondii in individuals with schizophrenia (56).
A study of 148 outpatients with bipolar disorder and 170 controls has also reported
an increase in T. gondii antibodies (Odds Ratio 5.4; p,0.001) (57).
Bipolar disorder is a complex human disease state that may represent the
interaction of genetic susceptibilities and environmental risk factors. These environ-
mental factors may include infections and the inﬂammatory response to infectious
agents. It is of note in this regard that there are several pathways by which

infectious agents can induce disease processes. In classic infectious diseases,
there is a clear cause-and-effect relationship between acquisition of the infectious
agent and the initiation of the disease process. This is the case for agents that
conform to Koch’s postulates of cause and effect. As depicted in Figure 1, this is
the pattern followed by highly contagious infections such as plague, cholera, andHypothesis of an Infectious Etiology in Bipolar Disorder 215

measles that cause disease in virtually all susceptible individuals who are exposed
to a suitably large infectious dose. However, microbial agents can also induce
disease by less direct pathogenic mechanisms. For example, there are agents that
only cause disease in a subset of infected individuals. The factors that determine
which individuals become infected are determined by both genetic susceptibilities
and environmental factors such as nutritional status (Fig. 2). Finally, there are
infectious agents that initiate disease processes that can also be initiated by nonin-
fectious agents such as toxins. As depicted in Figure 3, these agents generally cause
chronic diseases of organ systems. In light of the above discussion concerning
genetic factors, it is likely that if infectious agents are involved in the pathogenesis
of bipolar disorder and other human psychiatric diseases, they are operating
following the model outlined in Figure 2 or 3. However, it is of note that for both

FIGURE 1 Model for infectious diseases for which there is a correspondence between a single
infectious agent and a deﬁned disease process. The mediators of the disease process are
designated within the box.
FIGURE 2 Model for infectious diseases where infection may or may not lead to a disease state,
depending on the microbial and host factors designated within the box.
FIGURE 3 Model for infectious diseases in which infectious agents may combine with other
environmental factors to initiate a disease process. The expression of the disease process is also
modulated by the microbial and host factors designated in the box.216 Yolken and Torrey

models the successful prevention or treatment of the infectious agent would
result in a substantial decrease in both disease incidence and morbidity.
The identiﬁcation of speciﬁc environmental factors related to bipolar disorder
would result in the development of improved strategies for the diagnosis and
management of this devastating disease.
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B12 EEGs and ERPs in Bipolar Disorders
School of Neurology, Neurobiology, and Psychiatry, University of Newcastle
upon Tyne, Newcastle upon Tyne, U.K.
The ﬁrst report of an electroencephalographic (EEG) recording from a mammal was
made more than a century ago (1) and the ﬁrst human recording over 65 years ago
(2). A search of PubMed for papers referring to EEG or event-related potentials
(ERPs) and bipolar disorder (BD) ﬂags nearly three hundred items (between 1966
and December 2005). However, of these papers, over two-thirds are more than 10
years old. EEG and ERP studies are not new but certainly are not increasing at
the rate seen with other experimental methodologies in psychiatric illnesses, such
as functional magnetic resonance imaging (fMRI) and molecular studies. Put
bluntly, EEG is not a “sexy” topic. This stems largely from the technique not deli-
vering important ﬁndings after years of study, with a few notable exceptions

such as the diagnosis of epilepsy and sleep disorders. However, EEG and ERP tech-
niques still have much to offer in the further elucidation of the pathophysiology of
mood disorders if used in appropriate ways. In the past, much reliance has been
placed on the visual inspection of paper and ink EEG recordings and rather
simple ERP paradigms with no a priori hypothetical rationale behind their
design. While this situation continues in clinical electrophysiology to a large
extent, the increasing use of novel computational analysis of EEG and ERP data,
often coupled with speciﬁc pharmacological or cognitive challenges, offers exciting
prospects for the future. This chapter is a selective review of EEG and ERP data to
illustrate this argument. It is not a comprehensive review of all of the EEG studies in

BD. In particular, sleep EEG research is not covered at all. The chapter is written
with the non-EEG specialist bipolar researcher in mind.
THE NORMAL EEG
The EEG [together with magneto-encephalography (MEG)] has an advantage over
any other form of functional imaging, such as fMRI or positron emission tomogra-
phy (PET), in that it records signals that are the direct result of electrical activity of
neurons, rather than some “downstream” consequence such as changes in oxygen
utilization or blood ﬂow. Partly as a result of this, EEG and MEG have temporal
resolutions that are generally an order of magnitude better than fMRI or PET.
EEG also has an advantage of being relatively inexpensive, easy to conduct, and
well-tolerated compared with both fMRI and PET and does not require the use of

radio-ligands as in PET. This facilitates multiple recordings in subjects, such as in
cross-over or longitudinal studies. However, the EEG does have some drawbacks,
most notably problems of spatial resolution. This relates to how and what EEG
electrodes record.
221

The EEG is generated by inhibitory and excitatory postsynaptic potentials at
cortical neuronal synapses. These postsynaptic potentials summate in the cortex
and can be recorded at the scalp as EEG. Action potentials probably do not contrib-
ute signiﬁcantly to the EEG because there is little penetration of these into extra-
cellular space and hence transmission to the scalp. Rather, scalp EEG electrodes
record the summation of postsynaptic potentials of large areas of pyramidal
neurons in the underlying cortex. For a signal to be detectable these neurons
must be ﬁring simultaneously with the cells oriented in parallel at 90 8to the
plane of the scalp. Knowing this, one might wonder that it is possible to record
any electrical activity at the scalp. However, many cortical areas have intrinsic oscil-
latory activity that occurs synchronously across large groups of cells generating
rhythmic EEG activity. Cortical neuronal ﬁring is heavily inﬂuenced by the thala-

mus which also has intrinsic oscillatory activity. In addition, many systems
project from the brainstem and basal forebrain areas and are able to alter cortical
rhythmic activity such as by desynchronizing cell ﬁring. However, it should be
remembered that the EEG only directly records activity from superﬁcial cortical
areas. Another problem in interpreting EEG data is that the polarity of the signal
is not determined simply by whether the postsynaptic potentials are excitatory or
inhibitory, but also by the location and orientation of the neurons. As a result it is
not possible to deduce an electrical response as reﬂecting activation or inhibition
in a neuronal network from the polarity of the EEG. The electrical activity from
neurons must pass through the tissue between them and the EEG electrodes

(brain, CSF, skull, and scalp) and is attenuated and modiﬁed by this. The degree
of attenuation is determined by the degree of synchronization of the postsynaptic
potentials, the orientation of the neurons, and the size of the participating area of
cortex. All of these factors mitigate against localizing the source of the electrical
activity recorded at the scalp. In fact, there is no unique solution that can be calcu-
lated for any recording. Instead, source localization methods must make certain
assumptions to be able to ﬁnd a solution (e.g., that the activity originates in grey
matter, that there are a limited number of electrical sources, and /or that activity
at any particular location closely resembles neighboring locations). Different tech-
niques make different assumptions and hence localize scalp EEG activity as

having originated in different intracranial locations. This is a major weakness of
EEG studies. For a full and detailed understanding of the spatial location of cortical
networks involved in any particular task, as well as the temporal relationship
between the various components of the network, both EEG (or MEG) need to be
conducted alongside other neuroimaging techniques such as fMRI.
In the past, EEG was recorded from a few scalp electrodes, often placed on the
midline of the head, with an analog signal passing to a pen and paper chart recor-
der. The resultant tracers were analyzed simply by inspection by experienced EEG
analysts. Such individuals are able to identify aberrant activity, particularly that
associated with epilepsy. They are also able to identify gross changes in the quan-

tities of the common frequencies seen in the EEG (delta ,4 Hz, theta 4–8 Hz, alpha
9–13 Hz, and beta .13 Hz). Nowadays, EEG recordings can be made from dozens,
if not hundreds, of electrodes placed across the scalp. Signals are digitized, allowing
computer-based analysis, such as Fast Fourier Transformations (FFTs) that calculate
the “amount” of different frequencies in the whole EEG, and attempts at source
localization. An additional method of obtaining extra information from the EEG
is to record this while a subject is performing a particular cognitive task. The
EEG record is subsequently divided into epochs time-locked to the presentation222 McAllister-Williams

of a stimulus or the subject’s response. Several epochs associated with particular
stimuli and /or responses can then be averaged together. This is what is meant by
“event-related potentials” (ERPs). By doing this, “noise” (unrelated EEG activity)
is averaged out, leaving only the electrical activity that relates to the task
the subject was performing. Over the years there have been a number of ERP para-
digms developed using visual or verbal stimuli such as the “P300” and “miss-
match negativity” (MMN). Unfortunately, many of these tasks depend to a large
extent on a whole variety of psychological processes and so their interpretation is
at times difﬁcult.
CLINICAL EEG ABNORMALITIES IN BIPOLAR DISORDER
The obvious starting point for considering EEG abnormalities in BD patients are
observations that patients with epilepsy have high rates of mood disorders (3) and
bipolar patients are not infrequently treated with anticonvulsants (4). However,

while epidemiological studies demonstrate that up to half of patients with epilepsy
have clinically signiﬁcant depression and /or anxiety (3), BD does not occur with a
higher than expected frequency (5). Classic bipolar I disorder is rarely seen, and
manic episodes occur almost exclusively in the setting of postictal psychosis or
after epilepsy surgery (6,7). This raises the question whether affective disorders in
epilepsy are different from those seen in nonepileptic patients. It is possible that epi-
lepsy is associated with a speciﬁc interictal dysphoric syndrome related to limbic
dysfunction (7) that differs from the pathophysiology underlying nonepilepsy
related depression. Nevertheless, it is of interest to note that depression is more
common in patients with left temporal lobe epilepsy (8), which does suggest that

it is not simply psychosocial factors that account for the high rates of comorbidity.
Intriguingly, the nature and even the direction of the causality between depression
and epilepsy is not clear given ﬁndings that depressive illness is associated with a
sixfold increase in the risk of the development of seizures in an elderly population
(9). Perhaps the association between the two conditions may be merely a reﬂection
of some common underlying pathology.
Despite the observation of no increase in the rate of BD in epilepsy, Post has
previously suggested that a possible pathophysiological process in BD is similar
to one seen in epilepsy, namely “kindling” (see Chapter 18) (10). This hypothesis
is based on physiological ﬁndings showing that intermittent subthreshold electrical

stimuli produce increasingly strong neuronal depolarization in the brain through a
process of sensitization. It is suggested that processes such as kindling predict that in
BD, psychosocial stressors would be more frequent earlier in the course of illness,
with the severity of stressor needed to precipitate an episode of illness decreasing
over time leading to the frequency of episodes increasing as originally observed
by Kraeplin and subsequently by others (11). If this is the case, then it may be that
some subictal electrical dysrhythmia may be associated with the development of
BD and be evident in EEG recordings from patients.
Reviews of the EEGs of bipolar patients do reveal an abnormal slowing of delta
and theta EEG activity (12) and the presence of various small spikes and focal slow

waves, usually in the frequency range of 4 Hz to 7 Hz (13,14). Abnormalities are
reported in 15% to 50% of patients (15–17). Most studies report that abnormalities
are seen bilaterally, though reports of unilateral bias more commonly relate to the
right (16,18,19) rather than the left hemispheres (17). As already stated, the EEG
abnormalities may, however, simply reﬂect an underlying brain abnormality thatEEGs and ERPs in Bipolar Disorders 223

predisposes both to BD and abnormal EEGs. There may also be a difference in
the underlying pathophysiology of bipolar patients with and without EEG abnormal-
ities since the former are less likely to have a family history of the disorder (12,15–17)
than the latter. The spike and slow wave abnormalities are also not speciﬁc to
BD (13,14), though they are reported more often in bipolar and schizoaffective than
schizophrenic patients (14).
The obvious clinical question that follows from these observations is whether
or not the presence of an EEG abnormality in a patient with BD has therapeutic
implications. It has been shown that EEG abnormalities are a risk factor for treat-
ment resistance in BD (20). A small observational study suggests that the presence
of EEG abnormalities is predictive of a poor lithium response (21), while another
supports this and suggests that EEG abnormalities do not mitigate against response

to valproate (22). Further, one nonrandomized study in 115 patients who were pre-
dominantly lithium refractory found that, perhaps not surprisingly, patients with a
history of seizures were more likely to respond to the anticonvulsant valproate.
However, those patients who simply had some EEG abnormality but no previous
seizures only “tended” to respond better to valproate (23). To date there are no
randomized controlled trials of BD patients who exhibit EEG abnormalities. Until
there are, it is difﬁcult to be clear about the implications of any abnormalities
detected in clinical practice, though they may reﬂect a subset of BD patients with
no family history of the disorder and perhaps a different underlying pathology.
EFFECTS OF LITHIUM ON THE EEG

From a clinical perspective, the EEG currently has one main utility in BD: to identify
lithium neurotoxicity. Lithium has a narrow therapeutic range with serious side
effects seen at high plasma concentrations. Toxic symptoms become increasingly
common above serum levels of 1.2 mmol /L and affect the gastrointestinal tract, cer-
ebellum, and cerebrum. Early signs are mental lassitude sometimes occurring with
agitation. This can progress to confusion with vomiting and diarrhea, coarse tremor,
Parkinsonism, ataxia, and dysarthria. Finally, seizures, coma, and death can result.
Of great concern is that long-term neurological deﬁcits can result from acute lithium
toxicity in about 10% of cases (24). The problem the clinician faces is that neurotoxi-

city can occur at therapeutic plasma concentrations of lithium (25). The most
common presentation is of an encephalopathy, but (rarely) focal neurological
disturbances, psychotic episodes, or cognitive deﬁcits can occur (26). Lithium neu-
rotoxicity appears to be more common in patients with pre-existing EEG abnorm-
alities [particularly temporal lobe epilepsy (27)]. Prompt diagnosis and treatment of
neurotoxicity may decrease the risk of long term sequelae. Essentially, the diagnosis
is made on clinical grounds, with lithium plasma levels being of little value unless
clearly raised. However, the EEG has a characteristic pattern in lithium neurotoxi-
city and so can aid diagnosis. There is an increase in theta and delta activity
with diffuse slowing and background disorganization (28). While clinical improve-

ment can be paralleled by improvements in the EEG, full resolution of all EEG
abnormalities can be delayed by some months.
CONVENTIONAL ERP ABNORMALITIES IN BIPOLAR DISORDER
Perhaps the most studied conventional ERP paradigm in BD is the auditory evoked
“P300” (or “P3”). This usually involves presentation of auditory tones to subjects,224 McAllister-Williams

the majority of which are identical with random deviant tones occurring at a low
frequency (perhaps 1 in 10 tones). When the ERPs related to the standard tones
are compared with those related to deviant ones, the “deviant ERPs” show a
large positive going deﬂection occurring around 300 ms following the onset of
the tone. These “P300” deﬂections reﬂect multiple cognitive processes including
attention, working memory, and higher auditory processing and originate from
multiple cortical areas (29). In BD, as in schizophrenia (30) and depression (31),
there are reports of a delay in the latency of the P300 component compared with
that seen in healthy subjects (30,32,33). However, while in schizophrenia there
are also reports of a reduction in P300 amplitude (30), this is a more equivocal
ﬁnding in BD (30,33,34). The problem comes from interpreting these ﬁndings and
considering their implications. It has been found that an increased P300 latency cor-

relates with ratings of insomnia in patients (31) and may reﬂect impaired atten-
tional processing (31,33). Alternatively or additionally, prolonged P300 latency
may indicate possible abnormalities with auditory processing itself, though the
case for this is stronger in schizophrenic patients. This is argued on the basis that
abnormalities of earlier auditory ERP components (N1 and P2) are abnormal in
some studies of schizophrenic but not bipolar patients (33). This may relate to
psychosis per se rather than particular diagnoses since abnormalities in early audi-
tory ERP components in bipolar patients have been reported to correlate with a
longitudinal history of psychosis (35). It has also been suggested that the P300
may predict response to certain treatments, such that a “normal” P300 predicts

rapid response to ECT in melancholic depression (36). However, there are few
such studies in BD. Perhaps of greatest signiﬁcance is a suggestion that P300
abnormalities may be a manifestation of some underlying trait abnormality since
they are seen at an increased frequency in at least some families of patients with
BD (32). It has subsequently been shown that P300 amplitude and latency cosegre-
gates with the recently described DISC1 and DISC2 genes on chromosome 1 (37)
that are risk factors for both schizophrenia and BD (38). It may be that these ERP
ﬁndings can thus be used as a biological marker of genetic risk.
Another auditory ERP that has been extensively studied in psychiatric popu-
lations is the MMN paradigm. This ERP technique involves presenting subjects

with auditory stimuli that follow some regular pattern. When there is some
deviation to this standard pattern, a negative deﬂection is seen around 150 ms
after the onset of the stimulus, even when subjects do not attend to the task. It
is argued that this deﬂection reﬂects sound processing (39). Of particular import-
ance, the MMN has been shown in animal and human studies to index N-methyl-
D-aspartate (NMDA) functioning (40,41). This is of interest since the MMN is
reliably found to be abnormal in schizophrenia (42–44), supporting hypotheses
of a glutamate abnormality underlying this illness. It is reported that the MMN
is normal in BD (44), though it would be of interest to explore this further exam-
ining for abnormalities in patients who have experienced or are experiencing
psychotic phenomena.

FUTURE OPPORTUNITIES FOR EEG AND ERP STUDIES
IN BIPOLAR DISORDER
With the exception of the diagnosis of lithium neurotoxicity, the EEG has little
current clinical utility in the management of BD. Further, conventional EEG analy-
sis and classical ERP studies have proved of limited value in the study of theEEGs and ERPs in Bipolar Disorders 225

etiopathogenesis of the disorder. However, to disregard EEG techniques in the study
of BD is to discard a potentially valuable technique that supplements other research
methodologies. The utility of the EEG in the study of any psychiatric illness is ham-
pered by the largely unsolved problem of extracting the relevant information from
the recording in a theory-guided manner. However, there are an increasing
number of ways that this problem can be solved. This relates to new statistical
methods of examining the EEG and coupling recordings with pharmacological
and/or cognitive challenges. This will be illustrated below.
Evolving Quantitative EEG Techniques
As described above, in the past, analog EEG signals were recorded on pen and ink
chart recorders. Now it is possible to digitize the signal for storage and analysis on
computers. Quantitative analysis of the EEG (qEEG) using FFTs is able to identify
alterations in the frequency components of the signal that would not be visible to

the naked eye. Such techniques have extended the previous observations of abnor-
mal EEGs in BD, for example showing increases in right temporal lobe theta and left
occipital beta frequencies (45). However, perhaps the most exciting of the new
methods of EEG analysis relate to methods for analyzing alterations in the synchro-
nization of various frequency components. It has been argued that synchronous
neuronal activity (precisely that recordable by EEG techniques), particularly at
high frequencies (upper alpha, 10–13 Hz; beta, 13–30 Hz; and gamma, .30 Hz)
is a mechanism by which there can be a functional integration of brain networks
during cognitive tasks. For example, during a working memory task, EEG record-
ings demonstrate an increase in synchronization of beta activity across bilateral

sites (46). By simultaneously recording EEG and fMRI it is possible to show that
this change in beta synchronization is associated with linkage between cross-hemi-
spheric regions (left angular gyrus and right superior parietal gyrus) and among
anterior–posterior regions (right dorsolateral prefrontal cortex, putamen, and
right superior temporal gyrus) (46). These are interesting observations not least
because they illustrate that by combining EEG and fMRI techniques, the advantages
of both (the ability to directly record neuronal electrical activity with high temporal
resolution, and high spatial resolution, respectively) can be combined. Using this
EEG methodology, it has been shown, for example, that synchronization decreases
with age and correlates with decrease in executive function performance (47), and is

lower in Alzheimer’s disease (48) and schizophrenia (49). It has been argued that
these ﬁndings reﬂect a breakdown of the synchrony of neural networks and that
this underlies the cognitive impairment seen in these conditions. There have been rela-
tively few similar studies in BD, but it has been reported that long-range synchrony is
reduced (50) and that there is abnormal high frequency synchronization (51). The great
importance of synchronization experimentally is that it can be studied in vivo and in
vitro in animals. This has, for example, allowed the demonstration that nicotinic
acetylcholine receptor alpha subunits (52) and GABA Aalpha 5receptors (53) play an
important role in the regulation of gamma oscillations in hippocampus. It is hoped

that as knowledge of the physiology and pharmacology of this brain oscillatory beha-
vior becomes increasingly understood, the EEG will be able to act as an important tool
to explore hypothesized abnormalities in various psychiatric conditions including BD
and assess the effects of pharmacological challenges. In this regard, it is interesting to
note that repetitive transcranial magnetic stimulation (rTMS) has been shown to inﬂu-
ence gamma activity in prefrontal cortex (54) and that perhaps this plays a role in the
therapeutic activity of this treatment.226 McAllister-Williams

A number of studies have speciﬁcally linked changes in synchronous EEG
activity with various cognitive functions. The increase in synchronization of beta
activity during working memory tasks has been described above (46), which is
of interest given the ﬁndings of working memory deﬁcits in BD (55). Another
example that may also be relevant to BD are ﬁndings suggesting that the ratio
between delta and beta frequency activity is a biological maker of motivation, par-
ticularly the subject’s relative balance between reward- and punishment-driven
behavior (56). Interestingly, this ratio of delta to beta activity is inﬂuenced by
endogenous cortisol concentrations as a result, it has been argued, of cortisol-
enhancing subcortical–cortical communication, particularly strengthening cortical
control of subcortical drives (57). This provides a possible mechanism by which
motivation and behavior is inﬂuenced by stress as well as in BD, given ﬁndings

of abnormal hypothalamic-pituitary-adrenal (HPA) axis functioning (58).
There are clearly a number of lines of investigation needed to further clarify
these potential interactions.
Pharmaco-EEG Techniques
Pharmaco-EEG offers promise to the study of BD by following the example of
MMN studies in schizophrenia (described above) in identifying EEG indices of
neurotransmitter function. A number of possibilities exist. For example, it has
been shown by a number of groups that the systemic administration of buspirone
to healthy subjects leads to a negative shift of the awake EEG frequency spectrum
(due to an increase in theta and decrease in alpha activity) following buspirone
(59–62). Although buspirone is a relatively nonselective drug, the effects on the
EEG frequency spectrum may be mediated by somatodendritic 5-HT 1Areceptors.

This is supported by a number of observations. Firstly, the shift in EEG frequency
spectrum is mimicked by other more selective 5-HT 1Apartial agonists in man
(62,63) and is seen in animals following administration of buspirone as well as
the highly selective full 5-HT 1Areceptor agonist 8-OH-DPAT (64). Secondly,
source localization of the effect of buspirone using low resolution electromagnetic
tomographic analysis (LORETA) demonstrates a signiﬁcant increase in theta EEG
activity in the hippocampus as well as neighboring cortical areas (62). Hippocam-
pal theta activity is well-known to be under ascending serotonergic control (65).
Animal studies using local application of 8-OH-DPAT into the raphe have
indicated that activation of somatodendritic 5-HT 1Areceptors causes a decrease

in hippocampal theta (66,67), an effect blocked by 5-HT 1Aantagonists (68).
Thirdly, a somatodendritic location for a 5-HT 1Areceptor-mediated negative
shift in the EEG frequency spectrum in man is also inferred from ﬁndings of
acute administration of SSRIs causing such a shift (69) and that pindolol
mimics, rather than blocks, the effect of buspirone on the awake EEG (70). Follow-
ing acute administration, SSRIs increase concentrations of 5-HT in the raphe nuclei
leading to somatodendritic 5-HT 1Aactivation (71); pindolol acts as a 5-HT 1A
antagonist at postsynaptic receptors but a partial agonist at somatodendritic recep-
tors (72). Taken together, these data indicate that the effect of buspirone on the
EEG frequency spectrum is a potentially valid index of somatodendritic 5-HT 1A

receptor function. Using this methodology, it has recently been reported that
drug-free depressed patients have an increase in this autoreceptor function that
would be predicted as leading to a decrease in the overall activity of the seroto-
nergic system (73). It would be of great interest to extend these studies into
BD patients.EEGs and ERPs in Bipolar Disorders 227

Cognitive ERP Techniques
In the same way as identifying the pharmacological basis of various EEG or ERP
measures can provide valuable information when studied in patient populations,
so can linking cognitive function with EEG techniques. This is being increasingly
done with measures of synchronization as described above. However, traditional
ERP methods are also able to provide information regarding neuronal activity
underlying cognitive function that is not available with other methodologies.
A good example of this relates to the study of episodic memory retrieval.
When a past episodic memory is recollected, such as when a subject is pre-
sented with a “retrieval cue,” a mental representation of the past event is generated
involving a conscious reconstruction (74). It has been argued that there are “prere-
trieval” processes operating on the retrieval cue and “postretrieval” processes
operating on the products of retrieval (75). This hypothesis, and its neural under-

pinning, can be examined by studying the effects of brain lesions. For example,
bilateral damage to temporal lobes leads to an impairment of acquisition of new
memories and recollection of premorbid events, while prefrontal cortex lesions
have a limited effect unless highly elaborate encoding or retrieval is required
(76). The problem with lesion studies is that it is impossible to separate effects on
encoding and retrieval. To do this, functional imaging is required. fMRI studies
have shown that episodic memory retrieval is associated with bilateral parietal
lobe activation, reﬂecting activation of hippocampal memory stores (75).
However, in addition, complex retrieval tasks also lead to activation of the right
dorsolateral prefrontal cortex (75). This has been hypothesized to reﬂect the moni-

toring and evaluation of the products of retrieval, since the activity is greatest when
the information being retrieved is more ambiguous (77). ERP studies using speciﬁc
episodic memory retrieval paradigms have been used to explore the temporal
relationship between these two areas of activity and conﬁrms that the right prefron-
tal activation begins later after stimulus presentation compared with the bilateral
parietal activity (78,79) consistent with the hypothesis. This illustrates the
utility of EEG studies in parallel with other forms of functional imaging in the
investigation of cognitive function.
This episodic memory retrieval ERP paradigm has been used to explore the
effects of corticosteroids given theories of a casual link between hypercortisolemia

and cognitive impairment in affective disorders (80). This has shown that cortisol
not only impairs recollection performance but also alters frontal cortex activity
(79), while the glucocorticoid functional antagonist dehydroepiandrosterone
(DHEA) improves performance apparently mediated by effects on parietal lobe
activity (81). Currently this ERP technique is being implemented in a cohort of
BD patients undergoing treatment with a glucocorticoid receptor antagonist and
the results are eagerly awaited.
EEG recordings have a role in the clinical management of patients with BD in aiding
diagnosis of lithium neurotoxicity. They have also demonstrated that there is a sig-
niﬁcant minority of patients with a diagnosis of BD who exhibit EEG abnormalities.

Intriguingly, these patients may have a rather different underlying pathophysiology
as suggested by the lack of a family history of affective disorders. It is disappointing
that this has not been followed up to any extent to date. Likewise, while there are
hints that such patients may respond differently to medication, with a preferential228 McAllister-Williams

response to anticonvulsants, there have been few if any attempts to develop speciﬁc
EEG criteria to classify this subgroup of patients or randomized controlled trials
(RCTs) performed to establish if there really is a management implication in
this differentiation.
The future holds immense potential for modern EEG techniques to add a
great deal of knowledge regarding the pathophysiology of BD. Quantitative analy-
sis, for example examining synchronous neuronal activity, may offer a window into
neuronal activity not available by any other experimental technique. Such studies,
in parallel with in vitro pharmacological investigations as well as neurocognitive
and molecular genetics, hold great promise. Similarly, the use of increasingly
speciﬁc cognitive and pharmacological challenges in combination with EEG and
ERP recordings offers the possibility of testing speciﬁc hypotheses regarding
brain function in patients.
Nevertheless, EEG techniques have not, so far, delivered the number and

importance of ﬁndings in BD (or psychiatric illness in general) that might have
been hoped for when they ﬁrst became available for use in humans over 65 years
ago. The subsequent pessimism regarding EEGs that is found in many psychiatric
researchers, however, ignores some of the important ﬁndings that have been made
to date (which have often been inadequately followed up), but more importantly
fails to recognize the complementary role EEGs can play along side other research
techniques such as neuroimaging, cognitive neuroscience, neuropharmacology, and
neuroendocrinology. These opportunities are coming about because of exciting
developments in EEG methodology and analysis. In illustrating a number of poten-
tial future avenues for research in BD using EEGs it is hoped that the vital role these

techniques can play will not be underestimated.
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B13 Genetics of Bipolar Disorder
Department of Psychological Medicine, Wales School of Medicine,
Cardiff University, Cardiff, U.K.
Mental disorders in general, and mood (affective) disorders in particular, are
leading causes of morbidity which affect human populations around the world (1).
The term “affective disorder” includes a wide variety of conditions, from mild and
common mood variations to some of the most severe episodes of psychotic illness
seen in clinical practice. Co-occurrence of other clinical syndromes, such as anxiety
or substance abuse, is common. Genetic factors are known to play an important role
in inﬂuencing susceptibility to all these illnesses (2). Here, discussion will be
restricted to bipolar spectrum illness.
DIAGNOSIS AND EPIDEMIOLOGY
Affective disorders are complex genetic disorders in which the core feature is a
pathological disturbance of mood ranging from extreme elation or mania to

severe depression. Other symptoms also found in these disorders include disturb-
ances in thinking and behavior, which may include psychotic symptoms, such as
delusions and hallucinations. Historically, affective disorders have been classiﬁed
in a number of ways, with distinctions between endogenous and reactive episodes,
psychotic and neurotic symptomatology, and affective disorders arising de novo
(primary) and those episodes arising in the context of another disorder (secondary)
(3,4). The main nosological division in modern classiﬁcation systems such as ICD-
10 (5) or DSM-IV (6) is between the unipolar and bipolar forms of the condition. The
diagnosis of bipolar disorder (BD) (also known as manic depressive illness)
requires that an individual has suffered one or more episodes of mania with or

without episodes of depression at other times during the life history. This require-
ment for the occurrence of an episode of mania at some time during the course of
illness distinguishes BD from unipolar disorder (also commonly known as unipolar
major depression, or simply unipolar depression) in which individuals suffer one or
more episodes of depression without ever experiencing episodes of pathologically
elevated mood. Although bipolar and unipolar disorders are not completely dis-
tinct nosological entities, their separation for the purposes of diagnosis and research
is supported by evidence from outcome, treatment, and genetic studies (4,7).
Indeed, it was family-genetic studies that persuaded the ﬁeld to move to classiﬁ-
cations that separated bipolar and unipolar mood disorders (8,9). In DSM-IV, BD

is sub-classiﬁed into bipolar I disorder, in which episodes of clear-cut mania
occur, and bipolar II disorder, in which only milder forms of mania (so-called
“hypomania”) occur. Although there is evidence to support this distinction (10),
the validity of this sub-classiﬁcation awaits robust validation. The lifetime
233

prevalence of narrowly deﬁned BD is in the region of 0.5% to 1.5% with similar rates
in males and females and a mean age of onset around the age of 21 years (11).
Unipolar disorder is substantially more common than bipolar illness, but
measured prevalence rates differ markedly according to the diagnostic criteria,
methodology, and sample employed. For example, the large U.S. multi-site Epide-
miological Catchment Area (ECA) study reported a lifetime population prevalence
for DSM-III major depression of approximately 4.4% (12), whereas the U.S. National
Comorbidity Survey estimated the lifetime prevalence of DSM-IIIR major dep-
ression to be 17.1% with 10.3% of the population experiencing a major depressive
episode in the preceding 12 months (13). In contrast to bipolar illness, the rate of
unipolar disorder for women is about twice that for men: 21.3% and 12.7%, respec-
tively, in the U.S. National Comorbidity Survey (13), and this gender difference is a

consistent ﬁnding, at least in studies in the developed world. Affective disorders are
associated with high levels of service utilisation and morbidity and often prove
fatal, with up to 15% of patients eventually committing suicide (14). Reasonably
effective treatments are available for both manic and depressive episodes (15),
but current treatments have undesirable side effects, are not effective in all patients,
and the pathogenesis of affective disorders remains poorly understood. These facts
act as a major motivation for genetic investigation of affective illness with its
promise of improved understanding of etiology and more effective treatments.
CLASSICAL GENETIC EPIDEMIOLOGY OF BIPOLAR DISORDER
Many classical genetic studies of mood disorders have been undertaken. As men-

tioned above, prior to the mid-1960s, family studies of mood disorder did not
make the bipolar /unipolar distinction. However, these studies provided evidence
for familial aggregation of the broad mood disorder phenotype (16 ). Subsequent
family studies have provided persuasive evidence of familial aggregation of both
bipolar and unipolar disorder; twin and adoption studies point to genes as an
important cause of this familial resemblance (17–19). In all, there is a consistent
and impressive body of evidence that supports the existence of mood disorder sus-
ceptibility genes. These studies also demonstrate a graduation in risk of mood dis-
order between various classes of relatives with monozygotic co-twin showing
highest risk, through ﬁrst degree relative to unrelated member of the general popu-

lation showing the lowest risk. Because of differences in methodologies and diag-
nostic classiﬁcations, the absolute measures of estimated lifetime risk vary
between studies. Table 1 shows a representative range of estimates for relative
risks and heritabilities.
As can be seen from Table 1, the classical genetic epidemiology literature
demonstrates that there is not a neat genetic separation between bipolar and uni-
polar disorders. It is not only bipolar illness that is found in the families of
bipolar probands. Other affective disorders also occur at increased rates compared
TABLE 1 Genetic Epidemiology of Mood Disorders
Bipolar disorder Unipolar depression
Recurrence risk in sibling of a proband ( lS) 5–10 2.5–3.5
Proband-wise MZ twin concordance 45–70% 40–50%
Heritability estimate 80–90% 33–42%234 Craddock

with the population. Indeed, the absolute risk of unipolar depression in ﬁrst-degree
relatives of bipolar probands is actually numerically greater than the absolute risk
of bipolar illness. However, the background population prevalence is much higher
for unipolar illness than for BD (of the order of 10% vs. 1%) and therefore the relative
increase in risk is much lower, at approximately a doubling of risk (20). According
to one estimate, two-thirds to three-quarters of cases of unipolar depression in the
relatives of a bipolar individual can be considered to be “genetically bipolar,” that
is, they share a common genetic susceptibility with the bipolar form of affective
illness (21).
Mode of Inheritance
Although rare, it is likely that some families exist in which single genes may play
the major role in determining disease susceptibility. Early segregation analyses
on large multiply affected pedigrees produced mixed results with some studies

consistent with single gene models (22–25) and others unable to demonstrate
major locus transmission (26–28). However, caution is required in interpreting
these early positive results because of the limited power of the studies to dis-
tinguish between single gene and oligogenic models and because of the failure to
take account of an important parameter, the recurrence risk in monozygotic (iden-
tical) cotwins of a bipolar proband (29). The observed very rapid decrease
in recurrent risk from identical co-twins to ﬁrst degree relatives and back to the
general population (as shown in Table 1) is not consistent with single gene
modes of inheritance (30). Rather, the substantial body of data from classical
genetic epidemiological studies is consistent with models of inheritance that

include multiple genes that interact with each other (often referred to in genetics
as “epistasis”) and environmental factors to confer susceptibility to illness (30).
As a consequence, the default model used for most current genetic studies is that
multiple genes interact with each other and with multiple environmental factors
to inﬂuence susceptibility to illness. This is essentially the traditional multifactorial
model. Other genetic /molecular mechanisms that are known to produce complex
patterns of inheritance and have been suggested as possible contributors to BD
include mitochondrial inheritance (31), and dynamic mutation (32).
X-linkage : Several large pedigrees were reported to show cosegregation of X-
linked markers (e.g., color-blindness or glucose-6-phosphatase deﬁciency) and BD

(33–35). These reports have been criticized on methodological grounds (36), and,
despite over half a century of debate, the contribution of X-linked genes to the
pathogenesis of BD remains uncertain. If X-linked genes do contribute, analyses
suggest that they can only account for a modest proportion of cases (26,37).
CHROMOSOME STUDIES
A potential shortcut to identifying the genomic location of susceptibility genes for a
disorder is recognition of the co-occurrence of the disorder and gross changes at the
chromosomal level. Affective disorders have not been found to be consistently
associated with chromosome abnormalities, although a number of such reports
have appeared in the literature (38). One interesting observation is that individuals
with trisomy 21 appear to be less susceptible to mania than are members of the

general population (39). This is consistent with the existence of a bipolar suscepti-
bility gene on chromosome 21, a possibility that ﬁnds support from some linkageGenetics of Bipolar Disorder 235

studies. In contrast, chromosomal abnormalities have had an important inﬂuence
on the molecular genetic investigation of schizophrenia. The velocardiofacial syn-
drome (VCFS), caused by deletions at chromosome 22q11, is associated with a
high lifetime risk of psychosis. This has focused attention on the chromosome
22q11 region as likely to harbor one or more genes involved in susceptibility to psy-
chosis (40). The chromosome 1q42 region similarly was implicated through its invol-
vement in a chromosomal translocation in a large Scottish pedigree in which
multiple members had both psychiatric illness and the translocation (41). Study of
this pedigree resulted in identiﬁcation of a gene that was disrupted by the transloca-
tion, and this was named Disrupted in Schizophrenia 1 (DISC-1) (42). Of relevance to
the current chapter, and as will be discussed later, there is increasing evidence that
the psychiatric phenotypes associated with the chromosomal abnormalities at 1q42

and 22q11 have a substantial mood component and may, therefore, contribute to
bipolar spectrum illness.
MOLECULAR GENETIC STUDIES
Molecular genetic approaches have already achieved great success in discovering
the mutations that lead to simple (mendelian) genetic diseases. The continuing
challenge is to use the developing methodologies to uncover susceptibility genes
for complex diseases, such as BD. Conceptually, molecular genetic studies can be
divided into positional and candidate gene approaches. The positional approach
assumes no knowledge of disease pathophysiology but determines the broad
chromosomal locations of susceptibility genes, usually by linkage studies using
multiply affected families. The candidate gene approach, however, involves the

investigator making educated guesses at what genes may be involved in the patho-
physiology of a condition and then testing the involvement of these genes, usually
by association studies in which a set of cases is compared with a set of controls.
The candidate gene approach is built on the assumption that the investigator has
sufﬁcient understanding of disease biology to be able to recognise suitable
candidate genes. In practice, both positional and candidate approaches are often
combined (43,44).
Linkage Studies in Bipolar Disorder
Linkage studies employing very large pedigrees and based on the assumption of
a single major gene are appropriate for simple mendelian disorders, but when
applied to complex disorders this approach can be problematic. In the late 1980s

two high-proﬁle claims for linkage appeared in the journal Nature : Baron et al.
(35) reported linkage to X-chromosome markers in several Israeli pedigrees and
Egeland et al. (45) reported linkage to markers on chromosome 11p15 in a large ped-
igree of the Old Order Amish community. Other workers were unable to replicate
these ﬁndings and eventually in both cases the original groups published updated
and extended analyses of their own data in which the signiﬁcant evidence of
linkage all but vanished (46,47). Reasons for this dramatic change in ﬁndings
included: ( i) family members originally diagnosed as unaffected became ill for
the ﬁrst time during follow-up, ( ii) new family members were examined who did
not show evidence for linkage, and ( iii) additional DNA markers were examined

which reduced the evidence for linkage. More detailed discussion of this issue236 Craddock

and subsequent linkage ﬁndings in the 11p15 chromosomal region can be found
elsewhere (48).
Such a major setback was of course a disappointment but the ﬁeld moved
forward with the development of methodologies more appropriate for the study
of complex genetic traits including a trend towards the use of smaller families (par-
ticularly affected sibling pairs) and analyses less sensitive to diagnostic changes
(44). Large, systematic molecular genetic linkage studies have been reported and
are ongoing in several centers around the globe. A variety of types of sample set
have been used, ranging from large densely affected pedigrees in genetic isolates
to large numbers of affected sibling pairs. The pattern of ﬁndings is consistent
with there being no gene of major effect to explain the majority of cases of BD and
with that expected in the search for genes for a complex disorder (49–51). Chromo-
somal regions of interest are typically broad (often .20–30 cM). No ﬁnding repli-

cates in all datasets and for individual positive ﬁndings levels of statistical
signiﬁcance and estimated effect sizes are usually modest. Table 1 shows chromoso-
mal regions that have received support with genome-wide signiﬁcance in at least
one study. Several regions have been implicated repeatedly by individual studies,
but usually at a lower level of signiﬁcance and not sufﬁciently consistently to be
highlighted by meta-analyses.
Two meta-analyses of BD genome scans have been conducted. Badner and
Gershon (52) found the strongest evidence for susceptibility loci on 13q and 22q
when examining seven published genome scans for BD. However, the more
recent and detailed meta-analysis of Segurado et al. (53) conducted using the bin-
ranking methodology did not ﬁnd genome-wide signiﬁcant evidence for linkage

but provided a more modest level of support for regions on chromosomes
9p22.3–21.1, 10q11.21–22.1, 14q24.1–32.12, and regions of chromosome 18. This
meta-analysis demonstrated lesser consistency in the ﬁndings from bipolar scans
than from schizophrenia scans (54). Possible causes for this difference are discussed
elsewhere (55).
Since publication of the meta-analyses, several further genome-wide scans in
independent samples have been published, with several regions identiﬁed that
meet genome-wide signiﬁcant or suggestive evidence for linkage. Of particular
note is the 6q21–q25 region which was not implicated in either meta-analysis,
but which is supported by one genome-wide signiﬁcant (56) and three genome-
wide suggestive signals (57–59), making it one of the best-supported regions for

BD. Indeed, in the recent combined collaborative analysis of eleven bipolar
linkage scans, this region achieved genome wide signiﬁcance (60).
Figure 1 shows chromosomal regions that have received genome-wide
signiﬁcant support in at least one scan of BD. Of particular note are the 6q21–q25
region mentioned above and the 12q23–q24 region, which has two genome scans
reporting genome-wide signiﬁcance (58,61) and is also supported by linkage analy-
sis in unipolar disorder (62) and by linkage of this region in two pedigrees that
show cosegregation bipolar spectrum illness and an autosomal dominant skin
disease, Darier’s disease (63).
Gene Studies of BD
To date there has not been unambiguous demonstration of a susceptibility gene
identiﬁed for BD by positional cloning. Potentially interesting ﬁndings have

come from the study of functional candidates and, most recently, investigation ofGenetics of Bipolar Disorder 237

genes ﬁrst implicated in schizophrenia (some of which map in linkage regions of
interest in BD). However, none of the ﬁndings yet achieve the level of support
that dysbindin and neuregulin 1 (NRG1) have received in schizophrenia (55).
Functional Candidates
Most studies in the literature have focused on neurotransmitter systems inﬂuenced
by medications employed in the management of the disorder, particularly the dopa-
mine, serotonin, and noradrenaline systems (64). For most genes studied, the usual
pattern has been for one or a few positive studies along with an even greater
number of negative replications. However, polymorphisms of known functional
relevance in three of the genes have been reported as signiﬁcant at the P,0.05
level in at least some published meta-analyses: MAOA (65), COMT (66), and
5HTT (67,68), all with modest effect sizes (odds ratios, OR /C282). The ﬁndings for
these functional polymorphisms remain to be tested in the necessary number of

independent, large samples that will be required to determine unambiguously
whether and to what extent variation within these genes contributes to suscepti-
bility to BD, or to some intermediate clinical phenotype (69,70). It is of interest
that COMT has also been implicated in schizophrenia (71) and has received
support from the same group in a modestly sized study of BD (72) although an
updated meta-analysis of the literature available in December 2005 found no sig-
niﬁcant evidence for association at COMT (70).
FIGURE 1 Chromosome ideograms showing locations of genome-wide signiﬁcant linkages
for bipolar spectrum phenotypes. The predominant phenotype used in the analysis is shown as:
BP: bipolar disorder; SABP: schizoaffective disorder, bipolar type. Note that most genome scans

of bipolar disorder have used a range of deﬁnitions of the bipolar phenotype from narrow (only
bipolar I disorder) to broad (including also bipolar II disorder, schizoaffective disorder, and unipolar
disorder).238 Craddock

Most of the candidate gene reports in the literature describe studies in mod-
estly sized samples (a few hundred individuals) that are likely to be underpowered
for plausible effects sizes (69,70). As for all complex disorders, the trend in candi-
date gene studies of BD is for the use of larger samples, with increased power to
detect modest or small effect sizes, and examination of candidate genes predicated
on more sophisticated models of pathogenesis or directed by positional information
from linkage studies. Recently, replicable positive ﬁndings have started to emerge
from these approaches.
D-Amino Acid Oxidase Activator (G72) /G30 Locus
At least ﬁve independent datasets contribute evidence that variation at the DAOA /
G30locus on chromosome 13q inﬂuences susceptibility to BD. This locus was impli-
cated originally as being involved in susceptibility to schizophrenia (73). It was a
novel locus with a designation of G72. The locus was renamed as D-amino acid

oxidase activator (DAOA), because biological studies suggested that the gene
product activated the enzyme, D-amino acid oxidase (DAO); genetic evidence
was also found in this original study for association of alleles at DAO with suscep-
tibility to schizophrenia. Subsequently linkage disequilibrium (LD) at the DAOA
locus was also reported with BD in two U.S. family samples (74), and this was repli-
cated in a further U.S. family sample (75), German case-control sample (76), and our
own large U.K. case-control sample (77). In all studies, evidence for LD came from
individual single nucleotide polymorphisms (SNPs) as well as multilocus haplo-
types, although there is variation between studies in the SNPs and haplotypes
showing LD. No pathologically relevant variant has yet been identiﬁed and the bio-

logical mechanism remains to be elucidated. It is of interest that DAO lies in the
12q23 region implicated in linkage studies of both bipolar and unipolar disorder
(Fig. 1). DAO has been examined in only one study of BD (76), which found no evi-
dence of LD. However, in view of the ﬁndings with DAOA, DAO warrants more
thorough study in BD.
Brain Derived Neurotrophic Factor
A functional candidate gene that has attracted a great deal of recent interest is Brain
Derived Neurotrophic factor (BDNF ) (78). BDNF is a member of the neurotrophin
superfamily. Neurotrophins are synthesized in neurons as proforms that can be
cleaved intra- or extracellularly, and both their synthesis and secretion depends
upon neuronal activity. BDNF plays an important role in promoting and modifying

growth, development, and survival of neuronal populations and, in the mature
nervous system, is involved in activity-dependent neuronal plasticity (79). These
processes are prominent in the synaptic plasticity hypothesis of mood disorder,
which focuses on the functional and structural changes induced by stress and anti-
depressants at the synaptic level. The BDNF gene lies on the reverse strand of
chromosome 11p13 and encodes a precursor peptide (pro BDNF ), which is
cleaved proteolytically to form the mature protein (80). The 11p13 chromosomal
location of BDNF has been implicated in some linkage studies of BD, but not in
meta-analyses of linkage studies.
Consistent with the strong evolutionary conservation of the BDNF coding
sequence across species, only one frequent, nonconservative polymorphism in

the human BDNF gene has been identiﬁed, a SNP at nucleotide 196 within
the 50pro-BDNF sequence that causes an amino acid substitution of valine to meth-
ionine at codon 66 (Val66Met). There is cross-species conservation of the precursorGenetics of Bipolar Disorder 239

portion of pro BDNF that is consistent with potential functional importance, and it is
possible that the common Val66Met polymorphism could itself have a functionally
relevant effect by modifying the processing and trafﬁcking of BDNF (81).
There have been three positive reports using family based association studies
of Caucasian BD samples of European-American origin and the Val66Met SNP: two
were based on adult bipolar samples (82,83) and one was based on a small childhood
onset sample (84). All have shown over-transmission of the common Val allele. Evi-
dence with multilocus haplotypes was stronger in one study (83). There have been
four case-control association studies [of European (85,86), Chinese (87), and Japanese
origin (88)] to date, in which there is no evidence for an allelic or genotypic associ-
ation. In our own Caucasian bipolar case-control sample ( N¼3062) we found no
overall evidence of allele or genotype association. However, we found signiﬁcant

association with disease status in the subset of cases that had experienced rapid
cycling (four or more episodes per year) at some time, and a similar association on
reanalysis of our previously reported family-based association sample (89). This
suggests that variation at the Val66Met polymorphism of BDNF may not play a
major role in inﬂuencing susceptibility to BD as a whole but, rather, may be associ-
ated with susceptibility to a speciﬁc aspect of the clinical bipolar phenotype. This
receives support from reanalysis of one of the original family-based samples that
shows the over-transmission of Val alleles is explained by the rapid cycling individ-
uals in the sample (90). It should, however, be noted that the Val66Met polymorph-
ism lies within a large haplotype block so it is difﬁcult to determine which variant(s)

within the block is (are) pathogenically relevant.
Substantial additional genetic and biological work will be required to conﬁrm
(or refute) the role of BDNF in inﬂuencing susceptibility to BD. Systematic study of
variation across the whole gene is required with study in further independent
samples.
Other Genes
We will brieﬂy mention three other genes that have recently received attention as
potential BD susceptibility genes. Two of these are in the 22q chromosome
linkage region of interest. G-protein receptor kinase 3 (GRK3 ) was implicated
through positional follow-up of a linkage signal in a set of U.S. pedigrees and
was supported also by expression data in a rodent model of mania (91).
However, this has not yet received independent support. XBP1 , a pivotal gene in

the endoplasmic reticulum (ER) stress response, was reported to show association
at a promoter polymorphism with BD susceptibility in two small association
samples (92). Some degree of circumstantial biological support for a functional
role for this polymorphism came from a cellular model of the action of mood-stabil-
izer medications. However, this report is highly likely to be a type I error because
the putative functionally relevant variant was found to have no inﬂuence on sus-
ceptibility in independent family-based and case-control association samples six
times larger than those in the initial report (93). This illustrates the caution that is
required in interpreting weakly supported putative genetic effects even in the
face of substantial biological plausibility (70). More promisingly, but as yet not

widely tested, is the report that P2X7 , in the 12q24 region of linkage interest, inﬂu-
ences susceptibility to both BD and unipolar depression (94). It can be expected that
several, probably many, other susceptibility genes will be identiﬁed over the
coming years—no single study will be deﬁnitive and the true status of each candi-
date is unlikely to become clear until several thousand cases have been studied.240 Craddock

CONSIDERATION OF THE CLINICAL PHENOTYPE: CLINICAL
COVARIATES AND SUBTYPES
As discussed elsewhere (17), mood disorder researchers have been taking an inter-
est in a variety of clinical subtypes and covariates over recent years, as a way of
testing subsets of cases with increased clinical (and hopefully genetic) homogeneity.
Examples include rapid cycling (95), lithium responsiveness (96). bipolar affective
puerperal psychosis (triggering of bipolar episodes in females by parturition)
(97,98), early age at onset (99), and occurrence of psychotic features during illness
(100–102).
Consideration of the occurrence of psychotic features in BD raises the interest-
ing and biologically important issue of the overlap in genetic ﬁndings in BD and
schizophrenia. This is discussed in the next section.
OVERLAP IN FINDINGS BETWEEN BIPOLAR DISORDER
AND SCHIZOPHRENIA
Traditionally, psychiatric research in general, and the search for predisposing genes

in particular, has proceeded under the assumption that schizophrenia and mood
disorder are separate disease entities with separate underlying etiologies (and treat-
ments): the so-called “Kraepelinian dichotomy.” This distinction has pervaded
Western psychiatry since Emil Kraepelin’s inﬂuential nosological writings (103)
and survives in current operational classiﬁcation systems such as ICD-10 (5) and
DMS-IV (6), although some workers, such as Crow, have argued for a continuum
approach to psychosis (104). The clinical reality is that many individuals with
severe psychiatric illness have features that fall between these two “extremes”
and have bothprominent mood and psychotic features (often classiﬁed as “schizoaf-
fective disorder” or some similar atypical diagnosis). This suggests that there may

not be a neat biological distinction between schizophrenia and BD. This possibility
ﬁnds support in several observations from genetic research, including the
Family Studies
Although schizophrenia and BD may “breed true” (105–107), families are known
where there are multiple cases of schizophrenia, BD, and cases with both psychosis
and mood disorder (108). Further, some studies have shown statistically signiﬁcant
evidence that BD occurs at an increased rate in the relatives of probands with schizo-
phrenia (109) and that BD occurs at an increased frequency in the relatives of bipolar
probands (110). Schizoaffective disorder has been shown to occur at an increased
rate in the families of probands with schizophrenia (111), and in the families of pro-

bands with BD (112). Both schizophrenia and BD have been shown to occur at
increased rates in the families of probands with schizoaffective disorder (112).
Together, these data suggest a more complex relationship between the psychoses
than is reﬂected in the conventional dichotomous view.
Twin Studies
Only one twin study has used an analysis that was unconstrained by the diagnostic
hierarchy inherent in current classiﬁcation systems (i.e., the principle that schizo-
phrenia “trumps” mood disorder in diagnosis). This study demonstrated a clearGenetics of Bipolar Disorder 241

overlap in the genetic susceptibility to syndromally deﬁned mania and schizo-
phrenia (113). The ﬁndings suggested the existence of some susceptibility genes
that are speciﬁc to schizophrenia, others that are speciﬁc to BD, and yet others
that inﬂuence susceptibility to schizoaffective disorder, schizophrenia, and BD.
Linkage Studies
Genetic linkage studies have identiﬁed some chromosome regions that show con-
vergent or overlapping regions of interest in BD and schizophrenia, including
regions of 13q, 22q, 18 (52,114), and 6q. The hypothesis that loci exist that inﬂuence
susceptibility across the schizophrenia-bipolar divide receives further support from
the observation that a genome scan, using families ascertained on the basis of a
proband with schizoaffective disorder (a form of illness with prominent features
of both schizophrenia and BD), demonstrated genome-wide signiﬁcance at 1q42
and suggestive linkage at 22q11, with linkage evidence being contributed equally

from “schizophrenia families” (i.e., where other members had predominantly
schizophrenia) and “bipolar families” (i.e., where other members had predomi-
nantly BD) (115).
Gene Studies
Most persuasively, several recent reports implicate variation at the same loci as
inﬂuencing susceptibility to both schizophrenia and BD.
Currently the best-supported locus for BD is G72(DAOA) /G30 on chromo-
some 13q (74–77), which also has positive association reported in schizophrenia
(73,76,116,117).
The DISC-1 locus at 1q42 receives linkage support in schizophrenia
(42,118,119), BD (120) and schizoaffective disorder (115) and, although it has been
named Disrupted in Schizophrenia 1 , the family in which the translocation was
observed contained cases of both psychosis and mood disorder (42). Evidence for

allelic association at polymorphisms at this locus has been reported for schizo-
phrenia, BD, and schizoaffective disorder (121).
Neuregulin 1 is one of the best supported schizophrenia susceptibility genes
with several studies showing evidence that a so-called Icelandic “core haplotype”
is associated with increased risk in Icelandic, Scottish, and U.K. populations
(122–124). We have found that this same haplotype is signiﬁcantly associated
with risk for BD and that it may exert a speciﬁc effect in the subset of functional psy-
chosis that has both manic and mood-incongruent psychotic features (125).
The COMT gene lies at 22q11, a region implicated in BD and schizophrenia
(and the region usually deleted in VCFS) (52). It is extremely likely that genetic vari-

ation in this region inﬂuences susceptibility across the psychosis spectrum (71,72),
although it is not yet clear that COMT itself is the (or the major) susceptibility gene
at this locus.
These gene ﬁndings provide strong evidence that, as suggested by the family
and twin data, there are genetic loci that contribute susceptibility across the Krae-
pelinian divide to schizophrenia, BD, and schizoaffective disorders. These ﬁndings
have important implications for classiﬁcation of the major psychiatric disorders
because they demonstrate an overlap in the biological basis of disorders that,
over the last one hundred years, have been assumed to be distinct entities (126).
Molecular genetic ﬁndings are likely to catalyze a reappraisal of psychiatric nosol-

ogy as well as providing a path to understanding the pathophysiology that will242 Craddock

facilitate development of improved treatments. Rather than classifying psychosis as
a dichotomy, a more useful formulation may be to conceptualize a spectrum of clini-
cal phenotype with susceptibility conferred by overlapping sets of genes (126).
Positive ﬁndings are emerging from molecular genetic studies of BD. Replication in
large, well-characterized samples are required to determine their robustness and
generalizability. It will be necessary to undertake detailed phenotype-
genotype studies across the mood-psychosis spectrum as well as functional
biological studies to determine how biological variation inﬂuences clinical
phenotype. It can be expected that some current ﬁndings will prove to be false posi-
tives and there will be many more susceptibility or disease-modifying genes to be
identiﬁed in future studies. New methodologies including whole genome associ-
ation studies can be expected to complement existing approaches to facilitate
progress.

progress.
In the past, psychiatric genetics has often attracted the pessimistic view that it
is an area of endeavor that is so complex that advances were unlikely. However,
promising ﬁndings are now emerging and the potential beneﬁts for the practice
of clinical psychiatry should not be underestimated (127). In addition to facilitating
the development of treatments better targeted at the biochemical lesions involved
in disease, it is also likely to lead to the development of a more rational etiologi-
cally-based classiﬁcation system which will provide a much better guide to treat-
ment and prognosis than current systems. Importantly, identifying susceptibility
genes will facilitate the identiﬁcation of environmental factors that alter risk.
Once these environmental factors are characterized, it may prove possible to

provide helpful occupational, social, and psychological advice to individuals at
genetic risk of affective disorders. It is also likely that along this path we will
learn much about the biological basis of normal affective responses.
In addition to the undoubted beneﬁts, the potential costs must also be con-
sidered (127). Major advances raise major ethical issues. Many of these issues are
no different from those that arise in the context of other complex familial disorders,
but the combination of genetics and mental illness raises particular concerns and
has justiﬁably received close scrutiny of ethical and psychosocial issues (128). It
is important that we continue to address potential problems such as the availability
of services, the right to information, and the testing of individuals below the age of

consent. The challenge is to translate advances in understanding of the complex
etiology of affective disorders into tangible improvements in clinical care.
SUMMARY
Key points are listed in Table 2. The enormous public health importance of mood
disorders, when considered alongside their substantial heritabilities, has stimulated
much work, predominantly in BD, aimed at identifying susceptibility genes using
both positional and functional molecular genetic approaches. Several regions of
interest have emerged in linkage studies and, recently, evidence implicating speciﬁc
genes has been reported; the best supported include BDNF and DAOA but further
replications are required and phenotypic relationships and biological mechanisms
need investigation. The complexity of psychiatric phenotypes is demonstrated by

the evidence accumulating for an overlap in genetic susceptibility across theGenetics of Bipolar Disorder 243

traditional classiﬁcation systems that divide disorders into schizophrenia and
mood disorders. Although no clear examples of gene–environment interaction
have yet been demonstrated in BD, it is to be expected that such mechanisms
will contribute to the genetic complexity.
The author is grateful for research support to the U.K. Medical Research Council
and the Wellcome Trust and is indebted to all the individuals who have participated
in the studies.
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B14 Neurocognitive Findings in
David C. Glahn
Department of Psychiatry and Research Imaging Center, University of Texas Health
Science Center at San Antonio, San Antonio, Texas, U.S.A.
Carrie E. Bearden
Semel Institute for Neuroscience and Human Behavior, University of California,
Los Angeles, California, U.S.A.
The study of neuropsychological functioning in patients with bipolar disorder
(BD) is expanding rapidly. Indeed, there was a threefold increase in the number
of peer-reviewed publications on this topic from 2000 to 2005, as compared with
the preceding ﬁve-year period (Fig. 1). Although signiﬁcant increase in publication
rate is expected in areas of new exploration, the study of neuropsychological
functioning in BD is neither new nor dependent upon the development of novel
technologies. Rather, this increase in scientiﬁc interest is driven by a recognition
that poor neuropsychological functioning in patients with BD is at least partially

independent of mood state (1–5), that cognitive problems may contribute signi-
ﬁcantly to lack of full functional recovery from affective episodes (6,7), and that
neuropsychological deﬁcits may provide clues into the neurophysiologic and neu-
roanatomic abnormalities implicated in the pathophysiology of the illness (8,9).
While it is unclear at this time how common cognitive impairments are among
individuals diagnosed with BD, a signiﬁcant portion of patients with BD complain
of cognitive difﬁculties (10,11). However, formal neuropsychological deﬁcits have
also been documented in asymptomatic patients who do not complain of cognitive
difﬁculties (10,11), indicating that neuropsychological impairments may be more
widespread than clinical experience would suggest.

In this chapter, we review the current literature on the cognition of BD.
While earlier reviews of this literature have been conducted by our group and
others (12–14), the exponential increase in recent publications warrants an
updated review and synthesis of the literature. Our review is organized around a
set of guiding questions:
BIs neuropsychological dysfunction limited to speciﬁc cognitive domains in BD?
BTo what extent are impairments explained by current mood state?
BDoes the course of illness impact neuropsychological functioning?
BIs neuropsychological dysfunction in BD explained by comorbid psychiatric
illnesses (e.g., substance abuse, anxiety)?
BIs impairment secondary to the use of psychotropic medications?
251

TAXONOMY OF COGNITION
As more is learned about how information is processed in the brain, parcellation
of cognitive processes into theoretically distinct domains becomes increasingly
difﬁcult. Current neuroscience models propose that most neuropsychological
processes are supported by distributed large scale neural networks with numerous
spatially distinct brain regions (15). In such networks, regional specialization is best
discussed in terms of a continuum, where several regions may be responsible, to
varying degrees, for similar types of information processing (16). Furthermore,
there is increasing evidence that speciﬁc brain regions (17) and even speciﬁc
neurons (18,19) can be engaged in putatively distinct cognitive processes.
Despite growing evidence that the organization of the central nervous system
is complex and does not easily map on to a simple taxonomy (e.g., memory, atten-
tion, problem-solving), the organization of cognitive processes into speciﬁc

domains or functions has been embraced in clinical and experimental neuropsy-
chology and is a useful way to conceptualize an individual’s functional impairment
or disability (20). In this chapter we review evidence for neuropsychological
dysfunction in BD using organizing principles developed for the measurement
and treatment research to improve cognition in schizophrenia (MATRICS) initiative
(21). As part of this initiative, a panel of experts was convened to determine the
cognitive domains implicated in schizophrenia that are relatively independent of
each other. Based on empirical evidence and expert opinion, the panel concluded
that treatment research in schizophrenia should focus on the following cognitive
domains: attention /vigilance, working memory, verbal learning and memory,

visual learning and memory, reasoning and problem solving, and speed of proces-
sing (21,22). Although these domains were originally designed to assess cognitive
change in schizophrenia, applying them to BD is a natural extension, given that
measures assessing these same domains are also commonly applied in studies of
cognition in BD patients. Since the intent of this panel was to develop a consensus
cognitive performance battery to be used in clinical trials of promising pro-cognitive
agents, general verbal ability or intelligence was excluded because of its marked
resistance to change (20). As our goal is to review cognitive dysfunction in BD
more generally, we will additionally include a discussion of general intellectual
ability. Thus, we focus on seven putatively distinct cognitive domains.

FIGURE 1 The number of peer-reviewed journals involving neurocognitive impairment in bipolar
affective disorder.252 Glahn and Bearden

ATTENTION /VIGILANCE
Attention is the ability to focus “awareness” to a speciﬁc stimulus in the environment
and, often, to respond to that stimulus. Although a myriad of potential attentional
subsystems have been proposed, one important distinction is that of top-down
versus bottom-up processing (23). Top-down processing refers to the ﬂow of
information from “higher” to “lower” brain regions (24), conveying knowledge
derived from previous experience rather than sensory stimulation in preparing
and applying goal-directed selection for stimuli and responses. This system is also
modulated by the detection of stimuli (25,26). A complex network of brain
systems serves top-down attentional processing, including parts of the intraparietal
cortex and superior frontal cortex (27,28). Bottom-up processing refers to infor-
mation processing that proceeds in a single direction from sensory input, through
perceptual analysis, towards motor output, without involving feedback informa-

tion ﬂowing backwards from “higher” to “lower” cortices (23). This system is
specialized for the detection of behaviorally relevant stimuli, particularly when
they are salient or unexpected (25). Bottom-up processing is associated with
temporo-parietal and inferior frontal cortices (29,30), and is largely lateralized to
the right hemisphere.
While attentional dysfunction can denigrate performance on a wide variety
of cognitive measures, attention is most often measured with a continuous
performance task (CPT) (31). During the CPT, subjects attend to a series of
stimuli and respond in some way when a particular stimulus or groups of
stimuli appear. CPT tasks involve several aspects of top-down attention including
vigilance, rapid encoding of stimuli, response readiness, and stimulus-response

mapping. Dependent measures of the CPT include target detection, or how often a
subject responds when the appropriate stimulus is present, and false alarms, or
how often a subject responds to inaccurate stimuli. Other (less commonly used)
attentional measures include the span of apprehension task (SPAN), a sustained
attention measure (32); the dichotic listening task (a test of auditory selective
attention); and the stroop color and word tests (SCWT), which measure attentional
interference (33).
Evidence for Impairment
At the level of clinical observation, patients with BD have difﬁculty concentrating
for extended periods of time and are often quite distractible (34), suggesting that
attentional dysfunction is associated with the illness. Consistent with these obser-

vations, clinically stable but symptomatic patients with BD are impaired on
measures of target detection from the CPT (35–38). This impairment appears to
be relatively independent of potential working memory confounds (39).
Visual backward masking measures are associated with bottom-up atten-
tional processes and have been used to investigate early sensory processing
in bipolar illness. The prototypical visual backward masking paradigm presents
a target stimulus followed quickly (e.g., 20–50 milliseconds) by a masking
stimulus designed to remove any sensory trace of the target. The object is to deter-
mine the extent to which a subject can process the target stimulus before the mask
disrupts ongoing visual processing. Backward masking deﬁcits have been reported

in manic bipolar patients, and these impairments persist when mania resolves (40).
MacQueen et al. (41) also reported that euthymic bipolar patients were signiﬁcantly
slower and had more errors than healthy controls on two complementary visualNeurocognitive Findings in Bipolar Disorder 253

backward masking tasks: one requiring subjects to locate a target stimulus, the
other requiring identiﬁcation of a target stimulus.
Effect of Mood State
Several studies have documented an association between poor CPT performance and
the severity of manic symptoms (36,42–47). Clark and Goodwin (43) report that while
manic patients with BD have impaired target detection and increased rates of false
alarms, euthymic patients only show target detection deﬁcits, even after controlling
for residual affective symptoms. Elsewhere, Clark et al. (35) report that after statisti-
cally controlling for residual symptoms, the only neuropsychological measure that
distinguished euthymic patients with BD from matched healthy controls was target
detection on the CPT. Given that two additional groups have replicated this ﬁnding
(3,5), poor target detection may represent a trait marker for BD (13,43). However,
currently there is little evidence that unaffected relatives of patients with bipolar

illness suffer attentional deﬁcits (48).
Impact of Clinical Course
While most investigators report that attentional processing is negatively correlated
with duration or severity of illness (43,49,50), others ﬁnd no relationship (37).
Although hospitalized patients with bipolar illness improve from admission to
discharge, their target detection remains signiﬁcantly worse than the general popu-
lation (36), suggesting that the extremes of depressive or manic symptoms exacerbate
attentional dysfunction already present in these patients. Finally, visual backward
masking performance may be sensitive to the total number of depressive episodes (41).
SPEED OF PROCESSING
Speed of processing is the time needed for one to complete a simple cognitive
task (20), which often includes encoding some information, making a decision

about that information, and formulating and executing a response. The cognitive
demands of speed-of-processing tests are relatively simple, involving perceptual
and motor components, and emphasize speed of performance. For example,
neuropsychological tests of speed of processing assess the speed with which
digit /symbol pairings can be completed (Digit Symbol), target symbols can be
located (letter or symbol cancellation), number or number /letter sequences on a
page can be identiﬁed and connected (Trails A /B), and colors can be named
(stroop color-word interference test). Although verbal ﬂuency is traditionally
thought of as a language or semantic task, since the dependent measure is typically
the number of words starting with a given letter that can be generated in a brief time

period, it is also conceptualized as a speed-of-processing task (22).
While speed-of-processing measures can be inﬂuenced by a host of environ-
mental or illness-related factors and by age-related declines (51), these measures are
thought to index neuronal efﬁciency and to be sensitive to subtle brain dysfunction
(52). Current cognitive neuroscience models of processing-speed tasks highlight the
timely interplay of a prefrontal decision-making node and posterior heteromodal
cortical regions, including parietal and temporal regions (53,54). These models
emphasize the integration of information across spatially distinct brain regions,
rather than the activity of a speciﬁc region, suggesting that cognitive slowing as
indexed by processing rate is directly related to neuronal efﬁciency (52).254 Glahn and Bearden

Depending on the speciﬁc measure employed, neuropsychological investigations of
BD that include measures tapping this construct tend to ﬁnd evidence for some
degree of impairment (14); speciﬁcally, on a rapid visual-information processing
task (35), the digit-symbol subtest of the Wechsler Adult Intelligence Scale
version III (WAIS-III) (5), Trail-making Tests A and B (2,55,56), and verbal ﬂuency
measures (3). Moreover, performance on the digit-symbol subtest discriminated
patients with BD with a family history of psychosis from bipolar patients without
history of psychosis (57).
Slow processing speed can reduce neuropsychological performance on a
wide variety of tests (58), particularly learning and memory measures (59,60).
Speed-of-processing impairments have also been reported in unipolar depression,
and may mediate memory deﬁcits found in these patients (61). Kieseppa et al.
found that reduced speed of processing is related to poor verbal learning and

memory in euthymic patients with BD (62). However, others have not replicated
this ﬁnding (63).
Clinical observation would suggest that speed of processing increases in mania and
decreases with depression. Depressed mood is related to impairment on speed-
of-processing tests in both unipolar (61) and bipolar disorders (9,64). Contrary to clini-
cal intuition, manic or hypomanic patients also show cognitive slowing on neuropsy-
chological measures (9,64–66). This may be because manic patients have difﬁculty
focusing on the task at hand, and thus perform more slowly. Euthymic bipolar
patients are signiﬁcantly impaired on the digit-symbol substitution test (5), a classic
speed-of-processing measure. In contrast, Martinez-Aran et al. (3) reported that

depressed bipolar patients generated fewer words than manic or euthymic bipolar
patients, who did not differ from comparison subjects, suggesting that verbal
ﬂuency may be inﬂuenced by mood state. Together, these data suggest that speed
of processing is impaired in BD; however, the speciﬁc neuropsychological measure
employed is important, and there are no consistent ﬁndings across mood state.
Denicoff and colleagues (49) report that with increasing illness duration, perform-
ance on a timed letter-cancellation task decreased signiﬁcantly. Similarly, with
increasing number of manic episodes, patients’ performance on the letter ﬂuency
test is reduced (67). Others have reported poorer performance on processing
speed measures to be associated with both overall illness duration (3,5) and more

hospitalization episodes (56), suggesting that both duration and severity of
illness may reduce speed of processing. While it is tempting to posit that history
of psychotropic medication usage is associated with reduced processing speed,
Clark and coworkers (35) found that current or past medication usage did not
impact this measure. Furthermore, when this sample was limited to those patients
not on medications (n ¼11), patients were still signiﬁcantly slower than healthy
comparison subjects.
WORKING MEMORY
The information-processing capacity of the central nervous system is limited,
necessitating a time-restricted approach to the processing of ambient sensoryNeurocognitive Findings in Bipolar Disorder 255

information (15,68,69). One conceptualization of working memory is that it
provides the temporary storage facilities needed to prolong the neuronal response
to a brief sensory event beyond the duration of the actual event or its iconic (or
echoic) representation, and thus allows for ‘higher’ cognitive processes such
as reasoning, planning, language, and other forms of abstract thought (69a,70).
Baddeley proposed a tripartite organization of working memory consisting of a
central executive component, which controls the manipulation of information
held in memory and the distribution of ﬁnite processing resources (e.g., attention),
and two slave systems, the articulatory loop and visuospatial scratch pad, which
maintain mental representations of verbal and visuospatial information, respect-
ively (71,72). Generally, the results of neuroimaging studies are consistent with
the functional and anatomical segregation of the storage aspects of working

memory into separate systems specialized for verbal and spatial information
(73–77). These systems appear to follow the general pattern of hemispheric
specialization, with verbal material maintained primarily in left hemisphere
regions and spatial material maintained primarily in right hemisphere regions
(73) and with segregated regions for passive storage versus active rehearsal
within each domain (77). Executive or manipulation processes rely on prefrontal
processing, speciﬁcally in the dorsolateral prefrontal cortex (74,77).
Neuropsychological measures of working memory include those designed to
assess maintenance [e.g., delayed response task (78)] and manipulation [e.g.,
letter-number sequencing (79) or n-back paradigms (80)] with either verbal or

visual spatial information. Several papers report that patients are not impaired
on the forward condition of the digit span subtest of the WAIS-III (3,81,82), a
measure associated with verbal memory capacity and attention. Using the
CANTAB computerized neurocognitive test battery, Rubinsztein et al. (83) found
that clinically remitted bipolar patients showed impairment on tests assessing
recognition for geometric patterns and spatial locations (Table 1). Using the
same tests in a larger sample of euthymic bipolar patients, Thompson et al. (5)
observed impairment only on spatial (but not pattern) recognition memory, with
additional deﬁcits in paired associate learning, a measure assessing memory
for location of speciﬁc visual patterns, and on a delayed (but not simultaneous).

Matching to Sample task, suggesting difﬁculty with the memory component
of this task. In addition, while Ferrier et al. (2) described signiﬁcant impairment
in delayed visuospatial memory in remitted bipolar patients, this measure was
no longer signiﬁcantly impaired after covarying for affective symptoms.
While some reports suggest that bipolar patients are not impaired on spatial
delayed match to sample tests (35,82,84,85), others ﬁnd spatial maintenance
impairments, particularly in the manic phase of the illness (9,86). Discrepant
results may be due to heterogeneity across patient samples, or differences in the
speciﬁc task demands of the working memory measures employed. Indeed,
Glahn et al. found that all clinically stable but symptomatic patients with

BD were impaired on a verbal manipulation task [backwards digit span subtest
of the WAIS-III (The psychological Corporation 1997)]; however, only patients
with a lifetime history of psychosis were impaired on a spatial delayed response
task (81).
Many investigators report dysfunction on tasks requiring on-line manipu-
lation of information in patients with BD (3,5,83,87,88); however this ﬁnding256 Glahn and Bearden

is not universal (9,35). To date, few studies have employed the same measures of
cognitive manipulation, making it difﬁcult to interpret inconsistent results.
Most reports of clinically symptomatic (82,84) and symptom-free (35) patients with
BD do not show evidence for impaired short-term maintenance of information in
BD. However, Sweeney et al. (9) found that, with increasing delay interval, both
depressed and mixed /manic patients with BD were impaired, and that with a 12
second delay, the mixed /manic patients performed signiﬁcantly worse than
depressed patients with BD. As most reports of working memory maintenance
did not include such long delay intervals, it is difﬁcult to determine if these ﬁndings
are at odds with other reports. In contrast, working memory tests that require the
manipulation of remembered information appear to be impaired across phases of
illness to a comparable degree (3,5,50), but see (9).

Rubinsztein and associates (83) reported a signiﬁcant association between the number
of months hospitalized and visual working memory impairment. Thompson et al. (5)TABLE 1 Visual Spatial Memory Tasks
Visual-spatial memory task Description
Pattern recognition test (85a) 12 abstract colored visual patterns are presented
sequentially. In the recognition phase, the same patterns
(each paired with a novel pattern) are presented in the
reverse order and subjects are asked to respond by
touching the pattern that they have already seen.
Spatial recognition test (130) Five squares are presented sequentially in different
locations. In the recognition phase, each square is
presented again, now paired with a novel location.
Subjects must touch the correct location of the box they
had been presented with earlier.
Rey-Osterreith complex

ﬁgure test (124)The subject copies a complex ﬁgure and then, after a
delay, reproduces the ﬁgure from memory.
Simultaneous and delayed
matching to sample task (130)This task assesses subjects’ ability to recognize complex
visual designs after different delay intervals (0, 4, and 12
sec). Subjects are shown a target at screen center, and
after the delay interval four surrounding stimuli are
presented.
Pattern recognition memory
task (130)After a series of patterns is displayed, subjects are
presented pairs of patterns, one shown previously and
one being a novel pattern. They are asked to indicate the
pattern they were shown previously.
Visual-spatial paired associate
learning task (130)Designs are presented in boxes on the screen at varying
locations. The designs are then presented sequentially

in the center of the screen and subjects are instructed to
indicate the box in which each design was initially
Spatial recognition memory
task (130)Five squares are presented in sequence at different
locations on the screen, and then subjects are presented
a pair of squares and asked to identify which is at a
location where a square was previously presented.Neurocognitive Findings in Bipolar Disorder 257

documented signiﬁcant relationships between total number of hospitalizations and
spatial working memory. In contrast, Clark et al. (35) reported no signiﬁcant relation-
ships with the total number of hospital admissions, but found that the number of
admissions speciﬁcally for depressive episodes was positively related to errors on a
spatial working memory task. While Frangou and coworkers (143) report that
increased duration of illnessimpacts executive functioning, others report that duration
of illness and /or number of hospitalizations does not signiﬁcantly affect working
memory performance in bipolar patients (81,89). At issue may be the exact measures
used, as Frangou and colleagues (143) only found an association between duration of
illness and executive dysfunction on just one of several working memory measures
employed. Current use of antipsychotic medications was associated with poorer
manipulation of information held online in BD (50).
LEARNING AND MEMORY: VERBAL AND VISUAL

The explicit recall of previously learned information is known as declarative
memory. In contrast to working memory, which involves the ability to maintain
and/or manipulate information over a brief time period, this process relies on the
ability to adequately encode, store, and retrieve information from long-term
memory (90,91). Encoding refers to the process that converts a perceived event
into a lasting neurophysiological trace (91), while retrieval involves reactivation
of a stored representation, leading to an explicit ‘memory’ of the event. These cog-
nitive functions (encoding, storage, and retrieval) are thought to be subserved by
distinct brain regions. In particular, the temporal-hippocampal system has been
demonstrated by both animal and human work to play a critical role in both encod-

ing and retrieval of verbal information (92–94), while strategic or executive aspects
of memory are heavily dependent upon prefrontal cortical function (95,96).
In studies of adult lesion patients, there appears to be a distinction between
visual and verbal memory circuits that mirrors the hemispheric organization of
the rest of the brain; that is, lesions to the right hippocampus or right temporal
lobes have been shown to impair memory of visual and spatial information, includ-
ing recall of complex geometric ﬁgures, paired-associate learning of nonsense
ﬁgures, and performance on maze-learning, face-recognition, and spatial memory
span tasks (97–101), while left-sided lesions appear to differentially impair
memory for verbal information (99,100,102,103). Such ﬁndings have been validated
by neuroimaging studies (104–106).

Evidence for Impairment: Verbal Learning and Memory
Verbal declarative memory impairments are among the most consistently reported
cognitive difﬁculties in patients with BD (7,63,65,88,89,107–113). Given that these
deﬁcits have been observed in euthymia (2,3,5), have also been observed in
unaffected relatives of patients with bipolar illness (48,114), and may lead to
clinically signiﬁcant impairment in everyday functioning (1,2,4,6), declarative
memory dysfunction may represent a vulnerability marker for bipolarity.
Despite the potential importance of memory deﬁcits for psychosocial and
occupational outcome of patients with bipolar illness (6), the nature of these impair-
ments is not well understood. There is some evidence that poor memory perform-

ance is secondary to strategic or organizational dysfunction rather than impaired
memory processes per se (110); given that executive functions (i.e., the ability to
plan and reason, and inhibit behaviors) are known to play a signiﬁcant role in258 Glahn and Bearden

learning and memory performance (115), and are frequently shown to be impaired in
bipolar patients (see discussion above), this seems unsurprising. However, few
studies have directly investigated the role of learning strategies in memory perform-
ance in bipolar illness; while Deckersbach et al. (110) found that recall difﬁculties in
euthymic bipolar patients were partially accounted for by poor semantic clustering
strategies, our group did not replicate this ﬁnding (63). Rather, we ﬁnd that verbal
declarative memory deﬁcits are more consistent with encoding impairments in
adults and children with BD (63,116).
Effect of Mood State: Verbal Learning and Memory
Sweeney et al. (9) identiﬁed widely distributed cognitive deﬁcits in mixed /manic
bipolar patients, while depressed bipolar and unipolar patients demonstrated
impairments only on an episodic memory test, suggesting a more selective dysfunc-
tion in mesial temporal lobe function during depressive episodes. Moreover,

Henry et al. (117) found that bipolar patients in the manic state displayed poorer
performance on a verbal learning task relative to their own performance when
clinically remitted. However, they were not impaired on short-term free recall,
regardless of mood state, suggesting that manic or depressive symptomatology
may affect complex processing or memory functions, but not simpler cognitive
processes (117).
Using the California verbal learning test (CVLT) (118), two studies of acutely ill
inpatients in various mood states demonstrated signiﬁcantly decreased recognition
performance relative to healthy comparison subjects (65,108). Several studies using
similar verbal learning tests have found that euthymic patients have normal perform-
ance on recognition measures (3,5,88,107,111,112), suggesting that verbal recognition

deﬁcits may be state-related, rather than a core deﬁcit of BD (119). In contrast to recog-
nition memory, free recall deﬁcits appear to be relatively independent of mood state
(3,63), suggesting that retrieval of verbal information from memory may reﬂect a
trait-related impairment in patients with BD.
Impact of Clinical Course: Verbal Learning and Memory
Verbal memory performance may be adversely affected by severity of illness, as
measured by number of hospitalizations, number and duration of manic and /or
depressive episodes, and age at onset (35,56,109,120). Five out of six studies
found at least one signiﬁcant correlation between number of manic episodes and
poorer verbal memory performance (3,35,109,110,113). In particular, four of these
investigations found a relationship between past manic episodes and poorer

delayed verbal memory (recall or recognition of a word list after a delay) (121).
However, other studies have found no relationship between illness variables and
memory performance (1,122).
Although one study found the number of depressive episodes to be inversely
correlated with verbal memory performance (110), four others failed to ﬁnd a
relationship between number of depressive episodes and verbal memory perform-
ance (3,5,109,112). Martı ´nez-Ara ´n et al. (3) found a signiﬁcant relationship between
the total number of hospitalizations and poorer verbal memory performance.
However, there is little evidence that age at illness onset bears relationship
to verbal declarative memory performance, with several studies showing no
relationship (3,5,119,123). Similarly, of the few existing studies that have examined

length of time euthymic in relation to cognitive function (5,35,87), none have found
an association between these variables.Neurocognitive Findings in Bipolar Disorder 259

Evidence for Impairment: Visual Learning and Memory
In general, there is less consistent evidence for impairment in nonverbal memory
processes in patients with bipolar illness than exists for the verbal domain (12,14).
However, this may be attributable to fact that relatively few studies have examined
aspects of visual and spatial memory in bipolar patients, and those that have rarely
employed the same measures, leading to difﬁculty synthesizing information across
studies. Two studies found euthymic bipolar patients to be impaired on the
Rey-Osterrieth complex ﬁgure test (ROCFT) (124), a nonverbal memory test that
allows assessment of organizational strategies during learning (107,119). Further-
more, Deckersbach et al. (119) found that, compared with control participants,
euthymic bipolar-I patients relied less on organizational strategies during encoding
on this test. However, other studies have reported no impairment on this task

(125,126). In addition, visuo-constructive ability, as measured by the WAIS Block
Design task, appears unimpaired in euthymic bipolar patients (113,127).
Effect of Mood State: Visual Learning and Memory
There is increasing evidence that nonverbal memory impairment is not purely a
function of mood state (107,119). However, visual and spatial memory impairments
may be exacerbated during the mixed /manic phase of illness, and thus are not
entirely state-independent (9).
Impact of Clinical Course: Visual Learning and Memory
One study reported a relationship between the number of both manic and
depressive episodes and increasing impairment on a visual memory task, the
ROCFT (110), although others found no signiﬁcant relationships between manic
episodes and performance on computerized measures of visuospatial memory

(41,83). Thompson et al. (5) additionally noted poorer performance on the Paired
Associates Learning task in those with longer duration of illness. Of studies that
have instead examined the total number of mood episodes, regardless of polarity,
El-Badri and colleagues (87) observed that number of episodes was negatively
related to visual memory performance. However, other studies have found
no relationship between number of lifetime mood episodes and both verbal and
visual memory performance (88). Furthermore, Ferrier and co-workers categorized
patients based on number of episodes (no more than two major mood episodes
in the past ﬁve years, vs. three or more major mood episodes) and found no
differences between the groups on any neuropsychological measure.
REASONING AND PROBLEM SOLVING

The MATRICS group notes that the label Reasoning and Problem Solving has
the advantage of distinguishing this domain from the executive processes of
working memory (128) and demonstrate that this domain is empirically dissociable
(based on factor analyses) from working memory (22). That being said, many of the
tasks included in the reasoning and problem-solving domain are often discussed as
measures of executive functioning. The primary differences between ‘executive’
working memory and reasoning and problem-solving tasks is that working memory
tasks tend to have explicit memory demands (e.g., n-back paradigms) or are designed
to determine working memory capacity (e.g., letter-number sequencing).
Cognitive measures conceptualized as Reasoning and Problem Solving

include sorting cards using an abstract principle that changes over time260 Glahn and Bearden

[e.g., Wisconsin Card Sorting Test (WCST) (129), ID /ED shift (130)], nonverbal
reasoning to complete a sequence of visual patterns [e.g., Matrix Reasoning (131)
or the Raven’s Progressive Matrices (131a)] or to construct a visual pattern [e.g.,
Block Design (131)], moving round disks between pegs in the smallest number of
steps to achieve a speciﬁc order [e.g., Tower of London (130)], and similar verbal
and nonverbal problem-solving tasks (Table 2). Such higher-level cognitive pro-
cesses often demand relatively intact lower-level processes, but also involve
additional complex strategic planning and decision-making skills. While these
tasks involve a myriad of cognitive processes, they tend to be highly correlated
and are often described as ‘frontal lobe’ measures (132). Human functional neuroi-
maging studies demonstrate that reasoning and problem-solving tasks engage a
wide range of brain regions, including prefrontal, temporal, parietal, occipital,

TABLE 2 Reasoning and Problem Solving Findings in Bipolar Patients
Article Task Finding
Altshuler et al.,
2004Wisconsin card sort Clinically stable bipolar patients (n ¼40) had
more perseverative errors and fewer
categories than healthy subjects (n ¼22)
Frangou et al.,
2005Wisconsin card sort Euthymic bipolar patients (n ¼44) did not differ
from healthy subjects (n ¼44)
Martinez-Aran
et al., 2004bWisconsin card sort Depressed (n ¼30), manic /hypomanic
(n¼34), and euthymic (n ¼44) bipolar
patients had more perseverative errors than
healthy subjects (n ¼30)
Zubieta et al.,
2001Wisconsin card sort Euthymic bipolar patients (n ¼15) had more
perseverative errors and fewer correct
responses than healthy subjects (n ¼15)
Clark et al., 2001 ID /ED shift Manic bipolar patients (n ¼15) had more

reversal and extradimensional shifting errors
than healthy subjects (n ¼30)
Clark et al., 2002 ID /ED shift Euthymic bipolar patients (n ¼30) had more
extradimensional shifting errors than healthy
subjects (n ¼30)
Olley et al., 2005 ID /ED shift Euthymic bipolar patients (n ¼15) did not differ
from healthy subjects (n ¼13)
Glahn et al.,
2006aProgressive matrices Bipolar outpatients in various clinical states
(n¼60) did not differ on a standard
progressive matrices from healthy
comparison subjects (n ¼60)
Badcock et al.,
2005Tower of London /
stockings of
CambridgeManic bipolar patients (n ¼14) did not differ
from healthy comparison subjects (n ¼33)
Rubinsztein
et al., 2000Tower of London Euthymic bipolar patients (n ¼18) took longer to
provide correct responses than healthy
comparison subjects (n ¼18)
Thompson et al.,

2005Tower of London Euthymic bipolar patients (n ¼63) were required
more moves and longer times than healthy
comparison subjects (n ¼63)
Olley et al., 2005 Tower of London /
CambridgeEuthymic bipolar patients (n ¼15) did not differ
Clark et al., 2002 Tower of London Euthymic bipolar patients (n ¼30) did not differ
from healthy subjects (n ¼30)Neurocognitive Findings in Bipolar Disorder 261

and cerebellar cortices (133–135). Although these data suggest that reasoning and
problem solving tasks evoke large-scale cortical networks, Duncan and Owen (132)
note that three prefrontal regions are consistently recruited: the mid-dorsolateral,
mid-ventrolateral, and dorsal anterior cingulate regions.
Table 2 presents ﬁndings from four prototypical Reasoning and Problem Solving
tests. Patients with BD appear to be impaired on speciﬁc reasoning and problem-
solving measures (e.g., WCST), but not on other measures (e.g., progressive
matrices). On other measures like the ID-ED shift task and the Tower of London
(Stockings of Cambridge) task, ﬁndings are mixed, with some investigators report-
ing impairments and others not (Table 2). The inconsistency of ﬁndings suggests
that the reasoning and problem-solving domain includes clearly dissociable
cognitive processes, only some of which may be disrupted in BD. Patients with

BD consistently make more perseverative errors than healthy comparison subjects
on the WCST, suggesting difﬁculties with cognitive ﬂexibility (3,107,123). However,
ﬁndings on the ID-ED test, which is conceptually very similar to the WCST, are
mixed, indicating that other cognitive factors (e.g., strategy or poor inhibition)
may lead to at least some of the observed impairments on the WCST. Alternately,
differences in the composition of the patient and comparison samples studied
may lead to discrepant results.
While most investigators ﬁnd that planning, as indexed by the Tower of London
task, is impaired in BD (5,83), others ﬁnd no evidence for impairment (35,136). Olley
et al. (137) found that patients with BD trended towards impairment on this
measure (p ¼0.068).

Patients with BD do not appear to be impaired on progressive matrices. As
these measures are closely related to general intellectual processing and given that
there is little evidence that bipolar patients have reduced intellectual abilities
(12,14), it is unsurprising that performance on progressive matrices is intact (138).
While several investigators propose that cognitive ﬂexibility (83,139) and planning
(65) are markedly more impaired in mania, others report no differences between
depressed, manic, or euthymic patients on these same measures (3). In one of the
more detailed examinations of a reasoning and problem-solving test, Murphy
and colleagues (64) measured decision making in manic and depressed bipolar

patients and healthy comparison patients. To do so, they employed an experimental
risk-taking task previously shown to engage inferior and orbital prefrontal cortex
(140) where subjects were asked to win as many points as possible by choosing
outcomes based on variably-weighted probabilities and by placing ‘bets’ on each
decision. Depressed and manic patients were impaired on this task (64), as
evidenced by slower deliberation times, a failure to accumulate as many points
as controls, and suboptimal betting strategies. Interestingly, manic, but not
depressed, patients made suboptimal decisions this measure. However, manic
patients were not impaired on a conceptually similar gambling task (65).
Given the variability of ﬁndings discussed above, it is difﬁcult to draw clear con-

clusions concerning the effects of clinical course on performance on reasoning262 Glahn and Bearden

and problem-solving tests in BD. Clark et al. (35) report that Tower of London per-
formance was negatively correlated with duration of illness in euthymic patients,
potentially explaining some of the variable results reported in the literature on
this measure. In addition, there is some evidence that rule learning and cognitive
ﬂexibility (as measured by the Wisconsin Card Sort) are impaired prior to illness
onset and impairment on this measure in children at risk for BD predicts latter
illness onset (141). Furthermore, performance on this measure worsens with
increasing numbers of manic or depressive episodes (123) and longer duration of
illness (3).
GENERAL INTELLECTUAL FUNCTIONING
Given that the frontal lobes occupy 30% to 40% of the neocortex (142), many theor-
ists ascribe intellectual capabilities to frontal lobe function. To date, the cognitive
neuroscience of general intellectual function is underdeveloped, largely because

there is little evidence to suggest regional speciﬁcity in brain regions underlying
these functions (132,134). Nevertheless, some researchers have proposed that
working memory capacity, or the capability for executive attention, is the psycho-
logical core of the construct of general intelligence, or “g” (143). Because the
dorsolateral prefrontal cortex (DLPFC) is critical to working memory capacity,
normal individual differences in both working memory capacity and “g” may be
mediated by individual differences in DLPFC function (132,142).
There is little evidence for impairment in global cognitive abilities in patients with
bipolar illness, particularly during periods of euthymia (12,14). Although early
studies reported relatively lower nonverbal or performance IQ (PIQ) than verbal

IQ (VIQ) in bipolar patients (144,145), both verbal and performance IQ were well
within the normal range. In addition, because the majority of these earlier studies
did not describe the patients’ clinical state at the time of testing, it is not clear
what impact current clinical symptomatology may have had on IQ performance.
Further, in contrast to patients with schizophrenia, epidemiologic studies offer
little evidence for impairment in premorbid intellectual ability in patients with
BD (146,147).
In one of the few test-retest investigations of IQ in BD, Donnelly and colleagues
found evidence that the same patients, when in a hypomanic or euthymic state,
have higher IQs than when depressed (148). This ﬁnding was not attributable to

practice effects, as the patients’ IQ scores declined again when retested in the
depressed state. However, this ﬁnding has yet to be replicated with patients
meeting current diagnostic criteria for bipolar illness. Little is currently known
about the effects of clinical course on IQ.
COMORBID PSYCHIATRIC ILLNESSES
While the effects of comorbid attention deﬁcit hyperactivity disorder (ADHD) have
been investigated in the small number of studies examining neurocognitive func-
tion in pediatric bipolar patients (149,159), cognitive differences as a function of
psychiatric comorbidity have only been examined in a few studies of adult patientsNeurocognitive Findings in Bipolar Disorder 263

with BD. In particular, van Gorp et al. (113) found that bipolar patients both with
and without alcohol dependence performed more poorly than controls on tests of
verbal memory; however, bipolar subjects with a history of alcohol dependence
had additional decrements in executive functions as compared with controls.
While our group also found that current substance abuse was associated with
poorer verbal learning and memory in bipolar patients, this association did not
reach statistical signiﬁcance after correcting for multiple comparisons (63). In
addition, comorbid anxiety disorder did not affect verbal memory performance.
Given that 30% to 50% of patients with BD have comorbid substance abuse (151),
as well as very high rates of other comorbidities, particularly anxiety and personal-
ity disorders (152), the impact of comorbid disorders on cognitive function in
bipolar illness clearly warrants further investigation.

While gender differences have rarely been investigated in studies of cognition
in BD, there is some evidence that gender may modulate the severity of cognitive
deﬁcits in BD, with male patients demonstrating poorer neurocognitive perform-
ance (9). Other clinical factors, particularly history of psychosis, may adversely
impact cognitive function (81), though systematic, large-scale investigations of
the effect of psychosis on neuropsychological functioning in BD have not yet
been published.
EFFECTS OF PSYCHOTROPIC MEDICATIONS
Although current and past use of psychotropic medications could impact neurocog-
nitive functioning, systematic investigation of the cognitive impact of these agents
in patients with BD has been limited. A prior qualitative review concluded that
while lithium had a negative effect on memory and speed of information

processing, patients were often unaware of these deﬁcits (153). Although Kessing
et al. (120) found both the number of episodes and length of lithium treatment to
be inversely correlated with performance on two of ﬁve tests of global cognitive
function, Engelsmann and coworkers (154) found that mean memory test scores
remained quite stable over a six-year interval in lithium-treated bipolar patients.
Further, there were no signiﬁcant differences between patients with short- versus
long-term lithium treatment on any measure, after controlling for age and initial
memory scores, suggesting that long-term lithium usage is unlikely to cause
progressive cognitive decline (154).
Some antidepressant medications have been shown to have adverse cognitive
effects, particularly those with anticholinergic properties (155). Although evidence

to date does not indicate cognitive side effects of selective serotonin reuptake
inhibitors (e.g., paroxetine, sertraline), the long-term impact of these medications
on cognition is not yet known (155). While few studies have examined neuro-
cognitive performance in unmedicated bipolar patients, we previously found
comparably impaired verbal memory in patients receiving psychotropic medi-
cation (n ¼32) and those who were drug-free (n ¼17) (63). Further, Strakowski
and colleagues recently studied euthymic, unmedicated bipolar subjects with
functional MRI, while performing a sustained attention task, the continuous
performance task-identical pairs version (CPT-IP) (156,157). Despite comparable
task performance to controls, the bipolar patients showed a different pattern of

brain activation, involving overactivation of anterior limbic areas, with correspond-
ing abnormal activation in visual associational cortical areas. Taken together, these
ﬁndings suggest that cognitive deﬁcits, and underlying abnormalities in neuronal264 Glahn and Bearden

activation, in patients with bipolar illness are not primarily attributable to the use of
psychotropic medications. However, large-scale, longitudinal investigations of
bipolar patients on different medication regimens are warranted to fully address
this question.
Table 3 summarizes our ﬁndings of cognitive dysfunction in BD. In rather broad
strokes, we ﬁnd evidence for neuropsychological impairment in six of the seven
cognitive domains reviewed.
However, this impairment is often subtle, or presents only speciﬁc measures
of a cognitive construct and not others. Indeed, by closely examining the types of
tests on which patients with BD show impairment, we conclude that the pattern
of deﬁcits suggests dysfunction in prefrontal and medial temporal lobe circuits.
Evidence for frontal lobe dysfunction includes poor top-down attention as
indexed by CPT tests, reduced speed-of-processing measures that include decision

making (e.g., digit-symbol coding), impairment on working memory tasks requir-
ing manipulation of information, and reduced cognitive ﬂexibility and planning
abilities. Evidence for temporal lobe dysfunction includes poor recall of verbal
and nonverbal information. At this time, it is impossible to determine if these
impairments are independent or interactive with one another or even if these
impairments are seen in the same patients. Indeed, it is possible that patients
with different pathologies are included in the overarching bipolar diagnostic
category, and that neuropsychological measures may be useful in dissociating sub-
groups of patients. While the current review cannot address this issue, as sample
sizes increase, such segregation analyses become possible. Such analyses could

potentially delineate different groups of bipolar patients with distinct neuropsycho-
logical proﬁles, and potentially with different functional outcomes or treatment
responses.
Relatively few of the cognitive deﬁcits reported in BD are entirely explained
by mood state at the time of assessment. In general, acute manic or depressive
symptoms appear to intensify neuropsychological impairments found in euthymia.
However, there are a number of notable exceptions to this generalization.
For example, recognition of verbal memoranda is seemingly disrupted in manic
and depressed patients but generally intact in euthymic patients. Other neuropsy-
chological measures, particularly those involving verbal or semantic ﬂuency, are
reduced in bipolar patients when depressed, but not in manic or euthymic patients.

Yet, deﬁcits on most measures requiring cognitive ﬂexibility or planning, vigilance,
manipulation of information held on line, or recall of verbal or visual information
appear to be present regardless of mood state. It should be noted that very few
longitudinal neuropsychological studies have been conducted with bipolar patients
and that within subject measurements are needed to deﬁnitively address this issue.
The impact of clinical course is difﬁcult to estimate. Most current investi-
gations correlate the number of manic or depressive episodes or total duration of
illness or hospitalizations with cognitive measures. However these indices of clini-
cal course are often dependent upon accurate patient report. For example, the
number of manic or depressive episodes is difﬁcult to determine in patients with

mixed manic and depressive symptoms, and does not provide an indication of
how long these symptoms persisted, or the intensity of these symptoms. Duration
of illness is difﬁcult to accurately determine, given that illness onset is often subtleNeurocognitive Findings in Bipolar Disorder 265

and the measure does not provide an indication of clinically signiﬁcant mood
changes. Depending on health care availability, the number of hospitalizations
could be biased by the socioeconomic status of the patient rather than his or her
degree of psychiatric distress. Perhaps a better measure of clinical course would
be the number of days well (or sick) in a given time period. However, thisTABLE 3 Neuropsychological Findings in Bipolar Disorder
Cognitive
domainImpairment in
bipolar disorderEffect of
mood stateImpact of clinical
course
Attention Consistent evidence for
top-down and
bottom-up impairmentsManic and depressive
mood states
exacerbate poor
attentional
processing found in
euthymic patientsPoor clinical course
is associated
with increased
Speed of
processingEvidence for consistent
deﬁcits on measures
other than verbal
ﬂuency. Verbal ﬂuency
impairments reports
in some studies.
Impairments may be
associated with
memory difﬁculties.Depressed and manic

patients are impaired
on numerous
measures. Euthymic
on the digit-symbol
testPoor clinical course
Working memory Little evidence for
impaired maintenance
of information;
signiﬁcant evidence
for manipulation /
executive dysfunction.Depressed, manic and
euthymic patients are
impaired on
manipulation /
executive measures.Reports are mixed
whether duration
of illness is
associated
with poor
executive
processing
Verbal learning
and memoryConsistent evidence for
impairment in recall
of verbal informationRecognition
impairments are
linked to mood state,
recall deﬁcits are notNumber of manic
episodes and
number of
hospitalizations
are negatively
correlated with
memory
Visual learning
and memoryAlthough there are
relatively few studies,

number of
memory
consistent evidence
for impairmentEuthymic patients are
measures of visual
recallUnclear
Reasoning and
problem solvingImpairment on speciﬁc
problem solving or
planning measures,
but not progressive
matricesManic and depressive
mood states may
problem solving
performance found in
euthymic patientsDuration of illness
and number of
manic episodes
cognitive ﬂexibility
and planning
General intellectual
functioningLittle evidence for
impairmentUnknown Unknown266 Glahn and Bearden

measure is subject to a number of the same concerns, particularly in cross-sectional
studies. These difﬁculties point to the importance of obtaining collateral infor-
mation (i.e., hospital records, informant reports) to more accurately quantify
history of illness variables. Despite the difﬁculties with standard indices of clinical
course, the literature to date generally indicates that patients with more severe clini-
cal presentations tend to have poorer memory functioning and cognitive ﬂexibility.
It is unclear whether these patients truly represent a “severe” subgroup distinct
from patients with less severe clinical course, or if the increased impairment in
those patients with a more chronic, severe illness course are secondary to different
medication regimens or other clinical or behavioral factors. In addition, while early
studies often failed to characterize current mood state in cognitive studies of bipolar

illness, researchers are increasingly employing rigorous deﬁnitions of euthymia
(based not only on current symptom ratings, but length of time euthymic) to
characterize patient samples. This practice should become the “gold standard” in
all future studies of neurocognition in bipolar illness.
Patients with BD are often prescribed multiple psychotropic medications as
well as other nonpsychiatric agents. This practice makes determining the effects
of a single medication on cognitive processing difﬁcult. There are a number of
studies currently underway on medication-naı ¨ve or -free subjects and we should
soon have a better understanding of the neuropsychological function of BD inde-
pendent of psychotropic medications. Ultimately, the study of bipolar patients

alone cannot determine whether neurocognitive deﬁcits are the result of the under-
lying, pre-existing pathophysiology or the result of the illness itself and related
factors (such as sub-syndromal symptoms, acute or chronic medication effects, or
permanent structural changes wrought by prior episodes of acute illness). One
potential way to address these issues is to study those without overt symptom
expression, but with high genetic risk for BD. Although several manuscripts
focusing on unaffected siblings and relatives of bipolar patients have been pub-
lished in the last year (48,62,114,125,158–160), to date the majority of these
studies include relatively small sample sizes, limiting potential conclusions.
However, current ﬁndings do tend to corroborate ﬁndings in euthymic patients

of subtle learning and memory deﬁcits (62,114,125) and possibly impaired planning
and attentional function as well (48,161,162). Further study of such at-risk individ-
uals will elucidate neurocognitive and neurobiological vulnerability markers that
can provide important clues into the underlying pathophysiology of the illness.
Cognitive impairment in patients with bipolar illness is increasingly under-
stood as both persistent during symptom-free periods, and to be associated
with functional outcome. Improving our understanding of the clinical implications
of such neurocognitive dysfunction, and its effects on psychosocial and occu-
pational functioning, is of primary importance in improving long-term outcome
for this highly disabling mental illness.

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B15 Biology vs. Environment: Stressors in the
Morgen A. R. Kelly
Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine,
Pittsburgh, Pennsylvania, U.S.A.
Stefanie A. Hlastala
Children’s Hospital and Regional Medical Center, Seattle, Washington, U.S.A.
Ellen Frank
Fifty years after the discovery of lithium (1), bipolar disorder (BD) remains a major
therapeutic challenge. Extensive research has demonstrated that people with BD
typically suffer multiple recurrences of mania and /or depression throughout
their lifetimes, often despite continuous maintenance pharmacotherapy (2–6).
Markar and Mander (4), for example, followed a group of bipolar patients on
lithium prophylaxis and found that only 30% to 40% remained well over a three-

year period. Recently, clinical research has begun to examine the efﬁcacy of
adding psychosocial treatments to pharmacotherapy for BD (7). Outcomes in
these studies are often measured both in terms of symptom reduction and in
terms of the duration of well periods (8–10). The inclusion of time to relapse as
an outcome measure in these studies presumes that most individuals with BD
will relapse over time, often despite use of so-called maintenance medications.
The occurrence of breakthrough episodes coupled with the poor work, family,
and social functioning found over the long-term course of illness in patients with
BD (11) makes it critical that we examine environmental as well as biological
factors in an effort to better understand mechanisms underlying the pathophysiol-
ogy of BD.

ogy of BD.
Examining the role that environmental stressors play in the onset, recovery,
and recurrence of bipolar episodes provides a way to understand how psychosocial
factors may inﬂuence the course of a disorder that is often thought of as purely bio-
logically driven. Indeed, our own clinical experience would suggest that changes in
social roles (e.g., getting a divorce, becoming a parent), changes in routines (e.g.,
travel across multiple time zones), and interpersonal losses (e.g., death of a loved
one) are frequently associated with the onset of new episodes in bipolar patients.
In this chapter, we review research that has examined the relationship between
life stress and the long-term course of BD as well as the methodological inconsisten-

cies that are found in this research. We also address some of the biological and beha-
vioral processes that may modify this relationship. Additionally, the question of
275

whether stress plays a greater role earlier as opposed to later in the course of illness
is examined.
METHODOLOGICAL ISSUES
Before embarking on an examination of the relationship between environmental
stressors and the long-term course of BD, the pervasive methodological inconsis-
tencies and inadequacies found in the previous research on life stress and the
course of BD need to be discussed. Two methods of life event measurement have
dominated research on stress and BD: checklist measures and personal interview
measures. Checklist approaches have several weaknesses. Often the items on
these lists are ambiguous, which may lead to inaccurate interpretations and unreli-
able reports of basic information by respondents (12,13). Checklists often allow a
wide range of severity in one category (e.g., a bad ﬂu, terminal cancer, and
chronic arthritis could all be reported under a “serious illness” category). Addition-

ally, idiosyncratic interpretations inﬂuence checklist events such as “serious illness
of close family member” by allowing the respondent to determine which illnesses
are “serious” and which family members are “close” (14).
Perhaps one of the greatest problems that can arise when examining the role
of psychosocial events in episode onset is that events may occur as a result rather
than a cause of the disorder. Checklist measures are unable to sort out this confound
because of the lack of speciﬁcity in the timing of events in relation to the onset of
symptoms of a new episode. Studies using checklist methods are more likely to
misdate distant events into a more recent time period (15,16). One-on-one inter-
viewing, on the other hand, is more effective in obtaining accurate answers and

dating (17), which is critical when trying to separate the events from early symp-
toms of psychopathology. The optimal strategy involves the use of reliable and
accurate techniques for dating episode onset in relation to the occurrence of a life
event. Such techniques are more likely to be associated with interview methods.
Many studies use retrospective designs that include prolonged recall periods
and questionnaire methods that contribute to biased or incomplete reporting, errors
in recall, inadequate sampling of important events, and inaccuracies in dating event
onset and duration. One of the main problems with retrospective designs is the
limitations in the long-term recall of stressful life events. Additionally, patients
may experience some memory bias regarding life stress over time to ﬁt their experi-

ence to their conceptualization of their illness (i.e., a “search after meaning”).
Another prominent issue in stress disorder research is whether to use objec-
tive ratings (investigators’ interpretations of threat level) or subjective ratings
(respondents’ interpretations of threat level) of stress. Selye (18), for example,
noted the importance of differentiating between objective external stressors and
perceived stress, stating “the stressor effects depend not so much upon what we
do or what happens to us but on how we take it.” However, research examining
the role stress might play in the etiology and course of a disorder is complicated
by the fact that it can be difﬁcult to distinguish a person’s perception of stress
from the disorder itself or some prodromal sign of it. Moreover, psychological pro-

cesses such as minimization, denial, and exaggeration may lead to a respondent
being unable to report accurately on his or her response to an event. However, if
one takes the respondent entirely out of the equation and merely looks at the
event isolated from any personal context, the meaning may be entirely lost and
the process does indeed become “arbitrary” as Selye noted.276 Kelly et al.

In an effort to integrate all the aforementioned concerns, the Bedford College
Life Events and Difﬁculties Schedule (LEDS) (19) uses a contextual interview-based
approach to obtain an accurate portrayal of a subject’s life events and difﬁculties. In
the LEDS system, “an assessment of meaning or understanding on part of an inves-
tigator can take into account not only the immediate situation (a woman losing a
job) but the wider context (she is unmarried, in debt, and living with her school-
aged child)” (20). The contextual severity of threat and a variety of other dimen-
sions are rated using the “event dictionary” that contains extensive rules, criteria,
and more than 2000 case exemplars of life events and difﬁculties. Contextual
ratings of threat are based on the notion of the likely response of an average
person to an event occurring in the context of a particular set of biographical cir-
cumstances. The ratings reﬂect the threat associated with an event, taking into

account the subject’s particular set of circumstances while excluding both the
respondent’s emotional reaction and any psychiatric or physical symptoms that fol-
lowed the event.
The LEDS system enables researchers to obtain information on life events in a
way that minimizes self-report problems including denial, minimization, lack of
spontaneous recall, and exaggeration of past life events. Additionally, the use of
a semistructured interview format allows comprehensive assessment of events
across broad domains. Interviewers use “anchors” (e.g., holidays, birthdays) as
probes to date events accurately within the period of interest. Most important,
the LEDS system has the capability of taking life circumstances into account so
that the meaning of the event is not lost. This approach to the assessment of life

events has yielded consistently strong associations between life stress and the
onset or recurrence of a variety of physical and psychiatric illnesses (20). Of note,
differing treatment outcome results were found in a comparison of checklist and
LEDS methodologies (21). Results indicated that LEDS events predicted decreased
likelihood of remission while the checklist method was not associated with differ-
ential outcome in the same sample. Because of the relative strength of interview
and/or LEDS-based methodology, the following review places more emphasis on
research using those methods.
STRESSORS IN DEPRESSION AND MANIA
A vast amount of evidence indicates a role for life events in the onset and course of
unipolar depression (14,19). The effects of life events on BD, on the other hand, have

not been as extensively studied. The lack of strong research in this area may be a
result of the long-held assumption that biological factors play a more important
role than psychosocial factors in the onset and timing of new episodes in BD.
Despite this, a handful of relatively well-designed studies have recently been pub-
lished regarding the relationship between life stress and the onset or recurrence of
bipolar episodes. Although the existing evidence remains limited, the data have
suggested that stressful life events inﬂuence the onset of both ﬁrst and subsequent
episodes of BD (22).
EPISODE ONSET
Among the ﬁrst questions that may be answered using life event methodology is
“are stressful life events related to the initial onset of BD?” Despite the fact that

the study of disorder onset is exceedingly difﬁcult to conduct, two studies haveBiology vs. Environment 277

demonstrated an association between life stress and the initial onset of mood dis-
orders in general or BD in speciﬁc. Hillegers et al. (23) adapted the LEDS for use
with adolescents and administered the interview to 140 children of bipolar
parents. They found that overall life event load was associated with about a 10%
increase in the risk of mood disorder onset for these children. Unfortunately, this
study was not able to determine the relationship between life events and onset of
bipolar versus unipolar depression, given that this determination is impossible in
cases where a depressive episode is the initial episode of a mood disorder. Using
the Holmes-Rahe Social Readjustment scale, Glassner and Haldipur (24) found evi-
dence that individuals with late onset BD (deﬁned as onset after age 20) retrospec-
tively reported more life events associated with both their ﬁrst and their most recent
mood episodes. These studies provide some evidence that life stress may be related

to the onset of mood episodes, but are methodologically limited as well.
Perhaps because of the challenges of assessing the impact of stress on ﬁrst
episodes of mood disorder as well as the clinical importance of understanding
relapse triggers, most extant research in this area has concentrated on the associ-
ation between life stress and either recurrence or exacerbation of mood episodes.
Although the balance of evidence suggests that stressful life events are associated
with return or increase of mood symptoms, not all studies ﬁnd such a relationship.
Studies using checklist methodologies for assessing life events have generally failed
to ﬁnd a relationship between life events and bipolar episode onset (25,26) (see
Table 1 for more speciﬁc methodological information). Yet each study had extensive

design ﬂaws that limit the strength of its results. Hall et al. (25) studied 38 bipolar I
patients who were asked to complete a questionnaire consisting of 86 events over a
10-month period. They found that the 17 patients who relapsed into an episode of
either depression or hypomania did not differ in frequency of life events from the 21
patients who did not relapse within the 10-month interval. However, the study may
not have used an adequate observation period and did not control for the effects of
medication compliance. Additionally, because depressive and manic episodes were
deﬁned as deviations from normal mood, the patients categorized as relapsers may
have been relatively similar to those who did not relapse, thus resulting in no sig-

niﬁcant differences. Finally, the time studied was not limited to three months or less
before episode onset, which may be a more accurate predictor of relapse. Mayo (26)
also found no excess of stressful events in the six months before hospitalization in
28 bipolar, 7 unipolar, and 5 schizoaffective patients. However, this study also had
methodological ﬂaws (e.g., no analyses by diagnostic group; life event recall went
back, on average, 18 years).
Most studies using more rigorous interview-based life event assessment
methods have found a signiﬁcant relationship between life events and episode
onset (30–35). The only exceptions are Chung et al. (36) and McPherson et al.
(37). Using the interview-based LEDS system, Chung et al. (36) assessed life

event rates in the six months before episode onset and did not ﬁnd a signiﬁcant
difference between hypomanic patients and surgical control subjects, schizophrenic
patients, and schizophreniform patients. The hypomanic patients and control sub-
jects did not exhibit a signiﬁcant difference in the number of events experienced
over six months. However, given the basic differences typically found between
bipolar I and II patients [e.g., differences in episode severity and genetics (38,39)],
it is questionable whether life event data on hypomanic episodes are generalizable
to bipolar I patients. McPherson et al. (37) interviewed 61 bipolar I inpatients at
three-month intervals over a two-year period. Life events were collected using278 Kelly et al.

TABLE 1 Studies Finding No Signiﬁcant Relationship Between Life Events and Episode Onset
Study Sample Comparison group Life events measureLife events
time periodDeﬁnition of episode
onset
Hall et al. (1977) 38 bipolar I, rapid
cyclers excluded17 relapsers vs. 21
nonrelapsersSLE questionnaire 10 mo Feighner criteria
McPherson
et al. (1993)58 bipolar I Within subject
control periodsRLE interview 3 mo SADS
Mayo (1970) 28 bipolar I 6 mo before and
after hospitalizationInterview based on
checklist6 mo Structured interview
Chung et al. (1986) 14 hypomanic
patientsSurgical control
subjectsLEDS 6 mo DSM-III
Reilly-Harrington
et al. (1999)49 with lifetime
bipolar97 with lifetime
unipolar
depression; 23 with
no diagnosisLES 1 mo between
assessmentsSADS
Abbreviations : LEDS, life events and difﬁculties schedule (19); LES, life experiences survey (27); SADS, schedule for affective disorders and schizophrenia (28) ; SLE, modiﬁed
recent life events questionnaire (29).Biology vs. Environment 279

the semistructured Interview for Recent Life Events (40). The events were also rated
for threat and independence using modiﬁed LEDS criteria. Onset of relapse was
taken from the time of the ﬁrst clear symptom. Fourteen of 61 (23%) manic /hypo-
manic relapses and 9 of 32 (28%) depressive relapses were preceded by a moderate
to severe independent event in the previous month. However, these rates were not
signiﬁcantly greater than the life event rates occurring during control periods.
Although Hunt et al. (Table 2) (34) used the identical measures and design as
McPherson et al. (37) (Table 1), they did ﬁnd empirical support for a relationship
between life events and new episodes. In the patients who relapsed, 10 of 52
(19%) had at least one severe event in the month before relapse compared with 7
of 144 (5%) during control periods ( p,0.01). McPherson et al. suggest they may
have failed to ﬁnd a relationship because their sample was more seriously ill and

at a later stage of illness and because life events may play a more important role
in earlier episodes of the illness, as Post (46) has suggested. Additionally, their
sample was from a more afﬂuent area, in contrast to Hunt et al.’s inner-city
sample, which had a greater proportion of ethnic minorities. This suggests that
the threshold for relapse might be lowered by chronic psychosocial difﬁculties.
As seen in Table 2, many additional studies have found a relationship
between life events and bipolar episodes. For example, Kennedy et al. (30) com-
pared 20 manic inpatients with orthopedic outpatients and control subjects
matched for age, sex, marital status, social class, and immigration status who
were interviewed 6 to 21 months after hospital discharge. They found that rates

of events with severe, marked, or moderate objective negative impact were
elevated in the four months before psychiatric hospital admission when compared
with post-discharge rates. Ambelas (47) found that 28% of manic patients
experienced a stressful life event in the four weeks preceding their hospitalization,
compared with only 6% of surgical control subjects. Joffe et al. (48), using the PERI-
M (42), found that subjects with mania had signiﬁcantly more unanticipated and
uncontrollable events as compared with bipolar patients in an episode-free period.
The most methodologically strong studies have used interview-based assess-
ments of life events. Using the LEDS interview-based method, Sclare and Creed (33)
found that 11 of 24 (44%) bipolar I patients experienced a severe event in the 26

weeks before onset, compared with 5 of 24 (21%) experiencing a severe event in
the 26 weeks after recovery. Beside its use of a well-validated method of life
event measurement, another strength of this study was its use of symptom onset
as the deﬁnition of a new episode. Because hospitalization often does not occur
until several weeks after the onset of symptoms (49), one cannot be sure if an
event precipitated onset or if it occurred as a result of the disorder when hospital-
ization is used as the onset date.
Two other interview-based studies also found an association between life
events and episode onset. Using a modiﬁed version of the LEDS, Bebbington et
al. (35) found higher rates of severe life events in the six months before onset
than in a comparable period among normal control subjects. In a prospective

design, Ellicott et al. (32) examined the impact of life stress on the course of
bipolar illness over a 2-year period, while controlling for medication compliance.
Using a LEDS-based method of life stress assessment of 61 bipolar I outpatients,
they found that patients with a high level of stress were at 4.53 times higher risk
of experiencing a new episode than patients experiencing no stress. Patients with
low and average levels of stress did not have a greater risk of relapse than those
without stress, indicating a threshold at which a patient becomes vulnerable to280 Kelly et al.

TABLE 2 Studies Finding a Signiﬁcant Relationship Between Life Events and Episode Onset
Study Sample Comparison groupLife events
measureLife events
time periodDeﬁnition of
episode onset
Ambelas (1979) 67 manic or hypomanic
inpatients60 surgical controls Chart review 1 mo Feighner criteria
for chart
review
Glassner
et al. (1979)25 bipolar I 25 community
controlsModiﬁed SRA 1 yr Feighner criteria
Glassner and
Haldipur (1983)46 bipolar patients None Modiﬁed SRA One time
interviewDSM-III
diagnosis
by 2
independent
psychiatrists
Kennedy et al.
(1983)20 manic patients Orthopedic
outpatientsRLE interview 4 mo Renard
diagnostic
interview
Bidzinska (1984) 50 bipolar I and II 47 unipolar
patients, 100
controlsLife event
questionnaire3 mo Not reported
Miklowitz
et al. (1988)23 bipolar I Relapsers vs.
nonrelapsersCFI-expressed
emotion9 mo PSE-DSM-III
Joffe et al. (1989) 14 bipolar I in- and
outpatientsEpisode-free
matched bipolar
patientsPERI-M 1 yr SADS-RDC
(Continued )Biology vs. Environment 281

TABLE 2 Studies Finding a Signiﬁcant Relationship Between Life Events and Episode Onset ( Continued )
Ellicot et al. (1990) 61 bipolar I
outpatientsNone RLE and
LEDS-based
interview3 mo DSM-III-R
Sclare and
Creed (1990)25 manic inpatients Within-subject
control periodsLEDS 6 mo PSE
Hunt et al. (1992) 62 bipolar I patients Within-subject
Bebbington
et al. (1993)31 manic patients Psychiatric and
non-psychiatric
controlsModiﬁed LEDS 6 mo DSM-III
Johnson
et al. (2000)43 bipolar I
inpatientsNone LEDS Monthly Increased BMRS
or HRSD
scores
Malkoff-Schwartz et
al. (2000)66 bipolar I 44 unipolar
depressedLEDS 1 yr SCID interview
Johnson et al.
(2000)43 bipolar I inpatients None LEDS Monthly Increased BMRS
or HRSD
scores

or HRSD
scores
or HRSD
scores
Abbreviations : CFI, Camberwell family interview (41); LEDS, life events and difﬁculties schedule (19); LES, life experiences survey (27); PERI-M, psychiatric re search interview
modiﬁed life events scale (42); RDC, research diagnostic criteria (43); SADS, schedule for affective disorders and schizophrenia (28); SLE, modiﬁe d recent life events questionnaire
(29); SRA, Homes-Rahe social readjustment scale (44); BRMS, Bech-Rafaelgen Mania Scale (45); HRSD, Hamilton rating scale for depression (45).282 Kelly et al.

the impact of threatening events. There were also no signiﬁcant differences between
the group that relapsed and the group that did not in terms of maintenance medi-
cation levels or medication compliance ratings. More recently, Cohen and
colleagues (50), using Hammen’s interview for episodic stress, found a relationship
between level of stress and relapse rates over a one-year period.
As evidence suggesting a relationship between stressful events and mood dis-
turbance in BD has accumulated, researchers have begun to turn their attention to
the potentially differential impact of differing types of stress on recurrence of
depressed versus manic symptoms as well as to interaction effects between life
stress and cognitive or personality styles. In terms of type of episode triggered,
Johnson and colleagues (51), using LEDS methods, found that events having to
do with goal attainment were associated with increased manic symptoms even

when baseline level of mania was statistically controlled. Malkoff-Schwartz and col-
leagues (52) reported that patients who became manic endorsed more severe life
events in the 20 weeks prior to a recent episode compared with depressed
bipolar patients. Similarly, Joffe et al. (48) showed that, although manic and non-
manic bipolar patients did not differ in terms of severity of events or total
number of stressful events experienced, patients with recent mania reported
more uncontrollable or unexpected events prior to the onset of mania. In contrast,
Reilly-Harrington et al. (53) did not ﬁnd a relationship between the number of
events reported by bipolar and unipolar patients in terms of depressive symptom
onset. Cohen et al. (50) found a marginal trend suggesting that life stress may

play a larger role in the onset of depression than mania.
Other research has turned its attention to the impact of interactions between
personality types or cognitive styles and stressful events on mood episodes among
bipolar patients. Reilly-Harrington and colleagues (53) showed that negative cogni-
tive style and the occurrence of life events interacted to predict depressive symp-
toms in both unipolar and bipolar patients. Further, Alloy and colleagues (54)
found that negative attributional style interacted with life events to predict dys-
phoria and that positive attributional style interacted with positive events to
predict hypomania among hypomanic or dysthymic undergraduates. However,
these results were only found at the second assessment and not at baseline or

third assessment, calling the robustness of these ﬁndings into question. Two
other studies have examined the impact of events that are congruent with sociotro-
pic or autonomous personality styles. Hammen et al. (55) found that events congru-
ent with sociotropic or autonomous personality type were related to episode type
for unipolar but not bipolar individuals. This lack of association for bipolar individ-
uals was repeated in a later study from the same group (56).
Another area of related research has examined levels of familial expressed
emotion (EE), which is often conceptualized as chronic interpersonal stress. For
example, Miklowitz et al. (31) studied levels of familial EE and psychiatric
relapse in 23 bipolar manic patients over nine months. Ratings of EE were based

on the amount of criticism, hostility, and emotional overinvolvement found in
the key relatives of patients. Manic or depressive relapse was 5.5 times more
likely in patients from high EE homes than those from low EE homes. Priebe
et al. (57) conducted a small study of EE in the key relatives of 21 patients with
bipolar and schizoaffective disorder who had been well established on lithium
therapy. Patients living with high EE relatives were found to be less stable, both
in the three-year period before and in the nine-month period after the initial assess-
ment. Similarly, Yan and colleagues (58) found that EE was marginally predictive ofBiology vs. Environment 283

depressive relapse ( p,.06) but not manic relapse among 47 medicated bipolar
patients. Interestingly, Miklowitz and colleagues (59) found that although severity
of criticism received from relatives was not associated with symptom outcome or
proportion of well days at one year, the degree to which the patient was upset by
criticism did predict symptom severity ( p,.02) as well as well days ( p,.003
when controlling for several other factors). However, this may speak more to the
impact of individual differences in interpersonal sensitivity rather than EE per se.
Regardless, high levels of familial EE (or patient negative reaction to EE)
can easily be viewed as a chronic interpersonal stressor, and these results provide
additional evidence suggestive of a signiﬁcant association between stress
and relapse.
STRESS AND RECOVERY FROM AN EPISODE
Based on the assumption that “reactive” episodes may be more responsive to treat-

ment than “endogenous” episodes, several studies have set out to examine the con-
nections between stress and recovery from affective episodes. In unipolar
depressed patients, the ﬁndings have been mixed. Some studies reported that life
stress occurring before treatment entry predicted a positive treatment response
(60), whereas others found the opposite (61,62) or found no association at all (63).
Unfortunately, only two studies to date have looked at stress and recovery from
bipolar episodes. Johnson and Miller (64) found that bipolar I patients who experi-
enced at least one severe negative life event during an episode took more than three
times as long to achieve recovery as those without severe life events. However, a
study by Hlastala and colleagues (65) did not replicate these results. In that

sample of 96 bipolar I patients, the occurrence of acute and chronic stressors occur-
ring during treatment was not signiﬁcantly related to time to recovery from manic,
depressed, or mixed /cycling episodes. Several differences between the studies may
have contributed to these discrepant ﬁndings. Primary among these differences is
that patients in the Hlastala et al. study (65) were participating in a randomized
controlled study with strictly deﬁned treatment protocols. In contrast, the
Johnson and Miller study (64) was a naturalistic one with variable types, quantity,
and quality of treatments. Therefore, in the Hlastala et al. study, it is possible that
the “ceiling” effect of standardized treatment attenuated the impact of life events
on time to remission. Obviously, more research needs to focus on the relationship

between life stress and such important long-term course parameters as recovery
and treatment response.
SUMMARY
Although the methodological inconsistencies of the previous research make it
difﬁcult to draw any strong conclusions, stressful life events appear to operate as
contributing factors in a signiﬁcant number of patients with BD. Most previous
studies have shown evidence for this relationship, whereas the few studies that
were unable to conﬁrm the relationship were laden with methodological problems.
Many researchers who failed to ﬁnd a relationship between life events and episode
onset, in fact, concluded that the null ﬁndings may reﬂect the possibility that life
stress only plays a role in precipitating episodes early in the course of illness, as

Post (46) has suggested (see subsequently and Chapter 16 of this volume).284 Kelly et al.

BIPOLAR DISORDER-SPECIFIC MECHANISMS OF THE
STRESS-EPISODE RELATIONSHIP
Kindling and Behavioral Sensitization
According to the kindling /behavioral sensitization model of recurrent affective dis-
orders (46,66), the ﬁrst episodes of BD are more likely to be associated with major
psychosocial stressors than are episodes occurring later in the course of the illness.
The kindling model relies on two principles of neuropsychological research: elec-
trophysiological kindling (progressive vulnerability to seizures) and behavioral
sensitization (progressive change in psychomotor stimulant response). Research
on the development of amygdala-kindled seizures in response to electrical stimu-
lation has shown that after a sufﬁcient number of electrically induced seizures,
spontaneous epilepsy will occur, even in the absence of electrical triggers. When
used to understand recurrent affective disorders, the model is a nonhomologous

paradigm that hypothesizes that “exogenous” stress (i.e., a precipitating “stimu-
lant”) will be less likely to be associated with the onset of new episodes as the dis-
order progresses, resulting in spontaneous episodes and /or rapid cycling. In other
words, this model implies that bipolar patients become so sensitized to stress, as a
consequence of experiencing multiple episodes, that they eventually require only
the slightest stimulus to precipitate relapse.
Post (46) has described two types of sensitization: stressor sensitization and
episode sensitization. Episode sensitization is the phenomenon of increased sever-
ity, increased symptom proﬁle, and decreased time between episodes over the
course of the disorder. Some research has shown that cycle length tends to

shorten with each recurrence (67). However, this phenomenon is not found in all
bipolar patients. Roy-Byrne et al. (68) noted after following 50 bipolar patients
for over ﬁve years that approximately 52% showed a sensitization pattern of pro-
gressively shorter intervals during the course of the illness, whereas 48% showed
no particular pattern with longer intervals randomly distributed throughout the
course of the illness. Additionally, in those patients who experience a rapid-
cycling pattern, most return to non–rapid-cycling episode patterns within a
three-year period (69).
Stressor sensitization is said to occur when the provocation of new episodes,
later in the course of the illness, requires lower and lower levels of stress. The role of
psychosocial stressors in the initial onset of affective disorders was noted by early

descriptive psychopathologists. Kraepelin (70) stated that new episodes of manic-
depressive illness “begin not infrequently after the illness or death of a relative,”
but stress should not be viewed as necessary for the onset of recurrent episodes
because they may be “to an astonishing degree independent of external inﬂuences.”
Additionally, Stern (71) postulated that subsequent episodes, following the acti-
vation of the “manic mechanism,” require less in the way of stress.
Post (46), in his review of the evidence for the kindling model, based his con-
clusions primarily on studies examining recurrent unipolar depression. Only six
studies have looked at the possibility of differential effects of stress as a function
of the number of episodes experienced in bipolar I patients. Of those six studies,

three lend support to the model, whereas three do not. Dunner et al. (72) examined
the occurrence of stressful life events before the initial and subsequent episodes in
79 bipolar I patients. Fifty percent reported an event before the ﬁrst episode,
whereas only 15% reported an event preceding subsequent episodes. Ambelas
(73) also found a signiﬁcant difference in life event rates among bipolar patients
with one episode versus those with repeated episodes. Sixty-six percent of patientsBiology vs. Environment 285

in their ﬁrst episode of mania experienced a stressful event in the four weeks pre-
ceding onset, whereas only 50% of individuals in repeat admissions appeared to
have experienced an event.
Similarly, Glassner et al. (74) found a stronger association between stressful life
events and onset in the ﬁrst episode compared with subsequent episodes in 25
bipolar I patients. Seventy-ﬁve percent reported experiencing a life event in the
year before their ﬁrst episode, whereas 56% reported experiencing a life event in
the year before their most recent episode. However, after increasing their sample
size, they did not ﬁnd the same pattern (24). The rates of stressful life events in
bipolar patients who were classiﬁed as having either an early ( /C2020 years old) or
late onset were similar in the year before their ﬁrst episode or latest episode.
Swendsen et al. (75) used a LEDS-based methodology to examine the occur-

rence of stressful life events in 45 bipolar I patients for one year after achieving clini-
cal remission or their best clinical state. They found that patients who experienced
moderate to severe levels of stress were signiﬁcantly more likely to experience a
recurrence than patients who experienced no or minimal stress, regardless of
how many previous episodes they had experienced. High stress was also a signiﬁ-
cant predictor of recurrence among those with 12 or greater previous episodes. The
author concluded that these results, obtained using a more rigorous measure of life
stress than previous studies, are inconsistent with the kindling model.
In a more direct test of the kindling model, Hammen and Gitlin (76) followed
52 bipolar I patients for two years, while interviewing every three months for major

life events using a LEDS-based methodology. Over the two-year follow-up period,
36 patients experienced either a relapse or recurrence. The relapse /recurrence
group was more likely than the episode-free group to have experienced a severe
life event within the six months before the relapse /recurrence. Forty percent of
the subjects with eight or less previous episodes experienced a major life event in
the six months preceding relapse /recurrence, whereas an even greater proportion
(76%) of those subjects with nine or more previous episodes experienced a major
life event in the six months preceding relapse /recurrence. Interestingly, backward
survival analyses revealed that those with nine or more episodes relapsed more
rapidly after a major event than the group with fewer episodes. These results

seem to provide contradictory evidence when applied to the kindling model.
They suggest that patients with more episodes may be more reactive to stress
because they relapsed more quickly after a life event, which supports a model of
stressor sensitization. However, the data also suggest that patients with a greater
number of episodes may still need high levels of stress preceding onset, which con-
tradicts what has traditionally been viewed as support for the kindling model.
Our own work testing Post’s hypotheses (77) has not demonstrated compel-
ling evidence in support of the kindling model. Sixty-four bipolar I patients, who
were participants in the Pittsburgh Study of Maintenance Therapies in Bipolar Dis-
order, were interviewed about a year before onset of their index episode. The

Bedford College LEDS (19) was used to determine severe events (events with
threat level rated as the highest two points on a four-point scale) and nonsevere
events (events with threat level rated as the lowest two points on a four-point
scale) occurring during the three months before episode onset and during a three
month episode-free control period. Based on these ratings, each patient was cate-
gorized as having experienced either “high,” “moderate,” or “low” stress during
the three month observation periods. Cumulative logit analyses were used to
examine the relationship between number of previous episodes and the type of286 Kelly et al.

stress (i.e., high, moderate, and low) experienced in both the preonset and control
period. The analyses did not support the hypotheses that the number of episodes
experienced would predict stress level in the preonset and control periods.
However, age was found to be a signiﬁcant predictor of stress level in the preonset
period ( p¼0.03), with older subjects evidencing lower levels of stress before
episode onset than younger subjects. These results suggest that a more complex
relationship may exist among age, stress, and onset of new episodes than can be
adequately explained by the kindling model. Additionally, previous research sup-
porting a “kindling” process in bipolar patients may be an artifact of ignoring the
effects of age when examining a longitudinal process.
Summary
Although Post’s model has been accepted by many researchers and clinicians, the
evidence for kindling /behavioral sensitization in bipolar patients is equivocal at

Summary
best. The studies that appear to support the model have extensive methodological
weaknesses, including reliance on chart review (73) and self-report checklist ques-
tionnaires of stressful life events (72). Additionally, one study (74) expected the sub-
jects to recall as far back as 10 years or more to obtain information on life events
preceding their ﬁrst episodes. Although the studies that are inconsistent with the
kindling model (75–77) are methodologically stronger (i.e., interview- based
LEDS methodology and prospective design), further research is needed before
any strong conclusions can be made.
Finally, Post’s kindling model is a very difﬁcult model to test adequately
because of its internal inconsistencies. Implicit in this model are two distinct

phenomena that are tied together—kindling and sensitization. The kindling
aspect of the model presupposes that the illness becomes autonomous after experi-
encing a certain number of episodes and stressors. The sensitization aspect of the
model is inherently different, however. Implicit in a sensitization model is that
patients with recurrent affective disorder become increasingly sensitized to stress
as a function of how many affective episodes they have experienced. Thus, very
minor amounts of stress should play an increasingly greater role in the onset of
new episodes.
This inconsistency has led to multiple interpretations of past research, such
that depending on how the data are approached, the kindling /sensitization

models (which are really two distinct although conceptually linked models) may
or may not be “supported.” For example, Hammen and Gitlin (76), as described
previously, found that patients with a greater number of episodes relapsed more
quickly than patients with fewer episodes after a stressful life event. They con-
cluded that the data do not support the kindling model because these patients
did not have “autonomous” episodes (i.e., stress had an even greater effect on
episode onset among those who had experienced many episodes). However,
another conclusion from this data could be that those patients with more episodes
were “sensitized” to stress, thus they relapsed more quickly after a stressful event.
Although Post (46) concedes that “the processes involved in sensitization may be

more directly analogous to those occurring in the affective disorders because of
the behavioral rather than convulsive endpoints observed” (p.1001), the model con-
tinues to be interpreted in various ways by researchers and clinicians. For an excel-
lent review of these issues as they pertain to depression, see Monroe and Harkness’
2005 review (78).Biology vs. Environment 287

STRESS, HPA AXIS DYSFUNCTION, AND BIPOLAR EPISODES
A large body of research has shown a strong relationship between stress
and increased hypothalamic-pituitary-adrenal (HPA) axis activity. Elevations of
epinephrine, norepinephrine, and cortisol have repeatedly been found among
persons experiencing chronic and acutely stressful events (79). Thus, early studies
demonstrating elevated cortisol levels in depressed patients were generally
regarded as a normal adaptational response to a stressed state (i.e., depression)
(80). However, some investigators viewed such elevations as being the result of an
abnormality in the HPA system (81).
Extensive research on unipolar depressed patients partially supports this
hypothesis. Elevated levels of glucocorticoids in cerebrospinal ﬂuid, plasma,
saliva, and /or urine, which is commonly used as evidence for HPA axis dysfunc-
tion, have been found in more than one half of hospitalized depressed patients

(82,83). In addition, a large proportion of depressed patients show evidence of
impaired HPA feedback inhibition (84,85) and abnormal circadian regulation of
the HPA axis (86,87).
Unfortunately, the ﬁndings on the relationship between HPA axis dysfunction
and bipolar episodes are not as clear. In general, the previous research has found
more evidence for increased HPA activity in bipolar depression than in mania.
Some studies have found normal HPA activity in patients experiencing pure
manic episodes (88–90), although some studies have not (84,91). Some work has
shown that DST response is more exaggerated in bipolar depression than in uni-
polar depression, even when in recovery from a major depressive episode (92). In
a critical review of the literature on dexamethasone suppression test (DST) in

bipolar episodes, Goodwin and Jamison (67) concluded that DST nonsuppression
occurs more frequently in the depressive and mixed phases than pure manic
phases of the illness. One interesting study (93) found that among three rapid-
cycling patients, DST results were abnormal in and before depressed episodes
but normal during manic episodes. However, contradictory evidence can be
found in the work of Cervantes and colleagues (94). In their small sample of
patients with bipolar I disorder, abnormal cortisol levels were found among
patients in both depressed ( n¼5) and manic ( n¼5) states. Many studies agree
that HPA abnormality usually resolves itself after recovery from an episode
(95,96), indicating that DST nonsuppression is a state marker rather than an under-

lying biological abnormality. However, not all studies reach the same conclusion.
For example, Cervantes et al. (94) found elevated cortisol levels among even euthy-
mic bipolar patients ( n¼8) when compared with non-psychiatric controls.
There has been some evidence that HPA dysregulation may have utility in
predicting episode onset. Goodyer et al. (97) found that HPA abnormality prospec-
tively predicted the occurrence of major depressive episodes among adolescents at
high risk for depression. Further, Vieta and colleagues (98) found evidence that
remitted bipolar patients with elevated corticotrophin levels had higher incidents
of mania during the subsequent six months. One possibility is that HPA dysfunc-
tion is caused by acute or chronic stress in vulnerable individuals, promoting

mood episodes. Ellenbogen et al. (99) found that the non-disordered children of
bipolar parents showed abnormally elevated cortisol levels across the day. They
suggest that prolonged exposure to stress (due to the difﬁculties associated with
living with a psychiatrically ill parent) may have promoted HPA changes in
these children. Brown and colleagues further suggest that prolonged exposure to288 Kelly et al.

elevated cortisol levels may alter the structure of the hippocampus, both promoting
mild cognitive abnormalities and increasing vulnerability to stress (100). They
suggest that this feedback loop may be promoted by initial mood episodes and
may facilitate future episodes.
In addition to a more biological mechanism, hypercortisolemia as a result of
HPA axis dysfunction may play a role in the onset of bipolar episodes through its
ability to affect sleep rhythms. It has been well established that most patients
experiencing an episode of either mania or depression display speciﬁc disturbances
in their biological rhythms (101,102), particularly in their sleep-wake cycle
(101,103). Corticosteroids have an ability to disrupt sleep by causing increased
awakenings and decreased slow wave sleep (104). Thus, a person may experience
one or more “sleepness nights” not only because of the psychological sequelae, but
because of the hormonal effects of acute or chronic stress resulting in a bipolar

episode. This sleep disruption mechanism parallels another hypothesized
pathway to the onset of manic and depressive episodes in bipolar patients—
social rhythm disruption (105,106).
SOCIAL RHYTHM DISRUPTION AND BIPOLAR EPISODES
Another promising area of research connecting environmental stressors to the onset
of new episodes has been through their ability to disrupt social and circadian
rhythms (105,106). Goodwin and Jamison (67) have integrated large volumes of
research on the pathophysiology of bipolar episodes, postulating that “instability
is the fundamental dysfunction in manic depressive illness” (p.594). One particu-
larly salient contributor to this instability may be a disruption in a patient’s social
routines. The social zeitgeber and biological rhythm theory (105,106) articulates

this pathway, which is both biological and behavioral in nature, through which
life events may precipitate and /or exacerbate affective episodes.
This theory suggests that stressful life events can often act as “social agents of
circadian disruption” by causing alterations in social routines that ordinarily act to
synchronize circadian rhythms, leading to the onset of affective episodes in vulner-
able persons. For example, when an individual loses a typical “nine to ﬁve” job, he
or she may not only experience certain psychological aspects of this loss but also
lose a signiﬁcant social zeitgeber (i.e., social cues and demands that act to entrain
the biological clock.). Most likely that person will alter his or her regular sleeping
times, meal times, and times of activity and rest. Such disruptions in social routines

could act to disrupt circadian rhythms that have been implicated in the pathogen-
esis of both depression and mania (102,107–110).
To date, only one study has directly examined the role of social rhythm dis-
ruption (SRD) in the onset of depressive and manic episodes in bipolar I patients.
Our research group (111) rated life event descriptions obtained using LEDS (20)
for degree of SRD during eight-week preonset and control periods. Life events
that were classiﬁed as disrupting social routines (i.e., “SRD events”) were associ-
ated with the onset of manic, but not depressive, episodes. Because social rhythm
disruption may have more gradual effects on depressive compared with manic
onsets, the eight-week preonset window may have been of insufﬁcient duration

to observe an association between SRD events and bipolar depressive episodes.
Alternatively, SRD events may be important in the onset of manic but not depress-
ive episodes.Biology vs. Environment 289

Further evidence of the relationship between social rhythm disruption and
bipolar episodes comes from a treatment outcome study conducted in our clinic
(112). This study compared Interpersonal and Social Rhythm Therapy (IPSRT)
with intensive clinical management (ICM) for bipolar I disorder. The IPSRT treat-
ment emphasized increased schedule regularity (in addition to psychotherapy
and medication management) as one component of the treatment while the ICM
arm consisted of education about BD, sleep hygiene, non-speciﬁc support, and
medication management. Results indicated that participants who received IPSRT
in the active phase of treatment had longer survival time before a bipolar recurrence
and were less likely to have a recurrence in the two year maintenance phase.
Further, increased social rhythm regularity during the acute treatment phase was
associated with reduced odds of recurrence in the maintenance phase. This work

provides empirical support for the theory that social rhythms play an important
role in the course of BD.
External stressors appear to play a substantial role in the course of BD. Stressful life
events appear to inﬂuence not only the timing of initial and recurrent episodes but
also the recovery from what is often a difﬁcult, even excruciating, struggle to
recover from such episodes. Further elucidation of the mechanisms through
which stress may affect bipolar episodes is clearly needed. Unfortunately, not
enough is known about exactly how stress might precipitate bipolar episodes. Bio-
logical mechanisms, such as neuroendocrine abnormalities, and behavioral mech-
anisms, such as SRD, appear to yield interesting ﬁndings. Researchers and

clinicians alike would beneﬁt greatly from a better understanding of different bio-
logical, behavioral, and psychological pathways that relate external stressors to the
onset and maintenance of affective episodes.
Beside the speciﬁc mediators of stress that were discussed earlier, moderators
of the stress-episode relationship need to be examined. For example, in our own
work, it remains to be seen whether increasing the regularity of daily routines med-
iates the SRD–onset relationship. Analysis of this relationship will be undertaken
shortly. Other psychosocial variables such as personality factors, social support,
and self-esteem may play a large role in how a patient with BD reacts to both
chronic and acute stressors. Research on unipolar depressed patients suggests

that life stress may have more potent effects if it is related to a patient’s particular
personality or cognitive vulnerabilities (113,114). However, this area of research has
not received strong support in the literature so far. Although Hammen et al. (56)
were able to ﬁnd support for this phenomenon in unipolar depressed patients,
they did not in bipolar patients (55). Interestingly, events that were rated as inter-
personal in nature predicted higher symptom severity scores in all patients, regard-
less of their personality type. Perhaps bipolar patients are especially vulnerable to
problems that arise in the context of their relationships with others.
The effects of patient-generated stressors are also commonly ignored. It is
likely that patients with bipolar illness tend to generate moderately stressful

events as a result of their illness and that these events in turn serve to delay or
prevent remission or to provoke new symptomatic exacerbations. This idea is
similar to that proposed by Hammen (115), who concluded that women with290 Kelly et al.

recurrent unipolar depression tend to generate stressful conditions by their
symptoms, behaviors, characteristics, and the social context in which they ﬁnd
themselves. Both interpersonal and practical (e.g., lack of employment, housing,
etc.) problems that occur as a consequence of a manic or depressive episode
could contribute to a chronic or worsening course of illness over the long term.
Further emphasis on the role of stressors in the pathophysiology of BD is a
promising way to integrate biological and psychosocial perspectives on the
etiology and long-term course of BD. We must keep in mind that even the most
“biologically based” illnesses exist in a psychosocial context; thus, a more complete
understanding of psychosocial inﬂuences could provide useful information for the
treatment and prevention of future episodes in patients suffering from this often-
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B16 The Kindling /Sensitization Model:
Implications for the Pathophysiology
of Bipolar Disorder
Mood and Anxiety Disorders Program, National Institute of Mental Health,
Department of Health and Human Services, National Institutes of Health, Bethesda,
HISTORICAL OVERVIEW
It is remarkable that almost one hundred years ago Dr. Emil Kraepelin (1) described
the essential process of affective illness progression, based on his careful charting of
episodes of affective illness and the potential precipitating circumstances with
which they were associated. While he spoke of the inherent variability of the
illness course both within and between subjects, he noted an overall tendency for
the illness to increase in frequency over time, with a decreasing duration of well
intervals between successive episodes. At the same time, he noted that the ﬁrst epi-
sodes of mania or depression were often precipitated by psychosocial stressors, but

that with the appearance of enough episodes, they would begin to recur in a highly
similar form “quite without external occasion” (p. 181) (1). Thus, he captured the
ideas of both increasing automaticity and vulnerability to recurrence as a function
of number of prior episodes. He attributed this progression to inherent genetic
mechanisms interacting with recurrences of stressors and episodes themselves.
In dissecting the inherent course of bipolar illness and its response to
treatment, a careful Kraepelinian-like graphic depiction of episodes appeared fun-
damental to further understanding pathophysiology and treatment responsivity.
The new system, termed the National Institute of Mental Health—Life Chart Meth-
odology (NIMH-LCMTM) increased the detail of Kraepelin’s schema for document-

ing manic and depressive episodes (2–4). It also allowed for different levels of
manic and depressive episode severity (from mild to low and high moderate to
severe) based on the degree of dysfunction with which the manic and depressive
symptoms were associated. A self-rated version of the NIMH-LCM is also available
and includes a rating of mood from 0 to 100, with zero representing “most
depressed ever,” 50 representing “balanced or euthymic,” and anything over 50
toward 100 would be “activated, energized, or more speeded up than usual.”
On the patient’s rating form, not only was this subjective mood assessment
included, but number of hours of sleep, positive and negative life events and stres-
sors, side effects, and comorbid symptoms could also be entered on a daily basis.

These ratings and the severity of mania and depression are charted retrospectively
on a monthly basis along with the medications the patient may or may not have
taken, and prospectively on a daily basis including dose and numbers of pills taken.
In this way, the prior course of illness could be delineated in a retrospective
fashion and continued to be monitored in much greater detail prospectively in
order to assess eventual treatment response. A series of speciﬁc techniques were
297

used for enhancing recall from patients, family members, and previous physicians,
and hospital notes and records were examined to maximize the accuracy of the deli-
neation of the prior illness course. The prospective LCM form has been validated
against more conventional cross-sectional elements and, in addition, has inherent
face validity and the beneﬁt of a continuous rating system, not one that is intermit-
tently measured with the potential liability of missing major ﬂuctuations in mood
and behavior in the interval (5–7).
Using retrospective life chart data, we delineated the overall Kraepelinian
tendency for illness progression in our select group of treatment-refractory
unipolar and bipolar affectively-ill patients. There was also a small subgroup
who cycled very rapidly even from the onset of their illness. Examining the
course in those not responding adequately to treatment is a critical point to be

emphasized. It is more likely to mirror the Kraepelinian delineation of the course
of illness prior to the advent of major psychopharmacological interventions. It is
also an area subject to a great deal of misinterpretation, as some critics have
suggested that somehow the sensitization /kindling models employed to conceptu-
alize mechanisms underlying illness progression mean that this process is invari-
ably relentless and not subject to treatment intervention. On the contrary, episode
recurrence, cycle acceleration, and illness progression can most often be interrupted
with adequate treatment. However, intervention later rather than earlier in the
course of illness may be associated with greater difﬁculty in achieving remission
and require more complex treatment regimens (8).
Stress and Episode Sensitization: Homologous Models

for Affective Illness Prognosis
The fundamentals of the kindling and sensitization model and the predictions
derived from them have been spelled out in detail with appropriate supporting refer-
ences (9–15). Brieﬂy, the sensitization component of the model derives from obser-
vations that animals exposed to repeated doses of psychomotor stimulants, in the
same behavioral context, show increasing motor activity and stereotypic disorganiz-
ation to the same dose over time. The psychomotor stimulants in their early phase of
use in humans are excellent models for hypomania and mania, and later in the course
of use are associated with dysphoric mania and paranoid psychosis. Thus, the sen-
sitization model in animals provides potential mechanisms for considering how

recurrent manic episodes could increase severity and invulnerability to recurrence.
In addition, a second component to the sensitization model is important
in relationship to predictive validity. Stimulant-induced behavioral sensitization
shows cross-reactivity to a variety of stressors (16–18). Following the elucidation
of the cross-sensitization between stimulants and stressors, stress-sensitization
paradigms began to be studied in their own right. Depending on the quality,
intermittency, intensity, and phase of development, initial stressors could lead to
long-term increases in reactivity to subsequent stressors.
These preclinical data support evidence for long-lasting modiﬁcation of reac-
tivity in adults from early life experiences in newborns and infants (19,20). There is

also evidence for cross-reactivity between stressors and subsequent adoption of
cocaine self-administration habits (Table 1) (21–26), indicating that in some
instances there are bi-directional cross sensitivities between stressors and stimu-
lants. These data are particularly noteworthy from the perspective that there is a298 Post

markedly increased incidence of substance abuse in those with recurrent unipolar
and bipolar affective disorders compared with the general population (27,28).
Kindling as a Nonhomologous Model for Illness Progression
The kindling paradigm provides another, altogether different, model for under-
standing increased physiological and behavioral reactivity to repeated stimulation
of the brain. The most commonly studied type is amygdala kindling, where animals
are stimulated electrically once a day for one second at intensities below the
threshold for afterdischarges (ADs) (29). The repeated stimulation both lowers
the AD threshold, and the ADs emerge with increasing duration and complexity
in the amygdala, and subsequently spread throughout the brain. This AD spread
is associated with progressive increases in the severity of behavioral response
from stage 1 (behavior immobility with whisker twitching) to stage 3 (unilateral

forepaw convulsions) to generalized stage 5 (bilateral forepaw convulsions with
rearing and falling) (30,31). There is also a parallel spatiotemporal induction of neu-
rotrophic factors, immediate early genes, and late effector genes that likely mediate
both the primary long-lasting kindled “memory trace” and short-lived endogenous
anticonvulsant adaptations (32). The relative balance of these primary pathological
versus secondary adaptive changes in gene expression could explain the intermit-
tent emergence (or not) of seizures and affective episodes.
Goddard et al. (29), who ﬁrst described the kindling phenomenon, considered
it an interesting model for neuronal learning and memory because the effects
appeared to be long-lasting, if not permanent. Intermittent stimulation was import-

ant, because animals stimulated continuously or once every ﬁve minutes never
kindled, whereas more periodic stimulation, optimally at once every 24 hours,
led to kindling progression (29).TABLE 1 Relationship of Early and Concurrent Stressors to Acquisition, Maintenance, and
Reinstatement of Cocaine Self Administration (in Rodents)
Stressor Age Cocaine effect Authors
Social stress Adult Acquisition of cocaine
self-administrationHaney et al., 1995 (21)
Uncontrollable foot-
shockAdult Cocaine self-
administration (only if
corticosteroids
elevated)Goeders and Guerin,
1994 (22)
Social defeat /C24
(sensitization to
stress)Adult Cocaine amount (binge
size) Motor response
to stimulants (i.e.,
cross-sensitization)Covington and Miczek,
2001 (23)
Stressors or cocaine
cuesAdult Cocaine lever pressing
Reinstatement of
extinguished

2001 (23)
responseGoeders and Clampitt,
2002 (24)
Three hour maternal
deprivation stress
X 7 (neonate)Stress (neonate)
drug intake
(adult)Alcohol and cocaine self
(reversal with
treatment)Huot et al., 2001 (25);
Meaney et al., 2002
(26)The Kindling /Sensitization Model 299

If fully kindled animals are stimulated repeatedly, many will go on to have
spontaneous seizures, that is, identical appearing stage 4 and 5 behavioral convul-
sions to those observed before, but now occurring without amygdala stimulation or
even prior to the animal’s being picked up or handled. Although there is some hom-
ology of affective disorder behaviors and inducing factors in the preclinical models
of stress and psychomotor stimulant sensitization noted above, there is obviously
no behavioral homology in the kindling paradigm where seizures (as opposed to
affective episodes) are the endpoints of interest (33).
Nonetheless, the kindling paradigm is pertinent not only for considering
increased reactivity to the same stimulation over time, but also how this process
progresses and emerges into a new phenomenon of spontaneity or automaticity in
which seizures occur in the absence of the inducing stimuli. Understanding how

animals progress from triggered amygdala-kindled seizures to spontaneous ones
may give hints to similar transitions occurring in the affective disorders, especially
since initial episodes are often triggered by psychosocial stressors and later epi-
sodes can occur more spontaneously (10,14). However, a caveat is that the precise
neuroanatomical and neurotransmitter systems underlying seizure progression
are likely quite different from those underlying affective episode progression.
EVIDENCE FROM ANIMAL STUDIES
The potential mechanisms underlying behavioral sensitization to psychomotor
stimulants and amygdala-kindling seizure evolution are reviewed elsewhere
(34–42). Here we focus on selected newer data from animal studies which are par-
ticularly revealing, and potentially relevant to the clinical observations of long-

lasting increased vulnerability to stressors and the precipitation of pathological
affective behaviors.
Persisting Effects of Stress on Neurobiology and Behavior
One paradigm well-studied by Levine et al. (43,44) involves separation of rat pups
from their mothers for a period of 24 hours (while body temperature is maintained).
This results in a long-lasting increase in cortisol secretion and anxiety-like beha-
viors into adulthood. New data suggest that this one-day stressor is associated
with increases in preprogrammed cell death (apoptosis) (45) and in decreases in
brain-derived neurotrophic factor (BDNF) (45,46) and calcium calmodulin kinase-
II (CaMK-II) (47). These latter two changes are of considerable interest in relation
to the critical roles of BDNF and CaMK-II in long-term learning and memory.

Animal strains where either of these substances is knocked out fail to remember
how to navigate a previously learned water maze and show deﬁcits in long-term
potentiation (LTP) (48–50).
Animals subjected to repeated neonatal separation stress show long-lasting
decrements in not only hippocampal BDNF (51), but also BDNF in prefrontal
cortex (52). Again, these ﬁndings are particularly noteworthy, in that decrements
in plasma and brain BDNF have been noted in some studies of patients with affec-
tive disorders and in brain autopsy specimens (especially when these subjects were
not treated with antidepressants) (53–57). Decrements in prefrontal cortical CaMK-
II have also been observed selectively in BD, but not in patients with schizophrenia
or controls (58).300 Post

Interestingly, repeated stressors in neonatal rodents lead to deﬁcits in hippo-
campal volume and associative learning. In contrast, the amygdala increases in
size compared with litter-mate controls and is associated with increased anxiety-
like emotional hyper-reactivity (53,54). The elegant studies of Plotsky and Meany
deserve special focus because of their potential relevance to long-lasting changes
in neurochemistry, endocrinology, and behavior based on early life experience in
the rodent. Neonatal rat pups subjected to ten days of 15-minute periods of maternal
separation not only show few adverse consequences, but have increased hippocam-
pal volume and preserved learning and memory performance into old age.
In contrast, those neonatal rat pups subjected to repeated maternal separations
for three hours (rather than 15 minutes) show lifelong increases in the rat equivalent
of human cortisol (corticosterone) and in anxiety-like behaviors (59–62). These

stressors have now been associated with increased levels of corticotropin-releasing
hormone (CRH) both in hypothalamus and amygdala (59). These and related
studies indicate that depending on the quality, duration, and timing of early stres-
sors, the central nervous system (CNS) can have a lifelong change in its set point
for peptide, endocrine, and anxiety-related behaviors.
Interestingly, the mechanisms underlying these long-term changes greatly
depend on reactions in the infant /mother dyad. In the 15-minute separation para-
digm, the rat pup upon reunion is greeted with increased licking and grooming.
In contrast, in the three-hour separation paradigm, the frantic mother rodent no
longer recognizes the returned rat pup as her own and in her agitation ignores and

sometimes even tramples over the returned pup. If a substitute rat pup is put in
the litter during the separation period (i.e., the mother is not aware that one of her
pups is missing), she remains calm and the rat pup returning from the three-hour
separation is dealt with normally and never develops the hypercorticosteronemia
or anxiety-related behaviors.
Naturally occurring high-licking maternal behavior is associated with
offspring who are low in anxiety and corticosterone. Conversely, low-licking
mothers tend to have high anxious, high corticosterone offspring. This apparently
familial trait is not genetic because cross-fostering studies indicate that, again, it is
maternal behavior and not genetic inheritance that drives these long-lasting
changes. Moreover, if a rat pup born of a low-licking mother is fostered by a

high-licking mother and that pup has offspring as an adult, those pups retain the
high-licking, low-anxiety and low-corticosterone signature, indicating that there
can be transgenerational transmission of what may have previously been considered
a genetic trait (63).
More recent studies of Meaney et al. have implicated changes in DNA methyl-
ation in such transgenerational cross-fostering experiences (64). Moreover, the
elegant studies of Insel and associates have also revealed that many traits in
animals are based on either: ( i) in utero environmental experiences, or ( ii) those
occurring in early infancy, or both. These data were gleaned from pregnant
females who were cross-implanted or rat pups who were cross-fostered, or both (65).
We cite these studies in the current context to emphasize the environmentally-

based malleability to many different types of behavior and endocrine reactivity
that may have previously been thought to be transmitted on a genetic basis. In
parallel, these studies offer alternative insights for considering how pathological
changes in neurochemistry may occur in patients with BD, not only on the basis
of well-documented genetic vulnerability, but likely through environmental-
experiential routes as well.The Kindling /Sensitization Model 301

Bi-Directional Cross Sensitization Between Stressors
and Substances of Abuse
The stressor models noted previously show that maternal stress predisposes
animals to the adoption of substance self-administration (25,26), which is particu-
larly pertinent to the recurrent affective disorders. Patients with BD are at markedly
increased risk for the adoption of alcohol and substance abuse problems. Not only
is manic behavior associated with greater degrees of indiscretion and poor judg-
ment (66), but the stress and episode sensitization mechanisms occurring concur-
rently with the affective episodes themselves may yield increased vulnerability to
the adoption of substance abuse.
Obviously, the cooccurrence of two chronic, difﬁcult-to-treat illnesses (BD and
a substance abuse disorder) could markedly complicate treatment and overall
illness outcome (67). This result would also be consistent with the neurochemistry
data indicating that many of the changes in gene expression induced by chronic

stimulant administration appear to mirror (and potentially exacerbate) some of
the underlying pathophysiological processes occurring in BD (Fig. 1) (58,68–94).
However, this convergence and overlap of potential pathophysiological
mechanisms raises the possibility of treatment simpliﬁcation and a double
improvement effect from a single treatment intervention. This clinically optimistic
perspective so far is not in line with the available data indicating that those with
comorbid substance abuse have a more difﬁcult course of bipolar illness than
those without (95,96). Moreover, recent analyses indicate that even those with a
prior history of alcohol abuse (and not current problems) continue to have a
more difﬁcult course of BD than those without such a prior history of such difﬁcul-

ties (97). In support of the therapeutic viewpoint, however, are the data that many
patients who experience treatment-related stabilization of their bipolar illness are
able to abstain from alcohol and substance abuse (98). Moreover, a number of
FIGURE 1 Convergence of structural, biochemical, and functional abnormalities in bipolar illness.302 Post

medications have been found in controlled studies to be useful in primary
substance abuse problems, whether or not these agents are also mood stabilizers
(99,100).
EVIDENCE FROM THE COURSE OF ILLNESS AND
NEUROIMAGING STUDIES
The data of Kessing et al. (101) based on the Danish case registry, and the more
recent replication of this data in Switzerland (102), provide very strong evidence
for the episode sensitization phenomenon. These investigators ﬁnd that the best
predictor of increased incidence and shorter latency to a relapse is the number of
prior hospitalizations. It is also important and potentially disturbing to note that
this relapse occurred despite naturalistic treatment in the community, and one
looks forward to assessing whether optimal prophylactic intervention would
have prevented this general pattern in those who received it.
The stress sensitization component of recurrent affective disorders is most ele-

gantly dissected in the twin studies of Kendler et al. (103,104) in recurrent unipolar
depression. These investigators found that stressors were more likely to occur in
close relationship to the precipitation of the initial nine episodes of depression,
but became less relevant thereafter. They also examined how this sensitization /
kindling phenomenon interacted with genetic vulnerability. They noted that
those with higher risks related to the presence of a strong family history of affective
illness appeared to be prekindled, that is, those patients were found to have lesser
degrees of stress at the onset of even their initial episodes compared with those
without this genetic familial vulnerability.
These data are the precursors to elegant studies of environmental /genetic

interactions based on the delineation of common variants in single nucleotide poly-
morphisms (SNPs) that may be associated with illness onset or treatment response.
The data of Caspi et al. (105) provide a remarkable demonstration of such an inter-
action. They examined a large group of individuals who suffered early traumas in
childhood (typically physical or sexual abuse) who were then re-exposed to a stres-
sor in adulthood. The serotonin (5-HT) transporter (5-HT T) to which the serotonin-
selective reuptake inhibitor (SSRI) antidepressants bind and are thought, in part, to
exert their antidepressant actions, has two common variants, or SNPs. The long (l)
variant is a more efﬁcient transporter (5-HT-Tll) compared with the short (s) variant
(5-HT-Tss). In the study of Caspi et al. those patients at high risk for depression

because of previous life experience who had the long variant (5-HT Tll) appeared
relatively immune from stress-induced precipitation of a depressive episode
during adulthood. In contrast, those patients with the 5-HT Tss form, and to a
lesser extent, those with the sl SNP, showed a signiﬁcantly higher incidence of
depression following these stressors in adulthood.
These ﬁndings were partially replicated by Kendler et al. (106), and the para-
digm of potent environmental–SNP interactions was also revealed to be of critical
importance in another study by Caspi et al. (107). In this instance, marijuana
smoking during adolescence yielded an increased incidence of psychosis and
schizophrenia only in the subgroup of patients with increased genetic
vulnerability because of the catechol-O-methyltransferase polymorphism (COMT

val158val allele), which is associated with lesser degrees of prefrontal cortical
dopamine levels.The Kindling /Sensitization Model 303

One looks forward to the dissection of these types of more complex gene /
environmental interactions in bipolar illness, in which a variety of environmental
stressors and substance abuse comorbidities are known to be particularly prevalent.
Uncovering these dual vulnerability mechanisms at the level of SNPs and the
environment could also eventually assist in the earlier initiation of prophylactic
treatment, and in the choice of the most appropriate one.
Evidence of Stressor Involvement in the Onset and
Course of Bipolar Disorder
We have observed that childhood adversity (a self-reported history of physical or
sexual abuse) in bipolar illness is associated with an earlier illness onset, a more dif-
ﬁcult retrospective course of illness, and more Axis I, II, and III comorbidities com-
pared with bipolar patients without such a history (108). These retrospective
reports were validated prospectively by clinicians’ ratings of patients during natur-

alistic treatment, and those patients with a history of early adversity had an
increased severity of depression and more time depressed in prospective follow-
up compared with those without (108,109).
Interestingly, those with a history of early adversity had an increased inci-
dence of negative life events (but not positive events) at both the onset of their
illness and in relationship to the most recent episode compared with those
without this early adversity. These data raise the issue of not only stress vulner-
ability, but also of increased proclivity for exposure to stressful life events in
those with these early histories of adversity. The sensitization model postulates
increased stressor reactivity as a function of stressor recurrences rather than

decreased reactivity, so that such an association of increased negative life events
at illness onset and at the most recent episode does not contradict the sensitization
prediction. Nonetheless, in the relative absence of negative life events, the predic-
tion derived from the sensitization /kindling model would be that those patients
with a greater number of prior episodes would be more vulnerable to recurrence
than those with fewer episodes.
Neurochemistry and Neuroimaging Studies
We have previously reviewed some of the emerging evidence for functional and
neurochemical alterations in patients with affective disorder based on brain
imaging studies, and on autopsy specimens from those who died with this
illness, compared with other psychiatric illnesses and controls (110–113). As illus-

trated in Figure 1, there is converging evidence for frontal deﬁcits in both neuronal
and glial systems associated with decreased functioning of the prefrontal cortex,
especially during depression.
At the same time, there is also evidence for amygdala and ventral striatal
overactivity in adults with bipolar illness. One study by Altshuler et al. (79), but
not several others (74,114,115), indicated that increased amygdala volume was
directly related to the number of prior hospitalizations for mania. A series of neu-
roimaging studies have now been performed in children and adolescents with
bipolar illness, and the ﬁndings show that these youngsters had decreased
volume of the amygdala compared with controls (114,116–118), in contrast to the
preponderance of evidence for increases in amygdala volume in the adults

(80,81,119).304 Post

These changing alterations as a function of age and course of illness deserve
further attention and study. If replicated, they have very interesting clinical and
theoretical implications. Does the initially smaller volume of the amygdala in ado-
lescents relate to some of the neurocognitive and emotional facial recognition def-
icits (likely trait deﬁcits) that even children with early onset bipolar illness seem to
experience, and then with increasing age, course of illness, or other mechanisms
this deﬁcit changes to relative amygdala hypertrophy compared with controls
later in life? The rodent studies of McEwen (120) suggest that the occurrence of neo-
natal stressors is associated in adulthood with relative increases in amygdala size
and concordant prefrontal and hippocampal volume deﬁcits. Thus, it would be
important to examine the stress versus episode sensitization mechanisms (vs.
genetic mechanisms) that could account for these developmental changes, based

on comparing those patients with and without a history of early adversity for
various indices of amygdala volume and function.
The transition from a small to large amygdala as a function of age and devel-
opment could also be related to use-dependent neuroplasticity, similar to that
observed with taxi drivers in London who appear to have increased hippocampal
volumes compared with those whose work relies less on spatial navigation (121). Of
course, it is possible that the hippocampal differences predated engaging in the
taxi-driving occupation, and those who decided to become taxi drivers were self-
selected based on their spatial navigational skills (and attendant increased hippo-
campal volume).
Nonetheless, experience-dependent changes in neuronal volume and plas-

ticity have been demonstrated directly in a variety of other animal and human para-
digms, raising the possibility that the experience of many bouts of pathological
affect could be related to this change in trajectory of amygdala volume in those
with bipolar illness. Clearly, further work remains to assess these ﬁndings and
examine underlying pathophysiological mechanisms for an initially small amyg-
dala volume in childhood bipolar illness changing to a larger volume in adulthood
compared with controls.
Based on the sensitization /kindling hypothesis one would postulate neuro-
chemical abnormalities might emerge as a function of number, severity, and
duration of prior affective episodes and illness. A variety of neurobiological ﬁnd-
ings potentially compatible with such a hypothesis of illness progression have

now been reported (13,112,122) although causal mechanisms remain to be demon-
strated (Table 2) (13,79,83,123–133). It could be that those with increased brain path-
ology from the outset are more vulnerable to an adverse course of illness, rather
than the long duration or greater recurrence of illness driving these neurological
abnormalities.
Nonetheless, such course of illness and neurobiological correlates are worthy
of consideration and at least raise the possibility that more active illness interven-
tion and episode prevention could prevent some of these neurobiological
changes (134). One highly suspicious marker in this regard is the ﬁnding of
Kessing et al. (130) that the occurrence of one or two episodes of unipolar or
bipolar depression is associated with a normal risk of experiencing dementia in

late life compared with the general population. However, the occurrence of four
or more episodes approximately doubles the risk for such late life cognitive
impairment. Their more recent analysis further suggests that with every new
episode of illness there is an increasing 6% to 13% likelihood of such cognitive
difﬁculties.The Kindling /Sensitization Model 305

TABLE 2 Neurobiological Correlates of Number of Episodes, Hospitalizations, or Duration of
Recurrent Affective Illness
Finding UP /BP Correlates Authors
Hippocampus
Volume decreased (MRI) UP Increased number of
previous episodes,
longer illness durationMacQueen et al.,
2003 (123)
Volume decreased (MRI) UP Longer duration of
illnessSheline et al., 1999
(124)
Vermal brain regions
Vermal subregion V2
volume decreased (MRI)BP Increased number of
previous episodesMills et al., 2005
(125)
Amygdala
Volume increased (MRI) BP Increased number of
previous manic
episodesAltshuler et al., 2000
(79)
Left subgenual and rostral anterior cingulate
Decreased cerebral
glucose metabolismUP Increased number of
previous episodesKimbrell et al., 2002
(83)
Neurocognitive
Increased dysfunction and
disabilityBP Increased number of
longer illness durationDenicoff et al., 1999
(126)
BP Increased number of
hospitalizations,
longer illness durationThompson et al.,
2005 (127)

(126)
2005 (127)
hospitalization
episodesTham et al., 1997
(128)
previous months
hospitalizedRubinsztein et al.,
2000 (129)
Risk of dementia UP /BP Increased number of
previous episodesKessing et al., 2004
(130)
Endocrine
Increased dexamethasone-
CRH responseUP/BP Increased number of
previous episodesKunzel et al., 2003
(131)
UP/BP Increased number of
previous episodesHatzinger et al.,
2002 (132)
Decreased pharmacological response to
Lithium Increased number of
previous episodes or
hospitalizationsNine studies (Post
et al., 2003) (13)
Lamotrigine Increased number of
previous episodesObrocea et al., 2002
(133)
Gabapentin Increased number of
(133)

(133)
(133)
Abbreviations : BP, bipolar; CRH, corticotropin-releasing hormone; MRI, magnetic resonance imaging; UP, unipolar.306 Post

Regardless of whether or not adequate pharmacological prophylaxis would
prevent the increased incidence of late-life dementia syndromes associated with
four or more depressive episodes, from the clinical perspective there would still
be much merit in attempting to intervene in this fashion. Effective prophylactic
treatment would have at least prevented these several episodes of clinical
depression, which would have considerable beneﬁts whether or not the fundamen-
tal course or any of its neurobiological correlates (Table 2) were altered in a positive
fashion as well. In other words, there is little to lose and much to gain from more
aggressive attempts at pharmacological prophylaxis.
Early Age of Onset and Greater Number of Episodes:
Poor Prognosis Factors
The number of episodes of prior depression or the occurrence of rapid or faster
cycling may also be associated with a poor prognosis for affective illness recurrence

and eventual treatment response. Both adult- and childhood-onset illness is under-
diagnosed and under-recognized in the community and in clinical populations
(135–137). To the extent that episode sensitization is changing the long-term
course of illness in an adverse direction, altered strategies for early intervention
are strongly indicated.
A strategy for early intervention would be particularly important in child-
hood- and adolescent-onset bipolar illness, which is associated with serious long-
term consequences and poorer treatment response in adulthood (108,109,138,139).
However, childhood-onset illness (prior to age 13) several decades ago was associ-
ated with an average 16-year delay prior to the ﬁrst pharmacological treatment for

mania or depression, and adolescent-onset (ages 13–19) was also associated with a
disturbingly long average 12-year delay between the onset of ﬁrst symptoms of the
illness and ﬁrst treatment. In contrast, the delays are much shorter for early and late
adult-onset bipolar illness (139).
These ﬁndings, together with the observation that early onset bipolar illness is
associated with an extremely adverse outcome (even in adulthood at average age
40) when patients are treated naturalistically by experts, strongly point out the
need for earlier recognition, diagnosis, and treatment of these young children.
Again, it would be hoped that introducing such effective treatment would help
ameliorate the poor prognosis in adulthood, or potentially even prevent the devel-
opment of more full-blown illness altogether.

What is now remarkable, but not widely recognized in the community, are the
ﬁndings that lithium, valproate, and the antidepressants can all increase brain-
derived neutrotrophic factor (BDNF) and neurogenesis (54,140–143), potentially
ameliorating some of the neurobiological deﬁcits listed in Table 2. Thus, these
agents have clinical and theoretical support in not only helping to prevent episodes,
but also potentially either reversing or preventing the progression of biological
alterations in the illness (Table 3). Such a possible dual beneﬁt of treatment might
help some patients overcome their reluctance to start or sustain long-term prophy-
lactic treatment.
IMPLICATIONS FOR PSYCHOPHARMACOLOGICAL INTERVENTIONS
We have already outlined the strong clinical and theoretical rationale—based on the

kindling and stress sensitization models—for earlier and more effectiveThe Kindling /Sensitization Model 307

TABLE 3 Potential Neurotrophic and Neuroprotective Effects of Lithium, Valproate, and the Antidepressants: Opposite Effects of Illness
Stress Glucocorticoids Bipolar illness Lithium Valproate Antidepressants
Neurotrophic factors
BDNF ## " " (and block stress
effects)
Bcl-2 ""
Cell death factors
Bax, p53 "" # #
Stroke model
Severity "" " ,? ## (?)
Calcium signaling
Cai(intracellular calcium) "" Cai, white blood cells ( #) "
CaMK-II #Prefrontal cortex
CaMK-II"
GR #GR "
MR #MR "
New neurons and glia
Neurogenesis ## (#neurons) ""
Gliogenesis ( #glia) "
Neuronal integrity
N-acetylaspartate (prefrontal
cortex.hippocampus)#NAA "cortex "hippocampus
Gray matter on MRI #in prefrontal cortex,
anterior cingulate"
Clinical suicide " (") "" incidence # ? #?
Excess medical mortality
if depressed"" incidence # ??
Abbreviations : BDNF, brain-derived neurotrophic factor; CaMK-II, calcium calmodulin kinase II; GR, glucocorticoid receptors; MR, mineralocorticoid receptor s; MRI, magnetic

resonance imaging; ", increase; #, decrease; ?, unknown or not deﬁnite.308 Post

prophylactic treatment intervention in bipolar illness, for the possibility of not only
preventing episodes, but also preventing their associated episode sensitization,
stress sensitization, cross-sensitization to comorbid substance abuse, and the neuro-
biological alterations that may evolve and progress with each of these difﬁculties. In
addition to emphasizing the importance of early intervention, the kindling and sen-
sitization models help to conceptualize other psychopharmacological approaches
and treatment predictions noted below.
Effective Treatment May Differ as a Function of
Stage of Illness Intervention
Both the kindling and sensitization paradigms reveal that treatment effectiveness
may differ as a function of stage of illness intervention. Different psychopharmaco-
logical interventions prevent the development of behavioral sensitization as
opposed to its later expression. Similarly, the data are extremely clear that pharma-

cological interventions that prevent the development of kindling are not necessarily
the same that prevent the full-blown expression of completed amygdala-kindled
seizures (10,11,14).
While this might be expected, it is even more remarkable that once amygdala-
kindled animals have made the transition from triggered to spontaneous seizures,
there appears to be another pharmacological divergence. Most striking is the obser-
vation that diazepam, which is effective in the initial development and completed
middle phase of amygdala-kindled seizures, becomes ineffective in preventing the
late spontaneous seizures (144). Conversely, in a double-dissociation, phenytoin,
which is not effective in preventing kindling development and is ambiguous on
the completed amygdala-kindled seizure phase, becomes highly effective in pro-

phylaxis of the spontaneous variety.
These striking differences in pharmacological effectiveness of interventions as
a stage of syndrome evolution are consistent with the observations that the neuro-
chemical and neuroanatomical substrates involved in both sensitization and in
kindling likewise evolve over time. The initial effects on physiology, immediate
early genes, and peptides are largely conﬁned to the amygdala in the earliest
stages of kindling evolution, but then progressively become more widely distribu-
ted throughout the brain, involving unilateral and then bi-lateral hippocampal and
diverse cortical areas as full-blown kindled seizures are engendered (10,14). Like-
wise, the mechanisms underlying behavioral sensitization to the psychomotor
stimulants appear to evolve from those that are local in the ventral-tegmental

area (VTA) to those in the amygdala and nucleus accumbens (145,146), depending
on the context-speciﬁc nature of the sensitization, and then eventually into a variety
of cortical areas.
Thus, to the extent that bipolar illness also evolves from well-state vulner-
ability, to symptomatic illness, to fully-developed affective episodes initially trig-
gered but eventually occurring spontaneously with faster cycling and ultradian
switching of mood phases, one would also expect differences in pharmacological
responsivity as a function of these stages of illness evolution. This obviously
becomes critically important in assessing which very early interventions at ﬁrst
symptoms (secondary prevention), or primary prevention strategies in those at
highest risk, might be effective in preventing initial phases of illness development,

as opposed to the drug response data in adults that are acquired after the illness has
become fully manifest.The Kindling /Sensitization Model 309

A person’s age and developmental phase would also combine to produce
differences in neurochemistry. Drug responses in childhood might not be identical
with those observed in adulthood. For example, we know that the GABA-B agonist
baclofen is an effective anticonvulsant on amygdala-kindled seizures in very young
rodents (147), but not in adults. Similar questions arise in the therapeutics of BD as
to whether or not effective interventions in adults will apply in parallel to those in
the youngest children and adolescents. Clearly, more empirical data are needed in
this realm.
Combination Therapy May Be Required
In adults, a modicum of data support changes in illness responsivity as a function of
number of prior episodes and /or rapidity of cycling. With the exception of isolated
studies (148), most data suggest that prophylactic treatments are less effective in
those with a high number of prior episodes or rapid cycling compared with

those with fewer episodes or nonrapid cycling. This reduced responsiveness in
those with greater number of prior episodes not only includes response to
lithium, but also emerging studies on a poorer response to valproate, carbamaze-
pine, lamotrigine, and even more recently, the atypical antipsychotics (149–153).
Partially convergent with this perspective are the recent ﬁndings that the
majority of patients in a variety of clinical and academic treatment settings
require complex pharmacotherapy in order to bring the illness into partial or full
remission. The data of Frye et al. (8) are interesting in this regard because they illus-
trate the need over the past several decades for increasingly complex treatment (or
polypharmacy) in order to discharge bipolar patients from a clinical research hos-

pital and achieve approximately the same degree of success of about 80% improve-
ment. In the 1970s and 1980s, the average number of drugs required to achieve this
acute improvement at discharge were one and two, respectively, and this increased
to three in the 1990s, and in the most recently discharged cohorts, to an average of
3.5 to 4 drugs.
This increased need for complex combination therapy coincided with the
more recent patients having an earlier onset of their illness, greater amounts of
time depressed prior to coming to NIH, and increased rapid cycling, each of
which has been associated in some studies with greater degrees of treatment resist-
ance. Whether these population characteristics change over time relates to an
inherent selection bias toward more treatment-refractory patients in more recent

cohorts, or whether there is an increasing severity and difﬁculty in achieving
response to treatment in the general community, remains for further examination.
Many other clinics have observed this trend for the requirement of an average
of three or four medications during naturalistic treatment of bipolar illness, includ-
ing the Pittsburgh group (154,155), and the outpatient collaborative network as
described by Kupka et al. (156). In the Kupka et al. study, those patients with
rapid cycling required an average of 4.5 classes of psychopharmacological medi-
cations over a year of treatment in contrast to 3.5 in those without a history of
rapid cycling. Gitlin et al. (157) also report a high incidence of complex combination
treatment in their setting, as well as others (158,159).

This trend toward a greater need for combination treatment and polyphar-
macy appears to extend to childhood onset bipolar illness cohorts as well. The
majority of patients in the study of Kowatch et al. (160) required combination treat-
ment and the more recent studies of Findling et al. indicated a very high failure rate310 Post

on lithium or valproate monotherapy (161). A report from the American Psychiatric
Institute for Research and Education described children with bipolar illness as
having the most complex pharmacological regimens compared with all other chil-
dren with psychiatric diagnoses (162). Birmaher et al. (163) also described the need
for complex regimens in order to bring youngsters with bipolar illness into remis-
sion; this group not only required multiple medications, but 11.5 months on the
average until remission for bipolar I, 9.2 months for bipolar II, and most distress-
ingly, more than two years (34 months) for those with bipolar NOS.
In these instances and in the studies of Geller et al. (164), only a relatively
short period of time was required for what was considered a remission. Both of
these prospective cohorts found a very high incidence of relapse even in those
who had previously been “stabilized.” Thus, the nature and complexity of combi-

nation treatment optimally required to achieve and maintain remission in
childhood-onset bipolar illness requires much more concerted psychopharmacolo-
gical research attention than does the adult bipolar variety.
Despite having a large number of classes of psychopharmacological interven-
tions and a number of agents in each class, there is little systematic guidance for
clinicians and patients to choose among these agents, especially after the ﬁrst or
second treatment intervention. While a large variety of factors appear to contribute
to the increasing recognition of the generally poor prognosis of even adult-onset
bipolar illness in many academic settings, the failure to have a systematic database
from which to make informed clinical treatment decisions is likely an important

contributing factor. In the kindling model, combination treatment slows tolerance
development more effectively than monotherapy (14,15,165).
Difﬁculties in Achieving and Maintaining Remission
While many psychopharmacological studies describe clinically successful
endpoints of 50% improvement in manic or depressive symptomatology, this end-
point is often inadequate from a patient or clinician’s perspective. Here, one is striv-
ing for complete remission of bipolar symptomatology and return to one’s usual
employment, educational, or social role with a minimum of illness-related interfer-
ence. Not only is this state highly sought after, but preliminary evidence suggests
that minor mood ﬂuctuations may be precursors to more major ones and full-
blown episode breakthrough (135,166,167). Thus, there is increasing movement

toward the goal of achieving complete remission in both the unipolar and bipolar
recurrent affective disorders. This will likely also contribute to the need for increas-
ingly complex psychopharmacological regimens, because such “miracle” mono-
therapy treatment responses are less frequently observed than one would desire
(168). In the kindling paradigm, minor breakthrough episodes predict more com-
plete loss of drug effectiveness via tolerance (14,15).
Remission is not an endpoint with a high incidence rate in many
psychopharmacological studies, even in those in which patients are selected for
lack of comorbidities and symptom extremes such as suicidality. Since the majority
of bipolar patients experience considerable illness comorbidity and some 25% to 50%

of bipolar patients make a medically serious suicide attempt prior to average age 40
(169,170), the presence of these characteristics in representative patients often
requires highly individualized additional psychopharmacological approaches.
Fortunately, a variety of interventions have been demonstrated to be effective
in patients with the primary comorbidity of substance abuse (i.e., those with alcoholThe Kindling /Sensitization Model 311

or cocaine abuse in the absence of bipolar illness) based on double-blind controlled
clinical trials, but, unfortunately, relatively few of these options have been speciﬁ-
cally tested in patients with these comorbidities in the context of BD (99,100). Thus,
in this area as well, the patient and clinician are mostly building treatment regimens
based on indirect inferences and best guesses from other data sets, rather than a
strong body of controlled evidence. To the extent that inadequate deﬁnition of
appropriate treatment paradigms both for the primary illness and its comorbidities
contribute to illness progression and, eventually, treatment resistance, this tremen-
dous lack of systematic data requires major remedies. In the kindling tolerance
paradigm, increasing illness drive via increased intensity of stimulation facilitates
and speeds the loss of efﬁcacy via tolerance. In bipolar illness, comorbid conditions

may be conceptualized in formal ways of increasing illness drive that require
speciﬁc treatment.
Two Types of Acquired Treatment Resistance
A further complicating factor is that once a period of illness remission is achieved
in a given patient, there is still no guarantee that it can be maintained over the long
term. We and others have described two different types of acquired development of
treatment resistance, that is, the development of lack of responsivity to
a pharmacological agent after an initial extended period of good response. These
two types of treatment-resistance include ( i) tolerance and ( ii) treatment-discon-
tinuation-related refractoriness.
Tolerance
In a cohort of treatment-refractory bipolar patients, we have observed a consider-

Tolerance
able incidence of the development of gradual loss of efﬁcacy via a tolerance-like
process. We call it ‘tolerance-like’ because there is often a lack of incontrovertible
data that patients remained highly compliant and took the appropriate doses of
medication, achieving the same blood levels to which they had previously
responded. However, based on patient report this is often the case, and despite
excellent adherence, episodes begin to break through a previously effective
regimen with increasing frequency, severity, or duration. We have observed this
with lithium, valproate, and carbamazepine and potentially with lamotrigine and
gabapentin as well (10). Others have seen this phenomenon with lithium, such as
in the experience of Maj et al., where patients who were completely remitted on

lithium for a period of two years were then followed for a total of ﬁve years, and
a substantial subgroup of patients began to show illness re-emergence (171).
As described in detail elsewhere, tolerance to most anticonvulsant interven-
tions develops readily in the amygdala-kindled seizure model and provides a
basis for exploring treatment approaches that may sustain anticonvulsant efﬁcacy
for a longer period of time or indeﬁnitely (15). Based on these preclinical studies
we have observed that: ( i) some drugs such as valproate are much less susceptible
to tolerance development than others, such as carbamazepine, lamotrigine, or leve-
tiracetam; ( ii) higher or consistent doses appear less likely to be associated with tol-
erance than minimally effective doses that are gradually escalated; ( iii)

combinations of agents with different mechanisms of action may be more effective
than either agent alone; ( iv) intervening earlier in the development of
full-blown amygdala-kindled seizures, that is, shortly after these have begun to
be observed, also appears associated with a reduced likelihood of developing312 Post

tolerance compared with the same dose of drug given to animals late in their course
after many dozens of kindled seizures.
Once tolerance has developed, the preclinical tolerance model suggests both
the utility of adding drugs with a novel mechanism of action, or returning to an
originally effective drug after a brief period of time off that agent (11,165). None
of these predictions from the preclinical model have been directly tested in patients
with recurrent BD, although they clearly need to be.
One caveat that requires attention is that a considerably longer period of time
well (in remission) compared with that observed during previous well intervals
between episodes should be required prior to considering a putative psychophar-
macological agent likely effective in prophylaxis. It is only after this demonstration
of sustained efﬁcacy that one can begin to consider a true tolerance process. If only a

short well interval is observed on a given agent, it is not clear whether the drug was
effective, or ineffective and merely accompanied by the expected course-of-illness
variation between episodes.
Lithium Discontinuation-Induced Refractoriness
A second type of acquired treatment resistance is that exempliﬁed by lithium-
discontinuation-induced treatment refractoriness (172,173). In this instance, a sus-
tained and long period of illness remission has been observed on lithium (often six
to eight years of wellness) compared with much shorter well intervals observed
between episodes (on the order of months) prior to treatment. The patient and /or
physician then decides on this basis of sustained wellness that lithium could or
should be discontinued, and even after a very slow taper period, episodes of

illness re-emerge. However, the patient is no longer responsive to the reinitiation
of lithium treatment at equal or higher doses and blood levels than those that
had previously been effective (174).
This phenomenon is not common, but may occur in about 10–15% of patients,
and adds further indirect evidence for illness progression with the occurrence of
new episodes potentially heightening “illness drive” and the vulnerability to suc-
cessive recurrences. Also potentially complicating this process is the withdrawal
of a drug such as lithium which considerable evidence suggests may be neuropro-
tective or neurotrophic, which could further enhance the development of treatment
refractoriness. Moreover, an additional seizure episode in the kindling model may

propel the patient to a new stage of illness evolution that is no longer responsive to
the previously effective agent (15,165).
Neuroprotective Effects of the Mood Stabilizers
Lithium not only increases cell survival factors such as BDNF and Bcl-2, but it inhi-
bits cell death factors such as Bax and p53 (175,176). Lithium also facilitates the rate
of neurogenesis and has facilitatory effects on glial activity, growth, and survival as
well. Thus, new episodes occurring in the absence of lithium may be occurring in
the absence of lithium’s neurotrophic and neuroprotective effects, thus incurring
a greater degree of pathophysiological change than might have occurred if the
patient had continued lithium or some other maintenance treatment with similar

Whatever the mechanisms involved, we know a number of patients who have
experienced such a phenomenon, and each of these individuals greatly regrets ever
having stopped their previously effective lithium treatment. Whether similarThe Kindling /Sensitization Model 313

phenomena of discontinuation-induced refractoriness occur in a small percentage
of patients after discontinuation of other effective stabilizers remains to be deli-
neated. However, in recurrent unipolar illness, we have also observed a number
of individuals who have repeatedly responded acutely to traditional antidepress-
ants or monoamine oxidase inhibitors, but following repeated drug discontinu-
ations and depressive episode recurrences then begin to fail to respond to these
agents in subsequent episodes. Even if this pattern occurs in only a small percen-
tage of patients who repeatedly discontinue effective antidepressant treatment for
recurrent unipolar depression, it could have a substantial public health impact.
These preliminary observations are convergent with the data of Keller et al. (166)
that every episode of recurrent depression carries about a 10% increased risk of
the development of treatment-nonresponsive illness.

Developing clinical and biological markers to which patients may be vulner-
able to these types of acquired treatment resistance would have considerable
beneﬁt for clinical therapeutics. Similarly, there is only a modicum of data to
suggest which clinical factors may help increase the chance of a given patient’s
responding to a given mood stabilizer or atypical antipsychotic.
Prediction of Individual Treatment Response
Given the large number of agents potentially available, it would appear wise to
consider the suggestions of David Cox of Perlagen Sciences, Inc., for using a
proﬁle of some 25 to 30 SNPs, not to deﬁne new pathophysiological mechanisms
and treatment approaches, but in helping (more immediately) to delineate which
patients are likely to be responders to speciﬁc existing treatment or be subject to

their rare extreme adverse events (177). Use of multiple SNP illness vulnerability
factors could also help assess the risk of bipolar illness onset and, at the same
time, assist in the assessment of the risk-to-beneﬁt ratio for early treatment
initiation.
In this fashion, Cox argues that the expected beneﬁts of the molecular biology
revolution could be quite readily and rapidly applied for clinical therapeutic beneﬁt
a great many years before any of these factors are used to develop new illness
targets and therapeutic strategies aimed at such single dysfunctions. Gene-driven
new therapies appear to be an inordinately difﬁcult problem even in Huntington’s
disease where the single gene and protein defect are known. Treatment advances
based on this information have yet to be realized. In contrast, the process of

gene-driven therapeutics would appear extraordinarily more difﬁcult for most psy-
chiatric illnesses in which there are likely multiple genes of small effect. In this case,
even directly altering one or more such small pathophysiological defects may or
may not be therapeutically successful.
If using such SNP proﬁles in concert with a series of other clinical and biologi-
cal predictors of response, one might hope to be able to increase the percentage a
good initial treatment response from the approximately 50% range that is consist-
ently observed in acute studies in mania (for lithium, the mood stabilizing anticon-
vulsants, and the atypical antipsychotics) to an 80% or 90% likelihood of response.
In this fashion one might be able to intervene both earlier and more effectively with

the appropriate agent(s) and help prevent more recurrent episodes, but also their
potential adverse illness course consequences predicted by the kindling and sensit-
ization models.314 Post

SUMMARY OF FINDINGS
Bipolar disorder has emerged in the last several decades as an illness that is more
difﬁcult to treat than previously surmised. If the goal is long-term sustained remis-
sion, about two-thirds of the bipolar patients in academic outpatient settings would
be considered treatment-resistant. Several different studies suggest that on average,
patients with bipolar illness are ill about half the time despite treatment in the com-
munity or by experts in academia, and that time depressed exceeds time manic by a
factor of approximately three. Correlates of these more adverse and poor prognosis
outcomes include earlier age of onset of illness and more episodes experienced
prior to study entry.
Both the preclinical models of sensitization and kindling and the empirical
data on course of bipolar illness itself suggest that processes of illness progression
occur in the absence of effective treatment. While the basic tenets of the sensitization

and kindling model have been generally well-validated in the clinical literature (i.e.,
stress sensitization and episode sensitization), further precision is required to delin-
eate the neurobiological mechanisms underlying stress, episode, and substance
abuse sensitization, and how they may interact with each other and with genetic
vulnerability.
Even in the absence of compelling evidence for the course of illness modi-
ﬁcations induced by stressors and episodes as postulated in the sensitization and
kindling models, the utility of the clinical perspective derived from this longitudi-
nal view of the illness would appear to have merit in its own right. Helping to
ameliorate the impact of stressors and engage in the effective prevention of

manic and depressive episodes would, in any case, be a critical goal and help
avoid much suffering. To the extent that this model provides an additional theor-
etical rationale for early, effective, sustained prophylactic treatment for the recur-
rent affective disorders, it also may help support more active therapeutic and
public health measures directed toward these potentially disabling illnesses.
Most of the longitudinal course of illness predictions of the model are ultimately
directly testable, but some may be ethically difﬁcult and unjustiﬁed, such as ran-
domizing patients to early intervention versus delayed or no treatment. Indirect
inferences may nonetheless be gleaned from naturalistic treatment comparisons,
and many direct randomized controlled studies of the relative effectiveness of

two different early treatment approaches (178) are feasible and very much
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B17 Biologic Factors in Different Bipolar
Disorder Subtypes
Division of Bipolar Disorders Research, Department of Psychiatry, University
of Cincinnati College of Medicine, Cincinnati, Ohio, U.S.A.
Modern psychiatric nosology, and the classiﬁcation of mood disorders, did not
really take shape until the early twentieth century with the work of Emil Kraepelin.
Kraepelin was one of the pioneers in differentiating psychiatric conditions.
However, he combined most forms of mood disorder, including unipolar and
bipolar depression, into the large category of manic-depressive insanity (1). It
wasn’t until the late 1950s and 1960s that unipolar and bipolar depression were
separated into unique diagnostic syndromes [see Akiskal (2) for review]. The key
element that separates bipolar disorder (BD) and its subtypes from unipolar
disorder is the occurrence of mania or hypomania. Over the last three decades

there have been varying suggestions of how to subdivide BD (2). In this chapter,
we focus on what we feel are the most well-established subgroups within and
separate from BD type I, namely, BD type II, cyclothymic disorder, rapid cycling,
and psychotic mania. Type II BD and cyclothymia are speciﬁc diagnoses in the
DSM-IV (3), while rapid cycling and psychotic mania are DSM-IV speciﬁers that
can be applied to either type I or II BDs (Table 1).
This chapter extends an earlier comprehensive review chapter on the sub-
types of BD from the previous edition of this book (4). For each of the four major
subtypes covered, we will discuss epidemiology, etiology, and treatment of the
condition. The DSM-IV also includes two additional subtypes of BD: BD not other-
wise speciﬁed (NOS), and mood disorder due to a general medical condition. There

is very limited research on Bipolar Disorder NOS, hence this is not discussed in the
present review. Secondary mania is an important and large topic in itself but is not
discussed in this chapter. For a comprehensive review of secondary mania see
Strakowski et al. (5).
Before discussing these speciﬁc subtypes of BD in detail, a few general
remarks are warranted. Although much has been written on BD as a spectrum
illness (6), the scarcity of empirical evidence prevents meaningful speculation in
this regard. The major problem with the spectrum concept, and any other nosology
with multiple subtypes of BD, is that so little is known about the etiology of even the
most established (i.e., bipolar I) forms of the disorder. Hence multiple subtypes of
the disorder become difﬁcult to substantiate. Only when the molecular and neuroa-

natomic mechanisms of major subtypes (e.g., bipolar type I or II) are further under-
stood will it be possible to determine whether other variants of the disorder are
minor dysfunctions of the same systems or have separate and unique etiologies.
For example, even the biologic differences between unipolar and bipolar depression
325

remain to be elucidated (7,8). There is only limited research that compares and con-
trasts possible etiological mechanisms for the different subtypes of BD. Yet the rapid
advances in our knowledge of BD should leave us optimistic about future under-
standing of the subtypes of this condition. As more is learned about the etiology
of bipolar I, there will be molecular mechanisms and neuroanatomic circuits to
compare when studying the variant subtypes.
BIPOLAR DISORDER, TYPE II
Bipolar disorder, type II is characterized in the DSM-IV (3) by the occurrence of at
least one clear episode of hypomania (with no history of ever having a full manic
episode) and the occurrence of at least one major depressive episode.
Epidemiology
Although ﬁrst described by Dunner et al. in 1976 (9), BD type II was not recognized
as a separate diagnostic entity until the publication of the DSM-IV in 1994. There is
still considerable controversy surrounding estimates of the prevalence of bipolar II

disorder. Although a recent review cites a prevalence of 3% to 5% (10), there is
little consensus in the literature. Using the deﬁnition in DSM-III (11), the U.S.
National Epidemiologic Catchment Area Study (12) found a lifetime prevalence
of only 0.5% for hypomanic episodes. Angst (13) reviewed eight other studies
examining the epidemiology of bipolar II and found prevalence ranges between
0.3% and 2%.
Judd and Akiskal (14) reanalyzed the U.S. National Epidemiologic Catchment
Area data using less restrictive criteria for hypomania and found a prevalence of
6.4% for the bipolar spectrum. Similar results were found in the Zurich study,
another important study of the epidemiology of bipolar II that followed 4547
subjects from the canton of Zurich from 1979 to 1993 (13). They found a prevalence

rate of 5.5% for hypomania. Together, then, these estimates suggest that type II BD is
relatively common, probably occurring in 2% to 4% of the population.TABLE 1 Subtypes of Bipolar Disorder and Their DSM-IV Descriptors
Subtype DSM-IV description
Bipolar I At least one manic episode must occur; no
requirement for a depressive episode
Bipolar II At least one episode of hypomania and one
depressive episode
Cyclothymic disorder Two years of numerous periods of
hypomanic symptoms and depressive
symptoms, with no period of two or more
months without symptoms
Rapid cycling Applied to bipolar I disorder with four or
more manic, mixed, or depressive
episodes in one year; or bipolar type II
disorder with four or more hypomanic or
depressive episodes in one year
Psychotic mania Applied to bipolar I patients during a manic

or mixed episode with psychosis326 Cerullo and Strakowski

Biology
Genetic studies provide the strongest evidence to distinguish type I and II BDs.
Maier (15) compared the lifetime prevalence of affective disorders in relatives
of bipolar I and II patients. The risk of having bipolar I disorder was equivalent
in relatives of bipolar I and II patients. However, the risk of having bipolar II was
greater in relatives of patients with bipolar II (6.1%) compared with relatives of
patients with bipolar I (1.8%). Gershon et al. (16) also found a higher prevalence
of bipolar II disorder in relatives of patients with bipolar II and similar rates
of bipolar I illness in relatives of patients with bipolar I and II. However, these
conditions did not “breed true,” suggesting considerable overlap in familial risk.
There have been few neuroimaging studies that compare bipolar I and II
patients. The only structural MRI study comparing the two subtypes was by
Sassi et al. (17) in which they examined the pituitary volume in bipolar versus uni-

polar patients. They separated the bipolar patients into bipolar I ( n¼18) and
bipolar II ( n¼5), and did not ﬁnd any differences in pituitary volume between
these two groups. The small sample provided limited power, however, so that
these results are not particularly informative. Functional imaging studies
have also looked at differences between bipolar I and II disorder. A PET study
examining cerebral glucose metabolism during a continuous performance test
by Ketter et al. (18) compared 14 bipolar I and 29 bipolar II patients. The direct
comparison of the two groups showed no differences in global metabolism, but
bipolar I patients had increased metabolism in the supragenual anterior cingulate,
right middle frontal gyrus, and right inferior parietal lobule compared with

bipolar II patients. An fMRI study by Malhi et al. (19) examined 10 hypomanic
patients during an emotional task and found activation in the caudate and
thalamus compared with the control group. However, this study was limited in
that the hypomanic patients were not further diagnosed as having either bipolar
I or II illness.
A small number of magnetic resonance spectroscopy studies have compared
patients with bipolar I and II disorder. Winsberg et al. (20) looked at ratios of NAA,
choline, and myo-inositol to creatine-phosphocreatine (Cr-PCr) in the dorsolateral
prefrontal cortex in 10 bipolar I and 10 bipolar II patients during euthymia.
Compared with controls, bipolar I patients had lower NAA /Cr-PCr ratios in both
hemispheres, while bipolar II patients had lower NAA /Cr-PCr ratios compared

with controls only in the left hemisphere. When both groups were compared
directly, bipolar II patients had higher NAA /Cr-PCr ratios in both hemispheres.
Another study by Kato et al. (21) looked at the Cho /Cr-PCr ratio in the left subcor-
tical region (which included the basal ganglia) in 10 bipolar I patients and 9 bipolar
II patients during euthymia. The Cho /Cr-Pcr ratio was higher in the bipolar II
patients compared with the bipolar I patients.
Taken together, these results provide some evidence that there may be biologi-
cal differences between bipolar I and II disorder and provide incentive for further
comparative studies. The genetic studies are consistent with several possible
relationships between the two disorders, including the possibility that bipolar II is

a less severe variant of bipolar I and the possibility that the two disorders have sep-
arate but overlapping etiology. Neuroimaging research suggests that there may be
functional brain differences between the two groups in frontal brain networks,
but this ﬁnding is based only a single study and clearly needs replication. The mag-
netic resonance spectroscopy studies provide evidence for metabolic difference in
the dorsolateral prefrontal cortex and subcortical regions.Biologic Factors in Different Bipolar Disorder Subtypes 327

Treatment
Li
An early prospective study of lithium in bipolar type II patients suggested that
lithium was effective in preventing depressive relapse (22), but the small sample
size ( n¼18) and lack of statistical analysis limited the study. An early double-
blind placebo-controlled study looking at 22 bipolar II patients by Kane et al. (23)
showed that lithium was effective in preventing relapse. A retrospective study
(24) of 102 bipolar II patients showed that lithium was effective in preventing the
relapse of depression. A more recent retrospective study of lithium therapy in
188 bipolar I and 129 bipolar II patients who were followed for an average of 8.4
years (25) found lithium to be more effective in bipolar II than bipolar I patients
with decreased disease relapse, less percent of time spent ill, and fewer illness
episodes per year.
A double-blind, placebo-controlled study of lamotrigine as maintenance prophy-

laxis in rapid cycling BDs showed that in the subgroup of 52 bipolar II patients
(with rapid cycling) compared with placebo there was a signiﬁcantly higher
percentage of patients who were stable without relapse at six months (26).
Divalproex sodium monotherapy was shown to reduce Hamilton Depression
Scale ratings by 50% in 19 depressed bipolar II subjects in a 12-week open label
study (27).
Amsterdam and Brunswick (28) recently reviewed the use of antidepressants in
bipolar II depression. They concluded that the data supported the use of anti-
depressant therapy in bipolar II depression and that this use is associated with a
low risk of inducing switching to mania or hypomania. Amsterdam et al. published

several recent studies of the effectiveness of antidepressant treatment in bipolar II
patients. In one double-blind study, 89 bipolar II patients in remission from a
recent depressive episode were given either ﬂuoxetine or placebo for 52 weeks
(29). These subjects were compared with 89 unipolar patients matched for age
and gender and 661 unmatched unipolar patients. Relapse prevention rates were
equivalent to those in the unipolar patient groups. The rate of switching to mania
or hypomania was equivalent to the matched unipolar controls but increased com-
pared with the unmatched controls (3.8% vs. 0.3%). In another study, venlafaxine
was compared in 17 bipolar II patients and 31 matched unipolar patients, with
both groups in a current depressive episode (29). There was no difference in

response in the two groups, and there were no episodes of switching in the
bipolar II group. In a recent study by Amsterdam et al. (30), 37 bipolar II patients
were given ﬂuoxetine monotherapy for depression in an open label trial. Eleven
of 23 patients who completed the eight-week trial showed a reduction in Hamilton
Depression Rating scores greater than 50% and three patients (7.3%) had symptoms
suggestive of hypomania.
RAPID CYCLING
Rapid cycling is a speciﬁer in the DSM-IV (3) that can be applied to either bipolar I
or bipolar II disorder when patients have multiple mood episodes in one year.
In bipolar I disorder, rapid-cycling patients must have at least four manic, mixed,328 Cerullo and Strakowski

or depressive episodes in one year. Bipolar type II patients are required to have at
least four hypomanic or depressive episodes in one year.
Although psychiatrists have long been aware of rapid mood shifts in some patients,
not until 1974 did Dunner and Fieve (31) introduce the current nosology of rapid-
cycling BD in a paper studying factors correlated with poor lithium response in
bipolar patients. In their paper, Dunner and Fieve arbitrarily set the criteria to be
a minimum of four mood swings in a one year period. This nosology for rapid
cycling was then included as a speciﬁer in the DSM-IV for both bipolar I and
bipolar II disorders.
Kupka et al. (32) recently completed an important meta-analysis examining
every study of rapid-cycling BD published since 1974. Among 2054 bipolar I and
II patients in eight studies, 335 (16.3%) had rapid cycling. These studies included
both inpatient and outpatient subjects, and the prevalence of rapid cycling

ranged from 12% to 24% in the individual studies. Women and those with
bipolar II disorders showed higher rates of rapid cycling (although the overall
size of this effect was small) than men and those with bipolar I respectively. Since
this meta-analysis, there have been two other large studies looking at rapid-
cycling BD. A study by Schneck et al. (33) looked at the data for the ﬁrst 483
bipolar I or II patients enrolled in the Systematic Treatment Enhancement
Program (STEP) for one year after their diagnosis. They found an overall rate of
rapid cycling of 20%. There was a higher rate of rapid cycling among women
(23% vs. 16%), and rapid-cycling patients had an earlier age of onset of illness,
were more depressed at study entry, and had poorer global functioning in the

year before study entry. There was no signiﬁcant difference between the rate of
rapid cycling in bipolar I versus bipolar II disorder. The next major study was by
Kupka et al. (34). They followed 539 outpatients with bipolar I and II disorder for
one year and found that 38.2% had rapid cycling. They found no difference in
rate of rapid cycling between men and women. There was a signiﬁcantly higher
rate of rapid cycling in bipolar I (41.3%) versus bipolar II disorder (27.9%). The
rapid-cycling patients spent more time in both manic (and hypomanic) and
depressive states over the course of a year than those without rapid cycling.
They also found that rapid cycling was associated with a greater number of pre-
vious mood episodes, previous rapid cycling, a history of childhood physical

and/or sexual abuse, and lifetime drug abuse. The authors considered different
cut-off ranges for number of episodes in a one-year period. Increasing the cut-off
to eight episodes in a year, only 13.5% of the patients would meet criteria
for rapid cycling. However, none of the cut-off ranges showed any evidence of
nonlinearity that would suggest a natural cut-off point to separate rapid cyclers
from nonrapid cyclers.
In addition to the prevalence of rapid cycling, it is also important to under-
stand when it occurs during the course of bipolar illness and whether it is a tempor-
ary condition or a more long lasting subtype. Strakowski et al. (35) followed 144
subjects for up to ﬁve years after their ﬁrst hospitalization for mania. At the end
of the follow-up period, only 10% of patients had ever met the criteria for rapid

cycling. These results suggest that rapid cycling may develop with illness pro-
gression over time. Koukopoulos et al. (36) followed the course of illness in 109
rapid-cycling bipolar patients for up to 36 years (with a minimum period of
two years). They found that rapid cycling emerged in 96 patients (88%) afterBiologic Factors in Different Bipolar Disorder Subtypes 329

antidepressant and other medication treatment. The mean total duration of rapid
cycling was eight years while the mean total duration of affective episodes was
22 years. Baldessarini et al. (37) found that among patients who met the criteria
for rapid cycling at one time, these patients did not consistently maintain rapid-
cycling status and had only moderately greater lifetime rates of rapid cycling
compared with other bipolar patients. These last two results support the concept
of rapid cycling as a temporary condition during BD.
Biology
Unfortunately, there have been few studies directly examining the structural and
functional neuroanatomic networks or molecular mechanisms of bipolar patients
with rapid cycling. One area which has been studied involves thyroid function in
rapid-cycling patients. In their prior review, Gary et al. (4) discussed thyroid
axis dysfunction in rapid-cycling patients. Some, but not all, of the studies reviewed

suggested a higher prevalence of thyroid disorders in rapid-cycling versus
non–rapid-cycling bipolar patients. Two of the studies showed increased hypo-
thyroidism in rapid-cycling patients after treatment with lithium carbonate
(38,39). A recent meta-analysis by Kupka et al. (32) also looked at studies of
rapid-cycling that included measures of thyroid function, and only two of the
seven studies (39,40) found signiﬁcantly higher cases of hypothyroidism among
rapid-cycling patients.
In their discussion, Gary et al. (4) suggested that rapid-cycling patients may
be more severely ill and therefore more likely to be exposed to lithium, which in
turn leads to the greater proportion of patients with thyroid dysfunction. Two
recent papers looking at thyroid dysfunction in rapid-cycling patients address

this concern. Kupka et al. (41) found increased rates of thyroperoxidase antibodies
in bipolar patients, but this was not associated with either lithium treatment or
rapid-cycling BD, suggesting there are independent risk factors in bipolar patients
for developing hypothyroidism. Gyulai et al. (42) compared 20 rapid-cycling
patients with controls on a lithium challenge. Rapid-cycling bipolar patients had
a signiﬁcantly higher change in maximum thyroid-stimulating hormone (TSH)
after the lithium challenge than controls, supporting the idea that rapid-cycling
bipolar patients are more vulnerable to lithium-induced thyroid dysfunction.
Clearly, more studies are needed to help clarify these contradicting results.
Treatment
Li
The nosology of rapid-cycling arose from Dunner and Fieve’s (31) study looking at

Treatment
Li
bipolar patients unresponsive to lithium. They found that 82% of rapid cyclers
failed lithium compared with 41% of nonrapid cyclers. This result was then
replicated by Koukopoulos et al. (43) who found a poor response to lithium in 72%
of rapid cyclers. However, several recent studies have challenged this ﬁnding. The
meta-analysis by Kupka et al. (32) discussed previously also examined response to
lithium. In patients who were treated with lithium prophylaxis, there were no
differences in recurrence rates between rapid and non–rapid-cycling bipolar patients
(47% vs. 34%, respectively, which was nonsigniﬁcant).
The most recent and methodologically sound study looking at lithium treat-
ment in rapid cyclers was that by Baldessarini et al. (37). The authors followed 360

bipolar I and II patients over 13 years. Their results indicated that rapid-cycling BD330 Cerullo and Strakowski

was not associated with greater morbidity during lithium maintenance treatment.
There were no signiﬁcant differences in several critical outcome measures
between rapid and non–rapid-cycling bipolar patients, including: months remain-
ing stable on treatment, proportion of time spent in mania and depression, and
psychiatric hospitalizations.
Valproate
Calabrese et al. (44) examined the effectiveness of valproate in 78 rapid-cycling
bipolar patients in a 16-month open label trial. Valproate showed a good acute
response in 54% of patients in a manic state, 72% of those in mixed states, and
only 19% of those in a depressive state. A good prophylactic response was seen
in 72% of manic patients, 94% of mixed patients, and 33% of depressive patients.
Another open-label trial by Calabrese and Delucchi (45) examined 55 rapid-
cycling patients over eight months on valproate. The results were similar to the
Calabrese et al. study (44) but showed greater efﬁcacy in depression (47% in

acute depression and 76% in prophylactic treatment). Calabrese et al. (46) recently
completed a large randomized double-blind study of valproate versus lithium
in rapid-cycling bipolar patients. The chance of relapsing into either a manic
or depressive episode was not statistically different for lithium (56%) versus
valproate (50%).
Bowden et al. (47) looked at the efﬁcacy of lamotrigine in 41 rapid-cycling and 34
non–rapid-cycling patients with BD in a 48-week open label prospective study.
Patients with depressive and mild-to-moderate symptoms improved from baseline
on lamotrigine in both patient groups (with no signiﬁcant difference between
the groups). However, rapid-cycling patients with severe mania showed little
improvement in their symptoms.

A large double-blind, placebo-controlled study of lamotrigine as maintenance
prophylaxis in 324 patients with rapid-cycling bipolar I and II disorders (26)
showed a statistically signiﬁcant greater percent of the treatment group was
stable without relapse at six months compared with placebo (41% vs. 26%).
Another smaller double-blind placebo-controlled study of lamotrigine showed an
improved antidepressant response compared with placebo in rapid-cycling
patients (48).
Okuma (49) looked at 215 bipolar patients treated with lithium versus carbamaze-
pine in a retrospective study and found that rapid cycling (at the time of study or in
the past) predicted nonresponse to both medicines. Denicoff et al. (50) completed a

three-year double-blind crossover study of lithium, carbamazepine, and the combi-
nation of both medications in 52 outpatients with BD. Rapid-cycling patients
responded poorly to both lithium (28% response) and carbamazepine (19%
response), but did better on the combination (56.3% response).
Gonzalez-Pinto et al. (51) studied olanzapine as an add-on in an open-label trial in
13 bipolar I patients during a mixed mood episode. All patients had a history of
rapid cycling within the last year. Ten of the 13 patients responded to olanzapineBiologic Factors in Different Bipolar Disorder Subtypes 331

(in which response was deﬁned as a decrease of 50% score on the Young Mania
Rating Scale and the Hamilton Rating Scale for Depression).
A recent meta-analysis by Vieta et al. (52) pooled the data from two double-
blind placebo-controlled trials of olanzapine to include 90 patients with rapid
cycling. The results indicated that olanzapine was more effective in the early treat-
ment of mania in rapid-cycling versus non–rapid-cycling bipolar patients.
However, olanzapine was less effective in the long-term treatment of rapid
cyclers who were signiﬁcantly more likely to experience recurrence (especially
depression), to have rehospitalizations, and to have suicide attempts compared
with nonrapid cyclers.
Comparisons of Treatments
A recent meta-analysis of long-term treatment of rapid-cycling bipolar patients by
Tondo and Baldessarini (53) looked at treatments with carbamazepine, lamotrigine,
lithium, topiramate, and valproate. They found lower effectiveness of all treatments

in rapid-cycling versus non–rapid-cycling patients. They concluded that there
were few studies providing direct comparisons of the different medications and
there was no evidence of any medicine being superior.
Cyclothymic disorder appears as one of four subtypes of BD in the DSM-IV. The
diagnostic criteria require a period of hypomanic symptoms and depressive
symptoms (which do not meet the criteria for a major depressive episode) that
continue for at least two years with no period of two or more months without symp-
toms. The diagnosis also requires that no major depressive, manic, or mixed
episode be present during the ﬁrst two years of the disorder. If these episodes
occur after two years of the start of the cyclothymic symptoms, then the appropriate

mood disorder can be diagnosed concurrently with cyclothymic disorder.
Kraepelin considered cyclothymia as a possible constitutional disposition that
could lead to manic-depressive illness (54). In the DSM-II (55), cyclothymia was
considered a part of the affective personality disorders category. In the DSM-III
(11), cyclothymia was included in the mood disorders and the diagnosis required
numerous hypomanic and depressive symptoms to be present continuously for
at least two years without symptom-free periods of two months or greater. This
nosology persisted in the DSM-IV (3).
Unfortunately, there are no epidemiological studies looking at cyclothymic
disorder as deﬁned by the DSM-III or IV. Weissman and Myers (56) interviewed
1095 households and found a lifetime rate of cyclothymic personality of 0.4% as

deﬁned by the Schedule for Affective Disorders and Schizophrenia Diagnostic
Research Criteria. Placidi et al. (57) examined 1010 students between 14 and 26
years old and found a prevalence of 6.3% for cyclothymic temperament.
Biology
To our knowledge there are no studies that have attempted to examine the under-
lying molecular or neuroanatomic etiology of cyclothymic disorder.332 Cerullo and Strakowski

Treatment
There are no double-blind placebo-controlled studies examining treatments for
cyclothymic disorder. A retrospective study by Peselow et al. (24) looked at
cyclothymic patients taking lithium over a two-year period. The probability
of remaining free of a depressive episode was only 26% to 36% (compared with
42–55% for bipolar II patients and 31–42% for unipolar patients). The probability
of suffering a depressive episode severe enough to require hospitalization during
the two years was 69% in the cyclothymic patients (compared with 51% and 64%
for bipolar II and unipolar patients, respectively).
A prospective study by Jacobsen (58) looked at valproate in cyclothymia.
Twenty-six patients (15 cyclothymic, 11 bipolar II) out of 33 started on daily valpro-
ate doses between 125 and 250 mg and titrated up reported partial or complete
stabilization of their mood. The cyclothymic patients required lower doses and

blood levels to achieve stabilization compared with the bipolar II patients.
PSYCHOTIC MANIA
Psychosis is a speciﬁer in DSM-IV that can be added to bipolar I disorder during a
manic, mixed, or depressed episode. If psychosis is present the mood episode
becomes “severe with psychotic features.” In this chapter we are concerned with
psychosis that occurs during a manic or mixed episode. Whether the psychosis is
mood congruent or incongruent is also relevant, and most studies of psychotic
mania classify the manic episode as psychotic only when the psychosis is mood
incongruent.
Distinguishing mood from psychotic disorders has been one of the major challenges
of psychiatric nosology and was one of the major accomplishments of Kraepelin (1).
Yet, many questions remain about the overlap of these two major groups of illness.

The DSM-III (11) included psychosis as a speciﬁer for a manic or depressive
episode. In the DSM-IV (3), this speciﬁer can also be applied to mixed episodes.
A factor analytic study of 576 manic patients by Sato et al. (59) supports the
concept of psychotic mania as a subtype of acute mania. The subgroup of psychotic
mania was signiﬁcantly different from three other subgroups of mania (pure mania,
aggressive mania, and mixed mania) on measures of suicidality at admission,
global assessment of functioning score at discharge, number of residual symptoms
at discharge, and gender.
In their textbook on BD, Goodwin and Jamison (60) reviewed prior studies of
BD and found a lifetime prevalence of 60% for having at least one psychotic
symptom. More recent epidemiological ﬁgures are hard to come by, but Conus

and McGorry (61) estimated the prevalence of psychotic symptoms in the range
of 63–88% in the ﬁrst episode of mania based on their review of ﬁrst episode
bipolar studies. In another study (62), 90 out of 139 (65%) manic patients had psy-
chotic symptoms. Strakowski et al. (35) found that psychosis during mania was
more common in bipolar I patients who had alcohol use disorders one year prior
to the episode than patients with no history of alcohol use disorders. Two studies
(63,64) have found that psychotic symptoms are associated with an earlier age of
onset of illness in BD. Finally, a recent study of hallucinations in mood disorders
and schizophrenia found that only 11.2% of manic patients had hallucinations (65).Biologic Factors in Different Bipolar Disorder Subtypes 333

Biology
Toni et al. (66) studied the family history of mental illness in 155 manic inpatients,
86 with mood-incongruent psychosis. Those with mood-incongruent psychosis had
a family history of schizophrenia of 4% compared with 0% in those without mood-
incongruent psychosis. However, this study included those with schizoaffective
disorder as well as bipolar I, which limited the conclusions that could be drawn
regarding the genetics of BD. Potash et al. (67) looked at 65 families of probands
with bipolar I disorder. They found that psychotic symptoms during affective
episodes occurred more often in family members of bipolar I subjects with psycho-
sis than family members of bipolar I subjects without psychosis, suggesting that
psychotic symptoms cluster in certain bipolar pedigrees. Potash et al. (68) replicated
these results using 69 new BD pedigrees. Potash et al. (69) then performed genetic
linkage analysis on the ten families with the highest number of psychotic mood

disorders. They found linkage to chromosomal regions 13q31 and 22q12.
Strasser et al. (70) performed structural MRI scans on 23 bipolar subjects with
psychosis (21 with bipolar I and 2 with bipolar II), 15 bipolar subjects without psy-
chosis (nine with bipolar I and six with bipolar II), 33 schizophrenic subjects, and 44
healthy controls. Psychosis was deﬁned as the occurrence of hallucinations or
delusions during one affective episode (mania, mixed, or depressive). The bipolar
subjects with psychosis and the schizophrenic subjects had enlarged lateral and
third ventricles compared with healthy controls and bipolar patients without
psychosis. There was no difference in hippocampal volume when the two groups
of bipolar subjects were compared with each other or with healthy controls. In con-

trast, schizophrenic subjects showed reduced left hippocampal volume compared
with healthy controls. Two PET studies (71,72) have also found similarities
between schizophrenia and bipolar subjects with psychosis. Pearlson et al. (71)
found increased basal ganglia D 2dopamine receptor density in psychotic bipolar
and schizophrenic subjects compared with healthy controls and bipolar subjects
without psychosis. Wong et al. (72) found increased caudate D 2dopamine receptor
density in psychotic bipolar subjects compared with bipolar subjects without psy-
chosis and healthy controls, and increased caudate D 2dopamine receptor density in
schizophrenic subjects compared with healthy controls. These neuroimaging
studies suggest that there may be similar etiological mechanisms in BD with psy-

chosis and schizophrenia, although it is possible the changes are merely correlative
with psychosis.
Another major research focus in psychotic mania has been examining
whether there is a worse prognosis and increased severity of symptoms in psycho-
tic mania versus mania without psychosis. Although there have been several
studies of this question, there is no clear consensus. In a retrospective study,
Kessing (73) examined 149 manic patients without psychosis and 202 patients
with psychosis. The patients with psychotic mania had longer admissions
compared those without psychosis, but no difference was found in the risk of
relapse between the two groups.
Strakowski et al. (74) followed 50 manic patients for eight months after their
ﬁrst psychiatric hospitalization for BD. Those patients with mood incongruent psy-

chosis at hospitalization had signiﬁcantly more weeks during follow-up of both
mood-incongruent and mood-congruent psychosis as well as poorer overall func-
tioning during the outcome interval of eight months. MacQueen et al. (75)
studied 62 outpatients with bipolar I disorder (16 with psychosis) in a prospective
study. Although psychotic patients were more symptomatic during the acute manic334 Cerullo and Strakowski

episode there were no differences in ratings of function and well-being when both
groups were euthymic. In a prospective study, Miklowitz (76) examined 23 hospi-
talized manic patients, 11 with psychosis. Although the two groups did not differ in
rates of relapse, those with psychotic symptoms had poorer social adjustment and
were less medically compliant. Swann et al. (77) looked at the role of psychosis in
the severity of symptoms and treatment response in a randomized double-blind
treatment study of lithium, divalproex sodium, and placebo in 179 hospitalized
manic patients. Those patients with psychosis had lower Global Assessment
Scale scores but similar response to treatment.
Treatment
Li
In the prospective study of 139 bipolar patients (90 with psychotic mania) men-
tioned earlier, Coryell et al. (62) did not ﬁnd any difference in response to lithium
in psychotic mania versus mania without psychosis. As mentioned above, Swann

et al. (77) did not ﬁnd any differences in efﬁcacy between lithium and divalproex
in the treatment of psychotic mania. In a prospective study of 30 patients with
acute mania (24 with psychotic symptoms), Zemlan et al. (78) found that lithium
was more effective in those with psychotic symptoms. Rosenthal et al. (79)
studied 66 bipolar I patients, 44 whom had psychosis at some point during their
illness (30 during mania, 5 during depression, and 9 during both mania and
depression). They found that psychosis during mania was a predictor of good
response to lithium. However, in a retrospective study of 145 bipolar patients
(94 with psychotic mania), Yazici et al. (80) found a ﬁrst episode of mania that
included psychosis was one of four variables that predicted a poor response
to lithium.
Clozapine

Clozapine
Green et al. (81) studied clozapine in the treatment of refractory psychotic mania. In
an open-label trial, 22 psychotic manic patients were given clozapine for 12 weeks.
Clozapine proved effective in the treatment of these patients, showing a mean
improvement of 56.7%, 56.6%, and 39.1% on the Brief Psychiatric Rating Scale
(BPRS), Young Mania Rating Scale (YMRS), and Clinical Global Impressions
(CGI), respectively.
In an 18-month double-blind maintenance study of the prevention of relapse of
bipolar I disorder, Tohen et al. (82) looked at olanzapine versus placebo added to
valproate or lithium and found a signiﬁcant reduction of symptomatic relapse
with the addition of olanzapine. The presence of psychotic features had no effect

on the outcome. In a double-blind study of olanzapine versus divalproex in acute
mania (83), the subgroup of bipolar patients without psychosis showed decreased
YMRS scores with olanzapine compared with divalproex. The presence of psycho-
tic features had no effect on outcome. Tohen et al. (84) looked at olanzapine versus
haldol in a 12-week double-blind study of the treatment of acute mania. Patients
receiving olanzapine had signiﬁcant improvement in manic symptoms (lower
YMRS scores) in the subgroup of patients without psychosis, but not in the sub-
group of patients with psychosis. Chengappa et al. (85) combined the results
from two prior randomized double-blind studies of olanzapine versus placebo inBiologic Factors in Different Bipolar Disorder Subtypes 335

acute bipolar mania and found that olanzapine was signiﬁcantly better than
placebo at reducing manic symptoms (lower YMRS scores) in patients with
psychosis.
Sachs et al. (86) examined risperidone versus haldol or placebo as an add-on to
lithium or divalproex in a double-blind study of acute mania. Risperidone was
effective in lowering YMRS scores in patients without psychosis (mean change
213.3) and those with psychosis (mean change 215.4) compared with the placebo
group. Hirschfeld et al. (87) studied the effectiveness of risperidone versus
placebo for acute mania in a three-week double-blind trial. Risperidone was
effective in lowering YMRS scores in patients with and without psychosis. In a
double-blind study of risperidone compared with haldol and placebo in acute
mania, Smulevich et al. (88) showed that risperidone was effective in acute mania
(lower YMRS scores) compared with placebo at three weeks in patients with and
without psychosis.

McIntyre et al. (89) examined quetiapine versus haldol monotherapy in a 12-week
double-blind placebo-controlled study of acute mania. In patients without psycho-
sis, both quetiapine and haldol showed improvements in YMRS scores compared
with placebo on days 21 and 84. However, in the subgroup of patients with
psychosis, quetiapine did not show improvement in YMRS scores compared with
placebo on either day 21 or 84. Sachs et al. (90) examined quetiapine versus
placebo added to lithium or divalproex in a double-blind study of acute mania.
Quetiapine was superior to placebo in improving YMRS scores, and the presence
of psychotic symptoms did not show an interaction with the treatment effect,
indicating quetiapine was effective in bipolar patients with psychosis. Yatham et

al. (91) also looked at quetiapine versus placebo added to lithium or divalproex
in a double-blind study of acute mania. They also found that the presence of
psychosis did not alter the effectiveness of quetiapine.
SUMMARY
In this paper we reviewed the epidemiology, biology, and treatment of four sub-
types of BD: bipolar II, rapid cycling, cyclothymia, and psychotic mania. Among
the four disorders, bipolar II disorder has the strongest support for being a distinct
diagnostic entity. There is evidence suggesting bipolar II patients have different
genetic risk factors compared with bipolar I patients. The neuroimaging studies
reviewed are beginning to ﬁnd differences that if replicated could lead to elucida-
tion of different etiological mechanisms and risk factors between bipolar I and II.

Studies of BD with rapid cycling have focused on thyroid abnormalities and differ-
ent response to treatments. The evidence regarding thyroid abnormalities is incon-
sistent and more studies are needed before any conclusions can be drawn. The
studies of treatment response are also inconsistent, but the newer studies suggest
that lithium can be effective in bipolar patients with rapid cycling. In addition,
recent outcome studies suggest that rapid cycling may be a temporary condition
during the course of BD.
Regarding psychotic mania, genetic studies suggest it may cluster in certain
families, and biological studies have shown similar brain deﬁcits to those found336 Cerullo and Strakowski

in schizophrenic patients. Recent studies of psychotic mania have shown that aty-
pical antipsychotics are an effective treatment while studies regarding prognosis
remain mixed. Almost no research has been done on cyclothymia and even the
most basic epidemiological data remain uncertain in this disorder.
Clearly more research is needed to better understand the subtypes of BD. With so
little evidence it is premature to consider BD a spectrum illness. When the molecu-
lar and neuroanatomic aspects of bipolar I disorder are better understood this
should enable the comparison of the proposed subtypes to bipolar I disorder.
These comparative studies may lead to the elucidation of the etiology of each
subtype as well as the etiology of the entire spectrum of BDs.
In terms of treatment, we should also be wary of assuming that medications
that are effective for bipolar I will be effective for other possible subtypes of the

disorder. Only rigorous double-blind studies can assure us of the effectiveness of
medications, and more such studies are needed for many of the subtypes of BD.
While psychiatric nosology has come a long way since Kraepelin’s formu-
lation of manic-depressive insanity, there is still a long road ahead. The most
fundamental questions about the etiology of the mood disorders remain unan-
swered. Only an understanding of the etiology of the illnesses we treat can bring
us to the next level of nosology beyond Kraepelin and the DSM-IV.
Supported in part by the Stanley Medical Research Institute and NIMH awards
MH066626, 068801, 071931 (Strakowski).
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B18 Biological Factors in Bipolar Disorder
in Childhood and Adolescence
Department of Health and Human Services, National Institutes of Health,
Bethesda, Maryland, U.S.A.
From its earliest descriptions, clinicians, and researchers have observed bipolar
disorder (BD) in children and adolescents. Pediatric manifestations of BD were
recognized in antiquity by Aretaeus and documented in case reports in the 19th
century by Esquirol (1). However, despite this long history, the exact clinical pres-
entation of juvenile BD remains highly controversial. Clinical, neurocognitive, and
pathophysiological comparisons to adult BD require further study. In the past
decade, a growing number of studies on pediatric BD indicate unparalleled
academic interest in understanding the pathophysiology of the disorder and its

developmental trajectory (2).
DIAGNOSING BIPOLAR DISORDER IN CHILDREN
Pathophysiological studies in psychiatry typically involve intensive biological
assessments of a relatively small sample of patients. In such studies, investigators
try to recruit a clinically homogeneous sample, since clinical homogeneity should
be associated with decreased biological variability between patients, and thus
with an increased probability of ﬁnding signiﬁcant differences between patients
and controls in the pathophysiological variable of interest. In the case of pediatric
BD, considerable controversy has surrounded the diagnosis, complicating investi-
gators’ ability to recruit homogeneous patient samples and to compare results
across sites. Therefore, to understand the current state of research on the biological

underpinnings of BD in children, one must appreciate the nature of this diagnostic
controversy, and how the diagnosis is applied differently in different research
settings.
In diagnosing pediatric BD, researchers disagree as to whether distinct mood
episodes, and /or euphoria, should be required to make the diagnosis. Diagnostic
and Statistical Manual-Fourth Edition-Text Revision (DSM-IV-TR) clearly requires
episodes of mania or hypomania for the diagnosis; indeed, technically, one diag-
noses a manic episode, not mania per se. Criterion A of manic and hypomanic epi-
sodes requires “a distinct period of elevated, expansive, or irritable mood” (italics
added) lasting at least seven days in the case of mania, or four days in the case of
hypomania (3). However, based in part on earlier case reports (4), researchers

suggested that children with BD differ from adults in having less distinct episodes,
instead presenting with persistent and severe irritability accompanied by the “B”
343

symptoms of mania, such as agitation, distractibility, and pressured speech (5–7).
These investigators suggested that the clinical presentation of children with BD is
usually that of a chronic mixed mania (5,8).
Researchers also debate whether euphoria should be required for the diagno-
sis of mania in children. DSM-IV-TR states that a manic episode can be character-
ized by either irritability or elated mood. However, the issue is contentious in
pediatric psychiatry because irritability is very common in childhood psycho-
pathology (9). Indeed, if one does not require an episodic course for the diagnosis
of BD in children, then the boundary between BD and attention deﬁcit hyperactiv-
ity disorder (ADHD) accompanied by severe irritability, is unclear (10–12).
In response to the controversies described above, Leibenluft et al. (13)
proposed a phenotyping system for BD in children. This phenotyping system
was designed to facilitate research by creating homogeneous subgroups among

the various populations of children receiving the diagnosis. In this system, one sub-
group of children, the narrow phenotype (NP-BD), has the least equivocal pres-
entation; these children have had at least one distinct episode clearly meeting
DSM-IV-TR criteria for mania or hypomania, with a duration of at least four days
for hypomania and seven days for mania (Table 1). In fact, the criteria for narrow
phenotype illness in Leibenluft et al. are narrower than the DSM-IV-TR criteria
for a manic episode, since Leibenluft et al., like Geller et al. (14,15), require
elation or grandiosity to be the episode’s predominant mood state, whereas
DSM-IV-TR allows irritability.
Two intermediate phenotypes were designed to address the disagreements
concerning the required duration of an episode, and the question of whether

euphoria should be required to make the diagnosis of mania (13). One intermediate
phenotype includes children whose episodes meet full duration criteria for hypo-
mania or mania, but exhibit irritability rather than euphoria. The second
TABLE 1 Narrow Phenotype Diagnostic Criteria
Mania: (hypo)mania, with full-duration episodes and hallmark symptoms
Modiﬁcation to the DSM-IV-TR criteria for manic episode
The child must exhibit either elevated /expansive mood or grandiosity, while also meeting other
DSM-IV-TR criteria for a (hypo)manic episode.
Guidelines for applying the DSM-IV-TR criteria
Episodes must meet the full duration criteria (i.e., /C217 days for mania and /C214 days
for hypomania) and be demarcated by switches from other mood states (depression,
mixed state, euthymia).

Episodes are characterized by a change from baseline in the patient’s mood (DSM-IV-TR
criterion A) and simultaneously, by the presence of the associated symptoms
(DSM-IV-TR criterion B). For example, the distractibility of a child with ADHD would
count toward a diagnosis of (hypo)mania only if his /her distractibility worsened at the same
time that he /she experienced mood elevation.
Decreased need for sleep should be distinguished from insomnia (i.e., nonspeciﬁc difﬁculty
sleeping, which is associated with fatigue).
Poor judgment per se is not a diagnostic criterion for (hypo)mania; the poor judgment must
occur in the context of “increased goal-directed activity” or “excessive involvement in
pleasurable activities that have a high potential for painful consequences.”

Abbreviations : ADHD, attention deﬁcit hyperactivity disorder; DSM-IV-TR, Diagnostic and Statistical Manual-Fourth
Edition-Text Revision.344 Brotman et al.

intermediate phenotype includes children who exhibit distinct euphoric episodes
that are shorter than the four days required by DSM-IV-TR.
Finally, children meeting criteria for the “broad phenotype” exhibit chronic
impairing irritability accompanied by hyperarousal symptoms; the latter are
similar to those seen in children with ADHD. These youth have neither distinct epi-
sodes nor euphoria, and their receipt of a bipolar diagnosis has been perhaps the
major source of controversy in the literature. While acknowledging that children
with this clinical presentation have been called the “broad phenotype” of BD (16),
Leibenluft et al. (13) label them as having “severe mood and behavioral dysregulation
(SMD),” to emphasize the fact that the question of whether they are indeed suffering
from a phenotype of BD is open to empirical investigation. These SMD criteria of
Leibenluft et al. (Table 2) were designed to: ( i) operationalize clearly the criteria for

irritability (i.e., increased reactivity to negative emotional stimuli at least three
times a week); ( ii) ensure that the irritability was severe (speciﬁcally, severely impair-
ing in one setting and at least mildly impairing in a second); ( iii) ascertain a sample
who, in addition to irritable outbursts, exhibited abnormal baseline mood, in order to
exclude children with “tantrums” who are otherwise well-functioning; ( iv) capture
the population of children who exhibit those “B” criteria of mania that overlap
with symptoms of ADHD (i.e., exhibit three or more of the following: insomnia,
agitation, distractibility, pressured speech, ﬂight of ideas or racing thoughts, intru-
siveness); and ( v) exclude children with an episodic illness or any of the symptoms

speciﬁc to mania (i.e., euphoria, grandiosity, decreased need for sleep). In designing
these criteria, a major goal was to clearly deﬁne a population of children who could be
compared on a number of biological variables to children meeting narrow phenotype
criteria for BD.
TABLE 2 Severe Mood Dysregulation (SMD) Diagnostic Criteria
Inclusion criteria
Age 7–17 years, with symptom onset before age 12.
Abnormal mood (speciﬁcally, anger or sadness) present at least 1 /2 of the day most days and of
sufﬁcient severity to be noticeable by others (e.g., parents, teachers, or peers).
Hyperarousal, as deﬁned by /C213: insomnia, agitation, distractibility, racing thoughts or ﬂight of
ideas, pressured speech, or intrusiveness.
Compared with peers, the child exhibits markedly increased reactivity to negative emotional

stimuli manifest verbally or behaviorally—temper tantrums out of proportion to the inciting
event and /or child’s developmental stage—occurring .3 times /week during past four weeks.
Symptoms are present for /C2112 months without /C212 months symptom-free.
Symptoms are severe in at least 1 setting and at least mild in a second setting—e.g.,
school, home, peers.
Exclusion criteria
Child has any “cardinal” BD symptoms: elevated /expansive mood, grandiosity, or episodically
decreased need for sleep.
Distinct episodes /C214 days.
Individual meets diagnostic criteria for schizophrenia, schizophreniform disorder, schizoaffective
illness, pervasive developmental disorder, or post-traumatic stress disorder.
Individual meets criteria for substance use disorder in the past three months.
IQ,70.

IQ,70.
Symptoms are direct physiological effect of drug abuse or general medical /neurological condition.
Abbreviations : BD, bipolar disorder; IQ, intelligent quotient.Biological Factors in Childhood and Adolescence 345

PREVALENCE ESTIMATES OF PEDIATRIC BIPOLAR DISORDER
Despite the controversy surrounding the diagnostic boundaries of pediatric BD,
estimates across epidemiologic studies reveal a relatively consistent prevalence.
This consistency may be due to the fact that the epidemiologic studies have all
used DSM conventions in making the diagnosis in children, requiring clear epi-
sodes with the requisite duration (i.e., these studies exclude children with the
“broad phenotype” of the illness). Using the kiddie schedule for affective disorders
and schizophrenia for school-age children (K-SADS) (17) to examine DSM-III-R BD
in adolescents aged 14 to 18 years, Lewinsohn et al. (18) found a lifetime prevalence
of approximately 1%. Not surprisingly, the prevalence of youth with subsyndromal
BD (i.e., a distinct period of abnormally elevated, expansive, or irritable mood for
less than four days, or a hypomanic episode with no history of a depressive

episode) is higher (5.7%) than the prevalence of youth with BD (19,20). Similarly,
Carlson and Kashani (21) examined the rates of BD in 150 nonreferred 14- to 16-
year-old and found that approximately 1.5% met research diagnostic criteria
(RDC) (22) criteria for BD-II or cyclothymia. No child met DSM-III RDC criteria
for BD-I, because the degree of impairment was insufﬁcient. In another study exam-
ining 717 adolescents 10 to 20 years old (mean age 15 years), Johnson and colleagues
(23) found that 14 youth (1.9% of the sample) met criteria for BD according to the
diagnostic interview schedule for children (DISC) (24). An additional 10 adoles-
cents (1.4% of the sample) experienced subthreshold BD, as the number of their
hypo /manic symptoms was one symptom below threshold. In a younger sample,

data from the great smoky mountains study (GSMS) (25) found a 0.1% prevalence
of hypomania and no cases of mania in children aged 9 to 13 years old. Applying
Leibenluft et al.’s (13) phenotype criteria to the GSMS dataset, Brotman et al. (26)
found a 3.3% prevalence of SMD, or the broad phenotype of BD. Taken together,
epidemiologic data suggest that the prevalence of DSM-based BD is quite low;
not surprisingly, when criteria are relaxed, that is, not requiring clear episodes, or
allowing shorter episodes and /or fewer criteria “B” symptoms, population fre-
quency estimates increase.
COGNITIVE AND EMOTIONAL PROCESSING
Classical cognitive paradigms assessing memory and attention can help to eluci-
date the neuropsychological deﬁcits apparent in youth and adults with BD. Speciﬁ-

cally, the study of cognitive impairments can clarify the neurobiological substrates
of the disorder, such as deﬁcits in cortical functioning, and potentially demonstrate
the relationship between neural correlates and clinical symptoms (27,28). It is par-
ticularly important to differentiate nonspeciﬁc cognitive deﬁcits from those associ-
ated with BD. In addition, it is essential to parse deﬁcits that persist during
euthymia from those that occur only during acute mood episodes in order to deter-
mine the extent to which BD patients do not achieve functional and full cognitive
recovery during remission, and to identify possible endophenotypes of the
illness, that is, behavioral markers associated with risk (29). Neuropsychological

studies in BD adults have demonstrated state- and trait-related deﬁcits in set shift-
ing, planning, attention, and memory (27,30–36). However, as detailed below,
fewer studies have explored neuropsychological impairment in pediatric BD. In
addition, as also discussed below, more recent research has assessed patients’346 Brotman et al.

processing of emotional stimuli in an attempt to explore the emotional impairments
of BD youth (27).
Memory, Learning, and Attention
In BD adults, several studies have demonstrated impairments in memory and
verbal learning (35,37–39). Building on these studies, Dickstein et al. (40) used
the Cambridge neuropsychological test automated battery (CANTAB) (Cambridge
Cognition Ltd., Cambridge, U.K.) to assess visual /visuospatial memory and other
neuropsychological parameters in NP-BD children. Consistent with adult BD ﬁnd-
ings (41,42), NP-BD youth exhibited impairments in pattern recognition memory
(PRM). Moreover, NP-BD youth demonstrated decreased spatial memory span
relative to control children, again similar to impairments seen in adult BD patients
(42,43). Because such memory deﬁcits have been observed in adults with unipolar
depression (43) and adults with ADHD (44,45), it remains unclear if these impair-
ments are speciﬁc to BD.

Also consistent with studies in adult BD (37,39), McClure et al. (46) found
subtle memory deﬁcits in NP-BD youth on the California verbal learning test for
children (CVLT-C) (47). The impairments were particularly strong in NP-BD chil-
dren with comorbid ADHD. In a related study controlling for ADHD comorbidity,
Doyle et al. (28) found deﬁcits in sustained attention, working memory, and proces-
sing speed in BD youth. However, it is important to note that the criteria for BD in
these two studies differed. Whereas the former (46) employed Leibenluft et al.’s (13)
narrow phenotype BD criteria, the criteria for the latter study (28) included youth
with intense irritability, without euphoric /elated mood, and a nonepisodic illness.

In contrast to the developmental continuity of memory deﬁcits found in adult
and pediatric BD on the CANTAB and CVLT, studies using the continuous per-
formance test (CPT) to study sustained attention have revealed more discrepant
results. That is, while numerous adult BD studies have demonstrated attentional
deﬁcits with this task (34,48–50), results from pediatric BD studies have been less
conclusive. In a pilot study, DelBello et al. (51) found no differences in sustained
attention between adolescents with BD and controls. However, McClure et al.
(52) found that NP-BD subjects did not make more commission errors than did con-
trols, but did demonstrate lower discriminability (i.e., hit rate minus false alarms).
These results are not dissimilar from what one would expect in a sample of bipolar
adults (34).

Response Flexibility and Motor Inhibition
Response ﬂexibility, or the ability to modify one’s behavior based on changing con-
tingencies, is germane to the study of BD for several reasons. First, response ﬂexi-
bility is mediated by the ventral prefrontal cortex (VPFC), which has been
implicated in the pathophysiology of BD. Nonhuman primate and adult control
studies have shown that behavioral responses to changing contingencies engage
a neural circuit encompassing the amygdala, VPFC, and striatum (53). Both
lesion (54) and functional magnetic resonance imaging (fMRI) studies (55–61)
demonstrate functional abnormalities in these regions in patients with BD (see
below for neuroimaging in pediatric BD). Integrating neural ﬁndings with clinical

observation, our research group is testing the hypothesis that BD patients demon-
strate inﬂexibility in their responses to changes in emotional stimuli. Clinically,
depressed patients respond similarly to positive and negative stimuli, in thatBiological Factors in Childhood and Adolescence 347

neither are rewarding. On the other hand, manic patients cannot respond with
appropriate ﬂexibility to negative stimuli (e.g., they either deny the existence of
such stimuli, or become irritable in response to them). As detailed below, we
have demonstrated that children with BD, regardless of mood state, have deﬁcits
in adapting to changes in emotional contingencies. We hypothesize that such
response inﬂexibility, when present in euthymia, is a forme fruste of a more
marked deﬁcit that is present during mania or depression and is relevant to the
clinical symptoms of these aberrant mood states. Thus, the examination of impair-
ments in response ﬂexibility may elucidate the pathophysiology of pediatric BD.
Several studies, using different behavioral paradigms, have demonstrated
that NP-BD children and adolescents have impaired response ﬂexibility. Two
studies have used reversal learning, or the ability to reverse previously acquired

stimulus /reward associations, to measure cognitive and response ﬂexibility in
NP-BD subjects. In the ﬁrst, Dickstein et al. (40) showed that NP-BD subjects, com-
pared with typically developing youth, have impaired attentional set shifting,
speciﬁcally on the simple reversal stage, of the CANTAB’s intradimensional /extra-
dimensional (ID /ED) shift task (42). Similarly, Gorrindo et al. (62) found that euthy-
mic NP-BD subjects made more errors during probabilistic reversal and took longer
to learn the new rewarded object than did control subjects. In sum, two out of two
studies that have examined reversal learning in pediatric BD have shown that NP-
BD subjects have impaired response ﬂexibility.
Motor inhibition is a speciﬁc type of response ﬂexibility, because inhibiting a

prepotent response, or substituting an alternate response for an inhibited one,
requires cognitive and motor ﬂexibility. From a clinical perspective, deﬁcits in
motor inhibition may contribute to the impulsivity and affective aggression charac-
teristic of BD youth, as such youth may have difﬁculty inhibiting physical and
emotional responses to environmental triggers. To investigate motor control in chil-
dren with BD, McClure et al. (52) administered the stop and change paradigms (63).
Again demonstrating response inﬂexibility, compared with controls, NP-BD youth
had a signiﬁcantly longer reaction time when substituting an alternate response for
an inhibited behavior on the “change” task, and demonstrated a trend toward a
delay in their ability to inhibit a prepotent response on the “stop” task.
Attention-Emotion Interactions and Emotion Recognition

To elucidate the pathophysiology of the emotional dysregulation seen in BD
children, researchers have begun to explore the inﬂuence of emotional stimuli
on attention allocation. Adverse attention–emotion interactions may be important
in BD because the development of effective emotion regulation requires attentional
control; that is, children’s ability to deliberately control attention is essential
to moderating internal affective states (64,65). For example, directing attention
away from frustrating stimuli is a common method for modulating irritability
and anger.
Although the disrupting effects of emotional stimuli on attentional allocation
has received extensive study in patients with anxiety disorders (66) or depression
(67,68), only recently have investigators begun to explore impaired attention–

emotion interactions in pediatric BD. Rich et al. (65) used an affective Posner task
(69) in which subjects completed the same attentional task three times: ﬁrst at base-
line, then with contingencies (i.e., monetary reward and punishment), and ﬁnally in
the presence of frustration (i.e., rigged feedback). The BD patients, once again,348 Brotman et al.

demonstrated response inﬂexibility, in that controls, but not BD youth, responded
to the introduction of contingencies and frustration with decreased response time.
Furthermore, there was evidence that the patients’ response inﬂexibility might be
secondary to adverse attention–emotion interactions. Speciﬁcally, in controls, par-
ietal P300 evoked response potentials (ERPs) showed increased amplitude in the
frustration task compared with the other two tasks, whereas the P300 amplitude
in patients was unchanged across the three tasks. Given that P300 amplitude is
thought to be a measure of allocation of attention, these data indicate that controls
marshaled increased attentional resources in the presence of a heightened emotion-
al context, but BD youth were unable to do so (Fig. 1). These data further suggest
that the BD patients’ response inﬂexibility may be associated with deﬁcits in execu-
tive attention arising only in emotional, but not in nonemotional, contexts. Specu-

latively, it is possible that the BD children were unable to focus their attention on
the task while frustrated because they were distracted by the emotion that they
were experiencing.
Other studies have assessed processing deﬁcits and the inﬂuence of emotion
on attention by examining children’s ability to categorize facial displays of emotion.
Clinically, BD youth demonstrate social problems and experience high rates of peer
rejection. In addition, adults with BD display impaired recognition of facial
emotions, particularly during acute mood states (70,71). To examine such potential
impairments in BD youth, McClure et al. (52,72) administered the diagnostic analy-
sis of nonverbal accuracy scale (DANVA) (73) and found that NP-BD youth per-
formed worse than anxious adolescents and psychiatrically healthy control

subjects on a facial emotional recognition task. Yet, it remains unclear if these
impairments are speciﬁc to certain facial emotions, such as anger, or represent a
more general and extensive emotion recognition deﬁcit.
Further data by Rich et al. (74) suggest that BD children may mislabel facial
emotions because their affective response to the emotional expression impedes
the attention allocation needed for emotion categorization. Speciﬁcally, BD children
and controls completed emotional (e.g., “how afraid are you?”) and nonemotional
(i.e., “How wide is the nose?”) ratings of neutral faces. They found that compared
FIGURE 1 P3 ERP wave at parietal sites in the setting of frustration.Biological Factors in Childhood and Adolescence 349

with control youth, NP-BD children reported more fear when viewing these rela-
tively innocuous stimuli. However, NP-BD and control children did not differ in
nonemotional rating of the faces, again suggesting impaired attention–emotion
interactions in BD youth.
Once behavioral deﬁcits are identiﬁed in NP-BD youth, compared with
controls or other psychiatric populations, fMRI can be used to explore the brain
mechanisms mediating these between-group differences. MRI and other neuroima-
ging techniques are capable of elucidating aberrant biological mechanisms in pedi-
atric BD, including structural abnormalities and dysfunctional circuitry.
NEUROIMAGING IN PEDIATRIC BIPOLAR DISORDER
Unlike in adults, researchers cannot use positron emission tomography (PET) to
study BD youth, due to concerns about radiation exposure. However, numerous
groups have utilized magnetic resonance imaging (MRI) technology, which uses

no radiation and is noninvasive, to evaluate structural, chemical, and functional
alterations in pediatric psychopathology. Taken as a whole, these studies demon-
strate that fronto-amygdala-striatal abnormalities differentiate BD children and
adolescents from typically developing control youth (75).
STRUCTURAL NEUROIMAGING IN PEDIATRIC BIPOLAR DISORDER
The vast majority of published pediatric BD neuroimaging studies are structural
MRI studies, that is, studies that use MRI to determine volumetric differences in
brain structures between BD youth and controls. While size does not correlate
directly with function, structural MRI studies allow the identiﬁcation of regions-
of-interest (ROI) that may mediate the manifestations of BD.
The primary focus of structural MRI studies in pediatric BD has been on

limbic structures, most notably the amygdala. Studies have demonstrated that
the amygdala mediates numerous functions central to emotion regulation in
general, as well as to BD speciﬁcally. Such functions include modulating somatic
signs of negatively-valenced emotions, such as fear, anxiety, and depression
(76,77). The amygdala also shapes behavior in response to rewards and incentives
(78–80), which is germane to BD given the DSM-IV-TR clinical criteria of excessive
goal-directed activity and pleasure-seeking during mania, and of anhedonia during
depression. Of the six published studies that have evaluated amygdala volume in
pediatric BD, four showed that BD children and adolescents had decreased amyg-
dala volume, especially on the left, compared with typically developing youth

[including one (81) comparing NP-BD youth, in particular, to controls] (81–84).
In the ﬁfth study, a similar ﬁnding emerged as a trend (85). Only one study failed
to show decreased amygdala volume in pediatric BD subjects (86), possibly due
to the young average age of both BD and control subjects (mean age 11.3 +2.7
BD and 11.0 +2.6 controls) or due to BD subjects having a signiﬁcantly lower IQ
than controls (mean verbal IQ 99.2 +14.2 BD and 114.9 +11.4 controls). Moreover,
Blumberg et al. (87) recently published a two-year follow-up study demonstrating
that decreased amygdala volume in pediatric BD subjects remains a stable trait
feature compared with healthy controls. The consistency of these structural MRI
studies demonstrating decreased amygdala volume in pediatric BD subjects

stands in marked contrast to neuroimaging studies of BD adults that show either
increased or unchanged amygdala volume compared with controls (88–92). Such350 Brotman et al.

a consistent ﬁnding in pediatric BD suggests that there may be a neurobiological
difference between prepubertal- and adult-onset BD.
Structural MRI studies have also evaluated the hippocampus, another limbic
structure implicated in memory for emotional events. At present, two studies have
found decreased hippocampal volume in pediatric BD compared with controls
(82,86), while three have not (81,84,85). Frazier et al. (86), in the more recent of
the two studies demonstrating decreased hippocampal volume in BD adolescents,
found that this effect was driven by the female BD subjects. Again, structural MRI
studies of hippocampal volume in BD adults have found inconsistent results; one
study found decreased volume (93) while several others found no difference (89–
92,94). These negative studies should be interpreted with caution, however, due
to the possibility of type II errors.
Only recently have neuroimaging studies moved beyond the focus on limbic

regions to evaluate other regions, such as the frontal cortex. These studies ﬁnd that,
compared with controls, NP-BD youth have decreased volume of the left dorsolat-
eral prefrontal cortex (DLPFC) (Brodmann’s area 9—Fig. 2) (81), an area that exerts
top-down attentional control in response to emotionally-evocative stimuli (95).
Similar decreases in DLPFC volume and density have been found in BD adults
FIGURE 2 Pediatric BD subjects (N ¼20) show volume reduction of left dorsolateral prefrontal
cortex in comparison to age and gender matched controls (N ¼20). 1.5 Tesla magnetic
resonance imaging scan axial three-dimensional spoiled gradient recalled echo in the steady state
(FSPGR) analyzed with voxel-based morphometry. Note : Scale ( right) represents T-scores,

increasing from black to white. (x ¼232, y¼42, z¼32; t¼4.52, Z ¼4.01; p corrected ¼0.04).Biological Factors in Childhood and Adolescence 351

(96,97). Other structural MRI studies indicate that BD children and adolescents
have decreased volume in the anterior cingulate cortex (ACC) (98), an area that
mediates conﬂict monitoring, but BD youth do not appear to have decreased sub-
genual prefrontal cortex (PFC) volume (99), a region implicated in adult mood dis-
orders (100). Given the frontal lobe’s complex neuroanatomy and equally complex
role in psychopathology, additional work is required to elucidate the frontal neuro-
morphometric alterations associated with pediatric BD.
The striatum, a neural region encompassing basal ganglia structures includ-
ing the caudate, putamen, and accumbens area, is another area implicated by
recent studies in the pathophysiology of pediatric BD. The striatum plays an
important role in regulating attention and motor responses (101,102), as well as
in adjusting behavior in response to rewarding or pleasurable stimuli (103–107).

Thus far, four studies have evaluated striatal volume in pediatric BD, yielding
inconsistent results. Speciﬁcally, compared with typically developing controls,
one study showed that BD children and adolescents have greater basal ganglia
volume (108). Another study found that pediatric BD subjects had greater
putamen, but not caudate, volume (83). A third study did not ﬁnd between-
group differences in either caudate or putamen volume in BD versus control
youth; however, results indicated that in the BD group there was an inverse
relationship between age and volume of the caudate bilaterally and the left
putamen (109). The fourth study to evaluate striatal volume in pediatric BD utilized
voxel-based morphometry (VBM), an automated technique allowing volumetric

evaluations of small ROIs, such as the accumbens area, and found decreased
volume in the left accumbens area in NP-BD youth compared with controls (81).
To the best of our knowledge, no other study has measured accumbens volume
in BD subjects, whether pediatric or adult, largely due to the difﬁculty associated
with hand-tracing this region reliably. Given the role of the ventral striatum—
that is, accumbens area—in reward-processing, further work is necessary to deter-
mine the neurodevelopmental trajectory of striatal volumes in BD.
In sum, the most consistent structural MRI alteration found in BD children
and adolescents is decreased amygdala volume. However, in total, structural neu-
roimaging research in pediatric BD implicates a fronto-amygdala-striatal circuit as
mediating the pathophysiology of the disorder.

FUNCTIONAL NEUROIMAGING IN PEDIATRIC BIPOLAR DISORDER
The second neuroimaging technique used to examine the underlying pathophysiol-
ogy of pediatric BD is fMRI. This neuroimaging technique relies upon the fact that
the MR signal of blood is different when it is carrying oxygenated versus deoxyge-
nated blood. This blood-oxygen level dependent (BOLD) signal change can be
recorded from a subject’s brain across time; therefore, one can compare the
BOLD signal, and corresponding neural activity, occurring in speciﬁc brain
regions during different event types. For example, subjects may be scanned while
performing a computerized task designed to isolate a psychological process—for
example, recognizing angry or neutral faces. Although there are numerous fMRI
studies of BD adults, there are only two published fMRI studies of BD children

First, Blumberg et al. (56) demonstrated that, compared with controls, BD
adolescents had increased activation in the left putamen and thalamus during352 Brotman et al.

incongruent versus congruent trials on a Stroop color-naming task. In comparison,
previous fMRI studies of BD adults showed increased activation of the ventral PFC
during similar tasks requiring conﬂict monitoring (55,110). In the second fMRI
study in pediatric BD, Chang et al. (111) reported ﬁndings from two tasks: a visuos-
patial working memory task and a task with positively and negatively valenced pic-
tures. Pediatric BD subjects had increased activation on the two-back working
memory task in the bilateral ACC and left-sided putamen, thalamus, and DLPFC
compared with controls. In addition, pediatric BD subjects exhibited greater acti-
vation than controls in the bilateral DLPFC, inferior frontal gyrus, and right
insula while viewing negatively valenced nonface images. Finally, BD subjects
had greater activation in the bilateral caudate and thalamus, left middle /superior
frontal gyrus, and left ACC when viewing positively valenced pictures (111).

These fMRI studies are consistent with the structural MRI studies previously
discussed. In total, they support the hypothesis that pediatric BD subjects have both
structural and functional alterations of fronto-amygdala-striatal structures. Future
fMRI studies will likely address the extent to which these are trait abnormalities
versus mood-state dependent changes. Moreover, as high rates of comorbidity (par-
ticularly, ADHD and anxiety disorders) have been reported in BD youth (112),
additional work is needed to assess the role of comorbid diagnoses on the neural
abnormalities seen in BD youth. Finally, further research is necessary to determine
whether these patterns of altered neural activity are speciﬁc to pediatric BD or if
they are nonspeciﬁc markers of more generalized psychopathology.

The Neurochemistry of Pediatric Bipolar Disorder
The same MRI machines used for structural and functional imaging can also deter-
mine neurochemical alterations associated with psychopathology. This third form
of neuroimaging, known as magnetic resonance spectroscopy (MRS), relies on
the principle that the electron cloud surrounding all molecules is differentially
and characteristically shifted by the applied magnetic ﬁeld of the MR scanner.
Instead of recording spatial information (structural MRI) or BOLD signal change
(functional MRI), MRS records these characteristic chemical shifts in order to deter-
mine the concentration of known neurochemicals.
Spectroscopy studies of adults have advanced what is known about both the
pathophysiology of BD and the mechanism of action of commonly used anti-manic

medications, most notably lithium. Two chemicals in particular have been major
foci of research in BD: ( i)N-acetyl asparatate [(NAA), an intraneuronal marker
whose levels are decreased in neuropathology, such as brain tumors—increased
levels are thought to be markers of neuronal health] and ( ii) myo-inositol (a com-
ponent of the intracellular second messenger system). Several MRS studies have
demonstrated that BD adults have decreased NAA in comparison to healthy con-
trols in frontal ROIs (113), including the DLPFC (114). In addition, lithium increases
frontal NAA in both BD adults and controls (115), a ﬁnding which suggests that
lithium may have neuroprotective effects (116). Moreover, according to the “myo-

inositol depletion hypothesis of mania,” mania is due to an increase of second mes-
sengers, such as myo-inositol, causing an aberrant and excessive increase in cell sig-
naling; in turn, anti-manic agents, such as lithium, deplete this excessive supply of
myo-inositol, restoring balance to the cells and the patient (117). MRS studies indi-
cate that lithium and valproate decrease frontal myo-inositol concentrations when
taken by adults at therapeutic doses (118,119). However, although lithium canBiological Factors in Childhood and Adolescence 353

reduce myo-inositol to “normal” concentrations after only one week of treatment,
and these levels remain decreased with maintenance lithium treatment, there is
no signiﬁcant correlation between reduction in mania and reduction in myo-inosi-
tol in adults (118).
As with all neuroimaging, far fewer MRS studies have been conducted in BD
children and adolescents in comparison to the number done in BD adults. In fact,
only three MRS studies have been published in pediatric BD. The ﬁrst showed
that pediatric patients with familial BD had signiﬁcantly decreased NAA in the
DLPFC compared with controls (120). The second found that acute lithium treat-
ment (e.g., seven days) signiﬁcantly decreased myo-inositol in the ACC and that
this decrease was more prominent in lithium responders than in nonresponders
(121). The third MRS study, conducted by the same group, demonstrated that pedi-
atric BD subjects had signiﬁcantly increased ACC myo-inositol compared with both

controls and to youth with intermittent explosive disorder (122). Together, these
MRS studies conﬁrm that pediatric BD is characterized by speciﬁc neurochemical
alterations that change in response to psychopharmacological treatment. Moreover,
unlike in BD adults, these acute changes seem to correlate with treatment response
in BD children and adolescents.
Future MRS studies will facilitate greater understanding of the neurochemical
basis of BD in children and adolescents. Moreover, several research groups are
working to enable reliable quantiﬁcation of neurochemicals more directly linked
to BD and other mood and anxiety disorders, such as gamma-aminobutyric acid
(GABA). Additionally, MRS studies will allow the exploration of state versus trait
issues and the therapeutic effect of psychotropic medications. In turn, MRS will

enable the design of targeted interventions, including novel medications, to treat
or even prevent morbidity and mortality from BD.
FUTURE DIRECTIONS
What will be the future direction of research into the biological mechanisms of
pediatric BD? Forthcoming studies will likely expand upon those of the present
by evaluating children with different phenotypes of pediatric BD. For example,
future work may compare neuropsychological and imaging ﬁndings in NP-BD
and SMD youth. Studies determining pathophysiological similarities and differ-
ences between youth with NP-BD and those with ADHD or MDD will enable
researchers to ascertain speciﬁc neural and cognitive correlates of pediatric BD.
Moreover, researchers must continue to examine the inﬂuence of medications,

comorbidity status, and mood state while interpreting neuropsychological and
fMRI results. In addition, researchers can build on recent neuropsychological and
MRI work elucidating brain development (123) to determine how the brains of
children and adolescents with BD grow, develop, and prune differently than typi-
cally developing youth.
Finally, a consensus is emerging that the search for risk-related genes in BD
and other complex neuropsychiatric illnesses would be facilitated by the identiﬁ-
cation of endophenotypes, which are behavioral deﬁcits (e.g., impaired atten-
tion–emotion interactions) or biological ﬁndings (e.g., abnormalities in the
fronto-amygdala-striatal circuit) that are familial and associated with risk for an
illness (124,125). The identiﬁcation of such endophenotypes would allow the ﬁeld

to move beyond DSM-based phenotypic characterization of affected individuals
and those at risk. Speciﬁcally, if non-symptomatic children with a ﬁrst-degree354 Brotman et al.

relative with BD demonstrate similar deﬁcits to those observed in NP-BD patients
(e.g., deﬁcits in response reversal or emotion identiﬁcation), such impairments can
be conceptualized as endophenotypes, or trait-markers of BD. Employing this strat-
egy, researchers have begun to explore the psychiatric phenomenology of BD off-
spring (126) and to perform structural and functional neuroimaging in such
youth (84,111). These initial studies suggest structural and functional differences
in children at risk for BD compared with control youth. Studies are also beginning
to explore neurocognitive function in ﬁrst-degree relatives of BD patients (127,128)
and children temperamentally “at risk” for BD (129). Future studies should con-
tinue to explore potential neuropsychological deﬁcits in these at risk youth. Ulti-
mately, it is likely that research will begin to integrate at-risk studies with
behavioral and neuroimaging work, examining the relationship between endophe-

notypic markers, such as neuropsychological deﬁcits, genes, and brain
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B19 Biological Factors in Bipolar Disorders
in Late Life
Institute for Geriatric Psychiatry, Weill Medical College of Cornell University, and
New York Presbyterian Hospital, White Plains, New York, U.S.A.
HISTORICAL PERSPECTIVE
Current understanding of bipolar disorder (BD) in late life builds on early clinical
descriptions by European psychiatrists, and these descriptions emphasized links to
brain pathology. Manic signs and symptoms were described in the context of brain
lesions and disorders at least as early as the nineteenth century (1). Welt (2)
described behavioral “disinhibition” in patients with lesions of the orbital surface
of the frontal lobes. This was termed “Witzelsucht” by European psychiatrists (3),
and “pseudopsychopathic syndrome” by neurologists (4). These observations set
the stage for more recent investigations of brain pathology associated with mania

and depression in old age. Early writings mention the association between
brain vascular disease and mood disorder in late life (5). Kay et al. (6) and Post
(7) proposed that mood disorder with onset in late life reﬂects in part age-associated
brain changes.
In the mid-20th century, investigation of mood disorders in late life was
advanced by validation of the distinction between unipolar major depression
(UMD) and BD in younger patients (8). The introduction of lithium salts (9) and
other mood stabilizers reinforced the utility of the BD category across the age spec-
trum. It also encouraged both testing distinctions within BD such as atypical or type
II patients, and broadening the concept of BD.
Kraepelin discussed the incidence of ﬁrst episode mania, depression and

mixed states across the age span in “manic depressive insanity” (5). In a sample
of 903 cases, he observed that mania as ﬁrst episode of illness was less frequent
with increased age, although the incidence tended to increase between age 45 to
50 years. He also observed that, in contrast to depressive ﬁrst episodes, mixed
ﬁrst episodes declined consistently with age. Yet, he noted that affective episodes
could appear ﬁrst at “old-old” age, for example, 80 years. Kraepelin did not
differentiate UMD from BD, however.
Roth and colleagues (10) and other clinicians (7) commented on age and
symptom in BD patients. They suggested that although manic syndromes in the
elderly were similar qualitatively to those in younger patients, older patients
demonstrate attenuation or exaggeration of particular features, and had milder
features overall, compared with younger patients.

Those psychiatrists also pointed out that cognitive impairments frequently
accompany manic syndromes, particularly in aged manic patients; they described
disorientation, and delirium in these patients (5,7,10). Kraepelin observed
that dementia was not a necessary outcome of late onset affective episodes,
however.
361

As outlined below, BD in elders provides a potentially rewarding context for
studying biological factors mediating and moderating this illness and its treatment.
The literature now includes early results of the application of standardized
assessment methods and longitudinal characterization, in addition to cross-
sectional description. Beyond mood dysregulation, research has recently been
focused on comorbidities and behavioral dysfunction in this complex clinical popu-
lation. While most studies continue to target type I BD, there is new attention being
paid to other aspects of the BD spectrum in old age. Investigators have begun to
study bipolarity in elders treated in non-psychiatric settings. Research has also
begun to address causal factors, vulnerabilities, and pathophysiologies, and the
implications of social context and life events in BD elders.
CLINICAL OVERVIEW
Clinical Features and Differential Diagnosis

Reviews of clinical descriptive studies are available (11–13), and this material is
summarized in what follows.
Diagnostic criteria for BD, developed in young adult patients, need to be
applied in the elderly to test their limits. Exclusion criteria for studies need to be
considered carefully, as “casting a wide net” is appropriate to initial studies
of this poorly understood population. There has been little systematic investigation
of differences in intensity or frequency of particular psychopathologic features in
geriatric manic patients, and these reports have suggested extensive overlap with
younger patients (14).
The differential diagnosis of mania in late life overlaps that in younger
patients and it includes schizophrenic and schizoaffective disorders (15). In older
compared with younger patients, mood disorders related to illness or medical

treatment are more prevalent, particularly in late onset cases (16). Delirium and
dementia both can present manic signs and symptoms (10).
Elderly patients with manic states and BDs present relatively frequently to psychiatric
units serving the aged (17). These patients pose a growing public health challenge.
Manic states represent up to one ﬁfth of psychiatric hospitalizations among elders
(17). Assessments of community prevalence in elders have been low (18).
While the incidence of BDs is highest in early life, there is a wide range in age
at onset (11,19). First episodes of mania can occur in the hundredth decade.
A number of studies of geriatric manic inpatients found a median age at onset
for ﬁrst manic episode in the sixth decade (20,21). It appears that various selection

factors generate the spectrum of BD patients presenting at geriatric services. One
subset of geriatric BD patients has had recurrent early onset BD illness, while
another group has had recurrent depressive episodes prior to the late onset of a
manic episode (change in polarity), and another has new onset of mood disorder
in late life (22). This heterogeneity of antecedent illness course in geriatric BD
patients represents an opportunity for clinically and heuristically useful investi-
gation, including characterization using biological measures. Lin-Pl et al. (23)
suggest that since age at onset in mixed age patients not only deﬁnes subgroups
with differing clinical characteristics but also manifests familial aggregation, it
may be a characteristic of BD patients that may prove to be a useful phenotype

for genetic studies.362 Young et al.

Gender differences have received limited study in elders with BD. Two
studies have suggested that rates of ﬁrst hospitalization for mania increase in late
life in men but not in women (24,25).
Course
Chronicity, Relapse, Recurrence
Early reports suggested that aged manic patients are vulnerable to prolonged time
to recovery or to chronicity (26). Also, limited information regarding patterns of
relapse and recurrence in geriatric BD patients suggests that BD elders are at risk
for further episodes (13).
Cognitive Dysfunctions and Dementias
Cognitive impairments are described in BD patients when symptomatic and after
successful treatment, and these impairments are not explained by comorbid
substance abuse (27). Impairments occur in BD patients across the age spectrum
but may be more prominent with older age (28,29). Various domains of cognitive
function can be impaired. Deﬁcits are described in geriatric manic patients

(30,31), and they include executive dysfunction, memory, and speed of processing.
BD depressed elders demonstrate memory impairments (29), and although cogni-
tion improves with treatment in aged BD patients (32), and while deﬁcits can
improve with symptomatic improvement, successfully treated BD elders (31)
demonstrate impairments. The relationships between cognitive impairments and
other clinical dimensions in elderly BD patients appear complex. Some impair-
ments may reﬂect the consequences of illness, for example, illness episodes, associ-
ated hypothalamic-adrenocortical dysregulation, and somatic treatments. Yet these
cognitive impairments may offer a window into the dysfunction of speciﬁc brain
neuronal circuits in BD elders.
The relationship of BD to dementia is poorly understood. Recent investigation

(33) found greater dementia on follow-up in both BD and UMD elders compared
with comparison groups with medical illness; this is consistent with an earlier
report concerning cognitive performance (34).
Comorbid Substance Abuse
In BD elders there is little data regarding comorbid substance abuse (35).
Examination of one administrative database found excess substance abuse in BD
elders compared with aged controls, but less substance abuse in elder BD patients
compared with younger patients (36).
Mortality
Geriatric BD patients are at risk for high mortality, even compared with geriatric
patients with UMD (37). This increased mortality may reﬂect medical comorbidity
and other causes. Suicide rates in mixed-age BD illness are elevated but these rates
await study in the elderly.
Causal Factors

Age-associated causal factors may modify the form of illness, that is, clinical
features, in early-onset BD. On the causal factors involved in early life illness,
such as genetic characteristics, perinatal insults, and other early adverse life
events, aging would superimpose other causal factors, for example, effects of
illness episodes and treatments or other comorbid conditions.Biological Factors in Bipolar Disorders in Late Life 363

Age-associated causal factors may also contribute to late onset of BD illness.
These may include cardiovascular risk factors and other medical and neurological
conditions and their treatments. Late onset illness also may involve familial /genetic
mechanisms related to early life BD, and genetic factors related to neurological
disease and vascular disease.
Consideration of the s peciﬁcity of relationships between biological and other
causal factors and geriatric BD requires comparison with other aged patient
groups. In this discussion, we emphasize the comparison of BD with UMD in old
age; while the literature concerning causal factors in UMD in late life is more
extensive than that in BD, direct comparisons of aged UMD and BD patients are
few. Comparisons of ﬁndings in chronic psychoses with those in UMD are even
more sparse. Despite the possible link between BD in late life to increased risk of
dementia, direct comparisons of biological measures between the disorders are

not available.
Familial Inﬂuences
An important familial component to the etiology of type I BDs in young adults
has been established by twin and adoption studies (38). In geriatric patients, late
age-at-onset BD is associated with lower rates of familial mood disorder than
early onset illness (20); this is analogous to ﬁndings in mixed-age BD samples
(39). At the same time, age at onset of BD illness aggregates in families (23).
Vascular Disease and Stroke
A vascular component to pathogenesis has been postulated for BD (40), as it has in
major depression (41–43). This concept has in part been derived from comorbidity
data, and studies of stroke.
Systolic blood pressure in mixed-age manic patients is greater than in controls
(44); hypertension can also be noted in geriatric mania (45). Smoking is more

prevalent in mixed-age BD patients than in controls (45).
Patients with stroke and other brain lesions can develop mania (46). In a series
of eight patients with brain injuries who developed mania (47), all had damage to
the right hemisphere. Further, in a series of patients with BD associated with cer-
ebrovascular lesions (48), seven of nine had bilateral hemispheric damage, and
one had combined brain stem and bilateral hemispheric damage; none had
lesions exclusively located in the left hemisphere; subcortical damage tended to
be more frequent than cortical, brainstem, or cerebellar involvement; clinical sub-
types and patterns of cycling in these patients resembled those in idiopathic BD.
Differences in illness course has been linked to lesion location: unipolar mania

was associated with cortical lesions and BD course associated with subcortical
lesions in one report (49). In stroke patients, investigators have presented evidence
for interaction of causal factors; those with mania had higher rates of familial mood
disorder than non-manic patients (50).
Stroke associated with UMD appears to differ in neuroanatomic localization
compared with that associated with mania or BD illness. Although there has
been disagreement, left anterior lesions are predominant in UMD patients (51).
Other Medical Disorders and Treatments
Krauthammer and Klerman (16) and others have highlighted the association
between manic states and a range of medical disorders and treatments. Such “sec-
ondary” or “symptomatic” mania is noted more often in late-onset compared with
early-onset cases (20).364 Young et al.

Manic psychopathology can be detected in patients with dementia. Rates
of such co-occurrence may be low in ambulatory care settings (52). The diagnosis
of mania in demented patients may involve speciﬁc challenges, such as labeling
as agitation.
Psychosocial Adversity
A history of precipitating psychosocial events has been noted in some geriatric
manic patients (17), and lack of perceived social support is described in BD
elders (53). However, there was no systematic comparison to younger patients or
to elders with UMD.
LABORATORY MEASURES, VULNERABILITY AND PATHOPHYSIOLOGY
IN BIPOLAR ELDERS
Laboratory Measures
Structural neuroimaging has been applied in early studies of BD elders. There has
been scant investigation using other types of measures. The investigation of geria-
tric BDs is has primarily addressed type I disorder, and manic states related to
medical disorders. The following discussion focuses on studies that included a

sample of BD elders. We present examples of studies of age- or age-at-onset
effects in younger BD patients, and mention any direct comparisons with geriatric
UMD patients.
Genetic Variation
Studies of candidate genotypes focused on BD elders appear to be lacking. In
mixed-age BD patients with wide range of index ages and ages at onset (54), the
apolipoprotein (Apo)-E4 allele was linked to patients with both early age at onset
and psychotic features. Apo E polymorphisms have been linked to vulnerability
to degenerative dementia and to vascular risk factors.
Certain genetic inﬂuences associated with BD illness in young adults may be
“weaker” in later onset cases of BD (54), and other vulnerabilities such as medical /
neurologic comorbidities and other age-associated processes may be necessary to

trigger onset of illness in these patients. “Two-hit” pathogenetic models of late
onset BD have been discussed (55), which involve a genetic vulnerability to early
life BD interacting with other factors, either genetic or non-genetic. Possible
second genetic mechanisms proposed included triplet repeat expansion, damage
to mitochondrial DNA, and age-speciﬁc changes in gene expression.
Neuroimaging
Brain Morphology
There have been few structural neuroimaging studies of BD in older adult
(age.50–55 years) or elderly (age .60 years) patients. Table 1 summarizes these
studies, which use magnetic resonance imaging (MRI) and computed tomography
(CT). The table includes an aggregate of more than 200 patients. Subjects in several
studies (56–60) were only on their sixth decade of life. The studies differed metho-

dologically in their focus on global measures, regional volumes, and /or signal
hyperintensities (SHs). Of course, younger adults with BD illness also have abnor-
mal brain morphology, including volume abnormalities and SHs (61), and someBiological Factors in Bipolar Disorders in Late Life 365

TABLE 1 Structural Neuroimaging Studies in Older Adults and Elders with Bipolar Disorders
Author,
year Diag. NAge
(mean
yr)Age
(min.
yr) Imaging Focus AssessmentGroup
differencesAge at
onset
effect
Global
Broadhead
and Jacoby,
1990 (14)BP
NC35
3572.5
1.360 CT Hemispheres
Lateral vent
Third ventVisual and
computer
ratingsCortical atrophy:
BP.NC
VBR: BP ¼NC
Third vent: BP ¼NCNo
Young, et al.
1999 (112)BP
NC30
1871.4
74.460 CT Hemispheres
Lateral Vents
Third Vent
Frontal ventriclesCSW
VBR
3VR
FHRCSW scores: BP .NC
VBR scores: BP .NC
3VR: BP ¼NC
FHR: BP ¼NCCSW pos.
age at onset
of illness and
of mania
Rabins, et al.
2000 (67)BP
UMD
SZ
NC14
14
14
2173.0
69.3
70.1
Matched60 MRI Hemispheres CERAD Cortical atrophy:
BP, UMD .NC
Temp sulcus:
BP, UMD .NC
L Sylvian ﬁssure:
BP, UMD .NC
Regional
Beyer (a),
2004 (58)BP
NC36
2958.2a
61.0a50 MRI Temporal lobe
(hippoc) volumeL hippocampus
volume: BP .controlsNo
Beyer (b),
2004 (59)BP
NC36
3558.8a
63.2a50 MRI Basal ganglia volume

Regional
Beyer (a),
NC36
2958.2a
Beyer (b),
NC36
3558.8a
Total brain vol
Vent volR Caudate volume:
BP,controls
Tot br vol, vent vol:
BP¼NCTotal brain
volume neg.
assoc with
Signal hyperintensity /
lesions366 Young et al.

McDonald,
1991 (113)BP
NC12
1268.7a
68.3a55 MRI Ventricle size
Subcortical SH
PVHGlobal rating
SH size and
location
L versus R
Ant, mid,
or post thirdVentricle size: BP ¼NC
Pres of Lesions:
BP¼NC
Large lesion #: BP .NC
L¼R
Mid third: BP .NC
PVH: BP ¼NC
SH lesions: BP .NC
Fujikawa,
1995 (60)BP
UMD30
3061.3a
61.3aNA MRI SCI Area rated:
Perforating
Cortical
MixedSCI p: BP ¼UP (LOD)
SCI c: BP ¼UP (LOD)
SCI m: BP .UP (LOD)SCI total:
BP
(LOM).EOA
McDonald,
1999 (56)BP
NC32
4068.2
67.360 MRI PVH
SE
DWM
SCG 1,2Boyko scale PVH: BP ¼NC
SE: BP .NC
DWM: BP .NC
SCG 1: BP ¼NC
SCG 2: BP .NCNo
De Asis,
2006 (65)BP
NC40
1569.8
66.960 MRI Frontal DWM
SCGBoyko
scaleDWM: BP .NC
SCG: BP ¼NCFirst mania
DWM
LN
RY
SCG
LN
RN
aGrp age minimum ,60.
Diagnosis : BP, bipolar patients; UMD, unipolar major depression patients; SZ, schizophrenia patients; NC, normal comparisons; LOM, late onset mania; LOD, la te onset depression;
EOA, early onset affective [(B,UP)10 bipolar and 10 unipolar] patients.

Image : MRI, magnetic resonance imaging; CT, computerized tomography.
Focus : DWM, Deep white matter; SCG, subcortical gray (2 severity measures in McDonald,1999; SCG1, absent /punctate or conﬂuent; SCG2, absent /punctate, rounded with
smooth edges or irregular /conﬂuent); PVH, periventricular hyperintensities; SE, subenpendymal; SCI, silent cerebral infarcts: SCIp, subcortical gray and internal capsul e, belonging
to perforating branch system; SCIc, cerebral cortex and subcortical white matter; SCIm, combination.
Assessment : CERAD, consortium to establish a registry for alzheimer’s disease; CSW, cortical sulcal widening; VBR, ventricular brain ration; 3VR, third ventr icle ratio; FHR, frontal
horn ratio; SH, signal hyperintensities.
Note : N, non signiﬁcant correlation; NA, not available; Y, signiﬁcant.Biological Factors in Bipolar Disorders in Late Life 367

types of morphological abnormalities overlap those in patients with other disorders
such as schizophrenia (62,63).
The three studies that included global measures all found greater cortical
atrophy in the patients than in aged comparison subjects, and in one the atrophy
was associated with late age at onset. One of two studies that examined lateral
ventricle–brain ratio (VBR) (64) found higher values in BD patients.
Two studies (58,59) primarily examined regional volumes. One found signiﬁ-
cant caudate volume decrease on the right in patients, controlling for age and sex. In
the other, hippocampal volume on the left was larger in patients compared with
controls, and this was associated with lithium exposure. Total brain volume was
smaller in patients with later age at onset.
An early study of SHs in older adult and elderly BD patients (57) found
increased number of larger SHs with age. Two reports have found greater frontal

deep white matter SHs in BD elders compared with controls (56,65), while a difference
regarding subcortical gray was found in one (56). Fujikawa (60) found that patients
with late onset mania had greater silent cerebral infarcts than geriatric patients
with early onset mood disorders. In the deAsis et al. (65) study, right-sided frontal
deep white matter SHs were associated with later age at onset of BD illness.
An early study of mixed age BD patients using diffusion tensor imaging
found evidence of microstructural disorganization of white matter tracts involving
orbitofrontal cortex (66). Such ﬁndings are consistent with disconnection of circuits
involving subcortical and limbic structures.
Two structural imaging studies (67,60) compared aged BD and UMD patients.

The former found cortical atrophy in both BD and UMD aged patients. Fujikawa
(60) found that elderly BD patients had greater silent cerebral infarcts than aged
Causal factors implicated in BD in late life may be expressed as abnormal
brain morphology. In BD patients, brain morphology abnormalities have been
found to be related to familial risk (68). The relationships of SH to familial factors
and vascular burden in BD elders has not been examined directly, as they have
in UMD (69–71). SHs in normal elders are associated with genetic differences (72).
As with cognitive dysfunctions, some morphological abnormalities in BD
elders may be consequences of early life BD illness and its treatment. These
factors include effects of repeated episodes of illness, related endocrine dysregula-
tion, comorbid substance abuse, and effects of therapeutic drugs.

Functional Neuroimaging
Aged BD depressed patients examined under resting conditions using single
photon emission tomography (73) had lower cerebral blood ﬂow (CBF) in the pre-
frontal cortices and limbic and paralimbic areas compared with normal controls.
Similar differences were noted in geriatric UMD patients in this study, but the
patient groups were not directly compared.
Electrophysiological Studies
Studies of electroencephalographic (EEG) measures in geriatric BD appear to be
lacking. Age effects on EEG in normals have been described (74).
Neuroendocrine and Neurochemical Studies
With few exceptions, peripheral neuroendocrine function has not been investigated
in geriatric BD patients. Lithium antagonizes thyroid axis function in elders (75) as368 Young et al.

it does in younger patients; the rates of lithium induced-dysfunction may be greater
in old age. Change in thyroid axis function occurs in normals with age (76–79). We
are unaware of studies of thyroid axis response to lithium in geriatric UMD.
There is anecdotal evidence for gonadal hormone dysregulation in BD in
old age.
Late-onset mania has been reported during estrogen replacement (80),
consistent with reports of antidepressant effects in young adult UMD. Gonadal hor-
mones apparently have not been directly assessed in late life BD, however.
Catecholaminergic, serotonergic, GABAergic and acetylcholinergic neuro-
transmitter systems have all been implicated in the pathophysiology of BDs (81).
Neurotransmitter and metabolite concentrations in body ﬂuids have not been
evaluated in BD elders.
Indirect evidence suggests acetylcholinergic dysregulation in late life BD. Tri-
cyclic antidepressants, which have prominent anticholinergic effects, have been

linked to onset of mania in elders (82). Age effects on cholinergic neurons and
receptors have been reported in normals (83–85). On the other hand, cholinergic
agents can precipitate UMD in elders (86,87).
Signal transduction molecules that are altered by mood stabilizer treatments
have been implicated in the pathophysiology of dementia, for example, tau protein
(88); this association provides a rationale for preventative intervention trials. Data
concerning measures of these molecules in elderly BD patients are not available.
Preliminary investigation of nutrients in elderly psychiatric patients, includ-
ing BD patients, has suggested associations between serum homocysteine and
folate concentrations and abnormal brain morphology on neuroimaging (89).

High homocysteine levels were associated with greater SHs on MRI, while low
folate levels were associated with low volume of hippocampus and amygdala.
Some morphological abnormalities in BD elders may be consequences of early
life mood disorder and its treatment. These factors include effects of repeated epi-
sodes of illness and related endocrine dysregulation, comorbid substance abuse, or
effects of treatments.
Endophenotypes
The geriatric BD literature does not include study of laboratory measures of biologi-
cal factors in probands in relationship to presence or absence of familial mood dis-
orders. Endophenotypes (62) have been proposed for early onset BD. The criteria
for endophenotypes allow differentiation of abnormalities that are consequences
of existing illness from those that reﬂect causal factors. In young adults, proposed

endophenotypes have included cognitive dysfunctions (90) and neuroimaging
abnormalities (62,68), both of which are apparently characteristics of remitted
BD elders.
Pathophysiology
The pathophysiological abnormalities in geriatric BD are not understood. Models
of pathophysiology in BD have been proposed based on emerging concepts
derived from clinical ﬁndings in patients with coarse brain disease including
stroke, traumatic injury, and dementia (1), studies of mixed age BD patients
using functional neuroimaging (47), and animal models. While initially focusing
on location of lesions of speciﬁc brain structures, and differences between right
and left-sided lesions, current thinking emphasizes neuronal circuits or networks,Biological Factors in Bipolar Disorders in Late Life 369

that is, frontostriatal and anterior limbic (91,92), that link these structures. Nodal
points on these circuits include prefrontal cortex, thalamus, striatum, amygdala,
baso-temporal lobe /hippocampus, and cerebellum. Furthermore, functional MRI
in BD patients has suggested relative hyperactivity of ventral frontal and limbic
regions, for example, orbitofrontal cortex and perigenual cingulate and amygdala,
and hypoactivity of dorsal regions including dorsolateral prefrontal cortex and
dorsal anterior cingulate. Findings from preliminary structural imaging studies
and cognitive investigation in BD elders are consistent with aspects of these
models, but such research is at a very early stage.
BIOLOGICAL FACTORS AND THERAPEUTICS
Biological investigation can potentially contribute to management of aged BD
patients through characterization of subgroups of patients with poor tolerance
for pharmacotherapy or who may be resistant to somatic or psychosocial interven-

tions. This information may help elucidate mechanisms of effects of standard treat-
ments, and help identify patients for whom innovative therapeutic approaches can
be tested.
Pharmacokinetic Factors
Age-related changes in physiology, and comorbid conditions and their manage-
ment, have potential implications for dosing of mood stabilizers and other agents
in elderly BD patients. These include hepatic changes, decline in renal clearance,
changes in fat /lean body mass ratio, altered binding protein concentrations, and
drug–drug and drug–dietary interactions (93). Some of these changes can lead
to increased concentration /dose ratio. Unnecessarily high exposure to therapeutic
agents can lead to poor tolerability and related treatment failure.
Side Effects /Tolerability

While it is not clear how much age alone increases risks associated with exposure to
deﬁned mood stabilizer exposure, speciﬁc comorbidities identify elderly patients at
risk for toxicities. Himmelhoch (35) found that poor tolerance of acute lithium treat-
ment in geriatric manic patients was related to neurological disease; patients with
dementia or neurologic abnormalities did worse with lithium exposure. Similarly,
dementia patients with manic features tolerated moderate valproate doses poorly
in a randomized controlled trial (94).
Relationships between tolerated concentrations of mood stabilizers and acute
or long-term efﬁcacy are not clear. Identiﬁcation of clinical or laboratory predictors
of response to low dose and low concentration, either intended or necessitated by

limited tolerability, could help minimize side effects in such patients. Schaffer and
Garvey (95) reported a series of geriatric manic patients treated with 0.4–0.8 mEq /L
with favorable result in 14 cases. Other investigators (96) reported that concen-
trations above 0.8 mEq /L were associated with best anti-manic response.
Geriatric manic states associated with antidepressant treatment were
characterized in one study by later age at onset, but not by differing index age
(82); the antidepressants were primarily tricyclics. This ﬁnding is consistent with
ﬁndings of another study of tricyclic antidepressant pharmacotherapy (97);
it contrasts with a report in young patients (98), and suggests that risk factors for370 Young et al.

antidepressant-associated mania may differ with age; factors associated with late
onset may sensitize to some drug effects.
Laboratory predictors of low adverse outcomes in BD elders are not reported.
However, in UMD patients, neuroimaging abnormalities have been associated with
side effects of antidepressant agents (99). Genetic variation has also been linked to
adverse effects of psychotropics (100,101).
Therapeutic Effects
Age alone may attenuate anti-manic response to mood stabilizer treatment. An
early study noted decreased efﬁcacy of naturalistic acute lithium treatment across
the age spectrum (102). In another study (103), longer hospitalizations were associ-
ated with increased age in a mixed-age manic sample, only 10% of whom were aged
/C2160 years.
Neurological disease may modify anti-manic response to mood stabilizers.
Dementia may limit beneﬁt from lithium treatment of mania (35). Early ﬁndings
suggest a relationship between cognitive dysfunction and poor symptomatic

outcome of naturalistic inpatient treatment (104).
A retrospective study in young manic patients indicated better outcome of
valproate treatment in those with forms of neurological disorder (105). Whether
speciﬁc neurological dysfunctions predict therapeutic beneﬁt from anticonvulsant
treatment remains to be tested in elder BD patients.
Laboratory measures may prove useful in prediction of individual variation
in therapeutic response to adequate trials of pharmacotherapy in BD elders. In
an early report concerning geriatric BD manic patients, larger VBR was associated
with poorer response to naturalistic pharmacotherapy with lithium (106). SHs were
associated with poor outcomes in mixed-age patients with BD (107,108). Early
reports suggest that poorer outcomes of continuation-maintenance lithium treat-

ment of BD patients are mediated by several genetic polymorphisms (109).
Novel Treatment Strategies
Since some BD elders tolerated conventional treatments poorly or may have modest
beneﬁt from them, testing novel treatment approaches is an important aim for
research. Early ﬁndings regarding biological and clinical factors suggest that par-
ticular strategies may be rewarding: for example, cardiovascular interventions
such as smoking cessation, blood pressure management, and improved nutrition.
Given the overlap between BDs and cognitive impairments in elders, and an associ-
ation between anticholinergic agents and mania, studies of cholinergic agents may
be particularly relevant; cholinesterase inhibition can beneﬁt manic states in young
adulthood (110). Another example of innovative treatment is behavioral rehabilita-

tion: given the occurrence of behavioral dysfunction in geriatric BD patients (111),
disabilities can be a focus of interventions. Cognitive assessment and laboratory
characterization may aid the design of studies to test innovative treatments.
SUMMARY AND PROSPECTS
Age effects on clinical features of BD have received preliminary study, and there
is only limited information regarding the laboratory measures and age in BD.
Vascular changes and other forms of brain aging may contribute to onset of BDs
for the ﬁrst time late in life. Structural neuroimaging studies have supportedBiological Factors in Bipolar Disorders in Late Life 371

this concept. There has been virtually no application of genotyping or peripheral
physiological markers to the study of late life BD.
Preliminary evidence suggests that brain change in geriatric BD may predict
response to acute pharmacotherapeutic interventions. Evidence regarding predic-
tors of outcomes of long-term pharmacological and psychosocial interventions is
entirely lacking.
Ongoing demographic shifts and economic pressures necessitate a more ade-
quate knowledge base in BD elders regarding etiological factors, vulnerabilities,
pathophysiologies, and approaches to management. Recent advances regarding
genetics and molecular targets of mood stabilizers suggest new research opportu-
nities in late life BD. In BD elders, cognitive and affective neuroscience methods
may prove useful as aides in prognostic assessment and treatment. Studies of
pathophysiologies of late life BDs may also provide models for the pathophysiology
of early life BDs.

Supported by: MH 074511, MH068847, MH067028, HP00157, and MH63638.
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B20 Perspectives for New Pharmacological
Interventions
University of Texas Health Science Center at San Antonio,
ASSESSMENT OF CURRENT STATUS OF THERAPEUTICS
The range of treatments approved for bipolar disorder (BD) has broadened substan-
tially over the past decade, with all treatments other than lithium only having
received regulatory approval as of 1995 or later. The expanded range of treatments
has had the greatest impact on management of mania both acutely and in mainten-
ance care. Studies of mania have had several advantages over studies of depression
or other behavioral facets of BDs. A straightforward paradigm of studying a drug
versus placebo in hospitalized manic patients and employment of change in a short,
two-item scale has proved a robust model for all currently approved drugs (1,2).
Enrollment into such studies has been relatively easy to achieve, as hospitalization

is clinically indicated for most such patients, patients are readily assessed while in
an inpatient setting, and side effects are relatively well-tolerated for a short period
by manic patients.
Fewer studies and fewer treatments are available for depression in BD.
Complexities include difﬁculties in establishing prior manic or hypomanic episodes
when cross-sectionally evaluating patients while depressed, higher rates of
response on placebo in depression trials, and limited evidence regarding whether
depression in bipolar I and II patients can be equated (3–5).
Recent studies provide the ﬁrst well-designed evidence of maintenance effec-
tiveness of treatments, particularly lithium, lamotrigine, olanzapine, and dival-
proex, but not yet other bipolar drugs.

Studies of new molecules have been limited in part by current rating scales,
which, though adequately sensitive to identify overall reduction from syndromal
levels of severity, do not have sufﬁcient numbers of items to provide component
analyses that could establish the areas of behavior that might be speciﬁc to one
drug or a particular combination regimen. Therefore, a putative treatment that
might beneﬁt a particular spectrum of bipolar symptomatology, for example,
anxiety or irritability, is unlikely to be tested with adequate sensitivity by
primary scales. This limitation of both scales and current clinical trial study para-
digms has become more evident with data indicating higher comorbidity of BD
with other axis 1 disorders than any other axis 1 conditions and studies that estab-

lish a relatively consistent group of components, or domains of disturbed behavior
in BDs (Table 1) (6–9).
Relatedly, evidence indicates that there is relatively selective efﬁcacy of some
mood stabilizers on components of bipolar conditions, rather than across-the-board
efﬁcacy (10). Speciﬁcally, lithium and divalproex both were markedly superior to
placebo in reducing hyperactivity, only divalproex signiﬁcantly reduced irritability,
377

and neither drug signiﬁcantly reduced depressive or psychotic symptoms (10).
Other studies also support evidence of a pharmacodynamic effect of divalproex
on irritability (11–13).
The most recently systematically studied group of drugs, the atypical
antipsychotics, appear broadly efﬁcacious in mania. These drugs have a common
pharmacodynamic mechanism of blockade of dopamine type 2 (D2) receptors,
with lesser effects on serotonergic systems, particularly 5-hydroxy tryptamine
type 2 (5HT2) (14).
The behavioral effects of the class of drugs appears to be relatively similar,
with most reducing speciﬁc manic behaviors, but also nonspeciﬁc symptomatology
in mania as well, for example, impaired sleep, reduced appetite, and anxiety (15).
A broad range of drugs from other classes, but most with some anti-epileptic
properties, have been studied and appear to be ineffective in syndromal beneﬁts in
BDs. These include gabapentin, topiramate, levetiracetam, gabatril, verapamil, and

zonisamide (4,16,17). However, except for topiramate and gabapentin, the quality
of studies of these drugs is marginal.
With these drugs as well as those reviewed earlier, pharmaceutical companies
have limited laboratory and clinical investigative tools to test the spectrum of
efﬁcacy of new molecules. The exception in approach to characterization of spec-
trum efﬁcacy is lamotrigine, which was ﬁrst studied in BD in a large, open trial
of bipolar patients in all illness states, with systematic, open rating scales designed
to capture evidence of locus of behavioral beneﬁts (3). For the other drugs, research
pharmaceutical companies have generally made decisions regarding presumptive
area of beneﬁt, and moved directly to studies of that syndrome within BD.

However, animal models have been of limited beneﬁt in BD, whether for mania
or depression (18).
Speciﬁc Targets for New Treatment Development
Some facets of bipolar symptomatology can be understood from descriptive
studies. A substantial portion of patients treated with monotherapy regimens for
mania or depression continue to have syndromal mania or depression (19–22).
Only one randomized study has been conducted in speciﬁcally rapid-cycling
patients. Whereas lamotrigine was superior to placebo among bipolar II rapid-
cycling patients, it was not signiﬁcantly superior among bipolar I rapid cyclers
(23). Maintenance studies indicate that as monotherapy, all drugs tested in ade-
quate designs do not adequately control symptoms while achieving adequate toler-
ability for more than 30% of patients enrolled (24,25). Recent studies in mania,

depression, and maintenance indicate that 15% to 20% higher rates of responding
patients result when complementary medications are added to the primaryTABLE 1 Domains of Disturbed Behavior and Symptoms Identiﬁed in Studies of Bipolar Disorder
Bowden Suppes Cassidy Swann Altman Double
Elevated energy X X X X X
Psychosis X X X X X X
Irritability X X X X X
Affective instability X X X X X
Elated X X X X X
Anxious /depressed X X X X378 Bowden

monotherapy treatment. Such studies indicate that the strategy needed to achieve
such beneﬁt is generally to add the second drug to a ﬁrst medication which has
not alleviated manic or depressive symptoms despite a trial of reasonable duration
and dosage (20,26–28).
Studies that have commenced treatment with the combination regimen have
failed to show, or showed less robustly, a difference in favor of the combination
regimen over lithium or valproate alone (26). Mixed mania appears to be generally
more difﬁcult to treat effectively (29), although divalproex provides acutely better
efﬁcacy than lithium (30). However, during maintenance treatment, studies indicate
that patients with mixed features at the time of enrollment generally do less well
than initially euphoric manic patients, regardless of speciﬁc monotherapy treat-
ment, with evidence that such patients are more sensitive to adverse effects and
discontinue treatment more often for adverse effects (22).

Taken in the aggregate, these studies indicate that there is need for either new
drugs with different mechanisms from those currently in use, and /or for regimens
that combine currently available drugs in ways that broaden spectrum of
efﬁcacy while providing adequate tolerability. While the need would appear
more pressing for mixed mania, rapid cycling, and maintenance care than for
mania, all subtypes would appear to have a substantial portion of patients
who might have better symptomatic and functional outcomes with more effective
regimens and /or new drugs.
Novel Targets, Innovative Approaches
A series of studies indicate that lithium and valproate share substantial overlap of
effects on certain neuronal intracellular signaling systems. These include inositol
depletion, protein kinase C (PKC) activity, stimulation of the extracellular signal-

regulated kinase (ERK) pathway, the Wnt signaling pathway, and increased
phosphorylation of glycogen synthase kinase-3 (GSK-3) (31,32). An ERK kinase
inhibitor induced effects similar to those of amphetamines, suggesting that the
ERK pathway may contribute to antimanic effects of mood stabilizers (33).
In the search for a common mechanism of mood stabilizers, lithium signiﬁ-
cantly inhibits brain GSK-3 in vivo at concentrations relevant for the treatment of
BD (34). Lithium increased the phosphorylation of GSK-3 beta both in cells and
in mouse brain after chronic administration, but did not alter the phosphorylation
of Akt. GSK-3 is associated with functional roles in neuroprotection and circadian
rhythms. Bipolar patients have abnormal circadian rhythm activity in relationship

to levels of activity, interests, and sleep; thus this mechanism provides a possible
functional pathway by which valproate and lithium impact biological systems
that underpin manic behaviors (35).
Lithium and valproate reduce protein kinase C isozymes in rat brain. Both
drugs increase DNA binding of the activating protein-1 (AP-1) family of transcrip-
tion factors for PKC (36). Valproate, but not lithium, is incorporated into neuronal
membranes in an active saturable process, and binds at sites of naturally occurring
long chain phospholipids (37).
Having overlapping effects does not mean identical pharmacodynamic
properties. For example, the effect of lithium on GSK-3 is direct, while that of
valproate is indirect, probably through its inhibitory effects on histone deacetylase.

Valproate (VPA) blocks histone deacetylase. Inhibition of histone deacetylase is
linked to activation of Akt and thereby inhibition of the Akt /GSK-3beta signaling
pathway.Perspectives for New Pharmacological Interventions 379

Lithium and VPA induce similar changes in the morphology of axons by
increasing growth cone size, spreading, and branching (38). VPA increases the
DNA binding of AP-1 transcription factor, and the expression of genes regulated
by the ERK-AP-1 pathway (39).
Neurokinin (NK)-1-receptor antagonists may affect mood states and sub-
stance P (SP) may worsen mood. VPA dose-dependently inhibited SP-induced
interleukin (IL-6) synthesis, whereas carbamazepine and lithium showed no inhi-
bitory effect. VPA also downregulated the expression of the substance P receptor
(NK-1-receptor) (40).
VPA also activates the peroxisome proliferator-activated receptors (PPAR)-
gamma and delta, a mechanism not shared by other antibipolar drugs, and prob-
ably contributory to its augmenting insulin responsivity (41,42).
Lamotrigine produces use-dependent inhibition of sodium channels, in
a fashion differing from other sodium channel inhibiting anti-epileptic drugs

(43–45). Small studies suggest that some drugs that block calcium channels may
have some behavioral effects in BDs (46). These overlapping intracellular targets
thus provide possible pathways that could be used to identify, and compare in pre-
clinical testing, new molecules with plausible potential for efﬁcacy on some clinical
aspects of BDs.
Prospects for New Drug Development
Rating Scale Issues
Rating scales which encompass the spectrum of symptoms of BD should be avail-
able and utilized. The beneﬁts of such ratings are that proﬁles of a speciﬁc drug’s
actions can be identiﬁed, and patients selected in early clinical trials who have
characteristics are likely to respond to the drug. This strategy stands in contrast
to the current approach often used—deciding more on hunch than evidence that

a drug will have anti-manic or antidepressant effects, then studying the drug
solely or principally in such patients. One of the most persuasive indirect indicators
of the limitations of this strategy is that several drugs initially studied in and
approved for one disorder are eventually found to have clinically signiﬁcant
beneﬁts in component behaviors of the originally studied syndrome. Examples
are gabapentin, shown ineffective in mania (16) but efﬁcacious in social phobia
(47); topiramate, also ineffective in mania, but beneﬁcial in at least two conditions
associated with impulsivity, binge eating disorder, and alcoholism (48); and speciﬁc
serotonin receptor inhibitor (SSRIs), all initially studied and approved for
depression but more recently shown as efﬁcacious in various anxiety disorders.

Only an integrated scale is likely to provide principle behavioral component
factor ratings of use for the purpose of discrimination of the proﬁle of beneﬁt. Indi-
vidual item analysis can partially sufﬁce for this purpose, but items are inherently
less reliable than are factors composed of several statistically related items. Such a
scale can still provide manic and depressive subscales which are preferable for
certain purposes, for example, primary outcome measures for regulatory trials,
but not for new drug development.
Systematic, Open Trials
Open studies in a relatively broad spectrum of behaviorally disturbed individuals
can substantially aid in new drug development. Certainly in major depression and
BDs, but likely in most other axis I disorders, the range of fundamentally disturbed380 Bowden

behaviors is sufﬁciently broad that determination of the proﬁle of drug action will
beneﬁt from studies in a range of patients. The range should differ by severity, and
for BD, by syndromal subtype. The development of lamotrigine was speeded and
more efﬁciently targeted by employment of a ﬁrst large scale open study, rather
than a randomized study in a single phase of illness (49,50). An extension of this
strategy is that early studies should be considered for application in more than
one syndrome, if there is evidence that the component behavioral disturbances
on which the drug acts is found in several axis I conditions (31,36,51).
Study of Early Behavioral Effects
As reported previously for major depressive disorder, it is likely that early beha-
vioral improvements, especially if associated with eventually remitted states, will
be indicative of the primary proﬁle of a drug’s behavioral effects. Conversely, a

focus on change at the point that remission has taken place is likely to be less reveal-
ing of pharmacodynamic proﬁle, since once recovery is well underway, all aspects
of behavior are likely to show secondary, if not primary resolution. Phrased differ-
ently, well is well. We have shown major differences in the proﬁle of action of the
noradrenergic acting drug desipramine compared with the serotonergic acting
drug paroxetine in recent studies by means of these study designs (52,53).
Novel Use of Time to Event Analyses
Expanded application of time to recovered /remitted status has substantial potential
to aid in new drug development. Historically, psychotropic drug studies have been
short, and have taken global change from baseline to study endpoint as the primary

outcome measure, based on a single day’s ratings for patients with as little as one
day’s exposure to the drug, even though trial duration was up to 12 weeks or
longer. This chapter is not aimed at all considerations in deﬁning outcome measures
and selecting statistical tests, but there are data indicating that larger effect size
differences for drug versus placebo comparisons can be obtained when a degree
of symptomatic improvement must be maintained for several weeks (54). The
time duration can be selected in relationship to length of the study, and should
reﬂect contemporary clinical practices. The statistical techniques supportive of
these analyses include mixed model repeated measures, analysis of variance
(ANOVA), logistic regression, and Kaplan Meier and log rank survival analyses,

with the event required to be sustained. Because early discontinuation is not ran-
domly distributed across treatment arms in studies of BDs, it is generally invalid
to treat most, if not all, early discontinuations as right-censored (55).
Selection of Candidate Drugs
A greater emphasis on studies of drugs with novel mechanisms or extensions of
mechanisms associated with existing drugs should energize new drug develop-
ment in bipolar as well as other disorders. Although it is possible that other
drugs with D2 receptor blockade properties could prove to have quantitative as
opposed to small, incremental differences compared with currently available D2
blocking drugs, the possibility is low, given the overlap of actions of both
atypical antipsychotics, and traditional with atypical antipsychotics (56).

It is reasonable to test all new molecules which may have mechanisms related
to currently established treatments for BDs carefully. Mechanisms that would
bear consideration, but of course are not limited to the above discussed targets,
are: GSK-3 inhibition, ERK pathway stimulation, inositol pathway inhibition,Perspectives for New Pharmacological Interventions 381

Wnt signaling inhibition, use-dependent sodium channel inhibition, calcium
channel inhibition, and histone deacetylase inhibition. For some of these mechan-
isms, no truly established efﬁcacious drug is currently available. Nevertheless,
given small, positive studies with data from more than one drug, were a more
potent, or selective calcium channel blocker to be developed, it might have
behavioral effects of greater magnitude than drugs studied previously.
Attention to Anxiety
Anxiety states are both linked to BDs through lifetime combinations, and also
important components of the behavioral components of BDs. Although it is poss-
ible that adequate control of anxiety is provided by drugs such as benzodiazepines,
almost no primary analyses of anti-anxiety effects of treatments employed for BD
have been conducted. Anxiety disorders show the highest rates of comorbidity
with BD of any group of illnesses (6). Further, a lifetime diagnosis of anxiety

disorder predicted worse outcomes of bipolar depressed patients (54). Hypercorti-
solism, which is associated with anxiety and fearfulness, is elevated in bipolar
depression and mania, with the highest rates of elevation reported in mixed or dys-
phoric manic patients (57). Drugs that have some pharmacodynamic impacts on
hypothalamic pituitary adrenocortical function, for example, CRH antagonists,
would seem plausibly beneﬁcial in aspects of BDs, including anxiety /fearfulness.
The Role of Regulatory Agencies
In the United States, the Food and Drug Administration (FDA) conducts indepen-
dent analyses of data submitted for new drug indications. The quality of staff in
agencies that the author has had opportunities to interact with is consistently
high. However, there are often an inadequate number of personnel in relationship

to the prompt review of the complex data in multiple categories of documents that
must be reviewed, for each drug and each proposed indication. While it is occasion-
ally the case that political considerations inﬂuence priorities or policies, in general
scientiﬁc criteria and reasonable concerns about protection of public health interest
drive most actions.
An important point is that regulatory agencies do not set criteria in a vacuum,
nor ignore scientiﬁc evidence. Further, it is not the FDA or its equivalent that has
established criteria that have generally been employed in new drug indication clini-
cal research programs. For example, there is no written statement that submission
of a total score on the Montgomery Asberg Depression Rating Scale (MADRS) and

report of the proportion of patients who achieve 50% reduction in such score from
baseline is required for consideration of an indication for acute depressive episodes
in bipolar depression. Rather, regulatory agencies consider proposals from industry
scientists, weigh the reasonableness of the proposed study methodology, and
provide some, albeit limited, feedback if they recognize issues that seem important
but unresolved in the proposed plan of the study. It is the case that precedent plays
a major role. In part, this reﬂects an aim of equipoise within agencies. For reasons of
fairness to companies which compete, and some general guidelines that can
be understood by all stakeholders in new drug approval processing, agencies
are inclined to maintain in effect criteria that were applied in other recent, related

applications for a new indication.
However, as scientiﬁc evidence changes, considerations for novel endpoints
or study designs also change. An important simple example is the recent conduct
of studies combining two drugs for treatment of mania in BD. Until the late382 Bowden

1990s, no such studies had been conducted with large samples and with intent of
regulatory submission. Many scientists working with mood disorders doubted
that the addition of a second agent known to be an effective ﬁrst agent would
provide a statistically signiﬁcant advantage in a trial. With results that indicated
clear additional beneﬁt could be obtained, particularly when the second agent
was added to a drug that had not fully controlled manic symptomatology (in
effect an enriched, but clinically generalizable strategy) the FDA responded with
approval for the combination regimens (20,26). In instances where legitimate
major divergent opinion regarding interpretation of evidence-based study
designs, the FDA, scientiﬁc organizations, and industry have often utilized
regularly scheduled or single issue meetings to convene experts from appropriate
interest groups to work through the issues for purposes of developing policies.
SUMMARY

SUMMARY
This chapter summarizes factors that may facilitate or impede the development of
new drug treatments for BDs. What seems most evident as a guide to maximizing
opportunities for the much needed addition of new treatments for aspects of BD
care is that current paradigms are broadly inadequate. Even where aspects of
efﬁcacy are adequate, there are numerous drugs for which tolerability and safety
are still problematic. Strategies and solutions for these issues must be multifaceted.
The link of drug development strategies to animal and human evidence of targets in
central nervous system (CNS) neurons is a given that all persons involved in new
drug development recognize. Strategies that build on extension of drugs within a
class, although understandable, has had some undesirable consequences. At the

least, it impels pharmaceutical companies to overemphasize small differences
between compounds. Additionally, it sometimes misleads the lay public in believ-
ing that breakthroughs have occurred when differences are actually modest.
Further, it deploys limited resources, essentially reducing efforts that might be
more productively deployed elsewhere.
A rethinking of strategies for early phase I and II studies is suggested by this
author. Reliance on total scores from scales with incomplete spectrum of items to
cover the domains of behavioral disturbance in a disorder, certainly one with as
much established complexity as BD, can only inadequately establish the spectrum
of efﬁcacy of putative new treatments. The approach in terms of more scientiﬁcally

sophisticated use of rating scales also requires some rethinking about early clinical
studies. Research program planners should consider testing in a broader spectrum
of patients both within a single syndrome, using current Diagnostic and Statistical
Manual-IV (DSM-IV) criteria, but also beyond the bounds of a single syndrome
when there are lines of evidence to indicate pharmacodynamic actions that might
be clinically important in more than one syndrome.
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B21 Physical Comorbidity in Bipolar Disorder
School of Neurology, Neurobiology, and Psychiatry, University of Newcastle upon Tyne,
Newcastle upon Tyne, U.K.
A number of studies have reported that bipolar disorder (BD) is associated with a
mortality rate approximately twice that of the general population (1–5). Suicide is
the leading single cause of excess mortality, but natural deaths contribute signiﬁ-
cantly to reduced life expectancy. The precise magnitude of the problem of physical
comorbidity in BD is unclear, and an international project is currently underway
that aims to review the worldwide literature as it pertains to physical illness in
schizophrenia and mood disorders (6). It is hoped that this project will bring
together the various sources of evidence with a view to generating speciﬁc sugges-
tions for the improvement of care for people with mental illnesses. Research activity

in the ﬁeld of physical comorbidity in BD has increased considerably over recent
years, although output has lagged behind similar research in schizophrenia. It is
hoped that this welcome trend will continue, and ultimately lead to evidence-
based guidelines for detecting and managing physical illnesses in this population.
This chapter does not aim to provide a comprehensive overview of the
problem of physical illness in BD, but rather focuses upon speciﬁc disease areas
that have attracted the most research interest, namely cardiovascular disease, nutri-
tional and metabolic diseases, and endocrine diseases. All health professionals
involved in the management of BD will be acutely aware of the impact of many
of the psychotropic drugs on physical health (e.g., weight gain, thyroid dysfunc-

tion, etc.). Disentangling the effects of drugs on physical health from the impact
of genetic background and lifestyle issues, for example, is far from straightforward.
We also summarize the contribution of commonly prescribed psychotropic drugs to
physical comorbidity. The chapter concludes with a consideration of the possible
reasons for the observed excess of physical illness in people suffering from BD.
CARDIOVASCULAR DISEASE
Coronary heart disease (CHD) and stroke are the principle components of
cardiovascular disease (CVD). Approximately 80% of the worldwide burden of
CVD occurs in low-income and middle-income countries, but much of our
current understanding of the causes and outcome of CVD is derived from
developed countries (7). For example, CVD is the leading cause of death in the

United States, and stroke ranks third, accounting for nearly 40% of all deaths (8).
Almost one million people in the US die of CVD each year, and many of these
deaths are preventable (8). CVD is a leading cause of premature, permanent disabil-
ity, and the economic impact is considerable—around $394 billion in 2005, resulting
from health care expenditure, and loss of productivity from death and disability (8).
387

A recent case-control study in 52 countries has shown that nine easily
measured and potentially modiﬁable risk factors account for over 90% of the risk
of an initial acute myocardial infarction, and the effect of these risk factors is con-
sistent in men and women, across different geographic regions and ethnic groups
(7). Worldwide, the two most important risk factors are smoking and abnormal
lipids (7). Psychosocial factors, abdominal obesity, diabetes, and hypertension are
also associated with increased risk of myocardial infarction (7). Modiﬁcation of
these risk factors is of paramount importance in reducing the burden of cardiovas-
cular disease around the world.
There is a burgeoning literature examining the relationship between major
depressive disorder and cardiovascular disease, and some of the literature regard-
ing the epidemiology of comorbid coronary artery disease and depression has been
reviewed previously (9). The prevalence of depression in cardiac disease is reported

to be 17% to 27% (9), and a number of studies have reported that depression may
contribute to the progression of existing coronary disease and have a deleterious
effect on outcome (10–13). Possible pathophysiological mechanisms have been
reviewed previously (13–15). Patients with BD have also been shown to have
increased rates of cardiovascular mortality (1,16), although this has been a relatively
neglected area of research. Indeed a recent review of medical comorbidities in BD
(17) presents no speciﬁc data on cardiovascular morbidity in this population,
although mean rates are given for comorbid obesity (21%) and Type 2 diabetes
(10%), both risk factors for the development of CVD.
Despite the large number of studies examining the relationship between

depressive disorder and cardiovascular disease, there are few studies which have
investigated the burden of cardiovascular disease in BD. Kilbourne et al. (18)
report the prevalence of general medical conditions in a population-based
sample of patients diagnosed with BD in the Veterans Administration (VA). In a
cross-sectional study of 4310 patients receiving care at VA facilities within the
mid-Atlantic region of the United States, general medical conditions were identiﬁed
from ICD-9 codes recorded on the National Patient Care Database. The total count
of general medical conditions between the bipolar cohort and the national VA
cohort was compared. In the bipolar cohort the prevalence of hypertension was
34.8%, ischemic heart disease 10.6%, congestive heart failure 3.2%, peripheral vas-

cular disease 2.9%, and stroke 1.7%. It is noteworthy that there was a statistically
lower prevalence of cardiovascular diseases in the bipolar cohort compared with
the national VA cohort, although the bipolar sample was approximately four to
seven years younger than the national cohort with the same condition. Although
this is a valuable study that addresses an important gap in the literature, there
are several methodological limitations. The data are derived from administrative
data sets and diagnoses are not conﬁrmed by formalized procedures. As the
recorded conditions are those that have been observed by the provider, the true
prevalence of general medical comorbidity may have been underestimated. Con-
versely, only those patients receiving care (who are more likely to have multiple

diagnoses) are included in the database, which may overestimate the true preva-
lence of medical comorbidity.
The same group has published a similar study, using the same database,
which reports general medical comorbidity in older patients with serious mental
illness (schizophrenia, schizoaffective disorder, or BD) (19). Of the 8083 patients
included in the study, 2446 (30%) had a diagnosis of BD. Overall, older, versus388 Mackin and Ruttledge

younger, patients were more likely to be diagnosed with general medical comorbid-
ity. The most common comorbid condition among the whole cohort was cardiovas-
cular disease (30.7%); hypertension was 25.5%, congestive heart failure 2.6%,
peripheral vascular disease 1.8%, stroke 2.1%, and ischemic heart disease 6.7%.
The prevalence rates speciﬁc to BD are not given in this study.
Beyer et al. (20) also assessed the presence of general medical conditions in
1379 U.S. outpatients with a diagnosis of bipolar I disorder. Data were extracted
from the Duke University Medical Center database. The number of comorbid
medical conditions increased as a function of age. Diseases of the circulatory
system were present in 13% of patients with BD. Speciﬁc cardiovascular diseases
are not speciﬁed with the exception of “cardiac disease /hypertension,” which
had a prevalence of 10.7%. This study has similar methodological shortcomings

to that of Kilbourne et al. (18). In addition, the lack of a comparison group prevents
any evaluation of how medical comorbidity in BD compares with that in the general
One study has examined the prevalence of QTc prolongation in a cohort of 65
outpatients from the North East of England receiving antipsychotic drugs
(BD¼30.8%, schizophrenia ¼30.8%, schizoaffective disorder ¼13.8%, other
mood disorders ¼24.6%) (21). The QTc interval on the electrocardiogram is a
measure of ventricular repolarization, and prolongation of the QTc interval is
associated with cardiac arrhythmias and sudden death. Only two patients (3%)
had prolongation of the QTc interval, and there was a signiﬁcant correlation
between increasing age and QTc interval. The ﬁndings of this study should be con-

sidered preliminary given the small sample size and the cross-sectional nature of
the study, and further investigation of cardiac physiology and its relationship
with mood disorders and adverse outcomes is needed.
Strudsholm et al. (22) investigated the risk for pulmonary embolism in
patients with BD. Danish national registers were used to examine somatic and psy-
chiatric information on 25,834 patients with BD and 117,815 controls matched for
age and sex. Patients with BD had a signiﬁcantly increased occurrence of pulmon-
ary embolism [increased incidence rate ratio (IRR) ¼1.61; 95% CI ¼1.38–1.88]. The
authors offer several possible explanations for the association between BD and pul-
monary embolism, including the effects of restraint (as immobility predisposes to

deep vein thrombosis in the lower extremities and pelvis), antipsychotic-induced
apathy and consequent immobility, and infectious endocarditis resulting from
intravenous drug use. One of the strengths of this study is that all admitted patients
were included in the analysis. However, the lack of formalized diagnostic pro-
cedures, and the possibility of better detection of other medical conditions (such
as pulmonary embolism) in hospitalized patients may have inﬂuenced the results
of this study.
The paucity of studies of cardiovascular morbidity in patients with BD is of
some concern, particularly given that large cohort studies appear to indicate that
BD is associated with high levels of medical comorbidity, which includes cardiovas-
cular disease. Well-designed, prospective studies are needed in patients with BDs to

investigate in detail how genetic factors, structural /functional /hormonal changes,
and psychosocial stress contribute to the development of cardiovascular disease in
this population. In addition, studies assessing the effectiveness of psychosocial and
behavioral interventions in modifying the risk for cardiovascular disease are
urgently needed.Physical Comorbidity in Bipolar Disorder 389

NUTRITIONAL AND METABOLIC DISEASES
Obesity
In recent decades there has been a right-shift in the weight curve for the general
population, and the problem of obesity is now often referred to as a pandemic.
Obesity poses a particular problem in the management of patients with BD
because antipsychotic drugs (23), mood stabilizers such as lithium (24) and valpro-
ate (25), and many antidepressants (26,27) are all associated with weight gain.
Obesity, in turn, is a component of the metabolic syndrome (MS), and a risk
factor for type 2 diabetes mellitus (DM), hypertension, dyslipidemia, ischemic
heart disease, and some cancers (28). In addition to pharmacological treatment,
risk factors for weight gain and obesity in these patients include comorbid binge-
eating disorder, the number of previous depressive episodes, excessive carbo-
hydrate consumption, and low rates of exercise (29).
In a systematic review of 45 studies, patients with BD were at greater risk than

the general population for being overweight and obese (30). The prevalence of over-
weight, obesity, and extreme obesity in BD patients reﬂects the prevalence locally in
the general population—American patients had a higher Body Mass Index (BMI)
than European patients (29). A New Zealand study of 89 BD patients and 445
age- and sex-matched controls found that female patients were more often over-
weight (44% vs. 25%) and obese (20% vs. 13%) than female community control sub-
jects (31). Signiﬁcantly more patients receiving antipsychotic medications (APs)
were obese compared with patients not receiving APs. As a cross-sectional study,
it was not possible to tease apart important drug–disease state interactions, that
is, whether the higher prevalence of obesity among patients treated with APs

was due to the APs, or whether APs may have been associated with greater
illness severity, which, in turn, may have been associated with a greater risk of
obesity (30). A follow-up lifestyle study showed total ﬂuid intake and intake of
sweetened drinks were higher in BD, with total energy intake particularly higher
for female patients (31). BD patients reported fewer episodes of low-to-moderate
intensity and high intensity physical activity as compared with the “general popu-
lation.” This study was, however, based on self report only.
Drug-induced weight gain is a crucial issue in the management of BD. In a
study by Fagiolini et al. (32), most patients received lithium as their primary
mood stabilizer. Among the patients treated with lithium, during acute treatment,

14 of the 47 patients (30%) gained at least 5% of their baseline BMI, and during
maintenance treatment, 11 of the 45 patients (24%) gained more than 5% of their
BMI. The authors speculated that a greater number of prior depressive, but not
manic, episodes is associated with an increased likelihood of being overweight or
obese at study entry. Further, higher scores on the Hamilton Rating Scale for
Depression and negative scores on the Bech-Rafaelsen Mania Scale predicted an
increase in BMI during acute treatment. Weight at treatment initiation was inver-
sely related to weight gain during treatment, and the obese group had no signiﬁcant
weight gain during the acute phase of treatment.
Obesity has been associated with a shorter time to bipolar recurrence in the

maintenance phase and more depressive recurrences overall (33), but as some com-
mentators have pointed out, this study may have been confounded by a greater
number of previous bipolar episodes and higher baseline Hamilton Depression
Rating Scale in obese BD patients (28). Again, the direction of causation between
obesity and psychiatric outcome is still unclear.390 Mackin and Ruttledge

Metabolic Syndrome
Metabolic syndrome (MS) is a constellation of interrelated metabolic risk factors
that appear to directly promote the development of atherosclerotic cardiovascular
disease (ASCVD). Patients with MS are also at increased risk for developing type 2
diabetes mellitus (DM), which in turn is associated with increased cardiovascular
morbidity and mortality. Some atypical APs have been shown to increase the risk
of metabolic disturbances. Indeed, patients with BD exhibit risk factors for MS inde-
pendent of medication use and are predisposed to increased incidence of smoking,
poor nutrition, poor health care, and decreased energy expenditure, all of which are
risk factors for diabetes, obesity, and dyslipidemia (34).
There are only a few empirical studies of the prevalence of MS in BD patients.
In one survey of 103 patients from psychiatric outpatient services in the north of
England (32% BD), 12% of patients (overall) had impaired glucose homeostasis dis-

order (6% impaired fasting glucose and 6% with DM) and 8% met World Health
Organization criteria for MS (35). This is likely to be a conservative estimate as
measures of blood pressure or urinary albumin excretion were not available.
Diabetes Mellitus
Retrospective chart reviews show up to three times the prevalence of type 2 DM in
bipolar 1 disorder compared with national norms (36,37). In another chart review
study (38), BMI and psychiatric diagnosis but not medication were associated
with new-onset type 2 DM. Chart reviews of inpatients are, however, problematic
regarding selection bias and the reliability and validity of the diagnosis of both
type 2 DM and BD (28).
The mechanisms of the observed relationship between BD and DM are
unclear. It remains to be determined if susceptibility genes for BDs and glucose

homeostasis disorders cosegregate. Hypercortisolemia-induced insulin resistance
and abdominal adiposity is another mechanism that may account for the observed
increased incidence of DM in patients with BD.
There is clear and consistent evidence that commonly prescribed psychotropic
medication for the management of BD also contributes to the problem of increased
adiposity and disorders of glucose homeostasis in this patient population (39).
Currently available studies examining this complex area are usually small and con-
ducted in single sites, are prone to selection and ascertainment bias, are often retro-
spective, and rarely control for confounding factors. There is a dearth of systematic
research regarding predictive risk factors for weight gain and MS, and the impact

of psychiatric comorbidity [e.g., binge-eating disorder (30)], course of illness [e.g.,
number of depressive episodes (33)], and illness–treatment interactions (33,40).
ENDOCRINE DISEASES
Menstrual Abnormalities and Polycystic Ovarian Syndrome
Prospective studies have produced inconsistent ﬁndings as to whether there is an
association between mood symptoms and the menstrual cycle for women with
BD (41,42). Studies show that medications such as selective serotonin reuptake
inhibitors, alprazolam, and buspirone may precipitate premenstrual mood disturb-
ances (mania) in vulnerable individuals (43–45).
Although menstrual abnormalities are commonly reported in females prior
to diagnosis of BD and initiation of pharmacologic treatment, studies show aPhysical Comorbidity in Bipolar Disorder 391

correlation between menstrual abnormalities and the use of medications (46).
Polycystic ovarian syndrome (PCOS) is a syndrome of ovarian dysfunction and
is characterized by hyperandrogenism and menstrual irregularities (47). The
associated endocrine proﬁle is elevated testosterone and luteinizing hormone,
and low or normal follicle-stimulating hormone. Clinical symptoms include hir-
sutism, acne, and anovulation. Many women with PCOS also have obesity and
insulin resistance (47). Debate surrounds the possible role of anticonvulsants, par-
ticularly valproate, in the pathogenesis of PCOS. Much of the available data is
limited by the fact that it comes from research in women with epilepsy (48).
The relationship between the reproductive endocrine system and BD in women
is poorly deﬁned, and whatever data are available are hampered by small
patient numbers (49–51). In one of the few “larger” studies, Rasgon et al. (46)

in an investigation of the reproductive function and prevalence of PCOS in 80
females with BD found that 65% reported menstrual abnormalities, and 50%
reported such abnormalities prior to the diagnosis of BD. Valproic acid was
linked to menstrual abnormalities in all but one of these patients. A history of
menstrual abnormalities and obesity were predictors for menstrual and hormonal
abnormalities (including an increase in the levels of luteinizing hormone, follicle-
stimulating hormone, and testosterone over time) following treatment for BD. BMI
was signiﬁcantly positively correlated with free testosterone levels and insulin
resistance across all patients, regardless of medication used.
Women with PCOS often develop dyslipidemia, including increased levels of

cholesterol, triglycerides, and LDL cholesterol, and decreased levels of HDL choles-
terol (52), thus increasing further the risk of cardiovascular disease.
It is therefore important that a thorough history prior to the initiation of medi-
cation therapy be taken in order to determine the cause and risks of reproductive
endocrine disorders. Patients should be closely monitored for menstrual abnormal-
ities especially when receiving combination therapy with valproic acid to minimize
the risk of PCOS (46). Women of reproductive age should be informed of the risks
and beneﬁts of their pharmacologic treatment options, and should understand that
the impact of managing a chronic mood disorder on reproductive function requires
consideration from the outset (53).
Thyroid Abnormalities

Perturbations in the hypothalamic-pituitary-thyroid (HPT) axis, including state-
dependent blunting of the serum thyroid stimulating hormone (TSH) response to
thyrotropin-releasing hormone (TRH) have been demonstrated in depressed
patients (54,55). Thyroid function during manic episodes is less documented but
available data show blunted responses of TSH to TRH, similar to those described
during depression (56,57) as well as elevations in serum free thyroxine (FT4) index
(58) and decreases in serum T3 levels (59). Cassidy et al. (60) compared rates of pre-
viously diagnosed thyroid disease in 443 inpatients with BD along sex, race, and
manic subtype (mixed vs. pure). Overall, hypothyroidism was more frequent in
white patients and females, and increased with age. No differences were noted

between patients sampled during mixed or pure manic episodes. The participation
of inpatients and its implied severity of illness together with the lack of application of
research diagnostic criteria for hypothyroidism limit this study’s ﬁndings.
Using Danish register data, Thomsen and Kessing (61) examined the risks of
hyperthyroidism among three study cohorts of inpatients with a diagnosis of392 Mackin and Ruttledge

depression, BD, or osteoarthritis. There was a trend towards a signiﬁcant risk of
hyperthyroidism for patients with BD compared with patients with osteoarthritis.
The lack of formalized diagnostic procedures in this study, however, could have
inﬂuenced the results. Moreover, the use of individuals with osteoarthritis as a
control group in this study can be regarded as not ideal as the biological association
between osteoarthritis and hyperthyroidism is not yet clearly delineated.
Some studies have reported a correlation between rapid-cycling BD and
hypothyroidism (62–64). These ﬁndings, however, are limited by methodological
considerations such as medication status, recruitment bias, broad criteria for deﬁn-
ing hypothyroidism, and comparison groups (65). Furthermore, several studies
have failed to ﬁnd an association with hypothyroidism per se and have cast
doubt on the direction of causality (66,67).
Psychotropic Drugs
Antipsychotic Drugs

A recently published consensus statement (2004), developed by four North Amer-
ican medical associations, highlighted the problem of antipsychotic-induced meta-
bolic disturbances in patients receiving atypical APs (23). Among the atypical APs,
clozapine and olanzipine are associated with signiﬁcant increases in weight, while
ziprasidone and aripiprazole are associated with minimal weight change (68,69).
Risperidone and quetiapine appear to be associated with intermediate effects
with regard to their propensity to cause weight gain and glucose homeostasis dis-
turbances (23). Crucially, these differences may in turn affect compliance with medi-
cation and risk of relapse (40,70).
The consensus panel advised that there be monitoring at baseline and during

treatment with APs and suggested that history of obesity, diabetes, dyslipidemia,
hypertension, or cardiovascular disease (including family history) be obtained.
Further, they advised that height, weight (to calculate BMI), and waist circumfer-
ence are obtained, together with estimations of blood pressure, fasting blood
glucose concentrations, and lipid proﬁles. These parameters should be regularly
monitored following commencement of treatment in order to detect emerging
metabolic disease. The consensus statement recommends that if individuals gain
more than 5% of their initial weight, consideration should be given to switching
to another atypical AP. A “cost /beneﬁt” judgment should be made, of course, to

assess the psychiatric status of the patient and the potential beneﬁt of the atypical
APs before discontinuing (23).
More recently, results from the ﬁrst phase of the Clinical Antipsychotic Trials
of Intervention Effectiveness (CATIE) trial in patients with schizophrenia revealed
that patients taking olanzapine experienced more weight gain and metabolic
changes associated with an increased risk of diabetes than patients taking other aty-
pical APs (risperidone, quetiapine, and ziprasidone) (71). Similar large prospective
studies examining the impact of antipsychotic treatment on metabolic dysfunction
are needed in patients with BD.
The mechanism of AP-associated diabetes is unclear. Altered glucose homeo-
stasis may be mediated through a variety of mechanisms, including increased food

intake leading to increased adiposity and insulin resistance, effects on the insulin-
signaling pathway, and changes in pancreatic b-cell function causing altered insulin
release or altered hepatocyte /myocyte function resulting in impaired insulin
sensitivity.Physical Comorbidity in Bipolar Disorder 393

Hyperprolactinemia is a common side effect of some APs (34). Prolactin levels
may be elevated in patients treated with either typical or atypical APs. Hyperpro-
lactinemia can be distressing for the individual, and may cause menstrual irregula-
rities, sexual dysfunction, galactorrhea, and gynecomastia. The extent of prolactin
elevation appears to be dose related, and increases in prolactin sufﬁcient to sup-
press the sex steroid axis may result in hypogonadism and perturbations in bone
metabolism, including osteoporosis. Data regarding the effects of APs on bone
metabolism in relation to patients with BD is limited by small patient numbers,
the participation of patients with a schizophrenia diagnosis, limited controls, a
lack of prospective studies, and multiple confounders such as hypogonadism,
poor diet, and cigarette smoking (72). Hypergonadism may be more likely to
occur in women with schizophrenia compared with men taking typical APs:

Kinon et al. (73) reported prolactin levels 2.6 times higher in women compared
with men. There is no comparable study in BD. There appear to be clear differences
between antipsychotic agents with regard to their propensity to cause increases in
prolactin release. One study reported hyperprolactinemia in 88% of female patients
treated with risperidone (73). Other atypical APs such as olanzapine and quetiapine
result in more modest prolactin elevations than equivalent doses of risperidone (74)
or haloperidol (75).
Mood Stabilizers
Mood stabilizers are central to the pharmacologic treatment of BD. Some mood
stabilizers have been associated with weight gain, including valproic acid, carba-
mazepine, and lithium. In the case of lithium, both randomized controlled trials

and open-label naturalistic outcome studies show signiﬁcantly more BD patients
gaining weight (76,77). Lithium appears to exert insulin-like activity on carbo-
hydrate metabolism in some patients, leading to increased glucose absorption
into adipocytes. This effect may stimulate appetite indirectly. Lithium may also
have direct appetite-stimulating effects on the hypothalamus. Relieving thirst by
consuming high-calorie beverages has been proposed as another weight-gaining
mechanism (77). Lamotrigine has been studied in an 18 month randomized con-
trolled maintenance trial in 463 outpatients with bipolar 1 disorder (78). The
mean change in body weight at week 76 was 1.2 kg (2.7 lb) for patients receiving
placebo, 22.2 kg ( 24.9 lb) for lamotrigine, and 4.2 kg (9.3 lb) for lithium. While

there was no signiﬁcant difference in mean weight between patients receiving
lamotrigine versus placebo, the differences in weight change were statistically sig-
niﬁcant between the lamotrigine and lithium groups. The proportion of patients
who experienced /C217% increase in body weight from baseline to ﬁnal study visit
was 7% for the lamotrigine group, 10% for lithium, and 6% for placebo.
While there are few long-term randomized controlled studies of divalproex
(valproate) in the treatment of BD, weight gain greater than 5% from baseline
was signiﬁcantly more common in patients receiving divalproex (21%) compared
with placebo (7%) (76). As with lithium, similar mechanisms have been proposed
for this weight gain, including impaired fatty acid metabolism (79). Patients receiv-

ing carbamazepine with major depression, but not with mania, experienced a sig-
niﬁcant increase in body weight compared with placebo (80). In addition to
appetite stimulation, ﬂuid retention and edema have been reported as mechanisms
underlying this weight gain (81). Again, given the important role of mood stabil-
izers in managing BD, the psychiatric status of patients needs to be considered394 Mackin and Ruttledge

before switching medications possibly causing weight gain, to minimize the risk of
destabilizing the patient’s psychiatric condition.
Anticonvulsants such as carbamazepine and valproic acid have also been
associated with osteopenia (82,83), with the extent of bone loss being related to
the duration of treatment. Lithium also has a potential negative impact on bone
metabolism given its association with hyperparathyroidism (84,85).
The rate of hypothyroidism in lithium-naı ¨ve patients was found to be signiﬁ-
cantly lower than those treated with lithium (6.3–10.8% vs. 28.0–32.1%) (86). It has
been suggested that two categories of bipolar patients are more likely to be at high
risk for developing hypothyroidism in the course of lithium treatment. The ﬁrst cat-
egory comprises females who have had a longer course of illness predominated by
depressive episodes. The second category comprises those with rapid cycling and

mixed mania, that is, those who are diagnosed with moderate or severe mania and
have experienced a frequent recurrence of mood episodes. In contrast, hypothyr-
oidism is associated with longer illness course in lithium-naı ¨ve mania and with
more mood episodes in lithium-naı ¨ve bipolar depression (86). In a study of
adults over 65 years of age (87), lithium users were signiﬁcantly more likely to be
treated with T4 therapy (as a proxy for hypothyroidism) than were valproate
users, with hypothyroidism appearing to develop twice as frequently among this
age cohort than among a mixed-age population.
Barriers to Care
There are many reasons why people with BD may suffer from increased rates of
physical illnesses such as obesity, diabetes, and cardiovascular disease. Poor diet,

tobacco smoking, and lack of exercise are all associated with poor physical
health, and may play a signiﬁcant role in increasing physical morbidity in
BD (31). In addition, use of medical care often decreases after the onset of a psychia-
tric disorder (88), and even when patients are engaged in health care services,
rates of undiagnosed physical illnesses are often high (35). Other patient
characteristics may also contribute to poor detection and diagnosis of physical
illness such as impaired ability to verbalize concerns (89,90), poor insight into
illness (90), denial of illness (91), or an unwillingness to consult a doctor other
than their psychiatrist. When patients are cared for by psychiatrists, primary care
physicians, and physicians from other disciplines, there may be a shared assump-

tion that a colleague is taking responsibility for managing a particular medical
problem, when in fact the problem is not being attended to at all.
A study by Cradock-O’Leary et al. (92) used the Department of Veterans
Affairs database to examine the use of medical services by 17,653 patients who
were treated in Southern California and Nevada during the year 2000. Adults of
all ages with a diagnosis of BD had an especially high risk of not receiving general
medical services. The authors suggest interventions such as improving provider
competencies through education and proﬁling, and organizational interventions
such as computerized reminders to prompt mental health professionals to refer to
primary care for appropriate screening.
Although there is evidence that BD is associated with increased mortality,

some studies suggest that mortality may be reduced in some bipolar patient
groups. Attendance at lithium clinics and longer-term use of medication have
been shown to be associated with reduced mortality from all causes in people
with BD (93–95). These ﬁndings are not easy to explain, and may be attributablePhysical Comorbidity in Bipolar Disorder 395

to a number of factors such as the selection of speciﬁc patients to attend such clinics,
attendance at these clinics by individuals motivated to adhere to treatment and
therefore more likely to be motivated to take a greater interest in physical health
issues, or speciﬁc effects of medication on longevity.
There are few studies speciﬁcally examining the impact of differing models of
care on physical well-being and comorbidity in severe mental illness. One random-
ized trial from the United States valuated an integrated model of primary medical
care for a cohort of patients with serious mental disorders, and the authors con-
cluded that on-site, integrated primary care was associated with improved
quality and outcomes of medical care (96). There is a growing acknowledgment,
backed up by a burgeoning literature on physical comorbidity in severe mental
illness, that health professionals involved in the care of people with BD must be

mindful of the possibility of coexisting physical illness. There is a need for
greater communication and collaboration at the primary /secondary care interface,
and for the establishment of clear guidelines outlining responsibilities and proto-
cols for screening and managing physical health and disease in patients with BD.
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B22 Toward a Pathophysiology of
Bipolar Disorders
Department of Psychiatry and Behavioral Sciences, University of Washington,
Seattle, Washington, U.S.A.
Research ﬁndings regarding bipolar disorder (BD) continue to clarify the classiﬁ-
cation, mechanism of action, and treatment regarding these conditions. However,
much research needs to be done in order to elucidate deﬁnitive methods of classi-
ﬁcation and more precise treatment approaches. We stand on the verge of the
genomic period and its application to psychiatry and in particular our knowledge
about BD. This exciting opportunity will largely allow for more precise classiﬁ-
cation and treatment of these conditions. However, these research advances will
take some time. In this chapter, we review the recent advances in research involving
BD and discuss continued gaps in our knowledge regarding these conditions. We
also outline some areas for future research.

SUMMARY OF CLINICAL RESEARCH ADVANCES
Two major clinical areas of research should be noted. First of all, there is increasing
attention to the concept of bipolar spectrum disorder (BSD), or “soft” BD (1–3). The
relationship of patients with depression and mild and often times brief hypomanic
periods is a major focus of research interest. Several review articles and research
ﬁndings point toward a need to loosen the criteria for BD in DSM-V in order to
expand the concept of bipolar II and include many individuals who are currently
termed “bipolar disorder, not otherwise speciﬁed” as having true BD. Data
supporting the inclusion of these “soft” bipolar cases as true bipolars are largely
validated from family history studies.
Treatment studies of BD have recently pointed to the effects of lithium as an

antisuicidal agent (4,5). Although not deﬁnitively demonstrated by direct placebo-
controlled data, there is mounting evidence from a variety of research method-
ologies supporting the antisuicide effect of lithium. Since suicide is an unfortunate
outcome in many patients with BD, the use of lithium to reduce suicidal behavior
would seem to be an important clinical approach, and, hopefully, there will be an
increased use of lithium treatment for patents with bipolar conditions. Other treat-
ment studies have pointed toward the use of atypical neuroleptics not only for treat-
ment of mania but more recently for treatment of the acute depressed phase of BD
and perhaps for maintenance therapy to prevent recurrences of mania and
depression in bipolar patients (6,7). Additional research on anticonvulsants, such

as lamotrigine, has also added to our database regarding effective maintenance
therapies (8).
401

Neuroimaging studies have continued to point toward some abnormalities,
particularly in brain structure, of bipolar patients (9).
MAIN GAPS IN KNOWLEDGE AND METHODOLOGICAL
DIFFICULTIES: BASIC SCIENCES
Despite remarkable advances in the treatment of BD over the last generation, we
still have a limited understanding of its pathophysiology. We have no indication
of what causes the underlying biochemical changes associated with the symptoms
that we can observe and only clues about the mechanisms of action of the treat-
ments that we already use. This is different than many other human conditions
in which there is an understanding of at least some aspects of the pathophysiology.
For example, myocardial infarctions occur when inadequate oxygen is delivered to
the heart muscle, and treatments that change the metabolic supply and demand
dynamics may be useful therapeutics. In this example, we also have a clear sense
of the differences between causal and therapeutic mechanisms.

The problem of understanding the pathophysiology of BD has been tackled
using both human- and animal-based strategies. In humans, genetic associations
have been investigated using a variety of strategies and these are discussed
elsewhere in this volume. However, genetic strategies are hampered by the possible
mismatch between the timing of gene expression and manifestation of the illness.
Critical genes may be involved at early developmental stages in the pathogenesis of
BD and these may not be easily traced at later stages of adulthood (when symptoms
manifest) or in postmortem analyses. While the methodology for analyzing gene
expression and protein content in discrete brain regions has leaped forward in
recent years, it is possible that even consistent changes detected in brains of affected

individuals are not closely linked to the proximate genetic causes of bipolar illness.
For example, altered expression of a transcription factor or other regulatory protein
during brain maturation may lead to altered neuronal signaling or synaptic organiz-
ation at a later point that in turn destabilizes mood or impacts decision making or
other elements of behaviors associated with mania and depression. The biochemical
changes involved in such later events may be critical to the manifestation of symptoms
but may not be speciﬁc at all to BD. Ironically, time-tested histological methods may
give quite sensitive clues implicating altered expression or activity of regulatory
factors that guided neuronal development and circuitry wiring decades before the

appearance of affective or cognitive symptoms. Some genes may contribute to a
general susceptibility to one or more psychiatric disorders, while others may inﬂuence
a vulnerability to deterioration over time, speciﬁc features shared with diseases such
as schizophrenia or responsiveness to the therapeutic treatments (10). On the other
hand, the investigation of adult brain neurochemistry may yield valuable clues to
identify novel proteins or genes that can be targeted for treatment purposes, even if
the targets are not closely linked to the original pathophysiology in individuals
with BD.
A number of new treatments for BD have been developed in recent years, and
it is a natural strategy to try to determine which neurochemical effects of these

with BD.
medications are critical for stabilizing mood. This strategy is certainly likely to
lead to the identiﬁcation of novel treatments, but it may not explain why BD
occurs. Even if clues to the pathogenesis of BD are identiﬁed based on studies of
clinically useful medications, tracing back from effective treatments to biochemical
causes of BD will be difﬁcult. For example, there has been continued progress in our402 Neumaier and Dunner

understanding of the physiological effects of lithium. Recent evidence has focused
on lithium inhibition of inositol monophosphatase leading to depletion of phospho-
tidyl inositol or inhibition of glycogen synthase kinase-3, a member of the Wnt sig-
naling cascade (11); both of these observations are also reviewed in this volume.
Others have suggested that mitochondrial dysfunction lies at the core of BD (12),
but it is difﬁcult to separate cause from effect since depressive and manic states
may exact different metabolic demands on discrete brain circuits. In addition, the
neuroprotective features of lithium have also received considerable attention and
may bear on its long-term mechanism of action (13). Some investigators have
reasoned that biochemical effects that are common to more than one mood stabil-
izer are most likely to be essential factors in mood stabilization; however, this
presumes that different medications act on the same set of neurons to achieve

their therapeutic effects, which is unlikely to be the case. For example, consider
that both b-blockers and nitrates can alleviate angina, but they have unrelated mol-
ecular mechanisms and sites of action. Furthermore, this strategy may not detect
treatments with novel mechanisms of action if different points within a functional
neuronal circuit are involved. For example, dihydroxyphenylalanine (L-DOPA) and
anticholinergics both reduce the symptoms of Parkinsonism but act at different
points in the neural circuit. Similarly, atypical antipsychotics and anticonvulsants
are effective in treating BD, yet it is possible that the most easily identiﬁable neuro-
chemical effects of these medications are far removed from their eventual beneﬁts in
bipolar patients. Anticonvulsants can have quite immediate effects on the vulner-

ability to seizure activity by blocking sodium channels, but the therapeutic effects
of these medications develop over weeks to months in BD. Similarly, many investi-
gations have tried to discriminate between the immediate and delayed effects of
lithium and other mood stabilizers; each time a new acute or sustained effect of
these medications is discovered it raises the hope that a new class of improved medi-
cations will become possible. However, acute effects such as channel blockade may
or may not be critical to the sustained effects of these drugs (such as changes in gene
expression) involved in their ultimate mechanism of action.
We have recently learned from the example of the long and short polymorph-
isms in the serotonin transporter promoter (5HTTLPR) that genetics alone may not

predict the risk for developing depression; Caspi and colleagues have elegantly
demonstrated a critical interaction between genetic traits and environmental
exposure to stress in modulating the risk for depressive symptoms (14). Similarly, it
is well-established that stressful life experiences (15), drugs and alcohol (16), and
potentially many other factors inﬂuence the onset, severity, and course of BD.
Genes and environment are just as likely to interact to produce illness in BD as in
major depression. We do not know enough about the mechanistic aspects of how
stress inﬂuences mood episodes to say whether the stress effect is common or distinct
between these disorders. Besides the similarity that stress can exacerbate the course of
both unipolar depression and BD, antidepressants can treat the depressive features of

both conditions. While antidepressants reliably reduce the risk for relapse and recur-
rences in unipolar depression, these drugs can aggravate the course of cycling in some
bipolar individuals. This important difference suggests that the biological underpin-
nings of unipolar depression and BD are different, but we still do not know what brain
regions and neural circuits account for this. Furthermore, some bipolar individuals
seem much more vulnerable to antidepressant-induced cycling than others, and it
is possible that this reﬂects different “subtypes” at least in terms of the vulnerability
to changes in monoamine neurotransmission in mania and increased mood cycling.Toward a Pathophysiology of Bipolar Disorders 403

Animal models have been very helpful in developing new antidepressants
but have not led to new, validated treatments for BD. Even in schizophrenia,
another disorder with uncertain etiology, animal behavior has been useful in iden-
tifying potential neuroleptics that led to a new generation of antipsychotic drugs
(although this strategy led to the development of many similar medications, it
took the clinical observation that clozapine was unusually effective to open up
the conceptual constraints).
MAIN GAPS OF KNOWLEDGE AND METHODOLOGICAL
DIFFICULTIES
Clinical Studies
There are four major target areas important in the treatment of bipolar patients:
acute mania, acute depression, prevention of mania or hypomania, and prevention
of depression. Of these targeted areas, treatment of acute mania is robustly studied
with many types of treatments approved and /or shown to be effective. The same
cannot be said, however, for acute bipolar depression. This area remains an import-

ant area for research since most patients with BD spend the majority of their ill time
in the depressed phase. However, only one treatment (the combination of olanza-
pine and ﬂuoxetine) is ofﬁcially approved by the Food and Drug Administration
(FDA) for bipolar I depression and no treatments are speciﬁcally approved for
bipolar II depression. Treatment approaches for bipolar depression need to be
further researched.
Maintenance studies have suggested that olanzapine and lamotrigine are
effective for the prevention of recurrence of mania and depression in bipolar I
patients. The difﬁculties in conducting such studies, however, suggest that
further research into prevention of relapse may be limited.
Recently, the vagus nerve stimulator (VNS) has been approved in the United

States for patients with treatment-resistant depression. Approximately 10% of the
patients in the clinical trails using the VNS were bipolar, suggesting further research
of VNS into BD speciﬁcally may be of interest. One such study is currently underway
in rapid-cycling bipolar patients (17).
We previously have pointed to difﬁculties in placebo-controlled studies of
bipolar I patients because of ethical issues regarding the use of placebo in such
patients. We suggest that most patients with BD are not treated with monotherapy
and it might be useful for the pharmaceutical industry to change their research
designs to gain approval of “add-on” therapies. Knowledge of what works and
what does not work for the various phases of BD will be quite important as increas-
ing numbers of such patients are identiﬁed.

An important knowledge gap is the anticipated ﬁndings from genetic studies
that would point to a better system for classiﬁcation and perhaps a more direct
approach toward pathophysiology of BDs and direct treatments of these conditions.
Although genetic research in BD is certainly not stalled, it is interesting that major
ﬁndings continue to be elusive (18). Increasing methodological advances that
permit rapid identiﬁcation of genetic markers for conditions will likely be import-
ant in ultimately elucidating the multiple genes thought to be responsible for
bipolar conditions.
The clinical interface between neuroimaging techniques and BD also shows a
good deal of promise. Various neuroimaging techniques including magnetic reson-
ance imaging (MRI), CT scanning, magnetic resonance spectroscopy (MRS), and404 Neumaier and Dunner

others are currently being investigated regarding bipolar patients in order to
determine metabolic and structural changes associated with bipolar conditions.
The issue of diagnosis of mania in children is considerably problematic. It is our
belief that this controversy will likely be resolved through validation of diagnosis
likely from genetic studies. Until then, the issue of the existence and identiﬁcation
of children with BD, particularly mania, remains considerably problematic. Clinical
classiﬁcation studies and treatment studies will not seemingly solve the issue of the
correct diagnosis that might be applied to these individuals.
PATHOPHYSIOLOGY OF BIPOLAR DISORDER, INTEGRATION
OF AVAILABLE BASIC SCIENCE
Animal models of mental illnesses have always been strongly inﬂuenced by the pre-
vailing conceptual frame of the era. Therefore, animal models that have been pro-
posed have evolved from a focus on reﬂecting the behavioral states to

responsiveness to lithium and now to perturbations of the molecular signaling
pathways that are presumed to be involved in the disorder. Creating valid
disease models is a risky balance of circular reasoning that cannot be easily
avoided. BD, along with psychosis, has been particularly difﬁcult to model using
animal behavior. Some neurobehavioral disorders, such as seizures, are easier to
model than complex behavioral disorders because the manifestations (e.g., epilepti-
form activity with motor seizure) appear quite similar across species; even
depression and anxiety have been modeled using a variety of strategies that have
demonstrated good construct and predictive validity (19). This may be because it
is easier to interpret these behaviors objectively or because they are similarly

present in a range of species. Most attempts to model BD have focused on an
attempt to induce a depressive syndrome (these have been well validated) and
then a hyperactive syndrome to capture the manic phase. One example is the use
of amphetamine, which can induce hyperactivity, sleep disturbance, abnormal
sensory gating, etc. in rodents during acute exposure followed by a dysphoric syn-
drome upon drug discontinuation. Similar symptoms are encountered when
humans abuse stimulants, but this psychiatric presentation is very different from
BD in many ways. This strategy may also be limited because the amphetamine
may only model “downstream” behavioral aspects of mania or depression. Simi-
larly, other hyperdopaminergic states, including the dopamine transporter knock-

out mouse line, have been considered to model aspects of BD and some of these
behavioral effects are reversible by lithium (20). However, this rationale focuses
on the mood and activity components (which dopamine may indeed mediate in
part) but not the chronobiological aspect of BD. Sleep disturbance is a critical
feature of both manic and depressive episodes and sleep deprivation may precipi-
tate mania. There is a strong seasonal component in the cycling of some patients,
and the spontaneous development of an acute manic or depressive episode
without experimental provocation is an important component of a more valid
animal model. Since circadian rhythms usually oscillate predictably in the brain,
and lithium may regulate this (21), there is likely to be some link between dysfunc-

tion of these reliable biological clocks and the erratic ﬂuctuations that characterize
BD (22). It seems likely that this “lesion” lies upstream of dopaminergic function.
Thus, animal behavioral models based on mimicking some of the behaviors associ-
ated with BD may be useful in developing novel mood-stabilizing treatments, but
they are unlikely to capture the essential nature of BD.Toward a Pathophysiology of Bipolar Disorders 405

Lithium has also been noted to have activity-dependent effects on cyclic AMP
levels and other cellular effects (13,23); the idea that a mood stabilizer might have
state-dependent effects on signaling mechanisms is appealing and might be a
clue to improved animals models of BD. Thus, an improved animal model of
bipolar illness would ( i) show behaviors that reﬂect both depressive and manic
phases in the same animal over time; ( ii) mimic a range of mood, motivational, cog-
nitive, and activity features of mania and depression; ( iii) display spontaneous
switches between phases as well as precipitated episodes following exposure to
sleep deprivation, psychostimulants, antidepressants, etc; and ( iv) demonstrate
reduced behavioral symptoms after chronic administration of a variety of known
mood stabilizers. While this is a tall order to ﬁll, it provides caution that any
animal models that address only some of these components must be judged care-

fully so as to avoid overinterpreting the generalized applicability of associated
ﬁndings.
OF CLINICAL FINDINGS
Studies regarding the mechanism of action of lithium have continued in the
hope that elucidation of a deﬁnitive mechanism might lead to the development
of a distinct pathophysiology for BDs. There are similar studies regarding other
treatments of BD, such as atypical antipsychotics and certain anticonvulsants,
and it is hoped that knowledge of their mechanism of action might also lead
toward the pathophysiology of BD disorder. However, at this point in time, it
seems prudent to think of the future as being related to the development of the
genetic ﬁndings for BD and a pathophysiology being derived from such ﬁndings.

Treatment studies for BD continue, although, again, most of the attention for new
medication development has been focused on major depression and, in the case
of BD, on acute mania.
SUMMARY
We stand on the verge of very exciting ﬁndings that await the proper research
studies. Increasing attention to BD research is likely to have tremendous beneﬁt
in terms of our understanding the pathophysiology of these conditions as well as
identiﬁcation of individuals with these conditions and more direct approaches to
their treatment.
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BIndex
Acetylcholine (ACh), 35
dopamine neurotransmission,
modulating, 50
as a stress regulator, 80
Acquired treatment resistance, 312–313
lithium discontinuation-induced
refractoriness, 313
types of, 312
Adenylyl cyclases (AC), 111
Adrenergic (monoaminergic)-cholinergic
balance hypothesis, 67, 81
Adrenergic receptors, 35
Adrenocorticotropic hormone (ACTH), 91,
145, 191
Advanced sleep phase syndrome
(ASPS), 202
Affective disorder patients, spectroscopic
studies in, 75–80
acetycholine as stress regulator, 80
cholinomimetic drugs, 77–78
cardiovascular effects of, 77–78
changes in REM sleep in, 75–77
growth hormone supersensitivity, 78
hypothalamic-pituitary-adrenal axis
supersensitivity, 78–80
pilocarpine, supersensitive pupillary
responses to, 77
Affective psychosis, 213
Afterdischarges (ADs), 299
Aging, bipolar effects of, 365–370
brain morphology, 365–368
functional neuroimaging, 368
genetic variation, 365
laboratory measures, 365
neuroimaging, 365–368

structural neuroimaging studies in,
366–367
vulnerability and pathophysiology in,
365–370
Alphamethylparatyrosine (AMPT), 40
Alprazolam, 391
Alzheimer’s disease, 73, 226Amphetamine, 20, 41
behavioral excitation, 72
hyperactivity, 20
Amygdala, 150, 168
amygdala-kindled seizures, 309
Analysis of variance (ANOVA), 381
Animal studies, kindling /sensitization model
in, 300–303
high-licking maternal behavior, 301
low-licking maternal
behavior, 301
stress, effects on neurobiology and
behavior, 300–301
stressors and substances of abuse,
302–303
Anorexia nervosa, 213
Anticholinergic drugs
mood effects of, 70–71
Anticonvulsants, 328
Antidepressants, 328
monotherapy, 7
neurotrophic and neuroprotective
effects, 308
Antihypertensives, 109
Antimanic effects, of physostigmine, 69
Antipsychotic drugs, 393–394

Antipsychotics, atypical, 310, 381
Apoptosis /apoptotic cell death
in human hippocampus, 132–138
bipolars vs. controls, 135
FRET-based quantitative RT-PCR
validation, 137
genes associated with, 140
proapoptotic factors, mRNA expression
for, 133
schizophrenics vs. control, 134
Arginine vasopressin (AVP), 145
Atherosclerotic cardiovascular disease
(ASCVD), 391
Attention deﬁcit hyperactivity disorder
(ADHD), 263, 344
Atypical antipsychotics, 310, 381
409

basal ganglia, 170
Bech Rafaelsen Mania Scale (BR-MAS),
12, 390
Behavioral sensitization, 24
Beta-endorphin secretion, 79
Bioassays, 23
Biological rhythm dysfunction, 189–193
circadian abnormalities, evidence of,
190–192
seasonality in bipolar disorder, 192–193
timing of activity rest, irregularities in,
189–190
Bipolar Affective Disorder Dimension Scale
(BADDS), 11
Bipolar disorders (BD), see also mood disorder
animal models, 19–28
assessment of, 11–12
bioassays, 23
endophenotypes, modeling of, 26–27
problems and possible solutions, 22–27
psychostimulant-induced models, 19–21
variability, 25–26
in bipolar disorder subtypes, 325–337
bipolar spectrum concept, 9–11
brain imaging studies in, 161–179
catecholamine (CA) hypothesis of, 33–55
cellular endophenotype for, 131–141
in childhood and adolescence, 343–355
classiﬁcation, 1–14
DSM-IV , 2–4
ICD-10, 2–4
cyclothymic disorder, 332–333
depression, 5–6
disorder patients, studies of, 96–98, see also
under serotonergic dysfunction

genetics of, 233–244
hypomania, 4–5
hypothalamic–pituitary–adrenal axis in,
145–154
infectious etiology hypothesis in, 209–217
mania, 4–5
mixed states, 6–7
modeling, 22
neurocognitive ﬁndings in, 251–267
physical comorbidity in, 387–396
psychotic mania, 333–336
sleep and biological rhythms abnormalities
in, 189–203
stressors in, 275–291
subtypes, biologic factors in, 325–337
treatment, pharmacological agents in
action mechanism, 42–44[Bipolar disorders (BD)]
treatments for, 197–201
mania, 200
sleep–wake cycle manipulations,
197–200
Bipolar illness, 258
Bipolar remission, sleep in, 196–197
Bipolar spectrum concept, 9–11
Akiskal’s, 10
boundaries of, 10
objection, 10
Blood ﬂow studies, 45–46
and metabolism studies, 171–172
Blood-oxygen level dependent (BOLD)
signal, 352
Body mass index (BMI), 390

Borderline personality disorder, 8
Borna disease virus (BDV), 214
Brain derived neurotrophic factor (BDNF),
239–240
evolutionary conservation of, 239
Brain imaging studies, 161–179, see also
of catecholamine system in BD, 45–47
blood ﬂow studies, 45–46
genetic studies, 46–47
neurochemical studies, 46
structural brain imaging studies, 45
functional neuroimaging, 171–178
historical background, 161–162
structural neuroimaging, 162–170
Brain-derived neurotrophic factor (BDNF), 51,
300, 308
Breed true, 241
Brief Psychiatric Rating Scale (BPRS), 335
Brodmann’s areas, 164
Bunney-Hamburg Depression Scale, 69
Bupropion, 43
Buspirone, 391
Calcium calmodulin kinase-II (CaMK-II), 300
California verbal learning test (CVLT), 259
for children (CVLT-C), 347
Cambridge neuropsychological test

automated battery (CANTAB), 347
cAMP responding element binding protein
(CREB), 113
Carbamazepine, 310, 312, 331, 394–395
CAMP /PKA signaling cascade and,
115 – 116
effect on HPA axis, 153
Cardiovascular disease (CVD), 387–389410 Index

Cardiovascular effects
of cholinomimetic drugs, 77–78
Catecholamine (CA) hypothesis of BD, 33–55
abnormalities, 38–40
in norepinephrine and its metabolites,
39–40
in serum, urine, and CSF levels and their
tetabolites, 39
brain imaging of, 45–47, see also under brain
imaging
CA tracts from midbrain to MRS, 37
challenge studies, 40–42
depletion studies, 40
stimulation studies, 41
depression and antidepressants action
mechanism, 53
hormonal regulation of, 50
as modulators of MRC, 37–38
mood and, 36–38
mood regulation, 36–37
stress response, 36
neurochemistry and neurophysiology, 34
dopaminergic system, 34
reward mechanisms, 34
neuroendocrine challenge studies of,
41–42
dopamine receptor abnormalities, 41
neuroendocrine receptor abnormalities,
41–42
neurotransmission modulation and
implications, 47–52
ACh modulation, 50
5HT modulation, 48
excitatory amino acids modulation,
48–49
GABA modulation, 49
hormonal modulation, 50
by intracellular factors, 50–51
NE modulation of DA

48–49
neurotransmission, 47–48
neuropeptide modulation, 49–50
noradrenergic system, neurochemistry,
35–36
peripheral tissue, studies in, 43
postmortem studies in, 44–45
as translators of MRC activity, 38
Catechol-o-methyltransferase
(COMT), 43, 215
Caucasian BD samples, 240
Cell membrane and signal transduction
pathways, 109–123, see also under
signaling networksCellular endophenotype, for bipolar disorder,
131–141
apoptosis in human hippocampus, 132–138
in the hippocampus, 139–141
Cellular machinery
extracellular signal-regulated kinase (ERK)
pathway, 119–121
mood stabilizers and PI3K pathway, 118–119
neuroplastic events, 110–122
Central muscarinic regulation of cholino-
mimetic effects, 80–81
Cerebellum, 170
Cerebrospinal ﬂuid (CSF), 89, 94, 96
Childhood and adolescence, bipolar disorder

in, 343–355
broad phenotype diagnostic criteria, 345
cognitive and emotional processing,
346–350
in children, diagnosing, 343–345
narrow phenotype diagnostic criteria, 344
phenotyping system, 344
Choline, in bipolar patients, 75
Cholinergic 2 receptor (CHRM2) gene, 81
Cholinergic-muscarinic dysfunction in mood
disorders, 67–82
affective disorder patients, spectroscopic
behavioral ﬁndings, 68–75
biological ﬁndings, 75
central muscarinic regulation of cholino-
centrally active anticholinergic drugs,
70–71
choline in bipolar patients, 75
cholinomimetic agents, depressive effects
of, 72–75
cholinomimetic effects on manic symptoms,
68–69
cholinomimetic-catecholaminergic
interactions, 71–72
historical overview and highlights, 67–68
manic symptoms rebound, 69–70

of, 72–75
68–69
marijuana-physostigmine interactions, 71
muscarinic receptor gene and binding
alterations, 81
therapeutic implications, 81–82
Cholinomimetic agents
administration, 69–70
central muscarinic regulation of, 80–81
depressive effects of, 72–75
manic symptoms and, 68–69Index 411

Chromosome studies, 235–236
Chronic desipramine binding, 48
Chronic lithium treatment, 175
Chronic psychostimulant treatment, 20
Chronicity, 363
Cingulate hypermetabolism, 171
Cingulated, in bipolar disorder, 166
Circadian abnormalities, evidence
of, 190–192
Circadian phase advances, 199–200
Clinical Antipsychotic Trials of Intervention
Effectiveness (CATIE), 393
Clinical Global Impressions (CGI), 335
Clinical Global Impressions scale, Bipolar
Version (CGI-BP), 12
Clonidine, 43
Clozapine, in psychotic mania treatment, 335
Cognition, see also neurocognitive ﬁndings
attention-emotion interactions and emotion
recognition, 348–350
in childhood and adolescence bipolar
disorder, 346–350
memory, learning, and attention, 347
response ﬂexibility and motor inhibition,
347–348
taxonomy of, 252
Cognitive dysfunctions, 363
Cognitive ERP techniques, 228
Combination therapy, 310–311
Comorbid psychiatric illnesses, 263–264
Comorbid substance abuse, 363
Composite International Diagnostic Interview

(CIDI), 11
Continuous performance task
(CPT), 253, 347
identical pairs version (CPT-IP), 264
Core haplotype, 242
Coronary heart disease (CHD), 387
Corpus callosum, 167–168
Cortical–subcortical interaction, 55
Corticotropin releasing hormone (CRH),
145, 191
Cortisol-binding globulin levels, 149
Creatine-phosphocreatine
(Cr-PCr), 327
Cushing’s syndrome, 149, 151
Cyclic AMP (cAMP) signaling cascade and
PKA, 113–115
carbamazepine and, 115–116
lithium and, 115
Cyclicity in bipolar illness, 193
Cycloid psychosis, 8Cyclothymia, 1, 3, 8, 326, 332–333
biology, 332
epidemiology, 332
treatment, 333
D-amino acid oxidase (DAO), 239
D-amino acid oxidase activator
(DAOA), 239
Declarative memory, 258
Delirium, 362
Dementia, 362–363
Depression, 5–6
depressed mood, 255
depressive disorder NOS, 3
stressors in, 277

Desipramine treatment, 49
Dex/CRH test, 147, 152
Dexamethasone, 147
metabolism, 152
suppression test (DST), 146, 288
Diabetes mellitus (DM), 391
Diagnostic analysis of nonverbal accuracy
scale (DANVA), 349
Diagnostic and Statistical Manual of Mental
Disorders ,see under DSM
Diagnostic interview schedule for children
(DISC), 346
Disrupted in schizophrenia 1
(DISC-1), 236
Divalproex, 394
in psychotic mania treatment, 335
Dopaminergic system, 173–174
neurochemistry and
neurophysiology, 34
Dopamines, 199
ACh modulation of, 50
agonists, 109
blockers, 19
receptor abnormalities, 41
transporter (DAT), 41
b-hydroxylase (DBH), 43
Dorsolateral prefrontal cortex (DLPFC), 163,
263, 351
DSM-IV ( Diagnostic and Statistical Manual of
Mental Disorders -IV), 2–4
classifying mood disorders, 3, see also under
individual entries

263, 351
deﬁning bipolar II disorder, 2
describing mood disorders, 2, see also under
mood disorders
DSM-V , 13–14
Dyskinesia, 73412 Index

Dysphoric mania, 7
Dysthymia, 1, 3
Elation /grandiosity scores, 69, 71
Elderly, bipolar, 365–370
structural neuroimaging studies in, 366–367
365–370
Electroencephalographic (EEGs) and
event-related potentials (ERPs) in
bipolar disorders, 221–229
clinical EEG abnormalities, 223–224
cognitive ERP techniques, 228
conventional ERP abnormalities, 224–225
future opportunities, 225–228
lithium effect on, 224
normal EEG, 221–223
pharmaco-EEG techniques, 227
quantitative EEG techniques, 226–227
Endocrine diseases, 391–396
barriers to care, 395–396
menstrual abnormalities and polycystic
ovarian syndrome, 391–392
psychotropic drugs, 393–395
thyroid abnormalities, 392–393
Endophenotypes, 21
modeling, 26–27
Environmental risk factors, 213–215
Environmental stressors, 275–291
Enzyme studies, 43
Epidemiological Catchment Area (ECA)

study, 10, 234
Episode onset, 277–284
Hammen’s interview for, 283
life events and, relationship between, 279–282
non–rapid-cycling episode patterns, 285
stress–episode relationship, 285–287
Episodes, mood, 2
Epstein-Barr virus, 211–212
Euthymia, 258
Evoked response potentials (ERPs), 349
Excitatory amino acids (EAAs), 54
Expressed emotion (EE), 283
Extracellular signal regulated kinase (ERK),
119–121, 379
antidepressant effects on, 120
in CNS, 1205-HT 2Areceptor, 91
binding in platelets, 96
5-Hydroxytryptamine (5-HT), 35
5-Hydroxyindole-acetic acid (5-HIAA), 89
[18F]altanserin, 174
[18F]setoperone, 174–175
Fahr’s disease, 38
Fenﬂuramine, 91
Forskolin-induced hypoactivity
lithium inhibition of, 23
Free thyroxine (FT4) index, 392
Functional neuroimaging, 171–178
activation studies, 172–173

in bipolar elders, 368
electrophysiological studies, 368
endophenotypes, 369
neuroendocrine and neurochemical
studies, 368–369
pathophysiology, 369–370
blood ﬂow and metabolism studies,
171–172
neurochemical brain imaging, 173–178
GAD65, 131
GAD67, 131
Gamma aminobutyric acid (GABA), 35, 80
GABA modulation of CA neurotrans-
mission, 49
GABAergic interneurons, 131
Gene-driven therapeutics, 314
Genes and bipolar disorder, 201–202
Genetics, of bipolar disorder, 46–47, 233–244
bipolar disorder and schizophrenia,
241–243
chromosome studies, 235–236
classical genetic epidemiology, 234–235
clinical phenotype, 241
diagnosis and epidemiology, 233–234
in microbial infection, 209–212
mode of inheritance, 235
molecular genetic studies, 236–240
GenMapp algorithms, 133
Glucocorticoids, 150

Glutamate, glutamine, and GABA, 176
Glyceraldehyde-3-phosphate dehydrogenase
(G3PDH), 137
Glycogen synthase kinase-3 (GSK-3),
121–122
glycogen synthase kinase-3 beta (GSK3- b),
202
inhibition mechanisms, 121
subtypes, 121Index 413

G-proteins, 111–112
abnormalities in bipolar disorder, 112–113
G-protein receptor kinase 3 (GRK3), 240
G-protein-coupled-receptors (GPCRs), 111
lithium and, 112–113
small G proteins, 111
Great Smoky Mountains Study (GSMS), 346
Growth hormone supersensitivity, 78
Guanine nucleotide exchange factors
(GEFs), 111
Guanosine diphosphate (GDP), 111
Guanosine triphosphate (GTP), 111
Guanylyl cyclases (GC), 111
[3H]cyanoimipramine, 92
[3H]imipramine, 90, 92, 96
[3H]paroxetine, 90
Haemophilus inﬂuenzae ,2 1 1
Hamilton Rating Scale for Depression
(HAMD), 12, 332, 390
Helicobacter pylori ,2 1 1
High-licking maternal behavior, 301
Hippocampal acetylcholine, 80
Hippocampus, 150, 169
Holmes-Rahe Social Readjustment scale, 278
Hormonal modulation of catecholamines, 50
HPA axis abnormalities, 152
Huntington’s disease, 38
Hyperandrogenism, 392
Hypercortisolemia, 147, 150–152
Hyperparathyroidism, 395
Hyperprolactinemia, 394
Hypomania, 3–5
antidepressant-induced, 7–8
hypomanic episode, 3, 4

mixed hypomania, 7
Hypothalamic–pituitary–adrenal (HPA)
axis, 145–154, 392
abnormalities, 147
activity, 288
carbamazepine, 153
dysregulation, 191
functional integrity, 146
hypercortisolemia, 150–152
lithium, 152
patients with bipolar disorder, 147–149
patients with major depression, 146–147
patients with mood disorders, 149–150
physiology, 145–146
sodium valproate, 153
somatic treatments, 152–153
supersensitivity, 78–80ICD-10, 2–4, 11
Idazoxan, 43
Illness prognosis
homologous models, 298–299
kindling as a nonhomologous model, 299–300
Impairment, 253–254
Indoleamine hypothesis of depression, 89
Infectious etiology hypothesis, 209–217
environmental risk factors, 213–215
genetic determinants, 210
immunological activity, 210
microbial receptors, 210

speciﬁc infectious agents, 214–215
viral etiology, 213–214
viral infections of the CNS and bipolar
disorder, 212
Inhibitory syndrome, 73
Inositol depletion, 23, 116
Inositol monophosphatase, 176
Intellectual functioning, 263
impairment, 263
mood state, effect of, 263
Intensive clinical management (ICM), 290
International Classiﬁcation of Diseases-9
(ICD), 2
Interpersonal and Social Rhythm Therapy
(IPSRT), 290
Interview-based life event assessment
methods, 278–280
Inventory of Depressive Symptomatology
(IDS), 12
Janowsky-Davis Activation-Inhibition Scale,
71, 73–74
Kiddie schedule for affective disorders and
schizophrenia for school-age chil-
dren (K-SADS), 346
Kindling /sensitization model, 285–287,
297–315
animal studies, 300–303,
course of illness and neuroimaging studies,
303–307

297–315
303–307
age of onset and number of episodes, 307
neurochemistry, 304–307
stressor involvement, 304
historical overview, 297–300
homologous models for affective illness
prognosis, 298–299
mood stabilizers, neuroprotective effects of,
313–314414 Index

[Kindling /sensitization model]
as a nonhomologous model for illness
progression, 299–300
prediction of treatment response, 314
psychopharmacological interventions,
307–314
acquired treatment resistance,
312–313
combination therapy, 310–311
remission, 311–312
Kraepelinian dichotomy, 8, 241
Lamotrigine, 310, 331, 380, 394
Late life bipolar disorders, see also under elderly
biological factors, 361–372
pharmacodynamics, 370–371
pharmacokinetic factors, 370
side effects /tolerability, 370–371
therapeutics, 370–371
causal factors, 363–365
familial inﬂuences, 364
vascular disease and stroke, 364
clinical overview, 362–365
chronicity, relapse, recurrence, 363
cognitive dysfunctions and
dementias, 363
comorbid substance abuse, 363
course, 363
mortality, 363–364
epidemiology, 362–365
historical perspective, 361–362
novel treatment strategies, 371
psychosocial adversity, 365
Laterodorsal tegmental (LDT), 194
Learning and memory 258–260, see also verbal
learning and memory

Life Events and Difﬁculties Schedule (LEDS),
277
Limbic-hypothalamo-pituitary-adrenocortical
(LHPA), 27
Linkage studies, 236–237, 242
Lithium, 19, 312, 328, 330, 394
as antidepressant, 21–22
antimanic effects, 43
blocking hyperactivity, 20
EEG and, 224
HPA axis, 152
G proteins, 112–113
inhibiting forskolin-induced
hypoactivity, 23
refractoriness, 313[Lithium]
lithium-induced myo-inositol reductions,
116
potential neurotrophic and neuroprotective
psychotic mania treatment, 335
rapid cycling treatment, 330
type II bipolar disorder treatment, 328
Long-term potentiation (LTP), 300
Longitudinal sleep studies, 196
Low resolution electromagnetic tomographic
analysis (LORETA), 227
Low-licking maternal behavior, 301
Lysergic acid diethylamide (LSD), 96

MADRAS depression scale, 70
Magic bullets, 19
Magnetic resonance imaging (MRI), 161
Magnetic resonance spectroscopy
(MRS), 175
Magneto-encephalography (MEG), 221
Major depressive disorder (MDD), 3, 90
Malaria parasites, 210
Mammalian circadian rhythms, 191
Mania, 4–5, see also hypomania
cholinomimetic effects on, 68–69
“classic” mania, 4
dysphoric mania, 7
manic disorder, 3
Manic Intensity Scale scores, 69, 71
manic syndrome, 4
medication for, 200–201
serotonergic function in, 94–96
cerebrospinal ﬂuid, 94
challenge studies, 95
imaging studies, 95
medication studies, 95–96
platelet studies, 94–95
stressors, 277
treating and preventing, 200
MARCKS (myristoylated alanine rich C
kinase substrate), 117–118
Marijuana-physostigmine interactions, 71
Matrix reasoning, 261

Medial temporal structures, 168–169
Memory trace, 299
Menstrual abnormalities, 391–392
Mesocorticolimbic (MCL) system, 34, 39
Methamphetamine, 41
Methodological difﬁculties, 402–405
Microbial infection, genetic factors, 209–212Index 415

Mineralocorticoid receptors, 150
Mini International Neuropsychiatric
Interview (MINI), 11
Mismatch negativity (MMN), 223
Mixed depression, 9
Mixed disorder, 3
Mixed states, 6–7
Molecular genetic studies, 236–240
brain derived neurotrophic factor, 239–240
D-amino acid oxidase activator (G72) /G30
locus, 239
functional candidates, 238–239
gene studies, 237–240
linkage studies, 236–237
Monoamine oxidase (MAO), 43
Monoaminergic neurotransmitter systems,
109
Montgomery A ˚sberg Depression Rating Scale
(MADRS), 12, 70, 382
Mood disorders,
brief history, 1–2
catecholamine and, 36–38
cholinergic-muscarinic dysfunction in,
67–82, episodes, 2
genetic studies, 234
serotonergic dysfunction in, 89–98
speciﬁers, 2
Mood stabilizers, 394–395
neuroprotective effects, 313–314
PI3K pathway and, 118–119
Mood state, effect of, 254
Mood-regulating circuit (MRC), 36
catecholamines
tracts from midbrain to MRS, 37
as modulators, 37–38
Mortality, 363–364

Muscarinic receptor gene, 81
Mycobacteria tuberculosis ,2 1 1
Myo-inositol (mI), 176, 353
N-acetylaspartate (NAA), 175
N-methyl-D-aspartate (NMDA), 48, 225
Neocortex, 263
Neuregulin 1, 242
Neurochemical brain imaging, 173–178
PET and SPECT neuroreceptor studies,
173–178
biochemical ﬁndings, 175–178
dopaminergic system, 173–174
serotonergic system, 174–175
in unipolar disorder, 177–178Neurocognitive ﬁndings in bipolar disorder,
251–267
attention /vigilance, 253–254
clinical course, 254, 255
impairment, 253–257
intellectual functioning, 263
learning and memory, 258–260
mood state, 254, 255
neuropsychological ﬁndings, 266
attention, 266
intellectual functioning, 266
reasoning and problem solving, 266
verbal learning and memory, 266
visual learning and memory, 266
working memory, 266
reasoning and problem

solving, 260–263
speed of processing, 254–255, 266
working memory, 255–258
Neuroendocrine challenge studies
of CA receptor function in
BD, 41–42,
see also under catecholamines
depletion studies and, 91
Neuroendocrine receptor abnormalities,
41–42
in bipolar elders, 365
neuroimaging, structural, see under
structural imaging
in pediatric bipolar disorder, 350, see also
under pediatric bipolar disorder
Neurokinin (NK)-1-receptor antagonists, 380
Neuropeptide modulation of CA
neurotransmission, 49–50
Neuropeptide Y (NPY), 49
Neurotrophins, 239
neurotrophin-3 (NT-3), 51
NIMH-Life Chart Methodology
(NIMH-LCM), 12
Non–rapid-cycling episode
patterns, 285
Noradrenergic (NA) system, neurochemistry,
35–36
catecholamine abnormalities, 39–40
in reward mechanisms, 35–36

35–36
Nutritional and metabolic diseases, 390–391
atherosclerotic cardiovascular disease
diabetes mellitus (DM), 390–391
metabolic syndrome (MS), 391416 Index

Obesity, 390
Olanzapine, 163, 394
for psychotic mania, 335–336
for rapid cycling, 331–332
Opioid, 35
Paired Associates Learning task, 260
Parachlorophenylalanine (PCPA), 91
Parkinson’s disease, 50, 70, 199
Paroxetine, 264
Pattern recognition test, 257
Pediatric bipolar disorder
functional neuroimaging in, 352–354
neurochemistry, 353–354
neuroimaging, 350
prevalence, 346
structural neuroimaging in, 350–352
Pedunculopontine tegmental (PPT), 194
Peripheral cholinergic supersensitivity, 68
173–178
Pharmaco-EEG techniques, 227
Pharmacological agents, in BD treatment,
42–44
dopamine system, medication effects
on, 42
enzyme studies, 43
neuroendocrine system, medication
effects on, 42–43
in peripheral tissue, 43
receptor studies, 43–44
signal transduction mechanisms, 44
Pharmacological interventions 377–383
current status of therapeutics, 377–383
new drug development, 380–383
anxiety, 382
candidate drugs, 381–382
rating scale issues, 380

regulatory agencies, 382–383
study of early behavioral effects, 381
systematic open trials, 380–381
use of time to event analyses, 381
targets for new treatment development,
378–379
Phenotype diagnostic criteria, 344
Phosphatidylinositol 4,5-bisphosphate
[PI(4,5)P 2], 116
Phosphatidylinositol-3-kinase (PI3K)
signaling pathway, 118
Phosphodiesterases (PDE), 111
Phosphoinositide 3-kinases
(PI3Ks), 111Phosphoinositide signaling cascades
and protein kinase C (PKC),
116 – 118
Phosphoinositide-dependent kinase 1
(PDK1), 118
Phospholipase C (PLC), 111, 116
Phospholipases A2 (PLA2), 111
Phosphomonoester (PME) level, 176
Physical comorbidity in bipolar disorder,
387–396
cardiovascular disease, 387–389
endocrine diseases, 391–396
nutritional and metabolic diseases, 390–391
Physostigmine, 69, 78–79
anergic effects, 79

387–396
Pilocarpine, 68
supersensitive pupillary responses, 77
Platelet studies, 90–91, 94–95
Polycystic ovarian syndrome (PCOS),
391–392
Polyphosphate-1-phosphatase, 176
Porsolt forced swim test, 22
Positron emission tomography (PET),
93, 171, 221
Post-traumatic stress disorder, 26
Postmortem studies in bipolar disorder, 44–45
Post’s kindling model, 286
Prefrontal cortex, 163–167
cingulate in bipolar disorder, 166
subgenual prefrontal cortex, 165
Probenecid blocks, 94
Proﬁle of Mood States Scale, 74
Proliferator-activated receptors (PPAR), 380
Protein kinase C (PKC), 379
phosphoinositide signaling cascades and,
116 – 118
Proton echoplanar spectroscopic imaging
(PEPSI), 49
Psychostimulants, 109
lithium effects, 19
Psychotic illness, bipolar disorder and, 52

116 – 118
Psychotic mania, 326, 333–336
biology, 334–335
epidemiology, 333
treatment, 335–336
clozapine, 335
divalproex, 335
lithium, 335
olanzapine, 335–336
quetiapine, 336
risperidone, 336Index 417

Psychotropic drugs, 393–395
antipsychotic drugs, 393–394
mood stabilizers, 394–395
Psychotropic medications, effects of, 264–265
Quetiapine, 393, 394
in psychotic mania treatment, 336
Rapid cycling, 9, 14, 326, 328–332
biology, 330
epidemiology, 329–330
prevalence of, 329
treatment, 330–332
carbamazepine, 331
comparisons of treatments, 332
lamotrigine, 331
lithium, 330
olanzapine, 331–332
valproate, 331
Rapid eye movement (REM), 67,
75–77, 193
Rating scales, 380
Reasoning and problem solving, 260–263
clinical course, impact of, 262–263
impairment, evidence for, 262
Matrix Reasoning, 261
mood state, effect of, 262
Raven’s Progressive Matrices, 261
Wisconsin Card Sorting Test
(WCST), 261
Receptor studies, 43–44
Recurrence or relapse, 363
Remission, achieving and maintaining,
311–312
Research diagnostic criteria (RDC), 346
Reward mechanisms
dopamine, 34
norepinephrine, 35–36
Rey-Osterrieth complex ﬁgure test
(ROCFT), 257, 260
Rhythm stabilization, 200
Risperidone, 393–394

311–312
Schedules for Clinical Assessment in
Neuropsychiatry (SCAN), 11
Schistosoma mansoni , 210
Schizoaffective disorder, 3, 8, 52, 241
Schizophrenia /schizophrenics, 131,
213, 226
bipolar disorder and, 241–243
family studies, 241[Schizophrenia /schizophrenics
bipolar disorder and]
gene studies, 242–243
linkage studies, 242
twin studies, 241–242
core haplotype, 242
Disrupted in Schizophrenia 1 , 242
Neuregulin 1 , 242
Scopolamine, 70, 81
Seasonal affective disorder
(SAD), 193
Seasonality in bipolar disorder,
192–193
Selective serotonin reuptake inhibitors
(SSRIs), 42, 198, 391
Sensitization
kindling and behavioral, 285–287
episode sensitization, 285
stressor sensitization, 285
Serotonergic dysfunction in mood disorders,
89–98

89–98
cerebrospinal ﬂuid studies (CFS), 96
challenge studies, 97
genetic studies, 97–98
historical view, 89
in major depression, 90–91
cerebrospinal ﬂuid (CSF), 89
neuroendocrine challenge and depletion
studies, 91
platelet studies, 90–91
postmortem studies, 91
platelet studies, 96–97
postmortem studies, 97
serotonergic function in mania, 94–96
serotonin and 5-HIAA, 91–94
5-HT 2Areceptor, 92–93
HT 1Areceptor, 92
imaging studies, 93–94
serotonin transporter, 92
Serotonergic system, 174–175
Serotoninergic axons, 152
Sertraline, 264
Severe mood and behavioral dysregulation
(SMD) diagnostic criteria, 345
exclusion criteria, 345
inclusion criteria, 345
Signal transduction mechanisms /
pathways, 44
cell membrane, 109–123
Signaling networks, 110–122
carbamazepine and CAMP /PKA signaling
cascade, 115–116418 Index

[Signaling networks]
cyclic AMP (cAMP) signaling cascade and
glycogen synthase kinase-3 (GSK-3),
121–122
mood stabilizers and PI3K pathway,
118 – 119
phosphatidylinositol-3-kinase (PI3K)
phosphoinositide signaling cascades,
116 – 118
Simultaneous and delayed matching to
sample task, 257
Single manic disorder, 3
Sleep abnormalities, 193–197
biological rhythms abnormalities and,
189–203
in bipolar depression, 194–195
in bipolar mania, 195
genes and bipolar disorder, 201–202
longitudinal studies, 196
sleep and circadian rhythms, 200–201
biological rhythm dysfunction, 189–193
sleep deprivation, 197–198
mechanisms, 198–199
sleep in bipolar remission, 196–197
sleep regulation, 194
Slow processing speed, 255
Slow wave sleep (SWS), 193
Social rhythm disruption (SRD), 289–290
Sodium valproate, 176
Somatic treatments, effects of, 152–153
Somatostatin, 49

Span of apprehension task (SPAN), 253
Spatial recognition test, 257
speciﬁc serotonin receptor inhibitor (SSRIs), 380
Speciﬁers, mood, 2
longitudinal course speciﬁers, 2
Speed of processing, 254–255
Stanley Foundation Bipolar Network, 6
Stress and episode sensitization, 298–299
Stressful life events, 190
Stressors in bipolar disorder, 275–291
depression and mania, 277
episode onset, 277–284
HPA axis dysfunction and bipolar
episodes, 288–289
methodological issues, 276–277[Stressors in bipolar disorder]
Post’s hypotheses, 286
recovery from an episode, 284
social rhythm disruption and bipolar
episodes, 289–290
Stroop color and word tests (SCWT), 253
Structural neuroimaging, 162–170
cerebellum, 170
corpus callosum, 167–168
medial temporal structures, 168–169

in pediatric bipolar disorder, 350–352
prefrontal cortex, 163–167
thalamus, 169–170
total brain volume, 162–163
white matter, 167–168
Subtypes of bipolar disorder, 325–337
bipolar I, 326
bipolar II, 326-328
cyclothymic disorder, 326
psychotic mania, 326
rapid cycling, 326
biology of subtypes, 327
epidemiology of subtypes, 326
treatment, 328
Supersensitive pupillary responses
to pilocarpine, 77
Suprachiasmatic nucleus (SCN), 191
Systematic Treatment Enhancement Program
(STEP), 329
Temporal-hippocampal system, 258
Thalamus, 169–170
3-methoxy-4-hydroxyphenylglycol (MHPG),
39, 72
Thyroid abnormalities, 392–393
Thyrotropin-releasing hormone (TRH), 392
Toxoplasma gondii , 215
Treatment-discontinuation-related
refractoriness, 312
Tryptophan hydroxylase (TPH), 91, 97
Twin studies, 241–242

Unipolar depression, 90, 234
vs. bipolar depression and, 2, 51
Unipolar major depression (UMD), 361
Unipolar–bipolar dichotomy, 8
Vagus nerve stimulator (VNS), 404
Valproate, 310, 312, 331
neurotrophic and neuroprotective effects, 308Index 419

Valproic acid, 394–395
Vascular disease and stroke, 364
Velocardiofacial syndrome (VCFS), 43, 236
Venlafaxine, 120
Ventral prefrontal cortex (VPFC), 347
Ventral tegmental area (VTA), 34, 309
Verbal declarative memory impairments, 258
Verbal learning and memory
clinical course, impact of, 259–260
impairment, evidence for, 258–260
mood state, effect of, 259–260
Vermis area V3, 170
Viral etiology in bipolar disorder, 213–214
Viral infections of the CNS and bipolar
Visual backward masking, 253
Visual spatial memory tasks, 257
pattern recognition test, 257
spatial recognition test, 257
pattern recognition memory task, 257
Rey-Osterreith complex ﬁgure test, 257
simultaneous and delayed matching to
sample task, 257[Visual spatial memory tasks
spatial recognition test]
visual-spatial paired associate learning
task, 257
Voxel-based morphometry (VBM), 163, 352
Wechsler Adult Intelligence Scale version III
(WAIS-III), 255
White matter, 167–168

task, 257
Wisconsin Card Sorting Test (WCST), 261, 263
Working memory, 255–258
clinical course, impact of, 257–258
conceptualization, 256
impairment, 256–257
mood state, effect of, 257
tripartite organization of, 256
X-linkage, 235
Young Mania Rating Scale (YMRS), 12,
332, 335
Ziprasidone, 393420 Index

6TH EDITION  MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE  Puzantian & Carlat
Talia Puzantian, PharmD, BCPP
Daniel J. Carlat, MD
ARLATARLAT  PUBLISHING CC
SIXTH EDITIONMEDICATION FACT BOOK
FOR PSYCHIATRIC PRACTICE

MEDICATION FACT BOOK
Deputy Editor, The Carlat Report newsletters
Co-Author,  The Child Medication Fact Book for Psychiatric Practice
Professor of Clinical Sciences, Keck Graduate Institute School of Pharmacy and Health Sciences, 
Claremont, CA
Publisher, The Carlat Report newsletters and books
Associate Clinical Professor, Tufts University School of Medicine, Boston, MASIXTH EDITIONARLAT ARLAT  PUBLISHING PUBLISHING CC
Published by Carlat Publishing, LLC 
PO Box 626, Newburyport, MA 01950
Copyright © 2022 All Rights Reserved.

ARLAT ARLAT  PUBLISHING PUBLISHING CC
Medication Fact Book
For Psychiatric Practice
SIXTH EDITION
Published by Carlat Publishing, LLC
Publisher and Editor-in-Chief: Daniel J. Carlat, MD
Deputy Editor:  Talia Puzantian, PharmD, BCPP
Executive Editor: Janice Jutras
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Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   1Table of Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
ADHD Medications  ................................................................... 11
General Prescribing Tips  ......................................................................................... 11
Amphetamine (Adzenys XR-ODT, Dyanavel XR, Evekeo)  ........................................................... 19
Atomoxetine (Strattera)  ......................................................................................... 20
Clonidine (Catapres, Kapvay)  .................................................................................... 21
Dexmethylphenidate (Azstarys, Focalin, Focalin XR)  .............................................................. 22

Dextroamphetamine (Dexedrine, ProCentra, Zenzedi)  ............................................................ 23
Guanfacine (Intuniv, Tenex)  ..................................................................................... 24
Lisdexamfetamine (Vyvanse)  .................................................................................... 25
Methamphetamine (Desoxyn)  ................................................................................... 26
Methylphenidate IR (Methylin, Ritalin)  ........................................................................... 27
Methylphenidate ER (Concerta, Ritalin SR and LA, others)  ......................................................... 28
Methylphenidate Transdermal (Daytrana)  ........................................................................ 29

Mixed Amphetamine Salts (Adderall, Adderall XR, Mydayis)  ....................................................... 30
Viloxazine XR (Qelbree)  ......................................................................................... 31
Antidepressants  ..................................................................... 33
General Prescribing Tips  ......................................................................................... 33
Brexanolone (Zulresso)   ......................................................................................... 43
Bupropion (Wellbutrin, others)  .................................................................................. 44
Citalopram (Celexa)  ............................................................................................. 45

Clomipramine (Anafranil)  ....................................................................................... 46
Desvenlafaxine (Pristiq)  ......................................................................................... 47
Duloxetine (Cymbalta, Drizalma Sprinkle)  ........................................................................ 48
Escitalopram (Lexapro)  .......................................................................................... 49
Esketamine (Spravato)   .......................................................................................... 50
Fluoxetine (Prozac, Prozac Weekly)  ............................................................................... 51
Fluvoxamine (Luvox, Luvox CR)  .................................................................................. 52

Ketamine (Ketalar)  .............................................................................................. 53
Levomilnacipran (Fetzima)  ...................................................................................... 54
Mirtazapine (Remeron) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Monoamine Oxidase Inhibitors (MAOIs)  .......................................................................... 56
Nefazodone (Serzone)  .......................................................................................... 57
Paroxetine (Brisdelle, Paxil, Paxil CR, Pexeva)  ..................................................................... 58

Selegiline Transdermal (Emsam)  ................................................................................. 59
Sertraline (Zoloft)  ............................................................................................... 60
Thyroid (Cytomel, Synthroid, others)  ............................................................................. 61
Trazodone (Desyrel)  ............................................................................................. 62
Tricyclic Antidepressants (TCAs)  ................................................................................. 63
Venlafaxine (Effexor, Effexor XR)  ................................................................................. 64
Vilazodone (Viibryd)  ............................................................................................ 65

Vortioxetine (Trintellix)  .......................................................................................... 66
Antipsychotics  ....................................................................... 67
General Prescribing Tips  ......................................................................................... 67
Aripiprazole (Abilify)  ............................................................................................ 75

2  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONAsenapine (Saphris, Secuado)  ................................................................................... 76
Brexpiprazole (Rexulti)  .......................................................................................... 77
Cariprazine (Vraylar)  ............................................................................................ 78
Chlorpromazine (Thorazine)  ..................................................................................... 79
Clozapine (Clozaril, FazaClo, Versacloz)  ........................................................................... 80
Fluphenazine (Prolixin)  .......................................................................................... 83
Haloperidol (Haldol)  ............................................................................................ 84

Iloperidone (Fanapt)  ............................................................................................ 85
Loxapine (Adasuve, Loxitane) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
Lumateperone (Caplyta)  ........................................................................................ 87
Lurasidone (Latuda)  ............................................................................................. 88
Molindone (Moban)  ............................................................................................ 89
Olanzapine (Lybalvi, Symbyax, Zyprexa)  ......................................................................... 90

Paliperidone (Invega)  ........................................................................................... 91
Perphenazine (Trilafon)  ......................................................................................... 92
Pimavanserin (Nuplazid)  ........................................................................................ 93
Quetiapine (Seroquel, Seroquel XR)  .............................................................................. 94
Risperidone (Risperdal)  ......................................................................................... 95
Thioridazine (Mellaril)  ........................................................................................... 96
Thiothixene (Navane)  ........................................................................................... 97

Trifluoperazine (Stelazine)  ....................................................................................... 98
Ziprasidone (Geodon)  ........................................................................................... 99
Long-Acting Injectable (LAI) Antipsychotics  ..................................................................... 100
Anxiolytic and Hypnotic Medications  ................................................. 105
General Prescribing Tips for Anxiolytics  .......................................................................... 105
General Prescribing Tips for Hypnotics  .......................................................................... 105
Alprazolam (Xanax)  ............................................................................................ 112

Antihistamines (Diphenhydramine, others)  ..................................................................... 113
Buspirone (BuSpar)  ............................................................................................ 114
Clonazepam (Klonopin)  ........................................................................................ 115
Diazepam (Valium)  ............................................................................................ 116
Doxepin (Silenor)  .............................................................................................. 117
Eszopiclone (Lunesta)  .......................................................................................... 118
Flurazepam (Dalmane)  ......................................................................................... 119

Hydroxyzine (Atarax, Vistaril)  ................................................................................... 120
Lemborexant (Dayvigo)  ........................................................................................ 121
Lorazepam (Ativan, Loreev XR)  ................................................................................. 122
Prazosin (Minipress) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
Propranolol (Inderal)  ........................................................................................... 124
Ramelteon (Rozerem)  .......................................................................................... 125

Suvorexant (Belsomra)  ......................................................................................... 126
Temazepam (Restoril)  .......................................................................................... 127
Triazolam (Halcion)  ............................................................................................ 128
Zaleplon (Sonata)  .............................................................................................. 129
Zolpidem (Ambien, Edluar, Intermezzo, Zolpimist)  ............................................................... 130
Dementia Medications  .............................................................. 131
General Prescribing Tips  ........................................................................................ 131

Aducanumab (Aduhelm)  ....................................................................................... 135
Donepezil (Aricept)  ............................................................................................ 136
Galantamine (Razadyne, Razadyne ER)  .......................................................................... 137

Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   3Memantine (Namenda, Namenda XR)  ........................................................................... 138
Memantine ER/Donepezil (Namzaric)  ........................................................................... 139
Rivastigmine (Exelon, Exelon Patch)  ............................................................................ 140
Mood Stabilizers and Anticonvulsants  ................................................ 141
General Prescribing Tips  ........................................................................................ 141
Carbamazepine (Epitol, Equetro, Tegretol, others)  ............................................................... 145
Gabapentin (Gralise, Horizant, Neurontin)  ....................................................................... 146
Lamotrigine (Lamictal, Lamictal XR, Subvenite)  .................................................................. 147

Lithium (Eskalith, Lithobid)  ..................................................................................... 148
Oxcarbazepine (Oxtellar XR, Trileptal)  ........................................................................... 149
Pregabalin (Lyrica, Lyrica CR)  ................................................................................... 150
Topiramate (Eprontia, Qudexy XR, Topamax, Trokendi XR)  ........................................................ 151
Valproic Acid (Depakene, Depakote, others)  ..................................................................... 152
Natural Treatments  ................................................................. 153
General Prescribing Tips  ........................................................................................ 153

Lavender Essential Oil (CalmAid, Silexan)  ........................................................................ 154
L-Methylfolate (Deplin)  ......................................................................................... 155
L-Tryptophan  .................................................................................................. 156
Melatonin  ..................................................................................................... 157
N-Acetylcysteine (NAC)  ........................................................................................ 158
Omega-3 Fatty Acids (Fish Oil)  .................................................................................. 159
S-Adenosyl-L-Methionine (SAMe)  ............................................................................... 160

St. John’s Wort  ................................................................................................. 161
Vitamin D  ..................................................................................................... 162
Sexual Dysfunction Medications  ..................................................... 163
General Prescribing Tips  ........................................................................................ 163
Avanafil (Stendra)  .............................................................................................. 165
Bremelanotide (Vyleesi)  ........................................................................................ 166
Cyproheptadine (Periactin)  ..................................................................................... 167

Flibanserin (Addyi)  ............................................................................................. 168
Sildenafil (Viagra)  .............................................................................................. 169
Tadalafil (Cialis)  ................................................................................................ 170
Testosterone (various)  ......................................................................................... 171
Vardenafil (Levitra)  ............................................................................................. 172
Side Effect Management  ............................................................ 173
General Management Tips  ...................................................................................... 173

Amantadine (Gocovri, Symmetrel)  .............................................................................. 175
Benztropine (Cogentin)  ........................................................................................ 176
Deutetrabenazine (Austedo)  ................................................................................... 177
Metformin (Glucophage, Glumetza, Riomet)  .................................................................... 178
Tetrabenazine (Xenazine)  ...................................................................................... 179
Trihexyphenidyl (Artane)  ....................................................................................... 180
Valbenazine (Ingrezza)  ......................................................................................... 181
Symptoms

Symptoms
Akathisia  ....................................................................................................... 183
Bruxism  ........................................................................................................ 184

4  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONConstipation  ................................................................................................... 185
Diarrhea  ....................................................................................................... 186
Dry Mouth (Xerostomia)  ........................................................................................ 187
Dystonia  ....................................................................................................... 188
Excessive Sweating (Hyperhidrosis)  ............................................................................. 189
Fatigue  ........................................................................................................ 190
Nausea  ........................................................................................................ 191

Neuroleptic Malignant Syndrome (NMS)  ......................................................................... 192
Orthostatic Hypotension (Postural Hypotension)  ................................................................ 193
Parkinsonism  .................................................................................................. 194
Prolactinemia  .................................................................................................. 195
QT Interval Prolongation  ........................................................................................ 196
Serotonin Syndrome  ........................................................................................... 197
Sexual Dysfunction  ............................................................................................. 198

Sialorrhea (Hypersalivation) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
Tardive Dyskinesia  .............................................................................................. 200
Tremor  ......................................................................................................... 202
Weight Gain  ................................................................................................... 203
Sleep Disorder Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
General Prescribing Tips  ........................................................................................ 205

Armodafinil (Nuvigil)  ........................................................................................... 207
Dopamine Agonists (Mirapex, Neupro, Requip, Sinemet)  ........................................................ 208
Modafinil (Provigil) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
Oxybates (Xyrem, Xywav)  ...................................................................................... 210
Pitolisant (Wakix)  .............................................................................................. 211
Solriamfetol (Sunosi)  ........................................................................................... 212

Tasimelteon (Hetlioz)  .......................................................................................... 213
Somatic Treatments  ................................................................. 215
Bright Light Therapy   ........................................................................................... 216
Electroconvulsive Therapy (ECT)   ............................................................................... 217
Transcranial Magnetic Stimulation (TMS)   ....................................................................... 218
Vagus Nerve Stimulation (VNS)   ................................................................................ 219
Substance Use Disorder Medications  ................................................. 221

General Prescribing Tips  ........................................................................................ 221
Smoking Cessation  ............................................................................................. 227
Acamprosate (Campral)  ........................................................................................ 228
Buprenorphine (Sublocade)  .................................................................................... 229
Buprenorphine/Naloxone (Bunavail, Suboxone, Zubsolv)  ........................................................ 230
Bupropion SR (Zyban)  .......................................................................................... 231
Disulfiram (Antabuse)  .......................................................................................... 232

Lofexidine (Lucemyra)  ......................................................................................... 233
Methadone (Methadose)  ....................................................................................... 234
Naloxone (Kloxxado, Narcan Nasal Spray, Zimhi)  ................................................................. 235
Naltrexone (ReVia, Vivitrol)  ..................................................................................... 236
Nicotine Gum/Lozenge (Nicorette, others)  ...................................................................... 237
Nicotine Inhaled (Nicotrol Inhaler)  .............................................................................. 238
Nicotine Nasal Spray (Nicotrol NS)  .............................................................................. 239

Nicotine Patch (Nicoderm CQ, others)  ........................................................................... 240
Varenicline (Chantix)  ........................................................................................... 241

Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   5Appendices  ........................................................................ 243
Appendix A: Drug Interactions in Psychiatry  ..................................................................... 243
Appendix B: Psychiatric Medications in Pregnancy and Lactation  ................................................. 251
Appendix C: Classifications of Controlled Substances  ............................................................ 256
Appendix D: Lab Monitoring for Psychiatric Medications  ......................................................... 257
Appendix E: Urine Toxicology Screening  ......................................................................... 259
Appendix F: Pharmacogenetic Testing  ........................................................................... 261
Appendix G: Anticholinergic Agents Often Used in Psychiatry  .................................................... 263

Appendix H: Dosing of Psychotropic Medications in Patients With Hepatic or Renal Impairment  ................... 264
Index  .............................................................................. 268
LIST OF TABLES
Table 1: ADHD Medications  ...................................................................................... 14  
Table 2: Relative Equivalency and Conversion Guide for Stimulants  ................................................ 18
Table 3: Risk of Discontinuation Syndrome With Various Antidepressants and Recommendations for Management  ..34
Table 4: Recommended Strategies for Switching Antidepressants  .................................................. 35
Table 5: Antidepressants  ......................................................................................... 38

Table 5A: Selective Serotonin Reuptake Inhibitors (SSRIs)  .......................................................... 40
Table 6: Relative Side Effects of Antidepressants  .................................................................. 41
Table 7: Metabolic Monitoring Recommendations for Patients on Second-Generation Antipsychotics  ............... 69
Table 8: First-Generation Antipsychotics  ......................................................................... 71
Table 9: Second-Generation Antipsychotics  ....................................................................... 72
Table 10: Comparison of Relative Side Effects Among Antipsychotics  .............................................. 74
Table 11: Monitoring and Managing Patients on Clozapine  ....................................................... 81

Table 11A: ANC Monitoring for Clozapine Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
Table 12: Long-Acting Injectable Antipsychotics  ................................................................. 103
Table 13: Anxiolytic and Hypnotic Medications  .................................................................. 110
Table 13A: Benzodiazepine Dosage Equivalencies  ............................................................... 111
Table 14: Dementia Medications  ................................................................................ 134
Table 15: Mood Stabilizers  ...................................................................................... 144
Table 16: Anticonvulsants  ...................................................................................... 144

Table 17: Natural Treatments  ................................................................................... 153
Table 18: Sexual Dysfunction Medications  ...................................................................... 164
Table 19: Sleep Disorder Medications  ........................................................................... 206
Table 20: Substance Use Disorder Medications  .................................................................. 225
Appendix Table A1: CYP450 Drug Interactions for Some Common Psychiatric Medications  ......................... 244
Appendix Table A2: Most Common Clinically Significant Drug Interactions in Psychiatry  ........................... 248
Appendix Table A3: MAOI Dietary and Medication Restrictions  ................................................... 249

Appendix Table B: Psychiatric Medications in Pregnancy and Lactation  ........................................... 253
Appendix Table C: Classifications of Controlled Substances  ....................................................... 256
Appendix Table D: Recommended Laboratory Tests for Psychiatric Medications  ................................... 258
Appendix Table E: Urine Drug Testing  ........................................................................... 260
Appendix Table F: FDA Label Information Relevant to Pharmacogenetic Testing for Psychiatric Drugs  .............. 262
Appendix Table G: Some Commonly Used Highly Anticholinergic Medications  .................................... 263
Appendix Table H: Dosing of Psychotropic Medications in Patients With Hepatic or Renal Impairment  .............. 265
LIST OF TREATMENT ALGORITHMS

Adult ADHD  ..................................................................................................... 13
Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Treatment-Resistant Depression  ................................................................................. 37

6  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONPsychosis  ....................................................................................................... 70
Anxiety  ........................................................................................................ 108
Insomnia  ...................................................................................................... 109
Dementia  ...................................................................................................... 133
Bipolar Mania  .................................................................................................. 143
Alcohol Use Disorder  ........................................................................................... 223
Opioid Use Disorder  ............................................................................................ 224

Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   7
HOW TO USE THIS BOOK
Medication information is presented in three ways in this book:
 ⦁Fact sheets.  In-depth information for select medications, somatic treatments, and side effects. There are 164 fact 
sheets in this book. The medication fact sheets don’t cover all psychiatric medications, but we have included most of 
the commonly prescribed and newer medications.
 ⦁Quick-scan medication tables.  These are most often located at the beginning of each therapeutic category and list 
the very basics: generic and brand names, available strengths, starting doses, and target doses. These tables contain 
most of the commonly prescribed psychiatric medications.
 ⦁Treatment algorithms.  These quick-reference decision trees can serve as a memory aid and help in clinical decision 
making. They don’t cover every medical nuance but serve as general overviews.

⦁Treatment algorithms.  These quick-reference decision trees can serve as a memory aid and help in clinical decision 
CHANGES AND ADDITIONS TO THE SIXTH EDITION
We’ve updated the medication fact sheets to reflect availability of newer strengths and formulations, as well as 
generics. The fact sheets also reflect new clinical data where available. We’ve expanded our coverage of many 
categories of medications, including the Side Effect Management chapter; included in this edition are 16 new fact 
sheets, five new tables, and eight appendices. We’ve also added a new treatment algorithm to this edition: treatment-
resistant depression. 
CATEGORIES OF MEDICATIONS
We did our best to categorize medications rationally. However, in some cases a medication can fall into more than one 
category. In such cases, we categorized the medication with the types of disorders for which it is most often used. If

category. In such cases, we categorized the medication with the types of disorders for which it is most often used. If 
you’re having trouble finding a medication in a particular chapter, look in the index to find its page number.
MORE ON THE MEDICATION FACT SHEETS
The goal of these fact sheets is to provide need-to-know information (on a single page) that can be easily and quickly 
absorbed during a busy day of seeing patients. Please refer to the PDR  (Physicians’ Desk Reference) when you need 
more in-depth information.
For the most part, each fact sheet contains the following information:
 ⦁Drug names.  Each sheet lists both brand and generic names.
 ⦁Generic availability.  We include a [G] or (G) if a drug is available as a generic.
 ⦁Bottom line.  We begin with a super-condensed summary, including our overall assessment of the drug’s value 
in clinical practice. If you’re in a rush, you can get the basics from this alone.

⦁Bottom line.  We begin with a super-condensed summary, including our overall assessment of the drug’s value 
in clinical practice. If you’re in a rush, you can get the basics from this alone. 
 ⦁FDA-approved indications.  Psychiatric indications are in bold.
 ⦁Off-label uses.  We list the more common off-label uses, based on both the medical literature and our clinical 
experience. Just because we list a potential use does not imply that we endorse a medication as being particularly 
effective for that use. We are simply alerting you to the fact that there is some evidence for efficacy.
 ⦁Dosage forms,  along with available strengths.
 ⦁Dosage guidance.  We provide recommendations on how to dose medications; these are derived from a variety of 
sources, including package inserts, clinical trials, and common clinical practice. In other words, don’t be surprised 
when our dosing instructions are at odds with what you find in the PDR . New to this edition, we have added specific

when our dosing instructions are at odds with what you find in the PDR . New to this edition, we have added specific 
advice on whether to dose certain meds in the morning or at night—a common question from patients. 
 ⦁Lab monitoring recommendations.  We include the usual routine monitoring measures for each medication. Of course, 
you may need to think beyond the “routine” if the clinical picture warrants it.
 ⦁Cost information.  We obtained pricing information for a one-month supply of a common dosing regimen from the 
website GoodRx ( www.goodrx.com ), accessed in November 2021. These are the prices patients would have to pay 
if they had no insurance (GoodRx also offers coupons to purchase certain medications at reduced prices). Because 
of wide variations in price depending on the pharmacy, we list price categories rather than the price in dollars. The 
categories are:
 –$: Inexpensive (<$50/month)

8  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION –$$: Moderately expensive ($50–$100/month)
 –$$$: Expensive ($100–$200/month)
 –$$$$: Very expensive ($200–$500/month)
 –$$$$$: Extremely expensive ($500/month)
This begs the question, what should you do with knowledge of retail pricing? After all, most patients have some 
type of insurance and are therefore not going to pay retail price, but rather a co-pay. Since there’s no clear source 
for accurately predicting a co-pay, you can use the retail price as a clue. Meds that are inexpensive will likely require 
no co-pay, while the most expensive drugs will either require a very expensive co-pay or, more likely, will not be 
covered at all without an onerous pre-authorization process.
 ⦁Side effects information.  We break down side effects into “most common” vs “rare but serious” side effects. We

 ⦁Side effects information.  We break down side effects into “most common” vs “rare but serious” side effects. We 
generally define “most common” side effects as those that occurred in at least 5% of patients in clinical trials, and 
that were at least double the rate of the placebo group. Such information is usually found in tables in the drugs’ 
package inserts. We also used post-marketing clinical experience as a guide in determining which side effects were 
common enough to make the list.
 ⦁Mechanism of action.  While the mechanism of action is not well established for most psychiatric drugs, we thought it 
would be important to report the mechanisms most commonly cited.
 ⦁Pharmacokinetics, with a focus on drug metabolism and/or half-life.
 ⦁Drug interactions.
 ⦁Clinical pearls,  which typically comment on advantages or disadvantages of a medication in comparison to others in

⦁Drug interactions.
 ⦁Clinical pearls,  which typically comment on advantages or disadvantages of a medication in comparison to others in 
its therapeutic category, tips for dosing or for avoiding side effects, types of patients who seem to benefit the most, 
and so forth.
 ⦁Fun facts.
PREGNANCY AND LACTATION RISK INFORMATION
The risks and benefits of using psychiatric medications during pregnancy and breastfeeding are not as simple or 
clear as the previously used “ABCDX” letter categories might suggest. The FDA’s Pregnancy and Lactation Labeling 
Rule (PLLR) removed these categories in favor of a more detailed narrative describing available risk data. Rather than 
putting this information in the fact sheets, we cover the topic separately in Appendix B.
OTHER USEFUL INFORMATION IN THE APPENDICES
 ⦁Drug interactions in psychiatry.  While we do provide some information on drug interactions in the fact sheets,

 ⦁Drug interactions in psychiatry.  While we do provide some information on drug interactions in the fact sheets, 
we also have a more extensive discussion of the topic, as well as tables of interactions for commonly prescribed 
drugs, the most common clinically significant drug interactions in psychiatry, and MAOI dietary and medication 
considerations, all in Appendix A.
 ⦁Schedules of controlled substances.  Just in case you can’t remember which drugs are in which DEA schedule or what 
each schedule means, we have you covered with a handy table in Appendix C.
 ⦁Lab monitoring for psychiatric medications.  We’ve included a short easy-reference table listing medications with the 
recommended labs you should consider ordering, including serum level monitoring, in Appendix D. 
 ⦁Urine toxicology screening . As substance use treatment becomes an ever more important aspect of psychiatric

⦁Urine toxicology screening . As substance use treatment becomes an ever more important aspect of psychiatric 
practice, we have a table explaining common urine drug test detection periods, as well as agents that may 
potentially cause false positives, in Appendix E. 
 ⦁Pharmacogenetic testing.  Although we’re not big fans of routine pharmacogenetic testing, we provide some basic 
information on the topic in Appendix F.
 ⦁Anticholinergic agents. We provide a list of common medications that are highly anticholinergic in Appendix G. These 
can be particularly problematic in older patients. 
 ⦁Dosing of psychotropic medications in patients with hepatic or renal impairment.  Some psychiatric medications require 
more caution when treating patients with kidney or liver issues. You’ll find our recommendations in Appendix H. 
FINANCIAL DISCLOSURES
Dr. Puzantian and Dr. Carlat have disclosed that they have no relevant relationships or financial interests in any

Dr. Puzantian and Dr. Carlat have disclosed that they have no relevant relationships or financial interests in any 
commercial company pertaining to the information provided in this book.
DISCLAIMER
The medication information in this book was formulated with a reasonable standard of care and in conformity with 
current professional standards in the field of psychiatry. Medication prescribing decisions are complex, and you

Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   9should use these fact sheets as only one of many possible sources of medication information. This information is not a 
substitute for informed medical care. This book is intended for use by licensed professionals only.
If you have any comments or corrections, please let us know by writing to us at info@thecarlatreport.com  or 
The Carlat Psychiatry Report , P .O. Box 626, Newburyport, MA 01950.
CONTENT UPDATES AND ADDITIONAL RESOURCES
From time to time we will update content in this book as new research or FDA approvals come out. You can access 
those updates online at  www.thecarlatreport.com/mfb6e , which is also where you’ll get access to the 12 CME post-
test and the PDF/eBook versions of the book. You will also find additional resources including references and essential 
reading.

ADHD MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   11
ADHD Medications
GENERAL PRESCRIBING TIPS
Generally, when you have a patient with ADHD symptoms, your first choice will be one of the psychostimulants, 
because these are usually more effective than the alternatives—atomoxetine, bupropion, clonidine, guanfacine, and 
viloxazine. Which psychostimulant will you choose? Here are some of the factors that will influence your decision:
1. Long-acting vs short-acting.  Choosing between long- and short-acting stimulants is more art than science. Trial and 
error, combined with patient preference, will dictate the final regimen. Adults will often start with a long-acting 
agent so they can take a single dose in the morning and have it carry through their workday. Kids may do better 
with short-acting stimulants so that they will have an appetite when the medication wears off at lunch.

2. Amphetamines vs methylphenidates.  More recent data have suggested that, based on safety and efficacy, 
methylphenidates are a better choice in kids and adolescents whereas amphetamine-class agents are better 
in adults. Generally, this is a Coke vs Pepsi decision—some people like one better than the other, and you can’t 
predict their preference ahead of time. We recommend a methylphenidate over an amphetamine because 
amphetamines may have more side effects and are more likely to be abused or diverted but our algorithm starts 
with an amphetamine first given the efficacy data.
3. Stimulants vs non-stimulants.  Stimulants are more effective than non-stimulants, so they will be your first-line 
choice for most patients. If you have a patient with a substance use disorder, start with atomoxetine. Some

choice for most patients. If you have a patient with a substance use disorder, start with atomoxetine. Some 
special clinical circumstances seem to naturally call for other options. For example, bupropion is helpful for ADHD 
symptoms, as well as for depression, tobacco use, and being overweight, so it might be a great choice for patients 
with a combination of these problems. Alpha agonists, such as guanfacine and clonidine, are helpful for both 
ADHD and insomnia, another potential two-fer, though these meds tend to be used more frequently for children.
4. Fancy formulations.  Many new formulations of amphetamines and methylphenidates have been introduced 
over the last few years, including the use of various drug delivery technologies, enantiomers, prodrugs, salts, 
and dosage forms. While they may have been marketed to increase drug company profits, some of them may 
have clinical utility. Examples of potentially useful advances include Quillichew ER (a chewable long-acting

have clinical utility. Examples of potentially useful advances include Quillichew ER (a chewable long-acting 
methylphenidate), Cotempla XR-ODT (an ODT long-acting methylphenidate), Adzenys XR-ODT (an ODT long-acting 
amphetamine), Dyanavel XR (a long-acting liquid amphetamine), and most intriguingly, Jornay PM (a long-acting 
methylphenidate you take at night that kicks in the next morning). We cover these formulations in the ADHD 
Medications table. 
5. Cost.  Most ADHD meds are available generically, but some reasonable choices are still branded and therefore 
more expensive. The most popular of these is Vyvanse, which is a long-acting amphetamine. Vyvanse appears to 
have a genuine advantage over many other stimulants, mainly in terms of tolerability and less potential for abuse. 
However, you’ll have a hard time convincing insurance companies to cover the cost of Vyvanse unless you can 
clearly document intolerance in several other trials of stimulants.

Dose Equivalents and Switching Strategies
Most patients need to try different stimulants, or stimulant formulations, before settling on the one that works best 
for them. The dose equivalents are, luckily, fairly easy to remember.
1. From one amphetamine to another amphetamine
 ⦁With the exception of Vyvanse, all amphetamines, including both Adderall IR and XR, are roughly equivalent 
in potency. For example, if a patient is taking Dexedrine 10 mg TID, you can switch this to Adderall 15 mg BID 
or Adderall XR 30 mg QD. That said, some people believe that Dexedrine, being 100% dextroamphetamine, 
might be more potent than Adderall, which is 75% d-amphetamine and 25% l-amphetamine (eg, 30 mg/day of 
Dexedrine may be closer to 40 mg/day of Adderall). In reality, the difference is likely negligible in most people.

 ⦁Vyvanse is composed of both lysine and amphetamine, with amphetamine making up only about 30% of 
Vyvanse. This means that it’s much less potent than straight Dexedrine. So, when switching from another 
amphetamine to Vyvanse, you have to at least double the dose.
2. From one methylphenidate to another methylphenidate
 ⦁With the exception of Concerta and Focalin, all methylphenidate preparations are roughly equivalent in potency.
 ⦁Concerta, because of its complex delivery system, delivers less methylphenidate than implied by the mg amount 
you prescribe. The usual conversion percentage used is 83%, meaning that the body sees 83% of Concerta

12  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONin methylphenidate equivalents. Thus, Concerta 18 mg is equivalent to methylphenidate 15 mg, 36 mg is 
equivalent to 30 mg, and so on.
 ⦁Focalin is the dextro-isomer of methylphenidate, which is twice as potent as methylphenidate. Thus, use about 
half the dose when prescribing Focalin.
3. From a methylphenidate to an amphetamine (or vice versa)
 ⦁Methylphenidate is roughly half as potent as amphetamine, so Ritalin 10 mg = Dexedrine 5 mg, etc. Consistent 
with this equivalency, child psychiatrists often dose methylphenidate at 1 mg/kg, whereas they dose 
amphetamine at 0.5 mg/kg. Conversely, if you’re switching from Dexedrine to Ritalin, you would need to increase 
the dose by a factor of two.
4. From an oral methylphenidate to the methylphenidate patch (Daytrana)
 ⦁According to a clinical trial of patients switched from various versions of long-acting methylphenidate to the

 ⦁According to a clinical trial of patients switched from various versions of long-acting methylphenidate to the 
patch, you should dose the patch at about half the dose of the oral medication (Arnold LE et al, Curr Med Res Opin  
2010;26(1):129–137).
See Table 2 for dose-by-dose breakdowns.
How to Switch
Once you’ve determined the dose equivalence, the actual switching is easy. You don’t have to cross-taper; instead, 
have your patient take the last dose of stimulant A on day one and start stimulant B on day two. To be prudent, start 
the new stimulant at a somewhat lower dose than you calculate would be needed based on the equivalent dose rules 
of thumb. Those equivalencies are based on averages and may not apply to a given individual.
Side Effects and Class Warnings
The following apply to all stimulants:

 ⦁Potential to cause psychosis or aggression.  This is a rare and dose-related effect; it may be more likely in patients with 
a predisposition for psychosis.
 ⦁Worsening or new-onset Tourette’s or tic disorders.  Stimulants may unmask tics. Of stimulants, methylphenidate is 
favored. The non-stimulant guanfacine is an even better alternative.
 ⦁Seizures.  Stimulants may lower the seizure threshold, although data are contradictory; monitor patients with seizure 
disorders closely.
 ⦁Growth inhibition or weight loss.  With long-term use, some growth inhibition may occur occasionally in children, 
but this is generally not a major problem. Monitoring growth and considering “drug holidays” may limit growth 
suppression.

 ⦁Cardiovascular safety.  The FDA issued a serious class warning in 2006 with regard to cardiovascular safety. However, 
newer data, both in children and adults, have been reassuring. Cardiac events occurred at virtually the same or 
lower rates among people who took stimulants compared to those who did not. From a practical perspective, we 
recommend asking about cardiac problems and consulting the child’s pediatrician or cardiologist if a problem 
exists. Amphetamines should be avoided in patients with known or suspected cardiovascular disease.
 ⦁No refills. All stimulants are controlled substances (Schedule II), which means they can’t be refilled or called in. 
Patients must be given a new prescription every month. In most states, you are allowed to give patients post-dated 
prescriptions for convenience.

Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   13Comorbidities present
ADHD with 
bipolar disorder?
Stimulant plus 
mood stabilizer.ADHD with 
psychosis?
Avoid stimulant.Start with a short-acting 
amphetamine, usually mixed 
amphetamine salts (Adderall IR).
If this fails, switch to 
dextroamphetamine (Dexedrine).
Does patient prefer a long-
acting amphetamine for 
convenience or to prevent 
between-dose crash?
If so, start (or switch to) 
mixed amphetamine salts ER 
(Adderall XR).
lisdexamfetamine (Vyvanse).
Would patient benefit from a 
long-acting methylphenidate for 
convenience or to prevent  
If so, switch to methylphenidate ER 
(Concerta), adding 20% to the  
dose for equivalence.
dexmethylphenidate ER 
(Focalin XR).Too many side effects 
on amphetamine?
If so, switch to 
methylphenidate IR 
(Ritalin).
dexmethylphenidate 
(Focalin).ADHD alone?

Atomoxetine 
(Strattera).Comorbid 
depression?
Bupropion 
(Wellbutrin).Prominent insomnia/
nightmares/PTSD/tic 
disorder/hyperactivity?
Guanfacine ER (Intuniv) or 
clonidine ER (Kapvay).Stimulant contraindicated
 1. History of a heart attack or arrythmia—  
if so, cardiology clearance first.
2. Stimulant use disorder (stimulants or cocaine)—  
by self report, informant report, or PDMP .
ADHD with depression?
antidepressant; consider 
bupropion as a “two-fer. ”Stimulant not contraindicatedAdult ADHD Treatment Algorithm

14  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONTable 1:  ADHD Medications
Brand Name
(Generic Name, if different than heading) 
Year FDA Approved
[G] denotes generic availabilityAvailable Strengths 
(mg except  
where noted)Usual Dosage Range 
(starting–max)  
(mg)Onset of Action 
(minutes)
Can It Be Split?Ages Approved for 
ADHDDelivery System/Notes  
(IR = immediate, CR = controlled, 
DR = delayed, ER = extended release) Duration of Action 
(hours)
Methylphenidates
Short-Acting
Focalin [G]
(Dexmethylphenidate)
20012.5, 5, 10 2.5–10 BID 30–45 Yes (not scored) 6–17 Tablet; d-enantiomer of Ritalin; 2× more 
potent than methylphenidate3–4
Methylin CT [G]
20032.5, 5, 10 2.5 BID–20 TID 30–45 Yes 6–17, adults Chewable, grape-flavored tablet
3–4
Methylin oral solution [G]
20025 mg/5 mL, 10 mg/5 
mL 2.5 BID–20 TID 30–45 N/A (liquid) 6–17, adults Clear, grape-flavored liquid 
3–4
Ritalin [G]
19555, 10, 20 2.5 BID–20 TID 30–45 Yes 6–17, adults IR tablet 
3–4

3–4
3–4
Intermediate-Acting
Metadate ER [G] 
1999 (Branded generic of Ritalin SR)20 10 QAM–30 BID 60–90 No 6–17, adults CR tablet (less predictable because of 
wax matrix)6–8
Methylin ER [G] 
2000 (Branded generic of Ritalin SR)10, 20 20–60 QAM 60–90 No 6–17, adults Hydrophilic polymer tablet; possibly 
more continuous than others in category 4–8
Ritalin SR [G]
198210, 20 10−60 QAM 60–90 No 6–17, adults CR tablet (less predictable because of 
wax matrix)4–8
Long-Acting 
201925, 35, 45, 55, 70, 85 25–85 QAM 45–60 Can be sprinkled; do 
not crush or chew6–17, adults Capsule of 20% IR beads & 80% DR beads
10–16
201510, 15, 20, 30, 40, 
50, 6010–60 QAM 45–60 Can be sprinkled; do 
not crush or chew6–17, adults Capsule of 40% IR beads & 60% DR beads
8–12
Azstarys
(Serdexmethylphenidate/

10–16
8–12
Azstarys
dexmethylphenidate)
202126.1/5.2, 39.2/7.8, 
52.3/10.439.2/7.8–52.3/10.4 
QAM30–60 Can be sprinkled or 
added to water6–17, adults Combination of prodrug of 
dexmethylphenidate (70%) and d-MPH 
(30%); equivalent to 20, 30, 40 mg 
dexmethylphenidate (Focalin); twice as 
potent as methylphenidate8–13
Concerta [G]
200018, 27, 36, 54 18–72 QAM 45–60 No 6–17, adults CR tablet with 22% IR & 78% DR
10–12
1Strattera dosing: Weight <70 kg, start 0.5 mg/kg, target 1.2 mg/kg, max 1.4 mg/kg; weight >70 kg, 40−100 mg

ADHD MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   15Brand Name
(mg except  
(minutes)
(hours)
20178.6, 17.3, 25.9 17.3–51.8 QAM 45–60 No (ODT) 6–17 Orally disintegrating; ER with 25% IR & 
75% ER8–12
Daytrana patch
(Methylphenidate transdermal system)
200610, 15, 20, 30 10–30 QAM;
remove after 9 hrs120 No 6–17 CR patch; duration can be shortened by 
decreasing wear time; drug effects may 
persist for 5 hrs after removal 8–12
Focalin XR [G] 
(Dexmethylphenidate XR) 
20055, 10, 15, 20, 25, 30, 
35, 406−17 yrs: 5–30 QAM; 
Adults: 10–40 QAM30 Can be sprinkled; do

Adults: 10–40 QAM30 Can be sprinkled; do 
not crush or chew6–17, adults Capsule of 50% IR beads & 50% DR beads; 
mimics BID dosing; twice as potent as 
methylphenidate8–12
Jornay PM
201820, 40, 60, 80, 100 20–100 QPM 8–10 hrs Can be sprinkled; do 
not crush or chew6–17, adults ER capsule of DR beads; taken in evening 
between 6:30–9:30 p.m.8–12; after delay in 
onset
Metadate CD [G]
200110, 20, 30, 40, 50,
6020–60 QAM 60–90 Can be sprinkled; do 
not crush or chew6–17, adults Capsule of 30% IR beads & 70% DR beads; 
mimics BID dosing8−12
Quillichew ER
201520, 30, 40 20–60 QAM 45–60 Yes 6–17, adults Chewable ER for those who will not 
swallow pills or take liquids; 30% IR & 
70% ER8–12
Quillivant XR 
201225 mg/5 mL 20–60 QAM 45 N/A (liquid) 6–17, adults 20% IR & 80% ER in oral solution; shake 
prior to use8−12
Ritalin LA [G]

70% ER8–12
200210, 20, 30, 40, 60 20–60 QAM 60–90 Can be sprinkled; do 
not crush or chew6–17, adults Capsule of 50% IR beads & 50% DR beads
8–12
Amphetamines
Short-Acting 
Desoxyn [G]
(Methamphetamine)
19435 5 QAM–10 BID 30–45 Yes (scored) 6–17 Tablet
3–5
Dexedrine [G]
(Dextroamphetamine)
19765, 10 3−5 yrs: 2.5 QAM–20 
BID; 6−16 yrs: 5 
QAM–20 BID30–45 Yes 3–16 Scored tablet
3–5
Evekeo [G]
Evekeo ODT
(Amphetamine)
2012, 20195, 10
ODT: 2.5, 5, 10, 15, 203–5 yrs: 2.5 QAM–20 
BID; 6–17 yrs: 5 
QAM–20 BID30–45 Yes (scored)
No (ODT)3–17 Scored tablet or ODT; 1:1 ratio of l- and 
d-amphetamine 
3–5
ProCentra [G]
(Dextroamphetamine oral solution)
20085 mg/5 mL 5–20 BID 30–45 N/A (liquid) 3–16 Bubblegum-flavored liquid
3–5

3–5
3–5

16  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONBrand Name
(mg except  
(minutes)
(hours)
Zenzedi 
(Dextroamphetamine) 
20132.5, 5, 7.5, 10, 15, 
20, 303–5 yrs: 2.5 QD–20 
BID; 6–16 yrs: 5 
QAM–20 BID (same as 
Dexedrine dosing) 30–45 Yes 3–16 Tablet; 5 mg scored, 10 mg double 
scored, rest unscored
3–5
Adderall [G]
(Mixed amphetamine salts) 
19605, 7.5, 10, 12.5, 15, 
20, 303–5 yrs: 2.5
QAM–20 BID; 6–17 yrs: 
5 QAM–20 BID; Adults: 
5 QAM–20 BID45–60 Can be crushed 3–17, adults Tablet; mixed salt of l- and 
d-amphetamine
6–8
Long-Acting
Adderall XR [G]
(Mixed amphetamine salts)

6–8
20015, 10, 15, 20, 25, 30 6–12 yrs: 5–30 QAM; 
13–17 yrs: 10–40 QAM; 
Adults: 20–60 QAM45–60 Can be sprinkled; do 
mixed salt of l- and d-amphetamine; 
mimics BID dosing8–12
Adzenys XR-ODT
Adzenys ER oral suspension
2016, 20173.1, 6.3, 9.4, 12.5, 
15.7, 18.8
Oral suspension: 1.25 
mg/mL6–12 yrs: 6.3 (5 
mL)–18.8 (15 mL) 
QAM; 13–17 yrs: 6.3 
(5 mL)–12.5 (10 mL) 
QAM; Adults: 12.5 (10 
mL) QAM45–60 N/A (ODT/liquid) 6–17, adults 50% IR & 50% ER; ER ODT; 3.1 mg is 
equivalent to 5 mg mixed-salts product; 
increasing dose preparations are 
equivalent to 10 mg, 15 mg, 20 mg, 25 
mg, and 30 mg respectively. Solution: 
1.25 mg is equivalent to 2 mg Adderall 
XR.8–12
Dexedrine Spansules [G] 

XR.8–12
19765, 10, 15 5 QAM–20 BID 30–60 Can be sprinkled; do 
not crush or chew3–16 Capsule of 50% IR & 50% sustained-
release beads6–8
20155, 10, 15, 20
Oral suspension: 2.5 
mg/mL6–17 yrs: 2.5–20 QAM 45–60 No (oral suspension) 6–17 ER oral suspension allowing once-daily 
dosing (must shake well); 2.5 mg = 4 mg 
mixed amphetamine salts 8–12
Mydayis
201712.5, 25, 37.5, 50 13–17 yrs: 12.5–25 
QAM; Adults: 12.5–50 
QAM45–60 Can be sprinkled; do 
not crush or chew13–17, adults pH-dependent ER capsule formulation; 
may have effect up to 16 hrs
10–16
Vyvanse 
(Lisdexamfetamine) 
2007Capsule: 10, 20, 30, 
40, 50, 60, 70 
Chewable: 10, 20, 30, 
40, 50, 60 30–70 QAM 60–90 Capsules can be 
dissolved in water6−17, adults Lisdexamfetamine is prodrug of 
8–13

8–13

ADHD MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   17Brand Name
(mg except  
(minutes)
(hours)
Non-Stimulants
Intuniv [G]
(Guanfacine ER) 
20091, 2, 3, 4 1–4 QD (do not 
increase faster than 1 
mg/wk) (adolescents 7 
mg/day max)N/A No 6–17 ER tablet; do not stop abruptly (rebound 
hypertension); not a 1:1 conversion from 
IR; do not give with high-fat meals24
Kapvay [G]
(Clonidine XR)
20100.1, 0.2 0.1 QHS; increase by 
0.1 mg/day weekly 
and give divided BID; 
max 0.4 QDN/A No 6–17 ER tablet; titrate gradually (orthostatic 
hypotension); avoid abrupt 
discontinuation; somnolence12–16
Provigil [G]

(Modafinil) 
1998100, 200 100–400 QAM N/A Yes (200 mg tabs are 
scored)Not FDA approved 
for ADHDTablet; studies have shown modafinil to 
be helpful for ADHD, but low incidence of 
serious rash; minimal data in children 18–24
Qelbree
(Viloxazine ER)
2021100, 150, 200 100–400 QAM N/A Can be sprinkled 6–17, adults ER capsule; norepinephrine reuptake 
inhibitor24
Strattera [G]
(Atomoxetine) 
200210, 18, 25, 40, 60,
80, 100Dosage varies; see 
footnote 1 belowN/A No 6–17, adults Capsule; norepinephrine reuptake 
Tenex [G]
(Guanfacine IR) 
19861, 2 1–4 QD (do not 
mg/wk)N/A Can be crushed Not FDA approved 
for kids or ADHD;
approved only 
for adults 18+ for 
hypertensionTablet
17
Wellbutrin [G]
(Bupropion)
198575, 100 1.4–6 mg/kg/day N/A Yes Not FDA approved

17
198575, 100 1.4–6 mg/kg/day N/A Yes Not FDA approved 
for ADHDTablet; bupropion SR & XL versions exist
6–9

18  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONTable 2:  Relative Equivalency and Conversion 
Guide for Stimulants1
Alternative Formulation Regular Methylphenidate Equivalent
Adhansia XR 25 mg QAM 5 mg IR TID
Adhansia XR 100 mg QAM 20 mg IR TID
Aptensio XR 10 mg QAM 5 mg IR BID or 10 mg ER QAM
Concerta 18, 27, 36, 54 mg tablets 10–15, 15–20, 20–30, 30–45 mg/day, respectively; 
use 72 mg Concerta for 45–60 mg/day
Cotempla XR-ODT 8.6, 17.3, 25.9 mg tablets ER 10, 20, 30 mg, respectively
Daytrana patch 10 mg 5 mg IR BID or 10 mg ER QAM
Focalin 5 mg BID IR 10 mg BID
Focalin XR 10 mg QAM IR 20 mg QAM
Jornay PM 20 mg QPM 4 mg IR TID
Jornay PM 100 mg QPM 20 mg IR TID
Quillichew ER 20 mg QAM 10 mg IR BID or 20 mg ER QAM
Quillichew ER 30 mg QAM 15 mg IR BID or 30 mg ER QAM
Quillichew ER 40 mg QAM 20 mg IR BID or 40 mg ER QAM
Quillivant XR 10 mg (2 mL) QAM 5 mg IR BID or 10 mg ER QAM
Quillivant XR 20 mg (4 mL) QAM 10 mg IR BID or 20 mg ER QAM

Quillivant XR 30 mg (6 mL) QAM 15 mg IR BID or 30 mg ER QAM
Quillivant XR 40 mg (8 mL) QAM 20 mg IR BID or 40 mg ER QAM
Alternative Formulation Regular Mixed Amphetamine Salts Equivalent
Adzenys XR-ODT 3.1 mg QAM 2.5 mg IR BID or 5 mg ER QAM
Adzenys XR-ODT 6.3 mg QAM 5 mg IR BID or 10 mg ER QAM
Adzenys XR-ODT 9.4 mg QAM 7.5 mg IR BID or 15 mg ER QAM
Adzenys XR-ODT 12.5 mg QAM 10 mg IR BID or 20 mg ER QAM
Adzenys XR-ODT 15.7 mg QAM 12.5 mg IR BID or 25 mg ER QAM
Adzenys XR-ODT 18.8 mg QAM 15 mg IR BID or 30 mg ER QAM
Adzenys ER 3.125 mg (2.5 mL) QAM 2.5 mg IR BID or 5 mg ER QAM
Adzenys ER 6.25 mg (5 mL) QAM 5 mg IR BID or 10 mg ER QAM
Adzenys ER 9.375 mg (7.5 mL) QAM 7.5 mg IR BID or 15 mg ER QAM
Adzenys ER 12.5 mg (10 mL) QAM 10 mg IR BID or 20 mg ER QAM

Adzenys ER 15.625 mg (12.5 mL) QAM 12.5 mg IR BID or 25 mg ER QAM
Adzenys ER 18.75 mg (15 mL) QAM 15 mg IR BID or 30 mg ER QAM
Dyanavel XR 6.25 mg (2.5 mL) 5 mg IR BID or 10 mg ER QAM
Dyanavel XR 12.5 mg (5 mL) 10 mg IR BID or 20 mg ER QAM
Dyanavel XR 18.75 mg (7.5 mL) 15 mg IR BID or 30 mg ER QAM
Mydayis 37.5 mg QAM 25 mg ER QAM plus 12.5 mg IR eight hours later
Vyvanse 30 mg QAM 5 mg IR BID or 10 mg ER QAM
Vyvanse 50 mg QAM 10 mg IR BID or 20 mg ER QAM
Vyvanse 70 mg QAM 15 mg IR BID or 30 mg ER QAM
IR = immediate release; ER = extended release 
1These are approximate equivalencies provided as guidance; taper and titrate each agent based on recommended 
dosing when switching rather than direct substitution

ADHD MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   19AMPHETAMINE  (Adzenys XR-ODT, Dyanavel XR, Evekeo) Fact Sheet [G]
Bottom Line:
Amphetamine is a 50:50 racemic mixture of dextro- and levo-amphetamine. In clinical practice, the most commonly 
prescribed amphetamine is Adderall (mixed amphetamine salts; see fact sheet later in this chapter). Based on meta-
analyses, amphetamines are clearly the most effective option in both children and adults with ADHD. That doesn’t 
mean they should always be the first choice, though. Methylphenidates are often better tolerated and have relatively 
less abuse potential. Several newer formulations of amphetamine may be helpful for patients who don’t like to 
swallow pills—but they come with a price tag.  
FDA Indications:
ADHD  (Adzenys XR-ODT: adults and children ≥6; Dyanavel XR: children ≥6; Evekeo: children ≥3); narcolepsy (Evekeo); 
obesity (Evekeo).
Off-Label Uses:
Treatment-resistant depression.

Dosage Forms:
 ⦁Tablets (Evekeo, [G]):  5 mg, 10 mg (scored); (Evekeo ODT):  2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg.
 ⦁ER tablets (Dyanavel XR):  5 mg (scored), 10 mg, 15 mg, 20 mg.
 ⦁ER orally disintegrating tablets (Adzenys XR-ODT):  3.1 mg, 6.3 mg, 9.4 mg, 12.5 mg, 15.7 mg, 18.8 mg.
 ⦁ER oral suspension (Dyanavel XR): 2.5 mg/mL; (Adzenys ER):  1.25 mg/mL.
Dosage Guidance:
 ⦁Tablets (Evekeo, [G]):
 –Children 3–5: Start 2.5 mg QAM, increase in 2.5 mg/day increments weekly.
 –Children 6–17: Start 5 mg QAM, increase in 5 mg/day increments weekly to maximum of 40 mg/day in divided doses.
 –Narcolepsy: Start 5 mg QAM (ages 6–12) or 10 mg QAM (ages >12), increase by 5 or 10 mg/day increments weekly, 
respectively. Maximum 60 mg/day in divided doses.

–Narcolepsy: Start 5 mg QAM (ages 6–12) or 10 mg QAM (ages >12), increase by 5 or 10 mg/day increments weekly, 
 ⦁ER ODT (Adzenys XR-ODT) or Adzenys ER oral suspension:
 –Start 6.3 mg (5 mL) QAM, increase in 3.1 mg (2.5 mL)–6.3 mg (5 mL) per day increments weekly. Maximum of 18.8 
mg (15 mL)/day (ages 6–12) or 12.5 mg (10 mL)/day (ages 13–17 and adults).
 ⦁ER oral suspension (Dyanavel XR):
 –Children 6–12: Start 2.5–5 mg QAM, increase in 2.5–10 mg/day increments every four to seven days. Maximum 20 mg/day.
Monitoring:  ECG if history of cardiac disease.
Cost:  [G]: $$$; others: $$$$
Side Effects:
 ⦁Most common: Abdominal pain, decreased appetite, weight loss, insomnia, headache, nervousness.
 ⦁Serious but rare: See class warnings in chapter introduction.
Mechanism, Pharmacokinetics, and Drug Interactions:
 ⦁Stimulant that inhibits reuptake of dopamine and norepinephrine.
 ⦁Metabolized primarily via CYP2D6; t ½: 11 hours.

 ⦁Avoid use with MAOIs, antacids.
Clinical Pearls:
 ⦁These racemic forms of amphetamine differ from dextroamphetamine in that the l-isomer component is more 
potent than the d-isomer in peripheral activity (potentially resulting in more cardiovascular effects and tics).
 ⦁A racemic mixture may be less appetite suppressing compared to dextroamphetamine.
 ⦁Divide IR (Evekeo) doses by intervals of four to six hours.
 ⦁Approximate equivalence doses of Adzenys XR-ODT and mixed amphetamine salts XR (Adderall XR) are: 3.1 mg = 5 
mg, 6.3 mg = 10 mg, 9.4 mg = 15 mg, 12.5 mg = 20 mg, 15.7 mg = 25 mg, 18.8 mg = 30 mg.
 ⦁Dyanavel XR oral suspension: Shake well to get the intended extended-release effect. The approximate equivalence 
of 2.5 mg/mL is 4 mg of mixed amphetamine salts.
Fun Facts:

⦁Dyanavel XR oral suspension: Shake well to get the intended extended-release effect. The approximate equivalence 
Fun Facts:
The term “amphetamine” is the contracted name of the chemical “alpha-methylphenethylamine. ” Its first 
pharmacologic use was in 1934 when pharmaceutical company Smith, Kline and French sold amphetamine under the 
trade name Benzedrine as a decongestant inhaler.

20  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONATOMOXETINE  (Strattera) Fact Sheet [G]
Atomoxetine is a non-stimulant ADHD treatment that carries no abuse potential, causes less insomnia and anxiety, 
and is unlikely to worsen tics. Unfortunately, it is generally less effective than stimulants and takes longer to work (two 
to four weeks).
ADHD  (adults and children ≥6 years).
Capsules (G):  10 mg, 18 mg, 25 mg, 40 mg, 60 mg, 80 mg, 100 mg.
 ⦁Start 40 mg QAM for three days, ↑ to 80 mg QAM, may ↑ to 100 mg/day after two to four weeks if needed (max 100 
mg/day); may divide doses >40 mg/day (morning and late afternoon/early evening).
 ⦁Special dosing for children <70 kg: Start 0.5 mg/kg QAM for three days, ↑ to 1.2 mg/kg QAM, may ↑ to max 1.4 mg/

kg/day or 100 mg/day (whichever is less) after two to four weeks if needed; may divide doses >0.5 mg/kg/day.
Monitoring:  Baseline LFTs; follow up if signs of liver disease.
Cost:  $
 ⦁Most common: Children:  Headache, abdominal pain, decreased appetite, fatigue, nausea, vomiting.  
Adults:  Nausea, dry mouth, decreased appetite, insomnia, constipation, fatigue, erectile dysfunction, abdominal 
pain, dizziness, urinary hesitation.
 ⦁Serious but rare: Class warning for suicidal ideation in children and teens. Severe hepatic injury including  
increased hepatic enzymes (up to 40 times normal) and jaundice (bilirubin up to 12 times upper limit of  
normal). Increased blood pressure ( ↑ 15–20 mmHg) and heart rate ( ↑ 20 bpm).

 ⦁Selective norepinephrine reuptake inhibitor (NRI).
 ⦁Metabolized primarily via CYP2D6; t ½: 5 hours.
 ⦁Avoid use with MAOIs. Exercise caution with 2D6 inhibitors such as fluoxetine, paroxetine, and quinidine (increased 
atomoxetine serum levels); use slower titration and do not exceed 80 mg/day in presence of 2D6 inhibitors or in 2D6 
poor metabolizers.
 ⦁QAM and BID dosing are equally effective, but BID dosing has better GI tolerability. Can also be dosed at bedtime if 
it causes fatigue.
 ⦁Appears to be more effective in improving attention than in controlling hyperactivity.
Fun Fact:
Atomoxetine was originally known as “tomoxetine”; however, the FDA requested that the name be changed because 
the similarity to “tamoxifen” could lead to dispensing errors.

ADHD MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   21CLONIDINE  (Catapres, Kapvay) Fact Sheet [G]
Clonidine is an alpha-2 agonist that has no abuse potential, does not worsen tics, and does not cause insomnia. 
However, it’s less effective than stimulants and has a delayed onset of effect (two to four weeks); it is often added 
to a stimulant to prevent insomnia. Clonidine may be used as a second-line option for opioid detoxification if 
buprenorphine or methadone are not available.
Hypertension;  ADHD  (children ages 6–17), as monotherapy or adjunctive therapy to stimulants (not approved for 
ADHD in adults).
Conduct disorder; Tourette’s and motor tics; pervasive developmental disorders; migraine prophylaxis; opioid 
 ⦁IR tablets (Catapres, [G]):  0.1 mg, 0.2 mg, 0.3 mg.
 ⦁ER tablets (Kapvay, [G]):  0.1 mg, 0.2 mg.

 ⦁Patch (Catapres-TTS, [G]):  0.1 mg/day, 0.2 mg/day, 0.3 mg/day.
 ⦁IR: Start 0.1 mg BID, ↑ by 0.1 mg/day at weekly intervals; max 2 mg/day. For opioid withdrawal, may be dosed 
0.1–0.2 mg every four to six hours as needed. Daily dosing requirement can be established by tabulating the total 
amount administered over the first 24 hours and dividing this amount into a TID or QID schedule. Total dose should 
not exceed 1.2 mg the first 24 hours and 2 mg/day beyond that.
 ⦁ER: Start 0.1 mg QHS, ↑ by 0.1 mg/day at weekly intervals; max 0.4 mg/day. May divide doses >0.2 mg/day; divided 
doses may be unequal with higher dose given at bedtime.
Monitoring:  Blood pressure (hold doses for BP <90/60).
Cost:  $
 ⦁Most common: Dry mouth, somnolence, dizziness, constipation, fatigue, headache.

Cost:  $
 ⦁Serious but rare: Hypotension, syncope, orthostasis.
 ⦁Centrally acting, selective alpha-2 adrenergic agonist.
 ⦁Metabolized primarily through CYP2D6; t ½: 6–20 hours.
 ⦁Avoid use with MAOIs. Caution with 2D6 inhibitors (eg, paroxetine, fluoxetine, duloxetine).
 ⦁Not a controlled substance.
 ⦁Clonidine tends to be more sedating than guanfacine, another alpha agonist.
 ⦁When used in detox, clonidine relieves most opioid withdrawal symptoms but is less effective than methadone or 
buprenorphine. Therefore, adjunctive medications are often used with clonidine to manage insomnia, muscle pain, 
headache, agitation, and other symptoms. Even so, detox completion rates with clonidine are typically significantly 
lower than those with buprenorphine or methadone.

 ⦁The patch formulation is not typically used (except for hypertension) because clonidine’s effects on BP may be 
prolonged and continue even after patch removal. 
 ⦁If patient misses two or more consecutive doses, consider repeating titration.
 ⦁Minimize side effects, especially somnolence, by administering at bedtime.
 ⦁Monitor blood pressure, especially during initial dosing titration.
 ⦁Risk of nervousness, anxiety, and possibly rebound hypertension two to four days after abrupt discontinuation. 
Taper dose in no more than 0.1 mg/day decrements, every three to seven days.
Fun Fact:
The Federal Bureau of Prisons’ clinical guidance document, Detoxification of Chemically Dependent Inmates,  
recommends maintaining strict control over medication access to prevent diversion or misuse. It cites the example of

recommends maintaining strict control over medication access to prevent diversion or misuse. It cites the example of 
inmates eating clonidine patches to obtain a state of euphoria.

22  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONDEXMETHYLPHENIDATE  (Azstarys, Focalin, Focalin XR) Fact Sheet [G]
Dexmethylphenidate (Focalin) is the d-isomer of methylphenidate and is two times more potent than 
methylphenidate. Azstarys is a newly approved (and expensive) combination of Focalin and a prodrug version 
of Focalin—the Focalin is absorbed quickly while the prodrug is absorbed more slowly (it’s the Vyvanse of 
methylphenidate). There’s no clear advantage of Focalin over Ritalin—the main difference is that Focalin may mean 
fewer tablets for patients. Focalin XR only recently went generic, so it will likely remain quite expensive for a while. 
Azstarys may be less abusable than Focalin. 
ADHD in adults (Azstarys, Focalin XR) and in children ≥6 years (Azstarys, Focalin IR and XR).
Narcolepsy, obesity, treatment-resistant depression.

 ⦁Dexmethylphenidate tablets (Focalin, [G]):  2.5 mg, 5 mg, 10 mg.
 ⦁Dexmethylphenidate ER capsules (Focalin XR, [G]):  5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg.
 ⦁Serdexmethylphenidate/dexmethylphenidate ER capsules (Azstarys):  26.1/5.2 mg, 39.2/7.8 mg, 52.3/10.4 mg.
 ⦁d-MPH IR: Start 2.5 mg BID, ↑ by 5–10 mg/day every seven days. Max 20 mg/day; divide IR doses by at least four 
hours.
 ⦁d-MPH ER: Start 10 mg QAM, ↑ by 10 mg/day every seven days. Max 40 mg/day. For children, start 5 mg QAM, ↑ by 5 
mg/day every seven days. Max (children) 30 mg/day.
 ⦁Serdex-MPH/d-MPH: Start 39.2/7.8 mg QAM, ↑ to max dose of 52.3/10.4 mg after one week if indicated.
Cost:  IR: $; ER: $$; Azstarys: $$$$

 ⦁Most common: Decreased appetite, insomnia, anxiety, GI distress, irritability, tics, headache, tachycardia, 
hypertension, dry mouth.
 ⦁Serdexmethylphenidate (Serdex-MPH) is a prodrug of dexmethylphenidate (d-MPH). d-MPH is metabolized primarily 
via de-esterification, not CYP450; d-MPH t ½: 2–4.5 hours (2–3 hours in children); d-MPH ER delivers 50% of dose 
immediately and 50% about five hours later. Azstarys t ½: 6–12 hours; delivers 30% d-MPH immediately and 70% as 
prodrug.
 ⦁Avoid use with MAOIs.
 ⦁d-MPH is the d-isomer of methylphenidate and is two times more potent than methylphenidate, which is why it is

prodrug.
 ⦁d-MPH is the d-isomer of methylphenidate and is two times more potent than methylphenidate, which is why it is 
prescribed at about half the dose. Serdex-MPH is a prodrug, converted to d-MPH in the lower GI tract. 
 ⦁Use the same total daily dose of Focalin IR as Focalin XR. The combined dose of Azstarys 26.1/5.2, 39.2/7.8, or 
52.3/10.4 mg is equivalent to 20, 30, or 40 mg of Focalin, respectively.
 ⦁Focalin XR capsules contain two kinds of beads: Half are IR beads and half are enteric-coated DR beads. A single, 
once-daily XR capsule provides the same amount of dexmethylphenidate as two IR tablets given four hours apart.
 ⦁The ER capsules cannot be split in half. However, they can be opened and the beads sprinkled over food. The patient 
should then eat all that food—eating half won’t work to split the dose accurately because it won’t be possible to

should then eat all that food—eating half won’t work to split the dose accurately because it won’t be possible to 
determine if the eaten portion contains more immediate-release or delayed-release beads.
 ⦁Give with food if GI side effects occur.
Fun Fact:
With two stereoactive centers, methylphenidate has four possible stereoisomers. Of the four, dexmethylphenidate is 
the most active biologically.

ADHD MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   23DEXTROAMPHETAMINE  (Dexedrine, ProCentra, Zenzedi) Fact Sheet [G]
Dextroamphetamine is the dextro-isomer of racemic amphetamine. It has a long history of safe use in children, and is 
available in short- and long-acting formulations as generics.
ADHD (children ≥3 years);  narcolepsy (adults and children ≥6 years).
Obesity, treatment-resistant depression.
 ⦁Tablets (Dexedrine, [G]):  5 mg, 10 mg (scored).
 ⦁Tablets (Zenzedi):  2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg (5 mg scored, 10 mg double scored; rest 
unscored).
 ⦁ER capsules (Dexedrine Spansules, [G]):  5 mg, 10 mg, 15 mg.
 ⦁Liquid (ProCentra, [G]):  5 mg/5 mL.
 ⦁ADHD (IR and ER):
 –Adults and children ≥6 years: Start 5 mg QAM, ↑ by 5 mg/day at weekly intervals to max 60 mg/day, though doses

⦁Liquid (ProCentra, [G]):  5 mg/5 mL.
 –Adults and children ≥6 years: Start 5 mg QAM, ↑ by 5 mg/day at weekly intervals to max 60 mg/day, though doses 
≥40 mg/day are rarely more effective. Divide IR dose QD–TID.
 –Children 3−5 years: Start 2.5 mg QAM, ↑ by 2.5 mg/day weekly to max 60 mg/day, though doses >40 mg/day are 
rarely more effective. Divide IR dose QD–TID.
 ⦁Narcolepsy (IR and ER):
 –Start 10 mg QAM, ↑ by 10 mg/day weekly to max 60 mg/day. Divide IR dose QD–TID.
Cost:  IR/ER: $ (Zenzedi and ProCentra: $$$$)
 ⦁Most common: Abdominal pain, anorexia, nausea, tics, insomnia, tachycardia, headache.
 ⦁Metabolized primarily through CYP450 2D6 (minor) and glucuronidation; t ½: 12 hours.

⦁Stimulant that inhibits reuptake of dopamine and norepinephrine.
 ⦁Dextroamphetamine is the more potent d-isomer of amphetamine; it has potentially less peripheral effects (eg, 
motor tics) than a racemic mix (eg, mixed amphetamine salts like Adderall, amphetamine, or methamphetamine).
 ⦁IR tablets and oral solution: Doses can be given at intervals of four to six hours.
 ⦁Dextroamphetamine is the only stimulant, other than Adderall IR, approved for children <6 years (approved for 
children ≥3 years).
 ⦁The newer Zenzedi brand offers more dosing flexibility options, but it is more expensive than generic IR tablets.
 ⦁Also available as D,L racemic mixture of amphetamine as Evekeo tablets, Adzenys XR-ODT, and Dyanavel XR oral 
suspension (see amphetamine fact sheet).
Fun Fact:

⦁Also available as D,L racemic mixture of amphetamine as Evekeo tablets, Adzenys XR-ODT, and Dyanavel XR oral 
Fun Fact:
Dexys Midnight Runners, the British band famous for its song “Come On Eileen” (1982), derived their name from 
Dexedrine—“Dexys” after the drug’s name and “Midnight Runners” in reference to the energy it provides.

24  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONGUANFACINE  (Intuniv, Tenex) Fact Sheet [G]
Guanfacine is an alpha-2 agonist that has no abuse potential, does not worsen tics, and does not cause insomnia. 
However, it is less effective than stimulants and has a delayed onset of effect (two to four weeks). Guanfacine ER is 
now available in generic and is easier to use than IR.
ADHD  (children ages 6–17), as monotherapy or adjunctive therapy to stimulants (not approved for ADHD in adults).
 ⦁IR tablets (Tenex, [G]):  1 mg, 2 mg.
 ⦁ER tablets (Intuniv, [G]):  1 mg, 2 mg, 3 mg, 4 mg.
 ⦁IR dosing depends on weight:
 –27–40.5 kg (55–90 lbs): Start 0.5 mg QHS, ↑ by 0.5 mg/day at weekly intervals up to 1.5 mg/day, may ↑ to 2 mg/

day after two weeks; max 2 mg/day in two to four divided doses.
 –40.5–45 kg (90–99 lbs): Start 0.5 mg QHS, ↑ by 0.5 mg/day at weekly intervals; max 1 mg per dose, 3 mg/day.
 –>45 kg (>99 lbs): Start 1 mg QHS, ↑ by 1 mg/day at weekly intervals up to 3 mg/day, may ↑ to 4 mg/day after 2 
weeks; max 1 mg per dose, 4 mg/day.
 ⦁ER: Start 1 mg QHS, ↑ by 1 mg/day at weekly intervals; max 4 mg/day. Alternative: 0.05–0.12 mg/kg QD or QHS; max 
4 mg/day. Doses up to 7 mg/day ER studied as monotherapy in adolescents.
Monitoring:  Blood pressure.
Cost:  $

⦁Serious but rare: Hypotension, syncope, orthostasis.
 ⦁Metabolized primarily through CYP3A4; t ½: 13–14 hours in children (16–18 hours in adults).
 ⦁Avoid use with MAOIs. Caution with 3A4 inhibitors (eg, clarithromycin, fluvoxamine) and inducers (eg, St. John’s 
wort, carbamazepine).
 ⦁Guanfacine IR and ER are not interchangeable on a mg:mg basis. When switching from one formulation to the other, 
taper and re-titrate.
 ⦁Guanfacine tends to be less sedating than clonidine, another alpha agonist.
 ⦁ER tablets should not be taken with a high-fat meal due to increased medication exposure.

⦁Minimize side effects, especially somnolence, by administering at bedtime.
Taper dose in 1 mg/day decrements, every three to seven days.
Fun Fact:
Some prescribers have taken advantage of guanfacine’s sympatholytic properties for the treatment of nightmares and 
dissociative symptoms in PTSD.

ADHD MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   25LISDEXAMFETAMINE  (Vyvanse) Fact Sheet
Vyvanse may have a gentler, “smoother” side effect profile than other amphetamines, and it probably has a lower 
risk of diversion or abuse. However, its high cost means insurance companies don’t like to pay for it without prior 
authorization. 
ADHD  (adults and children ≥6 years); binge eating disorder  (BED).
Narcolepsy; obesity; treatment-resistant depression.
 ⦁Capsules:  10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg.
 ⦁Chewtabs:  10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg.
 ⦁ADHD (adults and children ≥6 years): Start 30 mg QAM, ↑ by 10–20 mg/day at weekly intervals. Target lowest 
effective dose; max 70 mg/day.
 ⦁BED: Start 30 mg QAM, ↑ by 20 mg/day at weekly intervals to target 50 mg/day; max 70 mg/day.
Cost:  $$$$

Cost:  $$$$
 ⦁Most common: Headache, insomnia, anorexia, abdominal pain, irritability, agitation, tics, decreased appetite, 
increased heart rate, jitteriness, anxiety.
 ⦁Metabolized primarily through non-CYP-mediated hepatic and/or intestinal metabolism; t ½: lisdexamfetamine 
(inactive prodrug) <1 hour; dextroamphetamine (active metabolite) 12 hours. Dextroamphetamine metabolized by 
CYP2D6.
 ⦁Avoid use with MAOIs and antacids. Caution with antihypertensives (decreased efficacy of antihypertensive). 
Caution with 2D6 inhibitors, which may increase stimulant effects.

⦁Avoid use with MAOIs and antacids. Caution with antihypertensives (decreased efficacy of antihypertensive). 
 ⦁Lisdexamfetamine is dextroamphetamine with the chemical lysine bound to it, which renders it inactive. It remains 
inactive until GI enzymes cleave off lysine and convert it to active dextroamphetamine. This means that drug 
abusers can’t get high by snorting or injecting it.
 ⦁Anecdotally, Vyvanse has a more gradual onset and offset than other stimulants, and it may cause fewer side effects 
than other amphetamines.
 ⦁Taking with food decreases the effect slightly and delays peak levels by an hour. If patients feel it’s not “kicking in” 
fast enough, have them take it earlier or on an empty stomach.
 ⦁Lisdexamfetamine 70 mg is equivalent to 30 mg of mixed amphetamine salts (Adderall).
 ⦁While indicated for BED, it is not approved for use as a weight loss or anti-obesity agent.
Fun Fact:

⦁Lisdexamfetamine 70 mg is equivalent to 30 mg of mixed amphetamine salts (Adderall).
Fun Fact:
The manufacturer of Vyvanse pursued an indication as an add-on medication for depression, but disappointing results 
in clinical trials put an end to this effort.

26  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONMETHAMPHETAMINE  (Desoxyn) Fact Sheet [G]
Methamphetamine is highly addictive when used in its crystal form (“crystal meth”), because it causes an immediate 
and intense high when snorted or smoked. Its use is generally not recommended. Watch the television show 
“Breaking Bad” if you’re not convinced!
ADHD  (children ≥6 years); obesity (adults and adolescents ≥12 years).
Tablets (G):  5 mg.
ADHD (adults and children ≥6 years): Start 5 mg QAM–BID, ↑ by 5 mg/day at weekly intervals to max 20 mg/day, 
divided BID.
Cost:  $$$$
 ⦁Most common: Anorexia, tachycardia, dizziness, insomnia, tremor, tics, restlessness, headache, constipation 
(decreased GI motility). Dental complications, such as poor dental hygiene, diffuse cavities, bruxism, and tooth wear, 
may develop with abuse.

 ⦁Metabolized primarily through CYP2D6 to active metabolite (amphetamine); t ½: 4–5 hours.
 ⦁Avoid use with MAOIs and antacids. Caution with 2D6 inhibitors, which may increase stimulant effects.
 ⦁High risk of abuse.
 ⦁Not widely used (DEA reports that there were only 16,000 prescriptions written in 2012). When prescribed for 
obesity, the recommendation is for short-term use only (ie, a few weeks) and as an adjunct to caloric restriction due 
to its high addiction and diversion potential.
 ⦁Methamphetamine’s CNS-stimulating effect is approximately equal to or greater than that of amphetamine but less

 ⦁Methamphetamine’s CNS-stimulating effect is approximately equal to or greater than that of amphetamine but less 
than that of dextroamphetamine; less blood pressure elevation than with amphetamine.
Fun Facts:
Desoxyn is the same as the abused street drug methamphetamine, just pharmaceutical grade. Although 
methamphetamine and amphetamine were long thought to be available only via laboratories, methamphetamine 
has been reported to occur naturally in certain acacia trees that grow in West Texas.

ADHD MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   27METHYLPHENIDATE  IR (Methylin, Ritalin) Fact Sheet [G]
Methylphenidate has a better side effect profile and somewhat lower abuse potential than amphetamines. However, 
patients often prefer the “kick” they get from Adderall.
ADHD  (adults and children ≥6 years); narcolepsy .
Obesity; treatment-resistant depression.
 ⦁Tablets (Ritalin, [G]):  5 mg, 10 mg, 20 mg.
 ⦁Chewable tablets (Methylin CT, [G]):  2.5 mg, 5 mg, 10 mg.
 ⦁Oral solution (Methylin, [G]):  5 mg/5 mL, 10 mg/5 mL.
 ⦁ADHD:
 –Adults: Start 5–10 mg BID, ↑ by 10 mg/day at weekly intervals to max 60 mg/day.
 –Children ≥6 years: Start 0.3 mg/kg BID or 2.5–5 mg BID before breakfast and lunch, increase by 0.1 mg/kg/dose or 
5–10 mg/day at weekly intervals to a max of 2 mg/kg/day or 60 mg/day.
 ⦁Narcolepsy: Same dosing as ADHD.

Cost:  $; chewable tabs: $$$
 ⦁Most common: Insomnia, headache, nervousness, abdominal pain, nausea, vomiting, anorexia, weight loss, affect 
lability, tics.
 ⦁Hepatic metabolism via carboxylesterase CES1A1, not CYP450 isoenzymes; t ½: 2–4 hours.
 ⦁Methylphenidate generally causes fewer side effects than amphetamine preparations—patients are less likely to 
report feeling “wired. ”
 ⦁While all stimulants may cause tics, a Cochrane review of eight randomized trials showed that methylphenidate did 
not worsen tics in children with ADHD and a tic disorder; in some cases it even improved tics.

 ⦁Methylin chewable tablets: Administer with at least eight ounces of water or other fluid.
Fun Fact:
Methylphenidate was synthesized by Ciba (now Novartis) chemist Leandro Panizzon. His wife, Marguerite, had low 
blood pressure and would take the stimulant before playing tennis. He named the substance “Ritaline” (yes, with the 
“e” on the end) after his wife’s nickname, Rita.

28  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONMETHYLPHENIDATE  ER (Concerta, Ritalin 
SR and LA, others) Fact Sheet [G]
There are many longer-acting methylphenidate preparations. Two good options are Concerta and Ritalin LA, both of 
which are now available generically.
Dosage Forms  (more commonly used):
 ⦁Tablets 
 –Ritalin SR, Metadate ER, Methylin ER, [G]:  10 mg, 20 mg.
 –Concerta, [G]:  18 mg, 27 mg, 36 mg, 54 mg (22% IR/78% ER).
 ⦁Capsules
 –Ritalin LA, [G]:  10 mg, 20 mg, 30 mg, 40 mg, 60 mg (50% IR/50% ER).
 –Metadate CD, [G]:  10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg (30% IR/70% ER).
 –Aptensio XR:  10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg (40% IR/60% ER).
 –Adhansia XR:  25 mg, 35 mg, 45 mg, 55 mg, 70 mg, 85 mg (20% IR/80% ER).

–Aptensio XR:  10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg (40% IR/60% ER).
 –Jornay PM:  20 mg, 40 mg, 60 mg, 80 mg, 100 mg (onset delayed 10 hours).
 ⦁Oral solution (Quillivant XR):  25 mg/5 mL (20% IR/80% ER).
 ⦁Chewable tablets (Quillichew ER):  20 mg, 30 mg (scored), 40 mg (scored) (30% IR/70% ER).
 ⦁Orally disintegrating tablets (Cotempla XR-ODT):  8.6 mg, 17.3 mg, 25.9 mg (25% IR/75% ER).
 ⦁Intermediate-acting (Ritalin SR, Metadate ER, Methylin ER):
 –Titrate to effective daily dose with IR, then switch to equivalent eight-hour SR or ER dose QAM–BID.
 ⦁Long-acting (Aptensio XR, Metadate CD, Ritalin LA, Quillivant XR, Quillichew ER):
 –Start 10–20 mg QAM, ↑ by 10−20 mg/day at weekly intervals; max 60 mg/day.
 ⦁Long-acting (Adhansia XR):
 –Start 25 mg QAM, ↑ by 10–15 mg/day at weekly intervals; max 70 mg/day (children) and 85 mg/day (adults).
 ⦁Long-acting (Cotempla XR-ODT):

⦁Long-acting (Adhansia XR):
 –Start 17.3 mg QAM, ↑ by 8.6–17.3 mg/day at weekly intervals; max 51.8 mg/day.
 –8.6 mg, 17.3 mg, 25.9 mg equivalent to 10 mg, 20 mg, 30 mg of other methylphenidate formulations, respectively.
 ⦁Long-acting (Concerta):
 –Start 18–36 mg QAM, ↑ by 18 mg/day at weekly intervals; max 72 mg/day.
 –Children ≥6 years: Start 18 mg QAM, ↑ by 18 mg/day in weekly intervals to max 54 mg/day (ages 6–12) or 72 mg/
day (age 13+).
 ⦁Jornay PM:
 –Start 20 mg daily in the evening and increase by 20 mg/day up to maximum of 100 mg/day. Adjust timing 
between 6:30 and 9:30 p.m.
 ⦁Narcolepsy: Start 10–20 mg ER QAM, ↑ by 10 mg/day at weekly intervals; max 60 mg/day.
Cost:  $$; Concerta: $$$; Aptensio XR, Cotempla XR-ODT, Jornay PM, Quillivant XR, Quillichew ER: $$$$

Side Effects and Mechanism, Pharmacokinetics, and Drug Interactions:
See methylphenidate IR fact sheet.
 ⦁ER capsules contain a mixture of 30% IR and 70% ER beads. Aptensio XR  contains a mixture of 40% IR and 60% ER 
beads, whereas Adhansia XR contains 20% IR and 80% ER. Ritalin LA  and its generic ER capsules are a combination 
of 50% IR and 50% DR beads. These products mimic BID dosing of IR. Cotempla XR-ODT delivers a mixture of 25% 
IR and 75% ER in an orally disintegrating extended-release formulation. Jornay PM  is dosed in the evening; if early-
morning awakening occurs, dose earlier in evening.
 ⦁Concerta is based on the OROS osmotic delivery system (also used for Invega). 22% of the dose is immediate (with 
effects in one to two hours) and 78% is delayed.

ADHD MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   29METHYLPHENIDATE TRANSDERMAL  (Daytrana) Fact Sheet
Daytrana is helpful for kids who, for whatever reason, cannot use any of the wide variety of oral stimulant 
preparations. Otherwise, we don’t recommend it due to high cost, lag time for onset of effect, and the side effect of 
rash, which is pretty common and unpleasant.
ADHD  (children ≥6 years).
Transdermal patch:  10 mg, 15 mg, 20 mg, 30 mg/9 hour.
Start 10 mg/9 hour patch QAM (for initial therapy or for patients switching from other methylphenidate preparations, 
regardless of dose). Apply to hip two hours before an effect is needed and remove nine hours after application (drug 
effects may persist for five hours after removal). Increase dose at weekly intervals by using next higher dose system.

effects may persist for five hours after removal). Increase dose at weekly intervals by using next higher dose system. 
May be removed sooner if shorter duration is desired or if late-day side effects occur. Rotate application sites. Max 
30 mg QD.
Cost:  $$$$
 ⦁Most common: Headache, insomnia, irritability, decreased appetite, anorexia, nausea, tics, application site reaction 
(10%–40% incidence in children).
 ⦁Serious but rare: Allergic contact dermatitis/sensitization, characterized by intense local reactions (eg, edema, 
papules) that may spread beyond patch site; sensitization may subsequently manifest systemically with other routes 
of methylphenidate administration.
 ⦁Hepatic metabolism via carboxylesterase CES1A1, not CYP450 isoenzymes; t ½: 3–4 hours.

 ⦁Apply patch to clean, dry area of the hip; don’t apply to waistline or to areas under tight clothes, as it may rub 
off. Alternate sites daily (eg, opposite hip). Absorption not affected by perspiration. Remove after nine hours. If 
dislodged, replace with a new patch but remove within the nine-hour total wear time.
 ⦁Clinical effect usually seen in two hours and lasts approximately 12 hours.
 ⦁Exposure of application site to a heat source (eg, hair dryer, heating pad, electric blanket) may increase the amount 
of drug absorbed.
 ⦁For localized skin reactions (redness at site), use cortisone cream (1%–2%). For more severe or systemic reactions, 
discontinue patch.
 ⦁In June 2015, the FDA added a warning that Daytrana could cause chemical leukoderma, a permanent loss of skin

 ⦁In June 2015, the FDA added a warning that Daytrana could cause chemical leukoderma, a permanent loss of skin 
color. These reactions are irreversible and not harmful but can be disfiguring. Instruct patients to contact their 
physician if they notice skin color changes or lightening of skin areas; in such cases an alternative medication should 
Fun Fact:
Since 2006, Shire Pharmaceuticals has issued at least 10 recalls of Daytrana patches because users have had difficulty 
removing the protective cover from the patch. Recall costs have reached into the millions.

30  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONMIXED AMPHETAMINE SALTS  (Adderall, 
Adderall XR, Mydayis) Fact Sheet [G]
Adderall contains 75% dextroamphetamine and 25% levoamphetamine. This ratio of amphetamine isomers is 
effective but is probably the most abused and diverted of all prescription stimulants.
ADHD  (adults and children ≥3 years for IR, ≥6 years for XR, ≥13 years for Mydayis); narcolepsy  (adults and children 
≥6 years).
 ⦁Tablets (G):  5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 30 mg.
 ⦁ER capsules (G):  5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg.
 ⦁ER capsules (Mydayis):  12.5 mg, 25 mg, 37.5 mg, 50 mg.
 ⦁ADHD:
 –Rule of thumb for both preparations: Initial dose should be 0.5 mg/kg, but shoot for a target dose of 1.0–1.2 mg/kg.
 –Adults:
 ◽IR: Start 5 QAM–BID, max 40 mg/day divided BID.

⦁ADHD:
 –Adults:
 ◽ER: Start 20 mg QAM, increase to max 60 mg/day QAM. For Mydayis, start 12.5 mg QAM, increase in increments 
of 12.5 mg/day weekly, to max 50 mg/day.
 –Children and adolescents:
 ◽IR: Start 2.5–5 mg BID, max 40 mg/day divided BID.
 ◽ER: Start 5–10 mg QAM, increase gradually to max 30 mg/day, or 40 mg/day QAM in adolescents. For Mydayis 
(adolescents ≥13 years), start 12.5 mg QAM, increase in increments of 12.5 mg/day weekly, to max 25 mg/day.
 ⦁Narcolepsy: Start 10 mg QAM, increase by 10 mg/day at weekly increments; max 60 mg/day.
Cost:  IR/ER: $; Mydayis: $$$$
 ⦁Most common: Insomnia, headache, decreased appetite, abdominal pain, weight loss, agitation.

 ⦁Metabolized primarily through CYP2D6; t ½: 9–14 hours. Duration of action: 6–8 hours (IR), 8–12 hours (XR).
 ⦁Avoid use with MAOIs, antacids. Caution with 2D6 inhibitors, which may increase stimulant effects.
 ⦁Each dose contains a mixture of amphetamine salts, resulting in a 75:25 ratio of dextro- and levo-isomers of 
amphetamine.
 ⦁When converting from IR to ER, use the same total daily dose, given QAM.
 ⦁Adderall may provide more of a “kick” than methylphenidate preparations. Roughly twice as potent (per mg) as 
methylphenidate.
 ⦁Mydayis is formulated with pH-dependent drug-releasing beads, with IR and DR beads that release drug at pH 5.5

 ⦁Mydayis is formulated with pH-dependent drug-releasing beads, with IR and DR beads that release drug at pH 5.5 
and 7.0. Duration of effect may be up to 16 hours.
 ⦁Dextroamphetamine and mixed amphetamine salts are the only stimulants approved for children <6 years 
(approved for children ≥3 years), with the exception of Mydayis, which causes very high rates of side effects 
(insomnia, reduced appetite) in children <13 years and should only be used in children ≥13 years.
Fun Fact:
Was briefly pulled from the market in Canada in 2005 because of cardiac concerns.

ADHD MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   31VILOXAZINE XR  (Qelbree) Fact Sheet
Like the first norepinephrine reuptake inhibitor for ADHD, atomoxetine, viloxazine has no abuse potential and is less 
likely than stimulants to cause insomnia, anxiety, or tics. However, it is generally less effective than stimulants and 
takes longer to work. It’s unclear if it has any advantage, and unlike atomoxetine, there’s no option for a cheaper 
generic.
ADHD  (adults, children ≥6 years). 
ER capsules:  100 mg, 150 mg, 200 mg. 
 ⦁Children 6–11: Start 100 mg QD, ↑ by 100 mg/day at weekly intervals to max 400 mg QD.
 ⦁Children 12–17: Start 200 mg QD, ↑ by 200 mg after one week to max 400 mg QD. 
Monitoring:  Baseline renal function.
Cost:  $$$$

⦁Children 12–17: Start 200 mg QD, ↑ by 200 mg after one week to max 400 mg QD. 
Cost:  $$$$
 ⦁Most common: Somnolence, decreased appetite, fatigue, nausea, vomiting, insomnia, irritability. 
 ⦁Serious but rare: Class warning for suicidal ideation in children and teens. Mania reported. May increase pulse and BP .
 ⦁Metabolized primarily via CYP2D6, UGT1A9, UGTB15; t ½: 7 hours.
 ⦁Avoid use with MAOIs. Strong 1A2 inhibitor; exercise caution with 1A2 substrates with narrow therapeutic index (eg, 
clozapine, duloxetine, ramelteon, tasimelteon, tizanidine, theophylline) as combination may increase side effects of 
substrate. 
 ⦁ER capsules, so do not cut, crush, or chew; can open and sprinkle contents in applesauce. 
 ⦁Adjust dose in severe renal impairment (eGFR <30 mL/min); max 200 mg/day.

 ⦁Adjust dose in severe renal impairment (eGFR <30 mL/min); max 200 mg/day. 
 ⦁Data from one of four studies suggest viloxazine may work a bit faster than atomoxetine (week one vs week three), 
but this finding is not based on head-to-head data and it’s hard to know whether it is clinically significant. 
Fun Fact:
Viloxazine has been studied for various indications since the 1970s and originally received an FDA orphan drug 
designation for narcolepsy.

AntidepressantsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   33
It’s particularly hard to suggest a first-line antidepressant prescription because antidepressants are effective for so 
many other conditions. Nonetheless, it’s helpful to review the most common clinical scenarios.
Medication-Naïve Patients With “Just” Depression
For these patients (admittedly unusual in a psychiatric practice), you want something effective and with minimal 
side effects. This means either an SSRI or bupropion. While most of us start with an SSRI, we recommend considering 
bupropion as your go-to first-line agent. With bupropion, you get an effective antidepressant with essentially 
no sexual side effects, no weight gain, no sedation, and a boost in attention. While it has not been approved for 
any anxiety disorders, bupropion is just as effective as SSRIs for the nonspecific anxiety that usually accompanies

any anxiety disorders, bupropion is just as effective as SSRIs for the nonspecific anxiety that usually accompanies 
depression. On the downside, you have potential insomnia, and, at doses above 300 mg/day, a small risk of seizure.
If you start with an SSRI, go with escitalopram or sertraline. Both have minimal side effects and minimal drug-drug 
Patients Who Have Comorbid Conditions
Patients with depression plus another psychiatric disorder can be tried on “two-fer” meds—that is, antidepressants that 
have clear efficacy for two conditions. Here are some of the common secondary conditions and meds that are effective 
for them: anxiety disorders (TCAs, SSRIs), bulimia (fluoxetine), smoking cessation (bupropion), ADHD (bupropion), 
fibromyalgia (duloxetine), diabetic neuropathic pain (duloxetine), and premenstrual dysphoric disorder (SSRIs). Finally, 
mirtazapine—an antidepressant sometimes shunned because it causes weight gain—is an excellent choice for patients

mirtazapine—an antidepressant sometimes shunned because it causes weight gain—is an excellent choice for patients 
with depression who are underweight and have insomnia, and it has the benefit of no sexual side effects.
Patients Who Have Been on Other Antidepressants
“Treatment-resistant depression” is usually defined as the failure of at least two prior trials of antidepressants at 
adequate doses and for adequate lengths of time. There are unfortunately no convincing data on what your next 
step should be. The STAR*D trial tried to tease out strategies such as switching vs augmenting, but it could not find 
statistical differences between the techniques. That means we’re left with a combination of the few clinical trials that 
have been published, leavened with a great deal of personal preference. Here’s a reasonable approach:
 ⦁First, try switching to an antidepressant in a different class (though some clinicians believe that the best next

⦁First, try switching to an antidepressant in a different class (though some clinicians believe that the best next 
step is to augment; see the bullet below). Assuming the treatment failures were on SSRIs, the usual sequence of 
subsequent trials would be: 1) bupropion or mirtazapine; 2) an SNRI (venlafaxine, duloxetine, levomilnacipran); 3) an 
MAOI or a tricyclic. 
 ⦁Second, try a combination. A suggested order of combinations is: 1) SSRI/SNRI + bupropion; 2) SSRI/SNRI + second-
generation antipsychotic; 3) SSRI/SNRI + lithium or thyroid supplementation (we’ve included a thyroid fact sheet in 
this chapter). There are many more combination possibilities, but these are probably the highest-yield options with 
which to begin.
 ⦁Third, consider the neurostimulation devices, such as ECT, TMS, and others. You’ll find more details on these options 
in our chapter on somatic treatments. 
Class Warnings

There are some side effects or warnings that apply to all antidepressants. They are listed here in order to minimize 
repetition in the fact sheets that follow:
 ⦁Suicide risk.  In 2004, the FDA added a black box warning to the labeling of all antidepressants regarding an 
increased risk of suicidal ideation in children and adolescents. The warning was based on retrospective reports 
that showed a very slight increase in suicidal ideation in patients on nine different antidepressants. The warning 
was revised in 2007 to include adolescents and young adults, up to age 24. Since then, more prospective data have 
emerged that do not support an association, and this warning has been called into question. For now, however, the

emerged that do not support an association, and this warning has been called into question. For now, however, the 
warning remains and is applied to the labeling of all medications approved for the treatment of depression. Thus, 
you should monitor all patients closely—especially early in therapy or after medication discontinuation—for clinical 
worsening, changes in behavior, or suicidality.
 ⦁Mania switch.  Activation of mania or hypomania may occur with the use of any antidepressant in individuals who 
are at risk. Antidepressants should be used with caution in patients with a history of mania or hypomania, or in 
those with a family history of bipolar disorder.

34  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION ⦁Serotonin syndrome.  A rare but potentially life-threatening condition called serotonin syndrome (agitation, 
hallucinations, other mental status changes, hyperthermia, tachycardia, labile BP , myoclonus, hyperreflexia, 
incoordination, nausea, vomiting, diarrhea) has been reported when serotonergic antidepressants are used with 
other serotonergic agents (including SSRIs, SNRIs, buspirone, lithium, and MAOIs). See our new fact sheet on 
serotonin syndrome in the Side Effect Management chapter.
 ⦁Discontinuation syndrome.  Abrupt discontinuation of antidepressants, particularly SSRIs and SNRIs, may result in a 
discontinuation syndrome. These symptoms usually begin within a few days of stopping the antidepressant. While 
not medically dangerous and generally self-limiting, the syndrome may be uncomfortable for patients. Symptoms

not medically dangerous and generally self-limiting, the syndrome may be uncomfortable for patients. Symptoms 
include dizziness, nausea, headache, irritability, insomnia, diarrhea, agitation, sensory disturbances (eg, electric 
shock sensations), lethargy, and abnormal dreams. In general, symptoms are more severe with higher-dose and 
longer-term antidepressant use. Agents that are particularly short-acting may have a higher likelihood of causing a 
discontinuation syndrome (eg, paroxetine, venlafaxine) compared to longer-acting agents (eg, fluoxetine). In cases 
of planned discontinuation, antidepressant dose should be gradually reduced; a rule of thumb is to taper by 25% 
each week for a four-week taper, but if there are discontinuation symptoms, you may have to slow this down to a 
several-month taper.
Table 3:  Risk of Discontinuation Syndrome With Various 
Antidepressants and Recommendations for Management
AntidepressantPossibility of 
Discontinuation SyndromeRecommendations

Paroxetine, fluvoxamine, venlafaxine Highest risk Very gradual taper (4–12 weeks); consider 
switching to fluoxetine, then taper 
Citalopram, duloxetine, escitalopram, MAOIs, 
sertraline, TCAs, vilazodone, vortioxetineModerate risk Gradual taper (1–4 weeks)
Bupropion, mirtazapine Low risk Rapid taper (2–7 days)
Fluoxetine Lowest risk Can be stopped abruptly
Strategies for minimizing discontinuation symptoms: 
 –Switch to fluoxetine for one to two weeks. Fluoxetine can then typically be stopped abruptly without 
discontinuation symptoms because it self-tapers due to a long half-life and active metabolite with even longer 
half-life. 
 –Benzodiazepines can be helpful in mitigating discontinuation symptoms such as anxiety and insomnia.

 ⦁Bleeding risk.  Increased bleeding episodes (eg, GI bleed, bruising, nosebleed) have been reported with serotonergic 
antidepressants, particularly when they are used concomitantly with aspirin, NSAIDs, anticoagulants, or antiplatelet 
agents. Occasionally, surgeons will request that patients stop SSRIs before surgery in order to decrease the bleeding 
risk. While this practice does not reflect the standard of care, it might be reasonable in situations where the risk of 
bleeding is especially high.
 ⦁Hyponatremia.  Antidepressants can cause hyponatremia particularly in elderly patients; the risk seems to be greater 
with SSRIs and SNRIs. In rare severe cases, this can lead to delirium, seizures, or death. Use caution in the elderly, 
especially if there is a comorbid risk for hyponatremia (eg, diuretic use, congestive heart failure, renal impairment,

especially if there is a comorbid risk for hyponatremia (eg, diuretic use, congestive heart failure, renal impairment, 
dehydration) and check the sodium level if a patient presents with confusion, weakness, or lethargy.
Switching Antidepressants
When switching from one antidepressant to another, you have two main choices: an immediate switch or a cross-
taper. The immediate switch is usually associated with switching between two meds with the same mechanism 
of action. For example, consider a patient who is switched from 50 mg of sertraline to 20 mg of citalopram. On 
the morning she starts citalopram, there will still be some sertraline in her serum, but there’s no significant drug 
interaction between them, and both drugs block serotonin reuptake. On the other hand, when switching from 
paroxetine to vortioxetine, you may need more caution. Any paroxetine in the serum could slow down vortioxetine’s

paroxetine to vortioxetine, you may need more caution. Any paroxetine in the serum could slow down vortioxetine’s 
metabolism, potentially causing doubling of vortioxetine levels and increasing risk of nausea. In this case, you would 
taper down the dose of paroxetine before starting vortioxetine—at a lower dose than normal. 
In the table below, we list a variety of switching situations along with recommendations on how the switching should 
be accomplished.

AntidepressantsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   35Table 4:  Recommended Strategies for Switching Antidepressants 
Switch From… Switch To… Recommended Strategy
SSRI Other SSRI, SNRI, bupropion, mirtazapine, 
vortioxetine, vilazodoneImmediate switch (stop SSRI, start new antidepressant the next day); 
exception is paroxetine, which should be tapered gradually
SSRI TCA Immediate switch if switching from citalopram, escitalopram, or 
sertraline; cross-taper if switching from fluoxetine or paroxetine (due to 
inhibition of TCA metabolism)
SNRI SNRI Immediate switch (stop SNRI, start new SNRI the next day)
Bupropion All antidepressants Switching to or from bupropion can be immediate, with the exception 
of switching from fluoxetine or paroxetine, both of which can increase 
blood levels and potentially incur the risk of seizure
MAOIs All antidepressants At least 1 week washout of SSRI (6 weeks if fluoxetine) and other

MAOIs All antidepressants At least 1 week washout of SSRI (6 weeks if fluoxetine) and other 
antidepressants before starting MAOI; 2 weeks washout if switching 
from MAOI to other agents due to irreversible inhibition of monoamine 
oxidase enzymes and the 2 weeks it takes to regenerate enzymes

36  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONNo anxiety 
disorderWith anxiety 
disorder
Bupropion
—
Best overall 
side effect 
profile Sertraline
—
Five anxiety indications; 
add clonazepam 
at initiation and 
discontinue after 2 weeksVenlafaxine
—
Three anxiety 
indicationsBupropion
—
Approved for tobacco 
dependence, effective 
for ADHDMirtazapine
—
Sedation and weight 
gain are side effectsVortioxetine 
—
May have 
better side 
effect profile 
than SSRIsSertraline + 2 weeks of hypnotic
—
Initiate hypnotic (eg, zolpidem, 
temazepam, trazodone) with plan 
to discontinue after 2 weeksEscitalopram 
+ 2 weeks of 
hypnotic
DuloxetineAugmentation of 
antidepressant 
with gabapentin 
or pregabalinAmitriptyline With tobacco dependence 
and/or ADHDWith insomnia, desire to 
avoid weight gain
With chronic pain With winter worsening With bipolar disorder With psychosisWith insomnia, and 
underweight
Bright light  
therapyBupropionCariprazine,

therapyBupropionCariprazine, 
lurasidone, or 
quetiapineAdd mood 
stabilizer 
(lithium, 
valproic acid, 
lamotrigine)Add 
to mood 
stabilizerSertraline/
escitalopram 
plus aripiprazoleRotate 
through your 
antipsychotics 
of choiceECT
Severe, inpatient
Tricyclic—amitriptyline/
nortriptylineTreatment-resistant depression
(has failed 2–3 antidepressants)
Augment antidepressant 
with aripiprazole
—
Most double-blind evidence 
of all augmentersAugment antidepressant 
with bupropion/lithiumSwitch to SNRI ECTEsketamine nasal or 
ketamine infusionMAOI (usually 
tranylcypromine)Depression Treatment Algorithm

Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   37Atypical 
—
Brexpiprazole 
Risperidone 
OlanzapineLithium
(0.6–0.8)Triiodothyronine 
(T3)Another 
(eg, bupropion, 
mirtazapine)TMS or ECT Natural
—
SAMe
Methylfolate
Omega-3
Lightbox
SNRIs
—
VenlafaxineTricyclics
—
DesipramineVortioxetine or 
vilazodoneAugmentation 
(preferred over switching)
Switching
MAOI TMS or ECT
Celecoxib Minocycline PramipexoleKetamine or 
esketamine
Augmentation options
(when all else fails)Treatment-Resistant Depression Treatment Algorithm

38  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONTable 5:  Antidepressants
Generic Name
(Brand Name)
[G] denotes generic availabilityRelevant FDA Indication(s) Available Strengths (mg)Usual Adult Dosage Range 
(starting–max) (mg)
Selective Serotonin Reuptake Inhibitors (SSRIs)
Citalopram [G]
(Celexa)
1998MDD 10, 20, 40, 10/5 mL 20–40
Escitalopram [G]
(Lexapro)
2002 MDD (12+ yrs), GAD 5, 10, 20, 5/5 mL 10–20
Fluoxetine [G]
(Prozac) 1987MDD (8+ yrs), OCD (7+ yrs), panic 
disorder, bulimia, PMDD10, 20, 40, 60, 20/5 mL 20–80
Fluoxetine DR [G]
(Prozac Weekly)
2001MDD maintenance 90 DR 90 Qweek
Fluvoxamine [G]
Luvox brand discontinued; generic only
1994 OCD (8+ yrs) 25, 50, 100 50–300
Fluvoxamine ER [G]
(Luvox CR)
2008OCD 100, 150 ER 100–300
Paroxetine [G]
(Paxil) 1992
(Pexeva) 2003
(Brisdelle) 2013MDD, OCD, panic disorder, social 
anxiety, GAD, PTSD, PMDD, menopausal 
hot flashes (as Brisdelle)7.5 (Brisdelle), 10, 20, 30, 40,

hot flashes (as Brisdelle)7.5 (Brisdelle), 10, 20, 30, 40, 
10/5 mL20–60
Paroxetine CR [G]
(Paxil CR)
1999MDD, panic disorder, social anxiety, 
PMDD12.5, 25, 37.5 ER 25–62.5
Sertraline [G]
(Zoloft)
1991MDD, OCD (6+ yrs), panic disorder, 
PTSD, PMDD, social anxiety25, 50, 100, 150, 200, 20/mL 50–200
Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)
Desvenlafaxine [G]
(Pristiq)
2008MDD 25, 50, 100 ER 50–100
Duloxetine [G]
(Cymbalta) 2004
(Drizalma Sprinkle) 2019MDD, GAD (7+ yrs)
(also diabetic peripheral neuropathy, 
fibromyalgia, chronic musculoskeletal 
pain)20, 30, 40, 60 DR 40–120
(Fetzima)
2013MDD 20, 40, 80, 120 ER 20–120
Venlafaxine [G]
1993
Effexor brand discontinued; generic onlyMDD 25, 37.5, 50, 75, 100 75–375
Venlafaxine ER [G]
(Effexor XR)
1997MDD, GAD, social anxiety disorder, panic 
disorder37.5, 75, 150, 225 ER 75–225

1993
Tricyclic Antidepressants (TCAs)
Amitriptyline [G]
Elavil brand discontinued; generic only
1961MDD 10, 25, 50, 75, 100, 150 50–300
Clomipramine [G]
(Anafranil)
1989OCD (10+ yrs) 25, 50, 75 25–250
Desipramine [G]
(Norpramin)
1964MDD 10, 25, 50, 75, 100, 150 50–300

AntidepressantsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   39Generic Name
Imipramine [G]
Tofranil brand discontinued; generic only
1984MDD 10, 25, 50, 75, 100, 125, 150 25–300 
Nortriptyline [G]
(Pamelor)
1977MDD 10, 25, 50, 75, 10/5 mL 25–150
Monoamine Oxidase Inhibitors (MAOIs)
(Marplan)
1959MDD 10 20–60
Phenelzine [G]
(Nardil)
1961MDD 15 45–90
Selegiline transdermal
(Emsam)
2006MDD 6, 9, 12/24 hr patch 6–12/24 hr
Tranylcypromine [G] 
(Parnate)
1961MDD 10 30–60
(Zulresso)
2019Postpartum depression 100 mg/20 mL vial for 
injection30–90 mcg/kg/hr 
continuous intravenous 
infusion over 60 hours
Bupropion [G]
(Wellbutrin)
1985MDD 75, 100 200–450
Bupropion SR [G]
(Wellbutrin SR)
1996MDD, smoking cessation 100, 150, 200 150–400
Bupropion XL [G]

(Forfivo XL, Wellbutrin XL)
2003MDD, seasonal affective disorder 150, 300 (Wellbutrin XL), 450 
(Forfivo XL)150–450
Esketamine 
(Spravato)
2019Treatment-resistant depression, MDD 
with suicidality; used in conjunction 
with oral antidepressant28 mg per nasal spray device 56–84 twice weekly to every 
2 weeks
Ketamine [G]
(Ketalar)
1970Not indicated but used for severe or 
suicidal depression10, 50, 100 mg/mL vial for 
injection0.5 mg/kg intravenous 
infusion over 40 minutes
Mirtazapine [G]
(Remeron)
1996MDD 7.5, 15, 30, 45 15–45
Mirtazapine ODT [G]
(Remeron SolTab)
2001MDD 15, 30, 45 15–45
Nefazodone [G]
Serzone brand discontinued; generic only
1994MDD 50, 100, 150, 200, 250 200–600
Trazodone [G]
Desyrel brand discontinued; generic only 
1981MDD 50, 100, 150, 300 50–600
(Viibryd)

(Viibryd)
2011MDD 10, 20, 40 10–40
(Trintellix)
2013MDD 5, 10, 20 10–20

40  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION Table 5A:  Selective Serotonin Reuptake Inhibitors (SSRIs)
[G] denotes generic 
availabilityUses (FDA-indicated uses in bold)Usual Dosage Range
(starting–max) (mg)Metabolized by 
(major pathways 
in bold)Inhibits (potent inhibition 
in bold)Elimination 
Half-LifeCost
(for generic, unless 
otherwise specified)
(Celexa)MDD, OCD, PTSD, social anxiety, GAD, panic 
disorder, PMDD20–40 QD
Increase by 20 mg/day in 7 days2C19, 3A4 2D6 (weak) 35 hrs $
(Lexapro)MDD (12+ yrs), GAD, OCD, PTSD, social 
anxiety, panic disorder, PMDD10–20 QD
Increase by 10 mg/day in 7 days2C19, 3A4 2D6 (weak) 27−32 hrs $
Liquid: $$
(Prozac, Prozac Weekly)MDD (8+ yrs), OCD (7+ yrs),
panic disorder, bulimia, PMDD, PTSD, social 
anxiety20–80 QAM
Increase by 10 mg/day after several 
weeks (Starting dose DR: 90 Qweek)2D6 2C9/19, 2D6, 3A4 4−6 days 
fluoxetine;

fluoxetine; 
9 days 
norfluoxetine 
(metabolite)$
Weekly: $$$
Sarafem: $$$$$
Fluvoxamine [G] 
(Luvox, Luvox CR)MDD, OCD (8+ yrs), panic disorder, GAD, 
PTSD50–300 QHS
Increase by 50 mg/day Qweek
(Starting dose CR: 100 QHS)1A2, 2D6 1A2, 2C9, 2C19, 3A4 16 hrs $
ER: $$$
(Brisdelle, Paxil, Paxil 
CR, Pexeva)MDD, OCD, panic disorder, social anxiety, 
GAD, PTSD, PMDD, menopausal hot flashes 
(as Brisdelle), premature ejaculation20–60 QHS CR: 25–62.5 QD
Increase by 10 mg/day Qweek; CR: 
12.5 mg/day Qweek2D6 2D6 21 hrs $
ER: $$
Brisdelle: $$$
Liquid, Pexeva: $$$$
(Zoloft)MDD, OCD (6+ yrs), panic disorder, PTSD, 
PMDD, social anxiety, GAD50–200 QD
Increase by 50 mg/day Qweek2C19, 2D6, 3A4 2D6 (weak; moderate at 
high dose), 3A4 (weak)26 hrs $

AntidepressantsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   41Table 6:  Relative Side Effects of Antidepressants
DrugNausea/ 
DiarrheaInsomnia/ 
AgitationSedation/ 
DrowsinessSexual 
DysfunctionWeight Gain AnticholinergicOrthostatic 
HypotensionIncreased BP , P , 
SweatingQT Prolongation
(Celexa)+ + - +++ + - - - +++
(Lexapro)+ + - +++ + - - - ++
(Prozac) + +++ - +++ - - - - +
(Luvox, Luvox CR) + + ++ +++ + - - - +
(Paxil, Paxil CR) + + ++ ++++ ++ + + - +
(Zoloft)++ + - +++ + - - - +
(Pristiq)++ + + ++ + - - + -
(Cymbalta, Drizalma)++ + - ++ + - - + -
(Fetzima)++ + - ++ + - - ++ -
(Effexor, Effexor XR) ++ + + ++ + - - + +

(Elavil)- - ++++ +++ +++ ++++ +++ - +++
(Anafranil)- + ++++ +++ +++ ++++ +++ - +++
(Norpramin)- + ++ +++ +++ ++ ++ - ++
(Tofranil)- - ++++ +++ +++ ++++ +++ - +++
(Pamelor)- - ++ +++ +++ ++ ++ - ++
(Marplan)- ++ + +++ ++ + ++ - -

42  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONDrugNausea/ 
(Nardil)- + ++ +++ ++ + ++ - -
(Emsam)- + - - - + + - -
(Parnate)- ++ + +++ + + ++ - -
(Wellbutrin SR, XL, Forfivo)+ +++ - - - - - - -
(Remeron)- - +++ - +++ - - - -
(Serzone)++ - +++ - - - ++ - -
(Desyrel)+ - ++++ + - - ++ - +
(Viibryd)++++ ++ - ++ - - - - -
(Trintellix)++++ - - ++ - - - - -

AntidepressantsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   43BREXANOLONE  (Zulresso) Fact Sheet 
Brexanolone is a novel, fast-acting option that is given intravenously for women with severe postpartum depression. 
However, its utility is limited by the lengthy infusion (60 hours) in a health care setting, potential for severe reactions 
and associated need for close monitoring, high cost ($34,000 for the drug alone, plus costs associated with providers 
and health care facilities), and lack of follow-up data beyond 30 days. 
Postpartum depression.
Vial for injection:  100 mg/20 mL. 
Dosing is gradually titrated up and then tapered off over a 60-hour administration period. Start 30 mcg/kg/hour for 
hours 0–4, 60 mcg/kg/hour for hours 4–24, 90 mcg/kg/hour for hours 24–52 (can use 60 mcg/kg/hour for those who

hours 0–4, 60 mcg/kg/hour for hours 4–24, 90 mcg/kg/hour for hours 24–52 (can use 60 mcg/kg/hour for those who 
don’t tolerate 90 mcg/kg/hour), 60 mcg/kg/hour for hours 52–56, and 30 mcg/kg/hour for hours 56–60.
Monitoring:  Pulse oximetry.
Cost:  $$$$$
 ⦁Most common: Sedation, somnolence, dry mouth, loss of consciousness, flushing. 
 ⦁Serious but rare: Excessive sedation or loss of consciousness, hypoxia.
 ⦁Gamma-aminobutyric acid A (GABAA) modulator.
 ⦁Metabolized by non-CYP450 pathways; t ½: 9 hours.
 ⦁Use caution or avoid use with CNS depressants such as benzodiazepines, which may have additive effects. 
 ⦁Brexanolone is a neurosteroid that is chemically identical to endogenous allopregnanolone, a hormone whose 
levels rise during pregnancy and then fall abruptly after childbirth. 
 ⦁Approval was based on positive results in two trials of pregnant women with moderate to severe postpartum

 ⦁Approval was based on positive results in two trials of pregnant women with moderate to severe postpartum 
depression; a statistically significant higher percentage of brexanolone patients remitted compared to placebo 
(51% vs 16% with 60 mcg/kg/hour and 61% vs 38% with 90 mcg/kg/hour infusion). In the higher-dose patients, 94% 
maintained response at 30 days. 
 ⦁Zulresso’s use is restricted to patients and health care facilities enrolled in the Zulresso REMS program ( www.
zulressorems.com ). Monitoring for sedation, sudden loss of consciousness, and hypoxia using continuous pulse 
oximetry with an alarm is required for the duration of the 60-hour infusion. 
 ⦁If patient experiences excessive sedation during non-sleep periods, the infusion should be stopped and can be 
resumed at the same or lower dose as clinically appropriate once symptoms resolve.

⦁If patient experiences excessive sedation during non-sleep periods, the infusion should be stopped and can be 
 ⦁For women wishing to breastfeed, sparse data involving 12 women indicate that brexanolone transfer to breast 
milk is minimal with a relative infant dose of 1%–2% of maternal weight-adjusted dosage. While the risks of adverse 
effects are not known, the concentrations of the drug in breast milk are low. 
 ⦁The DEA has designated brexanolone as a Schedule IV controlled substance. 
 ⦁Zuranolone, a two-week, once-daily oral medication with similar mechanism of action, is in development for 
postpartum depression.
Fun Fact:
Many psychiatric medications owe their discovery to chance or serendipity. Not so with brexanolone, which was 
developed by design starting with a series of basic and translational neuroscience studies dating back to the 1980s.

44  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONBUPROPION  (Wellbutrin, others) Fact Sheet [G]
May be particularly useful for individuals whose depression is associated with fatigue and poor concentration. 
Absence of sexual side effects and weight gain make this an appealing option for many depressed patients. Although 
not effective for anxiety disorders, it is effective for the anxiety that often accompanies depression. The seizure risk is 
not a concern for most patients when dosed appropriately.
Major depression; seasonal affective disorder; smoking cessation  (as Zyban).
ADHD; sexual dysfunction; bipolar depression.
 ⦁Tablets (G):  75 mg, 100 mg.
 ⦁SR tablets (G):  100 mg, 150 mg, 200 mg.
 ⦁ER tablets (G): 150 mg, 300 mg; Forfivo XL:  450 mg.
 ⦁ER tablets, hydrobromide salt formulation (Aplenzin): 174 mg, 348 mg, 522 mg (equivalent to 150 mg, 300 mg, 
450 mg, respectively).

⦁ER tablets (G): 150 mg, 300 mg; Forfivo XL:  450 mg.
 ⦁General comment: Timing of the dose can be tricky, because taking too much at once increases seizure risk (the risk 
increases from 300 mg on up). But splitting the dose BID can cause insomnia. For this reason, some clinicians choose 
to start all patients on the ER formulation, which is released slowly and minimizes peak serum levels—single doses 
of up to 450 mg are safe. 
 –IR: Start 100 mg BID, ↑ to 100 mg TID after >3 days; max dose 450 mg/day, 150 mg/dose; separate doses by at least 
six hours to minimize seizure risk.
 –SR: Start 150 mg QAM, ↑ to 150 mg BID (usual target dose) as early as fourth day; max dose 400 mg/day, 200 mg/
dose; separate doses by at least eight hours to minimize seizure risk.

–SR: Start 150 mg QAM, ↑ to 150 mg BID (usual target dose) as early as fourth day; max dose 400 mg/day, 200 mg/
 –ER: Start 150 mg QAM, ↑ to 300 mg QAM as early as fourth day; max dose 450 mg QAM.
 ⦁Seasonal affective disorder: Start 150 mg XR QAM, ↑ to 300 mg XR QAM after seven days (fall through spring). Taper 
to 150 mg XR QAM for two weeks to discontinue. 
 ⦁Smoking cessation: Start 150 mg SR QAM for three days, ↑ to 150 mg BID for seven to 12 weeks. Stop smoking after 
five to seven days of treatment.
Monitoring:  No routine monitoring recommended unless clinical picture warrants.
Cost:  IR/SR/ER: $; Forfivo: $$$; Aplenzin: $$$$$
 ⦁Most common: Agitation, insomnia, headache, nausea, vomiting, tremor, tachycardia, dry mouth, weight loss.
 ⦁Serious but rare: Seizures; risk higher with rapid and large dose increases and in patients at risk for seizures, including

⦁Serious but rare: Seizures; risk higher with rapid and large dose increases and in patients at risk for seizures, including 
those with a seizure history and patients with eating disorders (mainly those with purging-type bulimia). Risk of 
seizure depends on dose and formulation: IR: 300–450 mg/day (0.4%) vs 450–600 mg/day (4%). SR/ER: 100–300 mg/
day (0.1%) vs 400 mg/day (0.4%). Do not chew, divide, or crush SR or ER tablets as risk of seizures may be increased.
 ⦁Dopamine and norepinephrine receptor uptake inhibitor.
 ⦁Metabolized primarily through CYP2B6; inhibits CYP2D6; t ½: 21 hours.
 ⦁Before prescribing bupropion, ask patients if they’ve ever had a seizure or if they’ve had bulimia—both of which are 
relative contraindications. 
 ⦁Forfivo XL offers ease of use (one pill a day) for patients taking 450 mg/day, but it is more expensive.

 ⦁Aplenzin brand could also be a one-pill-a-day solution (the 522 mg is equivalent to 450 mg Wellbutrin) but 
otherwise doesn’t offer any real clinical advantage as a different salt (hydrobromide) formulation.
 ⦁Give ER dose as early in the morning as possible to minimize insomnia.
 ⦁Bupropion can cause false-positive urine test results for amphetamines.
Not-So-Fun Fact:
There have been case reports of teenagers, prisoners, and others snorting crushed tablets of bupropion (believing it 
to be a stimulant), with subsequent seizures.

AntidepressantsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   45CITALOPRAM  (Celexa) Fact Sheet [G]
Citalopram has a favorable profile in that it’s not particularly sedating or activating and has a low risk for drug 
interactions. However, it has fewer FDA indications than other SSRIs, and its higher risk for QT prolongation makes us 
favor escitalopram.  
Major depression. 
OCD; PTSD; social anxiety; generalized anxiety disorder; panic disorder; PMDD.
 ⦁Tablets (G): 10 mg, 20 mg (scored), 40 mg (scored). 
 ⦁Oral solution (G): 10 mg/5 mL.
 ⦁Start 10–20 mg QD; may ↑ by increments of 10–20 mg/day weekly to max 40 mg QD.
 ⦁Most patients take it in the morning, but bedtime dosing is OK if there is no insomnia. 
 ⦁Max dose is 20 mg/day in patients >60 years of age or in those taking CYP2C19 inhibitors, or who are CYP2C19 poor 
metabolizers.

⦁Max dose is 20 mg/day in patients >60 years of age or in those taking CYP2C19 inhibitors, or who are CYP2C19 poor 
Monitoring:  Sodium in patients at risk; ECG in patients on doses >40 mg/day, CYP2C19 poor metabolizers, or if 
cardiac disease.
Cost:  $
 ⦁Most common: Nausea, somnolence, sexual side effects, headache.
 ⦁Serious but rare: Hyponatremia, mainly in the elderly; gastrointestinal bleeding, especially when combined with 
NSAIDs such as ibuprofen.
 ⦁Serotonin reuptake inhibitor.
 ⦁Metabolized primarily through CYP2C19 and 3A4; t ½: 35 hours. 
 ⦁Avoid use with MAOIs (two-week washout period); avoid other serotonergic agents (serotonin syndrome).
 ⦁Use caution in patients taking CYP2C19 inhibitors including cimetidine, omeprazole (will increase citalopram levels 
and potential for QT prolongation).
Clinical Pearl:

⦁Use caution in patients taking CYP2C19 inhibitors including cimetidine, omeprazole (will increase citalopram levels 
The FDA reduced citalopram’s maximum daily dose from 60 mg/day to 40 mg/day in August 2011 due to data 
suggesting increased QTc interval prolongation at doses >40 mg/day. Mean QTc interval prolongation at 60 mg/day 
was 18.5 msec (vs ziprasidone, which has been shown to increase this interval by 20.6 msec). As of this writing, no 
comparable warning has been issued for escitalopram.
Fun Fact:
Citalopram given as an intravenous infusion in treatment-resistant OCD and depression has been studied over the last 
20 years and is available for use throughout Europe.

46  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONCLOMIPRAMINE  (Anafranil) Fact Sheet [G]
Clomipramine, which has more side effects than SSRIs, is usually considered a second-line medication for OCD. 
OCD.
Cataplexy in narcolepsy; sleep terrors; sleepwalking; major depression; panic disorder; pain.
Capsules (Anafranil, [G]):  25 mg, 50 mg, 75 mg.
 ⦁Start 25 mg QHS and ↑ by 25 mg/day every four to seven days to target dose 150–250 mg/day; max 250 mg/day.
 ⦁Using divided doses (BID to TID) may help with tolerability during initiation and titration, but can convert to QHS 
dosing to minimize daytime sedation. 
Monitoring:  Check clomipramine/norclomipramine levels (trough levels, 12 hours after last dose) in patients 
on higher doses (150 mg or higher) or in those with significant side effects. Optimal ranges: clomipramine +

on higher doses (150 mg or higher) or in those with significant side effects. Optimal ranges: clomipramine + 
norclomipramine 220–500 ng/mL. Check ECG if history of cardiac disease.
Cost:  $$
 ⦁Most common: Sedation, dry mouth, constipation, weight gain, sexual side effects, urinary hesitation, blurred vision.
 ⦁Serious but rare: Seizure (especially at doses greater than 250 mg/day), cardiac effects including orthostasis, 
arrhythmias, QT prolongation, AV block.
 ⦁As a tricyclic antidepressant, causes both serotonin and norepinephrine reuptake inhibition (more selective for 
serotonin). 
 ⦁Metabolized by CYP1A2, 2C19, 2D6, 3A4; t ½: 32 hours (69 hours for active metabolite).
 ⦁Avoid MAOIs and other serotonergic agents. Caution with other anticholinergic agents or potent CYP inhibitors.
 ⦁Clomipramine is the only tricyclic antidepressant that is FDA approved for OCD. Efficacy is likely due to greater

 ⦁Clomipramine is the only tricyclic antidepressant that is FDA approved for OCD. Efficacy is likely due to greater 
selectivity for serotonin reuptake inhibition.
 ⦁Used to be considered more effective than SSRIs for OCD, but recent studies show equivalent efficacy.  
 ⦁Overdose toxicity with potentially serious cardiac effects or fatality with as little as 10-day supply. 
 ⦁Pharmacokinetics are nonlinear, meaning higher-than-expected levels, longer t ½, and drug accumulation in the 
higher end of dosing range. Full effects of dosage increase in the higher range may not be seen for two weeks or 
longer.
 ⦁Like other serotonergic agents, discontinuation syndrome may occur with abrupt discontinuation; slow taper 
recommended. 
Fun Fact:
Clomipramine is on the World Health Organization’s Model List of Essential Medicines. This list includes the 
medications considered to be most effective and safe to meet the most important needs in a health system and is

medications considered to be most effective and safe to meet the most important needs in a health system and is 
frequently used by countries to help determine local essential medicines.

AntidepressantsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   47DESVENLAFAXINE  (Pristiq) Fact Sheet [G]
Desvenlafaxine is the active metabolite of venlafaxine, and it has some minor advantages in terms of drug 
interactions, ease of dosing, and longer half-life. One disadvantage is lack of FDA approval for anxiety disorders. At 
least for depression, since desvenlafaxine is now available in a low-cost generic version, some clinicians prefer it over 
venlafaxine XR. 
Major depression.
Fibromyalgia; vasomotor symptoms of menopause; generalized anxiety disorder  (GAD); social anxiety disorder; panic 
disorder; PTSD; PMDD.
ER tablets (G): 25 mg, 50 mg, 100 mg.
Start 50 mg QD, usually best in the morning due to risk of insomnia. Some patients require increase to 100 mg QD, but

Start 50 mg QD, usually best in the morning due to risk of insomnia. Some patients require increase to 100 mg QD, but 
dosing above this is not recommended as it only increases side effects without being more efficacious.  
Monitoring:  Periodic blood pressure.
Cost:  $
 ⦁Most common: Nausea, dizziness, insomnia, excessive sweating, constipation, dry mouth, somnolence, decreased 
appetite, anxiety, sexual side effects.
 ⦁Serious but rare: Dose-related increases in systolic and diastolic blood pressure (as likely with desvenlafaxine as 
venlafaxine). Monitor BP regularly, and if increases are sustained, consider reducing dose or discontinuing.
 ⦁Serotonin and norepinephrine reuptake inhibitor.
 ⦁Active metabolite of venlafaxine, metabolized primarily through conjugation and oxidation via CYP3A4 (minor). 
Minimally inhibits CYP2D6; t ½: 11 hours.

⦁Active metabolite of venlafaxine, metabolized primarily through conjugation and oxidation via CYP3A4 (minor). 
 ⦁Avoid use with MAOIs, other serotonergic medications. Not likely to cause other clinically significant interactions.
 ⦁Potential advantages vs venlafaxine: not significantly metabolized by 2D6, so less concern about drug interactions; 
less dosage titration needed (starting dose is usually effective, occasionally need to increase to 100 mg daily); longer 
half-life (11 vs six hours), so potentially less severe discontinuation syndrome. 
 ⦁Potential disadvantages vs venlafaxine: FDA approval limited to major depression (vs major depression plus GAD, 
panic disorder, and social anxiety disorder for venlafaxine); flat dose-response curve.
 ⦁Desvenlafaxine has not been shown to be any more effective than venlafaxine. 
 ⦁Recent low-cost generic versions of desvenlafaxine make it about as cheap as venlafaxine.

⦁Desvenlafaxine has not been shown to be any more effective than venlafaxine. 
 ⦁Desvenlafaxine is available in two forms: a succinate salt (Pristiq) and a base (Khedezla). Aside from small differences 
in half-life, there is no difference between these products—all efficacy studies were based on the original Pristiq 
studies.
Fun Fact:
Desvenlafaxine’s manufacturer withdrew its application for approval in the European Union, where regulatory bodies 
had said that desvenlafaxine was likely less effective than venlafaxine with no advantages in terms of safety and 
tolerability.

48  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONDULOXETINE  (Cymbalta, Drizalma Sprinkle) Fact Sheet [G]
Duloxetine is the main SNRI alternative to venlafaxine/desvenlafaxine. It has a niche for depressed patients with 
various comorbid pain syndromes. However, you should balance this advantage against its potentially serious (though 
rare) hepatic side effects.
Major depression; generalized anxiety disorder (GAD) (children ages 7+ and adults); diabetic peripheral 
neuropathic pain; fibromyalgia; chronic musculoskeletal pain (including osteoarthritis and chronic low back pain).
Other neuropathic or chronic pain disorders; other anxiety disorders; stress urinary incontinence.
Delayed-release capsules (Drizalma Sprinkle, [G]):  20 mg, 30 mg, 40 mg, 60 mg.
 ⦁Depression and GAD: Start 40–60 mg/day; may be divided (20 or 30 mg BID) or given as a single daily dose; target

 ⦁Depression and GAD: Start 40–60 mg/day; may be divided (20 or 30 mg BID) or given as a single daily dose; target 
dose 60 mg QD; for doses >60 mg/day, titrate in increments of 30 mg/day over one week to max 120 mg/day, 
although doses >60 mg/day not shown to be more effective.
 ⦁Fibromyalgia and chronic pain: Start 30 mg QD, increase to target 60 mg QD; max dose 60 mg/day.
 ⦁Diabetic neuropathy: Start, target, and maximum dose of 60 mg QD.
 ⦁Dose timing: Depends on patient preference, since it causes drowsiness in some but insomnia in others. Let patients 
experiment until they get it right. 
Monitoring:  LFTs if suspect liver disease; periodic blood pressure.
Cost:  $; Drizalma Sprinkle: $$$
 ⦁Most common: Nausea, dry mouth, constipation, diarrhea, decreased appetite, vomiting, fatigue, insomnia, 
dizziness, agitation, sweating, headache, urinary hesitation, and sexual side effects.

⦁Most common: Nausea, dry mouth, constipation, diarrhea, decreased appetite, vomiting, fatigue, insomnia, 
 ⦁Serious but rare: Rare cases of hepatic failure (including fatalities) have been reported (too rare to require routine 
LFTs in all patients). Hepatitis with abdominal pain, hepatomegaly, elevated transaminases >20 times normal, with 
and without jaundice observed. May cause orthostatic hypotension or syncope, especially in first week of therapy 
and after dose increases. Urinary retention reported; hospitalization and/or catheterization were necessary in 
some cases.
 ⦁Metabolized primarily through CYP1A2 and 2D6; inhibitor of CYP2D6; t ½: 12 hours.
 ⦁Avoid use with MAOIs, other serotonergic medications. Caution with drugs metabolized by CYP2D6 (eg, paroxetine,

⦁Metabolized primarily through CYP1A2 and 2D6; inhibitor of CYP2D6; t ½: 12 hours.
 ⦁Avoid use with MAOIs, other serotonergic medications. Caution with drugs metabolized by CYP2D6 (eg, paroxetine, 
fluoxetine, aripiprazole, iloperidone, risperidone, atomoxetine, beta blockers) as their levels may be increased. 
Potent inhibitors of CYP2D6 (eg, paroxetine, fluoxetine, quinidine) and CYP1A2 (eg, fluvoxamine, ciprofloxacin) may 
increase duloxetine levels.
 ⦁Duloxetine advantages vs venlafaxine: milder discontinuation symptoms; less hypertension; less toxic in overdose; 
FDA indications for pain syndromes. Duloxetine disadvantages vs venlafaxine: potential hepatic toxicity; greater 
potential for drug interactions.
 ⦁Since capsules are delayed release, they should be swallowed whole; do not chew or crush. Although the 
manufacturer does not recommend opening the capsules, their contents may be sprinkled on applesauce or in 
apple juice and swallowed immediately.

 ⦁Avoid in patients with a history of heavy alcohol use or chronic hepatic disease because of the possibility that 
duloxetine and alcohol may interact, causing hepatic injury, or the possibility that duloxetine may aggravate 
preexisting hepatic disease.
 ⦁Drizalma Sprinkle is a new formulation for use in patients with swallowing difficulty, either by sprinkling over 
applesauce or administering via nasogastric tube. 
Fun Fact:
Duloxetine is approved in Europe for stress urinary incontinence, but the FDA refused this indication in the US 
because of concerns regarding liver toxicity and potential suicidal ideation.

AntidepressantsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   49ESCITALOPRAM  (Lexapro) Fact Sheet [G]
Escitalopram is a good first-line SSRI option. It has the tolerability and minimal drug interaction potential of 
citalopram with less QTc prolongation risk.
Major depression (12+ years); generalized anxiety disorder.
OCD; PTSD; social anxiety disorder; panic disorder; PMDD.
 ⦁Tablets (G):  5 mg, 10 mg (scored), 20 mg (scored).
 ⦁Oral solution (G):  5 mg/5 mL.
 ⦁Adults: Start 5–10 mg QD; may  ↑ by increments of 5–10 mg/day weekly to target dose of 10 mg QD or max 20 mg QD.
 ⦁Ages 6–9 (off-label): Start 2.5 mg QD, increase by 5 mg/day increments weekly; max 20 mg/day.
 ⦁Ages 12–17: Start 5 mg QD, increase by 5–10 mg/day increments weekly; max 20 mg/day.
 ⦁Dose timing: Usually well tolerated in the morning. 
Monitoring:  Sodium in patients at risk.
Cost:  $

⦁Dose timing: Usually well tolerated in the morning. 
Cost:  $
 ⦁Most common: Nausea, sweating, insomnia, somnolence, sexual side effects, headache.
 ⦁Metabolized primarily through CYP2C19 and 3A4; t ½: 27–32 hours. 
 ⦁Avoid use with MAOIs (two-week washout); avoid other serotonergic agents (serotonin syndrome).
 ⦁Escitalopram (which is purified from the racemic mixture, citalopram) is considered the “purest” SSRI and has few, if 
any, drug-drug interactions.
 ⦁Similar to citalopram, escitalopram demonstrates dose-related QTc prolongation, but to a lesser extent (6.6 msec 
with 20 mg escitalopram vs 12.6 msec with equivalent 40 mg citalopram). Generally, this amount of prolongation is

with 20 mg escitalopram vs 12.6 msec with equivalent 40 mg citalopram). Generally, this amount of prolongation is 
not clinically significant in patients who don’t have additional risk factors.
Fun Fact:
A systematic review and network meta-analysis compared the safety and efficacy of nearly two dozen antidepressants 
and found escitalopram and sertraline were the most effective (Cipriani A et al, Lancet  2018; 391(10128):1357–1366).

50  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONESKETAMINE  (Spravato) Fact Sheet 
Note: See separate fact sheet for information on off-label ketamine treatment. 
Esketamine is the s-enantiomer of ketamine, given as a nasal spray. It is only modestly effective for treatment-resistant 
depression and suicidality; its main advantage is its speed of onset, which is typically 24 hours. FDA requirements 
mandate that it be given in a health care facility and that patients be monitored for two hours after each treatment. 
Most clinicians consider it less effective than the unapproved intravenous use of ketamine.  
Treatment-resistant major depression (TRD) or major depression with acute suicidal ideation or behavior 
(MDSI) , to be used in conjunction with an oral antidepressant.
Pain, migraine headache.

Nasal spray device: 28 mg per device, to be given in two sprays (one 14 mg spray in each nostril). 
 ⦁TRD:
 –Induction phase (weeks one to four): 56 mg on day one, then 56 mg or 84 mg twice a week.
 –Maintenance phase (subsequent weeks): 56 or 84 mg weekly or every two weeks, depending on response.
 ⦁MDSI:
 –Start and continue 84 mg twice weekly for four weeks.
 ⦁Use two devices (each 28 mg) for a 56 mg dose and three devices for an 84 mg dose, with a five-minute rest period 
after using each device to allow medication to absorb.
 ⦁Patients must be observed by a health care provider when they take the medication and for at least two hours after 
administration, and they will require transportation after treatment. 
 ⦁Patients cannot take the nasal spray device home; they must come into the office for all doses.

 ⦁Patients cannot take the nasal spray device home; they must come into the office for all doses. 
 ⦁Patients should avoid food for two hours before administration and liquids 30 minutes prior, because of the risk of 
nausea and vomiting. 
 ⦁Check patients’ blood pressure (for possible hypertension) both before dose and 40 minutes after dose. 
Monitoring:  BP (see Spravato REMS, mentioned in clinical pearls).
 ⦁Most common: Sedation, dissociation (including depersonalization and derealization), increased blood pressure 
(transient, lasts about four hours), cognitive impairment, impaired ability to drive. 
 ⦁Serious but rare: Hypertensive crisis. Contraindicated in aneurysmal vascular disease and history of intracerebral 
hemorrhage. Treatment-emergent suicidality may be more common than with standard antidepressants. 

 ⦁N-methyl-D-aspartate (NMDA) receptor antagonist. 
 ⦁Time to maximum concentration: 20–40 minutes.
 ⦁Metabolized primarily by CYP2B6 and CYP3A4; t ½: 7–12 hours.
 ⦁Avoid use with CNS depressants (eg, benzodiazepines, opioids, alcohol), MAOIs, and psychostimulants.
 ⦁Esketamine is the s-isomer of ketamine (which is a mixture of both s-ketamine and r-ketamine). One rationale for the 
development of esketamine is that the s-isomer is a more potent NMDA antagonist than the r-isomer of ketamine. 
 ⦁Efficacy: In three four-week trials, patients with TRD were randomly assigned to an oral antidepressant plus either 
esketamine or placebo nasal spray. Esketamine outperformed placebo in one of these trials. In a longer-term 
maintenance trial, patients were less likely to relapse when continuing on esketamine than placebo.

maintenance trial, patients were less likely to relapse when continuing on esketamine than placebo. 
 ⦁Efficacy may be seen as early as 24 hours after first dose. Appropriate duration of treatment remains unknown.
 ⦁Only available through a restricted distribution system, under a Risk Evaluation and Mitigation Strategy (REMS) 
program. In order to provide esketamine to patients, your clinic must become a “certified Spravato treatment center” 
(online certification: www.spravatorems.com ).
 ⦁Controlled substance (Schedule III) due to potential for misuse. 
Fun Fact: 
Esketamine was granted “breakthrough status” by the FDA. This designation is given to agents intended to treat a 
serious disease if preliminary evidence suggests they provide substantial improvement over existing treatments.

AntidepressantsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   51FLUOXETINE  (Prozac, Prozac Weekly) Fact Sheet [G]
Fluoxetine’s wide spectrum of indications and its long track record make it a go-to SSRI, and it is often favored in 
patients who could use some activation. Its main disadvantage is its high potential for drug interactions.
Major depression (8+ years); OCD (7+ years); panic disorder; bulimia; PMDD (as Sarafem).
PTSD; social anxiety disorder.
 ⦁Capsules (G): 10 mg, 20 mg, 40 mg.
 ⦁Tablets (G): 10 mg, 20 mg, 60 mg. 
 ⦁Oral solution (G): 20 mg/5 mL.
 ⦁Delayed-release capsules (G): 90 mg. 
 ⦁Start 10–20 mg QAM; may ↑ by 10–20 mg/day increments after several weeks; max dose 50 mg/day (depression), 60 
mg/day (bulimia, panic disorder). Target and max dose in OCD: 80 mg/day. 
 ⦁Start 5–10 mg QAM in panic disorder to minimize increased anxiety and panic.

 ⦁Start 5–10 mg QAM in panic disorder to minimize increased anxiety and panic. 
 ⦁DR capsules (Prozac Weekly): Start 90 mg Qweek seven days after last dose of 20 mg QAM.
 ⦁PMDD (Sarafem): 20 mg QAM continuously or only on cycle days 15–28 (14 days prior to anticipated onset of 
menstruation). 
 ⦁In children ages 6–7 (off-label): Start 5 mg QD, increase by 5 mg/day increments weekly; max 30 mg/day. Ages 8–17: 
Start 10 mg QD, increase by 10 mg/day increments weekly; max 60 mg/day. Many children and adolescents will 
show good treatment response at 10 mg/day. 
 ⦁Dose timing: Most respond best to morning dosing given its activating effects. 
Monitoring:  Sodium in patients at risk. 
Cost:  $; DR: $$
 ⦁Most common: Nausea, diarrhea, nervousness, insomnia, abnormal dreams, anorexia, sweating, tremor, sexual side 
effects, headache, rash.

 ⦁Metabolized primarily through CYP2D6; potent inhibitor of CYP2C9/2C19 and 2D6; t ½: 4–6 days (fluoxetine), 9 days 
(norfluoxetine metabolite). 
 ⦁Avoid use with MAOIs (five-week washout if switching to MAOI); avoid other serotonergic agents (serotonin 
syndrome). Caution with substrates of 2C9/19 and 2D6.
 ⦁Generally less favored in patients with bipolar disorder, as they may switch to mania due to fluoxetine’s long half-life 
(compared to other antidepressants that can be washed out more quickly).

⦁Generally less favored in patients with bipolar disorder, as they may switch to mania due to fluoxetine’s long half-life 
 ⦁Also due to long half-life, effects of dose changes will not be fully reflected for several weeks. 
 ⦁The benefit of the long half-life is that patients are much less likely to experience serotonin discontinuation 
symptoms after a missed dose or when discontinuing treatment. 
 ⦁Of the SSRIs, fluoxetine is most likely to cause rash. 
 ⦁Fluoxetine/olanzapine combination (Symbyax) is approved for acute depression in bipolar disorder and treatment-
resistant depression. See olanzapine fact sheet in Antipsychotics chapter. 
 ⦁Often considered a first-line agent for kids with depression and anxiety disorders. 
Fun Fact:
Eli Lilly was criticized for reformulating fluoxetine in a pink color and calling it “Sarafem” for PMDD. The drug’s

Fun Fact:
Eli Lilly was criticized for reformulating fluoxetine in a pink color and calling it “Sarafem” for PMDD. The drug’s 
aggressive marketing campaign included a commercial featuring a harried woman asking herself whether she has 
PMDD while grocery shopping.

52  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONFLUVOXAMINE  (Luvox, Luvox CR) Fact Sheet [G]
Fluvoxamine is used less often due to twice-daily dosing, sedation, risk for drug interactions, and fewer data for uses 
other than OCD, even though it’s likely just as effective as other SSRIs.
OCD (8+ years).
Major depression; panic disorder; generalized anxiety disorder; PTSD.
 ⦁Tablets (G): 25 mg, 50 mg (scored), 100 mg (scored). 
 ⦁ER capsules (G): 100 mg, 150 mg. 
 ⦁Start 50 mg QHS; may ↑ by 50 mg/day increments every four to seven days as tolerated; max dose 300 mg/day. 
Daily doses over 100 mg should be divided BID. 
 ⦁ER: Start 100 mg QHS; may ↑ by 50 mg/day increments weekly; max dose 300 mg/day.
 ⦁Children and adolescents (8–17 years): Start 25 mg QHS, ↑ by 25 mg/day increments every four to seven days; max

⦁ER: Start 100 mg QHS; may ↑ by 50 mg/day increments weekly; max dose 300 mg/day.
 ⦁Children and adolescents (8–17 years): Start 25 mg QHS, ↑ by 25 mg/day increments every four to seven days; max 
200 mg/day (8–11 years) or 300 mg/day (12–17 years). Daily doses over 50 mg should be divided BID. Due to limited 
dose availability, ER not appropriate for children.
Cost:  $; ER: $$
 ⦁Most common: Nausea, vomiting, somnolence, insomnia, nervousness, sexual side effects, sweating, tremor, 
headache.
 ⦁Metabolized primarily through CYP1A2 and 2D6; potent inhibitor of CYP1A2 and 2C19; moderate inhibitor of 
CYP2C9 and 3A4; t ½: 16 hours.

⦁Serotonin reuptake inhibitor.
CYP2C9 and 3A4; t ½: 16 hours. 
 ⦁Avoid use with MAOIs (two-week washout if switching to MAOI); avoid other serotonergic agents (serotonin 
syndrome). Caution with substrates of CYP1A2 and 2C19.
 ⦁Discontinuation symptoms tend to be worse with fluvoxamine compared to other SSRIs.
 ⦁Consider using ER in patients who experience daytime sedation or for whom twice-daily dosing is a challenge.
 ⦁Always ask patients about other medications, as fluvoxamine can interact with many of them.
 ⦁Fluvoxamine is effective and approved for use in other countries for treating depression.
 ⦁Low-dose fluvoxamine (25–50 mg/day) has been used to inhibit the metabolism of clozapine to norclozapine 
(metabolite associated with adverse effects) in order to achieve an optimal 1.5:2 ratio of clozapine to norclozapine. 
Fun Fact:

Fun Fact:
Preliminary data showed fluvoxamine use resulted in less clinical deterioration in patients with symptomatic COVID-
19 compared to placebo. Investigators are looking into whether its binding and activation of sigma-1 receptors and 
subsequent reduced cytokine production may help mitigate the severe inflammatory process associated with COVID-
19 infection.

AntidepressantsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   53KETAMINE  (Ketalar) Fact Sheet [G]
Note: See separate fact sheet for information on FDA-approved esketamine. 
Ketamine is an intravenous agent that appears uniquely effective for patients who need an ultra-rapid antidepressant, 
such as patients who are acutely suicidal. Its disadvantages are that it is not FDA approved for depression, and that it 
requires close medical monitoring during administration.  
Anesthesia.
Major depression, chronic pain, severe agitation (eg, in the ICU).
Vials for injection (G):  10 mg/mL, 50 mg/mL, 100 mg/mL. 
 ⦁Most commonly used dose in depression trials: 0.5 mg/kg given intravenously (IV) over 40 minutes, which is lower 
than the typical anesthetic dose (2 mg/kg).
 ⦁Administration may be repeated periodically, though there is no clear guidance regarding how often it should be

 ⦁Administration may be repeated periodically, though there is no clear guidance regarding how often it should be 
given, nor how many total infusions should be given. Currently available data and clinical practice suggest dosing 
two to three times weekly over two to four weeks. 
Monitoring:  ECG, blood pressure, and oxygen blood saturation are typically monitored during infusion because of 
concerns regarding spikes in blood pressure and heart rate. 
Cost:  $$$$$ 
 ⦁Most common: Confusion, blurred vision, poor coordination, feeling weird or spaced out, cardiac issues (30% of 
patients in three clinical trials experienced a spike in blood pressure over 180/100 mmHg and heart rates over 110 
beats per minute, but vital signs normalize quickly).
 ⦁Serious but rare: Serious reactions (dream-like states, delirium, respiratory depression) are typically associated with 
higher (anesthetic) doses.

⦁Serious but rare: Serious reactions (dream-like states, delirium, respiratory depression) are typically associated with 
higher (anesthetic) doses. 
 ⦁N-methyl-D-aspartate (NMDA) receptor antagonist.
 ⦁In one recent study, co-administration of ketamine with naltrexone (an opiate blocker) prevented its 
antidepressant effect, implying that ketamine may work in part via opioid receptors (Williams NR et al, Am J Psych  
2018;175(12):1205–1215. Epub 2018 Aug 29). 
 ⦁Non-CYP450 metabolism; t ½: 2.5 hours.
 ⦁Efficacy: Meta-analyses of placebo-controlled trials have reported that IV ketamine has an ultra-rapid antidepressant 
response (at 40 minutes) but that the response attenuates over the course of about one week (Kishimoto T et 
al, Psychol Med  2016;46(7):1459–1472. Epub 2016 Feb 12). Relapse rates are up to 90% four weeks following the 
ketamine treatment.

ketamine treatment. 
 ⦁Continuation therapy appears to be effective, with one study showing robust improvement over placebo after 15 
days when ketamine was administered two or three times per week. 
 ⦁The most common patient experience seems to be a sense of dissociation or disconnection from their bodies, lives, 
and problems. The therapeutic effect may relate to being able to more objectively examine the sources of their 
psychic pain. 
 ⦁“Ketamine: A Tale of Overcoming Treatment Resistance” is a brief documentary about ketamine for depression 
(www.youtube.com/watch?v=fTRCXr4dVF8 ).
 ⦁Can be prescribed in an intranasal formulation available from compounding pharmacies (but we recommend using 
esketamine product formulated for nasal administration). 
 ⦁Schedule III controlled substance due to potential for misuse.
Fun Fact:

Fun Fact:
Ketamine was developed in the 1960s and gained a reputation as an unusually safe anesthetic, because it did not 
slow down breathing or lower blood pressure. For that reason, it was implemented as a “buddy drug” in the Vietnam 
War, when each soldier carried a vial of ketamine for use in case another soldier required it while awaiting transport to 
a field hospital.

54  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONLEVOMILNACIPRAN  (Fetzima) Fact Sheet
Levomilnacipran is an enantiomer of milnacipran (Savella), which is an SNRI approved in the US for fibromyalgia and 
in other countries for depression. Levomilnacipran is effective for depression, but its higher cost, tendency to cause 
nausea, need for titration, and urinary effects make it a second-line SNRI after venlafaxine or duloxetine. It is the most 
adrenergic of all the SNRIs, which may explain its high side effect potential. 
Fibromyalgia; anxiety disorders; vasomotor symptoms of menopause; diabetic peripheral neuropathy; chronic 
musculoskeletal pain.
ER capsules:  20 mg, 40 mg, 80 mg, 120 mg.
Start 20 mg QD; increase to 40 mg QD after two days, then by increments of 40 mg/day every two or more days to 
max 120 mg QD.

Monitoring:  Periodic blood pressure and pulse.
Cost:  $$$$
 ⦁Most common: Nausea, vomiting, constipation, sweating, increased heart rate (7–9 beats/minute), erectile 
dysfunction, and urinary hesitation.
 ⦁Serious but rare: Urinary retention; increased blood pressure and tachycardia possible.
 ⦁Metabolized primarily through CYP3A4; t ½: 12 hours.
 ⦁Avoid use with MAOIs, other serotonergic medications. Use lower doses (no more than 80 mg/day) in presence of 
potent 3A4 inhibitors (eg, ketoconazole).
 ⦁Three eight-week studies showed greater efficacy than placebo at doses of 40 mg/day and greater. No head-to-head

 ⦁Three eight-week studies showed greater efficacy than placebo at doses of 40 mg/day and greater. No head-to-head 
studies versus other antidepressants are available to date.
 ⦁According to the manufacturer, levomilnacipran has greater potency for norepinephrine reuptake inhibition than 
for serotonin reuptake inhibition.
 ⦁Noradrenergic effects may contribute to urinary hesitation or retention in 4%–6% of patients and is dose related.
 ⦁Nausea may be severe for many patients, especially early in treatment. Start 20 mg/day and titrate slowly to 
minimize, as patients may develop tolerance.
 ⦁Do not cut, crush, chew, or dissolve; swallow extended-release tablets whole with fluid.
Fun Facts:
Milnacipran is the parent compound of levomilnacipran and is a 50-50 racemic mix of levo- and dextro-milnacipran. 
Due to placebo-controlled studies showing efficacy, it has been approved for depression in 45 countries worldwide.

Due to placebo-controlled studies showing efficacy, it has been approved for depression in 45 countries worldwide. 
However, since it was reaching the end of its patent life, the manufacturer did not submit it for FDA approval in the 
US, opting instead to isolate the l-isomer for testing and ultimate FDA approval. Fetzima enjoys market exclusivity 
until 2023.

AntidepressantsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   55MIRTAZAPINE  (Remeron) Fact Sheet [G]
Mirtazapine tends to cause weight gain and sedation, but no sexual dysfunction or GI side effects, and thus is 
particularly useful in depressed patients with anxiety or insomnia, those who have had sexual side effects with other 
antidepressants, and those who may benefit from appetite stimulation (eg, elderly, cancer patients).
Panic disorder; PTSD; generalized anxiety disorder; insomnia; nausea; appetite stimulant; methamphetamine use 
disorder.
 ⦁Tablets (G):  7.5 mg, 15 mg, 30 mg, 45 mg.
 ⦁Orally disintegrating tablets (Remeron SolTab, [G]): 15 mg, 30 mg, 45 mg.
Start 15 mg QHS, ↑ by 7.5 or 15 mg/day every one to two weeks. Max 45 mg/day. Best given at bedtime.
Monitoring:  Weight.
Cost:  $

Cost:  $
 ⦁Most common: Somnolence, increased appetite, weight gain.
 ⦁Serious but rare: Agranulocytosis or severe neutropenia (with or without infection) reported very rarely.
 ⦁Noradrenergic (via central presynaptic alpha-2 adrenergic receptor antagonist activity) and specific serotonergic (via 
postsynaptic 5-HT2 and 5-HT3 antagonist effects) antidepressant.
 ⦁Metabolized primarily through CYP1A2, 2D6, and 3A4; t ½: 20–40 hours.
 ⦁Avoid use with MAOIs. Caution with inducers of 1A2 or 3A4 (eg, carbamazepine), which could reduce efficacy of 
mirtazapine.
 ⦁One large meta-analysis reported that mirtazapine has a faster onset of action than other antidepressants.

 ⦁Rumor has it that higher doses of mirtazapine may be paradoxically less sedating than lower doses. However, there 
is no empirical support for this theory, which is based on the fact that mirtazapine has increased noradrenergic 
effect relative to antihistaminergic effect at higher doses. 
 ⦁The strategy of adding mirtazapine to venlafaxine (sometimes called “California Rocket Fuel” and a combination 
used in the STAR*D trial) was a promising one but has failed to show benefit in a handful of newer larger studies. 
 ⦁Two small studies in men with methamphetamine use disorder have shown promising effects of mirtazapine 30 mg 
nightly in reducing methamphetamine use. 
Fun Fact:
Esmirtazapine, the s-enantiomer, was under development for the treatment of insomnia and hot flashes associated 
with menopause, but the company pulled the plug in 2010.

56  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONMONOAMINE OXIDASE INHIBITORS  (MAOIs) Fact Sheet [G]
MAOIs are not commonly used due to side effects, dietary restrictions, and drug interactions; however, they should be 
considered for appropriate patients who do not tolerate or respond to other antidepressants.
Treatment-resistant depression; panic disorder; social anxiety disorder.
 ⦁Isocarboxazid,  tablets (Marplan):  10 mg (scored).
 ⦁Phenelzine,  tablets (Nardil, [G]): 15 mg.
 ⦁Tranylcypromine,  tablets (Parnate, [G]): 10 mg.
 ⦁Isocarboxazid: Start 10 mg BID, ↑ by 10 mg/day every two to four days, to 40 mg/day by end of the first week 
(divided BID–QID). After first week, may ↑ by up to 20 mg weekly to max 60 mg/day. Use caution in patients on 
>40 mg/day.

 ⦁Phenelzine: Start 15 mg BID, ↑ by 15 mg/day every two to four days, up to 60−90 mg/day divided BID.
 ⦁Tranylcypromine: Start 10 mg BID, ↑ by 10 mg/day every two to three weeks to maximum of 60 mg/day divided BID.
 ⦁Dose timing: Tranylcypromine is the best tolerated of the MAOIs, but it can be activating, so prescribe it in the 
morning initially. Since larger doses may cause orthostasis if taken at once, you may need to split up the dose as you 
titrate up, but the PM dose should be taken no later than noon. 
Cost:  Isocarboxazid: $$$$$; phenelzine: $; tranylcypromine: $$$
 ⦁Most common: Dizziness, headache, orthostatic hypotension, dry mouth, constipation, drowsiness, tremor, 
sweating, peripheral edema, sexual side effects, weight gain.

 ⦁Serious but rare: Hypertensive crisis (see drug interactions).
 ⦁Tranylcypromine is the best tolerated for most patients. 
 ⦁Non-selective monoamine oxidase inhibitors.
 ⦁Metabolized primarily through liver, limited data though likely through oxidative CYP450; t ½ irrelevant as 
irreversible inhibition effects continue for two weeks after discontinuation.
 ⦁Avoid with other antidepressants, serotonergic agents, stimulants, sympathomimetics, dextromethorphan, 
disulfiram, and meperidine. Do not use within five weeks of fluoxetine discontinuation or two weeks of other 
antidepressant discontinuation. Discontinue at least 10 days prior to elective surgery. Antihypertensives may 
exaggerate hypotensive effects.

 ⦁Avoid use with foods or supplements high in tyramine, tryptophan, phenylalanine, or tyrosine. Examples include 
aged cheese, air-dried or cured meats (eg, salami), fava or broad bean pods, tap/draft beers, Marmite concentrate, 
sauerkraut, soy sauce, or spoiled foods. 
 ⦁See Table A3 in Appendix A for more information on diet and drug interactions with MAOIs.
 ⦁Studies in the 1970s and 1980s showed that MAOIs were more effective than TCAs for atypical depression, 
characterized by overeating, oversleeping, rejection sensitivity, and mood reactivity.
 ⦁Rough dose equivalents: 20 mg of tranylcypromine = 40 mg of isocarboxazid = 45 mg phenelzine.
 ⦁When switching from an MAOI to another antidepressant, wait two weeks after MAOI discontinuation. This is

⦁When switching from an MAOI to another antidepressant, wait two weeks after MAOI discontinuation. This is 
because monoamine enzymes are irreversibly inhibited by MAOIs, and regeneration of enzymes takes two to three 
weeks after discontinuation.
Fun Fact:
MAOIs were the first antidepressants developed, after tuberculosis patients given the antibacterial agent isoniazid 
(INH) were found to have an elevated mood. Isoniazid was found to be an MAOI and was developed as the first 
antidepressant in the late 1950s.

AntidepressantsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   57NEFAZODONE  (Serzone) Fact Sheet [G]
Nefazodone was once popular due to the lack of sexual side effects, but is now rarely used due to rare hepatic effects. 
Anxiety; insomnia.
Tablets (G):  50 mg, 100 mg, 150 mg, 200 mg, 250 mg. 
Start 50–100 mg BID, increase in 50–100 mg/day increments weekly. Usual dose 300–500 mg/day; maximum 600 mg/
day divided BID. 
Monitoring:  LFTs, BP . 
Cost:  $$
 ⦁Most common: Nausea, somnolence, dry mouth, dizziness, lightheadedness, constipation, blurred vision, confusion; 
less orthostasis than trazodone.
 ⦁Serious but rare: Black box warning for hepatic toxicity; 1/200,000 to 1/300,000 risk (three to four times general 
incidence); cases of severe hepatotoxicity resulting in death or need for transplant have been reported; seems to

incidence); cases of severe hepatotoxicity resulting in death or need for transplant have been reported; seems to 
occur early in treatment; not necessarily associated with increased LFTs.
 ⦁Norepinephrine and serotonin reuptake inhibitor and 5-HT2 antagonist. 
 ⦁Metabolized by CYP3A4; potent inhibitor of CYP3A4; t ½: 2–4 hours.
 ⦁Caution with CYP3A4 inhibitors, inducers, and substrates. Avoid MAOIs and other serotonergic agents. 
 ⦁Similar to trazodone in chemical structure, but less sedating. 
 ⦁Minimal sexual side effects. 
 ⦁If patient tolerates, may be used QHS rather than BID to minimize daytime sedation and improve nighttime sleep. 
 ⦁Avoid in patients with active liver disease or elevated LFTs; monitor all patients for symptoms of hepatic impairment 
(jaundice, anorexia, GI complaints, lethargy). If patient is symptomatic or LFTs increase to three or more times upper

(jaundice, anorexia, GI complaints, lethargy). If patient is symptomatic or LFTs increase to three or more times upper 
limit of normal, discontinue and monitor patient; do not re-treat. 
Fun Fact:
After the drug was removed from the market in Canada and Europe, the nonprofit organization Public Citizen sued 
the FDA for failing to remove it from the US market. The suit was later withdrawn, but the manufacturer of the 
branded product Serzone stopped production due to weak sales; generic sales continue.

58  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONPAROXETINE  (Brisdelle, Paxil, Paxil CR, Pexeva) Fact Sheet [G]
Paroxetine is the least favored SSRI due to its side effect profile (greatest sexual side effects, weight gain, sedation, 
constipation), drug interaction profile, and risk for discontinuation syndrome. However, its wide range of FDA anxiety 
indications leads some clinicians to favor it for patients with significant anxiety. 
Major depression; OCD; panic disorder; social anxiety disorder; generalized anxiety disorder (GAD); PTSD; 
PMDD; vasomotor symptoms associated with menopause (Brisdelle).
Premature ejaculation. 
 ⦁Tablets (Paxil, Pexeva, [G]):  10 mg, 20 mg, 30 mg, 40 mg. 
 ⦁Capsules (Brisdelle, [G]):  7.5 mg.
 ⦁Oral suspension (Paxil, [G]): 10 mg/5 mL.
 ⦁ER tablets (Paxil CR, [G]):  12.5 mg, 25 mg, 37.5 mg. 

⦁Capsules (Brisdelle, [G]):  7.5 mg.
 ⦁Start 10–20 mg QD in evening or bedtime; may ↑ by 10 mg/day increments weekly.
 ⦁ER: Start 12.5–25 mg QD; may ↑ by 12.5 mg/day increments weekly. 
 ⦁Max dose: 50 mg/day (depression, GAD, PTSD); 60 mg/day (OCD, panic disorder, social anxiety disorder); 75 mg/day 
(ER). Max dose in elderly: 40 mg/day (IR); 50 mg/day (ER).
 ⦁PMDD: Start 12.5 mg ER QD; may ↑ to max 25 mg/day after one week. Or, 12.5–25 mg ER QD on cycle days 15–28 (14 
days prior to anticipated onset of menstruation). 
 ⦁Vasomotor menopausal symptoms: 7.5 mg QHS. 
 ⦁Dose timing: Usually best given at bedtime due to sedation.
Monitoring:  Sodium in patients at risk; ECG in patients on citalopram >40 mg/day or if cardiac disease.
Cost:  $; capsule: $$; oral suspension: $$$$

 ⦁Most common: Nausea, constipation, dry mouth, somnolence, sedation, sexual side effects, weight gain, sweating, 
tremor, headache.
 ⦁Metabolized primarily through 2D6; potent inhibitor of 2D6; t ½: 21 hours. 
syndrome). Caution with substrates of 2D6.
 ⦁Paroxetine has the widest range of FDA-approved indications; however, it is not approved for any use in children or 
adolescents.

adolescents. 
 ⦁Ideal medication for thin patients with insomnia and significant anxiety who are not very sexually active. 
 ⦁Caution with medications that require CYP2D6 to convert into active drug or active metabolite (eg, tamoxifen, 
tramadol, hydrocodone, codeine) as therapeutic effects will be lowered by paroxetine’s potent inhibition of CYP2D6. 
This is the opposite effect of the majority of 2D6 substrates, which will have their levels increased when combined 
with paroxetine. 
 ⦁Paroxetine seems to pose the greatest risk to a fetus in terms of cardiovascular malformation. Unless the benefits of 
paroxetine outweigh discontinuation or alternative antidepressants, a switch to another antidepressant should be 
considered. 
Fun Fact:

Fun Fact:
In 2012, paroxetine manufacturer GlaxoSmithKline was fined $3 billion by the U.S. Department of Justice for 
unlawfully promoting its use in kids based on misleading data from its infamous Study 329. New Scientist wrote in 
2015: “You may never have heard of it, but Study 329 changed medicine. ”

AntidepressantsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   59SELEGILINE TRANSDERMAL  (Emsam) Fact Sheet
Emsam is an MAOI patch with less likelihood of dietary interactions at 6 mg, and possibly at higher doses too. 
Probably fewer side effects than other MAOIs, such as weight gain and sexual side effects, and other potential 
advantages, including better compliance among patients who do not like swallowing pills and less suicide risk (it’s 
harder to overdose on a patch than with pills). When MAOIs are indicated, this may be the least risky option to try.
Treatment-resistant depression; panic disorder; treatment-resistant anxiety disorders.
Transdermal patch:  6 mg, 9 mg, 12 mg/24 hour patch.
 ⦁Start 6 mg/24 hours QD; may ↑ in increments of 3 mg/24 hours every two weeks or more, up to max 12 mg/24 
hours.

hours.
 ⦁Apply to clean, dry, intact skin to upper torso (below neck and above waist), upper thigh, or outer surface of upper 
arm; apply at the same time each day and rotate application sites; wash hands with soap and water after handling; 
avoid touching sticky side of patch.
 ⦁Most common: Headache, insomnia, application site reaction, hypotension, diarrhea, dry mouth.
 ⦁Serious but rare: Orthostatic hypotension; caution in patients at risk (elderly, cerebrovascular disease, cardiovascular 
disease, hypovolemia).
 ⦁Non-selective MAOI.

 ⦁Metabolized primarily through CYP2B6 (also 2C9, 3A4/5) to active (N-desmethylselegiline, amphetamine, 
methamphetamine) and inactive metabolites; t ½: 18−25 hours.
 ⦁Interactions with food: When using the 6 mg/day patch, no special diet is required. When using higher doses, a 
tyramine-restricted diet should be followed. See Table A3 in Appendix A for more information.
 ⦁Interactions with other meds are identical to oral MAOIs, so avoid with other antidepressants, serotonergic agents, 
stimulants, sympathomimetics, dextromethorphan, disulfiram, meperidine, and carbamazepine. Do not use within 
five weeks of fluoxetine discontinuation or two weeks of other antidepressant discontinuation. Discontinue at least 
10 days prior to elective surgery. Antihypertensives may exaggerate hypotensive effects. For doses higher than 6

10 days prior to elective surgery. Antihypertensives may exaggerate hypotensive effects. For doses higher than 6 
mg, avoid use with foods or supplements high in tyramine, tryptophan, phenylalanine, or tyrosine.
 ⦁Wait two weeks after discontinuing transdermal selegiline before initiating therapy with serotonergic or any other 
contraindicated drug.
 ⦁Oral selegiline (Eldepryl) used in Parkinson’s disease (≤10 mg/day) is a selective inhibitor of MAO-B, which 
metabolizes dopamine. When used transdermally as Emsam, selegiline achieves higher blood levels and non-
selectively inhibits both MAO-A and MAO-B. Its antidepressant effect is thought to be due to its MAO-A inhibition, 
which blocks the breakdown of other centrally active neurotransmitters (norepinephrine, serotonin).
 ⦁Patch may contain conducting metal (eg, aluminum); avoid exposure of application site to external heat source, 
which may increase the amount of drug absorbed.
Fun Fact:

⦁Patch may contain conducting metal (eg, aluminum); avoid exposure of application site to external heat source, 
Fun Fact:
Named “Emsam” after Emily and Samuel, the children of the CEO of Somerset Pharmaceuticals (original manufacturer).

60  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONSERTRALINE  (Zoloft) Fact Sheet [G]
Sertraline is a good first-line SSRI option for many patients due to its range of indications, flexible dosing, low drug 
interaction potential, and relative tolerability. 
Major depression; OCD (6+ years); panic disorder; PTSD; PMDD; social anxiety disorder.
Generalized anxiety disorder.
 ⦁Tablets (G): 25 mg (scored), 50 mg (scored), 100 mg (scored).
 ⦁Capsules (G):  150 mg, 200 mg.  
 ⦁Oral solution concentrate (G): 20 mg/mL (must be diluted prior to administration).
 ⦁Start 25–50 mg QD; may ↑ by 25–50 mg/day increments weekly; max 200 mg/day. 
 ⦁Ages 6–12: Start 12.5–25 mg QD, increase by 25–50 mg/day increments weekly; max 200 mg/day.
 ⦁Ages 13–17: Start 25–50 mg QD, increase by 25–50 mg/day increments weekly; max dose: 200 mg/day.

⦁Ages 6–12: Start 12.5–25 mg QD, increase by 25–50 mg/day increments weekly; max 200 mg/day.
 ⦁PMDD: Start 50 mg QD; may ↑ by 25–50 mg/day increments weekly; max 150 mg/day. Or, intermittent dosing 50 mg 
QD during luteal phase only (days 15–28); max 100 mg/day. 
 ⦁Dose timing: Can be taken in the morning or night, depending on patient preference. 
Cost:  $; capsule: $$$
 ⦁Most common: Nausea, diarrhea, tremor, decreased appetite, sexual side effects, headache.
 ⦁Metabolized primarily through CYP2C19 and to a lesser extent 2D6 and 3A4; moderate inhibitor of CYP2D6 at high 
doses (>150 mg/day); t ½: 26 hours.

doses (>150 mg/day); t ½: 26 hours. 
syndrome).  
 ⦁A meta-analysis of 12 newer antidepressants showed that sertraline and escitalopram have best efficacy and 
tolerability in acute depression (Cipriani A et al, Lancet  2018;391(10128):1357–1366).
 ⦁Considered one of the safest antidepressants to use during breastfeeding due to low levels of exposure to the fetus. 
 ⦁If using oral concentrate, use calibrated dropper (has 25 mg and 50 mg graduation marks only) and mix with 4 
ounces (½ cup) of water, ginger ale, lemon/lime soda, lemonade, or orange juice ONLY. After mixing, a slight haze 
may appear, which is normal.
 ⦁Oral concentrate is formulated in 12% alcohol. Avoid use with disulfiram. 
Fun Fact:

Fun Fact:
During the COVID-19 pandemic in 2020, there was increased demand for sertraline. The active pharmaceutical 
ingredients were in short supply, and the medication was backordered off and on for several months.

AntidepressantsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   61THYROID  (Cytomel, Synthroid, others) Fact Sheet [G]
Thyroid augmentation is often chosen for patients with depression-associated lethargy and fatigue. The usual 
formulation used is T3 (Cytomel). Response rates in clinical trials are mixed and only modest, but thyroid 
augmentation is inexpensive and well tolerated and may be worth a try, especially for patients on tricyclics (the 
evidence is less impressive for SSRI augmentation).  
Treatment of hypothyroidism.
Augmentation and acceleration of antidepressant response. 
 ⦁T3: Triiodothyronine (preferred for psychiatric uses):
Liothyronine tablets (Cytomel, [G]): 5 mcg, 25 mcg, 50 mcg.
 ⦁T4: Thyroxine (preferred for hypothyroidism):
Levothyroxine tablets (Synthroid, Levoxyl, Levothroid, [G]):  25 mcg, 50 mcg, 75 mcg, 88 mcg, 100 mcg, 112 mcg,

⦁T4: Thyroxine (preferred for hypothyroidism):
Levothyroxine tablets (Synthroid, Levoxyl, Levothroid, [G]):  25 mcg, 50 mcg, 75 mcg, 88 mcg, 100 mcg, 112 mcg, 
125 mcg, 137 mcg, 150 mcg, 175 mcg, 200 mcg, 300 mcg.
 ⦁Note: T4 is converted to T3 in the body.
 ⦁Thyroid product equivalencies: 100 mcg levothyroxine = 25 mcg liothyronine.
T3: 25 mcg daily for one to two weeks, increase to 50 mcg if no response (in elderly, start at 12.5 mg and increase 
gradually up to 50 mcg). Give in the morning. 
Monitoring:  Check TSH (thyroid stimulating hormone) level before treatment. Repeat every six to 12 months. 
Cost:  $
 ⦁Most common: At doses used in augmentation, there are rarely any side effects. 
 ⦁Serious but rare: Reduced bone density; hyperthyroidism, which might theoretically occur (watch for these 
symptoms: tremor, palpitations, heat intolerance, sweating, anxiety, increased frequency of bowel movements,

symptoms: tremor, palpitations, heat intolerance, sweating, anxiety, increased frequency of bowel movements, 
shortness of breath, and exacerbation of cardiac arrhythmia).
 ⦁Contraindications: Recent MI, adrenal insufficiency.
 ⦁Mechanism for depression not well understood; it may work by generally stimulating metabolism and energy. 
 ⦁Metabolized by CYP450; t ½: 1 day.
 ⦁Caution in patients with warfarin as blood thinning effects may be increased. 
 ⦁Efficacy: Mixed evidence.
 ⦁After two failed courses of antidepressants, augmentation with T3 or lithium was compared in the STAR*D trial. 
Remission rates were modest and numerically, but not statistically, higher with T3: 25% with T3 vs 16% with lithium, 
and lithium patients had more side effects.
 ⦁Majority of T3 augmentation studies were in patients taking TCAs, though there are some data with SSRIs and other 
antidepressants.

 ⦁Efficacy for augmentation in partial or non-responders is independent of baseline TSH. Goal TSH is at or below lower 
limit of normal range, but caution to avoid hyperthyroid symptoms. 
Fun Fact:
You may have patients ask you about taking “natural” thyroid. They may be referring to dessicated thyroid, which is 
derived from extracts of bovine or porcine thyroid glands and contains T3 and T4 in a 1:4 ratio (60 mg contains about 
38 mcg of T4 and 9 mcg of T3).

62  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONTRAZODONE  (Desyrel) Fact Sheet [G]
Trazodone is most commonly used as a hypnotic at low doses (25–50 mg), but at higher doses it is effective for 
depression, and has the advantage of fewer sexual side effects and less weight gain compared to other serotonergic 
Insomnia; anxiety.
Tablets (G): 50 mg, 100 mg, 150 mg, 300 mg (scored).
 ⦁Depression: Start 50 mg TID; ↑ by 50 mg/day every three to four days until response (usually 300–400 mg/day); max 
600 mg/day.
 ⦁Insomnia (off-label): Start 25–50 mg QHS; may ↑ by 50 mg increments up to 200 mg QHS.
 ⦁Dose timing: Generally best given at bedtime, though some patients find the medication stimulating and need to 
take it in the morning. 
Cost:  $

Cost:  $
 ⦁Most common: Drowsiness, dry mouth, dizziness or lightheadedness, orthostatic hypotension, headache, blurred 
vision, nausea, or vomiting.
 ⦁Serious but rare: Reports of priapism (painful erection lasting longer than six hours); may require surgical or 
pharmacologic (eg, epinephrine) intervention and may result in impotence or permanent impairment of erectile 
function. Orthostatic hypotension and syncope reported (less at hypnotic doses).
 ⦁Serotonin reuptake inhibitor, alpha-1 adrenergic receptor antagonist, and serotonin 5-HT2A and 5-HT2C receptor 
antagonist.
 ⦁Metabolized primarily through CYP3A4 to active metabolite (mCPP), which in turn is metabolized by 2D6; induces 
P-glycoprotein; t ½: 7–10 hours.

 ⦁Food delays absorption of trazodone for one to two hours, so it’s best taken on an empty stomach when used for 
insomnia. Trazodone’s hypnotic effects are not due to anticholinergic or antihistaminergic effects.
 ⦁Rarely used as antidepressant due to risk for over-sedation and orthostasis at therapeutic doses; majority of use 
currently is for insomnia.
Fun Fact:
As a consequence of the production of mCPP as a metabolite, patients taking trazodone may test positive on urine 
tests for the presence of MDMA (ecstasy).

AntidepressantsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   63TRICYCLIC ANTIDEPRESSANTS  (TCAs) Fact Sheet [G]
Not commonly used due to side effects and overdose toxicity risk; however, TCAs should be considered for 
appropriate patients who do not respond to other antidepressants.
Headache; migraine; neuropathic pain; fibromyalgia; anxiety disorders; insomnia; nocturnal enuresis; urinary 
incontinence.
Note:  There are nine TCAs approved by the FDA for depression (amitriptyline, amoxapine, desipramine, doxepin, 
imipramine, maprotiline, nortriptyline, protriptyline, trimipramine) and one approved for OCD (clomipramine). We’ve 
selected six TCAs to cover in this book. Doxepin is in the Anxiolytic and Hypnotic Medications chapter, clomipramine 
is in this chapter, and in this sheet we include four of the more commonly prescribed TCAs. 
 ⦁Tertiary TCAs (more sedating):

 –Amitriptyline tablets (G):  10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg.
 –Imipramine tablets and capsules (G):  10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg.
 ⦁Secondary TCAs (less sedating):
 –Desipramine tablets (Norpramin, [G]): 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg.
 –Nortriptyline capsules (Pamelor, [G]):  10 mg, 25 mg, 50 mg, 75 mg, and 10 mg/5 mL oral solution.
 ⦁Amitriptyline or imipramine: Start 25–50 mg QHS and ↑ by 25–50 mg/day intervals every two to three days to target 
dose 150–200 mg/day; max 300 mg/day. 
 ⦁Desipramine: Start 25–50 mg QHS and ↑ by 25–50 mg/day intervals every two to three days to target dose 150–200 
mg/day; max 300 mg/day.
 ⦁Nortriptyline: Start 25–50 mg QHS and ↑ by 25–50 mg/day intervals every two to three days to target dose 50–150 
mg/day; max 150 mg/day.

 –Once you reach a dose of 100 mg/day, check nortriptyline serum level to maintain in optimal therapeutic range of 
50–150 ng/mL (check trough level and wait for steady state after a given dose, about five days).
Monitoring:  ECG if history of cardiac disease. Nortriptyline level as described above. 
Cost:  $
 ⦁Serious but rare: Seizure; cardiac effects including orthostasis, arrhythmias, QT prolongation, AV block.
 ⦁Serotonin and norepinephrine reuptake inhibitors.
 ⦁Metabolized primarily through liver (limited data, though likely through oxidative CYP2D6 primarily); t ½: 18–44 
hours.

⦁Serotonin and norepinephrine reuptake inhibitors.
hours.
 ⦁Avoid use with other serotonergic antidepressants or agents with hypotensive or anticholinergic effects.
 ⦁Using divided doses (BID to TID) may help with tolerability during initiation and titration; but can convert to QHS 
dosing to minimize daytime sedation.
 ⦁Tertiary amines amitriptyline and imipramine are metabolized to secondary amines nortriptyline and desipramine, 
respectively. Secondary amines are generally better tolerated.
 ⦁Value of serum level monitoring most clearly established for nortriptyline; utility of monitoring for other TCAs is 
controversial. 
 ⦁Overdose toxicity with potentially serious cardiac effects or fatality with as little as 10-day supply.
Fun Fact:
Imipramine was the first antidepressant approved in the US, developed by tweaking the molecular structure of the

Fun Fact:
Imipramine was the first antidepressant approved in the US, developed by tweaking the molecular structure of the 
antipsychotic Thorazine. It didn’t work for psychosis, but was the first “wonder drug” for depression and anxiety.

64  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONVENLAFAXINE  (Effexor, Effexor XR) Fact Sheet [G]
Venlafaxine is probably somewhat more effective than SSRIs for depression, but its side effect disadvantages, such 
as blood pressure elevation and discontinuation symptoms, relegate it to second-line use. Venlafaxine’s active 
metabolite, desvenlafaxine, may be preferred by some over the parent compound—see our desvenlafaxine fact sheet 
in this chapter.  
Major depression; social anxiety disorder; generalized anxiety disorder; panic disorder.
PTSD; PMDD; vasomotor symptoms of menopause; diabetic peripheral neuropathy.
 ⦁Tablets (G):  25 mg, 37.5 mg, 50 mg, 75 mg, 100 mg (scored).
 ⦁ER tablets (G): 37.5 mg, 75 mg, 150 mg, 225 mg.
 ⦁Depression:
Start 75 mg/day in two or three divided doses or as XR once daily; ↑ dose by 75 mg/day at intervals of four or more

⦁ER tablets (G): 37.5 mg, 75 mg, 150 mg, 225 mg.
Start 75 mg/day in two or three divided doses or as XR once daily; ↑ dose by 75 mg/day at intervals of four or more 
days; max 375 mg/day (divided TID) or 225 mg/day XR given once daily. IR may be switched to nearest equivalent 
daily dose of XR QD.
 ⦁Anxiety:
XR: Start 75 mg QD, ↑ by 75 mg/day at weekly intervals; max 225 mg/day; for panic disorder, to minimize 
exacerbation of panic, start 37.5 mg QD, ↑ to 75 mg QD after one week then by 75 mg/day at weekly intervals; max 
225 mg/day.
Cost:  $
 ⦁Most common: Anorexia, constipation, dizziness, dry mouth, nausea, nervousness, somnolence, sweating, sexual 
side effects, headache, insomnia.
 ⦁Serious but rare: Sustained, dose-related hypertension reported. May cause hyponatremia or SIADH; use with 
caution in patients who are volume depleted, elderly, or taking diuretics.

⦁Serious but rare: Sustained, dose-related hypertension reported. May cause hyponatremia or SIADH; use with 
 ⦁Metabolized primarily through CYP2D6 to O-desmethylvenlafaxine (ODV), major active metabolite (an SNRI, 
marketed as Pristiq), and also by CYP3A4; t ½: 5 hours (11 hours for ODV).
 ⦁Avoid use with MAOIs, other serotonergic agents. Caution with CYP2D6 or 3A4 inhibitors, which may increase 
venlafaxine levels. Inhibits CYP2D6.
 ⦁For patients with nausea, start at lower dose, titrate more slowly, and give with food.
 ⦁May cause false-positive PCP in urine drug screen.
 ⦁Increase in blood pressure much more likely in doses >225 mg/day.
 ⦁Significant discontinuation syndrome, even with XR formulation.

⦁May cause false-positive PCP in urine drug screen.
 ⦁Theoretically functions as an SSRI in low doses (75 mg/day) and as an SNRI in moderate doses (150−225 mg/day), 
and affects all monoamines in high doses (>225 mg/day).
 ⦁No additional benefit seen with doses >225 mg/day in moderately depressed outpatients, but patients with more 
severe depression may respond to higher doses (350 mg/day).
Fun Fact:
Venlafaxine is structurally related to the atypical opioid analgesic tramadol (Ultram, itself a serotonergic agent), but 
not to any other antidepressant drugs.

AntidepressantsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   65VILAZODONE  (Viibryd) Fact Sheet
Vilazodone is essentially an SSRI with the addition of some buspirone-type effects. Early claims of sexual side effect 
advantages over other SSRIs are unproven. Disadvantages include the slow titration schedule, the need to take it with 
food in order to achieve a therapeutic blood level, and the many drug interactions. Until further notice, vilazodone 
should remain a second-line antidepressant.
OCD; other anxiety disorders.
Tablets: 10 mg, 20 mg, 40 mg.
 ⦁Start 10 mg QD for seven days; ↑ to 20 mg QD for seven days, then to recommended dose of 20–40 mg QD (with 
food). Purpose of dose titration is to minimize GI effects.
 ⦁Must take with food, otherwise serum levels are reduced by up to 50%.
 ⦁Dose timing: Best taken in the morning due to activating effects.

⦁Must take with food, otherwise serum levels are reduced by up to 50%.
 ⦁Dose timing: Best taken in the morning due to activating effects. 
Cost:  $$$$
 ⦁Most common: Diarrhea, nausea, vomiting, dry mouth, insomnia, dizziness.
 ⦁Serious but rare: Possible hyponatremia or SIADH; use with caution in patients who are volume depleted, elderly, or 
taking diuretics.
 ⦁SSRI plus 5-HT1A partial agonist (buspirone is also 5-HT1A partial agonist).
 ⦁Metabolized primarily through CYP3A4; t ½: 25 hours.
 ⦁Avoid use with MAOIs, other serotonergic agents. More P450 drug interactions possible with vilazodone than some 
other SSRIs. Use with 3A4 inhibitors or inducers may require dose adjustment.
 ⦁Sometimes marketed as having no or few sexual side effects, but FDA officials wrote an article for the Journal of

 ⦁Sometimes marketed as having no or few sexual side effects, but FDA officials wrote an article for the Journal of 
Clinical Psychiatry  clarifying that studies do not support this claim.
 ⦁Although the buspirone-like 5-HT1A effect suggests vilazodone may be especially effective in anxious depression, 
some patients report feeling a wired or somewhat stimulated effect like fluoxetine.
 ⦁Patients who experience nausea or activation, both dose-related effects, may not be able to reach a daily dose of 40 
mg due to tolerability but may respond to 20–30 mg per day.
Fun Guess:
The brand name “Viibryd” likely has two origins. First, it rhymes with “hybrid, ” and the mechanism of action is a hybrid 
of SSRI and 5-HT1A partial agonism. Second, the word calls to mind “virile, ” which could be a subliminal suggestion 
that it does not worsen sexual functioning.

66  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONVORTIOXETINE  (Trintellix) Fact Sheet
Vortioxetine is a newer “multimodal” antidepressant with diverse effects on neurotransmitters. Recent data suggest 
that vortioxetine may have pro-cognitive effects and may be less likely to cause sexual side effects than SSRIs. It is 
reasonable to try the drug in patients who have complained of SSRI-induced sexual dysfunction. A high prevalence of 
nausea and the high brand-name price tag are negative factors to consider. 
Generalized anxiety disorder; other anxiety disorders.
Tablets:  5 mg, 10 mg, 15 mg, 20 mg.
Start 10 mg QD; ↑ to 20 mg QD as tolerated. Consider 5 mg/day for those unable to tolerate higher doses (eg, due to 
nausea). May be taken in the morning or night. 
Cost:  $$$$

Cost:  $$$$
 ⦁Most common: Nausea, constipation, vomiting, sexual side effects, dry mouth, headache.
 ⦁Serious but rare: Serotonergic antidepressants have been rarely associated with bruising or bleeding.
 ⦁Multimodal antidepressant.
 ⦁Metabolized primarily through CYP2D6 and, to a lesser extent, via 3A4/5, 2C9/19, 2A6, 2C8, and 2B6;  
t ½: 66 hours.
 ⦁Avoid use with MAOIs, other serotonergic medications. Use lower doses in presence of potent 2D6 inhibitors.
 ⦁Vortioxetine is a “multimodal” antidepressant or a “serotonin modulator and stimulator. ” This means it has effects on 
several receptor sites. Like SSRIs, it is a serotonin reuptake inhibitor, but it also is an agonist at 5-HT1A receptors, a

several receptor sites. Like SSRIs, it is a serotonin reuptake inhibitor, but it also is an agonist at 5-HT1A receptors, a 
partial agonist at 5-HT1B receptors, and an antagonist at 5-HT3A, 5-HT1D, and 5-HT7 receptors.
 ⦁The Trintellix labeling was updated twice in 2018. First, data from studies examining cognitive functioning in 
patients treated for depression were included to note improved processing speed with vortioxetine. The second 
update was made to include head-to-head data showing greater improvement in treatment-emergent sexual side 
effects when patients were switched from SSRI to vortioxetine over escitalopram.
 ⦁The degree of cognitive improvement seen with vortioxetine has been compared to that of caffeine from a shot of 
espresso. Whether or how much that results in functional improvement remains to be seen. 
 ⦁Negative findings in some studies were attributed to dose being too low (5–10 mg/day). Higher-dose studies

 ⦁Negative findings in some studies were attributed to dose being too low (5–10 mg/day). Higher-dose studies 
showed vortioxetine to be as effective as both duloxetine and agomelatine, an antidepressant approved in Europe.
 ⦁Compared to SSRIs, vortioxetine has more GI side effects, including nausea, vomiting, diarrhea, and constipation. 
This may mean that some patients won’t be able to get beyond 5 or 10 mg per day. 
 ⦁Two studies looked at vortioxetine for cognitive symptoms in perimenopausal depression. One found benefits and 
the other did not, but both were small observational studies, not randomized and with no placebo group.
Fun Fact:
The original brand name of vortioxetine, Brintellix, was apparently crafted to subliminally suggest that the drug helps 
cognition (“ bring intelli gence”). It was changed to Trintellix in 2016 because of reports of dispensing errors between

cognition (“ bring intelli gence”). It was changed to Trintellix in 2016 because of reports of dispensing errors between 
Brintellix and Brilinta, the antiplatelet medication ticagrelor.

AntipsychoticsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   67
Which antipsychotic should you choose? There are dozens of options and approved indications. Here are some of the 
factors you should weigh as you decide which antipsychotic to prescribe for a given patient:
 ⦁Efficacy
 ⦁Side effects
 ⦁Cost
Efficacy
While there’s some debate about this, most experts consider clozapine to be the only antipsychotic that is clearly 
more effective than the others. Unfortunately, clozapine also happens to have one of the worst side effect profiles in 
psychiatry. Weight gain is the most prominent: You can expect half of all patients who take clozapine to have a 20% 
or more weight gain over time (Umbricht DS et al, J Clin Psychiatry  1994;55(suppl B):157–160). When you consider 
its other major side effects, like sedation, drooling, and life-threatening neutropenia, not to mention the necessity

its other major side effects, like sedation, drooling, and life-threatening neutropenia, not to mention the necessity 
of monthly blood draws, it’s no wonder that clozapine is used relatively rarely. Nonetheless, it’s incredibly helpful for 
certain treatment-resistant patients.
Next on the list of drugs that might be more effective than others is olanzapine, another side effect overachiever. It 
doesn’t cause as much weight gain as clozapine, but it’s close. In the CATIE trial, 30% of patients gained at least 7% of 
their initial weight.
Beyond this, there’s no consensus that any of the other second-generation antipsychotics (SGAs) differ in efficacy, at 
least for core symptoms of psychosis. It’s possible that SGAs have a broader spectrum of efficacy, given that many are 
approved for various mood syndromes as well as psychosis. Some people believe that SGAs are more effective than

approved for various mood syndromes as well as psychosis. Some people believe that SGAs are more effective than 
first-generation antipsychotics (FGAs) for negative symptoms. This probably stems from the fact that FGAs are more 
likely to cause side effects, like extrapyramidal symptoms (EPS), which can mimic negative symptoms. It is becoming 
more reasonable to choose SGAs over FGAs for most patients as more of the former go generic.
Below are some of the key antipsychotic side effects along with our best estimates of the liabilities of specific agents. 
You’ll find a more detailed comparison of relative side effects in Table 10. 
 ⦁Weight gain/hyperlipidemia/diabetes: 
 –Most weight gain: Clozapine, olanzapine
 –Moderate: Paliperidone, quetiapine, risperidone
 –Lower: Asenapine, brexpiprazole 
 –Least weight gain: Aripiprazole, lurasidone, ziprasidone, most first-generation antipsychotics (eg, haloperidol, 
perphenazine)
 ⦁Sedation:

–Lower: Asenapine, brexpiprazole 
 ⦁Sedation: 
 –Most sedating: Clozapine, olanzapine, quetiapine (note that sedation can sometimes be beneficial for agitated, 
anxious, or manic patients) 
 –Moderately sedating: Asenapine, cariprazine, lurasidone, risperidone, ziprasidone
 –Least sedating: Aripiprazole, brexpiprazole
 ⦁Cardiac issues (primarily prolonged QT interval): 
 –Most issues: Thioridazine, ziprasidone
 –Moderate: Chlorpromazine, haloperidol, iloperidone, paliperidone, quetiapine
 –Fewest issues: Aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, loxapine, lurasidone, olanzapine, 
 ⦁EPS: 
 –Most EPS: Fluphenazine, haloperidol, paliperidone, risperidone
 –Most akathisia: Aripiprazole, brexpiprazole 
 –Moderate: Asenapine, cariprazine, perphenazine

 ⦁EPS: 
 –Least EPS: Chlorpromazine, clozapine, iloperidone, olanzapine, quetiapine, ziprasidone

68  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONDiscontinuing Antipsychotics
Patients may elect to stop their antipsychotics for a variety of reasons, such as noxious side effects, a feeling of stigma, 
or simply a desire to see how their lives go when they’re off meds. Here are some potential issues to watch out for:
 ⦁Supersensitivity psychosis.  We know that relapse to mood or psychotic symptoms is more likely when patients stop 
medications. Med withdrawal psychosis might be “supersensitivity” psychosis—which is theoretically caused by an 
upregulation in the number or sensitivity of dopamine receptors due to chronic exposure to antipsychotics. Because 
antipsychotics block dopamine receptors, the brain responds by creating more receptors to “harvest” the missing 
dopamine. But once you remove those receptor blockers (by stopping the medication), suddenly there are many

dopamine. But once you remove those receptor blockers (by stopping the medication), suddenly there are many 
more receptors to accept dopamine, potentially worsening psychosis. According to this mechanism, withdrawal 
psychosis would then be more severe and more sudden than you’d otherwise predict. There’s not much you can 
do to prevent this, but you might want to let patients know about the risk, and taper meds more slowly if it has 
occurred before. 
 ⦁Withdrawal dyskinesia.  Withdrawal dyskinesia occurs when stopping or reducing the dose of an antipsychotic; 
it causes symptoms that look like tardive dyskinesia (such as lip puckering, tongue movements, hand or foot 
movements, and others). It sometimes goes away after a few weeks, but other times it persists and may require 
reintroducing an antipsychotic at low doses in order to quiet the movements. 
 ⦁Cholinergic rebound.  Antipsychotics such as clozapine and olanzapine are particularly anticholinergic. This can

 ⦁Cholinergic rebound.  Antipsychotics such as clozapine and olanzapine are particularly anticholinergic. This can 
lead to cholinergic supersensitivity, so that when these meds are stopped (or when you switch a patient to a 
less anticholinergic drug), symptoms of the parasympathetic nervous system can result. Many of us remember 
these symptoms with the medical mnemonic SLUD: salivation, lacrimation, urination, defecation. These are 
more commonly described as nausea, vomiting, diarrhea, headache, sweating, and insomnia. Rarely, cholinergic 
symptoms can even cause delirium and psychosis—which can be easily confused with relapse of psychotic 
symptoms. Cholinergic rebound is more likely when anticholinergic antipsychotics like clozapine, olanzapine, or 
chlorpromazine are discontinued too suddenly, or when accompanying benztropine is stopped suddenly. 
Switching Antipsychotics: Abrupt or Gradual?

We often switch antipsychotics due to side effects or lack of efficacy. There are two types of switches: immediate and 
cross-tapering. In the cross-taper, you gradually taper the old drug while gradually titrating up the dose of the new 
drug. We’ve likely all seen at least a case or two where an intended cross-taper stalled and resulted in unintended 
long-term polypharmacy. 
Anecdotally, it appears that most clinicians use the cross-tapering strategy, because it seems like the more cautious 
and reasonable approach. However, a recent study indicates that immediate switches are just as effective. This was a 
meta-analysis of nine randomized controlled trials that involved more than 1,400 patients. There was no clear benefit 
of gradual switching, and immediate switching was generally tolerated well. These trials covered discontinuation of

of gradual switching, and immediate switching was generally tolerated well. These trials covered discontinuation of 
the following agents: risperidone, olanzapine, ziprasidone, aripiprazole, iloperidone, and clozapine (Takeuchi H et al, 
Schiz Bull  2017;43(4):862–871).
What about switching from oral antipsychotics to long-acting injectables (LAIs)? Please see the fact sheet on 
LAIs for guidance on this topic. 
Cost
As of this writing, the following second-generation antipsychotics are available as generics, rendering them relatively 
inexpensive: aripiprazole, asenapine (sublingual), clozapine, olanzapine, paliperidone, quetiapine, risperidone, and 
ziprasidone.
On the other hand, the following antipsychotics are brand-name only and are often ridiculously expensive (up to, 
or even over, $1,000 per month): asenapine (Secuado transdermal), brexpiprazole (Rexulti), cariprazine (Vraylar), 
iloperidone (Fanapt), lumateperone (Caplyta), and lurasidone (Latuda).

All of the second-generation antipsychotics carry the same FDA class warnings. Rather than repeating these concerns 
on each fact sheet, we will mention them here:
 ⦁In 2003, the FDA required all manufacturers of second-generation antipsychotics to revise their package labeling to 
reflect the potential risks for weight gain, hyperglycemia, new-onset or worsening diabetes, and hyperlipidemias. 
While this has become a class warning, it’s clear that there are a handful of really bad actors here: Clozapine and 
olanzapine are the worst, quetiapine and risperidone relatively less so but still problematic for many.
 ⦁Patient-specific factors may also play a role. In general, the incidence and severity of weight gain and metabolic 
effects appear to be greater in the pediatric population.

AntipsychoticsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   69 ⦁A black box warning for all agents in this class suggests a substantially higher mortality rate in geriatric patients 
with dementia-related psychosis  receiving second-generation antipsychotics (4.5%) compared with those receiving 
placebo (2.6%). Although most fatalities resulted from cardiac-related events (eg, heart failure, sudden death) or 
infections (mostly pneumonia) as opposed to a clearly direct effect of medication, second-generation antipsychotics 
are not approved for the treatment of dementia-related psychosis, and such use should be avoided or minimized 
when possible.
 ⦁Adverse cerebrovascular events  (eg, stroke, TIA), sometimes fatal, have been reported in geriatric patients (ages 
73–97) with dementia-related psychosis. The FDA has issued a black box warning on second-generation

73–97) with dementia-related psychosis. The FDA has issued a black box warning on second-generation 
antipsychotics to reflect this risk; several studies have shown that cerebrovascular event risk is elevated with first-
generation antipsychotics, as well.
A 2004 consensus statement from the American Psychiatric Association and American Diabetes Association 
recommends the following monitoring protocol for patients on second-generation agents (Table 7). These are the 
minimum recommendations for monitoring; some patients—for example, individuals with elevated triglycerides or 
blood sugar—may necessitate more frequent monitoring.
Table 7:  Metabolic Monitoring Recommendations for 
Patients on Second-Generation Antipsychotics
Personal/Family History1Baseline, Annually
Weight (BMI) Baseline, every 4 weeks for the first 12 weeks, then every 3 months
Waist circumference Baseline, annually
Blood pressure, pulse, fasting blood

Blood pressure, pulse, fasting blood 
glucose, HgA1c, fasting lipidsBaseline, at 12 weeks, then annually
1Personal or family history of obesity, diabetes, hypertension, or cardiovascular disease
BMI = body mass index
Adapted from: The American Diabetes Association, from Diabetes Care  2004;27(2), and The American Psychiatric 
Association Practice Guideline for the Treatment of Patients With Schizophrenia, Third Edition (September 2020) 
Other warnings that should be considered for all antipsychotic agents (first and second generation) include the 
 ⦁Neuroleptic malignant syndrome (NMS),  a potentially fatal syndrome characterized by fever, severe muscle rigidity, 
and autonomic instability, has been reported in patients receiving antipsychotic agents. Treatment requires

and autonomic instability, has been reported in patients receiving antipsychotic agents. Treatment requires 
immediate discontinuation of the drug and intensive symptomatic treatment in a hospital setting.
 ⦁Tardive dyskinesia (TD),  a syndrome of potentially irreversible, involuntary dyskinetic movements, has been reported. 
TD is more common with first-generation antipsychotics than with second-generation agents.
 ⦁Extrapyramidal and withdrawal symptoms  in newborns have been reported with maternal use of first-generation 
antipsychotics during the third trimester of pregnancy. Symptoms may include agitation, feeding disorder, 
hypertonia or hypotonia, respiratory distress, and somnolence. These effects vary in severity and may be self-
limiting (subsiding within hours or days) or, in rare cases, require hospitalization.

70  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION
SE = side effects
ODT = orally disintegrating tabletsNot agitated
—
Moderate weight 
gain, long 
experience Olanzapine 
10 mg IM 
—
 May be as 
effective as 
standard 
cocktailLurasidone 
—
 Good SE profile, 
but expensiveZiprasidone 
20 mg IM 
—
 Calming but 
less sedating 
than othersAripiprazole
—
Fewest SE 
(other than 
akathisia)Cariprazine 
or 
clozapineAdd 
mirtazapine 
to any 
antipsychoticHaloperidol 5 mg, 
lorazepam 1 mg, and 
either benztropine 1 mg 
or diphenhydramine 
50 mg (all IM) 
—
 Standard cocktail, much 
Clozapine
—
Gold standard for treatment 
resistance, high SEOlanzapine
—
Fewer SE than clozapinePossibly more rapid control 
with valproate augmentation
—
Study showed more rapid control 
with valproate augmentationAntipsychotic 
combinations
Clozapine + aripiprazole
—
Research shows fewest 
rehospitalizationsClozapine + 
risperidoneAgitated, accepting meds

—
Olanzapine ODT 
—
Prevents 
cheekingQuetiapine
—
 Weight gain, 
but less than 
olanzapineAgitated, refusing meds,  
in acute settingNegative symptoms
Treatment resistantPsychosis Treatment Algorithm

AntipsychoticsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   71Table 8:  First-Generation Antipsychotics
 Generic Name 
 (Brand Name)
 Year FDA Approved
 [G] denotes generic 
availabilityRelevant FDA 
Indication(s)Available Strengths (mg)Dosage 
EquivalentsUsual Dosage 
Range
(starting–max)
(mg)Notes
Chlorpromazine [G]
(Thorazine1)
1957Psychosis, mania, 
nausea/vomitingTablet: 10, 25, 50, 100, 200
Liquid: 30 mg/mL, 100 mg/mL
IM injection: 25 mg/mL100 50–600 Injectable available; 
photosensitivity
Fluphenazine [G]
(Prolixin1, Prolixin 
Decanoate1)
1960Psychosis Tablet: 1, 2.5, 5, 10
Liquid: 2.5 mg/5 mL, 5 mg/mL
IM injection: 2.5 mg/mL
LAI: Decanoate (see fact sheet)2 2–20 Oral solution; injectables 
(short and LAI) available
Haloperidol [G]
(Haldol, Haldol Decanoate)
1967Psychosis, 
Tourette’s disorderTablet: 0.5, 1, 2, 5, 10, 20
Liquid: 2 mg/mL
IM injection: 5 mg/mL
LAI: Decanoate (see fact sheet)2 2–20 Oral solution; injectables

Loxapine [G]
(Adasuve, Loxitane1)
1975Schizophrenia Capsule: 5, 10, 25, 50
Inhaler: 1010 20–100 10 mg oral inhalation 
powder available as 
Adasuve since 2012; 
available only in enrolled 
health care facilities
Molindone [G]
(Moban1)
1974Schizophrenia Tablet: 5, 10, 25 10 50–100 Less weight gain than 
others
Perphenazine [G]
(Trilafon1)
1957Schizophrenia 
(12+), severe 
nausea/vomitingTablet: 2, 4, 8, 16 8 8–64 Mid-potency agent studied 
and compared to second-
generation agents in CATIE 
(see fact sheet)
Thioridazine [G]
(Mellaril1)
1962Schizophrenia Tablet: 10, 25, 50, 100 100 50–600 QT prolongation; 
irreversible retinal 
pigmentation at >800 mg/
day
Thiothixene [G]
(Navane1)
1967Schizophrenia Capsule: 1, 2, 5, 10 4 6–40 High-potency agent
Trifluoperazine [G]

day
(Navane1)
(Stelazine1)
1959Schizophrenia, 
nonpsychotic 
anxietyTablet: 1, 2, 5, 10 5 4–40 High-potency agent
1Brand discontinued; no longer available as brand
IM = intramuscular

72  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONTable 9:  Second-Generation Antipsychotics
Generic Name 
availabilityRelevant FDA Indication(s)
(pediatric ages specified where relevant)Available Strengths (mg)Usual Dosage 
Range
(starting–max) 
(mg)1Notes
Aripiprazole [G]
(Abilify, Abilify Discmelt)
2002Schizophrenia (13+)
Bipolar mania, monotherapy and 
adjunctive (10+)
Bipolar maintenance, monotherapy and 
adjunctive
Depression adjunct
Irritability in autism (6–17)
Tourette’s disorder (6–18)
Agitation in schizophrenia or bipolar 
(IM only)
Acute schizophrenia relapse (LAI 
Maintena only)Tablet: 2, 5, 10, 15, 20, 30
ODT: 10, 15, 20, 30
Liquid: 1 mg/mL
LAI: Maintena, Initio, 
Aristada (see fact sheet)10–30 QD Probably most 
“activating, ” though 
higher doses can be 
sedating
Asenapine [G]
(Saphris, Secuado)
2009
Generic not available for 
patchSchizophrenia
Bipolar mania, monotherapy and

sedating
2009
adjunctive (10+)SL tablet: 2.5, 5, 10
Patch: 3.8, 5.7, 7.6/24 hSL: 5–10 BID
TD: 3.8–7.6 QDAvoid food or drink for 
10 minutes after taking 
SL; sedating
(Rexulti)
2015Schizophrenia (13+)
Depression adjunctTablet: 0.25, 0.5, 1, 2, 3, 4 1–4 QD Newer agent with 
limited data; weight 
gain and akathisia most 
common adverse effects
Cariprazine 
(Vraylar) 
2015Schizophrenia
Bipolar I depression  
Bipolar mania and mixed episodesCapsule: 1.5, 3, 4.5, 6 1.5–6 QD Newest agent with 
limited data; possible 
negative symptom 
efficacy
Clozapine [G]
(Clozaril, FazaClo, Versacloz)
1989
oral suspensionTreatment-resistant schizophrenia
Recurrent suicidal behavior in 
schizophrenia or schizoaffective disordersTablet: 25, 50, 100, 200
ODT: 12.5, 25, 100,
150, 200

150, 200
Oral suspension: 50 mg/mL12.5–450 BID Probably most effective 
(Fanapt)
2009Schizophrenia Tablet: 1, 2, 4, 6, 8, 10, 12 2–12 BID Orthostatic dizziness; 
must be titrated
(Caplyta)
2019Schizophrenia
Bipolar I or II depressionCapsule: 10.5, 21, 42 42 QD Take with dinner
(Latuda)
2010Schizophrenia (13+)  
Bipolar I depression (10+)Tablet: 20, 40, 60, 80, 120 40–160 QD Sedating; must take 
with food
Olanzapine [G]
(Zyprexa, Zyprexa Zydis)
1996
Generic not available for LAISchizophrenia (13+)
adjunctive (13+)
Bipolar maintenance, monotherapy
Bipolar I depression (with fluoxetine) (10+)
Treatment-resistant depression (with 
fluoxetine)
(IM only)Tablet: 2.5, 5, 7.5, 10, 15, 20
ODT: 5, 10, 15, 20

IM injection: 10 mg/vial
LAI: Relprevv 
(see fact sheet)10–20 QD Greatest weight gain
Olanzapine/samidorphan
(Lybalvi)
2021Schizophrenia
Bipolar mania monotherapy and 
Bipolar maintenanceTablet: 5/10, 10/10, 15/10, 
20/10 10/10–20/10 
QDLess weight gain than 
olanzapine alone but 
still moderate weight 
gain; avoid in patients 
taking opioids
Paliperidone [G] 
(Invega)
2006
Generic not available for LAISchizophrenia (12+) 
Schizoaffective disorderER tablet: 1.5, 3, 6, 9
LAI: Sustenna, Trinza, 
Hafyera (see fact sheet)6–12 QD Good for those with 
hepatic impairment; 
increases prolactin
ODT = orally disintegrating tablet, LAI = long-acting injectable ER, XR = extended release, IM = intramuscular, SL = sublingual, TD = transdermal
1For schizophrenia indication

AntipsychoticsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   73Generic Name 
Range
(Nuplazid)
2016Parkinson’s disease psychosis Tablet: 10
Capsule: 3434 QD No data in schizophrenia
Quetiapine [G]
(Seroquel) 
(Seroquel XR) 
1997Schizophrenia (13+)
Bipolar mania, monotherapy 
and adjunctive (10+)
Bipolar disorder maintenance
Bipolar I or II depression
Depression adjunct (approved 
in ER form)Tablet: 25, 50, 100,
200, 300, 400
ER tablet: 50, 150, 200, 
300, 40050–800 
divided BID to 
TID; 300–800 
QHS for XRSedating
Risperidone [G] 
(Risperdal, Risperdal M-Tab)
1993
Irritability in autism (5–16)Tablet: 0.25, 0.5, 1, 2, 3, 4
ODT: 0.25, 0.5, 1, 2, 3, 4

1993
LAI: Consta, Perseris (see 
fact sheet)2–6 divided 
QD to BIDIncreases prolactin
Ziprasidone [G]
(Geodon)
2001 Schizophrenia
Bipolar mania, monotherapy
Bipolar maintenance, adjunctive
Agitation in schizophrenia (IM injection)Capsule: 20, 40, 60, 80
IM injection: 20 mg/mL20−80 BID Take with food

74  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONTable 10:  Comparison of Relative Side Effects Among Antipsychotics
Wt/
MetabolicSedationQT 
ProlongationOrthostasis AkathisiaEPS (Park/
Dyst)TD ProlactinAnti­
cholinergicSeizures
First Generation
Chlorpromazine + +++ ++++ +++ + + +++ + +++ ++
Fluphenazine + + ++ + +++ +++ +++ +++ + +
Haloperidol + + ++ + +++ +++ +++ +++ + +
Loxapine + ++ ++ ++ ++ ++ ++ ++ ++ +
Molindone 0/+ ++ ++ + ++ ++ ++ ++ + +
Perphenazine + ++ ++ ++ ++ ++ ++ ++ ++ +
Thioridazine + +++ ++++ +++ + + ++ ++ +++ ++
Thiothixene + + ++ + +++ +++ +++ +++ + +++
Trifluoperazine + + ++ + ++ ++ ++ ++ ++ +
Second Generation
Aripiprazole 0/+ + 0/+ + +++ + + + + +
Asenapine ++ ++ ++ ++ ++ + ++ ++ + +
Brexpiprazole 0/+ + ++ + +++ + + + + +
Cariprazine ++ ++ ++ + ++ + + + ++ +
Clozapine +++ +++ ++ +++ 0/+ 0/+ 0/+ + +++ +++
Iloperidone ++ ++ +++ +++ + + + ++ + +
Lumateperone + + + ++ + + + + + +
Lurasidone + ++ + + ++ ++ ++ + + +

Olanzapine +++ +++ ++ ++ ++ ++ + ++ ++ ++
Olanzapine/
samidorphan++ +++ ++ ++ ++ ++ + ++ ++ ++
Paliperidone ++ + ++ ++ ++ ++ ++ +++ + +
Pimavanserin 
(Parkinson’s 
psychosis only)+ + ++ + 0 0 0 0 0 +
Quetiapine ++ +++ ++ ++ 0/+ 0/+ + + ++ ++
Risperidone ++ ++ ++ ++ ++ ++ ++ +++ + +
Ziprasidone 0/+ ++ +++ ++ ++ + + ++ + +
Adapted from The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia,  Third Edition (September 2020).

AntipsychoticsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   75ARIPIPRAZOLE  (Abilify) Fact Sheet [G]
Aripiprazole is a good choice for minimizing risk of weight gain and metabolic side effects, but beware of akathisia. 
Large number of indications and reports of success at a variety of doses make it difficult to predict dosing for 
individual patients.
Schizophrenia  (adults, adolescents 13–17 years); bipolar disorder,  acute treatment of manic and mixed episodes 
(adults, children 10–17 years); bipolar disorder, maintenance treatment  (adults); major depression,  as adjunct 
(adults); irritability in autism  (children 6–17 years); Tourette’s disorder  (children 6–18 years).
Bipolar depression; behavioral disturbances.
 ⦁Tablets (G): 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg.
 ⦁Orally disintegrating tablets (G):  10 mg, 15 mg, 20 mg, 30 mg.
 ⦁Oral liquid (G):  1 mg/mL.

 ⦁IM depot: Abilify Maintena:  300 mg and 400 mg; Aristada:  441 mg, 662 mg, 882 mg, 1064 mg; Aristada Initio:  
675 mg (see LAI fact sheet and table).
 ⦁Tablet with sensor  (Abilify MyCite):  2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg.
 ⦁Schizophrenia and bipolar disorder: Adults: Start and target dose 10–15 mg/day; max 30 mg/day. Children: Start 2 
mg/day, increase on third day to 5 mg/day; may increase further by 5 mg/day increments weekly to target dose 10 
mg/day, max 30 mg/day.
 ⦁Irritability in autism (children): Start 2 mg/day, ↑ to 5 mg/day in weekly increments to target dose 5–10 mg/day, max 
15 mg/day.
 ⦁Depression: Start 2–5 mg/day, ↑ to usual dose 5–10 mg/day, as adjunct. Titrate gradually to prevent agitation/
akathisia (max 15 mg/day).

15 mg/day.
 ⦁Tourette’s: Start 2 mg/day, ↑ to target 5 mg/day, max 10 mg/day (<50 kg); 10 mg/day, max 20 mg/day (>50 kg).
 ⦁Depot: After oral dose tolerated, start Abilify Maintena 400 mg/four weeks (continue oral aripiprazole for first 14 
days), target dose 300–400 mg/four weeks. For Aristada: Start 441 mg, 662 mg, or 882 mg monthly—corresponds 
to 300 mg, 450 mg, and 600 mg of aripiprazole, respectively. Or, start 882 mg dose every six weeks or 1064 mg dose 
every two months. For all Aristada regimens, continue oral aripiprazole for first 21 days unless using concurrent 
Initio dose.
 ⦁Liquid dosing: Oral solution equivalent to tablet dose up to 25 mg; for 30 mg tablets, give 25 mg oral solution.
 ⦁Orally disintegrating tablet: Same as regular tablet dosing.

 ⦁Dose timing: Can be taken in the morning or at night; may unpredictably cause drowsiness or insomnia.
Monitoring:  Fasting glucose, lipids.
Cost:  $; ODT, liquid: $$$$
 ⦁Most common: Akathisia, anxiety, insomnia, sedation, tremors.
 ⦁Serious but rare: Rare reports of reversible pathologic gambling and other impulse control problems (eating, 
spending, sexual).
 ⦁Dopamine D2 and serotonin 5-HT1A receptor partial agonist and serotonin 5-HT2A receptor antagonist.
 ⦁Metabolized by CYP2D6 and 3A4; t ½: 3–6 days.
 ⦁Use ½ usual dose in presence of 2D6 or 3A4 inhibitors or in known 2D6 poor metabolizers; ¼ dose if both 2D6 
inhibitor/poor metabolizer and 3A4 inhibitor; double dose if also using 3A4 inducer.

 ⦁Some prescribers use low-dose aripiprazole to counteract antipsychotic-induced prolactinemia, given its partial 
agonist properties.
 ⦁In November 2017 FDA approved Abilify MyCite, which is aripiprazole with an embedded ingestible sensor to track 
adherence. After a “limited initial launch” in August 2018, the system is only available through a specialty pharmacy.
Fun Fact:
After aripiprazole’s generic launch, Otsuka followed up with brexpiprazole (see fact sheet), another dopamine partial 
agonist, approved for schizophrenia and depression (as adjunct) and in clinical trials for ADHD.

76  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONASENAPINE  (Saphris, Secuado) Fact Sheet [G]
Asenapine’s claim to fame is its availability in both sublingual and skin patch formulations, so it’s a good choice for 
patients who can’t or don’t want to swallow a pill. Mouth numbness (Saphris), sedation, dizziness, akathisia, weight 
gain, and potential for allergic reaction are significant liabilities. Not recommended for first-line use.
Schizophrenia;  bipolar disorder,  acute and maintenance treatment of manic or mixed episodes (adults, children 
10–17 years).
Bipolar depression; behavioral disturbances; impulse control disorders.
 ⦁SL tablets (G): 2.5 mg, 5 mg, 10 mg. (Must be taken sublingually because if swallowed, too much medication is 
metabolized by the liver during first-pass metabolism.)
 ⦁Transdermal patch (Secuado):  3.8 mg, 5.7 mg, 7.6 mg/24 hour patch.

 ⦁Schizophrenia: Start 5 mg SL BID, may ↑ after one week to max dose of 10 mg SL BID.
 ⦁Bipolar (adults): Same dosing as schizophrenia.
 ⦁Bipolar (children): Start 2.5 mg SL BID, increase as needed up to 10 mg SL BID.
 ⦁Do not swallow tablets. Avoid food or drink for 10 minutes after taking (they significantly reduce absorption and 
bioavailability).
 ⦁For patch: Start 3.8 mg/24 hours, may ↑ after one week to 5.7 mg/24 hours or to max dose of 7.6 mg/24 hours after 
one more week. Patch should be applied to hip, abdomen, upper arm, or upper back area.
Cost:  SL: $$$$; patch: $$$$$
 ⦁Most common: Akathisia (seems to be dose-related), oral hypoesthesia (numbing of the tongue or decreased oral 
sensitivity), somnolence, dizziness, EPS, weight gain.

 ⦁Serious but rare: Hypersensitivity reactions including anaphylaxis, angioedema, low blood pressure, rapid heart rate, 
swollen tongue, difficulty breathing, wheezing, or rash; orthostatic hypotension and syncope, particularly early in 
treatment (FDA warning, September 2011).
 ⦁Dopamine D2 and serotonin 5-HT2A receptor antagonist.
 ⦁Metabolized by glucuronidation and CYP1A2; t ½: 24 hours. Inhibitor of 2D6; may double paroxetine levels. Smoking 
may induce metabolism and may lower levels of asenapine via 1A2 induction; adjust dosing. CYP1A2 inhibitors (eg, 
fluvoxamine) may increase levels of asenapine; adjust dose.
 ⦁Caution with antihypertensive agents and other drugs that can cause additive hypotension or bradycardia.

 ⦁Has a receptor-binding profile similar to clozapine, although asenapine has very little anticholinergic activity.
 ⦁Weight gain seems to be a problem in many patients.
 ⦁Contraindicated in patients with severe hepatic impairment due to seven-fold higher levels.
 ⦁Most useful for patients who don’t like swallowing pills.
 ⦁Steady state with patch is achieved in 72 hours. Patch daily dose equivalence of 3.8 mg is 5 mg SL BID and 7.6 mg is 
10 mg SL BID. 
 ⦁Mnemonic for remembering the brand name: The first two letters of asenapine are A-S, or Asenapine-Saphris. 
Fun Fact:
Black cherry flavor was developed after patients complained about original tablets.

AntipsychoticsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   77BREXPIPRAZOLE  (Rexulti) Fact Sheet
Brexpiprazole is a cousin of aripiprazole and is also a partial dopamine agonist. It has a very similar efficacy profile 
(including efficacy for depression) and similar side effect profile, but is much more expensive. We recommend 
choosing the cheaper, generic aripiprazole.
Schizophrenia (adults, adolescents 13–17 years); depression adjunct.
Dementia-related psychosis; borderline personality disorder.
Tablets:  0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg.
 ⦁Schizophrenia: Start 1 mg/day on days one through four; ↑ to 2 mg/day on days five through seven; then up to 
max 4 mg/day based on patient response. Usual dose 2–4 mg/day. Children: Start 0.5 mg/day, increase on fifth day

max 4 mg/day based on patient response. Usual dose 2–4 mg/day. Children: Start 0.5 mg/day, increase on fifth day 
to 1 mg/day and 2 mg/day on eighth day; may increase further by 1 mg/day increments weekly to target dose of 
2-4 mg/day
 ⦁Depression adjunct: Start 0.5–1 mg/day, ↑ at weekly intervals up to target 2 mg/day, max 3 mg/day.
 ⦁Dose timing: Like aripiprazole, can be taken in the morning or at night; may unpredictably cause drowsiness or 
insomnia.
 ⦁Most common: Weight gain, akathisia, somnolence.
 ⦁Metabolized by CYP2D6 and CYP3A4; t ½: 91 hours.

⦁Dopamine D2 and serotonin 5-HT1A receptor partial agonist and serotonin 5-HT2A receptor antagonist.
 ⦁As the name suggests, brexpiprazole is chemically and structurally related to its manufacturer’s previous 
blockbuster aripiprazole (Abilify).
 ⦁Although the FDA-approved target dose for schizophrenia is 2–4 mg/day, 2 mg/day was no better than placebo in 
one of two preclinical registration studies.
 ⦁Unlike aripiprazole, brexpiprazole may not be effective in bipolar mania. It was no better than placebo at reducing 
symptoms in about 650 patients enrolled in two studies in acute mania. One study compared weight gain from 
brexpiprazole to aripiprazole and found a similar increase of about 5–10 pounds over a year.

brexpiprazole to aripiprazole and found a similar increase of about 5–10 pounds over a year. 
 ⦁Once-a-day dosing with no regard to meals makes this an easy-to-use option.
 ⦁Generic/brand name mnemonic: “Brex is Rex” (thanks to Dr. Raj Mago). 
Fun Fact:
Plan on seeing more trial results with Rexulti in the future, including those in patients with ADHD, PTSD, and agitation 
associated with Alzheimer’s dementia.

78  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONCARIPRAZINE  (Vraylar) Fact Sheet
Cariprazine, like aripiprazole and brexpiprazole, is a partial dopamine agonist. Some preliminary data imply that it 
might be effective for negative symptoms, but it’s too soon to tell. Beyond that, it appears similar to the other two 
partial dopamine agonists, with a high rate of EPS and akathisia but minimal weight gain. It is available as a brand 
name only and is therefore very expensive (as opposed to aripiprazole, which has gone generic). 
Schizophrenia; acute treatment of bipolar disorder (manic or mixed episodes); bipolar I depression.
Negative symptoms of schizophrenia; major depression.
Capsules:  1.5 mg, 3 mg, 4.5 mg, 6 mg.
 ⦁Schizophrenia and bipolar disorder: Start 1.5 mg/day, may ↑ to 3 mg/day as early as second day. Adjust by 1.5–3

 ⦁Schizophrenia and bipolar disorder: Start 1.5 mg/day, may ↑ to 3 mg/day as early as second day. Adjust by 1.5–3 
mg/day increments to usual dose 1.5–6 mg/day in schizophrenia and 3–6 mg/day in bipolar disorder.
 ⦁Bipolar depression: Start 1.5 mg QD, may ↑ to 3 mg QD after two weeks or longer; max dose 3 mg/day.
 ⦁Dose timing: Either morning or night; some patients experience restlessness that can interfere with sleep, in which 
case morning is preferred. 
 ⦁Most common: EPS, akathisia, weight gain, sedation.
 ⦁Dopamine D2 and D3 and serotonin 5-HT1A receptor partial agonist; serotonin 5-HT2A receptor antagonist.
 ⦁Metabolized primarily by CYP3A4; t ½: 2–4 days for cariprazine (1–3 weeks for active metabolites).

⦁Metabolized primarily by CYP3A4; t ½: 2–4 days for cariprazine (1–3 weeks for active metabolites).
 ⦁Caution with CYP3A4 inhibitors; 50% dose reduction may be necessary. Avoid use with 3A4 inducers.
 ⦁Most closely similar to aripiprazole with partial D2 agonism.
 ⦁Manufacturer and very early data suggest D3 activity may result in negative symptom improvement.
 ⦁While cariprazine showed enough efficacy to gain an indication for bipolar depression, this was only true in patients 
with bipolar type I. In trials with bipolar II patients, it was no better than placebo.
Fun Fact:
Cariprazine was developed by a Hungarian pharmaceutical company, Gedeon Richter, which was founded in 1901 by 
a pharmacist. Gedeon Richter initially processed extracts from plants to produce herbal drugs.

AntipsychoticsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   79CHLORPROMAZINE  (Thorazine) Fact Sheet [G]
Chlorpromazine was the first antipsychotic to be developed. Its long track record and good sedative properties make 
it popular for certain populations, especially patients with chronic psychosis, agitation, and mania, particularly when 
they are hospitalized. Its availability as an IM injection is an advantage for treating acute agitation. As a low-potency 
agent, it is less likely to cause EPS or TD than many other antipsychotics.  
Psychosis; mania; severe behavioral disorders  (6 months–17 years); nausea and vomiting; intractable hiccups.
Bipolar disorder; behavioral disturbances; impulse control disorders.
 ⦁Tablets (G):  10 mg, 25 mg, 50 mg, 100 mg, 200 mg.
 ⦁Oral concentrate (G):  30 mg/mL, 100 mg/mL.
 ⦁Injectable (G): 25 mg/mL.

 ⦁Schizophrenia: Start 10–25 mg TID; ↑ by 20–50 mg/day increments every three to four days to lowest effective dose. 
Dose range 200–600 mg/day in divided doses; max FDA-approved dose 1000 mg/day.
 ⦁IM for agitation: Usual dose is 25–50 mg; may repeat after one hour, with maximum dose of 200 mg/day. 
Monitoring:  ECG if cardiac disease.
Cost:  $$–$$$$ (depending on dose); oral concentrate: $$$$$
 ⦁Most common: Sedation, orthostasis, tachycardia, drowsiness, dry mouth, constipation, blurred vision, prolactin 
elevation (sexual side effects, amenorrhea, galactorrhea).
 ⦁Serious but rare: Skin pigmentation and ocular changes (both dose related); jaundice; QT prolongation; seizure.
 ⦁Dopamine D2 receptor antagonist.

 ⦁Metabolized primarily by CYP2D6, also CYP1A2 and CYP3A4. Patients who are poor metabolizers of CYP2D6 
metabolize the drug more slowly, potentially increasing its effects; t ½: 23–37 hours.
 ⦁CYP2D6 inhibitors (eg, fluoxetine, paroxetine, quinidine) may increase chlorpromazine levels.
 ⦁Chlorpromazine is a low-potency first-generation antipsychotic; this leads to less EPS compared to high-potency 
agents (eg, haloperidol, fluphenazine) and to more anticholinergic side effects compared to mid- and high-potency 
agents (eg, perphenazine and haloperidol, respectively).
 ⦁Extremely sedating agent and often used for this effect. Dosing limited by orthostasis and sedation.
Fun Fact:
Thorazine was developed by a French surgeon in 1948 to induce relaxation and indifference in surgical patients.

80  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONCLOZAPINE  (Clozaril, FazaClo, Versacloz) Fact Sheet [G]
Clozapine is the only drug with convincing evidence of superior efficacy over other antipsychotics for treatment-
resistant schizophrenia. Consider using it after two failed trials of other antipsychotics. Side effects can be a real 
challenge, including severe weight gain, constipation, drooling, sedation, and the potential for neutropenia. 
Treatment-resistant schizophrenia; reduction in risk of suicide in schizophrenia and schizoaffective disorder.
Treatment-resistant bipolar disorder; treatment-resistant aggression and violence.
 ⦁Tablets (Clozaril):  25 mg (scored), 100 mg (scored).
 ⦁Tablets (G):  25 mg (scored), 50 mg (scored), 100 mg (scored), 200 mg (scored).
 ⦁Orally disintegrating tablets (FazaClo, [G]):  12.5 mg, 25 mg, 100 mg, 150 mg, 200 mg.

⦁Tablets (G):  25 mg (scored), 50 mg (scored), 100 mg (scored), 200 mg (scored).
 ⦁Oral suspension (Versacloz):  50 mg/mL.
 ⦁Start 12.5 mg once or twice daily; ↑ gradually, in increments of 25–50 mg/day to target dose 300–450 mg/day by 
end of two weeks; may ↑ further in increments ≤100 mg and no more frequently than once or twice weekly. May 
require doses as high as 600–900 mg/day; max 900 mg/day (usually in two or three divided doses). May take four to 
six weeks, or as long as three to six months, for response.
 ⦁If dosing is interrupted for ≥48 hours, must be re-titrated from 12.5–25 mg/day; may be increased more rapidly than 
initial titration, as tolerated.
 ⦁Dose timing: Although it can be sedating, many patients develop tolerance and can take it twice daily without 
significant daytime fatigue. 
Monitoring:
 ⦁Fasting glucose, lipids.

⦁Dose timing: Although it can be sedating, many patients develop tolerance and can take it twice daily without 
 ⦁Before starting clozapine, ensure absolute neutrophil count (ANC) >1500; for benign ethnic neutropenia population, 
ensure two baseline ANCs ≥1000. Repeat ANC weekly for first six months, then every two weeks from months six to 
12, then monthly after 12 months. If ANC falls below 1500, guidelines become complex depending on how low the 
value is; consult clozapine Risk Evaluation and Mitigation Strategy (REMS) ( http://b.link/clozapine-rems ) for advice.
 ⦁Serum level monitoring can be useful; therapeutic response generally occurs at 350–450 ng/mL, though some 
patients may show response at lower levels. Upper limit is not well defined; increased risk of toxic effects at levels 
above 700 ng/mL.
Cost:  $$; oral suspension, ODT: $$$$$
Side Effects (see Table 11 for more detailed information):

 ⦁Most common: Sedation, orthostatic hypotension, hypersalivation (place towel on pillow), weight gain (15–30 
pound average weight gain after one year), constipation (risk of toxic megacolon if untreated), tachycardia (can 
treat with propranolol).
 ⦁Serious but rare: Potentially life-threatening neutropenia (1%–2%); periodic ANC testing must occur (as above, see 
prescribing information for monitoring details).
 ⦁Metabolized primarily by CYP4501A2, also CYP2D6 and CYP3A4; t ½: 12 hours.
 ⦁Avoid use with drugs that may cause bone marrow suppression (eg, carbamazepine, antineoplastics), lower seizure 
threshold, or have additive anticholinergic effects. Collapse, respiratory arrest, and cardiac arrest reported during

threshold, or have additive anticholinergic effects. Collapse, respiratory arrest, and cardiac arrest reported during 
initial clozapine treatment in patients taking benzodiazepines. Caution with P450 inhibitors and inducers. Smoking 
increases clozapine clearance by 30%–50%. 
 ⦁Risk of neutropenia greatest within first six months, then incidence declines but can still occur.
 ⦁Divided doses may minimize some adverse effects (eg, hypotension, seizures).
 ⦁A growing number of case reports have been published linking very high clozapine levels to infection. Monitor 
levels and symptoms of toxicity closely, especially in patients hospitalized for infection.
 ⦁FDA-mandated REMS program requires prescribers to be certified to prescribe clozapine (see www.clozapinerems.
com  for details).
Fun Fact:
The Quiet Room is a compelling memoir written by patient Lori Schiller, who was an early user of clozapine.

AntipsychoticsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   81Table 11:  Monitoring and Managing Patients on Clozapine
Occurrence Management Comments
Constipation/hypomotility Constipation 60%; 
obstruction 33%; 
ileus 1%–2%• Routinely monitor bowel function (frequency of bowel movements, 
abdominal pain or distension, absent bowel sounds, diarrhea due to 
overflow constipation, vomiting)
• Encourage hydration, exercise, prune juice
• For chronic constipation, use polyethylene glycol 17 g QD–TID or lactulose 
10–40 g QD; bisacodyl or senna are second-line options 
• For immediate response, use magnesium citrate, glycerin suppository, or 
sodium phosphate enema
• Discontinue anticholinergic agents• Risk factors: higher dose, concomitant anticholinergics or opioids
• In severe cases, potentially life threatening
• Necrosis, bowel obstruction, GI perforation, sepsis, and death have 
occurred

occurred
• Avoid bulk-forming laxatives such as psyllium as they may increase risk 
of perforation in slow-transit constipation
Hypotension/orthostasis 9% • Follow dosing titration guidelines
• Adjust to slower titration if hypotension occurs• Highest risk during initial dose titration, particularly if rapid or large 
• If patient misses >48 hours of clozapine, re-titrate to minimize 
orthostasis
• Rarely, syncope may occur
Myocarditis/
cardiomyopathy<1% • Early signs are nonspecific and include tachycardia, malaise, chest pain
• If suspected, check cardiac enzymes (troponin, C-reactive protein), ECG, 
chest x-ray
• If myocarditis, discontinue clozapine, give supportive care (diuretics, beta 
blockers, ACE inhibitors used)
• Rechallenge in confirmed myocarditis is controversial; use clinical

• Rechallenge in confirmed myocarditis is controversial; use clinical 
judgment based on risk/benefit• Myocarditis typically occurs early in therapy (first 8 weeks)
• Cardiomyopathy may develop after 6 months and may be a 
consequence of persistent tachycardia
• Detecting early can prevent serious outcomes including death in 
12%–24% of cases
Neutropenia/ 
agranulocytosis Neutropenia 3%–4%; 
agranulocytosis <1%• Check baseline and weekly ANC; if normal, can reduce frequency to every 2 
weeks after 6 months and then monthly after another 6 months
• See Table 11A (immediately below) for details • Risk is greatest in first 18 weeks
• Not dose related 
• “Do not rechallenge” list has been eliminated; if patient experiences 
severe neutropenia (ANC <500), continuation is based on clinical 
judgment 
Nocturnal enuresis 21% • Lower dose or slow titration schedule

judgment 
• Divide dose into BID–TID to lower dose burden at night• Common particularly early in dosing titration
Sedation/somnolence 40% • Lower dose or slow titration schedule
• Consolidate dosing to all at bedtime if tolerated• Early side effects for which many patients develop tolerance
Seizures 1%–5% depending 
on dose • Lower dose if clinically appropriate
• Add anticonvulsant for prophylaxis at higher doses (>600 mg/day), 
valproate often preferred; avoid carbamazepine due to additive risk for 
neutropenia • Dose related: 1%–2% at <300 mg/day, 3%–4% at 300–600 mg/day, 
5%+ at >600 mg/day
Sialorrhea Rates of 30%–90% 
reported• Nonpharmacologic: chew sugarless gum (assists with swallowing saliva, 
reduces pooling and drooling), use towel on pillow at night
• Atropine 1% ophthalmic drops (1–6 drops SL divided QD–TID): limited

• Atropine 1% ophthalmic drops (1–6 drops SL divided QD–TID): limited 
evidence, effect may not be sustained
• Benztropine 0.5–2 mg/day in divided doses: limited evidence, caution 
additive anticholinergic effects• More common and severe at night
• May impact medication adherence 
• May increase risk for aspiration pneumonia
• May be due to parotid gland inflammation and impaired swallowing

82  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONOccurrence Management Comments
Tachycardia 25% • Reduce dose or slow titration 
• Consider propranolol 10–20 mg QD–TID• Dose related and reversible
• Usually associated with initial dose titration and transient in many 
patients
• Persistent tachycardia may increase risk for cardiomyopathy
Weight gain, 
hyperglycemiaVery common • Educate regarding diet, exercise
• Use lowest effective dose
• Monitor weight, waist circumference, glucose, HgA1c, lipids regularly
• Consider metformin and topiramate for weight gain• Dose dependent
• Non-obese patients may gain more weight
• Monitor for signs of hyperglycemia (polyphagia, polydipsia, polyuria)
Therapeutic Drug Monitoring
• Order “clozapine, 
norclozapine, total level” 
• Draw at trough (generally 
in the morning, 12 hours 
after nighttime dose but 
before morning dose)N/A • Target clozapine level is >350 ng/mL

• Target clozapine to norclozapine ratio is 1.5:1 to 2:1
• Side effects and toxicity generally appear >750 ng/mL• Check in patients not responding to usual doses, or having side effects, 
or when non-adherence is suspected
• Wait a minimum of 3 full days at a new dosage before checking serum 
level to ensure steady state is reached
• Norclozapine generally associated with adverse effects; hence 
achieving target ratio of clozapine:norclozapine is associated with 
better clinical response and fewer side effects 
• If ratio <1.5:1, consider fluvoxamine 25–50 mg 
Table 11A:  ANC Monitoring for Clozapine Treatment
ANC (in / uL) Treatment Recommendation1ANC Monitoring
Baseline to initiate clozapine

Baseline to initiate clozapine  
≥1500 (BEN population: ≥1000)Obtain 1 baseline ANC, then initiate treatment Weekly for first 6 months; every 2 weeks for months 6–12; monthly after 12 
months
Mild neutropenia:  1000–1499 Continue treatment 3 times weekly until ANC ≥1500, then return to previous usual monitoring 
interval
Moderate neutropenia:  500–999 Hematology consult; hold clozapine; resume when 
ANC ≥1000Daily until ANC ≥1000, then 3 times weekly until ANC ≥1500, then weekly for 
4 weeks, then return to previous usual interval
Severe neutropenia:  <500 Hematology consult; discontinue clozapine; do not 
rechallenge unless benefits outweigh risksDaily until ANC ≥1000; 3 times weekly until ANC ≥1500; if rechallenge, resume 
as new patient

1Note: 25%–50% of Black individuals have benign ethnic neutropenia (BEN) and their clozapine monitoring protocol is modified; see https://www.clozapinerems.com/CpmgClozapineUI/rems/pdf/
resources/ANC_Table.pdf

AntipsychoticsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   83FLUPHENAZINE  (Prolixin) Fact Sheet [G]
Fluphenazine is an effective, inexpensive first-generation antipsychotic with a long history of experience and use, but 
clinical utility is limited in some patients due to EPS.
Psychosis.
 ⦁Tablets (G):  1 mg, 2.5 mg, 5 mg, 10 mg.
 ⦁Oral liquid (G):  2.5 mg/5 mL.
 ⦁Oral concentrate (G): 5 mg/mL.
 ⦁Injection (G):  2.5 mg/mL.
 ⦁Long-acting injection (G):  25 mg/mL (see LAI fact sheet and table).
Start 1–2.5 mg BID (5 mg BID for hospitalized patients); adjust to lowest effective dose. Dose range 2.5–20 mg/day 
divided BID; max FDA-approved dose is 40 mg/day, but doses >20 mg/day are difficult to tolerate and rarely more 
effective.

Cost:  $$
 ⦁Most common: EPS, headache, drowsiness, dry mouth, prolactin elevation (sexual side effects, amenorrhea, 
galactorrhea).
 ⦁Metabolized primarily by CYP2D6; t ½: 15 hours. Poor metabolizers of CYP2D6 metabolize the drug more slowly; 
may have increased effects.
 ⦁CYP2D6 inhibitors (eg, fluoxetine, paroxetine, quinidine) may increase fluphenazine levels.
 ⦁Fluphenazine is a high-potency first-generation antipsychotic; this leads to more EPS compared to mid- or low-
potency agents (eg, perphenazine or chlorpromazine, respectively) and to less sedation, less orthostasis, and fewer

potency agents (eg, perphenazine or chlorpromazine, respectively) and to less sedation, less orthostasis, and fewer 
anticholinergic side effects compared to low-potency agents (eg, chlorpromazine).
 ⦁Relatively lower seizure side effect risk compared to lower-potency agents. Long-acting injectable decanoate 
formulation allows option for patients who don’t take oral formation reliably.
 ⦁Availability of short-acting injectable and oral liquid formulations also allows for more flexibility in administration.
 ⦁Oral concentrate liquid must be diluted with at least two ounces of a liquid such as milk, tomato juice, fruit juice 
(but not apple juice), or a soft drink that does not contain caffeine.
Fun Fact:
Prolixin is the most well-known brand of fluphenazine, but there was also a branded fluphenazine on the market 
under the name Permitil.

84  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONHALOPERIDOL  (Haldol) Fact Sheet [G]
Haloperidol is an effective, inexpensive first-generation antipsychotic with low weight gain potential and a 
long history of experience and use, but clinical utility is limited due to EPS and potential for TD. It’s favored by 
many clinicians for treatment of acute agitation, especially when given in an IM “cocktail” with lorazepam and 
diphenhydramine. 
Psychosis (adults, 3–17 years); Tourette’s disorder (adults, 3–17 years); severe behavioral disorders (3–17 years).
Bipolar disorder; behavioral disturbances; impulse control disorders; delirium.
 ⦁Tablets (G):  0.5 mg (scored), 1 mg (scored), 2 mg (scored), 5 mg (scored), 10 mg (scored), 20 mg (scored).
 ⦁Oral concentrate (G):  2 mg/mL.
 ⦁Injection (G):  5 mg/mL.
 ⦁Long-acting injection (G): 50 mg/mL and 100 mg/mL (see LAI fact sheet and table).

⦁Oral concentrate (G):  2 mg/mL.
 ⦁Schizophrenia: Start 1–2 mg BID (5 mg BID for hospitalized patients); adjust to lowest effective dose.  
Usual dose range is 5–20 mg/day. Max FDA-approved dose is 100 mg/day, but doses >20 mg/day are rarely used.
 ⦁IM for agitation: 2.5–10 mg IM, often combined with lorazepam 1 mg IM and diphenhydramine 50 mg IM; maximum 
20 mg/day. 
 ⦁IV for severe agitation (generally in the ICU setting): 2.5–10 mg IV Q4–8 hours; maximum 20 mg/day.
Monitoring:  No routine monitoring recommended unless clinical picture warrants. Monitor ECG with IV use due to 
increased risk for QT prolongation. 
Cost:  $

⦁Most common: EPS, headache, drowsiness, dry mouth, prolactin elevation (sexual side effects, amenorrhea, 
 ⦁Metabolized primarily by CYP2D6 and CYP3A4; t ½: 21–24 hours. Patients who are poor metabolizers of CYP2D6 
metabolize the drug more slowly; may have increased effects.
 ⦁CYP2D6 inhibitors (eg, fluoxetine, paroxetine, quinidine) may increase haloperidol levels. May inhibit CYP2D6; 
caution with substrates of 2D6 as haloperidol may increase their levels and effects.
 ⦁Haloperidol is a high-potency first-generation antipsychotic; this leads to more EPS compared to mid- or low-

 ⦁Relatively lower seizure side effect risk compared to lower-potency agents.
 ⦁Short-acting injectable and oral liquid formulations allow for more flexibility in administration.
 ⦁Long-acting injectable decanoate formulation allows option for patients who don’t take oral formation reliably.
Fun Fact:
Haldol was discovered in 1958 by Paul Janssen, the founder of Belgian pharmaceutical company Janssen 
Pharmaceutica.

AntipsychoticsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   85ILOPERIDONE  (Fanapt) Fact Sheet
Iloperidone is not recommended as a first-choice agent due to twice-daily dosing, need for titration, QT prolongation 
(comparable to ziprasidone), dizziness, moderate weight gain, and increases in blood sugar; and because it appears 
less efficacious than other antipsychotics.
Schizophrenia.
Bipolar disorder; major depression; behavioral disturbances; impulse control disorders.
Tablets:  1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg.
Start 1 mg BID; ↑ to 2 mg BID on day two and then daily by 4 mg/day to a target dose of 6–12 mg BID daily; max 
12 mg BID.
 ⦁Most common: Dizziness (dose-related), dry mouth, fatigue, nasal congestion, orthostatic hypotension (can

12 mg BID.
 ⦁Most common: Dizziness (dose-related), dry mouth, fatigue, nasal congestion, orthostatic hypotension (can 
minimize by gradual dose titration), somnolence, tachycardia (dose-related), moderate weight gain.
 ⦁Serious but rare: Relatively moderate to high risk of QTc prolongation (risk is increased in patients taking potent 
CYP2D6 or CYP3A4 inhibitors, or at higher doses); avoid use in patients with bradycardia, history of MI, hypokalemia, 
hypomagnesemia, or concomitant use of other drugs that prolong QTc. Priapism reported rarely.
 ⦁Metabolized primarily through CYP2D6, also CYP3A4; t ½: 18 hours (33 hours in poor metabolizers).
 ⦁Avoid concomitant use of other drugs known to prolong the QTc interval.

⦁Metabolized primarily through CYP2D6, also CYP3A4; t ½: 18 hours (33 hours in poor metabolizers).
 ⦁Potent inhibitors of CYP2D6 (eg, paroxetine, fluoxetine, quinidine) or CYP3A4 (eg, ketoconazole, clarithromycin) may 
increase iloperidone levels; in such cases, decrease iloperidone dose by 50%.
 ⦁Must follow initial titration schedule if treatment has been interrupted for more than three days.
 ⦁Minimal data regarding long-term use in schizophrenia and uses other than schizophrenia.
 ⦁Avoid use in patients with severe hepatic impairment due to potential for elevated levels leading to QT interval 
prolongation.
 ⦁A network meta-analysis of 212 studies involving more than 43,000 patients found that olanzapine and risperidone 
improved core symptoms more than other second-generation antipsychotics, and that paliperidone improved core

improved core symptoms more than other second-generation antipsychotics, and that paliperidone improved core 
illness symptoms more than lurasidone and iloperidone ( American Psychiatric Association Practice Guideline for the 
Treatment of Patients With Schizophrenia , September 2020).
Fun Fact:
Iloperidone was initially on track for FDA approval in 2002, but its approval was delayed to 2009 due to multiple 
company mergers and out-licensing deals as well as the FDA’s request for more data.

86  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONLOXAPINE  (Adasuve, Loxitane) Fact Sheet [G]
Loxapine is being rediscovered as a well-tolerated first-generation antipsychotic—it is of medium potency, and causes 
minimal EPS or weight gain. An oldy-but-goody alternative to second-generation antipsychotics.
Schizophrenia; acute agitation associated with schizophrenia or acute bipolar mania.
 ⦁Capsules (G):  5 mg, 10 mg, 25 mg, 50 mg.
 ⦁Single-use disposable inhaler (Adasuve),  for acute agitation: 10 mg as inhalation powder.
 ⦁Schizophrenia: Start 10 mg BID; ↑ by 10 mg/day increments weekly and adjust to lowest effective dose. Dose range 
60–100 mg divided BID–TID; max FDA-approved dose is 250 mg/day, but doses >100 mg/day rarely used.

 ⦁Acute agitation (oral inhalation): Give one puff every 24 hours as needed (must be given by health care professional).
Cost:  Capsule: $; inhalation: $$$
galactorrhea), throat irritation (Adasuve).
 ⦁Metabolized primarily by CYP2D6 and CYP3A4; t ½: 4–8 hours.
 ⦁Caution with inhibitors of CYP2D6 and CYP3A4 and inducers of CYP3A4; adjust dose.
 ⦁Loxapine is an intermediate-potency first-generation antipsychotic; this leads to less EPS compared to high-potency

 ⦁Loxapine is an intermediate-potency first-generation antipsychotic; this leads to less EPS compared to high-potency 
agents (eg, haloperidol, fluphenazine) and to less sedation, less orthostasis, and fewer anticholinergic side effects 
compared to low-potency agents (eg, chlorpromazine).
 ⦁Loxapine belongs to the dibenzoxazepine class of antipsychotics and is structurally related to clozapine (which 
belongs to the chemically akin class of dibenzodiazepines). Some have argued that loxapine may behave as a 
second-generation antipsychotic.
 ⦁The newer Adasuve oral inhalation version has the advantage of treating agitation quickly without the need for 
swallowing or a shot. But the risks of bronchospasm and respiratory arrest, along with the contraindication in 
patients with asthma, COPD, or other lung disease, make this formulation rather unappealing overall.
Fun Fact:
Loxapine is metabolized to the tetracyclic antidepressant amoxapine.

AntipsychoticsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   87LUMATEPERONE  (Caplyta) Fact Sheet
Lumateperone is the newest second-generation antipsychotic, approved to treat adults with schizophrenia or bipolar 
disorder. It appears to have a good tolerability profile and the convenience of once-daily dosing and no titration. But 
for now, cost relegates it to second-line use. 
Schizophrenia; bipolar I or II depression.
Unipolar depression.
Capsules:  10.5 mg, 21 mg, 42 mg.
Start, target, and max dose of 42 mg QD with food; no titration needed.
 ⦁Most common: Somnolence, sedation, dry mouth, nausea, dizziness.

 ⦁Metabolized primarily by UGT 1A1, 1A4, 2B15 and CYP3A4, CYP2C8, CYP1A2; t ½: 18 hours.
 ⦁Avoid use with potent inhibitors and inducers of CYP3A4.
 ⦁Lumateperone may be better tolerated if taken at dinner due to sedating effects. 
 ⦁New indication for depression associated with bipolar I and bipolar II followed original schizophrenia indication. It is 
also currently being studied for unipolar depression with mixed features. 
 ⦁Lower affinity at D2 receptors means relatively lower risk for EPS. 
 ⦁In studies to date, lumateperone appears to have low levels of akathisia, weight gain, metabolic side effects, and 
prolactin elevation.

⦁In studies to date, lumateperone appears to have low levels of akathisia, weight gain, metabolic side effects, and 
prolactin elevation. 
 ⦁New lower dose capsules to be used for patients with moderate or severe hepatic impairment or those taking 
potent CYP3A4 inhibitors.
 ⦁A long-acting injectable of lumateperone is currently in development. 
Fun Fact:
This antipsychotic was expected to be approved a couple of years earlier, but a Phase 3 study in 2016 in nearly 700 
patients showed no difference from placebo at both 20 mg and 60 mg. This may have been a “failed trial” with a high 
placebo response rate, and risperidone also failed to separate from placebo in this study.

88  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONLURASIDONE  (Latuda) Fact Sheet
Lurasidone offers some advantages, including no need for titration, once-daily dosing, relatively low-moderate 
metabolic profile, and relatively low QTc prolongation risk. It is also one of three antipsychotics approved for bipolar 
depression (along with cariprazine and quetiapine). However, its use is limited by the need to administer with at least 
350 calories of food, potential for drug interactions, and side effects including sedation, akathisia, and EPS. In clinical 
practice, you might lump lurasidone with the other second-generation antipsychotics that cause little weight gain, 
such as aripiprazole and ziprasidone.
Schizophrenia  (adults, adolescents 13–17); bipolar I depression  (as monotherapy and adjunct; adults, children 10–17).
Mixed depression; treatment-resistant depression; impulse control disorders.

Tablets:  20 mg, 40 mg, 60 mg, 80 mg, 120 mg.
 ⦁Schizophrenia (adolescents and adults): Start 40 mg QD, with food (at least 350 calories); no titration required. Usual 
dose 40–120 mg/day. Max dose 160 mg QD (80 mg/day for adolescents).
 ⦁Bipolar depression (adults and children): Start 20 mg QD, with food (at least 350 calories); no titration required. 
Usual dose 20–120 mg/day (20–40 mg/day in kids). Max dose 120 mg QD (80 mg/day in kids), although doses >80 
mg/day rarely more effective.
 ⦁Most common: Sedation (dose-related), akathisia (dose-related), nausea, parkinsonism, agitation.
 ⦁Serious but rare: Orthostatic hypotension and syncope reported (rarely).

⦁Serious but rare: Orthostatic hypotension and syncope reported (rarely).
 ⦁Dopamine D2 and serotonin 5-HT2A and 5-HT7 antagonist; serotonin 5-HT1A partial agonist.
 ⦁Metabolized primarily through CYP3A4; t ½: 18 hours.
 ⦁Avoid use with medications that cause orthostasis, potent CYP3A4 inhibitors (eg, ketoconazole, clarithromycin), or 
inducers (eg, rifampin, St. John’s wort, carbamazepine). Exercise caution/monitor when using in combination with 
moderate 3A4 inhibitors (eg, diltiazem); decrease lurasidone dose by 50% in patients taking moderate CYP3A4 
inhibitors.
 ⦁Administration with food (at least 350 calories) increases bioavailability two-fold and peak serum levels roughly 
three-fold; fat content of meal is not important.
 ⦁Appears to be relatively weight-neutral, and cardiometabolic parameters were little affected in company-

sponsored trials, although post-marketing observations have been limited. In kids, weight gain was a common 
side effect in studies. 
 ⦁A network meta-analysis of 10 RCTs with 3,336 adults with schizophrenia found that 40 mg, 80 mg, 120 mg, and 160 
mg of lurasidone were effective but not 20 mg. The 160 mg dose was best for PANSS score reduction. Side effects, 
especially sedation and EPS, increased as dose went up. A good target may be 80 mg, which produced efficacy in 
50% of patients. If patients still symptomatic but tolerating, increase to 120–160 mg. 
 ⦁While using lurasidone in bipolar depression has not been associated with increase in the development of mania, its 
efficacy in treating manic episodes has not been established, so its use should be reserved for depressive episodes.
Fun Fact:

Fun Fact:
One unique feature of Latuda is its high affinity for the 5-HT7 receptor, which has been linked to depression, learning/
memory, cognition, anxiety, and pain. Unfortunately, to date, Latuda has shown no clear benefit over other second-
generation antipsychotics on these measures.

AntipsychoticsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   89MOLINDONE  (Moban) Fact Sheet [G]
Molindone is an effective, well-tolerated first-generation antipsychotic of medium potency—a solid medication that 
some clinicians have gained experience with and favor for select patients. Recently it has been reintroduced into the 
market, and is still generic and inexpensive.
Tablets (G):  5 mg, 10 mg, 25 mg.
Start 50–75 mg/day divided BID–QID; ↑ to 100 mg/day in three or four days. Max dose 225 mg/day divided TID–QID.
Cost:  $$$$
 ⦁Most common: Sedation (dose-related), EPS, agitation.
 ⦁Serious but rare: Rare reports of leukopenia and leukocytosis.

Cost:  $$$$
 ⦁Dopamine D2 antagonist.
 ⦁Metabolized primarily through CYP2D6; t ½: 1.5 hours.
 ⦁Molindone is an intermediate-potency first-generation antipsychotic; this leads to less EPS compared to high-
potency agents (eg, haloperidol, fluphenazine) and to less sedation, less orthostasis, and fewer anticholinergic side 
effects compared to low-potency agents (eg, chlorpromazine).
 ⦁Unlike most antipsychotics, molindone has been shown to reduce weight in some patients.
Fun Fact:
In 2010, the only manufacturer of molindone in the US (as brand Moban), Endo Pharmaceuticals, announced that they 
would be discontinuing production because of poor sales. In December 2015, Core Pharma launched a new generic 
version, bringing molindone back to life.

90  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONOLANZAPINE  (Lybalvi, Symbyax, Zyprexa) Fact Sheet [G]
Bottom Lin e:
Many consider olanzapine to be more effective than other antipsychotics and just below clozapine in effectiveness. 
Its high efficacy along with its once-daily dosing and low risk of QT interval prolongation are appealing. However, 
olanzapine’s high risk for weight gain and metabolic complications make it a second-line choice for many. The newly 
approved Lybalvi combines olanzapine with samidorphan to minimize weight gain—but it’s only moderately successful.  
Schizophrenia (adults and children ≥13 years); acute or mixed  bipolar  I manic episodes, as monotherapy or adjunct 
(adults and children ≥13 years); maintenance treatment of bipolar disorder ; bipolar I depression  (with fluoxetine, 
sold as Symbyax, adults and children ≥10 years); treatment-resistant unipolar depression  (with fluoxetine); acute

sold as Symbyax, adults and children ≥10 years); treatment-resistant unipolar depression  (with fluoxetine); acute 
agitation  in schizophrenia and bipolar mania (injectable form).
Behavioral disturbances; impulse control disorders; reduce weight gain in patients on olanzapine (as Lybalvi).
 ⦁Tablets (G):  2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg.
 ⦁Orally disintegrating tablets (Zyprexa Zydis, [G]):  5 mg, 10 mg, 15 mg, 20 mg.
 ⦁IM injection (G):  10 mg.
 ⦁Long-acting injection (Zyprexa Relprevv):  210 mg, 300 mg, 405 mg (see LAI fact sheet and table).
 ⦁Fixed-combination capsules with fluoxetine (Symbyax, [G]):  3/25 mg, 6/25 mg, 12/25 mg, 6/50 mg, 12/50 mg 
olanzapine/fluoxetine.
 ⦁Fixed-combination tablets with samidorphan (Lybalvi):  5/10 mg, 10/10 mg, 15/10 mg, 20/10 mg olanzapine/
samidorphan. 
 ⦁Schizophrenia, bipolar disorder, depression (adults): Start most patients at 5–10 mg QD; may ↑ by 5 mg QD, in

 ⦁Schizophrenia, bipolar disorder, depression (adults): Start most patients at 5–10 mg QD; may ↑ by 5 mg QD, in 
weekly increments, to target dose 10–20 mg QD.
 ⦁Acute mania (adults): Start 10–15 mg QD; may ↑ by 5 mg daily, in 24-hour increments, to target dose 10–20 mg QD.
 ⦁Max approved dose: 20 mg/day, although doses 30–50 mg/day have been used.
 ⦁For Lybalvi: Dose as above, using Lybalvi dose with equivalent olanzapine component. Do not divide or combine 
Lybalvi strengths. 
 ⦁Bipolar depression (Symbyax, adults): Start 6/25 mg QPM, ↑ as indicated to target dose 6–12/25–50 mg olanzapine/
fluoxetine.
 ⦁IM for agitation: Usual dose of 2.5–10 mg IM; maximum dose of 30 mg/day. Avoid concomitant use with IM 
benzodiazepines because of potential for excessive sedation and cardiorespiratory depression. 
Cost:  $; combination with fluoxetine: $$; Lybalvi: $$$$$ 

 ⦁Most common: Somnolence (dose related), dry mouth (dose related), constipation, weight gain (up to 40% 
incidence; may be substantial; 10–30 pounds weight gain is common), increased appetite, EPS (dose related).
 ⦁Serious but rare: Rare but potentially fatal drug reaction with eosinophilia and systemic symptoms (DRESS) possible; 
often starts as rash that may spread, fever, swollen lymph nodes, and elevated eosinophils.
 ⦁Metabolized primarily by CYP1A2, also CYP2D6 (minor), and direct glucuronidation; t ½: 1–2 days.
 ⦁CYP1A2 inducers (eg, carbamazepine, ritonavir, smoking) may reduce olanzapine levels by 50%; CYP1A2 inhibitors 
(eg, fluvoxamine) may increase olanzapine bioavailability by 50%–100%. Adjust olanzapine dosing in presence of 
1A2 inducers or inhibitors.

 ⦁Use in children and adolescents may result in increased weight gain and sedation, as well as greater increases in LDL 
cholesterol, total cholesterol, triglycerides, prolactin, and liver transaminase levels when compared to adults.
 ⦁Newly approved combination with opioid antagonist samidorphan reduces risk of weight gain, but patients are 
still at moderate risk. In a 24-week study, 17.8% experienced ≥10% weight gain (vs 29.8% on olanzapine alone) and 
27.5% experienced ≥7% weight gain (vs 42.7% on olanzapine alone). 
 ⦁Avoid using samidorphan combination product in patients taking opioids who may experience withdrawal effects 
or inadvertently take a high dose of opioid in order to overcome samidorphan’s opioid receptor blockade, leading 
to increased risk for overdose.
Fun Fact:

Fun Fact:
Olanzapi ne has been studied and is used for chemotherapy-induced nausea and vomiting.

AntipsychoticsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   91PALIPERIDONE  (Invega) Fact Sheet [G]
Paliperidone is the active metabolite of risperidone. In comparison with its parent compound, paliperidone has 
the advantages of no drug-drug interactions, an easy transition to several long-acting injectable formulations, and 
a unique FDA indication for schizoaffective disorder. Disadvantages include more QT interval prolongation than 
risperidone, more tachycardia, possibly more EPS, and the same amount of hyperprolactinemia. 
Schizophrenia in adults and children ≥12 years; schizoaffective disorder.
Dosage Forms (see LAI fact sheet and table for long-acting injections):
 ⦁Controlled-release tablets (G):  1.5 mg, 3 mg, 6 mg, 9 mg (not breakable).
 ⦁Monthly long-acting injection (Invega Sustenna):  39 mg, 78 mg, 117 mg, 156 mg, 234 mg.

⦁Controlled-release tablets (G):  1.5 mg, 3 mg, 6 mg, 9 mg (not breakable).
 ⦁Every-three-month long-acting injection (Invega Trinza):  273 mg, 410 mg, 546 mg, 819 mg.
 ⦁Every-six-month long-acting injection (Invega Hafyera):  1,092 mg, 1,560 mg.
 ⦁Schizophrenia/schizoaffective disorder (adults): Start 6 mg QAM, which may be the effective dose; if required, may ↑ 
by 3 mg/day at intervals of greater than five days to max 12 mg/day.
 ⦁Schizophrenia (adolescents): Start 3 mg QAM, ↑ by 3 mg/day at intervals of >5 days to max 6 mg/day (<51 kg) or 12 
mg/day (≥51 kg).
 ⦁Paliperidone 3 mg, 6 mg, 9 mg, and 12 mg roughly equivalent to 1–2 mg, 2–4 mg, 4–6 mg, and 6–8 mg risperidone, 
 ⦁Dose timing: The manufacturer recommends taking it in the morning; however, some patients experience 
drowsiness and should try nighttime dosing.

drowsiness and should try nighttime dosing. 
Monitoring:  Fasting glucose, lipids; prolactin if symptoms.
Cost:  $$$
 ⦁Most common: Akathisia, EPS (dose-related), tremor, tachycardia, insomnia, somnolence (especially adolescents), 
weight gain, orthostatic hypotension, headache, prolactin elevation.
 ⦁Serious but rare: Modest increase in QTc interval. Orthostatic hypotension and syncope reported. Rarely, controlled-
release tablet may get caught in GI tract and cause obstructive symptoms in patients with known strictures; avoid 
use in patients with severe, preexisting GI narrowing (either pathologic or iatrogenic). Esophageal dysmotility and 
aspiration possible; use caution in patients at risk for aspiration pneumonia (eg, those with advanced Alzheimer’s 
dementia).

 ⦁Not metabolized by liver; t ½: 23 hours.
 ⦁Avoid use with drugs known to prolong the QTc interval or to cause orthostasis. Paliperidone is the principal active 
metabolite of risperidone; therefore, avoid use with risperidone. Minimal drug interactions.
 ⦁Warn your patients that they may find what looks like intact capsules in their stool. These are actually empty 
“ghost pills. ” They appear because Invega is an extended-release tablet based on the OROS osmotic delivery 
system (as is Concerta; see fact sheet in ADHD chapter). Water from the GI tract enters through a semipermeable 
membrane coating the tablet, causing the drug to be expelled through laser-drilled holes in the coating. The shell is

membrane coating the tablet, causing the drug to be expelled through laser-drilled holes in the coating. The shell is 
nonabsorbable and will be expelled in the stool, but the drug itself is absorbed.
 ⦁Swallow whole, with fluids; do not chew, divide, or crush.
 ⦁Adjust dose in patients with renal impairment. 
 ⦁Studies suggest paliperidone is not highly effective in acute mania, either as monotherapy or in combination with 
lithium or valproate.
 ⦁Along with risperidone, causes the most EPS and hyperprolactinemia of all the second-generation antipsychotics.
Fun Fact:
First drug with FDA approval for schizoaffective disorder, allowing Janssen to carve out a marketing niche and 
separate this drug from its competitors (at least from a commercial and marketing perspective).

92  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONPERPHENAZINE  (Trilafon) Fact Sheet [G]
Perphenazine, first introduced in 1957, is an older first-generation agent that enjoyed a big boost in popularity 
after the 2005 CATIE trial found it to be as effective as most second-generation agents with minimal weight gain or 
metabolic problems. It has become a favorite go-to antipsychotic for many clinicians—an effective, well-tolerated, 
and inexpensive alternative to second-generation antipsychotics.
Schizophrenia  (children ≥12 years); severe nausea and vomiting.
Tablets (G):  2 mg, 4 mg, 8 mg, 16 mg.
 ⦁Schizophrenia: Start 4–8 mg TID (8–16 mg BID–QID for hospitalized patients); adjust to lowest effective dose. Dose

 ⦁Schizophrenia: Start 4–8 mg TID (8–16 mg BID–QID for hospitalized patients); adjust to lowest effective dose. Dose 
range 8–16 mg BID–QID; max FDA-approved dose for non-hospitalized patients is 24 mg/day, but hospitalized 
psychotic patients may be dosed up to 64 mg/day.
 ⦁Dose timing: Most patients take perphenazine BID, and the usual strategy is to give a larger amount at night due to 
sedation. If needed, you can dose it all at HS. 
Cost:  $
 ⦁Serious but rare: Tachycardia (especially with sudden marked increase in dose).

 ⦁Metabolized primarily by CYP2D6; t ½: 9–12 hours. May inhibit CYP2D6. Poor metabolizers of CYP2D6 metabolize 
the drug more slowly; may have increased effects.
 ⦁CYP2D6 inhibitors (eg, fluoxetine, paroxetine, quinidine) may increase perphenazine levels. Caution with substrates 
of 2D6 as perphenazine may increase their levels and effects.
 ⦁Perphenazine is an intermediate-potency first-generation antipsychotic; this leads to less EPS compared to high-
 ⦁Fewer metabolic effects (weight gain, glucose, lipids) than some antipsychotics.

 ⦁Based on an 18-month randomized trial of 1,493 patients with schizophrenia (CATIE trial), perphenazine appears 
similar in efficacy and EPS compared to second-generation antipsychotics (olanzapine, quetiapine, risperidone, 
ziprasidone).
Fun Fact:
Perphenazine has long been available in a formulation with amitriptyline (a tricyclic antidepressant) called Triavil. This 
combination antipsychotic/antidepressant was first available in 1965, foreshadowing the next such combination drug 
(Symbyax) by 38 years.

AntipsychoticsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   93PIMAVANSERIN  (Nuplazid) Fact Sheet
Pimavanserin is the only antipsychotic with virtually no effect on dopamine receptors. It is the only approved 
medication for psychosis in Parkinson’s disease, but we do not yet know if it has any efficacy advantages over 
quetiapine, which has generally been the go-to antipsychotic for this syndrome. Its lack of weight gain is a side effect 
advantage, but there are some concerns about increases in hospitalization and higher mortality in patients with 
Parkinson’s disease psychosis. 
Hallucinations and delusions  associated with Parkinson’s disease psychosis.
Depression.
 ⦁Tablets:  10 mg.
 ⦁Capsules:  34 mg.
Start and continue with 34 mg once daily (no titration). Use 10 mg tablet in patients taking concurrent CYP3A4 

⦁Capsules:  34 mg.
 ⦁Most common: Nausea, peripheral edema, confusion.
 ⦁Serious but rare: QT prolongation (dose related; mean prolongation of 5–8 msec at usual dose); class warning 
regarding increased mortality in elderly.
 ⦁Second-generation antipsychotic with combination of inverse agonist and antagonist activity at 5-HT2A and, less so, 
at 5-HT2C receptors.
 ⦁Metabolized by CYP3A4 and CYP3A5; t ½: 57 hours (200 hours for active metabolite).
 ⦁Caution with potent inhibitors or inducers of CYP3A4 (adjust dose per above). Avoid use with other medications 
that may increase QT interval.
 ⦁FDA approval based on a six-week placebo-controlled outpatient study of 185 patients that showed only modest

 ⦁FDA approval based on a six-week placebo-controlled outpatient study of 185 patients that showed only modest 
(but statistically significant) improvement in hallucinations and delusions compared to placebo.
 ⦁The study didn’t find any difference (improvement or worsening) in motor function between those who received 
Nuplazid or placebo.
 ⦁All in all, though, pimavanserin did not show statistically significant benefit in three out of four pre-approval clinical 
studies. 
 ⦁Reports of post-marketing deaths in patients who had taken Nuplazid have sparked investigation and controversy, 
though we still don’t know if it’s any more dangerous than clozapine or quetiapine use in Parkinson’s. 
 ⦁Preliminary data have shown antidepressant efficacy when pimavanserin is added to an SSRI or SNRI in patients with 
inadequate response. 
Fun Fact:

⦁Preliminary data have shown antidepressant efficacy when pimavanserin is added to an SSRI or SNRI in patients with 
Fun Fact:
The FDA rejected an indication bid for dementia-related psychosis due to lack of significantly meaningful effect in 
some subgroups of patients.

94  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONQUETIAPINE  (Seroquel, Seroquel XR) Fact Sheet [G]
Quetiapine’s low risk for EPS and broad spectrum of efficacy make it an appealing first-choice agent. However, 
sedation, weight gain, and orthostasis may limit use. Dosing at bedtime, or switching to XR, may help reduce daytime 
sedation.
Schizophrenia (adults and children ≥13 years); bipolar,  manic/mixed (adults and children ≥10 years); bipolar I or II 
depression;  maintenance treatment for bipolar;  major depression,  as adjunct.
Insomnia; anxiety disorders; behavioral disturbances; impulse control disorders.
 ⦁Tablets (G):  25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg.
 ⦁XR tablets (G):  50 mg, 150 mg, 200 mg, 300 mg, 400 mg.
 ⦁Schizophrenia (adults): Start 25 mg BID or 300 mg XR QHS. Target dose: 400–800 mg/day.

⦁XR tablets (G):  50 mg, 150 mg, 200 mg, 300 mg, 400 mg.
 ⦁Bipolar (adults): Start 50 mg BID or 300 mg XR QHS. Target dose: 400–800 mg/day (mania, maintenance), 300 mg/
day (depression).
 ⦁Adolescents: Start 25 mg BID or 50 mg XR QHS, increase to 100 mg/day (IR divided BID, XR taken QHS) on day two, 
then increase by 100 mg/day daily to target dose 400–600 mg/day (mania) or 400–600 mg/day (schizophrenia).
 ⦁Depression: Start 50 mg IR/XR QHS. Target dose: 150–300 mg/day.
 ⦁For all indications: May ↑ dose by 50–100 mg/day increments, given in divided doses, every one to four days (or as 
much as 300 mg/day XR increments in intervals of greater than one day) to target dose.
 ⦁Max daily dose in adults: 800 mg/day.
 ⦁Consider dosing slower and lower in pediatric, elderly, or debilitated patients.

⦁Max daily dose in adults: 800 mg/day.
 ⦁Dose timing: Usually dosed at bedtime due to sedation, but the XR formulation has been shown to be less sedating 
than IR and is often tolerated with morning dosing. 
Cost:  $
 ⦁Most common: Somnolence, hypotension, dry mouth, dizziness, constipation, weight gain, fatigue.
 ⦁Serious but rare: Orthostatic hypotension, particularly at high dose or with rapid titration.
 ⦁Metabolized by CYP3A4; t ½: 6 hours (XR: 7 hours).
 ⦁Avoid or use caution with agents that may cause additional orthostasis. CYP3A4 inducers (eg, carbamazepine) may 
lower quetiapine levels; CYP3A4 inhibitors (eg, erythromycin, ketoconazole) may increase quetiapine levels. Adjust

lower quetiapine levels; CYP3A4 inhibitors (eg, erythromycin, ketoconazole) may increase quetiapine levels. Adjust 
quetiapine dose in presence of CYP3A4 inducers or inhibitors.
 ⦁Swallow XR tablet whole; do not break, crush, or chew; switch between IR and XR at the same total daily dose; dose 
adjustments may be necessary based on response and tolerability.
 ⦁If patient discontinues drug for more than one week, re-titrate dose as with initial therapy.
 ⦁Quetiapine abuse has been reported, particularly in incarcerated populations.
Fun Fact:
Cataracts developed in initial studies with beagle dogs; human studies have not shown an association. However, the 
label still recommends a slit-lamp exam every six months.

AntipsychoticsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   95RISPERIDONE  (Risperdal) Fact Sheet [G]
Tried and true, risperidone’s moderate side effect profile has led to its wide use, and many clinicians consider it their 
antipsychotic of choice for first-episode psychotic disorders. Just be cautious when dosing higher than 4 mg daily, 
since akathisia and other side effects are more common. Hyperprolactinemia is fairly common, so be vigilant for 
symptoms such as lowered libido, amenorrhea, gynecomastia, and galactorrhea. 
Schizophrenia  (adults and children ≥13 years); bipolar disorder,  manic/mixed  (adults and children ≥10 years); 
irritability symptoms of autism  (children ≥5 years).
Bipolar depression; behavioral disturbances; impulse control disorders; Tourette’s syndrome.

 ⦁Tablets (G):  0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg.
 ⦁Oral solution (G):  1 mg/mL.
 ⦁Orally disintegrating tablets (Risperdal M-Tab, [G]):  0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg.
 ⦁Long-acting IM injection (Risperdal Consta):  12.5 mg, 25 mg, 37.5 mg, 50 mg.
 ⦁Long-acting SQ injection (Perseris):  90 mg, 120 mg.
 ⦁Schizophrenia, bipolar (adults): Start 1 mg BID; may ↑ by 1–2 mg/day at intervals ≥24 hours to a recommended 
dosage range of 4–6 mg/day; may be given as a single daily dose once maintenance dose achieved. Max approved 
dose is 16 mg/day, but daily dosages >6 mg provide no additional benefit, only higher risk for EPS, which is dose 
dependent.
 ⦁Children, elderly, first-episode psychosis: Lower initial dosages (eg, 0.5–1 mg daily) and slower titration to initial

 ⦁Children, elderly, first-episode psychosis: Lower initial dosages (eg, 0.5–1 mg daily) and slower titration to initial 
target dose of 2 mg daily.
 ⦁Autism (children ≥5 years): If <15 kg (33 lbs), use with caution. For 15–20 kg (33–44 lbs), start 0.25 mg/day, ↑ to 0.5 
mg/day after at least four days. If response insufficient, may ↑ by 0.25 mg/day in at least two-week intervals; give QD 
or BID. For ≥20 kg (44 lbs), start 0.5 mg/day; may ↑ to 1 mg/day after at least four days. If response insufficient, may 
↑ dose by 0.5 mg/day in at least two-week intervals; give QD or BID.
 ⦁Bipolar mania or schizophrenia (children): Start 0.5 mg QD; ↑ in increments of 0.5–1 mg/day at intervals ≥24 hours 
to target dose of 2–3 mg/day; doses >3 mg/day do not confer additional benefit and are associated with increased 
side effects.
 ⦁Dose timing: Usually well tolerated whether taken in the morning or night. 
Cost:  $

Cost:  $
 ⦁Most common: EPS, somnolence (particularly in children), anxiety, constipation, nausea, dyspepsia, dizziness, 
rhinitis, prolactin elevation, weight gain.
 ⦁Serious but rare: Orthostatic hypotension may occur, particularly at higher doses or with rapid titration. 
Hyperprolactinemia with clinical symptoms (sexual side effects, galactorrhea, amenorrhea).
 ⦁Metabolized primarily by CYP2D6; t ½: 20 hours.
 ⦁CYP2D6 inhibitors (eg, fluoxetine, paroxetine, quinidine) may increase effects of risperidone; reduce risperidone 
dose. Carbamazepine reduces levels and effects of risperidone; may need to double risperidone dose.

 ⦁Along with paliperidone, causes the most EPS and hyperprolactinemia of all the second-generation antipsychotics.
 ⦁When reinitiating after discontinuation, initial titration schedule should be followed.
 ⦁An ultra-long-acting extended-release weekly oral formulation of risperidone is in development to help address 
medication non-adherence in roughly 50% of patients with schizophrenia, without a needle. 
Fun Fact:
Risperdal M-Tabs are marketed in other countries as Risperdal Quicklets.

96  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONTHIORIDAZINE  (Mellaril) Fact Sheet [G]
Thioridazine prolongs the cardiac QT interval more than any other antipsychotic, rendering it too risky to use for the 
majority of patients.
Schizophrenia  (not for first-line use).
Anxiety, insomnia.
Tablets (G):  10 mg, 25 mg, 50 mg, 100 mg.
Start 50–100 mg TID; ↑ by 50–100 mg/day increments every three to seven days and adjust to lowest effective dose. 
Dose range 200–800 mg/day divided BID–QID; max FDA-approved dose is 800 mg/day due to ocular pigmentation at 
high doses.
Cost:  $
 ⦁Most common: EPS, headache, sedation, drowsiness, dry mouth, constipation, blurred vision, dizziness, prolactin 

Cost:  $
 ⦁Serious but rare: QT prolongation and torsades de pointes (highest risk of all antipsychotics); ocular pigmentation 
and degenerative retinopathies.
 ⦁Metabolized primarily by CYP2D6; t ½: 24 hours. May inhibit CYP2D6. Poor metabolizers of CYP2D6 metabolize the 
drug more slowly; may have increased effects.
 ⦁CYP2D6 inhibitors (eg, fluoxetine, paroxetine, quinidine) may increase thioridazine levels. Caution with substrates of 
CYP2D6 as thioridazine may increase their levels and effects.
 ⦁Thioridazine is a low-potency first-generation antipsychotic; this leads to less EPS and to more sedation, orthostasis,

 ⦁Thioridazine is a low-potency first-generation antipsychotic; this leads to less EPS and to more sedation, orthostasis, 
and anticholinergic side effects compared to high-potency agents (eg, haloperidol, fluphenazine).
 ⦁Efficacy has not been studied in refractory schizophrenia, but thioridazine is indicated only for and should be 
reserved for use only in patients who have failed to respond to other medications. This is due to the significant risks 
associated with thioridazine, particularly QT prolongation.
Fun Fact:
Thioridazine can kill antibiotic-resistant bacteria such as Staphylococcus aureus  (including MRSA) and extensively 
drug-resistant Mycobacterium tuberculosis . Researchers are studying how thioridazine does this (latest studies show a 
weakening of bacterial cell walls) in order to develop drugs that can target resistant bacteria.

AntipsychoticsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   97THIOTHIXENE  (Navane) Fact Sheet [G]
Thiothixene is one of the original high-potency first-generation antipsychotics—but most clinicians would opt 
for haloperidol or fluphenazine because of their greater familiarity and range of formulation options (eg, liquid, 
injectable, long-acting).
Capsules (G):  1 mg, 2 mg, 5 mg, 10 mg.
Start 2 mg TID–5 mg BID; ↑ by 2–5 mg/day increments every three to seven days and adjust to lowest effective dose. 
Usual dose range 20–30 mg/day divided BID–TID; max FDA-approved dose is 60 mg/day, but doses >40 mg/day are 
rarely used.
Cost:  $

Cost:  $
 ⦁Metabolized primarily by CYP1A2; t ½: 34 hours.
 ⦁Smoking status may affect thiothixene metabolism as smoking is a potent CYP1A2 inducer; smokers may need 
higher doses.
Thiothixene is a high-potency first-generation antipsychotic; this leads to more EPS compared to mid- and low-
Fun Fact:

Fun Fact:
Pfizer developed thiothixene in the 1960s, and the drug was found to be an effective antidepressant, as well as an 
antipsychotic. For commercial reasons, the company chose to market it for schizophrenia rather than depression.

98  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONTRIFLUOPERAZINE  (Stelazine) Fact Sheet [G]
Trifluoperazine, like thiothixene (Navane), is an effective older agent with similar potency to haloperidol or 
fluphenazine; however, given all our antipsychotic options, it sees only rare use these days. 
Schizophrenia; nonpsychotic anxiety.
Tablets (G):  1 mg, 2 mg, 5 mg, 10 mg.
Schizophrenia: Start 1–2 mg BID; ↑ by 2–5 mg/day increments every three to seven days and adjust to lowest effective 
dose. Usual dose range 5–10 mg BID; max FDA-approved dose 40 mg/day.
Cost:  $

Cost:  $
 ⦁Metabolized primarily by CYP1A2; t ½: 18 hours.
 ⦁Smoking status may affect trifluoperazine metabolism as smoking is a potent CYP1A2 inducer; smokers may need 
 ⦁Trifluoperazine is a high-potency first-generation antipsychotic; this leads to more EPS compared to mid- and low-
 ⦁Trifluoperazine was FDA approved for nonpsychotic anxiety at doses of no more than 6 mg/day used for no more 
than 12 weeks, but it is no longer used for this indication.
Fun Fact:

⦁Trifluoperazine was FDA approved for nonpsychotic anxiety at doses of no more than 6 mg/day used for no more 
Fun Fact:
Stelazine was marketed with the tagline “Calm, but still alert. ”

AntipsychoticsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   99ZIPRASIDONE  (Geodon) Fact Sheet [G]
Ziprasidone has an appealing weight and metabolic profile, but many clinicians get scared off by its reputation for 
lengthening the QT interval. This risk is overblown, and it should probably be prescribed more. 
Schizophrenia; bipolar disorder,  acute treatment of manic/mixed episodes;  maintenance treatment of bipolar 
disorder as adjunct; acute agitation  in patients with schizophrenia (IM only).
 ⦁Capsules (G):  20 mg, 40 mg, 60 mg, 80 mg.
 ⦁Injection (G):  20 mg/mL.
 ⦁Schizophrenia, bipolar disorder: Start 20 mg BID (40 mg BID for acute mania) with meals for two to three days; ↑ by 
40 mg/day increments; can usually ↑ rather quickly to target dose 60–80 mg BID. Max approved dose is 160 mg/day,

40 mg/day increments; can usually ↑ rather quickly to target dose 60–80 mg BID. Max approved dose is 160 mg/day, 
though can go higher in some patients; there are some safety data for doses up to 320 mg/day.
 ⦁Schizophrenia, acute agitation (IM injection): 10 mg Q2 hours or 20 mg Q4 hours; max 40 mg/day. Replace with oral 
therapy as soon as possible.
Monitoring:  Fasting glucose, lipids; ECG if cardiac disease.
Cost:  $
 ⦁Most common: Somnolence, dizziness, akathisia, rash (5%).
 ⦁Serious but rare: May result in minor QTc prolongation (dose related; 10 msec at 160 mg/day). Clinically relevant 
prolongation (>500 msec) rare (0.06%) and less than placebo (0.23%). Avoid in patients with hypokalemia, 
hypomagnesemia, bradycardia, persistent QTc intervals >500 msec, or those receiving other drugs that prolong 
QTc interval. Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported with ziprasidone

QTc interval. Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported with ziprasidone 
exposure. DRESS begins as a rash that can spread all over the body; it may also include swollen lymph nodes, fever, 
and damage to organs such as the heart, liver, pancreas, or kidneys, and is sometimes fatal; discontinue ziprasidone 
if DRESS is suspected.
 ⦁Metabolized in liver principally by aldehyde oxidase; less than one-third of clearance mediated by CYP3A4 and 
CYP1A2; t ½: 7 hours.
 ⦁Avoid use with other drugs that prolong QTc interval.
 ⦁Administer twice daily, ideally with meals; ingestion of several hundred calories is necessary to increase absorption 
up to two-fold.
 ⦁Causes less weight gain than clozapine, olanzapine, quetiapine, or risperidone.

 ⦁Average increase in QTc is greater than any other second-generation antipsychotics, although not much more than 
for quetiapine. Post-marketing surveillance has shown one or two instances of torsades de pointes possibly related 
to ziprasidone use.
Fun Fact:
The brand name Geodon has been suggested to bring to mind the phrase “down (don) to earth (geo), ” referring to the 
goals of the medication.

100  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONLONG-ACTING INJECTABLE  (LAI ) ANTIPSYCHOTICS
INTRODUCTION: DO LAI s WORK?
These formulations used to be known as “depot” antipsychotics, but the newer term “long-acting injectables” (LAIs) 
helps to remove some of the stigma associated with their use.
The potential advantages of LAIs are numerous and include the following:
 ⦁LAIs ensure that otherwise non-adherent patients have robust serum levels of antipsychotics
 ⦁Serum levels are more consistent over time than they are with oral meds
 ⦁Both families and clinicians spend less time struggling with patients about medication adherence
 ⦁LAIs present a lower risk of overdose because you aren’t providing your patient with large quantities of pills
Studies attempting to demonstrate advantages of LAIs have been mixed. One large meta-analysis found no difference

Studies attempting to demonstrate advantages of LAIs have been mixed. One large meta-analysis found no difference 
between LAIs and oral meds in relapse rates, with the exception of first-generation LAIs in older studies (Kishimoto 
T et al, Schiz Bull  2014;40(1):192–213). But a meta-analysis of 25 naturalistic observational studies, involving 5,940 
patients, found that switching these patients to LAIs strongly decreased the number of hospitalizations (Kishimoto T 
et al, J Clin Psychiatry 2013;74(10):957–965).
The bottom line is that patients who do poorly on pills because of non-adherence are likely to do better on LAIs—if 
you can get them to agree to an injection.
DECIDING AMONG THE LAI s
General Notes on LAIs
 ⦁It’s best to choose an LAI version of an oral medication that your patient has already taken, so that you can be more 
confident about the agent’s effectiveness and tolerability.

⦁It’s best to choose an LAI version of an oral medication that your patient has already taken, so that you can be more 
 ⦁Insurance coverage still often dictates the choice of good old haloperidol decanoate. Even when a patient’s 
insurance supposedly covers newer agents, the patient co-pay may be prohibitive, whereas haloperidol decanoate 
is almost always an affordable option. 
 ⦁Paliperidone has become the go-to for many clinicians because of a number of factors, including the lack of 
required oral overlap and the availability of every-three-month (Trinza) and every-six-month (Hafyera) formulations. 
 ⦁Be patient. The full therapeutic effect of LAIs can take longer than orals—ie, several months. Don’t adjust the LAI 
dose prematurely.
 ⦁Consider oral overlap. LAIs differ in how quickly the full dose is absorbed. Many formulations say in their package

 ⦁Consider oral overlap. LAIs differ in how quickly the full dose is absorbed. Many formulations say in their package 
insert that no oral overlap is required, and you’ll see that guidance in our LAI table. This means that, at least 
theoretically, on the day of the injection your patient’s serum level of the medication will immediately approximate 
a therapeutic level. In other cases, such as haloperidol decanoate or risperidone Consta, serum levels will take days 
to ramp up, and you will need to temporarily supplement with an overlapping oral dose. In the real world, even in 
“no oral overlap” meds, some patients will need additional oral doses to prevent breakthrough psychosis. This is a 
matter of clinical judgment and experience.  
 ⦁Never  initiate an LAI on a patient who has a history of neuroleptic malignant syndrome (NMS) on any antipsychotic. 
That’s just asking for trouble.
LAI Options

⦁Never  initiate an LAI on a patient who has a history of neuroleptic malignant syndrome (NMS) on any antipsychotic. 
There’s a pretty comprehensive table on the following pages that reports, for each LAI, the FDA indication(s), 
medication names, costs, available strengths, dosing information,  and pharmacokinetics  (need for oral overlap 
and dosing interval). But here, we’ll give you a shorthand version of the most relevant clinical pearls:
First-generation antipsychotics
 ⦁Fluphenazine (Prolixin Decanoate)— Dosed every two to three weeks. Injections are painful. Cheap, but relatively 
high risk of EPS and TD. Oral overlap required.
 ⦁Haloperidol (Haldol Decanoate)— Dosed monthly. As cheap as Prolixin, and since it’s dosed less often and has 
more predictable pharmacokinetics, it’s generally the better choice between the first-generation LAI antipsychotics.

more predictable pharmacokinetics, it’s generally the better choice between the first-generation LAI antipsychotics. 
Oral overlap required, although some use a “loading dose” method (20 times oral dose, followed by 10–15 times

AntipsychoticsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   101oral dose in subsequent months) that requires no oral overlap (Ereshefsky L et al, Hosp Community Psychiatry  
1993;44(12):1155–1161).
Second-generation antipsychotics
 ⦁Aripiprazole (Abilify Maintena)— Dosed monthly. Comes in two strengths (300 and 400 mg). Oral overlap required 
for 14 days. Deltoid or gluteal injection. Expensive, but a good side effect profile.
 ⦁Aripiprazole lauroxil (Aristada)— Dosed monthly, every six weeks, or every two months. Comes in four strengths. 
Smallest dose (441 mg monthly) may be given deltoid or gluteal; other doses must be given gluteal. Dosing interval 
flexibility makes this formulation appealing, although oral overlap is required for 21 days. You can forgo the oral 
overlap if you give your patient a dose of Aristada Initio  675 mg plus 30 mg oral aripiprazole on the same day as

overlap if you give your patient a dose of Aristada Initio  675 mg plus 30 mg oral aripiprazole on the same day as 
your first dose of Aristada. First dose of Aristada may be delayed up to 10 days after Initio. Expensive, but a good 
side effect profile. 
 ⦁Olanzapine (Zyprexa Relprevv)— Dosed either every two weeks or monthly, depending on the dose needed. 
Comes in three doses. Gluteal injection only. No oral overlap. May be the worst choice among all LAIs for multiple 
reasons. High potential for weight gain. There’s a small risk of a post-injection delirium/sedation syndrome, 
occurring in less than 1% of patients, caused by accidental intravascular injection. For this reason, you have to give 
the injection at a registered health care facility where patients can be continuously monitored for at least three 
hours after the injection. Restricted use requires physician and facility registration, and additional paperwork with

hours after the injection. Restricted use requires physician and facility registration, and additional paperwork with 
Eli Lilly’s program. High cost, restriction of use, monitoring requirement, and risk of adverse outcome all limit use 
severely. Expensive. 
 ⦁Paliperidone palmitate, monthly (Invega Sustenna)— Monthly dosing. Comes in five doses. First two doses 
deltoid; subsequent doses may be deltoid or gluteal. No oral overlap. Less painful injection than risperidone Consta 
or olanzapine Relprevv. Expensive, but appealing features include no oral overlap and potential to transition to 
every-three-month and every-six-month formulations.
 ⦁Paliperidone palmitate, every three months (Invega Trinza)— Dosed every three months, but your patient must 
have done well on monthly injections of Sustenna for at least four months before switching to Trinza. Deltoid or 
gluteal injection. Must shake syringe vigorously for at least 15 seconds to ensure uniform suspension of long-acting

gluteal injection. Must shake syringe vigorously for at least 15 seconds to ensure uniform suspension of long-acting 
particles and prevent clogging in needle. Expensive. 
 ⦁Paliperidone palmitate, every six months (Invega Hafyera)— Dosed every six months, but your patient must 
have done well on monthly injections of Sustenna for at least four months or on Trinza for at least one three-month 
cycle. Gluteal injection. Switching from lower doses of Sustenna (39, 78, 117 mg) or Trinza (273, 410 mg) was not 
studied so not recommended. Must shake syringe vigorously for at least 30 seconds to ensure uniform suspension 
and prevent clogging in needle. Expensive.
 ⦁Risperidone (Risperdal Consta) —Dosed every two weeks. Comes in four doses. Deltoid or gluteal injection. A 
three-week oral overlap and the need for a refrigerated solution make this LAI more cumbersome to use than 
some of its competitors. Painful injection. Must shake for at least 10 seconds to ensure uniform suspension of

some of its competitors. Painful injection. Must shake for at least 10 seconds to ensure uniform suspension of 
microspheres. Expensive.
 ⦁Risperidone (Perseris)— Monthly dosing option for risperidone, an improvement over the every-two-week dosing 
of Consta. Comes in two doses. No oral overlap. It’s the first LAI to be dosed subcutaneously (into the abdomen) 
rather than a deep and more painful IM injection. Note that the highest dose of Perseris is equivalent to 4 mg/day of 
oral risperidone, so this isn’t a good option for patients on higher doses. Expensive.
General Notes on Administration of LAIs
(Note: While it’s rare for prescribing clinicians to administer LAI injections, it may be useful for you to know what both 
nurses and patients have to be aware of when it comes time for your patients to actually get their shots!)
 ⦁Most LAIs are administered by deep IM injection (the exception is risperidone Perseris, which is administered

⦁Most LAIs are administered by deep IM injection (the exception is risperidone Perseris, which is administered 
subcutaneously). To ensure medication is delivered effectively into deep muscle and not subcutaneous fatty tissue 
(which would delay absorption significantly), administer to the ventrogluteal muscle (of the hip). This muscle is 
easily located and relatively free of major blood vessels and nerves. 
 ⦁Z-track technique should be used when administering fluphenazine or haloperidol decanoate to gluteal muscle. 
To do this, stretch and displace the skin by pulling it laterally away from the intended point of injection. Insert the 
needle into the site at a 90-degree angle; aspirate by pulling back on the plunger for five seconds, allowing time for 
any blood to travel from a penetrated vessel up the bore of the needle. If blood is aspirated, withdraw the needle 
and seal the wound; repeat at another site with new needle. If no blood is aspirated, give the injection, wait 10

and seal the wound; repeat at another site with new needle. If no blood is aspirated, give the injection, wait 10 
seconds, and then withdraw the needle and release the skin, allowing the displaced tissue to seal the needle track.

102  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONYou can use the Z-track technique with other agents also to ensure deep IM administration and minimize or prevent 
drug leakage.
 ⦁In general, women tend to have more fatty tissue in the gluteal area, especially in the dorsogluteal muscle, and this 
should be considered when choosing needle length. Longer needles should also be used in obese patients. When 
medication is delivered into fatty tissue inadvertently, the patient is at increased risk for granuloma, sterile abscess, 
redness and swelling, ulceration, or fat necrosis.
 ⦁Maximum recommended volume to be administered:
 –Gluteal: 3 mL
 –Deltoid: 2 mL
 ⦁Aspiration to ensure needle tip has not accidentally punctured a blood vessel is generally good practice. However, it 
is not possible with prefilled syringe formulations of Abilify Maintena, Aristada, or Aristada Initio due to the syringe 
design.

design.
 ⦁Administer dose immediately after suspending and/or shaking to avoid settling or needle occlusion. See product 
information for specific details on preparation and administration.
 ⦁Do not massage the injection site  (and advise patients not to massage the site) because this can promote 
dispersal into fatty tissue.

AntipsychoticsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   103Table 12:  Long-Acting Injectable Antipsychotics
Year FDA Approved 
Indication(s)Available 
StrengthsOral Overlap Dosing Interval Initial Dosing Maintenance Dose*Cost for Monthly 
Supply at 
Average Dose
(November 2021)
First-Generation Antipsychotics
decanoate [G]
(Prolixin 
1972Schizophrenia 25 mg/mL Continue total oral 
dose for 2–3 days, then 
↓ by 50% increments 
every 2–3 days until 
discontinued (by next 
injection)2-3 weeks 1.25× total daily oral dose Q2–3 
weeks (eg, 10 mg/day oral ~ 12.5 
mg IM Q2–3 weeks)Increase in increments of 12.5 mg; 
do not exceed 100 mg per dose; 
usual dose 6.25–25 mg Q2–3 
weeks$ [G]
(Haldol Decanoate)
1986Schizophrenia 50 mg/mL and 
100 mg/mL Decrease oral dose by 
50% after first injection, 
then discontinue after

weeks$ [G]
then discontinue after 
second injection (third 
for some patients);  
alternatively, no oral 
overlap if loading dose of 
20× oral given4 weeks 10–15× total oral daily dose (eg, 
10 mg/day oral ~ 100–150 mg 
IM). Alternatively, 20× total oral 
daily dose if loading dose with no 
oral overlap (eg, 10 mg/day oral ~ 
200 mg IM). 
First dose should be ≤100 mg; 
if higher dose needed, give 
remainder in 1–2 weeks.Continue 10–15× total oral daily 
dose Q4 weeks with either method 
(eg, 10 mg/day ~ 100–150 mg IM 
Q4 weeks)$ [G]
$$$$ Haldol Dec
Second-Generation Antipsychotics
(Abilify Maintena) 
2013Schizophrenia
Bipolar disorder 300 mg and 400 
mg vials and 
prefilled syringesFor 14 days 4 weeks 400 mg Q4 weeks 400 mg Q4 weeks; decrease to 
300 mg Q4 weeks if side effects 
(estimated equivalence is 20 mg/

day oral ~ 300 mg IM monthly 
and 30 mg/day oral ~ 400 mg IM 
monthly)$$$$$
Aripiprazole lauroxil 
(Aristada)
2015Schizophrenia 441, 662, 882, 
1064 mgFor 21 days Monthly, every 
6 weeks, or every 
2 months441, 662, or 882 mg monthly 
(equivalent to 10, 15, and 20 mg/
day); or 882 mg every 6 weeks 
(15 mg/day); or 1064 mg every 2 
months (15 mg/day)Continue initial dosing or adjust 
based on clinical response$$$$$
Aripiprazole lauroxil
(Aristada Initio)
2018Schizophrenia 675 mg syringes Aripiprazole 30 mg PO 
×1 doseSee Aristada 
aboveTo be given as single initial dose, 
in conjunction with Aristada as 
above (on same day or within 10 
days of Initio)See above $$$$$
1Brand discontinued; available as generic only

*Reducing the dosing interval may be preferable to dosage increase for patients who lose some efficacy prior to next scheduled dose

104  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONGeneric Name 
Supply at 
Olanzapine 
2009Schizophrenia 210, 300, 
405 mg vials No overlap 2–4 weeks 10 mg/day oral: 210 mg Q2 weeks 
×4 doses or 405 mg Q4 weeks ×2 
doses
15 mg/day oral: 300 mg Q2 weeks 
×4 doses
20 mg/day oral: 300 mg Q2 weeks10 mg/day oral: 150 mg Q2 weeks 
or 300 mg Q4 weeks
15 mg/day oral: 210 mg Q2 weeks 
or 405 mg Q4 weeks
20 mg/day oral: 300 mg Q2 weeks
Maximum dose: 300 mg Q2 weeks 
or 405 mg Q4 weeks$$$$$
Paliperidone 
palmitate
(Invega Sustenna) 
2009Schizophrenia
Schizoaffective 
disorder 
(monotherapy or 
adjunct)39, 78, 117, 
156, 234 mg in 
prefilled syringesNo overlap 4 weeks 234 mg IM in deltoid, then 156

palmitate
disorder 
prefilled syringesNo overlap 4 weeks 234 mg IM in deltoid, then 156 
mg 1 week later117 mg 3 weeks after second dose 
then Qmonth; may adjust monthly 
dose (maintenance given deltoid 
or gluteal).
Approx. equivalence: 
3 mg oral: 39–78 mg
6 mg oral: 117 mg
12 mg oral: 234 mg$$$$$
palmitate
(Invega Trinza)
2015Schizophrenia 
(only after at 
least 4 months 
of adequate 
treatment on 
Invega Sustenna)273, 410, 546, 819 
mg in prefilled 
syringes No overlap 3 months Based on previous monthly 
Invega Sustenna dose:
For 78 mg, give 273 mg Trinza
For 117 mg, give 410 mg Trinza
For 156 mg, give 546 mg Trinza
For 234 mg, give 819 mg TrinzaGive same conversion dose of 
Trinza every 3 months; adjust if 
necessary per patient response$$$$$
palmitate  
(Invega Hafyera)
2021Schizophrenia 
of adequate

palmitate  
Sustenna or 
3 months on 
Trinza)1,092, 1,560 mg in 
prefilled syringesNo overlap 6 months Based on previous monthly 
Sustenna dose:
For 156 mg, give 1,092 mg 
Hafyera
For 234 mg, give 1,560 mg 
Hafyera
Or 3-month Trinza dose:
For 546 mg, give 1,092 mg 
Hafyera
For 819 mg, give 1,560 mg 
HafyeraGive same conversion dose of 
Hafyera every 6 months; adjust if 
(Perseris)
2018Schizophrenia 90, 120 mg No overlap Monthly Start 90 or 120 mg SQ to 
abdomen monthlyApprox. equivalence:
90 mg monthly: 3 mg/day oral 
120 mg monthly: 4 mg/day oral$$$$$
(Risperdal Consta) 
2003Schizophrenia 
Bipolar, 
manic/mixed 
adjunct)12.5, 25, 37.5,
50 mg vialsWith usual oral dose for 
21 days2 weeks Start at 25 mg Q2 weeks; adjust

Bipolar, 
21 days2 weeks Start at 25 mg Q2 weeks; adjust 
dose no more frequently than Q4 
weeks as needed for response Approx. equivalence:
<4 mg/day oral: 25 mg
4–6 mg/day oral: 37.5 mg
>6 mg/day oral: 50 mg
Maximum dose: 50 mg Q2 weeks$$$$$

Anxiolytic and Hypnotic MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   105
Anxiolytic and Hypnotic Medications
GENERAL PRESCRIBING TIPS FOR ANXIOLYTICS
Although antidepressants are arguably the most effective medications for anxiety disorder, in this chapter we focus 
on benzodiazepines and other drugs used specifically for symptoms of anxiety or anxiety disorders.
Psychiatry has long had a love/hate relationship with benzodiazepines. They work quickly and predictably, but 
they often lead to misuse or dependence. That said, a history of substance use disorder doesn’t absolutely rule out 
prescribing a benzo—it just makes it more important to monitor use closely, including limiting the number of refills 
and consistently inquiring about substance use over the course of treatment. 
Here’s a reasonable approach to deciding on which anxiolytic medication to prescribe:

1. Start with a long-acting medication such as clonazepam. It’s somewhat less likely to lead to misuse because its 
onset and offset are more gradual.
2. Reserve short-acting benzos, like alprazolam or lorazepam, for patients who have occasional anxiety, and prescribe 
these on an as-needed basis.
3. If you are starting patients on an SSRI for an anxiety disorder, it’s good practice to simultaneously start a short 
course of a benzodiazepine. Tell them that in two weeks they will be able to stop taking the benzo because the 
antidepressant will have kicked in.
4. Give buspirone a chance, especially for generalized anxiety disorder. It may not work as reliably as benzos, but it 
lacks risk for misuse, dependence, and withdrawal.

5. Don’t forget propranolol, which can be very effective for patients who have strong somatic symptoms of anxiety, 
such as pounding heart and shortness of breath.
6. Alpha-2 agonist clonidine and alpha-1 antagonist prazosin are often helpful for both anxiety and insomnia; 
prazosin may be especially effective in patients with PTSD, though evidence is mixed. 
7. Hydroxyzine may be a particularly good option in patients who want an immediate (“as needed”) effect but have a 
substance use disorder history or risk. 
8. There are lots of other options for anxiety/insomnia, many of which are off-label. See the anxiety treatment 
algorithm for a handy graphical display of your choices. 
GENERAL PRESCRIBING TIPS FOR HYPNOTICS

The preferred way to treat insomnia is to treat the underlying cause, as opposed to reflexively writing scripts for 
hypnotics. There are plenty of reasons for our patients to lose sleep, including depression and anxiety, stressful 
life circumstances, and medication side effects. A common scenario, for example, is the patient who presents with 
major depression with insomnia as one of the depressive symptoms. In this case, we recommend either prescribing 
an antidepressant alone, or an antidepressant plus a two-week prescription for a hypnotic. In most cases, the 
antidepressant will have kicked in around the two-week point, and your patient will no longer need the hypnotic.
In addition to treating the underlying disorder, get into the habit of discussing sleep hygiene techniques with your 
patients. The key elements of sleep hygiene are:

 ⦁Avoid or reduce the use of substances that interfere with sleep, such as nicotine, caffeine, and alcohol. 
 ⦁Get more exercise.
 ⦁Make the bedroom more conducive to sleep—eg, keep the lighting dim, reduce screen time, get comfortable 
sheets, and reserve the bed for sleeping and sex. 
 ⦁Practice basic sleep restriction, which means reducing the time in bed to sleep time only. 
 ⦁Do some relaxation exercises, such as deep breathing, meditation, or progressive muscle relaxation. 
Another nonpharmacological intervention is cognitive behavioral therapy for insomnia (CBT-I), which is generally 
more effective than medications, especially for those with chronic insomnia. CBT-I decreases insomnia by about 50%, 
and unlike medications, 50%–70% of patients maintain their clinical gains after it is discontinued. Unfortunately,

and unlike medications, 50%–70% of patients maintain their clinical gains after it is discontinued. Unfortunately, 
it may be challenging to find a local therapist who is skilled in the techniques involved. If you are interested in 
becoming trained yourself, check out www.med.upenn.edu/cbti/cont_ed.html  and www.med.upenn.edu/cbti .

106  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONAssuming that you and your patient have resigned yourselves to a hypnotic, there’s a pretty long menu of 
reasonable offerings. The options below are not listed in any particular order, because we don’t have any specific 
recommendations one way or another. We tend to pick and choose among them, which often requires trials of more 
than one before hitting on the sleep ambrosia for a particular patient.
 ⦁“Z-drugs” (eszopiclone, zaleplon, zolpidem) bind selectively to specific subunits of the GABA receptors that 
induce sleep, but they don’t have the same relaxation effects of benzos and are probably somewhat less addictive. 
Zolpidem 5–10 mg has become an old standard. For patients who wake up in the middle of the night, use zaleplon 
instead because of its very short duration of action.
 ⦁Antihistamines (diphenhydramine, doxylamine, hydroxyzine) are over-the-counter agents that induce sedation

 ⦁Antihistamines (diphenhydramine, doxylamine, hydroxyzine) are over-the-counter agents that induce sedation 
by blocking histamine H1 receptors. Start with diphenhydramine 25 mg QHS and increase to 50 mg if needed. The 
older the patient, the less appropriate this option, as antihistamines can cause confusion when used chronically. 
While this can occur with anyone, it’s more common in the elderly.
 ⦁Benzodiazepines  do present the danger of tolerance; however, some patients take a small dose of one of the 
benzos every night and seem to suffer no ill effects, and there is often no dosage creep over many years or even 
decades. Use more caution in the elderly, whose risk for falls is increased.
 ⦁Melatonin is a natural compound secreted from the pineal gland in a 24-hour circadian rhythm, with levels 
naturally peaking in the middle of the night. Giving it exogenously as a supplement helps some people sleep,

naturally peaking in the middle of the night. Giving it exogenously as a supplement helps some people sleep, 
though the effect is not dramatic. 
 ⦁Ramelteon  is a melatonin agonist.
 ⦁Lemborexant and suvorexant  are in a new class of agents called dual orexin (OX1 and OX2) receptor 
antagonists,  or DORAs for short.
 ⦁Doxepin  (Silenor) was approved by the FDA for use as a hypnotic. It is an old drug in new clothing—a tricyclic 
antidepressant being used for its antihistamine properties. Because it is still expensive as a generic, we suggest 
using a low dose of generic doxepin to achieve the same effects as Silenor. This may entail prescribing the liquid 
version in order to get to doses in the 3 mg range.
 ⦁Trazodone,  another antidepressant, is commonly used for insomnia at a dose of 25–50 mg QHS. You can find the 
fact sheet for trazodone in the Antidepressants chapter.
 ⦁Mirtazapine  is a sedating antidepressant, and is quite effective for insomnia but causes weight gain.

 ⦁Mirtazapine  is a sedating antidepressant, and is quite effective for insomnia but causes weight gain. 
 ⦁Quetiapine  is the classic sedating antipsychotic, which is commonly prescribed at 25 mg and is quite popular as a 
non-addictive alternative for substance users. 
Potential Side Effects of Most Hypnotics
Although taken by millions, hypnotics are a high-risk class of medications, especially for the elderly, who are at greater 
risk for confusion, memory problems, and gait disturbances (sometimes leading to falls). Therefore, try to avoid 
hypnotics in the elderly, and when you do use them, use the lowest effective dose for the shortest duration of time 
possible.
Certain precautions apply to most hypnotics, and we’ll list them below to minimize repetition in the fact sheets:
 ⦁Daytime grogginess or hangover effect.  This effect is most likely to occur with antihistamines or with longer-acting

⦁Daytime grogginess or hangover effect.  This effect is most likely to occur with antihistamines or with longer-acting 
benzodiazepines or extended-release zolpidem.
 ⦁Anterograde amnesia.  This is  most likely to occur with benzodiazepines and Z-drugs. Among benzos, triazolam 
(Halcion) has a particularly bad rep. Just avoid triazolam—there’s no need to prescribe it given the wealth of 
alternatives.
 ⦁CNS depression.  Hypnotics may impair physical or mental abilities and alertness; advise patients to use caution when 
performing tasks that require alertness (eg, driving).
 ⦁Respiratory depression. Benzodiazepines in particular may depress respiration; avoid in patients at risk, including 
those with COPD or sleep apnea, or those taking other depressants such as opiates. In fact, the FDA issued a black 
box warning about the dangers of combining benzodiazepines with opiates due to a concerning incidence of

box warning about the dangers of combining benzodiazepines with opiates due to a concerning incidence of 
serious side effects with the combination, including profound sedation, respiratory depression, coma, and death 
(see the following page for more details on this warning).
 ⦁Paradoxical reactions.  Reports include hyperactive or aggressive behavior, and these reactions are particularly seen 
with benzodiazepines. Younger patients, the elderly, and those with head injury or organic brain syndromes are at 
greatest risk.

Anxiolytic and Hypnotic MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   107 ⦁Tolerance.  Patients generally develop tolerance  to the sedating effects of benzodiazepines after several weeks of 
continuous use (one-third of patients will experience tolerance after four weeks of use). Tolerance to anxiolytic 
effects occurs more slowly, and to anti-seizure effects very little or not at all. Psychological and physical dependence 
occurs with prolonged use.
 ⦁Discontinuation syndrome.  Withdrawal effects occur with most hypnotics and include rebound insomnia, agitation, 
anxiety, and malaise. Discontinuation syndromes from benzodiazepines are most severe with longer-term use, 
higher doses, and shorter-acting agents; in severe cases, discontinuation may include seizures. Hypnotics should 
not be abruptly discontinued; doses should be tapered gradually.

 ⦁Recreational use and misuse.  This is a risk  with many hypnotics, particularly the benzodiazepines. Avoid or minimize 
use in patients who have addiction risk or when abuse is suspected. Note that the FDA updated its class warning for 
all benzodiazepines in 2020 with a boxed warning (its most prominent warning) to emphasize the “risks of abuse, 
misuse, addiction, withdrawal, and physical dependence. ” They felt the previous prescribing information did not 
adequately convey these risks and the potential harm of these medications. 
 ⦁Complex sleep-related behaviors.  Sleep driving, sleep eating, sleep texting, and sleep sex have all been reported. 
Although these behaviors can occur when using benzodiazepines or Z-drugs alone and at usual therapeutic doses,

Although these behaviors can occur when using benzodiazepines or Z-drugs alone and at usual therapeutic doses, 
they often occur with high-dose use or in combination with other CNS depressants, including alcohol. Typically, these 
events occur when the individual is not fully awake, and often there will be no memory of the behavior. In 2019, the 
FDA added a black box warning specifying that these behaviors can lead to injury and death, and recommended 
against prescribing them to anyone who has experienced complex sleep-related behaviors in the past. 
Class Warnings Specific to Benzodiazepines
 ⦁Combining benzodiazepines with opiates. The FDA has issued a black box warning about the dangers of combining 
benzodiazepines with opiates due to the risks of profound sedation, respiratory depression, coma, and death. The 
FDA stipulates reserving the benzo/opioid combination for patients who have unsuccessfully tried alternative

FDA stipulates reserving the benzo/opioid combination for patients who have unsuccessfully tried alternative 
options, minimizing the dosage and duration of treatment, and monitoring patients closely for sedation and 
respiratory depression.
 ⦁Sleep architecture.  Benzodiazepines affect sleep architecture; thus, long-term use is discouraged.
 ⦁Use in elderly patients.  We worry about two potential risks when using benzodiazepines in the elderly: falls and 
cognitive impairment. A number of meta-analyses have reported about a 1.5-fold increased risk of falls in the elderly 
who are taking a benzo. Fall risk is greatest during the first two weeks of treatment, so use particular caution during 
this time. Lower doses reduce fall risk, but the data are conflicting as to whether short- or long-acting benzos 
are more dangerous. As for cognition, several earlier studies had hinted at a relationship between benzos and

are more dangerous. As for cognition, several earlier studies had hinted at a relationship between benzos and 
dementia, but a recent larger study with superior methodology did not support this connection—in fact, it found 
a lower  risk of dementia within two years after benzos or Z-drugs were prescribed (Osler M and Jorgensen MB,  Am J 
Psych  2020;177(6):497–505).

108  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONWith 
neuropathic painWith bipolar 
disorderWith comorbid depression UncomplicatedWith PTSD, nightmares, 
severe insomniaFor performance  
anxietyIf substance use 
disorder or risk
Pregabalin Quetapine Buspirone Clonidine Prazosin Hydroxyzine
Augmentation with 
antipsychotic if 
psychotic symptomsNote: Benzodiazepines are effective for all presentations of anxiety but should 
ideally be used short-term or as needed at lowest effective dose and should be 
avoided in those with substance use disorder or risk.SSRIs at 
high dosePropranolol GabapentinGAD, panic disorder, 
social anxiety disorder, PTSD
OCD
Refractory OCDFirst line:
SSRIs 
or SNRIsTreatment 
resistant:
TCAs 
or MAOIsAnxiety Treatment Algorithm

Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   109Nonpharmacologic 
interventionsShort-term insomnia:  
Non-benzodiazepine hypnotics (Z-drugs)
Long-term insomnia
UncomplicatedComorbid 
depressionComorbid PTSD, 
Comorbid psychosis,  
bipolar disorderComorbid neuropathic pain, 
seizuresTreatment resistantSleep hygieneSleep study (if evidence of 
sleep apnea, narcolepsy, or 
movement disorders)Cognitive 
behavioral therapy 
for insomnia (CBTI)
If ineffective, switch to benzodiazepine 
(temazepam, lorazepam, various)Zaleplon
—
Preferred due to 
shorter half-lifeZolpidem
Diphenhydramine, 
hydroxyzine
RamelteonMirtazapine Clonidine Prazosin Trazodone
Quetiapine Gabapentin PregabalinMelatonin
SuvorexantDoxepin Trazodone AmitriptylineIf ineffective, use 
pharmacotherapy
(continues below)
(continued)MirtazapineInsomnia Treatment Algorithm

110  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONTable 13:  Anxiolytic and Hypnotic Medications
Indication(s)Available Strengths
(mg)Onset of Action
(oral)Half-Life
(hours)Duration 
of Action
(hours)Usual Dosage 
Range
(mg)
Antihistamines
Diphenhydramine [G] 
(Benadryl, others) 
1946
Available OTC and RxInsomnia (adults 
and children 12+ 
years)Capsule: 25, 50
Tablet: 25
Liquid: 12.5 mg/mL1 hour 3.5−9 4−6 25–50 QHS
Doxepin [G]
(Silenor)
2010/1969Insomnia (sleep 
maintenance)Tablet: 3, 6
Capsule: 10, 25, 50, 75, 100, 150
Liquid: 10 mg/mL1 hour 15 4−6 3–6 QHS
Doxylamine [G] 
(Unisom, others)
1978
Available OTC and RxInsomnia Tablet: 25 1 hour 10 4−6 25–50 QHS
Hydroxyzine [G]
(Atarax, Vistaril) 
1956GAD Capsule: 25, 50, 100
Tablet: 10, 25, 50
Liquid: 10 mg/5 mL
Injection: 25 mg/mL, 50 mg/mL30 min 7–10 4–6 25–50 Q4–6H 
PRN or up to 
25–100 QID

PRN or up to 
25–100 QID
Alprazolam [G] 
(Xanax, Xanax XR) 
1981GAD
Panic disorderTablet: 0.25, 0.5, 1, 2
ER tablet: 0.5, 1, 2, 3
ODT: 0.25, 0.5, 1, 2
Liquid: 1 mg/mL30 min (IR, ODT)
1–2 hours (XR)11–16 3–4 (IR)
10 (XR)0.25–2 TID
0.5–3 QD (XR) 
Clonazepam [G]
(Klonopin, Klonopin Wafers1) 
1975Panic disorder
Insomnia 
(off-label)Tablet: 0.5, 1, 2
ODT: 0.125, 0.25, 0.5, 1, 21 hour 20–80 4–8 0.5 BID–2 TID
0.25–1 QHS
Diazepam [G]
(Valium) 
1963GAD
Alcohol withdrawalTablet: 2, 5, 10
Liquid: 5 mg/5 mL, 5 mg/mL
Injection: 5 mg/mL30 min >100 4–6 2 BID–10 QID
Flurazepam [G]
(Dalmane1)
1970Insomnia (short 
term)Capsule: 15, 30 30−60 min 40–100 7–8 15–30 QHS
Lorazepam [G]
(Ativan, Loreev XR) 
1977GAD
Insomnia 
ER capsule: 1, 2, 3

1977GAD
Insomnia 
Injection: 2 mg/mL, 4 mg/mL30–60 min 10–20 4–6 1–5 BID (QD 
for XR)
1–4 QHS
Temazepam [G]
(Restoril)
1981Insomnia (short 
term)Capsule: 7.5, 15, 22.5, 30 30−60 min 9−18 4−6 15–30 QHS
Triazolam [G]
(Halcion)
1982Insomnia (short 
term)Tablet: 0.125, 0.25 15−30 min 1.5−5.5 Unknown 0.25–0.5 QHS
Dual Orexin Receptor Antagonists (DORA)
(Dayvigo)
2019Insomnia (sleep 
onset and sleep 
maintenance)Tablet: 5, 10 30−60 min 17–19 6−8 5–10 QHS
(Belsomra)
2014Insomnia (sleep 
maintenance)Tablet: 5, 10, 15, 20 30–60 min 12 6–8 10–20 QHS
Z-Hypnotics
Eszopiclone [G] 
(Lunesta) 
2004Insomnia (sleep 
maintenance)Tablet: 1, 2, 3 30 min 6 6−8 1–3 QHS
Zaleplon [G] 
(Sonata)
1999Insomnia (short 
term, sleep onset)Capsule: 5, 10 30 min 1 4 10–20 QHS

Anxiolytic and Hypnotic MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   111Generic Name
of Action
Range
(mg)
Zolpidem [G]
(Ambien, Ambien CR, Edluar, 
Zolpimist)
1992
Edluar or Zolpimist SLInsomnia (IR: short 
term, sleep onset; 
CR: sleep onset and 
maintenance)Tablet: 5, 10
ER tablet: 6.25, 12.5
SL tablet: 5, 10
Oral spray: 5 mg/spray30 min 2.5−3 6−8 10, 12.5 CR (5, 
6.25 in
women)
Zolpidem low dose [G] 
2011Difficulty falling 
asleep after 
middle-of-the-
night awakeningSL tablet: 1.75, 3.5 30 min 2.5 4 1.75 women; 
3.5 men
Others
Buspirone [G]
(BuSpar1)
1986GAD Tablet: 5, 7.5, 10, 15, 30 1–2 weeks+ 2–3 N/A 5–20 TID
Clonidine
(Catapres, Kapvay)
1974Anxiety (off-label) Tablet: 0.1, 0.2, 0.3

3.5 men
Others
(BuSpar1)
Clonidine
ER tablet: 0.1, 0.2
Patch: 0.1 mg/day, 0.2 mg/day, 
0.3 mg/day30–60 min (oral)
1–2 days (patch)6–13 8–12 (IR)
8–24 
(patch)0.1–0.2 Q4–6H 
PRN (IR)
0.1–0.2 
QD–BID
Gabapentin [G]
(Neurontin)
1993Anxiety (off-label) Capsule: 100, 300, 400
Tablet: 600, 800
ER tablet: 300, 6001-2 hours 5–7 5–8 100 QHS–1200 
TID
Prazosin [G]
(Minipress) 
1976PTSD (off-label) Capsule: 1, 2, 5 1–2 hours 2–3 4–6 1–10 mg/day 
QHS or divided 
BID
Pregabalin [G]
(Lyrica)
2004Anxiety (off-label) Capsule: 25, 50, 75, 100, 200, 
225, 300
Oral solution: 20 mg/mL1–2 hours 6 8–12 75–300 BID
Propranolol [G]
(Inderal) 
1973Performance 
anxiety (off-label)Tablet: 10, 20, 40, 60, 80 60 min 3–6 4–6 10–40 PRN
Ramelteon [G]
(Rozerem) 
2005Insomnia (sleep 
onset)Tablet: 8 30 min 1−2.6 Unknown 8 QHS

(Rozerem) 
(Desyrel1, Oleptro1)
1981/2010Depression
Insomnia 
(off-label)Tablet: 50, 100, 150, 300
ER tablet: 150, 3001 hour 7−10 Unknown 25–200 QHS
Table 13A:  Benzodiazepine Dosage Equivalencies
Benzodiazepine Approximate Equivalent Dosage (mg)
Alprazolam (Xanax) 0.5
Chlordiazepoxide (Librium) 25
Clonazepam (Klonopin) 0.25–0.5
Clorazepate (Tranxene) 7.5
Diazepam (Valium) 5
Estazolam (ProSom) 1
Flurazepam (Dalmane) 15
Lorazepam (Ativan) 1
Oxazepam (Serax) 15
Quazepam (Doral) 15
Temazepam (Restoril) 15
Triazolam (Halcion) 0.25

112  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONALPRAZOLAM  (Xanax) Fact Sheet [G]
Alprazolam is fast acting and effective for GAD and panic disorder, but its short duration of action may contribute to 
breakthrough symptoms between doses and make withdrawal more difficult.
Generalized anxiety disorder (GAD); panic disorder.
Other anxiety disorders; insomnia; acute mania or psychosis; catatonia.
 ⦁Tablets (G):  0.25 (scored), 0.5 mg (scored), 1 mg (scored), 2 mg (scored).
 ⦁ER tablets (Xanax XR, [G]):  0.5 mg, 1 mg, 2 mg, 3 mg.
 ⦁Orally disintegrating tablets (G):  0.25 mg, 0.5 mg, 1 mg, 2 mg.
 ⦁Oral concentrate (G):  1 mg/mL.
 ⦁GAD: Start 0.25–0.5 mg TID; ↑ by 0.25–0.5 mg/day increments every three to four days as needed and tolerated to 
max dose 4 mg/day divided TID–QID.

 ⦁Panic disorder: Start 0.5 mg TID; ↑ by increments of no more than 1 mg/day every three to four days as needed to 
target dose 4–6 mg/day divided TID–QID. Max dose 10 mg/day.
 ⦁Panic disorder using XR: Start 0.5–1 mg QD; ↑ by increments of no more than 1 mg/day at intervals of three to four 
days to target dose 3–6 mg QD.
Cost:  $
 ⦁Most common: Sedation, somnolence, memory impairment, slurred speech, incoordination, dependence.
 ⦁Serious but rare: Anterograde amnesia, increased fall risk, paradoxical reaction (irritability, agitation), respiratory 
depression (avoid in patients with sleep apnea or on opioids).
 ⦁Binds to benzodiazepine receptors to enhance GABA effects.

 ⦁Metabolized primarily through CYP3A4; t ½: 11–16 hours.
 ⦁Avoid use with other CNS depressants, including alcohol and opioids (additive effects). Potent CYP3A4 inhibitors 
(eg, fluvoxamine, erythromycin) may increase alprazolam levels; CYP3A4 inducers (eg, carbamazepine) may 
decrease alprazolam levels.
 ⦁Schedule IV controlled substance.
 ⦁Benzodiazepines are very effective immediately for GAD and panic disorder, particularly in the early weeks of SSRI 
therapy while awaiting onset of therapeutic effect.
 ⦁Paradoxical reaction of aggression, agitation, and combativeness is more likely to occur in the elderly or those with 
brain injury.
 ⦁While benzodiazepines are highly abusable, patients with panic disorder rarely self-increase their dose when treated

 ⦁While benzodiazepines are highly abusable, patients with panic disorder rarely self-increase their dose when treated 
adequately, indicating that tolerance to anxiolytic effects does not occur.
Fun Fact:
There are many slang terms for alprazolam; some of the more common ones are bars, Z-bars, zannies, footballs, blues, 
or blue footballs.

Anxiolytic and Hypnotic MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   113ANTIHISTAMINES  (Diphenhydramine, others) Fact Sheet [G]
Antihistamines can be very effective sleep aids for many patients, although some patients may experience too 
much grogginess (“hangover”) in the morning. They are good first-line agents due to a low risk of drug tolerance, 
dependence, or abuse, but exercise caution in the elderly, who are more sensitive to cognitive and peripheral effects.
Insomnia  (adults, children 12–17 years); allergies; motion sickness;  antiparkinsonism.
Extrapyramidal symptoms; nausea and vomiting (morning sickness).
 ⦁Tablets, chewable tablets, caplets, capsules, and oral solutions, varies by brand: 25 mg, 50 mg.
 ⦁Common brand names:
 –Diphenhydramine:  Benadryl, Compoz, Nytol, Simply Sleep, Sleep-Eze, Sominex, Unisom SleepGels, Unisom 
SleepMelts, and generic.

⦁Common brand names:
 –Doxylamine:  NyQuil, Unisom SleepTabs, and generic.
 –Hydroxyzine:  Vistaril, Atarax, and generic (see fact sheet).
Insomnia: Start 25 mg, 30 minutes before bedtime. The dose required to induce sleep can be as low as 6.25 mg, but 
usual dose is 25 mg. Some patients may require 50 mg at bedtime.
Cost:  $
 ⦁Most common: Dry mouth, ataxia, urinary retention, constipation, drowsiness, memory problems.
 ⦁Serious but rare: Blurred vision, tachycardia.
 ⦁Histamine H1 antagonist.
 ⦁Metabolized by liver, primarily CYP2D6; t ½: for diphenhydramine, 3.5–9 hours; for doxylamine, 10 hours (12–15 in 
elderly).
 ⦁Avoid use with other antihistamines or anticholinergics (additive effects).

elderly).
 ⦁These antihistamines non-selectively antagonize central and peripheral histamine H1 receptors. They also have 
secondary anticholinergic effects, which can cause side effects including dry mouth and urinary retention, as well as 
cognitive impairment in susceptible populations.
 ⦁Be aware that anticholinergic drugs are often used to treat or prevent EPS in patients taking antipsychotics; 
diphenhydramine is often chosen and dosed at night to take advantage of its sedative effect.
 ⦁Antihistamines can be helpful for some patients with anxiety. See hydroxyzine fact sheet. 
Fun Fact:
The name NyQuil is a portmanteau of “night” and “tranquil. ”

114  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONBUSPIRONE  (BuSpar) Fact Sheet [G]
Buspirone is a reasonable option in patients for whom benzodiazepines are not appropriate. Don’t expect as robust a 
response, and make sure patients know it may take a week or two to kick in. 
Generalized anxiety disorder (GAD).
Treatment-resistant depression; anxiety symptoms in depression.
Tablets (G):  5 mg (scored), 7.5 mg (scored), 10 mg (scored), 15 mg (scored), 30 mg (scored).
Start 7.5 mg BID or 5 mg TID; ↑ by increments of 5 mg/day every two to three days to target dose 20–30 mg/day 
divided BID–TID; max 20 mg TID.
Cost:  $
Most common: Dizziness, nervousness, nausea, headache, jitteriness.
 ⦁Serotonin 5-HT1A receptor partial agonist.

Cost:  $
 ⦁Metabolized primarily through CYP3A4; t ½: 2–3 hours.
 ⦁Avoid use with MAOIs; caution with serotonergic agents due to additive effects and risk for serotonin syndrome. 
Caution with CYP3A4 inhibitors or inducers as they may affect buspirone serum levels; adjust dose.
 ⦁Similar to antidepressants, buspirone requires one or two weeks for onset of therapeutic effects, with full effects 
occurring over several weeks, and offers no “as-needed” benefits.
 ⦁Non-sedating, non-habit-forming alternative to benzodiazepines for anxiety. May be less effective or ineffective in 
patients who have previously responded to benzos.
 ⦁Has only shown efficacy in GAD, not in other anxiety disorders (PTSD, OCD, panic disorder).

 ⦁May potentiate antidepressant effects when used in combination with SSRIs in refractory depression.
Fun Fact:
Psychotropic agents with 5-HT1A partial agonist effects include aripiprazole, ziprasidone, and vilazodone, among 
others.

Anxiolytic and Hypnotic MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   115CLONAZEPAM  (Klonopin) Fact Sheet [G]
Due to its longer half-life, clonazepam causes fewer breakthrough symptoms compared to alprazolam when used for 
anxiety. May also work as a good short-term hypnotic, although development of dependence and long half-life limit 
this use.
Seizure disorders;  panic disorder.
 ⦁Tablets (G):  0.5 mg (scored), 1 mg (scored), 2 mg (scored).
 ⦁Orally disintegrating tablets (G):  0.125 mg, 0.25 mg, 0.5 mg, 1 mg, 2 mg.
 ⦁Dose varies based on patient characteristics (eg, age) and tolerance to benzodiazepines.
 ⦁Anxiety: Start 0.5 mg BID; ↑ by 0.5–1 mg/day increments every two to four days to max 6 mg/day divided BID–TID.

⦁Anxiety: Start 0.5 mg BID; ↑ by 0.5–1 mg/day increments every two to four days to max 6 mg/day divided BID–TID.
 ⦁Insomnia (off-label use): Start 0.25–0.5 mg QHS as needed for insomnia. Max 2 mg at bedtime.
 ⦁Use lower doses for elderly.
Cost:  $
 ⦁Most common: Somnolence, daytime grogginess, confusion, ataxia.
 ⦁Metabolized primarily through CYP3A4; t ½: 20–80 hours.
 ⦁Avoid concomitant use with other CNS depressants, including alcohol and opioids (additive effects). Potent CYP3A4 
inhibitors (eg, fluvoxamine, erythromycin) may increase clonazepam levels; CYP3A4 inducers (eg, carbamazepine)

inhibitors (eg, fluvoxamine, erythromycin) may increase clonazepam levels; CYP3A4 inducers (eg, carbamazepine) 
may decrease clonazepam levels.
 ⦁High-potency, long-acting benzodiazepine with active metabolites that may accumulate.
 ⦁Withdrawal effects may not be seen until three to five days after abrupt discontinuation and may last 10–14 days 
due to long half-life and active metabolites of clonazepam.
 ⦁Full effects of a particular dose may not be evident for a few days since active metabolites will accumulate with 
continual use (versus PRN use). Wait several days before increasing dose if patient is taking clonazepam regularly.
Fun Fact:
Klonopin tablets (or “K-pins”) have a street value of $2–$5 per tablet, depending on dose and geographic region.

116  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONDIAZEPAM  (Valium) Fact Sheet [G]
Diazepam has a long history of use with good efficacy for anxiety. Its long half-life makes it a particularly effective 
anxiolytic for some patients, and it is a good alternative to chlordiazepoxide for alcohol withdrawal. 
Generalized anxiety disorder; alcohol withdrawal;  seizures; muscle spasms.
 ⦁Tablets (G):  2 mg (scored), 5 mg (scored), 10 mg (scored).
 ⦁Oral liquid (G):  5 mg/5 mL, 5 mg/1 mL.
 ⦁Injection (G):  5 mg/1 mL.
 ⦁Rectal gel (Diastat, [G]):  2.5 mg, 10 mg, 20 mg per applicator. 
Anxiety: Start 2–5 mg BID; ↑ by 2–5 mg/day increments every two to four days to max 40 mg/day divided BID–QID.
Cost:  $

Cost:  $
 ⦁Metabolized primarily through CYP3A4 and CYP2C19; t ½: >100 hours.
 ⦁Avoid concomitant use with other CNS depressants, including alcohol and opioids (additive effects).
 ⦁Long-acting benzodiazepine with active metabolites that may accumulate.
 ⦁Tolerance to sedative effect may develop more rapidly (within two to four weeks of use) than tolerance to anti-
anxiety effect.

⦁Tolerance to sedative effect may develop more rapidly (within two to four weeks of use) than tolerance to anti-
due to long half-life and active metabolites of diazepam.
 ⦁Diazepam has the highest lipid solubility of all benzos, which means very rapid distribution into and out of the 
CNS, resulting in the greatest “rush” felt by patients using in a single-dose manner. This feature makes diazepam an 
especially abusable benzo.
Fun Fact:
Valium has been glorified in music more than once. The Rolling Stones’ “little yellow pill” in “Mother’s Little Helper” and 
Lou Reed’s “Walk on the Wild Side” (“Jackie is just speeding away/Thought she was James Dean for a day/Then I guess 
she had to crash/Valium would have helped that bash”) are two good examples.

Anxiolytic and Hypnotic MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   117DOXEPIN  (Silenor) Fact Sheet [G]
Doxepin may be a good agent to put in your arsenal, particularly for those patients in whom you want to avoid 
benzodiazepines or Z-drugs. Now that the low-dose (3 and 6 mg) generic version of Silenor is available, price is no 
longer a limitation.
Insomnia  (sleep maintenance). Generic doxepin (at higher doses) approved for depression, anxiety disorders.
Headache; neuropathic pain; fibromyalgia.
 ⦁Tablets (Silenor, [G]):  3 mg, 6 mg.
 ⦁Capsules (G):  10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg.
 ⦁Oral concentrate (G):  10 mg/mL.
Insomnia:
 ⦁Silenor: Start, target, and max dose 6 mg QHS, taken within 30 minutes of bedtime. Use 3 mg/day in elderly. Avoid 
meals within three hours of taking Silenor.

Insomnia:
 ⦁Doxepin: Start 10 mg capsule, or achieve a lower dose by using the oral concentrate or by opening the 10 mg 
capsule, dissolving it in a cup of juice, and drinking a portion of the juice.
Cost:  Generic 10 mg and up: $; Silenor, generic 3 and 6 mg: $$$
 ⦁Most common: Somnolence, nausea, dry mouth, constipation.
 ⦁Serious but rare: Orthostasis (more likely at higher doses).
 ⦁Tricyclic antidepressant with norepinephrine and serotonin reuptake inhibition and histamine H1 antagonism.
 ⦁Metabolized primarily through CYP2C19 and CYP2D6 (also CYP1A2 and CYP2C9 to lesser extent); t ½: 15 hours.

⦁Metabolized primarily through CYP2C19 and CYP2D6 (also CYP1A2 and CYP2C9 to lesser extent); t ½: 15 hours.
 ⦁Clinically significant drug interactions not likely at the low doses used for hypnotic effects.
 ⦁Silenor is a branded version of generic doxepin, but available in lower doses.
 ⦁Taking within three hours of eating delays therapeutic effect by up to three hours. For faster onset and to minimize 
next-day effects, don’t take within three hours of a meal.
Fun Fact:
Somaxon Pharmaceuticals, the original but fledgling manufacturer of Silenor, was acquired by Pernix, which hopes to 
eventually pursue over-the-counter approval.

118  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONESZOPICLONE  (Lunesta) Fact Sheet [G]
Like other Z-drugs, eszopiclone is an effective hypnotic with less potential for dependence than the benzodiazepines. 
Dosing is simple and, apart from the bitter aftertaste, its rapid onset and long duration of action make it well accepted 
among patients. As with all sedatives/hypnotics, nightly use should be discouraged.
Insomnia  (sleep onset and sleep maintenance).
Tablets (G):  1 mg, 2 mg, 3 mg.
Start 1 mg QHS; may ↑ to max 3 mg QHS. Use lower doses in elderly (max 2 mg QHS). Take immediately before falling 
asleep and at least seven to eight hours before planned awakening time. Avoid administering with a high-fat meal 
(delays onset of effect).
Cost:  $

Cost:  $
 ⦁Most common: Somnolence, headache, unpleasant taste, dizziness, dry mouth.
 ⦁Serious but rare: Anaphylaxis, complex sleep-related behavior (sleep driving, cooking, eating, phone calls).
 ⦁Selective GABA-A alpha-1 subunit agonist.
 ⦁Metabolized primarily through CYP3A4 and CYP2E1; t ½: 6 hours (9 hours in elderly).
 ⦁Avoid concomitant use with other CNS depressants, including alcohol (additive effects). Potent CYP3A4 inhibitors 
(eg, fluvoxamine, erythromycin) may increase effects of eszopiclone significantly, whereas CYP3A4 inducers (eg, 
carbamazepine) may decrease eszopiclone levels; adjust eszopiclone dosing.
 ⦁Non-benzodiazepine in structure, but binds to the GABA-benzodiazepine receptor complex like benzodiazepines

 ⦁Non-benzodiazepine in structure, but binds to the GABA-benzodiazepine receptor complex like benzodiazepines 
do; selective for the alpha receptor subtype (causing hypnotic effects but none of the other pharmacologic effects 
of benzodiazepines); one of the Z-drugs. Eszopiclone is the s-enantiomer of zopiclone (a hypnotic agent available in 
other countries).
 ⦁Unlike benzodiazepines, eszopiclone does not disrupt sleep architecture (stages).
 ⦁Taking after a large, high-fat meal will delay its onset of action (by about an hour). Because of its rapid onset of 
action, eszopiclone should be taken immediately before bedtime or once difficulty falling asleep has occurred.
 ⦁Higher doses increase next-day impairment of driving and alertness.
Fun Fact:
Sepracor, the manufacturer, tried to get Lunesta approved in Europe under the brand name Lunivia, but the European

⦁Higher doses increase next-day impairment of driving and alertness.
Fun Fact:
Sepracor, the manufacturer, tried to get Lunesta approved in Europe under the brand name Lunivia, but the European 
agency determined that eszopiclone was too similar to the already-marketed zopiclone to qualify as a patentable 
product. Sepracor, realizing that it might encounter future generic competition, withdrew its application.

Anxiolytic and Hypnotic MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   119FLURAZEPAM  (Dalmane) Fact Sheet [G]
Flurazepam is an older benzodiazepine that has fallen out of favor due to its very long half-life and its active 
metabolites. It is not our first choice of benzodiazepines for insomnia; we prefer temazepam or lorazepam instead. 
FDA Indications: 
Insomnia  (short term).
Anxiety disorders; acute mania or psychosis; catatonia.
Capsules (G):  15 mg, 30 mg.
Start 15 mg QHS. Max 30 mg nightly. Use lower doses in elderly.
Cost:  $
 ⦁Most common: Somnolence, dizziness, weakness, ataxia.

⦁Serious but rare: Anterograde amnesia, increased fall risk, paradoxical reaction (irritability, agitation), respiratory 
 ⦁Metabolized primarily through CYP3A4; t ½: 40–100 hours.
 ⦁Avoid concomitant use with other CNS depressants, including alcohol and opioids (additive effects). Avoid use 
with potent CYP3A4 inhibitors (eg, erythromycin, ketoconazole, fluvoxamine) as they may increase flurazepam 
levels significantly, whereas CYP3A4 inducers (eg, carbamazepine) may decrease flurazepam levels; adjust 
flurazepam dosing.
 ⦁Flurazepam is less favored than temazepam because of active metabolites, long half-life, potential for accumulation, 
and next-day grogginess.

 ⦁Tolerance to sedative effect may develop within two to four weeks of use, and benzodiazepines affect sleep 
architecture; thus, long-term use is discouraged.
Fun Fact:
Advertising for Dalmane in the 1970s featured a nightgown-clad woman trapped inside a giant eyeball sphere, trying 
to get out. The tagline: “One less concern for your patient with insomnia. ”

120  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONHYDROXYZINE  (Atarax, Vistaril) Fact Sheet [G]
Hydroxyzine is an antihistamine that is a good non-addictive option when your patient needs a rapid-acting 
anxiolytic. But beware of its anticholinergic effects, especially in patients who take many doses throughout the day. 
Generalized anxiety disorder (GAD); pruritis; pre-anesthetic sedative.
Other anxiety disorders; insomnia; anxiety and agitation related to opioid withdrawal.
 ⦁Hydroxyzine pamoate capsules (Vistaril, [G]):  25 mg, 50 mg, 100 mg. 
 ⦁Hydroxyzine hydrochloride tablets (Atarax, [G]):  10 mg, 25 mg, 50 mg.
 ⦁Hydroxyzine hydrochloride oral liquid (G):  10 mg/5 mL.
 ⦁Hydroxyzine hydrochloride injection (G):  25 mg/1 mL, 50 mg/1 mL.
 ⦁Anxiety: Start 25 mg Q4H or Q6H PRN; ↑ by 25 mg/day increments every three to five days to max 100 mg Q6H PRN.

⦁Hydroxyzine hydrochloride injection (G):  25 mg/1 mL, 50 mg/1 mL.
 ⦁Anxiety: Start 25 mg Q4H or Q6H PRN; ↑ by 25 mg/day increments every three to five days to max 100 mg Q6H PRN. 
May also be used with scheduled dosing, divided TID–QID. Max dose 400 mg/day. 
 ⦁Insomnia: Start 25 mg QHS; may ↑ by 25 mg/day increments every three to seven days to usual dosage range of 
25–100 mg QHS. 
Cost:  $
 ⦁Most common: Sedation, somnolence, daytime grogginess, dry mouth, constipation.
 ⦁Serious but rare: QT prolongation. 
 ⦁Metabolized primarily through liver, CYP enzymes unknown; t ½: 7–20 hours.
 ⦁Avoid concomitant use with other antihistamines or anticholinergics (additive effects).

⦁Metabolized primarily through liver, CYP enzymes unknown; t ½: 7–20 hours.
 ⦁Technically, the 1956 FDA indication is for “symptomatic relief of anxiety and tension associated with psychoneurosis 
and as an adjunct in organic disease states in which anxiety is manifested, ” which likely is closest to what we’d 
consider GAD today. 
 ⦁Hydroxyzine’s anticholinergic effects might raise concerns about memory problems, especially in the elderly, but it 
was tested against lorazepam and was found to be much more favorable in terms of both cognition and balance.
 ⦁May be useful as a “PRN” med but generally considered second line in anxiety disorders due to side effects and, 
unlike first-line SSRIs and SNRIs, lack of efficacy for usual comorbid disorders such as depression. 
Fun Fact:

Fun Fact:
Confusingly, there are two versions of hydroxyzine: hydroxyzine hydrochloride tablets, oral liquid, and injection 
(Atarax) and hydroxyzine pamoate capsules (Vistaril). Popular opinion is that the pamoate salt (Vistaril) may have 
greater solubility or lipophilicity, thereby making it better for anxiety and sedation while Atarax is better for itching, 
but this is a myth. Essentially, it doesn’t matter which you use.

Anxiolytic and Hypnotic MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   121LEMBOREXANT  (Dayvigo) Fact Sheet
Like the first agent in this class, Lemborexant is an orexin receptor antagonist. It is no more effective than benzos or 
Z-drugs, and it has a similar abuse liability. We’re concerned that next-day impairment is a potential side effect at the 
highest approved dose of 10 mg, particularly since sleepless patients may decide on their own to take even higher 
doses. It’s not a first-line hypnotic.
Insomnia (sleep onset and sleep maintenance).
Tablets:  5 mg, 10 mg.
Start 5 mg QHS, 30 minutes before bedtime and at least seven hours before planned awakening time. If tolerated but 
not effective, may increase to max 10 mg QHS. For more rapid onset, patients should wait at least an hour after a meal

not effective, may increase to max 10 mg QHS. For more rapid onset, patients should wait at least an hour after a meal 
before taking it. Avoid administering within an hour of a high-fat meal (delays therapeutic effect by about 1.5 hours).
Cost:  $$$$
 ⦁Most common: Somnolence, headache, abnormal dreams, dry mouth.
 ⦁Serious but rare: Impaired alertness and motor coordination, including impaired driving; worsening depression 
or suicidal ideation; sleep paralysis (inability to speak or move for up to a few minutes during the sleep-wake 
transition), hypnagogic/hypnopompic hallucinations (including vivid and disturbing perceptions), and cataplexy-
like symptoms (leg weakness for seconds up to a few minutes both in the nighttime and the daytime) reported, 
especially at higher doses.
 ⦁“DORA” or dual orexin (OX1 and OX2) receptor antagonist.

 ⦁Metabolized primarily through CYP3A4, with minor contribution from CYP3A5; t ½: 17–19 hours.
 ⦁Caution with CYP3A4 inhibitors and inducers; lemborexant dose adjustment recommended. Caution with alcohol 
and other CNS depressants.
 ⦁Schedule IV controlled substance. Data in recreational drug users found they “liked” lemborexant more than placebo 
and as much as zolpidem and suvorexant. 
 ⦁Lemborexant is contraindicated in patients with narcolepsy.
 ⦁Incidence of suicidal ideation or behavior was 0.3% (10 mg) and 0.4% (5 mg) compared to 0.2% in patients taking 
placebo. Closely monitor and assess patients for suicidality, especially those with depression.
 ⦁Lemborexant has a unique mechanism of action. Unlike other hypnotics, it does not act by stimulating GABA

⦁Lemborexant has a unique mechanism of action. Unlike other hypnotics, it does not act by stimulating GABA 
or melatonin receptors or by blocking histamine. Instead, lemborexant blocks orexin receptors (orexins are 
neurotransmitters that promote wakefulness).
 ⦁Risk of next-day impairment increases with dose; caution patients taking 10 mg against next-day driving and other 
activities requiring mental alertness.
Fun Fact:
Eisai, the drug company that pursued FDA approval and now markets Dayvigo, bought the rights to this medication in 
2015 from Purdue Pharma, the company that brought us OxyContin and pleaded guilty to criminal charges related to 
the opioid epidemic.

122  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONLORAZEPAM  (Ativan, Loreev XR) Fact Sheet [G]
When a benzodiazepine is appropriate for use (short-term; minimal risk of abuse), we consider lorazepam to be a first-
line agent.
Generalized anxiety disorder;  status epilepticus (IV route).
Other anxiety disorders; insomnia; acute mania or psychosis; catatonia; pre-operative sedation; chemotherapy related 
nausea and vomiting.
 ⦁ER capsules (Loreev XR):  1 mg, 2 mg, 3 mg.
 ⦁Injection (G):  2 mg/mL, 4 mg/mL.
 ⦁Anxiety: Start 1 mg BID; ↑ by 0.5–1 mg/day increments every two to four days up to 6 mg/day divided BID–TID. Max 
10 mg/day divided BID–TID.
 ⦁ER capsules for patients taking stable, evenly divided TID dosing with IR; to be taken once daily in morning.

 ⦁Insomnia (off-label use): Start 0.5–1 mg QHS, 20–30 minutes before bedtime; max 4 mg nightly.
 ⦁Use lower doses in elderly.
Cost:  $; Loreev XR: $$$$
 ⦁Metabolism primarily hepatic (non-CYP450) to inactive compounds; t ½: 10–20 hours.
 ⦁Avoid concomitant use with other CNS depressants, including alcohol and opioids (additive effects). No risk for 
CYP450 drug interactions.

⦁Avoid concomitant use with other CNS depressants, including alcohol and opioids (additive effects). No risk for 
 ⦁Lorazepam does not have a long half-life or active metabolites that could accumulate, and poses no CYP450 drug 
interaction risk.
 ⦁Withdrawal symptoms are usually seen on the first day after abrupt discontinuation and last five to seven days 
in patients receiving benzodiazepines with short to intermediate half-lives, such as lorazepam. A gradual taper is 
highly recommended, particularly if the patient is receiving prolonged treatment on a high dose.
Fun Fact:
Early Ativan marketing efforts included clever direct-to-consumer advertising campaigns. These included “Now it can

Fun Fact:
Early Ativan marketing efforts included clever direct-to-consumer advertising campaigns. These included “Now it can 
be yours—the Ativan experience” in 1977 and “In a world where certainties are few... no wonder Ativan is prescribed 
by so many caring clinicians” in 1987.

Anxiolytic and Hypnotic MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   123PRAZOSIN  (Minipress) Fact Sheet [G]
Prazosin is an alpha-1 antagonist (FDA approved for hypertension) that has become popular as a treatment for 
PTSD-associated insomnia/nightmares. More recent studies have cast doubt on its efficacy for nightmares, but many 
clinicians still believe it is useful. 
Hypertension.
PTSD; alcohol use disorder.
Capsules (G):  1 mg, 2 mg, 5 mg.
 ⦁PTSD (off-label): Titrate dose slowly to minimize possibility of “first-dose” orthostatic hypotension. Start 1 mg 
QHS ×3 days, then 2 mg QHS ×4 days. If tolerating but still symptomatic, increase to 3 mg QHS ×7 days. Dose can be 
increased further, based on response, to 4 mg QHS ×7 days. Target 1–5 mg/day.
 ⦁May dose-divide BID to target daytime PTSD-associated arousal symptoms.

Cost:  $
 ⦁Most common: Somnolence, dizziness, headache, weakness.
 ⦁Serious but rare: Orthostasis and syncope; prolonged erections and priapism have been reported.
 ⦁Alpha-1 adrenergic receptor antagonist.
 ⦁Metabolism primarily hepatic (non-CYP450); t ½: 2–3 hours.
 ⦁Caution with other antihypertensive agents, diuretics, and PDE5 inhibitors (eg, Viagra) that may have additive 
hypotensive effects.
 ⦁Initial studies showed improvement in trauma-related nightmares and sleep quality when dosed at bedtime, as well 
as positive effects on daytime PTSD symptoms when dosed BID. 
 ⦁Prazosin failed to work in a more recent controlled trial of military veterans with chronic PTSD. This was the largest

 ⦁Prazosin failed to work in a more recent controlled trial of military veterans with chronic PTSD. This was the largest 
study to date on this drug, but it had some flaws: The placebo rate was unusually high, and the investigators may 
have enriched their sample with patients who were less likely to respond to prazosin (Raskind MA et al,  N Engl J Med 
2018;378:507–517).
 ⦁Increasing data on efficacy in alcohol use disorder are promising, making prazosin a reasonable second-line option 
particularly for patients with any combination of anxiety, insomnia, nightmares, PTSD, or hypertension.
Fun Fact:
Prazosin is an older drug that is now rarely used for its original indication (hypertension). Aside from its uses in 
psychiatry, it is used most often as a second-line agent for urinary hesitancy in benign prostatic hyperplasia.

124  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONPROPRANOLOL  (Inderal) Fact Sheet [G]
Propranolol has several uses in psychiatry, including performance anxiety, drug-induced tremor, and akathisia. Some 
clinicians favor it as an “as needed” drug for a variety of anxiety issues, especially when benzos are contraindicated. 
Hypertension; angina; post-MI cardioprotection; atrial fibrillation; migraine prophylaxis; essential tremor.
Performance anxiety; tremor due to medication side effects (especially lithium); akathisia.
Tablets (G):  10 mg (scored), 20 mg (scored), 40 mg (scored), 60 mg (scored), 80 mg (scored).
 ⦁Performance anxiety (off-label): Give 10 mg about 60 minutes prior to performance; usual effective dose is 
10–40 mg.
 ⦁Medication-induced tremor (off-label): Start 10 mg BID as needed; can go up to 30–120 mg daily in two or three

10–40 mg.
 ⦁Medication-induced tremor (off-label): Start 10 mg BID as needed; can go up to 30–120 mg daily in two or three 
divided doses. Can also use Inderal LA, long-acting version of propranolol, 60–80 mg once a day.
 ⦁Akathisia (off-label): Start 10 mg BID; can go up to 30–90 mg daily in two or three divided doses.
Monitoring:  Periodic blood pressure/pulse.
Cost:  $
Most common: Dizziness, fatigue, bradycardia, and hypotension.
 ⦁Non-selective beta-1 and beta-2 adrenergic receptor antagonist.
 ⦁Metabolized primarily through CYP2D6, also CYP1A2 and CYP2C19; t ½: 3–6 hours.
 ⦁Caution with other antihypertensives (additive effects). CYP2D6 inhibitors, as well as inhibitors or inducers of 
CYP1A2 and CYP2C19, may affect propranolol levels.
With beta blockade, propranolol reduces some of the somatic symptoms of anxiety (tremor, sweating, flushing, 
tachycardia).
Fun Fact:

Fun Fact:
The list of notable people who suffer or have suffered from performance anxiety or stage fright is long. It includes 
Barbra Streisand, Carly Simon, Van Morrison, Frédéric Chopin, Renee Fleming, Jay Mohr, Hugh Grant, Laurence Olivier, 
Mahatma Gandhi, and Thomas Jefferson, among others.

Anxiolytic and Hypnotic MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   125RAMELTEON  (Rozerem) Fact Sheet [G]
Ramelteon is a melatonin receptor agonist. Compared to other hypnotics, ramelteon poses a lower risk for respiratory 
depression and hangover effect (morning grogginess). A good agent to have in your bag of tricks, but consider the 
possibility of rare hormonal effects. Also consider that over-the-counter melatonin (which ramelteon mimics) may do 
the same job, possibly at a lower price.
Insomnia  (sleep onset).
Jet lag; shift-work sleep disorder.
Tablets (G):  8 mg.
Start, target, and maximum dose 8 mg QHS, 30 minutes before bedtime. Avoid administering with high-fat meal 
(delays therapeutic effect by 45 minutes).
Cost:  $$

Cost:  $$
 ⦁Most common: Headache, somnolence, fatigue, dizziness, nausea.
 ⦁Serious but rare: Anaphylaxis, angioedema, complex sleep-related behavior (sleep driving, cooking, eating, phone 
calls), increased prolactin, abnormal cortisol or testosterone levels.
 ⦁Melatonin-1 and melatonin-2 receptor agonist.
 ⦁Metabolized primarily through CYP1A2 (major), and to a lesser extent CYP2C9 and CYP3A4; t ½: 1–2.6 hours.
 ⦁Avoid concomitant use with CNS depressants (additive effects). Exercise caution in patients taking potent CYP1A2 
inhibitors (eg, fluvoxamine), which could increase ramelteon’s effects.
 ⦁Because ramelteon’s mechanism of action relates to melatonin receptors and regulation of circadian rhythms, it

 ⦁Because ramelteon’s mechanism of action relates to melatonin receptors and regulation of circadian rhythms, it 
does not cause patients to “feel” sedated. Often patients say that it doesn’t start working for several days—however, 
clinical trials have shown efficacy from the first night of use. It’s good to warn patients about this ahead of time, or 
they may conclude it’s ineffective after a single night and stop using it.
 ⦁No evidence of abuse potential or physical dependence.
 ⦁Hormonal alterations occur very rarely and usually with high-dose (16 mg in one study) and longer-term use (six 
to 12 months). If unexplained amenorrhea, galactorrhea, decreased libido, or fertility problems occur, consider 
evaluating patient’s prolactin or testosterone levels.
Fun Fact:
Another melatonin agonist, agomelatine, has been studied as an antidepressant, partly because circadian rhythms are

Fun Fact:
Another melatonin agonist, agomelatine, has been studied as an antidepressant, partly because circadian rhythms are 
disrupted in depression. It is approved overseas, but the manufacturer scrapped its development in the US.

126  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONSUVOREXANT  (Belsomra) Fact Sheet
Suvorexant is an orexin receptor antagonist, and as such it treats insomnia differently from existing agents. Other 
than a new mechanism of action, suvorexant doesn’t have any clear advantages. It is no more effective than benzos 
or Z-drugs, and it has a similar abuse liability. We’re concerned that next-day impairment is a potential side effect at 
the highest approved dose of 20 mg, particularly since sleepless patients may decide on their own to take even higher 
Start 10 mg QHS, 30 minutes before bedtime and with at least seven hours remaining before planned awakening

Start 10 mg QHS, 30 minutes before bedtime and with at least seven hours remaining before planned awakening 
time. If tolerated but not effective, may increase to max 20 mg QHS. For more rapid onset, patients should wait at least 
an hour after a meal before taking it. Avoid administering within an hour of a high-fat meal (delays therapeutic effect 
by about 1.5 hours).
Cost:  $$$$
 ⦁Serious but rare: Impaired alertness and motor coordination, including impaired driving; dose-related worsening 
depression or suicidal ideation; sleep paralysis (inability to speak or move for up to a few minutes during the 
sleep-wake transition), hypnagogic/hypnopompic hallucinations (including vivid and disturbing perceptions), and

sleep-wake transition), hypnagogic/hypnopompic hallucinations (including vivid and disturbing perceptions), and 
cataplexy-like symptoms (leg weakness for seconds up to a few minutes both in the nighttime and the daytime) 
reported, especially at higher doses.
 ⦁Metabolized primarily through CYP3A4, with minor contribution from 2C19; t ½: 12 hours.
 ⦁Caution with CYP3A4 inhibitors and inducers; suvorexant dose adjustment recommended. Caution with alcohol and 
other CNS depressants.
 ⦁Schedule IV controlled substance. One study found that drug abusers “liked” suvorexant as much as Ambien.
 ⦁Suvorexant is contraindicated in patients with narcolepsy.
 ⦁The incidence of suicidal ideation reported with suvorexant seemed to be dose related, unlike lemborexant.

⦁Suvorexant is contraindicated in patients with narcolepsy.
 ⦁The incidence of suicidal ideation reported with suvorexant seemed to be dose related, unlike lemborexant. 
However, all patients taking suvorexant should be monitored for suicidality, particularly those with depression.
 ⦁Suvorexant has a unique mechanism of action. Unlike other hypnotics, it does not act by stimulating GABA 
or melatonin receptors or by blocking histamine. Instead, suvorexant blocks orexin receptors (orexins are 
 ⦁Risk of next-day impairment increases with dose; caution patients taking 20 mg against next-day driving and other 
 ⦁Suvorexant’s package label was updated in 2020 to include findings on its use in 285 patients with mild to moderate 
Alzheimer’s disease and insomnia. Suvorexant improved total sleep time and was well tolerated, with somnolence

Alzheimer’s disease and insomnia. Suvorexant improved total sleep time and was well tolerated, with somnolence 
(4% compared to 1% for placebo), dry mouth (2% compared to 1% for placebo), and falls (2% compared to 0% for 
placebo) as the most common side effects.
Fun Fact:
Merck expected to gain FDA approval for suvorexant in summer 2013. However, the FDA expressed concerns about 
safety with the proposed 30–40 mg dosing range and denied approval. It was finally approved in August 2014 at 
lower doses.

Anxiolytic and Hypnotic MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   127TEMAZEPAM  (Restoril) Fact Sheet [G]
Temazepam has the advantages of a short half-life and no active metabolites, and is therefore less likely to cause next-
day sedation. It’s a decent first-line agent for insomnia if a benzodiazepine is appropriate for use.
Capsules (G):  7.5 mg, 15 mg, 22.5 mg, 30 mg.
Cost:  15 mg, 30 mg: $; 7.5 mg, 22.5 mg: $$
 ⦁Serious but rare: Anterograde amnesia, increased fall risk, paradoxical reaction (irritability, agitation), respiratory

 ⦁Metabolized primarily through liver but no CYP450 involvement; t ½: 9–18 hours.
 ⦁Temazepam has long been a favored hypnotic for the elderly because of the lack of active metabolites, its short half-
life, and absence of drug interactions.
 ⦁If abruptly discontinued, withdrawal symptoms are usually seen on the first day and last for five to seven days in 
patients taking this type of short-intermediate half-life benzodiazepine.

⦁If abruptly discontinued, withdrawal symptoms are usually seen on the first day and last for five to seven days in 
Fun Fact:
The US Air Force uses temazepam as one of the approved “no-go pills” to help aviators and special duty personnel 
sleep in support of mission readiness; “ground tests” are required prior to authorization being issued to use the 
medication in an operational situation.

128  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONTRIAZOLAM  (Halcion) Fact Sheet [G]
Triazolam gained notoriety as the benzodiazepine that may have caused President George Bush to faint at a state 
dinner in 1992. It is rarely used due to the higher likelihood for adverse effects (anterograde amnesia, psychiatric 
disturbances) compared to other benzos.
Tablets (G):  0.125 mg, 0.25 mg (scored).
Start 0.25 mg QHS; max 0.5 mg QHS. Take immediately before bedtime. Use lower doses in elderly.
Cost:  $
 ⦁Most common: Drowsiness, headache, dizziness, ataxia.
 ⦁Serious but rare: Anterograde amnesia, increased fall risk, paradoxical reaction (irritability, agitation); respiratory

 ⦁Serious but rare: Anterograde amnesia, increased fall risk, paradoxical reaction (irritability, agitation); respiratory 
depression (avoid in patients with sleep apnea or opioid use).
 ⦁Metabolized primarily through CYP3A4; t ½: 1.5–5.5 hours.
with potent CYP3A4 inhibitors (eg, erythromycin, ketoconazole, fluvoxamine) as they may increase triazolam levels 
significantly, whereas CYP3A4 inducers (eg, carbamazepine) may decrease triazolam levels; adjust triazolam dosing.
 ⦁Rapid onset of effect; best to take when already in bed.
 ⦁Due to its short half-life, triazolam is not effective for patients who suffer from frequent awakenings or early

⦁Rapid onset of effect; best to take when already in bed.
 ⦁Due to its short half-life, triazolam is not effective for patients who suffer from frequent awakenings or early 
wakening; mostly useful for sleep onset.
 ⦁Rebound insomnia and other withdrawal symptoms are more likely and more severe with a short-acting 
benzodiazepine such as triazolam.
 ⦁May induce more anterograde amnesia than other benzodiazepines; concomitant use of alcohol or use of higher 
dose (0.5 mg) increases risk.
 ⦁Due to studies that suggest the frequency of severe psychiatric disturbances is higher with triazolam compared to 
other benzodiazepines, the United Kingdom and Brazil have banned it.
Serial killer Jeffrey Dahmer used triazolam to sedate his victims.

Anxiolytic and Hypnotic MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   129ZALEPLON  (Sonata) Fact Sheet [G]
Zaleplon is the only sleeping pill that can be taken at 3 or 4 a.m. without causing functional impairment when the 
patient gets out of bed a few hours later. It’s great for inducing sleep, but not great for sleep maintenance throughout 
the night.
Insomnia  (short term, sleep onset).
Capsules (G):  5 mg, 10 mg.
Start 10 mg QHS, which is the usual dose for most adults. Max 20 mg QHS in those who tolerate but don’t benefit from 
the usual 10 mg dose. Avoid administering with a high-fat meal (delays onset of effect by two hours). Use lower doses 
in elderly.
Cost:  $
 ⦁Most common: Somnolence, dizziness, headache.

Cost:  $
 ⦁Metabolized primarily through aldehyde oxidase and also CYP3A4; t ½: 1 hour.
inhibitors (eg, fluvoxamine, erythromycin) may increase effects of zaleplon significantly, whereas CYP3A4 inducers 
(eg, carbamazepine) may decrease zaleplon levels; adjust zaleplon dosing.
 ⦁Patients should take it immediately before going to bed or once they are in bed to minimize amnesic episodes.

 ⦁Because of zaleplon’s very short half-life, it rarely causes next-day impairment.
 ⦁Unlike benzodiazepines, zaleplon does not disrupt normal sleep stages.
 ⦁Most useful for sleep initiation disorders; does not substantially increase total sleep time or decrease number of 
awakenings.
 ⦁Classified as a Schedule IV drug, but at therapeutic doses, abuse potential is somewhat less than benzodiazepines. 
However, abuse potential at high doses (2.5–7.5 times recommended dose) is similar to that of benzodiazepines.
 ⦁Fewer withdrawal effects than with benzodiazepines, but abrupt discontinuation, particularly from higher doses, 
can cause withdrawal symptoms (mostly rebound insomnia).
Fun Fact:
The name “Sonata” calls to mind the classical music composition featuring three or four movements, much like the 
phases of sleep.

130  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONZOLPIDEM  (Ambien, Edluar, Intermezzo, Zolpimist) Fact Sheet [G]
Ambien is the original Z-drug, having been initially FDA approved in 1992. It is a good hypnotic that can also help 
with sleep maintenance, particularly in the ER formulation. The lower-dose sublingual version (Intermezzo) has a 
shorter duration of action and can be taken in the middle of the night—but we recommend using cheaper generic 
zaleplon instead for middle-of-the-night awakening.
Insomnia  (IR: short term, sleep onset; CR: sleep onset and maintenance; Intermezzo: difficulty falling asleep after 
middle-of-the-night awakening).
 ⦁Tablets (G):  5 mg, 10 mg.
 ⦁ER tablets (G):  6.25 mg, 12.5 mg.
 ⦁SL tablets (Edluar):  5 mg, 10 mg.
 ⦁SL tablets (Intermezzo, [G]):  1.75 mg, 3.5 mg.
 ⦁Oral spray (Zolpimist):  5 mg/spray.

⦁ER tablets (G):  6.25 mg, 12.5 mg.
 ⦁Start 10 mg QHS (5 mg in women). ER: Start 12.5 mg QHS (6.25 mg in women). Take immediately before bed, with at 
least seven to eight hours remaining before planned awakening time. Dose may be increased to max 10 mg (or 12.5 
mg ER) QHS if no daytime grogginess. Higher doses may lead to greater abuse potential. Use lower doses in elderly.
 ⦁Lower doses of 3.5 mg (men), 1.75 mg (women) SL QHS can be used with at least four hours remaining before 
wake time.
Cost:  $; Intermezzo, Zolpimist: $$; Edluar: $$$$
 ⦁Most common: Headache, somnolence, dizziness, diarrhea.
 ⦁Serious but rare: Complex sleep-related behavior (sleep driving, cooking, eating, phone calls).

⦁Serious but rare: Complex sleep-related behavior (sleep driving, cooking, eating, phone calls).
 ⦁Metabolized primarily through CYP3A4; t ½: 2.5–3 hours.
inhibitors may increase effects of zolpidem, whereas CYP3A4 inducers (eg, carbamazepine) may decrease zolpidem 
levels; adjust zolpidem dosing.
 ⦁Unlike benzodiazepines, zolpidem does not disrupt normal sleep stages.
 ⦁At therapeutic doses, abuse potential is somewhat less than with benzodiazepines.
 ⦁Less withdrawal effects than with benzodiazepines, but abrupt discontinuation, particularly from higher doses, can 
cause withdrawal symptoms (mostly rebound insomnia).

⦁Less withdrawal effects than with benzodiazepines, but abrupt discontinuation, particularly from higher doses, can 
 ⦁The CR formulation’s dual layer allows some medication to be released immediately, with the rest released gradually, 
resulting in higher levels through the night.
Fun Fact:
Bioavail Labs received FDA approval for an orally disintegrating tablet form of zolpidem called Tovalt in 2007. It has 
since been discontinued due to poor sales.

Dementia MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   131
Dementia Medications
Cognitive Impairment
While cholinesterase inhibitors do not improve patients’ memory, they do stop the decline of memory loss for six to 
12 months. After that reprieve, the clock starts ticking down again, and a person’s memory will decline along the same 
slope that it did before the medication was started. If the medication is interrupted, the person’s memory quickly 
drops by another six to 12 months of function—usually within a week or two. Unfortunately, the research shows that 
restarting the cholinesterase inhibitor will not bring the person’s memory back to where it was before the treatment 
interruption. 
For mild to moderate dementia, use one of the three approved cholinesterase inhibitors. These include donepezil,

For mild to moderate dementia, use one of the three approved cholinesterase inhibitors. These include donepezil, 
galantamine, and rivastigmine. We recommend starting with donepezil (we have the most data and experience with 
this agent, though the others are equally effective). Start with 5 mg daily for a month, then increase to 10 mg and 
maintain that dose if the patient is doing well. Later, if the patient is continuing to worsen, try to push the dose up to 
15 or 20 mg. The main limiting side effects are gastrointestinal issues and, occasionally, vivid dreams at night. 
Some clinicians start with 8 mg of sustained-release galantamine in the morning, increasing after a month to 16 mg, 
which is equivalent to 10 mg of donepezil. Increase to 24 mg of galantamine if needed. If the patient is bothered by 
vivid dreams, switch to immediate-release galantamine and start with 4 mg in the morning, increasing to 8 mg if 
tolerated.

tolerated. 
The rivastigmine patch is another option to consider, mainly for patients who are having intolerable GI side effects on 
one of the pills. While the patch causes fewer GI side effects, it’s more expensive than pills, and it’s more cumbersome 
because you need another person to take it off or put it on. The patch comes in 4.6 mg/24 hour, 9.5 mg/24 hour, and 
13.3 mg/24 hour doses. In general, start patients on the 4.6 mg patch and then move them up to the 9.5 mg. We rarely 
use the 13.3 mg dose, because that tends to cause the GI side effects that we are using the patch to avoid. 
In patients with moderate to severe Alzheimer’s dementia, for an FDA-approved approach, you can start with either 
memantine IR or high-dose donepezil (either by combining two 10 mg tablets or using the 23 mg version). Reserve

memantine IR or high-dose donepezil (either by combining two 10 mg tablets or using the 23 mg version). Reserve 
the more expensive memantine XR for those rare situations in which IR is poorly tolerated.
An alternative approach is to follow the same protocol for all your patients with dementia, whether or not it is “severe” 
or “moderate. ” Start with a combination of donepezil and memantine, and for patients who have trouble taking two 
pills, consider Namzaric, which is the combination donepezil/memantine.
The FDA’s approval of the amyloid beta monoclonal antibody aducanumab (Aduhelm) for treating mild cognitive 
impairment in Alzheimer’s disease has been fraught with controversy. Two pivotal Phase 3 trials showed decreases in 
amyloid plaque in the brain but showed minimal to no slowing of cognitive decline. In fact, these studies were closed 
early because the drug didn’t seem to be helping patients. Based on this, the FDA Advisory Committee took a pass on

early because the drug didn’t seem to be helping patients. Based on this, the FDA Advisory Committee took a pass on 
the drug in 2020, but it was later given accelerated approval in 2021. We don’t recommend it, due to its questionable 
efficacy, its potential serious side effects, and its high cost ($62,000 per year). 
When working with these patients, don’t forget to review their medications for agents that may be worsening 
cognition or causing confusion. These include benzodiazepines, non-benzo Z-drugs, and anticholinergic agents. You’ll 
find a list of medications with a heavy anticholinergic load in Appendix G.
Behavioral and Psychological Symptoms of Dementia (BPSD)
90% of patients with dementia have secondary symptoms, including agitation, aggression, wandering, psychosis, 
depression, and anxiety. Because of the frailty of this population, you should prioritize nonpharmacological

depression, and anxiety. Because of the frailty of this population, you should prioritize nonpharmacological 
treatments such as recreational therapy, art and music therapy, and habilitation therapy. However, meds are often 
needed to maintain safety, and here is a brief run-down of your options:
 ⦁Cholinesterase inhibitors.  The medications we discussed above not only delay cognitive decline but also often help 
with behavioral issues. They may be especially helpful in patients with dementia due to Parkinson’s or Lewy body 
disease. 
 ⦁SSRIs.  Several studies have shown that SSRIs help with mild to moderate levels of agitation, including psychomotor 
restlessness, irritability, hostility, and tearful dysphoria. While the largest study was done with citalopram, it has 
become less popular due to a recent FDA warning about QT interval prolongation. Thus, many clinicians prefer to

132  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONuse escitalopram (begin with 5 mg and titrate gradually to 20 mg) or sertraline (begin with 12.5 mg and titrate as 
high as 100 mg). Be wary of the possibility of upper GI bleeding and hyponatremia, both of which are uncommon 
SSRI side effects but more likely in the elderly. 
 ⦁Mirtazapine (Remeron).  Mirtazapine is helpful for insomnia as well as symptoms of depression. This drug has two 
other nice features for the elderly: It is less likely than SSRIs to cause hyponatremia, and it does not cause nausea (in 
fact, mirtazapine is an effective treatment for hyperemesis gravidarum, the severe nausea during pregnancy). Start 
at 7.5 mg at bedtime and titrate up as needed. 
 ⦁Benzodiazepines . We try to avoid these agents in the elderly because of potential side effects that include loss 
of balance, impaired cognition, and paradoxical agitation. If you do use benzos, it’s best to choose short-acting

of balance, impaired cognition, and paradoxical agitation. If you do use benzos, it’s best to choose short-acting 
agents such as lorazepam 0.25 mg as needed, which may be more effective in patients with a history of alcohol use 
disorder. For patients with REM sleep disorder, use the longer-acting clonazepam at bedtime. 
 ⦁Antipsychotics . In 2005, the FDA required a black box warning on the use of antipsychotics in dementia because of 
a 1.7-fold increase in mortality and an increased risk of stroke. It’s important to put this statistic into perspective. 
This is a proportional increase; in the long-term care setting, it would represent a change in the 180-day cumulative 
mortality rate from 15.1% to 16.6% (Gill SS,  Ann Intern Med  2007;146(11):775–786). In both Canada and the United 
Kingdom, risperidone is approved for short-term treatment of BPSD. The bottom line is that you should consider

Kingdom, risperidone is approved for short-term treatment of BPSD. The bottom line is that you should consider 
antipsychotics in the elderly when they display psychotic symptoms or severe aggression. Start with low-dose 
risperidone (0.125 mg to 0.25 mg) at bedtime and slowly titrate upwards. Switch to twice-daily dosing if there are 
breakthrough symptoms during the day. Avoid risperidone in patients with Parkinson’s disease—in these patients, 
use quetiapine or clozapine, or try the newly approved (but currently prohibitively expensive) pimavanserin 
(Nuplazid) if the others are not tolerated or effective.
 ⦁Mood stabilizers and anticonvulsants.  Gabapentin appears to be the most commonly used of the anticonvulsants, 
because it is well tolerated and effective for agitation. The usual dose is 100 mg timed to symptoms. Other 
lower side effect medications to consider are lamotrigine and oxcarbazepine. Depakote is used for impulsivity

lower side effect medications to consider are lamotrigine and oxcarbazepine. Depakote is used for impulsivity 
and disinhibition, though it can cause hyperammonemia leading to confusion. Lithium, though effective, is less 
commonly prescribed because of a range of side effects, risk for toxicity, and the need for blood level monitoring. 
 ⦁Other agents: 
 –Acetaminophen, oddly enough, is often helpful to prescribe to dementia patients, probably because it eases pain 
syndromes that are so common and underdiagnosed in the elderly. Prescribe 500 mg BID or TID, generally on a 
standing basis, since patients’ impaired cognition makes it unlikely that they will be able to communicate their 
needs for medication. 
 –Opiates. While on the subject of pain relief, we should mention low-dose opiates, which are highly effective 
for agitation related to pain. Use Roxanol liquid (morphine sulfate), beginning with 2.5 mg daily. Monitor for

for agitation related to pain. Use Roxanol liquid (morphine sulfate), beginning with 2.5 mg daily. Monitor for 
increased confusion or fall risk, especially early in therapy.
 –Trazodone, at a starting dose of 12.5 mg, is helpful both for agitation and insomnia, and can be given either at 
bedtime or at midday. 
 –Prazosin is well tolerated. Start with 1 mg at bedtime and titrate as needed up to 4 mg or more, divided BID, 
watching for blood pressure changes. 
 –Clonidine patch, 0.1 mg, is often effective for anxiety and agitation, and has the added benefit of ensuring 
compliance for patients who resist oral meds (as long as the patient can’t take it off). 
 –Dronabinol (Marinol) is a preparation of cannabinoids that is FDA approved for weight loss in AIDS and nausea in 
chemotherapy, but it is often used off-label for agitation in dementia. Start at 2.5 mg daily, increasing to 5 mg as 
needed.

needed. 
*We gratefully acknowledge the contributions of Dr. Andrew Budson and Dr. Alexis Freedberg for their practical 
advice regarding treatment of dementia and BPSD.

Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   133Mild to moderate 
dementia
Mood lability or 
impulse controlInsomniaAgitation/
psychosisAnorexia, 
weight lossDepression only PainGalantamine (second-
line alternative)
Valproic acid; 
other options 
include lithium, 
oxcarbazepine, 
carbamazepineAcetaminophen Dronabinol TrazodoneOpiate (for 
severe pain)MegestrolClonidine, 
prazosinAntipsychotics, 
benzodiazepines, 
gabapentin, trazodone, 
valproic acidAnxiety/
insomnia:  
SSRIs, 
mirtazapinePsychomotor 
retardation:
bupropion,
methylphenidateRivastigmine patch (for 
patients with GI side 
effects on pills)Memantine (up to 20 mg) 
plus donepezil (20–23 mg) or 
combination productDonepezil (most 
experience)Moderate to severe 
dementiaCognitive
Behavioral and 
psychological symptoms  
of dementia (BPSD)
Supportive and environmental measures (eg, music therapy, structured activity,

Supportive and environmental measures (eg, music therapy, structured activity, 
supportive staff, walking) should be tried before medications.Dementia Treatment Algorithm

134  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONTable 14:  Dementia Medications
Generic Name (Brand Name)
availabilityRelevant FDA Indication(s)Available Strengths
(mg except where noted)Usual Dosage Range
(mg)
Aducanumab
(Aduhelm)
2021Mild Alzheimer’s dementia Injection: 170 mg/1.7 mL, 300 
mg/3 mL10 mg/kg IV Q4 weeks
Donepezil [G]
(Aricept, Aricept ODT)
1996Mild to moderate Alzheimer’s dementia 
(5, 10 mg)
Moderate to severe Alzheimer’s dementia 
(10, 23 mg)Tablet: 5, 10, 23
ODT: 5, 10 5–23 QAM
Galantamine [G]
(Razadyne)
2001Mild to moderate Alzheimer’s dementia Tablet: 4, 8, 12
Liquid: 4 mg/mL 4–12 BID
Galantamine ER [G]
(Razadyne ER)
2004Mild to moderate Alzheimer’s dementia ER capsule: 8, 16, 24 8–24 ER QAM
Memantine [G]
(Namenda)
2003Moderate to severe Alzheimer’s dementia Tablet: 5, 10
Liquid: 2 mg/mL5 QAM–10 BID
Memantine ER [G]
(Namenda XR)

(Namenda)
2010Moderate to severe Alzheimer’s dementia ER capsule: 7, 14, 21, 28 7–28 QD
Memantine ER/donepezil [G]
(Namzaric)
2014Moderate to severe Alzheimer’s dementia 
(in patients already stabilized on both 
medications)ER capsule: 7/10, 14/10, 21/10, 
28/10Patients on memantine (10 mg BID 
or 28 mg XR QD) and donepezil 10 
mg QD can be switched to Namzaric 
28/10 mg QPM
Rivastigmine [G]
(Exelon)
2000Mild to moderate Alzheimer’s dementia
Mild to moderate dementia associated 
with Parkinson’s diseaseCapsule: 1.5, 3, 4.5, 6 1.5–6 BID
(Exelon Patch)
2007Mild to moderate and severe Alzheimer’s 
dementia
with Parkinson’s diseaseER patch: 4.6, 9.5, 13.3/24 hr 4.6–13.3/24 hr QD

Dementia MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   135ADUCANUMAB  (Aduhelm) Fact Sheet
Aducanumab is an antibody that attacks and dissolves the amyloid protein that is thought to contribute to 
Alzheimer’s dementia. It is the first new drug approved for Alzheimer’s since 2003. Unfortunately, it is marginally 
effective at best, requires monthly IV infusion, has cumbersome monitoring requirements, and carries potentially 
significant side effects, all at very high cost. We don’t recommend it. 
Mild Alzheimer’s dementia.
Injection:  170 mg/1.7 mL, 300 mg/3 mL.
Start 1 mg/kg IV infused over one hour Q4 weeks for the first two infusions; ↑ to 3 mg/kg IV Q4 weeks for the next two 
infusions; ↑ to 6 mg/kg IV Q4 weeks for infusions five and six; ↑ and continue recommended dose of 10 mg/kg IV Q4 
weeks for infusion seven and beyond.

weeks for infusion seven and beyond. 
Monitoring:  Baseline brain magnetic resonance imaging (MRI), repeat MRI prior to the seventh and 12th infusions. If 
there are 10 or more incident microhemorrhages or more than two focal areas of superficial siderosis, continue with 
caution only if follow-up MRI shows stabilization. 
 ⦁Most common: Amyloid-related imaging abnormalities in 41% of patients including edema, headache, 
microhemorrhage, superficial siderosis; confusion; dizziness; nausea; falls. 
 ⦁Serious but rare: Angioedema, urticarial; discontinue if hypersensitivity reaction occurs. 
 ⦁Recombinant human immunoglobulin gamma-1 (IgG1) anti-amyloid beta monoclonal antibody.
 ⦁Degraded into small peptides and amino acids through catabolic pathways, similar to endogenous IgG; t ½: 25 days.

⦁Degraded into small peptides and amino acids through catabolic pathways, similar to endogenous IgG; t ½: 25 days.
 ⦁No drug interactions known.
 ⦁Aducanumab was granted accelerated approval based on reduction in amyloid beta plaques; continued approval 
may be contingent on verification of clinical benefit in further studies.
 ⦁Aducanumab, if used, should only be used in patients with mild cognitive impairment. There are no data on its 
effects in earlier or later stages. 
 ⦁Amyloid-related imaging abnormalities are very common. Associated clinical symptoms, most commonly headache, 
confusion, dizziness, visual disturbance, and nausea, were present in 24% of patients treated with aducanumab.
Fun Fact:
Allegations about improper collaboration between the FDA and aducanumab’s manufacturer Biogen have led to calls 
for an investigation by the inspector general. A number of health systems have publically stated they will not use the

for an investigation by the inspector general. A number of health systems have publically stated they will not use the 
drug until more convincing data are available.

136  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONDONEPEZIL  (Aricept) Fact Sheet [G]
Donepezil is the cholinesterase inhibitor with the longest track record and with which we have the most experience. 
It is generally considered the first-line agent for dementia. Though not a cure, it delays dementia progression by six to 
12 months. 
Mild to moderate Alzheimer’s dementia  (5 mg, 10 mg); moderate to severe Alzheimer’s dementia   
(10 mg, 23 mg).
Other memory disorders; mild cognitive impairment.
 ⦁Tablets (G):  5 mg, 10 mg, 23 mg.
 ⦁Orally disintegrating tablets (Aricept ODT, [G]):  5 mg, 10 mg.
 ⦁Mild to moderate dementia: Start 5 mg QAM and ↑ to 10 mg QAM after four to six weeks.
 ⦁Moderate to severe dementia: May ↑ further to 23 mg QAM after at least three months (range 10–23 mg/day).

⦁Moderate to severe dementia: May ↑ further to 23 mg QAM after at least three months (range 10–23 mg/day).
Cost:  $
 ⦁Most common: Dose-related diarrhea, nausea, vomiting, weight loss (especially 23 mg/day dose), anorexia, 
insomnia, abnormal dreams.
 ⦁Serious but rare: Cholinesterase inhibitors may have vagotonic effects that may cause bradycardia and/or heart 
block with or without a history of cardiac disease; syncope reported.
 ⦁Acetylcholinesterase (AChE) inhibitor.
 ⦁Metabolized primarily through CYP2D6 and CYP3A4; t ½: 70 hours.
 ⦁Avoid use with anticholinergic agents as they will diminish therapeutic effects; avoid beta blockers due to risk of 
bradycardia. P450 interactions not usually clinically important.
 ⦁Donepezil is our first-line AChE inhibitor because of its good track record and tolerability.

 ⦁Donepezil is the second drug to be approved for dementia after tacrine, which was pulled from the market due to 
liver toxicity; donepezil is also the most prescribed of the three cholinesterase inhibitors. It received additional FDA 
approval for use in severe dementia (in addition to its initial approval for mild to moderate dementia).
 ⦁Although the manufacturer recommends bedtime dosing, we recommend starting it in the morning to minimize 
insomnia and vivid dreams.
 ⦁GI side effects usually resolve in one to two weeks.
 ⦁Based on a Cochrane review, donepezil causes fewer side effects than rivastigmine.
Fun Fact:
Donepezil has been studied in children for autism, pervasive developmental disorders, ADHD, and tic disorders; 
however, the minimal data do not support such use.

Dementia MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   137GALANTAMINE  (Razadyne, Razadyne ER) Fact Sheet [G]
Galantamine has no appreciable benefit over donepezil; however, its availability in a liquid formulation is helpful for 
patients who have difficulty swallowing pills. 
Mild to moderate Alzheimer’s dementia.
 ⦁Tablets (G):  4 mg, 8 mg, 12 mg.
 ⦁ER capsules (Razadyne ER, [G]):  8 mg, 16 mg, 24 mg.
 ⦁Oral solution (G):  4 mg/mL.
 ⦁IR: Start 4 mg BID (breakfast and dinner), ↑ by 4 mg BID increments every four weeks.
 ⦁ER: Start 8 mg QAM (breakfast), ↑ by 8 mg/day every four weeks.
 ⦁For both, max 24 mg/day (target dose: 16–24 mg/day).
 ⦁If using oral solution, mix dose with three to four ounces of any nonalcoholic beverage; mix well and drink 
immediately.

⦁For both, max 24 mg/day (target dose: 16–24 mg/day).
 ⦁If therapy is interrupted for three or more days, restart at the lowest dose and increase to current dose.
Cost:  $$; liquid: $$$
 ⦁Most common: Diarrhea, nausea, vomiting, weight loss, anorexia, insomnia, abnormal dreams.
 ⦁Acetylcholinesterase (AChE) inhibitor and cholinergic nicotinic receptor modulator.
 ⦁Metabolized primarily through CYP2D6 and CYP3A4; t ½: 7 hours.

⦁Acetylcholinesterase (AChE) inhibitor and cholinergic nicotinic receptor modulator.
bradycardia. CYP450 interactions not usually clinically important.
 ⦁Galantamine’s claim to fame is that it has a “dual” mechanism of action, modulating cholinergic nicotinic receptors in 
addition to inhibiting AChE. The manufacturer may use this factoid to argue that galantamine is more effective than 
the other cholinesterase inhibitors. However, accumulating evidence seems to show no difference in efficacy (Birks J, 
Cochrane Database Syst Rev  2006;(1):CD005593).
 ⦁ER formulation seems to be used more often due to ease of once-daily dosing.
Fun Fact:
Razadyne was approved in 2001 with its original name, Reminyl. However, pharmacists sometimes confused written

Fun Fact:
Razadyne was approved in 2001 with its original name, Reminyl. However, pharmacists sometimes confused written 
scripts for Reminyl with Amaryl, a diabetes medication. In April 2005, the trade name was changed to Razadyne to 
avoid future dispensing errors.

138  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONMEMANTINE  (Namenda, Namenda XR) Fact Sheet [G]
Memantine’s indication (moderate to severe dementia only) may limit its use, but it does boast a unique mechanism 
of action and has some data to support its usefulness as an augmenter of donepezil. Many prescribers put the 
majority of their dementia patients on a combination of one of the cholinesterase inhibitors and memantine; we 
recommend adding memantine when dementia has progressed to the moderate or severe level, possibly earlier. 
There’s no clinical benefit to using the more expensive XR version.
Moderate to severe Alzheimer’s dementia.
Mild to moderate Alzheimer’s dementia; other memory disorders; mild cognitive impairment; chronic pain.
 ⦁Oral solution (G):  2 mg/1 mL.
 ⦁ER capsules (Namenda XR, [G]): 7 mg, 14 mg, 21 mg, 28 mg.

 ⦁IR: 5 mg QD week one; 5 mg BID week two; 10 mg QAM and 5 mg QHS week three; 10 mg BID week four and 
beyond.
 ⦁XR: Start 7 mg QD; ↑ by 7 mg/day in increments of at least one week to max dose 28 mg/day (10 mg BID equivalent 
to 28 mg XR QD). Can be opened and sprinkled on food.
Cost:  IR: $; ER: $$; liquid: $$$
Most common: Dizziness (XR), transient confusion (IR), headache (XR), diarrhea (XR), constipation, sedation.
 ⦁Metabolism primarily hepatic, but not CYP450; t ½: 60–80 hours.
 ⦁Pharmacokinetic interactions unlikely.

⦁N-methyl-D-aspartate (NMDA) receptor antagonist.
 ⦁FDA approved for moderate to severe Alzheimer’s dementia only; may also be effective as augmentation added to 
donepezil in patients with moderate to severe Alzheimer’s dementia (see memantine ER/donepezil fact sheet).
 ⦁Data comparing 10 mg BID and 20 mg QD of IR formulation, as well as pharmacokinetic profile, support use of once-
daily IR dosing; IR is used QD in Europe.
Fun Fact:
Forest Pharmaceuticals had announced it was discontinuing sales of the IR formulation as of August 15, 2014, in order 
to “focus on” the XR formulation—just ahead of the IR patent expiration. However, the New York attorney general 
filed an antitrust lawsuit, claiming this was an anticompetitive move, and Forest was forced to continue offering both 
Namenda IR and Namenda XR.

Dementia MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   139MEMANTINE  ER/ DONEPEZIL  (Namzaric) Fact Sheet
Namzaric combines donepezil and memantine in a single capsule. It is helpful for patients who are already on this 
combination regimen but who have trouble taking two pills.
Mild to moderate Alzheimer’s dementia; other memory disorders; mild cognitive impairment.
Capsules:  7 mg/10 mg, 14 mg/10 mg, 21 mg/10 mg, 28 mg/10 mg memantine ER and donepezil.
 ⦁Patients should first be stabilized on the individual medications; patients on memantine (10 mg BID or 28 mg XR 
QD) and donepezil 10 mg QD can be switched to Namzaric 28 mg/10 mg QPM.
 ⦁Patients with severe renal impairment on memantine 5 mg BID or 14 mg XR QD and donepezil 10 mg QD can be 
switched to Namzaric 14 mg/10 mg QPM.

⦁Patients with severe renal impairment on memantine 5 mg BID or 14 mg XR QD and donepezil 10 mg QD can be 
Cost:  $$$$
 ⦁Most common: Headache, diarrhea, dizziness, vomiting, weight loss, anorexia, insomnia, abnormal dreams.
 ⦁N-methyl-D-aspartate (NMDA) receptor antagonist and acetylcholinesterase (AChE) inhibitor.
 ⦁Metabolism: Memantine hepatic but not CYP450, and donepezil primarily through CYP2D6 and CYP3A4; t ½: 60–80 
hours (memantine) and 70 hours (donepezil).
 ⦁Avoid use with anticholinergic agents as they will diminish therapeutic effects; avoid beta blockers due to risk of

 ⦁Many experts now stabilize patients on an AChE inhibitor like donepezil and then add memantine.
 ⦁The manufacturer recommends bedtime dosing, but taking it in the morning may prevent the insomnia and vivid 
dreams some patients report with donepezil.
 ⦁Once-a-day dosing makes this agent easiest to use.
 ⦁Be mindful of other medications that may have intrinsic anticholinergic activity; these will counteract donepezil’s 
therapeutic effects.
Fun Fact:
In 2014, Actavis Pharmaceuticals acquired Forest Pharmaceuticals, manufacturer of Namzaric. That same year, Actavis 
also acquired Allergan, manufacturer of Botox, another medication targeting the aging process but in a different way.

140  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONRIVASTIGMINE  (Exelon, Exelon Patch) Fact Sheet [G]
Rivastigmine is the only cholinesterase inhibitor available in patch form, which may be an advantage for patients who 
refuse or have difficulty swallowing medication. We generally consider rivastigmine a second-line agent due to the 
need for twice-daily dosing, its high cost, and its high rate of nausea and vomiting.
Mild to moderate Alzheimer’s dementia  (capsules); mild to moderate and severe Alzheimer’s dementia  (patch); 
dementia associated with Parkinson’s disease  (capsules and patch).
 ⦁Capsules (G):  1.5 mg, 3 mg, 4.5 mg, 6 mg.
 ⦁Transdermal patches (G):  4.6 mg/24 hour, 9.5 mg/24 hour, 13.3 mg/24 hour, containing rivastigmine 9 mg, 18 mg, 
and 27 mg, respectively.

⦁Transdermal patches (G):  4.6 mg/24 hour, 9.5 mg/24 hour, 13.3 mg/24 hour, containing rivastigmine 9 mg, 18 mg, 
 ⦁Start 1.5 mg BID with meals for four weeks, ↑ by 1.5 mg BID increments every four weeks, up to max 6 mg BID with 
meals.
 ⦁Patch: For mild to moderate dementia, start 4.6 mg/24 hours; if tolerated, ↑ after at least four weeks to 9.5 mg/24 
hours (target and max dose). For severe dementia, titrate to 13.3 mg/24 hours (effective and max dose).
 ⦁Converting oral to patch: <6 mg/day: Use 4.6 mg/24 hour patch; 6–12 mg/day: Use 9.5 mg/24 hour patch; apply 
patch on next day following last oral dose.
Cost:  Oral: $; patch: $$$
 ⦁Most common: Dizziness, headache, diarrhea, anorexia, nausea, vomiting, skin reactions (patch).
 ⦁Serious but rare: Cholinesterase inhibitors may have vagotonic effects that may cause bradycardia and/or heart

⦁Serious but rare: Cholinesterase inhibitors may have vagotonic effects that may cause bradycardia and/or heart 
 ⦁Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitor.
 ⦁Metabolized extensively, although CYP enzymes minimally involved; t ½: 1.5 hours (oral); 3 hours (after patch 
removal).
bradycardia. P450 interactions not likely.
 ⦁Only cholinesterase inhibitor with additional indication for Parkinson’s-related dementia.
 ⦁Rivastigmine inhibits both AChE and the nonspecific BuChE (also known as pseudocholinesterase), which is mostly 
found in the liver and GI tract; this may explain why rivastigmine causes significant GI side effects.
 ⦁Rivastigmine transdermal patches may cause less nausea and vomiting.

Fun Fact:
Exelon is also the name of a corporation that provides energy services (electric and natural gas) and is the largest 
nuclear operator in the United States.

Mood Stabilizers and Anticonvulsants                                                                   Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   141
Mood Stabilizers and Anticonvulsants
In this chapter, we focus on the non-antipsychotic mood stabilizers—meaning lithium, valproic acid, lamotrigine, 
carbamazepine, and oxcarbazepine. The antipsychotics, most of which are effective for bipolar disorder, are covered 
in their own chapter. This chapter also includes anticonvulsants that may not be particularly useful in treating bipolar 
but may be used from time to time in psychiatric practice.
Here are some general observations:
 ⦁Manic episodes.  Generally the most effective drugs for rapid control of acute mania are antipsychotics and mood 
stabilizers, often combined with benzodiazepines. While head-to-head studies are scant, clinical lore has it that

stabilizers, often combined with benzodiazepines. While head-to-head studies are scant, clinical lore has it that 
olanzapine, quetiapine, and haloperidol are the most rapidly effective antipsychotics in highly agitated and 
psychotic patients. Unfortunately, all three medications are highly likely to cause side effects. 
 ⦁Bipolar depression.  The medications with FDA indications for the treatment of bipolar depression include the 
combination of fluoxetine and olanzapine (Symbyax), quetiapine (Seroquel), lurasidone (Latuda), and most recently 
cariprazine (Vraylar) and lumateperone (Caplyta). All five have their drawbacks, related to side effects (Symbyax and 
Seroquel) or cost (Latuda, Vraylar, and Caplyta). There’s good evidence for lithium, lamotrigine, and aripiprazole for 
bipolar depression, and you can add bupropion to any mood stabilizer—bupropion being the antidepressant least 
likely to cause a manic switch.

likely to cause a manic switch. 
 ⦁Maintenance treatment of bipolar disorder.  Maintenance treatment should include a mood stabilizer with a proven 
record of reducing cycling and increasing the time period between acute episodes. Only a few meds have such a 
record. These include lithium (more effective at preventing mania than depression), lamotrigine (more effective 
at preventing depression than mania), and some second-generation antipsychotics (olanzapine, aripiprazole, 
quetiapine, and ziprasidone, all more effective at preventing mania than depression). In addition, valproic acid and 
carbamazepine are commonly used as maintenance treatment. 
Several mood stabilizers are also classified as anticonvulsants, and you should note that the FDA issued a black

Several mood stabilizers are also classified as anticonvulsants, and you should note that the FDA issued a black 
box warning regarding suicide for anticonvulsants as a class. The warning is based on pooled analysis of 199 trials 
involving various antiepileptics (regardless of indication) that showed an increased risk of suicidal thoughts/behavior 
(incidence rate: 0.43% of treated patients compared to 0.24% of patients receiving placebo). The risk was observed as 
early as one week after initiation and continued through duration of trials (most of which were ≤24 weeks). The risk 
was higher for patients with seizure disorders compared to those receiving anticonvulsants for other indications.
Another class warning for the anticonvulsants regards a potentially serious, sometimes fatal multi-organ 
hypersensitivity reaction syndrome (drug rash with eosinophilia and systemic symptoms, or DRESS), which has

hypersensitivity reaction syndrome (drug rash with eosinophilia and systemic symptoms, or DRESS), which has 
rarely been reported with some antiepileptic drugs. Symptoms may include fever, rash, and/or lymphadenopathy; 
monitor for signs and symptoms of possible disparate manifestations associated with lymphatic, hepatic, renal, and/
or hematologic organ systems. Early symptoms of hypersensitivity reaction (eg, lymphadenopathy, fever) may occur 
without rash. If this occurs, discontinuation and conversion to alternate therapy may be required.
Switching or Discontinuing Mood Stabilizers
Patients with bipolar disorder are at relatively high risk for relapsing to either manic or depressive episodes. For this 
reason, switching or discontinuing mood stabilizers requires special caution. For instance, patients who discontinue 
maintenance lithium have a 60%–90% risk of recurrence of a mood episode within a year. And this risk is greater the

maintenance lithium have a 60%–90% risk of recurrence of a mood episode within a year. And this risk is greater the 
more abruptly the lithium is stopped: Discontinuing lithium over two to four weeks is significantly less likely to lead to 
relapse than discontinuing in two weeks or less (Baldessarini RJ et al,  Am J Psychiatry  1997;154(4):551).
While we don’t have as much data on how to discontinue mood stabilizers other than lithium, it’s reasonable to assume 
that relapse risks are higher with more rapid tapering. When switching among lithium, valproate, carbamazepine, or 
lamotrigine, you should cross-taper as gradually as is feasible—typically over at least a two-week period. 
Here’s an example of how you might take two weeks to gradually transition a patient from lithium 1500 mg daily to a 
therapeutic dose of valproate: 
 ⦁Days one to three: Continue lithium at 1500 mg daily as you start valproate at 250–500 mg QHS.

 ⦁Days one to three: Continue lithium at 1500 mg daily as you start valproate at 250–500 mg QHS. 
 ⦁Days four to six: Decrease lithium to 1200 mg daily. Increase valproate to 750–1000 mg QHS.

142  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION ⦁Days seven to nine: Decrease lithium to 900 mg daily. Increase valproate to 1000–1250 mg daily QHS or in 
divided doses. 
 ⦁Days 10–12: Decrease lithium to 600 mg daily. Increase valproate or hold depending on side effects/blood level. 
 ⦁Days 13–15: Decrease lithium to 300 mg daily. Maintain valproate dose. 
 ⦁Day 16: Discontinue lithium. Maintain valproate dose.
This guideline is applicable to most switches, with the exception of switching from any mood stabilizer to lamotrigine, 
which requires a very slow dosing schedule to lower the risk of a serious rash. In switching to lamotrigine, you 
will typically maintain the first mood stabilizer at a nearly full therapeutic dose while titrating lamotrigine in small 
increments (see lamotrigine fact sheet for details) up to 100 mg daily, which requires about four weeks. You can

increments (see lamotrigine fact sheet for details) up to 100 mg daily, which requires about four weeks. You can 
then start tapering the first medication as you continue to increase lamotrigine. In the special case of switching from 
valproate to lamotrigine, you must slow down the titration even more. 
There’s a great tradition in psychiatry of adopting antiepileptic drugs for use in psychiatric syndromes. In some cases, 
as above, this strategy has yielded effective treatments. But for gabapentin, pregabalin, and topiramate, the payoff 
has been fairly scant. All three were initially touted as having efficacy in bipolar disorder, based on uncontrolled trials. 
However, subsequent data from randomized controlled trials did not support this indication.
Nonetheless, these drugs have found their places in other spheres, especially disorders related to anxiety or substance

Nonetheless, these drugs have found their places in other spheres, especially disorders related to anxiety or substance 
use. For example, pregabalin is approved for generalized anxiety disorder in parts of Europe. It also has pretty 
convincing data for effectiveness in helping patients discontinue benzodiazepines. Topiramate seems to have a niche 
for patients with alcohol dependence and for any patient who wants to lose weight. Gabapentin is a non-addictive 
alternative to benzodiazepines for anxiety and alcohol dependence.
The newer anticonvulsants are appealing because they are generally less toxic than the older agents, do not require 
serum level monitoring, and in most cases have a lower risk of drug interactions. However, the antiepileptics have a 
class warning for increased risk of suicidal thoughts and behavior; this warning stems from pooled analysis of trials

class warning for increased risk of suicidal thoughts and behavior; this warning stems from pooled analysis of trials 
(for seizure disorders as well as other indications) that showed a nearly doubled incidence of suicidal thought and 
behavior (0.43% for anticonvulsants vs 0.24% for placebo).
You’ll note that the DEA has deemed pregabalin a controlled substance (Schedule V). Some states are reclassifying 
gabapentin as a controlled substance or mandating reporting to prescription drug monitoring programs (PDMPs). 
Reports of diversion and misuse of both pregabalin and gabapentin have been accumulating. Recreational use 
seems to be higher among individuals with opioid use disorder, and this may be related to the potentiation of 
euphoria described when the two are used together. Similar to combining benzos with opioids, the combination of 
gabapentinoids and opioids also increases the risk of opioid-related death. When using these in patients, be sure to

gabapentinoids and opioids also increases the risk of opioid-related death. When using these in patients, be sure to 
monitor for misuse or diversion.

Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   143Classic euphoric
Lithium plus an 
CarbamazepineGeneric 
olanzapine 
10 mg IM
—
May be as effective 
as standard cocktail
Tamoxifen
—
Meta-analysis 
comprising 
69 patients 
showed benefitValproic acid 
alone or with an 
ClozapineZiprasidone 
20 mg IM
—
Calming but 
than othersLithium
Lithium plus valproic 
acid plus antipsychoticHaloperidol 5 mg, 
 lorazepam 1 mg,  
benztropine 1 mg/diphenhydramine 50 mg  
(all IM)
—
Standard cocktail, much experience
Allopurinol
—
433 patients 
showed benefitOther 
anticonvulsants 
(lamotrigine, 
gabapentin, 
oxcarbazepine)Mixed manic
Treatment resistantAntipsychoticAntipsychotic 
plus valproic acid 
or lithiumAgitated in acute setting, refusing 
oral meds
When everything else has 
been triedProbably not effective
Consider adding lorazepam 1 mg as needed for all 
patients in an acute manic episode

oral meds
SE = side effects Bipolar Mania Treatment Algorithm

144  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONTable 15:  Mood Stabilizers
Year FDA Approved for Bipolar 
Disorder or Mania
[G] denotes generic availabilityRelevant FDA Indication(s) Available Strengths (mg)Usual Dosage Range
(mg)
Carbamazepine [G]
(Carbatrol, Epitol, Equetro, Tegretol, 
Tegretol XR, Teril)
2004Bipolar disorder (Equetro: Acute 
mania)CH: 100, 200
IR: 100, 200, 300, 400
ER: 100, 200, 300, 400
Oral solution: 100 mg/5 mL200–800 BID
Lamotrigine [G]
(Lamictal, Lamictal CD, Lamictal 
ODT, Lamictal XR, Subvenite)
2003Bipolar disorder (maintenance) IR: 25, 50, 100, 150, 200
CH: 2, 5, 25
ODT: 25, 50, 100, 200
ER: 25, 50, 100, 200, 250, 30025 QD–100 BID
25 QD–50 BID if on VPA
Lithium [G]
(Eskalith, Lithobid)
1970Acute mania
Bipolar maintenanceIR: 150, 300, 600
ER: 300, 450
Oral solution: 300 mg/5 mL300–600 QHS–1200 BID
Oxcarbazepine [G]
(Oxtellar XR, Trileptal)
2000Not approved for any bipolar

2000Not approved for any bipolar 
indicationIR: 150, 300, 600
ER: 150, 300, 600
Oral suspension: 300 mg/5 mL300–1200 BID
Valproic acid [G]
(Depakene, Depakote, Depakote 
ER, Depakote Sprinkles)
1995Bipolar disorder (acute mania) IR: 250
Liquid: 250 mg/5 mL
DR: 125, 250, 500
ER: 250, 500250–500 QHS–2000 BID
CH = chewable, IR = immediate release, ER = extended release, ODT = orally disintegrating tablet, DR = delayed release
Table 16:  Anticonvulsants
[G] denotes generic availabilityOff­Label Psychiatric Uses Available Strengths (mg)Usual Dosage Range 
(Gralise, Horizant, Neurontin)
1993Anxiety disorders
Withdrawal from alcohol or 
Alcohol dependenceCapsule: 100, 300, 400

ER tablet: 300, 600100 QHS–300 TID
(Lyrica, Lyrica CR)
2004Generalized anxiety disorder
Alcohol dependenceCapsule: 25, 50, 75, 100, 150, 200, 
225, 300
Oral solution: 20 mg/mL
ER tablet: 82.5, 165, 33075–300 BID 
Topiramate [G]
(Eprontia, Qudexy XR, Topamax, 
Trokendi XR)
1996Alcohol dependence
PTSD
Binge-eating disorder
ObesityTablet: 25, 50, 100, 200
Capsule: 15, 25
ER capsule: 25, 50, 100, 150, 200
Oral solution: 25 mg/mL25–150 BID

Mood Stabilizers and Anticonvulsants                                                                   Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   145CARBAMAZEPINE  (Epitol, Equetro, Tegretol, others) Fact Sheet [G]
Equetro is the only FDA-approved formulation of carbamazepine for bipolar disorder, but use of other formulations 
would result in the same effects at a lower price. Generally, carbamazepine is not considered a first-line treatment for 
bipolar disorder due to its side effect profile and high likelihood of significant drug interactions.
Bipolar disorder  (Equetro: acute mania); seizures; trigeminal neuralgia.
Bipolar maintenance; impulse control disorders; violence and aggression.
 ⦁Chewable tablets (G):  100 mg, 200 mg (scored).
 ⦁Tablets (Tegretol, Epitol, [G]):  100 mg, 200 mg, 300 mg, 400 mg (scored).
 ⦁ER tablets (Tegretol XR, [G]):  100 mg, 200 mg, 400 mg.

 ⦁ER capsules (Equetro, Carbatrol, [G]):  100 mg, 200 mg, 300 mg.
 ⦁Oral solution (Tegretol, Teril, [G]):  100 mg/5 mL.
 ⦁Bipolar disorder: Start at 200 mg BID and gradually ↑ by 200 mg/day every three to four days, to target 400–600 mg 
BID (guided by clinical response). Max 800 mg BID. Dosing is the same for IR and ER versions of carbamazepine; both 
are BID.
 ⦁Extended-release formulations of carbamazepine are better tolerated than immediate release. 
Monitoring:  Carbamazepine level, complete blood count, sodium, LFT, pregnancy test, HLA-B*1502 in Asians.
Cost:  $
 ⦁Most common: Dizziness, somnolence, nausea, headache. 
 ⦁Serious but rare: Hematologic abnormalities including agranulocytosis, aplastic anemia, neutropenia, leukopenia,

Cost:  $
 ⦁Serious but rare: Hematologic abnormalities including agranulocytosis, aplastic anemia, neutropenia, leukopenia, 
thrombocytopenia, and pancytopenia reported; hepatic complications including slight increases in hepatic 
enzymes, cholestatic and hepatocellular jaundice, hepatitis and (rarely) hepatic failure, hyponatremia, SIADH; rash 
(5%–10%), including exfoliation, reported. Severe reactions including toxic epidermal necrolysis and Stevens-
Johnson syndrome are rare, but can be fatal.
 ⦁Sodium channel blocker.
 ⦁Metabolized primarily through CYP3A4; t ½: 15 hours (initially 25–65 hours, but induces its own metabolism within 
two to four weeks and then stabilizes).
 ⦁High potential for significant interactions: Potent inducer of CYP1A2, CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP3A4,

 ⦁High potential for significant interactions: Potent inducer of CYP1A2, CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP3A4, 
P-glycoprotein; use caution with medications significantly metabolized through these pathways as their levels 
may become subtherapeutic; caution in patients taking strong CYP3A4 inducers or inhibitors that can affect 
carbamazepine levels.
 ⦁Avoid concomitant use with oral contraceptives (can lower serum levels of these contraceptives and cause 
unplanned pregnancies) and with clozapine (additive risk of agranulocytosis).
 ⦁ER capsules such as Carbatrol have been shown to cause less fluctuation in serum CBZ level and fewer side effects, 
so start with this formulation when possible (some insurance companies might require pre-authorization). 
 ⦁Therapeutic levels: 4–12 mcg/mL in seizure disorders. Studies in bipolar haven’t shown correlation between levels 
and clinical response, so it’s best dosed clinically.

⦁Therapeutic levels: 4–12 mcg/mL in seizure disorders. Studies in bipolar haven’t shown correlation between levels 
 ⦁Lab monitoring:  Baseline and periodic (at six weeks and every three months) CBC and LFTs.
 ⦁Patients of Asian descent should be screened for the variant HLA-B*1502 allele prior to starting carbamazepine; 
this variant is associated with significantly increased risk of developing Stevens-Johnson syndrome and/or toxic 
epidermal necrolysis. Avoid use in such patients.
Fun Fact:
Carbamazepine may cause a false-positive serum TCA screen—indeed, its chemical structure contains the familiar 
tricyclic nucleus common to all TCAs.

146  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONGABAPENTIN  (Gralise, Horizant, Neurontin) Fact Sheet [G]
Gabapentin used to be considered a non-addictive medication for anxiety and for alcohol dependence, but we now 
know it may be misused and diverted for its euphoriant effect. If monitored closely, it can still be helpful for anxiety 
and insomnia, especially if your patient also suffers from one of the approved indications—such as neuropathic pain 
and restless legs syndrome.
Partial seizures (Neurontin); post-herpetic neuralgia (Gralise, Neurontin); restless legs syndrome (Horizant).
Anxiety disorders; withdrawal from alcohol or benzodiazepines; alcohol dependence.
 ⦁Capsules (G):  100 mg, 300 mg, 400 mg.
 ⦁Tablets (G):  600 mg, 800 mg.
 ⦁Oral solution (G):  50 mg/mL.
 ⦁Tablets, ER (Gralise):  300 mg, 600 mg.

 ⦁Tablets, ER (Horizant): 300 mg, 600 mg (gabapentin enacarbil, a prodrug with better bioavailability).
 ⦁Anxiety (off-label): Start 100 mg QHS and ↑ by 100 mg/day increments every few days as tolerated to 300 mg 
TID. Max 3600 mg/day (highest doses often used for pain indications). Use lower doses in patients with renal 
 ⦁Restless legs syndrome: Use gabapentin enacarbil (Horizant) 600 mg QD at 5 p.m.
Cost:  IR: $; ER: $$$$$
 ⦁Most common: Dizziness, somnolence, ataxia, weight gain.
 ⦁Serious but rare: Potentially serious, sometimes fatal multiorgan hypersensitivity (also known as drug reaction with 
eosinophilia and systemic symptoms, or DRESS); respiratory depression.

⦁Serious but rare: Potentially serious, sometimes fatal multiorgan hypersensitivity (also known as drug reaction with 
 ⦁Blocks voltage-dependent calcium channels and modulates excitatory neurotransmitter release.
 ⦁Not metabolized; excreted unchanged by kidneys; t ½: 5–7 hours.
 ⦁Few significant drug interactions, although you may see additive sedative effects with other sedating drugs. 
Analgesic control may be affected when gabapentin is added to opiates, including decreased levels of hydrocodone 
(Vicodin) or increased levels of morphine.
 ⦁Gabapentin is structurally related to GABA. However, it does not bind to GABA-A or GABA-B receptors, and it does 
not appear to influence synthesis or uptake of GABA.
 ⦁Controlled trials have shown no effect as monotherapy or adjunctive therapy for bipolar disorder.

 ⦁Data with acute alcohol or benzodiazepine withdrawal (both inpatient and outpatient) are limited but promising.
 ⦁There have been reports of recreational use of gabapentin in correctional facilities, some of which have restricted 
its use.
 ⦁Recreational use and abuse in the general population is also increasing and seems to occur more often with 
pregabalin than gabapentin, often at supratherapeutic dosing for the euphoric effects. Those with opioid use 
disorders have much higher gabapentin and pregabalin abuse rates.
 ⦁FDA added a warning regarding potential for respiratory depression particularly in combination with other CNS 
depressants (especially opioids) or in patients at risk (eg, elderly, those with COPD).
Fun Fact:

Fun Fact:
Gabapentin recently was reclassified as a controlled substance in Kentucky (Schedule V). Prescribers must have a DEA 
license, and prescriptions will be logged in the state’s PDMP database. More states and the federal government likely 
will follow.

Mood Stabilizers and Anticonvulsants                                                                   Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   147LAMOTRIGINE  (Lamictal, Lamictal XR, Subvenite) Fact Sheet [G]
Lamotrigine is a good choice for maintenance treatment of bipolar disorder, especially to prevent depressive 
episodes. It has a good side effect profile. Its main disadvantage is the very slow titration schedule recommended to 
decrease the risk of Stevens-Johnson syndrome—as well as its ineffectiveness in the treatment of manic episodes. 
Bipolar disorder  (maintenance) in adults; seizures in adults and children.
Bipolar depression; neuropathic pain; major depression.
 ⦁Tablets (Lamictal, Subvenite, [G]):  25 mg, 50 mg, 100 mg, 150 mg, 200 mg (scored).
 ⦁Chewable tablets (Lamictal CD, [G]):  2 mg, 5 mg, 25 mg.

 ⦁Orally disintegrating tablets (Lamictal ODT, [G]):  25 mg, 50 mg, 100 mg, 200 mg.
 ⦁ER tablets (Lamictal XR, [G]):  25 mg, 50 mg, 100 mg, 200 mg, 250 mg, 300 mg.
 ⦁Bipolar disorder: Start 25 mg QD for two weeks, ↑ to 50 mg QD for two weeks, then 100 mg QD; max 200 mg/day; 
can increase up to 400 mg/day if needed. 
 ⦁Patients on valproic acid: Start 25 mg QOD (every other day) for two weeks, ↑ to 25 mg QD for two weeks, then 50 
mg QD; max 100 mg/day (VPA doubles lamotrigine levels).
 ⦁Dosing is the same with all versions of lamotrigine. However, patients taking more than 200 mg should either split 
the dose or take the Lamictal XR formulation. 
 ⦁Dose timing: Can be taken either in the morning or night; it rarely causes drowsiness.

 ⦁Dose timing: Can be taken either in the morning or night; it rarely causes drowsiness. 
Cost:  IR: $; ER: $$
 ⦁Most common: Dizziness, headache, nausea, sedation, benign rash (7%).
 ⦁Serious but rare: Skin reactions (black box warning): Severe, potentially life-threatening skin rashes requiring 
hospitalization reported; incidence is higher in pediatric patients; risk increased by co-administration with valproic 
acid, higher than recommended starting doses, and exceeding recommended dose titration. The majority of cases 
occur in the first eight weeks, but isolated cases may occur beyond eight weeks or even in patients without risk 
factors. Discontinue at first sign of rash and do not reinitiate unless rash is clearly not drug-related; rare cases of

factors. Discontinue at first sign of rash and do not reinitiate unless rash is clearly not drug-related; rare cases of 
Stevens-Johnson syndrome, toxic epidermal necrolysis, and angioedema reported. Cardiac arrhythmias (slowed 
ventricular conduction and widening of the QRS) in susceptible patients.
 ⦁Metabolism primarily hepatic (non-P450); t ½: 25–33 hours (with VPA 48–70 hours; with carbamazepine 13–14 hours).
 ⦁Caution with enzyme-inducing medications (eg, carbamazepine), which may decrease lamotrigine levels. Caution 
with hormonal contraceptives, which may decrease lamotrigine levels; lamotrigine maintenance dose may need 
to be increased (two-fold). Gradual increases of lamotrigine levels may occur during the inactive “pill-free” week. 
Lamotrigine may decrease levels of some hormonal contraceptives (greater effect with estrogens than progestins);

Lamotrigine may decrease levels of some hormonal contraceptives (greater effect with estrogens than progestins); 
alternative birth control methods should be considered. Valproic acid may double lamotrigine levels, necessitating 
dosage adjustments (as above).
 ⦁Lamotrigine is useful for the maintenance treatment of bipolar disorder, with best efficacy in the prophylaxis of 
depressive episodes. Not useful in acute episodes.
 ⦁If lamotrigine has been stopped/missed for more than five half-lives (see above), consider restarting according to 
initial dosing recommendations to minimize rash risk.
 ⦁Routine baseline ECG is not necessary, but similar to use of other mood stabilizers that can affect heart rhythm 
(lithium, carbamazepine, oxcarbazepine), monitor or get consultation in patients with cardiac conduction delay or 
significant ischemic or structural heart disease.
Fun Fact:

Fun Fact:
The first FDA-approved drug for bipolar disorder (not just acute mania) since lithium, a drug approved more than 30 
years earlier (2003 for lamotrigine; 1970 for lithium).

148  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONLITHIUM  (Eskalith, Lithobid) Fact Sheet [G]
Lithium is the gold standard for bipolar disorder. It is more useful for euphoric mania than for mixed and rapid-cycling 
types of bipolar disorder, but it is effective for depressive episodes and maintenance treatment of bipolar disorder. It 
is also known for its antisuicide effects in bipolar and unipolar mood disorders. It is likely underprescribed due to side 
effect concerns—though most patients tolerate lithium quite well. 
Acute mania; bipolar disorder  (maintenance) in children and adults.
Bipolar depression; treatment-resistant depression; neutropenia; vascular headache.
 ⦁Capsules (lithium carbonate, [G]):  150 mg, 300 mg, 600 mg.
 ⦁Tablets (lithium carbonate, [G]): 300 mg.
 ⦁ER tablets (Lithobid, [G]):  300 mg.
 ⦁ER tablets (Eskalith CR, [G]):  450 mg (scored).

⦁Capsules (lithium carbonate, [G]):  150 mg, 300 mg, 600 mg.
 ⦁Oral solution (lithium citrate, [G]):  300 mg/5 mL.
 ⦁Start 300–600 mg QHS; gradually ↑ by 300–600 mg/day every two to three days to target serum lithium level of 0.8 
mEq/L (usually 900–1200 mg/day). Can be dosed BID–TID or all QHS. Max 2400 mg/day.
 ⦁Extended-release formulations of lithium are better tolerated than immediate release. 
Monitoring:  Lithium level, TSH, BUN/creatinine, pregnancy test, ECG if cardiac disease.
Cost:  $
 ⦁Most common: Nausea/diarrhea (take with meals, split dosing, switch to ER), fine tremor (lower dose or use 
propranolol), polyuria/excessive thirst (dose all at bedtime), memory problems, weight gain, hypothyroidism 
(7%–8%; nine times more common in women), acne or worsening psoriasis, benign increase in WBC.

 ⦁Serious but rare: Chronic use may result in diminished renal concentrating ability (nephrogenic diabetes insipidus); 
usually reverses when discontinued, or treat with hydrochlorothiazide 25–50 mg/day or amiloride 5–10 mg 
twice daily. Cardiac: Bradycardia, cardiac arrhythmia, flattened or inverted T waves, sinus node dysfunction may 
occur rarely.
 ⦁Alters neuronal sodium transport.
 ⦁Eliminated by kidneys; t ½: 18–24 hours.
 ⦁Drugs that ↑ lithium levels: “ No ACE in the Hole” ( NSAIDs, ACE inhibitors, and HCTZ); excess sweating can ↑ levels; 
low-sodium diet may ↑ lithium levels. Caffeine may ↓ levels.
 ⦁Check lithium level, TSH/T4, BUN/Cr, electrolytes after one week of treatment, at one to two months, then every six

 ⦁Check lithium level, TSH/T4, BUN/Cr, electrolytes after one week of treatment, at one to two months, then every six 
to 12 months. Target levels for acute mania: 0.8–1.2 mEq/L; maintenance: 0.6–1.0 mEq/L; toxicity >1.5 mEq/L but 
may see signs at lower levels, especially in elderly.
 ⦁An increase or decrease of 300 mg/day will change serum level by roughly 0.25±0.1 mEq/L.
 ⦁Dehydration: Use with caution in patients with significant fluid loss (protracted sweating, diarrhea, or prolonged 
fever); temporary reduction or discontinuation may be necessary.
 ⦁Some evidence suggests that patients with bipolar disorder who are treated with lithium have better concentration 
and memory over the long term. Lithium has also been associated with reduced rate of dementia. In some patients, 
though, it can cause cognitive side effects like mental slowing.
Fun Fact:

Fun Fact:
The soft drink 7-Up was originally called “Bib-Label Lithiated Lemon-Lime Soda” and contained lithium until 1950.

Mood Stabilizers and Anticonvulsants                                                                   Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   149OXCARBAZEPINE  (Oxtellar XR, Trileptal) Fact Sheet [G]
Oxcarbazepine, an analog of carbamazepine, is popular because of its reputation as a kinder, gentler carbamazepine, 
which it’s gained due to its more favorable side effect and drug interaction profile. However, due to the paucity 
of efficacy data in bipolar disorder, it is reserved for second-line use after lithium and valproic acid, and even after 
carbamazepine. 
Seizure disorders in adults and children.
Bipolar disorder.
 ⦁Tablets (G):  150 mg, 300 mg, 600 mg (scored).
 ⦁Oral suspension (G):  300 mg/5 mL.
 ⦁ER tablets (Oxtellar XR):  150 mg, 300 mg, 600 mg.

 ⦁Bipolar disorder (off-label): Start 300 mg BID; ↑ by 300 mg/day every three days or 600 mg/day weekly to target 
dose 600–1200 mg BID. Max 2400 mg/day. No data on use of XR for bipolar disorder; caution as higher doses of XR 
likely needed when converting from IR to XR (not interchangeable on dose-for-dose basis).
 ⦁Dose timing: It can cause sedation; the entire dose can be taken at bedtime if needed. 
Monitoring:  Sodium, HLA-B*1502 in Asians.
Cost:  IR: $; ER: $$$$
 ⦁Most common: Dizziness, somnolence, headache, ataxia, nausea, vomiting.
 ⦁Serious but rare: Potentially serious, sometimes fatal, dermatologic reactions (eg, Stevens-Johnson, toxic epidermal 
necrolysis) reported; monitor for skin reactions. Rare cases of anaphylaxis and angioedema reported, even after

necrolysis) reported; monitor for skin reactions. Rare cases of anaphylaxis and angioedema reported, even after 
initial dosing; permanently discontinue should symptoms occur.
 ⦁Use caution in patients with previous hypersensitivity to carbamazepine (cross-sensitivity occurs in 25%–30%). 
Clinically significant hyponatremia (serum sodium <125 mmol/L) may develop (1%–3%; higher rate than with 
carbamazepine); monitor serum sodium, particularly during first three months of therapy, especially in patients at 
risk for hyponatremia.
 ⦁Sodium channel blocker and neuronal membrane stabilizer.
 ⦁Metabolized primarily through CYP450; potent inducer of CYP3A4 and inhibitor of CYP2C19; t ½: 2 hours (9 hours 
for active metabolite).
 ⦁No auto-induction of metabolism and fewer interactions than with carbamazepine. However, there is still potential

 ⦁No auto-induction of metabolism and fewer interactions than with carbamazepine. However, there is still potential 
for interactions. Avoid concomitant use with medications metabolized by CYP3A4 since oxcarbazepine may reduce 
their levels. Oxcarbazepine may reduce efficacy of oral contraceptives; nonhormonal measures recommended.
 ⦁Oxcarbazepine is the 10-keto analog of carbamazepine (its “chemical cousin”).
 ⦁Not bioequivalent to carbamazepine. Increase total daily dose by 20%–30% if switching from carbamazepine to 
oxcarbazepine.
 ⦁Patients of Asian descent should be screened for the variant HLA-B*1502 allele prior to starting oxcarbazepine; this 
variant may increase risk of developing Stevens-Johnson syndrome and/or toxic epidermal necrolysis. Avoid use in 
such patients.
 ⦁Oxcarbazepine failed to work in patients with bipolar disorder in two small and flawed placebo-controlled studies.

 ⦁Oxcarbazepine failed to work in patients with bipolar disorder in two small and flawed placebo-controlled studies. 
Some limited data suggest it may fare better when used as augmentation with other mood stabilizers.
Fun Fact:
While first synthesized in 1965, oxcarbazepine first appeared on the US market in 2000. In 2010, Novartis pleaded 
guilty to marketing oxcarbazepine for non-FDA-approved uses, including neuropathic pain and bipolar disorder, in 
2000 and 2001.

150  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONPREGABALIN  (Lyrica, Lyrica CR) Fact Sheet [G]
Pregabalin is structurally related to gabapentin and is likely more effective for psychiatric disorders, especially 
generalized anxiety disorder and social anxiety disorder. It can also be helpful for patients struggling to discontinue 
benzodiazepines. Now that the generic is available, it’s no longer more expensive than gabapentin and preferable in 
most cases.  
Diabetic peripheral neuropathy; spinal cord injury–associated neuropathic pain; post-herpetic neuralgia; partial 
seizures; fibromyalgia.
Generalized anxiety disorder; withdrawal from alcohol or benzodiazepines; alcohol dependence.
 ⦁Capsules (G):  25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, 300 mg.
 ⦁Oral solution:  20 mg/mL.
 ⦁ER tablets (G): 82.5 mg, 165 mg, 330 mg. 

 ⦁Start 75 mg BID and ↑ by 75–150 mg/day every week as tolerated to max 300 mg BID (based on trials for 
generalized anxiety disorder, an off-label use). Use lower doses in renal impairment.
 ⦁Dose timing: Although the package insert recommends BID dosing, it can cause sedation, so consider starting it at 
bedtime. 
Cost:  IR: $; liquid, ER: $$$
 ⦁Most common: Peripheral edema, dizziness, somnolence, ataxia, weight gain.
 ⦁Serious but rare: Hypersensitivity reactions, including skin redness, blistering, hives, rash, dyspnea, and wheezing. 
Angioedema, possibly life threatening, reported; use with caution in patients with a history of angioedema or

Angioedema, possibly life threatening, reported; use with caution in patients with a history of angioedema or 
patients on ACE inhibitors. Increases in CPK and rare cases of rhabdomyolysis reported.
 ⦁Binds alpha-2 delta subunit of calcium channels and reduces neurotransmitter release.
 ⦁Negligible metabolism; mostly excreted unchanged by kidneys; t ½: 6 hours.
 ⦁No significant drug interactions, although you may see additive sedative effects with other sedating drugs.
 ⦁Schedule V controlled substance (same category as cough suppressants containing codeine). Following abrupt 
withdrawal, patients may experience insomnia, nausea, headache, or diarrhea; this may be suggestive of physical 
 ⦁Recreational use and abuse seems to occur more often with pregabalin than gabapentin, often at supratherapeutic

 ⦁Recreational use and abuse seems to occur more often with pregabalin than gabapentin, often at supratherapeutic 
dosing for the euphoric effects. Those with opioid use disorders have much higher gabapentin and pregabalin 
abuse rates.
 ⦁Pregabalin is related in structure to gabapentin, which is (so far, according to the DEA) not a controlled substance 
but is more potent, with faster absorption and greater bioavailability.
 ⦁For generalized anxiety disorder, pregabalin appears more effective than placebo, but data comparing it to 
benzodiazepines are inconsistent.
Fun Fact:
Other drugs related to gabapentin and pregabalin are being studied; Pfizer was developing atagabalin for use in 
insomnia, but it discontinued development due to disappointing trial results.

Mood Stabilizers and Anticonvulsants                                                                   Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   151TOPIRAMATE  (Eprontia, Qudexy XR, Topamax, 
Trokendi XR) Fact Sheet [G]
Topiramate is a reasonable off-label choice for alcohol use disorder and antipsychotic-induced weight gain. 
Otherwise, relegate it to the “try when out of other ideas” category.
Seizure disorders for patients ≥2 years; migraine prophylaxis.
Alcohol dependence; bipolar disorder; PTSD; binge-eating disorder; obesity.
 ⦁Tablets (G):  25 mg, 50 mg, 100 mg, 200 mg.
 ⦁Capsules (G):  15 mg, 25 mg.
 ⦁Capsules, ER (Trokendi XR, Qudexy XR, [G]):  25 mg, 50 mg, 100 mg, 150 mg, 200 mg.
 ⦁Oral solution (Eprontia):  25 mg/mL.
Seizures/migraine: Start 25–50 mg QHS and ↑ by 50 mg/day in weekly increments. Doses used in psychiatry have

⦁Oral solution (Eprontia):  25 mg/mL.
Seizures/migraine: Start 25–50 mg QHS and ↑ by 50 mg/day in weekly increments. Doses used in psychiatry have 
typically been 50–300 mg/day, divided BID (ER can be given QHS).
Monitoring:  Baseline and periodic serum bicarbonate.
Cost:  IR: $; ER: $$$
 ⦁Most common: Somnolence, dizziness, nervousness, ataxia, speech problems, memory difficulties, confusion, 
anorexia.
 ⦁Serious but rare: Decreases in serum bicarbonate (metabolic acidosis) relatively common but usually mild to 
moderate; more severe cases, including marked reductions to <17 mEq/L, may occur more rarely. Watch for kidney 
stones, osteomalacia.
 ⦁Not metabolized, excreted primarily unchanged; t ½: 21 hours (56 hours for XR); mild CYP3A4 inducer.
 ⦁Avoid concomitant use with hydrochlorothiazide, which can increase risk for hypokalemia; monitor potassium.

⦁Avoid concomitant use with hydrochlorothiazide, which can increase risk for hypokalemia; monitor potassium. 
Avoid in patients with metabolic acidosis taking concomitant metformin. Additive effects with sedatives or alcohol. 
Concurrent use with valproic acid may increase risk of hyperammonemia and associated encephalopathy. Higher 
doses (>200 mg/day) may decrease levels of some drugs, including contraceptives (P450 induction).
 ⦁Many published articles have shown some efficacy in a wide range of disorders, including bipolar disorder, PTSD, 
alcohol dependence, binge-eating disorder, and obesity.
 ⦁Most compelling data are for preventing relapse in alcoholism.
 ⦁Some patients may lose weight, but this is not common; greatest decrease in weight seems to occur in heaviest 
patients (>100 kg). When weight loss occurs, it is often not a large effect (mean of 6 kg) nor is it a sustained effect 
(patients return to pretreatment weight after 12–18 months).

 ⦁A combination of extended-release topiramate and phentermine was FDA approved in 2012 for the long-term 
treatment of obesity as Qsymia (Vivus Pharmaceuticals).
Fun Fact:
Dose-related cognitive effects of topiramate have led some to refer to Topamax as “Dopamax. ”

152  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONVALPROIC ACID  (Depakene, Depakote, others) Fact Sheet [G]
Valproic acid is the go-to antimanic agent for acute manic episodes, featuring faster onset of response and better 
adverse effect profile compared to lithium, fewer drug interactions than carbamazepine, and efficacy for rapid cycling 
and relapse prevention.
Bipolar disorder (acute mania);  migraine prophylaxis; seizures.
 ⦁Capsules (valproic acid, [G]):  250 mg.
 ⦁Oral liquid (Depakene, [G]):  250 mg/5 mL.
 ⦁Delayed-release tablets (Depakote, [G]):  125 mg, 250 mg, 500 mg.
 ⦁Delayed-release capsules (Depakote Sprinkles, [G]):  125 mg.
 ⦁ER tablets (Depakote ER, [G]):  250 mg, 500 mg.
 ⦁Acute mania: Start 250–500 mg QHS; ↑ rapidly to effective dose (serum level 50–125 mcg/mL, target 1000–1500

⦁ER tablets (Depakote ER, [G]):  250 mg, 500 mg.
 ⦁Acute mania: Start 250–500 mg QHS; ↑ rapidly to effective dose (serum level 50–125 mcg/mL, target 1000–1500 
mg/day); max 4000 mg/day, or 60 mg/kg.
 ⦁Depakote ER is generally better tolerated in terms of side effects. When converting from regular Depakote to 
Depakote ER, be aware that patients will get about 20% less valproic acid with the ER formulation.
Monitoring:  Valproic acid level, LFTs, CBC for platelets, pregnancy test, ammonia if confusion.
Cost:  $
 ⦁Most common: Somnolence, nausea, fatigue, dizziness, hair loss, tremor, thrombocytopenia (up to 24% of patients; 
dose-related; reversible).
 ⦁Serious but rare: Hepatotoxicity—rare idiosyncratic reaction, not dose related; most cases occur within  
three months; risk factors: age <2 years, multiple anticonvulsants, and presence of neurologic disease in addition

three months; risk factors: age <2 years, multiple anticonvulsants, and presence of neurologic disease in addition 
to epilepsy. Asymptomatic elevations of liver enzymes may occur, not necessarily associated with hepatic 
dysfunction. Pancreatitis (rare but potentially fatal). Polycystic ovary syndrome (PCOS) in about 10% of women. 
Hyperammonemia, encephalopathy (sometimes fatal) reported and may present with normal liver enzymes.
 ⦁Metabolized primarily by liver with only minimal (10%) role of CYP450 enzymes (2A6, 2B6, 2C9); t ½: 9–16 hours.
 ⦁VPA causes ↑ levels of lamotrigine and risk for rash. Taking with topiramate can lead to encephalopathy.
 ⦁ER tablets have 10%–20% less fluctuation in serum concentration than delayed-release (DR) tablets. Divalproex 
sodium ER and DR tablets are not bioequivalent; increase total daily dose by 10%–20% if switching from DR to ER.

 ⦁ER formulation should be dosed QAM so that peak levels and sedation occur in the evening.
 ⦁Elevations of ammonia can often occur at normal doses and serum levels of VPA. Reducing dose when clinically 
appropriate typically reverses ammonia elevation. Treating with L-carnitine is also effective.
 ⦁Once steady state levels reached (within two to four days of initiation or dose adjustment), trough serum levels 
should be drawn just before once daily ER dose in the morning (21–24 hours post administration) and 12-post dose 
with IR formulation. Target levels between 50–125 mcg/mL.
 ⦁Several major malformations, most notably neural tube defects, have been clearly associated with first-trimester 
exposure to valproic acid. Educate and exercise caution in women of childbearing age. 
Fun Fact:

Fun Fact:
Valproic acid was first synthesized in 1882 by B.S. Burton as an analogue of valeric acid, found naturally in valerian.

Natural TreatmentsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   153
Natural Treatments
If you’re interested in natural treatments (also known as complementary and alternative medicine, or CAM), you will 
likely recommend various strategies other than the nine medications we cover in this chapter. These would include 
exercise (helpful for depression and for preventing cognitive impairment), light therapy (for seasonal affective 
disorder), massage, meditation, and other modalities.
We have included fact sheets on those natural products that have been shown to be effective via standard 
randomized controlled trials. Some natural products not included here might be effective but have not been 
adequately tested vs placebo (eg, adaptogens such as ashwagandha and rhodiola).
Because most of these products are not regulated by the FDA, there are quality control issues. The amount of active

Because most of these products are not regulated by the FDA, there are quality control issues. The amount of active 
constituents can vary not only from brand to brand, but also from batch to batch, and some products may be 
adulterated with other herbs, chemicals, drugs, or toxins. We recommend that patients stick to well-known brands 
sold by trusted retailers.
For additional information, you may also find these resources helpful:
 ⦁NIH National Center for Complementary and Integrative Health: https://www.nccih.nih.gov/health/herbsataglance  
 ⦁National Library of Medicine: www.medlineplus.gov/druginfo/herb_All.html
 ⦁Natural Medicines Comprehensive Database (requires subscription): http://naturaldatabase.therapeuticresearch.com
 ⦁ConsumerLab (requires subscription): www.consumerlab.com
Table 17:  Natural Treatments
Name
(Brand name, if applicable)Commonly Available Strengths

⦁ConsumerLab (requires subscription): www.consumerlab.com
Name
(Brand name, if applicable)Commonly Available Strengths 
(mg)Reported Uses in PsychiatryUsual Dosage Range
Lavender essential oil 
(Silexan, CalmAid)80 Generalized anxiety disorder 80–160 QHS
L-methylfolate 
(Deplin and others)0.4, 0.8, 1, 3, 5, 7.5, 15 Depression (adjunct) 15 QD
L-tryptophan 500 Depression 500–2000 divided BID or TID
Melatonin 0.5, 1, 2.5, 3, 5, 10 Insomnia 1–20 QHS
N-acetylcysteine 500, 600, 750, 1000 OCD, trichotillomania, nail biting, 
skin picking1200–2400 divided BID
Omega-3 fatty acids
(fish oil)500, 1000, 1200 Depression (unipolar, bipolar) 500–2000 QD or divided BID–TID
S-adenosyl-L-methionine 
(SAMe)100, 200, 400 Depression 800 BID
St. John’s wort 100, 300, 450 Depression 300 TID
Vitamin D 1000 IU, 2000 IU, 5000 IU, 10,000 
IU (as D3)Depression 1000–5000 IU QD

154  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONLAVENDER ESSENTIAL OIL  (CalmAid, Silexan) Fact Sheet [G]
Lavender essential oil is a reasonable option in patients who have not responded to FDA-approved treatments for 
generalized anxiety disorder (GAD) or in patients who request a natural alternative. 
None.
GAD.
Softgels (CalmAid): 80 mg.
Start 80 mg QHS; ↑ to 160 mg QHS after one week if needed.
Cost:  $
 ⦁Most common: Lavender-flavored burping; well tolerated in most.
 ⦁Serious but rare: Weak estrogenic properties may contribute to rare cases of breast development in adolescents 
(avoid in those under 18).
 ⦁Several mechanisms proposed, but most relevant may be serotonin-1A agonism.

 ⦁Drug metabolism pathway unclear; t ½: 9 hours.
 ⦁Drug interactions: Limited information, though studies thus far show no inhibition or induction of P450 enzymes by 
Silexan. 
 ⦁Silexan is a proprietary blend of linalool and linalyl acetate, along with over 100 compounds from the lavender 
plant.
 ⦁In a large randomized, double-blind controlled study, Silexan 80 mg and 160 mg both beat out paroxetine 20 mg/
day and placebo on the Hamilton Anxiety Rating Scale with a large effect size of 0.87. Silexan also performed best 
on secondary outcome measures such as depression, sleep quality, and quality of life. 
 ⦁One smaller study found Silexan 80 mg/day was comparable to lorazepam 0.5 mg/day in patients with GAD. 
 ⦁Benefits are typically seen after two weeks and continue to build over three months.

⦁One smaller study found Silexan 80 mg/day was comparable to lorazepam 0.5 mg/day in patients with GAD. 
 ⦁Benefits are typically seen after two weeks and continue to build over three months. 
 ⦁While Silexan is not sedating, patients report improved sleep quality, likely secondary to its anxiolytic effect.
Fun Fact:
Silexan is regulated as a prescription and licensed for anxiety in 14 countries. In the US, it is available over the counter 
as CalmAid, through Schwabe’s “Nature’s Way” line.

Natural TreatmentsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   155L-METHYLFOLATE  (Deplin) Fact Sheet [G]
L-methylfolate is a metabolite of dietary folic acid, and is necessary for the synthesis of the main neurotransmitters 
relevant to psychiatric disorders. Though the data are not robust, folate supplementation might be effective for some 
patients with depression, but we recommend that patients try the cheap stuff (folic acid) before springing for Deplin 
(L-methylfolate).
None.
Adjunctive treatment for depression (considered a “medical food product” by the FDA, not an FDA-approved drug 
product, although available as prescription only).
 ⦁Capsules (Deplin):  7.5 mg, 15 mg.
 ⦁Tablets and capsules (various other L-methylfolate products, [G]):  0.4 mg, 0.8 mg, 1 mg, 3 mg, 5 mg.
Depression (Deplin only): Start 7.5 mg QD; target and max dose 15 mg/day.

⦁Tablets and capsules (various other L-methylfolate products, [G]):  0.4 mg, 0.8 mg, 1 mg, 3 mg, 5 mg.
Cost:  [G]: $$; Deplin: $$$
 ⦁Most common: Not well known; likely well tolerated.
 ⦁Serious but rare: Folic acid supplementation may mask symptoms of vitamin B12 deficiency (administration of folic 
acid may reverse the hematological signs of B12 deficiency, including megaloblastic anemia, while not addressing 
neurological manifestations). L-methylfolate may be less likely than folic acid to mask B12 deficiency, though the 
possibility should be considered.
 ⦁May enhance synthesis of monoamine neurotransmitters.
 ⦁No typical drug metabolism pathway as it is naturally stored and used by body; t ½: 3 hours.

⦁May enhance synthesis of monoamine neurotransmitters.
 ⦁Drug interactions generally unlikely, although L-methylfolate may decrease anticonvulsant levels (including 
carbamazepine and valproic acid). Drugs that lower folate, such as anticonvulsants (including carbamazepine, 
valproic acid, and lamotrigine), may necessitate higher doses of L-methylfolate.
 ⦁Dietary folic acid is normally transformed to L-methylfolate by the enzyme MTHFR, and L-methylfolate is necessary 
for the synthesis of monoamines (serotonin, norepinephrine, dopamine). The marketing pitch for prescribing Deplin 
is that in about 50% of the population, genetic variations impair the function of MTHFR, leading to low levels of 
methylfolate. A recent review of the data on one of these genetic polymorphisms (called C677T) found that overall,

methylfolate. A recent review of the data on one of these genetic polymorphisms (called C677T) found that overall, 
it did not put people at any higher risk of depression (in fact, schizophrenia was more common).
 ⦁A few small studies over the years have shown that both folate (over the counter) and L-methylfolate may be 
somewhat helpful as adjunctive agents in the treatment of depression, particularly in those with low baseline 
folate levels.
Fun Fact:
“Medical foods” are foods that are specially formulated and intended for the dietary management of a disease with 
distinctive nutritional needs that cannot be met by normal diet alone. These include total parenteral nutrition as well 
as nasogastric tube feeds and oral rehydration products. Depression has no accepted distinctive nutritional needs.

156  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONL-TRYPTOPHAN  Fact Sheet [G]
L-tryptophan is an amino acid that is eventually converted to serotonin. The evidence base to support using 
L-tryptophan in depression is extremely limited, but more and more patients are turning to it, especially in 
combination “serotonin boost” products being marketed today. We recommend sticking to the serotonergic agents 
we know to be safe and effective: SSRIs and SNRIs.
None.
Depression; premenstrual dysphoric disorder (PMDD); smoking cessation.
Capsules:  500 mg.
For depression, doses as low as 300 mg/day in combination with antidepressants have been used. For other uses, dose 
is typically 500–1000 mg BID or 500 mg TID. PMDD dosing studied is 6 g/day.
Cost:  $$

Cost:  $$
 ⦁Most common: Abdominal pain, nausea, vomiting, diarrhea, flatulence, headache.
 ⦁Serious but rare: Over 1,500 reports of eosinophilia-myalgia syndrome (EMS) and 37 deaths were reported in the US, 
leading to it being pulled from the market in 1990; nearly all cases were tied to contaminated batches out of Japan. 
Symptoms of EMS include eosinophilia, fatigue, myalgia, neuropathy, rash, and inflammation. There have been no 
reported recurrences of these reactions since that outbreak.
 ⦁Essential amino acid found in plant and animal proteins. Absorbed from dietary protein sources and converted to 
5-hydroxytryptophan (5-HTP) and then to serotonin (5-hydroxytryptamine).
 ⦁Metabolized by non-P450 liver pathway; t ½: 3–4 hours.

 ⦁Combining with serotonergic antidepressants may increase risk of serotonin syndrome. Avoid use with MAOIs.
 ⦁Best efficacy in PMDD and smoking cessation. Evidence for use in depression is limited but suggestive.
 ⦁L-tryptophan has also been studied in ADHD, anxiety, depression, fibromyalgia, insomnia, and migraines, but there 
is insufficient evidence to support these uses.
 ⦁While both L-tryptophan and 5-HTP can cross the blood-brain barrier, L-tryptophan more readily does so.
 ⦁Combination formulations are sold as “serotonin boosters” and include amino acids (tryptophan, 5-HTP , SAMe), 
vitamins (B6, B9, B12, C, D), minerals (magnesium, zinc), and herbs (theanine, curcumin, garcinia, rhodiola). These 
formulations all have extremely limited evidence to support efficacy in depression.
Fun Fact:

Fun Fact:
Especially around Thanksgiving, many will talk about “turkey coma” as a result of ingesting too much tryptophan 
contained in turkey. Actually, the drowsiness is more likely due to all the carbs eaten with the turkey. Turkey has no 
more tryptophan than other meats.

Natural TreatmentsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   157MELATONIN  Fact Sheet [G]
Melatonin is secreted by the pineal gland, and its rise in serum levels correlates with the time course of natural sleep. 
Short-term melatonin treatment appears to only modestly reduce the time it takes to fall asleep (about 12 minutes, 
which might not be considered clinically relevant) and does not appear to significantly improve overall sleep time. 
However, some patients report minor improvement in subjective feelings of sleep quality. It is cheaper than the 
melatonin agonist ramelteon (Rozerem); however, like ramelteon, it lacks good long-term safety data, especially with 
regard to effects on hormones.
None.
Insomnia; jet lag; shift-work sleep disorder.
Supplied over the counter (OTC) in various forms including liquid, tablet, capsule, sublingual, and time-release

None.
Supplied over the counter (OTC) in various forms including liquid, tablet, capsule, sublingual, and time-release 
formulations; usually in 0.5 mg, 1 mg, 2.5 mg, 3 mg, 5 mg, and 10 mg.
 ⦁Insomnia (adults): 0.5–20 mg in early evening. Emerging data suggest lower doses are effective; start low (0.5–1 mg) 
and gradually increase to desired effect (“normal” melatonin levels vary widely among individuals, and the same 
dose can induce different levels depending on age or health).
 ⦁Jet lag: 1–3 mg on day of departure at a time that corresponds to the anticipated bedtime at arrival destination, 
followed by 1–3 mg at bedtime for next three to five days.
Cost:  $
 ⦁Most common: Generally well tolerated in the short term. Drowsiness, headaches, and dizziness most common but

Cost:  $
 ⦁Most common: Generally well tolerated in the short term. Drowsiness, headaches, and dizziness most common but 
at similar rates to placebo; next-day grogginess or irritability (higher doses); vivid dreams or nightmares (higher 
doses).
 ⦁Serious but rare: No serious side effects reported; however, long-term human studies have not been conducted. 
Theoretically, melatonin may alter other hormones (inhibiting ovulation in women and gonadal development in 
children and adolescents); avoid use in women who are pregnant or are attempting to become pregnant, and use 
caution in children.
 ⦁Melatonin receptor agonist.
 ⦁Metabolized primarily through CYP1A2, may inhibit CYP1A2; t ½: 35–50 minutes.
 ⦁Some suggest melatonin may reduce glucose tolerance and insulin sensitivity and may increase efficacy of calcium 
channel blockers for blood pressure.

⦁Some suggest melatonin may reduce glucose tolerance and insulin sensitivity and may increase efficacy of calcium 
 ⦁Melatonin is secreted from the pineal gland in a 24-hour circadian rhythm. It rises at sunset and peaks in the middle 
of the night, regulating the normal sleep/wake cycle.
 ⦁Melatonin should only be taken in its synthetic form; the “natural” form comes from ground-up cow pineal glands 
and may spread disease (eg, mad cow disease).
 ⦁Melatonin taken at bedtime doesn’t seem to affect nocturnal sleep. Taken in the early evening, it appears to be 
similar to temazepam in hypnotic effect.
 ⦁Although melatonin products have been available OTC in the US since the mid-1990s, many countries require a 
prescription, and some do not permit its sale.
Fun Fact:
Foods containing melatonin include cherries, bananas, grapes, rice, cereals, herbs, olive oil, wine, and beer.

158  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONN-ACETYLCYSTEINE  (NAC) Fact Sheet [G]
NAC is a glutamate modulator and is derived from the amino acid cysteine. It has been tested for many psychiatric 
conditions, but is most likely effective as an add-on treatment to SSRIs in OCD, trichotillomania, nail biting, and skin 
picking. 
None.
OCD; trichotillomania; nail biting; skin picking.
Capsules: 500 mg, 600 mg, 750 mg, 1000 mg.
NAC doses studied have ranged from 600 mg to 6000 mg/day, with the majority of the studies using 1200–2400 mg/
day. Divide dose BID to minimize GI side effects.
Cost:  $
 ⦁Most common: Usually well tolerated with nausea/vomiting, diarrhea, cramping, flatulence being most common.
 ⦁Serious but rare: May exacerbate asthma.

Cost:  $
 ⦁NAC is derived from the amino acid cysteine, a precursor of a key brain antioxidant, glutathione. It works as a 
glutamate modulator, which may have effects on oxidative stress, mitochondrial dysfunction, inflammatory 
mediators, neurotransmission, and neural plasticity.
 ⦁Metabolized extensively by liver with minimal P450 involvement; t ½: 6 hours.
 ⦁No known drug interactions; not likely an issue for the majority of patients.
 ⦁Amino acid derivate with antioxidant properties.
 ⦁NAC is most recognized for its use as a treatment for acetaminophen overdose.
 ⦁Although NAC has been studied in autism, Alzheimer’s, cocaine and cannabis addiction, bipolar disorder,

⦁NAC is most recognized for its use as a treatment for acetaminophen overdose.
 ⦁Although NAC has been studied in autism, Alzheimer’s, cocaine and cannabis addiction, bipolar disorder, 
depression, trichotillomania, nail biting, skin picking, OCD, and schizophrenia, the results are generally mixed. Best 
data are in patients with OCD, trichotillomania, nail biting, and skin picking (including Prader-Willi syndrome).
 ⦁Most patients develop tolerance to GI symptoms, and they go away after a few weeks.
 ⦁No long-term data; most studies were eight weeks long, and a few followed patients for three to six months.
Fun Fact:
Many of the published studies have come from an individual Australian researcher who holds a patent on a particular 
formulation of NAC, raising the issue of bias or a potential conflict of interest.

Natural TreatmentsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   159OMEGA -3 FATTY ACIDS  (Fish Oil) Fact Sheet [G]
Omega-3 fatty acids form the lipid bilayers of cell membranes, and supplementing our natural dietary supply may 
have psychological and cardiological benefits. Based on the limited data available, the best use of omega-3 fatty acids 
(particularly 1–2 g with at least 60% EPA) is as an adjunct in the treatment of unipolar and bipolar depression. There is 
not enough evidence to recommend omega-3 fatty acids in other psychiatric disorders at this time. 
High triglycerides (as Lovaza).
Unipolar and bipolar depression.
 ⦁Supplied over the counter in various dosages and formulations; 500 mg, 1000 mg, and 1200 mg softgel capsules 
most common.
 ⦁By prescription only: Lovaza: 1000 mg softgel capsules (GSK). Dosage on label usually reflects fish oil dosage, which

 ⦁By prescription only: Lovaza: 1000 mg softgel capsules (GSK). Dosage on label usually reflects fish oil dosage, which 
is not the same as omega-3 fatty acid dosage (eg, 1000 mg fish oil in some brands may provide 300 mg of omega-3 
fatty acids, including EPA and DHA). Dosing recommendations are based on mg of fish oil.
Effective dose unclear, but studies have used 300 mg–6 g QD. For depression, start 500 mg/day, increase as tolerated 
(target dose 1–2 g/day); doses >3 g/day should be used cautiously. Dividing dose BID–TID helps with side effect 
Cost:  $
 ⦁Most common: Well tolerated up to 4 g/day. Nausea, loose stools, fishy aftertaste.
 ⦁Serious but rare: Caution in those who are allergic to seafood. Increased risk of bleeding, particularly at higher doses.

⦁Serious but rare: Caution in those who are allergic to seafood. Increased risk of bleeding, particularly at higher doses.
 ⦁Exact mechanism unknown, but may improve cell membrane fluidity and membrane function, change 
neurotransmitter binding, and promote anti-inflammatory effects.
 ⦁Metabolism is hepatic, primarily through CYP450; t ½: Unknown.
 ⦁For most patients, drug interactions not likely an issue; however, may prolong bleeding time. Fish oils may lower 
blood pressure and have additive effects when used with antihypertensives.
 ⦁Fish oils contain eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA); both are omega-3 fatty acids. 
Although the body can synthesize these fats from alpha-linolenic acid (ALA), this is believed to be inefficient in 
many people.
 ⦁EPA and DHA are derived from fish; ALA is derived from flax seed and other vegetable matter. Mercury accumulates

 ⦁EPA and DHA are derived from fish; ALA is derived from flax seed and other vegetable matter. Mercury accumulates 
in fish meat more than in fish oil, which might explain the lack of detectable mercury in most fish oil supplements. 
Also, the manufacturing process that is used to deodorize fish oil supplements seems to lower the levels of PCBs 
and other contaminants.
 ⦁Omega-3 fatty acids have been tested in the treatment of schizophrenia, bipolar disorder, depression, anxiety, OCD, 
ADHD, autism, aggression, borderline personality disorder, substance use disorder, anorexia nervosa, and dementia. 
With the exception of depressive disorders, overall consensus is still lacking for the majority of these uses due to 
limited sample sizes, selection of patients, doses and formulations used, and study durations.
 ⦁Omega-3 fatty acids appear helpful as augmentation in unipolar depression in some individual studies, but several

⦁Omega-3 fatty acids appear helpful as augmentation in unipolar depression in some individual studies, but several 
meta-analyses have not been able to show robust benefit. In positive studies, most benefit seen at 1 g/day, with EPA 
more effective than DHA and more severely ill patients showing greater improvement.
Fun Fact:
Inuit people have been reported to ingest up to 16 g/day (via fish) with no dangerous side effects.

160  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONS-ADENOSYL -L-METHIONINE  (SAMe) Fact Sheet [G]
SAMe is a natural methyl donor important in neurotransmitter synthesis and function. Several clinical studies (lasting 
up to 42 days) have shown that taking SAMe is more effective than placebo and appears to be as effective as tricyclic 
antidepressants, though the studies were limited in various ways. Consider using it for those patients with mild to 
moderate depression who are interested in using alternative therapies, or as an augmentation strategy in partial 
responders.
None.
Depression; osteoarthritis; cirrhosis and fatty liver disease.
Supplied over the counter most often as 100 mg, 200 mg, 400 mg tablets, usually enteric coated.
Effective dose is variable, but most antidepressant studies have used doses of about 400–1600 mg/day (1600 mg most

Effective dose is variable, but most antidepressant studies have used doses of about 400–1600 mg/day (1600 mg most 
common), usually divided BID.
Cost:  $
 ⦁Most common: Well tolerated. Higher doses may result in flatulence, nausea, vomiting, diarrhea, constipation, 
dry mouth, headache, mild insomnia, anorexia, sweating, dizziness, and nervousness. Anxiety and tiredness have 
occurred in people with depression, and hypomania has occurred in people with bipolar disorder.
 ⦁Serious but rare: Theoretical concern of elevated homocysteine since SAMe is converted to this during normal 
metabolism. No reports to date, but some recommend taking folate and vitamin B supplements anyway.
 ⦁Methyl group donor that may increase synthesis of neurotransmitters, increase responsiveness of neurotransmitter

 ⦁Methyl group donor that may increase synthesis of neurotransmitters, increase responsiveness of neurotransmitter 
receptors, and increase fluidity of cell membranes through the production of phospholipids.
 ⦁Metabolism similar to endogenous SAMe (transmethylation, trans-sulphuration, and aminopropylation);  
t ½: 100 minutes.
 ⦁No drug interactions reported. Theoretically, serotonin syndrome possible but risk likely minimal.
 ⦁SAMe is produced by our bodies as a derivative of the amino acid methionine. It is necessary for the production of 
serotonin and norepinephrine (and in more than 100 other biochemical reactions) throughout virtually all body 
tissues and fluids. Concentrations are highest in childhood and decrease with age.
 ⦁SAMe is difficult to formulate as a stable oral salt, and the FDA halted trials of an investigational prescription product

⦁SAMe is difficult to formulate as a stable oral salt, and the FDA halted trials of an investigational prescription product 
in 1993 due to concerns about tablet dissolution; concerns have been raised that some supplements may also have 
these problems.
Fun Facts:
SAMe has been available as a dietary supplement in the US since 1999, but it has been used as a prescription drug 
in Italy since 1979, in Spain since 1985, and in Germany since 1989. Patients in trials of SAMe for depression noted 
improvement in their arthritis symptoms, suggesting another possible use.

Natural TreatmentsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   161ST. JOHN’S WORT  Fact Sheet [G]
St. John’s wort can be considered an option along with conventional antidepressants for short-term treatment of mild 
depression; however, be wary of its many drug interactions.
None.
Supplied over the counter most commonly as 100 mg, 300 mg, 450 mg tablets and capsules.
For mild to moderate depression, most clinical trials have used St. John’s wort extract containing 0.3% hypericin and/
or 3% hyperforin; most common dose is 300 mg TID. Doses of 1200 mg QD have also been used. Some studies have 
also used a 0.2% hypericin extract dosed at 250 mg BID. A St. John’s wort extract standardized to 5% hyperforin and 
dosed at 300 mg TID has also been used.
Cost:  $

Cost:  $
 ⦁Most common: Well tolerated at recommended doses. Insomnia (decrease dose or take in morning), vivid dreams, 
restlessness, anxiety, agitation, irritability, gastrointestinal discomfort, diarrhea, fatigue, dry mouth, dizziness, and 
headache reported. Sexual dysfunction may occur, but less often than with SSRIs.
 ⦁Serious but rare: Risk of severe phototoxic skin reactions and photosensitivity at high doses (2–4 g/day).
 ⦁Thought to exert antidepressant effects by modulating effects of monoamines, and may inhibit reuptake of these 
neurotransmitters.
 ⦁Metabolized primarily through the liver; t ½: 24–48 hours.
 ⦁Avoid concomitant use with serotonergic agents: Rare cases of serotonin syndrome reported. Potent inducer of

 ⦁Avoid concomitant use with serotonergic agents: Rare cases of serotonin syndrome reported. Potent inducer of 
many CYP450 enzymes (3A4, 2C9, 1A2) and P-glycoprotein transporter, which results in increased metabolism and 
reduced plasma concentrations of a large number of drugs. St. John’s wort can decrease oral contraceptive levels by 
13%–15%, resulting in bleeding or unplanned pregnancy; women should use an additional or nonhormonal form of 
birth control.
 ⦁Also known as Hypericum perforatum ; active constituents (predominantly hypericin and hyperforin) are derived from 
the flowering buds.
 ⦁St. John’s wort is more effective than placebo, likely as effective as low-dose tricyclic antidepressants and SSRIs 
in milder forms of depression; however, a study in JAMA  found it no more effective than placebo or sertraline for 
moderate to severe depression.

 ⦁Avoid abrupt discontinuation due to the risk of withdrawal effects.
Fun Facts:
Although not indigenous to Australia and long considered a weed, St. John’s wort is now grown as a cash crop, and 
Australia produces 20% of the world’s supply. The use of St. John’s wort dates back to the ancient Greeks; Hippocrates 
documented the medical use of St. John’s wort flowers. St. John’s wort is so named because it blooms near June 24th, 
which is the birthday of John the Baptist. “Wort” is an old English word for plant.

162  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONVITAMIN  D Fact Sheet [G]
Vitamin D supplementation may be beneficial in depression, but reserve its use for those who have low vitamin D 
levels, and make sure patients take adequate doses, in the range of 1000–5000 IU daily.
None.
Supplied over the counter as vitamin D2 and D3, as tablets, capsules, and softgels in “international units” (IU) dosing. 
We recommend D3: 1000 IU, 2000 IU, 5000 IU, 10,000 IU.
Dosing guidelines vary. For depression, use 1000–5000 IU per day.
Monitoring:  Periodic vitamin D [25(OH)D] levels.
Cost:  $
 ⦁Most common: Well tolerated.
 ⦁Serious but rare: Vitamin D toxicity possible but very rare.
 ⦁Thought to play a role in brain plasticity, neuroimmunomodulation, and inflammation.

 ⦁Metabolized by liver and kidneys; t ½: 12–50 days (varies based on level, source, dose, obesity, and race).
 ⦁No known significant interactions.
 ⦁Sources of vitamin D include exposure to sunlight, dietary intake, and supplements.
 ⦁It’s difficult to obtain sufficient daily needs from dietary intake alone. Two types of vitamin D are obtained from 
dietary sources: D2 (ergocalciferol) from plant sources such as mushrooms and soy milk and D3 (cholecalciferol) 
from animal sources such as raw fish, mackerel, smoked salmon). D3 is approximately three times stronger than D2.
 ⦁Majority of vitamin D is produced through conversion of 7-dehydrocholesterol via ultraviolet B, after penetration of 
sunlight on the skin, to vitamin D3.

⦁Majority of vitamin D is produced through conversion of 7-dehydrocholesterol via ultraviolet B, after penetration of 
 ⦁Vitamin D is metabolized in the liver to 25-hydroxyvitamin D or 25(OH)D and then in the kidneys to its active form 
calcitriol, or 1,25-dihydroxyvitamin D. There is no consensus about the optimal total 25(OH)D level, which may vary 
with the assay used. Many labs report 25(OH)D level of 30–60 ng/mL as normal range, 21–29 ng/mL as insufficiency, 
and ≤20 ng/mL as deficiency.
 ⦁Several meta-analyses have found no beneficial effects of vitamin D supplementation on depression. When 
studies were limited to depressed patients with both vitamin D insufficiency at baseline and adequate dosing of 
supplementation (>800 mg/day), statistically significant benefits were seen.
 ⦁Studies in anxiety, psychosis, and dementia have not shown positive results of supplementation.
Fun Fact:

Fun Fact:
A number of things affect your vitamin D status, including how far away you live from the equator, the air quality in 
your community, your skin color, and your use of sunscreen.

Sexual Dysfunction MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   163
Sexual Dysfunction Medications
Many psychiatric medications cause sexual dysfunction. Most antidepressants (the main exceptions being bupropion 
and mirtazapine) cause sexual problems, which can include low libido, anorgasmia, and erectile dysfunction. 
Antipsychotics often lower libido, whether due to increased prolactin or other unknown factors.
Before jumping to treat the side effect of one medication with another medication, try other potential solutions: 
decreasing the dose of the offending medication, switching medications, adding an “antidote” such as bupropion or 
mirtazapine in the case of antidepressant-induced effects, or prescribing two- or three-day drug holidays. If none of 
these strategies work, you might want to prescribe one of the medications in this chapter.

For men with erectile dysfunction, prescribe one of the four PDE-5 inhibitors. Sildenafil (Viagra) has the benefit of 
being well known, which might enhance the placebo effect. Tadalafil (Cialis) has the advantage of a long duration 
of action (up to 36 hours). Avanafil (Stendra) works a little more quickly than Viagra: 15 minutes as opposed to 
30 minutes. Vardenafil (Levitra) is available as a peppermint-flavored orally disintegrating pill—though it has no 
therapeutic advantages beyond whatever aphrodisiac power peppermint might provide, as its onset of action is no 
faster than the regular Levitra tablet. 
For women with low sexual desire (hypoactive sexual desire disorder), there are two approved medications—
flibanserin (Addyi) and bremelanotide (Vyleesi). Low sexual desire can stem from a number of psychological,

flibanserin (Addyi) and bremelanotide (Vyleesi). Low sexual desire can stem from a number of psychological, 
physiological, or other factors such as stress, and there’s controversy around how to diagnose, whether to treat 
with medication, and how well the medications work. When medication is used, there are differences between the 
two: Flibanserin must be taken by mouth daily and alcohol must be avoided within two hours of taking it, whereas 
bremelanotide can be taken as needed but must be injected. For both men and women who suffer sexual dysfunction 
from serotonergic antidepressants, you can try off-label cyproheptadine. It works pretty well sometimes, but other 
times it doesn’t work at all. As above, adjunctive bupropion or mirtazapine sometimes helps as well.
For men with low testosterone, prescribe... testosterone. It will add zip to patients who suffer low libido as a result of

For men with low testosterone, prescribe... testosterone. It will add zip to patients who suffer low libido as a result of 
low T. However, don’t get roped into prescribing this for anyone who asks for it, since there’s no evidence it helps men 
with normal T levels.
Class Warning for PDE-5 Inhibitors
Avoid concomitant use with nitrates in any form—eg, nitroglycerin, isosorbide dinitrate, amyl nitrite (“poppers”).

164  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONTable 18:  Sexual Dysfunction Medications
Strengths (mg)Starting Dose
(mg)Usual Dosage Range
(mg)Special Features
Avanafil 
(Stendra)
2012Erectile dysfunction 50, 100, 200 100 50–200 More rapid onset (15 minutes); 
food doesn’t affect absorption
(Vyleesi)
2019Hypoactive sexual 
desire disorder in 
premenopausal women1.75 mg/0.3 mL 1.75 1.75 Subcutaneous autoinjector; no 
more than 1 dose per 24 hours 
or 8 doses per month
Cyproheptadine [G] 
1961
Brand name Periactin 
discontinued; generic onlyNone 4; 2/5 mL 4 4–12 Sedating; most effective for 
anorgasmia
Flibanserin 
(Addyi)
2015Hypoactive sexual 
premenopausal women100 100 100 Can’t be combined with alcohol
Sildenafil [G]
(Viagra) 
1998
Generic only available as

(Addyi)
(Viagra) 
1998
Generic only available as 
20 mg tabletErectile dysfunction 25, 50, 100 25 25–100 Takes 30 minutes; fatty meals 
decrease absorption
Tadalafil [G]
(Cialis) 
2003Erectile dysfunction 2.5, 5, 10, 20 5 5–20 Takes one hour, lasts 36 hours; 
no meal effect
Testosterone Hypogonadism Various formulations and dosages; see fact sheet for 
detailsNo evidence of beneficial effect 
in the absence of low T
Vardenafil [G] 
(Levitra) 
2003Erectile dysfunction 2.5, 5, 10, 20 10 10–20 Works in 30 minutes; fatty 
meals decrease absorption
Vardenafil ODT 
(Staxyn)
2010Erectile dysfunction 10 ODT 10 10 Peppermint flavored

Sexual Dysfunction MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   165AVANAFIL  (Stendra) Fact Sheet
Avanafil is the newest PDE-5 inhibitor to come to market. Its potential advantage is a somewhat faster onset than any 
of the other ED drugs.
Erectile dysfunction.
Tablets:  50 mg, 100 mg, 200 mg.
 ⦁Start 100 mg ×1 taken 15 minutes before sexual activity. Max dose 200 mg/dose, up to one dose/24 hours.
 ⦁May be taken with or without food.
Cost:  $$$$
 ⦁Most common: Headache, nasal congestion, flushing.
 ⦁Serious but rare: May cause dose-related impairment of color discrimination. Sudden decrease or loss of hearing has 
been reported rarely; hearing changes may be accompanied by tinnitus and dizziness. Decreases in blood pressure

been reported rarely; hearing changes may be accompanied by tinnitus and dizziness. Decreases in blood pressure 
may occur due to vasodilator effects; concurrent use with alpha-adrenergic antagonists or substantial alcohol 
consumption may cause symptomatic hypotension. Avoid use with nitrates (see below). Painful erection greater 
than six hours in duration (priapism) may occur rarely.
 ⦁Phosphodiesterase type 5 (PDE-5) inhibitor.
 ⦁Metabolized primarily through CYP3A4, also 2C9/19 to a lesser degree; t ½: 5 hours.
 ⦁Avoid concomitant use with nitrates in any form (eg, nitroglycerin, isosorbide dinitrate, amyl nitrite “poppers”). Use 
with caution in patients taking alpha-adrenergic blockers; may cause symptomatic hypotension (maximum of 50 
mg in 24 hours). Use with caution in patients taking strong CYP3A4 inhibitors, which may increase or extend effects 
of avanafil (maximum of 50 mg in 24 hours).

Onset of effect is usually 15–30 minutes after a dose (and not affected by meals). About two-thirds of men will have 
therapeutic effect within 15 minutes. Usual duration is approximately two hours.
Fun Fact:
Avanafil was initially approved with the recommendation to take it 30 minutes before sexual activity. Its manufacturer 
decided it was tough to compete with blockbusters like Viagra and Cialis without some sort of competitive edge, so it 
presented some data to the FDA and had the dosing changed to “as early as approximately 15 minutes before sexual 
activity. ” Spontaneity became the hallmark of the drug’s marketing campaign, with taglines like “This time, he was 
ready before dessert. ”

166  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONBREMELANOTIDE  (Vyleesi) Fact Sheet
Bremelanotide (marketed as the “female Viagra”) is a melanocortin receptor agonist that is modestly effective in 
increasing sexual desire in women, though it doesn’t affect sexual functioning. Disadvantages include the fact that 
it requires self-injection and carries a 40% rate of nausea as a side effect. It’s worth trying in some patients, but don’t 
expect miracles. 
Hypoactive sexual desire disorder in premenopausal women.
Subcutaneous self-injection:  1.75 mg/0.3 mL.
Patient to self-inject 1.75 mg subcutaneously via the autoinjector to the abdomen or thigh, as needed, at least 45 
minutes before anticipated sexual activity. Do not use more than one dose within 24 hours or eight doses per month.
Cost:  $$$$

Cost:  $$$$
 ⦁Most common: Nausea (seen in 40% of women in clinical trials), flushing, injection site reactions, headache, and 
vomiting. 
 ⦁Serious but rare: Transient increase in blood pressure and decrease in heart rate may occur after each dose; usually 
resolves within 12 hours. Focal hyperpigmentation has been reported by 1% of patients, including involvement of 
the face, gingiva, and breasts; higher risk in patients with darker skin. Hyperpigmentation may resolve in about half 
of patients; discontinue if it develops. 
 ⦁Melanocortin receptor agonist.
 ⦁As a peptide with seven amino acids, metabolism primarily involves hydrolysis (non-P450); t ½: 2.7 hours.
 ⦁Avoid concomitant use with naltrexone; bremelanotide significantly decreases systemic exposure of oral naltrexone. 

⦁Avoid concomitant use with naltrexone; bremelanotide significantly decreases systemic exposure of oral naltrexone. 
 ⦁Bremelanotide has not been studied in postmenopausal women or in men.
 ⦁Bremelanotide does not enhance sexual performance; rather, it increases interest.
 ⦁In the two preclinical trials, nearly 40% dropped out of the trial and only 4%–8% benefited over placebo. 
Fun Fact:
Even before the FDA approved Vyleesi, its manufacturer was sponsoring a campaign called “unblush” to spread the 
word on hypoactive sexual desire disorder ( www.unblush.com ).

Sexual Dysfunction MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   167CYPROHEPTADINE  (Periactin) Fact Sheet [G]
Cyproheptadine is sometimes effective in reversing SSRI-induced anorgasmia, but with continued use it could 
interfere with antidepressant efficacy. As-needed occasional use is the best strategy.
Allergic rhinitis; urticaria.
Antidepressant-induced sexual dysfunction; anorexia and bulimia nervosa; appetite stimulant; acute management of 
serotonin syndrome.
 ⦁Tablets (G):  4 mg (scored).
 ⦁Syrup (G):  2 mg/5 mL syrup.
Take 4–12 mg one to two hours before sexual activity.
Cost:  $
Most common: Sedation, confusion, weight gain, anticholinergic effects, potential reversal of antidepressant 
therapeutic effect.

 ⦁Histamine H1 receptor antagonist with mild antiserotonergic effects.
 ⦁Metabolized primarily through hepatic glucuronidation via UGT1A; t ½: 16 hours.
 ⦁Avoid concomitant use with MAOIs. Additive effects with other sedating agents.
 ⦁Appears to work best for anorgasmia. Average effective dose in one study was 8.6 mg.
 ⦁Excessive sedation may impede therapeutic efficacy in some patients.
Fun Facts:
Cyproheptadine’s antagonistic effects at serotonin receptors have been shown to be useful as part of the 
management of serotonin syndrome. It’s been used to counteract the more rarely occurring serotonergic side effects 
of serotonergic antidepressants, such as sweating and vivid dreams. It is also the most commonly used appetite 
stimulant for cats.

168  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONFLIBANSERIN  (Addyi) Fact Sheet
Flibanserin, marketed as the “pink Viagra, ” is mildly effective for enhancing sexual desire, but with potentially 
significant side effects and precautions regarding alcohol use around the time of administration. 
Tablets:  100 mg.
Start and continue 100 mg QHS; taking during the daytime may increase risk of hypotension, syncope, and CNS 
depression. Discontinue after eight weeks if no improvement.
Cost:  $$$$
 ⦁Most common: Dizziness, somnolence, nausea, fatigue, insomnia, dry mouth.
 ⦁Serious but rare: May have potential to cause severe hypotension or syncope.

⦁Serious but rare: May have potential to cause severe hypotension or syncope.
 ⦁Mixed agonist-antagonist on postsynaptic serotonergic receptors with 5-HT1A agonist and 5-HT2A antagonist 
effects.
 ⦁Metabolized primarily through CYP3A4 and to a lesser extent, 2C19; t ½: 11 hours.
 ⦁Avoid concomitant use with alcohol, with CYP3A4 inhibitors, or in patients with hepatic impairment as there may be 
an increased risk for hypotension and syncope.
 ⦁Flibanserin has not been studied in postmenopausal women or in men.
 ⦁Flibanserin does not enhance sexual performance; rather, it increases interest.
 ⦁While studies of Viagra show around 80% of men improving (50%–60% more than placebo), only 8%–13% more 
women on flibanserin had benefits over placebo.
 ⦁The manufacturer wanted the black box warning and contraindication about alcohol removed, so the FDA reviewed

 ⦁The manufacturer wanted the black box warning and contraindication about alcohol removed, so the FDA reviewed 
postmarketing studies. The FDA decided to modify rather than remove the warning. They determined that there 
is still cause for concern about drinking alcohol close in time to taking flibanserin but that it doesn’t have to be 
avoided completely. Now the warning specifies that women shouldn’t drink two hours before or at least until the 
morning after taking flibanserin at bedtime.
Fun Fact:
Based on mediocre efficacy data, Dr. Carlat has made the analogy that “if Viagra is a Starbucks triple espresso, 
flibanserin is a Dixie cup of cafeteria coffee. ”

Sexual Dysfunction MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   169SILDENAFIL  (Viagra) Fact Sheet [G]
Sildenafil is the original PDE-5 inhibitor, and as such it has the best evidence and longest track record.
Erectile dysfunction;  pulmonary arterial hypertension (Revatio brand name).
Tablets (G):  25 mg, 50 mg, 100 mg.
Start 50 mg ×1 (25 mg if >65 years old or with CYP3A4 inhibitors) from 30 minutes to four hours before sexual activity. 
Max 100 mg/dose and one dose/day. Avoid taking with a high-fat meal.
Cost:  $
 ⦁Most common: Headache, dyspepsia/heartburn, flushing.
 ⦁Serious but rare: May cause dose-related impairment of color discrimination. Sudden decrease or loss of hearing has

Cost:  $
 ⦁Metabolized primarily through CYP3A4 and to a lesser extent, 2C9; t ½: 4 hours.
 ⦁Avoid concomitant use with nitrates in any form (eg, nitroglycerin, isosorbide dinitrate, amyl nitrite “poppers”). Use

⦁Avoid concomitant use with nitrates in any form (eg, nitroglycerin, isosorbide dinitrate, amyl nitrite “poppers”). Use 
with caution in patients taking alpha-adrenergic blockers; may cause symptomatic hypotension (use 25 mg dose). 
Use with caution in patients taking strong CYP3A4 inhibitors, which may increase or extend effects of sildenafil 
(maximum of 25 mg in 48 hours).
Onset of effect is usually 15–20 minutes after a dose (but may be delayed 60 minutes by a high-fat meal), and usual 
duration is approximately two hours.
Fun Fact:
Sildenafil has been used recreationally. Some users mix it with MDMA (ecstasy) to counteract the erectile dysfunction 
MDMA can cause; this combination is known as “sextasy. ”

170  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONTADALAFIL  (Cialis) Fact Sheet [G]
We have fewer data for tadalafil in the psychiatric setting; however, compared to other agents in the class, its long 
duration of action may improve spontaneity, and the lack of interaction with meals may offer advantages. Tadalafil is 
an especially good choice for men who have both prostatic hypertrophy and erectile dysfunction. 
Erectile dysfunction; benign prostatic hyperplasia; pulmonary arterial hypertension (Adcirca brand name).
Tablets (G):  2.5 mg, 5 mg, 10 mg, 20 mg.
 ⦁PRN dosing: Start 10 mg ×1, 30–60 minutes prior to sexual activity; adjust dose to 5–20 mg based on response. Max 
20 mg/dose and one dose/24 hours.
 ⦁Daily dosing: Start 2.5 mg QD; may increase to max of 5 mg QD based on response.
Cost:  $

⦁Daily dosing: Start 2.5 mg QD; may increase to max of 5 mg QD based on response.
Cost:  $
 ⦁Most common: Headache, dyspepsia/nausea, flushing, back pain, muscle aches.
 ⦁Metabolized primarily through CYP3A4; t ½: 15–17.5 hours.

with caution in patients taking alpha-adrenergic blockers; may cause symptomatic hypotension (use lower tadalafil 
dose). Use with caution in patients taking strong CYP3A4 inhibitors, which may increase or extend effects of tadalafil 
(maximum of 10 mg/dose and one dose/72 hours with PRN dosing or 2.5 mg/day with daily dosing).
 ⦁Onset of effect of tadalafil is usually within one hour, and its effects may last 36 hours.
 ⦁Daily tadalafil has the advantage of allowing users to always be “ready, ” but it can also cause daily side effects.
Fun Fact:
Cialis’ 36-hour effectiveness earned it the nickname “the weekend pill. ”

Sexual Dysfunction MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   171TESTOSTERONE  (various) Fact Sheet [G]
Successful marketing has convinced the public that “low T” is a public health scourge, leading to over-prescribing of 
testosterone for patients who don’t need it. Prescribe it only for men with demonstrably low testosterone levels and 
accompanying symptoms.
Hypogonadism.
 ⦁Capsules (Android):  10 mg methyltestosterone.
 ⦁Buccal ER tablet (Striant):  30 mg.
 ⦁Topical gel (AndroGel, Androderm, others):  1%, 2%.
 ⦁Long-acting depot injection (Depo-Testosterone, [G]):  100 mg/mL, 200 mg/mL.
 ⦁Dosing varies from daily dosing of oral, buccal, and topical agents to Q2–4 week or Q3–6 month dosing of injectable 
formulations.
 ⦁Schedule III controlled substance.
Monitoring:  Hematocrit, bone density, LFTs.
Cost:  Capsule: $$$$$; buccal: $$$$$; gel: $$$$; depot injectable: $

 ⦁Most common: Nausea, headache, insomnia, anxiety, acne, water and electrolyte retention, local effects (eg, gum 
irritation with buccal formulation, application site irritation with gel, injection site pain with injectables).
 ⦁Serious but rare: Thromboembolic events (DVT, PE), myocardial infarction, stroke, worsening BPH, risk of prostate 
cancer.
 ⦁Anabolic and andronergic testosterone receptor agonist.
 ⦁Metabolized primarily through liver (non-CYP450); t ½: Varies.
 ⦁Hypogonadism may play a significant role in erectile dysfunction, and a threshold level of testosterone may be 
necessary for normal erectile function. However, testosterone levels needed for normal sexual function vary widely;

necessary for normal erectile function. However, testosterone levels needed for normal sexual function vary widely; 
some men may have normal function even with age-adjusted lower normal range levels. Testosterone replacement 
may be appropriate when both clinical symptoms and biochemical evidence of hypogonadism exist.
 ⦁Available data indicate that all testosterone products may be equally effective and associated with similar side effect 
profiles.
Fun Fact:
Stephen Braun, a medical writer, described how he was funded by Abbott Pharmaceuticals to help write a “consensus 
panel” statement for a physician’s organization. Two of his paragraphs casting doubt on the dangers of low 
testosterone were deleted from the final document (Braun S, JAMA Internal Medicine  2013;173(15):1458–1460).

172  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONVARDENAFIL  (Levitra) Fact Sheet [G]
Vardenafil doesn’t offer any benefits compared to sildenafil, which has more data in the psychiatric setting, more 
clinical experience, and lower cost.
 ⦁Tablets (Levitra, [G]):  2.5 mg, 5 mg, 10 mg, 20 mg.
 ⦁Orally disintegrating tablets (Staxyn): 10 mg.
 ⦁Start 10 mg ×1 one hour prior to sexual activity (5 mg if >65 years old). Max 20 mg/dose and one dose/day.
 ⦁Orally disintegrating tablets (Staxyn): Start 10 mg ×1 one hour prior to sexual activity. Max 10 mg/day.
 ⦁Taking with a high-fat meal may decrease serum vardenafil levels by as much as 50%.
Cost:  $$$
 ⦁Most common: Flushing, headache, nasal congestion, heartburn.

Cost:  $$$
 ⦁Metabolized primarily through CYP3A4 and to a lesser extent, 2C9; t ½: 4–5 hours.

with caution in patients taking alpha blockers; may cause symptomatic hypotension (use 5 mg dose). Use with 
caution in patients taking strong CYP3A4 inhibitors, which may increase or extend effects of vardenafil (maximum of 
2.5 mg/day).
Usual onset of effect of vardenafil is within one hour of a dose; effects usually last two hours.
Fun Fact:
Staxyn, the orally disintegrating tablet form of vardenafil, is peppermint flavored.

Side Effect ManagementCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   173Side Effect Management
GENERAL MANAGEMENT TIPS
If you’re like most psychiatrists, you probably severely underestimate the number of side effects your patients are 
experiencing. According to one survey, patients on antidepressants reported 20 times  more side effects than were 
actually recorded by their psychiatrists (Zimmerman M et al,  J Clin Psychiatry  2010;71(4):484–490).
Sometimes we don’t ask about side effects because we’re not sure what to do about them. In order to help you 
expand your side effect battling arsenal, we have provided this side effect management chapter. We’ve included 20 
fact sheets, including three new ones (diarrhea, neuroleptic malignant syndrome, and serotonin syndrome), covering 
some of the most common side effects you are likely to encounter in your patients. We had to pick and choose which

some of the most common side effects you are likely to encounter in your patients. We had to pick and choose which 
ones to include, so if there are important symptoms that are missing, please let us know so we can add them to the 
next edition.
In addition to the side effect management sheets, we’ve included seven regular medication fact sheets on agents that 
we use primarily to treat side effects. These include amantadine, benztropine, and trihexyphenidyl for extrapyramidal 
symptoms of antipsychotics; deutetrabenazine, tetrabenazine, and valbenazine for tardive dyskinesia; and metformin 
for weight gain caused by psychotropic drugs.
Here’s a quick orientation to the side effect fact sheet format:
 ⦁Characteristics:  We describe what the side effect feels like for patients and how you can recognize it.
 ⦁Meds That Cause It:  These are the medications that are most likely to cause the side effect in question. We include 
only psychotropics in this list.

⦁Meds That Cause It:  These are the medications that are most likely to cause the side effect in question. We include 
 ⦁Mechanism:  Although we usually don’t know exactly how psychotropics cause most side effects, we posit 
mechanisms that seem to be most popular with experts.
 ⦁General Management:  This refers to everything other than prescribing specific antidotes. Included here are things 
like watchful waiting, reducing the dose, switching to a different medication, shifting the timing of the dose (usually 
to bedtime), taking with food, and so on. Mostly these are commonsense interventions, which you should try before 
prescribing a new anti–side effect medication.
 ⦁First-Line Medications:  In some cases, most experts agree on a few medications that are most likely to be effective 
for managing specific side effects. That said, since there are very few clinical trials testing meds for side effects,

for managing specific side effects. That said, since there are very few clinical trials testing meds for side effects, 
judgments about what qualifies as a first-line vs a second-line medication are fallible, and we won’t be offended if 
you disagree.
 ⦁Second-Line Medications:  This section is reserved for the various nostrums—drugs that have been tried by various 
people and might work. You would likely resort to these only out of desperation.
 ⦁Clinical Pearls:  Hard-won wisdom from the trenches.
 ⦁Fun Fact:  Sometimes entertaining, sometimes intriguing... and sometimes just present.
A note on information sources: It’s not easy to find reliable information on side effect management. There are very 
few well-designed clinical trials on such uses, meaning that we must rely on uncontrolled trials, small case series, 
anecdotes, or simply expert opinion. In doing research for the symptom fact sheets in this chapter, we relied primarily

anecdotes, or simply expert opinion. In doing research for the symptom fact sheets in this chapter, we relied primarily 
on the following three sources, supplemented by various articles and our own clinical experiences:
 ⦁Annamalai A. Medical Management of Psychotropic Side Effects . New York, NY: Springer Publishing; 2017.
 ⦁Goldberg JF and Ernst CL. Managing the Side Effects of Psychotropic Medications . 2nd ed. Arlington, VA: American 
Psychiatric Association; 2019.
 ⦁Mago R. Side Effects of Psychiatric Medications . Createspace Independent Pub; 2014.

Side Effect Management: MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   175AMANTADINE  (Gocovri, Symmetrel) Fact Sheet [G]
Amantadine is a dopaminergic medication used primarily in Parkinson’s disease, but it is also helpful in drug-induced 
Parkinsonism and has fewer anticholinergic side effects (eg, cognitive impairment, dry mouth, constipation) than 
other anti-EPS meds like benztropine. 
Drug-induced extrapyramidal symptoms (EPS); Parkinson’s disease; influenza A.
Tardive dyskinesia; ADHD; enuresis; treatment-resistant depression; OCD.
 ⦁Capsules (G):  100 mg.
 ⦁Tablets (G):  100 mg.
 ⦁Oral solution (G):  50 mg/5 mL.
 ⦁ER capsules (Gocovri):  68.5 mg, 137 mg.
 ⦁IR: Start 100 mg HS or BID. Max 300 mg/day.
 ⦁ER: Start 137 mg QHS; increase after one week to usual and max dose of 274 mg QHS.

⦁ER capsules (Gocovri):  68.5 mg, 137 mg.
Cost:  $; ER: $$$$$
 ⦁Most common: Nausea, dizziness, orthostatic hypotension, insomnia, blurred vision, constipation, dry mouth.
 ⦁Serious but rare: Rare cases of intense urges to gamble, spend money, or have sex reported.
 ⦁Weak NMDA antagonist and potentiates dopaminergic neurons. Antiviral (inhibits replication of influenza A virus).
 ⦁Not metabolized; excreted primarily through kidneys; t ½: 17 hours.
 ⦁Minimal clinically significant drug interactions.
 ⦁Because of dopaminergic effects, theoretically amantadine could worsen psychosis. At doses typically used to 
manage EPS, though, this doesn’t generally happen.

 ⦁Typically used when anticholinergic side effects of other anti-EPS medications (benztropine, trihexyphenidyl) are 
intolerable.
 ⦁Adjust dose in elderly patients or those with impaired renal function.
 ⦁Gocovri is an extended-release once-daily version of amantadine, approved for treatment of dyskinesia in Parkinson’s 
patients taking levodopa. It costs patients an estimated $45 per capsule, ringing in at over $30,000 per year.
Fun Fact:
Memantine (Namenda), an NMDA antagonist used in dementia, is an analogue of amantadine.

176  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONBENZTROPINE  (Cogentin) Fact Sheet [G]
Benztropine is an anticholinergic medication that is the go-to agent for treating and preventing antipsychotic-
induced EPS.
Drug-induced extrapyramidal symptoms (EPS); Parkinson’s disease.
Sialorrhea (excessive salivation); hyperhidrosis (excessive sweating).
 ⦁Tablets (G):  0.5 mg, 1 mg, 2 mg.
 ⦁Injectable:  1 mg/mL.
 ⦁Start 1 mg BID; ↑ by 1–2 mg/day every three to seven days as needed; max 3 mg BID. May be taken once daily at 
bedtime.
 ⦁For acute dystonic reactions, use 1–2 mg IM ×1 and continue with oral, as above, to prevent recurrence.
Cost:  $
 ⦁Most common: Dry mouth, blurred vision, constipation, urinary retention, sedation.

Cost:  $
 ⦁Serious but rare: In those at risk (elderly patients), may cause confusion or delirium; may worsen angle-closure 
glaucoma.
 ⦁Anticholinergic, antihistaminergic.
 ⦁Metabolized primarily through liver via unknown P450; t ½: 12–24 hours.
 ⦁Minimal clinically significant drug interactions; avoid combining with other anticholinergic agents due to additive 
effects.
If starting a patient on a high-potency antipsychotic such as haloperidol or risperidone, some clinicians will start 
benztropine prophylactically to prevent EPS. If you do so, consider taper and withdrawal of benztropine after one or 
two weeks to see if it’s really needed.
Fun Fact:
Veterinarians use benztropine to treat priapism in stallions.

Side Effect Management: MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   177DEUTETRABENAZINE  (Austedo) Fact Sheet
Deutetrabenazine was the second of the VMAT inhibitors to be approved for the treatment of tardive dyskinesia (TD) 
in 2017. Its advantage over off-label tetrabenazine is less frequent dosing and less likelihood of causing depression. 
However, it is extremely expensive—about $6,000/month as opposed to $400/month for tetrabenazine. 
TD; Huntington’s chorea.
Tourette’s and other tic disorders.
Tablets: 6 mg, 9 mg, 12 mg.
Start 6 mg BID with food. Titrate at weekly intervals by 6 mg/day increments; increase to maximum dose of 48 mg/day 
with food (doses ≥12 mg/day should be divided BID).
 ⦁Most common: Sedation, somnolence, fatigue, diarrhea.

 ⦁Serious but rare: QT interval prolongation; caution in those with increased risk (congenital long QT syndrome, 
electrolyte disturbances, poor 2D6 metabolizers, concomitant 2D6 inhibitors).
 ⦁Reversible inhibitor of vesicular monoamine transporter 2 (VMAT2). This prevents VMAT2 from transporting 
monoamines including dopamine back into presynaptic vesicles, resulting in metabolism of monoamines, 
ultimately leading to depletion of monoamine stores and less dopamine being around. This treats TD symptoms, 
which are likely caused by hypersensitivity to dopamine.
 ⦁Metabolized primarily by CYP450 2D6; t ½: 9–10 hours.
 ⦁Avoid MAOIs. Decrease deutetrabenazine dose in presence of 2D6 inhibitors or poor metabolizers.

⦁Metabolized primarily by CYP450 2D6; t ½: 9–10 hours.
 ⦁Deutetrabenazine is a deuterated form of tetrabenazine (Xenazine), a similar VMAT2 inhibitor, which is approved for 
treatment of Huntington’s chorea.
 ⦁Increased depression and suicidality have been reported with tetrabenazine. Paucity of long-term data with 
deutetrabenazine makes it difficult to determine whether it will pose these concerns as well.
 ⦁A one-year course costs over $70,000.
Fun Fact:
Chemistry course refresher! Deuterated drugs are created by replacing one or more of the hydrogen atoms of the 
drug molecule with deuterium. This may significantly slow drug metabolism, resulting in a longer half-life of the drug.

178  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONMETFORMIN  (Glucophage, Glumetza, Riomet) Fact Sheet [G]
Metformin is a medication for type 2 diabetes that increases insulin sensitivity and decreases appetite. It’s somewhat 
effective for antipsychotic-induced weight gain (average of 3 kg weight loss) and might work better if started 
prophylactically as a way to prevent excessive weight gain in the first place. It’s quite safe and well tolerated (with 
some GI side effects) and is becoming a standard add-on treatment in patients taking clozapine or olanzapine.  
Diabetes mellitus, type 2.
Antipsychotic-induced weight gain; polycystic ovary syndrome; prediabetes; female infertility.
 ⦁Tablets (G):  500 mg, 850 mg, 1000 mg.
 ⦁ER tablets (Glucophage XR, Glumetza, [G]):  500 mg, 750 mg, 1000 mg.
 ⦁Oral solution (Riomet, [G]):  500 mg/5 mL.

 ⦁IR: Start 500 mg BID; ↑ by 500 mg/day increments weekly; max 2250 mg/day.
 ⦁ER: Start 500 mg QPM; ↑ by 500 mg/day increments weekly; max 2000 mg/day.
 ⦁ER formulation is preferred because it minimizes GI side effects. Better tolerated with taken with meals. 
Cost:  $; liquid: $$$
 ⦁Most common: Diarrhea; nausea; abdominal bloating, flatulence, and discomfort.
 ⦁Serious but rare: Rare cases of lactic acidosis reported.
 ⦁Decreases glucose production by liver and increases insulin sensitivity.
 ⦁Not metabolized; excreted primarily through kidneys; t ½: 4–9 hours.

⦁Not metabolized; excreted primarily through kidneys; t ½: 4–9 hours.
 ⦁In psychiatry, metformin is used primarily to prevent or reverse weight gain in patients taking certain antipsychotic 
medications. The best-studied and most widely used dose is 500–1000 mg BID, which typically produces an average 
of 3 kg of weight loss in patients. 
 ⦁A recent meta-analysis of 12 studies, representing a total of 743 patients, found metformin use resulted in more 
weight loss (an average of about 7 lbs) and BMI reduction than placebo in patients taking antipsychotics (de Silva 
VA et al, BMC Psychiatry  2016;16:341).
 ⦁Another review of patients with schizophrenia who were treated with antipsychotics found metformin also 
improved insulin resistance and decreased lipids (Mizuno Y et al, Schiz Bull  2014;40(6):1385–1403).

 ⦁Taking with food or using XR formulation helps to minimize the nausea and diarrhea that occurs in up to 50% of 
patients.
 ⦁Adjust dose in patients with eGFR less than 60 mL/minute (see Appendix H for guidance).
Fun Fact:
Metformin was introduced in the US in 1995, but it’s been used in France since 1957.

Side Effect Management: MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   179TETRABENAZINE  (Xenazine) Fact Sheet
Tetrabenazine was the original VMAT inhibitor brought to market and approved for the treatment of Huntington’s 
disease. It’s an off-label alternative to deutetrabenazine and valbenazine for treating tardive dyskinesia (TD). Although 
it’s much less expensive, it requires more frequent dosing and may have a higher likelihood of causing depression. 
Huntington’s chorea.
TD; Tourette’s and other tic disorders.
Tablets: 12.5 mg, 25 mg.
Start 12.5 mg QAM for one week. Titrate at weekly intervals by 12.5 mg/day increments; increase to maximum dose of 
100 mg/day. Should be given in divided doses of BID to QID with no more than 25 mg/dose.
Cost:  $$

Cost:  $$
 ⦁Serious but rare: Risk of depression and suicidality; QT interval prolongation; caution in those with increased risk 
(congenital long QT syndrome, electrolyte disturbances, poor 2D6 metabolizers, concomitant 2D6 inhibitors).
 ⦁Metabolized primarily by CYP450 2D6; t ½: 5–7 hours.
 ⦁Avoid MAOIs. Decrease tetrabenazine dose in presence of 2D6 inhibitors or poor metabolizers.

⦁Metabolized primarily by CYP450 2D6; t ½: 5–7 hours.
 ⦁One double-blind study and seven open-label studies support the efficacy of tetrabenazine for TD.
 ⦁Increased depression and suicidality have been reported with tetrabenazine; use caution in patients with a history 
of depression and monitor all patients for symptoms.
 ⦁Genotyping for 2D6 metabolism is recommended for doses >50 mg/day. 
Fun Fact:
Tetrabenazine was initially developed in the 1950s as an antipsychotic to replace reserpine because it had less severe 
depressive and hypotensive effects.

180  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONTRIHEXYPHENIDYL  (Artane) Fact Sheet [G]
Trihexyphenidyl is an anticholinergic medication that is less favored than benztropine because it must be dosed TID 
and is only available in oral formulations. Use as a second-line option.
 ⦁Tablets (G):  2 mg, 5 mg.
 ⦁Oral solution:  2 mg/5 mL.
Start 2 mg QD; ↑ by 2 mg/day increments every three to five days as needed, up to maximum 5 mg TID.
Cost:  $
glaucoma.

⦁Serious but rare: In those at risk (elderly patients), may cause confusion or delirium; may worsen angle-closure 
glaucoma.
 ⦁Metabolized primarily through liver via unknown P450; t ½: 3–4 hours.
effects.
trihexyphenidyl prophylactically to prevent EPS. If you do so, consider taper and withdrawal of trihexyphenidyl after 
one or two weeks to see if it’s really needed.
Fun Fact:
There have been many reports of recreational use of trihexyphenidyl over the years: by Iraqi soldiers and police to 
relieve combat stress, as a more intense substitute for LSD in the 1960s, and by the late Oliver Sacks, who reportedly

relieve combat stress, as a more intense substitute for LSD in the 1960s, and by the late Oliver Sacks, who reportedly 
took 20 trihexyphenidyl pills and hallucinated an entire conversation with friends (check out his book, Hallucinations , 
to read about his experimentation with a range of drugs).

Side Effect Management: MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   181VALBENAZINE  (Ingrezza) Fact Sheet
Valbenazine was the first of the VMAT inhibitors to be approved for the treatment of tardive dyskinesia (TD) in 
2017. Its advantage over off-label tetrabenazine is less frequent dosing (once daily) and less likelihood of causing 
depression. However, it is extremely expensive—about $6,000/month as opposed to $400/month for tetrabenazine. 
TD.
Tourette’s and other tic disorders; Huntington’s chorea.
Capsules: 40 mg, 60 mg, 80 mg.
Start 40 mg once daily. After one week, ↑ to usual dose of 80 mg once daily.
 ⦁Most common: Sedation, somnolence, akathisia, restlessness.
 ⦁Serious but rare: QT interval prolongation; caution in those with increased risk (congenital long QT syndrome,

electrolyte disturbances, poor 2D6 metabolizers, concomitant 2D6 or 3A4 inhibitors).
 ⦁Metabolized by CYP450 2D6 and 3A4 (primary); t ½: 15–22 hours.
 ⦁Avoid MAOIs. Decrease valbenazine dose in presence of 2D6 or 3A4 inhibitors.
 ⦁Clinical trials of valbenazine for TD found an impressive 40% response rate (meaning a 50% improvement in TD

 ⦁Clinical trials of valbenazine for TD found an impressive 40% response rate (meaning a 50% improvement in TD 
symptoms) vs a 9% response rate for patients taking placebo.
 ⦁Increased depression and suicidality have been reported with use of a similar VMAT2 inhibitor, tetrabenazine 
(Xenazine, used for Huntington’s chorea). Paucity of long-term data with valbenazine makes it difficult to determine 
whether this will be of concern with valbenazine as well.
 ⦁A one-year course costs over $72,000.
Fun Fact:
Reserpine, an antihypertensive and antipsychotic used in the 1950s, was a VMAT1/VMAT2 inhibitor. Cases of 
depression reported with its use led to the monoamine hypothesis of depression.

Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   183
Side Effect Management: Symptoms Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   183Akathisia
Characteristics:  A sense of restlessness, causing the patient to appear fidgety, to have difficulty sitting still, and 
to rock from one leg to the other while standing. It can present as an inner sense of restlessness without obvious 
movement. Can lead to agitation and even suicidal ideation.
Meds That Cause It:  Antipsychotics, especially high-potency first-generation antipsychotics (such as haloperidol), 
but second-generation agents may also cause it (especially aripiprazole, brexpiprazole, paliperidone, risperidone). 
Occasionally SSRIs and buspirone.
Mechanism:  D2 blockade.
General Management:
 ⦁Reduce dose.
 ⦁Switch to lower-potency first-generation or second-generation agent with lower potential for akathisia (see 
Table 10).
First-Line Medications:

Table 10).
 ⦁Propranolol (Inderal). Start 10 mg BID; ↑ by 10–20 mg/day increments; can go up to 30–90 mg daily in two or three 
divided doses. SE: Dizziness, fatigue, syncope, low BP .
 ⦁Inderal LA. Long-acting version of propranolol that can be dosed once a day. 60–80 mg daily.
 ⦁Benzodiazepines. Any of them will work (eg, lorazepam [Ativan] 0.5–1 mg BID). Dosed at the equivalent of diazepam 
(Valium) 10 mg BID or more frequently as needed.
Second-Line Medications:
 ⦁Benztropine (Cogentin) 1 mg BID.
 ⦁Cyproheptadine (Periactin) 8–16 mg/day.
 ⦁Amantadine (Symmetrel) 100–200 mg BID.
 ⦁Clonidine (Klonopin) 0.2–0.8 mg/day.
 ⦁Gabapentin (Neurontin) 1200 mg/day.
 ⦁Trazodone (Desyrel) 100 mg/day.
 ⦁Mirtazapine (Remeron) 15 mg/day.

⦁Clonidine (Klonopin) 0.2–0.8 mg/day.
 ⦁May manifest in a number of ways, such as pacing, inability to sit still, crossing and uncrossing one’s legs, rocking 
back and forth, or other purposeless repetitive motions; patients may complain of crawling feeling under skin or 
“shocks. ”
 ⦁Don’t confuse akathisia with agitation due to the underlying psychiatric disorder—you might make the mistake of 
increasing the antipsychotic, thus worsening the akathisia.
 ⦁Risk factors include high dose, high-potency antipsychotics, and rapid dose escalation; use of caffeine, other 
stimulants, or illicit drugs may also exacerbate akathisia.
 ⦁May appear within first few hours of antipsychotic exposure, but usually takes days to weeks to appear.
 ⦁Can occur in a tardive form, with symptoms lasting for greater than six months after discontinuation of the 
offending agent.

⦁Can occur in a tardive form, with symptoms lasting for greater than six months after discontinuation of the 
 ⦁Clozapine and quetiapine cause no more akathisia than placebo.
Fun Fact:
Akathisia is from the Greek a-kathisis , “no sitting. ” The English word “cathedral” is from the same root: Kathedra  is a 
bishop’s seat or throne, while a cathedral is a church in which the bishop’s seat is placed.

184  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION 184  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONBruxism
Characteristics:  Involuntary grinding of teeth, which especially occurs during sleep but can also occur in 
the daytime. In 5% of cases this can cause severe health problems, such as destruction of tooth structure, 
temporomandibular joint dysfunction, myofascial pain, and sleep disturbances.
Meds That Cause It:  A variety of medications, including antidepressants (especially SSRIs and the SNRI venlafaxine), 
psychostimulants, and antipsychotics; drugs of abuse such as methamphetamine, cocaine, and ecstasy.
Mechanism:  Unclear, but likely involves central dopaminergic and serotonergic systems.
 ⦁Reduce dose or switch medication.
 ⦁Wear dental guards at night.
 ⦁Treat anxiety, which worsens bruxism.
 ⦁Decrease or stop using tobacco, caffeine, and alcohol.

⦁Reduce dose or switch medication.
Buspirone (BuSpar) 10 mg BID or TID.
 ⦁Benzodiazepines, such as clonazepam (Klonopin) 0.5–1 mg at bedtime.
 ⦁Gabapentin (Neurontin) 300 mg QHS.
 ⦁Frequency of bruxism varies from day to day, but symptoms are usually induced or worsened by anxiety and stress.
 ⦁Watching and waiting may be indicated as spontaneous remission can occur after one month.
 ⦁Botulinum toxin (Botox) injections into the masseter muscle are effective for persistent bruxism.
 ⦁Risk factors include obstructive sleep apnea and parasomnias, anxiety, heavy alcohol use, loud snoring, caffeine 
intake, smoking, and other psychiatric and neurologic disorders.
Fun Fact:
People with bruxism are referred to as “bruxists” or “bruxers. ”

Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   185
Side Effect Management: Symptoms Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   185Constipation
Characteristics:  Straining to have bowel movements, often with hard stools, and a sensation of incomplete 
evacuation. Not necessarily infrequent stools—patients may have a bowel movement every day, but if they strain, 
they are constipated.
Meds That Cause It:  Antipsychotics (especially clozapine and olanzapine, but all can cause it); antidepressants, 
including SSRIs (particularly paroxetine); SNRIs; mirtazapine; tricyclics; benztropine; antihistamines (eg, 
diphenhydramine, hydroxyzine); opiates.
Mechanism:  Usually due to anticholinergic effects, which lead to decrease in bowel motility.
 ⦁Decrease dose or switch agents.
 ⦁Increase fluid intake.
 ⦁Increase dietary fiber (cereals, fruits, bran) and eat prunes.
 ⦁Increase physical activity.

 ⦁Bulk-forming laxative (SE: Gas, bloating):
 –Psyllium (Metamucil) or methylcellulose (Citrucel) one tablespoon three times daily.
 –Avoid in patients taking clozapine as it may increase risk of perforation in slow-transit constipation. 
 ⦁Stool softener (SE: Diarrhea):
 –Docusate sodium (Colace) 100–250 mg twice daily. Must be taken with full glass of water.
 ⦁Osmotic laxatives (SE: Bloating, gas, watery stools):
 –Lactulose (Kristalose) 15–30 mL daily or every other day.
 –Polyethylene glycol solution (MiraLax) 8–34 g in eight ounces of fluid.
 –Magnesium citrate 150–300 mL daily.
 ⦁Stimulant laxatives (SE: Diarrhea, cramps):
 –Sennosides (Ex-Lax, Senokot), available in different formulations (usual dose is one to two 8.6 mg tablets QD to 
BID as needed).

⦁Stimulant laxatives (SE: Diarrhea, cramps):
 –Bisacodyl (Dulcolax), available as suppository (usual dose is 5–15 mg daily, max 30 mg/day).
 –Magnesium hydroxide (milk of magnesia) 30–60 mL QD as needed (available also in chewable tablet form).
Constipation can be caused by various illnesses, including irritable bowel syndrome (usually diarrhea interspersed 
with constipation), hypothyroidism, and colon cancer (red flags include blood in stool and weight loss).
Fun Fact:
According to a crossover trial of 40 patients, prunes worked better than psyllium, producing more spontaneous bowel 
movements (3.5 vs 2.8 per week) and better stool consistency (Attaluri A, Aliment Pharmacol Ther  2011;33(7):822).

186  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION 186  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONDiarrhea
Characteristics:  Passing of loose or watery stools, at least three times in a 24-hour period. Often due to infectious 
etiology (eg, rotovirus, norovirus, adenoviruses, E. coli ) but can occur as a side effect to medications. Most cases 
resolve with routine over-the-counter treatment.
Meds That Cause It:  Antibiotics, proton pump inhibitors, donepezil, galantamine, memantine, rivastigmine, 
sertraline, acamprosate, lithium, stool softeners and other laxatives, rapid discontinuation of anticholinergic agents 
(cholinergic rebound).
Mechanism:  Increased water content of stool, usually due to impaired water absorption and/or active water secretion 
by the bowel. 
 ⦁Push fluids and suggest dietary adjustments like the BRAT diet (bananas, rice, applesauce, and toast). Avoid high-fat 
foods.

foods.
 ⦁Get a travel and food history.
 ⦁Ask about recent antibiotic use. 
 ⦁Assess for serotonin syndrome (presence of mental status changes, hyperthermia, hyperreflexia, autonomic 
instability).
 ⦁If on lithium, check serum lithium level for toxicity. 
 ⦁Antimotility agents: Loperamide (Imodium) two tablets (4 mg) initially, then 2 mg after each loose stool for no more 
than two days with a max dose of 16 mg/day. Avoid if fever or blood in stool. 
 ⦁Bismuth salicylate (Pepto-Bismol) 30 mL or two tablets every 30 minutes, up to eight doses.
 ⦁Diphenoxylate/atropine (Lomotil) is an alternative antimotility agent that binds to opioid receptors in the gut. Start 
two tablets QID for no more than two days. 

⦁Diphenoxylate/atropine (Lomotil) is an alternative antimotility agent that binds to opioid receptors in the gut. Start 
 ⦁Loperamide is also an agonist at opioid receptors in the gut; misuse and abuse of this over-the-counter drug has 
increased in recent years. Those using opioids know it can help with withdrawal-related diarrhea. Some have 
discovered that in high doses (100–200 mg/day), it can produce euphoria. In rare cases, high dose use has resulted 
in hospitalization for arrhythmias and death. 
 ⦁If persistent, bloody, or accompanied by severe pain or volume depletion (dry mucous membranes, low BP), refer for 
further evaluation including need for stool testing.
Fun Fact:
Clear liquids like water, ginger ale, and electrolyte-rich sports drinks (eg, Gatorade) are often recommended for fluid 
repletion during bouts of diarrhea. Probiotic drinks may help too.

Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   187
Side Effect Management: Symptoms Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   187Dry Mouth (Xerostomia)
Characteristics:  An uncomfortable sensation of dryness due to diminished saliva; can lead to dental caries, because 
saliva has an antibacterial effect. Can also cause decreased taste and inflammation of gums.
Meds That Cause It:  Most psychotropic meds, especially antipsychotics, antidepressants (including SSRIs), 
lithium, psychostimulants, and medications used to treat or prevent extrapyramidal symptoms (benztropine, 
diphenhydramine, trihexyphenidyl).
Mechanism:  Anticholinergic and other effects.
 ⦁Encourage aggressive oral hygiene, including more frequent dental cleanings.
 ⦁Chew sugarless gum to stimulate saliva production (especially gum containing xylitol, which can also reduce dental 
caries).
 ⦁Sip water frequently.

⦁Chew sugarless gum to stimulate saliva production (especially gum containing xylitol, which can also reduce dental 
caries).
 ⦁Suck on ice chips.
 ⦁Biotene line of products, over the counter (most contain lubricants and humectants to “seal in” moisture):
 –Biotene gum, use as needed.
 –Biotene toothpaste, use as with any toothpaste.
 –Biotene oral rinse (mouthwash), rinse up to five times per day.
 –Biotene Oralbalance Gel, use one inch on tongue as needed (comes out of a tube).
 –Biotene moisturizing mouth spray, spray on tongue as needed.
 ⦁Many saliva substitutes are available, such as Oralube saliva substitute, Oasis mouth spray, and others. No studies 
have demonstrated superiority of any single brand.
 ⦁Procholinergic drugs:
 –Pilocarpine (Salagen) 5–10 mg two or three times daily (SE: Sweating, congestion, diarrhea; start with 2.5 mg test 
dose to ensure tolerability).

 –Cevimeline (Evoxac) 30 mg up to three times daily.
 ⦁Caffeine can worsen dry mouth, so recommend decreasing caffeine use.
 ⦁Don’t shy away from trying procholinergic drugs—some patients prefer them over having to constantly use saliva 
substitute products.
Fun Fact:
Medications are often blamed, particularly in older patients, but aging itself is a common cause of dry mouth.

188  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION 188  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONDystonia
Characteristics:  Involuntary contractions of muscles due to some antipsychotics. Can include torticollis (twisting 
neck), opisthotonos (arching spine or neck), oculogyric crisis (eyes rolling back), and trismus (jaw clenching). Rare but 
serious is tongue swelling, which can block the airway or cause choking when eating.
Meds That Cause It:  Antipsychotics, especially high-potency first-generation antipsychotics. May rarely occur with 
second-generation antipsychotics.
First-Line Medications  (give these IM or IV if dystonia is severe):
 ⦁Benztropine (Cogentin) 1–2 mg once or twice per day (SE: Dry mouth, blurred vision, constipation, urinary retention, 
and cognitive changes).
 ⦁Diphenhydramine (Benadryl) 50 mg/day.

⦁Benztropine (Cogentin) 1–2 mg once or twice per day (SE: Dry mouth, blurred vision, constipation, urinary retention, 
 ⦁If dystonia is severe, stop the offending drug, and give either of the above agents IM or IV once or twice to stop the 
dystonia. Then prescribe two to three days of the oral version to prevent another episode.
 ⦁Benzodiazepines (especially diazepam [Valium] 5–10 mg).
 ⦁Amantadine (Symmetrel) 100–200 mg BID (no injectable available).
 ⦁Trihexyphenidyl (Artane) 1–2 mg TID (no injectable available).
 ⦁Earliest of the extrapyramidal symptoms, with an onset of hours to days after antipsychotic is started or dose is 
increased; 90% of reactions occur within first five days.
 ⦁Risk factors include young male patients, high-potency first-generation antipsychotics, or high dose.

 ⦁Prophylaxis with anticholinergic agent for first month of treatment in those with high risk or previous history.
 ⦁May be very frightening and painful for the patient.
Fun Fact:
Dystonia has many causes other than antipsychotics, and it is the third most common movement disorder in the 
United States, following essential tremor and Parkinson’s disease. Neurologists use botulinum toxin (Botox) to treat 
some dystonias, especially cervical dystonias.

Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   189
Side Effect Management: Symptoms Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   189Excessive Sweating (Hyperhidrosis)
Characteristics:  Excessive sweating, which tends to be more prominent in the face, neck, and chest, and less 
prominent in the armpits and palms.
Meds That Cause It:  Antidepressants, especially SNRIs (venlafaxine, duloxetine, levomilnacipran) and bupropion.
Mechanism:  Dysregulation of cholinergically innervated sweat glands.
Reduce dose or switch agents.
 ⦁Terazosin (Hytrin) alpha-1 blocker; start 1 mg at bedtime, then gradually ↑ by 1 mg/day increments up to 4–6 mg 
(SE: Dizziness, dry mouth, hypotension, rebound hypertension if stopped abruptly).
 ⦁Clonidine (Catapres) 0.1 mg daily.

 ⦁Glycopyrrolate (Robinul); start 1 mg twice daily and ↑ gradually by 1 mg/day increments up to 2 mg three times a 
day. Can be used PRN.
 ⦁Oxybutynin (Ditropan) 5–10 mg daily or twice daily.
 ⦁Mirtazapine (Remeron) up to 60 mg daily as adjunct.
 ⦁Cyproheptadine (Periactin) 4 mg daily or twice daily.
 ⦁Aripiprazole (Abilify) 10 mg daily (one trial showed it alleviated hyperhidrosis due to fluoxetine or duloxetine).
 ⦁Patients may not need to take medication for sweating in the winter.
 ⦁Often occurs in people who tended to sweat a lot before taking the medication.
Fun Fact:
Glycopyrrolate is so effective at reducing sweating that the label warns it can reduce the body’s ability to cool off by 
sweating—which, in very high temperatures, can cause fever and heatstroke.

190  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION 190  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONFatigue
Characteristics:  Sleepiness as a result of medications, usually due to antidepressants. Typically, patients say they 
sleep more than enough at night, yet they feel like they could fall asleep at any point throughout the day.
Meds That Cause It:  Antidepressants (especially paroxetine, mirtazapine, and tricyclics; bupropion is least  likely to 
cause fatigue); antipsychotics (especially clozapine, quetiapine, olanzapine, ziprasidone, but all can cause it); mood 
stabilizers; benztropine; antihistamines (eg, diphenhydramine, hydroxyzine); opiates.
Mechanism:  Various mechanisms, often due to antihistamine or anticholinergic effects.
 ⦁Watchful waiting for spontaneous resolution (not usually effective).
 ⦁Change dosing to bedtime.
Medications:

 ⦁If not clinically contraindicated, psychostimulants such as methylphenidate or dextroamphetamine. Depending on 
the response, you may switch to a long-acting stimulant eventually.
 ⦁Modafinil (Provigil) 100–300 mg daily in divided doses.
 ⦁Armodafinil (Nuvigil) 150–250 mg daily in divided doses.
 ⦁If a serotonergic antidepressant is causing fatigue, consider switching to bupropion.
 ⦁Rule out common non-medication causes of fatigue, such as obstructive sleep apnea, hypothyroidism, and anemia.
 ⦁Fatigue can be a residual symptom of partially treated depression.
 ⦁If patients are taking a benzodiazepine for anxiety or insomnia, this could be causing daytime fatigue. Consider 
decreasing the dose or switching to a different agent.
Fun Fact:

⦁If patients are taking a benzodiazepine for anxiety or insomnia, this could be causing daytime fatigue. Consider 
Fun Fact:
Some consider the US to be the most overworked developed country. The number of hours Americans work (86% of 
men and 67% of women work more than 40 hours weekly) and the absence of a national paid parental leave benefit 
contribute to this distinction, as does the lack of federal laws requiring maximum work week length, paid sick leave, or 
vacation days. No wonder so many experience fatigue.

Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   191
Side Effect Management: Symptoms Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   191Nausea
Characteristics:  Nausea or sensation of upset stomach beginning soon after first dose of a new medication.
Meds That Cause It:  Serotonergic antidepressants (especially vilazodone and vortioxetine), lithium, valproic acid, 
naltrexone.
Mechanism:  Various; may be related to stimulation of 5-HT3 receptors.
 ⦁Wait one or two weeks, since nausea is often transient.
 ⦁Switch to a nonserotonergic antidepressant.
 ⦁Start drug at half the usual dose and go up gradually.
 ⦁Take medication just after meals.
 ⦁Split the dose into BID or TID dosing.
 ⦁Switch to a delayed-release, extended-release, or enteric-coated formulation, if available (eg, valproic acid, lithium).
 ⦁Take a spoonful of peanut butter before taking the medication.

⦁Switch to a delayed-release, extended-release, or enteric-coated formulation, if available (eg, valproic acid, lithium).
Medications  (SE: Most well tolerated especially when used PRN; sedation common with many):
 ⦁Ginger root capsules two to three times per day, two capsules per dose.
 ⦁Trimethobenzamide (Tigan) 300 mg TID PRN.
 ⦁Promethazine (Phenergan) 12.5–25 mg BID PRN.
 ⦁Ondansetron (Zofran) 4–8 mg Q8 hours PRN (5-HT3 blocker).
 ⦁Mirtazapine (Remeron) 15 mg daily (5-HT3 blocker).
 ⦁Metoclopramide (Reglan) 10 mg three times a day as needed.
 ⦁Prochlorperazine (Compazine) 5–10 mg Q8 hours PRN.
 ⦁Both metoclopramide and prochlorperazine are phenothiazines and, like others in that class, may cause 
extrapyramidal symptoms if continued for too long.
 ⦁Patients with preexisting GERD may be more susceptible to med-induced nausea. Try prescribing a proton pump

 ⦁Patients with preexisting GERD may be more susceptible to med-induced nausea. Try prescribing a proton pump 
inhibitor, such as omeprazole (Prilosec), along with the offending agent.
Fun Fact:
Antipsychotics rarely cause nausea—in fact, several are FDA-approved antiemetics.

192  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION 192  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONNeuroleptic Malignant Syndrome (NMS)
Characteristics:  A rare but potentially life-threatening drug reaction presenting with muscle rigidity (“lead pipe”), 
hyperthermia, and altered mental status. May present similarly to serotonin syndrome although may be less acute in 
onset (within days vs hours).
Meds That Cause It:  Antipsychotics. Occasionally other antidopaminergic medications (eg, metoclopramide).
 ⦁Discontinue antidopaminergic agents.
 ⦁Monitor vital signs and creatinine kinase levels to assess severity and to guide supportive care, including stabilizing 
vital signs and intravenous fluids if necessary.
Benzodiazepines. Any of them will work (eg, lorazepam [Ativan] 0.5–1 mg BID or diazepam [Valium] 10 mg BID).

 ⦁Bromocriptine (Parlodel) 2.5–5 mg Q6–8 hours.
 ⦁For severe rigidity, dantrolene (Dantrium) 3–5 mg/kg IV divided TID or 100–400 mg/day oral divided QID. Monitor 
liver function. 
 ⦁Bromocriptine or dantrolene should be continued for 10 days beyond symptom resolution.
 ⦁Most cases, especially if caught early, will resolve quickly after antipsychotic discontinuation. 
 ⦁Avoid bromocriptine if serotonin syndrome is not ruled out (eg, patient taking both antipsychotics and serotonergic 
agents). Bromocriptine has some proserotonergic activity and could worsen serotonin syndrome.
 ⦁Up to 50% of patients who have experienced NMS may have another episode. To minimize risk of recurrence in 
patients who require ongoing antipsychotic therapy, wait until symptoms have completely resolved (at least two

patients who require ongoing antipsychotic therapy, wait until symptoms have completely resolved (at least two 
weeks). Choose a different agent, ideally a second-generation antipsychotic as they are less likely to cause NMS. 
Never use a long-acting antipsychotic injection in patients with a history of NMS. 
Fun Fact:
Mortality rates from NMS had previously been reported to be as high as 20%–38%. In more recent years, the mortality 
rate has fallen to below 10%. This has been attributed to earlier recognition and better management.

Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   193
Side Effect Management: Symptoms Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   193Orthostatic Hypotension (Postural Hypotension)
Characteristics:  Orthostatic hypotension (OH) is caused by blood pooling in the lower extremities when people 
stand up, causing less blood flow to the brain and consequent dizziness. Usually caused by medications that block the 
alpha-1 receptors, which are responsible for telling the body to constrict blood vessels (and maintain blood pressure) 
after standing up. Patients will report feeling faint when they get up, and occasionally a sense of the room spinning 
(vertigo).
Meds That Cause It:  Antipsychotics, especially clozapine, risperidone, quetiapine, and lower-potency first-generation 
agents. Antidepressants, especially tricyclics, MAOIs, trazodone, sometimes mirtazapine.

Mechanism:  Alpha-1 receptor blockade, also anticholinergic effects.
 ⦁Review all meds, including nonpsychiatric, since many blood pressure and cardiac meds, as well as alpha blockers 
like prazosin (Minipress) and tamsulosin (Flomax) used for benign prostatic hyperplasia, can cause OH.
 ⦁Start at lower dose and titrate more slowly, especially when using higher-risk agents in higher-risk patients.
 ⦁Change dosing to minimize peak blood levels (eg, split dosing or switch to an extended-release version).
 ⦁Instruct patient to stand up slowly.
 ⦁Prevent dehydration by drinking enough fluids.
 ⦁Use compression stockings, also known as TED stockings.
 ⦁Increase salt intake (if no hypertension).
 ⦁Limit alcohol use.
 ⦁Fludrocortisone (Florinef) 0.1 mg daily; can ↑ by 0.1 mg/day increments weekly to 0.3 mg daily. SE: Hypokalemia.

⦁Increase salt intake (if no hypertension).
 ⦁Fludrocortisone (Florinef) 0.1 mg daily; can ↑ by 0.1 mg/day increments weekly to 0.3 mg daily. SE: Hypokalemia. 
Use only in severe cases where other measures have not worked.
 ⦁Midodrine 10 mg three times daily. SE: Goose bumps, paresthesias. Use only in severe cases where other measures 
have not worked.
 ⦁OH is defined as a 20 mm drop in systolic pressure or a 10 mm drop in diastolic pressure within three minutes of a 
patient moving from lying to standing position.
 ⦁Ask patients when the symptom is worse; if it is worse an hour or two after taking the medication, it is most likely 
medication induced.
 ⦁More common and problematic in elderly; may contribute to fall risk.
Fun Fact:
A recent epidemiologic observational study out of Johns Hopkins, following nearly 12,000 individuals over 20 years,

⦁More common and problematic in elderly; may contribute to fall risk.
Fun Fact:
A recent epidemiologic observational study out of Johns Hopkins, following nearly 12,000 individuals over 20 years, 
recently suggested that OH in middle age increases risk of cognitive decline and later dementia.

194  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION 194  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONParkinsonism
Characteristics:  Also known as pseudoparkinsonism, these drug-induced symptoms mimic those of Parkinson’s 
disease:
 ⦁Tremor (especially apparent in the hands as a resting, “pill rolling” tremor).
 ⦁Rigidity (cog-wheel rigidity).
 ⦁Bradykinesia (slow movement), decreased arm swing.
 ⦁Shuffling gait.
 ⦁Slurred speech.
 ⦁Mask-like facies, stooped posture, drooling.
 ⦁Psychological side effects, such as cognitive dulling (bradyphrenia), worse negative symptoms (neuroleptic-induced 
deficit syndrome), worse depression (neuroleptic dysphoria).
Meds That Cause It:  Antipsychotics, especially first-generation agents, but second-generation antipsychotics may 
also cause it. Least likely to cause it are clozapine, olanzapine, quetiapine, and ziprasidone.

Mechanism:  D2 blockade, disruption of the balance between dopaminergic vs cholinergic neurons.
Decrease dose or switch to a different antipsychotic.
 ⦁Benztropine (Cogentin) 1–2 mg once or twice per day.
 ⦁Trihexyphenidyl (Artane) 2–5 mg once or twice per day.
Amantadine (Symmetrel) 100–200 mg twice per day (enhances dopamine release).
 ⦁May occur at any time, but typically seen within one to two months after antipsychotic is initiated.
 ⦁Highest-risk patients: Female, older, those taking higher-potency agents or higher doses.
 ⦁In patients at high risk of parkinsonism, start benztropine (or one of the other first-line agents) at the same time as 
starting the antipsychotic.

⦁In patients at high risk of parkinsonism, start benztropine (or one of the other first-line agents) at the same time as 
 ⦁Try discontinuing the anticholinergic agent after several weeks; many patients will not need to remain on it long 
term.
Fun Fact:
Parkinson’s disease is named after Dr. James Parkinson (1755–1824), the doctor who first identified the condition. It’s 
caused by loss of neurons in the substantia nigra, where most dopamine is produced.

Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   195
Side Effect Management: Symptoms Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   195Prolactinemia 
Characteristics:  Elevated prolactin levels (>29 ng/mL in nonpregnant, nonlactating women, >18 ng/mL in men) that 
can cause the following symptoms:
 ⦁Women: Menstrual irregularity or amenorrhea, infertility, lowered libido, galactorrhea, decreased bone density, 
increase or thickening of hair in unexpected areas such as face. 
 ⦁Men: Breast enlargement (gynecomastia), erectile dysfunction, low libido, infertility, galactorrhea. 
Meds That Cause It:  Antipsychotics, especially risperidone, paliperidone, and haloperidol. Other potential 
medications that cause it include estrogen, metoclopramide, and verapamil. Other causes: Hypothyroidism, 
pregnancy, kidney disease, polycystic ovarian syndrome, pituitary adenoma. 

 ⦁Reduce dose or discontinue offending medication. Prolactin levels normalize within two to four days after 
discontinuation. 
 ⦁Switch to a different agent (eg, aripiprazole, quetiapine).
First-Line Medications (if stopping the causative drug is not feasible):
Add aripiprazole 5–20 mg daily.
 ⦁Add a dopamine agonist, such as cabergoline (Dostinex) 0.25 mg twice a week ( not twice a day) or bromocriptine 
(Parlodel) 1.25–2.5 mg daily. 
 ⦁Add an oral contraceptive agent to prevent bone loss in women and treat testosterone deficiency in men (it does 
not treat hyperprolactinemia). 
 ⦁Risperidone is the drug that causes the highest elevation, up to 300–400 mg/mL, whereas other drugs rarely cause 
elevations higher than 100 ng/mL.

elevations higher than 100 ng/mL. 
 ⦁If your patient has a mild elevation (such as up to 40 ng/mL), get another level, but this time make sure it’s a fasting 
level. Mild elevation can be caused by stress. 
 ⦁While galactorrhea is often mentioned in discussions of high prolactin, this is a pretty rare symptom, much less 
common than amenorrhea, low libido, and infertility. 
 ⦁Patients with levels >100 ng/mL are generally referred for an MRI to rule out a pituitary adenoma, even if they are 
taking a drug known to increase prolactin. 
 ⦁Use lowest effective dose of dopaminergic agent as higher doses may worsen psychosis. 
Fun Fact:
While prolactin’s main function is to promote breast milk during lactation, it has other functions, such as promoting

Fun Fact:
While prolactin’s main function is to promote breast milk during lactation, it has other functions, such as promoting 
weight gain and modulating anxiety. Some research shows that men have increased prolactin when they become 
fathers.

196  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION 196  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONQT Interval Prolongation
Characteristics:  The QT interval in the cardiac cycle represents depolarization (contraction) and repolarization 
(relaxation) of ventricles (these interval times are corrected to account for variations in heart rate, specified as “QTc”). 
ClassificationQTc Adult 
Women (msec)QTc Adult Men 
(msec)
Normal <450 <430
Borderline 451–470 431–450
Prolonged >470 >450
QT prolongation can lead to serious arrhythmias, including torsades de pointes (TdP), and sudden death. While the 
link between QT and TdP is not clear, QTc above 500 msec is a significant risk factor for TdP .
Meds That Cause It:  First-generation antipsychotics (especially thioridazine, high doses of chlorpromazine, and 
intravenous haloperidol). Of second-generation antipsychotics, ziprasidone has greatest risk of prolonging QT,

intravenous haloperidol). Of second-generation antipsychotics, ziprasidone has greatest risk of prolonging QT, 
though to a lower degree. Of SSRIs, higher-dose citalopram (>40 mg/day) most likely. Of tricyclic antidepressants, 
amitriptyline and maprotiline. Methadone. In overdose, a large number of medications can prolong QT. A good 
resource to keep on hand: www.crediblemeds.org  (free but requires registration).
Mechanism:  The mechanism depends on the offending drug. For example, TCAs prolong the QT through blockade of 
sodium and calcium channels, while citalopram and chlorpromazine do so through blockade of potassium channels.
Management:
 ⦁Prevent: Identify risk factors (see below), get baseline electrolytes, ECG, and monitor periodically in patients at risk.
 ⦁Manage reversible factors such as repleting electrolytes, hydration.
 ⦁With prolonged QTc (>500 msec), obtain a cardiologist consult.
 ⦁In patients with a borderline QTc, switch to a less risky agent.

⦁With prolonged QTc (>500 msec), obtain a cardiologist consult.
 –Lower-risk antipsychotics: Aripiprazole has minimal risk; asenapine, lurasidone, olanzapine, and quetiapine are 
also good options.
 –Lower-risk antidepressants: All antidepressants at usual therapeutic doses are relatively safe (avoid citalopram >40 
mg/day). However, sertraline may be the best choice because it is the most studied in cardiac patients and has few 
drug interactions.
 ⦁Risk factors: Congenital (long QT syndrome), female gender, older age, electrolyte abnormalities (low potassium, 
calcium, magnesium), and other conditions such as hepatic dysfunction, diabetes, hypothyroidism, AIDS, and 
hypertension.
 ⦁Heart conditions that increase a patient’s risk are bradycardia, left ventricular dysfunction, heart failure, mitral valve 
prolapse, and myocardial infarction.

 ⦁Caution in situations that may affect electrolytes, including eating disorders, diuretic use, hypoglycemia, renal 
dysfunction, and pituitary insufficiency.
 ⦁Other common medications that are not related to psychiatry can also be culprits, including antiarrhythmics such 
as sotalol, amiodarone, and quinidine; macrolide antibiotics such as azithromycin; quinolone antibiotics such as 
levofloxacin; some antifungals; antimalarials; and other medications such as tamoxifen.
 ⦁Overdose with psychotropic medication, even “low risk” agents, can lead to QT prolongation.
Fun Fact:
Torsades de pointes  translates to “twisting of the points, ” illustrating the chaotic nature of the heart rhythm that can 
lead to sudden death.

Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   197
Side Effect Management: Symptoms Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   197Serotonin Syndrome
Characteristics:  A rare but potentially life-threatening drug reaction that can range from mild to severe. Presents 
with muscle rigidity (typically hypertonicity, hyperreflexia, clonus), hyperthermia, and altered mental status. While 
very similar to neuroleptic malignant syndrome (NMS) in presentation, serotonin syndrome typically has a much more 
acute onset (drastic change from baseline within three to four hours). 
Meds That Cause It:  Any drugs that can increase serotonin activity either with increased serotonin release, inhibition 
of serotonin metabolism, inhibition of serotonin reuptake, or activation of serotonin receptors. Most common culprits

of serotonin metabolism, inhibition of serotonin reuptake, or activation of serotonin receptors. Most common culprits 
include MAOIs, SSRIs, SNRIs, buspirone, lithium. Consider nonpsychiatric medications that can have serotonergic 
effects (eg, fentanyl, meperidine, tramadol, linezolid, dextromethorphan).
Mechanism:  Excess serotonergic activity. 
 ⦁Discontinue any serotonergic medications. 
 ⦁Consider differential diagnoses, including NMS. 
 ⦁Monitor vital signs and creatinine kinase levels to assess severity and guide supportive care, including stabilizing 
vital signs and providing intravenous fluids if necessary.
Cyproheptadine (Periactin) 12 mg followed by 2 mg Q2 hours until improvement, then 8 mg Q8 hours until resolution.

 ⦁The combination of triptans (eg, sumatriptan) and other serotonergic medications like SSRIs will often trigger 
an alert in your EMR or at the pharmacy. While triptans are serotonergic, they are fairly weakly serotonergic and 
typically taken sporadically. Hence, this combination is less likely to result in serotonin syndrome.
 ⦁Caution with CYP450 inhibitors, which can raise levels of serotonergic medications and thereby increase risk of 
serotonin syndrome. 
 ⦁The most severe cases of serotonin syndrome often involve MAOIs combined with other serotonergic agents or 
overdose situations involving serotonergic drugs. 
 ⦁Clonus is more specific to serotonin syndrome (vs “lead pipe” rigidity seen in NMS) and presents as involuntary,

 ⦁Clonus is more specific to serotonin syndrome (vs “lead pipe” rigidity seen in NMS) and presents as involuntary, 
rhythmic muscle contractions. Clonus tends to happen more in the lower rather than upper extremities, so be sure 
to check the patient’s legs (flex the patient’s foot upward and look for a rhythmic beating of the foot and ankle).
 ⦁Avoid using cyproheptadine if anticholinergic syndrome cannot be ruled out as it may exacerbate. 
 ⦁Patient may be restarted on serotonergic medication 24–48 hours after complete resolution, but limit number of 
serotonergic agents and use minimally effective dose.
MDMA (ecstasy) in combination with SSRI can lead to serotonin syndrome. This has been a factor in a number of 
deaths, particularly in adolescents and young adults, at popular music festivals.

198  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION 198  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONSexual Dysfunction
Characteristics:  Impairment of some aspect of sexual functioning, including low libido, anorgasmia, decreased 
sensation, erectile dysfunction, or delayed or retrograde ejaculation (in men).
Meds That Cause It:  Antidepressants (paroxetine most likely, but all SSRIs and SNRIs can cause it); antipsychotics 
(primarily risperidone and paliperidone); some mood stabilizers (valproic acid and carbamazepine).
Mechanism:  Various, including activation of 5-HT2 receptors by antidepressants; hyperprolactinemia by 
antipsychotics such as risperidone; and anticholinergic and antiadrenergic effects in other antipsychotics, especially 
first-generation.
 ⦁Watchful waiting—works in 10%–20% of patients.

 ⦁Drug holiday—no dose Friday or Saturday, resume Sunday or Monday. (Not a good idea with paroxetine or 
venlafaxine due to discontinuation syndrome, nor with fluoxetine due to long half-life.)
 ⦁Decrease dose.
 ⦁Switch to a medication with low sexual side effects (eg, bupropion, mirtazapine, or an antipsychotic that does not 
affect prolactin).
 ⦁Add a PDE-5 inhibitor, such as sildenafil (Viagra) or tadalafil (Cialis). Works best for erectile dysfunction, but may help 
with low libido as well. Less effective in women.
 ⦁Add bupropion (possibly more effective in women than men).
 ⦁Buspirone (BuSpar) 30–60 mg daily.
 ⦁Cyproheptadine (Periactin) 8 mg 30 minutes before sex.
 ⦁Amantadine (Symmetrel) 100 mg daily.
It can be hard to know if sexual dysfunction (SD) is caused by a medication, the underlying psychiatric condition, or a

⦁Amantadine (Symmetrel) 100 mg daily.
It can be hard to know if sexual dysfunction (SD) is caused by a medication, the underlying psychiatric condition, or a 
separate problem predating the medication. For this reason, you should try to obtain a sexual history in your patients 
before starting medications that can cause SD.
Fun Fact:
Early estimates of SD incidence from antidepressants were very low (in the range of 2%–16%) because researchers 
relied on spontaneous self-reporting. By contrast, in a prospective study of 1,022 outpatients, all of whom were asked 
specifically about sexual functioning, the authors estimated that SSRIs and venlafaxine caused rates of SD ranging 
from 58% to 73% (Montejo AL,  J Clin Psych  2001;62 Suppl 3:10–21).

Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   199
Side Effect Management: Symptoms Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   199Sialorrhea (Hypersalivation)
Characteristics:  Excessive drooling, usually more severe at night.
Meds That Cause It:  Clozapine is the most common cause (30%–80% incidence). Can be caused by olanzapine, 
risperidone, or quetiapine.
Mechanism:  Procholinergic effect.
 ⦁Chew sugarless gum, which encourages more frequent swallowing of saliva.
 ⦁Place towel over pillow if main bothersome symptom is nocturnal sialorrhea.
Glycopyrrolate (Robinul): Start 1 mg at bedtime, then ↑ to 1–2 mg twice daily if symptoms are prominent during the 
day. Unlike other anticholinergics, glycopyrrolate does not cross the blood-brain barrier, so there are fewer central 
anticholinergic side effects. SE: Constipation, dry mouth, blurred vision, urinary retention.

 ⦁Ipratropium (Atrovent) 0.03% nasal spray; use one to two sprays sublingually (rather than intranasally).
 ⦁Oxybutinin (Ditropan) 5 mg twice daily.
 ⦁Alpha agonists such as clonidine (Catapres) 0.05–0.1 mg daily or weekly transdermal patch 0.1–0.2 mg or 
guanfacine (Tenex).
 ⦁Benztropine (Cogentin) 1 mg twice daily.
 ⦁Trihexyphenidyl (Artane) 5 mg twice daily.
 ⦁Atropine 1% ophthalmic drops; use one drop TID PRN sublingually.
 ⦁Dose reduction of clozapine usually is not helpful in diminishing symptoms.
 ⦁Clozapine has strong anticholinergic properties, so its procholinergic effect of excessive drooling is puzzling. 
Theories explaining this include specific stimulation of cholinergic salivary receptors and impairment in the 
autonomically mediated swallowing mechanism (which may also contribute to clozapine-related dysphagia and 
pneumonia).

Fun Fact:
Ayurvedic medicine recommends a number of natural treatments for hypersalivation, including chewing cloves, 
drinking cinnamon tea, and eating a combination of pepper, ginger, and honey.

200  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION 200  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONTardive Dyskinesia
Characteristics:  Involuntary movements, usually occurring after months or years of antipsychotic treatment. The 
most common symptoms are oro-buccal-lingual, such as chewing, lip smacking, and tongue protrusion. Occasionally 
causes movements of fingers or toes and rarely, in severe cases, may affect torso and gait.
Meds That Cause It:  Antipsychotics, especially first-generation antipsychotics (3%–5% per year); the risk is smaller 
with second-generation antipsychotics. Among second-generation antipsychotics, risperidone confers the highest risk.
Mechanism:  D2 blockade leading to dopamine receptor supersensitivity.
 ⦁Monitor all patients taking antipsychotics regularly with a test such as the AIMS (Abnormal Involuntary Movement 
Scale).

Scale).
 ⦁Switch to a different antipsychotic, preferably a second-generation antipsychotic with low dopamine occupancy, 
such as quetiapine or clozapine.
 ⦁Valbenazine (Ingrezza) 40 mg/day; increase to 80 mg/day after a week. SE: Sedation, akathisia. FDA approved for TD.
 ⦁Deutetrabenazine (Austedo): Start 6 mg BID; ↑ weekly by 6 mg/day increments to maximum dose of 48 mg/day 
(divide doses >12 mg/day BID).
 ⦁Tetrabenazine (Xenazine): Start 12.5 mg QD for one week, increase by 12.5 mg/day increments weekly to usual dose 
of 75–150 mg QD (divided doses >37.5 mg TID). SE: Sedation, akathisia, tremor. FDA approved for Huntington’s 
disease.
 ⦁Amantadine (Symmetrel) 100–300 mg/day.
 ⦁Gingko biloba extract 240 mg/day.
 ⦁Vitamin E 400–600 IU/day.

disease.
 ⦁Benzodiazepines (eg, clonazepam [Klonopin] or lorazepam [Ativan] 0.5–1 mg daily or BID).
 ⦁Risk factors for TD include first-generation antipsychotics more so than second-generation antipsychotics, higher-
potency agents, duration of exposure, higher dose, elderly age, and Black ethnicity.
 ⦁Increasing the dose of the antipsychotic will improve symptoms temporarily but probably make them worse in the 
long run.
 ⦁Decreasing or discontinuing antipsychotics may often worsen the symptoms temporarily (“withdrawal dyskinesia”) 
or even unmask TD symptoms that were not apparent.
Fun Fact:
Antipsychotics aren’t the only medications that may cause TD. Prolonged use of medications for nausea and reflux like 
metoclopramide (Reglan) and prochlorperazine (Compazine), which also block dopamine, have also been associated 
with TD.

with TD.
The Abnormal Involuntary Movement Scale (AIMS) is the best tool for assessing for and monitoring severity of TD. 
The test has 12 items to be rated and can be completed in about 10 minutes. The patient should not have anything 
in their mouth (dentures, gum) and should be seated in a firm, armless chair. See the following page for the full AIMS 
and instructions on how to use it.

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Side Effect Management: Symptoms Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   201
119Instructions
There are two parallel procedures, the examination procedure ,
which tells the patient what to do, and the scoring procedure , which
tells the clinician how to rate what he or she observes.
Examination Procedure
Either before or after completing the examination procedure,
observe the patient unobtrusively at rest (e.g., in the waiting room).
The chair to be used in this examination should be a hard, firm one
without arms.
1. Ask the patient whether there is anything in his or her mouth
(such as gum or candy) and, if so, to remove it.
2. Ask about the ‘current’ condition of the patient’s teeth. Ask if
he or she wears dentures. Ask whether teeth or dentures
bother the patient ‘now’.
3. Ask whether the patient notices any movements in his or her

mouth, face, hands, or feet. If yes, ask the patient to describe
them and to indicate to what extent they ‘currently’ bother the
patient or interfere with activities.
4. Have the patient sit in the chair with hands on knees, legs
slightly apart, and feet flat on floor. (Look at the entire body for
movements while the patient is in this position.)
5. Ask the patient to sit with hands hanging unsupported – if male,
between his legs, if female and wearing a dress, hanging over her
knees. (Observe hands and other body areas).
6. Ask the patient to open his or her mouth. (Observe the tongue
at rest within the mouth.) Do this twice.
7. Ask the patient to protrude his or her tongue. (Observe
abnormalities of tongue movement.) Do this twice.
8. Ask the patient to tap his or her thumb with each finger as

rapidly as possible for 10 to 15 seconds, first with right hand,
then with left hand. (Observe facial and leg movements.)
[±activated ]
9. Flex and extend the patient’s left and right arms, one at a time.
10. Ask the patient to stand up. (Observe the patient in profile.
Observe all body areas again, hips included.)
11. Ask the patient to extend both arms out in front, palms down.
(Observe trunk, legs, and mouth.) [activated ]
12. Have the patient walk a few paces, turn, and walk back to the
chair. (Observe hands and gait.) Do this twice. [activated ]
Scoring Procedure
Complete the examination procedure before making ratings.
For the movement ratings (the first three categories below), rate the
highest severity observed. 0 = none, 1 = minimal (may be extreme

normal), 2 = mild, 3 = moderate, and 4 = severe. According to the
original AIMS instructions, one point is subtracted if movements are
seen only on activation, but not all investigators follow that
convention.
Facial and Oral Movements
1. Muscles of facial expression,
e.g., movements of forehead, eyebrows, periorbital area, cheeks.
Include frowning, blinking, grimacing of upper face.
0 1 2 3 42. Lips and perioral area,
e.g., puckering, pouting, smacking.
0 1 2 3 4
3. Jaw,
e.g., biting, clenching, chewing, mouth opening, lateral
movement.
0 1 2 3 4
4. Tongue.
Rate only increase in movement both in and out of mouth, not
inability to sustain movement.
0 1 2 3 4
Extremity Movements
5. Upper (arms, wrists, hands, fingers).
Include movements that are choreic (rapid, objectively

0 1 2 3 4
purposeless, irregular, spontaneous) or athetoid (slow, irregular,
complex, serpentine). Do not include tremor (repetitive,
regular, rhythmic movements).
0 1 2 3 4
6. Lower (legs, knees, ankles, toes),
e.g., lateral knee movement, foot tapping, heel dropping, foot
squirming, inversion and eversion of foot.
0 1 2 3 4
Trunk Movements
7. Neck, shoulders, hips,
e.g., rocking, twisting, squirming, pelvic gyrations. Include
diaphragmatic movements.
0 1 2 3 4
Global Judgments
8. Severity of abnormal movements.
0 1 2 3 4
based on the highest single score on the above items.
9. Incapacitation due to abnormal movements.
0 = none, normal
1 = minimal
2 = mild
3 = moderate
4 = severe
10. Patient’s awareness of abnormal movements.
0 = no awareness
1 = aware, no distress
2 = aware, mild distress
3 = aware, moderate distress

1 = minimal
2 = mild
4 = severe
4 = aware, severe distress
Dental Status
11. Current problems with teeth and/or dentures.
0 = no
1 = yes
12. Does patient usually wear dentures?
0 = no
1 = yesAbnormal Involuntary Movement Scale (AIMS)
Reproduced from Guy W. ECDEU Assessment Manual for Psychopharmacology: Revised (DHEW publication number ADM 76-338). Rockville, 
MD, US Department of Health, Education and Welfare, Public Health Service, Alcohol, Drug Abuse and Mental Health Administration, NIMH 
Psychopharmacology Research Branch, Division of Extramural Research Programs, 1976: 534–7

202  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION 202  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONTremor
Characteristics:  Rapid regular movements of body parts, especially hands. Classified as fine vs coarse, and as resting 
vs postural vs intention.
Meds That Cause It:  Lithium (fine intention tremor), valproic acid (fine), lamotrigine, bupropion, antipsychotics 
(Parkinsonian, resting coarse tremor), especially high-potency first-generation agents, risperidone. Occasionally SSRIs 
and buspirone.
Mechanism:  Multiple mechanisms depending on cause. Medication-induced tremor may be induced by excitability 
in muscle receptors and neuronal reflexes.
 ⦁Rule out unrelated causes, such as essential tremor or hyperthyroidism.
 ⦁Most drug tremors are fine postural tremor (seen best when patient is holding a fixed posture, such as holding 
hands up with arms extended).

⦁Most drug tremors are fine postural tremor (seen best when patient is holding a fixed posture, such as holding 
 ⦁Reduce use of caffeine, which can worsen all tremors.
 ⦁Change dosing to minimize peak blood levels (eg, split dosing, switch to an extended-release version, or give full 
dose before sleep).
 ⦁Reduce dose or switch agents.
 ⦁Propranolol (Inderal) 10 mg BID as needed, ↑ by 10–20 mg/day increments weekly; can go up to 30–120 mg daily in 
two or three divided doses. SE: Dizziness, fatigue, syncope, low BP .
 ⦁Inderal LA. Long-acting propranolol that can be dosed 60–80 mg once a day.
 ⦁Benztropine (Cogentin) 1 mg BID for Parkinsonian tremor (due to antipsychotics).
 ⦁Primidone (Mysoline) 100 mg three times a day.
 ⦁Vitamin B6 for lithium tremor 900–1200 mg daily.
 ⦁Amantadine (Symmetrel) 100–200 mg BID for Parkinsonian tremor (due to antipsychotics).

⦁Primidone (Mysoline) 100 mg three times a day.
 ⦁Various anticonvulsants such as topiramate (Topamax), gabapentin (Neurontin), oxcarbazepine (Trileptal).
 ⦁Try to systematically track the severity of the tremor over time. Options include taking a quick video at each 
appointment, having patients copy a design or write their name and address, or having them drink a cup of water. 
Take notes or include samples during visits.
 ⦁Don’t forget that tremor can signal alcohol or benzodiazepine withdrawal—something you might want to ask 
patients about.
Fun Fact:
One in five people over the age of 65 may have essential tremor (not associated with medication).

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Side Effect Management: Symptoms Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   203Weight Gain
Characteristics:  Typically, patients will report food craving and binging. Weight gain is rapid in the first three months, 
more gradual over the following year, then often plateaus. Rapid initial weight gain is correlated with greater eventual 
cumulative weight gain. FDA definition of weight gain is ≥7% increase in weight from baseline.
Meds That Cause It:  Antipsychotics, especially clozapine, olanzapine, and quetiapine. Somewhat less weight gain 
with risperidone and paliperidone. Least weight gain with aripiprazole, haloperidol, ziprasidone, and lurasidone. 
Antidepressants: Mirtazapine, tricyclics, paroxetine. Mood stabilizers: Lithium, valproic acid.
Mechanism:  Blockade of histamine and serotonin 2A receptors, leading to increased hunger.

 ⦁Monitoring: Weight, BMI, waist circumference every four weeks for three months, then every three months.
 ⦁Lifestyle modification, including exercise and dietary changes, is helpful for patients who are motivated; several 
studies have shown some benefit, but in actual clinical settings it may be difficult to match their results.
 ⦁Switch to a medication that is more weight neutral.
First-Line Medications (some evidence specifically for reducing psychotropic-induced weight gain):
 ⦁Topiramate (Topamax) 100–300 mg/day; SE: Cognitive dulling.
 ⦁Metformin XR (Glucophage XR, Glumetza) 500–2000 mg: Take with largest meal, split into two doses if needed 
(based on GI side effects).
 ⦁Olanzapine/samidorphan (Lybalvi) as an alternative to olanzapine alone to reduce weight gain.
 ⦁Orlistat (Xenical) 120 mg three times daily after meals. Interferes with fat absorption; SE: Diarrhea.

⦁Orlistat (Xenical) 120 mg three times daily after meals. Interferes with fat absorption; SE: Diarrhea.
 ⦁Aripiprazole (Abilify) 15 mg/day. Antipsychotic. May be useful for olanzapine-induced weight gain as adjunct.
Second-Line Medications (effective for weight loss, but little or no evidence specifically for psychotropic-induced 
weight gain):
 ⦁Bupropion SR (Wellbutrin SR) 300–400 mg daily.
 ⦁Any psychostimulant either methylphenidate or amphetamine class.
 ⦁Naltrexone/bupropion (Contrave) 8 mg/90 mg up to two tabs twice daily. Anti-obesity drug.
 ⦁Phentermine (Suprenza) 15–37.5 mg daily. Anti-obesity drug.
 ⦁Phentermine/topiramate (Qsymia) 7.5 mg/46 mg up to two tabs daily. Anti-obesity drug.
 ⦁Glucagon-like peptide-1 agonists (GLP1 agonists), such as liraglutide (Saxenda) or semaglutide (Ozempic).
 ⦁Nizatidine (Axid) 150–300 mg daily. Antacid, H2 blocker, available over the counter.

⦁Nizatidine (Axid) 150–300 mg daily. Antacid, H2 blocker, available over the counter.
 ⦁Weight gain is most likely in the first six weeks of taking an antipsychotic, and it’s difficult for patients to ever lose 
this weight. As such, you should monitor weekly initially, and switch to a more weight-neutral agent at the first sign 
of weight gain.
 ⦁If patient gains 5% or more of body weight, switch to a different drug.
 ⦁Ziprasidone and aripiprazole are probably the most weight-neutral antipsychotics and may even cause weight loss, 
especially if switching from another agent.
 ⦁Weight gain tends to be most severe in patients who are taking an antipsychotic for the first time.
 ⦁Ask weight-gaining patients about dry mouth; many psychotropics cause this, and such patients may gain weight 
from drinking sugary beverages to deal with this side effect.
Fun Fact:

⦁Ask weight-gaining patients about dry mouth; many psychotropics cause this, and such patients may gain weight 
Fun Fact:
Some researchers have hypothesized that treatment-emergent weight gain is related to and predictive of clinical 
response, but others argue it may be a marker for medication adherence instead.

Sleep Disorder Medications Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   205
Sleep Disorder Medications
There are seven medications plus one medication class in this chapter—armodafinil (Nuvigil), modafinil (Provigil), 
pitolisant (Wakix), sodium oxybate (Xyrem) plus its mixed-salts close cousin Xywav, solriamfetol (Sunosi), tasimelteon 
(Hetlioz), and the dopamine agonists used for restless legs syndrome (RLS). In reality, very few of you will ever 
prescribe Xyrem, Xywav, or Hetlioz. Xyrem and Xywav are approved for narcolepsy with cataplexy, which is a rare 
illness treated by sleep specialists, and Hetlioz is used for another rare condition seen primarily in the blind: non-24-
hour sleep-wake disorder.
The two “vigil” drugs, on the other hand, are heavily prescribed by psychiatrists for all manner of situations, including

The two “vigil” drugs, on the other hand, are heavily prescribed by psychiatrists for all manner of situations, including 
shift-work sleep disorder, jet lag, and antidepressant-induced sleepiness. These meds, along with the stimulants, are 
sometimes requested for off-label use as “cognitive enhancers” by overachievers. Sunosi is a newer agent and, like the 
“vigil” drugs, it’s a Schedule IV controlled drug approved to be used in excessive daytime sedation due to narcolepsy 
or apnea. Wakix is the newest on the scene, approved only for cataplexy and excessive sedation in narcolepsy, and its 
primary distinction is that it’s not a controlled substance.
These “wake promoting” agents are often prescribed when patients complain of excessive fatigue. In these clinical 
scenarios, we recommend a thorough workup to determine potential alternative strategies (eg, labs to rule out

scenarios, we recommend a thorough workup to determine potential alternative strategies (eg, labs to rule out 
hypothyroidism, anemia, and other conditions; a sleep study to rule out apnea or RLS; a review of medications or 
other substances potentially contributing to daytime sedation; and education on good sleep habits).
There’s no clear guidance on which of the wake-promoting agents to prescribe. Nuvigil lasts a few hours longer than 
Provigil, which can be a blessing for those who want to stay awake longer or a curse for those who find it causes them 
insomnia. We have less experience with Sunosi and Wakix, which are newer and more expensive. Clear benefits have 
not yet been identified; trial and error is the way to go with these agents. 
We’ve added the dopamine agonists fact sheet to this chapter because psychiatrists may at times manage patients 
with RLS. Dopamine agonists (pramipexole, ropinirole, rotigotine) are considered first-line treatments for RLS.

with RLS. Dopamine agonists (pramipexole, ropinirole, rotigotine) are considered first-line treatments for RLS. 
Carbidopa/levodopa is not FDA approved for this condition but is used for intermittent RLS since regular or routine 
use often leads to worsening of symptoms. Gabapentin enacarbil (Horizant) is a prodrug of gabapentin, which is 
approved for RLS. We’ve included this in our table, but you’ll find the gabapentin fact sheet in the Mood Stabilizers 
and Anticonvulsants chapter.

206  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONTable 19:  Sleep Disorder Medications
[G] denotes generic availabilityRelevant FDA Indication(s) Rx Status Available Strengths Usual Dosage Range 
Armodafinil [G]
(Nuvigil)
2007Excessive sleepiness 
(obstructive sleep apnea, 
narcolepsy, shift-work sleep 
disorder)Schedule IV 50, 150, 200, 250 mg 150–250 mg/day
Calcium, magnesium, potassium, 
and sodium oxybates
(Xywav)
2020Cataplexy and excessive 
daytime sedation (narcolepsy)
Idiopathic hypersomniaSchedule III 0.5 g/mL 6–9 g/night
Carbidopa/levodopa [G]
(Sinemet)
1975 (for Parkinson’s)Not FDA approved but used for 
restless legs syndromeRx 10/100, 25/100, 25/250 mg
ODT: 10/100, 25/100, 25/250 mg
ER: 25/100, 50/200 mg12.5/50–75/300 mg/day
Gabapentin enacarbil
(Horizant)
2011Restless legs syndrome Rx 300, 600 mg 600 mg/day
Modafinil [G]
(Provigil)
1998Excessive sleepiness

1998Excessive sleepiness 
disorder)Schedule IV 100, 200 mg 100–400 mg/day
(Wakix)
2019Cataplexy and excessive 
sleepiness (narcolepsy)Rx 4.45, 17.8 mg 17.8–35.6 mg/day
Pramipexole [G]
(Mirapex, Mirapex ER)
2007 (for RLS)Restless legs syndrome Rx 0.125, 0.25, 0.5, 0.75, 1, 1.5 mg
ER: 0.375, 0.75, 1.5, 2.25, 3, 3.75, 
4.5 mg0.125–0.5 mg/day
Ropinirole [G]
(Requip, Requip XL)
2005 (for RLS)Restless legs syndrome Rx 0.25, 0.5, 1, 2, 3, 4, 5 mg
ER: 2, 4, 6, 8, 12 mg0.25–4 mg/day
Rotigotine transdermal patch 
(Neupro) 
2012Restless legs syndrome Rx Patch: 1, 2, 3, 4, 6, 8 mg 1–3 mg/day
Sodium oxybate [G]
(Xyrem)
2002Cataplexy and excessive 
daytime sedation (narcolepsy)Schedule III 0.5 g/mL 6–9 g/night
Solriamfetol
(Sunosi)
2019Excessive sleepiness

(Xyrem)
(Sunosi)
2019Excessive sleepiness 
narcolepsy)Schedule IV 75, 150 mg 37.5–150 mg/day
(Hetlioz)
2014Non-24-hour sleep-wake 
disorderRx 20 mg
Liquid: 4 mg/mL20 mg/night

Sleep Disorder Medications Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   207ARMODAFINIL  (Nuvigil) Fact Sheet [G]
Armodafinil is an effective wake-promoting agent with some potential for abuse and for drug interactions. It lasts a bit 
longer than modafinil.
Excessive sleepiness associated with obstructive sleep apnea, narcolepsy, or shift-work sleep disorder.
ADHD; fatigue; treatment-resistant depression.
Tablets (G):  50 mg, 150 mg, 200 mg, 250 mg.
 ⦁Obstructive sleep apnea or narcolepsy: 150–250 mg QAM.
 ⦁Shift-work sleep disorder: 150 mg QD, one hour before start of work shift.
Cost:  $
 ⦁Most common: Headache, nausea, dizziness, insomnia, anxiety, irritability.
 ⦁Serious but rare: Serious rash, including Stevens-Johnson syndrome, multi-organ hypersensitivity reaction,

⦁Most common: Headache, nausea, dizziness, insomnia, anxiety, irritability.
 ⦁Serious but rare: Serious rash, including Stevens-Johnson syndrome, multi-organ hypersensitivity reaction, 
angioedema, and anaphylaxis reported rarely. Rare cases of mania, psychosis, and agitation reported.
 ⦁Dopamine reuptake inhibitor.
 ⦁Metabolized primarily by non-CYP450 liver pathways, but also to some degree by CYP3A4; t ½: 15 hours.
 ⦁Duration of action about eight hours.
 ⦁Potentially induces CYP1A2 and 3A4 and inhibits 2C19. Avoid concomitant use with steroidal contraceptives 
(hormone levels may be decreased due to 3A4 induction) and with CYP2C19 substrates (eg, omeprazole, phenytoin, 
diazepam); levels of these medications may be increased.
 ⦁Armodafinil is, as the name implies, the r-modafinil enantiomer (modafinil is a 1:1 mixture of both r- and 
s-enantiomers).

 ⦁Schedule IV controlled substance due to abuse potential, mostly for euphoric and stimulant-like effects.
 ⦁Increased heart rate and blood pressure may occur, particularly in patients who don’t suffer from excessive sedation 
or fatigue and when used at higher doses.
Fun Fact:
In 2010, the FDA declined to approve use of Nuvigil to treat jet lag.

208  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONDOPAMINE AGONISTS  (Mirapex, Neupro, Requip, Sinemet) 
Fact Sheet [G]
Dopamine agonists are effective first-line agents for restless legs syndrome (RLS), though rates of problematic 
impulsive or compulsive behaviors can be high. Reserve carbidopa/levodopa for intermittent use.
Parkinson’s disease; RLS  (except Sinemet, only approved for Parkinson’s).
Treatment-resistant depression;  cluster headache.
 ⦁Carbidopa/levodopa tablets (Sinemet, Sinemet CR, [G]): IR: 10/100 mg, 25/100 mg, 25/250 mg; ER: 25/100 mg, 
50/200 mg; ODT: 10/100 mg, 25/100 mg, 25/250 mg.
 ⦁Pramipexole tablets (Mirapex, Mirapex ER, [G]): IR: 0.125 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.5 mg; ER: 0.375 
mg, 0.75 mg, 1.5 mg, 2.25 mg, 3 mg, 3.75 mg, 4.5 mg.
 ⦁Ropinirole tablets (Requip, Requip XL, [G]): IR: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg; ER: 2 mg, 4 mg, 6

 ⦁Ropinirole tablets (Requip, Requip XL, [G]): IR: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg; ER: 2 mg, 4 mg, 6 
mg, 8 mg, 12 mg.
 ⦁Rotigotine transdermal patches (Neupro): 1 mg, 2 mg, 3 mg, 4 mg, 6 mg, 8 mg.
 Dosage Guidance:
 ⦁Carbidopa/levodopa: Start ½ of 25/100 mg tablet QHS PRN, then increase by ½ tablet every three days as necessary 
to max three 25/100 mg tablets.
 ⦁Pramipexole: Start 0.125 mg taken one to three hours before HS, then double dose Q4–7 days; max 0.5 mg/day.
 ⦁Ropinirole: Start 0.25 mg taken one to three hours before HS, then increase to 0.5 mg after two to three days, 1 mg 
after seven days, then increase by 0.5 mg weekly until 3 mg/day, then increase by 1 mg/day to maximum 4 mg/day 
if necessary.
 ⦁Rotigotine transdermal patch: Start 1 mg/24 hours applied QD, can increase by 1 mg/24 hours at weekly intervals to 
maximum 3 mg/24 hours.

Cost:  $; pramipexole ER: $$; rotigotine: $$$$$
 ⦁Most common: Nausea, headache, dizziness, anxiety, insomnia. Newer data suggest nearly half of patients will 
develop compulsive behaviors (eg, gambling, shopping, eating, sexual activity). 
 ⦁Serious but rare: Hallucinations, agitation (less common than when treating Parkinson’s). 
 ⦁Dopamine agonist.
 ⦁Metabolized primarily by: CYP450 (carbidopa/levodopa, rotigotine), renal elimination (pramipexole), CYP1A2 
(ropinirole); t ½: 0.75–1.5 hours (carbidopa/levodopa), 8 hours (pramipexole), 6 hours (ropinirole), 5–7 hours 
(rotigotine).

 ⦁Avoid rotigotine in patients with sulfite allergies because it contains sodium metabisulfite, which may induce 
anaphylaxis or respiratory symptoms in sensitive patients. Those with history of asthma have an increased risk of 
sulfite sensitivity.
 ⦁Lower doses are used for RLS compared to Parkinson’s.
 ⦁Onset of action: Pramipexole takes effect upon first dose. Ropinirole takes four to 10 days. Rotigotine has onset with 
first dose but may require up to one week for full effect.
 ⦁Caution patients about compulsive behaviors (gambling, shopping, eating). These occur commonly and can be 
devastating. Lower dose if such behaviors develop or discontinue if severe.
 ⦁Pramipexole showed modest efficacy for treatment-resistant depression in a controlled study. Open-label studies

 ⦁Pramipexole showed modest efficacy for treatment-resistant depression in a controlled study. Open-label studies 
suggest it may work in patients who have not responded to electroconvulsive therapy.
Fun Fact:
Some Parkinson’s patients have experienced an increased sex drive when taking these medications, sparking off-label 
use of these agents for managing low libido. Mirasex, anyone?

Sleep Disorder Medications Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   209MODAFINIL  (Provigil) Fact Sheet [G]
While modafinil can be helpful for many causes of excessive sleepiness, realize that many people end up using it off-
label for lifestyle enhancement, such as working, studying, and partying.
Excessive sleepiness  associated with obstructive sleep apnea, narcolepsy, or shift-work sleep disorder.
Tablets (G):  100 mg, 200 mg.
 ⦁Obstructive sleep apnea or narcolepsy: 100–400 mg QAM (usually 200 mg QAM).
 ⦁Shift-work sleep disorder: 100–400 mg QD (usually 200 mg QAM), one hour before start of work shift.
 ⦁ADHD (off-label): 100–400 mg QAM.
 ⦁Treatment-resistant depression, bipolar or unipolar (off-label): 100–400 mg QAM added to antidepressant.

⦁ADHD (off-label): 100–400 mg QAM.
Cost:  $
 ⦁Most common: Increased heart rate and blood pressure, headache, nausea, jitteriness, rhinitis, diarrhea, back pain, 
and insomnia.
 ⦁Duration of action about six hours.
 ⦁Potentially induces CYP1A2 and 3A4 and inhibits 2C19. Avoid concomitant use with steroidal contraceptives

⦁Duration of action about six hours.
(hormone levels may be decreased due to 3A4 induction) and with CYP2C9/19 substrates (eg, omeprazole, 
phenytoin, diazepam); levels of these medications may be increased.
or fatigue and at higher doses.
Fun Fact:
An ADHD indication was rejected by the FDA because of modafinil’s possible association with Stevens-Johnson 
syndrome.

210  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONOXYBATES  (Xyrem, Xywav) Fact Sheet [G]
Xyrem is often used by sleep specialists as a first-line agent for narcolepsy with cataplexy. It’s unlikely that many 
psychiatrists will prescribe it, given its side effect profile and potential for misuse. Pitolisant, which is easier to use and 
is not a controlled substance, may be a better option for most patients with both cataplexy and excessive daytime 
sedation (EDS) associated with narcolepsy.
Cataplexy and EDS in narcolepsy (ages 7 and up); idiopathic hypersomnia (Xywav).
Fibromyalgia; chronic pain; neuropathic pain.
 ⦁Sodium oxybate oral solution (Xyrem, [G]):  0.5 g/mL.
 ⦁Calcium, magnesium, potassium, and sodium oxybate oral solution (Xywav): 0.5 g/mL.
Start 4.5 g nightly, given in two equal, divided doses (because of extremely short half-life): 2.25 g at bedtime and 2.25

Start 4.5 g nightly, given in two equal, divided doses (because of extremely short half-life): 2.25 g at bedtime and 2.25 
g taken 2.5 to four hours later. Titrate to effect in increments of 1.5 g/night at weekly intervals (0.75 g at bedtime and 
0.75 g taken 2.5 to four hours later). Usual dose 6–9 g per night. Max 9 g/night.
 ⦁Most common: Nausea, dizziness, vomiting, somnolence, enuresis, tremor, parasomnias (sleepwalking).
 ⦁Serious but rare: Respiratory depression, depression and suicidality, impaired motor and cognitive function.
 ⦁CNS depressant.
 ⦁Metabolized primarily by conversion to carbon dioxide and then eliminated by expiration; t ½: 0.5–1 hour.
 ⦁Avoid concomitant use with alcohol, sedative hypnotics, and other CNS depressants. Valproic acid increases oxybate

⦁Avoid concomitant use with alcohol, sedative hypnotics, and other CNS depressants. Valproic acid increases oxybate 
levels by 25%; adjust valproic acid dose by at least 20%.
 ⦁Sodium oxybate is the sodium salt of gamma hydroxybutyrate (GHB), a Schedule I controlled substance (“date 
rape” drug).
 ⦁Sodium oxybate is a Schedule III controlled substance and is available only through a restricted distribution 
program called the Xyrem REMS Program using a centralized pharmacy. Prescribers and patients must enroll in the 
program ( www.xyremrems.com  or 1-866-XYREM88).
 ⦁Patient must wait at least two hours after eating before taking a dose. Both doses should be prepared (dilute in 
provided vials with water) before bedtime. Dose must be taken while in bed, and patient is to lie down after dosing.
 ⦁Most patients find the taste of Xyrem to be awful.
 ⦁Xyrem alone was just as effective as modafinil alone for excessive daytime sedation, but the combination was

⦁Most patients find the taste of Xyrem to be awful.
 ⦁Xyrem alone was just as effective as modafinil alone for excessive daytime sedation, but the combination was 
significantly better than either medication used alone in one narcolepsy study.
 ⦁While a generic version has been approved, it’s not yet available due to patent litigation.
 ⦁Xywav is the newer “mixed salts” version (patent extender?) and delivers 92% less sodium than Xyrem. 
 ⦁A new indication was granted by the FDA for using Xywav to treat idiopathic hypersomnia, a rare and debilitating 
neurologic sleep disorder characterized by EDS, prolonged but non-restorative nighttime sleep, and severe sleep 
inertia (prolonged difficulty waking).
Fun Fact:
Xyrem, an orphan drug, is expensive, between $108,000 and $160,000 per year depending on the nightly dose. Jazz 
Pharmaceuticals is looking to expand its use by testing it in obstructive sleep apnea, Parkinson’s, chronic fatigue,

Pharmaceuticals is looking to expand its use by testing it in obstructive sleep apnea, Parkinson’s, chronic fatigue, 
schizophrenia, binge eating, and cluster headache.

Sleep Disorder Medications Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   211PITOLISANT  (Wakix) Fact Sheet
Pitolisant is the only non-DEA-scheduled treatment option approved for patients with narcolepsy, but limited 
experience and data, plus a higher price tag, make it a second-line option after the “vigil” drugs. However, for patients 
with both cataplexy and excessive daytime sleepiness, it may be a better option than Xyrem or Xywav.
Cataplexy or excessive sleepiness  associated with narcolepsy.
Tablets:  4.45 mg, 17.8 mg.
Start 8.9 mg QAM for week one. If tolerated, may increase to 17.8 mg QAM for week two. If needed, in week three or 
beyond, may increase to maximum dose of 35.6 mg QAM. Use lower doses in hepatic or renal impairment.

 ⦁Most common: Insomnia, nausea, anxiety.
 ⦁Serious but rare: QT interval prolongation (4.2 msec at therapeutic doses; 16 msec at doses greater than maximum 
recommended).
 ⦁Antagonist/inverse agonist of the histamine-3 (H3) receptor.
 ⦁Metabolized primarily by CYP2D6 and, to a lesser extent, CYP3A4; t ½: 20 hours.
 ⦁Strong CYP2D6 inhibitors or in poor metabolizers: Maximum recommended dosage is 17.8 mg once daily. Strong 
CYP3A4 inducers may reduce pitolisant levels by 50%; adjust dose. Avoid H1 antihistaminergic agents, which may 
decrease effectiveness of pitolisant.

 ⦁The H3 receptor is mainly found in the brain where it regulates wakefulness, appetite, and memory. Pitolisant blocks 
the H3 receptor, which has downstream effects of increased dopamine and acetylcholine in the prefrontal cortex.
 ⦁A head-to-head “non-inferiority” study with modafinil found pitolisant had nearly similar efficacy but was better 
tolerated. 
Fun Fact:
Pitolisant is also being studied for efficacy in ADHD, dementia, obesity, and cognitive symptoms of schizophrenia.

212  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONSOLRIAMFETOL  (Sunosi) Fact Sheet
Solriamfetol is a wakefulness promoter with a different mechanism of action from modafinil and armodafinil. Patients 
may ask you about it given all the TV ads, but time will tell how it compares with these more established (and 
cheaper) agents. 
Excessive daytime sedation (EDS) associated with narcolepsy or obstructive sleep apnea (OSA).
ADHD; fatigue; treatment-resistant depression. 
Tablets:  75 mg, 150 mg (scored). 
Start 37.5 mg QAM for sleep apnea or 75 mg QAM for narcolepsy. Increase dose at intervals of at least three days. Max 
dose 150 mg/day.
 ⦁Most common: Headache, nausea, decreased appetite, and anxiety.

 ⦁Most common: Headache, nausea, decreased appetite, and anxiety. 
 ⦁Serious but rare: Increased blood pressure and pulse; psychosis or mania may occur. 
 ⦁Dopamine and norepinephrine reuptake inhibitor (DNRI).
 ⦁Not metabolized, renally eliminated; t ½: 7 hours.
 ⦁Avoid MAOIs. 
 ⦁This new wake-promoting drug was approved based on four studies of more than 900 adults with narcolepsy or 
OSA. For example, in a 12-week randomized double-blind controlled trial of 239 adults with narcolepsy, 150 mg/day 
of Sunosi (but not 75 mg/day) showed statistically significant improvement on tests of wakefulness. 
 ⦁In a similar study of 476 adults with OSA, patients receiving 37.5 mg/day, 75 mg/day, and 150 mg/day of Sunosi 
showed statistically significant improvement over placebo at week 12.

⦁In a similar study of 476 adults with OSA, patients receiving 37.5 mg/day, 75 mg/day, and 150 mg/day of Sunosi 
 ⦁Maintenance of efficacy of up to 50 weeks was shown in two open-label extension studies of patients with EDS 
associated with either narcolepsy or OSA.
 ⦁Given that Sunosi is a DNRI (like bupropion) there has been interest in studying the drug for depression, though 
clinical trials have not yet been conducted. 
 ⦁Sunosi has demonstrated abuse potential, particularly at doses higher than recommended for EDS, and has been 
classified as a controlled substance (Schedule IV).
Fun Fact:
Sunosi is manufactured by Jazz Pharmaceuticals, the company that sold $1.4 billion of Xyrem (sodium oxybate) in 
2018. Now that generic versions of Xyrem have been approved by the FDA, Jazz will likely be looking at Sunosi as their 
biggest profit-maker.

Sleep Disorder Medications Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   213TASIMELTEON  (Hetlioz) Fact Sheet
Tasimelteon is a melatonin receptor agonist approved for non-24-hour sleep-wake disorder (N24SWD), which 
occurs primarily in blind people. Due to its high price (over $13,000 for a month’s supply), you may want to consider 
ramelteon instead. While ramelteon hasn’t been studied in patients with N24SWD, it’s reasonable to try because it is 
so similar pharmacologically yet much more affordable.
N24SWD.
None recommended; potentially may be used for insomnia, jet lag, shift-work sleep disorder.
 ⦁Capsules:  20 mg.
 ⦁Oral suspension (Hetlioz LQ):  4 mg/mL.
Start 20 mg QHS at the same time every night.

 ⦁Most common: Headache, increased LFTs, nightmares or unusual dreams.
 ⦁Serious but rare: None reported.
 ⦁Melatonin receptor agonist (at both MT1 and MT2 receptors).
 ⦁Metabolized primarily by CYP1A2 and 3A4; t ½: 1 hour.
 ⦁Smoking may reduce tasimelteon levels by 40% and lower its efficacy. Caution with 3A4 inhibitors and inducers.
 ⦁Like ramelteon, tasimelteon binds melatonin receptors. Tasimelteon has greater affinity for the MT2 receptor, 
whereas ramelteon has greater affinity for the MT1 receptor. Both are fairly non-selective, though (meaning they 
both bind to both MT1 and MT2), so making a clinical distinction is difficult.
 ⦁Approved as an orphan drug (a drug for rare diseases that affect fewer than 200,000 people).

 ⦁N24SWD is a circadian rhythm disorder commonly seen in blind patients with no light perception. Due to absence 
of environmental input, these patients experience a constant gradual shift of their sleep cycles by roughly 30 
minutes per day, realigning with the 24-hour clock only once every 48 days.
 ⦁Should be used daily to maintain therapeutic effect.
Fun Fact:
The advocacy group Public Citizen accused the FDA of allowing tasimelteon’s manufacturer to list N24SWD as the 
drug’s indication without specifying that it was for use in totally blind people with N24SWD, the originally filed 
indication for consideration. Rather than correcting the error and adjusting the drug’s label, the FDA sent out a press

indication for consideration. Rather than correcting the error and adjusting the drug’s label, the FDA sent out a press 
release officially expanding the approved indication to any patients with N24SWD (there are sighted individuals with 
this disorder, likely with a genetic basis).

Somatic TreatmentsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   215
Somatic Treatments
While devices have a long and somewhat disreputable history in psychiatry (remember Wilhelm Reich’s 
orgonoscope?), they’ve undergone a resurgence, and several have been FDA approved. With the addition of this 
chapter in our now less accurately named “Medication” Fact Book, we created fact sheets for the four most legitimate 
devices in psychiatry—bright light therapy, electroconvulsive therapy, transcranial magnetic stimulation, and vagus 
nerve stimulation. 
There are many other devices available for prescription and purchase, though none of them yet meet the Carlat 
standards for clinical evidence. But several are close; in particular, keep an eye out for:
 ⦁Cranial electric stimulation (CES).  Several have been FDA cleared for depression and anxiety, but the efficacy evidence

⦁Cranial electric stimulation (CES).  Several have been FDA cleared for depression and anxiety, but the efficacy evidence 
is quite weak. A couple of well-known models are the Fisher Wallace Stimulator and Alpha-Stim. 
 ⦁External trigeminal nerve stimulation (eTNS).  Recently cleared by the FDA for treatment of ADHD in kids 7–12 who are 
not on medication. Scant evidence; not yet available. 
 ⦁Deep brain stimulation (DBS). A neurosurgical procedure, DBS is effective for some neurological conditions (such 
as Parkinson’s disease and tremor), but its only approval in psychiatry thus far is a humanitarian use for treatment-
resistant OCD.

216  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONBright Light Therapy Fact Sheet 
Light therapy is an effective treatment for seasonal affective disorder (SAD) and possibly for nonseasonal depression 
as well. 
Main Uses:
SAD (not an FDA-approvable device). 
Alternative Uses:
Nonseasonal depression. 
Procedure:
 ⦁Establish the diagnosis of SAD, based on a clear lifelong pattern of mood worsening in the fall and winter, and 
improving in the spring and summer. Some clinicians use the Seasonal Pattern Assessment Questionnaire to aid 
with the diagnosis (free download at www.tinyurl.com/vy6ewcs2 ).
 ⦁Light boxes emit full-spectrum light with either fluorescent or LED bulbs (fluorescent is usually recommended). 
Light intensity is measured in lux, and the standard minimum intensity required is 10,000 lux (similar to light 
experienced if standing outside 30 minutes after sunrise).

experienced if standing outside 30 minutes after sunrise). 
 ⦁Light boxes should be large enough to deliver the required light intensity at a comfortable distance (usually about 
24 inches away). Smaller fixtures are effective but produce more glare. 
 ⦁Dawn simulator lamps are likely as effective as light boxes (Terman M and Terman JS, Am J Psychiatry  
2006;163(12):2126–2133). These devices can be plugged into a standard lamp and cause the intensity of light to 
gradually increase over about an hour to mimic sunrise, with the brightness increasing to about 250 lux. Patients do 
not have to sit in front of these lamps after awakening. 
Pre–Light Therapy Workup:  No specific labs are required. No medical contraindications, but patients with 
ophthalmological conditions, such as glaucoma or cataracts, should be cleared by their ophthalmologist before

ophthalmological conditions, such as glaucoma or cataracts, should be cleared by their ophthalmologist before 
starting the treatment. 
Cost:  $$; insurance coverage of light boxes is unpredictable and varies by company. Have patients contact their 
insurers directly; occasionally you will be asked to write a letter to support reimbursement. 
 ⦁Most common: Eye strain and headaches. 
 ⦁Uncommon: Mania in patients with bipolar disorder, insomnia, anxiety. 
Mechanism, Treatment Course, and Drug Interactions:
 ⦁Bright light apparently works by entering the eye and stimulating retinal cells, which connect to the optic nerve. The 
optic nerve projects to the hypothalamic suprachiasmatic nucleus, which communicates to the pineal gland, where 
melatonin is produced. Bright light suppresses melatonin production. 
 ⦁Medications and light therapy: All psychiatric medications may be continued during light therapy. 

 ⦁Bright light is likely most effective for patients with atypical depressive symptoms such as hypersomnia and 
hyperphagia. 
 ⦁Meta-analyses of randomized controlled trials have reported robust response rates of bright light therapy in the 
range of 60% (Golden RN et al, Am J Psychiatry  2005;162(4):656–662). Patients who respond tend to do so in three to 
seven days.
 ⦁Patients should sit in front of the light box for about 30 minutes soon after awakening, preferably at the same 
time every morning. They can do any activity during exposure (such as reading, computer work, or running on a 
treadmill) as long as the light box is oriented appropriately to face them. 
 ⦁While morning light is indicated for most patients, some do better with evening light. Patients can fill out the

 ⦁While morning light is indicated for most patients, some do better with evening light. Patients can fill out the 
Automated Morningness-Eveningness Questionnaire to help them decide the optimal timing for their treatment. It’s 
available free online ( www.cet.org/assessments/ ). 
Fun Fact:
According to Norman Rosenthal, the “father” of light treatment, the first person to receive the therapy was an engineer 
who had carefully mapped out the seasonal rhythms of his depression and suggested that NIMH devise a way of 
giving increased periods of light every day. Rosenthal and colleagues gave him an early version of the treatment, and 
he recovered from his depression ( The Carlat Psychiatry Report,  October 2006).

Somatic TreatmentsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   217Electroconvulsive Therapy (ECT) Fact Sheet 
ECT is one of the most effective treatments in psychiatry, but cognitive side effects understandably make patients 
reluctant to try it. We should recommend it to any patient with severe treatment-resistant depression or psychosis. 
Treatment-resistant or  severe depression (either unipolar or bipolar); catatonia.
Psychotic depression; severe schizophrenia; suicidality; neuroleptic malignant syndrome.
 ⦁Appropriate leads are placed to monitor cardiac function (via ECG), brain waves (via EEG), muscle activity (via EMG), 
oxygen blood saturation, and blood pressure and pulse. 
 ⦁Electrodes are positioned in different areas of the scalp (bilateral, right unilateral, or bifrontal) depending on the 
patient and the judgment of the psychiatrist.

⦁Electrodes are positioned in different areas of the scalp (bilateral, right unilateral, or bifrontal) depending on the 
patient and the judgment of the psychiatrist. 
 ⦁Patients receive both an IV anesthetic medication (usually methohexital) to put them to sleep, and a very short-
acting muscle relaxant (usually succinylcholine) to relax the muscles and thereby prevent injury during the ECT-
induced seizure. Sometimes patients will also receive an anticholinergic medication to prevent bradycardia and oral 
secretions, as well as a beta blocker to prevent tachycardia. 
 ⦁Once the patient is anesthetized, an electrical stimulus is delivered through the electrodes. The dose of the stimulus 
varies and is adjusted based on the patient’s seizure threshold (which is determined during the first treatment). The 
stimulus is delivered via a brief pulse lasting anywhere from 0.5 to two milliseconds. 
 ⦁Seizures usually last 30–60 seconds.

 ⦁Seizures usually last 30–60 seconds. 
Pre-ECT Workup:  No specific labs are required. There are no absolute medical contraindications. All patients should 
have a medical consultation prior to ECT. 
Cost:  $$$
 ⦁Most common: Acute confusion for 30 minutes after each treatment in all patients; persistent memory loss for 
events occurring during the treatment period and a few weeks before and after (most patients); tension headache 
(30%); nausea; jaw pain. 
 ⦁Longer-term memory loss occurs in about 25% of patients. 
 ⦁Bilateral lead placement (electrodes on both temples) is most effective but also causes more cognitive side effects 
than unilateral lead placement (electrodes on right temple and scalp apex). 
 ⦁Can be safely administered during pregnancy.

 ⦁ECT produces a generalized seizure that has antidepressant/antipsychotic effects via unknown mechanisms—
possibly by increasing monoamine neurotransmission. 
 ⦁Treatments are given two or three days a week, and response usually begins after three to six treatments (one to 
two weeks). Patients receive seven to 10 treatments on average. 
 ⦁ECT may be continued on a maintenance basis (typically, weekly ECT for two to four weeks, then tapering down to 
monthly or as required based on symptoms). Maintenance ECT lasts six months or more, depending on response 
and side effects. 
 ⦁ECT can be administered on an inpatient or outpatient basis.
 ⦁All psychiatric medications may be continued during ECT. Lithium dose should be decreased to minimize cognitive

 ⦁All psychiatric medications may be continued during ECT. Lithium dose should be decreased to minimize cognitive 
side effects, and benzodiazepines and anticonvulsants should be withheld the night before ECT so as not to 
interfere with the seizure. 
 ⦁ECT is the most effective treatment for depression, with a remission rate of 70%–90%.
 ⦁Elderly patients probably respond better to ECT than younger patients.
 ⦁Although ECT can be very effective, relapse rates are high in the months following treatment. Consider maintenance 
ECT, an antidepressant plus lithium augmentation, or psychotherapy as best approaches to maintain response. 
Fun Fact:
The first ECT was conducted in 1938 by Dr. Ugo Cerletti on an Italian engineer who was hallucinating and having 
delusions that he was being “telepathically influenced. ” After 11 high-voltage treatments (without anesthesia), he

delusions that he was being “telepathically influenced. ” After 11 high-voltage treatments (without anesthesia), he 
made a full recovery and was discharged from the hospital.

218  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONTranscranial Magnetic Stimulation (TMS) Fact Sheet 
Botto m Line:
TMS is a reasonable option for patients who have failed several antidepressant trials and who are willing to commit to 
daily clinic visits for up to six weeks. 
Depression that has not responded to one prior medication trial; OCD; migraine pain.  
Post-stroke depression; Parkinson’s disease; Alzheimer’s disease; PTSD; chronic pain.
 ⦁There are several FDA-cleared TMS devices, and they all include magnetic coils, controller equipment, and a 
comfortable adjustable seat. 
 ⦁Parameters of treatment include frequency (number of pulses per second, or hertz, typically 10–20), intensity (usually 
expressed as percentage of motor threshold—the threshold being the intensity of magnetic field required to elicit a

expressed as percentage of motor threshold—the threshold being the intensity of magnetic field required to elicit a 
motor response), train duration (how many seconds of pulsing occurs, typically four seconds), inter-train interval (time 
between trains, typically 26 seconds), and number of trains per session (eg, 80, assuming two trains per minute). 
 ⦁During the first session, the optimal spot for stimulation is chosen by positioning the coil to elicit a motor twitch in 
the hand; the coil is then shifted 5 cm forward from that area. 
 ⦁The standard protocol is high frequency, which is 10 hertz, or 10 pulses per second. 
Pre-TMS Workup:  No specific labs are required. Contraindicated in patients with increased risk for seizure or with 
implanted metallic hardware (such as pacemakers, cochlear implants, or aneurysm clips). All patients should have a 
standard history and physical prior to TMS.

standard history and physical prior to TMS. 
Cost:  $$$; insurance companies will often pay for the procedure if you can document several prior antidepressant 
treatment trials and failures. 
 ⦁Most common: Scalp discomfort, especially with high-frequency TMS, described by some patients as feeling like a 
woodpecker tapping on their head. 
 ⦁Serious but rare: Instances of grand mal seizures and hearing loss. 
 ⦁TMS produces a magnetic field that modulates the activity of neurons in the cortical brain regions targeted by the 
coil. Theoretically, the left dorsolateral prefrontal cortex is underactive in depression, and high-frequency TMS (10 
hertz) increases that activity. Low-frequency TMS (1 hertz) inhibits  cortical activity, so it is administered over the 
right dorsolateral prefrontal cortex.

right dorsolateral prefrontal cortex. 
 ⦁Treatments are given five days a week; sessions are 30–40 minutes, and response usually begins after about 
20 treatments (four weeks). Average number of treatments is about 30, or a six-week course. There is usually a 
three-week taper-down phase decreasing to three treatments in week one, two treatments in week two, and one 
treatment in week three. Some clinics do maintenance treatments of one or two treatments per month. 
 ⦁TMS can be administered by trained non-MD staff. There is no requirement that the psychiatrist see patients during 
each appointment, and it’s common for a trained operator to administer the daily treatments while the psychiatrist 
sees the patient once a week. 
 ⦁In most naturalistic open-label studies, response rates have been in the range of 60%.

 ⦁In most naturalistic open-label studies, response rates have been in the range of 60%. 
 ⦁Long-term response: About 60% of patients maintain a response at 12 months (Dunner DL et al, J Clin Psychiatry 
2014;75(12):1394–1401). 
 ⦁Medications and TMS: All psychiatric medications may be continued during TMS, but the treatment may work better 
for patients who can discontinue benzodiazepines or anticonvulsants. 
 ⦁In deciding between ECT and TMS, consider that ECT works faster and is the device of choice for suicidal or 
psychotic depression. Patients may like the fact that TMS has fewer side effects and does not require anesthesia. 
 ⦁The most commonly used form of TMS is repetitive TMS (rTMS), which stimulates the surface cortex. Deep TMS 
(dTMS) stimulates deeper regions. Express TMS is a rapid form of TMS for depression that reduces treatment time

(dTMS) stimulates deeper regions. Express TMS is a rapid form of TMS for depression that reduces treatment time 
from 20–38 minutes to three minutes using a high-intensity magnet that produces something called intermittent 
theta burst stimulation (iTBS). 
 ⦁The first TMS devices were approved by the FDA in October 2008. 
Fun Fact:
The book 3,000 Pulses Later  describes advertising executive Martha Rhodes’ positive experiences with TMS, which she 
credits with treating her refractory depression. “3,000 pulses” refers to the typical number of pulses delivered during a 
single TMS session.

Somatic TreatmentsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   219Vagus Nerve Stimulation (VNS) Fact Sheet 
The efficacy of VNS remains too controversial to recommend its use in all but the most desperate clinical situations. 
Noninvasive VNS devices may become available for depression treatment in the future. 
Treatment-resistant depression (adults); refractory seizure disorder (ages 12 and up) . 
Autoimmune and chronic inflammatory disorders such as rheumatoid arthritis, Crohn’s disease, irritable bowel 
syndrome, and fibromyalgia.
In a surgical procedure, a small stimulator device is implanted under the skin in the chest, and wires from the device 
are wound around one of the vagus nerves in the neck. After full recovery from the surgery (about two weeks), the 
device is programmed using a handheld transmitter. Pulses are delivered to stimulate the vagus nerve at regular

device is programmed using a handheld transmitter. Pulses are delivered to stimulate the vagus nerve at regular 
intervals—usually for a 30-second period every five minutes. 
Pre-VNS Evaluation:  No specific labs are required. Patients will typically have a full medical workup in preparation 
for surgery.
Cost:  $$$$$; insurance company coverage is unlikely in most cases. 
 ⦁Most common: Voice hoarseness or alteration (over 50%), headache, cough, neck pain, shortness of breath which 
may be managed by altering the stimulus parameters.
 ⦁Serious but rare: Infection, nerve damage. 
 ⦁VNS’s mechanism is unknown. The vagus nerve (cranial nerve X) sends fibers to the median raphe nucleus and locus 
coeruleus, key areas of serotonergic and noradrenergic innervation relevant to depression. Stimulation of the nerve 
may modulate levels of both serotonin and norepinephrine.

may modulate levels of both serotonin and norepinephrine. 
 ⦁The device is left implanted for years, and periodic visits with neurologists and psychiatrists are necessary to 
monitor the device and the response. 
 ⦁Medications and VNS: All psychiatric medications may be continued after implantation of VNS. 
 ⦁The efficacy of VNS for depression is controversial. The only randomized controlled trial that randomized patients 
to VNS vs sham VNS found no significant difference in response rates after 10 weeks (15% for VNS vs 10% for sham). 
Long-term follow-up studies imply that benefits may accrue over time, with a five-year cumulative response rate of 
67.6%; however, there was no comparable control group, so this could represent a nonspecific response.

67.6%; however, there was no comparable control group, so this could represent a nonspecific response. 
 ⦁LivaNova’s VNS Therapy System is a small battery-powered stimulator that requires battery removal and 
replacement approximately every six years.
 ⦁Noninvasive devices that stimulate the vagus nerve have been approved in Europe for depression, epilepsy, and 
pain. Recently, a similar device was FDA cleared in the US for cluster headache treatment ( www.tinyurl.com/
y6c6frv4 ).
Fun Fact:
Patients with seizure disorders can sometimes tell if a seizure is about to happen, and seizure patients who have VNS 
implanted can swipe a magnet over the stimulator area to send an extra burst of stimulation to the brain—which may 
prevent the seizure.

Substance Use Disorder MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   221
Substance Use Disorder Medications
Although medications are helpful in substance use disorders, you should combine them with other approaches, such 
as therapy and 12-step programs. Most patients with substance use issues have co-occurring psychiatric disorders. 
Some clinicians prefer to get the substance use under control before treating other disorders, under the theory that 
substances can both obscure and aggravate the underlying psychiatric symptoms. In practice, however, it takes 
patients a very long time to stop use, and treatment of other conditions usually can’t wait. For more detailed practical 
guidance on treating addiction, check out Addiction Treatment: A Carlat Guide by Michael Weaver, MD.
Opioid Dependence
 ⦁Methadone was first approved by the FDA for use in opioid dependence in 1947. It is a substitution therapy, and

 ⦁Methadone was first approved by the FDA for use in opioid dependence in 1947. It is a substitution therapy, and 
while it rarely gets patients off of opioids, it does help decrease the use of illicit forms of opioids. The problem is 
that patients must show up at methadone clinics to receive their dose (though they can often eventually qualify for 
limited take-home doses), making it hard to carve out a normal work or family life. A methadone taper can be used 
as part of opioid withdrawal protocols. 
 ⦁Buprenorphine/naloxone (Suboxone and others) was approved in 2002, and although it is also a substitution 
therapy, it has advantages over methadone. You can give patients a 30-day supply, allowing them to avoid the 
methadone lifestyle. It’s becoming easier to get a suboxone waiver. As of April 2021, as long as you are treating no 
more than 30 patients at a time, you don’t need to do any special training and can simply apply to SAMHSA for the

more than 30 patients at a time, you don’t need to do any special training and can simply apply to SAMHSA for the 
waiver. By the way, many clinicians don’t realize that buprenorphine alone is responsible for all of buprenorphine/
naloxone’s beneficial effects in treating opioid use disorder, including its important ceiling effect. The naloxone is 
added purely to discourage users from injecting it. 
 ⦁Naltrexone (ReVia, Vivitrol) blocks a specific type of opioid receptor in the brain and prevents people from feeling 
high when using opioids. In one study, the monthly IM formulation was found to be as effective as buprenorphine 
substitution for preventing opioid relapse, but only for highly motivated patients who can tolerate being opioid free 
for at least seven days before starting naltrexone. 
 ⦁A note on terminology: Both buprenorphine/naloxone and methadone are sometimes referred to as either

 ⦁A note on terminology: Both buprenorphine/naloxone and methadone are sometimes referred to as either 
“substitution therapy” or “opioid agonist treatment. ” Sometimes you’ll see the term “full agonist treatment, ” which 
refers typically to methadone, whereas “partial agonist treatment” refers to buprenorphine. On the other hand, 
“opioid antagonist treatment” may be used to refer to naltrexone—either in the pill version (ReVia) or the long-
acting injectable version (Vivitrol). 
 ⦁A standard opioid withdrawal protocol relies on tapering doses of either buprenorphine (with or without naloxone) 
or methadone. Buprenorphine is more commonly used because it is safer than methadone and more available. 
 ⦁Comfort meds:
 –Acetaminophen or ibuprofen for flu-like aches and pains
 –Clonidine for anxiety
 –Baclofen for muscular spasms
 –Benzodiazepines for anxiety/agitation

⦁Comfort meds:
 –Hypnotics for insomnia (such as trazodone, low-dose quetiapine, diphenhydramine)
 –Antinausea medications (such as ondansetron, trimethobenzamide)
 –Antidiarrhea medications (such as loperamide)
Alcohol Dependence
 ⦁Disulfiram (Antabuse) is an aversive treatment, causing patients to become ill if they drink while taking the 
medication. For a long time it was the only approved medication for treating alcohol dependence, and it still has 
a place in treatment for patients who are very highly motivated to not drink at all (for example, those who are on 
probation after a DUI, or those who are about to lose jobs or partners if they go on just one more bender).
 ⦁Naltrexone (ReVia, Vivitrol) blocks a specific type of opioid receptor in the brain and is thought to act by reducing

⦁Naltrexone (ReVia, Vivitrol) blocks a specific type of opioid receptor in the brain and is thought to act by reducing 
cravings and the rewarding effects of alcohol. Most substance use specialists consider it the treatment of choice for 
alcohol use disorder.

222  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION ⦁Acamprosate (Campral) is effective in maintaining abstinence after detox. It is thought to “normalize” the brain 
glutamate system, which becomes unstable after many years of heavy alcohol use. It may work best in patients 
who are not using other substances, who are alcohol free before starting it, and who have a strong commitment to 
 ⦁Combining medications is another strategy. For example, the combination of acamprosate and disulfiram seems to 
be more effective than acamprosate alone; however, the combination of naltrexone and acamprosate has not been 
shown to be more effective than naltrexone alone.
 ⦁The most common medications used for alcohol withdrawal are benzodiazepines, which, like ethanol, act by 
enhancing the effects of the neurotransmitter GABA. It is thought that chronic alcohol causes overstimulation of

enhancing the effects of the neurotransmitter GABA. It is thought that chronic alcohol causes overstimulation of 
GABA receptors, and those receptors compensate by becoming less sensitive to GABA. When there’s no alcohol 
around, those less sensitive receptors cannot get enough GABA endogenously and get “thirsty” for more GABA—
leading to typical alcohol withdrawal symptoms such as anxiety, tremor, sweating, etc. When benzos are given, they 
act as substitute GABA juice and stop withdrawal symptoms. 
 ⦁Among benzodiazepines, the most common drugs used are chlordiazepoxide (Librium) and diazepam (Valium). 
Both have long half-lives and active metabolites, factors that help ensure benzo serum levels stay consistent 
between doses, preventing breakthrough symptoms. For patients with significant liver disease (eg, cirrhosis) or 
elderly patients, however, levels of chlordiazepoxide and diazepam (plus their metabolites) can build up, causing

elderly patients, however, levels of chlordiazepoxide and diazepam (plus their metabolites) can build up, causing 
excess sedation. In these patients, we tend to choose either oxazepam (Serax) or more often lorazepam (Ativan), 
both of which have shorter half-lives and no active metabolites. 
 ⦁Other medications to consider: 
 –Anticonvulsants are sometimes used, both for core withdrawal symptoms and to prevent seizures—most 
commonly carbamazepine, valproic acid, or gabapentin. 
 –For elevated vital signs and anxiety, consider adrenergic agents (eg, clonidine, propranolol). 
 –Baclofen, a muscle relaxant, can be helpful in addition to benzodiazepines for core symptoms, dosed at 5–10 mg 
TID. 
 –Miscellaneous comfort meds, eg, acetaminophen or ibuprofen for headache, bismuth (Pepto-Bismol) or 
trimethobenzamide (Tigan) for nausea, trazodone for insomnia. 
Smoking Cessation
See our special smoking cessation fact sheet in this chapter for more information.

Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   223Alcohol withdrawal, inpatient
Symptom-triggered 
oxazepam or lorazepam 
taper (for older patients 
or those with poor liver 
function)Comfort meds (acetaminophen 
for pain, ondansetron for 
nausea, loperamide for diarrhea, 
clonidine or hydroxyzine for 
anxiety, trazodone for insomnia)Chlordiazepoxide 
or lorazepam 
five-day 
scheduled taper
Naltrexone oral 
(can start while 
drinking)
Transition to 
naltrexone monthly 
injectable if 
appropriateGabapentin 
five-day 
Acamprosate 
(best started 
after abstinence, 
preferred if liver 
disease)Carbamazepine 
five-day 
Topiramate 
(heavier side 
effect burden)May add baclofen 
or clonidine to any 
of these tapers 
as needed
Disulfiram (for 
highly motivated 
patients; supervised 
administration may 
improve outcomes)Other meds to try: 
baclofen, gabapentin, 
ondansetronSymptom-triggered 
chlordiazepoxide

as needed
chlordiazepoxide  
taperAlcohol withdrawal, outpatient
Alcohol dependenceAlcohol Use Disorder Treatment Algorithm

224  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONOpioid withdrawal
Methadone taper 
(generally more 
complicated than 
buprenorphine)Clonidine or lofexidine 
(best used as adjunct to 
opiate taper, but can be 
used along with comfort 
meds if opiates not 
available or indicated)Comfort meds (acetaminophen or 
ibuprofen for muscle aches and 
pain, ondansetron for nausea, 
loperamide for diarrhea, dicyclomine 
for abdominal cramping, baclofen 
for muscle spasms, hydroxyzine for 
anxiety, trazodone for insomnia)
Buprenorphine/
naloxoneMethadoneNaltrexone monthly injectable 
(requires patient to be opiate 
free for seven to 10 days 
before initiation)Buprenorphine/
naloxone taper 
(eg, five-day taper 
from 12 mg)
Opioid dependenceOpioid Use Disorder Treatment Algorithm

Substance Use Disorder MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   225Table 20:  Substance Use Disorder Medications
Year FDA Approved (Rx status)
[G] denotes generic availabilityRelevant FDA Indication(s)Available Strengths
(mg)
Acamprosate [G]
(Campral)
2004 (Rx)Alcohol use. Best when started after a period 
of abstinence. 333 666 TID
Buprenorphine [G]
(Belbuca, Buprenex, Butrans)
2002 (Schedule III)Opioid use. Substitution therapy. 2, 8 SL (Subutex [G])
0.075, 0.15, 0.3, 0.45, 0.6, 0.75, 0.9 buccal film (Belbuca, 
[G]) (used for pain)
0.3 mg/mL injection (Buprenex, [G]) (used for pain)
5, 7.5, 10, 15, 20 mcg/hr patch (Butrans) (used for pain)8–16 QD SL
Buprenorphine extended-release injection 
(Sublocade)
2017 (Schedule III)Opioid use. Substitution therapy. 100, 300 300 mg monthly ×2 doses, then 100 mg 
monthly
Buprenorphine and naloxone [G]
(Bunavail, Suboxone, Zubsolv)

monthly
2002 (Schedule III)
Generic available for 2/0.5, 8/2 mg SL tablets 
and SL film strips onlyOpioid use. Substitution therapy formulated 
to prevent misuse and diversion. 2.1/0.3, 4.2/0.7, 6.3/1 buccal film (Bunavail)
2/0.5, 4/1, 8/2, 12/3 SL film strip (Suboxone, [G])
2/0.5, 8/2 SL tablet (generic only)
0.7/0.18, 1.4/0.36, 2.9/0.71, 5.7/1.4, 8.6/2.1, 11.4/2.9 SL 
tablet (Zubsolv)4–24 QD
(Zyban)
1997 (Rx)Tobacco use. Decreases craving. 150 150 QAM–150 BID
Clonidine [G]
1974 (Rx)Opioid use. Decreases withdrawal symptoms. 0.1, 0.2, 0.3 IR tablet
0.1, 0.2 ER tablet
0.1, 0.2, 0.3 mg/day patch0.1–0.2 Q4–Q6 hours PRN (IR tablet)
Disulfiram [G]
(Antabuse)
1951 (Rx)Alcohol use. Aversive treatment. 250, 500 125–500 QPM
(Lucemyra)

2018 (Rx)Opioid use. Decreases withdrawal symptoms. 0.18 3–4 tablets QID, then taper
Methadone [G]
(Dolophine, Methadose)
1947 (Schedule II)Opioid use. Substitution therapy. 5, 10, 40
10 mg/mL, 10 mg/5 mL, 5 mg/5 mL oral liquid20–120 QD
Naloxone [G]
(Narcan Nasal Spray, Kloxxado, Zimhi)
2015 (intranasal) (Rx)Opioid use. Emergency opioid overdose 
rescue.4 mg/0.1 mL intranasal (Narcan)
8 mg/0.1 mL intranasal (Kloxxado)
5 mg/0.5 mL intramuscular or subcutaneous (Zimhi)×1; may repeat every 2–3 minutes

226  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONGeneric Name (Brand Name)
(mg)
Naltrexone [G] 
(ReVia) 
1984 (Rx)Alcohol use. Decreases alcohol euphoria.
Opioid use. Blocks opioid effects. 50 25–50 QD
Naltrexone ER 
(Vivitrol) 
2006 (Rx) 380 380 Q4week
Nicotine inhaled 
(Nicotrol Inhaler) 
1997 (Rx) Tobacco use. Substitution therapy. 4 mg delivered/cartridge 6–16 cartridges per day
Nicotine nasal spray 
(Nicotrol NS)
1996 (Rx) 0.5 mg delivered/spray 1–2 sprays/hour PRN
Nicotine polacrilex [G] 
(Nicorette Gum, others) 
1992 (OTC)2, 4 1 piece PRN up to 24/day
(Nicorette Lozenge, others) 
2009 (OTC)2, 4 1 piece PRN up to 20/day
Nicotine transdermal [G] 
(Habitrol, Nicoderm CQ, others) 
1991 (OTC)7, 14, 21/24 hr 14–21 QD
Varenicline [G]
(Chantix)

(Chantix)
2006 (Rx) Tobacco use. Decreases craving. 0.5, 1 0.5 QD–1 BID

Substance Use Disorder MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   227Smoking Cessation
(The following is adapted from a Carlat One-Pager that was originally created for the June 2015 issue of the 
Carlat Addiction Treatment Report . See that issue for the full article.)
DSM-5: “Problematic pattern” of tobacco use leading to “significant distress” that lasts at least 12 months.
1. Determine daily nicotine use.  How many packs per day (20 mg nicotine is typically absorbed per 20-cigarette pack)? 
E-cigarettes (nicotine varies)? Chewing tobacco (one pouch = ¼ pack)? Hookah?
2. Determine the usage pattern.  When does the patient have their first cigarette of the day? Does the patient smoke 
when sick?
3. Determine past quitting techniques. Have any worked—or not worked?
Pharmacological Treatment: Which to Choose?
 ⦁Nicotine replacement therapy (NRT).  Start most patients on NRT. Prescribe patch based on nicotine load: One

 ⦁Nicotine replacement therapy (NRT).  Start most patients on NRT. Prescribe patch based on nicotine load: One 
cigarette delivers about 1 mg of nicotine; so one pack per day = 21 mg patch. Place it at the same time each day, 
usually in the morning. Start above the heart and rotate left around the body to prevent skin irritation. Use 0.5% 
cortisone cream for irritation/rash. Initial dose for four to eight weeks, then taper monthly or every two months. 
Advise no smoking—patients may note nausea or racing heart if they do.
 ⦁Combination NRT.  As effective as varenicline. If there are cravings throughout the day even with a patch, add a 
short-acting agent (gum, lozenge, spray, inhaler). Discuss chewing technique for gum: Chew a few times to activate 
the release (the sign is bad peppery taste), then park between cheek and gum, switching sides every few minutes.

the release (the sign is bad peppery taste), then park between cheek and gum, switching sides every few minutes. 
Each piece is 2 mg or 4 mg and lasts about 30 minutes. Spray and inhaler are available by prescription only. 
 ⦁Varenicline (Chantix). Most effective single medication for smoking.  Start 0.5 mg per day for three days, increase 
to twice daily for seven to 10 days, then quit smoking, then increase gradually to 1 mg twice daily for three months. 
Discuss possible insomnia and vivid dreams (common). Psychiatric side effects, such as depression, suicidal ideation, 
and aggression, are unusual and likely caused by nicotine withdrawal rather than varenicline.
 ⦁Bupropion (Wellbutrin SR, Zyban). Effective, but less effective than varenicline.  150 mg/day is just as effective 
as the manufacturer’s recommended dose of 150 mg BID and carries fewer side effects. Possible side effects of

as the manufacturer’s recommended dose of 150 mg BID and carries fewer side effects. Possible side effects of 
insomnia, nervousness, weight loss (potentially good, especially since many people gain weight after quitting).
Tips to Improve Success of Treatment
 ⦁Normalize failure. Most people need multiple quit attempts before success; if patients know this in advance, they 
might be more willing to come back and try again.
 ⦁The first week after quitting is the hardest in terms of craving. Craving spells last 10–20 minutes; distraction 
techniques can work to deal with them. Patients can try drinking a large glass of cold water, playing a video game, etc.
 ⦁Warn patients that they might cough temporarily after they quit—this is a normal lung response to healing.
 ⦁Give phone number 1-800-QUIT-NOW for free support.

228  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONACAMPROSATE  (Campral) Fact Sheet [G]
Acamprosate is best for maintaining abstinence in patients who have already quit, but it can be helpful even after 
patients relapse. Naltrexone is the better choice for patients who are still drinking, since it is better at helping patients 
quit. Acamprosate is also preferred over naltrexone in patients with hepatic impairment.
Alcohol dependence.
Delayed-release tablets (G):  333 mg.
 ⦁Start 666 mg TID. Give 333 mg TID in patients with renal impairment.
 ⦁Can give 999 mg twice a day if patients can’t remember to take it three times daily. 
Cost:  $$
 ⦁Most common: Diarrhea (dose related, transient), weakness, peripheral edema, insomnia, anxiety.

Cost:  $$
 ⦁Serious but rare: Acute renal failure reported in a few cases; suicidal ideation, attempts, and completions rare but 
greater than with placebo in studies.
 ⦁Mechanism of action is not fully defined; it appears to work by promoting a balance between the excitatory and 
inhibitory neurotransmitters, glutamate and GABA, respectively (GABA and glutamate activities appear to be 
disrupted in alcohol dependence).
 ⦁Not metabolized, cleared unchanged by kidneys; t ½: 20–33 hours.
 ⦁No significant drug interactions.
 ⦁Approved by the FDA in 2004, but it has been used in France and other countries since 1989.
 ⦁Does not eliminate or treat symptoms of alcohol withdrawal. Usually prescribed for maintenance of abstinence; may 
continue even if patient relapses with alcohol.

⦁Does not eliminate or treat symptoms of alcohol withdrawal. Usually prescribed for maintenance of abstinence; may 
 ⦁Clinically, acamprosate has demonstrated efficacy in more than 25 placebo-controlled trials and has generally been 
found to be more effective than placebo in reducing risk of returning to any drinking and increasing the cumulative 
duration of abstinence. However, in reducing heavy drinking, acamprosate appears to be no better than placebo.
 ⦁Acamprosate can be used with naltrexone or disulfiram (different mechanism of action), although the combination 
with naltrexone may not increase efficacy per available studies.
 ⦁Taking with food is not necessary, but it may help compliance to do so.
 ⦁Compared to naltrexone and disulfiram, acamprosate is not metabolized by the liver and is not impacted by alcohol 
use, so it can be administered to patients with hepatitis or liver disease and to patients who continue drinking

use, so it can be administered to patients with hepatitis or liver disease and to patients who continue drinking 
alcohol.
Fun Fact:
Each 333 mg tablet contains 33 mg of elemental calcium (because it is available as acamprosate calcium salt).

Substance Use Disorder MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   229BUPRENORPHINE  (Sublocade) Fact Sheet [G]
Buprenorphine (Subutex, available now only as generic) is the active ingredient in Suboxone (buprenorphine/
naloxone) and is responsible for the effectiveness of the combination medication in opioid use disorder. In the past, 
buprenorphine alone was preferred for the initial (induction) phase of treatment, while Suboxone was preferred for 
maintenance treatment (unsupervised administration). Currently, the combination is favored for both induction and 
maintenance as it decreases abuse or diversion potential.
Opioid dependence: induction, maintenance  (Sublocade); moderate-severe pain (Belbuca, Buprenex, Butrans).  
 ⦁SL tablets (G):  2 mg, 8 mg (scored).
 ⦁Extended-release injection (Sublocade):  100 mg/0.5 mL, 300 mg/1.5 mL prefilled syringes.

 ⦁Buccal film (Belbuca, [G]): 0.075 mg, 0.15 mg, 0.3 mg, 0.45 mg, 0.6 mg, 0.75 mg, 0.9 mg (used for pain).
 ⦁Injection (Buprenex, [G]): 0.3 mg/mL (used for pain).
 ⦁Transdermal patch (Butrans): 5 mcg/hr, 7.5 mcg/hr, 10 mcg/hr, 15 mcg/hr, 20 mcg/hr (used for pain).
 ⦁Induction procedure: 
 –Begin at least four hours after last use of heroin or other short-acting opioids and when first signs of withdrawal 
appear; otherwise, you may trigger withdrawal symptoms. 
 –Start 2–8 mg SL day one; then 8–16 mg SL QD (usual initial dose range is 12–16 mg/day and accomplished over 
three to four days). 
 –Other than extended-release injection, not for maintenance treatment; patients should be switched to the 
buprenorphine/naloxone combination product for maintenance and unsupervised therapy.

–Other than extended-release injection, not for maintenance treatment; patients should be switched to the 
buprenorphine/naloxone combination product for maintenance and unsupervised therapy. 
 ⦁Patients with moderate to severe opioid use disorder who have been stabilized with SL or buccal buprenorphine for 
greater than seven days may convert to monthly subcutaneous injections. Start 300 mg monthly for two months, 
then give 100 mg monthly maintenance doses. Some patients may require higher doses.
Cost:  SL: $$; monthly injection: $$$$$
 ⦁Most common: Headache, pain, insomnia, nausea, anxiety.
 ⦁Serious but rare: Hepatitis reported rarely, ranging from transient, asymptomatic transaminase elevations to 
hepatic failure; in many cases, patients had preexisting hepatic dysfunction. QT prolongation with higher doses of 
transdermal patch.

 ⦁Opioid agonist (delta and mu receptors) and antagonist (kappa receptors).
 ⦁Metabolized primarily through CYP3A4; t ½: 24–48 hours.
 ⦁Avoid concomitant use with opioid analgesics (diminished pain control). Additive effects with CNS depressants. 
CYP3A4 inhibitors and inducers may affect levels of buprenorphine.
 ⦁Schedule III controlled substance. Prescribing of SL tablets for opioid dependence is limited to providers who have 
met qualification criteria and have received a DEA number specific to buprenorphine (see www.buprenorphine.
samhsa.gov ).
 ⦁Monthly injection offers alternative that may be convenient for some patients.
Fun Fact:
The subcutaneous implant formulation of buprenorphine (Probuphine) was discontinued. Its use was severely

⦁Monthly injection offers alternative that may be convenient for some patients.
Fun Fact:
The subcutaneous implant formulation of buprenorphine (Probuphine) was discontinued. Its use was severely 
limited as it was invasive, expensive, and an option only for patients stable on ≤8 mg/day. Other implants currently in 
development include medications for schizophrenia, breast cancer, photosensitivity, and Parkinson’s disease.

230  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONBUPRENORPHINE/NALOXONE  (Bunavail, Suboxone, Zubsolv) 
Buprenorphine/naloxone is the definitive partial agonist treatment for opioid use disorder. The combination product 
is preferred over buprenorphine alone for maintenance because the addition of naloxone lowers its potential for 
injection abuse. The SL film formulation is priced a little higher than the SL tablets yet provides very little (if any) 
meaningful benefit; generic SL tablets should be used as a cost-saving measure.
Opioid dependence  (induction and maintenance).
 ⦁SL tablets (G):  2/0.5 mg, 8/2 mg (scored).
 ⦁SL film strips (Suboxone, [G]): 2/0.5 mg, 4/1 mg, 8/2 mg, 12/3 mg.
 ⦁SL tablets (Zubsolv): 0.7/0.18 mg, 1.4/0.36 mg, 2.9/0.71 mg, 5.7/1.4 mg, 8.6/2.1 mg, 11.4/2.9 mg.
 ⦁Buccal film (Bunavail): 2.1/0.3 mg, 4.2/0.7 mg, 6.3/1 mg.
 ⦁Induction procedure:

⦁Buccal film (Bunavail): 2.1/0.3 mg, 4.2/0.7 mg, 6.3/1 mg.
 ⦁Maintenance treatment: give combination product (Suboxone or [G]) daily in the equivalent buprenorphine dose on 
last day of induction; adjust dose in increments of 2 mg or 4 mg to a level that maintains treatment and suppresses 
opioid withdrawal symptoms (usually 4–24 mg/day); max 32 mg/day.
 ⦁Zubsolv 5.7/1.4 mg SL tablet provides equivalent buprenorphine to a Suboxone 8/2 mg SL tablet.
 ⦁Bunavail 4.2/0.7 mg buccal film provides equivalent buprenorphine to a Suboxone 8/2 mg SL tablet.

⦁Bunavail 4.2/0.7 mg buccal film provides equivalent buprenorphine to a Suboxone 8/2 mg SL tablet.
Cost:  SL tablet, film, Bunavail: $–$$ depending on dose; Zubsolv: $$$$
 ⦁Most common: Headache, pain, vomiting, sweating.
 ⦁Serious but rare: Hepatitis reported rarely, ranging from transient, asymptomatic transaminase elevations to hepatic 
failure; in many cases, patients had preexisting hepatic dysfunction.
 ⦁Buprenorphine: Opioid agonist (delta and mu receptors) and antagonist (kappa receptors); naloxone: Opioid 
 ⦁Metabolized primarily through CYP3A4; t ½: 24–48 hours (naloxone: 2–12 hours).

⦁Avoid concomitant use with opioid analgesics (diminished pain control). Additive effects with CNS depressants. 
 ⦁Schedule III controlled substance. Prescribing is limited to physicians who have met qualification criteria and have 
received a DEA number specific to buprenorphine (see www.buprenorphine.samhsa.gov ).
 ⦁Naloxone is an opioid antagonist that is active only when injected; it is added to buprenorphine in order to reduce 
misuse via intravenous injection of a dissolved tablet.
 ⦁The SL film formulation’s manufacturer claims it dissolves faster and tastes better than SL tablets. Actually, it is more 
likely a way for the manufacturer to switch users to a “new” product (with patent protection until 2025) rather than 
lose patients to generics.
 ⦁SL film should be placed at base of tongue to the side of midline; this allows patient to use two films at the same 
time if dose dictates.

 ⦁Zubsolv and Bunavail formulations have better bioavailability, hence the dose equivalencies noted above.
 ⦁Prescribers should be aware of the risk for diversion and sale of buprenorphine films and tablets. Some regular 
opioid users periodically buy buprenorphine “off the street” and use it to combat cravings and withdrawal 
symptoms if their drug of choice is not readily available.
Fun Fact:
The manufacturer of Suboxone, Reckitt Benckiser, generates most of its revenue from selling home and personal care 
products like Lysol cleaners and Durex condoms.

Substance Use Disorder MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   231BUPROPION  SR (Zyban) Fact Sheet [G]
Bupropion SR is somewhat less effective in smoking cessation than varenicline, but given the high rate of comorbidity 
between smoking and depression, it is an attractive option for many patients. It is also a particularly good choice for 
patients who are not able to set a quit date prior to initiating treatment.
Smoking cessation.
SR tablets (G):  150 mg ER.
Start 150 mg QAM for three days, then 150 mg BID; separate doses by at least eight hours and administer last dose no 
later than 6 p.m. to minimize insomnia. Target smoking quit dates are generally in the second week of treatment.
Cost:  $

Cost:  $
 ⦁Serious but rare: Seizures; risk higher with rapid and large dose increases and in patients at risk for seizures. 
Anaphylactoid reactions (eg, pruritus, urticaria, angioedema, dyspnea) reported rarely; reports include Stevens-
Johnson syndrome and anaphylactic shock. Class warning regarding suicide risk (see Antidepressants chapter).
 ⦁Norepinephrine and dopamine reuptake inhibitor.
 ⦁Metabolized primarily through CYP2B6; may inhibit CYP2D6; t ½: 21 hours.
 ⦁Avoid use with MAOIs. Levels of drugs metabolized by CYP2D6 (eg, paroxetine, fluoxetine, aripiprazole, iloperidone, 
atomoxetine, beta blockers) may be increased. Successful cessation of smoking may alter pharmacokinetic

atomoxetine, beta blockers) may be increased. Successful cessation of smoking may alter pharmacokinetic 
properties of other medications (eg, clozapine, olanzapine, theophylline, warfarin, insulin).
 ⦁If patient successfully quits smoking after seven to 12 weeks, may consider maintenance therapy based on 
individual patient risk-benefit. Efficacy of maintenance therapy (150 mg BID) has been shown for up to six months. 
However, if patient has not made significant progress by the seventh week of therapy, success is unlikely and 
discontinuation should be considered.
 ⦁Bupropion slows the weight gain that often occurs in the initial weeks after smoking cessation, but with time, this 
effect becomes negligible.
 ⦁Bupropion and nicotine replacement therapy show similar quit rates: About 25% of patients, or double that seen 
with placebo, are abstinent at six months.
 ⦁Equally effective in smokers with or without history of depression.
Fun Fact:

Fun Fact:
Much of the initial direct-to-consumer advertising that was done for Zyban was via print ads in smoke-free places 
such as airports.

232  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONDISULFIRAM  (Antabuse) Fact Sheet [G]
Disulfiram is an aversive treatment, causing a buildup of ethanol’s metabolite acetaldehyde in the serum, which in 
turn causes symptoms such as flushing, dizziness, nausea, and vomiting. Since disulfiram does not reduce cravings 
and any alcohol ingestion could result in a reaction, noncompliance can be common. Its use should be reserved for 
selective, highly motivated patients in conjunction with supportive and psychotherapeutic treatment.
Tablets (G): 250 mg, 500 mg.
Start 125 mg QPM (must be abstinent from alcohol >12 hours); increase to 250 mg QPM after several days. Maintenance 
is usually 250–500 mg QPM, but some patients can drink alcohol without a reaction at the 250 mg/day dose.
Monitoring:  LFTs if liver disease is suspected.
Cost:  $

Cost:  $
 ⦁Most common: Skin eruptions (eg, acne, allergic dermatitis), drowsiness, fatigue, impotence, headache, metallic taste.
 ⦁Serious but rare: Severe (very rarely fatal) hepatitis or hepatic failure reported and may occur in patients with or 
without prior history of abnormal hepatic function. Rare psychotic episodes have been reported. Rarely may cause 
peripheral neuropathy or optic neuritis.
 ⦁Aldehyde dehydrogenase inhibitor.
 ⦁Metabolized primarily through CYP450; t ½ is not defined, but elimination from body is slow, and effects may persist 
for one or two weeks after last dose.
 ⦁While taking disulfiram, and for one to two weeks after stopping, avoid concomitant use of any medications

 ⦁While taking disulfiram, and for one to two weeks after stopping, avoid concomitant use of any medications 
containing alcohol (including topicals), metronidazole, or “disguised” forms of ethanol (cough syrup, some 
mouthwashes, oral solutions or liquid concentrates containing alcohol such as sertraline). Avoid vinegars, cider, 
extracts, and foods containing ethanol.
 ⦁Disulfiram inhibits the enzyme aldehyde dehydrogenase; when taken with alcohol, acetaldehyde levels are 
increased by five- to 10-fold, causing unpleasant symptoms that include flushing, nausea, vomiting, palpitations, 
chest pain, vertigo, hypotension, and (in rare instances) cardiovascular collapse and death. This is the basis for its 
use as aversion therapy. Common advice to patients: “You’ll wish you were dead, but it likely won’t kill you. ”
 ⦁Reaction may last from 30–60 minutes to several hours or as long as alcohol remains in the bloodstream.

⦁Reaction may last from 30–60 minutes to several hours or as long as alcohol remains in the bloodstream.
 ⦁Advise patients to carry an identification card or a medical alert bracelet that states they are taking the medication 
and lists the symptoms of the reaction and clinician contact information.
 ⦁Therapy lasts until the patient is fully recovered and a basis for permanent self-control has been established; 
maintenance therapy may be required for months or even years.
Fun Fact:
Disulfiram’s anti-protozoal activity may be effective in Giardia and Trichomonas infections.

Substance Use Disorder MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   233LOFEXIDINE  (Lucemyra) Fact Sheet
Lofexidine is an alpha-2 agonist (similar to clonidine and guanfacine) that is used to reduce the intensity of opioid 
withdrawal symptoms. It effectively blunts some of the most disturbing symptoms of detox such as anxiety and 
tachycardia, but is generally not effective for withdrawal pain symptoms such as myalgias and headache, so it should 
be used with an analgesic like ibuprofen or acetaminophen. Some data indicate that lofexidine is more effective than 
clonidine for management of opioid withdrawal; however, given its much higher price tag, we recommend you stick 
to clonidine. 
Opioid withdrawal.
Tablets: 0.18 mg.
 ⦁Start three 0.18 mg tablets QID at five- to six-hour intervals during peak withdrawal symptoms (typically the first

 ⦁Start three 0.18 mg tablets QID at five- to six-hour intervals during peak withdrawal symptoms (typically the first 
five to seven days after last use of opioid). Withdrawal symptoms should be used clinically to guide gradual dose 
reduction.
 ⦁Maximum daily dose is 2.88 mg (16 tablets), and no single dose should exceed 0.72 mg (four tablets).
 ⦁Discontinue over a two- to four-day period by gradually reducing in increments of one tablet per dose every one to 
two days. Treatment course should be no more than 14 days.  
Monitoring:  Monitor blood pressure and pulse. Monitor ECG in patients with congestive heart failure, 
bradyarrhythmia, or risk for QT prolongation. 
 ⦁Most common: Orthostatic hypotension, bradycardia, dizziness, somnolence, sedation, dry mouth. 
 ⦁Serious but rare: Syncope, QT interval prolongation. 

⦁Serious but rare: Syncope, QT interval prolongation. 
 ⦁Alpha-2 receptor agonist. 
 ⦁Metabolized primarily by CYP450 2D6; t ½: 11–12 hours.
 ⦁Caution when used with CYP450 2D6 inhibitors (such as paroxetine) or in poor 2D6 metabolizers as there may be an 
increased risk for hypotension. Caution with other agents that may increase QT interval (eg, methadone). Caution 
when used with CNS depressants (additive CNS depression).
 ⦁Analog of clonidine, another alpha-2 agonist, available since 1992 in the UK (you can find the clonidine fact sheet in 
the ADHD Medications chapter).
 ⦁Has been approved for use in Europe since the 1990s, but was not approved by the FDA until 2018. Approval was 
based on two randomized, double-blind, placebo-controlled clinical trials of 866 adults with opioid dependence; 
lofexidine lessened severity of withdrawal symptoms more than placebo.

lofexidine lessened severity of withdrawal symptoms more than placebo. 
 ⦁Decide on how rapidly to taper the dose by using a symptom-triggered assessment such as the Clinical Opiate 
Withdrawal Scale (COWS), an 11-item scale measuring opioid withdrawal symptoms including stomach cramps, 
muscle spasms/twitching, feeling of coldness, heart pounding, muscle tension, aches, pains, yawning, runny eyes, 
and insomnia or sleep problems.
 ⦁Lower the dose if symptomatic hypotension or bradycardia occurs, and in patients with impaired hepatic or renal 
function. 
 ⦁Some patients may experience markedly increased blood pressure when lofexidine is discontinued. 
 ⦁Has been studied for alcohol withdrawal but was not found to be effective.
Fun Fact:
Case reports support its use for hot flashes associated with menopause.

234  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONMETHADONE  (Methadose) Fact Sheet [G]
Methadone is a long-acting opioid and is one of the mainstays of opioid substitution therapy, along with 
buprenorphine. Although it is tantamount to replacing one addiction for another, it has the harm reduction benefits 
of avoiding the infectious diseases that accompany sharing needles and preventing dangerous behaviors used to 
obtain illicit opioids (such as theft or prostitution). Disadvantages include the need to go to a methadone clinic daily, 
the potential for diversion, and the potential for accumulation with repeated doses. 
Opioid dependence; severe pain.
 ⦁Tablets (G):  5 mg, 10 mg, 40 mg (scored).
 ⦁Oral solution (G): 10 mg/5 mL, 5 mg/5 mL.
Start 15–30 mg single dose; then 5–10 mg every two to four hours. Adjust dose to prevent withdrawal symptoms; max

⦁Oral concentrate (G):  10 mg/mL.
Start 15–30 mg single dose; then 5–10 mg every two to four hours. Adjust dose to prevent withdrawal symptoms; max 
40 mg on day one. 80–120 mg per day is a common maintenance dose for opioid dependence.
Cost:  $
 ⦁Most common: Constipation, dizziness, sedation, nausea, sweating.
 ⦁Serious but rare: May prolong the QTc interval and increase risk for torsades de pointes; caution in patients at risk for 
QTc prolongation; usually with doses >100 mg/day. Severe respiratory depression may occur; use extreme caution 
during initiation, titration, and conversion from other opioids to methadone. Respiratory depressant effects occur 
later and persist longer than analgesic effects, possibly contributing to cases of overdose.
 ⦁Opioid agonist.
 ⦁Metabolized primarily through CYP2B6, 2C19, and 3A4 (major); inhibits CYP2D6; t ½: 8–59 hours.

 ⦁High potential for interactions. Avoid concomitant use with other potent sedatives or respiratory depressants. Use 
with caution in patients on medications that are metabolized by CYP2D6, inhibit CYP3A4, prolong the QTc interval, 
or promote electrolyte depletion.
 ⦁Schedule II controlled substance; distribution of 40 mg tablets restricted to authorized opioid addiction treatment 
facilities.
 ⦁May only be dispensed according to the SAMHSA Center for Substance Abuse Treatment guidelines. Regulations 
vary by area; consult regulatory agencies and/or methadone treatment facilities.
 ⦁Methadone accumulates with repeated doses; dose may need reduction after three to five days to prevent CNS 
depressant effects.
Fun Fact:

⦁Methadone accumulates with repeated doses; dose may need reduction after three to five days to prevent CNS 
Fun Fact:
A persistent but untrue urban legend claims the name “Dolophine” was coined in tribute to Adolf Hitler by its German 
creators. The name was in fact created after the war by the American branch of Eli Lilly, and the pejorative term 
“adolphine” (never an actual name of the drug) didn’t appear in the US until the early 1970s.

Substance Use Disorder MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   235NALOXONE  (Kloxxado, Narcan Nasal Spray, Zimhi) Fact Sheet [G]
Naloxone is an opioid antagonist that is used to rapidly reverse opioid overdose. It’s important to prescribe this life-
saving treatment to all your opioid-dependent patients.  
Emergency treatment of known or suspected opioid overdose.
 ⦁Intranasal (Narcan Nasal Spray):  4 mg/0.1 mL.
 ⦁Intranasal (Kloxxado):  8 mg/0.1 mL.
 ⦁Injectable prefilled syringe (Zimhi):  5 mg/0.5 mL.
 ⦁Generic intranasal kit may be assembled using 2 mg/2 mL prefilled needleless syringe and a mucosal atomization 
device nasal adapter (requires assembly at time of administration).
Intranasal: Bystander to spray in one nostril; may repeat into other nostril with additional doses every two to three

Intranasal: Bystander to spray in one nostril; may repeat into other nostril with additional doses every two to three 
minutes if no or minimal response and until emergency response arrives. The drug is absorbed automatically into the 
nasal mucosa, which is why it is effective in patients who are unconscious and cannot sniff it. 
Cost:  Intranasal: $$$; generic kit: $
Most common: Symptoms of opioid withdrawal, including body aches, fever, sweating, runny nose, sneezing, 
piloerection, yawning, weakness, shivering or trembling, nervousness, restlessness or irritability, diarrhea, nausea or 
vomiting, abdominal cramps, increased blood pressure, and tachycardia.
 ⦁Opioid antagonist.
 ⦁Metabolized primarily by conjugation (non-P450) in the liver; t ½: 1.36 hours.

 ⦁Because treatment of overdose with this opioid antagonist must be performed by someone other than the patient, 
instruct prescription recipients to inform those around them that they have naloxone rescue and ensure that those 
people have been instructed in recognizing overdose symptoms and administering the medication.
 ⦁Evzio 2 mg auto-injector offered a novel device with voice instructions but was very expensive; it has been 
discontinued by the manufacturer and is no longer available. Zimhi is a new injectable (intramuscular or 
subcutaneous) prefilled syringe for layperson use but comes in a much higher 5 mg dose and delivers nearly 
five-fold higher peak serum concentrations, which could result in very severe precipitated withdrawal symptoms.

 ⦁Most opioids have a longer duration of action than naloxone, so it’s likely that overdose symptoms (CNS depression 
and respiratory depression) will return after initial improvement. Therefore, patients should continue to be 
monitored and should receive medical attention after emergency dose(s) provided.
 ⦁Intranasal forms of naloxone rescue administration, if broadly distributed to those at risk, could make overdose 
rescue a more acceptable and widespread practice.
 ⦁Like Zimhi, Kloxxado is a higher-dose formulation that was developed to combat the presumed need for repeated 
doses of naloxone after overdose with higher-potency opioids such as fentanyl. Whether multiple doses are 
required has been controversial, and use of this ultra-potent antagonist could result in severe precipitated

required has been controversial, and use of this ultra-potent antagonist could result in severe precipitated 
withdrawal. Kloxxado is likely overkill for most patients—stick to the 4 mg nasal formulation.
 ⦁Check out the Prescribe to Prevent website ( www.prescribetoprevent.org ) for prescriber resources such as webinars, 
toolkits, patient education materials, and medical-legal resources. This website also provides guidance to physicians 
on writing a prescription for naloxone.
Fun Fact:
Naloxone was first approved for opioid overdose treatment in 1971 and is available as a very inexpensive injectable 
generic. Newer formulations come at a much higher price because of the way they are formulated, making them 
easier to use by non-emergency provider bystanders.

236  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONNALTREXONE  (ReVia, Vivitrol) Fact Sheet [G]
Naltrexone, an opioid antagonist, is the first-line medication for alcohol use disorder—though it is also approved for 
opioid use disorder. By reducing the endorphin-mediated euphoria of drinking, it helps people moderate, preventing 
that first drink from leading to several more. Avoid naltrexone in patients with hepatic impairment or those taking 
opioid-based pain medications. For opioid dependence, methadone and buprenorphine are more effective for most, 
although naltrexone may be appropriate for highly motivated opioid-dependent patients, with injectable preferred 
over oral.
Alcohol dependence; opioid addiction  (relapse prevention following detox).
Self-injurious behavior.
 ⦁Tablets (ReVia, [G]):  50 mg (scored).
 ⦁Long-acting injection (Vivitrol): 380 mg.

 ⦁Opioid dependence: Start 25 mg for one day; if no withdrawal signs, increase to and maintain 50 mg/day (with 
food); doses >50 mg may increase risk of hepatotoxicity.
 ⦁Alcohol dependence: Start at 50 mg QD; can increase to 100 mg QD after 12 weeks if no response. 
 ⦁Injection: 380 mg IM (gluteal) Q4 weeks (for opioid or alcohol dependence). Do not initiate therapy until patient is 
opioid free for at least seven to 10 days (by urinalysis).
Cost:  Tablet: $; injection: $$$$$
 ⦁Most common: Headache, nausea, somnolence, vomiting.
 ⦁Serious but rare: Black box warning regarding dose-related hepatocellular injury; the difference between apparent 
safe and hepatotoxic doses appears to be five-fold or less (narrow therapeutic window). Discontinue if signs/

symptoms of acute hepatitis develop.
 ⦁Metabolized primarily through non-CYP450 pathway; t ½: 4 hours (5–10 days for IM).
 ⦁No significant interactions other than avoiding use with opioids (see below).
 ⦁May precipitate acute withdrawal (pain, hypertension, sweating, agitation, and irritability) in opioid-using patients; 
ensure patient is opioid free for at least seven to 10 days prior to initiating.
 ⦁In naltrexone-treated patients requiring emergency pain management, consider alternatives to opioids (eg, regional 
analgesia, non-opioid analgesics, general anesthesia). If opioid therapy is required, patients should be under the 
direct care of a trained anesthesia provider.
 ⦁Efficacy of oral naltrexone in alcohol dependence (craving and relapse) is more convincing than in opioid

 ⦁Efficacy of oral naltrexone in alcohol dependence (craving and relapse) is more convincing than in opioid 
dependence. In opioid dependence, craving is not decreased but euphoric effects are blocked. Monthly IM 
naltrexone may be more effective than oral at maintaining abstinence in opioid dependence, without concern for 
daily medication adherence.
Fun Fact:
Methylnaltrexone, a closely related drug, is marketed as Relistor for the treatment of opioid-induced constipation.

Substance Use Disorder MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   237NICOTINE GUM/LOZENGE  (Nicorette, others) Fact Sheet [G]
First-line intervention for those patients who can stop smoking at initiation of therapy; nicotine in the form of gum or 
lozenge may act as a substitute oral activity, which may aid in behavior modification.
 ⦁Gum (G): 2 mg, 4 mg (over the counter).
 ⦁Lozenge (G): 2 mg, 4 mg (over the counter).
 ⦁For gum: Chew one piece of gum PRN urge to smoke, up to 24 pieces/day. Patients who smoke <25 cigarettes/day 
should start with the 2 mg strength; patients smoking ≥25 cigarettes/day should start with the 4 mg strength. Use 
the following 12-week dosing schedule: For weeks one through six, chew a piece of gum every one to two hours;

the following 12-week dosing schedule: For weeks one through six, chew a piece of gum every one to two hours; 
to increase chances of quitting, chew at least nine pieces/day. For weeks seven through nine, chew a piece of gum 
every two to four hours. For weeks 10–12, chew a piece of gum every four to eight hours. Patients should not chew 
more than one piece of gum at a time.
 ⦁For lozenges: Patients who smoke their first cigarette within 30 minutes of waking should use the 4 mg strength; 
otherwise the 2 mg strength is recommended. Use the following 12-week dosing schedule: For weeks one through 
six, use a lozenge every one to two hours; to increase chances of quitting, use at least nine lozenges/day. For weeks 
seven through nine, use a lozenge every two to four hours. For weeks 10–12, use a lozenge every four to eight 
hours. Maximum dose is five lozenges every six hours or 20 lozenges/day. Patients should not use more than one 
lozenge at a time.

 ⦁Patients should be advised to completely stop smoking upon initiation of therapy.
Cost:  $
Most common: Headache; indigestion; nausea; hiccups; tongue, mouth, and throat irritation or tingling; jaw ache 
(gum).
 ⦁Nicotinic-cholinergic receptor agonist.
 ⦁Metabolized primarily through liver as well as kidneys and lungs; t ½: 1–2 hours.
 ⦁Minimal risk for drug interactions. Successful cessation of smoking may increase serum levels of medications 
metabolized by CYP1A2 (eg, clozapine, olanzapine, theophylline), which is induced by hydrocarbons in smoke; 
nicotine itself has no effect.
 ⦁Chew gum slowly until it tingles (about 15 chews), then park gum between cheek and gum until tingle is gone

 ⦁Chew gum slowly until it tingles (about 15 chews), then park gum between cheek and gum until tingle is gone 
(about one minute); repeat until most of tingle is gone (~30 minutes).
 ⦁Lozenges should not be chewed or swallowed; allow them to dissolve slowly (~20–30 minutes).
 ⦁Heavy smokers should use higher-dose gum or lozenge and at least nine pieces/day to maximize chances of 
success. Do not use more than one piece at a time.
 ⦁Each 4 mg lozenge or gum results in 2 mg of absorbed nicotine, equivalent to two cigarettes.
Fun Fact:
Nicotine gum is available in a variety of flavors (fruit, mint, cinnamon, orange, cherry, and “original”).

238  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONNICOTINE INHALED  (Nicotrol Inhaler) Fact Sheet
Inhaled nicotine is expensive and can cause unpleasant side effects, both of which make this form of nicotine 
replacement therapy difficult to recommend as a first-line option since no single therapy has been shown to be more 
effective than another.
Cartridge: 4 mg delivered per 10 mg cartridge (prescription required).
 ⦁Use frequent continuous puffing for 20 minutes with each cartridge; 80 deep inhalations over 20 minutes releases 
4 mg nicotine, of which 2 mg is absorbed. Use six to 16 cartridges per day. Taper after six to 12 weeks of use by 
gradual dose reduction over six to 12 additional weeks.
Cost:  $$$$

⦁Patients should be advised to completely stop smoking upon initiation of therapy.
Cost:  $$$$
Most common: Headache, mouth/throat irritation, dyspepsia, cough, unpleasant taste, rhinitis, tearing, sneezing.
 ⦁Insert cartridge into inhaler and push hard until it pops into place. Replace mouthpiece and twist the top and 
bottom so that markings do not line up. Inhale deeply into the back of the throat or puff in short breaths. Nicotine

bottom so that markings do not line up. Inhale deeply into the back of the throat or puff in short breaths. Nicotine 
in cartridge is used up after about 20 minutes of active puffing.
 ⦁Do not eat or drink 15 minutes before or during use. To minimize coughing, puff lightly rather than inhaling into lungs.
 ⦁Local irritation in the mouth and throat may occur in as many as 40% of patients; coughing (32%) and rhinitis (23%) 
are also common. These effects are generally mild and occur less frequently with continued use. Use with caution in 
patients with bronchospastic disease due to potential airway irritation (other forms of nicotine replacement may be 
preferred).
 ⦁Higher ambient temperatures deliver more nicotine; lower temperatures deliver less.
 ⦁One cartridge delivers 80 puffs or about 2 mg of absorbed nicotine. Roughly 10 cartridges per day is equivalent to 
the nicotine of smoking one pack per day.
Fun Fact:

⦁One cartridge delivers 80 puffs or about 2 mg of absorbed nicotine. Roughly 10 cartridges per day is equivalent to 
Fun Fact:
A nicotine inhaler is not really a true inhaler; puffing deposits the nicotine into the mouth, and it is then absorbed in 
the same manner as the nicotine gum or lozenge preparations.

Substance Use Disorder MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   239NICOTINE NASAL SPRAY  (Nicotrol NS) Fact Sheet
The idea of nasal administration of nicotine is appealing in that it more closely approximates the time course of 
plasma nicotine levels observed after cigarette smoking than other dosage forms; however, the high cost and 
unpleasant side effects make this difficult to recommend as a first-line treatment, especially since no one form of 
nicotine replacement therapy has been shown to be more effective than another.
10 mL bottle: 10 mg/mL delivering 0.5 mg/spray in 200 sprays (prescription required).
 ⦁Use one or two sprays/hour as needed; do not exceed more than five doses (10 sprays) per hour. Max dose is 40 
doses/day (80 sprays). Each dose (two sprays) contains 1 mg of nicotine.

⦁Use one or two sprays/hour as needed; do not exceed more than five doses (10 sprays) per hour. Max dose is 40 
 ⦁After initial eight weeks of treatment, taper dose gradually over four to six weeks.
Cost:  $$$$
Most common: Headache, dyspepsia, rhinitis, nasal irritation, sneezing, coughing.

 ⦁Prime pump prior to first use. Blow nose gently prior to use. Tilt head back slightly, breathe through mouth, and 
spray once in each nostril. Do not sniff, swallow, or inhale through nose.
 ⦁Moderate to severe nasal irritation in 94% of patients in the first two days of use; severity decreases over time. Nasal 
congestion and transient changes in sense of smell and taste also reported. Avoid in patients with chronic nasal 
disorders (eg, allergy, rhinitis, nasal polyps, and sinusitis). Exacerbations of bronchospasm reported in patients with 
asthma.
 ⦁Heavy smokers may well use the maximum amount of 80 sprays/day, meaning they would need a new bottle every 
two to three days. This can be tremendously and prohibitively expensive.

asthma.
 ⦁Potential for abuse and dependence appears to be greater than with other nicotine replacement therapies.
Fun Fact:
In a published case report (Myrick H et al, Am J Psychiatry 2001;158(3):498), a 54-year-old man who could no longer 
afford his Nicotrol NS prescription found a commercial source for nicotine on the internet (sold as an insecticide). He 
purchased 25 g in a 1 g/mL solution for $30, diluted the nicotine solution with distilled water to 10 mg/mL, and then 
placed the solution into empty spray bottles.

240  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONNICOTINE PATCH  (Nicoderm CQ, others) Fact Sheet [G]
Nicotine patches are a first-line intervention in patients who are able to quit smoking at initiation of treatment and 
who are regular and constant smokers.
Transdermal patch (G): 7 mg, 14 mg, 21 mg/24 hour (over the counter).
 ⦁Patients smoking >10 cigarettes/day: Start with 21 mg/day for six weeks, then 14 mg/day for two weeks, then 
7 mg/day for two weeks. Patients smoking ≤10 cigarettes/day: Start with 14 mg/day for six weeks, then 7 mg/day 
for two weeks.
 ⦁Apply new patch every 24 hours (same time each day, usually after awakening) to non-hairy, clean, dry skin on 
the upper body or upper outer arm; each patch should be applied to a different site. Adjustment may be required

the upper body or upper outer arm; each patch should be applied to a different site. Adjustment may be required 
during initial treatment (move to higher dose if experiencing withdrawal symptoms, or lower dose if side effects are 
experienced). 
Cost:  $
Most common: Application site reactions (itching, burning, or redness), diarrhea, dyspepsia, abdominal pain.
 ⦁Metabolized primarily through liver as well as kidneys and lungs; t ½: 3–6 hours.

 ⦁Patch may be worn for 16 or 24 hours. If craving upon awakening, wear patch for 24 hours; if vivid dreams or sleep 
disruptions occur, wear patch for 16 hours, removing at bedtime.
 ⦁Do not cut patch; this causes rapid evaporation, making the patch useless.
 ⦁Up to 50% of patients will experience a local skin reaction, which is usually mild and self-limiting but may worsen 
with continued treatment. Local treatment with hydrocortisone cream 1% or triamcinolone cream 0.5% and rotating 
patch sites may help. In fewer than 5% of patients, such reactions require discontinuation.
Fun Facts:
Studies have found that smoking seems to provide short-term relief from symptoms of ulcerative colitis; recent data 
have suggested the use of nicotine patches in some patients with flare-ups of ulcerative colitis (not maintenance 
treatment).

Substance Use Disorder MedicationsCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   241VARENICLINE  (Chantix) Fact Sheet [G]
Varenicline is the most effective tobacco cessation medication. Psychiatric side effects are usually limited to insomnia 
or abnormal dreams, but more dramatic reactions are possible, though rare.
Tablets (G):  0.5 mg, 1 mg.
Start 0.5 mg QD for three days; ↑ to 0.5 mg BID for four days then ↑ to 1 mg BID for 11 weeks. Titrate slowly and take 
with food and a full glass of water to decrease GI upset. Start one week before target quit date; consider setting a quit 
date up to 35 days after starting varenicline (may improve likelihood of abstinence).
Cost:  $$$$
 ⦁Most common: Nausea, insomnia, headache, abnormal dreams, constipation, flatulence.

Cost:  $$$$
 ⦁Serious but rare: Warning for serious neuropsychiatric events (including depression, suicidal thoughts, suicide, 
psychosis, hostility), even in those without preexisting psychiatric disease, guidance was recently revised to indicate 
that risk is lower than previously suspected.
 ⦁Nicotine receptor partial agonist.
 ⦁Excreted mostly unchanged with minimal hepatic (non-CYP450) metabolism; t ½: 24 hours.
 ⦁Potential lowered tolerance to alcohol, with psychiatric reactions. H2 blockers, quinolones, and trimethoprim 
may increase varenicline levels. Successful cessation of smoking may alter pharmacokinetic properties of other 
medications (eg, clozapine, olanzapine, theophylline, warfarin, insulin).

 ⦁Dual mechanism of action: Partial agonist at nicotinic receptors, mimicking nicotine effects on the brain and 
reducing withdrawal symptoms; blocks nicotine from binding to these receptors, thereby decreasing the reinforcing 
effect of smoking.
 ⦁If patient successfully quits smoking after 12 weeks, may continue for another 12 weeks. If not successful in first 12 
weeks, then discontinue and reassess factors contributing to failure.
 ⦁Similar quit rates as bupropion at six months (25%), but higher quit rates compared to bupropion at one year if a 
second 12-week course of varenicline is used.
 ⦁Can be combined with bupropion; use with nicotine replacement therapies likely to lead to increased side effects, 
particularly nausea, headache, vomiting, and dizziness.
 ⦁Generic varenicline has been newly approved; look for a significant price drop in the months to come.
Fun Fact:

Fun Fact:
The show Saturday Night Live aired a parody of a Chantix commercial suggesting that side effects of quitting smoking 
could be dangerous (it’s on YouTube).

AppendicesCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   243
Appendices
APPENDIX A: DRUG INTERACTIONS IN PSYCHIATRY
In this appendix you’ll find three tables related to drug interactions. For an in-depth discussion of the complexities 
of drug interactions, please read our new Carlat Guide , Prescribing Psychotropics: From Drug Interactions to 
Pharmacogenetics . See www.thecarlatreport.com/prescribing  for more information.
Generally, when pressed for time, most clinicians will use one of the following online drug interaction checkers: 
Free
 ⦁Medscape ( https://reference.medscape.com/drug-interactionchecker )
 ⦁www.epocrates.com  (you’ll need to register first)
 ⦁www.drugs.com/drug_interactions.html
Paid
 ⦁Lexi-Interact ( https://www.wolterskluwer.com/en/solutions/lexicomp ), $119 for one-year subscription
However, it’s helpful to review drug interaction tables occasionally because they will give you context and allow

However, it’s helpful to review drug interaction tables occasionally because they will give you context and allow 
you to begin to memorize which medications are most likely to cause troublesome interactions. The majority of 
interactions in psychiatry will not result in a serious outcome. Many interactions, however, may result in decreased 
efficacy or increased adverse effects, and these can be easily avoided.
To understand drug-drug interactions, you’ll need to refamiliarize yourself with some basic terms. Drugs are 
substrates of specific enzymes (the medication relies on specific enzymatic pathway(s) for metabolism). An inhibitor 
is a drug that binds more tightly to an enzyme than the usual substrate and prevents the enzyme from doing its job; 
as a result, the substrate for that enzyme gets stuck in a game of musical chairs as it scurries around looking for a 
free enzyme system to break it down. Since this drug is not getting metabolized as quickly as it otherwise would (the

free enzyme system to break it down. Since this drug is not getting metabolized as quickly as it otherwise would (the 
inhibitor is preventing it from doing so), its serum levels become higher than expected. On the other hand, inducers 
stimulate the production of extra enzymes. With more enzymes around, the substrate for that enzyme is broken down 
more rapidly, leading to lower serum drug levels.
Another important concern with drug interactions is timing. Inhibition  happens quickly. It can occur with the 
first dose of a medication and can subside quickly when an inhibitor is discontinued. How long it takes to subside 
depends on the inhibitor’s half-life. Generally, the inhibition will stop after five half-lives of the inhibitor drug. On the 
other hand, for induction  to occur, the body has to synthesize more CYP450 enzymes, and this can take up to four 
weeks. This accounts for the delayed “auto-induction” of carbamazepine. Likewise, for induction to subside, these

weeks. This accounts for the delayed “auto-induction” of carbamazepine. Likewise, for induction to subside, these 
extra enzymes need to be broken down, a process that could also take several weeks. As a general rule of thumb, 
any drug prescribed with its inhibitor should be started at half the usual dose and titrated more slowly. Conversely, 
a drug prescribed with its inducer may need to be dosed higher after the few weeks it takes for induction to occur. 
One exception to the rule of inhibitors increasing substrate levels is when the substrate is a prodrug. Tamoxifen, 
hydrocodone, and tramadol are prodrugs that rely on CYP450 2D6 to be converted into an active metabolite. In the 
presence of a potent inhibitor like fluoxetine or paroxetine, patients may see a drop in therapeutic effects rather than 
increased effects.
Practical Tips for Quickly Identifying Significant Drug Interactions

 ⦁Identify the 10 drugs that you most commonly prescribe and memorize the major drug interactions for each one.
 ⦁Antidepressants, antipsychotics, antibiotics, antiretrovirals, and older anticonvulsants have a high likelihood of 
significant drug interactions—so be particularly vigilant if your patient is taking any of these.
 ⦁Recognize the drugs with a narrow therapeutic window, ie, drugs for which the toxic dose is not much higher than 
the therapeutic dose. Commonly used drugs with narrow therapeutic windows include lithium, carbamazepine 
(Tegretol), warfarin (Coumadin), digoxin (Lanoxin), phenytoin (Dilantin), and phenobarbital.
 ⦁Recognize drugs that cause serious side effects and outcomes if blood levels are significantly increased or decreased 
(eg, oral contraceptives, lamotrigine, clozapine, tricyclic antidepressants, warfarin).

 ⦁Drugs with long half-lives, such as diazepam (Valium) or aripiprazole (Abilify), can be particularly troublesome when 
involved in drug interactions, because metabolic inhibitors—or hepatic dysfunction—can make them ultra-long 
lasting. Be cautious with any new or rarely prescribed drugs: Neither you nor anybody else has had much experience 
with them, and unreported drug interactions can appear.
 ⦁The risk of drug interactions can increase exponentially as the number of drugs increases. Setting a threshold to 
check for interactions is helpful (eg, any patient on three or more drugs).

244  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONAppendix Table A1: CYP450 Drug Interactions for Some Common Psychiatric Medications
CYP450 Family Inducers Inhibitors Substrates (“Victim” Drugs) Symptoms When Induced Symptoms When Inhibited
1A2 Armodafinil
Carbamazepine 
Cigarette smoke
Modafinil
St. John’s wortFluvoxamine
MelatoninAsenapine Loss of efficacy (psychosis) Insomnia/EPS
Caffeine Withdrawal headaches Jitteriness
Clozapine Loss of efficacy (psychosis) Seizures/sedation/anticholinergic effects
Duloxetine Loss of efficacy (depression) Increased blood pressure
Fluvoxamine Loss of efficacy (depression/OCD) GI/sedation
Melatonin Loss of efficacy (insomnia) Sedation
Mirtazapine Loss of efficacy (depression) Sedation
Olanzapine Loss of efficacy (psychosis) Sedation
Ramelteon Loss of efficacy (insomnia) Sedation
Ropinirole Loss of efficacy (RLS, Parkinson’s) Insomnia/anxiety/compulsive behavior
Thiothixene Loss of efficacy (psychosis) Sedation/EPS

Trifluoperazine Loss of efficacy (psychosis) Sedation/EPS
2B6 Carbamazepine
PhenobarbitalBupropion Loss of efficacy (depression) N/A
Methadone Opioid withdrawal N/A
Selegiline Loss of efficacy (depression) N/A
2C9 Carbamazepine 
St. John’s wortFluoxetine
Fluvoxamine Methadone Opioid withdrawal CNS and respiratory depression
2C19 Carbamazepine
Phenytoin Armodafinil
Modafinil
OxcarbazepineBarbiturates Loss of efficacy (insomnia/anxiety/seizures) Sedation/barb intoxication
Citalopram Loss of efficacy (depression/anxiety) GI effects
Diazepam Loss of efficacy (insomnia/anxiety/seizures) Sedation/BZD intoxication
Doxepin Loss of efficacy (depression/anxiety/insomnia) Seizures/arrhythmia/anticholinergic effects
Escitalopram Loss of efficacy (depression/anxiety) GI effects

Methadone Opioid withdrawal CNS and respiratory depression
Sertraline Loss of efficacy (depression/anxiety) GI effects
( ) indicates less potent inhibitory effect, therefore generally less of a risk except at higher doses

AppendicesCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   245CYP450 Family Inducers Inhibitors Substrates (“Victim” Drugs) Symptoms When Induced Symptoms When Inhibited
2D6 Not inducible Asenapine
Bupropion
Methadone
Venlafaxine Amphetamine N/A Insomnia/decreased appetite
Aripiprazole N/A Akathisia/sedation
Atomoxetine N/A GI/constipation
Brexpiprazole N/A Akathisia/sedation
Chlorpromazine N/A Seizures/sedation/anticholinergic effects
Clonidine N/A Hypotension/dizziness/sedation
Clozapine N/A Seizures/sedation/anticholinergic effects
Codeine/hydrocodone N/A Less/no analgesia (not converted to morphine)
Deutetrabenazine N/A Sedation/QT prolongation
Dextroamphetamine N/A Insomnia/decreased appetite
Dextromethorphan N/A Difficulty breathing, dizziness, drowsiness, anxiety, or confusion
Diphenhydramine N/A Sedation/anticholinergic
Donepezil N/A GI effects
Doxepin N/A Sedation/anticholinergic

Doxylamine N/A Sedation/anticholinergic
Duloxetine N/A Increased BP
Fluoxetine N/A GI effects
Fluphenazine N/A EPS
Fluvoxamine N/A GI effects/sedation
Galantamine N/A GI effects
Haloperidol N/A EPS
Iloperidone N/A Tachycardia/hypotension/stiffness
Lisdexamfetamine (prodrug 
of dextroamphetamine)N/A Insomnia/decreased appetite
Lofexidine N/A Hypotension/dizziness/sedation
Loxapine N/A EPS/sedation
Methamphetamine N/A Insomnia/decreased appetite
Mirtazapine N/A Somnolence
Mixed amphetamine salts N/A Insomnia/decreased appetite
Paroxetine N/A GI effects/anticholinergic/sedation
Perphenazine N/A EPS/sedation
Pitolisant N/A Insomnia/anxiety
Propranolol N/A Decreased BP/pulse

246  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONCYP450 Family Inducers Inhibitors Substrates (“Victim” Drugs) Symptoms When Induced Symptoms When Inhibited
Bupropion
Methadone
VenlafaxineRisperidone N/A EPS/orthostasis
Thioridazine N/A Seizures/sedation/anticholinergic effects/QT prolongation
Trazodone N/A Sedation
Tricyclics N/A Seizures/arrhythmia/anticholinergic
Valbenazine N/A Sedation/QT prolongation
Venlafaxine N/A GI effects
Vortioxetine N/A GI effects
3A4 Armodafinil
Modafinil
Oxcarbazepine 
Grapefruit juice
NefazodoneAlprazolam Loss of efficacy (insomnia/anxiety/seizures) Sedation/BZD intoxication
Aripiprazole Loss of efficacy (psychosis) Akathisia/sedation
Armodafinil Loss of efficacy (narcolepsy) Insomnia/increased pulse
Avanafil Loss of efficacy (sexual dysfunction) Headache/flushing/prolonged erection

Brexpiprazole Loss of efficacy (psychosis) Akathisia/sedation
Buprenorphine Opioid withdrawal CNS and respiratory depression
Buspirone Loss of efficacy (anxiety) GI effects/jitteriness
Carbamazepine Loss of efficacy/seizures Sedation/arrhythmia
Cariprazine Loss of efficacy (psychosis) Akathisia/sedation
Clonazepam Loss of efficacy (insomnia/anxiety/seizures) Sedation/BZD intoxication
Eszopiclone Loss of efficacy (insomnia) Sedation/confusion
Flibanserin Loss of efficacy (sexual desire) Nausea/dizziness/sedation

Flurazepam Loss of efficacy (insomnia) Sedation/BZD intoxication
Galantamine Loss of efficacy (dementia) GI effects
Guanfacine Loss of efficacy (ADHD) Sedation/dry mouth/dizziness
Iloperidone Loss of efficacy (psychosis) Sedation/dizziness
Lemborexant Loss of efficacy (insomnia) Sedation/confusion
Levomilnacipran Loss of efficacy (depression) GI effects
Loxapine Loss of efficacy (psychosis) EPS/sedation
Lurasidone Loss of efficacy (psychosis) Sedation/akathisia
Mirtazapine Loss of efficacy (depression/insomnia) Somnolence

AppendicesCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   247CYP450 Family Inducers Inhibitors Substrates (“Victim” Drugs) Symptoms When Induced Symptoms When Inhibited
Modafinil
NefazodoneModafinil Loss of efficacy (narcolepsy) Insomnia/increased pulse
Nefazodone Loss of efficacy (depression) Sedation/orthostasis
Oral contraceptives Loss of efficacy (pregnancy) GI effects
Pimavanserin Loss of efficacy (psychosis) Nausea/confusion
Pitolisant Loss of efficacy (EDS) Insomnia/anxiety
Quetiapine Loss of efficacy (psychosis) Sedation/orthostasis
Sildenafil Loss of efficacy (sexual dysfunction) Headache/flushing/prolonged erection
Suvorexant Loss of efficacy (insomnia) Sedation/confusion
Tadalafil Loss of efficacy (sexual dysfunction) Headache/flushing/prolonged erection
Trazodone Loss of efficacy (insomnia) Sedation/orthostasis

Triazolam Loss of efficacy (insomnia) Sedation/BZD intoxication
Tricyclics Loss of efficacy (depression/anxiety) Seizures/arrhythmia/anticholinergic
Vardenafil Loss of efficacy (sexual dysfunction) Headache/flushing/prolonged erection
Vilazodone Loss of efficacy (depression/anxiety) GI effects
Zaleplon Loss of efficacy (insomnia) Sedation/confusion
Ziprasidone Loss of efficacy (psychosis) Sedation/akathisia
Zolpidem Loss of efficacy (insomnia) Sedation/confusion

248  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONAppendix Table A2:  Most Common Clinically Significant Drug Interactions in Psychiatry
Clinical Consequence Medications Most Commonly Contributing Comments
Decreased efficacy of 
psychiatric medicationsCarbamazepine, St. John’s wort, cigarette smoking strongly 
induce metabolism and decrease serum levels of many 
psychotropics (see Table A1 for details)Smoking may reduce olanzapine, clozapine 
levels; carbamazepine can reduce levels of many 
medications 
opioidsPotent 2D6 inhibitors (paroxetine, fluoxetine, duloxetine, 
bupropion) prevent conversion of certain opioids (codeine, 
hydrocodone, oxycodone) to active metabolites, thereby 
decreasing pain reliefUse alternative antidepressants (eg, sertraline, 
citalopram, escitalopram)
Decreased efficacy of oral 
contraceptive pills (OCPs)Carbamazepine, St. John’s wort, cigarette smoking strongly

contraceptive pills (OCPs)Carbamazepine, St. John’s wort, cigarette smoking strongly 
induce metabolism and decrease serum levels of OCPsAvoid these meds in women taking OCPs
Increased side effects 
or toxicity of psychiatric 
medicationsThe most common and potent CYP450 inhibitors are 
paroxetine, fluoxetine, duloxetine, bupropion, valproic acid, 
asenapine, and grapefruit juice—all may lead to increased 
substrate levels and increased side effects or toxicity (see Table 
A1 for interaction details)Adjust dose of substrate or use alternative 
Serotonin syndrome High doses or combinations of the following: SSRIs, SNRIs, 
TCAs, MAOIs, buspirone, dextromethorphan, lithium, 
tramadol, trazodoneCaution patients to report new sudden onset 
of fever, agitation, tremor, sweating, diarrhea; 
discontinue offending agents and provide 
supportive care
QT prolongation Monotherapy or combined therapy with the following:

QT prolongation Monotherapy or combined therapy with the following: 
ziprasidone, thioridazine, TCAs, methadone, and certain 
cardiac meds and antibiotics (amiodarone, ciprofloxacin, 
clarithromycin, erythromycin, ketoconazole, quinidine)May lead to potentially fatal arrhythmias; 
monitor ECG and electrolytes and use alternative 
medications in patients with borderline or increased 
QT interval
Increased risk for bleeding Serotonergic antidepressants (SSRIs, SNRIs) especially when 
combined with anticoagulants (warfarin), antiplatelets 
(aspirin), or NSAIDsMay lead to bruising or minor bleeding (nosebleed, 
gum bleed); GI bleeds and more severe bleeding 
also rarely reported; use alternative in patients at 
highest risk, such as the elderly
Lowered seizure threshold Bupropion, clozapine Use with caution in patients with a history of

Lowered seizure threshold Bupropion, clozapine Use with caution in patients with a history of 
seizures, electrolyte disturbances, or head trauma; 
consider concomitant antiepileptic for seizure 
Lithium toxicity Lithium used in combination with NSAIDs, ACE inhibitors, 
angiotensin II receptor blockers, diuretics (especially thiazides)Use alternative agents or monitor lithium levels 
closely and adjust dosing
Anticholinergic delirium Anticholinergics (benztropine, trihexyphenidyl), 
antihistamines (diphenhydramine, doxylamine), low-potency 
first-generation antipsychotics (chlorpromazine), olanzapine, 
clozapine, TCAs, others (oxybutynin)High anticholinergic burden may lead to confusion 
and delirium, particularly in older patients; minimize 
use or use alternative medications

AppendicesCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   249What Causes the MAOI-Food Interaction?
Tyramine is an amino acid naturally found in our bodies and in some foods. It’s responsible for norepinephrine 
release, which can lead to elevated blood pressure. Normally, the monoamine oxidase (MAO) enzyme breaks down 
norepinephrine, keeping blood pressure in check. Blocking MAO-A in the GI tract with an MAOI, combined with 
eating foods high in tyramine, can lead to a “cheese reaction” or hypertensive crisis. Patients taking any MAOI (with 
the exception of the lowest dose of the selegiline patch) should adhere to this diet while they are taking the MAOI 
and for two weeks after stopping the MAOI (that’s the time it takes to regenerate new MAO enzymes after irreversible 
inhibition by the MAOI).
Appendix Table A3: MAOI Dietary and Medication Restrictions
Food or  
Drink CategoryAvoid Minimize Intake1Allowed2
Meat, poultry,

Food or  
Meat, poultry, 
fish• Aged, air dried, fermented, smoked, pickled, or 
cured meats, poultry, fish (cacciatore), bacon, aged 
or dried sausage, salami, mortadella, corned beef, 
pastrami, pickled herring, lox, smoked salmon, 
smoked trout, shrimp paste, liverwurst, meat 
extracts (flavor cubes, bouillon)
• Spoiled or improperly stored meat, poultry, fish, or 
animal livers (discolored, malodorous, or moldy)• Processed meats, cooked ham, hot 
dogs, pepperoni, bologna
• Properly stored smoked fish• Fresh, fresh frozen, or fresh 
processed (not aged or 
smoked) meat, poultry, fish
• Fresh breakfast sausage
• Fresh gravy
Dairy, eggs, 
cheeseAged cheeses: blue/bleu, camembert, cheddar, 
gorgonzola, gouda, gruyere, provolone, Roquefort, 
Stilton, Swiss (fermentation holes, strong smells, 
salty or biting taste)• Cheeses: Parmesan, Romano
• Soy milk

• Soy milk
• (limit these to 1 half-cup serving)
• 1–2 slices of pizza from large chain 
commercial outlets (generally made 
with low-tyramine cheese); avoid 
larger quantities, extra cheese, or 
pizzas containing aged cheese• Cheeses: mozzarella, American, 
ricotta, cottage, cream, farmer, 
or pot
• Fresh pasteurized milk
• Pasteurized cream
• Yogurt
• Sour cream
• Ice cream
• Pudding
• Butter
• Eggs
Fruit • Overly ripened banana, banana peel
• Overly ripened avocado
• Dried fruit• Avocado (not over-ripened)
• Canned figs
• RaspberriesFresh, frozen, or canned and 
properly stored fruits and fruit 
juices
Vegetables • Broad bean pods (fava beans, Italian green beans)
• Soy beans
• Bean pastes
• Edamame beans
• Kimchee (kimchi)
• Snow peasChili peppers • Fresh, frozen, canned, or dried 
and properly stored vegetables,

• Soy beans
and properly stored vegetables, 
leafy salad greens, lentils, beans 
(except fava and soy)
• Veggie burgers containing no 
soy product
Soy Soy products (soy sauce, tofu, tempeh) Soy milk (1 half-cup serving)
Beverages • Tap (draft) beer, non-pasteurized beer, Korean 
beer (including non-alcoholic)
• Vermouth• Caffeine-containing drinks
• Clear alcoholic spirits (gin, vodka, 
rum)
• Red or white wine (no more than 
two 4-oz servings per day)
• Bottled or canned beer, including 
non-alcoholic (no more than two 
12-oz servings per day)Decaffeinated beverages (coffee, 
tea)
Breads, cereal, 
crackers• Sourdough bread
• Crackers and breads that contain aged cheeseCommercial yeast breads, hot 
and cold cereals, most crackers 
(containing no aged cheese)
Condiments and 
miscellaneous• Concentrated yeast extract (marmite, vegemite)

• Soy products (soy sauce, tofu, teriyaki, soy paste, 
Thai or Vietnamese fish sauce)
• SauerkrautChocolate (limit to 2 oz, or 4 oz of 
chocolate-containing dessert)• Brewer’s yeast or baker’s yeast
• Monosodium glutamate (MSG)
• Ketchup, mustard, mayonnaise, 
salt, spices, herbs
• Non-cheese salad dressings
• Worcestershire sauce
1 “Minimize Intake” items should be eaten only occasionally; no more than one serving (½ cup) of one to three of these per day.
2 “Allowed” items become “Avoid” items if spoiled or improperly stored. No leftover, improperly stored, handled, or spoiled foods of any type should be consumed. Purchase 
and consume only fresh meats, poultry, and fish that are properly wrapped and stored under refrigeration and eaten the same day or frozen right away. Fresh produce

and consume only fresh meats, poultry, and fish that are properly wrapped and stored under refrigeration and eaten the same day or frozen right away. Fresh produce 
should be consumed within 48 hours of purchase and not eaten if overripe.

250  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONFood or  
Pain 
medicationsOpioids including meperidine (Demerol), 
propoxyphene (Darvon), tramadol (Ultram), 
fentanyl, methadoneAcetaminophen
Ibuprofen
Cold/allergy 
medicationsAny combination product with a “-D” for 
decongestant (eg, Zyrtec-D)
Dextromethorphan (Delsym)
Pseudoephedrine (Sudafed)
Decongestant nasal spraysMenthol lozenges
Plain nasal saline spray
Robitussin alone (guaifenesin)
Cetirizine (Zyrtec), fexofenadine 
(Allegra), loratadine (Claritin) 
without the “-D” for decongestant
Antidepressants Avoid all unless prescribed by doctor who has 
experience prescribing MAOIs; includes buspirone, 
OTC antidepressants (St. John’s wort, SAMe)
Stimulants Avoid all use including prescription, illicit stimulants 
(methamphetamine, cocaine, ecstasy), or OTC diet 
pills (may contain stimulants)

 ⦁Flockhart DA. Dietary restrictions and drug interactions with monoamine oxidase inhibitors: an update. J Clin 
Psychiatry  2012;73 Suppl 1:17–24. doi:10.4088/JCP .11096su1c.03.

 ⦁Gardner DM et al. The making of a user friendly MAOI diet. J Clin Psychiatry  1996;57(3):99–104.
 ⦁Hirsch M & Birnbaum RJ. Monoamine oxidase inhibitors (MAOIs) for treating depressed adults. UpToDate  2018.

AppendicesCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   251APPENDIX B: PSYCHIATRIC MEDICATIONS IN PREGNANCY AND LACTATION
Determining the risk of medications in pregnancy used to be a simple matter of looking up a drug’s pregnancy 
categorization in the PDR . This went from category “A, ” the lowest risk, to “X, ” contraindicated in pregnancy. But this 
ABCDX system provided very little practical or clinically useful information. In 2014, the FDA came up with a new 
system of labeling, which requires descriptive subsections on different aspects of pregnancy and lactation, and omits 
the letter categories—though you’ll still see the old system in use for drugs approved before 2015.
Pregnancy presents a unique problem to the psychiatrist. Contrary to what many may think or assume, pregnancy 
does not protect a woman from an acute episode, a recurrence, or an exacerbation of psychiatric illness. Withholding

does not protect a woman from an acute episode, a recurrence, or an exacerbation of psychiatric illness. Withholding 
medications during pregnancy can sometimes be an appropriate option, but this is generally not recommended. And 
since all psychotropic medications cross the placenta to at least some degree, their potential effects on the fetus, on 
labor and delivery, and on the neonate must be considered and balanced with the risk of not treating the mother with 
medication (see our July/August 2016 double issue of TCPR  for an overview). A similar risk-benefit assessment must be 
considered in the case of a mother who wishes to breastfeed her child, as psychotropic medications are excreted into 
breast milk to varying degrees.
One of us (TP) is a pharmacist specializing in psychopharmacology who is commonly consulted by psychiatrists 
to provide updated information on the safety of medications in pregnancy and breastfeeding. It is a difficult task,

to provide updated information on the safety of medications in pregnancy and breastfeeding. It is a difficult task, 
because the quantity and quality of data vary greatly. The accompanying table was developed by pulling together 
a variety of sources, including isolated case reports, case series, birth registries, retrospective surveys, prospective 
comparative cohort studies, case control studies, and meta-analyses. Making judgments about which medication 
to use—or not use—in a pregnant or lactating woman is a delicate balancing act, involving an assessment of the 
severity of the underlying illness versus the uncertainties inherent in prescribing medications when the available data 
are limited.
In reading the table, keep the following in mind: In the general US population, the baseline rate of major 
malformations is between 1% and 4%, depending on the population studied and the definitions of “malformations”

malformations is between 1% and 4%, depending on the population studied and the definitions of “malformations” 
used. If treatment is necessary, monotherapy with the lowest effective dose and for the shortest duration is 
prudent. Safety data are generally more robust with older agents, and for that reason older agents—with a few key 
exceptions—are more preferable than newer drugs with less established safety profiles.
Almost all drugs enter breast milk. The exposure to the infant is described as a percentage of the maternal dose—that 
is, how much of the weight-adjusted maternal dose is actually excreted into the breast milk. When less than 10% of a 
mother’s dose of medication is excreted into the breast milk, it is generally considered compatible with breastfeeding 
(with some exceptions) since these low serum levels are unlikely to lead to adverse effects in the infant.
While the table summarizes the current knowledge about psychotropic medication in pregnancy and lactation,

While the table summarizes the current knowledge about psychotropic medication in pregnancy and lactation, 
information in this area is constantly evolving. If you regularly treat women of childbearing age, we suggest that you 
keep up with new data, consult with experts, and use resources such as: 
 ⦁Organization of Teratology Information Specialists at www.mothertobaby.org  or 866-626-6847
 ⦁LactMed peer-reviewed database of the National Library of Medicine, updated monthly at https://www.ncbi.nlm.
nih.gov/books/NBK501922
 ⦁MGH Center for Women’s Mental Health at www.womensmentalhealth.org
 ⦁The CDC’s wide range of offerings at https://www.cdc.gov/pregnancy/meds  
And, if you don’t mind paying a fee (or if you are a trainee and have free access), you can check out www.reprotox.
org, an online database of summaries. Another source of information can be the drug labeling, which, as of 2015, is

org, an online database of summaries. Another source of information can be the drug labeling, which, as of 2015, is 
more detailed than in the past. These resources, along with our table, provide information based upon the available 
evidence (or lack thereof), but the ultimate clinical decision comes down to careful and individualized consideration 
between the physician and the patient and her family.
Additional References
 ⦁Besag FM. ADHD treatment and pregnancy. Drug Saf 2014;37(6):397–408.
 ⦁Chisolm MS et al. Management of psychotropic drugs during pregnancy. BMJ 2016;352:h5918.
 ⦁Khan SJ et al. Bipolar disorder in pregnancy and postpartum: Principles of management. Curr Psychiatry Rep 
2016;18(2):13.
 ⦁McLafferty LP et al. Guidelines for the management of pregnant women with substance use disorders. 
Psychosomatics 2016;57(2):115–130.
 ⦁Muzik M et al. Use of antidepressants during pregnancy?: What to consider when weighing treatment with

 ⦁Muzik M et al. Use of antidepressants during pregnancy?: What to consider when weighing treatment with 
antidepressants against untreated depression. Matern Child Health J  2016;20(11):2268–2279.
 ⦁Ornoy A et al. Antidepressant, antipsychotics, and mood stabilizers in pregnancy: What do we know and how should 
we treat pregnant women with depression? Birth Defects Res  2017:109(12):933–956.

252  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION ⦁Oyebode F et al. Psychotropics in pregnancy: Safety and other considerations. Pharmacol Ther  2012;135(1):71–77.
 ⦁Payne JL. Psychopharmacology in pregnancy and breastfeeding. Med Clin North Am  2019;103(4):629–650.
 ⦁Rowe H et al. Maternal medication, drug use, and breastfeeding. Child Adolesc Psychiatr Clin N Am  2015;24(1):1–20.
 ⦁Sachs HC et al. The transfer of drugs and therapeutics into human breast milk: An update on selected topics. 
Pediatrics  2013;132(3):e796–e809.
 ⦁Vigod S et al. Depression in pregnancy. BMJ 2016;352:i547.

AppendicesCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   253 Appendix Table B: Psychiatric Medications in Pregnancy and Lactation
Medication Pregnancy Breastfeeding Recommendations
Anxiolytics/Hypnotics
(various agents)Possible increased incidence of cleft lip or palate (with 
first trimester exposure); floppy infant syndrome (with 
exposure just before delivery); neonatal withdrawal 
syndrome; lower Apgar scoresExcretion less than 10%. Excessive sedation 
in infant, lethargy with consequent feeding 
difficulty and weight loss reported.• Try to avoid in first trimester and late in pregnancy (although 
intermittent use less likely to induce withdrawal symptoms in neonate)
• Lorazepam (Ativan) may be best in class to use due to lack of active 
metabolites and relatively shorter half-life
• Monitor sedation in breastfed infants; use of shorter-acting agents 
preferred
Buspirone

preferred
Buspirone
(BuSpar)Minimal data; difficult to determine risks Low to undetectable infant levels reported • Avoid in pregnancy due to limited data
• Likely safe in breastfeeding
Diphenhydramine 
(Benadryl)Fairly consistent data show lack of associated 
malformationsLarger doses or more prolonged use may cause 
adverse effects in the infant• Considered to be the safest hypnotic in pregnancy and breastfeeding
Non-benzodiazepines: 
Eszopiclone (Lunesta)
Zaleplon (Sonata)
Zolpidem (Ambien)No increased risk of malformations, but data fairly 
sparseRelatively low levels in breast milk. Most data 
are with zolpidem. Zolpidem is relatively 
hydrophilic and excreted rapidly; therefore, may 
be favored.• Reserve for second-line use due to paucity of data
• Zolpidem at low dose is the best option when non-benzos are needed
Suvorexant (Belsomra),

lemborexant (Dayvigo)No data No data • Use other agents with more data and longer record of experience
Trazodone Fewer data show no increased risk of malformations <1% excretion; not expected to cause adverse 
effects in breastfed infants• Probably safe in pregnancy and breastfeeding
(Tegretol)Rate of major malformation 2.2%–7.9%. Neural 
tube defects (0.5%–1%), craniofacial defects, 
cardiovascular malformations, and hypospadias 
reported.Relatively high levels in breast milk but with 
few adverse effects reported. Sedation, poor 
sucking, withdrawal reactions, and three cases 
of hepatic dysfunction have been reported.• Avoid if possible
• If use unavoidable, add high-dose (4 mg) folic acid supplementation
(Lamictal)Rate of major malformations 1%–5.6%. Increased risk

(Lamictal)Rate of major malformations 1%–5.6%. Increased risk 
of oral clefts (0.4%).Based on limited data, thought to be safe; 
however, infant exposure can be high and can 
vary widely (reports of 18%–60% of maternal 
concentrations); monitor infant. Relatively 
high infant exposure (22.7%); avoid or exercise 
caution.• Safest of the anticonvulsants in pregnancy, though good safety data 
are sparse. Serum levels should be monitored; levels usually decrease 
over course of pregnancy.
Lithium
(Eskalith, Lithobid)Rate of major malformations 4%–12%. Risk of 
Ebstein’s anomaly (cardiac problem) is lower than 
previously thought (0.05%–0.1%). Increased maternal 
risk of diabetes, polyhydramnios, thyroid dysfunction 
during pregnancy.30%–50% excretion; not recommended due to 
high risk of toxicity• Try to avoid, particularly in first trimester

• If first trimester use required, fetal echocardiogram recommended
• Check serum levels and thyroid function frequently during pregnancy, 
since changes in metabolism and total body water require dose 
adjustments, particularly in third trimester
• Avoid in breastfeeding if possible
Oxcarbazepine (Trileptal) Danish study showed no increased risk of major 
malformation. However, data are limited.Possible adverse effects in breastfed infants; 
monitor infant for drowsiness, adequate weight 
gain, and developmental milestones• Relatively safe, though more data are needed

254  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONMedication Pregnancy Breastfeeding Recommendations
Valproate
(Depakote)Most teratogenic of all mood stabilizers, with a 6.2%–
20.3% rate of congenital malformations, with neural 
tube defects most prominent. Teratogenic effects are 
dose-related with greatest risk at doses >1000 mg per 
day. Recently, exposure linked to autism.Relatively low excretion (0.68%); considered 
compatible with breastfeeding• Avoid in pregnancy unless absolutely required
• Safe in breastfeeding
First-generation No increased risk of malformations seen with 
high-potency agents. Small increased risk with low-
potency agents such as chlorpromazine (Thorazine). 
Transient extrapyramidal side effects; sedation; 
withdrawal symptoms in neonates.Relatively low excretion reported although 
little data available. Sedation and Parkinsonism

little data available. Sedation and Parkinsonism 
effects possible in breastfed infants.• Haloperidol (Haldol), fluphenazine (Prolixin) favored during pregnancy 
because of long history of safe use
• Relatively safe in breastfeeding
Second-generation Fewer data available, most showing no increased risk 
of malformations. Maternal hyperglycemia, impaired 
glucose tolerance, and weight gain may lead to 
maternal complications. Large-for-gestational-age 
infants reported. Floppy infant syndrome reported in 
clozapine exposure; monitor neutrophils in neonate 
for six months.Excretion low, usually <3%, with exception of 
clozapine (Clozaril), which is seen in relatively 
high concentrations in breast milk• Overall, relatively safe in pregnancy; not treating serious mental 
illness in pregnancy poses greater risk. Most data with risperidone, 
olanzapine, quetiapine.

• Avoid clozapine in breastfeeding if possible.
Bupropion
(Wellbutrin)No increased risk of malformation <1% excretion with no adverse outcomes 
reported• Safe for use in pregnancy and breastfeeding
(Cymbalta)Little data No published data, though exposure is low • Not enough data to recommend
Levomilnacipran 
(Fetzima)No data No published data • Not enough data to recommend
(Remeron)Sparse data, but one small study suggests no 
increased rate of major malformationLow excretion; compatible with breastfeeding • Likely safe in pregnancy and breastfeeding
SSRIs Controversial data regarding cardiovascular 
malformation with first trimester paroxetine (Paxil) 
exposure. Larger and more recent studies show no

exposure. Larger and more recent studies show no 
overall increased risk for malformations with SSRIs. 
Conflicting reports, with some showing decreased 
gestational age, low birth weight, poor neonatal 
adaptation, low Apgar scores (some of which could be 
due to underlying depression or anxiety). Conflicting 
reports regarding SSRI use in later pregnancy 
and persistent pulmonary hypertension (PPHN). 
Neonatal toxicity reported as transient jitteriness, 
tremulousness, and tachypnea. No problems detected 
in behavioral or cognitive development—greatest 
data with fluoxetine (Prozac).Relatively low excretion, varies by agent:
Citalopram (Celexa): 5%–10%
Fluoxetine: 3%–9%
Fluvoxamine (Luvox): <2%
Paroxetine: <4%
Sertraline (Zoloft): <2%• SSRIs are relatively safe in pregnancy; avoid paroxetine if possible
• Sertraline is safest in breastfeeding

• Avoid fluoxetine in breastfeeding due to long half-life and active 
metabolite

AppendicesCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   255Medication Pregnancy Breastfeeding Recommendations
Tricyclics Relatively large database; recent meta-analysis of 
300,000 live births revealed no increased risk of 
malformations. Neonatal anticholinergic effects. 
Transient neonatal withdrawal symptoms reported.<1%–5% excretion; appear relatively safe 
during breastfeeding, with possible exception 
of doxepin• Safe in pregnancy; desipramine and nortriptyline preferred due to 
lower anticholinergic and orthostatic hypotension risks
• Relatively safe in breastfeeding; monitor infant for sedation
Venlafaxine (Effexor)/
desvenlafaxine
(Pristiq)Earlier data regarding major malformations 
reassuring, but one more recent study suggested a 
possible association with birth defects; additional 
studies needed. Increased maternal blood pressure 
may be a concern during pregnancy, particularly at 
higher doses.2%–9.2% excretion; no adverse outcomes

higher doses.2%–9.2% excretion; no adverse outcomes 
reported• Less recommended than other antidepressants
(Viibryd)No data No published data • Not enough data to recommend
(Trintellix)No data No published data • Not enough data to recommend
Amphetamines and 
methylphenidatesNo apparent congenital malformations; may constrict 
blood flow to placenta, which reduces oxygen 
flow to developing fetus. May cause premature 
delivery, small for gestational age and low-birth-
weight babies; however, data inconclusive. Neonatal 
withdrawal possible.0.2% excreted into breast milk; adverse effects 
usually not observed• Not recommended in pregnancy due to possibility of vasoconstriction 
and ability to disrupt blood flow to the fetus

256  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONAPPENDIX C: CLASSIFICATIONS OF CONTROLLED SUBSTANCES
In 1970, under the Controlled Substances Act, the FDA created classification schedules that organize drugs into 
groups based on their risk of abuse or harm. There are five classifications of controlled substances (Schedule I, II, III, IV, 
and V), and drugs with the highest risk-to-benefit ratio are considered Schedule I drugs. Most drugs used in psychiatry 
are not scheduled at all (antidepressants, antipsychotics, etc). Some of us get confused about whether the most 
restricted drugs are Schedule I or V. Here’s a mnemonic: The number 1 looks like a needle, and a needle is used to 
inject heroin—which is the prototypical Schedule I drug. The DEA’s more comprehensive and regularly updated listing 
can be found here: http://goo.gl/Mo6KEQ
Prescription drug monitoring programs (PDMPs) are searchable databases that can help prescribers identify

Prescription drug monitoring programs (PDMPs) are searchable databases that can help prescribers identify 
potential abuse or diversion of controlled substances in individual patients. If you prescribe controlled substances 
like benzodiazepines and stimulants, it’s a good idea to learn about your state’s PDMP laws, consider your search 
results in the context of all available information, and watch for regulatory changes over the next few years. To find 
your state’s program, check with the PDMP Training and Technical Assistance Center ( www.pdmpassist.org/content/
state-pdmp-websites ).
Appendix Table C:  Classifications of Controlled Substances
Schedule Description Prescribing Implications Some Examples
I No accepted medical use, 
high potential for abuse, 
illegal to possess or useCan’t be prescribed at all (with the exception of 
medical marijuana in some states)• Heroin, LSD, ecstasy, and others

• Marijuana (though legalized in some states, it is still 
illegal at the federal level)
II High potential for abuse, 
but legal for medical useCan be prescribed only 1 month at a time, cannot 
be refilled, cannot be called in, and patient must 
give pharmacy a paper script (unless you use an 
e-prescribing program that is certified by DEA to 
allow prescribing of controlled substances)• All psychostimulants, such as amphetamine and 
• Opiates that are especially potent, such as oxycodone, 
fentanyl, and others
• Vicodin (hydrocodone and acetaminophen) was 
recently reclassified from Schedule III to Schedule II
III Lower potential for abuse 
than Schedule I or II, but 
still pretty abusableCan be refilled up to 5 times (no more than 6

still pretty abusableCan be refilled up to 5 times (no more than 6 
months), can be called in• Anabolic steroids
• Barbiturates
• Dronabinol (Marinol)
• Esketamine (Spravato)
• Ketamine
• Suboxone (buprenorphine/naloxone)
• Xyrem (sodium oxybate)
• Xywav (mixed-salts oxybate)
IV Lower potential for abuse 
than Schedule IIICan be refilled up to 5 times (no more than 6 
months), can be called in• All benzodiazepines (eg, clonazepam, lorazepam, etc)
• Carisoprodol (Soma)
• Lorcaserin (Belviq), an anti-obesity drug
• Tramadol (Ultram)
• Various hypnotics, like lemborexant (Dayvigo), 
suvorexant (Belsomra), zaleplon, zolpidem 
• Wake-promoting agents, like modafinil and 
armodafinil and solriamfetol (Sunosi)
V Lowest potential for 
abuseCan be refilled as many times as prescriber 
chooses (eg, for 1 year or more), can be called in• Antidiarrheal Lomotil (diphenoxylate/atropine)

• Cough preparations with small amounts of codeine, 
such as Robitussin AC
• Pregabalin (Lyrica)
An updated and more complete list of the schedules is published annually in Title 21 Code of Federal Regulations  and can be found here: www.deadiversion.usdoj.gov/
schedules/orangebook/c_cs_alpha.pdf

AppendicesCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   257APPENDIX D: LAB MONITORING FOR PSYCHIATRIC MEDICATIONS
This is a short and sweet table listing the medications that most psychiatrists would agree require lab monitoring. Our 
recommendations are quite abbreviated, and we haven’t spelled out whether you should order labs before or after 
starting the medications, nor how you should do follow-up monitoring. There’s just too much variation in practice 
for us to give authoritative detailed guidelines. These medications are mainly here to jog your memory so you don’t 
forget to at least consider what type of monitoring to do.

258  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONAppendix Table D:  Recommended Laboratory Tests for Psychiatric Medications
Medications Recommended Laboratory Tests
Acamprosate BUN/creatinine if renal impairment is suspected
Amantadine BUN/creatinine if renal impairment is suspected
Antipsychotics—second-generation, primarily clozapine, 
olanzapine, quetiapine, paliperidone, risperidone1, 2 Fasting glucose and lipids
Atomoxetine LFTs
Carbamazepine Complete blood count (CBC), sodium, LFTs, pregnancy test, HLA-B*1502 in Asians3
Carbamazepine level (at least 3 days on stable dose, trough level, 12 hours after last 
dose); target: 4–12 mcg/mL
Chlorpromazine ECG if cardiac disease
Citalopram ECG if cardiac disease, dose ≥40 mg/day
Clomipramine Clomipramine/norclomipramine levels (at least 5 days on stable dose, trough level, 12 
hours after last dose); target: 220–500 ng/mL
Clozapine Fasting glucose and lipids, CBC

Clozapine/norclozapine level (at least 3 days on stable dose, trough level, 12 hours after 
last dose); target: >350 ng/mL; toxicity >700 ng/mL
Desvenlafaxine Periodic BP 
Deutetrabenazine ECG if cardiac disease
Disulfiram LFTs if liver disease is suspected
Duloxetine LFTs if liver disease is suspected4
Gabapentin BUN/creatinine if renal impairment is suspected
Levomilnacipran Periodic BP/pulse rate 
Lithium TSH, BUN/creatinine5, pregnancy test, ECG if cardiac disease 
Lithium level (at least 5 days on stable dose, trough level, 12 hours after last dose); 
target: 0.8–1.2 mEq/L (acute mania) and 0.6–1.0 mEq/L (maintenance)
Methadone ECG if cardiac disease
Mirtazapine Lipids
Naltrexone LFTs if liver disease is suspected

Nortriptyline Nortriptyline level (at least 5 days on stable dose, trough level, 12 hours after last dose); 
target: 50–150 ng/mL
Oxcarbazepine Sodium, HLA-B*1502 in Asians3
Paliperidone Prolactin if symptoms, fasting glucose and lipids
Pregabalin BUN/creatinine if renal impairment is suspected
Risperidone Prolactin if symptoms, fasting glucose and lipids
SSRIs Sodium in elderly if fatigue, dizziness, confusion
Stimulants ECG if cardiac disease
Thioridazine ECG if cardiac disease
Topiramate Bicarbonate 
Tricyclic antidepressants ECG if cardiac disease 
Valbenazine ECG if cardiac disease
Valproic acid LFTs, CBC for platelets, pregnancy test, ammonia if confusion 
Valproic acid level (at least 3 days on stable dose, trough level, 12 hours after last dose 
with IR or 21–24 hours with ER); target: 50–125 mcg/mL

Venlafaxine Periodic BP 
Ziprasidone ECG if cardiac disease
1 Some guidelines recommend monitoring glucose and lipids with all second-generation antipsychotics.
2 Utility of routine therapeutic monitoring is unclear for antipsychotic medications other than clozapine; reference ranges are available for many agents, and blood levels 
may help in establishing whether a patient is taking the medication.
3 HLA-B*1502 is a gene that increases the risk of developing toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) in response to taking carbamazepine. 
Asians, especially Han Chinese, are much more likely to have the gene than other populations. 
4 Duloxetine should not be prescribed in patients with significant alcohol use or evidence of chronic liver disease as it can lead to hepatic failure in rare cases (Cymbalta

4 Duloxetine should not be prescribed in patients with significant alcohol use or evidence of chronic liver disease as it can lead to hepatic failure in rare cases (Cymbalta 
prescribing information). While the manufacturer does not recommend baseline LFTs for all patients, some clinicians do so anyway to be extra cautious.
5 The serum creatinine is used to compute the estimated glomerular filtration rate (eGFR), a more precise measure of kidney functioning. Increasingly, laboratory test 
results include the eGFR. You can calculate it yourself using an online calculator at www.niddk.nih.gov/health-information/communication-programs/nkdep/laboratory-
evaluation/glomerular-filtration-rate-calculators . See also Appendix H for dosing in renal disease.

AppendicesCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   259APPENDIX E: URINE TOXICOLOGY SCREENING
Drug screening is a routine part of psychiatric practice. It can help assessment and diagnosis, monitoring of 
therapeutic goals in patients with substance use disorders, and identifying diversion of controlled substances. 
Specimens of urine, blood, hair, saliva, sweat, and even nails can be used to do lab drug testing, and some tests 
are more specific, sensitive, and accurate than others. Urine drug screening is most commonly used because it’s 
noninvasive, available in large volume, and generally has high concentrations of drug and metabolites, which allows 
for longer detection than in blood. 
Remember that a drug screen, while quick and inexpensive, should be considered preliminary as it may be 
subject to false results or unable to detect all substances. A more accurate, sensitive, and reliable test, such as gas

subject to false results or unable to detect all substances. A more accurate, sensitive, and reliable test, such as gas 
chromatography-mass spectrometry or high-performance liquid chromatography, may be ordered for confirmation.

260  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONAppendix Table E:  Urine Drug Testing
Drug Detection Period Agents Potentially Causing Positive Result
Alcohol 7–12 hours (80 hours for alcohol metabolites 
EtG and EtS)Short-chain alcohols (eg, isopropyl alcohol)
Amphetamine/methamphetamine 1–2 days ADHD medications (atomoxetine, stimulants)
Amantadine (Symmetrel)
Antipsychotics (aripiprazole, chlorpromazine, thioridazine)
Bupropion (Wellbutrin)
Ephedrine (Primatene, Bronkaid)
Isometheptene (Midrin)
MDMA (ecstasy)
Phentermine (Adipex-P , Qsymia)
Phenylephrine (Sudafed PE)
Promethazine (Phenergan)
Ranitidine (Zantac)
Selegiline (Eldepryl, Emsam)
TCAs (desipramine, trimipramine)
Trazodone (Desyrel)
Trimethobenzamide (Tigan)
Barbiturates 2–4 days (2–3 weeks for long-acting 
phenobarbital)Ibuprofen (Advil, Motrin)
Naproxen (Naprosyn)
Benzodiazepines (alprazolam, 
clonazepam, lorazepam, triazolam

clonazepam, lorazepam, triazolam 
may not be detected on some assays)24 hours (short-acting); 2–4 days (long-
acting); >7 days for chlordiazepoxide, 
diazepamOxaprozin (Daypro)
Cocaine 6–8 hours (2–4 days for benzoylecgonine 
metabolite)Coca leaf tea
Topical anesthetics containing cocaine
LSD 2–4 days Trazodone (Desyrel) 
Marijuana 3 days for single use; 5–7 days for moderate 
use (4x/week); 10–15 days for daily use; >30 
days for long-term heavy useDronabinol (Marinol)
Efavirenz (Sustiva)
Hemp-containing foods
NSAIDs
Proton pump inhibitors
MDMA 1–2 days
Nicotine 12 hours
Opioids:
Codeine
Heroin, hydromorphone, morphine, 
oxycodone
Methadone2–3 days (5–7 days for metabolites)
1–2 days
2–4 days
2–3 days; 7–9 days for chronic useDextromethorphan (Robitussin DM)
Diphenhydramine (Benadryl)

oxycodone
1–2 days
2–4 days
Doxylamine (Unisom)
Poppy seeds
Quinolones
Rifampin (Rifadin)
Verapamil (Calan)
PCP 2–8 days; up to 30 days for chronic use Dextromethorphan (Robitussin DM)
Ibuprofen (Motrin)
Ketamine (Ketalar, Spravato)
MDPV (bath salts)
Meperidine (Demerol)
Tramadol (Ultram)
Venlafaxine (Effexor), desvenlafaxine (Pristiq)
Adapted from: Moeller KE et al, Mayo Clin Proc  2008;83(1):66–76; Moeller KE et al, Mayo Clin Proc  2017;92:774–796; Verebey KG, Meenan G. Diagnostic laboratory: Screening 
for drug abuse. In: Ruiz P , Strain E, eds. Lowinson and Ruiz’s Substance Abuse: A Comprehensive Textbook.  5th ed. Philadelphia: Wolters Kluwer, Lippincott Williams & Wilkins,

for drug abuse. In: Ruiz P , Strain E, eds. Lowinson and Ruiz’s Substance Abuse: A Comprehensive Textbook.  5th ed. Philadelphia: Wolters Kluwer, Lippincott Williams & Wilkins, 
2011:123–137; Warner EA, Sharma N. Laboratory diagnosis. In: Ries RK, Miller SC, Fiellen DA, Saitz R, eds. Principles of Addiction Medicine.  4th ed. Philadelphia: Lippincott 
Williams & Wilkins; 2009:295–304

AppendicesCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   261APPENDIX F: PHARMACOGENETIC TESTING
The Basics
Variations in patients’ genetic profiles can affect how they respond to medications. While the actual clinical 
importance of this phenomenon is not yet clear, it’s likely that genetic variations in pharmacokinetic genes have 
some effect on serum levels of medications in many patients. Based on these CYP450 polymorphisms, individuals are 
categorized in different ways with respect to specific enzymes:
 ⦁Extensive metabolizers.  Otherwise known as “normal” metabolizers, these people have normally active CYP450 genes 
on both chromosomes, meaning that they see an average level of drug in the body.
 ⦁Intermediate metabolizers.  These people metabolize drugs a bit more slowly than extensive metabolizers, but not 
dramatically so.
 ⦁Poor metabolizers.  These people carry inactive or partially active CYP450 genes, and therefore metabolize drugs

 ⦁Poor metabolizers.  These people carry inactive or partially active CYP450 genes, and therefore metabolize drugs 
significantly more slowly than extensive metabolizers. This may result in more side effects since serum drug levels 
are higher.
 ⦁Ultrarapid metabolizers.  With extra copies of certain genes, these people metabolize drugs more quickly than 
extensive metabolizers, sometimes requiring unusually high doses of medications to achieve a therapeutic level.
There are also genetic variations in pharmacodynamic genes that might increase or decrease the efficacy of drugs, but 
the evidence for this effect is less robust than for pharmacokinetic effects.
Pharmacogenetic Testing in Clinical Practice
The science of pharmacogenetic testing is complex, which makes it hard for us mere mortals to evaluate the claims of 
the many commercial test kits flooding the market.

In March 2017, TCPR  explored this topic and focused on three tests: Genesight, Genecept, and CNSDose. We 
concluded that the evidence was not yet robust enough to recommend any of these tests. However, we did review 
information from FDA drug labels and created a table listing FDA recommendations for pharmacogenetic testing 
relevant to specific psychotropic drugs.
Many of the recommendations are to lower starting doses in patients who are poor metabolizers. For example, 
in aripiprazole’s label, you’ll read: “Dosing recommendation in patients who are classified as CYP450 2D6 poor 
metabolizers (PM): The aripiprazole dose in PM patients should initially be reduced to one-half (50%) of the usual dose 
and then adjusted to achieve a favorable clinical response. ”

While the FDA does not specifically ask you to order genetic testing, you will not know whether your patient is a 
poor metabolizer unless someone has ordered it. Therefore, a case could be made for selectively ordering CYP450 
testing to ensure you dose drugs in accordance with FDA labeling. Whether you do this is a judgment call; most of 
us are content to skip the genetic testing, and instead choose to start most medications at a low dose and titrate up 
gradually in order to prevent side effects.

262  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONAppendix Table F:  FDA Label Information Relevant to Pharmacogenetic Testing for Psychiatric Drugs
Medication FDA Recommendations Clinical Rationale
Lofexidine 
Pimozide
Pitolisant 
Tetrabenazine
VortioxetineReduce dose in CYP2D6 PMs1Usual starting dose is too high in PMs, so start lower 
and increase gradually
Clozapine
Doxepin
TrimipramineMonitor levels in CYP2D6 PMs These medications, most of which are tricyclic 
antidepressants, can cause life-threatening side 
effects if levels are too high; consider monitoring 
serum levels in PMs
OxcarbazepineAvoid or use cautiously in individuals with the HLA-B*1502 allele 
(applicable to Asians)Risk of serious rashes such as Stevens-Johnson

(applicable to Asians)Risk of serious rashes such as Stevens-Johnson 
syndrome
Citalopram Maximum recommended daily dose of 20 mg (rather than 40 mg) 
for CYP2C19 PMsRisk of QT prolongation and cardiac arrhythmia
Flibanserin Monitor for adverse reactions in CYP2C9 PMs Risk of hypotension and dizziness
Pimozide In CYP2D6 PMs, dose should not exceed 4 mg/day in adults Risk of QT prolongation and cardiac arrhythmia
Thioridazine Contraindicated in CYP2D6 PMs, due to risk of QT prolongation Risk of QT prolongation and cardiac arrhythmia
1 PM = poor metabolizer
Source: www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations

AppendicesCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   263APPENDIX G: ANTICHOLINERGIC AGENTS OFTEN USED IN PSYCHIATRY
Medications with a high anticholinergic “load” can negatively affect memory and cognition, particularly in the elderly. 
This is often a dose-related effect, with a potential for high doses to cause confusion and delirium. Use alternatives to 
these medications when possible, especially in older patients or those with dementia.
Appendix Table G:  Some Commonly Used 
Highly Anticholinergic Medications
Therapeutic Class Medication
Antidepressants Amitriptyline (Elavil)
Clomipramine (Anafranil)
Doxepin >6 mg (Sinequan)
Antiemetics Prochlorperazine (Compazine)
Antihistamines (first generation) Brompheniramine (Dimetapp)
Chlorpheniramine (Chlor-Trimeton)

Cyproheptadine (Periactin)
Dicyclomine (Bentyl)
Dimenhydrinate (Dramamine)
Hydroxyzine (Vistaril, Atarax)
Meclizine (Antivert)
Antimuscarinics (urinary incontinence) Fesoterodine (Toviaz)
Oxybutynin (Ditropan)
Tolterodine (Detrol)
Antiparkinsonian agents Benztropine (Cogentin)
Trihexyphenidyl (Artane)
Antipsychotics Chlorpromazine (Thorazine)
Clozapine (Clozaril)
Loxapine (Loxitane)
Skeletal muscle relaxants Cyclobenzaprine (Flexeril)
Methocarbamol (Robaxin)
Orphenadrine (Norflex)

264  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONAPPENDIX H: DOSING OF PSYCHOTROPIC MEDICATIONS IN PATIENTS WITH HEPATIC OR 
RENAL IMPAIRMENT
Hepatic and renal disease (whether hepatitis, alcohol related, or cirrhosis) can significantly affect the 
pharmacokinetics of medications by altering metabolism, protein binding, and elimination. When prescribing 
psychiatric medications for these patients, sound clinical judgment would dictate to use lower doses and titrate more 
slowly. Some medications require extra consideration, and we’ve included those here. For patients with severe hepatic 
or renal impairment, consider consultation with specialists.

AppendicesCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   265Appendix Table H: Dosing of Psychotropic Medications in  
Patients With Hepatic or Renal Impairment
Medication Hepatic Impairment Renal Impairment
Atomoxetine Mod: Decrease dose by 50%
Sev: Decrease dose by 75%No change
Lisdexamfetamine Consider dose reduction CrCl 15–30 mL/min: Max 50 mg/day
CrCl <15 mL/min: Max 30 mg/day
Viloxazine Avoid use Sev: Reduce dose by 50%
Bupropion Mod-sev: Max 75 mg/day or 150 SR/XL mg QOD Consider dose reduction
Citalopram Sev: Max 20 mg/day Sev: Use with caution
Desvenlafaxine Mod: Max 100 mg/day
Sev: Max 50 mg/dayMod: Max 50 mg/day
Sev: Max 50 mg QOD
Duloxetine Avoid use Mild-mod: Consider dose reduction
Sev: Avoid use
Escitalopram Sev: Max 10 mg/day Sev: Use with caution
Esketamine Mod: Use caution
Sev: Avoid useUse caution
Isocarboxazid Avoid use Mild-mod: Use with caution
Ketamine Use caution Use caution

Levomilnacipran No change Mod: Max 80 mg/day
Sev: Max 40 mg/day
ESRD: Avoid use
Mirtazapine Consider dose reduction Use with caution
Mod-sev: Consider dose reduction
Nefazodone Avoid use No change
Paroxetine Sev: Max 40 mg/day Sev: Max 40 mg/day
Phenelzine Avoid use Mild-mod: Use with caution
Venlafaxine Mild-mod: Reduce dose by 50%
Sev: Use with cautionMild-mod: Reduce dose by 25%
Sev: Reduce dose by 50% or more
Brexpiprazole Mod-sev: Max 3 mg/day Mod-sev: Max 3 mg/day
Lumateperone Mod-sev: Avoid use Use with caution
Lurasidone Mod: Max 80 mg/day
Sev: Max 40 mg/dayMod-sev: Max 80 mg/day
Paliperidone Sev: Use with caution CrCl 50–70 mL/min: Max 6 mg/day
CrCl 10–49 mL/min: Max 3 mg/day
LAI: Adjust dose in CrCl 50–79 mL/min; avoid use CrCl <50 mL/min

Risperidone Mild-mod: Consider dose reduction
Sev: Max 4 mg/dayMild-mod (CrCl ≥30 mL/min): Consider dose reduction
Sev (CrCl <30 mL/min): Max 4 mg/day
Ziprasidone No change PO: No change
Use IM with caution (cyclodextrin excipient renally eliminated)
Buspirone Sev: Avoid use Mild-mod: Consider dose reduction
Clonazepam Sev: Avoid use Use with caution
Diazepam Mild-mod: Use with caution
Sev: Avoid useUse with caution
CrCl = creatinine clearance; Mild (Child-Pugh Class A or CrCl 51–80 mL/min); Mod = moderate (Child-Pugh Class B or CrCl 31–50 mL/min); Sev = severe (Child-Pugh Class C 
or CrCl ≤30 mL/min); ESRD = end-stage renal disease (CrCl <10 mL/min): LAI = long-acting injectable

266  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONMedication Hepatic Impairment Renal Impairment
Lorazepam Sev: Consider dose reduction, avoid IM/IV Use with caution
Sev: Avoid IM/IV
Aducanumab Use with caution Use with caution
Galantamine Mod: Max 16 mg/day
Sev: Avoid useCrCl 9–59 mL/min: Max 16 mg/day
CrCl <9 mL/min: Avoid use
Memantine Sev: Use caution CrCl 5–29 mL/min: Max 10 mg/day
CrCl <5 mL/min: Avoid use
Rivastigmine Mild-mod: Max 4.6 mg/day patch
Sev: Use cautionNo change
Hypnotics
Eszopiclone Sev: Max 2 mg/day No change
Flurazepam Mild-mod: Use with caution
Lemborexant Mod: Max 5 mg/day
Sev: Avoid useNo change
Zaleplon Mild-mod: Max 5 mg/day
Sev: Avoid useSev: Use with caution
Zolpidem Mild-mod: Max 5 mg/day
Gabapentin No change CrCl 30–59 mL/min: Max 1400 mg/day divided BID
CrCl 16–29 mL/min: Max 700 mg/day

CrCl ≤15 mL/min: 100–300 mg/day
Lamotrigine Mod-sev: Reduce dose by 25%
Sev with ascites: Reduce dose by 50%Use with caution 
Mod-sev: Reduce dose by 25%
ESRD: Max 100 mg QOD
Lithium No change Mild-mod: Consider dose reduction
Sev: Avoid use  
Oxcarbazepine Sev: Use with caution Sev: Reduce dose by 25%–50%
Pregabalin No change CrCl 30–59 mL/min: Max 300 mg/day divided BID–TID
CrCl 16–29 mL/min: Max 150 mg/day given QD–BID
CrCl ≤15 mL/min: 25–75 mg/day QD
Topiramate Use with caution Mod-sev: Reduce dose by 50%
Valproic acid Mild-mod: Use with caution
Sev: Avoid useConsider dose reduction (reduced protein binding may result 
in higher active free fraction not reflected in total serum level)
Side Effect Medications
Amantadine Use with caution CrCl 30–50 mL/min: Max 100 mg/day
CrCl 15–29 mL/min: Max 100 mg QOD

CrCl <15 mL/min: 200 mg Qweek
Metformin Avoid use Mild-mod: Use with caution
Valbenazine Mod-sev: Max 40 mg/day No change
Armodafinil Sev: Reduce dose by 50% Use with caution
Carbidopa/levodopa Use with caution CrCl <50 mL/min: Reduce dose by up to 50%
Modafinil Sev: Reduce dose by 50% Use with caution
Oxybates Reduce dose by 50% Use with caution
Pitolisant Mod: Max 17.8 mg/day
Sev: Avoid useMild: Use with caution  
Mod: Max 17.8 mg/day
Pramipexole No change CrCl 20–60 mL/min: Max 0.5 mg/day
CrCl <20 mL/min: Avoid use
CrCl = creatinine clearance; Mild (Child-Pugh Class A or CrCl 51–80 mL/min); Mod = moderate (Child-Pugh Class B or CrCl 31–50 mL/min); Sev = severe (Child-Pugh Class C

AppendicesCarlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   267Medication Hepatic Impairment Renal Impairment
Solriamfetol Use with caution Mild-mod: Max 75 mg/day
Sev: Max 37.5 mg/day
Acamprosate Sev: Use with caution CrCl 30–50 mL/min: 333 mg TID
CrCl <30 mL/min: Avoid use
Buprenorphine Mod-sev: Use with caution No change
Bupropion SR Mod-sev: Max 150 SR mg QOD Consider dose reduction
Disulfiram Use with caution Use with caution
Lofexidine Mild: Max 3 tabs Q5–6H
Mod: Max 2 tabs Q5–6H
Sev: Max 1 tab Q5–6HCrCl 30–89 mL/min: Max 2 tabs Q5–6H
CrCl <30 mL/min: Max 1 tab Q5–6H
Methadone Consider reduced dose ESRD: Reduce dose by 25%–50%
Naltrexone Sev: Use with caution Sev: Use with caution
Varenicline No change CrCl <30 mL/min: Max 0.5 mg BID

268  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION
Index
Note: Trade names are capitalized, bolded page numbers are for fact sheets, italic page numbers are for treatment 
algorithms, and non-bolded page numbers are for quick-scan tables and other miscellaneous entries.
A
Abilify, 72, 75
Abilify Discmelt, 72
Abilify Maintena, 75, 103
Abilify MyCite, 75
Abnormal Involuntary Movement 
Scale (AIMS), 201
acamprosate, 225, 228,  258, 267
ACE inhibitors, 248
Adasuve, 71, 86
Adderall, 16, 30
Adderall XR, 16, 30
Addyi, 164, 168
Adhansia XR, 14, 18, 28
ADHD medications, 11–12, 13, 
14–18, 265
aducanumab, 134, 135,  266
Aduhelm, 134, 135
Adzenys ER oral suspension, 16, 18
Adzenys XR-ODT, 16, 18, 19
akathisia, 183
alcohol use disorder, 223
alprazolam, 110, 111, 112,  246
amantadine, 175,  258, 266
Ambien, 111, 130,  253
Ambien CR, 111
amiodarone, 248
amitriptyline, 38, 41, 63
amphetamine, 15, 16, 18, 19, 245, 
255, 260
Anafranil, 38, 41, 46
Androderm, 164, 171

255, 260
AndroGel, 164, 171
Android, 164, 171
angiotensin II receptor blockers, 248
Antabuse, 225, 232
anticholinergic delirium, 248
anticholinergics, 248, 263
anticonvulsants, 141–142, 143,  144, 
266
antidepressants, 33–35, 36–37,  
38–42, 254, 263, 265
antiemetics, 263
antihistamines, 110, 113,  248, 263
antimuscarinics, 263
antiparkinsonian agents, 263
antipsychotics, 67–69, 70, 71–74, 
248, 254, 258, 263, 265
anxiety, 108anxiolytic medications, 105–107, 
108,  110–111, 265–266
anxiolytics/hypnotics, 253
Aplenzin, 44
Aptensio XR, 14, 18, 28
Aricept, 134, 136
Aricept ODT, 134, 136
aripiprazole, 72, 74, 75, 103, 245, 246
aripiprazole lauroxil, 103
Aristada, 75, 103
Aristada Initio, 75, 103
armodafinil, 206, 207,  244, 246, 247, 
266
Artane, 180
asenapine, 72, 74, 76, 244, 245, 246, 
248
aspirin, 248

266
248
Atarax, 110, 120
Ativan, 110, 111, 122
atomoxetine, 17, 20, 245, 258, 265
Austedo, 177
avanafil, 164, 165,  246
Azstarys, 14, 22
B
barbiturates, 244, 260
Belbuca, 225, 229
Belsomra, 110, 126,  253
Benadryl, 110, 253
benzodiazepines, 110, 111, 253, 260
benztropine, 176,  248
bipolar mania, 143
bleeding risk, 248
bremelanotide, 164, 166
brexanolone, 39, 43
brexpiprazole, 72, 74, 77, 245, 246, 
265
bright light therapy, 216
Brisdelle, 38, 40, 58
bruxism, 184
Bunavail, 225, 230
Buprenex, 225, 229
buprenorphine, 225, 229,  246, 260, 
267
buprenorphine extended-release 
injection, 225
buprenorphine/naloxone, 225, 230bupropion, 17, 39, 42, 44, 244, 245, 
246, 248, 254, 265
bupropion SR, 39, 44, 225, 231,  267
bupropion XL, 39, 44
BuSpar, 111, 114,  253
buspirone, 111, 114,  246, 248, 253, 
265
Butrans, 225, 229
C

265
C
caffeine, 244
calcium, magnesium, potassium, and 
sodium oxybates, 206, 210,  266
CalmAid, 153, 154
Campral, 225, 228
Caplyta, 72, 87
carbamazepine, 144, 145,  244, 246, 
247, 248, 253, 258
Carbatrol, 144, 145
carbidopa/levodopa, 206, 208,  266
cariprazine, 72, 74, 78, 246
Catapres, 21, 111, 225
Celexa, 38, 40, 41, 45
Chantix, 226, 241
chlordiazepoxide, 111
chlorpromazine, 71, 74, 79, 245, 248, 
258
Cialis, 164, 170
cigarette smoke, 244, 248
cigarette smoking cessation, 227
ciprofloxacin, 248
citalopram, 38, 40, 41, 45, 244, 246, 
258, 265
clarithromycin, 248
clomipramine, 38, 41, 46, 258
clonazepam, 110, 111, 115,  246, 265
clonidine, 21, 111, 225, 245
clonidine XR, 17
clorazepate, 111
clozapine, 72, 74, 80, 81–82, 244, 
245, 246, 248, 258
Clozaril, 72, 80
cocaine, 260
codeine, 260
codeine/hydrocodone, 245, 248
Cogentin, 176

Concerta, 14, 18, 28
constipation, 185

Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   269controlled substance classifications, 
256
Cotempla XR-ODT, 15, 18, 28
Cymbalta, 38, 41, 48, 254
CYP450 drug interactions, 244–247
cyproheptadine, 164, 167
Cytomel, 61
D
Dalmane, 110, 111, 119
Daytrana patch, 15, 18, 29
Dayvigo, 110, 121 , 253
dementia medications, 131–132, 
133,  134, 266
Depakene, 144, 152
Depakote, 144, 152,  254
Depakote ER, 144, 152
Depakote Sprinkles, 144, 152
Deplin, 153, 155
Depo-Testosterone, 164, 171
desipramine, 38, 41, 63
Desoxyn, 15, 26
desvenlafaxine, 38, 41, 47, 255, 258, 
265
Desyrel, 39, 42, 62, 111
deutetrabenazine, 177,  245, 258
Dexedrine, 15, 23
Dexedrine Spansules, 16, 23
dexmethylphenidate, 14, 22
dexmethylphenidate XR, 15
dextroamphetamine, 15, 16, 23, 245
dextroamphetamine oral solution, 15
dextromethorphan, 245, 248, 250
diarrhea, 186
Diastat, 116
diazepam, 110, 111, 116,  244, 246, 
265
diphenhydramine, 110, 113,  245, 
248, 253

265
248, 253
disulfiram, 225, 232,  258, 267
diuretics, 248
Dolophine, 225
donepezil, 134, 136,  245
dopamine agonists, 208
Doral, 111
doxepin, 110, 117,  244, 245
doxylamine, 110, 113,  245, 248
Drizalma Sprinkle, 38, 41, 48
drug interactions, 243–247, 248
dry mouth (xerostomia), 187
dual orexin receptor antagonists 
(DORA), 110
duloxetine, 38, 41, 48, 244, 245, 246, 
248, 254, 258, 265
Dyanavel XR, 16, 18, 19
dystonia, 188E
Edluar, 111, 130
Effexor, 38, 41, 64, 255
Effexor XR, 38, 41, 64
Elavil, 38, 41
electroconvulsive therapy (ECT), 217
Emsam, 39, 42, 59
Epitol, 144, 145
Eprontia, 144, 151
Equetro, 144, 145
erythromycin, 248
escitalopram, 38, 40, 41, 49, 244, 
246, 265
Eskalith, 144, 148,  253
esketamine, 39, 50, 265
estazolam, 111
eszopiclone, 110, 118,  246, 253, 266
Evekeo, 15, 19
Evekeo ODT, 15

246, 265
excessive sweating (hyperhidrosis), 
189
Exelon, 134, 140
Exelon Patch, 134, 140
F
Fanapt, 72, 85
fatigue, 190
FazaClo, 72, 80
FDA labeling information, 262
Fetzima, 38, 41, 54, 254
fish oil, 153, 159
flibanserin, 164, 168,  246
fluoxetine, 38, 40, 41, 51, 244, 245, 
246, 248
fluoxetine DR, 38, 51
fluphenazine, 71, 74, 83, 245
fluphenazine decanoate, 103
flurazepam, 110, 111, 119,  246, 266
fluvoxamine, 38, 40, 41, 52, 244, 245, 
246, 247
Focalin, 14, 18, 22
Focalin XR, 15, 18, 22
Forfivo XL, 39, 42, 44
G
gabapentin, 111, 144, 146,  258, 266
gabapentin enacarbil, 206
galantamine, 134, 137,  245, 246, 266
galantamine ER, 134
Geodon, 73, 99
Glucophage, 178
Glumetza, 178
Gocovri, 175
Gralise, 144, 146
grapefruit juice, 246, 247, 248
guanfacine, 17, 24, 246H
Habitrol, 226
Halcion, 110, 111, 128

Haldol, 71, 84
Haldol Decanoate, 71, 103
haloperidol, 71, 74, 84, 245, 246
haloperidol decanoate, 103
hepatic impairment, 264–267
heroin, 260
Hetlioz, 206, 213
Horizant, 144, 146,  206
hydromorphone, 260
hydroxyzine, 110, 113,  120
hyperhidrosis (excessive sweating), 
189
hypersalivation (sialorrhea), 199
hypnotic medications, 105–107, 109,  
110–111, 266
I
iloperidone, 72, 74, 85, 245, 246
imipramine, 39, 41, 63
Inderal, 111, 124
Ingrezza, 181
insomnia, 109
Intermezzo, 111, 130
Intuniv, 17, 24
Invega, 72, 91
Invega Hafyera, 91, 104
Invega Sustenna, 91, 104
Invega Trinza, 91, 104
isocarboxazid, 39, 41, 56, 265
J
Jornay PM, 15, 18, 28
K
Kapvay, 17, 21, 111, 225
Ketalar, 39, 53
ketamine, 39, 53, 265
ketoconazole, 248
Klonopin, 110, 111, 115
Klonopin Wafers, 110
Kloxxado, 225, 235
L

J
K
L
laboratory monitoring, 257–258
lactation, 251–255
Lamictal, 144, 147,  253
Lamictal CD, 144, 147
Lamictal ODT, 144, 147
Lamictal XR, 144, 147
lamotrigine, 144, 147,  253, 266
Latuda, 72, 88
lavender essential oil, 153, 154

270  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONlemborexant, 110, 121,  246, 253, 266
Levitra, 164, 172
levomilnacipran, 38, 41, 54, 246, 254, 
258, 265
Levothroid, 61
levothyroxine, 61
Levoxyl, 61
Lexapro, 38, 40, 41, 49
Librium, 111
liothyronine, 61
lisdexamfetamine, 16, 25, 245, 265
lithium, 144, 148,  248, 253, 258, 266
lithium toxicity, 248
Lithobid, 144, 148,  253
L-methylfolate, 153, 155
lofexidine, 225, 233,  245, 267
long-acting injectable (LAI) 
antipsychotics, 100–102, 103–104
lorazepam, 110, 111, 122,  266
Loreev XR, 110, 122
lowered seizure threshold, 248
loxapine, 71, 74, 86, 245, 246
Loxitane, 71, 86
LSD, 260
L-tryptophan, 153, 156
Lucemyra, 225, 233
lumateperone, 72, 74, 87, 265
Lunesta, 110, 118,  253
lurasidone, 72, 74, 88, 246, 265
Luvox, 38, 40, 41, 52
Luvox CR, 38, 40, 41, 52
Lybalvi, 72, 90
Lyrica, 111, 144, 150
Lyrica CR, 144, 150
M
marijuana, 260
Marplan, 39, 41, 56
MDMA, 260
melatonin, 153, 157,  244
Mellaril, 71, 96

M
MDMA, 260
memantine, 134, 138,  266
memantine ER/donepezil, 134, 139
Metadate CD, 15, 28
Metadate ER, 14, 28
metformin, 178,  266
methadone, 225, 234,  244, 245, 246, 
248, 258, 260, 267
Methadose, 225, 234
methamphetamine, 15, 26, 245, 260
Methylin, 27
Methylin CT, 14, 27
Methylin ER, 14, 28
Methylin oral solution, 14, 27
methylphenidate, 14, 18, 255methylphenidate ER, 28
methylphenidate IR, 27
methylphenidate transdermal 
system, 15, 29
Minipress, 111, 123
Mirapex, 206, 208
Mirapex ER, 206, 208
mirtazapine, 39, 42, 55, 244–246, 
254, 258, 265
mirtazapine ODT, 39, 55
mixed amphetamine salts, 16, 30, 
245
Moban, 71, 89
modafinil, 17, 206, 209,  244, 246, 
247, 266
molindone, 71, 74, 89
(MAOIs), 39, 41–42, 56, 248, 
249–250
mood stabilizers, 141–142, 143,  144, 
253–254, 266

247, 266
249–250
morphine, 260
Mydayis, 16, 18, 30
N
N-acetylcysteine (NAC), 153, 158
naloxone, 225, 235
naltrexone, 226, 236,  258, 267
naltrexone ER, 226
Namenda, 134, 138
Namenda XR, 134, 138
Namzaric, 134, 139
Narcan Nasal Spray, 225, 235
Nardil, 39, 42, 56
natural treatments, 153
nausea, 191
Navane, 71, 97
nefazodone, 39, 42, 57, 246, 247, 265
neuroleptic malignant syndrome 
(NMS), 192
Neurontin, 111, 144, 146
Neupro, 206, 208
Nicoderm CQ, 226, 240
Nicorette Gum, 226, 237
Nicorette Lozenge, 226, 237
nicotine, 260
nicotine inhaled, 226, 238
nicotine nasal spray, 226, 239
nicotine polacrilex, 226
nicotine transdermal patch, 226, 240
Nicotrol Inhaler, 226, 238
Nicotrol NS, 226, 239
nonsteroidal anti-inflammatory 
drugs (NSAIDs), 248
Norpramin, 38, 41, 63nortriptyline, 39, 41, 63, 258
Nuplazid, 73, 93

Nuvigil, 206, 207
O
olanzapine, 72, 74, 90, 104, 244, 248, 
258
olanzapine/samidorphan, 72, 74
Oleptro, 111
omega-3 fatty acids, 153, 159
opioids, 248, 260
opioid use disorder, 224
oral contraceptives, 247, 248
orthostatic hypotension (postural 
hypotension), 193
oxazepam, 111
oxcarbazepine, 144, 149,  244, 246, 
247, 253, 258, 266
Oxtellar XR, 144, 149
oxybates, 206, 210,  266
oxybutynin, 248
oxycodone, 248, 260
P
paliperidone, 72, 74, 91, 258, 265
paliperidone palmitate, 104
Pamelor, 39, 41, 63
parkinsonism, 194
Parnate, 39, 42, 56
paroxetine, 38, 40, 41, 58, 245, 246, 
248, 265
paroxetine CR, 38, 41, 58
Paxil, 38, 40, 41, 58
Paxil CR, 38, 40, 41, 58
PCP , 260
Periactin, 164, 167
perphenazine, 71, 74, 92, 245
Perseris, 95, 104
Pexeva, 38, 40, 58
pharmacogenetic testing, 261–262
phenelzine, 39, 42, 56, 265

PCP , 260
phenobarbital, 244
phenytoin, 244
pimavanserin, 73, 74, 93, 247
pitolisant, 206, 211,  245, 247, 266
postural hypotension (orthostatic 
pramipexole, 206, 208,  266
prazosin, 111, 123
pregabalin, 111, 144, 150,  258, 266
pregnancy, 251–255
Pristiq, 38, 41, 47, 255
ProCentra, 15, 23
prolactinemia, 195
Prolixin, 71, 83
Prolixin Decanoate, 71, 103

Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITION   271propranolol, 111, 124,  245
ProSom, 111
Provigil, 17, 206, 209
Prozac, 38, 40, 41, 51
Prozac Weekly, 38, 40, 51
Q
Qelbree, 17, 31
QT interval prolongation, 196,  248
quazepam, 111
Qudexy XR, 144, 151
quetiapine, 73, 74, 94, 247, 258
Quillichew ER, 15, 18, 28
Quillivant XR, 15, 18, 28
quinidine, 248
R
ramelteon, 111, 125,  244
Razadyne, 134, 137
Razadyne ER, 134, 137
Remeron, 39, 42, 55, 254
Remeron SolTab, 39, 55
renal impairment, 264–267
Requip, 206, 208
Requip XL, 206, 208
Restoril, 110, 111, 127
ReVia, 226, 236
Rexulti, 72, 77
Riomet, 178
Risperdal, 73, 95
Risperdal Consta, 95, 104
Risperdal M-Tab, 73, 95
risperidone, 73, 74, 95, 104, 246, 258, 
265
Ritalin, 14, 27
Ritalin LA, 15, 28
Ritalin SR, 14, 28
rivastigmine, 134, 140,  266
ropinirole, 206, 208,  244
rotigotine transdermal patch, 206, 
208
Rozerem, 111, 125
S
S-adenosyl-L-methionine (SAMe), 
153, 160
Saphris, 72, 76
Secuado, 72, 76

208
S
153, 160
selective serotonin reuptake 
inhibitors (SSRIs), 38, 40, 41, 248, 
254, 258
selegiline transdermal, 39, 42, 59, 
244
Serax, 111serdexmethylphenidate/
Seroquel, 73, 94
Seroquel XR, 73, 94
serotonin norepinephrine reuptake 
inhibitors (SNRIs), 38, 41, 248
serotonin syndrome, 197,  248
sertraline, 38, 40, 41, 60, 244
Serzone, 39, 42, 57
sexual dysfunction, 198
sexual dysfunction medications, 
163–164
sialorrhea (hypersalivation), 199
side effect management, 173, 266
sildenafil, 164, 169,  247
Silenor, 110, 117
Silexan, 153, 154
Sinemet, 206, 208
Sinemet CR, 208
skeletal muscle relaxants, 263
sleep disorder medications, 205–
206, 266–267
smoking cessation, 227
sodium oxybate, 206, 210
solriamfetol, 206, 212,  267
somatic treatments, 215
Sonata, 110, 129,  253

Spravato, 39, 50
Staxyn, 164, 172
Stelazine, 71, 98
Stendra, 164, 165
stimulants, 255, 258
St. John’s wort, 153, 161,  244, 246, 
247, 248
Strattera, 17, 20
Striant, 164, 171
Sublocade, 225, 229
Suboxone, 225, 230
substance use disorder medications, 
221–222, 223–224,  225–226, 267
substrates, 244–247
Subvenite, 144, 147
Sunosi, 206, 212
suvorexant, 110, 126,  247, 253
Symbyax, 90
Symmetrel, 175
Synthroid, 61
T
tadalafil, 164, 170,  247
tardive dyskinesia, 200
tasimelteon, 206, 213
Tegretol, 144, 145,  253
Tegretol XR, 144, 145
temazepam, 110, 111, 127
Tenex, 17, 24Teril, 144, 145
testosterone, 164, 171
tetrabenazine, 179
thiazides, 248
thioridazine, 71, 74, 96, 245, 246, 
248, 258
thiothixene, 71, 74, 97, 244
Thorazine, 71, 79
thyroid augmentation, 61
Tofranil, 39, 41
Topamax, 144, 151
topiramate, 144, 151,  258, 266

248, 258
tramadol, 248
transcranial magnetic stimulation 
(TMS), 218
Tranxene, 111
tranylcypromine, 39, 42, 56
trazodone, 39, 42, 62, 111, 246, 247, 
248, 253
tremor, 202
triazolam, 110, 111, 128,  247
tricyclic antidepressants, 38–39, 41, 
63, 246, 247, 248, 255, 258
trifluoperazine, 71, 74, 98, 244
trihexyphenidyl, 180,  248
Trilafon, 71, 92
Trileptal, 144, 149,  253
Trintellix, 39, 42, 66, 255
Trokendl XR, 144, 151
U
Unisom, 110
urine toxicology screening, 259–260
V
vagus nerve stimulation (VNS), 219
valbenazine, 181,  246, 247, 258, 266
Valium, 110, 111, 116
valproate, 254
valproic acid, 144, 152,  248, 258, 266
vardenafil, 164, 172,  247
vardenafil ODT, 164, 172
varenicline, 226, 241,  267
venlafaxine, 38, 41, 64, 245, 246, 255, 
258, 265
venlafaxine ER, 38, 64
Versacloz, 72, 80

258, 265
Viagra, 164, 169
Viibryd, 39, 42, 65, 255
vilazodone, 39, 42, 65, 247, 255
viloxazine, 265
viloxazine XR, 17, 31
Vistaril, 110, 120
vitamin D, 153, 162
Vivitrol, 226, 236
vortioxetine, 39, 42, 66, 246, 255

272  Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SIXTH EDITIONVraylar, 72, 78
Vyleesi, 164, 166
Vyvanse, 16, 18, 25
W
Wakix, 206, 211
warfarin, 248
weight gain, 203
Wellbutrin, 17, 39, 44, 254
Wellbutrin SR, 39, 42, 44
Wellbutrin XL, 39, 42, 44X
Xanax, 110, 111, 112
Xanax XR, 110, 112
Xenazine, 179
xerostomia (dry mouth), 187
Xyrem, 206, 210
Xywav, 206, 210
Z
zaleplon, 110, 129,  247, 253, 266
Zenzedi, 16, 23
Z-hypnotics, 110–111Zimhi, 225, 235
ziprasidone, 73, 74, 99, 247, 248, 
258, 265
Zoloft, 38, 40, 41, 60
zolpidem, 111, 130,  247, 253, 266
zolpidem low dose, 111
Zolpimist, 111, 130
Zubsolv, 225, 230
Zulresso, 39, 43
Zyban, 225, 231
Zyprexa, 72, 90
Zyprexa Relprevv, 90, 104
Zyprexa Zydis, 72, 90

ARLATARLAT  PUBLISHING CCThe Medication Fact Book  is a comprehensive reference 
guide covering all the important facts, from cost to 
pharmacokinetics, about the most commonly prescribed 
medications in psychiatry. Composed of single-page, 
reader-friendly fact sheets, treatment algorithms, and 
quick-scan medication tables, this book offers guidance, 
clinical pearls, and bottom-line assessments of more 
than 100 of the most common medications you use and 
are asked about in your practice. 
Get the information you need at a glance:
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 ●Mechanisms of action
 ●Cost information
 ●Bottom-line impressions
This revised edition features:
 ●164 fact sheets, 16 of which are new
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 ●Plus, eight appendices and 10 treatment algorithms“An essential reference for busy clinicians.”
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●33 updated reference tables, five of which are new
Professor of Psychiatry, UCSF School of Medicine
“A most useful desk-side book for the clinician who needs accurate and practical  
information about commonly used medications.”
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“The facts you need as a prescriber are right here.”
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Traumatic Stress Disorders (CATSD), Massachusetts General Hospital
“Provides great information in a concise, thoughtfully developed format that is perfect  
for busy clinicians.”
Stephen Strakowski, MD
Professor of Psychiatry and Associate Vice President of Regional Mental Health, Dell Medical School,

Professor of Psychiatry and Associate Vice President of Regional Mental Health, Dell Medical School,  
University of Texas at AustinMedication Fact Book for Psychiatric Practice, Sixth Edition
AUTHORS
Talia Puzantian, PharmD, BCPP ,  is a 
professor of clinical sciences at Keck 
Graduate Institute School of Pharmacy 
and Health Sciences in Claremont, CA. 
She is the deputy editor of The Carlat 
Report  newsletters and co-author of 
the Child Medication Fact Book for 
Psychiatric Practice .
Daniel J. Carlat, MD,  is the founder 
and president of Carlat Publishing 
and is associate clinical professor of 
psychiatry at Tufts University School 
of Medicine.

Art & science | management theory
Correspondence
GmitchellO8@qub.ac.uk
Gary Mitchell is a doctoral
student at the school of
nursing and midwifery.
Queen's University, Belfast
Date of submission
October 22 2012
Date of acceptance
February 4 2013
Peer review
This article has been subject to
double-blind review and checked
using antipiagiarism software
Author guidelines
www.nursingmanagement.co.ukSelecting the best theory to
implement planned change
Improving the workplace requires statf to be involved
and innovations to be maintained. Gary Mitchell
discusses the theories that can help achieve this
Abstract
Planned change in nursing practice is necessary for
a wide range of reasons, but it can be challenging
to implement. Understanding and using a change
theory framework can help managers or other change
agents to increase the likelihood of success. This article
considers three change theories and discusses how one
in particular can be used in practice.
Keywords

Keywords
Theory of change, implementing change,
organisational change
THERE ARE many ways of implementing change.
However, planned change, which is a purposeful,
calculated and collaborative effort to bring about
improvements with the assistance of a change
agent (Roussel 2006), is the most commonly
adopted (Bennett 2003, Jooste 2004, Murphy 2006,
Schifalacqua et al 2009a).
The Nursing and Midwifery Council (NMC) (2008)
says nurses 'must deUver care based on the best
available evidence or best practice', which suggests
there is a continual need to update, or make changes
to, practice. However, implementing change is more
challenging than it is sometimes perceived. Szabla
(2007), for example, estimates that two thirds of
organisational change projects fail, while Burnes
(2004a) suggests that the figure is even higher.

Various forces drive change in health care
(Burritt 2005), including rising costs of treatments,
workforce shortages, professional obligations, such
as clinical governance and codes of conduct, advances
in science, an ageing population, the potential to
increase patient satisfaction, and promotion of
patient and staff safety. These are invariably coupledwith restraining forces, such as poorly developed
action plans, under-motivated staff. Ineffective
communication and inappropriate leadership
(Arkowitz 2002, O'Neal and Manley 2007). Price (2008)
adds that nurses now feel 'bound by corporate
policies' and that health care currently changes
through 'revolution rather than evolution'.
Change is vital to progress, yet the nursing
Uterature identifies numerous complexities associated

with transforming plans into action, and attempts
at change often fail because change agents take
an unstructured approach to implementation
(Wright 1998).
It is important, therefore, that managers, or
change agents, identify an appropriate change theory
or model to provide a framework for implementing,
managing and evaluating change (Pearson ef al 2005).
Equally Important are the attributes of change
agents who are, according to Marquis and Huston
(2008), skOled in the theory and implementation of
planned change and who are often nurse managers.
This is discussed in more detail later in the article.
Change theories
Many authors have attempted to address how and
why changes occur, but the pioneer is, perhaps,
Kurt Lewin. Lewin (1951) identified three stages

through which change agents must proceed before
change becomes part of a system (Figure 1):
• Unfreezing (when change is needed).
• Moving (when change is initiated).
• Refreezing (when equilibrium is established).
He also discussed how certain forces can affect
change, which he called force-field analysis.
Lewin's work was expanded and modified by
Rogers (2003), who described five phases of plarmed
change: awareness, interest, evaluation, trial and
M April 2013 I Volume 20 | Number 1 NURSING MANAGEMENT

adoption. Another change theorist, Ronald Lippitt
(lippitt et al (1958), identified seven phases.
Tomey (2009) suggests that Lippitt's seven phases
and Rogers' five can be clustered within Lewin's
three (Box 1). Box 1 also shows how change agents are
motivated to change and affected members of staff
are made aware of the need for change during Lewin's
unfreezing stage. The problem is identified and,
through collaboration, the best solution is selected.
Roussel (2006) suggests that unfreezing occurs
when disequilibrium is introduced into the system,
creating a need for change. This corresponds directly
to phase 1 of Rogers' theory: awareness.
Lippitt's theory, meanwhile, uses simuar language
to the nursing process (Tomey 2009) (Box 2), a model
of nursing that has been used by nurses in the UK for
a number of years. It is comprised of four elements
(Pearson et al 2005) that are intrinsically linked:
• Assessment The nurse makes a detailed
assessment of the patient that includes

biographical details, relevant clinical history, social
details and medical observations. This phase is
normally considered to be the initial part of the
nursing process, even though activities continue
throughout a patient's period of care.
• Planning Following assessment, the nurse
collaborates with the patient, relatives and
multidiscipUnary team wherever possible to
determine how to address the needs of the patient.
• Implementation This phase relates to the nurse
carrying out and documenting the care previously
agreed at the planning stage.
• Evaluation This occurs often points during the
parison of change theories
Lewin
UnfreezingRogers LippittExamine
status quo
Increase (Jriving
forces for changeTake action
Make changes
Involve peopleMake ^
changes permanent
Establish new way
of things

Lewin
status quo
of things
VReward desired outcomes
period of care. Evaluation is ongoing and links
back to the assessment phase of the nursing
process. This provides opportunity for regular
assessment of patient needs, which can become
more or less important during the care period.
Lippitt's assessment stage, or phase 1, incorporates
Lewin's unfreezing stage and Rogers' awareness
phase, but it also offers much more of a framework
for change agents and includes assessment
of motivation.
During Lewin's movement stage and Rogers'
interest, evaluation and trial phases, change agents
gather all available information and solve any
problems, develop a detailed plan of change and test
the innovation (Marquis and Huston 2008).
This corresponds with lippitt's phase 2
(Box 2), which includes, for example, selection of

'progressive change objectives', and is the stage at
which deadlines and responsibilities are assigned
to team members.
Lewin's refreezing stage corresponds with Rogers'
adoption stage and Lippitt's implementation and
IjWJL Lippitt's theory compared with the nursing process
^^ "
Nursing process elements Lippitt's theory
Awareness Phase 1. Diagnose the problem
Phase 2. Assess motivation
and capacity for change
Phase 3. Assess change agent's
motivation and resources
Moving
RefreezingInterest
Evaluation
Trial
AdoptionPhase 4. Select progressive
change objective
Phase 5. Choose appropriate
role of the change agent
Phase 6. Maintain change
Phase 7. Terminate the helping
relationship
(Adapted from Roussel 2006)Assessment* Phase 1. Diagnose the problem
Phase 2. Assess motivation/capacity for change

Phase 3. Assess change agent's motivation
and resources
Planning! Phase 4. Select progressive change objective
Implementation^:
Evaluation^:Phase 5. Choose appropriate role of the
change agent
Phase 7. Terminate the helping relationship
Key: 'Assessment = Lewin's unfreezing stage
t Planning/implementation = Lewin's moving stage
t Implementation/evaluation = Lewin's refreezing stage
(Lewin 1951, Lippitt ei a/1958, Pearson ef a/2005)
NURSING MANAGEMENT April 2013 i Volume 20

Art & science management theory
evaluation stages (Box 2, phases 6 and 7). At this
point, the change has been successftüly integrated
in the system and strategies are developed to prevent
a return to previous practices. Lippitt's stage of
'maintaining the change' is crucial because successftü
change can often regress to former, outdated
practices (Carney 2000, Cork 2005).
Whüe the three change theories described
above are simuar problem-solving approaches to
implementing planned change, they are also subtly
different. It is up to nurse managers to select the
most appropriate model based on the specific
circumstances of their work environment. It is also
worth noting that, although these three theories
are the most widely used, there are many others,
including Reddin (1989), Havelock (1995) and Leavitt
(Leavitt and Bahrami 1988).
Bumes (2004b) acknowledges the relevance
of Lewin's work half a century on, but highlights
that his three-tiered approach attracts major

criticisms. It is argued, for example, that it is only
suitable for small change projects, that it ignores
organisational powers and poUtics, that it is top
down and management driven, and that it assumes
that orgarüsations operate in stable states.
Lippitt's work is more detailed. Whüe it requires
a greater level of understanding of change theory, it is
likely to be more useful to nurse meinagers because it
incorporates a more detaued plan of how to generate
change and it is tmderpinned by the four elements
of the nursing process: assessment, planning.
^^Qplhar'acteristics of three leadership styles ^|
Autocratic
Strong control
maintained over group.
Others motivated by
coercion.
Others are directed by
commands.
Communication flows
downward.
Decision mai<ing does
not involve others.
Emphasis on different

coercion.
commands.
downward.
status ('you' and T).
Criticism is punitive.Democratic
Less control maintained.
Economic and ego awards
are used fo motivate.
Others are directed through
guidance and suggestions.
Communication flows up
and down.
Decision making involves
others.
Emphasis is on 'we' rather
than 'you' and '1'.
Criticism is constructive.Laissez-faire
Little or no control.
Motivated by support
when requested.
Provides little or no
direction.
Uses upward-downward
Disperses decision making
throughout the group.
Places emphasis on group.
Does not criticise.
(Adapted from Marquis and iHuston 2008)implementation and evaluation (Pearson et al 2005).
Throughout the remainder of the paper, Lippitt's
theory is therefore used to demonstrate how
managers can implement planned change.
Leadership styles

Before embarking on change, managers may first
consider their strengths and weaknesses in terms
of their leadership skills, because these can greatly
affect the outcome of a change project (Cutcliffe
and Bassett 1997). As various authors point out,
good leadership is not a prerequisite of management
(Gerrish 2003, Outhwaite 2003, Salter et al 2009).
The literature suggests that leadership, effective
communication and teamworking are among the most
important elements for planned change (Hewison and
Stanton 2003, Jooste 2004, Schifalacqua et al 2009a).
The role of leaders is multifaceted. Schifalacqua
et al (2009a) state that an 'impassioned champion' is
essential in au change models, because they provide
inspiration, vision and support to everyone involved.
Murphy (2006), meanwhüe, suggests that leaders

shotüd be seen as team players with the same goals
as the rest of their team, rather than as stereotypical
organisational leaders.
Jooste (2004) sets out attributes of
effective leadership:
Influence: leaders have an enormous role to play
in influencing foüowers in the right direction,
and shortcomings in leaders' characteristics
can lead to problems among followers.
Í Clarity: are workers clear about their tasks?
E Commitment: what do workers need from
their leaders?
• Self-image: do foUowers know their own abuities,
what they can and cannot accomphsh?
• Price: what is the price foüowers pay or the
rewards they receive for working weü.
• Behaviour: does the leadership style promote
positive and effective behaviours among foüowers?
There are various leadership styles, including
autocratic, democratic and laissez-faire (Marqtiis emd

Huston (2008) (Box 3), and whichever one is adopted
WÜ1 affect the change in question.
Autocracy Autocratic leadership is regarded as
predictable, with a high level of productivity, but
often with low motivation, creativity and morale
(Marquis and Huston 2008). However, it can be useftü
in crisis situations and is frequently seen in large
bureaucracies. Autocracy is applicable when change
is demanded, for example through the use of a top-
down approach, whue democratic leadership is more
appropriate for groups working together and where
autonomy is promoted (Rycroft-Malone et al 2002).
April 2013 I Volume 20 | Number 1 NURSING MANAGEMENT

Democracy Democratic leadership is useful when
co-operation and co-ordination between groups are
necessary, so it is therefore a more appropriate style
for implementing change (Tomey 2009). However,
Marquis and Huston (2008) wam that it is often less
efficient than authoritative leadership.
Laissez-faire MectnwhQe, a laissez-faire leadership
style can be non-directional and frustrating,
and managers who adopt it tend to allow their
subordinates to take control (Roussel 2006). It is not
generally a useful style for planned changes, but it
can work when team members are highly motivated
and self-directed, and can lead to greater creativity,
motivation and autonomy than autocratic or
democratic leaderships (Benton 1999).
This style does, however, require multiple change
agents and often there is much resistance from group
members (Delmas and Toffel 2008), where democracy
tends to lead to better results in plarmed chcinge
(Richens 2004).
Having considered which change theory to adopt

and what style of leadership best suits the project,
managers or change agents can begin to work
towards achieving change.
Using Lippitt's change theory
Uppitt's theory, alongside a democratic style of
leadership, is a popular and effective combination.
Phase 1 (Boxes 2 and 3) is concerned with diagnosing
the problem and is when a need for change
has been noticed. Bermett (2003) reconamends
undertaking a comprehensive literature review at
this point, or delegating this task to someone with
good criticcd appraisal skills, to assess all available
data and to use the findings to bolster the change
agent's position.
Phase 1 Project management begins at this
stage because this provides the framework for
implementing change (Schifalacqua et al 2009a).
It involves developing a detailed plan or draft

guideline of the proposed change, which should be
given to everyone likely to be affected (Bennett 2003,
Guy and Gibbons 2003). However, Roussel (2006)
warns nurse managers not to overplan and to leave
some room for people to exercise their initiative.
It is also important to have an agreed and
appropriate timescale, which can prevent alienation
and increase the likelihood of success (Carney 2000).
Schifalacqua et al (2009a) warn not to underestimate
the 'power of the grapevine', so effective
communication should begin at phase 1 (Snow 2001)
and is, in fact, integral to the entire change process
(Tomey 2009).Ejcample of a force-field analj
Positive factors/driving forces
Boost job satisfaction
Reduce workload in medium term
Increase patient autonomyNegative factors/restraining forces

Additional time costs in
normal consultations
Resistance from patients
Closer working with local pharmacists
IVIore appropriate workload
•
Opportunities for professional
developmentTrouble insisting on staff conforming
Time spent inducting new staff
Once driving and restraining forces have been identified, change agents can
determine their relative strengths and rank these by numbers or, as illustrated,
by the thickness of arrows.
(Chambers ef al 2006)
Phase 2 At this stage, motivation and capacity for
change are assessed. It involves communicating With
those who might be affected, responding to concerns
cind, if required, justifying the change. Focus group
interviews are one way to achieve this (Carney 2000).
This phase should also address resistance or,

as Lewin (1951) puts it, the 'driving and restraining
forces'. He suggests that both driving forces
(facilitators) and restraining forces (barriers)
operate during change, with driving forces advancing
a system towards change, while restraining forces
impede it (Marquis and Huston 2008).
Resistance to change is inevitable, and managers
would be naive to think otherwise (Baulcomb
2003, Cork 2005, Price 2008). Meanwhile, Roussel
(2006) suggests that change induces stress
that in turn leads to resistance. However, using
force-field analysis can counter this resistance.
Force-field analysis This is a framework for problem
solving and plaimed change, developed by Lewin
(1951). It illustrates that restraining forces cannot
be removed and they can be countered only by
increasing driving forces. One simple example can

be used to illustrate this. A staff nurse does not
believe that a new infusion pump is better than a
previous model. The change agent cannot remove
this restraining force but can bolster the driving
NURSING MANAGEMENT April 2013 I Volume 20 | Number 1

force by explaining why the new pump is more
effective and by organising training in how to use it.
Figure 2 provides an example of a force-field analysis.
When the force-field analysis is completed,
change agents must develop strategies to reduce
the restraining forces, which include issues such
as fear of losing job satisfaction, or fataüsm based
on previous faüed change attempts (Tomey 2009).
They must also strengthen the driving forces by,
for example, increasing remuneration, promotional
incentive, better recognition (Marquis and
Huston 2008).
Phase 3 With the capacity for change addressed,
Lippitt turns to phase 3: assessment of the change
agent's motivation (Box 2). Change agents are not
always managers (Murphy 2006), nor do they have
to be part of the organisation where chcinge is being
introduced. Fxternal change agents can be more
objective than internal ones, but can be costly,
take more time to assimüate duties and be seen

as a threat by other team members (Roussel 2006,
Marquis and Huston 2008, Tomey 2009).
Phase 4 This phase, the planning stage, is the point
at which the chiinge process is defined and a final
draft of the plan is developed, taking into account
the force-field analysis, change agents' status, staff
attributes and cost. A timetable is drawn up to
ensure cost-effective implementation of the change
(Benton 1999) and each team member is assigned
a responsibüity. At this stage, change agents might
consider some broad change strategies.
Change strategies Bermis et al (1985) describe
three groups of change strategies that are
appropriate for nurses wishing to implement change:
Figure 3 Î Herzberg two-factor motivation theory
Motivators
• Promotion opportunities.
• Opportunities for personal growth.

• Recognition.
• Responsibility.
• Achievement.
Hygiene factors
• Quality of supervision.
• Pay.
• Organisational policies.
• Physical working conditions.
• Relations with others.
• Job security.Job contextJob
satisfaction
Job contextJob
dissatisfaction
(Adapted from Cubbon 2000, Cork 2005)• Empirical-rational.
• Power-coercive.
•I Normative re-educative.
One of these can be selected at phase 5 to help guide
change (McPhail 1997).
The empirical-rational strategy assumes that
people are rational and wül adopt change if it can
be justified and is in their self-interest. Meanwhile,
power-coercive strategy is top down and assumes
that people obey instructions from higher
authorities, although CutcUffe and Bassett (1997)
note that these instructions are usually accompanied

by some sense of threat, such as job loss. Finally,
the normative re-educative strategy assumes that
providing information and education will change
people's usual behaviour patterns and help them
develop new ones (Tomey 2009). Most successful
change projects require a combination of these
strategies (Strurüc 1995).
Phase 5 This phase focuses on choosing an
appropriate role for the change agent. Cooke
(1997, 1998) says that change agents are an active
part of the change process, particularly in terms
of managing staff and supporting change, and will
aim to transform intentions into actual change
efforts at this stage. It might be useful to undertake
another force-field analysis now, as resistance can
intensify at this point (McPhaü 1997, Benton 1999,
Roussel 2006, Tomey 2009).

Phase six This phase corresponds to the
implementation stage of the nursing process
(Box 2) (Pearson et al 2005) and is concerned with
maintaining the change so that it becomes a stable
part of the system (Cooke 1998). During this phase
the emphasis is on communication, feedback on
progress, teamwork and motivation.
Change agents need to use their interpersonal
sküls to inspire change, and having an
understanding of motivation theory can support
this. For example, the Herzberg (1959) two-
factor motivation theory (Figure 3) proposes that
individuals have intrinsic and extrinsic needs,
described as satisfiers (motivators) or dissatisfiers
(hygiene factors), which need to be fulfüled
(Bennett 2003).
If change agents strive to meet staff's intrinsic
motivational needs, this is likely to increase

job satisfaction and improve co-operation and
performance, and could be achieved through praise,
continual feedback and effective communication
(Cubbon 2000).
Ongoing training is important in this phase.
Martin (2006) recommends training to support

change because it allows the change to be
embraced more effectively. Conversely, Cork
(2005) suggests that training shows only how to
behave in a certain system and not how to change
it. However, Schifalacqua et al (2009b) found that
staff education and training was a pivotal part of
the change process. They claim that the relationship
between training and stabilising change is
not accidental.
Good communication is a prominent feature
of every phase of the change process and almost
all researchers cite it as fundamental to effective
implementation (Robb 2004). Strong, open
communication across teams strengthens the
chance of firmly embedding change by supporting
the development of therapeutic relationships and
removing barriers (Murphy 2006).
Phase 7 The final phase, 'terminating the helping
process', is evaluation and withdrawal of the change
agent on an agreed date, although Roussel (2006)recommends that change agents remain available

for advice and reinforcement, since past behaviours
can re-emerge and render even successful change
useless.
Finally, any change must be evaluated
to determine whether standards have improved.
This can be done through clinical audit or patient
satisfaction surveys.
Conclusion
Attempts to implement plarmed change face
numerous barriers, but using a framework, such as
Lippitt's, proactively rather than retrospectively can
help eliminate some of the potential problems, and
address and act on others.
However, while this wül not guarantee success,
since planned changes are vulnerable to failure
at every stage m all change theories, careful
consideration of change theory can simpUfy the
process for change agents and help those affected
by change to be more receptive to it.Online archive

For related information, visit
our online archive of more
than 7,000 articles and
search using the keywords
Conflict of interest
None declared
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Baulcomb J (2003) Management of change
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Bennett M (2003) The manager as agent of
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NURSING MANAGEMENT April 2013 I Volume 20 Number 1

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1 | Page   
 
MEDICAID BEHAVIORAL HEALTH 
 STATE PLAN SERVICES  
 
PROVIDER REQUIREMENTS AND 
REIMBURSEMENT MANUAL  
 
Version: 1.26 
Published on 12/01/2023 
Effective on 12/01/2023 
 
The most recent version may be found at: 
bh.medicaid.ohio.gov/manuals

2 | Page  Medicaid Behavioral Health State Plan Services  
Provider Requirements and Reimbursement Manual  
Version  Description of Changes  Last Editor  Release Date  
Version 1.0  Initial Draft  State Policy 
Team  6-14-16 
Version 1.1  Cont’d Draft Manual Development  State Policy 
Team  6-24-16 
Version 1.2  Third Party Coordination of Benefits  
Coordination of Benefits for clients assigned to Managed Care Plans  
Modifier- position of modifier 
Treatment Plans/plan updates -provisionally active timeframe/review/update timeframes  
Supervision- Supervisor Absences  
False Claims Act -New Section  
Time Based CPT codes  -New Section  
ECG -Chart updated  
Adult Vaccines language added  
TBS Removed pharmacist as an approved provider  
POS added to individual charts  
SUD Assessment Chart update 
CLIA certificate Types added  
PERM Audits  
OTP and Methadone administration codes  
TBS Chart  
SUD Nursing Chart 
ACT 
Claims Rolling 
ASAM Staffing Levels updated  State Policy

TBS Chart  
ACT 
ASAM Staffing Levels updated  State Policy 
Team  1-31-17 
Version 1.3  Correction to U6 and U7 modifier in 3 code charts  
Supervisor clarification to SUD residential code charts  
HQ and UB corrections in 2 charts 
Place of service modifications 
H0014 rate correction  State Policy 
Team  3-1-17 
Version 1.4  Definition of place of service 99  
Add information on GT modifier for select codes 
Rate correction for H0005  State Policy 
Team  3-10-17 
Version 1.5  Remove MH and SUD nursing limit  
Add GT modifier to applicable codes 
QMHS +3 yrs experience – TBS Group Hourly/Per Diem  
POS revisions to selected codes  
 State Policy 
Team  3-17-17 
Version 1.6  Collateral contacts  
Add 96372  
Clarify rate reduction for TBS/PSR in excess of 6 units per day  State Policy 
Team  3-31-2017  
Version 1.7  Procedure modifier added for oral naltrexone

Add 96372  
Version 1.7  Procedure modifier added for oral naltrexone  
Clarified that 96372 medication administration code is not available to SUD residential providers  
Add POS 99 to MH nursing codes  
Add POS 04 homeless shelter to TBS Group Hourly/Per Diem  
Added modifiers HN and HO to peer recovery to reflect educational level 
Added POS 99 to H0004 SUD counseling when provided for crisis  
Added POS 99 to SUD nursing  
Added POS 11 and 57 to group SUD nursing  
Rates paid for trainees and assistance with and without supervision  
Removed collateral examples  
96372 rate correction  State Policy 
Team  4-14-2017  
Version 1.8  Add RN/LPN to 96372  
POS 99 added to 90838, 90840  
Clarify SUD residential needs rendering practitioner  
PSY assistant rate correction for 96116, 96118  
PSY assistant rate clarification for CPT codes

PSY assistant rate clarification for CPT codes  
Clarification that crisis codes (with UT) can be done in POS 23, 99  State Policy 
Team  5-10-2017  
Final Version 
1.0 Addition of MD, DO, CNS, CNP, PA to +99355  
QMHS +3 rate for TBS Group  per diem  
POS 99 added to 90846 and 90847  
Update Table 1 -3 for peer support modifiers  State Policy 
Team  6-16-2017  
1.1 Corrected ACT modifiers for CNS, CNP in Table 1 -4 
Clarify direct and general supervision language  
Correct rates for 96101 and 96111  State Policy 
Team  8-3-2017

3 | Page  Add MH H0004  
Add dependently licensed practitioners to SUD H0004  
Add “Day Treatment” to rate chart for H2012, H2020  
Final  
Version 1.2  Rendering Practitioner section modified (page 10)  
Paraprofessional enrollment language (pages 13, 17)  
Procedure modifier UT added to applicable rate ch arts 
Remove POS 99 from H0004 UT as POS 99 always available 
SUD residential codes now in Section 5  
Edited legal disclaimer  
Implementation dates updated  State Policy 
Team  9-29-2017  
Final  
Version 1.3  Replace UT modifier with KX  State Policy 
Team  11-15-2017  
Final  
Version 1.4  Clarified places of service for CPT codes for 84s and 95s  
Clarified for CPT codes, LICDC, LCDC, CDC -A are for SUD agencies  only 
H0001 is now an encounter code  State Policy 
Team  12-4-2017  
1.5 Multi –licensure for independent and medical practitioners  
H0014 AT  
Clarification for ASAM Levels 3.2 and 3.7  
+99355 unit correction

H0014 AT  
+99355 unit correction  
Clarification for ACT Master’s and Bachelor’s levels  State Policy 
Team  1-30-2018  
Final  
Version 1.6  Update psych testing codes  
Update MHAS certification information  
H0014 AT rates added  
Remove hyperlinks no longer working 
Various other updates  State Policy 
Team  12-15-2018  
Final  
Version 1.7  Updated psych testing section to include new codes and rates, description of the new codes, and 
edits/audits when PA needed  
Rendering clarifications  
Noted practitioner modifiers are optional unless dually licensed and referenced MCP Resource 
Guide 
Referenced dual licensure grid on BH site  
Removed language about not reporting NPI if second license is dependent since all report NPIs 
now 
Added SUD Peer Recovery to the PA table (4 hours per day maximum)  
99354 for first 60 minutes

now 
99354 for first 60 minutes  
Updated laboratory section about enrolling as a laboratory  
TBS service chart – not for high school QMHS  
H0001 place of service 57  
Kept H0004 MH/SUD for historical reference  
H0014 AT rate  
Updated SUD residential to clearly state per diems do not include room and board costs/payments  
Updated hyperlinks  
General cleanup  State Policy 
Team  3-4-2019  
Final  
Version 1. 8 August 1, 2019 rate increases  
Additional practitioners rendering H2019  
E&M, diagnostic evaluation rate increases for CNS, CNP, PA  
New smoking cessation codes added  – Table 3 -6.5 
Pregnancy lab code added for MH and SUD  State Policy 
Team  7-23-2019  
Final  
Version 1.9   Addition of modifier AT to Table 1 -4 
Addition of place of service 18 to 99406- 07 
Column headings for 90849, page 51

Final  
Column headings for 90849, page 51  
H2019 modifiers for group for LSW, LPC, LMFT  
Clarify H2019 Psy Asst with Bachelor’s  
Updated OTP two week admin  procedure modifier to UB  State Policy 
Team  7-26-2019  
Final  
Version 1.10 Add POS 99 to H0005  
Updated language regarding dependently licensed enrolling in Medicaid  State Policy 
Team  11-27-2019  
1.11 Emergency Version issued to identify additional procedure codes now available with GT modifier  State Policy 
Team  4-1-2020  
1.12 Emergency Version updated  State Policy 
Team  6-17-2020  
1.13 Emergency Version updated  State Policy 
Team  7-17-2020

4 | Page  Final Version 
1.14 GT modifier requirement  
90785 covered under telehealth  State Policy 
Team  11-2-2020  
1.15 E&M coding changes effective 1/1/2021  State Policy 
Team  12-31-2020  
1.16 Addition of pharmacist as an eligible provider type for certain services  State Policy 
Team  1-17-2021  
1.17 Addition of COVID -19 vaccine services  (Pfizer and Moderna)  State Policy 
Team  2-11-2021  
1.18 Addition of COVID -19 vaccine services  (Johnson & Johnson)  State Policy 
Team  3-18-2021  
1.19  Prolonged services coding changes effective  1/1/2022  
Addition of R eport of Pregnancy  code (T1023)  
Inclusion of additional claims rollup examples  
Addition of “community” as allowable POS for vaccine administration  
Addition of Hep B Vaccine code  (90759)  
Updated  COVID -19 vaccine services resources  State Policy 
Team  12-3-2021 
Final Version

1.20 Addition of  Table  4-3 (SUD  individual  counseling)  which was removed from version 1.19 in error   State Policy 
Team  12-23-2021  
1.21 Addition of  Table  3-15(b) reflecting IHBT changes effective 3/1/2022   
Addition of  Preventive Medicine Counseling code (99401 & 99402)  
 
Team  2-1-2022  
Final Version  
1.22 Addition of table 2-12 for CANS Assessment  
Addition of Table 2-13, 2- 14, 2- 15 for MRSS services  
Addition of Section 8 for OhioRISE  State Policy 
Team  5-27-2022  
1.23 Clarified CANS assessments must be entered in Ohio’s CANS IT system to establish and maintain 
OhioRISE eligibility  
Updated Table 3 -15(b) to clarify for dates of service between March 1,2022 –  June 30, 2022. Effective 
July 1, 2022, services in table 3 -15(b) will be available only under OhioRISE  State Policy

July 1, 2022, services in table 3 -15(b) will be available only under OhioRISE  State Policy 
Team  6-14-2022  
1.24 Update d provider enrollment references throughout given PNM implementation effective 10/1/2022   
Clarifications to MRSS services section  State Policy 
Team  9-29-2022  
1.25 
 CPT coding changes (including prolonged services updates)  effective 1/1/2023  
Additions to Table 2 -9: Provider Administered Pharmaceuticals  
Updated CANS rate effective 1/1/2023  
Updated Table 2 -4 to remove coverage for code 99343 effective 1/1/2023  
Updated tables 2 -5 and 3- 4 to remove coverage for prolonged services codes 99354 and 99355 when the 
codes are used with E&M home visits and individual and group psychotherapy services effective 
1/1/2023

1/1/2023  
Additions to  Table 1 -5 to clarify that PA for these services was required for dates of service between 
March 1, 2022 – June 30, 2022  
Addition to  Table 3 -11 to cla rify HM as a required modifier to indicate PSR versus MH LPN nursing  State Policy 
Team  
 12-19-2022  
1.26 Upda ted Table 1 -3 to include Psych Intern and Psych Trainee practitioner  type numbers in the PSY 
Assistant definition  
Additions of TD and TE modifiers to Table 1 -3 to indicate RN and LPN  
Updated Table 1 -5 to include MRSS and explain the authorization requirements for stabilization 
services  
Updated Care Management Specialist (CMS) description  
Updated Documentation Guidelines for E&M services references  
Addition of information previously found in Opioid Treatment Program Manual to Section 6  (Opioid 
Treatment Program), including tables 6 -1 through 6- 4

Treatment Program), including tables 6 -1 through 6- 4 
Addition of tables 7 -1 (SRS Supported Employment) and 7- 2 (SRS Peer Recovery Support) to Section 7 
(SRS Program)  
Removed detailed summary of Vaccines for Children section and added ODH VFC resources  
Replaced False Claim Act summary language with reference to OAC rule 5160 -1-29 
Removed interactive complexity narrative, adding reference to CPT book  
Removed psychological testing narrative, adding reference to CPT book  
Removed table 3 -15(a)  (Intensive Home Based Treatment for dates of service prior to March 1, 2022)  
Removed table 5 -1 (SUD Withdrawal Management with Extended On Site Monitoring)  
Replaced list of requirements for BHP- Ps with reference to OAC rule 5160 -27-01 
Removed modifier columns from tables when modifiers were not relevant  State Policy 
Team  
 12/01/2023

5 | Page   
Contents  
SECTION 1  ............................................................................................................................................... 10 
Introduction ............................................................................................................................................... 10 
Organization of the Provider Manual  ...................................................................................................... 10 
Provider Enrollment –  OhioMHAS-certified providers (organizations)  ............................................. 10 
Provider Type 84 or 95  ........................................................................................................................... 11 
Federally Qualified Health Centers (FQHCs) and Rural Health Clinics (RHCs)  ................................... 11

Federally Qualified Health Centers (FQHCs) and Rural Health Clinics (RHCs)  ................................... 11 
Out of State MH/SUD Providers  ............................................................................................................ 11 
Rendering Practitioners  ........................................................................................................................... 11 
Paraprofessionals .................................................................................................................................... 12 
Multi-licensed Practitioners  .................................................................................................................... 12 
Qualified Providers Overview .................................................................................................................. 12

Qualified Providers Overview .................................................................................................................. 12 
Medical Behavioral Health Practitioners (M -BHPs)  .............................................................................. 13 
Licensed Independent Behavioral Health Practitioners (I -BHPs) ........................................................... 13 
Behavioral Health Practitioners (BHPs)  .................................................................................................  13 
Behavioral Health Paraprofessional Practitioners (BHP -Ps) .................................................................. 14 
Overview of Supervision  ........................................................................................................................... 15 
Table 1 -1: Supervision for Current Procedural Terminology (CPT®) Codes ................................ 15

Table 1 -1: Supervision for Current Procedural Terminology (CPT®) Codes ................................ 15 
Table 1 -2: Supervision for Healthcare Common Procedure Coding System (HCPCS) Codes  ..... 16 
Incident to Services  ................................................................................................................................... 16 
Practitioner Modifiers  .............................................................................................................................. 16 
Table 1 -3: Practitioner Modifiers  ........................................................................................................ 17 
Procedure Modifiers  .................................................................................................................................  18 
Table 1 -4: Procedure Modifiers  ........................................................................................................... 18

Table 1 -4: Procedure Modifiers  ........................................................................................................... 18 
Place of Service (POS)  .............................................................................................................................. 18 
Claims Detail Rollup for Same Day Services  .......................................................................................... 19 
Third Party Payer (TPP) Coordination of Benefits (COB)  ................................................................... 19 
Benefits and Prior Authorization ............................................................................................................ 20 
Table 1 -5: Prior Authorization  ............................................................................................................ 21

Table 1 -5: Prior Authorization  ............................................................................................................ 21 
Non-Covered Services  ............................................................................................................................... 22 
Fraud, Waste, and Abuse  ......................................................................................................................... 22 
Review of Provider Records ..................................................................................................................... 23 
Payment Error Rate Measurement (PERM)  .......................................................................................... 23

6 | Page  Medicaid National Correct Coding Initiative  ......................................................................................... 23 
NCCI Procedure -To-Procedure (PTP) Edits  ........................................................................................... 23 
Medically Unlikely Edits (MUEs)  .......................................................................................................... 24 
Time -Based CPT Codes  ............................................................................................................................ 25 
Prolonged Services  .................................................................................................................................... 25 
SECTION 2  ............................................................................................................................................... 26

SECTION 2  ............................................................................................................................................... 26 
Behavioral Health Services  ...................................................................................................................... 26 
Evaluation and Management Codes  ........................................................................................................ 27 
Table 2 -1: Evaluation & Management Office Visit  ........................................................................... 27 
Table 2 -2: Prolonged Service codes for E&M Office Visits  .............................................................. 28 
Table 2 -3 Evaluation and Management Office Visit - Report of Pregnancy  ................................... 29 
Table 2 -4: Evaluation & Management Home Visit  ............................................................................ 30

Table 2 -4: Evaluation & Management Home Visit  ............................................................................ 30 
Table 2 -5: Prolonged Service codes for E&M Home Visits  .............................................................. 31 
Table 2 -6: Preventive Medicine Counseling  ....................................................................................... 31 
Table 2 -7: Psychiatric Diagnostic Evaluation ..................................................................................... 32 
Table 2 -8 – Electrocardiogram  ............................................................................................................ 33 
Table 2 -9: Provider Administered Pharmaceuticals ......................................................................... 34 
National Drug Code (NDC)  ...................................................................................................................... 35

National Drug Code (NDC)  ...................................................................................................................... 35 
Laboratory Services  .................................................................................................................................. 36 
Table 2 -10: Laboratory Services  ......................................................................................................... 36 
Laboratory Codes  ..................................................................................................................................... 36 
Vaccines  ..................................................................................................................................................... 37 
Table 2 -11: Covered Vaccines for Behavioral Health Providers ...................................................... 37

Table 2 -11: Covered Vaccines for Behavioral Health Providers ...................................................... 37 
COVID-19 Vaccine Administration  ....................................................................................................... 38 
Vaccines for Children (VFC) Program  ................................................................................................... 38 
Vaccines for Adults .................................................................................................................................  39 
Child and Adolescent Needs Strengths (CANS) Assessment  ................................................................ 39 
Table 2 -12: Child and Adolescent Needs and Strengths (CANS) Assessment  .................................  40 
Mobile Response and Stabilization Service (MRSS) .............................................................................. 41

Mobile Response and Stabilization Service (MRSS) .............................................................................. 41 
Table 2 -13: MRSS Crisis Mobile Response  ........................................................................................ 42 
Table 2 -14: MRSS Crisis Mobile Response Follow Up  ...................................................................... 44 
Table 2 -15: MRSS Stabilization Service  ............................................................................................. 45 
SECTION 3  ............................................................................................................................................... 47 
Psychotherapy Services  ............................................................................................................................ 47 
Table 3 -1: Psychotherapy for Crisis  .................................................................................................... 47

7 | Page  Table 3 -2: Individual Psychotherapy  .................................................................................................. 49 
Table 3 -3: Family Psychotherapy  ........................................................................................................ 52 
Table 3 -4: Prolonged Service Codes for Psychotherapy  ................................................................... 55 
Table 3 -5: Group Psychotherapy  ......................................................................................................... 57 
Interactive Complexity  ............................................................................................................................. 58 
Table 3 -6: Interactive Complexity  ....................................................................................................... 58

Table 3 -6: Interactive Complexity  ....................................................................................................... 58 
Psychological Testing  ................................................................................................................................ 59 
Table 3 -7: Psychological Testing  ......................................................................................................... 59 
Table 3 -7.5: Smoking Cessation ........................................................................................................... 64 
Healthcare Common Procedure Coding System (HCPCS) Mental Health Services  .......................... 66 
Table 3 -8: Therapeutic Behavioral Services (TBS)  ............................................................................ 66 
Table 3 -9: RN and LPN Nursing Services  .......................................................................................... 69

Table 3 -9: RN and LPN Nursing Services  .......................................................................................... 69 
Table 3 -10: TBS Group Service -Hourly and Per Diem (Day Treatment)  ....................................... 70 
Table 3 -11: Psychosocial Rehabilitation (PSR)  .................................................................................. 72 
Table 3 -12: Screening, Brief Intervention and Referral to Treatment  ............................................ 73 
Table 3 -13: Community Psychiatric Supportive Treatment (CPST)  ............................................... 74 
Assertive Community Treatment (ACT)  ................................................................................................ 76 
Table 3 -14: Assertive Community Treatment (ACT)  ........................................................................ 76

Table 3 -14: Assertive Community Treatment (ACT)  ........................................................................ 76 
Intensive Home Based Treatment (IHBT)  .............................................................................................. 77 
SECTION 4  ............................................................................................................................................... 77 
Substance Use Disorder (SUD) Coverage ............................................................................................... 77 
Table 4 -1: SUD Assessment  .................................................................................................................. 77 
Table 4 -2: SUD Peer Recovery Support  ............................................................................................. 78 
Table 4 -3: Individual Counseling  ........................................................................................................ 78

Table 4 -3: Individual Counseling  ........................................................................................................ 78 
Individual Counseling  ............................................................................................................................. 78 
Table 4 -4: Group Counseling  ............................................................................................................... 79 
Table 4 -5: SUD Case Management  ...................................................................................................... 80 
Table 4 -6: SUD Drug Screening  .......................................................................................................... 81 
Table 4 -7: SUD RN and LPN Nursing Services  ................................................................................. 82 
Table 4 -8: Intensive Outpatient Level of Care Group Counseling  ................................................... 83

Table 4 -8: Intensive Outpatient Level of Care Group Counseling  ................................................... 83 
Table 4 -9: Partial Hospitalization (PH) Level of Care Group Counseling  ...................................... 84 
Table 4 -10: SUD Withdrawal Management with Extended On Site Monitoring  ........................... 85 
SUD Residential Treatment  ..................................................................................................................... 85 
SUD Withdrawal Management with Extended On Site Monitoring  ....................................................... 85 
Table 5 -1: Clinically Managed Low -Intensity Residential Treatment  ............................................. 86

8 | Page  Table 5 -2: Clinically Managed Residential Withdrawal Management  ............................................ 86 
Table 5 -3: Clinically Managed Population-Specific High Intensity Residential Treatment (Adults)
 ................................................................................................................................................................ 87 
Table 5 -4: Clinically Managed High Intensity Residential Treatment  ............................................ 87 
Table 5 -5: Medically Monitored Intensive Inpatient Treatment (Adults) and Medically 
Monitored High-Intensity Inpatient Services (Adolescent)  ............................................................... 88 
Table 5 -6: Medically Monitored Inpatient Withdrawal Management  ............................................ 88 
SECTION 6  ............................................................................................................................................... 89

SECTION 6  ............................................................................................................................................... 89 
Opioid Treatment Programs  .................................................................................................................... 89 
Provider Network Management (PNM) Enrollment for Opioid Treatment Programs ........................... 89 
Buprenorphine Administration for SUD Treatment Programs ............................................................... 89 
OTP Billing Guidance  ............................................................................................................................. 89 
Table 6 -1: Opioid Treatment Programs  ............................................................................................. 91 
Table 6 -2: Opioid Treatment Programs  ............................................................................................. 92

Table 6 -2: Opioid Treatment Programs  ............................................................................................. 92 
Coordination of Benefits: Medicare Opioid Treatment Program Benefit  ........................................... 93 
Table 6 -3: Medicare Opioid Treatment “Bundle” Billing Codes  ..................................................... 94 
SECTION 7  ............................................................................................................................................... 95 
Specialized Recovery Services (SRS) Program [1915(i)]  ....................................................................... 95 
Table 7 -1: SRS Supported Employment  ............................................................................................. 96 
Table 7 -2: SRS Peer Recovery Support  .............................................................................................. 96

Table 7 -2: SRS Peer Recovery Support  .............................................................................................. 96 
SECTION 8  ............................................................................................................................................... 97 
OhioRISE  ................................................................................................................................................... 97 
Appendix: Ohio Medicaid List of Place of Service Codes  ..................................................................... 98 
 
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9 | Page  Legal Disclaimer:  Ohio Department of Medicaid ( ODM ) strives to make the information in this manual 
as accurate, complete, reliable, and timely as possible. However, ODM makes no claims, promises, or 
guarantees about the accuracy, completeness, or adequacy of this information. This is the mo st current 
version of the Medicaid Behavioral Health State Plan Services-Provider Requirements and 
Reimbursement M anual, which is being released as an informational and educational tool; however, this 
manual is subject to change and future revisions as the implementation and operations of the Ohio 
Medicaid program changes. ODM, its employees, agents, or others who provide the answers will not be 
liable or responsible to you for any claim, loss, injury, liability, or damages related to your use of or 
reliance upon this information. This manual is intended solely as an informational and educational

reliance upon this information. This manual is intended solely as an informational and educational 
resource for providers intending to participate in the Medicaid behavioral health programs and for the 
public. The information contained in this manual is not intended to set new s tandards and requirements 
beyond the scope of those standards and requirements found in the Ohio Administrative Code.  In the case 
of any conflict between the information contained in this manual and Ohio Administrative Code or Ohio 
Revised Code, the Ohio Administrative Code or Ohio Revised Code, as applicable, prevails. This 
information is not intended to be a substitute for professional legal, financial, or business advice. This manual does not create, nor is it intended to create, an attorney -client relat ionship between you and Ohio.

You are urged to consult with your attorney, accountant, or other qualified professional if you require advice or opinions tailored to your specific needs and circumstances.

10 | Page  SECTION 1 
Introduction  
The Ohio Department of Medicaid  (ODM) has created this manual to help providers of community 
behavioral health services understand coverage and reimbursement for services provided under the fee -
for-service program.  For purposes of this manual, community behavioral health providers are those who 
are certified by the Ohio Department of Mental Health and Addiction Services (OhioMHAS)  as described 
in Ohio Administrative Code (OAC) rule 5160-27 -01. The Ohio Administrative Code contains specific 
regulatory information that is the basis for the information contained in this manual. Chapter 5160-1 
contains regulatory information on the Medicaid  program in general.  Additional information is available 
in the following administrative rule  chapters: 
• Chapter 5160 -1 General Provisions  (includes telehealth) 
• Chapter 5160 -4 Medical and Surgical Services  
• Chapter 5160 -8 Therapeutic and Diagnostic Services

• Chapter 5160 -8 Therapeutic and Diagnostic Services  
• Chapter 5160 -27 Community Mental Health Agency Services  
• Chapter 5160 -28 Federally Qualified Health Center  and Rural Health C linic Services  
• Chapter 5160 -43 Specialized Recovery Services Program  
 
Organization of the Provider Manual  
This manual is organized in to eight sections.   
• Section 1 includes information regarding provider enrollment, rendering provider, supervisor 
requirements, benefit and claims related requirements, and information on fraud, waste and abuse.   
• Section 2 is dedicated to medical and behavioral health services that can be provided by both 
mental health and substance use disorder (SUD) agencies.  
• S ection 3 provides specific service requirements and claims billing information for services

• S ection 3 provides specific service requirements and claims billing information for services 
which can only  be performed by mental health agencies. This section includes evidence-based 
practices.   
• S ection 4 provides specific service requirements and claims billing information for services 
which can only  be performed by SUD outpatient agencies.  
• Section 5 provides specific service requirements and claims billing information for services which can only  be performed by SUD residential agencies. 
• Section 6 provides information on Opioid Treatment Programs (OTPs) . . 
• Section 7 provides information on the Specialized Recovery Services (SRS) program and related 
resources.  
• Section 8 provides information on OhioRISE (Resilience through Integrated Systems and Excellence) , a program to help children who have complex and serious behavioral health needs.

• Section 8 provides information on OhioRISE (Resilience through Integrated Systems and Excellence) , a program to help children who have complex and serious behavioral health needs.  
Provider Enrollment – OhioMHAS -certified providers (organizations) 
All provider enrollment applications must be submitted using Ohio Medicaid’s Provider Network 
Management (PNM) module. T he PNM module is  the single point for providers to complete provider 
enrollment, centralized credentialing, and provider self -service.  For more information about the PNM 
please visit www.managedcare.medicaid.ohio.gov/managed-care/centralized -credentialing .  
 To participate in the Ohio Medicaid program, including contracting with the managed care plans, 
OhioMHAS -certified provider s must enroll in the Ohio Medicaid pro gram. The IT system that supports 
Ohio Medicaid provider functions is the Provider Network Management (PNM) module . There are two

11 | Page  provider types  associated with behavioral health benefit s; provider type 84 is used for accessing the 
mental health benefit while provider type 95 is used for accessing the substance use disorder benefit . 
Organization s that will be  providing both benefits  will need to enroll as BOTH provider types.   
 
Provider Type 84 or 95   
Prior to enrollment  in the Ohio Medicaid program , a provider must be certified by OhioMHAS as a 
provider of behavioral  health  (BH) services. Information on OhioMHAS ’s service certification can be 
obtained from the OhioMHAS Bureau of Licensure & Certification by calling 614-752 -8880 or by 
visiting the OhioMHAS licensure and certif ication webpage here:  Licensure & Certification | Department 
of Mental Health and Addiction Services (ohio.gov) . On ce certified by OhioMHAS as a BH service 
provider, an online application or applications for enrollment in the Ohio Medicaid program m ust be

provider, an online application or applications for enrollment in the Ohio Medicaid program m ust be 
submitted using the PNM module . There may be an application fee for applying as provider type 84 
and/or 95. During the enrollment process, a provider specialty will need to be selected for each provider 
type. ODM will add or change specialties as necessary based upon the OhioMHAS/SAMHSA 
certification(s) and/or OhioMHAS licensure documentation received with  the application. 
For more information about  enrolling as a Medicaid provider, please visit t he following link:   
https://managedcare.medicaid.ohio.gov/managed-care/centralized -credentialing/about -pnm   
 
Federally Qualified Health Centers (FQHCs) and Rural Health Clinics (RHCs) 
FQHCs and RHCs may be certified by OhioMHAS for the provision of community behavioral health

FQHCs and RHCs may be certified by OhioMHAS for the provision of community behavioral health 
services by enroll ing as a provider type 84 and/or 95. OAC Rule 5160-28 -03 describes requirements for 
FQHC and RHC services, including services that are considered FQHC and RHC  Prospective Payment 
System (PPS) services. For OhioMHAS certified  providers who are also FQHCs or RHCs , behavioral 
health services that are not FQHC or RHC PPS services are covered under OAC Chapter 27  and may be 
billed under th eir Ohio Medicaid Provider type 84 or 85 enrollment  and will be paid in accordance with  
OAC Chapter 27  as described  in this m anual.  
Out of State MH/SUD Providers  
Pursuant to Ohio Administrative Code ( OAC ) rule 5160-27- 01, MH and/or SUD agencies/programs 
operating outside of the state of Ohio must be recognized (regulated) in the state in which it operate s as a

operating outside of the state of Ohio must be recognized (regulated) in the state in which it operate s as a 
provider of community-based MH and/or SUD services. That documentation must be submitted along 
with the organization’s Medicaid application.  
 
Rendering Practitioners   
ODM require s that the  rendering practitioner for behavioral health services be listed on claims submitted  
to Ohio Medicaid for payment. T heir personal NPI must be reported in the rendering field on the claim 
for each service they provide.  
All rendering practition ers are required to have a National Provider Identifier (NPI) to render services to 
Medicaid enrollees AND they will be required to enroll in the Ohio Medicaid program  and affiliate with 
their employing/contracting  agency . An NPI can be obtained by visiting 
https://nppes.cms.hhs.gov/NPPES .  
Once the provider has obtained an NPI , they must visit the PNM and enroll as a provider  in the Ohio

Once the provider has obtained an NPI , they must visit the PNM and enroll as a provider  in the Ohio 
Medicaid Program. More details on this process are available at:  
https://managedcare.medicaid.ohio.gov/managed-care/centralized -credentialing /about -pnm

12 | Page  Paraprofessionals  
• Paraprofessionals, practitioners without a professional license,  may render some mental health 
and/or SUD services.  They must enroll in Ohio  Medicaid following the instructions above. The 
provider type in Ohio’s PNM  system is “ 96”. Paraprofessionals may select more than one 
specialty.  For example, one could enroll as a Q ualified Mental Health S pecialist (QMHS ) and 
may also enroll as a Care Management Specialist (CMS) by selecting specialties 960 (QMHS) 
and 962 (CMS).  
If a QMHS or CMS  practitioner obtains additional educational credentials or years of experience after 
their initial enrollment, the employing/contracting agency should provide documentation of the 
educational credential or experience by submitting a provider update to the ODM Provider Enrollment 
mailbox: medicaid_provider_update@medicaid.ohio.gov . Once the documentation has been received and

mailbox: medicaid_provider_update@medicaid.ohio.gov . Once the documentation has been received and 
approved, the provider’s enrollment status will be updated to match. (See more information below about 
QMHS, CMS and Peer Specialists) . 
 
Multi -licens ed Practitioners  
ODM recognizes that some individuals may hold more than one (1) license or an assistant/trainee 
credential with differing scopes of practice. In order to allow these practitioners to operate under the 
scope of multiple professional credentials, ODM is allowing these practitioners to add a multi-license 
specialty . This multi-license specialty will allow the practitioner to render services available under their  
second license or credential . Please refer to the  Dual Licensure Grid located at 
https://bh.medicaid.ohio.gov/manuals  under the Billing Resources section.  
 To enroll with multi-license specialty:

 To enroll with multi-license specialty:  
If a practitioner has more than one credential/paraprofessional recognition, please include a comment in the Notes section of the enrollment application indicating what additional credential/paraprofessional 
recognition is held. Paraprofessionals can  select a primary, a secondary or multiple secondary specialty . 
Be certain to upload the necessary documentation for each license/certificate.  If already enrolled with 
ODM , email  medicaid_provider_update@medicaid.ohio.gov
 with necessary information to support the 
second specialty.  
 
Claim submission: 
• Reporting additional licensure on claims - P ractitioners with  the multi‐licensed practitioner 
specialty submit claims as follows: 
o For their original license according to information found elsewhere in this manual: 
rendering NPI, applicable procedure modifiers, etc.

rendering NPI, applicable procedure modifiers, etc.  
o For services under their additional license(s), the claims will require an additional 
modifier to reflect under what additional license they are operating. 
o For example, a person enrolled with ODM  as an RN who is also an LPCC must have the 
UH modifier in addition to their individual practitioner NPI  on to the detail line of the 
claim in order for ODM’s claims payment system  to recognize this practitioner as an 
allowable renderer of the service.  
 
See the “Modifiers” tab on the Dual Licensure Grid referenced above. 
Qualified Provider s Overview  
It is the state’s expectation that a practitioner will work within their scope of practice.

13 | Page  Medical Behavioral Health Practitioners (M -BHP s) 
Medical Behavioral Health Providers are professionals who are licensed by a professional board in the 
state of Ohio and are authorized to practice some level of general medicine and have specialty experience 
and/or training related to persons with behavioral health conditions. M -BHPs are:  
 
• Physicians  as defined in Chapter 4731 of the Ohio Revised Code  who are licensed by the state of 
Ohio Medical Board  and legally authorized to practice in the state of Ohio . 
• Clinical nurse specialists (CNS) , certified  nurse practitioners (NP), registered nurses (RN) , 
and licensed practical nurses (LPN) as defined in Chapter 4723 of the Ohio Revised Code who 
are licensed and certified by the state of Ohio Nursing Board  and legally authorized to practice in 
the state of Ohio . 
• Physician assistants  as defined in Chapter 4730 of the Ohio Revised Code who are licensed by

• Physician assistants  as defined in Chapter 4730 of the Ohio Revised Code who are licensed by 
the state of Ohio Medical Board  and legally authorized to practice in the state of Ohio . 
• Pharmacists as defined in OAC rule 5160-8-52  who are licensed by the state of Ohio Board of 
Pharmacy . Tables 2 -1, 2-6 and 2-9 provide further details.  
 
Licensed Independent Behavioral Health P ractitioners  (I-BHP s) 
The following are  professionals who are licensed by a professional board in the state of Ohio and are 
authorized to practice independently (they are not subject to professional supervision) and have specialty experience and/or training related to persons with behavioral he alth conditions. I -BHPs are:  
• Psychologists  and school psychologists  as defined in Chapter 4732 of the Ohio Revised Code 
who are licensed by the state of Ohio Board of Psychology and legally authorized to practice in the state of Ohio .

who are licensed by the state of Ohio Board of Psychology and legally authorized to practice in the state of Ohio .  
• Licensed p rofessional clinical counselors  (LPCC), licensed independent social workers 
(LISW), and l icensed independent marriage and family therapists  (LIMFT) as defined in 
Chapter 4757 of the Ohio Revised Code  who are licensed by the state of Ohio Counselor, Social 
Worker, and Marriage & Family Therapist Board  and legally authorized to practice in the state of 
Ohio.  
o For the purposes of this manual, L IMFT has the same meaning as I MFT as used by the  
Counselor, Social Worker, and Marriage & Family Therapist  Board .  
• Licensed independent chemical dependency counselors  (LICDC)  as defined in Chapter 4758 
of the Ohio Revised Code  who are licensed by the Ohio Chemical Dependency Professionals 
Board and legally authorized to practice in the state of Ohio . 
 
Behavioral Health Practitioners  (BHP s)

Behavioral Health Practitioners  (BHP s) 
Please Note: In the following descriptions, the term “registered with the state of Ohio”  means an individual 
is known to the state professional and/or licensing boards as a practitioner who has met the applicable 
professional requirements.  
The following  are professionals who are licensed by a professional board in the state of Ohio and are 
authorized to practice under direct or general clinical supervision and have specialty experience and/or 
training related to persons with behavioral health conditions  These paraprofessionals must be  enrolled 
with ODM  and affiliated with their community behavioral health agency.  BHPs are:  
 Licensed  
• Board licensed school psychologists  as defined in Chapter 3301 of the Ohio Revised Code and

 Licensed  
• Board licensed school psychologists  as defined in Chapter 3301 of the Ohio Revised Code and 
who are licensed by the Ohio Department of Education and legally authorized to practice in the state of Ohio.

14 | Page  • Licensed professional counselors  (LPC),  licensed social workers (LSW), and licensed 
marriage and family therapists  (LMFT) licensed by the Ohio Counselor, Social Worker, and 
Marriage & Family Therapist Board in accordance with Chapter 4757 of the Ohio Revised Code 
and legally authorized to practice in the state of Ohio .  
o For the purposes of this manual, LMFT has the same meaning as MFT as used by the 
Counselor, Social Worker, and Marriage & Family Therapist Board.   
• Licensed chemical dependency counselor III s and licensed chemical depend ency counselor 
IIs licensed by the Ohio Chemical Dependency Professional Board in accordance with Chapter 
4758 of the Ohio Revised Code and legally authorized to practice in the state of Ohio.   
 
Trainees/Assistants  
• Psychology assistant/intern/trainee s working under the supervision of a psychologist licensed 
by the Ohio Board of Psychology  and legally authorized to practice in the state of Ohio.

by the Ohio Board of Psychology  and legally authorized to practice in the state of Ohio.  
• School psychology assistant/intern/trainee s working under the supervision of a psychologist or 
school psychologist licensed by the Ohio Board of Psychology and legally authorized to practice 
in the state of Ohio.  
• Counselor trainee s registered with the Ohio Counselor, Social Worker, and Marriage & Family 
Therapist Board in accordance with Chapter 4757 of the Ohio Revised Code  and legally 
authorized to practice in the state of Ohio . A counselor trainee is seeking licensure as a 
professional counselor and is enrolled in a practicum or internship in a counselor education program.  
• Social work trainees  registered with the Ohio Counselor, Social Worker, and Marriage & Family 
Therapist Board in accordance with Chapter 4757 of the Ohio Revised Code  and legally

authorized to practice in the state of Ohio . A social work trainee is completing their school 
approved field placement under a council on social work education accredited master’s level program . 
• Social work assistant s registered with the Ohio Counselor, Social Worker, and Marriage & 
Family Therapist Board in accordance with Chapter 4757 of the Ohio Revised Code  and legally 
authorized to practice in the state of Ohio . 
• Marriage and family therapist trainee s registered with the Ohio Counselor, Social Worker, and 
Marriage & Family Therapist Board in accordance with Chapter 4757 of the Ohio Revised Code  
and legally authorized to practice in the state of Ohio . A marriage and family therapist trainee is a 
student enrolled in a marriage and family therapist practicum or internship in Ohio.

student enrolled in a marriage and family therapist practicum or internship in Ohio.  
• Chemical dependency counselor assistant s certified by the Ohio Chemical Dependency 
Professionals Board in accordance with Chapter 4758 of the Ohio Revised and legally authorized 
to practice in the state of Ohio .  
 
Behavioral Health Paraprofessional  Practitioners  (BHP -Ps) 
The following  are eligible  paraprofessionals who are NOT  licensed by a professional board in the state of 
Ohio but are specially trained to provide a specialty service or services to persons with or in recovery from substance use disorders (SUDs) and/or mental health (MH) conditions.  BHP -Ps are:  
• Peer Recovery Supporter (PRS) : For purposes of this manual, “ peer recovery supporter ” (PRS) 
has the same meaning as a “certified peer supporter ” as certified by OhioMHAS . This includes

has the same meaning as a “certified peer supporter ” as certified by OhioMHAS . This includes  
certified peer recovery supporter s, certified youth peer supporter s, and certified family peer 
supporter s as described in  OAC rule 5122-29- 15.1.  
• Care Management Specialist (CMS)  - An individual who has received training for or education 
in alcohol and other drug addiction, abuse, and recovery and who has demonstrated, prior to or within ninety days of hire, competencies in fundamental alcohol and other drug addiction, abuse, 
and recovery.

15 | Page  • Qualified Mental Health Specialist (QMHS)  - an individual who has received training or 
education in mental health competencies and who has demonstrated, prior to or within ninety 
days of hire, competencies in basic mental health skills along with competencies established by 
the agency, and who are not otherwise designated as providers or supervisors, and who are not 
required to perform duties covered under the scope of practice according to Ohio professional licensure. Additional information may be found in OAC rule 5160 -27-01
. 
• Qualified Mental Health Specialist +3 (QMHS +3)  - an individual who has received training or 
education in mental health competencies and has a minimum of three years of relevant work experience and has demonstrated, prior to or within ninety days of hire, competencies in basic 
mental health skills alon g with competencies established by the agency, and who are not

mental health skills alon g with competencies established by the agency, and who are not 
otherwise designated as providers or supervisors, and who are not required to perform duties 
covered under the scope of practice according to Ohio  professional licensure.  
Overview of Supervision  
Ohio Medicaid covers services provided by practitioners who, under state licensing, require supervision.  
The types of practitioners who may supervise are determined according to the appropriate licensing 
boards. 
General supervision : The supervising practitioner must be available by telephone to provide assistance 
and direction if needed.  
Direct supervision: The supervising practitioner must be “immediately available” and “interruptible” to 
provide assistance and direction throughout the performance of the procedure; however, he or she does not need to be present in the room when the procedure is performed.

provide assistance and direction throughout the performance of the procedure; however, he or she does not need to be present in the room when the procedure is performed.  
Ohio Medicaid requires the  following practitioners to practice under  eithe r direct or general supervision.  
Reporting the supervising NPI on the claim is optional .  For those practitioners listed below with direct 
supervision, the service will be paid at direct supervisor ’s rate when supervisor NPI  is included in the 
header of the  claim . If the supervisor NPI is not included  on the claim indicating  the service is provided 
under general supervision, the service will be paid at 72 .25% of maximum fee.  
 
Table 1 -1: Supervision for C urrent P rocedural T erminology (CPT®) Codes  
Practitioner Providing the Service:  Type of Supervision  
Licensed professional counselor  General  
Licensed chemical dependency counselor II or III  General  
Licensed social worker  General

Licensed social worker  General  
Licensed marriage and family therapist  General  
Psychology assistant, intern, trainee  Direct/ General  
Chemical dependency counselor assistant  Direct /General  
Counselor trainee  Direct /General  
Social worker trainee  Direct /General  
Marriage and family therapist trainee  Direct /General

16 | Page  Table 1 -2: Supervision for Healthcare Common Procedure Coding System ( HCPCS) Codes  
Psychology assistant, intern, trainee  General  
Chemical dependency counselor assistant  General  
Counselor trainee  General  
Social worker assistant  General  
Social worker trainee  General  
Marriage and family therapist trainee  General  
Qualified Mental Health Specialist  General  
Care Management Specialist  General  
Certified peer supporters  General  
 
Practitioners requiring supervision must have supervision available to them  at all times, including 
supervisor sick da ys, trainings, vacations, etc. Each licensing board regulates supervision requirements for 
their provider types and may have specific requirements pertaining to super visor coverage during 
absences.  In the absence of board guidance on supervisor coverage, Ohio Medicaid does not require

absences.  In the absence of board guidance on supervisor coverage, Ohio Medicaid does not require 
practitioners to be assigned to a specific supervisor, therefore, any qualified supervising practitioner 
permitted by the practitioner’s respective licensing board’s OAC may provide coverage during absences but must assume all supervision responsibilities, including signing off on servic es provided. The 
following websites contain further guidance on supervision:  
• State of Ohio Medical Board  - http://med.ohio.gov/
 
• Ohio Nursing Board - http://www.nursing.ohio.gov/  
• Counselor, Social Worker and Marriage and Family Therapist Board –  
https://cswmft.ohio.gov/wps/portal/gov/cswmft/home   
• Ohio Chemical Dependency  Professionals Board - http://ocdp.ohio.gov/  
• Ohio Board of Psychology - http://psychology.ohio.gov/

• Ohio Board of Psychology - http://psychology.ohio.gov/  
 
*This is a brief overview concerning licensure and scope of practice. It is each agency or provider’s 
responsibility to understand the  laws, rules, and  requirements applicable to their licensure and scope 
of practice.  
Incident to Services  
The term “incident to” refers to the services or supplies that are a key part of the physician’s personal professional services in the course of diagnosis or treatment of an illness or injury. In plain language: 
under the “incident to” provision of Medicare, services are submitted under the physician’s NPI but are 
actually performed by som eone else. There are restrictions on the types of services that ancillary 
personnel may perform under this provision. Ohio Medicaid follows the CMS guidelines on “incident to

personnel may perform under this provision. Ohio Medicaid follows the CMS guidelines on “incident to 
services”. More information is available in The “Incident To” Provision of Medicare Fact Sheet.
  
Additional Resources for CMS “incident to” billing information: 
• Medicare Benefit Policy Manual, Chapter 15 Section 60.1  
• CMS Medicare Learning Network Articles  
Practitioner Modifiers   
In order to communicate detailed information in an efficient, standardized way , modifiers are two -
character suffixes that healthcare providers or coders attach to a CPT  or HCPCS  code to provide 
additional information about the practitioner or procedure. It is extremely important to accurately report

17 | Page  modifiers as they are used to count towards soft limits, price services, and adj udicate claims 
appropriately. Modifiers are always two characters in length. They may consist of two numbers, two 
letters, or a combination of a letter and a number  (alphanumeric). Ohio Medicaid will accept modifiers in 
any order, however, modifier fields on the claim must be populated in order from one to four (the first 
modifier field must be populated before the second modifier field, etc.).  
 
Table 1 -3: Practitioner Modifier s 
Practitioner P roviding the S ervice:  Professional Abbreviation Practitioner 
Modifier  
Licensed professional counselor  LPC U2* 
Licensed chemical dependency counselor III  LCDC III  U3* 
Licensed chemical dependency counselor II  LCDC II  U3* 
Licensed social worker LSW U4* 
Licensed marriage and family therapist LMFT U5* 
Licensed practical nurse LPN  TE* 
Registered nurse  RN TD*

Registered nurse  RN TD* 
Psychology assistant, psychology intern, psychology trainee  PSY assistant  U1* 
Chemical dependency counselor assistant  CDC -A U6* 
Counselor trainee  C-T U7* 
Social worker assistant  SW-A U8* 
Social worker trainee  SW-T U9* 
Marriage and family therapist trainee MFT-T UA* 
QMHS – high school  QMHS  HM 
QMHS – Associate’s QMHS  HM 
QMHS – Bachelor’s QMHS  HN 
QMHS – Master ’s QMHS  HO 
QMHS  – 3 years’ experience QMHS  UK 
Care management specialist – high school  CMS HM 
Care management specialist – Associate ’s CMS HM 
Care management specialist – Bachelor’s CMS HN 
Care management  specialist  – Master ’s CMS HO 
Peer recovery supporter  – high school  PRS HM 
Peer recovery supporter – Associate’s  PRS HM 
Peer recovery supporter – Bachelor’s  PRS HN

Peer recovery supporter – Bachelor’s  PRS HN 
Peer recovery supporter – Master’s  PRS HO 
*For fee for service, these modifiers are optional except when  the rendering practitioner holds multi -
license specialt ies and is rendering a service only available under a secondary  license/certificate. 
Additional modifiers ( HM, HN, HO, and UK)  to designate education level are required for services as 
listed in this table. For information on MCP requirements, please refer to 
https://bh.medicaid.ohio.gov/Provider/Medicaid-Managed -Care-Plans .

18 | Page  Procedure Modifiers  
The following modifiers are required to describe specific circumstances that may occur during a service:  
 
Table 1 -4: Procedure Modifiers  
Service Circumstance  Modifier  
Group service  HQ 
Physician, team member (ACT)   AM 
CNP team member (ACT)  UC 
PA or CNS, team member (ACT)  SA 
Master’s level, RN, LPN, team member (ACT)  HO 
Bachelor’s level, team member (ACT)  HN 
Peer recovery supporter , team member (ACT)  HM 
Required to indicate PSR ( rather than  MH LPN nursing services)  HM 
Pregnant/parenting women’s program  HD 
Complex/ high tech level of care  TG 
Cognitive Impairment (SUD residential ASAM level 3.3)  HI 
Licensed practitioners providing TBS Group Hourly/Per Diem  (day treatment) or SUD 
intensive outpatient, partial hospitalization , or group counseling  HK 
OTP Daily Administration  HF 
OTP One Week Administration  (2 – 7 Days)  TV 
OTP Two Week Administration  (8 – 14 Days)  UB

OTP Two Week Administration  (8 – 14 Days)  UB 
OTP Three Week Administration  (15 – 21 Days)  TS 
OTP Four Week Administration  (22 – 28 Days)  HG 
Significant, separately identifiable Evaluation & Management (E &M) service by 
physician or other qualified health professional on the same day of the procedure or 
other service  25 
NCCI modifiers (See NCCI Section ) 59, XS, XE, XU and XP  
CLIA waived test - certificate of waiver – CMS certificate type code 2 or higher 
required  QW 
Crisis  modifier used on T1002, H2017 (PSR only , not LPN nursing service ), H2019, 
H0004 and 90832  KX 
Physician delivering SUD group counseling  AF 
The GT Modifier is required for any service delivered via secured  video -conferencing 
or other allowable telehealth delivery methods in accordance with OAC 5160 -1-18

or other allowable telehealth delivery methods in accordance with OAC 5160 -1-18 
(See the rule appendices  for the list of  services  that may be delivered via telehealth )  GT 
Withdrawal management 2 -3 hours  AT 
Place of Service (POS)  
Providers must accurately identify and report on each claim detail line where a service took place using 
the most appropriate  CMS place of service code . Each billing chart in this manual will list the place of 
service codes covered by Medicaid .  
 
“Other Place of Service” Setting

19 | Page  Place of service “99 -Other Place of Service” has been redefined for Ohio Medicaid as “ Community”. See 
this manual’s Appendix for a more complete definition of this and other  places of service.  
Claims Detail Rollup  for Same Day Services   
When the same service is rendered to the same client by the same practitioner at more than one time 
during the same day, those services should be “rolled up”  into a single detail line on a claim. However , if 
anything differs except the time the service was rendered, the claims should be reported separately.  
Services that need  to be rolled must be rolled by the same date of service, same client, same HCPCS code,  
same modifier(s), same individual rendering pr actitioner  NPI, same supervisor NPI, and same place of 
service. Services that are not appropriately rolled up may result in a denial for duplicate services.  
Example  1: Amy Smit h, RN  renders TBS to  a client in the office in the morning and then again in the

Example  1: Amy Smit h, RN  renders TBS to  a client in the office in the morning and then again in the 
office later that  afternoon. This is acceptable to roll up the two patient contacts into the same claim line 
because there is the same service, the same rendering practitioner, the same client, and the same place of 
service.  
Example 2: Amy Smit h, RN renders TBS to  a client in the office in the morning and then again in the 
client’s home  later that  afternoon. T he services should be reported on separate detail lines with 
appropriate place of service identifying home or office .  
Third Party Payer (TPP) Coordination of Benefits  (COB)  
Coordination of benefits is the process of determining  the payment obligations of each health plan,

Coordination of benefits is the process of determining  the payment obligations of each health plan, 
insurance policy, or third-party resource when two or more resources cover the same benefits for a Medicaid recipient. Coordination of benefits is a federal requirement set forth in 42 CFR 433 Subpart D and includes specific activities for state Medicaid agencies related to third -party liability (TPL). 
Medicaid, or a Medicaid Managed Care Entity (MCE) must be the payer of last resort, except as allowed in OAC rules 5160-1-08 and 5160-26 -09.1 . 
  
After  a provider has gone through all reasonable measures to obtain all third-party payments as described 
in OAC rules  5160-1-08 and 5160-26 -09.1 a claim may be submitted to ODM/MCEs requesting 
reimbursement for the rendered service(s). Providers who have received a zero payment from a third -

party payer (TPP) or a partial payment will need to use the appropriate claim adjustment reason codes (CARCs) from the primary’s Explanation of Benefits (EOB) on the claim submission to ODM/MCEs.  
 ODM  maintains a list of specific service procedure codes or combinations of procedure codes and 
rendering providers that are covered by Ohio Medicaid but are not generally covered by commercial 
payers or Medicare.  This list, known as the BH Medicare and TPL list is located at 
https://medicaid.ohio.gov/resources -for-providers/bh/manuals
 under Billing Resources/Medicar e and TPL 
Bypass list . The list is separated into three sections – Medicare, Medicare Opioid Treatment Program 
(OTP), and TPL Bypass (for commercial payers).

under Billing Resources/Medicar e and TPL 
(OTP), and TPL Bypass (for commercial payers).  
• The Medicare list includes procedure codes and procedures code/ rendering provider  type 
combinations  not covered  by Medicare.  
• The Medicare OTP list is  only applicable to opioid treatment providers serving individuals with 
Medicare coverage.  
• The TPL Bypass list is applicable to other payers (other than Medicare or Medicaid pa yers).  
For the procedure code s on each of these payer lists, respectively, the provider may “bypass” the 
requirement to first bill the Third Party Payer (commercial or Medicare payer) and submit the claim 
directly to Medicaid.

20 | Page  The BH Medicare and TPL Bypass List  was created to allow payment for certain services ODM identified 
that are not typically covered by TPPs. However, if TPP coverage is later discovered through ODM’s or 
an MCE’s post payment recovery process, payment may be recouped in accordance with federal 
Medicaid requirements. Therefore, if a provider is unsure of a specific TPP’s coverage policy for any of 
the services or procedure codes, the provider should confirm coverage prior to billing for the service directly to Medicaid to avoid a future recoupment. As Medicare and commercial insurance coverage changes, the Bypass List will be updated.  
 
The BH Medicare and TPL Bypass L ist only applies to claims submitted by Medicaid provider types 84 
(Community Mental Health Agencies) and 95 (Substance Use Disorder Treatment Providers).  ODM 
recommends:  
• BH providers require individuals to provide TPP information at the time of service as a best 
practice.

practice.  
• BH providers should use the El ectronic Data Interchange 270/271 eligibility transaction, check 
the payer portal, and exhaust any other sources for any TPP information on file, prior to 
submitting a claim to Medicaid. 
• BH providers are required to bill the TPP prior to billing Medicaid for all services except for the 
service procedure codes listed on the BH Medicare and TPL Bypass L ist. 
• BH providers should always notify ODM when they identify incorrect TPL information.  
Benefits and Prior Authorization  
In the behavioral health benefit package, there are services and/or levels of care that are subject to prior 
authorization. T able 1-5 summarizes those services/levels of care and their associated prior authorization 
policy . Certain services may have prior authorization requirements when provided on the same day as

policy . Certain services may have prior authorization requirements when provided on the same day as 
other services. Please refer  to OAC Chapter 5160-27  and rule 5160-8-05  for service-specific 
requirements.

21 | Page  Table 1 -5: Prior Authorization  
Description and Code  Benefit Period  Authorization Requirement  
Assertive Community Treatment (ACT)  
H0040  Based on prior 
authorization 
approval  ACT must be prior authorized and 
SUD services above ASAM level 
1 must be prior authorized for 
ACT enrollees.  
Intensive Home Based Treatment (IHBT) H2015  
Functional Family Therapy (FFT) H2015 TF 1 Both  services are 
based  on prior 
approval  Both services  must be prior 
authorized.  
SUD Partial Hospitalization  
H0015 TG  Calendar y ear Prior authorization is required for 
this level of care for adults and 
adolescents.  
Psychiatric Diagnostic Evaluations  
90791, 90792  Calendar year  1 encounter per person per 
calendar year per code per billing agency  for 90791 and 90792. Prior 
authorization is required for 
additional service.  
Psychological Testing  
96112, 96113, 96116, 96121, 96130, 96131, 96132, 96133,

96112, 96113, 96116, 96121, 96130, 96131, 96132, 96133, 
96136, 96137  Calendar year  Up to 20 hours/encounters per 
patient per calendar year for all psychological testing codes . Prior 
Screening Brief Intervention and Referral to Treatment 
(SBIRT) G0396, G0397  Calendar year  One of each code (G0396 and 
G0397), per billing agency , per 
patient, per year. Cannot be billed by provider type 95. Prior authorization is required for 
Alcohol or Drug Assessment H0001  Calendar year  2 assessments  per patient per 
calendar year per billing agency . 
Does not count toward ASAM level of care benefit limit. Prior authorization is required for 
TBS Group Per Diem  
H2020  Calendar year  1 per day . Prior authorization  is 
required for an additional per diem service to the same client on the

required for an additional per diem service to the same client on the 
same day rendered by a different 
billing agency .

22 | Page  Description and Code  Benefit Period  Authorization Requirement  
SUD Residential  
H2034, H2036 Calendar year  Up to 30 consecutive days without 
prior authorization. Prior authorization then must support the medical necessity of continued stay, if not, only the initial 30 
consecutive days are reimbursed. 
This applies to first two stay s. 
Third and subsequent  stays in the 
same year require prior 
authorization  from the first day of 
admission.  
SUD Peer Recovery  
H0038  Calendar year  Up to 4 hours per day  without 
prior authorization. Prior 
authorization  would be needed to 
cover more than 4 hours in a day 
once limit is reached . 
MRSS Stabilization Service  
S9482   Based on prior 
approval  Prior Authorization is needed for 
stabilization services rendered more than six weeks from the 
completion of a mobile response.  
1 For dates of service between  March 1, 2022 – June 30, 2022. Effective July 1, 2022, these services are

1 For dates of service between  March 1, 2022 – June 30, 2022. Effective July 1, 2022, these services are 
available only under OhioRISE 
Fee for service p rior authorization instructions are available on the ODM website -
http://medicaid.ohio.gov/PROVIDERS/PriorAuthorizationRequirements.aspx . Training on how to submit 
a fee for service prior authorization request for a behavioral health service is available at 
http://bh.medicaid.ohio.gov/training . Information regarding prior authorization requests for Medicaid 
clients enrolled with a managed care or MyCare Ohio  plan can be found in the Medicaid Managed Care 
Plan Resource Guide .  
Requirements for m edical n ecessity are found here: OAC 5160-1-01  
Non-Covered Services  
Non-covered services are described in OAC rules 5160-1-61 and  5160-27 -02 . Additionally, Ohio  
Medicaid  does not cover services to individuals that meet the criteria described in OAC rule 5160:1-1-03 .

Medicaid  does not cover services to individuals that meet the criteria described in OAC rule 5160:1-1-03 .  
A missed appointment is considered a non -service and is not reimbursable by Ohio Medicaid  as described 
in OAC rule 5160-1-13.1 . 
Fraud, Waste, and Abuse  
OAC rule 5160-1-29  sets forth the Ohio Medicaid policy on Medicaid Fraud, Waste , and Abuse. Under 
the Ohio Medicaid provider agreement, providers are required to comply with the terms of the agreement, 
Ohio Revised Code, Administrative Code, and federal statutes and rules. In Ohio, the Attorney General is 
authorized under ORC 109.85 to create a Medicaid Fraud and Control Unit (MFCU) for investigating and

23 | Page  prosecuting Medicaid provider fraud in Ohio . Additional information regarding Ohio’s Medicaid Fraud 
Control unit can be found on their website, Health Care Fraud - Ohio Attorney General Dave Yost .  
Review of Provider Records  
OAC rule 5160-1-27  sets for th the Ohio Medicaid policy on Review of Provider Records. Please review 
this rule for more information about Ohio Medicaid audit and review activities.  
Payment Error Rate Measurement (PERM)  
The CMS Payment Error Rate Measurement (PERM) program measures and reports  improper payments 
in Medicaid and Children’s Health Insurance Program ( CHIP). Please visit CMS’ PERM website  for 
more information .  
Medicaid  National Correct Coding Initiative  
The National Correct Coding Initiative (NCCI) was established by the Centers for Medicare & Medicaid  
Services (CMS) to promote national correct coding methodologies with the goal to reduce improper

Services (CMS) to promote national correct coding methodologies with the goal to reduce improper 
coding that results in inappropriate payments for both Medicare and Medicaid . A complete and up -to-date 
list of NCCI edits can be found at  https://www.medicaid.gov/medicaid/program -integrity/national-
correct -coding-initiative/medicaid -ncci -edit-files/index.html . These edits are updated quarterly.  
 NCCI procedure -to-procedure (PTP) edits and medically unlikely edits (MUEs) are only applicable to a 
single provider to a single individual  on the same date of service.  NCCI contains two types of edits:  
 
NCCI P rocedure -To-P rocedure (PTP) Edits  
PTP edits define pairs of Healthcare Common Procedure Coding System (HCPCS) / Current Procedural 
Terminology (CPT) codes that should not be reported together for a variety of reasons. The purpose of the 
PTP edits is to prevent improper payments when incorrect code combinations are reported.

PTP edits is to prevent improper payments when incorrect code combinations are reported.  
  Example 1 : The same physician performs a psychotherapy service and Evaluation and Management 
(E&M) service on the same day for the same client (significant and separately identifiable services). 
NCCI will not allow the psychotherapy code 90834 to be billed with an E& M office visit code 99212, as 
there are separate add -on codes (+90833, +90836, and +90838) for psychotherapy services provided in 
conjunction with E&M services.  
 Example 2: A qualified practitioner working for ABC Behavioral Health Agency renders 90791, a 
psychiatric diagnostic assessment, for a client. On the same day, the same client receives an “evaluation 
and manage ment” primary care service (e.g. 99202 -99205) rendered by another qualified practitioner

and manage ment” primary care service (e.g. 99202 -99205) rendered by another qualified practitioner 
working for ABC Behavioral H ealth Agency. According to the NCCI practitioner to practitioner (PTP) 
edit guidance, this is acceptable because in this scenario, the services were rendered by two different rendering practitioners. The NCCI PTP edits apply only to the same practitioner.  
 
Medicaid  PTP, MUE edits , and other relevant information can be found at:  
https://www.medicaid.gov/medicaid/program -integrity/ncci/edit-files/index.html
. 
 
For PTP edits that have a Correct Coding Modifier Indicator (CCMI) of “0,” the codes should never be reported together by the same provider for the same individual  on the same date of service. If they are

24 | Page  reported on the same date of service, the column one code is eligible for payment and the column two 
code is denied.  
 For PTP edits that have a CCMI of “1,” the codes may be reported together only in defined circumstances which are identified on the claim by the use of specific NCCI -associated modifiers. Where services are 
“separate and distinct,” it may be necessary to o verride the procedure -to-procedure edit using a specific 
modifier : 
• XE – “Separate encounter, A service that is distinct because it occurred during a separate 
encounter” (This modifier should only be used to describe separate encounters on the same date of service). 
• XS – “Separate Structure, A service that is distinct because it was performed on a separate 
organ/structure .” 
• XP – “Separate Practitioner, A service that is distinct because it was performed by a different 
practitioner .” 
• XU – “Unusual Non -Overlapping Service, The use of a service that is distinct because it does not

• XU – “Unusual Non -Overlapping Service, The use of a service that is distinct because it does not 
overlap usual components of the main service .” 
 Documentation must support a different session, different procedure or surgery, different site or organ system, separate incision/excision, separate lesion, or separate injury (or area of injury in extensive injuries) not ordinarily encountered or performe d on the same day by the same individual. However, 
when another already established modifier is appropriate, it should be used rather than modifier 59. Modifier 59 should only be utilized if no other more specific modifier is appropriate.   
 
Medically Unlikely Edits (MUEs) 
MUEs define for each HCPCS / CPT code the maximum units of service (UOS) that a provider would report under most circumstances for a single individual  on a single date of service.  MUEs cannot be 
overridden with the 59, XE, XS, XP, XU modifiers.

overridden with the 59, XE, XS, XP, XU modifiers. 
 Example 1: The same physician performs two diagnostic evaluations (2 units of 90791) to the same client on the same day. NCCI will deny the second evaluation, as it is medically unlikely that one client would need two complete diagnostic evaluations in the same day.   
 There is extensive guidance regarding Medicaid  agencies and national correct coding  available at 
The 
National Correct Coding Initiative in Medicaid .

25 | Page  Time -Based CPT Codes  
When billing time -based codes,  the CPT/HCPCS time rule applies, unless otherwise specified : For the 
minimum billable service of the code, divide the time by two and add one minute in order to determine if 
that code can be billed.  For example; 90832 = 30 minutes, therefore the minimum length of service must 
be 16 minutes (30/2 = 15 then 15 + 1 = 16) in order for the service to be billable.  
  
Conversion Chart  
Reported in 15 Minute Increments  
 
Minimum  Maximum  Billing  
Minutes  Minutes  Unit(s)  
Hour 1  
0 7 N/A 
8 22 1 
23 37 2 
38 52 3 
53 67 4 
Hour 2  
68 82 5 
83 97 6 
98 112 7 
113 127 8 
Hour 3  
128 142 9 
143 157 10 
158 172 11 
173 187 12 
Hour 4  
188 202 13 
203 217 14 
218 232 15 
233 247 16 
Prolonged Services  
Effective January 1, 2023, the American Medical Association ( AMA) discontinued prolonged service 
codes 99354 and 99355 for use with psychotherapy codes . ODM  and MCE billing systems were updated

codes 99354 and 99355 for use with psychotherapy codes . ODM  and MCE billing systems were updated 
to reflect this change. Providers should refer to AMA and National Correct Coding Initiative (NCCI)  
guidance with regard to billing psychotherapy codes for dates of service on or after January 1, 2023.  
Effective January 1, 2022, ODM adopted for Medicaid community behavioral health providers the use of 
AMA procedure codes of 99415 and 99416 to indicate prolonged E&M services. Providers should refer to 
the CPT manual for additional information about appropriate use of codes 99415 and 99416.  
Also effective January 1, 2022, ODM’s claims payment system was updated to follow NCCI  Procedure to 
Procedure (PTP) edits to  not allow the use of 99354 and 99355 with E&M codes 99202-99205 and 
99211-99215.  Conversion Chart
Hour Based Services
Reported in Whole Unit Increments

Minimum Maximum Billing
Minutes Minutes Increment
1 30 N/A
31 90 1
91 150 2
151 210 3
211 270 4
271 330 5
331 390 6
391 450 7
451 510 8
511 570 9

26 | Page  Providers serving individuals with primary insurance coverage other than Medicaid are advised to follow 
billing guidance for the primary payer when determining which prolonged services code to use before submitting to Medicaid for secondary payment.  
For more information regarding prolonged services codes, please review the prolonged services section of the latest edition of the CPT manual. The link to  the CPT website can be found here
. 
SECTION 2  
Behavioral Health Services  
For behavioral health billing, CPT service codes consist of E& M office visits, psychotherapy, psychiatric 
diagnostic evaluations, psychiatric testing , and appropriate add-on codes. The American Medical 
Association (AMA) publishes annual CPT reference books, which provide the CPT l codes, their 
associated descriptions, and guidance on appropriate use, including use of add- on codes . Please note,

associated descriptions, and guidance on appropriate use, including use of add- on codes . Please note, 
providers are responsible for utilizing the appropriate AMA and/or CMS guidance for documentation and 
billing. Therefore, it is recommended that all providers obtain a copy of a current CPT manual and, for 
those providers/practitioners that participate in the Original Medicare program, the most current guidance is available through the Medicare Learning Network (MLN)
. This section also includes billing guidance 
for HCPCS codes that  are also available to both MH and SUD agencies. Practitioner abbreviations are 
used in the service tables provided in the remaining sections of this manual.  The chart below may be used 
as a reference to these abbreviations. 
 
Practitioner Abbreviations Key  
MD/DO  Physician  LSW  Licensed social worker

MD/DO  Physician  LSW  Licensed social worker  
CNS  Clinical nurse specialist  LMFT Licensed marriage and family 
therapist  
CNP  Certified nurse practitioner  LPC  Licensed professional counselor  
PA Physician assistant  LCDC II or LCDC 
III Licensed chemical dependency 
counselor II or III  
RN Registered nurse  SW-A Social worker assistant  
LPN  Licensed practical nurse  SW-T Social worker trainee  
PSY  Psychologist  MFT -T Marriage and family therapist 
trainee  
LISW  Licensed independent social worker  C-T Counselor trainee  
LIMFT  Licensed independent marriage and family 
therapist  CDC-A Chemical dependency counselor 
assistant  
LPCC  Licensed professional clinical counselor  CMS  Care management specialist  
LICDC  Licensed independent chemical 
dependency counselor  QMHS  Qualified mental health specialist  
Lic

Lic 
school PSY  Board licensed school psychologist  QMHS +3  Qualified mental health specialist  
with 3 years’ experience  
PSY 
assistant  Psychology assistant  PRS  Peer recovery supporter  
RPH  Pharmacist

27 | Page  Evaluation and Management Codes  
 
Table 2 -1: Evaluation & Management Office Visit  
MH / SUD  
Service  Provider Type  Code  Rate  through  
December 31, 2023  Rate effective  
January 1, 2024  
E&M New Patient  MD/DO  99202  
99203  
99204  
99205  $84.67  
$122.93  
$188.51  
$236.92  $93.14  
$135.22  
$207.36  
$260.61  
CNS  
CNP  
PA  
99202  
99203  
99204  
99205  
 $84.67  
$122.93  
$188.51  
$135.22  
$207.36  
$260.61  
RPH 99202  
99203  $33.09  
$49.09  $35.08  
$52.04  
E&M Established 
Patien t MD/DO   
99211  
99212  
99213  
99214  
99215  
 $22.31  
 $48.97  
 $82.85  
$122.27  
$165.15   
$24.54  
$53.87  
$91.14  
$134.50  
$181.67  
CNS  
CNP  
PA  
99211  
99212  
99213  
99214  
99215  
 $22.31  
 $48.97  
 $82.85  
$122.27  
$165.15   
$24.54  
$53.87  
$91.14  
$134.50  
$181.67  
RN 
LPN  99211  $22.31  $24.54  
RPH 99211  
99212  
99213   
$12.32  
$22.72  
$37.06  
  
$13.06  
$24.42  
$39.30  
Unit Value  Encounter

$24.54  
$53.87  
$91.14  
$134.50  
$181.67  
RN 
RPH 99211  
99212  
99213   
$12.32  
$22.72  
$37.06  
  
$13.06  
$24.42  
$39.30  
Unit Value  Encounter  
Permitted POS  11, 13, 31, 32  
MH also has 53  
SUD also has 57 Telehealth allowed with GT modifier.  GT modifier is required when 
service rendered via telehealth.

28 | Page  Table 2- 2: Prolonged Service codes for E&M Office Visits 
MH / SUD  
Service  Provider Type  Code  Rate  through 
December 31, 2023  Rate effective 
 
Prolonged Visit – 
First 60 minutes  
  MD/DO  
CNS  
CNP  
PA +99415  -  
$12.03  
Each Additional 30 
Minutes  MD/DO  
CNS  
CNP  
PA +99416  -  
$6.18  
Each Additional 15 
Minutes 
(for use with codes 
99205 and 99215 
only)  MD/DO  +99417   
$38.53   
$42.38  
CNS  
CNP  
PA +99417   
$38.53   
$42.38  
Minutes 
only)  MD/DO  +G2212   
$38.53   
$42.38  
CNS  
CNP  
PA +G2212   
$38.53   
$42.38  
Unit Value  +99415 – first 60 minutes  
+99416 – each additional 30 minutes  
+99417 – each additional 15 minutes  
+G2212 – each additional 15 minutes  
Permitted POS  Same as base code Telehealth allowed with GT modifier . GT modifier is required 
when service rendered via telehealth.

29 | Page  Table 2 -3 Evaluation and Management Office Visit - Report of Pregnancy  
MH / SUD  
Report of 
Pregnancy* MD/DO  
CNS  
CNP  
PA T1023  $30.00  $30.00  
 
HCPCS code T1023 is to be used for a “Report of Pregnancy”  (ROP). Payment may be made for one 
report of a pregnancy diagnosed in conjunction with an E&M service that is not associated with a normal 
obstetrics/gynecology visit. The report must be submitted through NurtureOhio, available here: 
https://progesterone.nurtureohio.com/login .  The report of pregnancy must occur in conjunction with an 
E&M service and be rendered by a physician, advanced practice registered nurse, or physician assistant. 
The payment is paid in addition to the E&M visit.

The payment is paid in addition to the E&M visit. 
To access the ROP on the NurtureOhio site, the user needs to have an OH|ID linked to their provider in the PNM. For additional information and NurtureOhio login instructions, review the Provider User Guide 
here: https://progesterone.nurtureohio.com/media/PRAFProviderUserGuide10-1-22.pdf
.

30 | Page  Table 2 -4: Evaluation & Management Home Visit  
MH / SUD  
Service  Provider 
Type  Code  Rate  through  
E&M Home Visit 
New Patient  MD/DO   
99341  
99342  
  99343* 
99344  
99345  
 $63.65  
$91.90  
$150.80  
$210.7  
$255.5   
$70.02  
$101.09  
* 
$231.86  
$281.13  
CNS  
CNP  
PA  
99341  
99342  
  99343* 
99344  
99345  
 $63.65  
$91.90  
$150.80  
$210.78  
$255.57   
$70.02  
$101.09  
* 
$231.86  
$281.13  
Established 
Patient  MD/DO   
99347  
99348  
99349  
99350  
 $64.00  
$97.38  
$148.16  
$205.79   
$70.40  
$107.12  
$162.98  
$226.37  
CNS  
CNP  
PA 99347  
99348  
99349  
99350   
$64.00  
$97.38  
$148.16  
$205.79  
  
$70.40  
$107.12  
$162.98  
$226.37  
Permitted POS  04, 12, 16  
 
*CPT® code 99343  has been deleted effective January 1, 202 3. For dates of service on or after January 1,

$107.12  
$162.98  
$226.37  
 
*CPT® code 99343  has been deleted effective January 1, 202 3. For dates of service on or after January 1, 
2023 , providers should report appropriate evaluation and management codes in accordance with the 
AMA.

31 | Page  Table 2 -5: Prolonged Service codes for E&M Home Visits 
For dates of service prior to  January 1, 2023*  
MH / SUD  
Service  Provider Type  Code  Rate  
 
(Use in conjunction 
with covered BH 
codes 99341 -
99350) 
 MD/DO   
+99354  $89.90  
CNS  
CNP  
PA +99354  $76.42  
minutes 
99350)  MD/DO  +99355  $89.24  
CNS  
CNP  
PA +99355  $75.85  
Unit Value  +99354 – first 60 minutes  
+99355 – each additional 30 minutes  
Permitted POS  Same as base code  Telehealth allowed with GT modifier.  GT modifier is required when 
service rendered via telehealth.  
 
Table 2 -6: Preventive Medicine Counseling  
MH / SUD  
Service  Provider Type  Code  Rate s 
 
Preventive 
Medicine 
Counseling – 15 
minutes 
 
 MD/DO  
CNS  
CNP  
PA 
RPH  
+99401  
For rates, see the Medicine, Surgery, Radiology a nd

MH / SUD  
 
Medicine 
minutes 
 
 MD/DO  
CNS  
CNP  
PA 
RPH  
+99401  
For rates, see the Medicine, Surgery, Radiology a nd 
Imaging, and Additional Procedures (Non-Institutional 
Services) schedule  on the Fee Schedule and Rates page  
of the ODM website.  Preventive 
Medicine 
Counseling – 30 
minutes 
 MD/DO  
CNS  
CNP  
PA 
RPH +99402  
Unit Value  See code description  

32 | Page  Table 2 -7: Psychiatric Diagnostic Evaluation  
MH / SUD  
Service  Provider Type  Code  Practitioner 
Modifier  Rate  through  
Psychiatric 
Diagnostic 
Evaluation w/o 
Medical  MD/DO  
PSY 90791  - $130.72  $147.39  
CNS  
CNP  
PA  
90791  
  
- 
 
 $130.72   
 
$147.39  
LISW  
LIMFT 
LPCC  
LICDC (SUD only)  
Lic school PSY  90791   $111.11  $125.28  
LSW  
LMFT 
LPC  
LCDC III (SUD only)  
LCDC II (SUD only)  90791  U4 
U5 
U2 
U3 
U3 $111.11  $125.28  
PSY assistant  90791  U1 Paid at direct 
supervisor rate when 
supervisor NPI on 
claim. Paid at 85% of 
maximum fee if 
supervisor NPI not 
included  Paid at direct 
included  
SW-T 
MFT-T 
CDC -A (SUD only)  
C-T 90791  U9 
UA 
U6 
U7  
Paid at direct 
claim . Paid at 72.25% 
of maximum fee if 
supervisor NPI not

included  
SW-T 
MFT-T 
UA 
U6 
U7  
included  
 Paid at direct 
claim. Paid at 
72.25% of maximum 
fee if supervisor NPI 
not included  
Evaluation w/ 
Medical  MD/DO  90792  -  
$144.35  
  
$162.75  
 
CNS  
CNP  
PA 90792  - $144. 35 $162.75  
 Permitted POS  03, 04, 11, 12, 13, 14,  16, 18,  31, 32, 99 
SUD also has 57  Telehealth allowed with GT modifier.  GT 
modifier is required when service rendered via 
telehealth.

33 | Page  Table 2 -8 – Electrocardiogram  
MH / SUD  
December 31, 202 3 Rate effective  
Electrocardiogram - at 
least 12 leads w/ 
interpretation and 
report  MD/DO  93000  $15.90  $17.49  
CNS  
CNP  93000  $13.52  $14.87  
PA 93000  $13.52  $14.87  
Electrocardiogram - 
tracing only w/o 
report  MD/DO  93005  $6.90  $7.59  
CNS  
CNP  93005  $5.87  $6.45  
PA 93005  $5.87  $6.45  
report only  MD/DO  93010  $7.90  $8.69  
CNS  
CNP  93010  $6.72   
$7.39 
PA 93010  $6.72  $7.39  
Unit Value  Encounte r 
Permitted POS  11 
MH also has 53 
SUD also has 57

34 | Page  Table 2 -9: Provider A dministered P harm aceuticals  
MH / SUD  
Service  Medication  Code  Procedure  
Modifier  Rate  
Medication 
Administered by 
Medical Personnel 
(J-Codes)  Injection, aripiprazole (Abilify), intramuscular, 
0.25 mg  J0400  None  
For rates, see the 
Provider 
Administered 
Pharmaceuticals 
schedule on the Fee 
Schedule and Rates 
page  o f the ODM 
website.  Injection, aripiprazole (Abilify), 1 mg  J0401  None  
Cogentin (benztropine mesylate ), per 1  mg J0515  None  
Buprenorphine, oral, 1 mg  J0571  None  
Diphenhydramine hcl (Benadryl), up to 50 mg  J1200  None  
Haloperidol injection, up to 5 mg  J1630  None  
Haloperidol Decanoate injection , per 50 mg  J1631  None  
Injection, aristada initio, 1mg  J1943  None  
Injection, aripiprazole  lauroxil , 1 mg  J1944  None  
Lorazepam injection, 2  mg J2060  None  
Injection, methylnaltrexone (Relistor), 0.1  mg J2212  None  
Injection, naloxone (Narcan), 1  mg J2310  None

Injection, naloxone (Narcan), 1  mg J2310  None  
Injection, naloxone hydrochloride (zimhi), 
1mg J2311  None  
Injection, naltrexone (Vivitrol), depot form,  
1 mg  J2315  None  
Olanzapine long acting injectable , 1 mg  J2358  None  
Paliperidone Palmitate injection (Invega 
Sustenna or Invega Trinza), 1 mg  J2426  None  
Injection, Invega Hafyera/Trinza  J2427  None  
Fluphenazine Decanoate injection , 25 mg  J2680  None  
Risperidone, long acting, .5 mg  J2794  None  
Naloxone (nasal route)  J3490  None  
Valium injection, up to 5 mg  J3360  None  
Oral Naltrexone  J8499  HG 
Unit Value  Based on HCPCS descriptor  
Unit Value  03, 04, 11, 12, 14  
SUD also has 55, 57

35 | Page  MH / SUD  * 
Service  Description  Provider 
Type Code  Rate  through  
December 31, 
2023  Rate effective  
January 1, 2024 
Other Medication 
Administration  Therapeutic, 
prophylactic, or 
diagnostic injection 
(specify substance or 
drug); subcutaneous or 
intramuscular  MD/DO 
CNS  
CNP  
PA 
RN/LPN  
RPH  *96372  $21.39  $23.53 
Unit Value  CPT designation  
Permitted POS  03, 04, 11, 12, 14, 16, 18  
SUD also has 57  
* 96372 is not covered in substance use disorder (SUD) residential treatment programs (provider type 95 
with provider specialty 954) due to the per diem payment methodology for SUD residential treatment .  
National Drug Code (NDC)  
Federal law requires that any claim detail line   for a drug covered by Medicaid  must be submitted with the 
11-digit NDC assigned to each drug package. The NDC specifically identifies the manufacturer, product

11-digit NDC assigned to each drug package. The NDC specifically identifies the manufacturer, product 
and package size. Each NDC is an 11 -digit number, sometimes including dashes in the format 55555-
4444- 22. When submitting claims to Medicaid, providers should submit each NDC using the 11-digit 
NDC without dashes or spaces. The NDC included on the claim must be the exact NDC that is on the 
package used by the provider.  
  Some drug packages include a 10-digit NDC. In this case, the provider should convert the 10 digits to 11 digits when reporting this on the claim. When converting a 10- digit NDC to an 11-digit NDC, a leading 
zero should be added to only one segment:  
• If the first segment contains only four digits, add a leading zero to the segment;  
• If the second segment contains only three digits, add a leading zero to the segment;  
• If the third segment contains only one digit, add a leading zero to the segment.

• If the third segment contains only one digit, add a leading zero to the segment.  
All claims reporting NDC information must be submitted either as an Electronic Data Interchange (EDI) 
transaction or through the Provider Network Management (PNM) module
. The NDC will be required at 
the detail level when a claim is submitted with a code that represents a drug (e.g., J-codes and Q-codes).

36 | Page  Laboratory Services  
Table 2 -10: Laboratory Services  
MH / SUD  
Service  Service  Code  Rate  
Laboratory 
Services  Skin test; tuberculosis, 
intradermal  86580  
For rates, see the Medicine, Surgery, Radiology and 
Imaging, and Additional Procedures (Non-
Institutional Services) schedule on the Fee Schedule 
and Rates page  o f the ODM website.  Collection of venous blood by 
venipuncture  36415  
Alcohol (ethanol), breath  82075  
Urine pregnancy test  81025  
Permitted POS  03, 04, 11, 12, 14  
SUD also has 55, 57  
Other 
Considerations  Code 36415 collection of venous blood by venipuncture may be billed for blood draws associated 
with covered external lab services.  
Laboratory Codes  
Community substance use disorder (SUD) treatment providers (provider type 95) with appropriate CLIA 
certification are provided the laboratory contract . This provides coverage for  clinical laboratory services

certification are provided the laboratory contract . This provides coverage for  clinical laboratory services 
provided  on-site if the provider has the appropriate CLIA certificate for the clinical lab services being 
performed.  See Chap Medicaid -11 for Medicaid coverage policies related to laboratory services. 
 
CLIA Certification Overview  
To bill laboratory codes besides those listed above , a provider must obtain the appropriate CLIA 
certification and enroll as a laboratory Medicaid  provider with Ohio Medicaid. ODM must have the CLIA 
certification on file for the SUD provider to access the appropriate laboratory codes. Once the certificate 
is uploaded to the PNM, the appropriate laboratory contract will be made available to the SUD agency.   
 More information on the CLIA certification process can be found at: https://odh.ohio.gov/wps/portal/gov/odh/home
.

37 | Page  Vaccines   
Ohio Medicaid allows BH providers to receive reimbursement for certain  vaccines to their adult clients 
and to children under the Vaccines for Children program, operated by the Ohio Department of Health 
(ODH).  Vaccines are covered when  administered at the following places of service: office, inpatient and 
outpatient residential facilities, in the community , and Community Mental Health Centers ( CMHC ). 
 The Vaccines for Children (VFC) program is a federally funded  program overseen by the Centers for 
Disease Control and Prevention (CDC) and administered by ODH. More information about the VFC program can be found on ODH’s website and CDC’s website
.  
 
Table 2 -11: Covered Vaccines for Behavioral Health Providers 
Vaccine 
Administration Code  Description  
90460  Immunization administration through 18 years of age via any route of administration, with 
counseling by physician or other health care professional; first or only component of each

counseling by physician or other health care professional; first or only component of each 
vaccine or toxoid administered  
90471  Immunization administration (includes percutaneous, intradermal, or intramuscular 
injections); 1 vaccine (single or combination vaccine/toxoid)  
 +90472 (add -on to 
90471)  Immunization administration; each additional vaccine. List separately in addition to code 
for primary procedure  
90473  Administration of 1 nasal or oral vaccine  
90474  Immune administration oral or nasal additional  
Vaccine CPT  Description  
90633  Hepatitis A vaccine (HepA), pediatric/adolescent dosage-2 dose schedule, for intramuscular use 
90634  Hepatitis A vaccine (HepA), pediatric/adolescent dosage -3 dose schedule, for intramuscular 
use 
90632  Hepatitis A vaccine (HepA), adult dosage, for intramuscular use

use 
90632  Hepatitis A vaccine (HepA), adult dosage, for intramuscular use  
90371  Hepatitis B immune globulin (HBIg), human, for intramuscular use  
90650  Human Papillomavirus vaccine, types 16, 18, bivalent (2vHPV), 3 dose schedule, for 
intramuscular use  
90649  Human Papillomavirus vaccine, types 6, 11, 16, 18, quadrivalent (4vHPV), 3 dose schedule, for intramuscular use  
90644  Vaccine for meningococcal and Hemophilus influenza B (4 dose schedule) injection into muscle, children 6 weeks- 18 months of age  
90698  Diphtheria, tetanus toxoids, acellular pertussis vaccine, Haemophilus influenza type b, and 
inactivated poliovirus vaccine (DTaP -IPV/Hib), for intramuscular use  
90654  Influenza virus vaccine, trivalent (IIV3), split virus, preservative-free, for intradermal use  
90658  Vaccine for influenza for administration into muscle, 0.5 ml dosage

90658  Vaccine for influenza for administration into muscle, 0.5 ml dosage  
90660  Influenza virus vaccine, trivalent, live (LAIV3), for intranasal use  
90670  Pneumococcal conjugate vaccine, 13 valent (PCV13), for intramuscular use  
90680  Rotavirus vaccine, pentavalent (RV5), 3 dose schedule, live, for oral use  
90681  Rotavirus vaccine, human, attenuated (RV1), 2 dose schedule, live, for oral use

38 | Page  Vaccine CPT  Description  
90696  Diphtheria, tetanus toxoids, acellular pertussis vaccine and inactivated poliovirus vaccine 
(DTaP -IPV), when administered to children 4 through 6 years of age, for intramuscular use  
90713  Poliovirus vaccine, inactivated (IPV), for subcutaneous or intramuscular use  
90707  Measles, mumps and rubella virus vaccine (MMR), live, for subcutaneous use 
90710  Measles, mumps, rubella, and varicella vaccine (MMRV), live, for subcutaneous use  
90714  Tetanus and diphtheria toxoids adsorbed (Td), preservative free, when administered to 
individuals 7 years or older, for intramuscular use  
90715  Tetanus, diphtheria toxoids and acellular pertussis vaccine (Tdap), when administered to 
90716  Varicella virus vaccine (VAR), live, for subcutaneous use  
90736  Shingles vaccine (HZV), live, for subcutaneous injection (individuals 60+ years old)

90736  Shingles vaccine (HZV), live, for subcutaneous injection (individuals 60+ years old)  
90732  Pneumococcal polysaccharide vaccine, 23 -valent (PPSV23), adult or immunosuppressed 
patient dosage, when administered to individuals 2 years or older, for subcutaneous or 
90733  Meningococcal polysaccharide vaccine, serogroups A, C, Y, W -135, quadrivalent 
(MPSV4), for subcutaneous use  
90734  Vaccine for meningococcus for administration into muscle  
90740  Hepatitis B vaccine (HepB), dialysis or immunosuppressed patient dosage, 3 dose schedule, 
for intramuscular use  
90746  Hepatitis B vaccine (HepB), adult dosage, 3 dose schedule, for intramuscular use  
90747  Hepatitis B vaccine (HepB), dialysis or immunosuppressed patient dosage, 4 dose schedule, 
90759  Hepatitis B vaccine (HepB) 10 mcg dosage, 3 dose schedule, for intramuscular use

90759  Hepatitis B vaccine (HepB) 10 mcg dosage, 3 dose schedule, for intramuscular use  
For rates, s ee the Medicine, Surgery, Radiology and Imaging, and Additional Procedures (Non -Institutional Services) 
schedule  on the Fee Schedule and Rates page  of the ODM website.  
For rates and coding information regarding COVID -19 vaccine counseling and administration, please refer to the ODM 
COVID -19 resource page  for guidance.  
 
COVID-19 Vaccine Administration  
Please refer to the ODM COVID-19 resource page  for COVID -19 vaccine administration guidance.  
 
Vaccines for Children (VFC) Program  
Ohio’s Vaccines for Children Program is administered by the Ohio Department of Health. For more 
information about the program  and eligibility criteria for children visit the ODH website resources here:   
• Vaccines for Children (VFC) | Ohio Department of Health  
• ODH VFC FAQs

39 | Page   
Vaccines for Adults  
Each year, the Advisory Committee on Immunization Practices (ACIP) approves immunization schedules 
recommended for persons living in the United States. The adult immunization schedule provides a 
summary of ACIP recommendations on the use of licensed vaccines routinely recommended for adults 
aged 19 years or older. The adult immunization schedule is also approved by the American College of 
Physicians ( ACP ), the American Academy of Family Physicians ( AAFP ), the American College of 
Obstetricians and Gynecologists ( ACOG ), and the American College of Nurse-Midwives ( ACNM ). 
Medicaid may not cover all recommended vaccinations. See Table 2-11 above for the list of covered 
vaccines for behavioral health providers.  
Child and Adolescent Needs Strengths  (CANS) Assessment   
 
The CANS is completed at prescribed intervals or whenever there is a significant change in a member's

The CANS is completed at prescribed intervals or whenever there is a significant change in a member's 
condition or circumstances.  CANS assessors should aim to conduct minimally invasive practice and 
maintain the best interest of youth/caregivers throughout the assessment process. Accordingly, assessors should not over -assess youth/caregivers or ask them to tell their stories multiple times. The Ohio 
Children’s Initiative CANS assessment and the state CANS IT system supports the practice of building upon what we alread y know about the youth/caregiver’s story and avoiding over -assessment. Prior to 
engaging the youth/caregiver in the CANS assessment process, the CANS assessors should access the CANS IT System to determine if a recent CANS assessment has been completed wit h the

engaging the youth/caregiver in the CANS assessment process, the CANS assessors should access the CANS IT System to determine if a recent CANS assessment has been completed wit h the 
youth/caregiver. If a recent CANS assessment is available in the CANS IT system, the assessor should use their professional judgment to determine if an update needs to occur or if the most recent assessment can be used.   
 
The Ohio Children’s Initiative CANS was launched for use in October 2021. While waiting for the  
system work necessary to identify this as a stand -alone service, ODM issued interim billing guidance that  
allowed for billing of community psychiatric supportive treatment (CPST), therapeutic behavioral service  
(TBS), and/or psychiatric diagnostic evaluation for administration of a CANS assessment. Beginning July

(TBS), and/or psychiatric diagnostic evaluation for administration of a CANS assessment. Beginning July 
1, 2022, the Ohio Children’s Initiative CANS assessment may only be billed using the H2000 code. CPST, TBS, and/or psychiatric diagnostic evaluation may no longer be billed for administration of a 
CANS assessment for dates of service on/after July 1, 2022.  
 Requirements for Billing:  
• Rendering practitioner must be appropriately certified and trained in the administration of the Ohio Children’s Initiative CANS assessment  
• The rendering practitioner must have an NPI, be enrolled in Medicaid, add the “ORC” specialty 
to the  individual Ohio Medicaid enrollment and be affiliated with the billing provider (a dd 
specialty by sending email request to MEDICAID_PROVIDER_UPDATE@medicaid.ohio.gov
) 
• CANS assessments must be entered in Ohio’s CANS IT system  to establish and maintain 
OhioRISE eligibility

40 | Page  Table 2-12: Child and Adolescent Needs and Strengths (CANS) Assessment  
MH/SUD  
Requires the addition of the “ORC” specialty to the rendering provider’s enrollment   
Service  Rendering 
Provider Type  Code  Practitioner 
(dates of service 
7/1/2022-
12/31/2022)  Rate  
1/1/2023-
12/31/2023 ) Rate effective  
January 1, 
2024 
Child and 
Adolescent 
Needs and 
Strength 
(CANS) 
Assessment   MD/DO   H2000   * $341.60   $527.25  $594.47  
PA  
CNS   
CNP    H2000  *   
$211.74  $324.67  $366.07  
PSY 
LPCC   
LISW  
LIMFT  
LICDC  
Lic school PSY   H2000  * $112.86  $170.43  $192.16  
LPC  
LSW  
LMFT  
LCDC II  
LCDC III  H2000  * $109.38  $165.00  $186.04  
PSY assistant  
SW-A  
SW-T  
MFT-T  
C-T  
CDC -A  
QMHS  
CMS   H2000  * $98.31  $147.72  $166.55  
Unit Value   Per Assessment  (Brief or Comprehensive) 
Permitted POS   Any valid place of service code may be used  
Billing

MFT-T  
C-T  
CDC -A  
QMHS  
Billing 
Instructions • If the CANS is completed over multiple dates of service, the claim date of service is the date the 
CANS was completed  
• Telehealth allowed with GT modifier. GT modifier is required when service rendered via telehealth.   
Diagnosis code is required – any valid ICD -10 diagnosis code may be used, including “Z -codes”  
 *For individuals with a primary enrollment in Medicaid as one of the allowable provider types listed in Table 2 -12 above, a practitioner modifier is not required. However, a practitioner modifier (see Table 1 -3) 
may be required if an individual is enrolled with additional specialties and the primary enrollment is not one of the allowable provider types listed above. P lease refer to the “Modifiers” worksheet found in the

“Dual Licensure Grid” at bhmedicaid.ohio.gov
 for additional information.   
 The CANS billing Table 2 -12 above is specific to those services billed by Ohio Medicaid Provider types 
84, 95, and OhioRISE Care Management Entities (CME). Other relevant billing providers will follow the 
claims submission policies consistent with their billing provider type.

41 | Page  Mobile Response and Stabilization Service (MRSS)  
Information about service descriptions, eligibility, clinical criteria , and limitations can be found in OAC 
rules 5160-27-13 (ODM)  and 5122-29 -14 (O hioMHAS) . The MRSS Practice Standards and other 
provider resources can be found on the OhioMHAS MRSS site: https://mha.ohio.gov/community-
partners/early -childhood-children -and-youth/resources/mobile -response-stabilization -services.  
 
Requirements for Billing:  
• Addition of the “ORM” specialty to the primary Ohio Medicaid billing provider type  
• The rendering practitioner must have an NPI, be enrolled in Medicaid, and be affiliated with 
the billing provider  
• MRSS hourly and 15-minute codes cannot be billed for time spent administering a CANS 
assessment during an MRSS event

42 | Page  Table 2 -13: MRSS Crisis Mobile Response  
MH/SUD  
Requires the billing provider have the “ORM” specialty  
Crisis Mobile Response  PSY 
LPCC  
LISW  
LIMFT 
Licensed school 
PSY 
LICDC  S9485  * $476.64  $537.41  
LPC 
LSW  
LMFT 
LCDC II  
LCDC III  S9485  * $466.34  $525.80  
SW-A  
SW-T  
MFT-T  
C-T 
CDC -A 
QMHS  
CMS  S9485  * $432.63  $487 .79 
PRS S9485  * $365.55  $412.16  
Unit Value  Per diem  
Permitted POS  Any valid place of service code may be used  
Billing Information  • Billed on the date the initial mobile response is initiated  by the MRSS provider; or 
to report the MRSS team’s first encounter after the crisis response is initiated**  
• Code can be billed by all practitioners participating in the initial mobile response 
• May not be billed more than once in the Mobile Response period

• May not be billed more than once in the Mobile Response period  
• Do not use for follow -up after the initial mobile response  
• Diagnosis code is required – any valid ICD -10 code may be used, including “Z -
codes”  
• Telehealth allowed in accordance with MRSS practice standards - GT modifier is 
required when service rendered via telehealth  
  
*For individuals with a primary enrollment in Medicaid as one of the allowable provider types listed in 
Table 2 -13 above, a practitioner modifier is not required. However, a practitioner modifier (see Table 1 -3) 
may be required if an individual is enrolled with additional specialties and the primary enrollment is not one of the allowable provider types listed above. P lease refer to the “Modifiers” worksheet found in the 
 for additional information.

43 | Page   ** For MRSS providers using an external entity that is not part of the MRSS billing provider agency to 
support 24/7 coverage , as allowed during an MRSS provider’s first year of initial certification, there may 
be situations where the external entity initiates the crisis response prior to handing off to the MRSS 
provider. When this occurs, the MRSS provider will use the initial Crisis Mobile Response code S9485 to 
report services provided during the MRSS team’s first encounter with the youth/family after ha nd-off 
from the external entity who initiated the crisis response. If the external entity is a Medicaid provider, the external entity may bill for any Medicaid -covered services rendered prior to handing-off to the MRSS 
team (e.g. psychotherapy for crisis).  After the first encounter by the MRSS team reported using the initial 
Crisis Mobile Response code S9485, subsequent services rendered by the MRSS team during the mobile

Crisis Mobile Response code S9485, subsequent services rendered by the MRSS team during the mobile 
response phase are billed using the Crisis Mobile Response Follow- up code , S9484.  
 
Table 2-13 is specific to Community BH Agency (Ohio Medicaid PT 84 and 95) billing. Hospitals 
certified to provide this service should use the code set and billing instructions for 
Outpatient Hospital 
Behavioral Health Services .

44 | Page  Table 2-14: MRSS Crisis Mobile Response Follow Up  
MH/SUD  
Requires the billing provider have the “ORM” specialty   
Service  Provider Type   Code   Practitioner 
Modifier  Rate  through 
Crisis Mobile Response 
Follow- Up   PSY  
LPCC   
LISW  
LIMFT  
PSY 
LICDC  S9484   *  $139.92   
 
$157.76  
LPC  
LSW  
LMFT  
LCDC II  
LCDC III  S9484   *   $136.49    
 
$153.89  
PSY assistant   
SW-A  
SW-T  
MFT-T  
C-T  
CDC -A  
 QMHS   
 CMS  S9484   *    
 $125.25    
  
$141.22  
PRS S9484   *  $102.89  $116.01  
Unit Value  Per hour   
Billing Information  • Billed for follow -up activities during the mobile response phase (up to 72 hours 
from the initial mobile response)  
• Dates of service should be within 3 calendar days of the initial mobile response

• Dates of service should be within 3 calendar days of the initial mobile response  
• The initial mobile response (S9485) code must be billed before this code can be 
billed  
• Code can be billed by all practitioners participating in the follow up response  
• Can be billed on the same date of service as the initial response if the initial response concluded and follow -up activities were provided later the same date  
• Code  may not be billed for time spent administering the CANS assessment  
codes”  
• Telehealth allowed - GT modifier is required when service rendered via telehealth.   
  
*For individuals with a primary enrollment in Medicaid as one of the allowable provider types listed in Table 2 -14 above, a practitioner modifier is not required. However, a practitioner modifier (see Table 1 -3)

may be required if an individual is enrolled with additional specialties and the primary enrollment is not

45 | Page  one of the allowable provider types listed above. Please refer to the “Modifiers” worksheet found in the 
“Dual Licensure Grid” at bhmedicaid.ohio.gov  for additional information.   
 Table 2-14 is specific to Community BH Agency (Ohio Medicaid PT 84 and 95) billing. Hospitals 
certified to provide this service should use the code set and billing instructions for  
Behav ioral Health Services .  
 
Table 2 -15: MRSS Stabilization Service  
MH/SUD  
Provider Type  Code   Practitioner 
MRSS Stabilization Service  PSY  
LPCC   
LISW  
LIMFT  
Licensed school PSY  
LICDC  S9482   *  $34.95  $39.41  
LPC  
LSW  
LMFT  
LCDC II  
LCDC III  S9482   *   
 
$34.01   
 
$38.35 
SW-A  
SW-T  
MFT-T  
C-T  
CDC -A  
 QMHS  
CMS  S9482   *  $30.92  $34.86  
PRS S9482   * $24.77   $27.93

LSW  
LMFT  
LCDC II  
 
$34.01   
 
$38.35 
SW-A  
SW-T  
MFT-T  
C-T  
CDC -A  
 QMHS  
PRS S9482   * $24.77   $27.93  
Unit Value  Per 15 minutes  
Billing Information  • The initial mobile response (S9485) code must be billed before this code can be 
billed  
• Code can be billed by all practitioners providing the  stabilization service 
• Requires prior authorization to extend beyond 6 weeks from the end of the de -
escalation phase  
• Cannot be billed for youth enrolled in IHBT, MST, FFT or ACT 
codes”  
• Telehealth allowed - GT modifier is required when service rendered via telehealth

codes”  
• Telehealth allowed - GT modifier is required when service rendered via telehealth  
  
*For individuals with a primary enrollment in Medicaid as one of the allowable provider types listed in Table 2 -15 above, a practitioner modifier is not required. However, a practitioner modifier (see Table 1 -3

46 | Page  Behavioral Health Manual ) may be required if an individual is enrolled with additional specialties and the 
primary enrollment is not one of the allowable provider types listed above. Please refer to the “Modifiers” 
worksheet found in the “Dual Licensure Grid” at bhmedicaid.ohio.gov  for additional information.   
  
Table 2-15 is specific to Community BH Agency (Ohio Medicaid PT 84 and 95) billing. Hospitals 
certified to provide this service should use the code set and billing instructions for Outpatient Hospital 

47 | Page  SECTION 3  
Psychotherapy Services   
 
Table 3 -1: Psychotherapy for Crisis 
MH / SU D 
Psychotherapy for 
Crisis – first 60 
minutes 
 MD/DO  
PSY 90839  - $171.70   
$193.59  
 
CNS  
CNP  
PA 
LISW 
LIMFT 
 LPCC  
 LICDC (SUD only)  
Lic school PSY   
90839  
 - $145.95  $164.55  
LSW  
LMFT 
LPC  
LCDC III (SUD 
only)  
LCDC II (SUD 
only)  90839  U4 
U5 
U2 
U3 
U3 $145.95  $164.55  
PSY assistant  90839  U1 Paid at direct 
included . Paid at direct 
included.  
SW-T 
MFT-T 
C-T 90839  
 U9 
UA 
U6 
U7 Paid at direct 
claim  
Paid at 72.25% of 

included.  
SW-T 
MFT-T 
C-T 90839  
 U9 
UA 
U6 
claim  
included. Paid at direct 
claim  
included.

48 | Page  MH / SU D 
Crisis – add’l 30 
minutes 
 MD/DO  
PSY +90840  - $81.95  $92.40  
CNS  
CNP  
PA 
LISW 
LIMFT 
 LPCC  
+90840  
 - $69.65  $78.54  
LSW  
LMFT 
LPC  
only)  
only)  +90840  U4 
U5 
U2 
U3 
U3 $69.65  $78.54  
PSY assistant  +90840  U1 Paid at direct 
included.  
SW-T 
MFT-T 
C-T +90840  U9 
UA 
U6 
claim  
claim  
Paid at 72.25% of

claim  
claim  
included.  
Unit Value  +90839: 1 which represents first 60 minutes  
+90840: 1 which represents each additional 30 minutes  
Permitt ed PO S 01, 03, 04, 11, 12, 13, 14, 15, 16, 17, 18, 20,  
23, 24, 25, 31, 32, 33, 34, 41, 42, 99   
SUD also has 57  Telehealth allowed with GT modifier.  
GT modifier is required when service rendered 
via telehealth.

49 | Page  Table 3 -2: Individual Psychotherapy  
MH / SUD  
Individual 
Psychotherapy – 
30 minutes  MD/DO  
PSY 90832  - $63.11  
$82.04 (KX)  $71.16  
$92.50 (KX)  
CNS  
CNP  
PA 
LISW 
LIMFT 
LPCC  
90832  
  
- 
  
$53.64  
$69.73 (KX)  
  
$60.49  
$78.63 (KX)  
 
LSW 
LMFT 
LPC 
only)  
 LCDC II (SUD 
only)  90832  U4 
U5 
U2 
U3 
U3 $53.64  
$69.73 (KX)  $60.49  
PSY assistant  90832  U1 Paid at direct 
included (both KX 
and non-KX).  Paid at direct 
supervisor rate 
when supervisor 
NPI on claim. Paid 
at 85% of maximum 
fee if supervisor 
NPI not included. 
(both KX and non-
KX). 
SW trainee  
MFT trainee  
C-T 90832  U9 
UA 
U6 
U7 Paid at direct

KX). 
SW trainee  
UA 
U6 
claim  
and non -KX). Paid at direct 
KX).

50 | Page  MH / SUD  
 
45 minutes 
 MD/DO  
PSY 90834  - $82.05  $92.51  
CNS  
CNP  
PA 
LISW 
LIMFT 
 LPCC  
Lic school PSY  90834  - $69.74  $78.63  
LSW  
LMFT 
LPC  
only)  
only)  90834  U4 
U5 
U2 
U3 
U3 $69.74             $78.63  
PSY assistant  90834  U1 Paid at direct 
included.  Paid at direct 
NPI not included.  
SW trainee  
C-T 90834  U9 
UA 
U6 
claim  
NPI on claim

claim  
NPI on claim  
included . 
 
60+ minutes 
 
 MD/DO  
PSY 90837  - $120.36  $135.71- 
CNS  
CNP  
PA 90837  - $102.31  $115.35-

51 | Page  MH / SUD  
(continued)  LISW  
LIMFT 
 LPCC  
Lic school PSY  90837   
- 
 
 $102.31  $115.35- 
LSW  
LMFT 
LPC  
only)  LCDC II 
(SUD only)   
90837  U4 
U5 
U2 
U3 $102.31  $115.35- 
PSY assistant  90837  U1 Paid at direct 
NPI not included  - 
SW-T 
MFT-T 
C-T 90837  U9 
UA 
U6 
Supervisor NPI on 
claim  
when Supervisor 
included. -

included. - 
Psychotherapy w/ 
E&M Service MD/DO  +90833  
+90836  
+90838  - $65.37  
$83.03  
$109.53  $73.70  
$93.62  
$123.50- 
CNS  
CNP  
PA +90833  
+90836  
+90838  - $55.56  
$70.58  
$93.10  $62.65  
$79.58  
$104.98- 
Unit Value  1 which represents encounter  
Permitted POS  03, 04, 11, 12, 13, 14, 16, 18, 31, 32, 34, 99 
For 90832 KX – POS 23 is also available  Telehealth allowed with GT modifier.  90832 
KX t elehealth allowed with GT modifier. GT 
modifier is required when service rendered 
via telehealth.  
Crisis 
psychotherapy of 
16 to 30 minutes  Add KX modifier to 90832 to indicate when service is crisis psychotherapy between 16 and 30 
minutes , as allowable within the practitioner’s scope of practice.  For crisis psychotherapy of 31

minutes , as allowable within the practitioner’s scope of practice.  For crisis psychotherapy of 31 
or more minutes, please use crisis psychotherapy coding above.

52 | Page  Table 3 -3: Family Psychotherapy  
MH / SUD  
Type  Code  Practitioner 
Modifier  Rate  through December 
31, 2023  Rate effective  
Family 
Psychotherapy 
w/o patient  – 
50 minutes 
 MD/DO  
PSY 90846  - $102.28  $115.32  
CNS  
CNP  
PA 
LISW 
LIMFT 
LPCC  
LICDC (SUD 
only)  
Lic school 
PSY 90846   
 
- 
  $86.94  $98.02 
LSW  
LMFT 
LPC 
LCDC III 
(SUD only)  
 LCDC II 
(SUD only)  90846  U4 
U5 
U2 
U3 
U3 $86.94  $98.02  
PSY assistant  90846  U1 Paid at direct supervisor rate 
when supervisor NPI on 
maximum fee if supervisor 
NPI not included . Paid at direct supervisor 
rate when supervisor 
NPI on claim. Paid at 
85% of maximum fee if 
included.  
SW-T 
MFT-T 
CDC -A (SUD 
only)  
C-T 90846  U9 
UA 
U6 
U7 Paid at direct supervisor rate 
claim  
Paid at 72 .25% of maximum 
fee if supervisor NPI not 
included. Paid at direct supervisor 
rate when supervisor

UA 
U6 
claim  
included.  
 
Family 
psychotherapy 
(conjoint, w/ 
patient 
present) – 50 
minutes  MD/DO  
PSY 90847  - $100.72  $113.56

53 | Page  MH / SUD  
Family 
patient 
minutes 
(continued)  CNS  
CNP  
PA 
LISW 
LIMFT 
LPCC  
LICDC (SUD 
only)  
Lic school 
PSY  
90847  
  
- 
 $85.61  $96.53  
LSW  
LMFT 
LPC 
LCDC III 
(SUD only)  
 LCDC II 
(SUD only)   
90847  U4 
U5 
U2 
U3 
U3 $85.61  $96.53  
PSY assistant  90847  U1 Paid at direct supervisor rate 
NPI not included.  Paid at direct supervisor 
included.  
 
SW trainee  
CDC -A (SUD 
only)  
C-T 90847  U9 
UA 
U6 
claim  
Paid at 72.25% of maximum 
included.  Paid at direct supervisor 

U6 
claim  
included.  
 
Multiple -
family group 
psychotherapy MD/DO  
PSY 90849  - $40.66  $45.84  
CNS  
CNP  
PA 
LISW 
LIMFT 
 LPCC  
 LICDC (SUD 
only)  
Lic school 
PSY 90849  - $34.57  $38.96

54 | Page  MH / SUD  
Multiple -
(continued)  LSW  
LMFT 
LPC  
LCDC III 
(SUD only)  
LCDC II 
(SUD only)   
90849  U4 
U5 
U2 
U3 
U3 $34.57  $38.96  
PSY assistant  90849  U1 Paid at direct supervisor rate 
included.  
SW-T 
MFT-T 
CDC -A (SUD 
only)  
C-T 90849  U9 
UA 
U6 
claim  
 Paid at 72.25% of 
included.  
Unit Value  1 which represents an encounter 
Permitted

included.  
Permitted 
POS 03, 04, 11, 12, 13, 14, 16, 31, 32, 34  
For 90846 and 90847 – 99 is also 
available  Telehealth allowed with GT modifier.  GT modifier is 
required when service rendered via telehealth.

55 | Page  Table 3 -4: Prolonged Service Codes for Psychotherapy  
Rate through December 31, 2022 *  
MH / SUD  
Modifier  Rate through December 
31, 2022  
 
Prolonged Visit – First 60 
minutes 
(Use in conjunction with 
covered BH codes 90837, 
90847) 
 
 MD/DO  
PSY +99354  - $89.90  
CNS  
CNP  
PA 
LISW 
LIMFT 
 LPCC  
Lic school PSY  +99354  - $76.42  
LSW  
LMFT 
LPC 
only)  
only)   
+99354  U4 
U5 
U2 U3 
U3 $76.42  
PSY assistant  +99354  U1 Paid at direct supervisor rate 
NPI not included . 
SW-T 
MFT-T 
C-T  
CDC -A (SUD only)  +99354  U9 
UA 
U7 U6 Paid at direct supervisor rate 
when supervisor NPI on claim  
included.

56 | Page  Prolonged Visit – Each 
Additional 30 Minutes 
90847 ) 
 MD/DO  
PSY +99355  - $89.24  
CNS  
CNP  
PA 
LISW 
 LIMFT 
 LPCC  
Lic school PSY  +99355  - $75.85  
LSW  
LMFT 
LPC  
only)  
only)   
+99355  U4 U5 U2 U3  
U3 $75.85  
PSY assistant  +99355  U1 Paid at direct supervisor rate 
SW-T 
MFT-T 
C-T 
 CDC -A (SUD only)  +99355  U9 
UA 
U7 U6 Paid at direct supervisor rate  
included . 
Permitted POS  Same as base code  Telehealth allowed with GT modifier.  GT modifier is 

required when service rendered via telehealth.  
*CPT® code s 99354 and 99355 have  been deleted effective January 1, 202 3. Providers can refer to AMA 
and NCCI guidance with regard to billing psychotherapy for dates of service on or after January 1, 2023.

57 | Page  Table 3 -5: Group Psychotherapy  
MH / SUD  
Group 
(not multi-
family group)  MD/DO  
PSY 90853  - $33.09  $37.31  
CNS  
CNP  
PA 
LISW 
LIMFT 
 LPCC  
 LICDC (SUD 
only)  
Lic school PSY  90853   
 
- 
 
 $28.12  $31.71  
LSW  
LMFT 
LPC  
only)  
only)  
  
90853  U4 
U5 
U2 
U3 
U3 $28.12  $31.71  
PSY assistant  90853  U1 Paid at direct 
included . 
SW-T 
MFT-T 
C-T 90853  U9 
UA 
U6 
supervisor rate when

UA 
U6 
claim. Paid at 72.25% 
included.  
Unit Value  1 which represents an encounter  
Permitted POS  03, 04, 11, 12, 13, 14, 16, 31, 32, 34, 99 

58 | Page   
Interactive Complexity  
The use of interactive complexity codes is further described in CPT guidance. For more information, 
please reference the CPT book.  
Table 3 -6: Interactive Complexity  
MH / SUD  
Interactive 
Complexity MD/DO  
PSY +90785  - $13.81  $15.57  
CNS  
CNP  
PA 
LISW 
LIMFT 
 LPCC  
+90785   
- 
 $11.74  $13.23  
LSW  
LMFT 
LPC  
 LCDC II  (SUD only)   
+90785  U4 
U5 
U2 
U3 
U3 $11.74 $13.23  
PSY assistant  +90785  U1 Paid at direct 
included . 
SW-T  
MFT-T 
C-T +90785  U9 
UA 
U6 

included . 
SW-T  
MFT-T 
UA 
U6 
claim  
Paid at 72 .25% of 
claim  
included . 
Interactive Complexity is an add-on code that is only valid in conjunction with codes as determined by the AMA. 
Permitted 
POS POS must be the same 
as the base code to 
which interactive 
complexity is being 
added .  Telehealth allowed with GT modifier for dates of service on and after 
November 15, 2020.  GT modifier is required on claim when service rendered 

59 | Page   
The use of psychological testing codes is further described in CPT guidance. For more information, 
Table 3 -7: Psychological Testing  
MH / SUD  
Service  Provider  
Janu ary 1, 2024  
Psychological 
Testing 
Administration  
 MD/DO  
PSY 
PA 
CNS  
CNP  
LISW 
LIMFT 
 LPCC  
Lic school 
PSY 96136  - $30.86  $34.79  
LSW  
LMFT 
LPC  
PSY assistant  96136  U4 
U5 
U2 
U1 $30.86  $34.79  
SW-T 
MFT-T 
C-T 96136  U9 
UA  
U7 $30.86  $34.79  
MD/DO  
PSY 
PA 
CNS  
CNP  
LISW 
LIMFT 
 LPCC  
Lic school 
PSY +96137  - $28.39  $32.01

60 | Page  MH / SUD  
Testing 
Administration 
LMFT 
LPC  
PSY assistant  +96137  U4 
U5 
U2 
U1 $28.39  $32.01  
SW-T 
MFT-T 
C-T +96137  U9 
UA  
U7 $28.39  $32.01  
Testing Evaluation 
 MD/DO  
PSY 
PA 
CNS  
CNP  
LISW 
LIMFT 
 LPCC  
Lic school 
PSY 96130 - $59.26  $66.82  
LSW  
LMFT 
LPC  
PSY assistant  96130 U4 
U5 
U2 
U1 $59.26  $66.82  
SW-T 
MFT-T 
C-T 96130 U9 
UA  
U7 $59.26  $66.82

61 | Page  MH / SUD  
(continued)  MD/DO  
PSY 
PA 
CNS  
CNP  
LISW 
LIMFT 
 LPCC  
Lic school 
PSY +96131  - $59.26  $68.22  
LSW  
LMFT 
LPC  
PSY assistant  +96131  U4 
U5 
U2 
SW-T 
MFT-T 
C-T +96131  U9 
UA  
U7 $59.26  $66.82  
Developmental 
Testing  MD/DO  
PSY 
CNS  
CNP  
PA 
LISW 
LIMFT 
 LPCC  
Lic school 
PSY 9611 2 - $56.11  $63.26  
LSW  
LMFT 
LPC  
PSY assistant  9611 2 U4 
U5 
U2 
U1 $56.11  $63.26  
SW-T 
MFT-T 
C-T 9611 2 U9 
UA 
U7 $56.11  $63.26

62 | Page  MH / SUD  
Testing   
PSY 
CNS  
CNP  
PA 
LISW 
LIMFT 
 LPCC  
Lic school 
PSY +96113  - $28.06  $31.64  
LSW  
LMFT 
LPC  
PSY assistant  +96113  U4 
U5 
U2 
U1 $28.06  $31.64  
SW-T 
MFT-T 
C-T +96113  U9 
UA 
U7 $28.06  $31.64  
Neurobehavioral 
Status Exam  MD/DO  
PA 
PSY 
CNS  
CNP  96116  - $64.10  $72.27  
PSY assistant  96116  U1 $64.10  $72.27  
MD/DO  
PA 
PSY 
CNS  
CNP  +96121  - $64.10  $72.27  
PSY assistant  +96121  U1 $64.10  $72.27

63 | Page   MH / SUD  
Neuropsychological 
Testing 
Administration  MD/DO  
PA 
PSY 
CNS  
CNP  96136  - $30.86  $34.79  
PSY assistant  96136  U1 $30.86  $34.79  
MD/DO  
PA 
PSY 
CNS  
CNP  +96137  - $28.39  $32.01  
PSY assistant  +96137  U1 $28.39  $32.01  
Testing Evaluation  MD/DO  
PA 
PSY 
CNS  
CNP  96132 - $97.37  $109.78  
PSY assistant  96132 U1 $97.37  $109.78  
MD/DO  
PA 
PSY 
CNS  
CNP  +96133  - $78.31  $88.29  
PSY assistant  +96133  U1 $78.31  $88.29  
Unit Value  96112, 96116, 96130, 96132: first 60 minutes  
96136: first 30 minutes  
+96113, +96137: additional 30 minutes  
+96121, +96131, +96133: additional 60 minutes  
Permitted POS  03, 04, 11, 12, 13, 14, 16, 31 
SUD also has 57 Telehealth allowed with GT modifier.  GT 
telehealt h.

64 | Page  Table 3 -7.5: Smoking Cessation  
MH / SU D 
Service  Provider Type Code  Practitioner 
Smoking and 
Tobacco Use 
Cessation 
Counseling – 
Intermediate: 
Greater than 3 
minutes and up 
to 10 minutes  MD/DO  
PSY 99406  - $9.43  $10.37  
CNS  
CNP  
PA 
 99406  - $9.43   
 
$10.37  
LISW 
LIMFT 
 LPCC  
Lic school PSY  99406   
 
- 
 
 $8.02   
 
$8.81  
LSW  
LMFT 
LPC  
LCDC II (SUD only)  
 99406  U4 
U5 
U2 
U3 
U3 $8.02  $8.81  
PSY assistant  99406  U1 Paid at direct supervisor 
included . 
SW-T 
MFT-T 
C-T 99406  U9 
UA 
U6 
U7 Paid at direct supervisor 

included . 
SW-T 
MFT-T 
UA 
U6 
claim  
included.

65 | Page  MH / SU D 
Cessation 
Intensive: 
Greater than 10 
PSY 99407  - $19.00  $20.90  
CNS  
CNP  
PA 99407  - $19.00   
$20.90  
LISW  
LIMFT 
 LPCC  
Lic school PSY  99407  - $16.15   
 
$17.77  
LSW  
LMFT 
LPC  
 99407  U4 
U5 
U2 
U3 
U3 $16.15  $17.77  
PSY assistant  99407  U1 Paid at direct supervisor 
included . 
SW-T 
MFT-T 
C-T 99407  U9 
UA 
U6 
included. Paid at direct

MFT-T 
UA 
U6 
claim  
included . 
Permitted POS  03, 04, 11, 12, 13, 14, 16, 18, 31, 32, 34, 99  
SUD also has 57  Telehealth allowed with GT modifier.  GT modifier is 

66 | Page  Healthcare Common Procedure Coding System (HCPCS) Mental Health Services  
 
Table 3 -8: Therapeutic Behavioral Services (TBS)  
MH 
Individual Therapeutic Behavioral Services (TBS) – 15 minutes  
Service Code Provider Type  Code  Modifiers Rate  through 
December 31, 2023  Rate effective  January 
1, 2024  
Therapeutic 
Behavioral 
Services (TBS) – 
15 minutes 
 MD/DO  
CNS  
CNP  
PA 
PSY 
LISW 
LIMFT 
 LPCC  
Lic school PSY  H2019  - $22.47 in office  
$28.59 in community 
 
$29.21 in office (KX)  
$37.17 in community 
(KX)   
$25.33 in office  
$32.34 in community 
 
$32.93 in office (KX)  
$41.91 in community (KX)  
 
LSW  
LMFT 
LPC H2019  U4 
U5 
U2 $22.47 in office  
$28.59 in community  
 
$29.21 in office  (KX)  
$37.17 (KX)  $25.33 in office  
 
(Master’s)  H2019  U1 and HO $22.47 in office  
$28.59  
 
$37.17 in community

$28.59  
 
$37.17 in community  
(KX)  $25.33 in office  
 
SW-T 
(Master’s)  H2019  U9 and HO $22.47  in office  
 
SW-T  
(Bachelor’s)  H2019  U9 and HN $19.96  in office  
$25.46 in community  
 
$25.95 in office  (KX)  
$33.10 in community  
(KX)  $22.50 in office  
$28.71 in community 
 
$29.26 in office (KX)  
$37.32 in community (KX)  
SW-A 
(Master’s)  H2019  U8 and HO $22.47 in office  
 
(KX)   
 
$41.91 in community (KX)

67 | Page  Individual 
15 minutes 
 SW-A 
(Bachelor’s)  H2019  U8 and HN $19.96 in office  
 
(KX)   
$22.50 in office  
 
MFT-T 
(Master’s)  H2019  UA and 
HO $22.47 in office  
 
(KX)   
 
(Bachelor’s)  H2019  UA and 
HN $19.96 in office  
 
(KX)   
 
C-T 
(Master’s)  H2019  U7 and HO $22.47 in office  
 
$22.47 in office  (KX)  
(KX)   
 
$32.93 in office (KX)

C-T 
 
(KX)   
 
C-T 
(Bachelor’s)  H2019  U7 and HN $19.96 in office  
 
(KX)   
 
QMHS  
(Bachelor’s)  H2019  HN $19.96 in office  
 
(KX)   
$22.50 in office 
 
QMHS 
(Master’s)  H2019  HO $22.47 in office  
 
(KX)   
 
68 | Page  Individual 
15 minutes 
(continued)  QMHS (3 yrs+ 
Exp.)  H2019  UK  $19.96 in office  
 
(KX)   
$28.71 in community  
 
Group Therapeutic Behavioral Services (TBS) – 15 minutes  
December 31, 2023 Rate effective January 
1, 2024 
Group 
15 minutes 
 MD/DO  
CNS  
CNP  
PA 
PSY 
LISW 
LIMFT 
 LPCC  
Lic school PSY  H2019  HQ $8.99  $10.14  
LSW  
LMFT 
LPC H2019  U2, HQ  
U4, HQ  
U5, HQ  $8.99  $10.14  
(Master’s)  H2019  U1, HO  
HQ $7.31  $8.24  
SW-T (Master’s)  H2019  U9, HO 
SW-T  
(Bachelor’s)  H2019  U9, HN 
HQ $6.49  $7.32  
SW-A 
(Master’s)  H2019  U8, HO 
(Bachelor’s)  H2019  U1, HN, 
SW-A

SW-T  
SW-A 
SW-A 
(Bachelor’s)  H2019  U8, HN 
MFT-T 
 (Master’s)  H2019  UA, HO 
MFT-T 
(Bachelor’s)  H2019  UA, HN 
C-T 
(Master’s)  H2019  U7, HO 
C-T 
(Bachelor’s)  H2019  U7, HN 
HQ $6.49  $7.32

69 | Page  Group 
15 minutes 
(continued)  QMHS 
(Bachelor’s)  H2019  HN 
QMHS 
(Master’s)  H2019  HO 
QMHS (3 yrs+ 
Exp.)  H2019  UK 
HQ  $6.49  $7.32  
Unit Value  15 minutes  
Permitted POS  Individual TBS – 03, 04, 11, 12, 13, 14, 
16, 18, 23, 31, 32, 34, 53, 99  
Group TBS – 11, 53  
If more than six (6) units are delivered 
on the same date of service by the same agency in places of service 11 and/or 53, subsequent units will be paid at 50% of 
the above rates.   Telehealth allowed with GT modifier.  
GT modifier is required when service rendered via telehealth.  
TBS to address 
a crisis  Add KX modifier to indicate TBS provided when a patient is experiencing a crisis, as allowable 
within the practitioner’s scope of practice.  
 
Table 3 -9: RN and LPN Nursing Services  
MH 
Type  Code  Procedure 
December 31, 2023  Rate effective  January

MH 
1, 2024  
Nursing Services 
– Individual RN H2019  - $31.92 in office  
$41.00 in community  $35.99  in office  
$46.23 in  community  
LPN  H2017  - $22.54  in office  
$29.13  in community  $25.41  in office  
$32.84  in community  
– Group  RN H2019  HQ $10.37 $11.69  
Permitted POS  Individual RN/LPN nursing services - 03, 
04, 11, 12, 13, 14, 16, 18, 31, 32, 34, 53 , 99 
Group RN nursing services – 11, 53  
For H2019 KX – POS 23 is also available . Telehealth allowed with GT modifier.  
GT modifier is required when service rendered via 
telehealth.  
RN nursing 
service to 
address a crisis  Add KX modifier to indicate RN nursing service provided when a patient is experiencing a crisis,

RN nursing 
service to 
address a crisis  Add KX modifier to indicate RN nursing service provided when a patient is experiencing a crisis, 
as allowable within the practitioner’s scope of practice. KX is not allowable with group RN nursing services (HQ modifier).

70 | Page  Table 3 -10: TBS Group Service -Hourly and Per Diem  (Day Treatment)  
MH 
TBS Group 
Service (Day 
Treatment) per 
hour less than 2.5 
hours (See hour-
based services, 
pg. 27)  PSY H2012  HK 
HQ $36.53  $41.19  
LISW  
LIMFT 
 LPCC  
 Lic school PSY  H2012  HK 
LSW  
LMFT 
LPC  H2012  U4, HK, HQ  
U5, HK, HQ  
U2, HK, HQ  $36.53  $41.19  
(Master’s)  
 SW-T (Master’s)  
SW-A (Master’s)  
MFT-T (Masters)  
C-T (Master’s)  
QMHS (Master’s)  H2012  U1, HO, HQ  
U9, HO, HQ  
U8, HO, HQ  
UA, HO, HQ  
U7, HO, HQ  
HO, HQ  $27.37  $30.86  
PSY asst 
(Bachelor’s)  
SW-T (Bachelor’s) 
SW-A (Bachelor’s)  
MFT-T 
C-T (Bachelor’s) 
QMHS 
(Bachelor’s)  H2012  U1, HN, HQ  
U9, HN, HQ  
U8, HN, HQ  
UA, HN, HQ  
U7, HN, HQ  
HN, HQ  $24.10  $27.17  
Exp.)  H2012  UK, HQ  $24.10  $27.17

71 | Page  TBS Group 
Treatment)  
2.5 or m ore hours  
(per diem) Provider Type  Code  Modifiers  Rate  through 
PSY H2020  HK $182.66  $205.95  
LISW  
LIMFT 
 LPCC  
Lic school PSY  H2020  HK $182.66  $205.95  
LSW  
LMFT 
LPC  H2020  U4,HK 
U5,HK 
U2,HK $182.66   
$205.85  
 
MFT-T (Master’s)  
QMHS (Master’s)  H2020  U1,HO 
U9,HO 
U8,HO 
UA,HO 
U7,HO 
HO $152.17   
 
$171.57  
PSY asst  
MFT-T 
QMHS 
(Bachelor’s)  H2020  U1,HN  
U9,HN 
U8,HN 
UA,HN 
U7,HN 
HN $135.92  $153.25  
Exp.)  H2020  UK $135.92  $153.25  
Unit Value  H2012: Hourly, maximum of 2 per day  
H2020: Per diem  
 Permitted POS   03, 04, 11,  14, 53  Telehealth allowed with GT modifier.  

72 | Page  Table 3 -11: Psychosocial Rehabilitation (PSR)  
MH 
Psychosocial 
Rehabilitation  SW-T H2017  U9 and HM  $15.84  in office  
$20.32 in  community  
 
$20.59 (KX)  in office 
$26.42 (KX)  in 
community  $17.86 in office  
$22.91 in  community  
 
$23.22 (KX)  in office 
$29.79 (KX)  in 
community  
SW-A H2017  U8 and HM  $15.84  in office  
 
community  $17.86  in office  
 
community  
MFT-T H2017  UA and HM  $15.84  in office  
 
community  
C-T H2017  U7 and HM  $15.84  in office  
 
$26.42 (KX)  in

community  
 
community  
QMHS (high 
school)  H2017  HM $15.84  in office  
 
community  
QMHS 
(Associate’s)  H2017  HM $15.84  in office  
 
$23.22 (KX)  in office  
community  
Permitted POS  03, 04, 11, 12, 13, 14, 16, 18, 23, 31, 32, 34, 
53, 99 
If more than six (6) units are delivered on the

community  
53, 99 
If more than six (6) units are delivered on the 
same date of service by the same agency in places of service 11 and/or 53, subsequent units will be adjudicated at 50% of the above 
rates . Telehealth allowed with GT modifier.  
GT modifier is required when service rendered via telehealth.  HM modifier is 
required when billing PSR to differentiate PSR and MH LPN nursing.

73 | Page  MH 
PSR to address a 
crisis  Add KX modifier to indicate PSR provided when a patient is experiencing a crisis, as allowable 
Table 3 -12: Screening, Brief Intervention and Referral to Treatment  
MH 
Service  Provider  Type  Code  Practitioner 
Screening, Brief 
Intervention and 
Referral to 
Treatment 
(SBIRT)  MD/DO  
CNS  
CNP  
PA 
PSY 
RN 
LPN  
LISW 
LIMFT 
LPCC  
Lic school PSY  G0396  - $25.05   
 
$27.56  
LSW  
LMFT 
LPC G0396  U4 
U5 
U2 $25.05   
$27.56  
SW-T 
MFT-T 
C-T G0396  U1 
U9  
UA  
U7 $25.05  $27.56  
Treatment 
CNS  
CNP  
PA 
PSY 
RN 
LPN  
LISW 
LIMFT 
LPCC  
Lic school PSY  G0397  - $47.68   
  
$52.45  
LSW  
LMFT 
LPC G0397  U4 
U5 
U2 $47.68   
$52.45  
SW-T 
MFT-T 
C-T G0397  U1 
U9  
UA  
U7 $47.68  $52.45

LISW 
LIMFT 
LPCC  
  
$52.45  
LSW  
LMFT 
U5 
U2 $47.68   
$52.45  
SW-T 
MFT-T 
U9  
UA  
U7 $47.68  $52.45  
Unit Value  G0396: Encounter from 15 to 30 minutes  
G0397: Encounter over 30 minutes  
Permitted POS  03, 04, 11, 12, 13, 14, 16, 31, 32, 53  Telehealth allowed with GT modifier.  

74 | Page   
Table 3 -13: Community Psychiatric Supportive Treatment (CPST) 
MH 
Modifier  Procedure 
January 1, 
2024  
Community 
Supportive 
Treatment – 
Individual MD/DO  H0036  - - $19.54  $22.03  
CNS  
CNP  
PA 
PSY H0036  - - $19.54  $22.03  
LISW  
LIMFT 
 LPCC  
Lic school PSY  H0036  - - $19.54  $22.03  
LSW  
LMFT 
LPC  H0036  U4 
U5 
U2 - $19.54   
$22.03  
SW-T 
SW-A 
MFT-T 
C-T H0036  U1 
U9  
U8  
UA  
U7  - $19.54   
 
$22.03  
Exp.)  
QMHS (high 
school)  
QMHS 
(Associate’s)  
QMHS 
QMHS 
(Master’s)  H0036  UK 
HM 
HM 
HN 
HO - $19.54  $22.03  
Community 
Group MD/DO  H0036  - HQ $8.99  $10.14  
CNS  
CNP  
PA 
PSY H0036  - HQ $8.99  $10.14

75 | Page  MH 
January 1, 
2024  
Community 
Group 
(continued)  LISW 
LIMFT 
 LPCC  
Lic school PSY  H0036  - HQ $8.99  $10.14  
LSW  
LMFT 
LPC H0036  U4 
U5 
U2 HQ $8.99  $10.14  
SW-T 
SW-A 
MFT-T 
U9 
U8 
UA 
U7 HQ $8.99  $10.14  
Exp.)  
QMHS (high 
school)  
QMHS 
QMHS 
QMHS 
HM 
HM 
HN 
HO HQ $8.99  $10.14  
Unit Value  15 minut es 
Permitted POS  03, 04, 11, 12, 13, 14, 16, 18, 23, 31, 32, 
33, 34, 53, 99 
If more than six (6) units are delivered on 
the same date of service by the same agency, subsequent units will be 
adjudicated at 50% of the above rates.  Telehealth allowed with GT modifier.  GT modifier is 

76 | Page  Assertive Community Treatment (ACT) 
 
Table 3 -14: Assertive Community Treatment (ACT) 
MH 
Assertive 
Community 
Treatment  
 MD/DO  H0040  AM $615.64  $694.13  
CNP  
CNS  
PA H0040  UC 
SA 
SA $352.75  $397.73  
Licensed 
practitioner  
* H0040  HO $251.91  $284.03  
Unlicensed  
practitioner   H0040  HN $199.70  $225.16  
Peer recovery 
supporter  H0040  HM $159. 24 $179.54  
Unit Value  1 representing a per diem  
Permitted POS  03, 04, 11, 12, 13, 14, 16, 17, 18, 20, 53 , 99 Telehealth allowed with GT modifier.  
*Please refer to Ohio Administrative Code 5160- 27-04 (L) (2) for information on which practitioners are 
included in this level.

77 | Page  Intensive Home Based Treatment (IHBT ) 
For information on billing IHBT, refer to the OhioRISE Provider Enrollment and Billing Guidance . 
 
SECTION 4  
Substance Use Disorder (SUD) Coverage  
OAC rule 5160-27- 09 establishes the American Society of Addiction Medicine (ASAM) placement 
criteria as the standard for Ohio Medicaid coverage of substance use disorder treatment services. The 
SUD services described in this section are covered when provided by eligible providers as defined in 
5160- 27-01.  
 
Table 4 -1: SUD Assessment  
SUD  
SUD Assessment  PSY assistant  H0001  U1 $77.22  $87.07  
SW-T H0001  U9 $77.22  $87.07  
MFT-T H0001  UA $77.22  $87.07  
CDC -A H0001  U6 $77.22  $87.07  
C-T H0001  U7 $77.22  $87.07  
Permitted POS  03, 04, 11, 12, 13, 14, 16, 18, 23, 31, 32, 34,

57, 99 Telehealth allowed with GT modifier.  GT 

78 | Page  Table 4 -2: SUD Peer Recovery Support  
SUD  
SUD 
Peer 
Recovery 
Support  PRS H0038  HM, HN, HO  - $15.51  $17.49  
SUD Group 
Peer 
Recovery 
Support  PRS H0038  HM, HN, HO  HQ $1.94  $2.19  
Permitted 
POS 03, 04, 11, 12, 13, 
14, 16, 18, 23, 31, 
32, 33, 34, 53, 57, 
99 Telehealth allowed with GT modifier.  
GT modifier is required when service rendered via telehealth. 
 
Table 4 -3: Individual Counseling  
SUD  
January 1, 
2024  
Counseling  PSY assistant  H0004  U1 $19.31  
$25.10 (KX)  $21.77  
$28.30 (KX)  
SW-T H0004  U9 $19.31  
MFT-T H0004  UA $19.31  
CDC -A  H0004  U6 $19.31

CDC -A  H0004  U6 $19.31  
C-T H0004  U7 $19.31  
Permitted POS  03, 04, 11, 12, 13, 14, 16,  18, 31, 32, 34, 
57, 99 
H0004 KX - POS 23 also available  Telehealth allowed with GT modifier. GT 
counseling to 
address a crisis  Add KX modifier to indicate behavioral health counseling provided when a patient is 
experiencing a crisis, as allowable within the practitioner’s scope of practice.

79 | Page  Table 4 -4: Group Counseling  
SUD  
Group 
Counseling MD/ DO  H0005  AF $11.02  $12.43  
CNS  
CNP  
PA 
PSY 
LISW 
LIMFT 
 LPCC  
 LICDC  H0005  HK $9.37  $10.56  
LSW  
LMFT 
LPC  
LCDC III, LCDC II  H0005  U4 and HK 
U5 and HK 
U2 and HK 
U3 and HK  $9.37  $10.56  
PSY assistant  H0005  U1 $8.37  $9.44  
SW-T H0005  U9 $8.37  $9.44  
MFT -T H0005  UA $8.37  $9.44  
CDC -A H0005  U6 $8.37  $9.44  
C-T H0005  U7 $8.37  $9.44  
Permitted POS  03, 04, 11, 12, 13, 14, 16, 31, 32, 34, 57  
and 
99 Telehealth allowed with GT modifier.  GT modifier 
is required when service rendered via telehealth.

80 | Page  Table 4 -5: SUD Case Management  
SUD  
SUD Case 
Management  MD/DO  H0006  - $19.54  $22.03  
CNS  
CNP  
PA 
PSY H0006  - $19.54 $22.03  
LISW 
LIMFT 
LPCC  
LICDC 
Lic school PSY  H0006  - $19.54  $22.03  
LSW  
LMFT 
LPC 
LCDC II or LCDC 
III H0006  U4 
U5 
U2 
U3 $19.54   
 
$22.03  
PSY assistant  H0006  U1 $19.54  $22.03  
SW-T H0006  U9 $19.54  $22.03  
SW-A H0006  U8 $19.54  $22.03  
MFT -T H0006  UA $19.54  $22.03  
CDC -A H0006  U6 $19.54  $22.03  
C-T H0006  U7 $19.54  $22.03  
CMS high school  
CMS Associate’s  
CMS Bachelor’s  
CMS Master’s  H0006  HM 
HM 
HN 
HO $19.54  $22.03  
Unit Value  15 minute s 
Permitted POS  03, 04, 11, 12, 13, 14, 16, 18, 23, 31, 32, 33, 34, 57, 99  
If more than six (6) units are delivered on the same date 
of service by the same agency, subsequent units will be

of service by the same agency, subsequent units will be 
adjudicated at 50% of the above rates.  Telehealth allowed with GT modifier. GT modifier is required 

81 | Page  Table 4 -6: SUD Drug Screening  
SUD  
Non-blood 
specimen collection 
for alcohol/other 
drug testing MD/DO  
CNS  
CNP  
PA 
RN, LPN  
PSY 
LISW 
LIMFT 
 LPCC  
 LICDC 
Lic school PSY  H0048  
 - $14.48  
 
$16.33  
LSW  
LMFT 
LPC  
LCDC III, LCDC II  H0048  U4 
U5 
U2 
U3 $14.48 $16.33  
SW-T 
SW-A 
MFT-T 
CDC -A 
C-T 
CMS Master’s  H0048  U1 
U9 
U8 
UA 
U6 
U7 
HM 
HM 
HN 
HO $14.48 $16.33  
Permitted  POS  11, 57

82 | Page  Table 4 -7: SUD RN and LPN Nursing Services  
SUD  
Type  Code  Modifier  Rate  through 
1, 2024  
Nursing 
Services – 
Individual RN T1002  - $31.92 –in office  
$41.00 –in community  $35.99 - in office  
$46.23 - in community  
LPN  T1003  -  
$22.54  
$29.13  
  
$25.41  
$32.84  
Nursing 
Services – 
Group RN T1002  HQ $10.37  $11.69  
Unit Value  15 minutes   
Permitted 
POS Individual RN/LPN nursing services - 03, 
04, 11, 12, 13, 14, 16, 18, 31, 32, 33, 34, 
57, 99 
Group RN nursing services – 11 and 57  
For T1002 KX – POS 23 is also available  Telehealth allowed with GT modifier.  
RN nursing 
service to 
address a

RN nursing 
service to 
address a 
crisis  Add KX modifier to indicate RN nursing service provided when a patient is experiencing a crisis, as allowable within the practitioner’s scope of practice.  KX is not allowable with group RN nursing services (HQ modifier).

83 | Page  Table 4-8: Intensive Outpatient Level of Care Group Counseling  
SUD  
Service  Provider Type  Code  Modifier  Rate  through 
Group 
Counseling IOP 
Level of Care*  MD/DO  
CNS  
CNP  
PA 
PSY H0015  HK $149.88  $168.99  
LISW  
LIMFT 
 LPCC  
 LICDC  H0015  HK $149.88  $168.99  
LSW  
LMFT 
LPC  
LCDC III, LCDC II  H0015  U4, HK  
U5, HK  
U2, HK  
U3, HK  $149.88  $168.99  
SW-T 
MFT-T 
CDC -A 
C-T H0015  U1 
U9 
UA 
U6 
U7 $103.04  $116.18  
Unit Value  Per diem. For IOP group counseling when provided to a client for  a minimum length of  2 hours . 
and 1 minute . 
Permitted  POS 03, 04, 11,  14, 16,  57 Telehealth allowed with GT modifier.  
* When practitioner s are co-facilitating an IOP group counseling service, it is up to the agency to determine under which

* When practitioner s are co-facilitating an IOP group counseling service, it is up to the agency to determine under which 
practitioner to bill, to ensure billing for this per diem service is not duplicative , and to ensure the practitioner to patient 
ratio of no more than 1:12 is maintained .

84 | Page  Table 4 -9: Partial Hospitalization (PH) Level of Care Group Counseling  
*When practitioner s are co-facilitating a PH  group counseling service, it is up to the agency to determine 
under which practitioner to bi ll, to ensure billing for this per diem service is not duplicative, and to ensure 
the practitioner to patient ratio of no more than 1:12 is maintained . 
 
  SUD  
January 1, 
2024  
Group 
Counseling 
PH Level of 
Care*  MD/DO  
CNS  
CNP  
PA 
PSY H0015  HK TG $224.82  $253.48  
LISW  
LIMFT 
 LPCC  
 LICDC 
 H0015  HK TG $224.82   
 
$253.48  
LSW  
LMFT 
LPC 
LCDC III  
LCDC II  H0015  U4, HK  
U5, HK  
U2, HK  
U3, HK  
U3, HK  TG $224.82   
 
$253.48  
SW-T 
MFT-T 
CDC -A 
U9 
UA 
U6 
U7 TG $154.56   
 
$174.27

LPC 
LCDC III  
U5, HK  
U2, HK  
U3, HK  
 
$253.48  
SW-T 
MFT-T 
CDC -A 
U9 
UA 
U6 
 
$174.27  
Unit Value  Per diem. For PH group counseling when provided to a client for a minimum  length  of 3 hours and 1 
minute . 
Permitted 
POS  03, 04, 11,  14, 16,  57 Telehealth allowed with GT modifier.  
GT modifier is required when service rendered via telehealth.

85 | Page  Table 4 -10: SUD Withdrawal Management with Extended On Site Monitoring  
SUD  
Service  Provider Type  Code  Procedure 
Withdrawal 
Management 
Hourly ASAM 2 
WM RN H0014  - $127.68  $143.96  
RN H0014  AT $338.35  $381.49  
LPN  H0014  - $90.16  $101.66  
LPN  H0014  AT $238.92  $269.38  
Management Per 
Diem ASAM 2  
WM MD/DO  
CNS  
CNP  
PA H0012  - $360.36  $406.31  
Unit Value  H0012: Per diem  
H0014: 1 hour  
H0014 AT: 2 -3 hours  
Permitted POS  11, 55, 57  Telehealth allowed with GT modifier.  
 
SECTION  5 
SUD Residential Treatment  
Providers  must be certified  by OhioMHAS for residential and withdrawal management substance use 
disorder services to bill for SUD residential treatment. Provider s must have the ODM  provider specialty

disorder services to bill for SUD residential treatment. Provider s must have the ODM  provider specialty 
“954 – SUD RESIDENTIAL FACILITY” for provider type “95 – OMHAS CERTIFIED/LICENSED 
TREATMENT PROGRAM”  to bill using the SUD residential treatment benefit package.  
In order to bill a SUD residential per diem  at least one documented face-to-face service must be provided 
by one of the clinical/treatment team members to the patient at the SUD residential treatment program 
site. Per diem payments do not include room and board.  
SUD Withdrawal Management with Extended On Site Monitoring  
For information on billing Withdrawal Management Per Diem ASAM 2 WM, refer to Table 4 -10 (SUD 
Withdrawal Management with Extended On Site Monitoring)

86 | Page  Table 5-1: Clinically Managed Low -Intensity Residential Treatment  
SUD  
Service  Provider Type  Code  Rate  through December 
31, 2023  Rate effective  January 1, 
2024  
Clinically 
Managed Low -
Intensity 
Residential 
Treatment ASAM 
3.1 Any 
independently 
licensed 
practitioner with 
an SUD scope of 
practice  H2034  $152.57   
 
$172.02  
Permitted POS  55 Telehealth allowed with GT modifier.  
 
Table 5-2: Clinically Managed Residential Withdrawal Management 
 
SUD   
December 31, 2023  Rate effective  January 1, 
2024  
Managed 
ASAM 3.2 WM Any 
licensed 
practice  H0010  $256.33   
 
$289.01  

87 | Page  Table 5-3: Clinically Managed Population -Specific High Intensity Residential Treatment  
(Adults)  
SUD  
Clinically Managed 
Population- Specific 
High Intensity 
3.3 (Adults)  Any 
licensed 
practice  H2036  HI $213.70  $240.95  
 
Table 5-4: Clinically Managed High Intensity Residential Treatment  
SUD  
Type  Code  Rate  through December 
2024  
3.5 Any 
licensed 
an SUD scope 
of practice  H2036  $213. 70 $240.95  
Unit Value  Per diem

3.5 Any 
licensed 
GT modifier is required when service 
rendered via telehealth.

88 | Page  Table 5-5: Medically Monitored Intensive Inpatient Treatment (Adults) and Medically 
Monitored High -Intensity Inpatient Services (Adolescent)  
SUD  
Medically 
Monitored 
Intensive Inpatient 
Treatment (Adults) 
and Medically 
Monitored High-
Intensity Inpatient 
Services 
(Adolescent) 
ASAM 3.7  Any 
licensed 
practice  H2036  TG $303.49   
 
$342.18  
 
Table 5-6: Medically Monitored Inpatient Withdrawal Management  
SUD  
Type  Code  Rate  through December 31, 
2023  Rate effective  January 1, 
2024  
Medically 
Monitored 
Inpatient 
ASAM 3.7  
WM Any 
licensed 
an SUD scope

2024  
Medically 
Monitored 
Inpatient 
ASAM 3.7  
WM Any 
licensed 
of practice  H0011  $392.86  $442.95  
Permitted 
POS 55 Telehealth allowed with GT modifier.  

89 | Page  SECTION 6  
Opioid Treatment Programs  
 
This section includes services provided by Opioid Treatment Programs  (OTPs) licensed by OhioMHAS 
as a methadone administration program and/or certified by the Substance Abuse and Mental Health 
Services Administration (SAMHSA) as an OTP .   
 
Provider Network Management (PNM) Enrollment  for Opioid Treatment Programs  
OTP providers must be enroll ed with Ohio Medicaid  as provider type 95, community substance use 
disorder treatment provider, with the 950 provider  specialty.  Additionally, to bill Medicaid  for OTP 
specialty services, the provider agency must be licensed as an OTP by OhioMHAS and certified by the 
Substance Abuse and Mental Health Services Administration (SAMHSA). Medicaid OTP provider 
specialties differ by type : 
• Providers of Methadone enroll as Medicaid provider specialty 951.   
• Providers of Buprenorphine enroll as Medicaid provider specialty 953.

• Providers of Buprenorphine enroll as Medicaid provider specialty 953.   
• Providers of both Methadone and Buprenorphine  enroll with  both specialties 951 and 953.   
These specialties can be added  by request  through the ODM Provider Network Management (PNM) 
system . OTPs will need to upload their documentation of OhioMHAS licensure and SAMHSA 
Certification. Once submitted, the request for a new provider specialty and the supporting 
documentation will be reviewed by ODM Provider Enrollment and the provider will be notified when the specialty is added  or if additional information is needed .   
 
Buprenorphine Administration for SUD Treatment Programs  
For information on billing Buprenorphine, refer to Table 2-9 : Provider Administered Pharmaceuticals  
OTP Billing Guidance  
 1. Daily Administration. H0020 with the HF modifier is used for daily methadone

 1. Daily Administration. H0020 with the HF modifier is used for daily methadone 
administration , including  single  take-home doses provided in accordance with Ohio 
Administrative Code 5122- 40-06.  T1502 is used for daily buprenorphine administration, 
including single take home doses provided in accordance with Ohio Administrative Code 
5122- 40-06.     
a. If patient is seen every day in order to receive methadone or buprenorphine , 
modifier HF must be used with H0020 and T1502 respectively.   
b. The date of service for H0020 or T1502 with modifier HF is the date of 
administration of the medication  or in the case of a daily  take-home dose, the 
date the patient will take the dose.  
2. Weekly Administration. H0020 or T1502 with a modifier representing 1, 2, 3 or 4 weeks 
(see Table 6 -1) is used for weekly medication administration  that includes  take-home doses  
provided in accordance with  42 Ohio Administrative Code 5122-40 -06. The OTP must

provided in accordance with  42 Ohio Administrative Code 5122-40 -06. The OTP must 
maintain documentation in the patient record that supports the number of take-home doses 
administered.  
a. If any weekly administration modifier has been billed, the OTP cannot bill H0020  
or T1502 again during that time period (1, 2, 3, or 4 weeks) . 
b. Date of service on the claim must be the date the patient was seen in the office by the OTP in order to receive their  take-home medication.

90 | Page  3. OTPs  administering  buprenorphine  must bill the appropriate J code (see chart below) for 
the medication that was administered. OTPs may bill for take -home doses using S5000 
or S5001.  
4. 99211 may be used  for the nasal administration of naloxone (J2310). This coding 
combination is only used when the naloxone is administered nasally on site.  
5. 96372 may be used  for the injectable administration of naloxone (J2310). This coding  
combination is only used when the naloxone is administered by injection on site.  
6. J2310 is used for injectable/nasal naloxone administered in accordance with the Ohio 
Board of Pharmacy requirements.  
7. OTPs may bill for the cost of oral naltrexone (J8499) under their Ohio Board of Pharmacy 
license.  
8. OTPs may bill for the collection of blood using venipuncture (36415), per draw when the 
sample is sent to an outside laboratory for testing.

license.  
sample is sent to an outside laboratory for testing.  
9. All of the OTP services must be performed by one of the following medical professionals within their scope of practice: physician, clinical nurse specialist, c ertified nurse 
practitioner, physician assistant, registered nurse, or a  licensed practical nurse.  
10. Please reference Table 6 -1 for additional information on service coding, rates and 
modifiers.

91 | Page  Table 6 -1: Opioid Treatment Programs  
Provider  Type 95/951 – State Licensed  Methadone  Program 
Service Descripti on Provider 
Type  Code  Modifier  Rate through 
January 1, 202 4 
Methadone 
Administration  Daily  MD/DO, 
CNS, NP, 
PA, RN, LPN  H0020  HF $16.38  $18.47  
Weekly (2 – 7 days)  
MD/DO, 
CNS, NP, 
PA, RN, LPN  H0020  TV $114.66  $129.28  
Two Weeks (8 – 14 
days)  UB $229.32  $258.56  
Three Weeks (15 – 21 
days)  TS $343.98  $387.84  
Four Weeks (22 – 28 
days)  HG $458.64  $517.12  
 
Medications Oral Naltrexone, per  
50 mg tablet  - J8499  HG $1.20  $1.35  
Injection/Nasal,  
naloxone (Narcan), 
1mg   
-  
J2310   
- See Medicaid  fee 
schedule in effect   for date of service.  
Services  Collection of venous 
blood by venipuncture  Per CPT 
guidelines 1   
36415   
- See Medicaid fee schedule  in effect   
for date of service. 
Unit  Value  CPT or HCPCS  designation

92 | Page  Table 6-2: Opioid Treatment Programs  
Provider Type 95/953 – 
SAMHSA Certified Opioid Treatment Program  
Service  Description  Provider  
 
Buprenorphine/ 
Naloxone 
Administration  Daily  
 
MD/DO, 
CNS, 
CNP, PA,  
RN, LPN  T1502  HF $16.38  $18.47  
Weekly (2 – 7 
days)  TV $114.66  $129.28  
Three Weeks (15 –  
21 days)  TS $343.98  $387.84  
Four Weeks (22 – 
28 days)  HG $458.64  $517.12  
Medications  Buprenorphine, 
oral, 1 mg.   
-  
J0571   
- See Medicaid fee schedule  in effect for date 
of service. 
Buprenorphine/nal
oxone,  oral, less 
than or equal to 3 
mg.  
-  
J0572   
-  
See Medicaid fee schedule  in effect for date 
 
oxone,  oral, greater 
than 3 mg, but less 
than or equal to 6 
mg.  
-  
J0573   

mg.  
-  
J0573   
oxone, oral, greater 
than 6 mg, but less 
than or equal to 10 
mg.  
-  
J0574   
than 10 mg.   
-  
J0575   
of service.

93 | Page  Provider Type 95/953 – 
Medications 
(continued)  Buprenorphine/nal
oxone, generic , per 
1mg 
buprenorphine/0.25
mgnaloxone   
-  
S5000   
- $1.20  $1.35  
Buprenorphine  
generic, per 1 mg.   
-  
S5000   
HD $0.55  $0.62  
oxone,  
brand , per 1mg   
-  
S5001   
- $2.30  $2.59  
Buprenorphine/0.2
5mg 
naloxone   
-  
-  
Oral Naltrexone, 
per 50mg tablet  - J8499  HG $1.20  $1.35  
Injection/Nasal, 
1mg - J2310  - See Medicaid fee schedule  in effect for date 
Services  Collection of 
venous blood by 
venipuncture  Per CPT 
guidelines
1 36415  - See Medicaid fee schedule  in effect for date 
Unit Value  CPT or HCPCS Designation

Unit Value  CPT or HCPCS Designation  
 
1 Separate billing for  collection of venous blood is only allowable when a provider draws the blood and 
sends it to a non -related outside facility without performing any testing.  
Coordination of Benefits: Medicare  Opioid Treatment Program Benefit 
ODM is required by CMS to coordinate Medicaid payment for OTP services to individuals with Medicare  
to ensure services and costs that are covered by  the Medicare OTP are not being paid by Medicaid or a 
Medicaid managed care entity. Based on the Medicare OTP benefit as of the date this manual was 
published, Table 6 -4 identifies OTP services covered by Medicaid that are included in the Medicare 
bundled payment, as well as those that are not part of the Medicare bundled payment. Medicaid claims for

bundled payment, as well as those that are not part of the Medicare bundled payment. Medicaid claims for 
dually eligible recipients will need to show proof of Medicare denial and  valid reason for non -payment 
prior t o Medicaid making any payment for the OTP services that are designated as included in the 
Medicare bundled payment.  The Medicare OTP benefit is subject to change; therefore, Table 6 -4 should 
be used as reference. OTP providers are responsible for billing Medicare prior to Medicaid payers for services that are included in the Medicare OTP bundle .

94 | Page  Table 6-3: Medicare Opioid Treatment “Bundle ” Billing Codes  
Medicaid  procedure c odes c overed  under Medicare OTP payment  
 ASAM Level 1  ASAM Level 2  ASAM Level 3  
Ohio Medicaid Codes 
Covered by Medicare H0020/T1502 – med admin  
90791-92, H0001 – 
assessment  
99201-05, 99211-15, 
99341-50  
H0004 – individual 
counseling  
H0005 – group counseling  
H0048 –non-blood 
specimen collection for 
alcohol/other drug testing  
90832-38 – individual 
90853 – group counseling  
96372 – injection admin  H0020/T1502 
90791-92, H0001  
99341-50  
H0004  
H0005  
H0048  
90832-38  
90853  
96372  H0020/T1502 
 
Ohio Medicaid 
Medication codes 
Covered by Medicare  S5000- 01, J0571-75, J2310, J8499  
Ohio Medicaid Lab D rug 
Testing C odes Covered 
by Medicare 80305-07, 80320-36, 80338 -77, 83992, G0480-83  
Medicaid procedure codes not covered under Medicare OTP payment  
NOT Covered by

NOT Covered by 
Medicare  H0006 – care management 
H0038 - peer recovery  
T1002 – RN services  
T1003 – LPN services  H0015 – IOP 
H0015 TG – PH 
H0012 – detox  
H0014 – detox  
H0006  
H0038  
T1002  
T1003  H2034 – residential 
H2036 – residential 
H0010 – detox  
H0011 – detox

95 | Page  SECTION 7 
Specialized Recovery Services (SRS) Program [1915(i)] 
 
The SRS program is available to individuals who meet certain financial criteria and have been diagnosed 
with a serious and persistent mental illness (SPMI)  or another chronic medical condition listed in Ohio 
Administrative Code 5160- 43-02. Individual eligibility and program enrollment criteria are detailed in 
Administrative Code rule 5160-43 -02. In addition to full Medicaid coverage, individuals enrolled in the 
SRS program have access to additional services: Individualized Placement and Support -Supported 
Employment (IPS-SE) and  Peer Recovery Support (PRS). In order to deliver and submit claims for 
payment for PRS or IPS -SE services through the SRS program,  providers must meet all of the 
requirements listed in Administrative Code rule 5160- 43-04 .  
For behavioral health agencies to provide IPS -SE, the agency must be certified by OhioMHAS and

For behavioral health agencies to provide IPS -SE, the agency must be certified by OhioMHAS and 
enrolled with Ohio Medicaid with the IPS-SE specialty (specialty 964). Providers must provide 
certification to provide the IPS-SE service listing eligible practice locations when enrolling or adding this specialty to their provider file. For behavioral health agencies to provide PRS through the SRS program, 
the agency must have individuals on staff who have been trained and certified as Peer Recovery 
Supporters through OhioMHAS. Providers may only submit claims for these services delivered to 
individuals enrolled in the SRS program.  
SRS program services are covered when rendered via telehealth. For details on the requirements to render 
SRS program services, refer to Administrative Code rule 5160-43- 04
.

96 | Page  Table 7- 1: SRS Supported Employment  
MH 
SRS Supported 
Employment, 
Initial  Any unlicensed practitioners 
per OAC 5016-27-01, except 
PRS and “supervised trainees” 
under general supervision . H2023 $19.53  $22.02  
Subsequent Any unlicensed practitioners 
under general supervision . H2025 $19.53  $22.02  
Permitted POS  03, 04, 11, 12, 13, 14, 16, 17, 18, 19, 20, 23, 
53, 55, 56, 57 
*POS 56 not allowable for initial service  
 Telehealth allowed with GT modifier.  
via telehealth . 
   
Table 7 -2: SRS Peer Recovery Support  
MH 
SRS Peer 
Recovery Support,

MH 
SRS Peer 
Recovery Support, 
Individual PRS H0038  - $15.51  $17.49  
SRS Peer 
Group PRS H0038  HQ $1.94  
$2.19  
Permitted POS  Not allowed in 02, 05, 06, 07, 08, 41, 42, 55 Telehealth allowed with GT modifier.  

97 | Page  SECTION 8 
OhioRISE  
 
The Ohio Department of Medicaid (ODM) supported by the Governor’s Family and Children First 
Cabinet Council, and in partnership with state sister agencies, stakeholders, and providers, developed 
Ohio’s first -ever integrated program to help children who have complex and serious behavioral health 
needs. OhioRISE  (Resilience through Integrated Systems and Excellence) , launched on July 1, 2022,  aims 
to improve care and outcomes for these children and their families or caregivers by:  
• Creating a seamless delivery system for children and youth, families/caregivers, and system 
partners.  
• Providing a “locus of accountability” by offering community-driven comprehensive care coordination through local Care Management Entities (CMEs).

partners.  
• Providing a “locus of accountability” by offering community-driven comprehensive care coordination through local Care Management Entities (CMEs).  
• Expanding access to critical behavioral health treatment services and supports needed for this population such as Intensive and Moderate Care Coordination, Mobile Response and Stabilization, Behavioral Health Respite, Intensive Home -Based Treatment, and Flexible 
Funds.  
• Assisting youth, families, state, and local child serving agencies, and other health providers to 
locate and use these services.  
The OhioRISE program covers a range of behavioral health (BH) services for youth that are comprised of 
existing, enhanced, and new behavioral health and care coordination services. For more information about 
billing for the new and enhanced services  for youth enrolled in OhioRISE , please refer to the 
OhioRISE 
Provider Enrollment and Billing Guidance . F or youth enrolled in OhioRISE, existing behavioral health

OhioRISE 
Provider Enrollment and Billing Guidance . F or youth enrolled in OhioRISE, existing behavioral health 
services will be covered in accordance with the OhioRISE Mixed Services Protocol  and will be billed 
consistent with the billing policies outlined in the appropriate provider type billing guidelines.

98 | Page  Appendix: Ohio Medicaid List of Place of Service Codes  
 
Listed below are places of service that are included in the above tables.  For a complete list of place of service codes, 
please see CMS Place of Service Code Set . 
 
For services delivered via telehealth , providers may use either the place of service code that reflects the location of 
the practitioner or the location of the patient. The appendix to OAC 5160- 27-03 includes a list of allowable place s of 
service codes for each procedure code. Please note, place of service code 02 is not allowed . Providers should use the 
GT modifier to identify telehealth services.   
 
Code(s)  Place of Service Name  Place of Service Description  
01 Pharmacy  A facility or location where drugs and other medically related items and services 
are sold, dispensed, or otherwise provided directly to patients.  
03 School  A facility whose primary purpose is education.

03 School  A facility whose primary purpose is education.  
04 Homeless Shelter  A facility or location whose primary purpose is to provide temporary housing to 
homeless individuals (e.g., emergency shelters, i ndividual or family shelters).  
11 Office  Location, other than a hospital, skilled nursing facility (SNF), military treatment 
facility, community health center, State or local public health clinic, or intermediate care facility (ICF), where the health professional routinely provides health examinations, diagnosis, and treatment of illness or injury on an 
ambulatory basis.  
12 Home  Location, other than a hospital or other facility, where the patient receives care 
in a private residence.  
13 Assisted Living Facility  Congregate residential facility with self -contained living units providing 
assessment of each resident's needs and on -site support 24 hours a day, 7 days a

assessment of each resident's needs and on -site support 24 hours a day, 7 days a 
week, with the capacity to deliver or arrange for services including some health 
care and other serv ices. 
14 Group Home  A residence, with shared living areas, where clients receive supervision and 
other services such as social and/or behavioral services, custodial service, and 
minimal services (e.g., medication administration).  
16 Temporary Lodging  A short -term accommodation such as a hotel, campground , hostel, cruise ship or 
resort where the patient receives care, and which is not identified by any other 
POS code.  
17 Walk -in Retail Health 
Clinic  A walk -in health clinic, other than an office, urgent care facility, pharmacy or 
independent clinic and not described by any other Place of Service code, that is located within a retail operation and provides, on an ambulatory basis,

independent clinic and not described by any other Place of Service code, that is located within a retail operation and provides, on an ambulatory basis, 
prevent ive and primary care services.  
18 Place of Employment/Worksite  A location, not described by any other POS code, owned or operated by a public 
or private entity where the patient is employed, and where a health professional provides on- going or episodic occupational medical, therapeutic or rehabilitative 
services to th e individual.

99 | Page  Code(s)  Place of Service Name  Place of Service Description  
20 Urgent Care Facility  Location, distinct from a hospital emergency room, an office, or a clinic, whose 
purpose is to diagnose and treat illness or injury for unscheduled, ambulatory 
patients seeking immediate medical attention.  
22 On Campus -Outpatient 
Hospital  A portion of a hospital which provides diagnostic, therapeutic (both surgical and 
nonsurgical), and rehabilitation services to sick or injured persons who do not 
require hospitalization or institutionalization.  
23 Emergency Room - 
Hospital  A portion of a hospital where emergency diagnosis and treatment of illness or 
injury is provided.  
24 Ambulatory Surgical 
Center  A freestanding facility, other than a physician's office, where surgical and 
diagnostic services are pr ovided on an ambulatory basis.  
25 Birthing Center  A facility, other than a hospital's maternity facilities or a physician's office,

25 Birthing Center  A facility, other than a hospital's maternity facilities or a physician's office, 
which provides a setting for labor, delivery, and immediate postpartum care as 
well as immediate care of newborn  infants.  
31 Skilled Nursing Facility  A facility which primarily provides inpatient skilled nursing care and related 
services to patients who require medical, nursing, or rehabilitative services but 
does not provide the level of care or treatment available in a hospital.  
32 Nursing Facility  A facility which primarily provides to residents skilled nursing care and related 
services for the rehabilitation of injured, disabled, or sick persons, or, on a 
regular basis, health -related care services above the level of custodial care to 
other than individuals with intellectual disabilities.   
33 Custodial Care Facility  A facility which provides room, board and other personal assistance services,

33 Custodial Care Facility  A facility which provides room, board and other personal assistance services, 
generally on a long- term basis, and which does not include a medical 
component.  
34 Hospice  A facility, other than a patient's home, in which palliative and supportive care 
for terminally ill patients an d their families are provided.   
41 Ambulance - Land  A land vehicle specifically designed, equipped and staffed for lifesaving and 
transporting the sick or injured.  
42 Ambulance - Air or Water  An air or water vehicle specifically designed, equipped and staffed for lifesaving and transporting the sick or injured.  
53 Community Mental Health Center  A facility that provides the following services: outpatient services, including 
specialized outpatient services for children, the elderly, individuals who are chronically ill, and residents of the CMHC's mental health services area who

specialized outpatient services for children, the elderly, individuals who are chronically ill, and residents of the CMHC's mental health services area who 
have been discharged from inpatient treatment at a mental health faci lity; 24 
hour a day emergency care services; day treatment, other partial hospitalization 
services, or psychosocial rehabilitation services; screening for patients being 
considered for admission to State mental health facilities to determine the 
appropriateness of such admission; and consultation and education services.  If 
the facility is not certified by Medicare as a CMHC, POS should be 11, 
indicating office.

100 | Page Code(s)  Place of Service Name  Place of Service Description  
55 Residential Substance 
Abuse Treatment Facility  A facility which provides treatment for substance (alcohol and drug) abuse to 
live-in residents who do not require acute medical care. Services include 
individual and group therapy and counseling, family counseling, laboratory 
tests, drugs and supplies, psychological testing, and room and board.  
57 Non-residential Substance 
Abuse Treatment Facility  A location which provides treatment for substance (alcohol and drug) abuse on 
an ambulatory basis. Services include individual and group therapy and counseling, family counseling, laboratory tests, drugs and supplies, and 
psychological testing.  
99 Other Place of Service   
Other place of service not identified above. May be used when a more specific 
place of service in not available, including  community.

M etabolic Syndrome  01
 Overview  
 BMI
 W eight Management Test  
 Associated conditions  02
 C ardiovascular disease  
 P olycystic ovarian syndrome  
 Fatty liver  
 Sleep apnea  
 Type 2 diabetes    
 Contributing factors  03
 Inflammation  
 N utrient deficiencies  
 Dietary excess  
 Lack of ex ercise  
 E nvironmental toxin exposure  
 Stress  
 Supplements  05
 MediBolic® 
 Super EPA Pro  
 Meriva 500-SF  
 Diet  06
 M odified Mediterranean Diet  
 G lycemic index / load   
 Carb count  Table of contents
 F oods to eat & avoid  08
 Vegetables 
 Fruits / juices  
 Legumes 
 Grains 
 Protein 
 Sweeteners 
 Fats 
 O ther items to avoid  
 Activities 11
 I mportance of exercise  
 H elpful exercise tips  
 T ips to reduce stress  
 S ample meal plan  12
 Recipes 13
 Shakes 
 Breakfast 
 Lunch & dinner  
 Soups & stews  
 Salads 
 Side dishes  
 Snacks 
 Desserts 
 Health journal  27
 Final word  28

Metabolic syndrome
Overview
Metabolic syndrome is a constellation of conditions that can result in one or more negative impacts on your heart, blood vessels, and liver, as well as your ability 
to metabolize sugar and fat.
Also referred to as syndrome X or insulin resistance, it is estimated that 25% of the world’s adult population (and it is believed to be closer to 34% in the United 
States) has signs and symptoms associated with metabolic syndrome.1
While metabolic syndrome can seriously impact your health, there are steps that can be taken to reduce or reverse these potential negative health consequences. 
In this guide, you will learn about the potential causes of metabolic syndrome, what factors help determine a metabolic syndrome diagnosis, and what 
nutritional and lifestyle recommendations can help guide you along the path toward good health.
Metabolic syndrome is defined as 3 or more of the following:

 lIncreased waist circumference (>102 cm/40 inches men and >88 cm/34 inches women)  
 lElevated blood pressure (>130/85 mmHg)
 lElevated blood sugar (fasting glucose ≥100 mg/dL)
 lHigh triglycerides (>150 mg/dL)
 lLow high-density lipoprotein (HDL) cholesterol (<40 mg/dL in men and <50 mg/dL in women)
Body mass index (BMI)
Your risk for having metabolic syndrome generally increases as you age and when your body mass index (or BMI) increases. A person’s body mass index takes 
into account height and weight, although it does not take into account body fat percentage. Thus, if you are a person who exercises regularly and you are muscular, your BMI could be higher than your risk for developing metabolic syndrome. 
BMI Classification
< 18.5 Underweight
18.5-24 Normal
24-29.9 Overweight
30-40 Obese

40+ Extremely obeseWhat does my number mean? Find your BMI
Imperial methodWeight (lbs) x 703
Height (in)2BMI =
Metric methodWeight (kg)
Height (m)2BMI =BMI and metabolic syndrome risk
Men
Baseline
6x
32x< 25
25-29.9
30+BMI Prevalence Risk
7%
30%
65%Women
Baseline
5.5x
17x< 25
25-29.9
9%
33%
56%*
*Compared to normal weight *Compared to normal weight*
Are you interested in exploring what factors might be affecting your weight? Consider taking the Thorne Weight Management Test.  Discover how to reach 
your weight goal. This at-home blood and saliva test provides insights by measuring key biomarkers associated with weight management. Results include a 
personalized health plan.
01

Associated conditions
Cardiovascular disease
Individuals with MetS are three times  more likely than those without 
MetS to have a stroke or a heart attack, and twice as likely to die 
from these events.2Fatty liver
Fatty liver (technically called nonalcoholic fatty liver disease or NAFLD) is the most common liver disease in the Western world and, according to the American Liver Foundation, 25% of Americans have fatty liver. Broken down by age, 30-40% of adults and 5-10% of children probably have fatty liver.
4 Insulin resistance, 
obesity, and other aspects of metabolic syndrome are all associated with increased risk for fatty liver.
Sleep apnea
Obesity is at the heart of the worldwide increase in sleep apnea, a condition commonly associated with MetS. In addition to obesity being a cause of sleep apnea, sleep apnea seems to contribute to MetS. For example, studies show sleep apnea can  increase 
cortisol levels , which are in turn associated with obesity and insulin 
resistance.
5

5 
It also appears that imbalances brought on by sleep apnea contribute to some symptoms seen in MetS. Studies indicate sleep apnea increases cortisol levels, which are in turn associated with obesity and insulin resistance.Polycystic ovarian syndrome
Many aspects of metabolic syndrome are also seen in women with PCOS — including insulin resistance, obesity in some cases, and elevated cholesterol. Statistics indicate approximately 30% 
of women  with PCOS have impaired glucose tolerance, while an 
additional 7.5% have diabetes.
3
Type 2 diabetes
The risk of developing type 2 diabetes is five times higher in those 
with MetS.2

Contributing factors
Inflammation
Obesity is known to be associated with low-level inflammation. The inflammation occurs first in the adipocytes, with an increase in tumor necrosis factor-alpha 
(TNF-α).6 TNF-α (marker of inflammation) stimulates a more general inflammatory state that can ultimately result in insulin resistance and problems with blood 
pressure.
Nutrient deficiencies
Although it is easy to consider metabolic syndrome attributable to excesses, there are several nutrient deficiencies associated with this condition.  
The most extensively researched deficiencies are magnesium, vitamin D, and chromium.
Magnesium – 31% higher rate of MetS in people who are low in magnesium

Magnesium – 31% higher rate of MetS in people who are low in magnesium 
Magnesium is one of the most clearly identified nutrient deficiencies in metabolic syndrome. Prior to identifying it as “metabolic syndrome,” researchers were examining the combination of insulin resistance, hyperinsulinemia, essential hypertension, ischemic heart disease, and magnesium deficiency (and called it Reaven-Modan syndrome after the researchers).
7 Here’s what the research says:
 lStudies clearly show that insulin sensitivity declines in healthy subjects when a state of magnesium deficiency is induced.8 
 lA large 15-year study of young American adults found a 31% increase in MetS in the group of subjects with the lowest magnesium intake.9 
 lA study on hair mineral content found lower magnesium-to-calcium ratios in individuals with insulin resistance.10

lA study on hair mineral content found lower magnesium-to-calcium ratios in individuals with insulin resistance.10 
 lLower intakes and lower blood levels of magnesium are associated with an elevation in inflammatory markers, while higher magnesium intakes and 
higher blood levels demonstrate a protective effect.7 As discussed above, these inflammatory markers are associated with MetS. 
Vitamin D – associated with a 51% increase in metabolic syndrome
Vitamin D plays a role in metabolic syndrome. Studies show vitamin D has a role in immune system function, inflammation, pancreatic beta-cell function, and 
mineral balances that are associated with MetS.11 What does the research say? A meta-analysis of 28 studies showed that, when compared to higher vitamin D 
levels, lower vitamin D levels were associated with:
 l55% increase in diabetes
 l33% increase in the risk of cardiovascular disease
 l51% increase in metabolic syndrome12
Chromium – deficiency seen in 80% of Americans

l55% increase in diabetes
Chromium – deficiency seen in 80% of Americans 
Chromium is not found in sufficient amounts in food to replenish tissue stores or to support healthy carbohydrate metabolism. Here are some facts:
 l80% of Americans are deficient in this essential mineral nutrient, and diets high in simple sugars can deplete chromium from the body.13 
 lIn a study of 123 males (63 with MetS; 60 controls), those with MetS had lower hair chromium concentrations than healthy controls.10Association between obesity, inflammation, & metabolic
*Adiponectin increases with weight loss, improves insulin sensitivity, decreases inflammation, and decreases atherogenesis
03

Dietary excess
Sugar-sweetened sodas: not so good 
Forty-eight percent of Americans drink an average of one soda daily (28% one soda daily; 20% two or more sodas daily). When examining the effects of sugar-
sweetened beverages on MetS parameters, researchers found plasma triglycerides and waist circumference, both aspects of MetS, increased as the number of sugared beverages increased.
14 
Diet sodas: worse
As awareness of the negative effects of sugar-sweetened sodas has increased, many people who choose diet sodas have the misconception that these beverages provide a healthier choice. Unfortunately, data indicates the opposite to be true. Individuals with an “at least daily” intake of diet soda were shown to have a 36% greater risk of developing metabolic syndrome and a 67% greater risk of developing type 2 diabetes compared to individuals who consumed no diet beverages.
15 
High-fructose corn syrup (HFCS): the worst

15 
Studies comparing HFCS-sweetened beverages to sugar-sweetened beverages show HFCS-containing beverages increase MetS symptoms at a higher rate than other sugar-containing beverages.
16,17 Other research has outlined the potential health outcomes associated with HFCS such as:18
 lWeight gain / obesity
 lInsulin resistance lFatty liver
 lIncreased triglycerides lLeptin resistance
 lIncreased protein glycosylation lType 2 diabetes
Other dietary excess 
Questionnaires from 3,782 participants found that over a nine-year period, consumption of a Western dietary pattern — high in meat, fried foods, and diet sodas — promoted development of MetS.
19
Lack of exercise
Lack of physical activity has long been associated with adverse impacts on metabolic health, including an increase in abdominal fat and a decrease in insulin sensitivity. As a person becomes less active, BMI, waist-hip ratio, waist circumference, and obesity go up.

20 Even in adolescents, lack of exercise and low cardio-
respiratory fitness are associated with increased risk for MetS.21
Environmental toxin exposure
Increasing evidence over the past decade indicates that chemicals in the environment can contribute to the hormonal imbalances that result in metabolic disruption in society at large. Human epidemiological data and numerous animal studies specifically associate endocrine-disrupting chemicals, such as organochlorine pesticides (like DDT), dioxins (like PCBs), and flame retardants (PBDEs), with metabolic syndrome. Studies also link exposure to the plasticizing agents bisphenol-A (BPA) and phthalates to insulin resistance, obesity, and liver abnormalities. Researchers are concerned that the effects of these chemicals will be amplified because chemical production now exceeds 400 million tons globally.
22 BPA has been shown to have significant adverse effects on estrogen

22 BPA has been shown to have significant adverse effects on estrogen 
signaling, even at small doses.23 This signaling can alter glucose transporter function, cause hyperglycemia, interfere with hypothalamic regulation of weight, 
result in adiposity, and impair energy expenditure.24
Stress
Stress is a well-known contributing factor to obesity. In a study of 10,308 men and women ages 35-55, workplace stress measured over a 14-year period was positively associated with an increased risk for metabolic syndrome. Employees with chronic work stress were twice as likely to develop MetS than individuals without work stress.
25 
Stress causes the body to secrete cortisol from the adrenals, which can cause increased cravings for sugary foods and increased blood sugar. All this can cause more fat production, leading to weight gain.
The connection between chronic stress & obesity
Food cravings / blood sugar Cortisol Insulin Fat production Chronic stress Obesity
04

Supplements
Nutritional supplementation is an important factor in helping to reverse the course of metabolic syndrome and improving your metabolism. 
MediBolic®
The cornerstone of a good program to reverse metabolic syndrome is a powdered nutritional supplement called MediBolic.* MediBolic combines protein and 
fiber with a complete assortment of vitamins, minerals, nutrients, and botanicals to address various aspects of metabolic syndrome* – all in a delightful vanilla cinnamon flavored product that is gluten-free and dairy-free. MediBolic can be mixed with water or the beverage of your choice. Each serving of MediBolic will provide you with 10 grams of easily digestible fiber. MediBolic provides you with protein, fiber, and a complete assortment of vitamins, minerals, nutrients, and botanicals. MediBolic tastes great when simply mixed with water, or you can make a smoothie using other ingredient combinations to add extra nutrition and flavor.
Super EPA Pro

Fish oil (Super EPA Pro) is an essential component of a well-rounded nutritional supplement program for general health.* Fish oil has particular importance in the case of metabolic syndrome because it helps maintain healthy levels of insulin and blood fats (cholesterol and triglycerides) and helps maintain healthy, elastic blood vessels.*
Meriva 500-SF
Meriva 500-SF helps maintain a healthy inflammatory response throughout the body.* Meriva® is the most clinically studied curcumin on the market with 29x 
greater absorption than ordinary curcumin.*2 gelcaps
twice daily
2 capsulestwice daily2 scoops w/
12-14 oz. water
Additional recommendations

Diet
Thorne's Modified Mediterranean Diet 
The largest body of evidence in relation to what is the best diet for metabolic syndrome clearly points toward what is referred to as the “Mediterranean Diet.” 
Long-term research has conclusively demonstrated that the diet eaten in the regions surrounding the Mediterranean Sea provides protection against a number of diseases and disorders, including the health markers associated with metabolic syndrome.
26

26
The Mediterranean Diet consists of large amounts of fruits and vegetables (of a variety of colors), in addition to whole grains, beans, nuts, and seeds. Fish, and to a lesser extent low-fat meat and poultry, are eaten in moderation. Fresh fruit is the typical daily dessert and olive oil is the primary fat source. The Thorne Modified Mediterranean Diet goes a step further to help assure you are not including common allergens, such as gluten, in your diet that can contribute to inflammation and weight gain. The dietary guidelines will also help steer you toward lower carbohydrate foods to help manage healthy blood sugar levels.
 lBarley 
 lSweet potatoes
 lMost vegetables
 lYogurt lRice
 lMost fruits
 lPasta
 lOatmeal lWhite bread
 lProcessed foods
 lSoda
 lBagels
High GI (70 or more)
 Medium GI (55-69)
Low GI (54 or less)Glycemic index / load

lMost vegetables
 lPasta
 lSoda
 lBagels
Low GI (54 or less)Glycemic index / load 
The glycemic index (GI) is a way to rank carbohydrates on a scale of 0-100, based on the extent to which the carbohydrates in food increase fasting blood sugar in healthy people. The lower the glycemic index number the lower the food’s impact on blood sugar. The glycemic load is based on the glycemic index but it takes into account the amount of carbohydrates in a specific serving. The recommended value of a foods glycemic index is 55 or less and 10 or less for the glycemic load. Glycemicindex.com  allows you to type in a food and receive its glycemic index and glycemic load. Use it as a general guide. Whenever possible, 
replace highly processed grains, cereals, and sugars with minimally processed whole grain products. Hydrate
Be active
(at least 20 minutes per day)Dairy
- Organic eggs

Be active
- Yogurt- Milk- Other dairy products
Protein
- Fish (wild)- Seafood- Poultry- Meat- Tofu
Vegetables, fruit,  
whole grains, beans,  nuts, seeds, & healthy oils
The most common food intolerances / allergies
Gluten Eggs Dairy Peanuts Corn Soy
06

Carb count
Carbohydrate-containing foods can increase your blood sugar and triglyceride levels, making it hard to lose weight and stay healthy. Total carb count should 
not exceed 75 grams daily (50 grams or less if you have diabetes or pre-diabetes). Your health-care practitioner might advise a different guideline based on your specific needs.
Grains
Steel-cut oats 14 g
Wild rice 17 g
Buckwheat 18 g
Quinoa 20 g
Millet 20 g
Brown rice 21 g
White rice 22 g
Amaranth 23 g
Teff 25 g
Tapioca 67 gLegumes
Lima beans 18 g
White beans 20 g
Mung beans 20 g
Black-eyed peas 20 g
Lentils 20 g
Black beans 20 g
Kidney beans 20 g
Soy beans 20 g
Split peas 21 g
Pinto beans 22 gStarchy Vegetables
Carrots 6 g
Beets 7 g
Parsnips 10 g
Pumpkin 10 g
Winter squash 10 g
Yellow corn 15 g
Green peas 15 g
Yams 20 g
Sweet potatoes 20 g
White potatoes 30 gFruits
Watermelon 6 g
Strawberries 6 g
Oranges 8 g
Cantaloupe 8 g
Honeydew 8 g
Raspberries 8 g
Blueberries 10 g
Pears 14 g
Bananas 15 g

Yams 20 g
Oranges 8 g
Pears 14 g
Grapes 15 gCarbs per 1/2 c. (cooked) Carbs per 1/2 c. (cooked) Carbs per 1/2 c. (cooked) Carbs per 1/2 c. (raw)
1. Ervin RB. Prevalence of metabolic syndrome among adults 20 years of age and over, 
by sex, age, race and ethnicity, and body mass index: United States, 2003-2006. Natl 
Health Stat Report  2009;13:1-7.
2. https:/ /www.nhlbi.nih.gov/health-topics/metabolic-syndrome [Accessed February 21, 2018]
3. Sharpless JL. Polycystic ovary syndrome and the metabolic syndrome. Clin Diabetes  
2003;21:154-161.
4. Kim CH, Younossi ZM. Nonalcoholic fatty liver disease: a manifestation of the meta -
bolic syndrome. Cleveland Clin J Med  2008;75:721-728.

5. Calvin AD, Albuquerque FN, Lopez-Jimenez F, Somers VK. Obstructive sleep apnea, inflammation, and the metabolic syndrome. Metab Syndr Relat Disord  2009;7:271-
278.
6. Emanuela F, Grazia M, Marco de R, et al. Inflammation as a link between obesity and metabolic syndrome. J Nutr Metab  2012;2012:476380.
7. Weglicki WB. Hypomagnesemia and inflammation: clinical and basic aspects. Annu 
Rev Nutr 2012;32:55-71.
8. Nadler JL, Buchanan T, Natarajan R, et al. Magnesium deficiency produces insulin resistance and increased thromboxane synthesis. Hypertension 1993;21:1024-1029. 
9. He K, Liu K, Daviglus ML, et al. Magnesium intake and incidence of metabolic syn -
drome among young adults. Circulation 2006;113:1675-1682.

drome among young adults. Circulation 2006;113:1675-1682. 
10. Chung JH, Yum KS. Correlation of hair mineral concentrations with insulin resistance in Korean males. Biol Trace Elem Res  2012;150:26-30.
11. Sung CC, Liao MT, Lu KC, et al. Role of vitamin D in insulin resistance. J Biomed 
Biotechnol 2012;2012:634195. 
12. Parker J, Hashmi O, Dutton D, et al. Levels of vitamin D and cardiometabolic disor -
ders: systematic review and meta-analysis. Maturitas 2010;65:225-236. 
13. Vincent J. The biochemistry of chromium.  J Nutr  2000;130:715-718.
14. Mattei J, Malik V, Hu FB, et al. Substituting homemade fruit juice for sugar-sweet -

ened beverages is associated with lower odds of metabolic syndrome among Hispanic adults. J Nutr 2012;142:1081-1087.15. Nettleton JA, Lutsey PL, Wang Y, et al. Diet soda intake and risk of incident metabolic syndrome and type 2 diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA). Diabetes Care 2009;32:688-694. 
16.  Bocarsly ME, Powell ES, Avena NM, et al. High-fructose corn syrup causes charac -
teristics of obesity in rats: increased body weight, body fat and triglyceride levels. Pharmacol Biochem Behav  2010;97:101-106.
17. Stanhope KL, Havel PJ. Endocrine and metabolic effects of consuming beverages sweetened with fructose, glucose, sucrose, or high-fructose corn syrup.  Am J Clin Nutr 
2008;88:1733S-1737S.

2008;88:1733S-1737S. 
18. Parker K, Salas M, Nwosu VC. High fructose corn syrup: production, uses, public health concerns. Biotechnol Mol Biol Rev 2010;5:71-78. 
19. Lutsey PL, Steffen LM, Stevens J. Dietary intake and the development of the metabolic syndrome: the Atherosclerosis Risk in Communities study. Circulation 
2008;117:754-761.
20. Golbidi S, Mesdaghinia A, Laher I. Exercise in the metabolic syndrome. Oxid Med Cell 
Longev 2012;2012:349710. 
21. Neto A, Sasaki J, Mascarenhas L, et al. Physical activity, cardiorespiratory fitness, and metabolic syndrome. BMC Public Health  2011;11:674-680.
22. Casals-Casas C, Desvergne B. Endocrine disruptors: from endocrine to metabolic disruption. Annu Rev Physiol 2011;73:135-162. 
23. Alonso-Magdalena P, Ropero A, Soriano S, et al. Bisphenol-A acts as a potent estro -

gen via non-classical estrogen triggered pathways. Mol Cell Endocrinol 2012;355:201-
207. 
24. Alonso-Magdalena P, Ropero A, Soriano S, et al. Bisphenol-A: a new diabetogenic factor? Hormones 2010;9:118-126. 
25. Chandola T, Brunner E, Marmot M. Chronic stress at work and the metabolic syn -
drome: prospective study. BMJ 2006;332:521-525.
26. Kesse-Guyot E, Ahluwalia N, Lassale C, et al. Adherence to Mediterranean diet reduc -
es the risk of metabolic syndrome: a 6-year prospective study. Nutr Metab Cardiovasc 
Dis 2013;23:677-683.
07

Vegetables
Fresh – either raw, steamed, grilled, roasted, sautéed in olive oil, juiced
Optimal sources
Arugula
AsparagusArtichokesBean sproutsBell peppersBok choyBroccoliBrussels sproutsCabbageCarrotsCauliflowerCeleryCollard greensCucumbersEggplantEndiveEscaroleGreen beansJicamaKaleMushroomsOkraParsnips PeasRadishes Rutabaga SpinachSweet potatoes
+ Swiss chardSquashTaroTomatoes TurnipsYamsZucchini
Fruits / juices (in moderation)
Fresh, frozen, dried, canned without sugar or other added sweeteners
ApplesApricotsAvocados BananasBlackberries BlueberriesCherriesCranberries GrapesLemons LimesKiwis Mangos Melons Nectarines Oranges PapayasPearsPeaches PlumsPomegranates RaspberriesStrawberriesTangerines+Potatoes should be eaten in moderation because they have a high glycemic index
Avoid
Deep fried vegetablesCanned vegetables
Avoid
Fruit canned in sugarSweetened fruit juices

Avoid
Avoid
Note:  Dried fruit and unsweetened fruit juices should be limited due to high natural sugar content.Foods to eat & avoid
These foods are low on the glycemic index, and provide the protein, fiber, vitamins, and minerals needed to sustain your body’s daily demands. Remember to 
use the Mediterranean Diet food pyramid to help guide your daily intake of these foods.
08

Protein
Meats and fish should be organic when possible. 
Optimal Sources
Beef+
Chicken 
Lamb+
Mackerel
Avoid
Fried fishFried chickenBacon+OccasionalPork+
SalmonSardinesTurkeyGrains
Amaranth Buckwheat Millet OatsQuinoa Teff Whole grain riceWild riceLegumes
Adzuki beansRed beansBlack beans
Avoid
Cakes Cookies CerealsPancakes PastriesNavy beans ChickpeasLima beansPinto beans Mung beans LentilsSplit peas Soybeans
Wild gameTofu Tempeh
SausageProcessed meats
09

Other items to avoid
Soft drinks (sodas)
Diet sodasFruit beveragesSweeteners
Coconut sugarSteviaMonk fruitHoney
Avoid
High fructose corn syrupSugar Artificial sweeteners
Fats
Olive oil (source of monosaturated fat)Coconut oilNuts & seedsAvocados
Avoid
Trans fats (hydrogenated and partially 
hydrogenated vegetable oil)
Refined oils (e.g., safflower, corn)

Activities
The importance of exercise
Regular exercise is an essential component for helping to reverse the conditions associated with metabolic syndrome. Physical inactivity is associated with 
undesirable increases in body mass index, waist circumference, and several other risk factors for metabolic syndrome. Exercise can increase lean muscle mass, increase the uptake of sugar from the bloodstream, have a positive effect on blood pressure, reduce stress, and increase levels of “good cholesterol” (HDL-cholesterol). Work closely with your health-care practitioner when starting any new exercise program.
Helpful exercise tips
 lWhatever you choose for exercise, start gradually  and increase your intensity and duration little by little.
 lWhen given a choice between walking up two flights of stairs or taking the elevator, choose the stairs.
 lWhen going to the grocery store, park further  from the entrance than you normally do.

lWhen given a choice between walking up two flights of stairs or taking the elevator, choose the stairs.
 lPlace an exercise step, treadmill, or elliptical machine in front of the television and work out while you watch your favorite TV show. You can also 
use this venue to do abdominal and other floor exercises.
 lFind a walking buddy so you can encourage each other.
 lParticularly in winter, regularly go to a local shopping mall just to walk .
 lFind a variety of exercises you enjoy doing and switch them up.
 lEnroll in an exercise class that meets regularly (dance, yoga, Zumba, etc.)
 lIf you have a job that requires sitting for long periods, stand up, stretch, and walk  around every hour or so.
 lUse half of your lunch break  for a short 15-30 minute walk, or do squats and abdominal exercises in your office when you can’t get outside.
Think happy thoughts

lUse half of your lunch break  for a short 15-30 minute walk, or do squats and abdominal exercises in your office when you can’t get outside.
Doing something as simple as thinking thoughts of gratitude has been shown to reduce stress hormones and slow down and regulate heart rhythms.Breathe deeply
When you are driving, working at your desk, or watching television, take deep, abdomen-filling breaths. The more often you practice deep breathing, the more likely it will become your normal way of breathing.
Exercise
Regular exercise is one of the best stress-reducing activities you can do. If you have time to exercise before work, it will make your entire work day more peaceful.Take up yoga

Exercise
Enroll in a yoga class or get a yoga DVD and practice at home. Yoga decreases the production of cortisol and increases a brain chemical called GABA (gamma-aminobutyric acid). GABA acts as a brake during times of runaway stress. You can also consider Thorne's nutritional supplement product PharamGABA
®.Tips to reduce stress

Sample meal plan
Starting the week with a menu plan can make organizing ingredients and preparing food easier. 
Day 1
Breakfast MediBolic® coconut cashew banana smoothie
Lunch Italian white bean soup+ (1 cup) 
Mixed greens (1 cup) with oil / vinegar dressing (2 tbsp)  
Dinner Poached salmon with spring onions and white wine+
Quinoa tabouli+ (1/2 cup)
Roasted veggies
Snack Spicy unsalted roasted nuts (pecans, almonds, pistachios, pumpkin seeds, cashews; toss in bowl with spices of choice, spread one 
layer on olive oil-greased baking sheet; roast at 325˚ for 15-20 minutes, stirring once; eat 1/4 cup)
Day 2
Breakfast Zucchini almond pancakes+
MediBolic mixed in water
Lunch Quinoa salmon burger+ 
Carrot sticks (1/2 cup)
Dinner Moroccan roasted chicken+
Mixed greens (1 cup) with oil/vinegar dressing (1-2 tbsp)
Herb & olive oil hummus+ (1/2 cup) with cucumber slices (1 cup)
Dessert Berry parfait with orange cashew cream+
Day 3
Breakfast MediBolic Greek honey yogurt smoothie+

Day 3
Lunch Lettuce wraps – (large lettuce leaf spread with guacamole, shredded carrots,  
sprouts, and shredded organic chicken breast)Curried lima bean soup
+
Dinner Adzuki bean and yam hash (1 cup)+
Greek salad with chick peas (1 cup with 2 tbsp dressing)+
Dessert Chocolate sunbutter cookie+
+Recipe included in Recipe section
12

Shake recipes
Although you can take MediBolic any time of day, starting with a MediBolic shake is a great way to jump-start your day. The following recipes have been chosen 
as being extra tasty. If you split a daily serving in half during the day (i.e., take one scoop twice daily), then cut in half each of the recipes below. These smoothie recipes work best when blended in a high-speed blender.
Pumpkin
Ingredients
2 scoops  M ediBolic
12-14 oz  C oconut milk (another type of milk can be substituted)
3-4 tbsp  Canned or ganic pumpkin
For extra richness, two tbsp of yogurt can be added (plain, vanilla, or honey yogurt, or a non-
dairy “yogurt” such as yogurt made from coconut milk can be substituted). 
For additional spice,  a dash of pumpkin pie spice can be added.Latte and a cinnamon roll
12-14 oz  or ganic non-fat milk (or nut milk of choice)
1 shot  espr esso
1-2  ic e cubes
For extra thickness,  1/2 banana can be addedGreek honey yogurt

12-14 oz  S pring water
2 tbsp  G reek honey yogurt (or a non-dairy yogurt substitute)

Apple pie
4 oz  U nsweetened organic applesauce 
12-14 oz  W ater or milk of choice 
For an extra cold shake,  freeze single serving containers of 
applesauce.Coconut cashew banana 
8-10  F inely ground cashews
12-14 oz  C oconut milk
1 tbsp  C oconut milk yogurt
1/2 B anana
Almond cinnamon roll
12-14 oz  A lmond milk
1/8 tsp  A lmond extract
For extra richness,  one tbsp of plain, honey, or vanilla yogurt, 
or one-half of a banana, or several almonds ground to a powder 
can be added.
Pecan coconut
1 tbsp  F inely ground pecans
2  I ce cubesNutty vanilla
1/4 cup  Cashe ws blended with 4 oz. of water until creamy
12-14 oz  Water
1/8 tsp  O rganic vanilla powder or vanilla extract
1 tbsp  Chia seeds
For a strawberry twist,  add 1/2 cup organic strawberries
14

Breakfast recipes
Raw breakfast tacos
Serves: 4-6
This is a good recipe for a busy morning. If you make the filling the night before, all you need to do in the morning is slice an avocado and mango and put 
everything into a lettuce leaf. Romaine lettuce or napa cabbage work well for the “taco shell” but any variety of lettuce will work. Add the whole chili pepper, seeds and all, if you like it really hot.
1 cup  R aw almonds, soaked for 8-10 hours 
3-4  B razil nuts, soaked for 8-10 hours
3  Green onions, ends trimmed 
1  Hot pepper (serrano or jalapeño, seeded)
1 small  Lim e, juiced
1/2 tsp  S ea salt or Herbamare®
1 handful  F resh cilantro
Garnishes  
Lettuce leaves 
Sliced avocado Sliced mango Lime wedgesDirections
To soak the nuts,  place them in a bowl and cover with an inch of filtered water. Leave 
them on the counter to soak overnight  or for the day, about 8-10 hours. When they are 
done, drain and rinse.

done, drain and rinse. 
Place the soaked nuts into a food processor fitted with the “s”blade and add the remaining 
filling ingredients. Pulse/process until the nuts and vegetables are ground to the desired 
consistency. Taste and add salt if necessary. 
To assemble the tacos,  place a few dollops of the filling into  
a lettuce leaf and top with avocado and mango slices. Serve with lime wedges.
Zucchini almond pancakes
Serves 3-4
Make these savory, grain-free, protein-packed pancakes on a summer morning before you head out for the day. 
Combined with a MediBolic® smoothie they create an energizing breakfast! They store well in the refrigerator, but if you 
prefer a smaller batch, halve the recipe. Top each pancake with a dollop of sour cream (or sour cream alternative) and chopped parsley or scallions. One serving is 3 pancakes.
4 large   O rganic eggs
3 cups   G rated zucchini

1 cup   A lmond flour
1/2 cup   M inced onion
1 tsp   H erbamare® or sea salt 
Etc Freshly ground black pepper   
 Olive oil for cooking
Kitchen tip:  A well-seasoned cast iron skillet keeps pancakes from sticking to the pan.Directions 
Mix all ingredients except the oil together in a medium-sized bowl. Batter will thin a little as it sits. 
Heat a 10-inch stainless steel or cast iron skillet over medium-low heat. Heat your pan 
long enough before adding the oil and batter, otherwise the pancakes will stick. Add about 1 tbsp olive oil to pan. Drop  batter by the 1/4-cup into the hot skillet. Cook for 
a few minutes on each side.Repeat with remaining batter, adding a little oil or butter to the skillet before  
cooking each pancake. 
These recipes were selected from the book, Nourishing Meals: Healthy, Gluten-free Recipes for the Whole Family, by Alissa Sergersten and Tom Malterre, MSN, CN.

These recipes were selected from the book, Nourishing Meals: Healthy, Gluten-free Recipes for the Whole Family, by Alissa Sergersten and Tom Malterre, MSN, CN. 
Not only are these recipes helpful for avoiding gluten, but they generally focus on ingredients with a low carbohydrate content and follow the Mediterranean Diet.
15

Nutty granola
Yield: 4-5 cups
This grain-free granola is packed with protein and healthy fats. With just a smidgen of sweetener to help hold it together and boost flavors you can enjoy this 
treat for breakfast sprinkled over your favorite dairy or dairy-free yogurt. Top it off with fresh berries or diced bananas for a balanced breakfast or snack.
1 cup  r aw almonds
2 tsp  cinnamon
1 cup  r aw pecans  
1/4 tsp  nutm eg
1 cup  r aw walnuts  
1/4 tsp  sea salt
1/2 cup  r aw sunflower seeds  
1/4 cup  maple s yrup
1/2 cup  r aw pumpkin seeds  
1/2-1 cup  dried cr anberries or raisins 
2-3 tbsp  whole chia seeds  
1/4 cup  c oconut oil, meltedNutrition Tip: Soaking nuts and seeds overnight and then dehydrating them until crisp not only 
makes them more digestible, but also allows their nutrients to become more bioavailable. You can do this before using them in the granola recipe above.Directions

Preheat oven to 300 degrees . Line a large baking dish, rimmed cookie sheet, or jelly roll pan with 
parchment paper. 
Place the almonds, pecans, and walnuts into a food processor fitted with the“s”blade and process  
until you have a chunky, coarse meal. Pour into a medium-sized mixing bowl. Add the sunflower seeds, pumpkin seeds, chia seeds, 
cinnamon, nutmeg, and sea salt.  Stir together to evenly distribute the spices and salt. 
Add the syrup and mix together using a large spoon. Spread on the parchment-lined cookie sheet 
and bake for 35-40 minutes. 
Remove from oven and stir in the dried cranberries or raisins. Let cool completely on the cookie 
sheet then transfer to a glass jar for storage.
16

Lunch & dinner recipes
Kitchen Tip: A stainless steel fish-poaching pan creates a gorgeous presentation. You could also use a 10-inch skillet, although you would need to cut the fish fillet in 
half to make it fit correctly. Coho salmon is best for poached salmon recipes because it is thin and cooks evenly in the poaching liquid.Poached salmon  with spring onions & white wine
2 lbs  W ild salmon fillet 
2  Spring onions
3-4 sprigs  F resh thyme
3 tbsp  Extr a virgin olive oil
1/2 cup  W hite wine
Etc Herbamare  
 Freshly ground black pepperDirections
Rinse the fish fillet and pat dry. Place into pan skin-side  down. 
Trim the ends off the onions and cut in half lengthwise; run under cool  
water to remove any dirt or sand. 
Place the onions and fresh thyme on top of the salmon. Drizzle  with olive oil. 
Add the white wine to the pan and then season the fillet  with Herbamare and freshly ground

Add the white wine to the pan and then season the fillet  with Herbamare and freshly ground 
black pepper. Cover and poach  over medium/medium-low heat for 10-12 minutes. Serve immediately.
Quinoa salmon burgers
Yield: 6 burgers
These burgers go nicely with a raw green salad and homemade parsnip fries. It is easier to remove the bones if you use wild king salmon instead of sockeye 
salmon. Use your hands or tweezers to pull the bones out. If you don't want to bother re- moving the skin, have it done when you purchase the fish. Once you have the patties formed you can refrigerate them in between pieces of waxed paper for a few days or freeze them the same way.
3-4  G reen onions, ends trimmed 
1 large  H andful fresh cilantro
1-2 tsp  L emon zest (optional) 
1 tsp  H erbamare®
1-1.5 lbs  W ild salmon, skinned and deboned 
1 cup  C ooked quinoa
Etc Freshly ground black pepper

Etc Freshly ground black pepper  
 Olive oil or coconut oil for cookingDirections
Place the green onions, cilantro, lemon zest, Herbamare, and black pepper into a food processor fitted with the“s”blade and process until it is finely minced. 
Add the salmon and quinoa and process again until desired consistency.  Form  into patties and 
place onto a plate. 
Heat a large skillet over medium to medium-high heat and add a tablespoon of oil and place 
a few patties in the skillet (3 at a time in a 10-inch skillet). If the pan is hot it should only take 
2-3 minutes per side to cook. If the pan is not quite heated it will take about 5 minutes per side and they may stick a little. 
Remove  patties from skillet and set onto a plate. They will continue to cook when off the stove 
so do not overcook them.

Variation:  Try fresh dill and parsley in place of the cilantro.  
You could also add 1/2 teaspoon of chipotle chili powder and  
use lime zest in place of the lemon zest.
17

Balsamic roasted chicken with figs & sweet onions
Serves: 6-8
1 whole  O rganic chicken (about 3.5-4 lbs) 
1/4 cup  Extr a virgin olive oil 
1/4 cup  B alsamic vinegar
1 large  S weet onion, chopped  
1 tbsp  M aple syrup
8-10  F resh figs  
Etc H erbamare  
 Freshly ground black pepper  
 Fresh rosemary sprigsDirections
Preheat oven to 450 degrees. Rinse chicken under cold running water and place it in a 9 x 13-inch 
baking dish or other roasting pan. Generously sprinkle with Herbamare and freshly ground black 
pepper. 
Put the chopped onion  inside the cavity of the chicken and on the bottom of the pan. Place the figs 
around the chicken. Whisk together the balsamic vinegar, olive oil, and maple syrup in a small bowl and pour over the 
chicken. Place a few rosemary sprigs on and around the chicken. Add 1/2 cup of water to the bottom of the pan and roast the chicken for about 20 minutes to seal in

chicken. Place a few rosemary sprigs on and around the chicken. Add 1/2 cup of water to the bottom of the pan and roast the chicken for about 20 minutes to seal in 
the juices. Reduce heat to 325 degrees and continue to cook until juices run clear, about another 1.5 hours. Remove the chicken from the pan and place on a platter. Wait 10 minutes  before carving to let the 
juices return to the meat. Place the cooked figs and sweet onions on the platter with the sliced chicken. Drizzle  pan juices over 
chicken and serve.
Moroccan roasted chicken
This is an easy meal that can be ready for the oven in 10 minutes. Serve it over cooked millet with a salad, sautéed kale, or steamed green beans.
3-4 S plit organic chicken breasts
1 tsp  G round coriander
1 tsp  G round cardamom
1 small  R ed onion, cut into large chunks  
1 tsp  G round black pepper 
1  Lemon, cut into wedges  
1/2 tsp  T urmeric
1/2-1 cup  D ried apricots  
Pinch  Ca yenne pepper

1 tsp  H erbamare or sea salt  
2-3 tbsp  O rganic butter or coconut oil
1 tsp  G round cumin
Garnish  Choppe d parsley or cilantro
Nutrition Tip: Purchase organic, sulfite-free apricots. Sulfite is a preservative that reduces discoloration and oxidation. Organic apricots are a dark brownish-orange

Nutrition Tip: Purchase organic, sulfite-free apricots. Sulfite is a preservative that reduces discoloration and oxidation. Organic apricots are a dark brownish-orange 
color because they don’t have any sulfites added. The FDA estimates that 1 out of 100 individuals has a reaction to sulfites. A sensitivity to sulfites can lead to difficulty with breathing, hives, excessive sneezing, or throat swelling. This may be exacerbated by a deficiency in molybdenum, a mineral commonly found in legumes. Sulfites listed on a food label could appear as sulfur dioxide, sodium sulfite, sodium bisulfite, potassium bisulfite, sodium metabisulfite, or potassium metabisulfite.Directions
Preheat the oven to 425 degrees. Rinse the chicken breasts and place them into a casserole dish or 9 x 
13-inch pan in a single layer. 
Place the onion chunks, lemon wedges, and dried apricots around the chicken. In a small bowl, mix together the salt and spices. Sprinkle spice mixture over the chicken. Dot with

Place the onion chunks, lemon wedges, and dried apricots around the chicken. In a small bowl, mix together the salt and spices. Sprinkle spice mixture over the chicken. Dot with 
butter or coconut oil. 
Roast for 30 to 40 minutes, depending on the size of the breasts, or until the juices run clear. Slice chicken from the bone and serve it with the apricots, red onions, and juices at the bottom of the 
roasting dish. 
Garnish with chopped parsley or cilantro. 
Slow-Cooked Variation: If you have more time, you can slow-cook the chicken in the oven to create 
more flavorful, tender chicken, which is also more digestible. Heat oven to 325 degrees and cook for 
60-75 minutes or until juices run clear.
18

Soup & stew recipes
Curried lima bean soup
Serves: 10
Baby lima beans are often called butter beans because of their soft buttery texture. They can be found in bulk at your local food co-op or health food store. Be 
sure to soak them in warm water for at least 12 hours, preferably 24 hours, to aid in digestibility. Feel free to add any vegetables to the soup in place of the yams and peas, such as carrots, potatoes, kale, or zucchini.
3 cups  D ry baby lima beans, soaked for 12-24 hours 
2 tbsp  C oconut oil
1 large  O nion, chopped
1 tbsp  C urry powder 
1 tsp  G round coriander 
12 cups  Water
2 medium  Y ams, peeled and cut into cubes 
2-3 cups  F resh or frozen peas
2-3 tsp  H erbamare® or sea salt 
Etc Freshly ground black pepper, to taste  
 Choppe d cilantro
Directions
Heat an 8-quart pot over medium heat and add olive oil, then add onion; sauté  for 8-10 minutes or until soft and beginning to change color.

Choppe d cilantro
Heat an 8-quart pot over medium heat and add olive oil, then add onion; sauté  for 8-10 minutes or until soft and beginning to change color. 
Add garlic, spices, and herbs; sauté one minute more. Then add carrots, celery, and green beans; sauté for 2 minutes. 
Then add stock, tomatoes, and tomato paste, and cover and simmer  for 20-25 minutes or until the vegetables are tender. 
Stir in cooked beans, kale, and parsley; simmer 5 minutes more. Add salt; taste and adjust salt and seasonings if necessary. Store leftovers in the refrigerator for up to a week.Italian white bean soup
Serves: 12
2-3 tbsp  Extr a virgin olive oil  
12 cups  Chick en stock 
1 large  O nion, chopped  
4 cups  D iced tomatoes
3-4 cloves  G arlic, crushed  
3-4 tbsp  T omato paste
1 tsp  P aprika
6 cups  C ooked navy beans1 tsp  G round black pepper
2-3 cups  T hinly sliced kale
2 tbsp  I talian seasoning  
1/2-1 cup  Choppe d parsley
4-5  Carrots, diced

4-5  Carrots, diced  
3 tsp  H erbamare or sea salt
3-4 stalks  C elery, chopped  
1/2 lb  G reen beans, cut into 2-inch piecesDirections 
Sort through the beans and remove discolored, shriveled, or moldy ones. Rinse the 
beans and add them to a large bowl; cover with a few inches of warm water. 
Leave the bowl on the counter and let the beans soak for 12-24 hours.  Drain and rinse 
using a large colander and then set aside. Heat an 8-quart stockpot over medium heat. Add the oil, then add onions; sauté  for 
5-10 minutes or until softened and beginning to change color. Add the spices; sauté a 
minute more. 
Add the soaked beans and water, cover, bring to a boil then reduce heat to low and 
simmer for 45-60 minutes or until the beans are tender and cooked through.

simmer for 45-60 minutes or until the beans are tender and cooked through. 
Add yams, peas, salt, and black pepper; simmer uncovered  for another 20 minutes or 
until vegetables are tender. Taste and adjust salt and seasonings if necessary. Garnish  each bowl with chopped cilantro. Leftovers can be frozen.
19

Chipotle black bean & yam stew
When using canned black beans it will take about four cans. Be sure to save the bean cooking liquid from the cans. 
Bean cooking liquid rather than water works better in this recipe to create a thicker stew. You can also substitute the yams in this recipe with a small butternut squash that has been peeled and diced.
2 tbsp  Extra virgin olive oil  
6 cups  C ooked black beans
1 medium  Y ellow onion, chopped  
4 cups  B ean cooking liquid or water 
2 tsp  G round cumin  
1 medium  R ed bell pepper, diced
1/2 tsp  D ried oregano  
1  Lime, juiced (2-3 tbsp)
1/2-1 tsp  Chipo tle chili powder  
4  Cloves garlic, crushed 
2-3 tsp  H erbamare or sea salt
2 medium  Y ams, peeled & diced (~4 cups)Nutrition Tip: More and more research points to the importance of consuming foods that make your

2 medium  Y ams, peeled & diced (~4 cups)Nutrition Tip: More and more research points to the importance of consuming foods that make your 
intestinal bacterium happy. Researchers in Mexico have found that black beans do a great job at this. Black beans contain a higher quantity of fiber that is not digestible by our enzymes, but are digested by organisms in our intestines. These undigested black bean portions feed certain beneficial bacteria and allow them to produce a substance called butyric acid, which is one of the preferred sources of energy for the cells lining the colon, allowing them to function properly and remain healthy.Directions
Heat a 6- or 8-quart pot over medium heat. 
Add the oil, then add onions; sauté  for 5-7 minutes. Then add  
the spices, Herbamare, yams, and garlic, and sauté a few minutes more. 
Add the black beans and bean cooking liquid; simmer uncovered for 10-15 minutes or until yams

Add the black beans and bean cooking liquid; simmer uncovered for 10-15 minutes or until yams 
are barely tender  but not yet cooked (timing will depend on the size of the diced yams). 
Add diced peppers and simmer for 10 minutes more. 
Taste and adjust  salt and spices if necessary. Remove from heat and  stir in lime juice.
Slow cooker chicken stew
Using a slow cooker the flavors come together beautifully and the chicken is very tender. Serve this stew over cooked long-grain brown rice with a salad of romaine lettuce on the side.
1 cup  D iced shallots 
3 stalks  C elery, diced
4  Carrots, peeled and diced
1.5 lbs  B oneless chicken breast, cut into chunks 
14 oz  Canned crushed fir e-roasted tomatoes
1 cup  Water1/3 cup  D ry white wine
1/4 cup  Extr a virgin olive oil
1 tbsp  I talian seasoning
1-2 tsp  H erbamare or sea salt 
Etc F reshly ground black pepper

Add all ingredients to a slow cooker and cook on high for 4-5 hours or on low for 6-8 hours. 
Oven Variation:  Place all ingredients in a covered casserole dish and bake for 2.5 hours at 300 degrees.

Salads
Blanched kale & salmon salad and green apple dressing
Serves: 4
Blanching kale begins to break down its tough fibers while still keeping its nutrient levels intact. Also, blanching for a minute or less will turn the kale a beautiful 
bright green color that is very attractive in a salad. 
2 bunches  C urly kale, chopped 
1 cup  C ooked salmon
1/2 cup  S unflower seeds, toasted
1  Pomegranate, arils removed
Green apple dressing
1 medium  G ranny Smith apple
1/2 cup  Water
1/3 cup  Extr a virgin olive oil 
1-2 cloves  G arlic
1-inch  P iece of fresh ginger, peeled 
Etc Herbamare or sea salt to taste
Greek salad with chickpeas
Serves: 6
1 head  R omaine lettuce, rinsed and spun dry 
2 cups  Cherry  tomatoes, cut into halves  
2 cups  C ooked chickpeas, rinsed and drained 
1 cup  P itted kalamata olives, sliced  
1/2 small  R ed onion, diced  
1 large  C ucumber, sliced  
Etc Fresh mint leaves (optional)  
 Crumbled feta cheese (optional)Greek Dressing

1/2 cup  Extr a virgin olive oil
6 tbsp  S queezed lemon juice 
2 tbsp  F resh oregano leaves
1/2 tsp  S ea salt
1/2 tsp  F reshly ground black pepperDirections 
Fill an 8-quart stockpot with filtered water about 3/4-full and bring to a rapid boil. 
Quickly add the kale, pushing it down with a large spoon. Blanch  for 60 seconds or 
until bright green and tender. Pour kale and boiling water through a colander and immediately run icy cold water over 
the kale to stop it from cooking. Gently squeeze the water from the kale. Place desired amount of kale onto each plate, 
top with cooked salmon, pomegranate arils, and toasted sunflower seeds. 
To make the dressing , place ingredients into a blender and blend 60 seconds or until

To make the dressing , place ingredients into a blender and blend 60 seconds or until 
smooth and creamy. Taste, add more salt if needed, and blend again. Drizzle dressing  over each salad. 
Store leftover dressing in a sealed glass jar in the refrigerator for up to a week. Store 
remaining kale in the refrigerator in a sealed glass container.
Chop the romaine lettuce, place it in a large salad bowl, and top with the remaining salad ingredients. Add fresh mint leaves and feta cheese.
Place  dressing ingredients into a blender and blend until smooth. Pour the dressing over the salad and toss together . Store extra salad in the refrigerator for up 
to two days. Dressing will last about 10 days in the refrigerator.
Variation:  To make this dressing citrus-free, replace the lemon juice with organic red or white wine vinegar.
21

Side dishes
Quinoa tabouli
6 cups  C ooked quinoa
1 large  C ucumber, diced (~3 cups) 
2 cups  F resh tomatoes, diced
1/2 cup  F resh mint, finely chopped
1/2 cup  P arsley, finely choppedDirections
Place cooled quinoa into a large bowl. Add diced cucumber, tomatoes, 
fresh mint, and parsley. 
In a small bowl whisk the ingredients for the dressing. Pour dressing 
over quinoa and vegetables. Toss together and serve. 
Store leftovers in the refrigerator for up to five days. Dressing
1/2 cup  F resh lemon juice
2 cloves  G arlic, crushed
1 tsp  H erbamare
Coconut-lime cauliflower “rice”
Using cauliflower is a great grain-free option to rice. By grinding it up in the food processor you get the look and consistency of white rice but with more 
nutrients and cancer-fighting compounds such as sulforaphane. Serve this“rice”dish with baked fish or roasted chicken and a green salad.
1 medium  H ead cauliflower

1 medium  H ead cauliflower  
1 cup  C oconut milk  
1-2 tsp  G rated ginger
1/2 cup  W ater or chicken stock  
1/2-1 tsp  C rushed red chili flakes 
1-2 tbsp  F reshly squeezed lime juice  
1/2 tsp  H erbamare® or sea saltDirections
Break or cut the cauliflower into small pieces  and place into a food 
processor fitted with the “s” blade and pulse until it is coarsely ground . 
Over-processing will turn the cauliflower to mush. 
In a large skillet or wide pot, heat the coconut milk, water or stock, 
lime juice, garlic, ginger, chili flakes, and salt over medium heat. 
When the mixture is simmering add the ground cauliflower. Stir 
together and simmer uncovered  for 10-15 minutes, stirring every few

together and simmer uncovered  for 10-15 minutes, stirring every few 
minutes, or until the cauliflower is cooked to your liking. Garnish with green onions, chopped cilantro, and lime zest.Garnishes
Sliced green onions 
Chopped cilantro Lime zestAdzuki bean & yam hash
Serves: 4-6 
2 tbsp  Extr a virgin olive oil
1 small  O nion, diced
2 small  Y ams, peeled & diced
2 cups  C ooked adzuki beans
4 C ollard Greens, choppedDirections
Heat a 12-inch skillet over medium heat. Add olive oil, onion, and a 
few dashes of salt. Sauté until softened, then add yams, cumin, and 
chili flakes; sauté for a few minutes uncovered. 
Cover the pan and cook for 15-20 minutes, stirring occasionally, until 
yams are tender. Watch carefully so the yams don't burn. Add adzuki beans and collard greens. Sauté until collards are tender. 
Add Herbamare and pepper to taste. Top with cilantro and serve.Etc

 Choppe d cilantro   
 H erbamare & black pepper  
 C rushed red chili flakes

Snacks
Place  all ingredients except  for the fresh herbs into a food processor fitted with the “s” blade and process until smooth and creamy . You will want to taste the 
hummus to see if it needs more lemon, tahini, garlic, or salt. 
Add more water if needed for a thinner consistency and process again. Add the fresh herbs and pulse until combined, but not completely pureed. 
Place the hummus into small serving dishes and sprinkle with extra chopped herbs and a drizzle of extra virgin olive oil if desired. Store in a covered glass 
container in the refrigerator for up to a week.
Nutrition Tip: The Mediterranean Diet has protective effects on our hearts. Some researchers attribute this to the beneficial phenolic compounds found in the fruits,  
vegetables, and the high-quality olive oil used in the Mediterranean Diet. One study found that when people used olive oil exclusively in food preparation, the likeli-

hood of coronary heart disease reduced by 47%. When saturated fat was replaced with olive oil, total cholesterol dropped 13.4% and LDL-cholesterol dropped 18%.Herb & olive oil hummus
Yield: 4 cups
Hummus is a traditional Middle Eastern dish made from garbanzo beans, also called chickpeas, and tahini. Use it as a dip for raw vegetables.
3 cups  C ooked garbanzo beans, or 2 cans drained  
1/4 cup  B ean cooking liquid or water  
1/2 cup  S esame tahini  
1/2 cup  S queezed lemon juice  
1/4 cup  Extr a virgin olive oil  2-3 cloves  G arlic, crushed  
1-2 tbsp  F resh marjoram leaves
1-2 tsp  S ea salt or Herbamare
Small  H andful fresh parsley
2-3 tbsp  F resh oregano leaves
Grain-free chicken nuggets

Using low-glycemic almond flour, organic chicken breasts, and heat-stable coconut oil makes these nuggets nutritious.
2 large  O rganic chicken breasts (~1.5 lbs) 
2-3 tsp  P oultry seasoning
1 tsp  H erbamare® or sea salt 
4 tbsp  A rrowroot powder
4 tbsp  Water 
1.5 cups  A lmond flour
6 tbsp  C oconut oilDirections
Set out two shallow, wide  bowls. 
In one bowl mix together the poultry seasoning, Herbamare, arrowroot powder, and 
water. In the other bowl add the almond flour. 
Rinse the chicken breasts and cut them into small chunks , making sure to keep the size 
of each piece relatively even. Place the chicken breast chunks into the arrowroot slurry and mix them around to coat evenly, then toss a few at a time into the almond flour. The

of each piece relatively even. Place the chicken breast chunks into the arrowroot slurry and mix them around to coat evenly, then toss a few at a time into the almond flour. The 
almond flour will feel moist. You can press some of it into each nugget to help coat them.
Heat a deep 12-inch skillet over  medium heat and add 3 tbsp of coconut oil. When the 
oil has heated for 30-60 seconds, place half of the chicken nuggets into the pan and cook 
for about three minutes on each side. 
Add the remaining coconut oil to the pan and cook the rest of the nuggets.
23

Toasted sunflower seeds with coconut aminos
Yield: 1 cup
Coconut aminos can be used to replace tamari in any recipe. They are a great soy-free soy sauce! This recipe is so easy it only takes five minutes to prepare. 
They are also delicious sprinkled on a green salad.
1 cup  R aw sunflower seeds
1 tbsp  C oconut aminos 
Pinch  S ea salt
Nutrition Tip: Sunflower seeds are a good source of magnesium. Magnesium is nature’s nerve calmer. It helps to relax tight muscles and maintain normal blood 
pressure. One-quarter cup of sunflower seeds provides 115 mg of magnesium.Directions
Heat a large, 11-inch skillet over medium heat for a few minutes or until the pan is hot. 
Add the sunflower seeds; use a spatula to keep them moving in the pan. Toast them for 11/2-2 minutes. 
Turn off heat and add coconut aminos and sea salt. Immediately stir the mixture to coat the seeds  evenly. 
Let cool on a plate then transfer to a glass jar for storage.

Dessert
Berry parfait with orange cashew cream
This is a favorite recipe to make during the summer months when berries are in abundance. Serve it for breakfast, a healthy snack, or dessert. Use any berries 
that are fresh and available, especially blueberries, strawberries, blackberries, and raspberries.
1 cup  R aw cashews, soaked for 3 hours
1/2 cup  F reshly squeezed orange juice  
2  D ates, pitted
1/2 tsp  O range zest 
Dash  M aple syrup (optional)
4 cups  F resh organic berries
Etc H emp seeds
Nutrition Tip: Making your own orange juice from fresh oranges is much more nutritious than buying it store-bought. Pasteurization 
will kill harmful bacteria to prolong shelf life, but it will also destroy live enzymes and vitamins. Fresh orange juice contains all of the enzymes, vitamin C, and antioxidants present in the orange, which makes the juice far more digestible and easier to assimilate.Directions

To make the cashew cream,  drain and rinse the cashews, place them into a blender 
along with the orange juice, dates, orange zest, and salt. 
Blend on high until smooth and creamy . You might need to turn off the blender, 
scrape down the sides, and blend again a few times. Taste and add a dash of maple 
syrup for a sweeter cream and blend again if needed. 
Set out 4-6 parfait cups or clear juice glasses. Add a layer of berries to the bottom 
of each cup or glass, then a thin layer of the cashew cream, then another layer of 
berries, then a final layer of cashew cream. 
Sprinkle the top layer with hemp seeds. Chocolate sunbutter cookies
Yield: 12-15 cookies
These cookies provide great nutrition and high fiber in every bite! Sunbutter is made from ground roasted sunflower seeds. It is a great high-protein alternative 
to nut butters. Serve these grain-free, vegan cookies with a glass of raw almond milk or a green smoothie for a healthy afternoon treat.
Wet ingredients

1 cup  O rganic Sunbutter 
1/3 cup  C oconut nectar
1 tbsp  G round chia seeds 
3 tbsp  Water
1 tsp  V anilla
Dry ingredients
1/4 cup  C ocoa powder
1/2 tsp  B aking soda
1/4 tsp  S ea salt
1/2 cup  M ini chocolate chips (optional)Directions
Preheat oven to 350 F. Lightly grease a cookie sheet with coconut oil. 
In a medium-sized mixing bowl, using an electric mixer, beat together the wet ingredients until 
light and fluffy. 
Add the dry ingredients. Beat together until thickened and combined then mix in the chocolate 
chips. 
Roll equal-sized balls of dough in your hands making 12-15 balls. Press dough ball down using the 
tongs of a fork into a crisscross pattern. 
Bake for approximately 12-15 minutes. Cool on a wire rack. Cookies will be fragile and crumbly 
when hot but will firm up when completely cooled.
25

Kitchen Tip: Coconut butter is made from both the oil and the meat of the coconut. Sometimes it is labeled 
with different names such as coconut mana or coconut cream concentrate, but it is all the same thing.Raw berry tart with coconut pastry cream
Crust
2 cups  R aw almonds or pecans 
1 cup  P itted medjool dates (~10)
1 tbsp  C oconut oil
Pastry Cream
1 cup  R aw cashews
1/4 cup  Water
1/4 cup  F reshly squeezed orange juice
3 tbsp  C oconut nectar or honey
3/4 cup  S oftened coconut butter
1 tsp  P ure vanilla extract
1 tsp  O rganic almond flavoring 
Garnishes
Berries of choiceDirections
To make the crust,  place the nuts into a food processor fitted with the "s" blade and process until finely

Garnishes
To make the crust,  place the nuts into a food processor fitted with the "s" blade and process until finely 
ground. 
Add the dates, coconut oil, and sea salt. Process  again until the dates are ground and evenly incorporated 
into the nuts. It should stick together, if not, add another tablespoon of coconut oil.Pour the crust mixture  into a 9 or 10-inch lightly oiled tart pan and evenly press  into the bottom and up 
the sides.To make the filling,  place the cashews, water, orange juice, coconut nectar into a high-powered blender. 
Blend until smooth and  ultra creamy , stopping and starting the blender if necessary. Your coconut butter 
should be soft enough to add if you are living in a hot climate; if not, place the amount called for into a 
small pan and warm on the lowest heat. 
Add the softened coconut butter to the blender along with the vanilla and almond flavoring. Blend until

Add the softened coconut butter to the blender along with the vanilla and almond flavoring. Blend until 
smooth. Pour into the crust and spread evenly.Arrange berries over filling into your own unique design. 
Chill, uncovered, until ready to serve . When ready to serve, push the bottom of the pan up through the rim 
and place onto a platter to serve.

Health journal
Monday Tuesday Wednesday Thursday Friday Saturday Sunday
Breakfast
Lunch
DinnerSnackSupplementsFoodMonday Tuesday Wednesday Thursday Friday Saturday Sunday
Mood
Appetite
Stress levelSleep durationSleep qualityInjury / illnessPsycheMonday Tuesday Wednesday Thursday Friday Saturday Sunday
Activity
DurationExercise
27

A final word
We hope you have found this guide to be informative and helpful and we encourage you to reference it frequently as you monitor your progress.
As you can see, healthy lifestyle choices play a major factor in reducing or reversing the potential negative health consequences associated with metabolic 
syndrome.
The right combination of diet, exercise, stress reduction, and nutritional supplementation can assist you in your quest to regain and maintain optimal health. At 
Thorne, we consider ourselves your partner in managing your health.

MetS-Guide_V02_02.02.21 | Copyright© 2021, Thorne Research, Inc. All rights reserved. 800-228-1966  |  support@thorne.com  |  thorne.com

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5c
CHAPTER
11
CHAPTER 1 IAN OVERVIEW OF PHYSICAL EXAMINATION AND HISTORY TAKING 1The techniques of physical examination and history taking that you are about
to learn embody time-honored skills of healing and patient care. Your abil-ity to gather a sensitive and nuanced history and to perform a thorough andaccurate examination deepens your patient relationships, focuses your patientassessment, and sets the direction of your clinical thinking. The quality of yourhistory and physical examination governs your next steps with the patient andguides your choices from the initially bewildering array of secondary testingand technology. Over the course of becoming an accomplished clinician, youwill polish these important relational and clinical skills for a lifetime.
As you enter the realm of patient assessment, you begin integrating the es-

sential elements of clinical care: empathic listening; the ability to interviewpatients of all ages, moods, and backgrounds; the techniques for examiningthe different body systems; and, ﬁnally, the process of clinical reasoning. Yourexperience with history taking and physical examination will grow and expand,and the steps of clinical reasoning will soon begin with the ﬁrst moments ofthe patient encounter: identifying problem symptoms and abnormal ﬁnd-ings; linking ﬁndings to an underlying process of pathophysiology or psycho-pathology; and establishing and testing a set of explanatory hypotheses. Work-ing through these steps will reveal the multifaceted proﬁle of the patient beforeyou. Paradoxically, the very skills that allow you to assess all patients also shapethe image of the unique human being entrusted to your care.
Clinical Assessment: The Road Ahead

This chapter provides a road map to clinical proﬁciency in three critical areas:the health history, the physical examination, and the written record, or“write-up.” It describes the components of the health history and how to or-
ganize the patient’s story; it gives an approach and overview to the physical ex-amination and suggests a sequence for ensuring patient comfort; and, ﬁnally,it provides an example of the written record, showing documentation of ﬁnd-ings from a sample p atient history and physical examination. By studying the
subsequent chapters of the book and perfecting the skills of examination andhistory taking described, you will cross into the world of patient assessment—gradually at ﬁrst, but then with growing satisfaction and expertise.
After you work through this chapter to chart the tasks ahead, you will be

directed by subsequent chapters in your journey to clinical competence.Chapter 2, Interviewing and the Health History, expands on the techniques
An Overview of 
Physical Examination and History TakingAn Overview of 
Physical Examination and History Taking

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTHE HEALTH HISTORY: STRUCTURE AND PURPOSES
2 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGand skills of good interviewing; Chapters 3 through 16 detail techniques for
examining the different body systems. Once you master the elements of theadult history and examination, you will extend and adapt these techniques tochildren and adolescents. Children and adolescents evolve rapidly in bothtemperament and physiology; therefore, the special approaches to the inter-view and examination of children at different ages are consolidated in Chap-ter 17, Assessing Children: Infancy Through Adolescence. Finally, Chapter 18,Clinical Reasoning, Assessment, and Plan, explores the clinical reasoningprocess and how to document your evaluation, diagnoses, and plan. From thisblend of mutual trust, respect, and clinical expertise emerges the timeless re-wards of the clinical professions.
THE HEALTH HISTORY: 
STRUCTURE AND PURPOSES

As you read about successful interviewing, you will ﬁrst learn the elements
of the Comprehensive Health History. For adults, the comprehensive his-
tory includes Identifying Data and Source of the History, Chief Complaint(s),
Present Illness, Past History, Family History, Personal and Social History, and
Review of Systems. As you talk with the patient, you must learn to elicit and
organize all of these elements of the patient’s health. Bear in mind that dur-ing the interview this information will not spring forth in this order! How-ever, you will quickly learn to identify where to ﬁt in the different aspects ofthe patient’s story.
As you gain experience assessing patients in different settings, you will ﬁnd
that new patients in the ofﬁce or in the hospital merit a comprehensive health
history; however, in many situations a more ﬂexible focused, or problem-
oriented, interview may be appropriate. Like a tailor ﬁtting a special garment,

you will adapt the scope of the health history to a number of factors: the pa-tient’s concerns and problems; your goals for assessment; the clinical setting(inpatient or outpatient; specialty or primary care); and the amount of timeavailable. Knowing the content and relevance of all components of the com-prehensive health history allows you to choose those elements that will bemost helpful for addressing patient concerns in different contexts.
The components of the comprehensive health history structure the patient’s
story and the format of your written record, but the order shown hereshould not dictate the sequence of the interview. Usually the interview willbe more ﬂuid and will follow the patient’s leads and cues, as described inChapter 2. Each segment of the history has a speciﬁc purpose, which is sum-marized below.

These components of the comprehensive adult health history are more fully
described in the next few pages. The comprehensive pediatric history appears
in Chapter 17. These sample adult and pediatric health histories follow stan-

CHAPTER 1 IAN OVERVIEW OF PHYSICAL EXAMINATION AND HISTORY TAKING 3Identifying Data
Reliability
Chief Complaint(s)Present Illness
Past History
Personal and Social History
Review of SystemsIIdentifying data —such as age, gender,
occupation, marital status
ISource of the history —usually the patient, but
can be family member, friend, letter ofreferral, or the medical record
IIf appropriate, establish source of referral,
since a written report may be needed.
Varies according to the patient’s memory,
trust, and mood
The one or more symptoms or concerns
causing the patient to seek care
IAmpliﬁes the Chief Complaint, describes
how each symptom developed
IIncludes patient’s thoughts and feelingsabout the illness
IPulls in relevant portions of the Review of
Systems (see below)
IMay include medications, allergies, habits of
smoking and alcohol, since these are

frequently pertinent to the present illness
ILists childhood illnesses
ILists adult illnesses with dates for at leastfour categories: medical; surgical; obstetric/gynecologic; and psychiatric
IIncludes health maintenance practices suchas: immunizations, screening tests, lifestyleissues, and home safety
IOutlines or diagrams of age and health, orage and cause of death of siblings, parents,and grandparents
IDocuments presence or absence of speciﬁcillnesses in family, such as hypertension,coronary artery disease, etc.
Describes educational level, family of origin,
current household, personal interests, andlifestyle
Documents presence or absence of common
symptoms related to each major body systemComponents of the Health History
dard formats for written documentation, which will be useful for you to

learn. As you review these histories, you will encounter a number of techni-cal terms for symptoms. Deﬁnitions of terms, together with ways to ask aboutsymptoms, can be found in each of the regional examination chapters.
As you acquire the techniques of the history taking and physical examination,
remember the important differences between subjective information and ob-
jective information, as summarized in the table below. Knowing these dif-
ferences helps you apply clinical reasoning and cluster patient information.These distinctions are equally important for organizing written and oral pre-sentations concerning the patient.

4 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGThe Comprehensive Adult Health History
Date and Time of History. The date is always important. You are
strongly advised to routinely document the time you evaluate the patient,especially in urgent, emergent, or hospital settings.
Identifying Data. Includes age, gender, marital status, and occupa-
tion. The source of history or referral can be the patient, a family member or
friend, an ofﬁcer, a consultant, or the medical record. Patients requestingevaluations for schools, agencies, or insurance companies may have specialpriorities compared to patients seeking care on their own initiative. Desig-nating the source of referral helps you to assess the type of information pro-
vided and any possible biases.
Reliability. Should be documented if relevant. For example, “The patient

is vague when describing symptoms and unable to specify details.” This judg-ment reﬂects the quality of the information provided by the patient and isusually made at the end of the interview.
Chief Complaint(s)
Make every attempt to quote the patient’s own words. For example, “Mystomach hurts and I feel awful.” Sometimes patients have no overt com-plaints, in which case you should report their goals instead. For example,“I have come for my regular checkup”; or “I’ve been admitted for a thoroughevaluation of my heart.”
Present Illness

This section of the history is a complete, clear, and chronologic account of theproblems prompting the patient to seek care. The narrative should include theonset of the problem, the setting in which it has developed, its manifestations,and any treatments. The principal symptoms should be well-characterized,with descriptions of (1) location, (2) quality, (3) quantity or severity, (4) tim-ing, including onset, duration, and frequency, (5) the setting in which theyoccur, (6) factors that have aggravated or relieved the symptoms, and (7) as-
Subjective Data Objective Data
What the patient tells you
The history, from chief complaint
through Review of Systems
Example: Mrs. G is a 54-year-old
hairdresser who reports pressure overher left chest “like an elephant sittingthere,” which goes into her left neckand arm.What you detect on the examination
All physical examination ﬁndings
Example: Mrs. G is an older white female,

deconditioned, pleasant, and cooperative.BP 160/80, HR 96 and regular,respiratory rate 24, afebrile.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5csociated manifestations. These seven attributes are invaluable for under-
standing all patient symptoms (see p. ___). It is also important to include“pertinent positives” and “pertinent negatives” from sections of the Review
of Systems related to the Chief Complaint(s). These designate the presence
or absence of symptoms relevant to the differential diagnosis, which refers to
the most likely diagnoses explaining the patient’s condition. Other informa-tion is frequently relevant, such as risk factors for coronary artery disease in pa-tients with chest pain, or current medications in patients with syncope. The pre-
sent illness should reveal the patient’s responses to his or her symptoms and
what effect the illness has had on the patient’s life. Always remember, the data
ﬂows spontaneously from the patient, but the task of organization is yours .
Medications should be noted, including name, dose, route, and frequency of

use. Also list home remedies, nonprescription drugs, vitamins, mineral orherbal supplements, birth control pills, and medicines borrowed from familymembers or friends. It is a good idea to ask patients to bring in all of their med-ications so you can see exactly what they take. Allergies, including speciﬁc re-
actions to each medication, such as rash or nausea, must be recorded, as well as
allergies to foods, insects, or environmental factors. Note tobacco use, includ-
ing the type used. Cigarettes are often reported in pack-years (a person whohas smoked 1
1⁄2packs a day for 12 years has an 18-pack-year history). If some-
one has quit, note for how long. Alcohol anddrug useshould always be queried
(see p. ___ for suggested questions). (Note that tobacco, alcohol, and drugs may

also be included in the Personal and Social History; however, many cliniciansﬁnd these habits pertinent to the Present Illness.)
Childhood illnesses, such as measles, rubella, mumps, whooping cough,
chicken pox, rheumatic fever, scarlet fever, and polio are included in the PastHistory. Also included are any chronic childhood illnesses. You should pro-vide information relative to Adult Illnesses in each of four areas: Medical (such
as diabetes, hypertension, hepatitis, asthma, HIV disease, information abouthospitalizations, number and gender of partners, at-risk sexual practices); sur-
gical (include dates, indications, and types of operations); Obstetric/gynecologic

(relate obstetric history, menstrual history, birth control, and sexual function);and Psychiatric (include dates, diagnoses, hospitalizations, and treatments).
You should also cover selected aspects of Health Maintenance, including Im-
munizations, such as tetanus, pertussis, diphtheria, polio, measles, rubella,
mumps, inﬂuenza, hepatitis B, Haemophilus inﬂuenza type b, and pneumo-
coccal vaccines (these can usually be obtained from prior medical records),and Screening Tests, such as tuberculin tests, Pap smears, mammograms, stools
for occult blood, and cholesterol tests, together with the results and the datesthey were last performed. If the patient does not know this information, writ-ten permission may be needed to obtain old medical records.
Under Family History, outline or diagram the age and health, or age and cause

of death, of each immediate relative, including parents, grandparents, sib-
THE HEALTH HISTORY: STRUCTURE AND PURPOSES
CHAPTER 1 IAN OVERVIEW OF PHYSICAL EXAMINATION AND HISTORY TAKING 5

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5clings, children, and grandchildren. Review each of the following conditions
and record if they are present or absent in the family: hypertension, coronaryartery disease, elevated cholesterol levels, stroke, diabetes, thyroid or renaldisease, cancer (specify type), arthritis, tuberculosis, asthma or lung disease,headache, seizure disorder, mental illness, suicide, alcohol or drug addiction,and allergies, as well as symptoms reported by the patient.
The Personal and Social History captures the patient’s personality and inter-

ests, sources of support, coping style, strengths, and fears. It should include:occupation and the last year of schooling; home situation and signiﬁcantothers; sources of stress, both recent and long-term; important life experi-ences, such as military service, job history, ﬁnancial situation, and retirement;leisure activities; religious afﬁliation and spiritual beliefs; and activities ofdaily living (ADLs). Baseline level of function is particularly important inolder or disabled patients (see p. ___ for the ADLs frequently assessed inolder patients). The Personal and Social History also conveys lifestyle habits
that promote health or create risk such as exercise and diet, including fre-

quency of exercise, usual daily food intake, dietary supplements or restric-tions, and use of coffee, tea, and other caffeine-containing beverages andsafety measures, including use of seat belts, bicycle helmets, sunblock, smoke
detectors, and other devices related to speciﬁc hazards. You may want to in-clude any alternative health care practices.
You will come to thread personal and social questions throughout the inter-
view to make the patient feel more at ease.
Review of Systems
Understanding and using Review of Systems questions is often challenging
for beginning students. Think about asking series of questions going from“head to toe.” It is helpful to prepare the patient for the questions to comeby saying, “The next part of the history may feel like a million questions,but they are important and I want to be thorough.” Most Review of Systems

questions pertain to symptoms, but on occasion some clinicians also include
diseases like pneumonia or tuberculosis. (If the patient remembers impor-tant illnesses as you ask questions within the Review of Systems, you should
record or present such important illnesses as part of the Present Illness or
Past H istory. )
Start with a fairly general question as you address each of the different sys-
tems. This focuses the patient’s attention and allows you to shift to morespeciﬁc questions about systems that may be of concern. Examples of start-ing questions are: “How are your ears and hearing?” “How about your lungsand breathing?” “Any trouble with your heart?” “How is your digestion?”
6 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5c“How about your bowels?” Note that you will vary the need for additional
questions depending on the patient’s age, complaints, general state of health,and your clinical judgment.
The Review of Systems questions may uncover problems that the patient has
overlooked, particularly in areas unrelated to the present illness. Signiﬁcant
health events, such as a major prior illness or a parent’s death, require fullexploration. Remember that major health events should be moved to the present
illness or past history in your write-up. Keep your technique ﬂexible. Inter-
viewing the patient yields a variety of information that you organize into for-mal written format only after the interview and examination are completed.
Some clinicians do the Review of Systems during the physical examination,

asking about the ears, for example, as they examine them. If the patient hasonly a few symptoms, this combination can be efﬁcient. However, if thereare multiple symptoms, the ﬂow of both the history and the examination canbe disrupted and necessary note-taking becomes awkward. Listed below is astandard series of review-of-system questions. As you gain experience, the“yes or no” questions, placed at the end of the interview, will take no morethan several minutes.
General. Usual weight, recent weight change, any clothes that ﬁt more
tightly or loosely than before. Weakness, fatigue, fever.
Skin. Rashes, lumps, sores, itching, dryness, color change, changes in
hair or nails.
Head, Eyes, Ears, Nose, Throat (HEENT). Head: Headache, head in-
jury, dizziness, lightheadedness. Eyes: Vision, glasses or contact lenses, last

examination, pain, redness, excessive tearing, double vision, blurred vision,spots, specks, ﬂashing lights, glaucoma, cataracts. Ears: Hearing, tinnitus, ver-
tigo, earaches, infection, discharge. If hearing is decreased, use or nonuse ofhearing aids. Nose and sinuses: Frequent colds, nasal stufﬁness, discharge, or
itching, hay fever, nosebleeds, sinus trouble. Throat (or mouth and pharynx):
Condition of teeth, gums, bleeding gums, dentures, if any, and how theyﬁt, last dental examination, sore tongue, dry mouth, frequent sore throats,hoarseness.
Neck. Lumps, “swollen glands,” goiter, pain, or stiffness in the neck.
Breasts. Lumps, pain or discomfort, nipple discharge, self-examination
practices.
Respiratory. Cough, sputum (color, quantity), hemoptysis, dyspnea,

wheezing, pleurisy, last chest x-ray. You may wish to include asthma, bron-chitis, emphysema, pneumonia, and tuberculosis.
Cardiovascular. Heart trouble, high blood pressure, rheumatic fever,
heart murmurs, chest pain or discomfort, palpitations, dyspnea, orthopnea,THE HEALTH HISTORY: STRUCTURE AND PURPOSES
CHAPTER 1 IAN OVERVIEW OF PHYSICAL EXAMINATION AND HISTORY TAKING 7

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cparoxysmal nocturnal dyspnea, edema, past electrocardiographic or other
heart test results.
Gastrointestinal. Trouble swallowing, heartburn, appetite, nausea,
bowel movements, color and size of stools, change in bowel habits, rectalbleeding or black or tarry stools, hemorrhoids, constipation, diarrhea. Ab-dominal pain, food intolerance, excessive belching or passing of gas. Jaundice,liver or gallbladder trouble, hepatitis.
Urinary. Frequency of urination, polyuria, nocturia, urgency, burning
or pain on urination, hematuria, urinary infections, kidney stones, inconti-nence; in males, reduced caliber or force of the urinary stream, hesitancy,dribbling.
Genital. Male: Hernias, discharge from or sores on the penis, testicu-

lar pain or masses, history of sexually transmitted diseases and their treat-ments. Sexual habits, interest, function, satisfaction, birth control methods,condom use, and problems. Exposure to HIV infection. Female: Age at

menarche; regularity, frequency, and duration of periods; amount of bleed-ing, bleeding between periods or after intercourse, last menstrual period;dysmenorrhea, premenstrual tension; age at menopause, menopausal symp-toms, postmenopausal bleeding. If the patient was born before 1971, expo-sure to diethylstilbestrol (DES) from maternal use during pregnancy. Vagi-nal discharge, itching, sores, lumps, sexually transmitted diseases andtreatments. Number of pregnancies, number and type of deliveries, numberof abortions (spontaneous and induced); complications of pregnancy; birthcontrol methods. Sexual preference, interest, function, satisfaction, any prob-lems, including dyspareunia. Exposure to HIV infection.
Peripheral Vascular. Intermittent claudication, leg cramps, varicose
veins, past clots in the veins.
Musculoskeletal. Muscle or joint pains, stiffness, arthritis, gout, and

backache. If present, describe location of affected joints or muscles, presenceof any swelling, redness, pain, tenderness, stiffness, weakness, or limitationof motion or activity; include timing of symptoms (for example, morning orevening), duration, and any history of trauma.
Neurologic. Fainting, blackouts, seizures, weakness, paralysis, numb-
ness or loss of sensation, tingling or “pins and needles,” tremors or other in-voluntary movements.
Hematologic. Anemia, easy bruising or bleeding, past transfusions
and/or transfusion reactions.
Endocrine. Thyroid trouble, heat or cold intolerance, excessive sweat-
ing, excessive thirst or hunger, polyuria, change in glove or shoe size.
Psychiatric. Nervousness, tension, mood, including depression, mem-

ory change, suicide attempts, if relevant.THE HEALTH HISTORY: STRUCTURE AND PURPOSES
8 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING

THE PHYSICAL EXAMINATION:
APPROACH AND OVERVIEW
In this section, we outline the comprehensive physical examination and pro-
vide an overview of all its components. You will conduct a comprehensive
physical examination on most new patients or patients being admitted to thehospital. For more problem-oriented, or focused, assessments, the presenting
complaints will dictate what segments of the examination you elect to per-form. You will ﬁnd a more extended discussion of the approach to the ex-amination, its scope (comprehensive or focused), and a table summarizingthe examination sequence in Chapter 3, Beginning the Physical Examination:General Survey, and Vital Signs. Information about anatomy and physiology,
interview questions, techniques of examination, and important abnormali-ties are detailed in Chapters 3 through 16 for each of the segments of thephysical examination described below.

It is important to note that the key to a thorough and accurate physical ex-
amination is developing a systematic sequence of examination. At ﬁrst, you
may need notes to remember what to look for as you examine each regionof the body; but with a few months of practice, you will acquire a routinesequence of your own. This sequence will become habit and often promptyou to return to an exam segment you may have inadvertently skipped, help-ing you to become thorough.
As you develop your own sequence of examination, an important goal is to
minimize the number of times you ask the patient to change position from

supine to sitting, or standing to lying supine. Some segments of the physi-cal examination are best obtained while the patient is sitting, such as exam-inations of the head and neck and of the thorax and lungs, whereas othersare best obtained supine, as are the cardiovascular and abdominal examina-tions. Some suggestions for patient positioning during the different seg-ments of the examination are indicated in the right-hand column in red.
Most patients view the physical examination with at least some anxiety. They

feel vulnerable, physically exposed, apprehensive about possible pain, anduneasy about what the clinician may ﬁnd. At the same time, they appreciatethe clinician’s concern about their problems and respond to your attentive-ness. With these considerations in mind, the skillful clinician is thoroughwithout wasting time, systematic without being rigid, gentle yet not afraidto cause discomfort should this be required. In applying the techniques ofinspection, palpation, auscultation, and percussion, the skillful clinician ex-amines each region of the body, and at the same time senses the whole pa-tient, notes the wince or worried glance, and shares information that calms,explains, and reassures.
For an overview of the physical examination, study the following example of
the sequence of examination now. Note that clinicians vary in where they

place different segments of the examination, especially the examinations of theTHE PHYSICAL EXAMINATION: APPROACH AND OVERVIEW
CHAPTER 1 IAN OVERVIEW OF PHYSICAL EXAMINATION AND HISTORY TAKING 9

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTHE PHYSICAL EXAMINATION: APPROACH AND OVERVIEW
10 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGmusculoskeletal system and the nervous system. Some of these options are in-
dicated below. With practice, you will develop your own sequence, keepingthe need for thoroughness and patient comfort in mind. After you completeyour study and practice the techniques described in the regional examina-tion chapters, reread this overview to see how each segment of the exami-nation ﬁts into an integrated whole.
The Comprehensive Physical Examination
General Survey. Observe the patient’s general state of health, height,

build, and sexual development. Obtain the patient’s weight. Note posture,motor activity, and gait; dress, grooming, and personal hygiene; and anyodors of the body or breath. Watch the patient’s facial expressions and notemanner, affect, and reactions to persons and things in the environment. Lis-ten to the patient’s manner of speaking and note the state of awareness orlevel of consciousness.
Vital Signs. Measure height and weight. Measure the blood pressure.
Count the pulse and respiratory rate. If indicated, measure the body tem-perature.
Skin. Observe the skin of the face and its characteristics. Identify any
lesions, noting their location, distribution, arrangement, type, and color.Inspect and palpate the hair and nails. Study the patient’s hands. Continueyour assessment of the skin as you examine the other body regions.

Head, Eyes, Ears, Nose, Throat (HEENT). Head: Examine the hair,
scalp, skull, and face. Eyes: Check visual acuity and screen the visual ﬁelds.
Note the position and alignment of the eyes. Observe the eyelids and inspectthe sclera and conjunctiva of each eye. With oblique lighting, inspect eachcornea, iris, and lens. Compare the pupils, and test their reactions to light.Assess the extraocular movements. With an ophthalmoscope, inspect the oc-ular fundi. Ears: Inspect the auricles, canals, and drums. Check auditory acu-
ity. If acuity is diminished, check lateralization (Weber test) and compare airand bone conduction (Rinne test). Nose and sinuses: Examine the external
nose; using a light and a nasal speculum, inspect the nasal mucosa, septum,and turbinates. Palpate for tenderness of the frontal and maxillary sinuses.Throat (or mouth and pharynx): Inspect the lips, oral mucosa, gums, teeth,
tongue, palate, tonsils, and pharynx. (You may wish to assess the cranial nerves

during this portion of the examination.)
Neck. Inspect and palpate the cervical lymph nodes. Note any masses or
unusual pulsations in the neck. Feel for any deviation of the trachea. Ob-serve sound and effort of the patient’s breathing. Inspect and palpate thethyroid gland.
Back. Inspect and palpate the spine and muscles of the back.
The survey continues throughout
the history and examination.
The patient is sitting on the 
edge of the bed or examiningtable, unless this position is contra-indicated. You should be standingin front of the patient, moving toeither side as needed.
The room should be darkened for
the ophthalmoscopic examination.This promotes papillary dilationand visibility of the fundi.
Move behind the sitting patient 
to feel the thyroid gland and to examine the back, posterior thorax,and the lungs.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cPosterior Thorax and Lungs. Inspect and palpate the spine and mus-
cles of the upper back. Inspect, palpate, and percuss the chest. Identify the
level of diaphragmatic dullness on each side. Listen to the breath sounds;identify any adventitious (or added) sounds, and, if indicated, listen to thetransmitted voice sounds (see p.___).
Breasts, Axillae, and Epitrochlear Nodes. In a woman, inspect the
breasts with her arms relaxed, then elevated, and then with her hands pressedon her hips. In either sex, inspect the axillae and feel for the axillary nodes.Feel for the epitrochlear nodes.
A Note on the Musculoskeletal System: By this time, you have made some

preliminary observations of the musculoskeletal system. You have inspectedthe hands, surveyed the upper back, and at least in women, made a fair es-timate of the shoulders’ range of motion. Use these and subsequent obser-vations to decide whether a full musculoskeletal examination is warranted.If indicated, with the patient still sitting, examine the hands, arms, shoulders,
neck, and temporomandibular joints. Inspect and palpate the joints andcheck their range of motion. (You may choose to examine upper extremity
muscle bulk, tone, strength, and reﬂexes at this time, or you may decide to waituntil later.)
Palpate the breasts, while at the same time continuing your inspection.
Anterior Thorax and Lungs. Inspect, palpate, and percuss the chest.
Listen to the breath sounds, any adventitious sounds, and, if indicated,transmitted voice sounds.
Cardiovascular System. Observe the jugular venous pulsations, and

measure the jugular venous pressure in relation to the sternal angle. Inspectand palpate the carotid pulsations. Listen for carotid bruits.
Inspect and palpate the precordium. Note the location, diameter, amplitude,
and duration of the apical impulse. Listen at the apex and the lower sternalborder with the bell of a stethoscope. Listen at each auscultatory area withthe diaphragm. Listen for the ﬁrst and second heart sounds, and for physi-ologic splitting of the second heart sound. Listen for any abnormal heartsounds or murmurs.
Abdomen. Inspect, auscultate, and percuss the abdomen. Palpate lightly,
then deeply. Assess the liver and spleen by percussion and then palpation.Try to feel the kidneys, and palpate the aorta and its pulsations. If you sus-pect kidney infection, percuss posteriorly over the costovertebral angles.

Lower Extremities. Examine the legs, assessing three systems while the
patient is still supine. Each of these three systems can be further assessedwhen the patient stands.THE PHYSICAL EXAMINATION: APPROACH AND OVERVIEW
CHAPTER 1 IAN OVERVIEW OF PHYSICAL EXAMINATION AND HISTORY TAKING 11The patient is still sitting. Move to
the front again.
The patient position is supine.
Ask the patient to lie down. Youshould stand at the right side ofthe patient’s bed.
Elevate the head of the bed to
about 30° for the cardiovascular
examination, adjusting as necessaryto see the jugular venous pulsations.
Ask the patient to roll partly onto
the left side while you listen at theapex. Then have the patient rollback to the supine position whileyou listen to the rest of the heart.The patient should sit, lean forward,and exhale while you listen for themurmur of aortic regurgitation.
Lower the head of the bed to the
ﬂat position. The patient should
be supine.
The patient is supine .

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cExamination with the patient supine
IPeripheral Vascular System. Palpate the femoral pulses, and if indicated,
the popliteal pulses. Palpate the inguinal lymph nodes. Inspect for lowerextremity edema, discoloration, or ulcers. Palpate for pitting edema.
IMusculoskeletal System. Note any deformities or enlarged joints. If indi-
cated, palpate the joints, check their range of motion, and perform anynecessary maneuvers.
INervous System. Assess lower extremity muscle bulk, tone, and strength;
also sensation and reﬂexes. Observe any abnormal movements.
Examination with the patient standing
IPeripheral Vascular System. Inspect for varicose veins.
IMusculoskeletal System. Examine the alignment of the spine and its range
of motion, the alignment of the legs, and the feet.
IGenitalia and Hernias in Men. Examine the penis and scrotal contents
and check for hernias.

INervous System. Observe the patient’s gait and ability to walk heel-to-toe,
walk on the toes, walk on the heels, hop in place, and do shallow kneebends. Do a Romberg test and check for pronator drift.
Nervous System. The complete examination of the nervous system can
also be done at the end of the examination. It consists of the ﬁve segmentsdescribed below: mental status, cranial nerves (including funduscopic ex-
amination), motor system, sensory system, and reﬂexes.
Mental Status. If indicated and not done during the interview, assess
the patient’s orientation, mood, thought process, thought content, abnor-mal perceptions, insight and judgment, memory and attention, informationand vocabulary, calculating abilities, abstract thinking, and constructionalability.
Cranial Nerves. If not already examined, check sense of smell, strength

of the temporal and masseter muscles, corneal reﬂexes, facial movements,gag reﬂex, and strength of the trapezia and sternomastoid muscles.
Motor System. Muscle bulk, tone, and strength of major muscle groups.
Cerebellar function: rapid alternating movements (RAMs), point-to-point
movements, such as ﬁnger-to-nose (F →N) and heel-to-shin (H →S); gait.
Sensory System. Pain, temperature, light touch, vibration, and dis-
crimination. Compare right with left sides and distal with proximal areas onthe limbs.The patient is standing . You
should sit on a chair or stool.
The patient is sitting or supine .THE PHYSICAL EXAMINATION: APPROACH AND OVERVIEW
12 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING

RECORDING YOUR FINDINGS
Now you are ready to review an actual written record documenting a patient’s
history and physical ﬁndings, illustrated below using the example of “Mrs. N.”The history and physical examination form the database for your subsequentassessment(s) of the patient and your plan(s) with the patient for management
and next steps. Your written record organizes the information from the his-tory and physical examination and should clearly communicate the patient’sclinical issues to all members of the health care team. You will ﬁnd that fol-lowing a standardized format is often the most efﬁcient and helpful way totransfer this information.
Your written record should also facilitate clinical reasoning and communi-

cate essential information to the many health professionals involved in yourpatient’s care. Chapter 18, Clinical Reasoning, Assessment, and Plan, willprovide more comprehensive information for formulating the assessment and
plan, and additional guidelines for documentation.
If you are a beginner, organizing the Present Illness may be especially chal-
lenging, but do not get discouraged. Considerable knowledge is needed tocluster related symptoms and physical signs. If you are unfamiliar with hyper-thyroidism, for example, it may not be apparent that muscular weakness,heat intolerance, excessive sweating, diarrhea, and weight loss, all representa Present Illness. Until your knowledge and judgment grow, the patient’s
story and the seven key attributes of a symptom (see p. ___) are helpful andnecessary guides to what to include in this portion of the record.RECORDING YOUR FINDINGS

CHAPTER 1 IAN OVERVIEW OF PHYSICAL EXAMINATION AND HISTORY TAKING 13Reﬂexes. Including biceps, triceps, brachioradialis, patellar, Achilles
deep tendon reﬂexes; also plantar reﬂexes or Babinski reﬂex (see p. ___).
Additional Examinations. The rectal and genital examinations are
often performed at the end of the physical examination. Patient positioningis as indicated.
Rectal Examination in Men. Inspect the sacrococcygeal and perianal
areas. Palpate the anal canal, rectum, and prostate. If the patient cannotstand, examine the genitalia before doing the rectal examination.
Genital and Rectal Examination in Women. Examine the external
genitalia, vagina, and cervix. Obtain a Pap smear. Palpate the uterus andadnexa. Do a rectovaginal and rectal examination.The patient is lying on his left side
for the rectal examination.

The patient is supine in the lithot-
omy position . You should be
seated during examination withthe speculum, then standing during bimanual examination ofthe uterus, adnexa, and rectum.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTIPS FOR A CLEAR AND ACCURATE WRITE-UP
You should write the record as soon as possible, before the data fade from your
memory. At ﬁrst, you will probably prefer to take notes when talking with the pa-tient. As you gain experience, however, work toward recording the Present Illness ,
the Past Medical History , the Family History , the Personal and Social History , and the
Review of Systems in ﬁnal form during the interview. Leave spaces for ﬁlling in
details later. During the physical examination , make note immediately of speciﬁc
measurements, such as blood pressure and heart rate. On the other hand, record-ing multiple items interrupts the ﬂow of the examination, and you will soon learnto remember your ﬁndings and record them after you have ﬁnished.
Several key features distinguish a clear and well-organized written record. Pay
special attention to the order and the degree of detail as you review the record

below and later when you construct your own write-ups. Remember that if hand-written, a good record is always legible!
Order of the Write-Up
The order should be consistent and obvious so that future readers, including yourself,can easily ﬁnd speciﬁc points of information. Keep items of history in the history, forexample, and do not let them stray into the physical examination. Offset your head-ings and make them clear by using indentations and spacing to accent your organiza-tion. Create emphasis by using asterisks and underlines for important points. Arrangethe present illness in chronologic order, starting with the current episode and then ﬁll-

ing in the relevant background information. If a patient with long-standing diabetes ishospitalized in a coma, for example, begin with the events leading up to the comaand then summarize the past history of the patient’s diabetes.
Degree of Detail
The degree of detail is also a challenge. It should be pertinent to the subject or
problem but not redundant. Review the record of Mrs. N, then turn to the check-list in Chapter 18 on pp. _____. Decide if you think the order and detail includedmeet the standards of a good medical record.
The Case of Example of Mrs. N
8/30/02Mrs. N is a pleasant, 54-year-old widowed saleswoman residing in Amarillo, Texas.Referral . None
Source and Reliability . Self-referred; seems reliable.
Chief Complaint: “My head aches.”
For about 3 months, Mrs. N has had increasing problems with frontal headaches.

These are usually bifrontal, throbbing, and mild to moderately severe. She hasmissed work on several occasions due to associated nausea and vomiting.Headaches now average once a week, usually related to stress, and last 4 to 6 hours. They are relieved by sleep and putting a damp towel over the forehead.There is little relief from aspirin. No associated visual changes, motor-sensorydeﬁcits, or paresthesias.
“Sick headaches” with nausea and vomiting began at age 15, recurred throughout
her mid-20s, then decreased to one every 2 or 3 months and almost disappeared.
14 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cThe patient reports increased pressure at work from a new and demanding
boss; she is also worried about her daughter (see Personal and Social History ).
Thinks her headaches may be like those in the past, but wants to be sure becauseher mother died of a stroke. She is concerned that they interfere with her work andmake her irritable with her family. She eats three meals a day and drinks three cupsof coffee per day; cola at night.
IMedications. Aspirin, 1 to 2 tablets every 4 to 6 hours as needed. “Water pill” in
the past for ankle swelling, none recently.
I*Allergies. Ampicillin causes rash.
ITobacco. About 1 pack of cigarettes per day since age 18 (36 pack-years).
IAlcohol/drugs. Wine on rare occasions. No illicit drugs.
Childhood Illnesses. Measles, chickenpox. No scarlet fever or rheumatic fever.
Adult Illnesses. Medical: Pyelonephritis, 1982, with fever and right ﬂank pain;

treated with ampicillin; develop generalized rash with itching several days later.Reports kidney x-rays were normal; no recurrence of infection. Surgical:
Tonsillectomy, age 6, appendectomy, age 13. Sutures for laceration, 1991, afterstepping on glass. Ob/gyn: G3P3, with normal vaginal deliveries. 3 living children.
Menarche age 12. Last menses 6 months ago. Little interest in sex, and notsexually active. No concerns about HIV infection. Psychiatric: None.
Health Maintenance. Immunizations: Oral polio vaccine, year uncertain; tetanus
shots ×2, 1991, followed with booster 1 year later; ﬂu vaccine, 2000, no reaction.
Screening tests: Last Pap smear, 1998, normal. No mammograms to date.
A note on recording the Family History . There are two methods of recording the

A note on recording the Family History . There are two methods of recording the 
Family History: a diagram or a narrative. The diagram format is more helpful than
the narrative for tracing genetic disorders. The negatives from the family historyshould follow either format.RECORDING YOUR FINDINGS
CHAPTER 1 IAN OVERVIEW OF PHYSICAL EXAMINATION AND HISTORY TAKING 15*Add an asterisk or underline important points.UNFIG 1-1

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cRECORDING YOUR FINDINGS
16 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGor:
Father died at age 43 in train accident. Mother died at age 67 of stroke; had vari-
cose veins, headaches
One brother, 61, with hypertension, otherwise well; one brother, 58, well except
for mild arthritis; one sister, died in infancy of unknown cause
Husband died at age 54 of heart attackDaughter, 33, with migraine headaches, otherwise well; son, 31, with headaches;
son, 27, well
No family history of diabetes, tuberculosis, heart or kidney disease, cancer, anemia,
epilepsy, or mental illness.
Born and raised in Lake City, ﬁnished high school, married at age 19. Worked assales clerk for 2 years, then moved with husband to Amarillo, had 3 children. Re-turned to work 15 years ago because of ﬁnancial pressures. Children all married.

Four years ago Mr. N died suddenly of a heart attack, leaving little savings. Mrs. Nhas moved to small apartment to be near daughter, Dorothy. Dorothy’s husband,Arthur, has an alcohol problem. Mrs. N’s apartment now a h aven for Dorothy and
her 2 children, Kevin, 6 years, and Linda, 3 years. Mrs. N feels res ponsible for help-
ing them; feels tense and nervous but denies depression. She has friends butrarely discusses family problems: “I’d rather keep them to myself. I don’t like gos-sip.” No church or other organizational support. She is typically up at 7:00 
A.M.,
works 9:00 to 5:30, eats dinner alone.
IExercise and diet. Gets little exercise. Diet high in carbohydrates.
ISafety measures. Uses seat belt regularly. Uses sunblock. Medications kept in an
unlocked medicine cabinet. Cleaning solutions in unlocked cabinet below sink.Mr. N’s shotgun and box of shells in unlocked closet upstairs.
*General. Has gained about 10 lb in the past 4 years.

Skin. No rashes or other changes.
Head, Eyes, Ears, Nose, Throat (HEENT). See Present Illness . No history of head
injury. Eyes: Reading glasses for 5 years, last checked 1 year ago. No symptoms.
Ears: Hearing good. No tinnitus, vertigo, infections. Nose, sinuses: Occasional
mild cold. No hay fever, sinus trouble. *Throat (or *mouth and pharynx):
Some bleeding of gums recently. Last dental visit 2 years ago. Occasional cankersore.
Neck. No lumps, goiter, pain. No swollen glands.
Breasts. No lumps, pain, discharge. Does self-breast exam sporadically.
Respiratory. No cough, wheezing, shortness of breath. Last chest x-ray, 1986, St.
Mary’s Hospital; unremarkable.
Cardiovascular. No known heart disease or high blood pressure; last blood
pressure taken in 1998. No dyspnea, orthopnea, chest pain, palpitations. Hasnever had an electrocardiogram (ECG).

*Gastrointestinal. Appetite good; no nausea, vomiting, indigestion. Bowel
movement about once daily, though sometimes has hard stools for 2 to 3 dayswhen especially tense; no diarrhea or bleeding. No pain, jaundice, gallbladder orliver problems.
*Urinary. No frequency, dysuria, hematuria, or recent ﬂank pain; nocturia ×1,
large volume. Occasionally loses some urine when coughs hard.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cGenital. No vaginal or pelvic infections. No dyspareunia.
Peripheral Vascular. Varicose veins appeared in both legs during ﬁrst pregnancy.
For 10 years, has had swollen ankles after prolonged standing; wears light elasticpantyhose; tried “water pill” 5 months ago, but it didn’t help much; no history ofphlebitis or leg pain.
Musculoskeletal. Mild, aching, low-back pain, often after a long day’s work; no ra-
diation down the legs; used to do back exercises but not now. No other joint pain.
Neurologic. No fainting, seizures, motor or sensory loss. Memory good.
Hematologic. Except for bleeding gums, no easy bleeding. No anemia.
Endocrine. No known thyroid trouble, temperature intolerance. Sweating aver-
age. No symptoms or history of diabetes.
Psychiatric. No history of depression or treatment for psychiatric disorders. See
also Present Illness and Personal and Social History .
Physical Examination

Mrs. N is a short, moderately obese, middle-aged woman, who is animated and re-
sponds quickly to questions. She is somewhat tense, with moist, cold hands. Herhair is ﬁxed neatly and her clothes are immaculate. Her color is good and she liesﬂat without discomfort.
Vital Signs. Ht (without shoes) 157 cm (5 ′2″). Wt (dressed) 65 kg (143 lb). BP
164/98 right arm, supine; 160/96 left arm, supine; 152/88 right arm, supine withwide cuff. Heart rate (HR) 88 and regular. Respiratory rate (RR) 18. Temperature(oral) 98.6 °F.
Skin. Palms cold and moist, but color good. Scattered cherry angiomas over
upper trunk. Nails without clubbing, cyanosis.
Head, Eyes, Ears, Nose, Throat (HEENT). Head: Hair of average texture. Scalp with-

out lesions, normocephalic/atraumatic (NC/AT). Eyes: Vision 20/30 in each eye. Visual
ﬁelds full by confrontation. Conjunctiva pink; sclera white. Pupils 4 mm constrictingto 2 mm, round, regular, equally, reactive to light. Extraocular movements intact.Disc margins sharp, without hemorrhages, exudates. No arteriolar narrowing or A-V nicking. Ears: Wax partially obscures right tympanic membrane (TM); left canal
clear, TM with good cone of light. Acuity good to whispered voice. Weber midline.AC > BC. Nose: Mucosa pink, septum midline. No sinus tenderness. Mouth: Oral
mucosa pink. Several interdental papillae red, slightly swollen. Dentition good.Tongue midline, with 3 ×4 mm shallow white ulcer on red base on undersurface
near tip; tender but not indurated. Tonsils absent. Pharynx without exudates.

Neck. Neck supple. Trachea midline. Thyroid isthmus barely palpable, lobes not felt.
Lymph Nodes. Small (<1 cm), soft, nontender, and mobile tonsillar and posterior
cervical nodes bilaterally. No axillary or epitrochlear nodes. Several small inguinalnodes bilaterally, soft and nontender.
Thorax and Lungs. Thorax symmetric with good excursion. Lungs resonant.
Breath sounds vesicular with no added sounds. Diaphragms descend 4 cm bilaterally.
Cardiovascular. Jugular venous pressure 1 cm above the sternal angle, with
head of examining table raised to 30 °. Carotid upstrokes brisk, without bruits.
Apical impulse discrete and tapping, barely palpable in the 5th left interspace, RECORDING YOUR FINDINGS
CHAPTER 1 IAN OVERVIEW OF PHYSICAL EXAMINATION AND HISTORY TAKING 17

18 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING8 cm lateral to the midsternal line. Good S 1, S2; no S 3or S 4. A II/VI medium-pitched
midsystolic murmur at the 2nd right interspace; does not radiate to the neck. No di-astolic murmurs.
Breasts. Pendulous, symmetric. No masses; nipples without discharge.
Abdomen. Obese. Well-healed scar, right lower quadrant. Bowel sounds active.
No tenderness or masses. Liver span 7 cm in right midclavicular line; edge smooth,palpable 1 cm below right costal margin (RCM). Spleen and kidneys not felt. Nocostovertebral angle tenderness (CVAT).
Genitalia. External genitalia without lesions. Mild cystocele at introitus on

straining. Vaginal mucosa pink. Cervix pink, parous, and without discharge.Uterus anterior, midline, smooth, not enlarged. Adnexa not palpated due toobesity and poor relaxation. No cervical or adnexal tenderness. Pap smeartaken. Rectovaginal wall intact.
Rectal. Rectal vault without masses. Stool brown, negative for occult blood.
Extremities. Warm and without edema. Calves supple, nontender.
Peripheral Vascular. Trace edema at both ankles. Moderate varicosities of
saphenous veins both lower extremities. No stasis pigmentation or ulcers. Pulses (2 + = brisk, or normal):
Musculoskeletal. No joint deformities. Good range of motion in hands, wrists,
elbows, shoulders, spine, hips, knees, ankles.
Neurologic. Mental Status: Tense but alert and cooperative. Thought coherent.
Oriented to person, place, and time. Cranial Nerves. II–XII intact. Motor: Good

muscle bulk and tone. Strength 5/5 throughout (see p. ___ for grading system).Rapid alternating movements (RAMs), point-to-point movements intact. Gaitstable, ﬂuid. Sensory: Pinprick, light touch, position sense, vibration, and stereog-
nosis intact. Romberg negative. Reﬂexes: Two methods of recording may be used,
depending upon personal preference: a tabular form or a stick picture diagram, asshown below and at right. 2+ = brisk, or normal; see p. ___ for grading system.Radial Femoral Popliteal Dorsalis Pedis Posterior Tibial
RT 2 + 2+ 2+ 2+ 2+
LT 2 + 2+ 2+ Absent 2 +
Biceps Triceps Brachi Aborad Patellar Achilles Plantar
RT 2 + 2+ 2+ 2+/2+ 2+ 1+↓
LT 2 + 2+ 2+ 2+ 2+/2+ 1+↓UNFIG 1-2

CHAPTER 1 IAN OVERVIEW OF PHYSICAL EXAMINATION AND HISTORY TAKING 19Learning History Taking and Physical Examination
Now that you have surveyed the tasks ahead, the overviews of the health his-
tory and physical examination, and the patient record of Mrs. N, you areready to turn to the chapters on history taking and physical examination.Chapter 18, Clinical Reasoning, Assessment, and Plan, provides more com-prehensive information on how to formulate your Assessment and Plan, the
ﬁnal steps of patient assessment, and the remaining two sections of the writ-ten record. In Chapter 18 you will also ﬁnd guidelines for documentationand the assessment and plan for Mrs. N. The rewards of mastering the skillsof patient assessment lie just ahead!

Interviewing and the 
Health HistoryCHAPTER
Interviewing and the Health History22
CHAPTER 2 IINTERVIEWING AND THE HEALTH HISTORY 21The health history interview is a conversation with a purpose. As a clinician,

you will draw on many of the interpersonal skills that you use every day, butwith unique and important differences. Unlike social conversation, in whichyou express your own needs and interests with responsibility only for yourself,the primary goal of the clinician–patient interview is to improve the well-beingof the patient. At its most basic level, the purpose of conversation with a pa-tient is threefold: to establish a trusting and supportive relationship, to gatherinformation, and to offer information. Communicating and relating thera-peutically with patients are the most valued skills of clinical care. As a begin-ning clinician, you will focus your energies on gathering information. At thesame time, by using techniques that promote trust and communication, youwill allow the patient’s story to unfold in its most full and detailed form. Es-tablishing a supportive interaction enhances information-gathering and itselfbecomes part of the therapeutic process of patient care.

As a clinician facilitating the patient’s story, you will come to generate a series
of hypotheses about the nature of the patient’s concerns. You will then testthese various hypotheses by asking for more detailed information. You willalso explore the patient’s feelings and beliefs about his or her problem. Even-tually, as your clinical experience grows, you will respond with your under-standing of the patient’s concerns. Even if you discover that little can be donefor the patient’s disease, discussing the patient’s experience of being ill can betherapeutic. In the example that follows, a research protocol made the patientineligible for treatment of her long-standing and severe arthritis.
The patient had never talked about what the symptoms meant to her. She had
never said “This means that I can’t go to the bathroom by myself, put myclothes on, even get out of bed without calling for help.”
When we ﬁnished the physical examination, I said something like “Rheumatoid

arthritis really has not been nice to you.” She burst into tears, and so did herdaughter, and I sat there, very close to losing it myself.
She said “You know, no one has ever talked about it as a personal thing before.
No one’s ever talked to me as if this were a thing that mattered, a personal event.”
That was the signiﬁcant thing about the encounter. I didn’t really have much
else to offer . . . But something really signiﬁcant had happened between us,something that she valued and would carry away with her.
1
1Hastings C: The lived experiences of the illness: Making contact with the patient. In Benne P, Wrubel J.
The Primacy of Caring: Stress and Coping in Health and Illness. Menlo Park, CA, Addison-Wesley, 1989.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cAs you can see from this story, interviewing patients consists of much more
than just asking a series of questions.
You will ﬁnd that the interviewing process differs signiﬁcantly from the for-
mat for the health history presented in Chapter 1. Both are fundamental toyour work with patients, but each serves a different purpose. The health his-tory format is a structured framework for organizing patient information inwritten or verbal form: it focuses the clinician’s attention on speciﬁc pieces ofinformation that must be obtained from the patient. The interviewing processthat actually generates these pieces of information is more ﬂuid. It requiresknowledge of the information you need to obtain, the ability to elicit accu-rate and detailed information, and interpersonal skills that allow you to re-spond to the patient’s feelings.
As you learned in Chapter 1, the kinds of questions you ask as you elicit the

health history vary according to several factors. The scope and degree of detaildepend on the patient’s needs and concerns, the clinician’s goals for the en-counter, and the clinical setting (e.g., inpatient or outpatient, amount of timeavailable, primary care or subspecialty). For new patients, regardless of the set-ting, you will do a comprehensive health history, described for adults in Chap-
ter 1. For other patients who seek care for a speciﬁc complaint, such as a coughor painful urination, a more limited interview tailored to that speciﬁc problemmay be indicated, sometimes known as a problem-oriented history. In a primary

care setting, clinicians frequently choose to address issues of health promo-tion, such as tobacco cessation or reduction of high-risk sexual behaviors. Asubspecialist may do an in-depth history to evaluate one problem that incor-porates a wide range of areas of inquiry. Knowing the content and relevanceof all the components of a comprehensive health history, reviewed for youbelow, enables you to select the kinds of information that will be most help-ful for meeting both clinician and patient goals.
22 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGTHE FORMAT OF THE COMPREHENSIVE HEALTH HISTORY
Identifying Data
Source and Reliability of HistoryChief ComplaintHistory of Present Illness
Medications, Allergies, Tobacco, Alcohol and Drugs
Childhood IllnessAdult Illness: Medical, Surgical, Ob/Gyn, Psychiatric, Health Maintenance
Family HistoryPersonal and Social HistoryReview of Systems
This chapter introduces you to the essential skills of interviewing for gather-

ing the health history—skills that you will continually use and reﬁne through-out your career. You will learn the guiding principles for how clinicians talk

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cwith patients and forge trusting relationships with them. You will read about
preparing for the interview, the sequence of the interviewing process, impor-tant interviewing techniques, and strategies for addressing a variety of chal-lenges that frequently arise in encounters with patients.
Getting Ready: The Approach to the Interview
Interviewing patients to obtain a health history requires planning. You are un-doubtedly eager to begin your relationship with the patient, but you shouldﬁrst consider several points that are crucial to success.
Taking Time for Self-Reﬂection. As clinicians, we encounter a wide

variety of people, each one of whom is unique. Establishing relationshipswith individuals from a broad spectrum of ages, social classes, races, ethnic-ities, and states of health or illness is an uncommon opportunity and privi-lege. Being consistently open and respectful toward individual differences isone of the clinician’s challenges. Because we bring our own values, assump-tions, and biases to every encounter, we must look inward to clarify how ourown expectations and reactions may affect what we hear and how we behave.Self-reﬂection is a continual part of professional development in clinical work.It brings a deepening personal awareness to our work with patients and is oneof the most rewarding aspects of providing patient care.
Reviewing the Chart. Before seeing the patient, review his or her med-

ical record, or chart. The purpose of reviewing the chart is partly to gather in-formation and partly to develop ideas about what to explore with the patient.Look closely at the identifying data (age, gender, address, health insurance),the problem list, the medication list, and other details, such as the documen-tation of allergies. The chart often provides valuable information about pastdiagnoses and treatments; however, you should not let the chart prevent youfrom developing new approaches or ideas. Remember that information in thechart comes from different observers, and that standardized forms reﬂect dif-ferent institutional norms. Moreover, the chart often fails to capture theessence of the person you are about to meet. Data may be incomplete or evendisagree with what you learn from the patient—understanding such discrep-ancies may prove helpful to the patient’s care.

Setting Goals for the Interview. Before you begin talking with a pa-
tient, it is important to clarify your goals for the interview. As a student, yourgoal may be to obtain a complete health history so that you can submit a write-up to your teacher. As a clinician, your goals can range from completingforms needed by the health care facility or insurance companies to testinghypotheses generated by your review of the chart. A clinician must balancethese provider-centered goals with patient-centered goals. There can be ten-sion between the needs of the provider, the institution, and the patient andfamily. Part of the clinician’s task is to consider these multiple agendas. Bytaking a few minutes to think through your goals ahead of time, you will ﬁndit easier to strike a healthy balance among the various purposes of the inter-view to come.
GETTING REASY: THE APPROACH TO THE INTERVIEW
CHAPTER 2 IINTERVIEWING AND THE HEALTH HISTORY 23

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cReviewing Clinician Behavior and Appearance. Just as you observe
the patient throughout the interview, the patient will be watching you.
Consciously or not, you send messages through both your words and yourbehavior. Be sensitive to those messages and manage them as well as you can.
Posture, gestures, eye contact, and tone of voice can all express interest, at-tention, acceptance, and understanding. The skilled interviewer seems calmand unhurried, even when time is limited. Reactions that betray disapproval,embarrassment, impatience, or boredom block communication, as do behav-iors that condescend, stereotype, criticize, or belittle the patient. Althoughthese types of negative feelings are unavoidable at times, you must take painsnot to express them. Guard against them not only when talking to patientsbut also when discussing patients with your colleagues.

Your personal appearance can also affect your clinical relationships. Patients
ﬁnd cleanliness, neatness, conservative dress, and a name tag reassuring. Tryto consider the patient’s perspective. Remember that you want the patientto trust you.
Improving the Environment. Try to make the setting as private and
comfortable as possible. Although you may have to talk with the patientunder difficult circumstances, such as a two-bed room or the corridor of abusy emergency department, a proper environment improves communica-tion. If there are privacy curtains, ask permission to pull them shut. Suggestmoving to an empty room rather than having a conversation in a waiting area.As the clinician, part of your job is to make adjustments to the location and seat-ing that make the patient and you more comfortable. Doing so is always worth
the time.
Taking Notes. As a novice you will need to write down much of what you

the time.
learn during the interview. Even though experienced clinicians seem to re-member a great deal of the interview without taking notes, no one can re-member all the details of a comprehensive history. Jot down short phrases,speciﬁc dates, or words rather than trying to put them into a ﬁnal format. Donot, however, let note-taking or using written forms distract you from the pa-tient. Maintain good eye contact, and whenever the patient is talking aboutsensitive or disturbing material, put down your pen. Most patients are accus-tomed to note-taking, but for those who ﬁnd it uncomfortable, explore theirconcerns and explain your need to create an accurate record.
Learning About the Patient: 
The Process of Interviewing

Once you have devoted time and thought to preparing for the interview, youare fully ready to listen to the patient, elicit the patient’s concerns, and learnabout the patient’s health. In general, an interview moves through severalstages. Throughout this sequence, you, as the clinician, must always be attuned
to the patient’s feelings, help the patient express them, respond to their content,and validate their signiﬁcance. A typical sequence follows.
LEARNING ABOUT THE PATIENT: THE PROCESS OF INTERVIEWING
24 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cAs a student, you will concentrate primarily on gathering the patient’s story
and creating a shared understanding of the problem. As you become a prac-ticing clinician, negotiating a plan for further evaluation and treatment willbecome more important. Whether the interview is comprehensive or focused,you should move through this sequence while closely attending to the pa-tient’s feelings and affect.
Greeting the Patient and Establishing Rapport. The initial mo-
ments of your encounter with the patient lay the foundation for your on-going relationship. How you greet the patient and other visitors in the room,provide for the patient’s comfort, and arrange the physical setting all shapethe patient’s ﬁrst impressions.
As you begin, greet the patient by name and introduce yourself, giving your

own name. If possible, shake hands with the patient. If this is the ﬁrst contact,explain your role, including your status as a student and how you will be in-volved in the patient’s care. Repeat this part of the introduction on subsequentmeetings until you are conﬁdent that the patient knows who you are. “Goodmorning, Mr. Peters. I’m Susan Jones, a 3rd-year medical student. You mayremember me. I was here yesterday talking with you about your heart prob-lems. I’m part of the medical team that’s taking care of you.”
Using a title to address the patient (e.g., Mr. O’Neil, Ms. Washington) is al-

ways best. Except with children or adolescents, avoid ﬁrst names unless youhave speciﬁc permission from the patient or family. Addressing an unfamiliaradult as “granny” or “dear” tends to depersonalize and demean. If you are un-sure how to pronounce the patient’s name, don’t be afraid to ask. You can say“I’m afraid of mispronouncing your name. Could you say it for me?” Thenrepeat it to make sure that you heard it correctly.
When visitors are in the room, be sure to acknowledge and greet each one in
turn, inquiring about each person’s name and relationship to the patient.Whenever visitors are present, it is important for you to maintain conﬁden-
tiality. Let the patient decide if visitors or family members should remain in

the room, and ask for the patient’s permission before conducting the inter-view in front of them. For example, “I’m comfortable with having your sisterstay for the interview, Mrs. Jones, but I want to make sure that this is also whatLEARNING ABOUT THE PATIENT: THE PROCESS OF INTERVIEWING
CHAPTER 2 IINTERVIEWING AND THE HEALTH HISTORY 25THE SEQUENCE OF THE INTERVIEW
IGreeting the patient and establishing rapport
IInviting the patient’s story
IEstablishing the agenda for the interview
IExpanding and clarifying the patient’s story; generating and testing diagnostic
hypotheses
ICreating a shared understanding of the problem(s)
INegotiating a plan (includes further evaluation, treatment, and patient education)
IPlanning for follow-up and closing the interview.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cyou want” or “Would you prefer if I spoke to you alone or with your sister
present?”
It is important to be attuned to the patient’s comfort. In the ofﬁce or clinic, be
sure there is a suitable place other than the patient’s lap for coats and belong-ings. In the hospital, after greeting the patient, ask how the patient is feelingand if you are coming at a convenient time. Look for signs of discomfort, suchas frequent changes of position or facial expressions that show pain or anxiety.Arranging the bed to make the patient more comfortable or allowing a fewminutes for the patient to say goodbye to visitors or ﬁnish using the bedpanmay be the shortest route to a good history.
Consider the best way to arrange the room and how far you should be from

the patient. Remember that cultural background and individual taste inﬂuencepreferences about interpersonal space. Choose a distance that facilitates con-versation and good eye contact. You should probably be within several feet,close enough to be intimate but not intrusive. Pull up a chair and, if possible,try to sit at eye level with the patient. Move any physical barriers between youand the patient, such as desks or bedside tables, out of the way. In an outpa-tient setting, sitting on a rolling stool, for example, allows you to change dis-tances in response to patient cues. Avoid arrangements that connote disrespector inequality of power, such as interviewing a woman already positioned for apelvic examination. Such arrangements are unacceptable. Lighting also makesa difference. If you sit between a patient and a bright light or window, al-though your view might be ﬁne, the patient may have to squint uncomfort-ably to see you, making the interaction more like an interrogation than a

supportive in terview.
Give the patient your undivided attention. Try not to look down to take notes
or read the chart, and spend enough time on small talk to put the patientat ease.
Inviting the Patient’s Story. Now that you have established rapport,
you are ready to pursue the patient’s reason for seeking health care, or chief
complaint. Begin with open-ended questions that allow full freedom of re-
sponse. “What concerns bring you here today?” or “How can I help you?”Note that these questions encourage the patient to express any possible con-cerns and do not restrict the patient to a limited and minimally informative“yes” or “no” answer. Listen to the patient’s answers without interrupting.After you have given the patient the opportunity to respond fully, inquire againor even several times, “Anything else?” You may need to lead the patient backseveral times to additional concerns or issues he or she may want to tell youabout.

Some patients may want only a blood pressure check or routine examination,
without having a speciﬁc complaint or problem. Others may say they just wanta physical examination but feel uncomfortable bringing up an underlying con-cern. In all these situations, it is still important to start with the patient’s story.
Helpful open-ended questions are “Was there a speciﬁc health concern thatprompted you to schedule this appointment?” and “What made you decideto come in for health care now?”LEARNING ABOUT THE PATIENT: THE PROCESS OF INTERVIEWING
26 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cIt is important to train yourself to follow the patient’s leads. Good interviewing
techniques include using verbal and nonverbal cues that prompt patients torecount their stories spontaneously. If you intervene too early and ask speciﬁcquestions prematurely, you risk trampling on the very information you areseeking. Your role, however, is far from passive. You should listen actively andmake use of continuers, especially at the outset. Examples include nodding
your head and using phrases such as “uh huh,” “go on,” and “I see.” Addi-tional facilitative techniques (p. ___) help keep you from missing any of thepatient’s concerns.
Establishing the Agenda for the Interview. The clinician often ap-

proaches the interview with speciﬁc goals in mind. The patient also has spe-ciﬁc questions and concerns. It is important to identify all these issues at thebeginning of the encounter. Doing so allows you to use the time available ef-fectively and to make sure that you address all the patient’s issues. As a student,
you may have enough time to cover the breadth of both your concerns andthe patient’s in one visit. For a clinician, however, time management is almostalways an issue. As a clinician, you may need to focus the interview by askingthe patient which problem is most pressing. For example, “You have told meabout several different problems that are important for us to discuss. I alsowanted to review your blood pressure medication. We need to decide whichproblems to address today. Can you tell me which one you are most concerned

about?” Then you can proceed with questions such as, “Tell me about thatproblem.” Once you have agreed upon a manageable list, stating that the otherproblems are also important and will be addressed during a future visit givesthe patient conﬁdence in your ongoing collaboration.
Expanding and Clarifying the Health History (the Patient’s
Perspective). You can then guide the patient into elaborating areas of the
health history that seem most signiﬁcant. For the clinician, each symptom hasattributes that must be clariﬁed, including context, associations, and chronol-ogy, especially for complaints of pain. For all symptoms, it is critical to fullyunderstand their essential characteristics. Always pursue the following elements.LEARNING ABOUT THE PATIENT: THE PROCESS OF INTERVIEWING
CHAPTER 2 IINTERVIEWING AND THE HEALTH HISTORY 27THE SEVEN ATTRIBUTES OF A SYMPTOM
1.Location. Where is it? Does it radiate?
2.Quality. What is it like?

3.Quantity or severity. How bad is it? (For pain, ask for a rating on a scale of 
1 to 10.)
4.Timing. When did (does) it start? How long did (does) it last? How often did
(does) it come?
5.Setting in which it occurs. Include environmental factors, personal activities,
emotional reactions, or other circumstances that may have contributed to theillness.
6.Remitting or exacerbating factors. Does anything make it better or worse?
7.Associated manifestations. Have you noticed anything else that 
accompanies it?
As you explore these attributes, be sure that you use language that is under-
standable and appropriate to the patient. Although you might ask a trained

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5chealth professional about “dyspnea,” the customary term to use for patients is
“shortness of breath.” It is easy to slip into using medical language with pa-tients, but beware. Technical language confuses the patient and often blockscommunication. Appropriate questions about symptoms are suggested in eachof the chapters on the regional physical examinations. Whenever possible,however, use the patient’s words, making sure you clarify their meaning.
To ﬁll in speciﬁc details, learn to facilitate the patient’s story by using differ-
ent types of questions and the techniques of skilled interviewing described onpp. ___–___. Often you will need to use directed questions (see p. ___) that ask
for speciﬁc information the patient has not already offered. In general, an in-
terview moves back and forth from an open-ended question to a directed questionand then on to another open-ended question.

Establishing the sequence and time course of the patient’s symptoms is im-
portant. You can encourage a chronologic account by asking such questionsas “What then?” or “What happened next?”
Generating and Testing Diagnostic Hypotheses (the Clinician’s
Perspective). As you listen to the patient’s concerns, you will begin to
generate and test diagnostic hypotheses about what disease process might be
the cause. Identifying the various attributes of the patient’s symptoms andpursuing speciﬁc details are fundamental to recognizing patterns of diseaseand differentiating one disease from another. As you learn more about diag-nostic patterns, listening for and asking about these attributes will becomemore automatic. For additional data that will contribute to your analysis, useitems from relevant sections of the Review of Systems . In these ways you build

evidence for and against the various diagnostic possibilities. This kind of clin-ical thinking is illustrated by the tables on symptoms found in the regionalexamination chapters and further discussed in Chapter 18, Clinical Reason-ing, Assessment, and Plan.
Creating a Shared Understanding of the Problem. Recent litera-
ture makes clear that delivering effective health care requires exploring thedeeper meanings patients attach to their symptoms. While the “seven attri-butes of a symptom” add important details to the patient’s history, the dis-
ease/illness distinction model helps you understand the full range of what every
good interview needs to cover. This model acknowledges the dual but verydifferent perspectives of the clinician and the patient. Disease is the explana-
tion that the clinician brings to the symptoms. It is the way that the clinician

organizes what he or she learns from the patient into a coherent picture thatleads to a clinical diagnosis and treatment plan. Illness can be deﬁned as how
the patient experiences symptoms. Many factors may shape this experience,
including prior personal or family health, the effect of symptoms on everydaylife, individual outlook and style of coping, and expectations about medicalcare. The health history interview needs to take into account both of these views of
reality.
Even a chief complaint as straightforward as sore throat can illustrate these di-
vergent views. The patient may be most concerned about pain and difﬁcultyswallowing, a cousin who was hospitalized with tonsillitis, or missing timeLEARNING ABOUT THE PATIENT: THE PROCESS OF INTERVIEWING
28 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cfrom work. The clinician, however, may focus on speciﬁc points in the history
that differentiate streptococcal pharyngitis from other etiologies or on a ques-tionable history of allergy to penicillin. To understand the patient’s expecta-tions, the clinician needs to go beyond just the attributes of a symptom. Learn-ing about the patient’s perception of illness means asking patient-centeredquestions in the six domains listed below. Doing so is crucial to patient satis-faction, effective health care, and patient follow-through.LEARNING ABOUT THE PATIENT: THE PROCESS OF INTERVIEWING
CHAPTER 2 IINTERVIEWING AND THE HEALTH HISTORY 29EXPLORING THE PATIENT’S PERSPECTIVE
IThe patient’s thoughts about the nature and the cause of the problem
IThe patient’s feelings, especially fears, about the problem
IThe patient’s expectations of the clinician and health care
IThe effect of the problem on the patient’s life

IPrior personal or family experiences that are similar
ITherapeutic responses the patient has already tried
The clinician should ask about the cause of the problem by saying, for exam-
ple, “Why do you think you have this stomachache?” To uncover the patient’sfeelings, you might ask, “What concerns you most about the pain?” A patientmay worry that the pain is a symptom of serious disease and want reassurance.Alternatively, the patient may be less concerned about the cause of the painand just want relief. You need to ﬁnd out what the patient expects from you,the clinician, or from health care in general . . . “I’m glad that the pain is al-most gone. How speciﬁcally can I help you now?” Even if the stomach pain isalmost gone, the patient may need a work excuse to take to an employer.

It may be helpful to ask the patient about previous experiences, what he or
she has tried so far, and any related changes in daily activities.
Clinician: “Has anything like this happened to you or your family before?”
Patient: “I was worried that I might have appendicitis. My Uncle Charlie died
from a ruptured appendix.”
Explore what the patient has done so far to take care of the problem. Most pa-
tients will have tried over-the-counter medications, traditional remedies, oradvice from friends or family. Ask how the illness has affected the patient’slifestyle and level of activity. This question is especially important for a patientswith chronic illness. “What can’t you do now that you could do before?”“How has your backache (shortness of breath, etc.) affected your ability towork?” . . . “Your life at home?” . . . “Your social activities?” . . . “Your role asa parent?” . . . “Your role as a husband or wife?” . . . “The way you feel aboutyourself as a person?”

Negotiating a Plan. Learning about the disease and conceptualizing the
illness give you and the patient the opportunity to create a complete pictureof the problem. This multifaceted picture then forms the basis for planningfurther evaluation (physical examination, laboratory tests, consultations, etc.)

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cand negotiating a treatment plan. More speciﬁc techniques for negotiating a
plan can be found in Chapter 18. Advanced skills, such as steps for motivat-ing change and the therapeutic use of the clinician–patient relationship, arebeyond the scope of this book.
Planning for Follow-Up and Closing. You may ﬁnd that ending the

interview is difﬁcult. Patients often have many questions and, if you have doneyour job well, they are enjoying talking with you. Giving notice that the endof the interview is approaching allows time for the patient to ask any ﬁnal ques-tions. Make sure the patient understands the agreed-upon plans you have de-veloped. For example, before gathering your papers or standing to leave theroom, you can say “We need to stop now. Do you have any questions aboutwhat we’ve covered?” As you close, reviewing future evaluation, treatments,and follow-up is helpful. “So, you will take the medicine as we discussed, getthe blood test before you leave today, and make a follow-up appointment for4 weeks. Do you have any questions about this?” Address any related concernsor questions that the patient brings up.
The patient should have a chance to ask any ﬁnal questions; however, the

last few minutes are not the time to bring up new topics. If that happens(and the concern is not life-threatening), simply reassure the patient of yourinterest and make plans to address the problem at a future time. “That kneepain sounds concerning. Why don’t you make an appointment for next weekso we can discuss it?” Reafﬁrming that you will continue working to improvethe patient’s health is always appreciated.
Facilitating the Patient’s Story: 
The Techniques of Skilled Interviewing
Skilled interviewing requires the use of speciﬁc learnable techniques. You needto practice these techniques and ﬁnd ways to be observed or recorded so thatyou can receive feedback on your progress. Several of these fundamental skillsare listed in the following box and described in more detail throughout thissection.
FACILITATING THE PATIENT’S STORY: THE TECHNIQUES OF SKILLED INTERVIEWING

30 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGTHE TECHNIQUES OF SKILLED INTERVIEWING
IActive listening
IAdaptive questioning
INonverbal communication
IFacilitation
IEchoing
IEmpathic responses
IValidation
IReassurance
ISummarization
IHighlighting transitions

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cActive Listening. Underlying all these speciﬁc techniques is the practice
of active listening. Active listening is the process of fully attending to what thepatient is communicating, being aware of the patient’s emotional state, andusing verbal and nonverbal skills to encourage the speaker to continue and ex-pand. Active listening takes practice. It is easy to drift into thinking about yournext question or the differential diagnosis; however, you and the patient arebest served by your concentration on listening.
Adaptive Questioning. There are several ways you can ask questions that
add detail to the patient’s story yet facilitate the ﬂow of the interview. Learnto adapt your questioning to the patient’s verbal and nonverbal cues.FACILITATING THE PATIENT’S STORY: THE TECHNIQUES OF SKILLED INTERVIEWING
CHAPTER 2 IINTERVIEWING AND THE HEALTH HISTORY 31ADAPTIVE QUESTIONING: 
OPTIONS FOR CLARIFYING THE PATIENT’S STORY

IDirected questioning—from general to speciﬁc
IQuestioning to elicit a graded response
IAsking a series of questions, one at a time
IOffering multiple choices for answers
IClarifying what the patient means
Directed questioning is useful for drawing the patient’s attention to speciﬁc
areas of the history. It should follow several principles to be effective. Directed
questioning should proceed from the general to the speciﬁc. A possible sequence,
for example, might be “Tell me about your chest pain?” (Pause) “What else?”(Pause) “Where did you feel it?” (Pause) “Show me. Anywhere else?” (Pause)“Did it travel anywhere?” (Pause) “To which arm?” Directed questions should
not be leading questions that call for a “yes” or “no” answer. If a patient says

yes to “Did your stools look like tar?” you run the risk of turning your wordsinto the patient’s words. A better phrasing is “Please describe your stools.”
If necessary, ask questions that require a graded response rather than a single
answer. “What physical activity do you do that makes you short of breath?” isbetter than “How many steps can you climb before you get short of breath?”which is better than “Do you get short of breath climbing stairs?” Be sure toask one question at a time. “Any tuberculosis, pleurisy, asthma, bronchitis,
pneumonia?” may lead to a negative answer out of sheer confusion. Try “Doyou have any of the following problems?” Be sure to pause and establish eyecontact as you list each problem.
Sometimes patients seem quite unable to describe their symptoms without
help. To minimize bias, offer multiple-choice answers. “Is your pain aching,

sharp, pressing, burning, shooting, or what?” Almost any direct question canprovide at least two possible answers. “Do you bring up any phlegm with yourcough, or is it dry?”
At times patients use words that are ambiguous or have unclear associations.
To understand their meaning, you need to request clariﬁcation, as in “Tell me
exactly what you meant by ‘the ﬂu’” or “You said you were behaving just likeyour mother. What did you mean?”

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cNonverbal Communication. Communication that does not involve
speech occurs continuously and provides important clues to feelings and emo-tions. Becoming more sensitive to nonverbal messages allows you to both “readthe patient” more effectively and to send messages of your own. Pay close at-tention to eye contact, facial expression, posture, head position and movementsuch as shaking or nodding, interpersonal distance, and placement of the armsor legs, such as crossed, neutral, or open. Matching your position to the pa-tient’s can be a sign of increasing rapport. Moving closer or engaging in phys-ical contact (like placing your hand on the patient’s arm) can convey empathyor help the patient gain control of feelings. Bringing nonverbal communica-tion to the conscious level is the ﬁrst step to using this crucial form of patientinteraction. You also can mirror the patient’s paralanguage, or qualities of

speech such as pacing, tone, and volume, to increase rapport.
Facilitation. You use facilitation when, by posture, actions, or words, you
encourage the patient to say more but do not specify the topic. Pausing witha nod of the head or remaining silent, yet attentive and relaxed, is a cue for thepatient to continue. Leaning forward, making eye contact, and using contin-uers like “Mm-hmm,” “Go on,” or “I’m listening” all maintain the ﬂow ofthe patient’s story.
Echoing. Simple repetition of the patient’s words encourages the patient
to express both factual details and feelings, as in the following example:
Patient: The pain got worse and began to spread. (Pause)
Response: Spread? (Pause)Patient: Yes, it went to my shoulder and down my left arm to the ﬁngers. It was
so bad that I thought I was going to die. (Pause)
Response: Going to die?Patient: Yes, it was just like the pain my father had when he had his heart attack,
and I was afraid the same thing was happening to me.

This reﬂective technique has helped to reveal not only the location and
severity of the pain but also its meaning to the patient. It did not bias thestory or interrupt the patient’s train of thought.
Empathic Responses. Conveying empathy is part of establishing and
strengthening rapport with patients. As patients talk with you, they mayexpress—with or without words—feelings they have not consciously acknowl-edged. These feelings are crucial to understanding their illnesses and to estab-
lishing a trusting relationship. To empathize with your patient you must ﬁrst
identify his or her feelings. When you sense important but unexpressed feel-

ings from the patient’s face, voice, words, or behavior, inquire about themrather than assume how the patient feels. You may simply ask “How did youfeel about that?” Unless you let patients know that you are interested in feel-ings as well as in facts, you may miss important insights.FACILITATING THE PATIENT’S STORY: THE TECHNIQUES OF SKILLED INTERVIEWING
32 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cOnce you have identiﬁed the feelings, respond with understanding and ac-
ceptance. Responses may be as simple as “I understand,” “That sounds up-setting,” or “You seem sad.” Empathy may also be nonverbal—for example,offering a tissue to a crying patient or gently placing your hand on the pa-tient’s arm to show understanding. When you give an empathic response, besure that you are responding correctly to what the patient is feeling. If yourresponse acknowledges how upset a patient must have been at the death of aparent, when, in fact, the death relieved the patient of a long-standing ﬁnan-cial and emotional burden, you have misunderstood the situation.
Validation. Another important way to make a patient feel accepted is to

legitimize or validate his or her emotional experience. A patient who has beenin a car accident but has no signiﬁcant physical injury may still be experienc-ing distress. Stating something like “Being in that accident must have beenvery scary. Car accidents are always unsettling because they remind us of ourvulnerability and mortality. That could explain why you still feel upset” reas-sures the patient. It helps the patient feel that such emotions are legitimateand understandable.
Reassurance. When you are talking with patients who are anxious or upset,
it is tempting to reassure them. You may ﬁnd yourself saying “Don’t worry.Everything is going to be all right.” While this may be appropriate in non-professional relationships, in your role as a clinician such comments are usuallycounterproductive. You may fall into reassuring the patient about the wrong

thing. Moreover, premature reassurance may block further disclosures, espe-cially if the patient feels that exposing anxiety is a weakness. Such admissionsrequire encouragement, not a cover-up. The ﬁrst step to effective reassurance is
identifying and accepting the patient’s feelings without offering reassurance atthat moment. Doing so promotes a feeling of security. The actual reassurance
comes much later after you have completed the interview, the physical exam-ination, and perhaps some laboratory studies. At that point, you can interpretfor the patient what you think is happening and deal openly with the realconcerns.
Summarization. Giving a capsule summary of the patient’s story in the

course of the interview can serve several different functions. It indicates to thepatient that you have been listening carefully. It can also identify what youknow and what you don’t know. “Now, let me make sure that I have the fullstory. You said you’ve had a cough for 3 days, it’s especially bad at night, andyou have started to bring up yellow phlegm. You have not had a fever or feltshort of breath, but you do feel congested, with difﬁculty breathing throughyour nose.” Following with an attentive pause or “Anything else?” lets the pa-tient add other information and conﬁrms that you have heard the story cor-rectly. You can use summarization at different points in the interview to struc-ture the visit, especially at times of transition (see below). This technique alsoallows you, the clinician, to organize your clinical reasoning and to conveyyour thinking to the patient, which makes the relationship more collaborative.

Highlighting Transitions. Patients have many reasons to feel worried
and vulnerable. To put them more at ease, tell them when you are changingFACILITATING THE PATIENT’S STORY: THE TECHNIQUES OF SKILLED INTERVIEWING
CHAPTER 2 IINTERVIEWING AND THE HEALTH HISTORY 33

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cdirections during the interview. This gives patients a greater sense of control.
As you move from one part of the history to another and on to the physicalexamination, orient the patient with brief transitional phrases like “Now I’dlike to ask some questions about your past health.” Make clear what the patientshould expect or do next . . . “Now I’d like to examine you. I’ll step out for afew minutes. Please get completely undressed and put on this gown.” Speci-fying that the gown should open in the back may earn the patient’s gratitudeand save you some time.
Adapting Interviewing Techniques 
to Speciﬁc Situations
Interviewing patients may precipitate several behaviors and situations thatseem particularly vexing or perplexing. Your skill at handling these situationswill evolve throughout your career. Always remember the importance of listen-
ing to the patient and clarifying the patient’s agenda.

The Silent Patient. Novice interviewers may be uncomfortable with pe-

riods of silence and feel obligated to keep the conversation going. Silence hasmany meanings and many purposes. Patients frequently fall silent for short pe-riods to collect thoughts, remember details, or decide whether they can trustyou with certain information. The period of silence usually feels much longerto the clinician than it does to the patient. The clinician should appear atten-tive and give brief encouragement to continue when appropriate (see facilita-tive techniques on pp ___–___ and pp. ___–___). During periods of silence,watch the patient closely for nonverbal cues, such as difﬁculty controllingemotions. Alternatively, patients with depression or dementia may lose theirusual spontaneity of expression, give short answers to questions, then quicklybecome silent afterwards. You may need to shift your inquiry to the symptomsof depression or begin an exploratory mental status examination (see Chapter16, The Nervous System, pp. ___–___).

At times, silence may be the patient’s response to how you are asking ques-
tions. Are you asking too many direct questions in rapid sequence? Have youoffended the patient in any way, for example, by signs of disapproval or criti-cism? Have you failed to recognize an overwhelming symptom such as pain,nausea, or dyspnea? If so, you may need to ask the patient directly, “You seemvery quiet. Have I done something to upset you?”
Finally, some patients are naturally laconic. Be accepting and try asking the pa-
tient for suggestions about other sources to help you gather more informa-tion. With the patient’s permission, talking with family members or friendsmay be worthwhile.
The Talkative Patient. The garrulous, rambling patient may be just as

difﬁcult. Faced with limited time and the need to “get the whole story,” youmay grow impatient, even exasperated. Although this problem has no perfectsolutions, several techniques are helpful. Give the patient free rein for the ﬁrst5 or 10 minutes and listen closely to the conversation. Perhaps the patient sim-
ADAPTING INTERVIEWING TECHNIQUES TO SPECIFIC SITUATIONS
34 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cply has lacked a good listener and is expressing pent-up concerns. Maybe the
patient’s style is to tell stories. Does the patient seem obsessively detailed orunduly anxious? Is there a ﬂight of ideas or disorganized thought process thatsuggests a psychosis or confabulation?
Try to focus on what seems most important to the patient. Show your inter-

est by asking questions in those areas. Interrupt if you must, but courteously.Remember that part of your task is to structure the interview. It is acceptableto be directive and set limits when necessary. A brief summary may help youchange the subject yet validate any concerns (see p. ___). “Let me make surethat I understand. You’ve described many concerns. In particular, I heardabout two different kinds of pain, one on your left side that goes into yourgroin and is fairly new, and one in your upper abdomen after you eat thatyou’ve had for months. Let’s focus just on the side pain ﬁrst. Can you tell mewhat it feels like?” Finally, do not show your impatience. If there is no moretime, explain the need for a second meeting. Setting a time limit for the nextappointment may be helpful. “I know we have much more to talk about. Canyou come again next week? We’ll have a full hour then.”

The Anxious Patient. Anxiety is a frequent and normal reaction to sick-
ness, treatment, and the health care system itself. For some patients, anxiety isa ﬁlter for all their perceptions and reactions; for others it may be part of theirillness. Again, watch for nonverbal and verbal cues. Anxious patients may sittensely, ﬁdgeting with their ﬁngers or clothes. They may sigh frequently, lickdry lips, sweat more than average, or actually tremble. Carotid pulsations maybetray a rapid heart rate. Some anxious patients fall silent, unable to speakfreely or conﬁde. Others try to cover their feelings with words, busily avoid-ing their own basic problems. When you detect anxiety, reﬂect your impres-sion back to the patient and encourage him or her to talk about any underly-ing concerns. Be careful not to transmit your own anxieties about completingthe interview to the patient!
The Crying Patient. Crying signals strong emotions, ranging from sad-

ness to anger or frustration. If the patient is on the verge of tears, pausing,gentle probing, or responding with empathy allows the patient to cry. Usuallycrying is therapeutic, as is your quiet acceptance of the patient’s distress or pain.Offer a tissue and wait for the patient to recover. Make a facilitating or sup-portive remark like “I’m glad that you got that out.” Most patients will sooncompose themselves and resume their story. Aside from cases of acute griefor loss, it is unusual for crying to escalate and become uncontrollable.
Crying makes many people uncomfortable. If this is true for you, as a clini-
cian, you will need to work through your feelings so that you can support pa-tients at these signiﬁcant times.
The Confusing Patient. Some patients are confusing because they
have multiple symptoms. They seem to have every symptom that you ask

about, or “a positive review of systems.” Although they may have multiplemedical illnesses, a somatization disorder is more likely. With these patients,focus on the meaning or function of the symptom and guide the interviewADAPTING INTERVIEWING TECHNIQUES TO SPECIFIC SITUATIONS
CHAPTER 2 IINTERVIEWING AND THE HEALTH HISTORY 35

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cinto a psychosocial assessment. There is little proﬁt to exploring each symp-
tom in detail.
At other times you may be bafﬂed, frustrated, and confused yourself. The his-

tory is vague and difﬁcult to understand, ideas are poorly related to one an-other, and language is hard to follow. Even though you word your questionscarefully, you cannot seem to get clear answers. The patient’s manner of re-lating to you may also seem peculiar, distant, aloof, or inappropriate. Patientsmay describe symptoms in bizarre terms: “My ﬁngernails feel too heavy” or“My stomach knots up like a snake.” Using various facilitative techniques, tryto learn more about the unusual qualities of the symptoms. Perhaps there is amental status change such as psychosis or delirium, a mental illness such asschizophrenia, or a neurologic disorder (see Chapter 16, The Nervous Sys-tem). Watch for delirium in acutely ill or intoxicated patients and for demen-tia in the elderly. Such patients give histories that are inconsistent and cannotprovide a clear chronology about what has happened. Some may even con-fabulate to ﬁll in the gaps in their memories.

When you suspect a psychiatric or neurologic disorder, do not spend too
much time trying to get a detailed history. You will only tire and frustrate boththe patient and yourself. Shift to the mental status examination, focusing onlevel of consciousness, orientation, and memory. You can work in the initialquestions smoothly by asking “When was your last appointment at the clinic?Let’s see . . . that was about how long ago?” “Your address now is . . . ? . . . andyour phone number?” You can check these responses against the chart, as-suming that the chart is accurate, or by getting permission to speak with fam-ily members or friends and then doing so.
The Angry or Disruptive Patient. Many patients have reasons to be

angry: they are ill, they have suffered a loss, they lack their accustomed con-trol over their own lives, and they feel relatively powerless in the health caresystem. They may direct this anger toward you. It is possible that hostility to-ward you is justiﬁed . . . were you late for your appointment, inconsiderate,insensitive, or angry yourself? If so, acknowledge the fact and try to makeamends. More often, however, patients displace their anger onto the clinicianas a reﬂection of their pain.
Accept angry feelings from patients and allow them to express such emotions

without getting angry in return. Beware of joining such patients in their hos-tility toward another provider, the clinic, or the hospital, even when you areprivately in sympathy. You can validate their feelings without agreeing withtheir reasons. “I understand that you felt very frustrated by the long wait andanswering the same questions over and over. The complex nature of ourhealth care system can seem very unsupportive when you’re not feeling well.”After the patient has calmed down, you can help ﬁnd steps that will avert suchsituations in the future. Rational solutions to emotional problems are not al-ways possible, however, and people need time to express and work throughtheir angry feelings.
Some angry patients become hostile and disruptive. Few people can disrupt

the clinic or emergency department more quickly than patients who are angry,belligerent, or uncontrolled. Before approaching such patients, alert theADAPTING INTERVIEWING TECHNIQUES TO SPECIFIC SITUATIONS
36 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5csecurity staff—as a clinician, you have the right to feel and be safe. It is espe-
cially important to stay calm, appear accepting, and avoid being challenging inreturn. Keep your posture relaxed and nonthreatening and your hands looselyopen. At ﬁrst, do not try to make disruptive patients lower their voices or stopif they are cursing you or the staff. Listen carefully and try to understand whatthey are saying. Once you have established rapport, gently suggest moving toa different location that is not upsetting to other patients or families.
The Patient With a Language Barrier. Nothing will convince you

more surely of the importance of the history than having to do without one.When your patient speaks a different language, make every possible effort toﬁnd an interpreter. A few broken words and gestures are no substitute forthe full story. The ideal interpreter is a neutral objective person who is fa-miliar with both languages and cultures. Beware of using family members orfriends as interpreters—conﬁdentiality may be violated, meanings may bedistorted, and transmitted information may be incomplete. Untrained in-terpreters may try to speed up the interview by telescoping lengthy repliesinto a few words, losing much of what may be signiﬁcant detail.
As you begin working with the interpreter, establish rapport and review what
information would be most useful. Explain that you need the interpreter totranslate everything, not to condense or summarize. Make your questions

clear, short, and simple. You can also help the interpreter by outlining your
goals for each segment of the history. After going over your plans with theinterpreter, arrange the room so that you have easy eye contact and non-verbal communication with the patient. Then speak directly to the patient,asking “How long have you been sick?” rather than “How long has the pa-tient been sick?” Having the interpreter close by keeps you from movingyour head back and forth as though you were watching a tennis match!
When available, bilingual written questionnaires are invaluable, especially for

the Review of Systems. First be sure patients can read in their language; oth-erwise, ask for help from the interpreter. Some clinical settings have speaker-phone translators; use them if there are no better options.ADAPTING INTERVIEWING TECHNIQUES TO SPECIFIC SITUATIONS
CHAPTER 2 IINTERVIEWING AND THE HEALTH HISTORY 37GUIDELINES FOR WORKING WITH AN INTERPRETER
IChoose a professional interpreter in preference to a hospital worker, volunteer,
or family member. Use the interpreter as a resource for cultural information.
IOrient the interpreter to the components you plan to cover in the interview; include reminders to translate everything the patient says.
IArrange the room so that you and the patient have eye contact and can readeach other’s nonverbal cues.
ISeat the interpreter next to you and allow the interpreter and the patient to establish rapport.

IAddress the patient directly. Reinforce your questions with nonverbal behaviors.
IKeep sentences short and simple. Focus on the most important concepts tocommunicate.
IVerify mutual understanding by asking the patient to repeat back what he or shehas heard.
IBe patient. The interview will take more time and may provide less information.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cThe Patient With Reading Problems. Before giving written instruc-
tions, it is wise to assess the patient’s ability to read. Literacy levels are highlyvariable, and marginal reading skills are more prevalent than commonly be-lieved. People cannot read for many reasons, including language barriers, learn-

ing disorders, poor vision, or lack of education. Some people may try to hidetheir inability to read. Asking about educational level may be helpful but canbe misleading. “I understand that this may be difﬁcult to discuss, but do youhave any trouble with reading?” Ask the patient to read whatever instructionsyou have written. Literacy skills may be the reason the patient has not followedthrough on taking medications or adhered to recommended treatments. Sim-ply handing the patient written material upside-down to see if the patient turnsit around may settle the question. Respond sensitively, and remember that il-literacy and lack of intelligence are not synonymous.
The Patient With Impaired Hearing. Communicating with the deaf

presents many of the same challenges as communicating with patients whospeak a different language. Even individuals with partial hearing may deﬁnethemselves as Deaf, a distinct cultural group. Find out the patient’s preferredmethod of communicating. Patients may use American Sign Language, whichis a unique language with its own syntax, or various other communicationforms combining signs and speech. Thus, communication is often truly cross-cultural. Ask when hearing loss occurred relative to the development of speechand other language skills and the kinds of schools that the patient has at-tended. These questions help you determine whether the patient identiﬁeswith the Deaf or the Hearing culture. If the patient prefers sign language,make every effort to ﬁnd an interpreter and use the principles identiﬁed above.Although very time-consuming, handwritten questions and answers may bethe only solution, though literacy skills may also be an issue.

When patients have partial hearing impairment or can read lips, face them di-
rectly, in good light. Speak at a normal volume and rate, and do not let yourvoice trail off at the ends of sentences. Avoid covering your mouth or lookingdown at papers while speaking. Remember that even the best lip readers com-prehend only a percentage of what is said, so having patients repeat what youhave said is important.
Hearing deﬁcits vary. If the patient has a unilateral hearing loss, sit on the hear-
ing side. If the patient has a hearing aid, ﬁnd out if he or she is using it. Makesure it is working. Eliminate background noise such as television or hallwayconversation as much as possible. Patients who wear glasses should use themso that they can pick up visual cues that will help them understand you better.Written questionnaires are also useful. When closing, supplement any oral in-structions with written ones. A person who is hard of hearing may or may not

be aware of the problem, a situation you will have to tactfully address.
The Patient With Impaired Vision. When meeting with a blind pa-
tient, shake hands to establish contact and explain who you are and why youare there. If the room is unfamiliar, orient the patient to the surroundingsand report if anyone else is present. Remember to use words wheneveryou respond to such patients, because postures and gestures are unseen.ADAPTING INTERVIEWING TECHNIQUES TO SPECIFIC SITUATIONS
38 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cEncourage visually impaired patients to wear glasses, if available, to ease
The Patient With Limited Intelligence. Patients of moderately limited

intelligence can usually give adequate histories. In fact, you may even over-look their limitations and omit their dysfunction from disability evaluations orgive them instructions they cannot understand. If you suspect such problems,pay special attention to the patient’s schooling and ability to function inde-pendently. How far have such patients gone in school? If they didn’t ﬁnish,why not? What kinds of courses are (were) they taking? How did they do?Have they had any testing done? Are they living alone? Do they get help withany activities, for example, transportation or shopping? The sexual history isequally important and often overlooked. Find out if the patient is sexually ac-tive and provide any information needed about pregnancy or sexually trans-mitted diseases. If you are unsure about the patient’s level of intelligence, youcan make a smooth transition to the mental status examination and assess sim-ple calculations, vocabulary, memory, and abstract thinking (see Chapter 16).

For patients with severe mental retardation, you will have to obtain the his-
tory from the family or caregivers. Identify the person who accompaniesthem, but always show interest ﬁrst in the patient. Establish rapport, makeeye contact, and engage in simple conversation. As with children, avoid “talk-ing down” or using affectations of speech or condescending behavior. Thepatient, family members, caretakers, or friends will notice and appreciate yourrespect.
The Poor Historian. Some patients are totally unable to give their own

histories because of age, dementia, or other limitations. Others may be unableto relate certain parts of the history, such as events during a seizure. Underthese circumstances, you must try to ﬁnd a third person who can give you thestory. Even when you have a reasonably comprehensive knowledge of the pa-tient, other sources may offer surprising and important information. A spouse,for example, may report significant family strains, depressive symptoms, ordrinking habits that the patient has denied.
For patients who are mentally competent, you must obtain their consent be-

fore you talk about their health with others. Assure patients that any infor-mation he or she has already told you is conﬁdential, and clarify what can beshared. Even if patients can communicate only by facial expressions or ges-tures, you must maintain conﬁdentiality and elicit their input. It is usuallypossible to divide the interview into two parts—one with the patient aloneand the other with both the patient and the second person. Each part has itsown value. Remember that data from others are also conﬁdential.
The basic principles of interviewing apply to your conversations with relatives

or friends. Find a private place to talk. Introduce yourself, state your purpose,inquire how they are feeling under the circumstances, and recognize and ac-knowledge their concerns. As you listen to their versions of the history, be alertto the quality of their relationship with the patient. It may color their credi-bility or give you helpful ideas for planning the patient’s care. It is also im-ADAPTING INTERVIEWING TECHNIQUES TO SPECIFIC SITUATIONS
CHAPTER 2 IINTERVIEWING AND THE HEALTH HISTORY 39

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cportant to establish how they know the patient. For example, when a child is
brought in for health care, the accompanying adult may not be the primary oreven frequent caregiver, just the most available ride. Always seek out the best-informed source. Occasionally, a relative or friend insists on being with the pa-tient during your evaluation. Try to ﬁnd out why and also the patient’s wishes.
The Patient With Personal Problems. Patients may ask you for ad-

vice about personal problems outside the range of their health care. For ex-ample, should the patient quit a stressful job, move out of state, or have anabortion? Before responding, explore the different approaches the patient hasconsidered and their pros and cons, whom else they have discussed the prob-lem with, and what supports are available for different choices. Letting the pa-tient talk through the problem with you is usually much more valuable andtherapeutic than any answer you could give.
Special Aspects of Interviewing

Clinicians talk with patients about various subjects that are emotionally ladenor sensitive. These discussions can be particularly difﬁcult for inexperiencedclinicians or during evaluations of patients clinicians do not know well. Evenseasoned clinicians have some discomfort with certain topics: abuse of alcoholor drugs, sexual orientation or activities, death and dying, ﬁnancial concerns,racial and ethnic experiences, family interactions, domestic violence, psychi-atric illnesses, physical deformities, bowel function, and others. These areas aredifﬁcult to explore in part because of societal taboos. We all know, for exam-ple, that talking about bowel habits is not “polite table talk.” In addition,many of these topics evoke strong cultural, societal, and personal values. Race,drug use, and homosexual practices are three obvious examples of issues thatcan raise biased attitudes and pose barriers during the interview. This sectionexplores challenges to the clinician in these and other

homosexual practices are three obvious examples of issues thatcan raise biased attitudes and pose barriers during the interview. This sectionexplores challenges to the clinician in these and other important and some-times sensitive areas, including domestic violence, the dying patient, and men-tal illness.

Several basic principles can help guide your response to sensitive topics. The
single most important rule is to be nonjudgmental. The clinician’s role is to learn
about the patient and help the patient achieve better health. Disapproval ofbehaviors or elements in the health history will only interfere with this goal.Explain why you need to know certain information —doing so makes patients
less apprehensive. For example, say to patients “Because sexual practices putpeople at risk for certain diseases, I ask all of my patients the following ques-tions.” You should use speciﬁc language. Refer to genitalia with explicit words
such as penis or vagina and avoid phrases like “private parts.” Choose words that
the patient understands. “By intercourse, I mean when a man inserts his penis
into a woman’s vagina.” Find opening questions for sensitive topics and learn
the speciﬁc kinds of data needed for your assessments.
Other strategies for becoming more comfortable with sensitive areas include

general reading about these topics in medical and lay literature; talking toselected colleagues and teachers openly about your concerns; taking special
SPECIAL ASPECTS OF INTERVIEWING
40 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5ccourses that help you explore your own feelings and reactions; and ultimately,
reﬂecting on your own life experience. Take advantage of all these resources.Whenever possible, listen to experienced clinicians, then practice similar dis-cussions with your own patients. The range of topics that you can explore withcomfort will widen progressively.
Cultural Competence. Developing the ability to interact and commu-
nicate effectively with patients from many backgrounds is a lifelong profes-sional goal. The following examples illustrate how communication barriers,cultural differences, and unconscious biases can inﬂuence patient care.
A 28-year-old taxi driver from Ghana who had recently moved to the United

States complained to a friend about U.S. medical care. He had gone to the clinicbecause of fever and fatigue. He described being weighed, having his temperaturetaken, and having a cloth wrapped tightly, to the point of pain, around his arm.The clinician, a 36-year-old from Washington, DC, had asked the patient manyquestions, examined him, and wanted to take blood—which the patient had re-fused. The patient’s ﬁnal comment was “ . . . and she didn’t even give me chloro-quine!”—his primary reason for seeking care. The man from Ghana was expect-ing few questions, no examination, and treatment for malaria, which is what feverusually means in Ghana.
In this example, cross-cultural miscommunication is understandable and un-
threatening. Bias and miscommunication, however, occur in many clinicalinteractions and are usually subtler.
A 16-year-old high school student came to the local teen health center because

of painful menstrual cramps that were interfering with school. She was dressed ina tight top and short skirt and had multiple piercings, including in her eyebrow.The 30-year-old male clinician asked the following questions: “Are you passingall of your, classes?” . . . “What kind of job do you want after high school?” . . .“What kind of birth control do you want?” The teenager felt pressured into ac-cepting birth control pills, even though she had clearly stated that she had neverhad intercourse and planned to postpone it until she got married. She was anhonor student, planning to go to college, but the clinician did not elicit thesegoals. The clinician glossed over her cramps by saying “Oh, you can just takesome ibuprofen. Cramps usually get better as you get older.” The patient will nottake the birth control pills that were prescribed, nor will she seek health care soonagain. She experienced the encounter as an interrogation, so failed to gain trustin her clinician. In addition, the

the birth control pills that were prescribed, nor will she seek health care soonagain. She experienced the encounter as an interrogation, so failed to gain trustin her clinician. In addition, the questions implied incorrect assumptions abouther health. She has received ineffective health care because of conﬂicting culturalvalues and clinician bias.

In both of these cases, the failure arises from the clinician’s mistaken assump-
tions or biases. In the ﬁrst case, the clinician did not consider the many vari-ables that shape patient beliefs about health and expectations for medical care.In the second case, the clinician allowed stereotypes to dictate the agenda in-stead of listening to the patient and respecting her as an individual. Each of ushas our own cultural background and our own biases. These do not simplyfade away as we become clinicians.
As you provide care for an ever-expanding and diverse group of patients, it is
increasingly important to understand how culture shapes not just the patient’sSPECIAL ASPECTS OF INTERVIEWING
CHAPTER 2 IINTERVIEWING AND THE HEALTH HISTORY 41

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cbeliefs, but your own. Culture is a system of shared ideas, rules, and meanings

that inﬂuences how we view the world, experience it emotionally, and behavein relation to other people. It can be understood as the “lens” through whichwe perceive and make sense out of the world we inhabit. This deﬁnition of cul-ture is broader than the term “ethnicity.” The inﬂuence of culture is not lim-ited to minority groups—it is relevant to everyone. While learning about spe-ciﬁc cultural groups is important, without a framework, this may lead to itsopposite, group stereotypes. For example, you may think that Asians havemore rice in their diets than those from other cultural groups. For people ofAsian descent in the United States, however, this may not be the case at all.Work on an appropriate and informed clinical approach to all patients by be-coming aware of your own values and biases, developing communication skillsthat transcend cultural differences, and building therapeutic partnerships basedon respect for each patient’s life experience. This type of framework,

and biases, developing communication skillsthat transcend cultural differences, and building therapeutic partnerships basedon respect for each patient’s life experience. This type of framework, describedin the following section, will allow you to approach each patient as unique anddistinct.SPECIAL ASPECTS OF INTERVIEWING

42 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGCLINICIAN GOALS FOR CULTURAL COMPETENCE
ISelf-awareness. Learn about your own biases . . . we all have them.
IEnhanced communication. Work to eliminate assumptions about what is 
“normal.” Learn directly from your patients—they are the experts on their culture and illness.
ICollaborative partnerships. Build your relationships with patients on respect
and mutually acceptable plans.
Self-awareness. Start by exploring your own cultural identity. How
do you describe yourself in terms of ethnicity, class, region or country of ori-gin, religion, and political afﬁliation? Don’t forget the characteristics that weoften take for granted—gender, life roles, sexual orientation, physical ability,and race—especially if you are from majority groups in these areas. What as-pects of your family of origin do you identify with and how are you differentfrom your family of origin? How do these identities inﬂuence your beliefs andbehaviors?

Another more challenging aspect of learning about ourselves is the task of
bringing our own values and biases to a conscious level. Values are the stan-
dards we use to measure our own and others’ beliefs and behaviors. These mayappear to be absolutes. Biases are the attitudes or feelings that we attach to per-

ceived differences. Being attuned to difference is normal; in fact, in the distantpast, detecting differences may have preserved life. Intuitively knowing mem-bers of one’s own group is a survival skill that we have outgrown as a societybut it is still actively at work. We often feel so guilty about our biases that it ishard to recognize and acknowledge them. Start with less threatening con-structs, such as the way an individual relates to time, which can be a culturallydetermined phenomenon. Are you always on time—a positive value in thedominant Western culture? Or do you tend to run a little late? How do youfeel about people whose habits are opposite to yours? Next time you attend ameeting or class, notice who is early, on time, or late. Is it predictable? Think

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cabout the role of physical appearance. Do you consider yourself thin, mid size,
or heavy? How do you feel about your weight? What does prevailing U.S. cul-ture teach us to value in physique? How do you feel about people who havedifferent weights?
Enhanced Communication and Learning from the Patient. Given

the complexity of culture, no one can possibly know the health beliefs andpractices of every culture and subculture. Therefore, remember that your pa-tients are the experts on their own unique cultural perspectives. Patients maynot be able to identify or deﬁne their values or beliefs in the abstract butshould be able to respond to speciﬁc questions. Find out about the patient’scultural background. Use some of the same questions discussed in “Ex-panding and Clarifying the Health History” (see p. ___). Maintain an open,respectful, and inquiring attitude. “What did you hope to get from thisvisit?” If you have established rapport and trust, patients will be willing toteach you. Be ready to acknowledge your ignorance or bias. “I know verylittle about Ghana. What would have happened at a clinic there if you hadthese concerns?” Or, with the second patient and with much more difﬁculty,“I mistakenly made assumptions about you that are not right. I apologize.Would you be willing to tell me more

there if you hadthese concerns?” Or, with the second patient and with much more difﬁculty,“I mistakenly made assumptions about you that are not right. I apologize.Would you be willing to tell me more about yourself and your future goals?”

Learning about speciﬁc cultures is still valuable because it broadens what you,
as a clinician, identify as areas you need to explore. Do some reading aboutthe life experiences of individuals in ethnic or racial groups in your region. Goto movies that are made in different countries or explicitly present the per-spective of different groups. Learn about the concerns of different consumergroups with visible health agendas. Seek out and establish collegial relation-ships with healers of different disciplines. Most importantly, be open to learn-ing from your patients.
Collaborative Partnerships. Through continual work on self-awareness

and seeing through the “lens” of others, the clinician lays the foundation forthe collaborative relationship that best supports the patient’s health. Com-munication based on trust, respect, and a willingness to reexamine assump-tions helps allow patients to express concerns that may run counter to thedominant culture. These concerns may be associated with strong feelingssuch as anger or shame. You, the clinician, must be willing to listen to and tovalidate these feelings, and not let your own feelings prevent you from ex-ploring painful areas. You must also be willing to reexamine your beliefsabout what is the “right approach” to clinical care in a given situation. Makeevery effort to be ﬂexible and creative in your plans, respectful of patients’knowledge about their own best interests, and consciously committed to clar-ifying the truly acute or life-threatening risks to the patient’s health. Re-member that if the patient stops listening, fails to follow your advice, or doesnot

and consciously committed to clar-ifying the truly acute or life-threatening risks to the patient’s health. Re-member that if the patient stops listening, fails to follow your advice, or doesnot return, your health care has not been successful.

The Alcohol and Drug History. One difﬁcult area for many clinicians is
asking patients about their use of alcohol and drugs, either illegal or prescribed.Use of alcohol and drugs often directly contributes to symptoms and the needfor care and treatment. Despite their high lifetime prevalence (in the UnitedSPECIAL ASPECTS OF INTERVIEWING
CHAPTER 2 IINTERVIEWING AND THE HEALTH HISTORY 43

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cStates, more than 13% for alcohol and 4% for illegal drugs), substance abuse
disorders are under diagnosed.
Do not let personal feelings interfere with your role as a clinician. It is your
job to gather data, assess the impact on the patient’s health, and plan a ther-apeutic response. Clinicians should routinely ask about current and past useof alcohol or drugs, patterns of use, and family history.
Questions about alcohol and other drugs follow naturally after questions

about caffeine and cigarettes. “What do you like to drink?” or “Tell me aboutyour use of alcohol” are good opening questions that avoid the easy yes orno response. Remember to ask what patients mean by alcohol, since for somepatients the term does not include wine or beer. Asking about alcohol usemay not be that helpful for detecting problem drinking, but you can makeuse of several well-validated short screening tools that do not take much time.Try two additional questions: “Have you ever had a drinking problem?” and“When was your last drink?” An afﬁrmative answer to the ﬁrst question, alongwith a drink within 24 hours, has been shown to suggest problem drinking.The most widely used screening questions are the CAGE questions aboutCutting down, Annoyance if criticized, Guilty feelings, and Eye-openers.SPECIAL ASPECTS OF INTERVIEWING
44 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGTHE CAGE QUESTIONNAIRE

IHave you ever felt the need to Cut down on drinking?
IHave you ever felt Annoyed by criticism of drinking?
IHave you ever felt Guilty about drinking?
IHave you ever taken a drink ﬁrst thing in the morning (Eye-opener) to steady
your nerves or get rid of a hangover?
Adapted from Mayﬁeld D, MeLeod G, Hall P: The CAGE questionnaire: Validation of a new alco-
holism screening instrument. Am J Psychiatry 131:1121–1123, 1974.
Two or more afﬁrmative answers to the CAGE Questionnaire suggest alco-
holism. They indicate that you need to ask more questions about blackouts(loss of memory for events during drinking), seizures, accidents or injurieswhile drinking, job loss, marital conﬂict, or legal problems. Also ask specif-ically about drinking while driving or operating machinery.
Questions about drugs are similar. “How much marijuana do you use? Co-

caine? Heroin? Amphetamines? (ask about each one by name). “How aboutprescription drugs such as sleeping pills?” “Diet pills?” “Pain-killers?” Anotherapproach is to adapt the CAGE questions to screening for substance abuse byadding “or drugs” to each question. If the patient is using illegal substances,ask further questions such as “How do you feel when you take it?” . . . “Haveyou had any bad reactions?” “What happened?” . . . “Any drug-related acci-dents, injuries, or arrests?” “Job or family problems?” . . . “Have you ever triedto quit? Tell me about it.”
Talking about drug use with adolescents can be even more challenging. It
may be helpful to ask about substance use by friends or family members ﬁrst.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5c“A lot of young people are using drugs these days. How about at your
school? Any of your friends?” Once patients realize you are concerned andnonjudgmental, they may be more open about their own patterns of use.Remember that alcohol and drug use can start at young ages. These topicsshould be introduced, along with tobacco use, in front of the parent withchildren at ages 6 or 7.
The Sexual History. Asking questions about sexual function and prac-

tices can be life-saving. Sexual practices determine risks for pregnancy and sex-ually transmitted diseases (STDs), including AIDS—good interviewing helpsprevent or reduce these risks. Sexual practices may be directly related to thepatient’s symptoms and integral to both diagnosis and treatment. Many pa-tients have questions or concerns about sexuality that they would discuss morefreely if you have asked about sexual health. Finally, sexual dysfunction mayresult from use of medication or from misinformation that, if recognized, maybe readily addressed.
You can introduce questions about sexual function and practices at multiple

points in a patient’s history. If the Chief Complaint involves genitourinarysymptoms, include the sexual history in the Present Illness. Chronic illnessor serious symptoms such as pain or shortness of breath may also affect sex-ual function. For women, you can ask these questions as part of the Obstet-ric/Gynecologic section of the Past Medical History. You can include themduring discussions about Health Maintenance, along with diet, exercise, andscreening tests, or as part of the lifestyle issues or important relationshipscovered in the Personal and Social History. Or, in a comprehensive history,you can query about sexual practices during the Review of Systems.
An orienting sentence or two is often helpful. “Now I’d like to ask you some

questions about your sexual health and practices.” or “I routinely ask all pa-tients about their sexual function.” For more speciﬁc complaints, you mightstate “To ﬁgure out why you have this discharge and what we should doabout it, I need to ask some questions about your sexual activity.”
In general, ask about both speciﬁc sexual behaviors and satisfaction with sex-
ual function. Speciﬁc questions are included in the chapters on Male Geni-talia and Hernias (pp. ___–___) and Female Genitalia (pp. ___–___). Be sureto ask such questions as:
I“When was the last time you had intimate physical contact with anyone?”“Did that contact include sexual intercourse?” Using the term “sexuallyactive” can be ambiguous. Patients have been known to reply “No, I justlie there.”

I“Do you have sex with men, women, or both?” The health implicationsof heterosexual, homosexual, or bisexual experiences are signiﬁcant. In-dividuals may have sex with persons of the same gender, yet they may notconsider themselves gay, lesbian, or bisexual.
I“How many sexual partners have you had in the last 6 months?” “In thelast 5 years?” “In your lifetime?” Again, these questions give the patientan easy opportunity to acknowledge multiple partners.SPECIAL ASPECTS OF INTERVIEWING
CHAPTER 2 IINTERVIEWING AND THE HEALTH HISTORY 45

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cIIt is important to ask all patients “Do you have any concerns about HIV
disease or AIDS?” because no explicit risk factors may be present. Ask alsoabout routine use of condoms.
Note that these questions make no assumptions about marital status, sexual
preference, or attitudes toward pregnancy or contraception. Listen to each ofthe patient’s responses and ask additional questions as indicated. When pa-tients are uncomfortable using sexual terminology, you may have to initiatemore of the discussion.
Remember that sexual behavior, too, can start at a young age. Encourage par-
ents to talk to their children about sexuality during their early years. It is fre-quently easier to discuss normal physiologic functions before children havebeen heavily socialized outside the home. For adolescents, because they oftenkeep sexual behaviors from parents, be sensitive to the need for conﬁdential-ity (see p. ___ “Talking With Adolescents”).

Domestic and Physical Violence. Because of the high prevalence of
physical, sexual, and emotional abuse, many authorities recommend the rou-tine screening of all female patients for domestic violence. Some men are alsoat risk. As with other sensitive topics, start this part of the interview with gen-eral “normalizing” questions: “Because abuse is common in many women’slives, I’ve begun to ask about it routinely.” “Are there times in your relation-ships that you feel unsafe or afraid?” “Many women tell me that someone athome is hurting them in some way. Is this true for you?” “Within the last year,have you been hit, kicked, punched, or otherwise hurt by someone you know?If so, by whom?” As in other parts of the history, use a pattern that goes fromgeneral to speciﬁc, less difﬁcult to more difﬁcult.
Physical abuse—often not mentioned by either victim or perpetrator—
should be considered in the following settings:

IIf injuries are unexplained, seem inconsistent with the patient’s story, areconcealed by the patient, or cause embarrassment
IIf the patient has delayed getting treatment for trauma
IIf there is a past history of repeated injuries or “accidents”
IIf the patient or a person close to the patient has a history of alcohol ordrug abuse.
Also be suspicious if a partner tries to dominate the interview, will not leave
the room, or seems unusually anxious or solicitous.
When you suspect abuse, it is important to spend part of the encounter alone

with the patient. You can use the transition to the physical examination as anexcuse to ask the other person to leave the room. If the patient is also resis-tant, you should not force the situation, potentially placing the victim in jeop-ardy. Be aware that certain diagnoses have a higher association with abuse,such as pregnancy and somatization disorder.SPECIAL ASPECTS OF INTERVIEWING
46 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cChild abuse is also common. Asking parents about their approach to disci-
pline is a routine part of well-child care. You can also ask parents how theycope with a baby who will not stop crying or a child who misbehaves. “Mostparents get very upset when their baby cries (or their child has been naughty).How do you feel when your baby cries?” “What do you do when your babywon’t stop crying?” “Do you have any fears that you might hurt your child?”You should also inquire about how other caretakers or companions handlethese situations.
The Mental Health History. Many cultures make ingrained distinc tions

between mental and physical illnesses causing marked differences in socialacceptance and attitudes. Think how easily people talk about diabetes andtaking insulin compared to discussing schizophrenia and using psy-chotropic medication. Use both open-ended and directed questions toelicit the individual and family history of mental illness. For example, youmight begin by asking “Have you ever had any problem with emotional ormental illnesses?” Then move to more speciﬁc questions such as “Have youever visited a counselor or psychotherapist?” . . . “Have you or has anyonein your family ever been hospitalized for an emotional or mental healthproblem?”
For patients with depression or thought disorders such as schizophrenia, a

careful history is in order. Depression is common worldwide but still remainsunderdiagnosed and undertreated. For such patients, be open to their changesin mood or symptoms such as fatigue, unusual tearfulness, weight loss, insom-nia, and vague somatic complaints. Two opening questions are “How haveyour mood or spirits been over the past month?” and “What about your levelof interest or pleasure in each day’s activities?” For serious depression, be sureto ask about thoughts of suicide . . . “Have you ever thought about hurtingyourself or ending your life?” As with chest pain, you must evaluate severity—both are potentially lethal. For further approaches, turn to the mental statussections of Chapter 16, The Nervous System.
Many patients with schizophrenia or other psychotic disorders can function

in the community and tell you about their diagnoses, symptoms, hospital-izations, and current medications. You should feel free to ask about symp-toms and assess any impact on mood or daily activities.
Death and the Dying Patient. There is a growing and important focus
in professional education and the literature on the need to address the issuesof death and dying. Topics such as end-of-life decision-making, grief andbereavement, and advance directives are beyond the scope of this chapter.Basic concepts are appropriate even for beginning students, however, sinceyou will care for patients near the end of their lives.
Many clinicians avoid the subject of death because of their own discomforts

and anxieties. You will need to work through your own feelings with thehelp of reading and discussion. Kubler-Ross has described ﬁve stages in aperson’s response to loss or the anticipatory grief of impending death:SPECIAL ASPECTS OF INTERVIEWING
CHAPTER 2 IINTERVIEWING AND THE HEALTH HISTORY 47

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cIDenial and isolation
IAnger
IBargaining
IDepression or sadness
IAcceptance
These stages may occur sequentially or overlap in different combinations. At
each stage, follow the same approach. Be alert to patients’ feelings and to cuesthat they want to talk about them. Use facilitative techniques to help them tobring out their concerns. Make openings for them to ask questions: “I won-der if you have any concerns about the procedure?” . . . “Your illness?” . . .“What it will be like when you go home?” Explore these concerns and pro-vide whatever information the patient requests. Be wary of inappropriate re-assurance. If you can explore and accept patients’ feelings, answer their ques-tions, and demonstrate your commitment to staying with them throughouttheir illness, reassurance will grow where it really matters—within the patientsthemselves.
Dying patients rarely want to talk about their illnesses all the time, nor do they

wish to conﬁde in everyone they meet. Give them opportunities to talk andthen listen receptively, but if they prefer to stay at a social level, you need notfeel like a failure. Remember that illness—even a terminal one—is only onesmall part of the total person. A smile, a touch, an inquiry after a family mem-ber, a comment on the day’s events, or even some gentle humor all recognizeand afﬁrm other areas of the patient’s individuality and help sustain the livingperson. To communicate appropriately, you have to get to know the patient;that is part of the helping process.
Understanding the patient’s wishes about treatment at the end of life is an

important part of a clinician’s role. Failing to establish this communicationis widely viewed as a flaw in clinical care. Even if discussions of death anddying are difficult for you, you must learn to ask specific questions. Thecondition of the patient and the health care setting often determine whatneeds to be discussed. For patients who are acutely ill and in the hospital,discussing what the patient wants to have done in the event of a cardiac orrespiratory arrest is usually mandatory. Asking about “ DNR status ” (Do

Not Resuscitate) is often difficult when the clinician has no previous rela-tionship with the patient and lacks knowledge of the patient’s values or lifeexperience. Patients may also be unrealistic about the effectiveness of re-suscitation based on information in the media. Find out about the patient’sframe of reference. “What experiences have you had with the death of aclose friend or relative?” “What do you know about cardiopulmonary re-suscitation (CPR)?” Educate patients about the likely success of CPR, es-pecially if they are chronically ill or advanced in age. Assure them that re-lieving pain and taking care of their other spiritual and physical needs willbe a priority.SPECIAL ASPECTS OF INTERVIEWING
48 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cIn general, it is important to encourage any adult, but especially the elderly
or chronically ill, to establish a health proxy, an individual who can act for the
patient in life-threatening situations. This can be part of the interview aimedat a “values history” that identiﬁes what is important to the patient and makeslife worth living, and the point when living would no longer be worthwhile.Ask about how patients spend their time every day, what brings them joy, andwhat they look forward to. Make sure to clarify the meaning of statementslike “You said that you don’t want to be a burden to your family. What ex-actly do you mean by that?” In addition, explore the patient’s religious orspiritual frame of reference so you and the patient can make the most appro-priate decisions about health care.
Sexuality in the Clinician–Patient Relationship. Clinicians occa-

sionally ﬁnd themselves physically attracted to their patients. The emotionaland physical intimacy of the clinician–patient relationship may lead to sexualfeelings. If you become aware of such feelings, accept them as a normal humanresponse and bring them to the conscious level so they will not affect your be-havior. Denying these feelings makes it more likely for you to act inappropri-ately. Anysexual contact or romantic relationship with patients is unethical;
keep your relationship with the patient within professional bounds and seekhelp if you need it.
Occasionally, clinicians meet patients who are frankly seductive or make sex-

ual advances. Calmly but ﬁrmly make it clear that your relationship is profes-sional, not personal. You may also wish to reﬂect on your image. Have youbeen overly warm with the patient? Expressed your affection physically?Sought his or her emotional support? Has your clothing or demeanor beenunconsciously seductive? It is your responsibility to avoid these problems.
Ethical Considerations
You may wonder why an introductory chapter on interviewing contains a sec-tion on ethics. What is it about the process of talking with patients that callsfor responses beyond our innate sense of morality? Ethics are a set of princi-
ples that have been created through reﬂection and discussion to guide our be-havior. Medical ethics, which guide our professional behavior, are not static,

but several principles have guided clinicians throughout the ages. Usually ourethical approach is instinctive, but even as students you will face situations thatcall for applications of ethical principles.
Some of the traditional and still fundamental maxims are as follows:
INonmaleﬁcence or primum non nocere is commonly stated as “First, do
no harm.” In the context of an interview, giving information that is incor-rect or not really related to the patient’s problem can do harm. Avoidingrelevant topics or creating barriers to open communication can also doharm. Your success in facilitating the patient’s full expression of experiences,thoughts, and feelings determines the quality of your assessment.
ETHICAL CONSIDERATIONS
CHAPTER 2 IINTERVIEWING AND THE HEALTH HISTORY 49

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cIBeneﬁcence is the dictum that the clinician needs to “do good” for the pa-
tient. As clinicians, our actions need to be motivated by what is in the pa-tient’s best interest.
IAutonomy reminds us that patients have the right to determine what is in
their own best interest. This principle has become increasingly importantover time and is consistent with collaborative rather than paternalistic pa-tient relationships.
IConﬁdentiality can be one of the most challenging principles. As clini-
cians, we are obligated not to tell others what we learn from our patients.This privacy is fundamental to our professional relationships with patients.In the daily ﬂurry of activity in a hospital, it must be carefully guarded.
Issues in health care that extend beyond our direct care of individual patients

to complicated choices about the distribution of resources and the well-beingof society continue to emerge. A broadly representative group that initiallymet in Tavistock Square in London in 1998 has continued to work on anevolving document of ethical principles to guide behavior in health care forboth individuals and institutions. A current iteration of the Tavistock Princi-ples is provided below.ETHICAL CONSIDERATIONS
50 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGTHE TAVISTOCK PRINCIPLES
Rights: People have a right to health and health care.
Balance: Care of individual patients is central, but the health of populations is also
our concern.
Comprehensiveness: In addition to treating illness, we have an obligation to
ease suffering, minimize disability, prevent disease, and promote health.
Cooperation: Health care succeeds only if we cooperate with those we serve,

each other, and those in other sectors.
Improvement: Improving health care is a serious and continuing responsibility.
Safety: Do no harm.
Openness: Being open, honest, and trustworthy is vital in health care.
As students you will learn about some of the ethical challenges that will con-
front you later as a practicing clinician. However, there are dilemmas uniqueto the role of student that you will face from the time that you begin tak-ing care of patients. The following vignettes capture some of the most com-mon experiences. They raise a variety of ethical and practical issues that areoverlapping.
Scenario #1

You are a 3rd-year medical student on your ﬁrst clinical rotation in the hospital.It is late in the evening when you are ﬁnally assigned to the patient that you areresponsible for “working up” and presenting the next day at preceptor rounds.You go to the patient’s room and ﬁnd the patient exhausted from the day’sevents and clearly ready to settle down for the night. You know that your internand attending have already done their evaluations. Do you proceed with a his-

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5ctory and physical examination that is likely to take 1 to 2 hours? Is this process
only for your education? Do you ask permission before you start? What do youinclude?
Here you are confronted with the tension between the need to learn by doing
and doing no harm to patients. There is a utilitarian ethical principle that re-
minds us that if clinicians-in-training do not learn, then there will be no fu-ture caregivers. Yet the dictums to do no harm and prioritize what is in thepatient’s best interests are clearly in conﬂict with that future need. As a stu-dent this dilemma will arise often.
Obtaining informed consent is the process for addressing this ethical dilemma.

Making sure the patient realizes that you are in training and new at patientevaluation is always important. It is impressive how often patients willingly letstudents be involved in their care. It is an opportunity for patients to give backto their caregivers. Even when clinical activities appear to be purely for edu-cational purposes, there may be a beneﬁt to the patient. Multiple caregiversprovide multiple perspectives. This scenario invokes the Tavistock Principlesof openness, balance, and safety.
Scenario #2

You and your supervisor are on your way to draw an urgent blood sample froma patient. The patient was admitted with hypernatremia (a high sodium level) andneeds to have his electrolytes monitored closely. It is already past the time for arepeat blood draw. Just then your supervisor is paged to an emergency and asksyou to draw the sample on your own. You have seen several done but have onlydone one yourself and that was a few weeks ago.
In this situation you are being asked to be responsible for clinical care that ex-

ceeds your capability. This can happen in a number of situations, such as beingasked to evaluate a clinical situation without proper backup or to completeDNR forms with a patient before you have been taught how. In the settingabove, you may have the following thoughts: the patient will beneﬁt by hav-ing a test that needs to be obtained; or, the risk to the patient from a venipunc-ture is more one of discomfort or pain rather than one that threatens his orher life, and you have already drawn blood once before. There is educationalvalue to the learner in being pushed to the limits of his or her knowledge tosolve problems and to gain conﬁdence in functioning independently. But whatis the right thing to do in this situation? In this scenario, think about the Tavi-stock Principles of openness, cooperation, and safety. You may need to ﬁnd an-

other person who is more qualiﬁed to do the procedure; or you may chooseto attempt the venipuncture after alerting the patient to your inexperience andobtaining the patient’s consent.
Scenario #3
You are assigned to a clinical team taking care of 25 patients who must be seenand have notes written on them before other commitments start at 7 
A.M. There
are four of you: the resident, an intern, a 4th-year medical student, and you, amid-year clinical clerk. It is now 5:30 
A.M. After the patients are divided among
the three more senior members of the team, with time allowed for writing ordersETHICAL CONSIDERATIONS
CHAPTER 2 IINTERVIEWING AND THE HEALTH HISTORY 51

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cand notes, there are barely 5 minutes to assess each patient at the bedside. After
seeing nine patients with the resident, you are asked to write three of the notes.You have questions about the care of several of the patients but realize that
there is no time to ask. Feeling uncomfo rtable, you write the notes to the best
of your ability.
This situation relates to the Tavistock Principles of comprehensiveness, cooper-
ation, openness, and improvement . As these scenarios illustrate, clinical students

are under pressure to go along with practices already in place. The context maybe the way a team works on an in-patient service or the standard approach topatients in an emergency room or an outpatient clinic. You may ﬁnd yourselfchoosing between cooperating as a member of a team and delivering care thatis not consistent with your individual sense of quality. In addition, often youare working with clinicians who are evaluating your performance as a student.You may ﬁnd yourself doing tasks that make you uncomfortable because ofpressures to be a “team player.”
As you can see, ethical dilemmas frequently occur in the life of clinical stu-

dents. Because, as a student, you are often in a hierarchical situation where youhave relatively less power, ethical conﬂicts that you have no control over mayarise more often than when you are a practicing clinician. You can also see thatoften there are no clear or easy answers in such situations. What responses areavailable to you to address these and other quandaries?
You need to reﬂect on your beliefs and assess your level of comfort with a
given situation. In some situations there may be alternative solutions. For ex-ample, in Scenario #1, the patient may really be willing to have the history
and physical examination done at that hour, or perhaps you can renegotiatethe time for the next morning. In Scenario #2, you might look for an alter-

native supervisor for the venipuncture. You will need to choose which situa-tions warrant voicing your concerns, even at the risk of a bad evaluation. Seekout coaching on how to express your reservations in a way that maximizes
that they will be heard. As a clinical student, you will need settings for dis-
cussing these immediately relevant ethical issues with other students and withmore senior trainees and faculty. Small groups that are structured to addressthese kinds of issues are particularly useful in providing validation and sup-port. Avail yourself of these opportunities whenever possible.
Interviewing Patients of Different Ages

As patients move through different stages of life, you will need to make cer-tain adaptations in your interviewing style. This section provides suggestionsfor talking with children, adolescents, and the elderly.
Talking With Children. Unlike adults, children usually are accompa-
nied by a parent or caregiver. Even when adolescents are alone, they are oftenseeking health care at the request of their parents—indeed, the parent is
usually sitting in the wa iting room. When interviewing a child, you need to
consider the needs and perspectives of both the child and the caregivers. In
INTERVIEWING PATIENTS OF DIFFERENT AGES
52 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cadditi on, the d ictates of “well child care” may preset the clinician’s agenda to-
ward immunizations, anticipatory guidance, or developmental assessment.
Establishing Rapport. Begin the interview by greeting and establish-
ing rapport with each person present. Refer to the infant or child by namerather than by “him,” “her,” or “the baby.” Clarify the role or relationship ofall the adults and children. “Now, are you Jimmy’s grandmother?” “Pleasehelp me by telling me Jimmy’s relationship to everyone here.” Address theparents as “Mr. Smith” and “Ms. Smith” rather than by their ﬁrst names or“Mom” or “Dad.” When the family structure is not immediately clear, youmay avoid embarrassment by asking directly about other members. “Who elselives in the home?” “Who is Jimmy’s father?” “Do you live together?” Do notassume that just because parents are separated that only one parent is activelyinvolved in the child’s life.

To establish rapport, the key is to meet children on their own level. Use your
personal experiences with children to guide how you interact in a health caresetting. Maintaining eye contact at their level (for example, sit on the ﬂoor ifneeded), participating in playful engagement, and talking about what inter-ests them are always good strategies. Ask children about their clothes, one oftheir toys, what book or TV show they like, or their adult companion in anenthusiastic but gentle style. Spending time at the beginning of the interviewto calm down and connect with an anxious child or crying infant can put boththe child and the caregiver at ease.
Working With Families. One of the biggest challenges when several

people are present is deciding to whom to direct your questions. While even-tually you need to get information from both the child and the parent(s), itis useful to start with the child if he or she can talk. Even at age 3 years, somechildren can tell you about the speciﬁc problem. Asking simple open-endedquestions such as “Are you sick? . . . Tell me about it.” followed by more spe-ciﬁc questions often provides much of the History of the Present Illness. Theparents can then verify the information, add details that give you the largercontext, and identify other issues you need to address. You need to charac-terize symptom attributes the same way you do with adults. Sometimes chil-dren are embarrassed to begin, but once the parent has started the conversa-tion, you can direct the questions back to the child.
I“Your mother tells me that you get a lot of stomachaches. Tell me aboutthem.”

I“Show me where you get the pain. What does it feel like?”
I“Is it sharp like a pinprick, or does it ache?”
I“Does it stay in the same spot, or does it move around?”
I“Anything else about feeling sick?”
I“What helps make it go away?”INTERVIEWING PATIENTS OF DIFFERENT AGES
CHAPTER 2 IINTERVIEWING AND THE HEALTH HISTORY 53

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cI“What do you think causes it?”
I“How about missing school a lot?”
The presence of family members also provides a rich opportunity to observe
how they interact with the child. As you talk with the parent, see how a youngchild relates to a new environment. It is normal for a toddler to open draw-ers, pull at paper, and wander around the room. An older child may be ableto sit still or may get restless and start ﬁdgeting. Watch how the parents setlimits on the child or fail to set limits when appropriate.
MULTIPLE AGENDAS. Each individual in the room, including the clinician,

may have a different idea about the nature of the problem and what needs tobe done about it. It is your job to discover as many of these perspectives andagendas as possible. Family members who are not present (the absent parentor grandparent) may also have concerns. It is a good idea to ask about thoseconcerns too. “If Suzie’s father were here today, what questions or concernswould he have?” “Have you, Mrs. Jones, discussed this with your mother oranyone else?” “What does she think?” Mrs. Jones brings Suzie in for abdom-inal pain because she is worried that Suzie may have an ulcer. She is also wor-ried about Suzie’s eating habits. Suzie is not worried about the belly pain—itrarely interferes with what she wants to do. She is uneasy about the changesin her body, especially her belief that she is getting fat. Mr. Jones thinks thatSuzie’s schoolwork is not getting enough attention. You, as the clinician, needto balance these concerns with what you see as a healthy 12-year-old girl

that she is getting fat. Mr. Jones thinks thatSuzie’s schoolwork is not getting enough attention. You, as the clinician, needto balance these concerns with what you see as a healthy 12-year-old girl inearly puberty with some mild functional abdominal pain. Your goals need toinclude helping the family to be realistic about the range of “normal” and uncovering the concerns of Mr. and Mrs. Jones and Suzie.

THE FAMILY AS A RESOURCE. Much of the information you obtain about a
child comes from the family. In general, family members provide most of thecare and are your natural allies in promoting the child’s health. Being opento a wide range of parenting behaviors helps to make this alliance. Raising achild reﬂects cultural, socioeconomic, and family practices. It is important torespect the tremendous variation in these practices. A good strategy is to viewthe parents as experts in the care of their child and you as their consultant.This demonstrates respect for the parents’ care and minimizes their likelihoodof discounting or ignoring your advice. Most parents face many challengesraising children, so practitioners need to be supportive, not judgmental.Comments like “Why didn’t you bring him in sooner?” or “What did you dothat for!” do not improve your rapport with the parent. Statements ac-knowledging the hard work of parenting and praising successes are alwaysappreciated.

HIDDEN AGENDAS. Finally, as with adults, the chief complaint may not re-
late to the real reason the parent has brought the child to see you. The com-plaint may be a “ticket to care” or bridge to concerns that may not seemlegitimate. Try to create a trusting atmosphere that allows parents to be openabout all their concerns. Ask facilitating questions like the following:INTERVIEWING PATIENTS OF DIFFERENT AGES
54 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cI“Do you have any other concerns about Randy that you would like to tell
me about?”
I“What did you hope I would be able to do for you today?”
I“Was there anything else that you wanted to tell or ask me today?”
Talking With Adolescents. Adolescents, like most other people, usually
respond positively to anyone who demonstrates a genuine interest in them. Itis important to show interest early and then sustain the connection if commu-nication is to be effective. Adolescents are more likely to open up when the in-terview is focused on them rather than on their problems. In contrast to mostother interviews, start with speciﬁc directed questions to build trust and rapport

and start the conversation. You may have to do more talking than usual. Agood way to begin is to chat informally about friends, school, hobbies, andfamily. Using silence in an attempt to get adolescents to talk or asking aboutfeelings directly is usually not a good idea. It is particularly important to usesummarization (see p. ___) and transitional statements (see p. ___) and to ex-plain what you are going to do during the physical examination. The phys-ical examination can also be an opportunity to get the young person talking.Once you have established rapport, return to more open-ended questions.At that point, make sure to ask what concerns or questions the adolescentmay have.
Remember also that adolescents’ behavior is related to their developmental

stage and not necessarily to chronologic age or physical maturation. Theirage and appearance may fool you into assuming that they are functioning ona more future-oriented and realistic level. The reverse also can be true, espe-cially in teens with delayed puberty or chronic illness.
Issues of conﬁdentiality are important in adolescence. Explain to both par-
ents and adolescents that the best health care allows adolescents some degreeof independence and conﬁdentiality. It helps if the clinician starts asking theparent to leave the room for part of the interview when the child is age 10 or11 years. This prepares both caregivers and young people for future visitswhen the patient spends time alone with the clinician.
Before the parent leaves the room, get any relevant medical history from the

parent, for example, certain elements of Past History, and clarify the parent’sagenda for the visit. Also discuss the need for conﬁdentiality. Explain that thepurpose of conﬁdentiality is to improve health care, not to keep secrets. Ado-lescents need to know that you will hold in conﬁdence what they discuss withyou. However, never make conﬁdentiality unlimited. Always state explicitlythat you may need to act on information that makes you concerned aboutsafety . . . “I will not tell your parents what we talk about unless you give mepermission or I am concerned about your safety—for example, if you were totalk to me about killing yourself and I thought there were a risk that you wouldactually try it.”INTERVIEWING PATIENTS OF DIFFERENT AGES
CHAPTER 2 IINTERVIEWING AND THE HEALTH HISTORY 55

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cYour goal is to help adolescents bring their concerns or questions to their par-
ents. Encourage adolescents to discuss sensitive issues with their parents andoffer to be present or help. While young people may believe that their parentswould “kill them if they only knew,” you may be able to promote more opendialogue. This entails a careful assessment of the parents’ perspective and theyoung person’s full and explicit consent.
Talking With Aging Patients. At the other end of the life cycle, aging

patients also have special needs and concerns. Their hearing and vision may beimpaired, their responses and explanations may be slow or lengthy, and theymay have chronic illnesses with associated disabilities. Elderly people may notreport their symptoms. Some may be afraid or embarrassed; others may be try-ing to avoid the medical expenses or the discomforts of diagnosis and treat-ment. They may think their symptoms are merely part of aging, or they maysimply have forgotten about them. They may be inhibited by fears of losingtheir independence.
As you proceed with the interview, give elderly patients time to respond to

your questions. Speak slowly and clearly but do not shout or raise your voice.A comfortable room, free of distractions and noise, is helpful. Ask about turn-ing off the radio or television. Remember that visual cues may be important,so make sure that your face is well lit. If they wear glasses, make sure they putthem on. Do not try to accomplish everything in one visit. Several visits maybe less fatiguing and more productive.
From middle age on, people begin to measure their lives in terms of the years
left rather than years lived. Older people often reminisce about the past andreﬂect upon previous experiences. Listening to this process of life review cangive you important insights and help you support patients as they workthrough painful feelings or recapture joys or accomplishments.
Although some generalizations are useful, learn to recognize and avoid stereo-

types that block your appreciation of each individual patient. Find out howpatients see themselves and their situation, as well as each patient’s unique pri-orities, goals, and patterns for handling problems. This knowledge will helpyou as you collaborate on treatment plans. For example, “Can you tell me howyou feel about getting older?” “What kinds of things do you ﬁnd most satis-fying?” “What kinds of things worry you?” “What would you change if youcould?”
Functional Assessment. Learning how the elderly, and those with
chronic illness, function in terms of daily activities is essential and provides abaseline for future comparisons. There are two standard categories of assess-ment: physical activities of daily living (ADLs) and instrumental activities ofdaily living (IADLs).
Can the patients perform the ADLs independently, do they need some help,

or are they entirely dependent? Instead of asking about each area separately,have the patient go through a typical day, in detail. Start with an open-endedINTERVIEWING PATIENTS OF DIFFERENT AGES
56 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5crequest—“Tell me about your day yesterday”—and then guide the story to a
greater level of detail. “You got up at 8? How is it getting out of bed?” “Whatdid you do next?” Ask how things have changed, who is available for help, andwhat helpers actually do. Remember that increasing dependence on others isvery difﬁcult for most people to accept, but promoting safety is one of yourimportant priorities.INTERVIEWING PATIENTS OF DIFFERENT AGES
CHAPTER 2 IINTERVIEWING AND THE HEALTH HISTORY 57ACTIVITIES OF DAILY LIVING (ADLs)
Physical ADLs Instrumental ADLs
Bathing Using the telephone
Dressing ShoppingToileting Preparing foodTransfers HousekeepingContinence LaundryFeeding TransportationManaging moneyTaking medicine

Beginning the Physical
Examination: General Surveyand Vital SignsCHAPTER
Beginning the PhysicalExamination: General Surveyand Vital Signs33
CHAPTER 3 IBEGINNING THE PHYSICAL EXAMINATION: GENERAL SURVEY AND VITAL SIGNS 59Once you understand the patient’s concerns and have elicited a careful his-

tory, you are ready to begin the physical examination. At ﬁrst you may feelunsure of how the patient will relate to you. With practice, your skills in phys-ical examination will grow, and you will gain conﬁdence. Through study andrepetition the examination will ﬂow more smoothly, and you will soon shiftyour attention from technique and how to handle instruments to what youhear, see, and feel. Touching the patient’s body will seem more natural, andyou will learn to minimize any discomfort to the patient. You will becomemore responsive to the patient’s reactions and provide reassurance whenneeded. Before long, as you gain proﬁciency, what once took between 1 and2 hours will take considerably less time.
This chapter addresses skills and techniques needed for initial assessment as

you begin the physical examination. Under “Anatomy and Physiology” youwill ﬁnd information on how to measure height, weight, and Body MassIndex (BMI), and guidelines for nutritional assessment. There is clinical in-formation on the relevant health history, health promotion and counseling(“The General Survey”), and a preview of how to record the patient’s over-all appearance (“The Vital Signs”). The section on “Techniques of Exami-nation” describes the initial steps of the physical examination: preparing forthe examination, conducting the general survey, and taking the vital signs.
ANATOMY AND PHYSIOLOGY
As you begin the physical examination, you will survey the patient’s general ap-

pearance and measure the patient’s height and weight. These data provide in-formation about the patient’s nutritional status and amount of body fat. Bodyfat consists primarily of adipose in the form of triglyceride and is stored in sub-cutaneous, intra-abdominal, and intramuscular fat depots. These stores are in-accessible and difﬁcult to measure, so it will be important to compare your mea-surements of height and weight to standardized ranges of normal. In the past,tables of desirable weight-for-height have been based on life insurance data,which often did not adjust for the effects of smoking and selected weight-in-ducing medical conditions such as diabetes, and tended to overstate desirableweight. For those wishing to continue using such tables, see Table 3-1, p. ___.
More recently, however, many government and scientiﬁc health organizations

have promoted use of the Body Mass Index, which incorporates estimated but

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cANATOMY AND PHYSIOLOGY
60 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGUnit of Measure Method of Calculation
Weight in pounds, height in inches
Weight in kilograms, height in 
meters squared
Either
*Several organizations use 704.5, but the variation in BMI is negligible.
Conversion formulas: 2.2 lbs =1 kg; 1.0 inch =2.54 cm; 100 cm =1 meter
Source: National Institute of Diabetes and Digestive and Kidney Diseases. www.niddk.nih.gov/health/nutrit/pubs/
statobes.htm ,Accessed 2/1/01.(1) Body Mass Index Chart 
(see table on p. ___)
(2) Body Mass Index Nomogram 
(3)
(4)
(5) “BMI Calculator” at website
www.nhlbisupport.com/bmiWeight (kg)
Height (m )2Height (lbs) 700*
Height (inches)Height (inches)× 

Methods to Calculate Body Mass Index (BMI)more accurate measures of body fat than weight alone. BMI standards are de-


rived from two surveys: the National Health Examination Survey, consistingof three survey cycles between 1960 and 1970, and the National Health andNutrition Examination Survey, with three cycles from the 1970s to the 1990s.
More than half of U.S. adults are overweight (BMI >25), and nearly one fourth
are obese (BMI >30), so assessing and educating patients about their BMI arevital for promoting health. Being overweight or obese are proven risk factors fordiabetes, heart disease, stroke, hypertension, osteoarthritis, and some forms ofcancer. Remember that these BMI criteria are not rigid cutpoints but guidelinesfor increasing risks for health and well-being. Note that persons over age 65 havea disproportionate risk of undernutrition when compared to younger adults.

Height and weight in childhood and adolescence reﬂect the many behavioral,
cognitive, and physiologic changes of growth and development. Develop-mental milestones, markers for growth spurts, and sexual maturity ratings canbe found in Chapter 17, Assessing Children: Infancy Through Adolescence.With aging, some of these changes reverse—height may decrease, posturemay become more stooping from kyphosis of the thoracic spine, and exten-sion of the knees and hips may diminish. The abdominal muscles may relax,changing the abdominal contour, and fat may accumulate at the hips andlower abdomen. Be alert to these changes and those described in the sectionscalled “Changes With Aging” in the upcoming chapters.
Calculating the BMI. There are a number of ways to calculate the

BMI. Choose the method most suited to your practice. The National Insti-tute of Diabetes and Digestive and Kidney Diseases cautions that peoplewho are very muscular may have a high BMI but still be healthy. Likewise,the BMI for elderly or other individuals with low muscle mass and reducednutrition may appear inappropriately “normal.” If you ﬁnd the BMI difﬁ-cult to use, you can use the nomogram on p. ___, which gives BMI valuesfor weight in pounds or kilograms and height in feet or centimeters.

CHAPTER 3 IBEGINNING THE PHYSICAL EXAMINATION: GENERAL SURVEY AND VITAL SIGNS 61Another option is to measure the patient’s waist circumference. With the pa-
tient standing, measure the waist just above the hip bones. The patient mayhave excess body fat if the waist measures:
I≥35 inches for women
I≥40 inches for men
Interpreting and Acting on the BMI. If the BMI falls above 25, or the

weight is greater than the upper limit of recommended weight for height, a nu-trition assessment is in order. Engage the patient in a 24-hour dietary recall andcompare the intake of food groups and number of servings per day with cur-rent recommendations. Or choose a screening tool and provide appropriatecounseling or referral. You may wish to review the types of foods in differentfood groups, using the helpful diagram found in Table 3-5, “Food Guide Pyra-mid: A Guide to Daily Food Choices” (p. ___). Remember that carbohydratesand protein furnish 4 calories per gram, and fat yields 9 calories per gram.
If the BMI falls below 17, or the weight is less than the low end of the range

of weight for height, be concerned about possible anorexia nervosa, bulimia,or other medical conditions. These conditions are summarized in Table 3-6,Eating Disorders and Excessively Low BMI, p. ___. (See also p. ___ for healthpromotion and counseling for overweight or underweight patients.)
UNFIG 3-1
Source: Clinical Guidelines on the Identiﬁcation, Evaluation, and Treatment of
Overweight and Obesity in Adults, National Institutes of Health and NationalHeart, Lung, and Blood Institute. June 1998.See also Table 3-1, Height and
Weight Tables for Adults Age 25and Over, p. ___.
See Table 3-2, Healthy Eating: Food
Groups and Servings per Day, p. ___. For screening tools, seeTable 3-3, Rapid Screen for DietaryIntake, p. ___, and Table 3-4, Nutri-tion Screening Checklist, p. ___.EXAMPLES OF ABNORMALITIES

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cChanges in Weight. Changes in weight result from changes in body
tissues or body ﬂuid. Weight gain occurs when caloric intake exceeds caloric
expenditure over a period of time and typically appears as increased bodyfat. Weight gain may also reflect abnormal accumulation of body fluids.When the retention of ﬂuid is relatively mild, it may not be visible, but sev-eral pounds of ﬂuid usually appear as edema.
Good opening questions include “How often do you check your weight?”
“How is it compared to a year ago?” For changes, ask “Why do you thinkit has changed?” “What would you like to weigh?” If weight gain or lossappears to be a problem, ask about the amount of change, its timing, thesetting in which it occurred, and any associated symptoms.THE HEALTH HISTORY
62 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGEXAMPLES OF ABNORMALITIES
UNFIG 3-2
Source: Katz DL: Nutrition in Clinical Practice.

UNFIG 3-2
Philadelphia, Lippincott Williams & Wilkins, 2001:340.
Common or Concerning Symptoms
IChanges in weight
IWeakness and fatigue
IFever, chills, night sweats
THE HEALTH HISTORY
Rapid changes in weight (over a
few days) suggest changes in bodyﬂuids, not tissues.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTHE HEALTH HISTORY
CHAPTER 3 IBEGINNING THE PHYSICAL EXAMINATION: GENERAL SURVEY AND VITAL SIGNS 63In the overweight patient, for example, when did the weight gain begin?
Was the patient heavy as an infant or a child? Using milestones appropri-ate to the patient’s age, inquire about weight at the following times: birth,kindergarten, high school or college graduation, discharge from militaryservice, marriage, after each pregnancy, menopause, and retirement. Whatwere the patient’s life circumstances during the periods of weight gain? Hasthe patient tried to lose weight? How? With what results?
Weight loss is an important symptom that has many causes. Mechanisms in-

clude one or more of the following: decreased intake of food for reasons suchas anorexia, dysphagia, vomiting, and insufﬁcient supplies of food; defectiveabsorption of nutrients through the gastrointestinal tract; increased meta-bolic requirements; and loss of nutrients through the urine, feces, or injuredskin. A person may also lose weight when a ﬂuid-retaining state improves orresponds to treatment.
Try to determine if the drop in weight is proportional to any change in food
intake, or whether it has remained normal or even increased.
Symptoms associated with weight loss often suggest a cause, as does a good
psychosocial history. Who cooks and shops for the patient? Where does thepatient eat? With whom? Are there any problems with obtaining, storing,preparing, or chewing food? Does the patient avoid or restrict certain foodsfor medical, religious, or other reasons?

Throughout the history, be alert for signs of malnutrition. Symptoms may
be subtle and nonspecific, such as weakness, easy fatigability, cold intol-erance, flaky dermatitis, and ankle swelling. Securing a good history of eat-ing patterns and quantities is mandatory. It is important to ask generalquestions about intake at different times throughout the day, such as “Tellme what you typically eat for lunch.” “What do you eat for a snack?”“When?”
Fatigue and Weakness. Like weight loss, fatigue is a relatively non-

speciﬁc symptom with many causes. It refers to a sense of weariness or lossof energy that patients describe in various ways. “I don’t feel like getting upin the morning” . . . “I don’t have any energy” . . . “I just feel blah”. . . .“I’m all done in” . . . “I can hardly get through the day” . . . “By the time Iget to the ofﬁce I feel as if I’ve done a day’s work.” Because fatigue is a nor-mal response to hard work, sustained stress, or grief, try to elicit the life cir-Causes of weight loss include: 
gastrointestinal diseases, endocrinedisorders (diabetes mellitus, hyper-thyroidism, adrenal insufﬁciency),chronic infections; malignancy;chronic cardiac, pulmonary, orrenal failure; depression; andanorexia nervosa or bulimia (see Table 3-6, Eating Disordersand Excessively Low BMI, p. ___).
Weight loss with relatively high

food intake suggests diabetes mellitus, hyperthyroidism, or malabsorption. Consider also bingeeating (bulimia) with clandestine vomiting.
Poverty, old age, social isolation,
physical disability, emotional ormental impairment, lack of teeth,ill-ﬁtting dentures, alcoholism, anddrug abuse increase the likelihoodof malnutrition.
See Table 3-4, Nutrition Screening
Checklist, p. ___.
Fatigue is a common symptom of
depression and anxiety states, butalso consider infections (such ashepatitis, infectious mononucleosis,and tuberculosis); endocrine dis-orders (hypothyroidism, adrenal insufﬁciency, diabetes mellitus,EXAMPLES OF ABNORMALITIES

64 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGcumstances in which it occurs. When fatigue is unrelated to such situations,
further investigation is needed.
Use open-ended questions to explore the attributes of the patient’s fa-
tigue, and encourage the patient to fully describe what he or she is expe-riencing. Important clues about etiology are often found in a good psy-chosocial history, exploration of sleep patterns, and a thorough review ofsystems.
Infants and children cannot describe fatigue verbally, so inquire about any
changes in behavior, such as withdrawal from normal activities, irritability,loss of interest in their surroundings, and excessive sleeping.
Weakness is different from fatigue. It denotes a demonstrable loss of mus-
cle power and will be discussed later with other neurologic symptoms (seepp. ___–___).
Fever and Chills. Fever refers to an abnormal elevation in body temper-

ature (see p. ___ for deﬁnitions of normal). Ask about fever if patients havean acute or chronic illness. Find out whether the patient has used a ther-mometer to measure the temperature. (Errors in technique can lead to un-reliable information.) Has the patient felt feverish or unusually hot, notedexcessive sweating, or felt chilly and cold? Try to distinguish between sub-jective chilliness and a shaking chill, with shivering throughout the body
and chattering of teeth.
Feeling cold, goosebumps, and shivering accompany a rising temperature,
while feeling hot and sweating accompany a falling temperature. Normallythe body temperature rises during the day and falls during the night. Whenfever exaggerates this swing, night sweats occur. Malaise, headache, and pain
in the muscles and joints often accompany fever.

Fever has many causes. Focus your questions on the timing of the illness
and its associated symptoms. Become familiar with patterns of infectiousdiseases that may affect your patient. Inquire about travel, contact with sickpersons, or other unusual exposures. Be sure to inquire about medications,since they may cause fever. In contrast, recent ingestion of aspirin, aceta-minophen, corticosteroids, and nonsteroidal anti-inﬂammatory drugs maymask it and affect the temperature recorded at the time of the physical ex-amination.panhypopituitarism); heart failure;
chronic disease of the lungs, kidneys, or liver; electrolyte imbal-ance; moderate to severe anemia;malignancies; nutritional deﬁcits;medications.
Weakness, especially if localized in
a neuroanatomic pattern, suggestspossible neuropathy or myopathy.
Recurrent shaking chills suggest
more extreme swings in tempera-ture and systemic bacteremia.
Feelings of heat and sweating also

accompany menopause. Nightsweats occur in tuberculosis andmalignancy.EXAMPLES OF ABNORMALITIES

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cOptimal Weight and Nutrition. Less than half of U.S. adults main-
tain a healthy weight (BMI ≥19 but ≤25). Obesity has increased in every
segment of the population, regardless of age, gender, income, ethnicity,or socioeconomic group. More than half of people with non-insulin-dependent diabetes and roughly 20% of those with hypertension or ele-vated cholesterol are overweight or obese. Increasing obesity in childrenhas been linked to rising rates of childhood diabetes. Once excess weightor unhealthy nutritional patterns are detected, take advantage of the ex-cellent materials available to promote weight loss and good nutrition. Evenreducing weight by 5% to 10% can improve blood pressure, lipid levels, and glucose tolerance and reduce the risk of developing diabetes or hy-pertension.
Once you have assessed food intake and nutritional status and the patient’s

motivation to change eating behaviors, you are ready to begin healthcounseling. First, explain the components of a healthy diet and encouragepatients to select appropriately sized servings from each of the five majorfood groups: grains such as bread, cereal, rice, and pasta; fruits; vegetables;dairy products; and meat and beans. Be prepared to help adolescents andadults over age 50 identify foods rich in calcium. Advise pregnant womento increase intake of iron and folic acid, and older adults to increase intakeof vitamin D.
Exercise. Fitness is a key component of both weight control and weight
loss. Currently, 30 minutes of moderate activity, deﬁned as walking 2 milesin 30 minutes on most days of the week or its equivalent, is recommended.Patients can increase exercise by such simple measures as parking further awayfrom their place of work or using stairs instead of elevators. A safe goal forweight loss is

1⁄2to 2 pounds per week.
Blood Pressure and Diet. With respect to blood pressure, there is
reliable evidence that regular and frequent exercise, decreased sodium intake and increased potassium intake, and maintaining a healthy weightwill reduce risk of developing hypertension as well as lower blood pressurein adults who are already hypertensive. Explain to patients that most of the sodium in our diet comes from salt (sodium chloride). Inform your patients that the recommended daily allowance (RDA) of sodium is HEALTH PROMOTION AND COUNSELING
CHAPTER 3 IBEGINNING THE PHYSICAL EXAMINATION: GENERAL SURVEY AND VITAL SIGNS 65See Table 3-2, Healthy Eating:
Food Groups and Servings per Day,p. ___, and Table 3-5. Food GuidePyramid, p. ___.
See Table 3-7, Nutrition Counsel-
ing: Sources of Nutrients, p. ___.
See Table 3-8, Patients With Hyper-
tension: Recommended Changesin Diet, p. ___.EXAMPLES OF ABNORMALITIES
HEALTH PROMOTION AND COUNSELING

Important Topics for Health Promotion and Counseling
IOptimal weight and nutrition
IExercise
IBlood pressure and diet

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cHEALTH PROMOTION AND COUNSELING
66 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGPreview: Recording the Physical Examination—
The General Survey and Vital Signs
Your write-up of the physical examination begins with a general descrip-

tion of the patient’s appearance, based on the General Survey. Note thatinitially you may use sentences to describe your ﬁndings; later you will usephrases. The style below contains phrases appropriate for most write-ups.Unfamiliar terms are explained in the next section, “Techniques of Exami-nation.” Choose vivid and graphic adjectives, as if you are painting a pic-ture in words. Avoid cliches such as “well-developed” or “well-nourished”or “in no acute distress,” since they could apply to any patient and do notconvey the special features of the patient before you.Record the vital signs taken at the time of your examination. They arepreferable to those taken earlier in the day by other providers. (Commonabbreviations for blood pressure, heart rate, and respiratory rate are self-explanatory.)

“Mrs. Scott is a young, healthy-appearing woman, well-groomed, ﬁt,and in good spirits. Height is 5 ′4″, weight 135 lbs, BP 120/80, HR 72
and regular, RR 16, temperature 37.5 °C.”
OR:
“Mr. Jones is an elderly male who looks pale and chronically ill. He isalert, with good eye contact but unable to speak more than two orthree words at a time due to shortness of breath. He has intercostalmuscle retraction when breathing and sits upright in bed. He is thin,with diffuse muscle wasting. Height is 6 ′2″, weight 175 lbs, BP 160/95,
HR 108 and irregular, RR 32 and labored, temperature 101.2 °F.”<2400 mg, or 1 teaspoon, per day. Patients need to read food labels
closely, especially the Nutrition Facts panel. Low sodium foods are thosewith sodium listed at less than 5% of the RDA of <2400 mg. For nutri-tional interventions to reduce risk of cardiac disease, turn to pp. ___ andpp. ___.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cCHAPTER 3 IBEGINNING THE PHYSICAL EXAMINATION: GENERAL SURVEY AND VITAL SIGNS 67TECHNIQUES OF EXAMINATION
Before you begin the physical examination, take time to prepare for the tasks
ahead. Think through your approach to the patient, your professional de-meanor, and how to make the patient feel comfortable and relaxed. Reviewthe measures that promote the patient’s physical comfort and make any ad-justments needed in the lighting and the surrounding environment. Make
sure that you wash your hands in the presence of the patient before beginningthe examination. This is a subtle yet much appreciated gesture of concern forthe patient’s welfare.
Approaching the Patient. When ﬁrst examining patients, feelings of

insecurity are inevitable, but these will soon diminish with experience. Bestraightforward. Let the patient know you are a student and try to appearcalm, organized, and competent, even when you feel differently. If you for-get to do part of the examination, this is not uncommon, especially at ﬁrst!Simply examine those areas out of sequence, but smoothly. It is not unusualto go back to the bedside and ask to check one or two items that you mighthave overlooked.
As a beginner, you will need to spend more time than experienced clinicians
on selected portions of the examination, such as the ophthalmoscopic ex-amination or cardiac auscultation. To avoid alarming the patient, warn thepatient ahead of time by saying, for example, “I would like to spend extratime listening to your heart and the heart sounds, but this doesn’t mean Ihear anything wrong.”
Over time, you will begin sharing your ﬁndings with the patient. Clinicians

have different approaches as to how and when this occurs. As a beginner, youshould avoid interpreting your ﬁndings. You are not the patient’s primarycaretaker, and your views may be conﬂicting or in error. As you grow in ex-perience and responsibility, sharing ﬁndings will become more appropriate.If the patient has speciﬁc concerns, you may even provide reassurance as youﬁnish examining the relevant area. Be selective, however—if you ﬁnd an un-expected abnormality, you may wish you had kept a judicious silence. At times,
TECHNIQUES OF EXAMINATION
BEGINNING THE EXAMINATION: 
SETTING THE STAGE
Important Areas for Examination
IReﬂect on your approach to the patient
IDecide on the scope of the examination
IChoose the examination sequence
IAdjust the lighting and the environment
IMake the patient comfortable

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5c68 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGTECHNIQUES OF EXAMINATION
you may discover abnormalities such as an ominous mass or a deep oozing
ulcer. Always avoid showing distaste, alarm, or other negative reactions.
Scope of the Examination: How Complete Should It Be? There
is no simple answer to this common question. Chapter 1 provided someguidelines to help you choose whether to do a comprehensive or focused ex-
amination . As a general principle, a new patient warrants a complete exami-
nation, regardless of chief complaint or setting. You may choose to abbrevi-ate the examination for patients making routine ofﬁce visits or seeking urgentcare. A more limited examination may also be appropriate for patients withsymptoms restricted to a speciﬁc body system or with patients you know well.
A comprehensive examination does more than assess the body systems. The

physical examination is a source of fundamental and personalized knowledgeabout the patient and strengthens the clinician–patient relationship. Mostpeople seeking health care have speciﬁc worries or symptoms. The physicalexamination helps to identify or rule out related physical causes. It gives in-formation for answering patient questions and serves as a baseline for futurecomparisons. The physical examination also provides important opportuni-ties for health promotion through education and counseling, and increasesthe credibility and conviction of the clinician’s reassurance and advice.Furthermore, students must repeatedly perform such examinations to gainproﬁciency, and clinicians need ongoing practice to maintain their skills.How to best divide the usually limited time allotted to a patient visit betweenlistening, discussion, or counseling on the one hand, and the physical ex-amination on the other, takes both judgment and experience.

For the focused examination, select the methods relevant to assessing the
problem as precisely and carefully as possible. The patient’s symptoms, age,and health history help determine the scope of your examination, as doesyour knowledge of disease patterns. Out of all the patients with sore throat,for example, you will need to decide who may have infectious mononucleosisand warrants careful palpation of the liver and spleen and who, in contrast,has a common cold and does not need this examination. The clinical think-ing that underlies and guides such decisions is discussed in Chapter 18.
What about the need for a periodic physical examination for screening and

prevention? The utility of the comprehensive physical examination for thepurposes of screening and prevention of illness, in contrast to evaluation ofsymptoms, has been scrutinized in a number of studies. Studies have validateda number of physical examination techniques: blood pressure measurement,assessment of central venous pressure from the jugular venous pulse, listen-ing to the heart for evidence of valvular disease, the clinical breast examina-tion, detection of hepatic and splenic enlargement, and the pelvic examina-tion with Papanicolaou smears. Recommendations for examination andscreening have been further expanded by various consensus panels and expertadvisory groups. Bear in mind, however, that when used for screening (ratherthan assessment of complaints), not all components of the examination havebeen validated as ways to reduce future morbidity and mortality.

Choosing the Examination Sequence, Examining Position, and
Handedness. Remember that the sequence of the comprehensive or

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTHE PHYSICAL EXAMINATION: SUMMARY OF SUGGESTED SEQUENCE
UNBOX 3.3focused examination should maximize the patient’s comfort, avoid unnec-
essary changes in position, and enhance the clinician’s efﬁciency. In general,move from “head to toe.” An important goal for you as a student is to de-velop your own sequence of examination with these principles in mind. Forexample, avoid examining the patient’s feet or genital areas before checkingthe face or mouth.
Turn back to Chapter 1, pp. ___, to review a suggested examination se-
quence, and look over the outline of such a sequence below.TECHNIQUES OF EXAMINATION
CHAPTER 3 IBEGINNING THE PHYSICAL EXAMINATION: GENERAL SURVEY AND VITAL SIGNS 69

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTECHNIQUES OF EXAMINATION
70 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGThis book recommends examining the patient from the patient’s right side,
moving to the opposite side or foot of the bed or examining table as neces-sary. This is the standard position for the physical examination and has sev-eral advantages compared to the left side: It is more reliable to estimate jugu-lar venous pressure from the right, the palpating hand rests more comfortablyon the apical impulse, the right kidney is more frequently palpable than theleft, and examining tables are frequently positioned to accommodate a right-handed approach.
Left-handed students are encouraged to adopt right-sided positioning,
even though at ﬁrst it may seem awkward. It still may be easier to use theleft hand for percussing or for holding instruments such as the otoscope orreﬂex hammer.

Often you will need to examine the supine patient. This may dictate changes
in your sequence of examination. Some patients, for example, are unable tosit up in bed or stand. You can examine the head, neck, and anterior chestwith the patient lying supine. Then roll the patient onto each side to listento the lungs, examine the back, and inspect the skin. Roll the patient backand ﬁnish the rest of the examination with the patient again in the supineposition.
Adjusting Lighting and the Environment. Surprisingly, a num-

ber of environmental factors affect the calibre and reliability of your phys-ical findings. To achieve superior techniques of examination, it is impor-tant to “set the stage” so that both you and the patient are comfortable.As the examiner, you will find that awkward positions impair the qualityof your observations. Take the time to adjust the bed to a convenientheight (but be sure to lower it when finished!), and ask the patient to movetoward you if this makes it easier to examine a region of the body morecarefully.
Good lighting and a quiet environment make important contributions to
what you see and hear but may be hard to arrange. Do the best you can. Ifa television interferes with listening to heart sounds, politely ask the nearbypatient to lower the volume. Most people cooperate readily. Be courteousand remember to thank them as you leave.
Tangential lighting is optimal for inspecting a number of structures such as

the jugular venous pulse, the thyroid gland, and the apical impulse of theheart. It casts light across body surfaces that throws contours, elevations, anddepressions, whether moving or stationary, into sharper relief.
When light is perpendicular to the surface or diffuse, as shown on the next
page, shadows are reduced and subtle undulations across the surface arelost. Experiment with focused, tangential lighting across the tendons onthe back of your hand; try to see the pulsations of the radial artery at yourwrist.

CHAPTER 3 IBEGINNING THE PHYSICAL EXAMINATION: GENERAL SURVEY AND VITAL SIGNS 71Promoting the Patient’s Comfort. Your access to the patient’s body
is a unique and time-honored privilege of your role as a clinician. Showingconcern for privacy and patient modesty must be ingrained in your profes-sional behavior. These attributes help the patient feel respected and at ease.Be sure to close nearby doors and draw the curtains in the hospital or exam-ining room before the examination begins.
You will acquire the art of draping the patient with the gown or draw sheet
as you learn each segment of the examination in the chapters ahead. Your
goal is to visualize one area of the body at a time. This preserves the patient’s

modesty but also helps you to focus on the area being examined. With thepatient sitting, for example, untie the gown in back to better listen to thelungs. For the breast examination, uncover the right breast but keep the leftchest draped. Redrape the right chest, then uncover the left chest and pro-ceed to examine the left breast and heart. For the abdominal examination,only the abdomen should be exposed. Adjust the gown to cover the chestand place the sheet or drape at the inguinal area.
To help the patient prepare for segments that might be awkward, it is con-

siderate to brieﬂy describe your plans before starting the examination. Asyou proceed with the examination, keep the patient informed, especiallywhen you anticipate embarrassment or discomfort, as when checking for thefemoral pulse. Also try to gauge how much the patient wants to know. Is thepatient curious about the lung ﬁndings or your method for assessing the liveror spleen?
Make sure your instructions to the patient at each step in the examination
are courteous and clear. For example, “I would like to examine your heartnow, so please lie down.”
As in the interview, be sensitive to the patient’s feelings and physical com-
fort. Watching the patient’s facial expressions and even asking “Is it okay?”
TANGENTIAL LIGHTING PERPENDICULAR LIGHTING

72 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGas you move through the examination often reveals unexpressed worries or
sources of pain. To ease discomfort, it may help to adjust the slant of the pa-tient’s bed or examining table. Rearranging the pillows or adding blanketsfor warmth shows your attentiveness to the patient’s well-being.
When you have completed the examination, tell the patient your general im-
pressions and what to expect next. For hospitalized patients, make sure the pa-tient is comfortable and rearrange the immediate environment to the patient’ssatisfaction. Be sure to lower the bed to avoid risk of falls, reapply any restraintsyou may have removed, and raise the bedrails if needed. As you leave, washyour hands, clean your equipment, and dispose of any waste materials.
THE GENERAL SURVEY
The General Survey of the patient’s build, height, and weight begins with

the opening moments of the patient encounter, but you will ﬁnd that yourobservations of the patient’s appearance crystallize as you start the physicalexamination. The best clinicians continually sharpen their powers of obser-vation and description, like naturalists identifying birds from silhouettesbacklit against the sky. It is important to heighten the acuity of your clinicalperceptions of the patient’s mood, build, and behavior. These details enrichand deepen your emerging clinical impression. A skilled observer can depictdistinguishing features of the patient’s general appearance so well in wordsthat a colleague could spot the patient in a crowd of strangers.
Many factors contribute to the patient’s body habitus—socioeconomic sta-

tus, nutrition, genetic makeup, degree of ﬁtness, mood state, early illnesses,gender, geographic location, and age cohort. Recall that many of the char-acteristics you scrutinize during the General Survey are affected by the pa-
tient’s nutritional status: height and weight, blood pressure, posture, moodand alertness, facial coloration, dentition and condition of the tongue andgingiva, color of the nail beds, and muscle bulk, to name a few. Be sure tomake the assessment of height, weight, BMI, and risk of obesity a routinepart of your clinical practice.
You should now recapture the observations you have been making since

the first moments of your interaction and sharpen them throughout yourassessment. Does the patient hear you when greeted in the waiting roomor examination room? Rise with ease? Walk easily or stiffly? If hospitalizedwhen you first meet, what is the patient doing—sitting up and enjoyingtelevision? . . . or lying in bed? . . . What occupies the bedside table—a magazine? . . . a flock of “get well” cards? . . . a Bible or a rosary? . . . anemesis basin? . . . or nothing at all? Each of these observations should raiseone or more tentative hypotheses about the patient for you to considerduring future assessments.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cApparent State of Health. Try to make a general judgment based on
observations made throughout the encounter. Support it with the signiﬁ-cant details.
Level of Consciousness. Is the patient awake, alert, and responsive to
you and others in the environment?
Signs of Distress. For example, does the patient show evidence of these
problems?
ICardiac or respiratory distress
IPain
IAnxiety or depression
Height and Build. If possible, measure the patient’s height in stocking
feet. Is the patient unusually short or tall? Is the build slender and lanky,muscular, or stocky? Is the body symmetric? Note the general body propor-tions and look for any deformities.
Weight. Is the patient emaciated, slender, plump, obese, or somewhere
in between? If the patient is obese, is the fat distributed evenly or concen-trated over the trunk, the upper torso, or around the hips?
Whenever possible, weigh the patient with shoes off. Weight provides one

index of caloric intake, and changes over time yield other valuable diagnos-tic data. Remember that changes in weight can occur with changes in bodyﬂuid status, as well as in fat or muscle mass.
Skin Color and Obvious Lesions. See Chapter 4, The Skin, for details.
Dress, Grooming, and Personal Hygiene. How is the patient
dressed? Is clothing appropriate to the temperature and weather? Is it clean,properly buttoned, and zipped? How does it compare with clothing wornby people of comparable age and social group?EXAMPLES OF ABNORMALITIES TECHNIQUES OF EXAMINATION
CHAPTER 3 IBEGINNING THE PHYSICAL EXAMINATION: GENERAL SURVEY AND VITAL SIGNS 73Acutely or chronically ill, frail, 
feeble, robust, vigorous
If not, promptly assess the level of
consciousness (see p. ___).
Clutching the chest, pallor, 
diaphoresis; labored breathing,wheezing, cough
Wincing, sweating, protectiveness
of painful area

Anxious face, ﬁdgety movements,
cold moist palms; inexpressive orﬂat affect, poor eye contact,psychomotor slowing
Very short stature is seen in
Turner’s syndrome, childhoodrenal failure, achondroplastic andhypopituitary dwarﬁsm. Longlimbs in proportion to the trunk is seen in hypogonadism and Mar-fan’s syndrome
Generalized fat in simple obesity;
truncal fat with relatively thinlimbs in Cushing’s syndrome andsyndrome X
Causes of weight loss include ma-
lignancy, diabetes mellitus, hyper-thyroidism, chronic infection, de-pression, diuresis, and successfuldieting
Pallor, cyanosis, jaundice, rashes,
bruises
Excess clothing may reﬂect 
the cold intolerance of hypo-thyroidism, hide skin rash or needlemarks, or signal personal lifestylepreferences.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cGlance at the patient’s shoes. Have holes been cut in them? Are the laces
tied? Or is the patient wearing slippers?
Is the patient wearing any unusual jewelry? Where? Is there any body piercing?
Note the patient’s hair, ﬁngernails, and use of cosmetics. They may be clues
to the patient’s personality, mood, or lifestyle. Nail polish and hair coloringthat have “grown out” may signify decreased interest in personal appearance.
Do personal hygiene and grooming seem appropriate to the patient’s age,
lifestyle, occupation, and socioeconomic group? These are norms that varywidely, of course.
Facial Expression. Observe the facial expression at rest, during con-
versation about specific topics, during the physical examination, and ininteraction with others. Watch for eye contact. Is it natural? Sustained andunblinking? Averted quickly? Absent?
Odors of the Body and Breath. Odors can be important diagnostic

clues, such as the fruity odor of diabetes or the scent of alcohol. (For thescent of alcohol, the CAGE questions, p. ___, will help you determine pos-sible misuse.)
Never assume that alcohol on a patient’s breath explains changes in mental
status or neurologic ﬁndings.
Posture, Gait and Motor Activity. What is the patient’s preferred
posture?
Is the patient restless or quiet? How often does the patient change position?
How fast are the movements?Cut-out holes or slippers may 
indicate gout, bunions, or otherpainful foot conditions. Untiedlaces or slippers also suggestedema.
Copper bracelets are sometimes
worn for arthritis. Body piercingmay appear on any part of thebody.
“Grown-out” hair and nail polish
can help you estimate the lengthof an illness if the patient cannotgive a history. Fingernails chewedto the quick may reﬂect stress.
Unkempt appearance may be

Unkempt appearance may be 
seen in depression and dementia,but this appearance must be compared with the patient’s prob-able norm.
The stare of hyperthyroidism; the
immobile face of parkinsonism;the ﬂat or sad affect of depression.Decreased eye contact may be cul-tural, or may suggest anxiety, fear,or sadness.
Breath odors of alcohol, acetone
(diabetes), pulmonary infections,uremia, or liver failure
Alcoholics may have other serious
and potentially correctable prob-lems such as hypoglycemia, subdural hematoma, or post-ictalstate
Preference for sitting up in left-
sided heart failure, and for leaningforward with arms braced inchronic obstructive pulmonary disease
Fast, frequent movements of
hyperthyroidism; slowed activity of hypothyroidismTECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES

74 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTremors or other involuntary
movements; paralyses. See Table 16-8, Involuntary Move-ments, (pp. ___–___).
See Table 16-13, Abnormalities of
Gait and Posture (pp. ___–___).
See Table 3-9, Abnormalities of the
Arterial Pulse and Pressure Waves(p. ___). See Table 3-12 Abnormal-ities in Rate and Rhythm of Breath-ing (p. ___).
Cuffs that are too short or too nar-
row may give falsely high readings.Using a regular-size cuff on anobese arm may lead to a false diagnosis of hypertension.EXAMPLES OF ABNORMALITIES TECHNIQUES OF EXAMINATION
CHAPTER 3 IBEGINNING THE PHYSICAL EXAMINATION: GENERAL SURVEY AND VITAL SIGNS 75
THE VITAL SIGNS
Now you are ready to measure the Vital Signs —the blood pressure, heart

rate, respiratory rate, and temperature. You may ﬁnd that the vital signs arealready taken and recorded in the chart; if abnormal, you may wish to repeatthem yourself. (You can also make these important measurements later asyou start the cardiovascular and thorax and lung examinations, but oftenthey provide important initial information that inﬂuences the direction ofyour evaluation.)
Check either the blood pressure or the pulse ﬁrst. If the blood pressure is

high, measure it again later in the examination. Count the radial pulse withyour ﬁngers, or the apical pulse with your stethoscope at the cardiac apex.Continue either of these techniques and count the respiratory rate withoutalerting the patient. (Breathing patterns may change if patient becomes awarethat someone is watching.) The temperature is taken with glass thermo-meters, tympanic thermometers, or digital electronic probes. Further detailson techniques for ensuring accuracy of the vital signs are provided in thefollowing pages.
BLOOD PRESSURE
Choice of Blood Pressure Cuff (Sphygmomanometer). As many

as 50 million Americans have elevated blood pressure. To measure bloodpressure accurately, you must carefully choose a cuff of appropriate size. Theguidelines below will help you advise patients wishing to purchase bloodpressure cuffs as well.Is there any apparent involuntary motor activity? Are some body parts im-
mobile? Which ones?
Does the patient walk smoothly, with comfort, self-conﬁdence, and balance,
or is there a limp or discomfort, fear of falling, loss of balance, or any move-ment disorder?
SELECTING THE CORRECT BLOOD PRESSURE CUFF
IWidth of the inﬂatable bladder of the cuff should be about 40% of upper arm
circumference (about 12–14 cm in the average adult)
ILength of inﬂatable bladder should be about 80% of upper arm circumference(almost long enough to encircle the arm)
IIf anaeroid, recalibrate periodically before use

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
76 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGGETTING READY TO MEASURE BLOOD PRESSURE
IIdeally, ask the patient to avoid smoking or drinking caffeinated beverages for 
30 minutes before the blood pressure is taken and to rest for at least 5 minutes.
ICheck to make sure the examining room is quiet and comfortably warm.
IMake sure the arm selected is free of clothing. There should be no arteriovenous
ﬁstulas for dialysis, scarring from prior brachial artery cutdowns, or signs of lymphedema (seen after axillary node dissection or radiation therapy).
IPalpate the brachial artery to conﬁrm that it has a viable pulse.
IPosition the arm so that the brachial artery, at the antecubital crease, is at heart
level—roughly level with the 4th interspace at its junction with the sternum.
IIf the patient is seated, rest the arm on a table a little above the patient’s waist; if

standing, try to support the patient’s arm at the midchest level.
Bladder Cuff
If the brachial artery is much below
heart level, blood pressure appearsfalsely high. The patient’s own effort to support the arm may raisethe blood pressure.
A loose cuff or a bladder that bal-
loons outside the cuff leads tofalsely high readings.The blood pressure cuff may be either the aneroid or the mercury type. Be-
cause an aneroid instrument often becomes inaccurate with repeated use, itshould be recalibrated regularly.
Technique. Before assessing the blood pressure, you should take several

steps to make sure your measurement will be accurate. Once these steps aretaken, you are ready to measure the blood pressure. Proper technique is im-portant and reduces the inherent variability arising from the patient or ex-aminer, the equipment, and the procedure itself.
Now you are ready to measure the blood pressure. Center the inﬂatable
bladder over the brachial artery. The lower border of the cuff should beabout 2.5 cm above the antecubital crease. Secure the cuff snugly. Positionthe patient’s arm so that it is slightly ﬂexed at the elbow.
To determine how high to raise the cuff pressure, ﬁrst estimate the systolic
pressure by palpation. As you feel the radial artery with the ﬁngers of one hand,

EXAMPLES OF ABNORMALITIES TECHNIQUES OF EXAMINATION
CHAPTER 3 IBEGINNING THE PHYSICAL EXAMINATION: GENERAL SURVEY AND VITAL SIGNS 77An unrecognized auscultatory 
gap may lead to serious under-estimation of systolic pressure(e.g., 150 ⁄ 98 in the example on p. ___) or overestimation of diastolic pressure.
If you ﬁnd an auscultatory gap,
record your ﬁndings completely(e.g., 200⁄ 98 with an auscultatorygap from 170–150).
In some people, the mufﬂing point
and the disappearance point arefarther apart. Occasionally, as inaortic regurgitation, the soundsnever disappear. If there is morethan 10 mm Hg difference, recordboth ﬁgures (e.g., 154/80/68).
rapidly inﬂate the cuff until the radial pulse disappears. Read this pressure on

the manometer and add 30 mm Hg to it. Use of this sum as the target for sub-sequent inﬂations prevents discomfort from unnecessarily high cuff pressures.It also avoids the occasional error caused by an auscultatory gap—a silent in-terval that may be present between the systolic and the diastolic pressures.
Deﬂate the cuff promptly and completely and wait 15 to 30 seconds.Now place the bell of a stethoscope lightly over the brachial artery, taking care
to make an air seal with its full rim. Because the sounds to be heard ( Korotkoff
sounds ) are relatively low in pitch, they are heard better with the bell.
Inﬂate the cuff rapidly again to the level just determined, and then deﬂate it
slowly at a rate of about 2 to 3 mm Hg per second. Note the level at whichyou hear the sounds of at least two consecutive beats. This is the systolicpressure.

Continue to lower the pressure slowly until the sounds become mufﬂed and
then disappear. To conﬁrm the disappearance of sounds, listen as the pres-sure falls another 10 to 20 mm Hg. Then deﬂate the cuff rapidly to zero.The disappearance point, which is usually only a few mm Hg below the muf-ﬂing point, enables the best estimate of true diastolic pressure in adults.

78 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGBy making the sounds less audible,
venous congestion may produceartiﬁcially low systolic and high di-astolic pressures.
Pressure difference of more than
10–15 mm Hg suggests arterialcompression or obstruction on theside with the lower pressure.A fall in systolic pressure of 20 mm Hg or more, especiallywhen accompanied by symptoms,indicates orthostatic (postural) hypotension. Causes includedrugs, loss of blood, prolongedbed rest, and diseases of the auto-nomic nervous system.
120160
80
40mm Hg
Arterial
pulsetracingEffect of cuff
on arterial blood flowAuscultatory
findingsArtery 
occluded;no flow
Artery
compressed;blood flowaudible
Artery not
compressed;flow freeand audibleSilence
SilenceSystolic
pressure
Diastolic
pressureSounds ofturbulent flow
Read both the systolic and the diastolic levels to the nearest 2 mm Hg. Wait

Artery not
pressure
Diastolic
2 or more minutes and repeat. Average your readings. If the ﬁrst two read-ings differ by more than 5 mm Hg, take additional readings.
When using a mercury sphygmomanometer, keep the manometer vertical
(unless you are using a tilted ﬂoor model) and make all readings at eye levelwith the meniscus. When using an aneroid instrument, hold the dial so thatit faces you directly. Avoid slow or repetitive inﬂations of the cuff, becausethe resulting venous congestion can cause false readings.
Blood pressure should be taken in both arms at least once. Normally, there
may be a difference in pressure of 5 mm Hg and sometimes up to 10 mm Hg.Subsequent readings should be made on the arm with the higher pressure.
In patients taking antihypertensive medications or patients with a history of

fainting, postural dizziness, or possible depletion of blood volume, take theblood pressure in three positions—supine, sitting, and standing (unless con-traindicated). Normally, as the patient rises from the horizontal to a stand-ing position, systolic pressure drops slightly or remains unchanged whilediastolic pressure rises slightly. Another measurement after 1 to 5 minutesof standing may identify orthostatic hypotension missed by earlier readings.This repetition is especially useful in the elderly.
Definitions of Normal and Abnormal Levels. In 1997, the Joint
National Committee on Detection, Evaluation, and Treatment of HighBlood Pressure recommended that hypertension should be diagnosed only

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cAssessment of hypertension also
includes its effects on target organs—the eyes, the heart, thebrain, and the kidneys. Look forevidence of hypertensive retinop-athy, left ventricular hypertrophy,and neurologic deﬁcits suggestinga stroke. (Renal assessment requiresurinalysis and blood tests.)
A pressure of 110/70 would usually
be normal, but could also indicatesigniﬁcant hypotension if past pres-sures have been high.
A femoral pulse that is smaller and
later than the radial pulse suggestscoarctation of the aorta or occlu-sive aortic disease. Blood pressureis lower in the legs than in thearms in these conditions.EXAMPLES OF ABNORMALITIES TECHNIQUES OF EXAMINATION
CHAPTER 3 IBEGINNING THE PHYSICAL EXAMINATION: GENERAL SURVEY AND VITAL SIGNS 79when a higher than normal level has been found on at least two or more

visits after initial screening. Either the diastolic blood pressure (DBP) or thesystolic blood pressure (SBP) may be considered high. For adults (aged 18or over), the Committee has categorized six levels of DBP and SBP:
Relatively low levels of blood pressure should always be interpreted in the
light of past readings and the patient’s present clinical state.
SPECIAL PROBLEMS
The Apprehensive Patient. Anxiety is a frequent cause of high blood
pressure, especially during an initial visit. Try to relax the patient. Repeatyour measurements later in the encounter. Some patients will say their bloodpressure is only elevated in the ofﬁce (“white coat hypertension”) and mayneed to have their blood pressure measured several times at home or in acommunity setting.
The Obese or Very Thin Arm. For the obese arm, it is important to

use a wide cuff (15 cm). If the arm circumference exceeds 41 cm, use a thighcuff (18 cm wide). For the very thin arm, a pediatric cuff may be indicated.
Leg Pulses and Pressures. To rule out coarctation of the aorta, two
observations should be made at least once with every hypertensive patient:
ICompare the volume and timing of the radial and femoral pulses.
ICompare blood pressures in the arm and leg.
To determine blood pressure in the leg, use a wide, long thigh cuff that has
a bladder size of 18 ×42 cm, and apply it to the midthigh. Center the blad-
der over the posterior surface, wrap it securely, and listen over the poplitealartery. If possible, the patient should be prone. Alternatively, ask the supinepatient to ﬂex one leg slightly, with the heel resting on the bed. When cuffsof the proper size are used for both the leg and the arm, blood pressuresCategory Systolic (mm Hg) Diastolic (mm Hg)

Stage 3 (severe) ≥180 ≥110
Stage 2 (moderate) 160–179 100–109Stage 1 (mild) 140–159 90–99
High Normal 130–139 85–89Normal <130 <85Optimal <120 <80
*When the systolic and diastolic levels indicate different categories, use the higher category. For example,
170/92 mm Hg is moderate hypertension and 170/120 mm Hg is severe hypertension.
In isolated systolic hypertension, systolic pressure is 140 mm Hg or more and diastolic pressure is less than 
90 mm Hg.Blood Pressure Classiﬁcation (Adults)*

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cshould be equal in the two areas. (The usual arm cuff, improperly used on
the leg, gives a falsely high reading.) A systolic pressure lower in the legs thanin the arms is abnormal.
Weak or Inaudible Korotkoff Sounds. Consider technical prob-
lems such as erroneous placement of your stethoscope, failure to make fullskin contact with the bell, and venous engorgement of the patient’s
arm from repeated inflations of the cuff. Consider also the possibility of
shock.
When you cannot hear Korotkoff sounds at all, you may be able to estimate
the systolic pressure by palpation. Alternative methods such as Doppler tech-niques or direct arterial pressure tracings may be necessary.
To intensify Korotkoff sounds, one of the following methods may be helpful:
IRaise the patient’s arm before and while you inﬂate the cuff. Then lower
the arm and determine the blood pressure.

IInﬂate the cuff. Ask the patient to make a ﬁst several times, and then deter-mine the blood pressure.
Arrhythmias. Irregular rhythms produce variations in pressure and there-
fore unreliable measurements. Ignore the effects of an occasional prematurecontraction. With frequent premature contractions or atrial fibrillation,determine the average of several observations and note that your measure-ments are approximate.
HEART RATE AND RHYTHM
By examining arterial pulses, you can count the rate of the heart and deter-mine its rhythm, assess the amplitude and contour of the pulse wave, andsometimes detect obstructions to blood ﬂow.
Heart Rate. The radial pulse is

commonly used to assess the heartrate. With the pads of your index andmiddle ﬁngers, compress the radialartery until a maximal pulsation isdetected. If the rhythm is regularand the rate seems normal, count therate for 15 seconds and multiply by4. If the rate is unusually fast or slow,however, count it for 60 seconds.
When the rhythm is irregular, the rate should be evaluated by cardiac aus-
cultation, because beats that occur earlier than others may not be detectedperipherally and the heart rate can thus be seriously underestimated.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
80 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGIrregular rhythms include atrial ﬁ-
brillation and atrial or ventricularpremature contractions.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cRhythm. To begin your assessment of rhythm, feel the radial pulse. If
there are any irregularities, check the rhythm again by listening with yourstethoscope at the cardiac apex. Is the rhythm regular or irregular? If irreg-ular, try to identify a pattern: (1) Do early beats appear in a basically regularrhythm? (2) Does the irregularity vary consistently with respiration? (3) Isthe rhythm totally irregular?
RESPIRATORY RATE AND RHYTHM
Observe the rate, rhythm, depth, and effort of breathing. Count the number
of respirations in 1 minute either by visual inspection or by subtly listeningover the patient’s trachea with your stethoscope during your examination ofthe head and neck or chest. Normally, adults take 14 to 20 breaths a minutein a quiet regular pattern. An occasional sigh is normal. Check to see if ex-piration is prolonged.
TEMPERATURE

Although you may choose to omit measuring the temperature in ambula-tory patients, it should be checked whenever you suspect an abnormality.The average oral temperature, usually quoted at 37 °C (98.6°F), ﬂuctuates
considerably. In the early morning hours it may fall as low as 35.8 °C
(96.4°F), and in the late afternoon or evening it may rise as high as 37.3 °C
(99.1°F). Rectal temperatures are higher than oral temperatures by an aver-
age of 0.4 to 0.5 °C (0.7 to 0.9 °F), but this difference is also quite variable.
(In contrast, axillary temperatures arelower than oral temperatures by ap-
proximately 1 degree, but take 5 to 10 minutes to register and are generallyconsidered less accurate than other measurements.)
Most patients prefer oral to rectal temperatures. However, taking oral

temperatures is not recommended when patients are unconscious, rest-less, or unable to close their mouths. Temperature readings may be in-accurate and thermometers may be broken by unexpected movements ofthe patient’s jaws.
For oral temperatures, you may choose either a glass or electronic thermo-
meter. When using a glass thermometer, shake the thermometer down to35°C (96°F) or below, insert it under the tongue, instruct the patient to

close both lips, and wait 3 to 5 minutes. Then read the thermometer, re-insert it for a minute, and read it again. If the temperature is still rising,repeat this procedure until the reading remains stable. Note that hot orcold liquids, and even smoking, can alter the temperature reading. Inthese situations it is best to delay measuring the temperature for 10 to 15 minutes.EXAMPLES OF ABNORMALITIES TECHNIQUES OF EXAMINATION
CHAPTER 3 IBEGINNING THE PHYSICAL EXAMINATION: GENERAL SURVEY AND VITAL SIGNS 81Palpation of an irregularly irregular
rhythm reliably indicates atrial ﬁb-rillation. For all other irregular pat-terns, an ECG is needed to identifythe arrhythmia.
See Table 3-10, Selected Heart
Rates and Rhythms (p. ___) andTable 3-11, Selected IrregularRhythms (p. ___).
See Table 3-12, Abnormalities in
Rate and Rhythm of Breathing (p. ___)

Prolonged expiration suggests
narrowing in the bronchioles.
Fever or pyrexia refers to an 
elevated body temperature. Hyperpyrexia refers to extreme 
elevation in temperature, above41.1°C (106°F), while hypothermia
refers to an abnormally low temper-ature, below 35 °C (95°F) rectally.
Rapid respiratory rates tend to 
increase the discrepancy betweenoral and rectal temperatures. Inthis situation, rectal temperaturesare more reliable.
Causes of fever include infection,
trauma (such as surgery or crushinjuries), malignancy, blood dis-orders (such as acute hemolyticanemia), drug reactions, and immune disorders (such as collagenvascular disease).

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cThe chief cause of hypothermia is
exposure to cold. Other predispos-ing causes include reduced move-ment as in paralysis, interferencewith vasoconstriction as from sepsisor excess alcohol, starvation, hypothyroidism, and hypoglycemia.Elderly people are especially suscep-tible to hypothermia and also lesslikely to develop fever.If using an electronic thermometer, carefully place the disposable cover over
the probe and insert the thermometer under the tongue. Ask the patient toclose both lips, and then watch closely for the digital readout. An accuratetemperature recording usually takes about 10 seconds.
For a rectal temperature, ask the patient to lie on one side with the hip ﬂexed.
Select a rectal thermometer with a stubby tip, lubricate it, and insert it about3 cm to 4 cm (1
1⁄2inches) into the anal canal, in a direction pointing to the

umbilicus. Remove it after 3 minutes, then read. Alternatively, use an elec-tronic thermometer after lubricating the probe cover. Wait about 10 secondsfor the digital temperature recording to appear.
Taking the tympanic membrane temperature is an increasingly common
practice and is quick, safe, and reliable if performed properly. Make sure theexternal auditory canal is free of cerumen. Position the probe in the canal sothat the infrared beam is aimed at the tympanic membrane (otherwise themeasurement will be invalid). Wait 2 to 3 seconds until the digital temper-ature reading appears. This method measures core body temperature, whichis higher than the normal oral temperature by approximately 0.8 °C (1.4°F).TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
82 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 3-1 IHeight and Weight Tables for Adults Age 25 and Over
CHAPTER 3 IBEGINNING THE PHYSICAL EXAMINATION: GENERAL SURVEY, AND VITAL SIGNS 83
TABLE 3-1 IHeight and Weight Tables for Adults
Age 25 and Over
Weight in Pounds (without clothing)
Height (without shoes) Small Frame Medium Frame Large Frame
Men
5′1″ 105–113 111–122 119–134
5′2″ 108–116 114–126 122–137
5′3″ 111–119 117–129 125–141
5′4″ 114–122 120–132 128–145
5′5″ 117–126 123–136 131–149
5′6″ 121–130 127–140 135–154
5′7″ 125–134 131–145 140–159
5′8″ 129–138 135–149 144–163
5′9″ 133–143 139–153 148–167
5′10″ 137–147 143–158 152–172
5′11″ 141–151 147–163 157–177
6′0″ 145–155 151–168 161–182
6′1″ 149–160 155–173 168–187
6′2″ 153–164 160–178 171–192
6′3″ 157–168 165–183 175–197
Women
4′9″ 90–97 94–106 102–118
4′10″ 92–100 97–109 106–121
4′11″ 95–103 100–112 108–124
5′0″ 98–106 103–116 111–127
5′1″ 101–109 106–118 114–130
5′2″ 104–112 109–122 117–134

Women
5′3″ 107–115 112–126 121–138
5′4″ 110–119 116–131 125–142
5′5″ 114–123 120–136 129–146
5′6″ 118–127 124–139 133–150
5′7″ 122–131 128–143 137–154
5′8″ 126–136 132–147 141–159
5′9″ 130–140 136–151 145–164
5′10″ 134–144 140–155 149–169
From Clinician’s Handbook of Preventive Services. Washington, DC: U.S. Department of Health and
Human Services, 1994:142–143.These data are derived from an insured population. Note that assessment of the size of the body frameis subjective and must be estimated visually. Weights at the lower end of the range of normal may beadvisable for patients with cardiovascular disease and diabetes.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 3-2 IHealthy Eating: Food Groups and Servings per Day
84 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 3-2 IHealthy Eating: Food Groups 
and Servings per Day
Food Group
Bread, rice, cereal,
pasta (grains) group,especially whole grain
Vegetable groupFruit groupMilk, yogurt, and
cheese (dairy) group—preferably fat free orlow fat
Dry beans, eggs,
nuts, ﬁsh, and meatand poultry group—preferably lean or low fatWomen, Some
Older Adults,
Children Ages
2–6 yrs (about
1,600 cal)*
6
3
2
2–3**
2, for a total 
of 5 ozActive Women,
Most Men, Older
Children, Teen
Girls (about
2,200 cal)*
9
4
3
2–3**
of 6 ozActive Men, 
Teen Boys
(about 
2,800 cal)*
11
5
4
2–3**
3, for a total 
of 7 oz
Source: Adapted from U.S. Department of Agriculture, Center for Nutrition Policy and Promotion.

Teen Boys
(about 
11
5
4
2–3**
of 7 oz
The Food Guide Pyramid, Home and Garden Bulletin Number 252, 1996.*These are the calorie levels if low-fat, lean foods are chosen from the 5 major food groups and foodsfrom the fats, oil, and sweets group are used sparingly.**Older children and teenagers (ages 9–18 yrs) and adults over the age of 50 need 3 servings daily.During pregnancy and lactation, the recommended number of dairy group servings is the same as fornonpregnant women.
TABLE 3-3 IRapid Screen for Dietary Intake
Portions Consumed 
by Patient Recommended
Grains, cereals, bread group _____ 6–11
Fruit group _____ 2–4Vegetable group _____ 3–5Meat/meat substitute group _____ 2–3Dairy group _____ 2–3Sugars, fats, snack foods _____ —Soft drinks _____ —Alcoholic beverages _____ <2

Instructions. Ask the patient for a 24-hour dietary recall (perhaps two of these) before com-
pleting the form.
Source: Nestle M. Nutrition. In: Woolf SH, Jonas S, Lawrence RS, eds. Health Promotion and Disease
Prevention in Clinical Practice. Baltimore: Williams & Wilkins, 1996.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 3-4 INutrition Screening Checklist
CHAPTER 3 IBEGINNING THE PHYSICAL EXAMINATION: GENERAL SURVEY AND VITAL SIGNS 85
TABLE 3-4 INutrition Screening Checklist
I have an illness or condition that made me
change the kind and/or amount of food I eat.
I eat fewer than 2 meals per day.I eat few fruits or vegetables, or milk products.I have 3 or more drinks of beer, liquor, or wine
almost every day.
I have tooth or mouth problems that make it
hard for me to eat.
I don’t always have enough money to buy the
food I need.
I eat alone most of the time.I take 3 or more different prescribed or over-the-
counter drugs each day.
Without wanting to, I have lost or gained 
10 pounds in the last 6 months.
I am not always physically able to shop, cook
and/or feed myself.
Instructions. Check “yes” for each condition that applies, then total the nutritional score. For

total scores between 3–5 points (moderate risk) or ≥6 points (high risk), further evaluation
is needed (especially for the elderly).
Source: The Nutrition Screening Initiative, American Academy of Family Physicians. aafp.org/nsi/
e-check1.html. Accessed 7/22/01.Yes (2 pts) _____
Yes (3 pts) _____
Yes (2 pts) _____Yes (2 pts) _____
Yes (2 pts) _____Yes (4 pts) _____Yes (1 pt) _____
Yes (1 pt) _____
TOTAL _____

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5c86 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGTABLE 3-5 IFood Guide Pyramid: A Guide to Daily Food Choices
TABLE 3-5 IFood Guide Pyramid: A Guide to Daily Food Choices
TABLE 3-5
UNFIG 1

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cCHAPTER 3 IBEGINNING THE PHYSICAL EXAMINATION: GENERAL SURVEY AND VITAL SIGNS 87TABLE 3-5 IFood Guide Pyramid: A Guide to Daily Food ChoicesThe Food Guide Pyramid shows a range of daily servings for each food group. The
number of servings that is right for you depends on how many calories you need.Calories are a way to measure food energy. The energy your body needs dependson your age, sex, and size. It also depends on how active you are.In general, daily intake should be:
I1,600 calories for most women and older adults
I2,200 calories for children, teen girls, active women, and most men
I2,800 calories for teen boys and active men.

Those with lower calorie needs should select the lower number of servings fromeach food group. Their diet should include 2 servings of protein for a total of 5ounces. Those with average calorie needs should select the middle number of serv-ings from each food group. They should include 2 servings of protein for a total of6 ounces. Those with higher calorie needs should select the higher number of serv-

ings from each food group. Their diet should include 3 servings of protein for a totalof 7 ounces. Also, pregnant or breast-feeding women, teens, and young adults upto age 24 should consume 3 servings of dairy foods daily.The amount of food that counts as one serving is listed below. If you eat a largerportion, it is more than one serving. For example a slice of bread is one serving. Ahamburger bun is two servings.For mixed foods, estimate the food group servings of the main ingredients. Forexample, a large piece of sausage pizza would count in the bread group (crust),the milk group (cheese), the meat group (sausage), and the vegetable group(tomato sauce). Likewise, a helping of beef stew would count in the meat groupand the vegetable group. How Many Servings Do You Need?
What Counts as a Serving?
Bread, Cereal, Rice,
& Pasta
1 slice bread
1 tortilla
1⁄2c cooked rice,pasta or cereal
1 oz ready-to-eat 
cereal
1⁄2hamburger roll,bagel or English mufﬁn

& Pasta
1 tortilla
cereal
3–4 plain crackers (sm)1 pancake (4 ″)
1⁄2croissant (lg)
1⁄2doughnut or
danish (med)
1⁄16cake (average)
2 cookies (med)
1⁄12pie (2-crust, 8 ″)Vegetable
1⁄2c chopped raw or
cooked vegetables
1 c raw, leafy vegetables
3⁄4c vegetable juice
1⁄2c scalloped potatoes
1⁄2c potato salad
10 French friesFruit
1 piece fruit or
melon wedge
3⁄4c fruit juice
1⁄2c chopped,cooked orcanned fruit
1⁄4c dried fruitMilk, Yogurt, &
Cheese
1 c milk or yogurt
11⁄2oz natural cheese
2 oz process cheese1
1⁄2c ice cream or ice milk
1 c frozen yougurtMeat, Poultry,
Fish, Dry Beans,Eggs, & Nuts
2 1⁄2to 3 oz cooked
lean beef, pork, lamb,veal, poultry or ﬁsh
1⁄2c cooked beans or
1 egg or 2 T peanutbutter or 
1⁄3c nuts
count as 1 oz of meat
Lean Beef Choices
Eye of roundTop roundRound tipTop sirloinBottom roundTop loinTenderloinFats, Oils

1⁄3c nuts
& Sweets
Use sparingly
Adapted from U.S. Department of Agriculture, Human Nutrition Service. The Food Guide Pyramid, Home and Garden Bulletin Number 2 52, 1996.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 3-6 IEating Disorders and Excessively Low BMI
88 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGIn the United States an estimated 5 to 10 million women and one million men suffer from
eating disorders. These severe disturbances of eating behavior are often difﬁcult to detect,especially in teens wearing baggy clothes, or in individuals who binge then induce vomiting orevacuation. Be familiar with the two principal eating disorders, anorexia nervosa and bulimia
nervosa. Both conditions are characterized by distorted perceptions of body image and weight.
Early detection is important, since prognosis improves when treatment occurs in the earlystages of these disorders.
Clinical Features
Anorexia Nervosa Bulimia Nervosa
IRefusal to maintain minimally normal
body weight (or BMI above 17.5 kg/m2)
IAfraid of appearing fat
IFrequently starving but in denial; lackinginsight
IOften brought in by family members

IMay present as failure to make expectedweight gains in childhood or adolescence,amenorrhea in women, loss of libido orpotency in men
IAssociated with depressive symptoms suchas depressed mood, irritability, socialwithdrawal, insomnia, decreased libido
IAdditional features supporting diagnosis:self-induced vomiting or purging,excessive exercise, use of appetitesuppressants and/or diuretics
IBiological complications
INeuroendocrine changes: amenorrhea,
increased corticotropin-releasing factor,cortisol, growth hormone, serotonin;decreased diurnal cortisol ﬂuctuation,luteinizing hormone, follicle-stimulatinghormone, thyroid-stimulating hormone
ICardiovascular disorders: bradycardia,
hypotension, arrhythmias,cardiomyopathy
IMetabolic disorders: hypokalemia,

hypochloremic metabolic alkalosis,increased BUN, edema
IOther: dry skin, dental caries, delayed
gastric emptying, constipation, anemia,osteoporosis
TABLE 3-6 IEating Disorders and Excessively Low BMI
IRepeated binge eating followed by 
self-induced vomiting, misuse oflaxatives, diuretics or other medications,fasting; or excessive exercise
IOvereating at least twice a week during3-month period; large amounts of foodconsumed in short period ( ∼2 hrs)
IPreoccupation with eating; craving and
compulsion to eat; lack of control overeating; alternating with periods ofstarvation
IDread of fatness but may be obese
ISubtypes of
IPurging: bulimic episodes accompanied
by self-induced vomiting or use oflaxatives, diuretics, or enemas
INonpurging: bulimic episodes
accompanied by compensatorybehavior such as fasting, exercise butwithout purging.

See changes listed for anorexia nervosa,
especially weakness, fatigue, mildcognitive disorder; also erosion of dentalenamel, parotitis, pancreaticinﬂammation with elevated amylase, mildneuropathies, seizures, hypokalemia,hypochloremic metabolic acidosis,hypomagnesemia
Sources: World Health Organization: The ICD-10 Classiﬁcation of Mental and Behavorial Disorders:
Diagnostic Criteria for Research. At World Health Organization, Geneva, 1993. American PsychiatricAssociation: DSM-IV-TR: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. AmericanPsychiatric Association, Washington, DC, 1994. Halmi, KA: Eating Disorders: In: Kaplan, HI,Sadock BJ, eds. Comprehensive Textbook of Psychiatry, 7th ed. Philadelphia, Lippincott Williams &Wilkins; 2000:1663–1676.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 3-7 INutrition Counseling: Sources of Nutrients
CHAPTER 3 IBEGINNING THE PHYSICAL EXAMINATION: GENERAL SURVEY AND VITAL SIGNS 89
TABLE 3-7 INutrition Counseling: Sources of Nutrients
Nutrient Food Source
Calcium
Iron
Folate
Vitamin D
Source: Adapted from Dietary Guidelines Committee, 2000 Report. “Nutrition and Your Health:
Dietary Guidelines for Americans,” Washington, DC, Agricultural Research Service, U.S. Departmentof Agriculture.Dairy foods such as yogurt, milk, and natural cheeses
Breakfast cereal, fruit juice with calcium supplementsDark green leafy vegetables such as collards, turnip greens
Shellﬁsh
Lean meat, dark turkey meatCereals with iron supplementsSpinach, peas, lentilsEnriched and whole-grain bread
Cooked dried beans and peas
Oranges, orange juiceDark-green leafy vegetables
Milk (fortiﬁed)
Eggs, butter, margarineCereals (fortiﬁed)
TABLE 3-8 IPatients With Hypertension:
Recommended Changes in Diet

Dietary Change Food Source
Increase foods high in potassium
Decrease foods high in sodium
Dietary Guidelines for Americans,” Washington, DC, Agricultural Research Service, U.S. Departmentof Agriculture.Baked white or sweet potatoes, cooked greens
such as spinachBananas, plantains, many dried fruits, orange juice
Canned foods (soups, tuna ﬁsh)
Pretzels, potato chips, pickles, olivesMany processed foods (frozen dinners, ketchup,mustard)Batter-fried foodsTable salt, including for cooking

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5c90 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGTABLE 3-9 IAbnormalities of the Arterial Pulse and Pressure Waves
Normal
Small, Weak Pulses
Large, Bounding Pulses
Bisferiens Pulse
Pulsus Alternans
Bigeminal Pulse
Paradoxical Pulse
TABLE 3-9 IAbnormalities of the Arterial Pulse and Pressure Waves
The pulse pressure is about 30–40 mm Hg. The pulse contour is smooth and
rounded. (The notch on the descending slope of the pulse wave is notpalpable.)
The pulse pressure is diminished, and the pulse feels weak and small. The upstroke
may feel slowed, the peak prolonged. Causes include (1) decreased stroke volume,as in heart failure, hypovolemia, and severe aortic stenosis, and (2) increasedperipheral resistance, as in exposure to cold and severe congestive heart failure.
The pulse pressure is increased and the pulse feels strong and bounding. The

rise and fall may feel rapid, the peak brief. Causes include (1) an increased strokevolume, a decreased peripheral resistance, or both, as in fever, anemia, hyper-thyroidism, aortic regurgitation, arteriovenous ﬁstulas, and patent ductusarteriosus, (2) an increased stroke volume due to slow heart rates, as in bradycardiaand complete heart block, and (3) decreased compliance (increased stiffness) of theaortic walls, as in aging or atherosclerosis.
A bisferiens pulse is an increased arterial pulse with a double systolic peak. Causes
include pure aortic regurgitation, combined aortic stenosis and regurgitation, and,though less commonly palpable, hypertrophic cardiomyopathy.
The pulse alternates in amplitude from beat to beat even though the rhythm is

basically regular (and must be for you to make this judgment). When thedifference between stronger and weaker beats is slight, it can be detected only bysphygmomanometry. Pulsus alternans indicates left ventricular failure and isusually accompanied by a left-sided S
3.
This is a disorder of rhythm that may masquerade as pulsus alternans. A bigeminal
pulse is caused by a normal beat alternating with a premature contraction. Thestroke volume of the premature beat is diminished in relation to that of the normalbeats, and the pulse varies in amplitude accordingly.
A paradoxical pulse may be detected by a palpable decrease in the pulse’s

amplitude on quiet inspiration. If the sign is less pronounced, a blood-pressurecuff is needed. Systolic pressure decreases by more than 10 mm Hg duringinspiration. A paradoxical pulse is found in pericardial tamponade, constrictivepericarditis (though less commonly), and obstructive lung disease.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 3-10 ISelected Heart Rates and Rhythms
CHAPTER 3 IBEGINNING THE PHYSICAL EXAMINATION: GENERAL SURVEY AND VITAL SIGNS 91
ECG Pattern Usual Resting Rate
FAST 
(>100) 
NORMAL 
(60–100) 
SLOW 
(<60)
RHYTHMICALLY 
OR SPORADICALLYIRREGULAR
TOTALLY
IRREGULARSinus tachycardia
Supraventricular (atrial or nodal) tachycardiaAtrial ﬂutter with a regular ventricular responseVentricular tachycardia
Normal sinus rhythm
Second-degree AV blockAtrial ﬂutter with a regular ventricular response
Sinus bradycardia
Second-degree AV blockComplete heart block
Atrial or nodal (supraventricular) 
Early beats premature contractions
Ventricular premature 
Sinus arrhythmia contractions
Atrial ﬁbrillation
Atrial ﬂutter with 
varying block100–180
150–250100–175110–250
60–100
60–10075–100
<60
30–60
<40
See Table 3-11TABLE 3-10 ISelected Heart Rates and Rhythms

60–100
<60
30–60
<40
Cardiac rhythms may be classiﬁed as regular or irregular. When rhythms are irregular or rates are fast or slow, an ECG is
required to identify the origin of the beats (sinus node, AV node, atrium, or ventricle) and the pattern of conduction.Note that with AV (atrioventricular) block, arrhythmias may have a fast, normal, or slow ventricular rate.







REGULAR — WHAT IS THE RATE? 
IS THE RHYTHM 
REGULAR 
OR IRREGULAR?
IRREGULAR —WHAT IS THE PATTERN
OF IRREGULARITY?

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5c92 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGTABLE 3-11 ISelected Irregular RhythmsType of Rhythm ECG Waves and Heart Sounds Rhythm Heart Sounds
Atrial or Nodal 
PrematureContractions(Supraventricular )
Ventricular Premature 
Contractions
Sinus Arrhythmia
Atrial Fibrillation 
and Atrial Flutter With Varying AV Block
TABLE 3-11 ISelected Irregular Rhythms
S1may differ in intensity
from the S 1of normal
beats, and S 2may be
decreased. Both sounds areotherwise similar to thoseof normal beats.
S
1may differ in intensity
from the S 1of the normal
decreased. Both sounds are likely to be split.
Normal, although S
1may
vary with the heart rate.
S1varies in intensity.A beat of atrial or nodal
origin comes earlier thanthe next expected normalbeat. A pause follows andthen the rhythm resumes.
A beat of ventricular

A beat of ventricular 
origin comes earlier thanthe next expected normalbeat. A pause follows andthe rhythm resumes.
The heart varies cyclically,
usually speeding up withinspiration and slowingdown with expiration.
The ventricular rhythm is
totally irregular, althoughshort runs of the irregularventricular rhythm mayseem regular.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 3-12 IAbnormalities in Rate and Rhythm of Breathing
CHAPTER 3 IBEGINNING THE PHYSICAL EXAMINATION: GENERAL SURVEY AND VITAL SIGNS 93
Normal
The respiratory rate is about 
14–20 per min in normal adults andup to 44 per min in infants.
Cheyne–Stokes Breathing
Periods of deep breathing alternatewith periods of apnea (no breathing).Children and aging people normallymay show this pattern in sleep. Othercauses include heart failure, uremia,drug-induced respiratory depression,and brain damage (typically on bothsides of the cerebral hemispheres ordiencephalon).Rapid Shallow Breathing
(Tachypnea)
Rapid shallow breathing has a
number of causes, includingrestrictive lung disease, pleuritic chestpain, and an elevated diaphragm.
Ataxic Breathing 
(Biot’s Breathing)
Ataxic breathing is characterized

Ataxic breathing is characterized 
by unpredictable irregularity.Breaths may be shallow or deep, andstop for short periods. Causesinclude respiratory depression andbrain damage, typically at themedullary level.Rapid Deep Breathing
(Hyperpnea, Hyperventilation)
Rapid deep breathing has several
causes, including exercise, anxiety,and metabolic acidosis. In thecomatose patient, consider infarction,hypoxia, or hypoglycemia affectingthe midbrain or pons. Kussmaul
breathing is deep breathing due to
metabolic acidosis. It may be fast,normal in rate, or slow.
Sighing Respiration
Breathing punctuated by frequentsighs should alert you to thepossibility of hyperventilationsyndrome—a common cause ofdyspnea and dizziness. Occasionalsighs are normal.Slow Breathing (Bradypnea)
Slow breathing may be secondary to

such causes as diabetic coma, drug-induced respiratory depression, andincreased intracranial pressure.
Obstructive Breathing
In obstructive lung disease,expiration is prolonged becausenarrowed airways increase theresistance to air ﬂow. Causes include asthma, chronic bronchitis,and COPD.TABLE 3-12 IAbnormalities in Rate and Rhythm of Breathing
When observing respiratory patterns, think in terms of rate, depth, and regularity of the patient’s breathing. Describe
what you see in these terms. Traditional terms, such as tachypnea, are given below so that you will understand them, butsimple descriptions are recommended for use.

The SkinCHAPTER
The Skin 44
CHAPTER 4 ITHE SKIN 95
The major function of the skin is to keep the body in homeostasis despite the
daily assaults of the environment. It provides boundaries for body ﬂuids whileprotecting underlying tissues from microorganisms, harmful substances, andradiation. It modulates body temperature and synthesizes vitamin D.
The skin is the heaviest single organ
of the body, accounting for approx-imately 16% of body weight andcovering an area of roughly 1.2 to2.3 m eters squared. It contains three
layers: the epidermis, the dermis,and the subcutaneous tissues.
The most superﬁcial layer, the epi-
dermis, is thin, devoid of blood ves-
sels, and itself divided into two lay-ers: an outer horny layer of deadkeratinized cells and an inner cellularlayer where both melanin and ker-atin are formed.
The epidermis depends on the un-
derlying dermis for its nutrition. The

dermis is well supplied with blood. Itcontains connective tissue, seba-ceous glands, sweat glands, and hairfollicles. It merges below with sub-
cutaneous tissue, or adipose , also
known as fat.
Hair, nails, andsebaceous andsweat glands are considered appendages of the
skin. Adults have two types of hair: vellus hair, which is short, ﬁne, incon-
spicuous, and relatively unpigmented; and terminal hair, which is coarser,
thicker, more conspicuous, and usually pigmented. Scalp hair and eyebrowsare examples of terminal hair.
Hair shaft
Horny layer
Cellular layer
Sebaceous
gland
Muscle that
erects hair shaft
Sweat gland
Hair follicle
Vein
Nerve
ArteryDuct of
sweat gland
Epidermis
Dermis
Subcutaneous
tissue

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cNails protect the distal ends of the ﬁngers and toes. The ﬁrm, rectangular,
and usually curving nail plate gets its pink color from the vascular nail bed
to which the plate is ﬁrmly attached. Note the whitish moon ( lunula ) and
the free edge of the nail plate. Roughly a fourth of the nail plate (the nail
root) is covered by the proximal nail fold. The cuticle extends from this fold
and, functioning as a seal, protects the space between the fold and the platefrom external moisture. Lateral nail folds cover the sides of the nail plate.
Note that the angle between the proximal nail fold and the nail plate is nor-mally less than 180°.ANATOMY AND PHYSIOLOGY
96 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Lateral 
nail fold LunulaProximal
nail fold
Nail plate Cuticle Free
edge
Fingernails grow at about 0.1 mm daily; toenails grow more slowly.
Sebaceous glands produce a fatty substance that is secreted to the skin surface

nail fold
edge
through the hair follicles. These glands are present on all skin surfaces exceptthe palms and soles. Sweat glands are of two types: eccrine and apocrine. The
eccrine glands are widely distributed, open directly onto the skin surface, and
by their sweat production help to control body temperature. In contrast, theapocrine glands are found chieﬂy in the axillary and genital regions, usually
open into hair follicles, and are stimulated by emotional stress. Bacterial de-composition of apocrine sweat is responsible for adult body odor.
The color of normal skin depends primarily on four pigments: melanin,
carotene, oxyhemoglobin, and deoxyhemoglobin. The amount of melanin,

the brownish pigment of the skin, is genetically determined and is increasedby sunlight. Carotene is a golden yellow pigment that exists in subcutaneous
fat and in heavily keratinized areas such as the palms and soles.
Hemoglobin, which circulates in the red cells and carries most of the oxygen
of the blood, exists in two forms. Oxyhemoglobin, a bright red pigment, pre-
dominates in the arteries and capillaries. An increase in blood ﬂow throughthe arteries to the capillaries of the skin causes a reddening of the skin, whilethe opposite change usually produces pallor. The skin of light-colored per-sons is normally redder on the palms, soles, face, neck, and upper chest.
As blood passes through the capillary bed, some of the oxyhemoglobin loses
its oxygen to the tissues and changes to deoxyhemoglobin —a darker and
Nail root
Proximal nail fold

Nail root
Nail plate
Cross section
of nail plate
Nail bed
Distal phalanx

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5csomewhat bluer pigment. An increased concentration of deoxyhemoglobin
in cutaneous blood vessels gives the skin a bluish cast known as cyanosis.
Cyanosis is of two kinds, depending on the oxygen level in the arterial blood.
If this level is low, cyanosis is central. If it is normal, cyanosis is peripheral.
Peripheral cyanosis occurs when cutaneous blood ﬂow decreases and slows,and tissues extract more oxygen than usual from the blood. Peripheralcyanosis may be a normal response to anxiety or a cold environment.
Skin color is affected not only by pigments but also by the scattering of light
as it is reﬂected back through the turbid superﬁcial layers of the skin or ves-sel walls. This scattering makes the color look more blue and less red. Thebluish color of a subcutaneous vein is a result of this effect; it is much bluerthan the venous blood obtained on venipuncture.
Changes With Aging

As people age their skin wrinkles, becomes lax, and loses turgor. The vascu-larity of the dermis decreases and the skin of light-skinned persons tends tolook paler and more opaque. Comedones (blackheads) often appear on thecheeks or around the eyes. Where skin has been exposed to the sun it looksweatherbeaten: thickened, yellowed, and deeply furrowed. Skin on the backsof the hands and forearms appears thin, fragile, loose, and transparent, andmay show whitish, depigmented patches known as pseudoscars. Well-demarcated, vividly purple macules or patches, termed actinic purpura, mayalso appear in the same areas, fading after several weeks. These purpuric spotscome from blood that has leaked through poorly supported capillaries andhas spread within the dermis. Dry skin (asteatosis)—a common problem—isﬂaky, rough, and often itchy. It is frequently shiny, especially on the legs,where a network of shallow ﬁssures often creates a mosaic of small polygons.

Some common benign lesions often accompany aging: cherry angiomas
(p. __), which often appear early in adulthood, seborrheic keratoses (p. __),and, in sun-exposed areas, actinic lentigines or “liver spots” (p. __) and ac-tinic keratoses (p. __). Elderly people may also develop two common skincancers: basal cell carcinoma and squamous cell carcinoma (p. __).
Nails lose some of their luster with age and may yellow and thicken, espe-
cially on the toes.
Hair on the scalp loses its pigment, producing the well-known graying. As
early as 20, a man’s hairline may start to recede at the temples; hair loss atthe vertex follows. Many women show a less severe loss of hair in a similarpattern. Hair loss in this distribution is genetically determined.
In both sexes, the number of scalp hairs decreases in a generalized pattern,
and the diameter of each hair diminishes.
Less familiar, but probably more important clinically, is the normal hair

loss elsewhere on the body: the trunk, pubic areas, axillae, and limbs.
CHAPTER 4 ITHE SKIN 97

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cThese changes will be discussed in later chapters. Coarse facial hairs appear
on the chin and upper lip of many women by about the age of 55, but donot increase further thereafter.
Many of the observations described here pertain to lighter-skinned persons
and do not necessarily apply to others. For example, Native American menhave relatively little facial and body hair compared to lighter-skinned men,and should be evaluated according to their own norms.HEALTH PROMOTION AND COUNSELING
98 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGCauses of generalized itching 
without obvious reason include dryskin, aging, pregnancy, uremia,jaundice, lymphomas andleukemia, drug reaction, and lice.
EXAMPLES OF ABNORMALITIES
IHair loss
IRash
IMoles
Start your inquiry about the skin with a few open-ended questions: “Have

IHair loss
IRash
IMoles
you noticed any changes in your skin?”. . . your hair? . . . your nails?. . .“Have you had any rashes? . . . sores? . . . lumps? . . . itching?” “Have younoticed any moles that have changed in appearance?” “Where?” “When?”
It is usually best to defer further questions about the skin until the physical
examination, when you can see what the patient is talking about.THE HEALTH HISTORY
IRisk factors for melanoma
IAvoidance of excessive sun exposure

Clinicians play an important role in counseling patients about protectivemeasures for skin care and the hazards of excessive sun exposure. Basal celland squamous cell carcinomas are the most common cancers in the UnitedStates and are found most frequently in sun-exposed areas, particularlythe head, neck, and hands. Malignant melanoma, although rare, is the mostrapidly increasing U.S. malignancy, now occurring in 1 in 74 Americans.Although melanoma often arises in non–sun-exposed areas, it is associated

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cwith intermittent and intense sun exposure and blistering sunburns in
childhood. Other risk factors include family history of melanoma, lightskin, presence of atypical moles (dysplastic nevi) or ≥50 common moles,
and immunosuppression.
Protective measures are three-fold: avoiding unnecessary sun exposure,

using sunscreen, and inspecting the skin. Caution patients to minimize di-rect sun exposure, especially at midday when ultraviolet B rays (UV-B), themost common cause of skin cancer, are most intense. Sunscreens fall intotwo categories—thick pastelike ointments that block all solar rays, and light-absorbing sunscreens rated by “sun protective factor” (SPF). The SPF is aratio of the number of minutes for treated versus untreated skin to reddenwith exposure to UV-B. An SPF of at least 15 is recommended and protectsagainst 93% of UV-B. (There is no scale for UV-A, which causes photoaging,or UV-C, the most carcinogenic ray but blocked in the atmosphere byozone.) Water-resistant sunscreens that remain on the skin for prolongedperiods are preferable.
Detection of skin cancer rests on visual inspection, preferably of the total

body surface. Current detection rates are higher for clinicians than patients,but the beneﬁts of self-examination are not well studied. Recommendationsabout screening intervals are variable. The American Cancer Society rec-ommends monthly self-examination, clinician screening at 3-year intervalsfor persons aged 20 to 39, and annual clinical examination for persons overage 40. Clinicians and patients should know the “ABCDEs” for melanoma:
Afor asymmetry, Bfor irregular borders, Cfor color variation or change
(especially blue or black), Dfor diameter larger than 6 mm, and Efor eleva-

tion. Look in sun-exposed areas for ulcerated nodules with translucent orpearly surfaces (seen in basal cell carcinoma) and roughened patches of skinwith accompanying erythema (common in squamous cell carcinoma). Pa-tients with suspicious lesions should be referred to a dermatologist for fur-ther evaluation and biopsy.HEALTH PROMOTION AND COUNSELING
CHAPTER 4 ITHE SKIN 99EXAMPLES OF ABNORMALITIES
Preview: Recording the Physical Examination—The Skin
Note that initially you may use sentences to describe your ﬁndings; later
you will use phrases. The style below contains phrases appropriate formost write-ups. Unfamiliar terms are explained in the next section, “Tech-niques of Examination.”
“Color good. Skin warm and moist. Nails without clubbing or cyanosis.No suspicious nevi. No rash, petechiae, or ecchymoses.”
OR

OR
“Marked facial pallor, with circumoral cyanosis. Palms cold and moist.Cyanosis in nailbeds of ﬁngers and toes. One raised blue-black nevus,1×2 cm, with irregular border on right forearm. No rash.”
OR
“Facial plethora. Skin icteric. Spider angioma over anterior torso. Singlepearly papule with depressed center and telangiectasias, 1 ×1 cm, on
posterior neck above collarline. No suspicious nevi. Nails with clubbingbut no cyanosis.”Suggests central cyanosis and pos-
sible melanoma
Suggests possible liver disease and
basal cell carcinoma

100 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGPallor due to decreased redness is
seen in anemia and in decreasedblood ﬂow, as in fainting or arterialinsufﬁciency.
Causes of central cyanosis include
advanced lung disease, congenitalheart disease, and abnormal hemoglobins.
Cyanosis in congestive heart fail-
ure is usually peripheral, reﬂectingdecreased blood ﬂow, but in pul-monary edema it may also be cen-tral. Venous obstruction may causeperipheral cyanosis.
Jaundice suggests liver disease or
excessive hemolysis of red bloodcells.Artiﬁcial light often distorts colors
and masks jaundice.
See Table 4-1, Basic Types of Skin
Lesions (pp. __–__), and Table 4-2,Skin Colors (p. __).
Observe the skin and related structures during the General Survey and
throughout the rest of your examination. The entire skin surface should be

inspected in good light, preferably natural light or artiﬁcial light that re-sembles it. Correlate your ﬁndings with observations of the mucous mem-branes. Diseases may manifest themselves in both areas, and both are neces-sary for assessing skin color. Techniques of examining these membranes aredescribed in later chapters.
To make your observations more astute, acquaint yourself now with some
of the skin lesions and colors that you may encounter.
Skin
Inspect and palpate the skin. Note these characteristics:
Color. Patients may notice a change in their skin color before the clini-
cian does. Ask about it. Look for increased pigmentation (brownness), lossof pigmentation, redness, pallor, cyanosis, and yellowing of the skin.
The red color of oxyhemoglobin and the pallor due to a lack of it are best

assessed where the horny layer of the epidermis is thinnest and causes theleast scatter: the ﬁngernails, the lips, and the mucous membranes, particu-larly those of the mouth and the palpebral conjunctiva. In dark-skinned per-sons, inspecting the palms and soles may also be useful.
Central cyanosis is best identiﬁed in the lips, oral mucosa, and tongue. The
lips, however, may turn blue in the cold, and melanin in the lips may simu-late cyanosis in darker-skinned people.
Cyanosis of the nails, hands, and feet may be central or peripheral in origin.
Peripheral cyanosis may be caused by anxiety or a cold examining room.
Look for the yellow color of jaundice in the sclera. Jaundice may also appear
in the palpebral conjunctiva, lips, hard palate, undersurface of the tongue,tympanic membrane, and skin. To see jaundice more easily in the lips, blanchout the red color by pressure with a glass slide.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cFor the yellow color that accompanies high levels of carotene, look at the
palms, soles, and face.
Moisture. Examples are dryness, sweating, and oiliness.
Temperature. Use the backs of your ﬁngers to make this assessment. In
addition to identifying generalized warmth or coolness of the skin, note thetemperature of any red areas.
Texture. Examples are roughness and smoothness.
Mobility and Turgor. Lift a fold of skin and note the ease with which
it lifts up (mobility) and the speed with which it returns into place (turgor).
Lesions. Observe any lesions of the skin, noting their characteristics:
ITheir anatomic location and distribution over the body. Are they gener-
alized or 1ocalized? Do they, for example, involve the exposed surfaces,the intertriginous (skin fold) areas, or areas exposed to speciﬁc allergensor irritants such as wrist bands, rings, or industrial chemicals?

ITheir arrangement. For example, are they linear, clustered, annular (in a
ring), arciform (in an arc), or dermatomal (covering a skin band that cor-responds to a sensory nerve root; see pp. __–__)?
IThe type(s) of skin lesions (e.g., macules, papules, vesicles, nevi). If possi-
ble, ﬁnd representative and recent lesions that have not been traumatizedby scratching or otherwise altered. Inspect them carefully and feel them.
ITheir color.
EVALUATING THE BEDBOUND PATIENT
People who are conﬁned to bed, especially when they are emaciated, elderly,
or neurologically impaired, are particularly susceptible to skin damage andulceration. Pressure sores result when sustained compression obliterates arte-

riolar and capillary blood ﬂow to the skin. Sores may also result from theshearing forces created by bodily movements. When a person slides down inbed from a partially sitting position, for example, or is dragged rather thanlifted up from a supine position, the movements may distort the soft tissuesof the buttocks and close off the arteries and arterioles within. Friction andmoisture further increase the risk.Carotenemia
Dryness in hypothyroidism; oiliness
in acne
Generalized warmth in fever, 
hyperthyroidism; coolness in hypothyroidism. Local warmth ofinflammation or cellulitis
Roughness in hypothyroidismDecreased mobility in edema, 
scleroderma; decreased turgor indehydration
Many skin diseases have typical

distributions. Acne affects theface, upper chest, and back; psoriasis, the knees and elbows(among other areas); and Candida infections, the inter-
triginous areas.
Vesicles in a unilateral dermatomal
pattern are typical of herpes zoster.
Lesions (pp. __–__); Table 4-3, Vascular and Purpuric Lesions ofthe Skin (p. __); Table 4-4, SkinTumors (p. __); and Table 4-5, Be-nign and Malignant Nevi (p.__).
See Table 4-6, Pressure Ulcers 
(p. __).EXAMPLES OF ABNORMALITIES TECHNIQUES OF EXAMINATION
CHAPTER 4 ITHE SKIN 101

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cLocal redness of the skin warns of
impending necrosis, althoughsome deep pressure sores developwithout antecedent redness. Ulcersmay be seen.
See Table 4-7, Findings In or Near
the Nails (pp. __–__).
Alopecia refers to hair loss—diffuse,
patchy, or total.
Sparse hair in hypothyroidism; ﬁne
silky hair in hyperthyroidism
See Table 4-8, Skin Lesions in Con-
text (pp. __–__).TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
102 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGHair
Inspect and palpate the hair. Note its quantity, distribution, and texture.
Skin Lesions in Context
After familiarizing yourself with the basic types of lesions, review their ap-

pearances in Table 4-8 and in a well-illustrated textbook of dermatology.Whenever you see a skin lesion, look it up in such a text. The type of lesions,their location, and their distribution, together with other information fromthe history and the examination, should equip you well for this search and,in time, for arriving at speciﬁc dermatologic diagnoses.
Assess every susceptible patient by carefully inspecting the skin that overlies
the sacrum, buttocks, greater trochanters, knees, and heels. Roll the patientonto one side to see the sacrum and buttocks.
Nails
Inspect and palpate the ﬁngernails and toenails. Note their color and shape,and any lesions. Longitudinal bands of pigment may be seen in the nails ofnormal people who have darker skin.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 4-1 IBasic Types of Skin Lesions
CHAPTER 4 ITHE SKIN 103
TABLE 4-1 IBasic Types of Skin Lesions
Primary Lesions (May Arise From Previously Normal Skin)
Circumscribed, Flat, Nonpalpable
Changes in Skin Color
Macule— Small ﬂat spot, up
to 1.0 cm
Examples: freckle, petechiaPatch— Flat spot, 1.0 cm or
largerPalpable Elevated Solid Masses
Papule— Up to 1.0 cm.
Example: an elevated nevus
Plaque— Elevated superﬁcial
lession 1.0 cm or larger,often formed by coalescenceof papules 
Nodule— Marble-like lesion
larger than 0.5 cm, oftendeeper and ﬁrmer than apapule
Wheal— A somewhat
irregular, relatively transient,superﬁcial area of localizedskin edema. Examples:mosquito bite, hiveCircumscribed Superﬁcial Elevations of
the Skin Formed by Free Fluid in aCavity Within the Skin Layers
Vesicle— Up to 1.0 cm; ﬁlled
with serous ﬂuid. Example:herpes simplex
Bulla— 1.0 cm or larger;
ﬁlled with serous ﬂuid.Example: 2nd-degree burn

Pustule— Filled with pus.
Examples: acne, impetigo
Secondary Lesions (Result From Changes in Primary Lesions)
Loss of Skin Surface
Erosion— Loss of the
superﬁcial epidermis; surfaceis moist but does not bleed.Example: moist area after therupture of a vesicle, as inchickenpox
Material on the Skin Surface
Crust— The dried residue of
serum, pus, or blood.Example: impetigoUlcer— A deeper loss of
epidermis and dermis; maybleed and scar. Examples:stasis ulcer of venousinsufﬁciency, syphiliticchancreFissure— A linear crack in
the skin. Example: athlete’sfoot
Scale— A thin ﬂake of
exfoliated epidermis.Examples: dandruff, dry skin,psoriasis
(table continues next page)

104 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 4-1 IBasic Types of Skin Lesions (Continued)
Miscellaneous Lesions
Excoriation— An abrasion or scratch
mark. It may be linear, as illustrated, orrounded, as in a scratched insect bite.
Scar— Replacement of
destroyed tissue by ﬁbroustissue. May be thick andpink (hypertrophic) or thinand white (atrophic), butdoes not extend beyondthe injured areaBurrow of Scabies— A person with scabies has
intense itching. Skin lesions include smallpapules, pustules, lichenified areas, andexcoriations. With a magnifying lens, look forthe burrow of the mite that causes it. A
burrow is a minute, slightly raised tunnel inthe epidermis and is commonly found on thefinger webs and on the sides of the fingers. Itlooks like a short (5–15 mm), linear or curved,gray line and may end in a tiny vesicle.
Additional Terms:

IComedo— The common blackhead that marks the plugged opening of a sebaceous gland, frequently seen with acne
INevus— The common mole; appears ﬂat to slightly elevated, round and evenly pigmented; however, some nevi look quite different, as in t he pigmented nevi of
melanoma.
ITelangiectasias— Dilated small vessels (can be venules, arterioles, including spider angiomas, or capillaries) that look either red or bluish. M ay appear by
themselves or as parts of other lesions, as in a basal cell carcinoma or radiodermatitis (skin injury from ionizing radiation).
(Sources of photos: Licheniﬁcation, Excoriation, Scar, Burrow of Scabie s—Goodheart HP: A Photoguide of Common Skin Disorders: Diagnosis and Management. Philadelphia,
Lippincott Williams & Wilkins, 1999; Atrophy— Fitzpatrick JE, Aeling JL: Dermatology Secrets in Color, 2nd ed. Philadelphia, Lippincott Williams & Wilkins, 2000)
Licheniﬁcation— Thickening and

roughening of the skin with increasedvisibility of the normal skin furrows.Example: atopic dermatitisAtrophy— Thinning of the skin with loss
of the normal skin furrows; the skin looksshinier and more translucent than normal.Example: arterial insufﬁciency

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 4-2 ISkin Colors 
CHAPTER 4 ITHE SKIN 105
TABLE 4-2 ISkin Colors
Jaundice
Jaundice makes the skin diffusely yellow.
Note this patient’s skin color, contrastedwith the examiner’s hand. The color ofjaundice is seen most easily and reliably inthe sclera, as shown here. It may also bevisible in mucous membranes. Causesinclude liver disease and hemolysis of redblood cells.
Carotenemia
The yellowish palm ofcarotenemia, shown on the left,is compared with a normally pinkpalm—a useful technique for asometimes subtle ﬁnding. Unlikejaundice, carotenemia does notaffect the sclera, which remainswhite. The cause is a diet high incarrots and other yellowvegetables or fruits. Carotenemiais not harmful, but indicates theneed for assessing dietary intake.
Cyanosis

Cyanosis
Cyanosis is the somewhat bluishcolor that is visible in thesetoenails and toes. Compare thiscolor with the normally pinkﬁngernails and ﬁngers of thesame patient. Impaired venousreturn in the leg caused thisexample of peripheral cyanosis.Cyanosis, especially when slight,may be hard to distinguish fromnormal skin color.Café-Au-Lait Spot
The common café-au-lait spot is aslightly but uniformly pigmentedmacule or patch with a somewhatirregular border. Most of these spotsare 0.5 cm to 1.5 cm in diameter andare of no consequence. Six or moresuch spots, each with a diameter of>1.5 cm, however, suggest neuro-ﬁbromatosis (p. __). (The small,darker macules are unrelated.)
Tinea Versicolor

More common than vitiligo is thissuperﬁcial fungus infection of theskin. It causes hypopigmented,slightly scaly macules on the trunk,neck, and upper arms. They are easierto see in darker skin and may becomemore obvious after tanning. In lighterskin, the macules may look reddish ortan instead of pale. The macules maybe much more numerous than in thisexample.
Vitiligo
In vitiligo, depigmented macules
appear on the face, hands, feet, andother regions and may coalesce intoextensive areas that lack melanin. Thebrown pigment on this woman’s legsis her normal skin color; the pale areasare due to vitiligo. The condition maybe hereditary. These changes may bedistressing to the patient.Changes in Melanin
A widespread increase in melanin may be caused by Addison’s disease (hypofunctionof the adrenal cortex) or some pituitary tumors. More common are local areas ofincreased or decreased pigment:

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 4-3 IVascular and Purpuric Lesions of the Skin
106 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 4-3 IVascular and Purpuric Lesions of the Skin
Vascular Purpuric
Spider Angioma Spider Vein Cherry Angioma Petechia/Purpura Ecchymosis
Color
Size
Shape
Pulsatility
Effect of
Pressure
DistributionSigniﬁcanceFiery red
From very small to 
2 cm
Central body,
sometimes raised,surrounded byerythema andradiating legs
Often demonstrable in
the body of the spider,when pressure with aglass slide is applied
Pressure on the body
causes blanching ofthe spider.
Face, neck, arms, and
upper trunk; almostnever below the waist
Liver disease,
pregnancy, vitamin Bdeﬁciency; also occursnormally in somepeopleBluish
Variable, from very small
to several inches
Variable. May resemble a
spider or be linear,irregular, cascading
Absent
Pressure over the center
does not cause blanching,but diffuse pressureblanches the veins.

Absent
Most often on the legs,
near veins; also on theanterior chest
Often accompanies
increased pressure in thesuperﬁcial veins, as invaricose veinsBright or ruby red; 
may become brownishwith age
1–3 mm
Round, ﬂat or
sometimes raised, maybe surrounded by apale halo
Absent
May show partial
blanching, especially ifpressure is applied withthe edge of a pinpoint
Trunk; also extremities
None; increase in size
and numbers withagingDeep red or reddish
purple, fading away overtime
Petechia, 1–3 mm;
purpura, larger
Rounded, sometimes
irregular; ﬂat
AbsentNoneVariable
Blood outside the vessels;
may suggest a bleedingdisorder or, if petechiae,emboli to skinPurple or purplish blue,
fading to green, yellow,and brown with time
Variable, larger than
petechiae
Rounded, oval, or

petechiae
irregular; may have acentral subcutaneous ﬂatnodule (a hematoma)
Absent
NoneVariable
Blood outside the
vessels; often secondaryto bruising or trauma;also seen in bleedingdisorders
(Sources of photos: Spider Angioma— Marks R: Skin Disease in Old Age. Philadelphia, JB Lippincott, 1987; Petechia/Purpura— Kelley WN: Textbook of Internal Medicine. Philadelphia,
JB Lippincott, 1989)

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 4-4 ISkin Tumors
CHAPTER 4 ITHE SKIN 107
TABLE 4-4 ISkin Tumors
Basal Cell Carcinoma
A basal cell carcinoma, though malignant, grows
slowly and seldom metastasizes. It is mostcommon in fair-skinned adults over age 40, andusually appears on the face. An initial translucentnodule spreads, leaving a depressed center and aﬁrm, elevated border. Telangiectatic vessels areoften visible.Squamous Cell Carcinoma
Squamous cell carcinoma usually appears on sun-exposed skin of fair-skinned adults over 60. It maydevelop in an actinic keratosis. It usually growsmore quickly than a basal cell carcinoma, is ﬁrmer,and looks redder. The face and the back of thehand are often affected, as shown here.Kaposi’s Sarcoma in AIDS

When Kaposi’s sarcoma, a malignant tumor,accompanies AIDS, it may appear in many forms:macules, papules, plaques, or nodules almostanywhere on the body. Lesions are often multipleand may involve internal structures. On the left areovoid, pinkish red plaques that typically lengthenalong the skin lines. They may become pigmented.On the right is a purplish red nodule on the foot.Seborrheic Keratosis
Seborrheic keratoses are common, benign,yellowish to brown, raised lesions that feel slightlygreasy and velvety or warty. Typically multiple andsymmetrically distributed on the trunk of olderpeople, they may also appear on the face andelsewhere. In black people, often younger women,they may appear as small, deeply pigmentedpapules on the cheeks and temples (dermatosispapulosa nigra).
(Sources of photos: Basal Cell Epithelioma: Rapini R. Squamous Cell Carcinoma, Actinic Keratosis, and Seborrheic Keratosis —Sauer GC: Manual of Skin Diseases, 5th ed. Philadelphia, JB

Lippincott, 1985; Kaposi’s Sarcoma in AIDS —DeVita VT Jr, Hellman S, Rosenberg SA [eds]: AIDS: Etiology, Diagnosis, Treatment, and Prevention. Philadelphia, JB Lippincott , 1985)
Actinic Keratosis
Actinic keratoses are superﬁcial, ﬂattened papules
covered by a dry scale. Often multiple, they maybe round or irregular, and are pink, tan, orgrayish. They appear on sun-exposed skin of older,fair-skinned persons. Though themselves benign,these lesions may give rise to squamous cellcarcinoma (suggested by rapid growth, induration,redness at the base, and ulceration). Keratoses onface and hand, typical locations, are shown.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 4-5 IBenign and Malignant Nevi
108 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 4-5 IBenign and Malignant Nevi
Benign Nevus
Thebenign nevus , or common mole, usually appears in
the ﬁrst few decades. Several nevi may arise at the sametime, but their appearance usually remains unchanged.Note the following typical features and contrast themwith those of atypical nevi and melanoma:
IRound or oval shape
ISharply deﬁned borders
IUniform color, especially tan or brown
IDiameter < 6 mm
IFlat or raised surface
Changes in these features raise the the spectre of
atypical (dysplastic) nevi, or melanoma. Atypical nevi
are varied in color but often dark and larger than 6mm, with irregular borders that fade into thesurrounding skin. Look for atypical nevi primarily onthe trunk. They may number more than 50 to 100.
IAsymmetry (Fig. A)
IIrregular Borders , especially notching (Fig. B)

IVariation in Color, especially mixtures of black,
blue, and red (Figs. B, C)
IDiameter >6 mm (Fig. C)
IElevation , though also may be ﬂat (Fig. C).
Review melanoma risk factors such as intense year-
round sun exposure, blistering sunburns inchildhood, fair skin that freckles or burns easily(especially if blond or red hair), family history ofmelanoma, and nevi that are changing or atypical,especially if >50. Changing nevi may have newswelling or redness beyond the border, scaling,oozing, or bleeding, or sensations such as itching,burning, or pain.
On darker skin, look for melanomas under the
nails, on the hands, or on the soles of the feet.
(Courtesy of American Cancer Society; American Academy of Dermatology)
Malignant Melanoma
Learn the “ ABCDEs ” of melanoma from these
reference standard photographs from theAmerican Cancer Society:
A
BC

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 4-6 IPressure Ulcers
CHAPTER 4 ITHE SKIN 109
Risk Factors for Pressure Ulcers
IDecreased mobility, especially if accompanied by increased pressure or
movement causing friction or shear stress
IDecreased sensation, from brain or spinal cord lesions or peripheral nerve disease
IDecreased blood ﬂow from hypotension or microvascular disease such asdiabetes or atherosclerosisIFecal or urinary incontinence
IPresence of fracture
IPoor nutritional status or low albuminTABLE 4-6 IPressure Ulcers
Pressure ulcers, also termed decubitus ulcers, usually develop over body promi-
nences subject to unrelieved pressure, resulting in ischemic damage to underlyingtissue. Prevention is as important as identiﬁcation and treatment: inspect the skinthoroughly for early warning signs of erythema that blanches with pressure,

especially in patients with risk factors. Pressure ulcers form most commonly overthe sacrum, ischial tuberosities, greater trochanters, and heels. A commonly appliedstaging system, based on depth of destroyed tissue, is illustrated below. How-ever, note in Stage I the skin is still intact and is not yet an ulcer; ulcers withnecrosis or eschar must be débrided before they can be staged; and ulcers do notnecessarily progress sequentially through the four stages. Inspect ulcers for signs

of infection, including drainage, odor, cellulitis, or necrosis. Fever, chills, and painsuggest possible underlying osteomyelitis. Assessment should address the patient’soverall physical and mental health, including: comorbid conditions such as vasculardisease, diabetes, immune deficiencies, collagen vascular disease, malignancy,psychosis, or depression; nutritional status; pain and level of analgesia; risk ofrecurrence; psychosocial factors such as learning ability, social supports, andlifestyle; and any evidence of polypharmacy, overmedication, or abuse of alcohol,tobacco, or illicit drugs.
Stage I
Pressure-related alterationof intact skin, withchanges in temperature(warmth or coolness),consistency (ﬁrm orboggy), sensation (pain oritching), or color (red,blue, or purple on darkerskin; red on lighter skin)
Stage II
Partial-thickness skin lossor ulceration involving theepidermis, dermis, or bothStage III

Stage II
Full-thickness skin loss,with damage to or necrosisof subcutaneous tissue thatmay extend to, but notthrough, underlyingmuscle
Stage IV
Full-thickness skin loss,with destruction, tissuenecrosis, or damage tounderlying muscle, bone,or supporting structures
(Source of photos: National Pressure Ulcer Advisory Panel. Reston, VA)

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 4-7 IFindings In or Near the Nails
110 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 4-7 IFindings in or Near the Nails
Clubbing of the Fingers
In clubbing, the distal phalanx of each ﬁnger is rounded and bulbous. The nail
plate is more convex, and the angle between the plate and the proximal nailfold increases to 180° or more. The proximal nail fold, when palpated, feelsspongy or ﬂoating. Causes are many, including chronic hypoxia from heartdisease or lung cancer and hepatic cirrhosis.Paronychia
A paronychia is an inﬂammation of the proximal and lateral nail folds. It may beacute or, as illustrated, chronic. The folds are red, swollen, and often tender.The cuticle may not be visible. People who frequently immerse their nails inwater are especially susceptible. Multiple nails are often affected.
Onycholysis

Onycholysis refers to a painless separation of the nail plate from the nail bed.It starts distally, enlarging the free edge of the nail to a varying degree.Several or all nails are usually affected. Causes are many.Terry’s Nails
Terry’s nails are mostly whitish with a distal band of reddish brown. The lunulaeof the nails may not be visible. These nails may be seen with aging and in peoplewith chronic diseases such as cirrhosis of the liver, congestive heart failure, andnon-insulin-dependent diabetes.

CHAPTER 4 ITHE SKIN 111White Spots (Leukonychia)
Trauma to the nails is commonly followed by white spots that grow slowly out
with the nail. Spots in the pattern illustrated are typical of overly vigorous andrepeated manicuring. The curves in this example resemble the curve of thecuticle and proximal nail fold.Transverse White Lines (Mees’ Lines)
These are transverse lines, not spots, and their curves are similar to those of
the lunula, not the cuticle. These uncommon lines may follow an acute orsevere illness. They emerge from under the proximal nail folds and grow outwith the nails.
Psoriasis
Small pits in the nails may be early signs of psoriasis but are not speciﬁc for it.Additional ﬁndings, not shown here, include onycholysis and a circumscribedyellowish tan discoloration known as an “oil spot” lesion. Marked thickening ofthe nails may develop.Beau’s Lines

Beau’s lines are transverse depressions in the nails associated with acute severeillness. The lines emerge from under the proximal nail folds weeks later andgrow gradually out with the nails. As with Mees’ lines, clinicians may be able toestimate the timing of a causal illness.
(Sources of photos: Clubbing of the Fingers, Paronychia, Onycholyis, Terry’s Nails —Habif TP: Clinical Dermatology: A Color Guide to Diagnosis and Therapy, 2nd ed. St. Louis, CV
Mosby, 1990; White Spots, Transverse White Lines, Psoriasis, Beau’s Lines— Sams WM Jr, Lynch PJ: Principles and Practice of Dermatology. New York, Churchill Livingstone, 1990)

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 4-8 ISkin Lesions in Context
112 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 4-8 ISkin Lesions in Context
This table shows a variety of primary and secondary skin lesions. Try to identify them, including those indicated by letters,
before reading the accompanying text.
Macules on the dorsum of the hand, wrist,
and forearm (actinic lentigines)
Pustules on the palm (in pustular psoriasis)
Vesicles on the chin (in pemphigus)
 (A) Bulla (in erythema multiforme), 
(B) target (or iris) lesion (A) Telangiectasia, (B) nodule, (C) ulcer (in squamous cell
carcinoma)
B
C
APapules on the knee (in lichen planus)
AB

CHAPTER 4 ITHE SKIN 113
Wheals (urticaria) in a drug eruption
in an infant
(A) Patch, (B) nodules—a
combination typical ofneuroﬁbromatosis. This patch is acafé-au-lait spot.
A
BB
(A) Vesicle, (B) pustule, (C) erosions, (D) crust, on
the back of a knee (in infected atopic dermatitis)
A
BDC
Plaques with scales on the front of a
knee (in psoriasis)
(A) Excoriation, (B) licheniﬁcation on the leg
(in atopic dermatitis)
A
B
(Source of all photos except for Macules: Sauer GC: Manual of Skin Diseases, 5th ed. Philadelphia, JB Lippincott, 1985)

The Head and NeckCHAPTER
The Head and Neck 55
CHAPTER 5 ITHE HEAD AND NECK 115
The Head
Regions of the head take their names
from the underlying bones of theskull (e.g., frontal area). Knowing thisanatomy helps to locate and describephysical ﬁndings.
Two paired salivary glands lie near the
mandible: the parotid gland, superﬁ-
cial to and behind the mandible (bothvisible and palpable when enlarged),and the submandibular gland, lo-
cated deep to the mandible. Feel forthe latter as you bow and press yourtongue against your lower incisors.Its lobular surface can often be feltagainst the tightened muscle. Theopenings of the parotid and sub-mandibular ducts are visible withinthe oral cavity (see p. 130).
The superﬁcial temporal artery passes
upward just in front of the ear, whereit is readily palpable. In many normalpeople, especially thin and elderlyones, the tortuous course of one ofits branches can be traced across theforehead.
The Eye

The Eye
Gross Anatomy. Identify the structures illustrated. Note that the upper
eyelid covers a portion of the iris but does not normally overlap the pupil.
Vertex of head
Parietal bone
Temporal
bone
Superficial 
temporalartery
Occipital
bone
Mastoid portion
of temporal boneMastoid process
Styloid processParotid 
gland
Parotid
ductSubmandibular
glandSubmandibular 
ductMandibleMaxillaZygomatic 
boneNasal boneOrbitFrontal bone

The opening between the eyelids is called the palpebral ﬁssure. The white
sclera may look somewhat buff-colored at its extreme periphery. Do not mis-
take this color for jaundice, which is a deeper yellow.
The conjunctiva is a clear mucous membrane with two easily visible com-
ponents. The bulbar conjunctiva covers most of the anterior eyeball, adher-
ing loosely to the underlying tissue. It meets the cornea at the limbus. The
palpebral conjunctiva lines the eyelids. The two parts of the conjunctiva
merge in a folded recess that permits the eyeball to move.
Within the eyelids lie ﬁrm strips of connective tissue called tarsal plates. Each
plate contains a parallel row of meibomian glands, which open on the lid
margin. The levator palpebrae muscle, which raises the upper eyelid, is in-
nervated by the oculomotor nerve (Cranial Nerve III). Smooth muscle, in-nervated by the sympathetic nervous system, contributes to raising this lid.

A film of tear fluid protects the conjunctiva and cornea from drying, in-
hibits microbial growth, and gives a smooth optical surface to the cornea.This fluid comes from three sources: meibomian glands, conjunctival
glands, and the lacrimal gland. The lacrimal gland lies mostly within the
bony orbit, above and lateral to the eyeball. The tear ﬂuid spreads across the eye and drains medially through two tiny holes called lacrimal puncta.
The tears then pass into the lacrimal sac and on into the nose through the
nasolacrimal duct. (You can easily ﬁnd a punctum atop the small elevation
of the lower lid medially. You cannot detect the lacrimal sac, which rests ina small depression inside the bony orbit.)
The eyeball is a spherical structure that focuses light on the neurosensory

elements within the retina. The muscles of the iriscontrol pupillary size.
Muscles of the ciliary body control the thickness of the lens, allowing the
eye to focus on near or distant objects.ANATOMY AND PHYSIOLOGY
116 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Lateral canthusUpper eyelid
Medial canthus
Pupil
Limbus Iris Lower e yelidSclera covered
by conjunctiva

Lacrimal gland
(within the bony
orbit)
PunctaCanaliculiLacrimal sac
(within thebony orbit)
NasolacrimalductANATOMY AND PHYSIOLOGY
CHAPTER 5 ITHE HEAD AND NECK 117
Levator palpebrae
Bulbar
conjunctiva
Palpebral
Cornea
ScleraEyelashesMeibomian
glandTarsalplate
SAGITTAL SECTION OF ANTERIOR EYE WITH LIDS CLOSED

FoveaFovea
MaculaVein
ArteryPhysiologic
cup
Physiologic cup 
in optic discOptic 
discOptic 
nerveCentral retinal
artery and veinRetina
ScleraExtraocular 
muscleVitreous body
Choroid
Ciliary body
Iris
PupilCornea
Anterior 
chamber
Posterior chamberLens
The posterior part of the eye that is seen through an ophthalmoscope is
often called the fundus of the eye. Structures here include the retina,
choroid, fovea, macula, optic disc, and retinal vessels. The optic nerve withits retinal vessels enters the eyeball posteriorly. You can find it with an oph-CROSS SECTION OF THE RIGHT EYE FROM ABOVE SHOWING A PORTION OF THE
FUNDUS COMMONLY SEEN WITH THE OPHTHALMOSCOPEA clear liquid called aqueous humor ﬁlls the anterior and posterior chambers
of the eye. Aqueous humor is produced by the ciliary body, circulates from 
the posterior chamber through the pupil into the anterior chamber, anddrains out through the canal of Schlemm. This circulatory system helpsto control the pressure inside the eye.

Canal of SchlemmCiliary body
Cornea
Posterior chamberLensAnterior chamber
Anterior chamber
CIRCULATION OF AQUEOUS HUMORANATOMY AND PHYSIOLOGY
118 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING

thalmoscope at the optic disc.Lateral and slightly inferior to the disc, there
is a small depression in the retinal surface that marks the point of centralvision. Around it is a darkened circular area called the fovea. The roughly
circular macula (named for a microscopic yellow spot) surrounds the
fovea but has no discernible margins. It does not quite reach the opticdisc. You do not usually see the normal vitreous body, a transparent mass
of gelatinous material that fills the eyeball behind the lens. It helps tomaintain the shape of the eye.
Visual Fields. A visual field is the entire area seen by an eye when it

looks at a central point. Fields are conventionally diagrammed on circlesfrom the patient’s point of view. The center of the circle represents thefocus of gaze. The circumference is 90° from the line of gaze. Each visualfield, shown by the white areas below, is divided into quadrants. Note thatthe fields extend farthest on the temporal sides. Visual fields are normallylimited by the brows above, by the cheeks below, and by the nose medi-ally. A lack of retinal receptors at the optic disc produces an oval blindspot in the normal field of each eye, 15° temporal to the line of gaze.ANATOMY AND PHYSIOLOGY
CHAPTER 5 ITHE HEAD AND NECK 119
Upper
temporal
Lower
temporalLower
nasalUpper
nasal90°
Blind spot
Normal visual
field
When a person is using both

Upper
temporal
Lower
nasal90°
Blind spot
field
When a person is using both 
eyes, the two visual fields over-lap in an area of binocular vision. Laterally, vision is mono-cular.
Visual Pathways. For an
image to be seen, light reﬂectedfrom it must pass through thepupil and be focused on sensoryneurons in the retina. The imageprojected there is upside downand reversed right to left. An
Binocular vision
Monocular visionLEFT EYE RIGHT EYE

image from the upper nasal visual ﬁeld thus strikes the lower temporal quad-
rant of the retina.
Nerve impulses, stimulated by light, are conducted through the retina, optic
nerve, and optic tract on each side, and then on through a curving tractcalled the optic radiation. This ends in the visual cortex, a part of the occip-
ital lobe.
Pupillary Reactions. Pupillary size changes in response to light and to
the effort of focusing on a near object.
The Light Reaction. A light beam shining onto one retina causes
pupillary constriction in both that eye (the direct reaction to light) and the
opposite eye (the consensual reaction ). The initial sensory pathways are
similar to those described for vision: retina, optic nerve, and optic tract.The pathways diverge in the midbrain, however, and impulses are trans-mitted through the oculomotor nerve to the constrictor muscles of the irisof each eye.
The Near Reaction. When a person shifts gaze from a far object to a

near one, the pupils constrict. This response, like the light reaction, is me-diated by the oculomotor nerve. Coincident with this pupillary reaction (butnot part of it) are (1) convergence of the eyes, an extraocular movement, and
(2) accommodation, an increased convexity of the lenses caused by contrac-
tion of the ciliary muscles. This change in shape of the lenses brings near ob-jects into focus but is not visible to the examiner.
Autonomic Nerve Supply to the Eyes. Fibers traveling in the

oculomotor nerve and producing pupillary constriction are part of theparasympathetic nervous system. The iris is also supplied by sympatheticfibers. When these are stimulated, the pupil dilates and the upper eyelidrises a little, as if from fear. The sympathetic pathway starts in the hypo-thalamus and passes down through the brainstem and cervical cord intothe neck. From there, it follows the carotid artery or its branches into theANATOMY AND PHYSIOLOGY
120 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Center of gazeO
A
A Blind spot
Object seenImage on retina
Fovea
Optic nerve

CHAPTER 5 ITHE HEAD AND NECK 121
Optic tract
To visual cortexOculomotor nerveOptic nerveTo iris
(consensual reaction)Light
To iris
(direct reaction)
KeyBlue––SensoryRed––Motor
PATHWAYS OF THE LIGHT REACTION
THE NEAR REACTION

122 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGTemporal 
Right Eye  Left EyeNasal Temporal Nasal
Optic chiasm
Optic
radiation
Visual cortexVISUAL FIELDS
orbit. A lesion anywhere along this pathway may impair sympathetic effects
on the pupil.
Extraocular Movements. The movement of each eye is controlled by
the coordinated action of six muscles, the four rectus and two obliquemuscles. You can test the function of each muscle and the nerve that sup-plies it by asking the patient to move the eye in the direction controlled by that muscle. There are six such cardinal directions, indicated by the

lines on the figure on p. 123. When a person looks down and to the right,for example, the right inferior rectus (Cranial Nerve III) is principally responsible for moving the right eye, while the left superior oblique (Cranial Nerve IV) is principally responsible for moving the left. If one ofthese muscles is paralyzed, the eye will deviate from its normal position inthat direction of gaze and the eyes will no longer appear conjugate, or parallel.VISUAL PATHWAYS FROM THE RETINA TO THE VISUAL CORTEX

CHAPTER 5 ITHE HEAD AND NECK 123The Ear
Anatomy. The ear has three compartments: the external ear, the middle
ear, and the inner ear.
The external ear comprises the auricle and ear canal. The auricle consists
chieﬂy of cartilage covered by skin and has a ﬁrm, elastic consistency.
Superior
rectus (III)
Lateral
rectus
(VI)
Inferior
rectus (III)Superior
Lateral
rectus(VI)
Inferior
rectus (III)Superior 
oblique (IV)Medial
rectus (III)Inferior
oblique (III)
CARDINAL DIRECTIONS OF GAZE
IncusOssicles
Malleus Stapes
Cochlear
nerve
Cochlea
Eustachian tube
Middle ear cavityTympanic
membrane
BoneMastoid processCartilageEar canalAuricle
The ear canal opens behind the tragus and curves inward about 24 mm.

Cochlear
nerve
Cochlea
membrane
Its outer portion is surrounded by cartilage. The skin in this outer portionis hairy and contains glands that produce cerumen (wax). The inner por-tion of the canal is surrounded by bone and lined by thin, hairless skin.Pressure on this latter area causes pain—a point to remember when you ex-amine the ear.

124 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGRIGHT EARDRUMThe bone behind and below the ear
canal is the mastoid part of the tempo-ral bone. The lowest portion of thisbone, the mastoid process, is palpablebehind the lobule.
At the end of the ear canal lies the tym-
panic membrane (eardrum), marking
the lateral limits of the middle ear. The
middle ear is an air-ﬁlled cavity that
transmits sound by way of three tinybones, the ossicles. It is connected bythe eustachian tube to the nasopharynx.
The eardrum is an oblique membrane
held inward at its center by one of theossicles, the malleus. Find the handle
and the short process of the malleus—the two chief landmarks. From the
umbo, where the eardrum meets the tip of the malleus, a light reflection
called the cone of light fans downward and anteriorly. Above the short
process lies a small portion of the eardrum called the pars flaccida. The re-

mainder of the drum is the pars tensa. Anterior and posterior malleolar
folds, which extend obliquely upward from the short process, separate thepars flaccida from the pars tensa but are usually invisible unless the eardrumis retracted. A second ossicle, the incus, can sometimes be seen throughthe drum.
Helix
Antihelix
Entrance
to earcanalTragus
Lobule
Much of the middle ear and all of the inner ear are inaccessible to direct ex-
amination. Some inferences concerning their condition can be made, how-ever, by testing auditory function.
Pathways of Hearing. Vibrations of sound pass through the air of the
external ear and are transmitted through the eardrum and ossicles of the

CHAPTER 5 ITHE HEAD AND NECK 125middle ear to the cochlea, a part of the inner ear. The cochlea senses and
codes the vibrations, and nerve impulses are sent to the brain through thecochlear nerve. The ﬁrst part of this pathway—from the external ear throughthe middle ear—is known as the conductive phase, and a disorder here causes
conductive hearing loss. The second part of the pathway, involving thecochlea and the cochlear nerve, is called the sensorineural phase; a disorder
here causes sensorineural hearing loss.
Conductive phase
Air conduction
Bone conduction
Sensorineural phase
Air conduction describes the normal ﬁrst phase in the hearing pathway. An
alternate pathway, known as bone conduction, bypasses the external and the
middle ear and is used for testing purposes. A vibrating tuning fork, placedon the head, sets the bone of the skull into vibration and stimulates thecochlea directly. In a normal person, air conduction is more sensitive.

Equilibrium. The labyrinth within the inner ear senses the position and
movements of the head and helps to maintain balance.
The Nose and Paranasal Sinuses
Review the terms used to describe the external anatomy of the nose.
Approximately the upper third of the nose is supported by bone, the lower
two thirds by cartilage. Air enters the nasal cavity by way of the anterior naris
on either side, then passes into a widened area known as the vestibule and on
through the narrow nasal passage to the nasopharynx. The medial wall of
each nasal cavity is formed by the nasal septum which, like the external
nose, is supported by both bone and ca rtilage. It is covered by a mucous
membrane well supplied with blood. The vestibule, unlike the rest of thenasal cavity, is lined with hair-bearing skin, not mucosa.

Laterally, the anatomy is more com-
plex. Curving bony structures, theturbinates, covered by a highly vascu-
lar mucous membrane, protrude intothe nasal cavity. Below each turbinateis a groove, or meatus, each namedaccording to the turbinate above it.Into the inferior meatus drains thenasolacrimal duct; into the middlemeatus drain most of the paranasalsinuses. Their openings are not usu-ally visible.
The additional surface area provided
by the turbinates and the mucosacovering them aids the nasal cavitiesin their principal functions: cleans-ing, humidiﬁcation, and tempera-ture control of inspired air.
Inspection of the nasal cavity through the anterior naris is usually limited to
the vestibule, the anterior portion of the septum, and the lower and middleturbinates. Examination with a nasopharyngeal mirror is required for detec-tion of posterior abnormalities. This technique is beyond the scope of thisbook.
The paranasal sinuses are air-ﬁlled cavities within the bones of the skull. Like

the nasal cavities into which they drain, they are lined with mucous mem-brane. Their locations are diagrammed below. Only the frontal and maxil-lary sinuses are readily accessible to clinical examination.ANATOMY AND PHYSIOLOGY
126 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Ala nasi
VestibuleAnterior
narisTipBridge
Cranial cavity
Sphenoid sinus
Bony portion
of nasal septum
Soft palateHard palateCartilaginous portion
of nasal septumFrontal sinus
MEDIAL WALL—LEFT NASAL CAVITY (MUCOSA REMOVED)

CHAPTER 5 ITHE HEAD AND NECK 127
Opening to
eustachiantube
Hard palateVestibuleInferior turbinateMiddle turbinateSuperior turbinateFrontal sinus
Nasopharynx
Soft
palate
LATERAL WALL—RIGHT NASAL CAVITY
Frontalsinus
Orbit
Middle
turbinate
Maxillar
y
sinus
Inferior
turbinateInferior
meatusMiddle
meatusEthmoid
sinus
Frontal sinus
Maxillary sinusCROSS SECTION OF NASAL CAVITY—ANTERIOR VIEW

128 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGThe Mouth and Pharynx
The lipsare muscular folds that surround the entrance
to the mouth. When opened, the gums (gingiva) andteeth are visible. Note the scalloped shape of the gin-
gival margins and the pointed interdental papillae.
The gingiva is firmly attached to the teeth and to the
maxilla or mandible in which they are seated. Inlighter-skinned people, the gingiva is pale or coralpink and lightly stippled. In darker-skinned people, itmaybe diffusely or partly brown as shown below. Amidline mucosal fold, called a labial frenulum, con-
nects each lip with the gingiva. A shallow gingival
sulcus between the gum’s thin margin and each tooth
is not readily visible (but is probed and measured bydentists). Adjacent to the gingiva is the alveolar mu-
cosa, which merges with the labial mucosa of the lip.
Gingival margin Upper lip
(everted)Interdental
papillae
Gingiva
Alveolar
mucosa
Labial
mucosa
Gingiva

papillae
Gingiva
Alveolar
mucosa
Labial
mucosa
Gingiva
Alveolar
mucosa
Labial
mucosaLabial
frenulum

CHAPTER 5 ITHE HEAD AND NECK 129
Crown
Gingival
margin
Gingiva
Pulp
chamber
Bone
Root
Pulp
canal
ApexEnamel
Gingival
sulcus
Dentin
Medial (central)incisorLateral
incisorCanine 
(cuspid)
Premolars
(bicuspids)
1st molar
(6-year molar)
2nd molar
(12-year   molar)
3rd molar(wisdom   tooth)Each tooth, composed mostly of dentin, lies rooted in a bony socket with
only its enamel-covered crown exposed. Small blood vessels and nerves enterthe tooth through its apex and pass into the pulp canal and pulp chamber.
The dorsum of the tongue is covered with papillae, giving it a rough surface.
Some of these papillae look like red dots, which contrast with the thin whitecoat that often covers the tongue. The undersurface of the tongue has nopapillae. Note the midline lingual frenulum that connects the tongue to the
ﬂoor of the mouth. At the base of the tongue the ducts of the submandibu-The 32 adult teeth (16 in each jaw) are identiﬁed below.

130 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGlar gland (Wharton’s ducts) pass forward and medially. They open on papil-
lae that lie on each side of the lingual frenulum.
Each parotid duct (Stensen’s duct) empties into the mouth near the upper
2nd molar, where its location is frequently marked by a small papilla. Thebuccal mucosa lines the cheeks.
Lingual
frenulum
Papilla
Duct of
submandibularglandVein
Buccal
mucosaOpening of the
parotid duct
Papilla
Upper lip
(retracted)
Above and behind the tongue rises an arch formed by the anterior and pos-
terior pillars, soft palate, and uvula. In the following example, the right ton-
silcan be seen in its fossa (cavity) between the anterior and posterior pillars.
In adults, tonsils are often small or absent, as exempliﬁed on the left side

CHAPTER 5 ITHE HEAD AND NECK 131here. A meshwork of small blood vessels may web the soft palate. Between
the soft palate and tongue the pharynx is visible.
The Neck
For descriptive purposes, each side of the neck is divided into two triangles
by the sternomastoid (sternocleidomastoid) muscle. The anterior triangle is
bounded above by the mandible, laterally by the sternomastoid, and medi-ally by the midline of the neck. The posterior triangle extends from the ster-
Posterior
pillar
Anterior
pillar
Right
tonsilHard palate
Soft palate
Uvula
Pharynx
Tongue
Posterior 
triangle
Omohyoid
muscle
Clavicle Manubrium of
the sternumAnterior
triangleSternomastoid
muscleTrapezius muscle

132 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGnomastoid to the trapezius and is bounded below by the clavicle. A portion
of the omohyoid muscle crosses the lower portion of the posterior triangleand can be mistaken by the uninitiated for a lymph node or mass.
Deep to the sternomastoids run the great vessels of the neck: the carotid
artery and internal jugular vein. The external jugular vein passes diagonally
over the surface of the sternomastoid.
Now identify the following midline structures: (1) the mobile hyoid bone just
below the mandible, (2) the thyroid cartilage, readily identiﬁed by the notch
on its superior edge, (3) the cricoid cartilage, (4) the tracheal rings, and
(5) the thyroid gland. The isthmus of the thyroid gland lies across the trachea
External
jugular vein
Carotid sinus
Carotid artery
Internal jugular vein
Clavicular and sternal heads
of the sternomastoid muscle
Thyroidcartilage
Cricoid
cartilage
Lobe
IsthmusThyroid
gland
Sternal

External
Cricoid
cartilage
Lobe
gland
Sternal
notch
Manubrium
of sternumHyoid bone
Sternomastoid
muscle
Trachea
Clavicle

CHAPTER 5 ITHE HEAD AND NECK 133below the cricoid. The lateral lobes of this gland curve posteriorly around
the sides of the trachea and the esophagus. Except in the midline, the thy-roid gland is covered by thin straplike muscles, among which only the ster-nomastoids are visible.
Women have larger and more easily palpable glands than men.The lymph nodes of the head and neck have been classiﬁed in a variety of
ways. One classiﬁcation is shown here, together with the directions of lym-phatic drainage. The deep cervical chain is largely obscured by the overlyingsternomastoid muscle, but at its two extremes the tonsillar node and supra-clavicular nodes may be palpable. The submandibular nodes lie superﬁcial tothe submandibular gland, from which they should be differentiated. Nodesare normally round or ovoid, smooth, and smaller than the gland. The glandis larger and has a lobulated, slightly irregular surface (see p. 115).
Posterior
auricularOccipital
Superficial

Posterior
cervical
Posterior
cervical
Supraclavicular
Deep cervical
chainSubmandibula rSubmentalTonsillarPreauricular
Note that the tonsillar, submandibular, and submental nodes drain portions
of the mouth and throat as well as the face.
Knowledge of the lymphatic system is important to a sound clinical habit:
whenever a malignant or inﬂammatory lesion is observed, look for involve-ment of the regional lymph nodes that drain it; whenever a node is enlargedor tender, look for a source such as infection in the area that it drains.

134 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGChanges With Aging
Tonsils, which are also composed of lymphoid tissue, become gradually smaller
after the age of 5 years. In adulthood, they become inconspicuous or invisible.The frequency of palpable cervical nodes gradually diminishes with age, andaccording to one study falls below 50% sometime between the ages of 50and 60. In contrast to the lymph nodes, the submandibular glands becomeeasier to feel in older people.
The eyes, ears, and mouth bear the brunt of old age. Visual acuity remains

fairly constant between the ages of 20 and 50 and then diminishes, gradu-ally until about age 70 and then more rapidly. Nevertheless, most elderlypeople retain good to adequate vision—20/20 to 20/70 as measured bystandard charts. Near vision, however, begins to blur noticeably for virtu-ally everyone. From childhood on, the lens gradually loses its elasticity andthe eye grows progressively less able to focus on nearby objects. This lossof accommodative power, called presbyopia, usually becomes noticeable in
one’s 40s.
External lymphatic drainage
Internal lymphatic drainage (e.g., from mouth and throat)

Aging also affects the tissues in and around the eyes. In some elderly people
the fat that surrounds and cushions the eye within the bony orbit atrophies,allowing the eyeball to recede somewhat in the orbit. The skin of the eye-lids becomes wrinkled, occasionally hanging in loose folds. Fat may push thefascia of the eyelids forward, creating soft bulges, especially in the lower lidsand the inner third of the upper ones (p. 175). Combinations of a weakenedlevator palpebrae, relaxation of the skin, and increased weight of the uppereyelid may cause a senile ptosis (drooping). More important, the lower lidmay fall outward away from the eyeball or turn inward onto it, resulting inectropion and entropion, respectively (p. 177). Because their eyes producefewer lacrimal secretions, aging patients may complain of dryness of the eyes.
Corneal arcus ( arcus senilis ) is common in elderly persons and in them has

no clinical signiﬁcance (p. 180). The corneas lose some of their luster. Thepupils become smaller—a characteristic that makes it more difﬁcult to ex-amine the fundi of elderly people. The pupils may also become slightly ir-regular but should continue to respond to light and near effort. Except forpossible impairment in upward gaze, extraocular movements should remainintact.
Lenses thicken and yellow with age, impairing the passage of light to the

retinas, and elderly people need more light to read and do ﬁne work. Whenthe lens of an elderly person is examined with a ﬂashlight it frequently looksgray, as if it were opaque, when in fact it permits good visual acuity andlooks clear on ophthalmoscopic examination. Do not depend on your ﬂash-light alone, therefore, to make a diagnosis of cataract—a true opacity of thelens (p. 180). Cataracts do become relatively common, however, affecting1 out of 10 people in their 60s and 1 out of 3 in their 80s. Because the lenscontinues to grow over the years, it may push the iris forward, narrowingthe angle between iris and cornea and increasing the risk of narrow-angle
glaucoma (p. 148).
Ophthalmoscopic examination reveals fundi that have lost their youthful
shine and light reﬂections. The arteries look narrowed, paler, straighter, andless brilliant (p. 190). Drusen (colloid bodies) may be seen (p. 187). On a

more anterior plane you may be able to see some vitreous ﬂoaters—degen-erative changes that may cause annoying specks or webs in the ﬁeld of vision.You may also ﬁnd evidence of other, more serious, conditions that occurmore often in elderly people than in younger ones: macular degeneration,glaucoma, retinal hemorrhages, or possibly retinal detachment.
Acuity of hearing, like that of vision, usually diminishes with age. Early

losses, which start in young adulthood, involve primarily the high-pitchedsounds beyond the range of human speech and have relatively little func-tional signiﬁcance. Gradually, however, loss extends to sounds in the mid-dle and lower ranges. When a person fails to catch the upper tones of wordswhile hearing the lower ones, words sound distorted and are difﬁcult to un-derstand, especially in noisy environments. Hearing loss associated withaging, known as presbycusis, becomes increasingly evident, usually after the
age of 50.ANATOMY AND PHYSIOLOGY
CHAPTER 5 ITHE HEAD AND NECK 135

136 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGDiminished salivary secretions and a decreased sense of taste have been at-
tributed to aging, but medications or various diseases probably account formost of these changes. Teeth may wear down or become abraded over time,or they may be lost to dental caries or other conditions (pp. 203–205). Per-iodontal disease is the chief cause of tooth loss in most adults (p. 203). If a person has no teeth, the lower portion of the face looks small andsunken, with accentuated “purse-string” wrinkles radiating out from themouth. Overclosure of the mouth may lead to maceration of the skin atthe corners— angular cheilitis (p. 198). The bony ridges of the jaws that
once surrounded the tooth sockets are gradually resorbed, especially in thelower jaw.THE HEALTH HISTORY
See Table 5-1, Headaches,
pp. 170–173. Tension and mi-graine headaches are the mostcommon kinds of recurringheadaches.
Tension headaches often arise in

the temporal areas; clusterheadaches may be retro-orbital.
Changing or progressively severe
headaches increase the likelihoodof tumor, abscess, or other masslesion. Extremely severe headachessuggest subarachnoid hemorrhageor meningitis.The Head
Headache is an extremely common symptom that always requires careful
evaluation, since a small fraction of headaches arise from life-threateningconditions. It is important to elicit a full description of the headache and allseven attributes of the patient’s pain (see p. 27). Is the headache one-sidedor bilateral? Steady or throbbing? Continuous or comes and goes? Afteryour usual open-ended approach, ask the patient to point to the area of pain
or discomfort.
The most important attributes of headache are the chronologic pattern and

severity . Is the problem new and acute? Chronic and recurring, with little
change in pattern? Chronic and recurring but with recent change in patternor progressively severe? Does the pain recur at the same time every day?
IHeadache
IChange in vision: hyperopia, presbyopia, myopia, scotomas
IDouble vision, or diplopia
IHearing loss, earache; tinnitus
IVertigo
INosebleed, or epistaxis
ISore throat; hoarseness
ISwollen glands
IGoiter
THE HEALTH HISTORYEXAMPLES OF ABNORMALITIES

Ask about associated symptoms. Inquire speciﬁcally about associated nausea
and vomiting and neurologic symptoms such as change in vision or motor-sensory deﬁcits.
Ask whether coughing, sneezing, or changing the position of the head have
any effect (better, worse, or no effect) on the headache.
Ask about family history.
The Eyes
Start your inquiry about eye and vision problems with open-ended questions
such as “How is your vision?” and “Have you had any trouble with youreyes?” If the patient reports a change in vision, pursue the related details:
IIs the onset sudden or gradual?
IIs the problem worse during close work or at distances?
IIs there blurring of the entire field of vision or only parts of it? If thevisual field defect is partial, is it central, peripheral, or only on one side?
IAre there specks in the vision or areas where the patient cannot see (scotomas )? If so, do they move around in the visual field with shifts in
gaze or are they fixed?

IHas the patient seen lights ﬂashing across the ﬁeld of vision? This symp-tom may be accompanied by vitreous ﬂoaters.
IDoes the patient wear glasses?
Visual aura or scintillating 
scotomas with migraine. Nauseaand vomiting common with migraine but also occur withbrain tumors and subarachnoidhemorrhage.
Such maneuvers may increase
pain from brain tumor and acutesinusitis.
Family history may be positive in
patients with migraine.
Refractive errors most commonly
explain gradual blurring. Highblood sugar levels may cause blurring.
Sudden visual loss suggests retinal
detachment, vitreous hemorrhage,or occlusion of the central retinalartery.
Difficulty with close work sug-
gests hyperopia (farsightedness) or
presbyopia (aging vision); with dis-
tances, myopia (near-sightedness).
Slow central loss in nuclear cataract

(p. 180), macular degeneration(p. 155); peripheral loss in ad-vanced open-angle glaucoma(p. 148); one-sided loss in hemi-anopsia and quadrantic defects(p. 145).
Moving specks or strands suggest
vitreous ﬂoaters; ﬁxed defects(scotomas) suggest lesions in theretinas or visual pathways.
Flashing lights or new vitreous
floaters suggest detachment ofvitreous from retina. Prompt eyeconsultation is indicated.
CHAPTER 5 ITHE HEAD AND NECK 137THE HEALTH HISTORY EXAMPLES OF ABNORMALITIES

Ask about pain in or around the eyes, redness, and excessive tearing or 
watering.
Check for presence of diplopia, or double vision. If present, ﬁnd out whether
the images are side by side (horizontal diplopia) or on top of each other(vertical diplopia). Does diplopia persist with one eye closed? Which eye isaffected?
One kind of horizontal diplopia is physiologic. Hold one ﬁnger upright about
6 inches in front of your face, a second at arm’s length. When you focus oneither ﬁnger, the image of the other is double. A patient who notices thisphenomenon can be reassured.
The Ears
Opening questions for the ears are “How is your hearing?” and “Have youhad any trouble with your ears?” If the patient has noticed a hearing loss,
does it involve one or both ears? Did it start suddenly or gradually? What arethe associated symptoms, if any?
Try to distinguish between two basic types of hearing impairment: conduc-
tive loss, which results from problems in the external or middle ear, and sen-

sorineural loss, from problems in the inner ear, the cochlear nerve, or its
central connections in the brain. Two questions may be helpful . . . Does thepatient have special difﬁculty understanding people as they talk? . . . Whatdifference does a noisy environment make?
Symptoms associated with hearing loss, such as earache or vertigo, help you
to assess likely causes. In addition, inquire speciﬁcally about medications thatmight affect hearing and ask about sustained exposure to loud noise.
Complaints of earache, or pain in the ear, are especially common in ofﬁce
visits. Ask about associated fever, sore throat, cough, and concurrent upperrespiratory infection.
138 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGTHE HEALTH HISTORY
See Table 5-7, Red Eyes, p. 179.
Diplopia in adults may arise from a

lesion in the brainstem or cerebel-lum, or from weakness or paralysisof one or more extraocular musclesas in horizontal diplopia from palsyof CN III or VI, or vertical diplopiafrom palsy of CN III or IV. Diplopiain one eye, with the other closed,suggests a problem in the corneaor lens.
See Table 5-19, Patterns of Hearing
Loss, pp. 196–197.
Persons with sensorineural loss
have particular trouble under-standing speech, often complain-ing that others mumble; noisyenvironments make hearingworse. In conductive loss, noisyenvironments may help.
Infants may fail to respond to the
parent’s voice or to sounds in theenvironment (see p. 677). Toddlersmay exhibit a delay in developingspeech. Such ﬁndings deservethorough investigation.
Medications that affect hearing
include aminoglycosides, aspirin,NSAIDs, quinine, furosemide, andothers.

Pain suggests a problem in the
external ear, such as otitis externa,
or, if associated with symptoms of respiratory infection, in theinner ear, as in otitis media. It 
may also be referred from otherstructures in the mouth, throat, or neck.EXAMPLES OF ABNORMALITIES

CHAPTER 5 ITHE HEAD AND NECK 139Ask about discharge from the ear, especially if associated with earache or
trauma.
Tinnitus is a perceived sound that has no external stimulus—commonly, a
musical ringing or a rushing or roaring noise. It can involve one or both ears.Tinnitus may accompany hearing loss and often remains unexplained. Oc-casionally, popping sounds originate in the temporomandibular joint, or vas-cular noises from the neck may be audible.
Vertigo refers to the perception that the patient or the environment is rotat-
ing or spinning. These sensations point primarily to a problem in the labyrinthsof the inner ear, peripheral lesions of CN VIII or lesions in its central path-ways, or nuclei in the brain.
Vertigo is a challenging symptom for you as clinician, since patients differ

widely in what they mean by the word “dizzy.” “Are there times when youfeel dizzy?” is an appropriate ﬁrst question, but patients often ﬁnd it difﬁ-cult to be more speciﬁc. Ask “Do you feel unsteady, as if you are going tofall or black out? . . . Or do you feel the room is spinning (true vertigo)?”Get the story without biasing it. You may need to offer the patient severalchoices of wording. Ask if the patient feels pulled to the ground or off toone side. And if the dizziness is related to a change in body position. Pursueany associated feelings of clamminess or ﬂushing, nausea, or vomiting.Check if any medications may be contributing.
The Nose and Sinuses
Rhinorrhea refers to drainage from the nose and is often associated with
nasal congestion, a sense of stufﬁness or obstruction. These symptoms are fre-
quently accompanied by sneezing, watery eyes, and throat discomfort, and

also by itching in the eyes, nose, and throat.
Assess the chronology of the illness. Does it last for a week or so, especially
when common colds and related syndromes are prevalent, or does it occurseasonally when pollens are in the air? Is it associated with speciﬁc contactsor environments? What remedies has the patient used? For how long? Andhow well do they work?
Inquire about drugs that might cause stufﬁness.
Are there symptoms in addition to rhinorrhea or congestion, such as pain
and tenderness in the face or over the sinuses, local headache, or fever?
Is the patient’s nasal congestion limited to one side? If so, you may be deal-
ing with a different problem that requires careful physical examination.
Unusually soft wax, debris from

Unusually soft wax, debris from 
inﬂammation or rash in the earcanal, or discharge through a perforated eardrum secondary toacute or chronic otitis media
Tinnitus is a common symptom,
increasing in frequency with age.When associated with hearing lossand vertigo it suggests Ménière’sdisease.
See Table 5-2, Vertigo, p. 174.
Feeling unsteady, light-headed, 
or “dizzy in the legs” sometimessuggests a cardiovascular etiology.A feeling of being pulled suggeststrue vertigo from an inner earproblem or a central or peripherallesion of CN VIII.
Causes include viral infections, 
allergic rhinitis (“hay fever”), andvasomotor rhinitis. Itching favorsan allergic cause.
Relation to seasons or environmen-
tal contacts suggests allergy.
Excessive use of decongestants can
worsen the symptoms.
Oral contraceptives, reserpine,
guanethidine, and alcohol
These together suggest sinusitis.

Consider a deviated nasal septum,
foreign body, or tumor.EXAMPLES OF ABNORMALITIES

140 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGEpistaxis means bleeding from the nose. The blood usually originates from
the nose itself, but may come from a paranasal sinus or the nasopharynx. Thehistory is usually quite graphic! However, in patients who are lying down,or whose bleeding originates in posterior structures, blood may pass into thethroat instead of out the nostrils. You must identify the source of the bleed-ing carefully—is it from the nose or has it been coughed up or vomited? As-sess the site of bleeding, its severity, and associated symptoms. Is it a recurrentproblem? Has there been easy bruising or bleeding elsewhere in the body?
The Mouth, Throat, and Neck
Sore throat is a frequent complaint, usually developing in the setting of acute
upper respiratory symptoms.
A sore tongue may be caused by local lesions as well as by systemic illness.
Bleeding from the gums is a common symptom, especially when brushing

teeth. Ask about local lesions and any tendency to bleed or bruise elsewhere.
Hoarseness refers to an altered quality of the voice, often described as husky,
rough, or harsh. The pitch may be lower than before. Hoarseness usuallyarises from disease of the larynx, but may also develop as extralaryngeallesions press on the laryngeal nerves. Check for overuse of the voice, allergy,smoking or other inhaled irritants, and any associated symptoms. Is the prob-lem acute or chronic? If hoarseness lasts more than 2 weeks, visual examina-tion of the larynx by indirect or direct laryngoscopy is advisable.
Asking “Have you noticed any swollen glands or lumps in your neck?” is
advisable, since patients are more familiar with the lay terms than with“lymph nodes. ”

Assess thyroid function and ask about any evidence of an enlarged thyroid
gland or goiter. To evaluate thyroid function, ask about temperature intol-
erance and sweating . Opening questions include “Do you prefer hot or cold
weather?” “Do you dress more warmly or less warmly than other people?”“What about blankets . . . do you use more or fewer than others at home?”“Do you perspire more or less than others?” “Any new palpitations orchange in weight?” Note that as people grow older, they sweat less, have lesstolerance for cold, and tend to prefer warmer environments. 
HEALTH HISTORY
Local causes of epistaxis include
trauma (especially nose picking),inﬂammation, drying and crustingof the nasal mucosa, tumors, andforeign bodies.
Bleeding disorders may contribute
to epistaxis.
Fever, pharyngeal exudates, and

anterior lymphadenopathy, espe-cially in the absence of cough,suggest streptococcal pharyngitis,or strep throat (p. 200)
Aphthous ulcers (p. 207); sore
smooth tongue of nutritional deﬁciency (p. 206).
Bleeding gums are most often
caused by gingivitis (p. 203).
Overuse of the voice (as in cheer-
ing) and acute infections are themost likely causes.
Causes of chronic hoarseness in-
clude smoking, allergy, voiceabuse, hypothyroidism, chronicinfections such as tuberculosis,and tumors.
Enlarged tender lymph nodes com-
monly accompany pharyngitis.
With goiter, thyroid function may
be increased, decreased, or normal.
Intolerance to cold, preference for

warm clothing and many blankets,and decreased sweating suggesthypothyroidism; the oppositesymptoms, palpitations and invol-untary weight loss suggest hyper-thyroidism (p. 208).EXAMPLES OF ABNORMALITIES

CHAPTER 5 ITHE HEAD AND NECK 141Important Topics for Health Promotion and Counseling
IChanges in vision: cataracts, macular degeneration, glaucoma
IHearing loss
IOral health
Vision and hearing, critical senses for experiencing the world around us, are
two areas of special importance for health promotion and counseling. Oralhealth, often overlooked, also merits clinical attention.
Disorders of vision shift with age. Healthy young adults generally have re-
fractive errors. Up to 25% of adults over 65 have refractive errors; however,cataracts, macular degeneration, and glaucoma become more prevalent. Thesedisorders reduce awareness of the social and physical environment and con-tribute to falls and injuries. To improve detection of visual defects, test visualacuity with a Snellen chart or handheld card (p. 675). Examine the lens andfundi for clouding of the lens ( cataracts ); mottling of the macula, variations

in the retinal pigmentation, subretinal hemorrhage or exudate ( macular de-
generation ); and change in size and color of the optic cup ( glaucoma ). After
diagnosis, review effective treatments—corrective lenses, cataract surgery,photocoagulation for choroidal neovascularization in macular degeneration,and topical medications for glaucoma.
Surveillance for glaucoma is especially important. Glaucoma is the leading

cause of blindness in African Americans and the second leading cause ofblindness overall. There is gradual loss of vision with damage to the opticnerve, loss of visual ﬁelds beginning usually at the periphery, and pallor andincreasing size of the optic cup (enlarging to more than half the diameter ofthe optic disc). Elevated intraocular pressure (IOP) is seen in up to 80% ofcases and is linked to damage of the optic nerve. Risk factors include age over65, African American origin, diabetes mellitus, myopia, family history of glau-coma, and ocular hypertension (IOP ≥21 mm Hg). Screening tests include
tonometry to measure IOP, ophthalmoscopy or slit-lamp examination of theoptic nerve head, and perimetry to map the visual ﬁelds. In the hands of gen-eral clinicians, however, all three tests lack accuracy, so attention to risk fac-tors and referral to eye specialists remain important tools for clinical care.

Hearing loss can also trouble the later years. More than a third of adults over
age 65 have detectable hearing deﬁcits, contributing to emotional isolationand social withdrawal. These losses may go undetected—unlike vision pre-requisites for driving and vision, there is no mandate for widespread testingand many seniors avoid use of hearing aids. Questionnaires and hand-heldaudioscopes work well for periodic screening. Less sensitive are the clinical
“whisper test,” rubbing ﬁngers, or use of the tuning fork. Groups at risk are

142 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGthose with a history of congenital or familial hearing loss, syphilis, rubella,
meningitis, or exposure to hazardous noise levels at work or on the battleﬁeld.
Clinicians should play an active role in promoting oral health: up to half of all

children ages 5 to 17 have from one to eight cavities, and the average US adulthas 10 to 17 teeth that are decayed, missing, or ﬁlled. In adults, the prevalenceof gingivitis and periodontal disease is 50% and 80% respectively. In the U.S.,more than half of all adults over age 65 have no teeth at all!* Effective screen-ing begins with careful examination of the mouth. Inspect the oral cavity fordecayed or loose teeth, inﬂammation of the gingiva, and signs of periodontaldisease (bleeding, pus, recession of the gums, and bad breath). Inspect themucous membranes, the palate, the oral ﬂoor, and the surfaces of the tonguefor ulcers and leukoplakia, warning signs for oral cancer and HIV disease.
To improve oral health, counsel patients to adopt daily hygiene measures. Use

of ﬂuoride-containing toothpastes reduces tooth decay, and brushing andﬂossing retard periodontal disease by removing bacterial plaques. Urge pa-tients to seek dental care at least annually to receive the beneﬁts of more spe-cialized preventive care such as scaling, planing of roots, and topical ﬂuorides.
Diet, tobacco and alcohol use, changes in salivary ﬂow from medication, and
proper use of dentures should also be addressed.** As with children, adultsshould avoid excessive intake of foods high in reﬁned sugars, such as sucrose,which enhance attachment and colonization of cariogenic bacteria. Use ofall tobacco products and excessive alcohol, the principal risk factors for oralcancers, should be avoided.
Saliva cleanses and lubricates the mouth. Many medications reduce salivary

ﬂow, increasing risk of tooth decay, mucositis, and gum disease from xero-stomia, especially for the elderly. For those wearing dentures, be sure tocounsel removal and cleaning each night to reduce bacterial plaque and riskof malodor. Regular massage of the gums relieves soreness and pressure fromdentures on the underlying soft tissue.
*U.S. Preventive Services Task Force: Guide to Clinical Preventive Services (2nd ed), pp. 711–721.
Baltimore, Williams & Wilkins, 1996.**Greene JC, Greene AR: Chapter 15: Oral Health. In Woolf SH, Jonas S, Lawrence RS (eds): HealthPromotion and Disease Prevention in Clinical Practice, pp. 315–334. Baltimore, Williams & Wilkins,1996.

CHAPTER 5 ITHE HEAD AND NECK 143Preview: Recording the Physical Examination—
The Head, Eyes, Ears, Nose, and Throat (HEENT)
you will use phrases. The style below contains phrases appropriate formost write-ups. Unfamiliar terms are explained in the next section, Techniques of Examination.
HEENT: Head —The skull is normocephalic/atraumatic (NC/AT). Hair
with average texture. Eyes—Visual acuity 20/20 bilaterally. Sclera white,
conjunctiva pink. Pupils are 4 mm constricting to 2 mm, equally roundand reactive to light and accommodations. Disc margins sharp; nohemorrhages or exudates, no arteriolar narrowing. Ears—Acuity good
to whispered voice. Tympanic membranes (TMs) with good cone oflight. Weber midline. AC > BC. Nose—Nasal mucosa pink, septum mid-
line; no sinus tenderness. Throat (or Mouth) —Oral mucosa pink, denti-
tion good, pharynx without exudates.

Neck—Trachea midline. Neck supple; thyroid isthmus palpable, lobes
not felt.
Lymph Nodes —No cervical, axillary, epitrochlear, inguinal adenopathy.
ORHead —The skull is normocephalic/atraumatic. Frontal balding. Eyes—
Visual acuity 20/100 bilaterally. Sclera white; conjunctiva infected.Pupils constrict 3 mm to 2 mm, equally round and reactive to light andaccommodation. Disc margins sharp; no hemorrhages or exudates. Arteriolar-to-venous ratio (AV ratio) 2:4; no A-V nicking. Ears—Acuity di-
minished to whispered voice; intact to spoken voice. TMs clear. Nose—
Mucosa swollen with erythema and clear drainage. Septum midline.Tender over maxillary sinuses. Throat —Oral mucosa pink, dental caries
in lower molars, pharynx erythematous, no exudates.
Neck—Trachea midline. Neck supple; thyroid isthmus midline, lobes
palpable but not enlarged.

Lymph Nodes —Submandibular and anterior cervical lymph nodes tender,
1 ×1 cm, rubbery and mobile; no posterior cervical, epitrochlear, axillary,
or inguinal lymphadenopathy.EXAMPLES OF ABNORMALITIES
Suggests myopia and mild arteriolarnarrowing. Also upper respiratoryinfection.

TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
144 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGFine hair in hyperthyroidism; coarse
hair in hypothyroidism. Tiny whiteovoid granules that adhere to hairsmay be nits, or eggs of lice.
Redness and scaling in seborrheic
dermatitis, psoriasis; pilar cysts(wens)
Enlarged skull in hydrocephalus,
Paget’s disease of bone. Tender-ness after trauma
See Table 5-3, Selected Facies 
(p. 175).
Acne in many adolescents. Hirsutism
(excessive facial hair) in somewomen
The Head
Because abnormalities covered by the hair are easily missed, ask if the patient
has noticed anything wrong with the scalp or hair. If you note a hairpiece orwig, ask the patient to remove it.
Examine:
The Hair. Note its quantity, distribution, texture, and pattern of loss, if
any. You may see loose ﬂakes of dandruff.
The Scalp. Part the hair in several places and look for scaliness, lumps,
nevi, or other lesions.

The Skull. Observe the general size and contour of the skull. Note any
deformities, depressions, lumps, or tenderness. Familiarize yourself with theirregularities in a normal skull, such as those near the suture lines betweenthe parietal and occipital bones.
The Face. Note the patient’s facial expression and contours. Observe for
asymmetry, involuntary movements, edema, and masses.
The Skin. Observe the skin, noting its color, pigmentation, texture,
thickness, hair distribution, and any lesions.
The Eyes
Important Areas of Examination
IVisual acuity IFundi, including
IVisual ﬁelds Optic disc and cup
IConjunctiva and sclera Retina
ICornea, lens, and pupils Retinal vessels
IExtraocular movements
Visual Acuity. To test the acuity of central vision use a Snellen eye chart,

if possible, and light it well. Position the patient 20 feet from the chart.Patients who use glasses other than for reading should put them on. AskVision of 20/200 means that at 
20 feet the patient can read printthat a person with normal vision

CHAPTER 5 ITHE HEAD AND NECK 145could read at 200 feet. The larger
the second number, the worse thevision. “20/40 corrected” meansthe patient could read the 40 linewith glasses (a correction).
Myopia is impaired far vision.
Presbyopia is the impaired near 
vision, found in middle-aged andolder people. A presbyopic personoften sees better when the card isfarther away.
In the United States, a person is
usually considered legally blindwhen vision in the better eye, corrected by glasses, is 20/200 orless. Legal blindness also resultsfrom a constricted ﬁeld of vision:20° or less in the better eye.
Field defects that are all or partly
temporal include homonymous
hemianopsia,
bitemporal hemianopsia ,
andquadrantic defects.
Review these patterns in Table 5-4,
Visual Field Defects, p. 176.the patient to cover one eye with a card (to prevent peeking through the
ﬁngers) and to read the smallest line of print possible. Coaxing to attempt the

next line may improve performance. A patient who cannot read the largestletter should be positioned closer to the chart; note the intervening distance.Determine the smallest line of print from which the patient can identify morethan half the letters. Record the visual acuity designated at the side of this line,along with use of glasses, if any. Visual acuity is expressed as two numbers(e.g., 20/30): the ﬁrst indicates the distance of patient from chart, and thesecond, the distance at which a normal eye can read the line of letters.
Testing near vision with a special handheld card helps to identify the need

for reading glasses or bifocals in patients over age 45. You can also use thiscard to test visual acuity at the bedside. Held 14 inches from the patient’seyes, the card simulates a Snellen chart. You may, however, let patientschoose their own distance.
If you have no charts, screen visual acuity with any available print. If patients
cannot read even the largest letters, test their ability to count your upraisedﬁngers and distinguish light (such as your ﬂashlight) from dark.
Visual Fields by Confrontation
Screening. Screening starts in the temporal ﬁelds because most de-
fects involve these areas. Imagine the patient’s visual ﬁelds projected onto a

glass bowl that encircles the front of the patient’s head. Ask the patient to
look with both eyes into your eyes. While you return the patient’s gaze, placeyour hands about 2 feet apart, lateral to the patient’s ears. Instruct the pa-tient to point to your ﬁngers as soon as they are seen. Then slowly move thewiggling ﬁngers of both your hands along the imaginary bowl and towardthe line of gaze until the patient identiﬁes them. Repeat this pattern in theupper and lower temporal quadrants.
Normally, a person sees both sets of ﬁngers at the same time. If so, ﬁelds are
usually normal.
Further Testing. If you ﬁnd a defect, try to establish its boundaries.

Test one eye at a time. If you suspect a temporal defect in the left visual ﬁeld,for example, ask the patient to cover the right eye and, with the left one, tolook into your eye directly opposite. Then slowly move your wiggling ﬁn-gers from the defective area toward the better vision, noting where the pa-tient ﬁrst responds. Repeat this at several levels to deﬁne the border.
A temporal defect in the visual ﬁeld of one eye suggests a nasal defect in the
other eye. To test this hypothesis, examine the other eye in a similar way,again moving from the anticipated defect toward the better vision.
Small visual ﬁeld defects and enlarged blind spots require a ﬁner stimulus.

Using a small red object such as a red-headed matchstick or the red eraseron a pencil, test one eye at a time. As the patient looks into your eye directlyopposite, move the object about in the visual ﬁeld. The normal blind spotcan be found 15° temporal to the line of gaze. (Find your own blind spotsfor practice.)TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
146 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGWhen the patient’s left eye
repeatedly does not see your ﬁngersuntil they have crossed the line ofgaze, a left temporal hemianopsia ispresent. It is diagrammed from thepatient’s viewpoint.
A left homonymous hemianopsia
may thus be established.
An enlarged blind spot occurs in
conditions affecting the optic nerve,e.g., glaucoma, optic neuritis, andpapilledema.
Covered
LEFT RIGHT
LEFT RIGHT

Inward or outward deviation of the
eyes; abnormal protrusion inGraves’ disease or ocular tumors
Scaliness in seborrheic dermatitis;
lateral sparseness in hypothyroidism
See Table 5-5, Variations and Ab-
normalities of the Eyelids (p. 177).Blepharitis is an inﬂammation of
the eyelids along the lid margins,often with crusting or scales.
Failure of the eyelids to close 
exposes the corneas to seriousdamage.
See Table 5-6, Lumps and Swellings
In and Around the Eyes (p. 178).
Excessive tearing may be due to 
increased production or impaireddrainage of tears. In the ﬁrst group,causes include conjunctival inﬂam-mation and corneal irritation; in thesecond, ectropion (p. 177) and nasolacrimal duct obstruction.
A yellow sclera indicates jaundice.EXAMPLES OF ABNORMALITIES TECHNIQUES OF EXAMINATION
CHAPTER 5 ITHE HEAD AND NECK 147
Position and Alignment of the Eyes. Stand in front of the patient

and survey the eyes for position and alignment with each other. If one orboth eyes seem to protrude, assess them from above (see p. 167).
Eyebrows. Inspect the eyebrows, noting their quantity and distribution
and any scaliness of the underlying skin.
Eyelids. Note the position of the lids in relation to the eyeballs. Inspect
for the following:
IWidth of the palpebral ﬁssures
IEdema of the lids
IColor of the lids (e.g., redness)
ILesions
ICondition and direction of the eyelashes
IAdequacy with which the eyelids close. Look for this especially when theeyes are unusually prominent, when there is facial paralysis, or when thepatient is unconscious.
Lacrimal Apparatus. Brieﬂy inspect the regions of the lacrimal gland
and lacrimal sac for swelling.

Look for excessive tearing or dryness of the eyes. Assessment of dryness may
require special testing by an ophthalmologist. To test for nasolacrimal ductobstruction, see pp. 167–168.
Conjunctiva and Sclera. Ask
the patient to look up as you depressboth lower lids with your thumbs,exposing the sclera and conjunctiva.Inspect the sclera and palpebral con-junctiva for color, and note the vas-cular pattern against the white scleralbackground. Look for any nodules orswelling.

The local redness below is due to
nodular episcleritis:
For comparisons, see Table 5-7,
Red Eyes (p. 179).
See Table 5-8, Opacities of the
Cornea and Lens (p. 180).
Occasionally the iris bows abnor-
mally far forward, forming a verynarrow angle with the cornea. Thelight then casts a crescentic shadow.
This narrow angle increases the risk
of acute narrow-angle glaucoma —
a sudden increase in intraocularpressure when drainage of theaqueous humor is blocked.
Miosis refers to constriction of the
pupils, mydriasis to dilation.If you need a fuller view of the eye,
rest your thumb and ﬁnger on thebones of the cheek and brow, re-spectively, and spread the lids.
Ask the patient to look to each side
and down. This technique gives youa good view of the sclera and bulbarconjunctiva, but not of the palpebralconjunctiva of the upper lid. For thispurpose, you need to evert the lid(see p. 168).
Cornea and Lens. With oblique lighting, inspect the cornea of each eye

for opacities and note any opacities in the lens that may be visible throughthe pupil.
Iris. At the same time, inspect each iris. The markings should be clearly
deﬁned. With your light shining directly from the temporal side, look for acrescentic shadow on the medial side of the iris. Since the iris is normallyfairly ﬂat and forms a relatively open angle with the cornea, this lighting castsno shadow.
In open-angle glaucoma—the common form of glaucoma—the normal spa-
tial relation between iris and cornea is preserved and the iris is fully lit.
Pupils. Inspect the size, shape, and symmetry of the pupils. If the pupils
are large (>5 mm), small (<3 mm), or unequal, measure them. A card withblack circles of varying sizes facilitates measurement.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
148 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Light
Light

CHAPTER 5 ITHE HEAD AND NECK 149Pupillary inequality of less than 0.5 mm ( anisocoria ) is visible in about 20%
of normal people. If pupillary reactions are normal, anisocoria is consideredbenign.
Test the pupillary reactions to light. Ask the patient to look into the distance,
and shine a bright light obliquely into each pupil in turn. (Both the distantgaze and the oblique lighting help to prevent a near reaction.) Look for:
IThe direct reaction (pupillary constriction in the same eye)
IThe consensual reaction (pupillary constriction in the opposite eye)
Always darken the room and use a bright light before deciding that a light
reaction is absent.
If the reaction to light is impaired or questionable, test the near reaction in

normal room light. Testing one eye at a time makes it easier to concentrateon pupillary responses, without the distraction of extraocular movement.Hold your ﬁnger or pencil about 10 cm from the patient’s eye. Ask the pa-tient to look alternately at it and into the distance directly behind it. Watchfor pupillary constriction with near effort.
Extraocular Muscles. From about 2 feet directly in front of the patient,
shine a light onto the patient’s eyes and ask the patient to look at it. Inspect
the reﬂections in the corneas. They should be visible slightly nasal to the cen-
ter of the pupils.Compare benign anisocoria with
Horner’s syndrome, oculomotornerve paralysis, and tonic pupil. SeeTable 5-9, Pupillary Abnormalities(p. 181).
Testing the near reaction is helpful

in diagnosing Argyll Robertson andtonic (Adie’s) pupils (see p. 181).
Asymmetry of the corneal reﬂec-
tions indicates a deviation fromnormal ocular alignment. A tempo-ral light reﬂection on one cornea,for example, indicates a nasal devi-ation of that eye. See Table 5-10,Deviations of the Eyes (p. 182).
See Table 5-10, Deviations of the
Eyes (p. 182).
1 2 3 4 5 6 7 mm
A cover –uncover test may reveal a slight or latent muscle imbalance not
otherwise seen (see p. 182).
Now assess the extraocular movements, looking for:
IThe normal conjugate movements of the eyes in each direction, or any
deviation from normal

150 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGINystagmus, a ﬁne rhythmic oscillation of the eyes. A few beats of nystag-
mus on extreme lateral gaze are within normal limits. If you see it, bringyour ﬁnger in to within the ﬁeld of binocular vision and look again.
IA lid lag as the eyes move from above downward.
To make these observations, ask the patient to follow your ﬁnger or pencil as

you sweep through the six cardinal directions of gaze. Making a wide H inthe air, lead the patient’s gaze (1) to the patient’s extreme right, (2) to theright and upward, and (3) down on the right; then (4) without pausing inthe middle, to the extreme left, (5) to the left and upward, and (6) down onthe left. Pause during upward and lateral gaze to detect nystagmus. Moveyour ﬁnger or pencil at a comfortable distance from the patient. Becausemiddle-aged or older people may have difﬁculty focusing on near objects,make this distance greater for them than for young people. Some patientsmove their heads to follow your ﬁnger. If necessary, hold the head in theproper midline position.Sustained nystagmus within the
binocular ﬁeld of gaze is seen in avariety of neurologic conditions.See Table 16-9, Nystagmus (pp. 610–611).
Lid lag of hyperthyroidism

In paralysis of the CN VI, illustrated
below, the eyes are conjugate inright lateral gaze but not in left lat-eral gaze (left infranuclear ophthal-moplegia)
1
2
34
5
6
If you suspect a lid lag or hyperthyroidism, ask the patient to follow your ﬁn-
ger again as you move it slowly from up to down in the midline. The lidshould overlap the iris slightly throughout this movement.In the lid lag of hyperthyroidism, a
rim of sclera is seen between theupper lid and iris; the lid seems tolag behind the eyeball.LOOKING RIGHT
LOOKING LEFT

CHAPTER 5 ITHE HEAD AND NECK 151Finally, test for convergence. Ask the patient to follow your ﬁnger or pencil
as you move it in toward the bridge of the nose. The converging eyes nor-mally follow the object to within 5 cm to 8 cm of the nose.
Ophthalmoscopic Examination. In general health care, you should
usually examine your patients’ eyes without dilating their pupils. Your viewis therefore limited to the posterior structures of the retinal surface. To seemore peripheral structures, to evaluate the macula well, or to investigate un-explained visual loss, ophthalmologists dilate the pupils with mydriatic dropsunless this is contraindicated.
At first, using the ophthalmoscope

may seem awkward, and it may bedifficult to visualize the fundus.With patience and practice of propertechnique, the fundus will comeinto view, and you will be able toassess important structures such asthe optic disc and the retinal ves-sels. Remove your glasses unless youhave marked nearsightedness orsevere astigmatism. (However, if thepatient’s refractive errors make itdifﬁcult to focus on the fundi, it maybe easier to keep your glasses on.)Poor convergence in hyper-
thyroidism
Contraindications for mydriatic
drops include (1) head injury andcoma, in which continuing obser-vations of pupillary reactions areessential, and (2) any suspicion ofnarrow-angle glaucoma.
Aperture
Indicator of
diopters
Lens discCONVERGENCE

152 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGReview the components of the ophthalmoscope pictured on the previous
page. Then follow the steps for using the ophthalmoscope, and your exam-ination skills will improve over time.
Absence of a red reﬂex suggests 
an opacity of the lens (cataract) orpossibly of the vitreous. Less commonly, a detached retina or, in children, a retinoblastoma mayobscure this reﬂex. Do not befooled by an artiﬁcial eye, which,of course, has no red reﬂex.STEPS FOR USING THE OPHTHALMOSCOPE
IDarken the room. Switch on the ophthalmoscope light and turn the lens disc
until you see the large round beam of white light.* Shine the light on the back ofyour hand to check the type of light, its desired brightness, and the electricalcharge of the ophthalmoscope.

ITurn the lens disc to the 0 diopter (a diopter is a unit that measures the power ofa lens to converge or diverge light). At this diopter the lens neither convergesnor diverges light. Keep your ﬁnger on the edge of the lens disc so you can turnthe disc to focus the lens when you examine the fundus.
IRemember, hold the ophthalmoscope in your right hand to examine the patient’s
right eye; hold it in your left hand to examine the patient’s left eye. This keeps you
from bumping the patient’s nose and gives you more mobility and closer rangefor visualizing the fundus. At ﬁrst, you may have difﬁculty using the nondominanteye, but this will abate with practice.

IHold the ophthalmoscope firmly braced against the medial aspect of yourbony orbit, with the handle tilted laterally at about a 20° slant from the verti-cal. Check to make sure you can see clearly through the aperture. Instruct thepatient to look slightly up and over your shoulder at a point directly ahead onthe wall.
IPlace yourself about 15 inches away from the patient and at an angle 15° lateralto the patient’s line of vision. Shine the light beam on the pupil and look for theorange glow in the pupil—the red reﬂex . Note any opacities interrupting the red
reﬂex.

reﬂex.
INow, place the thumb of your other hand across the patient’s eyebrow (thistechnique helps keep you steady but is not essential). Keeping the light beam focused on the red reﬂex, move in with the ophthalmoscope on the 15° angletoward the pupil until you are very close to it, almost touching the patient’s eyelashes.
Try to keep both eyes open and relaxed, as if gazing into the distance, to help
minimize any ﬂuctuating blurriness as your eyes attempt to accommodate. 
You may need to lower the brightness of the light beam to make the examina-
tion more comfortable for the patient, avoid hippus (spasm of the pupil), and im-
prove your observations.
*Some clinicians like to use the large round beam for large pupils, the small round beam for small pupils.

The other beams are rarely helpful. The slitlike beam is sometimes used to assess elevations or concavi-ties in the retina, the green (or red-free) beam to detect small red lesions, and the grid to make mea-surements. Ignore the last three lights and practice with the large round white beam.

CHAPTER 5 ITHE HEAD AND NECK 153Now you are ready to inspect the optic disc and the retina. You should be
seeing the optic disc—a yellowish orange to creamy pink oval or round struc-ture that may ﬁll your ﬁeld of gaze or even exceed it. Of interest, the oph-thalmoscope magniﬁes the normal retina about 15 times and the normal irisabout 4 times. The optic disc actually measures about 1.5 mm.When the lens has been removed
surgically, its magnifying effect islost. Retinal structures then lookmuch smaller than usual, and youcan see a much larger expanse offundus.
In a refractive error, light rays from
a distance do not focus on theretina. In myopia, they focus ante-rior to it; in hyperopia, posterior toit. Retinal structures in a myopiceye look larger than normal.
See Table 5-11, Normal Variations
of the Optic Disc (p. 183), andTable 5-12, Abnormalities of theOptic Disc (p. 184).
An enlarged cup suggests chronic
open-angle glaucoma.
Artery

Artery
Vein
Optic disc
Physiologic cup
Follow the steps below for this important segment of the physical examination:
STEPS FOR EXAMINING THE OPTIC DISC AND THE RETINA
IFirst, locate the optic disc. Look for the round yellowish orange structure de-
scribed above. If you do not see it at ﬁrst, follow a blood vessel centrally untilyou do. You can tell which direction is central by noting the angles at which ves-sels branch—the vessel size becomes progressively larger at each junction as youapproach the disc.
INow, bring the optic disc into sharp focus by adjusting the lens of your ophthal-

moscope. If both you and the patient have no refractive errors, the retinashould be in focus at 0 diopters. (A diopter is a unit that measures the powerof a lens to converge or diverge light.) If structures are blurred, rotate the lensdisc until you find the sharpest focus.
For example, if the patient is myopic (nearsighted), rotate the lens disc counter-
clockwise to the minus diopters; in a hyperopic (farsighted) patient, move thedisc clockwise to the plus diopters. You can correct your own refractive error inthe same way.
IInspect the optic disc. Note the following features:
–The sharpness or clarity of the disc outline. The nasal portion of the disc margin
may be somewhat blurred, a normal ﬁnding.
–The color of the disc, normally yellowish orange to creamy pink. White or pig-
mented crescents may ring the disc, a normal ﬁnding.

–The size of the central physiologic cup, if present. It is usually yellowish white.
The horizontal diameter is usually less than half the horizontal diameter of the disc.LEFT EYE

154 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING–The presence of venous pulsations. In a normal person, pulsations in the retinal
veins as they emerge from the central portion of the disc may or may not bepresent.
–The comparative symmetry of the eyes and ﬁndings in the fundi
IInspect the retina, including arteries and veins as they extend to the periphery,
arteriovenous crossings, the fovea, and the macula. Distinguish arteries fromveins based on the features listed below.Loss of venous pulsations in patho-
logic conditions like head trauma,meningitis, or mass lesions may bean early sign of elevated intra-cranial pressure.
See Table 5-13, Retinal Arteries and
Arteriovenous Crossings: Normaland Hypertensive (p. 185).
See Table 5-14, Red Spots and
Streaks in the Fundi (p. 186).
See Table 5-15, Light-Colored
Spots in the Fundi (pp. 187–188).
See Table 5-16, Ocular Fundi 
(pp. 189–191).
Macular degeneration is an impor-

tant cause of poor central vision in the elderly. Types include dry 
atrophic (more common but less
severe) and wet exudative, or 
neovascular. Undigested cellulardebris, called drusen, may be hard
and sharply deﬁned, or soft andconﬂuent with altered pigmenta-tion, as seen on the followingpage.Arteries Veins
Color Light red Dark red
Size Smaller (2⁄3to 4⁄5the diameter of veins) Larger
Light Reﬂex Bright Inconspicuous or absent
(reﬂection )
14
25
3
Sequence of inspection 
from disc to maculaIFollow the vessels peripherally in each
of four directions, noting their relative
sizes and the character of the arterio-venous crossings. Identify any lesions of the surrounding retina and

note their size, shape, color, and dis-tribution. As you search the retina,move your head and instrument as aunit, using the patient’s pupil as animaginary fulcrum. At first, you mayrepeatedly lose your view of theretina because your light falls out ofthe pupil. You will improve withpractice.
IFinally, by directing your light beam laterally or by asking the patient to lookdirectly into the light, inspect the fovea and surrounding macula. Except in
older people, the tiny bright reflection at the center of the fovea helps to ori-ent you. Shimmering light reflections in the macular area are common inyoung people.

ILesions of the retina can be measured in terms of “disc diameters” from theoptic disc. For example, among the cotton-wool patches illustrated on thenext page, note the irregular patches between 11 and 12 o’clock, 1 to 2 disc diameters from the disc. It measures about one-half by one-half disc diameters.LEFT EYE

CHAPTER 5 ITHE HEAD AND NECK 155IThe elevated optic disc of papilledema can be measured by noting the differ-
ences in diopters of the two lenses used to focus clearly on the disc and on theuninvolved retina. Note that at the retina, 3 diopters of elevation +1 mm.
IInspect the anterior structures. Look for opacities in the vitreous orlens by rotating
the lens disc progressively to diopters of around +10 or +12. This technique allowsyou to focus on the more anterior structures in the eye.Papilledema signals increased 
intracranial pressure from such serious conditions as trauma, masslesions, subarachnoid hemorrhage,or meningitis.
Vitreous ﬂoaters may be seen as
dark specks or strands between thefundus and the lens. Cataracts aredensities in the lens (see p. 180).
Optic discMacula
FoveaLight
reflection
Clear focus here
at + 3 dioptersClear focus here
at –1 diopter
+ 3 – (–1) = 4, therefore, a 
disc elevation of 4 diopters

MACULAR DEGENERATION OF AGING
RIGHT EYE
Tasman W, Jaeger E (eds): The Wills Eye Hospital Atlas of Clinical
Ophthalmology, 2nd ed. Philadelphia, Lippincott Williams & Wilkins,2001.COTTON WOOL PATCHES
PAPILLEDEMA
Photos above from Tasman W, Jaeger E (eds): The Wills
Eye Hospital Atlas of Clinical Ophthalmology, 2nd ed.Philadelphia, Lippincott Williams & Wilkins, 2001.

156 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGThe Ears
The Auricle. Inspect each auricle and surrounding tissues for deformi-
ties, lumps, or skin lesions.
If ear pain, discharge, or inﬂammation is present, move the auricle up and
down, press the tragus, and press ﬁrmly just behind the ear.
Ear Canal and Drum. To see
the ear canal and drum, use an oto-scope with the largest ear speculumthat the canal will accommodate.Position the patient’s head so thatyou can see comfortably through theinstrument. To straighten the earcanal, grasp the auricle ﬁrmly butgently and pull it upward, backward,and slightly away from the head.
Holding the otoscope handle between your thumb and ﬁngers, brace your

hand against the patient’s face. Your hand and instrument thus follow un-expected movements by the patient. (If you are uncomfortable switchinghands for the left ear, as shown below, you may reach over that ear to pullit up and back with your left hand and rest your otoscope-holding right handon the head behind the ear.)
Insert the speculum gently into the ear canal, directing it somewhat down and
forward and through the hairs, if any.
See Table 5-17, Lumps On or Near
the Ear (pp. 192–193).
Movement of the auricle and tragus
(the “tug test”) is painful in acute
otitis externa (inflammation of the
ear canal), but not in otitis media
(inﬂammation of the middle ear).Tenderness behind the ear may bepresent in otitis media.
Nontender nodular swellings cov-
ered by normal skin deep in the earcanals suggest exostoses. These are
nonmalignant overgrowths, whichmay obscure the drum.

CHAPTER 5 ITHE HEAD AND NECK 157Inspect the ear canal, noting any discharge, foreign bodies, redness of the
skin, or swelling. Cerumen, which varies in color and consistency from yel-
low and ﬂaky to brown and sticky or even to dark and hard, may wholly orpartly obscure your view.In acute otitis externa , shown 
below, the canal is often swollen,
narrowed, moist, pale, and tender.It may be reddened.
In chronic otitis externa , the skin of
the canal is often thickened, red,
and itchy.
Red bulging drum of acute
purulent otitis media, amber drumof a serous effusion
An unusually prominent short
process and a prominent handlethat looks more horizontal suggesta retracted drum.
See Table 5-18, Abnormalities of
the Eardrum (pp. 194–195).
A serous effusion, a thickened
drum, or purulent otitis mediamay decrease mobility.
Inspect the eardrum, noting its color and contour. The cone of light—usually
easy to see—helps to orient you.

Identify the handle of the malleus, noting its position, and inspect the short
process of the malleus.
Gently move the speculum so that you can see as much of the drum as pos-
sible, including the pars ﬂaccida superiorly and the margins of the pars tensa.Look for any perforations. The anterior and inferior margins of the drummay be obscured by the curving wall of the ear canal.
Mobility of the eardrum can be evaluated with a pneumatic otoscope.
Auditory Acuity. To estimate hearing, test one ear at a time. Ask the
patient to occlude one ear with a ﬁnger or, better still, occlude it yourself.

When auditory acuity on the two sides is different, move your ﬁnger rapidly,but gently, in the occluded canal. The noise so produced will help to pre-vent the occluded ear from doing the work of the ear you wish to test. Then,standing 1 or 2 feet away, exhale fully (so as to minimize the intensity of yourvoice) and whisper softly toward the unoccluded ear. Choose numbers orother words with two equally accented syllables, such as “nine-four,” or“baseball.” If necessary, increase the intensity of your voice to a mediumwhisper, a loud whisper, and then a soft, medium, and loud voice. To makesure the patient does not read your lips, cover your mouth or obstruct thepatient’s vision.
Air and Bone Conduction. If hearing is diminished, try to distinguish
between conductive and sensorineural hearing loss. You need a quiet room andRIGHT EARDRUM

158 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGa tuning fork, preferably of 512 Hz
or possibly 1024 Hz. These frequen-cies fall within the range of humanspeech (300 Hz to 3000 Hz)—func-tionally the most important range.Forks with lower pitches may lead tooverestimating bone conduction andcan also be felt as vibration.
Set the fork into light vibration by
briskly stroking it between thumband index ﬁnger         or by tappingit on your knuckles.
ITest for lateralization (Weber test).
Place the base of the lightly vi-brating tuning fork ﬁrmly on topof the patient’s head or on themidforehead.
Ask where the patient hears it: on one or both sides. Normally the sound
is heard in the midline or equally in both ears. If nothing is heard, tryagain, pressing the fork more ﬁrmly on the head.
ICompare air conduction (AC) and bone conduction (BC) (Rinne test).

Place the base of a lightly vibrating tuning fork on the mastoid bone, be-hind the ear and level with the canal. When the patient can no longer hearthe sound, quickly place the fork close to the ear canal and ascertainwhether the sound can be heard again. Here the “ U” of the fork should
face forward, thus maximizing its sound for the patient. Normally thesound is heard longer through air than through bone (AC > BC).
In unilateral conductive hearing
loss, sound is heard in (lateralizedto) the impaired ear. Visible expla-nations include acute otitis media,perforation of the eardrum, andobstruction of the ear canal, as by cerumen.
In unilateral sensorineural hearing
loss, sound is heard in the good ear.
In conductive hearing loss, sound

is heard through bone as long asor longer than it is through air (BC = AC or BC > AC). In sensori-neural hearing loss, sound is heardlonger through air (AC > BC). SeeTable 5-19, Patterns of Hearing Loss(pp. 196–197).—/H20690→→

CHAPTER 5 ITHE HEAD AND NECK 159The Nose and Paranasal Sinuses
Inspect the anterior and inferior surfaces of the nose. Gentle pressure on the
tip of the nose with your thumb usually widens the nostrils and, with the aidof a penlight or otoscope light, you can get a partial view of each nasalvestibule. If the tip is tender, be particularly gentle and manipulate the noseas little as possible.
Note any asymmetry or deformity of the nose.
Test for nasal obstruction, if indicated, by pressing on each ala nasi in turn
and asking the patient to breathe in.
Inspect the inside of the nose with an otoscope and the largest ear speculum
available.
‡Tilt the patient’s head back a bit and insert the speculum gently

into the vestibule of each nostril, avoiding contact with the sensitive nasalseptum. Hold the otoscope handle to one side to avoid the patient’s chinand improve your mobility. By directing the speculum posteriorly, then up-ward in small steps, try to see the inferior and middle turbinates, the nasalseptum, and the narrow nasal passage between them. Some asymmetry ofthe two sides is normal.
Tenderness of the nasal tip or alae
suggests local infection such as afuruncle.
Deviation of the lower septum is
common and may be easily visible,as illustrated below. Deviation seldom obstructs air ﬂow.
In viral rhinitis the mucosa is 
reddened and swollen; in allergicrhinitis it may be pale, bluish, or red.
Nasal
passage
Septum
Inferior
turbinateMiddle
turbinate
Observe:

Nasal
passage
Septum
Inferior
turbinate
Observe:
IThe nasal mucosa that covers the septum and turbinates. Note its color
and any swelling, bleeding, or exudate. If exudate is present, note its char-acter: clear, mucopurulent, or purulent. The nasal mucosa is normallysomewhat redder than the oral mucosa.
Vestibule
‡A nasal illuminator, equipped with a short wide nasal speculum but lacking an otoscope’s magniﬁca-
tion, may also be used, but structures look much smaller. Otolaryngologists use special equipment notwidely available to others.

160 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGIThe nasal septum. Note any deviation, inﬂammation, or perforation of the
septum. The lower anterior portion of the septum (where the patient’sﬁnger can reach) is a common source of epistaxis (nosebleed).
IAny abnormalities such as ulcers or polyps.
Make it a habit to place all nasal and ear specula outside your instrument case
after use. Then discard them or clean and disinfect them appropriately.(Check the policies of your institution.)
Palpate for sinus tenderness. Press up on the frontal sinuses from under the
bony brows, avoiding pressure on the eyes. Then press up on the maxillary
sinuses.Fresh blood or crusting may be
seen. Causes of septal perforationinclude trauma, surgery, and the intranasal use of cocaine oramphetamines.
Polyps are pale, semitranslucent
masses that usually come from themiddle meatus. Ulcers may resultfrom nasal use of cocaine.

Local tenderness, together with
symptoms such as pain, fever, and nasal discharge, suggestsacute sinusitis involving the frontalor maxillary sinuses. Transillumina-tion may be diagnostically useful.For this technique, see p. 169.
Bright red edematous mucosa 
underneath a denture suggestsdenture sore mouth. There maybe ulcers or papillary granulationtissue.
Cyanosis, pallor. See Table 5-20,
Abnormalities of the Lips (pp. 198–199).
The Mouth and Pharynx
If the patient wears dentures, offer a paper towel and ask the patient to remove
them so that you can see the mucosa underneath. If you detect any suspiciousulcers or nodules, put on a glove and palpate any lesions, noting especially anythickening or inﬁltration of the tissues that might suggest malignancy.
Inspect the following:
The Lips. Observe their color and moisture, and note any lumps, ulcers,

cracking, or scaliness.
The Oral Mucosa. Look into the patient’s mouth and, with a good light
and the help of a tongue blade, inspect the oral mucosa for color, ulcers,

white patches, and nodules. The wavy
white line on this buccal mucosa de-veloped where the upper and lowerteeth meet. Irritation from suckingor chewing may cause or intensify it.
The Gums and Teeth. Note the color of the gums, normally pink. Patchy
brownness may be present, especially but not exclusively in black people.
Inspect the gum margins and the interdental papillae for swelling or ulceration.
Inspect the teeth. Are any of them missing, discolored, misshapen, or ab-
normally positioned? You can check for looseness with your gloved thumband index ﬁnger.
The Roof of the Mouth. Inspect the color and architecture of the hard
palate.
The Tongue and the Floor of
the Mouth. Ask the patient to
put out his or her tongue. Inspectit for symmetry—a test of the hypo-glossal nerve (Cranial Nerve XII).
Note the color and texture of the
dorsum of the tongue.
Inspect the sides and undersurface of the tongue and the ﬂoor of the mouth.

These are the areas where cancer most often develops. Note any white orreddened areas, nodules, or ulcerations. Because cancer of the tongue isAn aphthous ulcer on the labial
mucosa is shown by the patient.
See p. 207 and Table 5-21, Find-
ings in the Pharynx, Palate, andOral Mucosa (pp. 200–202).
Redness of gingivitis, black line of
lead poisoning
Swollen interdental papillae in
gingivitis. See Table 5-22, Findingsin the Gums and Teeth(pp. 203–205).
Torus palatinus, a midline lump
(see p. 201)
Asymmetric protrusion suggests a
lesion of Cranial Nerve XII, asshown below.
Cancer of the tongue is the second
most common cancer of themouth, second only to cancer ofEXAMPLES OF ABNORMALITIES TECHNIQUES OF EXAMINATION
CHAPTER 5 ITHE HEAD AND NECK 161

the lip. Any persistent nodule 
or ulcer, red or white, must be suspect. Induration of the lesionfurther increases the possibility ofmalignancy. Cancer occurs mostoften on the side of the tongue,next most often at its base.
A carcinoma on the left side of a
tongue:
See Table 5-23, Findings In or
Under the Tongue (pp. 206–207).
In Cranial Nerve X paralysis, the
soft palate fails to rise and the uvula deviates to the opposite side.
See Table 5-21, Findings in the
Pharynx, Palate, and Oral Mucosa(pp. 200–202).TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
162 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGmore common in men over age 50, especially in those who use tobacco and

drink alcohol, palpation is indicated for these patients. Explain what you planto do and put on gloves. Ask the patient to protrude his tongue. With yourright hand, grasp the tip of the tongue with a square of gauze and gentlypull it to the patient’s left. Inspect the side of the tongue, and then palpateit with your gloved left hand, feeling for any induration (hardness). Reversethe procedure for the other side.
The Pharynx. Now, with the patient’s mouth open but the tongue not
protruded, ask the patient to say “ah” or yawn. This action may let you see

the pharynx well. If not, press a tongue blade ﬁrmly down upon the mid-point of the arched tongue—far enough back to get good visualization ofthe pharynx but not so far that you cause gagging. Simultaneously, ask foran “ah” or a yawn. Note the rise of the soft palate—a test of Cranial Nerve X(the vagal nerve).
Inspect the soft palate, anterior and posterior pillars, uvula, tonsils, and phar-
ynx. Note their color and symmetry and look for exudate, swelling, ulcera-tion, or tonsillar enlargement. If possible, palpate any suspicious area forinduration or tenderness. Tonsils have crypts, or deep infoldings of squa-mous epithelium. Whitish spots of normal exfoliating epithelium may some-times be seen in these crypts.
Discard your tongue blade after use.
Failure
to riseDeviated
to left(Photo reprinted by permission of the

Failure
New England Journal of Medicine, 328:186, 1993—arrows added)

The Neck
Inspect the neck, noting its symmetry and any masses or scars. Look for en-
largement of the parotid or submandibular glands, and note any visiblelymph nodes.
Lymph Nodes. Palpate the lymph nodes. Using the pads of your index
and middle ﬁngers, move the skin over the underlying tissues in each area.The patient should be relaxed, with neck ﬂexed slightly forward and, ifneeded, slightly toward the side being examined. You can usually examineboth sides at once. For the submental node, however, it is helpful to feelwith one hand while bracing the top of the head with the other.
Feel in sequence for the following nodes:
1. Preauricular—in front of the ear2. Posterior auricular—superﬁcial to the mastoid process3. Occipital—at the base of the skull posteriorly4. Tonsillar—at the angle of the mandible
5. Submandibular—midway between the angle and the tip of the mandible.
These nodes are usually smaller and smoother than the lobulated sub-mandibular gland against which they lie.

6. Submental—in the midline a few centimeters behind the tip of the
mandible
7. Superﬁcial cervical—superﬁcial to
the sternomastoid
8. Posterior cervical—along the ante-
rior edge of the trapezius
9. Deep cervical chain—deep to the
sternomastoid and often inaccessi-ble to examination. Hook yourthumb and ﬁngers around eitherside of the sternomastoid muscle toﬁnd them.
10. Supraclavicular—deep in the angle
formed by the clavicle and the ster-nomastoid
CHAPTER 5 ITHE HEAD AND NECK 163A scar of past thyroid surgery may
be the clue to unsuspected thyroiddisease.
A “tonsillar node” that pulsates is
really the carotid artery. A small,hard, tender “tonsillar node” highand deep between the mandibleand the sternomastoid is probablya styloid process.

Enlargement of a supraclavicular
node, especially on the left, suggestspossible metastasis from a thoracicor an abdominal malignancy.
1
2
3
4567
8
910
Internal lymphatic drainage
(e.g.,from mouth and throat)

164 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGNote their size, shape, delimitation (discrete or matted together), mobility,
consistency, and any tenderness. Small, mobile, discrete, nontender nodes,sometimes termed “shotty,” are frequently found in normal persons.
Using the pads of the 2nd and 3rd
fingers, palpate the preauricular nodeswith a gentle rotary motion. Thenexamine the posterior auricular andoccipital lymph nodes.
Palpate the anterior cervical chain, located anterior and superficial to the
sternomastoid. Then palpate the posterior cervical chain along the trapez-ius (anterior edge) and along the sternomastoid (posterior edge). Flex thepatient’s neck slightly forward toward the side being examined. Examinethe supraclavicular nodes in the angle between the clavicle and the ster-nomastoid.Tender nodes suggest inﬂamma-
tion; hard or ﬁxed nodes suggestmalignancy.

Enlarged or tender nodes, if unexplained, call for (1) reexamination of the
regions they drain, and (2) careful assessment of lymph nodes elsewhereso that you can distinguish between regional and generalized lymph-adenopathy.

CHAPTER 5 ITHE HEAD AND NECK 165Occasionally you may mistake a band of muscle or an artery for a lymph
node. You should be able to roll a node in two directions: up and down, andside to side. Neither a muscle nor an artery will pass this test.
The Trachea and the Thyroid Gland. To orient yourself to the
neck, identify the thyroid and cricoid cartilages and the trachea below them.
IInspect the trachea for any devia-
tion from its usual midline posi-tion. Then feel for any deviation.
Place your ﬁnger along one side ofthe trachea and note the space be-tween it and the sternomastoid.Compare it with the other side.The spaces should be symmetric.
IInspect the neck for the thyroid gland. Tip the patient’s head back a bit.
Using tangential lighting directed downward from the tip of the patient’schin, inspect the region below the cricoid cartilage for the gland. The

lower, shadowed border of each thyroid gland shown here is outlined byarrows.Diffuse lymphadenopathy raises
the suspicion of infection fromhuman immunodeﬁciency virus(HIV) or acquired immunodeﬁ-ciency syndrome (AIDS).
Masses in the neck may push the
trachea to one side. Tracheal devi-ation may also signify importantproblems in the thorax, such as amediastinal mass, atelectasis, or alarge pneumothorax (see p. 243).
The lower border of this large thy-
roid gland is outlined by tangentiallighting. Goiter is a general term
for an enlarged thyroid gland.
Thyroid
cartilage
Cricoid
cartilage
Thyroidgland
AT REST

166 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGAsk the patient to sip some water and to extend the neck again and swallow.
Watch for upward movement of the thyroid gland, noting its contour andsymmetry. The thyroid cartilage, the cricoid cartilage, and the thyroid glandall rise with swallowing and then fall to their resting positions.With swallowing, the lower border
of this large gland rises and looksless symmetrical.
Until you become familiar with this examination, check your visual obser-
vations with your ﬁngers from in front of the patient. This will orient you tothe next step.
You are now ready to palpate the thyroid gland. This may seem difﬁcult at

ﬁrst. Use the cues from visual inspection. Find your landmarks, adopt goodtechnique, and follow the steps on the next page, which outline the poste-rior approach (technique for the anterior approach is similar). With experi-ence you will become more adept. The thyroid gland is usually easier to feelin a long slender neck than in a short stocky one. In shorter necks, added ex-tension of the neck may help. In some persons, however, the thyroid glandis partially or wholly substernal and not amenable to physical examination.
Cricoid
cartilag eSWALLOWING

CHAPTER 5 ITHE HEAD AND NECK 167The Carotid Arteries and Jugular Veins. You will probably defer a
detailed examination of these vessels until the patient lies down for thecardiovascular examination. Jugular venous distention, however, may be vis-ible in the sitting position and should not be overlooked. You should alsobe alert to unusually prominent arterial pulsations. See Chapter 7 for furtherdiscussion.
Special Techniques
For Assessing Prominent Eyes. Inspect unusually prominent eyes from
above. Standing behind the seated patient, draw the upper lids gently upward,and then compare the positions of the eyes and note the relationship of thecorneas to the lower lids. Further assessment can be made with an exophthal-mometer, an instrument that measures the prominence of the eyes from theside. The upper limits of normal for eye prominence are increased in AfricanAmericans.

For Nasolacrimal Duct Obstruction. This test helps to identify the
cause of excessive tearing. Ask the patient to look up. Press on the lower lidclose to the medial canthus, just inside the rim of the bony orbit. You are thus
compressing the lacrimal sac.
Although physical characteristics
of the thyroid gland, such as size,shape, and consistency, are diag-nostically important, they tell youlittle if anything about thyroidfunction. Assessment of thyroidfunction depends upon symptoms,signs elsewhere in the body, andlaboratory tests. See Table 5-24,Thyroid Enlargement and Function(p. 208).
Soft in Graves’ disease; ﬁrm in
Hashimoto’s thyroiditis, malignancy.Benign and malignant nodules,tenderness in thyroiditis
A localized systolic or continuous
bruit may be heard in hyper-thyroidism.
Exophthalmos is an abnormal 
protrusion of the eye (see p. 177).STEPS FOR PALPATING THE THYROID GLAND
IAsk the patient to ﬂex the neck slightly forward to relax the sternomastoid muscles.

IPlace the ﬁngers of both hands on the patient’s neck so that your index ﬁngers
are just below the cricoid cartilage.
IAsk the patient to sip and swallow water as before. Feel for the thyroid isthmusrising up under your ﬁnger pads. It is often but not always palpable. 
IDisplace the trachea to the right with the ﬁngers of the left hand; with the right-hand ﬁngers, palpate laterally for the right lobe of the thyroid in the space be-tween the displaced trachea and the relaxed sternomastoid. Find the lateralmargin. In similar fashion, examine the left lobe.
The lobes are somewhat harder to feel than the isthmus, so practice is needed.
The anterior surface of a lateral lobe is approximately the size of the distal phalanxof the thumb and feels somewhat rubbery.

INote the size, shape, and consistency of the gland and identify any nodules or
tenderness .
If the thyroid gland is enlarged, listen over the lateral lobes with a stethoscope
to detect a bruit, a sound similar to a cardiac murmur but of noncardiac origin.

168 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGLook for ﬂuid regurgitated out of the
puncta into the eye. Avoid this test ifthe area is inﬂamed and tender.
For Inspection of the Upper Palpebral Conjunctiva. Adequate
examination of the eye in search of a foreign body requires eversion of theupper eyelid. Follow these steps:
IInstruct the patient to look down.Get the patient to relax the eyes—by reassurance and by gentle, as-sured, and deliberate movements.Raise the upper eyelid slightly sothat the eyelashes protrude, andthen grasp the upper eyelashesand pull them gently down andforward.
IPlace a small stick such as an ap-plicator or a tongue blade at least1 cm above the lid margin (andtherefore at the upper border ofthe tarsal plate). Push down on thestick as you raise the edge of the lid,thus everting the eyelid or turningit “inside out.” Do not press onthe eyeball itself.

ISecure the upper lashes againstthe eyebrow with your thumb andinspect the palpebral conjunctiva.After your inspection, grasp theupper eyelashes and pull themgently forward. Ask the patient tolook up. The eyelid will return toits normal position.Regurgitation of mucopurulent
ﬂuid from the puncta suggests anobstructed nasolacrimal duct.
This view allows you to see the
upper palpebral conjunctiva andlook for a foreign body that mightbe lodged there.

Swinging Flashlight Test. This test helps you to decide whether 
reduced vision is due to ocular disease or to optic nerve disease. For anadequate test, vision must not be entirely lost. In dim room light, note thesize of the pupils. After asking the patient to gaze into the distance, swingthe beam of a penlight back and forth from one pupil to the other, eachtime concentrating on the pupillary size and reaction in the eye that is lit.Normally, each illuminated eye looks or promptly becomes constricted.The opposite eye also constricts consensually.
When ocular disease, such as a cata-
ract, impairs vision, the pupils re-spond normally.
Transillumination of the Sinuses. When sinus tenderness or other

symptoms suggest sinusitis, this test can at times be helpful but is not highlysensitive or speciﬁc for diagnosis. The room should be thoroughly darkened.Using a strong, narrow light source, place the light snugly deep under eachbrow, close to the nose. Shield the light with your hand. Look for a dim redglow as light is transmitted through the air-ﬁlled frontal sinus to the forehead.
Ask the patient to tilt his or her head back with mouth opened wide. (An
upper denture should ﬁrst be removed.) Shine the light downward from justbelow the inner aspect of each eye. Look through the open mouth at thehard palate. A reddish glow indicates a normal air-ﬁlled maxillary sinus.EXAMPLES OF ABNORMALITIES TECHNIQUES OF EXAMINATION
CHAPTER 5 ITHE HEAD AND NECK 169Absence of glow on one or both

sides suggests a thickened mucosaor secretions in the frontal sinus,but it may also result from devel-opmental absence of one or bothsinuses.
Absence of glow suggests thickened
mucosa or secretions in the maxil-lary sinus. See p. 681 for an alter-native method of transilluminatingthe maxillary sinuses.When the optic nerve is damaged,
as in the left eye below, the sen-sory (afferent) stimulus sent to the midbrain is reduced. Thepupil, responding less vigorously,dilates from its prior constrictedstate. This response is an afferent
pupillary defect (Marcus Gunn
pupil). The opposite eye respondsconsensually.
LEFT RIGHTLEFT RIGHT

TABLE 5-1 IHeadaches
170 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Quality andTiming
Problem Process Location Severity Onset Duration
Tension
Headaches
Migraine
Headaches(“Classicmigraine” incontrast to“commonmigraine” isdistinguished by visual orneurologicsymptomsduring the halfhour before theheadache.)
Toxic Vascular
Headachesdue to fever,toxic substances,or drugwithdrawal
Cluster
Headaches
Headaches
With EyeDisordersErrors ofRefraction(farsightednessand astigma-tism, but notnearsightedness)
Acute GlaucomaUnclear
Dilatation of
arteries outside orinside the skull,possibly ofbiochemical origin;often familial
arteries, mainlyinside the skull
Unclear
Probably the sus-
tained contractionof the extraocularmuscles, andpossibly of thefrontal, temporal,and occipitalmuscles
Sudden increase in
intraocular pressure(see p. 148)Usually bilateral; may
be generalized orlocalized to the backof the head andupper neck or to thefrontotemporal area

Typically frontal or
temporal, one orboth sides, but alsomay be occipital orgeneralized. “Classicmigraine” is typicallyunilateral.
Generalized
One-sided; high in
the nose, and behindand over the eye
Around and over the
eyes, may radiate tothe occipital area
In and around one
eyeMild and aching or a
nonpainful tightnessand pressure
Throbbing or
aching, variable inseverity
Aching, of variable
severity
Steady, severe
Steady, aching, dull
Steady, aching, often
severeGradual
Fairly rapid,
reaching a peak in1–2 hours
Variable
Abrupt, often 
2–3 hours afterfalling asleep
Gradual
Often rapidVariable: hours or
days, but oftenweeks or months
Several hours to 
1–2 days
Depends on cause
Roughly 1–2 hours
Variable
Variable, may
depend on treatment

Gradual
1–2 days
Variable
Blanks appear in these tables when the categories are not applicable or are not usually helpful in assessing the problem.

CHAPTER 5 ITHE HEAD AND NECK 171
Factors That Convenient
Associated Aggravate Factors That Categories 
Course Symptoms or Provoke Relieve of Thought
Often recurrent or
persistent over longperiods
Often begins between
childhood and earlyadulthood. Typicallyrecurrent at intervals ofweeks, months, or years,usually decreasing withpregnancy and advancingage
Typically clustered in
time, with several eachday or week and thenrelief for weeks ormonths
Variable
Variable, may depend on
treatmentSymptoms of anxiety,
tension, and depressionmay be present.
Often nausea and
vomiting. A minority ofpatients have precedingvisual disturbances(local ﬂashes of light,blind spots) orneurologic symptoms(local weakness, sensorydisturbances, and othersymptoms).
Unilateral stuffy, runny
nose, and reddeningand tearing of the eye
Eye fatigue, “sandy”
sensations in the eyes,redness of theconjunctiva
Diminished vision,

sometimes nausea andvomitingSustained muscular
tension, as in driving ortyping; emotional
May be provoked by
alcohol, certain foods,or tension. Morecommon premen-strually. Aggravated bynoise and bright light
Fever, carbon
monoxide, hypoxia,withdrawal of caffeine,other causes
During a cluster, may
be provoked byalcohol
Prolonged use of the
eyes, particularly forclose work
Sometimes provoked by
drops that dilate thepupilsPossible massage,
relaxation
Quiet, dark room;
sleep; sometimestransient relief frompressure on theinvolved artery, if earlyin the course
Rest of the eyesThe two most
common kinds ofheadache
Vascular headaches
Face pains
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172 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 5-1 IHeadaches (Continued)
Headaches
With AcuteParanasalSinusitis
Trigeminal
Neuralgia
Giant Cell
Arteritis
Chronic
SubduralHematoma
Post-
concussionSyndrome
Meningitis
Subarachnoid
Hemorrhage
Brain TumorMucosal
inﬂammation ofthe paranasalsinuses and theiropenings
Mechanism
variable, oftenunknown
Chronic
inﬂammation ofthe cranial arteries,cause unknown,often associatedwith polymyalgiarheumatica
Bleeding into the
subdural space aftertrauma, followed byslow accumulationof ﬂuid thatcompresses thebrain
Mechanism unclear
Infection of the
meninges thatsurround the brain
Bleeding, most
often from aruptured intra-cranial aneurysm
Displacement of or
traction on pain-sensitive arteriesand veins orpressure on nerves,all within the skullUsually above the eye
(frontal sinus) or inthe cheekbone area(maxillary sinus), oneor both sides
Cheek, jaws, lips, or

gums (second andthird divisions of thetrigeminal nerve)
Localized near the
involved artery (mostoften the temporal,also the occipital);may becomegeneralized
Variable
May be localized to
the injured area, butnot necessarily
Varies with the
location of the tumorAching or throbbing,
variable in severity
Sharp, short, brief,
lightninglike jabs;very severe
Aching, throbbing,
or burning, oftensevere
Steady, aching
Variable
Steady or throbbing,
very severe
Very severe, “the
worst of my life”
Aching, steady,
variable in intensityVariable
AbruptGradual or rapid
Gradual onset
weeks to monthsafter the injury
Within a few hours
of the injury
Fairly rapidUsually abrupt.
Prodromalsymptoms mayoccur
VariableOften several hours
at a time, recurringover days or longer
Each jab is transient,
but jabs recur inclusters at intervals ofseconds or minutes
Variable
Often depends on

Variable
surgical intervention
Weeks, months, or
even years
Variable, usually daysVariable, usually
days
Often briefTABLE 5-1 IHeadaches

CHAPTER 5 ITHE HEAD AND NECK 173
Often recurrent in a
repetitive daily pattern:starting in the morning(frontal) or in theafternoon (maxillary)
Pain may be troublesome
for months, then dis-appears for months, butoften recurs. It isuncommon at night.
Recurrent or persistent
over weeks to months
Progressively severe but
may be obscured byclouded consciousness
Tends to diminish over
time
A persistent headache in
an acute illness
Often intermittent, but
progressiveLocal tenderness, nasal
congestion, discharge,and fever
Exhaustion from
recurrent pain
Tenderness of the
adjacent scalp; fever,malaise, fatigue, andanorexia; muscularaches and stiffness;visual loss or blindness
Alterations in
consciousness, changesin personality, andhemiparesis (weaknesson one side of thebody). The injury isoften forgotten.
Poor concentration,

giddiness or vertigo,irritability, restlessness,tenseness, and fatigue
Fever, stiff neck
Nausea, vomiting,
possibly loss ofconsciousness, neck pain
Neurologic and mental
symptoms and nauseaand vomiting maydevelop.May be aggravated by
coughing, sneezing, orjarring the head
Typically triggered by
touching certain areas ofthe lower face or mouth,or by chewing, talking,or brushing teeth
Mental and physical
exertion, straining,stooping, emotionalexcitement, alcohol
May be aggravated by
coughing, sneezing, orsudden movements ofthe headNasal decongestants
RestFace pains
Consider these three
in older adults.
Headaches following
head trauma
Acute illnesses with
very severe headaches
An underlying
concern of patientand clinician alike
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174 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 5-2 IVertigo
Other 
Problem Onset Duration Course Hearing Tinnitus Symptoms
Benign
PositionalVertigo
Vestibular
Neuronitis(acutelabyrinthitis)
Ménière’s
Disease
Drug 
Toxicity(as from amino-glycosides or alcoholintoxication)
Tumor,
Pressing on the 8th NerveSudden, on
rolling over ontothe affected sideor tilting thehead up
Sudden
Sudden
Insidious or acute
Insidious**Brief, a few
seconds tominutes
Hours to days, up
to 2 weeks
Several hours to a
day or more 
VariablePersists a few
weeks, mayrecur 
May recur over
12–18 months
Recurrent
VariableNot affected
Not affected
Sensorineural
hearing loss thatimproves andrecurs, eventuallyprogresses; one orboth sides*
May be impaired,
both sides
Impaired, one sideAbsent
Absent
Present,
ﬂuctuating*
May be
present
PresentSometimes
nausea andvomiting
Nausea,
vomiting
Nausea,
vomiting,pressure orfullness in theaffected ear
Nausea,
vomiting
Those of

Absent
Present,
May be
present
Nausea,
vomiting
Nausea,
Nausea,
vomiting
Those of
pressure onCranialNerves V, VI,and VIIMay or may not be reversible
Partial adaptation occursTiming
Additional disorders of the brainstem or cerebellum may also cause vertigo. These include ischemia secondary toatherosclerosis, tumors, and multiple sclerosis. Additional neurologic symptoms and signs are usually present.
*Hearing impairment, tinnitus, and rotary vertigo do not always develop concurrently. Time is often required to make this diagn osis.
**Persistent unsteadiness is more common, but vertigo may occur.TABLE 5-2 IVertigo

TABLE 5-3 ISelected Facies
CHAPTER 5 ITHE HEAD AND NECK 175
Acromegaly
The increased growth hormone
of acromegaly producesenlargement of both bone andsoft tissues. The head iselongated, with bonyprominence of the forehead,nose, and lower jaw. Soft tissuesof the nose, lips, and ears alsoenlarge. The facial featuresappear generally coarsened.Cushing’s Syndrome
The increased adrenalhormone production ofCushing’s syndrome producesa round or “moon” face withred cheeks. Excessive hairgrowth may be present in themustache and sideburn areasand on the chin.
Myxedema
The patient with severehypothyroidism ( myxedema ) has
a dull, puffy facies. The edema,often particularly pronouncedaround the eyes, does not pitwith pressure. The hair andeyebrows are dry, coarse, andthinned. The skin is dry.Parotid Gland
Enlargement
Chronic bilateral asymptomatic

parotid gland enlargement maybe associated with obesity,diabetes, cirrhosis, and otherconditions. Note the swellingsanterior to the ear lobes andabove the angles of the jaw.Gradual unilateral enlargementsuggests neoplasm. Acuteenlargement is seen in mumps.
Brow
prominent
Soft tissues
of nose, ears,lips enlarged
Jawprominent
Red cheeks
Hirsutism
Moon face
Hair dry,
coarse, sparse
Lateral
eyebrowsthin
Periorbital
edema
Puffy dullface withdry skin
Local
swellingobscuresear lobe
Nephrotic Syndrome
The face is edematous and often
pale. Swelling usually appearsﬁrst around the eyes and in themorning. The eyes may becomeslitlike when edema is severe.
edema
Puffy pale
face
Lips maybe swollenParkinson’s Disease
Decreased facial mobility

edema
Puffy pale
face
blunts expression. A masklikeface may result, withdecreased blinking and acharacteristic stare. Since theneck and upper trunk tend toﬂex forward, the patient seemsto peer upward toward theobserver. Facial skin becomesoily, and drooling may occur.
Stare
Decreasd
mobility

TABLE 5-4 IVisual Field Defects
176 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Diagrammed From Patient’s 
Visual Pathway Lesions Visual Field Defects Viewpoint
  VISUAL FIELDS
Temporal 
Optic
radiation
Visual cortex1
2
43
5
61 Horizontal Defect
Occlusion of a branch of the central retinal
artery may cause a horizontal (altitudinal)defect. Shown is the lower ﬁeld defectassociated with occlusion of the superiorbranch of this artery.
2 Blind Right Eye (right optic nerve)
A lesion of the optic nerve, and of course ofthe eye itself, produces unilateral blindness.
3 Bitemporal Hemianopsia (optic
chiasm)
A lesion at the optic chiasm may involve only
the ﬁbers that are crossing over to theopposite side. Since these ﬁbers originate inthe nasal half of each retina, visual lossinvolves the temporal half of each ﬁeld.
4 Left Homonymous Hemianopsia 
(right optic tract)

A lesion of the optic tract interrupts ﬁbers
originating on the same side of both eyes.Visual loss in the eyes is therefore similar(homonymous) and involves half of eachﬁeld (hemianopsia).
5 Homonymous Left Superior
Quadrantic Defect (right opticradiation, partial)
A partial lesion of the optic radiation may
involve only a portion of the nerve ﬁbers,producing, for example, a homonymousquadrantic defect.
6 Left Homonymous Hemianopsia 
(right optic radiation)
A complete interruption of ﬁbers in the optic
radiation produces a visual defect similar tothat produced by a lesion of the optic tract.1
2
3
4
5
6
LEFT RIGHT

TABLE 5-5 IVariations and Abnormalities of the Eyelids
CHAPTER 5 ITHE HEAD AND NECK 177
Ptosis
Ptosis is a drooping of the upper lid.
Causes include myasthenia gravis,damage to the oculomotor nerve, anddamage to the sympathetic nerve supply(Horner’s syndrome ). A weakened
muscle, relaxed tissues, and the weightof herniated fat may cause senile ptosis.Ptosis may also be congenital.Retracted Lid
A wide-eyed stare suggests retractedeyelids—in this case, the upper lid.Note the rim of sclera between theupper lid and the iris. Retracted lidsand a lid lag (p. 150) are often dueto hyperthyroidism but may be seenin normal people. The eye does notprotrude forward unlessexophthalmos coexists.Exophthalmos

In exophthalmos the eyeball protrudesforward. When bilateral, it suggeststhe inﬁltrative ophthalmopathy ofGraves’ disease, a form ofhyperthyroidism. Edema of the eyelidsand conjunctival injection may beassociated. Unilateral exophthalmosmay be due to Graves’ disease or to atumor or inﬂammation in the orbit.Epicanthus
An epicanthus (epicanthal fold) is avertical fold of skin that lies over themedial canthus. It is normal amongmany Asian peoples. These folds arealso seen in Down’s syndrome and in afew other congenital conditions. Theymay falsely suggest a convergentstrabismus (see p. 182).
Ectropion
In ectropion the margin of the lower
lid is turned outward, exposing thepalpebral conjunctiva. When thepunctum of the lower lid turnsoutward, the eye no longer drainssatisfactorily and tearing occurs.Ectropion is more common in theelderly.Entropion

Entropion, more common in theelderly, is an inward turning of the lidmargin. The lower lashes, which areoften invisible when turned inward,irritate the conjunctiva and lowercornea. Asking the patient to squeezethe lids together and then open themmay reveal an entropion that is notobvious.Periorbital Edema
Because the skin of the eyelids isloosely attached to underlyingtissues, edema tends to accumulatethere easily. Causes include allergies,local inﬂammation, cellulitis,myxedema, and ﬂuid-retaining statessuch as the nephrotic syndrome.Herniated Fat
Puffy eyelids may be caused by fat. Itpushes weakened fascia in the eyelidsforward, producing bulges that involvethe lower lids, the inner third of theupper ones, or both. These bulgesappear more often in elderly peoplebut may affect younger ones.
(Source of photos: Ptosis, Ectropion, Entropion —Tasman W, Jaeger E (eds): The Wills Eye Hospital Atlas of Clinical Ophthalmology, 2nd ed. Philadelphia, Lippincott Williams &
Wilkins, 2001.)

TABLE 5-6 ILumps and Swellings In and Around the Eyes
178 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Pinguecula
A yellowish, somewhat triangular nodule in the
bulbar conjunctiva on either side of the iris, apinguecula is harmless. Pingueculae appear frequentlywith aging, ﬁrst on the nasal and then on thetemporal side.Sty (Acute Hordeolum)
A painful, tender, red infection in a gland at themargin of the eyelid, a sty looks like a pimple or boilpointing on the lid margin.Chalazion
A chalazion is a subacute nontender nodule involvinga meibomian gland. A beady nodule in an otherwisenormal lid, it is usually painless. Occasionally a chala-zion becomes acutely inﬂamed but, unlike a sty, usu-ally points inside the lid rather than on the lid margin.
Episcleritis

Episcleritis is a localized ocular redness frominﬂammation of the episcleral vessels. In naturallight, vessels appear salmon pink and are movableover the scleral surface. Usually benign and self-limited, episcleritis may be nodular, as shown here, or may show only redness and dilatedvessels.Inﬂammation of the Lacrimal Sac
(Dacryocystitis)
A swelling between the lower eyelid and nose 
suggests inﬂammation of the lacrimal sac. An acute
inﬂammation (illustrated) is painful, red, and tender.Chronic inﬂammation is associated with obstruction
of the nasolacrimal duct. Tearing is prominent, andpressure on the sac produces regurgitation ofmaterial through the puncta of the eyelids.Xanthelasma
Slightly raised, yellowish, well-circumscribedplaques in the skin, xanthelasmas appear along thenasal portions of one or both eyelids. They may accompany lipid disorders (e.g., hypercholesterolemia), but may also occur independently.

(Source of photos: Tasman W, Jaeger E (eds): The Wills Eye Hospital Atlas of Clinical Ophthalmology, 2nd ed. Philadelphia, Lipp incott Williams & Wilkins, 2001.)

TABLE 5-7 IRed Eyes
CHAPTER 5 ITHE HEAD AND NECK 179
Corneal Injury or Subconjunctival
Conjunctivitis Infection Acute Iritis Glaucoma Hemorrhage
Pattern of
Redness
Pain
Vision
Ocular
Discharge
Pupil
CorneaSigniﬁcanceConjunctival injection:
diffuse dilatation ofconjunctival vessels withredness that tends to bemaximal peripherally
Mild discomfort rather
than pain
Not affected except for
temporary mild blurringdue to discharge
Watery, mucoid, or
mucopurulent
ClearBacterial, viral, and
other infections; allergy;irritationModerate to severe,
superﬁcial
Usually decreased
Watery or purulent
Not affected unless iritis
develops
Changes depending on
cause
Abrasions, and other
injuries; viral and bacterialinfectionsModerate, aching, deep
Decreased
Absent
May be small and, with
time, irregular
Clear or slightly clouded
Associated with many
ocular and systemicdisordersSevere, aching, deep
Decreased
Absent
Dilated, ﬁxedSteamy, cloudyAcute increase in

Decreased
Absent
intraocular pressure—an emergencyLeakage of blood outside
of the vessels, producinga homogeneous, sharplydemarcated, red area thatfades over days to yellowand then disappears
Absent
Absent
Not affectedClearOften none. May result
from trauma, bleedingdisorders, or a suddenincrease in venouspressure, as from coughCiliary infection: dilation of deeper vessels that are visible as radiating vessels or a reddish
violet ﬂush around the limbus. Ciliary infection is an important sign of these threeconditions but may not be apparent. The eye may be diffusely red instead. Other clues ofthese more serious disorders are pain, decreased vision, unequal pupils, and a less thanperfectly clear cornea.

TABLE 5-8 IOpacities of the Cornea and Lens
180 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
A corneal arcus is a thin grayish white arc
or circle not quite at the edge of thecornea. It accompanies normal aging butmay also be seen in younger people,especially African Americans. In youngpeople, a corneal arcus suggests thepossibility of hyperlipoproteinemia butdoes not prove it. Some surveys haverevealed no relationship.Corneal Arcus
 Cataracts
Cross Section of Lens
Capsule
Nuclear
cataractCortex
Cortical
cataractA cataract is an opacity of the lens and is
seen through the pupil. Cataracts areclassiﬁed in many ways, including causeand location. Old age is the mostcommon cause. Two kinds of age-relatedcataract are illustrated below. In eachexample, the pupil has been widelydilated.
A corneal scar is a superﬁcial grayish white

opacity in the cornea, secondary to an oldinjury or to inﬂammation. Size and shapeare variable. It should not be confused withthe opaque lens of a cataract, visible on adeeper plane and only through the pupil.
Corneal Scar
 Nuclear Cataract
A nuclear cataract looks gray when seen
by a ﬂashlight. If the pupil is widelydilated, the gray opacity is surrounded bya black rim. Through an ophthalmoscope,the cataract looks black against the redreﬂex.
A pterygium is a triangular thickening of the
bulbar conjunctiva that grows slowly acrossthe outer surface of the cornea, usually fromthe nasal side. Reddening may occurintermittently. A pterygium may interferewith vision as it encroaches upon the pupil.
Pterygium
A peripheral cataract produces spokelike
shadows that point inward—gray againstblack as seen with a ﬂashlight, or blackagainst red with an ophthalmoscope. Adilated pupil, as shown here, facilitatesthis observation.Peripheral Cataract

TABLE 5-1 ILesions of the Vulva
CHAPTER 5 ITHE HEAD AND NECK 181TABLE 5-9 IPupillary Abnormalities
CHAPTER 5 ITHE HEAD AND NECK 181
TABLE 5-9 IPupillary Abnormalities
Unequal Pupils ( Anisocoria )
When anisocoria is greater in bright light than in dim light, the larger pupil cannot constrict properly. Causes include blunt trauma to the eye, open-angle
glaucoma (p. 148), and impaired parasympathetic nerve supply to the iris, as in tonic pupil and oculomotor nerve paralysis. Whe n anisocoria is greater in dim light,
the smaller pupil cannot dilate properly, as in Horner’s syndrome, which is caused by an interruption of the sympathetic nerve supply.
Tonic Pupil (Adie’s Pupil)
A tonic pupil is large, regular, and usually unilateral. Its
reaction to light is severely reduced and slowed, or evenabsent. The near reaction, though very slow, is present.Slow accommodation causes blurred vision. Deeptendon reﬂexes are often decreased.
Oculomotor Nerve (CN III) Paralysis

The dilated pupil (about 6–7 mm) is ﬁxed to light
and near effort. Ptosis of the upper eyelid andlateral deviation of the eye, as shown here, are often but not always present. (An even moredilated [8–9 mm] and ﬁxed pupil may be due tolocal application of atropine-like agents.)
Horner’s Syndrome
The affected pupil, though small, reacts briskly
to light and near effort. Ptosis of the eyelid ispresent, perhaps with loss of sweating on theforehead of the same side. In congenitalHorner’s syndrome, the involved iris is lighter incolor than its fellow ( heterochromia ).
Equal Pupils and One Blind Eye
Unilateral blindness does not cause anisocoria as long as the sympathetic and parasympathetic innervation to
both irises is normal. A light directed into the seeing eye produces a direct reaction in that eye and a consensualreaction in the blind eye. A light directed into the blind eye, however, causes no response in either eye.
Blind eye
Light
Blind eye
Light

Blind eye
Light
Blind eye
Light
Small Irregular Pupils
Small, irregular pupils that do not react to light
but do react to near effort indicate Argyll
Robertson pupils. They are usually but not always
caused by central nervous system syphilis.
See also Table 16-15, Pupils in Comatose Patients, p. 621.

TABLE 5-10 IDeviations of the Eyes
182 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Deviation of the eyes from their normally conjugate position is termed strabismus or squint. Strabismus may be classiﬁed
into two groups: (1) nonparalytic, in which the deviation is constant in all directions of gaze, and (2) paralytic, in which
the deviation varies depending on the direction of gaze.
Nonparalytic Strabismus
Nonparalytic strabismus is caused by an imbalance in ocular muscle tone. Ithas many causes, may be hereditary, and usually appears early in childhood.Deviations are further classiﬁed according to direction:
Convergent Strabismus Divergent Strabismus
(Esotropia) (Exotropia)
A cover–uncover test may be helpful. Here is what you would see in the
right monocular esotropia illustrated above.Paralytic Strabismus

Paralytic strabismus is usually caused by weakness or paralysis of one or moreextraocular muscles. Determine the direction of gaze that maximizes the deviation.For example:
Corneal reﬂections are
asymmetric.
The right eye moves outward to
ﬁx on the light. (The left eye isnot seen but moves inward tothe same degree.)
The left eye moves outward to
ﬁx on the light. The right eyedeviates inward again.A Left Cranial
Nerve VIParalysis
A Left Cranial
Nerve IVParalysis
Nerve IIIParalysisEyes are conjugate.
Esotropia appears.
Esotropia is
maximum.
The left eye cannot
look down whenturned inward.Deviation is maximumin this direction.
The eye is pulled
outward by action ofthe 6th nerve. Upward,downward, and inwardmovements areimpaired or lost. Ptosisand pupillary dilationmay be associated.

COVER–UNCOVER TESTLOOKING TO THE RIGHT
LOOKING STRAIGHT AHEAD
LOOKING TO THE LEFT
LOOKING DOWN AND TO THE RIGHT
LOOKING STRAIGHT AHEADCOVER
UNCOVER

TABLE 5-11 INormal Variations of the Optic Disc
CHAPTER 5 ITHE HEAD AND NECK 183
Physiologic Cupping
The physiologic cup is a small whitish depression in
the optic disc from which the retinal vessels appearto emerge. Although sometimes absent, the cup isusually visible either centrally or toward the temporalside of the disc. Grayish spots are often seen at itsbase.Rings and Crescents
Rings and crescents are often seen around theoptic disc. These are developmental variations inwhich you can glimpse either white sclera, blackretinal pigment, or both, especially along thetemporal border of the disc. Rings and crescentsare not part of the disc itself and should not beincluded in your estimates of disc diameters.Medullated Nerve Fibers
Medullated nerve ﬁbers are a much less common butdramatic ﬁnding. Appearing as irregular whitepatches with feathered margins, they obscure the discedge and retinal vessels. They have no pathologicsigniﬁcance.

TABLE 5-12 IAbnormalities of the Optic Disc
184 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Normal Optic Atrophy Papilledema Glaucomatous Cupping
Process
AppearanceTiny disc vessels give
normal color to the disc.
Color yellowish orange to
creamy pink
Disc vessels tiny
Disc margins sharp (except
perhaps nasally)
The physiologic cup is
located centrally orsomewhat temporally. It may be conspicuous orabsent. Its diameter fromside to side is usually lessthan half that of the disc.Death of optic nerve ﬁbers leads
to loss of the tiny disc vessels.
Color white
Disc vessels absentVenous stasis leads to
engorgement and swelling.
Color pink, hyperemic
Disc vessels more visible,
more numerous, curve overthe borders of the disc
Disc swollen with margins
blurred
The physiologic cup is not
visible.Increased pressure within the
eye leads to increased cupping(backward depression of thedisc) and atrophy.
The base of the enlarged cup 
is pale.

blurred
is pale.
The physiologic cup is enlarged,
occupying more than half of the disc’s diameter, at timesextending to the edge of thedisc. Retinal vessels sink in andunder it, and may be displacednasally.

TABLE 5-13 IRetinal Arteries and Arteriovenous Crossings
CHAPTER 5 ITHE HEAD AND NECK 185
TABLE 5-13 IRetinal Arteries and Arteriovenous Crossings: Normal and Hypertensive
Normal Retinal Artery and Arteriovenous (A-V) Crossing
The normal arterial wall is transparent. Only the
column of blood within it can usually be seen.The normal light reﬂex is narrow—about onefourth the diameter of the blood column.Because the arterial wall is transparent, a
vein crossing beneath the artery can beseen right up to the column of bloodon either side.
The vein appears to taper down on either side
of the artery.The vein appears to stop abruptly on either side
of the artery.The vein is twisted on the distal side of the artery
and forms a dark, wide knuckle.    Arterial wall (invisible) 
    Column of blood     Light reflexVein
Arterial WallArtery
Focal  
narrowing
Retinal Arteries in Hypertension
In hypertension, the arteries may show areas of focal

Column of blood     Light reflexVein
Focal  
narrowing
or generalized narrowing. The light reﬂex is alsonarrowed. Over many months or years, the arterialwall thickens and becomes less transparent.Sometimes the arteries, especially those close
to the disc, become full and somewhattortuous and develop an increased light reﬂexwith a bright coppery luster. Such a vessel iscalled a copper wire artery.Occasionally a portion of a narrowed artery develops
such an opaque wall that no blood is visible withinit. It is then called a silver wire artery. This changetypically occurs in the smaller branches.
Arteriovenous Crossing
When the arterial walls lose their transparency, changes appear in the arteriovenous crossings. Decreased transparencyof the retina probably also contributes to the ﬁrst two changes shown below.
TAPERING BANKING CONCEALMENT OR
A–V NICKINGNarrowed  column of blood

Narrowed light 
reflex

TABLE 5-14 IRed Spots and Streaks in the Fundi
186 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Superﬁcial Retinal Hemorrhages
Superﬁcial retinal hemorrhages are small, linear, ﬂame-shaped, red streaks in the fundi. They are shaped by
the superﬁcial bundles of nerve ﬁbers that radiate from the optic disc in the pattern illustrated (O = opticdisc; F = fovea). Sometimes the hemorrhages occur in clusters and then simulate a larger hemorrhage, butthe linear streaking at the edges shows their true nature. Superﬁcial hemorrhages are seen in severehypertension, papilledema, and occlusion of the retinal vein, among other conditions.
An occasional superﬁcial hemorrhage has a white center consisting of ﬁbrin. White-centered retinal
hemorrhages have many causes.Deep Retinal Hemorrhages

Deep retinal hemorrhages are small, rounded,slightly irregular red spots that are sometimescalled dot or blot hemorrhages. They occurin a deeper layer of the retina than ﬂame-shaped hemorrhages. Diabetes mellitus is acommon cause.
Preretinal Hemorrhage
A preretinal (subhyaloid) hemorrhage developswhen blood escapes into the potential spacebetween retina and vitreous. This hemorrhage istypically larger than retinal hemorrhages. Because itis anterior to the retina, it obscures any underlyingretinal vessels. In an erect patient, red cells settle,creating a horizontal line of demarcation betweenplasma above and cells below. Causes include asudden increase in intracranial pressure.Microaneurysms

Microaneurysms are tiny, round, red spots seencommonly but not exclusively in and around themacular area. They are minute dilatations of verysmall retinal vessels, but the vascular connectionsare too small to be seen ophthalmoscopically.Microaneurysms are characteristic of diabeticretinopathy but not speciﬁc to it.Neovascularization
Neovascularization refers to the formation of newblood vessels. They are more numerous, moretortuous, and narrower than other blood vessels inthe area and form disorderly looking red arcades.A common cause is the late, proliferative stage ofdiabetic retinopathy. The vessels may grow intothe vitreous, where retinal detachment orhemorrhage may cause loss of vision.F O

TABLE 5-15 ILight-Colored Spots in the Fundi
CHAPTER 5 ITHE HEAD AND NECK 187
Cotton-Wool Patches ( Soft Exudates )
Cotton-wool patches are white or grayish, ovoid lesions with irregular
(thus “soft”) borders. They are moderate in size but usually smallerthan the disc. They result from infarcted nerve ﬁbers and are seen withhypertension and many other conditions.Hard Exudates
Hard exudates are creamy or yellowish, often bright lesions with well-deﬁned (thus “hard”) borders. They are small and round (as shown in the lower group of exudates) but may coalesce into larger irregular spots(as shown in the upper group). They often occur in clusters or in circular,linear, or star-shaped patterns. Causes include diabetes and hypertension.
Drusen

Drusen
Drusen are yellowish round spots that vary from tiny to small. Theedges may hard, as here, or soft. They are haphazardly distributed butmay concentrate at the posterior pole. Drusen appear with normal agingbut may also accompany various conditions, including age-relatedmacular degeneration.Healed Chorioretinitis
Here inﬂammation has destroyed the superﬁcial tissues to reveal a well-deﬁned, irregular patch of white sclera marked with dark pigment. Sizevaries from small to very large. Toxoplasmosis is illustrated. Multiple,small, somewhat similar-looking areas may be due to laser treatments.Here there is also a temporal scar near the macula.
(table continues next page )

188 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 5-15 ILight-Colored Spots in the Fundi (Continued)
Coloboma
A coloboma of the choroid and retina is a developmental abnormality.
A well demarcated, moderate-sized to large, white oval of sclera isvisible below the disc, often extending well beyond the limits of yourexamination. Its borders may be pigmented.Proliferative Diabetic Retinopathy
Bands or strands of white ﬁbrous tissue develop in the late proliferativestage of diabetic retinopathy. They lie anterior to the retinal vessels andtherefore obscure them. Neovascularization (p. 186) is typicallyassociated.
(Source of illustrations: Cotton-Wool Patches, Hard Exudates; Drusen, Healed Chorioretinitis, Coloboma— Tasman W, Jaeger E (eds): The Wills Eye Hospital Atlas of Clinical

Ophthalmology, 2nd ed. Philadelphia, Lippincott Williams & Wilkins, 2001; Proliferative Diabetic Retinopathy —Early Treatment Diabetic Retinopathy Study Research Group.
Courtesy of M.F. Davis, MD, University of Wisconsin, Madison.)

TABLE 5-16 IOcular Fundi
CHAPTER 5 ITHE HEAD AND NECK 189
Normal Fundus of a Fair-Skinned Person
Find and inspect the optic disc. Follow the major vessels in four directions, noting their relative
sizes and the nature of the arteriovenous crossings—both normal here. Inspect the macular area.The slightly darker fovea is just discernible; no light reﬂex is visible in this subject. Look for anylesions in the retina. Note the striped, or tessellated, character of the fundus, especially in the lowerﬁeld. This comes from normal choroidal vessels that are unobscured by pigment.
Normal Fundus of a Dark-Skinned Person

Again, inspect the disc, the vessels, the macula, and the retinal background. The ring around thefovea is a normal light reﬂection. Compare the color of the fundus to that in the illustration above.It has a grayish brownish, almost purplish cast, which comes from pigment in the retina and thechoroid. This pigment characteristically obscures the choroidal vessels, and no tessellation isvisible. In contrast to either of these two ﬁgures, the fundus of a light-skinned person withbrunette coloring is redder.Out of a piece of paper, cut a circle about the size of an optic disc shown below. The circle simulates an ophthalmoscope’s
light beam. Lay it on each illustration, and inspect each fundus systematically.

190 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 5-16 IOcular Fundi (Continued)
Normal Fundus of an Older Person
Inspect the fundus as before. What differences do you observe? Two characteristics of the aging fundus can be
seen in this example. The blood vessels are straighter and narrower than those in younger people, and thechoroidal vessels can be seen easily. In this person the optic disc is less pink, and pigment may be seen temporalto the disc and in the macular area.
Hypertensive Retinopathy
Inspect the fundus. The nasal border of the optic disc is blurred. The lightreﬂexes from the arteries just above and below the disc are increased. Notevenous tapering—at the A–V crossing, about 1 disc diameter above thedisc. Note tapering and banking at 4:30 o’clock, 2 disc diameters from thedisc, also punctate hard exudates and a few deep hemorrhages.Hypertensive Retinopathy With Macular Star

Punctate exudates are readily visible: some are scattered; others radiate
from the f ovea to form a macular star. Note the two small, soft exudates
about 1 disc diameter from the disc. Find the ﬂame-shaped hemorrhages
sweeping toward 4 o’clock and 5 o’clock; a few more may be seen toward 2 o’clock. These fundi show changes typical of accelerated (malignant)hypertension and are often accompanied by a papilledema (p. 184).
(Source of illustrations: Normal Fundus of a Fair-Skinned Person, Normal Fundus of a Dark-Skinned Person, Normal Fundus of an Older Person, Hypertensive Retinopathy, Hypertensive
Retinopathy With Macular Star— Michaelson IC: Textbook of the Fundus of the Eye [3rd ed.], Edinburgh, Churchill Livingstone, 1980.)

CHAPTER 5 ITHE HEAD AND NECK 191TABLE 5-16 IOcular Fundi
CHAPTER 5 ITHE HEAD AND NECK 191Nonproliferative Retinopathy, Moderately Severe
Note tiny red dots or microaneurysms. Note also the ring of hard
exudates (white spots) located supero-temporally. Retinal thickening oredema in the area of the hard exudates can impair visual acuity if itextends into the center of the macula (detection requires specializedstereoscopic examination).Proliferative Retinopathy, With Neovascularization
Note new preretinal vessels arising on the disc and extending across the
disc margins. Visual acuity is still normal, but the risk of visual loss ishigh (photocoagulation reduces this risk by >50%).
Nonproliferative Retinopathy, Severe
In the superior temporal quadrant, note the large retinal hemorrhage

between two cotton-wool patches, beading of the retinal vein just abovethem, and tiny tortuous retinal vessels above the superior temporal artery.Proliferative Retinopathy, Advanced
This is the same eye, but 2 years later and without treatment.
Neovascularization has increased, now with ﬁbrous proliferations,distortion of the macula, and reduced visual acuity.Diabetic Retinopathy
Study carefully the fundi in the series of photographs below. They represent a national standard used by ophthalmologists to assess diabetic retinopathy.
(Source of photos: Nonproliferative Retinopathy, Moderately Severe; Proliferative Retinopathy, With Neovascularization; Nonproliferative Retinopathy, Severe; Proliferative Retinopathy,
Advanced —Early Treatment Diabetic Retinopathy Study Research Group. Courtesy of MF Davis, MD, University of Wisconsin, Madison.)

TABLE 5-17 ILumps On or Near the Ear
192 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Chondrodermatitis Helicis
This chronic inﬂammatory lesion starts
as a painful, tender papule that isusually on the helix but may be on theantihelix. Typically the lesion is single,but in this case two are visible. Thelower papule is an early lesion; theupper lesion illustrates the later stageof ulceration and crusting. Reddeningmay occur. Older men are usuallyaffected. To distinguish chondro-dermatitis from carcinoma, a biopsy isneeded.
Squamous Cell Carcinoma
Squamous cell carcinoma is most
common in light-skinned people whohave been frequently exposed to sunlight.This location on the helix and the raised,crusted border with central ulceration areboth frequently seen. Biopsy conﬁrms thediagnosis. A suture is present here. Asquamous cell carcinoma spreads locally.Occasionally it metastasizes, most often toregional lymph nodes.
Cutaneous Cyst

This cyst behind the ear used to be
called a sebaceous cyst. It is a benign,closed, ﬁrm sac that lies in the dermis,forming a dome-shaped lump. It canbe moved over underlying tissues butis attached to the epidermis. A darkdot (blackhead) may be visible on itssurface. Histologically, one of twodiagnoses is likely: (1) epidermoid cyst,
which is common on the face andneck, and (2) pilar (trichilemmal) cyst,
which is common in the scalp. Eachmay become inﬂamed.
The raised nodule behind this ear shows
the lustrous surface and telangiectaticvessels that suggest basal cell carcinoma,a slow-growing and common malignancythat rarely metastasizes. Ulceration mayoccur, and in the absence of treatmentextends in width and depth. Likesquamous cell carcinoma, basal cellcarcinoma occurs more frequently in fair-skinned people who have been muchexposed to sunlight.

(Sources of photos: Chondrodermatitis Helicis, Cutaneous Cyst —Young EM Jr, Newcomer VD, Kligman AM: Geriatric Dermatology: Color Atlas and Practitioner’s Guide.
Philadelphia, Lea & Febiger, 1993; Squamous Cell Carcinoma, Basal Cell Carcinoma —Reprinted, by permission of the N Engl J Med, 326:169–170, 1992.)

CHAPTER 5 ITHE HEAD AND NECK 193(Sources of photos: Tophi, Lepromatous Leprosy —From Atlas of Clinical Dermatology, 2nd ed, by Anthony du Vivier. London, UK, Gower Medical Publishing, 1993; Rheumatoid
Nodules —Champion RH, Burton JL, Ebling FJG (eds): Rook/Wilkinson/Ebling Textbook of Dermatology, 5th ed. Oxford, Blackwell Scientiﬁc P ublications Limited, 1992; Keloid —
Sams WM Jr, Lynch PJ (eds): Principles and Practice of Dermatology. Edinburgh, Churchill Livingstone, 1990.)Tophi
A tophus is a deposit of uric acid crystals
characteristic of chronic tophaceous gout.Tophi appear as hard nodules in the helixor antihelix and may discharge theirchalky white crystals through the skin.Tophi may also appear near the joints, asin the hands (p. 530), feet, and otherareas. Tophi usually develop only afteryears of sustained high blood levels ofuric acid. With better control ofhyperuricemia by drugs, tophi arebecoming less common.Rheumatoid Nodules

In a patient with chronic arthritis, one
or more small lumps on the helix orantihelix may be rheumatoid nodules ofrheumatoid arthritis, as shown here. Donot mistake such lumps for tophi. Lookfor additional nodules elsewhere, e.g.,on the hands, along the surface of theulna distal to the elbow (pp. 528, 529),on the knees, and on the heels.Ulceration may result from repeatedsmall injuries. Rheumatoid nodules mayantedate the arthritis.
Keloid
A keloid is a ﬁrm, nodular, hypertrophic
mass of scar tissue that extends beyondthe area of injury. It may develop in anyscarred area, but is most common on theshoulders and upper chest. A keloid onan earlobe that was pierced for earringsmay be especially troublesome becauseof its cosmetic effects. Darker-skinnedpeople are more likely than lighter onesto develop keloids. Recurrence of thegrowth may follow treatment.Lepromatous Leprosy
The ear is one of the sites for leproma-

tous leprosy, a form of Hansen’sdisease, which results from infection byMycobacterium leprae. The multiple
papules and nodules on this auricle aredue to this chronic infection. Similarlesions would probably be visible onthe face and elsewhere in the body.Now seldom seen in the United States,leprosy is still a worldwide problem.Other forms of the disease havedifferent manifestations.

TABLE 5-18 IAbnormalities of the Eardrum
194 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGNormal Eardrum
This normal right eardrum (tympanic membrane)

is pinkish gray. The handle of the malleus lies in asomewhat oblique position behind the upper partof the drum. The short process of the malleuspushes the membrane laterally, creating a smallwhite elevation. Above the short process lies asmall portion of the eardrum called the parsﬂaccida. The remainder of the drum is the parstensa. Anterior and posterior malleolar folds,which extend obliquely upward from the shortprocess, separate the pars ﬂaccida from the parstensa, but they are often invisible unless theeardrum is retracted. From the umbo the brightcone of light fans anteriorly and downward. Otherlight reﬂections seen in this photo are artifactual.Posterior to the malleus, part of the incus is visiblebehind the drum. The small blood vessels thatcourse along the handle of the malleus are withinthe range of normal and do not indicateinﬂammation. The ear canal, which surrounds theeardrum, looks ﬂatter than it really is because ofdistortion inherent in the photographic

the malleus are withinthe range of normal and do not indicateinﬂammation. The ear canal, which surrounds theeardrum, looks ﬂatter than it really is because ofdistortion inherent in the photographic technique.Perforation of the Drum

Perforations are holes in the eardrum that usually
result from purulent infections of the middle ear.They are classiﬁed as central perforations, which
do not extend to the margin of the drum, andmarginal perforations, which do involve the
margin.
The more common central perforation is
illustrated here. In this case a reddened ring ofgranulation tissue surrounds the perforation,indicating a chronic infectious process. Theeardrum itself is scarred and no landmarks arediscernible. Discharge from the infected middleear may drain out through such a perforation, butnone is visible here.
A perforation of the eardrum often closes in the
healing process, as illustrated in the next photo.The membrane covering the hole may beexceedingly thin and transparent.Tympanosclerosis
In the inferior portion of this left eardrum there is

a large, chalky white patch with irregular margins.It is typical of tympanosclerosis: a deposition ofhyaline material within the layers of the tympanicmembrane that sometimes follows a severe episodeof otitis media. It does not usually impair hearing,and is seldom clinically signiﬁcant.
Other abnormalities in this eardrum include a
healed perforation (the large oval area in the upper
posterior drum) and signs of a retracted drum. A
retracted drum is pulled medially, away from theexaminer’s eye, and the malleolar folds aretightened into sharp outlines. The short processoften protrudes sharply, and the handle of themalleus, pulled inward at the umbo, looksforeshortened and more horizontal.

(Sources of photos: Normal Eardrum —Hawke M, Keene M, Alberti PW: Clinical Otoscopy: A Text and Colour Atlas. Edinburgh, Churchill Livingstone, 1984; Perforation of the Drum,
Tympanosclerosis —Courtesy of Michael Hawke, MD, Toronto, Canada.)

CHAPTER 5 ITHE HEAD AND NECK 195Serous Effusion
Serous effusions are usually caused by viral upper
respiratory infections ( otitis media with serous
effusion ) or by sudden changes in atmospheric
pressure as from ﬂying or diving ( otitic barotrauma ).
The eustachian tube cannot equalize the air pressurein the middle ear with that of the outside air. Air ispartly or completely absorbed from the middle earinto the bloodstream, and serous ﬂuid accumulatesthere instead. Symptoms include fullness andpopping sensations in the ear, mild conductionhearing loss, and perhaps some pain.
Amber ﬂuid behind the eardrum is characteristic,
as in this left drum of a patient with otiticbarotrauma. A ﬂuid level, a line between air aboveand amber ﬂuid below, can be seen on either sideof the short process. Air bubbles (not alwayspresent) can be seen here within the amber ﬂuid.Acute Otitis Media With 
Purulent Effusion

Acute otitis media with purulent effusion is caused
by bacterial infection. Symptoms include earache,fever, and hearing loss. The eardrum reddens,loses its landmarks, and bulges laterally, towardthe examiner’s eye.
In this right ear the drum is bulging and most
landmarks are obscured. Redness is most obviousnear the umbo, but dilated vessels can be seen inall segments of the drum. A diffuse redness of theentire drum often develops. Spontaneous rupture(perforation) of the drum may follow, withdischarge of purulent material into the ear canal.
Moving the auricle and pressing on the tragus do
not cause pain in otitis media as they usually do inacute otitis externa. Hearing loss is of theconductive type. Acute purulent otitis media ismuch more common in children than in adults.Bullous Myringitis
Bullous myringitis is a viral infection

characterized by painful hemorrhagic vesicles thatappear on the tympanic membrane, the ear canal,or both. Symptoms include earache, blood-tingeddischarge from the ear, and hearing loss of theconductive type.
In this right ear, at least two large vesicles (bullae)
are discernible on the drum. The drum isreddened, and its landmarks are obscured.Several different viruses may cause this condition.
(Sources of photos: Serous Effusion —Hawke M, Keene M, Alberti PW: Clinical Otoscopy: A Text and Colour Atlas. Edinburgh, Churchill Livingstone, 1984; Acute Otitis Media,
Bullous Myringitis —The Wellcome Trust, National Medical Slide Bank, London, UK.)

TABLE 5-19 IPatterns of Hearing Loss
196 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Hearing loss is of two major types. In conductive hearing loss, a disorder of the external or middle ear impairs the
conduction of sound to the inner ear. In sensorineural hearing loss, a disorder of the inner ear, the cochlear nerve, or its
central connections impairs the transmission of nerve impulses to the brain. A mixed hearing loss has both deﬁcits.
Conductive Loss Sensorineural Loss
Distortion of Sounds That
Impairs the Understanding of Words
Effect of a Noisy EnvironmentPatient’s Own Voice
Usual Age of OnsetEar Canal and DrumRelatively minor
Hearing may seem to improve.
Tends to be soft: the patient’s voice is conducted
through bone to a normal inner ear and cochlear nerve.
Most often in childhood and young adulthood, up to
age 40
An abnormality is usually visible, except in otosclerosis.Often present as the upper tones of words are

age 40
disproportionately lost
Hearing typically worsens.
May be loud: the patient has trouble hearing his or her
own voice.
Most often in the middle or later years.
The problem is not visible.

CHAPTER 5 ITHE HEAD AND NECK 197
Weber Test (in unilateral hearing loss)
Rinne Test
Causes Include:The sound lateralizes to the impaired ear. Because this
ear is not distracted by room noise, it can detect thetuning fork’s vibrations better than normal. (Testyourself while plugging one ear with your ﬁnger.) Thislateralization disappears in an absolutely quiet room.The sound lateralizes to the good ear. The impaired
inner ear or cochlear nerve is less able to transmitimpulses no matter how the sound reaches the cochlea.The sound is therefore heard in the better ear.
Sensorineural phaseBone conduction lasts longer than or is equal to air
conduction (BC > AC or BC = AC). While air conduc-tion through the external or middle ear is impaired,vibrations through bone bypass the problem to reachthe cochlea.
Obstruction of the ear canal, otitis media, a perforated

or relatively immobilized eardrum, and otosclerosis (a ﬁxation of the ossicles by bony overgrowth)Air conduction lasts longer than bone conduction 
(AC > BC). The inner ear or cochlear nerve is less ableto transmit impulses regardless of how the vibrationsreach the cochlea. The normal pattern prevails.
Sustained exposure to loud noise, drugs, infections of
the inner ear, trauma, tumors, congenital andhereditary disorders, and aging (presbycusis)
Further evaluation is done by audiometry and other specialized procedures.

TABLE 5-20 IAbnormalities of the Lips
198 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Herpes Simplex (Cold Sore, Fever Blister)
The herpes simplex virus (HSV) produces recurrent and painful vesicular
eruptions of the lips and surrounding skin. A small cluster of vesicles ﬁrstdevelops. As these break, yellow-brown crusts form, and healing ensues within10 to 14 days. Both of these stages are visible here.
Angular Cheilitis
Angular cheilitis starts with softening of the skin at the angles of the mouth,
followed by ﬁssuring. It may be due to nutritional deﬁciency or, morecommonly, to overclosure of the mouth, as in persons with no teeth or withill-ﬁtting dentures. Saliva wets and macerates the infolded skin, often leadingto secondary infection with Candida, as in this example.
Actinic Cheilitis
Actinic cheilitis results from excessive exposure to sunlight and affects

primarily the lower lip. Fair-skinned men who work outdoors are most oftenaffected. The lip loses its normal redness and may become scaly, somewhatthickened, and slightly everted. Because solar damage also predisposes tocarcinoma of the lip, be alert to this possibility.
Carcinoma of the Lip
Like actinic cheilitis, carcinoma usually affects the lower lip. It may appear as a
scaly plaque, as an ulcer with or without a crust, or as a nodular lesion, illustratedhere. Fair skin and prolonged exposure to the sun are common risk factors.
(Sources of photos: Herpes Simplex, Angular Cheilitis —From Neville B et al: Color Atlas of Clinical Oral Pathology. Philadelphia, Lea & Febiger, 1991. Used with permission; Actinic
Cheilitis —From Langlais RP, Miller CS: Color Atlas of Common Oral Diseases. Philadelphia, Lea & Febiger, 1992. Used with permission; Carcinoma of the Lip —Tyldesley

Cheilitis —From Langlais RP, Miller CS: Color Atlas of Common Oral Diseases. Philadelphia, Lea & Febiger, 1992. Used with permission; Carcinoma of the Lip —Tyldesley 
WR: A Colour Atlas of Orofacial Diseases, 2nd ed. London, Wolfe Medical Publications, 1991.)

CHAPTER 5 ITHE HEAD AND NECK 199Hereditary Hemorrhagic Telangiectasia
Multiple small red spots on the lips strongly suggest hereditary hemorrhagic
telangiectasia. Spots may also be visible on the face and hands and in themouth. The spots are dilated capillaries and may bleed when traumatized.Affected people often have nosebleeds and gastrointestinal bleeding.Angioedema
Angioedema is a diffuse, nonpitting, tense swelling of the dermis andsubcutaneous tissue. It develops rapidly, and typically disappears oversubsequent hours or days. Although usually allergic in nature and sometimesassociated with hives, angioedema does not itch.
Chancre of Syphilis
This lesion of primary syphilis may appear on the lip rather than on the
genitalia. It is a ﬁrm, buttonlike lesion that ulcerates and may become crusted.A chancre may resemble a carcinoma or a crusted cold sore. Because it isinfectious, use gloves to feel any suspicious lesion.
Peutz-Jeghers Syndrome

When pigmented spots on the lips are more prominent than freckling of the
surrounding skin, suspect this syndrome. Pigment in the buccal mucosa helpsto conﬁrm the diagnosis. Pigmented spots may also be found on the face andhands. Multiple intestinal polyps are often associated.
(Sources of photos: Angioedema —From Neville B et al: Color Atlas of Clinical Oral Pathology. Philadelphia, Lea & Febiger, 1991. Used with permission; Chancre of Syphilis —
Wisdom A: A Colour Atlas of Sexually Transmitted Diseases (2nd ed.) London, Wolfe Medical Publications, 1989; Hereditary Hemorrhagic Telangiectasia —From Langlais RP, Miller
CS: Color Atlas of Common Oral Diseases. Philadelphia, Lea & Febiger, 1992. Used with permission; Peutz–Jeghers Syndrome —Robinson HBG, Miller AS: Colby, Kerr, and
Robinson’s Color Atlas of Oral Pathology. Philadelphia, JB Lippincott, 1990.)

TABLE 5-21 IFindings in the Pharynx, Palate, and Oral Mucosa
200 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Pharyngitis
These two photos show reddened throats without exudate. In A,redness and vascularity of the pillars and uvula are mild to moderate. In B,redness is diffuse and
intense. Each patient would probably complain of a sore throat, or at least a scratchy one. Possible causes include several kinds of viruses and bacteria. If the patient
has no fever, exudate, or enlargement of cervical lymph nodes, the chances of infection by either of two common and important c auses— group A streptococci and
Epstein-Barr virus (infectious mononucleosis)—are very small.
Large Normal Tonsils
Normal tonsils may be large without being infected, especially in children. They

may protrude medially beyond the pillars and even to the midline. Here theytouch the sides of the uvula and obscure the pharynx. Their color is withinnormal limits. The white marks are light reﬂections, not exudate.Exudative Tonsillitis
This red throat has a white exudate on the tonsils. This, together with feverand enlarged cervical nodes, increases the probability of group A strepto-
coccal infection , or infectious mononucleosis. Some anterior cervical lymph
nodes are usually enlarged in the former, posterior nodes in the latter. 
(Sources of photos: Pharyngitis [A and B], Large Normal Tonsils, Exudative Tonsillitis —The Wellcome Trust, National Medical Slide Bank, London, UK.)A B

CHAPTER 5 ITHE HEAD AND NECK 201Thrush on the Palate (Candidiasis)
Thrush is a yeast infection due to Candida. Shown here on the palate, it
may appear elsewhere in the mouth (see p. 206). Thick, white plaques are
somewhat adherent to the underlying mucosa. Predisposing factors include(1) prolonged treatment with antibiotics or corticosteroids, and (2) AIDS.Kaposi’s Sarcoma in AIDS
The deep purple color of these lesions, although not necessarily present,strongly suggests Kaposi’s sarcoma. The lesions may be raised or flat.Among people with AIDS, the palate, as illustrated here, is a commonsite for this tumor.
(Sources of photos: Diphtheria— Reproduced with permission from Harnisch JP et al: Diphtheria among alcoholic urban adults. Ann Intern Med 1989; 111:77; Thrush on the Palate —

The Wellcome Trust, National Medical Slide Bank, London, UK; Kaposi’s Sarcoma in AIDS —Ioachim HL: Textbook and Atlas of Disease Associated With Acquired Immune
Deﬁciency Syndrome. London, UK, Gower Medical Publishing, 1989.)Diphtheria
Diphtheria (an acute infection caused by Corynebacterium diphtheriae ) is
now rare but still important. Prompt diagnosis may lead to life-saving
treatment. The throat is dull red, and a gray exudate (pseudomembrane) ispresent on the uvula, pharynx, and tongue. The airway may becomeobstructed.Torus Palatinus
A torus palatinus is a midline bony growth in the hard palate that is fairlycommon in adults. Its size and lobulation vary. Although alarming at ﬁrstglance, it is harmless. In this example, an upper denture has been ﬁttedaround the torus.

202 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 5-21 IFindings in the Pharynx, Palate, and Oral Mucosa (Continued)
Petechiae
Petechiae are small red spots that result when blood escapes from capillaries into the
tissues. Petechiae in the buccal mucosa, as shown, are often caused by accidentally
biting the cheek. Oral petechiae may be due to infection or decreased platelets, as well as to trauma.Leukoplakia
A thickened white patch ( leukoplakia ) may occur anywhere in the oral
mucosa. The extensive example shown on this buccal mucosa resultedfrom frequent chewing of tobacco, a local irritant. This kind of irritationmay lead to cancer.
(Sources of photos: Koplik’s Spots, Petechiae —The Wellcome Trust, National Medical Slide Bank, London, UK; Fordyce Spots —From Neville B et al: Color Atlas of Clinical Oral Pathology.

Philadelphia, Lea & Febiger, 1991. Used with permission; Leukoplakia —Robinson HBG, Miller AS: Colby, Kerr, and Robison’s Color Atlas of Oral Pathology. Philadelphia, JB Lippincott,
1990)
Koplik’s Spots
Koplik’s spots are an early sign of measles (rubeola). Search for small white specks
that resemble grains of salt on a red background. They usually appear on the buccalmucosa near the ﬁrst and second molars. In this photo, look also in the upper thirdof the mucosa. The rash of measles appears within a day.Fordyce Spots (Fordyce Granules)

Fordyce spots are normal sebaceous glands that appear as small yellowishspots in the buccal mucosa or on the lips. A worried person who hassuddenly noticed them may be reassured. Here they are seen best anteriorto the tongue and lower jaw. These spots are usually not so numerous.

TABLE 5-22 IFindings in the Gums and Teeth
CHAPTER 5 ITHE HEAD AND NECK 203
(Sources of photos: Marginal Gingivitis, Acute Necrotizing Ulcerative Gingivitis —Tyldesley WR: A Colour Atlas of Orofacial Diseases, 2nd ed. London, Wolfe Medical Publications,
1991; Chronic Gingivitis and Periodontitis (Courtesy of Dr. Tom McDavid), Gingival Hyperplasia (Courtesy of Dr. James Cottone)—From Langlais RP, Miller CS: Color Atlas of
Common Oral Diseases. Philadelphia, Lea & Febiger, 1992. Used with permission.)Marginal Gingivitis
Marginal gingivitis is common among teenagers and young adults. The
gingival margins are reddened and swollen, and the interdental papillae areblunted, swollen, and red. Brushing the teeth often makes the gums bleed.Plaque —the soft white ﬁlm of salivary salts, protein, and bacteria that covers
the teeth and leads to gingivitis—is not readily visible.Acute Necrotizing Ulcerative Gingivitis

This uncommon form of gingivitis occurs suddenly in adolescents and youngadults and is accompanied by fever, malaise, and enlarged lymph nodes.Ulcers develop in the interdental papillae. Then the destructive (necrotizing)process spreads along the gum margins, where a grayish pseudomembranedevelops. The red, painful gums bleed easily; the breath is foul.
Chronic Gingivitis and Periodontitis
Chronic, untreated gingivitis may progress to periodontitis—inﬂammation of
the deeper tissues, that normally hold the teeth in place. Attachments betweengums and teeth are gradually destroyed, the gum margins recede, and theteeth eventually loosen. Calculus (calciﬁed plaque), seen here as hard, cream-
colored deposits on the teeth, contributes to the inﬂammation.Gingival Hyperplasia

Gums enlarged by hyperplasia are swollen into heaped-up masses that mayeven cover the teeth. The redness of inﬂammation may coexist, as in thisexample. Causes include Dilantin therapy (as in this case), puberty, pregnancy,and leukemia.

204 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGPregnancy Tumor (Epulis, Pyogenic Granuloma)
Gingival enlargement may be localized, forming a tumorlike mass that usually
originates in an interdental papilla. It is red and soft and usually bleeds easily.The estimated incidence of this lesion in pregnancy is about 1%. Note theaccompanying gingivitis in this example.Kaposi’s Sarcoma in AIDS
In people with AIDS, Kaposi’s sarcoma may appear in the gums, as in otherstructures. The shape of the lesions in this advanced example might suggesthyperplasia, but the color suggests Kaposi’s sarcoma. Be alert for less obviouslesions.
Lead Line
Now rare, a bluish-black line on the gums may signal chronic lead poisoning.
The line is about 1 mm from the gum margin, follows its contours, and is absentwhere there are no teeth. In this example, as is common, periodontitis coexists.Dental Caries

Dental caries is ﬁrst visible as a chalky white area in the enamel surface of atooth. This area may then turn brown or black, become soft, and cavitate.Special dental techniques, including x-rays, are necessary for early detection.
TABLE 5-22 IFindings in the Gums and Teeth (Continued)
(Sources of photos: Pregnancy Tumor, Dental Caries —From Langlais RP, Miller CS: Color Atlas of Common Oral Diseases. Philadelphia, Lea & Febiger 1992. Used with permission;
Kaposi’s Sarcoma in AIDS —Kelley WN (ed): Textbook of Internal Medicine, 2nd ed. Philadelphia, JB Lippincott, 1992; Lead Line —Courtesy of Dr. R. A. Cawson, from Cawson RA:
Oral Pathology, 1st ed. London, UK, Gower Medical Publishing, 1987.)

CHAPTER 5 ITHE HEAD AND NECK 205Attrition of Teeth; Recession of Gums
In many elderly people, the chewing surfaces of the teeth have been worn
down by repetitive use so that the yellow-brown dentin becomes exposed—a process called attrition. Note also the recession of the gums, which has
exposed the roots of the teeth, giving a “long in the tooth” appearance.Erosion of Teeth
Teeth may be eroded by chemical action. Note here the erosion of the enamelfrom the lingual surfaces of the upper incisors, exposing the yellow-browndentin. This results from recurrent regurgitation of stomach contents, as inbulimia.
Hutchinson’s Teeth
Hutchinson’s teeth are smaller and more widely spaced than normal and are

notched on their biting surfaces. The sides of the teeth taper toward thebiting edges. The upper central incisors of the permanent (not the deciduous)teeth are most often affected. These teeth are a sign of congenital syphilis.Abrasion of Teeth With Notching
The biting surface of the teeth may become abraded or notched by recurrenttrauma, such as holding nails or opening bobby pins between the teeth.Unlike Hutchinson’s teeth, the sides of these teeth show normal contours;size and spacing of the teeth are unaffected.
(Sources of photos: Attrition of Teeth, Erosion of Teeth —From Langlais RP, Miller CS: Color Atlas of Common Oral Diseases. Philadelphia, Lea & Febiger, 1992. Used with permission;
Hutchinson’s Teeth, Abrasion of Teeth —Robinson HBG, Miller AS: Colby, Kerr, and Robinson’s Color Atlas of Oral Pathology. Philadelphia, JB Lippincott, 1990.)

TABLE 5-23 IFindings In or Under the Tongue
206 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
(Sources of photos: Fissured Tongue, Candidiasis —Robinson HBG, Miller AS: Colby, Kerr, and Robinson’s Color Atlas of Oral Pathology. Philadelphia, JB Lippincott, 1990; Smooth
Tongue —Courtesy of Dr. R. A. Cawson, from Cawson RA: Oral Pathology, 1st ed. London, UK, Gower Medical Publishing, 1987; Geographic Tongue —The Wellcome Trust,
National Medical Slide Bank, London, UK; Hairy Leukoplakia —Ioachim HL: Textbook and Atlas of Disease Associated With Acquired Immune Deﬁciency Syndrome. London, UK,
Gower Medical Publishing, 1989.)Fissured Tongue
Fissures may appear in the tongue with increasing
age. Their appearance has led to the alternateterm, scrotal tongue. Although food debris may
accumulate in the crevices and become irritating,a ﬁssured tongue usually has little signiﬁcance.
Hairy Tongue

The “hair” of hairy tongue consists of elongated
papillae on the dorsum of the tongue, and isyellowish to brown or black. Hairy tongue mayfollow antibiotic therapy but may also occurspontaneously, without known cause. It isharmless.
Geographic Tongue
The dorsum of a geographic tongue shows
scattered smooth red areas that are denuded ofpapillae. Together with the normal rough andcoated areas, they give a maplike pattern thatchanges over time. Of unknown cause, thecondition is benign.
Smooth Tongue (Atrophic Glossitis)
A smooth and often sore tongue that has lost its
papillae suggests a deﬁciency in riboﬂavin, niacin,folic acid, vitamin B
12, pyridoxine, or iron.
Speciﬁc diagnosis is often difﬁcult. Anticancerdrugs may also be responsible.Hairy Leukoplakia
Whitish raised areas that have a feathery or

corrugated pattern suggest hairy leukoplakia.Unlike candidiasis, these areas cannot be scrapedoff. The sides of the tongue are most often affected.This lesion is seen in HIV infection and AIDS.Candidiasis
The thick white coat on this tongue is due to
Candida infection. A raw red surface is left where
the coat was scraped off. This infection may alsocause redness of the tongue without the whitecoat. AIDS, among other factors, predisposes tothis condition.

CHAPTER 5 ITHE HEAD AND NECK 207 (Sources of photos: Mucous Patch, Leukoplakia, Carcinoma —Robinson HBG, Miller AS: Colby, Kerr, and Robinson’s Color Atlas of Oral Pathology. Philadelphia, JB Lippincott,
1990; Varicose Veins —From Neville B et al: Color Atlas of Clinical Oral Pathology. Philadelphia, Lea & Febiger, 1991. Used with permission.)Varicose Veins
Small purplish or blue-black round swellings may
appear under the tongue with age. They aredilatations of the lingual veins and have no clinicalsigniﬁcance. Reassure a worried patient. Thesevaricosities are also called caviar lesions.
Aphthous Ulcer (Canker Sore)
A painful, small, round or oval ulcer that is white
or yellowish gray and surrounded by a halo ofreddened mucosa typiﬁes the common aphthousulcer. These ulcers may be single or multiple.They heal in 7 to 10 days, but may recur.
Leukoplakia
A persisting painless white patch in the oral mucosa

is often called leukoplakia until biopsy reveals itsnature. Here, the undersurface of the tongue looksas if it had been painted white. Smaller patches aremore common. Leukoplakia of any size raises thepossibility of malignant change.
Mucous Patch of Syphilis
This painless lesion occurs in the secondary stage
of syphilis and is highly infectious. It is slightlyraised, oval, and covered by a grayish membrane.Mucous patches may be multiple and occurelsewhere in the mouth.
Tori Mandibulares
Tori mandibulares are rounded bony protuberances
that grow from the inner surfaces of the mandible.They are typically bilateral and asymptomatic. Theoverlying mucosa is normal in color. Like a toruspalatinus (p. 201), these tori are harmless.
Carcinoma, Floor of the Mouth
This ulcerated lesion is in a common location for

carcinoma, which also occurs on the side of thetongue. Medial to the carcinoma, note thereddened area of mucosa, called erythroplakia. Like
leukoplakia, erythroplakia warns of possiblemalignancy.

TABLE 5-24 IThyroid Enlargement and Function
208 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Evaluation of the thyroid gland includes a description of the gland and a functional assessment.
Diffuse Enlargement
A diffusely enlarged gland includes the isthmus and
the lateral lobes, but there are no discretely palpablenodules. Causes include Graves’ disease, Hashimoto’sthyroiditis, and endemic goiter (related to iodinedeﬁciency, now uncommon in the United States).Sporadic goiter refers to an enlarged gland with noapparent cause.
Multinodular Goiter
This term refers to an enlarged thyroid gland that
contains two or more identiﬁable nodules. Multiplenodules suggest a metabolic rather than a neoplasticprocess, but irradiation during childhood, a positivefamily history, enlarged cervical nodes, or continuingenlargement of one of the nodules raises thesuspicion of malignancy.
Single Nodule

A clinically single nodule may be a cyst, a benign
tumor, or one nodule within a multinodular gland,but it also raises the question of a malignancy. Priorirradiation, hardness, rapid growth, ﬁxation tosurrounding tissues, enlarged cervical nodes, andoccurrence in males increase the probability ofmalignancy.
Weight loss despite an increased
appetite
Excessive sweating and heat
Frequent bowel movementsMuscular weakness of the proximal
type and tremorFatigue, lethargy
Modest weight gain with anorexiaDry, coarse skin and cold intoleranceSwelling of face, hands, and legs
ConstipationWeakness, muscle cramps,
arthralgias, paresthesias, impairedmemory and hearingTachycardia or atrial ﬁbrillation
Increased systolic and decreased
diastolic blood pressures
Hyperdynamic cardiac pulsations
with an accentuated S
1
Warm, smooth, moist skin
Tremor and proximal muscle
weakness
With Graves’ disease, eye signs such

1
weakness
as stare, lid lag, and exophthalmosBradycardia and, in late stages,
hypothermia
Decreased systolic and increased
Intensity of heart sounds sometimes
decreased
Dry, coarse, cool skin, sometimes
yellowish from carotene, withnonpitting edema and loss of hair
Impaired memory, mixed hearing
loss, somnolence, peripheralneuropathy, carpal tunnel syndrome
Periorbital pufﬁnessSymptoms of Thyroid Dysfunction Signs of Thyroid Dysfunction
Hyperthyroidism Hypothyroidism Hyperthyroidism Hypothyroidism

The Thorax and LungsCHAPTER
The Thorax and Lungs 66
CHAPTER 6 ITHE THORAX AND LUNGS 209
Study the anatomy of the chest wall, identifying the structures illustrated.
Note that an interspace between two ribs is numbered by the rib above it.
Manubrium of sternum
Body of sternum
Xyphoid process
Costal angleCostochondral
junctionsSuprasternal notch
Sternal angle
2nd costal
cartilage
Cardiac notchof left lung2nd rib
2nd ribinterspace

210 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Suprasternal notch Sternal angle
2nd rib
2
3
4
5
6
7
8
9
10
11122
3
4
5
6
7
8
911
Note that the costal cartilages of the ﬁrst seven ribs articulate with the ster-
num; the cartilages of the 8th, 9th, and 10th ribs articulate with the costalcartilages just above them. The 11th and 12th ribs, the “ﬂoating ribs,” haveno anterior attachments. The cartilaginous tip of the 11th rib can usually befelt laterally, and the 12th rib may be felt posteriorly. On palpation, costalcartilages and ribs feel identical.Locating Findings on the Chest. Describe abnormalities of the chest in
two dimensions: along the vertical axis and around the circumference of the chest.
To make vertical locations, you must be able to count the ribs and interspaces.
The sternal angle, also termed the angle of Louis, is the best guide: place your

ﬁnger in the hollow curve of the suprasternal notch, then move your ﬁngerdown about 5 cm to the horizontal bony ridge joining the manubrium to thebody of the sternum. Then move your ﬁnger laterally and ﬁnd the adjacent 2ndrib and costal cartilage. From here, using two ﬁngers, you can “walk down theinterspaces,” one space at a time, on an oblique line illustrated by the red num-bers below. Do not try to count interspaces along the lower edge of the ster-num; the ribs there are too close together. In a woman, to ﬁnd the interspaceseither displace the breast laterally or palpate a little more medially than illus-trated. Avoid pressing too hard on tender breast tissue.

Posteriorly, the 12th rib is another possible starting point for counting
ribs and interspaces: it helps locate findings on the lower posterior chestand provides an option when the anterior approach is unsatisfactory. Withthe fingers of one hand, press in and up against the lower border of the12th rib, then “walk up” the interspaces numbered in red below, or fol-low a more oblique line up and around to the front of the chest.
The inferior tip of the scapula is another useful bony marker—it usually lies
at the level of the 7th rib or interspace.ANATOMY AND PHYSIOLOGY
CHAPTER 6 ITHE THORAX AND LUNGS 211
2
3
4
5
6
7
8
9
10
10
11
122
3
4
5
6
7
8
9
11Spinous process of C7 Spinous process of T1
Inferior angle
of scapula
7th rib
The spinous processes of the vertebrae are also useful anatomic landmarks.

2
3
4
5
6
7
8
9
10
10
11
122
3
4
5
6
7
8
9
of scapula
7th rib
When the neck is ﬂexed forward, the most protruding process is usually thevertebra of C7. If two processes are equally prominent, they are C7 and T1.You can often palpate and count the processes below them, especially whenthe spine is ﬂexed.
To locate ﬁndings around the circumference of the chest, use a series of verti-
cal lines, shown in the next three illustrations. The midsternal and vertebral
linesare precise; the others are estimated. The midclavicular line drops ver-
tically from the midpoint of the clavicle. To ﬁnd it, you must identify bothends of the clavicle accurately (see p. 469). The anterior and posterior axil-
lary lines drop vertically from the anterior and posterior axillary folds, the
muscle masses that border the axilla. The midaxillary line drops from the

apex of the axilla.

212 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Anterior
axillaryline
Posterior
axillarylineMidaxillary
line
Midsternalline
Midclavicular
line
Anterior
ANTERIOR VIEW RIGHT ANTERIOR OBLIQUE VIEW
Lungs, Fissures, and Lobes. The lungs and their ﬁssures and lobes can
be mentally pictured on the chest wall. Anteriorly, the apex of each lung risesabout 2 cm to 4 cm above the inner third of the clavicle. The lower border ofthe lung crosses the 6th rib at the midclavicular line and the 8th rib at the mid-axillary line. (Because ribs slant, a fairly horizontal line can drop a rib or moreas it passes across the chest.) Posteriorly, the lower border of the lung lies atabout the level of the T10 spinous process. On inspiration, it descends farther.
Each lung is divided roughly in half by an oblique (major) ﬁssure. This ﬁs-
sure may be approximated by a string that runs from the T3 spinous process
Scapular line
Vertebralline

POSTERIOR VIEWPosteriorly, the verte-
bral line overlies the
spinous processes ofthe vertebrae. Thescapular line dropsfrom the inferior angleof the scapula.

obliquely down and around the chest to the 6th rib at the midclavicular line.
The right lung is further divided by the horizontal (minor) ﬁssure. Anteri-
orly, this ﬁssure runs close to the 4th rib and meets the oblique ﬁssure in themidaxillary line near the 5th rib.ANATOMY AND PHYSIOLOGY
CHAPTER 6 ITHE THORAX AND LUNGS 213
Apex 
of lung
Horizontal
fissure
ObliquefissureRUL
RML
RLLLUL
LLL
LUL
LLLRUL
RLLSpinous
processof T3
Inspiratorydescent
POSTERIOR VIEW ANTERIOR VIEW
The right lung is thus divided into upper, middle, and lower lobes. The left
lung has only two lobes, upper and lower.
Left obliquefissureLUL
LLL
RUL
RLLRML
RIGHT AND LEFT LATERAL VIEWS

214 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGLocations on the Chest. Be familiar with general anatomic terms used
to locate chest ﬁndings, such as:
Supraclavicular—above the clavicles
Infraclavicular—below the claviclesInterscapular—between the scapulaeInfrascapular—below the scapulaBases of the lungs—the lowermost portionsUpper, middle, and lower lung ﬁelds
You may then infer what part(s) of the lung(s) are affected by an abnormal
process. Signs in the right upper lung ﬁeld, for example, almost certainlyoriginate in the right upper lobe. Signs in the right middle lung ﬁeld later-ally, however, could come from any of three different lobes.
The Trachea and Major Bronchi. Breath sounds over the trachea

and bronchi have a different quality than breath sounds over the lungparenchyma. Be sure you know the location of these structures. The tra-chea bifurcates into its mainstem bronchi at the levels of the sternal angleanteriorly and the T4 spinous process posteriorly.
The Pleurae. The pleurae are serous membranes that cover the outer
surface of each lung, the visceral pleura, and also line the inner rib cage and
upper surface of the diaphragm, the parietal pleura . Their smooth opposing
surfaces, lubricated by pleural ﬂuid, allow the lungs to move easily within therib cage during inspiration and expiration. The pleural space is the potential
space between visceral and parietal pleurae.POSTERIOR VIEW ANTERIOR VIEW
Trachea
Left main
bronchus
Right main
bronchus

Sternal
head
Clavicular
headof the
sternomastoidmuscleBreathing. Breathing is largely an automatic act, controlled in the brain-
stem and mediated by the muscles of respiration. The dome-shaped di-
aphragm is the primary muscle of inspiration. When it contracts, it descends
in the chest and enlarges the thoracic cavity. At the same time it compressesthe abdominal contents, pushing the abdominal wall outward. Muscles inthe rib cage and neck expand the thorax during inspiration, especially theparasternals, which run obliquely from sternum to ribs, and the scalenes,
which run from the cervical vertebrae to the ﬁrst two ribs.
During inspiration, as these muscles contract, the thorax expands. Intra-
thoracic pressure decreases, drawing air through the tracheobronchial treeinto the alveoli, or distal air sacs, and expanding the lungs. Oxygen diffuses
into the blood of adjacent pulmonary capillaries, and carbon dioxide diffusesfrom the blood into the alveoli.

After inspiratory effort stops, the expiratory phase begins. The chest wall and
lungs recoil, the diaphragm relaxes and rises passively, air ﬂows outward, andthe chest and abdomen return to their resting positions.
Normal breathing is quiet and easy—barely audible near the open mouth as
a faint whish. When a healthy person lies supine, the breathing movementsof the thorax are relatively slight. In contrast, the abdominal movements areusually easy to see. In the sitting position, movements of the thorax becomemore prominent.
During exercise and in certain diseases, extra work is required to breathe,
and accessory muscles join the inspiratory effort. The sternomastoids are themost important of these, and the scalenes may become visible. Abdominalmuscles assist in expiration.ANATOMY AND PHYSIOLOGY
CHAPTER 6 ITHE THORAX AND LUNGS 215

As people age, their capacity for exercise decreases. The chest wall becomes
stiffer and harder to move, respiratory muscles may weaken, and the lungslose some of their elastic recoil. The speed of breathing out with maximaleffort gradually diminishes. Skeletal changes associated with aging may ac-centuate the dorsal curve of the thoracic spine, producing kyphosis and in-creasing the anteroposterior diameter of the chest. The resulting “barrelchest,” however, has little effect on function.
216 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGSee Table 6-1. Chest Pain, 
pp. 234–235.
Angina pectoris, myocardial 
PericarditisDissecting aortic aneurysmBronchitisPericarditis, pneumoniaCostochondritis, herpes zosterReﬂux esophagitis, esophageal
spasm
Cervical arthritis, biliary colic, 
gastritisComplaints of chest pain or chest discomfort raise the specter of heart disease,

spasm
but often arise from structures in the thorax and lung as well. To assess thissymptom, you must pursue a dual investigation of both thoracic and cardiaccauses. Sources of chest pain are listed below. For this important symptom,you must keep all of these in mind.
IThe myocardium
IThe pericardium
IThe aorta
IThe trachea and large bronchi
IThe parietal pleura
IThe chest wall, including the musculoskeletal system and skin
IThe esophagus
IExtrathoracic structures such as the neck, gallbladder, and stomach.
This section focuses on pulmonary complaints , including general questions
about chest symptoms, dyspnea, wheezing, cough, and hemoptysis. ForEXAMPLES OF ABNORMALITIES
IChest pain
IDyspnea
IWheezing
ICough
IBlood-streaked sputum (hemoptysis)

health history questions about exertional chest pain, palpitations, orthop-
nea, paroxysmal nocturnal dyspnea, and edema, see Chapter 7, The Cardio-vascular System.
Your initial questions should be as broad as possible. “Do you have any dis-
comfort or unpleasant feelings in your chest?” As you proceed to the full his-tory, ask the patient to point to where the pain is in the chest. Watch for anygestures as the patient describes the pain. You should elicit all seven attri-butes of this symptom (see p. 27) to distinguish among the various causesof chest pain.
Lung tissue itself has no pain ﬁbers. Pain in lung conditions such as pneu-

monia or pulmonary infarction usually arises from inﬂammation of the ad-jacent parietal pleura. Muscle strain from prolonged recurrent coughing mayalso be responsible. The pericardium also has few pain ﬁbers—the pain ofpericarditis stems from inﬂammation of the adjacent parietal pleura. (Chestpain is commonly associated with anxiety, too, but the mechanism remainsobscure.)
Dyspnea is a nonpainful but uncomfortable awareness of breathing that is in-
appropriate to the level of exertion. This serious symptom warrants a full ex-planation and assessment, since dyspnea commonly results from cardiac orpulmonary disease.
Ask “Have you had any difﬁculty breathing?” Find out when the symptom
occurs, at rest or with exercise, and how much effort produces onset. Be-cause of variations in age, body weight, and physical ﬁtness, there is no ab-solute scale for quantifying dyspnea. Instead, make every effort to determine

its severity based on the patient’s daily activities. How many steps or ﬂights of
stairs can the patient climb before pausing for breath? What about work suchas carrying bags of groceries, mopping the ﬂoor, or making the bed? Hasdyspnea altered the patient’s lifestyle and daily activities? How? Carefullyelicit the timing and setting of dyspnea, any associated symptoms, and re-lieving or aggravating factors.
Most patients with dyspnea relate shortness of breath to their level of activ-
ity. Anxious patients present a different picture. They may describe difﬁcultytaking a deep enough breath, or a smothering sensation with inability to getenough air, along with paresthesias, or sensations of tingling or “pins and
needles” around the lips or in the extremities.
Wheezes are musical respiratory sounds that may be audible both to the pa-
tient and to others.
Cough is a common symptom that ranges in significance from trivial to

ominous. Typically, cough is a reflex response to stimuli that irritate re-THE HEALTH HISTORY
CHAPTER 6 ITHE THORAX AND LUNGS 217A clenched fist over the sternum
suggests angina pectoris; a finger
pointing to a tender area on thechest wall suggests musculoskele-tal pain; a hand moving fromneck to epigastrum suggestsheartburn.
Anxiety is the most frequent 
cause of chest pain in children;costochondritis is also common.
See Table 6-2, Dyspnea, 
pp. 236–237.
Anxious patients may have
episodic dyspnea during both restand exercise, and hyperventilation,
or rapid, shallow breathing. At other times they may have frequent sighs.
Wheezing suggests partial 
airway obstruction from secre-tions, tissue inflammation, or aforeign body.
See Table 6-3, Cough and 
Hemoptysis, p. 238.EXAMPLES OF ABNORMALITIES

ceptors in the larynx, trachea, or large bronchi. These stimuli include
mucus, pus, and blood, as well as external agents such as dusts, foreignbodies, or even extremely hot or cold air. Other causes include inflamma-tion of the respiratory mucosa and pressure or tension in the air passagesfrom a tumor or enlarged peribronchial lymph nodes. Although coughtypically signals a problem in the respiratory tract, it may also be cardio-vascular in origin.
For complaints of cough, a thorough assessment is in order. Ask whether the
cough is dry or produces sputum, or phlegm. Ask the patient to describe the
volume of any sputum and its color, odor, and consistency.
To help patients quantify volume, a multiple-choice question may be

helpful . . . “How much do you think you cough up in 24 hours; a tea-spoon, tablespoon, a quarter cup, half cup, cupful?” If possible, ask thepatient to cough into a tissue; inspect the phlegm and note its character-istics. The symptoms associated with a cough often lead you to its cause.
Hemoptysis is the coughing up of blood from the lungs; it may vary from
blood-streaked phlegm to frank blood. For patients reporting hemoptysis,assess the volume of blood produced as well as the other sputum attributes;ask about the related setting and activity and any associated symptoms.
Before using the term “hemoptysis,” try to conﬁrm the source of the bleed-

ing by both history and physical examination. Blood or blood-streaked ma-terial may originate in the mouth, pharynx, or gastrointestinal tract and iseasily mislabeled. When vomited, it probably originates in the gastrointesti-nal tract. Occasionally, however, blood from the nasopharynx or the gastro-intestinal tract is aspirated and then coughed out.HEALTH PROMOTION AND COUNSELING
218 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGCough is an important symptom of
left-sided heart failure.
Dry hacking cough in Mycoplasmal
pneumonia; productive cough in bronchitis, viral or bacterialpneumonia
Mucoid sputum is translucent,
white, or gray; purulent sputum is
yellowish or greenish.
Foul-smelling sputum in anaerobic
lung abscess; tenacious sputum incystic ﬁbrosis
Large volumes of purulent sputum
in bronchiectasis or lung abscess
Diagnostically helpful symptoms

include fever, chest pain, dyspnea,orthopnea, and wheezing.
See Table 6-3, Cough and Hemop-
tysis, p. 238. Hemoptysis is rare ininfants, children, and adolescents; itis seen most often in cystic ﬁbrosis.
Blood originating in the stomach is
usually darker than blood from therespiratory tract and may be mixedwith food particles.
HEALTH PROMOTION AND COUNSELINGEXAMPLES OF ABNORMALITIES
ITobacco cessation

Despite declines in smoking over the past several decades, more than 27% of
Americans age 12 and older still smoke.* All adults, pregnant women, par-ents, and adolescents who smoke should be counseled regularly to stopsmoking. Smoking has been definitively linked to significant pulmonary,cardiovascular, and neoplastic disease, and accounts for one out of every ﬁvedeaths in the United States.
†It is considered the leading cause of preventable
death. Nonsmokers exposed to smoke are also at increased risk for lung can-cer, ear and respiratory infection, asthma, low birthweight, and residentialﬁres. Smoking exposes patients not only to carcinogens, but also to nicotine,an addictive drug. Be especially alert to smoking by teenagers, the age groupwhen tobacco use often begins, and by pregnant women, who may continuesmoking during pregnancy.
The disease risks of smoking drop signiﬁcantly within a year of smoking ces-

sation. Effective interventions include targeted messages by clinicians, groupcounseling, and use of nicotine-replacement therapies. Clinicians are advisedto adopt the four “As”:
IAsk about smoking at each visit.
IAdvise patients regularly to stop smoking in a clear personalized message.
IAssist patients to set stop dates and provide educational materials for self-
help.
IArrange for follow-up visits to monitor and support progress. HEALTH PROMOTION AND COUNSELING
CHAPTER 6 ITHE THORAX AND LUNGS 219Preview: Recording the Physical Examination—
The Thorax and Lungs
“Thorax is symmetric with good expansion. Lungs resonant. Breath

sounds vesicular; no rales, wheezes, or rhonchi. Diaphragms descend 4 cm bilaterally.”
OR“Thorax symmetric with moderate kyphosis and increased anteroposterior
(AP) diameter, decreased expansion. Lungs are hyperresonant. Breathsounds distant with delayed expiratory phase and scattered expiratorywheezes. Fremitus decreased; no bronchophony, egophony, or whis-pered pectoriloquy. Diaphragms descend 2 cm bilaterally.”
* Substance Abuse and Mental Health Services Administration, 1999 National Household Survey.
www.samhsa.gov/hhsurvey/content/1999 . Accessed 8/13/01.
†Centers for Disease Control and Prevention. Cigarette Smoking: Attributable Mortality and Years of
Potential Life Cost—United States. MMWR 42: 645–649, 1993.EXAMPLES OF ABNORMALITIES
Suggests chronic obstructive lung
disease

220 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGSee Table 3-12, Abnormalities in
Rate and Rhythm of Breathing (p. 93). Prolonged expiration sug-gests narrowed lower airways.
It is helpful to examine the posterior thorax and lungs while the patient is
sitting, and the anterior thorax and lungs with the patient supine. Proceedin an orderly fashion: inspect, palpate, percuss, and auscultate. Try to visu-alize the underlying lobes, and compare one side with the other, so the pa-tient serves as his or her own control. Arrange the patient’s gown so that youcan see the chest fully. For women, drape the gown over each half of the an-terior chest as you examine the other half. Cover the woman’s anterior chestwhen you examine the back.
With the patient sitting, examine the posterior thorax and lungs. The pa-

tient’s arms should be folded across the chest with hands resting, if possible,on the opposite shoulders. This position moves the scapulae partly out ofthe way and increases your access to the lung ﬁelds. Then ask the patient tolie down.
With the patient supine, examine the anterior thorax and lungs. The supine
position makes it easier to examine women because the breasts can be gen-tly displaced. Furthermore, wheezes, if present, are more likely to be heard.(Some authorities, however, prefer to examine both the back and the frontof the chest with the patient sitting. This technique is also satisfactory).
For patients unable to sit up without aid, try to get help so that you can ex-

amine the posterior chest in the sitting position. If this is impossible, roll thepatient to one side and then to the other. Percuss the upper lung, and aus-cultate both lungs in each position. Because ventilation is relatively greaterin the dependent lung, your chances of hearing wheezes or crackles aregreater on the dependent side.
Initial Survey of Respiration and the Thorax
Even though you may have already recorded the respiratory rate when youtook the vital signs, it is wise to again observe the rate, rhythm, depth, and ef-
fort of breathing. A normal resting adult breathes quietly and regularly about
Combining clinician and group counseling with nicotine replacement ther-
apy is especially effective for highly addicted patients.
Relapses are common and should be expected. Nicotine withdrawal, weight

gain, stress, social pressure, and use of alcohol are often cited as explanations.Help patients to learn from these experiences: work with the patient to pin-point the precipitating circumstances and develop strategies for alternativeresponses and health-promoting behaviors.

14 to 20 times a minute. An occasional sigh is to be expected. Note whether
expiration lasts longer than usual.
Always inspect the patient for any signs of respiratory difﬁculty.
IAssess the patient’s color for cyanosis. Recall any relevant ﬁndings from ear-
lier parts of your examination, such as the shape of the ﬁngernails.
IListen to the patient’s breathing. Is there any audible wheezing? If so, where
does it fall in the respiratory cycle?
IInspect the neck . During inspiration, is there contraction of the sterno-
mastoid or other accessory muscles, or supraclavicular retraction? Is thetrachea midline?
Also observe the shape of the chest. The anteroposterior (AP) diameter may in-
crease with aging.
Examination of the Posterior Chest
INSPECTION
From a midline position behind the patient, note the shape of the chest and
the way in which it moves, including:
IDeformities or asymmetry
IAbnormal retraction of the interspaces during inspiration. Retraction is

most apparent in the lower interspaces. Supraclavicular retraction is oftenassociated.
IImpaired respiratory movement on one or both sides or a unilateral lag(or delay) in movement.
PALPATION
As you palpate the chest, focus on areas of tenderness and abnormalities inthe overlying skin, respiratory expansion, and fremitus.
Identify tender areas. Carefully palpate any area where pain has been re-
ported or where lesions or bruises are evident.
CHAPTER 6 ITHE THORAX AND LUNGS 221Cyanosis signals hypoxia. Club-
bing of the nails (see p. 110) inchronic obstructive pulmonarydisease (COPD) or congenitalheart disease
Audible stridor, a high-pitched
wheeze, is an ominous sign of airway obstruction in the larynx ortrachea.
Inspiratory contraction of the

Inspiratory contraction of the 
sternomastoids at rest signals severe difﬁculty breathing. Lateraldisplacement of the trachea inpneumothorax, pleural effusion, or atelectasis
The AP diameter also may increase
in COPD.
See Table 6-4, Deformities of the
Thorax (p. 239).
Retraction in severe asthma, COPD,
or upper airway obstruction.
Unilateral impairment or lagging 
of respiratory movement suggestsdisease of the underlying lung orpleura.
Intercostal tenderness over in-
ﬂamed pleura
Bruises over a fractured rib

222 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGTest chest expansion . Place your thumbs at about the level of the 10th ribs,
with your ﬁngers loosely grasping and parallel to the lateral rib cage. As youposition your hands, slide them medially just enough to raise a loose  fold ofskin on each side between your thumb and the spine. 
Ask the patient to inhale deeply. Watch the distance between your thumbs
as they move apart during inspiration, and feel for the range and symmetryof the rib cage as it expands and contracts.
Feel for tactile fremitus. Fremitus refers to the palpable vibrations transmit-

ted through the bronchopulmonary tree to the chest wall when the patientspeaks. To detect fremitus, use either the ball (the bony part of the palm atthe base of the ﬁngers) or the ulnar surface of your hand to optimize the vi-bratory sensitivity of the bones in your hand. Ask the patient to repeat thewords “ninety-nine” or “one-one-one.” If fremitus is faint, ask the patientto speak more loudly or in a deeper voice.
Use one hand until you have learned the feel of fremitus. Some clinicians
ﬁnd using one hand more accurate. The simultaneous use of both hands tocompare sides, however, increases your speed and may facilitate detection ofdifferences.Causes of unilateral decrease or

delay in chest expansion includechronic ﬁbrotic disease of the underlying lung or pleura, pleuraleffusion, lobar pneumonia, pleuralpain with associated splinting, andunilateral bronchial obstruction.
Fremitus is decreased or absent
when the voice is soft or whenthe transmission of vibrationsfrom the larynx to the surface ofthe chest is impeded. Causes in-clude an obstructed bronchus;COPD; separation of the pleuralsurfaces by fluid (pleural effusion),fibrosis (pleural thickening), air (pneumothorax), or an infil-trating tumor; and also a verythick chest wall.
Assess any observed abnormalities such as masses or sinus tracts (blind, in-
ﬂammatory, tubelike structures opening onto the skin)Although rare, sinus tracts usually

indicate infection of the underlyingpleura and lung (as in tuberculosis,actinomycosis).

Palpate and compare symmetric areas
of the lungs in the pattern shown inthe photograph. Identify and locateany areas of increased, decreased, orabsent fremitus. Fremitus is typicallymore prominent in the interscapulararea than in the lower lung ﬁelds,and is often more prominent on theright side than on the left. It dis-appears below the diaphragm.
Tactile fremitus is a relatively rough
assessment tool, but as a scoutingtechnique it directs your attentionto possible abnormalities. Later inthe examination you will check anysuggested findings by listening forbreath sounds, voice sounds, andwhispered voice sounds. All theseattributes tend to increase or de-crease together.
PERCUSSION

Percussion is one of the most important techniques of physical examination.Percussion of the chest sets the chest wall and underlying tissues into mo-tion, producing audible sound and palpable vibrations. Percussion helps youestablish whether the underlying tissues are air-ﬁlled, ﬂuid-ﬁlled, or solid. Itpenetrates only about 5 cm to 7 cm into the chest, however, and thereforewill not help you to detect deep-seated lesions.
The technique of percussion can be practiced on any surface. As you prac-
tice, listen for changes in percussion notes over different types of materialsor different parts of the body. The key points for good technique, describedfor a right-handed person, are as follows:

IHyperextend the middle fingerof your left hand, known as thepleximeter ﬁnger. Press its distalinterphalangeal joint firmly onthe surface to be percussed. Avoidsurface contact by any other partof the hand, because this dampensout vibrations. Note that thethumb, 2nd, 4th, and 5th ﬁngersare not touching the chest.
IPosition your right forearm quiteclose to the surface, with the handcocked upward. The middle ﬁngershould be partially ﬂexed, relaxed,and poised to strike.TECHNIQUES OF EXAMINATION
CHAPTER 6 ITHE THORAX AND LUNGS 223
1 1
2
32
3
44
LOCATIONS FOR FEELING FREMITUS

IWith a quick sharp but relaxed
wrist motion, strike the pleximeter
ﬁnger with the right middle ﬁn-ger, or plexor ﬁnger. Aim at yourdistal interphalangeal joint. Youare trying to transmit vibrationsthrough the bones of this joint tothe underlying chest wall.
Strike using the tip of the plexor
ﬁnger, not the ﬁnger pad. Your
ﬁnger should be almost at rightangles to the pleximeter. A shortﬁngernail is recommended toavoid self-injury.
IWithdraw your striking ﬁngerquickly to avoid damping the vi-brations you have created.
In summary, the movement is at the
wrist. It is directed, brisk yet relaxed,and a bit bouncy.TECHNIQUES OF EXAMINATION
224 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Percussion Notes. With your plexor or tapping ﬁnger, use the lightest
percussion that produces a clear note. A thick chest wall requires heavier per-cussion than a thin one. However, if a louder note is needed, apply more

pressure with the pleximeter ﬁnger (this is more effective for increasing per-
cussion note volume than tapping harder with the plexor ﬁnger).
When percussing the lower posterior chest, stand somewhat to the side rather
than directly behind the patient. This allows you to place your pleximeterﬁnger more ﬁrmly on the chest and your plexor is more effective, making abetter percussion note.
When comparing two areas, use the same percussion technique in both areas.
Percuss or strike twice in each location. It is easier to detect differences inpercussion notes by comparing one area with another than by striking repet-itively in one place.

Learn to identify ﬁve percussion notes. You can practice four of them on your-
self. These notes differ in their basic qualities of sound: intensity, pitch, andduration. Train your ear to distinguish these differences by concentrating onone quality at a time as you percuss ﬁrst in one location, then in another. Re-view the table below. Normal lungs are resonant.TECHNIQUES OF EXAMINATION
CHAPTER 6 ITHE THORAX AND LUNGS 225While the patient keeps both arms crossed in front of the chest, percuss the
thorax in symmetric locations from the apices to the lung bases.
Percuss one side of the chest and then the other at each level, as shown by the
numbers below. Omit the areas over the scapulae—the thickness of muscleand bone alters the percussion notes over the lungs. Identify and locate thearea and quality of any abnormal percussion note.Relative Relative Relative
Intensity Pitch Duration Example of LocationPercussion Notes and Their Characteristics

* Distinguished mainly by its musical timbre.Flatness
DullnessResonanceHyperresonanceTympanySoft
MediumLoudVery loudLoudHigh
MediumLowLowerHigh*Short
MediumLongLonger*Thigh
LiverNormal lungNone normallyGastric air bubble or
puffed-out cheek
Pathologic Examples
Large pleural effusion
Lobar pneumoniaSimple chronic bronchitisEmphysema, pneumothorax
Large pneumothorax
Dullness replaces resonance 
when ﬂuid or solid tissue replacesair-containing lung or occupies the pleural space beneath yourpercussing ﬁngers. Examples include: lobar pneumonia, in whichthe alveoli are ﬁlled with ﬂuid andblood cells; and pleural accumula-tions of serous ﬂuid (pleural effusion), blood (hemothorax), pus (empyema), ﬁbrous tissue, or tumor.
Generalized hyperresonance may

be heard over the hyperinﬂatedlungs of emphysema or asthma,but it is not a reliable sign. Unilat-eral hyperresonance suggests alarge pneumothorax or possibly alarge air-ﬁlled bulla in the lung.
1
2
3
4
51
2
3
4
56 6
7 7
LOCATIONS FOR PERCUSSION AND AUSCULTATION

An abnormally high level suggests
pleural effusion, or a high diaphragm as in atelectasis or diaphragmatic paralysis.
Sounds from bedclothes, paper
gowns, and the chest itself cangenerate confusion in auscultation.Hair on the chest may cause crack-ling sounds. Either press harder orwet the hair. If the patient is coldor tense, you may hear musclecontraction sounds—mufﬂed, low-pitched rumbling or roaring noises.A change in the patient’s positionmay eliminate this noise. You canTECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
226 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGIdentify the descent of the diaphragms, or diaphragmatic excursion. First, de-
termine the level of diaphragmatic dullness during quiet respiration. Holding
the pleximeter ﬁnger above and parallel to the expected level of dullness,

percuss downward in progressive steps until dullness clearly replaces reso-nance. Conﬁrm this level of change by percussion near the middle of the he-mothorax and also more laterally.
Resonant
Level of
diaphragm
DullLocation
and sequenceof percussion
Dull
Note that with this technique you are identifying the boundary between the
resonant lung tissue and the duller structures below the diaphragm. You arenot percussing the diaphragm itself. You can infer the probable location ofthe diaphragm from the level of dullness.
Now, estimate the extent of diaphragmatic excursion by determining the dis-
tance between the level of dullness on full expiration and the level of dull-ness on full inspiration, normally about 5 cm or 6 cm. This estimate doesnot correlate well, however, with radiologic assessment of diaphragmaticmovement.
AUSCULTATION

Auscultation of the lungs is the most important examining technique for as-sessing air ﬂow through the tracheobronchial tree. Together with percus-sion, it also helps the clinician to assess the condition of the surroundinglungs and pleural space. Auscultation involves (1) listening to the soundsgenerated by breathing, (2) listening for any adventitious (added) sounds,and (3) if abnormalities are suspected, listening to the sounds of the patient’sspoken or whispered voice as they are transmitted through the chest wall.
Breath Sounds (Lung Sounds). You will learn to identify patterns of
breath sounds by their intensity, their pitch, and the relative duration of theirinspiratory and expiratory phases. Normal breath sounds are:

CHAPTER 6 ITHE THORAX AND LUNGS 227IVesicular, or soft and low pitched. They are heard through inspiration,
continue without pause through expiration, and then fade away about onethird of the way through expiration.
IBronchovesicular, with inspiratory and expiratory sounds about equal in
length, at times separated by a silent interval. Differences in pitch and in-tensity are often more easily detected during expiration.
IBronchial, or louder and higher in pitch, with a short silence between in-
spiratory and expiratory sounds. Expiratory sounds last longer than inspi-ratory sounds.
The characteristics of these three kinds of breath sounds are summarized in
the table below. Also shown are the tracheal breath sounds—very loud,
harsh sounds that are heard by listening over the trachea in the neck.reproduce this sound on yourself
by doing a Valsalva maneuver(straining down) as you listen toyour own chest.
If bronchovesicular or bronchial

breath sounds are heard in loca-tions distant from those listed, sus-pect that air-ﬁlled lung has beenreplaced by ﬂuid-ﬁlled or solid lungtissue. See Table 6-5, Normal andAltered Breath and Voice Sounds(p. 240).Intensity of Pitch of Locations
Duration of Expiratory Expiratory Where Heard
Sounds Sound Sound NormallyCharacteristics of Breath Sounds
* The thickness of the bars indicates intensity; the steeper their incline, the higher the pitch.Vesicular*
Broncho-
vesicular
Bronchial
TrachealInspiratory sounds
last longer thanexpiratory ones.
Inspiratory and
expiratory soundsare about equal.
Expiratory sounds
last longer thaninspiratory ones.
expiratory soundsare about equal.Soft
Intermediate
Loud
Very loudRelatively low
Relatively high
Relatively highOver most of
both lungs
Often in the 
1st and 2ndinterspacesanteriorly andbetween thescapulae

Loud
both lungs
Over the manu-
brium, if heardat all
Over the trachea
in the neck
Listen to the breath sounds with the diaphragm of a stethoscope after in-
structing the patient to breathe deeply through an open mouth. Use the pat-tern suggested for percussion, moving from one side to the other and com-paring symmetric areas of the lungs. If you hear or suspect abnormal sounds,auscultate adjacent areas so that you can fully describe the extent of any ab-normality. Listen to at least one full breath in each location. Be alert for pa-tient discomfort due to hyperventilation (e.g., light headedness, faintness),and allow the patient to rest as needed.

228 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGNote the intensity of the breath sounds. Breath sounds are usually louder
in the lower posterior lung ﬁelds and may also vary from area to area. If thebreath sounds seem faint, ask the patient to breathe more deeply. You maythen hear them easily. When patients do not breathe deeply enough orwhen they have a thick chest wall, as in obesity, breath sounds may remaindiminished.
Is there a silent gap between the inspiratory and expiratory sounds?
Listen for the pitch, intensity, and duration of the expiratory and inspiratory
sounds. Are vesicular breath sounds distributed normally over the chest wall?
Or are there bronchovesicular or bronchial breath sounds in unexpectedplaces? If so, where are they?
Adventitious (Added) Sounds. Listen for any added, or adventitious,

sounds that are superimposed on the usual breath sounds. Detection of ad-ventitious sounds— crackles (sometimes called rales), wheezes, and rhonchi —
is an important part of your examination, often leading to diagnosis of car-diac and pulmonary conditions. The most common kinds of these soundsare described below:Breath sounds may be decreased
when air ﬂow is decreased (as byobstructive lung disease or muscu-lar weakness) or when the trans-mission of sound is poor (as inpleural effusion, pneumothorax, oremphysema).
A gap suggests bronchial breath
sounds.
For further discussion and other
added sounds, see Table 6-6, Ad-ventitious (Added) Lung Sounds:Causes and Qualities (p. 241).
DISCONTINUOUS SOUNDS (CRACKLES OR RALES) are intermittent,
nonmusical, and brief—like dots in time

Fine crackles ( ) are soft, high pitched, and very brief (5–10 msec).
Coarse crackles ( ) are somewhat louder, lower in pitch, and not quite so 
brief (20–30 msec).
CONTINUOUS SOUNDS are > 250 msec, notably longer than crackles—like dashes
in time—but do not necessarily persist throughout the respiratory cycle. Unlikecrackles, they are musical.
Wheezes ( ) are relatively high pitched (around 400 Hz or higher) and have a 
hissing or shrill quality.
Rhonchi ( ) are relatively low pitched (around 200 Hz or lower) and have a
snoring quality.Adventitious Lung Sounds
Crackles may be due to abnormalities ofthe lungs (pneumonia, ﬁbrosis, earlycongestive heart failure) or of the air-ways (bronchitis, bronchiectasis).
Wheezes suggest narrowed airways, as in
asthma, COPD, or bronchitis.

Rhonchi suggest secretions in large
airways.
If you hear crackles, especially those that do not clear after cough, listen
carefully for the following characteristics. These are clues to the underlyingcondition:
ILoudness, pitch, and duration (summarized as ﬁne or coarse crackles)
INumber (few to many)Fine late inspiratory crackles that
persist from breath to breath suggest abnormal lung tissue.

ITiming in the respiratory cycle
ILocation on the chest wall
IPersistence of their pattern from breath to breath
IAny change after a cough or a change in the patient’s position
In some normal people, crackles may be heard at the lung bases anteriorly
after maximal expiration. Crackles in dependent portions of the lungs mayalso occur after prolonged recumbency.
If you hear wheezes or rhonchi, note their timing and location. Do they
change with deep breathing or coughing?
Transmitted Voice Sounds. If you hear abnormally located broncho-
vesicular or bronchial breath sounds, continue on to assess transmitted voicesounds. With a stethoscope, listen in symmetric areas over the chest wall asyou:
IAsk the patient to say “ninety-nine.” Normally the sounds transmittedthrough the chest wall are mufﬂed and indistinct.
IAsk the patient to say “ee.” You will normally hear a mufﬂed long Esound.

IAsk the patient to whisper “ninety-nine” or “one-two-three.” The whis-pered voice is normally heard faintly and indistinctly, if at all.
Examination of the Anterior Chest
The patient, when examined in the supine position, should lie comfortablywith arms somewhat abducted. A patient who is having difﬁculty breathingshould be examined in the sitting position or with the head of the bed ele-vated to a comfortable level.
CHAPTER 6 ITHE THORAX AND LUNGS 229Clearing of crackles, wheezes, or
rhonchi after cough suggests thatsecretions caused them, as inbronchitis or atelectasis.
Increased transmission of voice
sounds suggests that air-ﬁlled lunghas become airless. See Table 6-5,Normal and Altered Breath andVoice Sounds (p. 240).
Louder, clearer voice sounds are

called bronchophony.
When “ee” is heard as “ay,” 
an E-to-A change (egophony) is 
present, as in lobar consolidationfrom pneumonia. The qualitysounds nasal.
Louder, clearer whispered 
sounds are called whispered 
pectoriloquy.
Persons with severe COPD may
prefer to sit leaning forward, withlips pursed during exhalation andarms supported on their knees ora table.

230 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGINSPECTION
Observe the shape of the patient’s chest andthe movement of the chest wall.
Note:
IAbnormal retraction of the lower interspaces during inspiration
ILocal lag or impairment in respiratory movement
PALPATION
Palpation has four potential uses:
IIdentiﬁcation of tender areas
IAssessment of observed abnormalities
IFurther assessment of chest expansion. Place your thumbs along each costal
margin, your hands along the lateral rib cage. As you position your hands,slide them medially a bit to raise loose skin folds between your thumbs.Ask the patient to inhale deeply. Observe how far your thumbs diverge asthe thorax expands, and feel for the extent and symmetry of respiratorymovement.See Table 6-4, Deformities of the
Severe asthma, COPD, or upper
airway obstruction
Underlying disease of lung or pleura

Tender pectoral muscles or costal
cartilages tend to corroborate, butdo not prove, that chest pain has amusculoskeletal origin.
IAssessment of tactile fremitus. Compare both sides of the chest, using the
ball or ulnar surface of your hand. Fremitus is usually decreased or absentover the precordium. When examining a woman, gently displace thebreasts as necessary.

CHAPTER 6 ITHE THORAX AND LUNGS 231PERCUSSION
Percuss the anterior and lateral chest, again comparing both sides. The heart
normally produces an area of dullness to the left of the sternum from the 3rdto the 5th interspaces. Percuss the left lung lateral to it.Dullness replaces resonance 
when ﬂuid or solid tissue replacesair-containing lung or occupies thepleural space. Because pleural ﬂuidusually sinks to the lowest part ofthe pleural space (posteriorly in asupine patient), only a very largeeffusion can be detected anteriorly.
The hyperresonance of COPD may
totally replace cardiac dullness.
1 1
2 2
33
1 1
2 2
3 3
4 4 5 5
6 6LOCATIONS FOR FEELING FREMITUS

232 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGIn a woman, to enhance percussion, gently displace the breast with your left
hand while percussing with the right.The dullness of right middle lobe
pneumonia typically occurs behindthe right breast. Unless you dis-place the breast, you may miss theabnormal percussion note.
A lung affected by COPD often
displaces the upper border of theliver downward. It also lowers thelevel of diaphragmatic dullnessposteriorly.Alternatively, you may ask the patient to move her breast for you.
Identify and locate any area of abnormal percussion note.With your pleximeter ﬁnger above and parallel to the expected upper bor-

der of liver dullness, percuss in progressive steps downward in the right mid-clavicular line. Identify the upper border of liver dullness. Later, during theabdominal examination, you will use this method to estimate the size of theliver. As you percuss down the chest on the left, the resonance of normallung usually changes to the tympany of the gastric air bubble.

CHAPTER 6 ITHE THORAX AND LUNGS 233AUSCULTATION
Listen to the chest anteriorly and laterally as the patient breathes with mouth
open, somewhat more deeply than normal. Compare symmetric areas of thelungs, using the pattern suggested for percussion and extending it to adja-cent areas as indicated.
Listen to the breath sounds, noting their intensity and identifying any varia-
tions from normal vesicular breathing. Breath sounds are usually louder inthe upper anterior lung ﬁelds. Bronchovesicular breath sounds may be heardover the large airways, especially on the right.
Identify any adventitious sounds, time them in the respiratory cycle, and
locate them on the chest wall. Do they clear with deep breathing?
If indicated, listen for transmitted voice sounds.
Clinical Assessment of Pulmonary Function. A simple but infor-

mative way to assess the complaint of breathlessness in an ambulatory pa-tient is to walk with the patient down the hall or climb one ﬂight of stairs.Observe the rate, effort, and sound of the patient’s breathing.
Forced Expiratory Time. This test assesses the expiratory phase of
breathing, which is typically slowed in obstructive pulmonary disease. Askthe patient to take a deep breath in and then breathe out as quickly and com-pletely as possible with mouth open. Listen over the trachea with the di-aphragm of a stethoscope and time the audible expiration. Try to get threeconsistent readings, allowing a short rest between efforts if necessary.
Identiﬁcation of a Fractured Rib. Local pain and tenderness of one

or more ribs raise the question of fracture. By anteroposterior compressionof the chest, you can help to distinguish a fracture from soft-tissue injury.With one hand on the sternum and the other on the thoracic spine, squeezethe chest. Is this painful, and where?
See Table 6-6, Adventitious
(Added) Lung Sounds: Causes andQualities (p. 241), and Table 6-7,Physical Findings in Selected ChestDisorders (pp. 242–243).
If the patient understands and 
cooperates in performing the test,a forced expiration time of 6 ormore seconds suggests obstructivepulmonary disease.
An increase in the local pain 
(distant from your hands) suggestsrib fracture rather than just soft tissue injury.

TABLE 6-1 IChest Pain
234 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGProblem Process Location Quality Severity
Cardiovascular
Angina Pectoris
Myocardial 
Infarction
Pericarditis
Dissecting Aortic
Aneurysm
Pulmonary
Tracheobronchitis
Pleural Pain
Gastrointestinal and
other
Reﬂex Esophagitis
Diffuse 
Esophageal Spasm
Chest Wall Pain
AnxietyTemporary myocardial
ischemia, usually secondary tocoronary atherosclerosis
Prolonged myocardial ischemia,
resulting in irreversible muscledamage or necrosis
IIrritation of parietal pleuraadjacent to the pericardium
IMechanism unclear
A splitting within the layers of
the aortic wall, allowing passageof blood to dissect a channel
Inﬂammation of trachea and
large bronchi
Inﬂammation of the parietal
pleura, as from pleurisy,pneumonia, pulmonaryinfarction, or neoplasm
Inﬂammation of the esophageal
mucosa by reﬂux of gastric acid
Motor dysfunction of the
esophageal muscle
Variable, often unclear
UnclearRetrosternal or across the

anterior chest, sometimesradiating to the shoulders,arms, neck, lower jaw, orupper abdomen
Same as in angina
Precordial, may radiate to
the tip of the shoulderand to the neck
RetrosternalAnterior chest, radiating
to the neck, back, orabdomen
Upper sternal or on either
side of the sternum
Chest wall overlying the
process
Retrosternal, may radiate
to the back
to the back, arms, and jaw
Often below the left
breast or along the costalcartilages; also elsewhere
Precordial, below the left
breast, or across theanterior chestPressing, squeezing,
tight, heavy,occasionallyburning
Sharp, knifelikeCrushing
Ripping, tearing
Burning
Sharp, knifelike
Burning, may be
squeezing
Usually squeezing
Stabbing, sticking,
or dull, aching
or dull, achingMild to moderate,

Burning
squeezing
sometimes perceivedas discomfort ratherthan pain
Often but not always
a severe pain
Often severe
Severe
Very severe
Mild to moderate
Mild to severe
Mild to severeVariable
Variable
Note: Remember that chest pain may be referred from extrathoracic structures such as the neck (arthritis) and abdomen
(biliary colic, acute cholecystitis). Pleural pain may be due to abdominal conditions such as subdiaphragmatic abscess.

CHAPTER 6 ITHE THORAX AND LUNGS 235Associated
Timing Factors That Aggravate Factors That Relieve Symptoms
Usually 1–3 min but up to
10 min. Prolonged episodesup to 20 min
20 min to several hrPersistentPersistent
Abrupt onset, early peak,
persistent for hours or more
Variable
Persistent
Variable
VariableFleeting to hours or days
Fleeting to hours or dayExertion, especially in the cold; meals;
emotional stress. May occur at rest
Breathing, changing position,
coughing, lying down, sometimesswallowing
Coughing
Breathing, coughing, movements of
the trunk
Large meal; bending over, lying down
Swallowing of food or cold liquid;
emotional stress
Movement of chest, trunk, arms
May follow effort, emotional stressRest, nitroglycerin
Sitting forward may relieve it.
Lying on the involved side may
relieve it.
Antacids, sometimes belching
Sometimes nitroglycerinSometimes dyspnea,
nausea, sweating
sweating, weakness
Of the underlying illness

Syncope, hemiplegia,
paraplegia
Cough
Sometimes regurgitation,
dysphagia
Dysphagia
Often local tenderness
Breathlessness,
palpitations, weakness,anxiety

TABLE 6-2 IDyspnea
236 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Problem Process Timing
Left-Sided Heart Failure 
(left ventricular failure or mitral stenosis)
Chronic Bronchitis*Chronic Obstructive Pulmonary
Disease (COPD)*
Asthma
Diffuse Interstitial Lung Diseases
(such as sarcoidosis, widespreadneoplasms, asbestosis, andidiopathic pulmonary ﬁbrosis)
Pneumonia
Spontaneous Pneumothorax
Acute Pulmonary Embolism
Anxiety With HyperventilationElevated pressure in pulmonary capillary
bed with transudation of ﬂuid intointerstitial spaces and alveoli, decreasedcompliance (increased stiffness) of thelungs, increased work of breathing
Excessive mucus production in bronchi,
followed by chronic obstruction ofairways
Overdistention of air spaces distal to
terminal bronchioles, with destructionof alveolar septa and chronic obstructionof the airways
Bronchial hyperresponsiveness involving

release of inﬂammatory mediators,increased airway secretions, andbronchoconstriction
Abnormal and widespread inﬁltration of
cells, ﬂuid, and collagen into interstitialspaces between alveoli. Many causes 
Inﬂammation of lung parenchyma from
the respiratory bronchioles to the alveoli
Leakage of air into pleural space
through blebs on visceral pleura, withresulting partial or complete collapse ofthe lung
Sudden occlusion of all or part of
pulmonary arterial tree by a blood clotthat usually originates in deep veins oflegs or pelvis
Overbreathing, with resultant
respiratory alkalosis and fall in thepartial pressure of carbon dioxide in the bloodDyspnea may progress slowly, or
suddenly as in acute pulmonaryedema.
Chronic productive cough followed
by slowly progressive dyspnea
Slowly progressive dyspnea; relatively

mild cough later
Acute episodes, separated by
symptom-free periods. Nocturnalepisodes are common.
Progressive dyspnea, which varies in
its rate of development with the cause
An acute illness, timing varies with
the causative agent
Sudden onset of dyspnea
Episodic, often recurrent
*Chronic bronchitis and chronic obstructive pulmonary disease (COPD) may coexist.

CHAPTER 6 ITHE THORAX AND LUNGS 237Factors That
Aggravate Factors That Relieve Associated Symptoms Setting
Exertion, lying down
Exertion, inhaled irritants,
respiratory infections
Exertion
Variable, including
allergens, irritants,respiratory infections,exercise, and emotion 
Exertion
More often occurs at rest
than after exercise. Anupsetting event may not be evident.Rest, sitting up, though dyspnea
may become persistent 
Expectoration; rest, though
dyspnea may become persistent
Rest, though dyspnea may
become persistent
Separation from aggravating
factors
Breathing in and out of a paper
or plastic bag sometimes helpsthe associated symptoms. Often cough, orthopnea,
paroxysmal nocturnal dyspnea;sometimes wheezing
Chronic productive cough,
recurrent respiratory infections;wheezing may develop
Cough, with scant mucoid
sputum
Wheezing, cough, tightness in
chest
Often weakness, fatigue. Cough
less common than in other lungdiseases

sputum
chest
Pleuritic pain, cough, sputum,
fever, though not necessarilypresent
Pleuritic pain, cough
Often none. Retrosternal
oppressive pain if the occlusionis massive. Pleuritic pain, cough,and hemoptysis may follow anembolism if pulmonaryinfarction ensues. Symptoms ofanxiety (see below).
Sighing, lightheadedness,
numbness or tingling of thehands and feet, palpitations,chest painHistory of heart disease or its
predisposing factors 
History of smoking, air
pollutants, recurrentrespiratory infections
pollutants, sometimes a familialdeﬁciency in alpha
1-antitrypsin
Environmental and emotional
Varied. Exposure to one of
many substances may becausative.
Varied
Often a previously healthy
young adult
Postpartum or postoperative

Varied
periods; prolonged bed rest;congestive heart failure,chronic lung disease, andfractures of hip or leg; deepvenous thrombosis (often notclinically apparent)
Other manifestations of anxiety

TABLE 6-3 ICough and Hemoptysis
238 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 6-3 ICough and Hemoptysis*
Problem Cough and Sputum Associated Symptoms and Setting
Acute Inﬂammation
Laryngitis
TracheobronchitisMycoplasma and Viral
Pneumonias
Bacterial Pneumonias
Chronic Inﬂammation
Postnasal Drip
Chronic Bronchitis
BronchiectasisPulmonary Tuberculosis
Lung AbscessAsthmaGastroesophageal Reﬂux
Neoplasm
Cancer of the Lung
Cardiovascular Disorders
Left Ventricular Failure or 
Mitral Stenosis
Pulmonary EmboliIrritating Particles,
Chemicals, or GasesDry cough (without sputum), may become
productive of variable amounts of sputum
Dry cough, may become productive (as
above)
Dry hacking cough, often becoming
productive of mucoid sputum
Pneumococcal: sputum mucoid or
purulent; may be blood-streaked, diffuselypinkish, or rusty
Klebsiella: similar; or sticky, red, and jellylike
Chronic cough; sputum mucoid or
Chronic cough; sputum mucoid to

purulent, may be blood-streaked or evenbloody
Chronic cough; sputum purulent, often
copious and foul-smelling; may be blood-streaked or bloody
Cough dry or sputum that is mucoid or
purulent; may be blood-streaked or bloody
Sputum purulent and foul-smelling; may be
bloody
Cough, with thick mucoid sputum,
especially near end of an attack
Chronic cough, especially at night or early
in the morning
Cough dry to productive; sputum may be
blood-streaked or bloody
Often dry, especially on exertion or at night;
may progress to the pink frothy sputum ofpulmonary edema or to frank hemoptysis
Dry to productive; may be dark, bright red,
or mixed with blood
Variable. There may be a latent period
between exposure and symptoms.An acute, fairly minor illness with hoarseness.

Often associated with viral nasopharyngitis
An acute, often viral illness, with burning
retrosternal discomfort
An acute febrile illness, often with malaise,
headache, and possibly dyspnea
An acute illness with chills, high fever,
dyspnea, and chest pain. Often is preceded byacute upper respiratory infection.
Typically occurs in older alcoholic men
Repeated attempts to clear the throat.
Postnasal discharge may be sensed by patientor seen in posterior pharynx. Associated withchronic rhinitis, with or without sinusitis
Often longstanding cigarette smoking.
Recurrent superimposed infections. Wheezingand dyspnea may develop.
Recurrent bronchopulmonary infections
common; sinusitis may coexist
Early, no symptoms. Later, anorexia, weight
loss, fatigue, fever, and night sweats

A febrile illness. Often poor dental hygiene
and a prior episode of impaired consciousness
Episodic wheezing and dyspnea, but cough
may occur alone. Often a history of allergy
Wheezing, especially at night (often mistaken
for asthma), early morning hoarseness, andrepeated attempts to clear the throat. Often ahistory of heartburn and regurgitation
Usually a long history of cigarette smoking.
Associated manifestations are numerous.
Dyspnea, orthopnea, paroxysmal nocturnal
dyspnea
Dyspnea, anxiety, chest pain, fever; factors
that predispose to deep venous thrombosis
Exposure to irritants. Eyes, nose, and throat
may be affected.
*Characteristics of hemoptysis are printed in red.

TABLE 6-4 IDeformities of the Thorax
CHAPTER 6 ITHE THORAX AND LUNGS 239
Normal Adult
The thorax in the normal adult is wider than it is
deep. Its lateral diameter is larger than itsanteroposterior diameter.
Barrel Chest
A barrel chest has an increased anteroposterior
diameter. This shape is normal during infancy,and often accompanies normal aging and chronicobstructive pulmonary disease.
Traumatic Flail Chest
If multiple ribs are fractured, paradoxical
movements of the thorax may be seen. As descentof the diaphragm decreases intrathoracic pressureon inspiration, the injured area caves inward; onexpiration, it moves outward.
Expiration
InspirationCross Section 
of ThoraxCross Section 
of Thorax
Funnel Chest ( Pectus Excavatum )
A funnel chest is characterized by a depression in
the lower portion of the sternum. Compressionof the heart and great vessels may causemurmurs.
Pigeon Chest ( Pectus Carinatum )

In a pigeon chest, the sternum is displaced
anteriorly, increasing the anteroposteriordiameter. The costal cartilages adjacent to theprotruding sternum are depressed.
Depressed costal cartilages
Anteriorly displaced sternum
Thoracic Kyphoscoliosis
In thoracic kyphoscoliosis, abnormal spinal
curvatures and vertebral rotation deform thechest. Distortion of the underlying lungs maymake interpretation of lung ﬁndings very difﬁcult.Cross Section 
of ThoraxCross Section
of Thorax
Ribs widely
separatedSpinal convexity to the right
(patient bending forward)
Ribs close
together

TABLE 6-5 INormal and Altered Breath and Voice Sounds
240 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
The origins of breath sounds are still unclear. According to leading theories, tur-
bulent air ﬂow in the central airways produces the tracheal and bronchial breathsounds. As these sounds pass through the lungs to the periphery, lung tissue ﬁl-ters out their higher-pitched components and only the soft and lower-pitchedcomponents reach the chest wall, where they are heard as vesicular breath sounds.Normally, tracheal and bronchial sounds may be heard over the trachea and main-stem bronchi; vesicular breath sounds predominate throughout most of the lungs.When lung tissue loses its air, it transmits high-pitched sounds much better. If the

tracheobronchial tree is open, bronchial breath sounds may replace the normalvesicular sounds over airless areas of the lung. This change is seen in lobar pneu-monia when the alveoli ﬁll with ﬂuid, red cells, and white cells—a process calledconsolidation. Other causes include pulmonary edema or hemorrhage. Bronchial
breath sounds usually correlate with an increase in tactile fremitus and transmit-ted voice sounds. These ﬁndings are summarized below.
Normal Air-Filled Lung Airless Lung, as in Lobar Pneumonia
Breath Sounds
Transmitted Voice Sounds
Tactile FremitusPredominantly vesicular
Spoken words mufﬂed and indistinct
Spoken “ee” heard as “ee”Whispered words faint and indistinct, if heard at all
NormalBronchial or bronchovesicular over the involved area
Spoken words louder, clearer ( bronchophony )
Spoken “ee” heard as “ay” ( egophony )
Whispered words louder, clearer ( whispered pectoriloquy )
Increased

TABLE 6-6 IAdventitious (Added) Lung Sounds: Causes and Qualities
CHAPTER 6 ITHE THORAX AND LUNGS 241
Crackles
Crackles have two leading explanations. (1) They result from a series of tiny explosions when small airways, deﬂated during exp iration, pop open during inspiration.
This mechanism probably explains the late inspiratory crackles of interstitial lung disease and early congestive heart failure.  (2) Crackles result from air bubbles
ﬂowing through secretions or lightly closed airways during respiration. This mechanism probably explains at least some coarse c rackles.
Wheezes and Rhonchi
Stridor
Pleural Rub
Mediastinal Crunch
(Hamman’s Sign )
Inspiration Expiration
Late inspiratory crackles may begin in the ﬁrst half of inspiration but must continue into late inspiration. They are

Stridor
usually ﬁne and fairly profuse, and persist from breath to breath. These crackles appear ﬁrst at the bases of the lungs,spread upward as the condition worsens, and shift to dependent regions with changes in posture. Causes includeinterstitial lung disease (such as ﬁbrosis) and early congestive heart failure.
Early inspiratory crackles appear soon after the start of inspiration and do not continue into late inspiration. They are
often but not always coarse and are relatively few in number. Expiratory crackles are sometimes associated. Causesinclude chronic bronchitis and asthma.
Midinspiratory and expiratory crackles are heard in bronchiectasis but are not speciﬁc for this diagnosis. Wheezes and
rhonchi may be associated.

Wheezes occur when air ﬂows rapidly through bronchi that are narrowed nearly to the point of closure. They are often
audible at the mouth as well as through the chest wall. Causes of wheezes that are generalized throughout the chestinclude asthma, chronic bronchitis, COPD, and congestive heart failure (cardiac asthma). In asthma, wheezes may beheard only in expiration or in both phases of the respiratory cycle. Rhonchi suggest secretions in the larger airways. Inchronic bronchitis, wheezes and rhonchi often clear with coughing.
Occasionally in severe obstructive pulmonary disease, the patient is no longer able to force enough air through the
narrowed bronchi to produce wheezing. The resulting silent chest should raise immediate concern and not be
mistaken for improvement.

A persistent localized wheeze suggests a partial obstruction of a bronchus, as by a tumor or foreign body. It may be
inspiratory, expiratory, or both.
A wheeze that is entirely or predominantly inspiratory is called stridor. It is often louder in the neck than over the
chest wall. It indicates a partial obstruction of the larynx or trachea, and demands immediate attention.
Inﬂamed and roughened pleural surfaces grate against each other as they are momentarily and repeatedly delayed by
increased friction. These movements produce creaking sounds known as a pleural rub (or pleural friction rub).
Pleural rubs resemble crackles acoustically, although they are produced by different pathologic processes.

Pleural rubs resemble crackles acoustically, although they are produced by different pathologic processes. 
The sounds may be discrete, but sometimes are so numerous that they merge into a seemingly continuous sound. Arub is usually conﬁned to a relatively small area of the chest wall, and typically is heard in both phases of respiration.When inﬂamed pleural surfaces are separated by ﬂuid, the rub often disappears.
A mediastinal crunch is a series of precordial crackles synchronous with the heart beat, not with respiration. Best
heard in the left lateral position, it is due to mediastinal emphysema (pneumomediastinum).

TABLE 6-7 IPhysical Findings in Selected Chest Disorders
242 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
The black boxes in this table suggest a framework for clinical assessment. Start with
the three boxes under Percussion Note: resonant, dull, and hyperresonant. Thenmove from each of these to other boxes that emphasize some of the key differencesamong various conditions. The changes described vary with the extent and severityof the disorder. Abnormalities deep in the chest usually produce fewer signs than
superﬁcial ones, and may cause no signs at all. Use the table for the direction oftypical changes, not for absolute distinctions.
Tactile Fremitus
Percussion Adventitious and Transmitted
Condition Note Trachea Breath Sounds Sounds Voice Sounds
Normal
The tracheobronchial tree and
alveoli are clear; pleurae arethin and close together;mobility of the chest wallis unimpaired.

Normal
The bronchi are chronicallyinﬂamed and a productivecough is present. Airwayobstruction may develop.
(Early )
Increased pressure in the
pulmonary veins causescongestion and interstitialedema (around the alveoli);bronchial mucosa may becomeedematous.
Consolidation
Alveoli ﬁll with ﬂuid or bloodcells, as in pneumonia,pulmonary edema, orpulmonary hemorrhage.Resonant
ResonantResonant
Dull over the
airless areaMidline
MidlineMidline
MidlineVesicular, except perhaps
bronchovesicular andbronchial sounds overthe large bronchi andtrachea respectively
Vesicular (normal)
Vesicular
Bronchial over the
involved areaNone, except perhaps 
a few transient inspiratorycrackles at the bases of thelungs
None; or scattered coarse
crackles in early inspiration
and perhaps expiration; orwheezes or rhonchi
Late inspiratory crackles in

the dependent portions ofthe lungs; possibly wheezes
Late inspiratory crackles
over the involved areaNormal
NormalNormal
Increased over the
involved area, withbronchophony,egophony, and
whisperedpectoriloquy

CHAPTER 6 ITHE THORAX AND LUNGS 243Atelectasis 
(Lobar Obstruction )
When a plug in a mainstem
bronchus (as from mucus or aforeign object) obstructs airﬂow, affected lung tissuecollapses into an airless state.
Pleural Effusion
Fluid accumulates in thepleural space, separates air-ﬁlled lung from the chest wall,blocking the transmission ofsound.
Pneumothorax
When air leaks into the pleuralspace, usually unilaterally, thelung recoils from the chestwall. Pleural air blockstransmission of sound.
Chronic Obstructive
Pulmonary Disease(COPD)
Slowly progressive disorder in
which the distal air spacesenlarge and lungs becomehyperinﬂated. Chronicbronchitis is often associated.
Asthma
Widespread narrowing of thetracheobronchial treediminishes airﬂow to aﬂuctuating degree. Duringattacks, airﬂow decreasesfurther and lungs hyperinﬂate.Dull over the
airless area
Dull to ﬂat 
over the ﬂuid
Hyperresonant
or tympaniticover the pleuralair
Diffusely

Dull to ﬂat 
Diffusely
hyperresonant
Resonant to
diffuselyhyperresonantUsually absent when
bronchial plug persists.Exceptions include rightupper lobe atelectasis,where adjacent trachealsounds may betransmitted.
Decreased to absent, but
bronchial breath soundsmay be heard near top oflarge effusion.
Decreased to absent over
the pleural air
Decreased to absent
Often obscured by wheezesUsually absent when
the bronchial plugpersists. Inexceptions, e.g.,right upper lobeatelectasis, may beincreased
Decreased to absent,
but may be increasedtoward the top of alarge effusion
over the pleural air
Decreased
DecreasedMay be shifted
toward involvedside
Shifted toward
opposite side in a
large effusion
opposite side if
much air
MidlineMidlineNone
None, except a possible
pleural rub
None, or the crackles,
wheezes, and rhonchi ofassociated chronicbronchitis

much air
Wheezes, possibly crackles

The Cardiovascular SystemCHAPTER
The Cardiovascular System 77
CHAPTER 7 ITHE CARDIOVASCULAR SYSTEM 243
Surface Projections of the Heart and Great Vessels
Learn to visualize the underlying structures of the heart as you examine
the anterior chest. Understanding cardiac anatomy and physiology is par-ticularly important in the examination of the cardiovascular system.
Note that the right ventricle occupies most of the anterior cardiac surface.
This chamber and the pulmonary artery form a wedgelike structure be-hind and to the left of the sternum.
Pulmonary artery
Right ventricle

244 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING*Because the most prominent cardiac impulse may not be apical, some authorities discourage use of
this term.The inferior border of the right ventricle lies below the junction of the ster-
num and the xiphoid process. The right ventricle narrows superiorly and meetsthe pulmonary artery at the level of the sternum or “base of the heart”—a clin-ical term that refers to the right and left 2nd interspaces close to the sternum.
The left ventricle, behind the right ventricle and to the left, forms the left
lateral margin of the heart. Its tapered inferior tip is often termed the cardiac“apex.” It is clinically important because it produces the apical impulse, some-
times called the point of maximal impulse, orPMI.* This impulse locates the

left border of the heart and is usually found in the 5th interspace 7 cm to9 cm lateral to the midsternal line. It is about the size of a quarter, roughly1 to 2.5 cm in diameter.
The right heart border is formed by the right atrium, a chamber not usually
identifiable on physical examination. The left atrium is mostly posterior
and cannot be examined directly, although its small atrial appendage maymake up a segment of the left heart border between the pulmonary and the
left ventricle.
Pulmonary
artery
Right
pulmonaryarteryLeft
pulmonaryartery
Right ventricleLeft ventricleAorta
Right atrium
Apical impulseSuperior vena cava

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cAbove the heart lie the great vessels. The pulmonary artery, already men-
tioned, bifurcates quickly into its left and right branches. The aorta curves
upward from the left ventricle to the level of the sternal angle, where itarches backward to the left and then down. On the right, the superior venacava empties into the right atrium.
Although not illustrated, the inferior vena cava also empties into the right
atrium. The superior andinferior venae cavae carry venous blood to the heart
from the upper and lower portions of the body.
Cardiac Chambers, Valves, and Circulation
Circulation through the heart is shown in the diagram below, which identi-ﬁes the cardiac chambers, valves, and direction of blood ﬂow. Because oftheir positions, the tricuspid and mitral valves are often called atrioventric-
ular valves. The aortic and pulmonic valves are called semilunar valves be-

cause each of their leaﬂets is shaped like a half moon. Although this diagramshows all valves in an open position, they are not all open simultaneously inthe living heart.
CHAPTER 7 ITHE CARDIOVASCULAR SYSTEM 245Pulmonary artery
(to lungs)Superior vena cava
Pulmonic valve
Tricuspid valve
Inferior vena cava
RA = Right atrium
RV = Right ventricleLA = Left atrium
LV = Left ventricleCourse of 
unoxygenated bloodCourse of 
oxygenated bloodAortic valveMitral valvePulmonary veins
(from lungs)Aorta
RALA
RVLV
As the heart valves close, the heart sounds arise from vibrations emanating
from the leaﬂets, the adjacent cardiac structures, and the ﬂow of blood. It isessential to understand the positions and movements of the valves in rela-tion to events in the cardiac cycle.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cEvents in the Cardiac Cycle
The heart serves as a muscular pump that generates varying pressures as its
chambers contract and relax. Systole is the period of ventricular contraction.
In the diagram shown below, pressure in the left ventricle rises from less than5 mm Hg in its resting state to a normal peak of 120 mm Hg. After the ven-tricle ejects much of its blood into the aorta, the pressure levels off and startsto fall. Diastole is the period of ventricular relaxation. Ventricular pressure
falls further to below 5 mm Hg, and blood ﬂows from atrium to ventricle.Late in diastole, ventricular pressure rises slightly during inﬂow of bloodfrom atrial contraction.
246 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
120
Ømm Hg
Systole DiastoleLeft ventricle pressure curve
Note that during systole the aortic valve is open, allowing ejection of blood

120
Ømm Hg
from the left ventricle into the aorta. The mitral valve is closed, preventingblood from regurgitating back into the left atrium. In contrast, during di-
astole the aortic valve is closed, preventing regurgitation of blood from the
aorta back into the left ventricle. The mitral valve is open, allowing blood toﬂow from the left atrium into the relaxed left ventricle.
Understanding the interrelationships of the pressures in these three cham-
bers—left atrium, left ventricle, and aorta—together with the position andmovement of the valves is fundamental to understanding heart sounds.These changing pressures and the sounds that result are traced here throughone cardiac cycle. Note that during auscultation the ﬁrst and second heartsounds deﬁne the duration of systole and diastole.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cDuring diastole, pressure in the
blood-ﬁlled left atrium slightly ex-ceeds that in the relaxed left ventri-cle, and blood ﬂows from left atriumto left ventricle across the open mi-tral valve. Just before the onset ofventricular systole, atrial contrac-tion produces a slight pressure risein both chambers.
During systole, the left ventricle starts
to contract and ventricular pressurerapidly exceeds left atrial pressure,thus shutting the mitral valve. Clo-
sure of the mitral valve produces theﬁrst heart sound, S
1.†
As left ventricular pressure continuesto rise, it quickly exceeds the pres-sure in the aorta and forces the aor-tic valve open. In some pathologicconditions, opening of the aorticvalve is accompanied by an early sys-tolic ejection sound (Ej). Normally,maximal left ventricular pressure cor-responds to systolic blood pressure.
As the left ventricle ejects most of its

blood, ventricular pressure begins tofall. When left ventricular pressuredrops below aortic pressure, the aor-tic valve shuts. Aortic valve closure
produces the second heart sound, S
2,
and another diastole begins.ANATOMY AND PHYSIOLOGY
CHAPTER 7 ITHE CARDIOVASCULAR SYSTEM 247†An extensive literature deals with the exact causes of heart sounds. Possible explanations include actual
closure of valve leaﬂets, tensing of related structures, leaﬂet positions and pressure gradients at the timeof atrial and ventricular systole, and the impact of columns of blood. The explanations given here areoversimpliﬁed but retain clinical usefulness.Atrial contraction
Left atrial pressure
Left ventricular pressure
Left atrial pressureLeft ventricular pressure Mitral
valve
closes
S1
Aortic pressureAortic
valve
opens
S1Ej
Left atrial pressureLeft ventricular pressureAortic valve closes
S1 S2 EjAortic pressure

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cIn diastole, left ventricular pressure
continues to drop and falls belowleft atrial pressure. The mitral valveopens. This is usually a silent event,but may be audible as a pathologicopening snap (OS) if valve leafletmotion is restricted, as in mitralstenosis.
After the mitral valve opens, there
is a period of rapid ventricular fill-ing as blood flows early in diastolefrom left atrium to left ventricle. Inchildren and young adults, a thirdheart sound, S
3, may arise from rapid
deceleration of the column of bloodagainst the ventricular wall. In older
adults, an S
3, sometimes termed
“an S 3gallop,” usually indicates a
pathologic change in ventricularcompliance.
Finally, although not often heard in
normal adults, a fourth heart sound,S
4, marks atrial contraction. It im-
mediately precedes S 1of the next
beat, and also reﬂects a pathologicchange in ventricular compliance.
The Splitting of Heart Sounds

While these events are occurring on the left side of the heart, similarchanges are occurring on the right, involving the right atrium, right ven-tricle, tricuspid valve, pulmonic valve, and pulmonary artery. Right ven-tricular and pulmonary arterial pressures are significantly lower than cor-responding pressures on the left side. Furthermore, right-sided eventsusually occur slightly later than those on the left. Instead of a single heartsound, you may hear two discernible components, the first from left-sided
248 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGAortic pressure
Mitral valve opens
S1 S2OS EjLeft atrial pressure
Period of rapid
ventricular filling
S1 S2S3OS Ej
Augmented ventricular
filling due toatrial contraction
S
1 S2S3 S4 OS Ej
Diastole Systole

S1 S1
EXPIRATION INSPIRATIONS2 S2A2P2ANATOMY AND PHYSIOLOGY
CHAPTER 7 ITHE CARDIOVASCULAR SYSTEM 249aortic valve closure, or A 2, and the second from right-sided closure of the
pulmonic valve, or P 2.
Consider the second heart sound and its two components, A 2and P 2, which
come from closure of the aortic and pulmonic valves respectively. Duringexpiration, these two components are fused into a single sound, S
2. During
inspiration, however, A 2and P 2separate slightly, and S 2may split into its
two audible components.
Current explanations of inspiratory splitting cite increased capacitance in the
pulmonary vascular bed during inspiration, which prolongs ejection of bloodfrom the right ventricle, delaying closure of the pulmonic valve, or P
2. Ejec-
tion of blood from the left ventricle is comparatively shorter, so A 2occurs
slightly earlier. 
Of the two components of the second heart sound, A 2is normally louder,

2. Ejec-
reﬂecting the high pressure in the aorta. It is heard throughout the pre-cordium. P
2, in contrast, is relatively soft, reﬂecting the lower pressure in the
pulmonary artery. It is heard best in its own area—the 2nd and 3rd left in-terspaces close to the sternum. It is here that you should search for splittingof the second heart sound.
S
1also has two components, an earlier mitral and a later tricuspid sound.
The mitral sound, its principal component, is much louder, again reﬂectingthe high pressures on the left side of the heart. It can be heard throughout the
precordium and is loudest at the cardiac apex. The softer tricuspid compo-nent is heard best at the lower left sternal border, and it is here that you mayhear a split S
1. The earlier louder mitral component may mask the tricuspid

sound, however, and splitting is not always detectable. Splitting of S 1does
not vary with respiration.
Heart Murmurs
Heart murmurs are distinguishable from heart sounds by their longer dura-tion. They are attributed to turbulent blood ﬂow and may be “innocent,”as with ﬂow murmurs of young adults, or diagnostic of valvular heart dis-ease. A stenotic valve has an abnormally narrowed valvular oriﬁce that ob-
structs blood ﬂow, as in aortic stenosis, and causes a characteristic murmur.So does a valve that fails to fully close, as in aortic regurgitation or insufﬁ-

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cciency. Such a valve allows blood to leak backward in a retrograde direction
and produces a regurgitant murmur.
To identify murmurs accurately, you must learn to assess the chest wall loca-
tion where they are best heard, their timing in systole or diastole, and theirqualities. In the section on Techniques of Examination, you will learn to in-tegrate several characteristics, including murmur intensity, pitch, duration,and direction of radiation (see pp. __–__).
Relation of Auscultatory Findings 
to the Chest Wall
The locations on the chest wall where you hear heart sounds and murmurs

help to identify the valve or chamber where they originate. Sounds and mur-murs arising from the mitral valve are usually heard best at and around thecardiac apex. Those originating in the tricuspid valve are heard best at ornear the lower left sternal border. Murmurs arising from the pulmonic valveare usually heard best in the 2nd and 3rd left interspaces close to the ster-num, but at times may also be heard at higher or lower levels, and those orig-inating in the aortic valve may be heard anywhere from the right 2nd inter-space to the apex. These areas overlap, as illustrated below, and you will needto correlate auscultatory ﬁndings with other portions of the cardiac exami-nation to identify sounds and murmurs accurately.
250 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Aortic
TricuspidPulmonic
Mitral

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cThe Conduction System
An electrical conduction system stim-
ulates and coordinates the contrac-tion of cardiac muscle.
Each normal electrical impulse is
initiated in the sinus node , a group
of specialized cardiac cells located inthe right atrium near the junction ofthe vena cava. The sinus node actsas the cardiac pacemaker and auto-matically discharges an impulseabout 60 to 100 times a minute.This impulse travels through bothatria to the atrioventricular node , a
specialized group of cells located lowin the atrial septum. Here the im-pulse is delayed before passing down the bundle of His and its branches to the ventricular myocardium. Muscu-lar contraction follows: ﬁrst the atria, then the ventricles. The normal con-duction pathway is diagrammed in simpliﬁed form at the right.
The electrocardiogram, or ECG, records these events. Contraction of car-

diac smooth muscle produces electrical activity, resulting in a series of waveson the ECG. The components of the normal ECG and their duration are
brieﬂy summarized here, but you will need further instruction and practiceto interpret recordings from actual patients.
IThe small P wave of atrial depo-
larization (duration up to 8 milli-seconds; PR interval up to 20 milli-
seconds)
IThe larger QRS complex of ventric-
ular depolarization (up to 10 milli-seconds), consisting of one or moreof the following:
–the Q wave , a downward deﬂec-
tion from septal depolarization
–the R wave , an upward deﬂection
from ventricular depolarization
–the S wave , a downward deﬂec-
tion following an R wave
IA T wave of ventricular repolariza-
tion, or recovery (duration relatesto QRS).
CHAPTER 7 ITHE CARDIOVASCULAR SYSTEM 251UNFIG 7-9
UNFIG 7-10

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cThe Heart as a Pump
The left and right ventricles pump blood into the systemic and pulmonary
arterial trees, respectively. Cardiac output, the volume of blood ejected from
each ventricle during 1 minute, is the product of heart rate and stroke vol-
ume. Stroke volume (the volume of blood ejected with each heartbeat) de-
pends in turn on preload, myocardial contractility, and afterload.
Preload refers to the load that stretches the cardiac muscle prior to contrac-

tion. The volume of blood in the right ventricle at the end of diastole, then,constitutes its preload for the next beat. Right ventricular preload is in-creased by increasing venous return to the right heart. Physiologic causesinclude inspiration and the increased volume of blood that ﬂows from exer-cising muscles. The increased volume of blood in a dilated ventricle of con-gestive heart failure also increases preload. Causes of decreased right ven-tricular preload include exhalation, decreased left ventricular output, andpooling of blood in the capillary bed or the venous system.
Myocardial contractility refers to the ability of the cardiac muscle, when
given a load, to shorten. Contractility increases when stimulated by actionof the sympathetic nervous system, and decreases when blood ﬂow or oxy-gen delivery to the myocardium is impaired.

Afterload refers to the vascular resistance against which the ventricle must
contract. Sources of resistance to left ventricular contraction include thetone in the walls of the aorta, the large arteries, and the peripheral vasculartree (primarily the small arteries and arterioles), as well as the volume ofblood already in the aorta.
Pathologic increases in preload and afterload, called volume overload and
pressure overload respectively, produce changes in ventricular function that
may be clinically detectable. These changes include alterations in ventricu-lar impulses, detectable by palpation, and in normal heart sounds. Patho-logic heart sounds and murmurs may also develop.

252 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGThe electrical impulse slightly precedes the myocardial contraction that it
stimulates. The relation of electrocardiographic waves to the cardiac cycle isshown below.
QRS QRS
PP TT
Systole DiastoleElectrocardiagram
Heart sounds
S4S1 S2 S2 S4S1

120
80
40
0Systole DiastoleDiastolic pressurePulse pressureSystolic pressuremm HgArterial Pulses and Blood Pressure
With each contraction, the left ventricle ejects a volume of blood into the aorta
and on into the arterial tree. The ensuing pressure wave moves rapidly throughthe arterial system, where it is felt as the arterial pulse. Although the pressure
wave travels quickly—many times faster than the blood itself—a palpable delaybetween ventricular contraction and peripheral pulses makes the pulses in thearms and legs unsuitable for timing events in the cardiac cycle.
Blood pressure in the arterial system varies during the cardiac cycle, peaking
in systole and falling to its lowest trough in diastole. These are the levels thatare measured with the blood pressure cuff, or sphygmomanometer. The dif-ference between systolic and diastolic pressures is known as the pulse pressure.

CHAPTER 7 ITHE CARDIOVASCULAR SYSTEM 253The principal factors inﬂuencing arterial pressure are:
ILeft ventricular stroke volume
IDistensibility of the aorta and the large arteries
IPeripheral vascular resistance, particularly at the arteriolar level
IVolume of blood in the arterial system.
Changes in any of these four factors alter systolic pressure, diastolic pressure,
or both. Blood pressure levels fluctuate strikingly through any 24-hourperiod, varying with physical activity, emotional state, pain, noise, environ-
mental temperature, the use of coffee, tobacco, and other drugs, and eventhe time of day.

254 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Posterior auricular artery
Occipital artery
Descending branch
Diagastric muscleSternomastoid branch
Sternomastoid branchInt. carotid artery
Asc. pharyngeal arteryExt. carotid artery
Common carotid artery
Common carotid arteryOmohyoid muscleJugular Venous Pressure and Pulses
Jugular Venous Pressure (JVP). Systemic venous pressure is much

lower than arterial pressure. Although venous pressure ultimately dependson left ventricular contraction, much of this force is dissipated as bloodpasses through the arterial tree and the capillary bed. Walls of veins containless smooth muscle than walls of arteries, which reduces venous vascular toneand makes veins more distensible. Other important determinants of ve-nous pressure include blood volume and the capacity of the right heart toeject blood into the pulmonary arterial system. Cardiac disease may alterthese variables, producing abnormalities in central venous pressure. For ex-ample, venous pressure falls when left ventricular output or blood volume issigniﬁcantly reduced; it rises when the right heart fails or when increasedpressure in the pericardial sac impedes the return of blood to the rightatrium. These venous pressure changes are reflected in the height of thevenous column of blood in the internal jugular veins, termed the jugular
venous pressure or JVP.

Pressure in the jugular veins reﬂects right atrial pressure, giving clinicians an
important clinical indicator of cardiac function and right heart hemo-dynamics. Assessing the JVP is an essential, though challenging, clinical skill.
The JVP is best estimated from the internal jugular vein, usually on the right
side, since the right internal jugular vein has a more direct anatomic channel
into the right atrium.
The internal jugular veins lie deep to the sternomastoid muscles in the neck
and are not directly visible, so the clinician must learn to identify the pulsa-

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5ctions of the internal jugular vein that are transmitted to the surface of the
neck, making sure to carefully distinguish these venous pulsations from pul-sations of the carotid artery. If pulsations from the internal jugular vein can-not be identiﬁed, those of the external jugular vein can be used, but they areless reliable.
To estimate the level of the JVP, you will learn to ﬁnd the highest point of
oscillation in the internal jugular vein or, if necessary, the point above which
the external jugular vein appears collapsed. The JVP is usually measured invertical distance above the sternal angle , the bony ridge adjacent to the
second rib where the manubrium joins the body of the sternum.
Study the illustrations below very carefully. Note that regardless of the pa-

tient’s position, the sternal angle remains roughly 5 cm above the right atrium.In this patient, however, the pressure in the internal jugular vein is somewhatelevated.
IIn Position A, the head of the bed is raised to the usual level, about 30 °,
but the JVP cannot be measured because the meniscus, or level of oscil-lation, is above the jaw and therefore not visible.
IIn Position B, the head of the bed is raised to 60 °.The “top” of the in-
ternal jugular vein is now easily visible, so the vertical distance from thesternal angle or right atrium can now be measured.
IIn Position C, the patient is upright and the veins are barely discernible
above the clavicle, making measurement untenable.ANATOMY AND PHYSIOLOGY
CHAPTER 7 ITHE CARDIOVASCULAR SYSTEM 255
30° 60° 90°Height of venou s
pressure from
sternal angle
5 cm

5 cm
Note that the height of the venous pressure as measured from the sternal
angle is the same in all three positions, but your ability to measure the height
of the column of venous blood, or JVP, differs according to how you posi-tion the patient. Jugular venous pressure measured at more than 4 cm aboveAB C

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cthe sternal angle, or more than 9 cm above the right atrium, is considered
elevated or abnormal. The techniques for measuring the JVP are fully de-scribed in Techniques of Examination on pp. __–__.
Jugular Venous Pulsations. The oscillations that you see in the in-
ternal jugular veins (and often in the externals as well) reﬂect changing pres-sures within the right atrium. The right internal jugular vein empties moredirectly into the right atrium and reﬂects these pressure changes best.
Careful observation reveals that the
undulating pulsations of the internaljugular veins (and sometimes the ex-ternals) are composed of two quickpeaks and two troughs.
The ﬁrst elevation, the a wave, re-
ﬂects the slight rise in atrial pressurethat accompanies atrial contraction.It occurs just before the ﬁrst heartsound and before the carotid pulse. The following trough, the x descent, starts with atrial relaxation. It contin-

ues as the right ventricle, contracting during systole, pulls the ﬂoor of theatrium downward. During ventricular systole, blood continues to ﬂow intothe right atrium from the venae cavae. The tricuspid valve is closed, thechamber begins to ﬁll, and right atrial pressure begins to rise again, creatingthe second elevation, the v wave. When the tricuspid valve opens early in di-
astole, blood in the right atrium ﬂows passively into the right ventricle andright atrial pressure falls again, creating the second trough or y descent. To
remember these four oscillations in a somewhat oversimpliﬁed way, think ofthe following sequence: atrial contraction, atrial relaxation, atrial ﬁlling, andatrial emptying. (You can think of the awave as a
trial contraction and the 
vwave as v enous ﬁlling.)
To the naked eye, the two descents are the most obvious events in the nor-
mal jugular pulse. Of the two, the sudden collapse of the xdescent late in

systole is the more prominent, occurring just before the second heart sound.The ydescent follows the second heart sound early in diastole.
Cardiovascular ﬁndings vary signiﬁcantly with age. Aging may affect the lo-
cation of the apical impulse, the pitch of heart sounds and murmurs, the stiff-ness of the arteries, and blood pressure.
The Apical Impulse and Heart Sounds. The apical impulse is usu-
ally felt easily in children and young adults; as the chest deepens in its an-teroposterior diameter, the impulse gets harder to ﬁnd. For the same reason,splitting of the second heart sound may be harder to hear in older people as its
pulmonic component becomes less audible. A physiologic third heart sound,
256 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
xyva

xyva
S1 S1 S2 S2
Systole Diastole

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5ccommonly heard in children and young adults, may persist as late as the age
of 40, especially in women. After approximately age 40, however, an S 3
strongly suggests either ventricular failure or volume overload of the ventri-cle from valvular heart disease such as mitral regurgitation. In contrast, afourth heart sound is seldom heard in young adults unless they are well con-
ditioned athletes. An S
4may be heard in apparently healthy older people,
but is also frequently associated with decreased ventricular compliance fromheart disease. (See Table 7-5, Extra Heart Sounds in Diastole, p. __.)
Cardiac Murmurs. At some time over the life span, almost everyone
has a heart murmur. Most murmurs occur without other evidence of
cardiovascular abnormality and may therefore be considered innocent nor-mal variants. These common murmurs vary with age, and familiarity withtheir patterns helps you to distinguish normal from abnormal.

Children, adolescents, and young adults frequently have an innocent systolic
murmur, often called a ﬂow murmur, that is felt to reﬂect pulmonic blood
ﬂow. It is usually heard best in the 2nd to 4th left interspaces (see p. __).
Late in pregnancy and during lactation, many women have a so-called mam-
mary soufﬂe
‡secondary to increased blood ﬂow in their breasts. Although
this murmur may be noted anywhere in the breasts, it is often heard mosteasily in the 2nd or 3rd interspace on either side of the sternum. A mam-mary soufﬂe is typically both systolic and diastolic, but sometimes only thelouder systolic component is audible.
Middle-aged and older adults commonly have an aortic systolic murmur.

This has been heard in about a third of people near the age of 60, and in wellover half of those reaching 85. Aging thickens the bases of the aortic cuspswith ﬁbrous tissue, calciﬁcation follows, and audible vibrations result. Tur-bulence produced by blood ﬂow into a dilated aorta may contribute to thismurmur. In most people, this process of ﬁbrosis and calciﬁcation—knownas aortic sclerosis —does not impede blood ﬂow. In some, however, the valve
cusps become progressively calciﬁed and immobile, and true aortic stenosis,
or obstruction of ﬂow, develops. A normal carotid upstroke may help dis-tinguish aortic sclerosis from aortic stenosis (in which the carotid upstrokeis delayed), but clinical differentiation between benign aortic sclerosis andpathologic aortic stenosis may be difﬁcult.
A similar aging process affects the mitral valve, usually about a decade later

than aortic sclerosis. Here degenerative changes with calciﬁcation of the mi-tral annulus, or valve ring, impair the ability of the mitral valve to close nor-mally during systole, and cause the systolic murmur of mitral regurgitation.
Because of the extra load placed on the heart by the leaking mitral valve, amurmur of mitral regurgitation cannot be considered innocent.
Murmurs may originate in large blood vessels as well as in the heart. The
jugular venous hum, which is very common in children and may still be heard
through young adulthood, illustrates this point (see p. __). A second, moreANATOMY AND PHYSIOLOGY
CHAPTER 7 ITHE CARDIOVASCULAR SYSTEM 257‡Soufﬂe is pronounced soó-ﬂ, not like cheese soufﬂé. Both words come from a French word meaning puff.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cimportant example is the cervical systolic murmur or bruit. In older people,
systolic bruits heard in the middle or upper portions of the carotid arteriessuggest, but do not prove, a partial arterial obstruction secondary to athero-sclerosis. In contrast, cervical bruits in younger people are usually innocent.In children and young adults, systolic murmurs (bruits) are frequently heardjust above the clavicle. Studies have shown that, while cervical bruits can beheard in almost 9 out of 10 children under the age of 5, their prevalence fallssteadily to about 1 out of 3 in adolescence and young adulthood and to lessthan 1 out of 10 in middle age.
Arteries and Blood Pressure. The aorta and large arteries stiffen with
age as they become atherosclerotic. As the aorta becomes less distensible, agiven stroke volume causes a greater rise in systolic blood pressure; systolic

hypertension with a widened pulse pressure often ensues. Peripheral arteries
tend to lengthen, become tortuous, and feel harder and less resilient.These changes do not necessarily indicate atherosclerosis, however, andyou can make no inferences from them as to disease in the coronary orcerebral vessels. Lengthening and tortuosity of the aorta and its branchesoccasionally result in kinking or buckling of the carotid artery low in theneck, especially on the right. The resulting pulsatile mass, which occurschiefly in hypertensive women, may be mistaken for a carotid aneurysm—a true dilatation of the artery. A tortuous aorta occasionally raises the pres-sure in the jugular veins on the left side of the neck by impairing theirdrainage within the thorax.
In Western societies, systolic blood pressure tends to rise from childhood

through old age. Diastolic blood pressure stops rising, however, roughlyaround the sixth decade. On the other extreme, some elderly people developan increased tendency toward postural (orthostatic) hypotension —a sudden
drop in blood pressure when they rise to a sitting or standing position. El-derly people are also more likely to have abnormal heart rhythms. These ar-rhythmias, like postural hypotension, may cause syncope, or temporary loss
of consciousness.THE HEALTH HISTORY
258 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGSee Table 6-1, Chest Pain, 
pp. __–__.
IChest Pain
IPalpitations
IShortness of breath, orthopnea, or paroxysmal dyspnea
ISwelling or edema
Chest pain or discomfort is one of the most important symptoms you will as-

sess as a clinician. As you listen to the patient’s story, you must always keepserious adverse events in mind, such as angina pectoris, myocardial infarc-
tion, or even a dissecting aortic aneurysm. This section approaches chest symp-EXAMPLES OF ABNORMALITIES

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5ctoms from the cardiac standpoint, including chest pain, palpitations, orthop-
nea, paroxysmal nocturnal dyspnea (PND), and edema. For this complaint,however, it is wise to think through the range of possible cardiac, pulmonary,and extrathoracic etiologies. You should review the Health History section ofChapter 6, The Thorax and Lungs, which enumerates the various possiblesources of chest pain: the myocardium, the pericardium, the aorta, the tracheaand large bronchi, the parietal pleura, the esophagus, the chest wall, and ex-trathoracic structures such as the neck, gallbladder, and stomach. This reviewis important, since symptoms such as dyspnea, wheezing, cough, and even he-moptysis (see pp.__–__) can be cardiac as well as pulmonary in origin.
Your initial questions should be broad . . . “Do you have any pain or dis-

comfort in your chest?” Ask the patient to point to the pain and to describeall seven of its attributes. After listening closely to the patient’s description,move on to more speciﬁc questions such as “Is the pain related to exertion?”and “What kinds of activities bring on the pain?” Also “How intense is thepain, on a scale of 1 to 10?” . . . “Does it radiate into the neck, shoulder,back, or down your arm?” . . . “Are there any associated symptoms likeshortness of breath, sweating, palpitations, or nausea?” . . . “Does it everwake you up at night?” . . . “What do you do to make it better?”
Palpitations are an unpleasant awareness of the heartbeat. When reporting

these sensations, patients use various terms such as skipping, racing, flut-tering, pounding, or stopping of the heart. Palpitations may result from anirregular heartbeat, from rapid acceleration or slowing of the heart, or fromincreased forcefulness of cardiac contraction. Such perceptions, however,also depend on the sensitivities of patients to their own body sensations.Palpitations do not necessarily mean heart disease. In contrast, the mostserious dysrrhythmias, such as ventricular tachycardia, often do not pro-duce palpitations.
You may ask directly about palpitations, but if the patient does not under-

stand your question, reword it. “Are you ever aware of your heartbeat? Whatis it like?” Ask the patient to tap out the rhythm with a hand or ﬁnger. Wasit fast or slow? Regular or irregular? How long did it last? If there was anepisode of rapid heartbeats, did they start and stop suddenly or gradually?(For this group of symptoms, an electrocardiogram is indicated.)
You may wish to teach selected patients how to make serial measurements
of their pulse rates in case they have further episodes.
Shortness of breath is a common patient concern and may be reported as dys-
pnea, orthopnea, or paroxysmal nocturnal dyspnea. Dyspnea is an uncomfort-
able awareness of breathing that is inappropriate to a given level of exertion.This complaint is often made by patients with cardiac and/or pulmonaryproblems, as discussed in Chapter 6, The Thorax and Lungs, p. __.

Orthopnea is dyspnea that occurs when the patient is lying down and im-
proves when the patient sits up. Classically, it is quantiﬁed according to theTHE HEALTH HISTORY
CHAPTER 7 ITHE CARDIOVASCULAR SYSTEM 259Exertional chest pain with radiation
to the left side of the neck anddown the left arm in angina pectoris;
sharp pain radating into the back orinto the neck in aortic dissection.
See Table 3-10 and 3-11 for 
selected heart rates and rhythms(pp. __–__)
Symptoms or signs of irregular
heart action warrant an electrocar-diogram. Only atrial ﬁbrillation,
which is “irregularly irregular,” canbe reliably identiﬁed at the bedside.
Clues in the history include tran-
sient skips and ﬂipﬂops (possiblepremature contractions); rapid reg-ular beating of sudden onset andoffset (possible paroxysmalsupraventricular tachycardia); a rapid regular rate of less than 120 beats per minute, especially if starting and stopping more grad-ually (possible sinus tachycardia).

Orthopnea suggests left ventricular
heart failure or mitral stenosis; itEXAMPLES OF ABNORMALITIES

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cnumber of pillows the patient uses for sleeping, or by the fact that the pa-
tient needs to sleep sitting up. (Make sure, however, that the patient usesextra pillows or sleeps upright because of shortness of breath when supineand not for other reasons.)
Paroxysmal nocturnal dyspnea, or PND, describes episodes of sudden dyspnea
and orthopnea that awaken the patient from sleep, usually 1 or 2 hours aftergoing to bed, prompting the patient to sit up, stand up, or go to a window forair. There may be associated wheezing and coughing. The episode usually sub-sides but may recur at about the same time on subsequent nights.
Edema refers to the accumulation of excessive ﬂuid in the interstitial tissue

spaces and appears as swelling. Questions about edema are typically includedin the cardiac history, but edema has many other causes, both local and gen-eral. Focus your questions on the location, timing, and setting of theswelling, and on associated symptoms. “Have you had any swelling any-where? Where? . . . Anywhere else? When does it occur? Is it worse in themorning or at night? Do your shoes get tight?”
Continue with “Are the rings tight on your ﬁngers? Are your eyelids puffy
or swollen in the morning? Have you had to let out your belt?” Also, “Haveyour clothes gotten too tight around the middle?” It is useful to ask patientswho retain ﬂuid to record daily morning weights, since edema may not beobvious until several liters of extra ﬂuid have accumulated.HEALTH PROMOTION AND COUNSELING
260 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGmay also accompany obstructive
lung disease .

PND suggests left ventricular heart
failure or mitral stenosis and may
be mimicked by nocturnal asthma
attacks.
See Table __, Mechanisms and 
Patterns of Edema, pp. __–__.
Dependent edema appears in the
lowest body parts (the feet andlower legs) when sitting or thesacrum when bedridden. Causesmay be cardiac (congestive heartfailure), nutritional (hypoalbu-minemia), or positional.
Edema occurs in renal and liver dis-
ease: periorbital pufﬁness, tightrings in nephrotic syndrome; en-
larged waistline from ascites and
liver failure.
Despite improvements in risk factor modiﬁcation, cardiovascular disease re-
mains the leading cause of death for both men and women, accounting forabout one third of all U.S. deaths. Both primary prevention, in those with-
out evidence of cardiovascular disease, and secondary prevention, in those

with known cardiovascular events such as angina or myocardial infarction,remain important priorities for the ofﬁce, the hospital, and the nation’s pub-lic health. Education and counseling will guide your patients to maintain op-timal levels of cholesterol, weight, and exercise.Common or Concerning Symptoms
ICholesterol level
ILifestyle management: diet, weight reducgtion, exercise, smoking
IScreening for hypertensionEXAMPLES OF ABNORMALITIES

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cIn May 2001 the National Heart, Lung, and Blood Institute of the National
Institutes of Health published the Third Report of the National CholesterolEducation Program Expert Panel, which sets standards for the detection,evaluation, and treatment of high cholesterol levels in adults.
§Students and
clinicians are well-advised to review the Panel’s recommended guidelines,which can be summarized only brieﬂy here.
First, obtain a fasting lipid proﬁle in all adults aged 20 years or older once
every 5 years. Your counseling and interventions should be based on thepatient’s levels of low- and high-density lipoproteins, or LDL and HDL,and on the presence of cardiac risk factors. The report notes that the risk ofcardiac disease increases continuously as the LDL levels range from low tohigh. It sets new targets for optimal lipid levels (mg/dL):
ILDL cholesterol <100
ITotal cholesterol <200
IHDL cholesterol <40 is low; ≥60 is high

Second, assess additional major risk factors and “risk equivalents.” Risk factors
are smoking, hypertension if blood pressure is greater than 140/90 mm Hgor the patient is on medication, HDL less than 40 mg/dL, family history ofpremature coronary heart disease (affected male ﬁrst degree relative youngerthan 55 years; affected female younger than 65 years), and age, namely men45 years or older and women 55 years or older. Risk equivalents include di-
abetes; other forms of atherosclerotic disease—peripheral vascular disease,abdominal aortic aneurysm, and symptomatic carotid artery disease; and 2or more risk factors, raising the 10-year risk of coronary heart disease tomore than 20%. The report includes tables for assessing 10-year risk for menand for women if multiple risk factors are present.
The desired goal for the patient’s LDL level varies according to the number
of risk factors, as shown below.

Risk Category LDL Level Goal (mg/dL)
0–1 risk factor <160
2+ or multiple risk factors <130
Coronary heart disease (CHD) <100
or CHD risk equivalents
Additional treatment is recommended if the triglyceride level exceeds 
200 mg/dL.
Once risk is assessed, your advice about risk reduction should cover lifestyle
changes, including diet, weight reduction, and exercise, as well as drug ther-HEALTH PROMOTION AND COUNSELING
CHAPTER 7 ITHE CARDIOVASCULAR SYSTEM 261§Third Report of the National Cholesterol Education Program (NCEP) Expert Panel. Detection, Eval-
uation, and Treatment of High Blood Cholesterol in Adults—Executive Summary. National CholesterolEducation Program, National Heart, Lung, and Blood Institute, National Institutes of Health. NIHPublication No. 01-3670. May 2001. www.nhbi.nih.gov/guidelines/cholesterol/index.htm
. Accessed
8/31/01.

262 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGapy when indicated. Dietary recommendations should begin with a dietary
history (see pp.__–__), then target low intake of saturated fats (less than 7%of total calories) and cholesterol (less than 200 mg per day) and high intakeof ﬁber, up to 20 to 30 grams per day. Together with the patient, review thebasic principles for all healthy diets: high intake of fruits, vegetables, andgrains; use of low-fat dairy products and lean meats, substituting chickenand fish when possible; and minimal intake of processed food and addedsalt and sugar, both when cooking and at the table. Eggs with yolks, themost concentrated source of cholesterol, should be limited to two to fourper week. Sources of ﬁber include whole-grain breads; pasta; and oat, wheat,corn, or multigrain cereals.
For counseling about weight, apply the principles for assessing body mass

index enumerated in Chapter 3 (pp. __–__). To maintain a desirable body
weight, energy expended must balance calories consumed. Excess caloriesare stored as fat. Metabolism of food fat, which contains 9 calories of po-tential energy per gram, uses up fewer calories than metabolism of foodshigh in carbohydrate or protein, which provide 4 calories of energy pergram. Patients with high fat intake are more likely to accumulate body fatthan patients with increased protein and carbohydrate intake (and patientswith low-fat diets may lose weight more quickly). Review the patient’s eat-ing habits and weight patterns in the family. Set realistic goals that will helpthe patient maintain healthy eating patterns for life.
Regular exercise is the number one recommendation of the U.S. Public
Health Service’s Healthy People 2000. To reduce risk for coronary artery dis-

ease, counsel patients to pursue aerobic exercise, or exercise that increases mus-
cle oxygen uptake. ( Anaerobic exercise relies on energy sources within con-
tracting muscles rather than inhaled oxygen and is usually nonsustained.)Deep breathing, sweating in cool temperatures, and pulse rates exceeding 60%of the maximum normal age-adjusted heart rate (220 minus the person’s age)are markers of aerobic exercise. Since the cardiovascular beneﬁts of exerciseare long term, to help motivate patients be sure to emphasize that the patientwill look and feel better as soon as exercise begins. Before selecting an exer-cise regimen, do a thorough evaluation of any cardiovascular, pulmonary, ormusculoskeletal conditions presenting a risk for exercise. Guiding the patientto make time to exercise as a regular activity is often more important than the

type of exercise chosen. For cardiovascular beneﬁt, patients should exerise for20 to 60 minutes at least 3 times a week. For patients losing weight, para-doxically, the metabolic rate may drop when caloric intake declines, known asthe starvation response. Regular exercise will counteract this response.
During the physical examination, it is important to screen for hypertension
and for lipid-containing nodules on the skin, known as xanthomas. Hyper-
tension (see p. __) contributes significantly to death from CHD andstroke. Recommended blood pressure screening for healthy adults is gen-erally once every 2 years. Search for xanthomas in patients with familiallipoprotein disorders. These may appear around the eyelids, over extensortendons, and occasionally as small eruptive papules on the extremities, but-tocks, and trunk.

CHAPTER 7 ITHE CARDIOVASCULAR SYSTEM 263Preview: Recording the Physical Examination—
The Cardiovascular Examination
Note that initially you may use sentences to describe your ﬁndings; later you will
use phrases. The style below contains phrases appropriate for most write-
ups. Unfamiliar terms are explained in the next section, Techniques of Ex-amination.
“The jugular venous pulse (JVP) is 3 cm above the sternal angle with
the head of bed elevated to 30 °. Carotid upstrokes are brisk, without
bruits. The point of maximal impulse (PMI) is tapping, 7 cm lateral tothe midsternal line in the 5th intercostal space. Good S
1and S 2. No
murmurs or extra sounds.”
OR
“The JVP is 5 cm above the sternal angle with the head of bed elevated
to 50°. Carotid upstrokes are brisk; a bruit is heard over the left carotid

1and S 2. No
OR
artery. The PMI is diffuse, 3 cm in diameter, palpated at the anterior ax-illary line in the 5th and 6th intercostal spaces. S
1and S 2are soft. S 3pre-
sent. Harsh 2/6 holosystolic murmur best heard at the apex, radiatingto the lower left sternal border (LLSB). No S
4or diastolic murmurs.”Suggests possible congestive heart
failure with possible left carotid oc-clusion and mitral regurgitationEXAMPLES OF ABNORMALITIES

264 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
As you begin the cardiovascular examination, review the blood pressure and
heart rate recorded during the General Survey and Vital Signs at the start ofthe physical examination. If you need to repeat these measurements, or if theyhave not already been done, take the time to measure the blood pressure andheart rate using optimal technique (see Chapter 3, Beginning the Physical Ex-amination: General Survey and Vital Signs, especially pp. __–__).
In brief, for blood pressure, after letting the patient rest for at least 5 minutes in

a quiet setting, choose a correctly sized cuff and position the patient’s arm atheart level, either resting on a table if seated or supported at midchest level ifstanding. Make sure the bladder of the cuff is centered over the brachial artery.Inﬂate the cuff about 30 mm Hg above the pressure at which the radial pulsedisappears. As you deﬂate the cuff, listen ﬁrst for the sounds of at least two con-secutive heartbeats—these mark the systolic pressure. Then listen for the dis-
appearance point of the heartbeats, which marks the diastolic pressure. For
heart rate, measure the radial pulse using the pads of your index and middle
ﬁngers, or assess the apical pulse using your stethoscope (see pp. __–__).
Now you are ready to systematically assess the components of the cardio-
vascular system:
IThe jugular venous pressure
IThe carotid upstrokes and presence or absence of bruits

IThe point of maximal impulse (PMI) and any heaves, lifts, or thrills
IThe ﬁrst and second heart sounds, S 1and S 2
IPresence or absence of extra heart sounds such as S 3or S 4
IPresence or absence of any cardiac murmurs.
Jugular Venous Pressure and Pulsations
Jugular Venous Pressure (JVP). Estimating the JVP is one of the most

important and frequently used skills of physical examination. At ﬁrst it will seemdifﬁcult, but with practice and supervision you will ﬁnd that the JVP providesvaluable information about the patient’s volume status and cardiac function.As you have learned, the JVP reﬂects pressure in the right atrium, or centralvenous pressure, and is best assessed from pulsations in the right internal jugu-lar vein. Note, however, that the jugular veins and pulsations are difﬁcult tosee in children younger than 12 years of age, so they are not useful for evalu-ating the cardiovascular system in this age group (see Chapter 17, pp. __–__).
To assist you in learning this portion of the cardiac examination, steps for

assessing the JVP are outlined on the next page. As you begin your assess-ment, take a moment to reﬂect on the patient’s volume status and considerhow you may need to alter the elevation of the head of the bed or examin-

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cEXAMPLES OF ABNORMALITIES
ing table. The usual starting point for assessing the JVP is to elevate the head
of the bed to 30 °. Identify the external jugular vein on each side, then ﬁnd
the internal jugular venous pulsations transmitted from deep in the neck tothe overlying soft tissues. The JVP is the elevation at which the highest os-cillation point, or meniscus, of the jugular venous pulsations is usually evi-dent in euvolemic patients. In patients who are hypovolemic, you may antici-
pate that the JVP will be low, causing you to subsequently lower the head of the
bed,sometimes even to 0 °, to see the point of oscillation best. Likewise, in
volume-overloaded or hypervolemic patients, you may anticipate that the JVP
will be high, causing you to subsequently raise the head of the bed.TECHNIQUES OF EXAMINATION
CHAPTER 7 ITHE CARDIOVASCULAR SYSTEM 265A hypovolemic patient may have

to lie ﬂat before you see the veins.In contrast, when jugular venouspressure is increased, an elevationup to 60 °or even 90 °may be re-
quired. In all these positions, thesternal angle usually remains about5 cm above the right atrium, as di-agrammed on p. __.
The following features help to distinguish jugular from carotid artery
pulsations:STEPS FOR ASSESSING THE JUGULAR VENOUS PRESSURE (JVP)
IMake the patient comfortable. Raise the head slightly on a pillow to relax the
sternomastoid muscles.
IRaise the head of the bed or examining table to about 30 °. Turn the patient’s head
slightly away from the side you are inspecting.
IUse tangential lighting and examine both sides of the neck. Identify the external
jugular vein on each side, then ﬁnd the internal jugular venous pulsations.

IIf necessary, raise or lower the head of the bed until you can see the oscillation point
or meniscus of the internal jugular venous pulsations in the lower half of the neck.
IFocus on the right internal jugular vein. Look for pulsations in the suprasternal
notch, between the attachments of the sternomastoid muscle on the sternumand clavicle, or just posterior to the sternomastoid. The table below helps youdistinguish internal jugular pulsations from those of the carotid artery.
IIdentify the highest point of pulsation in the right internal jugular vein. Extend a

long rectangular object or card horizontally from this point and a centimeterruler vertically from the sternal angle, making an exact right angle. Measure thevertical distance in centimeters above the sternal angle where the horizontalobject crosses the ruler. This distance, measured in centimeters above the sternal
angle or the atrium, is the JVP.
Internal Jugular Pulsations Carotid Pulsations 
Rarely palpable
Soft, rapid, undulating quality, usually 
with two elevations and two troughs per heart beat
Pulsations eliminated by light pressure 
on the vein(s) just above the sternal end of the clavicle
Level of the pulsations changes with 
position, dropping as the patient becomes more upright.
Level of the pulsations usually descends 
with inspiration.Palpable
A more vigorous thrust with a single
outward component
Pulsations not eliminated by this pressure
Level of the pulsations unchanged by
position

position
Level of the pulsations not affected by
inspiration

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cVenous pressure measured at greater than 3 cm or possibly 4 cm above the
sternal angle, or more than 8 cm or 9 cm in total distance above the rightatrium, is considered elevated above normal.
If you are unable to see pulsations in the internal jugular veins, look for them
in the external jugulars, although they may not be visible here. If you seenone, use the point above which the external jugular veins appear to collapse.
Make this observation on each side of the neck. Measure the vertical distanceof this point from the sternal angle.
The highest point of venous pulsations may lie below the level of the sternal
angle. Under these circumstances, venous pressure is not elevated and sel-dom needs to be measured.
Even though students may not see clinicians making these measurements

very frequently in clinical settings, practicing exact techniques for measur-ing the JVP is important. Eventually, with experience, clinicians and cardi-ologists come to identify the JVP and estimate its height visually.
Jugular Venous Pulsations. Observe the amplitude and timing of the
jugular venous pulsations. In order to time these pulsations, feel the left
carotid artery with your right thumb or listen to the heart simultaneously.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
266 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGEstablishing the true vertical and horizontal lines to measure the JVP is dif-

ﬁcult, much like the problem of hanging a picture straight when you are closeto it. Place your ruler on the sternal angle and line it up with something inthe room that you know to be vertical. Then place a card or rectangularobject at an exact right angle to the ruler. This constitutes your horizontalline. Move it up or down—still horizontal—so that the lower edge rests atthe top of the jugular pulsations, and read the vertical distance on the ruler.Round your measurement off to the nearest centimeter.Increased pressure suggests right-
sided heart failure or, less com-monly, constrictive pericarditis,tricuspid stenosis, or superior venacava obstruction.
In patients with obstructive lung
disease, venous pressure may appear elevated on expiration only;the veins collapse on inspiration.This finding does not indicatecongestive heart failure.

Unilateral distention of the external
jugular vein is usually due to localkinking or obstruction. Occasion-ally, even bilateral distention has alocal cause.
Prominent awaves indicate 
increased resistance to right atrialcontraction, as in tricuspid stenosis

The awave just precedes S 1and the carotid pulse, the xdescent can be seen
as a systolic collapse, the vwave almost coincides with S 2, and the ydescent
follows early in diastole. Look for absent or unusually prominent waves.
Considerable practice and experience are required to master jugular venous
pulsations. A beginner is probably well-advised to concentrate primarily onjugular venous pressure.
The Carotid Pulse
After you measure the JVP, move on to assessment of the carotid pulse. The
carotid pulse provides valuable information about cardiac function and is es-pecially useful for detecting stenosis or insufﬁciency of the aortic valve. Takethe time to assess the quality of the carotid upstroke, its amplitude and con-tour, and presence or absence of any overlying thrills or bruits.
To assess amplitude and contour, the patient should be lying down with the

head of the bed still elevated to about 30 °. When feeling for the carotid
artery, ﬁrst inspect the neck for carotid pulsations. These may be visible justmedial to the sternomastoid muscles. Then place your left index and middleﬁngers (or left thumb
||) on the right carotid artery in the lower third of the
neck, press posteriorly, and feel for pulsations.
CHAPTER 7 ITHE CARDIOVASCULAR SYSTEM 267or, more commonly, the decreased
compliance of a hypertrophiedright ventricle. The awaves 
disappear in atrial ﬁbrillation.Larger vwaves characterize 
tricuspid regurgitation.
For irregular rhythms, see 
Table 3-10, Selected Heart Ratesand Rhythms (p. __), and Table 3-4,Selected Irregular Rhythms (p.__).
A tortuous and kinked carotid
artery may produce a unilateralpulsatile bulge.
Decreased pulsations may be

caused by decreased stroke volume,but may also be due to local factorsin the artery such as atheroscleroticnarrowing or occlusion.
a
xyv
S1 S1S2 S2
||Although there is a widespread prejudice against using thumbs to assess pulses, they are useful for pal-
pating large arteries.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cPress just inside the medial border of a well-relaxed sternomastoid muscle,
roughly at the level of the cricoid cartilage. Avoid pressing on the carotid
sinus, which lies at the level of the top of the thyroid cartilage. For the left
carotid artery, use your right fingers or thumb. Never press both carotidsat the same time. This may decrease blood flow to the brain and inducesyncope.
Slowly increase pressure until you feel a maximal pulsation, then slowly de-
crease pressure until you best sense the arterial pressure and contour. Try toassess:
IThe amplitude of the pulse. This correlates reasonably well with the pulse
pressure.
IThe contour of the pulse wave, namely the speed of the upstroke, the du-
ration of its summit, and the speed of the downstroke. The normal up-stroke is brisk. It is smooth, rapid, and follows S
1almost immediately. The

summit is smooth, rounded, and roughly midsystolic. The downstroke isless abrupt than the upstroke.
IAny variations in amplitude, either from beat to beat or with respiration.
Thrills and Bruits. During palpation of the carotid artery, you may de-
tect humming vibrations, or thrills, that feel like the throat of a purring cat.
Routinely, but especially in the presence of a thrill, you should listen overboth carotid arteries with the diaphragm of your stethoscope for a bruit, a
murmur-like sound of vascular rather than cardiac origin.
You should also listen for bruits over the carotid arteries if the patient is
middle-aged or elderly or if you suspect cerebrovascular disease. Ask the pa-tient to hold breathing for a moment so that breath sounds do not obscurethe vascular sound. Heart sounds alone do not constitute a bruit.

Further examination of arterial pulses is described in Chapter 14, The Pe-
ripheral Vascular System.
The Brachial Artery. The ca-
rotid arteries reﬂect aortic pulsationsmore accurately, but in patients withcarotid obstruction, kinking, or thrills,they are unsuitable. If so, assess thepulse in the brachial artery, applying
the techniques described above fordetermining amplitude and contour.
Use the index and middle ﬁngers or
thumb of your opposite hand. Cup TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
268 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGPressure on the carotid sinus may
cause a reﬂex drop in pulse rate orblood pressure.
Arterial Pulse and Pressure Waves(p. __).
Small, thready, or weak pulse in
cardiogenic shock; bounding pulse
in aortic insufﬁciency (see p. __).
Delayed carotid upstroke in aortic
stenosis
Pulsus alternans, bigeminal pulse
(beat-to-beat variation); paradoxi-cal pulse (respiratory variation)

stenosis
A carotid bruit with or without a
thrill in a middle-aged or older per-son suggests but does not provearterial narrowing. An aortic mur-mur may radiate to the carotidartery and sound like a bruit.

your hand under the patient’s elbow and feel for the pulse just medial to the
biceps tendon. The patient’s arm should rest with the elbow extended, palmup. With your free hand, you may need to ﬂex the elbow to a varying degreeto get optimal muscular relaxation.
The Heart
For most of the cardiac examination, the patient should be supine with theupper body raised by elevating the head of the bed or table to about 30°.Two other positions are also needed: (1) turning to the left side, and (2)leaning forward. The examiner should stand at the patient’s right side.
The table below summarizes patient positions and a suggested sequence for
the examination.
CHAPTER 7 ITHE CARDIOVASCULAR SYSTEM 269Accentuated Findings
Low-pitched extra sounds (S 3, opening
snap, diastolic rumble of mitralstenosis)
Soft decrescendo diastolic murmur of
aortic insufﬁciencyPatient Position Examination

Supine, with the head elevated 30°
Left lateral decubitus
Supine, with the head elevated 30 °
Sitting, leaning forward, after 
full exhalationInspect and palpate the precordium: the 2nd
interspaces; the right ventricle; and the leftventricle, including the apical impulse(diameter, location, amplitude, duration).
Palpate the apical impulse if not previously
detected. Listen at the apex with the bell ofthe stethoscope.
Listen at the tricuspid area with the bell.Listen at all the auscultatory areas with the
diaphragm.
Listen along the left sternal border and at the
apex.Sequence of the Cardiac Examination
During the cardiac examination, remember to correlate your ﬁndings with

the patient’s jugular venous pressure and carotid pulse. It is also importantto identify both the anatomic location of your ﬁndings and their timing inthe cardiac cycle.
INote the anatomic location of sounds in terms of interspaces and their dis-
tance from the midsternal, midclavicular, or axillary lines. The midsternal lineoffers the most reliable zero point for measurement, but some feel that themidclavicular line accommodates the different sizes and shapes of patients.
IIdentify the timing of impulses or sounds in relation to the cardiac cycle.
Timing of sounds is often possible through auscultation alone. In mostpeople with normal or slow heart rates, it is easy to identify the pairedheart sounds by listening through a stethoscope. S
1is the ﬁrst of these

sounds, S 2is the second, and the relatively long diastolic interval separates
one pair from the next.

270 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGThe relative intensity of these sounds may also be helpful. S 1is usually louder
than S 2at the apex; more reliably, S 2is usually louder than S 1at the base.
Even experienced clinicians are sometimes uncertain about the timing of
what they hear, especially when they encounter extra heart sounds and mur-murs. “Inching” can then be helpful. Return to a place on the chest—mostoften the base—where it is easy to identify S
1and S 2. Get their rhythm clearly
in mind. Then inch your stethoscope down the chest in steps until you hearthe new sound.
Auscultation alone, however, can be misleading. The intensities of S
1and S 2,

1and S 2,
for example, may be abnormal. At rapid heart rates, moreover, diastoleshortens, and at about a rate of 120 the durations of systole and diastole be-come indistinguishable. Use palpation of either the carotid pulse or the api-
cal impulse to guide the timing of your observations. Both occur in early sys-
tole, right after the ﬁrst heart sound.
INSPECTION AND PALPATION
Careful inspection of the anterior chest may reveal the location of the apical
impulse orpoint of maximal impluse (PMI), or less commonly, the ventric-
ular movements of a left-sided S 3or S 4. Tangential light is best for making
these observations.
Use palpation to conﬁrm the characteristics of the apical impulse. Palpation
is also valuable for detecting thrills and the ventricular movements of an S 3

or S 4. Be sure to assess the right ventricle by palpating the right ventricular
area at the lower left sternal border and in the subxiphoid area, the pul-monary artery in the left 2nd interspace, and the aortic area in the right 2ndinterspace. Review the diagram on the next page. Note that the “areas” des-
ignated for the left and right ventricle, the pulmonary artery, and the aortapertain to the majority of patients whose hearts are situated in the left chest,with normal anatomy of the great vessels.
Begin with general palpation of the chest wall. First palpate for impulses using
your ﬁngerpads. Hold them ﬂat or obliquely on the body surface, using lightpressure for an S
3or S 4, and ﬁrmer pressure for S 1and S 2. Ventricular impulses

may heave or lift your ﬁngers. Then check for thrills by pressing the ball of
your hand ﬁrmly on the chest. If subsequent auscultation reveals a loud mur-mur, go back and check for thrills over that area again.For example, S 1is decreased in
ﬁrst-degree heart block, and S 2is
decreased in aortic stenosis.
SystoleS1 S2 S1 S2
Thrills may accompany loud,
harsh, or rumbling murmurs as in aortic stenosis, patent ductus arteriosus, ventricular septal defect,and, less commonly, mitral stenosis.They are palpated more easily inpatient positions that accentuatethe murmur.

CHAPTER 7 ITHE CARDIOVASCULAR SYSTEM 271On rare occasions, a patient has
dextrocardia —a heart situated on
the right side. The apical impulsewill then be found on the right. Ifyou cannot ﬁnd an apical impulse,percuss for the dullness of heartand liver and for the tympany ofthe stomach. In situs inversus, all
three of these structures are onopposite sides from normal. Aright-sided heart with a normallyplaced liver and stomach is usuallyassociated with congenital heartdisease.
Apex left
ventricularareaRight 2ndinterspace—aorticareaLeft 2nd
interspace—pulmonic area
Epigastric
(subxiphoid)Left sternalborder rightventriculararea
The Apical Impulse or Point of Maximal Impulse (PMI)—Left
Ventricular Area. The apical impulse represents the brief early pulsation

of the left ventricle as it moves anteriorly during contraction and touches thechest wall. Note that in most examinations the apical impulse is the point ofmaximal impulse, or PMI; however, some pathologic conditions may pro-duce a pulsation that is more prominent than the apex beat, such as an en-larged right ventricle, a dilated pulmonary artery, or an aneurysm of the aorta.
If you cannot identify the apical impulse with the patient supine, ask the pa-
tient to roll partly onto the left side—this is the left lateral decubitus position.

Palpate again using the palmar surfaces of several ﬁngers. If you cannot ﬁndthe apical impulse, ask the patient to exhale fully and stop breathing for a fewseconds. When examining a woman, it may be helpful to displace the leftbreast upward or laterally as necessary; alternatively, ask her to do this for you.EXAMPLES OF ABNORMALITIES

272 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGOnce you have found the apical impulse, make ﬁner assessments with your
ﬁngertips, and then with one ﬁnger.
With experience, you will learn to feel the apical impulse in a high percent-
age of patients, but obesity, a very muscular chest wall, or an increased an-teroposterior diameter of the chest may make it undetectable. Some apicalimpulses hide behind the rib cage, despite positioning.
Now assess the location, diameter, amplitude, and duration of the apical im-
pulse. You may wish to have the patient breathe out and brieﬂy stop breath-ing to check your ﬁndings.
ILocation. Try to assess location with the patient supine, since the left lat-

eral decubitus position displaces the apical impulse to the left. Locate twopoints: the interspaces, usually the 5th or possibly the 4th, which give thevertical location; and the distance in centimeters from the midsternal line,which gives the horizontal location. (Note that even though the apical im-pulse normally falls roughly at the midclavicular line, measurements fromthis line are less reproducible since clinicians vary in their estimates of themidpoint of the clavicle.)See Table 7-1, Variations and 
Abnormalities of the VentricularImpulses (p. __).
The apical impulse may be dis-
placed upward and to the left by
pregnancy or a high left diaphragm.
Lateral displacement from cardiac

enlargement in congestive heartfailure, cardiomyopathy, ischemicheart disease. Displacement in deformities of the thorax and mediastinal shift.
Apical
pulse
Midsternal lineMidclavicular
line2
3
4
5

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cEXAMPLES OF ABNORMALITIES TECHNIQUES OF EXAMINATION
CHAPTER 7 ITHE CARDIOVASCULAR SYSTEM 273IDiameter. Assess the diameter of the apical impulse. In the supine patient,
it usually measures less than 2.5 cm and occupies only one interspace. Itmay be larger in the left lateral decubitus position.
IAmplitude. Estimate the amplitude of the impulse. It is usually small and
feels brisk and tapping . Some young persons have an increased amplitude,
or hyperkinetic impulse, especially when excited or after exercise; its du-ration, however, is normal.In the left lateral decubitus position,
a diameter greater than 3 cm indi-cates left ventricular enlargement.
Increased amplitude may also reﬂect
hyperthyroidism, severe anemia,pressure overload of the left ven-tricle (e.g., aortic stenosis), or vol-ume overload of the left ventricle(e.g., mitral regurgitation).
A sustained, high-amplitude impulse

that is normally located suggests leftventricular hypertrophy from pres-sure overload (as in hypertension). If such an impulse is displaced lat-erally, consider volume overload.
A sustained low-amplitude
(hypokinetic) impulse may resultfrom dilated cardiomyopathy.
A brief middiastolic impulse
indicates an S
3; an impulse just be-
fore the systolic apical beat itselfindicates an S
4.
Normal HyperkineticS1 S2 S1 S2
IDuration. Duration is the most useful characteristic of the apical impulse
for identifying hypertrophy of the left ventricle. To assess duration, listento the heart sounds as you feel the apical impulse, or watch the movementof your stethoscope as you listen at the apex. Estimate the proportion ofsystole occupied by the apical impulse. Normally it lasts through the ﬁrsttwo thirds of systole, and often less, but does not continue to the secondheart sound.
IS3and S 4.By inspection and palpation, you may detect ventricular move-

ments that are synchronous with pathologic third and fourth heartsounds. For the left ventricular impulses, feel the apical beat gently withone ﬁnger. The patient should lie partly on the left side, breathe out, andbrieﬂy stop breathing. By inking an X on the apex you may be able to seethese movements.
The Left Sternal Border in the 3rd, 4th, and 5th Interspaces—
Right Ventricular Area. The patient should rest supine at 30°. Place
the tips of your curved ﬁngers in the 3rd, 4th, and 5th interspaces and try tofeel the systolic impulse of the right ventricle. Again, asking the patient tobreathe out and then brieﬂy stop breathing improves your observation.
S1 S2
Normal SustainedS1 S2
S1 S2

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cA marked increase in amplitude
with little or no change in durationoccurs in chronic volume overloadof the right ventricle, as from anatrial septal defect.
An impulse with increased
amplitude and duration occurswith pressure overload of the rightventricle, as in pulmonic stenosisor pulmonary hypertension.
In obstructive pulmonary disease,
hyperinflated lung may preventpalpation of an enlarged rightventricle in the left parasternalarea. The impulse is felt easily,however, high in the epigastriumand heart sounds are also oftenheard best here.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
274 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGIf an impulse is palpable, assess its location, amplitude, and duration. A brief
systolic tap of low or slightly increased amplitude is sometimes felt in thin orshallow-chested persons, especially when stroke volume is increased, as byanxiety.

The diastolic movements of right-sided third and fourth heart sounds may
be felt occasionally. Feel for them in the 4th and 5th left interspaces. Timethem by auscultation or carotid palpation.
In patients with an increased anteroposterior (AP) diameter, palpation of the
right ventricle in the epigastric or subxiphoid area is also useful. With your
hand ﬂattened, press your index ﬁnger just under the rib cage and up towardthe left shoulder and try to feel right ventricular pulsations.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cAsking the patient to inhale and brieﬂy stop breathing is helpful. The inspi-
ratory position moves your hand well away from the pulsations of the ab-dominal aorta, which might otherwise be confusing. The diastolic move-ments of S
3and S 4, if present, may also be felt here.
The Left 2nd Interspace—Pulmonic Area. This interspace overlies
the pulmonary artery. As the patient holds expiration, look and feel for an
impulse and feel for possible heart sounds. In thin or shallow-chested pa-tients, the pulsation of a pulmonary artery may sometimes be felt here, es-pecially after exercise or with excitement.
The Right 2nd Interspace—Aortic Area. This interspace overlies
the aortic outﬂow tract. Search for pulsations and palpable heart sounds.

In most cases, palpation has replaced percussion in the estimation of cardiacsize. When you cannot feel the apical impulse, however, percussion may sug-gest where to search for it. Occasionally, percussion may be your only tool.Under these circumstances, cardiac dullness often occupies a large area.Starting well to the left on the chest, percuss from resonance toward cardiacdullness in the 3rd, 4th, 5th, and possibly 6th interspaces.
Overview. Auscultation of heart sounds and murmurs is a rewarding and
important skill of physical examination that leads directly to several clinicaldiagnoses. In this section, you will learn the techniques for identifying S
1and
S2, extra sounds in systole and diastole, and systolic and diastolic murmurs.

1and
S2, extra sounds in systole and diastole, and systolic and diastolic murmurs. 
Review the auscultatory areas on the next page with the following caveats:(1) some authorities discourage use of these names since murmurs of morethan one origin may occur in a given area; and (2) these areas may not applyto patients with dextrocardia or anomalies of the great vessels. Also, if theheart is enlarged or displaced, your pattern of auscultation should be alteredaccordingly.
Listen to the heart with your stethoscope in the right 2nd interspace close to
the sternum, along the left sternal border in each interspace from the 2nd
through the 5th, and at the apex. Recall that the upper margins of the heart

are sometimes termed the “base” of the heart. Some clinicians begin aus-cultation at the apex, others at the base. Either pattern is satisfactory. Theroom should be quiet. You should also listen in any area where you detectan abnormality and in areas adjacent to murmurs to determine where theyare loudest and where they radiate.EXAMPLES OF ABNORMALITIES TECHNIQUES OF EXAMINATION
CHAPTER 7 ITHE CARDIOVASCULAR SYSTEM 275A prominent pulsation here 
often accompanies dilatation orincreased flow in the pulmonaryartery. A palpable S
2suggests 
increased pressure in the pulmonary artery (pulmonaryhypertension).
A palpable S
2suggests systemic 
hypertension. A pulsation heresuggests a dilated or aneurysmalaorta.
A markedly dilated failing heart

may have a hypokinetic apical impulse that is displaced far to theleft. A large pericardial effusion maymake the impulse undetectable.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cHeart sounds and murmurs that
originate in the four valves are illus-trated in the diagram below. Pul-monic sounds are usually heardbest in the 2nd and 3rd left inter-spaces, but may extend further.
This position accentuates or brings
out a left-sided S
3and S 4and mitral
murmurs, especially mitral stenosis.You may otherwise miss these important ﬁndings.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
276 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGKnow your stethoscope! It is important to understand the uses of both the
diaphragm and the bell.
IThe diaphragm. The diaphragm is better for picking up the relatively high-
pitched sounds of S 1and S 2, the murmurs of aortic and mitral regurgita-
tion, and pericardial friction rubs. Listen throughout the precordium with
the diaphragm, pressing it ﬁrmly against the chest.
IThe bell. The bell is more sensitive to the low-pitched sounds of S 3and S 4

and the murmur of mitral stenosis. Apply the bell lightly, with just enough
pressure to produce an air seal with its full rim. Use the bell at the apex,
then move medially along the lower sternal border. Resting the heel of your
hand on the chest like a fulcrum may help you to maintain light pressure.
Pressing the bell ﬁrmly on the chest makes it function more like the di-
aphragm by stretching the underlying skin. Low-pitched sounds such as S 3
and S 4may disappear with this technique—an observation that may help
to identify them. In contrast, high-pitched sounds such as a midsystolicclick, an ejection sound, or an opening snap, will persist or get louder.
Listen to the entire precordium with the patient supine. For new patients

and patients needing a complete cardiac examination, use two other im-portant positions to listen for mitral stenosis and aortic regurgitation.
IAsk the patient to roll partly onto the left side into the left lateral decubitus
position, bringing the left ventricle close to the chest wall. Place the bell
of your stethoscope lightly on the apical impulse.
2nd right
interspace –aortic area2nd left
interspace –pulmonic area
Lower left
sternal border –tricuspid areaApex –mitral area
Mitral TricuspidPulmonic Aortic
(Redrawn from Leatham A: Introduction tothe Examination of the CardiovascularSystem, 2nd ed. Oxford, Oxford UniversityPress, 1979)

CHAPTER 7 ITHE CARDIOVASCULAR SYSTEM 277This position accentuates or brings
out aortic murmurs. You may easilymiss the soft diastolic murmur ofaortic regurgitation unless you usethis position.
IAsk the patient to sit up, lean forward, exhale completely, and stop breath-
ing in expiration. Pressing the diaphragm of your stethoscope on the
chest, listen along the left sternal border and at the apex, pausing period-ically so the patient may breathe.
Listening for Heart Sounds. Throughout your examination, take
your time at each auscultatory area. Concentrate on each of the events in the cardiac cycle listed on the next page and sounds you may hear insystole and diastole.

278 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGAttributes of Heart Murmurs. If you detect a heart murmur, you
must learn to identify and describe its timing, shape, location of maximal in-
tensity, radiation or transmission from this location, intensity, pitch, and
quality.
ITiming. First decide if you are hearing a systolic murmur, falling between
S1and S 2, or a diastolic murmur, falling between S 2and S 1. Palpating the
carotid pulse as you listen can help you with timing. Murmurs that coin-cide with the carotid upstroke are systolic.
Systolic murmurs are usually midsystolic or pansystolic. Late systolic murmurs
may also be heard.Diastolic murmurs usually indicate
valvular heart disease. Systolicmurmurs may indicate valvular disease, but often occur when theheart is entirely normal.See Table 7-2, Variations in the First
Heart Sound (p. __).

See Table 7-3, Variations in the Second
When either A 2or P 2is absent, as in
disease of the respective valves, S 2is
persistently single.
Expiratory splitting suggests an
abnormality (p. __).
Persistent splitting results from 
delayed closure of the pulmonic valve or early closure of the aorticvalve.
A loud P
2suggests pulmonary
The systolic click of mitral valve prolapse
is the most common of these sounds.See Table 7-4, Extra Heart Sounds inSystole (p. __).
See Table 7-5, Extra Heart Sounds 
in Diastole (p. __).
See Table 7-6, Midsystolic Murmurs
(pp. __–__), Table 7-7, Pansystolic(Holosystolic) Murmurs (p. __), and
Table 7-8, Diastolic Murmurs (p. __).Heart Sounds Guides to Auscultation
S1
S2
Split S 2
Extra Sounds
in Systole
in Diastole
Systolic and

S1
S2
Split S 2
in Systole
Diastolic MurmursNote its intensity and any apparent splitting. Normal
splitting is detectable along the lower left sternal border.
Note its intensity.Listen for splitting of this sound in the 2nd and 3rd left
interspaces. Ask the patient to breathe quietly, and thenslightly more deeply than normal. Does S
2split into its two
components, as it normally does? If not, ask the patient to(1) breathe a little more deeply, or (2) sit up. Listen again.A thick chest wall may make the pulmonic component of S
1
inaudible.
Width of split. How wide is the split? It is normally quite
narrow.
Timing of split. When in the respiratory cycle do you hear
the split? It is normally heard late in inspiration.
Does the split disappear as it should, during exhalation? If
not, listen again with the patient sitting up.

Intensity of A 2and P 2.Compare the intensity of the two
components, A 2and P 2. A2is usually louder.
Such as ejection sounds or systolic clicksNote their location, timing, intensity, and pitch, and the
effects of respiration on the sounds.
Such as S
3, S4, or an opening snap
Note the location, timing, intensity, and pitch, and the
effects of respiration on the sounds. (An S 3or S 4in athletes
is a normal ﬁnding.)
Murmurs are differentiated from heart sounds by their
longer duration.Auscultatory Sounds

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cMidsystolic murmurs most often
are related to blood ﬂow across thesemilunar (aortic and pulmonic)valves. See Table 7-6, MidsystolicMurmurs (pp. __–__).
Pansystolic murmurs often occur
with regurgitant (backward) ﬂowacross the atrioventricular valves.See Table 7-7, Pansystolic(Holosystolic) Murmurs (p. __).
This is the murmur of mitral valve
prolapse and is often, but not al-ways, preceded by a systolic click(see p. __).
Early diastolic murmurs typically
accompany regurgitant ﬂow acrossincompetent semilunar valves.
Middiastolic and presystolic mur-
murs reﬂect turbulent ﬂow acrossthe atrioventricular valves. SeeTable 7-8, Diastolic Murmurs (p. __).
The combination of systolic and di-
astolic murmurs, each with its owncharacteristics, may have similartiming. See Table 7-9, Cardiovas-cular Sounds With Both Systolicand Diastolic Components (p. __).A midsystolic murmur begins after S 1
and stops before S 2. Brief gaps are

audible between the murmur andthe heart sounds. Listen carefully forthe gap just before S
2. It is heard
more easily and, if present, usuallyconﬁrms the murmur as midsystolic,not pansystolic.
A pansystolic (holosystolic) murmur
starts with S
1and stops at S 2, without
a gap between murmur and heartsounds.
A late systolic murmur usually starts
in mid- or late systole and persists upto S
2.
Diastolic murmurs may be early diastolic, middiastolic, orlate diastolic.
An early diastolic murmur starts
right after S 2, without a discernible
gap, and then usually fades intosilence before the next S
1.
A middiastolic murmur starts a short
time after S 2. It may fade away, as 
illustrated, or merge into a late dias-tolic murmur.
A late diastolic (presystolic) murmur
starts late in diastole and typicallycontinues up to S
1.
An occasional murmur, such as the murmur of a patent ductus arteriosus,

1.
starts in systole and continues without pause through S 2into but not 
necessarily throughout diastole. It is then called a continuous murmur.
Other cardiovascular sounds, such as pericardial friction rubs or venoushums, have both systolic and diastolic components. Observe and describe
these sounds according to the characteristics used for systolic and dias-tolic murmurs.EXAMPLES OF ABNORMALITIES TECHNIQUES OF EXAMINATION
CHAPTER 7 ITHE CARDIOVASCULAR SYSTEM 279
S1 S1 S2
S1 S1 S2
S1 S1 S2
S1
S1
S1S2
S2
S2

280 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGIShape . The shape or conﬁguration of a murmur is determined by its in-
tensity over time.
A crescendo murmur grows louder.
A decrescendo murmur grows softer.
A crescendo–descrescendo murmur ﬁrst
rises in intensity, then falls.
A plateau murmur has the same in-
tensity throughout.
ILocation of Maximal Intensity. This is determined by the site where the
murmur originates. Find the location by exploring the area where youhear the murmur. Describe where you hear it best in terms of the inter-space and its relation to the sternum, the apex, or the midsternal, the mid-clavicular, or one of the axillary lines.
IRadiation or Transmission from the Point of Maximal Intensity. This re-

ﬂects not only the site of origin but also the intensity of the murmur andthe direction of blood ﬂow. Explore the area around a murmur and de-termine where else you can hear it.
IIntensity. This is usually graded on a 6-point scale and expressed as a frac-
tion. The numerator describes the intensity of the murmur wherever it isloudest, and the denominator indicates the scale you are using. Intensityis inﬂuenced by the thickness of the chest wall and the presence of inter-vening tissue.
Learn to grade murmurs using the 6-point scale below. Note that grades 4
through 6 require the added presence of a palpable thrill.The presystolic murmur of mitral
stenosis in normal sinus rhythm
The early diastolic murmur of aor-
tic regurgitation
The midsystolic murmur of aortic
stenosis and innocent ﬂow murmurs
The pansystolic murmur of mitral
regurgitation
For example, a murmur best

heard in the 2nd right interspaceusually originates at or near theaortic valve.
A loud murmur of aortic stenosis
often radiates into the neck (in thedirection of arterial ﬂow).
An identical degree of turbulence
would cause a louder murmur in athin person than in a very muscularor obese one. Emphysematouslungs may diminish the intensity ofmurmurs.
S2 S1
S2 S1
S2 S1
S2 S1
Grade Description
Grade 1
Grade 2
Grade 3Grade 4Grade 5
Grade 6Very faint, heard only after listener has “tuned in”; may not be heard in
all positions
Quiet, but heard immediately after placing the stethoscope on the chestModerately loudLoud, with palpable thrillVery loud, with thrill. May be heard when the stethoscope is partly off
the chest

the chest
Very loud, with thrill. May be heard with stethoscope entirely off the chestGradations of Murmurs

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cIPitch. This is categorized as high, medium, or low.
IQuality. This is described in terms such as blowing, harsh, rumbling, and
musical.
Other useful characteristics of murmurs—and heart sounds too—include
variation with respiration, with the position of the patient, or with other spe-cial maneuvers.
A Note on Cardiovascular Assessment
A good cardiovascular examination requires more than observation. Youneed to think about the possible meanings of your individual observations,ﬁt them together in a logical pattern, and correlate your cardiac ﬁndings withthe patient’s blood pressure, arterial pulses, venous pulsations, jugular ve-nous pressure, the remainder of your physical examination, and the patient’shistory.
Evaluating the common systolic murmur illustrates this point. In examining

an asymptomatic teenager, for example, you might hear a grade 2/6 midsys-tolic murmur in the 2nd and 3rd left interspaces. Since this suggests a mur-mur of pulmonic origin, you should assess the size of the right ventricle bycarefully palpating the left parasternal area. Because pulmonic stenosis andatrial septal defects can occasionally cause such murmurs, listen carefully tothe splitting of the second heart sound and try to hear any ejection sounds.Listen to the murmur after the patient sits up. Look for evidence of anemia,hyperthyroidism, or pregnancy that could produce such a murmur by in-creasing the ﬂow across the aortic or the pulmonic valve. If all your ﬁndingsare normal, your patient probably has an innocent murmur —one with no
pathologic signiﬁcance.
Aids to Identify Systolic Murmurs. Elsewhere in this chapter you

have learned how to improve your auscultation of heart sounds and mur-murs by placing the patient in different positions. Two additional techniqueswill help you distinguish the murmurs of mitral valve prolapse and hyper-trophic cardiomyopathy from aortic stenosis.
(1) Standing and Squatting. When a person stands, venous return
to the heart decreases as does peripheral vascular resistance. Arterial bloodpressure, stroke volume, and the volume of blood in the left ventricle all de-cline. On squatting, changes occur in the opposite direction. These changes
CHAPTER 7 ITHE CARDIOVASCULAR SYSTEM 281A fully described murmur might
be: a “medium-pitched, grade 2/6,blowing decrescendo murmur,heard best in the 4th left inter-space, with radiation to the apex”(aortic regurgitation).
Murmurs originating in the right

side of the heart tend to changemore with respiration than left-sided murmurs.
In a 60-year-old person with
angina, you might hear a harsh 3/6midsystolic crescendo–decrescendomurmur in the right 2nd interspaceradiating to the neck. These ﬁnd-ings suggest aortic stenosis, but
could arise from aortic sclerosi s
(leaﬂets sclerotic but not stenotic),a dilated aorta, or increased ﬂowacross a normal valve. Check theapical impulse for left ventricularenlargement. Listen for aortic regur-
gitation as the patient leans forward
and exhales. 
Assess any delay in the carotid up-
stroke and the blood pressure forevidence of aortic stenosis. Put allthis information together to makea tentative hypothesis about theorigin of the murmur.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5chelp (1) to identify a prolapsed mitral valve, and (2) to distinguish hyper-
trophic cardiomyopathy from aortic stenosis.
Secure the patient’s gown so that it will not interfere with your examination,
and ready yourself for prompt auscultation. Instruct the patient to squat nextto the examining table and hold on to it for balance. Listen to the heart withthe patient in the squatting position and again in the standing position.
(2) Valsalva Maneuver. When a person strains down against a closed
glottis, venous return to the right heart is decreased and after a few secondsleft ventricular volume and arterial blood pressure both fall. Release of theeffort has the opposite effects. These changes help to distinguish prolapse ofthe mitral valve and hypertrophic cardiomyopathy from aortic stenosis.
The patient should be lying down. Ask the patient to “bear down,” or place

one hand on the midabdomen and instruct the patient to strain against it.By adjusting the pressure of your hand you can alter the patient’s effort tothe desired level. Use your other hand to place your stethoscope on the pa-tient’s chest.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
282 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGAlternately loud and soft 
Korotkoff sounds or a sudden dou-bling of the apparent heart rate asthe cuff pressure declines indicatesa pulsus alternans (see p. __).
The upright position may accentu-
ate the alternation.Maneuvers to Identify Systolic Murmurs
Standing;
Strain Phaseof Valsalva
Squatting;
Release ofValsalvaDecreased left ventricular 
volume from ↓ venous return to heart
Decreased vascular tone:
↓arterial blood pressure;
↓peripheral vascular resistance
Increased left ventricular
volume from ↑venous return 
to heart
Increased vascular tone:

to heart
↑arterial blood pressure;
↑peripheral vascular resistance↑prolapse of
mitral valve
Click moves
earlier in systoleand murmurlengthens
↑intensity of
murmur
↓prolapse of
Delay of click and
murmurshortens
↓intensity of
murmur↑outﬂow
murmur
↓outﬂow
murmur↓blood volume
ejected into aorta
murmur
↑blood volume
↑ intensity of
murmurEffect on Systolic Sounds and Murmurs
Mitral Valve Hypertrophic
Maneuver Cardiovascular Effect Prolapse Cardiomyopathy Aortic Stenosis


















Pulsus Alternans. If you suspect left-sided heart failure, feel the pulse



















speciﬁcally for alternating amplitudes. These are usually felt best in the ra-dial or the femoral arteries. A blood-pressure cuff gives you a more sensitivemethod. After raising the cuff pressure, lower it slowly to the systolic leveland then below it. While you do this, the patient should breathe quietly orstop breathing in the respiratory midposition. If dyspnea prevents this, helpthe patient to sit up and dangle both legs over the side of the bed.

Paradoxical Pulse. If you have noted that the pulse varies in amplitude
with respiration or if you suspect pericardial tamponade (because of in-creased jugular venous pressure, a rapid and diminished pulse, and dyspnea,for example), use a blood-pressure cuff to check for a paradoxical pulse. Thisis a greater than normal drop in systolic pressure during inspiration. As thepatient breathes, quietly if possible, lower the cuff pressure slowly to the sys-tolic level. Note the pressure level at which the ﬁrst sounds can be heard.Then drop the pressure very slowly until sounds can be heard throughoutthe respiratory cycle. Again note the pressure level. The difference betweenthese two levels is normally no greater than 3 or 4 mm Hg.TECHNIQUES OF EXAMINATION
CHAPTER 7 ITHE CARDIOVASCULAR SYSTEM 283The level identiﬁed by ﬁrst hearing

Korotkoff sounds is the highest systolic pressure during the respi-ratory cycle. The level identiﬁed byhearing sounds throughout thecycle is the lowest systolic pressure.A difference between these levelsof more than 10 mm Hg indicatesa paradoxical pulse and suggestspericardial tamponade, possiblyconstrictive pericarditis, but mostcommonly obstructive airway disease (see p. __).

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 7-1 IVariations and Abnormalities of the Ventricular Impulses
284 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 7-1 IVariations and Abnormalities of the Ventricular Impulses 
When a ventricle works under conditions of chronic pressure overload or increased
afterload , its walls gradually thicken or hypertrophy . Volume overload ( increased
preload ), in contrast, produces dilatation of the ventricle as well as thickening ofits walls. A hyperkinetic impulse results from increased stroke volume and does
not necessarily signify heart disease. An impulse may feel hyperkinetic when thechest wall is unusually thin.
Left Ventricle Right Ventricle
Pressure Volume Pressure Volume 
Normal Hyperkinetic Overload Overload Normal Hyperkinetic Overload Overload
The Impulse
Location
Diameter
Amplitude
Duration
Examples of 
Causes5th or possibly
4th left inter-space, medial to the mid-clavicular line
Little more

Location
Diameter
Amplitude
Duration
than 2 cm inadults (1 cm inchildren); 3 cmor less in left-sided position
Small, gentle
Usually less
than 
2⁄3of
systole; theimpulse stopsbefore S
2Normal
Normal,
thoughincreasedamplitude maymake it seemlarger
Increased
Normal
Anxiety,
hyperthyroid-ism, severeanemiaDisplaced to
the left andpossiblydownward
Increased
Increased
Often slightly
prolonged
Aortic or mitral
regurgitationIndeterminate
Indeterminate
Not palpable
beyondinfancy
IndeterminateNormal
Increased
Increased
Prolonged, may
be sustained upto S
2
Aortic stenosis,hypertension3rd, 4th, or 5th
left interspaces
Not useful
Slightly
increased
Normal
Anxiety,
hyperthyroidism,severe anemia3rd, 4th, or
5th left inter-spaces, alsosubxiphoid 
Not useful
Increased
Prolonged
Pulmonic
stenosis,pulmonaryhypertensionLeft sternal

Slightly
increased
Normal
Anxiety,
Not useful
Increased
Prolonged
Pulmonic
border, extendingtoward the leftcardiac border,also subxiphoid
Not useful
Slightly to
markedlyincreased
Normal to
slightlyprolonged
Atrial septal
defect

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 7-2 IVariations in the First Heart Sound
CHAPTER 7 ITHE CARDIOVASCULAR SYSTEM 285
TABLE 7-2 IVariations in the First Heart Sound
Normal
Variations
Accentuated S 1
Diminished S 1
Varying S 1
Split S 1S1is softer than S 2at the base(right and left 2nd interspaces).
S1is often but not always louder than S 2at the apex.
S1is accentuated in (1) tachycardia, rhythms with a short PR interval, and high cardiac
output states (e.g., exercise, anemia, hyperthyroidism), and (2) mitral stenosis. In theseconditions, the mitral valve is still open wide at the onset of ventricular systole, and then closes quickly.
S
1is diminished in ﬁrst-degree heart block (delayed conduction from atria to ventricles).
Here the mitral valve has had time after atrial contraction to ﬂoat back into an almostclosed position before ventricular contraction shuts it. It closes less loudly. S
1is also

1is also
diminished (1) when the mitral valve is calciﬁed and relatively immobile, as in mitralregurgitation, and (2) when left ventricular contractility is markedly reduced, as incongestive heart failure or coronary heart disease.
S
1varies in intensity (1) in complete heart block, when atria and ventricles are beating
independently of each other, and (2) in any totally irregular rhythm (e.g., atrialﬁbrillation). In these situations, the mitral valve is in varying positions before being shut by ventricular contraction. Its closure sound, therefore, varies in loudness.
S
1may be split normally along the lower left sternal border where the tricuspid
component, often too faint to be heard, becomes audible. This split may sometimes beheard at the apex, but consider also an S

4, an aortic ejection sound, and an early systolic
click. Abnormal splitting of both heart sounds may be heard in right bundle branchblock and in premature ventricular contractions.
S1 S2
S1 S2
S1 S2
S1 S2
S1 S2
S1 S2
S1 S2

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 7-3 IVariations in the Second Heart Sound
286 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 7-3 IVariations in the Second Heart Sound
Physiologic
Splitting
Pathologic
Splitting
(All of 
these involvesplittingduringexpirationand allsuggest heartdisease.)Physiologic splitting of the second heart sound can usually be detected in the 2nd or 3rd
left interspace. The pulmonic component of S 2is usually too faint to be heard at the
apex or aortic area, where S 2is single and derived from aortic valve closure alone.
Normal splitting is accentuated by inspiration and usually disappears on expiration. Insome patients, however, especially younger ones, S
2may not become completely single
on expiration. It may do so when the patient sits up.
Wide splitting of S 2refers to an increase in the usual splitting that persists throughout

the respiratory cycle. Wide splitting can be caused by delayed closure of the pulmonicvalve (e.g., by pulmonic stenosis or right bundle branch block). As illustrated here, rightbundle branch block also causes splitting of S
1into its mitral and tricuspid components.
Wide splitting can also be caused by early closure of the aortic valve, as in mitralregurgitation.
Fixed splitting refers to wide splitting that does not vary with respiration. It occurs in
atrial septal defect and right ventricular failure.
Paradoxical or reversed splitting refers to splitting that appears on expiration and
disappears on inspiration. Closure of the aortic valve is abnormally delayed so that A
2
follows P 2in expiration. Normal inspiratory delay of P 2makes the split disappear. The

2
most common cause of paradoxical splitting is left bundle branch block.
S1 S2 S1 S2A2P2
S1 S2 S1 S2
S1 S2 S1 S2
S1 S2P2A2
S1 S2
Increased Intensity of A 2in the Right Second Interspace 
(where only A 2can usually be heard) occurs in systemic hypertension because
of the increased pressure. It also occurs when the aortic root is dilated,probably because the aortic valve is then closer to the chest wall.
A Decreased or Absent A 2in the Right Second Interspace 
is noted in calciﬁc aortic stenosis because of immobility of the valve. If A 2is
inaudible, no splitting is heard.Increased Intensity of P 2. When P 2is equal to or louder than A 2,

pulmonary hypertension may be suspected. Other causes include a dilatedpulmonary artery and an atrial septal defect. Splitting of the second heart soundthat is heard widely, even at the apex and the right base, indicates anaccentuated P
2.
A Decreased or Absent P 2is most commonly due to the increased
anteroposterior diameter of the chest associated with aging. It can also resultfrom pulmonic stenosis. If P
2is inaudible, no splitting is heard.Expiration Inspiration

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 7-4 IExtra Heart Sounds in Systole
CHAPTER 7 ITHE CARDIOVASCULAR SYSTEM 287
TABLE 7-4 IExtra Heart Sounds in Systole
Extra heart sounds in systole are of two kinds: (1) early ejection sounds, and (2) clicks, most commonly heard in mid-
and late systole.
Early Systolic
Ejection Sounds
Systolic ClicksEarly systolic ejection sounds occur shortly after the ﬁrst heart sound, coincident with the opening of the aortic
and pulmonic valves. They are relatively high in pitch, have a sharp, clicking quality, and are heard better withthe diaphragm of the stethoscope. An ejection sound indicates cardiovascular disease.
An aortic ejection sound is heard at both base and apex and may be louder at the apex. It does not usually vary
with respiration. An aortic ejection sound may accompany a dilated aorta or aortic valve disease, such ascongenital stenosis or a bicuspid valve.

A pulmonic ejection sound is heard best in the 2nd and 3rd left interspaces. When the ﬁrst heart sound, usually
relatively soft in this area, appears to be loud, you may instead be hearing a pulmonic ejection sound. Itsintensity often decreases with inspiration. Causes include dilatation of the pulmonary artery, pulmonaryhypertension, and pulmonic stenosis.
Systolic clicks are usually due to mitral valve prolapse —an abnormal systolic ballooning of part of the mitral

valve into the left atrium. The clicks are usually mid- or late systolic. Prolapse of the mitral valve is a commoncardiac condition, affecting about 5% of the general population. It is now felt to have equal prevalence in menand women. The click is usually single, but more than one may be heard. A click is heard best at or medial tothe apex but may also be heard at the lower left sternal border. It is high-pitched and heard better with thediaphragm. The click is often followed by a late systolic murmur, which usually represents mitralregurgitation—a ﬂow of blood from left ventricle to left atrium. The murmur usually crescendos up to S
2.
Systolic clicks may also be of extracardial or mediastinal origin.
Auscultatory ﬁndings are notably variable. Most patients have only a click, some have only a murmur, and

2.
some have both. Findings vary from time to time and often change with body position. Several positions arerecommended to identify the syndrome: supine, seated, squatting, and standing. Squatting delays the click andmurmur; standing moves them closer to S
1.
S1Ej S2
S1C1S2
S1C1Squatting
S2
S1C1Standing
S2

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 7-5 IExtra Heart Sounds in Diastole
288 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 7-5 IExtra Heart Sounds in Diastole
Opening Snap
S3
S4The opening snap is a very early diastolic sound usually produced by the opening of a stenotic
mitral valve. It is heard best just medial to the apex and along the lower left sternal border. Whenit is loud, an opening snap radiates to the apex and to the pulmonic area, where it may bemistaken for the pulmonic component of a split S
2. Its high pitch and snapping quality help to
distinguish it from an S 2. It is heard better with the diaphragm.
A physiologic third heart sound is heard frequently in children. It may persist in young adults to the

age of 35 or 40. It is common during the last trimester of pregnancy. Occurring early in diastoleduring rapid ventricular ﬁlling, it is later than an opening snap, dull and low in pitch, and heardbest at the apex in the left lateral decubitus position. The bell of the stethoscope should be usedwith very light pressure.
A pathologic S
3or ventricular gallop sounds just like a physiologic S 3. An S 3in a person over age
40 (possibly a little older in women) is almost certainly pathologic. Causes include decreasedmyocardial contractility, myocardial failure, and volume overloading of a ventricle, as in mitralor tricuspid regurgitation. A left-sided S
3is heard typically at the apex in the left lateral
position. A right-sided S 3is usually heard along the lower left sternal border or below the

xiphoid with the patient supine. It is louder on inspiration. The term gallop comes from thecadence of three heart sounds, especially at rapid heart rates, and sounds like “Kentucky.”
An S
4(atrial sound or atrial gallop ) occurs just before S 1. It is dull, low in pitch, and heard
better with the bell. An S 4is heard occasionally in an apparently normal person, especially in
trained athletes and older age groups. More commonly, it is due to increased resistance toventricular ﬁlling following atrial contraction. This increased resistance is related to decreasedcompliance (increased stiffness) of the ventricular myocardium. Causes of a left-sided S
4include
hypertensive heart disease, coronary artery disease, aortic stenosis, and cardiomyopathy. A left-sided S

4include
4is heard best at the apex in the left lateral position; it may sound like “Tennessee.” The
less common right-sided S 4is heard along the lower left sternal border or below the xiphoid. It
often gets louder with inspiration. Causes of a right-sided S 4include pulmonary hypertension
and pulmonic stenosis.
An S 4may also be associated with delayed conduction between atria and ventricles. This delay
separates the normally faint atrial sound from the louder S 1and makes it audible. An S 4is never
heard in the absence of atrial contraction, as occurs with atrial ﬁbrillation.
Occasionally, a patient has both an S 3and an S 4, producing a quadruple rhythm of four heart
sounds. At rapid heart rates the S 3and S 4may merge into one loud extra heart sound, called a
summation gallop.
S1 S1 S2OS
S1 S2S3 S1
S1 S1 S2 S4

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 7-6 IMidsystolic Murmurs
CHAPTER 7 ITHE CARDIOVASCULAR SYSTEM 289
TABLE 7-6 IMidsystolic Murmurs
Midsystolic ejection murmurs are the most common kind of heart murmur. They
may be (1) innocent —without any detectable physiologic or structural abnormality;
(2) physiologic —from physiologic changes in body metabolism; or (3) pathologic —
arising from a structural abnormality in the heart or great vessels. Midsystolic mur-murs tend to peak near midsystole and usually stop before S 2. The crescendo–
decrescendo or “diamond” shape is not always audible, but the gap between themurmur and S
2helps to distinguish midsystolic from pansystolic murmurs.
MechanismMurm ur Associated Findings
Innocent Murmurs
Murmurs
Murmurs
PulmonicStenosisInnocent murmurs result from turbulent

Murmurs
Murmurs
blood ﬂow, probably generated by leftventricular ejection of blood into the aorta.Occasionally, turbulence from rightventricular ejection may also cause them.There is no evidence of cardiovasculardisease. Innocent murmurs—very commonin children and young adults—may also beheard in older people.
Turbulence due to a temporary increase 
in blood ﬂow causes this murmur.Predisposing conditions include anemia,pregnancy, fever, and hyperthyroidism.
Stenosis of the pulmonic valve impairs ﬂow
across the valve, increasing afterload on theright ventricle. It is congenital and mostoften found in children. Pathologically
increased ﬂow across the pulmonic valve may
mimic the murmur of pulmonic stenosis.The systolic murmur of an atrial septaldefect originates from this ﬂow, not thedefect itself.Location. 2nd to 4th left interspaces

between the left sternal border andthe apex
Radiation. Little
Intensity. Grade 1 to 2, possibly 3
Pitch. Medium
Quality. Variable
Aids. Usually decreases or disappears
on sitting
Similar to innocent murmurs
Location. 2nd and 3rd left
interspaces
Radiation. If loud, toward the left
shoulder and neck
Intensity. Soft to loud; if loud,
associated with a thrill
Quality. Often harshNone: normal splitting, no ejection
sounds, no diastolic murmurs, andno palpable evidence of ventricularenlargement. Occasionally, apatient has both an innocentmurmur and another kind ofmurmur.
Possible signs of a likely cause
In severe stenosis, S
2is widely split
and P 2is diminished. When P 2is
inaudible, no splitting is heard.
An early pulmonic ejection sound
is common.
A right-sided S 4may be present.

is common.
The right ventricular impulse isoften increased in amplitude andmay be prolonged.
S1 S2
S1 A2P2Ej
S1 S2
(table continues on next page)

290 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGAortic Stenosis
Hypertrophic
Cardiomyopathy
TABLE 7-6 IMidsystolic Murmurs (Continued)
S1 S2May be
decreased
S1 S2Signiﬁcant stenosis of the aortic valve
impairs blood ﬂow across the valve,causing turbulence, and increases theafterload on the left ventricle. Causes arecongenital, rheumatic, and degenerative,and ﬁndings may differ with each cause.
Other conditions may mimic the murmur
of aortic stenosis without obstructing ﬂow:
IAortic sclerosis, a stiffening of aortic
valve leaﬂets associated with aging
IA bicuspid aortic valve, a congenital
condition, which may not berecognized until adulthood
IA dilated aorta, as from arteriosclerosis,
syphilis, or Marfan’s syndrome
IA pathologically increased ﬂow across
the aortic valve during systole, as in
aortic regurgitation

Massive hypertrophy of ventricular muscle
is associated with unusually rapid ejectionof blood from the left ventricle duringsystole. Obstruction to ﬂow may coexist.Accompanying distortion of the mitralvalve may cause mitral regurgitation.Location. Right 2nd interspace
Radiation. Often to the neck and
down the left sternal border, even tothe apex
Intensity. Sometimes soft but often
loud, with a thrill
Pitch. Medium; at the apex, it may
be higher
Quality. Often harsh; at the apex it
may be more musical
Aids. Heard best with the patient
sitting and leaning forward
Location. 3rd and 4th left
Radiation. Down the left sternal
border to the apex, possibly to thebase, but not to the neck
Intensity. Variable
Quality. Harsh
Aids. Decreases with squatting,
increases with straining downA

2decreases as the stenosis
worsens. A 2may be delayed,
merging with P 2to form a single
expiratory sound or causingparadoxical splitting. An S
4,
reﬂecting the decreasedcompliance of the hypertrophiedleft ventricle, may be present atthe apex. An aortic ejectionsound, if present, suggests acongenital cause. A sustainedapical impulse often reveals leftventricular hypertrophy. Thecarotid artery impulse may riseslowly and feel small in amplitude.
An S
3may be present.
An S 4is often present at the apex
(unlike mitral regurgitation).
The apical impulse may be
sustained and have two palpablecomponents.
The carotid pulse rises quickly
(unlike the pulse in aorticstenosis).

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 7-7 IPansystolic (Holosystolic) Murmurs
CHAPTER 7 ITHE CARDIOVASCULAR SYSTEM 291
TABLE 7-7 IPansystolic (Holosystolic) Murmurs
Pansystolic (holosystolic) murmurs are pathologic. They are heard when blood
ﬂows from a chamber of high pressure to one of lower pressure through a valve orother structure that should be closed. The murmur begins immediately with S 1
and continues up to S 2.
Mitral Regurgitation
Tricuspid Regurgitation
Ventricular Septal DefectWhen the mitral valve fails to close fully in
systole, blood regurgitates from left ventricleto left atrium, causing a murmur. This leakagecreates a volume overload on the left ventricle,with subsequent dilatation and hypertrophy.Several structural abnormalities cause thiscondition, and ﬁndings may vary accordingly.
When the tricuspid valve fails to close fully in

systole, blood regurgitates from right ventricleto right atrium, producing a murmur. Themost common cause is right ventricular failureand dilatation, with resulting enlargement ofthe tricuspid oriﬁce. Either pulmonaryhypertension or left ventricular failure is theusual initiating cause.
A ventricular septal defect is a congenital
abnormality in which blood ﬂows from therelatively high-pressure left ventricle into thelow-pressure right ventricle through a hole.The defect may be accompanied by otherabnormalities, but an uncomplicated lesion isdescribed here.Location. Apex
Radiation. To the left axilla, less often
to the left sternal border
associated with an apical thrill
Pitch. Medium to high
Quality. Blowing
Aids. Unlike tricuspid regurgitation, it
does not become louder in inspiration.
Location. Lower left sternal border
Radiation. To the right of the

sternum, to the xiphoid area, andperhaps to the left midclavicular line,but not into the axilla
Aids. Unlike mitral regurgitation, the
intensity may increase slightly withinspiration.
Location. 3rd, 4th, and 5th left
Radiation. Often wide
Intensity. Often very loud, with a thrill
Pitch. High
Quality. Often harshS
1is often decreased.
An apical S 3reﬂects volume
overload on the left ventricle.
The apical impulse is increased in
amplitude and may be prolonged.
The right ventricular impulse is
increased in amplitude and may beprolonged.
An S
3may be audible along the
lower left sternal border. Thejugular venous pressure is oftenelevated, and large vwaves may be
seen in the jugular veins.
A
2may be obscured by the loud
murmur.

An S
A
murmur.
Findings vary with the severity of
the defect and with associatedlesions.
Decreased
S1 S2S3
S1S2
S1 S2S3

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 7-8 IDiastolic Murmurs
292 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 7-8 IDiastolic Murmurs
Diastolic murmurs almost always indicate heart disease. There are two basic types.
Early decrescendo diastolic murmurs signify regurgitant ﬂow through an incompetentsemilunar valve, more commonly the aortic. Rumbling diastolic murmurs in mid- or
late diastole suggest stenosis of an atrioventricular valve, more often the mitral.
Aortic Regurgitation
Mitral StenosisMechanismMurm ur Associated Findings
Location. 2nd to 4th left interspaces
Radiation. If loud, to the apex,
perhaps to the right sternal border
Intensity. Grade 1 to 3
Pitch. High. Use the diaphragm.
Quality. Blowing; may be mistaken
for breath sounds
Aids. The murmur is heard best with
the patient sitting, leaning forward,with breath held in exhalation.
Location. Usually limited to the apex
Radiation. Little or none
Intensity. Grade 1 to 4

Pitch. Low. Use the bell.
Aids. Placing the bell exactly on the
apical impulse, turning the patientinto a left lateral position, and mildexercise all help to make the murmuraudible. It is heard better inexhalation.An ejection sound may be present.
An S
3or S 4, if present, suggests severe
regurgitation.
Progressive changes in the apical impulse
include increased amplitude,displacement laterally and downward,widened diameter, and increasedduration.
The pulse pressure increases, and
arterial pulses are often large andbounding. A midsystolic ﬂow murmur or
an Austin Flint murmur suggests largeregurgitant ﬂow.
S
1is accentuated and may be palpable at
the apex.
An opening snap (OS) often follows S 2
and initiates the murmur.If pulmonary hypertension develops, P
2

S
the apex.
2
is accentuated and the right ventricular
impulse becomes palpable.
Mitral regurgitation and aortic valve
disease may be associated with mitralstenosis.
S1S2
S2OS S1Accentuated
The leaﬂets of the aortic valve fail to close
completely during diastole, and bloodregurgitates from the aorta back into the leftventricle. Volume overload on the leftventricle results. Two other murmurs may beassociated: (1) a midsystolic murmur fromthe resulting increased forward ﬂow acrossthe aortic valve, and (2) a mitral diastolic(Austin Flint ) murmur. The latter is
attributed to diastolic impingement of theregurgitant ﬂow on the anterior leaﬂet of themitral valve.
When the leaﬂets of the mitral valve thicken,

stiffen, and become distorted from theeffects of rheumatic fever, the valve fails toopen sufﬁciently in diastole. The resultingmurmur has two components: (1)middiastolic (during rapid ventricularﬁlling), and (2) presystolic (during atrialcontraction). The latter disappears if atrialﬁbrillation develops, leaving only amiddiastolic rumble.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 7-9 ICardiovascular Sounds
CHAPTER 7 ITHE CARDIOVASCULAR SYSTEM 293
TABLE 7-9 ICardiovascular Sounds With Both Systolic and Diastolic Components
Some cardiovascular sounds are not confined to one portion of the cardiac cycle.
Three examples are: (1) a pericardial friction rub, produced by inflammation of
the pericardial sac; (2) patent ductus arteriosus, a congenital abnormality in
which an open channel persists between aorta and pulmonary artery; and (3) avenous hum, a benign sound produced by turbulence of blood in the jugularveins (common in children). Their characteristics are contrasted below. Con-
tinuous murmurs begin in systole and continue through the second sound into
all or part of diastole. Therefore the murmur of patent ductus arteriosus may beclassified as continuous.
Timing
Location
Radiation
Intensity
Quality
PitchPericardial Friction Rub Patent Ductus Arteriosus Venous Hum

Timing
Location
Radiation
Intensity
Quality
Continuous murmur in both systole and diastole,
often with a silent interval late in diastole. Isloudest in late systole, obscures S
2, and fades in
diastole
Left 2nd interspaceToward the left clavicle
Usually loud, sometimes associated with a thrill
Harsh, machinerylike
MediumContinuous murmur without
a silent interval. Loudest indiastole
Above the medial third of the
clavicles, especially on theright
1st and 2nd interspacesSoft to moderate. Can be
obliterated by pressure on thejugular veins
Humming, roaringLow (heard better with a bell)
Ventricular
diastoleAtrial
systoleVentricular
systole
S1S2 S1
S1S2 S1
May have three short components, each associated

systole
S1S2 S1
S1S2 S1
May have three short components, each associated 
with cardiac movement: (1) atrial systole, (2) ventricularsystole, and (3) ventricular diastole. Usually the ﬁrst twocomponents are present; all three make diagnosis easy;only one (usually the systolic) invites confusion with amurmur.
Variable, but usually heard best in the 3rd interspace to
the left of the sternum
Little
Variable. May increase when the patient leans forward,
exhales, and holds breath (in contrast to pleural rub)
Scratchy, scraping
High (heard better with a diaphragm)
S1S2 S1

The Breasts and AxillaeThe Breasts and AxillaeCHAPTER
88
CHAPTER 8 ITHE BREASTS AND AXILLAE 297
The female breast lies against the anterior thoracic wall, extending from the
clavicle and 2nd rib down to the 6th rib, and from the sternum across to themidaxillary line. Its surface area is generally rectangular rather than round.The breast overlies the pectoralis major and at its inferior margin, the serra-tus anterior.
Pectoralis major
Serratus anteriorNipple
AreolaSubclavian vein
Subclavian 
lymph nodes
Axillary vein
Axillary 
Gland lobulesFat

To describe clinical findings, the
breast is often divided into four quad-rants based on horizontal and verticallines crossing at the nipple. An axillarytail of breast tissue extends toward theanterior axillary fold. Alternatively,findings can be localized as the timeon the face of a clock (e.g., 3 o’clock)and the distance in centimeters fromthe nipple.
The breast is hormonally sensitive
tissue, responsive to the changes ofmonthly cycling and aging. Glan-
dular tissue, namely secretory tubu-
loalveolar glands and ducts, forms 15to 20 septated lobesradiating around
the nipple. Within each lobe are
many smaller lobules. These drain into
milk-producing ducts and sinuses thatopen onto the surface of the areola, or
nipple. Fibrous connective tissue pro-
vides structural support in the formof ﬁbrous bands or suspensory liga-ments connected to both the skin andthe underlying fascia. Adipose tissue, or

fat, surrounds the breast, predomi-nantly in the superﬁcial and periph-eral areas. The proportions of thesecomponents vary with age, the gen-eral state of nutrition, pregnancy,exogenous hormone use, and otherfactors.ANATOMY AND PHYSIOLOGY
298 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Upper
innerquadrant
Lower
innerquadrantUpper
outerquadrant
Lower
outerquadrantTail
9
612
3
Suspensory ligamentPectoral
muscleClavicle
Duct
FatGlandular tissue

The surface of the areola has small,
rounded elevations formed by seba-ceous glands, sweat glands, and ac-cessory areolar glands. A few hairsare often seen on the areola.
Both the nipple and the areola are
well supplied with smooth muscle
that contracts to express milk from theductal system during breast-feeding.Rich sensory innervation, especially inthe nipple, triggers “milk letdown”following neurohormonal stimula-tion from infant sucking. Tactile stimulation of the area, includingthe breast examination, makes thenipple smaller, ﬁrmer, and more erect,while the areola puckers and wrinkles.These normal smooth muscle reﬂexesshould not be mistaken for signs ofbreast disease.
Occasionally, one or more extra or supernumerary nipples are located along
the “milk line,” illustrated on the right. Only a small nipple and areola areusually present, often mistaken for a common mole. There may be under-lying glandular tissue. An extra nipple has no pathologic signiﬁcance.

The male breast consists chieﬂy of a small nipple and areola. These overlie a
thin disc of undeveloped breast tissue that may not be distinguishable clini-cally from the surrounding tissues. A ﬁrm button of breast tissue 2 cm or morein diameter has been described in roughly one out of three adult men. Thelimits of normal have not yet been clearly established.
Adulthood. The normal adult breast may be soft, but it often feels gran-
ular, nodular, or lumpy. This uneven texture is normal and may be termedphysiologic nodularity. It is often bilateral. It may be evident throughout the
breast or only in parts of it. The nodularity may increase premenstrually—atime when breasts often enlarge and become tender or even painful. For breastchanges during adolescence and pregnancy, see p. 409 and pp. 699–700.
CHAPTER 8 ITHE BREASTS AND AXILLAE 299
Smooth muscle
Nipple
Duct opening
Sebaceous gland
Areola

Aging. The breasts of an aging woman tend to diminish in size as glan-
dular tissue atrophies and is replaced by fat. Although the proportion of fatincreases, its total amount may also decrease. The breasts often become ﬂac-cid and more pendulous. The ducts surrounding the nipple may becomemore easily palpable as ﬁrm, stringy strands. Axillary hair diminishes.
Lymphatics
Lymphatics from most of the breast drain toward the axilla. Of the axillary
lymph nodes, the central nodes are palpable most frequently. They lie along
the chest wall, usually high in the axilla and midway between the anterior andposterior axillary folds. Into them drain channels from three other groups oflymph nodes, which are seldom palpable:
IPectoral nodes—anterior, located along the lower border of the pectoralis
major inside the anterior axillary fold. These nodes drain the anterior chestwall and much of the breast.
ISubscapular nodes —posterior, located along the lateral border of the

scapula; palpated deep in the posterior axillary fold. They drain the pos-terior chest wall and a portion of the arm.
ILateral nodes —located along the upper humerus. They drain most of the arm.
300 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Infraclavicular
Subscapular
(posterior)
Pectoral
(anterior)Central
(deep within the axillae)Lateral
Lymph drains from the central axillary nodes to the infraclavicular and
supraclavicular nodes.
Not all the lymphatics of the breast drain into the axilla. Malignant cells from
a breast cancer may spread directly to the infraclavicular nodes or into deepchannels within the chest.ARROWS INDICATE DIRECTION OF LYMPH FLOW

EXAMPLES OF ABNORMALITIES HEALTH PROMOTION AND COUNSELING
CHAPTER 8 ITHE BREASTS AND AXILLAE 301Lumps may be physiologic or
pathologic, ranging from cysts andﬁbroadenomas to breast cancer.See Table 8-1, Visible Signs of BreastCancer (p. 314), and Table 8-2,Common Breast Masses, (p. 315).
A milky bilateral discharge, or
galactorrhea, may reﬂect pregnancy
or prolactin or other hormonal imbalance.
A nonmilky unilateral discharge
suggests local breast disease.
Women may experience a wide range of changes in breast tissue and sensa-
tion, from cyclic swelling and nodularity to a distinct lump or mass. The ex-amination of the breast provides a meaningful opportunity for the clinicianand the woman patient to explore concerns important to women’s health—what to do if a lump or mass is detected, risk factors for breast cancer, andscreening measures such as breast self-examination, the clinical breast ex-amination (CBE) by a skilled clinician, and mammography.

Breast masses show marked variation in etiology, from ﬁbroadenomas and
cysts seen in younger women, to abscess or mastitis, to primary breast can-cer. All breast masses warrant careful evaluation. On initial assessment, thewoman’s age and physical characteristics of the mass provide clues to its ori-gin, but deﬁnitive diagnostic measures should be pursued.
Questions about a woman’s breasts may be included in the history or deferred
to the physical examination. Ask “Do you examine your breasts?” . . . “Howoften?” In menstruating women, inquire “When during your monthlycycle?” Ask if she has any lumps, pain, or discomfort in her breasts. Approxi-
mately 50% of women have palpable lumps or nodularity in their breasts. Pre-menstrual enlargement and tenderness are common.
Also ask about any discharge from the nipples and when it occurs. If it appears

only after squeezing the nipple, it is considered physiologic. If the discharge isspontaneous and seen on the underwear or nightclothes without local stimu-lation, ask about its color, consistency, and quantity. Is it unilateral or bilateral?Common or Concerning Symptoms
IBreast lump or mass
IBreast pain or discomfort
INipple discharge
IRisk factors for breast cancer
IBreast cancer screening
IBreast self-examination (BSE)

Risk Factors for Breast Cancer. Breast cancer is the most common
cause of cancer in women worldwide, accounting for 18% of all female malig-nancies. In the United States, a woman has more than a 12% lifetime risk of de-veloping breast cancer and an approximately 22% risk of dying from the dis-ease.* Although 70% of affected women have no known predisposing factors,deﬁnite risk factors are well-established. The clinician and the inquiring patientshould understand and review factors such as age, family history, reproductivehistory, and previous history of benign breast disease, especially if a previousbiopsy showed atypical hyperplasia or lobular carcinoma in situ.
To calculate an individual woman’s risk of breast cancer, you may wish to
make use of the Breast Cancer Risk Assessment Tool of the National Can-cer Institute (www.brca.nci.gov
) or other available clinical models such as

the Gail model (see Bibliography). Advise your patients that more than twothirds of new cases of breast cancer localized to the breast are attributed toearlier detection.
Age. Although one in eight women will eventually develop breast can-
cer, it is important to note that this is a cumulative lifetime risk that increaseswith age. More than three fourths of breast cancer cases occur in women50 years or older; more than half in women older than age 65. For womenbetween the ages of 35 and 55 without major risk factors, the chance of de-veloping breast cancer is approximately 2.5%.
Family History. The relative risk (or risk relative to an individual with-
out a given risk factor) of breast cancer associated with menstrual history, preg-HEALTH PROMOTION AND COUNSELING

302 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGAge Common Lesion Characteristics
15–25 Fibroadenoma Usually ﬁne, round, 
mobile, nontender
25–50 Cysts Usually soft to ﬁrm, 
round, mobile; often tender
Fibrocystic changes Nodular, ropelikeCancer Irregular, stellate, ﬁrm, not 
clearly delineated from surrounding tissue
Over 50 Cancer until proven As above
otherwise
Pregnancy/lactation Lactating adenomas, cysts, As above
mastitis, and cancerPalpable Masses of the Breast
Adapted from Schultz MZ, Ward BA, Reiss M: Ch. 149. Breast Diseases. In Noble J, Greene HL, Levinson W,
Modest GA, Young MJ (eds): Primary Care Medicine, 2nd ed. St. Louis, Mosby, 1996.
*Harris JR, Morrow M, Bonadonna G: Cancer of the breast. In DeVita VT, Hellman S, Rosenberg SA

(eds): Cancer Principles & Practice of Oncology, 5th ed. Philadelphia, Lippincott-Raven, 1997.

nancy, and breast conditions and diseases is summarized in the table above.
Risk from familial breast cancer falls into two patterns: family history of breastcancer and genetic predisposition. First-degree relatives, namely a mother orsister with breast cancer, establish a “positive family history.” Within thisgroup, menopausal status and extent of disease play a key role. Having ﬁrst-degree relatives with breast cancer who are premenopausal with bilateral dis-ease confers the highest risk. Even when a mother and a sister have bilateralbreast cancer, however, the probability of breast cancer is only 25%.
Inherited disease in women carrying mutations in the breast cancer suscepti-

bility genes BRCA1 and BRCA2 accounts for only 5% to 10% of breast can-cers. However, these genes confer a 50% risk of the disease in women under50, and an 80% risk by age 65. Red ﬂags for possible inherited disease includemultiple relatives (maternal or paternal) with breast cancer, a family history ofcombined breast cancer and ovarian cancer, and a family history of bilateraland/or early onset of breast cancer.
Menstrual History and Pregnancy. Early menarche, delayed meno-
pause, and ﬁrst live birth after age 35 or no pregnancy all raise the risk of breastcancer two- to three-fold. 
Breast Conditions and Diseases. Benign breast disease with biopsy
ﬁndings of atypical hyperplasia or lobular carcinoma in situ carry signiﬁcantlyincreased relative risks—4.4 and 6.9 to 12.0, respectively.HEALTH PROMOTION AND COUNSELING
CHAPTER 8 ITHE BREASTS AND AXILLAE 303Factor Relative Risk (%)

First-degree relative with breast cancer 1.2–3.0
Premenopausal 3.1Premenopausal and bilateral 8.5–9.0Postmenopausal 1.5Postmenopausal and bilateral 4.0–5.4
Menstrual History
Age at menarche <12 1.3Age at menopause >55 1.5–2.0
Pregnancy
First live birth from ages 25–29 1.5First live birth after age 30 1.9First live birth after age 35 2.0–3.0Nulliparous 3.0
Breast Conditions and Diseases
Nonproliferative disease 1.0Proliferative disease 1.9Proliferative with atypical hyperplasia 4.4Lobular carcinoma in situ 6.9–12.0Summary of Breast Cancer Risk Factors
Adapted from Bilmoria MM and Morrow M: The woman at increased risk for breast cancer: evaluation and
management strategies. Ca 45(5):263, 1995. See also American Cancer Society, www.cancer.org .

Breast Cancer Screening. Although not yet conﬁrmed as a method for
increasing detection, it is wise to teach all women the breast self-examination
to promote health awareness (see pp. 312–313). To enhance early detec-tion, the American Cancer Society recommends monthly breast self-examination beginning at age 20, clinical breast examination (CBE) by a
health care professional every 3 years for women between the ages of 20 and39, and annually after age 40, and yearly mammography for women 40 and
older.* For women at increased risk, many clinicians advise a screeningmammogram at age 35 or 40, then every 2 to 3 years until age 50. Mam-mography is less accurate when breast tissue is more glandular and dense,especially before menopause, resulting in different recommendations aboutthe beneﬁts of mammography for women in the 40-to-50 age group.
†For

†For
women aged 50 to 69, mammography and CBE are widely recommendedevery 1 to 2 years. After age 70, the beneﬁts of mammography are less wellstudied, and testing should be considered on an individual basis.HEALTH PROMOTION AND COUNSELING
304 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGPreview: Recording the Physical Examination—Breasts and Axillae
you will use phrases. The style below contains phrases appropriate formost write-ups. Unfamiliar terms are explained in the next section, Tech-niques of Examination.
“Breasts symmetric and without masses. Nipples without discharge.”
(Axillary adenopathy usually included after Neck in section on LymphNodes, see p. 143.)
OR:“Breasts pendulous with diffuse ﬁbrocystic changes. Single ﬁrm 1 ×1 cm
mass, mobile and nontender, with overlying peau d’orange appearancein right breast, upper outer quadrant at 11 o’clock.”

*American Cancer Society. www.cancer.org . Accessed 9/1/01.
†U.S. Preventive Services Task Force: “Screening for Breast Cancer” in Guide to Clinical Preventive Ser-
vices, 2nd ed. Baltimore: Williams & Wilkins, pp. 73–87, 1996.Suggests possible breast cancer

CHAPTER 8 ITHE BREASTS AND AXILLAE 305Risk factors for breast cancer 
include previous breast cancer, anaffected mother or sister, biopsyshowing atypical hyperplasia, increasing age, early menarche,late menopause, late or no preg-nancies, and previous radiation tothe chest wall.
See Patient Instructions for the
Breast Self-Examination, p. 313.
The Female Breast
The clinical breast examination is an important component of women’s health

care: it enhances detection of breast cancers that mammography may missand provides an opportunity to demonstrate techniques for self-examinationto the patient. Clinical investigation has shown, however, that variations inexaminer experience and technique affect the value of the clinical breast ex-amination. Clinicians are advised to adopt a more standardized approach, es-pecially for palpation, and to use a systemic and thorough search pattern,varying palpation pressure, and a circular motion with the ﬁngerpads.* Thesetechniques will be discussed in more detail in the following pages. Inspectionis routinely recommended, but its value in breast cancer detection is less wellstudied.
As you begin the examination of the breasts, be aware that women and girls

may feel apprehensive. Be reassuring and adopt a courteous and gentle ap-proach. Before you begin, let the patient know that you are about to examineher breasts. This may be a good time to ask if she has noticed any lumps orother problems and if she performs a monthly breast self-examination. If shedoes not, teach her good technique and watch as she repeats the steps of ex-amination after you, giving helpful correction as needed.
An adequate inspection requires full exposure of the chest, but later in the
examination you may find it helpful to cover one breast while you are pal-pating the other. Because breasts tend to swell and become more nodularbefore menses as a result of increasing estrogen stimulation, the best timefor examination is 5 to 7 days after the onset of menstruation. Nodules ap-
pearing during the premenstrual phase should be reevaluated at this latertime.

Inspect the breasts and nipples with the patient in the sitting position and dis-robed to the waist. A thorough examination of the breast includes careful in-spection for skin changes, symmetry, contours, and retraction in four views—arms at sides, arms over head, arms pressed against hips, and leaning forward.When examining an adolescent girl, assess her breast development accordingto Tanner’s sex maturity ratings described on page 700.
*Barton MB, Harris R, and Fletcher S: Does This Patient Have Breast Cancer? The Screening Clinical
Breast Examination: Should It be Done? How? JAMA 282 (13); 1270–1280, 1999.

306 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGArms at Sides. Note the clinical features listed below.
IThe appearance of the skin, including
Color
Thickening of the skin and unusually prominent pores, which may ac-
company lymphatic obstruction
IThe size and symmetry of the breasts. Some difference in the size of the breasts,
including the areolae, is common and is usually normal, as shown in thephotograph below.
IThe contour of the breasts. Look for changes such as masses, dimpling, or
ﬂattening. Compare one side with the other.Redness from local infection or 
inﬂammatory carcinoma
Thickening and prominent pores
suggest a breast cancer.
Flattening of the normally convex
breast suggests cancer. See Table 8-1, Visible Signs of BreastCancer (p. 314).
Asymmetry of directions in which
nipples point suggests an under-lying cancer. Rash or ulceration inPaget’s disease of the breast (see p. 314).

Recent or ﬁxed ﬂattening or depres-
sion of the nipple suggests nippleretraction. A retracted nipple mayalso be broadened and thickened,suggesting an underlying cancer.
IThe characteristics of the nipples, including size and shape, direction in which
they point, any rashes or ulceration, or any discharge.
Occasionally, the shape of the nipple
in inverted, or depressed below the
areolar surface. It may be envelopedby folds of areolar skin, as illustrated.Long-standing inversion is usually anormal variant of no clinical conse-quence, except for possible difﬁcultywhen breast-feeding.ARMS AT SIDES

CHAPTER 8 ITHE BREASTS AND AXILLAE 307Dimpling or retraction of the
breasts in these positions suggestsan underlying cancer. When a can-cer or its associated ﬁbrous strandsare attached to both the skin andthe fascia overlying the pectoralmuscles, pectoral contraction candraw the skin inward, causingdimpling.
Occasionally, these signs may be
associated with benign lesionssuch as posttraumatic fat necrosisor mammary duct ectasia, but theymust always be evaluated withgreat care.
This position may reveal an asym-
metry of the breast or nipple nototherwise visible. Retraction of thenipple and areola suggests an un-derlying cancer. See Table 8-1, Vis-ible Signs of Breast Cancer (p. 314).
ARMS OVER HEAD
HANDS PRESSED AGAINST HIPS
LEANING FORWARDArms Over Head; Hands Pressed Against Hips; Leaning Forward.
To bring out dimpling or retraction that may otherwise be invisible, ask the

patient to raise her arms over her head, then press her hands against her hipsto contract the pectoral muscles. Inspect the breast contours carefully in eachposition. If the breasts are large or pendulous, it may be useful to have the pa-tient stand and lean forward, supported by the back of the chair or the exam-iner’s hands.

308 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGPALPATION
The Breast. Palpation is best performed when the breast tissue is ﬂattened.
The patient should be supine. Plan to palpate a rectangular area extendingfrom the clavicle to the inframammary fold or bra line, and from the midster-nal line to the posterior axillary line and well into the axilla for  the tail of thebreast.
A thorough examination will take 3 minutes for each breast. Use the ﬁnger-
padsof the 2nd, 3rd, and 4th ﬁngers, keeping the ﬁngers slightly ﬂexed. It is
important to be systematic. Although a circular or wedge pattern can be used,
the vertical strip pattern is currently the best validated technique for detect-
ing breast masses. Palpate in small, concentric circles at each examining point,

if possible applying light, medium, and deep pressure. You will need to pressmore ﬁrmly to reach the deeper tissues of a large breast. Your examinationshould cover the entire breast, including the periphery, tail, and axilla.
ITo examine the lateral portion of the breast, ask the patient to roll onto the
opposite hip, placing her hand on her forehead but keeping the shoulderspressed against the bed or examining table. This ﬂattens the lateral breasttissue. Begin palpation in the axilla, moving in a straight line down to thebra line, then move the ﬁngers medially and palpate in a vertical strip up thechest to the clavicle. Continue in vertical overlapping strips until you reachthe nipple, then reposition the patient to ﬂatten the medial portion of thebreast.When pressing deeply on the

breast, you may mistake a normalrib for a hard breast mass.
Nodules in the tail of the breast are
sometimes mistaken for enlargedaxillary lymph nodes (and viceversa).
Tender cords suggest mammary
duct ectasia, a benign but some-
times painful condition of dilatedducts with surrounding inﬂamma-ITo examine the medial portion of the breast, ask the patient to lie with her
shoulders ﬂat against the bed or examining table, placing her hand at herneck and lifting up her elbow until it is even with her shoulder. Palpate ina straight line down from the nipple to the bra line, then back to the clav-icle, continuing in vertical overlapping strips to the midsternum.
Examine the breast tissue carefully for:
IConsistency of the tissues. Normal consistency varies widely, depending in
part on the relative proportions of ﬁrmer glandular tissue and soft fat.Physiologic nodularity may be present, increasing before menses. Theremay be a ﬁrm transverse ridge of compressed tissue along the lower mar-

CHAPTER 8 ITHE BREASTS AND AXILLAE 309gin of the breast, especially in large breasts. This is the normal inframam-
mary ridge, not a tumor.
ITenderness, as in premenstrual fullness
INodules . Palpate carefully for any lump or mass that is qualitatively differ-
ent from or larger than the rest of the breast tissue. This is sometimes calleda dominant mass and may reﬂect a pathologic change that requires evalua-tion by mammogram, aspiration, or biopsy. Assess and describe the char-acteristics of any nodule:
Location —by quadrant or clock, with centimeters from the nipple
Size—in centimeters
Shape —round or cystic, disclike, or irregular in contour
Consistency —soft, ﬁrm, or hard
Delimitation —well circumscribed or not
TendernessMobility —in relation to the skin, pectoral fascia, and chest wall. Gently
move the breast near the mass and watch for dimpling.tion, sometimes with associated
masses.
See Table 8-2, Common Breast
Masses (p. 315).

masses.
Hard, irregular, poorly circum-
scribed nodules, ﬁxed to the skinor underlying tissues, strongly sug-gest cancer.
Cysts, inﬂamed areas, some 
cancers may be tender
A mobile mass that becomes ﬁxed
when the arm relaxes is attachedto the ribs and intercostal muscles;if ﬁxed when the hand is pressedagainst the hip, it is attached tothe pectoral fascia.
Next, try to move the mass itself while the patient relaxes her arm and
then while she presses her hand against her hip.

310 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGThe Nipple. Palpate each nipple, noting its elasticity.
The Male Breast
Examination of the male breast may be brief but is sometimes important.
Inspect the nipple and areola for nodules, swelling, or ulceration. Palpate the
areola and breast tissue for nodules. If the breast appears enlarged, distinguish
between the soft fatty enlargement of obesity and the ﬁrm disc of glandularenlargement, called gynecomastia.
The Axillae
Although the axillae may be examined with the patient lying down, a sitting
position is preferable.
Inspect the skin of each axilla , noting evidence of:
IRash
IInfection
IUnusual pigmentation
PALPATION
To examine the left axilla, ask the patient to relax with the left arm down. Help

IRash
PALPATION
by supporting the left wrist or hand with your left hand. Cup together thefingers of your right hand and reach as high as you can toward the apex of theaxilla. Warn the patient that this may feel uncomfortable. Your ﬁngers shouldlie directly behind the pectoral muscles, pointing toward the midclavicle. Nowpress your ﬁngers in toward the chest wall and slide them downward, tryingto feel the central nodes against the chest wall. Of the axillary nodes, these arethe most often palpable. One or more soft, small ( <1 cm), nontender nodes
are frequently felt.
Thickening of the nipple and loss
of elasticity suggest an underlyingcancer.
Gynecomastia is attributed to an

imbalance of estrogens and andro-gens, sometimes drug-related. Ahard, irregular, eccentric, or ulcer-ating nodule is not gynecomastiaand suggests breast cancer.
Deodorant and other rashes
Sweat gland infection ( hidradenitis
suppurativa )
Deeply pigmented, velvety axillary
skin suggests acanthosis nigricans,
one form of which is associatedwith internal malignancy.
Enlarged axillary nodes from infec-
tion of the hand or arm, recent immunizations or skin tests in thearm, or part of a generalizedlymphadenopathy. Check theepitrochlear nodes and othergroups of lymph nodes.
Nodes that are large ( ≥1 cm) and
ﬁrm or hard, matted together, or ﬁxed to the skin or to under-lying tissues suggest malignant involvement.

CHAPTER 8 ITHE BREASTS AND AXILLAE 311Use your left hand to examine the right axilla.
If the central nodes feel large, hard, or tender, or if there is a suspicious lesion
in the drainage areas for the axillary nodes, feel for the other groups of axillarylymph nodes:
IPectoral nodes —grasp the anterior axillary fold between your thumb and
ﬁngers, and with your ﬁngers palpate inside the border of the pectoralmuscle.
ILateral nodes —from high in the axilla, feel along the upper humerus.
ISubscapular nodes —step behind the patient and with your ﬁngers feel in-
side the muscle of the posterior axillary fold.
Also, feel for infraclavicular nodes and reexamine the supraclavicular nodes.
Assessment of Spontaneous Nipple Discharge. If there is a history

of spontaneous nipple discharge, try to determine its origin by compressingthe areola with your index ﬁnger, placed in radial positions around the nipple.Watch for discharge appearing through one of the duct openings on the nip-ple’s surface. Note the color, consistency, and quantity of any discharge andthe exact location where it appears.
Milky discharge unrelated to a
prior pregnancy and lactation iscalled nonpuerperal galactorrhea .
Leading causes are hormonal andpharmacologic.

312 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGExamination of The Mastectomy Patient. The woman with a mas-
tectomy warrants special care on examination. Inspect the mastectomy scarand axilla carefully for any masses or unusual nodularity. Note any change incolor or signs of inﬂammation. Lymphedema may be present in the axilla andupper arm from impaired lymph drainage after surgery. Palpate gently alongthe scar—these tissues may be unusually sensitive. Use a circular motion withtwo or three ﬁngers. Pay special attention to the upper outer quadrant andaxilla. Note any enlargement of the lymph nodes or signs of inﬂammation orinfection.
It is especially important to carefully palpate the breast tissue and incision lines
of women with breast augmentation or reconstruction.
Instructions for The Breast Self-Examination. The ofﬁce or hos-

pital visit is an important time to teach the patient how to perform the breastself-examination (BSE). A high proportion of breast masses are detected bywomen examining their own breasts. Although BSE has not been shown toreduce breast cancer mortality, monthly BSE is inexpensive and may promotestronger health awareness and more active self-care. For early detection ofbreast cancer, the BSE is most useful when coupled with regular breast ex-amination by an experienced clinician and mammography. The BSE is besttimed just after menses, when hormonal stimulation of breast tissue is low.A nonmilky unilateral discharge
suggests local breast disease. Thecausative lesion is usually benign,but may be malignant, especiallyin elderly women. A benign intra-ductal papilloma is shown above inits usual subareolar location. Notethe drop of blood exuding from aduct opening.

Masses, nodularity, change in color
or inﬂammation, especially in theincision line, suggest recurrence ofbreast cancer.
Papilloma

CHAPTER 8 ITHE BREASTS AND AXILLAE 313PATIENT INSTRUCTIONS FOR THE BREAST 
SELF-EXAMINATION (BSE)
Lying Supine
1. Lie down with a pillow under your
right shoulder. Place your right armbehind your head.
2. Use the ﬁnger pads of the three mid-
dle ﬁngers on your left hand to feelfor lumps in the right breast. The ﬁn-ger pads are the top third of eachﬁnger.
3. Press ﬁrmly enough to know how
your breast feels. A ﬁrm ridge inthe lower curve of each breast isnormal. If you’re not sure howhard to press, talk with your healthcare provider, or try to copy theway the doctor or nurse does it.
Standing
1. Repeat the examination of both

Standing
breasts while standing, with one arm behind your head. The uprightposition makes it easier to check the upper outer part of the breasts (toward your armpit). This is whereabout half of breast cancers arefound. You may want to do the upright part of the BSE while you are in the shower. Your soapy hands will make it easy to check 4. Press ﬁrmly on the breast in an
up-and-down or “strip” pattern.You can also use a circular orwedge pattern, but be sure to usethe same pattern every time.Check the entire breast area, andremember how your breast feelsfrom month to month.
5. Repeat the examination on your
left breast, using the ﬁnger padsof the right hand.
6. If you ﬁnd any changes, see your
doctor right away.
how your breasts feel as they glide
over the wet skin.
2. For added safety, you might want to

check your breasts by standing infront of a mirror right after your BSEeach month. See if there are anychanges in the way your breasts look,such as dimpling of the skin, changesin the nipple, redness, or swelling.
3. If you ﬁnd any changes, see your
Adapted from the American Cancer Society, www.cancer.org . Accessed 9/1/01.

TABLE 8-1 IVisible Signs of Breast Cancer
314 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Retraction Signs
Mechanism
As breast cancer advances, it causes ﬁbrosis (scar
tissue). Shortening of this ﬁbrotic tissue producesretraction signs, including dimpling, changes incontour, and retraction or deviation of the nipple.Other causes of retraction include fat necrosis andmammary duct ectasia.
Skin Dimpling
Look for this sign with the patient’s arm at rest,during special positioning, and on moving orcompressing the breast, as illustrated here.Edema of the Skin
Edema of the skin is produced by lymphaticblockade. It appears as thickened skin withenlarged pores—the so-called peau d’orange
(orange peel) sign. It is often seen ﬁrst in the
lower portion of the breast or areola.
Cancer
Dimpling
Retracted
nipple
Abnormal Contours
Look for any variation in the normal convexity of

Cancer
Dimpling
Retracted
nipple
each breast, and compare one side with the other.Special positioning may again be useful. Shown hereis marked ﬂattening of the lower outer quadrant ofthe left breast.Nipple Retraction and Deviation
A retracted nipple is flattened or pulled inward, as illustrated here. It may also be broadened, andfeels thickened. When involvement is radiallyasymmetric, the nipple may deviate, i.e., point in adifferent direction from its normal counterpart,typically toward the underlying cancer.Paget’s Disease of the Nipple
This is an uncommon form of breast cancer thatusually starts as a scaly, eczemalike lesion. Theskin may also weep, crust, or erode. A breast massmay be present. Suspect Paget’s disease in anypersisting dermatitis of the nipple and areola.
Dermatitis of 
areola
Erosion of nipple

TABLE 8-2 ICommon Breast Masses
CHAPTER 8 ITHE BREASTS AND AXILLAE 315
Fibroadenoma Cysts Cancer
Usual Age
NumberShape
ConsistencyDelimitation
MobilityTenderness
Retraction
Signs30–50, regress after menopause except with
estrogen therapy
Single or multiple
Round
Soft to ﬁrm, usually elasticWell delineated
MobileOften tender
Absent15–25, usually puberty and young adulthood,
but up to age 55
Usually single, may be multiple
Round, disclike, or lobular
May be soft, usually ﬁrmWell delineated
Very mobileUsually nontender
Absent30–90, most common over 50 in
middle-aged and elderly women
Usually single, although may coexist
with other nodules
Irregular or stellateFirm or hardNot clearly delineated from
surrounding tissues
May be ﬁxed to skin or underlying
tissues
Usually nontenderMay be present
TABLE 8-2 ICommon Breast Masses 
The three most common kinds of breast masses are ﬁbroadenoma (a benign tumor),
cysts, and breast cancer. The clinical characteristics of these masses are listed below.

However, any breast mass should be carefully evaluated and usually warrants furtherinvestigation by ultrasound, aspiration, mammography, or biopsy. The masses de-picted below are rather large, for purposes of illustration. Ideally, breast cancer shouldbe identiﬁed early, when the mass is small. Fibrocystic changes, not illustrated, are also
commonly palpable as nodular, ropelike densities in women ages 25–50. They maybe tender or painful. They are considered benign and are not considered a risk fac-tor for breast cancer.

The AbdomenCHAPTER
The Abdomen 99
CHAPTER 9 ITHE ABDOMEN 317
Inspect the abdominal wall and pelvis, and visualize or palpate the landmarks
illustrated. The rectus abdominis muscles become more prominent when thepatient raises the head and shoulders from the supine position.
Rectus abdominis
muscle
Umbilicus
Inguinal ligament
Pubic tubercleXiphoid process
Costal margin
Midline, overlying
linea alba
Anterior superior
iliac spine
Symphysis pubisIliac crest

For descriptive purposes, the ab-
domen is often divided by imaginarylines crossing at the umbilicus, form-ing the right upper, right lower, leftupper, and left lower quadrants. An-other system divides the abdomeninto nine sections. Terms for three ofthem are commonly used: epigastric,umbilical, and hypogastric, or supra-pubic.
When examining the abdomen, you
may be able to feel several normalstructures. The sigmoid colon is fre-
quently palpable as a ﬁrm, narrowtube in the left lower quadrant, whilethe cecum and part of the ascendingcolon form a softer, wider tube in theright lower quadrant. Portions of thetransverse and descending colon mayalso be palpable. None of these struc-tures should be mistaken for a tumor.Although the normal liver often ex-

tends down just below the rightcostal margin, its soft consistencymakes it difﬁcult to feel through theabdominal wall. The lower margin ofthe liver, the liver edge, is often pal-pable. Also in the right upper quad-rant, but usually at a deeper level, liesthe lower pole of the right kidney. Itis occasionally palpable, especially inthin individuals with relaxed abdom-inal muscles. Pulsations of the ab-
dominal aorta are frequently visible
and usually palpable in the upper ab-domen, while the pulsations of theiliac arteries may sometimes be felt in
the lower quadrants.
The abdominal cavity extends up under the rib cage to the dome of the di-
aphragm. In this protected location, beyond the reach of the palpating hand,are much of the liver and stomach and all of the usual normal spleen. The
spleen lies against the diaphragm at the level of the 9th, 10th, and 11th ribs,

mostly posterior to the left midaxillary line. It is lateral to and behind thestomach, and just above the left kidney. The tip of a normal spleen is palpa-ble below the left costal margin in a small percentage of adults.
Most of the normal gallbladder lies deep to the liver and cannot be distin-
guished from it clinically. The duodenum and pancreas lie deep in the upper
abdomen, where they are not normally palpable.ANATOMY AND PHYSIOLOGY
318 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Liver
Lower pole of
right kidney
Ascending colon
Sacral
promontory
Pregnant
uterusXiphoid 
process
Aorta
Transverse colon
Descending and
sigmoid colon
Full bladderCecum
Iliac artery
RUQ
LLQLUQ
RLQ
Umbilical
Hypogastric
or 
suprapubic

A distended bladder may be palpable above the symphysis pubis. The blad-
der accommodates roughly 300 ml of urine ﬁltered by the kidneys into therenal pelvis and the ureters. Bladder expansion stimulates contraction of blad-der smooth muscle, the detrusor muscle, at relatively low pressures. Rising
pressure in the bladder triggers the conscious urge to void.
Increased intraurethral pressure can overcome rising pressures in the blad-
der and prevent incontinence. Intraurethral pressure is related to such fac-tors as smooth muscle tone in the internal urethral sphincter, the thicknessof the urethral mucosa, and in women, sufﬁcient support to the bladder andproximal urethra from pelvic muscles and ligaments to maintain properanatomic relationships. Striated muscle around the urethra can also contractvoluntarily to interrupt voiding.
Neuroregulatory control of the bladder functions at several levels. In infants,

the bladder empties by reﬂex mechanisms in the sacral spinal cord. Volun-tary control of the bladder depends on higher centers in the brain and onmotor and sensory pathways between the brain and the reﬂex arcs of thesacral spinal cord. When voiding is inconvenient, higher centers in the braincan inhibit detrusor contractions until the capacity of the bladder, about 400to 500 ml, is exceeded. The integrity of the sacral nerves that innervate thebladder can be tested by assessing perirectal and perineal sensation in the S2,S3, and S4 dermatomes (see p. 546).
Other structures sometimes palpable in the lower abdomen include the uterus
enlarged by pregnancy or ﬁbroids, which may also rise above the symphysispubis, and the sacral promontory , the anterior edge of the ﬁrst sacral vertebra.

Until you are familiar with this normal structure, you may mistake its stony hardoutlines for a tumor. Another stony hard lump that can sometimes mislead you,and may occasionally alarm a patient, is a normal xiphoid process .
The kidneys are posterior organs. Their upper portions are protected by the
ribs. The costovertebral angle —the angle formed by the lower border of theANATOMY AND PHYSIOLOGY
CHAPTER 9 ITHE ABDOMEN 319
Liver
Gallbladder
DuodenumSpleen
Stomach
Pancreas
ANTERIOR VIEW

12th rib and the transverse processes of the upper lumbar vertebrae—deﬁnes
the region to assess for kidney tenderness.
During the middle and later years, fat tends to accumulate in the lower ab-domen and near the hips, even when total body weight is stable. This accu-mulation, together with weakening of the abdominal muscles, often producesa potbelly. Occasionally a person notes this change with alarm and interpretsit as ﬂuid or evidence of disease.
Old age may blunt the manifestations of acute abdominal disease. Pain may
be less severe, fever is often less pronounced, and signs of peritoneal inﬂam-mation, such as muscular guarding and rebound tenderness (p. 335), maybe diminished or even absent.
320 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Costovertebral
angle
12th rib11th rib
Kidney
POSTERIOR VIEW
Gastrointestinal Disorders
IIndigestion or anorexia
INausea, vomiting, or 
hematemesis
IAbdominal pain

angle
Kidney
IDysphagia and/or odynophagia
IChange in bowel function
IConstipation or diarrhea
IJaundiceUrinary and Renal Disorders
ISuprapubic pain
IDysuria, urgency, or frequency
IHesitancy, decreased stream inmales
IPolyuria or nocturia
IUrinary incontinence
IHematuria
IKidney or ﬂank pain
IUreteral colic

You will encounter a wide variety of gastrointestinal and urinary complaints
in clinical practice. Careful interviewing will often lead you to the underlyingdisorder. This section addresses such gastrointestinal concerns as indigestion,
anorexia, nausea or vomiting, hematemesis, abdominal pain, dysphagia or
odynophagia, change in bowel function, constipation and diarrhea, and
jaundice. There is also health history information on disorders of the urinary
tract, including complaints of suprapubic pain, dysuria, urgency, frequency,
hesitancy or decreased stream in males, polyuria, nocturia, incontinence,
hematuria, kidney pain, and ureteral colic.
The Gastrointestinal Tract
“How is your appetite ?” is a good starting question and may lead into other
important areas such as indigestion, nausea, vomiting, and anorexia. Patients
often complain of indigestion, a common complaint that refers to distress as-

sociated with eating, but patients use the term for many different symptoms.Find out just what your patient means. Possibilities include:
IHeartburn, or a sense of burning or warmth that is retrosternal and may
radiate from the epigastrium to the neck. It usually originates in the esoph-agus. If persistent, especially in the epigastric area, it may raise the ques-tion of heart disease. Some patients with coronary artery disease describetheir pain as burning, “like indigestion.” Pay special attention to whatbrings on the discomfort and what relieves it. Is it precipitated by exertionand relieved by rest, suggesting angina, or is it related to meals and madeworse during or after eating, suggesting gastroesophageal reﬂux?
IExcessive gas, especially with frequent belching, abdominal bloating or dis-

tention, or ﬂatus , the passage of gas by rectum, normally about 600 ml
per day. Find out if these symptoms are associated with eating speciﬁcfoods. Ask if symptoms are related to ingestion of milk or milk products.
IUnpleasant abdominal fullness after meals of normal size, or early satiety,
the inability to eat a full meal.
INausea and vomiting
CHAPTER 9 ITHE ABDOMEN 321Anorexia, nausea, vomiting in
many gastrointestinal disorders;also in pregnancy, diabetic ketoacidosis, adrenal insufﬁciency, hypercalcemia, uremia, liver disease, emotional states, adverse drug reactions, and other conditions. Induced butwithout nausea in anorexia/bulimia.
Heartburn suggests gastric acid

Heartburn suggests gastric acid 
reﬂux into the esophagus; oftenprecipitated by a heavy meal, lying down, or bending forward,also by ingested alcohol, citrusjuices, or aspirin. If chronic, consider reﬂux esophagitis. See Table 6-1, Chest Pain, pp. 234–235.
Belching, but not bloating or excess
ﬂatus, normally seen in aerophagia ,
or swallowing air. Also considerlegumes and other gas-producingfoods, intestinal lactase deﬁciency,irritable bowel syndrome.
Consider diabetic gastroparesis,
anticholinergic drugs, gastric out-let obstruction, gastric cancer;early satiety in hepatitis.

Anorexia is a loss or lack of appetite. Find out if it arises from intolerance to
certain foods or reluctance to eat due to anticipated discomfort. Nausea ,
often described as “feeling sick to my stomach,” may progress to retchingor vomiting. Retching describes the spasmodic movements of the chest and
diaphragm that precede and culminate in vomiting, the forceful expulsion of
gastric contents out through the mouth.
Some patients may not actually vomit but raise esophageal or gastric con-
tents in the absence of nausea or retching, called regurgitation.
Ask about any vomitus or regurgitated material and inspect it yourself if pos-
sible. What color is it? What does the vomitus smell like? How much hasthere been? Ask speciﬁcally if it contains any blood and try to determine howmuch. You may have to help the patient with the amount . . . a teaspoon?Two teaspoons? A cupful?
Gastric juice is clear or mucoid. Small amounts of yellowish or greenish bile

are common and have no special signiﬁcance. Brownish or blackish vomituswith a “coffee-grounds” appearance suggests blood altered by gastric acid.Coffee-grounds emesis or red blood are termed hematemesis.
Do the patient’s symptoms suggest any complications of vomiting such as
aspiration into the lungs, seen in elderly, debilitated, or obtunded patients?
Is there dehydration or electrolyte imbalance from prolonged vomiting, orsigniﬁcant loss of blood?
Abdominal pain has several possible mechanisms and clinical patterns and
warrants careful clinical assessment. Be familiar with three broad categoriesof abdominal pain:
IVisceral pain occurs when hollow abdominal organs such as the intestine

or biliary tree contract unusually forcefully or when they are distended orstretched. Solid organs such as the liver can also become painful whentheir capsules are stretched. Visceral pain may be difﬁcult to localize. It istypically, though not necessarily, palpable near the midline, at levels thatvary according to the structure involved, as illustrated on the next page.
Visceral pain varies in quality and may be gnawing, burning, cramping, or
aching. When it becomes severe, it may be associated with sweating, pal-lor, nausea, vomiting, and restlessness.
IParietal pain originates in the parietal peritoneum and is caused by in-

ﬂammation. It is a steady aching pain that is usually more severe than vis-ceral pain and more precisely localized over the involved structure. It istypically aggravated by movement or coughing. Patients with this type ofpain usually prefer to lie still.THE HEALTH HISTORY
322 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGAnorexia, nausea, vomiting in
many gastrointestinal disorders;also in pregnancy, diabetic keto-acidosis, adrenal insufﬁciency,hypercalcemia, uremia, liver dis-
ease, em otional states, adverse drug
reactions. Induced but without nausea in anorexia/bulimia nervosa.
Regurgitation in esophageal narrow-
ing from stricture or cancer; alsowith incompetent gastroesophagealsphincter
Fecal odor in small bowel obstruc-
tion or gastrocolic ﬁstula
Hematemesis in duodenal or pep-

tic ulcer, esophageal or gastricvarices, gastritis
Symptoms of blood loss such as
light-headedness or syncope de-pend on the rate and volume ofbleeding, and rarely appear untilblood loss ≥500 ml.
See Table 9-1, Abdominal Pain 
(pp. 350–351).
Visceral pain in the right upper
quadrant from liver distentionagainst its capsule in alcoholic hepatitis
Visceral periumbilical pain in early
acute appendicitis from distentionof inﬂamed appendix, graduallychanging to parietal pain in theright lower quadrant from inﬂam-mation of the adjacent parietalperitoneumEXAMPLES OF ABNORMALITIES

IReferred pain is felt in more distant sites, which are innervated at approx-
imately the same spinal levels as the disordered structure. Referred painoften develops as the initial pain becomes more intense and thus seems toradiate or travel from the initial site. It may be felt superﬁcially or deeplybut is usually well localized.
Pain may also be referred to the abdomen from the chest, spine, or pelvis,
thus complicating the assessment of abdominal pain.
Ask patients to describe the abdominal pain in their own words, then ask them
to point to the pain. If clothes interfere, repeat the question during the phys-
ical examination. You may need to pursue important details: “Where doesthe pain start?” “Does it radiate or travel anywhere?” “What is the pain like?”If the patient has trouble describing the pain, try a multiple-choice questionsuch as “Is it aching, burning, gnawing, or what?”
You need to ask “How severe is the pain?” “How about on a scale of 1 to

10?” Find out if it is bearable and if it interferes with the patient’s usual activities. Does it make the patient lie down?
The description of the severity of the pain may tell you something about the
patient’s responses to pain and its impact on the patient’s life, but it is notconsistently helpful in assessing the pain’s cause. Sensitivity to abdominalpain varies widely and tends to diminish over the later years, masking acuteabdominal problems in older people, especially those in or beyond their 70s.THE HEALTH HISTORY
CHAPTER 9 ITHE ABDOMEN 323Pain of duodenal or pancreatic ori-
gin may be referred to the back;pain from the biliary tree, to theright shoulder or the right poste-rior chest.
Pain from pleurisy or acute myo-
cardial infarction may be referredto the upper abdomen.
Cramping colicky pain often is 
related to peristalsis.
Right upper quadrant or
epigastric pain from thebiliary tree and liver

Suprapubic or sacral
pain from the rectumEpigastric pain from
the stomach, duodenum,or pancreas
Periumbilical pain
from the smallintestine, appendix,or proximal colon
Hypogastric pain
from the colon,bladder, or uterus.Colonic pain maybe more diffusethan illustrated.EXAMPLES OF ABNORMALITIES

Careful timing of the pain , on the other hand, is particularly helpful. Did it
start suddenly or gradually? When did the pain begin? How long does it last?What is its pattern over a 24-hour period? Over weeks and months? Are youdealing with an acute illness or a chronic or recurring one?
Determine what factors aggravate or relieve the pain, with special reference
to meals, antacids, alcohol, medications (including aspirin and aspirinlikedrugs and any over-the-counter drugs), emotional factors, and body posi-tion. Also, is the pain related to defecation, urination, or menstruation? Youalso need to elicit any symptoms that are associated with the pain , such as fever
or chills, and ask in what sequence they occur.
Less commonly, patients may report difﬁculty swallowing, or dysphagia , the

sense that food or liquid is sticking, hesitating, or “won’t go down right.”Dysphagia may result from esophageal disorders or from difﬁculty transfer-ring food from the mouth to the esophagus. The sensation of a lump in thethroat or in the retrosternal area, unassociated with swallowing, is not truedysphagia.
Ask the patient to point to where the dysphagia occurs and describe with
what types of food. Does it occur with relatively solid foods such as meat,with softer foods such as ground meat and mashed potatoes, or with hot orcold liquids? Has the pattern changed?
Establish the timing. When did it start? Is it intermittent or persistent? Is it
progressing? If so, over what period of time? What are the associated symp-toms and medical conditions?
Odynophagia , or pain on swallowing, may occur in two forms. A sharp,

burning pain suggests mucosal inﬂammation, while a squeezing, crampingpain suggests a muscular cause. Odynophagia may accompany dysphagia,but either symptom may occur independently.
With respect to the lower gastrointestinal tract, you will frequently need to
assess bowel function. Start with open-ended questions: “How are your
bowel movements?” “How frequent are they?” “Do you have any difﬁcul-ties?” “Have you noticed any change in your bowel habits?” Frequency ofbowel movements normally ranges from about three times a day to twice aweek. A change in pattern within these limits, however, may be signiﬁcantfor an individual patient.
Patients vary widely in their views of constipation and diarrhea. Be sure to clar-
ify what the patient means by these terms. For example, is constipation . . . a

decrease in frequency of bowel movements? . . . The passage of hard and per-haps painful stools? . . . The need to strain unusually hard? . . . A sense of in-complete defecation or pressure in the rectum? Ask if the patient actually looksat the stool. If yes, what does the stool look like in terms of color and bulk?What remedies has the patient tried? Do medications, stress, unrealistic ideasTHE HEALTH HISTORY
324 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGCitrus fruits may aggravate the
pain of reﬂux esophagitis; possiblelactase deﬁciency if abdominal discomfort from milk ingestion
For types of dysphagia, see 
Table 9-2, Dysphagia, p. 352.
Pointing to the throat suggests a
transfer or esophageal disorder;pointing to the chest suggests anesophageal disorder.
Dysphagia with solid food in

Dysphagia with solid food in 
mechanical narrowing of theesophagus; dysphagia related toboth solids and liquids suggests adisorder of esophageal motility.
Mucosal inﬂammation in reﬂux
esophagitis or infection from Candida , herpesvirus, or cyto-
megalovirus.
See Table 9-3, Constipation 
(p. 353).
Thin pencil-like stool in an obstruct-
ing “apple-core” lesion of the sigmoid colonEXAMPLES OF ABNORMALITIES

about normal bowel habits, or time and setting allotted for defecation play a
role? Occasionally there is complete constipation with no passage of eitherfeces or gas, or obstipation .
Inquire about the color of the stools and ask about any black tarry stools,
suggesting melena, or red blood in the stools , known as hematochezia. If either
condition is present, ﬁnd out how long and how often. If the blood is red,how much is there? Is it pure blood mixed in with stool or on the surface ofthe stool? Is there blood on the toilet paper?
Diarrhea is an excessive frequency in the passage of stools that are usually
unformed or watery. Ask about size, frequency, and volume. Are the stoolsbulky or small? How many episodes of diarrhea occur each day?
Ask for descriptive terms. Are the stools greasy or oily? Frothy? Foul smelling?
Floating on the surface because of excessive gas, making them difﬁcult toﬂush? Accompanied by mucus, pus, or blood?

Assess the course of diarrhea over time. Is it acute, chronic, or recurrent? Or
is your patient experiencing the ﬁrst acute episode of a chronic or recurrentillness?
Look into other factors as well. Does the diarrhea awaken the patient at
night? What seem to be the aggravating or relieving factors? Does the pa-tient get relief from a bowel movement, or is there an intense urge withstraining but little or no result, known as tenesmus . What is the setting? Does
it entail travel, stress, or a new medication? Do family members or compan-ions have similar symptoms? Are there associated symptoms?
In some patients, you will be struck by jaundice or icterus , the yellowish dis-

coloration of the skin and sclerae from increased levels of bilirubin, a bilepigment derived chieﬂy from the breakdown of hemoglobin. Normally thehepatocytes conjugate, or combine, unconjugated bilirubin with other sub-stances, making the bile water soluble, and then excrete it into the bile. Thebile passes through the cystic duct into the common bile duct, which alsodrains the extrahepatic ducts from the liver. More distally the common bileduct and the pancreatic ducts empty into the duodenum at the ampulla ofVater. Mechanisms of jaundice include:
IIncreased production of bilirubin
IDecreased uptake of bilirubin by the hepatocytes
IDecreased ability of the liver to conjugate bilirubinTHE HEALTH HISTORY
CHAPTER 9 ITHE ABDOMEN 325Obstipation in intestinal obstruction
See Table 9-5, Black and Bloody
Stools, p. 356.
Blood on the stool surface and on
toilet paper in hemorrhoids
Consistently large diarrheal

Consistently large diarrheal 
stools often in small bowel or proximal colon disorders; small frequent stools with urgency ofdefecation in left colon or rectaldisorders
Large yellowish or gray greasy foul
smelling, sometimes frothy orﬂoating stools in steatorrhea , or
fatty stools—seen in malabsorption
See Table 9-4, Diarrhea 
(pp. 354–355).
Nocturnal diarrhea suggests a
pathophysiologic cause.
Relief after passing feces or gas sug-
gests left colon or rectal disorders;tenesmus in rectal conditions nearthe anal sphincter
Predominantly unconjugated
bilirubin from the ﬁrst three mech-anisms, as in hemolytic anemia (increased production) andGilbert’s syndromeEXAMPLES OF ABNORMALITIES

IDecreased excretion of bilirubin into the bile, resulting in absorption of
conjugated bilirubin back into the blood.
Intrahepatic jaundice can be hepatocellular , from damage to the hepato-
cytes, or cholestatic , from impaired excretion due to damaged hepatocytes
or intrahepatic bile ducts. Extrahepatic jaundice arises from obstruction
of the extrahepatic bile ducts, most commonly the cystic and commonbile ducts.
As you assess the jaundiced patient, pay special attention to the associated
symptoms and the setting in which the illness occurred. What was the color
of the urine as the patient became ill? When the level of conjugated bilirubin
increases in the blood, it may be excreted into the urine, turning the urinea dark yellowish brown or tea color. Unconjugated bilirubin is not water-soluble so is not excreted into urine.
Ask also about the color of the stools. When excretion of bile into the intes-

tine is completely obstructed, the stools become gray or light-colored, oracholic , without bile.
Does the skin itch without other obvious explanation? Is there associated
pain? What is its pattern? Has it been recurrent in the past?
Are there risk factors for liver diseases such as:
IHepatitis: Travel or meals in areas of poor sanitation, ingestion of con-
taminated water or foodstuffs (hepatitis A); parenteral or mucous mem-brane exposure to infectious body ﬂuids such as blood, serum, semen, andsaliva, especially through sexual contact with an infected partner or use ofshared needles for injection drug use (hepatitis B); intravenous illicit druguse or blood transfusion (hepatitis C)
IAlcoholic hepatitis or alcoholic cirrhosis (interview the patient carefully
about alcohol use)
IToxic liver damage from medications, industrial solvents, or environmental
toxins

toxins
IGallbladder disease or surgery that may result in extrahepatic biliary 
IHereditary disorders in the Family HistoryTHE HEALTH HISTORY
326 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGImpaired excretion of conjugated
bilirubin in viral hepatitis, cirrhosis,primary biliary cirrhosis, drug-induced cholestasis, as with oralcontraceptives, methyl testosterone,chlorpromazine
Obstruction of the common bile
duct by gallstones or pancreaticcarcinoma
Dark urine from bilirubin indicates
impaired excretion of bilirubin intothe gastrointestinal tract.
Acholic stools brieﬂy in viral 
hepatitis, common in obstructivejaundice
Itching in cholestatic or obstructive
jaundice; pain from a distendedliver capsule, biliary cholic, pancreatic cancerEXAMPLES OF ABNORMALITIES

The Urinary Tract
General questions for a urinary history include: “Do you have any difﬁculty
passing your urine?” “How often do you go?” “Do you have to get up atnight? How often?” “How much urine do you pass at a time?” “Is there anypain or burning?” “Do you ever have trouble getting to the toilet in time?”“Do you ever leak any urine? Or wet yourself involuntarily?” Does the pa-tient sense when the bladder is full and when voiding occurs?
Ask women if sudden coughing, sneezing, or laughing makes them lose
urine. Roughly half of young women report this experience even beforebearing children. Occasional leakage is not necessarily signiﬁcant. Ask oldermen “Do you have trouble starting your stream?” “Do you have to standclose to the toilet to void?” “Is there a change in the force or size of yourstream, or straining to void?” “Do you hesitate or stop in the middle of void-ing?” “Is there dribbling when you’re through?”
What color is the urine? Has it ever been reddish or brown?

Disorders in the urinary tract may cause pain in either the abdomen or the
back. Bladder disorders may cause suprapubic pain . In bladder infection ,
pain in the lower abdomen is typically dull and pressurelike. In suddenoverdistention of the bladder, pain is often agonizing; in contrast, chronicbladder distention is usually painless.
Infection or irritation of either the bladder or urethra often provokes several
symptoms. Frequently there is pain on urination , usually felt as a burning
sensation. Some clinicians refer to this as dysuria , while others reserve the
term dysuria for difﬁculty voiding. Women may report internal urethral dis-comfort, sometimes described as a pressure, or an external burning from theﬂow of urine across irritated or inﬂamed labia. Men typically feel a burningsensation proximal to the glans penis. In contrast, prostatic pain is felt in the
perineum and occasionally in the rectum.

Commonly, there are other associated symptoms. Urinary urgency is an un-
usually intense and immediate desire to void, sometimes leading to invol-untary voiding or urge incontinence . Urinary frequency , or abnormally
frequent voiding, may occur. Ask about any related fever or chills, blood inthe urine, or any pain in the abdomen, ﬂank, or back (see the next page).Men with partial obstruction to urinary outﬂow often report hesitancy in
starting the urine stream, straining to void, reduced caliber and force of the
urinary stream, or dribbling as voiding is completed.
Three additional terms describe important alterations in the pattern of uri-
nation. Polyuria refers to a signiﬁcant increase in 24-hour urine volume,
CHAPTER 9 ITHE ABDOMEN 327See Table 9-6, Frequency, Nocturia,
and Polyuria (p. 357).
Involuntary voiding or lack of
awareness suggests cognitive orneurosensory deﬁcits.
Stress incontinence from decreased

intraurethral pressure (see below)
Common in men with partial blad-
der outlet obstruction from benignprostatic hyperplasia; also seenwith urethral stricture
Hematuria , or blood in the urine
Pain of sudden overdistention in
acute urinary retention
Painful urination with cystitis or
urethritis
Also consider bladder stones, 
foreign bodies, tumors; also acuteprostatitis. In women, internalburning in urethritis, externalburning in vulvovaginitis
Urgency in bladder infection or 
irritation. In men, painful urinationwithout frequency or urgency suggests urethritis.
Abnormally high renal production
of urine in polyuria. FrequencyEXAMPLES OF ABNORMALITIES

roughly deﬁned as exceeding 3 liters. It should be distinguished from uri-
nary frequency, which can involve voiding in high amounts, seen in polyuria,or in small amounts, as in infection. Nocturia refers to urinary frequency at
night, sometimes deﬁned as awakening the patient more than once; urinevolumes may be large or small. Clarify any change in nocturnal voiding pat-terns and the number of trips to the bathroom.
Up to 30% of older patients are concerned about urinary incontinence , an

involuntary loss of urine that may become socially embarrassing or causeproblems with hygiene. If the patient reports incontinence, ask when it hap-pens and how often. Find out if the patient has leaking of small amounts ofurine with increased intra-abdominal pressure from coughing, sneezing,laughing, or lifting. Or is it difﬁcult for the patient to hold the urine oncethere is an urge to void, and loss of large amounts of urine? Is there a sen-sation of bladder fullness, frequent leakage or voiding of small amounts butdifﬁculty emptying the bladder?
As described earlier, bladder control involves complex neuroregulatory and
motor mechanisms (see p. 319). A number of central or peripheral nerve le-sions may affect normal voiding. Can the patient sense when the bladder isfull? And when voiding occurs? Although there are four broad categories ofincontinence, a patient may have a combination of causes.

In addition, the patient’s functional status may have a signiﬁcant impact on
voiding behaviors even when the urinary tract is intact. Is the patient mo-bile? Alert? Able to respond to voiding cues and reach the bathroom? Isalertness or voiding affected by medications?
Blood is the urine, or hematuria , is an important cause for concern. When
visible to the naked eye, it is called gross hematuria . The urine may appearTHE HEALTH HISTORY
328 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGwithout polyuria during the day or
night in bladder disorder or impair-ment to ﬂow at or below the blad-der neck
See Table 9-7, Urinary Inconti-
nence (pp. 358–359).
Stress incontinence with increased
intra-abdominal pressure from de-creased contractility of urethralsphincter or poor support of blad-der neck; urge incontinence if un-
able to hold the urine, fromdetrusor overactivity; overﬂow in-
continence when the bladder can-

not be emptied until bladderpressure exceeds urethral pressure,from anatomic obstruction by pro-static hypertrophy or stricture, alsoneurogenic abnormalities
Functional incontinence from im-
paired cognition, musculoskeletalproblems, immobility
Kidney pain
Ureteral painEXAMPLES OF ABNORMALITIES

frankly bloody. Blood may be detected only during microscopic urinaly-
sis, known as microscopic hematuria . Smaller amounts of blood may tinge
the urine with a pinkish or brownish cast. In women, be sure to distinguishmenstrual blood from hematuria. If the urine is reddish, ask about inges-tion of beets or medications that might discolor the urine. Test the urinewith a dipstick and microscopic examination before you settle on the termhematuria.
Disorders of the urinary tract may also cause kidney pain , often reported as
ﬂank pain at or below the posterior costal margin near the costovertebral
angle. It may radiate anteriorly toward the umbilicus. Kidney pain is a vis-ceral pain usually produced by distention of the renal capsule and typicallydull, aching, and steady. Ureteral pain is dramatically different. It is usually

severe and colicky, originating at the costovertebral angle and radiatingaround the trunk into the lower quadrant of the abdomen, or possibly intothe upper thigh and testicle or labium. Ureteral pain results from sudden dis-tention of the ureter and associated distention of the renal pelvis. Ask aboutany associated fever or chills, or hematuria.HEALTH PROMOTION AND COUNSELING
CHAPTER 9 ITHE ABDOMEN 329Kidney pain occurs in acute
pyelonephritis.
Renal or ureteral colic is caused by
sudden obstruction of a ureter, asby urinary stones or blood clots.
Health promotion and counseling relevant to the abdomen include screen-

ing for alcoholism, risk of infectious hepatitis, and risk of colon cancer. Cluesfrom social patterns and behavioral problems in the history and ﬁndings ofliver enlargement or tenderness on physical examination often alert the clin-ician to possible alcoholism or risk of infectious hepatitis. Past medical his-tory and family history are important when assessing risk of colon cancer.
The impact of alcohol and substance abuse on public health may be even

greater than that of illicit drugs. Assessing patients for use of alcohol andother substances is a primary responsibility of all clinicians. The clinicianshould focus on detection, counseling, and, for signiﬁcant impairment, spe-cific recommendations for treatment. These interventions need not betime-consuming. Use the four CAGE questions, validated across manystudies, to screen for alcohol dependence or abuse in all adolescents andadults, including pregnant women (see p. 413). Brief counseling interven-tions have been shown to reduce alcohol consumption by up to 25%.*
*U.S. Preventive Services Task Force: Guide to Clinical Preventive Services (2nd ed.). Baltimore, Williams
& Wilkins, p. 572, 1996.EXAMPLES OF ABNORMALITIES
IScreening for alcohol and substance abuse
IRisk factors for hepatitis A, B, and C
IScreening for colon cancer

Focus on (1) sharing concern about the adverse effects of alcohol and 
education about harmful consequences, and (2) setting goals for behavioralchange and follow-up. Tailor recommendations for treatment to the sever-ity of the problem, ranging from support groups to inpatient detoxiﬁcationto more extended rehabilitation.
Protective measures against infectious hepatitis include counseling about

how the viruses are spread and the need for immunization. Transmission ofhepatitis A is fecal–oral: fecal shedding in food handlers leads to contamina-tion of water and foods. Illness occurs approximately 30 days after exposure.Hepatitis A vaccine is recommended for travelers to endemic areas, foodhandlers, military personnel, caretakers of children, Native Americans andAlaskan natives, and selected health care, sanitation, and laboratory workers.Vaccination is also recommended for homosexual contacts and injectiondrug users. For immediate protection and prophylaxis for household con-tacts and travelers, consider administering immune serum globulin.
Hepatitis B poses more serious threats to patients’ health, including risk of

fulminant hepatitis as well as chronic infection and subsequent cirrhosis andhepatocellular carcinoma. Transmission occurs during contact with infectedbody ﬂuids, such as blood, semen, saliva, and vaginal secretions. Adults be-tween the ages of 20 and 39 are most affected, especially injection drug usersand sex workers. Up to a tenth of infected adults become chronically in-fected asymptomatic carriers. Behavioral counseling and serologic screeningare advised for patients at risk. Because up to 30% of patients have no iden-tiﬁable risk factors, hepatitis B vaccine is recommended for all young adultsnot previously immunized, injection drug users and their sexual partners,persons at risk for sexually transmitted disease, travelers to endemic areas,recipients of blood products as in hemodialysis, and health care workers withfrequent exposure to blood products. Many of these groups should also bescreened for HIV infection.

It is also important to screen patients for colorectal cancer, second highest

of the malignancies in both prevalence and mortality. Risk factors includefamily history of colonic polyps, history of colorectal cancer or adenoma ina ﬁrst-degree relative, and a personal history of ulcerative colitis, adenoma-tous polyps, or prior diagnosis of endometrial, ovarian, or breast cancer. TheU.S. Preventive Services Task Force recommends annual testing of all per-sons over age 50 with the fecal occult blood test (FOBT), sigmoidoscopy,or both, but details several caveats.** The FOBT has a highly variable sen-sitivity (26%–92%), but good speciﬁcity (90%–99%). It produces many falsepositives related to diet, selected medications, and gastrointestinal condi-tions such as ulcer disease, diverticulosis, and hemorrhoids. The beneﬁts ofsigmoidoscopy are linked to the length of the sigmoidoscope and its depthof insertion. Detection rates for colorectal cancer and insertion depths areroughly as follows: 25%–30% at 20 cm; 50%–55% at 35 cm; 40%–65% atHEALTH PROMOTION AND COUNSELING

330 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING**U.S. Preventive Services Task Force: Guide to Clinical Preventive Services (2nd ed.). Baltimore,
Williams & Wilkins, pp. 89–103, 1996.

CHAPTER 9 ITHE ABDOMEN 331Preview: Recording the Physical Examination—
The Abdomen
“Abdomen is protuberant with active bowel sounds. It is soft and non-
tender; no masses or hepatosplenomegaly. Liver span is 7 cm in theright midclavicular line; edge is smooth and palpable 1 cm below theright costal margin. Spleen and kidneys not felt. No costovertebralangle (CVA) tenderness.”
OR“Abdomen is ﬂat. No bowel sounds heard. It is ﬁrm and boardlike, with
increased tenderness, guarding, and rebound in the right midquadrant.Liver percusses to 7 cm in the midclavicular line; edge not felt. Spleenand kidneys not felt. No CVA tenderness.Suggests peritonitis from possible

appendicitis (see pp. 347–348 andpp. 363–364)40–50 cm. Full colonoscopy or air contrast barium enema detects 80%–95%
of colorectal cancers, but these procedures are more uncomfortable andcolonoscopy is more expensive. When counseling patients about prevention,there is preliminary but inconsistent evidence that diets high in ﬁber mayreduce risk of colorectal malignancy.EXAMPLES OF ABNORMALITIES

332 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGAn arched back thrusts the
abdomen forward, thus tighteningthe abdominal muscles.
For a good abdominal examination you need (1) good light, (2) a relaxed
patient, and (3) full exposure of the abdomen from above the xiphoidprocess to the symphysis pubis. The groin should be visible. The genitaliashould remain draped. The abdominal muscles should be relaxed to enhanceall aspects of the examination, but especially palpation.
Steps for Enhancing Examination of the Abdomen
IThe patient should have an empty bladder.
IMake the patient comfortable in a supine position, with a pillow for the
head and perhaps another under the knees. Slide your hand under thelow back to see if the patient is relaxed and ﬂat on the table.

IHave the patient keep arms at the sides or folded across the chest. Oftenpatients raise their arms over their heads, but this stretches and tightensthe abdominal wall, making palpation difﬁcult.
IBefore you begin palpation, ask the patient to point to any areas of painand examine these areas last.
IWarm your hands and stethoscope, and avoid long ﬁngernails. You mayneed to rub your hands together or warm them up with hot water; youcan also begin palpation through the patient’s gown to absorb warmthfrom the patient’s body before exposing the abdomen properly. Anxietymay make the hands cool, a problem that decreases over time.
IApproach slowly and avoid quick unexpected movements. Watch thepatient’s face closely for any signs of pain or discomfort.

IDistract the patient if necessary with conversation or questions. If thepatient is frightened or ticklish, begin palpation with the patient’s handunder yours. After a few moments, slip your hand underneath to palpatedirectly.
Visualize each organ in the region you are examining. Stand at the pa-
tient’s right side and proceed in an orderly fashion with inspection, aus-cultation, percussion, and palpation. Assess the liver, spleen, kidneys, andaorta.
Starting from your usual standing position at the right side of the bed, in-spect the abdomen. As you look at the contour of the abdomen and watchfor peristalsis, it is helpful to sit or bend down so that you can view theabdomen tangentially.

Note:
IThe skin, including:
Scars. Describe or diagram their location.
Striae. Old silver striae or stretch marks, as illustrated above, are normal.
Dilated veins. A few small veins may be visible normally.
Rashes and lesions
IThe umbilicus . Observe its contour and location, and any signs of inﬂam-
mation or hernia
IThe contour of the abdomen
Is it flat, rounded, protuberant, or scaphoid (markedly concave or
hollowed)?
Do the ﬂanks bulge or are there any local bulges? Include in this survey
the inguinal and femoral areas.
Is the abdomen symmetric?Are there visible organs or masses? Look for an enlarged liver or spleen
that has descended below the rib cage.TECHNIQUES OF EXAMINATION
CHAPTER 9 ITHE ABDOMEN 333Pink–purple striae of Cushing’s 
syndrome
Dilated veins of hepatic cirrhosis or
of inferior vena cava obstruction
See Table 9-8, Localized Bulges in
the Abdominal Wall (p. 360).
See Table 9-9, Protuberant
Abdomens (p. 361).
Bulging ﬂanks of ascites; supra-

pubic bulge of a distended bladderor pregnant uterus; hernias
Asymmetry due to an enlarged
organ or mass
Lower abdominal mass of an ovar-
ian or a uterine tumor

Aorta
Renal artery
Femoral arteryIPeristalsis. Observe for several minutes if you suspect intestinal obstruction.
Peristalsis may be visible normally in very thin people.
IPulsations. The normal aortic pulsation is frequently visible in the epi-
gastrium.
Auscultation provides important information about bowel motility. Listen to
the abdomen before performing percussion or palpation, since these maneuversmay alter the frequency of bowel sounds . You should practice auscultation until
you are thoroughly familiar with variations in normal bowel sounds and candetect changes suggestive of inﬂammation or obstruction. Auscultation mayalso reveal bruits , vascular sounds resembling heart murmurs, over the aorta
or other arteries in the abdomen, which suggest vascular occlusive disease.
Place the diaphragm of your stethoscope gently on the abdomen. Listen for

bowel sounds and note their frequency and character. Normal sounds consistof clicks and gurgles, occurring at an estimated frequency of 5 to 34 perminute. Occasionally you may hear borborygmi —long prolonged gurgles of
hyperperistalsis—the familiar “stomach growling.” Because bowel sounds arewidely transmitted through the abdomen, listening in one spot, such as theright lower quadrant, is usually sufﬁcient.
If the patient has high blood pressure, listen in the epigastrium and in each
upper quadrant for bruits . Later in the examination, when the patient sits
up, listen also in the costovertebral angles. Epigastric bruits conﬁned to sys-tole may be heard in normal persons.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
334 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGIncreased peristaltic waves of in-
testinal obstruction

Increased pulsation of an aortic
aneurysm or of increased pulsepressure
Bowel sounds may be altered in
diarrhea, intestinal obstruction,paralytic ileus, and peritonitis. See Table 9-10, Sounds in the Abdomen (p. 362).
A bruit in one of these areas that
has both systolic and diastoliccomponents strongly suggestsrenal artery stenosis as the cause ofhypertension.

If you suspect arterial insufﬁciency in the legs, listen for bruits over the aorta,
the iliac arteries, and the femoral arteries. Bruits conﬁned to systole are rel-atively common, however, and do not necessarily signify occlusive disease.
Listening points for bruits in these vessels are illustrated on p. 334.If you suspect a liver tumor, gonococcal infection around the liver, or splenic
infarction, listen over the liver and spleen for friction rubs.
Percussion helps you to assess the amount and distribution of gas in the ab-
domen and to identify possible masses that are solid or ﬂuid ﬁlled. Its use inestimating the size of the liver and spleen will be described in later sections.
Percuss the abdomen lightly in all four quadrants to assess the distribution
of tympany and dullness . Tympany usually predominates because of gas in
the gastrointestinal tract, but scattered areas of dullness due to ﬂuid andfeces there are also typical.

INote any large dull areas that might indicate an underlying mass or en-larged organ. This observation will guide your palpation.
IOn each side of a protuberant abdomen, note where abdominal tympanychanges to the dullness of solid posterior structures.
Brieﬂy percuss the lower anterior chest, between lungs above and costal mar-
gins below. On the right, you will usually ﬁnd the dullness of liver; on theleft, the tympany that overlies the gastric air bubble and the splenic ﬂexureof the colon.
PALPATION
Light Palpation. Feeling the abdomen gently is especially helpful in
identifying abdominal tenderness, muscular resistance, and some superﬁcialorgans and masses. It also serves to reassure and relax the patient.
Keeping your hand and forearm on a horizontal plane, with ﬁngers together

and ﬂat on the abdominal surface, palpate the abdomen with a light, gentle,dipping motion. When moving your hand from place to place, raise it justoff the skin. Moving smoothly, feel in all quadrants.
Identify any superﬁcial organs or masses and any area of tenderness or in-
creased resistance to your hand. If resistance is present, try to distinguish vol-untary guarding from involuntary muscular spasm. To do this:
ITry all the relaxing methods you know (see p. 332).TECHNIQUES OF EXAMINATION
CHAPTER 9 ITHE ABDOMEN 335Bruits with both systolic and dia-
stolic components suggest the tur-bulent blood ﬂow of partial arterialocclusion. See Table 9-10, Soundsin the Abdomen (p. 362).
See Table 9-10, Sounds in the 
Abdomen (p. 362).
A protuberant abdomen that is
tympanitic throughout suggests in-testinal obstruction. See Table 9-9,Protuberant Abdomens (p. 361).
Pregnant uterus, ovarian tumor,

distended bladder, large liver orspleen
Dullness in both ﬂanks indicates
further assessment for ascites (see pp. 345–347).
In situs inversus (rare), organs are
reversed: air bubble on the right,liver dullness on the left.
Involuntary rigidity (muscular
spasm) typically persists despitethese maneuvers. It indicates peritoneal inﬂammation.

336 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGAbdominal masses may be catego-
rized in several ways: physiologic(pregnant uterus), inﬂammatory(diverticulitis of the colon), vascu-lar (an aneurysm of the abdominalaorta), neoplastic (carcinoma ofthe colon), or obstructive (a dis-tended bladder or dilated loop ofbowel).
IFeel for the relaxation of abdominal muscles that normally accompanies
exhalation.
IAsk the patient to mouth-breathe with jaw dropped open.
Voluntary guarding usually decreases with these maneuvers.
Deep Palpation. This is usually required to delineate abdominal masses.
Again using the palmar surfaces of your ﬁngers, feel in all four quadrants.Identify any masses and note their location, size, shape, consistency, tender-ness, pulsations, and any mobility with respiration or with the examininghand. Correlate your palpable ﬁndings with their percussion notes.
TWO-HANDED DEEP PALPATION

Abdominal pain on coughing or
with light percussion suggests peritoneal inﬂammation. See Table 9-11, Tender Abdomens (pp. 363–364).
Rebound tenderness suggests peri-
toneal inﬂammation. If tendernessis felt elsewhere than where youwere trying to elicit rebound, thatarea may be the real source of theproblem.
The span of liver dullness is increased
when the liver is enlarged.
The span of liver dullness is de-
creased when the liver is small, or
when free air is present below thediaphragm, as from a perforatedhollow viscus. Serial observationsmay show a decreasing span ofdullness with resolution of hepatitisor congestive heart failure or, lesscommonly, with progression of fulminant hepatitis.
Liver dullness may be displaced
downward by the low diaphragmof chronic obstructive lung disease.Span, however, remains normal.EXAMPLES OF ABNORMALITIES
Assessment for Peritoneal Inﬂammation. Abdominal pain and ten-

derness, especially when associated with muscular spasm, suggest inﬂammationof the parietal peritoneum. Localize the pain as accurately as possible. First,even before palpation, ask the patient to cough and determine where the cough
produced pain. Then, palpate gently with one ﬁnger to map the tender area.
Pain produced by light percussion has similar localizing value. These gentlemaneuvers may be all you need to establish an area of peritoneal inﬂammation.
If not, look for rebound tenderness. Press your ﬁngers in ﬁrmly and slowly, and

then quickly withdraw them. Watch and listen to the patient for signs ofpain. Ask the patient (1) to compare which hurt more, the pressing or theletting go, and (2) to show you exactly where it hurt. Pain induced or in-creased by quick withdrawal constitutes rebound tenderness. It results fromthe rapid movement of an inﬂamed peritoneum.
The Liver
Because most of the liver is sheltered by the rib cage, assessing it is difﬁcult.Its size and shape can be estimated by percussion and perhaps palpation,however, and the palpating hand may enable you to evaluate its surface, con-sistency, and tenderness.
Measure the vertical span of liver dullness in the right midclavicular line.
Starting at a level below the umbilicus (in an area of tympany, not dullness),lightly percuss upward toward the liver. Ascertain the lower border of liverdullness in the midclavicular line.

Next, identify the upper border of liver dullness in the midclavicular line.
Lightly percuss from lung resonance down toward liver dullness. Gently dis-place a woman’s breast as necessary to be sure that you start in a resonantarea. The course of percussion is shown below.
CHAPTER 9 ITHE ABDOMEN 337
PERCUSSING LIVER SPAN

Now measure in centimeters the distance between your two points—the
vertical span of liver dullness. Normal liver spans, shown below, are gener-ally greater in men than in women, in tall people than in short. If the liverseems to be enlarged, outline the lower edge by percussing in other areas.
Although percussion is probably the most accurate clinical method for esti-
mating the vertical size of the liver, it typically leads to underestimation.
PALPATION
Place your left hand behind the patient, parallel to and supporting the right11th and 12th ribs and adjacent soft tissues below. Remind the patient torelax on your hand if necessary. By pressing your left hand forward, the pa-tient’s liver may be felt more easily by your other hand.
Place your right hand on the patient’s right abdomen lateral to the rectus

muscle, with your ﬁngertips well below the lower border of liver dullness.Some examiners like to point their ﬁngers up toward the patient’s head,while others prefer a somewhat more oblique position, as shown on the nextpage. In either case, press gently in and up. 
Ask the patient to take a deep breath. Try to feel the liver edge as it comes
down to meet your ﬁngertips. If you feel it, lighten the pressure of your pal-pating hand slightly so that the liver can slip under your ﬁnger pads and youcan feel its anterior surface. Note any tenderness. If palpable at all, the edgeof a normal liver is soft, sharp, and regular, its surface smooth. The normalliver may be slightly tender.
On inspiration, the liver (on the following page) is palpable about 3 cm
below the right costal margin in the midclavicular line.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES

338 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGDullness of a right pleural effusion
or consolidated lung, if adjacent toliver dullness, may falsely increasethe estimate of liver size.
Gas in the colon may produce tym-
pany in the right upper quadrant,obscure liver dullness, and falselydecrease the estimate of liver size.
Firmness or hardness of the liver,
bluntness or rounding of its edge,and irregularity of its contour sug-gest an abnormality of the liver.
An obstructed, distended gall-
bladder may form an oval massbelow the edge of the liver andmerging with it. It is dull to percussion.
4 – 8 cm in
midsternal line
6 – 12 cm
in rightmidclavicularline
NORMAL LIVER SPANS

CHAPTER 9 ITHE ABDOMEN 339
Some people breathe more with their chests than with their diaphragms. It
may be helpful to train such a patient to “breathe with the abdomen,” thusbringing the liver, as well as the spleen and kidneys, into a palpable positionduring inspiration.
Try to trace the liver edge both laterally and medially. Palpation through the
rectus muscles, however, is especially difﬁcult. Describe or sketch the liver edge,and measure its distance from the right costal margin in the midclavicular line.
In order to feel the liver, you may have to alter your pressure according to
the thickness and resistance of the abdominal wall. If you cannot feel it,move your palpating hand closer to the costal margin and try again.See Table 9-12, Liver Enlargement:
Apparent and Real (pp. 365–366).
The edge of an enlarged liver may
be missed by starting palpation toohigh in the abdomen, as shownbelow.

The “hooking technique” may be helpful, especially when the patient is obese.
Stand to the right of the patient’s chest. Place both hands, side by side, onthe right abdomen below the border of liver dullness. Press in with your ﬁn-gers and up toward the costal margin. Ask the patient to take a deep breath.The liver edge shown below is palpable with the ﬁngerpads of both hands.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
340 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGTenderness over the liver suggests
inﬂammation, as in hepatitis, orcongestion, as in heart failure.
Dullness, as shown on the follow-
ing page, raises the question ofsplenomegaly.
Assessing Tenderness of a Nonpalpable Liver. Place your left
hand ﬂat on the lower right rib cage and then gently strike your hand withthe ulnar surface of your right ﬁst. Ask the patient to compare the sensationwith that produced by a similar strike on the left side.
The Spleen

The Spleen
When a spleen enlarges, it expands anteriorly, downward, and medially, oftenreplacing the tympany of stomach and colon with the dullness of a solidorgan. It then becomes palpable below the costal margin. Percussion cannotconﬁrm splenic enlargement but can raise your suspicions of it. Palpation canconﬁrm the enlargement, but often misses large spleens that do not descendbelow the costal margin.
Two techniques may help you to detect splenomegaly, an enlarged spleen:
IPercuss the left lower anterior chest wall between lung resonance above and
the costal margin (an area termed Traube’s space ). As you percuss along
the routes suggested by the arrows in the following ﬁgures, note the lat-eral extent of tympany.

This is variable, but if tympany is prominent, especially laterally,
splenomegaly is not likely. The dullness of a normal spleen is usually hid-den within the dullness of other posterior tissues.
ICheck for a splenic percussion sign. Percuss the lowest interspace in the left
anterior axillary line, as shown below. This area is usually tympanitic. Thenask the patient to take a deep breath, and percuss again. When spleen sizeis normal, the percussion note usually remains tympanitic.TECHNIQUES OF EXAMINATION
CHAPTER 9 ITHE ABDOMEN 341
Anterior axillary
line
Midaxillary
line
Normal spleen
Anterior axillaryline
line
InspiratorymovementPercusshere
If either or both of these tests is positive, pay extra attention to palpating the
spleen.
PALPATION
With your left hand, reach over and around the patient to support and press

spleen.
PALPATION
forward the lower left rib cage and adjacent soft tissue. With your right handbelow the left costal margin, press in toward the spleen. Begin palpation lowFluid or solids in the stomach or
colon may also cause dullness inTraube’s space.
A change in percussion note from
tympany to dullness on inspirationsuggests splenic enlargement. Thisis a positive splenic percussion sign.
The splenic percussion sign may
also be positive when spleen size isnormal.
An enlarged spleen may be missed
if the examiner starts too high in theabdomen to feel the lower edge.NEGATIVE SPLENIC PERCUSSION SIGN
POSITIVE SPLENIC PERCUSSION SIGN

342 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Umbilicusenough so that you are below a possibly enlarged spleen. (If your hand is
close to the costal margin, moreover, it is not sufﬁciently mobile to reach upunder the rib cage.) Ask the patient to take a deep breath. Try to feel the tipor edge of the spleen as it comes down to meet your ﬁngertips. Note anytenderness, assess the splenic contour, and measure the distance between thespleen’s lowest point and the left costal margin. In a small percentage of nor-mal adults, the tip of the spleen is palpable. Causes include a low, ﬂat di-aphragm, as in chronic obstructive pulmonary disease, and a deep inspiratorydescent of the diaphragm.
Repeat with the patient lying on the right side with legs somewhat ﬂexed at
hips and knees. In this position, gravity may bring the spleen forward and tothe right into a palpable location.A palpable spleen tip, though not

necessarily abnormal, may indicatesplenic enlargement. The spleentip below is just palpable deep tothe left costal margin.
The enlarged spleen shown below
is palpable about 2 cm below the left costal margin on deepinspira tion.
PALPATING THE SPLEEN—PATIENT LYING ON RIGHT SIDE

CHAPTER 9 ITHE ABDOMEN 343The Kidneys
PALPATION
Although kidneys are not usually palpable, you should learn and practice the
techniques. Detecting an enlarged kidney may prove to be very important.
Palpation of the Left Kidney. Move to the patient’s left side. Place

your right hand behind the patient just below and parallel to the 12th rib,with your fingertips just reaching the costovertebral angle. Lift, trying todisplace the kidney anteriorly. Place your left hand gently in the left upperquadrant, lateral and parallel to the rectus muscle. Ask the patient to takea deep breath. At the peak of inspiration, press your left hand firmly anddeeply into the left upper quadrant, just below the costal margin, and tryto “capture” the kidney between your two hands. Ask the patient to breatheout and then to stop breathing briefly. Slowly release the pressure of yourleft hand, feeling at the same time for the kidney to slide back into its ex-piratory position. If the kidney is palpable, describe its size, contour, andany tenderness.
Alternatively, try to feel for the left kidney by a method similar to feeling for

the spleen. With your left hand, reach over and around the patient to lift theleft loin, and with your right hand feel deep in the left upper quadrant. Askthe patient to take a deep breath, and feel for a mass. A normal left kidneyis rarely palpable.
Palpation of the Right Kidney. To capture the right kidney, return
to the patient’s right side. Use your left hand to lift from in back, and yourright hand to feel deep in the left upper quadrant. Proceed as before.
A left ﬂank mass (see the solid line
on photo on previous page) mayrepresent marked splenomegaly oran enlarged left kidney. Suspectsplenomegaly if notch palpated onmedial border, edge extends be-yond the midline, percussion isdull, and your ﬁngers can probedeep to the medial and lateral bor-ders but not between the mass andthe costal margin. Conﬁrm ﬁnd-ings with further evaluation.
Attributes favoring an enlarged

kidney over an enlarged spleeninclude preservation of normal
tympany in the left upper quadrantand the ability to probe with yourﬁngers between the mass and thecostal margin but not deep to itsmedial and lower borders.

A normal right kidney may be palpable, especially in thin, well-relaxed women.
It may or may not be slightly tender. The patient is usually aware of a captureand release. Occasionally, a right kidney is located more anteriorly than usualand then must be distinguished from the liver. The edge of the liver, if palpa-ble, tends to be sharper and to extend farther medially and laterally. It cannotbe captured. The lower pole of the kidney is rounded.
Assessing Kidney Ten-
derness. You may note
tenderness when examiningthe abdomen, but also searchfor it at each costovertebralangle. Pressure from yourfingertips may be enough toelicit tenderness, but if not,use fist percussion. Place theball of one hand in the cos-tovertebral angle and strikeit with the ulnar surface ofyour fist. Use enough forceto cause a perceptible butpainless jar or thud in a nor-mal person.
To save the patient needless
exertion, integrate this assess-ment with your examinationof the back (see p. 10).
The Bladder

The bladder normally cannot be examined unless it is distended above thesymphysis pubis. On palpation, the dome of the distended bladder feelssmooth and round. Check for tenderness. Use percussion to check for dull-ness and to determine how high the bladder rises above the symphysis pubis.
The Aorta
Press ﬁrmly deep in the upper abdomen, slightly to the left of the midline,and identify the aortic pulsations. In persons over age 50, try to assess thewidth of the aorta by pressing deeply in the upper abdomen with one handon each side of the aorta, as illustrated. In this age group, a normal aorta is
344 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGCauses of kidney enlargement 
include hydronephrosis, cysts, andtumors. Bilateral enlargement suggests polycystic disease.
Pain with pressure or ﬁst percus-

sion suggests pyelonephritis , but
may also have a musculoskeletalcause.
Bladder distention from outlet 
obstruction due to urethral stric-ture, prostatic hyperplasia; alsofrom medications and neurologicdisorders such as stroke, multiplesclerosis.
Suprapubic tenderness in bladder
infection
In an older person, a periumbilical
or upper abdominal mass with expansile pulsations suggests anaortic aneurysm .
ASSESSING COSTOVERTEBRAL ANGLE TENDERNESS

Tympany
DullnessEXAMPLES OF ABNORMALITIES TECHNIQUES OF EXAMINATION
CHAPTER 9 ITHE ABDOMEN 345not more than 3.0 cm wide (average
2.5 cm). This measurement does notinclude the thickness of the abdom-inal wall. The ease of feeling aorticpulsations varies greatly with thethickness of the abdominal wall andwith the anteroposterior diameter ofthe abdomen.
An aortic aneurysm is a pathologic
dilatation of the aorta, usually dueto arteriosclerosis. A merely tortu-ous abdominal aorta, however,may be difﬁcult to distinguish froman aneurysm on clinical grounds.
Although an aneurysm is usually
painless, pain may herald its most dreaded and frequent complication—rupture of theaorta.
Apparent enlargement of the
aorta indicates assessment by ultrasound.
ASSESSING POSSIBLE ASCITES
A protuberant abdomen with bulging ﬂanks suggests the possibility of ascitic

ﬂuid. Because ascitic ﬂuid characteristically sinks with gravity, while gas-ﬁlledloops of bowel ﬂoat to the top, percussion gives a dull note in dependentareas of the abdomen. Look for such a pattern by percussing outward in sev-eral directions from the central area of tympany. Map the border betweentympany and dullness.Assessment Techniques for:
IAscites
IAppendicitis
IAcute cholecystitisIVentral hernia
IMass in abdominal wall

346 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGTwo further techniques help to conﬁrm the presence of ascites, although
both signs may be misleading.
ITest for shifting dullness. After mapping the borders of tympany and dull-
ness, ask the patient to turn onto one side. Percuss and mark the bordersagain. In a person without ascites, the borders between tympany and dull-ness usually stay relatively constant.
ITest for a fluid wave. Ask the patient or an assistant to press the edges of
both hands firmly down the midline of the abdomen. This pressurehelps to stop the transmission of a wave through fat. While you tap oneflank sharply with your fingertips, feel on the opposite flank for an im-pulse transmitted through the fluid. Unfortunately, this sign is oftennegative until ascites is obvious, and it is sometimes positive in peoplewithout ascites.In ascites, dullness shifts to the

more dependent side, while tym-pany shifts to the top.
An easily palpable impulse suggests
ascites.
Tympany
Dullness

CHAPTER 9 ITHE ABDOMEN 347Identifying an Organ or a Mass in an Ascitic Abdomen. Try
to ballotte the organ or mass, exempliﬁed here by an enlarged liver. Straighten
and stiffen the fingers of one hand together, place them on the abdominalsurface, and make a brief jabbing movement directly toward the antici-pated structure. This quick movement often displaces the fluid so that yourfingertips can briefly touch the surface of the structure through the ab-dominal wall.
The pain of appendicitis 
classically begins near the umbilicus, then shifts to the right lower quadrant, wherecoughing increases it. Elderly patients report this pattern less frequently than youngerones.
Localized tenderness anywhere 
in the right lower quadrant, evenin the right ﬂank, may indicate appendicitis.
Early voluntary guarding may be
replaced by involuntary muscularrigidity.
Right-sided rectal tenderness

Right-sided rectal tenderness 
may be caused by, for example, inﬂamed adnexa or an inﬂamedseminal vesicle, as well as by an inﬂamed appendix.
ASSESSING POSSIBLE APPENDICITIS
IAsk the patient to point to where the pain began and where it is now. Ask
the patient to cough. Determine whether and where pain results.
ISearch carefully for an area of local tenderness.
IFeel for muscular rigidity.
IPerform a rectal examination and, in women, a pelvic examination. These
maneuvers may not help you to discriminate well between a normal andan inﬂamed appendix, but they may help to identify an inﬂamed appen-dix atypically located within the pelvic cavity. They may also suggest othercauses of the abdominal pain.

348 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGSome additional techniques are sometimes helpful.
ICheck the tender area for rebound tenderness. (If other signs are typically
positive, you can save the patient unnecessary pain by omitting this test.)
ICheck for Rovsing’s sign and for referred rebound tenderness. Press deeply
and evenly in the leftlower quadrant. Then quickly withdraw your ﬁngers.
ILook for a psoas sign. Place your hand just above the patient’s right knee
and ask the patient to raise that thigh against your hand. Alternatively, askthe patient to turn onto the left side. Then extend the patient’s right legat the hip. Flexion of the leg at the hip makes the psoas muscle contract;extension stretches it.
ILook for an obturator sign. Flex the patient’s right thigh at the hip, with

the knee bent, and rotate the leg internally at the hip. This maneuverstretches the internal obturator muscle. (Internal rotation of the hip is de-scribed on p. 510.)
ITest for cutaneous hyperesthesia. At a series of points down the abdom-
inal wall, gently pick up a fold of skin between your thumb and indexfinger, without pinching it. This maneuver should not normally bepainful.
ASSESSING POSSIBLE ACUTE CHOLECYSTITIS
When right upper quadrant pain and tenderness suggest acute cholecystitis,look for Murphy’s sign. Hook your left thumb or the ﬁngers of your right
hand under the costal margin at the point where the lateral border of therectus muscle intersects with the costal margin. Alternatively, if the liver isenlarged, hook your thumb or ﬁngers under the liver edge at a comparablepoint below. Ask the patient to take a deep breath. Watch the patient’sbreathing and note the degree of tenderness.

ASSESSING VENTRAL HERNIAS
Ventral hernias are hernias in the abdominal wall exclusive of groin hernias.If you suspect but do not see an umbilical or incisional hernia, ask the pa-tient to raise both head and shoulders off the table.Rebound tenderness suggests 
peritoneal inﬂammation, as fromappendicitis.
Pain in the right lower quadrant
during left-sided pressure 
suggests appendicitis (a positiveRovsing’s sign). So does rightlower quadrant pain on quick withdrawal ( referred rebound 
tenderness ).
Increased abdominal pain on either
maneuver constitutes a positivepsoas sign, suggesting irritation ofthe psoas muscle by an inﬂamedappendix.
Right hypogastric pain consti-
tutes a positive obturator sign,suggesting irritation of the obtu-rator muscle by an inflamed appendix.
Localized pain with this maneuver,
in all or part of the right lowerquadrant, may accompany appendicitis.
A sharp increase in tenderness with

a sudden stop in inspiratory effortconstitutes a positive Murphy’ssign of acute cholecystitis. Hepatictenderness may also increase withthis maneuver, but is usually lesswell localized.
The bulge of a hernia will usually
appear with this action (see p. 360).

Inguinal and femoral hernias are discussed in the next chapter. They can give
rise to important abdominal problems and must not be overlooked.
MASS IN THE ABDOMINAL WALL
To Distinguish an Abdominal Mass From a Mass in the Abdom-
inal Wall. An occasional mass is in the abdominal wall rather than inside
the abdominal cavity. Ask the patient either to raise the head and shouldersor to strain down, thus tightening the abdominal muscles. Feel for the massagain.TECHNIQUES OF EXAMINATION
CHAPTER 9 ITHE ABDOMEN 349The cause of intestinal obstruction
or peritonitis may be missed byoverlooking a strangulated femoralhernia.
A mass in the abdominal wall 
remains palpable; an intra-abdom-inal mass is obscured by muscularcontraction.

TABLE 9-1 IAbdominal Pain
350 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Problem Process Location Quality
Peptic Ulcer and
Dyspepsia (These
disorders cannot bereliably differentiatedby symptoms and signs.)
Cancer of the
Stomach
Acute PancreatitisChronic
Pancreatitis
Pancreas
Biliary Colic
Acute Cholecystitis
Acute Diverticulitis
Acute AppendicitisAcute Mechanical
IntestinalObstruction
Mesenteric
IschemiaPeptic ulcer refers to a demonstrable
ulcer, usually in the duodenum orstomach. Dyspepsia causes similarsymptoms but no ulceration. Infectionby Helicobacter pylori is often present.
A malignant neoplasm
An acute inﬂammation of the pancreas
Fibrosis of the pancreas secondary to
recurrent inﬂammation
Sudden obstruction of the cystic duct or
common bile duct by a gallstone
Inﬂammation of the gallbladder, usually
from obstruction of the cystic duct by agallstone
Acute inﬂammation of a colonic

diverticulum, a saclike mucosaloutpouching through the colonicmuscle
Acute inﬂammation of the appendix
with distention or obstruction
Obstruction of the bowel lumen, most
commonly caused by (1) adhesions orhernias (small bowel), or (2) cancer ordiverticulitis (colon)
Blood supply to the bowel and
mesentery blocked from thrombosis orembolus (acute arterial occlusion), orreduced from hypoperfusionEpigastric, may radiate to the back
Epigastric, may radiate to the back
or other parts of the abdomen; maybe poorly localized
Epigastric, radiating through to
the back
Epigastric and in either upper
quadrant; often radiates to the back
Epigastric or right upper quadrant;
may radiate to the right scapula andshoulder
Right upper quadrant or upper
abdominal; may radiate to the rightscapular area

Left lower quadrant
IPoorly localized periumbilical
pain, followed usually by
IRight lower quadrant pain
ISmall bowel: periumbilical or
upper abdominal
IColon: lower abdominal or
generalized
May be periumbilical at ﬁrst, then
diffuseVariable: gnawing
burning, boring, aching,pressing, or hungerlike
Variable
Usually steady
Steady, deepSteady, deepSteady, aching; not
colicky
Steady, achingMay be cramping at
ﬁrst, but becomes steady
IMild but increasing,possibly cramping
ISteady and moresevere
ICramping
ICramping
Cramping at ﬁrst, then
steady

CHAPTER 9 ITHE ABDOMEN 351
Factors 
That May Factors That Associated Symptoms 
Timing Aggravate May Relieve and Setting
Intermittent. Duodenal ulcer is
more likely than gastric ulcer ordyspepsia to cause pain that (1) wakes the patient at night,and (2) occurs intermittentlyover a few weeks, then disappearsfor months, and then recurs.
The history of pain is typically
shorter than in peptic ulcer. Thepain is persistent and slowlyprogressive.
Acute onset, persistent pain
Chronic or recurrent coursePersistent pain; relentlessly
progressive illness
Rapid onset over a few minutes,
lasts one to several hours andsubsides gradually. Oftenrecurrent
Gradual onset; course longer
than in biliary colic
Often a gradual onset
ILasts roughly 4–6 hr
IDepends on intervention
IParoxysmal; may decrease as
bowel mobility is impaired
IParoxysmal, though typicallymilder
Usually abrupt in onset, then
persistentVariable
Often food
Lying supine
Alcohol, heavy
or fatty meals

Often food
Jarring, deep
breathing
IMovement orcoughFood and antacids may bring
relief, but not necessarily in anyof these disorders and leastcommonly in gastric ulcer.
Notrelieved by food or antacids
Leaning forward with trunk
ﬂexed
Possibly leaning forward with
trunk ﬂexed; often intractable 
trunk ﬂexed; often intractable
IIf it subsides temporarily,suspect perforation of theappendix.Nausea, vomiting, belching, bloating;
heartburn (more common in duodenalulcer); weight loss (more common ingastric ulcer). Dyspepsia is morecommon in the young (20–29 yr),gastric ulcer in those over 50 yr, andduodenal ulcer in those from 30–60 yr.
Anorexia, nausea, early satiety, weight
loss, and sometimes bleeding. Mostcommon in ages 50–70
Nausea, vomiting, abdominal distention,

fever. Often a history of previous attacksand alcohol abuse or gallstones
Symptoms of decreased pancreatic
function may appear: diarrhea with fattystools (steatorrhea) and diabetes mellitus.
Anorexia, nausea, vomiting, weight loss,
and jaundice. Emotional symptoms,including depression
Anorexia, nausea, vomiting, restlessness
Anorexia, nausea, vomiting, and fever
Fever, constipation. There may be initial
brief diarrhea.
Anorexia, nausea, possibly vomiting,
which typically follow the onset of pain;low fever
IVomiting of bile and mucus (highobstruction) or fecal material (lowobstruction). Obstipation develops.
IObstipation early. Vomiting late if atall. Prior symptoms of underlyingcause.
Vomiting, diarrhea (sometimes bloody),
constipation, shock



TABLE 9-2 IDysphagia
352 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Aspiration into the lungs
or regurgitation into thenose with attempts toswallow. Neurologicevidence of stroke, bulbarpalsy, or other neuro-muscular conditions
Usually none
A long history of heart-
burn and regurgitation
Pain in the chest and back
and weight loss, especiallylate in the course of illness
Chest pain that mimics
angina pectoris ormyocardial infarction andlasts minutes to hours;possibly heartburn
Heartburn. Other
manifestations ofscleroderma
Regurgitation, often at
night when lying down,with nocturnal cough;possibly chest painprecipitated by eatingAssociated
Factors That Factors That Symptoms and
Process and Problem Timing Aggravate Relieve Conditions
Transfer Dysphagia,
due to motor disorders
affecting the pharyngealmuscles
Esophageal Dysphagia
Mechanical Narrowing
IMucosal rings and webs
IEsophageal stricture
IEsophageal cancer
IDiffuse esophageal
spasm

spasm
IScleroderma
IAchalasiaAcute or gradual onset
and a variable course,depending on theunderlying disorder
Intermittent
Intermittent, may
become slowlyprogressive
May be intermittent at
ﬁrst; progressive overmonths
progress slowly
progressAttempts to start the
swallowing process
Solid foods
Solid foods, with
progression to liquids
Solids or liquids
Solids or liquidsRegurgitation of
the bolus of food
Regurgitation of
Maneuvers
described below;sometimesnitroglycerin
Repeated
swallowing,movements such asstraightening theback, raising thearms, or a Valsalvamaneuver (strainingdown against aclosed glottis)










TABLE 9-3 IConstipation
CHAPTER 9 ITHE ABDOMEN 353
Problem Process Associated Symptoms and Setting
Life Activities and Habits
Inadequate Time or Setting for the Defecation Reﬂex
False Expectations of 
Bowel Habits
Diet Deﬁcient in Fiber
Irritable Bowel
Syndrome
Mechanical Obstruction
Cancer of the Rectum orSigmoid Colon
Fecal Impaction
Other Obstructing 
Lesions 
(such as
diverticulitis, volvulus,intussusception, or hernia)
Painful Anal Lesions
Drugs
DepressionNeurologic DisordersMetabolic ConditionsIgnoring the sensation of a full rectum inhibits
the defecation reﬂex.
Expectations of “regularity” or more frequent
stools than a person’s norm
Decreased fecal bulk
A common disorder of bowel motility
Progressive narrowing of the bowel lumen
A large, ﬁrm, immovable fecal mass, most often
in the rectum
Narrowing or complete obstruction of the
bowel
Pain may cause spasm of the external sphincter
and voluntary inhibition of the defecationreﬂex.
A variety of mechanisms

bowel
A disorder of mood. See Table 16-1, Disorders
of Mood.
Interference with the autonomic innervation of
the bowel
Interference with bowel motilityHectic schedules, unfamiliar surroundings, 
bed rest
Beliefs, treatments, and advertisements that
promote the use of laxatives
Other factors such as debilitation and
constipating drugs may contribute.
Small, hard stools, often with mucus. Periods of
diarrhea. Cramping abdominal pain. Stress mayaggravate.
Change in bowel habits; often diarrhea,
abdominal pain, and bleeding. In rectal cancer,tenesmus and pencil-shaped stools
Rectal fullness, abdominal pain, and diarrhea
around the impaction. Common in debilitated,bedridden, and often elderly patients
Colicky abdominal pain, abdominal distention,
and in intussusception, often “currant jelly”stools (red blood and mucus)

Anal ﬁssures, painful hemorrhoids, perirectal
abscesses
Opiates, anticholinergics, antacids containing
calcium or aluminum, and many others
Fatigue, feelings of depression, and other
somatic symptoms
Spinal cord injuries, multiple sclerosis,
Hirschsprung’s disease, and other conditions
Pregnancy, hypothyroidism, hypercalcemia

TABLE 9-4 IDiarrhea
354 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGProblem Process Characteristics  of Stool
Acute Diarrhea
Secretory Infections
Inﬂammatory InfectionsDrug-Induced Diarrhea
Chronic Diarrhea
Diarrheal Syndromes
IIrritable bowel syndrome
ICancer of the sigmoid colon
Inﬂammatory Bowel Disease
IUlcerative colitis
ICrohn’s disease of the small bowel
(regional enteritis) or colon(granulomatous colitis)
Voluminous Diarrheas
IMalabsorption syndromes
IOsmotic diarrheas
Lactose intolerance
Abuse of osmotic purgatives
ISecretory diarrheas from bacterial
infection, secreting villous adenoma,fat or bile salt malabsorption,hormone-mediated conditions(gastrin in Zollinger–Ellisonsyndrome, vasoactive intestinalpeptide [VIP])Infection by viruses, preformed bacterial toxins
(such as Staphylococcus aureus, Clostridium
perfringens, toxigenic Escherichia coli, Vibrio
cholerae ), cryptosporidium, Giardia lamblia
Colonization or invasion of intestinal mucosa

Colonization or invasion of intestinal mucosa 
(nontyphoid Salmonella, Shigella, Yersinia,
Campylobacter, enteropathic E. coli, Entamoeba
histolytica)
Action of many drugs, such as magnesium-
containing antacids, antibiotics, antineoplastic agents, and laxatives
A disorder of bowel motility with alternating
diarrhea and constipation
Partial obstruction by a malignant neoplasmInﬂammation of the mucosa and submucosa of the
rectum and colon with ulceration; cause unknown
Chronic inﬂammation of the bowel wall, 
typically involving the terminal ileum and/orproximal colon
Defective absorption of fat, including fat-soluble
vitamins, with steatorrhea (excessive excretion offat) as in pancreatic insufﬁciency, bile saltdeﬁciency, bacterial overgrowth
Deﬁciency in intestinal lactaseLaxative habit, often surreptitious
VariableWatery, without blood, pus, or
mucus

mucus
Loose to watery, often with blood,
pus, or mucus
Loose to watery
Loose; may show mucus but no
blood. Small, hard stools withconstipation
May be blood-streaked
From soft to watery, often
containing blood
Small, soft to loose or watery, usually
free of gross blood (enteritis) or withless bleeding than ulcerative colitis(colitis)
Typically bulky, soft, light yellow to
gray, mushy, greasy or oily, andsometimes frothy; particularly foul-smelling; usually ﬂoats in the toilet
Watery diarrhea of large volumeWatery diarrhea of large volume
Watery diarrhea of large volume

CHAPTER 9 ITHE ABDOMEN 355Timing Associated Symptoms Setting, Persons at Risk
Duration of a few days, possibly
longer. Lactase deﬁciency maylead to a longer course.
An acute illness of varying
duration
Acute, recurrent, or chronic
Often worse in the morning.
Diarrhea rarely wakes the patientat night.
Variable
Onset ranges from insidious to
acute. Typically recurrent, may bepersistent. Diarrhea may wake thepatient at night.
Insidious onset, chronic or
recurrent. Diarrhea may wakethe patient at night.
Onset of illness typically
insidious
Follows the ingestion of milk
and milk products; is relieved byfasting
Variable
Variable
Nausea, vomiting, periumbilical cramping pain.
Temperature normal or slightly elevated
Lower abdominal cramping pain and often
rectal urgency, tenesmus; fever
Possibly nausea; usually little if any pain
Crampy lower abdominal pain, abdominal
distention, ﬂatulence, nausea, constipation
Change in usual bowel habits, crampy lower
abdominal pain, constipation

Crampy lower or generalized abdominal pain,
anorexia, weakness, fever
Crampy periumbilical or right lower quadrant
(enteritis) or diffuse (colitis) pain, withanorexia, low fever, and/or weight loss.Perianal or perirectal abscesses and ﬁstulas
Anorexia, weight loss, fatigue, abdominal
distention, often crampy lower abdominal pain.Symptoms of nutritional deﬁciencies such asbleeding (vitamin K), bone pain and fractures(vitamin D), glossitis (vitamin B), and edema(protein)
Crampy abdominal pain, abdominal
distention, ﬂ atulence
Often noneWeight loss, dehydration, nausea, vomiting,
and cramping abdominal painOften travel, a common food source, or an
epidemic
Travel, contaminated food or water. Men and
women who have had frequent analintercourse.
Prescribed or over-the-counter medications

epidemic
Young and middle-aged adults, especially
women
Middle-aged and older adults, especially over
55 yr
Often young people
Often young people, especially in the late
teens, but also in the middle years. Morecommon in people of Jewish descent
Variable, depending on cause
African Americans, Asians, Native Americans
Persons with anorexia nervosa or bulimia
nervosa
Variable depending on causeTABLE 9-4 IDiarrhea

TABLE 9-5 IBlack and Bloody Stools
356 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Problem Selected Causes Associated Symptoms and Setting
Melena
Melena refers to the passage of black, tarry
(sticky and shiny) stools. Tests for occultblood are positive. Melena signiﬁes the loss ofat least 60 ml of blood into the gastrointestinaltract (less in infants and children), usually fromthe esophagus, stomach, or duodenum. Lesscommonly, when intestinal transit is slow, theblood may originate in the jejunum, ileum, orascending colon. In infants, melena may resultfrom swallowing blood during the birthprocess.
Black, Nonsticky Stools
Black stools may result from other causes andthen usually give negative results when testedfor occult blood. (Ingestion of iron or othersubstances, however, may cause a positive testresult in the absence of blood.) These stoolshave no pathologic signiﬁcance.
Red Blood in the Stools

Red blood usually originates in the colon,rectum, or anus, and much less frequently inthe jejunum or ileum. Upper gastrointestinalhemorrhage, however, may also cause redstools. The amount of blood lost is then usuallylarge (more than a liter). Transit time throughthe intestinal tract is accordingly rapid, givinginsufﬁcient time for the blood to turn black.
Reddish But Nonbloody StoolsPeptic ulcer
Gastritis or stress ulcers
Esophageal or gastric varices
Reﬂux esophagitis
Mallory–Weiss tear, amucosal tear in theesophagus due to retchingand vomiting
Ingestion of iron, bismuth
salts as in Pepto-Bismol,licorice, or even commercialchocolate cookies
Cancer of the colon
Benign polyps of the colonDiverticula of the colonInﬂammatory conditions ofthe colon and rectum
IInfectious dysenteries
IProctitis (various causes)in men or women whohave had frequent analintercourse
Ischemic colitis
HemorrhoidsAnal ﬁssure

The ingestion of beetsOften, but not necessarily, a history of
epigastric painRecent ingestion of alcohol, aspirin, or otheranti-inﬂammatory drugs; recent bodily trauma,severe burns, surgery, or increased intracranialpressureCirrhosis of the liver or other cause of portalhypertensionHistory of heartburnRetching, vomiting, often recent ingestion ofalcohol
Often a change in bowel habits
Often no other symptomsOften no other symptoms
See Table 9-5, Diarrhea.
See Table 9-5, Diarrhea.Rectal urgency, tenesmus
Lower abdominal pain and sometimes fever or
shock in persons over age 50 yrBlood on the toilet paper, on the surface ofthe stool, or dripping into the toiletBlood on the toilet paper or on the surface ofthe stool; anal pain
Pink urine, which usually precedes the reddish
stool

TABLE 9-6 IFrequency, Nocturia, and Polyuria
CHAPTER 9 ITHE ABDOMEN 357
Problem Mechanisms Selected Causes Associated Symptoms
Frequency 
Nocturia
With High Volumes
With Low Volumes
PolyuriaDecreased capacity of the bladder
IIncreased bladder sensitivity to
stretch because ofinﬂammation
IDecreased elasticity of thebladder wall
IDecreased cortical inhibitionof bladder contractions
Impaired emptying of the bladder,
with residual urine in the bladder
IPartial mechanical obstructionof the bladder neck orproximal urethra
ILoss of peripheral nerve supply to the bladder
Most types of polyuria (see pp.
327–328)
Decreased concentrating ability of
the kidney with loss of the normaldecrease in nocturnal urinary output
Excessive ﬂuid intake before
bedtime
Fluid-retaining, edematous states.
Dependent edema accumulatesduring the day and is excreted whenthe patient lies down at night.
Frequency 
Voiding while up at night without

bedtime
Frequency 
a real urge, a “pseudo-frequency”
Deﬁciency of antidiuretic hormone
(diabetes insipidus)
Renal unresponsiveness to
antidiuretic hormone (nephrogenicdiabetes insipidus)
Solute diuresis
IElectrolytes, such as sodium
salts
INonelectrolytes, such as glucose
Excessive water intakeInfection , stones, tumor, or
foreign body in the bladder
Inﬁltration by scar tissue or
tumor
Motor disorders of the central
nervous system, such as a stroke
Most commonly, benign
prostatic hyperplasia; alsourethral stricture and otherobstructive lesions of the bladderor prostate
Neurologic disease affecting the
sacral nerves or nerve roots, e.g.,diabetic neuropathy
Chronic renal insufﬁciency due
to a number of diseases
Habit, especially involving
alcohol and coffee
Congestive heart failure,

nephrotic syndrome, hepaticcirrhosis with ascites, chronicvenous insufﬁciency
Insomnia
A disorder of the posterior
pituitary and hypothalamus
A number of kidney diseases,
including hypercalcemic andhypokalemic nephropathy; drugtoxicity, e.g., from lithium
Large saline infusions, potent
diuretics, certain kidney diseasesUncontrolled diabetes mellitus
Primary polydipsiaBurning on urination, urinary
urgency, sometimes grosshematuriaSymptoms of associatedinﬂammation (see above) arecommon.Urinary urgency; neurologicsymptoms such as weakness andparalysis
Prior obstructive symptoms:
hesitancy in starting the urinarystream, straining to void,reduced size and force of thestream, and dribbling during orat the end of urinationWeakness or sensory defects
Possibly other symptoms of
renal insufﬁciency

Edema and other symptoms of
the underlying disorder. Urinaryoutput during the day may bereduced as ﬂuid reaccumulates inthe body. See Table 14-4, SomePeripheral Causes of Edema.
Variable
Thirst and polydipsia, often
severe and persistent; nocturia
Variable
Thirst, polydipsia, and nocturia
Polydipsia tends to be episodic.
Thirst may not be present.Nocturia is usually absent.

TABLE 9-7 IUrinary Incontinence
358 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 9-7 IUrinary Incontinence*
Problem Mechanisms
Stress Incontinence
The urethral sphincter is weakened so that transient increases in
intraabdominal pressure raise the bladder pressure to levels thatexceed urethral resistance.
Urge Incontinence
Detrusor contractions are stronger than normal and overcomethe normal urethral resistance. The bladder is typically small.
Overﬂow Incontinence
Detrusor contractions are insufﬁcient to overcome urethralresistance. The bladder is typically large, even after an effort to void.
Functional Incontinence
This is a functional inability to get to the toilet in time becauseof impaired health or environmental conditions.
Incontinence Secondary to Medications
Drugs may contribute to any type of incontinence listed.In women, most often a weakness of the pelvic ﬂoor with

inadequate muscular support of the bladder and proximalurethra and a change in the angle between the bladder and theurethra. Suggested causes include childbirth and surgery. Localconditions affecting the internal urethral sphincter, such aspostmenopausal atrophy of the mucosa and urethral infection,may also contribute.
In men, stress incontinence may follow prostatic surgery.
IDecreased cortical inhibition of detrusor contractions, as by
strokes, brain tumors, dementia, and lesions of the spinal cordabove the sacral level
IHyperexcitability of sensory pathways, caused by, forexample, bladder infections, tumors, and fecal impaction
IDeconditioning of voiding reﬂexes, caused by, for example,frequent voluntary voiding at low bladder volumes
IObstruction of the bladder outlet, as by benign prostatichyperplasia or tumor

IWeakness of the detrusor muscle associated with peripheralnerve disease at the sacral level
IImpaired bladder sensation that interrupts the reﬂex arc, asfrom diabetic neuropathy
Problems in mobility resulting from weakness, arthritis, poor
vision, or other conditions. Environmental factors such as anunfamiliar setting, distant bathroom facilities, bedrails, orphysical restraints
Sedatives, tranquilizers, anticholinergics, sympathetic blockers,
and potent diuretics
*Patients may have more than one kind of incontinence.

CHAPTER 9 ITHE ABDOMEN 359
Symptoms Physical Signs
Momentary leakage of small amounts of urine concurrent with
stresses such as coughing, laughing, and sneezing while theperson is in an upright position. A desire to urinate is notassociated with pure stress incontinence.
Incontinence preceded by an urge to void. The volume tends to
be moderate.
UrgencyFrequency and nocturia with small to moderate volumesIf acute inﬂammation is present, pain on urination
Possibly “pseudo-stress incontinence”—voiding 10–20 sec afterstresses such as a change of position, going up or down stairs,and possibly coughing, laughing, or sneezing
A continuous dripping or dribbling incontinence
Decreased force of the urinary streamPrior symptoms of partial urinary obstruction or other
symptoms of peripheral nerve disease may be present.
Incontinence on the way to the toilet or only in the early
morning

morning
Variable. A careful history and chart review are important.The bladder is not detected on abdominal examination.
Stress incontinence may be demonstrable, especially if the
patient is examined before voiding and in a standing position.
Atrophic vaginitis may be evident.
The bladder is not detectable on abdominal examination.
When cortical inhibition is decreased, mental deﬁcits or motor
signs of central nervous system disease are often, though notnecessarily, present.
When sensory pathways are hyperexcitable, signs of local pelvic
problems or a fecal impaction may be present.
An enlarged bladder is often found on abdominal examination
and may be tender. Other possible signs include prostaticenlargement, motor signs of peripheral nerve disease, a decreasein sensation including perineal sensation, and diminished toabsent reﬂexes.

The bladder is not detectable on physical examination. Look for
physical or environmental clues to the likely cause.
Variable

TABLE 9-8 ILocalized Bulges in the Abdominal Wall
360 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Umbilical Hernia
Umbilical hernias protrude through a defective
umbilical ring. They are most common in infantsbut also occur in adults. In infants, but not inadults, they usually close spontaneously within ayear or two.Incisional Hernia
An incisional hernia protrudes through an operativescar. By palpation, note the length and width of thedefect in the abdominal wall. A small defect, throughwhich a large hernia has passed, has a greater risk ofcomplications than a large defect.Epigastric Hernia
An epigastric hernia is a small midline protrusionthrough a defect in the linea alba, somewherebetween the xiphoid process and the umbilicus.With the patient’s head and shoulders raised (orwith the patient standing), look for it, and runyour ﬁngerpad down the linea alba to feel it.
Diastasis Recti

A rectus diastasis is a separation of thetwo rectus abdominis muscles, throughwhich abdominal contents bulge to forma midline ridge when the patient raiseshead and shoulders. Repeatedpregnancies, obesity, and chronic lungdisease may predispose to it. It has noclinical consequences.Lipoma
Lipomas are common,benign, fatty tumors usuallylocated in the subcutaneoustissues almost anywhere inthe body, including theabdominal wall. Small orlarge, they are usually softand often lobulated. Whenyour ﬁnger presses down onthe edge of a lipoma, thetumor typically slips out fromunder it.
Ridge
Localized bulges in the abdominal wall include ventral hernias (defects in the wall through which tissue protrudes) and

Ridge
subcutaneous tumors such as lipomas. The more common ventral hernias are umbilical, incisional, and epigastric.Hernias and a rectus diastasis usually become more evident when the patient raises head and shoulders from a supineposition.
INFANT

TABLE 9-9 IProtuberant Abdomens
CHAPTER 9 ITHE ABDOMEN 361
Fat
Fat is the most common cause of a protuberant abdomen
and is associated with generalized obesity. The abdominalwall is thick. Fat in the mesentery and omentum alsocontributes to abdominal size. The umbilicus may appearsunken. The percussion note is normal. A pannus, orapron of fatty tissue, may extend below the inguinalligaments. Lift it to look for inﬂammation in the skin foldor even for a hidden hernia.
Pregnancy
Pregnancy is a common cause of a pelvic “mass.”Listen for the fetal heart (see pp. 421–422).Gas
Gaseous distention may be localized or generalized.It causes a tympanitic percussion note. Increasedintestinal gas production due to certain foods maycause mild distention. More serious are intestinalobstruction and adynamic (paralytic) ileus. Note thelocation of the distention. Distention becomes moremarked in colonic than in small bowel obstruction.
Ascitic Fluid

Ascitic ﬂuid seeks the lowest point in the abdomen, producing bulging ﬂanks that are dull to percussion.The umbilicus may protrude. Turn the patient onto one side to detect the shift in position of the ﬂuid level(shifting dullness). (See pp. 345–347 for the assessment of ascites.)Tumor
A large, solid tumor, usually rising out of thepelvis, is dull to percussion. Air-ﬁlled bowelis displaced to the periphery. Causes includeovarian tumors and uterine myomata.Occasionally, a markedly distended bladdermay be mistaken for such a tumor.
Tympany
Dullness
Bulging
flankUmbilicus may be 
protuberantTympany
Dullness
Tympany
Dullness
Tympany
Dullness

TABLE 9-10 ISounds in the Abdomen
362 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Bowel Sounds
Bowel sounds may be:
IIncreased , as from diarrhea or
early intestinal obstruction
IDecreased , then absent, as in
adynamic ileus and peritonitis .
Before deciding that bowelsounds are absent, sit down andlisten where shown for 2 min oreven longer.
High-pitched tinkling sounds
suggest intestinal ﬂuid and airunder tension in a dilated bowel.Rushes of high-pitched soundscoinciding with an abdominalcramp indicate intestinalobstruction.Bruits
A hepatic bruit suggests
carcinoma of the liver oralcoholic hepatitis.Arterial bruits with both
systolic and diastoliccomponents suggestpartial occlusion of theaorta or large arteries.Partial occlusion of arenal artery may causeand explain hypertension.
Aorta
Venous Hum
A venous hum is rare. It is a soft

Aorta
Venous Hum
humming noise with both systolicand diastolic components. Itindicates increased collateralcirculation between portal andsystemic venous systems, as inhepatic cirrhosis.Friction Rubs
Friction rubs are rare.They are grating soundswith respiratory variation.They indicateinﬂammation of theperitoneal surface of anorgan, as from a livertumor, chlamydial orgonococcal perihepatitis,recent liver biopsy, orsplenic infarct. When asystolic bruitaccompanies a hepaticfriction rub, suspectcarcinoma of the liver.
and
umbilical
Hepatic
Splenic

TABLE 9-11 ITender Abdomens
CHAPTER 9 ITHE ABDOMEN 363
Tenderness may originate in the abdominal wall. When the patient raises head
and shoulders, this tenderness persists, whereas tenderness from a deeperlesion (protected by the tightened muscles) decreases.
Superficial tender
area
Deep tenderareasAbdominal Wall Tenderness
The structures shown may be tender to deep palpation. Usually the discomfort
is dull and there is no muscular rigidity or rebound tenderness. A reassuringexplanation to the patient may prove quite helpful.
Enlarged liver
Normal cecumNormal aorta
Normal or spastic
sigmoid colonVisceral Tenderness
Acute Pleurisy
Abdominal pain and tenderness may be due to acute pleural inﬂammation.
When unilateral, it may mimic acute cholecystitis or appendicitis. Reboundtenderness and rigidity are less common; chest signs are usually present.
Unilateral orbilateral, upperor lower abdomen
Acute Salpingitis

Frequently bilateral, the tenderness of acute salpingitis (inﬂammation of the
fallopian tubes) is usually maximal just above the inguinal ligaments. Reboundtenderness and rigidity may be present. On pelvic examination, motion of theuterus causes pain.
Tenderness From Disease in the Chest and Pelvis

364 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 9-11 ITender Abdomens (Continued)
Tenderness associated with peritoneal inﬂammation is more severe than visceral tenderness. Muscular rigidity and re-
bound tenderness are frequently but not necessarily present. Generalized peritonitis causes exquisite tendernessthroughout the abdomen, together with boardlike muscular rigidity. Local causes of peritoneal inﬂammation include:
Signs are maximal in the right upper quadrant. Check for Murphy’s sign (see p. 348).
Acute Pancreatitis
In acute pancreatitis, epigastric tenderness and rebound tenderness are usually
present, but the abdominal wall may be soft.
Acute Appendicitis
Right lower quadrant signs are typical of acute appendicitis, but may be absent
early in the course. The typical area of tenderness is illustrated. Explore otherportions of the right lower quadrant as well as the right ﬂank.
Just below the
middle of a line

joining the 
umbilicus and the 
anterior superior 
Right rectaltenderness
Acute diverticulitis most often involves the sigmoid colon and then resembles a
left-sided appendicitis.
Tenderness of Peritoneal Inﬂammation

TABLE 9-12 ILiver Enlargement: Apparent and Real
CHAPTER 9 ITHE ABDOMEN 365
A palpable liver does not necessarily indicate hepatomegaly (an enlarged liver), but more often results from a change in
consistency—from the normal softness to an abnormal ﬁrmness or hardness, as in cirrhosis. Clinical estimates of liver sizeshould be based on both percussion and palpation, although even then they are far from perfect.
Downward Displacement of the Liver by a Low Diaphragm
This is a common ﬁnding (e.g., in emphysema) when the diaphragm is low. Theliver edge may be readily palpable well below the costal margin. Percussion,however, reveals a low upper edge also, and the vertical span of the liver is normal.
Upper
borderlow
Height bypercussionnormal
Normal Variations in Liver Shape
In some persons, especially those with a lanky build, the liver tends to be

Upper
borderlow
somewhat elongated so that its right lobe is easily palpable as it projectsdownward toward the iliac crest. Such an elongation, sometimes calledRiedel’s lobe, represents a variation in shape, not an increase in liver
volume or size. This variant illustrates the basic limitations of assessingliver size. We can only estimate the upper and lower borders of an organthat has three dimensions and differing shapes. Some error isunavoidable.
Elongatedright lobe

366 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 9-12 ILiver Enlargement: Apparent and Real (Continued)
Smooth Large Nontender Liver
Cirrhosis may produce an enlarged liver with a ﬁrm nontender edge. The liver is not always enlarged in this
condition, however, and many other diseases may produce similar ﬁndings.
Smooth Large Tender Liver
An enlarged liver with a smooth tender edge suggests inﬂammation, as in
hepatitis, or venous congestion, as in right-sided heart failure.
Large Irregular Liver
An enlarged liver that is ﬁrm or hard and has an irregular edge or surface
suggests malignancy. There may be one or more nodules. The liver may ormay not be tender.

Vas deferens
Blood vessels
Urethra
Corona
Glans
Prepuce
Urethral meatus Spermatic cord
Epididymis
TestisScrotumCavity of
tunica vaginalisCorpus 
cavernosum
Corpus spongiosum
Male Genitalia and HerniasCHAPTER
Male Genitalia and Hernias 10
CHAPTER 10 IMALE GENITALIA AND HERNIAS 367
Review the anatomy of the male genitalia.10

The shaft of the penis is formed by three columns of vascular erectile tissue:
the corpus spongiosum, containing the urethra, and two corpora cavernosa .
The corpus spongiosum forms the bulb of the penis, ending in the cone-shaped glans with its expanded base, or corona . In uncircumsized men, the
glans is covered by a loose, hoodlike fold of skin called the prepuce or fore-
skin where smegma, or secretions of the glans, may collect .The urethra is lo-
cated ventrally in the shaft of the penis; urethral abnormalities may sometimesbe felt there. The urethra opens into the vertical, slitlike urethral meatus, lo-
cated somewhat ventrally at the tip of the glans.
The scrotum is a loose, wrinkled pouch divided into two compartments, each
of which contains a testis or testicle. The testes are ovoid, somewhat rubbery

structures, about 4.5 cm long in the adult, with a range from 3.5 cm to 5.5 cm. The left usually lies somewhat lower than the right. On the postero-lateral surface of each testis is the softer, comma-shaped epididymis. It is most
prominent along the superior margin of the testis. The epididymis may be lo-cated anteriorly in 6% to 7% of males. Surrounding the testis, except posteri-orly, is the tunica vaginalis, a serous membrane enclosing a potential cavity.
The testes produce spermatozoa and testosterone. Testosterone stimulates
the pubertal growth of the male genitalia, prostate, and seminal vesicles. Italso stimulates the development of masculine secondary sex characteristics,including the beard, body hair, musculoskeletal development, and enlargedlarynx with the associated low-pitched voice.

The vas deferens, a cordlike structure, begins at the tail of the epididymis, as-
cends within the scrotal sac, and passes through the external inguinal ringon its way to the abdomen and pelvis. Behind the bladder it is joined by theduct from the seminal vesicle and enters the urethra within the prostategland. Sperm thus pass from the testis and the epididymis through the vasdeferens into the urethra. Secretions from the vasa deferentia, the seminalvesicles, and the prostate all contribute to the semen. Within the scrotumeach vas is closely associated with blood vessels, nerves, and muscle ﬁbers.These structures make up the spermatic cord.
Male sexual function depends on normal levels of testosterone, adequate ar-
terial blood ﬂow to the inferior epigastric artery and its cremasteric and pubicbranches, and intact neural innervation from α-adrenergic and cholinergic

pathways. Erection from venous engorgement of the corpora cavernosa re-sults from two types of stimuli. Visual, auditory, or erotic cues trigger sym-pathetic outﬂow from higher brain centers to the T11 through L2 levels ofthe spinal cord. Tactile stimulation initiates sensory impulses from the gen-italia to S
2–S4reﬂex arcs and parasympathetic pathways via the pudendal
nerve. Both sets of stimuli appear to increase levels of nitric oxide and cyclicGMP, resulting in local vasodilation.
Lymphatics. Lymphatics from the penile and scrotal surfaces drain into
the inguinal nodes. When you find an inflammatory or possibly malignant
lesion on these surfaces, assess the inguinal nodes especially carefully for en-ANATOMY AND PHYSIOLOGY
368 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING

largement or tenderness. The lymphatics of the testes, however, drain into
the abdomen, where enlarged nodes are clinically undetectable. See page452 for further discussion of the inguinal nodes.
Anatomy of the Groin. Because hernias are relatively common, it is
important to understand the anatomy of the groin. The basic landmarks arethe anterior superior iliac spine, the pubic tubercle, and the inguinal liga-ment that runs between them. Find these on yourself or a colleague.
The inguinal canal, which lies above
and approximately parallel to the in-guinal ligament, forms a tunnel forthe vas deferens as it passes throughthe abdominal muscles. The exterioropening of the tunnel—the external
inguinal ring —is a triangular slitlike

structure palpable just above and lat-eral to the pubic tubercle. The inter-nal opening of the canal—or internalinguinal ring—is about 1 cm abovethe midpoint of the inguinal liga-ment. Neither canal nor internal ringis palpable through the abdominalwall. When loops of bowel forcetheir way through weak areas of theinguinal canal they produce ingui-nal hernias, as illustrated on pp.381–382.
Another potential route for a herniating mass is the femoral canal. This lies
below the inguinal ligament. Although you cannot see it, you can estimateits location by placing your right index ﬁnger, from below, on the rightfemoral artery. Your middle ﬁnger will then overlie the femoral vein; yourring ﬁnger, the femoral canal. Femoral hernias protrude here.

Note that in about 80% of men, pubic hair spreads farther up the abdomenin a triangular pattern pointing toward the umbilicus. Because this kind ofspread, known as stage 6, is not completed until the mid-20s or later, it isnot considered a pubertal change.
Testosterone levels decline with aging and may affect both libido and sexual
function. Erection becomes more dependent on tactile stimulation and lessresponsive to erotic cues. Pubic hair may decrease and become gray. The penisdecreases in size and the testicles drop lower in the scrotum. Although thetestes often decrease in size with protracted illnesses, they do not necessarilychange size with aging per se .
CHAPTER 10 IMALE GENITALIA AND HERNIAS 369Internal inguinal
ring
Site of femoral 
canal External inguinal
ringInguinal canal
Spermatic cord
Pubic tubercleFemoral artery
Femoral veinAnterior superior

For men, questions about the genital system follow naturally after those
dealing with the urinary system. You will need to review sexual function andscreen for symptoms of infection. Begin with general questions such as“How is sexual function for you?” “Are you satisﬁed with your sexual life?”“What about your ability to perform sexually?” If the patient reports a sex-ual problem, ask him to tell you about it. Ask if there has been any changein desire or level of sexual activity in recent years. What does he think hascaused it, what has he tried to do about it, and what are his hopes? Identifythe patient’s sexual preference as to partners (male, female, or both). Findout if the patient’s partner has any concerns.
Direct questions help you to assess each phase of the sexual response. To as-
sess libido, or desire, ask “Have you maintained an interest in sex?” For the
arousal phase, ask “Are you able to achieve and maintain an erection?” Ex-

plore the timing, severity, setting, and any other factors that may be con-tributing. Have any changes in the relationship with his partner or in his lifecircumstances coincided with onset of the problem? Are there circumstanceswhen erection is normal? On awakening in the early morning or during thenight? With other partners? With masturbation?
Other questions relate to the phase of orgasm and ejaculation of semen. If

ejaculation is premature, or early and out of control, ask “About how longdoes intercourse last?” “Do you climax too soon?” “Do you feel like you haveany control over climaxing?” “Do you think your partner would like inter-course to last longer?” For reduced or absent ejaculation, “Do you ﬁnd thatyou cannot have orgasm even though you can have an erection?” Try to de-termine if the problem involves the pleasurable sensation of orgasm, the ejac-ulation of seminal ﬂuid, or both. Review the frequency and setting of theproblem, medications, surgery, and neurologic symptoms.
To assess the possibility of genital infection from sexually transmitted dis-
eases (STDs), ask about any discharge from the penis, dripping, or staining of
underwear. If penile discharge is present, assess the amount, its color andconsistency, and any fever, chills, rash, or associated symptoms.THE HEALTH HISTORY

370 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGLack of libido may arise from 
psychogenic causes such as depression, endocrine dysfunction,or side effects of medications.
Erectile dysfunction from psycho-
genic causes, especially if earlymorning erection preserved; alsofrom decreased testosterone, decreased blood ﬂow in hypo-gastric arterial system, impairedneural innervation
Premature ejaculation is common,
especially in young men. Less common is reduced or absent ejaculation affecting middle-agedor older men. Possible causes aremedications, surgery, neurologicdeﬁcits, or lack of androgen. Lackof orgasm with ejaculation is usually psychogenic.
Penile discharge in gonococcal
(usually yellow) and non-gonococcal urethritis (may be clearor white)Common or Concerning Symptoms
ISexual function, sexual preference

ISexual response: libido, arousal, orgasm, ejaculation
IPenile discharge or lesions
IScrotal pain, swelling, or lesions

Inquire about sores or growths on the penis, and any pain or swelling in the
scrotum. Ask about previous genital symptoms or a past history of diseases
such as herpes, gonorrhea, or syphilis. A patient who has multiple partners,is homosexual, uses illicit drugs, or has a prior history of STDs is at in-creased risk for STDs.
Because STDs may involve other parts of the body, additional questions are
often indicated. An introductory explanation may be useful. “Sexually trans-mitted diseases can involve any body opening where you have sex. It’s im-portant for you to tell me which openings you use.” And further, as needed,“Do you have oral sex? Anal sex?” If the patient’s answers are afﬁrmative, askabout symptoms such as sore throat, diarrhea, rectal bleeding, and anal itch-ing or pain.
For the many patients without symptoms or known risk factors, it is wise to

ask, “Do you have any concerns about HIV infection?” and to continue withthe more general questions suggested on pp. 45–46.HEALTH PROMOTION AND COUNSELING
CHAPTER 10 IMALE GENITALIA AND HERNIAS 371See Table 10-1, Abnormalities of
the Penis (p. 378) and Table 10-2,Abnormalities of the Male Genitalia(pp. 379–380). In addition toSTDs, many skin conditions affectthe genitalia; likewise some STDshave minimal symptoms or signs.
Infections from oral–penile 
transmission include gonorrhea,Chlamydia , syphilis, and herpes.
Symptomatic or asymptomaticproctitis may follow anal intercourse.
IPrevention of STDs and HIV
ITesticular self-examination
Health promotion and counseling should address patient education about

STDs and HIV, early detection of infection during history taking and phys-ical examination, and identiﬁcation and treatment of infected partners. Dis-cussion of risk factors for STDs and HIV is especially important for adoles-cents and younger patients, the age groups that are most adversely affected.Clinicians must be comfortable with eliciting the sexual history and withasking frank but tactful questions about sexual practices. A minimal historyincludes identifying the patient’s sexual orientation, the number of sexualpartners in the past month, and any history of STDs (see Chap. 2, p. 45).Questions should be clear and nonjudgmental. You should also identifyuse of alcohol and drugs, particularly injection drugs. Counsel patients at risk about limiting the number of partners, using condoms, and estab-lishing regular medical care for treatment of STDs and HIV. It is impor-tant for men to seek prompt attention for any genital lesions or penile discharge.

The U.S. Preventive Services Task Force recommends counseling and test-
ing for HIV infection in the following groups: all persons at increased riskEXAMPLES OF ABNORMALITIES

for infection with HIV, STDs, or both; men with male partners; past or pres-
ent injection drug users; any past or present partners of individuals with HIVinfection, bisexual practices, or injection drug use; and patients with a his-tory of transfusion between 1978 and 1985.
In addition, encourage men, especially those between the ages of 15 and
35, to perform monthly testicular self-examinations and to seek physicianevaluation for the following findings: any painless lump, swelling, or en-largement in either testicle; pain or discomfort in a testicle or the scro-tum; a feeling of heaviness or a sudden fluid collection in the scrotum; ora dull ache in the lower abdomen or the groin. (See p. 377 for instruc-tions to patients.)HEALTH PROMOTION AND COUNSELING
372 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGSuspicious for testicular carcinoma,
the most common form of cancerin men between the ages of 15and 35Preview: Recording the Physical Examination—
Male Genitalia and Hernias

“Circumsized male. No penile discharge or lesions. No scrotal swelling
or discoloration. Testes descended bilaterally, smooth, without masses.Epididymis nontender. No inguinal or femoral hernias.”
OR“Uncircumsized male; prepuce easily retractible. No penile discharge 
or lesions. No scrotal swelling or discoloration. Testes descended bilaterally; right testicle smooth; 1 ×1 cm ﬁrm nodule on left lateral 
testicle. It is ﬁxed and nontender. Epididymis nontender. No inguinal orfemoral hernias.”EXAMPLES OF ABNORMALITIES

CHAPTER 10 IMALE GENITALIA AND HERNIAS 373See Table 10-1, Abnormalities of
the Penis (p. 378).
Phimosis is a tight prepuce that
cannot be retracted over the glans.Paraphimosis is a tight prepuce
that, once retracted, cannot be returned. Edema ensues.
Balanitis (inﬂammation of the
glans); balanoposthitis (inﬂamma-
tion of the glans and prepuce)
Pubic or genital excoriations sug-
gest the possibility of lice (crabs) orsometimes scabies.
Hypospadias is a congenital, ventral
displacement of the meatus on thepenis (p. 378).
Profuse yellow discharge in 
gonococcal urethritis; scanty white or clear discharge in non-gonococcal urethritis. Deﬁnitive diagnosis requires Gram stain andculture.
Many students feel uneasy about examining a man’s genitalia. “How will the

patient react?” “Will he have an erection?” “Will he let me examine him?”It may be reassuring to explain each step of the examination so the patientknows what to expect. A male patient may occasionally have an erection. Ifso, you should explain that this is a normal response, ﬁnish your examina-tion, and proceed with an unrufﬂed demeanor. If the man refuses to be ex-amined, you should respect his wishes.
A good genital examination can be done with the patient either standing or
supine. To check for hernias or varicoceles, however, the patient shouldstand, and you should sit comfortably on a chair or stool. A gown conve-niently covers the patient’s chest and abdomen. Wear gloves throughout theexamination. Expose the genitalia and inguinal areas. For younger patients,review the sexual maturity ratings on p. 707.
The Penis
Inspect the penis, including:
IThe skin

The Penis
IThe skin
IThe prepuce (foreskin). If it is present, retract it or ask the patient to re-
tract it. This step is essential for the detection of many chancres and car-cinomas. Smegma, a cheesy, whitish material, may accumulate normallyunder the foreskin.
IThe glans . Look for any ulcers, scars, nodules, or signs of inﬂammation.
Check the skin around the base of the penis for excoriations or inﬂamma-
tion. Look for nits or lice at the bases of the pubic hairs.
Note the location of the urethral
meatus.
Compress the glans gently between
your index ﬁnger above and yourthumb below. This maneuver shouldopen the urethral meatus and allowyou to inspect it for discharge. Nor-mally there is none.

374 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGInduration along the ventral surface
of the penis suggests a urethralstricture or possibly a carcinoma.Tenderness of such an induratedarea suggests periurethral inﬂam-mation secondary to a urethralstricture.
See Table 10-2, Abnormalities of
the Male Genitalia (pp. 379–380).
Rashes, epidermoid cysts, rarely
skin cancer
A poorly developed scrotum on
one or both sides suggests crypt-
orchidism (an undescended testicle).
Common scrotal swellings includeindirect inguinal hernias, hydro-celes, and scrotal edema. Tender,painful scrotal swelling in acute epi-didymitis, acute orchitis, torsion ofthe spermatic cord, or a strangu-lated inguinal hernia.
Any painless nodule in the testis

must raise the possibility of testicu-lar cancer, a potentially curablecancer with a peak incidence be-tween the ages of 15 and 35 years.If the patient has reported a discharge but you do not see any, ask him to strip,
or milk, the shaft of the penis from its base to the glans. Alternatively, do ityourself. This maneuver may bring some discharge out of the urethral meatusfor appropriate examination. Have a glass slide and culture materials ready.
PALPATION
Palpate any abnormality of the penis, noting any tenderness or induration.Palpate the shaft of the penis between your thumb and ﬁrst two ﬁngers, not-ing any induration. Palpation of the shaft may be omitted in a young, asymp-tomatic male patient.
If you retract the foreskin, replace it before proceeding on to examine the
scrotum.
The Scrotum and Its Contents
Inspect the scrotum, including:
IThe skin. Lift up the scrotum so that you can see its posterior surface.

scrotum.
IThe scrotal contours . Note any swelling, lumps, or veins.
PALPATION
Palpate each testis and epididymis 
between your thumb and ﬁrst twoﬁngers.
Note size, shape, consistency, and
tenderness; feel for any nodules.Pressure on the testis normally pro-duces a deep visceral pain.

CHAPTER 10 IMALE GENITALIA AND HERNIAS 375Palpate each spermatic cord, including
the vas deferens, between your thumband ﬁngers from the epididymis tothe superﬁcial inguinal ring.
Note any nodules or swellings.
Swelling in the scrotum other than the testicles can be evaluated by transil-
lumination. After darkening the room, shine the beam of a strong ﬂashlightfrom behind the scrotum through the mass. Look for transmission of thelight as a red glow.
Hernias
Inspect the inguinal and femoral areas carefully for bulges. While you con-
tinue your observation, ask the patient to strain down.
PALPATION
Palpate for an inguinal hernia . Using in turn your right hand for the pa-

PALPATION
tient’s right side and your left hand for the patient’s left side, invaginateloose scrotal skin with your index ﬁnger. Start at a point low enough to besure that your ﬁnger will have enough mobility to reach as far as the inter-nal inguinal ring if this proves possible. Follow the spermatic cord upwardto above the inguinal ligament and find the triangular slitlike opening ofthe external inguinal ring. This is just above and lateral to the pubic tuber-cle. If the ring is somewhat enlarged, it may admit your index ﬁnger. If pos-sible, gently follow the inguinal canal laterally in its oblique course. Withyour ﬁnger located either at the external ring or within the canal, ask thepatient to strain down or cough. Note any palpable herniating mass as ittouches your ﬁnger.
Multiple tortuous veins in this area,

usually on the left, may be palpa-ble and even visible. They indicatea varicocele (p. 380).
The vas deferens, if chronically 
infected, may feel thickened orbeaded. A cystic structure in thespermatic cord suggests a hydro-cele of the cord.
Swellings containing serous 
ﬂuid, as in hydroceles, light upwith a red glow, or transillumi-nate. Those containing blood ortissue, such as a normal testis, atumor, or most hernias, do not.
A bulge that appears on straining
suggests a hernia.
See Table 10-3, Course and Presen-
tation of Hernias in the Groin (p. 381).
See Table 10-4, Differentiation of
Hernias in the Groin (p. 382).

Palpate for a femoral hernia by placing your ﬁngers on the anterior thigh in
the region of the femoral canal. Ask the patient to strain down again orcough. Note any swelling or tenderness.
Evaluating a Possible Scrotal Hernia. If you ﬁnd a large scrotal mass
and suspect that it may be a hernia, ask the patient to lie down. The massmay return to the abdomen by itself. If so, it is a hernia. If not:
ICan you get your ﬁngers above the mass in the scrotum?
IListen to the mass with a stethoscope for bowel sounds.
If the ﬁndings suggest a hernia, gently try to reduce it (return it to the ab-
dominal cavity) by sustained pressure with your ﬁngers. Do not attempt thismaneuver if the mass is tender or the patient reports nausea and vomiting.
History may be helpful here. The patient can usually tell you what happens
to his swelling on lying down and may be able to demonstrate how he re-duces it himself. Remember to ask him.
THE TESTICULAR SELF-EXAMINATION

The incidence of testicular cancer is low, about 4 per 100,000 men, but it is the most common cancer of young men between ages 15 and 35. Althoughthe testicular self-examination (TSE) has not been formally endorsed as ascreen for testicular carcinoma, you may wish to teach your patient the TSEto enhance health awareness and self-care. When detected early, testicular
376 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGIf you can, suspect a hydrocele.
Bowel sounds may be heard over a
hernia, but not over a hydrocele.
A hernia is incarcerated when its
contents cannot be returned to the abdominal cavity. A hernia isstrangulated when the blood sup-

ply to the entrapped contents iscompromised. Suspect strangula-tion in the presence of tenderness,nausea, and vomiting, and con-sider surgical intervention.
Inguinal
ligament External
inguinal
ringAnterior
superioriliac spine

CHAPTER 10 IMALE GENITALIA AND HERNIAS 377carcinoma has an excellent prognosis. Risk factors include: cryptorchidism,
which confers a high risk of testicular carcinoma in the undescended testi-cle; a history of carcinoma in the contralateral testicle; mumps orchitis; aninguinal hernia; and a hydrocele in childhood.
PATIENT INSTRUCTIONS FOR THE TESTICULAR 
SELF-EXAMINATION
This examination is best performed after a warm bath or shower. The heat relaxes
the scrotum and makes it easier to ﬁnd anything unusual.
IStanding in front of a mirror, check for any swelling on the skin of the scrotum.
IExamine each testicle with both hands. Cup the index and middle ﬁngers underthe testicle and place the thumbs on top.
IRoll the testicle gently between the thumbs and ﬁngers. One testicle may belarger than the other . . . that’s normal, but be concerned about any lump orarea of pain.

IFind the epididymis. This is a soft, tubelike structure at the back of the testiclethat collects and carries sperm, not an abnormal lump.
IIf you ﬁnd any lump, don’t wait. See your doctor. The lump may just be an infection, but if it is cancer, it will spread unless stopped by treatment.
*Adapted from the National Cancer Institute. Rex.nih.gov/WTNK_PUBS/testicular/testexam.htm .
Accessed 9/27/01.

TABLE 10-1 IAbnormalities of the Penis
378 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Venereal Wart 
(Condyloma acuminatum)
Venereal warts are rapidly growing excrescences
that are moist and often malodorous. They resultfrom infection by human papillomavirus.Genital Herpes
A cluster of small vesicles, followed by shallow,painful, nonindurated ulcers on red bases, suggests a herpes simplex infection. The lesions may occuranywhere on the penis. Usually there are fewerlesions when the infection recurs.Syphilitic Chancre
A syphilitic chancre usually appears as an oval orround, dark red, painless erosion or ulcer with anindurated base. Nontender enlarged inguinal lymphnodes are typically associated. Chancres may bemultiple, and when secondarily infected may bepainful. They may then be mistaken for the lesions of herpes. Chancres are infectious.
Hypospadias
Hypospadias is a congenital displacement of the

urethral meatus to the inferior surface of the penis.A groove extends from the actual urethral meatusto its normal location on the tip of the glans.Peyronie’s Disease
In Peyronie’s disease, there are palpable nontenderhard plaques just beneath the skin, usually along thedorsum of the penis. The patient complains ofcrooked, painful erections.Carcinoma of the Penis
Carcinoma may appear as an indurated nodule or ulcer that is usually nontender. Limited almostcompletely to men who are not circumcised inchildhood, it may be masked by the prepuce. Anypersistent penile sore must be considered suspicious.

TABLE 10-2 IAbnormalities of the Male Genitalia
CHAPTER 10 IMALE GENITALIA AND HERNIAS 379
Hydrocele
A hydrocele is a nontender, ﬂuid-ﬁlled
mass within the tunica vaginalis. Ittransilluminates and the examiningﬁngers can get above the mass within the scrotum.Scrotal Hernia
A hernia within the scrotum is usually anindirect inguinal hernia . It comes through
the external inguinal ring, so the examiningﬁngers cannot get above it in the scrotum. Scrotal Edema
Pitting edema may make the scrotalskin taut. This may accompany thegeneralized edema of congestive heartfailure or nephrotic syndrome.Cryptorchidism
In cryptorchidism, the testis isatrophied and may lie in theinguinal canal or the abdomen,resulting in an undevelopedscrotum as above. There is nopalpable left testis or epididymis.Cryptorchidism markedly raisesthe risk of testicular cancer.
Fingers can
get abovemass
Acute Orchitis 
The testis is acutely inﬂamed, painful,

tender, and swollen. It may be difﬁcultto distinguish from the epididymis. Thescrotum may be reddened. Seen inmumps and other viral infections; usuallyunilateral.Small Testis
In adults, the length is usually ≤3.5 cm.
Small ﬁrm testes in Klinefelter’s syndrome,
usually ≤2 cm. Small soft testes suggesting
atrophy seen in cirrhosis, mytonic dystrophy,use of estrogens, hypopituitarism; may alsofollow orchitis.As a testicular neoplasm grows
and spreads, it may seem toreplace the entire organ. Thetesticle characteristically feelsheavier than normal.Tumor of the Testis
Usually appears as a painless nodule.Any nodule within the testis warrantsinvestigation for malignancy. 
Early
Late
Fingers cannotget abovemass

380 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 10-2 IAbnormalities of the Male Genitalia (Continued)
Acute Epididymitis
An acutely inﬂamed epididymis is tender and
swollen and may be difﬁcult to distinguish fromthe testis. The scrotum may be reddened, and thevas deferens inﬂamed. It occurs chieﬂy in adults.Coexisting urinary tract infection or prostatitissupports the diagnosis.Spermatocele and Cyst of the Epididymis
A painless, movable cystic mass just above the testissuggests a spermatocele or an epididymal cyst. Bothtransilluminate. The former contains sperm and thelatter does not, but they are clinically indistinguishable.Tuberculous Epididymitis
The chronic inﬂammation of tuberculosisproduces a ﬁrm enlargement of the epididymis,which is sometimes tender, with thickening orbeading of the vas deferens.
Varicocele
Varicocele refers to varicose veins of the spermatic

cord, usually found on the left. It feels like a soft“bag of worms” separate from the testis, andslowly collapses when the scrotum is elevated inthe supine patient. Infertility may be associated.Torsion of the Spermatic Cord
Torsion, or twisting, of the testicle on its spermaticcord produces an acutely painful, tender, and swollenorgan that is retracted upward in the scrotum. Thescrotum becomes red and edematous. There is noassociated urinary infection. Torsion, most common inadolescents, is a surgical emergency because ofobstructed circulation.Epidermoid Cysts
These are ﬁrm, yellowish, nontender,cutaneous cysts up to about 1 cm in diameter.They are common and frequently multiple.

TABLE 10-3 ICourse and Presentation of Hernias in the Groin
CHAPTER 10 IMALE GENITALIA AND HERNIAS 381
Internal inguinal ring
COURSE AND
PRESENTATION OF
DIRECT INGUINAL
HERNIA
Femoral artery
Femoral veinInguinal canal
External inguinal ringCOURSE AND
PRESENTATION OFFEMORAL HERNIA
COURSE AND
PRESENTATION OFINDIRECTINGUINAL HERNIA

TABLE 10-4 IDifferentiation of Hernias in the Groin
382 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Inguinal
Indirect Direct FemoralTABLE 10-4 IDifferentiation of Hernias in the Groin
Differentiation among these hernias is not always clinically possible. Understanding their features, however, improves your obs ervation.
Frequency
Age and Sex
Point of Origin
Course
With the examining ﬁnger in the
inguinal canal during straining orcoughMost common, all ages, both sexes
Often in children, may be in adults
Above inguinal ligament, near 
its midpoint (the internal inguinalring)
Often into the scrotum
The hernia comes down the
inguinal canal and touches theﬁngertip.Less common
Usually in men over age 40, rare in
women
Above inguinal ligament, close to the
pubic tubercle (near the externalinguinal ring)
Rarely into the scrotum
The hernia bulges anteriorly and
pushes the side of the ﬁnger forward.
Least common
More common in women than in men
Below the inguinal ligament; appears

more lateral than an inguinal herniaand may be hard to differentiate fromlymph nodes
Never into the scrotumThe inguinal canal is empty.

Mons pubis
Prepuce
Clitoris
Urethral meatus
Opening of
paraurethral(Skene's) gland
Vestibule
Introitus
PeriniumLabium majus
Labium minus
Hymen
Vagina
Opening of
Bartholin's gland
Anus
Female GenitaliaCHAPTER
Female Genitalia 1111
CHAPTER 11 IFEMALE GENITALIA 381
Review the anatomy of the external female genitalia (vulva), including the
mons pubis, a hair-covered fat pad overlying the symphysis pubis; the labia
majora, rounded folds of adipose tissue; the labia minora, thinner pinkish
red folds that extend anteriorly to form the prepuce; and the clitoris. The
vestibule is the boat-shaped fossa between the labia minora. In its posterior
portion lies the vaginal opening ( introitus ), which in virgins may be hidden
by the hymen. The term perineum, as commonly used clinically, refers to the
tissue between the introitus and the anus.
The urethral meatus opens into the vestibule between the clitoris and the

vagina. Just posterior to it on either side lie the openings of the paraurethral
(Skene’s) glands.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cSacrum
Rectum
Isthmus of uterusRectouterine pouc h
CervixFornix
VaginaFallopian tube
Ovary
Uterus
Bladder
Urethra
Introitus
PerineumThe openings of Bartholin’s glands are located posteriorly on either side of
the vaginal opening, but are not usually visible. Bartholin’s glands themselvesare situated more deeply.
The vagina is a hollow tube extending upward and posteriorly between the
urethra and the rectum. Its upper third takes a horizontal plane and termi-nates in the cup-shaped fornix. The vaginal mucosa lies in transverse folds,
or rugae.
At almost right angles to the vagina sits the uterus, a ﬂattened ﬁbromuscu-
lar structure shaped like an inverted pear. The uterus has two parts: the body(corpus) and the cervix, which are joined together by the isthmus. The con-vex upper surface of the body is called the fundus of the uterus. The lower
part of the uterus, the cervix, protrudes into the vagina, dividing the fornix

into anterior, posterior, and lateral fornices.ANATOMY AND PHYSIOLOGY
Location of
Bartholin's glands
The vaginal surface of the cervix, the ectocervix, is seen easily with the help
of a speculum. At its center is a round, oval, or slitlike depression, the exter-
nal os of the cervix, which marks the opening into the endocervical canal.
The ectocervix is covered by epithelium of two possible types: a plushy, redcolumnar epithelium surrounding the os, which resembles the lining of theendocervical canal; and a shiny pink squamous epithelium continous withthe vaginal lining. The boundary between these two types of epithelium isthe squamocolumnar junction. In puberty, the broad band of columnar ep-
ithelium encircling the os, called ectropion, is gradually replaced by columnar

epithelium. The squamocolumnar junction migrates toward the os, creatingthe transformation zone. (This is the area at risk for later dysplasia, which is
sampled by the Papanicolaou, or Pap, smear.)
A fallopian tube with a fanlike tip extends from each side of the uterus to-
ward the ovary. The two ovaries are almond-shaped structures that vary con-

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5csiderably in size but average about 3.5 ×2 ×1.5 cm from adulthood through
menopause. The ovaries are palpable on pelvic examination in roughly halfof women during the reproductive years. Normally, fallopian tubes cannotbe felt. The term adnexa (a plural Latin word meaning appendages) refers
to the ovaries, tubes, and supporting tissues.
The ovaries have two primary functions: the production of ova and the se-
cretion of hormones, including estrogen, progesterone, and testosterone. In-creased hormonal secretions during puberty stimulate the growth of the
uterus and its endometrial lining. They enlarge the vagina and thicken its ep-ithelium. They also stimulate the development of secondary sex characteris-tics, including the breasts and pubic hair.
The parietal peritoneum extends downward behind the uterus into a cul de
sac called the rectouterine pouch (pouch of Douglas). You can just reach this
area on rectovaginal examination.

The pelvic organs are supported by a sling of tissues composed of muscle,
ligaments, and fascia, through which the urethra, vagina, and rectum all pass.
Lymphatics. Lymph from the vulva and the lower vagina drains into the
inguinal nodes. Lymph from the internal genitalia, including the uppervagina, ﬂows into the pelvic and abdominal lymph nodes, which are not pal-pable clinically.
CHANGES WITH AGING

During the pubertal years, the vulva and the internal genitalia grow andchange to their adult proportions. Assessment of sexual maturity in girls, asclassiﬁed by Tanner, depends not on internal examination, however, but onthe growth of pubic hair and the development of breasts. Tanner’s stages,or sexual maturity ratings, as they relate to pubic hair and breasts are shownin Chapter 17, Assessing Children: Infancy Through Adolescence.
In most women, pubic hair spreads downward in a triangular pattern, point-
ing toward the vagina. In 10% of women, it may form an inverted triangle,pointing toward the umbilicus. This growth is usually not completed untilthe middle 20s or later.
Just before menarche there is a physiologic increase in vaginal secretions—

a normal change that sometimes worries a girl or her mother. As mensesANATOMY AND PHYSIOLOGY
CHAPTER 11 IFEMALE GENITALIA 383
External os  of
the cervix
Transformation
zoneColumnar eithelium
Squamocolumnar junction
Squamous epithelium

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTHE HEALTH HISTORY EXAMPLES OF ABNORMALITIES
384 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGbecome established, increased secretions ( leukorrhea ) coincide with ovula-
tion. They also accompany sexual arousal. These normal kinds of dischargesmust be differentiated from those of infectious processes.
Ovarian function usually starts to diminish during a woman’s 40s, and men-
strual periods cease on the average between the ages of 45 and 52, some-times earlier and sometimes later. Pubic hair becomes sparse as well as gray.As estrogen stimulation falls, the labia and the clitoris become smaller. Thevagina narrows and shortens and its mucosa becomes thin, pale, and dry.The uterus and ovaries diminish in size. Once menopause has occurred, theovaries may no longer be palpable. The suspensory ligaments of the adnexa,uterus, and bladder may also relax.
The dates of previous periods may

alert you to possible pregnancy ormenstrual irregularities.
Unlike the normal dark red men-
strual discharge, excessive ﬂowtends to be bright red and may in-clude “clots” (not true ﬁbrin clots).Common or Concerning Symptoms
IMenarche, menstruation, menopause
IPregnancy
IVulvovaginal symptoms
ISexual activity
Questions in this section focus on menstruation, pregnancy and related top-
ics, vulvovaginal symptoms, and sexual function.
Menarche, Menstruation, Menopause. For the menstrual history,
ask the patient how old she was when her monthly, or menstrual, periodsbegan (age at menarche ). When did her last period start, and, if possible, the

one before that? How often do the periods come (as measured by the inter-vals between the ﬁrst days of successive periods)? How regular or irregularare they? How long do they last? How heavy is the ﬂow? What color is it?Flow can be assessed roughly by the number of pads or tampons used daily.Because women vary in their practices for sanitary measures, however, askthe patient whether she usually soaks a pad or tampon, spots it lightly, etc.Further, does she use more than one at a time? Does she have any bleedingbetween periods? Any bleeding after intercourse or after douching?
Does the patient have any discomfort or pain before or during her periods?

If so, what is it like, how long does it last, and does it interfere with her usualactivities? Are there other associated symptoms? Ask a middle-aged or olderwoman if she has stopped menstruating. When? Did any symptoms accom-pany her change? Has she had any bleeding since?
Questions about menarche, menstruation, and menopause often give you an
opportunity to explore the patient’s need for information and her attitude

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5ctoward her body. When talking with an adolescent girl, for example, opening
questions might include: “How did you ﬁrst learn about monthly periods?How did you feel when they started? Many girls worry when their periodsaren’t regular or come late. Has anything like that bothered you?” You canexplain that girls in the United States usually begin to menstruate between theages of 9 and 16 years, and often take a year or more before they settle into areasonable, regular pattern. Age at menarche is variable, depending on geneticendowment, socioeconomic status, and nutrition. The interval between peri-ods ranges roughly from 24 to 32 days; the ﬂow lasts from 3 to 7 days.
Menopause, the absence of menses for 12 consecutive months, usually oc-

curs between the ages of 45 and 52 years. Associated symptoms includehot ﬂashes, ﬂushing, sweating, and disturbances of sleep. Often you will ask,“How do (did) you feel about not having your periods anymore? Has it af-fected your life in any way?” Postmenopausal bleeding is deﬁned as bleeding
that occurs after 6 months without periods and warrants further investigation.
Amenorrhea refers to the absence of periods. Failure to initiate periods is
called primary amenorrhea, while the cessation of periods after they have
been established is termed secondary amenorrhea. Pregnancy, lactation, and
menopause are physiologic forms of the secondary type. Oligomenorrhea refers
to infrequent periods, which may also be irregular. This pattern is commonfor as long as 2 years after menarche, and it also occurs before menopause.
Dysmenorrhea is pain with menstruation, and is usually felt as a bearing

down, aching, or cramping sensation in the lower abdomen and pelvis.Women may report premenstrual syndrome (PMS), a complex of symptoms
occurring 4 to 10 days before a period. PMS symptoms include tension, ner-vousness, irritability, depression, and mood swings; weight gain, abdominalbloating, edema, and tenderness of the breasts; and headaches. Though usu-ally mild, PMS symptoms may be severe and disabling.
Polymenorrhea means abnormally frequent periods, and menorrhagia refers
to an increased amount or duration of ﬂow. Bleeding may also occur be-tween periods, termed metrorrhagia or intermenstrual bleeding, after inter-
course ( postcoital bleeding ), or after other vaginal contact from practices such
as douching.
Pregnancy. Questions relating to pregnancy include: “Have you ever

been (or how often have you been) pregnant? Have you ever had a miscar-riage or an abortion? How often? How many living children do you have?”Inquire about any difﬁculties with the pregnancies and the timing and thecircumstances of any abortion (spontaneous or induced). What kind of birthcontrol methods, if any, have the patient and her partner used, and how sat-isﬁed is she with them?
If amenorrhea suggests a current pregnancy, inquire about the history of
intercourse and common early symptoms: tenderness, tingling, or increased size
of the breasts; urinary frequency; nausea and vomiting; easy fatigability; andfeelings that the baby is moving (the last usually noted at about 20 weeks).THE HEALTH HISTORY
CHAPTER 11 IFEMALE GENITALIA 385Postmenopausal bleeding raises the

question of endometrial cancer,although it also has other causes.Other causes of secondary amenor-rhea include low body weight fromany cause, including malnutritionand anorexia nervosa, stress,chronic illness, and hypothalamic–pituitary–ovarian dysfunction.
Increased frequency, increased
ﬂow, or bleeding between periodsmay have systemic causes or maybe dysfunctional. Postcoital bleed-ing suggests cervical disease (e.g., polyps, cancer) or, in anolder woman, atrophic vaginitis.
Amenorrhea followed by heavy
bleeding suggests a threatenedabortion or dysfunctional uterinebleeding related to lack of ovulation.EXAMPLES OF ABNORMALITIES

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cBe alert to the patient’s feelings in discussing all these topics and explore
them as seems indicated. (See also Chapter 12, The Pregnant Woman).
Vulvovaginal Symptoms. The most common vulvovaginal symptoms
are vaginal discharge and local itching. Follow your usual approach. If the pa-
tient reports a discharge, inquire about its amount, color, consistency, andodor. Ask about any local soresor lumps in the vulvar area. Are they painful
or not? Because patients vary in their understanding of anatomic terms, beprepared to try alternative phrasing such as “Any itching (or other symptoms)near your vagina? . . . between your legs? . . . where you urinate?”
Sexual Activity. Start with general questions such as “How is sex for

you?” Or “Are you having any problems with sex?” You can also ask, “Areyou satisﬁed with your sex life as it is now? Has there been any signiﬁcantchange in the last few years? Are you satisﬁed with you ability to perform sex-ually? How satisﬁed do you think your partner is? Do you feel that your part-ner is satisﬁed with the frequency of sexual activity?”
If the patient seems to have a sexual problem, ask her to tell you about it.
Direct questions help you assess each phase of the sexual response: desire,arousal, and orgasm. “Do you have an interest in (appetite for) sex?” in-quires about the desire phase. For the orgasmic phase, “Are you able toreach climax (reach an orgasm or ‘come’)?” “Is it important for you to reachclimax?” For arousal, “Do you get sexually aroused? Do you lubricate easily(get wet or slippery)? Do you stay too dry?”
Ask also about dyspareunia, or discomfort or pain during intercourse. If pres-

ent, try to localize the symptom. Is it near the outside, occurring at the startof intercourse, or does she feel it farther in, when her partner is pushing deeper?Vaginismus refers to an involuntary spasm of the muscles surrounding the vagi-
nal oriﬁce that makes penetration during intercourse painful or impossible.
In addition to ascertaining the nature of a sexual problem, ask about its

onset, severity (persistent or sporadic), setting, and factors, if any, that makeit better or worse. What does the patient think is the cause of the prob-lem, what has she tried to do about it, and what does she hope for? Thesetting of sexual dysfunction is an important but complicated topic, in-volving the patient’s general health, medications and drugs, including useof alcohol, her partner’s and her own knowledge of sexual practices andtechniques, her attitudes, values, and fears, the relationship and commu-nication between her and her partner(s), and the setting in which sexualactivity takes place.
Local symptoms or ﬁndings on physical examination may raise the possibility
of sexually transmitted diseases (STDs). After establishing the usual attributes

of any symptoms, identify the sexual preference as to partners (male, female,THE HEALTH HISTORY
386 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGSee Table 11-5, Vaginitis, p. ___.
See Table 11-1, Lesions of the
Vulva p. ___.
Sexual dysfunctions are classiﬁed
by the phase of sexual response. A woman may lack desire, she mayfail to become aroused and to attain adequate vaginal lubrication,or, despite adequate arousal, shemay be unable to reach orgasmmuch or all of the time. Causes include lack of estrogen, medicalillness, and psychiatric conditions.
Superﬁcial pain suggests local 
inﬂammation, atrophic vaginitis, orinadequate lubrication; deeper painmay be due to pelvic disorders orpressure on a normal ovary. Thecause of vaginismus may be physicalor psychological.
More commonly, however, a sexual

problem is related to situational orpsychosocial factors.EXAMPLES OF ABNORMALITIES

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cor both). Inquire about sexual contacts and establish the number of sexual
partners in the prior month. Ask if the patient has concerns about HIV in-fection, desires HIV testing, or has current or past partners at risk. Also askabout oral and anal sex and, if indicated, about symptoms involving themouth, throat, anus, and rectum. Review the past history of venereal disease.“Have you ever had herpes? . . . any other problems such as gonorrhea? . . .syphilis? . . . pelvic infections?” Continue with the more general questionssuggested on pp. ___.HEALTH PROMOTION AND COUNSELING
CHAPTER 11 IFEMALE GENITALIA 387Important Topics for Health Promotion and Counseling
IThe Pap smear
IOptions for family planning
ISexually transmitted diseases and HIV
IChanges in menopause
The Pap Smear. Widespread testing by Papanicolaou (Pap) smear has con-

tributed to a signiﬁcant drop in the incidence of invasive cervical cancer. Care-ful technique to ensure sampling of endocervical cells at the squamocolumnarjunction and use of accredited laboratories to interpret smears improve ac-curacy of the test. Screening should begin at age 18 or with onset of sexualactivity. Recommendations about frequency of testing are undergoing re-vision. Annual testing until age 65 has been common, but does not appearto improve detection compared to longer intervals. A number of profes-sional organizations recommend annual Pap smears for 3 years and then, ifthese are normal, less frequent testing based on clinician discretion. TheU.S. Preventive Health Services Task Force recommends a 3-year intervalbeginning with onset of sexual activity. More frequent testing is warrantedfor women at increased risk—those with early onset of sexual activity, mul-tiple partners, infection with human papillomavirus or HIV, or limited ac-cess to regular medical care. The

is warrantedfor women at increased risk—those with early onset of sexual activity, mul-tiple partners, infection with human papillomavirus or HIV, or limited ac-cess to regular medical care. The upper age limit for the Pap smear testingis not well established. For women over 65, continued testing is indicated ifrecent tests have been abnormal or screening over the prior 10 years hasbeen incomplete. Women who have never had sexual intercourse or withcomplete hysterectomies (cervix removed) do not require screening.

Options for Family Planning. It is important to counsel women, particularly
adolescents, about the timing of ovulation in the menstrual cycle and how toplan or prevent pregnancy. Survey data indicate that more than half of U.S.pregnancies are unintended, affecting up to 80% of the one million teen preg-nancies each year.* Clinicians should be familiar with the numerous optionsfor family planning and their effectiveness. These include: natural methods(periodic abstinence, withdrawal, lactation); barrier methods (condom, di-aphragm, cervical cap); implantable methods (intrauterine device, subdermal

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cimplant); pharmacologic interventions (spermicide, birth control pill, subder-
mal implant of levonorgestrel, estrogen/progesterone injectables); andsurgery (tubal ligation). The clinician must take the time to understand thepatient or couple’s concerns and preferences and respect these preferenceswhenever possible. Continued use of a preferred method is superior to a moreeffective method that is abandoned. For teenagers, providing a conﬁdentialsetting eases discussion of topics that may seem private and difﬁcult to explore.
STDs and HIV. As with men, the clinician should assess risk factors for in-

fection with STDs and HIV by taking a careful sexual history and counsel-ing patients about spread of disease and ways to reduce high-risk practices(see Chap. 2, p. ___ and Chap. 12, p. ___). Women with STDs are at higherrisk for asymptomatic infection and loss of fertility. Learn to assess womenfor genital and pelvic infections through careful examination and collectionof appropriate cultures and to apply recommended guidelines for serologictesting for infection with HIV (see Chap. 12, p. ___).
Changes in Menopause. For middle-aged and older women, the clinician
should be familiar with the psychological and physiologic changes ofmenopause—mood shifts and changes in self-concept, vasomotor changes(“hot ﬂashes”), accelerated bone loss, increases in total and LDL choles-terol, and vulvo-vaginal atrophy leading to symptoms of vaginal drying,

dysuria, and sometimes dyspareunia. The clinician must be knowledgeableabout estrogen and progesterone replacement therapy and help the patientto weigh the beneﬁts and risks of treatment, taking into account the personaland family history of cardiovascular disease and osteoporosis (risk of devel-oping these conditions decreases with hormone treatment) and breast can-cer and endometrial cancer (treatment increases risk). Counseling patientsabout these decisions may extend over several visits.HEALTH PROMOTION AND COUNSELING
388 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING*U.S. Preventive Health Services Task Force: Guide to Clinical Preventive Services, 2nd ed. Baltimore,
Williams & Wilkins, ___ pp. ___–___.Preview: Recording the Pelvic Examination—
Female Genitalia
Suggests bacterial vaginosis.Note that initially you may use sentences to describe your ﬁndings; later

“No inguinal adenopathy. External genitalia without erythema or le-
sions; no lesions or masses. Vaginal mucosa pink. Cervix parous, pink, andwithout discharge. Uterus anterior, midline, smooth, and not enlarged.No adnexal tenderness. Pap smear obtained. Rectovaginal wall intact.”OR
”Bilateral spotty inguinal adenopathy. External genitalia without ery-

thema or lesions. Vaginal mucosa and cervix coated with thin white ho-mogeneous discharge with mild ﬁshy odor. After swabbing cervix, nodischarge visible in cervical os. Uterus midline; no adnexal masses. Rec-tal vault without masses. Stool brown and hemoccult negative.”EXAMPLES OF ABNORMALITIES

CHAPTER 11 IFEMALE GENITALIA 389
External Examination Internal Examination
IMons pubis
ILabia majora and minora
IUrethral meatus, clitoris
IVaginal introitus
IPerineumIVagina, vaginal walls
ICervix
IUterus, ovaries
IPelvic muscles
IRectovaginal wall
Many students feel anxious or uncomfortable when ﬁrst examining the gen-
italia of another person. At the same time, patients have their own concerns.Some women have had painful, embarrassing, or even demeaning experi-ences during previous pelvic examinations, while others may be facing theirﬁrst examination. Patients may fear what the clinician will ﬁnd and how theseﬁndings may affect their lives.
The woman’s reactions and behavior give important clues to her feelings and

to attitudes toward sexuality. If she adducts her thighs, pulls away, or expressesnegative feelings during the examination, you can gently confront her as youwould during the interview. “I notice you are having some trouble relaxing.Is it just being here, or are you troubled by the examination? . . . is anythingworrying you?” Behaviors that seem to present an obstacle to your examina-tion may become the key to understanding your patient’s concerns. Adversereactions may be a sign of prior abuse, and these issues should be explored.
A patient who has never had a pelvic examination is often unsure of what to

expect. Try to shape the experience so that she learns about her body and thesteps of the pelvic examination, and becomes more comfortable with them.Before she undresses, explain the relevant anatomy with the help of three-dimensional models. Show her the speculum and other equipment and en-courage her to handle them during the examination so that she can betterunderstand your explanations and procedures. It is especially important toavoid hurting the patient during her ﬁrst encounter.
Indications for a pelvic examination during adolescence include menstrual
abnormalities such as amenorrhea, excessive bleeding, or dysmenorrhea, un-explained abdominal pain, vaginal discharge, the prescription of contraceptives,bacteriologic and cytologic studies in a sexually active girl, and the patient’sown desire for assessment.
Regardless of age, rape merits special evaluation, usually requiring gyneco-

logic consultation and documentation.

390 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGBe sure always to wear gloves, both during the examination and when han-
dling equipment and specimens. Plan ahead, so that any needed equipmentor culture media are readily at hand.
Helping the patient to relax is essen-
tial for an adequate examination. Besensitive to her feelings. Adoptingthe tips above will help ensure thepatient’s comfort.
ChoosingEquipment. You should
have within reach a good light, a
vaginal speculum of appropriate size,water-soluble lubricant, and equip-ment for taking Papanicolaou smears,bacteriologic cultures, or other diag-nostic tests. Review the supplies andprocedures of your own facility before taking cultures and othersamples.
Specula are made of metal or plastic,

and come in two basic shapes, namedfor Pedersen and Graves. Both areavailable in small, medium, and largesizes. The medium Pedersen specu-lum is usually most comfortable forsexually active women. The narrow-bladed Pedersen speculum is best forthe patient with a relatively small in-troitus, such as a virgin or an elderlywoman. The Graves specula are bestsuited for parous women with vagi-nal prolapse.TIPS FOR THE SUCCESSFUL PELVIC EXAMINATION
The Patient The Examiner
IAvoids intercourse, douching,
or use of vaginal suppositoriesfor 24 to 48 hours before examination
IEmpties bladder before examination
ILies supine, with head andshoulders slightly elevated,arms at sides or folded acrosschest to reduce tightening ofabdominal musclesIExplains each step of the examination in advance
IDrapes patient from mid-abdomen to knees;depresses drape between knees to provideeye contact with patient
IAvoids unexpected or sudden movements

IWarms speculum with tap water
IMonitors comfort of the examination bywatching the patient’s face
IUses excellent but gentle technique, especiallywhen inserting the speculum (see p. ___ ).
Speculae, from left to right: small metal Pedersen, medium metal Pedersen,
medium metal Graves, large metal Graves, and large plastic Pedersen

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cBefore using a speculum, become thoroughly familiar with how to open and
close its blades, lock the blades in an open position, and release them again.Although the instructions in this chapter refer to a metal speculum, you caneasily adapt them to a plastic one by handling the speculum before using it.
Plastic specula typically make a loud click or may pinch when locked or re-
leased. Forewarning the patient helps to avoid unnecessary surprise.
Male examiners should be accompanied by female assistants. Female examin-
ers should also be assisted if the patient is physically or emotionally disturbed.
Positioning the Patient. Drape the patient appropriately and then as-

sist her into the lithotomy position. Help her to place ﬁrst one heel and thenthe other into the stirrups. She may be more comfortable with shoes on thanwith bare feet. Then ask her to slide all the way down the examining table untilher buttocks extend slightly beyond the edge. Her thighs should be ﬂexed,abducted, and externally rotated at the hips. A pillow should support her head.
EXTERNAL EXAMINATION
Assess the Sexual Maturity of an Adolescent Patient. You can
assess pubic hair during either the abdominal or the pelvic examination.Note its character and distribution, and rate it according to Tanner’s stagesdescribed on p. ___.
Inspect the Patient’s External Genitalia. Seat yourself comfort-
ably and inspect the mons pubis, labia, and perineum. Separate the labiaand inspect:
IThe labia minora
IThe clitoris
IThe urethral meatus

IThe vaginal opening, or introitus
Note any inﬂammation, ulceration,
discharge, swelling, or nodules. Ifthere are any lesions, palpate them.
If there is a history or an appearance
of labial swelling, check Bartholin’sglands. Insert your index ﬁnger intothe vagina near the posterior end ofthe introitus. Place your thumb out-side the posterior part of the labiumEXAMPLES OF ABNORMALITIES TECHNIQUES OF EXAMINATION
CHAPTER 11 IFEMALE GENITALIA 391Delayed puberty is often familial or
related to chronic illness. It mayalso be due to abnormalities in thehypothalamus, anterior pituitarygland, or ovaries.
Excoriations or itchy, small, red
maculopapules suggest pediculosispubis (lice or “crabs”). Look fornits or lice at the bases of thepubic hairs.
Enlarged clitoris in masculinizing
Urethral caruncle, prolapse of the
urethral mucosa (p. ___)

Syphilitic chancre, epidermoid
cyst. See Table 11-1, Lesions of theVulva (p. ___).
A Bartholin’s gland may become
acutely or chronically infected andthen produce a swelling. SeeTable 11-2, Bulges and Swelling ofVulva, Vagina, and Urethra (p. ___).
PALPATING BARTHOLIN’S GLAND

392 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGmajus. On each side in turn, palpate between your ﬁnger and thumb for
swelling or tenderness. Note any discharge exuding from the duct openingof the gland. If any is present, culture it.
INTERNAL EXAMINATION
Assess the Support of the Vaginal Walls. With the labia separated
by your middle and index ﬁngers, ask the patient to strain down. Note anybulging of the vaginal walls.
Insert the Speculum. Select a speculum of appropriate size and shape,

and lubricate it with warm water. (Other lubricants may interfere with cyto-logic studies and bacterial or viral cultures.) You can enlarge the vaginal in-troitus by lubricating one ﬁnger with water and applying downward pressureat its lower margin. (You may also wish to check the location of the cervix tohelp angle the speculum more accurately.) Enlarging the introitus greatlyeases insertion of the speculum and the patient’s comfort. With your otherhand (usually the left), introduce the closed speculum past your ﬁngers at asomewhat downward slope. Be careful not to pull on the pubic hair or pinchthe labia with the speculum. Separating the labia majora with your other handcan help to avoid this.Bulging from a cystocele or recto-
cele. See Table 11-2, Bulges andSwelling of Vulva, Vagina, and Ure-thra (p. ___).

An imperforate hymen occasionally
delays menarche. Be sure to checkfor this possibility when menarcheseems unduly late in relation to thedevelopment of a girl’s breasts andpubic hair.
THE SMALL INTROITUS
Many virginal vaginal oriﬁces admit a single examining ﬁnger. Modify your tech-
nique so as to use your index ﬁnger only. A small Pedersen speculum may make in-spection possible. When the vaginal oriﬁce is even smaller, a fairly good bimanualexamination can be performed by placing one ﬁnger in the rectum rather than inthe vagina.
Similar techniques may be indicated in elderly women in whom the introitus
has become atrophied and tight.

CHAPTER 11 IFEMALE GENITALIA 393Two methods help you to avoid placing pressure on the sensitive urethra.
(1) When inserting the speculum, hold it at an angle (shown below on theleft), and then (2) slide the speculum inward along the posterior wall ofthe vagina.
See retroversion of the uterus, 
p. ___.
ENTRY ANGLE ANGLE AT FULL INSERTION
Inspect the Cervix. Open the speculum carefully. Rotate and adjust the
speculum until it cups the cervix and brings it into full view. Position thelight until you can visualize the cervix well. When the uterus is retroverted,the cervix points more anteriorly than illustrated. If you have difﬁculty ﬁnd-ing the cervix, withdraw the speculum slightly and reposition it on a differ-ent slope. If discharge obscures your view, wipe it away gently with a largecotton swab.After the speculum has entered the vagina, remove your ﬁngers from the in-

troitus. You may wish to switch the speculum to the right hand to enhancemaneuverability of the speculum and subsequent collection of specimens.Rotate the speculum into a horizontal position, maintaining the pressureposteriorly, and insert it to its full length. Be careful not to open the bladesof the speculum prematurely.

394 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGInspect the cervix and its os. Note the color of the cervix, its position, the
characteristics of its surface, and any ulcerations, nodules, masses, bleeding,or discharge.
Maintain the open position of the speculum by tightening the thumb screw.
Obtain Specimens for Cervical Cytology (Papanicolaou Smears).
Obtain one specimen from the endocervix and another from the ecto-
cervix, or a combination specimen using the cervical brush (“broom”). Forbest results the patient should not be menstruating. She should avoid in-tercourse and use of douches or vaginal suppositories for 24 to 48 hoursbefore the examination.See Table 11-3, Variations in the
Cervix (p. ___), and Table 11-4,Abnormalities of the Cervix (p. ___).
A yellowish discharge on the

A yellowish discharge on the 
endocervical swab suggests a mucopurulent cervicitis, commonlycaused by Chlamydia trachomatis,
Neisseria gonorrhoeae, or herpes
simplex (p. ___).
OBTAINING THE PAP SMEAR: 
OPTIONS FOR SPECIMEN COLLECTION
Cervical Scrape and Endocervical Brush
Cervical Scrape. Place the longer end of
the scraper in the cervical os. Press, turn, and scrape in a full circle, makingsure to include the transformation zone
and the squamocolumnar junction. Smear
the specimen on a glass slide. Set theslide in a safe spot that is easy to reach.Note that doing the cervical scrape firstreduces obscuring cells with blood,which sometimes appears with use of theendocervical brush.

CHAPTER 11 IFEMALE GENITALIA 395Inspect the Vagina. Withdraw the speculum slowly while observing the
vagina. As the speculum clears the cervix, release the thumb screw and main-tain the open position of the speculum with your thumb. Close the specu-lum as it emerges from the introitus, avoiding both excessive stretching andpinching of the mucosa. During withdrawal inspect the vaginal mucosa, not-ing its color and any inﬂammation, discharge, ulcers, or masses.
Perform a Bimanual Examination. Lubricate the index and middle
ﬁngers of one of your gloved hands, and from a standing position insert them

into the vagina, again exerting pressure primarily posteriorly. Your thumbshould be abducted, your ring and little ﬁngers ﬂexed into your palm. Press-ing inward on the perineum with your ﬂexed ﬁngers causes little if any dis-comfort and allows you to position your palpating ﬁngers correctly. Noteany nodularity or tenderness in the vaginal wall, including the region of theurethra and the bladder anteriorly.
Palpate the cervix, noting its position, shape, consistency, regularity, mobil-
ity, and tenderness. Normally the cervix can be moved somewhat withoutpain. Feel the fornices around the cervix.
Palpate the uterus. Place your other hand on the abdomen about midway be-
tween the umbilicus and the symphysis pubis. While you elevate the cervixSee Table 11-5, Vaginitis (p. ___).
Cancer of the vagina
Stool in the rectum may simulate a

rectovaginal mass, but unlike atumor mass can usually be dentedby digital pressure. Rectovaginal ex-amination conﬁrms the distinction.
Pain on movement of the cervix,
together with adnexal tenderness,suggests pelvic inﬂammatory disease.Endocervical Brush. Now take the endocer-
vical brush and place it in the cervical os.Roll it between your thumb and index ﬁn-ger, clockwise and counterclockwise. Re-move the brush and pick up the slide youhave set aside. Smear the slide with thebrush, using a gentle painting motion toavoid destroying any cells. Place the slideinto an ether–alcohol solution at once, orspray it promptly with a special ﬁxative.
Note that for pregnant women, a 
cotton-tip applicator, moistened withsaline, is advised in place of the endo-cervical brush.
Cervical Broom

Many clinicians now use a plastic brushtipped with a broomlike fringe for collec-tion of a single specimen containing bothsquamous and columnar epithelial cells.Rotate the tip of the brush in the cervicalos, in a full clockwise direction, thenstroke each side of the brush on the glassslide. Promptly place the slide in solutionor spray with a ﬁxative as describedabove.

396 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGand uterus with your pelvic hand, press your abdominal hand in and down,
trying to grasp the uterus between your two hands. Note its size, shape, con-sistency, and mobility, and identify any tenderness or masses. See Table 11-6, Abnormalities 
and Positions of the Uterus (pp. ___–___).
Uterine enlargement suggests
pregnancy or benign or malignanttumors.
Nodules on the uterine surfaces
suggest myomas (see p. ___).
See retroversion and retroﬂexion
of the uterus (p. ___).
Three to ﬁve years after menopause,
the ovaries have usually atrophiedand are no longer palpable. If you can feel an ovary in a post-menopausal woman, consider an abnormality such as a cyst or a tumor.
Adnexal masses include ovarian

cysts, tumors, and abscesses, alsothe swollen fallopian tube(s) ofpelvic inﬂammatory disease, and atubal pregnancy. A uterine myomamay simulate an adnexal mass.See Table 11-7, Adnexal Masses(p. ___).Now slide the ﬁngers of your pelvic hand into the anterior fornix and pal-
pate the body of the uterus between your hands. In this position your pelvicﬁngers can feel the anterior surface of the uterus, and your abdominal handcan feel part of the posterior surface.
If you cannot feel the uterus with either of these maneuvers, it may be tipped
posteriorly (retrodisplaced). Slide your pelvic ﬁngers into the posteriorfornix and feel for the uterus butting against your ﬁngertips. An obese orpoorly relaxed abdominal wall may also prevent you from feeling the uteruseven when it is located anteriorly.

Palpate each ovary. Place your abdominal hand on the right lower quadrant,
your pelvic hand in the right lateral fornix. Press your abdominal hand inand down, trying to push the adnexal structures toward your pelvic hand.Try to identify the right ovary or any adjacent adnexal masses. By movingyour hands slightly, slide the adnexal structures between your ﬁngers, if pos-sible, and note their size, shape, consistency, mobility, and tenderness. Re-peat the procedure on the left side.
Normal ovaries are somewhat tender. They are usually palpable in slender,
relaxed women but are difﬁcult or impossible to feel in others who are obeseor poorly relaxed.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cImpaired strength may be due to
age, vaginal deliveries, or neuro-logic deficits. Weakness may beassociated with urinary stress incontinence.EXAMPLES OF ABNORMALITIES TECHNIQUES OF EXAMINATION
CHAPTER 11 IFEMALE GENITALIA 397Retroverted
uterusAssess the Strength of the Pelvic Muscles. Withdraw your two ﬁn-
gers slightly, just clear of the cervix, and spread them to touch the sides ofthe vaginal walls. Ask the patient to squeeze her muscles around them ashard and long as she can. A squeeze that compresses your ﬁngers snugly,moves them upward and inward, and lasts 3 seconds or more is full strength.
Do a Rectovaginal Examination. Withdraw your ﬁngers. Lubricate

your gloves again if necessary. (See note on using lubricant p. ___.) Thenslowly reintroduce your index ﬁnger into the vagina, your middle ﬁnger intothe rectum. Ask the patient to strain down as you do this so that her analsphincter will relax. Tell her that this examination may make her feel as if shehas to move her bowels but that she will not do so. Repeat the maneuversof the bimanual examination, giving special attention to the region behindthe cervix that may be accessible only to the rectal ﬁnger.
Rectovaginal palpation is 
especially valuable in assess-ing a retrodisplaced uterus,as illustrated.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cProceed to the rectal examination (see Chapter 13). If a hemoccult test is
planned, you should change gloves to avoid contaminating fecal materialwith any blood provoked by the Pap smear. After the examination, wipe offthe external genitalia and rectum, or offer the patient some tissue so she cando it herself.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
398 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGAn indirect inguinal hernia is the
most common hernia that occursin the female groin. A femoral hernia ranks next in frequency.
Urethritis may arise from infection
with Chlamydia trachomatis or
Neisseria gonorrhoeae.
MILKING THE URETHRAUSING LUBRICANTS
If you use a large tube of lubricant during a pelvic or rectal examination, you may

inadvertently contaminate it by touching the tube with your gloved ﬁngers aftertouching the patient. To avoid this problem, let the lubricant drop onto yourgloved ﬁngers without allowing contact between the tube and the gloves. If you oryour assistant should inadvertently contaminate the tube, discard it. Small dispos-able tubes for use with one patient circumvent this problem.
HERNIAS
Hernias of the groin occur in women as well as in men, but they are much
less common. The examination techniques (see p. ___) are basically the sameas for men. A woman too should stand up to be examined. To feel an indi-rect inguinal hernia, however, palpate in the labia majora and upward to justlateral to the pubic tubercles.
SPECIAL TECHNIQUES

If you suspect urethritis or inﬂam-mation of the paraurethral glands,insert your index ﬁnger into thevagina and milk the urethra gentlyfrom inside outward. Note any dis-charge from or about the urethralmeatus. If present, culture it.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 11-1 ILesions of the Vulva
CHAPTER 11 IFEMALE GENITALIA 399
TABLE 11-1 ILesions of the Vulva
Epidermoid Cyst
Small, ﬁrm, round cystic nodules in the labia
suggest epidermoid cysts. They are sometimesyellowish in color. Look for the dark punctummarking the blocked opening of the gland.Venereal Wart 
(Condyloma Acuminatum)
Warty lesions on the labia and within the vestibulesuggest condylomata acuminata. They are due toinfection with human papillomavirus.Genital Herpes
Shallow, small, painful ulcers on red bases suggest aherpes infection. Initial infection may be extensive, asillustrated here. Recurrent infections are usuallyconﬁned to a small local patch.
Cystic nodule
in skin
Warts
Shallow ulcer s
on red bases
Syphilitic Chancre
A ﬁrm, painless ulcer suggests the chancre ofprimary syphilis. Since most chancres in womendevelop internally, they often go undetected.Secondary Syphilis
(Condyloma Latum)

Slightly raised, ﬂat, round or oval papules coveredby a gray exudate suggest condylomata lata. Theseconstitute one manifestation of secondary syphilisand are contagious.Carcinoma of the Vulva
An ulcerated or raised red vulvar lesion in an elderlywoman may indicate vulvar carcinoma.
Flat, graypapules

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 11-2 IBulges and Swelling of the Vulva, Vagina, and Urethra
400 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 11-2 IBulges and Swelling of the Vulva, Vagina, and Urethra
Cystocele
A cystocele is a bulge of the anterior vaginal wall,
together with the bladder above it, that resultsfrom weakened supporting tissues. The upper twothirds of the vaginal wall are involved.Cystourethrocele
When the entire anterior vaginal wall, together withthe bladder and the urethra, is involved in the bulge,a cystourethrocele is present. A groove sometimesdeﬁnes the border between urethrocele and cystocele,but is not always present.Rectocele
A rectocele is a herniation of the rectum into theposterior wall of the vagina, resulting from aweakness or defect in the endopelvic fascia.
Bartholin’s Gland Infection
Causes of a Bartholin’s gland infection includegonococci, Chlamydia trachomatis, and other

organisms. Acutely, it appears as a tense, hot, verytender abscess. Look for pus coming out of theduct or erythema around the duct opening.Chronically, a nontender cyst is felt. It may belarge or small.Urethral Caruncle
A urethral caruncle is a small, red, benign tumorvisible at the posterior part of the urethral meatus. Itoccurs chieﬂy in postmenopausal women, and usuallycauses no symptoms. Occasionally, a carcinoma of theurethra is mistaken for a caruncle. To check for this,palpate the urethra through the vagina forthickening, nodularity, or tenderness, and feel foringuinal lymphadenopathy.Prolapse of the Urethral Mucosa
Prolapsed urethral mucosa forms a swollen red ringaround the urethral meatus. It usually occurs beforemenarche or after menopause. Identify the urethralmeatus at the center of the swelling to make thisdiagnosis.
Urethrocele
Cystocele
Bulge
Labial

Cystocele
Bulge
Labial
swelling
Caruncle
Prolapsedurethralmucosa

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 11-3 IVariations in the Cervix
CHAPTER 11 IFEMALE GENITALIA 401
TABLE 11-3 IVariations in the Cervix
The normal cervical os may be round, oval, or slitlike. The trauma of one or more vaginal deliveries may tear the cervix, produ cing lacerations. Illustrated here, from
left to right, are an oval os, a slitlike os, and lacerations described as unilateral transverse, bilateral transverse, and ste llate.
Two kinds of epithelia may cover the cervix: (1) shiny pink squamous epithelium, which resembles the vaginal epithelium, and (2) deep red, plushy columnar epithelium,
which is continuous with the endocervical lining. These two meet at the squamocolumnar junction. When this junction is at or in side the cervical os, only squamous ep-
ithelium is seen. A ring of columnar epithelium is often visible to a varying extent around the os—the result of a normal proce ss that accompanies fetal development,

menarche, and the ﬁrst pregnancy.*
With increasing estrogen stimulation during adolescence, all or part of this columnar epithelium is transformed into squamous e pithelium by a process termed metaplasia.
This change may block the secretions of columnar epithelium and cause retention cysts (sometimes called nabothian cysts). These appear as one or more translucent nod-
ules on the cervical surface and have no pathologic signiﬁcance.
*Terminology is in ﬂux. Other terms for the columnar epithelium that is visible on the ectocervix are ectropion, ectopy, and ev ersion.Shapes of the Cervical Os
Variations in the Cervical Surface
Retention cyst
Squamous epitheliumColumnar epithelium

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 11-4 IAbnormalities of the Cervix
402 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 11-4 IAbnormalities of the Cervix
Fetal Exposure to Diethylstilbestrol (DES)*
Daughters of women who took DES during pregnancy are at much higher risk
for a number of abnormalities, including (1) columnar epithelium that coversmost or all of the cervix, (2) vaginal adenosis, i.e., extension of this epitheliumto the vaginal wall, and (3) a circular collar or ridge of tissue, of varying shapes,between cervix and vagina. Much less common is an otherwise rare carcinomaof the upper vagina.
*In the United States, exposure to DES diminished in the late 1960s and stopped in 1971 when the drug was banned.Carcinoma of the Cervix

Carcinoma of the cervix begins in an area of metaplasia. In its earlieststages, it cannot be distinguished from a normal cervix. In a late stage, anextensive, irregular, cauliﬂowerlike growth may develop. Early frequentintercourse, multiple partners, smoking, and infection with humanpapillomavirus increase the risk for cervical cancer.Mucopurulent Cervicitis
Mucopurulent cervicitis produces purulent yellow drainage from the cervicalos, usually due to infection from Chlamydia trachomatis, Neisseria gonorrhoeae,
or herpes. These infections are sexually transmitted, and may occur withoutsymptoms or signs.Cervical Polyp

A cervical polyp usually arises from the endocervical canal, becoming visiblewhen it protrudes through the cervical os. It is bright red, soft, and ratherfragile. When only the tip is seen, it cannot be differentiated clinically from apolyp originating in the endometrium. Polyps are benign but may bleed.
Vaginal adenosis
Columnar epitheli u
Collar

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 11-5 IVaginitis
CHAPTER 11 IFEMALE GENITALIA 403
Trichomonas Vaginitis Candida Vaginitis Bacterial Vaginosis* Atrophic Vaginitis
Cause
Discharge
Other
Symptoms
Vulva
Vaginal
Mucosa
Laboratory
EvaluationTrichomonas vaginalis, a
protozoa. Often but not alwaysacquired sexually.
Yellowish green or gray, possibly
frothy; often profuse and pooledin the vaginal fornix; may bemalodorous
Pruritus (though not usually as
severe as with Candida
infection), pain on urination(from skin inﬂammation orpossibly urethritis), anddyspareunia
The vestibule and labia minora
may be reddened.
May be diffusively reddened,
with small red granular spots orpetechiae in the posterior fornix.In mild cases, the mucosa looksnormal.
Scan saline wet mount for
trichomonads.Candida albicans, a yeast (a normal
vaginal inhabitant). Many factorspredispose.
White and curdy; may be thin but
typically thick; not as profuse as inTrichomonas infection; not

malodorous
Pruritus, vaginal soreness, pain on
urination (from skin inﬂammation),and dyspareunia
The vulva and even the
surrounding skin are ofteninﬂamed and sometimes swollen to a variable extent.
Often reddened, with white, often
tenacious patches of discharge. Themucosa may bleed when thesepatches are scraped off. In mildcases, the mucosa looks normal.
Scan potassium hydroxide (KOH)
preparation for branching hyphaeof Candida.Unknown; probably
anaerobic bacteria. May betransmitted sexually
Gray or white, thin,
homogeneous, malodorous;coats the vaginal walls.Usually not profuse, may beminimal
Unpleasant ﬁshy or musty
genital odor
Usually normal

clue cells (epithelial cellswith stippled borders); snifffor ﬁshy odor after applyingKOH (“whiff test”).Decreased estrogen
production after menopause
Variable in color,
consistency, and amount;may be blood-tinged; rarelyprofuse
Pruritus, vaginal soreness,
or burning and dyspareunia
Atrophic
Atrophic, dry, pale; may be
red, petechial, orecchymotic; bleeds easily;may show erosions or ﬁlmyadhesions
* Previously termed Gardnerella vaginitis.TABLE 11-5 IVaginitis
The vaginal discharge that often accompanies vaginitis must be distinguished

from a physiologic discharge. The latter is clear or white and may contain whiteclumps of epithelial cells; it is not malodorous. It is also important to dis-tinguish vaginal from cervical discharges. Use a large cotton swab to wipe offthe cervix. If no cervical discharge is present in the os, suspect a vaginal origin
and consider the causes below. Remember that diagnosis of cervicitis or vaginitis hinges on careful collection and analysis of the appropriate laboratoryspecimens.

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 11-6 IAbnormalities and Positions of the Uterus
404 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 11-6 IAbnormalities and Positions of the Uterus
Myomas of the Uterus (Fibroids)
Myomas are very common benign uterine tumors. They may be single or
multiple and vary greatly in size, occasionally reaching massive proportions.They feel like ﬁrm, irregular nodules in continuity with the uterine surface.Occasionally, a myoma projecting laterally can be confused with an ovarianmass; a nodule projecting posteriorly can be mistaken for a retroﬂexeduterus. Submucous myomas project toward the endometrial cavity and arenot themselves palpable, although they may be suspected because of anenlarged uterus.Prolapse of the Uterus

Prolapse of the uterus results from weakness of the supporting structures of thepelvic ﬂoor, and is often associated with a cystocele and rectocele. In progressivestages, the uterus becomes retroverted and descends down the vaginal canal tothe outside. In ﬁrst-degree prolapse, the cervix is still well within the vagina. Insecond-degree prolapse, it is at the introitus. In third-degree prolapse(procidentia), the cervix and vagina are outside the introitus.
Myomas
Normal position

CHAPTER 11 IFEMALE GENITALIA 405Retroversion of the Uterus
Retroversion of the uterus refers to a tilting backward of the entire uterus, including both body and
cervix. It is a common variant occurring in about 1 out of 5 women. Early clues on pelvic examinationare a cervix that faces forward and a uterine body that cannot be felt by the abdominal hand. Inmoderate retroversion, shown on the left, the body may not be palpable with either hand. In markedretroversion, shown on the right, the body can be felt posteriorly, either through the posterior fornixor through the rectum. A retroverted uterus is usually both mobile and asymptomatic. Occasionally,such a uterus is ﬁxed and immobile, held in place by conditions such as endometriosis or pelvicinﬂammatory disease.Retroﬂexion of the Uterus

Retroﬂexion of the uterus refers to a backwardangulation of the body of the uterus in relation tothe cervix. The cervix maintains its usual position.The body of the uterus is often palpable through theposterior fornix or through the rectum.
Both retroversion and retroﬂexion are usually
normal variants.
May be palpable 
through rectumAngled back
Palpable through rectumNormal angle
maintained
Cervix faces
forward
Body of the uterusmay not be palpable

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 11-7 IAdnexal Masses
406 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 11-7 IAdnexal Masses
Adnexal masses most commonly result from disorders of the fallopian tubes or ovaries. Three examples—often hard
to differentiate—are described. In addition, inﬂammatory disease of the bowel (such as diverticulitis), carcinoma of thecolon, and a pedunculated myoma of the uterus may simulate an adnexal mass.
Ovarian Cysts and Tumors
Ovarian cysts and tumors may be detected as adnexal masses on one or bothsides. Later, they may extend out of the pelvis. Cysts tend to be smooth andcompressible, tumors more solid and often nodular. Uncomplicated cysts andtumors are not usually tender.
Small (≤6 cm in diameter), mobile, cystic masses in a young woman are usually
benign and often disappear after the next menstrual period.
Ruptured Tubal Pregnancy

A ruptured tubal pregnancy spills blood into the peritoneal cavity, causing severe abdominal pain and tenderness. Guarding and rebound tenderness aresometimes associated. A unilateral adnexal mass may be palpable, but tendernessoften prevents its detection. Faintness, syncope, nausea, vomiting, tachycardia,and shock may be present, reﬂecting the hemorrhage. There may be a priorhistory of amenorrhea or other symptoms of a pregnancy.
Pelvic Inﬂammatory Disease
Pelvic inﬂammatory disease (PID) is most often a result of sexually transmittedinfection of the fallopian tubes (salpingitis) or of the tubes and ovaries (salpingo-oophoritis). It is caused by Neisseria gonorrhoeae, Chlamydia trachomatis, and
other organisms. Acute disease is associated with very tender, bilateral adnexal

masses, although pain and muscle spasm usually make it impossible to delineatethem. Movement of the cervix produces pain. If not treated, a tuboovarian
abscess or infertility may ensue.
Infection of the fallopian tubes and ovaries may also follow delivery of a baby or
gynecologic surgery.

The Pregnant WomanCHAPTER
The Pregnant Woman 1212
CHAPTER 12 ITHE PREGNANT WOMAN 409This chapter focuses on the evaluation of the healthy adult woman who is

pregnant. The techniques of history-taking and examination for pregnantand nonpregnant women are similar. However, it is important to recognizethe changes in anatomy and physiology that are related to pregnancy ratherthan an abnormality. This chapter emphasizes the common changes inanatomy and physiology that evolve throughout pregnancy, special concernsfor the health history, and recommendations for nutrition and exercise.There is also information on screening pregnant women for domestic vio-lence. Next are the techniques of examination for initial and follow-up care.Ideally, the pregnant woman begins her prenatal visits 6 to 8 weeks afterconception. For those women seeking initial care in the second or thirdtrimesters, the modiﬁed Leopold’s maneuvers are reviewed to help you as-sess the woman presenting late in pregnancy.Joyce E. (Beebe) Thompson

As you begin thinking about the pregnant woman, you may wish to re-
view the sections on anatomy and physiology in Chapter 8, The Breastsand Ax illae, and in Chapter 11, Female Genitalia. During pregnancy, there
are changes in the thyroid gland, breasts, abdomen, and pelvis. You may alsodetect minor skin changes such as the mask of pregnancy and abdominalstriae.
During pregnancy, the thyroid gland and the breasts undergo moderate
enlargement due to hormonal stimulation and increased vascularity andhyperplasia of glandular tissue. There may be tenderness and tingling inthe breasts that makes them more sensitive during examination. By thethird month of gestation, the breasts become more nodular, requiringcareful palpation to avoid discomfort as you examine for any breast masses.The nipples become larger and more erectile. From mid to late pregnancy,colostrum, a thick, yellowish secretion rich in nutrients, may be expressed

from the nipples. The areolae darken, and Montgomery’s glands are moreprominent. The venous pattern over the breasts becomes increasingly visi-ble as pregnancy progresses.

The abdomen’s most notable change is distention, primarily from the in-
creasing size of the growing uterus and fetus. Early distention from ﬂuid re-tention and relaxation of abdominal muscles may be noted before the uterusbecomes an abdominal organ (12–14 weeks of gestation). The expectedgrowth patterns of the normal uterus and fetus are illustrated on the right,and the standing contours of the primigravid abdomen in each trimester ofpregnancy are illustrated below.ANATOMY AND PHYSIOLOGY
410 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
36 wks
32 wks
28 wks
24 wks
20-22 wks
16 wks
12-14 wks
First Trimester
Second TrimesterThird TrimesterEXPECTED HEIGHT OF THE UTERINE
FUNDUS BY MONTH OF PREGNANCY
CHANGING CONTOURS OF THE PRIMIGRAVID ABDOMEN

As the skin stretches to accommodate the growth of the fetus, purplish striae
may appear. The linea nigra, a brownish black pigmented line following the
midline of the abdomen, may become evident. Muscle tone is diminished aspregnancy advances, and diastasis recti, or separation of the rectus muscles
at the midline of the abdomen, may be noticeable in the later trimesters ofpregnancy. If diastasis is severe, as it may be in multiparous women, only alayer of skin, fascia, and peritoneum covers most of the anterior uterine wall.The fetus is felt easily through this muscular gap.
Many anatomical changes take place in the pelvis through the course of preg-

nancy. The early diagnosis of pregnancy is based in part on changes in thevagina and the uterus. With the increased vascularity throughout the pelvicregion, the vagina takes on a bluish or violet color. The vaginal walls appearthicker and deeply rugated because of increased thickness of the mucosa,loosening of the connective tissue, and hypertrophy of smooth muscle cells.Vaginal secretions are thick, white, and more profuse. Vaginal pH becomesmore acidic due to the action of Lactobacillus acidophilus on the increased
levels of glycogen stored in the vaginal epithelium. This change in pH helpsprotect the woman against some vaginal infections, but increased glycogenmay contribute to higher rates of vaginal candidiasis (see p. 405).
The uterus is the organ most af-

fected. Early in pregnancy, it losesthe ﬁrmness and resistance of thenonpregnant organ. The palpablesoftening at the isthmus, calledHegar’s sign, is an early diagnostic
sign of pregnancy, and is illustratedon the right.
Over the course of 9 months, the uterus increases in both weight and size. Its
weight grows from 2 ounces to 2 pounds, chieﬂy due to larger muscle cells,more extensive ﬁbrous and elastic tissue, and the considerable increase in thesize and number of blood vessels and lymphatics. The size of the uterusincreases 500- to 1000-fold, with a capacity of approximately 10 liters bythe end of the pregnancy.
As the uterus grows, it changes shape and position. The nongravid uterus

may be anteverted, retroverted, or retroflexed. Up to 12 weeks of gesta-tion, the gravid uterus is still a pelvic organ. Regardless of its initial posi-tioning, the enlarging uterus becomes anteverted and quickly fills spaceusually occupied by the bladder, triggering frequent voiding. By 12 weeks’gestation, the uterus straightens and rises out of the pelvis and can be feltwhen palpating the abdomen.ANATOMY AND PHYSIOLOGY
CHAPTER 12 ITHE PREGNANT WOMAN 411
Soft
HEGAR’S SIGN

412 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGThe enlarging uterus pushes the intestinal contents laterally and superiorly and
stretches its supporting ligaments, sometimes causing pain in the lower quad-rants. It adapts to fetal growth and positions and tends to rotate to the rightto accommodate to the rectosigmoid structures in the left side of the pelvis.
The cervix also looks and feels quite different. Pronounced softening and
cyanosis appear very early after conception and continue throughout pregnancy(Chadwick’s sign ). The cervical canal is ﬁlled with a tenacious mucous plug that
protects the developing fetus from infection. Red, velvety mucosa around theos is common on the cervix during pregnancy and is considered normal.
Common Concerns Time in Pregnancy Explanation and Effects on Woman’s Body
Throughout
1st trimester1st trimester1st trimester
2nd trimester:
14–20 weeks
1st/3rd trimesters
3rd trimester

ThroughoutContinued high levels of estrogen, progesterone, and human chorionic
gonadotropin following fertilization of the ovum build up the endometrium tosupport the developing pregnancy, averting menses and shedding of theendometrial lining.
Possible causes include hormonal changes of pregnancy leading to slowed
peristalsis throughout the GI tract, changes in taste and smell, the growinguterus, or emotional factors. Women may have a modest (2–5 lb) weight lossin the ﬁrst trimester.
The hormones of pregnancy stimulate the growth of breast tissue. As the breasts
enlarge throughout pregnancy, women may experience upper backache fromtheir increased weight. There is also increased blood ﬂow throughout thebreasts, increasing pressure on the tissue.
If a woman experiences nausea and vomiting, she may not be eating normally in

early pregnancy (see nausea above).
Rapid uterine growth early in second trimester causes tension and stretching of
round ligaments, causing spasm with sudden movement or change of position.
There is increased blood volume and increased ﬁltration rate in the kidneys with
increased urine production. Due to less space for the bladder from pressurefrom the growing uterus (ﬁrst trimester) or from the descent of the fetal head(third trimester), the woman needs to empty her bladder more frequently.
Rapid change in energy requirements; hormonal changes (progesterone has a
sedative effect); in third trimester, weight gain, changes in mechanics ofmovement, and sleep disturbances contribute.
There is increased venous pressure in the legs, obstruction of lymphatic ﬂow, and
reduced plasma colloid osmotic pressure.
Relaxation of the lower esophageal sphincter allows stomach contents to back up

into the lower esophagus. The decreased GI motility caused by pregnancyhormones slows peristalsis and causes constipation. Constipation may cause oraggravate existing hemorrhoids.
Hormonally induced relaxation of joints and ligaments and the minor lordosis
required to balance the growing uterus sometimes result in a lower backache.Pathologic causes must be ruled out.
Increased secretions from the cervix and the vaginal epithelium, due to the
hormones and vasocongestion of pregnancy, result in an asymptomatic milkywhite vaginal discharge.Common Concerns During Pregnancy and Their Explanations
No menses
(amenorrhea )
Nausea with or
without vomiting
Breast tenderness,
tingling
Weight loss
Groin/lower
abdominal pain
Urinary frequency
(nonpathologic)
FatigueEdema
Heartburn,
Backache
Leukorrhea

The ovaries and fallopian tubes undergo changes as well, but few are no-
ticeable during physical examination. Early in pregnancy, the corpus lu-
teum, the ovarian follicle that has discharged its ovum, may be sufﬁciently
prominent to be felt on the affected ovary as a small nodule, but it disappearsby midpregnancy. It is important to examine the fallopian tubes to rule outa tubal pregnancy (see p. 408).THE HEALTH HISTORY
CHAPTER 12 ITHE PREGNANT WOMAN 413Common or Concerning Symptoms
ISymptoms of pregnancy
IToxic exposures, use of illicit drugs, domestic violence
IPrior complications of pregnancy
IChronic illnesses in patient or family members
An accurate history is essential for assessing the pregnant woman’s health. It
also shapes the order and content of the physical examination, which is di-rected primarily to conﬁrming the woman’s suspicion of pregnancy. Thewoman will usually have many questions for you about her pregnancy andseek understanding of her symptoms.

During the initial visit, focus the history on the woman’s current state of
health and on risk factors for any conditions that could adversely affect her
or the developing fetus. Ask about symptoms of pregnancy such as breasttenderness, nausea or vomiting, urinary frequency, change in bowel habits,and fatigue (see table on p. 412). Review her attitude toward the pregnancy,and if she plans to continue to term. Look into her eating patterns and qual-ity of nutrition. Does she smoke or drink alcohol? What about her incomeand her social support network?
Although best identiﬁed and addressed before conception, are there any
sources of high-level stress? If she works, has there been any exposure to ter-atogenic drugs or toxic substances? What about any use of illicit drugs? Isthere any history of domestic violence that may escalate during pregnancy?
What about prior pregnancies, since past obstetrical problems tend to recur?

Has she had any major complications of pregnancy or problems with laboror delivery? Has she had a premature or growth-retarded infant? Ask alsoabout her past medical history, especially any chronic diseases like hyper-
tension, diabetes, or cardiac conditions. You should also review her family
history for these conditions.
In addition, the clinician should get information needed for calculating the
expected weeks of gestation by dates. This is currently counted in weeks from
either (1) the ﬁrst day of the last menstrual period ( LMP), known as men-

strual age, or (2) the date of conception, if this is known ( conception age ).
Menstrual age is used most frequently to express the weeks of gestation cal-culated by dates. The ﬁrst day of the LMP is also used to calculate the expected
date of conﬁnement (EDC ) or projected time of term labor and birth for
women with regular 28- to 30-day cycles. The EDC can be determined byadding 7 days to the ﬁrst day of the LMP, subtracting 3 months, and addingone year ( Naegele’s rule ). This information is often one of the ﬁrst questions
the pregnant woman asks when seeking conﬁrmation of pregnancy.
The weeks of gestation at the time of examination tell you the expected size of

the uterus if the LMP was normal, the dates were remembered accurately, andconception actually occurred. You should estimate this size before examiningthe woman. You can then compare the expected size by dates with what youactually palpate during the bimanual examination, or abdominally, if pregnancyis beyond 14 weeks of gestation. Uterine size is measured by the palpable sizeof the uterus if still within the pelvic cavity, or by the height of the fundus ifabove the symphysis pubis. If there is a discrepancy, you need to look for thecauses. Accurately dating the pregnancy is best done early, and contributes togood decision-making later in pregnancy if the fetus is not growing well, ifpreterm labor is suspected, or if the pregnancy goes beyond 42 weeks of ges-tation. If the woman does not remember her LMP or has irregular menstrualcycles, dating the pregnancy is done by palpation and subsequent monitoringof the growth curve (see p. 410) along with the time of ﬁrst fetal move-ments. In

remember her LMP or has irregular menstrualcycles, dating the pregnancy is done by palpation and subsequent monitoringof the growth curve (see p. 410) along with the time of ﬁrst fetal move-ments. In some cases, ultrasound is an appropriate adjunct for dating an earlypregnancy.

As you begin preparing the patient for the physical examination, ask the
woman if she has ever had a complete pelvic examination. If not, take the timeto explain what is involved and seek her cooperation for each of its compo-nents. Explaining what you do and what you ﬁnd is important if you are tostrengthen rapport and help her to understand the changes in her body andits response to pregnancy, and how she can best maintain her health. Be sureto ask in a sensitive and conﬁdential manner if she has ever experienced a sex-ual assault, since this may cause her to resist any examination of the pelvis.HEALTH PROMOTION AND COUNSELING
414 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGImportant Topics for Health Promotion and Counseling
INutrition
IWeight gain
IExercise
IScreening for domestic violence
Counseling about nutrition and exercise is important to the health of the

IExercise
pregnant woman and baby. Evaluate the nutritional status of the woman atthe ﬁrst prenatal visit, including a diet history, measurement of height and

CHAPTER 12 ITHE PREGNANT WOMAN 415weight, and screening for anemia by checking the hematocrit. Be sure to ex-
plore the woman’s habits and attitudes about eating and weight gain, as wellas her use of needed vitamin and mineral supplements. Develop a nutritionplan that is appropriate to the woman’s cultural preferences. Be sure there isa balanced increase in calories and protein, since protein will be used for en-ergy, rather than growth, unless sufﬁcient calories are consumed. Womenwith low incomes should be helped to obtain additional food. At each visit,monitor weight gain and review nutritional goals for women at risk.
Ideal weight gain during pregnancy follows a pattern: very little gain the ﬁrst
trimester, rapid increase in the second, and a mild slowing of the increase inthe third trimester. Women should be weighed at each visit, with the resultsplotted on a graph for the woman and health care provider to review anddiscuss.

Exercise is an important part of the lifestyle of many women. Guidelines
are contradictory, but the recommendations of the American College ofObstetrics and Gynecology (1994) suggest that in the absence of eitherobstetric or medical complications, most women can perform moderateexercise to maintain cardiorespiratory and muscular ﬁtness thr oughout preg-

nancy and the postpartum period. Women exercising regularly prior to preg-nancy can continue mild to moderate exercise, preferably for short periodsthree times a week. Women initiating exercise during pregnancy should bemore cautious, and consider programs developed speciﬁcally for pregnantwomen. After the ﬁrst trimester, women should avoid exercise in the supineposition, which can compress the inferior vena cava and decrease blood ﬂowto the placenta. The pregnant woman should stop exercise when she feelsfatigued or uncomfortable and avoid overheating and dehydration. Since thecenter of gravity shifts in the third trimester, advise her that exercises thatcould cause loss of balance are unwise.
Pregnancy may be a time when women are more likely to be abused by an
intimate partner or when patterns of abuse may intensify, increasing the riskPrepregnancyRecommended Total Gain
Weight-for-Height Category lb kg
Low (BMI <19.8) 28–40 12.5–18

Normal (BMI 19.8 to 26.0) 25–35 11.5–16High (BMI 26.0 to 29.0) 15–25 7.0–11.5Obese (BMI >29.0) ≥15 ≥7.0
Figures are for single pregnancies. The range for women carrying twins is 35 to 45 lb
(16 to 20 kg). Young adolescents (<2 years after menarche) should strive for gains atthe upper end of the range. Short women (<62 in. or <157 cm) should strive for gainsat the lower end of the range.
Institute of Medicine. Nutrition During Pregnancy. Part I, Weight Gain. Committee on Nutritional Status During
Pregnancy and Lactation, Food and Nutrition Board, National Academy Press, Washington, DC, 1990.Recommended Total Weight Gain Ranges for Pregnant Women

Preview: Recording the Physical Examination — 
The Pregnant Woman
“Abdomen: No surgical scars. Active bowel sounds. Soft, nontender; no
palpable hepatosplenomegaly or masses. Fundus palpable 2 ﬁngerbreadthsbelow the umbilicus; shape is ovoid and smooth. Fetal heart rate 144. Noinguinal adenopathy. External genitalia: midline episiotomy scar present.
No lesions, discharge, or signs of infection. Bimanual examination: cervixmidline, soft; external os admits ﬁngertip, internal os closed. No painelicited on movement of cervix; no adnexal masses. Fundus enlarged to20 weeks’ size, midline, smooth; vaginal tone reduced.”
OR“Abdomen: Low transverse surgical scar. Active bowel sounds. Soft,

nontender; no palpable hepatosplenomegaly or masses. Fundus: barelypalpable above symphysis pubis. Fetal heart rate not heard. No inguinaladenopathy. Bimanual examination: cervix midline, soft, internal osclosed. No pain on movement of cervix. Right ovary palpable, left non-palpable; no other adnexal masses. Fundus anteverted, enlarged to 14–16 weeks’ size; moderate vaginal tone.”of miscarriage and low-birthweight babies, as well as late prenatal care. Abuse
in pregnancy ranges from 8% to 22%, and may result in femicide. Becauseviolence survivors often disclose their experiences to their health care provider

before conﬁding in their family, clergy, or friends, many experts consider uni-versal screening an ethical imperative. No woman deserves to be hurt. Safetyand legal concerns also surround domestic violence, but the woman needs tobe supported and offered multiple opportunities to talk about any form ofabuse or violence in the safety and privacy of a prenatal visit. When to ask,how to bring up the subject, and how to respond when the woman revealsthat she is or has been abused are important questions to consider beforescreening for violence and abuse. Direct questioning in a nonjudgmentalmanner in a private setting is recommended at each prenatal visit. Validationof positive responses and marking the area of any injury on a body map is sug-gested. Above all, in situations of admitted abuse, ask the woman how youmight help her. Offer information on safe shelters, counseling centers, hot-line telephone numbers to call*, and other sources of help when she is readyto take advantage of

ask the woman how youmight help her. Offer information on safe shelters, counseling centers, hot-line telephone numbers to call*, and other sources of help when she is readyto take advantage of these. Clues to physical violence may also arise frombehavior during the interview or from frequent changes in appointments atthe last minute to avoid detection of bruises or other signs of injury.HEALTH PROMOTION AND COUNSELING

416 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGDescribes examination of healthy
pregnant woman at 20 weeks’ ges-
tation, third pregnancy
Describes examination of healthy
pregnant woman reporting datesof 20-week gestation but with examination consistent with 16-week gestation
*National Domestic Violence Hotline: 1-800-799-SAFE (7233)
National Domestic Violence Resource Center: 1-800-537-2238

This position is especially important when examining a woman with an ad-
vanced pregnancy. Prolonged periods of lying on the back should beavoided because the uterus then lies directly on the woman’s vertebral col-umn and may compress the descending aorta and inferior vena cava, in-terfering with return of venous blood from the lower extremities and thepelvic vessels. Therefore, abdominal palpation should be efficient in timeand results.
Encourage the woman to sit again brieﬂy before proceeding to the pelvic
evaluation. This pause also provides time for the woman to empty her blad-der again. Make sure, however, that she is acclimated to sitting before allow-ing her to stand up. The pelvic examination should likewise be relativelyTECHNIQUES OF EXAMINATION
CHAPTER 12 ITHE PREGNANT WOMAN 417Supine hypotension is a severe
form of this diminished circulationand may lead the woman to feeldizzy and faint, especially whenlying down.

As with all patients, as you begin your examination of the pregnant woman
show consideration for her comfort and sense of privacy, as well as for herindividual needs and sensitivities. Have the needed equipment readily athand. If you have not met the woman before, taking the history before ask-ing her to gown shows respect for her right to be treated with dignity. Askthe woman to put on the gown with the opening in front to ease the ex-amination of both the breasts and the pregnant abdomen. Draping for theabdominal and pelvic examinations is similar to that discussed in earlierchapters.
Positioning. Positioning is important when examining the abdomen of

a pregnant woman given the added time and attention needed to palpate theuterus and listen to the fetal heart. The semi-sitting position with the kneesbent, as shown below, affords the greatest comfort, as well as protectionfrom the negative effects of the weight of the gravid uterus on abdominalorgans and vessels.

quick. All other examination procedures should be done in the sitting or
left-side–lying position.
Equipment. The examiner’s hands are the primary “equipment” for ex-
amination of the pregnant woman; they should be warm and ﬁrm yet gen-tle in palpation. Whenever possible the ﬁngers should be together and ﬂatagainst the abdominal or pelvic tissue to minimize discomfort. Likewise, alltouching and palpation should be done with smooth continuous contactagainst the skin rather than kneading or abrupt motion. The more sensitivepalmar surfaces of the ends of the ﬁngers yield the greatest amount of in-formation. Avoid tender areas on the woman’s body until the end of theexamination.
The gynecologic speculum is used for inspecting the cervix and the vagina

and for taking specimens for cytologic or bacteriologic study. Because thevaginal walls are relaxed during pregnancy and may fall medially, obscuringyour view, a speculum of larger than expected size may be needed. The re-laxation of perineal and vulvar structures allows you to use it with minimaldiscomfort for the woman. Because of the increased vascularity of the vagi-nal and cervical structures, insert and open the speculum gently. You willthus avoid tissue trauma and bleeding, which interfere with the interpreta-tion of Pap smears.
The cervical brush is not recommended for Pap smears in pregnant women
because it often causes bleeding. The Ayre wooden spatula and/or cotton-tipped applicator is appropriate.
General Inspection

Inspect the overall health, nutritional status, neuromuscular coordination,and emotional state as the woman walks into the exam room and climbs onthe examination table. Discussion of the woman’s priorities for the exami-nation, her responses to pregnancy, and her general health provide useful in-formation and help to put the woman at ease.
Vital Signs and Weight
Take the blood pressure. A baseline reading helps to determine the woman’s
usual range. In midpregnancy, blood pressure is normally lower than in thenonpregnant state.
Measure the weight. First-trimester weight loss related to nausea and vomit-
ing is common but should not exceed 5 pounds.
418 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGReview Chapter 11 for instruments

and techniques used to take cervi-cal smears.
High blood pressure prior to 
24 weeks indicates chronic hyper-tension. After 24 weeks, furtherevaluation is required to diagnoseand treat pregnancy-induced hyper-
tension (PIH).
Weight loss of more than 5 pounds
during the ﬁrst trimester may bedue to excessive vomiting or hyperemesis.

Facial edema after 24 weeks of ges-
tation suggests PIH.
Localized patches of hair loss should
not be attributed to pregnancy.
Anemia of pregnancy may cause
pallor.
Nosebleeds are more common
during pregnancy. Signs of cocaineuse may be present.
Gingival enlargement with bleed-
ing (p. 203) is common duringpregnancy.
Marked or asymmetric enlargement
is not due to pregnancy.
If signs of respiratory distress are
noted, examine the lungs thor-oughly. Expect respiratory alkalosisin later trimesters.
These murmurs may also accom-
pany anemia.
An inverted nipple needs attention
if breast-feeding is planned.Head and Neck
Stand facing the seated woman and observe the head and neck, including
the following features:
IFace. The mask of pregnancy, chloasma, is normal. It consists of irregular
brownish patches around the eyes or across the bridge of the nose.
IHair, including texture, moisture, and distribution. Dryness, oiliness, and
sometimes minor generalized hair loss may be noted.

IEyes. Note the conjunctival color.
INose, including the mucous membranes and the septum. Nasal conges-
tion is common during pregnancy.
IMouth, especially the gums and teeth.
IThyroid gland. Inspect and palpate the gland. Symmetric enlargement is
expected.
Thorax and Lungs
Inspect the thorax for the pattern of breathing. Although women late in
pregnancy sometimes report difﬁculty in breathing, there are usually no ab-normal physical signs.
Heart
Palpate the apical impulse. In advanced pregnancy, it may be slightly
higher than normal because of dextrorotation of the heart due to the higherdiaphragm.
Auscultate the heart. Soft, blowing murmurs are common during preg-
nancy, reﬂecting increased blood ﬂow in normal vessels.
Breasts

Breasts
Inspect the breasts and nipples for symmetry and color. The venous pattern
may be marked, the nipples and areolae are dark, and Montgomery’s glandsare prominent.
CHAPTER 12 ITHE PREGNANT WOMAN 419

Palpate for masses. During pregnancy, breasts are tender and nodular.
Compress each nipple between your index ﬁnger and thumb. This maneuver
may express colostrum from the nipples.
Abdomen
Position the pregnant woman in a semi-sitting position with her knees ﬂexed(see p. 417).
Inspect any scars or striae, the shape and contour of the abdomen, and the
fundal height. Purplish striae and linea nigra are normal in pregnancy. Theshape and contour may indicate pregnancy size (see ﬁgures on p. 410).
Palpate the abdomen for:
IOrgans or masses. The mass of pregnancy is expected.
IFetal movements. These can usually be felt by the examiner after 24 weeks
(and by the mother at 18–20 weeks).
IUterine contractility. The uterus contracts irregularly after 12 weeks and

often in response to palpation during the third trimester. The abdomenthen feels tense or ﬁrm to the examiner, and it is difﬁcult to feel fetal parts.If the hand is left resting on the fundal portion of the uterus, the ﬁngerswill sense the relaxation of the uterine muscle.
420 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGA pathologic mass may be difﬁcult
to isolate.
A bloody or purulent discharge
should not be attributed to pregnancy.
Scars may conﬁrm the type of prior
surgery, especially cesarean section.
If movements cannot be felt after
24 weeks, consider error in calcu-lating gestation, fetal death ormorbidity, or false pregnancy.
Prior to 37 weeks, regular uterine

contractions with or without painor bleeding are abnormal, suggest-ing preterm labor.
© B. Proud

Measure the fundal height with a tape measure if the woman is more than
20 weeks’ pregnant. Holding the tape as illustrated and following the mid-line of the abdomen, measure from the top of the symphysis pubis to thetop of the uterine fundus. After 20 weeks, measurement in centimetersshould roughly equal the weeks of gestation. For estimating fetal height be-tween 12 and 20 weeks, see p. 410.
Auscultate the fetal heart, noting its rate (FHR), location, and rhythm. Use
either:
IA doptone, with which the FHR is audible after 12 weeks, or
IA fetoscope, with which it is audible after 18 weeks.TECHNIQUES OF EXAMINATION
CHAPTER 12 ITHE PREGNANT WOMAN 421If fundal height is more than 2 cm
higher than expected, considermultiple gestation, a big baby,extra amniotic fluid, or uterinemyomata. If it is lower than expected by more than 2 cm,consider missed abortion, trans-verse lie, growth retardation, orfalse pregnancy.
Lack of an audible fetal heart may

indicate pregnancy of fewer weeksthan expected, fetal demise, orfalse pregnancy.
An FHR that drops noticeably
near term with fetal movementcould indicate poor placental circulation.
After 24 weeks, auscultation of
more than one FHR with varyingrates in different locations suggestsmore than one fetus.
The rateis usually in the 160s during early pregnancy, and then slows to the
120s to 140s near term. After 32 to 34 weeks, the FHR should increase withfetal movement.
The location of the audible FHR is in the midline of the lower abdomen

from 12 to 18 weeks of gestation. After 28 weeks, the fetal heart is heardbest over the fetal back or chest. The location of the FHR then depends onhow the fetus is positioned. Palpating the fetal head and back helps you iden-tify where to listen. (See Modiﬁed Leopold’s Maneuvers, pp. 424–426.) Ifthe fetus is head down with the back on the woman’s left side, the FHR isheard best in the lower left quadrant. If the fetal head is under the xiphoidprocess ( breech presentation ) with the back on the right, the FHR is heard in
the upper right quadrant.DOPTONE (LEFT) AND FETOSCOPE (RIGHT)

422 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGRhythm becomes important in the third trimester. Expect a variance of 10
to 15 beats per minute (BPM) over 1 to 2 minutes.
Genitalia, Anus, and Rectum
Inspect the external genitalia, noting the hair distribution, the color, and
any scars. Parous relaxation of the introitus and noticeable enlargement ofthe labia and clitoris are normal. Scars from an episiotomy, a perineal incision
to facilitate delivery of an infant, or from perineal lacerations may be presentin multiparous women.
Inspect the anus for hemorrhoids. If these are present, note their size and
location.
Palpate Bartholin’s andSkene’s glands. No discharge or tenderness should be
present.
Check for a cystocele orrectocele.
Speculum Examination. Inspect the cervix for color, shape, and healed
lacerations. A parous cervix may look irregular because of lacerations (seep. 403).

present.
Take Pap smears and, if indicated, other vaginal or cervical specimens. The
cervix may bleed more easily when touched due to the vasocongestion ofpregnancy.
Inspect the vaginal walls for color, discharge, rugae, and relaxation. A bluish
or violet color, deep rugae, and an increased milky white discharge, leukor-
rhea, are normal.
Bimanual Examination. Insert two lubricated ﬁngers into the introi-

tus, palmar side down, with slight pressure downward on the perineum.Slide the ﬁngers into the posterior vaginal vault. Maintaining downwardpressure, gently turn the ﬁngers palmar side up. Avoid the sensitive urethralstructures at all times. With the relaxation of pregnancy, the bimanual ex-amination is usually easier to accomplish. Tissues are soft and the vaginalwalls usually close in on the examining ﬁngers, giving the sensation of beingimmersed in a bowl of oatmeal. It may be difﬁcult to distinguish the cervixat ﬁrst because of its softer texture.
Place your ﬁnger gently in the os, then sweep it around the surface of the
cervix. A nulliparous cervix should be closed, while a multiparous cervix may

admit a ﬁngertip through the external os. The internal os—the narrow pas-sage between the endocervical canal and the uterine cavity—should be
Lack of beat-to-beat variability 
late in pregnancy suggests fetalcompromise.
Some women have labial vari-
cosities that become tortuous and painful.
Varicosities often engorge later in
pregnancy. They may be painfuland bleed.
May be pronounced due to the
muscle relaxation of pregnancy
A pink cervix suggests a nonpreg-
nant state.
Vaginal infections are more com-
mon during pregnancy, and speci-mens may be needed for diagnosis.
A pink vagina suggests a non-
pregnant state. Vaginal irritationand itching with discharge suggestinfection.

closed in both situations. The surface of a normal multiparous cervix may
feel irregular due to the healed lacerations from a previous birth.
Estimate the length of the cervix by
palpating the lateral surface of thecervix from the cervical tip to the lat-eral fornix. Prior to 34 to 36 weeks,the cervix should retain its normallength of about 1.5 to 2 cm.
Palpate the uterus for size, shape, consistency, and position. These depend
on the weeks of gestation. Early softening of the isthmus, Hegar’s sign, is
characteristic of pregnancy. The uterus is shaped like an inverted pear until8 weeks, with slight enlargement in the fundal portion. The uterus becomesglobular by 10 to 12 weeks. Anteﬂexion or retroﬂexion is lost by 12 weeks,with the fundal portion measuring about 8 cm in diameter.
With your internal ﬁngers placed at either side of the cervix, palmar surfaces up-

ward, gently lift the uterus toward the abdominal hand. Capture the fundalportion of the uterus between your two hands and gently estimate uterine size.
Palpate the left and right adnexa. The corpus luteum may feel like a small
nodule on the affected ovary during the ﬁrst few weeks after conception.Late in pregnancy, adnexal masses may be difﬁcult to feel.
Palpate for pelvic muscle strength as you withdraw your examining ﬁngers.
A rectovaginal examination may be done if you need to conﬁrm uterine size
or the integrity of the rectovaginal septum. A pregnancy of less than 10 weeksin a retroverted and retroﬂexed uterus lies totally in the posterior pelvis. Itssize can be conﬁrmed only by this examination.
Extremities
General inspection may be done with the woman seated or lying on herleft side.
Inspect the legs for varicose veins.

Inspect the hands and legs for edema. Palpate for pretibial, ankle, and pedal
edema. Edema is rated on a 0 to 4+ scale. Physiologic edema is more commonin advanced pregnancy, during hot weather, and in women who stand a lot.
Obtain knee and ankle reﬂexes.
CHAPTER 12 ITHE PREGNANT WOMAN 423A shortened effaced cervix prior to
32 weeks may indicate pretermlabor.
An irregularly shaped uterus suggests
uterine myomata or a bicornuate
uterus, which has two distinct uter-
ine cavities separated by a septum.
Early in pregnancy, it is important
to rule out a tubal ( ectopic ) preg-
nancy. See Table 11-7 AdnexalMasses, p. 408.
Varicose veins may begin or
worsen during pregnancy.
Pathologic edema associated with
PIH is often 3+ or more pretibially;it also affects the hands and face.
After 24 weeks, reﬂexes greater

than 2+ may indicate PIH.

424 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGInterpretation
Common deviations include breech
presentation (the fetal buttocks 
presenting at the outlet of the maternal pelvis) and absence of thepresenting part well down into thematernal pelvis at term. Neither situation necessarily precludes vaginal birth. The most seriousﬁndings are a transverse lie close to
term and slowed fetal growth thatcould represent intrauterine growth 
retardation (IUGR).
Most commonly, the fetal but-
tocks are at the upper pole. Theyfeel ﬁrm but irregular, and lessglobular than the head. The fetalhead feels ﬁrm, round, andsmooth. 
© B. Proud (photograph).Special Techniques
MODIFIED LEOPOLD’S MANEUVERS
These maneuvers are important adjuncts to palpation of the pregnant ab-

domen beginning at 28 weeks of gestation. They help determine where thefetus is lying in relation to the woman’s back (longitudinal or transverse),what end of the fetus is presenting at the pelvic inlet (head or buttocks),where the fetal back is located, how far the presenting part of the fetus hasdescended into the maternal pelvis, and the estimated weight of the fetus.This information is necessary to assess the adequacy of fetal growth and theprobability of successful vaginal birth.
First Maneuver (Upper Pole). Stand at the woman’s side facing her
head. Keeping the ﬁngers of both examining hands together, palpate gentlywith the ﬁngertips to determine what part of the fetus is in the upper poleof the uterine fundus.

CHAPTER 12 ITHE PREGNANT WOMAN 425The hand on the fetal back feels a
smooth, ﬁrm surface the length ofthe hand (or longer) by 32 weeksof gestation. The hand on the fetalarms and legs feels irregularbumps, and also perhaps kicking ifthe fetus is awake and active.
If the fetal head is presenting, the
ﬁngers feel a smooth, ﬁrm,rounded surface on both sides.
If the hands diverge, the present-
ing part is descending into thepelvic inlet, as illustrated.
If the hands stay together and you
can gently depress the tissue overthe bladder without touching thefetus, the presenting part is aboveyour hands.
Third Maneuver (Lower
Pole). Turn and face the
woman’s feet. Using the ﬂatpalmar surfaces of the ﬁn-gers of both hands and, at
the start, touching the ﬁn-gertips together, palpate thearea just above the sym-physis pubis. Note whetherthe hands diverge withdownward pressure or staytogether. This tells you

whether or not the present-ing part of the fetus, heador buttocks, is descendinginto the pelvic inlet.Second Maneuver (Sides
of the Maternal Ab-domen).
Place one hand
on each side of the woman’sabdomen, aiming to cap-ture the body of the fetusbetween them. Use onehand to steady the uterusand the other to palpatethe fetus.
© B. Proud (photograph).

426 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGIf the presenting fetal part is descending, palpate its texture and ﬁrmness. If
not, gently move your hands up the lower abdomen and capture the pre-senting part between your hands.
Fourth Maneuver (Conﬁrmation of the Presenting Part). With
your dominant hand grasp the part of the fetus in the lower pole, and with yournondominant hand, the part of the fetus in the upper pole. With this maneu-ver, you may be able to distinguish between the head and the buttocks.The fetal head feels smooth, ﬁrm,
and rounded; the buttocks, ﬁrmbut irregular.
Most commonly, the head is in the
lower pole and the fetal buttocksare in the upper pole. If the head isabove the pelvic inlet, it movessomewhat independently of therest of the fetal body.
Concluding the Visit
Once the examination is completed and the woman is dressed, review the

ﬁndings with her. If further data are necessary to conﬁrm pregnancy, discusshow these may be obtained. Reinforce the importance of regular prenatalcare. Record all your ﬁndings on the prenatal record.

The Anus, Rectum, 
and ProstateCHAPTER
The Anus, Rectum, and Prostate1313
CHAPTER 13 ITHE ANUS, RECTUM, AND PROSTATE 425
The gastrointestinal tract terminates in a short segment, the anal canal . Its
external margin is poorly demarcated, but the skin of the anal canal can usu-ally be distinguished from the surrounding perianal skin by its moist, hairlessappearance. The anal canal is normally held in a closed position by the mus-cle action of the voluntary external anal sphincter and involuntary internal
anal sphincter, the latter an extension of the muscular coat of the rectal wall.
The direction of the anal canal on a line roughly between anus and umbili-
cus should be noted carefully. Unlike the rectum above it, the canal is lib-erally supplied by somatic sensory nerves, and a poorly directed finger orinstrument will produce pain.
Valve of HoustonPeritoneal
Rectum
ProstateAnorectal junction

Rectum
Anorectal canalBladder
MEDIAN SECTION—VIEW FROM THE LEFT SIDE

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cThe anal canal is demarcated from the rectum superiorly by a serrated line
marking the change from skin to mucous membrane. This anorectal junction,often called the pectinate or dentate line , also denotes the boundary between
somatic and visceral nerve supplies. It is readily visible on proctoscopic ex-amination, but is not palpable.
Above the anorectal junction, the rectum balloons out and turns posteriorly
into the hollow of the coccyx and the sacrum. In the male, the three lobesof the prostate gland surround the urethra. The two lateral lobes lie against
the anterior rectal wall, where they are readily palpable as a rounded, heart-shaped structure about 2.5 cm in length. They are separated by a shallowmedian sulcus or groove, also palpable. The third, or median, lobe is ante-rior to the urethra and cannot be examined.  The seminal vesicles, shaped like

rabbit ears above the prostate, are also not normally palpable.ANATOMY AND PHYSIOLOGY
426 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Valve of HoustonSeminal vesicle
Rectum
Anorectal junction
Internal anal sphincter External anal sphincter
AnalcanalMedian sulcus
Lateral lobeProstate
Levater ani muscle
In the female, the uterine cervix can usually be felt through the anterior wall
of the rectum.
The rectal wall contains three inward foldings, called valves of Houston. The
lowest of these can sometimes be felt, usually on the patient’s left. Most ofthe rectum that is accessible to digital examination does not have a peri-toneal surface. The anterior rectum usually does, however, and you mayreach it with the tip of your examining ﬁnger. You may thus be able to iden-tify the tenderness of peritoneal inﬂammation or the nodularity of peritonealmetastases.

The prostate gland is small during boyhood, but between puberty and theage of about 20 years it increases roughly ﬁve-fold in size. Starting in aboutthe 5th decade, further enlargement is increasingly common as the gland be-comes hyperplastic (see p. __).
CORONAL SECTION OF THE ANUS AND RECTUM. 
VIEW FROM BEHIND, SHOWING THE ANTERIOR WALL

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cMany questions concerning symptoms related to the anorectal area and the
prostate have been addressed in other chapters. For example, you will needto ask if there has been any change in the pattern of bowel function or thesize or caliber of the stools. What about diarrhea or constipation? You willneed to ask about the color of the stools. Turn to pp. __–__ and review thehealth history regarding these symptoms, as well as queries about blood in
the stool, ranging from black stools, suggesting melena , to the red blood of
hematochezia to bright red blood per rectum . Has there been any mucus pres-
ent in the stool?
Is there any pain on defecation? Any itching? Any extreme tenderness in
the anus or rectum? Is there any mucopurulent discharge or bleeding? Anyulcerations? Does the patient have anal intercourse?
Is there any history of anal warts, or anal ﬁssures?

In men, review the pattern of urination (see pp. __–__). Does the patient
have any difﬁculty starting the urine stream or holding back urine? Is theﬂow weak? What about frequent urination, especially at night? Or pain orburning as urine is passed? Any blood in the urine or semen or pain withejaculation? Is there frequent pain or stiffness in the lower back, hips, orupper thighs?THE HEALTH HISTORY
CHAPTER 13 ITHE ANUS, RECTUM, AND PROSTATE 427See Table 9-???, Black and 
Bloody Stools, and Table 9-???,Constipation.
Change in bowel pattern, espe-
cially stools of thin pencil-like cal-iber, may warn of cancer. Blood inthe stool from polyps or cancer,also from gastrointestinal bleeding,local hemorrhoids, mucus in villous adenoma.
Proctitis with anorectal pain,

Proctitis with anorectal pain, 
pruritus, tenesmus, discharge orbleeding in anorectal infectionfrom gonorrhea, Chlamydia, 
lymphogranuloma venereum; ulcerations in herpes simplex,chancre in primary syphilis. Mayarise from receptive anal inter-course. Itching in younger patients from pinworms.
Genital warts from human papillo-
mavirus, condylomata lata in sec-
ondary syphilis. Anal ﬁssures inproctitis, Crohn’s disease
These symptoms suggest urethral
obstruction as in benign prostatichyperplasia or prostate cancer, especially in men older than age 70.Common or Concerning Symptoms
IChange in bowel habits
IBlood in the stool
IPain with defecation, rectal bleeding, or tenderness
IAnal warts or ﬁssures
IWeak stream of urine
IBurning with urination

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cAlso in men, is there any feeling of discomfort or heaviness in the prostate
area at the base of the penis? Any associated malaise, fever, or chills?HEALTH PROMOTION AND COUNSELING
428 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGImportant Topics for Health Promotion and Counseling
IScreening for prostate cancer
IScreening for polyps and colorectal cancer.
Clinicians should discuss screening issues related to prostate cancer to pro-
mote health for men, and provide screening recommendations to both menand women for detection of colorectal cancer and adenomatous colonicpolyps.
Prostate cancer is the leading cancer diagnosed in men in the United States,

and the second leading cause of death in North American men. Ethnicityand age strongly inﬂuence risk. African American men have the highest in-cidence rate of prostate cancer in the world, and Asian and native Americanmen have the lowest rates. Sixty percent of all new cases and approximately80% of deaths occur in men age 70 or older. Also at risk are men with a fam-ily history of prostate cancer.
To educate patients about prostate cancer, clinicians must be knowledge-
able about several issues related to general screening of patients without
symptoms . Prognosis is most favorable when the cancer is conﬁned to the

prostate, and worsens with extracapsular or metastatic spread. Autopsy stud-ies show that many men over 50, and even some who are younger, have nestsof cancerous prostate cells that never cause disease. Since many of these tu-mors are quiescent, early detection may increase unnecessary testing andtreatment without affecting survival. A further complication in decisionsabout screening is that currently available screening tests are not highly ac-curate, which heightens patient concern and leads to additional noninvasiveand invasive testing.
The two principal screening tests for prostate cancer are the digital rectal ex-

amination (DRE) and the prostate-speciﬁc antigen test (PSA). Each of thesetests has distinct limitations that warrant careful review with the patient.*The DRE reaches only the posterior and lateral surfaces of the prostate, miss-ing 25% to 35% of tumors in other areas. Sensitivity of the DRE for prostate
*U.S. Preventive Health Services Task Force. Guide to Clinical Preventive Services, 2nd ed. Baltimore,
Williams & Wilkins, pp. 119–134, 1996.Suggests possible prostatitisEXAMPLES OF ABNORMALITIES

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5ccancer is low, ranging from 20% to 68%. In addition, because the DRE has
a high rate of false positives, further testing by transrectal ultrasound or evenbiopsy is common. Many professional societies recommend annual DRE be-tween the ages of 40 or 50 and 70. In contrast, the U.S. Preventive HealthServices Task Force currently recommends against routine screening by DREuntil there is more deﬁnitive evidence of increased survival from early detec-tion and of decreased adverse effects from testing and even surgery (prosta-tectomy carries up to a 20% risk of impotence and a 5% risk of urinaryincontinence). Instead, the Task Force advises clinicians to counsel all menrequesting screening about the utility of testing and “the beneﬁts and harmsof early detection and treatment.”
The beneﬁts of PSA testing are equally unclear. The PSA can be elevated in

benign conditions like hyperplasia and prostatitis, and its detection rate forprostate cancer is low, about 28% to 35% in asymptomatic men. Severalgroups recommend annual combined screening with PSA and DRE for menover 50 and for African Americans and men over age 40 with a positive fam-ily history. Other groups, including the U.S. Preventive Health Services TaskForce, do not recommend routine PSA screening until its beneﬁts are moreﬁrmly established.
For men with symptoms of prostate disorders, the clinician’s role is more

straightforward. As men approach 50, risk of prostate cancer begins to in-crease. Review the symptoms of prostate disorders—incomplete emptyingof the bladder, urinary frequency or urgency, weak or intermittent stream orstraining to initiate ﬂow, hematuria, nocturia, or even bony pains in thepelvis. Men may be reluctant to report such symptoms, but should be en-couraged to seek evaluation and treatment early.
To increase detection of colorectal cancer, clinicians can make use of three

screening tests that are currently available: the DRE, the fecal occult bloodtest (FOBT), and sigmoidoscopy. Both the DRE and the FOBT have signif-icant limitations. The DRE permits the clinician to examine only 7 to 8 cmof the rectum (usually about 11 cm long)—only about 10% of colorectalcancers arise in this zone. The FOBT (see discussion on p. __) detects only2% to 11% of colorectal cancers and 20% to 30% of adenomas in individualsover age 50, and results in a high rate of false positives. Among advocates,the DRE and FOBT are usually performed annually after age 40 to 50. Flex-ible sigmoidoscopy (also discussed on p. __) permits good surveillance ofthe distal third of the colon. It is generally recommended every 3 to 5 yearsfor patients over 50. Patients over 40 with familial polyposis, inflammatorybowel disease, or history of colon cancer in a first-degree relative shouldbe advised to obtain a colonoscopy or air contrast barium enema every 3 to5 years.HEALTH PROMOTION AND

inflammatorybowel disease, or history of colon cancer in a first-degree relative shouldbe advised to obtain a colonoscopy or air contrast barium enema every 3 to5 years.HEALTH PROMOTION AND COUNSELING

430 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGRaises concern of proctitis from in-
fectious cause
Raises concern of prostate cancerPreview: Recording the Physical Examination—
The Anus, Rectum, and Prostate
you will use phrases. The style below contains phrases appropriate for mostwrite-ups. Unfamiliar terms are explained in the next section, Techniques ofExamination.
“No perirectal lesions or ﬁssures. External sphincter tone intact. Rectal
vault without masses. Prostate smooth and nontender with palpablemedian sulcus. (Or in a female, uterine cervix nontender). Stool brownand hemoccult negative.”
OR“Perirectal area inflamed; no ulcerations, warts, or discharge. Unable

to examine external sphincter, rectal vault, or prostate because ofspasm of external sphincter and marked inflammation and tendernessof anal canal.”
OR“No perirectal lesions or ﬁssures. External sphincter tone intact. Rectal
vault without masses. Left lateral prostate lobe with 1 ×1 cm ﬁrm hard
nodule; right lateral lobe smooth; median sulcus is obscured. Stoolbrown and hemoccult negative.”EXAMPLES OF ABNORMALITIES

CHAPTER 13 ITHE ANUS, RECTUM, AND PROSTATE 431No matter how you position the
patient, your examining ﬁngercannot reach the full length of therectum. If a rectosigmoid cancer issuspected or screening is war-ranted, inspection by sigmoid-oscopy is necessary.
For many patients, the rectal examination is probably the least popular seg-

ment of the physical examination. It may cause discomfort for the patient,perhaps embarrassment, but, if skillfully done, should not be truly painful inmost circumstances. Although you may choose to omit a rectal examinationin adolescents who have no relevant complaints, you should do one in adultpatients. In middle-aged and older persons, omission risks missing an asymp-tomatic carcinoma. A successful examination requires gentleness, slow move-ment of your ﬁnger, a calm demeanor, and an explanation to the patient ofwhat he or she may feel.
Male

Male
The anus and rectum may be examined with the patient in one of several po-sitions. For most purposes, the side-lying position is satisfactory and allowsgood views of the perianal and sacrococcygeal areas. This is the position de-scribed below. The lithotomy position may help you to reach a cancer high inthe rectum. It also permits a bimanual examination, enabling you to delineatea pelvic mass. Some clinicians prefer to examine a patient while he stands withhis hips ﬂexed and his upper body resting across the examining table.
Ask the patient to lie on his left side with his buttocks close to the edge of
the examining table near you. Flexing the patient’s hips and knees, especiallyin the top leg, stabilizes his position and improves visibility. Drape the pa-tient appropriately and adjust the light for the best view. Glove your handsand spread the buttocks apart.

432 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGIInspect the sacrococcygeal and perianal areas for lumps, ulcers, inﬂamma-
tion, rashes, or excoriations. Adult perianal skin is normally more pig-mented and somewhat coarser than the skin over the buttocks. Palpateany abnormal areas, noting lumps or tenderness.
IExamine the anus and rectum. Lubricate your gloved index finger, ex-
plain to the patient what you are going to do, and tell him that the ex-amination may make him feel as if he were moving his bowels but thathe will not do so. Ask him to strain down. Inspect the anus, noting anylesions.
As the patient strains, place the pad of your lubricated and gloved index ﬁn-
ger over the anus. As the sphincter relaxes, gently insert your ﬁngertip intothe anal canal, in a direction pointing toward the umbilicus. Anal and perianal lesions include

hemorrhoids, venereal warts, her-pes, syphilitic chancre, and carci-noma. A perianal abscess producesa painful, tender, indurated, andreddened mass. Pruritus ani causesswollen, thickened, ﬁssured skinwith excoriations.
Soft, pliable tags of redundant skin
at the anal margin are common.Though sometimes due to pastanal surgery or previously throm-bosed hemorrhoids, they are oftenunexplained.
See Table 13-1, Abnormalities of
the Anus, Surrounding Skin, andRectum (pp. __–__).
Sphincter tightness in anxiety, in-
ﬂammation, or scarring; laxity insome neurologic diseasesIf you feel the sphincter tighten, pause and reassure the patient. When in a

moment the sphincter relaxes, proceed. Occasionally, severe tenderness pre-vents you from examining the anus. Do not try to force it. Instead, placeyour ﬁngers on both sides of the anus, gently spread the oriﬁce, and ask thepatient to strain down. Look for a lesion, such as an anal ﬁssure, that mightexplain the tenderness.
If you can proceed without undue discomfort, note:
IThe sphincter tone of the anus. Normally, the muscles of the anal sphinc-
ter close snugly around your ﬁnger.
ITenderness, if any
MEDIAN SECTIONS—VIEW FROM THE PATIENT’S RIGHT SIDE. PATIENT LYING ON HIS 
LEFT SIDEAB

CHAPTER 13 ITHE ANUS, RECTUM, AND PROSTATE 433IInduration
IIrregularities or nodules
Insert your ﬁnger into the rectum as far as possible. Rotate your hand clock-
wise to palpate as much of the rectal surface as possible on the patient’sright side, then counterclockwise to palpate the surface posteriorly and onthe patient’s left side.
Note any nodules, irregularities,
or induration. To bring a possi-ble lesion into reach, take yourﬁnger off the rectal surface, askthe patient to strain down, andpalpate again.Induration may be due to inﬂam-
mation, scarring, or malignancy.
The irregular border of a rectal
cancer is shown below.
Then rotate your hand further counterclockwise so that your finger can 
examine the posterior surface of the prostate gland. By turning your body

somewhat away from the patient, you can feel this area more easily. Tellthe patient that you are going to feel his prostate gland, and that it maymake him want to urinate but he will not do so.
Sweep your ﬁnger carefully over the prostate gland, identifying its lateral
lobes and the median sulcus between them. Note the size, shape, and con-sistency of the prostate, and identify any nodules or tenderness. The normalprostate is rubbery and nontender.
See Table 13-2, Abnormalities of
the Prostate (p. __).

434 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGIf possible, extend your ﬁnger above the prostate to the region of the seminal
vesicles and the peritoneal cavity. Note nodules or tenderness.
Gently withdraw your ﬁnger, and wipe the patient’s anus or give him tissues
to do it himself. Note the color of any fecal matter on your glove, and testit for occult blood.
Female
The rectum is usually examined after the female genitalia, while the patientis in the lithotomy position. If a rectal examination alone is indicated, thelateral position offers a satisfactory alternative. It affords a much better viewof the perianal and sacrococcygeal areas.
The technique is basically similar to that described for males. The cervix is

usually felt readily through the anterior rectal wall. Sometimes, a retroverteduterus is also palpable. Neither of these, nor a vaginal tampon, should bemistaken for a tumor.
A rectal “shelf” of peritoneal metas-
tases (see p. __) or the tendernessof peritoneal inﬂammation
PALPATING THE PROSTATE—
VIEW FROM BELOW

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 13-1 IAbnormalities of the Anus, Surrounding Skin, and Rectum
CHAPTER 13 ITHE ANUS, RECTUM, AND PROSTATE 435
TABLE 13-1 IAbnormalities of the Anus, Surrounding Skin, and Rectum
Pilonidal Cyst and Sinus Anorectal Fistula
A pilonidal cyst is a fairly common, probably congenital abnormality

located in the midline superﬁcial to the coccyx or the lower sacrum. Itis clinically identiﬁed by the opening of a sinus tract. This opening mayexhibit a small tuft of hair and be surrounded by a halo of erythema.Although pilonidal cysts are generally asymptomatic except perhaps forslight drainage, abscess formation and secondary sinus tracts maycomplicate the picture.Anal FissureAn anorectal ﬁstula is an inﬂammatory tractor tube that opens at one end into the anusor rectum and at the other end onto theskin surface (as shown here) or intoanother viscus. An abscess usually antedatessuch a ﬁstula. Look for the ﬁstulousopening or openings anywhere in the skinaround the anus.
An anal ﬁssure is a very painful oval

ulceration of the anal canal, found mostcommonly in the midline posteriorly, lesscommonly in the midline anteriorly. Itslong axis lies longitudinally. Inspection mayshow a swollen “sentinel” skin tag justbelow it, and gentle separation of the analmargins may reveal the lower edge of theﬁssure. The sphincter is spastic; theexamination painful. Local anesthesia maybe required.
Location
Fistula
Fissure
Sentinel tag
Opening

436 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 13-1 IAbnormalities of the Anus, Surrounding Skin, and Rectum (Continued)
External Hemorrhoids
(Thrombosed)
External hemorrhoids are dilated
hemorrhoidal veins that originate belowthe pectinate line and are covered withskin. They seldom produce symptomsunless thrombosis occurs. This causesacute local pain that is increased bydefecation and by sitting. A tender,swollen, bluish, ovoid mass is visible atthe anal margin.
Internal hemorrhoids are an

enlargement of the normal vascularcushions that are located above thepectinate line. Here they are not usuallypalpable. Sometimes, especially duringdefecation, internal hemorrhoids maycause bright red bleeding. They mayalso prolapse through the anal canal andappear as reddish, moist, protrudingmasses, typically located in one or moreof the positions illustrated.
On straining for a bowel movement the
rectal mucosa, with or without itsmuscular wall, may prolapse throughthe anus, appearing as a doughnut orrosette of red tissue. A prolapseinvolving only mucosa is relatively smalland shows radiating folds, as illustrated.When the entire bowel wall is involved,the prolapse is larger and covered byconcentrically circular folds.Polyps of the rectum are fairly common.
Variable in size and number, they candevelop on a stalk ( pedunculated ) or lie
on the mucosal surface ( sessile ). They

are soft and may be difﬁcult orimpossible to feel even when in reach ofthe examining ﬁnger. Proctoscopy isusually required for diagnosis, as isbiopsy for the differentiation of benignfrom malignant lesions.
Asymptomatic carcinoma of the rectum
makes routine rectal examinationimportant for adults. Illustrated here isthe ﬁrm, nodular, rolled edge of anulcerated cancer. Polyps, as notedabove, may also be malignant.
Widespread peritoneal metastases from
any source may develop in the area ofthe peritoneal reﬂection anterior to therectum. A ﬁrm to hard nodular rectal“shelf” may be just palpable with the tipof the examining ﬁnger. In a woman,this shelf of metastatic tissue develops inthe rectouterine pouch, behind thecervix and the uterus.
Internal Hemorrhoids
(Prolapsed)
Anterior
Posterior
Prolapse of the Rectum
Polyps of the Rectum
Cancer of the Rectum
Rectal Shelf

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5cTABLE 13-2 IAbnormalities of the Prostate
CHAPTER 13 ITHE ANUS, RECTUM, AND PROSTATE 437
TABLE 13-2 IAbnormalities of the Prostate
Normal Prostate Gland
 As palpated through the anterior rectal
wall, the normal prostate is a rounded,heart-shaped structure about 2.5 cm inlength. The median sulcus can be feltbetween the two lateral lobes. Only theposterior surface of the prostate ispalpable. Anterior lesions, includingthose that may obstruct the urethra, arenot detectable by physical examination.
Starting in the 5th decade of life,

benign prostatic hyperplasia becomesincreasingly prevalent. The affectedgland usually feels symmetricallyenlarged, smooth, and ﬁrm thoughslightly elastic. It seems to protrudemore into the rectal lumen. The mediansulcus may be obliterated. Finding anormal-sized gland by palpation,however, does not rule out thisdiagnosis. Prostatic hyperplasia mayobstruct urinary ﬂow, causingsymptoms, yet not be palpable.Cancer of the prostate is suggested by
an area of hardness in the gland. Adistinct hard nodule that alters thecontour of the gland may or may not bepalpable. As the cancer enlarges, it feelsirregular and may extend beyond theconﬁnes of the gland. The mediansulcus may be obscured. Hard areas inthe prostate are not always malignant.They may also result from prostaticstones, chronic inﬂammation, and otherconditions.
Acute prostatitis (illustrated here) is an

acute, febrile condition caused bybacterial infection. The gland is verytender, swollen, ﬁrm, and warm.Examine it gently.
Chronic prostatitis does not produce
consistent physical ﬁndings and must beevaluated by other methods.
Benign Prostatic HyperplasiaCancer of the Prostate
Prostatitis

The Peripheral 
Vascular SystemCHAPTER
The Peripheral Vascular System1414
CHAPTER 14 ITHE PERIPHERAL VASCULAR SYSTEM 441
Brachial arter y
Ulnar artery
Arterial archesRadial artery
This chapter focuses on circulation
to the arms and legs. It includes thearteries, the veins, the capillary bedthat connects them, and the lym-phatic system with its lymph nodes.
Arteries
Arterial pulses are palpable when anartery lies close to the body surface.In the arms, there are two or some-times three such locations. Pulsa-tions of the brachial artery can be
felt in and above the bend of theelbow, just medial to the biceps ten-don and muscle. The brachial arterydivides into the radial and ulnar ar-teries. Radial artery pulsations can
be felt on the ﬂexor surface of thewrist laterally. Medially, pulsationsof the ulnar artery may be palpable,
but overlying tissues frequently ob-scure them.
The radial and ulnar arteries are in-

terconnected by two vascular archeswithin the hand. Circulation to thehand and fingers is thereby doublyprotected against possible arterialocclusion.

In the legs, arterial pulsations can
usually be felt in four places. Thoseof the femoral artery are palpable
below the inguinal ligament, mid-way between the anterior superioriliac spine and the symphysis pubis.The femoral artery travels down-ward deep within the thigh, passesmedially behind the femur, and be-comes the popliteal artery. Popliteal
pulsations can be felt in the tissuesbehind the knee. Below the knee,the popliteal artery divides into twobranches, both of which continueto the foot. There the anterior branchbecomes the dorsalis pedis artery. Its
pulsations are palpable on the dor-sum of the foot just lateral to theextensor tendon of the big toe. Theposterior branch, the posterior tib-
ial artery, can be felt as it passes be-
hind the medial malleolus of theankle.
Like the hand, the foot is protected
by an interconnecting arch betweenits two chief arterial branches.
Veins

Veins
The veins from the arms, together with those from the upper trunk and thehead and neck, drain into the superior vena cava and on into the rightatrium. Veins from the legs and the lower trunk drain upward into the in-ferior vena cava. Because the leg veins are especially susceptible to dysfunc-tion, they warrant special attention.
The deep veins of the legs carry about 90% of the venous return from the
lower extremities. They are well supported by surrounding tissues.
442 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Symphysis pubis
Popliteal artery
Arterial archPosterior tibial artery
Dorsalis pedis artery

In contrast, the superficial veins are located subcutaneously, and are sup-
ported relatively poorly. The superficial veins include (1) the great saphe-
nous vein, which originates on the dorsum of the foot, passes just in front
of the medial malleolus, and then continues up the medial aspect of the legto join the deep venous system (the femoral vein) below the inguinal lig-ament; and (2) the small saphenous vein, which begins at the side of the
foot and passes upward along the back of the leg to join the deep systemin the popliteal space. Anastomotic veins connect the two saphenous veinssuperficially and, when dilated, are readily visible. In addition, communi-
cating (or perforating) veins connect the saphenous system with the deep
venous system.
Deep, superﬁcial, and communicating veins all have one-way valves. These

allow venous blood to ﬂow from the superﬁcial to the deep system and to-ward the heart, but not in the opposite directions. Muscular activity con-tributes importantly to venous blood ﬂow. As calf muscles contract in walk-ing, for example, blood is squeezed upward against gravity, and competentvalves keep it from falling back again.ANATOMY AND PHYSIOLOGY
CHAPTER 14 ITHE PERIPHERAL VASCULAR SYSTEM 443
Femoral vein
Great saphenous
vein
Small saphenou s
vein
Communicating
vein
Small saphenous
veinGreat saphenous
vein

The Lymphatic System and Lymph Nodes
The lymphatic system comprises an extensive vascular network that drains
fluid, called lymph, from bodily tissues and returns it to the venous circu-lation. The system starts peripherally as blind lymphatic capillaries, andcontinues centrally as thin vascular vessels and then collecting ducts thatfinally empty into major veins at the root of the neck. The lymph trans-ported in these channels is filtered through lymph nodes that are inter-posed along the way.
Lymph nodes are round, oval, or bean-shaped structures that vary in size
according to their location. Some lymph nodes, such as the preauriculars,if palpable at all, are typically very small. The inguinal nodes, in contrast,are relatively larger—often 1 cm in diameter and occasionally even 2 cm inan adult.
In addition to its vascular functions, the lymphatic system plays an impor-

tant role in the body’s immune system. Cells within the lymph nodes engulfcellular debris and bacteria and produce antibodies.
Only the superﬁcial lymph nodes are accessible to physical examination.
These include the cervical nodes (p. 133), the axillary nodes (p. 300), andnodes in the arms and legs.
444 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Infraclavicula r
node
Central
axillary nodesLateral
axillarynodesEpitrochlear
nodes

CHAPTER 14 ITHE PERIPHERAL VASCULAR SYSTEM 445
Femoral
vein
Great
saphenousveinVertical
groupFemoral
arteryHorizontal
groupRecall that the axillary lymph nodes drain most of the arm. Lymphatics
from the ulnar surface of the forearm and hand, the little and ring fingers,and the adjacent surface of the middle finger, however, drain first into theepitrochlear nodes. These are located on the medial surface of the arm about
3 cm above the elbow. Lymphatics from the rest of the arm drain mostlyinto the axillary nodes. A few may go directly to the infraclaviculars.
The lymphatics of the lower limb,
following the venous supply, consistof both deep and superﬁcial systems.Only the superﬁcial nodes are pal-pable. The superﬁcial inguinal nodes
include two groups. The horizontal
group lies in a chain high in the ante-

rior thigh below the inguinal liga-ment. It drains the superﬁcial portionsof the lower abdomen and buttock,the external genitalia (but not thetestes), the anal canal and perianalarea, and the lower vagina.
The vertical group clusters near the
upper part of the saphenous vein anddrains a corresponding region of theleg. In contrast, lymphatics from theportion of leg drained by the smallsaphenous vein (the heel and outeraspect of the foot) join the deep sys-tem at the level of the popliteal space.Lesions in this area, therefore, arenot usually associated with palpableinguinal lymph nodes.
Fluid Exchange and the Capillary Bed
Blood circulates from arteries to veins through the capillary bed. Here ﬂuidsdiffuse across the capillary membrane, maintaining a dynamic equilibrium be-tween the vascular and interstitial spaces. Blood pressure ( hydrostatic pressure )

within the capillary bed, especially near the arteriolar end, forces ﬂuid out intothe tissue spaces. In effecting this movement, it is aided by the relatively weakosmotic attraction of proteins within the tissues ( interstitial colloid oncotic
pressure ) and is opposed by the hydrostatic pressure of the tissues.
As blood continues through the capillary bed toward the venous end its
hydrostatic pressure falls, and another force gains dominance. This is the col-
loid oncotic pressure of plasma proteins, which pulls ﬂuid back into the vascular
tree. Net ﬂow of ﬂuid, which was directed outward on the arteriolar side ofthe capillary bed, reverses itself and turns inward on the venous side. Lym-phatic capillaries, which also play an important role in this equilibrium, removeexcessive ﬂuid, including protein, from the interstitial space.

446 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGSee Table 14-1, Painful Peripheral
Vascular Disorders and Their Mimics, pp. 460–461.Lymphatic dysfunction or disturbances in hydrostatic or osmotic forces can
all disrupt this equilibrium. The most common clinical result is the increasedinterstitial ﬂuid known as edema (see Table 14-4, Some Peripheral Causesof Edema, p. 464).
Aging itself brings relatively few clinically important changes to the peripheral

vascular system. Although arterial and venous disorders, especially athero-sclerosis, do afﬂict older people more frequently, they probably cannot beconsidered part of the aging process. Age lengthens the arteries, makes themtortuous, and typically stiffens their walls, but these changes develop with orwithout atherosclerosis and therefore lack diagnostic speciﬁcity. Loss of arte-rial pulsations is not a part of normal aging, however, and demands carefulevaluation. Skin may get thin and dry with age, nails may grow more slowly,and hair on the legs often becomes scant. Because these changes are com-mon, they are not speciﬁc for arterial insufﬁciency, although they are classi-cally associated with it.
IPain in the arms or legs
IIntermittent claudication
ICold, numbness, pallor in the legs, hair loss
IColor change in ﬁngertips or toes in cold weather

ISwelling in calves, legs, or feet
ISwelling with redness or tenderness
To assess possible peripheral vascular disease, begin by asking patients about
any pain in the arms and legs. Be aware that pain in the extremities may arise
from the skin, the peripheral vascular system, the musculoskeletal system, orthe nervous system. In addition, visceral pain may be referred to the ex-
Interstitial space
Artery
Capillary bedLymphatic vessel
VeinEXAMPLES OF ABNORMALITIES

tremities, like the pain of myocardial infarction that radiates to the left arm
or cervical arthritis that radiates to the shoulder.
To elicit symptoms of arterial peripheral vascular disease in the legs, in-
quire about intermittent claudication, which is exercise-induced pain that
is absent at rest, makes the patient stop exertion, and remits within about10 minutes. Ask “Have you ever had any pain or cramping in your legs whenyou walk or exercise?” and “How far can you walk without stopping to rest?”Also, “Does the pain get better with rest?” These questions clarify whatmakes the patient stop and how quickly the pain is relieved. Ask also aboutcoldness, numbness, or pallor in the legs or feet or loss of hair over the ante-
rior tibial surfaces.
Many patients with arterial peripheral vascular disease have few symptoms,

so it is important to identify background risk factors. Assess the patient’s his-tory of tobacco abuse. Ask if the patient has had hypertension, diabetes, orhyperlipidemia. Further, is there any history of myocardial infarction orstroke? Such patients warrant further evaluation, even if without symptomsin the extremities (see p. 448).
To elicit symptoms of arterial spasm in the fingers or toes, ask “Do your
fingertips ever change color in cold weather or when you handle cold ob-jects?” . . . “What color changes do you notice?” . . . “What about your toes?”
There may be symptoms of venous peripheral vascular disease, such as
swelling of the feet and legs. Ask about any ulcers on the lower legs, often the
near ankles.
The redness, swelling, and tenderness of local inflammation are seen in

some vascular disorders and in other conditions that mimic them. In con-trast, relatively brief leg cramps that commonly occur at night in other-wise healthy people do not indicate a circulatory problem, and cold handsand feet are so common in healthy people that they have relatively littlepredictive value.THE HEALTH HISTORY
CHAPTER 14 ITHE PERIPHERAL VASCULAR SYSTEM 447Atherosclerosis can cause sympto-
matic limb ischemia with exertion;distinguish this from spinal stenosis,
which produces leg pain with exertion that may be reduced byleaning forward (stretching thespinal cord in the narrowed verte-bral canal) and less readily relievedby rest.
Hair loss over the anterior tibiae in
decreased arterial perfusion. “Dry”or brown-black ulcers from gan-grene may ensue.
Only about 10% of affected pa-

tients have the classic symptoms ofexertional calf pain relieved by rest.
Digital ischemic changes of
blanching, followed by cyanosis,then rubor with cold exposure and rewarming in Raynaud’s phenomenon or disease
Hyperpigmentation, edema, and
possible cyanosis, especially whenlegs are dependent, in venous stasis
ulcers
Inﬂammation in cellulitis, superﬁcial
thrombophlebitis, and erythema 
nodosum
Etiology of common leg cramps
and “restless legs” not well under-stood. Leg cramps sometimes fromdiuretic use with hypokalemiaEXAMPLES OF ABNORMALITIES

448 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING*Hirsh AT, Criqui MH, Treat-Jacobson D, et al: Peripheral Arterial Disease: Detection, Awareness,
and Treatment in Primary Care. JAMA 286 (11):1317–1324, 2001; Hiatt WR: Medical Treatment of Peripheral Arterial Disease and Claudication. NEJM 344 (21):1608–1620, 2001.
IDetection of peripheral arterial disease (PAD)
IRisk factors for PAD
IScreening for PAD: the ankle–brachial index (ABI)
Peripheral arterial disease (PAD) generally refers to atherosclerotic occlusion

of arteries in the lower extremities. The femoral and popliteal arteries are in-volved most commonly, followed by the tibial and peroneal arteries. PADaffects from 12% to 25% of community populations; however, recent stud-ies* have shown that despite signiﬁcant associations with cardiovascular andcerebrovascular disease, PAD often is underdiagnosed in ofﬁce practices.Most patients with PAD have either no symptoms or a range of nonspeciﬁcleg symptoms, such as aching, cramping, numbness, or fatigue. The classictriad for vascular claudication, exercise-induced calf pain that causes stop-ping of exercise and results in relief of pain in 10 minutes or less, may bepresent in only about 10% of affected patients.*
Patients with current or past tobacco use, diabetes, hypertension, hyper-

lipidemia, or cardiovascular or cerebrovascular disease are at increased riskof atherosclerotic PAD. Such patients should be screened for subclinical PADand targeted for aggressive risk factor intervention. For screening, cliniciansshould consider use of the ankle–brachial index (ABI), a highly accurate testfor detecting 50% or greater stenoses of 50% or more in major vessels of thelegs. The ABI is readily performed by clinicians or ofﬁce staff, and consists ofmeasuring the systolic blood pressure with Doppler ultrasonography in eacharm and in the dorsalis pedis and posterior tibial pulses. The ABI is calcu-lated on both the right and left by dividing the higher right ankle pressureby the higher right arm pressure, and the higher left ankle pressure by thehigher left arm pressure. ABI values are as follows: 0.90–1.30 is considerednormal; 0.41–0.90—mild to moderate peripheral arterial disease, usuallywith symptoms of claudication; and 0.00–0.40—severe peripheral vasculardisease with

are as follows: 0.90–1.30 is considerednormal; 0.41–0.90—mild to moderate peripheral arterial disease, usuallywith symptoms of claudication; and 0.00–0.40—severe peripheral vasculardisease with critical leg ischemia.

The severity of peripheral vascular disease closely parallels the risk of myo-
cardial infarction, ischemic stroke, and death from vascular causes. Patientswith ABIs in the lowest category have a 20% to 25% annual risk of death.*A wide range of interventions is available to reduce both onset and progres-

CHAPTER 14 ITHE PERIPHERAL VASCULAR SYSTEM 449Suggests atherosclerotic peripheral
arterial diseasePreview: Recording the Physical Examination—
The Peripheral Vascular System
you will use phrases. The style below contains phrases appropriate formost write-ups. Unfamiliar terms are explained in the next section, Techniques of Examination .Recall that the written description of lymph
nodes appears after the Head and Neck section (see p.143). Likewise, assessment of the carotid pulse is recorded in the Cardiovascular section(see p. 265).
“Extremities are warm and without edema. No varicosities or stasis
changes. Calves are supple and nontender. No femoral or abdominalbruits. Brachial, radial, femoral, popliteal, dorsalis pedis (DP), and posterior tibial (PT) pulses are 2 +and symmetric.”
OR“Extremities are pale below the midcalf, with notable hair loss. Rubor

noted when legs dependent but no edema or ulceration. Bilateral femoralbruits; no abdominal bruits heard. Brachial and radial pulses 2 +; femoral,
popliteal, DP and PT pulses 1 +.” (Alternatively, pulses can be recorded as
below.)
Dorsalis Posterior
Radial Brachial Femoral Popliteal Pedis Tibial
RT 2 + 2+ 1+ 1+ 1+ 1+
LT 2 + 2+ 1+ 1+ 1+ 1+sion of subclinical PAD, including meticulous foot care and well-ﬁtting
shoes, tobacco cessation, treatment of hyperlipidemia, optimal control andtreatment of diabetes and hypertension, use of antiplatelet agents, and, ifneeded, surgical revascularization.
(Students should consult specialty texts for less common forms of vascular
occlusion from arterial or venous thrombosis or endarteritis from infection,inﬂammation, or autoimmune disease.)EXAMPLES OF ABNORMALITIES

450 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGLymphedema of arm and hand
may follow axillary node dissectionand radiation therapy.
Prominent veins in an edematous
arm suggest venous obstruction.
(Source of photo above: Marks R: Skin
Disease in Old Age. Philadelphia, JBLippincott, 1987) 
In Raynaud’s disease, wrist pulses
are typically normal but spasm ofmore distal arteries causes episodesImportant Areas of Examination
The Arms
ISize, symmetry, skin color
IRadial pulse, brachial pulse
IEpitrochlear lymph nodes
Assessment of the peripheral vascular system relies primarily on inspection of
the arms and legs, palpation of the pulses, and a search for edema. See Chap-ter 3 for a method of integrating these techniques into your examination of thelimbs. Additional techniques may be useful when you suspect an abnormality.
Arms
Inspect both arms from the ﬁngertips to the shoulders. Note:

Arms
ITheir size, symmetry, and any swelling
IThe venous pattern
IThe color of the skin and nail beds and the texture of the skin
Palpate the radial pulse with the pads
of your ﬁngers on the ﬂexor surfaceof the wrist laterally. Partially ﬂexingthe patient’s wrist may help you feelthis pulse. Compare the pulses inboth arms.
The Legs
IFemoral pulse and inguinal
IPopliteal, dorsalis pedis, and posterior tibial pulses
IPeripheral edema

There are several systems for grading the amplitude of the arterial pulses.
One system is to use a scale of 0 to 4, as below; however, you should checkto see what scale is used in your institution.TECHNIQUES OF EXAMINATION
CHAPTER 14 ITHE PERIPHERAL VASCULAR SYSTEM 451of sharply demarcated pallor of the
ﬁngers (see Table 14-1, Painful Peripheral Vascular Disorders andTheir Mimics, pp. 460–461).
Note that if an artery is widely di-
lated, it is aneurysmal.
Bounding carotid, radial, and
femoral pulses in aortic insufﬁ-ciency; asymmetric diminishedpulses in arterial occlusion fromatherosclerosis or embolism
An enlarged epitrochlear node
may be secondary to a lesion in its drainage area or may be associated with generalized lymphadenopathy.4+ Bounding
3+ Increased
2+ Brisk, expected
1+ Diminished, weaker than expected
0 Absent, unable to palpate
If you suspect arterial insufﬁciency,
feel for the brachial pulse. Flex the

patient’s elbow slightly, and with thethumb of your opposite hand palpatethe artery just medial to the bicepstendon at the antecubital crease. Thebrachial artery can also be felt higherin the arm in the groove between thebiceps and triceps muscles.
Feel for one or more epitrochlear
nodes. With the patient’s elbow ﬂexed
to about 90° and the forearm sup-ported by your hand, reach aroundbehind the arm and feel in the groovebetween the biceps and triceps mus-cles, about 3 cm above the medialepicondyle. If a node is present, noteits size, consistency, and tenderness.
Epitrochlear nodes are difﬁcult or
impossible to identify in most nor-mal people.
Legs

Legs
The patient should be lying down and draped so that the external genitaliaare covered and the legs fully exposed. A good examination is impossiblethrough stockings or socks!
Medial aspect of left arm
Right hand of examiner
Medial epicondyle of humerus

Inspect both legs from the groin and buttocks to the feet. Note:
ITheir size, symmetry, and any
swelling
IThe venous pattern and anyvenous enlargement
IAny pigmentation, rashes,scars, or ulcers
IThe color and texture of theskin, the color of the nailbeds, and the distribution ofhair on the lower legs, feet,and toes.
Palpate the superﬁcial inguinal
nodes, including both the hori-
zontal and the vertical groups.Note their size, consistency, anddiscreteness, and note any ten-derness. Nontender, discrete in-guinal nodes up to 1 cm or even2 cm in diameter are frequentlypalpable in normal people.
Palpate the pulses in order to assess the arterial circulation.
IThe femoral pulse. Press deeply, below the inguinal ligament and about
midway between the anterior superior iliac spine and the symphysis pubis.As in deep abdominal palpation, the use of two hands, one on top of theother, may facilitate this examination, especially in obese patients.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES

452 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Vertical
groupGreat
saphenousveinFemoral veinFemoral artery Horizontal
groupSee Table 14-2, Chronic Insufﬁ-
ciency of Arteries and Veins (p. 462).
See Table 14-3, Common Ulcers of
the Feet and Ankles (p. 463).
Lymphadenopathy refers to enlarge-
ment of the nodes, with or withouttenderness. Try to distinguish be-tween local and generalized lym-phadenopathy, respectively, byﬁnding either (1) a causative lesionin the drainage area, or (2) enlargednodes in at least two other non-contiguous lymph node regions.
A diminished or absent pulse indi-
cates partial or complete occlusionproximally; for example, at theaortic or iliac level, all pulses distalto the occlusion are typically affected. Chronic arterial occlusion,usually from atherosclerosis,causes intermittent claudication,
(pp. 460–461), postural colorchanges (p. 458), and trophicchanges in the skin (p. 462)
An exaggerated, widened femoral

pulse suggests a femoral aneurysm,a pathologic dilatation of the artery.

IThe popliteal pulse. The patient’s knee should be somewhat ﬂexed, the leg
relaxed. Place the ﬁngertips of both hands so that they just meet in themidline behind the knee and press them deeply into the popliteal fossa.The popliteal pulse is often more difﬁcult to ﬁnd than other pulses. It isdeeper and feels more diffuse.TECHNIQUES OF EXAMINATION
CHAPTER 14 ITHE PERIPHERAL VASCULAR SYSTEM 453An exaggerated, widened popliteal
pulse suggests an aneurysm of thepopliteal artery. Neither poplitealnor femoral aneurysms are com-mon. They are usually due to atherosclerosis, and occur primarilyin men over age 50.
Atherosclerosis (arteriosclerosis
obliterans) most commonly ob-structs arterial circulation in thethigh. The femoral pulse is thennormal, the popliteal decreased or absent.
If you cannot feel the popliteal pulse with this approach, try with the patient

prone. Flex the patient’s knee to about 90°, let the lower leg relax againstyour shoulder or upper arm, and press your two thumbs deeply into thepopliteal fossa.

IThe dorsalis pedis pulse. Feel the
dorsum of the foot (not the ankle)just lateral to the extensor tendonof the great toe. If you cannot feela pulse, explore the dorsum of thefoot more laterally.
IThe posterior tibial pulse. Curve
your ﬁngers behind and slightlybelow the medial malleolus of theankle. (This pulse may be hard tofeel in a fat or edematous ankle.)
Tips on feeling difﬁcult pulses: (1) Position your own body and examining
hand comfortably; awkward positions decrease your tactile sensitivity. (2) Pl ace your hand properly and linger there, varying the pressure of your
ﬁngers to pick up a weak pulsation. If unsuccessful, then explore the area de-liberately. (3) Do not confuse the patient’s pulse with your own pulsatingﬁngertips. If you are unsure, count your own heart rate and compare it withthe patient’s. The rates are usually different. Your carotid pulse is convenientfor this comparison.
Note the temperature of the feet and legs with the backs of your ﬁngers. Com-

pare one side with the other. Bilateral coldness is most often due to a coldenvironment or anxiety.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
454 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGThe dorsalis pedis artery may be
congenitally absent or may branchhigher in the ankle. Search for apulse more laterally.
Decreased or absent foot 
pulses (assuming a warm environ-ment) with normal femoral and popliteal pulses suggest occlusive disease in the lowerpopliteal artery or its branches—a pattern often associated with diabetes mellitus.
Sudden arterial occlusion, as by em-
bolism or thrombosis, causes painand numbness or tingling. The limbdistal to the occlusion becomescold, pale, and pulseless. Emergencytreatment is required. If collateralcirculation is good, only numbnessand coolness may result.
Coldness, especially when uni-

lateral or associated with othersigns, suggests arterial insuffi-ciency from inadequate arterialcirculation.

CHAPTER 14 ITHE PERIPHERAL VASCULAR SYSTEM 455
Look for edema. Compare one foot and leg with the other, noting their rel-
ative size and the prominence of veins, tendons, and bones.
Check for pitting edema. Press ﬁrmly but gently with your thumb for at least
5 seconds (1) over the dorsum of each foot, (2) behind each medial malle-olus, and (3) over the shins. Look for pitting —a depression caused by pres-
sure from your thumb. Normally there is none. The severity of edema isgraded on a four-point scale, from slight to very marked.Edema causes swelling that may
obscure the veins, tendons, andbony prominences.
See Table 14-4, Some Peripheral
Causes of Edema (p. 464).
Shown below is 3 +pitting edema.

If you suspect edema, measurement of the legs may help you to identify it and
to follow its course. With a ﬂexible tape, measure (1) the forefoot, (2) thesmallest possible circumference above the ankle, (3) the largest circumfer-ence at the calf, and (4) the midthigh a measured distance above the patellawith the knee extended. Compare one side with the other. A difference ofmore than 1 cm just above the ankle or 2 cm at the calf is unusual in normalpeople and suggests edema.
If edema is present, look for possible causes in the peripheral vascular sys-
tem. These include (1) recent deep venous thrombosis, (2) chronic venousinsufﬁciency due to previous deep venous thrombosis or to incompetenceof the venous valves, and (3) lymphedema. Note the extent of the swelling.How far up the leg does it go?
Is the swelling unilateral or bilateral? Are the veins unusually prominent?
Try to identify any venous tenderness that may accompany deep venous

thrombosis. Palpate the groin just medial to the femoral pulse for tender-ness of the femoral vein. Next, with the patient’s leg ﬂexed at the knee andrelaxed, palpate the calf. With your ﬁngerpads, gently compress the calf mus-cles against the tibia, and search for any tenderness or cords. Deep venousthrombosis, however, may have no demonstrable signs, and diagnosis oftendepends on high clinical suspicion and other testing.
Note the color of the skin.
IIs there a local area of redness? If so, note its temperature, and gently try
to feel the ﬁrm cord of a thrombosed vein in the area. The calf is mostoften involved.
IAre there brownish areas near the ankles?
INote any ulcers in the skin. Where are they?
IFeel the thickness of the skin.
Ask the patient to stand, and inspect the saphenous system for varicosities. The

standing posture allows any varicosities to ﬁll with blood and makes themvisible. You can easily miss them when the patient is in a supine position.Feel for any varicosities, noting any signs of thrombophlebitis.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
456 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGConditions such as muscular 
atrophy can also cause differentcircumferences in the legs.
In deep venous thrombosis, the 
extent of edema suggests the location of the occlusion: the calfwhen the lower leg or the ankle isswollen, the iliofemoral veins whenthe entire leg is swollen.
Venous distention suggests a venous
cause of edema.
A painful, pale swollen leg, together
with tenderness in the groin overthe femoral vein, suggests deepiliofemoral thrombosis. Approxi-
mately half of patients with deep

venous thrombosis in the calf have
tenderness and cords deep in thecalf. Calf tenderness is nonspeciﬁc,however, and may be presentwithout thrombosis.
Local swelling, redness, warmth,
and a subcutaneous cord suggestsuperﬁcial thrombophlebitis.
A brownish color or ulcers just
above the ankle suggest chronicvenous insufﬁciency.
Thickened brawny skin occurs 
in lymphedema and advanced venous insufﬁciency.
Varicose veins are dilated and tor-
tuous. Their walls may feel some-what thickened. Many varicoseveins can be seen in the leg on p. 459.

Release your pressure over the ulnar artery. If the ulnar artery is patent, the
palm ﬂushes within about 3 to 5 seconds.
Patency of the radial artery may be
tested by releasing the radial arterywhile still compressing the ulnar.EXAMPLES OF ABNORMALITIES
Evaluating the Arterial Supply
to the Hand. If you suspect arte-
rial insufﬁciency in the arm or hand,try to feel the ulnar pulse as well as
the radial and brachial pulses. Feelfor it deeply on the ﬂexor surface ofthe wrist medially. Partially ﬂexingthe patient’s wrist may help you. Thepulse of a normal ulnar artery, how-ever, may not be palpable.
The Allen test gives further information. This test is also useful to assure the
patency of the ulnar artery before puncturing the radial artery for blood sam-ples. The patient should rest with hands in lap, palms up.
Ask the patient to make a tight ﬁst with one hand; then compress both ra-

dial and ulnar arteries ﬁrmly between your thumbs and ﬁngers. Next, askthe patient to open the hand into a relaxed, slightly flexed position. Thepalm is pale.
CHAPTER 14 ITHE PERIPHERAL VASCULAR SYSTEM 457Arterial occlusive disease is much
less common in the arms than inthe legs. Absent or diminishedpulses at the wrist in acute embolicocclusion and in Buerger’s disease,
or thromboangiitis obliterans.
Extending the hand fully may
cause pallor and a falsely positivetest.
Persisting pallor indicates occlusion
of the ulnar artery or its distalbranches.

Postural Color Changes of
Chronic Arterial Insufﬁciency.
If pain or diminished pulses suggest
arterial insufﬁciency, look for pos-tural color changes. Raise both legs,as shown at the right, to about 60° until maximal pallor of the feet develops—usually within a minute.In light-skinned persons, either main-tenance of normal color, as seen in
this right foot, or slight pallor isnormal.
Then ask the patient to sit up with
legs dangling down. Compare bothfeet, noting the time required for:
IReturn of pinkness to the skin, nor-mally about 10 seconds or less
IFilling of the veins of the feet andankles, normally about 15 seconds.
This right foot has normal color and
the veins on the foot have ﬁlled.These normal responses suggest anadequate circulation.
Look for any unusual rubor (dusky redness) to replace the pallor of the de-
pendent foot. Rubor may take a minute or more to appear.
Normal responses accompanied by diminished arterial pulses suggest that a

good collateral circulation has developed around an arterial occlusion.
Color changes may be difficult to see in darker-skinned persons. Inspect
the soles of the feet for these changes, and use tangential lighting to seethe veins.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
458 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGThe foot below is still pale and the
veins are just starting to ﬁll—signsof arterial insufﬁciency.
Persisting rubor on dependency
suggests arterial insufﬁciency (seep. 462). When veins are incompe-tent, dependent rubor and thetiming of color return and venousﬁlling are not reliable tests of arte-rial insufﬁciency.Marked pallor on elevation sug-
gests arterial insufﬁciency.
(Source of foot photos: Kappert A, Winsor T: Diagnosis of Peripheral Vascular Disease. Philadelphia, FA
Davis, 1972).

Mapping Varicose Veins. You
can map out the course and connec-tions of varicose veins by transmit-ting pressure waves along the blood-filled veins. With the patient standing,place your palpating fingers gentlyon a vein and, with your other handbelow it, compress the vein sharply.Feel for a pressure wave transmittedto the fingers of your upper hand.A palpable pressure wave indicatesthat the two parts of the vein areconnected.
A wave may also be transmitted
downward, but not as easily.
Evaluating the Competency of Venous Valves. By the retrograde
ﬁlling (Trendelenburg) test, you can assess the valvular competency in both
the communicating veins and the saphenous system. Start with the patientsupine. Elevate one leg to about 90° to empty it of venous blood.
Next, occlude the great saphenous vein in the upper thigh by manual com-

pression, using enough pressure to occlude this vein but not the deeper ves-sels. Ask the patient to stand. While you keep the vein occluded, watch forvenous filling in the leg. Normally the saphenous vein fills from below,taking about 35 seconds as blood flows through the capillary bed into thevenous system.
After the patient has stood for 20 seconds, release the compression and look
for any sudden additional venous ﬁlling. Normally there is none: competentvalves in the saphenous vein block retrograde flow. Slow venous filling continues.
When both steps of this test are normal, the response is termed negative–
negative. Negative–positive and positive–negative responses may also occur.TECHNIQUES OF EXAMINATION
CHAPTER 14 ITHE PERIPHERAL VASCULAR SYSTEM 459Rapid filling of the superficial

veins while the saphenous vein isoccluded indicates incompetentvalves in the communicating veins.Blood ﬂows quickly in a retrogradedirection from the deep to thesaphenous system.
Sudden additional ﬁlling of super-
ﬁcial veins after release of compres-sion indicates incompetent valvesin the saphenous vein.
When both steps are abnormal,
the test is positive–positive.
Feel for a
pressure wave
Compress sharply

TABLE 14-1 IPainful Peripheral Vascular Disorders and Their Mimics
460 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Problem Process Location of Pain
Arterial Disorders
Atherosclerosis
(arteriosclerosis obliterans)
IRest pain
Acute Arterial Occlusion
Raynaud’s Disease 
and Phenomenon
Venous Disorders
Superﬁcial Thrombophlebitis
Deep Venous ThrombosisChronic Venous 
Insufﬁciency (deep)
Thromboangiitis
Obliterans (Buerger’s
disease)
Acute Lymphangitis
Mimics*
Acute Cellulitis
Erythema NodosumEpisodic muscular ischemia induced by exercise,
due to obstruction of large or middle-sized arteriesby atherosclerosis
Ischemia even at rest
Embolism or thrombosis, possibly superimposed
on arteriosclerosis obliterans
Raynaud’s disease: Episodic spasm of the small
arteries and arterioles; no vascular occlusion.Raynaud’s phenomenon: Syndrome is secondary to

other conditions such as collagen vascular disease,arterial occlusion, trauma, drugs
Clot formation and acute inflammation in a
superficial vein
Clot formation in a deep vein
Chronic venous engorgement secondary to venous
occlusion or incompetency of venous valves
Inﬂammatory and thrombotic occlusions of small
arteries and also of veins, occurring in smokers
Acute bacterial infection (usually streptococcal)
spreading up the lymphatic channels from a portalof entry such as an injured area or an ulcer
Acute bacterial infection of the skin and
subcutaneous tissues
Subcutaneous inﬂammatory lesions associated with
a variety of systemic conditions such as pregnancy,sarcoidosis, tuberculosis, and streptococcal infectionsUsually the calf, but also may be in the

buttock, hip, thigh, or foot, depending onthe level of obstruction
Distal pain, in the toes or forefoot
Distal pain, usually involving the foot 
and leg
Distal portions of one or more ﬁngers.
Pain is usually not prominent unlessﬁngertip ulcers develop. Numbness andtingling are common.
Pain in a local area along the course of a
superﬁcial vein, most often in thesaphenous system
Pain, if present, is usually in the calf, but
the process more often is painless.
Diffuse aching of the leg(s)
IIntermittent claudication, particularly in
the arch of the foot
IRest pain in the ﬁngers or toes
An arm or a leg
Arms, legs, or elsewhere
Anterior surfaces of both lower legs
* Mistaken primarily for acute superﬁcial thrombophlebitis.

CHAPTER 14 ITHE PERIPHERAL VASCULAR SYSTEM 461Factors That
Timing Aggravate Factors That Relieve Associated Manifestations
Fairly brief; pain usually
forces the patient to rest.
Persistent, often worse at
night
Sudden onset; associated
symptoms may occurwithout pain.
Relatively brief (minutes)
but recurrent
An acute episode lasting
days or longer
Often hard to determine
because of lack ofsymptoms
Chronic, increasing as the
day wears on
IFairly brief but recurrent
IChronic, persistent, maybe worse at night
Pain associated with a series
of lesions over several weeksExercise such as walking
Elevation of the feet, as 
in bed
Exposure to cold,
emotional upset
Prolonged standing
IExerciseRest usually stops the pain
in 1–3 min.
Sitting with legs dependent
Warm environment
Elevation of the leg(s)
IRest
IPermanent cessation of

in 1–3 min.
IRest
smoking helps both kindsof pain (but patientsseldom stop)Local fatigue, numbness, diminished
pulses, often signs of arterialinsufﬁciency (see p. 462)
Numbness, tingling, trophic signs and
color changes of arterial insufﬁciency(see p. 462)
Coldness, numbness, weakness,
absent distal pulses
Color changes in the distal ﬁngers:
severe pallor (essential for thediagnosis) followed by cyanosis andthen redness
Local redness, swelling, tenderness, 
a palpable cord, possibly fever
Possibly swelling of the foot and calf
and local calf tenderness; oftennothing
Chronic edema, pigmentation,
possibly ulceration (see pp. 462, 463)
Distal coldness, sweating, numbness,
and cyanosis; ulceration and gangreneat the tips of ﬁngers or toes;migratory thrombophlebitis
Red streak(s) on the skin, with

tenderness, enlarged, tender lymphnodes, and fever
A local area of diffuse swelling,
redness, and tenderness withenlarged, tender lymph nodes andfever; no palpable cord
Raised, red, tender swellings recurring
in crops; often malaise, joint pains,and fever

TABLE 14-2 IChronic Insufﬁciency of Arteries and Veins
462 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Chronic Arterial Insufﬁciency (Advanced) Chronic Venous Insufﬁciency (Advanced)
Pain
PulsesColor
Temperature
Edema
Skin Changes
Ulceration
GangreneIntermittent claudication, progressing to pain at rest
Decreased or absentPale, especially on elevation; dusky red on dependency
Cool
Absent or mild; may develop as the patient tries to relieve rest
pain by lowering the leg
Trophic changes: thin, shiny, atrophic skin; loss of hair over the
foot and toes; nails thickened and ridged
If present, involves toes or points of trauma on feet
May developNone to an aching pain on dependency
Normal, though may be difﬁcult to feel through edemaNormal, or cyanotic on dependency. Petechiae and then
brown pigmentation appear with chronicity.
NormalPresent, often marked
Often brown pigmentation around the ankle, stasis

dermatitis, and possible thickening of the skin and narrowingof the leg as scarring develops
If present, develops at sides of ankle, especially mediallyDoes not develop
(Sources of photos: Arterial Insufﬁciency —Kappert A, Winsor T: Diagnosis of Peripheral Vascular Disease. Philadelphia, FA Davis, 1972; Venous Insufﬁciency —Marks R: Skin Disease
in Old Age. Philadelphia, JB Lippincott, 1987)

TABLE 14-3 ICommon Ulcers of the Feet and Ankles
CHAPTER 14 ITHE PERIPHERAL VASCULAR SYSTEM 463
Arterial Insufﬁciency Chronic Venous Insufﬁciency Neuropathic Ulcer
Location
Skin Around
the Ulcer
Pain
Associated
Gangrene
SignsToes, feet, or possibly in areas of
trauma (e.g., the shin)
No callus or excess of pigment; may
be atrophic
Often severe, unless neuropathy
masks it
May be present
Decreased pulses, trophic changes,
pallor of the foot on elevation, duskyrubor on dependencyInner or sometimes outer ankle
Pigmented, sometimes ﬁbrotic
Not severeAbsentEdema, pigmentation, stasis
dermatitis, and possibly cyanosis ofthe foot on dependencyPressure points in areas with
diminished sensation, as in diabeticpolyneuropathy
Calloused
Absent (and therefore the ulcer may
go unnoticed)
In uncomplicated neuropathic ulcer,
absent
Decreased sensation, absent ankle
jerks

Calloused
absent
jerks
(Source of photos: Marks R: Skin Disease in Old Age. Philadelphia, JB Lippincott, 1987)

TABLE 14-4 ISome Peripheral Causes of Edema
464 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
About one third of total body water is extracellular, or outside the body’s cells.
About 25% of extracellular ﬂuid is plasma and the remainder is interstitial ﬂuid. Atthe arteriolar end of the capillaries, hydrostatic pressure in the blood vessels and the
colloid oncotic pressure in the interstitium cause ﬂuid to move into the tissues; at
the venous end of the capillaries and in the lymphatics, hydrostatic pressure in theinterstitium and the colloid oncotic pressure of plasma proteins cause ﬂuid to re-
turn to the vascular compartment. A number of clinical conditions disrupt this bal-ance, resulting in edema, or a clinically evident accumulation of interstitial ﬂuid.
Not depicted below is capillary leak syndrome, where protein leaks into the inter-stitial space, seen in burns, angioedema, snake bites, and allergic reactions.
Chronic Venous

Pitting Edema Insufﬁciency Lymphedema
Nature of Edema
Skin Thickening
UlcerationPigmentationEdema of FootBilateralityExamples/
MechanismsSoft, pits on pressure
Absent
AbsentAbsentPresentAlways↑Interstitial ﬂuid from: legs dependent
from prolonged standing or sitting →↑
hydrostatic pressure in veins, capillaries;congestive heart failure →↓cardiac
output, ↑hydrostatic pressure in veins,
capillaries; nephrotic syndrome, cirrhosis,malnutrition →low albumin, ↓intra-
vascular colloid oncotic pressure; drugsSoft, pits on pressure; later may become
brawny (hard)
May be present, especially near ankleCommonCommonOften presentOccasionallyChronic obstruction or valvular
incompetence of the deep veinsSoft in early stages, then becomes
indurated, hard, nonpitting

Becomes markedRareAbsentPresent, including toesOftenLymph channels obstructed by tumor,
ﬁbrosis, inﬂammation; also from axillarynode dissection, radiation
Pitting
Swollen foot
AdvancedPitting
Pigment
Ulcer
No pitting
Skin thick
Foot swollen

The Musculoskeletal SystemCHAPTER
The Musculoskeletal System 1515
CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 465
This section reviews the structure and function of the major joints and
their connecting bony structures, muscles, and soft tissues. To lay thefoundation for skilled assessment of the musculoskeletal system, it is essen-tial for you to learn both the surface landmarks and underlying anatomy ofeach of the major joints. Anatomy and Physiology follows a “head to toe”
sequence, beginning with the jaw and joints of the upper extremities, thenproceeding to the spine and hip and the joints of the lower extremities. Foreach joint there are subsections on Overview, Bony Structures and Joints,
andMuscle Groups and Additional Structures. The Overview should help

orient you to the distinguishing anatomic and functional features of eachjoint. As you study Anatomy and Physiology, practice identifying the im-portant surface landmarks on yourself or a fellow student. Then turn toTechniques of Examination, also “head to toe,” to learn the fundamental
steps for examining the joints—inspection; palpation of bony landmarksand soft-tissue structures; assessment of range of motion, or the directionsof joint movement; and maneuvers to test joint function.
It is helpful to begin by reviewing some anatomic terminology. Articular
structures include the joint capsule and articular cartilage, the synovium and
synovial ﬂuid, intra-articular ligaments, and juxta-articular bone. Nonartic-
ular structures include periarticular ligaments, tendons, bursae, muscle, fas-

cia, bone, nerve, and overlying skin. You will need to visualize and assess allthese structures to care for your patients with joint complaints. Note thatligaments are ropelike bundles of collagen ﬁbrils that connect bone to bone.
Tendons are collagen fibers connecting muscle to bone. Another type of
collagen matrix forms the cartilage that overlies bony surfaces. Bursae are
pouches of synovial ﬂuid that cushion the movement of tendons and mus-cles over bone or other joint structures.
Structure and Function of Joints
To understand joint function, begin by reviewing the various types of joints
and how they articulate, or interconnect, and the role of bursae in easingjoint movement.
C1
72
5T1
L1123
4
56
72
3
4
2
3
45
6
8
9
10
11Cervical
curve
Thoracic
curve
Lumbar
curve
Sacral
curve

Types of Joints. There are three primary types of joint articulation—
synovial, cartilaginous, and fibrous—allowing varying degrees of jointmovement.
In synovial joints, the bones do not
touch each other, and the joint artic-ulations are freely moveable. The
bones are covered by articular car-
tilage and separated by a synovial
cavity that cushions joint movement,
as shown. A synovial membrane lines
the synovial cavity and secretes asmall amount of viscous lubricatingfluid—the synovial fluid. The mem-
brane is attached at the margins ofthe articular cartilage and pouchedor folded to accommodate jointmovement. Surrounding the synovialmembrane is a ﬁbrous joint capsule,
which is strengthened by ligamentsextending from bone to bone.
Cartilaginous joints, such as those
between vertebrae and the symphysispubis, are slightly moveable. Fibro-
cartilaginous discs separate the bonysurfaces. At the center of each discis the nucleus pulposus, ﬁbrocartilag-
inous m aterial that serves as a cushion

or shock absorber between bonysurfaces.
In fibrous joints, such as the sutures
of the skull, intervening layers of fibrous tissue or cartilage hold thebones together. The bones are almostin direct contact, which allows no
appreciable movement.ANATOMY AND PHYSIOLOGY
466 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGType of Joint Extent of Movement Example
Synovial Freely movable Knee, shoulder
Cartilaginous Slightly movable Vertebral bodies of the spine
Fibrous Immovable Skull sutures
Synovial
membrane
Articular
cartilage
Synovial
cavity
LigamentBone
Joint
capsuleJointspace
LigamentDiscVertebral
bodyNucleus pulposusof the disc
FIBROUSCARTILAGINOUSSYNOVIAL

As you learn about the examination of the musculoskeletal system, think
about how the anatomy of the joint relates to its movement. Many of thejoints we examine are synovial, or movable, joints. The shape of the articu-
lating surfaces of synovial joints determines the type of motion in the joint.Spheroidal joints have a ball-and-socket conﬁguration—a rounded convex
surface articulating with a cuplike cavity, allowing a wide range of rotatorymovement as in the shoulder and hip. Hinge joints are ﬂat, planar, or slightly
curved, allowing a gliding motion in one plane only, as in ﬂexion and exten-sion of the digits. In condylar joints, such as the knee, the articulating surfaces
are convex or concave, and referred to as condyles.
Bursae. Easing joint action are bursae, roughly disc-shaped synovial sacs

that allow adjacent muscles or muscles and tendons to glide over each otherduring movement. They lie between the skin and the convex surface of abone or joint (as in the prepatellar bursa of the knee, p. 481) or in areaswhere tendons or muscles rub against bone, ligaments, or other tendons ormuscles (as in the subacromial bursa of the shoulder, p. 472).
Knowledge of the underlying joint anatomy and movement will help you
assess joi nts subjected to trauma. Your knowledge of the soft-tissue struc-
tures, ligaments, tendons, and bursae will help you evaluate the changes ofaging, as well as arthritis.
Temporomandibular Joint
Overview, Bony Structures, and Joints. The temporomandibular
joint is the most active joint in the body, opening and closing up to 2000times a day. It is formed by the fossa and articular tubercle of the temporal

CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 467Type of Joint Articular Shape Movement Example
Spheroidal 
(ball and socket)
Hinge
CondylarConvex surface in
concave cavity
Flat, planarConvex or concaveWide-ranging ﬂexion,
extension, abduction,adduction, rotation,circumduction
Motion in one plane;
ﬂexion, extension
Movement of two
articulating surfacesnot dissociableShoulder, hip
Interphalangeal
joints of hand andfoot; elbow
Knee; temporo-
mandibular jointSynovial JointsSPHEROIDAL JOINT
(BALL AND SOCKET)
HINGE JOINT
CONDYLAR JOINT

bone and the condyle of the man-
dible. It lies midway between theexternal acoustic meatus and thezygomatic arch.
A ﬁbrocartilaginous disc cushions the
action of the condyle of the mandibleagainst the synovial membrane andcapsule of the articulating surfacesof the temporal bone. Hence, it is acondylar synovial joint.
Muscle Groups and Additional
Structures. The principal mus-
cles opening the mouth are the ex-
ternal pterygoids. Closing the mouth
are the muscles innervated by CranialNerve V, the trigeminal nerve (seep. 538)—the masseter, the tempo-
ralis, and the internal pterygoids.ANATOMY AND PHYSIOLOGY
468 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Articular tubercleExternal acoustic meatusTemporal bone
Condyle of mandibleArticular discZygomatic arch
Articular disc of
temporomandibular jointTemporalis (cut)
External pterygoid
Internal pterygoid
Masseter (cut)

The Shoulder
Overview. The shoulder is distinguished by wide-ranging movement in
all directions. The humerus virtually dangles from the scapula, suspendedfrom the shallow glenoid fossa by the joint capsule, the intra-articular cap-sular ligaments, the glenoid labrum, and a meshwork of muscles and ten-dons. The shoulder derives its mobility from a complex interconnectedstructure of four joints, three large bones, and three principal musclegroups, often referred to as the shoulder girdle. The clavicle and acromion
stabilize the shoulder girdle, allowing the humerus to swing out and awayfrom the body, giving the shoulder its remarkable range of motion.
Bony Structures. The bony structures of the shoulder include the
humerus, the clavicle, and the scapula. The scapula is anchored to the axialskeleton only by the sternoclavicular joint and inserting muscles, often calledthe scapulothoracic articulation since it is not a true joint.

CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 469AcromionAcromioclavicular joint
Greater tubercle
Bicipital groove
Lesser tubercle
Scapula
(anterior surface)Coracoid process
Clavicle
Sternoclavicular joint
ManubriumGlenoid fossa
Humerus
Glenohumeral joint
Identify the manubrium, the sternoclavicular joint, and the clavicle. With
your ﬁngers, trace the clavicle laterally. Now, from behind, follow the bonyspine of the scapula laterally and upward until it becomes the acromion, the
summit of the shoulder. Its upper surface is rough and slightly convex. Iden-tify the anterior tip of the acromion ( A) and mark it with ink. With your
index ﬁnger on top of the acromion, just behind its tip, press medially to ﬁnd

the slightly elevated ridge that marks the distal end of the clavicle at the
acromioclavicular joint (shown by the arrow). Move your ﬁnger laterally and
down a short step to the next bony prominence, the greater tubercle of the
humerus (B).Mark this with ink. Now sweep your ﬁnger medially until you
feel a large bony prominence, the coracoid process of the scapula ( C). Mark
this also. These three points—the tip of the acromion, the greater tubercleof the humerus, and the coracoid process—orient you to the anatomy of theshoulder.
Joints. Three different joints articulate at the shoulder:
IThe glenohumeral joint. In this joint, the head of the humerus articulates
with the shallow glenoid fossa of the scapula. This joint is deeply situatedand not normally palpable. It is a ball-and-socket joint, allowing the armits wide arc of movement—ﬂexion, extension, abduction (movementaway from the trunk), adduction (movement toward the trunk), rotation,and circumduction.

IThe sternoclavicular joint. The convex medial end of the clavicle articu-
lates with the concave hollow in the upper sternum.
IThe acromioclavicular joint. The lateral end of the clavicle articulates with
the acromion process of the scapula.
Muscle Groups. Three groups of muscles attach at the shoulder:
The Scapulohumeral Group.
This group extends from the scapulato the humerus and includes the mus-cles inserting directly on the humerus,known as “SITS muscles” of the rota-
tor cuff:
ISupraspinatus— runs above the gle-
nohumeral joint; inserts on thegreater tubercle
IInfraspinatus and teres minor —
cross the glenohumeral joint poste-riorly; insert on the greater tubercle
ISubscapularis (not illustrated)—
originates on the anterior surfaceof the scapula and crosses the jointanteriorly; inserts on the lessertubercle.ANATOMY AND PHYSIOLOGY
470 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
A
BC
Axioscapular group (pulls shoulder backward)

A
BC
Scapulohumeral group (rotates shoulder laterally; includes rotator cuff)Latissimus
dorsiRhomboids
Trapezius
Infraspinatus
DeltoidLevator 
scapulae
Teres
minor
Posterior viewAxioscapular group
Scapulohumeral
group
Supraspinatus

The scapulohumeral group rotates the
shoulder laterally (the rotator cuff )and depresses and rotates the head ofthe humerus. (See pp. 526–527 fordiscussion of rotator cuff injuries.)
The Axioscapular Group.
This group attaches the trunk to thescapula and includes the trapezius,rhomboids, serratus anterior, andlevator scapulae. These muscles rotatethe scapula.
The Axiohumeral Group.
This gr oup attaches the trunk to
the humerus and includes the pec-
toralis major and minor and the latis-simus dorsi. These muscles produceinternal rotation of the shoulder.
The biceps and triceps, which connect the scapula to the bones of the
forearm, are also involved in shoulder movement, particularly abduction.
Additional Structures. Also important to shoulder movement are the
articular capsule and bursae. Surrounding the glenohumeral joint is a ﬁbrous

articular capsule formed by the tendon insertions of the rotator cuff andother capsular muscles. The loose ﬁt of the capsule allows the shoulder bonesto separate, and contributes to the shoulder’s wide range of movement. Thecapsule is lined by a synovial membrane with two outpouchings—the sub-scapular bursa and the synovial sheath of the tendon of the long head of thebiceps.
To locate the biceps tendon, rotate the arm externally and ﬁnd the tendinous
cord that runs just medial to the greater tubercle. Roll it under your ﬁngers.This is the tendon of the long head of the biceps. It runs in the bicipital groove
between the greater and lesser tubercles.
The principal bursa of the shoulder is the subacromial bursa, positioned

between the acromion and the head of the humerus and overlying the supra-spinatus tendon. Abduction of the shoulder compresses this bursa. Normally,the supraspinatus tendon and the subacromial bursa are not palpable. How-ever, if the bursal surfaces are inﬂamed (subacromial bursitis), there may betenderness just below the tip of the acromion, pain with abduction and rota-tion, and loss of smooth movement.
The Elbow
Overview, Bony Structures, and Joints. The elbow helps position
the hand in space and stabilizes the lever action of the forearm. The elbow
CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 471
Axiohumeral group (rotates shoulder internally)Latissimus
dorsiPectoralis
minorPectoralis
major
Anterior view

AcromionCoracoid process
Supraspinatus tendon
Greater tubercleSubacromial bursa
Long head of
biceps tendonLesser tubercleSupraspinatus
joint is formed by the humerus and the two bones of the forearm, the radius
and the ulna. Identify the medial and lateral epicondyles of the humerus andthe olecranon process of the ulna.
These bones have three articulations:
the humeroulnar joint , the radio-
humeral joint , and the radioulnar
joint. All three share a large common
articular cavity and an extensive syno-vial lining.
Structures. Muscles traversing the
elbow include the biceps and brachio-
radialis (ﬂexion), the triceps (exten-
sion), the pronator teres (pronation),
and the supinator (supination).ANATOMY AND PHYSIOLOGY
472 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGHumerus
Medial epicondyle
Humeroulnar joint
Radioulnar joint
Brachioradialis
RadiusSupinator
Pronator teresLateral epicondyle
Radiohumeral joint
Ulna
LEFT ELBOW—ANTERIOR VIEW

Note the location of the olecranon
bursa between the olecranon process
and the skin. The bursa is not nor-mally palpable but swells and becomestender when inflamed. The ulnar
nerve runs posteriorly between the
medial epicondyle and the olecranonprocess. On the ventral forearm, themedian nerve is just medial to the
brachial artery.
The Wrist and Hands
Overview. The wrist and hands form a complex unit of small, highly
active joints used almost continuously during waking hours. There is littleprotection from overlying soft tissue, increasing vulnerability to traumaand disability.
Bony Structures. The wrist in-
cludes the distal radius and ulna andeight small carpal bones. At the wrist,identify the bony tips of the radiusand the ulna.
The carpal bones lie distal to the wrist
joint within each hand. Identify thecarpal bones, each of the ﬁve meta-carpals, and the proximal, middle,and distal phalanges. Note that thethumb lacks a middle phalanx.
Joints. The numerous joints of

the wrist and hand lend unusual dex-terity to the hands.
IWrist joints. The wrist joints in-
clude the radiocarpal or wrist joint ,
the distal radioulnar joint , and
the intercarpal joints . The joint
capsule, articular disc, and synovialmembrane of the wrist join theradius to the ulna and to the prox-imal carpal bones. On the dorsum
of the wrist, locate the groove ofthe radiocarpal joint.
CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 473
Radial nerveSynovial
membrane(distended)Olecranon
bursaOlecranon process
Medial epicondyleUlnar nerve
Radius UlnaScaphoidTrapeziumProximal
interphalangeal
joint (PIP)
Metacarpophalangeal
joint (MCP)Distal
joint (DIP)
LunateTriquetrumHamateCapitate
Trapezoid
Radio-
carpaljointIntercarpal joints
Distal radioulnar jointLEFT ELBOW—POSTERIOR VIEW

IHand joints. The joints of the
hand include the metacarpopha-
langeal joints (MCPs), the proxi-
mal interphalangeal joints (PIPs),
and the distal interphalangeal joints
(DIPs). Flex the hand and ﬁnd thegroove marking the MCP jointof each finger. It is distal to theknuckle and is best felt on eitherside of the extensor tendon.
Muscle Groups. Wrist ﬂexion arises from the two carpal muscles, located
on the radial and ulnar surfaces. Two radial and one ulnar muscle providewrist extension. Supination and pronation result from muscle contraction inthe forearm.
The thumb is powered by three muscles that form the thenar eminence and
provide ﬂexion, abduction, and opposition. The muscles of extension areat the base of the thumb along the radial margin. Movement in the digitsdepends on action of the ﬂexor and extensor tendons of muscles in the fore-arm and wrist.
The intrinsic muscles of the hand attaching to the metacarpal bones are

involved in ﬂexion ( lumbricals ), abduction ( dorsal interossei ), and adduction
(palmar interossei ) of the ﬁngers.
Additional Structures. Soft-tissue structures, especially tendons and
tendon sheaths, are extremely important in the wrist and hand. Six extensortendons and two ﬂexor tendons pass across the wrist and hand to insert onthe ﬁngers. Through much of their course these tendons travel in tunnel-like sheaths, generally palpable only when swollen or inﬂamed.
Be familiar with the structures in the
carpal tunnel, a channel beneath the
palmar surface of the wrist and prox-imal hand. The canal contains thesheath and ﬂexor tendons of the fore-arm muscles and the median nerve.
Holding the tendons and tendon
sheath in place is a transverse liga-ment, the flexor retinaculum. The

median nerve lies between the ﬂexorretinaculum and the tendon sheath.It provides sensation to the palmand the palmar surface of most of thethumb, the second and third digits,and half of the fourth digit. It alsoinnervates the thumb muscles of ﬂex-ion, abduction, and opposition.ANATOMY AND PHYSIOLOGY
474 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Metacarpo-
phalangealjoint
Carpal tunnel
Median nerveFlexor retinaculum

The Spine
Overview. The vertebral column, or spine, is the central supporting struc-
ture of the trunk and back. Note the concave curves of the cervical and lum-
bar spine and the convex curves of the thoracic and sacrococcygeal spine.
These curves help distribute upper body weight to the pelvis and lower ex-tremities and cushion the concussive impact of walking or running.
The complex mechanics of the back
reﬂect the coordinated action of:
IThe vertebrae and intervertebraldiscs
IAn interconnecting system of liga-ments between anterior vertebraeand posterior vertebrae, ligamentsbetween the spinous processes, andligaments between the lamina oftwo adjacent vertebrae
ILarge superﬁcial muscles, deeperintrinsic muscles, and muscles ofthe abdominal wall.
Viewing the patient from behind,
identify the following landmarks:
1. Spinous processes, usually more
prominent at C7 and T1 and moreevident on forward ﬂexion
2. Paravertebral muscles on either
side of the midline

3. Scapulae4. Iliac crests5. Posterior superior iliac spines, usu-
ally marked by skin dimples. 
A line drawn above the posterior iliac
crests crosses the spinous process of L4.
CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 475C1
72
5T1
L1123
4
56
72
3
4
2
3
45
6
8
9
10
curve
Thoracic
curve
Lumbar
curve
Sacral
curve
Paravertebral
muscles
Spinous process
of L4
Iliac crestPosterior 
Sacroiliac joint
Ischial 
tuberosityand site of ischial bursaSciatic nerve

Intervertebral foramen
Superior articular proces s
Inferior articular process
T12
L1Vertebral
foramen
PedicleLaminaSuperior articular
process
Transverse process
Spinous processTransverse processSuperior articular process
C4
C5Spinous
process
Vertebral
bodyTransverseforamenVertebral
foramen
PedicleVertebral archLamina
Superior articular facet
Bony Structures. The vertebral column contains 24 vertebrae stacked on
the sacrum and coccyx. A typical vertebra contains sites for joint articulations,weight bearing, and muscle attachments, as well as foramina for the spinalnerve roots and peripheral nerves.Anteriorly, the vertebral body sup-
ports weight bearing. The pos-terior vertebral arch encloses the
spinal cord. Review the location ofthe vertebral processes and foram-ina, with particular attention to:
IThe spinous process projecting
posteriorly in the midline andthe two transverse processes at the junction of the pedicle and

the lamina. Muscles attach at
these processes.
IThe articular processes —two on
each side of the vertebra, onefacing up and one facing down,at the junction of the pediclesand laminae, often called artic-
ular facets
IThe vertebral foramen, which
encloses the spinal cord, theintervertebral foramen, formed
by the inferior and superior ar-ticulating process of adjacentvertebrae, creating a channelfor the spinal nerve roots; andin the cervical vertebrae, thetransverse foramen for the ver-
tebral artery.
The proximity of the spinal cord
and spinal nerve roots to theirbony vertebral casing  and theintervertebral discs makes themespecially vulnerable to disc herni-ation, impingement from degener-ative changes in the vertebrae, andtrauma.
Joints. The spine has slightly

movable cartilaginous joints be-tween the vertebral bodies and between the articular facets. Be-tween the vertebral bodies are theintervertebral discs, each consistingANATOMY AND PHYSIOLOGY
476 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGREPRESENTATIVE CERVICAL AND LUMBAR VERTEBRAE
C4–5 Coronal and Lateral Views
T12–L1 Coronal and Lateral Views

Trapezius
(neck extension;
overlies small
intrinsic neck
muscles of neck
extension, rotation)
Latissimus dorsiDeltoidSternocleidomastoid
(neck flexion, rotation)
Teres minor
Teres majorSplenius capitis
(neck extension)
Spinous process T12
Iliac crestExternal abdominal oblique
Gluteus maximusof a soft mucoid central core, the nucleus pulposus , rimmed by the tough
fibrous tissue of the annulus ﬁbrosis . The intervertebral discs cushion move-
ment between vertebrae and allow the vertebral column to curve, ﬂex, andbend. The ﬂexibility of the spine is largely determined by the angle of thearticular facet joints relative to the plane of the vertebral body, and varies atdifferent levels of the spine. Note that the vertebral column angles sharplyposterior at the lumbosacral junction and becomes immovable. The mechan-
ical stress at this angulation contributes to the risk of disc herniation and sub-luxation, or slippage, of L5 on S1.
Muscle Groups. The trapezius

and latissimus dorsi form the large
outer layer of muscles attaching toeach side of the spine. They overlietwo deeper muscle layers—a layerattaching to the head, neck, andspinous processes ( splenius capitis,
splenius cervicis, and sacrospinalis )
and a layer of smaller intrinsic mus-cles between vertebrae. Muscles at-taching to the anterior surface of thevertebrae, including the psoas muscle
and muscles of the abdominal wall,assist with ﬂexion.
Muscles moving the neck and lower
vertebral column are summarizedbelow.ANATOMY AND PHYSIOLOGY
CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 477Movement Principal Muscle Group 
Cervical Spine (neck)
Flexion Sternocleidomastoid, scalene, and prevertebral muscles

Extension Splenius, trapezius, small intrinsic neck musclesRotation Sternocleidomastoid, small intrinsic neck musclesLateral bending Scalene and small intrinsic neck muscles
Lumbar Spine
Flexion Psoas major, psoas minor, quadratus lumborum;
abdominal muscles such as the internal and externalobliques and rectus abdominis, attaching to theanterior vertebrae
Extension Intrinsic muscles of the back, sacrospinalisRotation Abdominal muscles, intrinsic muscles of the backLateral bending Abdominal muscles, intrinsic muscles of the back

The Hip
Overview. The hip joint is deeply embedded in the pelvis, and is notable
for its strength, stability, and wide range of motion. The stability of the hipjoint, so essential for weight bearing, arises from the deep ﬁt of the head ofthe femur into the acetabulum , its strong ﬁbrous articular capsule, and the
powerful muscles crossing the joint and inserting below the femoral head,providing leverage for movement of the femur.
Bony Structures and Joints. The hip joint lies below the middle third
of the inguinal ligament but in a deeper plane. It is a ball-and-socket joint—note how the rounded head of the femur articulates with the cuplike cavityof the acetabulum. Because of its overlying muscles and depth, it is not read-ily palpable. Review the bones of the pelvis—the acetabulum , the ilium , and
the ischium —and the connection inferiorly at the symphysis pubis and poste-
riorly with the sacroiliac bone.
On the anterior aspect of the hip,
identify the iliac crest at the upper

margin of the pelvis at the level ofL4. Follow the downward anteriorcurve and locate the iliac tubercle,
marking the widest point of thecrest, and continue tracking down-ward to the anterior superior iliac
spine. Place your thumbs on the an-
terior superior spines and move yourﬁngers downward from the iliac tu-bercles to the greater trochanter of
the femur. Then move your thumbsmedially and obliquely to the pubic
symphysis, which lies at the same level
as the greater trochanter.
On the posterior aspect of the hip,
locate the posterior superior iliac
spine directly underneath the visible
dimples just above the buttocks.Placing your left thumb and indexfinger over the posterior superioriliac spine, next locate the greater
trochanter laterally with your ﬁngers

at the level of the gluteal fold andplace your thumb medially on theischial tuberosity. The sacroiliac joint
is not palpable. Note that an imag-inary line between the posterior su-perior iliac spines crosses the jointat S2.
478 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Wing of ilium
Pubic symphysisIschium Ischial bursaTrochanteric 
bursaGreater trochanter
(femur)Anterior superior
AcetabulumIliac crest
Iliac tubercle
Psoas bursa
Ischial bursa Ischial tuberosityGreater
trochanter(femur)Iliac crest
Sacroiliac
joint
SacrumSpinous process
Trochanteric
bursaPosteriorsuperioriliac spine
POSTERIOR VIEWANTERIOR VIEW

Muscle Groups. Four powerful
muscle groups move the hip. To re-member these groups, try to picturewhere muscles need to cross jointsto move limbs such as the femur ina given direction. The flexor group
lies anteriorly and flexes the thigh.The primary hip flexor is the iliop-
soas, extending from above the iliac
crest to the lesser trochanter. The ex-
tensor group lies posteriorly and ex-
tends the thigh. The gluteus maximus
is the primary extensor of the hip. Itforms a band crossing from its originalong the medial pelvis to its inser-tion below the trochanter.
The adductor group is medial and
swings the thigh toward the body.The muscles in this group arise fromthe rami of the pubis and ischiumand insert on the posteromedial aspect of the femur. The abductor
group is lateral, extending from the
iliac crest to the head of the femur,and moves the thigh away from thebody. This group includes the gluteus
medius and minimus. These muscles

help stabilize the pelvis during thestance phase of gait.
Additional Structures. A strong dense articular capsule, extending
from the acetabulum to the femoral neck, encases and strengthens the hipjoint, reinforced by three overlying ligaments and lined with synovial mem-brane. There are three principal bursae at the hip. Anterior to the joint is theiliopectineal (or iliopsoas ) bursa, overlying the articular capsule and the psoas
muscle. Find the bony prominence lateral to the hip joint—the greater
trochanter of the femur. The large multilocular trochanteric bursa lies on its
posterior surface. The ischiogluteal bursa —not always present—lies under
the ischeal tuberosity, on which a person sits. Note their proximity to the
sciatic nerve, as shown on p. 475.
The Knee

The Knee
Overview. The knee joint is the largest joint in the body. It involves three
bones: the femur, the tibia, and the patella (or knee cap), with three articu-lar surfaces, two between the femur and the tibia and one between the femur
CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 479
Iliopsoas
Gluteus
maximus
ADDUCTOR GROUP ABDUCTOR GROUPEXTENSOR GROUP
FLEXOR GROUP

Adductor tubercle
Medial epicondyleFemur
Lateral epicondyle
Lateral collateral
ligament
Anterior cruciate
ligament
Lateral meniscus
Lateral condyle 
of tibia
Head of fibula
FibulaMedial meniscus
Medial condyle 
of tibia
Medial collateral
ligament
Tibia
Tibial tuberosityPosterior cruciate
ligamentand the patella. Note how the two rounded condyles of the femur rest on the
relatively ﬂat tibial plateau. There is no inherent stability in the knee jointitself, m aking it dependent on ligaments to hold its articulating bones in place.
This feature, in addition to the lever action of the femur on the tibia and lackof padding from fat or muscle, makes the knee highly vulnerable to injury.
Bony Structures. Landmarks in and around the knee will orient you to
this complicated joint. Bring your ﬁngertips ﬁrmly down the medial surfaceof the thigh along a line analogous to the inner seam of a pant leg. Your ﬁn-gers will run up against an abrupt bony prominence, the adductor tubercle.

Just below this is the medial epicondyle. The lateral epicondyle is comparably
situated on the other side.ANATOMY AND PHYSIOLOGY
480 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGIdentify the ﬂat medial surface of the tibia—the shin. Follow its anterior bor-der upward to the tibial tuberosity (A). Mark this point with a dot of ink. Now
follow the medial border of the tibia upward until it merges into a bonyprominence—the medial condyle of the tibia ( B). This is somewhat higher
than the tibial tuberosity. In a comparable location on the other side of theknee, ﬁnd a similar prominence—the lateral condyle (C). Mark both condyles
with ink. These three points form an isosceles triangle. On the lateral surfaceof the knee, somewhat below the level of the lateral tibial condyle, ﬁnd thehead of the ﬁbula.
The patella rests on the anterior articulating surface of the femur, midway

Femur
Medial
meniscus
TibiaMedial
collateralligamentSemimembranosus 
bursa (synovial cavity distended)Suprapatellar
pouch
FibulaTibial
tuberosityQuadriceps 
femoris
Patella
Patellar
tendonPrepatella 
bursa
CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 481Sartorius
SemimembranosusSemitendinosusInner hamstring muscles
Gracilis
Vastus medialisRectus femorisQuadriceps femoris
Vastus lateralis
LATERAL VIEW ANTERIOR VIEWJoints. Two condylar tibiofemoral
joints are formed by the convex curves
of the medial and lateral condylesof the femur as they articulate withthe concave condyles of the tibia.The third articular surface is thepatellofemoral joint. The patella slides
in a groove on the anterior aspect ofthe distal femur, called the trochlear
groove, during ﬂexion and extension
of the knee.
With the knee ﬂexed about 90°, you

can press your thumbs—one on eachside of the patellar tendon—into thegroove of the tibiofemoral joint. Notethat the patella lies just above thisjoint line. As you press your thumbsdownward, you can feel the edge ofthe tibial plateau, the upper surfaceof the tibia. Follow it medially, thenlaterally until you are stopped by theconverging femur and tibia. By mov-ing your thumbs upward toward themidline to the top of the patella, youcan follow the articulating surface ofthe femur and identify the marginsof the joint.
Muscle Groups. Powerful muscles move and support the knee. The
quadriceps femoris extends the leg, covering the anterior, medial, and lateral
aspects of the thigh. The hamstring muscles lie on the posterior aspect of the
thigh and ﬂex the knee.LEFT KNEE—MEDIAL VIEW

Additional Structures. Two important pairs of ligaments, the collat-
eral ligaments and the cruciate ligaments, and the menisci provide stabilityto the knee (see drawing on pp. 480 and 481).
IThe medial collateral ligament (MCL), not easily palpable, is a broad ﬂat
ligament connecting the medial condyles of the femur and the tibia. Tolocate the anatomic region of the MCL, move your ﬁngers medially andposteriorly along the joint line, then palpate along the ligament from itsorigin to insertion.
IThe lateral collateral ligament (LCL) connects the lateral femoral condyle
and the head of the ﬁbula. To feel the LCL, cross one leg so the ankle restson the opposite knee and find the firm cord that runs from the lateralepicondyle of the femur to the head of the fibula. The MCL and LCLprovide medial and lateral stability to the knee.
IThe anterior cruciate ligament (ACL) crosses obliquely from the lateral

femoral condyle to the medial tibia, preventing the tibia from slidingforward on the femur.
IThe posterior cruciate ligament (PCL) crosses from the lateral tibia and
lateral meniscus to the medial femoral condyle, preventing the tibia fromslipping backward on the femur. Since these ligaments lie within the kneejoint, they are not palpable. They are nonetheless crucial to the antero-posterior stability of the knee.
IThe medial and lateral menisci cushion the action of the femur on the tibia.
These crescent-shaped ﬁbrocartilaginous discs add a cuplike surface to theotherwise ﬂat tibial plateau. Palpate the medial meniscus by pressing on the
medial soft-tissue depression along the upper edge of the tibial plateau.Place the knee in slight ﬂexion and palpate the lateral meniscus along the
lateral joint line.
Observe the concavities that are usually evident at each side of the patella

and also above it. Occupying these areas is the synovial cavity of the knee,the largest joint cavity in the body. This cavity includes an extension 6 centi-meters above the upper border of the patella, lying upward and deep to thequadriceps muscle—the suprapatellar pouch. The joint cavity covers the
anterior, medial, and lateral surfaces of the knee, as well as the condylesof the femur and tibia posteriorly. Although the synovium is not normallydetectable, these areas may become swollen and tender when the joint isinflamed.
Several bursae lie near the knee. The prepatellar bursa lies between the
patella and the overlying skin. The anserine bursa lies 1 to 2 inches below
the knee joint on the medial surface and cannot be palpated due to over-lying tendons. Now identify the large semimembranosus bursa that com-

municates with the joint cavity, also on the posterior and medial surfacesof the knee.ANATOMY AND PHYSIOLOGY
482 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING

The Ankle and Foot
Overview. The total weight of the body is transmitted through the ankle
to the foot. The ankle and foot must balance the body and absorb the impactof the heel strike and gait. Despite thick padding along the toes, sole, andheel and stabilizing ligaments at the ankles, the ankle and foot are frequentsites of sprain and bony injury.
Bony Structures and Joints.
The ankle is a hinge joint formedby the tibia, the ﬁbula, and the talus.
The tibia and fibula act as a mortise,stabilizing the joint while bracingthe talus like an inverted cup.
The principal joints of the ankle are
the tibiotalar joint , between the tibia
and the talus, and the subtalar (talo-
calcaneal) joint .
Note the principal landmarks of the
ankle: the medial malleolus, the bony
prominence at the distal end of thetibia, and the lateral malleolus, at
the distal end of the fibula. Lodgedunder the talus and jutting posteri-orly is the calcaneus, or heel.

An imaginary line, the longitudinal arch, spans the foot, extending from the
calcaneus of the hind foot along the tarsal bones of the midfoot (seecuneiforms, navicular, and cuboid bones below) to the forefoot metatarsalsand toes. The heads of the metatarsals are palpable in the ball of the foot. In
the forefoot, identify the metatarsophalangeal joints, proximal to the webs
of the toes, and the proximal and distal interphalangeal joints of the toes.
Structures. Movement at the
ankle joint is limited to dorsiﬂexionand plantar ﬂexion. Plantar ﬂexion is
powered by the gastrocnemius, theposterior tibial muscle, and the toeﬂexors. Their tendons run behindthe malleoli. The dorsiﬂexors include

the anterior tibial muscle and the toeextensors. They lie prominently onthe anterior surface, or dorsum, ofthe ankle, anterior to the malleoli.
Ligaments extend from each mal-
leolus onto the foot. Medially, thetriangle-shaped deltoid ligament fans
CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 483
Lateral
malleolus
Posterior
talofibularligamentAnterior
talofibular ligament
Calcanofibular
ligament
DistalphalanxProximal 
phalanxTransverse tarsal joint
First metatarsal
Metatarsophalangeal 
joint
CuboidNavicular bone
Cuneiforms
Achilles
tendon
Subtalar
joint
CalcaneusMedial malleolus
Tibiotalar joint
Deltoid ligament
Longitudinal
arch
Hindfoot Midfoot Forefoot
MEDIAL VIEW
LATERAL VIEW

out from the inferior surface of the medial malleolus to the talus and proxi-
mal tarsal bones, protecting against stress from eversion (ankle bows inward).The three ligaments on the lateral side are less substantial, with higher risk ofinjury: the anterior taloﬁbular ligament —most at risk in injury from inver-
sion (ankle bows outward) injuries; the calcaneoﬁbular ligament ; and the
posterior taloﬁbular ligament . The strong Achilles tendon inserts on the heel
posteriorly.
Musculoskeletal changes continue through the adult years. Soon after ma-turity adults begin to lose height subtly, and signiﬁcant shortening becomesobvious in old age. Most loss of height occurs in the trunk as intervertebraldiscs become thinner and the vertebral bodies shorten or even collapse be-cause of osteoporosis. Flexion at the knees and hips may contribute to short-ened stature. The limbs of an elderly person thus tend to look long inproportion to the trunk.

The alterations in discs and vertebrae contribute too to the kyphosis of aging
and increase the anteroposterior diameter of the chest, especially in women.
With aging, skeletal muscles decrease in bulk and power, and ligaments lose
some of their tensile strength. Range of motion diminishes, partly becauseof osteoarthritis.
484 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGCommon or Concerning Symptoms
ILow back pain
INeck pain
IMonoarticular or polyarticular joint pain
IInﬂammatory or infectious joint pain
IJoint pain with systemic features such as fever, chills, rash, anorexia,
weight loss, weakness
IJoint pain with symptoms from other organ systems
Joint pain is a common complaint of patients seeking health care. The health
history is especially important in guiding you to the correct assessment.
You may wish to begin with “Any pains in your back?” since backache is the

most common and widespread disorder of the musculoskeletal system. Usingyour usual interviewing style, get a clear picture of the problem, especially itsSee Table 15-1, Low Back Pain, 
p. 522.

location. Establish whether the pain is on midline, in the area of the vertebrae,
or off the midline. If the pain radiates into the legs, ask about any associatednumbness, tingling, or weakness.
Neck pain is also common, especially after trauma. Approach it in the same
manner. For both neck and back pain, be especially alert for symptoms suchas weakness, loss of sensation, or loss of bladder or bowel function.
To pursue other musculoskeletal disorders, ask “Do you have any pains in
your joints?” If yes, you will need to determine whether the pain is localized
or widespread, acute or chronic, inﬂammatory or noninﬂammatory.
Joint pain may be localized, diffuse, or systemic. Ask the patient to point
to the pain. If the joint pain is localized and involves only one joint, it is
monoarticular. Pain originating in the small joints of the hands and feet is

more sharply localized than that from the larger joints. Pain from the hipjoint is especially deceptive. Although it is typically felt in the groin or but-tock, it is sometimes felt in the anterior thigh or partly or solely in the knee.
More diffuse joint pain may be polyarticular, involving several joints. Ask
whether the pain involves one joint or several joints. If polyarticular, what isthe pattern of involvement . . . migrating from joint to joint or steadilyspreading from one joint to multiple joint involvement? Is the involvementsymmetric, affecting similar joints on both sides of the body?
Note that joint pain may also be nonarticular, involving bones, muscles, and
tissues around the joint such as the tendons, bursae, or even overlying skin.Generalized “aches and pains” are called myalgias if in muscles and arthral-

giasif there is pain but no evidence of arthritis.
Assess the timing, quality, and severity of the joint symptoms. Timing is es-
pecially important. Did the pain or discomfort develop rapidly over the courseof a few hours or insidiously over weeks or even months? Has the pain pro-gressed slowly or ﬂuctuated, with periods of improvement and worsening?How long has the pain lasted? What is it like over the course of a day? . . .In the morning? . . . As the day wears on?
If more rapid in onset, how did the pain arise? Was there an acute injury or
overuse from repetitive motion of the same part of the body? If the paincomes from trauma, what was the mechanism of injury or the series of events
that caused the joint pain? Further, what aggravates or relieves the pain?What are the effects of exercise, rest, and treatment?THE HEALTH HISTORY

CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 485Causes of midline back pain include
musculoskeletal strain, vertebralcollapse, disc herniation, or spinalcord metastases. Pain off the mid-line may arise from sacroiliitis,trochanteric bursitis, sciatica, orarthritis in the hips.
See Table 15-2, Pains in the Neck,
p. 523.
Motor or sensory deﬁcits, loss of
bladder or bowel function in spinalcord compression at S2–S4
Pain in one joint suggests trauma,
monoarticular arthritis, possibletendinitis, or bursitis. Hip pain nearthe greater trochanter suggeststrochanteric bursitis.
Migratory pattern of spread in
rheumatic fever or gonococcalarthritis; progressive additive pat-tern with symmetric involvementtypically in rheumatoid arthritis
Problems in tissues around joints
include inﬂammation of bursae(bursitis ), tendons ( tendinitis ), or

tendon sheaths ( tenosynovitis ); also
sprains from stretching or tearing
of ligaments
Severe pain of rapid onset in a
swollen joint in the absence oftrauma seen in acute septic arthritisor gout. In children consider osteo-myelitis in bone contiguous to ajoint.
See Table 15-3, Patterns of Pain In
and Around the Joints, pp. 524–525.EXAMPLES OF ABNORMALITIES

Try to determine if the problem is inﬂammatory or noninﬂammatory. Is
there tenderness, warmth, or redness? These features are best assessed on ex-
amination, but patients can sometimes guide you to points of tenderness.Ask about systemic symptoms such as fever or chills.
Additional symptoms can help you decide if the pain is articular in origin,
such as swelling, stiffness, or decreased range of motion. Localize any swelling
as accurately as possible. If stiffness is present, it may be difﬁcult to assess be-

cause people use the term differently. In the context of musculoskeletalproblems, stiffness refers to a perceived tightness or resistance to movement,the opposite of feeling limber. It is often associated with discomfort or pain.If the patient does not report stiffness spontaneously, ask about it and try tocalculate its duration. Find out when the patient gets up in the morning andwhen the joints feel the most limber. Healthy people experience stiffness andmuscular soreness after unusually strenuous muscular exertion; such symp-toms tend to peak around the second day after exertion.
To assess limitations of motion, ask about changes in level of activity because

of problems with the involved joint. When relevant, inquire speciﬁcallyabout the patient’s ability to walk, stand, lean over, sit, sit up, rise from a sit-ting position, climb, pinch, grasp, turn a page, open a door handle or jar,and care for bodily needs such as combing hair, brushing teeth, eating,dressing, and bathing.
Finally, some joint problems have systemic features such as fever, chills, rash,
anorexia, weight loss, and weakness.
Other joint disorders may be linked to organ systems outside the musculo-
skeletal system. Symptoms elsewhere in the body can give important clues to
these conditions. Be alert to such symptoms as:
ISkin conditions
A butterﬂy rash on the cheeksThe scaly rash and pitted nails of psoriasisA few papules, pustules, or vesicles on reddened bases, located on the
distal extremities
An expanding erythematous patch early in an illnessHives

Erosions or scale on the penis and crusted scaling papules on the soles and
palmsTHE HEALTH HISTORY
486 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGFever, chills, warmth, redness in
septic arthritis; also consider goutor possible rheumatic fever
Pain, swelling, loss of active 
and passive motion, “locking,” deformity in articular joint pain; loss
of active but not passive motion,tenderness outside the joint, absence of deformity often innonarticular pain
Stiffness and limited motion after
inactivity, sometimes called gelling,
in degenerative joint disease butusually lasts only a few minutes;stiffness lasting ≥30 minutes in
rheumatoid arthritis and other in-ﬂammatory arthritides Stiffnessalso with ﬁbromyalgia and
polymyalgia rheumatica (PMR)
Generalized symptoms are com-
mon in rheumatoid arthritis, sys-
temic lupus erythematosus (SLE),PMR, and other inﬂammatory

arthritides. High fever and chillssuggest an infectious cause.
Systemic lupus erythematosus
Psoriatic arthritisGonococcal arthritis
Lyme disease
Serum sickness, drug reactionReiter’s syndrome, which also 
includes arthritis, urethritis, andureitisEXAMPLES OF ABNORMALITIES

The maculopapular rash of rubella
Clubbing of the ﬁngernails (see p. 110)
IRed, burning, and itchy eyes ( conjunctivitis )
IPreceding sore throat
IDiarrhea, abdominal pain, cramping
ISymptoms of urethritis
IMental status change, facial or other weakness, stiff neck.HEALTH PROMOTION AND COUNSELING
CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 487Arthritis of rubella
Hypertrophic osteoarthropathyReiter’s syndrome, Behçet’s 
syndrome
Acute rheumatic fever or gonococ-
cal arthritis
Arthritis with ulcerative colitis, re-
gional enteritis, scleroderma
Reiter’s syndrome or possibly
gonococcal arthritis
Lyme disease with central nervous
system involvement
IBalanced nutrition, exercise, appropriate weight
ILifting and the biomechanics of the back
IRisk factor screening and prevention of falls
ICounseling about prevention and treatment of osteoporosis

Maintaining the integrity of the musculoskeletal system brings many features
of daily life into play—balanced nutrition, regular exercise, appropriateweight. As shown in this chapter, each joint has its speciﬁc vulnerabilities totrauma and wear. Care with lifting, avoidance of falls, household safety mea-sures, and, for selected postmenopausal women, hormone replacement ther-apy help to protect and preserve well-functioning muscles and joints.
The habits of a healthy lifestyle convey direct beneﬁt to the skeleton. Good

nutrition supplies calcium needed for bone mineralization and bone density.Exercise appears to maintain and possibly increase bone mass, in addition toimproving outlook and management of stress. Weight appropriate to heightand body frame reduces excess mechanical wear on weight-bearing joints suchas hips and knees. (For further discussion of these topics, see pp. 59–62.)
One of the most vulnerable parts of the skeleton is the low back, especially
L5–S1, where the sacral vertebrae make a sharp posterior angle. More than80% of the population experiences low back pain at least once in a lifetime.Usually symptoms are short lived, but there is a pattern of recurrence in 30%EXAMPLES OF ABNORMALITIES

to 60% of individuals when onset is work related. Exercises to strengthen the
low back, especially in flexion and extension, are often recommended (al-though studies have not consistently demonstrated a reduction in sick daysfrom work). Alternatively, general ﬁtness exercises appear equally effective.Education on lifting strategies, posture, and the biomechanics of injury isprudent for patients doing repetitive lifting such as nurses, heavy-machineryoperators, and construction workers.
Among elderly persons in the United States, falls exact a heavy toil in mor-
bidity and mortality. They are the leading cause of nonfatal injuries andaccount for a dramatic rise in death rates after age 65, increasing from

~5/100,000 in the general population to ~10/100,000 between the agesof 65 and 74 to ~147/100,000 after age 85.* Approximately 5% of fallsresult in fractures, usually of the wrist, hip, pelvis, or femur. Risk factors areboth cognitive and physiological, including unstable gait, imbalanced pos-ture, reduced strength, cognitive loss as in dementia, deficits in vision andproprioception, and osteoporosis. Poor lighting, stairs, chairs at awkwardheights, slippery or irregular surfaces, and ill-ﬁtting shoes are environmen-tal dangers that can often be corrected. Clinicians should work with patientsand families to help modify such risks whenever possible. Medications affect-ing balance, especially benzodiazepines, vasodilators, and diuretics, shouldbe scrutinized. Home health assessments have proven useful in reducingenvironmental hazards, as have exercise programs to improve patient balanceand strength.
Finally, it is important to counsel selected postmenopausal women about hor-

mone replacement therapy and osteoporosis, deﬁned as bone density >2.5standard deviations below normal bone mass in young women.
†Bone density
reﬂects the interaction between bone mass (highest in the second decade),new bone formation, and bone resorption. A 10% drop in bone mineral den-sity, equivalent to one standard deviation, is associated with a 20% increase inrisk of fracture. Most fractures in patients over age 45 are attributable to post-menopausal osteoporosis. The decline in bone mass begins in the third decadeand then accelerates in early menopause, especially in the trabecular bone ofthe vertebrae. At highest risk are women of Caucasian origin, slender build,or prior history of bilateral oophorectomy before menopause.
A number of agents inhibit bone resorption—calcium, vitamin D, calcitonin,

bisphosphonates, and estrogen—but consensus on several clinical manage-ment decisions has yet to emerge. Criteria are unclear for identifying thosewomen at menopause at greatest risk of bone loss and fractures one to twodecades later. In addition, guidelines for tailoring dosage of medication tolevel of bone density have yet to be determined. Estrogen therapy appearsto prevent vertebral trabecular bone resorption, and is most beneﬁcial whenstarted near menopause. Lifetime use is recommended because bone lossHEALTH PROMOTION AND COUNSELING
488 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING*U.S. Preventive Services Task Force: “Counseling to Prevent Household and Recreational Injuries,”
In Guide to Clinical Preventive Services. Baltimore, Williams & Wilkins, pp. 659–685, 1996.
†U.S. Preventive Services Task Force: In Guide to Clinical Preventive Services. Baltimore, Williams &

Wilkins,  pp. 509–516, 1996.

resumes once therapy is discontinued. Although hormone replacement pro-
tects against osteoporosis and possibly cardiovascular disease, use of estro-gen must be weighed carefully in each patient against risk of breast cancer,endometrial cancer (risk is decreased by progesterone), and thrombosis.Cognitive, environmental, and other physiologic risk factors for falls andfractures should also be addressed.HEALTH PROMOTION AND COUNSELING
CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 489Suggests osteoarthritis
Suggests partial tear of medial
meniscus and ACL, possibly fromsports injury or traumaPreview: Recording the Examination—
The Musculoskeletal System
The examples below contain phrases appropriate for most write-ups. 
Unfamiliar terms are explained in the next section, Techniques of Examination.
Note that use of the anatomic terms speciﬁc to the structure and function ofindividual joint problems makes your write-up of musculoskeletal ﬁndingsmore meaningful and informative.

“Good range of motion in all joints. No evidence of swelling or 
deformity.”
OR“Good range of motion in all joints. Hand with degenerative changes of
Heberden’s nodes at the distal interphalangeal joints, Bouchard’s nodesat proximal interphalangeal joints. Mild pain with ﬂexion, extension,and rotation of both hips. Good range of motion in the knees, withmoderate crepitus; no effusion but boggy synovium and osteophytesalong the tibiofemoral joint line bilaterally. Both feet with hallux valgusat the ﬁrst metatarsophalangeal joints.”
OR“Right knee with moderate effusion and tenderness over medial meniscus

along the joint line. Moderate laxity of anterior cruciate ligament (ACL)on anterior drawer test; posterior cruciate ligament (PCL) and medialand lateral collateral ligaments (MCL, LCL) intact—no posterior drawersign or tenderness with varus or valgus stress. Patellar tendon intact—patient able to extend lower extremity. All other joints with good rangeof motion, no other deformity or swelling.”EXAMPLES OF ABNORMALITIES

490 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGAcute involvement of only one
joint suggests trauma, septicarthritis, gout. Rheumatoid arthri-tis typically involves several joints,symmetrically distributed.
Dupuytren’s contracture (p. 531),
bowlegs or knock-knees (p. 779)
Subcutaneous nodules in rheuma-
toid arthritis or rheumatic fever; effusions in trauma; crepitus overinﬂamed joints, in osteoarthritis, orinﬂamed tendon sheathsImportant Areas of Examination for Each of the Major Joints
IInspection for joint symmetry, alignment, bony deformities
IInspection and palpation of surrounding tissues for skin changes, nodules,muscle atrophy, crepitus
IRange of motion and maneuvers to test joint function and stability, integrity of ligaments, tendons, bursae, especially if pain or trauma
IAssessment of inﬂammation or arthritis, especially swelling, warmth,tenderness, redness

As you examine the musculoskeletal system, direct your attention to func-
tion as well as structure. During the interview you have evaluated the pa-tient’s ability to carry out normal activities of daily living. Keep these abilitiesin mind during your physical examination.
In your initial survey of the patient you have assessed general appearance,
body proportions, and ease of movement. Now, as you apply techniquesof examination to the musculoskeletal system, visualize the underlyinganatomy and recall the key elements of the history—for example, the mech-anism of injury if there is trauma, or the time course of symptoms and limi-tations in function in arthritis.
Your examination should be systematic. It should include inspection, palpation

of bony landmarks as well as related joint and soft-tissue structures, assessmentof range of motion, and special maneuvers to test speciﬁc movements. These
steps are described for each of the major joints. Recall that the anatomic shapeof each joint determines its range of motion. This range is greatest in synovialor ball-and-socket joints.
Remember the following clues to guide your examination.
IDuring inspection, it is especially important to note symmetry of involve-
ment. Is there a symmetric change in joints on both sides of the body, oris the change only in one or two joints? 
Also note any joint deformities or malalignment of bones.
IUse inspection and palpation to assess the surrounding tissues, noting skin
changes, subcutaneous nodules, and muscle atrophy. Note any crepitus,

an audible and/or palpable crunching during movement of tendons orligaments over bone. This may occur in normal joints but is more signif-icant when associated with symptoms or signs.

Decreased range of motion in
arthritis, inﬂammation of tissuesaround a joint, ﬁbrosis in or arounda joint, or bony ﬁxation ( ankylosis ).
Ligamentous laxity of the ACL inknee trauma
Muscle atrophy or weakness in
Palpable bogginess or doughiness
of the synovial membrane indi-cates synovitis, which is often accompanied by effusion. Palpa-ble joint fluid in effusion, tender-ness over the tendon sheaths intendinitis
Arthritis, tendinitis, bursitis, 
osteomyelitis
Tenderness and warmth over a
thickened synovium may suggestarthritis or infection.
Redness over a tender joint sug-
gests septic or gouty arthritis, orpossibly rheumatoid arthritis.
Swelling, tenderness, and decreased
range of motion suggest an in-ﬂamed joint.EXAMPLES OF ABNORMALITIES
ITesting range of motion and maneuvers (described for each joint) may
demonstrate limitations in range of motion or increased mobility and
joint instability from excess mobility of joint ligaments, called ligamen-
tous laxity.

IFinally, testing muscle strength may aid in the assessment of joint function
(for these techniques, see Chap. 16).
Be especially alert to signs of inﬂammation and arthritis.
ISwelling. Palpable swelling may involve: (1) the synovial membrane,
which can feel boggy or doughy; (2) effusion from excess synovial ﬂuidwithin the joint space; or (3) soft-tissue structures such as bursae, tendons,and tendon sheaths.
IWarmth. Use the backs of your ﬁngers to compare the involved joint with
its unaffected contralateral joint, or with nearby tissues if both joints areinvolved.
ITenderness. Try to identify the speciﬁc anatomic structure that is tender.
Trauma may also cause tenderness.
IRedness. Redness of the overlying skin is the least common sign of 
inflammation near the joints.

If the person has painful joints, move the person gently. Patients may move
more comfortably by themselves. Let them show you how they manage. Ifjoint trauma is present, consider an x-ray before attempting movement.
The detail needed for examining the musculoskeletal system may vary widely.
This section presents examination techniques for both comprehensive and tar-geted assessment of joint function. Patients with extensive or severe musculo-skeletal problems will require more time. A briefer survey for those withoutmusculoskeletal symptoms is outlined in Chapter 3 (see p. 69).
The Temporomandibular Joint (TMJ)
Inspect the joint for swelling or redness. Swelling may appear as a roundedbulge about 1 inch anterior to the external auditory meatus.
CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 491

Dislocation of the TMJ may be seen
in trauma.
Swelling, tenderness, and de-
creased range of motion suggestarthritis.
Palpable crepitus or clicking may
occur in poor occlusion, meniscusinjury, or synovial swelling fromtrauma.
Muscle atrophy points to lesions 
in the cervical nerves.
Scoliosis may cause elevation 
of one shoulder. With anterior dislocation of the shoulder, the rounded lateral aspect of the shoulder appears flattened.
With posterior dislocation of 
the shoulder (relatively rare), theanterior aspect of the shoulder isﬂattened and the humeral headappears more prominent.
A signiﬁcant amount of synovial
ﬂuid is needed before the jointcapsule appears distended.To locate and palpate the joint, place
the tips of your index fingers just infront of the tragus of each ear andask the patient to open his or hermouth. The ﬁngertips should drop

into the joint spaces as the mouthopens. Check for smooth range ofmotion; note any swelling or tender-ness. Snapping or clicking may befelt or heard in normal people.
RANGE OF MOTION
AND MANEUVERS
The temporomandibular joint has glide and hinge motions in its upper and
lower portions, respectively. Grinding or chewing consists primarily of glid-ing movements in the upper compartments.
Range of motion is three-fold: ask the patient to demonstrate opening and
closing, protrusion and retraction (by jutting the jaw forward), and lateral,or side-to-side, motion. Normally as the mouth is opened wide, three ﬁn-gers can be inserted between incisors. During normal protrusion of the jaw,the bottom teeth can be placed in front of the upper teeth.

Observe the shoulder and shoulder girdle anteriorly, and inspect the scapu-lae and related muscles posteriorly. Note any swelling, deformity, or muscleatrophy or fasciculations (ﬁne tremors of the muscles).
Look for swelling of the joint capsule anteriorly or a bulge in the subacro-
mial bursa under the deltoid muscle. Survey the entire upper extremity forcolor change, skin alteration, or abnormal positioning.
492 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGAcromionCoracoid process
Glenoid
fossa
Humerus
ANTERIOR DISLOCATION 
OF HUMERUS

See Table 15-4, Painful Shoulders
(pp. 526–527). 
Inability to perform these move-
ments may reﬂect weakness orsoft-tissue changes from bursitis,capsulitis, rotator cuff tears orsprains, or tendinitis.EXAMPLES OF ABNORMALITIES
PALPATION
If there is a history of shoulder pain, ask the patient to point to the painful
area. The location of the pain may provide clues as to its origin:
ITop of the shoulder, radiating toward the neck—acromioclavicular joint
ILateral aspect of the shoulder, radiating toward the deltoid insertion—rotator cuff
IAnterior shoulder—bicipital tendon
Now identify the bony landmarks of the shoulder and then palpate the area
of pain. Locate the acromion process and press medially to locate the distal
tip of the clavicle at the acromioclavicular joint. Palpate laterally and down
a short step to the greater tubercle of the humerus, and then press mediallyto locate the coracoid process of the scapula. Next palpate the painful area and
identify the structures involved.

RANGE OF MOTION AND MANEUVERS
The six motions of the shoulder girdle are flexion, extension, abduction,adduction, and internal and external rotation.TECHNIQUES OF EXAMINATION
CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 493
Watch for smooth, ﬂuid movement as you stand in front of the patient and
ask the patient to (1) raise ( abduct ) the arms to shoulder level (90°) with
palms facing down (tests pure glenohumeral motion); (2) raise the arms toa vertical position above the head with the palms facing each other (testsscapulothoracic motion for 60°, and combined glenohumeral and scapulo-thoracic motion during adduction for the final 30°; (3) place both handsbehind the neck, with elbows out to the side (tests external rotation and
abduction ); and (4) place both hands behind the small of the back (tests

internal rotation and adduction ). (Placing your hand on the shoulder during
these movements allows you to detect any crepitus.)

The examination of the shoulder often requires selective evaluation of the
acromioclavicular joint, the subacromial and subdeltoid bursae, the rotatorcuff, the bicipital groove and tendon, and the articular capsule and synovialmembrane of the glenohumeral joint. Techniques for examining these struc-tures are described on following pages.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
494 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGLocalized tenderness or pain with
adduction suggests inflammation orarthritis of the acromioclavicular joint.See Table 15-4, Painful Shoulders(pp. 526–527).
Localized tenderness arises from
subacromial or subdeltoid bursitis,degenerative changes or calciﬁcdeposits in the rotator cuff.
Swelling suggests a bursal tear with
communication into the articularcavity.
Tenderness over the “SITS” muscle

insertions and inability to lift the armabove shoulder level are seen insprains, tears, and tendon rupture ofthe rotator cuff, most commonly thesupraspinatus. See Table 15-4, Painful
Shoulders (pp. 526–527).Structure Techniques for Examining the Shoulder
Acromioclavicular Joint
Subacromial and 
Subdeltoid Bursae
Rotator CuffPalpate and compare both joints for swelling or tenderness.
Adduct the patient’s arm across the chest, sometimes calledthe “crossover test. ”
Passively extend
the shoulder bylifting the elbowposteriorly. Thisexposes thebursae anteriorto the acromion.
Palpate carefully
over the sub-acromial andsubdeltoidbursae.
With the patient’s arm hanging at the side, palpate the three
“SITS” muscles that insert on the greater tuberosity of thehumerus. (The fourth muscle, the subscapularis, insertsanteriorly and is not palpable.)

ISupraspinatus—directly under the acromion
IInfraspinatus—posterior to supraspinatus
ITeres minor—posterior and inferior to the supraspinatus
Passively extend the
shoulder by liftingthe elbowposteriorly. Thismaneuver alsomoves the rotatorcuff out fromunder theacromion. Palpatethe rounded SITSmuscle insertionsnear the greatertuberosity of thehumerus.
Subacromial bursa
Rotator cuff

CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 495If the patient is unable to hold the arm
fully abducted at shoulder level, the“drop arm” test is positive, indicatinga tear in the rotator cuff.
See also Bicipital Tendinitis in Table 15-4
Painful Shoulders (pp. 526–527).
Tenderness or pain against resistance
occurs with tenosynovitis of thebicipital tendon sheath, tendinitis, orbiceps tendon rupture.
Tenderness and effusion suggest synovitis
of the glenohumeral joint. If themargins of the capsule and synovialmembrane are palpable, a moderate tolarge effusion is present. Minimaldegrees of synovitis at the glenohumeraljoint cannot be detected on palpation.Structure Techniques for Examining the Shoulder
Bicipital Groove 
and Tendon
Articular Capsule, 
Synovial Membrane, and Glenohumeral JointCheck the “drop-arm” sign. Ask the patient to fully abduct

and Tendon
the arm to shoulder level (or up to 90°) and lower itslowly. (Note that abduction above shoulder level, from90° to 120°, reﬂects action of the deltoid muscle.)
Rotate the arm 
and forearmexternally andlocate the bicepsmuscle distally near the elbow.Track the muscleand its tendonproximally into the bicipital groove along theanterior aspect of the humerus. As you check for tendontenderness, rolling the tendonunder the ﬁngertipsmay be helpful.
Finally, hold the patient’s elbow against the body with the
forearm ﬂexed at a right angle. Ask the patient tosupinate the forearm against resistance.
The ﬁbrous articular capsule and the broad ﬂat tendons of the

rotator cuff are so closely associated that they must beexamined simultaneously. Swelling in the capsule andsynovial membrane is often best detected by looking downon the shoulder from above. Palpate the capsule and synovialmembrane beneath the anterior and posterior acromion.
The following maneuvers test individual muscles of the shoulder girdle and
help localize pain. Note that medial rotation against resistance also tests the pec-toralis major, teres major, and latissimus dorsi. Additional evaluation of musclestrength, sensation over the neck, shoulder, and arm, and upper extremity re-ﬂexes is often warranted to complete your assessment (see pp. 573–575).
Supraspinatus: Patient abducts
against resistance.Subscapularis: Patient rotates forearm
medially against resistance. PALPATION OF THE 
BICIPITAL GROOVE AND TENDON

496 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGThe Elbow
Support the patient’s forearm with
your opposite hand so the elbow isflexed to about 70°. Identify the me-dial and lateral epicondyles and theolecranon process of the ulna. Inspectthe contours of the elbow, includ-ing the extensor surface of the ulnaand the olecranon process. Note anynodules or swelling.
Palpate the olecranon process and press on the epicondyles for tenderness.
Note any displacement of the olecranon.
Palpate the grooves between the epicondyles and the olecranon, noting any
tenderness, swelling, or thickening. The synovium is most accessible to ex-amination between the olecranon and the epicondyles. (Normally neithersynovium nor bursa is palpable.) The sensitive ulnar nerve can be felt poste-riorly between the olecranon process and the medial epicondyle.

Range of motion includes ﬂexion and extension at the elbow and pronation
and supination of the forearm. To test ﬂexion and extension, ask the patient
to bend and straighten the elbow.
See Table 15-5, Swollen or Tender
Elbows (p. 528).
Swelling over the olecranon
process in olecranon bursitis; in-ﬂammation or synovial ﬂuid inarthritis.
Tenderness in lateral epicondylitis
(tennis elbow) and in medial 
epicondylitis (pitcher’s or golfer’s
elbow)
The olecranon is displaced 
posteriorly in posterior dislocation
of the elbow and supracondylar
fracture .Infraspinatus, teres minor: Patient rotates 
forearm laterally against resistance.Thoracohumeral group: Patient adducts 
forearm against resistance.
POSTERIOR DISLOCATION OF THE ELBOW

With the patient’s arms at the sides and elbows ﬂexed to minimize shoulder
movement, ask the patient supinate , or turn up the palms, and to pronate ,
or turn down the palms.
The Wrist and Hand
Observe the position of the hands in motion to see if movements are smooth
and natural. At rest the ﬁngers should be slightly ﬂexed and aligned almostin parallel.
Inspect the palmar and dorsal surfaces of the wrist and hand carefully for
swelling over the joints.
Note any deformities of the wrist, hand, or ﬁnger bones, as well as any angu-
lation from radial or ulnar deviation.
Observe the contours of the palm, namely the thenar and hypothenar 
eminences.
Note any thickening of the flexor tendons or flexion contractures in the
fingers.
PALPATION

fingers.
PALPATION
At the wrist, palpate the distal radiusand ulna on the lateral and medialsurfaces. Palpate the groove of eachwrist joint with your thumbs on thedorsum of the wrist, your ﬁngers be-neath it. Note any swelling, boggi-ness, or tenderness.
CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 497Guarded movement suggests 
injury. Poor ﬁnger alignment isseen in ﬂexor tendon damage.
Diffuse swelling in arthritis or infec-
tion; localized swelling or gangliafrom cystic enlargement. See Table15-6, Swellings and Deformities ofthe Hands (pp. 529–531).
In osteoarthritis, Heberden’s nodes
at the DIP joints, Bouchard’s nodesat the PIP joints. In rheumatoidarthritis, symmetric deformity inthe PIP, MCP, and wrist joints, withulnar deviation
Thenar atrophy in median nerve

compression from carpal tunnelsyndrome; hypothenar atrophy inulnar nerve compression.
Flexion contractures in the ring,
5th and 3rd ﬁngers, or Dupuytren’s
contractures , arise from thickening
of the palmar fascia (see p. 531).
Tenderness over the distal radius in
Colles’ fracture . Any tenderness or
bony step-offs are suspicious forfracture.
Swelling and/or tenderness suggests
rheumatoid arthritis if bilateral andof several weeks’ duration.
SUPRACONDYLAR FRACTURE 
OF THE ELBOW

Palpate the anatomic snuffbox, a
hollowed depression just distal to theradial styloid process formed by theabductor and extensor muscles ofthe thumb. The “snuffbox” becomes
more visible with lateral extension ofthe thumb away from the hand.
Palpate the eight carpal bones lying distal to the wrist joint, and then each
of the ﬁve metacarpals and the proximal, middle, and distal phalanges.
Palpate any other area where you suspect an abnormality.Compress the MCP joints by squeez-
ing the hand from each side betweenthe thumb and ﬁngers. Alternatively,use your thumb to palpate each MCPjoint just distal to and on each sideof the knuckle as your index fingerfeels the head of the metacarpal in thepalm. Note any swelling, bogginess,or tenderness.
Now examine the ﬁngers. Palpate the medial and lateral aspects of each PIP
joint between your thumb and index ﬁnger, again checking for swelling,bogginess, bony enlargement, or tenderness.

Using the same techniques, examine the DIP joints.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
498 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGGonococcal infection may involve
the wrist joint (arthritis) or thetendon sheaths at the wrist(gonococcal tenosynovitis).
Tenderness over the “snuffbox”
suggests a scaphoid fracture.
Synovitis in the MCPs is painful
with this pressure—a point to remember when shaking hands.
The MCPs are often boggy or 
tender in rheumatoid arthritis (butrarely involved in osteoarthritis).
PIP changes seen in rheumatoid
arthritis; Bouchard’s nodes in osteoarthritis
Hard dorsolateral nodules on the
DIP joints, or Heberden’s nodes,
common in osteoarthritis

In any area of swelling or inﬂammation, palpate along the tendons inserting
on the thumb and ﬁngers.
Now assess range of motion for the wrists, ﬁngers, and thumbs. At the wrist,
test ﬂexion, extension, and ulnar and radial deviation.
IFlexion. With the patient’s forearm
stabilized, place the wrist in exten-sion and place your fingertips inthe patient’s palm. Ask the patientto flex the wrist against gravity,then against graded resistance.
IExtension. With the patient’s fore-
arm stabilized, place the wrist inflexion and put your hand on thepatient’s dorsal metacarpals. Askthe patient to extend the wristagainst gravity, then against gradedresistance.
IUlnar and radial deviation. With
palms down, ask the patient tomove the wrists laterally and medially.
Test ﬂexion, extension, abduction,
and adduction of the ﬁngers:
IFlexion and extension. Ask the patient to make a tight ﬁst with each hand,

thumb across the knuckles, and then extend and spread the fingers. Thefingers should close and open smoothly and easily. At the MCPs, theTECHNIQUES OF EXAMINATION
CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 499Tenderness and swelling in
tenosynovitis, or inﬂammation of
the tendon sheaths. De Quervain’s
tenosynovitis over the extensor and
abductor tendons of the thumb asthey cross the radial styloid
Conditions that impair range of
motion include arthritis, tenosyn-ovitis, Dupuytren’s contracture.See Table 15-6, Swelling and Deformities of the Hands (pp. 529–531).
FLEXION
EXTENSION
ULNAR AND RADIAL
DEVIATION

fingers may extend beyond the neutral position. Also test flexion and
extension at the PIP and DIP joints.
IAbduction and adduction. Ask the patient to spread the ﬁngers apart (ab-
duction) and back together (adduction). Check for smooth, coordinatedmovement.
At the thumb , assess ﬂexion, exten-
sion, abduction, adduction, and oppo-
sition. Ask the patient to move the
thumb across the palm and touchthe base of the 5th ﬁnger to test ﬂex-
ion, and then to move the thumb
back across the palm and away fromthe ﬁngers to test extension.
Next, ask the patient to place the ﬁn-
gers and thumb in the neutral posi-tion with the palm up, then have thepatient move the thumb anteriorlyaway from the palm to assess abduc-
tionand back down for adduction .
To test opposition, or movements of
the thumb across the palm, ask thepatient to touch the thumb to eachof the other ﬁngertips.
Test sensation in the ﬁngers only along the lateral and medial surfaces to iso-

late any alterations in the digital nerves. Test median, ulnar, and radial nervefunction by checking sensation as follows:TECHNIQUES OF EXAMINATION
500 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
FLEXION EXTENSION
ABDUCTION AND
ADDUCTIONOPPOSITION

IPulp of the index ﬁnger—median
nerve
IPulp of the 5th ﬁnger—ulnar nerve
IDorsal web space of the thumb andindex ﬁnger—radial nerve
The Spine
Begin by observing the patient’s posture, including the position of bothneck and trunk, when entering the room.
Assess the patient for erect position of the head, smooth, coordinated neck
movement, and ease of gait.
Drape or gown the patient to expose the entire back for complete inspec-
tion. If possible, the patient should be upright in the patient’s natural stand-ing position—with feet together and arms hanging at the sides. The headshould be midline in the same plane as the sacrum, and the shoulders andpelvis should be level.
Inspect the patient from the side. Evaluate the spinal curvatures.
CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 501Neck stiffness signals arthritis,
muscle strain, or other underlyingpathology that should be pursued.
Lateral deviation and rotation of

the head suggests torticollis , from
contraction of the sternocleido-mastoid muscle.Radial nerveUlnar
nerveMedian nerve
Ulnar
nerve
Radial nerveMedian nerveVOLAR SURFACE
DORSAL SURFACE

502 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGIncreased thoracic kyphosis occurs 
with aging. In children a correctablestructural deformity should bepursued.
In scoliosis, there is lateral and rotatory
curvature of the spine to bring thehead back to midline. Scoliosis oftenbecomes evident during adolescence,before symptoms appear.
Unequal shoulder heights seen in
Sprengel’s deformity of the scapula(from the attachment of an extra boneor band between the upper scapulaand C7); in “winging” of the scapula(from loss of innervation of theserratus anterior muscle by the longthoracic nerve), and in contralateralweakness of the trapezius.
Unequal heights of the iliac crests, or pelvic
tilt, suggest unequal lengths of the legs
and disappear when a block is placedunder the short leg and foot. Scoliosisand hip abduction or adduction mayalso cause a pelvic tilt. “Listing” of thetrunk to one side is seen with aherniated lumbar disc.

Birthmarks, port-wine stains, hairy
patches, and lipomas often overliebony defects such as spina biﬁda.
Café-au-lait spots (discolored patches
of skin), skin tags, and fibrous tumors
in neurofibromatosisView of 
Patient Focus of Inspection
From the side Cervical, thoracic, and
lumbar curves.
From behind Upright spinal 
column (an imaginary line should fall from C7 through the gluteal cleft)
Alignment of the
shoulders, the iliac crests, and the skin creases below the buttocks (gluteal folds)
Skin markings, tags, 
or massesInspection of the Spine
Cervical
concavity
Thoracic
convexity
Lumbar
concavity

PALPATION
From a sitting or standing position, palpate the spinous processes of each ver-
tebra with your thumb.
In the neck, also palpate the facet joints that lie between the cervical verte-
brae about 1 inch lateral to the spinous processes of C2–C7. These jointslie deep to the trapezius muscle and may not be palpable unless the neckmuscles are relaxed.
In the lower lumbar area, check carefully for any vertebral “step-offs” to de-
termine if one spinous process seems unusually prominent (or recessed) inrelation to the one above it. Identify any tenderness.
Palpate over the sacroiliac joint, often identiﬁed by the dimple overlying the
posterior superior iliac spine.
You may wish to percuss the spine for tenderness by thumping, but not too
roughly, with the ulnar surface of your ﬁst.
Inspect and palpate the paravertebral muscles for tenderness and spasm.
Muscles in spasm feel ﬁrm and knotted and may be visible.

With the hip flexed and the patient lying on the opposite side, palpate the
sciatic nerve, the largest nerve in the body, consisting of nerve roots fromL4, L5, S1, S2, and S3. The nerve lies midway between the greatertrochanter and the ischial tuberosity as it leaves the pelvis through the sci-atic notch.TECHNIQUES OF EXAMINATION
CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 503Tenderness suggests fracture or
dislocation if preceded by trauma,underlying infection, or arthritis.
Tenderness occurs with arthritis,
especially at the facet joints betweenC5 and C6.
Step-offs in spondylolisthesis, or 
forward slippage of one vertebra,which may compress the spinalcord. Vertebral tenderness is suspicious for fracture or infection.
Tenderness over the sacroiliac

joint pinpoints a common causeof low back pain. Ankylosingspondylitis may produce sacroiliactenderness.
Pain on percussion may arise 
from osteoporosis, infection, ormalignancy.
Spasm occurs in degenerative and
inﬂammatory processes of muscles,prolonged contraction from abnor-mal posture, or anxiety.
Sciatic nerve tenderness suggests a
herniated disc or mass lesion im-pinging on the contributing roots.
Sciatic nerve 
Greater trochanter
Ischial tuberosity

Palpate for tenderness in any other areas that are suggested by the patient’s
symptoms. Recall that low back pain warrants careful assessment for cordcompression, the most serious cause of pain due to risk of paralysis of theaffected limb.
The neck is the most mobile portion of the spine, remarkable for its seven
fragile vertebrae supporting the 10- to 15-pound ball of the head. Flexionand extension occur primarily between the skull and C1 (the atlas), rotationat C1–C2 (the axis), and lateral bending at C2–C7.
Ask the patient to perform the following maneuvers, and check for smooth,
coordinated motion:
IFlexion. Touch the chin to the chest.
IExtension. Look up at the ceiling.
IRotation. Turn the head to each side, looking directly over the shoulder.
ILateral bending. Tilt the head, touching each ear to the corresponding
shoulder.
Tenderness, loss of sensation, or impaired movement warrants careful neuro-
logic testing of the neck and upper extremities.

shoulder.
Now assess range of motion in the spinal column.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
504 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
musclesSpinous process of
5th lumbar vertebra
Posterior 
Ischial 
tuberosityand site of ischial bursaSciatic nerveSacrosciatic
notchIntervertebral jointbetween L5 and sacrumHerniated intervertebral discs,
most common between L5 and S1or between L4 and L5, may pro-duce tenderness of the spinousprocesses, the intervertebraljoints, the paravertebral muscles,the sacrosciatic notch, and the sciatic nerve.
Rheumatoid arthritis may also
cause tenderness of the inter-vertebral joints.
Remember that tenderness in the
costovertebral angles may signifykidney infection rather than amusculoskeletal problem.
See Table 15-1, Low Back Pain 
(p. 522).

(p. 522).
Limitations in range of motion may
reﬂect stiffness from arthritis, painfrom trauma, or muscle spasmsuch as torticollis.
It is important to assess any 
complaints or ﬁndings of neck,shoulder, or arm pain or numbnessfor possible cervical cord or nerveroot compression. See Table 15-2,Pains in the Neck (p. 523).
Tenderness at C1–C2 in rheumatoid
arthritis suggests possible risk ofsubluxation and high cervical cordcompression.

IFlexion. Ask the patient to bend
forward to touch the toes (ﬂex-ion). Note the smoothness andsymmetry of movement, the rangeof motion, and the curve in thelumbar area. As ﬂexion proceeds,the lumbar concavity should ﬂat-ten out.
You may wish to measure the degree
of ﬂexion of the spine with the pa-tient standing and bending forward.Mark the spine at the lumbosacraljunction, then 10 cm above and 5 cmbelow this point. A 4-cm increasebetween the two upper marks is nor-mally seen The distance between
the lower two marks should be un-
changed.
IExtension. Place your hand on the posterior superior iliac spine, with your
ﬁngers pointing toward the midline, and ask the patient to bend backwardas far as possible.
IRotation. Stabilize the pelvis by placing one hand on the patient’s hip and
the other on the opposite shoulder. Then rotate the trunk by pulling theshoulder and then the hip posteriorly. Repeat these maneuvers for theopposite side.EXAMPLES OF ABNORMALITIES TECHNIQUES OF EXAMINATION

CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 505
10+ cmNormally
increases by up to 4 cm
5 cmDeformity of the thorax on forward
bending in scoliosis.
Persistence of lumbar lordosis sug-
gests muscle spasm or ankylosingspondylitis.
10 cm
5 cm
Decreased spinal mobility in osteo-
arthritis and ankylosing spondylitis,among other conditions

506 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGILateral bending. Again stabilize the pelvis by placing your hand on the
patient’s hip. Ask the patient to lean to both sides as far as possible.
Underlying cord or nerve root
compression should be considered.Note that arthritis or infection inthe hip, rectum, or pelvis maycause symptoms in the lumbarspine. See Table 15-1, Low BackPain (p. 522).Lateral bendin gRotation Extension
As with the neck, pain or tenderness with these maneuvers, particularly
with radiation into the leg, warrants careful neurologic testing of the lowerextremities.
The Hip
Inspection of the hip begins with careful observation of the patient’s gait onentering the room. Observe the two phases of gait:

Most problems appear during the
weight-bearing stance phase.
A wide base suggests cerebellar
disease or foot problems.
Hip dislocation, arthritis, or abduc-
tor weakness can cause the pelvisto drop on the opposite side, producing a waddling gait.
Lack of knee ﬂexion interrupts the
smooth pattern of gait.
Loss of lordosis may reﬂect para-
vertebral spasm; excess lordosis sug-gests a ﬂexion deformity of the hip.
Changes in leg length are seen in
abduction or adduction deformi-ties and scoliosis. Leg shorteningand external rotation suggest hipfracture.EXAMPLES OF ABNORMALITIES TECHNIQUES OF EXAMINATION
CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 507IStance —when the foot is on the ground and bears weight (60% of the
walking cycle)
ISwing —when the foot moves forward and does not bear weight (40% of
the cycle)
Observe the gait for the width of the

the cycle)
base, the shift of the pelvis, and ﬂex-ion of the knee. The width of the baseshould be 2 to 4 inches from heel toheel. Normal gait has a smooth, con-tinuous rhythm, achieved in part bycontraction of the abductors of theweight-bearing limb. Abductor con-traction stabilizes the pelvis and helpsmaintain balance, raising the oppo-site hip. The knee should be flexedthroughout the stance phase, exceptwhen the heel strikes the ground tocounteract motion at the ankle.
Observe the lumbar portion of the spine for slight lordosis and, with the
patient supine, assess the length of the legs for symmetry. (To measure leglength, see Special Techniques, pp. 520–521).
Inspect the anterior and posterior surfaces of the hip for any areas of muscle
atrophy or bruising.
Heelstrike Foot flat Midstance Push-off
2"–4"THE STANCE PHASE OF GAIT

PALPATION
Review the surface landmarks of the hip. On the anterior surface locate the
iliac crest, the iliac tubercle, and the anterior superior iliac spine. On the pos-
terior surface identify the posterior superior iliac spine, the greater trochanter,
the ischial tuberosity , and the sciatic nerve.
With the patient supine, ask the pa-
tient to place the heel of the leg beingexamined on the opposite knee. Thenpalpate along the inguinal ligament,
which extends from the anterior superior iliac spine to the pubic tu-bercle. The femoral nerve, artery,and vein bisect the overlying inguinalligament; lymph nodes lie medially.The mnemonic NAVEL may help
you remember the lateral-to-medialsequence of Nerve— Artery— Vein—
Empty space— Lymph node.
If the hip is painful, palpate the iliopectineal (iliopsoas) bursa, below the
inguinal ligament but on a deeper plane.
With the patient resting on one side
and the hip ﬂexed and internally ro-tated, palpate the trochanteric bursa

lying over the greater trochanter.Normally, the ischiogluteal bursa,
over the ischial tuberosity, is notpalpable unless inflamed.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
508 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGBulges along the ligament may
suggest an inguinal hernia or, on
occasion, an aneurysm.
Enlarged lymph nodes suggest 
infection in the lower extremity orpelvis.
Tenderness may be due to synovitis
of the hip joint, bursitis, or possiblypsoas abscess.
Swelling with tenderness suggests
trochanteric bursitis. Tenderness
without swelling on the postero-lateral surface of the greatertrochanter suggests localized tendinitis or muscle spasm from referred hip pain. 
Tenderness and swelling in ischio-
gluteal bursitis or “weaver’s bottom”—because of the adjacentsciatic nerve, this may mimic sciatica.
Inguinal

Inguinal
ligament
Femoral nerve
Trochanteric bursa
Ischiogluteal
bursa
TROCHANTERIC BURSA
ISCHIOGLUTEAL BURSA

Motions at the hip include ﬂexion, extension, abduction, adduction, and ro-
tation. Note that the hip can ﬂex farther when the knee is also ﬂexed. Rota-
tion at the hip while the knee is ﬂexed may be confusing at ﬁrst: when thelower leg swings laterally, the femur rotates internally. It is the motion of thefemur at the hip joint that identiﬁes these movements.
IFlexion. With the patient supine, place your hand under the patient’s lum-
bar spine. Ask the patient to bend each knee in turn up to the chest andpull it ﬁrmly against the abdomen. Note when the back touches yourhand, indicating normal ﬂattening of the lumbar lordosis—further ﬂex-ion must arise from the hip joint itself. TECHNIQUES OF EXAMINATION
CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 509In ﬂexion deformity of the hip, 
as the opposite hip is ﬂexed (with the thigh against the chest), the affected hip does not allow full legextension and the affected thighappears ﬂexed.

Flexion deformity may be masked
by an increase, rather than flat-tening, in lumbar lordosis and ananterior pelvic tilt.
Restricted abduction is common in
hip disease from osteoarthritis.As the thigh is held against the abdomen, observe the degree of ﬂexion at the
hip and knee. Normally the anterior portion of the thigh can almost touchthe chest wall. Note whether the opposite thigh remains fully extended, rest-ing on the table.
IExtension. With the patient lying face down, extend the thigh toward you
in a posterior direction.
IAbduction. Stabilize the pelvis by pressing down on the opposite anterior
superior iliac spine with one hand. With the other hand, grasp the ankleand abduct the extended leg until you feel the iliac spine move. This move-ment marks the limit of hip abduction.

Alternatively, stand at the foot of the table, grasp both ankles, and spread
them maximally, abducting both extended legs at the hips. This method
HIP FLEXION AND FLATTENING OF LUMBAR LORDOSIS

provides easy comparison of two sides when movements are restricted, but
it is impractical when range of motion is full.
IAdduction. With the patient supine, stabilize the pelvis, hold one 
ankle, and move the leg medially across the body and over the oppositeextremity.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
510 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGRestriction of internal rotation 
is an especially sensitive indicatorof hip disease such as arthritis. External rotation is also often restricted.
IRotation. Flex the leg to 90° at hip and knee, stabilize the thigh with one
hand, grasp the ankle with the other, and swing the lower leg—mediallyfor external rotation at the hip and laterally for internal rotation.

The Knee and Lower Leg
Observe the gait for a smooth, rhythmic ﬂow as the patient enters the room.
The knee should be extended at heel strike and ﬂexed at all other phases ofswing and stance.
Check the alignment and contours of the knees. Observe any atrophy of the
quadriceps muscles.
Look for loss of the normal hollows around the patella, a sign of swelling in
the knee joint and suprapatellar pouch; note any other swelling in or aroundthe knee.
PALPATION
Ask the patient to sit on the edge of the examining table with the knees inﬂexion. In this position, bony landmarks are more visible and the muscles,tendons, and ligaments are more relaxed, making them easier to palpate.
First review the important bony landmarks of the knee. Facing the knee,
place your thumbs in the soft-tissue depressions on either side of the patel-
lar tendon. On the medial aspect, move your thumb upward and then down-

ward and identify the medial femoral condyle and the upper margin of the
medial tibial plateau. Trace the patellar tendon distally to the tibial tubercle.
The adductor tubercle is posterior to the medial femoral condyle.
CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 511Stumbling or pushing the knee into
extension with the hand duringheel strike suggests quadricepsweakness.
Bowlegs ( genu varum ) and knock-
knees ( genu valgum ) are common;
ﬂexion contracture (inability to extend fully) in limb paralysis
Swelling over the patella suggests
prepatellar bursitis. Swelling over the
tibial tubercle suggests infrapatellar
or, if more medial, pes anserine
bursitis.

Lateral to the patellar tendon, identify the lateral femoral condyle and the
lateral tibial plateau. The medial and lateral femoral epicondyles are lateral
to the condyles with the knee in ﬂexion. Locate the patella.
Palpate the ligaments, the borders of the menisci, and the bursae of the knee,
paying special attention to any areas of tenderness. Pain is a common com-plaint in knee problems, and localizing the structure causing pain is impor-tant for accurate evaluation.
In the patellofemoral compartment, palpate the patellar tendon and ask the
patient to extend the leg to make sure the tendon is intact.
With the patient supine and the knee extended, push the patella against the
underlying femur. Ask the patient to tighten the quadriceps as the patellamoves distally in the trochlear groove. Check for a smooth sliding motion(the patellofemoral grinding test ).
Now assess the medial and lateral compartments of the tibiofemoral joint.

Flex the patient’s knee to about 90°. The patient’s foot should rest on theexamining table. Palpate the medial collateral ligament (MCL) between the
medial femoral epicondyle and the femur; then palpate the cordlike lateralTECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
512 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGTenderness over the tendon or 
inability to extend the leg suggestsa partial or complete tear of thepatellar tendon.
Pain and crepitus suggest roughen-
ing of the patellar undersurface thatarticulates with the femur. Similarpain may occur with climbing stairsor getting up from a chair.
Pain with patellar movement during
quadriceps contraction suggestschondromalacia, or degenerative
patella.
MCL tenderness after injury is sus-
picious for an MCL tear. (The LCLis less subject to injury.)
Medial femoral
condyle
epicondyle
Patellar tendon
Medial tibial
plateau

patella.
condyle
plateau
Tibial tuberosityAdductor
tubercle
Medial
collateralligament
Pesanserinebursa

collateral ligament (LCL) between the lateral femoral epicondyle and the
ﬁbular head.
Palpate the medial and lateral menisci along the medial and lateral joint
lines. It is easier to palpate the medial meniscus if the tibia is internally rotated.Note any swelling or tenderness.
Note any irregular bony ridges along the joint margins.
Try to feel any thickening or swelling in the suprapatellar pouch and along
the sides of the patella. Start 10 centimeters above the superior border of thepatella (well above the pouch) and feel the soft tissues between your thumband ﬁngers. Move your hand distally in progressive steps, trying to identifythe pouch. Continue your palpation along the sides of the patella. Note anytenderness or warmth greater than in the surrounding tissues.TECHNIQUES OF EXAMINATION
CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 513Tenderness from tears following 
injury are more common in themedial than in the lateral meniscus.

Bony ridges along the joint margins
may be felt in osteoarthritis.
Swelling above and adjacent to the
patella suggests synovial thickeningor effusion in the knee joint.
Thickening, bogginess, or warmth
in these areas indicates synovitisor nontender effusions from osteoarthritis.
Prepatellar bursitis (“housemaid’s
knee”) from excessive kneeling.Anserine bursitis from running, 
valgus knee deformity, ﬁbromyal-gias, osteoarthritis. A popliteal or
“baker’s” cyst from distention of
the gastrocnemius semimembra-nosus bursa
A ﬂuid wave or bulge on the medial
side between the patella and thefemur is considered a positive bulgesign consistent with an effusion.
Check three other bursae for bogginess or swelling. Palpate the prepatellar
bursa, and over the anserine bursa on the posteromedial side of the knee

between the medial collateral ligament and the tendons inserting on themedial tibial and plateau. On the posterior surface, with the leg extended,check the medial aspect of the popliteal fossa.
Three further tests will help you detect ﬂuid in the knee joint.
IThe Bulge Sign (for minor effusions ). With the knee extended, place the left
hand above the knee and apply pressure on the suprapatellar pouch, dis-placing or “milking” ﬂuid downward. Stroke downward on the medial as-pect of the knee and apply pressure to force ﬂuid into the lateral area. Tapthe knee just behind the lateral margin of the patella with the right hand.

IThe Balloon Sign (for major effusions). Place the thumb and index ﬁnger of
your right hand on each side of the patella; with the left hand, compress thesuprapatellar pouch against the femur. Feel for ﬂuid entering (or ballooninginto) the spaces next to the patella under your right thumb and index ﬁnger.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
514 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGWhen the knee joint contains a
large effusion, suprapatellar com-pression ejects ﬂuid into the spacesadjacent to the patella. A palpableﬂuid wave signiﬁes a positive “balloon sign.” A returning ﬂuidwave into the suprapatellar pouchconﬁrms an effusion.
Palpable ﬂuid returning into the
pouch further conﬁrms the presenceof a large effusion.
A palpable patellar click with com-
pression may also occur, but yieldsmore false positives.
Milk downward
Tap and watch
for fluid wave
Apply medial
pressure
IBallotting the patella. To assess

pressure
large effusions, you can also com-press the suprapatellar pouch and“ballotte” or push the patellasharply against the femur. Watchfor ﬂuid returning to the suprap-atellar pouch.

The principal movements of the knee are ﬂexion, extension, and internal and
external rotation. Ask the patient to ﬂex and extend the knee while sitting.To check internal and external rotation, instruct the patient to rotate thefoot medially and laterally. Knee ﬂexion and extension can also be assessedby asking the patient to squat and stand up—provide support if needed tomaintain balance.
You will often need to test ligamentous stability and integrity of the menisci,
particularly when there is a history of trauma or palpable tenderness. Alwaysexamine both knees and compare ﬁndings.TECHNIQUES OF EXAMINATION
CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 515Pain or a gap in the medial joint line
points to ligamentous laxity and apartial tear of the medial collateral
ligament. Most injuries are on the
medial side.
Pain or a gap in the lateral joint line
points to ligamentous laxity and apartial tear of the lateral collateral
ligament.

ligament.
A few degrees of forward movement are
normal if equally present on theopposite side.
A forward jerk showing the contours 
of the upper tibia is a positive anterior
drawer sign and suggests a tear of 
the ACL.Structure Maneuver
ligament (MCL)
ligament (LCL)
ligament (ACL)Abduction Stress Test. With the
patient supine and the kneeslightly ﬂexed, move the thighabout 30° laterally to the side ofthe table. Place one hand againstthe lateral knee to stabilize thefemur and the other handaround the medial ankle. Pushmedially against the knee andpull laterally at the ankle toopen the knee joint on themedial side ( valgus stress ).
Adduction Stress Test. Now, with

the thigh and knee in the sameposition, change your position soyou can place one hand againstthe medial surface of the kneeand the other around the lateralankle. Push medially against theknee and pull laterally at theankle to open the knee joint onthe lateral side ( varus stress ).
Anterior Drawer Sign. With the
patient supine, hips ﬂexed andknees ﬂexed to 90º and feet ﬂaton the table, cup your handsaround the knee with thethumbs on the medial and lateraljoint line and the ﬁngers on themedial and lateral insertions ofthe hamstrings. Draw the tibiaforward and observe if it slidesforward (like a drawer) fromunder the femur. Compare thedegree of forward movementwith that of the opposite knee.Techniques for Examining the Knee

Palpate the gastrocnemius and soleus muscles on the posterior surface of the
lower leg. Their common tendon, the Achilles, is palpable from about thelower third of the calf to its insertion on the calcaneus.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
516 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGSigniﬁcant forward excursion indicates
an ACL tear.
Isolated PCL tears are rare.
A click or pop along the medial joint
with valgus stress, external rotation,and leg extension suggests a probabletear of the posterior portion of the
medial meniscus.
A defect in the muscles with 
tenderness and swelling in a ruptured Achilles tendon; tender-
ness and thickening of the tendonabove the calcaneus, sometimeswith a protuberant posterolateralbony process of the calcaneus inAchilles tendinitisStructure Maneuver
Posterior cruciate
ligament (PCL)
Medial meniscus
and lateralmeniscusLachman Test. Place the knee in

15° of ﬂexion and externalrotation. Grasp the distal femurwith one hand and the uppertibia with the other. With thethumb of the tibial hand on thejoint line, simultaneously movethe tibia forward and the femurback. Estimate the degree offorward excursion.
Posterior Drawer Sign. Position
the patient and place yourhands in the positionsdescribed for the anteriordrawer test. Push the tibiaposteriorly and observe thedegree of backward movementin the femur.
McMurray Test. If a click is felt or
heard at the joint line duringﬂexion and extension of theknee, or if tenderness is notedalong the joint line, furtherassess the meniscus for aposterior tear.
With the patient supine, grasp

With the patient supine, grasp 
the heel and ﬂex the knee. Cup your other hand over theknee joint with ﬁngers andthumb along the medial andlateral joint line. From the heel,rotate the lower leg internallyand externally. Then push onthe lateral side to apply a valgusstress on the medial side of the joint. At the same time,rotate the leg externally andslowly extend it.Techniques for Examining the Knee (Continued)

To test the integrity of the Achilles tendon, place the patient prone with the
knee and ankle ﬂexed at 90º, or alternatively, ask the patient to kneel on achair. Squeeze the calf and watch for plantar ﬂexion at the ankle.
Observe all surfaces of the ankles and feet, noting any deformities, nodules,or swellings, and any calluses or corns.
PALPATION
With your thumbs, palpate the anterior aspect of each ankle joint,
noting any bogginess, swelling, ortenderness.
Feel along the Achilles tendon for
nodules and tenderness.
Palpate the heel, especially the pos-
terior and inferior calcaneus, and theplantar fascia for tenderness.
Palpate the metatarsophalangeal joints
for tenderness. Compress the forefootbetween the thumb and ﬁngers. Exertpressure just proximal to the heads ofthe 1st and 5th metatarsals.
CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 517Absence of plantar ﬂexion is a

CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 517Absence of plantar ﬂexion is a 
positive test indicating rupture ofthe Achilles tendon. Sudden severepain “like a gunshot wound,” anecchymosis from the calf into theheel, and a ﬂat-footed gait withabsence of “toe-off” may also bepresent.
See Table 15-7, Abnormalities of
the Feet and Toes (pp. 532–533).
Localized tenderness in arthritis,
ligamentous injury, or infection ofthe ankle
Rheumatoid nodules; tenderness 
in Achilles tendinitis, bursitis, orpartial tear from trauma
Bone spurs may be present on 
the calcaneus; pain over the plantar fascia suggests plantar
fasciitis.
Tenderness on compression is an
early sign of rheumatoid arthritis.Acute inﬂammation of the ﬁrstmetatarsophalangeal joint is associated with gout.

Palpate the heads of the ﬁve meta-
tarsals and the grooves between themwith your thumb and index ﬁnger.Place your thumb on the dorsum ofthe foot and your index ﬁnger on theplantar surface.
Range of motion at the ankle includes ﬂexion and extension at the ankle
(tibiotalar) joint and, in the foot, inversion and eversion at the subtalar and
transverse tarsal joints.
IThe Ankle (Tibiotalar) Joint. Dorsiflex and plantar flex the foot at the
ankle.
IThe Subtalar (Talocalcaneal) Joint. Stabilize the ankle with one hand,
grasp the heel with the other, and invert and evert the foot.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
518 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGPain and tenderness, called
metatarsalgia, seen in trauma,
arthritis, vascular compromise
Pain during movements of the
ankle and the foot helps to localizepossible arthritis.
An arthritic joint is frequently

painful when moved in any direc-tion, while a ligamentous sprainproduces maximal pain when theligament is stretched. For example,in a common form of sprainedankle, inversion and plantar flex-ion of the foot cause pain, whileeversion and plantar flexion arerelatively pain free.
IThe Transverse Tarsal Joint. Stabilize the heel and invert and evert the
forefoot.
IFor the Metatarsophalangeal joints , ﬂex the toes in relation to the feet.
INVERSION EVERSION

For the Carpal Tunnel Syndrome. Pain and numbness on the ven-
tral surface of the ﬁrst three digits of the hand (but not in the palm), espe-cially at night, suggest median nerve compression in the carpal tunnel, whichlies between the carpal bones dorsally and a ventral band of more superﬁcialfascia, the ﬂexor retinaculum .
Appropriate symptoms and objective loss of sensation on the ventral surface
of the hand in the distribution of the median nerve (see p. 473 and p. 474),and weak abduction of the thumb on muscle strength testing are the most
helpful for making the diagnosis. Two additional clinical tests are also used—when positive, Tinel’s test appears more likely to be confirmed by furtherdiagnostic testing.
Thumb Abduction. Ask the

patient to raise the thumb perpendic-ular to the palm as you apply down-ward pressure on the distal phalanx.(This maneuver reliably tests thestrength of the abductor pollicis bre-vis, which is innervated only by themedian nerve.)
Tinel’s Sign. With your ﬁnger,
percuss lightly over the course of themedian nerve in the carpal tunnel atthe spot indicated by the arrow.
CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 519Onset often related to repetitive
motion with wrists ﬂexed (e.g., keyboard use, mail-sorting),pregnancy, rheumatoid arthritis,diabetes, hypothyroidism
Thenar atrophy may also be 
present.
Tingling or electric sensations in
the distribution of the mediannerve constitute a positive test,suggesting carpal tunnel syndrome.

Phalen’s Test. Hold the pa-
tient’s wrists in acute flexion for 60 seconds. Alternatively, ask thepatient to press the backs of bothhands together to form right angles.These maneuvers compress the me-dian nerve.
For Low Back Pain With Radiation Into the Leg. If the patient has
noted low back pain that radiates down the leg, check straight leg raisingon each side in turn. The patient should be lying supine. Raise the patient’srelaxed and straightened leg until pain occurs. Then dorsiﬂex the foot.
Record the degree of elevation at which pain occurs, the quality and distri-
bution of the pain, and the effects of dorsiﬂexion. Tightness and mild dis-comfort in the hamstrings with these maneuvers are common and do notindicate radicular pain.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
520 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGIf numbness and tingling develop

over the distribution of the mediannerve (e.g., the palmar surface ofthe thumb, and the index, middle,and part of the ring ﬁngers), thesign is positive, suggesting carpaltunnel syndrome.
Sharp pain radiating from the
back down the leg in an L5 or S1distribution ( radicular pain ) sug-
gests tension on or compressionof the nerve root(s), often causedby a herniated lumbar disc. Dorsi-flexion of the foot increases thepain. Increased pain in the affectedleg when the opposite leg is raisedstrongly conﬁrms radicular painand constitutes a positive crossed
straight leg-raising sign.
See Table 15-1 Low Back Pain 
(p. 522).
Unequal leg length may explain a
scoliosis.
Examine the patient neurologically, focusing on the motor and sensory
functions and the reﬂexes at the lumbosacral levels. These are outlined in thenext chapter.
Measuring the Length of Legs. If you suspect that the patient’s legs

are unequal in length, measure them. Get the patient relaxed in the supine

position and symmetrically aligned with legs extended. With a tape, measure
the distance between the anterior superior iliac spine and the medial malle-olus. The tape should cross the knee on its medial side.
Describing Limited Motion of a Joint. Although measurement of
motion is seldom necessary, limitations can be described in degrees. Pocketgoniometers are available for this purpose. In the two examples shownbelow, the red lines indicate the range of the patient’s movement and theblack lines suggest the normal range.TECHNIQUES OF EXAMINATION
CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 521Observations may be described 
in several ways. The numbers inparentheses are suitably abbreviatedrecordings.
A. The elbow ﬂexes from 45° to
90° (45° ➝90°), 
-or-
The elbow has a ﬂexion defor-mity of 45° and can be ﬂexedfarther to 90° (45° ➝90°).
B. Supination at elbow = 30°
(0°➝30°) 
Pronation at elbow = 45°(0°➝45°)
123456789101112131415161718192021222324252627282930313233343536373839
Neutral
0˚
30˚
45˚

(0°➝30°) 
Neutral
0˚
30˚
45˚
90˚90˚EXAMPLES OF ABNORMALITIES
0˚45˚90˚160˚A
B

TABLE 15-1 ILow Back Pain
522 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Patterns Possible Causes Possible Physical Signs
Mechanical Low Back Pain
Acute, often recurrent, or possibly
chronic aching pain in the lumbosacralarea, possibly radiating into theposterior thighs but not below theknees. The pain is often precipitated oraggravated by moving, lifting, ortwisting motions and is relieved by rest.Spinal movements are typically limitedby pain. This is the back pain commonfrom the teenage years through the 40s.
Radicular Low Back Pain
A radicular (nerve root) pain, usuallysuperimposed on low back pain. Thesciatic pain is shooting and radiatesdown one or both legs, usually to below the knee(s) in a dermatomaldistribution, often with associatednumbness and tingling and possiblylocal weakness. The pain is usuallyworsened by spinal movement such asbending and by sneezing, coughing, orstraining.
Back and Leg Pain From 
Lumbar Stenosis

Pseudoclaudication is a pain in the back
or legs that worsens with walking andimproves with ﬂexing of the spine, as bysitting or bending forward.
Chronic Persistent Low 
Back Stiffness
Aching Nocturnal Back Pain,
Unrelieved by Rest
Back Pain Referred From the
Abdomen or Pelvis
Usually a deep, aching pain, the level of
which varies with the sourceThe exact cause cannot usually be
proven. Intervertebral disc disease isprobably involved in many cases.Congenital disorders of the spine, suchas spondylolisthesis, may be present in asmall percentage. In older women or inpersons on long-term corticosteroidtherapy, consider osteoporosiscomplicated by a collapsed vertebra.
A herniated intervertebral disc with

compression or traction of nerve root(s)is the most common cause in personsunder age 50. The nerve roots of L5 orS1 are most often affected. Spinal cordtumors or abscesses are much lesscommon causes. Compared to a disc,they tend to affect more nerve roots andto produce more neurologic deﬁcits.
Lumbar stenosis, which is a combination
of degenerative disc disease andosteoarthritis that narrows the spinalcanal and impinges on the spinalnerves. It is a common cause of painafter age 60.
Ankylosing spondylitis, a chronic
inﬂammatory polyarthritis, mostcommon in young men
Diffuse idiopathic skeletal hyperostosis
(DISH), which affects middle-aged andolder men
Consider metastatic malignancy in the
spine, as from cancer of the prostate,breast, lung, thyroid, and kidney, andmultiple myeloma.
Peptic ulcer, pancreatitis, pancreatic

cancer, chronic prostatitis,endometriosis, dissecting aorticaneurysm, retroperitoneal tumor, andother causesLocal tenderness, muscle spasm, pain on
movement of the back, and loss of thenormal lumbar lordosis, but no motoror sensory loss or reﬂex abnormalities.In osteoporosis there may be a thoracickyphosis, percussion tenderness over aspinous process, or fractures elsewheresuch as in the thoracic spine or in a hip.
Pain on straight leg raising (see pp. 520),
tenderness of the sciatic nerve, loss ofsensation in a dermatomal distribution,local muscular weakness and atrophy,and decreased to absent reﬂex(es),especially affecting the ankle jerks.Dermatomal signs and reﬂex changesmay be absent when only a single rootis affected.
The posture may become ﬂexed forward.

Motor weakness and hyporeﬂexia in thelower extremities may be present.
Loss of the normal lumbar lordosis,
muscle spasm, and limitation of anteriorand lateral ﬂexion
Flexion and immobility of the spine
Variable with the source. Local bone
tenderness may be present.
Spinal movements are not painful and
range of motion is not affected. Lookfor signs of the primary disorder.

TABLE 15-2 IPains in the Neck
CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 523
“Simple Stiff Neck”
Acute, episodic, localized pain in the
neck, often appearing on awakeningand lasting 1–4 days. No dermatomalradiation
Aching Neck
A persistent dull aching in the back ofthe neck, often spreading to the occiput.This is common with postural strain, aswith prolonged typing or studying, andmay also accompany tension anddepression.
“Cervical Sprain”
Acute and often recurrent neck painsthat are often more severe and lastlonger than simple stiff neck. There maybe a precipitating factor such as awhiplash injury, heavy lifting, or asudden movement, but there is nodermatomal radiation.
Neck Pain With Dermatomal
Radiation
Neck pain as in cervical sprain, but with
radiation of the pain to the shoulder,back, or arm in a dermatomaldistribution. This radicular pain istypically sharp, burning, or tingling inquality.

Neck Pain From Possible
Compression of the CervicalSpinal Cord
Associated here is weakness or paralysis
of the legs, often with a decrease in orloss of sensation. These symptoms mayoccur in addition to the radicularsymptoms or by themselves. The neckpain may be mild or even absent.The mechanisms are not understood.
Poorly understood; may be related to
sustained muscle contraction
Poorly understood
Compression of one or more nerve
roots caused by either a herniatedcervical disc or degenerative disease ofthe intervertebral discs with bonyspurring*
Compression of the spinal cord in the
neck caused by either a herniatedcervical disc or degenerative disease ofthe intervertebral discs with bonyspurring. Trauma may also be thecause.*Local muscular tenderness and pain on
certain movements

Local muscular tenderness. When areas
of pain and tenderness are also presentelsewhere in the body, consider theﬁbromyalgia syndrome (see Table 15-3,Patterns of Pain In and Around theJoints).
Local tenderness and pain on movement
Muscle tenderness and spasm, a limited
range of neck motion, increase in thepain on coughing or straining, andpossible sensory loss, weakness, muscularatrophy, and decreased reﬂexes in theareas involved
Limited range of motion in the neck,
weakness or paralysis in the legs of thecentral nervous system type, Babinskiresponses, loss of position and vibrationsense in the legs, and, less commonly,loss of pain and temperature sensation.Radicular signs in the arms may also bepresent.
* Tumors or abscesses of the cervical spinal cord, though less common, should also be considered.

TABLE 15-3 IPatterns of Pain In and Around the Joints
524 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Common Pattern of Progression
Problem Process Locations Spread Onset and Duration
Rheumatoid
Arthritis
Osteoarthritis
(degenerativejoint disease)
Gouty Arthritis
Acute Gout
Chronic
TophaceousGout
Polymyalgia
Rheumatica
SyndromeChronic
inﬂammation ofsynovial membraneswith secondaryerosion of adjacentcartilage and bone,and damage toligaments andtendons
Degeneration and
progressive loss ofcartilage within thejoints, damage tounderlying bone,and formation ofnew bone at themargins of thecartilage
An inﬂammatory
reaction tomicrocrystals ofsodium urate
Multiple local
accumulations ofsodium urate in thejoints and othertissues (tophi), withor withoutinﬂammation
A disease of unclear
nature seen inpeople over age 50,especially women;may be associatedwith giant cellarteritis
Widespread

musculoskeletal painand tender points.May accompanyother diseases.Mechanisms unclearHands (proximal
interphalangeal andmetacarpo-phalangeal joints),feet (metatarsopha-langeal joints),wrists, knees,elbows, ankles
Knees, hips, hands
(distal, sometimesproximal inter-phalangeal joints),cervical and lumbarspine, and wrists(ﬁrst carpometacarpaljoint); also jointspreviously injured ordiseased
Base of the big toe
(the ﬁrst metatarso-phalangeal joint),the instep or dorsumof feet, the ankles,knees, and elbows
Feet, ankles, wrists,
ﬁngers, and elbows
Muscles of the hip
girdle and shouldergirdle; symmetric
“All over,” but
especially in theneck, shoulders,hands, low back, and kneesSymmetrically
additive: progressesto other joints whilepersisting in theinitial ones
Additive; however,
only one joint maybe involved.
Early attacks are
usually conﬁned toone joint.
Additive, not so

symmetric asrheumatoid arthritis
Shifts unpredictably
or worsens inresponse toimmobility, excessiveuse, or chillingUsually insidious
Usually insidious
Sudden, often at
night, often afterinjury, surgery,fasting, or excessivefood or alcoholintake 
Gradual develop-
ment of chronicitywith repeated attacks
Insidious or abrupt,
even appearingovernight
VariableOften chronic, with
remissions andexacerbations
Slowly progressive,
with temporaryexacerbations afterperiods of overuse
Occasional isolated
attacks lasting daysup to 2 weeks; theymay get morefrequent and severe,with persistingsymptoms.
Chronic symptoms
with acuteexacerbations
Chronic but
ultimately self-limiting
Chronic, with “ups
and downs”
The vagueness of these characteristics is in itself a clue to the ﬁbromyalgia syndrome.




and downs”



CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 525
Associated Symptoms
Redness, Warmth, Limitation of Generalized
Swelling and Tenderness Stiffness Motion Symptoms
Frequent swelling of synovial
tissue in joints or tendonsheaths; also subcutaneousnodules
Small effusions in the joints
may be present, especially inthe knees; also bonyenlargement.
Present, within and around
the involved joint
Present, as tophi, in joints,
bursae, and subcutaneoustissues
None
NoneTender, often warm,
but seldom red
Possibly tender,
seldom warm, andrarely red
Exquisitely tender,
hot, and red
Tenderness, warmth,
and redness may bepresent duringexacerbations.
Muscles often tender,
but not warm or red
Multiple speciﬁc and
symmetric tender“trigger points,”often not recognizeduntil the examinationProminent, often for an
hour or more in themornings, also afterinactivity
Frequent but brief
(usually 5–10 min), inthe morning and afterinactivity
Not evident
Present

Present
Prominent, especially in
Present, especially in the
morningOften develops
Often develops
Motion is limited
primarily by pain.
Present
Absent, though
stiffness is greaterat the extremes ofmovementWeakness, fatigue, weight
loss, and low fever arecommon.
Usually absent
Fever may be present.
Possibly fever; patient
may also developsymptoms of renal failureand renal stones.
Malaise, a sense of
depression, possiblyanorexia, weight loss,and fever, but no trueweakness
A disturbance of sleep,
usually associated withmorning fatigue

TABLE 15-4 IPainful Shoulders
526 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Rotator Cuff Tendinitis
Repeated shoulder motion, as in throwing or
swimming, can cause edema and hemorrhagefollowed by inﬂammation, most commonlyinvolving the supraspinatus tendon. Acute,recurrent, or chronic pain may result, oftenaggravated by activity. Patients may report sharpcatches of pain, grating, and weakness when liftingthe arm overhead. When the supraspinatus tendonis involved, tenderness is maximal just below thetip of the acromion. Patients are typicallyathletically active.Rotator Cuff Tears

When the arm is raised in forward ﬂexion, therotator cuff may impinge against the undersurfaceof the acromion and the coracoacromial ligament.Injury from a fall or repeated impingement mayweaken the rotator cuff, causing a partial orcomplete tear, usually after age 40. Weakness,atrophy of the supraspinatus and infraspinatusmuscles, pain, and tenderness may ensue. In acomplete tear of the supraspinatus tendon(illustrated), active abduction and forward ﬂexionat the glenohumeral joint is severely impaired,producing a characteristic shrugging of theshoulder.Calciﬁc Tendinitis

Calciﬁc tendinitis refers to a degenerative processin the tendon that is associated with the depositionof calcium salts. Like rotator cuff tendinitis, itusually involves the supraspinatus tendon. Acute,disabling attacks of shoulder pain may occur,usually in patients over 30 years of age and moreoften in women. The arm is held close to the side,and all motions are severely limited by pain.Tenderness is maximal below the tip of theacromion. The subacromial bursa, which overliesthe supraspinatus tendon, may become involved inthe inﬂammation. Chronic, less severe pain mayalso occur.
Shoulder –
shrugging effort
Limited abduction Normal abduction

CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 527Bicipital Tendinitis
Inﬂammation of the long head of the biceps
tendon and its sheath causes anterior shoulderpain that may resemble rotator cuff tendinitis andmay coexist with it. Often this is a sign ofshoulder instability. This tendon, like the cuff,may suffer impingement injury. Tenderness ismaximal in the bicipital groove. By externallyrotating and abducting the arm, you can moreeasily separate this area from the subacromialtenderness of supraspinatus tendinitis. With thepatient’s arm at the side, elbow ﬂexed to 90°, askthe patient to supinate the forearm against yourresistance. Increased pain in the bicipital grooveconﬁrms this condition.Acromioclavicular Arthritis

Acromioclavicular arthritis is not a common causeof shoulder pain. When present, it usually is theresult of direct injury to the shoulder girdle withresulting degenerative changes. Tenderness islocalized over the acromioclavicular joint.Although motion in the glenohumeral joint is notpainful in acromioclavicular arthritis, as it is inmany other painful conditions of the shoulder,movements of the scapula, such as shouldershrugging, are.Adhesive Capsulitis (Frozen Shoulder)

Adhesive capsulitis refers to a mysterious ﬁbrosisof the glenohumeral joint capsule, manifested bydiffuse, dull, aching pain in the shoulder andprogressive restriction of active and passive rangeof motion, but usually no localized tenderness.The condition is usually unilateral and occurs inpersons aged 50 to 70. There is often anantecedent painful disorder of the shoulder orpossibly another condition (such as myocardialinfarction) that has decreased shouldermovements. The course is chronic, lasting monthsto years, but the disorder often resolvesspontaneously, at least partially.

TABLE 15-5 ISwollen or Tender Elbows
528 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Olecranon Bursitis
Swelling and inﬂammation of the olecranon bursa may result from trauma
or may be associated with rheumatoid or gouty arthritis. The swelling issuperﬁcial to the olecranon process.Arthritis of the Elbow
Synovial inﬂammation or ﬂuid is felt best in the grooves between the olecranonprocess and the epicondyles on either side. Palpate for a boggy, soft, orﬂuctuant swelling and for tenderness.
Olecranon
bursitis
Arthritis
Rheumatoid Nodules
Subcutaneous nodules may develop at pressure points along the extensor
surface of the ulna in patients with rheumatoid arthritis or acute rheumaticfever. They are ﬁrm and nontender, and are not attached to the overlyingskin. They may or may not be attached to the underlying periosteum.Although they may develop in the area of the olecranon bursa, they oftenoccur more distally.Epicondylitis

Lateral epicondylitis (tennis elbow) follows repetitive extension of the wrist or
pronation–supination of the forearm. Pain and tenderness develop at thelateral epicondyle and possibly in the extensor muscles close to it. When thepatient tries to extend the wrist against resistance, pain increases.Medial epicondylitis (pitcher’s, golfer’s, or Little League elbow) follows
repetitive wrist ﬂexion, as in throwing. Tenderness is maximal at the medialepicondyle. Wrist ﬂexion against resistance increases the pain.
Rheumatoidnodules
Epicondylitis

TABLE 15-6 ISwellings and Deformities of the Hands
CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 529
Osteoarthritis (Degenerative Joint Disease) Acute Rheumatoid Arthritis
Chronic Rheumatoid ArthritisTender, painful, stiff joints
characterize rheumatoid arthritis.Symmetric involvement on both sidesof the body is typical. The proximalinterphalangeal, metacarpo-phalangeal, and wrist joints arefrequently affected; the distalinterphalangeal joints are rarely so.Patients with acute disease often havefusiform or spindle-shaped swellingof the proximal interphalangealjoints.Nodules on the dorsolateral aspects
of the distal interphalangeal joints(Heberden’s nodes ) are due to the

bony overgrowth of osteoarthritis.Usually hard and painless, they affectthe middle-aged or elderly and often,although not always, are associatedwith arthritic changes in other joints.Flexion and deviation deformitiesmay develop. Similar nodules on theproximal interphalangeal joints(Bouchard’s nodes ) are less common.
The metacarpophalangeal joints arespared.
Radial deviation of distal phalanx
Heberden's 
node
Bouchard's
node
Metacarpophalangealjoints uninvolved
Swollen,
thickened
nodule
Muscular atrophyUlnar
      deviation
Tender,swollen
Boutonniere deformity
Swan neck deformityAs the arthritic process continues and worsens, chronic swelling
and thickening of the metacarpophalangeal and proximalinterphalangeal joints appear. Range of motion becomes limitedand the ﬁngers may deviate toward the ulnar side. The interosseousmuscles atrophy. The ﬁngers may show “swan neck” deformities

(i.e., hyperextension of the proximal interphalangeal joints withﬁxed ﬂexion of the distal interphalangeal joints). Less common is aboutonnière deformity (i.e., persistent ﬂexion of the proximal
interphalangeal joint with hyperextension of the distalinterphalangeal joint).
Rheumatoid nodules may accompany either the acute or the
chronic stage.

530 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 15-6 ISwellings and Deformities of the Hands (Continued)
Chronic Tophaceous Gout Ganglion
Tendon Sheath and Palmar Space Infections
Acute Tenosynovitis Acute Tenosynovitis and Thenar Space Involvement
Infection of the ﬂexor tendon
sheaths (acute tenosynovitis) may follow local injury, even ofapparently trivial nature. Unlikein arthritis, tenderness andswelling develop not in the jointbut along the course of thetendon sheath, from the distalphalanx to the level of themetacarpophalangeal joint. Theﬁnger is held in slight ﬂexion;attempts to extend it are verypainful.
Swollen
Knobby swelling Draining tophus
Cystic swelling
Pain on extension
Finger held
in slight flexionSwelling andtenderness alongtendon sheath
Puncture wound
Tender, swollenThe deformities that develop in long-

standing chronic tophaceous goutcan sometimes mimic those ofrheumatoid and osteoarthritis. Jointinvolvement is usually not sosymmetric as in rheumatoid arthritis.Acute inﬂammation may be present.Knobby swellings around the jointssometimes ulcerate and dischargewhite chalklike urates.Ganglia are cystic, round, usually
nontender swellings located alongtendon sheaths or joint capsules. Thedorsum of the wrist is a frequent siteof involvement. Flexion of the wristmakes ganglia in this location moreprominent; extension tends toobscure them. Ganglia may alsodevelop elsewhere on the hands,wrists, ankles, and feet.
If the infection progresses, it may

escape the bounds of the tendonsheath to involve one of the adjacentfascial spaces within the palm.Infections of the index ﬁnger andthenar space are illustrated.Early diagnosis and treatment areimportant.

CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 531Felon Dupuytren’s Contracture
Trigger Finger Thenar Atrophy
A trigger ﬁnger is caused by a painless
nodule in a ﬂexor tendon in the palm,near the head of the metacarpal. Thenodule is too big to enter easily intothe tendon sheath when the persontries to extend the ﬁngers from aﬂexed position. With extra effort orassistance, the ﬁnger extends with apalpable and audible snap as thenodule pops into the tendon sheath.This snap may also be evident duringﬂexion. Watch and listen as the patientﬂexes and extends the ﬁngers, and feelfor both the nodule and the snap.Injury to the ﬁngertip may result in
infection in the enclosed fascialspaces of the ﬁnger pad. Severe pain,localized tenderness, swelling, anddusky redness are characteristic. Earlydiagnosis and treatment areimportant.The ﬁrst sign of a Dupuytren’s

contracture is a thickened plaqueoverlying the ﬂexor tendon of thering ﬁnger and possibly the littleﬁnger at the level of the distal palmarcrease. Subsequently, the skin in thisarea puckers, and a thickened ﬁbroticcord develops between palm andﬁnger. Flexion contracture of theﬁngers may gradually ensue.
Normal
hypothenareminence
Flattenedthenareminence
Swollen, tender,
dusky red
Flexion contraction
Cord
Muscular atrophy localized to the
thenar eminence suggests a disorderof the median nerve or itscomponents. Pressure on the nerve atthe wrist is a common cause ( carpal
tunnel syndrome ). Hypothenar
atrophy suggests an ulnar nervedisorder.

TABLE 15-7 IAbnormalities of the Feet and Toes
532 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Acute Gouty Arthritis
The metatarsophalangeal joint of the great toe
may be the ﬁrst joint involved in acute goutyarthritis. It is characterized by a very painful andtender, hot, dusky red swelling that extendsbeyond the margin of the joint. It is easilymistaken for a cellulitis. Acute gout may alsoinvolve the dorsum of the foot.Hallux Valgus
In hallux valgus, the great toe is abnormallyabducted in relationship to the ﬁrst metatarsal,which itself is deviated medially. The head of theﬁrst metatarsal may enlarge on its medial side, anda bursa may form at the pressure point. This bursamay become inﬂamed.Flat Feet

Signs of ﬂat feet may be apparent only when thepatient stands, or they may become permanent.The longitudinal arch ﬂattens so that the soleapproaches or touches the ﬂoor. The normalconcavity on the medial side of the foot becomesconvex. Tenderness may be present from themedial malleolus down along the medial-plantarsurface of the foot. Swelling may develop anteriorto the malleoli. Inspect the shoes for excess wearon the inner side of the soles and heels.
Hot, red, tender, swollen
Medial border becomes convex
Sole touches floor
Ingrown Toenail
The sharp edge of a toenail may dig into and
injure the lateral nail fold, resulting ininﬂammation and infection. A tender,reddened, overhanging nail fold, sometimeswith granulation tissue and purulent discharge,results. The great toe is most often affected.Hammer Toe

Most commonly involving the second toe, ahammer toe is characterized by hyperextensionat the metatarsophalangeal joint with ﬂexion atthe proximal interphalangeal joint. A cornfrequently develops at the pressure point overthe proximal interphalangeal joint.Corn
A corn is a painful conical thickening of skinthat results from recurrent pressure onnormally thin skin. The apex of the conepoints inward and causes pain. Cornscharacteristically occur over bony prominences(e.g., the 5th toe). When located in moistareas (e.g., at pressure points between the 4th and 5th toes), they are called soft corns.
Red, tender
Granulation
tissue
Hyperextended
Flexed
Red, thickened

CHAPTER 15 ITHE MUSCULOSKELETAL SYSTEM 533Callus
Like a corn, a callus is an area of greatly
thickened skin that develops in a region ofrecurrent pressure. Unlike a corn, however, acallus involves skin that is normally thick, suchas the sole, and is usually painless. If a callus ispainful, suspect an underlying plantar wart.Plantar Wart
A plantar wart is a common wart (verrucavulgaris) located in the thickened skin of thesole. It may look somewhat like a callus oreven be covered by one. Look for thecharacteristic small dark spots that give astippled appearance to a wart. Normal skinlines stop at the wart’s edge.Neuropathic Ulcer

When pain sensation is diminished or absent(as in diabetic neuropathy, for example),neuropathic ulcers may develop at pressurepoints on the feet. Although often deep,infected, and indolent, they are painless. Callusformation about the ulcer is diagnosticallyhelpful. Like the ulcer itself, it results fromchronic pressure.

This section deals brieﬂy with structures, functions, and concepts that relate
directly to the neurologic examination. After a short description of the brain,spinal cord, cranial and peripheral nerves, and reﬂexes, it summarizes im-portant motor and sensory pathways. Common or concerning symptoms,health promotion and counseling, and a preview of the pertinent write-upthen follow. Next comes Techniques of Examination for the nervous system,
including mental status, the cranial nerves, the motor and sensory systems,and reﬂexes.
As you review this material, note that the central nervous system consists of
the brain and the spinal cord. The peripheral nervous system consists of the
12 pairs of cranial nerves and the spinal and peripheral nerves. Most of theperipheral nerves contain both motor and sensory ﬁbers.
The Nervous SystemCHAPTER
The Nervous System 1616
CHAPTER 16 ITHE NERVOUS SYSTEM 535
Frontal lobe
Pituitary glandParietal lobe
Occipital lobe

BrainstemMidbrain
CerebellumPons
MedullaDiencephalon
RIGHT HALF OF THE BRAIN, MEDIAL VIEW LEFT LATERAL VIEW OF THE BRAIN
Frontal lobeParietal lobe
Temporal lobe
BrainstemCerebellum

Deep in the brain lie additional clusters of gray matter. These include the
basal ganglia, which affect movement, and the thalamus and the hypothal-
amus (structures in the diencephalon). The thalamus processes sensory im-
pulses and relays them to the cerebral cortex. The hypothalamus maintains
homeostasis and regulates temperature, heart rate, and blood pressure. Thehypothalamus affects the endocrine system and governs emotional behav-iors such as anger and sexual drive. Hormones secreted in the hypothalamusact directly on the pituitary gland.
In contrast, note the internal capsule, a white matter structure where mye-
linated ﬁbers converge from all parts of the cerebral cortex and descend intothe brainstem. The brainstem, which connects the upper part of the brain with
the spinal cord, has three sections: the midbrain, the pons, and the medulla.ANATOMY AND PHYSIOLOGY
536 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Gray matter
White matter
Optic tractInternal
capsule

capsule
Basal 
ganglia
ThalamusCorpus callosum
CORONAL SECTION OF THE BRAINCentral Nervous System
THE BRAIN
The brain has four regions: the cerebrum, the diencephalon, the brainstem,
and the cerebellum. The cerebral hemispheres contain the greatest mass ofbrain tissue. Each hemisphere is subdivided into frontal, parietal, temporal,and occipital lobes.
The brain is a vast network of interconnecting neurons (nerve cells). These
consist of cell bodies and their axons —single long ﬁbers that conduct im-
pulses to other parts of the nervous system.
Brain tissue may be gray or white. Gray matter consists of aggregations of
neuronal cell bodies. It rims the surfaces of the cerebral hemispheres, form-ing the cerebral cortex. White matter consists of neuronal axons that are
coated with myelin. The myelin sheaths, which create the white color, allownerve impulses to travel more rapidly.

CHAPTER 16 ITHE NERVOUS SYSTEM 537C2 cord segment
C2 nerve root
T1 nerve root
L1 cord segment
S1 cord segmentT1 cord segmentC8 nerve root
S1 nerve rootAnterior PosteriorSpinous process T1
vertebra
Spinous process L1
vertebra
Cauda equinaC1
C2
C3
C4
C5
C6
C7
T8
T9T1
T2
T3
T4
T5
L1
L2
L3
L4
L5
S1
S2
S3
S4S5T6
T7
T11T10
T12
THE SPINAL CORD, LATERAL VIEW
THE SPINAL CORD
The spinal cord is a cylindrical mass of nerve tissue encased within the bony
vertebral column, extending from the medulla to the ﬁrst or second lum-bar vertebra. It contains important motor and sensory nerve pathways thatexit and enter the cord via anterior and posterior nerve roots and spinal andperipheral nerves. The spinal cord also mediates reﬂex activity of the deeptendon (or spinal nerve) reflexes. Motor and sensory tracts and the deeptendon reﬂexes are further discussed on pp. 541–546).
The spinal cord is divided into ﬁve segments: cervical (C1–8), thoracic

(T1–12), lumbar (L1–5), sacral (S1–5), and coccygeal.Consciousness depends on the interaction between intact cerebral hemi-
spheres and an important structure in the diencephalon and upper brain-stem, the reticular activating (arousal) system.
The cerebellum, which lies at the base of the brain, coordinates all movement
and helps maintain the body upright in space.

Note that the spinal cord is not as long as the vertebral canal. The level of
the nerve roots exiting the cord differs from the adjacent vertebral level. Thelumbar and sacral roots travel the longest intraspinal distance. These rootsfan out like a horse’s tail at L1–2, giving rise to the term cauda equina.
(To avoid injury to the cord, most lumbar punctures are performed at theL3–4 vertebral interspace.)
Peripheral Nervous System
THE CRANIAL NERVES
Twelve pairs of special nerves called cranial nerves emerge from within the
skull or cranium . Cranial Nerves II through XII arise from the diencephalon
and the brainstem, as illustrated below. (Cranial Nerves I and II are actuallyﬁber tracts emerging from the brain.) Some cranial nerves are limited to gen-eral motor or sensory functions, whereas others are specialized, producingsmell, vision, or hearing (I, II, VIII).
Functions of the cranial nerves (CN) most relevant to physical examination
are summarized on the next page.

538 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Pituitary gland
CN I olfactory
MIDBRAIN
CN III oculomotor
CN IV trochlear
MEDULLA
CN IX
glossopharyngeal
CN X
vagus
CN XI
spinalaccessory
CN XII
hypoglossalCerebellumCN VIII
acousticCN VII facialCN VI abducensCN V
trigeminalPONSCN II optic tractCN II optic nerveDIENCEPHALON
INFERIOR SURFACE OF THE BRAIN
THE PERIPHERAL NERVES
In addition to cranial nerves, the peripheral nervous system also includes spinal
and peripheral nerves that carry impulses to and from the cord. Thirty-onepairs of nerves attach to the spinal cord: 8 cervical, 12 thoracic, 5 lumbar,

CHAPTER 16 ITHE NERVOUS SYSTEM 539RIGHT EYE (CN III, IV, VI)
CN V—SENSORY
CN XI—MOTORNo. Cranial Nerve Function
I Olfactory Sense of smell
II Optic Vision
III Oculomotor Pupillary constriction, opening the eye, and most 
extraocular movements
IV Trochlear Downward, inward movement of the eye
VI Abducens Lateral deviation of the eye
V Trigeminal Motor —temporal and masseter muscles (jaw 
clenching), also lateral movement of the jaw
Sensory —facial. The nerve has three divisions: 
(1) ophthalmic, (2) maxillary, and (3) mandibular.
VII Facial Motor —facial movements, including those of facial 
expression, closing the eye, and closing the mouth
Sensory —taste for salty, sweet, sour, and bitter 
substances on the anterior two thirds of the tongue
VIII Acoustic Hearing (cochlear division) and balance (vestibular 
division)
IX Glossopharyngeal Motor —pharynx
Sensory —posterior portions of the eardrum and ear

division)
Sensory —posterior portions of the eardrum and ear 
canal, the pharynx, and the posterior tongue,including taste (salty, sweet, sour, bitter)
X Vagus Motor —palate, pharynx, and larynx
Sensory —pharynx and larynx
XI Spinal accessory Motor —the sternomastoid and upper portion of the 
trapezius
XII Hypoglossal Motor —tongueCN V—MOTOR
Temporal muscle
Masseter muscle
IIIIII III
III
IVVI
(1)
(2)
(3)C2
Trapezius muscle
muscle

MuscleEfferent
motor fiber
Anterior root Anterior
horn cellAnterior
hornPosterior horn
Posterior root Posterior root
ganglion
Afferent
sensoryfiber5 sacral, and 1 coccygeal. Each nerve has an anterior (ventral) root contain-
ing motor ﬁbers, and a posterior (dorsal) root containing sensory ﬁbers. Theanterior and posterior roots merge to form a short ( <5 mm) spinal nerve.
Spinal nerve ﬁbers commingle with similar ﬁbers from other levels to formperipheral nerves. Most peripheral nerves contain both sensory (afferent) and
motor (efferent) ﬁbers.
Like the brain, the spinal cord contains both gray matter and white matter.
Nuclei of gray matter, which are aggregations of nerve cell bodies, are sur-rounded by white tracts of nerve ﬁbers connecting the brain to the periph-eral nervous system. Note the butterﬂy appearance of the gray matter nuclei,with anterior and posterior horns.ANATOMY AND PHYSIOLOGY
540 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGTHE SPINAL CORD, CROSS SECTION

Spinal Reﬂexes: The Deep Tendon Response
The deep tendon or muscle stretch reﬂexes are relayed over structures ofboth the central and peripheral nervous systems. Recall that a reﬂex is an in-
voluntary stereotypical response that may involve as few as two neurons, oneafferent (sensory) and one efferent (motor), across a single synapse. Thedeep tendon reﬂexes in the arms and legs are such monosynaptic reﬂexes.They illustrate the simplest unit of sensory and motor function. (Other re-ﬂexes are polysynaptic, involving interneurons interposed between sensoryand motor neurons.)
To elicit a deep tendon reﬂex, briskly tap the tendon of a partially stretched

muscle. For the reﬂex to ﬁre, all components of the reﬂex arc must be intact:sensory nerve ﬁbers, spinal cord synapse, motor nerve ﬁbers, neuromuscularjunction, and muscle ﬁbers. Tapping the tendon activates special sensoryﬁbers in the partially stretched muscle, triggering a sensory impulse that trav-els to the spinal cord via a peripheral nerve. The stimulated sensory ﬁber

synapses directly with the anterior horn cell innervating the same muscle.
When the impulse crosses the neuromuscular junction, the muscle suddenlycontracts, completing the reﬂex arc.
Because each deep tendon reﬂex involves speciﬁc spinal segments, together
with their sensory and motor ﬁbers, an abnormal reﬂex can help you to lo-cate a pathologic lesion. You should know the segmental levels of the deeptendon reﬂexes. You can remember them easily by their numerical sequencein ascending order from ankle to triceps: S1—L2, 3, 4,—C5, 6, 7.
Ankle reﬂex Sacral 1 primarily
Knee reﬂex Lumbar 2, 3, 4Supinator (brachioradialis) reﬂex Cervical 5, 6Biceps reﬂex Cervical 5, 6Triceps reﬂex Cervical 6, 7
Reﬂexes may be initiated by stimulating skin as well as muscle. Stroking the
skin of the abdomen, for example, produces a localized muscular twitch.These superﬁcial (cutaneous) reﬂexes and their corresponding spinal seg-ments include:
Abdominal reﬂexes—upper Thoracic 8, 9, 10

—lower Thoracic 10, 11, 12
Plantar responses Lumbar 5, Sacral 1
Motor Pathways
Motor pathways contain upper motor neurons, synapses in the brainstem orspinal cord, and lower motor neurons. Nerve cell bodies or upper motor neu-
ronslie in the motor strip of the cerebral cortex and in several brainstem nu-
clei; their axons synapse with motor nuclei in the brainstem (for cranialnerves) and in the spinal cord (for peripheral nerves). Lower motor neurons
have cell bodies in the spinal cord, termed anterior horn cells; their axonstransmit impulses through the anterior roots and spinal nerves into periph-eral nerves, terminating at the neuromuscular junction.
Three kinds of motor pathways impinge on the anterior horn cells: the cor-

ticospinal tract, the basal ganglia system, and the cerebellar system. Thereare additional pathways originating in the brainstem that mediate ﬂexor andextensor tone in limb movement and posture; most notable in coma (seeTable 16-16, p. 622).
All of these higher motor pathways affect movement only through the lower
motor neurons—sometimes called the “ﬁnal common pathway.” Any move-ment, whether initiated voluntarily in the cortex, “automatically” in the
CHAPTER 16 ITHE NERVOUS SYSTEM 541

basal ganglia, or reﬂexly in the sensory receptors, must ultimately be trans-
lated into action via the anterior horn cells. A lesion in any of these areas willaffect movement or reﬂex activity.
When the corticospinal tract is damaged or destroyed, its functions are re-
duced or lost below the level of injury. When upper motor neurons are dam-
aged above the crossover of its tracts in the medulla, motor impairment devel-ops on the opposite or contralateral side. In damage below the crossover, motorimpairment occurs on the same or ipsilateral side of the body. The affected limb
becomes weak or paralyzed, and skilled, complicated, or delicate movementsare performed especially poorly when compared to gross movements. Mus-cle tone is increased and deep tendon reﬂexes are exaggerated.
Damage to the lower motor neurons causes ipsilateral weakness and paral-
ysis, but in this case muscle tone and reﬂexes are decreased or absent.

Disease of the basal ganglia system or cerebellar system does not cause
paralysis, but can be disabling. Damage to the basal ganglia system pro-duces changes in muscle tone (most often an increase), disturbances inposture and gait, a slowness or lack of spontaneous and automatic move-ments termed bradykinesia , and a variety of involuntary movements. Cere-
bellar damage impairs coordination, gait, and equilibrium, and decreasesmuscle tone.
Sensory Pathways
Sensory impulses not only participate in reﬂex activity, as previously de-scribed, but also give rise to conscious sensation, calibrate body position in
542 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGTHE PRINCIPAL MOTOR PATHWAYS
IThe corticospinal (pyramidal) tract .The corticospinal tracts mediate voluntary

movement and integrate skilled, complicated, or delicate movements by stimu-lating selected muscular actions and inhibiting others. They also carry impulsesthat inhibit muscle tone, the slight tension maintained by normal muscle even
when it is relaxed. The corticospinal tracts originate in the motor cortex of thebrain. Motor ﬁbers travel down into the lower medulla, where they form ananatomical structure resembling a pyramid. There most of these ﬁbers cross tothe opposite or contralateral side of the medulla, continue downward, and
synapse with anterior horn cells or with intermediate neurons. Tracts synapsingin the brainstem with motor nuclei of the cranial nerves are termed corticobulbar.
IThe basal ganglia system .This exceedingly complex system includes motor

pathways between the cerebral cortex, basal ganglia, brainstem, and spinalcord. It helps to maintain muscle tone and to control body movements, espe-cially gross automatic movements such as walking.
IThe cerebellar system .The cerebellum receives both sensory and motor input
and coordinates motor activity, maintains equilibrium, and helps to control posture.

A complex system of sensory receptors relays impulses from skin, mucous
membranes, muscles, tendons, and viscera. Sensory fibers registering sen-sations such as pain, temperature, position, and touch, pass through theperipheral nerves and posterior roots and enter the spinal cord. Once inside the cord, sensory impulses reach the sensory cortex of the brain ANATOMY AND PHYSIOLOGY
CHAPTER 16 ITHE NERVOUS SYSTEM 543Knee
Hip
Trunk
Hand
Face
Tongue
Basal
gangliaThalamus
Internal
 capsule
MIDBRAIN
LOWER MEDULLA
SPINAL CORDCorticospinal tracts
Lateral corticospinal
tract
Anterior corticospinal
tractCorticobulbar tract
Pyramids
MOTOR PATHWAYS: CORTICOSPINAL AND CORTICOBULBAR TRACTSspace, and help regulate internal autonomic functions like blood pressure,
heart rate, and respiration.

via one of the two pathways: the
spinothalamic tracts or the poste-rior columns.
Within one or two spinal segments
from their entry into the cord, ﬁbersconducting the sensations of pain
and temperature pass into the pos-
terior horn of the spinal cord andsynapse with secondary sensoryneurons. Fibers conducting crude
touch —a sensation perceived as light
touch but without accurate localiza-tion—also pass into the posteriorhorn and synapse with secondaryneurons. The secondary neuronsthen cross to the opposite side andpass upward in the spinothalamic
tract into the thalamus.
Fibers conducting the sensations of
position and vibration pass directly
into the posterior columns of the
cord and travel upward to themedulla, together with fibers trans-mitting fine touch —touch that is

accurately localized and finely dis-criminating. These fibers synapse inthe medulla with secondary sensoryneurons. Fibers projecting fromsecondary neurons cross to the op-posite side at the medullary leveland continue on to the thalamus.
At the thalamic level, the general
quality of sensation is perceived(e.g., pain, cold, pleasant and un-pleasant), but ﬁne distinctions are not made. For full perception, a thirdgroup of sensory neurons sends impulses from the thalamus to the sensory
cortex of the brain. Here stimuli are localized and discriminations made
among them.
Lesions at different points in the sensory pathways produce different kinds

of sensory loss. Patterns of sensory loss, together with their associated motorﬁndings, help you to identify where the causative lesions might be. A lesionin the sensory cortex may not impair the perception of pain, touch, andposition, for example, but does impair finer discrimination. A person soaffected cannot appreciate the size, shape, or texture of an object by feelingit and therefore cannot identify it. Loss of position and vibration sense withANATOMY AND PHYSIOLOGY
544 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGPARIETAL LOBEThigh area
Trunk
area
Arm area
Face
area
THALAMUS
Posterior column:
 Position and vibration Fine touch
Posterior root
Posterior roo
t
ganglionSpinothalamic tract:
 Pain and temperature Crude touch
SPINAL CORD T5
SPINAL CORD L4LOWER MEDULLA

THALAMUS
t
SENSORY PATHWAYS: SPINOTHALAMIC TRACT AND POSTERIOR COLUMNS

Radial 
nerve
Median
nerveUlnar 
nerve
Lateral
cutaneousnerve of thigh
Lateral
cutaneousnerve of calf
peronealnerveAnteriorfemoralcutaneousnerve
Cutaneousbranches ofsaphenousnerve
C2
C3C3 Front of neck
C4
C5
C5C5
C6 C6C6 Thumb
C7 C7 C8C8
C8 Ring and
little fingersT8
T9T7T6T5T4 T4 NipplesT3T2T1
T10T10 Umbilicus
T11
T12
L1
L1 InguinalL2 L2
L3 L3
L4 L4
L4 Knee
L5 L5
L5 Anterior ankle
and foot
L5 L5S1 S1S2,3preservation of other sensations points to disease of the posterior columns,
while loss of all sensations from the waist down, together with paralysis andhyperactive reﬂexes in the legs, indicates transection of the spinal cord (seeTable 16-5, p. 603). Crude and light touch are often preserved despitepartial damage to the cord because impulses originating on one side of thebody travel up both sides of the cord.
A knowledge of dermatomes also aids in localizing neurologic lesions. A

dermatome is the band of skin innervated by the sensory root of a single spinalnerve. Dermatome patterns are mapped in the next two figures. Their lev-ANATOMY AND PHYSIOLOGY
CHAPTER 16 ITHE NERVOUS SYSTEM 545AREAS INNERVATED BY PERIPHERAL
NERVES DERMATOMES INNERVATED BY POSTERIOR ROOTS

els are considerably more variable than the diagrams suggest, and derma-
tomes overlap each other. The sensory nerves from each side of the bodyoverlap slightly across the midline. The distribution of a few key peripheralnerves is shown in the inserts on the left.
Do not try to memorize all the der-
matomes. It is useful, however, toremember the locations of some,such as those shaded in yellow onthe right side of the diagrams.ANATOMY AND PHYSIOLOGY
546 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Radial 
nerve
Median
nerve
Lateral
Lateral
peronealnervePosterior
femoralcutaneousnerve
Suralnerve
C2
C3
C3 Back of neckC4
C5
C6
C6
C6 
ThumbC7C8
C6
C7C7
C8C8
C8 Ring 
and little fingersT8
T9T7T6T5T4T3T2T1
T10
T11
T12
L1L2
L3
L4
L5
L5 L5L4 Anterior ankle
and foot
L5 Foot
L4S1
S1S2
S2S3
S4
S5
S5 Perianal
AREAS INNERVATED BY
PERIPHERAL NERVES DERMATOMES INNERVATED BY POSTERIOR ROOTS

Aging may affect all aspects of the nervous system, from mental status to
motor and sensory function and reﬂexes. Age-related losses may take theirtoll on the mental function of an elderly person. These include the deaths ofloved ones and friends, retirement from valued employment, diminution inincome, decreased physical capacities including impairments in vision andhearing, and perhaps decreased stimulation or growing isolation. In addi-tion, biologic changes affect the aging brain. Brain volume and the numberof cortical brain cells decrease, and both microanatomic and biochemicalchanges have been identiﬁed. Nevertheless, most men and women adaptwell to getting older. They maintain their self-esteem, they alter their activ-ities in ways that are appropriate to their changing capacities and circum-stances, and eventually they ready themselves for death.
In assessing the nervous system of an older person, it is sometimes difﬁcult

to distinguish the changes of normal aging from those of age-related orother diseases. Some ﬁndings that you would consider abnormal in youngerpeople, however, occur often enough in the elderly that you may attributethem to aging alone. Alterations in hearing, vision, extraocular movements,and pupillary size, shape, and reactivity have been described in Chapter 5(see pp. 134–136).
Changes in the motor system are common. Older persons move and react

with less speed and agility than younger ones, and skeletal muscles decreasein bulk. The hands of an aged person often look thin and bony because theirsmall muscles have atrophied. Look for such muscular wasting in the backs ofthe hands, where atrophy of the dorsal interosseous muscles may leave con-cavities or grooves. As illustrated on page 572, this change is often most evi-dent between the thumb and the hand (1st and 2nd metacarpals) but may alsobe seen between the other metacarpals. Atrophy of small muscles may also ﬂat-ten the thenar and hypothenar eminences of the palms. Muscle strength,though diminished, is relatively well maintained. Arm and leg muscles may alsoshow atrophy. This sometimes exaggerates the apparent size of adjacent joints.
Occasionally, an older person develops a benign essential tremor in the head,

jaw, lips, or hands that may be confused with parkinsonism (p. 608). Unlikeparkinsonian tremors, however, benign tremors are slightly faster and dis-appear at rest, and there is no associated muscle rigidity.
Vibration sense is frequently decreased or lost in the feet and ankles (but not
in the ﬁngers or over the shins). Less commonly, position sense may dimin-ish or disappear.
Aging may also alter some of the reﬂexes. The gag reﬂex may be diminished
or absent. Ankle reﬂexes may be symmetrically decreased or absent, evenwhen reinforced. Less commonly, knee reﬂexes are similarly affected. Ab-dominal reﬂexes may diminish or disappear and, partly because of musculo-skeletal changes in the feet, the plantar responses become less obvious andmore difﬁcult to interpret.
CHAPTER 16 ITHE NERVOUS SYSTEM 547

If changes such as those described are accompanied by other neurologic ab-
normalities, or if atrophy and reﬂex changes are asymmetric, you shouldsearch for an explanation other than age alone.
Most elderly people do well on a mental status examination, but functional
impairments may become evident, especially at advanced ages. Many olderpeople complain about their memories. “Benign forgetfulness” is the usualexplanation and may occur at any age. This term refers to a difﬁculty in re-calling the names of people or objects or certain details of speciﬁc events.Naming this common phenomenon, when appropriate, may help to reassurea person who is worried that it signiﬁes Alzheimer’s disease. In addition tothis circumscribed forgetfulness, elderly people retrieve and process datamore slowly, and they take more time to learn new material. Their motorresponses may slow, and their ability to perform complex tasks may becomeimpaired.

The clinician must often try to distinguish these age-related changes from
the manifestations of specific mental disorders, some of which are moreprevalent with aging, such as depression and dementia. Sorting out theseailments from medical complaints may be difﬁcult, particularly since bothmood disturbances and cognitive changes may impair the patient’s abilityto recognize or report symptoms. Older patients are also more susceptibleto delirium, a temporary confusional state that may be the ﬁrst clue to in-fection or problems with medications. The clinician must learn to recog-nize these conditions promptly and to protect the patient from harm. (In-formation on detection of these conditions can be found on pp. 549–551,the Health History, on pp. 551–553, Health Promotion and Counseling,and in Table 16-1, Disorders of Mood, p. 599, and Table 16-5, Deliriumand Dementia, p. 603.)THE HEALTH HISTORY
548 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGCommon or Concerning Symptoms

IChanges in mood, attention, or speech
IChanges in orientation, memory, insight, or judgment
IDelirium or dementia
IHeadache
IDizziness or vertigo
IGeneralized, proximal, or distal weakness
INumbness, abnormal or loss of sensations
ILoss of consciousness, syncope, or near-syncope
ISeizures
ITremors or involuntary movements

Much of the information about the patient’s mental status becomes evident
during the interview. As you talk to the patient and listen to the patient’sstory, you should assess level of consciousness, general appearance and mood,
and ability to pay attention, remember, understand, and speak. By placing the
patient’s vocabulary and general fund of information in the context of thepatient’s cultural and educational background, you can often make a roughestimate of intelligence. Likewise, the patient’s responses to illness and lifecircumstances often tell you about his or her degree of insight and judgment.
If the patient has unusual thoughts, preoccupations, beliefs, or perceptions,you should explore them as they arise during the interview. If you suspect aproblem in orientation and memory, you can ask, “Let’s see, your last clinic

appointment was when . . . ?” . . . “And the date today?” The more you canintegrate your exploration of mental status into a sensitive patient history,the less it will seem like an interrogation.
For some patients, you will need to supplement your interview with ques-
tions in speciﬁc areas. You may determine the need to go further and pur-sue a formal mental status examination. The components of the mental sta-tus examination are described in the section on Techniques of Examination,pp. 556–557.
All patients with documented or suspected brain lesions, psychiatric symptoms,

or reports of vague or changed behavioral symptoms by family members needfurther systematic assessment. Patients may have subtle behavioral changes, dif-ﬁculty taking medications properly, problems attending to household choresor paying bills, or loss of interest in their usual activities. Other patients may be-have strangely after surgery or during an acute illness. Each problem should beidentiﬁed as expeditiously as possible. Mental function inﬂuences the ability tohold a job and is often important in evaluating disability.
Two of the most common symptoms in neurologic disorders are headache
and dizziness. Turn to p. 136 and p. 139 to review the health history perti-
nent to these symptoms.
For headache, be sure to ask about location, severity, how long it lasts, and

any associated symptoms, such as visual changes, weakness, or loss of sensa-tion. Ask if the headache is affected by coughing, sneezing, or sudden move-ments of the head.
The complaint of dizziness can have many meanings. You will need to elicit
exactly what the patient has experienced. Is the patient light-headed orfeeling faint? Or is there vertigo, a perception that the room is spinning or
rotating?THE HEALTH HISTORY
CHAPTER 16 ITHE NERVOUS SYSTEM 549See Table 16-1, Disorders of Mood,
p. 599, and Table 16-2, Disordersof Speech, p. 600.
See Table 16-3, Anxiety Disorders,
p. 601, and Table 16-4, PsychoticDisorders, p. 602.
Possible signs of depression or 
dementia
See Table 16-5, Delirium and 
Dementia, p. 603.
See Table 5-1, Headaches, pp.
170–173.
Subarachnoid hemorrhage may

dementia
170–173.
evoke “the worst headache of mylife.” Dull headache affected bysuch maneuvers, especially onawakening and recurring in thesame location, is seen with mass lesions such as a brain tumor.
Light-headedness in palpitations,
near syncope from vasovagal stimulation, low blood pressure,febrile illness, and others. Vertigoin middle-ear conditions, brainstemtumor. See Table 5-2, p. 174.EXAMPLES OF ABNORMALITIES

Especially in older patients, are any medications contributing to the dizzi-
ness? Are there any associated symptoms such as double vision, or diplopia,
difﬁculty forming words, or dysarthria, or difﬁculty with gait or balance, or
ataxia ?
What about any associated weakness, either generalized or in the face or a
part of the body? Weakness is another common symptom and requires care-ful attention to detail. Probe for exactly what it means to the patient. Ex-plore whether there is any paralysis, or inability to move a part or side of the
body. Did the weakness start slowly or suddenly? Has it progressed? How?What areas of the body are involved? Does the weakness affect one or bothsides? What movements are affected?
For weakness without light-headedness, try to distinguish between proxi-
maland distal weakness. For proximal weakness, ask about combing hair, try-

ing to reach something on a high shelf, or difﬁculty getting up out of a chairor taking a high step up. Does the weakness increase with repeated effortand improve after rest? Are there associated sensory or other symptoms? Fordistal weakness in the arms, inquire about hand movements such as openinga jar or can, or using hand tools such as scissors, pliers, or a screwdriver. Fordistal weakness in the legs, ask about frequent tripping.
Find out if the patient has had any loss of sensation. Ask if there has been
any numbness, but clarify its meaning and location. Has there been loss of
sensation, difficulty moving a limb, or altered sensations such as tinglingor pins and needles? There may be peculiar sensations without an obviousstimulus, called paresthesias. These occur commonly when an arm or leg

“goes to sleep” following compression of a nerve, and may be described astingling, prickling, or feelings of warmth, coldness, or pressure. Dysesthe-
siasare distorted sensations in response to a stimulus and may last longer
than the stimulus itself. For example, a person may perceive a light touchor pinprick as a burning or tingling sensation that is irritating or unpleas-ant. Pain may arise from neurologic causes but is usually reported with
symptoms of other body systems, such as the head and neck or the mus-culoskeletal system.
“Have you ever fainted or passed out?” leads the discussion to any loss of con-
sciousness. It is important to begin by exploring what the patient means by
loss of consciousness. Did the patient black out completely, or could voicesbe heard throughout the episode, indicating some consciousness? Be sure touse descriptive terms carefully and precisely. Syncope is the sudden but tem-

porary loss of consciousness that occurs with decreased blood ﬂow to thebrain, commonly described as fainting. Symptoms of feeling faint, light-
headed, or weak, but without actual loss of consciousness, are called near
syncope or presyncope.THE HEALTH HISTORY
550 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGDiplopia, dysarthria, ataxia in pos-
terior circulation transient ischemicattack (TIA) or stroke
Weakness or paralysis in transient
ischemic attack or stroke
Focal weakness may arise from 
ischemic, vascular, or mass lesionsin the central nervous system; also from peripheral nervous system disorders, neuromusculardisorders, or the muscles themselves.
Bilateral proximal weakness in my-
opathy. Bilateral, predominantlydistal weakness in polyneuropathy.Weakness made worse with re-peated effort and improved withrest suggests myasthenia gravis.
Loss of sensation, paresthesias, and

dysesthesias in central lesions inthe brain and spinal cord, as wellas disorders of peripheral sensoryroots and nerves; paresthesias inthe hands and around the mouthin hyperventilation.
170–173, Table 15-2, Pains in theNeck, p. 523, and Table 15-1, LowBack Pain, p. 522.
See Table 16-6, Syncope and Simi-
lar Disorders, pp. 604–605.EXAMPLES OF ABNORMALITIES

Get as complete and unbiased a description of the event as you can. What
brought on the episode? Were there any warning symptoms? Was the patientstanding, sitting, or lying down when the episode began? How long did itlast? Could voices be heard while passing out and coming to? How rapidlydid the patient recover? In retrospect, were onset and offset slow or fast?
Also ask if anyone observed the episode. If so, what did the patient look like
before losing consciousness, during the episode, and afterward? Was thereany seizure-like movement of the arms or legs? Any incontinence of the blad-der or bowel? Any drowsiness or impaired memory after the episode ended?
A seizure is a paroxysmal disorder caused by sudden excessive electrical dis-

charge in the cerebral cortex or its underlying structures. Seizures can be ofseveral types. Depending on the type, there may or may not be loss of con-sciousness. With some types of seizures, there may be abnormal feelings,thought processes, and sensations, including smells, as well as abnormalmovements. Asking “Have you ever had any seizures or ‘spells’?” . . . “Anyﬁts or convulsions?” can open the discussion. As with syncope, aim for a fulland complete description, including precipitating circumstances, warnings,and behavior and feelings both during the attack and afterward. Ask aboutage at onset, frequency, any change in frequency or symptom pattern, anduse of medications. Is there any history of prior head injury or other condi-tions that may be causally related?
Tremors and other involuntary movements occur with or without additional

neurologic manifestations. Ask about any trembling, shakiness, or bodymovements that the patient seems unable to control.
Distinct from these symptoms is an almost indescribable restlessness of the legs
that typically develops at rest and is accompanied by an urge to move about.Walking gives relief.HEALTH PROMOTION AND COUNSELING
CHAPTER 16 ITHE NERVOUS SYSTEM 551Young people with emotional stress
and warning symptoms of ﬂushing,warmth, or nausea may have vasodepressor (or vasovagal) syncopeof slow onset, slow offset. Cardiac
syncope from arrhythmias, more
common in older patients, oftenwith sudden onset, sudden offset.
Tonic-clonic motor activity, blad-
der or bowel incontinence, andpostictal state suggest a general-
ized seizure. Unlike syncope, injury
such as tongue biting or bruisingof limbs may occur.
See Table 16-7, Seizure Disorders,
pp. 606–607.
See Table 16-8, Involuntary 
Movements, pp. 608–609.

The common but often over-
looked restless legs syndrome,usually benign
IScreening for depression and suicidality
IScreening for dementia
IPrevention of TIAs or stroke

Up to a third of all primary care visits involve mental health—depressed
mood, anxiety, somatic concerns, and more serious disorders of mood andmental function. The burden of suffering imposed by these disorders isgreat. For the general population, focus health promotion and counsel-ing on depression, suicidality, and dementia, three important conditionsoften overlooked. You should also screen for use of drugs or alcohol (seepp. 43–45).
The lifetime prevalence of major depression meeting formal diagnostic cri-

teria is 5% to 10% in men and 10% to 20% in women. Primary-care providersfail to diagnose major depression in up to 50% of affected patients, oftenmissing early clues such as low self-esteem, anhedonia (failure to ﬁnd plea-sure in daily activities), sleep disorders, and difﬁculty in concentrating ormaking decisions. Routine general screening has not been shown to improveoutcomes; rather, target diagnosis and treatment to patients who are symp-tomatic. Watch carefully for depressive symptoms, especially in patients whoare young, female, single, divorced, separated, seriously or chronically ill, orbereaved. Patients with a prior history of depression or positive family his-tory are also at risk. Failure to diagnose depression can have consequencesthat are fatal—suicide rates in patients with major depression are eight timeshigher than in the general population.*

Clinicians must be adept at eliciting suicidal ideation or intent (see Chap 2,
p. 47). Suicide rates are highest among men over age 65, but have been in-creasing in teenagers and young adults. Risk factors include any history ofpsychiatric illness (especially if linked to a hospital admission), substanceabuse, personality disorder, prior suicide attempt, or family history of sui-cide. Clinicians should ask about domestic ﬁrearms and screen for alcoholdependence: guns are present in the home of more than half of all suicidevictims, and alcohol intoxication is associated with nearly 25% of suicidedeaths. Any evidence of suicidal ideation must be further assessed. Has aweapon been obtained? Is there a plan or a note? Such patients should bepromptly referred for mental health and psychiatric care and for treatmentof any related problems of alcohol or drug abuse.
Dementia, a “global impairment of cognitive function that interferes with
normal activities,”

†affects 16% of Americans over 65. Prominent features
include short- and long-term memory deficits and impaired judgment.Thought processes are impoverished and speech may be hesitant due todifficulty in finding words. Loss of orientation to place may make navigat-ing by foot or car problematic or even dangerous. Most dementias repre-sent Alzheimer’s disease (~50%–85%) or vascular multi-infarct dementia(~10%–20%). Be watchful for Alzheimer’s disease in individuals with a pos-HEALTH PROMOTION AND COUNSELING
552 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING*U.S. Preventive Services Task Force: Ch. 49: “Screening for Depression.” In Guide to Clinical Pre-
ventive Services. Baltimore, Williams and Wilkins, pp. 541–546, 1996.
†U.S. Preventive Services Task Force: Ch. 48: “Screening for Dementia.” In Guide to Clinical Preven-

tive Services. Baltimore, Williams and Wilkins, pp. 531–541, 1996.

itive family history, since their risk is three times higher than in the general
Dementia often has a slow, insidious onset and may escape detection by both

families and clinicians, especially in its initial stages. Currently there are noreliable screening tests to help you detect dementia early in its course. Clin-icians should be alert to evidence of change in cognitive function or activi-ties of daily living, and to family complaints about new or unusual patientbehaviors. Use of the Mini-Mental State Examination is helpful for assess-ing cognitive impairment (although scores may be affected by level of edu-cation and cultural variables such as language). Once cognitive change isidentiﬁed, be sure to address the possible role of medications, depression, ormetabolic abnormalities. Couple cognitive and behavioral assessment witha careful neurologic examination during your evaluation of the patient. Besure to look for other medical and psychiatric conditions that could becontributing to changes in behavior or level of daily activity. For dementedpatients and affected families, counseling about the potential for disruptivebehavior,

psychiatric conditions that could becontributing to changes in behavior or level of daily activity. For dementedpatients and affected families, counseling about the potential for disruptivebehavior, accidents and falls, and termination of driving privileges is war-ranted. Clinicians can foster discussion of legal matters such as power of at-torney and advanced directives while the patient is still able to contribute todecision-making.

Finally, direct clinical attention to averting cerebrovascular accidents (CVAs).
Strokes, or CVAs, are the third leading cause of death in the United Statesand contribute to extensive disability in the workforce and general popula-tion. The incidence of stroke increases with age and is 60% higher in AfricanAmericans compared to Caucasians. The clinician’s first task in stroke pre-vention is to control hypertension. Hypertension accelerates atheroscleroticchanges in the carotid, vertebral, and cerebral arteries and disturbs auto-regulation of cerebral blood pressure. It is the leading risk factor for bothischemic and hemorrhagic stroke, which account for approximately 85% andapproximately 10% of all CVAs, respectively. In addition, clinicians shouldcounsel patients to modify conditions contributing to atherosclerosis: smok-ing, hyperlipidemia, and diabetes. Drug users should be warned of the linkbetween stroke and cocaine.

Clinicians should be alert to symptoms of transient ischemic attacks (TIAs),
generally deﬁned as neurologic events that resolve within 24 hours. TIAscan be viewed as CVA warning signals, the anginal equivalent of the brain.In the first year after a TIA, risk of CVA is 6%–7%, and the CVA usually occurs in the same vascular distribution as the TIA. Common symptoms ofTIAs include visual loss (especially transient monocular blindness from em-boli), aphasia, dysarthria, and changes in facial movement or sensation. ForTIAs affecting motor or sensory pathways, watch for clumsiness, weakness,paralysis, or tingling or paresthesias of the arm, leg, or hemibody.HEALTH PROMOTION AND COUNSELING
CHAPTER 16 ITHE NERVOUS SYSTEM 553

554 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGSuggests left hemispheric CVA 
in distribution of the left middlecerebral artery, with right-sidedhemiparesisPreview: Recording the Examination—The Nervous System
Note that initially you may use sentences to describe your ﬁndings; lateryou will use phrases. The style below contains phrases appropriate formost write-ups. Unfamiliar terms are explained in the next section, Techniques of Examination. Note that there are ﬁve components to the examination and write-up of the nervous system.
“Mental Status: Alert, relaxed, and cooperative. Thought process 
coherent. Oriented to person, place, and time. Detailed cognitive test-ing deferred. Cranial Nerves: I—not tested; II through XII intact. 
Motor: Good muscle bulk and tone. Strength 5/5 throughout. 
Cerebellar: Rapid alternating movements (RAMs), ﬁnger-to-nose (F →N),
heel-to-shin (H →S) intact. Gait with normal base. Romberg—maintains

balance with eyes closed. No pronator drift. Sensory: Pinprick, light
touch, position, and vibration intact. Reﬂexes: 2+ and symmetric with
plantar reﬂexes downgoing.”
OR“Mental Status: The patient is alert and tries to answer questions but
has difﬁculty ﬁnding words. Cranial Nerves: I—not tested; II—visual
acuity intact; visual ﬁelds full; III, IV, VI—extraocular movements intact;V motor—temporal and masseter strength intact, sensory corneal re-ﬂexes present; VII motor—prominent right facial droop and ﬂatteningof right nasolabial fold, left facial movements intact, sensory—taste nottested; VIII—hearing intact bilaterally to whispered voice; IX, X—gag intact; XI—strength of sternomastoid and trapezius muscles 5/5; XII—tongue midline. Motor: strength in right biceps, triceps, iliopsoas,

gluteals, quadriceps, hamstring, and ankle ﬂexor and extensor muscles3/5 with good bulk but increased tone and spasticity; strength in com-parable muscle groups on the left 5/5 with good bulk and tone. Gait—unable to test. Cerebellar—unable to test on right due to rightarm and leg weakness; RAMs, F →N, H →S intact on left. Romberg—
unable to test due to right leg weakness. Right pronator drift present.Sensory: decreased sensation to pinprick over right face, arm, and leg;
intact on the left. Stereognosis and two-point discrimination nottested. Reﬂexes (can record in two ways):
RT 4+ 4+ 4+ 4+ 4+
LT 2+ 2+ 2+ 2+ 1+  Biceps Triceps Brach Knee Ankle PI
OREXAMPLES OF ABNORMALITIES

CHAPTER 16 ITHE NERVOUS SYSTEM 555Important Areas of Examination
IMental status: appearance and behavior, speech and language, mood,
thoughts and perceptions, cognition
ICranial Nerves I through XII
IMotor system: muscle bulk, tone, and strength; coordination, gait, and stance
ISensory system: pain and temperature, position and vibration, lighttouch, discrimination
IDeep tendon, abdominal, and plantar reﬂexes
Three important questions govern the neurologic examination:
IIs the mental status intact?
IAre right-sided and left-sided ﬁndings symmetric?
IAnd, if the ﬁndings are asymmetric or otherwise abnormal, does the
causative lesion lie in the central nervous system or the peripheral nervoussystem?
In this section, you will learn the techniques for a practical and reasonably

comprehensive examination of the nervous system. It is important to mas-ter the techniques for a thorough examination. At ﬁrst these techniques mayseem difﬁcult, but with practice, dedication, and supervision you will cometo feel comfortable evaluating neurologic symptoms and disease. You shouldbe active in your learning and ask your instructors or even neurologists toreview your skills.
The detail of an appropriate neurologic examination varies widely. As you
gain experience, you will ﬁnd that in healthy persons your examination willcome to be relatively brief. When you detect abnormal ﬁndings, your ex-amination will become more comprehensive. Be aware that neurologists mayuse many other techniques in speciﬁc situations.
For efﬁciency, you should integrate certain portions of the neurologic as-

sessment with other parts of your examination. Survey the patient’s mentalstatus and speech during the interview, for example, even though you maywish to do further testing during your neurologic evaluation. Assess someof the cranial nerves as you examine the head and neck, and inspect the armsand legs for neurologic abnormalities while you also observe the peripheralvascular and musculoskeletal systems. Chapter 3 provides an outline for thiskind of integrated approach. Think about and describe your ﬁndings, how-ever, in terms of the nervous system as a unit.

556 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGOrganize your thinking into ﬁve categories: (1) mental status, speech and
language, (2) cranial nerves, (3) the motor system, (4) the sensory system,and (5) reﬂexes. If your ﬁndings are abnormal, begin to group them intopatterns of central or peripheral disorders.
Mental Status
Your assessment of mental status, such as the General Survey, begins withthe ﬁrst words of the interview. As you gather the health history, you willquickly discern the patient’s level of alertness and orientation, mood, atten-
tion, and memory. As the history unfolds, you will learn about the patient’s
insight and judgment, as well as any recurring or unusual thoughts or percep-
tions. For some, you will need to supplement your interview with speciﬁc

questions and a more formal evaluation of mental status. Just as symptoms,blood pressure, and valvular murmurs help you to distinguish, for example,health from disease in the cardiovascular system, speciﬁc components ofmental function illuminate the workings of the mind. Although these com-ponents do not encompass all the aspects of human thought and feeling,they serve as useful and continually important clinical tools.
Components of the mental status examination include:
IAppearance and behavior
ISpeech and language
IMood
IThoughts and perceptions
ICognitive function, including memory, attention, information and vo-
cabulary, calculations, and abstract thinking and constructional ability.
Many of these terms are familiar to you from social conversation. Take the

time to learn their special meaning in the context of a formal mental statusevaluation.
COMPONENTS OF THE MENTAL STATUS EXAMINATION
Level of consciousness Alertness or state of awareness of the environment
Attention The ability to focus or concentrate over time on one 
task or activity—an inattentive or distractible per-son with impaired consciousness has difﬁcultygiving a history or responding to questions.
Memory The process of registering or recording information, 
tested by asking for immediate repetition of material, followed by storage or retention of information. Recent or short-term memory covers
minutes, hours, or days; remote or long-term 
memory refers to intervals of years.

Distinguishing the interplay of body and mind in relation to these attributes
is very important but not always easy. Mental disorders such as anxiety ordepression may take the form of somatic complaints. Likewise, physical ill-ness can cause mental and emotional responses and in older patients, can im-pair mental function without causing typical symptoms or signs such as feveror pain. Always look carefully for physical or pharmacologic causes as youtry to understand the context and emotional meaning of changes in mentalstatus. Some mental status evaluations are complicated by personality fac-tors, psychodynamics, or the patient’s personal experiences, areas that canbe explored during the interview (but not covered in this chapter). By inte-grating and correlating all the relevant data, the clinician tries to understandthe person as a whole.
As a student, you may feel reluctant to perform mental status examinations,

wondering if they will upset patients, invade their privacy, or result in label-ing their thoughts or behavior as pathologic. Such concerns are understand-able and appropriate. An insensitive examination of mental status may alarmTECHNIQUES OF EXAMINATION
CHAPTER 16 ITHE NERVOUS SYSTEM 557Orientation Awareness of personal identity, place, and time; 
requires both memory and attention
Perceptions Sensory awareness of objects in the environment 
and their interrelationships (external stimuli); also refers to internal stimuli such as dreams orhallucinations
Thought processes The logic, coherence, and relevance of the patient’s 
thought as it leads to selected goals, or how
people think
Thought content What the patient thinks about, including level of 
insight and judgment
Insight Awareness that symptoms or disturbed behaviors

Insight Awareness that symptoms or disturbed behaviors 
are normal or abnormal; for example, distinguish-ing between daydreams and hallucinations thatseem real
Judgment Process of comparing and evaluating alternatives 
when deciding on a course of action; reﬂects values that may or may not be based on realityand social conventions or norms
Affect An observable, usually episodic, feeling tone 
expressed through voice, facial expression, anddemeanor
Mood A more sustained emotion that may color a person’s 
view of the world (mood is to affect as climate isto weather)
Language A complex symbolic system for expressing, receiving, 
and comprehending words; as with consciousness,attention, and memory, language is essential forassessing other mental functions
Higher cognitive functions Assessed by vocabulary, fund of information,

Higher cognitive functions Assessed by vocabulary, fund of information, 
abstract thinking, calculations, construction ofobjects that have two or three dimensions

a patient, and even a skillful examination may bring to conscious awareness
an embarrassing or upsetting deﬁcit that the patient was trying to ignore.You may wish to discuss some of these concerns with your instructor orother experienced clinicians. As with other realms of interviewing and as-sessment, your skills and conﬁdence will improve with practice and rewardswill follow. Remember that many patients will appreciate an understandinglistener, and some will owe their health, their safety, or even their lives toyour attention.
The format that follows should help to organize your observations, but it is

not intended as a step-by-step guide. When a full examination is indicated,you should be ﬂexible in your approach but thorough in what you cover. Insome situations, however, sequence is important. If during your initial in-terview the patient’s consciousness, attention, comprehension of words, orability to speak seems impaired, assess this attribute promptly. Such a patientcannot give a reliable history and you will not be able to test most of theother mental functions.
APPEARANCE AND BEHAVIOR
Use here all the relevant observations made throughout the course of yourhistory and examination. Include these areas:
Level of Consciousness. Is the patient awake and alert? Does the pa-
tient seem to understand your questions and respond appropriately and rea-sonably quickly, or is there a tendency to lose track of the topic and fall silentor even asleep?

If the patient does not respond to your questions, escalate the stimulus in
steps:
ISpeak to the patient by name and in a loud voice.
IShake the patient gently, as if awakening a sleeper.
If there is no response to these stimuli, promptly assess the patient for stupor
or coma—severe reductions in the level of consciousness (see p. 595).
Posture and Motor Behavior. Does the patient lie in bed, or prefer
to walk about? Note body posture and the patient’s ability to relax. Observethe pace, range, and character of movements. Do they seem to be under vol-untary control? Are certain parts immobile? Do posture and motor activitychange with topics under discussion or with activities or people around thepatient?TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES

558 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGSee the table on Level of Con-
sciousness (Arousal), p. 595.
Lethargic patients are drowsy but
open their eyes and look at you,respond to questions, and then fallasleep.
Obtunded patients open their eyes
and look at you, but respond slowlyand are somewhat confused.
Tense posture, restlessness, and ﬁd-
getiness of anxiety; crying, pacing,and handwringing of agitated de-pression; hopeless, slumped postureand slowed movements of depres-sion; singing, dancing, and expan-sive movements of a manic episode.

dressed? Is clothing clean, pressed, and properly fastened? How does it com-pare with clothing worn by people of comparable age and social group? Notethe patient’s hair, nails, teeth, skin, and, if present, beard. How are theygroomed? How do the person’s grooming and hygiene compare with thoseof other people of comparable age, lifestyle, and socioeconomic group?Compare one side of the body with the other.
Facial Expression. Observe the face, both at rest and when the patient
is interacting with others. Watch for variations in expression with topicsunder discussion. Are they appropriate? Or is the face relatively immobilethroughout?
Manner, Affect, and Relationship to Persons and Things. Using

your observations of facial expressions, voice, and body movements, assessthe patient’s affect. Does it vary appropriately with topics under discussion,or is the affect labile, blunted, or ﬂat? Does it seem inappropriate or extremeat certain points? If so, how? Note the patient’s openness, approachability,and reactions to others and to the surroundings. Does the patient seem tohear or see things that you do not or seem to be conversing with someonewho is not there?
SPEECH AND LANGUAGE
Throughout the interview, note the characteristics of the patient’s speech,including the following:
Quantity. Is the patient talkative or relatively silent? Are comments spon-
taneous or only responsive to direct questions?
Rate. Is speech fast or slow?
Loudness. Is speech loud or soft?
Articulation of Words. Are the words spoken clearly and distinctly? Is
there a nasal quality to the speech?

Fluency. This involves the rate, ﬂow, and melody of speech and the con-
tent and use of words. Be alert for abnormalities of spontaneous speech suchas these:
IHesitancies and gaps in the ﬂow and rhythm of words
IDisturbed inﬂections, such as a monotone
ICircumlocutions, in which phrases or sentences are substituted for a wordthe person cannot think of, such as “what you write with” for “pen”TECHNIQUES OF EXAMINATION
CHAPTER 16 ITHE NERVOUS SYSTEM 559Grooming and personal hygiene
may deteriorate in depression,schizophrenia, and dementia. Excessive fastidiousness may beseen in an obsessive–compulsivedisorder. One-sided neglect mayresult from a lesion in the oppositeparietal cortex, usually the non-dominant side.
Expressions of anxiety, depression,
apathy, anger, elation. Facial immobility of parkinsonism

Anger, hostility, suspiciousness, or
evasiveness of paranoid patients.Elation and euphoria of the manicsyndrome. Flat affect and remote-ness of schizophrenia. Apathy(dulled affect with detachmentand indifference) in dementia.Anxiety, depression
Slow speech of depression; acceler-
ated rapid, loud speech in mania
Dysarthria refers to defective articu-
lation. Aphasia refers to a disorder
of language. See Table 16-2, Disor-ders of Speech, p. 600.
These abnormalities suggest apha-
sia. The patient may have so muchdifﬁculty in talking or in understand-ing others that you may not be ableto obtain a history. You may alsofalsely suspect a psychotic disorder.

IParaphasias, in which words are malformed (“I write with a den”), wrong
(“I write with a bar”), or invented (“I write with a dar”).
If the patient’s speech lacks meaning or ﬂuency, proceed with further test-
ing as outlined in the following table.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
560 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGMoods include sadness and deep
melancholy; contentment, joy, euphoria, and elation; anger andrage; anxiety and worry; and detachment and indifference.
For depressive and bipolar dis-
orders, see Table 16-1, Disordersof Mood, p. 599.Word Comprehension
Repetition
Naming
Reading ComprehensionWritingAsk the patient to follow a one-stage
command, such as “Point to your nose.”Try a two-stage command: “Point to yourmouth, then your knee.”
Ask the patient to repeat a phrase of one-
syllable words (the most difﬁcult repetitiontask): “No ifs, ands, or buts.”

Ask the patient to name the parts of a watch.Ask the patient to read a paragraph aloud.Ask the patient to write a sentence.Testing for Aphasia
These tests help you to decide what kind
of aphasia the patient may have.Remember that deﬁciencies in vision,hearing, intelligence, and education mayalso affect performance. Two commonkinds of aphasia—Wernicke’s andBroca’s—are compared in Table 16-2,Disorders of Speech, p. 600.
A person who can write a correct
sentence does not have aphasia.
MOOD
Assess mood during the interview by exploring the patient’s own percep-
tions of it. Find out about the patient’s usual mood level and how it has var-ied with life events. “How did you feel about that?”, for example, or, moregenerally, “How are your spirits?” The reports of relatives and friends maybe of great value.

What has the patient’s mood been like? How intense has it been? Has it been
labile or fairly unchanging? How long has it lasted? Is it appropriate to thepatient’s circumstances? In case of depression, have there also been episodesof an elevated mood, suggesting a bipolar disorder?
If you suspect depression, assess its depth and any associated risk of suicide.
A series of questions such as the following is useful, proceeding as far as thepatient’s positive answers warrant.
Do you get pretty discouraged (or depressed or blue)?
How low do you feel?What do you see for yourself in the future?Do you ever feel that life isn’t worth living? Or that you would just as
soon be dead?
Have you ever thought of doing away with yourself?How did (do) you think you would do it?What would happen after you were dead?
Asking about suicidal thoughts does not implant the idea in the patient’s
mind, and it may be the only way to get the information. Although many

student clinicians feel uneasy about exploring this topic, most patients can
discuss their thoughts and feelings about it freely with you, sometimes withconsiderable relief. By such discussion, you demonstrate your interest andconcern for what may well be the patient’s most serious and threateningproblem. By avoiding the issue, you may miss the most important feature ofthe patient’s illness.
THOUGHT AND PERCEPTIONS
Thought Processes. Assess the logic, relevance, organization, and co-
herence of the patient’s thought processes as they are revealed in words andspeech throughout the interview. Does speech progress in a logical mannertoward a goal? Here you are using the patient’s speech as a window into thepatient’s mind. Listen for patterns of speech that suggest disorders ofthought processes, as outlined in the table below.TECHNIQUES OF EXAMINATION
CHAPTER 16 ITHE NERVOUS SYSTEM 561Circumstantiality
(Loosening ofAssociations)
Flight of Ideas

Neologisms
Incoherence
Blocking
Confabulation
PerseverationEcholaliaClangingSpeech characterized by indirection and delay in reaching the
point because of unnecessary detail, although the components ofthe description have a meaningful connection. Many peoplewithout mental disorders speak circumstantially.
Speech in which a person shifts from one subject to others that are
unrelated or only obliquely related without realizing that thesubjects are not meaningfully connected. Ideas slip off the trackbetween clauses, not within them.
An almost continuous ﬂow of accelerated speech in which a person
changes abruptly from topic to topic. Changes are usually basedon understandable associations, plays on words, or distractingstimuli, but the ideas do not progress to sensible conversation.
Invented or distorted words, or words with new and highly
idiosyncratic meanings

Speech that is largely incomprehensible because of illogic, lack of
meaningful connections, abrupt changes in topic, or disorderedgrammar or word use. Shifts in meaning occur within clauses.Flight of ideas, when severe, may produce incoherence.
Sudden interruption of speech in midsentence or before
completion of an idea. The person attributes this to losing thethought. Blocking occurs in normal people.
Fabrication of facts or events in response to questions, to ﬁll in the
gaps in an impaired memory
Persistent repetition of words or ideas
Repetition of the words and phrases of othersSpeech in which a person chooses a word on the basis of sound
rather than meaning, as in rhyming and punning speech. Forexample, “Look at my eyes and nose, wise eyes and rosy nose.Two to one, the ayes have it!”Variations and Abnormalities in Thought Processes
Observed in obsessional persons
Observed in schizophrenia, manic

episodes, and other psychoticdisorders
Most frequently noted in manic
episodes
Observed in schizophrenia, other
psychotic disorders, and aphasia
Observed in severely disturbed psychotic
persons (usually schizophrenic)
Blocking may be striking in schizo-
phrenia.
Common with amnesiaOccurs in schizophrenia and other
psychotic disorders
Occurs in manic episodes and schizo-
phrenia
Occurs in schizophrenia and manic
episodes

562 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGThought Content. You should ascertain most of the information rele-
vant to thought content during the interview. Follow appropriate leads asthey occur rather than using stereotyped lists of speciﬁc questions. For ex-ample, “You mentioned a few minutes ago that a neighbor was responsiblefor your entire illness. Can you tell me more about that?” Or, in another sit-uation, “What do you think about at times like these?”
You may need to make more speciﬁc inquiries. If so, couch them in tactful
and accepting terms. “When people are upset like this, they sometimes can’tkeep certain thoughts out of their minds,” or “. . . things seem unreal. Haveyou experienced anything like this?”
In these ways ﬁnd out about any of the patterns shown in the following
table.
Compulsions
Obsessions
PhobiasAnxieties
Feelings of Unreality
Feelings of

table.
DelusionsRepetitive behaviors or mental acts that a person feels
driven to perform in order to produce or prevent somefuture state of affairs, although expectation of such aneffect is unrealistic
Recurrent, uncontrollable thoughts, images, or impulses
that a person considers unacceptable and alien
Persistent, irrational fears, accompanied by a compelling
desire to avoid the stimulus
Apprehensions, fears, tensions, or uneasiness that may 
be focused (phobia) or free ﬂoating (a general sense of ill-deﬁned dread or impending doom)
A sense that things in the environment are strange, unreal, 
or remote
A sense that one’s self is different, changed, or unreal, 
or has lost identity or become detached from one’s mindor body
False, ﬁxed, personal beliefs that are not shared by other

or remote
members of the person’s culture or subculture. Examplesinclude:
IDelusions of persecution
IGrandiose delusions
IDelusional jealousy
IDelusions of reference, in which a person believes that
external events, objects, or people have a particular andunusual personal signiﬁcance (e.g., that the radio ortelevision might be commenting on or givinginstructions to the person)
IDelusions of being controlled by an outside force
ISomatic delusions of having a disease, disorder, or
physical defect
ISystematized delusions, a single delusion with many
elaborations or a cluster of related delusions around a single theme, all systematized into a complex networkAbnormalities of Thought Content
Compulsions, obsessions, phobias, and

anxieties are often associated withneurotic disorders. See Table 16-3,Anxiety Disorders (p. 601).
Delusions and feelings of unreality or
depersonalization are more oftenassociated with psychotic disorders.See Table 16-4, Psychotic Disorders(p. 602). Delusions may also occur indelirium, severe mood disorders, anddementia.

Perceptions. Inquire about false perceptions in a manner similar to that
used for thought content. For example, “When you heard the voice speak-ing to you, what did it say? How did it make you feel?” Or, “After you’vebeen drinking a lot, do you ever see things that aren’t really there?” Or,“Sometimes after major surgery like this, people hear peculiar or frighten-ing things. Have you experienced anything like that?” In these ways ﬁnd outabout the following abnormal perceptions.TECHNIQUES OF EXAMINATION
CHAPTER 16 ITHE NERVOUS SYSTEM 563Patients with psychotic disorders
often lack insight into their illness.Denial of impairment may accom-pany some neurologic disorders.
Judgment may be poor in delirium,
dementia, mental retardation, and psychotic states. Judgment isaffected also by anxiety, mood disorders, intelligence, education,socioeconomic options, and cultural values.
Disorientation occurs especially

when memory or attention is impaired, as in delirium.Insight and Judgment. These attributes are usually best assessed dur-
ing the interview.
Insight. Some of your very ﬁrst questions to the patient often yield im-
portant information about insight: “What brings you to the hospital?”“What seems to be the trouble?” “What do you think is wrong?” Morespeciﬁcally, note whether or not the patient is aware that a particular mood,thought, or perception is abnormal or part of an illness.
Judgment. You can usually assess judgment by noting the patient’s
responses to family situations, jobs, use of money, and interpersonal con-ﬂicts. “How do you plan to get the help you’ll need after leaving the hospi-tal?” “How are you going to manage if you lose your job?” “If your hus-band starts to abuse you again, what will you do?” “Who will attend to yourﬁnancial affairs while you are in the nursing home?”

Note whether decisions and actions are based on reality or, for example, on
impulse, wish fulﬁllment, or disordered thought content. What values seemto underlie the patient’s decisions and behavior? Allowing for cultural vari-ations, how do these compare with mature adult standards? Because judg-ment is part of the maturational response, it may be variable and unpre-dictable during adolescence.
COGNITIVE FUNCTIONS
Orientation. By skillful questioning you can often determine the pa-
tient’s orientation in the context of the interview. For example, you canask quite naturally for specific dates and times, the patient’s address andIllusions
HallucinationsMisinterpretations of real external stimuli
Subjective sensory perceptions in the absence

of relevant external stimuli. The personmay or may not recognize the experiencesas false. Hallucinations may be auditory,visual, olfactory, gustatory, tactile, orsomatic. (False perceptions associated withdreaming, falling asleep, and awakening arenot classiﬁed as hallucinations.)Abnormalities of Perception
Illusions may occur in grief reactions,
delirium, acute and posttraumaticstress disorders, and schizophrenia.
Hallucinations may occur in delirium,
dementia (less commonly), post-traumatic stress disorder,schizophrenia, and alcoholism.

telephone number, the names of family members, or the route taken to the
hospital. At times—when rechecking the status of a delirious patient, forexample—simple, direct questions may be indicated.
“Can you tell me what time it is now . . . and what day is it?” In either of
these ways, determine the patient’s orientation for the following:
ITime (e.g., the time of day, day of the week, month, season, date and year,
duration of hospitalization)
IPlace (e.g., the patient’s residence, the names of the hospital, city, 
and state)
IPerson (e.g., the patient’s own name, and the names of relatives and pro-
fessional personnel)
Attention. These tests of attention are commonly used:
Digit Span. Explain that you would like to test the patient’s ability to

concentrate, perhaps adding that people tend to have trouble with that whenthey are in pain, or ill, or feverish. Recite a series of digits, starting with twoat a time and speaking each number clearly at a rate of about one per sec-ond. Ask the patient to repeat the numbers back to you. If this repetition isaccurate, try a series of three numbers, then four, and so on as long as thepatient responds correctly. Jotting down the numbers as you say them helpsto ensure your own accuracy. If the patient makes a mistake, try once morewith another series of the same length. Stop after a second failure in a singleseries.
In choosing digits you may use street numbers, zip codes, telephone num-

bers, and other numerical sequences that are familiar to you, but avoid con-secutive numbers, easily recognized dates, and sequences that possibly arefamiliar to the patient.
Now, starting again with a series of two, ask the patient to repeat the num-
bers to you backward.
Normally, a person should be able to repeat correctly at least ﬁve digits for-
ward and four backward.
Serial 7s. Instruct the patient, “Starting from a hundred, subtract 7,
and keep subtracting 7. . . .” Note the effort required and the speed and ac-curacy of the responses. (Writing down the answers helps you keep up withthe arithmetic.) Normally, a person can complete serial 7s in 1
1⁄2minutes,
with fewer than four errors. If the patient cannot do serial 7s, try 3s or count-ing backward.
Spelling Backward. This can substitute for serial 7s. Say a ﬁve-letter

word, spell it, e.g., W-O-R-L-D, and ask the patient to spell it backward.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
564 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGCauses of poor performance 
include delirium, dementia, mentalretardation, and performance anxiety.
Poor performance may be due to
delirium, the late stage of dementia,mental retardation, loss of calcu-lating ability, anxiety, or depres-sion. Also consider the possibilityof limited education.

Remote Memory. Inquire about birthdays, anniversaries, social security
number, names of schools attended, jobs held, or past historical events suchas wars relevant to the patient’s past.
Recent Memory (e.g., the events of the day). Ask questions with an-
swers that you can check against other sources so that you will know whetheror not the patient is confabulating (making up facts to compensate for a de-fective memory). These might include the day’s weather, today’s appoint-ment time, and medications or laboratory tests taken during the day. (Ask-ing what the patient had for breakfast may be a waste of time unless you cancheck the accuracy of the answer.)
New Learning Ability. Give the patient three or four words such as

“83 Water Street and blue,” or “table, flower, green, and hamburger.”Ask the patient to repeat them so that you know that the information hasbeen heard and registered. This step, like digit span, tests registration andimmediate recall. Then proceed to other parts of the examination. Afterabout 3 to 5 minutes, ask the patient to repeat the words. Note the accu-racy of the response, awareness of whether or not it is correct, and any ten-dency to confabulate. Normally, a person should be able to remember thewords.
HIGHER COGNITIVE FUNCTIONS
Information and Vocabulary. Information and vocabulary, when

observed clinically, provide a rough estimate of a person’s intelligence. As-sess them during the interview. Ask a student, for example, about favoritecourses, or inquire about a person’s work, hobbies, reading, favorite televi-sion programs, or current events. Explore such topics ﬁrst with simple ques-tions, then with more difﬁcult ones. Note the person’s grasp of information,the complexity of the ideas expressed, and the vocabulary used.
More directly, you can ask about speciﬁc facts, such as these:
The name of the president, vice president, or governor
The names of the last four or ﬁve presidentsThe names of ﬁve large cities in the country
Calculating Ability. Test the patient’s ability to do arithmetical calcu-
lations, starting at the rote level with simple addition (“What is 4 /H110013? . . .
8 /H110017?”) and multiplication (“What is 5 /H110036? . . . 9 /H110037?”). The task can be

made more difﬁcult by using two-digit numbers (“15 /H1100112” or “25 /H110036”)
or longer, written examples.
Alternatively, pose practical and functionally important questions, such as
“If something costs 78 cents and you give the clerk one dollar, how muchshould you get back?”TECHNIQUES OF EXAMINATION
CHAPTER 16 ITHE NERVOUS SYSTEM 565Remote memory may be impaired
in the late stage of dementia.
Recent memory is impaired in 
dementia and delirium. See Table 16-5, Delirium and Demen-tia, p. 603. Amnestic disorders
impair memory or new learningability signiﬁcantly and reduce aperson’s social or occupationalfunctioning, but they do not havethe global features of delirium ordementia. Anxiety, depression, andmental retardation may also impairrecent memory.
If considered in the context of cul-

tural and educational background,information and vocabulary arefairly good indicators of intelligence.They are relatively unaffected byany but the most severe psychiatricdisorders, and may be helpful fordistinguishing mentally retardedadults (whose information and vocabulary are limited) from thosewith mild or moderate dementia(whose information and vocabularyare fairly well preserved).
Poor performance may be a useful
sign of dementia or may accom-pany aphasia, but it must be assessed in terms of the patient’sintelligence and education.

Abstract Thinking. The capacity to think abstractly can be tested in
two ways.
Proverbs. Ask the patient what people mean when they use some of
the following proverbs:
A stitch in time saves nine.
Don’t count your chickens before they’re hatched.The proof of the pudding is in the eating.A rolling stone gathers no moss.The squeaking wheel gets the grease.
Note the relevance of the answers and their degree of concreteness or ab-
stractness. For example, “You should sew a rip before it gets bigger” is con-crete, while “Prompt attention to a problem prevents trouble” is abstract.Average patients should give abstract or semiabstract responses.
Similarities. Ask the patient to tell you how the following are alike:
An orange and an apple A church and a theater
A cat and a mouse A piano and a violinA child and a dwarf Wood and coal
Note the accuracy and relevance of the answers and their degree of con-

creteness or abstractness. For example, “A cat and a mouse are both animals”is abstract, “They both have tails” is concrete, and “A cat chases a mouse”is not relevant.
Constructional Ability. The task here is to copy ﬁgures of increasing
complexity onto a piece of blank unlined paper. Show each ﬁgure one at atime and ask the patient to copy it as well as possible.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
566 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING(Strub RL, Black FW: The Mental Status
Examination in Neurology, 2nd ed.Philadelphia, FA Davis, 1985)Concrete responses are often given
by persons with mental retarda-tion, delirium, or dementia, butmay also be simply a function oflimited education. Schizophrenicsmay respond concretely or withpersonal, bizarre interpretations.

The three diamonds below are
rated poor, fair, and good (but notexcellent).

The Cranial Nerves
Overview. The examination of the cranial nerves (often abbreviated as
CN) can be summarized as follows:
I Smell
II Visual acuity, visual ﬁelds, and ocular fundiII, III Pupillary reactionsIII, IV, VI Extraocular movementsV Corneal reﬂexes, facial sensation, and jaw movementsVII Facial movementsVIII HearingIX, X Swallowing and rise of the palate, gag reﬂexV, VII, X, XII Voice and speechXI Shoulder and neck movementsXII Tongue symmetry and position
Cranial Nerve I—Olfactory. Test the sense of smell by presenting the pa-

tient with familiar and nonirritating odors. First be sure that each nasal passageis open by compressing one side of the nose and asking the patient to sniffthrough the other. The patient should then close both eyes. Occlude one nos-tril and test smell in the other with such substances as cloves, coffee, soap, orvanilla. Ask if the patient smells anything and, if so, what. Test the other side.A person should normally perceive odor on each side, and can often identify it.
Cranial Nerve II—Optic. Test visual acuity (see pp. 144–145).
Inspect the optic fundi with your ophthalmoscope, paying special attention
to the optic discs (see pp. 151–155).
Screen the visual ﬁelds by confrontation (see pp. 145–146). Occasionally—in

a stroke patient, for example—screening indicates a visual ﬁeld defect, suchas a homonymous hemianopsia, that you cannot conﬁrm by testing one eyeat a time. This screening observation, nevertheless, is signiﬁcant.
CHAPTER 16 ITHE NERVOUS SYSTEM 567(Strub RL, Black FW: The Mental Status Examination in Neurology, 2nd ed. Philadelphia, FA
Davis, 1985)If vision and motor ability are 
intact, poor constructional abilitysuggests dementia or parietal lobedamage. Mental retardation mayalso impair performance.
Loss of smell has many causes, in-
cluding nasal disease, head trauma,smoking, aging, and the use ofcocaine. It may be congenital.
Optic atrophy, papilledema
These ﬁndings suggest visual 
extinction, a subtle impairment

extinction, a subtle impairment 
detectable only when testing botheyes simultaneously. It suggests alesion in the parietal cortex.In another approach, ask the patient to draw a clock face complete with
numbers and hands. The example below is rated excellent.
These three clocks are poor, fair,
and good.

Cranial Nerves II and III—Optic and Oculomotor. Inspect the
size and shape of the pupils, and compare one side with the other. Test thepupillary reactions to light ; if these are abnormal, examine the near response
also (see p. 149).
Cranial Nerves III, IV, and VI—Oculomotor, Trochlear, and
Abducens. Test the extraocular movements in the six cardinal directions
of gaze, and look for loss of conjugate movements in any of the six direc-tions. Check convergence of the eyes. Identify any nystagmus, noting thedirection of gaze in which it appears, the plane in which movements occur(horizontal, vertical, rotary, or mixed), and the direction of the quick andslow components (see pp. 149–151).
Look for ptosis (drooping of the upper eyelids). A slight difference in the width
of the palpebral ﬁssures may be noted in about one third of all normal people.
Cranial Nerve V—Trigeminal
Motor. While palpating the temporal and masseter muscles in turn,

ask the patient to clench his or her teeth. Note the strength of musclecontraction.
Sensory. After explaining what
you plan to do, test the forehead,cheeks, and jaw on each side for pain
sensation. Suggested areas are indi-
cated by the circles. The patient’s eyesshould be closed. Use a safety pin orother suitable sharp object,* occa-sionally substituting the blunt end forthe point as a stimulus. Ask the pa-tient to report whether it is “sharp”or “dull” and to compare sides.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
568 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGSee Table 5-9, Pupillary Abnor-
malities (p. 181).
See Table 16-9, Nystagmus 
(pp. 610–611).
Ptosis in 3rd nerve palsy, Horner’s
syndrome (ptosis, meiosis, anhidrosis), myasthenia gravis

Weak or absent contraction of the
temporal and masseter muscles onone side suggests a lesion of CN V.Bilateral weakness may result fromperipheral or central involvement.When the patient has no teeth, thistest may be difﬁcult to interpret.
Unilateral decrease in or loss of fa-
cial sensation suggests a lesion ofCN V or of interconnecting highersensory pathways. Such a sensoryloss may also be associated with aconversion reaction.
*To avoid transmitting infection, use a new object with each patient. You can create a sharp wood splinter
by breaking or twisting a cotton swab. The cotton end of the swab can also be used as a dull stimulus.PALPATING TEMPORAL MUSCLES PALPATING MASSETER MUSCLES

If you ﬁnd an abnormality, conﬁrm it by testing temperature sensation. Two
test tubes, ﬁlled with hot and ice-cold water, are the traditional stimuli. Atuning fork may also be used. It usually feels cool. If you are near runningwater, the fork is easily made colder or warm. Dry it before use. Touch theskin and ask the patient to identify “hot” or “cold.”
Then test for light touch, using a ﬁne wisp of cotton. Ask the patient to re-
spond whenever you touch the skin.
Test the corneal reﬂex. Ask the patient to look up and away from you. Ap-
proaching from the other side, out of the patient’s line of vision, and avoid-ing the eyelashes, touch the cornea (not just the conjunctiva) lightly with aﬁne wisp of cotton. If the patient is apprehensive, however, ﬁrst touchingthe conjunctiva may allay fear.TECHNIQUES OF EXAMINATION
CHAPTER 16 ITHE NERVOUS SYSTEM 569Absence of blinking suggests a

CHAPTER 16 ITHE NERVOUS SYSTEM 569Absence of blinking suggests a 
lesion of CN V. A lesion of CN VII(the nerve to the muscles that closethe eyes) may also impair this reﬂex.
Flattening of the nasolabial fold
and drooping of the lower eyelidsuggest facial weakness.
A peripheral injury to CN VII, as in
Bell’s palsy, affects both the upperand the lower face; a central lesionaffects mainly the lower face. SeeTable 16-10, Types of Facial Paraly-sis (pp. 612–613).
Look for blinking of the eyes, the normal reaction to this stimulus. (The sen-
sory limb of this reﬂex is carried in CN V, the motor response in CN VII.)Use of contact lenses frequently diminishes or abolishes this reﬂex.
Cranial Nerve VII—Facial. In-
spect the face, both at rest and dur-ing conversation with the patient.Note any asymmetry (e.g., of thenasolabial folds), and observe any ticsor other abnormal movements.
Ask the patient to:1. Raise both eyebrows.2. Frown.

3. Close both eyes tightly so that you cannot open them. Test muscular
strength by trying to open them, as illustrated.
4. Show both upper and lower teeth.5. Smile.6. Puff out both cheeks.Note any weakness or asymmetry.
Cranial Nerve VIII—Acoustic. Assess hearing. If hearing loss is pre-
sent, (1) test for lateralization, and (2) compare air and bone conduction
(see pp. 156–158).
Speciﬁc tests of vestibular function are seldom included in the usual neuro-
logic examination. Consult textbooks of neurology or otolaryngology as theneed arises.
Cranial Nerves IX and X—Glossopharyngeal and Vagus. Listen
to the patient’s voice. Is it hoarse or does it have a nasal quality?
Is there difﬁculty in swallowing?Ask the patient to say “ah” or to yawn as you watch the movements of the soft
palate and the pharynx. The soft palate normally rises symmetrically, the uvula

remains in the midline, and each side of the posterior pharynx moves medi-ally, like a curtain. The slightly curved uvula seen occasionally in a normal per-son should not be mistaken for a uvula deviated by a 10th nerve lesion.
Warn the patient that you are going to test the gag reﬂex. Stimulate the back
of the throat lightly on each side in turn and note the gag reﬂex. It may besymmetrically diminished or absent in some normal people.
Cranial Nerve XI—Spinal Accessory. From behind, look for atrophy
or fasciculations in the trapezius muscles, and compare one side with theTECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
570 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGIn unilateral facial paralysis, the
mouth droops on the paralyzedside when the patient smiles or grimaces.

Loss (pp. 196–197).
Nystagmus may indicate vestibular
dysfunction. See Table 16-9, Nystagmus (pp. 610–611).
Hoarseness in vocal cord paralysis; a
nasal voice in paralysis of the palate
Pharyngeal or palatal weakness
The palate fails to rise with a bilat-
eral lesion of the vagus nerve. Inunilateral paralysis, one side of thepalate fails to rise and, togetherwith the uvula, is pulled towardthe normal side (see p. 162).
Unilateral absence of this reﬂex
suggests a lesion of CN IX, perhapsCN X.
Weakness with atrophy and fascic-
ulations indicates a peripheralnerve disorder. When the trapeziusis paralyzed, the shoulder droopsand the scapula is displaced down-ward and laterally.

other. Ask the patient to shrug both shoulders upward against your hands.
Note the strength and contraction of the trapezii.
Ask the patient to turn his or her
head to each side against your hand.Observe the contraction of the op-posite sternomastoid and note theforce of the movement against yourhand.
Cranial Nerve XII—Hypoglossal. Listen to the articulation of the pa-
tient’s words. This depends on Cranial Nerves V, VII, and X as well as XII.Inspect the patient’s tongue as it lies on the ﬂoor of the mouth. Look forany atrophy or fasciculations (ﬁne, ﬂickering, irregular movements in small

groups of muscle ﬁbers). Some coarser restless movements are often seen ina normal tongue. Then, with the patient’s tongue protruded, look for asym-metry, atrophy, or deviation from the midline. Ask the patient to move thetongue from side to side, and note the symmetry of the movement. In am-biguous cases, ask the patient to push the tongue against the inside of eachcheek in turn as you palpate externally for strength.
The Motor System
As you assess the motor system, focus on body position, involuntary move-ments, characteristics of the muscles (bulk, tone, and strength), and coordi-nation. These components are described below in sequence. You may eitheruse this sequence or check each component in the arms, legs, and trunk inturn. If you see an abnormality, identify the muscle(s) involved. Think aboutwhether the abnormality is central or peripheral in origin, and begin to learnwhich nerves innervate the affected muscles.

Body Position. Observe the patient’s body position during movement
and at rest.
Involuntary Movements. Watch for involuntary movements such as
tremors, tics, or fasciculations. Note their location, quality, rate, rhythm, andamplitude, and their relation to posture, activity, fatigue, emotion, and otherfactors.
CHAPTER 16 ITHE NERVOUS SYSTEM 571A supine patient with bilateral
weakness of the sternomastoidshas difﬁculty raising the head offthe pillow.
For poor articulation, or dysarthria ,
see Table 16-2, Disorders ofSpeech (p. 600). Atrophy and fas-ciculations in amyotrophic lateralsclerosis, polio
In a unilateral cortical lesion, the
protruded tongue deviates tran-siently in a direction away from theside of the cortical lesion.
Abnormal positions alert you 
to neurologic deﬁcits such as paralysis.
Movements (pp. 608–609).

Muscle Bulk. Compare the size and contours of muscles. Do the mus-
cles look ﬂat or concave, suggesting atrophy? If so, is the process unilateralor bilateral? Is it proximal or distal?
When looking for atrophy, pay particular attention to the hands, shoul-
ders, and thighs. The thenar and hypothenar eminences should be full andconvex, and the spaces between the metacarpals, where the dorsal in-terosseous muscles lie, should be full or only slightly depressed. Atrophyof hand muscles may occur with normal aging, however, as shown on theright below.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
572 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Hand of a 44-year-old woman
 Hand of an 84-year-old womanFlattening of the thenar
eminence due to mild atrophyHypothenar eminence
 Hand of an 84-year-old womanAtrophyMuscular atrophy refers to a loss of

muscle bulk (wasting). It resultsfrom diseases of the peripheralnervous system such as diabeticneuropathy, as well as diseases ofthe muscles themselves. Hyper-
trophy refers to an increase in bulk
with proportionate strength, whileincreased bulk with diminishedstrength is called pseudohypertrophy
(seen in the Duchenne form ofmuscular dystrophy).
Flattening of the thenar and hypo-
thenar eminences and furrowingbetween the metacarpals suggestatrophy. Localized atrophy of thethenar and hypothenar eminencessuggests damage to the medianand ulnar nerves, respectively.
Other causes of muscular atrophy
include motor neuron diseases,disuse of the muscles, rheumatoidarthritis, and protein-calorie malnutrition.

Be alert for fasciculations in atrophic muscles. If you see none, a tap on the
muscle with a reﬂex hammer may stimulate them.
Muscle Tone. When a normal muscle with an intact nerve supply is re-
laxed voluntarily, it maintains a slight residual tension known as muscle tone.This can be assessed best by feeling the muscle’s resistance to passive stretch.Persuade the patient to relax. Take one hand with yours and, while sup-porting the elbow, ﬂex and extend the patient’s ﬁngers, wrist, and elbow,and put the shoulder through a moderate range of motion. With practice,these actions can be combined into a single smooth movement. On eachside, note muscle tone—the resistance offered to your movements. Tensepatients may show increased resistance. You will learn the feel of normal re-sistance only with repeated practice.
If you suspect decreased resistance, hold the forearm and shake the hand

loosely back and forth. Normally the hand moves back and forth freely butis not completely ﬂoppy.
If resistance is increased, determine whether it varies as you move the limb
or whether it persists throughout the range of movement and in both di-rections, for example, during both ﬂexion and extension. Feel for any jerki-ness in the resistance.
To assess muscle tone in the legs, support the patient’s thigh with one hand,
grasp the foot with the other, and ﬂex and extend the patient’s knee andankle on each side. Note the resistance to your movements.
Muscle Strength. Normal individuals vary widely in their strength, and
your standard of normal, while admittedly rough, should allow for such vari-ables as age, sex, and muscular training. A person’s dominant side is usuallyslightly stronger than the other side. Keep this difference in mind when youcompare sides.

Test muscle strength by asking the patient to move actively against your re-
sistance or to resist your movement. Remember that a muscle is strongestwhen shortest, and weakest when longest.
If the muscles are too weak to overcome resistance, test them against gravity
alone or with gravity eliminated. When the forearm rests in a pronated posi-tion, for example, dorsiﬂexion at the wrist can be tested against gravity alone.When the forearm is midway between pronation and supination, extensionat the wrist can be tested with gravity eliminated. Finally, if the patient failsto move the body part, watch or feel for weak muscular contraction.TECHNIQUES OF EXAMINATION
CHAPTER 16 ITHE NERVOUS SYSTEM 573Fasciculations suggest lower
motor neuron disease as a causeof atrophy.
Decreased resistance suggests 
disease of the peripheral nervoussystem, cerebellar disease, or theacute stages of spinal cord injury.See Table 16-11, Disorders of Muscle Tone (p. 614).
Marked ﬂoppiness indicates hypo-

tonic or ﬂaccid muscles.
Increased resistance that varies,
commonly worse at the extremesof the range, is called spasticity. Re-
sistance that persists throughoutthe range and in both directions iscalled lead-pipe rigidity.
Impaired strength is called weak-
ness ( paresis ). Absence of strength
is called paralysis ( plegia ). Hemi-
paresis refers to weakness of one
half of the body; hemiplegia to
paralysis of one half of the body.Paraplegia means paralysis of the
legs; quadriplegia, paralysis of all
four limbs.
See Table 16-12, Disorders of the
Central and Peripheral NervousSystems (pp. 615–617).

More experienced clinicians make further distinctions by using plus or minus
signs toward the stronger end of this scale. Thus 4+ indicates good but notfull strength, while 5 /H11002means a trace of weakness.
Methods for testing the major muscle groups are described below. The
spinal root innervations and the muscles affected are shown in parentheses.To localize lesions in the spinal cord or the peripheral nervous system moreprecisely, additional testing may be necessary. For these specialized meth-ods, refer to detailed texts of neurology.
Test ﬂexion (C5, C6—biceps) and extension (C6, C7, C8—triceps) at the
elbow by having the patient pull and push against your hand.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
574 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGWeakness of extension is seen in

574 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGWeakness of extension is seen in 
peripheral nerve disease (e.g., radialnerve damage) and in central nervous system disease producinghemiplegia (e.g., stroke or multiplesclerosis).Muscle strength is graded on a 0 to 5 scale:
0—No muscular contraction detected
1—A barely detectable ﬂicker or trace of contraction2—Active movement of the body part with gravity eliminated3—Active movement against gravity4—Active movement against gravity and some resistance5—Active movement against full resistance without evident fatigue. This is normal
muscle strength.
Test extension at the wrist (C6, C7,
C8, radial nerve) by asking the pa-tient to make a ﬁst and resist yourpulling it down.FLEXION
EXTENSION AT WRISTEXTENSION

Test the grip (C7, C8, T1). Ask the patient to squeeze two of your ﬁngers as
hard as possible and not let them go. (To avoid getting hurt by hardsqueezes, place your own middle ﬁnger on top of your index ﬁnger.) Youshould normally have difﬁculty removing your ﬁngers from the patient’sgrip. Testing both grips simultaneously with arms extended or in the lap facilitates comparison.TECHNIQUES OF EXAMINATION
CHAPTER 16 ITHE NERVOUS SYSTEM 575A weak grip may be due to either
central or peripheral nervous sys-tem disease. It may also result frompainful disorders of the hands.
Weak ﬁnger abduction in ulnar
nerve disorders
Test ﬁnger abduction (C8, T1, ulnar nerve). Position the patient’s hand with
palm down and ﬁngers spread. Instructing the patient not to let you movethe ﬁngers, try to force them together.

Weak opposition of the thumb in
median nerve disorders such ascarpal tunnel syndrome
Symmetric weakness of the proxi-
mal muscles suggests a myopathy
or muscle disorder; symmetricweakness of distal muscles sug-gests a polyneuropathy, or disorder
of peripheral nerves.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
576 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGTest opposition of the thumb (C8, T1, median nerve). The patient should try
to touch the tip of the little ﬁnger with the thumb, against your resistance.
Assessment of muscle strength of the trunk may already have been made in
other segments of the examination. It includes:
IFlexion, extension, and lateral bending of the spine, and
IThoracic expansion and diaphragmatic excursion during respiration
Test ﬂexion at the hip (L2, L3, L4—iliopsoas) by placing your hand on the
patient’s thigh and asking the patient to raise the leg against your hand.

Test adduction at the hips (L2, L3, L4—adductors). Place your hands ﬁrmly
on the bed between the patient’s knees. Ask the patient to bring both legstogether.

CHAPTER 16 ITHE NERVOUS SYSTEM 577Test abduction at the hips (L4, L5, S1—gluteus medius and minimus). Place
your hands ﬁrmly on the bed outside the patient’s knees. Ask the patient tospread both legs against your hands.
Test extension at the hips (S1—gluteus maximus). Have the patient push the
posterior thigh down against your hand.
Test extension at the knee (L2, L3, L4—quadriceps). Support the knee in
ﬂexion and ask the patient to straighten the leg against your hand. Thequadriceps is the strongest muscle in the body, so expect a forceful response.
EXTENSION AT THE KNEE
FLEXION AT THE KNEETest ﬂexion at the knee (L4, L5, S1, S2—hamstrings) as shown below. Place
the patient’s leg so that the knee is ﬂexed with the foot resting on the bed.Tell the patient to keep the foot down as you try to straighten the leg.

Test dorsiﬂexion (mainly L4, L5) and plantar ﬂexion (mainly S1) at the ankle
by asking the patient to pull up and push down against your hand.TECHNIQUES OF EXAMINATION
578 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
DORSIFLEXION
PLANTAR FLEXION
Coordination. Coordination of muscle movement requires that four
areas of the nervous system function in an integrated way:
IThe motor system, for muscle strength
IThe cerebellar system (also part of the motor system), for rhythmic move-ment and steady posture

IThe vestibular system, for balance and for coordinating eye, head, and
body movements
IThe sensory system, for position sense.
To assess coordination, observe the patient’s performance in:
IRapid alternating movements
IPoint-to-point movements
IGait and other related body movements
IStanding in speciﬁed ways.
Rapid Alternating Movements
ARMS. Show the patient how to
strike one hand on the thigh, raisethe hand, turn it over, and thenstrike the back of the hand down onthe same place. Urge the patient torepeat these alternating movementsas rapidly as possible.
Observe the speed, rhythm, and
smoothness of the movements. Re-peat with the other hand. The non-dominant hand often performssomewhat less well.
Show the patient how to tap the dis-
tal joint of the thumb with the tip ofthe index ﬁnger, again as rapidly aspossible. Again, observe the speed,rhythm, and smoothness of themovements. The nondominant sideoften performs less well.TECHNIQUES OF EXAMINATION

CHAPTER 16 ITHE NERVOUS SYSTEM 579In cerebellar disease, one move-
ment cannot be followed quicklyby its opposite and movementsare slow, irregular, and clumsy.This abnormality is called dysdiadochokinesis. Upper motor
neuron weakness and basal gangliadisease may also impair rapid alternating movements, but notin the same manner.

LEGS. Ask the patient to tap your hand as quickly as possible with the
ball of each foot in turn. Note any slowness or awkwardness. The feet nor-mally perform less well than the hands.
Point-To-Point Movements
ARMS. Ask the patient to touch your index ﬁnger and then his or her
nose alternately several times. Move your ﬁnger about so that the patient hasto alter directions and extend the arm fully to reach it. Observe the accuracyand smoothness of movements and watch for any tremor. Normally the pa-tient’s movements are smooth and accurate.
Now hold your ﬁnger in one place so that the patient can touch it with one

arm and ﬁnger outstretched. Ask the patient to raise the arm overhead andlower it again to touch your ﬁnger. After several repeats, ask the patient toclose both eyes and try several more times. Repeat on the other side. Nor-mally a person can touch the examiner’s ﬁnger successfully with eyes openor closed. These maneuvers test position sense and the functions of both thelabyrinth and the cerebellum.
LEGS. Ask the patient to place one heel on the opposite knee, and then
run it down the shin to the big toe. Note the smoothness and accuracy ofthe movements. Repetition with the patient’s eyes closed tests for positionsense. Repeat on the other side.
Gait. Ask the patient to:
IWalk across the room or down the hall, then turn, and come back. Observe

posture, balance, swinging of the arms, and movements of the legs. Nor-mally balance is easy, the arms swing at the sides, and turns are accomplishedsmoothly.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
580 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGDysdiadochokinesis in cerebellar
disease
In cerebellar disease, movements
are clumsy, unsteady, and inappropriately varying in theirspeed, force, and direction. The finger may initially overshootits mark, but finally reaches itfairly well. Such movements aretermed dysmetria. An intention
tremor may appear toward the end of the movement (see p. 608).
Cerebellar disease causes incoor-
dination that may get worse with eyes closed. Inaccuracy that appears with eyes closed suggests loss of position sense.Repetitive and consistent devia-tion to one side (referred to aspast pointing ), worse with the eyes

closed, suggests cerebellar orvestibular disease.
In cerebellar disease, the heel 
may overshoot the knee and thenoscillate from side to side down the shin. When position sense islost, the heel is lifted too high and the patient tries to look. With eyes closed, performance is poor.
Abnormalities of gait increase risk
of falls.
A gait that lacks coordination, 
with reeling and instability, iscalled ataxic. Ataxia may be 
due to cerebellar disease, loss of position sense, or intoxication. See Table 16-13, Abnormalities of Gait and Posture(pp. 618–619).

IWalk heel-to-toe in a straight line—
a pattern called tandem walking.
IWalk on the toes, then on the heels —
sensitive tests respectively for plan-tar ﬂexion and dorsiﬂexion of theankles, as well as for balance.
IHop in place on each foot in turn
(if the patient is not too ill). Hop-ping involves the proximal mus-cles of the legs as well as the distalones and requires both good posi-tion sense and normal cerebellarfunction.
IDo a shallow knee bend, ﬁrst on
one leg, then on the other. Sup-port the patient’s elbow if youthink the patient is in danger offalling.
IRising from a sitting position without arm support and stepping up on a
sturdy stool are more suitable tests than hopping or knee bends when pa-tients are old or less robust.
Stance. The following two tests can often be performed concur-

rently. They differ only in the patient’s arm position and in what you arelooking for. In each case, stand close enough to the patient to prevent a fall.TECHNIQUES OF EXAMINATION
CHAPTER 16 ITHE NERVOUS SYSTEM 581Tandem walking may reveal an
ataxia not previously obvious.
Walking on toes and heels may re-
veal distal muscular weakness inthe legs. Inability to heel-walk is asensitive test for corticospinal tractweakness.
Difﬁculty with hopping may be
due to weakness, lack of positionsense, or cerebellar dysfunction.
Difﬁculty here suggests proximal
weakness (extensors of the hip),weakness of the quadriceps (theextensor of the knee), or both.
People with proximal muscle weak-
ness involving the pelvic girdle andlegs have difﬁculty with both ofthese activities.

THE ROMBERG TEST. This is mainly a test of position sense. The patient
should ﬁrst stand with feet together and eyes open and then close both eyesfor 20 to 30 seconds without support. Note the patient’s ability to maintainan upright posture. Normally only minimal swaying occurs.
TEST FOR PRONATOR DRIFT. The patient should stand for 20 to 30 seconds
with both arms straight forward, palms up, and with eyes closed. A personwho cannot stand may be tested for a pronator drift in the sitting position.In either case, a normal person can hold this arm position well.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
582 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGIn ataxia due to loss of position
sense, vision compensates for thesensory loss. The patient standsfairly well with eyes open butloses balance when they areclosed, a positive Romberg sign.
In cerebellar ataxia, the patienthas difficulty standing with feettogether whether the eyes areopen or closed.

The pronation of one forearm 
suggests a contralateral lesion in the corticospinal tract; downward drift of the arm withﬂexion of ﬁngers and elbow mayalso occur. These movements are called a pronator drift, shown
below.
A sideward or upward drift, 
sometimes with searching,writhing movements of the hands, suggests loss of positionsense.
A weak arm is easily displaced 
and often remains so. A patientlacking position sense may notrecognize the displacement and, if told to correct it, does so poorly. In cerebellar incoordi-nation, the arm returns to its original position but overshootsand bounces.
Now, instructing the patient to keep the arms up and eyes shut, as shown
above, tap the arms briskly downward. The arms normally return smoothly
to the horizontal position. This response requires muscular strength, coor-dination, and a good sense of position.

The Sensory System
To evaluate the sensory system, you will test several kinds of sensation:
IPain and temperature (spinothalamic tracts)
IPosition and vibration (posterior columns)
ILight touch (both of these pathways)
IDiscriminative sensations, which depend on some of the above sensations
but also involve the cortex
Familiarize yourself with each kind of test so that you can use it as indicated.
When you detect abnormal ﬁndings, correlate them with motor and reﬂexactivity. Is the underlying lesion central or peripheral?
Patterns of Testing. Because sensory testing quickly fatigues many pa-

tients and then produces unreliable results, conduct the examination as ef-ﬁciently as possible. Pay special attention to those areas (1) where there aresymptoms such as numbness or pain, (2) where there are motor or reﬂex ab-normalities that suggest a lesion of the spinal cord or peripheral nervous sys-tem, and (3) where there are trophic changes, such as absent or excessivesweating, atrophic skin, or cutaneous ulceration). Repeated testing at an-other time is often required to conﬁrm abnormalities.
The following patterns of testing help you to identify sensory deﬁcits accu-
rately and efﬁciently.
ICompare symmetric areas on the two sides of the body, including the
arms, legs, and trunk.
IWhen testing pain, temperature, and touch sensation, also compare the

distal with the proximal areas of the extremities. Further, scatter the stim-
uli so as to sample most of the dermatomes and major peripheral nerves(see pp. 542–546). One suggested pattern includes both shoulders (C4),the inner and outer aspects of the forearms (C6 and T1), the thumbs andlittle ﬁngers (C6 and C8), the fronts of both thighs (L2), the medial andlateral aspects of both calves (L4 and L5), the little toes (S1), and the me-dial aspect of each buttock (S3).
IWhen testing vibration and position sensation, ﬁrst test the ﬁngers andtoes. If these are normal, you may safely assume that more proximal areaswill also be normal.
IVary the pace of your testing. This is important so that the patient does not
merely respond to your repetitive rhythm.

CHAPTER 16 ITHE NERVOUS SYSTEM 583See Table 16-12, Disorders of the
Meticulous sensory mapping helps
to establish the level of a spinalcord lesion and to determine if amore peripheral lesion is in a nerveroot, a major peripheral nerve, orone of its branches.
Hemisensory loss due to a lesion in
the spinal cord or higher pathways
Symmetric distal sensory loss 
suggests a polyneuropathy, as described in the example on thenext page. You may miss this ﬁnd-ing unless you compare distal andproximal areas.

IWhen you detect an area of sensory
loss or hypersensitivity, map out its
boundaries in detail. Stimulate ﬁrst
at a point of reduced sensation,and move by progressive steps untilthe patient detects the change. Anexample is shown at right.
By identifying the distribution of sensory abnormalities and the kinds of sen-
sations affected, you can infer where the causative lesion might be. Anymotor deﬁcit or reﬂex abnormality also helps in this localizing process.
Before each test below, show the patient what you plan to do and what re-
sponses you want. Unless otherwise speciﬁed, the patient’s eyes should beclosed during actual testing.
Pain. Use a sharp safety pin or other suitable tool. Occasionally, sub-
stitute the blunt end for the point. Ask the patient, “Is this sharp or dull?”or, when making comparisons, “Does this feel the same as this?” Applythe lightest pressure needed for the stimulus to feel sharp, and try not todraw blood.

To prevent transmitting a blood-borne infection, discard the pin or other
device safely. Do not reuse it on another person.
Temperature. (This is often omitted if pain sensation is normal, but in-
clude it if there is any question.) Use two test tubes, ﬁlled with hot and coldwater, or a tuning fork heated or cooled by water. Touch the skin and askthe patient to identify “hot” or “cold.”
Light Touch. With a ﬁne wisp of cotton, touch the skin lightly, avoid-
ing pressure. Ask the patient to respond whenever a touch is felt, and tocompare one area with another. Calloused skin is normally relatively insen-sitive and should be avoided.
Vibration. Use a relatively low-

pitched tuning fork of 128 Hz . Tapit on the heel of your hand and placeit ﬁrmly over a distal interphalangealjoint of the patient’s ﬁnger, thenover the interphalangeal joint of thebig toe. Ask what the patient feels.If you are uncertain whether it ispressure or vibration, ask the patientto tell you when the vibration stops,and then touch the fork to stop it. If TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
584 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGHere all sensation in the hand is
lost. Repetitive testing in a proximaldirection reveals a gradual changeto normal sensation at the wrist.This pattern ﬁts neither a peripheralnerve nor a dermatome (see pp.542–546). If bilateral, it suggeststhe “glove and stocking” sensoryloss of a polyneuropathy, oftenseen in alcoholism and diabetes.
Analgesia refers to absence of pain
sensation, hypalgesia to decreased
sensitivity to pain, and hyperalgesia
to increased sensitivity.

Anesthesia is absence of touch 
sensation, hypesthesia is decreased
sensitivity, and hyperesthesia is 
increased sensitivity.
Vibration sense is often the ﬁrst
sensation to be lost in a peripheralneuropathy. Common causes include diabetes and alcoholism.Vibration sense is also lost in poste-rior column disease, as in tertiarysyphilis or vitamin B
12deﬁciency.
Testing vibration sense in the trunk
may be useful in estimating thelevel of a cord lesion.

vibration sense is impaired, proceed to more proximal bony prominences
(e.g., wrist, elbow, medial malleolus, patella, anterior superior iliac spine,spinous processes, and clavicles).
Position. Grasp the patient’s big toe, holding it by its sides between your
thumb and index ﬁnger, and then pull it away from the other toes so as to
avoid friction. (These precautionsprevent extraneous tactile stimulifrom revealing position changes thatmight not otherwise be detected.)Demonstrate “up” and “down” asyou move the patient’s toe clearlyupward and downward. Then, withthe patient’s eyes closed, ask for a re-sponse of “up” or “down” whenmoving the toe in a small arc.
Repeat several times on each side, avoiding simple alternation of the stim-
uli. If position sense is impaired, move proximally to test it at the ankle joint.In a similar fashion, test position in the ﬁngers, moving proximally if indi-cated to the metacarpophalangeal joints, wrist, and elbow.

Discriminative Sensations. Several additional techniques test the abil-
ity of the sensory cortex to correlate, analyze, and interpret sensations. Becausediscriminative sensations are dependent on touch and position sense, they areuseful only when these sensations are either intact or only slightly impaired.
Screen a patient with stereognosis, and proceed to other methods if indicated.
The patient’s eyes should be closed during all these tests.
IStereognosis. Stereognosis refers to
the ability to identify an object byfeeling it. Place in the patient’shand a familiar object such as acoin, paper clip, key, pencil, orcotton ball, and ask the patient totell you what it is. Normally a pa-tient will manipulate it skillfullyand identify it correctly. Askingthe patient to distinguish “heads”from “tails” on a coin is a sensitivetest of stereognosis.
INumber identiﬁcation (graphes-thesia). When motor impairment,
arthritis, or other conditions pre-TECHNIQUES OF EXAMINATION

CHAPTER 16 ITHE NERVOUS SYSTEM 585Loss of position sense, like loss of
vibration sense, suggests eitherposterior column disease or a lesionof the peripheral nerve or root.
When touch and position sense are
normal or only slightly impaired, adisproportionate decrease in orloss of discriminative sensationssuggests disease of the sensory cor-tex. Stereognosis, number identiﬁ-cation, and two-point discrimina-tion are also impaired by posteriorcolumn disease.
Astereognosis refers to the inability
to recognize objects placed in thehand.
The inability to recognize numbers,
like astereognosis, suggests a lesionin the sensory cortex.

vent the patient from manipulat-
ing an object well enough to iden-tify it, test the ability to identifynumbers. With the blunt end of apen or pencil, draw a large num-ber in the patient’s palm. A nor-mal person can identify most suchnumbers.
ITwo-point discrimination. Using
the two ends of an opened paper clip, or the sides of two pins, touch a ﬁnger pad in two places simultane-ously. Alternate the double stimulus irregularly with a one-point touch.Be careful not to cause pain.
Find the minimal distance at which the patient can discriminate one from
two points (normally less than 5 mm on the ﬁnger pads). This test maybe used on other parts of the body, but normal distances vary widely fromone body region to another.
IPoint localization. Brieﬂy touch a point on the patient’s skin. Then ask the
patient to open both eyes and point to the place touched. Normally a per-son can do so accurately. This test, together with the test for extinction,is especially useful on the trunk and the legs.

IExtinction. Simultaneously stimulate corresponding areas on both sides
of the body. Ask where the patient feels your touch. Normally both stim-uli are felt.
Deep Tendon Reﬂexes
To elicit a deep tendon reﬂex, per-
suade the patient to relax, positionthe limbs properly and symmetri-cally, and strike the tendon briskly,using a rapid wrist movement. Yourstrike should be quick and direct,not glancing. You may use either thepointed or the ﬂat end of the ham-mer. A properly weighted hammeris important. The pointed end isuseful in striking small areas, such asyour ﬁnger as it overlies the bicepstendon, while the ﬂat end gives thepatient less discomfort over the bra-chioradialis. Hold the reﬂex ham-mer between your thumb and index 

586 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGLesions of the sensory cortex in-
crease the distance between tworecognizable points.
Lesions of the sensory cortex im-
pair the ability to localize points ac-curately.
With lesions of the sensory cortex,
only one stimulus may be recog-nized. The stimulus on the sideopposite the damaged cortex isextinguished.

ﬁnger so that it swings freely within the limits set by your palm and other
ﬁngers. Note the speed, force, and amplitude of the reﬂex response. Alwayscompare one side with the other.TECHNIQUES OF EXAMINATION
CHAPTER 16 ITHE NERVOUS SYSTEM 587Hyperactive reﬂexes suggest cen-
tral nervous system disease. Sus-tained clonus conﬁrms it. Reﬂexesmay be diminished or absent whensensation is lost, when the relevantspinal segments are damaged, orwhen the peripheral nerves aredamaged. Diseases of muscles andneuromuscular junctions may alsodecrease reﬂexes.Reﬂexes are usually graded on a 0 to 4+ scale:
4+ Very brisk, hyperactive, with clonus (rhythmic oscillations between ﬂexion 
and extension)
3+ Brisker than average; possibly but not necessarily indicative of disease
2+ Average; normal
1+ Somewhat diminished; low normal
0 No response
Reﬂex response depends partly on the force of your stimulus. Use no more

force than you need to provoke a deﬁnite response. Differences betweensides are usually easier to assess than symmetric changes. Symmetrically di-minished or even absent reﬂexes may be found in normal people.
If the patient’s reflexes are symmetrically diminished or absent, use re-
inforcement, a technique involving isometric contraction of other muscles
that may increase reflex activity. In testing arm reflexes, for example, askthe patient to clench his or her teeth or to squeeze one thigh with the op-posite hand. If leg reflexes are diminished or absent, reinforce them by ask-ing the patient to lock fingers and pull one hand against the other. Tell thepatient to pull just before you strike the tendon.
REINFORCEMENT OF KNEE REFLEX

Observe ﬂexion at the elbow, and watch for and feel the contraction of the
biceps muscle.
The Triceps Reﬂex (C6, C7). Flex the patient’s arm at the elbow, with
palm toward the body, and pull it slightly across the chest. Strike the tricepstendon above the elbow. Use a direct blow from directly behind it. Watchfor contraction of the triceps muscle and extension at the elbow.
If you have difﬁculty getting the pa-
tient to relax, try supporting theupper arm as illustrated on the right.Ask the patient to let the arm golimp, as if it were “hung up to dry.”Then strike the triceps tendon.
The Biceps Reﬂex (C5, C6). The patient’s arm should be partially
ﬂexed at the elbow with palm down. Place your thumb or ﬁnger ﬁrmly onthe biceps tendon. Strike with the reﬂex hammer so that the blow is aimeddirectly through your digit toward the biceps tendon.TECHNIQUES OF EXAMINATION
588 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGPATIENT SITTING PATIENT LYING DOWN

PATIENT SITTINGPATIENT LYING DOWN

CHAPTER 16 ITHE NERVOUS SYSTEM 589EXAMPLES OF ABNORMALITIES
The Supinator or Brachio-
radialis Reﬂex (C5, C6). The
patient’s hand should rest on the ab-domen or the lap, with the forearmpartly pronated. Strike the radiusabout 1 to 2 inches above the wrist.Watch for ﬂexion and supination ofthe forearm.
The Abdominal Reﬂexes. Test
the abdominal reﬂexes by lightly butbriskly stroking each side of the ab-domen, above (T8, T9, T10) andbelow (T10, T11, T12) the umbili-cus, in the directions illustrated. Usea key, the wooden end of a cotton-tipped applicator, or a tongue bladetwisted and split longitudinally. Notethe contraction of the abdominalmuscles and deviation of the um-bilicus toward the stimulus. Obesitymay mask an abdominal reflex. Inthis situation, use your finger to retract the patient’s umbilicus away fromthe side to be stimulated. Feel with your retracting ﬁnger for the muscularcontraction.TECHNIQUES OF EXAMINATION
Abdominal reﬂexes may be absent

in both central and peripheral ner-vous system disorders.
PATIENT SITTING
The Knee Reﬂex (L2, L3, L4). The patient may be either sitting or
lying down as long as the knee is ﬂexed. Briskly tap the patellar tendon just

590 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGbelow the patella. Note contraction of the quadriceps with extension at the
knee. A hand on the patient’s anterior thigh lets you feel this reﬂex.
Two methods are useful when examining the supine patient. Supporting
both knees at once, as shown below on the left, allows you to assess smalldifferences between knee reﬂexes by repeatedly testing one reﬂex and thenthe other. Sometimes, however, supporting both legs is uncomfortable forboth the examiner and the patient. You may wish to rest your supportingarm under the patient’s leg, as shown below on the right. Some patients ﬁndit easier to relax with this method.
The slowed relaxation phase of 
reflexes in hypothyroidism isoften easily seen and felt in theankle reflex.
The Ankle Reﬂex (primarily S1). If the patient is sitting, dorsiﬂex the

foot at the ankle. Persuade the patient to relax. Strike the Achilles tendon.Watch and feel for plantar ﬂexion at the ankle. Note also the speed of relax-ation after muscular contraction.
When the patient is lying down, ﬂex one leg at both hip and knee and rotate
it externally so that the lower leg rests across the opposite shin. Then dorsi-ﬂex the foot at the ankle and strike the Achilles tendon.

CHAPTER 16 ITHE NERVOUS SYSTEM 591A Babinski response may also be
seen in unconscious states due todrug or alcohol intoxication or inthe postictal period following aseizure.
PATIENT LYING DOWN
The Plantar Response (L5, S1). With an object such as a key or the
wooden end of an applicator stick, stroke the lateral aspect of the sole fromthe heel to the ball of the foot, curving medially across the ball. Use thelightest stimulus that will provoke a response, but be increasingly ﬁrm if nec-essary. Note movement of the toes, normally ﬂexion.Dorsiﬂexion of the big toe, often
accompanied by fanning of theother toes, constitutes a Babinskiresponse. It often indicates a central nervous system lesion inthe corticospinal tract.

Some patients withdraw from this stimulus by ﬂexing the hip and the knee.
Hold the ankle, if necessary, to complete your observation. It is sometimesdifﬁcult to distinguish withdrawal from a Babinski response.
Clonus. If the reﬂexes seem hyperactive, test for ankle clonus. Support the
knee in a partly ﬂexed position. With your other hand, dorsiﬂex and plantarﬂex the foot a few times while encouraging the patient to relax, and thensharply dorsiﬂex the foot and maintain it in dorsiﬂexion. Look and feel forrhythmic oscillations between dorsiﬂexion and plantar ﬂexion. In most nor-mal people, the ankle does not react to this stimulus. A few clonic beats maybe seen and felt, especially when the patient is tense or has exercised.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
592 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGA marked Babinski response is oc-
casionally accompanied by reﬂexﬂexion at hip and knee.
Sustained clonus indicates central

nervous system disease. The ankleplantar ﬂexes and dorsiﬂexes repet-itively and rhythmically.
Clonus may also be elicited at other joints. A sharp downward displacement
of the patella, for example, may elicit patellar clonus in the extended knee.
Mini-Mental State Examination (MMSE). This brief test is useful
in screening for cognitive dysfunction or dementia and following theircourse over time. For more detailed information regarding the MMSE, con-tact the Publisher, Psychological Assessment Resources, Inc., 16204 NorthFlorida Avenue, Lutz, Florida 33549.
Asterixis. Asterixis helps identify a metabolic encephalopathy in patients

whose mental functions are impaired. Ask the patient to “stop trafﬁc” by ex-tending both arms, with hands cocked up and ﬁngers spread. Watch for 1 to2 minutes, coaxing the patient as necessary to maintain this position.
Sudden, brief, nonrhythmic ﬂexion
of the hands and ﬁngers indicatesasterixis.

CHAPTER 16 ITHE NERVOUS SYSTEM 593Winging of the Scapula. When the shoulder muscles seem weak or
atrophic, look for winging. Ask the patient to extend both arms and pushagainst your hand or against a wall. Observe the scapulae. Normally they lieclose to the thorax.In winging, shown below, 
the medial border of the scapulajuts backward. It suggests weakness of the serratus anteriormuscle, as in muscular dystrophyor injury to the long thoracicnerve.
Pain in the neck and resistance 
to ﬂexion can arise from meningealinﬂammation, arthritis, or neck injury.
Flexion of the hips and knees 
is a positive Brudzinski’s sign
and suggests meningeal inﬂammation.
Pain and increased resistance to
extending the knee are a positive
Kernig’s sign. When bilateral, it 
suggests meningeal irritation.In very thin but normal people, the scapulae may appear “winged” even
when the musculature is intact.

Meningeal Signs. Testing for these signs is important if you suspect
meningeal inﬂammation from infection or subarachnoid hemorrhage.
Neck Mobility. First make sure there is no injury to the cervical ver-
tebrae or cervical cord. (In settings of trauma, this may require evaluationby x-ray.) Then, with the patient supine, place your hands behind the pa-tient’s head and ﬂex the neck forward, until the chin touches the chest if pos-sible. Normally the neck is supple and the patient can easily bend the headand neck forward.
Brudzinski’s Sign. As you flex the neck, watch the hips and knees
in reaction to your maneuver. Normally they should remain relaxed andmotionless.
Kernig’s Sign. Flex the patient’s leg at both the hip and the knee, and

then straighten the knee. Discomfort behind the knee during full extensionoccurs in many normal people, but this maneuver should not produce pain.

Anal Reﬂex. Using a dull object, such as a cotton swab, stroke outward
in the four quadrants from the anus. Watch for reﬂex contraction of the analmusculature.
The Stuporous or Comatose Patient. Coma signals a potentially
life-threatening event affecting the two hemispheres, the brainstem, or both.The usual sequence of history, physical examination, and laboratory evalua-tion does not apply. Instead, you must:
IFirst assess the ABCs (airway, breathing, and circulation)
IEstablish the patient’s level of consciousness
IExamine the patient neurologically. Look for focal or asymmetric ﬁndings,and determine whether impaired consciousness arises from a metabolic ora structural cause.
Interview relatives, friends, or witnesses to establish the speed of onset and
duration of unconsciousness, any warning symptoms, precipitating factors,or previous episodes, and the prior appearance and behavior of the patient.Any history of past medical and psychiatric illnesses is also useful.

As you proceed to the examination, remember two cardinal DON’T s:1.Don’t dilate the pupils, the single most important clue to the underlying
cause of coma (structural vs. metabolic), and
2.Don’t ﬂex the neck if there is any question of trauma to the head or neck.
Immobilize the cervical spine and get an x-ray ﬁrst to rule out fracturesof the cervical vertebrae that could compress and damage the spinal cord.
Airway, Breathing, and Circulation. Quickly check the patient’s
color and pattern of breathing. Inspect the posterior pharynx and listen overCompression of a lumbosacral
nerve root may also cause resis-tance, together with pain in thelow back and the posterior thigh.Only one leg is usually involved.
Loss of the anal reﬂex suggests a
lesion in the S2–3–4 reﬂex arc, asin a cauda equina lesion.
See Table 16-14, Metabolic and
Structural Coma (p. 620).TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
594 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING

CHAPTER 16 ITHE NERVOUS SYSTEM 595the trachea for stridor to make sure the airway is clear. If respirations are
slowed or shallow, or if the airway is obstructed by secretions, consider in-tubating the patient as soon as possible while stabilizing the cervical spine.
Assess the remaining vital signs: pulse, blood pressure, and rectal tempera-
ture. If hypotension or hemorrhage is present, establish intravenous accessand begin intravenous ﬂuids. (Further emergency management and labora-tory studies are beyond the scope of this text.)
Level of Consciousness. Level of consciousness primarily reﬂects the
patient’s capacity for arousal, or wakefulness. It is determined by the level ofactivity that the patient can be aroused to perform in response to escalatingstimuli from the examiner.
Five clinical levels of consciousness are described in the table below, together

with the techniques that may be used to elicit their characteristics. Increase yourstimuli in a stepwise manner, depending on the patient’s response.
When you examine patients with an altered level of consciousness, de-
scribe and record exactly what you see and hear. Summary terms such aslethargy, obtundation, stupor, or coma may have different meanings forother examiners.
Level Technique
Speak to the patient in a normal tone of voice. An alert patient
opens the eyes, looks at you, and responds fully and appropriatelyto stimuli (arousal intact).
Speak to the patient in a loud voice. For example, call the patient’s
name or ask “How are you?”
Shake the patient gently as if awakening a sleeper.
Apply a painful stimulus. For example, pinch a tendon, rub the
sternum, or roll a pencil across a nail bed. (No stronger stimulineeded!)

Apply repeated painful stimuli.Level of Consciousness (Arousal): Techniques and Patient Response
Abnormal Response
A lethargic patient appears drowsy
but opens the eyes and looks atyou, responds to questions, andthen falls asleep.
An obtunded patient opens the eyes
and looks at you, but respondsslowly and is somewhat confused.Alertness and interest in theenvironment are decreased.
A stuporous patient arouses from sleep
only after painful stimuli. Verbalresponses are slow or even absent.The patient lapses into anunresponsive state when the stimulusceases. There is minimal awarenessof self or the environment.
A comatose patient remains
unarousable with eyes closed. Thereis no evident response to inner need
or external stimuli.Alertness
LethargyObtundation
Stupor
Coma

Neurologic Evaluation
RESPIRATIONS. Observe the rate, rhythm, and pattern of respirations. Be-
cause neural structures that govern breathing in the cortex and brainstemoverlap those that govern consciousness, abnormalities of respiration oftenoccur in coma.
PUPILS. Observe the size and equality of the pupils and test their reaction
to light. The presence or absence of the light reaction is one of the most im-portant signs distinguishing structural from metabolic causes of coma. Thelight reaction often remains intact in metabolic coma.
OCULAR MOVEMENT. Observe the position of the eyes and eyelids at rest.
Check for horizontal deviation of the eyes to one side ( gaze preference ).
When the oculomotor pathways are intact, the eyes look straight ahead.
OCULOCEPHALIC REFLEX (DOLL’S EYE
MOVEMENTS). This reﬂex helps to as-

sess brainstem function in a co-matose patient. Holding open theupper eyelids so that you can see theeyes, turn the head quickly, ﬁrst toone side and then to the other.(Make sure the patient has no neckinjury before performing this test.)
In a comatose patient with an intact
brainstem, as the head is turned theeyes move toward the opposite side(the doll’s eye movements). In the ad-jacent photo, for example, the pa-
tient’s head has been turned to theright; her eyes have moved to theleft. Her eyes still seem to gaze atthe camera. The doll’s eye move-ments are intact.
OCULOVESTIBULAR REFLEX (WITH CALORIC STIMULATION). If the oculocephalic
reﬂex is absent and you seek further assessment of brainstem function, testthe oculovestibular reﬂex. Note that this test is almost never performed inan awake patient.

Make sure the eardrums are intact and the canals clear. You must elevate the
patient’s head to 30° to perform the test accurately. Place a kidney basin underthe ear to catch any overﬂowing water. With a large syringe, inject ice waterTECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
596 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGSee Table 16-14, Metabolic and
Structural Coma (p. 620), andTable 3-12, Abnormalities in Rateand Rhythm of Breathing (p. 93).
See Table 16-15, Pupils in Co-
matose Patients (p. 621).
Structural lesions such as stroke
may lead to asymmetrical pupilsand loss of light reaction.
In structural hemispheric lesions,
the eyes “look at the lesion” in theaffected hemisphere.
In irritative lesions due to epilepsy
or early cerebral hemorrhage, theeyes “look away” from the affectedhemisphere.

In a comatose patient with absence
of doll’s eye movements, shownbelow, the ability to move botheyes to one side is lost, suggestinga lesion of midbrain or pons.

CHAPTER 16 ITHE NERVOUS SYSTEM 597through a small catheter that is lying in (but not plugging) the ear canal.
Watch for deviation of the eyes in the horizontal plane. You may need to useup to 120 ml of ice water to elicit a response. In the comatose patient with anintact brainstem, the eyes drift toward the irrigated ear. Repeat on the oppo-
site side, waiting 3 to 5 minutes if necessary for the ﬁrst response to disappear.
POSTURE AND MUSCLE TONE. Observe the patient’s posture. If there is no
spontaneous movement, you may need to apply a painful stimulus (see p. 595).Classify the resulting pattern of movement as:
INormal–avoidant —the patient pushes the stimulus away or withdraws.
IStereotypic —the stimulus evokes abnormal postural responses of the trunk
and extremities.
IFlaccid paralysis or no response
Test muscle tone by grasping each forearm near the wrist and raising it to a

vertical position. Note the position of the hand, usually only slightly ﬂexedat the wrist.
Then lower the arm to about 12 or 18 inches off the bed and drop it. Watch
how it falls. A normal arm drops somewhat slowly.
Support the patient’s ﬂexed knees. Then extend one leg at a time at the knee
and let it fall (see next page). Compare the speed with which each leg falls.
No response to stimulation 
suggests brainstem injury.
See Table 16-16, Abnormal 
Postures in the Comatose Patient(p. 622).
Two stereotypic responses pre-
dominate: decorticate rigidity
and decerebrate rigidity (see 
Table 16-16, Abnormal Postures in the Comatose Patient, p. 622).
No response on one side suggests
a corticospinal tract lesion.
The hemiplegia of sudden cerebral
accidents is usually ﬂaccid at ﬁrst.The limp hand drops to form aright angle with the wrist.

A ﬂaccid arm drops rapidly, like 
a ﬂail.
In acute hemiplegia, the ﬂaccid leg
falls more rapidly

falls rapidly into extension, withexternal rotation at the hip.
Meningitis, subarachnoid 
hemorrhage.
Alcohol, liver failure, uremiaJaundice, cyanosis, cherry red color
of carbon monoxide poisoning
Bruises, lacerations, swelling
Papilledema, hypertensive
retinopathy
Reﬂex loss in coma and lesions 
affecting CN V or CN VII
Blood or cerebrospinal ﬂuid in the
nose or the ears suggests a skullfracture; otitis media suggests apossible brain abscess.
Tongue injury suggests a seizure.TECHNIQUES OF EXAMINATION EXAMPLES OF ABNORMALITIES
598 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGFlex both legs so that the heels rest on the bed and then release them. The
normal leg returns slowly to its original extended position.
Further Examination
As you complete the neurologic examination, check for facial asymmetry andasymmetries in motor, sensory, and reﬂex function. Test for meningeal signsif indicated.

As you proceed to the general physical examination, check for unusual odors.Look for abnormalities of the skin, including color, moisture, evidence of
bleeding disorders, needle marks, and other lesions.
Examine the scalp and skull for signs of trauma.Examine the fundi carefully.
Check to make sure the corneal reﬂexes are intact. (Remember that use of
contact lenses may abolish these reﬂexes.)
Inspect the ears and nose, and examine the mouth and throat.
Be sure to evaluate the heart, lungs, and abdomen.
Tables 16-1 through 16-7 summarize the manifestations of selected disorders. They show
how the data collected can be used diagnostically, and will help you to recognize and thinkabout certain patterns of illness.
Tables 16-1, 16-3, and 16-4 are based, with permission, on the Diagnostic and Statistical

Manual of Mental Disorders, Fourth Edition, Text Revision (DSM IV-TR) Washington, D.C.,
American Psychiatric Association, 2000. For further details and criteria, the reader should con-sult this manual, its successor, or comprehensive textbooks of psychiatry.

TABLE 16-1 IDisorders of Mood
CHAPTER 16 ITHE NERVOUS SYSTEM 599
Mood disorders may be either depressive or bipolar. A bipolar disorder includes manic or hypomanic features as well as
depressive ones. Four types of episodes, described below, are combined in different ways in diagnosis of mood disorders. A
major depressive disorder includes only one or more major depressive episodes. A bipolar I disorder includes one or more
manic or mixed episodes, usually accompanied by major depressive episodes. A bipolar II disorder includes one or more
major depressive episodes accompanied by at least one hypomanic episode.
Dysthymic and cyclothymic disorders are chronic and less severe conditions that do not meet the criteria of the other dis-
orders. Mood disorders due to general medical conditions or substance abuse are classiﬁed separately.
At least ﬁve of the symptoms listed below (including one of the

ﬁrst two) must be present during the same 2-week period. Theymust also represent a change from the person’s previous state.
IDepressed mood (may be an irritable mood in children andadolescents) most of the day, nearly every day
IMarkedly diminished interest or pleasure in almost all activitiesmost of the day, nearly every day
ISigniﬁcant weight gain or loss (not dieting) or increased ordecreased appetite nearly every day
IInsomnia or hypersomnia nearly every day
IPsychomotor agitation or retardation nearly every day
IFatigue or loss of energy nearly every day
IFeelings of worthlessness or inappropriate guilt nearly every day
IInability to think or concentrate or indecisiveness nearly every day
IRecurrent thoughts of death or suicide, or a speciﬁc plan foror attempt at suicide

The symptoms cause signiﬁcant distress or impair social,
occupational, or other important functions. In severe cases,hallucinations and delusions may occur.
Mixed Episode
A mixed episode, which must last at least 1 week, meets thecriteria for both manic and major depressive episodes.Manic Episode
A distinct period of abnormally and persistently elevated,expansive, or irritable mood must be present for at least aweek (any duration if hospitalization is necessary). Duringthis time, at least three of the symptoms listed below havebeen persistent and signiﬁcant. (Four of the these symptomsare required if the mood is only irritable).
IInﬂated self-esteem or grandiosity
IDecreased need for sleep (feels rested after sleeping 3 hours)
IMore talkative than usual or pressure to keep talking
IFlight of ideas or racing thoughts
IDistractibility

IIncreased goal-directed activity (either socially at workor school, or sexually) or psychomotor agitation
IExcessive involvement in pleasurable high-risk activities(buying sprees, foolish business ventures, sexualindiscretions)
The disturbance is severe enough to impair social or
occupational functions or relationships. It may necessitatehospitalization for the protection of self or others. In severecases, hallucinations and delusions may occur.
Hypomanic Episode
The mood and symptoms resemble those in a manic episodebut are less impairing, do not require hospitalization, do notinclude hallucinations or delusions, and have a shorterminimum duration—4 days.
Cyclothymic Episode

Numerous periods of hypomanic and depressive symptomsthat last for at least 2 years (1 year in children andadolescents). Freedom from symptoms lasts no more than 2 months at a time.Dysthymic Disorder
A depressed mood and symptoms for most of the day, for moredays than not, over at least 2 years (1 year in children andadolescents). Freedom from symptoms lasts no more than 2 months at a time.

TABLE 16-2 IDisorders of Speech
600 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Disorders of speech fall into three groups: those affecting (1) the voice, (2) the articulation of words, and (3) the pro-
duction and comprehension of language.
Aphonia refers to a loss of voice that accompanies disease affecting the larynx or its nerve supply. Dysphonia refers to
less severe impairment in the volume, quality, or pitch of the voice. For example, a person may be hoarse or only able tospeak in a whisper. Causes include laryngitis, laryngeal tumors, and a unilateral vocal cord paralysis (Cranial Nerve X).
Dysarthria refers to a defect in the muscular control of the speech apparatus (lips, tongue, palate, or pharynx). Words may
be nasal, slurred, or indistinct, but the central symbolic aspect of language remains intact. Causes include motor lesions ofthe central or peripheral nervous system, parkinsonism, and cerebellar disease.

Aphasia refers to a disorder in producing or understanding language. It is often caused by lesions in the dominant
cerebral hemisphere (usually the left).
Compared below are two common types of aphasia: (1) Wernicke’s, a ﬂuent (receptive) aphasia, and (2) Broca’s, a non-
ﬂuent (or expressive) aphasia. There are other less common kinds of aphasia, which may be distinguished from each otherby differing responses on the speciﬁc tests listed. Neurologic consultation is usually indicated.
Qualities of Spontaneous
Speech
Word Comprehension
RepetitionNamingReading ComprehensionWritingLocation of LesionFluent; often rapid, voluble, and
effortless. Inﬂection and articulation are good, but sentences lack meaningand words are malformed (paraphasias)or invented (neologisms). Speech maybe totally incomprehensible.
ImpairedImpairedImpairedImpairedImpairedPosterior superior temporal lobeNonﬂuent; slow, with few words and laborious effort.

Inﬂection and articulation are impaired but words aremeaningful, with nouns, transitive verbs, and importantadjectives. Small grammatical words are often dropped.
Fair to good
ImpairedImpaired, though the patient recognizes objectsFair to goodImpairedPosterior inferior frontal lobe
While it is important to recognize aphasia early in your encounter with a patient, its full diagnostic meaning does not be-
come clear until you integrate this information with your neurologic examination.Wernicke’s Aphasia Broca’s Aphasia

TABLE 16-3 IAnxiety Disorders
CHAPTER 16 ITHE NERVOUS SYSTEM 601
Anxiety disorders cause great distress and impair function, but those affected are not psychotic. The disorders are distin-
guished by the symptoms, the entities feared, or the stressors.
Speciﬁc Phobia
Social PhobiaObsessive–
CompulsiveDisorder
Acute Stress
Disorder
Posttraumatic 
Stress Disorder
Generalized 
Anxiety DisorderA panic disorder is deﬁned by recurrent, unexpected panic attacks, at least one of which has been followed
by a month or more of persistent concern about further attacks, worry over their implications orconsequences, or a signiﬁcant change in behavior in relation to the attacks.
A panic attack is a discrete period of intense fear or discomfort that develops abruptly and peaks within

A panic attack is a discrete period of intense fear or discomfort that develops abruptly and peaks within 
10 minutes. It involves at least four of the following symptoms: (1) palpitations, pounding heart, oraccelerated heart rate, (2) sweating, (3) trembling or shaking, (4) shortness of breath or a sense ofsmothering, (5) a feeling of choking, (6) chest pain or discomfort, (7) nausea or abdominal distress, (8) feeling dizzy, unsteady, lightheaded, or faint, (9) feelings of unreality or depersonalization, (10) fearof losing control or going crazy, (11) fear of dying, (12) paresthesias (numbness or tingling), (13) chillsor hot ﬂushes.
Panic disorder may occur with or without agoraphobia.Agoraphobia is an anxiety about being in places or situations where escape may be difﬁcult or
embarrassing or help for sudden symptoms unavailable. Such situations are avoided, require a companion,or cause marked anxiety.

A speciﬁc phobia is a marked, persistent, and excessive or unreasonable fear that is cued by the presence or
anticipation of a speciﬁc object or situation, such as dogs, injections, or ﬂying. The person recognizes thefear as excessive or unreasonable, but exposure to the cue provokes immediate anxiety. Avoidance or fearimpairs the person’s normal routine, occupational or academic functioning, or social activities orrelationships.
A social phobia is a marked, persistent fear of one or more social or performance situations that involve

exposure to unfamiliar people or to scrutiny by others. Those afﬂicted fear that they will act in embarrassingor humiliating ways, as by showing their anxiety. Exposure creates anxiety and possibly a panic attack, andthe person avoids precipitating situations. He or she recognizes the fear as excessive or unreasonable.Normal routines, occupational or academic functioning, or social activities or relationships are impaired.
This disorder involves obsessions or compulsions that cause marked anxiety or distress. While they are
recognized at some point as excessive or unreasonable, they are very time consuming and interfere with theperson’s normal routine, occupational functioning, or social activities or relationships.
The person has been exposed to a traumatic event that involved actual or threatened death or serious injury

to self or others and responded with intense fear, helplessness, or horror. During or immediately after thisevent, the person has at least three of these dissociative symptoms: (1) a subjective sense of numbing,detachment, or absence of emotional responsiveness; (2) a reduced awareness of surroundings, as in a daze;(3) feelings of unreality; (4) feelings of depersonalization; and (5) amnesia for an important part of theevent. The event is persistently reexperienced, as in thoughts, images, dreams, illusions, and ﬂashbacks, ordistress from reminders of the event. The person is very anxious or shows increased arousal and tries toavoid stimuli that evoke memories of the event. The disturbance causes marked distress or impairs social,occupational, or other important functions. The symptoms occur within 4 weeks of the event and last from2 days to 4 weeks.

The event, the fearful response, and the persistent reexperiencing of the traumatic event resemble those in
acute stress disorder. Hallucinations may occur. The person has increased arousal, tries to avoid stimulirelated to the trauma, and has numbing of general responsiveness. The disturbance causes marked distress,impairs social, occupational, or other important functions, and lasts for more than a month.
This disorder lacks a speciﬁc traumatic event or focus for concern. Excessive anxiety and worry, which the
person ﬁnds hard to control, are about a number of events or activities. At least three of the followingsymptoms are associated: (1) feeling restless, keyed up, or on edge, (2) being easily fatigued, (3) difﬁcultyin concentrating or mind going blank, (4) irritability, (5) muscle tension, (6) difﬁculty in falling or stayingasleep, or restless, unsatisfying sleep. The disturbance causes signiﬁcant distress or impairs social,occupational, or other important functions.

TABLE 16-4 IPsychotic Disorders
602 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Psychotic disorders involve grossly impaired reality testing. Speciﬁc diagnoses depend on the nature and duration of the
symptoms and on a cause when it can be identiﬁed. Seven disorders are outlined below.
Schizophreniform
Disorder
Delusional DisorderBrief Psychotic Disorder
Psychotic Disorder Due
to a General MedicalCondition
Substance-Induced
Psychotic DisorderSchizophrenia impairs major functioning, as at work or school or in interpersonal relations or self

care. For this diagnosis, performance of one or more of these functions must have decreased for asigniﬁcant time to a level markedly below prior achievement. In addition, the person mustmanifest at least two of the following for a signiﬁcant part of 1 month: (1) delusions, (2)hallucinations, (3) disorganized speech, (4) grossly disorganized or catatonic behavior,* and (5) negative symptoms such as a ﬂat affect, alogia (lack of content in speech), or avolition (lackof interest, drive, and ability to set and pursue goals). Continuous signs of the disturbance mustpersist for at least 6 months.
Subtypes of this disorder include paranoid, disorganized, and catatonic schizophrenia.A schizophreniform disorder has symptoms similar to those of schizophrenia but they last less

than 6 months, and the functional impairment seen in schizophrenia need not be present.
A schizoaffective disorder has features of both a major mood disturbance and schizophrenia. The
mood disturbance (depressive, manic, or mixed) is present during most of the illness and must,for a time, be concurrent with symptoms of schizophrenia (listed above). During the sameperiod of time, there must also be delusions or hallucinations for at least 2 weeks withoutprominent mood symptoms.
A delusional disorder is characterized by nonbizarre delusions that involve situations in real life,

such as having a disease or being deceived by a lover. The delusion has persisted for at least amonth, but the person’s functioning is not markedly impaired and behavior is not obviously oddor bizarre. The symptoms of schizophrenia except for tactile and olfactory hallucinations relatedto the delusion have not been present.
In this disorder, at least one of the following psychotic symptoms must be present: delusions,
hallucinations, disordered speech such as frequent derailment or incoherence, or grosslydisorganized or catatonic behavior. The disturbance lasts at least 1 day but less than 1 month,and the person returns to his or her prior functional level.
Prominent hallucinations or delusions may be experienced during a medical illness. For this

diagnosis, they should not occur exclusively during the course of delirium. The medicalcondition should be documented and judged to be causally related to the symptoms.
Prominent hallucinations or delusions may be induced by intoxication or withdrawal from a
substance such as alcohol, cocaine, or opioids. For this diagnosis, these symptoms should notoccur exclusively during the course of delirium. The substance should be judged to be causallyrelated to the symptoms.
*Catatonic behaviors are psychomotor abnormalities that include stupor, mutism, negativistic resistance to instructions or atte mpts to move the
person, rigid or bizarre postures, and excited, apparently purposeless activity.

TABLE 16-5 IDelirium and Dementia
CHAPTER 16 ITHE NERVOUS SYSTEM 603
Delirium and dementia are common and very important disorders that affect multiple aspects of mental status. Both have
many possible causes. Some clinical features of these two conditions and their effects on mental status are compared below.A delirium may be superimposed on dementia.
OnsetCourseDurationSleep/Wake CycleGeneral Medical Illness 
or Drug Toxicity
Mental StatusLevel of Consciousness
BehaviorSpeech
Mood
Thought ProcessesThought Content
PerceptionsJudgment
OrientationAttentionMemoryExamples of CauseAcute
Fluctuating, with lucid intervals; worse at nightHours to weeksAlways disruptedEither or both present
Disturbed. Person less clearly aware of the
environment and less able to focus, sustain, orshift attention
Activity often abnormally decreased
(somnolence) or increased (agitation,hypervigilance)

May be hesitant, slow or rapid, incoherentFluctuating, labile, from fearful or irritable to
normal or depressed
Disorganized, may be incoherent
Delusions common, often transient
Illusions, hallucinations, most often visualImpaired, often to a varying degree
Usually disoriented, especially for time. 
A known place may seem unfamiliar.
Fluctuates. Person easily distracted, unable to
concentrate on selected tasks
Immediate and recent memory impaired
Delirium tremens (due to withdrawal from
alcohol)
UremiaAcute hepatic failureAcute cerebral vasculitisAtropine poisoningInsidious
Slowly progressiveMonths to yearsSleep fragmentedOften absent, especially in Alzheimer’s disease
Usually normal until late in the course of the
illness
Normal to slow; may become inappropriate

illness
Difﬁculty in ﬁnding words, aphasia
Often ﬂat, depressed
Impoverished. Speech gives little information.Delusions may occur.
Hallucinations may occur.Increasingly impaired over the course of the
illness
Fairly well maintained, but becomes impaired
in the later stages of illness
Usually unaffected until late in the illness
Recent memory and new learning especially
impaired
Reversible: Vitamin B
12 deﬁciency, thyroid
disorders
Irreversible: Alzheimer’s disease, vascular
dementia (from multiple infarcts), dementiadue to head traumaDelirium Dementia

TABLE 16-6 ISyncope and Similar Disorders
604 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Vasodepressor Syncope 
(the common faint)
Postural (orthostatic) 
Cough Syncope
Micturition SyncopeCardiovascular Disorders
Arrhythmias
Aortic Stenosis and Hypertrophic
Myocardial InfarctionMassive Pulmonary EmbolismDisorders Resembling
Syncope
Hypocapnia (decreased carbon
dioxide) Due to Hyperventilation
Hysterical Fainting Due to a
Conversion Reaction*Sudden peripheral vasodilatation, especially in
the skeletal muscles, without a compensatoryrise in cardiac output. Blood pressure falls.
IInadequate vasoconstrictor reﬂexes in both
arterioles and veins, with resultant venouspooling, decreased cardiac output, and lowblood pressure
IHypovolemia, a diminished blood volume
insufﬁcient to maintain cardiac output andblood pressure, especially in the uprightposition
Several possible mechanisms associated with

increased intrathoracic pressure
Unclear
Decreased cardiac output secondary to rhythms
that are too fast (usually more than 180) or tooslow (less than 35–40)
Vascular resistance falls with exercise, but
cardiac output cannot rise.
Sudden arrhythmia or decreased cardiac outputSudden hypoxia or decreased cardiac output
Constriction of cerebral blood vessels secondary
to hypocapnia that is induced by hyperventilation
Insufﬁcient glucose to maintain cerebral
metabolism; secretion of epinephrinecontributes to symptoms.
The symbolic expression of an unacceptable
idea through body languageA strong emotion such as fear or pain
IStanding up
IStanding up after hemorrhage or
dehydration
Severe paroxysm of coughing
Emptying the bladder after getting
out of bed to void
A sudden change in rhythm
Exercise
Variable
Variable

Exercise
Variable
Variable
Possibly a stressful situation
Variable, including fasting
Stressful situationProblem Mechanism Precipitating Factors
* Important diagnostic observations in hysterical fainting include normal skin color and normal vital signs, sometimes bizarre and purposive movements,
and occurrence in the presence of other people.

CHAPTER 16 ITHE NERVOUS SYSTEM 605
Fatigue, hunger, a hot,
humid environment
IPeripheral neuropathiesand disorders affectingthe autonomic nervoussystem; drugs such asantihypertensives andvasodilators; prolongedbed rest
IBleeding from the GItract or trauma, potentdiuretics, vomiting,diarrhea, polyuria
Chronic bronchitis in a
muscular man
Nocturia, usually in elderly or
adult men
Organic heart disease and old
age decrease the tolerance toabnormal rhythms.
Cardiac disorders
Deep venous thrombosis
A predisposition to anxiety
attacks and hyperventilation
Insulin therapy and a variety
of metabolic disorders
Hysterical personality traitsRestlessness, weakness,
pallor, nausea, salivation,sweating, yawning
IOften none
ILightheadedness andpalpitations (tachycardia)on standing up
Often none except for coughOften none
Often none
Often none. Onset is sudden.
Often none
Often none
Dyspnea, palpitations, chest

Often none
Often none
Often none
discomfort, numbness andtingling of the hands andaround the mouth lasting for several minutes.Consciousness is oftenmaintained.
Sweating, tremor,
palpitations, hunger;headache, confusion,abnormal behavior, coma.True syncope is uncommon.
VariableUsually occurs when
standing, possibly whensitting
IOccurs soon after theperson stands up
IUsually occurs soon afterthe person stands up
May occur in any position
Standing to void
Occurs with or after exercise
A slump to the ﬂoor, often
from a standing positionwithout injuryPrompt return of
consciousness when lyingdown, but pallor, weakness,nausea, and slight confusionmay persist for a time.
IPrompt return to normalwhen lying down

IImprovement on lyingdown
Prompt return to normal
unless brain damage hasresulted
Usually a prompt return to
normal
VariableVariable
Slow improvement as
hyperventilation ceases
Variable, depending on
severity and treatment
Variable, may be prolonged,
often with ﬂuctuatingresponsivenessProdromal 
Predisposing Factors Manifestations Postural Associations Recovery

TABLE 16-7 ISeizure Disorders
606 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Partial seizures are those that start with focal manifestations. They are further divided into simple partial seizures, which
do not impair consciousness, and complex partial seizures, which do. Each of these two types may remain localized or
progress into a third type, partial seizures that become generalized. Partial seizures of all kinds usually indicate a structural
lesion in the cerebral cortex, such as a scar, tumor, or infarction. The quality of such seizures helps the clinician to local-ize the causative lesion in the brain.
Partial Seizures
Simple Partial Seizures
IWith motor symptoms 
Jacksonian
Other motor
IWith sensory symptoms
IWith autonomic
symptoms
IWith psychiatric symptoms
Complex Partial Seizures
May start with simple partialseizures or with impairedconsciousness. Automatismsmay develop.
Partial Seizures That
Become GeneralizedNormal consciousness

Normal consciousnessNormal consciousnessNormal consciousness
Normal consciousness
The patient may remember initial autonomic
or psychic symptoms (which are then termedan aura), but is amnesic for the rest of the
seizure. Temporary confusion and headachemay occur.
As in a tonic–clonic seizure, described on the
next page. Two attributes indicate a partial
seizure that has become generalized: (1) therecollection of an aura, and (2) a unilateralneurologic deﬁcit during the postictal period.Problem Clinical Manifestations Postictal (Postseizure) State
Tonic and then clonic movements that start
unilaterally in the hand, foot, or face andspread to other body parts on the same side
Turning of the head and eyes to one side, or
tonic and clonic movements of an arm or legwithout the Jacksonian spread

Numbness, tingling; simple visual, auditory, or
olfactory hallucinations such as ﬂashing lights,buzzing, or odors
A “funny feeling” in the epigastrium, nausea,
pallor, ﬂushing, lightheadedness
Anxiety or fear; feelings of familiarity (déjà vu)
or unreality; dreamy states; fear or rage;ﬂashback experiences; more complexhallucinations
The seizure may or may not start with the
autonomic or psychic symptoms that areoutlined above. Consciousness is impaired andthe person appears confused. Automatismsinclude automatic motor behaviors such aschewing, smacking the lips, walking about, andunbuttoning clothes; also more complicatedand skilled behaviors such as driving a car.
Partial seizures that become generalized
resemble tonic–clonic seizures (see next page).Unfortunately, the patient may not recall thefocal onset and observers may overlook it.

CHAPTER 16 ITHE NERVOUS SYSTEM 607
Generalized Seizures
Tonic–Clonic Convulsion
(grand mal)*
Absence
Atonic Seizure, or Drop
Attack
Myoclonus
Pseudoseizures
May mimic seizures but
are due to a conversionreaction (a psychologicaldisorder).The person loses consciousness suddenly,
sometimes with a cry, and the body stiffens intotonic extensor rigidity. Breathing stops and theperson becomes cyanotic. A clonic phase ofrhythmic muscular contraction follows.Breathing resumes and is often noisy, withexcessive salivation. Injury, tongue biting, andurinary incontinence may occur.
A sudden brief lapse of consciousness, with
momentary blinking, staring, or movements ofthe lips and hands but no falling. Two subtypesare recognized. Petit mal absences last less than
10 sec and stop abruptly. Atypical absences may
last more than 10 sec.
Sudden loss of consciousness with falling but
no movements. Injury may occur.
Sudden, brief, rapid jerks, involving the trunk

or limbs. Associated with a variety of disorders
The movements may have personally symbolic
signiﬁcance and often do not follow aneuroanatomic pattern. Injury is uncommon.Confusion, drowsiness, fatigue, headache,
muscular aching, and sometimes thetemporary persistence of bilateral neurologicdeﬁcits such as hyperactive reﬂexes andBabinski responses. The person has amnesiafor the seizure and recalls no aura.
No aura recalled. In petit mal absences, a
prompt return to normal; in atypical absences,some postictal confusion
Either a prompt return to normal or a brief
period of confusion
Variable
VariableProblem Clinical Manifestations Postictal (Postseizure) State

Variable
*Febrile convulsions that resemble brief tonic–clonic seizures may occur in infants and young children. They are usually benign but occasionally may
be the ﬁrst manifestation of a seizure disorder.Generalized seizures, in contrast to partial ones, begin with either bilateral bodily movements or impairment of conscious-

ness, or both. They suggest a widespread, bilateral cortical disturbance that may be either hereditary or acquired. When gen-eralized seizures of the tonic–clonic (grand mal) variety start in childhood or young adulthood, they are often hereditary.When tonic–clonic seizures begin after the age of 30, suspect either a partial seizure that has become generalized or a gen-eral seizure caused by a toxic or metabolic problem. Toxic and metabolic causes include withdrawal from alcohol or othersedative drugs, uremia, hypoglycemia, hyperglycemia, hyponatremia and water intoxication, and bacterial meningitis.TABLE 16-7 ISeizure Disorders (Continued)

TABLE 16-8 IInvoluntary Movements
608 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Tremors are relatively rhythmic oscillatory movements, which may be roughly subdivided into three groups: resting (or static) t remors, intention tremors, and postural tremors.Tremors
Resting (Static) Tremors
These tremors are most prominent at rest, and
may decrease or disappear with voluntarymovement. Illustrated is the common, relativelyslow, ﬁne, pill-rolling tremor of parkinsonism,about 5 per second.Postural Tremors
These tremors appear when the affected part isactively maintaining a posture. Examples includethe ﬁne, rapid tremor of hyperthyroidism, thetremors of anxiety and fatigue, and benignessential (and sometimes familial) tremor. Tremormay worsen somewhat with intention.
Oral–Facial Dyskinesias

Oral–Facial Dyskinesias 
Oral–facial dyskinesias are rhythmic, repetitive, bizarre movements that chieﬂyinvolve the face, mouth, jaw, and tongue: grimacing, pursing of the lips,protrusions of the tongue, opening and closing of the mouth, and deviations ofthe jaw. The limbs and trunk are involved less often. These movements may be alate complication of psychotropic drugs such as phenothiazines, and have thenbeen termed tardive (late) dyskinesias. They also occur in long-standing
psychoses, in some elderly individuals, and in some edentulous persons.Intention Tremors
Intention tremors, absent at rest, appear withactivity and often get worse as the target isneared. Causes include disorders of cerebellarpathways, as in multiple sclerosis.

CHAPTER 16 ITHE NERVOUS SYSTEM 609Tics
Tics are brief, repetitive, stereotyped, coordinated movements occurring at
irregular intervals. Examples include repetitive winking, grimacing, andshoulder shrugging. Causes include Tourette’s syndrome and drugs such asphenothiazines and amphetamines.
Dystonia
Dystonic movements are somewhat similar to athetoid movements, butoften involve larger portions of the body, including the trunk. Grotesque,twisted postures may result. Causes include drugs such as phenothiazines,primary torsion dystonia and, as illustrated, spasmodic torticollis.Chorea
Choreiform movements are brief, rapid, jerky, irregular, and unpredictable.They occur at rest or interrupt normal coordinated movements. Unlike tics,they seldom repeat themselves. The face, head, lower arms, and hands areoften involved. Causes include Sydenham’s chorea (with rheumatic fever)and Huntington’s disease.
Athetosis

Athetosis
Athetoid movements are slower and more twisting and writhing thanchoreiform movements, and have a larger amplitude. They most commonlyinvolve the face and the distal extremities. Athetosis is often associated withspasticity. Causes include cerebral palsy.

TABLE 16-9 INystagmus
610 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Nystagmus is a rhythmic oscillation of the eyes, analogous to a tremor in other parts
of the body. Its causes are multiple, including impairment of vision in early life, dis-orders of the labyrinth and the cerebellar system, and drug toxicity. Nystagmus oc-curs normally when a person watches a rapidly moving object (e.g., a passing train).
Observe the three characteristics of nystagmus listed below and on the followingpage. Then refer to textbooks of neurology for differential diagnosis.
Direction of the Quick and Slow Components
Example: Nystagmus to the Left—A Slow Drift to the Right, Then aQuick Jerk to the Left in Each Eye
Nystagmus usually has both fast and slow movements, but is deﬁned by its fast
phase. For example, if the eyes jerk quickly to the patient’s left and drift backslowly to the right, the patient is said to have nystagmus to the left.

Occasionally, nystagmus consists only of coarse oscillations without quick and
slow components. It is then said to be pendular.
Rotary NystagmusThe movements of nystagmus may occur in one or more planes (i.e.,
horizontal, vertical, or rotary). It is the plane of the movements, not thedirection of the gaze, that deﬁnes this variable.
Plane of the Movements
Horizontal Nystagmus
Vertical Nystagmus

CHAPTER 16 ITHE NERVOUS SYSTEM 611Direction of Gaze in Which Nystagmus Appears
Example: Nystagmus on Right Lateral Gaze
Although nystagmus may be present in all directions of gaze, it may appear or
become accentuated only on deviation of the eyes (e.g., to the side or upward).On extreme lateral gaze, the normal person may show a few beats resemblingnystagmus. Avoid making assessments in such extreme positions, and observefor nystagmus only within the ﬁeld of full binocular vision.
Nystagmus Present (Right Lateral Gaze)
Nystagmus Not Present (Left Lateral Gaze)

TABLE 16-10 ITypes of Facial Paralysis
612 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Motor cortex
CN VII 
peripheral
lesionSynapses in
the pons
Facial nerve
Closing Eyes
Eye does not close;
eyeball rolls up
Flat nasolabial fold
Raising Eyebrows
Forehead not wrinkled;
eyebrow not raised
Paralysis of lower faceCN VII—Peripheral Lesion
Peripheral nerve damage to CN VII paralyzes the entire right side of the face, including the forehead.Facial weakness or paralysis may result either (1) from a peripheral lesion of CN
VII, the facial nerve, anywhere from its origin in the pons to its periphery in theface, or (2) from a central lesion involving the upper motor neurons between thecortex and the pons. A peripheral lesion of CN VII, exempliﬁed here by a Bell’spalsy, is compared with a central lesion, exempliﬁed by a left hemispheric cere-

brovascular accident. Note their different effects on the upper part of the face, bywhich they can be distinguished.

CHAPTER 16 ITHE NERVOUS SYSTEM 613
CN VII 
centrallesion
Synapses in
the pons
Flat nasolabial foldEye closes, perhapswith slight weakness
Forehead wrinkled;
eyebrow raised
Paralysis of lower faceCN VII—Central Lesion
The lower part of the face normally is controlled by upper motor neurons located
on only one side of the cortex—the opposite side. Left-sided damage to these path-
ways, as in a stroke, paralyzes the right lower face. The upper face, however, is con-
trolled by pathways from both sides of the cortex. Even though the upper motorneurons on the left are destroyed, others on the right remain and the right upper
face continues to function fairly well.

TABLE 16-11 IDisorders of Muscle Tone
614 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Spasticity Rigidity Flaccidity Paratonia
Lesion
Common CauseUpper motor neuron of the
corticospinal tract at any pointfrom the cortex to the spinalcord
Increased muscle tone
(hypertonia ) that is rate-
dependent. Tone is greaterwhen passive movement israpid, and less when passivemovement is slow. Tone is alsogreater at the extremes of themovement arc. During rapidpassive movement, initialhypertonia may give waysuddenly as the limb relaxes.This spastic “catch” andrelaxation is known as “clasp-knife” resistance.
Stroke, especially late or chronic
stageBasal ganglia system
Increased resistance that persists
throughout the movement arc,independent of rate ofmovement, is called lead-pipe
rigidity. With ﬂexion and
extension of the wrist orforearm, a superimposedrachetlike jerkiness is calledcogwheel rigidity.
ParkinsonismLower motor neuron at any

point from the anterior horncell to the peripheral nerves
Loss of muscle tone ( hypotonia ),
causing the limb to be loose orﬂoppy. The affected limbs maybe hyperextensible or even ﬂail-like.
Guillain–Barré syndrome; also
initial phase of spinal cordinjury (spinal shock) or strokeBoth hemispheres, usually in
the frontal lobes
Sudden changes in tone with
passive range of motion.Sudden loss of tone thatincreases the ease of motion iscalled mitgehen (moving
with). Sudden increase in tonemaking motion more difﬁcultis called gegenhalten (holding
against).
Dementia

TABLE 16-12 IDisorders of the Central and Peripheral Nervous Systems
CHAPTER 16 ITHE NERVOUS SYSTEM 615
Central Nervous System DisordersTABLE 16-12 IDisorders of the Central and Peripheral Nervous Systems
KneeHip
Hand
Face
Tongue
Basal 
gangliaTrunk
MIDBRAIN
Corticobulbar tractCorticospinal tracts
(2)(4)(1)
Thalamus
Internal
capsule
Pyramids
tractSPINAL CORD
tract(3)

616 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 16-12 IDisorders of the Central and Peripheral Nervous Systems (Continued)
Central Nervous System Disorders
Typical Findings
Deep Tendon
Location of Lesion Motor Sensory Reﬂexes Examples of Cause
Cerebral Cortex (1)
Brainstem (2)
Spinal Cord (3)
Subcortical Gray
Matter: BasalGanglia (4)
Cerebellar (not
illustrated)Chronic contralateral upper motor
neuron weakness and spasticity.Flexion is stronger than extension inthe arm, plantar ﬂexion is strongerthan dorsiﬂexion in the foot, and theleg is externally rotated at the hip.
Weakness and spasticity as above,
plus cranial nerve deﬁcits such asdiplopia (from weakness of theextraocular muscles) and dysarthria
Weakness and spasticity, as 
above, but often affecting both sides(when cord damage is bilateral),causing paraplegia or quadriplegiadepending on the level of injury
Slowness of movement

(bradykinesia), rigidity, and tremor
Hypotonia, ataxia, and other
abnormal movements, includingnystagmus, dysdiadochokinesis, anddysmetriaContralateral sensory loss on the
limbs and trunk on the same sideas the motor deﬁcits
Variable. No typical sensory
ﬁndings
Dermatomal sensory deﬁcit on
the trunk bilaterally at the levelof the lesion, and sensory lossfrom tract damage below thelevel of the lesion
Sensation not affected
Sensation not affected↑
↑
↑
Normal or ↓
Normal or ↓Cortical stroke
Brainstem stroke,
acoustic neuroma
Trauma, causing cord
compression
Cerebellar stroke, brain
tumor

CHAPTER 16 ITHE NERVOUS SYSTEM 617Typical Findings
Anterior Horn 
Cell (1)
Spinal Roots and
Nerves (2)
Peripheral Nerve—
Mononeuropathy (3)
Polyneuropathy (4)
Neuromuscular
Junction (5)
Muscle (6)Weakness and atrophy in a
segmental or focal pattern;fasciculations
Weakness and atrophy in a root-
innervated pattern; sometimes withfasciculations
Weakness and atrophy in a
peripheral nerve distribution;sometimes with fasciculations
Weakness, and atrophy more distal
than proximal; sometimes withfasciculations
Fatigability more than weakness
Weakness usually more proximal
than distal; fasciculations rareSensation intact
Corresponding dermatomal
sensory deﬁcits
Sensory loss in the pattern of that
nerve
Sensory deﬁcits, commonly in
stocking–glove distribution
Sensation intactSensation intact↓
↓↓↓
Normal

nerve
↓↓↓
Normal
Normal or ↓Polio, amyotrophic lateral
sclerosis
Herniated cervical or
lumbar disc
Trauma
Peripheral polyneuropathy
of alcoholism, diabetes
Myasthenia gravisMuscular dystrophyPeripheral Nervous System Disorders
Posterior horn
hornPosterior root
ganglion
Afferent
sensoryfiber
Efferent
Muscle(1)(1) (2)
(3) (4) (5)
(6)

TABLE 16-13 IAbnormalities of Gait and Posture
618 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Underlying Defect
Spastic Hemiparesis
Associated with lesion in
corticospinal tract, as with stroke
One arm is held immobile and close
to the side, with elbow, wrist, andinterphalangeal joints ﬂexed. The legis extended, with plantar ﬂexion ofthe foot. On walking, the patienteither drags the foot, often scrapingthe toe, or circles it stifﬂy outwardand forward ( circumduction ).Scissors Gait
Associated with bilateral spastic
paresis of the legs
The gait is stiff. Each leg is advanced
slowly, and the thighs tend to crossforward on each other at each step.The steps are short. The patientappears to be walking through water.Steppage Gait
Associated with foot drop, usuallysecondary to lower motor neurondisease
These patients either drag their feet

or lift them high, with knees ﬂexed,and bring them down with a slaponto the ﬂoor, thus appearing to bewalking up stairs. They are unable towalk on their heels. The steppage gaitmay involve one or both sides.

CHAPTER 16 ITHE NERVOUS SYSTEM 619Underlying Defect
DescriptionSensory Ataxia
Associated with loss of
position sense in the legs, asfrom polyneuropathy orposterior column damage
The gait is unsteady and wide
based (with feet wide apart).These patients throw their feetforward and outward andbring them down, ﬁrst on theheels and then on the toes,with a double tapping sound.They watch the ground forguidance while walking. Witheyes closed, they cannot standsteadily with feet together (a positive Romberg sign) andthe staggering gait worsens.Cerebellar Ataxia
Associated with disease of thecerebellum or associated tracts
The gait is staggering,
unsteady, and wide based,with exaggerated difﬁculty onthe turns. These patientscannot stand steadily with feettogether, whether their eyesare open or closed.Parkinsonian Gait
Associated with the basalganglia defects of Parkinson’sdisease
The posture is stooped, with

head and neck forward andhips and knees slightly ﬂexed.Arms are ﬂexed at elbows andwrists. The patient is slow ingetting started. Steps are shortand often shufﬂing. Armswings are decreased and thepatient turns around stifﬂy—“all in one piece.”Gait of Older Age
The aging process
Speed, balance, and agility
decrease with aging. Stepsbecome short, uncertain, andeven shufﬂing. The legs maybe ﬂexed at hips and knees. Acane may bolster lostconﬁdence.

TABLE 16-14 IMetabolic and Structural Coma
620 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Although there are many causes of coma, most can be classiﬁed as either structural or metabolic. Findings vary widely in
individual patients; the features listed are general guidelines rather than strict diagnostic criteria. Remember that psychi-atric disorders may mimic coma.
Toxic–Metabolic Structural
IRespiratory pattern
IPupillary size and reaction
ILevel of consciousness
Examples of CauseArousal centers poisoned or critical substrates depleted
If regular, may be normal or hyperventilation. If irregular,
usually Cheyne–Stokes
Equal, reactive to light. If pinpoint from opiates or
cholinergics, you may need a magnifying glass to see thereaction.
May be unreactive if ﬁxed and dilated from
anticholinergics or hypothermia

Changes after pupils changeUremia, hyperglycemiaAlcohol, drugs, liver failureHypothyroidism, hypoglycemiaAnoxia, ischemiaMeningitis, encephalitisHyperthermia, hypothermiaLesion destroys or compresses brainstem arousal areas,
either directly or secondary to more distant expandingmass lesions.
Irregular, especially Cheyne–Stokes or ataxic breathing
Unequal or unreactive to light (ﬁxed)
Midposition, ﬁxed —suggests midbrain compression
Dilated, ﬁxed —suggests compression of CN III from
herniation
Changes before pupils change
Epidural, subdural, or intracerebral hemorrhageCerebral infarct or embolusTumor, abscessBrainstem infarct, tumor, or hemorrhageCerebellar infarct, hemorrhage, tumor, or abscess

TABLE 16-15 IPupils in Comatose Patients
CHAPTER 16 ITHE NERVOUS SYSTEM 621
Pupillary size, equality, and light reactions help in assessing the cause of coma and in determining the region of the brain
that is impaired. Remember that unrelated pupillary abnormalities, including miotic drops for glaucoma or mydriaticdrops for a better view of the ocular fundi, may have preceded the coma.
Small or Pinpoint Pupils
Bilaterally small pupils (1–2.5 mm) suggest (1)
damage to the sympathetic pathways in thehypothalamus, or (2) metabolic encephalopathy(a diffuse failure of cerebral function that hasmany causes, including drugs). Light reactionsare usually normal.
Pinpoint pupils (< 1 mm) suggest (1) a
hemorrhage in the pons, or (2) the effects ofmorphine, heroin, or other narcotics. The lightreactions may be seen with a magnifying glass.Midposition Fixed Pupils
Pupils that are in the midposition or slightly
dilated (4–6 mm) and are ﬁxed to light suggest

structural damage in the midbrain.
One Large Pupil
A pupil that is ﬁxed and dilated warns of
herniation of the temporal lobe, causingcompression of the oculomotor nerve andmidbrain.Large Pupils
Bilaterally ﬁxed and dilated pupils may be due to
severe anoxia and its sympathomimetic effects, asseen after cardiac arrest. They may also resultfrom atropinelike agents, phenothiazines, ortricyclic antidepressants.
Bilaterally large reactive pupils may be due to
cocaine, amphetamine, LSD, or othersympathetic nervous system agonists.

TABLE 16-16 IAbnormal Postures in Comatose Patients
622 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Decorticate Rigidity (Abnormal Flexor Response)
In decorticate rigidity, the upper arms are held tight to the sides with elbows,
wrists, and ﬁngers ﬂexed. The legs are extended and internally rotated. The feetare plantar ﬂexed. This posture implies a destructive lesion of the corticospinaltracts within or very near the cerebral hemispheres. When unilateral, this is theposture of chronic spastic hemiplegia.Hemiplegia (Early)

Sudden unilateral brain damage involving the corticospinal tract may producea hemiplegia (one-sided paralysis), which early in its course is ﬂaccid.Spasticity will develop later. The paralyzed arm and leg are slack. They fallloosely and without tone when raised and dropped to the bed. Spontaneousmovements or responses to noxious stimuli are limited to the opposite side.The leg may lie externally rotated. One side of the lower face may beparalyzed, and that cheek puffs out on expiration. Both eyes may be turnedaway from the paralyzed side.
Decerebrate Rigidity (Abnormal Extensor Response)

In decerebrate rigidity, the jaws are clenched and the neck is extended. The armsare adducted and stifﬂy extended at the elbows, with forearms pronated, wrists andﬁngers ﬂexed. The legs are stifﬂy extended at the knees, with the feet plantar ﬂexed.This posture may occur spontaneously or only in response to external stimuli suchas light, noise, or pain. It is caused by a lesion in the diencephalon, midbrain, orpons, although severe metabolic disorders such as hypoxia or hypoglycemia mayalso produce it.
 Flexed
 Flexed Adducted Internally rotated Plantar flexed
Plantar flexed Flexed Pronated Extended Adducted
Externally rotated Flaccid

Assessing Children: 
Infancy Through AdolescenceCHAPTER
Assessing Children: Infancy Through Adolescence1717
CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 623Peter G. Szilagyi, MD, MPH
Before you can effectively talk to and examine a child, you need to under-
stand children and their development. Children are anatomically and physi-ologically different from adults, and many techniques for assessment, physicalﬁndings, and abnormalities in young patients differ as well. Children displaytremendous variations in physical, cognitive, and social development com-pared with adults. This chapter opens with the section on Child Developmentto help you assess children at all ages and to distinguish normal from abnor-mal symptoms and signs.

ASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE
624 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGHealth promotion and counseling are central to children’s health care and
should almost always be addressed whenever health care providers are exam-ining children. The section on Health Promotion and Counseling outlinessome critical areas to consider.
Children change rapidly, and it is important to understand the milestones
for normal development for children at any age. Normal for a 2-year-oldmay be abnormal for a 10-year-old. Table 17-4, Growth Charts, (pp. 742–749) has key parameters of children’s growth and development.
The major section of this chapter, Techniques of Examination, details the

physical examination of regional systems as in the rest of the book and fol-lows a head-to-toe sequence. The section on Approach to the Examina-tion of Children at Different Ages provides particular strategies useful foreach age group. The section is divided by age group: infancy (the first
year), early childhood (years 1 through 4), and middle childhood (years 5
through 10). The physical examination of adolescents (years 11 through

20) is similar to that of adults, although cognitively and emotionally they
are far from alike!
The Tables of Abnormalities (pp. 780–782) follow the order of the chapter
and highlight major pediatric abnormalities.CHILD DEVELOPMENT
CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 625
CHILD DEVELOPMENT
When I approach a child, he inspires in me two sentiments: tenderness for what he is,
and respect for what he may become.
—Louis Pasteur
Key Principles
Childhood is a period of remarkable growth and change, by far the great-
est in a person’s lifetime. During a few short years, a child will physicallyincrease in size 20-fold, mature into an adult, acquire sophisticated lan-guage and reasoning, and develop complex psychosocial interactions.What a journey!
The first principle of child development is that it proceeds along a predictable
pathway governed by the maturing brain. You can measure age-

specific milestones and characterize a child’s development as normal orabnormal according to established criteria. Once a milestone is achieved, the
child proceeds to the next. Loss of milestones is concerning. Because yourphysical examination takes place at one point in time, you need to learn wherethe child ﬁts within a developmental trajectory.
The second principle is that the range of normal development is wide . It is
critical to recognize that children mature at different rates.
The third principle recognizes that a variety of physical, disease-related, social,
and environmental factors affect child development and health . For example,

chronic diseases and social problems such as child abuse and poverty can re-sult not only in detectable physical abnormalities but in alterations in the rateand course of developmental advancement. Children with physical or cog-nitive disabilities may not follow the expected age-speciﬁc developmentaltrajectory outlined here. Tailor the physical examination to the child’s de-velopmental level.
A fourth principle, specific to the pediatric examination, is that the child’s
developmental level affects the nature of the medical history and physical ex-amination . For example, interviewing a 5-year-old is fundamentally dif-
ferent from interviewing an adolescent—the physical examination of a

626 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGSocial and
emotionalCognitive
Milestones
AgeNormal
range
Physical
Every age has its pleasures, its style of wit, and its own ways.
—Nicholas Boileau-Despreaux
Infancy: The First Year of Life
Physical Development. The rate of physical growth during the ﬁrst
year of life is the most rapid of any age. By 1 year of age, the child shouldtriple the birth weight and increase in height by 50%. Body proportionschange, and the head becomes smaller relative to the body.
The figure on p. 628 shows the amazing developmental progression from
birth to 1 year of age. Even a newborn has cognitive abilities that may sur-prise you. For example, a newborn can fix upon and follow a human faceand respond to voices. Neurologic development progresses in a central toperipheral direction. Thus, a newborn learns head control before trunkcontrol and use of arms and legs before use of hands and fingers.
Every child is born a genius.

—R. Buckminster Fuller
rambunctious toddler who is dismantling the examination room has little
in common with that of a shy teenager. Both order and style are quite dif-ferent from the traditional examination of an adult. You will be faced simultaneously with adjusting your physical examination to the develop-mental level of the child while attempting to ascertain that developmentallevel. An understanding of normal child development helps you achievethese tasks.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 627By 3 months, the normal infant will lift up his head and clasp his hands. By
6 months, the infant will roll over, reach for objects, turn to voices, and maysit with support. Learning occurs through activity, exploration, and manip-ulation of the environment. As peripheral coordination increases, the infantlearns to reach for objects, to transfer from hand to hand, to crawl, to standby holding on, and to play with objects by banging and grabbing. A 1-year-old may be standing, exploring the environment, and putting everything inher mouth.
Cognitive and Language Development. With this exploration

comes an increased understanding of the infant’s self and environment. Theinfant learns about cause and effect (such as shaking a rattle to produce asound), the permanence of objects, and the use of tools to explore the en-vironment. By 9 months of age, the child may recognize you as a strangerdeserving wary cooperation, seek comfort from parents during the exami-nation, and actively manipulate objects within reach (such as your clothes).Language development proceeds from cooing at 2 months, to babbling at6 months, to 1 to 3 words by 1 year.
Social and Emotional Development. An infant’s understanding of

self and family also matures. Social tasks include bonding, attachment tocaregivers, and trust that loved ones will meet needs. This may result in areluctance to play with a strange examiner. Temperaments vary greatly.Some infants are predictable, adaptable, and respond positively to new stim-uli; others are less adaptable and respond intensely or negatively to new stim-uli. Because social development is affected by the environment, observe thechild’s interactions with caretakers.

Early Childhood: 1 Through 4 Years
Physical Development. After
1 year of age, the rate of physicalgrowth slows to half that of in-fancy. After age 2 years, toddlersgain about 2 to 3 kg and grow 5 cmper year. Growth can proceed inspurts. Physical changes are im-pressive, and during a few shortyears, children are transformedfrom chubby, clumsy toddlers intoleaner, more muscular preschool-ers. Even more significant are thechanges in motor and cognitivedevelopment.
Gross motor skills develop quickly
during this period. Most childrenwalk by 15 months, run well by2 years, and pedal a tricycle and jump around by 3 years. These new skillsmake the world a dangerous place for toddlers and pose inherent challengesduring your examination. Fine motor skills develop through neurologic
628 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGInfancySocial/EmotionalBonds, develops trust
Regards face
Responds to sounds
Habituates
Fixes and follows
Head control
Birth      Sits

Birth      Sits
   Rolls overBears weight on legsPulls to standStandsWalks
Monosyllable
ReachesFeeds self
Looks for toyFew words
UnderstandswordsPointsExplores room
Shows wantsPlays simple games
6m 12mCognitive/Language
Physical/Motor

maturation and experience with manipulation of the environment. The
18-month-old who scribbles fleetingly, develops into a 2-year-old whoimitates lines, and a 4-year-old who draws and copies circles.
Children are the keys of paradise.
—Richard StoddardCHILD DEVELOPMENT
CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 629Cognitive and Language Development. Intellectually, a toddler
makes the transition from learning about the environment through touch-ing and looking (sensorimotor learning), to symbolic thinking, simpleproblem-solving, remembering songs, and imitating through play. Takeadvantage of these changes by making your examination seem like you are playing.
Language develops at extraordinary speed. An 18-month-old with 10 to

20 words emerges as a 2-year-old with two- to three-word sentences, and thena 3-year-old who converses well, asks “why” repeatedly, and entertains youwith songs and often uproariously illogical symbolic stories. By 4 years of age,preschoolers form complex sentences. Recall that these ambitious and cre-ative youngsters are still preoperational in thinking and lack sustained logicalthought processes.
Social and Emotional Development. The toddler’s march to new in-

tellectual pursuits is only surpassed by a new drive for independence. Expecta struggle during parts of your examination. Because toddlers are impulsive,temper tantrums are common. Don’t get into a battle of wills with a 2-year-old! Also, don’t ask a toddler “May I listen to your chest?” After all, what willyou do when the toddler emphatically says “No!”? Just tell the toddler gentlywhat you will do. Note interactions between toddlers and caregivers, as-sessing both strengths and areas of concern.

630 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGMiddle Childhood: 5 Through 10 Years
Despite Freud’s viewpoint, the middle childhood years are certainly not la-
tent. Rather, this period is marked by goal-directed exploration of the world,increasing physical and cognitive abilities and achievements, and trials anderrors. The physical examination is more straightforward in this age group,but keep in mind the developmental stages and tasks facing these school-agechildren.
Physical Development. Physically, children in this age group grow
steadily but at a slower rate than during the preschool and adolescent peri-ods. Nevertheless, you will see major improvements in strength and coordi-nation, leading to increasing participation in activities. This is also a timewhen children with physical disabilities or chronic illnesses begin to face theirlimitations.
Cognitive and Language Development. Children become “con-

crete operational”—capable of limited logical thinking and increasinglycomplicated learning, yet still rooted in the present, with little ability to understand consequences or abstract issues. A tremendous amount of learning from school and family takes place, and this is greatly influ-enced by environmental factors. A major developmental task is the achieve-ment of self-efficacy, or the knowledge and ability to thrive in differentsituations. Moral development remains simple, with a clear sense of “right
Social/EmotionalPlays simple games
(peek-a-boo)
Two or
three words
Walks
1 yrImitates activities
Two or three
word phrases
Throws
Kicks
2 yrFeeds self
Sentences
Jumps in place
Balances on one foot
3 yrImaginative
Sings, talksabout experiences
Speech all
understandable
Balances on each foot
Hops, pedals tricycle
4 yrDresses self
Plays games
Copies figures
Defines wordsSome numbers
Skips and 
balanceswell
5 yrCognitive/Language

Speech all
Skips and 

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 631and wrong.” Language becomes increasingly complex during this age 
period.
You know children are growing up when they start asking questions 
that have answers.
—John Plomp
Social and Emotional Development. School-age children become
progressively more independent, initiating their own activities and enjoy-ing their own accomplishments. This is a period of achievements and a crit-
Developmental
Task Characteristic Health Care Needs
Physical Enhanced strength Screening for strengths, assessing
and coordination problems
Competence on a variety Involvement of parents in 
of tasks and activities competence
Support for disabilities or problemsAnticipatory guidance about safety
Cognitive “Concrete operational”: Emphasis on short-term conse-
focus on the present quences
Achievement of knowledge Support; screening about skills
and skills, self-efﬁcacy

Social Achieving good “ﬁt” with Assessment, support, advice about
family, friends, school interactions
Sustained self-esteem SupportReconciling individuality Conﬁdentiality, understanding, 
with conformity advice
Evolving self-identity Understanding, supportMiddle Childhood
ical time for developing self-esteem and an appropriate “fit” within the
child’s major social structures—the family, the school, and peer activitygroups. Guilt and poor self-esteem can also appear. The child’s family and environment are crucial to the achievement of a positive self-image.Moral and value systems mature, though they remain relatively simple andconcrete.
Adolescence: 11 Through 20 Years

Adolescence can be divided into three stages: early, middle, and late, as shownin the table on p. 633. You need to understand the physical, cognitive,and social/emotional stage of each adolescent, because your interviewand examination techniques will vary widely depending on the adoles-cent’s level of development.

632 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Physical Development. Adolescence is the period of transition from
childhood to adulthood. The physical transformation generally occurs overa period of years, beginning at an average age of 10 in girls and 11 in boys.On average, girls end pubertal development with a growth spurt by age 14and boys by age 16. The age of onset and duration of puberty varies widely,although the stages are predictable. Early adolescents are preoccupied withthese physical changes.
A boy becomes an adult three years before his parents think he does, and about two
years after he thinks he does.
—Lewis B. Hershey
Cognitive Development. Although not as obvious, cognitive changes

during adolescence are as dramatic as changes in physique. Most adolescentsprogress from concrete to formal operational thinking, acquiring an ability toreason logically and abstractly and to consider future implications of currentactions. Although the interview and examination resemble those of adults,keep in mind the wide variability in cognitive development of adolescents andtheir often erratic and still limited ability to see beyond simple solutions. Moralthinking becomes sophisticated, with lots of time spent debating issues.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 633Social and Emotional Development. Adolescence is a tumultuous
time, marked by the transition from family-dominated inﬂuences to in-creasing autonomy and peer inﬂuence. The struggle for identity, indepen-dence, and eventually intimacy leads to much stress, many health-relatedproblems, and, often, high-risk behaviors. This struggle also provides youwith an important opportunity for health promotion.
Early Adolescence (10–14-year-olds)
Physical Puberty (F: 10–14; Conﬁdentiality; privacy
M: 11–16) variable
Cognitive “Concrete operational”: Emphasis on immediate conse-
Social
Identity Am I normal? Peers Reassurance and positive attitude
increasingly important
Independence Ambivalence (family, Support for growing autonomy
self, peers)
Middle Adolescence (15–16-year-olds)

Physical Females more comfortable, Support if patient varies from 
males awkward “normal”
Cognitive Transition to formal Problem-solving; decision-making; 
operational; many ideas teaching
Social
Identity Who am I? Much intro- Nonjudgmental acceptance
spection; global issues
Independence Limit testing; “experimental” Consistency; limit-setting
behaviors; dating
Late Adolescence (17–20-year-olds)
Physical Adult appearance; slow Minimal needs, except if chronic 
changes illness
Cognitive “Formal operational”; Approach as an adult
thinking about future
Social
Identity Role with respect to others; Encouragement of identity to 
sexuality; future allow growth
Independence Separation from family; Support
toward real independenceAdolescence

634 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
An ounce of prevention is worth a pound of cure.
—Benjamin Franklin
The heart of pediatrics is health promotion. Pediatric health care clinicians
dedicate substantial time to health supervision visits and health promotionactivities. The sage saying above is particularly true for children and adoles-cents because prevention at a young age can result in improved health out-comes for many decades.
Several national and international organizations have identiﬁed guidelines
for health promotion for children. Current concepts of health promotion in-clude not only the detection and prevention of disease, but active promo-tion of the well-being of children and their families, spanning physical,cognitive, emotional, and social health.
Every interaction with a child and family is an opportunity for health promo-

tion! From your interview questions to your detailed physical examination,
think about your interactions as having two opportunities: the traditionaldetection of normality and medical problems, and the ability to promotehealth. What a priceless gift!
Key components of pediatric health promotion are shown below. Not every
issue is relevant for each visit or age. Tailor your health promotion to the rel-evant developmental phase of your patient.
KEY COMPONENTS OF HEALTH PROMOTION 
FOR CHILDREN AND ADOLESCENTS
1. Age-appropriate developmental achievement of the child
IPhysical (maturation, growth, puberty)
IMotor (gross and ﬁne motor skills)
ICognitive (achievement of milestones, language, school performance)
IEmotional (self-efﬁcacy and mastery, self-esteem, independence, morality)
ISocial (social competence, self-responsibility, integration with family and 
community)
2. Health supervision visits

IPeriodic assessment of medical and oral health, per health supervision sched-
ules (see p. 637)
IAdjustment of frequency for children or families with special needs
3. Integration of physical examination ﬁndings (assure normality, relate ﬁndings to
healthy lifestyle)
4. Immunizations5. Screening procedures6. Anticipatory guidance
IHealthy habits IEmotional and mental health
INutrition and healthy eating IOral health
(continued)

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 635Promotion of development should be age-appropriate. Health promotion is de-
velopmental and most effective if encouraged over multiple visits. Promotionregarding development includes suggestions about stimulation (reading,conversing, music, optimizing opportunities for gross and ﬁne motor devel-opment). Advise parents about upcoming developmental stages and needs ofchildren to help them promote their child’s development. Remember, par-ents are the major agent of health promotion in children, and your advice isimplemented through them.KEY COMPONENTS OF HEALTH PROMOTION 
FOR CHILDREN AND ADOLESCENTS (Continued)
ISafety and prevention of injury IPrevention or recognition of illness
ISexual development and sexuality IPrevention of risky behaviors and 
addictions
ISelf-responsibility and efﬁcacy ISchool and vocational achievement
IFamily relationships (interactions, IPeer relationships

strengths, supports)
ICommunity interactions (childcare, school)
7. Partnership between health care provider and child, adolescent, and family
EXAMPLES OF ANTICIPATORY GUIDANCE 
DURING HEALTH SUPERVISION VISITS
1-Year-Old 16-Year-Old
Development Development
Walking, language, social games School, social, self, physical
Nutrition Nutrition
Nutritious snacks Healthy meals, dieting, preventionChoking of obesity
Oral health Oral health
Brushing Brushing, dentist No bottle in bed Braces
Safety and prevention of injury Safety and prevention of injury
Safety in home, car, childcare Seat belts, driving, and alcoholExposures: smoke, drugs Violence, abuse preventionIpecac for poisoning Protective gear for activities
Self-efﬁcacy, behavior Self-efﬁcacy

Praising good behavior Competence, self worth, futureSetting limits Managing stressDiscipline Mental health, depression
Family relationships Family relationships
Siblings, spending individual time Communication Sharing meals and activities Separation
Sexuality
Advice, information, pubertySaying no, safer sex, HIV and STDs
Community and peer interactions Community and peer interactions
Assessing child care Peers, signiﬁcant othersCommunity resources and services Positive activities, ﬁnancial, culture

The American Academy of Pediatrics (AAP) publishes guidelines for health
supervision visits and key age-appropriate components of these visits (p. 637).
Remember that children and adolescents who have a chronic illness or arefrom high-risk family or environmental circumstances will probably requiremore frequent visits and more intensive health promotion.
Integrate explanations of your physical ﬁndings with health promotion. For
example, provide advice about expected maturational changes or how healthbehaviors can impact physical ﬁndings (e.g., exercise may reduce blood pres-sure and obesity). It is particularly powerful to demonstrate the relationshipbetween healthy lifestyles and physical health.
Childhood immunizations are a mainstay for health promotion and have
been recognized as the most signiﬁcant medical achievement of publichealth worldwide. The childhood immunization schedule changes yearlyand updates are widely disseminated.

Screening procedures are performed at certain ages. For all children, these in-
clude growth parameters and developmental screening at all ages, bloodpressure after infancy, and vision and hearing screening at certain key ages.Screening procedures that are particularly recommended for high-risk pa-tients include tests for lead poisoning, tuberculosis exposure, anemia, cho-lesterol, urinary tract infections, and sexually transmitted diseases. There isvariation worldwide in recommendations for screening tests; the AAP rec-ommendations are provided on the next page.
Anticipatory guidance is a major component of the pediatric visit. Key areas

are shown in the Recommendations for Preventive Pediatric Health Careand cover a broad range of topics, from purely “medical” to social and emo-tional health. The examples of anticipatory guidance (p. 635) for a 1-year-oldand a 16-year-old highlight key components for two different age groups.The health of children is affected by all of these factors. If we are to achievea healthier world, we must emphasize comprehensive and broadly deﬁned
health promotion during childhood. Our children’s future depends on it!APPROACH TO THE EXAMINATION OF CHILDREN AT DIFFERENT AGES
636 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
APPROACH TO THE EXAMINATION 
OF CHILDREN AT DIFFERENT AGES
Each child is an adventure into a better life—an opportunity to change the old
pattern and make it new.
—Hubert H. Humphrey
Often, neophyte (and some veteran) examiners are intimidated when ap-

proaching a tiny baby or a screaming child, especially under the critical eyesof anxious parents. Although it takes a bit of courage, you will come to ac-cept the challenge easily and to enjoy almost all such encounters. This sec-tion provides guidelines for a reassuring yet thorough approach to childrenin the various age groups.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 637INFANCY EARL Y
CHILDHOOD
By
1 moMIDDLE
CHILDHOODADOLESCENCE
AGE
HISTORY
Initial / Interval
MEASUREMENTS
Height and Weight
Head Circumference
Blood Pressure
SENSORY SCREENING
Vision
Hearing
DEVELOPMENTAL/
BEHAVIORAL ASSESSMENT 2
PHYSICAL EXAMINATION 3
1. For newborns discharged in less than 48 hours after delivery2. By history and appropriate physical examination: if suspicious, by specific objective development testing
3. At each visit, a complete physical examination is essential, with infant
 totally unclothed, older child undressed and suitably draped2-4
days12 mo 4 mo 6 mo 8 mo 10 mo12 mo15 mo18 mo 24 mo 3 y 4 y 5 y 6 y 8 y 10 y 12 y 14 y 16 y 18 y 11 y 13 y 15 y 17 y 19 y 20 y+
SSSSSSSSSSSOOOOOOSOSSOSSOSS S
SSSSSSSSSSSSOOOOOSOSSOSSOSS S
Key: = to be performed     S = subjective, by history
  = objective, by a standard testing method O

Adapted from Recommendations For Preventive Pediatric Health Care promulgated by the American Academy of Pediatrics
Committee on Practice and Ambulatory Medicine. Pediatrics 96:373, 1995. Additional recommendations made by theCommittee regarding screening for metabolic disorders, tuberculosis, anemia, and urinary tract diseases, administration ofimmunizations, provision of anticipatory guidance, and initial dental referral are not included in the above summation.Recommendations for Preventive Pediatric Health Care
Each child and family is unique; therefore, these Recommendations are designed for the care of children who are receiving compe tent parenting,
have no manifestations of any important health problems, and are growing and developing in satisfactory fashion. Additional vis its may become

necessary if circumstances suggest variations from normal.

APPROACH TO THE EXAMINATION OF CHILDREN AT DIFFERENT AGES
638 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGSOME TIPS FOR EXAMINING YOUNG CHILDREN (1–4-YEAR-OLDS)
Useful Strategies for Examination Useful Toys and Aids
“Blow out” the otoscope light.
“Beep” the stethoscope on your nose.Make tongue-depressor puppets.
Use the child’s own toys for play.Jingle your keys to test for hearing.
Shine the otoscope through the tip of
your ﬁnger, “lighting it up,” andthen examine the child’s ears with it.Examine a child sitting on parent’s lap.
Try to be at the child’s eye level.
First examine the child’s toy or teddy
bear, then the child.
Let the child do some of the exam
(e.g., move the stethoscope).Then go back and “get the places we missed.”
Ask the toddler who keeps pushing
you away to “hold your hand.”Then have the toddler “help you”with the exam.
Some toddlers believe that if they can’t

see you, then you aren’t there.Perform the exam while the childstands on the parent’s lap, facingthe parent.
If 2-year-olds are holding something
in each hand (such as tongue de-pressors), they can’t fight or resist!An important and unique aspect of examining younger children is that par-
ents are usually watching and taking part in the interaction, providing youthe opportunity to observe the parent–child interaction. Note whether thechild displays age-appropriate behaviors. Assess the “goodness of ﬁt” be-tween parents and child. While some abnormal interactions may be due tothe unnatural setting of the examination room, others may be due to inter-actional problems. Careful observation of the child’s interactions with par-

ents and the child’s unstructured play in the examination room can revealabnormalities in physical, cognitive, and social development.
Normal toddlers are occasionally terrified, more commonly angry at the
examiner, and often completely uncooperative. Most eventually warm up.If this behavior continues and is not developmentally appropriate (e.g.,stranger anxiety of the infant or shyness of the early adolescent), there maybe an underlying behavioral or developmental abnormality.
Sequence of the Examination. Begin by reviewing Chapter 3, Be-
ginning the Physical Examination: General Survey and Vital Signs, for themethods and sequence of examining adults. When examining infants andchildren, the sequence should vary according to the child’s age and comfortlevel. Perform nondisturbing maneuvers early on and potentially distressing
maneuvers near the end of the examination. For example, palpate the head

and neck and auscultate the heart and lungs early, and examine the ears andmouth and palpate the abdomen near the end. If the child reports pain inone area, examine that part last.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 639The format of the pediatric medical record is the same as that of the adult
record, so although the sequence of the physical examination may vary,you should then convert your written findings back into the traditional format.
Assessing the Newborn
The ﬁrst year of life, infancy, is divided into the neonatal period (the ﬁrst 28days) and the postneonatal period (29 days to 1 year). Often, the ﬁrst pedi-atric examination outside the delivery room is performed in the hospitalwithin 24 hours of birth.
If possible, do the physical examination in front of the parents so that they

can interact with you and ask questions. Often parents have speciﬁc ques-tions about their baby’s physical appearance, so stating normal ﬁndings asyou go can be quite reassuring. This is also an excellent time to observeparental bonding with the newborn, and to observe how well the breast-feeding baby latches and sucks. To detect problems early, try to observebreast-feeding ﬁrsthand. Breast-feeding is physiologically and psychologi-cally optimal, but many mothers will need help and support. Early detec-tion of difficulties and anticipatory guidance can promote and sustainhealthy breast-feeding.

Newborns are most responsive 1 to 2 hours after a feeding, when they are nei-
ther too satiated (becoming less responsive) nor too hungry (and often agi-tated). It is helpful to start with the newborn swaddled and comfortable. Thenundress the newborn as the examination proceeds, for gradual stimulation andarousal. If the newborn becomes agitated, use a paciﬁer or a bottle of formula(if not breast-feeding), or allow the baby to suck on your gloved ﬁnger or thebaby’s own hand. You can also try reswaddling to silence the baby longenough to complete the parts of the examination that require a quiet baby.
A child is fed with milk and praise.
—Mary LambAPPROACH TO THE EXAMINATION OF CHILDREN AT DIFFERENT AGES
640 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGTIPS FOR EXAMINING NEWBORNS
IExamine the newborn in the presence of the parents.
ISwaddle and then undress the newborn as the examination proceeds.
IDim the lights and rock the baby back and forth to encourage the baby’s eyes

to open.
IObserve feeding if possible (particularly breast-feeding).
IDemonstrate calming maneuvers to parents (swaddling, holding techniques,use of paciﬁer).
IObserve transitions as baby arouses, and teach parents about these transitions.
IA typical sequence for the newborn examination (for minimal disruption of the baby):
Careful observationHead, neck, heart, lungs, abdomen, genitourinary systemLower extremities, backEars, mouthEyes, whenever they are spontaneously openSkin, as you go alongNeurologic systemHips
ASSESSMENT OF NEWBORNS
A number of techniques help you assess the developmental level of new-
borns. These techniques are often part of a limited-screening pediatric phys-ical examination performed immediately after birth.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 6411-Minute Apgar Score 5-Minute Apgar Score
0–4
5–7
8–10Severe depression, 
requiring immediateresuscitation
Some nervous system 
Normal0–7
8–10High risk for subsequent 
central nervous systemand other organ systemdysfunction
NormalAssigned Score
Clinical Sign 0 1 2
Heart rate
Respiratory effortMuscle tone
Reﬂex irritability*Color
*Reaction to suction of nares with bulb syringeThe Apgar Scoring System
Absent
AbsentFlaccid
No responsesBlue, pale<100
Slow and irregularSome ﬂexion of the
arms and legs
Grimace
Pink body, blue 
extremities>100
Good; strongActive movement
Crying vigorously, 
sneeze, or cough
Pink all overImmediate Assessment at Birth: Adaptation to Extrauterine
Life. Examining newborns immediately after birth is important for deter-

mining the general condition, developmental status, abnormalities in gesta-tional development, and presence of congenital abnormalities. Theexamination may reveal diseases of cardiac, respiratory, or neurologic origin.Listen to the anterior thorax with your stethoscope, palpate the abdomen,and inspect the head, face, oral cavity, extremities, genitalia, and perineum.
Apgar Score. The Apgar score is the key initial assessment of the baby

immediately after birth. It contains ﬁve components for classifying the new-born’s neurologic recovery from the birth process and immediate adaptationto extrauterine life. Score each newborn according to the following table, at1 and 5 minutes after birth. Scoring is based on a 3-point scale (0, 1, or 2)for each component. Total scores may range from 0 to 10. Scoring may con-tinue at 5-minute intervals until the score is greater than 7. If the 5-minuteApgar score is 8 or more, proceed to a more complete examination.
Gestational Age and Birthweight. Once newborns have successfully
adapted to their new environment, it is important to classify them by birthweight and gestational age (maturity). These classiﬁcations help predictmedical problems and morbidity.

642 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGCategory Abbreviation Percentile
Small for gestational age SGA <10th
Appropriate for gestational age AGA 10–90thLarge for gestational age LGA >90th
(Reprinted with permission from Korones SB: High-Risk Newborn Infants: The Basis for Intensive
Nursing Care, 4th ed. St. Louis, CV Mosby, 1986.)Gestational age is based on speciﬁc neuromuscular signs and physical char-
acteristics that change with gestational maturity. Several scores have beendeveloped to estimate gestational age using these characteristics.
The Ballard scoring system estimates gestational age to within 2 weeks, even in
extremely premature infants. Table 17-1 (p. 737) includes a complete Ballardscoring system, with instructions for assessing neuromuscular and physical maturity.
A useful classiﬁcation includes both birth weight and gestational age com-

ponents, and is based on the birth weight of the newborn on the intrauterinegrowth curve.CLASSIFICATION BY BIRTH WEIGHT AND GESTATIONAL AGE
Birth Weight
Classiﬁcation Weight
IExtremely low birth weight <1000 grams
IVery low birth weight <1500 grams
ILow birth weight <2500 grams
INormal birth weight ≥2500 grams
Gestational Age
Classiﬁcation Gestational Age
IPreterm < 37 wks (<259th day)
ITerm 37–42 wks
IPostterm > 42 wks (>294th day)

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 643Preterm AGA infants are more
prone to respiratory distress syn-drome, apnea, patent ductus arte-riosus with left-to-right shunt, andinfection. Preterm SGA infants are
more likely to experience asphyxia,hypoglycemia, and hypocalcemia.The figure below shows the intrauterine growth curves for the 10th and
90th percentiles, and depicts the different categories of maturity for newborninfants based on birth weight and gestational age. The three babies shownon the previous page were all born at 32 weeks’ gestational age, and weighed600 g (SGA), 1400 g (AGA), and 2750 g (LGA).
Each of these categories has a different mortality rate, highest for preterm
SGA and AGA infants, and lowest for term AGA infants. 
25 27 29 31 33 35 37 39 41 43 455
4.5
4
3.5
3
2.5
2
1.5
1
0.590%
10%Birth weight (kg)
Weeks of GestationLarge for gestational age
Appropriate
for gestational age
Small for

4.5
4
3.5
3
2.5
2
1.5
1
0.590%
Small for
gestational age
Premature Term PostmatureABIntrauterine Growth Curves
Level of intrauterine growth based on birth weight and gestational age of
liveborn, single, white infants. Point A represents a premature infant, whilepoint B indicates an infant of similar birth weight who is mature but smallfor gestational age; the growth curves are representative of the 10thand 90th percentiles for all of the newborns in the sampling. (Adaptedfrom Sweet YA: Classification of the low-birth-weight infant. In KlausMH, Fanaroff AA: Care of the High-Risk Neonate, 3rd ed. Philadelphia,WB Saunders, 1986. Reproduced with permission.)EXAMPLES OF ABNORMALITIES
Examination Several Hours After Birth. During the ﬁrst day of life,
and optimally within 8 hours of birth, newborns should have a comprehen-

644 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGAPPROACH TO THE EXAMINATION OF CHILDREN AT DIFFERENT AGES EXAMPLES OF ABNORMALITIES
By 4 days after birth, tremors oc-
curring at rest signal central ner-vous system disease from a varietyof possible causes, ranging fromasphyxia todrug withdrawal. Asym-
metric movements of the arms orlegs at any time suggest the possi-bility of central or peripheral neuro-
logic deﬁcits, birth injury (such as a
fractured clavicle or brachial plexusinjury), or congenital anomalies .sive examination. Wait until 1 or 2 hours after a feeding, when the baby is
most responsive, and ask the parents to remain in the room.
Observe the baby, ﬁrst when lying undisturbed and then almost completely
undressed if the baby is quiet. Observe the baby’s color, size, body propor-tions, nutritional status, and posture, as well as respirations and movementsof the head and extremities.
Most normal, full-term newborns lie in a symmetric position, with the limbs

semiﬂexed and the legs partially abducted at the hip. 
Normally there is spontaneous motor activity, with ﬂexion and extension al-
ternating between the arms and legs. The ﬁngers are usually ﬂexed in a tightﬁst, but may extend in slow, athetoid posturing movements. Brief tremorsof the arms, legs, and body are commonly seen for a short time after birthduring vigorous crying, and even at rest.In breech babies , the legs and head
are extended; the legs of a frank
breech baby are abducted and ex-
ternally rotated.
Throughout the examination, and particularly during auscultation and pal-
pation, it is important to have the baby quiet to optimize your examination.Place the tip of your gloved ﬁnger in a crying baby’s mouth to quiet the babylong enough to complete these portions of the examination. The order ofthe examination is unimportant.
Studies by Dr. T. Berry Brazelton and others have demonstrated the wide

range of abilities in newborns. Demonstrating some of the abilities of new-borns during your comprehensive examination is both helpful for you andwonderful for the parents. Here are some of these newborn abilities:
WHAT A NEWBORN CAN DO: ABILITY FOR COMPLEX BEHAVIOR*
Core Elements
INewborns can use all ﬁve of their senses.
For example, they prefer to look at a human face and will turn to a parent’svoice.
INewborns are unique individuals, with wide variations in their abilities to interactwith their environment.
Marked differences exist in temperaments, personality, behavior, learning, andinteractions.
INewborns interact dynamically with their caregivers.
It is a two-way street! Newborns affect caregivers as much as caregivers inﬂuencenewborns.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 645APPROACH TO THE EXAMINATION OF CHILDREN AT DIFFERENT AGES
(Continued)
Examples of Complex Newborn Behavior
Habituation
AttachmentState Regulation
Perception
*Points from T. Berry Brazelton, MD.Ability of newborn to selectively and progressively shut
out negative stimuli (such as a repetitive sound)
A reciprocal, dynamic process of interacting and bond-
ing with the caregiver
A newborn’s ability to modulate the level of arousal
under different degrees of stimulation (e.g., ability toconsole self and calm down)
Newborn’s ability to regard faces, turn to voices, quiet
in presence of singing, track colorful objects, respondto touch, and recognize familiar scents
The potential possibilities of any child are the most intriguing and stimulating
in all creation.
—Ray L. Wilbur
Assessing the Infant
The key to a successful examination of the infant is using developmentally

appropriate methods such as distraction and play. Because infants usually payattention to only one thing at a time, it is relatively easy to bring the baby’sattention to something other than the examination being performed. Dis-tract the infant with a moving object, a ﬂashing light, a game of peek-a-boo,tickling, or any sort of noise. 
Start the examination with the infant sitting or lying in the parent’s lap. If
the infant is tired, hungry, or ill, you might ask the parent to hold himagainst the chest. Make sure there are appropriate toys, a blanket, or otherfamiliar objects nearby. A hungry infant may need to be fed before you canproceed with a complete examination.
If you cannot distract the infant or
make the awake infant attend toan object, your face, or a sound,consider a possible visual or hearing
deﬁcit.

646 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Observe parent–infant interactions. Watch the parent’s affect when talking
about the infant. Note the parent’s manner of holding, moving, and dress-ing the baby, and response to situations that produce any discomfort forthe infant. EXAMPLES OF ABNORMALITIES
Observation of the infant’s com-
munication with the parent can re-veal abnormalities such asdevelopmental delay, languagedelay, hearing deﬁcits , or inadequate
parental attachment . Likewise, ob-
servations of the parent–infant in-teraction may identify maladaptivenurturing patterns that may stemfrom maternal depression or inade-
quate social support.
Infants usually do not object to removal of their clothing. Indeed, most seem

to prefer being nude, perhaps because of greater tactile stimulation. To keepyourself and your surroundings dry, it is wise to leave the diaper in placethroughout the examination; remove it only to examine the genitals, rectum,lower spine, and hips.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 647TIPS FOR EXAMINING INFANTS
IApproach the older infant gradually, using a toy or object to distract the infant.
IDo as much of the examination as possible with the infant in the parent’s lap.
ISpeak softly to the infant or mimic the infant’s sounds to attract attention and to
keep the infant occupied.
IAsk a parent about the infant’s strengths to elicit useful developmental andparenting information.
IIf the infant is cranky, make sure he or she is well fed before proceeding with theexamination.APPROACH TO THE EXAMINATION OF CHILDREN AT DIFFERENT AGES
TESTING FOR DEVELOPMENTAL MILESTONES
Because you’ll want to measure the infant’s best performance, checking

milestones is best achieved at the end of the interview, just before the ex-amination. This “fun and games” interlude also enhances cooperation dur-ing the examination. Experienced clinicians can weave the developmentalexamination into the other parts of the examination. The graph at the bot-tom of p. 628 shows some key physical/motor, cognitive/language, andsocial/emotional milestones during the first year of life. The standard formeasuring developmental milestones throughout infancy and childhood isthe Denver Developmental Screening Test (DDST). The DDST is de-signed to detect developmen-tal delays in personal–social,fine motor–adaptive, language,and gross motor dimensionsfrom birth through 6 years ofage.
The DDST form is shown on

p. 738 in Table 17-2 and in-cludes instructions for record-ing speciﬁc observations. Eachtest item is represented on theform under the age by a bar,which indicates when 25%,50%, 75%, and 90% of chil-dren attain the milestones de-picted. It must be emphasized that the DDST is only a measure of develop-mental attainment in the categories indicated and not a measure of intel-ligence.

648 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
The DDST is a highly specific screening test, so most normal children
score as normal, but it is not very sensitive. Many children with mild de-velopmental delay also score as normal. In particular, the language sectionof the DDST is sparse; it will miss children with mild language delay. Whilethe DDST is a useful screening test, other more sophisticated tests areavailable for specialists to use to assess motor, language, and social devel-opment. You should use the DDST as an adjunct to a comprehensive de-APPROACH TO THE EXAMINATION OF CHILDREN AT DIFFERENT AGES
COMMON CAUSES OF DEVELOPMENTAL DELAY IN INFANTS*
In the largest group of children with developmental delay, the causes are un-
known. The following are some known causes:
Abnormality in Embryonic Development
Prenatal insult (e.g., intrauterine, drug)Chromosomal (e.g., Down syndrome)
Hereditary and Genetic Disorders

Inborn errors of metabolismPreconceptual genetic abnormalities
Environmental and Social Problems
Parental psychological/social problems with insufﬁcient stimulation of childChildhood mental health disease
Other Pregnancy or Perinatal Problems
Fetal (e.g., placental insufﬁciency)Perinatal (e.g., prematurity)
Childhood Diseases
Infection (e.g., meningitis)TraumaSevere chronic disease
*Many disorders cause delays in more than one milestone.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 649APPROACH TO THE EXAMINATION OF CHILDREN AT DIFFERENT AGES
velopmental examination. When delays are suspected from the general ex-
amination or DDST, further evaluation is warranted.
For babies born prematurely, adjust the expected developmental milestones
for the gestational age up to about 12 months of age.
All kids are gifted; some just open their packages earlier than others.
—Michael Carr
Assessing Early Childhood
One of the most difﬁcult challenges facing the clinician examining children
in this age group is avoiding a physical struggle, a crying child, or a dis-traught parent. Accomplishing this successfully is satisfying to all and is oneaspect of the “art of medicine” in the practice of pediatrics.
Gaining the child’s conﬁdence and allaying the child’s fears begin at the start

of the encounter. The approach varies with the circumstances of the visit. Ahealth supervision visit for a well child allows greater rapport than a visitwhen the child is acutely ill.
Letting the child remain dressed during the interview makes her less 
apprehensive. It also allows you to interact more naturally and observe the child playing, interacting with her parents, and undressing and dress-ing.
Toddlers who are 9 to 15 months may have stranger anxiety, a fear of
strangers that is developmentally normal. It signals the infant’s growingawareness that the stranger is “new.” You should not approach these infants

650 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGquickly. Make sure they remain solidly in their parent’s lap throughout much
of the examination.
Engage children in conversation
appropriate to their ages, andthen ask simple questions aboutthemselves, their illness, or theirtoys. It is helpful to complimentthem about their appearance orbehavior, tell a story, or play asimple game or trick to “breakthe ice.” If a child is shy and ret-
icent, turn your attention to theparent to allow the child towarm up to you gradually.
You can observe a lot just by watching.
—Yogi BerraAPPROACH TO THE EXAMINATION OF CHILDREN AT DIFFERENT AGES
THE “POWER OF OBSERVATION”: ABNORMALITIES THAT CAN
BE DETECTED WHILE OBSERVING PLAY
Behavioral Problems *
Poor parent–child interactionsSibling rivalryInappropriate parental discipline“Difﬁcult temperament”
Developmental Delay (see DDST)
Gross motor delayFine motor delayLanguage delay (expressive, receptive)Delay in social or emotional tasks

Social or Environmental Problems
Parental problem, e.g., stress, depressionRisk for abuse or neglect
Neurologic Problems
WeaknessAbnormal postureSpasticityClumsinessAttentional problems and hyperactivityAutistic features
Speciﬁc SystemsThe initial paragraphs of each section in this chapter describe components of the
examination that can be accomplished by observation alone.
*Note: The child’s behavior during the visit may not represent typical behavior, but your observa-
tions may serve as a springboard for discussion with parents.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 651The physical examination, with certain exceptions, does not need to take
place on the examining table; it can occur on the ﬂoor or with the child sit-ting on the parent’s lap. The key is to engage the child’s cooperation. For thefew young children who resist undressing, expose only the part of the bodybeing examined. When examining two or more siblings, it is wise to beginwith the older one, who is more likely to cooperate and set a good example.APPROACH TO THE EXAMINATION OF CHILDREN AT DIFFERENT AGES
Your approach to the child should be pleasant. Explain each step of the ex-
amination as you are performing it. Keep up a running conversation with theparent or the child during the examination to provide distraction.
Plan the order of the examination so that you do the least distressing pro-

cedures ﬁrst and the most distressing (which tend to involve the throat andears) last. Start with the parts that can be accomplished while the child issitting—for example, examination of the eyes, palpation of the neck, per-cussion, and auscultation. 
Lying down may make the child feel more vulnerable and more likely to re-
sist further examination, so make this change with care. Once the child issupine, examine the abdomen ﬁrst, saving either the throat and ears or gen-italia for last.

652 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGAssessing Middle Childhood
Usually you will ﬁnd little difﬁculty in examining children after they reach
school age. While some may have unpleasant memories of previous clinicalencounters, most children will respond well when the examiner is attunedto their level of development.
Remember that the physical examination is designed to gather essential in-
formation, and an incomplete examination is frustrating for both you andthe parents. Thus, patience, distraction, play, ﬂexibility in the order of theexamination, and a caring but ﬁrm and gentle approach are all keys to suc-cessfully examining the young child.
Usually, resistance to the examination is developmentally appropriate. Many

toddlers will strive to stay upright and seek the comfort of their parents. Inthese cases, avoid conveying frustration and reassure the parents that this be-havior is normal. Some parents become embarrassed and scold the child,compounding the problem. Involve the parent in the examination (by re-moving diapers or palpating the abdomen) and play with the child. Ifneeded, pause to allow the child to recover. Learn which techniques workbest for you and which approach you ﬁnd most comfortable. It is not un-usual to require a parent’s help to restrain the child for examination of theears or throat. However, use of formal restraints is not appropriate.APPROACH TO THE EXAMINATION OF CHILDREN AT DIFFERENT AGES
SOME MORE TIPS FOR EXAMINING THE YOUNG CHILD
Let the child see and touch the tools you will be using during the examination.

Use a reassuring voice throughout the examination.Avoid asking permission to examine a body part because you will do the examina-
tion anyway. Instead, ask the child which ear or which part of the body he orshe would like you to examine “ﬁrst.”
Examine an apprehensive child in the parent’s lap, and let the parent undress 
the child.
If unable to console the child, complete the examination expediently or give the
child a short break.
Make a game out of the examination! For example, “Let’s see how big your
tongue is!” or “Is Barney in your ear? Let’s see!”

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 653As in middle childhood, modesty is important. The patient should remain
dressed until the examination begins, and you should leave the room while thepatient gowns. Most adolescents older than age 13 prefer to be examined with-out a parent in the room, but thisdepends on the patient’s develop-mental level, familiarity with theexaminer, relati onship with the par-
ent, and medical issues. For youngeradolescents, ask the adolescent andparent their preferences. While theexamination of the adolescent canbe anxiety-provoking for the noviceclinician, with practice, these in-teractions can be very rewardingfor both the adolescent and theclinician.Many children at this age are modest. It is wise to provide gowns and to

leave underwear in place until removal is required. It is also helpful to havechildren disrobe behind a curtain. Consider leaving the room when the chil-dren change with parents’ help. Some children may prefer that siblings ofthe opposite sex depart, but most prefer to have a parent of either sex remainin the room, and parents of children under 11 years should remain withthem. The order of the examination now begins to follow that used foradults. As at any age, examine painful areas last, and forewarn children aboutareas you are going to examine. If a child resists part of the examination, youcan return to it at the end.
Assessing the Adolescent
The key to successfully examining adolescents is a comfortable, conﬁdentialenvironment. This makes the examination more relaxed and informative.Consider the cognitive and social development of the adolescent when de-ciding issues of privacy, parental involvement, and conﬁdentiality.

654 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGThe sequence and content of the physical examination are similar to that of
the adult. However, pay particular attention to issues unique to adolescents,such as puberty, growth, development, family and peer relationships, sexu-ality, decision-making, and risk behaviors.
It is important to have a chaperone (parent or nurse) present during the gen-
ital examination of adolescent females.
Now that you have formed your approach to the child before you, you are
ready to begin the physical examination.
Children need models rather than critics.
—Joseph JoubertAPPROACH TO THE EXAMINATION OF CHILDREN AT DIFFERENT AGES

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 655Failure to thrive is inadequate
weight gain for age. Common scenarios are:
IGrowth <5th percentile for age
IGrowth drop >2 percentiles in6 months
IWeight for height <5th percentile
Causes include environmental or
psychosocial, and a variety of 
gastrointestinal, neurologic, cardiac,endocrine, renal, and other diseases.
Important components of the physical examination of children include mea-
surement of body size (height, weight, and head circumference) and vitalsigns (blood pressure, pulse, respiratory rate, and temperature). Table 17-3,Blood Pressure, and Table 17-4, Growth Charts, (pp. 740–749) show

norms for blood pressure, height, weight, body mass index (BMI), andhead circumference. Deviations from normal may be the first and only in-dicators of disease (see Table 17-5, Abnormal Growth Patterns in Infancyand Childhood, pp. 750–759). Except for body temperature, it is impor-tant to compare the child’s vital signs or body proportions to age-speciﬁc
norms, because they change dramatically as children grow older. Recently,an increasing number of pediatric practitioners are also assessing pain on aregular basis, using standardized pain scales.
General Survey
SOMATIC GROWTH: HEIGHT, WEIGHT, 
AND HEAD CIRCUMFERENCE
Measurement of growth is one of the most important indicators of the
health of children, and deviations from normal may provide an early indica-tion of an underlying problem. To assess growth, it is important to comparea child’s growth parameters with respect to
INormal values according to age and sex
IPrior readings on the same child to assess trends

To be clinically meaningful, growth parameters should be measured care-
fully, using a consistent technique and, optimally, the same scales to mea-sure height and weight.
The most important tools for assessing somatic growth are growth charts,
which recently have been modified and published by the National Centerfor Health Statistics. These charts include height, weight, and head cir-cumference for age, with one set for children up to 36 months and a sec-ond set for children ages 2 to 18 years. Charts plotting weight by lengthare also available. These growth charts have percentile lines indicating thepercentage of normal children above and below the child’s measurementby chronologic age. Table 17-4, Growth Charts, pp. 742–749, displaysthese growth charts.
Table 17-5, pp. 750–759, shows
several common abnormal growth
patterns.

656 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGHeight. For children older than age 2 years, measure standing height, op-
timally using wall-mounted stadiometers. Have the child stand with heels,back, and head against a wall or the back of the stadiometer. If using a wallwith a marked ruler, make sure to place a ﬂat board or surface against thetop of the child’s head and at right angles to the ruler. Stand-up weightscales with a height attachment are not very accurate.
Rule of thumb on height: After age 2 years, children should grow at least 5 centi-
meters per year. 
For children under the age of 2 years, measure body length by placing the
child supine on a measuring board or in a measuring tray, as shown on the

following page. Direct measurement of the infant using a tape measure isinaccurate unless an assistant holds the child still with hips and knees ex-tended. Velocity growth curves, such as the one on the next page, are help-ful in older children, especially those who are suspected of having endocrinedisorders.
Weight. Weigh infants directly with an infant scale; this is more accurate
than an indirect method based on weighing the parent and child together andsubtracting the weight of the parent from the total weight. Infants should beclothed only in a diaper or weighed naked.
Children who can stand should be wei ghed in their underpants on a stand-

up scale. While initially nervous, most young children can be coaxed onto suchscales. School-age children and adolescents can wear gowns. This is particu-Short stature, deﬁned as subnormal
height for age, can be a normalvariant or due to endocrine orother diseases. Normal variants in-clude familial short stature and con-
stitutional delay. Chronic diseases
include growth hormone deﬁciency,
other endocrine diseases, gastro-
intestinal disease (e.g., inﬂamma tory
bowel disease or celiac disease),renal or metabolic disease, and 
genetic syndromes.180
140100
60
20
0 4 8 12 16
20Growth Patterns of Various
Systems
Percent of 20-Y ear-Old Size
Birth Age in Y earsL YMPHOID
BRAIN AND
HEAD
GENERAL
REPRODUCTIVE
Reduced growth in height may in-
dicate endocrine disease , other
causes of short stature , or, if weight
is also low, other chronic diseases .

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 657larly important for adolescent girls being evaluated for underweight problems.
Ideally, serial weights (and heights) should use the same scales.
Head Circumference. The head circumference of infants should be
measured during the ﬁrst 2 years of life, but measurement can be useful atany age to assess growth of the head. The head circumference in infants re-ﬂects the rate of growth of the cranium and the brain. In older children, headA small head size may be due to
premature closure of the sutures or
to microcephaly. Microcephaly may
be familial or due to a variety ofchromosomal abnormalities, congen-ital infections, maternal metabolicdisorders, and neurologic insults.
Velocity curves for length and height for boys and girls based on intervals of 1 year. 
(From Lowrey GH: Growth and development of children, ed 8, Chicago, 1986, Mosby.)

658 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGsize is affected by genetic factors, and it may be useful to measure the head
circumference of parents when children have abnormal head sizes.
To measure head circumference, place the measuring tape over the occipi-
tal, parietal, and frontal prominences to obtain the maximum circumference.During infancy this is done best with the patient supine. You may need tomake several measurements and use the largest one. Measurements of chestand abdominal circumference are not clinically useful.
An abnormally large head size
(>97th percentile or 2 standard deviations above the mean) ismacrocephaly, which may be 
due to hydrocephalus, subdural
hematoma, or rare causes like brain
tumor or inherited syndromes. Famil-ial megaloencephaly (large head) is
a benign familial condition withnormal brain growth.
Group BMI-for-Age
Underweight <5th percentile
At risk of overweight ≥85th percentile

Overweight ≥95th percentileInterpreting BMI in ChildrenBODY MASS INDEX-FOR-AGE
Age- and sex-speciﬁc charts are now available to assess body mass index
(BMI) in children (see the following table). BMI in children is associated withbody fat, related to health risks of obesity, and measurements are helpful forchildren over the age of 2 years.
Vital Signs
Although there are special challenges to obtaining accurate blood pressurereadings in young infants, this measurement, nevertheless, is important andshould be part of the physical examination of every child older than 2 yearsof age, and of any younger child whose history or physical examination sug-gests that the blood pressure may be abnormal. Hypertension during childhood

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 659is more common than previously thought, and it is important to recognize, con-
ﬁrm, and appropriately manage it.
Children have elevated blood pressure during exercise, crying, and anxiety.
Although young children may be anxious at ﬁrst, when the procedure is ex-plained and demonstrated beforehand, most children are cooperative. If theblood pressure is initially elevated, you can perform blood pressure readingsagain at the end of the examination; one trick is to leave the cuff on the arm(deﬂated) and repeat the reading later. Elevated readings must always beconﬁrmed by subsequent measurements.
Select the blood pressure cuff as you would in adults. It should be wide enough

to cover two thirds of the upper arm or leg. A narrower cuff falsely elevates theblood pressure reading, while a wider cuff lowers it and may interfere withproper placement of the stethoscope diaphragm over the artery. Thus, a proper
cuff size is essential for accurate determinations of blood pressure in children.
With children, as with adults, the point at which the Korotkoff sounds dis-
appear constitutes the diastolic pressure. At times, especially among chubbyyoung children, the Korotkoff sounds are not easily heard. In such instances,you can use palpation to determine the systolic blood pressure (see pp. 76–77), remembering that the systolic pressure is approximately 10 mm Hglower by palpation than by auscultation.
A relatively inaccurate means is to use “inspection.” Watch for the needle to

bounce about 10 mm Hg higher than it does in auscultation. While this tech-nique is suboptimal, in squirming children sometimes it is all you can get.The most frequent “cause” of an
elevated blood pressure in childrenis probably an improperly performed
examination, often due to an incor-
rect cuff size.
In children, as in adults, blood
pressure readings from the thighare approximately 10 mm Hghigher than those from the upperarm. If they are the same or lower,coarctation of the aorta should be
suspected.
The most easily used measure of the systolic blood pressure of infants and
young children is obtained with the Doppler method, which detects arterial
blood ﬂow vibrations, converts them to systolic blood pressure levels, andtransmits them to a digital read-out device. However, Doppler instrumentsare expensive, and readings tend to be higher than by auscultation.

The systolic blood pressure gradually increases throughout infancy and child-
hood. For example, normal systolic pressure in males is about 70 mm Hg

660 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGat birth, 85 mm Hg at 1 month, and 90 mm Hg at 6 months. Turn to
Table 17-3, pp. 740–741, for normal blood pressure levels by year of lifefor boys and girls, including percentiles specific to age and height.
In 1995, the National Heart, Lung, and Blood Institute’s National High
Blood Pressure Working Group on Hypertension Control in Children andAdolescents deﬁned normal, high-normal, and high blood pressure as fol-lows, with measurements on at least three separate occasions:Although most adults with hyper-
tension have normal blood pressureas children, essential hypertension
often is detectable in adolescents.
It is also important not to falsely
label a child or adolescent as 
having hypertension, because of
Average Systolic and/or Diastolic Blood 
Blood Pressure Category Pressure for Age, Sex, and Height
Normal <90th percentile

High Normal 90th–95th percentileHigh ≥95th percentile
Children who have hypertension should be evaluated extensively to deter-
mine the cause. For infants and young children, a speciﬁc cause can usually befound. In older children and adolescents, however, an increasing proportion

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 661PULSE
The heart rate of infants and children is quite variable. It is more sensitive to
the effects of illness, exercise, and emotion than that of adults. Average heartrates are shown in the table below:the stigmata of labeling, potential
limitations to activities, and possi-ble side effects of treatment.
A pulse rate that is too rapid to
count (usually >180–200/min) usu-ally indicates paroxysmal supraven-
tricular tachycardia.
Bradycardia in infants or young
children may be due to drug inges-
tion, hypoxia, intracranial or neuro-
logic conditions, or, rarely, cardiac
arrhythmia such as heart block.
Bradycardia in a thin adolescent
female may be due to anorexia
nervosa.
Extremely rapid and shallow respi-
ratory rates are seen in newbornswith cyanotic cardiac disease whoNewborn Middle Childhood

nervosa.
Renal artery disease (stenosis, thrombosis) Renal parenchymal or arterial disease
Congenital renal malformations Primary hypertensionCoarctation of the aorta Coarctation of the aorta
Infancy and Early Childhood Adolescence
Renal parenchymal or artery disease Primary hypertension
Coarctation of the aorta Renal parenchymal disease
Drug inducedCauses of Sustained Hypertension in Children
You may have trouble obtaining an accurate pulse rate in a squirming infant
or child. The best strategy is to palpate the femoral arteries in the inguinalarea or the brachial arteries in the antecubital fossa, or to auscultate the heart.In older children who are cooperative, palpate the radial artery at the wrist.
To measure the man, measure his heart.
—Malcolm Stevenson Forbes
RESPIRATORY RATE

As with heart rate, compared to that of adults, the respiratory rate in infants
and children has a greater range and is more responsive to illness, exercise,and emotion. The rate of respirations per minute ranges between 30 and 60has essential or primary hypertension. In all cases, it is important to repeat
measurements to reduce the possibility that the elevation reﬂects anxiety.Sometimes repeating measurements in school is a way to obtain readings ina more relaxed environment.
Age Average Rate Range (Two Standard Deviations)
Birth 140 90–190
1st 6 months 130 80–1806–12 months 115 75–1551–2 years 110 70–1502–6 years 103 68–1386–10 years 95 65–12510–14 years 85 55–115Average Heart Rate of Infants and Children at Rest

662 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGin the newborn, 20 and 40 during early childhood, and 15 and 25 during
late childhood, reaching adult levels at age 15 years.
The respiratory rate may vary considerably from moment to moment in new-
born infants, with alternating periods of rapid and slow breathing. The sleep-ing respiratory rate is most reliable. However, respiratory rates during activesleep compared to quiet sleep may be up to 10 breaths per minute faster.The respiratory pattern should be observed for at least 60 seconds. In in-fancy and early childhood, diaphragmatic breathing is predominant; thoracicexcursion is minimal.
For young children, observe the movements of the chest wall for two 30-

second intervals or over 1 minute, preferably prior to stimulating them. Di-rect auscultation of the chest or placing the stethoscope in front of themouth is also useful for counting respirations, but the measurement may befalsely elevated if the child becomes agitated. For older children, use thesame technique as used for adults.
Commonly accepted cutoffs for deﬁning tachypnea are:
Infants 0–2 months >60/min
Infants 2–12 months >50/minChildren >12 months >40/min
Because fever is so common in children, obtaining an accurate body tem-perature is helpful whenever you suspect infection, collagen vascular disease,or malignancy. The techniques for obtaining rectal, oral, and auditory canaltemperatures in adults are described on pp. 81–82. Axillary and thermal-tape(temporal artery) skin temperature recordings in children are inaccurate.
In children and adolescents, auditory canal temperature recordings are

preferable because they can be obtained quickly with essentially no discom-fort. For infants under 2 months of age, rectal temperatures are preferredbecause clinical guidelines for evaluating serious bacterial infections use rec-tal temperature levels as a major criterion.
The technique for obtaining the rectal temperature is relatively simple. One
method is illustrated on the next page. Place the infant or child prone on theexamining table, on the parent’s lap, or on your own lap. While you separatethe buttocks with the thumb and foreﬁnger on one hand, with the other handgently insert a well-lubricated rectal thermometer, inclined approximately 20 °
from the table or lap, through the anal sphincter to a depth of approximately2 to 3 centimeters. Keep the thermometer in place for at least 2 minutes.have normal lungs but right-to-left
shunting, and in conditions ofmetabolic acidosis.

Children with respiratory diseases
such as bronchiolitis or pneumonia
have rapid respirations (up to80–90/min), but alsoincreased
work of breathing such as grunting,nasal ﬂaring, or use of accessorymuscles.
The best single physical ﬁnding for
ruling out pneumonia is an absence
of tachypnea.
Fever can raise respiratory rates in
infants. In the absence of pneumo-nia, an infant’s respiratory rate canincrease by up to 10 respirationsper minute for each degree centi-grade of fever.
Fever (>38.0 °C or >100.0 °F) in 
infants <2–3 months may be a signof serious infection or disease. These
infants should be evaluatedpromptly.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 663During early childhood, extremely
high fever (up to 104 °F or 40 °C)
is common, even with minor infections.
Anxiety may elevate the body 
temperature of children. Excessive
bundling of infants may elevate the
skin but not the core temperature.
Cutis marmorata is prominent in
premature infants, and in infants
with congenital hypothyroidism and
Down syndrome.
If acrocyanosis does not disappear
within 8 hours or with warming,cyanotic congenital heart diseaseshould be considered.Body temperature in infants and children is less constant than in adults. The
average rectal temperature is higher in infancy and early childhood, usuallynot falling below 99.0 °F (37.2 °C) until after age 3 years. Body temperature
may ﬂuctuate as much as 3 °F during a single day, approaching 101 °F
(38.3 °C) in normal children, particularly in late afternoon and after vigor-
ous activity.
The Skin

The Skin
NEWBORN AND EARLY INFANCY
The newborn infant’s skin has a unique characteristic texture and appear-
ance. The texture is soft and smooth because it is thinner than the skin of
older children. Within the ﬁrst 10 minutes after birth, a normal newbornprogresses from generalized cyanosis to pinkness. In lighter-skinned infants,an erythematous ﬂush, giving the skin the appearance of a “boiled lobster,”is common during the ﬁrst 8 to 24 hours, then the normal pale pink color-ing predominates.
Vasomotor changes in the dermis and subcutaneous tissue—a response to
cooling or chronic exposure to radiant heat—can produce a latticelike, bluishmottled appearance ( cutis marmorata ), particularly on the trunk, arms, and
legs. This response to cold may last for months in normal infants. Acro-

cyanosis, a blue cast to the hands and feet when exposed to cold (see the photo
on the next page), is very common in newborns for the ﬁrst few days, and mayrecur throughout early infancy. Occasionally in newborns, a striking colorchange ( harlequin dyschromia ) appears with transient cyanosis of one half of
the body or one extremity, presumably due to temporary vascular instability.

664 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGThe amount of melanin in the skin of
newborns varies, affecting pigmen-
tation. Black newborns may have a
lighter skin color initially than lateron, except in the nail beds and geni-talia, which are dark at birth. A darkor bluish pigmentation over the but-tocks and lower lumbar regions is
common in newborns of African,
Asian, and Mediterranean descent.These areas, formerly called Mongo-lian spots, are due to the presence ofpigmented cells in the deep layers ofthe skin; they become less noticeablewith age and usually disappear dur-ing childhood. It is important todocument these pigmented areas toavoid later concern about bruising.
At birth there is a ﬁne, downy growth of hair called lanugo over the entire

body, but especially the shoulders and back. This hair is shed within the ﬁrstfew weeks. Lanugo is prominent in premature infants. Hair thickness on thehead varies considerably among newborns, and fortunately is not predictiveof later hair growth. All of the original hair is shed within months, replacedwith a new crop, sometimes of a different color.
Inspect the newborn closely for a series of common skin conditions. At birth,
a cheesy white material called vernix caseosa, composed of sebum and
desquamated epithelial cells, covers the body. Some newborns have edema
over their hands, feet, lower legs, pubis, and sacrum; this disappears withina few days. Superﬁcial desquamation of the skin is often noticeable 24 to 36hours after birth.
You should be able to identify four common dermatologic conditions in
newborns. None is clinically significant. Milia, pinhead-sized smooth,

white raised areas without surrounding erythema on the nose, chin, andforehead, are caused by retention of sebum in the openings of the seba-ceous glands. While occasionally present at birth, milia usually appearwithin the first few weeks and disappear over several weeks. Miliaria rubra
consists of scattered vesicles on an erythematous base, usually on the faceand trunk, caused by sweat gland duct obstruction; it also disappears spon-taneously within weeks. Erythema toxicum, which usually appears on the
2nd or 3rd day of life, consists of erythematous macules with central pin-point vesicles scattered diffusely over the entire body, appearing much likeflea bites. These lesions are of unknown etiology, but disappear within aweek after birth. Pustular melanosis, seen more commonly in black infants,

is present at birth as small vesiculopustules over a brown macular base andcan last for several months.Central cyanosis in a baby or child
of any age should raise suspicion ofcongenital heart disease. The best
area to look for central cyanosis isthe tongue and oral mucosa, notthe nail beds or the extremities.
Pigmented light-brown lesions
(<1–2 cm at birth) are café-au-lait
spots . Isolated lesions have 
no significance, but multiple lesions with smooth borders may suggest neurofibromatosis
(see Table 17-6, p. 761).
Skin desquamation at birth occurs
in some normal babies, and frequently in post-term babies
(>40 wks gestation). Rarely, it is asign of placental circulatory insufﬁ-ciency or congenital ichthyosis.
Midline hair tufts over the lum-
bosacral spine region suggest aspinal cord defect.
Both erythema toxicum and pus-
tular melanosis may appear similarto the pathologic vesicular rash ofherpes simplex or staphylococcus
aureus skin infection, which are

aureus skin infection, which are 
serious infections requiring rapidtreatment.
Acrocyanosis in the ﬁrst half hour of
life in a 32-week infant. (FromFletcher M: Physical Diagnosis inNeonatology, Philadelphia,Lippincott-Raven Publishers, 1998.)

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 665A common vascular marking,
found in 40% of newborns, isthe “salmon patch” (also knownas nevus simplex, telangiectatic
nevus, or capillary heman-gioma). These ﬂat, irregular,light pink patches are mostoften seen on the nape of theneck (“stork bite”), upper eye-lids, forehead, or upper lip(“angel kisses”). They are nottrue nevi, but are due to dis-tended dermal capillaries; theyalmost all disappear by 1 year ofage. Darker, purplish lesions onthe face or extremities are “portwine stains” and do not fade.Note any signs of trauma from the birth process and the use of forceps or
suction; these signs disappear but should prompt a careful neurologic examination.
Normal “physiologic” jaundice, which occurs in half of all newborns, ap-

pears on the 2nd or 3rd day, peaks at about the 5th day, and usually dis-appears within a week. Jaundice can best be appreciated in natural daylightrather than artiﬁcial light. Newborn jaundice seems to progress from headto toe, with more intense jaundice on the upper body and less intense yel-low color in the lower extremities. To detect jaundice, apply pressure to theskin as shown below to press the normal pink or brown color out. Look forthe presence of a yellowish “blanching,” which indicates jaundice. Anothertechnique is to press a glass slide against the skin to empty the capillary bedand observe for color contrast. Also see Table 17-7, p. 762.
Jaundice that appears within the
first 24 hours of birth is likely tobe pathologic jaundice due to hemolytic disease of the newborn.
Jaundice that persists beyond

Jaundice that persists beyond 
2–3 weeks should raise suspicionsof biliary obstruction or liver disease.
A unilateral port wine stain over
the distribution of the ophthalmicbranch of the trigeminal nerve may be a sign of Sturge-Weber 
syndrome, which is associated with
seizures, hemiparesis, glaucoma,and mental retardation.
Pressing the red color from the skin allows
better recognition of the yellow of jaundice.Infant with no appreciable jaundice at chestlevel. (From Fletcher M: Physical Diagnosis inNeonatology, Philadelphia, Lippincott-RavenPublishers, 1998.)Infant with bilirubin level of 13 mg/d
(222 µmol/L). (From Fletcher M: PhysicalDiagnosis in Neonatology, Philadelphia,Lippincott-Raven Publishers, 1998.)
Nuchal salmon patch at hairline. (From Fletcher
M: Physical Diagnosis in Neonatology,Philadelphia, Lippincott-Raven Publishers, 1998.)

666 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGThe examination of the skin should
include palpation to assess the degreeof hydration or turgor. Roll a fold of
loosely adherent skin on the abdominalwall between your thumb and fore-ﬁnger to determine its consistency. Theskin in well-hydrated infants and chil-dren returns to its normal position im-mediately upon release.
EARLY AND LATE CHILDHOOD
After a child’s ﬁrst year of life, the techniques of examination are the sameas those for the adult (see Chap. 4, The Skin).
The Head
In examining the head and neck, tailor your examination to the child’s stageof growth and development.
Even before touching the child, carefully observe the shape of the head, its

The Head
symmetry, and the presence of abnormal facies. Next, measure the head cir-cumference in children under 2 years (described on p. 657). At birth, ababy’s head may seem relatively large to you. A newborn’s head accounts forone fourth of the body length and one third of the body weight; these pro-portions change, so that by adulthood the head accounts for one eighth ofthe body length and about one tenth of the body weight.
INFANCY
Examine the sutures and fontanelles carefully (see the ﬁgure on the next
page). The bones of the skull are separated from one another by membra-nous tissue spaces called sutures. The areas where the major sutures intersect
in the anterior and posterior portions of the skull are known as fontanelles.
On palpation, the sutures feel like ridges and the fontanelles like soft con-

cavities. The anterior fontanelle at birth measures 4 cm to 6 cm in diameter
and usually closes between 4 and 26 months of age (90% between 7–19 mos).The posterior fontanelle measures 1 cm to 2 cm at birth and usually closes by
2 months.
Signiﬁcant edema of the hands
and feet of a newborn girl may besuggestive of Turner’s syndrome.
Delay in return to normal skin po-
sition as shown on the left, a phe-nomenon called “tenting,” usuallyoccurs in children with significant dehydration.
An enlarged posterior fontanelle
may be present in congenital hypo-
thyroidism.
A bulging, tense fontanelle is ob-
served in infants with increased in-
tracranial pressure, which may be
due to central nervous system infec-
tions, neoplastic disease, or hydro-
cephalus (obstruction of the

circulation of cerebrospinal ﬂuidwithin the ventricles of the brain).From Zitelli BJ and Davis HW: Atlas of
Pediatric Diagnosis, ed. 3, St. Louis,1997, Mosby-Year Book.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 667Careful examination of the fontanelle is important because the fullness of the
fontanelle reﬂects intracranial pressure. It is best to palpate the fontanelle
while the baby is sitting quietly or being held upright. Experienced pediatrichealth care providers often have the habit of palpating the fontanelles at thebeginning of the examination. In normal infants, the anterior fontanelle is softand ﬂat. Increased intracranial pressure produces a bulging, full anteriorfontanelle and is seen when a baby cries, vomits, or has underlying pathology.Pulsations of the fontanelle reﬂect the peripheral pulse.
Inspect the scalp veins carefully to assess for dilatation.Assess the symmetry of the skull. A number of conditions can cause asymme-
try of the skull in newborns and infants; some are normal or benign, whileothers reﬂect underlying pathology.A depressed anterior fontanelle

may be a sign of dehydration.
Overlap of the cranial bones at the
sutures at birth, called molding,
results from passage of the headthrough the birth canal; it dis-appears within 2 days.
Dilated scalp veins are indicative of
long-standing increased intracranial
pressure.
Another type of localized swelling
of the scalp is a cephalohematoma,
due to subperiosteal hemorrhage
 A newborn’s scalp is often swollen from localized subcutaneous edema over
the occipitoparietal region, called caput succedaneum, caused by distension
of capillaries and extravasation of blood and ﬂuid resulting from the vacuumAnterior fontanelle
Posterior fontanelle
Lambdoidal suture
Sagittal
suture
Coronal
suture
Metopicsuture

668 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGeffect of rupture of the amniotic sac. This swelling often crosses over suture
lines and resolves in 1 to 2 days.
The premature infant’s head at birth is relatively long in the occipitofrontal
diameter and narrow in the bitemporal diameter ( dolichocephaly ). Usually
the skull shape normalizes within 1 to 2 years.
Asymmetry of the cranial vault ( plagiocephaly ) occurs when an infant lies
mostly on one side, resulting in a ﬂattening of the parieto-occipital regionon the dependent side and a prominence of the frontal region on the oppo-site side. It disappears as the baby becomes more active and spends less timein one position, and symmetry is almost always restored. Interestingly, thecurrent trend to have newborns sleep on their backs to reduce the risk forsudden infant death syndrome has resulted in more cases of plagiocephaly.

Measure the head circumference (p. 658) to detect abnormally large head
size ( macrocephaly ) or small head ( microcephaly ), which may be due to an
underlying disorder affecting the brain.
Examine the skull. You can perform the following maneuvers with care:
IOn palpation of the infant’s skull, you may note that the cranial bones ap-
pear “soft” or pliable; they will become ﬁrmer with increasing gestationalage. An exception occurs in a condition known as craniotabes, which is
found in some normal infants but also in some with diseases. In this con-dition, the cranial bones feel pliable and springy, much as a ping-pong ballsprings back upon pressure.
IPercuss the parietal bone on each side of the skull using your index ormiddle ﬁnger. This will produce a “cracked pot” sound ( Macewen’s sign )
in normal infants prior to closure of the cranial sutures.
Auscultation of the skull is not useful in young children because a systolic or

continuous bruit may be heard over the temporal areas in many normal chil-dren. Older children with signiﬁcant anemia may have a cranial bruit.
Transillumination of the skull may be helpful in the evaluation of an infant
with possible central nervous system disease. In a completely darkenedroom, place a bright ﬂashlight ﬁtted with a soft rubber collar ﬂush againstthe skull at various points. In normal infants, a 2-cm halo of light is presentaround the circumference of the ﬂashlight placed over the frontoparietalarea, and a 1-cm halo when placed over the occipital area.
Check the faceof infants for symmetry. In utero positioning may result in
transient facial asymmetries. If the head is ﬂexed on the sternum, a short-ened chin ( micrognathia ) may result. Pressure of the shoulder on the jaw

may create a temporary lateral displacement of the mandible.from the trauma of birth. This
swelling does not cross over suturelines and resolves within 3 weeks.As the hemorrhage resolves andcalciﬁes, there may be a palpablebony rim with a soft center.
While plagiocephaly may be due to
positioning, it may also reﬂectpathology such as torticollis from
injury to the sternocleidomastoidmuscle at birth, or lack of stimula-
tionof the infant.
Premature closure of one or morecranial sutures causes craniosynos-
tosis, with an abnormally shaped
skull. Sagittal suture synostosis
causes a narrow head due to lackof growth of the parietal bones.Palpation may reveal a raised bonyridge at the suture line.Craniotabes can be due to in-
creased intracranial pressure as inhydrocephaly, metabolic distur-
bances such as rickets, and infec-

tion (e.g., congenital syphilis ).
Macewen’s sign is noted in older in-
fants with high intracranial pres-sure that causes closed cranial sutures to separate (e.g., due tolead encephalopathy, brain tumor,or hydrocephalus ).
An arteriovenous ﬁstula in the brain
can produce a loud bruit.
If the entire head “lights up,” 
hydranencephaly or reduced size of
the cerebral cortex is suspected. Lo-
calized bright spots may be seenwith subdural effusions and poren-
cephalic cysts.
Micrognathia may also be part of a
syndrome, such as the Pierre Robin
syndrome.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 669“PEARLS” TO EVALUATE A CHILD WITH POTENTIALLY 
ABNORMAL FACIES
Carefully review the history, especially:
IFamily history
IPerinatal history
Note abnormalities on other parts of the physical examination, especially:
IGrowth
IDevelopment
IOther dysmorphic somatic features
Perform measurements (and plot percentiles), especially
IHead circumference
IHeight
IWeight
Consider the three mechanisms of facial dysmorphogenesis.
IDeformations due to intrauterine constraint
IDisruptions due to amniotic bands or disruption from fetal tissue
IMalformations due to an intrinsic abnormality in either the face/head or the brain
Examine the parents and siblings.
ISimilarity to a parent may be reassuring (e.g., large head) or may represent a
familial disorder.
Try to determine whether the facial features ﬁt a recognizable syndrome, compar-
ing to:

ing to:
IReferences (including measurements) and pictures of syndromes
ITables/databases of combinations of features. Examine the face for an overall impression of the facies; it is helpful to com-
pare to the face of the parents. There are diagnostic facies in childhood(Table 17-12, pp. 768–769, shows several) that reﬂect chromosomal ab-normalities, endocrine defects, chronic illness, and other disorders. While it is
often difﬁcult to disti nguish abnormal facies from normal variants, here are
some “pearls.”
A child with abnormal shape or
length of palpebral ﬁssures:
Upslanting (Down syndrome)Down-slanting (Noonan’s 
syndrome)
Short (fetal alcohol effects)
A positive Chvostek’s sign pro-

syndrome)
duces facial grimacing caused byrepeated contractions of the facial muscles. A Chvostek sign isnoted in cases of hypocalcemic
tetany, tetanus and tetany due tohyperventilation.Percussion of the cheek is useful to check for Chvostek’s sign, which is pres-
ent in some metabolic disturbances and occasionally in normal infants.Percuss at the top of the cheek just below the zygomatic bone in front ofthe ear, using the tip of your index or middle finger. 
The examination of the head in later childhood is the same as that for adults.Abnormal facies may not be apparent until later in childhood; therefore,carefully examine the face as well as the head of all children.

670 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGThe Neck
Beyond infancy, the techniques for examining the neck are the same as for
adults. Several important and somewhat unique aspects of the pediatricexamination of the neck are described below.
Palpate the lymph nodes of the neck and assess the presence of any additional
masses such as congenital cysts. Because the necks of infants are short, it is
best to palpate the neck while infants are lying supine, whereas older chil-dren are best examined while sitting. Check the position of the thyroid car-tilage and trachea.
Lymphadenopathy is unusual during infancy but very common during child-

hood. As shown on p. 656, the child’s lymphatic system reaches its zenithof growth at 12 years, and cervical or tonsillar lymph nodes reach their peaksize between 8 and 16 years. The vast majority of enlarged lymph nodes inchildren are due to infections (mostly viral but frequently bacterial) and notto malignant disease, even though the latter is a concern for many parents.It is important to differentiate normal lymph nodes from abnormal ones orfrom congenital cysts of the neck.
The following ﬁgure illustrates the typical location of congenital cysts, in-
cluding thyroglossal duct cysts, branchial cleft cysts, cystic hygromas, epi-dermal (dermoid) cysts, and preauricular cysts or sinuses.
Lymphadenopathy is usually due to
viral or bacterial infections (seeTable 17-13, Abnormalities of theNeck, p. 770).
Malignancy is more likely if the node

is greater than 2 cm, is hard or ﬁxedto the skin or underlying tissues (i.e., not mobile), is accompaniedby serious systemic signs such asweight loss, and, in the case of cervical lymph nodes, if the chest x-ray ﬁndings are abnormal.
In young children with small
necks, it may be difﬁcult to differ-entiate low posterior cervicallymph nodes from supraclavicular
lymph nodes (which are always 
abnormal and raise suspicion formalignancy).
Branchial cleft cysts appear as small
dimples or openings anterior tothe midportion of the sternocleido-mastoid muscle. They may be asso-ciated with a sinus tract.
Preauricular cysts and sinuses are
common, pinhole-size pits, usuallylocated anterior to the helix of theear. They are often bilateral andmay occasionally be associatedwith hearing deﬁcits.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 671Check for neck mobility. It is important to ensure that the neck of all in-
fants and children is supple and easily mobile in all directions. This is par-ticularly important when the patient is holding the head in an asymmetricmanner, and when central nervous system disease such as meningitis issuspected.
In infants and children, the presence of nuchal rigidity is a more reliable in-
dicator of meningeal irritation than Brudzinski’s sign or Kernig’s sign . To

detect nuchal rigidity in older children, ask the child to sit with legs extendedon the examining table. Normally, children should be able to sit upright andtouch their chins to their chests. Younger children can be persuaded to ﬂextheir necks by having them follow a small toy or light beam. You also cantest for nuchal rigidity with the child lying on the examining table, as shownon the next page. Nearly all children with nuchal rigidity will be extremelysick, irritable, and difﬁcult to examine.Thyroglossal duct cysts are located
at the midline of the neck, justabove the thyroid cartilage. Thesesmall, ﬁrm, mobile masses moveupward with tongue protrusion orwith swallowing. They are usuallydetected after 2 years.
Congenital torticollis, or a “wry

neck,” is due to bleeding into thesternocleidomastoid muscle dur-ing the stretching process ofbirth. A firm fibrous mass is feltwithin the muscle 2–3 weeks afterbirth and generally disappearsover months.
Nuchal rigidity is marked resistance
to movement of the head in anydirection. It suggests meningeal ir-ritation due to meningitis, bleed-
ing, tumor, or other causes. These
children are extremely irritableand difficult to console and mayhave “paradoxical irritability”—increased irritability when being held.
SubmentalSubmandibular
SupraclavicularPosterior
cervicalAnterior
cervicalTonsillar
OccipitalPosterior
auricularPreauricular
Epidermoid cyst
2nd branchial
cleft cystCystic hygroma
Thyroglossal duct cyst

672 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGIn newborns, palpate the clavicles and look for evidence of a fracture. If pres-
ent, you may feel a break in the contour of the bone, tenderness, crepitus atthe fracture site, and limited movement of the arm on the affected side.
The Eye
We must teach our children to dream with their eyes open.
—Harry Edwards
You will have to be clever to examine the eyes of infants and young children
and use some tricks to get them to cooperate. Small colorful toys are usefulas ﬁxation devices in examining the eyes.
INFANCY

INFANCY
Newborns keep their eyes closed except during brief awake periods. If youattempt to separate their eyelids, they will tighten them even more. Brightlight causes infants to blink, so use subdued lighting. If you awaken the babygently, turn down the lights, and support the baby in a sitting position, youwill often ﬁnd that the eyes open. The eyes of many newborns are edema-tous from the birth process.
A fracture of the clavicle may 
occur during delivery, particularlyduring difficult arm or shoulderextractions.When meningeal irritation is pres-
ent, the child assumes the tripod
position and is unable to assume a
full upright position to perform thechin-to-chest maneuver.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 673Newborns may look at your face and follow a bright light if you catch
them during an alert period. You can even get some newborns to followyour face and turn their heads 90 °to each side, much to the delight of
new parents.
The photo below shows one way to examine young infants for eye move-
ments. Hold the baby upright, supporting the head. Rotate yourself with the
baby slowly in one direction. This usually causes the baby’s eyes to open, al-lowing you to examine the sclerae, pupils, irides, and extraocular move-ments. The baby’s eyes gaze in the direction you are turning. When therotation stops, the eyes look in the opposite direction, after a few nystag-moid movements.If a newborn fails to gaze at you
and follow your face during alertperiods, pay particular attentionto the rest of the ocular examina-tion. This may still be a normalchild, but may indicate visual

and follow your face during alertperiods, pay particular attentionto the rest of the ocular examina-tion. This may still be a normalchild, but may indicate visual 
Nystagmus (wandering or shaking
eye movements) persisting after afew days or persisting after the ma-neuver described on the left mayindicate poor vision or central ner-
vous system disease.
Alternating convergent or diver-
gent strabismus persisting beyond
3 months, or persistent strabismusof any type, may indicate ocular
motor weakness or another abnor-
mality in the visual system.
Colobomas (p. 188) may be seen
with the naked eye, and representdefects in the iris.
During the ﬁrst 10 days of life, the eyes may be ﬁxed, staring in one direc-
tion if just the head is turned without moving the body ( doll’s eye reﬂex ).
During the ﬁrst few months of life, some infants have intermittent crossedeyes ( intermittent alternating convergent strabismus, or esotropia ) or inter-

mittent laterally deviated eyes ( intermittent alternating divergent strabismus,
or exotropia ).
Look for abnormalities or congenital problems in the sclerae and pupils. Sub-
conjunctival hemorrhages are common in newborns.
Pupillary reactions can be observed either by response to light or by cover-
ing each eye with your hand and then uncovering it. Although there may besome initial asymmetry in the size of the pupils, over time they should beequal in size and reaction to light.

674 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGInspect the irides carefully for abnormalities.
Examine the conjunctiva for swelling or redness. Chemical conjunctivitis is
common following application of silver nitrate at birth as prophylaxis againstgonorrheal conjunctivitis (ophthalmia neonatorum). Most newborn nurs-eries have switched to using erythromycin ointment because it produces lessirritation.
You will not be able to measure the visual acuity of newborns or infants. You
can use visual reﬂexes to indirectly assess vision: direct and consensual pupil-lary constriction in response to light, blinking in response to bright light(optic blink reﬂex ), and blinking in response to quick movement of an ob-
ject toward the eyes. During the ﬁrst year of life, visual acuity sharpens as theability to focus improves. Infants achieve the following visual milestones:
Birth Blinks, may regard face
1 month Fixes on objects1

1⁄2–2 months Coordinated eye movements
3 months Eyes converge, baby reaches12 months Acuity around 20/50
For the ophthalmoscopic examination, with the newborn awake and eyes
open, examine the red retinal (fundus) reﬂex by setting the ophthalmoscopeat 0 diopters and viewing the pupil from about 10 inches. Normally, a redor orange color is reﬂected from the fundus through the pupil.
A thorough ophthalmoscopic examination is difﬁcult in young infants, but
may be needed if ocular or neurologic abnormalities are noted. Occasion-ally, a mydriatic solution may be required to examine the fundus successfully(e.g., using one drop of 2.5% phenylephrine with 0.5% cyclopentolate ineach eye); this is usually done with the help of a neurologist or ophthalmol-ogist. The cornea can ordinarily be seen at +20 diopters, the lens at +15
diopters, and the fundus at 0 diopters.

Examine the optic disc area as you would for an adult. In infants, the optic
disk is lighter in color. There may be less macular pigmentation, and thefoveal light reflection may not be visible. Look carefully for retinal hem-orrhages. Papilledema is rare in infants because the fontanelles and opensutures accommodate any increased intracranial pressure, sparing theoptic discs.
EARLY CHILDHOOD
The two most important aspects of the eye examination for young childrenare to test visual acuity in each eye and to determine whether the gaze is con-jugate or symmetric. Brushﬁeld spots are a ring of white
specks in the iris (see Table 17-14,p. 771). While sometimes presentin normal children, these stronglysuggest Down syndrome.
Persistent ocular discharge and
tearing since birth may be due todacryocystitis or nasolacrimal duct
obstruction.
Failure to progress along these 
visual developmental milestonesmay indicate delayed visual 
maturation.

Cloudiness of the cornea may be
caused by congenital glaucoma. Adark light reﬂex can be caused bycataracts, retinopathy of prematurity,or other disorders. A white retinalreﬂex ( leukokoria ) is abnormal and
cataract, retinal detachment, chori-oretinitis, or retinoblastoma should
be suspected.
Small retinal hemorrhages may
occur in normal newborns. Exten-sive hemorrhages may suggest severe anoxia, subdural hematoma,
subarachnoid hemorrhage, or severe
trauma.
Pigment changes in the retina can
occur in newborns with congenital
toxoplasmosis, cytomegalovirus, or
rubella.
Strabismus (see Table 17-14,
p. 771) in children requires treat-ment by an ophthalmologist.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 675It may not be possible to measure the visual acuity of children under 3 years
of age who cannot identify pictures on an eye chart. For these children, thesimplest examination is to assess for ﬁxation preference by alternately cover-ing one eye; the child with normal vision will not object, but a child withpoor vision in one eye will object to having the good eye covered. In all testsof visual acuity, it is important that both eyes show the same result.
3 months Eyes converge, baby reaches
12 months ∼20/200
Less than 4 years 20/404 years and older 20/30
As shown on the next page, visual acuity in children 3 years and older can

usually be formally tested using an eye chart with one of a variety of opto-types (characters or symbols). A child who does not know letters or num-bers reliably can be tested using pictures, symbols, or the “E” chart. Usingthe “E” chart, most children will cooperate by telling you in which direc-tion the “E” is pointing.
The visual ﬁelds can be examined in infants and young children with the
child sitting on the parent’s lap. One eye should be tested at a time with theother eye covered. Hold the child’s head in the midline while bringing anobject such as a toy into the ﬁeld of vision from behind the child. The over-all method is the same as that for adults, except that you will have to makethis into a game for your patient.Use the methods described in Chapter 7 for adults to assess conjugate gaze,

or the position and alignment of the eyes, and the function of the extraocular
muscles. The corneal light reﬂex test and the cover–uncover test are partic-ularly useful in young children.
You can perform the cover–uncover test as a game by having the young child
watch your nose or tell you if you are smiling or not while you cover one ofthe child’s eyes.
Both ocular strabismus and ani-
sometropia (eyes with signiﬁcantly
different refractive errors) can re-sult in amblyopia , or reduced vision
in an otherwise normal eye. Ambly-
opiacan lead to a “lazy eye,” with
permanently reduced visual acuityif not corrected early (generally by6 years).
Any difference in visual acuity be-
tween the eyes (e.g., 20/20 on theleft and 20/30 on the right) is abnormal, and the patient shouldbe referred to an ophthalmologist.

676 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGLATE CHILDHOOD AND ADOLESCENCE
The methods used to examine the eye, including testing for visual acuity, are
the same as those for adults. Refractive errors become common, and it is im-portant to test visual acuity monocularly at regular intervals, such as duringthe annual health supervision visit.
The Ear
The physical examination of the ear of infants and children is important be-cause many abnormalities can be detected, including structural abnormali-ties of the ear, otitis media, and hearing loss. This means that you must honeyour skills with the otoscope!
INFANCY
The major goals are to determine if the position, shape, and features of the ear

INFANCY
are normal and to detect abnormalities. Note the position of the ears in re-lation to the eyes. An imaginary line drawn across the inner and outer can-thi of the eyes should cross the pinna or auricle; if the pinna is below this linethen the infant has low-set ears.
Examination of the newborn’s ear with an otoscope can only detect patency
of the ear canal because the tympanic membrane is obscured by accumu-
lated vernix caseosa for the ﬁrst few days of life. In infancy, the ear canal isdirected downward from the outside; therefore, you may want to pull theauricle gently downward rather than upward for the best view of the eardrum. Once the tympanic membrane becomes visible, you may note that thelight reﬂex is diffuse and does not become cone-shaped for several months.
The acoustic blink reﬂex is a blinking of the infant’s eyes in response to a sud-

den sharp sound; you can produce this by snapping your ﬁngers or using abell, beeper, or other noisemaking device about a foot from the infant’s ear.Be sure that you are not producing an airstream that may cause the infant to
Small, deformed, or low-set 
auricles may indicate associatedcongenital defects, especially renal
disease.
A small skin tab, cleft, or pit found
just forward of the tragus representsa remnant of the ﬁrst branchial cleft
and usually has no signiﬁcance.
Perinatal problems raising the risk
for hearing defects include birth
weight <1500 grams, anoxia,treatment with potentially ototoxic

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 677medications, congenital infections,
severe hyperbilirubinemia, andmeningitis.
Many children with hearing deﬁcits
are not diagnosed until as old as 2 years. Clues to hearing deﬁcitsinclude parental concern abouthearing, delayed speech, and lackof developmental indicators ofhearing.
You may feel as if you need 10 hands and a bag of tricks to examine the ear
of toddlers and young children, who are sensitive to examining the ear canal
and drum and fearful because they cannot observe the procedure. With a lit-
tle practice you can master this technique. Unfortunately, many young chil-dren will need to be brieﬂy restrained during this part of the examination,which is why you may want to leave it for the end.
If the child is not too fearful, you may be able to do the examination while

the child is sitting on his parent’s lap. It is helpful to make a game out of theotoscopic examination, such as ﬁnding an imaginary object in the child’s ear,or talking playfully throughout the examination to allay any fears. It is some-times helpful to place the otoscopic speculum gently into the external audi-tory canal of one ear and then withdraw it to have the child get used to theprocedure, before performing the actual examination. Ask the parent for apreference regarding the positioning of the child for the examination.
There are two common positions—the child lying down and restrained, and

the child sitting in the parent’s lap. If the child is being held supine, have theparent hold the arms either extended or close to the sides to limit motions.You can hold the head and retract the tragus with one hand while you holdthe otoscope with your other hand. If the child is on the parent’s lap, thechild’s legs should be between the parent’s legs. The parent could help withgentle restraint by placing one arm around the child’s body and a secondarm to steady the head.
Many students have difﬁculty even visualizing a child’s tympanic membrane.

In young children, the external auditory canal is directed upward and back-ward from the outside, and the auricle must be pulled upward, outward, andbackward to afford the best view. Hold the child’s head with one hand (yourleft hand if you are right-handed), and with that same hand pull up on theauricle. With your other hand, position the otoscope.Age Signs That an Infant Can Hear
0–2 months Startle response and blink to a sudden noise
Calming down with soothing voice or music
2–3 months Change in body movements in response to sound
Change in facial expression to familiar sounds
3–4 months Turning eyes and head to sound6–7 months Turning to listen to voices and conversationblink. The reﬂex may be difﬁcult to elicit during the ﬁrst 2 to 3 days of life.
After it is elicited several times, the reﬂex will disappear, a phenomenonknown as habituation. This is a crude test of hearing, and certainly does not

determine normal hearing. Currently, there is an increased movement to-ward universal hearing screening of all newborns in addition to those at highrisk for hearing problems.

678 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGTECHNIQUES OF EXAMINATION
Not only are there two positions for the child lying down or sitting, there
are two ways to hold the otoscope, as illustrated by the following photos.The ﬁrst is the method generally used in adults, with the otoscope handlepointing upward while you pull up on the auricle. Hold the lateral aspect ofyour hand that has the otoscope against the child’s head to provide a bufferagainst sudden movements by the patient.TIPS FOR CONDUCTING THE OTOSCOPIC EXAMINATION
Use the best angle of the otoscope.
Use the largest possible speculum.
A larger speculum will allow you to visualize the tympanic membrane better.A small speculum may not provide a seal for pneumatic otoscopy.
Don’t apply too much pressure.
Too much pressure will cause the child to cry and may cause false–positives onpneumatic otoscopy.
Insert the speculum 
1⁄4to 1⁄2inch into the canal.
First ﬁnd the landmarks.

Sometimes the ear canal resembles the tympanic membrane— don’t be fooled!
Note whether the tympanic membrane is abnormal.Remove cerumen if it is blocking your view, using
Special plastic curettesA moistened microtipped cotton swabFlushing of ears for older childrenSpecial instruments that can also be purchased.
The second technique (see p. 679) is used by many pediatricians because of
the different angle of the auditory canal in children. This involves holdingthe otoscope with the handle pointing down toward the child’s feet whileyou pull up on the auricle. Hold the head and pull up on the auricle withone hand, while you hold the otoscope with the other hand.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 679Learn to use a pneumatic otoscope to improve your accuracy of diagnosis of
otitis media in children. This allows you to assess the mobility of the tym-panic membrane as you increase or decrease the pressure in the external au-
ditory canal by squeezing the rubber bulb of the pneumatic otoscope.
First, check the pneumatic otoscope
for leaks by placing your ﬁnger overthe tip of the speculum and squeez-ing the bulb. Note the pressure onthe bulb. Then insert the speculum,obtaining a proper seal; this is criti-cal because failure to obtain a sealcan produce a false–positive ﬁnding(lack of movement of the tympanicmembrane).
When air is introduced into the
normal ear canal, the tympanic mem-
brane and its light reflex move in-

ward. When air is removed, thetympanic membrane moves outward,toward you. This to-and-fro move-ment of the tympanic membranehas been likened to the luffing of asail. If the tympanic membrane fails 
to move perceptibly as you introduce positive or negative pressure, then thechild is likely to have a middle ear effusion. A child with acute otitis media mayﬂinch because of pain due to the air pressure.
Gently move and pull on the pinna before or during your otoscopic exam-
ination. Carefully inspect the area behind the pinna, over the mastoid bone.Acute otitis media is a common con-
dition of childhood. A symptomaticchild has a red, bulging tympanicmembrane, with a dull or absentlight reﬂex and diminished move-ment on pneumatic otoscopy. Purulent material may also be seenbehind the tympanic membrane.See Table 17-14, Abnormalities ofthe Eyes and Ears, p. 771.

This movement of the tympanic
membrane is absent in middle eareffusion ( otitis media with effusion ).
Signiﬁcant, temporary hearing loss
for several months can accompanyotitis media with effusion.
With otitis externa (but not otitis
media), movement of the pinnaelicits pain.
With acute mastoiditis, the 
auricle may protrude forward,

680 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGAlthough formal hearing testing is necessary for accurate detection of
hearing deficits in young children, you can grossly test for hearing by whis-
pering at a distance of 8 feet, asking the child questions or giving simplecommands. All children above age 4 years should have a full-scale acousticscreening test.and the area over the mastoid
bone will be red, swollen, and tender.
Younger children who fail these
screening maneuvers or who have speech delay should have audiometric testing.
LATE CHILDHOOD AND ADOLESCENCE
As the child grows, the ease and techniques of examining the ears and
testing the hearing approach the methods used for adults. There are noear abnormalities or variations of normal unique to this age group. Ofcourse, parents of older children routinely refer to the normal conditionof “selective deafness,” defined as choosing to hear what the child wishesto hear.

INFANCY
The most important component of the examination of the nose of newborns
is to test for patency of the nasal passages. You can do this by gently oc-cluding each nostril alternately while holding the infant’s mouth closed. Thiswill not cause stress in a normal baby, because most newborns are nasalbreathers. Indeed, some infants are obligate nasal breathers and have difﬁ-
culty breathing through their mouths. Do not occlude both nares simulta-neously—this will cause considerable distress!
Inspect the nose to ensure that the nasal septum is midline. You can gently
insert a wide nasal speculum of the otoscope into the nose.
At birth, only the ethmoid sinuses are developed. Palpation of the sinuses of
newborns is not helpful.
The nasal passages in newborns
may be obstructed in choanal atre-
sia.In severe cases, nasal obstruc-
tion can be assessed by attemptingto pass a No. 8 feeding tubethrough each nostril into the pos-terior pharynx.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 681EARLY AND LATE CHILDHOOD
You can inspect the anterior portion of the nose by using a large speculum
on your otoscope. Inspect the nasal mucous membranes, noting their colorand condition. Look for nasal septal deviation and the presence of polyps.Pale, boggy nasal mucous mem-
branes are found in children withchronic (perennial) allergic rhinitis.
Purulent rhinitis is common in viral
infections, but may be part of theconstellation of symptoms of si-
nusitis.
Foul-smelling purulent, unilateral
discharge from the nose may bedue to a foreign body in the nose.
Rarely, supernumerary teeth are
noted. These are usually dysmor-phic and are shed within days butare removed to prevent aspiration.
Epstein’s pearls, tiny white or 
yellow rounded mucous retentioncysts, are located along the poste-rior midline of the hard palate.They disappear within months.
Although unusual, a prominent,

protruding tongue may signal congenital hypothyroidism or Down
syndrome.
Maxillary sinuses are noted on x-rays by age 4 years, sphenoid sinuses by
age 6, and frontal sinuses by age 6 to 7. The sinuses of older children can bepalpated like adult sinuses, looking for tenderness. Traditionally, transillu-mination of the paranasal sinuses of younger children has been taught; how-ever, this technique has poor sensitivity and speciﬁcity for diagnosing sinusitisor ﬂuid in the sinuses.
The face of a child can say it all, especially the mouth part of the face.
—Jack Handley
INFANCY
Use both inspection (with a tongue blade and ﬂashlight) and palpation to

INFANCY
inspect the mouth and pharynx of newborns. The newborn’s mouth is eden-tulous, and the alveolar mucosa is smooth, with ﬁnely serrated borders. Oc-casionally, pearl-like retention cysts are seen along the alveolar ridges and areeasily mistaken for teeth—they disappear within a month or two. Petechiaeare commonly found on the soft palate after birth. Palpate the upper hardpalate to make sure it is intact.
Infants produce little saliva during the ﬁrst 3 months, but you will note that
older infants produce lots of saliva and drool frequently.
Inspect the tongue. The frenulum of the tongue varies, sometimes extend-
ing almost to the tip and other times being thick and short, limiting pro-trusion of the tongue ( ankyloglossia, or tongue tie ); these variations rarely
interfere with speech or function.

682 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGYou will often see a whitish covering on the tongue. If this coating is due to
milk, it can be easily removed by scraping or wiping it away.
The pharynx of the infant is best seen while the baby is crying. You will likely
have difﬁculty using a tongue blade because it produces a strong gag reﬂex.Do not expect to be able to visualize the tonsils.
Listen to the quality of the infant’s cry. Normal infants have a lusty, strong
cry. The following box lists some unusual types of infant cries.Oral candidiasis (thrush) is common
in infants. The lesions are difﬁcultto wipe away and have an erythe-matous raw base (see Table 17-15,Abnormalities of the Mouth andTeeth, p. 772).
INFANT CRIES
Type Possible Related Condition
Increased intracranial pressure. Such
cries also occur in newborn infantsborn to narcotic-addicted mothers.
Hypocalcemic tetany or congenital
hypothyroidism

Caused by upper airway obstruction
due to a variety of lesions (e.g., apolyp or hemangioma), a relativelysmall larynx ( infantile laryngeal
stridor ), or a delay in the develop-
ment of the cartilage in the tracheal rings ( tracheomalacia )
Suggests severe illness, vocal cord
paralysis, or profound brain damageShrill or high-pitched
Hoarse
Continuous inspiratory and expiratory
stridor
Absence of cry

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 683EARLY AND LATE CHILDHOOD
For anxious or young children, you may want to leave this part of the ex-
amination toward the end, because it may require parental restraint. Theyoung, cooperative child may be more comfortable sitting in the parent’slap, as shown below.
The following ﬁgure demonstrates some tricks to getting children to open their
mouths. The child who can say “ahhh” will usually offer a sufficient (albeitbrief) view of the posterior pharynx so that a tongue blade is unnecessary.Healthy children are more likely to cooperate with this examination than sickchildren, especially if the sick child sees the tongue blade or has had previ-ous experience with throat cultures.TECHNIQUES OF EXAMINATION
HOW TO GET CHILDREN TO OPEN THEIR MOUTHS 
(AKA, “WOULD YOU PLEASE SAY ‘AHHH’?”)
ITurn it into a game.
I“Now let’s see what’s in your mouth.”
I“Can you stick out your whole tongue ?”

I“I bet you can’t open your mouth really wide !”
I“Let me see the inside of your teeth.”
I“Is Barney stuck in there?”
IDon’t show a tongue blade unless really necessary.
IDemonstrate ﬁrst on an older sibling (or even the parent).
IOffer enthusiastic praise for opening their mouths a little and encourage them to
open even wider!
If you need to use the tongue blade, the best technique is to push down and
pull slightly forward toward yourself while the child says “ahhh,” being care-ful not to place the blade too far posteriorly, eliciting a gag reﬂex. Sometimesyoung and anxious children will need to be restrained and will clamp their

684 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGteeth and purse their lips. In these cases, you will need to carefully slip the
tongue depressor between the teeth and onto the tongue. This will eitherallow you to push down on the tongue or elicit a gag reflex, which shouldpermit a brief look at the posterior pharynx and tonsils. Remember, an un-planned, direct frontal assault on the front teeth will only meet with fail-ure and a splintered tongue blade; careful planning and parental help areneeded.
Examine the teeth for the timing and sequence of eruption, number, char-
acter, condition, and position. Abnormalities of the enamel may reﬂect localor general disease.
Carefully inspect the inside of the upper teeth, as shown in the ﬁgure below.
This is a common location for nursing bottle caries.
Dental caries are caused by bacter-

ial activity. Caries are more likelyamong young children who have prolonged bottle-feeding(“nursing-bottle caries”). See Table 17-15, Abnormalities of theMouth and Teeth, p. 772, for dif-ferent stages of caries.
Staining of the teeth may be 
intrinsic or extrinsic. Intrinsicstains may be due to tetracyclineuse prior to 8 years (yellow, gray,or brown stain). Iron preparation(black stain) is an example of extrinsic stain. Extrinsic stains can be polished off; intrinsic stains cannot (see Table 17-15,Abnormalities of the Mouth andTeeth, p. 772).
As in most developmental changes of childhood, there is a predictable pro-

gression of tooth eruption and also a wide variation in the age of eruption.A rule of thumb is that the infant will have one tooth for each month of agebetween 6 and 26 months, up to the full complement of 20 primary teeth.The table below displays a common pattern of teeth eruption. In general,lower teeth erupt a bit earlier than upper teeth.
Approximate Age of Eruption
Tooth Type Primary (mos) Permanent (yrs)
Central incisor 5–8 6–8
Lateral incisor 5–11 7–9Cuspids 24–30 11–12First bicuspids — 10–12Second bicuspids — 10–12First molars 16–20 6–7Second molars 24–30 11–13Third molars — 17–22Tooth Types and Age of Eruption

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 685Look for abnormalities of the position of the teeth. These include malocclu-
sion, maxillary protrusion ( overbite ), and mandibular protrusion ( underbite ).
You can demonstrate the latter two by asking the child to bite down hard andpart the lips. Observe the true bite. In normal children, the lower teeth arecontained within the arch formed by the upper teeth.
Carefully inspect the tongue, including the underside. Most children will
happily stick their tongue out at you, move it from side to side, and demon-strate its color (the blue tongue below is from eating candy!)
Note the size, position, symmetry, and appearance of the tonsils. The peak

growth of tonsillar tissue is between 8 and 16 years (see ﬁgure on p. 656). Thesize of the tonsils varies considerably in children and is often categorized on ascale of 1 +to 4+, with 1 +being easy visibility of the gap between the tonsils,
and 4 +being tonsils that touch in the midline with the mouth wide open. The
tonsils in children often appear more obstructive than they really are.
Tonsils in children usually have deep crypts on their surfaces, which often
have white concretions or food particles protruding from their depths. Thisdoes not indicate disease.Malocclusion and misalignment of
teeth is often due to excessivethumb sucking and is reversible ifthe habit is arrested by 6 or 7 years.Malocclusion can also be a heredi-tary condition, or due to prematureloss of primary teeth.
Common abnormalities include
coated tongue in viral infections,
congenital geographic tongue,and strawberry tongue found in

scarlet fever.
Streptococcal pharyngitis typically
produces a strawberry tongue,white exudates on the tonsils,beefy-red uvula, and palatal petechiae.
A peritonsillar abscess is suggested
by asymmetric enlargement of thetonsils and lateral displacement ofthe uvula.
Look for clues of a submucosal cleft palate, such as notching of the poste-
rior margin of the hard palate or a biﬁd uvula. Because the mucosa is intact,
the underlying defect is easily missed.There is one condition— acute
epiglottitis —now thankfully rare in
the United States due to immu-nization against Hemophilus in-
ﬂuenzae type B, which is a
contraindication to examination ofthe throat because of potentialgagging and laryngeal obstruction.

686 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGYou may note an abnormal breath odor, which may help lead to a diagnosis.
INFANCY
The infant’s thorax is more rounded than that of older children and adults.
Also, the chest wall in infancy is thin, with little musculature, and thereforelung and heart sounds are transmitted quite clearly. The bony and cartilagi-nous rib cage is very soft and pliant. The tip of the xiphoid process is oftenseen protruding anteriorly immediately beneath the skin at the apex of thecostal angle.
Carefully assess respirations and the pattern of breathing. Newborn infants,
especially those born prematurely, exhibit irregular breathing characterizedby periods of breathing at normal rates (30 to 40 per minute) alternatingwith “periodic breathing,” during which the respiratory rate slows markedlyand may even cease for 5 to 10 seconds.

An important tip for the examination of the respiratory status of infants and
young children is notto rush to the stethoscope, but to observe the patient
carefully as demonstrated in the photograph and the table on the next page.Visual inspection is best done when infants are not crying; thus work withthe parents to settle the child. By observing infants for a signiﬁcant time(perhaps 1 minute), you can note the general appearance, respiratory rate,color, nasal component of breathing, audible breath sounds, and work ofbreathing, as described on p. 662.
Because infants are obligate nasal breathers, observe their nose as they breathe,
looking for nasal ﬂaring. Observe the breathing with the infant’s mouth closed
or with the infant nursing or sucking on a bottle to assess for nasal patency.
Listen to the sounds of the infant’s breathing and note any grunting, audi-
ble wheezing, or lack of breath sounds (obstruction).

It is important to evaluate, by observation, two aspects of the infant: audible
breath sounds and the work of breathing. These are particularly relevant in as-
Two types of chest wall abnormal-
ities noted in childhood includepectus excavatum, or “funnel
chest,” and pectus carinatum,
or “chicken breast deformity” (see p. 239).
Apnea is deﬁned as cessation of
breathing for more than 20 sec-onds. Apnea is often accompaniedby bradycardia and may indicatethe presence of a respiratory dis-
ease, central nervous system dis-ease, or, rarely, a cardiopulmonary
condition. Apnea is a high-risk 
factor for sudden infant death 
syndrome (SIDS).
In newborns and young infants,
nasal ﬂaring may be due simply toupper respiratory infections with
subsequent obstruction of theirsmall nares.Voice Change Possible Abnormality
Hypernasal speech Submucosal cleft palate

Nasal voice plus snoring Adenoidal hypertrophyHoarse voice plus cough Viral infection (croup)“Rocks in mouth” TonsillitisVoice Changes—Clues to Underlying AbnormalitiesNote the quality of the child’s voice. Certain abnormalities can change the
pitch and quality.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 687sessing both upper and lower respiratory illness. Studies in countries that have
poor access to chest radiographs have found that these signs are at least asuseful as auscultation in assessing both the upper and lower respiratory tract.
Any of the abnormalities listed at
the left should raise concern aboutunderlying respiratory pathology.
Lower respiratory infections, deﬁned
as infections below the vocal cords,are common in infants, and in-clude bronchiolitis and pneumonia.
Acute stridor is a potentially serious
condition; causes include laryngo-
tracheo-bronchitis (croup), epiglotti-tis, bacterial tracheitis, foreign body,or a vascular ring.
In infants, abnormal work of
breathing, combined with abnor-mal ﬁndings on auscultation, is thebest ﬁnding for ruling in pneumo-
nia.The best single sign for ruling
outpneumonia is the absence of
tachypnea.

Asymmetric chest movement may
be a clue to a space-occupying lesion, such as pleural effusion, 
hemothorax, or intrathoracic mass.
Type of Assessment Speciﬁc Observable Pathology
General appearance
Respiratory rate
ColorNasal component of breathing
Audible breath sounds
Work of breathingExamination of the Lungs in Infants—Before You Touch the Child!
Inability to feed or smile
Lack of consolability
Tachypnea (see p. 662)Pallor or cyanosisNasal ﬂaring (enlargement of both nasal
openings during inspiration)
Grunting (repetitive, short expiratory sound)
Wheezing (musical expiratory sound)Stridor (high-pitched, inspiratory noise)Obstruction (lack of breath sounds)
Nasal ﬂaring (see above)
Grunting (see above)Retractions (or chest indrawing):

Supraclavicular (soft tissue above clavicles)Intercostal (indrawing of the skin between ribs)Subcostal (just below the costal margin)
In healthy infants, the ribs do not move much during quiet breathing. If the
ribs do move, outward movement is produced by descent of the diaphragm.Descent of the diaphragm compresses the abdominal contents, which inturn shifts the lower ribs outward.
Pulmonary disease causes an increase in abdominal breathing in infants, and
can result in retractions (chest indrawing ), a sign commonly used by the
World Health Organization as an indicator of pulmonary disease in infantsyounger than 2 years of age. Chest indrawing is the inward movement of theribs (or more precisely, the skin between the ribs) during inspiration. Breath-

688 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGing is predominantly affected by movement of the diaphragm, with little as-
sistance from the thoracic muscles. As mentioned in the table on the previ-ous page, three types of retractions can be noted in infants: supraclavicular,intercostal, and subcostal.
Obstructive respiratory disease in infants can result in Hoover’s sign, or para-
doxical (seesaw) breathing, in which the abdomen moves outward while thechest moves inward during inspiration. Thoracoabdominal paradox, inward

movement of the chest and outward movement of the abdomen during in-spiration, is a normal ﬁnding in preterm and newborn infants. It continuesto persist during active, or REM, sleep even when it is no longer seen dur-ing wakefulness or quiet sleep because of the decreased muscle tone of ac-tive sleep. As muscle strength increases and chest wall compliance decreaseswith age and growth, paradox is no longer discernable as a normal ﬁnding.
Tactile fremitus can be assessed by palpation. Place your hand on the chest
when the infant cries or makes noise. Place your hand or ﬁngertips over eachside of the infant’s chest and feel for symmetry in the transmitted vibrations.Percussion is not helpful in infants except in extreme instances. The infant’schest is hyperresonant throughout, and it is difﬁcult to detect abnormalitieson percussion.

After performing these maneuvers, you are ready for auscultation. Breath
sounds are louder and harsher than those in adults because the stethoscopeis closer to the origin of the sounds. Also, it is often difﬁcult to distinguishtransmitted upper airway sounds from sounds originating in the chest. Thetable below has some useful hints. Upper airway sounds tend to be loud,transmitted symmetrically throughout the chest, and loudest as you moveyour stethoscope upward. They are usually inspiratory, coarse sounds. Lowerairway sounds are loudest over the site of pathology, are often asymmetric,and often have an expiratory phase.Children with muscle weakness may
be noted to have thoracoabdomi-nal paradox at several years of age.
Because of the excellent transmis-
sion of sounds throughout thechest, any abnormalities of tactilefremitus or on percussion suggest severe pathology, such as a largepneumonic consolidation.
Biphasic sounds imply severe

Biphasic sounds imply severe 
obstruction from intrathoracic airwaynarrowing or severe obstruction from
extrathoracic airway narrowing.
Technique Upper Airway Lower Airway
Compare sounds from 
nose/stethoscope
Listen to harshness of soundsNote symmetry (left/right)Compare sounds at different 
locations (higher or lower)
Inspiratory vs. expiratoryDistinguishing Upper Airway From Lower Airway Sounds
Same soundsOften harsh and loud
SymmetricSounds get louder as
stethoscope is movedup on the chest
Almost always inspiratoryOften different sounds
Variable
Often asymmetricSounds often louder lower
in chest
Often has expiratory phase
If you hear expiratory sounds, you can be relatively sure that they arise from

Variable
in chest
an intrathoracic source. On the other hand, inspiratory sounds typically arisefrom an extrathoracic airway such as the trachea. During expiration, the di-ameter of the intrathoracic airways decreases because radial forces from thesurrounding lung do not “tether” the airways open as occurs during inspi-

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 689ration. Higher ﬂow rates during inspiration produce turbulent ﬂow, result-
ing in appreciable sounds.
The characteristics of the breath sounds, such as vesicular and bronchovesic-

ular, and of the adventitious lung sounds, such as crackles, wheezes, andrhonchi, are the same as those for adults, except that they may be more dif-ﬁcult to distinguish in infants and often occur together. Wheezes and rhonchiare common in infants. Wheezes, often audible without the stethoscope,occur more frequently in infants because of the smaller size of the tracheo-bronchial tree. Wheezes usually reﬂect narrowing of smaller airways, or bron-chioles. Rhonchi reﬂect obstruction of larger airways, or bronchi. Crackles(rales) are discontinuous sounds (see p. 228), near the end of inspiration; theyare usually due to lung disorders and are far less likely to represent cardiacfailure in infants than in adults.

As children become older, the examination of the lungs begins to approachthat used in adults. Again, it is critical for children to cooperate with this ex-amination. Auscultation is often best accomplished when the child is barelyaware of the examination (as when he is in his parent’s lap). If a toddlerseems fearful of your stethoscope, you might let the child play with it beforetouching the chest.
If you ask young children to “take deep breaths,” they will often hold their
breath, making it even more difﬁcult for you to auscultate the lungs. Thusit is easier, for preschool children, to let them breathe normally. For olderchildren, you can demonstrate how to take nice, quiet, deep breaths, andmake a game out of it. A forced expiratory maneuver can be accomplishedby asking the child to blow out the candles on an imaginary birthday cake.Wheezes in infants occur com-
monly from asthma or bronchiolitis.
Crackles (rales) can be heard with

pneumonia and bronchiolitis.
In the presence of upper airway
obstruction such as croup, inspira-tion is prolonged and accompa-nied by other signs such as stridor,cough, or rhonchi. In the presenceof lower airway obstruction such asasthma, expiration is prolonged
In examining children, assess the relative proportion of time spent on inspi-
ration versus expiration. Normally, this ratio is about 1:1.

690 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGOlder children will be cooperative for the respiratory examination and can
even go through the maneuvers of assessing fremitus or listening to “E to A”changes (see p. 229). As children grow, the evaluation by observation dis-cussed on the previous page, such as assessing the work of breathing, nasalﬂaring, and grunting, becomes less helpful in evaluating for respiratorypathology, and palpation, percussion, and auscultation achieve greater im-portance in a careful examination of the thorax and lungs.
The Heart
The heart is the chief feature of a functioning mind.
—Frank Lloyd Wright
The examination of the heart and vascular systems in infants and children is

The Heart
similar to that in adults, but recognition of their fear, their inability to co-operate, and in many instances, their desire to play, will make the exam eas-ier and more productive. Use your knowledge of the developmental stageof each child, recognizingthat a 2-year-old may be eas-iest to examine while stand-ing or sitting on themother’s lap, facing hershoulder, as shown below.Give young children some-thing to hold in each hand.They cannot ﬁgure out howto drop the object andtherefore have no hand freeto push you away. Endlesschatter to small children willhold their attention and theywill forget you are examin-ing them. Letchildren movethe stethoscopethemselves, goingback to listenproperly. Useyour imaginationto make the ex-amination work!
and often accompanied by audible
wheezing.
Childhood asthma is an extremely

wheezing.
common condition throughout theworld. Children with acute asthmapresent with varying severity andoften have increased work ofbreathing. Expiratory wheezingand a prolonged expiratory phase,caused by reversible bron-chospasm, can be heard withoutthe stethoscope and are apparenton auscultation.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 691Inspection. Before examining the heart itself, observe the infant carefully
for the presence or absence of cyanosis. Acrocyanosis in the newborn is dis-cussed on p. 663. It is important to detect central cyanosis (Table 17-10,
Cyanosis in Children, p. 766) because it is always abnormal and many con-genital cardiac abnormalities, as well as respiratory diseases, present withcyanosis (see Table 17-16, Pathologic Findings: Heart Murmurs, pp.773–775).
A diffuse bulge outward of the left
side of the chest suggests long-standing cardiomegaly.Age of Onset Potential Cardiac Cause
Immediately at birth
Within a few days after birth
Weeks, months, or years of lifeCardiac Causes of Central Cyanosis in Children
Transposition of the great arteries
Pulmonary valve atresiaSevere pulmonary valve stenosisPossibly Ebstein’s malformation
All of the above plus:

Total anomalous pulmonary venous returnHypoplastic left heart syndromeTruncus arteriosus (sometimes)Single ventricle variants
Pulmonary vascular disease with atrial,
ventricular, or great vessel shunting
The recognition of minimal degrees of cyanosis requires care. Look where
the inside of the body can be seen without having to peer through skin (i.e.,the inside of the mouth, the tongue, the conjunctivae, and, to a lesser de-gree, the nail beds). A true pink is normal, while any hint of raspberry redsuggests desaturation. The distribution of the cyanosis should be evaluated.An oxymetry reading will conﬁrm desaturation.
Observe the infant for general signs of health. The infant’s nutritional status,

responsiveness, happiness, and irritability are all clues that may be useful inevaluating cardiac disease. Note that noncardiac ﬁndings can be present ininfants with cardiac disease.
COMMON NONCARDIAC FINDINGS IN INFANTS 
WITH CARDIAC DISEASE
Poor feeding Tachypnea
Failure to thrive HepatomegalyIrritability Clubbing
Observation of the respiratory rate and pattern is helpful in distinguishing
the degree of illness and cardiac versus pulmonary diseases. An increase inrespiratory effort is expected from pulmonary diseases, whereas in cardiacdisease there may be tachypnea, but not increased work of breathing untilcongestive heart failure becomes signiﬁcant.
While observing the respiratory pattern, note any abnormalities of the ster-
num as discussed on p. 686.

692 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGPalpation. The major branches of the aorta can be assessed by evalua-
tion of the peripheral pulses. All neonates should have an evaluation of all

pulses at the time of their newborn examination. In neonates and infants,the brachial artery pulse in the antecubital fossa is easier to feel than the ra-dial artery pulse at the wrist. Both temporal arteries should be felt just infront of the ear. It is important to feel the femoral pulses. They lie in themidline just below the inguinal crease, between the iliac crest and the sym-physis pubis. Take your time and search for femoral pulses; they are difﬁcultto detect in chubby, squirming infants. If you ﬁrst ﬂex the infant’s thighs onthe abdomen, this may overcome the reﬂex ﬂexion that occurs when youthen extend the legs. The dorsalis pedis and posterior tibial pulses inneonates and infants (see photo below) may be difﬁcult to feel unless thereis an abnormality involving aortic run-off. Normal pulses should have a sharprise, be ﬁrm, and well localized.
The absence or diminution of

femoral pulses is indicative ofcoarctation of the aorta. If you can’t
detect femoral pulses, measureblood pressures of the lower andupper extremities. If they are equalor lower in the legs, coarctation islikely to be present.
A weak or thready, difﬁcult-to-feel,
pulse may reﬂect myocardial dys-
function and congestive heart fail-
ure,particularly if associated with
an unusual degree of tachycardia.
Although the pulses in the feet of
neonates and infants are oftenfaint, several conditions can causefull pulses, such as patent ductus 
arteriosus or truncus arteriosus.
A “rolling” heave at the left sternal
border suggests an increase in right
ventricular work, while the same
kind of motion closer to the apexsuggests the same thing for the leftventricle.
As discussed on p. 658, carefully measure the blood pressure of infants and

children as part of the cardiac examination. It may be helpful to measure theblood pressure in both arms and one leg at one time around age 3 to 4 yearsto check for possible coarctation of the aorta. Thereafter, only the right arm
blood pressure needs to be measured.
The point of maximal impulse, or PMI, is not always palpable in infants and
is affected by respiratory patterns, a full stomach, and the infant’s position-ing. It is usually an interspace higher than in adults during the ﬁrst few yearsof life because the heart lies more horizontally within the chest.
Palpation of the chest wall will allow you to assess volume changes within
the heart. For example, a hyperdynamic precordium reﬂects a big volumechange.
Thrills are palpable when there is enough turbulence within the heart or

great vessels to be transmitted to the surface. Knowledge of the structuresbeneath the precordium will allow you to determine the origin of the thrill.Thrills are easiest to feel with your palm or the base of your ﬁngers, not yourﬁngertips. Thrills have a somewhat rough, vibrating quality. The ﬁgure thatfollows shows locations of thrills from various cardiac abnormalities thatoccur in infants and children.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 693Auscultation. The heart rhythm is more easily evaluated in infants by lis-
tening to the heart than by feeling the peripheral pulses, but in older chil-dren can be done either way. Children commonly have a normal sinusdysrhythmia, with the heart rate increasing on inspiration and decreasing onexpiration, sometimes quite abruptly. This is a normal ﬁnding and can beidentiﬁed by its repetitive nature, its correlation with respiration, and by itsinvolvement of several beats rather than a single beat.
Many children, particularly neonates, have premature atrial or ventricular

beats that are often appreciated as “skipped” beats. They can usually be erad-icated by increasing the intrinsic sinus rate by exercise, such as crying in aninfant or jumping in an older child, although they may be more frequent inthe postexercise period. In a completely healthy child, they are usually be-nign and rarely persist.
The S
1and S 2heart sounds should be evaluated carefully. They are normally
crisp. The second sounds (S 2) at the base are usually heard separately but
should fuse into a single sound in deep expiration. In the neonate, it shouldbe possible to detect a split second sound if the infant is examined whencompletely quiet or asleep; detecting this split eliminates many, but not all,of the more serious congenital cardiac defects.The most common dysrhythmia in
children is paroxysmal supraventric-
ular tachycardia, or paroxysmalatrial tachycardia (PSVT, or PAT). It

can occur at any age, including inutero. It is remarkably well toler-ated by some children and is foundon examination when the childlooks perfectly healthy, may bemildly pale or has tachypnea, buthas a rapid, sustained, completelyregular heart rate of 240 beats perminute or more. Other children,particularly neonates, appear veryill with this condition. In older chil-dren, this dysrhythmia is morelikely to be truly paroxysmal, withepisodes of varying duration andvarying frequency (see Table 17-5,p. 758).
Pathologic arrhythmias in children
can be due to structural cardiac 
lesions, but also to other causes
such as drug ingestion, metabolic
abnormalities, endocrine disorders,serious infections, and postinfectiousstates, or they may be related to
conduction disturbances withoutstructural heart disease.
Distant heart tones suggest pericar-
dial effusion; mushy, less distinct

heart sounds suggest myocardial
Aortic valve
stenosis
septal defectPulmonary valve
stenosis
Severe right ventricularoutflow tract obstruction atinfundibular level,Tetralogy of Fallot

694 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGIn addition to trying to detect splitting of the second heart sound, listen for
the intensity of A 2and P 2. The aortic, or ﬁrst component of the second sound
at the base, is normally louder than the pulmonic, or second component.A louder-than-normal pulmonic
component, particularly whenlouder than the aortic sound, sug-gests pulmonary hypertension.
Persistent splitting of S
2may indi-
cate a right ventricular volumeload such as atrial septal defect,
anomalies of pulmonary venous re-turn, or chronic anemia.Atrial Premature Contractions
Normal Sinus (APCs) or Ventricular Premature
Characteristics Arrhythmias Contractions (VPCs)
Most common age
Correlation with 
respiration
Effect of exercise 
on tachycardia
Characteristic of 
rhythm
Number of beats
SeverityCharacteristics of Normal Variants of Heart Rhythms in Children
After infancy
Throughout childhood
(less common inadults)

rhythm
Yes: Increases on 
Decreases on 
expiration
Disappears
Gradually faster with
Often suddenly slower
on expiration
Several beats, usually in
repetitive cycles
Benign (by deﬁnition)Neonates (but may occur at any
time)
No
Eradicated by exercise
May be more frequent postexercise
Skipped or missed beat
Irregularly occurring
Usually single abnormal beats
Usually benign
S1 S1 S2 S2A2 P2Expiration Inspiration
Third heart sounds, which are low-pitched, early diastolic sounds best heard
at the lower left sternal border, or apex, are frequently heard in children andare normal. They reﬂect rapid ventricular ﬁlling.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 695Fourth heart sounds, which are not often heard in children, are low-frequency,
late diastolic sounds, occurring just before the ﬁrst heart sound.
An apparent gallop, in the presence of a normal heart rate and rhythm, is a
frequent ﬁnding in normal children and does not represent pathology.
One of the most challenging aspects to the cardiac examination in children
is the evaluation of heart murmurs. In addition to the task of trying to listen

to a squirming, perhaps uncooperative child, a major challenge is to distin-guish common benign murmurs from unusual or pathologic ones. Heartmurmurs in children must be characterized by speciﬁc location (e.g., leftupper sternal border, not just left sternal border), timing, intensity, andquality. If each murmur is delineated that completely, the diagnosis is usu-ally made, and all that is needed is conﬁrmation and ampliﬁcation with lab-oratory tools such as ECG, chest x-ray, and echocardiography.
An important rule of thumb is that, by deﬁnition, benign murmurs in chil-
dren have no associated abnormal ﬁndings. Many (but not all) children with

serious cardiac malformations have signs and symptoms other than a heartmurmur obtainable on careful history or examination. Many will also haveother, noncardiac signs and symptoms as well, including evidence of geneticdefects that may offer helpful diagnostic clues.
Most children (indeed, some say nearly all) will have one or more functional,
or benign, heart murmur before reaching adulthood. It is important to iden-
tify functional murmurs by their speciﬁc qualities rather than by their soft-ness. The common functional murmurs of infancy and childhood should beeasily recognized by the practitioner and under most circumstances do notrequire evaluation.
The ﬁgure on the next page characterizes benign heart murmurs of children

according to their location, key characteristics, and typical ages of presenta-tion. These benign murmurs may be noted as children age:Fourth heart sounds represent de-
creased ventricular complianceand are associated with congestive
heart failure.
A gallop rhythm— tachycardia plus
a loud third and/or fourth heartsound—is pathologic and indicatescongestive heart failure and poor
ventricular function.
The presence of any of the non-
cardiac ﬁndings that frequently 
accompany cardiac disease in children markedly raises the possi-bility that a murmur that appearsbenign is really pathologic.
Many pathologic murmurs of con-
genital heart disease are present at
birth. Others are not apparent untillater, depending on their severity,drop in pulmonary vascular resis-tance following birth, or changesassociated with growth of thechild. Table 17-16 on pp. 773–775shows examples of pathologicmurmurs of childhood.

Neonates Closing ductus murmur
Peripheral pulmonary ﬂow murmur
Preschool or school-age Still’s murmur
Venous hum
Preschool or later Carotid bruitAdolescence Pulmonary ﬂow murmur

696 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGThe neonate may have a transient, soft, ejection murmur at the upper left
sternal border and to the left, as ﬂow continues through a closing ductus ar-
teriosus. This murmur usually disappears within a day or two after birth.A pathologic patent ductus arterio-
sustransmits a continuous murmur
at the upper left sternal border ofneonates, and is frequently accom-panied by a loud P
2, bounding
pulses, and developing congestiveheart failure.Typical Age Name Characteristics Description and LocationLocation and Characteristics of Benign Heart Murmurs in Children
Closing ductus
Peripheral pulmonary
ﬂow murmur
Still’s murmur
Venous hum
Carotid bruit
Pulmonary ﬂow murmurTransient, soft, ejection
Upper left sternal border
Soft, slightly ejectile, systolic
To left of upper left sternal border
and in lung ﬁelds and axillae
Grade I–II/VI, musical, vibratory

Multiple overtonesEarly and midsystolicMid/lower left sternal borderFrequently also a carotid bruit
Soft, hollow, continuous
Louder in diastoleUnder clavicleCan be eliminated by maneuvers
Early and midsystolic
Usually louder on leftEliminated by carotid compression
Grade I–II/VI soft, nonharsh
Ejection in timingUpper left sternal borderNormal P
2Newborn
Newborn to 1 year
Preschool or early
school age
school age
Preschool and later
Adolescence and later
Closing
ductus
Still'sCarotid
bruitVenous
hum
Pulmonary
flowLocation

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 697Some neonates and infants will have a soft, somewhat ejectile murmur heard,
not over the precordium, but over the lung ﬁelds, particularly in the axillae.This represents peripheral pulmonary artery ﬂow and is partly the result ofinadequate pulmonary artery growth in utero (when there is little pulmonaryblood ﬂow) and the sharp angle at which the pulmonary artery curves back-ward. In the absence of any physical ﬁndings to suggest additional underly-ing diseases, this peripheral pulmonary ﬂow murmur can be considered
benign and usually disappears by the age of 1 year.
Preschool and school-aged children often have benign murmurs. The most
common ( Still’s murmur ) is a grade I–II/VI, musical, vibratory, early and

midsystolic murmur with multiple overtones, located over the mid or lowerleft sternal border, but also frequently heard over the carotid arteries.Carotid artery compression will usually cause the precordial murmur to dis-appear. This murmur may be extremely variable and may be accentuatedwhen cardiac output is increased, as occurs with fever or exercise.
The murmur heard in the carotid area or just above the clavicles is known as
a carotid bruit. It is early and midsystolic, with a slightly harsh quality. It is
usually louder on the left and may be heard alone or in combination withthe Still’s murmur, as noted above. It may be completely eradicated bycarotid artery compression.A pulmonary ﬂow murmur in the

newborn who has signs of other dis-ease is more likely to be pathologic.Diseases may include Williams 
syndrome, congenital rubella syn-drome, and Alagille syndrome.
PHYSIOLOGIC BASIS FOR SOME PATHOLOGIC 
HEART MURMURS
Change in Pulmonary Vascular Resistance
Heart murmurs that are dependent on a postnatal drop in pulmonary vascular re-
sistance, allowing turbulent ﬂow from the high-pressured systemic circuit to thelower-pressured pulmonary circuit, are not audible until such a drop has occurred.Therefore, except in premature infants, murmurs of a ventricular septal defect or
patent ductus arteriosus are not expected in the ﬁrst few days of life and usually 
become audible after a week or 10 days.
Obstructive Lesions

Obstructive lesions, such as pulmonary and aortic stenosis, are caused by normal
blood ﬂow through two small valves, and, therefore, are not dependent on a dropin pulmonary vascular resistance and are audible at birth.
Pressure Gradient Differences
Murmurs of atrioventricular valve regurgitation are audible at birth because of the
high pressure gradient between the ventricle and its atrium.
Changes Associated With Growth of Children
Some murmurs do not follow the rules above, but are audible due to alterations innormal blood ﬂow and occur or change with growth. For example, even though it isan obstructive defect, aortic stenosis may not be audible until considerable growth

has occurred, and, indeed, is frequently not heard until adulthood, although a con-genitally abnormal valve is responsible. Similarly, the pulmonary ﬂow murmur of anatrial septal defect may not be heard for a year or more, as right ventricular compli-
ance gradually increases and the shunt becomes larger, eventually producing a mur-mur caused by too much blood ﬂow across a normal pulmonary valve.

698 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGAlso in preschool or school-aged children, you may detect a venous hum.
This is a soft, hollow, continuous sound, louder in diastole, heard just belowthe right clavicle. It can be completely eliminated by maneuvers that affectvenous return, such as lying supine, changing head position, or jugular venous compression. It has the same quality as breath sounds and thereforeis frequently overlooked.
A pulmonary ﬂow murmur accom-
panied by a ﬁxed split-second heartsound, suggests right-heart volumeload such as an atrial septal defect.
Characteristics of speciﬁc patho-
logic heart murmurs in children aredescribed in Table 17-16 on pp.773–775.
In adolescence, a pulmonary ﬂow murmur may be heard. It is a grade I–II/VI

soft, nonharsh murmur with the timing characteristics of an ejection mur-mur, beginning after the ﬁrst sound and ending before the second sound butwithout the marked crescendo–decrescendo quality of an organic ejectionmurmur. If you hear this murmur, make sure to evaluate whether the pul-monary closure sound is of normal intensity and whether splitting of the sec-ond heart sound is eliminated during expiration. An adolescent with a benignpulmonary ejection murmur will have normal intensity and normally split sec-ond heart sounds.
This pulmonary ﬂow murmur may also be heard in the presence of volume
overload from any reason, such as chronic anemia, pregnancy, and follow-ing exercise. It may persist into adulthood.
Review the ﬁgures on p. 696 and learn to identify the locations of benign

heart murmurs in children, and to understand the ages of presentation, char-acteristics, and qualities of these common murmurs.
When you detect any murmur in children, note all of the qualities as de-
scribed in Chapter 7, The Cardiovascular System, to help you distinguishpathologic murmurs from the benign murmurs just described. Heart mur-
murs that reﬂect underlying structural heart disease are easier to evaluate ifyou have a good knowledge of intrathoracic anatomy and the functional car-diac changes following birth and if you understand the physiologic basis forheart murmurs. Understanding these physiologic changes can help you todistinguish pathologic murmurs from benign heart murmurs in children.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 699The Breasts
INFANCY
The breasts of the newborn in both males and females are often enlarged.
This is due to maternal estrogen effect and may last several months. Thebreasts may also be engorged with a white liquid, sometimes colloquiallycalled “witch’s milk,” which may last a week or two.
OLDER CHILDREN AND ADOLESCENTS
The most important issues related to the examination of the breasts in olderchildren involve assessment of normal maturational development. For yearsthe established normal age range for onset of breast development was 8 to13 years of age (average age of 11 years), with breast development occur-ring before 8 years being abnormal. Some recent studies suggest that thelower age cutoff should be 7 years for Caucasian females and 6 years forAfrican-American (and probably Hispanic) females, though there remainssome controversy about the exact age.

Physical changes in a young girl’s breasts are one of the ﬁrst signs of puberty.
As in most developmental changes, there is a systematic progression of mat-urational changes. Generally, over a 4-year period, the breasts progressthrough ﬁve stages, called Tanner stages or Tanner sex maturity rating(SMR) stages, as shown on the next page. These progress from a preadoles-cent stage, to the appearance of breast buds, to subsequent enlargementand change in the contour of the breasts and areola. These stages are ac-companied by the development of pubic hair and other secondary sexualcharacteristics as shown on p. 713. Menarche usually occurs when a girl is in
breast stage 3 or 4, and by then she has passed her peak growth spurt (see theﬁgure on p. 700). These sequential changes in breast development are im-portant to understand in relation to overall pubertal changes, and are helpfulin counseling girls about their physical maturation.

In about 10% of girls, the breasts develop at different rates and considerable
asymmetry may result in either size or Tanner stage. This generally resolves,and reassurance to the patient is most helpful.
In older adolescent girls, a comprehensive breast examination should be ac-
companied by instructions for breast self-examination (p. 313).
In boys, the breasts consist of a small nipple and areola. During puberty,
about one third of boys develop a ﬁrm button of breast tissue 2 cm or morein diameter, and these are often noted in one breast only. Obese boys candevelop substantial breast tissue.
In premature thelarche, breast 
development occurs, most oftenbetween 6 months and 2 years ofage. Other signs of puberty or hormonal abnormalities are notpresent.
Supernumerary nipples occasion-

ally are found on the thorax or theabdomen along a vertical linebelow the true nipple(s), as shownon p. 714. They appear as small,round, ﬂat or slightly raised, pig-mented lesions, and are not clini-cally signiﬁcant.
Masses or nodules in the breasts of
adolescent girls should be exam-ined carefully. They are usually benign ﬁbroadenomas or cysts; less
likely etiologies include abscesses
or lipomas. Breast carcinoma is 
extremely rare in adolescence, andnearly always occurs in familieswith a strong family history of thedisease.
A substantial number of adolescent
boys develop gynecomastia, or
breast enlargement, on one orboth sides. While usually slight, theenlargement can be substantialand quite embarrassing. It gener-ally resolves within a few years.

700 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGThe Abdomen
NEWBORN PERIOD AND INFANCY
Inspect the abdomen with the infant lying supine, optimally while asleep.
The abdomen is protuberant due to poorly developed abdominal muscu-lature. You will easily notice abdominal wall blood vessels and intestinalperistalsis.
SEX MATURITY RATINGS IN GIRLS: BREASTS
Stage 1
Preadolescent. Elevation of nipple only
Stage 2 Stage 3
Breast bud stage. Elevation of breast Further enlargement of elevation of 
and nipple as a small mound; breast and areola, with no separation of enlargement of areolar diameter their contours
Stage 4 Stage 5
Projection of areola and nipple to Mature stage; projection of nipple only. 
form a secondary mound above the Areola has receded to general contour level of breast of the breast (although in some normal 
individuals the areola continues to form a secondary mound).

(Illustrations through the courtesy of W. A. Daniel, Jr., Professor Emeritus, Division of Adolescent
Medicine, University of Alabama, Birmingham.)

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 701Inspect the newborn’s umbilical cord to detect abnormalities. Normally,
there are two thick-walled umbilical arteries and one larger but thin-walledumbilical vein, which is usually located at the 12 o’clock position.
The umbilicus in the newborn may have a long cutaneous portion ( umbili-
cus cutis ), which is covered with skin, or an amniotic portion ( umbilicus am-
nioticus ), which is covered by a ﬁrm gelatinous substance. The amniotic
portion dries up and falls off within 2 weeks, while the cutaneous portion re-tracts to be ﬂush with the abdominal wall.
Inspect the area around the umbilicus for redness or swelling. Umbilical
hernias are detectable at a few weeks of age.
A diastasis recti may be noted in normal infants. This involves separation of

the two rectus abdominis muscles, causing a midline ridge, most apparenton contraction of the abdominal muscles. A benign condition in most cases,it resolves during early childhood. Chronic abdominal distention may alsopredispose to this condition.
Auscultation of a quiet infant’s abdomen is easy. Don’t be surprised if you
hear an orchestra of musical tinkling bowel sounds every 10 to 30 seconds.
You can percuss an infant’s abdomen as you would for an adult, but be pre-
pared to note greater tympanitic sounds due to the infant’s propensity toswallow air. Percussion is useful for determining the size of organs and ab-dominal masses.
You will ﬁnd it easy to palpate an infant’s abdomen because he likes being

touched. A useful technique to relax the infant, shown here, is to hold thelegs ﬂexed at the knees and hips with onehand and palpate the abdomen with theother. You may also want to use a paciﬁer orbottle to quiet the infant in this position.
Start gently palpating the liver of infants low
in the abdomen, moving upwards with yourfingers. This technique helps you avoid miss-ing an extremely enlarged liver that extendsdown into the pelvis. With a careful exami-nation, you can feel the liver edge in most in-fants, 1 to 2 cm below the right costalmargin.A single umbilical artery may be 
associated with congenital anom-alies, but also occurs in normal infants as an isolated anomaly.
An umbilical granuloma at the base
of the navel is the development ofpink granulation tissue formed dur-ing the healing process.
Umbilical hernias in infants are due

to a defect in the abdominal wall,and can be up to 6 cm in diameterand quite protuberant when intra-abdominal pressure is increased.Most disappear by 1 year, nearly allby 5 years.
An increase in pitch or frequency
of bowel sounds is heard with gas-
troenteritis or, rarely, with intestinal
A silent, tympanic, distended ab-
domen suggests peritonitis.
An enlarged, tender liver may be
due to congestive heart failure or to
storage diseases.

702 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGSimilarly, you can usually palpate the spleen tip. In fact, you may be able to
palpate the kidneys of infants by carefully placing the ﬁngers of one hand infront of and those of the other behind each kidney. The descending colonis a sausagelike mass in the left lower quadrant.
Once you have identiﬁed the normal structures in the infant’s abdomen, use
palpation to identify abnormal masses.
EARLY AND LATE CHILDHOOD, 
AND ADOLESCENCE
Toddlers and young children commonly have protuberant abdomens, most
apparent when they are upright. The examination can follow the same orderas for adults, except that you may need to open your bag of tricks to distractthe child during the examination.
Most children are ticklish when you ﬁrst place your hand on their abdomens
for palpation. This reaction tends to disappear, particularly if you distract the

child with conversation and place your whole hand ﬂush on the abdominalsurface for a few moments without probing. For children who are particu-larly sensitive and who tighten their abdominal muscles, you can start by plac-ing the child’s hand under yours as shown in the following photo. Eventuallyyou will be able to remove the child’s hand and palpate the abdomen freely.Abnormal abdominal masses in 
infants can be associated with thekidney (e.g., hydronephrosis ), 
bladder (e.g., urethral obstruction ),
bowel (e.g., Hirschsprung’s disease,
or intussusception ), and tumors.
In pyloric stenosis, deep palpation

in the right upper quadrant ormidline can reveal an “olive,” or a2-cm ﬁrm pyloric mass. While feed-ing, some infants with this condi-tion will have visible peristalticwaves pass across their abdomen,followed by projectile vomiting.
An exaggerated “pot-belly appear-
ance” may indicate malabsorptiondue to celiac disease, cystic ﬁbrosis,
or constipation or aerophagia.
You can also try ﬂexing the knees and hips to relax the child’s abdominal
wall. Palpate lightly in all areas, then deeply, leaving a site of potentialpathology to the end.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 703To detect abdominal tenderness, have the young child tell you which spe-
ciﬁc area is tender, and note a change in his facial expression or cry.
The liveris easily palpated in most children. The edge of the liver is normally
felt 1 cm to 2 cm below the right costal margin. It is sharp and soft and moveseasily when pushed from below upward during deep inspiration. As in infants,you should start feeling for the liver edge in the right lower quadrant andwork upwards, because a greatly enlarged liver can be missed in children.
The size of the liver is determined better by percussion than by palpation.
The table below shows the expected liver span noted by percussion in theright midclavicular line.Young children with respiratory ill-
ness and lung hyperinﬂation may

appear to have an enlarged liverand abdomen based on the liveredge being several cm below theright costal margin. Percussion willdetermine accurate liver size.
A pathologically enlarged liver in
children is usually palpable morethan 2 cm below the costal margin, has a round, ﬁrm edge,and is often tender. Causes in olderchildren include neoplasms, infec-
tious or inﬂammatory disease, meta-bolic or genetic diseases, and
congestive heart failure.
One method to determine the lower border of the liver involves the scratch
test,shown in the ﬁgure below. Place the diaphragm of your stethoscope just

above the right costal margin at the midclavicular line. With your ﬁngernail,lightly scratch the skin of the abdomen along the midclavicular line, movingfrom below the umbilicus toward the costal margin. When your scratchingﬁnger reaches the liver’s edge, you will hear a change in the scratching soundas it passes through the liver to your stethoscope.Mean Mean
Estimated Estimated
Liver Span (cm) Liver Span (cm)
Age in Years Males Females Age in Years Males Females
0.5 (6 mo) 2.4 2.8 8 5.6 5.1
1 2.8 3.1 10 6.1 5.42 3.5 3.6 12 6.5 5.63 4.0 4.0 14 6.8 5.84 4.4 4.3 16 7.1 6.05 4.8 4.5 18 7.4 6.16 5.1 4.8 20 7.7 6.3Expected Liver Span of Infants, Children, and Adolescents by Percussion

704 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGSplenomegaly can be caused 
by a variety of diseases, includinginfections, hematologic disorderssuch as hemolytic anemias, infiltra-
tive disorders, and inﬂammatory or
autoimmune diseases, as well as con-
gestion from portal hypertension.
In a child with an acute abdomen,
as in acute appendicitis, special
techniques are helpful, such aschecking for involuntary rigidity,rebound tenderness, a Rovsing’ssign, or a positive psoas or obturator sign (see p. 347–348).
A hypospadias is present when the
urethral oriﬁce appears at somepoint along the ventral surface ofthe glans or shaft of the penis (seeTable 17-17, The Male Genito-urinary System, p. 776). The foreskinis incompletely formed ventrally.
A ﬁxed, downward bowing of the
penis is a chordee; this may accom-
pany a hypospadias.
In newborns with an undescended
testicle (cryptorchidism ), the scro-

tum often appears underdevelopedand tight, and palpation reveals anabsence of scrotal contents (seeTable 17-17, The Male Genito-urinary System, p. 776).
Two common scrotal masses in
newborns are hydroceles and 
inguinal hernias; frequently bothThe spleen, like the liver, is felt easily in most children. It too is soft with a
sharp edge, and it projects downward like a tongue from under the left costalmargin. The spleen is moveable and rarely extends more than 1 cm to 2 cmbelow the costal margin.
Palpate the other abdominal structures. You will commonly note pulsations
in the epigastrium caused by the aorta. This is felt most easily to the left ofthe midline, on deep palpation.
Palpating for abdominal tenderness in an older child is the same as for the

adult; however, the causes of abdominal pain are often different, encom-passing a wide spectrum of acute and chronic diseases. Localization of ten-derness may help you pinpoint the abdominal structures most likely to becausing the abdominal pain.
Male Genitalia
Inspect the male genitalia with the infant in the supine position, noting the
appearance of the penis, testes, and scrotum. The foreskin completely cov-
ers the glans penis. It is nonretractable at birth, though you may be able toretract it enough to visualize the external urethral meatus. Retraction of theforeskin in the uncircumcised male occurs months to years later. The rate ofcircumcision has declined recently in North America and varies worldwide,depending on cultural practices.

Inspect the shaft of the penis, noting any abnormalities on the ventral sur-
face. Make sure the penis appears straight.
Scrotal edema may be present for several days following delivery due to the
effect of maternal estrogens.
Inspect the scrotum, noting rugae, which should be present by 40 weeks’
gestation. Palpate the testes in the scrotal sacs, proceeding downward fromthe external inguinal ring to the scrotum. If you feel a testis up in the in-guinal canal, gently milk it downward into the scrotum. The newborn’stestes should be about 10 mm in width and 15 mm in length and should liein the scrotal sacs most of the time.
In 3% of neonates, one or both testes cannot be felt in the scrotum or in-
guinal canal. This raises concern of cryptorchidism. In two thirds of these
cases, both testes are descended by 1 year of age.
Examine the testes for swelling within the scrotal sac and over the inguinal

ring. If you detect swelling in the scrotal sac, try to differentiate it from thetestis. Note whether the size changes when the infant increases abdominal

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 705pressure by crying. See if your
ﬁngers can get above the mass,trapping it in the scrotal sac. Ap-ply gentle pressure to try to re-duce the size of the mass and noteany tenderness. Note whether ittransilluminates.coexist, and both are more com-
mon on the right side. Hydrocelesoverlie the testes and the spermaticcord, are not reducible, and can betransilluminated (see photo at left).Most resolve by 18 months. Herniasare separate from the testes, areusually reducible, and often donot transilluminate. They do notresolve. Sometimes a thickenedspermatic cord is noted (called thesilk sign ).
In precocious puberty, the penis and
testes are enlarged, with signs ofpubertal changes. This is caused bya variety of conditions associatedwith excess androgens, includingadrenal or pituitary tumors. Other
pubertal changes also occur.
Cryptorchidism may be noted

Cryptorchidism may be noted 
at this age. It requires surgical correction. It should be differentiated from a retractibletestis.
A painful testicle requires rapid
treatment; common causes include infection such as epi-
didymitis or orchitis, torsion of 
the testicle, or torsion of the 
appendix testis.
Inguinal hernias in older boys pre-
sent as they do in adult men, withswelling in the inguinal canal, particularly following a Valsalvamaneuver.EARLY AND LATE CHILDHOOD
Inspect the penis. The size in prepubertal children has little signiﬁcance un-
less it is abnormally large. In obese boys, the fat pad over the symphysis pubismay obscure the penis.
There is an art to palpation of the young boy’s scrotum and testes because

many have an extremely active cremasteric reﬂex that may cause the testis toretract upwards into the inguinal canal and thereby appear to be unde-scended. Examine the child when he is relaxed, because anxiety stimulatesthe cremasteric reﬂex. With warm hands, palpate the lower abdomen, work-ing your way downward toward the scrotum along the inguinal canal. Thiswill minimize retraction of the testes into the canal.
A useful technique is to have the boy sit
cross-legged on the examining table, asshown here. You can also give him aballoon to inﬂate or an object to lift toincrease intra-abdominal pressure. Ifyou can detect the testis in the scrotum,it is descended even if it spends muchtime in the inguinal canal.
The cremasteric reﬂex can be tested by

scratching the medial aspect of thethigh. The testes will move upward.
Examine the inguinal canal as you would for adults, noting any swelling that
may reﬂect an inguinal hernia.
Fletcher M: Physical Diagnosis in Neonatology,
Philadelphia, Lippincott-Raven Publishers, 1998.

706 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Height spurt
Penis
Testis
Genital rating
Pubic hair
Age years10.5–16 1 3.5–17.5
10.5–14.5
9.0–13.5
9.0–14.013.5–17.012.5–16.5
23 4 5
23 4 5
8 9 10 11 12 13 14 15 16 178 9 10 11 12 13 14 15 16 17
Numbers below the bars indicate the ranges in age within which certain changes
occur. (Redrawn from Marshall WA, Tanner JM: Variations in the patterns ofpubertal changes in boys. Arch Dis Child 45:22, 1970)ADOLESCENCE
The genital examination of the adolescent boy proceeds like the examina-
tion of the adult male. Be particularly aware of the embarrassment of manyboys regarding this aspect of the examination.
Important anatomic changes in the male genitalia accompany puberty and

help to deﬁne its progress. The ﬁrst reliable sign of puberty, starting betweenages 9 and 13.5 years, is an increase in the size of the testes. Next, pubic hairappears, along with progressive enlargement of the penis. The completechange from preadolescent to adult anatomy requires about 3 years, with arange of 1.8 to 5 years.
An important goal when examining the adolescent male is to assign a sexual
maturity rating. The ﬁve stages of sexual development, ﬁrst described byTanner, are outlined and illustrated on the next page. These involve changesin the penis, testes, and scrotum. In addition, in about 80% of men, pubichair spreads farther up the abdomen in a triangular pattern pointing towardthe umbilicus; this phase is not completed until the 20s.

An important developmental principle is that physical pubertal changes
progress along a well-established sequence, as diagrammed below. Althoughthere are wide age ranges for the start and completion, the sequence for eachboy is nevertheless the same. This is helpful in counseling an anxious ado-lescent regarding his current and future maturation, and regarding the nor-mality of pubertal changes along a wide age range. It is also helpful fordetecting abnormal physical changes.Delayed puberty is suspected in
boys who have no signs of puber-tal development by 14 years ofage.
The most common cause of de-
layed puberty in males is constitu-
tional delay, a frequently familial
condition involving delayed boneand physical maturation but nor-mal hormonal levels.
While nocturnal or daytime ejacu-
lation tends to begin around Sex-ual Maturity Rating 3, a ﬁnding oneither history or physical examina-tion of penile discharge may indi-cate a sexually transmitted disease.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 707TECHNIQUES OF EXAMINATION
In assigning SMRs in boys, observe each of the three characteristics separately because they may develop at different rates. Re cord two
separate ratings: pubic hair and genital. If the penis and testes differ in their stages, average the two into a single ﬁgure f or the genital
rating.
Genital
Pubic Hair Penis Testes and Scrotum
Stage 1
Stage 2Sex Maturity Ratings in Boys
Preadolescent—no pubic hair
except for the ﬁne body hair(vellus hair) similar to thaton the abdomen
Sparse growth of long,
slightly pigmented, downyhair, straight or only slightlycurled, chieﬂy at the base ofthe penisPreadolescent—same size
and proportions as inchildhood
Slight or no enlargementPreadolescent—same size and
proportions as in childhood
Testes larger; scrotum larger,
somewhat reddened, andaltered in texture
Stage 3
Stage 4
Stage 5Darker, coarser, curlier hair
spreading sparsely over thepubic symphysis

Stage 3
Stage 4
Coarse and curly hair, as in
the adult; area coveredgreater than in stage 3 butnot as great as in the adultand not yet including thethighs
Hair adult in quantity and
quality, spread to themedial surfaces of the thighsbut not up over theabdomenLarger, especially in
length
Further enlarged in length
and breadth, withdevelopment of the glans
Adult in size and shapeFurther enlarged
Further enlarged; scrotal skin
darkened
Adult in size and shape
(Illustrations through the courtesy of W. A. Daniel, Jr., Professor Emeritus, Division of Adolescent Medicine, University of Ala bama, Birmingham.)

708 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGFemale Genitalia
Every health care provider should be familiar with the anatomy of a normal
female. It is difﬁcult to identify an abnormality unless you know what nor-mal is. The genital examination can be anxiety-provoking for the older childand adolescent (especially if you are of the opposite sex), for parents, and foryou; however, if not performed, a signiﬁcant ﬁnding may be missed. De-pending on the child’s developmental stage, explain what parts of the bodyyou will check, and that this is part of the routine examination.

In the newborn female, the genitalia will be prominent due to the effects ofmaternal estrogen. The labia majora and minora have a dull pink color inlight-skinned infants and may be hyperpigmented in dark-skinned infants.During the ﬁrst few weeks of life, there is often a milky white discharge thatmay be blood-tinged. This estrogenized appearance of the genitalia de-creases during the ﬁrst year of life.
Examine the female genitalia with the infant in the supine position. One of
the challenges is to determine the actual anatomy of the female infant’s gen-italia, which is shown below.
Ambiguous genitalia, involving mas-
culinization of the female externalgenitalia, is a rare condition causedby endocrine disorders such as con-
genital adrenal hyperplasia (see
Table 17-18, Abnormalities of theFemale Genitourinary System,p. 777).
Anterior commissure
Prepuce
Clitoris
Labia majora
Labia minora
Hymenal membrane
Hymenal orifice
(introitus)
Fossa navicularis

Prepuce
Clitoris
(vestibular fossa)
Posterior fourchette
(frenulum of labia)Urethral meatus
Para-urethral duct
orifice (skene)
Greater vestibular
glands of Bartholin
Examine the different structures systematically, including the size of the cli-
toris, the color and size of the labia majora, and the presence of rashes,bruises, or external lesions. Next, separate the labia majora at their midpointwith the thumb of each hand for young infants, or as shown in the diagramson p. 710 for early and late childhood. Infants will not mind the examinationas they are used to having their diapers changed and their bodies washed.
Inspect the urethral oriﬁce and the labia minora. Assess the hymen, which in
newborns and young infants is a thickened, avascular structure with a central

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 709oriﬁce, covering the vaginal opening. You should be able to note a vaginal
opening, although the hymen will be thickened and redundant. Note anydischarge.
After infancy, the labia majora and minora ﬂatten out, and the hymenal mem-brane becomes thin, translucent, and vascular, with the edges easily identiﬁed.
The genital examination is the same for all ages of children, from late infancy
until adolescence. Use a calm, gentle approach, including a developmentallyappropriate explanation as you do the examination. A bright light source isessential. Most children can be examined in the supine, frog-leg position.
If the child seems reluctant, it may be helpful to have the parent sit on the ex-

amination table with the child; alternatively, the exam may be performed whilethe child sits in the parent’s lap. Do not use stirrups as these may frighten thechild. The following diagram demonstrates a 5-year-old child sitting on herparent’s lap with the parent holding her knees outstretched.The appearance of pubic hair be-
fore the age of 7 years should beconsidered precocious puberty and
requires evaluation to determinethe cause.
A vaginal discharge in early child-
hood can be due to perineal irrita-
tion(e.g., bubble baths or soaps),
Examine the genitalia in an efﬁcient and systematic manner. Inspect the exter-
nal genitalia for the presence of pubic hair, the size of the clitoris, the color andsize of the labia majora, and the presence of rashes, bruises, or other lesions.
Next, visualize the structures by separating the labia with your ﬁngers as

shown at the left on the following page. You can also apply gentle tractionby grasping the labia between your thumb and index ﬁnger of each hand,

710 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGand separating the labia majora laterally and posteriorly to examine the inner
structures, as shown below. Labial adhesions, or fusion of the labia minora,
may be noted in prepubertal children and can obscure the vaginal and ure-thral oriﬁces. They may be a normal variant.foreign body, vaginitis, or a sexually
transmitted disease from sexual
abuse.
Vaginal bleeding is always concern-
ing. Etiologies include vaginal infec-
tion, accidental trauma, sexualabuse, foreign body , and tumors.
Precocious puberty from many
causes can induce menses in ayoung girl.
Purulent, profuse, malodorous, or
blood-tinged discharge should beevaluated for the presence of infec-
tion, foreign body, or trauma.
Note the condition of the labia mi-

nora, urethra, hymen, and proximalvagina. If you are unable to visualizethe edges of the hymen, ask thechild to take a deep breath to relaxthe abdominal muscles. Anotheruseful technique is to position her inthe knee-chest position as shown onthe right. These maneuvers willoften open the hymen. You can alsouse saline drops to make the edgesof the hymen less sticky.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 711Avoid touching the hymenal edges as the hymen is exquisitely tender with-
out the protective effects of hormones. Examine for discharge, labial adhe-sions, lesions, estrogenization (indicating onset of puberty), hymenalvariations (such as imperforate or septate hymen, which is rare), and hygiene.A thin, white discharge (leukorrhea) is often present. A speculum examina-tion of the vagina and cervix is not necessary in a prepubertal child unlessthere is suspicion of severe trauma or foreign body.
The normal hymen in infants and young children can have a variety of con-
ﬁgurations, as shown in the following ﬁgures.
The physical examination may reveal signs that suggest sexual abuse, and the

exam is particularly important if there are suspicious clues in the history. Bearin mind, that even with known abuse, the great majority of examinations willbe unremarkable. Mounds, notches, and tags on the hymen may all be nor-mal variants. The size of the oriﬁce can vary with age and the examinationtechnique. If the hymenal edges are smooth and without interruption in theinferior half, then the hymen is probably normal. Certain physical ﬁndings,however, suggest the possibility of sexual abuse and require more completeevaluation by an expert in the ﬁeld.Abrasions or signs of trauma of the
external genitalia can be due tobenign causes such as masturba-tion, irritants, or accidental trauma,but should also raise the possibilityof sexual abuse.
PHYSICAL SIGNS THAT MAY INDICATE SEXUAL ABUSE

PHYSICAL SIGNS THAT MAY INDICATE SEXUAL ABUSE 
IN CHILDREN*
1. Marked and immediate dilatation of the anus in knee–chest position, with no
constipation, stool in the vault, or neurologic disorders
2. Hymenal notch or cleft that extends greater than 50% of the inferior hymenal
rim (conﬁrmed in knee–chest position)
3. Condyloma acuminata in a child over 3 years4. Bruising, abrasions, lacerations, or bite marks of labia or perihymenal tissue5. Herpes of the anogenital area beyond the neonatal period6. Purulent or malodorous vaginal discharge in a young girl (all discharges should
be cultured and viewed under a microscope for evidence of a sexually transmit-ted disease)
PHYSICAL SIGNS THAT STRONGLY SUGGEST SEXUAL ABUSE 
1. Lacerations, ecchymoses, and newly healed scars of the hymen or the posterior
2. Absence of hymenal tissue from 3 to 9 o’clock (conﬁrmed in various positions)
3. Healed hymenal transections, especially between 3 and 9 o’clock (complete cleft)

4. Perianal lacerations extending to external sphincter
A child with concerning physical signs must be evaluated by a sexual abuse
expert for a complete history and sexual abuse examination.
*Any physical sign must be evaluated in light of the entire history, other parts of the physical exami-
nation, and laboratory data.

712 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGTECHNIQUES OF EXAMINATION
9-year-old girl with redundant labial tissue.
Greater traction or a knee–chest positionwould reveal a normal oriﬁce.12-year-old girl with annular-shaped oriﬁce and
hormonal inﬂuence of puberty, causing thick-ened, pink tissue
(Source of photos: Reece R, Ludwig S (eds): Child Abuse: Medical Diagnosis and Management, 2nd ed., Philadelphia, Lippincott 
Williams & Wilkins, 2001.)NORMAL CONFIGURATIONS OF THE HYMEN IN PREPUBERTAL AND ADOLESCENT FEMALES
15-month-old infant with annular hymenal oriﬁce 7-year-old girl with a crescent-shaped hymenal
oriﬁce
2-year-old with an annular oriﬁce, located off-
center, visible with labial traction6-year-old with a septate hymen causing two
oriﬁces. Traction is needed to visualize the twoopenings.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 713ADOLESCENCE
The external examination of adolescent female genitalia proceeds in the
same manner as for the school-aged child. If it is necessary to complete afull pelvic exam on an adolescent, the actual technique is the same as thatused for an adult. A full explanation of the steps of the examination,demonstration of the instruments, and a gentle, reassuring approach isnecessary because the adolescent is usually quite anxious. An adolescent’sfirst pelvic examination should be performed by an experienced health careprovider.
You should assign a sexual maturity rating to every female, irrespective of

chronologic age. The assessment of sexual maturity in girls is based on bothgrowth of pubic hair and the development of breasts. The assessment (Tan-ner staging) of pubic hair growth is shown in the ﬁgure illustrating the ﬁveTanner stages of sexual maturity, below. See p. 700 for breast developmentassessment.
Although there is a wide variation in the age of onset and completion of
puberty, remember that the stages occur in a predictable sequence, asshown here.
It is helpful to counsel girls about this sequence and their current matura-
tional stage. A girl’s initial signs of puberty are hymenal changes secondaryto estrogen, widening of the hips, and beginning of a height spurt, althoughthese changes are difﬁcult to detect. The ﬁrst easily detectable sign of pu-The presence of a vaginal discharge
in a young adolescent should betreated as in the adult. Causes in-clude physiologic leukorrhea, sexu-

ally transmitted disease s from
consensual sexual activity or sexual
abuse, bacterial vaginosis, foreignbody, and external irritants.
Menarche
Breast
Pubic hair
Age years9.5–14.5
10.0–16.5
7.0–13.0
7.0–14.013.0–18.02
23 4 534 5
Numbers below the bars indicate the ranges in age within which certain changes occur.
(Redrawn from Marshall WA, Tanner JM: Variations in the pattern of pubertal changes ingirls. Arch Dis Child 45:22, 1970)

714 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGTECHNIQUES OF EXAMINATION
Coarse and curly hair as in adults; area
covered greater than in stage 3 butnot as great as in the adult and notyet including the thighsHair adult in quantity and quality,
spread on the medial surfaces of thethighs but not up over the abdomenStage 4 Stage 5
(Illustration through the courtesy of W. A. Daniel, Jr., Professor Emeritus, Division of Adolescent
berty is usually the appearance of breast buds, although pubic hair some-
times appears earlier. The average age of the appearance of pubic hair hasdecreased in recent years, and current consensus is that the appearance ofpubic hair as early as 7 years can be normal, particularly in dark-skinned girlswho develop secondary sexual characteristics at an earlier age.SEX MATURITY RATINGS IN GIRLS: PUBIC HAIR
Stage 1
Preadolescent—no pubic hair except for the ﬁne body hair (vellus hair) similar to

Stage 1
that on the abdomen
Sparse growth of long, slightly pig-
mented, downy hair, straight oronly slightly curled, chieﬂy alongthe labiaDarker, coarser, curlier hair, spreading
sparsely over the pubic symphysis

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 715The Rectal Examination
The rectal examination is not part of the routine pediatric examination, but
should be done whenever intra-abdominal, pelvic, or perirectal disease issuspected.
The rectal examination of the young child can be performed with the child

either in the side-lying or lithotomy position. For many young children, thelithotomy position is less threatening and easier to perform. Have the childlie on the back with the knees and hips ﬂexed and the legs abducted. Drapethe child from the waist down. Provide frequent reassurance during the ex-amination, and ask the child to breathe in and out through the mouth torelax. Spread the buttocks and observe the anus. You can use your lubricatedgloved index ﬁnger, even in small children. Palpate the abdomen with yourother hand, both to distract the child and to note the abdominal structuresbetween your hands. The prostate gland is not palpable in young boys.
In young girls, a rectal examination is useful for detecting tenderness or

masses. The rectal examination for older girls who are undergoing a pelvicexamination should proceed as it does for the adult patient.
Enormous changes in the musculoskeletal system occur during infancy.Much of the newborn musculoskeletal exam focuses on detection of con-genital abnormalities, particularly in the hands, spine, hips, legs, and feet.With a little practice, you will be able to combine the musculoskeletal ex-amination with the neurologic and developmental examination.
The newborn’s hands are clenched. Because of the palmar grasp reﬂex (see
the discussion on the nervous system), you will need to help the infant ex-tend the ﬁngers. Inspect the ﬁngers carefully, noting any defects.
Palpate along the clavicle of the newborn, noting any lumps, tenderness, or
crepitus; these may indicate a fracture.

Inspect the spine carefully. While major defects of the spine such as menin-
gomyelocele are obvious and often detected by ultrasound prior to birth, sub-
tle abnormalities may include pigmented spots, hairy patches, or deep pits.These abnormalities, if present within 1 cm or so of the midline, may overlieexternal openings of sinus tracts that extend to the spinal canal. Do not probesinus tracts because of the potential risk of infection. Palpate the spine, par-ticularly in the lumbosacral region, noting any deformities of the vertebrae.
Examine the newborn and infant’s hipscarefully at each examination for
signs of dislocation. The following photos demonstrate the two major tech-
Anal skin tags are present in inﬂam-
matory bowel disease, but are more
often an incidental ﬁnding.
Tenderness noted on rectal exami-

nation of a child usually indicatesan infectious or inﬂammatorycause, such as an abscess, or ap-
pendicitis.
Skin tags, remnants of digits, poly-
dactyly (extra ﬁngers), or syndactyly
(webbed ﬁngers) are congenitaldefects noted at birth.
A fracture of the clavicle can occur
during a difﬁcult delivery.
Spina biﬁda occulta (a defect of 
the vertebral bodies) may be asso-ciated with defects of the spinalcord, which can cause severe neurologic dysfunction.

716 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGniques, one to test for the presence of a posteriorly dislocated hip ( Ortolani
test), and the second to test for the ability to sublux or dislocate an intact but
unstable hip ( Barlow test ).A soft audible “click” heard with
these maneuvers does not prove adislocated hip, but should prompta careful examination.
With a hip dysplasia, you feel a
“clunk” as the femoral head, whichlies posterior to the acetabulum,enters the acetabulum.
Make sure the baby is relaxed for the next two techniques, using a bottle or
paciﬁer if appropriate. For the Ortolani test, place the baby supine with the

legs pointing toward you. Flex the legs to form right angles at the hips andknees, placing your index ﬁngers over the greater trochanter of each femurand your thumbs over the lesser trochanters. Abduct both hips simultane-ously until the lateral aspect of each knee touches the examining table. A pal-pable movement of the femoral head back into place constitutes a positive
Ortolani sign.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 717For the Barlow test, place your hands in the same position as for the Ortolani
test. This time, press in the opposite direction with your thumbs movingdown toward the table and outward. Feel for any movement of the head ofthe femur laterally. Normally there is no movement and the hip feels “sta-ble.” If you feel the head of the femur slipping out onto the posterior lip ofthe acetabulum, this constitutes a positive Barlow’s sign. If you do feel this
dislocation movement, abduct the hip by pressing with your index and mid-dle ﬁngers back inward and feel for the movement of the femoral head as itreturns to the hip socket.
Children older than 3 months may
have a negative Ortolani or Barlowsign and still have a dislocated hip
due to tightening of the hip mus-cles and ligaments.
Severe bowing of the legs (genu

varum) may still be physiologicbowing and will spontaneously re-solve. Extreme bowing or unilateralbowing may be due to pathologiccauses such as rickets or tibia vara
(Blount’s disease ).
In addition to examining the hips, it is important to examine a newborn or
infant’s legs and feet to detect developmental abnormalities. Assess symme-
try, bowing, and torsion of the legs. There should be no discrepancy in leglength. It is common for normal infants to have asymmetric thigh skinfolds,but if you do detect asymmetry, make sure you perform the instability testsbecause dislocated hips are commonly associated with this ﬁnding.
Most newborns are bowlegged, reﬂecting their curled up intrauterine posi-

tion. During early infancy, there is a common and normal progression of in-creased bowlegged growth (as shown below, left), which begins to disappearat about 18 months of age, often followed by transition toward knock-knees.The knock-knee pattern (as shown below, right), is usually maximal by age 3
to 4 years, and gradually corrects by age 9 or 10 years.
A positive Barlow’s sign is not diag-
nostic of a dysplastic hip , but it in-
dicates laxity and a dislocatable hipprogressively, and the baby needsto be reexamined in the future.

718 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGAnother ﬁnding after 3 months of age is apparent femoral shortening ( pos-
itive Galeazzi or Alice test ). The picture below demonstrates this technique.
Place the feet together and note any difference in knee heights.
Pathologic tibial torsion occurs
only in association with deformities
of the feet or hips.
True deformities of the feet do not
return to the neutral position evenwith manipulation.
Some normal infants exhibit twisting or torsion of the tibia inwardly or out-
wardly on its longitudinal axis. Parents may be concerned about a toeing inor toeing out of the foot and an awkward gait, all of which are usually nor-mal. Tibial torsion corrects itself during the second year of life after monthsof weight bearing.
The presence of tibial torsion can be assessed in several ways; one method is

shown above. Have the toddler lie prone on the examination table, with theknees ﬂexed to 90 °, as shown. Note the thigh–foot axis. Usually there is
±10°of internal or external rotation.
Children may toe in when they begin to walk. This may increase up to 4 years
and then gradually disappear by around 10 years of age.
Now examine the feet of newborns and infants. At birth, the feet may ap-
pear deformed from retaining their intrauterine positioning, often turned inward as shown on the following page. Manipulate the affected foot—a

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 719normal foot should be easy to correct to the neutral and even to an over-
corrected position. Also, you can scratch or stroke along the outer edge tosee if the foot assumes a normal position.
Toddlers may acquire nursemaid’s
elbow or subluxation of the radial
head due to a tugging injury.
The normal newborn’s foot has several features that may initially concern you.
These features, shown on the next page, are benign. The newborn’s foot ap-pears ﬂat because of a plantar fat pad. There is often inversion of the foot, el-evating the medial margin. Other babies will have adduction of the forefootwithout inversion, called metatarsus adductus. Still others will have adduction

of the entire foot. Finally, most toddlers have some pronation during earlystages of weight bearing, with eversion of the foot. In all of these normal vari-ants, the abnormal position can be easily overcorrected past midline. They alltend to resolve within a year or two. The series of illustrations on the nextpage shows examples of pathologic foot deformities of newborns and infants.
In older children, abnormalities of the upper extremities are rare in the absence of injury.
The normal young child has increased lumbar concavity and decreased tho-
racic convexity compared with the adult, and often a protuberant abdomen.
Observe the child standing and walking barefoot. You can also ask the child
to touch the toes, rise from a sitting position, run a short distance, and pickup objects. You will detect most abnormalities by watching carefully from

720 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGboth front and behind. To indirectly assess the gait pattern of the child, you
can also note the soles of the shoes to see which side of the soles is worn down.
Inspect any child who can stand for scolio-
sisusing techniques described below.
Make sure to have the child bend forwardwith the knees straight ( Adams bend test ).
Evaluate any asymmetry in positioning orgait. Scoliosis in a young child is unusualand abnormal; mild scoliosis in an olderchild is not uncommon.
If you detect scoliosis, you can use a scolio-
meter to test for the degree of scoliosis.
With the child standing, look for asymme-try of the shoulder blades or gluteal folds.Have the child bend forward as described.
Several types of scoliosis may pre-
sent during childhood. Idiopathicscoliosis (75% of cases), seenmostly in girls, is usually detectedin early adolescence.Flat feet or pes planus due to laxity

of the soft tissue structures of thefoot
Pronation in a toddler. ( A) When viewed from behind, the hindfoot is everted.
(B) When viewed from the front, the forefoot is everted and abducted.Inversion of the foot ( varus ) Metatarsus adductus in a child. 
The forefoot is adducted and not inverted.
A B

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 721Look for prominence of the posterior ribs. Place the scoliometer over the spine
at a point of maximum prominence, making sure that the spine is parallel tothe ﬂoor at that point, as shown on the previous page. Have the child bendfully forward to assess lumbar scoliosis, and less so to assess thoracic scoliosis.
You can also use a plumb line, a string with a weight attached, to assess sym-
metry of the back. Place the top of the plumb line at C-7 and have the childstand straight. The plumb line should extend to the gluteal crease (notshown here).
Test for severe hip disease, with its as-
sociated weakness of the gluteus mediusmuscle—observe the child from behindas the child shifts weight from one legto the other. The pelvis should remainlevel when the weight is borne on theunaffected side, called a negative Tren-
delenburg’s sign.
Determine any leg shortening that may

accompany hip disease by comparingthe distance from the anterior superiorspine of the ilium to the medial malle-olus on each side. First, straighten outthe child by gently pulling on the legsand then compare the levels of the me-dial malleoli to each other. You can alsoput a small ink dot over the prominentmalleoli and touch them together togive you a contact point to measure.
Also, have the child stand straight and
place your hands horizontally over theiliac crests from behind, as shown in thephoto on the next page. Small discrep-ancies in leg length can be appreciated.If such a discrepancy is noted, a clevertrick is to place a book under theshorter leg; this should eliminate thediscrepancy.
The musculoskeletal examination of the
adolescent is similar to that of the adult.Pay particular attention to the possibil-ity of scoliosis.
More than 25 million children and

adolescents in the United States and alarge number in other countries par-ticipate in organized sports and often In severe hip disease, the pelvis 
tilts toward the unaffected hipwhen weight is borne on the affected side (an abnormal positive
Trendelenburg’s sign ).
Important risk factors for sudden
cardiovascular death during sportsinclude episodes of dizziness or pal-
pitations, prior syncope (particularly
if associated with exercise), or fam-ily history of sudden death in young
or middle-aged relatives.

722 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGrequire “medical clearance.” Start the exam with a thorough medical his-
tory, focusing on cardiovascular risk factors, prior surgeries, prior injuries,other medical problems, and a family history. The preparticipation physicalexam is often the only time a healthy adolescent will see a medical profes-sional, so it is important to include some screening questions and anticipa-tory guidance (see the discussion on Health Promotion and Counseling).Finally, perform a general physical, with special attention to the cardiac andlung exams and a vision and hearing screen. The preparticipation examshould then include a focused, thorough musculoskeletal exam, looking forweakness, limited range of motion, and evidence of previous injury.
A 2-minute preparticipation screening musculoskeletal examination has
been recommended.
During the preparticipation sports

physical, assess carefully for cardiacmurmurs and wheezing in the
lungs.
Speciﬁc Components of the Musculoskeletal Examination
Common Abnormalities
Positioning Instructions to Patients Due to Prior InjuryScreening Musculoskeletal Examination for Children Participating in Sports
1. Stand straight, facing
you.Asymmetry, swelling of
joints

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 723TECHNIQUES OF EXAMINATION
Positioning Instructions to Patients Due to Prior InjuryScreening Musculoskeletal Examination for Children Participating in Sports (Continued)
2. Move neck in all
directions—look at theceiling and ﬂoor, touchears to shoulders.
3. Shrug shoulders while
you hold them down.
4. Hold arms out to side
and lift arms while youpress down.Loss of range of motion
Weakness of shoulder, neck,
or trapezius muscles
Loss of strength of deltoid
muscle

724 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGTECHNIQUES OF EXAMINATION
5. Hold arms out to side
with elbows bent 90 °,
raise and lower arms.
6. Hold arms out,
completely bend andstraighten elbows.
7. Hold arms down, bend
elbows 90 °and pronate
and supinate forearm.
8. Make a ﬁst, clench and
then spread ﬁngers.Loss of external rotation and
injury to glenohumeraljoint
Reduced range of motion of
elbow
Reduced range of motion
from injury to forearm,elbow, or wrist
Protruding knuckle, reduced
range of motion of ﬁngersfrom prior sprain orfracture

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 725 725 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGSpeciﬁc Components of the Musculoskeletal Examination
9. Squat and duck-walk for
four steps toward you.
10. Stand straight with arms
at sides, back to you.
11. Bend forward with
knees straight andtouch toes.
12. Stand on heels and rise
to the toes.Inability to fully ﬂex knees
and difﬁculty standing updue to prior knee or ankleinjury
Asymmetry from scoliosis, or
leg-length discrepancy, orweakness from injury
Asymmetry from scoliosis,
and twisting of back fromlow back pain
Wasting of calf muscles from
ankle or Achilles tendoninjury

726 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGThe Nervous System
The examination of the nervous system in infants and children has several
special characteristics. The examination includes techniques that are highlyspeciﬁc to a particular age, especially for infants. Testing primitive reﬂexes isimportant in infants; they are only present at certain ages and then disappear.Absent reﬂexes or retention of these reﬂexes may signify abnormalities. Ingeneral, the examination of the nervous system of infants and young chil-dren is highly dependent on both internal and external factors listed here.
Persistent irritability in the newborn
may be a sign of neurologic insult, or
may reﬂect a variety of metabolic,
infectious, or other constitutional 
abnormalities, or environmental
conditions such as drug withdrawal.
Newborns with hypotonia often lie
in a frog-leg position, with armsUNIQUE ASPECTS OF THE PEDIATRIC

in a frog-leg position, with armsUNIQUE ASPECTS OF THE PEDIATRIC 
NEUROLOGIC EXAMINATION
IAge-speciﬁc
ISome reﬂexes are only present at certain ages.
IFindings are greatly affected by factors:
Internal: alertness, timing with respect to feeding and sleepingExternal: presence of parents, fearful stimuli
INeurologic changes often present as developmental abnormalities.
INeurologic and developmental examinations often are combined.
It is important to note that while many neurologic abnormalities in adults
produce asymmetric localized ﬁndings, neurologic abnormalities in infantsand young children often present as developmental abnormalities, such asfailure to do age-appropriate tasks. Therefore, the neurologic and develop-mental examinations need to proceed hand in hand. Finding a develop-mental abnormality should prompt you to pay particular attention to theneurologic examination.

The neurologic screening examination of all newborns should include as-sessment of mental status, gross and ﬁne motor function, tone, cry, deeptendon reﬂexes, and primitive reﬂexes. More detailed examination of cranialnerve function, sensory function, and less common primitive reﬂexes are in-dicated if you suspect any abnormalities from the history or screening. Theneurologic examination can reveal extensive disease but will not pinpointspeciﬁc functional deﬁcits or minute lesions.
Assess the mental status of newborns by observing many of the newborn ac-
tivities discussed on pp. 644–645 (“What newborns can do”). Make sureyou test the newborn during alert periods, and, if possible, return at a latertime if the baby is transiently too drowsy.
Assess the motor tone of newborns and infants, ﬁrst by carefully watching
their position at rest and testing their resistance to passive movement.
Then assess toneas you move each major joint through its range of motion,

noting any spasticity or ﬂaccidity. Hold the baby in your hands, as shown

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 727below, to determine if the tone is normal, increased, or decreased. Either in-
creased or decreased tone may indicate intracranial disease, although suchdisease is usually accompanied by a number of other signs.ﬂexed and hands near the ears.
Hypotonia can be caused by a variety of central nervous system
abnormalities and disorders of the
motor unit.
Persistent effects of anesthesia may
limit a newborn’s response to pain.If changes in facial expression orcry follow a painful stimulus but nowithdrawal occurs, paralysis may
be present.
A progressive increase in deep ten-
don reﬂexes during the ﬁrst year oflife may indicate central nervoussystem disease such as cerebral
palsy, especially if it is coupled with
increased tone.SIGNS OF SEVERE NEUROLOGIC DISEASE
IExtreme irritability
IPersistent asymmetry of posture
IPersistent extension of extremities

IConstant turning of head to one side
IMarked extension of head, neck, and extremities (opisthotonus)
ISevere ﬂaccidity
ILimited response to pain
You can only test for sensory function of the newborn in a limited way. Test
for pain sensation by ﬂicking the infant’s palm or sole with your ﬁnger. Ob-serve for withdrawal, arousal, and change in facial expression. Do not use apin to test for pain.
The cranial nerves of the newborn or infant can be tested, although you will
have to open your bag of tricks for special methods that differ from thoseused for the older child or adult. The table on the next page provides someuseful strategies.
The deep tendon reflexes are variable in newborns and infants because the

corticospinal pathways are not fully developed. Thus, their exaggeratedpresence or their absence has little diagnostic significance unless this re-sponse is different from results of previous testing, or extreme responsesare observed.

728 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGUse the same techniques to elicit deep tendon reﬂexes as you would for an
adult. You can substitute your index or middle ﬁnger for the neurologichammer, as shown below.
An absent anal reﬂex suggests 
loss of innervation of the externalsphincter muscle caused by aCranial Nerve Strategy
I
II
II, III
III, IV, VI
VVII
VIII
IX, X
XI
XIIStrategies to Assess Cranial Nerves in Newborns and Infants
OlfactoryVisual acuity
Response to light
Extraocular movements
MotorFacial
Acoustic
Swallow
Gag
Spinal accessoryHypoglossalDifﬁcult to test
Have baby regard your face and look for
facial response and tracking.
Darken room, raise baby to sitting position to
open eyes.
Use light and test for optic blink reﬂex
(blinking in response to light).
Use the otoscope (without a speculum) to
assess papillary responses.
Observe tracking as the baby regards your
smiling face move side-to-side.

Use light if needed.
Test rooting reﬂex.
Test sucking reﬂex (watch baby suck breast,
bottle, or possibly paciﬁer).
Observe baby crying and smiling, note
symmetry of face and forehead.
Test acoustic blink reﬂex (blinking of both
eyes in response to loud noise).
Observe tracking in response to sound.
Observe coordination during swallowing.
Test for gag reﬂex.
Observe symmetry of shoulders.Observe coordination of swallowing, sucking,
and tongue thrusting.
Pinch nostrils, observe reﬂex opening of
mouth with tip of tongue to midline.
The triceps, brachioradialis, and abdominal reﬂexes are difﬁcult to elicit be-
fore 6 months of age. The anal reﬂex is present at birth and important to
elicit if a spinal cord lesion is suspected.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 729Although a normal ﬂexion plantar response is obtained in 90% of infants, a pos-
itive Babinski response to plantar stimulation (dorsiﬂexion of big toe and fan-
ning of other toes) can be elicited in some normal infants until 2 years of age.
You can try to elicit the ankle reﬂex as for adults by tapping on the Achilles
tendon but often will not get a response. Another method shown below isto grasp the infant’s malleolus with one hand and abruptly dorsiﬂex theankle. Don’t be surprised if you note rapid, rhythmic plantar ﬂexion of thenewborn’s foot ( ankle clonus ) in response to this maneuver. Up to 10 beats
are normal in newborns and young infants; this is unsustained ankle clonus.spinal cord abnormality such as 
a congenital anomaly (e.g., spina
biﬁda ), tumor, or injury.
When the contractions are con-
tinuous ( sustained ankle clonus ),

central nervous system diseaseshould be suspected.
A neurologic or developmental ab-
normality is suspected if primitive
reﬂexes are
IAbsent at appropriate age
IPresent longer than normal
IAsymmetric
IAssociated with posturing ortwitching
The newborn and infant’s developing central nervous system can be evalu-
ated by assessing infantile automatisms, called primitive reﬂexes. These de-
velop during gestation, are generally demonstrable at birth, and disappear atdeﬁned ages. Abnormalities in these primitive reﬂexes suggest neurologicdisease and merit more intensive investigation. The most important primi-tive reﬂexes are illustrated on the next page.
There are additional primitive reﬂexes shown on p. 731 not usually used in

the general examination but helpful in a more extensive evaluation of an in-fant with abnormal neurologic ﬁndings. A summary of some general indica-tors of central nervous system disease in newborns and infants, includingmild disease, is provided here.
GENERAL INDICATORS OF CENTRAL NERVOUS SYSTEM DISEASE
DURING INFANCY
1. Abnormal localized neurologic ﬁndings
2. Asymmetry of movement of extremities3. Failure to elicit expected primitive reﬂexes4. Late persistence of primitive reﬂexes5. Reemergence of vanished primitive reﬂexes6. Delays in reaching developmental milestones
Gross motorFine motorCognitive and languageSocial and emotional

730 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGTECHNIQUES OF EXAMINATION
Primitive Reﬂex Maneuver Ages
Palmar 
Grasp Reﬂex
Plantar 
Moro 
Reﬂex (Startle Reﬂex)
Asymmetric 
Tonic Neck Reﬂex
Positive 
Support ReﬂexPrimitive Reﬂexes That Should Be Part of the Routine Neurologic
Examination of Infants
Place your ﬁngers into the
baby’s hands and pressagainst the palmarsurfaces.
The baby will ﬂex all
ﬁngers to grasp yourﬁngers.
Touch the sole at the base
of the toes.
The toes curl.
Hold the baby supine,
supporting the head,back, and legs. Abruptlylower the entire bodyabout 2 feet.
The arms abduct and
extend, hands open, andlegs ﬂex. Baby may cry.
With baby supine, turn
head to one side, holdingjaw over shoulder.
The arms/legs on side to
which head is turnedextend while theopposite arm/leg ﬂex.Repeat on other side.
Hold the baby around the
trunk and lower until thefeet touch a ﬂat surface.
The hips, knees, and

ankles extend, the babystands up, partiallybearing weight, sags after 20–30 seconds.Birth to 
3–4 mos
Birth to 
6–8 mos
Birth to 
4–6 mos
Birth to 
2 mos
Birth or 
2 mos until 6 mosPersistence beyond 4 mos suggests
cerebral dysfunction.
Persistence of clenched hand beyond 2
mos suggests central nervous systemdamage, especially if ﬁngers overlapthumb.
Persistence beyond 8 mos suggests
Persistence beyond 4 mos suggests
neurologic disease; beyond 6 mosstrongly suggests it.
Asymmetric response suggests fracture
of clavicle or humerus or brachialplexus injury.
Persistence beyond 2 mos suggests
neurologic disease.
Lack of reﬂex suggests hypotonia or
ﬂaccidity.
Fixed extension and adduction of legs
(scissoring) suggests spasticity due toneurologic disease.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 731Primitive Reﬂex Maneuver Ages
Rooting 
Reﬂex
Trunk 
Incurvation (Galant’s) Reﬂex
Placing 
and Stepping Reﬂexes
Landau 
Reﬂex
Parachute 
ReﬂexAdditional Primitive Reﬂexes That Should Be Tested If Neurologic
Abnormality Is Suspected
Stroke the perioral skin
at the corners of themouth.
The mouth will open
and baby will turnthe head toward thestimulated side andsuck.
Support the baby
prone with one hand,and stroke one sideof the back 1 cmfrom midline, fromshoulder to buttocks.
The spine will curve
toward thestimulated side.
Hold baby upright
from behind as inpositive supportreﬂex. Have one soletouch the tabletop.
The hip and knee of
that foot will ﬂex andthe other foot willstep forward.
Alternate stepping will
occur.
Suspend the baby
prone with one hand.
The head will lift up
and the spine willstraighten.
prone and slowlylower the headtoward a surface.
The arms and legs will

occur.
extend in a protectivefashion.Birth to 
3–4 mos
Birth to 
2 mos
Birth 
(bestafter 4days).Variableage todisappear
Birth to 
6 mos
4–6 mos
and doesnotdisappearAbsence of rooting indicates severe gen-
eralized or central nervous system dis-ease.
Absence suggests a transverse spinal cord
lesion or injury.
Persistence may indicate delayed devel-
opment.
Absence of placing may indicate paralysis.
Babies born by breech delivery may not
have placing reﬂex.
opment.
Delay in appearance may predict future
delays in voluntary motor development

732 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGRefer to the developmental milestones on pp. 626–628 and to the DDST
on pp. 738–739 to learn which age-speciﬁc developmental tasks to evaluate.The ﬁgure on this page pictorially displays the development of gross motor
skills in the ﬁrst year of life. By observation and play with the infant, you can
do both a developmental screening examination and an assessment for grossand ﬁne motor achievement. Speciﬁcally, look for weakness by observing sit-
ting, standing, and transitions. Note station, or the posture of sitting or
standing. Carefully observe the gaitof the toddler, including balance and

ﬂuidity of movements. Fine motor development can be assessed in a similarway, combining the neurologic and developmental exam. Again, refer to themilestones on pp. 626–628 and 738–739. Key milestones include the de-velopment of the pincer grasp, ability to manipulate objects with the hands,and more precise tasks, such as building a tower of cubes or scribbling, asﬁne motor development progresses in a proximal to distal direction.TECHNIQUES OF EXAMINATION
12
34
56
78
9101112
Cognitive and social/emotional development should also be assessed as you
proceed with the comprehensive neurologic and developmental examina-

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 733tion. Some neurologic abnormalities produce deﬁcits or slowing in cogni-
tive and social development. As stated, infants who have developmentaldelay may have abnormal ﬁndings on the neurologic examination becausemuch of the examination is based on age-speciﬁc norms.
A normative measure of development is the developmental quotient, which
is shown here:TECHNIQUES OF EXAMINATION
quotient=Developmenta l age
Chronologic age×100
The development of an infant or child can be assessed using standard scales
such as the DDST for each of the types of development. For example, youcan assign to a child a gross motor developmental quotient, a ﬁne motor de-velopmental quotient, a cognitive developmental quotient, and so forth.
DEVELOPMENTAL QUOTIENTS
>85 Normal
70–85 Possibly delayed; follow-up needed<70 Delayed
CASE EXAMPLES OF GROSS AND FINE MOTOR DEVELOPMENT
Gross Motor Development Fine Motor Development

>85 Normal
A 12-month-old child can transfer 
objects from hand to hand (a ﬁnemotor developmental age of 6 mos),rake objects into his palm (7 mos),and pull things (7 mos). He cannothold blocks in each hand and doesnot have thumb and ﬁnger grasp(8–9 mos).
He has normal primitive reﬂexes 
(most absent), increased tone, scis-soring of legs when held, spasticity,and delays on the gross motor partof the DDST.
This child’s ﬁne motor developmental
quotient is:
(
7—
12×100) =58
This child is delayed in ﬁne motor 
development and has signs of cerebral palsy.A 12-month-old child who is just
pulling to stand (gross motor devel-opmental age of 9 mos), cruising(10 mos), and walking when bothhands are held (10 mos) has a grossmotor developmental age of 10 months. This child’s gross motordevelopmental quotient is:
(
10—

(
10—
12×100) =83
This child is in the gray zone, is likely
to do well without intervention, butrequires close follow-up.

734 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGEARLY AND LATE CHILDHOOD
Beyond infancy, when the primitive reﬂexes have disappeared, the neurologic
examination includes the components evaluated in adults. Again, you shouldcombine the neurologic and developmental assessment and will need to turnthis into a game with the child. The goal is to assess optimal development andneurologic performance, and this requires the child to be cooperative.
Perform the DDST as described and shown on pp. 738–739. Children usu-
ally enjoy this component, and you can too. Remember that the DDST is bet-ter at detecting delays in motor skills than in language or cognitive milestones.
The cranial nerves can be assessed quite well using developmentally appro-
priate strategies as shown in the following table:Children with spastic diplegias will

often have hypotonia as infantsand then excessive tone with spas-ticity, scissoring, and perhapsclenched ﬁsts as toddlers andyoung children.
In children with uncoordinated
gait, be sure to distinguish ortho-
pedic causes such as positional Cranial Nerve Strategy
I
II
III, IV, VIV
VIIVIII
IX, X
XIXIIStrategies to Assess Cranial Nerves in Young Children
Olfactory
Visual acuity
Extraocular movementsMotor
FacialAcoustic
Swallow and
gag
Spinal accessory
HypoglossalTestable in older children.
Use Snellen chart after age 3 years.
Test visual ﬁelds as for an adult. A parent may
need to hold the child’s head.
Have the child track a light or an object (a
toy is preferable). A parent may need tohold the child’s head.
Play a game with a soft cotton ball to test
sensation.
Have the child clench the teeth and chew or
swallow some food.

Have the child “make faces” or imitate you
as you make faces (including moving youreyebrows), and observe symmetry and facialmovements.
Perform auditory testing after age 4 years.
Whisper a word or command behind the
child’s back and have the child repeat it.
Have the child stick the “whole tongue out”
or “say ‘ah’.” Observe movement of theuvula and soft palate.
Test the gag reﬂex.
Have the child push your hand away with his
head. Have the child shrug his shoulderswhile you push down with your hands to“see how strong you are.”
Ask the child to “stick out your tongue all
the way.”
An important part of the motor examination is to observe the child’s gait
while the child is walking and, optimally, running. Note any asymmetries,weakness, undue tripping or clumsiness. Follow the DDST examination

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 735milestones to test for appropriate maneuvers such as heel-to-toe walking
(photo below), hopping, and jumping. Use a toy to test for coordinationand strength of the upper extremities.
If you are concerned about the child’s strength,
have the child lie on the ﬂoor and then standup, and closely observe the stages. Most normalchildren will ﬁrst sit up, then ﬂex the knees andextend the arms to the side to push off from theﬂoor and stand up.
Hand preference is demonstrated in most chil-
dren by age 2 and rarely before 18 months
of age.
The sensory examination can be performed using a cotton ball or tickling the
child. This is best performed with the child’s eyes closed. Do not use pinpricks to evaluate sensation or else you will have a very uncooperative and un-happy patient!
Deep tendon reﬂexes can be tested as in adults. First demonstrate the use of

the reﬂex hammer on the child’s hand, assuring the child that it will not hurt.Children love to feel their legs bounce when you test their patellar reﬂexes.You will need to have the child cooperate and keep the eyes closed duringsome of this examination because tensing will disrupt the results.
You can ask children older than 3 years to draw a picture, copy objects as is
done in the DDST, and then discuss their pictures to test simultaneously forﬁne motor coordination, cognition, and language.
The cerebellar examination can be tested using ﬁnger to nose and rapid al-
ternating movements of the hands or ﬁngers. Children enjoy this game.Children older than 5 years should be able to tell right from left, so you canassign them right–left discrimination tasks as is done in the adult patient.deformities of the hip, knee, or
foot from neurologic abnormalities
such as cerebral palsy, ataxia, neu-

romuscular conditions producing
weakness, or degenerative diseases.
In certain forms of muscular dystro-
phywith weakness of the pelvic
girdle muscles, children will rise tostanding by rolling over prone andpushing off the ﬂoor with the armswhile the legs remain extended(Gower’s sign ).
It is important to distinguish be-
tween isolated delays in one aspectof development (e.g., coordinationor language) and more generalizeddelays that occur in several compo-nents. The latter is more likely toreﬂect global neurologic disorderssuch as mental retardation that can
be caused by a large number ofetiologies.

736 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGUse the expected milestones on the DDST and on pp. 628–631 to test for
language, cognitive, and social and emotional development. Rememberthat the neurologic and developmental examinations require a cooperativechild, so be patient, have fun, and don’t be embarrassed to play and inno-vate as you reﬁne your examination skills to the developmental level of yourpediatric patient.
THE ADOLESCENT
The neurologic examination of the adolescent and the adult is the same. Still,it is important to assess the adolescent’s developmental achievement accord-ing to age-speciﬁc milestones as described on pp. 631–633.Some children who have attention
deﬁcit disorder with hyperactivity(ADHD) will have a great deal of

difﬁculty cooperating with yourneurologic and developmental ex-amination due to problems focusing. These children oftenhave high energy levels, cannotstay still for extended periods, andhave a history of difﬁculty in schoolor structured situations.

TABLE 17-1 IBallard Scoring System
CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 737
TABLE 17-1 IBallard Scoring System for Determining
Gestational Age in Weeks
The Neuromuscular Maturity Criteria are depicted in the top half of the ﬁgure. Asphyxi-
ated neonates or neonates obtunded by anesthetic agents or drugs will score lower on neu-romuscular maturity criteria. In such instances, scoring should be repeated at 24 to 48hours of age. The Physical Maturity Criteria are shown in the bottom half of the ﬁgure andare self-explanatory. The scores for each criterion are again the numbers at the top of thecolumns. The sum of the scores for all of the neuromuscular and physical maturity itemsprovides an estimate of gestational age in weeks, using the maturity rating scale at the lowerright portion of the ﬁgure. (Figure from Ballard JL, et. al. J. Pediatr 119:417, 1991.)

TABLE 17-2 IDenver Developmental Screening Test
738 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Testing kits, test forms, and reference manuals (which must be used to ensure accuracy in administration
of the test) for the DDST may be ordered from Denver Developmental Materials Incorporated, P.O. Box6919, Denver, CO 80206-0919. (Reprinted with permission from William K. Frankenburg, M.D.)

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 739
TABLE 17-2 IDenver Developmental Screening Test (Continued)
DIRECTIONS FOR ADMINISTRATION
1. Try to get child to smile by smiling, talking or waving. Do not touch him/her.
2. Child must stare at hand several seconds.3. Parent may help guide toothbrush and put toothpaste on brush.4. Child does not have to be able to tie shoes or button/zip in the back.5. Move yarn slowly in an arc from one side to the other, about 8 /H11033above child’s face.
6. Pass if child grasps rattle when it is touched to the backs or tips of fingers.7. Pass if child tries to see where yarn went. Y arn should be dropped quickly from sight from tester ’s hand without arm move-
ment.
8. Child must transfer cube from hand to hand without help of body, mouth, or table.9. Pass if child picks up raisin with any part of thumb and finger.
10. Line can vary only 30 degrees or less from tester ’s line.

11. Make a fist with thumb pointing upward and wiggle only the thumb. Pass if child imitates and does not move any fingers other
than the thumb.
When giving items 12, 14, and 15, do not name the forms. Do not demonstrate 12 and 14.
16. When scoring, each pair (2 arms, 2 legs, etc.) counts as one part.17. Place one cube in cup and shake gently near child ’s ear, but out of sight. Repeat for other ear.
18. Point to picture and have child name it. (No credit is given for sounds only.)
If less than 4 pictures are named correctly, have child point to picture as each is named by tester.
19. Using doll, tell child: Show me the nose, eyes, ears, mouth, hands, feet, tummy, hair. Pass 6 of 8.
20. Using pictures, ask child: Which one flies?... says meow?... talks?... barks?... gallops? Pass 2 of 5, 4 of 5.

21. Ask child: What do you do when you are cold?... tired?... hungry? Pass 2 of 3, 3 of 3.22. Ask child: What do you do with a cup? What is a chair used for? What is a pencil used for?
Action words must be included in answers.
23. Pass if child correctly places 
and says how many blocks are on paper. (1, 5)
24. Tell child: Put block ontable; under table; in front of me, behind me. Pass 4 of 4.
(Do not help child by pointing, moving head or eyes.)
25. Ask child: What is a ball?... lake?... desk?... house?... banana?... curtain?... fence?... ceiling? Pass if defined in terms of use,
shape, what it is made of, or general category (such as banana is fruit, not just yellow). Pass 5 of 8, 7 of 8.
26. Ask child: If a horse is big, a mouse is __? If fire is hot, ice is __? If the sun shines during the day, the moon shines dur ing
the __? Pass 2 of 3.

27. Child may use wall or rail only, not person. May not crawl.28. Child must throw ball overhand 3 feet to within arm ’s reach of tester.
29. Child must perform standing broad jump over width of test sheet (8
1⁄2inches).
30. Tell child to walk forward, heel within 1 inch of toe. Tester may demonstrate.
Child must walk 4 consecutive steps.
31. In the second year, half of normal children are noncompliant.
OBSERVATIONS:12. Pass any enclosed
form. Fail continuous
round motions.13. Which line is longer?
(Not bigger.) Turn paper
upside down and repeat.
(pass 3 of 3 or 5 of 6)14. Pass any lines
crossing near
midpoint.15. Have child copy
first. If failed,
demonstrate.
Instructions printed on the back of the DDST form for administering some of the items contained in the Denver Developmental

Screening Test. (Reprinted with permission from William K. Frankenburg, M.D.)

TABLE 17-3 IBlood Pressure Levels for Boys Aged 1 to 17 Years
740 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 17-3 IBlood Pressure Levels for the 90th and 95th Percentiles of Blood Pressure for Boys Aged
1 to 17 Years by Percentiles of Height
BloodSystolic Blood Pressure by Percentile Diastolic Blood Pressure by 
Age, Pressureof Height, mm Hg†Percentile of Height, mm Hg†
y Percentile* 5% 10% 25% 50% 75% 90% 95% 5% 10% 25% 50% 75% 90% 95%
1 90th 94 95 97 98 100 102 102 50 51 52 53 54 54 55
95th 98 99 101 102 104 106 106 55 55 56 57 58 59 59
2 90th 98 99 100 102 104 105 106 55 55 56 57 58 59 59
95th 101 102 104 106 108 109 110 59 59 60 61 62 63 63
3 90th 100 101 103 105 107 108 109 59 59 60 61 62 63 63
95th 104 105 107 109 111 112 113 63 63 64 65 66 67 67
4 90th 102 103 105 107 109 110 111 62 62 63 64 65 66 66
95th 106 107 109 111 113 114 115 66 67 67 68 69 70 71
5 90th 104 105 106 108 110 112 112 65 65 66 67 68 69 69

95th 108 109 110 112 114 115 116 69 70 70 71 72 73 74
6 90th 105 106 108 110 111 113 114 67 68 69 70 70 71 72
95th 109 110 112 114 115 117 117 72 72 73 74 75 76 76
7 90th 106 107 109 111 113 114 115 69 70 71 72 72 73 74
95th 110 111 113 115 116 118 119 74 74 75 76 77 78 78
8 90th 107 108 110 112 114 115 116 71 71 72 73 74 75 75
95th 111 112 114 116 118 119 120 75 76 76 77 78 79 80
9 90th 109 110 112 113 115 117 117 72 73 73 74 75 76 77
95th 113 114 116 117 119 121 121 76 77 78 79 80 80 81
10 90th 110 112 113 115 117 118 119 73 74 74 75 76 77 78
95th 114 115 117 119 121 122 123 77 78 79 80 80 81 82
11 90th 112 113 115 117 119 120 121 74 74 75 76 77 78 78
95th 116 117 119 121 123 124 125 78 79 79 80 81 82 83
12 90th 115 116 117 119 121 123 123 75 75 76 77 78 78 79
95th 119 120 121 123 125 126 127 79 79 80 81 82 83 83

13 90th 117 118 120 122 124 125 126 75 76 76 77 78 79 80
95th 121 122 124 126 128 129 130 79 80 81 82 83 83 84
14 90th 120 121 123 125 126 128 128 76 76 77 78 79 80 80
95th 124 125 127 128 130 132 132 80 81 81 82 83 84 85
15 90th 123 124 125 127 129 131 131 77 77 78 79 80 81 81
95th 127 128 129 131 133 134 135 81 82 83 83 84 85 86
16 90th 125 126 128 130 132 133 134 79 79 80 81 82 82 83
95th 129 130 132 134 136 137 138 83 83 84 85 86 87 87
17 90th 128 129 131 133 134 136 136 81 81 82 83 84 85 85
95th 132 133 135 136 138 140 140 85 85 86 87 88 89 89
*Blood pressure percentile was determined by a single measurement.
†Height percentile was determined by standard growth curves.

Reproduced with permission from Update on the 1987 Task Force Report on High Blood Pressure in Children and Adolescents: A Work ing Group Report from the National High
Blood Pressure Education Program. Pediatrics 98:649, 1996.

TABLE 17-3 IBlood Pressure Levels for Girls Aged 1 to 17 Years
CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 741
TABLE 17-3 IBlood Pressure Levels for the 90th and 95th Percentiles of Blood Pressure for Girls Aged
1 90th 97 98 99 100 102 103 104 53 53 53 54 55 56 56
95th 101 102 103 104 105 107 107 57 57 57 58 59 60 60
2 90th 99 99 100 102 103 104 105 57 57 58 58 59 60 61
95th 102 103 104 105 107 108 109 61 61 62 62 63 64 65
3 90th 100 100 102 103 104 105 106 61 61 61 62 63 63 64
95th 104 104 105 107 108 109 110 65 65 65 66 67 67 68
4 90th 101 102 103 104 106 107 108 63 63 64 65 65 66 67
95th 105 106 107 108 109 111 111 67 67 68 69 69 70 71
5 90th 103 103 104 106 107 108 109 65 66 66 67 68 68 69

95th 107 107 108 110 111 112 113 69 70 70 71 72 72 73
6 90th 104 105 106 107 109 110 111 67 67 68 69 69 70 71
95th 108 109 110 111 112 114 114 71 71 72 73 73 74 75
7 90th 106 107 108 109 110 112 112 69 69 69 70 71 72 72
95th 110 110 112 113 114 115 116 73 73 73 74 75 76 76
8 90th 108 109 110 111 112 113 114 70 70 71 71 72 73 74
95th 112 112 113 115 116 117 118 74 74 75 75 76 77 78
9 90th 110 110 112 113 114 115 116 71 72 72 73 74 74 75
95th 114 114 115 117 118 119 120 75 76 76 77 78 78 79
10 90th 112 112 114 115 116 117 118 73 73 73 74 75 76 76
95th 116 116 117 119 120 121 122 77 77 77 78 79 80 80
11 90th 114 114 116 117 118 119 120 74 74 75 75 76 77 77
95th 118 118 119 121 122 123 124 78 78 79 79 80 81 81
12 90th 116 116 118 119 120 121 122 75 75 76 76 77 78 78
95th 120 120 121 123 124 125 126 79 79 80 80 81 82 82

13 90th 118 118 119 121 122 123 124 76 76 77 78 78 79 80
95th 121 122 123 125 126 127 128 80 80 81 82 82 83 84
14 90th 119 120 121 122 124 125 126 77 77 78 79 79 80 81
95th 123 124 125 126 128 129 130 81 81 82 83 83 84 85
15 90th 121 121 122 124 125 126 127 78 78 79 79 80 81 82
95th 124 125 126 128 129 130 131 82 82 83 83 84 85 86
16 90th 122 122 123 125 126 127 128 79 79 79 80 81 82 82
95th 125 126 127 128 130 131 132 83 83 83 84 85 86 86
17 90th 122 123 124 125 126 128 128 79 79 79 80 81 82 82
95th 126 126 127 129 130 131 132 83 83 83 84 85 86 86
*Blood pressure percentile was determined by a single reading.

TABLE 17-4 IGrowth Charts
742 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 743
TABLE 17-4 IGrowth Charts (Continued)

744 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 745

746 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 747

748 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 749

TABLE 17-5 IAbnormal Growth Patterns in Infancy and Childhood
750 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Genetic (familial) Short Stature
Normal birth size, deceleration by 2 yrs, then steady growth. Short adult height, like parents.2 to 20 years: Boys
Stature Weight-for-age percentiles -for-age andNAME
RECORD #
SOURCE: Developed b
(2000).y the National Center for Health Statistics in collaboration with
the National Center for Chronic Disease Prevention and Health Promotion
http://www.cdc.gov/growthchartsRevised and corrected November 28, 2000.W
E
I
G
H
T
W
E
I
G
H
TS
T
A
T
U
R
E
23 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20S
T
A
T
U
R
E7476
72
70
68
66
64
62
60in
lb3040506070809010011012013014015016017018019020021022023062
4244464860
58
525456in
303234363840
lb304050607080
kg10152025303580859095100105110115120125130135140150155cm
150155160165170175180185190
kg101520253035105

58
525456in
455055606570758085909510012 13 14 15 16 17 18 19 20
AGE (YEARS)AGE (YEARS)
Father’s height
Mother ’s height
4095
90
75
50
25
10
5
95
90
75
50
25
10
5160cm 11 345 6789 1 0
145DateMother ’s Stature Father ’s Stature
Age Weight Stature BMI*
50

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 751
TABLE 17-5 IAbnormal Growth Patterns in Infancy and Childhood (Continued)
Constitutional Delay of Puberty
Slowing growth from 3–10 yrs, delayed puberty, and normal ﬁnal adult height.2 to 20 years: Boys
RECORD #
E
I
G
H
T
W
E
I
G
H
TS
T
A
T
U
R
E
T
A
T
U
R
E7476
72
70
68
66
64
62
60in
58
525456in

58
525456in
4095
90
75
50
25
10
5
95
90
75
50
25
10
50

752 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Acquired Growth Hormone Deﬁciency
Profound deceleration in linear growth is noted, here starting at age 8 yrs.2 to 20 years: Boys
RECORD #
E
I
G
H
T
W
E
I
G
H
TS
T
A
T
U
R
E
T
A
T
U
R
E7476
72
70
68
66
64
62
60in
58
525456in

58
525456in
4095
90
75
50
25
10
5
95
90
75
50
25
10
50

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 753
Acute Weight Loss Due to Illness at 2 Months
The weight was regained rapidly, and there was no loss of height.

754 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Failure to Thrive
Beginning at 6 mos, the weight dropped off before the height. Intervention occurred at 12 mos.
Onset Major
Intervention

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 755
Exogenous Obesity
Note that in this child, obesity started by 5 yrs. The child is also tall and enters puberty at an early age.

756 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Hydrocephalus
Head circumference of a child with communicating hydrocephalus. A ventriculo-peritoneal shunt was placed at 6 mos of age; it
became nonfunctional at 15 mos and was revised.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 757
Craniosynostosis
Premature closure of one or more sutures causes microcephaly, deceleration of head growth, and abnormal head shape. Surgical
repair occurred at 4 mos in this child.

758 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Supraventricular Tachycardia
Paroxysmal supraventricular tachycardia (SVT) is the most common dysrhythmia in children. Some infants with SVT look quite
well or may be somewhat pale with tachypnea, but have a heart rate of 240 beats per min or greater. Others are quite ill and incardiovascular collapse.
SVT in infants is usually sustained, requiring medical therapy for conversion to a normal rate and rhythm. In older children, i t is
more likely to be truly paroxysmal, with episodes of varying duration and frequency.QRS T

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 759
Hypertension in Childhood
Hypertension can start in childhood. While young children with elevated blood pressure are more likely to have a renal, cardiac , or
endocrine cause, adolescents with hypertension are most likely to have primary or essential hypertension.
This child developed hypertension during adolescence, and it “tracked” into adulthood. Children tend to remain in the same
percentile for blood pressure as they grow. This tracking of blood pressure continues into adulthood, supporting the concept th at
adult essential hypertension begins during childhood.
The consequences of untreated hypertension can be severe.90
0123456789
AgeGirls Systolic Blood Pressure 95%ile
10 11 12 13 14 15 16 17120Systolic Blood Pressure
95100105110115125130135140
90

90
AgeBoys Systolic Blood Pressure 95%ile
Systolic 5%10 11 12 13 14 15 16 17120150Systolic Blood Pressure
95100105110115125130135140145
Systolic 50% Systolic 95% Patient

TABLE 17-6 IBenign Birthmarks 
760 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 17-6 IBenign Birthmarks Versus Pathologic Neurocutaneous Syndromes
When you detect a birthmark on a newborn or infant, you will need to differentiate common, benign birthmarks from
uncommon but neurologically significant neurocutaneous syndromes. Use these photographs to help you make thisdistinction.
Benign Birthmarks
Café-au-lait spots
These light-brown pigmented
lesions usually have raggedborders and are uniform. Theyare noted in more than 10% ofblack infants.
Salmon Patch
Also called “stork bite,” thissplotchy pink mark fadeswith age.Eyelid Patch
This birthmark fades,usually in the ﬁrst year.
Mongolian Spots
These are more common
among dark-skinned babies. Itis important to note them sothat they are not mistaken forbruises.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 761Neurocutaneous Syndromes
Tuberous Sclerosis
Findings in young children include adenoma sebaceum as shown
here (angioﬁbromas surrounding sweat glands). Older children mayhave oval, depigmented ash-leaf spots (not shown).
Neuroﬁbromatosis
Characteristic features include more than 5 café-au-lait spots and axillary freckling, both
shown above. Later ﬁndings include neuroﬁbromas and Lish nodules (not shown).
(Sources of photos: Café-au-lait Spots, Salmon Patch, Eyelid Patch, Mongolian Spots —Fletcher M: Physical Diagnosis in Neonatology, Philadelphia, Lippincott-Raven Publishers, 1998;
Neuroﬁbromatosis —Goodheart H: A Photoguide of Common Skin Disorders, Baltimore, Williams & Wilkins, 1999; Tuberous Sclerosis —Hall J: Sauer’s Manual of Skin Diseases, 8th ed.,
Philadelphia, Lippincott Williams & Wilkins, 2000.)

TABLE 17-7 ICommon Skin Rashes and Skin Findings in Newborns 
762 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 17-7 ICommon Skin Rashes and Skin Findings in Newborns and Infants
Newborns
Jaundice
More than half of newborns have
jaundice. This is best noted bypressing your ﬁnger or a glass slideagainst the skin.Neonatal Acne
Red pustules and papules are mostprominent over the cheeks and nose ofsome normal newborns.Erythema Toxicum
These yellow or white pustules are surrounded by a red baseand are commonly noted in normal newborns.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 763Infants
Seborrhea
The salmon red, scaly eruption often
involves the face, neck, axilla, diaperarea, and behind the ears.
Candidal Diaper Dermatitis
This bright red rash involves the intertriginous folds, with small
“satellite lesions” along the edges.
Contact Diaper Dermatitis
This irritant rash is secondary to
diarrhea or irritation and is noted alongcontact areas (here, the area touchingthe diaper).
(Sources of photos: Erythema Toxicum, Candidal Diaper Dermatitis —Fletcher M: Physical Diagnosis in Neonatology, Philadelphia, Lippincott-Raven Publishers, 1998; Neonatal Acne,
Seborrhea, Contact Diaper Dermatitis —Goodheart H: A Photoguide of Common Skin Disorders, Baltimore, Williams & Wilkins, 1999.)

TABLE 17-8 IWarts, Lesions that Resemble Warts
764 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 17-8 IWarts, Lesions that Resemble Warts, and Other Raised Lesions
Warts are commonly found in children. Since they often appear on the ﬁngers or the hands and on the soles of the feet,
you will need to examine the skin of children carefully.
Warts and Lesions that May Resemble Warts
Verruca Vulgaris
Dry, rough warts on hands
Molluscum Contagiosum
Dome-shaped, ﬂeshy lesionsVerruca Plana
Small, ﬂat warts
Plantar Warts
Tender warts on feet
Adolescent Acne
You will frequently note acne in adolescents. Differentiate between open comedones
(blackheads) and closed comedones (whiteheads) shown at the left, and inﬂamedpustules (right).Other Raised Lesions in Children
(Source of photos: Goodheart H: A Photoguide of Common Skin Disorders, Baltimore, Williams & Wilkins, 1999.)

TABLE 17-9 ICommon Skin Lesions During Childhood
CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 765
This table shows examples of common lesions of the skin, scalp, and hair of children. While these lesions are relatively
mild, all will respond to appropriate treatment.
Urticaria (hives)
This pruritic, allergic sensitivity reaction changes shape quickly.
Tinea Capitis
Scaling, crusting, and hair loss are seenin the scalp, along with a painfulplaque (kerion) and occipital lymphnode (arrow).Atopic Dermatitis (eczema)
Erythema, scaling, dry skin, and intense itching characterize this condition in children.
Tinea Corporis
This annular lesion has central clearing
and papules along the border.
(Source of all photos except Urticaria: Goodheart H: A Photoguide of Common Skin Disorders, Baltimore, Williams & Wilkins, 1999.)Insect Bites
Intensely pruritic, red, distinct papules
characterize these lesions.

TABLE 17-10 ICyanosis in Children
766 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
It is important for you to be able to recognize cyanosis. The best location to examine is the mucous membranes. Cyanosis
is a “raspberry” color, while normal mucous membranes should have a “strawberry color.” Try to identify the cyanosisin these photographs before reading the captions.
Generalized Cyanosis
This baby had total anomalouspulmonary venous return and anoxygen saturation level of 80%.
Bluish Lips, Giving 
Appearance of Cyanosis
Normal pigment deposition in the
vermilion border of the lips givesthem a bluish hue, but the mucousmembranes are pink.Perioral Cyanosis
This baby has mild cyanosis abovethe lips, but the mucous membranesremain pink.
Acrocyanosis 
This commonly appears on the feet
and hands of babies shortly afterbirth. This infant is a 32-weeknewborn.

(Source of photos: Fletcher M: Physical Diagnosis in Neonatology, Philadelphia, Lippincott-Raven Publishers, 1998.)

TABLE 17-11 IAbnormalities of the Head
CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 767
Cephalohematoma
Although not present at birth,
cephalohematomas appear within the ﬁrst 24 hours and are due to subperiostealhemorrhage involving the outer table of one ofthe cranial bones. The swelling, as above, doesnot extend across a suture, though it isoccasionally bilateral following a difﬁcultdelivery. The swelling is initially soft, thendevelops a raised bony margin within a few daysdue to calcium deposits at the edge of theperiosteum, and tends to resolve within severalweeks.Craniosynostosis is a condition of premature closure of one or more

sutures of the skull. This results in an abnormal growth and shape ofthe skull since growth will occur across sutures that are not affectedbut not across sutures that are affected. The ﬁgures above demon-strate different skull shapes associated with the various types ofcraniosynostosis. Scaphocephaly and frontal plagiocephaly are themore common types. The blue shading shows areas of maximalﬂattening. The red arrows show the direction of continued growthacross the sutures, which is normal.
In hydrocephaly, the anterior fontanelleis bulging and the eyes may be deviateddownward, revealing the upper sclerasand creating the “setting sun” sign, as
shown in the ﬁgure above. The settingsun sign is also seen brieﬂy in somenormal newborns. (From Zitelli, BJ &Davis, HW. [1997]. Atlas of PediatricPhysical Diagnosis, 3rd ed., St. Louis:Mosby–Year Book. Courtesy of Dr. Albert Briglan, Children’s Hospitalof Pittsburgh.)
Trigonocephaly
(metopic)Brachycephaly

(coronal, metopic)Frontal plagiocephaly
(unilateral coronal)
Occipital plagiocephaly
(unilateral lambdoid)Scaphocephaly
(sagittal)Anterior
NormalPosterior

TABLE 17-12 IDiagnostic Facies in Infancy and Childhood
768 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Babies born to women who are
chronic alcoholics are at increasedrisk for growth deﬁciency, micro-cephaly, and mental retardation.Facial characteristics shown hereinclude short palpebral ﬁssures, a wide and ﬂattened philtrum (the vertical groove in the midlineof the upper lip), and thin lips.In utero infection by Treponema
pallidum usually occurs after the
16th week of gestation and affectsvirtually all fetal organs. If it is nottreated, 25% of infected babies willdie before birth and another 30%shortly thereafter. Signs of illnessappear in survivors within the ﬁrstmonth of life. Facial stigmata shownhere include bulging of the frontalbones and nasal bridge depression(saddle nose ), both due to periostitis;
rhinitis from weeping nasal mucosallesions ( snufﬂes ); and a circumoral

rash. Mucocutaneous inﬂammationand ﬁssuring of the mouth and lips(rhagades ), not shown here, may also
occur as stigmata of congenitalsyphilis, as may craniotabes tibialperiostitis ( saber shins ) and dental
dysplasia ( Hutchinson’s teeth —
see p. 205).Peripheral (lower motor neuron)
paralysis of the facial nerve may bedue to (1) an injury to the nervefrom pressure during labor anddelivery, (2) inﬂammation of themiddle ear branch of the nerveduring episodes of acute or chronicotitis media, or (3) unknown causes(Bell’s palsy). See p. 612 and p. 613.The nasolabial fold on the affectedleft side is ﬂattened and the eye doesnot close. This is accentuated duringcrying, as shown here. Full recoveryoccurs in ≥90% of those affected,
usually within a few weeks.Fetal Alcohol Syndrome Congenital Syphilis Congenital Hypothyroidism Facial Nerve Palsy
The child with congenital hypo-

thyroidism (cretinism) has coarsefacial features, a low-set hair line,sparse eyebrows, and an enlargedtongue. Associated features include ahoarse cry, umbilical hernia, dry andcold extremities, myxedema, mottledskin, and mental retardation. It isimportant to note that the majorityof infants with congenital hypo-thyroidism have no physical stigmata;this has led to screening of allnewborns in the United States and inmost other developed countries, fordepressed thyroxin or elevatedthyroid-stimulating hormone levels.

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 769The child with Down syndrome
(trisomy 21) usually has a small,rounded head, a ﬂattened nasalbridge, oblique palpebral ﬁssures,prominent epicanthal folds, small,low-set, shell-like ears, and arelatively large tongue. Associatedfeatures include generalizedhypotonia, transverse palmar creases(simian lines ), shortening and
incurving of the 5th ﬁngers(clinodactyly ), Brushﬁeld’s spots 
(see p. 771), and mental retardation.The child who has been physically
abused (battered) may have old and

fresh bruises about the head and faceand may either look sad and forlornor be actively seeking to please,sometimes even particularly involvedwith and attentive to the abusingparent. Other stigmata include:bruises in areas (axilla and groin) notusually subject to injury rather thanthe bony prominences, x-rayevidence of fractures of the skull,ribs, and long bones in various stagesof healing, and skin lesions that aremorphologically similar toimplements used to inﬂict trauma(hand, belt buckle, strap, rope, coathanger, or lighted cigarette).Thyrotoxicosis ( Graves’ disease )

occurs in approximately 2 per 1,000 children under the age of 10 years. Affected children exhibithypermetabolism and acceleratedlinear growth. Facial characteristicsshown in this 6-year-old girl are “staring” eyes (not trueexophthalmos, which is rare inchildren) and an enlarged thyroidgland ( goiter ). See p. 208.Down Syndrome Battered-Child Syndrome Perennial Allergic Rhinitis Hyperthyroidism
The child suffering from perennial
allergic rhinitis has an open mouth(cannot breathe through the nose)and edema and discoloration of thelower orbitopalpebral grooves(“allergic shiners”). Such a child isoften seen to push the nose upwardand backward with a hand (“allergicsalute”) and to grimace (wrinkle thenose and mouth) to relieve nasalitching and obstruction. (Photographreproduced with permission fromMarks MB: Allergic shiners: Darkcircles under the eyes in children.Clin Pediatr 5:656, 1966)

TABLE 17-13 IAbnormalities of the Neck
770 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Lymphadenopathy
Enlarged and tender cervical lymph
nodes are common in children. Themost likely causes are viral and bacterialinfections. Lymph node enlargementcan be bilateral, as shown above.Lymphadenitis and Abscess
An infected cervical lymph node may turn into anabscess, with ﬂuctuance.
(Source of photo for: Lymphadenitis and Abscess —Fleisher G, Ludwig S: Textbook of Pediatric Emergency Medicine, 4th ed. Philadelphia, Lippincott Williams & Wilkins, 2000.)

TABLE 17-14 IAbnormalities of the Eyes and Ears
CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 771
Brushﬁeld’s Spots
These abnormal speckling spots on the
iris suggest Down syndrome.Strabismus
Strabismus, or misalignment of the eyes, can leadto visual impairment. Esotropia, shown here, isan inward deviation.Eye Abnormalities
Otitis Media
Otitis media is one of the most common conditions in young children. The spectrum of otitis media is shown here. (A)Typical acute otitis media with a red, distorted,
bulging tympanic membrane in a highly symptomatic child. (B)Acute otitis media with bullae formation and ﬂuid visible behind the tympanic membrane. (C)Otitis
media with effusion, showing a yellowish ﬂuid behind a retracted and thickened tympanic membrane.
Source of photos: Estropia —Fleisher G, Ludwig S: Textbook of Pediatric Emergency Medicine, 4th ed., Philadelphia, Lippincott Williams & Wilkins, 2000; Otitis Media —Courtesy of

Alejandro Hoberman, Children’s Hospital of Pittsburgh, University of Pittsburgh.
Ear Abnormalities
A B C

TABLE 17-15 IAbnormalities of the Mouth and Teeth
772 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Streptococcal Pharyngitis (“strep throat”)
This common childhood infection has a classic presentation of erythema of the
posterior pharynx and palatal petechiae (left). A foul-smelling exudate (right) isalso commonly noted.Oral Candidiasis (“thrush”)
This infection is common in infants.The white plaques do not rub off.Mouth Abnormalities
Dental Caries
Dental caries is a major public
health and pediatric problemthroughout the world. The photo-graphs on the left show differentcharacteristics of caries. (A)Early
nursing-bottle caries with dis-coloration on the inside of theupper incisors. (B)Erosion of
several teeth. (C)Severe erosion
and abscess formation.
Photos courtesy of American Academy of Pediatrics.Dental AbnormalitiesHerpetic Stomatitis
Tender ulcerations on the oral
mucosa are surrounded by erythema.
Staining of the Teeth

The teeth of children can become stained from a variety ofcauses, including intrinsic stains such as tetracycline (right)or extrinsic stains such as poor oral hygiene (not shown).Extrinsic stains can be removed.A B C

TABLE 17-16 IPathologic Findings: Heart Murmurs
CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 773
TABLE 17-16 IPathologic Findings of Some Common Congenital Cardiac Defects: Heart Murmurs
Congenital Defect Mechanism Characteristics of the Murmur Associated Findings
Pulmonary Valve Stenosis
Mild
ModerateSevereAortic Valve StenosisS1 A2
P2
S1 A2
P2
S1 A2
P2
S1 A2
P2Usually a normal valve anulus
with fusion of some or most ofthe valve leaﬂets, restrictingﬂow across the valve
Usually a bicuspid valve with
progressive obstruction, butthere may be a dysplastic valveor damage from rheumaticfever or degenerative disease.Usually a prominent ejection click in early
systole
The pulmonary component of the second
sounds at the base (P
2) becomes delayed and
softer, disappearing as obstruction increases.Inspiration may increase the murmur andexpiration may increase the click.
Growth is usually normal.Newborns with severe stenosis may be

cyanotic from right-to-left shunting at atriallevel and rapidly develop congestive heartfailure.
May be an associated ejection click
The aortic closure sound may be increased
in intensity. There may be a diastolicmurmur of aortic valve regurgitation.Children and adolescents are seldomsymptomatic, but newborns with severestenosis may have weak or absent pulsesand severe congestive heart failure. Unlessheart failure, growth is normal. May not beaudible until adulthood even though thevalve is congenitally abnormalLocation. Upper left sternal border
Radiation. In mild degrees of stenosis,
the murmur may be heard over thecourse of the pulmonary arteries in thelung ﬁelds.
Intensity. Increases in intensity and
duration as the degree of obstructionincreases
Quality. Ejection, peaking later in

systole as the obstruction increases
Location. Midsternum, upper right
sternal border
Radiation. To the carotid arteries and
suprasternal notch; may also be a thrill
Intensity. Varies, louder with
increasingly severe obstruction
Quality. An ejection, often harsh,
systolic murmurSome heart murmurs reﬂect underlying heart disease. If you understand the phys-

iologic causes for these heart murmurs, you will more readily be able to identifythem and distinguish them from innocent heart murmurs. Obstructive lesions arecaused by normal blood ﬂow through valves that are too small for normal ﬂow.Since this problem is not dependent on the drop in pulmonary vascular resistancethat occurs following birth, these murmurs are audible at birth. Defects with left-to-right shunts, on the other hand, are dependent on the drop in pulmonary vas-cular resistance and are, therefore, not heard until a week or more after birth inthe case of high-pressured shunts such as ventricular septal defect, patent ductus

arteriosus, and persistent truncus arteriosus. Low-pressured left-to-right shunts,such as in atrial septal defects, may not be heard for a considerably longer time,usually ﬁrst being noted at a year or more of age. It is important to note that manychildren with congenital cardiac defects have combinations of defects or varia-tions of abnormalities, so that findings on cardiac examination will not followthese classic patterns. This table shows a limited selection of the more commondefects.

774 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
TABLE 17-16 IPathologic Findings of Some Common Congenital Cardiac Defects: 
Heart Murmurs (Continued)
Complex defect with ventricular
septal defect, infundibular andusually valvular right ventricularoutﬂow obstruction, mal-rotation of the aorta, and right-to-left shunting at ventricularseptal level.
A severe defect with failure of
rotation of the great vessels,leaving the aorta to arise fromthe right ventricle and thepulmonary artery from the leftventricle
Blood going from a high-
pressured left ventricle througha defect in the septum to thelower-pressured right ventriclecreates turbulence, usuallythroughout systole.Normal pulses
The pulmonary closure sound is usually 
not heard. May have abrupt hypercyanoticspells with sudden increase in cyanosis, air hunger, altered level of awareness
Failure to gain weight with persistent and
increasingly severe cyanosis

Long-term persistence of cyanosis accom-
panied by clubbing of ﬁngers and toes
Persistent hypoxemia leads to polycythemia,
which will accentuate the cyanosis.
Single loud second sound of the anterior 
aortic valve
Frequent rapid development of congestive 
Frequent associated defects as described at
the left
With large shunts, there may be a low-
pitched middiastolic murmur of relativemitral stenosis at the apex.
As pulmonary artery pressure increases, the
pulmonic component of the second soundsat the base increases in intensity. Whenpulmonary artery pressure equals aorticpressure, there may be no murmur, and P
2will be very loud.
In low-volume shunts, growth is normal. General. Variable cyanosis, increasing
with activity
Location. Mid-to-upper left sternal

border. If pulmonary atresia, there isno systolic murmur but the continuousmurmur of ductus arteriosus ﬂow atupper left sternal border or in the back.
Radiation. Little, to upper left sternal
border, occasionally to lung ﬁelds
Intensity. Usually Grade III-IV
Quality. Midpeaking, systolic ejection
murmur
General. Intense generalized cyanosis
Location. No characteristic murmur. If
a murmur is present, it may reﬂect anassociated defect such as VSD orpatent ductus arteriosus.
Radiation. Depends on associated
abnormalities
Quality. Depends on associated
Intensity. Variable, only partially deter-

mined by the size of the shunt. Smallshunts with a high pressure gradientmay have very loud murmurs. Largedefects with elevated pulmonaryvascular resistance may have no murmur. Grade II-IV/VI with a thrillif Grade IV/VI or higher.Tetralogy of Fallot
With pulmonic stenosis
With pulmonic atresia
Transposition of the Great Arteries
Ventricular Septal Defect
Small to moderateS1 A2 S1
S1 A2P2
Small to
moderateCongenital Defect Mechanism Characteristics of the Murmur Associated Findings

CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 775Continuous ﬂow from aorta to
pulmonary artery throughoutthe cardiac cycle when ductusarteriosus does not close after birth
Left-to-right shunt through an
opening in the atrial septum,possible at various levelsIn larger shunts, congestive heart failure
may occur by 6–8 weeks; poor weight gain. 
Associated defects are frequent.
Full to bounding pulses
Noticed at birth in the premature infant
who may have bounding pulses, ahyperdynamic precordium, and an atypicalmurmur
Noticed later in the full-term infant as
pulmonary vascular resistance falls
May develop congestive heart failure at 4 to
6 weeks if large shunt
Poor weight gain related to size of shuntPulmonary hypertension affects murmur 
as above.
Widely split second sounds throughout all
phases of respiration, normal intensity
Usually not heard until after age of 1 yearGradual decrease in weight gain as shunt
increases

as above.
increases
Decreased exercise tolerance, subtle, 
not dramatic
Congestive heart failure is rare.Quality. Pansystolic, usually harsh,
may obscure S
1and S 2if loud enough
Location. Upper left sternal border and
to left
Radiation. Sometimes to the back
Intensity. Varies depending on size of
the shunt, usually Grade II-III/VI.
Quality. A rather hollow, sometimes
machinerylike murmur that iscontinuous throughout the cardiaccycle, although occasionally almostinaudible in late diastole,uninterrupted by the heart sounds,louder in systole
Location. Upper left sternal border
Radiation. To the back
Intensity. Variable, usually 
Grade II-III/VI
Quality. Ejection but without the
harsh qualityPatent Ductus Arteriosus
Small to moderate
Atrial Septal DefectS1 S1 A2P2
S1 A2P2

TABLE 17-17 IThe Male Genitourinary System
776 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Hypospadius
Hypospadius is the most common congenital
penile abnormality. The urethral meatus opensabnormally on the ventral surface of the penis.One form is shown above; more severe formsinvolve openings on the lower shaft or scrotum.Undescended Testicle
You should distinguish between undescendedtestes, shown above (with testes in theinguinal canals), from highly retractile testesdue to an active cremasteric reﬂex.
Source of photos: Hypospadius —Courtesy of Warren Snodgrass, MD, UT–Southwestern Medical Center at Dallas; Undescended Testicle —Fletcher M: Physical Diagnosis in Neonatology,
Philadelphia, Lippincott-Raven Publishers, 1998.Torsion
In school-age and adolescent boys, two types of

torsion can occur: torsion of the testis and torsion ofthe appendix testis. In torsion of the testis, boys haveacute severe testicular pain. Examination shows aswollen, tender testis and an absent cremasteric reﬂex.In torsion of the appendix testis (not shown), there isalso acute pain, although generally not as sever aswith torsion of the testis. You may note a bluishdiscoloration (blue dot sign) at the infarctedappendage. In these cases, the cremasteric reﬂex is usually present

TABLE 17-18 IAbnormalities of the Female Genitourinary System
CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 777
Ambiguous Genitalia
Some rare conditions result in ambiguous genitalia. This is a
case of congenital adrenal hyperplasia.Labial Adhesions
Fusion of the labia minora can obscurepart or all of the vaginal oriﬁce.
Labial
adhesion

778 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Sexual Abuse
Since sexual abuse is all too common, you will need to recognize genital abnormalities associated with sexual abuse. These incl ude:
(A) Acute hemorrhage and ecchymoses of tissues (10-mo old)
(B) Erythema and superﬁcial abrasions to the labia minora (5-yr old)
(C) Healed interruption of hymenal membrane at 9 o’clock (4-yr old)
(D) Narrowed posterior ring continuous with ﬂoor of vagina (12-yr old)
(E) Copious vaginal discharge and erythema (9-yr old)
(F) Extensive condylomata around the anus (2-yr old)
(Sources of photos: Ambiguous Genitalia —McMillan J, DeAngelis C, Feigin R, Warshaw J: Oski’s Pediatrics, 3rd ed., Philadelphia, Lippincott Williams & Wilkins, 1999; Sexual
Abuse, (A), (B), (C), (D), (E), (F) —Reece R, Ludwig S (eds.): Child Abuse Medical Diagnosis and Management, 2nd ed., Philadelphia, Lippincott Williams & Wilkins, 2001.)

DEFPhysical Signs of Sexual Abuse in Girls
AB C
TABLE 17-18 IAbnormalities of the Female Genitourinary System (Continued)

TABLE 17-19 IAbnormalities of the Musculoskeletal and Nervous Systems
CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 779
Orthopedic Abnormalities in Children
Scoliosis
Idiopathic scoliosis occurs most often in
adolescent girls. The rotation of the spineusually results in a right-sided prominence.
Bowing of Knees from Rickets
Severe bowing of the knees may be due to rickets.
Other clinical signs are usually present in thiscondition.
Syndactyly
A number of conditions occur involving congenital
failure of differentiation, such as synostosis of themiddle and ring ﬁngers shown here. (From: McMillan J,DeAngelis C, Feigin R, Warshaw J: Oski’s Pediatrics,3rd ed., Philadelphia, Lippincott Williams & Wilkins,1999.)

780 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
The Gower Maneuver
Certain forms of muscular dystrophy involve weakness of the
pelvic girdle muscles. Children with this disease rise from asupine to a standing position in a characteristic manner, byrolling over to a prone position, pushing off the ﬂoor withthe arms, bringing the legs to a ﬂexed position under thetrunk, and extending the legs with help of the hands.Neurologic Abnormalities in Children
TABLE 17-19 IAbnormalities of the Musculoskeletal and Nervous Systems (Continued)

TABLE 17-20 IThe Power of Prevention: Vaccine-Preventable Diseases
CHAPTER 17 IASSESSING CHILDREN: INFANCY THROUGH ADOLESCENCE 781
This table shows photographs of children with vaccine-preventable diseases.
Childhood vaccines have been named the single most important medical inter-vention in the world from the standpoint of impact on public health. Because ofvaccinations, we hope you will never see many of these conditions, but you
should be able to identify them. Try to identify the diseases before reading thecaptions.
Diphtheria
This child has the characteristic
gray coating on the posteriorpharynx.Polio
The deformed leg of this child isdue to polio.
Tetanus
Rigid newborn with neonatal tetanus
Measles 
Characteristic rash of measles

782 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING
Mumps
Submandibular
lymphadenopathy, extensiveedema and erythema frommumps.Haemophilus inﬂuenzae
type b
Periorbital cellulitis due to this
invasive bacterial diseaseVaricella
An infant with a severe form of varicella
Rubella
Infant born with congenital
rubella syndrome
(Sources of photos: Polio courtesy of World Health Organization; Haemophilus inﬂuenzae, courtesy of American Academy of Pediatrics; Varicella, courtesy of Barbara Watson, MD,
Albert Einstein Medical Center and Division of Disease Control, Philadelphia Department of Health; all others courtesy of Cente rs for Disease Control and Prevention.)
TABLE 17-20 IThe Power of Prevention: Vaccine-Preventable Diseases (Continued)

Clinical Reasoning,
Assessment, and PlanCHAPTER
Clinical Reasoning,Assessment, and Plan1818
CHAPTER 18 ICLINICAL REASONING, ASSESSMENT, AND PLAN 783Now that you have gained your patient’s trust, gathered a detailed history,
and completed the requisite portions of the physical examination, you havereached the critical step of formulating your Assessment(s) and Plan. It is
your task to analyze your ﬁndings and identify the patient’s problems. Fur-thermore, you must share your impressions with the patient, eliciting anyconcerns and making sure that he or she understands and agrees to the stepsahead. Finally, you must document your ﬁndings in the patient’s record ina succinct and legible format. A clear and well-organized record is essentialfor communicating the patient’s story and your clinical reasoning and planto other members of the health care team.
The comprehensive data you have collected, both subjective (the history, or

what the patient or family have told you) and objective (the physical exami-
nation and laboratory tests), make up the core elements of your patient’sdatabase. This information is primarily factual and descriptive. As you moveto Assessment, you go beyond description and observation to analysis and in-
terpretation. You select and cluster relevant pieces of information, analyzetheir possible meanings, and try to explain them logically using principles ofbiopsychosocial and biomedical science. The Assessment and Plan include
the patient’s responses to the problems identiﬁed and to your diagnostic andtherapeutic plans. A successful Plan requires good interpersonal skills and
sensitivity to the patient’s goals, economic means, competing responsibili-ties, and family structure and dynamics.
In this chapter, we describe the process of clinical reasoning and illustrate

the written Assessment andPlan using the case of Mrs. N from Chapter 1,
pp. 14–18. A series of guidelines outline principles for developing an accu-rate, clear, and logical patient record. A well-organized record facilitates clin-ical thinking, promotes communication and coordination among the manyprofessionals caring for your patient, and documents that patient’s problemsand management for medicolegal purposes. There is also a section describ-ing quantitative tools such as sensitivity and speciﬁcity to help strengthenyour skills of clinical reasoning.
Assessment and Plan: 
The Process of Clinical Reasoning
Generating Your Assessment. Because assessment takes place in the
clinician’s mind, the process of clinical reasoning often seems inaccessible

and even mysterious to the beginning student. Experienced clinicians often
think quickly, with little overt or conscious effort. They differ widely in per-sonal style, communication skills, clinical training, experience, and interests.Some clinicians may ﬁnd it difﬁcult to explain the logic behind their clinicalthinking. As an active learner, it is expected that you will ask teachers andclinicians to elaborate on the ﬁne points of their clinical reasoning and deci-sion making.
As you gain experience, your thinking process will begin at the outset of the

patient encounter, not at the end. Listed below are a set of principles thatunderlie the process of clinical reasoning and certain explicit steps to helpguide your thinking as you analyze the information you have compiled. Afterreading through this section, review the case of Mrs. N, introduced in Chap-ter 1, and use this as a sample database to practice the process of clinical rea-soning and assessment. As with all patients, focus on ﬁnding answers to thequestions “What is wrong with this patient?” “What are the problems anddiagnoses?” To reach these answers, try following the steps discussed below.Then turn to the Assessment and Plan for Mrs. N on pp. 14–18 and com-
pare them to your own insights and clinical thinking.CLINICAL REASONING, ASSESSMENT, AND PLAN
784 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGIDENTIFYING PROBLEMS AND MAKING DIAGNOSES: 
STEPS IN CLINICAL REASONING

IIdentify abnormal ﬁndings
ILocalize ﬁndings anatomically
IInterpret ﬁndings in terms of probable process
IMake hypotheses about the nature of the patient’s problem
ITest the hypotheses and establish a working diagnosis
IDevelop a plan agreeable to the patient
IIdentify abnormal ﬁndings. Make a list of the patient’s symptoms, the
signs you observed during the physical examination, and any laboratory
reports that are available to you.
ILocalize these findings anatomically. This step may be easy. The

symptom of scratchy throat and the sign of an erythematous inflamedpharynx, for example, clearly localize the problem to the pharynx. ForMrs. N, the complaint of headache leads you quickly to the structuresof the skull and brain. Other symptoms, however, may present greaterdifficulty. Chest pain, for example, can originate in the coronary arter-ies, the stomach and esophagus, or the muscles and bones of the chest.If the pain is exertional and relieved by rest, either the heart or the mus-culoskeletal components of the chest wall may be involved. If the pa-tient notes pain only when carrying groceries with the left arm, themusculoskeletal system becomes the likely culprit. When localizing find-ings, be as specific as your data allow, but bear in mind that you mayhave to settle for a body region, such as the chest, or a body system, suchas the musculoskeletal system. On the other hand, you may be able to

define the exact structure involved, such as the left pectoral muscle.
Some symptoms and signs cannot be localized, such as fatigue or fever,but are useful in the next set of steps.
IInterpret the ﬁndings in terms of the probable process. Patient prob-
lems often stem from a pathologic process involving diseases of a body
structure. There are a number of such processes, variably classiﬁed, in-cluding congenital, inﬂammatory or infectious, immunologic, neoplastic,metabolic, nutritional, degenerative, vascular, traumatic, and toxic. Pos-sible pathologic causes of headache, for example, include concussion fromtrauma, subarachnoid hemorrhage, or even compression from a braintumor. Fever and stiff neck, or nuchal rigidity, are two of the classic signsof headache from meningitis. Even without other signs such as rash orpapilledema, they strongly suggest an infectious process.
Other problems are pathophysiologic, reﬂecting derangements of biologic

functions, such as congestive heart failure or migraine headache. Stillother problems are psychopathologic, such as disorders of mood like de-
pression or headache as an expression of a somatization disorder.
IMake hypotheses about the nature of the patient’s problem. Here you
will draw on all the knowledge and experience you can muster, and it ishere that reading will be most helpful in learning about patterns of ab-normalities and diseases, and clustering your patient’s ﬁndings accord-ingly. Until you gain broader knowledge and experience, you may not beable to develop highly speciﬁc hypotheses, but proceed as far as you canwith the data and knowledge you have. The following steps should help:
1.Select the most speciﬁc and critical ﬁndings to support your hypothesis. If

the patient reports “the worst headache of her life,” nausea, and vom-iting, for example, and you ﬁnd mental status change, papilledema,and meningismus, build your hypothesis around elevated intracranialpressure rather than gastrointestinal disorders. Although other symp-toms are useful diagnostically, they are much less speciﬁc.
2. Using your inferences about the structures and processes involved,
match your ﬁndings against all the conditions you know that can producethem. For example, you can match your patient’s papilledema with a
list of conditions affecting intracranial pressure. Or you can comparethe symptoms and signs associated with the patient’s headache with thevarious infectious, vascular, metabolic, or neoplastic conditions thatmight produce this kind of clinical picture.
3.Eliminate the diagnostic possibilities that fail to explain the ﬁndings. You

might consider cluster headache as a cause of Mrs. N’s headaches, buteliminate this hypothesis because it fails to explain the patient’s throb-bing bifrontal localization with intermittent nausea and vomiting.Also, the pain pattern is atypical for cluster headache—it is not unilat-eral, boring, occurring repetitively at the same time over a period ofdays, nor is it associated with lacrimation or rhinorrhea.CLINICAL REASONING, ASSESSMENT, AND PLAN
CHAPTER 18 ICLINICAL REASONING, ASSESSMENT, AND PLAN 785

4.Weigh the competing possibilities and select the most likely diagnosis from
among the conditions that might be responsible for the patient’s ﬁnd-ings. You are looking for a close match between the patient’s clinical pre-
sentation and a typical case of a given condition. Other clues help in thisselection, too. The statistical probability of a given disease in a patient
of this age, sex, ethnic group, habits, lifestyle, and locality should greatlyinfluence your selection. You should consider the possibilities of osteoarthritis and metastatic prostate cancer in a 70-year-old man withback pain, for example, but not in a 25-year-old woman with the samecomplaint. The timing of the patient’s illness also makes a difference.
Headache in the setting of fever, rash, and stiff neck that develops sud-denly over 24 hours suggests quite a different problem than recurrentheadache over a period of years associated with stress, visual scotoma,and nausea and vomiting relieved by rest.

5. Finally, as you develop possible explanations for the patient’s problem,
give special attention to potentially life-threatening and treatable con-ditions such as meningococcal meningitis, bacterial endocarditis, pul-
monary embolus, or subdural hematoma. Here you make every effortto minimize the risk of missing conditions that may occur less frequentlyor be less probable but that, if present, would be particularly ominous.One rule of thumb is always to include “the worst case scenario” in your listof differential diagnoses and make sure you have ruled out that possibil-
ity based on your ﬁndings and patient assessment.
ITest your hypotheses. Now that you have made a hypothesis about the
patient’s problem, you will usually want to test your hypothesis. You are

likely to need further history, additional maneuvers on physical exami-nation, or laboratory studies or x-rays to confirm or rule out your ten-tative diagnosis or to clarify which of two or three possible diagnoses aremost likely. When the diagnosis seems clear-cut—a simple upper respi-ratory infection or a case of hives, for example—these steps may not benecessary.
IEstablish a working diagnosis. You are now ready to establish a work-
ing definition of the problem. Make this at the highest level of explic-itness and certainty that the data allow. You may be limited to a symptom,

such as “tension headache, cause unknown.” At other times, you candefine a problem explicitly in terms of its structure, process, and cause.Examples include “bacterial meningitis, pneumococcal,” “subarach-noid hemorrhage, left temporoparietal lobe,” or “hypertensive cardio-vascular disease with left ventricular enlargement and congestive heartfailure.”
Although medical diagnosis is based primarily on identifying abnormal
structures, altered processes, and speciﬁc causes, you will frequently seepatients whose complaints do not fall neatly into these categories. Somesymptoms defy analysis, and you may never be able to move beyond sim-ple descriptive categories such as “fatigue” or “anorexia.” Other problemsrelate to the patient’s life, rather than to the body. Events such as losingCLINICAL REASONING, ASSESSMENT, AND PLAN

a job or loved one may increase the risk of subsequent illness. Identifying
these events and helping the patient develop coping strategies are just asimportant as managing a headache or a duodenal ulcer.
Another increasingly prominent item on problem lists is Health Mainte-
nance. Routinely listing this category helps you track several important
health concerns more effectively: immunizations, screening measures(e.g., mammograms, prostate examinations), instructions regarding nu-trition and breast or testicular self-examinations, recommendations aboutexercise or use of seat belts, and responses to important life events.
IDevelop a plan agreeable to the patient. You should identify and record
a Plan for each patient problem. Your Plan will ﬂow logically from the

problems or diagnoses you have identiﬁed and specify which steps areneeded next. These steps range from tests to conﬁrm or further evaluatea diagnosis, to consultations for subspecialty evaluation, to additions, dele-tions, or changes in medication, to arranging a family meeting. You willﬁnd that you will follow many of the same diagnoses over time; however,your Plan is often more ﬂuid, encompassing changes and modiﬁcations
that emerge from each patient visit. The Plan should make reference to
diagnosis, therapy, and patient education.
Before ﬁnalizing your Plan, it is important to share your assessment and

clinical thinking with the patient and seek out his or her opinions, con-cerns, and willingness to proceed with any further testing or evaluation.Remember that patients may need to hear the same information multipletimes and ways before they comprehend it. Your relationship with the pa-tient will be enhanced if the patient is an active participant in the plan ofcare.
The Case of Mrs. N: Assessment and Plan
As you study the Assessment and Plan for Mrs. N, think carefully about the

clarity and organization of the clinical record. When creating a record, youdo more than simply list the patient’s story and your physical ﬁndings. Youmust review and organize your data, evaluate the importance and relevanceof each item, and construct a clear, concise, yet comprehensive report. Atﬁrst, it will be challenging to clearly and logically organize your patient as-sessment. Let the patient’s story and symptoms serve as guides, examine theappropriate areas of the body, and apply the steps of clinical reasoning todeepen your knowledge, judgment, and clinical acumen.
Using Mrs. N’s record, begin to make a checklist of the features of a good

medical record. Later, compare your list with the checklist on pp. 796–798.The following questions may help: Are the data easy to follow, orderly, andpresented in a readable format? Is there sufﬁcient detail, both positive andnegative, to formulate an Assessment and Plan? Is there excess repetition ofinformation or redundancy? Is the tone professional, avoiding disapprovingor moralizing comments?
CLINICAL REASONING, ASSESSMENT, AND PLAN
CHAPTER 18 ICLINICAL REASONING, ASSESSMENT, AND PLAN 787

788 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGASSESSMENT AND PLAN FOR MRS. N
1.Migraine headaches. 54-year-old woman with migraine headaches since
childhood, with a throbbing vascular pattern and frequent nausea and vomiting.Headaches are associated with stress and relieved by sleep and cold compresses.There is no papilledema, and there are no motor or sensory deﬁcits on theneurologic examination. The differential diagnosis includes tension headache,also associated with stress, but there is no relief with massage, and the pain ismore throbbing than aching. There are no fever, stiff neck, or focal ﬁndings tosuggest meningitis, and lifelong recurrent pattern makes subarachnoid
hemor rhage unlikely (usually described as “the worst headache of my life”).
Plan:
IDiscuss features of migraine vs. tension headaches.
IDiscuss biofeedback and stress management.
IAdvise patient to avoid caffeine, including coffee, colas, and other carbon-

Plan:
ated beverages.
IStart NSAIDs for headache, as needed.
IIf needed next visit, begin prophylactic medication, because patient is hav-ing more than three migraines per month.
2.Elevated blood pressure. Systolic hypertension with wide cuff is present.
May be related to obesity, also to anxiety from ﬁrst visit. No evidence of end-organ damage to retina or heart.
Plan:
IDiscuss standards for assessing blood pressure.
IRecheck blood pressure in 1 month, using wide cuff.
IReview urinalysis.
IIntroduce weight reduction and/or exercise programs (see #4).
IReduce salt intake.
3.Cystocele with occasional stress incontinence. Cystocele on pelvic ex-

amination, probably related to bladder relaxation. Patient is perimenopausal.Incontinence reported with coughing, suggesting alteration in bladder neckanatomy. No dysuria, fever, ﬂank pain. Not on any contributing medications.Usually involves small amounts of urine, no dribbling, so doubt urge or over-ﬂow incontinence.
Plan:
IExplain cause of stress incontinence.
IRecommend Kegel’s exercises.
IConsider topical estrogen cream to vagina next visit if no improvement.
4.Overweight. Patient 5 ′2″, weighs 143 lbs. BMI is ∼26.
Plan:
IExplore diet history, ask patient to keep food intake diary.
IExplore motivation to lose weight, set target for weight loss by next visit.
ISchedule visit with dietician.
IDiscuss exercise program, speciﬁcally, walking 30 minutes at least three
times a week.

5.Family stress. Son-in-law with alcohol problem; daughter and grandchildren
seeking refuge in patient’s apartment, leading to tensions in these relation-ships. Patient also has ﬁnancial constraints. Stress currently situational. No evi-dence of major depression at present.

Approaching the Challenges of Clinical Data
As you can see from the case of Mrs. N, organizing the patient’s clinical data
poses several challenges. The beginning student must decide whether tocluster the patient’s symptoms and signs into one problem or into severalproblems. The amount of data may appear unmanageable. The quality ofthe data may be prone to error. Guidelines to help you address these chal-lenges are provided in the following paragraphs.
Clustering Data Into Single Versus Multiple Problems. One of
the greatest difﬁculties facing students is how to cluster the clinical data. Doselected data ﬁt into one problem or several problems? The patient’s agemay
help—young people are more likely to have a single disease, while older peo-ple tend to have multiple diseases. The timing of symptoms is often useful.

For example, an episode of pharyngitis 6 weeks ago is probably unrelated tofever, chills, pleuritic chest pain, and cough that prompt an ofﬁce visit today.To use timing effectively, you need to know the natural history of various
CHAPTER 18 ICLINICAL REASONING, ASSESSMENT, AND PLAN 789Plan:
IExplore patient’s views on strategies to cope with sources of stress.
IExplore sources of support, including Al-Anon for daughter and ﬁnancial
counseling for patient.
IContinue to monitor for depression.
6.Occasional musculoskeletal low back pain. Usually with prolonged
standing. No history of trauma or motor vehicle accident. Pain does not radiate;no tenderness or motor-sensory deﬁcits on examination. Doubt disc or nerveroot compression, trochanteric bursitis, sacroiliitis.
Plan:

Plan:
IReview beneﬁts of weight loss and exercises to strengthen low back muscles.
7.Tobacco abuse. 1 pack per day for 36 years.
Plan:
ICheck peak ﬂow or FEV 1/FVC on ofﬁce spirometry.
IGive strong warning to stop smoking.
IOffer referral to tobacco cessation program.
IOffer patch, current treatment to enhance abstinence.
8.Varicose veins, lower extremities. No complaints currently.
9.History of right pyelonephritis, 1982.
10.Ampicillin allergy. Developed rash but no other allergic reaction.
11.Health maintenance. Last Pap smear 1998; has never had a mammogram.
Plan:
ITeach patient breast self-examination; schedule mammogram.
ISchedule Pap smear next visit.
IProvide three stool guaiac cards; next visit discuss screening flexible 
sigmoidoscopy.
ISuggest dental care for mild gingivitis.
IAdvise patient to move medications and caustic cleaning agents to lockedcabinet, if possible, above shoulder height.

diseases and conditions. A yellow penile discharge followed 3 weeks later by
a painless penile ulcer suggests two problems: gonorrhea and primarysyphilis. In contrast, a penile ulcer followed in 6 weeks by a maculopapularskin rash and generalized lymphadenopathy suggest two stages of the sameproblem: primary and secondary syphilis.
Involvement of different body systems may help you to cluster the clinical data.

If symptoms and signs occur in a single system, one disease may explain them.Problems in different, apparently unrelated systems often require more thanone explanation. Again, knowledge of disease patterns is necessary. You mightdecide, for example, to group a patient’s high blood pressure and sustained api-cal impulse together with ﬂame-shaped retinal hemorrhages, place them in thecardiovascular system, and label the constellation “hypertensive cardiovasculardisease with hypertensive retinopathy.” You would develop another explana-tion for the patient’s mild fever, left lower quadrant tenderness, and diarrhea.
Some diseases involve more than one body system. As you gain knowledge
and experience, you will become increasingly adept at recognizing multi-
system conditions and building plausible explanations that link together their

seemingly unrelated manifestations. To explain cough, hemoptysis, andweight loss in a 60-year-old plumber who has smoked cigarettes for 40 years,you probably even now would rank lung cancer high in your differential di-agnosis. You might support your diagnosis with your observation of the pa-tient’s clubbed ﬁngernails. With experience and continued reading, you willrecognize that his other symptoms and signs can be linked to the same di-agnosis. Dysphagia would reﬂect extension of the cancer to the esophagus,pupillary asymmetry would suggest pressure on the cervical sympatheticchain, and jaundice could result from metastases to the liver.
In another case of multisystem disease, a young man who presents with

odynophagia, fever, weight loss, purplish skin lesions, leukoplakia, general-ized lymphadenopathy, and chronic diarrhea is likely to have AIDS. Relatedrisk factors should be explored promptly.
Sifting Through an Extensive Array of Data. It is common to con-
front a relatively long list of symptoms and signs, and an equally long list ofpotential explanations. One approach is to tease out separate clusters of ob-
servations and analyze one cluster at a time, as just described. You can also
ask a series of key questions that may steer your thinking in one direction and

allow you to temporarily ignore the others. For example, you may ask whatproduces and relieves the patient’s chest pain. If the answer is exercise andrest, you can focus on the cardiovascular and musculoskeletal systems and setthe gastrointestinal system aside. If the pain is substernal, burning, andoccurs only after meals, you can logically focus on the gastrointestinal tract.A series of discriminating questions helps you form a decision tree or algo-rithm that is helpful in collecting and analyzing clinical data and reachinglogical conclusions and explanations.
Assessing the Quality of the Data. Almost all clinical information is
subject to error. Patients forget to mention symptoms, confuse the eventsCLINICAL REASONING, ASSESSMENT, AND PLAN
790 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING

of their illness, avoid recounting facts that are embarrassing, and often slant
their stories to what the clinician wants to hear. Clinicians misinterpret pa-tient statements, overlook information, fail to ask “the one key question,”jump prematurely to conclusions and diagnoses, or forget an important partof the examination, such as the testicular examination in a young man withasymptomatic testicular carcinoma. You can avoid some of these errors byacquiring the habits of skilled clinicians, summarized below.CLINICAL REASONING, ASSESSMENT, AND PLAN
CHAPTER 18 ICLINICAL REASONING, ASSESSMENT, AND PLAN 791TIPS FOR ENSURING THE QUALITY OF PATIENT DATA
IAsk open-ended questions and listen carefully and patiently to the patient’s
story.
ICraft a thorough and systematic sequence to history-taking and physical examination.
IKeep an open mind toward both the patient and the data.

story.
IAlways include “the worst-case scenario” in your list of possible explanations ofthe patient’s problem, and make sure it can be safely eliminated.
IAnalyze any mistakes in data collection or interpretation.
IConfer with colleagues and review the pertinent medical literature to clarify uncertainties.
IApply principles of data analysis to patient information and testing.
PRINCIPLES OF TEST SELECTION AND USE
Indicates how well repeated measurements of the same relatively stable phenome-non will give the same result, also known as precision. Reliability may be measuredfor one observer or for more than one observer.
Example: If on several occasions one clinician consistently percusses the same
span of a patient’s liver dullness, intraobserver reliability is good. If, on the other

hand, several observers ﬁnd quite different spans of liver dullness on the same patient, interobserver reliability is poor.
Validity
Indicates how closely a given observation agrees with “the true state of affairs,” or
the best possible measure of reality.
Example: Blood pressure measurements by mercury-based sphygmomanometers
are less valid than intra-arterial pressure tracings.Symptoms, physical ﬁndings, tests, and x-rays should help you reduce un-

certainty about whether a patient does or does not have a given condition.Clinical data, including laboratory work, however, are inherently imperfect.You can improve your assessment of clinical data and laboratory tests by ap-plying several key principles for selecting and using clinical data and tests.Learn to apply the principles of reliability, validity, sensitivity, speciﬁcity, and
predictive value to your clinical ﬁndings and the tests you order. These test
characteristics will help you decide how conﬁdent you can be of your ﬁndingsand test results as you assess the presence or absence of a disease or problem.

792 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGSensitivity
Identiﬁes the proportion of people who test positive in a group of people known to
have the disease or condition, or the proportion of people who are true positives
compared to the total number of people who actually have the disease. When theobservation or test is negative in persons who have the disease, the result is termedfalse negative. Good observations or tests have a sensitivity of over 90%, and help ruleout disease because there are few false negatives. Such observations or tests are espe-cially useful for screening.
Example: The sensitivity of Homan’s sign in the diagnosis of deep venous
thrombosis of the calf is 50%. In other words, compared to a group of patientswith deep venous thrombosis conﬁrmed by phlebogram, a much better test, only50% will have a positive Homan’s sign, so this sign, if absent, is not helpful, since50% of patients may have a DVT.
Speciﬁcity

Identiﬁes the proportion of people who test negative in a group of people known tobe without a given disease or condition, or the proportion of people who are “true
negatives” compared to the total number of people without the disease. When theobservation or test is positive in persons without the disease, the result is termed“false positive.” Good observations or tests have a speciﬁcity of over 90% and help“rule in” disease, because the test is rarely positive when disease is absent, andthere are few false positives.
Example: The speciﬁcity of serum amylase in patients with possible acute pan-
creatitis is 70%. In other words, of 100 patients without pancreatitis, 70% will havea normal serum amylase; in 30%, the serum amylase will be falsely elevated.
Predictive Value
Indicates how well a given symptom, sign, or test result—either positive or negative—predicts the presence or absence of disease.

Positive predictive value is the probability of disease in a patient with a positive
(abnormal) test, or the proportion of “true positives” out of the total populationtested.
Example: In a group of women with palpable breast nodules in a cancer
screening program, the proportion with confirmed breast cancer would consti-tute the positive predictive value of palpable breast nodules for diagnosing breast
cancer.
Negative predictive value is the probability of not having the condition or disease
when the test is negative, or normal, or the proportion of “true negatives” out ofthe total population tested.
Example: In a group of women without palpable breast nodules in a cancer
screening program, the proportion without conﬁrmed breast cancer constitutesthe negative predictive value of absence of breast nodules.

Displaying Clinical Data. To use these principles, it is important to
display the data in the 2 ×2 format diagrammed on the following page.
Always using this format will ensure the accuracy of your calculations ofsensitivity, specificity, and predictive value. Note that the presence or ab-sence of disease implies use of a “ gold standard ” to establish whether the
disease is truly present or absent. This is usually the best test available,such as a coronary angiogram for assessing coronary artery disease or a tis-sue biopsy for malignancy.

Note that the numbers related to presence or absence of disease, as deter-
mined by the “gold standard,” are always displayed down the table in the
left and right columns ( present =a +c; absent =b +d). Numbers related to
the observation or test are always displayed across the table in the upper
and lower rows ( test positive =a +b; test negative =c +d).CLINICAL REASONING, ASSESSMENT, AND PLAN
CHAPTER 18 ICLINICAL REASONING, ASSESSMENT, AND PLAN 793Sensitivity
SpecificityPositive predictive valueNegative predictive value=
+=
+×=
=
+=
+×=
=
+=
+×=
=
+=
+×=a
actrue positive observations (95)
total persons with disease (95
d
bdtrue negative observations (90)
total persons with disease (90 1
a
abtrue positive observations (95)
total positive observations (95 1
d
cdtrue negative observations (90)
total negative observations (905100 95
0100 90
0100 90 5
5100 94 7)%
)%
).%
).%
true positive
observationsPresent
ObservationAbsent
false negative
observationstrue negative

0100 90
0100 90 5
5100 94 7)%
)%
).%
).%
observationstotal negative
observationsfalse positive
observationstotal positive
observations95
90 95 510 105
a
cdb
100 100
total persons
with thediseasetotal persons
with thedisease
Now you are ready to make your calculations:
Now return to the table. Thevertical red bars designate sensitivity (a/a +c)
and speciﬁcity (d/b +d), and the horizontal red bars designate positive pre-
dictive value (a/a +b) and negative predictive value (d/c +d).The data dis-
played indicate that the hypothetical test has excellent test characteristics.The sensitivity and speciﬁcity of the test are both over 90%, as are the posi-tive and negative predictive values. Such a test would be clinically useful forassessing a disease or condition in your patient.
Note that the predictive value of a test or observation depends heavily on

the prevalence of the condition within the population studied. Prevalence is
the proportion of people in a deﬁned population at any given point in timewho have the condition in question. When the prevalence of a condition islow,the positive predictive value of the test will fall. When the prevalence is
high, the sensitivity, speciﬁcity, and positive predictive value are high, and
the negative predictive value approaches zero. To work further on these re-lationships, turn to the Appendix, Prevalence and Predictive Value, onpp. 801–802 to practice making the calculations described.

Building Your Case: The Interplay of Clinical
Reasoning and Assessment of Clinical Data
The concepts of sensitivity and speciﬁcity help in both the collection and

analysis of data. They even underlie some of the basic strategies of inter-viewing. Questions with high sensitivity, if answered in the afﬁrmative, maybe particularly useful for screening and for gathering evidence to support ahypothesis. For example, “Have you had any discomfort or pain in yourchest?” is a highly sensitive question for diagnosing angina pectoris. For pa-tients with this condition, there would be few false-negative responses. Thus,it is a good ﬁrst screening question. However, because there are many othercauses of chest discomfort, it is not all that speciﬁc. Pain that is retrosternal,pressing, and less than 10 minutes in duration—each a reasonably sensitiveattribute of angina—would add importantly to your growing evidence forthe diagnosis. To conﬁrm your hypothesis, a more speciﬁc question, if an-swered in the afﬁrmative, is needed, such as “Is the pain precipitated by ex-ertion?” or “Is the pain relieved by rest?”

Data for testing hypotheses also come from the physical examination. Heart
murmurs are good examples of ﬁndings with varying sensitivity and speci-ﬁcity. The vast majority of patients with signiﬁcant valvular aortic stenosis
have systolic ejection murmurs audible in the aortic area. Presence of a sys-tolic murmur has a high sensitivity for aortic stenosis. This ﬁnding is presentin most cases. The false-negative rate is low. On the other hand, many otherconditions produce systolic murmurs, such as increased blood ﬂow across anormal valve, or the sclerotic changes associated with aging, termed aorticsclerosis, so the ﬁnding of a systolic murmur is not very speciﬁc . . . there aremany false positives. Using such a murmur as your only criterion for diag-nosing aortic stenosis would lead to many false positives.
In contrast, a high-pitched, soft blowing decrescendo diastolic murmur best
heard along the left sternal border is quite speciﬁc for aortic regurgitation.

Such a murmur is almost never heard in normal people, and it is present invery few other conditions, so there are few false positives.
Combining data from the history and physical examination allows you to test
your hypotheses, screen for selected conditions, build your case, and clincha diagnosis even before obtaining further diagnostic tests. Consider the fol-lowing list of evidence: cough, fever, a shaking chill, left-sided pleuritic chestpain, dullness throughout the left lower posterior lung ﬁeld with crackles,bronchial breathing, and egophony. Cough and fever are good screeningitems for pneumonia, the next items support the hypothesis, and bronchialbreathing with egophony in this distribution is very speciﬁc for lobar pneu-monia. A chest x-ray would conﬁrm the diagnosis.

Absence of selected symptoms and signs is also diagnostically useful, espe-
cially when they are usually present in a given condition (i.e., their sensitiv-ity is high). For example, if a patient with cough and left-sided pleuritic chestpain does not have fever, bacterial pneumonia becomes much less likely (ex-
794 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING

cept possibly in infancy and old age). Likewise, in a patient with severe dys-
pnea, the absence of orthopnea makes left ventricular failure less probable asan explanation for shortness of breath.
Skilled clinicians use this kind of logic even if they are unaware of its statistical
underpinnings. They start to generate tentative hypotheses as soon as the pa-tient describes the Chief Complaint, then build evidence for one or more of
these hypotheses and discard others as they continue with the history and ex-amination. In developing a Present Illness, they borrow items from other parts
of the history, such as the Past Medical History, the Family History, and the
Review of Systems. In a 55-year-old man with chest pain, the skilled clinician

does not stop with the attributes of pain, but moves on to probe risk factorsfrom coronary artery disease such as family history, hypertension, diabetes,lipid abnormalities, and smoking. In both the history and physical examina-tion, the clinician searches explicitly for other possible manifestations of car-diovascular disease such as congestive heart failure or the claudication ordiminished lower extremity pulses of atherosclerotic peripheral vascular dis-ease. By generating hypotheses early and testing them sequentially, experi-enced clinicians improve their efﬁciency and enhance the relevance and valueof the data they collect. They dig and collect less ore but ﬁnd more gold.
This sequence of collecting data and testing hypotheses is diagrammed below.CLINICAL REASONING, ASSESSMENT, AND PLAN

CHAPTER 18 ICLINICAL REASONING, ASSESSMENT, AND PLAN 795
Subjective
data
(history)Identification of
problems
(diagnosis)
Identification of
patient’s responses
to illnessObjective
data
(physical findings
and
laboratory reports)Assessment
processPlan
After the plan has been implemented, the process recycles. The clinician
gathers more data, assesses the patient’s progress, modiﬁes the problem listif indicated, and adjusts the plan accordingly. As you gain experience, the in-terplay of assessment and data collection will become increasingly familiar.You will come to value the challenges and rewards of clinical reasoning andassessment that make patient care so meaningful.
Organizing the Patient Record
A clear, well-organized clinical record is one of the most important adjuncts

to your patient care. Your skill in recording your patient’s history and phys-ical examination should evolve in parallel with your growing skills in clinicalreasoning and your ability to formulate the patient’s Assessment and Plan.
Your goal should be a clear, concise, but comprehensive report that docu-ments the key ﬁndings of your patient assessment and communicates the pa-tient’s problems in a succinct and legible format to other providers and

members of the health care team. Note that a good record provides the sup-
porting data for the problems or diagnoses identiﬁed.
Regardless of your experience, certain principles will help you to organize a
good record. Think especially about the order and readability of the record
and the amount of detail needed. How much detail to include often poses a
vexing problem. As a student, you may wish (or you may be required) to bequite detailed. This helps to build your descriptive skills, vocabulary, andspeed—admittedly a painful and tedious process. Pressures of time, however,will ultimately force some compromises.
Run through the following checklist to make sure your record is clear, in-
formative, and easy to follow.CLINICAL REASONING, ASSESSMENT, AND PLAN
796 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGCHECKLIST FOR YOUR PATIENT RECORD
Is the order clear?
Do the data included contribute
directly to the assessment?
Are pertinent negatives speciﬁ-
cally described?

Are there overgeneralizations or
omissions of important data?Order is imperative. Make sure that future read-
ers, including yourself, can easily ﬁnd speciﬁcpoints of information. Keep the subjective items
of the history, for example, in the history; do notlet them stray into the physical examination. Didyou . . .
IMake the headings clear?
IAccent your organization with indentationsand spacing?
IArrange the Present Illness in chronologic
order, starting with the current episode, thenﬁlling in relevant background information?
You should spell out the supporting data—both
positive and negative—for every problem or diagnosis that you identify.
Often portions of the history or examination sug-
gest that an abnormality might exist or developin that area.Examples: For the patient with notable bruises,

record the “pertinent negatives,” such as theabsence of injury or violence, familial bleedingdisorders, or medications or nutritional deﬁcitsthat might lead to bruising.
For the patient who is depressed but not suici-
dal, record both facts. In the patient with atransient mood swing, on the other hand, acomment on suicide is unnecessary.
Remember that data not recorded are data lost.
No matter how vividly you can recall selecteddetails today, you will probably not rememberthem in a few months. The phrase “neurologicexam negative,” even in your own handwriting,may leave you wondering in a few months’ time,“Did I really do the sensory exam?”

CHAPTER 18 ICLINICAL REASONING, ASSESSMENT, AND PLAN 797Is there too much detail?
Are phrases and short words
used appropriately? Is thereunnecessary repetition ofdata?
Is the written style succinct? 
Is there excessive use of abbre-viations?Avoid burying important information in a mass
of excessive detail, to be discovered by only the most persistent reader. Omit most of your
negative ﬁndings unless they relate directly to 
the patient’s complaints or to speciﬁc exclusionsin your diagnostic assessment. Do not list 
abnormalities that you did not observe. Instead,concentrate on a few major ones, such as “no heart murmurs,” and try to describe struc-tures in a concise, positive way.Examples: “Cervix pink and smooth” indicates
you saw no redness, ulcers, nodules, masses,cysts or other suspicious lesions, but the de-scription is shorter and much more readable.
You can omit certain body structures even

though you examined them, such as normaleyebrows and eyelashes.
Omit unnecessary words, such as those in
parentheses in the examples below. This savesvaluable time and space.Examples: “Cervix is pink (in color).” “Lungs 
are resonant (to percussion).” “Liver is tender(to palpation).” “Both (right and left) earswith cerumen.” “II/VI systolic ejectionmurmur (audible).” “Thorax symmetric(bilaterally).”
Omit repetitive introductory phrases such as
“The patient reports no . . . ,” since readers assume the patient is the source of the historyunless otherwise speciﬁed.
Use short words instead of longer, fancier 
ones when they mean the same thing, such as “felt” for “palpated” or “heard” for “auscultated.”
Describe what you observed, not what you did.

“Optic discs seen” is less informative than“disc margins sharp,” even if it marks your ﬁrstglimpse as an examiner!
Records are scientiﬁc and legal documents, so
they should be clear and understandable.Using words and brief phrases instead of whole
sentences is common, but abbreviations andsymbols should be used only if they are readilyunderstood.
Likewise, an overly elegant style is less appealing
than a concise summary.
Be sure your record is legible, otherwise all 
that you have recorded is worthless to yourreaders.

Your institution or agency may have printed forms for recording patient infor-
mation, but you should always be able to create your own record. The recordof Mrs. N may be longer than what you might see in patient charts, yet it stilldoes not reﬂect every question and technique that you have learned to use. Theamount of detail varies, depending on the patient’s symptoms and signs andthe complexity of the clinician’s diagnoses and plans for management.
Generating the Problem List. Once you have completed your assess-
ment and written record, you will ﬁnd it helpful to generate a Problem List
that summarizes the patient’s problems for the front of the ofﬁce or hospitalchart. List the most active and serious problems ﬁrst, and record their date ofonset. Some clinicians make separate lists for active or inactive problems; others make one list in order of priority. You will ﬁnd that on follow-up vis-its the Problem List helps you remember to check the status of problems the

patient may not mention. The Problem List also allows other members of the
health care team to review the patient’s health status at a glance.
A sample Problem List for Mrs. N is provided on the following page. You
may wish to give each problem a number and use the number when refer-ring to speciﬁc problems in subsequent notes.CLINICAL REASONING, ASSESSMENT, AND PLAN
798 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGAre diagrams and precise 
measurements included whereappropriate?
Is the tone of the write-up 
neutral and professional?Diagrams add greatly to the clarity of the record.
Examples: Study the examples below:
To ensure accurate evaluations and future com-
parisons, make measurements in centimeters,not in fruits, nuts, or vegetables.Examples: “1 ×1 cm lymph node” versus a 
“pea-sized lymph node . . .” Or “2 ×2 cm 
mass on the left lobe of the prostate” versus a “walnut-sized prostate mass.”
It is important to be objective. Hostile, moralizing,

or disapproving comments have no place in thepatient’s record. Never use words, penmanship, orpunctuation that are inﬂammatory or demeaning.Example: Comments such as “Patient DRUNK and
LATE TO CLINIC AGAIN!!” are unprofessional and set a bad example for other providers reading the chart. They also might prove difﬁ-cult to defend in a legal setting.

CHAPTER 18 ICLINICAL REASONING, ASSESSMENT, AND PLAN 799Date Entered Problem No. Problem
Migraine headaches
Elevated blood pressureCystocele with occasional stress incontinenceOverweightFamily stressLow back painTobacco abuseVaricose veinsHistory of right pyelonephritisAllergy to ampicillinHealth maintenanceSample Problem List
123456789
10118/30/02
SAMPLE SOAP NOTE
1. Migraine headaches.
S:Has had only two headaches, both mild and without associated symptoms.
These are less troubling. Cannot detect any precipitating factors.
O:No tenderness over the temporal muscles. No papilledema.
A:Headaches improved, now without migraine features.
P:Call if symptoms recur.Clinicians organize problem lists differently, even for the same patient. Your

problem list for Mrs. N may look somewhat different from the one above.Note that problems can be symptoms, signs, or conditions. Good lists varyin emphasis, length, and detail, depending on the clinician’s philosophy,specialty, and role as a provider. The list illustrated here includes problemsthat need attention now, such as the headaches, as well as problems thatneed future observation or attention, such as the blood pressure and cys-tocele. Listing the allergy to ampicillin warns you not to prescribe medica-tions in the penicillin family.
Some of the items noted in the history and physical examination, such as the

canker sores and hard stools, do not appear in this problem list because theyare relatively common phenomena that do not currently demand attention.Such judgments may prove to be wrong; however, problem lists that arecluttered with relatively insigniﬁcant items diminish in value. Some clinicianswould ﬁnd this list too long; others would be more explicit about such prob-lems as “family stress” or “varicose veins.”
Writing the Progress Note. A month later, Mrs. N returns for a follow-
up visit. The style of the progress note is also quite variable, but it should fol-low the same standards as the initial assessment. It should be clear, sufﬁcientlydetailed, and easy to follow. It should reﬂect your clinical thinking and delin-eate your assessment and plan. The following note follows the SOAP note for-mat ( Subjective, Objective, Assessment, and Plan), but you will see many

other styles. Often clinicians record the history and physical examination, thenbreak out the patient’s problems into separate Assessments and Plans.

Clinical Assessment: The Journey to Excellence
The process of learning about a patient continues far beyond the ﬁrst few
encounters. Your understanding of patient care will grow in depth and com-plexity throughout your clinical career. Your prowess in history taking, phys-ical examination, clinical reasoning, and documenting the patient record islaunched. Now you must embark on repetitive practice, with supervision,and on the lifelong pursuit of polishing your newly acquired skills.
800 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKING

APPENDIX
CHAPTER 18 ICLINICAL REASONING, ASSESSMENT, AND PLAN 801PREVALENCE AND PREDICTIVE VALUE
Two examples further illustrate these principles and show how predictive values vary
with prevalence. Consider ﬁrst ( Example 1 ) an imaginary population Awith 1000 peo-
ple.The prevalence of disease Xin this population is high—40%. You can quickly
calculate that 400 of these people have X.You then set out to detect these cases
with an observation that is 90% sensitive and 80% speciﬁc. Of the 400 peoplewith X,the observation reveals .90 ×400, or 360 (the true positives). It misses the
other 40 (400 −360, the false negatives). Out of the 600 people without X,the
observation proves negative in .80 ×600, or 480. These people are truly free of X,
as the observation suggests (the true negatives). But the observation misleads you inthe remaining 120 (600 −480). These people are falsely labeled as having Xwhen
they are really free of it (the false positives). These ﬁgures are summarized below:

As a clinician who does not have perfect knowledge of who really does or does
not have disease X,you are faced with a total of 480 people with positive observa-
tions. You must try to distinguish between the true and the false positives and willundoubtedly use additional kinds of data to help you in this task. Given only thesensitivity and speciﬁcity of your observation, however, you can determine theprobability that a positive observation is a true positive, and you may wish to ex-plain it to the concerned patient. This probability is calculated as follows:
Thus, 3 out of 4 of the persons with positive observations really have the dis-
ease, and 1 out of 4 does not.
By a similar calculation, you can determine the probability that a negative ob-
servation is a true negative. The results here are reasonably reassuring to the in-volved patient:
360
observations120
false positive

360
observations480
total positive
observations
40
400
persons
with X600
persons
without X480
true negative
observations520
total negative
1000
total personsPresent AbsentDisease X
Observationa
cdb
Positive predictive value   a
abtrue positives (360)
total positives (360 )=+=+×=120100 75%Example 1. Prevalence of Disease X = 40%
APPENDIX

APPENDIX
802 BATES’ GUIDE TO PHYSICAL EXAMINATION AND HISTORY TAKINGAs prevalence of the disease in a population diminishes, however, the predictive
value of a positive observation diminishes remarkably, while the predictive value ofa negative observation rises further. In Example 2, in a second population, B,of
1000 people, only 1% have disease X.Now there are only 10 cases of Xand 990
people without X.If this population is screened with the same observation, which
has a 90% sensitivity and an 80% speciﬁcity, here are the results:
You are now confronted with possibly upsetting 207 people (all those with posi-

tive observations) to detect 9 out of the 10 real cases. The predictive value of apositive observation is only 4%. Improving the speciﬁcity of your observation with-out diminishing its sensitivity would be very helpful, if it were possible. For exam-ple, if you could increase the speciﬁcity of the observation from 80% to 98%(given the same prevalence of 1% and sensitivity of 90%), the positive predictivevalue of the observation would improve from 4% to 31%—scarcely ideal but cer-tainly better. Good observations or tests have a sensitivity and speciﬁcity of 90%.
Because prevalence strongly affects the predictive value of an observation,

prevalence too inﬂuences the assessment process. Because coronary artery diseaseis much more common in middle-aged men than in young women, you shouldpursue angina as a cause of chest pain more actively in the former group. The ef-fect of prevalence on predictive value explains why your odds of making a correctassessment are better when you hypothesize a common condition rather than arare one. The combination of fever, headache, myalgias, and cough probably hasthe same sensitivity and speciﬁcity for inﬂuenza throughout the year, but yourchance of making this diagnosis correctly by using this cluster of symptoms ismuch greater during a winter ﬂu epidemic than it is during a quiet August.
Prevalence varies importantly with clinical setting as well as with season. Chronic

bronchitis is probably the most common cause of hemoptysis among patients seen ina general medical clinic. In the oncology clinic of a tertiary medical center, however,lung cancer might head the list, while in a group of postoperative patients on a general surgical service, irritation from an endotracheal tube or pulmonary infarctionmight be most likely. In certain parts of Asia, in contrast, one should think ﬁrst of aworm called a lung ﬂuke. When you hear hoofbeats in the distance, according to thefamiliar saying, bet on horses, not on zebras, unless, of course, you’re visiting the zoo.
9
observations198
observations207
1
10
persons
with X990
persons
without X792
observations793
1000
cdbNegative predictive value   d

10
persons
with X990
persons
1000
cdtrue negatives (480)
total negatives (40 )=+=+×=480100 92%
Example 2. Prevalence of Disease X = 1%

/G28/G59/G44/G4f/G58/G44/G57/G4c/G52/G51/G3/G26/G52/G53/G5c 
  
Chapter 1.  An Overview of the Physical Examination and History-Taking 
 
AN OVERVIEW OF THE PHYSICAL EXAMINATION AND HISTORY-TAKING 
Clinical Assessment: The Road Ahead 
THE HEALTH HISTORY: STRUCTURE AND PURPOSES THE COMPREHENSIVE ADULT HEALTH HISTORY  Date and Time of History  Identifying Data  Reliability  Chief Complaints  Present Illness  Past History  Family History  Personal and Social History  Review of Systems   General 
  S k i n    HEENT   Neck   Breasts   Respiratory   Cardiovascular   Gastrointestinal   Urinary   Genital   Peripheral Vascular   Musculoskeletal   Neurologic   Hematologic   Endocrine   Psychiatric THE PHYSICAL EXAMINATION: APPROACH AND OVERVIEW THE COMPREHENSIVE PHYSICAL EXAMINATION 
General Survey Vital Signs    
 Skin  HEENT  Neck 
Back 
 Posterior Thorax and Lungs  Breasts, Axillae, and Epitrochlear Nodes  Anterior Thorax and Lungs  Cardiovascular System  Abdomen  Lower Extremities

  Nervous System 
  Mental Status 
  Cranial Nerves   Motor System   Sensory System   Reflexes  
 Additional Examinations   Rectal Examination In Men 
  Genital and Rectal Examination In Women  
RECORDING YOUR FINDINGS  Tips for a Clear and Accurate Write-Up   Order of the Write-Up 
  Degree of Detail  Example of Mrs. N   Chief Complaint 
  Present Illness 
  Past History     
   C h i l dhood Illnesses  
   A d u l t I l l n e s s e s     H e a l th  M a i n te n a n c e    Family History 
  Personal and Social History   Review of Systems    G e n e r a l     S k i n     H e a d ,  E y e s ,  E a r s ,  N o s e ,  a n d  T h r o a t ( H E E N T )     N e c k     B r e a s ts     R e s p i r a to r y     C a r d i o v ascular 
   G a s tr o i n te s ti n a l     U r i n a r y     G e n i ta l     P eripheral Vascular

G a s tr o i n te s ti n a l     U r i n a r y     G e n i ta l     P eripheral Vascular 
   M u s c u l o s k e l e ta l     N e u r o l o g i c     H e m a to l o g i c     Endocrine    P s y c h i a tr i c    Physical Examination 
   V i ta l  S i g n s  
Skin 
   H e a d ,  E y e s ,  E a r s ,  N o s e ,  a n d  T h r o a t ( H E E N T )     N e c k     L y m p h  N o d e s     Thorax and Lungs

    C a r d i o v ascular 
   B r e a s ts     A bdomen 
   G e n i ta l i a     R e c ta l     E x tr e m i ti e s     P eripheral Vascular 
   M u s c u l o s k e l e ta l     N e u r o l o g i c   Moving On to Patient Assessment   
Chapter 2.  Interviewing and the Health History  
GETTING READY: THE APPROACH TO THE INTERVIEW 
 Taking Time for Self-Reflection 
Reviewing the Chart Setting Goals for the Interview Reviewing Clinician Behavior and Appearance Improving the Environment Taking Notes 
LEARNING ABOUT THE PATIENT: THE PROCESS OF INTERVIEWING  
Greeting the Patient and Establishing Rapport Inviting the Patient’s Story Establishing the Agenda for the Interview Expanding and Clarifying the Health History (The Patient’s Perspective)  Generating and Testing Diagnostic Hypotheses (The Clinician’s Perspective) Creating a Shared Understanding of the Problem Negotiating a Plan Planning for Follow-Up and Closing

FACILITATING THE PATIENT’S STORY: THE TECHNIQUES OF SKILLED INTERVIEWING 
Active Listening Adaptive Questioning Nonverbal Communication  Facilitation Echoing Empathic Responses Validation Reassurance Summarization Highlighting Transitions 
ADAPTING INTERVIEWING TECHNIQUES TO SPECIFIC SITUATIONS 
The Silent Patient  
The Talkative Patient The Anxious Patient

 The Crying Patient 
The Confusing Patient The Angry or Disruptive Patient The Patient with a Language Barrier The Patient with Reading Problems The Patient with Impaired Hearing The Patient with Impaired Vision The Patient with Limited Intelligence The Poor Historian  The Patient with Personal Problems 
 SPECIAL ASPECTS OF INTERVIEWING 
Cultural Competence   
Self-Awareness Enhanced Communication and Learning from the Patient Collaborative Partnerships 
The Alcohol and Drug History The Sexual History Domestic and Physical Violence The Mental Health History Death and the Dying Patient Sexuality in the Clinician-Patient Relationship 
ETHICAL CONSIDERATIONS  INTERVIEWING PATIENTS OF DIFFERENT AGES 
Talking with Children 
Establishing Rapport 
  Working with Families 
Multiple Agendas The Family as a Resource Hidden Agendas 
Talking with Adolescents Talking with Aging Patients Functional Assessment

Talking with Adolescents Talking with Aging Patients Functional Assessment 
  
Chapter 3.  Beginning the Physical Examination: General Survey and Vital Signs 
 
ANATOMY AND PHYSIOLOGY  Calculating the BMI  Interpreting and Acting on the BMI THE HEALTH HISTORY  Changes in Weight  Fatigue and Weakness  Fever and Chills HEALTH PROMOTION AND COUNSELING TECHNIQUES OF EXAMINATION  Beginning the Examination: Setting the Stage

  Approaching the Patient 
 Scope of the Examination: How Complete Should It Be?  Choosing the Examination Sequence, Examining Position and Handedness  Adjusting Lighting and the Environment  Promoting the Patient’s Comfort THE GENERAL SURVEY  Apparent State of Health  Level of Consciousness  Signs of Distress  Height and Build  W e i g h t  Skin Color and Obvious Lesions  Dress, Grooming, and Personal Hygiene  Facial Expression  Odors of the Body and Breath  Posture, Gait and Motor Activity THE VITAL SIGNS  Blood Pressure   Choices of Blood Pressure Cuff (Sphygmomanometer) 
  Technique   Definitions of Normal and Abnormal Levels  Special Problems   The Apprehensive Patient 
  The Obese or Very Thin Arm   Leg Pulses and Pressures   Weak or Inaudible Korotkoff Sounds   Arrythmias  Heart Rate and Rhythm   Heart Rate 
  R h y t h m  
 Respiratory Rate and Rhythm  Temperature   
Chapter 4.  The Skin 
  
R h y t h m  
  
ANATOMY AND PHYSIOLOGY 
Changes with Aging Health History 
HEALTH PROMOTION AND COUNSELING TECHNIQUES OF EXAMINATION  S k i n       Color 
  Moisture   Temperature

   Texture 
  Mobility and Turgor  Evaluating the Bedbound Patient  Nails  Hair      
Chapter 5.  The Head and Neck 
 
ANATOMY AND PHYSIOLOGY  The Head  The Eye   Gross Anatomy 
  Visual Fields   Visual Pathways   Pupillary Reactions  
   The Light Reaction    T h e  N e a r  R e a c ti o n    Autonomic Nerve Supply to the Eyes 
  Extraocular Movements  The Ear   Anatomy 
  Pathways of Hearing   Equilibrium  
 The Nose and Paranasal Sinuses  The Mouth and Pharynx  The Neck  Changes with Aging THE HEALTH HISTORY  The Head  The Eyes  The Ears  The Nose and Sinuses 
The Mouth, Throat, and Neck 
HEALTH PROMOTION AND COUNSELING TECHNIQUES OF EXAMINATION  The Head   The Hair 
  The Scalp   The Skull   T h e  F a c e    The Skin  The Eyes  Visual Acuity  Visual Fields By Confrontation    Screening

   Further Testing 
 Position and Alignment of the Eyes  E y e b r o w s   Eyelids  Lacrimal Apparatus  Conjunctive and Sclera  Cornea and Lens  I r i s   Pupils  Extraocular Muscles   Ophthalmoscopic Examination  The Ears       The Auricle 
  Ear Canal and Drum   Auditory Acuity   Air and Bone Conduction  The Nose and Paranasal Sinuses  The Mouth and Pharynx   The Lips 
  The Oral Mucosa   The Gums and Teeth   The Roof of the Mouth   The Tongue and the Floor of the Mouth   The Pharynx  The Neck   Lymph Nodes 
  The Trachea and the Thyroid Gland  The Carotid Arteries and Jugular Veins  Special Techniques   For Assessing Prominent Eyes 
  For Nasolacrimal Duct Obstruction   For Inspection of the Upper Palpebral Conjunctiva   Swinging Flashlight Test   Transillumination of the Sinuses   
Chapter 6.  The Thorax and Lungs

For Nasolacrimal Duct Obstruction   For Inspection of the Upper Palpebral Conjunctiva   Swinging Flashlight Test   Transillumination of the Sinuses   
Chapter 6.  The Thorax and Lungs 
 
ANATOMY AND PHYSIOLOGY  Locating Findings on The Chest  Lungs, Fissures, and Lobes  Locations on the Chest  The Trachea and Major Bronchi  The Pleurae  Breathing  Changes with Aging

 THE HEALTH HISTORY 
HEALTH PROMOTION AND COUNSELING TECHNIQUES OF EXAMINATION  Initial Survey of Respiration and the Thorax  Examination of the Posterior Chest   Inspection 
  Palpation   Percussion  
Percussion Notes 
  Auscultation    B r e a th  Sounds (Lung Sounds) 
  Adventitious (Added) Sounds 
 Transmitted Voice Sounds 
 Examination of the Anterior Chest   Inspection 
  Palpation   Percussion   Auscultation  Special Techniques   Clinical Assessment of Pulmonary Function 
  Forced Expiratory Time   Identification of a Fractured Rib   
Chapter 7.  The Cardiovascular System

Forced Expiratory Time   Identification of a Fractured Rib   
Chapter 7.  The Cardiovascular System 
 
ANATOMY AND PHYSIOLOGY  Surface Projections of the Heart and Great Vessels  Cardiac Chambers, Valves, and Circulation  Events in the Cardiac Cycle  The Splitting of Heart Sounds  Heart Murmurs  Relation of Auscultatory Findings to the Chest Wall  The Conduction System  The Heart as a Pump  Arterial Pulses and Blood Pressure  Jugular Venous Pressure and Pulses   Jugular Venous Pressure (JVP) 
  Jugular Venous Pulsations  Changes With Aging   The Apical Impulse and Heart Sounds 
  Cardiac Murmurs   Arteries and Blood Pressure THE HEALTH HISTORY HEALTH PROMOTION AND COUNSELING TECHNIQUES OF EXAMINATION

  Jugular Venous Pressure and Pulsations 
  Jugular Venous Pressure (JVP)   Jugular Venous Pulsations  The Carotid Pulse   Thrills and Bruits 
  The Brachial Artery  The Heart SEQUENCE OF THE CARDIAC EXAMINATION  Inspection and Palpation   The Apical Impulse or Point of Maximal Impulse (PMI) – Left  
Ventricular Area 
  The Left Sternal Border in the 3
rd, 4th, and 5th Interspaces –  
Right Ventricular Area 
  The Left 2nd Interspace – Pulmonic Area 
  The Right 2nd Interspace – Aortic Area 
 Percussion  Auscultation   Overview 
  Listening for Heart Sounds   Attributes of Heart Murmurs  A Note on Cardiovascular Assessment  Special Techniques   Aids to Identify Systolic Murmurs 
Pulsus Alternans Paradoxical Pulse 
  
Chapter 8.  The Breasts and Axillae 
 
ANATOMY AND PHYSIOLOGY  Changes With Aging   Adulthood 
  A gi n g  Lymphatics THE HEALTH HISTORY HEALTH PROMOTION AND COUNSELING  Risk Factors for Breast Cancer   Age

  A gi n g  Lymphatics THE HEALTH HISTORY HEALTH PROMOTION AND COUNSELING  Risk Factors for Breast Cancer   Age 
  Family History SUMMARY OF BREAST CANCER RISK FACTORS  Menstrual History and Pregnancy  Breast Conditions and Diseases   Breast Cancer Screening  
TECHNIQUES OF EXAMINATION  The Female Breast   Inspection

    A r m s  A t S i d e s  
   A r m s  O v e r  H e a d ;  H a n d s  P ressed Against Hips; Leaning Forward 
  Palpation    The Breast 
The Nipple 
 The Male Breast  The Axillae   Inspection 
  Palpation  
 Special Techniques   Assessment of Spontaneous Nipple Discharge 
  Examination of the Mastectomy Patient 
Instructions for the Breast Self-Examination  
  
Chapter 9.  The Abdomen 
 
ANATOMY AND PHYSIOLOGY  Changes with Aging THE HEALTH HISTORY HEALTH PROMOTION AND COUNSELING TECHNIQUES OF EXAMINATION  The Abdomen   Inspection 
  Auscultation   Percussion   Palpation    L i g h t P a l p a ti o n     D e e p  P a l p a ti o n     A s s e s s m e n t f o r  P e r i to n eal Inflammation 
 The Liver   Percussion 
  Palpation    A s s e ssing Tenderness of a Nonpalpable Liver 
 T h e  S p l e e n            Percussion   Palpation  The Kidneys   Palpation

The Liver   Percussion 
 T h e  S p l e e n            Percussion   Palpation  The Kidneys   Palpation 
   Palpation of the Left Kidney    P a l p a ti o n  o f  th e  R i g h t K i d n e y     A ssessing Kidney Tenderness 
 The Bladder  The Aorta  Special Techniques

   Assessing Possible Ascites 
   I d e n ti f y i n g  a n  O r g a n  o r  a  M a s s  i n  a n  A s c i ti c  A b d o m e n    Assessing Possible Appendicitis 
  Assessing Possible Acute Cholecystitis   Assessing Ventral Hernias   Mass in Abdominal Wall 
To Distinguish an Abdominal Mass from a Mass in the Abdominal Wall  
 
Chapter 10.  Male Genitalia and Hernias 
 
ANATOMY AND PHYSIOLOGY  Lymphatics  Anatomy of the Groin  Changes with Aging THE HEALTH HISTORY HEALTH PROMOTION AND COUNSELING TECHNIQUES OF EXAMINATION  The Penis   Inspection 
  Palpation  
 The Scrotum and its Contents   Inspection 
  Palpation  Hernias 
Inspection 
  Palpation  
   Evaluating a Possible Scrotal Hernia  Special Techniques   The Testicular Self-Examination   
Chapter 11: Female Genitalia

Palpation  Hernias 
  Palpation  
Chapter 11: Female Genitalia 
 
ANATOMY AND PHYSIOLOGY  Lymphatics  Changes with Aging THE HEALTH HISTORY HEALTH PROMOTION AND COUNSELING  The Pap Smear  Options for Family Planning  STDs and HIV  Implications of Menopause TECHNIQUES OF EXAMINATION  Choosing Equipment

  Positioning the Patient 
 External Examination   Assess the Sexual Maturity of the Adolescent Patient 
  Inspect External Genitalia  Internal Examination   Assess the Support of the Vaginal Walls 
  Insert the Speculum   Inspect the Cervix   Obtain Specimens for Cervical Cytology (Papanicolaou Smears)   Inspect the Vagina   Perform a Bimanual Examination   Assess the Strength of the Pelvic Muscles   Do a Rectovaginal Examination  Hernias  
 Special Techniques   
Chapter 12.  The Pregnant Woman 
 
ANATOMY AND PHYSIOLOGY THE HEALTH HISTORY HEALTH PROMOTION AND COUNSELING TECHNIQUES OF EXAMINATION  Positioning  Equipment  General Inspection  Vital Signs and Weight  Head and Neck  Thorax and Lungs  Heart  B r e a s ts   Abdomen  Genitalia, Anus, and Rectum   Speculum Examination

Bimanual Examination  Extremities  Special Techniques   Modified Leopold’s Maneuvers    F i r s t M a n e u v e r  ( U p p e r  P o l e )     S e c ond Maneuver (Side of the Maternal Abdomen) 
  Third Maneuver (Lower Pole)   Fourth Maneuver (Confirmation of the Presenting Head) 
 Concluding the Visit

 Chapter 13.  The Anus, Rectum, and Prostate 
 
ANATOMY AND PHYSIOLOGY  Changes with Aging THE HEALTH HISTORY HEALTH PROMOTION AND COUNSELING TECHNIQUES OF EXAMINATION  Male  Female   
Chapter 14.  The Peripheral Vascular System 
 
ANATOMY AND PHYSIOLOGY  Arteries  Veins  The Lymphatic System and Lymph Nodes  Fluid Exchange and the Capillary Bed  Changes with Aging THE HEALTH HISTORY HEALTH PROMOTION AND COUNSELING TECHNIQUES OF EXAMINATION  Arms  L e g s   Special Techniques   Evaluating the Arterial Supply to the Hand 
  Postural Color Changes of Chronic Arterial Insufficiency   Mapping Varicose Veins   Evaluating the Competency of Venous Valves   
Chapter 15.  The Musculoskeletal System 
 
ANATOMY AND PHYSIOLOGY  Structure and Function of Joints  Types of Joints 
Bursae 
 Temporomandibular Joint 
 Overview, Bony Structures, and Joints 
 Muscle Groups and Additional Structures The Shoulder  Overview

Bursae 
 Muscle Groups and Additional Structures The Shoulder  Overview 
Bony Structures Joints Muscle Groups  
The Scapulohumeral Group

 The Axioscapular Group 
The Axiohumeral Group 
  Additional Structures  The Elbow   Overview, Bony Structures, and Joints 
  Muscle Groups and Additional Structures 
The Wrist and Hands  Overview 
Bony Structures Joints Muscle Groups  Additional Structures 
The Spine  Overview 
Bony Structures Joints Muscle Groups 
The Hip  Overview 
Bony Structures and Joints Muscle Groups 
  Additional Structures 
The Knee  Overview 
Bony Structures Joints Muscle Groups Additional Structures 
The Ankle and Foot  Overview 
Bony Structures and Joints Muscle Groups and Additional Structures  
Changes With Aging 
THE HEALTH HISTORY HEALTH PROMOTION AND COUNSELING TECHNIQUES OF EXAMINATION  The Temporomandibular Joint (TMJ) 
 Inspection and Palpation 
  Range of Motion and Maneuvers  The Shoulder   Inspection 
  Palpation   Range of Motion and Maneuvers  The Elbow   Inspection and Palpation 
  Range of Motion and Maneuvers

  The Wrist and Hand 
  Inspection  
  Palpation   Range of Motion and Maneuvers  
 The Spine 
Inspection Palpation 
  Range of Motion and Maneuvers  The Hip   Inspection  
 The Knee and Lower Leg   Inspection  
 The Ankle and Foot   Inspection  
  Palpation   Range of Motion and Maneuvers  Special Techniques   For the Carpal Tunnel Syndrome 
 Thumb Abduction 
   P i n e l ’ s  S i g n  
Phalen’s Test 
  For Low Back Pain with Radiation into the Leg 
  Measuring the Length of Legs   Describing Limited Motion of a Joint   
Chapter 16.  The Nervous System 
 
ANATOMY AND PHYSIOLOGY  Central Nervous System   The Brain 
The Spinal Cord 
 Peripheral Nervous System   The Cranial Nerves 
  The Peripheral Nerves  
 Spinal Reflexes: The Deep Tendon Response  Motor Pathways  Sensory Pathways 

THE HEALTH HISTORY HEALTH PROMOTION AND COUNSELING TECHNIQUES OF EXAMINATION

 Appearance and Behavior   Level of Consciousness 
  Posture and Motor Behavior   Dress, Grooming, and Personal Hygiene   Facial Expression   Manner, Affect, and Relationship to Persons and Things  Speech and Language   Quantity 
  R a t e    Loudness   Articulation of Words   Fluency  Mood 
Thought and Perceptions 
  Thought Processes 
  Thought Content   Perceptions   Insight and Judgment    I n s i g h t    J u d g m e n t 
Cognitive Functions 
 Orientation  Attention   Digit Span 
  Serial 7s   Spelling Backward   Remote Memory   Recent Memory   New Learning Ability  Higher Cognitive Functions 
Information and Vocabulary Calculating Ability Abstract Thinking 
Proverbs Similarities 
Constructional Ability 
The Cranial Nerves 
  Overview   
  Cranial Nerve I--Olfactory 
Cranial Nerve II—Optic 
 Cranial Nerves II and III—Optic and Oculomotor 
Cranial Nerves III, IV, and VI—Oculomotor, Trochlear, Abducens

Overview   
Cranial Nerves III, IV, and VI—Oculomotor, Trochlear, Abducens 
 Cranial Nerve V—Trigeminal, Motor, Sensory 
Cranial Nerve VII—Facial 
 Cranial Nerve VIII--Acoustic

 Cranial Nerves IX and X—Glossopharyngeal and Vagus 
 Cranial Nerve XI—Spinal Accessory 
Cranial Nerve XII—Hypoglossal 
The Motor System 
  Body Position 
  Involuntary Movements   Muscle Bulk   Muscle Tone   Muscle Strength   Coordination    R a p i d  A l te r n a ti n g  M o v e m e n ts      A r m s      L e g s     Point-to-Point Movements     A r m s      L e g s     Gait 
   S t ance 
    T h e  R o m b e r g  T e s t     T e s t f o r  P r o n a to r  D r i f t 
The Sensory System 
  Patterns of Testing 
 Vibration 
  Pain 
 Temperature 
  Light Touch 
 Position  Discriminative Sensations Deep Tendon Reflexes 
  The Biceps Reflex (C5, C6) 
  The Triceps Reflex (C6, C7)   The Supinator or Brachioradialis Reflex (C5, C6)   The Abdominal Reflexes   The Knee Reflex (L1, L3, L4) 
 The Ankle Reflex (Primarily S1) 
  The Plantar Response (L5, S1)   Clonus  

The Ankle Reflex (Primarily S1) 
Special Techniques 
                        Mini-Mental State Examination (MMSE)  
  Asterixis 
  Winging of the Scapula   Meningeal Signs    N e c k  M o b ility 
   B r u d z i n s k i ’ s  S i g n     K e r n i g ’ s  S i g n    Anal Reflex

   The Stuporous or Comatose Patient 
   A i r w a y ,  B r e a th i n g ,  and Circulation 
   L e v e l s  o f  C o n sciousness 
   N e u r o l o g i c  E v a l u a ti o n  
    R e s p i r a ti o n s      P u p i l s      O c u lar Movement 
    O c u l o c e p h a l i c  R e f l e x  ( D o l l ’s-Eye Movements) 
    O c u l o v e s ti b u lar Reflex (With Caloric Stimulation) 
    P o s tu r e  a n d  M u scle Tone 
   Further Examination 
  
Chapter 17.  Assessing Children: Infancy Through Adolescence 
 
CHILD DEVELOPMENT  Key Principles  Infancy: The First Year of Life   Cognitive and Language Development 
  Social and Emotional Development  
 Early Childhood: 1 Through 4 Years   Physical Development 
  Cognitive and Language Development   Social and Emotional Development  Middle Childhood: 5 Through 10 Years 
 Physical Development

Early Childhood: 1 Through 4 Years   Physical Development 
 Physical Development 
  Cognitive and Language Development   Social and Emotional Development  Adolescence: 11 Through 20 Years 
  Cognitive Development   Social and Emotional Development HEALTH PROMOTION AND COUNSELING APPROACH TO THE EXAMINATION OF CHILDREN AT DIFFERENT AGES  Sequence of the Examination 
Approach to the Newborn 
  Assessment of Newborns  
Immediate Assessment at Birth: Adaptation to Extrauterine Life  Apgar Score  Gestational Age and Birthweight Examination Several Hours After Birth 
 Approach to the Infant   Testing for Developmental Milestones  Approach in Early Childhood  Approach in Middle Childhood  Approach in Adolescence

 TECHNIQUES OF EXAMINATION 
 General Survey   Somatic Growth: Height, Weight and Head Circumference    H e i g h t    W e i g h t    H e a d  C i r c u m f e r e n c e    Body Mass Index-for-Age  Vital Signs   Blood Pressure 
  P u l s e    Respiratory Rate   Temperature  The Skin   Newborn and Early Infancy 
  Early and Late Childhood  The Head   Infancy 
  Early and Late Childhood  The Neck  The Eye   Infancy 
  Early Childhood   Late Childhood and Adolescence  The Ear   Infancy 
  Early Childhood   Late Childhood and Adolescence  The Nose and Paranasal Sinuses   Infancy 
  Early and Late Childhood  The Mouth and Pharynx   Infancy 
  Early Late Childhood  
 The Thorax and Lungs   Infancy 
  Early and Late Childhood  The Heart   Inspection 
  Palpation   Auscultation  The Breasts   Infancy 
  Older Children and Adolescents  The Abdomen   Newborn Period and Infancy 
  Early and Late Childhood, and Adolescence

  Male Genitalia 
  Newborn Period and Infancy 
  Early and Late Childhood 
Adolescence 
 Female Genitalia   Newborn Period and Infancy 
 The Rectal Examination  The Musculoskeletal System   Newborn Period and Infancy 
The Nervous System 
 Early and Late Childhood  The Adolescent 
   
Chapter 18.  Clinical Reasoning, Assessment, and Plan 
ASSESSMENT AND PLAN: THE PROCESS OF CLINICAL REASONING 
Generating Your Assessment 
 The Case Of Mrs. N: Assessment and Plan   Approaching the Challenges of Clinical Data 
 Clustering Data into Single Versus Multiple Problems  
 Sifting Through an Extensive Array of Data  Assessing the Quality of the Data  Displaying Clinical Data  
 Building Your Case: The Interplay of Clinical Reasoning and Assessment of Clinical Data  Organizing the Patient Record 
 Generating the Problem List

Building Your Case: The Interplay of Clinical Reasoning and Assessment of Clinical Data  Organizing the Patient Record 
 Generating the Problem List 
 Writing the Progress Note 
 Clinical Assessment: The Journey to Excellence

Errata 
 
Bates’ Guide to Physical Examination and History Taking 
Lynn S. Bickley 
 
Below is a table listing errors found in the initial printing along with their corrections, which have been made 
for all reprints. The table also contains some non-error changes made at the author’s request. 
 
Page Number Error Correction/Change 
viii  First paragraph: Christine Aronoff, MD 
viii  Second paragraph: Sandra Scheinin, Senior 
Production Editor, deserves special mention 
for her patience and responsiveness. 
x--xiii  Preview: Recording the Physical 
Examination boxes with page numbers have 
been added to appropriate chapters. 
21 Footnote reads Hastings C: The lived 
experience of the illness: Making contact 
with the patient. In Benne P, Wrubel . . .  Footnote reads: Hastings C: The lived 
with the patient. In Benner P, Wrubel . . . 
69 Physical Examination: Summary of 
Suggested Sequence: Tenth bulleted point

Suggested Sequence: Tenth bulleted point 
reads Cardiovascular, for 3S  and murmur of 
mitral stenosis Cardiovascular, for S 3 and murmur of mitral 
stenosis 
118 Lower figure: two lines indicate the macula. The second line is deleted. 
124 Lower figure: line indicating the umbo is 
incorrect. Leader line correctly identifies the umbo. 
133 Figure: occipital and posterior auricular 
labels are reversed. Labels have been corrected. 
153 Figure: “Left Eye” incorrectly identified at 
bottom. “Left Eye” has been deleted. 
155 Figure: Art has been incorrectly identified as 
“Right Eye.” Art correctly identified as “Left Eye.” 
182  Last two figures: fingers have been removed 
from eyes. 
212 Figure depicting the Right Anterior Oblique 
View: Anterior and posterior axillary lines 
are pointing to the wrong lines. Both correctly indicate the appropriate lines.

from eyes. 
are pointing to the wrong lines. Both correctly indicate the appropriate lines. 
304 Preview box: a colon appears after the word 
OR. The colon has been deleted. 
313 Figure: Arrows on breast do not have enough 
of a looped appearance. Arrows have been redrawn to show correct pattern. 
345 and 346  Figures depicted through line art. Figures depicted through photos. 
522 Third column, second row: Text reads Pain on straight leg raising (see pp. 520) . . . Text has been corrected to read (see p. 520) . . . 
554 Stick figure is incorrect. Stick figure has been accurately rendered. 
709  Art has been redrawn.

2 -1  
Chapter 2 
Interviewing and the Health History 
 
Multiple Choice 
 
1. A 55-year-old postal worker presents to the em ergency room with chest pain.  On a scale of 1 
to 10, he rates the pain a 9.  It started 30 mi nutes ago and hasn’t gone away.  He has never had 
it before.  He denies any injury or trauma; he has no medical conditions that are being treated.  
Nothing makes the pain better or worse.  When questioned further, he has noticed nausea and 
increased sweating with the pain. Based on this desc ription, which of the seven attributes of this 
symptom have not been addressed? 
 
(A) Remitting or exacerbating factors 
(B) Quality 
(C) Severity 
(D) Timing 
 
2. A 25-year-old graduate student presents to your  clinic; she is concerned about her exposure to 
a communicable disease that occurred at a party  she recently attended. You, the interviewer, 
enter the room and greet the patient  and then ask what brought her into your office today.  She

enter the room and greet the patient  and then ask what brought her into your office today.  She 
states that she wants to establish care, so y ou start by asking her if she has any specific 
concerns that she would like you to address.  S he states that she is concerned that she may have 
gotten an STD. You continue to maintain eye contact and state, “Go on.”  Which type of 
interviewing technique have you demonstrated? 
 
(A) Echoing

2 -2  
(B) Directed questioning 
(C) Facilitation 
(D) Reassurance 
 
3. A 42-year-old retail manager is sitting in your  clinic exam room, waiting for a routine checkup 
for hypertension. You enter the room and sit down, making eye contact, and move your body 
slightly toward the patient.  You nod your head as  the patient begins to bring you up to date on 
his life since his last appointment.  This interviewing technique is an example of: 
 
(A) Echoing 
(B) Adaptive questioning 
(C) Nonverbal communication 
(D) Empathic responses 
 
4. A 55-year-old legal secretary comes into your o ffice to establish care.  She starts the interview 
by telling you her whole life story, tells you about her husband, children, and grandchildren, and 
then pulls out a written list of 20 different items that  relate to her health that she wants to address 
with you in today’s interview. She is very friendl y and relaxed.  What specific type of patient is 
this? 
 
(A) Anxious patient

this? 
 
(A) Anxious patient 
(B) Talkative patient 
(C) Angry or disruptive patient 
(D) Silent patient

2 -3  
5. A 69-year-old woman presents to your office with the complaint of pain.  She was diagnosed 
with breast cancer that has metastasized to the bone 6 months ago.  At the time, she did not want 
radiation therapy even for relief of the pain.  Y ou then discussed with her that her prognosis is 
poor and that her time to live is limited.  She wa s not interested in hearing about it. You observe 
that she has lost more weight and that she is even more anorexic than at her previous visit 1 
month ago.  Today, she is frustrated because she hurts when she gets up and tries to walk 
around.  She has planned a trip to the Bahamas to take place in 4 more months.  What stage of grief is this patient currently in? 
 
(A) Denial 
(B) Anger 
(C) Bargaining 
(D) Depression or sadness 
(E) Acceptance

3 -1  
 
Chapter 3 
Beginning the Physical Examination:  General Survey and Vital Signs 
 
1. A 15-year-old high-school student presents to your  office for a sports physical   He is 65 inches 
in height and weighs 250 pounds.  His BMI falls in which category? 
 
(A) Underweight 
(B) Normal weight 
(C) Overweight 
(D) Obese 
 
2. A 16-year-old sophomore presents to the clinic for a sports physical; she is accompanied by 
her mother.  She is involved in gymnastics and has been since age 5.  In addition to training for 
the gymnastics team, she runs 10 miles per day.  S he is proud of her athleticism and states that 
she is still too fat and wants to lose more weight.   You note that her BMI is 15.  She denies 
eating excessively or making herself vomit.  The patient’s mother states she barely eats.  This 
patient is at risk for which medical problem? 
 
(A) Obesity 
(B) Bulimia 
(C) Anorexia nervosa 
(D) Not at risk; normal adolescence

3 -2  
 
3. A 38-year-old landscape designer presents to t he clinic to be evaluated for a cough.  His vital 
signs show a temperature of 103ºF, a pulse of 120, and a blood pressure of 88/55.  His 
respiratory rate is 28.  He appears to have labored breathing.  All of these indicators are signs of  
 
(A) Pain from the cough 
(B) Anxiety about the visit 
(C) Respiratory distress 
 
4. A 20-year-old college junior presents to the clinic for a physical; he is going to be a camp 
counselor for the summer.  He is healthy and exercises regularly.  His BMI is 22. You take his 
blood pressure and obtain a value of 160/100.  Which of the following is the most likely reason for 
the unexpected blood pressure measurement? 
 
(A) The width of the inflatable bladder of the cuff was 40% of the upper arm circumference 
(B) The length of the inflatable bladder was 50% of the upper arm circumference 
(C) The aneroid sphygmomanometer was calibrated just prior to measuring this patient’s

(C) The aneroid sphygmomanometer was calibrated just prior to measuring this patient’s 
blood pressure 
(D) The patient had sat for 15 minutes prior to the measurement of his blood pressure

3 -3  
5. A 22-year-old social worker comes into the clin ic for a routine checkup.  His blood pressure is 
155/102.  In each of his previous visits, including one 2 weeks ago for treatment of an upper 
respiratory infection, his blood pressure has be en 130s/80s.  He has no family history of high 
blood pressure.  He has no symptoms of headache, blurred vision, or chest pain.  What is the 
most likely reason for his bl ood pressure being elevated today? 
 
(A) He sat down for 10 minutes prior to this measurement being obtained 
(B) He drank a cup of coffee 10 minutes prior to his blood pressure measurement 
(C) His arm was bare when the blood pressure was measured 
(D) He was seated and his arm was supported a little above his waist when the 
measurement was obtained 
 
6. A 58-year-old college professor presents to your clinic to establish care. In taking vital signs, 
you feel the patient’s radial pulse.  The pulse pressure is diminished, and the pulse feels weak

you feel the patient’s radial pulse.  The pulse pressure is diminished, and the pulse feels weak 
and small.  The upstroke feels a little slow, and t he peak is prolonged.  You immediately suspect 
that this patient may have whic h of the following diagnoses? 
 
(A) Hypertrophic cardiomyopathy 
(B) Premature atrial contractions 
(C) Severe aortic stenosis 
(D) Constrictive pericarditis

4 -1  
Chapter 4 
The Skin 
 
1. A 7-year-old elementary school child presents wi th her mother to the clinic for evaluation of 
itching.  They deny any exposure to new soaps or detergents, pollens or grasses, or new foods.  
On physical examination, there are small papules, pustules, lichenified areas, and excoriations.  
Using a magnifying lens, you identify a burrow on the finger webs.  What is the most likely 
diagnosis? 
 
(A) Scabies 
(B) Atopic dermatitis 
(C) Acne 
(D) Telangiectasias 
 
2. A 68-year-old retired mechanic comes to the office for an annual checkup. He is concerned 
that the small red areas on his skin may be canc er.  On physical examination, you see round, 
bright, ruby-red lesions that are 1–3 mm in di ameter and scattered on the anterior chest; they 
partially blanch with pressure.  What is the most likely diagnosis? 
 
(A) Squamous cell carcinoma 
(B) Actinic keratosis 
(C) Cherry angioma 
(D) Spider angioma

4 -2  
 
3. A 55-year-old realtor presents  to your office for evaluation of a skin lesion that has been 
present for a long time.  She came in because her daughter had been reading about skin cancer 
in her favorite women’s magazine and was worried about her mother.  The lesion is located on 
her right cheek.  There is a central depression and a firm elevated border.  Initially, when it first 
appeared 5 years ago, it was translucent.  What is the most likely diagnosis? 
 
(A) Actinic keratosis 
(B) Seborrheic keratosis 
(C) Squamous cell carcinoma 
(D) Basal cell carcinoma 
 
4. A 35-year-old swimming teacher presents to the office for an annual skin examination.  She 
has several tan, flat, round and oval lesions wi th sharply defined borders. The lesions are less 
than 6 mm in diameter.  She has one lesion that is dark, 6.5 mm, and has an irregular border, 
which fades into the surrounding skin.  It is not el evated.  What is your most likely diagnosis of 
this lesion?

this lesion? 
 
(A) Benign nevus 
(B) Dysplastic nevus 
(C) Seborrheic keratosis 
(D) Actinic keratosis

4 -3  
5. You are on rounds at the nursing home when  you are asked to see an 83-year-old retired 
farmer who is bed-ridden.  The aide is concer ned because she has noticed an area on his coccyx 
that is broken down.  You examine the skin and determine that there is a partial thickness skin 
loss, which involves the epidermis.  What stage is this pressure ulcer? 
 
(A) Stage I 
(B) Stage II 
(C) Stage III 
(D) Stage IV 
 
6. A 68-year-old tax attorney is in the hospital with a stroke.  He has residual left-sided paralysis 
and is bed-ridden.  On examination of the skin, you notice an area on his sacrum that is red with 
a boggy consistency, and you diagnose a pressure ulcer.  What stage is this pressure ulcer? 
 
(A) Stage I 
 
7. A 15-year-old boy comes to your clinic co mplaining about pain for the past 2 weeks on the 
bottom of his left foot.  He states that he st epped on a sticker outside and ever since he has had

bottom of his left foot.  He states that he st epped on a sticker outside and ever since he has had 
a spot there that hurts.  He has no significant past medical history.  On exam, you note an 8-mm 
area of thickened skin just proximal to the great toe on his left foot.  There is no redness, warmth, 
or drainage from the area. There are, however,  small dark dots present underneath the thickened

4 -4  
skin.  Pressing against the area causes the patient si gnificant pain.  What disorder of the foot is 
most likely the diagnosis for his case? 
 
(A) Corn 
(B) Callus 
(C) Neuropathic ulcer 
(D) Plantar wart

5 -1 
Chapter 5 
Head and Neck 
 
1. A patient demonstrates left facial droop but  can wrinkle both sides of the forehead. The 
examiner should suspect a problem with: 
 
(A) Central innervation of cranial nerve VII (facial) 
(B) Cranial nerve V (trigeminal) 
(C) Peripheral innervation of cranial nerve VII 
(D) Frontalis muscle 
 
2. Mr. T. is complaining of a headache. He ha s just awakened from a nap and states that the 
headache always begins behind one eye, “feels like an icepick,” and is accompanied by tearing 
and a runny nose. You suspect Mr. T has: 
 
(A) Migraine headache 
(B) Tension  headache 
(C) Cluster headache 
(D) A stroke 
 
3. The muscles in the neck that are innervated by cranial nerve XI are: 
 
(A) Spinal accessory and omohyoid

5 -2 
(B) Sternomastoid and trapezius 
(C) Trapezius and sternomandibular 
(D) Sternomandibular and spinal accessory 
 
4. During your examination you note that your c lient’s eyes are puffy. Y ou further assess coarse 
and dry hair. You suspect: 
 
(A) Scleroderma 
(B) Cachexia 
(C) Myxedema 
(D) Cretinism 
 
5. You have just completed your examination and you document that the patient is unable to 
differentiate between sharp and dull touc h bilaterally. You interpret this as: 
 
(A) Bell’s palsy 
(B) Scleroderma of the face and cheeks 
(C) Damage to cranial nerve V (trigeminal nerve) 
(D) Paralysis 
 
6. You notice that your patient’s submental ly mph nodes are enlarged. You would then assess 
the: 
 
(A) Supraclavicular area

5 -3 
(B) Infraclavicular area 
(C) Area proximal to the enlarged node 
(D) Area distal to the enlarged node

ICase Studies
CASE STUDY # 3
CHIEF COMPLAINT: “ My eye is red and burning.”
History of Present Illness:
Mr. E. is a 55-year-old machinist who comes to your office complaining of pain in
his right eye for the past 24 hours. He describes the pain as severe, aching, anddeep; he has noticed a decline in his vision. He does not wear corrective lenses. Hedenies any work-related exposures. He denies any upper respiratory infection orallergies. He has a history of hypertension and sees his physician regularly forcheckups; he has been told that his blood pressure is controlled on his medication.He has not experienced nausea, vomiting, diaphoresis, or abdominal pain.
Mr. E. has smoked three packs of cigarettes daily for 40 years. He has never
had surgery.
What parts of the exam would you like to perform? (Circle the appropriate areas.)

General Survey Breasts and AxillaeVital Signs Female GenitaliaSkin Male GenitaliaHead and Neck Anus, Rectum, and ProstateThorax and Lungs Peripheral Vascular/ ExtremitiesCardiovascular MusculoskeletalAbdomen Nervous System
What physical findings are you looking for to help determine the diagnosis?CHAPTER 3
The Head and Neck M
Copyright © 2003. Lippincott Williams & Wilkins. Case Studies to Accompany Bates’ Guide to 
Physical Examination and History Taking , eighth edition, by Fiona R. Prabhu and Lynn S. Bickley 9

These are the actual findings on physical examination :
General Survey Alert, muscular, middle-aged man sitting on the 
examining table, holding his head in moderatediscomfort
Vital Signs BP 160/95 mm Hg; HR 90 bpm and regular; respiratory 
rate 12 breaths/min; temperature 98.4°F
Skin No rash; nails without clubbing or cyanosisHEENT Normocephalic, atraumatic
Visual acuity is measured at 20/100 in the right eye 
(O.D.) and 20/20 in the left eye (O.S.); the right pupilis dilated and fixed; the cornea appears cloudy; theright fundus is difficult to visualize
External ear canals patent, tympanic membranes with 
good cone of light 
Sinuses nontender
Oral mucosa pink; dentition good; pharynx is without 
exudates
Neck Supple, without thyromegaly; no cervical or
supraclavicular adenopathy
Thorax and Lungs Thorax symmetric, with increased AP diameter and 
slight hyperresonance over both lung fields
Breath sounds resonant; no wheezes or rhonchi

Cardiovascular JVP 6 cm above right atrium; carotid upstrokes brisk,
without bruits
PMI tapping and nondisplacedGood S
1, S2; no S 3 , S4; no murmurs, rubs, or clicks
Based on this information, what is your differential diagnosis?1. ___________________2. ___________________3. ___________________10
Chapter 3
Physical Examination and History Taking , eighth edition, by Fiona R. Prabhu and Lynn S. Bickley

CASE STUDY #4
CHIEF COMPLAINT:  “I have an earache.”
Johnny B. is a 15-year-old high school student who comes to the office
complaining of an earache that has persisted for the last 3 days. His mother saysJohnny’s forehead felt hot at home, but she did not have a thermometer to checkhis temperature. He has a decreased appetite and a runny nose with clear toyellow drainage. He has been sneezing but not coughing. Some of his classmatesare sick with similar symptoms. 
Johnny is healthy. He has never had surgery, and he does not smoke.
What parts of the exam would you like to perform ? (Circle the appropriate areas.)
What physical findings are you looking for to help determine the diagnosis?

Physical Examination and History Taking , eighth edition, by Fiona R. Prabhu and Lynn S. BickleyThe Head and Neck 11

These are the actual findings on physical examination:
General Survey Alert, interactive, well-nourished adolescent; appears
mildly ill 
Vital Signs BP 100/60 mm Hg; HR 80 bpm and regular; respiratory
rate 24 breaths/min; temperature 100.5°F
Skin No rashHEENT Normocephalic, atraumatic
Pupils equal, round, and reactive to light and
accommodation; constrict from 4 mm to 2 mm
Disc margins sharp; fundi without hemorrhages or
exudates
External ear canals patent, with small amount of
cerumen bilaterally 
Right tympanic membrane red and bulging; left tympanic
membrane dull
Sinuses nontenderNasal mucosa pinkOral mucosa pink without enlarged tonsils; pharynx is
without exudates
Neck Supple, with spotty anterior cervical adenopathy; no
thyromegaly
Thorax and Lungs Thorax symmetric, with good expansion
Lungs resonant; breath sounds vesicular
Cardiovascular JVP 7 cm above the right atrium; carotid arteries brisk,

Based on this information, what is your differential diagnosis?1. ___________________2. ___________________3. ___________________12
Chapter 3

CASE STUDY #5
CHIEF COMPLAINT: “My throat hurts.”
Ashley S., a 7-year-old elementary school student, is brought to your office by her
mother. She has had a fever and a sore throat for 24 hours. She is normallyhealthy and has never had any surgery. Other children in her classroom have beensick with similar symptoms. There are no smokers in her household. She has nodifficulty swallowing.
On review of systems, you elicit the information that she has had clear nasal
drainage and a nonproductive cough. She has not vomited or had diarrhea. Hermother states that Ashley has had a decreased appetite but is drinking liquids. 

Physical Examination and History Taking , eighth edition, by Fiona R. Prabhu and Lynn S. BickleyThe Head and Neck 13

General Survey Alert and interactive child; appears slightly flushed
Vital Signs BP 90/60 mm Hg; HR 100 bpm and regular; respiratory 
rate 20 breaths/min; temperature 103.5°F
Pupils equal, round, and reactive to light and 
External ear canals patent; tympanic membranes pearly 
gray, with good cone of light
Nasal mucosa pinkAnterior tonsils increased in size with purulent exudates 
bilaterally; no evidence of obstruction in the posteriorpharyngeal wall; gag reflex intact
Neck Supple, with no thyromegaly; anterior cervical nodes are 
enlarged to 2 cm; no stridor
Thorax and Lungs Thorax symmetric, diameter is appropriate for age
Breath sounds vesicular
Cardiovascular PMI nondisplaced
Good S
1, S2; no S 3, S4; no murmurs, rubs, or gallops
Abdomen Soft, with active bowel sounds; nontender, without 
hepatosplenomegaly or masses

Good S
Based on this information, what is your differential diagnosis?1. ___________________2. ___________________3. ___________________
IMultiple Choice
Choose the single best answer.
1. A 26-year-old woman presents for evaluation of hair loss. She also has noticed
increased weight loss and diarrhea. You diagnose Graves’ disease(hyperthyroidism). On physical examination of the hair, what would youexpect to find?
(A) Fine texture(B) Coarse texture(C) Oily hair(D) Dry hair14
Chapter 3

2. A 25-year-old swim instructor presents to your clinic complaining of an itchy
scalp. You diagnose seborrheic dermatitis. What physical findings are mostconsistent with this diagnosis?
(A) Erythema of the scalp(B) Pustules on the scalp(C) Dry, flaking areas on the scalp (D) Ecchymoses on the scalp
3. A 55-year-old construction worker presents to the clinic for evaluation of
fatigue and weakness. During the course of the interview, the patient revealsthat he has noticed both an increase in his ring size and his shoe size; you askto look at his driver’s license and also at any pictures that he has in his walletof himself from an earlier time period. Upon looking at these pictures, you areable to strongly theorize that he has acromegaly. Which physical finding ismost consistent with this diagnosis? 
(A) High forehead(B) Small, recessed jaw(C) Coarsening of the facial features(D) Ptosis
4. An 18-year-old college student presents to the clinic with the complaint that

her heart is “racing.” You obtain blood for thyroid studies and diagnose herwith Graves’ disease (hyperthyroidism). On physical examination of her eyes,what would you expect to see?
(A) Recession(B) Protrusion(C) Clouding of the cornea (D) Ciliary injection
5. A 75-year-old retired farmer presents to your office for a hospital follow-up
visit. He was diagnosed with a stroke and placed on medication. On review ofthe hospital chart, he was noted to have a stroke in the optic chiasm. Whatfindings do you expect on examination of his visual fields?
(A) Right homonymous hemianopsia(B) Horizontal defect(C) Bilateral visual field obliteration(D) Bitemporal hemianopsia
6. A 57-year-old auto mechanic comes to your office for evaluation of decreased

vision in his right eye. You perform a fundoscopic examination and diagnosea cataract. What did you see to make this diagnosis?
(A) Absence of the red reflex(B) Neovascularization(C) Hemorrhage in the fundus(D) Uveitis
7. A 38-year-old warehouse stocker presents to your office complaining of a
headache. He has had these headaches intermittently for several years, butthey have been increasing in frequency. In your clinic today, his blood pressure
Physical Examination and History Taking , eighth edition, by Fiona R. Prabhu and Lynn S. BickleyThe Head and Neck 15

is 170/110 mm Hg. His urine dipstick is positive for proteinuria only, and his
fingerstick glucose is 100 mg/dL. You diagnose him with uncontrolledhypertension. What finding on fundoscopic examination would support thisdiagnosis? 
(A) Cotton-wool spots(B) Arteriovenous (AV) nicking(C) Blurred optic disc margins(D) Macular star
8. A 50-year-old truck driver presents to your office for a routine physical
examination. He denies any medical problems; he has never had surgery; hetakes no medications or over-the-counter supplements. He has smoked 1 packof cigarettes daily for 30 years. He does not use alcohol or illicit drugs. Hisfamily history is remarkable for hypertension and stroke. On physicalexamination, you notice that one pupil is larger than the other by 0.4 mm;everything else is normal. What is the most likely diagnosis?
(A) Horner’s syndrome(B) Anisocoria(C) Brain tumor(D) Tonic pupil
9. A 78-year-old grandmother presents for evaluation of weakness in her face.

She has a long-standing history of hypertension that has been under faircontrol. On physical examination, you note that she has ptosis and miosis ofthe left eye, and left facial anhidrosis. What is your most likely diagnosis?
(A) Horner’s syndrome(B) Anisocoria(C) Acute angle-closure glaucoma(D) Myasthenia gravis
10. When you look at the tympanic membrane with the otoscope, what normal
landmark is present? 
(A) Umbo(B) Otoliths(C) Stapes(D) Tragus
11. A 3-year-old boy is brought to your office by his mother for evaluation of
fever, loss of appetite, and emesis. The symptoms have been present for 2days; the fever is only temporarily relieved with antipyretics. You perform aphysical examination and diagnose otitis media. What is your most likelyphysical finding on otoscopic examination?

(A) Erythematous, bulging tympanic membrane(B) Erythematous, retracted tympanic membrane(C) Erythematous, scaly external ear canal(D) Erythematous helix
12. A 15-year-old high school student presents to your clinic complaining of pain
in his left ear. He noticed that it occurred shortly after starting swimming16
Chapter 3

lessons at the local YMCA. Upon physical examination, you notice that the
external canal is swollen and tender during insertion of the speculum. What isyour most likely diagnosis?
(A) Otitis media(B) Serous otitis (C) Eustachian tube dysfunction(D) Otitis externa
13. A 15-year-old member of the high school marching band comes to your office
for evaluation of hearing loss. He had multiple ear infections as an infant andtoddler, and had to have myringotomy tubes inserted in his ears. Additionally,he suffers from many allergies. His hearing is diminished in the right ear.When you place a vibrating tuning fork on the top of his head, the soundlateralizes to the right ear. The name of this test is:
(A) Weber’s test(B) Rinne’s test(C) Whisper test (D) Romberg test
14. Next, you place a vibrating tuning fork on the teenager’s right mastoid

process, asking him to let you know when the sound is gone, thenimmediately place that same tuning fork near his right ear. He hears thesound equally in air as against his bone. The name of this test is:
15. A 22-year-old agricultural worker presents to your office for evaluation of
coughing. She has had this cough for 6 weeks; it is nonproductive and worstfirst thing in the morning. She denies fever, chills, weight loss, or night sweats;she does have clear rhinorrhea and itchy, watery eyes. You diagnose her withallergic rhinoconjunctivitis. On physical examination of the nasal mucosa,what would you expect to find?
(A) Erythematous, ulcerated mucosa(B) Pale to bluish, boggy mucosa(C) Pink mucosa(D) Ulcerated mucosa

16. A 2-week-old infant is brought into your clinic by his parents because they
have noticed that their child is having some difficulty with feeding and thatthere is something strange in his mouth. You diagnose thrush. What is themost likely physical finding you will see upon examination of his mouth?
(A) Koplik’s spots(B) White plaques(C) Erythematous plaques(D) Epstein’s pearls 
Physical Examination and History Taking , eighth edition, by Fiona R. Prabhu and Lynn S. BickleyThe Head and Neck 17

17. A 7-year-old elementary school child is brought into the clinic by her mother
for evaluation of fever and nausea. Upon further physical examination youdiagnose tonsillitis. What are you typically expecting to see on physicalexamination of the oropharynx?
(A) Exudates on the tonsils(B) Small tonsils(C) Hemorrhage of the tonsils(D) Pseudomembranes
18. A 28-year-old housewife presents to your office for a 6-week-postpartum
checkup. She complains of fatigue greater than expected and palpitations. Herhair is falling out as well. She denies sadness or depression symptoms. Beforethis, she had not had any medical problems. She is breast-feeding her childand is not on any birth control. She had her first period since giving birth lastweek. A pregnancy test done in the office is negative. What is your mostlikely diagnosis?
(A) Thyroiditis(B) Iron-deficiency anemia(C) Addison’s disease(D) Sheehan’s syndrome
19. When performing posterior palpation of the thyroid gland, you should do all

of the following EXCEPT: 
(A) Have the patient tip his or her head forward and slightly to the side.(B) Place your index fingers above the cricoid cartilage.(C) Palpate between the sternocleidomastoid muscle and the trachea for the
thyroid isthmus.
(D) Move your fingers laterally to palpate for the thyroid lobes.
IMatching
Match each numbered item with the appropriate lettered phrase or phrases.
EYES
_____ 1. Pupillary reaction to light
_____ 2. Anisocoria_____ 3. Extraocular movements_____ 4. Blind spot_____ 5. Normal visual acuity(A) CN III (oculomotor), CN IV (trochlear), and CN VI (abducens)
(B) 15 degrees temporal to the line of gaze(C) CN II (optic) and CN III (oculomotor)(D) 20/20(E) Pupillary inequality of less than 0.5 mm18
Chapter 3

Chapter 3

EARS
_____ 6. Weber’s test
_____ 7. Rinne’s test_____ 8. Enables optimal examination of adult’s 
tympanic membrane
_____ 9. Enables optimal examination of child’s 
NOSE
_____ 10. Turbinates that are visible on inspection 
_____ 11. Sinuses that are palpable
MOUTH AND PHARYNX
_____ 12. Normal number of adult teeth_____ 13. Raises soft palate_____ 14. Enables tongue protrusion
NECK
_____ 15. Anterior triangle boundaries_____ 16. Posterior triangle boundaries_____ 17. Normal position of the trachea_____ 18. Palpation of the thyroid gland_____ 19. Enlarged thyroid gland(A) Sternomastoid muscle, trapezius muscle,
clavicle
(B) Mandible, sternomastoid muscle, midline of
neck
(C) Presence of a bruit(D) Above the cricoid cartilage(E) Below the cricoid cartilage(F) Midline(A) 32
(B) 28(C) 40(D) CN XII (hypoglossal)(E) CN X (vagus)(F) CN VII (facial)(G) CN VI (abducens)(A) Middle turbinate

(B) Superior turbinate(C) Inferior turbinate(D) Maxillary sinus(E) Frontal sinus(F) Sphenoid sinus(A) Normally air conduction is two times
longer than bone conduction
(B) Lateralization of sound with tuning fork(C) External ear pulled up and backward(D) External ear pulled down and forward
Physical Examination and History Taking , eighth edition, by Fiona R. Prabhu and Lynn S. BickleyThe Head and Neck 19

6-1 
Chapter 6 
The Thorax and Lungs 
 
Case Study 
 
CHIEF COMPLAINT:  “I can’t catch my breath.” 
 
History of Present Illness: 
 Mary is a 25-year-old telemarketer who pres ents to the emergency room for evaluation of 
shortness of breath.  It started 1 week ago, right after a dust storm.  She states that she starts 
coughing, but then she can’t stop, so she feels like she can’t breathe after a while.  The coughing 
is so bad that she has vomited afterward.  T he cough is nonproductive.  She denies fever or 
chills.   She has noticed nasal congestion and a clear runny nose.  She feels like her ears are 
stopped up and she has noticed increased sneezing in the past 3 days prior to the onset of the 
shortness of breath.   She also has itchy, wate ry eyes.  She has a childhood history of asthma,

shortness of breath.   She also has itchy, wate ry eyes.  She has a childhood history of asthma, 
which she has outgrown.  The last time she had an asthma attack, she was 15 years old. 
 She takes oral contraceptives, but is not on any other medication. She has never had any 
surgeries.  When she had asthma as a child, she was never intubated. 
 She smokes 5 cigarettes per day and has since age 18.  She drinks alcohol socially.  She tried marijuana in high school, but denies any ongoing use. 
 Her mother has asthma and her father has high blood pressure. 
 
6-2 
 
General survey Breasts and axillae 
Vital signs Female genitalia 
Skin Male genitalia 
Head and neck Anus, rectum, prostate 
Thorax and lungs Peripheral vascular/extremities 
Cardiovascular Musculoskeletal 
Abdomen Nervous system 
 
6-3 
These are the actual findings on physical examination: 
 
General survey Patient is an alert, young woman, sitting and leaning forward on the 
exam table 
Vital signs BP 150/90 mm Hg; HR 90 bpm and regular; respiratory rate 28 
breaths/min; temperature 100.2°F 
HEENT Skull is normocephalic, atraumat ic.  Hair with average texture. 
Visual acuity 20/20.  Sclera white, conjunctiva with erythema.  Pupils 
constrict from 3 to 1.5 mm, equal, round, and reactive to light and 
accommodation; disc margins sharp without hemorrhages, exudates, 
or arteriolar narrowing 
External ear canals patent; tympanic membranes dull, with decreased 
cone of light 
Nasal mucosa pale and boggy; septum midline, no sinus tenderness. 
Oral mucosa pink, dentition good; pharynx without exudates 
Neck Trachea midline, neck supple without thyromegaly

Neck Trachea midline, neck supple without thyromegaly 
Lymph nodes No cervical, axillary, epitrochlear, or inguinal adenopathy 
Thorax and lungs Thorax symmetric with good expansion 
Lungs with decreased resonance.  Expi ratory wheezes diffusely in all 
lung fields 
Cardiovascular JVP 6 cm above the right at rium; carotid upstrokes brisk without bruits
PMI tapping, 7 cm lateral to the midsternal line in the 5th intercostal 
space.  
Good S1, S2; no S3, S4; no murmurs, or extra sounds 
 
Based on this information, what is your differential diagnosis?

6-4 
1. ______________ 
2. ______________ 
3. ______________ 
 
MULTIPLE CHOICE 
 
1. A patient complains of shortness of breath and productive cough. Consolidation is present in 
the lungs if you find: 
 
(A) Dullness to percussion over left base 
(B) Bronchial breath sounds throughout 
(C) Increased tactile fremitus throughout 
(D) Inspiratory and expiratory wheezes 
 
2. Which of the following is the best technique for assessing the supraclavicular lymph nodes? 
 
(A) Place the patient in a supine position and ask him to hold his breath while you palpate 
(B) Place the patient in Trendelenburg position and illuminate the nodes with a bright light 
(C) Standing behind the patient, palpate deepl y behind the clavicles as he takes a deep 
breath 
(D) Palpate lightly below the clavicles with the patient in a sitting position

breath 
(D) Palpate lightly below the clavicles with the patient in a sitting position 
 
3. The examiner notes an abnormally high diaphr agm on the right side and descent of 4 cm on 
the left side.  These findings suggest: 
 
(A) The patient may have a pleural effusion

6-5 
(B) The patient may have right middle lobe pneumonia 
(C) Asymmetrical findings, which are common in well-conditioned adults 
(D) A normal finding because the right lung is larger than the left lung 
 
4. The following findings indicate a possible pulmonary abscess: 
 
(A) Malodorous breath 
(B) Protrusion of the clavicle 
(C) Clubbing of the nail beds 
(D) Kussmaul respirations 
 
5. The patient has an undiagnosed tumor in the middle lobe of the right lung, causing atelectasis, 
as suggested by  
 
(A) Low-pitched grating sound heard du ring inspiration and expiration 
(B) Hyperresonance in the right middle lobe 
(C) Diminished or absent breath sounds in the right middle lobe 
(D)     An ammonia-like odor on the patient’s breath 
 
6. While auscultating the lungs of an obese patie nt, you would expect the heart sounds to be:

6. While auscultating the lungs of an obese patie nt, you would expect the heart sounds to be: 
 
(A) Louder and closer 
(B) Softer and more distant 
(C) Louder and more distant

6-6 
(D) Softer and closer 
 
7. To rule out a middle lobe pneumonia, you must make sure to auscultate: 
 
(A) Beneath the right breast 
(B) Beneath the left breast 
(C) Under the right axilla 
(D) Under the left axilla 
 
8. When percussing normal lungs, the expected percussion note would be: 
 
(A) Resonance  
(B) Tympany 
(C) Dullness 
(D) Stridor 
 
9. Expected findings in the healthy adult lung include the presence of: 
 
(A) Increased tactile fremitus and dull percussion tones 
(B) Adventitious sounds and limited chest expansion 
(C) Muffled voice sounds and symmetrical tactile fremitus 
(D) Absent voice sounds and hyperresonant percussion tones 
 
10. Dullness on percussion over the left lower lobe of the lung is most likely to reflect:

6-7 
 
(A) Consolidation 
(B) Asthma 
(C) Chronic obstructive pulmonary disease 
(D) Excess adipose tissue 
 
11. The most important technique when progress ing from one auscultory site on the thorax to 
another is: 
 
(A)  Top-to-bottom comparison 
(B) Side-to-side comparison 
(C) Posterior-to-anterior comparison 
(D) Interspace-by-in terspace comparison 
 
12. When auscultating the chest in an adult, you would: 
 
(A) Use the bell of the stethoscope held lightly against the chest to avoid friction 
(B) Use the diaphragm of the stetho scope held firmly against the chest 
(C) Instruct the client to breathe in and out through her nose 
(D) Instruct the patient to take deep, rapid breaths 
 
13. Decreased breath sounds would be most likely to occur: 
 
(A) When the bronchial tree is obstructed 
(B) When adventitious sounds are present

(B) When adventitious sounds are present 
(C)        In conditions of hyperresonance like COPD

6-8 
(D) In conjunction with whispered pectoriloquy 
 
14. A patient presents with an area of dullness to percussion and breath sounds that are 
decreased to absent, suggesting the following diagnosis: 
 
(A) Pneumothorax 
(B) COPD (emphysema) 
(C) Pleural effusion 
(D) Asthma 
 
15. A teenage boy presents to the emergency room  with complaints of sharp pain and trouble 
breathing. You find that the patient has cyanosis, tachypnea, tracheal deviation to the right, decreased tactile fremitus on the left, hyperreso nance on the left, and decreased breath sounds 
on the left. This is consistent with: 
 
(A) Acute pneumonia 
(B) An asthmatic attack 
(C) Bronchitis 
(D) A spontaneous pneumothorax 
 
16. Tachypnea, use of accessory muscles, prolong ed expiration, intercostal retraction, decreased

16. Tachypnea, use of accessory muscles, prolong ed expiration, intercostal retraction, decreased 
breath sounds, and expiratory wheezes are all symptomatic of: 
  
(A) Pleural effusion 
(B) Atelectasis 
(C) Asthma

6-9 
(D) Bronchitis 
 
17. Air passing through narrowed bronchioles woul d produce which of the following adventitious 
sounds: 
 
(A) Whispered pectoriloquy 
(B) Wheezes 
(C) Bronchophony 
(D) Muffled breath sounds 
 
18. The primary muscles of respiration include the: 
 
(A) Diaphragm and intercostals 
(B) Trapezius and rectus abdominus 
(C) Sternomastoids and scalenes 
(D) External obliques and pectoralis major

7-1 
Chapter 7 
The Cardiovascular System 
 
1. A 42-year-old receptionist presents to the offi ce for evaluation of fatigue.  The fatigue has been 
present for several months.  Upon auscultation of  the heart, the S1 sound is accentuated.  Which 
is the most likely cause of her accentuated S1 given her symptoms? 
 
(A) Anemia 
(B) Mitral regurgitation 
(C) Right bundle branch block 
(D) Atrial fibrillation 
 
2. A 38-year-old file clerk presents to your offi ce for evaluation of fatigue.  She has a 20-pack-a-
year history of smoking and had rheumatic heart fever in childhood.  On auscultation of her heart, the S2 sound is widely split; that is, it persists th roughout the respiratory cycl e.  What is the most 
likely cause of the widely split S2? 
 
(A) Physiologic cause 
(B) Pulmonic stenosis 
(C) Atrial septal defect

(C) Atrial septal defect 
(D) Left bundle branch block

7-2 
3. A 19-year-old college student presents to your office for evaluation of episodes of chest pain 
and shortness of breath.  She has no medical probl ems.  She does not smoke, drink alcohol, or 
use illicit drugs.  She is on the dean’s list and is st udying electrical engineering.   On auscultation 
of her heart, you hear a mid-systolic click at the apex.  What is her most likely diagnosis? 
 
(A) Bicuspid aortic valve 
(B) Pulmonary hypertension 
(C) Mitral valve prolapse 
(D) Mitral stenosis 
 
4. A 5-year-old child presents with his parents for a regular checkup.  He has normal growth and development and is appropriately physically active .  On auscultation of his heart, you hear a 
grade 2 murmur at the 2
nd through 4th left interspaces between the left sternal border and the

nd through 4th left interspaces between the left sternal border and the 
apex.  It has a medium pitch, and the quality of the sound is variable.  It does not radiate.  It disappears when the patient is sitting.  What is the most likely cause of this murmur? 
 
(A) Innocent 
(C) Physiologic 
(D) Bicuspid aortic valve 
 
5. A 62-year-old construction worker presents to your office for evaluation of fatigue.  He has an elevated blood pressure with a widened pulse pressure.  Upon auscultation of his heart, you hear 
a mid-systolic murmur at the right second interspace that radiates to the neck.  It has a medium

7-3 
pitch and a harsh quality.  It is best heard when y ou sit the patient up and lean him forward.  What 
is your most likely diagnosis? 
 
(A) Physiologic 
(C) Aortic stenosis 
(D) Hypertrophic cardiomyopathy 
 
6. A 52-year-old computer analyst presents to the office for a checkup.  He is doing well except 
that he has noticed increasing shortness of breath  with physical exertion, so he has cut down on 
his recreational activities.  On auscultation of the heart, you hear a blowing, medium-pitched 
pansystolic murmur at the apex.  It radiates to the left axilla and does not change with inspiration.  
This murmur is most likely: 
 
(A) Mitral regurgitation 
(B) Tricuspid regurgitation 
(C) Ventricular septal defect 
(D) Aortic stenosis

8- 1 
Chapter 8 
The Breast 
 
1. A 21-year-old female presents to your clinic for her annual exam.  She informs you that for the 
last 3 months, she has felt a lump in her left breast above the nipple.  She has had no discharge 
from the nipple.  Her past medical history is non significant.  She has not been sexually active and 
is on no medication.  She denies any tobacco, al cohol, or drug use.  Her paternal grandmother 
had breast cancer in her seventies and did well wi th surgery and radiation.  On physical exam, 
you feel a firm disc like lump at 12 o’clock on the left breast.  It is easily delineated, mobile, and is 
nontender.  The patient only has shoddy nodes in the left axilla.  There are no unusual skin 
changes.  The right breast and the remainder of  her heart, lung, abdominal, and pelvic exam are

changes.  The right breast and the remainder of  her heart, lung, abdominal, and pelvic exam are 
unremarkable. What form of breast mass is she most likely to have? 
 
(A) Fibroadenoma 
(B) Cysts 
(C) Cancer 
 
2. A 48-year-old homemaker comes to your office  complaining of a breast lump she found under 
her right arm while showering.  She says it hasn’t been there during past checks and it doesn’t 
hurt when she examined it.  She admits she hadn’t do ne a self-breast exam in almost 1 year. She 
states she has had three normal mammograms duri ng the last 8 years.  The last mammogram 
was 18 months ago.  Her past medical history is significant for one spontaneous vaginal delivery 
at age 38.  She went through menopause 3 years ago and is on estrogen and progesterone replacement.  She has smoked one pack of cigare ttes daily for the past 25 years but denies any

8- 2 
alcohol or drug abuse.  Past medical history reveals that her maternal aunt had breast cancer in 
her thirties and her maternal grandmother had ovarian cancer in her seventies.  Review of 
systems is noncontributory.  On exam, you feel a hard, approximately 2-cm lump in the tail of 
Spence under the patient’s right arm.  The lump is nontender, and you have difficulty finding the 
borders.  It is not adherent to anything, and you feel no lymphadenopathy in the axilla or 
supraclavicular areas. The skin over the breast appears normal.  Examination of the left breast is 
unremarkable. What type of breast mass is the patient most likely to have? 
 
(B) Cysts 
(C) Cancer 
 
3. A 31-year-old nurse presents to your office complaining about a painful lump in her right breast

(B) Cysts 
(C) Cancer 
 
3. A 31-year-old nurse presents to your office complaining about a painful lump in her right breast 
next to the nipple.  She states it has been there for several months and won’t go away.  She 
recently started taking birth control pills after re marrying.  Her past medical history is significant 
for asthma and two spontaneous vaginal deliveries.  Family history reveals no breast or ovarian 
disorders.  She denies any tobacco or drug use a nd drinks alcohol socially.  On exam, you feel a 
1-cm lump medial to her areola.  It is round so ft and very tender.  There are no skin retractions 
and no palpable lymph nodes in the axilla.  Her le ft breast also has a ½-cm soft lump medial to 
the areola that is not quite as tender.  The patient states she hadn’t noticed that area before. 
What type of breast mass is the most likely cause of her pain? 
 
(B) Cysts 
(C) Cancer

8- 3 
4. A 22-year-old woman comes to your office comp laining of a white discharge from her breasts, 
which has been occurring for 2 months.  She also states that she hasn’t had her period in 6 
months.  She denies any chance of pregnancy since she hasn’t been sexually active in over 1 
year.  She is on no medications except a multivitam in.  Her past medical history is significant for 
allergies only.  Past medical history reveals a mother with cystic breasts and a great aunt with 
breast cancer.  Review of systems is noncontri butory.  On exam, her breasts are symmetrical, 
with no skin changes.  You are able to express milky discharge from each nipple.  You feel no 
discrete masses, and her axillae are normal.  The remainder or her heart, lung, abdominal, and 
pelvic exam are unremarkable.  What cause of nipple discharge is the most likely in her

pelvic exam are unremarkable.  What cause of nipple discharge is the most likely in her 
circumstance? 
 
(A) Benign breast abnormality 
(B) Breast cancer 
(C) Nonpuerperal galactorrhea 
 
5. A 76-year-old widow comes to your clinic to es tablish care.  She admits that she hasn’t seen a 
clinician in over 5 years, but her daughter has been nagging her to be seen.  She states she has 
noticed that an area to the outside of her left breast feels enlarged, and there are some different 
changes to the skin in the area.  Her past m edical history is significant for two spontaneous 
vaginal deliveries and diet-controlled diabetes.  She denies any tobacco or drug use and no 
alcohol abuse.  Her review of systems is remarkable for a 10-pound weight loss in the last 6 
months and some recent fatigue.  On exam, you find an elderly woman appearing her stated age.

months and some recent fatigue.  On exam, you find an elderly woman appearing her stated age.  
Inspection of her left breast reveals some thick ening of the skin lateral to her areola, with 
enlarged pores. You feel a nontender 5-cm mass.  The axilla has at least two enlarged lymph 
nodes, which are adherent to the underlying ribs. The right breast and axilla are unremarkable. 
What visible skin change of the breast does she have?

8- 4 
(A) Nipple retraction 
(B) Paget’s disease 
(C) Peau d’orange sign

9 -1 
Chapter 9 
The Abdomen 
 
Case Study 
 
CHIEF COMPLAINT:   “My stomach hurts.” 
 
 Graham is a 55-year-old administrator who presents for evaluation of stomach pain.   The 
pain started 3 days ago.  He points to the left lowe r quadrant of the abdomen.  He describes it as 
a sharp pain that initially came, went, and is now constant. On a scale of 1–10, he rates it a 9 at 
the worst and a 2 at the least.  Nothing makes it be tter or worse.  There is no relation to eating.  
He has noticed some fever and chills along with nausea.  Prior to the onset of the pain, he had been constipated for almost 5 days and had to take a laxative to have a bowel movement.  He 
denies recent changes in weight; he denies shortn ess of breath, chest pain, vomiting, and bright

denies recent changes in weight; he denies shortn ess of breath, chest pain, vomiting, and bright 
red blood per rectum, melena, and dysuria.  He has never experienced this before. 
 He has a history of hypertension and gastroesophageal reflux disease.  He had a right 
inguinal hernia repair at age 22.  He takes three medications to keep his blood pressure under 
control, and one medication for the reflux. 
 His father had hypertension; he died of complications of colon cancer at age 75.  His 
mother had diabetes and hypertension; she died of a heart attack at age 60.

9 -2 
 
What parts of the exam would you like to perform? (Circle the appropriate areas.) 
 
Abdomen Nervous system

9 -3 

9 -4 
 
General survey Patient is an alert, older man, sitting on the examination table in 
obvious discomfort 
Vital signs BP 180/90 mm Hg; HR 100 bpm and regular; respiratory rate 20 
breaths/min.; temperature 100.5°F 
space.  
Abdomen Protuberant with active bowel sounds. 
Soft, tender to palpation in the left lower quadrant without rebound or 
guarding; no masses.  Liver span is 7 cm in the right mid-clavicular 
line; edge is smooth and palpable 1 cm below the right costal margin.  
Spleen and kidneys not felt.  No costovertebral angle tenderness.

Spleen and kidneys not felt.  No costovertebral angle tenderness. 
Anus, rectum, prostate No perirectal lesions or fissures.  External sphincter tone intact. 
Rectal vault without masses; tendern ess to palpation in the left side.  
Prostate smooth and non-tender with palpable median sulcus (uterine 
cervix nontender).  Stool br own and hemoccult positive.

9 -5 
Based on this information, what is your differential diagnosis? 
 
3. ______________

9 -6 
Case Study   
 
CHIEF COMPLAINT:   “My back hurts.” 
 
History of Present Illness 
 Jennifer is a 22-year-old law student who presents to the emergency room because of 
severe, cramping, left-sided back pain.  The pain initially came and went, but has been constant 
for the last 8 hours.  She has tried Tylenol and Motr in, but they only relieve the pain for a couple 
of hours.  The pain does not radiate.  She has fe lt feverish, but hasn’t taken her temperature.  
She states that the pain star ted 2 days ago.  She has been nauseated and has vomited today.  
She denies abdominal pain or diarrhea.  She states  that she started having pain with urination 2 
days ago and now she is having difficulty urinating at all.  She denies blood in her urine.  She 
denies vaginal discharge, she denies pain with intercourse.

denies vaginal discharge, she denies pain with intercourse. 
 She is normally healthy.  She has had severa l urinary tract infections over the past 5 
years, which resolved with antibiotics.  She ta kes oral contraceptives  and has since age 17. 
 She does not smoke.  She drinks alcohol on the weekends with friends.  She tried 
marijuana in high school, but doesn’t use any illicit drugs currently. 
 Her mother is healthy; her father has asthma.  
 
9 -7 
 
9 -8 

9 -9 
General survey Patient is an alert, young woman who is ill appearing.  She is sitting 
quietly on the examination table. 
Vital signs BP 105/75 mm Hg; HR 120 bpm and regular; respiratory rate 18 
breaths/min.; temperature 103°F 
space.  
Good S1, S2 with tachycardia; no S3, S4; no murmurs, or extra 
sounds 
Soft, tender to palpation in the lo wer abdomen, over the bladder 
without rebound or guarding; no masses or hepatosplenomegaly 
Liver span is 7 cm in the right mid- clavicular line; edge is smooth and 
palpable 1 cm below the right costal margin.  Spleen and kidneys not

palpable 1 cm below the right costal margin.  Spleen and kidneys not 
felt.  Costovertebral angle tenderness is present on the left side.  
Female genitalia No inguinal adenopathy.  External genitalia without erythema or 
lesions; no lesions or masses. Uterus anterior, midline, smooth, and not enlarged.  No cervical mo tion or adnexal tenderness.  
Rectovaginal wall intact. 
Rectal vault without masses.  Uterine cervix nontender.  Stool brown 
and hemoccult negative.

9 -10 
 
4. ______________ 
5. ______________ 
6. ______________

9 -11 
 
Case Study 
 
 Mariah is a 10-year old who is brought to the emergency room by her mother because 
she has complained of abdominal pain and had a fever of 101ºF at home.  Mariah’s mother 
notices that she has had a decreased appetite for the past day.  Mariah admits to feeling 
nauseous.  She vomited just before being brought to the clinic.  She has not had diarrhea.  The 
pain started out as all over the stomach, and has now gone into the bottom right side of her 
stomach.  It does not go anywhere else. She has not started her period yet.  She denies dysuria. 
 Mariah is normally healthy.  She has never had any surgeries.  She does not smoke.  
She has never tried illegal drugs. 
 Her mother is healthy.  Her father is healthy.

Mariah is normally healthy.  She has never had any surgeries.  She does not smoke.  
 Her mother is healthy.  Her father is healthy. 
 
9 -12 
 
9 -13 
 
9 -14 
 
General survey  
ED; PLEASE PROVIDE. 
 
Vital signs BP 100/60 mm Hg; HR 110 bpm and regular; respiratory rate 18 
breaths/min.; temperature 102°F 
Cardiovascular Good S1, S2; no S3, S4; no murmurs, or extra sounds 
Soft, tender to palpation in the right lower quadrant without rebound 
or guarding; no masses.  Spleen, liver, and kidneys not felt.  No 
costovertebral angle tenderness. 
Rectal vault without masses.  Ut erine cervix nontender.  Tenderness 
to palpation in the right side of  the rectal vault. Stool brown and 
hemoccult negative.

9 -15 
 
7. ______________ 
8. ______________ 
9. ______________

9 -16 
 
1. An 83-year-old woman presents to the ER the afternoon of Thanksgiving complaining of severe 
abdominal pain.  She states it was at first cr amping around her navel but has now radiated to the 
rest of her abdomen.  She also complains of some vomiting and bloody diarrhea.  About 1 hour 
before the pain started, she had a large traditional holiday meal.  She states she generally only 
eats about half a sandwich and some soup at m eals. She denies any earlier history of similar 
pain.  Her past medical history is significant for coronary artery disease, for which she has had a 
stent placed in the past.  She is only taking medicines related to her heart condition.  She denies 
any alcohol, drug, or tobacco use.  Her review of  systems is positive for soreness in her legs

any alcohol, drug, or tobacco use.  Her review of  systems is positive for soreness in her legs 
while walking and occasional chest pain on exertion.  On exam, you find an elderly woman in 
great distress.  She is pale and tachycardic.  Examining her abdomen, you hear decreased bowel 
sounds.  On palpitation, her abdomen is rigid with voluntary guarding and rebound.  Her rectal exam shows grossly bloody stool. What diagnosis for abdominal pain best describes her 
symptoms and signs? 
 
(A) Acute pancreatitis 
(B) Acute cholecystitis 
(C) Acute appendicitis 
(D) Mesenteric ischemia  
 
2. A 35-year-old male athlete comes into the ER complaining of severe lower abdominal pain and 
vomiting.  He relates the pain began several hours ago after he cycled at the gym and lifted

vomiting.  He relates the pain began several hours ago after he cycled at the gym and lifted 
weights.  He states he has had occasional lower abdominal pain with lifting weights in the past but nothing like this.  He has no significant past medical history and denies any tobacco, drug, or 
alcohol use.  On exam, you find a young man who appears very ill.  He is pale and vomiting clear

9 -17 
green liquid.  As you examine him, his emesis becomes darker and malodorous.  On exam, he 
has high-pitched increased bowel sounds and has voluntary guarding and rebound.  His testicles 
are descended bilaterally, and his right testicle seems tender and enlarged.  Auscultating it, you 
also hear bowel sounds.  What diagnosis is most likely the cause of his pain? 
 
(B) Acute mechanical intestinal obstruction 
(C) Acute cholecystitis 
(D) Mesenteric ischemia 
 
3. A 39-year-old seamstress presents to the ER complaining of severe upper abdominal 
pain that started about 2 hours ago.  She had eaten a cheeseburger and fries 45 minutes before the pain began.  She tried taking some calcium stomach tablets, but they 
didn’t help.  She states the pain is a 10 on a 10-point scale and is starting to hurt in her

didn’t help.  She states the pain is a 10 on a 10-point scale and is starting to hurt in her 
back.  She says she is nauseated and needs to vomit.   She does admit to having had 
milder pains similar in the past but never to this extent.  Her past medical history is 
significant for high blood pressure and two caesarean sections.  Her older sister and mother have had to have gallbladder surgery.  She denies any tobacco, drug, or alcohol 
use.  Her review of systems is noncontributor y.  On examination, you find a mildly obese 
woman in severe distress.  She is lying on the stretcher, but she cannot find a 
comfortable position.   Her blood pressure is mildly elevated at 140/85, and her heart 
rate is 110.  Her temperature is normal.  Her abdominal exam reveals normal bowel 
sounds, but she is tender in the right upper quadrant.  She has a positive Murphy’s sign.  
The remainder of her abdominal exam is normal.  Her rectal is heme negative, and her

9 -18 
pelvic exam is normal.  What etiology of abdominal pain is most likely causing her 
symptoms? 
 
(A) Peptic ulcer disease 
(B) Biliary colic 
(D) Acute pancreatitis 
 
4. A 68-year-old homemaker presents to your clinic complaining of difficulty swallowing.  It began several months ago when she would attempt to eat steak.  Over time, it has progressed to the point that she can only sip on soups and broths.  She has sometimes 
had to regurgitate her food back up to get relief from the pain in her chest when she 
attempts to eat.  Her past medical history is significant for diet controlled, type-2 
diabetes.   She had a 60-pack-year smoking history but quit smoking 15 years ago.  She 
denies any drug or alcohol abuse.  On review  of systems, she has lost approximately 15

denies any drug or alcohol abuse.  On review  of systems, she has lost approximately 15 
lbs in the past 3 months.  She denies any heartburn, constipation, or diarrhea.  On 
exam, you find a pleasant elderly woman in no acute distress.  Her cardiac, pulmonary, 
and abdominal exams are all normal.  What disorder of dysphagia is the most likely cause for her symptoms? 
 
(A) Esophageal stricture 
(B) Esophageal cancer 
(C) Esophageal spasm 
(D) Scleroderma

9 -19 
 
5. A 26-year-old woman follows up at your office for her 6-week postpartum visit.  She 
complains of severe constipation problems since the birth of her last child.  Although she says she is eating healthy and drinking plenty of fluids, the problem persists.  She does 
complain of pain with defecation.  She denies any abdominal pain, nausea, vomiting, or 
diarrhea.  She has never had problems with constipation except for during her 
pregnancies.  Her past medical history is significant for two vaginal deliveries.  She 
denies any tobacco, drug, or alcohol use.  She is currently taking only prenatal vitamins.  She has no family history of any bowel pr oblems.  On exam, she has normal bowel

denies any tobacco, drug, or alcohol use.  She is currently taking only prenatal vitamins.  She has no family history of any bowel pr oblems.  On exam, she has normal bowel 
sounds, and her abdomen is soft with no rebound or guarding.  Her pelvic exam reveals that her uterus has returned to nongravid size and that her episiotomy site has healed.  Her rectal exam is painful and is positive for occult blood.  What is the best choice for the 
cause of her constipation? 
 
(A) Obstructing lesion  
(B) Irritable bowel syndrome 
(C) Rectal cancer 
(D) Painful anal lesions 
 
6. A 19-year-old male college student presents to your clinic the week following spring 
break complaining of 1-day abdominal pain and watery diarrhea.  He thinks he has seen blood mixed with his stool. He has had some nausea but no vomiting.  He had recently 
traveled to Central America over the break to go scuba diving.  His past medical history

traveled to Central America over the break to go scuba diving.  His past medical history 
is not significant.  He drinks six to ei ght beers during the weekend but denies any

9 -20 
tobacco or drug use.  On review of symptoms, he does have night sweats and rigors.  
On exam, you find he is febrile at 102.3°F and he is tachycardic at 115 bpm.  Otherwise, 
his heart and lung exam are normal.  Upon auscultation, he has increased bowel 
sounds, and on palpation, he is diffusely tender.  He has no rebound or guarding, but his rectal is guaiac positive.  What cause of diarrhea is most likely? 
 
(A) Secretory infections 
(B) Inflammatory infections 
(C) Irritable bowel syndrome 
(D) Malabsorption syndrome 
 
7. A 38-year-old unemployed man presents to th e ER complaining of black tarry stools 
that now have blood in them.  He states he has also had some severe pain in his stomach for the last few days.  He vomited once and thinks he saw some blood.  His

that now have blood in them.  He states he has also had some severe pain in his stomach for the last few days.  He vomited once and thinks he saw some blood.  His 
past medical history is significant for pancreatitis and asthma.  He has smoked two 
packs of cigarettes for 25 years and drinks approximately 12 beers a day.  He denies any IV drug use. He has had no recent out-of- state travel. On review of symptoms, he 
notes that he has fainted in the last day.  On exam, you find a cachetic man appearing older than his stated age.   He is afebrile but tachycardic, at 120 bpm.  Otherwise, his heart and lung exam are normal.  On inspection, he has no dilated veins around his 
umbilicus or skin of an unusual color.  Increased bowel sounds are heard during 
auscultation.  Palpation reveals diffuse tenderness, which is more severe in the epigastric area.  His liver percusses 12 cm in the right midclavicular line, and he has no

auscultation.  Palpation reveals diffuse tenderness, which is more severe in the epigastric area.  His liver percusses 12 cm in the right midclavicular line, and he has no 
fluid wave.  He is grossly positive for blood on his rectal exam.  What cause of black 
stools most likely describes his symptoms and signs?

9 -21 
 
(A) Gastritis 
(B) Inflammatory infectious diarrhea 
(C) Mallory-Weiss tear 
(D) Esophageal varices 
 
8. A 37-year-old female bank teller presents to your office complaining about 
accidentally urinating on herself.  She relates this has happened several times in the last month.  She states she realizes that she has to go to the bathroom, but before she can 
make it to the toilet, she soils herself.  Upon further questioning, it is revealed that for 
years she has had to urinate frequently during the day and at night.  She had thought these were bladder infections, but the urine lab tests were always normal.  Her past 
medical history is significant for migraines and depression.  She denies any tobacco or 
drug use.  She drinks alcohol socially several times a year.  On review of systems, she

drug use.  She drinks alcohol socially several times a year.  On review of systems, she 
relates pelvic pain with sexual intercour se.  On exam, she has a normal abdominal, 
rectal, and pelvic exam.  Her bladder is appropriate in size, and her urinary analysis is negative for blood or signs of infection.  Which type of urinary incontinence does she 
have? 
 
(A) Stress incontinence 
(B) Urge incontinence 
(C) Overflow incontinence

■Case Studies M
CASE STUDY # 10
CHIEF COMPLAINT: “I have pain in my stomach.”
Ms. G. is a 42-year-old housewife who makes an appointment at your clinic
because she has been experiencing pain in her upper abdomen for the past 3months. She describes the pain as an “ache” that sometimes radiates into her rightupper back and right shoulder. The pain gets worse after eating fatty or greasyfoods, so she has eliminated these foods from her diet. She feels nauseated whenthe pain occurs and sometimes vomits. She denies fever or chills, weight loss, chestpain, diarrhea, constipation, melena, rectal bleeding, or dysuria. She has not beenexposed to anyone who has been sick.
Ms. G. is healthy. She does not smoke, drink, or use illicit drugs.Her family history is significant for hypertension in her mother and diabetes in
her father. Her mother had gallbladder surgery in her mid-40s.

What physical findings are you looking for to help determine the diagnosis?CHAPTER 7
The Abdomen M
Physical Examination and History Taking , eighth edition, by Fiona R. Prabhu and Lynn S. Bickley 35

General Survey Alert, obese, middle-aged woman, sitting comfortably on 
the examining table
Vital Signs BP 120/80 mm Hg; HR 80 bpm and regular; respiratory 
rate 16 breaths/min; temperature 99.2°F
accommodation; constrict from 5 mm to 3 mm
Disc margins sharp, fundi without hemorrhages or 
exudates
External ear canals patent; tympanic membranes with 
good cone of light
exudates
Neck Supple, without thyromegaly; no lymphadenopathyThorax and Lungs Thorax symmetric, with normal AP diameter
Lungs resonant and clear
Cardiovascular JVP 6 cm above right atrium; carotid upstrokes brisk, 
1, S2; no S 3, S4; no murmurs
Abdomen Abdomen is obese, with active bowel sounds
Abdomen is soft but tender to palpation in the right

Abdomen is soft but tender to palpation in the right 
upper quadrant during inspiration, with a liver span of9 cm in the right MCL
The liver edge is smooth and palpable one finger-breadth 
below the RCM
Spleen is nonpalpableNo CVA tenderness; no femoral or abdominal bruits 
Based on this information, what is your differential diagnosis?1. ___________________2. ___________________3. ___________________36
Chapter 7

■Multiple Choice
1. What is the preferred order for examination of the abdomen?
(A) Inspection, auscultation, percussion, palpation (B) Percussion, auscultation, palpation, inspection(C) Auscultation, inspection, palpation, percussion(D) Inspection, palpation, auscultation, percussion
2. You are in the emergency room assessing a patient with abdominal pain and
fever. You are performing an abdominal examination to assess for peritonealsigns. Which one of the following is NOT a peritoneal sign?
(A) Rebound tenderness(B) Involuntary guarding(C) Rigidity of the abdomen(D) Voluntary guarding
3. A 15-year-old high school student presents to the clinic with a 1-day history of
nausea and anorexia. He describes the pain as generalized yesterday, but todayit has localized to the right lower quadrant. You palpate the left lowerquadrant and the patient experiences pain in the right lower quadrant. What isthe name of this sign?

(A) Psoas sign(B) Obturator sign(C) Rovsing’s sign(D) Cutaneous hyperesthesia
4. A 25-year-old veterinarian presents to the clinic for evaluation of flank pain,
dysuria, nausea, and fever. A urine pregnancy test is negative. A urine dipstickis positive for leukocyte esterase. On physical examination, what would be themost likely sign expected?
(A) Psoas sign(B) CVA tenderness(C) Rovsing’s sign(D) Murphy’s sign
5. A 40-year-old flight attendant presents to your office for evaluation of
abdominal pain. It is worse after eating, especially if she has a meal that isspicy or high in fat. She has tried over-the-counter antacids, but they have nothelped the pain. After examining her abdomen, you strongly suspectcholecystitis. Which sign on examination increases your suspicion for thisdiagnosis?
(A) Psoas sign(B) Rovsing’s sign(C) Murphy’s sign(D) Grey Turner’s sign
Copyright © 2003. Lippincott Williams & Wilkins. Case Studies to Accompany Bates’ Guide to

Physical Examination and History Taking , eighth edition, by Fiona R. Prabhu and Lynn S. BickleyThe Abdomen 37

6. A 25-year-old celebrity with a known history of intravenous drug use presents
to the emergency room for evaluation of a 5-day history of nausea, emesis, andright-upper-quadrant abdominal pain. On general survey, he appears ill and hisskin is distinctly yellow. He has a temperature of 102.5°F and a heart rate of112 bpm. You provisionally diagnose him with acute hepatitis. What wouldyou expect to find on abdominal examination?
(A) Liver edge is tender and 4 to 5 finger-breadths below the RCM(B) Liver edge is nonpalpable(C) Liver edge is tender and 1 finger-breadth below the RCM(D) Liver edge is nontender and 4 to 5 finger-breadths below the RCM
■Matching
_____ 1. Liver edge
_____ 2. Spleen edge_____ 3. Rovsing’s sign_____ 4. Psoas sign_____ 5. Obturator sign_____ 6. Cutaneous hyperesthesia
■Labelling
Label the abdominal organs on the anterior view in the following figure.
1.
2.
3.4.
5.

1.
2.
3.4.
5.
6.(A) Palpable deep to the left costal margin during inspiration
(B) Palpable 6 cm below the right costal margin in the midclavicular
line during inspiration
(C) Pain elicited when the patient’s right thigh is flexed at the hip with
the knee bent, and the leg is internally rotated at the hip
(D) Examiner’s hand is placed on the patient’s right knee and the
patient is asked to raise his or her right thigh against the examiner’shand
(E) Pain elicited by gently picking up a fold of abdominal skin anteri-
orly
(F) Pain in the right lower quadrant during palpation of the left lower
quadrant38
Chapter 7

Label the abdominal organs on the posterior view in the following figure.
Label the arteries on the following figure.
11.
12.
13.
14.
7.
8.
9.
10.
Physical Examination and History Taking , eighth edition, by Fiona R. Prabhu and Lynn S. BickleyThe Abdomen 39

10-1 
Chapter 10 
Male Genitalia and Hernias 
 
1. When performing a genitourinary assessment, yo u note that the urethral meatus is positioned 
ventrally. This is most likely to be: 
 
(A) A stricture 
(B) Hypospadius 
(C) The result of a circumcision 
(D) Related to the aging process 
 
2. When performing a genitourinary assessment on an adolescent male you notice a swelling in 
the scrotum, which increases with increased intraabdominal pressure and decreases when lying 
down. The young man complains of pain when straining. This history best describes: 
 
(A) An incisional hernia 
(B) A direct inguinal hernia 
(C) An indirect inguinal hernia 
(D) A femoral hernia 
 
3. The following finding is considered normal when assessing an aging male: 
 
(A) A decrease in scrotal color 
(B) Enlargement of the testes and scrotum 
(C) A decrease in the size of the penis

(C) A decrease in the size of the penis 
(D) The presence of a hydrocele, or fluid in the scrotum

10-2 
 
4. When instructing patients about how to perform a testicular self-exam, which of the following 
statements is most correct: 
 
(A) “A good time to examine your testicle s is just before you take a shower.” 
(B) “Perform the testicular exam at least once  a week to detect the early stages of cancer.” 
(C) “The testicle should feel firm and has a lumpy consistency, be movable, and shaped like an 
egg.” 
(D) “If you notice any change from what you normally see or feel, ca ll your health care provider.” 
 
5. Which of the findings is a normal finding when examining the glands? 
 
(A) The skin is wrinkled and without lesions 
(B) The dorsal vein may be visible 
(C) Smegma may be present under the foreskin of an uncircumcised male 
(D) There is no hair 
 
6. Which of the following statements is true when performing a male genital examination?

6. Which of the following statements is true when performing a male genital examination? 
 
(A) Auscultate for the presence of bowel sounds over the scrotum in all males 
(B) Palpate for the vertical chain of lymph nodes along the groin inferior to the inguinal ligament 
(C) Palpate the inguinal canal only if there is a bulge present in the inguinal region during 
inspection 
(D) When palpating for a hernia on the right side,  have the client shift his standing weight onto 
the left leg

11- 1 
 
Chapter 11 
Female Genitalia 
 
1.  When observing the vestibule, you should be  able to see which of the following anatomic 
structures? 
 
(A) Urethral meatus and paraurethral (Skene’s) glands 
(B) Vaginal orifice and vestibular (Bartholin’s) glands 
(C) Urethral meatus and vaginal orifice 
(D) Paraurethral (Skene’s) and vestibular (Bartholin’s) glands 
 
2. To correctly insert the speculum: 
 
(A) Instruct the woman to bear down, open the speculum blades and apply in a swift upward 
movement 
(B) Press the inferior margin of the introitu s down to enlarge the vaginal opening, open, insert 
the speculum with the blades at an oblique downward angle, and apply gentle downward 
pressure 
(C) Insert the blades of the speculum on a horizontal plane, turning them to a 45° angle as

pressure 
(C) Insert the blades of the speculum on a horizontal plane, turning them to a 45° angle as 
you continue to insert them; ask the woman to bear down to ease insertion 
(D) Lock the blades open by turning the thumbscrew. Once you have them open, apply 
pressure to the introitus and insert the blade s at a 45° angle downward to bring the cervix 
into view

11- 2 
 
3.  In performing the bimanual examination, you note that the cervix  feels smooth and firm, 
is round, and is fixed. Your cervical palpation produces some pain. The best  
interpretation of these results is: 
 
(A) These findings are well within normal limits 
(B) It is unusual to have pain when palpating the ce rvix, but the rest of the findings are within 
normal limits 
(C) The cervix should move when palpated; an immobile cervix may indicate malignancy 
(D) The cervical consistency should be soft and velvety and not firm

12-1 
Chapter 12 
The Pregnant Woman 
 
Case Study 
 
CHIEF COMPLAINT:   “My periods are irregular.” 
 
A 16-year-old high school junior presents to t he clinic for evaluation of irregular menses.  
Her periods were regular until 4 months ago.  She first skipped a period then had some light 
spotting, which lasted for 2 or 3 days, and then it  went away.  Last week, the spotting returned 
and lasted 1 day.   
She has noticed increased tiredness and was nauseated for a few weeks, but it went 
away a couple of weeks ago.  She denies any fever or chills.  She denies abdominal pain or 
vaginal discharge.  She has noticed some intermitte nt low back pain.  She has not used any over-
the-counter medications to treat the pain.  
She states that her menses started at age 13; the menses last 5 days on average. She

She states that her menses started at age 13; the menses last 5 days on average. She 
has never been pregnant.  She is sexually active and is in a monogamous relationship.  She uses 
oral contraceptives for birth control; her partner uses a condom. 
 She is healthy; she has never taken any medications on a regular basis. 
 She does not smoke; she drinks alcohol on the weekends with friends, but no more than 1 or 2 drinks over the weekend; s he has never used illicit drugs.   
 
12-2 
 
12-3 
 
General survey Alert, young woman sitting comfortably on the examination table. 
Vital signs BP 105/72 mm Hg; HR 75 bpm and regular; respiratory rate 18 
breaths/min; temperature 98.5°F 
Soft, nontender, with a palpable mass below the umbilicus; there is 
no hepatosplenomegaly 
felt.  No costovertebral angle tenderness. 
lesions; no lesions or masses.  Vaginal mucosa pink.  Cervix 
nulliparous, purple, with a clear disc harge.  Uterus anterior, midline, 
smooth, and enlarged to 16 cm.  No  adnexal tenderness.  Pap smear

smooth, and enlarged to 16 cm.  No  adnexal tenderness.  Pap smear 
obtained.  Rectovaginal wall intact.

12-4 
 
Mutiple Choice 
 
1. Correct instructions about the se lf-breast examinat ion (BSE) are:  
 
(A) Tell the woman that the best time to perform BSE is in the middle of the menstrual cycle 
(B) Recommend that the best time to perform  BSE is 4–7 days after the first day of the 
menstrual period 
(C) Tell the woman that if s he is pregnant, she should not perform BSE until the baby is born 
(D) Urge the woman that she needs to do BSE bi monthly unless she has fibrocystic breast 
tissue  
 
2. You have just completed a vaginal examinat ion of a woman who is 6 weeks pregnant. You 
read on her chart that her cervix is softened and looks cyanotic. You know that she is exhibiting 
which of the following signs?

which of the following signs? 
 
(A) Chadwick’s sign and Hegar’s sign 
(B) Goodell’s sign and Chadwick’s sign 
(C) Hegar’s sign and Goodell’s sign 
(D) Tanner’s sign and Hegar’s sign

12-5 
 
3. During your examination of a woman in her second trimester of pregnancy, you note the 
presence of a small amount of yellow drainag e from the nipples. You know that this is: 
 
(A) Most likely to be colostrum and considered a normal finding this late in her pregnancy 
(B) A sign of breast cancer 
(C) Too early in the pregnancy for lactation to begin; the woman needs a referral to a 
specialist 
(D) An indication that the woman’s milk is forming 
 
4. When palpating the fundus, you know that: 
 
(A) Fundal height is usually less than the num ber of weeks gestation, unless there is an 
abnormal condition such as too much amniotic fluid present 
(B) The fundus should be hard and slightly tende r to palpation during the first trimester 
(C) After 20 weeks gestation, the number of centimeters should approximate the number of 
weeks gestation

weeks gestation 
(D) Fetal movement should be felt by the exam iner at the beginning of the second trimester 
 
5. You are palpating the abdomen of a 35-week pregnant woman and note that the fetal head is 
facing downward toward the pelvis. You would document this as: 
 
(A) Fetal lie 
(B) Fetal presentation 
(C) Fetal attitude

13- 1
Chapter 13 
The Anus, Rectum, and Prostate 
 
1. A 28-year-old bus driver presents to the emergency room for pain and drainage from an area 
at the bottom of her spine.  This has never occu rred before.   On examination of the rectum, a 
small opening is identified in the midline s uperficial to the lower sacrum.  There is a 
surrounding halo of erythema.  It is tender to palpation and purulent material is expressed.  
Your most likely diagnosis of this condition is? 
 
(A) Anorectal fistula 
(B) Pilonidal cyst 
(C) Anal fissure 
(D) Thrombosed external hemorrhoid 
 
2. A 24-year-old housewife and mother presents to the clinic for evaluation of rectal bleeding.  
She has intermittent constipation and frequently has to use a laxative to have a bowel movement.

She has intermittent constipation and frequently has to use a laxative to have a bowel movement.  
On examination of the anus, you see a reddish, mo ist, protruding mass located at the 5 o’clock 
position.  What is your most likely diagnosis? 
 
(A) Hemorrhoid 
(B) Internal hemorrhoid 
(C) External rectal prolapse 
(D) Rectal polyp

13- 2
 
3. A 35-year-old accountant presents to the clinic for evaluation of sudden onset of pain in his 
rectum.  On examination of the anus, you see a sw ollen, bluish, ovoid mass at the anal margin, 
located at the 8 o’clock position.  What is your most likely diagnosis? 
 
(A) External hemorrhoid 
(C) Rectal prolapse 
(D) Rectal polyp 
 
4. A 32-year-old farmer presents  to the clinic for evaluation of pain with defecation as well as 
rectal bleeding.  His family history is negative for inflammatory diseases of the bowel and for 
colon cancer.  On physical examination, there is a swollen skin tag, and, with gentle separation of 
the anal margin, a thin line of ulceration is visible.  What is your most likely diagnosis? 
 
(A) Pilonidal cyst 
(B) Anorectal fistula 
(C) External thrombosed hemorrhoid

(C) External thrombosed hemorrhoid 
(D) Anal fissure 
 
5. A 65-year-old gardener presents to the office for difficulty with urination.  Increasingly, he has 
noticed feeling like his bladder has not emptied completely and his urinary stream has a 
decreased force.  He experiences dribbling after he completes urination.   These symptoms have 
been going on for several years, but his level of discomfort has increased over the past few 
months.  On physical examination, you feel a symmetrically enlarged, smooth, and firm prostate

13- 3
gland, which seems to protrude more into the rectal  lumen without any discrete lesions.  What is 
your most likely diagnosis? 
 
(A) Normal prostate 
(B) Prostatitis 
(C) Benign prostatic hyperplasia 
(D) Prostate cancer 
 
6. A 36-year-old computer programmer presents to t he office with pain with urination, and fever.  
On palpation of the prostate, his gland is swoll en, tender, and warm to the touch.  Your most 
likely diagnosis is? 
 
(B) Benign prostatic hyperplasia 
(C) Prostate cancer 
(D) Prostatitis

14-1 
Chapter 14 
The Peripheral Vascular System 
 
1. A 55-year-old disabled Vietnam veteran comes into the ER complaining of severe pain in his 
left arm, which occurred suddenly approximately 2 hours ago.  He also states that the arm is 
numb and feels cold to him from the elbow down.  He has had similar episodes in the past with 
his legs, which required amputation at the mid-th igh bilaterally.  He has a 20-year history of 
hypertension and a 60-pack-year history of smoking.   He is a recovering alcoholic but denies any 
drug use.  His father passed away from a stroke  at the age of 65.  On exam, he is anxious and 
appears to be in a great deal of pain.  The le ft arm appears pale and cool to the touch.  No 
peripheral pulses in either the radial or ulna arteries are palpated.  The pulses also cannot be

peripheral pulses in either the radial or ulna arteries are palpated.  The pulses also cannot be 
elicited by Doppler.   Reflexes in the brachior adialis tendon are decreased.  He has decreased 
strength in his wrist and hand and cannot discer n two-point discrimination.  What peripheral 
vascular disorder best describes his situation? 
 
(A) Artherosclerosis obliterans 
(B) Acute arterial occlusion 
(C) Deep venous thrombosis 
(D) Cellulitis 
 
2. A 42-year-old homemaker presents to your office complaining of swelling and pain in her right 
lower leg.  She states it developed yesterday up on returning from a driving vacation to the Grand 
Canyon.  She also informs you that she hiked and climbed all through the canyon with no pain in 
her legs or shortness of breath. Her past medical history is significant for one spontaneous

14-2 
vaginal delivery and one caesarean section for fetal distress. She is on a daily multi-vitamin and a 
low-estrogen birth control pill.  She drinks so cially one to two times a month and denies any 
tobacco or drug use.  Her father  has type-2 diabetes since his early 50s. On exam, you see that 
her right lower leg does look larger than the left. You measure 15 cm above the heel on each leg 
and find that the right leg is 3 cm larger than the le ft.  There is no redness or  heat over the calf.  
Placing your thumb over the tibia shows pitting edema.  Palpating the back of her calf is negative 
for cords.  What is the peripheral vascular  disorder that best describes her problem? 
 
(A) Acute cellulitis 
(B) Raynaud’s disease 
(C) Atherosclerosis obliterans 
(D) Deep venous thrombosis

(D) Deep venous thrombosis 
 
3. A 22-year-old female college student presents to your clinic for a post-hospitalization follow-up.  
She was admitted last week for appendicitis and had an appendectomy.  She states that she is having no abdominal pain but is having pain on the back  of her left wrist.  She states that 2 days 
after she was discharged the area became painful , red, and swollen.  She does think there was 
an IV line there, but she isn’t sure.  Her past m edical history is non-significant and she denies any 
tobacco, drug, or alcohol use. On exam, the dorsum of her left hand is tender, warm, and red, 
with some minimal swelling.  On palpation, you f eel a hard knot 2 cm by 3 cm long. What is the 
peripheral vascular disorder most likely causing her problem? 
 
(A) Raynaud’s disease

(A) Raynaud’s disease 
(B) Superficial thrombophlebitis 
(C) Acute arterial occlusion 

14-3 
 
4. A 68-year-old house painter comes to your office complaining of an ulcer on his right foot.  He 
just noticed it yesterday, although he thinks it is quite large.  He finds this strange because it 
doesn’t hurt at all.  He wears heavy work boots a nd does a good deal of climbing on ladders.  He 
doesn’t recall stepping on any nails.  His past medical history is significant for 15 years of type-2 
diabetes.  He states the first 5 years following his diagnosis, he didn’t take the medicine as he 
should have and that he is now on insulin shots.  He also has 10 years of high blood pressure.  
He has smoked two packs of cigarettes for the last  50 years, but he denies recent alcohol or drug 
use.  His family history is significant for a mot her and aunt with high blood pressure and diabetes.

use.  His family history is significant for a mot her and aunt with high blood pressure and diabetes.  
On exam, you see a 2-cm ulcer over the plantar su rface of the foot proximal to the great toe.  
There is callus formation around the edge of the ulcer.  The patient is unable to distinguish 
vibration from pressure on his great toe.  T here are no color changes to his foot between 
elevation and dependency.  What type of co mmon ulcer best describes his problem? 
 
(A) Arterial insufficiency ulcer 
(B) Venous insufficiency ulcer 
(C) Naturopathic ulcer 
 
5. A 75-year-old widow presents to your office complaining of a painful black spot to her left third 
toe.  She states that it start ed smaller but has grown over the last few days.  Her past medical 
history is significant for an acute myocardial infarction 6 years ago, with three-vessel bypass surgery afterwards.  She has also had high blood pressure for 15 years and was diagnosed with

history is significant for an acute myocardial infarction 6 years ago, with three-vessel bypass surgery afterwards.  She has also had high blood pressure for 15 years and was diagnosed with 
type-2 diabetes last fall.  She denies any tobacco, alcohol, or drug use.  On review of systems, 
she does note that she is unable to walk a half-mile anymore without needing to stop due to pain 
in her legs.  On exam, you find an elderly patient in no acute distress.  She has no swelling or edema in her legs, although the skin color is fairly red. You can palpate a weak posterior tibia

14-4 
pulse but no dorsal pedis pulses.  The toe in questio n is black the last distal centimeter.  What 
peripheral vascular disorder is most likely the cause of her ulcer? 
 
(A) Insufficiency ulcer 
(C) Arterial neuropathic ulcer 
 
6. A 60-year-old homemaker presents to your office complaining of swelling to her left lower leg.   
She states that it has been developing over the last few weeks since her surgery for ovarian 
cancer.   She has a past medical history signifi cant for four spontaneous vaginal deliveries and 
the recent diagnosis of ovarian cancer.  She denies any drug, tobacco, or alcohol use.  On review 
of systems, she denies any chest pain, palpitation s, or shortness of breath.  On exam, you note 
that not only are her leg and ankle swollen but so are her toes.  The skin appears to be thicker

that not only are her leg and ankle swollen but so are her toes.  The skin appears to be thicker 
than usual, but there are no signs of ulceration.   What cause of peripheral edema is the most 
likely in her case? 
 
(A) Pitting edema 
(B) Chronic venous insufficiency 
(C) Lymphedema 
 
7. A 48-year-old unemployed man comes into the ur gent care clinic complaining of increased 
swelling in his lower extremities.  He states t hat he has had swelling for a number of months but 
that the swelling worsened last night. He complains of no ulcers or pain in the legs.  His medical 
history reveals a past diagnosis of “liver problems. ”  He isn’t sure what the exact diagnosis was.  
He states he used to drink a case of beer a night but he has recently cut back to a six-pack.  He 
has smoked one pack of cigarettes a day for over  30 years and denies any IV drug use.  On

14-5 
exam, you note that both legs are swollen, with no skin thickening or ulcerations.  Pressing your 
thumb against his tibia reveals soft edema.  Auscult ation of his lungs reveals no crackles.  His 
heart sounds are regular, with no murmurs, rubs, or gallops.  His abdomen reveals a small liver but no discernable fluid wave.  What diagnosis of peripheral causes of edema is most likely the 
cause of his problem? 
 
(C) Lymphedema

15-1 
Chapter 15 
The Musculoskeletal System 
 
1. A 42-year-old female office wo rker presents to your clinic complaining of awakening with an 
exquisitely tender, red, swollen right knee.  S he has never had this occur before and has had no 
history of trauma or recent illness.  She has no significant past medical history. A family history 
reveals that her father had similar problems in middle age.  On exam, she has a red, warm, 
tender right knee with decreased range of motion. Tapping the fluid in the knee showed no signs 
of infection indicating a probable arthritic cause.  The most likely form of arthritis would be: 
 
(A) Rheumatoid arthritis 
(B) Degenerative joint disease 
(C) Gouty arthritis 
(D) Polymyalgia rheumatica 
 
2. A 54-year-old woman who works at a dry cleaner s presents to your office complaining that she

2. A 54-year-old woman who works at a dry cleaner s presents to your office complaining that she 
cannot do overhead work with her right arm.  She states that she can no longer lift her arm over 
her head without using her other arm to prop it up.  She remembers no specific injury but has been doing overhead work at the dry cleaners for over 15 years.  Her past  medical history is 
significant for three spontaneous vaginal deliverie s and 15 years of hypertension.  On exam, she 
has demonstrative weakness with internal and external rotation on the right.  When she attempts 
to abduct her arm, there is obvious shrugging of the shoulder.  On inspection of her back, you 
note atrophy of the muscles surrounding the shoulder and scapula.  She is nontender over any

15-2 
boney prominence in the shoulder.  Her passive range of motion is normal, while on active range 
of motion she is unable to elevate her arm more than 12 inches and cannot raise it to shoulder 
level.  What shoulder problem is the most likely diagnosis? 
 
(A) Rotator cuff tendonitis 
(B) Bicipital tendonitis 
(C) Acrominoclavicular arthritis 
(D) Rotator cuff tear 
 
3. A 13-year-old boy is brought into the urgent care  clinic by his father with a complaint of swelling 
around his right elbow.  He is in 8th grade football and has been lifting weights, despite having just 
started puberty.  He has no significant past m edical history and recalls no specific incident of 
trauma to the elbow.  On exam, the patient has a soft swelling around the posterior of the elbow.

trauma to the elbow.  On exam, the patient has a soft swelling around the posterior of the elbow.  
He has no redness or warmth and minimal pain. He is nontender over the bony prominences of 
the ulna, radial head, and humorous.  What disorder  of the elbow is the most likely diagnosis? 
 
(A) Arthritis 
(B) Olecranon bursitis 
(C) Epicondylitis 
(D) Rheumatoid nodules 
 
4. A 28-year-old male waiter presents to your offi ce complaining of a growth on the back of his left 
hand.  He states it started slowly months ago but has now enlarged enough to be embarrassing.  
He states it only hurts when he is holding a tray of food up in the air with his left hand.  He has no 
significant past medical history and no one else in  the family has this problem.  On exam, you

15-3 
note a 2-cm round cystic-lik e lesion on the dorsum of his left wrist over the carpals.  It is more 
prominent when he flexes his wrist. What is the most likely cause of his hand swelling? 
 
(A) Ganglion 
(B) Chronic tophaceous gout 
(C) Acute rheumatoid arthritis 
(D) Heberden’s nodes 
 
5. A 32-year-old attorney comes to your clinic complaining of severe neck pain when he tries to 
turn his head to the right.  He reports to you t hat he was the restrained driver in a MVA the day 
before, when he was hit from behind at approximatel y 40 mph.  He states he did not hit his head 
and he did not lose consciousness.  He refused to  be evaluated by EMS at the scene.  He states 
he felt okay after the accident but today woke up in extreme pain.  He is having no numbness or

he felt okay after the accident but today woke up in extreme pain.  He is having no numbness or 
tingling in his right hand and states he has no problems holding a pen.  He has no symptoms 
below the neck.   He has no significant past m edical history.  On exam, he has difficulty turning 
his head to the right or tilting it to the right.  He  also has difficulty with extending his head.  He is 
able to flex his neck and turn and tilt to the left.  On palpation, he is  tender over the right trapezius 
and rhomboid muscles.  He has no tenderness along the cervical vertebrae or the clavicle or scapula.  He has normal reflexes in his biceps, triceps, and brachioradialis.  He has normal 
strength in his elbow and wrist and has normal two-point discrimination.   Having the patient 
cough does not increase his symptoms.  What type of neck pain best describes his problem? 
 
(A) Cervical sprain

(A) Cervical sprain 
(B) Muscle ache 
(C) Neck pain with dermatomal radiation  
(D) Neck pain from cervical spinal stenosis

15-4 
 
6. An 85-year-old retired secretary presents to y our office complaining of severe lower back pain.  
She states that it started 4–5 months ago and has gradually been getting worse.  She takes 
Daypro for arthritis but that hasn’t helped her very much.  She says that lying down or sleeping 
does not seem to help.  She doesn’t recall any trauma to her back. She has had no unusual 
problems with strength in her legs or bowel or bladder control.   Her past medical history is 
significant for 30 years of hypertension and right -sided breast cancer 10 years ago.  She had a 
mastectomy and radiation therapy.  She did not ta ke any chemotherapy.  She denies tobacco or 
alcohol use.  On exam, you find a thin, cachectic-appearing woman in no acute distress.  Her 
heart and lung exam are normal.  She is tender  over the L4 and L5 vertebrae.  She has normal

heart and lung exam are normal.  She is tender  over the L4 and L5 vertebrae.  She has normal 
sensation, strength, and reflexes in her lower extr emities.  She is nontender over the para spinal 
muscles around the lumbar region and has a negative straight leg rise bilaterally. 
 
(A) Mechanical low back pain 
(B) Radicular back pain 
(C) Back pain from metastatic disease 
(D) Spinal stenosis

16- 1 
Chapter 16 
 
1. A 24-year-old male graduate student is brought into the ER following a two-vehicle MVA.  He is 
on a backboard and has obvious bruises and lacerati ons to his head and extremities. On exam, 
he does not respond to either conversation or even shaking.  He does arouse to a deep sternal 
chest rub and mumbles incoherently.  When the stimulus ceases, he lapses back into an 
unresponsive state.  What level of co nsciousness best describes his response? 
 
(A) Lethargic 
(B) Obtunded 
(C) Stuporous 
(D) Comatose 
 
2. A 43-year-old female kindergarten teacher presents to your office with the complaint of fainting 
this morning.  She reports this occurred after standing up from her bed after having been sick all 
night with diarrhea and vomiting.  She has had no fever and is unable to keep fluids down. She

night with diarrhea and vomiting.  She has had no fever and is unable to keep fluids down. She 
has had no chest pain, shortness of breath, or palpi tations.  Her past medical history is significant 
for two spontaneous vaginal deliveries and a 10-yea r-history of hypothyroidism.  On exam, she 
has a fast heart rate of 110 bpm. Her abdomen is tender, with no signs of a surgery. What is the 
most likely underlying cause of her fainting? 
 
(A) Vasodepressor syncope 
(B) Postural (ortho static) hypotension

16- 2 
(C) Cardiac arrhythmia 
(D) Hysterical faint 
 
3. A 7-year-old boy is brought to the ER by EM S and is accompanied by his parents.  They report 
that he had a spell an hour before, during which his body stiffened, he lost consciousness, and 
then started jerking. They also r eport that he bit his tongue.  He was sitting quietly in the living 
room playing video games when this occurred.  The parents state that the child has never had 
any problems like this in the past.  Upon exam, he is pale and confused.  He says he is sleepy 
and would like every one to go away.  You notice blood in his mouth and that his shorts and 
underwear are soiled with urine.  What is the mostly likely reason for this “spell?” 
 
(A) Simple partial seizure 
(B) Complex partial seizure 
(C) Generalized tonic clonic (grand mal) seizure 
(D) Absence seizure

(D) Absence seizure 
 
4. A 55-year-old retired woman comes to your office complaining of worsening problems with 
walking accompanied by falling down.  She states that she has to watch the ground while she is 
walking or she will often misstep and fall.  She has a 20-year history of type-2 diabetes and has 
had a history of diabetic foot ulcers in the past.  She denies any smoking, drug, or alcohol use.  On exam, you note that she has decreased feeling on the planter surfaces of her feet. She cannot 
remain steady with her feet together and her eyes closed; she remains steady with her eyes 
open.  While watching her walk, you also note that  she has a wide gait with slapping motion with 
her feet on the floor. What abnormalities of gait best describe her symptoms and signs? 
 
(A) Sensory ataxia

16- 3 
(B) Cerebellar ataxia 
(C) Parkinsonian gait 
(D) Steppage gait 
 
5. A 19-year-old male college student presents to your clinic with a complaint of tremors in his 
hands. He states that it embarrass es him in front of his friends.  He notices it only when he isn’t 
doing anything with his hands; it gets better when  he drinks alcohol.  He has no significant past 
medical history but does relate that his older si ster and mother have had similar problems.  Upon 
exam, he holds his hands out in front of him re vealing a fine tremor.  There are no additional 
movements with his fingers.  When he does purposeful movement, the tremors disappear. 
What involuntary movement disorder best describes his symptoms and signs? 
 
(A) Resting tremors 
(B) Postural tremors 
(C) Intention tremors 
(D) Athetosis

(D) Athetosis 
 
6. A 63-year-old high school coach presents to your  office complaining of weakness in both of his 
hands.  He states that he has trouble writing out test questions and gripping the baseball bat in 
practice.  He also complains that the muscles in his forearms are twitching.   He has a 10-year 
history of hypertension, which is well controlled, and has no history of trauma.  He has a 50-year 
history of chewing tobacco and drinks three to f our beers two to three times per month.  He 
denies any cigarette or drug use.  On exam, his grip strength is greatly decreased bilaterally but 
his sensation is normal.  His brachioradialis reflexes are also decreased.  You note some wasting 
of the muscles between the thumbs and fingers on the dorsal surface of both hands. In what part

of the muscles between the thumbs and fingers on the dorsal surface of both hands. In what part 
of the peripheral nervous system is he most likely to have a disorder?

16- 4 
 
(A) Spinal roots 
(B) Neuromuscular junction 
(C) Anterior horn cells 
(D) Muscle fibers 
 
7. A 20-year-old college junior is brought to your office by classmates who state that she is acting 
strangely.  She has been seen talking to herself around campus and has told people that she has 
been awarded the Nobel Prize for her study in physi cs.  Her friends tell you that until 2 months 
ago she seemed a normal, happy young woman with no medical problems.  They had heard 
mention of an older brother with mental probl ems.  They tell you she drinks alcohol on the 
weekends but has never gotten drunk and has never done any drugs.  On exam, you find you 
cannot understand her because she speaks in a nonsensible manner by repeating phrases and 
shifting her ideas.  She is oriented to person, plac e, and time; her math calculations are correct,

shifting her ideas.  She is oriented to person, plac e, and time; her math calculations are correct, 
but she cannot explain any proverbs.  You also notice that her blouse is on backwards. 
What is the most likely cause of her mental health problem? 
 
(A) Major depression 
(B) Bipolar disorder 
(C) Generalized anxiety disorder 
(D) Schizophrenia 
 
8. A 71-year-old woman is brought to the ER by her family, who state that she is not acting like 
herself.  They say that several hours ago she b egan to slur her words as she started wandering 
around the house. They heard her calling to her  husband, who has been deceased for over 10 
years.  After several minutes of this, she said she wasn’t feeling well and laid down on the sofa;

16- 5 
she became sleepy.  When they tried to ask her what was wrong, she snapped at them.  
Although the woman is retired, she is very active in  her church and senior citizens club.  Her past 
medical history is significant for 3 vaginal deliv eries, 10 years of hyper tension, and 5 years of 
type-2 diabetes.  She does not smoke, drink alcohol , or take drugs.  Revi ew of systems reveals 
that she had mentioned to her daughter the day befor e that urinating is painful and that her back 
is sore. On exam, you find an elderly woman who is lethargic.  You have to speak loudly for her to 
answer questions. She is alert to person but not place or time. Her vital signs and exam of the 
head, heart, lungs, and abdomen are all normal.  She is tender at the costal angle on the right. 
What is the most likely cause of her mental status change?

What is the most likely cause of her mental status change? 
 
(A) Psychotic reaction to major depression 
(B) Delirium 
(C) Dementia

17-1 
Chapter 17 
Assessing Children 
 
Case Study 
 
CHIEF COMPLAINT:  “My baby won’t stop crying, and she feels hot.” 
 
A 6-week-old infant is brought to the emerge ncy room by her parents.  They are worried 
because she feels hot and hasn't stopped crying since she woke up 10 hours ago.   She has a 
decreased appetite (she hasn’t eaten) and has b een fussy, but is easily consoled. The number of 
wet diapers has decreased.  Yesterday, she had a runny nose and sounded congested. 
 She was a term spontaneous vaginal delivery with no complications.  Her mother 
received early prenatal care and was healthy throughout the pregnancy.   
There have been no sick contacts at home.  Neither parent smokes.  They do not have 
pets.  There is only city water in their household.

pets.  There is only city water in their household. 
 
17-2 
 
17-3 

17-4 
These are the actual findings on physical examination:   
 
General survey Patient is crying tear s and is held appropriately by mother. 
Vital signs HR 150 bpm and regular, respiratory rate unable to measure 
accurately secondary to crying ―65 breaths/min; temperature 102°F 
rectal. 
Skin Color good.  Skin warm and moist.  Petechiae are scattered diffusely 
on the torso, no rash or ecchymoses. 
HEENT Anterior fontanelle tense and bulging.  Hair scant. 
Sclera white, conjunctiva pink; red reflex present. 
External ear canals patent; tym panic membranes pearly gray, with 
good cone of light. 
Nasal mucosa pink. 
Oral mucosa moist and pink.  Pharynx without exudates. 
Neck Trachea midline, neck without thyromegaly 
Lymph nodes No cervical, axillary, epitrochlear, or inguinal adenopathy

Thorax and lungs Thorax symmetric with good expansion; no use of accessory muscles 
of respiration, although patient is crying. 
Lungs with transmitted crying sounds.  Breath sounds vesicular; no 
rales, wheezes, or rhonchi. 
Abdomen Protuberant with active bowel sounds.  Umbilicus clean, dry, and 
intact. 
Soft, nontender, nondistended, no masses or hepatosplenomegaly. 
Peripheral vascular/ 
extremities Capillary refill delayed to 5 seconds.  Femoral pulses 2+.  No femoral 
or abdominal bruits.  
lesions; no lesions or masses. 
Musculoskeletal Spine intact, no dimplin g, no tufts of hair, no skin opening

Musculoskeletal Spine intact, no dimplin g, no tufts of hair, no skin opening 
Neurologic Difficult to appreciate nuchal rigidity

17-5 
 
1. A 6-month-old is brought to your clinic by hi s mother for a routine checkup.  She is concerned, 
because he has large bluish marks on his buttocks  and back.  She is worried that people will think 
that she is harming him somehow.   Based on your physical examination, he is completely 
healthy and his development is on track for his age.  What is your most likely diagnosis of this 
skin rash? 
 
(A) Café au lait spots 
(B) Salmon patch/stork bite 
(C) Mongolian spots 
(D) Neurofibromatosis 
 
2. A 14-day-old infant presents to the clinic for a follow-up visit from the newborn nursery.  On 
examination, she has yellow–white pustules su rrounded by a red base, which are scattered

examination, she has yellow–white pustules su rrounded by a red base, which are scattered 
diffusely over the face and trunk.  What is  the most likely diagnosis for this rash? 
 
(A) Neonatal acne 
(B) Erythema toxicum 
(C) Seborrhea

17-6 
(D) Jaundice 
 
3. A newborn infant has a 1-minute Apgar score of 6.  Which of the following statements is 
correct? 
 
(A) This infant is normal 
(B) This infant has some nervous system depression 
(C) This infant has severe depressi on and requires immediate resuscitation 
(D) This infant is at high risk for subse quent central nervous system and other organ 
system dysfunction 
 
4. A 6-month-old infant presents with her parents for a routine chec kup.  You obtain a history and 
ask questions to obtain information on developm ental stage.  The answers given by the parents 
indicate that the infant is significantly behind in her development.  The infant is in the 50th 
percentile for weight, height, and head circumference.   Which of the following conditions is a 
potential cause of developmental delay? 
 
(A) Otitis media 
(B) Overfeeding

(B) Overfeeding 
(C) Gastroesophageal reflux 
(D) Neonatal meningitis 
 
5. A 2-year-old child presents for his annual checkup.  You obtain a history and perform a 
physical examination.  All of the findings are normal.  When you do a visual acuity test, what is 
your most likely finding?

A-1 
Answers and Explanations 
 
Chapter 2 
 
1. The correct answer is (B) Quality 
 
Quality is the only one of the seven attributes of a symptom listed that is not addressed. The 
patient has not described the kind of pain he is experi encing other than that it is in his chest.  Pain 
may be an ache, a sharp sensation, a pressure-like sensation, or a burning sensation, which are 
all important descriptors in helping to determine your differential diagnosis. 
 
Remitting or exacerbating factors would be an incorrec t choice in that the patient states during 
the history that nothing has made the pain better or worse. Likewise, severity is addressed in that 
the patient rates the pain as a 9 out of a 10-poin t scale. Timing is also covered when he states

the patient rates the pain as a 9 out of a 10-poin t scale. Timing is also covered when he states 
that the pain started 30 minutes prior to his arrival at the emergency room and has not gone 
away.   
 
2. The correct answer is (C) Facilitation 
 
Facilitation is the type of interviewing technique that you have demonstrat ed. By maintaining eye 
contact and asking the patient to “go on,” you have attempted to make her more comfortable in 
relating details about the concern that brought her into your office.

A-2 
Echoing would be an incorrect choice in that it is a simple repetition of the patient’s words; this 
was not done. Nor is direct questioning the correct choice since that is a technique in which you, 
the interviewer, use a series of questions to e licit more details about the patient’s concern. 
Reassurance is incorrect as well: As the inte rviewer, you have not made an attempt to tell her 
that  “everything will be alright,” or words to that effect. 
 
3. The correct answer is (C) Nonverbal communication 
 
You have used nonverbal communication through the techniques of eye contact, sitting down, 
moving your body in slightly toward the patient, and nodding. 
 
Echoing is not the correct response since it involv es simple repetition of the patient’s words, and,

Echoing is not the correct response since it involv es simple repetition of the patient’s words, and, 
as the interviewer in this scenario, you hav en’t repeated the patient’s words.  Adaptive 
questioning is also incorrect. It involves using va rious questions to clarify the patient’s story, and 
in this scenario, as the interviewer, you haven’t asked any questions yet. Empathic response is 
not correct. You have not identified the patient’s feelings; and she has not expressed any during 
the interview. 
 
4. The correct answer is (B) Talkative patient 
 
This patient wants to tell you her life’s story.  Remember to let this type of patient talk for 
approximately 5–10 minutes while you listen closel y to how she expresses her ideas, note the 
use of nonverbal cues, and so forth.  A helpful technique is to have the patient focus on the most

use of nonverbal cues, and so forth.  A helpful technique is to have the patient focus on the most 
important thing that concerns her at today’s vi sit and to schedule a follow-up appointment, setting 
a specific time limit on the follow-up as well.

A-3 
This patient is not anxious; she is relaxed and able  to address completely all of the problems that 
brought her into the office. An anxious patient may give nonverbal clues, such as fidgeting and 
sitting tensely.  Obviously, this patient is not angr y; she has not expressed any anger or hostility 
toward the interviewer. Nor is she disruptive; s he is friendly and interested in telling you all about 
herself. She is not silent: This  patient is far from silent! 
 
5. The correct answer is (A) Denial 
 
This patient has not yet accepted the fact that s he is dying.  She is making plans for the future 
that seem inappropriate given the diagnosis,  prognosis, and her overall physical decline. 
 
The patient does not seem angry. She has not ex pressed anger about her condition or about the

The patient does not seem angry. She has not ex pressed anger about her condition or about the 
“unfairness” of her prognosis, nor toward the clinician for the diagnosis has been made. This scenario does not illustrate any evidence of bargaining. The pat ient has not ex pressed sadness 
nor depression. She has clearly  not accepted her diagnosis. 
 
Chapter 3 
Beginning the Physical Examination: General Survey and Vital Signs 
 
1. The correct answer is (D) Obese

A-4 
The patient is obese. Obesity is defined as a BMI over 30. This patient has a calculated BMI of 
43. Underweight is defined as a BMI of less t han 17; normal weight is defined as a BMI between 
17 and 23; and Overweight is defined as a BMI between 23 and 30. 
 
2.  The correct answer is (C) Anorexia nervosa 
 
This patient has a preoccupation with her weight and feels that she is too fat.  She has a BMI of 
15, which is underweight, and does not see herself as  too thin.  The patient’s mother states that 
she barely eats, which is typi cal of patients with anorexia. 
 
With a BMI of 15 and a daily exercise routine, the patient is hardly at risk for obesity. Although 
this patient is difficult to classify without furthe r information, you believe her when she states that

this patient is difficult to classify without furthe r information, you believe her when she states that 
she doesn’t eat excessively or make herself vomit.  Patients with bulimia will go on binges of 
overeating, then make themselves vomit. Alt hough normal adolescents are concerned with their 
body image, they do not exercise to the extent that this girl does  nor do they typically have a BMI 
of 15 and barely eat. 
 
3. The correct answer is (D) Respiratory distress 
 
The patient has classic signs of respiratory distress.  He is tachypneic — his respiratory rate is greater than 20 breaths/minute and he appears to have labored breathing. Normal oral 
temperature is between 96.4º F and 99.1ºF, normal pulse is between 60 and 100 beats per 
minute, normal blood pressure is a systolic of 90/60 to 140/90, and a normal respiratory rate is 
between 14 and 20 breaths per minute.

A-5 
The patient’s signs are not consistent with pain from the cough. Pain may result in an elevated 
pulse and elevated respiratory rate; however, pain is unlikely to produce fever (temperature of 
103ºF) or a low blood pressure of 90/60. It is un likely that the signs are caused by anxiety about 
the visit. Anxiety can result in an elevated pulse, respiratory rate, and labored breathing; however, 
anxiety is unlikely to produce fever or hypotension.  
 
4. The correct answer is (B) The length of the inflatable bladder was 50% of the upper arm 
circumference 
 
The length of the inflatable bladder should be 80% of the upper arm circumference; if it is too 
short, then the blood pressure reading will be artificially increased. 
 
Choice (A) is incorrect since the widt h of the inflatable bladder of the cuff should normally be 40%

Choice (A) is incorrect since the widt h of the inflatable bladder of the cuff should normally be 40% 
of the upper arm circumference in order to accu rately measure the blood pressure of a patient. 
The anaeroid sphygnomanometer should be calibrated  routinely in order to maintain the accuracy 
of measurement.  Since it was just calibrated pr ior to the patient’s measurement, this is not a 
factor in an inaccurate reading. In order to obtain a more accurate bl ood pressure measurement, 
the patient should be seated for at least 5 minutes before the blood pressure is taken; waiting a 
longer time period does not make the blood pressure reading more inaccurate. 
 
5. The correct answer is (B) He drank a cup of  coffee 10 minutes prior to his blood pressure 
measurement 
 
Caffeine ingested within 30 minutes of checking a blood pressure measurement can artificially 
increase the patient’s blood pressure reading.

A-6 
Response (A) is not correct since,  under optimal conditions, the patient should be in a quiet room 
seated for at least 5 minutes prior to obtaining the blood pressure measurement. Response (C) is 
incorrect since a bare arm is part of optimal conditions for measuring blood pressure.  When the 
patient’s arm is clothed, the blood pressure reading can be artificially inflated. If the patient is 
seated when his blood pressure is measured, his arm should be  supported a little above the waist 
in order to obtain an optimal blood pressure measurement. 
 
6. The correct answer is (C) Severe aortic stenosis 
 
Severe aortic stenosis is one condition in which the pulse pressure is diminished and the pulse 
feels weak and small.  Other conditions that could result in this same type of pulse include heart

feels weak and small.  Other conditions that could result in this same type of pulse include heart 
failure, hypovolemia, exposure to cold, and severe congestive heart failure. 
 
Hypertrophic cardiomyopathy is not a correct response. The arterial pulse in hypertrophic 
cardiomyopathy is increased, with a double systolic peak, not small and weak. Premature 
contractions result in a bigeminal pulse, which is a normal beat alternating with a premature 
contraction; thus, choice (B) is not correct. Nor is constrictive per icarditis correct. It results in a 
paradoxical pulse, which is a palpable decrease in  the pulse’s amplitude with quiet inspiration. 
 
Chapter 4 
The Skin 
 
Multiple Choice

A-7 
1. The correct answer is (A) Scabies 
 
The presence of a burrow is most diagnostic of scabies. A burrow is a minute, slightly raised 
tunnel in the epidermis commonly found on the finge r webs and on the sides of the fingers.  The 
patient experiences intense itching, which resu lts in excoriations and lichenified areas secondary 
to the scratching. 
 
Atopic dermatitis is an incorrect choice. It is more  likely to present with thickening and roughening 
of the skin, with increased visibility of the norma l skin furrows.  There are burrows. Acne typically 
presents in the pubertal years and is characterized by comedones, which represents a plugged 
opening of a sebaceous gland. The comedones are more commonly found on the face as well as 
the upper back and chest, not in the finger webs. Choice (D) also is incorrect. Telangiectasias are

the upper back and chest, not in the finger webs. Choice (D) also is incorrect. Telangiectasias are 
more commonly found in an older population and ar e dilated small vessels that appear to be red 
or blue in color. 
 
2. The correct answer is (C) Cherry angioma 
 
Cherry angiomas are bright or ruby red, us ually 1–3 mm in diameter, and round and flat, which 
may show partial blanching with pressure.  They increase in size and number as a person ages and do not confer an increased risk of skin cancer. 
 
Squamous cell carcinoma is an incorrect answer.  It usually appears on sun-exposed skin; the 
face and back of the hands are areas typically affected.  The lesions are red and firm and raised 
in appearance. Actinic keratosis is also incorrec t. It is a skin lesion comprised of superficial, 
flattened papules covered by a dry scale. They are round or irregular and are pink, tan, or

A-8 
grayish. They typically appear on the face and hand s. Spider angiomas are fiery red and range in 
size from very small to 2 cm.  They have a central body and are sometimes raised, are 
surrounded by erythema, and have radiating legs.  They blanch with pressure.  The most 
common locations are on the face, neck, arms, and upper trunk. 
 
 3. The correct answer is (D) Basal cell carcinoma 
 
A basal cell carcinoma usually appears on the face.  Initially, it is a translucent nodule, which 
spreads, leaving a depressed center and a firm el evated border. Although it is a malignant tumor, 
it grows slowly and rarely metastasizes. 
 
Actinic keratoses are superficial, flattened papules covered by a dry scale.  There are often 
multiple lesions, which are usually pink, tan, or gr ayish in color.  The most typical locations are on

multiple lesions, which are usually pink, tan, or gr ayish in color.  The most typical locations are on 
the face and hands. Seborrheic keratoses are ye llowish to brown raised lesions, which feel 
slightly greasy and velvety or warty.  There are often multiple lesions, which are symmetrically 
distributed on the trunk of older people. Although squamous cell carcinomas can appear on the sun-exposed areas of the skin such as the face, they are firm and red in appearance. 
  
 4. The correct answer is (B) Dysplastic nevus 
 
A dysplastic nevus is varied in color, but oft en dark.  It is larger than 6 mm and has irregular 
borders, which fade into the surround skin.  Without further intervention, it is difficult to determine 
whether this patient’s lesion is an early malignant melanoma or not.

A-9 
 
A benign nevus is a flat or slightly raised, round or oval shaped lesion with sharply defined 
borders.  It is usually of a uniform tan or brow n color and less than 6 mm in diameter.  This 
patient has many benign nevi, but they are not t he lesion of concern in this scenario. Seborrheic 
keratoses are yellowish to brown raised lesions, which feel slightly greasy and velvety or warty.  
There are often multiple lesions, which are symm etrically distributed on the trunk of older people. 
the face and hands. 
 
5. The correct answer is  (B) Stage II

5. The correct answer is  (B) Stage II 
 
This patient has a stage II ulcer, which is a parti al-thickness skin loss or ulceration that involves 
the epidermis, dermis, or both layers.  
 
A stage I ulcer is defined as intact skin that has a change in temperature, consistency, sensation, 
or color.  The temperature can be warm or cool ; the consistency can be firm or boggy; the patient 
may experience pain or itching; the color may be red, blue, or purple. A stage III ulcer is a full-thickness skin loss, with evidence of damage to or  necrosis of subcutaneous tissue, which may 
extend to, but not through, the underlying muscle . A stage IV ulcer involves full-thickness skin 
loss with destruction, tissue necrosis, or damage to underlying muscle, bone, or supporting 
structures. 
 
6. The correct answer is (A) Stage I

A-10 
 
The patient has a stage I ulcer, which is defined as intact skin that has a change in temperature, 
consistency, sensation, or color.  The temper ature can be warm or cool; the consistency can be 
firm or boggy; the patient may experience pain or itching; the color may be red, blue, or purple. 
 
A stage II ulcer is a partial-thickness skin loss or ulceration, which involves the epidermis, dermis, 
or both layers. A stage III ulcer is a full-thickness skin loss with ev idence of damage to  or necrosis 
of subcutaneous tissue, which may extend to, but not through, the underlying muscle. A stage IV 
ulcer involves full-thickness skin loss with des truction, tissue necrosis, or damage to underlying 
muscle, bone, or supporting structures. 
 
7. The correct answer is (D) Plantar wart

7. The correct answer is (D) Plantar wart 
 
Plantar warts often occur on the metatarsal ar ea, heels, and toes, where there has been slight 
trauma in the past. They cause thickened skin and can be very painful upon pressure.  There are usually characteristic black dots associated with the wart, which are thrombosed capillaries.  
Corns are thickened skin, but they are caused by  pressure against the foot. They occur most 
commonly on the lateral side of the 5th toe and between the 4th and 5th toes. Callus formations 
also occur at pressure points but at places w here the skin is normally thick. Calluses are not 
painful and are usually located around the heel or ov er the plantar surface, just proximal to the 
great toe. They are not tender. Neuropathic ulce rs also develop at pressure points, usually

great toe. They are not tender. Neuropathic ulce rs also develop at pressure points, usually 
because of a lack of sensation.  Although often deep and infected, they are not painful. They are 
usually red, warm, and sometimes drain serosanguinous fluid. 
 
Chapter 5 
Head and Neck

A-11 
 
1. The correct answer is (A) Central in nervation of cranial nerve VII (facial) 
 
A review of the cranial nerves and their function  support the symptoms presented. Facial muscles 
are mediated by cranial nerve Vll. 
 
2. The correct answer is (C) Cluster headache 
 
A cluster headache produces pain around the eye, temple, forehead, and cheek; it is unilateral 
and always on the same side of the head. The pain may be excruciating and can occur as often 
as twice a day.  This type of headache is more common in men than in women. 
 
3. The correct answer is (B) Sternomastoid and trapezius 
 
The major anterior neck muscles are the trapezius  and sternomastoid. They form two triangles on 
the side of the neck, which can be used as landmarks for lymph nodes and other vessels. 
 
4. The correct answer is (C) Myxedema

4. The correct answer is (C) Myxedema 
 
Myxedema arises from hypothyroidism, or a deficiency of thyroid hormone. You may see a 
periorbital edema, coarse facial features, dry skin, and dry coarse hair and eyebrows.  
 
Sclerodema  is a rare autoimmune disorder affecting blood vessels and connective tissue, 
causing a tightening of the skin in the lower face. Cachexia refers to severe weight loss from poor

A-12 
nutrition, which may result in coarse hair but not puffiness. Cretinism arises from severe 
congenital hypothyroidism and is associated wi th dwarfism and mental retardation. 
 
5. The correct answer is (C) Damage to  cranial nerve V (trigeminal nerve) 
 
Facial sensations of pain or touc h are mediated by cranial nerve V. 
 
Facial paralysis can be central or peripheral.  Bell’s palsy results from a peripheral lesion of 
cranial nerve VII—the patient cannot wrinkle the forehead on the affected side nor make a smile, 
so both the upper and lower facial muscles are in volved. In central lesions of cranial nerve VII 
from cerebrovascular accidents, the patient can wrinkle both sides of the forehead but cannot 
make a smile. 
 
6. The correct answer is (C) Ar ea proximal to the enlarged node

6. The correct answer is (C) Ar ea proximal to the enlarged node 
 
When nodes are abnormal, check the area from which they drain. 
 
Chapter 6 
 
Case Study:  Shortness of Breath 
 
WHAT PARTS OF THE PHYSICAL EXA M WOULD YOU LIKE TO PERFORM? 
 General survey 
 Vital signs

A-13 
HEENT 
Thorax and lungs 
Cardiovascular 
 
BASED ON THIS INFORMATION, WHAT IS YOUR DIFFERENTIAL DIAGNOSIS? 
 
Allergic rhinitis 
Allergic rhinitis is a symptom complex that consists of paroxysms of sneezing; itching of the eyes, 
nose, and palate; rhinorrhea; and nasal obstruction.  It is often associated with post-nasal drip, 
cough, irritability, and fatigue.  This patient clea rly has allergic rhinitis; however, this is not a 
cause of her wheezing and shortness of breath. 
Goldman:  Cecil Textbook of Medicine, 21st ed.; Chapter 274 – Allergic Rhinitis 
Richard D. deShazo, pp 1445.  2000, W.B. Saunders Company  
Acute bronchitis  
Symptoms of acute bronchitis include: sputum pr oduction, dyspnea, wheezing, chest pain, fever, 
hoarseness, malaise, rhonchi, and rales.  Each of  these may be present in varying degrees or

hoarseness, malaise, rhonchi, and rales.  Each of  these may be present in varying degrees or 
may be absent altogether. Sputum may be clear, white, yellow, green, or even tinged with blood.   
On physical examination, the patient with acut e bronchitis may or may not have fever and has 
tachypnea, as well as pulmonary signs such as wheezing, rhonchi, and prolonged expiration.  In 
this case, the patient has no fever, and the cough is nonproductive.  Although an acute bronchitis 
can result in wheezing, it is less likely in th is scenario, especially when the patient also has 
features of allergic rhinitis. 
Diagnosis and Management of Acute Bronchitis.  Doug Knutson, M.D.; 
American Family Physician, Vol. 65, No. 10, May 15,2002 
 
Asthma exacerbation (most likely diagnosis)  
Most people with acute asthma present with a co nstellation of symptoms consisting of cough,

Most people with acute asthma present with a co nstellation of symptoms consisting of cough, 
dyspnea, and wheezing. These typically occur simu ltaneously.  Acute attacks are set of by some 
type of stimulant, and the patient has been exposed to some type of stimulant, which has

A-14 
produced an allergic response.  An asthma exacerbation may or may not be accompanied by 
fever, depending on the initiating trigger.  This patient is most likely having an acute asthma 
exacerbation, given her symptoms of shortne ss of breath, acute allergic symptoms, and the 
findings of wheezing on physical examination. 
Barnes:  Asthma and COPD Basic Mechanisms and Clinical Management, 1st Edition 
Chapter 65 – Acute Exacerbations of Asthma, Chakradhar Kotaru, 2002, Elsevier Science, pp. 669-692 
 
1. The correct answer is (A) Dullness to percussion over left base 
 
When alveoli are filled with purulent material, as in pneumonia, there is consolidation in the 
alveoli causing dullness to percussion. Breath sounds  in that area may be bronchial, or harsh, or

alveoli causing dullness to percussion. Breath sounds  in that area may be bronchial, or harsh, or 
even absent. Tactile fremitis is increased, but onl y in the area of consolidation and not throughout 
the lungfields.  Inspiratory and expiratory whee zes suggest narrowed airways as in asthma.  
 
2. The correct answer is (C) Standing behind t he patient, palpate deeply behind the clavicles as 
he takes a deep breath 
 
When the patient inspires, the supraclavicular lymph nodes may be more easily palpable, especially from a posterior position. 
 
3. The correct answer is (A) The patient may have a pleural effusion

A-15 
 
In pleural effusions, fluid accumulates in the pleural space, separating air-filled lung from the 
chest wall, blocking transmission of sound from unde rlying lung tissue.  This reduces detection of 
movement of the diaphragm on percussion.  
 
A right middle lobe pneumonia would not affect descent of the diaphragm. A pneumothorax is air 
leakage into the pleural space, causing loss of aerated lung tissue but not necessarily impairing 
descent of the diaphragm.  Normal lung findings are usually symmetrical in healthy adults.  The 
right lung has three lobes compared to two on the left but is not significantly larger. 
 
4. The correct answer is (A) Malodorous breath 
 
Lung abscesses are usually anaerobic, causing an unpleasant odor. 
 
The clavicle is not affected by a lung abscess.  Clubbing is seen in chronic lung or liver disease

The clavicle is not affected by a lung abscess.  Clubbing is seen in chronic lung or liver disease 
and in congenital heart disease.  Kussmaul breathi ng, or rapid deep breathing, is seen in anxiety, 
exercise, and metabolic acidosis. 
 
5. The correct answer is (C) Diminished or abs ent breath sounds in the right middle lobe 
 
Atelectasis occurs when air flow is obstructed by a tumor, a mucous plug, or a foreign object; the 
alveoli of affected lung tissue collapse into an ai rless state.  Percussion reveals dullness over the 
airless area, and breath sounds are absent.   Odor  and hyperresonance are not consistent with 
atelectasis. 
 
6. The correct answer is (B) Softer and more distant

A-16 
Fat and muscle can muffle heart sounds, making them more distant. 
 
7. The correct answer is (C) Under the right axilla 
 
Only the right lung had a middle lobe.  You must also examine the remaining areas of both lung 
fields to compare the quality of breath sounds at several locations. 
 
8. The correct answer is (A) Resonance  
 
Resonance is the expected finding in normally aerated lung tissue. 
 
9. The correct answer is (C) Muffled voice sounds and symmetrical  tactile fremitus 
 
Normal lung findings include: symmetric ches t expansion, resonance on percussion, vesicular 
breath sounds over the lung fields, no ad ventitious sounds, and muffled voice sounds. 
 
10. The correct answer is (A) Consolidation 
   
A dull percussion note indicates loss of aerated lung tissue (alveoli), or consolidation, as in

A dull percussion note indicates loss of aerated lung tissue (alveoli), or consolidation, as in 
pneumonia, pleural effusion, atelectasis, or tumor. In asthma and COPD, there is often 
hyperresonance from air trapping due to narrowing of the airways on expirati on. Adipose tissue is 
more likely to muffle breath sounds than to change the percussion note over normally aerated 
lung tissue.

A-17 
11. The correct answer is (B) Side to side comparison 
  
Side to side comparison, the “ladder” technique, helps pinpoint any asymmetries in the quality of 
the breath sounds.  Listen to at least one full respiration in each location. 
 
12. The correct answer is (B) Use the diaphragm of the stethoscope held firmly against the chest 
 
The diaphragm of the stethoscope held firmly on the chest is the correct way to auscultate breath 
sounds. The patient should be instructed to open the mouth and breathe in and out more deeply 
than usual, but not to hyperventilate. 
 
13. The correct answer is (A) When the bronchial tree is obstructed 
 
Decreased or absent breath sounds occur when the bronchial tree is obstructed as in pneumonia or pleural effusion.  Adventitious sounds are extr a sounds such as rales, wheezes, or rhonchi,

Decreased or absent breath sounds occur when the bronchial tree is obstructed as in pneumonia or pleural effusion.  Adventitious sounds are extr a sounds such as rales, wheezes, or rhonchi, 
heard in congestive heart failure, asthma, and bron chitis, respectively. In  COPD, there is often 
delayed expiration, but breath sounds are still hear d.  Whispered pectoriloquy pertains to the 
quality of transmitted spoken words, not breath sounds. 
 
14. The correct answer is (C) Pleural effusion 
   
In pneumothorax and COPD, there is hyperresonance and decreased-to-absent breath sounds.  In asthma, there is resonance or hyperresonan ce from air trapping, but breath sounds are often 
obscured by wheezing.

A-18 
See Chapter 6, The Thorax and Lungs, in Bates Physical Examination and History Taking, Table 
6--7.   
 
15. The correct answer is (D) A spontaneous pneumothorax 
Young men may present with acute shortness of  breath from spontaneous pneumothorax of 
unknown etiology.  With a pneumothorax, free air in the pleural space causes partial or complete 
lung collapse and deviation of the trachea to t he nonaffected side. If the pneumothorax is large, 
tachypnea and cyanosis may occur. See Chapter 6, The Thorax and Lungs, in Bates Physical 
Examination and History Taking, Table 6--7.   
 
16. The correct answer is (C) Asthma 
 
Asthma arises from hypersensit ivity to allergenic inhaled particles, producing inflammation and 
smooth muscle constriction in the bronchioles and increased airway resistance during expiration.

smooth muscle constriction in the bronchioles and increased airway resistance during expiration.  
This produces increased work of br eathing and use of accessory muscles. 
 
17. The correct answer is (B) Wheezes 
 
Wheezes are high-pitched musical breath sounds caused by air squeezed or compressed 
through narrowed inflamed small- and middle-cali ber airways.  Whisper ed pectoriloquy occurs 
when whispered voice sounds are transmitted more clearly through collapsed alveoli.  Bronchophony results from increased transmission of spoken voice sounds.  Usually muffled or 
absent breath sounds result from collapse,  not just narrowing, of the bronchioles. 
 
18. The correct answer is (A) Diaphragm and intercostals

A-19 
 
The major muscle of respiration is the diaphragm . The intercostals muscles lift the sternum and 
elevate the ribs during inspiration, in creasing the anteroposterior diameter. 
 
Chapter 7 
 
1. The correct answer is (A) Anemia  
 
An accentuated S1 occurs in tachycardia, rhythms with a short PR interval, and in high cardiac 
output states.  Anemia is one cause of a high cardiac output state and, along with this patient’s 
fatigue, is the most likely diagnosis. 
 
In mitral regurgitation, the S1 sound is dimini shed.  This occurs because the mitral valve is 
calcified and relatively immobile. In right bundle branch block, the S1 sound is split.  A right 
bundle branch block means that there is a delay in the interventricular conduction, which will

bundle branch block means that there is a delay in the interventricular conduction, which will 
result in two separate S1 sounds. Atrial fibrillation w ill result in a varying intensity of S1; the mitral 
valve is in varying positions before being shut by  ventricular contracti on, so its closure sound 
varies in loudness. 
 
2. The correct answer is (B) Pulmonic stenosis

A-20 
Pulmonic stenosis means that the pulmonic valve ha s delayed closure.  This results in a widely 
split S2, which means that the usual splitting is increased and persists throughout the respiratory 
cycle (including expiration).   
 
Physiologic splitting of the S2 sound means that it  varies with inspiration and expiration; it is 
usually accentuated with inspiration and disappear s with expiration.  It is best heard in the 2nd or 
3rd left interspace. Atrial septal defect means that there is a fixed splitting of the S2 sound, which 
does not vary with inspiration and expiration—it is al ways of the same intensity.  The fixed split of 
S2 can also occur with right ventricular failure. In a left bundle branch block, the split is 
paradoxical or reversed.  This means that the splitting of the S2 sound occurs with expiration and

paradoxical or reversed.  This means that the splitting of the S2 sound occurs with expiration and 
disappears with inspiration—this is the exact opposi te of what you would expect physiologically.  
This is caused by a delayed closure of the aortic valve, the most common cause of which is a left 
bundle branch block. 
 
3. The correct answer is (C) Mitral valve prolapse 
 
Given the patient scenario and the location and timing of the sound, the most likely diagnosis is 
mitral valve prolapse.  The click is heard best at or medial to the apex. 
 
A bicuspid aortic valve will result in an aortic ejection sound that is heard at both the base and the 
apex and does not vary with respiration. Pulm onary hypertension causes a pulmonic ejection 
sound that is heard best in the 2nd and 3rd left interspaces.  The intensity often decreases with

sound that is heard best in the 2nd and 3rd left interspaces.  The intensity often decreases with 
inspiration. The sound of mitral stenosis is an opening snap that is heard in very early diastole.  It 
is heard best just medial to the apex and along the lower left sternal border. 
 
4. The correct answer is (A) Innocent

A-21 
 
This is the most likely cause.  There ar e no associated findings of any pathologic or 
 
Pulmonic stenosis is not a correct response. With pulmonic stenosis, the murmur may radiate 
toward the left shoulder and neck.  The intensity is soft to loud, with a medium pitch and a harsh 
quality.  There are associated findings of a widely split S2 and diminished P2, especially in severe 
pulmonic stenosis. A physiologic murmur is also incorrect. A physiologic murmur results from a 
temporary increase in blood flow caused by such pathologic conditions as anemia, 
hyperthyroidism, and fever.  This patient is co mpletely healthy and exhibits no other signs of a 
systemic disease. Choice (D) lik ewise in incorrect. A bicuspid aor tic valve will result in aortic

systemic disease. Choice (D) lik ewise in incorrect. A bicuspid aor tic valve will result in aortic 
stenosis, which is characterized by a mu rmur that is located in the right 2nd interspace and that 
radiates to the neck, down the left sternal border, and even to the apex.  The pitch is medium and 
it has a harsh quality.  It is best heard with the patient sitting and leaning forward. It is unlikely to 
occur this early in life without any other findings of systemic disease. 
 
5. The correct answer is  (C) Aortic stenosis 
 
In aortic stenosis, the murmur is located in the right 2nd interspace and often radiates into the 
neck and down the left sternal border, even to the apex.  It is often loud and has a medium pitch 
with a harsh quality.  It is best heard wi th the patient sitting up and leaning forward.

with a harsh quality.  It is best heard wi th the patient sitting up and leaning forward. 
 
A physiologic murmur results from a temporary increase in blood flow caused by such pathologic conditions as anemia, hyperthyroidism, and fever.  This patient is completely healthy and exhibits 
no other signs of a systemic dise ase.  It is best heard in the 2
nd–4th interspaces between the left 
sternal border and the apex  and rarely radiates. Pulmonic stenosis is not a correct choice. 
With pulmonic stenosis, the murmur is located in the 2nd and 3rd left interspaces and may radiate 
toward the left shoulder and neck.  The intensity is soft-to-loud with a medium pitch and a harsh

A-22 
pulmonic stenosis. Likewise hypertrophic card iomyopathy is not the correct choice. In 
hypertrophic cardiomyopathy, the mid-systolic murmur is best heard in the 3rd and 4th left 
interspaces.  It can radiate down the left sterna l border to the apex and possibly the base, but 
NOT to the neck.  It has a medium pitch and a har sh quality.  It decreases with squatting and 
increases with straining down. 
 
6. The correct answer is (A) Mitral regurgitation 
 
The murmur of mitral regurgitation is best heard at the apex and radiates to the left axilla.  It is 
soft-to-loud in intensity with a medium-to-high pitch and a blowing quality.  It does not become 
louder with inspiration.

louder with inspiration. 
 
The murmur of tricuspid regurgitation is best heard at the lower left sternal border and radiates to 
the right of the sternum, to t he xiphoid area, NOT into the axilla.  It has a variable intensity, a 
medium pitch, and a blowing quality.  The intensit y of tricuspid regurgitation increases slightly 
with inspiration. The murmur of a ventri cular septal defect is located in the 3rd, 4th, and 5th left 
interspaces and has a wide range of radiation.  It has a very loud intensity and high pitch with a 
harsh quality. In aortic stenosis, the murmur is  mid-systolic and is located in the right 2nd 
interspace.  It often radiates into the neck and down the left sternal border, even to the apex.  The sound is often loud and has a medium pitch with a ha rsh quality.  It is best heard with the patient 
sitting up and leaning forward. 
 
Chapter 8 
The Breast

Chapter 8 
The Breast 
 
A-23 
 
1. The correct answer is (A) Fibroadenoma 
 
Fibroadenomas often start during puberty and young adulthood.  They may be single or multiple 
and are often round or disc-like.  They can be soft but are usually firm.  They are very mobile and 
delineated from the surrounding tissue.  They are generally nontender and show no signs of skin retraction. 
 
The lump is not a cyst. Cysts usually start betw een the ages of 30 to 50.  They are also round 
and well delineated.  An important distinction betwe en cysts and adenomas are that cysts tend to 
be tender and often change in size and throughout the menstrual cycle.  Retraction signs of the skin are also absent. The patient does not have cancer. Breast cancer is very rarely seen under 
the age of 30 and usually strikes middle-aged and elde rly women.  There is usually a single lump,

the age of 30 and usually strikes middle-aged and elde rly women.  There is usually a single lump, 
and it tends to be irregularly shaped and very hard.   It can be fixed to underlying or surrounding 
tissue.  Cancerous masses tend to be nontender, and, in advanced cases, skin retractions are 
noted. 
 
2. The correct answer is (C) Cancer 
 
Breast cancer can start either before or after t he menopause.  The masses are usually irregular in 
shape, hard, and nontender.  They can be fixed to underlying tissue.   
 
Fibroadenoma generally starts during adolescence or early adulthood. The lumps are well 
delineated and tend to be round or disc-like. Cyst s appear in the 30–50 age range, and  they are 
generally well delineated and tender.  They al so change size with the menstrual cycle.

A-24 
3. The correct answer is (B) Cysts 
 
Cysts often start in women between 30 and 50 year s of age.  They tend to be round but can be 
soft or firm.  They are mobile and well delineat ed.  Generally they are tender, and they can 
change in size during the menstrual cycle.  They become more pronounced in some women on 
oral contraceptives.  Careful evaluation is still warranted due the rare possibility of breast cancer 
in this age group. 
 
Fibroadenoma is incorrect.  Although fibroadenoma s often start during young adulthood, they 
tend to be nontender.  They may be single or multiple and are often round or disc-like.  They can 
be soft but are more likely to be firm.  They ar e very mobile and delineated from the surrounding 
tissue. Cancer is not a correct response.  It is  very rarely seen in the early thirties, generally

tissue. Cancer is not a correct response.  It is  very rarely seen in the early thirties, generally 
striking middle-aged and elderly women.  There is usually a single lump, and it tends to be 
irregularly shaped and very hard.  It can be fixed to underlying or surrounding tissue.  Cancerous 
masses tend to be nontender, and, in advanced cases, skin retractions are noted. 
 
4. The correct answer is (C) Nonpuerperal galactorrhea 
 
Galactorrhea, or milky discharge, when not due to  pregnancy or lactation is called nonpuerperal.  
It is usually has hormonal or pharmacologic associations.  In this case, a prolactinoma in the 
pituitary gland would be at the top of the differential, given the galactorrhea and the amenorrhea. 
 
Nipple discharge in benign breast abnormalities tends to be clear and unilateral. Nipple discharge 
in breast cancer is usually unilateral and can be clear or bloody.

A-25 
5. The correct answer is (C) Peau d’orange sign 
 
Peau d’orange, or orange-peel sign, is caused by  local lymphatic blockage due to tumor.  The 
involved skin then becomes thickened, and the pore s become more prominent.  This is usually a 
late sign of breast cancer. 
 
Choice (A) is incorrect. A retracted nipple is fl attened or pulled inward.  The surrounding skin is 
not thickened, nor are there enlarged pores. Paget’ s disease is also incorrect.  This uncommon 
form of breast cancer starts as an eczema-l ike scaly skin change around the areola.  The lesion 
may weep, crust, or erode. 
 
Chapter 9 
  
Case Study:  Left Lower Quadrant Abdominal Pain: Adult 
 
WHAT PARTS OF THE EXAM WO ULD YOU LIKE TO PERFORM? 
 Vital signs 
Abdomen 
Anus, rectum, prostate

Abdomen 
Anus, rectum, prostate 
 
Gastroenteritis

A-26 
 Gastroenteritis is characterized by na usea, vomiting, and diarrhea.  It can be 
accompanied by fever.  Cramping abdominal pain usually develops after the vomiting occurs.  
Our patient has been nauseated, but has not had vomi ting or diarrhea, in spite of the length of 
time that he has had symptoms. 
 
Appendicitis 
 In appendicitis the initial presenting symptom is generalized periumbilical abdominal pain, 
which localizes over a 24-hour time period to the right lower quadrant.  The pain is initially mild, 
but increasing to become steady and more severe .  It may be aggravated by movement or cough.  
The patient experiences anorexia, nausea, and poss ible vomiting.  These symptoms are found in 
classic appendicitis.  The more unusual presentat ions of appendicitis occur at the extremes of

classic appendicitis.  The more unusual presentat ions of appendicitis occur at the extremes of 
age, which this patient does not fall into.  A patient with a ruptured appendix would have worse 
vital signs and a rigid abdomen. 
 In our patient’s scenario, the location of the pain, which has not changed since the onset, 
is in the left lower quadrant, which is less likely to be caused by appendicitis. 
 
Diverticulitis 
Diverticulitis results from inflammation of a colonic diverticulum,  with subsequent 
microperforation.  The most common symptoms include left lower quadrant abdominal pain, which may be cramping in nature initially, but  then becomes steady, and fever.  Associated 
symptoms may include nausea, vomiting, constipatio n, diarrhea, dysuria, and urinary frequency.

symptoms may include nausea, vomiting, constipatio n, diarrhea, dysuria, and urinary frequency.  
The most common physical sign is tenderness in the left lower quadrant.  There may be other signs of localized peritoneal inflammation, such as involuntary guarding, and percussion 
tenderness in a localized area.  Occasionally, a tender mass, which represents a phlegmon, can 
be palpated.  There will be some tenderness  in the pelvis with rectal examination.  
 
Sleisenger & Fordtran’s Gastroin testinal and Liver Disease, 7th ed., 2002, Elsevier Science, Chapter 108- 
Diverticular Disease of the Colon, 
 Clifford L. Simmang and G. Thomas Shires, III, pp 2106--2107

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Bates’ Guide to Physical Examination and History Taking, 
 Chapter 9: The Abdomen, pp. 350--351 
 
Case Study:  Left-Sided Back Pain: Adult 
 
Abdomen 
Female genitalia 
Anus, Rectum 
 
Pelvic inflammatory disease 
In pelvic inflammatory disease, the patient has symptoms of nausea, vomiting, and fever, 
lower abdominal pain, and dysuria; however, she most likely will also have an abnormal vaginal 
discharge and/or abnormal uterine bleeding, dyspar eunia.  On physical examination, the patient 
will have cervical motion tenderness and may have adnexal tenderness or even an adnexal 
mass.  In this scenario, the patient has a normal pelvic exam without cervical motion tenderness,

mass.  In this scenario, the patient has a normal pelvic exam without cervical motion tenderness, 
which makes the diagnosis of pelvic inflammatory disease less likely. 
Ferri: Ferri's Clinical Advisor: Instant Diagnosis and Treatment, 2003 ed.,  
Pelvic Inflammatory Disease.  George T. Danakas M.D. Copyright © 2003 Mosby, Inc. pg. 613 
 
Kidney stone 
 The symptoms of a kidney stone are sudden onset of flank tenderness along with nausea 
and vomiting.  The patient experiences more colicky-type pain and moves around a lot, in an

A-28 
attempt to alleviate the pain.  In our scenario, t he patient is sitting quietly on the exam table and is 
not moving around.  There may be fever and chills if  the stone obstructs the ureter and causes a 
urinary tract infection.   To make the diagnosi s of a kidney stone, more testing needs to be done 
by obtaining a urinalysis.  In the case of a simple kidney stone, without infection, the urinalysis will 
only be positive for blood. 
Ferri: Ferri's Clinical Advisor: Instant Diagnosis and Treatment, 2003 ed. 
 Nephrolithiasis.  Fred F. Ferri M.D. Copyright © 2003 Mosby, Inc.  pp 651 
 
Pyelonephritis (most likely diagnosis)  
 Pyelonephritis is characterized by fever/rigo rs, flank pain, and dysuria or polyuria.  The 
patient will experience nausea and vomiting.  On  physical examination, the patient may appear

Pyelonephritis is characterized by fever/rigo rs, flank pain, and dysuria or polyuria.  The 
patient will experience nausea and vomiting.  On  physical examination, the patient may appear 
toxic and usually has costovertebral angle tenderness.  Given the patient’s symptoms and 
physical exam, the most likely diagnosis is pyelonephritis. 
 
Pyelonephritis. Joseph J. Lieber M.D. Copyright © 2003 Mosby, Inc. p. 687 
 
Case Study:  Abdominal Pain: Child 
 
Abdomen 
 
BASED ON THIS INFORMATION, WHAT  IS YOUR DIFFERENTIAL DIAGNOSIS?

A-29 
 
Gastroenteritis 
accompanied by fever.  Cramping abdominal pain usually develops after the vomiting occurs.   
(Behrman: Nelson Textbook of Pediatrics, 16th ed., Chapter 176 – Gastroenteritis.   
Larry K. Pickering & John D. Snyder.  Copyri ght © 2000 W. B. Saunders Company, pp 765-768) 
 
Mesenteric adenitis 
In mesenteric adenitis, children present with fever and abdominal pain, which is diffuse or 
localized to the right lower quadrant. Tenderness is  frequently elicited over the McBurney's point, 
and appendicitis is strongly suspected on a clinical  basis. At surgery, the terminal ileum is 
thickened and shiny with enlarged mesenteric lymph nodes, which may appear necrotic. The

thickened and shiny with enlarged mesenteric lymph nodes, which may appear necrotic. The 
appendix is normal or only mildly inflamed.  Therefore, this would be a diagnosis of exclusion and 
is high on the differential diagnosis.   In comparison to appendicitis, the pain may be more diffuse 
and the site of tenderness may shift when the patient’s position changes.  In appendicitis, the location of the tenderness tends to be fixed.   
(Behrman: Nelson Textbook of Pediatrics, 16th ed., Chapter 201 – Yersinia.   
Thomas G. Cleary. Copyright © 2000 W. B. Saunders Company,  p 859) 
 
(Mesenteric Adenitis.  Last updated: April 26, 2002 
e-Medicine.com. Brian Burke MD and Micha Ziprkowski MD)  
 
Appendicitis (most likely diagnosis) 
In appendicitis, the initial presenting symptom is generalized periumbilical abdominal

In appendicitis, the initial presenting symptom is generalized periumbilical abdominal 
pain, which localizes over a 24-hour time period to the right lower quadrant.  The pain is initially mild, but increasing to become steady and more  severe.  It may be aggravated by movement or 
cough.  The patient experiences anorexia, nausea, and possible vomiting.  These symptoms are 
found in classic appendicitis, and Mariah is in t he right age group to have the classic symptoms.  
This is the most likely diagnosis, and the most im portant one to rule out.  The true test would be

A-30 
more time for observation, or even obtaining a surgical  consultation, which could result in a trip to 
the operating room to confirm or refute the diagnosis. 
 
Annals of Emergency Medicine.  Volume 36 • Number 1 • July 2000.   
STATE OF THE ART:  Acute appendicitis in childr en: Emergency department diagnosis and management.   
Steven G. Rothrock MD and Joseph Pagane MD  
 
Bates’ Guide to Physical Examination and History Taking.  
Chapter 9: The Abdomen, pp 350--351 
 
1. The correct answer is (D) Mesenteric ischemia 
 
Mesenteric ischemia is caused from thrombos is, emboli, or hypoperfusion.  It often begins 
periumbilically, radiating diffusely.  Severe pain, vomiting, and bloody diarrhea are common.  In 
this patient it is not surprising, in light of kn own cardiac and peripheral vascular disease, that a

this patient it is not surprising, in light of kn own cardiac and peripheral vascular disease, that a 
large meal would have precipitated such a condition. 
 
Acute pancreatitis is an incorrect choice.  The pai n from acute pancreatitis is generally in the 
epigastric or left upper quadrant, radiating into the back.  Although there is vomiting associated 
with it, there is no diarrhea.  On exam, the pat ient will be tender but will not generally have a rigid 
abdomen.  Past medical history often reveals pr evious gallbladder problems and social history 
commonly reveals alcohol abuse. Acute cholecystitis is also incorrect.  The pain associated with acute cholecystitis generally is in the epigastric or right upper quadrant, radiating into the right 
scapular region.  There is often vomiting but no di arrhea associated with it.  On exam, there will 
often be a positive Murphy’s sign but no rigid abdomen. Likewise, acute appendicitis is incorrect.

often be a positive Murphy’s sign but no rigid abdomen. Likewise, acute appendicitis is incorrect.  
Although acute appendicitis begins with periumbilical pain, it localizes to the right lower quadrant.

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On exam, there is often involuntary guarding and rebound with decreased bowel sounds.  
Although anorexia and vomiting are associated with it, diarrhea is not.   
 
2. The correct answer is (B) Acute mechanical intestinal obstruction 
 
Mechanical obstructions are often cause by tumors, surgical adhesions, and, in this case, hernia. Often straining will cause a weakened inguinal area to herniated, leading to an incarcerated 
hernia.  Symptoms include bilious vomiting, which can become fecal in material, and the 
development of a rigid abdomen. 
 
Acute appendicitis is incorrect.  Although appendicitis often causes vomiting, the emesis is generally not fetid.  There often is involuntary guarding and rebound, but the testicular exam is 
usually normal. Acute cholecystitis is also incorrec t. The pain in acute cholecystitis is epigastric or

usually normal. Acute cholecystitis is also incorrec t. The pain in acute cholecystitis is epigastric or 
in the right upper quadrant.  Although bilious vomiting is common, fecal material in the emesis is 
not.  Mesenteric ischemia is lik ewise incorrect.  Ischemia is mo re common in the elderly with 
known peripheral vascular disease.  Although there is vomiting involved, bloody diarrhea is also common.  On exam, there is often involuntar y guarding and rebound, but the testicular exam 
should be normal. 
 
3. The correct answer is (B) Biliary colic 
 
Biliary colic is caused by a sudden obstruction in the cystic duct or the common bile duct by a 
gallstone.  A fatty meal can precipitate the attack.   The pain is usually severe and steady and can 
radiate to the scapula.  Nausea, vomiting, and restlessness are common.  A positive Murphy’s 
sign is often found.

A-32 
 
Peptic ulcer disease is not the correct choice.  Although the pain from peptic ulcer disease is 
epigastric in nature, it tends to hurt intermittently, and the pain varies from burning to gnawing to 
aching.  Often food and antacids can bring temporar y relief. Acute cholecysti tis is also incorrect. 
Although acute cholecystitis is also due to inflammation of the gallbladder due to duct obstruction, 
its onset is usually gradual. Nausea and vomiting are common, but fever and signs of sepsis are 
often seen. Nor is acute pancreatitis correct.  Ac ute pancreatitis also causes epigastric pain and 
radiates into the back, but it more often causes tenderness in the left upper quadrant.  There is no 
positive Murphy’s sign.  There is often a histor y of long-standing gallbladder disease or recent 
alcohol ingestion.

alcohol ingestion. 
 
4. The correct answer is (B) Esophageal cancer 
 
Esophageal cancer often is slowly progressive but invariably leads to difficulty in swallowing 
liquids.  Weight loss often develops as the dise ase progresses.  Risk factors include tobacco and 
alcohol use. 
 
Esophageal stricture is an incorrect response.  Al though it is also a slowly progressive disorder, 
difficulty drinking liquids is unassociated.  Usually there is a long-standing history of 
gastroesophageal reflux leading to heartburn. Esophageal spasm is also incorrect.  Like 
esophageal cancer, the dysphagias from esop hageal spasms include problems with food and 
liquids.  However, an important distinction is that the symptoms of esophageal spasms are

liquids.  However, an important distinction is that the symptoms of esophageal spasms are 
intermittent, while those of cancer are progressive.  Also the chest pain from esophageal spasm can be treated with medication or physical maneuver s (Valsalva). Scleroderma likewise is not the 
correct answer. The dysphagia from scleroderma pr ogresses from solid food to liquid much like 
that associated with esophageal cancer.  However,  physical maneuvers such as straining against

A-33 
a closed glottis or the Valsalva maneuver is often successful in relieving symptoms.  Scleroderma 
generally is accompanied by systemic manifestations such as thickened skin. 
 
5. The correct answer is (D) Painful anal lesions 
 
Any lesion around the anus, including hemorrhoids (common in pregnancy), or the repair of a perineal birth injury can cause pain severe enough t hat it can lead to constipation.  In this case, 
the positive occult blood was from enlarged painful internal hemorrhoids. 
 
Obstructing lesion is not a correct choice since all causes of obstructing lesions (such as diverticulitis, volvulus, intussusception, and hern ias) cause abdominal pain.  The constipation is 
from the narrowing or complete obstruction of t he bowel.  In this case, there was no abdominal

from the narrowing or complete obstruction of t he bowel.  In this case, there was no abdominal 
pain or vomiting. Although irritable bowel syndr ome is common in young women, it includes 
alternating constipation and diarrhea.  In this case, the fact that there is no prior history of 
abdominal pain and alternating constipation and diarrhea makes this diagnosis less likely. Rectal 
cancer does cause occult and gross bleeding in the stool, but the symptoms of constipation 
usually progress slowly as the tumor enlarges.  Also rectal cancer is more common in the elderly 
with a strong familial disposition. 
 
6. The correct answer is (B) Inflammatory infections 
 
Bloody diarrhea with a fever after foreign travel is often indicative of invasion of the intestinal 
mucosa by enteropathic bacteria.  An in-depth travel history of different foods and liquids is often 
warranted.

A-34 
Although often preceded by foreign travel, secretory infection causes watery diarrhea without 
blood because the infectious agents (viruses and bacterial toxins) do not invade the bowel wall, 
causing bleeding.  These infections also do not tend to cause high fever.  Vomiting is usually associated with the beginning of the illness. Irritable bowel syndrome should never have bloody 
diarrhea associated with fever. This syndrome is more likely found in young women with 
alternating symptoms of loose stools and consti pation. Malabsorption sy ndromes are caused by 
the intestinal tract’s inability to absorb nutrient s due to an enzymatic deficiency.  These stools 
tend to be bulky and greasy and often float in the toile t.  The onset is very insidious, and systemic 
symptoms often include weight loss and fatigue, but not fever.

symptoms often include weight loss and fatigue, but not fever. 
 
7. The correct answer is (A) Gastritis 
 
Severe gastritis is often caused by alcohol inge stion.  Bleeding from acute gastritis will be black 
when the transit time from the colon is slow.  Wh en the transit time increases, frank blood can be 
present.  Bowel sounds are often increased, and the abdomen can be diffusely tender. 
 
Inflammatory infectious diarrhea is incorrect.  Al though some types of infectious diarrhea cause 
blood to be present in the stool, it is very rarely black since the transit time from the colon is too 
short to cause melena.  Fever and a history of fo reign travel are also often found. Mallory-Weiss 
tear is incorrect.  Although vomiting can cause bleeding, this patient has only vomited once.

tear is incorrect.  Although vomiting can cause bleeding, this patient has only vomited once.  
Usually a great deal of retching must be present to  cause this significant of a bleed. Esophageal 
varices are often found in alcoholic patients, but only when they have a diagnosis of significant 
cirrhosis.  This patient has no symptoms of cirrhos is by exam, despite his alcohol use.  He has a 
normal size liver, no jaundice, no ascites, and no veins noted on the abdomen.  
 
8. The correct answer is (B) Urge incontinence

A-35 
 
Strong detrussor contractions of the bladder over come normal urethral resistance, causing urge 
incontinence.   In this patient’s case, a c ondition called interstitial cystitis has caused a 
deconditioning of voiding reflexes.  Frequency, urgency, and voiding small amounts of urine are 
also often associated with urge incontinence. 
 
On the other hand, stress incontinence usually occurs when the intraabdominal pressure goes up 
during coughing, sneezing, or laughing.  This is us ually due to a weakness of the pelvic floor, with 
inadequate muscle support of the bladder.  Vagi nal deliveries and pelvic surgery are often 
associated with these symptoms.  Usually fema le patients are postmenopausal when stress 
incontinence begins. Overflow incontinence is char acterized by continuous dripping of urine.  It is

incontinence begins. Overflow incontinence is char acterized by continuous dripping of urine.  It is 
often caused by obstruction of the bladder outlet, such as occurs with benign prostatic 
hypertrophy in men or with a pelvic mass in either sex.  In this case, the abdominal, pelvic, and 
rectal exams were all normal, making a tumor unlikely.  
 
Chapter 10 
 
1. The correct answer is (B) Hypospadius 
 
Hypospadius is a congenital displacement of the ur ethral meatus to the inferior surface of the 
penis. A groove extends from the displaced urethral meatus to its normal location on the tip of the 
glans. There is no association between aging and displacement of the urethral meatus.

A-36 
Strictures affect the internal lu men of the urethra, rather than t he meatus; circumcision affects the 
prepuce and glans, not the meatus. 
 
2. The correct answer is (C) An indirect inguinal hernia 
  
An indirect hernia generally causes pain with straining and a soft swelling in the scrotum that 
enlarges with increased intraabdominal pressure. It originates above the inguinal ligament near 
the midpoint and touches the examining finger duri ng examination. This is the most common type 
of hernia, found in all ages and both sexes. 
 
An incisional hernia is found in the suture line of a surgical intervention. A femoral hernia is 
relatively rare and occurs more often in women.  It is never found in the scrotum or pressing into 
the inguinal canal.  It is often hard to differentiate from lymph nodes. A direct hernia is more

the inguinal canal.  It is often hard to differentiate from lymph nodes. A direct hernia is more 
common in men over 40 and rare in women.  It originates above the inguinal ligament close to the 
pubic tubercle and rarely enters the scrotum.  It bulges anteriorly and pushes the side of the 
finger forward during examination. 
 
3. The correct answer is (C) A decrease in the size of the penis 
 
In the older male, you may note thinner, more sporadic gray pubic hair and a decrease in the size 
of the penis. A change in color, size, and scrotal fluid are symptoms requiring further investigation 
and are not associated with aging. 
 
4. The correct answer is (D) “If you notice any change from what you normally see or feel, call 
your health care provider.”

A-37 
 
A firm painless lump, a hard area, or an enlar ged testicle is each an abnormal and unexpected 
finding, which should be assessed by a trained clinic ian.  Time of week and time of day are not 
factors men should consider relating to self-testi cular examination. Regular examination should 
be encouraged, and changes or abnormal findings need to be reported.  
 
5. The correct answer is (C) Smegma may be present under the foreskin of an uncircumcised  
male 
 
Some cheesy smegma may collect under the fore skin of an uncircumcised male. The glans looks 
smooth and without lesions.  Pubic lice and nits se ttle in the base of the penis and excoriations or 
wrinkling may suggest activity. Hair distribution is variable. 
 
6. The correct answer is (D) When palpating for a her nia on the right side, have the client shift his

6. The correct answer is (D) When palpating for a her nia on the right side, have the client shift his 
standing weight onto the left leg 
 
Positioning to the left leg allows the examiner to follow the inguinal canal and document any 
hernia-related bulge. 
 
Chapter 11 
 
1. The correct answer is (C) Uret hral meatus and vaginal orifice

A-38 
 
The labial structures encircle a boat-shaped spac e called the vestibule. Within it are several 
openings. The urethral meatus appears as a sma ll, raised structure between the clitoris and the 
vagina. Just posterior to the urethral meatus at  the 5 and 7 o’clock positions are the tiny openings 
of the paraurethral (Skene’s) glands. The vaginal or ifice is posterior to the urethral meatus. On 
either side and posterior to the vaginal orifice are two vestibular (Bartholin’s) glands, which 
secrete a clear lubricating mucus during intercou rse. Their ducts are not visible but open in the 
groove between the labia minora and the hymen. 
 
2. The correct answer is (B) Press the inferior ma rgin of the introitus down to enlarge the vaginal 
opening, open, insert the speculum with t he blades at an oblique downward angle, and apply

opening, open, insert the speculum with t he blades at an oblique downward angle, and apply 
gentle downward pressure 
 
Hold the speculum in your right hand with  the index and the middle fingers surrounding 
the blades and your thumb under the thumbscrew. This prevents the blades from opening  
painfully during insertion. With your left index and middle fingers, push the introitus  
down and open to relax the pubococcygeal muscle.  Tilt the width of the blades at an  
oblique angle and insert the speculum past your left fingers, applying any pressure  
downward. This avoids pressure on the sens itive urethra above it. Ease insertion by  
asking the woman to bear down. This rela xes the perineal muscles and opens the  
introitus. As the blades pass your left fingers, withdraw the fingers. Now turn the width

introitus. As the blades pass your left fingers, withdraw the fingers. Now turn the width  
of the blades horizontally and continue to insert at a 45° angle downward toward  
the small of the woman’s back. This matches the angle of the vagina vault. 
 
3. The correct answer is (C) The cervix should move when palpated; an immobile cervix may 
indicate malignancy.

A-39 
 
Characteristics of a normal cervix  are: consistency is smooth and firm; contour is evenly rounded; 
and mobility is flexible. An abnormal cervix w ould be firm, fixed, possibly nodular, and painful 
when moved. 
 
Chapter 12 
 
Case Study:  Irregular Menses 
 
 Abdomen 
 Female genitalia 
 
Primary amenorrhea  
 Primary amenorrhea by definition means that  the patient has not had periods (usually by 
age 16).  In this case, the patient has been havin g regular menstruation until 4 months prior to the 
onset of amenorrhea.   
 
Missed abortion  
 This is less likely.  In the event of a missed abortion, the patient usually experiences

A-40 
vaginal bleeding that is heavier than her usual mens es.  This has not occurred in our patient.  Her 
menstruation has become less, not more. 
 
Pregnancy (most likely diagnosis) 
 The patient has not had a menstrual cycle in 4 months; she has experienced symptoms 
consistent with early pregnancy, such as nausea and fatigue.  Intermittent spotting can occur 
during pregnancy.  Intermittent spotting can be caus ed by vaginal or urinary tract infections, or 
sexual intercourse.  Upon physical examination, t he cervix will appear bluish and at the stage of 
development of our patient, may be more difficult to locate, secondary to being positioned more 
posteriorly.  Also, upon physical examination, an enlarged uterus is palpable in this scenario,

posteriorly.  Also, upon physical examination, an enlarged uterus is palpable in this scenario, 
which further increases the suspicion of pregnancy.  A urine or blood test will be required to confirm the diagnosis. 
 
Ryan: Kistner’s Gynecology & Women’s Health, 7th ed., Mosby, Inc. 1999. 
Chapter 12 – Pediatric and Adolescent Gynecology 
Marc R. Laufer and Donald P. Goldstein 
 
1. The correct answer is (B) Recommend that the best time to perform BSE is 4–7 days after 
the first day of the menstrual period 
 
Help each woman establish a regular schedule of self -care. The best time to conduct breast self-
examination is right after the menstrual period, or the fourth through the seventh day of the

examination is right after the menstrual period, or the fourth through the seventh day of the 
menstrual cycle, when estrogen stimulation is low and the breasts are least congested. Advise the pregnant woman or menopausal woman who is not having menstrual periods to select a

A-41 
familiar date to examine her breasts each month, for example, her bi rth date or the day the rent is 
due. 
 
2. The correct answer is (C) Hegar’s sign and Goodell’s sign 
 
Shortly after the first missed menstrual period, the female genitalia show signs of the hormonal 
changes of pregnancy. The cervix softens (Goode ll’s sign) at 4–6 weeks, and the vaginal mucosa 
and the isthmus of the uterus softens (Hegar’s sign) at 6–8 weeks. 
 
The cervix looks cyanotic (Cha dwick’s sign) at 8–12 weeks. These changes reflect increased 
vascularity and edema of the cervix, and hypertrophy  and hyperplasia of the cervical glands. 
Tanner’s signs refer to sexual maturity ratings in adolescents. 
 
3. Mrs. W is in her first trimester of preg nancy. She is experiencing significant nausea and 
vomiting and asks if it will get better.  Your response is:

vomiting and asks if it will get better.  Your response is:  
 
(A) “At about the time the baby moves, it will get better.’’ 
(B) “Many women experience nausea and vomiting until the third trimester.” 
(C) “Did your mother have significant nausea and vomiting?” 
(D) “Usually, by the beginning of the second trimester, t he nausea and vomiting improve.” 
 
The correct answer is (D) “Usually, by the begi nning of the second trimester, the nausea and 
vomiting improve.”

A-42 
The nausea, vomiting, and the fatigue of pregn ancy usually improve by weeks 12–16. Fetal 
movement occurs at approximately 20 weeks gestation. 
 
3. The correct answer is (A) Most likely to be colostrum and considered a normal finding this late 
in her pregnancy 
 
During the second trimester, colostrum, the precursor of breast milk, may appear. Colostrum is 
yellow in color and contains more minerals and protein, but less sugar and fat than breast milk. 
 
4. The correct answer is (C) After 20 weeks gestation, the number of centimeters should 
approximate the number of weeks’ gestation 
 
After 20 weeks, the number of centimeters shoul d approximate the number of weeks gestation. 
Also, at 20 weeks the examiner may feel fetal movement, and the head can be balloted. 
 
5. The correct answer is (B) Fetal presentation

5. The correct answer is (B) Fetal presentation 
 
Fetal presentation describes the part of the fetus that is entering the pelvis first. Fetal lie is orientation of the fetal spine to the maternal spine. Attitude is the position of the fetal parts in 
relation to each other, and fetal variety is the lo cation of the fetal back to the maternal pelvis. 
 
Chapter 13 

A-43 
 
1. The correct answer is  (B) Pilonidal cyst 
 
A pilonidal cyst is identified by the opening of a sinu s tract on the skin.  It is usually located in the 
midline superficial to the coccyx or the lower sa crum.  There may be a small tuft of hair at the 
opening, and it may be surrounded by a halo of erythema. 
 
An anorectal fistula is an inflammatory tract that  opens at one end of the anus or rectum and at 
the other end, onto the skin surface or another viscus.  The fistula opening is usually located 
around the anus, not at the lower sacrum. An anal fissure is a painful oval ulceration of the anal 
canal and is found most commonly in the midline posteriorly inside  the rectum/anal canal.  
Inspection of the anus may show a swollen “senti nel” skin tag just below it and gentle separation

Inspection of the anus may show a swollen “senti nel” skin tag just below it and gentle separation 
of the anal margins may reveal the lower edge of  the fissure. A thrombosed external hemorrhoid 
results in an acute onset of pain, which is incr eased by sitting and by defecation.  There is a 
tender, swollen, bluish, ovoid mass, which is visible at the anal margin.  There is no associated 
purulent drainage. 
 
2. The correct answer is (B) Internal hemorrhoid 
 
An internal hemorrhoid is an enlargement of the normal vascular cushions that are located above 
the pectinate line.  During defecation, they may c ause bleeding.  If they prolapse, they are visible 
as a reddish, moist, protruding mass.

A-44 
An external hemorrhoid is a dilation of the hemor rhoidal veins that originate below the pectinate 
line and are covered with skin.  They seldom pr oduce symptoms unless thrombosis occurs.  If 
thrombosis occurs, there may be a tender, swollen,  bluish, ovoid mass at the anal margin. A 
rectal prolapse appears as a doughnut or rosette of red tissue. If only the mucosa is involved, 
then the prolapse is relatively small and shows ra diating folds all the way around.  If the entire 
bowel wall is involved, the prolapse is larger and is covered by concentrically circular folds. A 
rectal polyp is a soft mass that can be pedunculate d or sessile; it is located inside the rectum and 
is not visible at the surface. Rectal polyps are soft and may be difficult to feel on rectal 
examination; usually they are diag nosed on proctoscopic examination.

examination; usually they are diag nosed on proctoscopic examination. 
 
3. The correct answer is (A) External hemorrhoid 
 
An external hemorrhoid is a dilation of the hemorrhoidal veins, which originate below the 
pectinate line and are covered with skin.  They seldom produce symptoms unless thrombosis 
occurs.  If thrombosis occurs, there is an acut e onset of local pain, which is increased by 
defecation and by sitting. A tender, swollen, bluish , ovoid mass may be visible at the anal margin. 
 
as a reddish, moist, protruding mass. A rectal prolapse appears as a doughnut or rosette of red 
tissue. If only the mucosa is involved, then the pr olapse is relatively small and shows radiating

tissue. If only the mucosa is involved, then the pr olapse is relatively small and shows radiating 
folds all the way around.  If the entire bowel wall is involved, the prolapse is larger and is covered 
by concentrically circular folds. A rectal polyp is  a soft mass that can be pedunculated or sessile. 
It is located inside the rectum and is not visible at the surface.  Rectal polyps are soft and may be 
difficult to feel on rectal examination; usually  they are diagnosed on proctoscopic examination.

A-45 
 
4. The correct answer is (D) Anal fissure 
 
An anal fissure is a painful oval ulceration of  the anal canal and is found most commonly in the 
midline posteriorly inside  the rectum/anal canal.  Inspection of the anus may show a swollen 
“sentinel” skin tag just below it, and gentle sepa ration of the anal margins may reveal the lower 
edge of the fissure. 
 
opening, and it may be surrounded by a halo of erythema.  There is no discrete opening in this patient’s scenario. An anorectal fistula is an inflammatory tract, which opens at one end of the

opening, and it may be surrounded by a halo of erythema.  There is no discrete opening in this patient’s scenario. An anorectal fistula is an inflammatory tract, which opens at one end of the 
anus or rectum and at the other end onto the skin surface or another viscus.  The fistula opening 
is usually located around the anus, and there is ty pically no swollen skin tag visible to accompany 
it. A thrombosed external hemorrhoid results in an acute onset of pain, which is increased by 
sitting and by defecation.  There is a tender, swolle n, bluish, ovoid mass, which is visible at the 
anal margin.  There are no areas of ulceration t hat are visible when you separate the anal margin. 
 
5. The correct answer is (C) Benign prostatic hyperplasia 
 
The patient’s symptoms and physical exam are most  consistent with benign prostatic hyperplasia.  
The affected prostate gland is symmetrically enlar ged, smooth and firm, although slightly elastic.

The affected prostate gland is symmetrically enlar ged, smooth and firm, although slightly elastic. 
It may protrude more into the rectal lumen.  The median sulcus may be obliterated as well.  
Further diagnostic tests may be required to rule out prostate cancer. 
 
As described in this scenario, the prostate gland is enlarged, not normal in size, and, given the 
patient’s urinary symptoms, this is not a normal pros tate. In prostatitis, the patient has fever.  The 
gland is very tender, swollen, firm, and warm to touch.  This is not the case as described.

A-46 
Prostate cancer is less likely in this scenario.   Prostate cancer is suggested by an area of 
hardness in the gland.  A discrete hard nodule ma y or may not be palpable.  Further diagnostic 
studies are needed to make a diagnosis of cancer. 
 
6. The correct answer is (D) Prostatitis 
 
In acute prostatitis, the patient typically has fe ver and dysuria. The gland is very tender, swollen, 
firm, and warm to touch. 
 
A normal prostate gland would be smooth, firm, and nontender to palpation.  In benign prostatic 
hyperplasia, the affected prostate gland is symmetrically enlarged, smooth and firm, although 
slightly elastic. It may protrude more into the re ctal lumen.  The median sulcus may be obliterated 
as well.  It is not usually tender to palpation. Prostate cancer is less likely in this scenario.

as well.  It is not usually tender to palpation. Prostate cancer is less likely in this scenario.  
Prostate cancer is suggested by an area of hardness  in the gland.  A discrete hard nodule may or 
may not be palpable.  The nodule is not tender, and there is no accompanying fever.  Further 
diagnostic studies are needed to make a diagnosis of cancer. 
 
Chapter 14 
 
1. The correct answer is (B) Acute arterial occlusion 
 
The throwing of an embolism, or thrombosis, causes sudden symptoms associated with a cold, pale, pulseless extremity.

A-47 
 
Artherosclerosis obliterans is incorrect. Generally it is preceded by episodic aching pain during 
exercise of the affected extremity.  Resting caus es the pain to abate within 1–3 minutes.  Pulses 
are often weakened but can be found by Doppler. Deep venous thrombosis is also an incorrect 
response. Pain often develops gradually from the clot  in the vein of the extremity.  There is also 
swelling of the extremity, with local tenderness.  Strength and reflexes are not affected.  If the 
peripheral pulses are diminished it is due to t he increase in tissue swelling; Doppler should still 
elicit pulses. Cellulitis is an infe ction of the superficial layer of sk in on the extremities.  This also 
develops slowly, and the systemic symptoms of malaise and fever are usually associated. 
 
2. The correct answer is (D ) Deep venous thrombosis

2. The correct answer is (D ) Deep venous thrombosis 
 
Deep venous thrombosis is from clot format ion in the deep draining veins of the calves and 
thighs.  It can cause an aching pain and swelling of  the extremity. Cords, which are associated 
with more superficial thrombosis, are generally not felt. 
 
Cellulitis is not a correct response . Since cellulitis is an infectious  process of the skin, there is 
usually profound redness and warmth involved.  Raynaud’s disease generally occurs in the 
extremities due to spasm of the small arteries, leading to transient color changes and pain. Often 
pallor is followed by cyanosis and redness.  There is no swelling of the extremities. 
Atherosclerosis obliterans is episodic muscular isch emia caused by exercise.  In this case, the 
patient had exercised with no problems.  There can also be local muscle fatigue and diminished 
pulses.

pulses. 
 
3. The correct answer is (B) Superficial thrombophlebitis

A-48 
 
Superficial thrombophlebitis is caused by the clotting of superficial veins; it is often due to trauma. 
There is localized redness, swelling, warmth , and pain.  It can be accompanied by fever. 
 
Raynaud’s disease is incorrect.  Raynaud’s generally occurs in the extremities due to spasm of the small arteries, leading to transient color changes and pain. Often pallor is followed by 
cyanosis and redness.  There is no localized swelling, tenderness, or warmth. Superficial 
thrombophlebitis is also an incorrect response. The throwing of an embolism, or thrombosis, 
causes sudden symptoms associated with a cold, pale, pulseless extremity.  There are no local 
areas of warmth or swelling.  Cords cannot be palpated.  Likewise, deep venous thrombosis is 
wrong. Deep venous thrombosis is from clot formation in the deep draining veins of the

wrong. Deep venous thrombosis is from clot formation in the deep draining veins of the 
extremities.  It can cause an aching pain and cause swelling of the extremity.  Cords that are 
associated with more superficial thrombosis are generally not felt. 
 
4. The correct answer is (C) Neuropathic ulcer 
 
Neuropathic ulcers appear at areas of pressure  points because the person affected is unable to 
perceive that there is pain in the area. The pe ripheral neuropathy accounts for the lack of pain 
and the occasional late diagnosis. 
 
Arterial insufficiency ulcers are caused by a lack of  arterial blood supply; so they tend to occur at 
the most distal areas, such as the toes. Ther e is no callus formation surrounding them, and they 
are usually quite painful.  The foot is usually  pale when elevated and dusky when dependent.

are usually quite painful.  The foot is usually  pale when elevated and dusky when dependent.  
Venous insufficiency ulcers occur because of ven ous stagnation in the foot, leading to edema.  
Due to this, the ulcers generally occur at the ankle in the areas of edema.  These ulcers tend to 
be located on skin with permanent color changes due to the accumulation of venous return.  The 
ulcers, although not as painful as arterial ulcers, do generally hurt.

A-49 
 
5. The correct answer is (A) Insufficiency ulcer 
 
Ulcers from a decrease in arterial blood flow are often found at the distal portion of the 
extremities, such as the toes.  T he foot is generally red in color with no swelling.  Pulses are often 
weak or absent. 
 
ulcers, although not as painful as arterial ulcers, do generally hurt. Arterial neuropathic ulcers are 
usually located in areas of pressure, such as the lateral side of the fifth digit and just proximal to

usually located in areas of pressure, such as the lateral side of the fifth digit and just proximal to 
the great toe on the plantar surface.  There is generally callus formation surrounding the ulcer. 
These ulcers tend not to hurt because there is a lack of pain sensation from neuropathy. 
 
6. The correct answer is (C) Lymphedema 
 
Lymphedema is swelling in the extremities ca used by blockage in lymphatic return. This 
obstruction is often due to tumor, trauma, infl ammation; it is rarely infectious. The swelling 
includes the toes and often causes thickening of the skin.  Ulcerations are rare. In this case, the damage to the lymph ducts occurred during surgery.  
 
Pitting edema is always found bilaterally and is caused when interstitial fluid leaks from the vessels due to congestive heart disease, nephroti c syndrome, cirrhosis, or malnutrition. Pitting 
edema can also be caused by prolonged dependency of  the lower extremities. There is no skin

edema can also be caused by prolonged dependency of  the lower extremities. There is no skin 
thickening and generally no ulcerations.  The edema associated with chronic venous insufficiency 
is caused by insufficiency of the valves in the deep veins of the legs.  The accumulated fluid is

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first soft and then hard.  The edema can occur either in just one extremity or in both. Ulceration is 
common; thickening is usually limited to the area around the ankle. 
 
7. The correct answer is (A) Pitting edema 
 
Pitting edema is the result of an interstitial leak  from the vessels due to hypervolemia or from a 
decrease in oncotic pressure of the fluid, allowi ng fluid to leave the vessels.  In this case, 
probable cirrhosis of the liver leads to malnutriti on, resulting in low albumin, which is causing the 
oncotic leak. The swelling in the extremities is alwa ys bilateral, with genera lly no skin thickening 
or ulcerations. 
 
Chronic venous insufficiency is not a correct res ponse. The edema associated with it results from 
insufficiency of the valves in the deep veins of the legs. Accumulated fluid is first soft and then

insufficiency of the valves in the deep veins of the legs. Accumulated fluid is first soft and then 
hard.  The edema can occur either in just one extremity or in both. Ulceration is common. 
Thickening is usually limited to the area around the ankle. Lymphedema is also incorrect.  
Lymphedema is swelling in the extremities due to blockage in lymphatic return.  This obstruction 
is often due to tumor, trauma, inflammation, and, rarely, infections.  The swelling includes the 
toes and often causes thickening of the skin.  Ulcerations are rare. 
 
Chapter 15 
 
1. The correct answer is (C) Gouty arthritis

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Gouty arthritis usually occurs spontaneously, after a night in bed or a large meal.  It results in 
swollen, red, warm, very tender joints.  It is caus ed by an increase in crystals within the joint. 
 
Rheumatoid arthritis generally develops slowly over  time and is symmetrical, with multiple joints 
affected.  Although the joints may be swollen and tender, they are usually neither red nor warm.  
There also tends to be generalized systemic co mplaints of fatigue, weight loss, fever, and 
weakness. This is believed to be autoimmune in origin.  Degenerative joint disease generally also 
develops slowly, but not necessarily symmetrically.  Joints are often tender but usually do not 
swell very much and are not red or warm. The di sease is caused by degeneration in the cartilage

swell very much and are not red or warm. The di sease is caused by degeneration in the cartilage 
of joints. Polymyalgia rheumatica can occur gr adually or overnight.  It generally affects the 
muscles surrounding the larger joints of the hips and shoulder.  Muscles are tender, but there is 
no redness or warmth around the joint. Th is is also autoi mmune in origin. 
 
2. The correct answer is (D) Rotator cuff tear 
 
Rotator cuff tear is often seen in people over 40 due to a sudden trauma or repeated impingement weakening the rotator cuff group.  Th is often eventually leads to a complete tear.  
Weakness is common, as is atrophy of the muscle s.  With a complete tear, active abduction and 
flexion causes shoulder shrugging. 
 
Although also often due to repetitive motion, rotator cuff tendonitis generally occurs in the athletic

Although also often due to repetitive motion, rotator cuff tendonitis generally occurs in the athletic 
context of swimming or throwing.  Activity aggr avates the pain.  Although there is weakness on 
exam with internal and external rotation, there is no shrugging of the shoulder with abduction or 
flexion. The tenderness in bicipital tendonitis centers over the long head of the bicipital tendon.  
There is generally no deficiency in range of moti on, and there is no shrugging of the shoulder in 
abduction. Acrominoclavicular arthritis is an uncommon cause of shoulder pain and usually

A-52 
occurs when there is a direct blow to the s houlder girdle.  Most tenderness is over the 
acromioclavicular joint. There is normal range of motion in the glenohumeral joint. 
 
3. The correct answer is (B) Olecranon bursitis 
 
Sudden and repetitive trauma often causes swellin g and inflammation in the bursa. In this case, 
the repetitive injury of inappropri ate weightlifting led to the accumula tion of fluid in the bursa sac. 
 
Arthritis is not a correct response. Degenerative joint disease is usually seen in older people and 
is caused by degeneration of the ca rtilage of the joint.  Any swelling is felt in the grooves between 
the olecranon process and the epic ondyles. The swelling usually feel s boggy and is very tender.  
Although epicondylitis is also often associated with repetitive motion in sports, there is no swelling

Although epicondylitis is also often associated with repetitive motion in sports, there is no swelling 
involved. There is, however, a great deal of point  tenderness over the medial epicondyle in tennis 
elbow and golfer’s elbow. Rheumatoid nodules are subcutaneous nodules, which develop along 
pressure points on the extensor surface of the ulna. They are firm and nontender. They are 
associated with longstanding rheumatoid arthritis or acute rheumatic fever. 
 
4. The correct answer is (A) Ganglion 
 
A ganglion is a growth along the tendon sheaths of joint capsules. Ganglions generally appear in 
young adults and are usually nontende r.  They are more prominent when the wrist is flexed. 
 
Chronic tophaceous gout is an incorrect response. These swellings tend to occur along the joints of the phalanges and metacarpals. The topha ceous gout swellings are knobbylike and can 
ulcerate, discharging white chalklike material.  The patient usually has a long history of gout.

ulcerate, discharging white chalklike material.  The patient usually has a long history of gout. 
Acute rheumatoid arthritis is also incorrect. The swelling from rheumatoid arthritis tends to be

A-53 
symmetric between both hands, affecting the phalanges.  There are no swellings along the 
dorsum of the wrist.  There are generally also systemic symptoms of fatigue, weight loss, 
weakness, and fever. Choice (D) is incorrect as well.  Herberden’s nodes are boney overgrowths 
located on the dorsal lateral surface of the dist al interphalangeal areas.  They are usually hard 
but not painful.  These are generally found in t he elderly who have had degenerative joint disease 
for many years. 
 
5. The correct answer is (A) Cervical sprain 
 
A cervical sprain is often associated with an injury such as occurs in a motor vehicle accident, heavy lifting, or impact against the neck.  There is local tenderness over the cervical muscles and 
a decreased range of motion of the neck.

a decreased range of motion of the neck. 
 
Although muscle ache is often associated with tenderness over the neck,  there is usually no 
precipitating injury.  Often this pain is from pos tural problems while typing or studying. Neck pain 
with dermatomal radiation is often associated with severe injury that causes a herniation of the 
disc. The affected patient complains about pain radiating down his arm.  He will often have 
decreased reflexes in the tendons of the affected arm and a dermatomal pattern of decreased 
sensation.  Often coughing  or straining will increase the pain.  Neck pain from spinal stenosis can 
cause severe pain to the neck radiating to the ar ms and trunk.  Often there will be weakness or 
paralysis in the arms or legs.  At the most extr eme, there can be loss of sensation.  Coughing or 
straining will also worsen symptoms. 
 
6. The correct answer is (C) Back  pain from metastatic disease

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Back pain from metastatic disease occurs even when the patient is at rest.  It generally does not 
radiate, and the patient has normal reflexes, st rength, and sensation.  Often there is point 
tenderness where the metastatic disease is located. The pain in this patient most likely 
represents breast cancer metastasis. 
 
Usually mechanical back pain causes symptoms of  aching in the back during activity, and it is 
relieved with rest. Radicular back pain is caused by pressure against the spinal root, usually 
through a herniated disc.  Pain originates in the lumbar area of the back but radiates down one or 
both legs.  Often there is weakness in the affe cted extremities and decreas ed sensation.  There 
are often decreased reflexes and a positive finding on straight leg raise.  Often there is a history

are often decreased reflexes and a positive finding on straight leg raise.  Often there is a history 
of trauma to the back. Although the type of back pa in associated with spinal stenosis is common 
in the elderly, it generally causes more pain with walking; flexing the spine improves the 
symptoms.  Spinal stenosis does cause loss of  muscle strength and hyporeflexia.  In severe 
cases, there can be loss of bowel or bladder func tion. Spinal stenosis is usually caused by severe 
degenerative disease narrowi ng the spinal canal. 
 
Chapter 16 
 
1. The correct answer is (C) Stuporous 
 
A stuporous patient only responds to painful stimu li such as a sternal rub or the pinching of a 
tendon.  When the painful stimulus is removed, he becomes unresponsive again.

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A lethargic patient awakens to conversation, ans wers questions, and then returns to sleep. An 
obtunded patient often must be shaken to respond. He often looks confused and gives slow 
answers. A comatose patient will not respond to any external stimuli and will remain in an 
unarousable state. 
 
Corns are thickened skin, which are caused by  pressure against the foot. They occur most 
commonly on the lateral side of the fifth t oe and between the fourth and fifth toes. Callus 
formations also occur at pressure points but at places where the skin is normally thick. Calluses 
are not painful and are usually located around the heel  or over the plantar surface just proximal to 
the great toe. Neuropathic ulcers also develop at pressure points usually due to a lack of

the great toe. Neuropathic ulcers also develop at pressure points usually due to a lack of 
sensation.  Although often deep and infected, they  are not painful.  They are usually red and 
warm and sometimes drain serosanguinous fluid. 
 
2. The correct answer is (B) Post ural (orthostatic) hypotension 
 
Orthostatic hypotension can often be due to hypovolemia, which in this case is from vomiting and diarrhea. It generally occurs upon standing up after being in a recumbent position. 
 
Vasodepressor syncope is generally precipitated by a strong emotional response, such as fear or 
pain.  Usually it occurs when a person is alre ady sitting or standing and is often accompanied by 
a feeling of weakness or sweat ing beforehand. In order for a cardiac arrhythmia to cause

a feeling of weakness or sweat ing beforehand. In order for a cardiac arrhythmia to cause 
syncope, the heart rate must be generally less than 40 or greater than 180 bpm.  It is usually associated with known cardiac disease. An hysterical faint is usually a symbolic expression of an unacceptable idea through the body language of fainting. It is usually seen in people with 
hysterical personality traits.

A-56 
3. The correct answer is (C) Generaliz ed tonic clonic (grand mal) seizure 
 
Patients who experience a grand mal seizure often lose consciousness suddenly, with a stiffening 
of the body. This is often followed by the clonic jerking of the muscles.  Tongue biting and urinary 
incontinence are often noted. The patient will then have a pronounced postictal state of confusion 
and drowsiness. 
 
In a simple partial seizure, the patient remain s fully conscious of his surroundings and is not 
drowsy after the seizure.  The patient can often have tonic clonic movements, but only on one 
side of the body. A complex partial seizure often begins with symptoms similar to those of the 
simple partial seizure, which can also cause im pairment in consciousness. Often automatisms,

simple partial seizure, which can also cause im pairment in consciousness. Often automatisms, 
such as chewing or lips smacking, will occur.  The patient may remember the beginning of his 
seizure. An absence seizure is generally a sudde n brief lapse of consciousness accompanied by 
staring or movements of the lips or hands. Generally, this lasts for less than 10 seconds and is 
followed by no postictal state. 
 
4. The correct answer is (A) Sensory ataxia 
 
Sensory ataxia is associated with loss of position of the feet and legs often due to peripheral 
neuropathies such as those asso ciated with diabetes. The gait is generally wide based and 
unsteady. The patients usually will throw their feet  down heavily forward and outward. They must 
also watch the ground for guidance and usually cannot stand steady with  their feet together 
(positive Rhomberg sign).

(positive Rhomberg sign). 
 
Cerebellar ataxia is usually associated with di seases that affect the cerebellum, such as 
alcoholism and stroke. Patients also have a wide st aggering gait, but they cannot stay steady with 
their eyes opened or closed.  Watching the ground does not help them walk. Parkinsonian gait is 
associated with basal ganglia defects from Park inson’s disease. Often the posture is stooped,

A-57 
with the head forward and the knees and hips flex ed. The patient has difficulty starting to walk; 
while walking, the steps are short and shuffling.   Steppage gait is associated with damage to the 
lower motor neurons, such as a herniated disc against a lumbar nerve root. The person lifts her 
foot high and slaps it to the floor, appearing as if she were trying to climb.  She cannot walk on 
her heels. 
 
5. The correct answer is (B) Postural tremors 
 
Postural tremors occur when a person is holding the affected part of his body in a postural 
position. These tremors are often associated with hyperthyroid ism, anxiety, and benign familial 
essential tremors, such as is the case here.  Intentional movement can either worsen or improve 
the tremors.

the tremors. 
 
Although resting tremors are present at rest and de crease with voluntary movement, they tend to 
have slow, fine pill rolling of the fingers.  These tremors are often associated with Parkinson’s 
disease. Intention tremors are abse nt at rest and occur with activity.  The tremors often worsen 
when the hands get closer to their intended target.  This is associated with cerebellar dysfunction, 
such as in alcoholism and multiple sclerosis. At hetosis is a movement disorder characterized 
more by slow writhing movements of the hands rath er than tremor-like motion. It often also affects 
the face and distal extremities.  It is associ ated with diseases such as cerebral palsy. 
 
6. The correct answer is (C) Anterior horn cells 
 
In anterior horn cell disease, there is both weakne ss and atrophy in a focal or segmental pattern.

In anterior horn cell disease, there is both weakne ss and atrophy in a focal or segmental pattern.  
Sensation remains intact, while reflexes are decr eased.  When seen in childhood, the problem is

A-58 
often polio; in older adults, it is often amyotr ophic lateral sclerosis (Lou Gehrig’s disease).  
Fasciculations in the muscle fibers are often felt and seen. 
 
Although in spinal root disease there is weakne ss in the muscle groups and decreased reflexes, 
there is also sensory deficits in the correspondi ng dermatomes.  Spinal root disease is often 
caused by a herniated disc from trauma. In neuromuscular junction disease, there can be 
weakness in the muscles but usually this oc curs after the muscles have been used for an 
extended time. This process is known as fatigability. The sensation also remains intact in the 
dermatomes, and the reflexes are normal.  Myast henia gravis is an example of neuromuscular 
junction disease. When muscle fibers are affected, there is pronounced weakness in the muscles,

junction disease. When muscle fibers are affected, there is pronounced weakness in the muscles, 
but sensation remains intact. Reflexes can be normal or decreased.  Muscular dystrophy is an 
example of this type of disorder. Muscle fasciculations are rare. 
 
7. The correct answer is (D) Schizophrenia 
 
Schizophrenia often starts suddenly in young adults  with strong family history of mental health 
problems.  Delusions, hallucinations, disorganized speech, disorganized behavior, and negative symptoms (flat affect, lack of interest or drive)  are often present.  In this case, the young woman 
has delusions (winning the Nobel Prize as a co llege student), hallucinations (apparent when she 
is seen having conversations with herself), di sorganized speech (with shifting of ideas and 
clanging speech), and disorganized behavior (wearing clothes backwards).

clanging speech), and disorganized behavior (wearing clothes backwards). 
 
People with major depression generally can expres s their thoughts coherently and do fairly well 
with proverbs.  Usually they seem sad and compla in about feelings of worthlessness and fatigue.  
They often have problems with eating and sleeping.   Sometimes they have thoughts of hurting or 
killing themselves. Those people with bipolar di sorder often have alternating feelings of 
depression and elation. They can have delusions or fantasies about themselves, but again they

A-59 
usually can express their thought s coherently.  Often they have pressured speech, but usually 
they do not repeat phrases. Peopl e with generalized anxiety disorder often worry about several 
different areas of their lives (e.g., money, relation ships, work, etc.). They can feel fatigued and act 
restless, but they generally are coherent in thought and speech. 
 
8. The correct answer is (B) Delirium 
 
The hallmark of delirium is that it occurs acutely.   The course can be fluctuating, and the level of 
consciousness is disturbed.  The patient can beco me somnolent, as in this case, or agitated.  
Illusions and hallucinations are common.  Patients are often disoriented to place and time but not 
to person.  Metabolic changes, poisonings, sepsis, and delirium tremens are causes. This

to person.  Metabolic changes, poisonings, sepsis, and delirium tremens are causes. This 
episode probably began as a urinary tract infection that became uroseptic. 
 
A psychotic reaction to major depression is not  a correct response. Although hallucinations are 
common in psychotic reactions, there is usually an underlying mental health disorder such as 
depression or mania.  lso psychosis does not ca use somnolence. Dementia is also incorrect.  
Dementia is a slowly progressive change in mental  status over months to years. The level of 
consciousness is generally unaffected.  Hallucinat ions and delusions may occur. Until late stages, 
patients are usually oriented to person, pl ace, and time. The most common causes are 
Alzheimer’s disease and multi-infarct dementia. 
 
Chapter 17 
 
Case Study:  Abdominal Pain

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 Skin 
 HEENT 
Thorax/Lungs 
Abdomen 
Peripheral Vascular/Extremities 
Musculoskeletal 
Neurologic 
 
Dehydration 
 In infants, the signs that suggest dehydration from decreas ed oral intake are a decreased 
number of wet diapers from the usual.  The signs of  dehydration in infants include the following: 
lethargy, sunken fontanelle, dry mucous membra nes, tachycardia, tachypnea, and tented or 
doughy skin.  In this scenario, the infant is crying and has moist mucous membranes.  The 
anterior fontanelle is tense and bulging instead of  sunken.  Therefore, this infant is not 
dehydrated.

dehydrated. 
Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 5th ed., Copyright  © 2002 Mosby, Inc.   
Chapter 166 - Infectious Diarr heal Disease and Dehydration. 
Roger M. Barkin, David G. Ward.  pp 2315--2316 
 
Colic 
 Infantile colic is paroxysms of irritability, fuss iness, or crying that lasts for a total of more 
than 3 hours each day and occurs on more than 3 days in any 1 week.  The cry is loud, high-

A-61 
pitched, and piercing.  The infant is inconsol able and the crying can last for hours, usually 
occurring in the evening.  The infant often has an irregular sleeping pattern and problems with 
feeding.  The symptoms develop suddenly during the newborn time period and disappear just as 
suddenly at 3–4 months of age.  The infant has a normal physical exam.  In this scenario, the 
patient has an abnormal physical exam with fever and a bulging, tense anterior fontanelle.  
Therefore, this infant is less likely to have colic. 
Primary Care; Clinics in Office Practi ce.  Vol. 27, No. 1, March 2000.   
Update In Maternity Care Issues in Newborn Care. 
 Robin M. Clemons MD, MPH, p. 251 
 
Meningitis (most likely diagnosis) 
 
 Features of meningitis in infants include many of the following symptoms and signs:

Robin M. Clemons MD, MPH, p. 251 
 
 Features of meningitis in infants include many of the following symptoms and signs: 
 
Symptoms:  lethargy, restlessness, paradoxical irritability, high-pitched cry or a vacant stare,  
altered feeding pattern, diarrhea, and vomiting. 
 
Signs:  apnea, tachypnea, hypothermia or hype rthermia, bradycardia on general survey; 
nystagmus, opisthotonos, seizures, altered tone, nuchal rigidity, and bulging fontanelle on 
neurologic exam; jaundice, cyanosis, petechiae, liv edo reticularis, and purpura may be visible, 
along with a delayed capillary refill time. Abdominal distention may also be present. 
 
In this scenario, the infant has paradoxical irritability, altered feeding pattern, hyperthermia, 
bulging fontanelle, petechiae, and a delayed capillary refill time.  In an infant less than 2 months 
of age, with the symptoms presented in this ca se, the most likely diagnosis is meningitis until

of age, with the symptoms presented in this ca se, the most likely diagnosis is meningitis until 
proven otherwise by further testing.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 5th ed. 
Chapter 168 - Neurologic Disorders.   
David H. Rubin, Edward E. Conway Jr., Stuart M. Caplen, Jonathan I. Singer, Dina Halpern Kornblau.   
2002, Mosby, Inc.  p. 2344.   
 
1. The correct answer is  (C) Mongolian spots  
 
Mongolian spots are more common among darker-sk inned babies.  They range from bluish–gray 
to deep brown or black.   They disappear after a few years and usually fade by puberty. 
 
Response (A) is incorrect. Café au lait spots ar e characteristically light -brown pigmented lesions, 
which usually have a ragged border. Response (B) is also incorrect. Salmon patch or stork bite 
lesions are splotchy pink in color and are oft en found on the back of the neck and the back of the

lesions are splotchy pink in color and are oft en found on the back of the neck and the back of the 
head of infants. They fade with age. Neurofibroma tosis is incorrect as well. Early findings in 
neurofibromatosis include more than five café au la it spots and axillary freckling.  Later findings 
include neurofibromas and Lish nodules. 
 
2. The correct answer is (B) Erythema toxicum  
 
Erythema toxicum consists of yellow or white pustules, which are surrounded by a red base.  The 
rash is scattered diffusely over the infant’s body and frequently changes location.  The palms and 
soles are often spared.

A-63 
On the other hand, neonatal acne consists of  red pustules and papules, which are most 
prominent over the cheeks and nose of the ne wborn infant. Seborrhea is a salmon-red, scaly 
eruption, which often involves the face, neck, axilla, diaper area, and the area behind the ears. 
Jaundice refers to the yellow–orange discolorat ion that appears on a newborn infant’s skin.  If it 
appears on the second day of life and is slow to spread, then it is most likely physiologic and will 
resolve on its own.  If it appears right at birth,  then other causes of jaundice must be suspected 
and worked up. 
 
3. The correct answer is (B) This infa nt has some nervous system depression 
 
An Apgar score that is between 5 and 7 at 1 minute of life indicates some nervous system 

depression. 
 
A normal Apgar score at 1 minute of life is betw een 8 and 10. An Apgar score of 0–4 at 1 minute 
of life indicates severe depression, requiring immediate resuscitation. An Apgar score at 5 
minutes  of life that is between 0 and 7 indicates that  the infant is at high risk for subsequent 
central nervous system and other  organ system dysfunction. 
 
4. The correct answer is (D) Neonatal meningitis 
 
Neonatal meningitis is a significant infection, wh ich can result in significant developmental delay. 
 
Although chronic otitis media may cause a delay in speech and language development, it occurs 
in children older in age than 6 months.  A single episode of otitis media does not result in 
developmental delay. Overfeeding is obviously an in correct response since this infant is well

developmental delay. Overfeeding is obviously an in correct response since this infant is well 
within range for weight and has no sign of overf eeding, which, in any case, does not result in

A-64 
significant developmental delay. Nor is gastroesopha geal reflux a correct answer since it does not 
result in developmental delay. 
 
5. The correct answer is (C) 20/40 
 
Children under 4 years of age have an expected visual acuity of 20/40. 
 
Eyes converging is an expected finding in children aged 0–3 months.  This patient is 2 years old. 
The second response (–20/200) is incorrect; this  is an expected finding in children who are 12 
months of age.  The fourth response (20/30) is  likewise incorrect. Children over the age of 4 have 
an expected visual acuity of 20/30.

Bickley 8/e. IM 1
INSTRUCTOR’S MANUAL TO ACCOMPANY BATES’ 
GUIDE TO PHYSICAL E XAMINATION AND HISTORY 
TAKING, 8TH  EDITION 
 
OVERVIEW 
This Instructor’s Manual to Accompany Bates’ Guide to 
Physical Examination and History Taking , 8th Edition, provides a 
course outline that will help you t each students the essential clinical 
skills of history taking and phys ical examination. The physical 
examination course is often the only point in the curriculum in which 
time is dedicated to student mast ery of these essential skills.  
This course requires a high level of interaction between teacher 
and student. Therefore, you should ex pect students to prepare for each 
workshop by reading the assigned chapter in the Bates’ Guide to 
Physical  Examination and History Taking, 8th Edition,  before coming 
to class. They should bring the textbook with them to class as an aid 
and reference for the techniques bein g taught each day. At the end of

and reference for the techniques bein g taught each day. At the end of 
each workshop, students find it helpful to  give a brief oral presentation 
and practice the vocabulary need ed to describe the regional 
examination findings of a healthy person. Also, to reinforce their learning, students submit a written version of that day’s regional 
examination to you within 24 hours. 
COURSE GOALS 
 The goals of a course on physical examination and history taking are as follows:

Bickley 8/e. IM 2
• Organize information gathered from effective patient-centered 
interviews into a standard written format integrating health 
history and psychosocial data and perspectives. 
• Acquire psychomotor skills to conduct a complete physical examination on adult and pediatric patients. 
COURSE OBJECTIVES 
Students should be able to demonstrate mastery of the following 
objectives by the end of the course: 
• Obtain and document a complete history for adult and pediatric patients. 
• Perform and document a complete physical examination for adult 
and pediatric patients. 
• Identify common medical proble ms using history and physical 
examination skills only. 
REQUIRED TEXT AND EQUIPMENT 
Bates' Guide to Physical Examination and History Taking , 8th Edition 
Stethoscope 
Penlight 
Reflex hammer 
Snellen eye chart (near vision card) 
Tuning fork (128 Hz and 256 Hz) 
Otoscope/ophthalmoscope; optional,  but strongly recommended  
Clear plastic ruler

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SUGGESTED READING LIST 
The following reading list is suggested for an 11-week course 
using Bates’ Guide to History Taking and Physical Examination , 8th 
Edition: 
Weeks 1 and 2: Chapter 1 – An Overview of the Physical                                                                              
Examination and History Taking 
            Chapter 2 – Interviewing and the Health History 
Chapter 18 – Clinical Reasoning, Assessment,                                                                      
and Plan 
Week 3: Chapter 3 – Beginning the Physical 
Examination: General Survey and Vital Signs 
   Chapter 4 – The Skin 
Week 4:  Chapter 5 – The Head and Neck 
Week 5:  Chapter 6 – The Thorax and Lungs 
Chapter 7 – The Cardiovascular System 
Week 6:  Chapter 9 – The Abdomen 
Week 7:  Chapter 14 – The Peripheral Vascular System Week 8:                       Chapter 15 – The Musculoskeletal System 
Week 9:  Chapter 16 – The Nervous System

Week 9:  Chapter 16 – The Nervous System 
Week 10:  Chapter 8 – The Breasts and Axillae 
Chapter 11 – Female Genitalia 
Week 11  Chapter 10 – Male Genitalia and Hernias 
Chapter 13 – The Anus, Rectum, and Prostate

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SUGGESTED COURSE ORGANIZATION 
 The authors of this manual have  successfully ta ught courses in 
Physical Examination and History Taking using a series of  
“workshops.” This section provides recommendations for setting up 
your class based on their successful model. 
 The authors recommend a 1-hour class for all enrolled students at the beginning of each week devoted to a video of that week’s 
regional examination, questions and answers on techniques, and a quiz 
on the required reading. The ideal du ration of each session is 2 hours, 1 
day per week. Student attendan ce should be MANDATORY. Split the 
class into “Workshop Teams” of 10 students. Each student should pick 
a partner of the same sex within his or her own team.  
 Each Workshop Team should have a Faculty Team Captain and 
four to five other clinicians w ho are responsible for teaching all 11 
workshops to their group of 8 to10 students. Preceptors are clinicians

workshops to their group of 8 to10 students. Preceptors are clinicians 
who supervise students as they practice the skills for each workshop. 
The Team Captains are responsible for scheduling the preceptors for 
each workshop. Preceptors should be on time and notify their Team 
Captain immediately if they are late. 
The following format for each workshop is recommended:  
• Students sign in. 
• Preceptors demonstrate key skills for that day’s workshop and 
review questions from prior workshops.

Bickley 8/e. IM 6
• Practice oral presentation skills for the history. 
• Review the “write-up”  of the history. 
Workshop Activities  
1. PRIOR  to the workshop, conduct an interview with a healthy 
patient. (Ask another classmate, friend, or family member. The 
information will remain confidential.) 
2. Discuss the format of a good oral presentation (Box 1). 
3. Verbally present the interview to your class or assigned 
workshop group (5 minutes per presentation). 
4. Submit the write-up of your interv iew to your faculty preceptor 
by the end of the workshop. 
 
Box 1: Tips for a Great Verbal Presentation 
Basics 
• Aim for your presentation to be  no longer than 5 minutes (3 
minutes for the history, 2 fo r the physical examination). 
• Use notes, but maintain good eye contact with y our listeners. 
• Remember, the history is subjective (what the patient says), and the 
examination is objective (what you observe).

examination is objective (what you observe). 
• Do not include everything in the oral presentation that you present 
in your write-up. Be selective! 
History of Present Illness (HPI) 
• Patient's age, sex, occupation

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• Symptoms (or immediate cause of admission) 
• Chronology and the seven characteristics of the current 
symptoms: 
1. Anatomic location 
2. Quality 
3. Quantity or severity 
4. Timing 
5. Setting in which the symptoms occur 
6. Aggravating or relieving factors 
7. Associated symptoms 
• Relevant  past medical history      
• Review of systems questions pertinent to the chief complaint 
and history of present illness of the system involved . (Note:  List 
each question as either pertinent positives or pertinent 
negatives) 
Example: "This is a 45-year-old teacher  who presents 
for evaluation of burning pain in her stomach…" (This 
opening statement combines th e chief complaint and the 
beginning of the history of present illness.) 
Medications/Allergies; Smoking/Alcohol Use1
• Medications and relevant home remedies, over-the-counter 
drugs, supplements, and any borrowed medications

drugs, supplements, and any borrowed medications 
                                                           
1 The authors recommend placing this important data at the end of the HPI, but note 
that these items are often listed elsewhere in the history.

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• Allergies to medications and re sulting allergic  symptoms (e.g., 
penicillin →rash) 
• Smoking and alcohol use 
Past Medical History 
• Childhood illnesses 
• Adult illnesses 
• Medical conditions 
• Surgeries 
• Obstetric/gynecologic  
• Psychiatric  
Family History (FH) 
 Major illnesses in the immediat e family (parents, grandparents, 
siblings) 
Personal and Social History (PSH) 
Personal status, occupation, education, home conditions, 
interests 
Review of Systems (ROS) 
In the oral presentation only “unremarkable except for …” 
(maximum of three or four item s), which are not in the history 
of present illness 
 
Required Reading  
Bates’ Chapter 1, An Overview of Physical Examination and History 
Taking, pp. 1–19.

Bickley 8/e. IM 9
 
Bates’ Chapter 2, Interviewing and the Health History, 21–57. 
Bates’ Chapter 18, Clinical Reas oning, Assessment, and Plan, pp. 783–
802. 
Tips for Learning  
You will polish your interviewing skills throughout your career. 
The flow of the interview will vary as much as the personalities of the 
many patients that you will encounter. Reading Chapters 1 and 2 is 
essential to learning the skills of good interviewing. Focus especially on “The Seven Attributes of a Symp tom” (p. 27) and “Facilitating the 
Patient’s Story: The Techniques of  Skilled Interviewing” (pp. 30–34). 
Although the shape and flow of the interview will differ for 
each patient, you must organize the patient’s history into the 
standardized format provided on p. 3. 
Workshop 2: Adapting to the Challenging Interview  
Learning Objectives and Outcomes  
• Identify techniques of verbal a nd nonverbal communication; review 
the principles of empathic interviewing.

the principles of empathic interviewing. 
• Learn strategies to address th e challenging interview (i.e., the 
talkative patient, the angry patient, etc.). 
• Discuss the model for cultural competence and guidelines for working with an interpreter.  
Workshop Activities

Bickley 8/e. IM 10
1. Students will role-play various practice cases, provide feedback 
to the student interviewer, and iden tify strategies that facilitate 
the challenging patient interview. 
2. Students will discuss the st ages of the interview and 
demonstrate techniques for establishing rapport. 
3. Students will demonstrate knowledge of open-ended versus close-ended questioning and subjec tive versus objective data 
from the patient. 
Bates’ Chapter 1, An Overview of P hysical Examination and History   
Taking, pp. 1–19. 
Bates’ Chapter 2, Interviewing and the Health History, pp. 21–57. 
802. 
You will come to remove the word “I” from your interviewing 
style. The key to a good interview is to focus on the patient’s  story and 
to use the skills of good interviewing to enhance and clarify what the 
patient tells you, especia lly the chronology of his or her symptoms.

patient tells you, especia lly the chronology of his or her symptoms.   
At the same time, through nonverbal behaviors, you will project 
your empathy and concern for the patient and learn to be attuned to the 
patient’s affect, or mood state. Y ou will find that it often helps to 
acknowledge directly th e patient’s sadness, nervousness, or anger by

including abnormalities, such as basic skin lesions, vascular and 
purpuric lesions, skin tumors, and abnormalities of the nails. 
1. Bring your stethoscope and penlight. 
2. Describe the general appearance of  
• Your partner  
• A hypothetical patient with congestive heart failure (CHF)

Bickley 8/e. IM 12
• A hypothetical patient with chronic obstructive pulmonary 
disease (COPD) 
3. Demonstrate accurate technique for measuring the four vital 
signs. 
4. Describe five components of optimal technique for recording blood pressure. 
5. Describe the difference between  systolic and diastolic blood 
pressure; define auscultatory gap. 
6. Describe macule, papule, vesi cle, basal cell carcinoma, 
squamous cell carcinoma, clubbing, spider angioma, psoriatic 
plaque, and skin findings in neurofibromatosis (including 
typical location, distribution, ar rangement, type, and color). 
Sample Verbal Presentation  
The patient is a healthy young male who appears fit and 
muscular. He is pleasant and coope rative. Blood pressure is 120/80; 
heart rate, 80 and regular; respiratio ns, 16; afebrile. Skin is warm and 
moist. Nails without clubbing or cy anosis. No rashes, petechiae, or 
ecchymoses. 
Required Reading

Bates’ Chapter 3: Beginning the Physical Examination: General Survey   
and Vital Signs, pp. 59–93. 
Bates’ Chapter 4: The Skin, pp. 95–113.  
Tips for Learning

Bickley 8/e. IM 13
 The General Survey begins with the first moments of your 
interview of the patient. You w ill come to sharpen your powers of 
observation and learn much about the patient from his or her demeanor. The Vital Signs are critical to all patient assessments, as are oral and 
written presentations. Learn to be sy stematic in presenting them. Hair, 
skin, and nails also provide many clue s to the patient’s state of health. 
Learning the proper descriptive terms for findings from the examination of the skin is important. 
Workshop 4: Head, Eyes, Ears, Nose, Throat (HEENT), Neck 
• Identify key anatomic structures basic to examination of the head 
and neck, especially regions of the skull; anatomic detail of the eye; 
the three bones of the middle ear,  auricle, and pinna; the nasal 
turbinates; the sinuses ; and the nine groups of cervical lymph 
nodes. 
• Demonstrate assessment techniques for visual acuity, extraocular

nodes. 
• Demonstrate assessment techniques for visual acuity, extraocular 
movements, pupillary reaction, aud itory acuity, oral and pharyngeal 
mucosa, gums, dentition, cervical lymph nodes, cricoid cartilage, 
and thyroid isthmus and lobes. Demonstrate appropriate 
funduscopic examination. 

Bickley 8/e. IM 14
1. Bring a penlight, eye card, and tuning fork (256 Hz). The 
instructor will provide the ophtha lmoscopes, otoscopes, tongue 
depressors, and cups for water. 
2. As you practice the skills of Ch apter 5, focus especially on use 
of the ophthalmoscope and examination of the fundi and on 
palpation of the thyroid gland. 
3. List six tips for use of the opht halmoscope: (1) always darken 
the room; (2) reduce maximum ophthalmoscope brightness by 20%; (3) go to the 
small  circular dot; (4) stand at a 30-degree 
angle to the patient; (5) place t humb on eyebrow to support your 
head as you move in; (6) look for the point where four retinal 
arteries merge together. It is also helpful to look with the 
ophthalmoscope toward the pati ent’s nose to locate the fundus 
more easily. 
4. Teach your partner verbally how  to examine a thyroid. For 
example, for the posterior approach, identify the cricoid 
cartilage, have the patient tip he r head slightly forward and to

cartilage, have the patient tip he r head slightly forward and to 
the side, and palpate between the sternocleidomastoid and 
trachea for rubbery tissue of the ipsilateral thyroid gland. 
5. Describe changes of hypertensi ve and diabetic retinopathy. 
The skull is normocephalic/atraumatic (NC/AT). Pupils are 4 
mm constricting to 2 mm and  equa l, round, and reactive to light and

Bickley 8/e. IM 15
accommodation (PERRLA). The discs are flat, without hemorrhages or 
exudates. TMs clear. Oral mucosa pink; dentition good; pharynx 
without exudates. Neck suppl e: without thyromegaly. No 
lymphadenopathy. 
Bates’ Chapter 5: The Head and Neck, pp. 115–208. 
The most challenging parts of ex amination of the head and neck 
are learning to use the ophtha lmoscope, seeing the fundi, and 
examining the thyroid. Don’t be disc ouraged if you can’t see the fundus 
on your first attempt. Remember, if you practice the correct techniques, 
you will succeed! Be sure to ask your preceptors for help. This 
workshop is your best opportunity to  learn the proper techniques well 
enough to teach them to your partner, so the tips for examining the fundi and thyroid described above are important. 
Workshop 5: Thorax, Lungs, and Cardiovascular System 
Learning Objectives and Outcomes

• Demonstrate the following techniques for examining the lungs: 
percussion, excursion, descent of diaphragms, and auscultation 
(including right middle lobe). 
• Demonstrate the proper technique  for assessing jugular venous 
pulsation (JVP) and carotid upstrokes. Please note that examination

Bickley 8/e. IM 16
of the JVP and carotid upstrokes is part of the cardiac  examination , 
even though they are in the neck. 
• Demonstrate techniques for palpati ng heaves, lifts, and thrills and 
point of maximal impulse (PMI). 
• Demonstrate use of bell and di aphragm in the six areas of 
auscultation. Distinguish S 1 from S 2 and systole from diastole. 
• Demonstrate maneuvers to elicit an S 3 or mitral stenosis and aortic 
insufficiency. 
1. Bring your stethoscope and a clear plastic ruler. 
2. Describe the pathophysiology of chronic obstructive pulmonary 
disease (COPD) and asthma. Be pr epared to present orally the 
physical findings of the lung examination for these two 
conditions. 
3. Describe the normal cardiac cycle. 
4. Describe two ways to report your measurement of the JVP: “x” cm above the right atrium or “x” cm above the sternal angle 
with the head of the bed elevated to “x” degrees. 
5. Describe the grading system for murmurs.

5. Describe the grading system for murmurs. 
6. Describe the pathophysiology of S 3, S4, mitral regurgitation, 
mitral stenosis, aortic regurgitation, aortic stenosis, and 
pericardial rubs. Give the best location for auscultating each of 
these murmurs. Demonstrate the maneuvers for eliciting low-

Bickley 8/e. IM 17
pitched sounds, like an S 3, or the murmur of mitral stenosis 
(isometric hand-grips) and fo r eliciting the soft, blowing 
decrescendo murmur of aortic insufficiency (pp. 226–229; 233; 
240–243). 
Thorax symmetric with good excu rsion. Diaphragms descend 4 
cm bilaterally. Lungs are resona nt, breath sounds vesicular; no 
wheezes, rales, or rhonchi.   
 JVP is 6 cm above the right at rium; carotid upstrokes brisk, no 
bruits. PMI tapping, 8 cm lateral to mi dsternal line in fifth intercostal 
space (ICS). Good S 1, S2; no murmurs or extra sounds.   
Bates’ Chapter 6: The Thorax and Lungs, pp. 209–243. 
Bates’ Chapter 7: The Cardiovascular System, pp. 245–295. 
Percussion is an art. Be sure  you aim for a medium-loud, clear 
percussion note. Your third fingernail will need to be short so you can 
tap against the distal knuckle of th e third finger of your “pleximeter”

tap against the distal knuckle of th e third finger of your “pleximeter” 
hand (see pp. 223–224). Do not damp out your percussion note by 
pressing too hard with your plex imeter finger or placing any other 
fingers on the chest wall. Listen for a dull percussion note by 
percussing over the scapula, compared with a resonant  percussion note

Bickley 8/e. IM 18
over the lower lung fields. Use th e ladder technique (p. 225), which 
helps you compare adjacent percussion sounds from each lung. 
Measuring the JVP is also an art that you will master with 
practice. One helpful tip is to thi nk about the patient’s volume status 
before you begin the cardiovascular examination. Is the patient 
euvolemic, hypovolemic, or hypervolemic? Begin by raising the head of the bed to the standa rd position of  30 degrees . Your goal is to see 
the meniscus, or top of the column of  blood in the intern al jugular vein. 
Remember that if the patient is  hypovolemic, as in dehydration or 
gastrointestinal (GI) bleeding, the JVP will be 
down  and you may need 
to lower  the head of the bed. If the patient is hypervolemic, as in 
congestive heart failure (CHF), the JVP may be up and you will need to 
raise  the head of the bed. Be sure to review p. 266 and p. 267 so that

raise  the head of the bed. Be sure to review p. 266 and p. 267 so that 
you understand the principles, techniques, and ways to report your measurement of the JVP.   
Another tip is to palpate the caro tid upstroke with your left hand 
as you listen to S 1 and S 2 with your stethoscope. The carotid upstroke 
coincides with systole, or  the interval between S 1 and S 2. Palpating the 
carotid artery will help you decide if murmurs are in systole or diastole. 
Remember, you should always turn the pa tient to the left side and listen 
for an S 3 with your bell. 
Workshop 6: Cardiovascular System and Abdomen 

Bickley 8/e. IM 19
• Practice the lung and cardiac examination; ask for spot checks by 
your preceptor. 
• Inspect the abdomen for symmetry, scars, and striae. Auscultate 
bowel sounds. Percuss the liver and measure the liver span. Perform 
light and deep palpation of the abdomen. Palpate the liver edge. 
Demonstrate correct technique for examining the spleen. Assess costovertebral angle (CVA) tenderness. 
• Demonstrate how to assess for guarding and rebound tenderness. 
• Listen for abdominal and inguinal bruits. 
1. Bring your stethoscope and plastic ruler. 
2. Demonstrate two methods for examining the spleen. 
3. Describe how to assess patients with possible ascites for 
shifting dullness. 
4. Describe at least four “peritoneal” signs.  
5. List six items to check when a ssessing for possible appendicitis 
(pp. 347–348). 
6. Describe Murphy’s sign. 
See the cardiac examin ation from Workshop 5.

See the cardiac examin ation from Workshop 5. 
Abdomen is scaphoid. Bowel sounds are active. The abdomen is 
soft, nontender. Liver span is 9 cm  in the right midclavicular line 
(MCL); edge is smooth, palpable one finger-breadth below the right

Bickley 8/e. IM 20
costal margin (RCM). Spleen not felt. No CVA tenderness, no 
abdominal or femoral bruits. 
Bates’ Chapter 9: The Abdomen, pp. 317–366. 
 When you palpate the abdomen, always watch the patient’s face for signs of pain or discomfort. This will help you to localize areas of 
tenderness. When there is tenderne ss, pain, guarding, or rebound, learn 
to think about the underlying organs in that quadrant, which might be 
involved. For example, for right upp er quadrant tenderness, consider 
biliary disease or cholecystitis, hepatitis, or peptic ulcer disease. 
Workshop 7: Extremities: Peripheral Vascular System and Lymph 
Nodes  
• Assess brachial, radial, femoral, popliteal, dorsalis pedis, and posterior tibial pulses. 
• Compare orthostatic edema to lymphedema. 
• Examine axillary, epitrochlear, and superficial inguinal lymph 
nodes.

nodes. 
• Demonstrate an appropriate sequ ence of examination, beginning 
with the General Survey and V ital Signs through the Peripheral 
Vascular examination. 

Bickley 8/e. IM 21
1. Bring your stethoscope, penlight, and ruler. (The instructor 
should provide the otoscope and ophthalmoscope.) 
2. Describe the superficial and d eep venous system of the legs. 
3. Report five ways to distinguish ar terial from venous occlusion. 
[In arterial occlusion, the patient complains of claudication; skin 
is cool, blanched, shiny, and atrophic with loss of hair and 
diminished pulses, progressing to ulceration, ischemia, and necrosis from gangrene. In venous occlusion, skin is 
hyperpigmented with the bluish-re d color of dependent edema, 
sometimes with swelling and cyan osis, progressing to pain and 
ulceration (see pp. 462–463)]. 
4. Describe indications for and t echniques of the Allen test. 
5. Be prepared for spot checks on examination techniques to date. 
(Option:  Instructors may want to grade student performance.) 
6. Be prepared to present verbally the physical examination 
findings of a healthy patient from the General Survey through

findings of a healthy patient from the General Survey through 
peripheral pulses. 
Radial, brachial, femoral, popliteal , dorsalis pedis, and posterior 
tibial pulses are 2+ and symmetric.  Extremities are warm and without 
edema. Calves are supple. No epitr ochlear, axillary, or inguinal 
adenopathy. 

Bickley 8/e. IM 22
Bates’ Chapter 14: The Periphe ral Vascular System, pp. 441–464. 
 As you begin the physical examin ation with the patient sitting 
on the examination table, note whether the patient develops dependent 
rubor with the extremities in a de pendent position. Edema may or may 
not be visible, so always check fo r pitting. Remember that claudication 
has two etiologies. It can be va scular, resulting from arterial 
insufficiency. It can also result from spinal stenosis or arthritis of the 
vertebra that compresses the spinal co rd when the patient is in certain 
positions (you will learn more about this during examination of the 
nervous system). Remember that yo u should always check to see if 
calves are supple, especially in pati ents on bed rest, but be aware that 
the sensitivity and specificity of Homans’ sign for deep venous 
thrombosis (DVT) is only 50%. If you suspect DVT, you must proceed 
to further testing.

to further testing. 
Workshop 8: The Musculoskeletal System  
• Understand the unique features of  each major joint and how, for 
joints, anatomy is destiny: Structure determines function. 
• Demonstrate techniques of examinat ion for the neck and spine; the 
shoulders, elbows, wrists, and finge rs; and the hips, knees, ankles, 
and feet.

Bickley 8/e. IM 23
• Demonstrate the maneuvers to assess rotator cuff sprain, hip 
arthritis, and the seven structures of the knee. 
• Demonstrate the bulge sign. 
• Describe maneuvers to asse ss carpal tunnel syndrome. 
1. Describe the three principle types of joints, including the three 
types of synovial joints. 
2. Describe the three bony landmarks of the shoulder and the three 
joints that articulate at the shoulder. 
3. Name the principal muscles of the back. 
4. Name the major muscle groups that move the femur and the tibia and fibula. 
5. Focus especially on the examination techniques for the shoulder, low back, hip, and knee. 
6. Describe at least six differences between rheumatoid arthritis 
and osteoarthritis. 
Good range of motion in all joints. No joint swelling or 
deformity. 
Bates’ Chapter 15:  The Mu sculoskeletal System, pp. 465–533. 

Bickley 8/e. IM 24
Each joint has its own personalit y. Learn the special features of 
each joint as determined by its structure. For example, the shoulder 
allows the widest range of rotatory motion, but it is bare ly attached to 
the axial skeleton. Only the four rotator cuff tendons and their muscle 
groups suspend the shoulder, so almost any bump or trauma causes 
shoulder pain and problems. In contra st, the hip joint is deep in the 
pelvis and highly stabilized by major bony structures and muscle 
groups. These features are essential fo r its role in carrying so much of 
the body’s weight. The hip joint is well padded and somewhat 
protected from fracture until older adulthood. Now, think about the 
knee. It is amazing that only seve n structures stabilize the knee and 
keep the femur from sliding off the tibial plateau: the medial collateral ligament (MCL), the lateral collateral ligament (LCL), the medial 
meniscus, the lateral meniscus, the anterior cruciate ligament (ACL),

meniscus, the lateral meniscus, the anterior cruciate ligament (ACL), 
the posterior cruciate ligament (PCL ), and the patellar tendon. So now 
you understand why knee problems are so common. Be sure to learn 
the maneuvers to test each of these knee structures and use the 
appropriate anatomic terminology.   
Workshop 9: The Nervous System 
• Review the organizing principles of the neurologic examination: 
symmetry vs. asymmetry and localization of findings to the central 
nervous system vs. the peripheral nervous system.

Bickley 8/e. IM 25
• Demonstrate the examination of the Cranial Nerves. 
• Demonstrate the examination of the motor system, including bulk, 
strength, tone, and cerebellar func tion; rapid alternating movements 
(RAM); finger to nose (F →N); heel to shin (H →S); and gait. Be 
sure you know how to grade motor strength. 
• Demonstrate examination of the sensory system, including pinprick 
and light touch, vibration, position, and two-point discrimination. 
• Demonstrate effective use of the reflex hammer and proper technique for eliciting reflexes, including the plantar response or 
Babinski sign. 
1. Bring your reflex hammer and tuning fork to class. Instructors will provide Q-tips to test sharp and dull.   
2. Describe the lobes of the brain and the three components of the 
brainstem, as well as their vascular supply. 
3. Know the functions of each Cranial Nerve.   
4. Recite the nerve roots for the fo llowing reflexes: biceps, triceps, 
knee, and ankle.

knee, and ankle. 
5. Know the neuroanatomy and physical findings of Bell’s palsy versus a central nervous system lesion causing facial weakness. 
6. Be prepared to describe the di fferences between metabolic and 
structural coma. 
7. Review the Glasgow Coma Scale.

Bickley 8/e. IM 26
8. Demonstrate maneuvers to elicit Kernig’s and Brudzinski’s 
signs. 
Note the following order for both verbal and written presentations: 
Mental Status, Cranial Nerves , Motor, Sensory, Reflexes. 
The patient is oriented to person, place, and time. Cranial  
Nerves  II through XII are intact. Motor: good bulk and tone. Strength is 
5/5 throughout. RAMs, F →N, H →S intact. Gait with normal base. 
Sensory : Pinprick and light touch are intact and symmetric throughout. 
Reflexes  : 2+ and symmetric with toes downgoing. 
Bates’ Chapter 16: The Nervous System, pp. 535–622. 
Always check for symmetry, comp aring findings on the right to 
findings on the left. Begin thinki ng about how neurologic disorders 
present in terms of symptoms and physical findings. There are many 
clinical syndromes in neurology, so you will learn how to interpret the

clinical syndromes in neurology, so you will learn how to interpret the 
findings in many diagnoses from at tendings and neurology consultants. 
Thus, it is especially important for st udents to obtain excellent histories 
and conduct careful and thorough neur ologic examinations. Be aware 
that many clinicians integrate examination of the cranial nerves and upper extremities into their examinati on of the head, neck, and thorax, 
respectively, while the patient is sitting. Likewise, clinicians often

Bickley 8/e. IM 27
assess lower extremity strength and ov erall sensation and reflexes when 
the patient is supine. 
Workshops 10 and 11: Complete Physical Examination and 
Standardized Patient Assessments 
Learning Objectives  
• Perform a complete adult physical examination. 
• Obtain a focused history a nd perform a focused physical 
examination on a standardized patient. 
Complete Physical Examination 
Students will perform these on th eir partners. Students should 
wear comfortable clothing (wom en should wear sport bras) in 
preparation for when they are “patients.” Neurologic and musculoskeletal examinations are EXPECTED. Male and female genitalia examinations are excluded. 
Standardized Patient Assessments  
“Standardized patients” are people  trained to act as patients. 
They are given a mock history and are expected to enact symptoms. 
(They do not really have the dis ease under discussion, although some 
appear really convincing!) These people will provide direct feedback

appear really convincing!) These people will provide direct feedback 
about students’ perfor mance of a focused history and physical 
examination. 
SAMPLE STUDENT EVALUATION

Bickley 8/e. IM 28
 The following is a system by which to evaluate and grade 
student performance. 
Knowledge  
• Weekly noncumulative quizzes based on required readings in 
Bates’ textbook = 40% 
• Cumulative written examination based on required readings in 
Bates textbook = 10% 
Skills 
• Physical examination workshop performance = 10% 
• Complete physical examination performance = 20% 
• Standardized patient assessment performance = 10% 
Attitude 
• Attendance and completion of all workshops = 10% 
TOTAL = 100%

The clinical summaries in the Guide are abridged versions of recommendations 
from the U.S. Preventive Services Task Force (USPSTF). To view the full 
recommendation statements, supporting evidence, or recommendations 
published after March 2014, go to www.USPreventiveServicesTaskForce.org .
The USPSTF Electronic Preventive Services Selector (ePSS) allows users to 
download the USPSTF recommendations to PDA, mobile, or tablet devices; 
receive notifications of updates; and search and browse recommendations 
online. Users can search the ePSS for recommendations by patient age, sex, and 
pregnancy status. To download, subscribe, or search, go to epss.ahrq.gov .
Recommendations made by the USPSTF are independent of the U.S. 
Government. They should not be construed as an official position of AHRQ or 
the U.S. Department of Health and Human Services.

The Guide to Clinical  
Preventive Services
2014
Recommendations of the U.S. 
Preventive Services Task Force

iiiForeword
Since 1998, the Agency for Healthcare Research and Quality (AHRQ) has convened 
the U.S. Preventive Services Task Force (USPSTF)—an independent, volunteer 
panel of national experts in prevention and evidence-based medicine. The Task Force 
makes recommendations to help primary care clinicians and patients decide together 
whether a preventive service is right for a patient’s needs. 
AHRQ staff provide scientific and administrative support for the Task Force, and 
assist in disseminating its findings and recommendations to key audiences. In that 
role, we are pleased to make The Guide to Clinical Preventive Services 2014  available 
to those who seek to ensure that their patients receive the highest quality clinical 
preventive services. 
I am gratified that AHRQ has been able to support the USPSTF in its efforts to 
engage the public and to ensure that its processes are transparent. Most notably, all

engage the public and to ensure that its processes are transparent. Most notably, all 
Task Force draft materials are now available for public comment online at www.
USPreventiveServicesTaskForce.org. 
Previous iterations of the USPSTF Guide to Clinical Preventive Services  are used 
around the Nation to provide appropriate and effective preventive care. The Guide  
is designed to be user-friendly for practicing clinicians. In addition, the Guide  lists 
resources that clinicians can use to educate their patients on appropriate preventive 
services, such as Stay Healthy  brochures and MyHealthfinder (see Appendixes).  Also 
included are brief descriptions of and links to tools that health care professionals can 
use to improve their practice, including the electronic Preventive Services Selector 
(ePSS) and the National Guideline Clearinghouse (see Appendixes).

(ePSS) and the National Guideline Clearinghouse (see Appendixes).   
As more information becomes available to clinicians and patients alike, AHRQ’s goal 
is to help improve patients’ health and well-being, and contribute to better health 
outcomes for the Nation overall.
Richard Kronick, Ph.D.  
Director  
Agency for Healthcare Research and Quality

vPreface
The U.S. Preventive Services Task Force (USPSTF) is mandated by Congress 
to conduct rigorous reviews of scientific evidence to create evidence-based 
recommendations for preventive services that may be provided in the primary care 
setting.
Since its inception, the USPSTF has made and maintained recommendations on 
dozens of clinical preventive services that are intended to prevent or reduce the risk 
for heart disease, cancer, infectious diseases, and other conditions and events that 
impact the health of children, adolescents, adults, and pregnant women. The Guide 
to Clinical Preventive Services 2014  includes both new and updated recommendations 
released from 2004-2014 in a brief, easily usable format meant for use at the point 
of patient care. The most up-to-date version of the recommendations, as well as 
the complete USPSTF recommendation statements, are available along with their 
supporting scientific evidence at www.USPreventiveServicesTaskForce.org .

supporting scientific evidence at www.USPreventiveServicesTaskForce.org . 
Recommendations for preventive care have evolved over time as it has become widely 
recognized that some “preventive” services were not actually beneficial.  Individual 
health care providers, professional organizations, integrated health systems, insurers 
(both private and public), as well as groups crafting health quality measures and 
national health objectives, have recognized the need to carefully balance potential 
benefits and harms using the highest quality of evidence, and have adopted the 
recommendations of the Task Force.  The primary audience for the USPSTF’s work 
remains primary care clinicians, and the recommendations are now considered 
by many to provide definitive standards for preventive services.  The work of the 
USPSTF is recognized by the Patient Protection and Affordable Care Act. Under the

USPSTF is recognized by the Patient Protection and Affordable Care Act. Under the 
law, preventive services with a Task Force grade of A or B must be covered without 
cost-sharing (e.g., copayment or deductible) under new health insurance plans or 
policies. 
In the last several years, the USPSTF has increased the transparency of its work, and 
these efforts have gained additional momentum in view of the enhanced importance 
of the recommendations under the new law.  Public comments are welcomed at 
multiple points in the development of each recommendation to encourage additional 
input from experts, advocates and other stakeholders to help the Task Force craft 
relevant and clear recommendation statements.  However, the USPSTF remains 
committed to evaluating evidence free from the influence of politics, special interests, 
and advocacy.

and advocacy.   
As the science around clinical practice guideline development has evolved, USPSTF 
methods continue to evolve as well. The Procedure Manual , which can be found on

vithe USPSTF Web site, details the most updated version of the process for evaluating 
the quality and strength of the evidence for a service, determining the net health 
benefit (benefit minus harms) associated with the service, and judging the level of 
certainty that providing these services will be beneficial in primary care. We continue 
to explore the appropriate use of mathematical modeling to help fill research gaps 
regarding the ages at which to start and stop providing a service, and at what time 
intervals. In addition, we are committed to improving the communication of our 
recommendations to a broader audience, including patients and policymakers.
The letter grade linked to each recommendation reflects both the magnitude of net 
benefit and the strength and certainty of the evidence supporting the provision of a 
specific preventive service. These grades translate to practice guidance for clinicians:

 ■Discuss services with “A” and “B” recommendation grades with eligible patients 
and offer them as a priority.
 ■Discourage the use of services with “D” recommendation grades unless there are 
unusual additional considerations.
 ■Give lower priority to services with “C” recommendation grades; they need not 
be provided unless there are individual considerations in favor of providing the 
service.
 ■Help patients understand the uncertainty surrounding services with “I” 
(insufficient evidence) statements, which reflect the conclusion that the evidence is 
insufficient to determine net benefit. The Clinical Considerations section of each 
full recommendation statement offers additional guidance.
The USPSTF recognizes that clinical decisions about patients involve more complex

The USPSTF recognizes that clinical decisions about patients involve more complex 
considerations than the evidence alone; clinicians should always understand the 
evidence but individualize decisionmaking to the specific patient and situation. The 
Clinical Considerations section of each USPSTF recommendation statement helps 
clinicians by offering practical information so they can tailor these recommendations 
to individual patients. 
We strongly encourage clinicians to visit the USPSTF Web site and read the complete 
recommendation statements for services relevant to their patients. Additional 
information is available to facilitate the delivery of the highest quality preventive 
care. For each topic, educational materials have been developed for use with patients 
and the public. Special materials developed for clinicians are also available on some

and the public. Special materials developed for clinicians are also available on some 
complex topics, such as prostate and lung cancer screening, along with links to 
informative Web sites.  In addition, the USPSTF Electronic Preventive Services

viiSelector (ePSS), available via PDA, smart phone, or on the Web at epss.ahrq.gov, 
allows users to search USPSTF recommendations by patient age and other clinical 
characteristics.
We hope you find the Guide to Clinical Preventive Services 2014  to be a useful tool as 
you care for patients. Based on the best medical evidence available, we are confident 
that by implementing these recommended services, you will help your patients live 
longer and healthier lives.
Michael L. LeFevre, M.D., M.S.P .H., Chair  
Albert L. Siu, M.D., M.S.P .H., Co-Vice Chair  
Kirsten Bibbins-Domingo, Ph.D., M.D., M.A.S., Co-Vice Chair  
U.S. Preventive Services Task Force

ixContents
Foreword  ............................................................................................................... iii
Preface  ..................................................................................................................... v
Preventive Services Recommended by the USPSTF  .............................................. 1
Clinical Summaries of Recommendations for Adults (alphabetical list)  .............. 5
Abdominal Aortic Aneurysm, Screening  .............................................................. 7
*Alcohol Misuse, Screening and Behavioral Counseling  ...................................... 8
Aspirin for the Prevention of Cardiovascular Disease, Preventive Medication  ......9
Aspirin or NSAIDS for Prevention of Colorectal Cancer, Preventive Medication  ....10
Bacterial Vaginosis in Pregnancy, Screening  ....................................................... 11

Bacteriuria, Screening  ........................................................................................ 12
Bladder Cancer, Screening  ................................................................................. 13
*BRCA-Related Cancer in Women, Screening  .................................................. 14
*Breast Cancer, Preventive Medications  ............................................................. 15
Breast Cancer, Screening  ................................................................................... 16
Breastfeeding, Counseling  ................................................................................. 17
Carotid Artery Stenosis, Screening  .................................................................... 18

Cervical Cancer, Screening  ................................................................................ 19
Chlamydial Infection, Screening  ....................................................................... 20
*Chronic Kidney Disease, Screening  ................................................................. 21
Chronic Obstructive Pulmonary Disease, Screening  .......................................... 22
*Cognitive Impairment in Older Adults, Screening  ........................................... 23
Colorectal Cancer, Screening  ............................................................................. 24
Coronary Heart Disease (Risk Assessment, Nontraditional Risk Factors),  
    Screening  ....................................................................................................... 25

*Coronary Heart Disease, Screening (With Electrocardiography)  ...................... 26
Depression in Adults, Screening  ........................................................................ 27
Diabetes Mellitus, Screening  ............................................................................. 28
*Falls in Older Adults, Counseling, Preventive Medication, and Other  
    Interventions  ................................................................................................. 29
Folic Acid Supplementation to Prevent Neural T ube Defects, Preventive  
    Medication  .................................................................................................... 30
Genital Herpes, Screening  ................................................................................. 31

*Gestational Diabetes Mellitus, Screening  ......................................................... 32
*Glaucoma, Screening  ....................................................................................... 33
Gonorrhea, Screening  ........................................................................................ 34
*Healthful Diet and Physical Activity, Counseling  ............................................. 35
*Hearing Loss in Older Adults, Screening  ......................................................... 36

xHemochromatosis, Screening  ............................................................................ 37
Hepatitis B Virus Infection in Pregnant Women, Screening  .............................. 38
*Hepatitis C Virus Infection in Adults, Screening  ............................................... 9
High Blood Pressure in Adults, Screening  .......................................................... 40
*HIV Infection, Screening  ................................................................................. 41
Illicit Drug Use, Screening  ................................................................................ 42
Impaired Visual Acuity in Older Adults, Screening  ........................................... 43
*Intimate Partner Violence and Elderly Abuse, Screening  .................................. 44
Lipid Disorders in Adults, Screening  ................................................................. 45

*Lung Cancer, Screening  ................................................................................... 46
*Menopausal Hormone Therapy for the Primary Prevention of Chronic  
    Conditions, Preventive Medication  ............................................................... 47
Motor Vehicle Occupant Restraints, Counseling  ............................................... 48
*Obesity in Adults, Screening and Counseling  .................................................. 49
*Oral Cancer, Screening  .................................................................................... 50
Osteoporosis, Screening ..................................................................................... 51
*Ovarian Cancer, Screening  ............................................................................... 52

*Peripheral Artery Disease and Cardiovascular Risk Assessment, Screening  ....... 53
*Prostate Cancer, Screening  ............................................................................... 54
Sexually T ransmitted Infections, Counseling  ..................................................... 55
*Skin Cancer, Counseling  .................................................................................. 56
Skin Cancer, Screening  ...................................................................................... 57
Suicide Risk, Screening  ...................................................................................... 58
Syphilis Infection (Pregnant Women), Screening  ............................................... 59
Testicular Cancer, Screening  .............................................................................. 60

Tobacco Use in Adults, Counseling and Interventions  ....................................... 61
*Vitamin D and Calcium Supplementation to Prevent Fractures, Preventive  
    Medication  .................................................................................................... 62
*Vitamin, Mineral, and Multivitamin Supplements for Primary Prevention  
    of Cardiovascular Disease and Cancer, Preventive Medication  ....................... 63
Clinical Summaries of Recommendations for Children and Adolescents  
(alphabetical list)  .................................................................................................. 65
Blood Lead Levels in Children and Pregnant Women, Screening  ...................... 67

*Child Maltreatment, Interventions to Prevent  ................................................. 68
Congenital Hypothyroidism, Screening  ............................................................. 69
Developmental Dysplasia of the Hip, Screening  ................................................ 70
Gonococcal Ophthalmia Neonatorum, Preventive Medication  .......................... 71

xiGonorrhea, Screening  ........................................................................................ 34
Hearing Loss in Newborns, Screening  ............................................................... 72
*High Blood Pressure in Children, Screening  .................................................... 73
Hyperbilirubinemia in Infants, Screening  .......................................................... 74
*Illicit and Prescription Drug Use in Children and Adolescents, Counseling  .....75
Iron Deficiency Anemia, Screening  ............................................................. 76, 77
Lipid Disorders in Children, Screening  ............................................................. 78
Major Depressive Disorder in Children and Adolescents, Screening  .................. 79

Obesity in Children and Adolescents, Screening  ................................................ 80
Phenylketonuria (PKU), Screening  .................................................................... 81
Sickle Cell Disease in Newborns, Screening  ....................................................... 82
Speech and Language Delay, Screening  .............................................................. 83

*Tobacco Use in Children and Adolescents, Primary Care Interventions  ........... 84
Visual Impairment in Children Ages 1-5, Screening  .......................................... 85
Immunizations  ..................................................................................................... 87
T opics in Progress  ................................................................................................. 91
Appendixes and Index  .......................................................................................... 95
Appendix A. How the U.S. Preventive Services Task Force Grades Its

Appendix A. How the U.S. Preventive Services Task Force Grades Its  
    Recommendations  ......................................................................................... 97
Appendix B. Members of the U.S. Preventive Services Task Force 2004-2014  ......101
Appendix C. Acknowledgements  ..................................................................... 104
Appendix D. About the U.S. Preventive Services Task Force  ............................ 107
Appendix E. More Resources  ........................................................................... 112
Appendix F . 2002 Breast Cancer Screening Recommendation  ......................... 115
Index. Recommendations, Cross-Referenced  ................................................... 117
*New recommendations released March 2012 to March 2014.

Preventive Services 
Recommended by the 
USPSTF
All clinical summaries in this Guide are abridged  
recommendations. To see the full recommendation statements  
and recommendations published after March 2014, go to  
www.USPreventiveServicesTaskForce.org .

1Section 1: Preventive Services Recommended by the USPSTF
The U.S. Preventive Services Task Force (USPSTF) recommends that clinicians discuss these preventive services with eligible patients and offer them as 
a priority. All these services have received an “A” or a “B” (recommended) grade from the Task Force. Refer to the endnotes for each recommendation for 
population-specific clinical considerations.
For definitions of all grades used by the USPSTF, see Appendix A (beginning on p. 97). The full listings of all USPSTF recommendations for adults begin on p. 5 
and recommendations for children begin on p. 65.
RecommendationAdults Special Populations
Men Women Pregnant WomenChildren/
Abdominal Aortic Aneurysm, Screening1P
Alcohol Misuse Screening and Behavioral Counseling P P P
Aspirin for the Prevention of Cardiovascular Disease2P P
Bacteriuria, Screening3P
BRCA-Related Cancer in Women, Screening4P
Breast Cancer, Preventive Medications5P
Breast Cancer, Screening6P

Breastfeeding, Counseling7P P
Cervical Cancer, Screening8P
Chlamydial Infection, Screening9P P
Colorectal Cancer, Screening10P P
Congenital Hypothyroidism, Screening11P
Depression in Adults, Screening12P P
Diabetes Mellitus, Screening13P P
Falls in Older Adults, Counseling, Preventive Medication, 
and Other Interventions14 P P

2Section 1: Preventive Services Recommended by the USPSTF (continued)
Folic Acid Supplementation to Prevent Neural Tube Defects, 
Preventive Medication15 P
Gestational Diabetes Mellitus, Screening16P
Gonococcal Ophthalmia Neonatorum, Preventive 
Medication17 P
Gonorrhea, Screening18P
Hearing Loss in Newborns, Screening19P
Hepatitis B Virus Infection in Pregnant Women, Screening20P
Hepatitis C Virus Infection in Adults, Screening21P P P P
High Blood Pressure in Adults, Screening P P
HIV Infection, Screening22P P P P
Intimate Partner Violence and Elderly Abuse, Screening23P
Iron Deficiency Anemia, Prevention24P
Iron Deficiency Anemia, Screening25P
Lipid Disorders in Adults, Screening26P P
Lung Cancer, Screening27P P
Major Depressive Disorder in Children and Adolescents, 
Screening28 P
Obesity in Adults, Screening29P P
Obesity in Children and Adolescents, Screening30P
Osteoporosis, Screening31P

3Section 1: Preventive Services Recommended by the USPSTF (continued)
Phenylketonuria (PKU), Screening32P
Sexually Transmitted Infections, Counseling33P P P
Sickle Cell Disease in Newborns, Screening34P
Skin Cancer, Counseling35P P P P
Syphilis Infection (Pregnant Women), Screening P
Tobacco Use in Adults, Counseling and Interventions36P P P
Tobacco Use in Children and Adolescents, Primary Care 
Interventions37 P
Visual Impairment in Children Ages 1 to 5, Screening38P
1One-time screening by ultrasonography in men aged 65 to 75 who have ever 
smoked.
2When the potential harm of an increase in gastrointestinal hemorrhage is 
outweighed by a potential benefit of a reduction in myocardial infarctions (men 
aged 45-79 years) or in ischemic strokes (women aged 55-79 years).
3Pregnant women at 12-16 weeks gestation or at first prenatal visit, if later.

4Refer women whose family history is associated with an increased risk for 
deleterious mutations in BRCA 1 or BRCA 2 genes for genetic counseling and 
evaluation for BRCA testing.
5Engage in shared, informed decisionmaking and offer to prescribe risk-
reducing medications, if appropriate, to women aged  ≥35 years without prior 
breast cancer diagnosis who are at increased risk.
6Biennial screening mammography for women aged 50 to 74 years. Note: 
The Department of Health and Human Services, in implementing the 
Affordable Care Act, follows the 2002 USPSTF recommendation for screening mammography, with or without clinical breast examination, every 1-2 years for 
women aged 40 and older.
7Interventions during pregnancy and after birth to promote and support 
breastfeeding.
8Screen with cytology every 3 years (women ages 21 to 65) or co-test

8Screen with cytology every 3 years (women ages 21 to 65) or co-test 
(cytology/HPV testing) every 5 years (women ages 30-65).
9Sexually active women 24 and younger and other asymptomatic women at 
increased risk for infection. Asymptomatic pregnant women 24 and younger 
and others at increased risk.
10Adults aged 50-75 using fecal occult blood testing, sigmoidoscopy, or 
colonoscopy.
11Newborns.
12When staff-assisted depression care supports are in place to assure 
accurate diagnosis, effective treatment, and followup.

413Asymptomatic adults with sustained blood pressure greater than 135/80 mg 
Hg.
14Provide intervention (exercise or physical therapy and/or vitamin D 
supplementation) to community-dwelling adults ≥65 years at increased risk for 
falls.
15All women planning or capable of pregnancy take a daily supplement 
containing 0.4 to 0.8 mg (400 to 800 µg) of folic acid.
16Asymptomatic pregnant women after 24 weeks of gestation.
17Newborns.
18Sexually active women, including pregnant women 25 and younger, or at 
increased risk for infection.
19Newborns.
20Screen at first prenatal visit.
21Persons at high risk for infection and adults born between 1945 and 1965.
22All adolescents and adults ages 15 to 65 years and others who are at 
increased risk for HIV infection and all pregnant women.
23Asymptomatic women of childbearing age; provide or refer women who 
screen positive to intervention services.
24Routine iron supplementation for asymptomatic children aged 6 to 12

24Routine iron supplementation for asymptomatic children aged 6 to 12 
months who are at increased risk for iron deficiency anemia.
25Routine screening in asymptomatic pregnant women.
26Men aged 20-35 and women over age 20 who are at increased risk for 
coronary heart disease; all men aged 35 and older.27Asymptomatic adults aged 55 to 80 years who have a 30 pack-year smoking 
history and currently smoke or have quit smoking within the past 15 years.
28Adolescents (age 12 to 18) when systems are in place to ensure accurate 
diagnosis, psychotherapy, and followup.
29Patients with a body mass index of 30 kg/m2 or higher should be offered or 
referred to intensive, multicomponent behavioral interventions.
30Screen children aged 6 years and older; offer or refer for intensive 
counseling and behavioral interventions.

31Women aged 65 years and older and women under age 65 whose 10-year 
fracture risk is equal to or greater than that of a 65-year-old white woman 
without additional risk factors. 
32Newborns.
33All sexually active adolescents and adults at increased risk for STIs.
34Newborns.
35Children, adolescents, and young adults aged 10 to 24 years.
36Ask all adults about tobacco use and provide tobacco cessation interventions 
for those who use tobacco; provide augmented, pregnancy-tailored counseling 
for those pregnant women who smoke.
37Provide interventions to prevent initiation of tobacco use in school-aged 
38Screen children ages 3 to 5 years.

Clinical 
Summaries of 
Recommendations 
for Adults
All clinical summaries in this Guide are abridged 
recommendations. To see the full recommendation statements 
and recommendations published after March 2014, go to 
www.USPreventiveServicesT askForce.org .

7Abdominal Aortic Aneurysm
Title Screening for Abdominal Aortic Aneurysm
PopulationMen ages 65 to 75 years who have 
ever smokedMen ages 65 to 75 years who have 
never smokedWomen ages 65 to 75 years
RecommendationScreen once for abdominal aortic 
aneurysm with ultrasonography. 
Grade: BNo recommendation for or against 
screening. 
Grade: CDo not screen for abdominal aortic 
aneurysm. 
Grade: D
Risk AssessmentThe major risk factors for abdominal aortic aneurysm include male sex, a history of ever smoking (defined as 100 cigarettes 
in a person’s lifetime), and age of 65 years or older. 
Screening TestsScreening abdominal ultrasonography is an accurate test when performed in a setting with adequate quality assurance (i.e., 
in an accredited facility with credentialed technologists). Abdominal palpation has poor accuracy and is not an adequate 
screening test.

Timing of ScreeningOne-time screening to detect an abdominal aortic aneurysm using ultrasonography is sufficient. There is negligible health 
benefit in re-screening those who have normal aortic diameter on initial screening. 
InterventionsOpen surgical repair of an aneurysm of at least 5.5 cm leads to decreased abdominal aortic aneurysm-related mortality in the 
long term; however, there are major harms associated with this procedure.
Balance of Benefits and 
HarmsIn men ages 65 to 75 years who have 
ever smoked, the benefits of screening 
for abdominal aortic aneurysm outweigh 
the harms.In men ages 65 to 75 years who have 
never smoked, the balance between 
the benefits and harms of screening 
for abdominal aortic aneurysm 
is too close to make a general 
recommendation for this population.The potential overall benefit of screening

recommendation for this population.The potential overall benefit of screening 
for abdominal aortic aneurysm among 
women ages 65 to 75 years is low 
because of the small number of 
abdominal aortic aneurysm-related 
deaths in this population and the harms 
associated with surgical repair.
Other Relevant USPSTF 
RecommendationsThe USPSTF has made recommendations on screening for carotid artery stenosis, coronary heart disease, high blood 
pressure, lipid disorders, and peripheral arterial disease. These recommendations are available at  
http://www.uspreventiveservicestaskforce.org/ .  
For a summary of the evidence systematically reviewed in making this recommendation, the full recommendation statement, and supporting documents,  
please go to http://www.uspreventiveservicestaskforce.org/ .

8Alcohol Misuse
Title Screening and Behavioral Counseling Interventions in Primary Care To Reduce Alcohol Misuse
Population Adults aged 18 years or older Adolescents
Recommendation Screen for alcohol misuse and provide brief behavioral 
counseling interventions to persons engaged in risky or 
hazardous drinking. 
Grade: B No recommendation. 
Grade: I (Insufficient Evidence)
Screening Tests Numerous screening instruments can detect alcohol misuse in adults with acceptable sensitivity and specificity. The USPSTF 
prefers the following tools for alcohol misuse screening in the primary care setting: 
1. AUDIT 
2. Abbreviated AUDIT-C  
3. Single-question screening, such as asking, “How many times in the past year have you had 5 (for men) or 4 (for women and all adults 
older than 65 years) or more drinks in a day?”
Behavioral Counseling 
InterventionsCounseling interventions in the primary care setting can improve unhealthy alcohol consumption behaviors in adults engaging

InterventionsCounseling interventions in the primary care setting can improve unhealthy alcohol consumption behaviors in adults engaging 
in risky or hazardous drinking. Behavioral counseling interventions for alcohol misuse vary in their specific components, 
administration, length, and number of interactions. Brief multicontact behavioral counseling seems to have the best evidence 
of effectiveness; very brief behavioral counseling has limited effect. 
Harms There is a moderate net benefit to alcohol misuse screening 
and brief behavioral counseling interventions in the primary 
care setting for adults aged 18 years or older. The evidence on alcohol misuse screening and brief 
behavioral counseling interventions in the primary care 
setting for adolescents is insufficient, and the balance of 
benefits and harms cannot be determined. 
Other Relevant USPSTF

Recommendations The USPSTF has made recommendations on screening for illicit drug use and counseling and interventions to prevent 
tobacco use. These recommendations are available at http://www.uspreventiveservicestaskforce.org/ . 
For a summary of the evidence systematically reviewed in making this recommendation, the full recommendation statement, and supporting documents, please go 
to http://www.uspreventiveservicestaskforce.org/ .

9Aspirin for the Prevention of Cardiovascular Disease
Title Aspirin for the Prevention of Cardiovascular Disease
Population Men age 45-79 years Women age 55-79 years Men age <45 years Women age <55 years Men & Women age ≥80 years
RecommendationEncourage aspirin use 
when potential CVD benefit 
(MIs prevented) outweighs 
potential harm of GI 
hemorrhage.Encourage aspirin use 
when potential CVD 
benefit (strokes prevented) 
outweighs potential harm 
of GI hemorrhage.Do not encourage aspirin 
use for MI prevention.Do not encourage aspirin 
use for stroke prevention.No Recommendation
Grade: A Grade: D Grade: I (Insufficient Evidence)
How to Use This 
RecommendationShared decisionmaking is strongly encouraged with individuals whose risk is close to (either above or below) the estimates of 10-year risk levels indicated below. As the 
potential CVD benefit increases above harms, the recommendation to take aspirin should become stronger.

To determine whether the potential benefit of MIs prevented (men) and strokes prevented (women) outweighs the potential harm of increased GI hemorrhage, both 10-year 
CVD risk and age must be considered.
Risk level at which CVD events prevented (benefit) exceeds GI harms     
Men 
10-year CHD riskWomen  
10-year stroke risk
Age 45-59 years ≥4% Age 55-59 years ≥3%
Age 60-69 years ≥9% Age 60-69 years ≥8%
Age 70-79 years ≥12% Age 70-79 years ≥11%
The table above applies to adults who are not taking NSAIDs and who do not have upper GI pain or a history of GI ulcers.
NSAID use and history of GI ulcers raise the risk of serious GI bleeding considerably and should be considered in determining the balance of benefits and harms. NSAID

NSAID use and history of GI ulcers raise the risk of serious GI bleeding considerably and should be considered in determining the balance of benefits and harms. NSAID 
use combined with aspirin use approximately quadruples the risk of serious GI bleeding compared to the risk with aspirin use alone. The rate of serious bleeding in aspirin 
users is approximately 2-3 times higher in patients with a history of GI ulcers.
Risk Assessment For men:  Risk factors for CHD include age, diabetes, total cholesterol level, HDL level, blood pressure, and smoking.  
CHD risk estimation tool: cvdrisk.nhlbi.nih.gov/calculator.asp  
For women:  Risk factors for ischemic stroke include age, high blood pressure, diabetes, smoking, history of CVD, atrial fibrillation, and left ventricular hypertrophy.  
Stroke risk estimation tool: http://www.westernstroke.org/index.php?header_name=stroke_tools.gif&main=stroke_tools.php
Other Relevant 
USPSTF

USPSTF 
RecommendationsThe USPSTF has made recommendations on screening for abdominal aortic aneurysm, carotid artery stenosis, coronary heart disease, high blood pressure, lipid 
disorders, and peripheral arterial disease. These recommendations are available at http://www.uspreventiveservicestaskforce.org .
Abbreviations:  CHD = coronary heart disease, CVD = cardiovascular disease, GI = gastrointestinal, HDL = high-density lipoprotein, MI = myocardial infarction, NSAIDs = nonsteroidal anti-inflammatory drugs .
For a summary of the evidence systematically reviewed in making these recommendations, the full recommendation statement, and supporting documents, please go to  
http://www.uspreventiveservicestaskforce.org .

10Aspirin or NSAIDs for Prevention Of Colorectal Cancer
TitleRoutine Aspirin or Nonsteroidal Anti-Inflammatory Drug (NSAID) Use for the Primary Prevention  
of Colorectal Cancer
Population Asymptomatic adults at average risk for colorectal cancer
RecommendationDo not use aspirin or NSAIDs for the prevention of colorectal cancer.
Grade: D
Risk AssessmentThe major risk factors for colorectal cancer are older age (older than age 50 years), family history (having two or more first- 
or second-degree relatives with colorectal cancer), and African American race.
Balance of Benefits and HarmsAspirin and NSAIDs, taken in higher doses for longer periods, reduce the incidence of adenomatous polyps. However, 
there is poor evidence that aspirin and NSAID use leads to a reduction in colorectal cancer-associated mortality.
Aspirin increases the incidence of gastrointestinal bleeding and hemorrhagic stroke; NSAIDs increase the incidence of

Aspirin increases the incidence of gastrointestinal bleeding and hemorrhagic stroke; NSAIDs increase the incidence of 
gastrointestinal bleeding and renal impairment, especially in the elderly.
The USPSTF concluded that the harms outweigh the benefits of aspirin and NSAID use for the prevention of colorectal 
cancer.
RecommendationsThe USPSTF has made recommendations on screening for colorectal cancer and aspirin use for the prevention of 
cardiovascular disease. These recommendations are available at http://www.uspreventiveservicestaskforce.org/ .

11Bacterial Vaginosis in Pregnancy
Title Screening for Bacterial Vaginosis in Pregnancy to Prevent Preterm Delivery
PopulationAsymptomatic pregnant women without risk factors for 
preterm deliveryAsymptomatic pregnant women with risk factors for 
preterm delivery
RecommendationDo not screen. 
Grade: D No recommendation. 
Risk AssessmentRisk factors of preterm delivery include:
 ●African-American women.
 ●Pelvic infection.
 ●Previous preterm delivery.
Bacterial vaginosis is more common among African-American women, women of low socioeconomic status, 
and women who have previously delivered low-birth-weight infants.
Screening Tests Bacterial vaginosis is diagnosed using Amsel’s clinical criteria or Gram stain.
When using Amsel’s criteria, 3 out of 4 criteria must be met to make a clinical diagnosis:
1. Vaginal pH >4.7.
2. The presence of clue cells on wet mount.
3. Thin homogeneous discharge.

4. Amine ‘fishy odor’ when potassium hydroxide is added to the discharge.
Screening Intervals Not applicable.
TreatmentTreatment is appropriate for pregnant women with symptomatic bacterial vaginosis infection.
Oral metronidazole and oral clindamycin, as well as vaginal metronidazole gel or clindamycin cream, are used 
to treat bacterial vaginosis. 
The optimal treatment regimen is unclear.1
1The Centers for Disease Control and Prevention (CDC) recommends 250 mg oral metronidazole 3 times a day for 7 days as the treatment for bacterial vaginosis in pregnancy.
For a summary of the evidence systematically reviewed in making these recommendations, the full recommendation statement, and supporting documents, please 
go to http://www.uspreventiveservicestaskforce.org .

12Bacteriuria
Title Screening for Asymptomatic Bacteriuria in Adults
Population All pregnant women Men and nonpregnant women
RecommendationScreen with urine culture. 
Grade: A Do not screen. 
Grade: D
Detection and Screening TestsAsymptomatic bacteriuria can be reliably detected through urine culture.
The presence of at least 105 colony-forming units per mL of urine, of a single uropathogen, and in a midstream clean-
catch specimen is considered a positive test result.
Screening IntervalsA clean-catch urine specimen should be collected for 
screening culture at 12-16 weeks’ gestation or at the first 
prenatal visit, if later.
The optimal frequency of subsequent urine testing during 
pregnancy is uncertain.Do not screen.
Benefits of Detection and Early 
TreatmentThe detection and treatment of asymptomatic bacteriuria 
with antibiotics significantly reduces the incidence of 
symptomatic maternal urinary tract infections and low

symptomatic maternal urinary tract infections and low 
birthweight.Screening men and nonpregnant women for asymptomatic 
bacteriuria is ineffective in improving clinical outcomes.
Harms of Detection and Early 
TreatmentPotential harms associated with treatment of asymptomatic bacteriuria include:
 ●Adverse effects from antibiotics.
 ●Development of bacterial resistance.
RecommendationsAdditional USPSTF recommendations involving screening for infectious conditions during pregnancy can be found at 
www.uspreventiveservicestaskforce.org/recommendations.htm#obstetric  and www.uspreventiveservicestaskforce.org/
recommendations.htm#infectious .
For a summary of the evidence systematically reviewed in making these recommendations, the full recommendation statement, and supporting documents,

For a summary of the evidence systematically reviewed in making these recommendations, the full recommendation statement, and supporting documents,  
please go to http://www.uspreventiveservicestaskforce.org .

13Bladder Cancer 
Title Screening for Bladder Cancer
Population Asymptomatic adults
RecommendationNo recommendation. 
Risk AssessmentRisk factors for bladder cancer include: 
 ●Smoking
 ●Occupational exposure to carcinogens (e.g., rubber, chemical, and leather industries)
 ●Male sex
 ●Older age
 ●White race
 ●Infections caused by certain bladder parasites
 ●Family or personal history of bladder cancer
Screening TestsScreening tests for bladder cancer include: 
 ●Microscopic urinalysis for hematuria
 ●Urine cytology
 ●Urine biomarkers
InterventionsThe principal treatment for superficial bladder cancer is transurethral resection of the bladder tumor, which may be combined with adjuvant 
radiation therapy, chemotherapy, biologic therapies, or photodynamic therapies. 
Radical cystectomy, often with adjuvant chemotherapy, is used in cases of surgically resectable invasive bladder cancer.

Balance of Benefits and HarmsThere is inadequate evidence that treatment of screen-detected bladder cancer leads to improved morbidity or mortality. 
There is inadequate evidence on harms of screening for bladder cancer.
Suggestions for PracticeIn deciding whether to screen for bladder cancer, clinicians should consider the following: 
 ●Potential preventable burden:  early detection of tumors with malignant potential could have an important impact on the mortality rate of 
bladder cancer.
 ●Potential harms:  false-positive results may lead to anxiety and unneeded evaluations, diagnostic-related harms from cystoscopy and 
biopsy, harms from labeling and unnecessary treatments, and overdiagnosis. 
 ●Current practice:  screening tests used in primary practice include microscopic urinalysis for hematuria and urine cytology; urine

●Current practice:  screening tests used in primary practice include microscopic urinalysis for hematuria and urine cytology; urine 
biomarkers are not commonly used in part because of cost. Patients with positive findings are typically referred to a urologist for further 
evaluation.
RecommendationsRecommendations on screening for other types of cancer can be found at www.uspreventiveservicestaskforce.org .
 
For a summa ry of the evidence systematically reviewed in making these recommendations, the full recommendation statement, and supporting documents, please go to  
http://www.uspreventives ervicestaskforce.org .

14BRCA-Related Cancer in Women
Title Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer In Women
Population Asymptomatic women who have not been diagnosed with BRCA-related cancer
RecommendationScreen women whose family history may be associated with 
an increased risk for potentially harmful BRCA mutations. 
Women with positive screening results should receive genetic 
counseling and, if indicated after counseling, BRCA testing. 
Grade: BDo not routinely recommend genetic counseling or BRCA 
testing to women whose family history is not associated with an 
increased risk for potentially harmful BRCA mutations. 
Grade: D
Risk AssessmentFamily history factors associated with increased likelihood of potentially harmful BRCA mutations include breast cancer diagnosis before age 
50 years, bilateral breast cancer, family history of breast and ovarian cancer, presence of breast cancer in ≥1 male family member, multiple

50 years, bilateral breast cancer, family history of breast and ovarian cancer, presence of breast cancer in ≥1 male family member, multiple 
cases of breast cancer in the family, ≥1 or more family member with 2 primary types of BRCA-related cancer, and Ashkenazi Jewish ethnicity. 
Several familial risk stratification tools are available to determine the need for in-depth genetic counseling, such as the Ontario Family History 
Assessment Tool, Manchester Scoring System, Referral Screening Tool, Pedigree Assessment Tool, and FHS-7.
Screening TestsGenetic risk assessment and BRCA mutation testing are generally multistep processes involving identification of women who may be at 
increased risk for potentially harmful mutations, followed by genetic counseling by suitably trained health care providers and genetic testing of 
selected high-risk women when indicated.

selected high-risk women when indicated. 
Tests for BRCA mutations are highly sensitive and specific for known mutations, but interpretation of results is complex and generally requires 
posttest counseling.
TreatmentInterventions in women who are BRCA mutation carriers include earlier, more frequent, or intensive cancer screening; risk-reducing 
medications (e.g., tamoxifen or raloxifene); and risk-reducing surgery (e.g., mastectomy or salpingo-oophorectomy).
Balance of Benefits and Harms In women whose family history is associated with an increased risk 
for potentially harmful BRCA mutations, the net benefit of genetic 
testing and early intervention is moderate.In women whose family history is not associated with an increased 
risk for potentially harmful BRCA mutations, the net benefit of genetic

risk for potentially harmful BRCA mutations, the net benefit of genetic 
testing and early intervention ranges from minimal to potentially 
harmful.
RecommendationsThe USPSTF has made recommendations on medications for the reduction of breast cancer risk and screening for ovarian cancer. These 
recommendations are available at www.uspreventiveservicestaskforce.org .
For a summary of the evidence systematically reviewed in making this recommendation, the full recommendation statement, and supporting documents, please go to  
www.uspreventiveservicestaskforce.org .

15Breast Cancer (Preventive Medications)
 Title Medications for Risk Reduction of Primary Breast Cancer in Women
PopulationAsymptomatic women aged ≥35 years without a prior 
diagnosis of breast cancer who are at increased risk for the 
diseaseAsymptomatic women aged ≥35 years without a prior 
diagnosis of breast cancer who are not at increased risk for 
the disease
Recommendation Engage in shared, informed decision making and offer 
to prescribe risk-reducing medications, if appropriate. 
Grade: B Do not prescribe risk-reducing medications. 
Grade: D
Risk Assessment Important risk factors for breast cancer include patient age, race/ethnicity, age at menarche, age at first live childbirth, 
personal history of ductal or lobular carcinoma in situ, number of first-degree relatives with breast cancer, personal history of 
breast biopsy, body mass index, menopause status or age, breast density, estrogen and progestin use, smoking, alcohol use, 
physical activity, and diet.

physical activity, and diet. 
Available risk assessment models can accurately predict the number of breast cancer cases that may arise in certain study 
populations, but their ability to accurately predict which women will develop breast cancer is modest. 
Preventive Medications The selective estrogen receptor modulators tamoxifen and raloxifene have been shown to reduce the incidence of invasive 
breast cancer in women who are at increased risk for the disease. Tamoxifen has been approved for this use in women 
age 35 years or older, and raloxifene has been approved for this use in postmenopausal women. The usual daily doses for 
tamoxifen and raloxifene are 20 mg and 60 mg, respectively, for 5 years. 
Harms There is a moderate net benefit from use of tamoxifen and 
raloxifene to reduce the incidence of invasive breast cancer

raloxifene to reduce the incidence of invasive breast cancer 
in women who are at increased risk for the disease. The potential harms of tamoxifen and raloxifene outweigh 
the potential benefits for breast cancer risk reduction in 
women who are not at increased risk for the disease. 
Potential harms include thromboembolic events, endometrial 
cancer, and cataracts. 
Recommendations The USPSTF has made recommendations on risk assessment, genetic counseling, and genetic testing for  
BRCA-related cancer, as well as screening for breast cancer. These recommendations are available at  
http://www.uspreventiveservicestaskforce.org/ . 

16Breast Cancer (Screening) 
Title Screening for Breast Cancer: Using Film Mammography
Population Women aged 40-49 years Women aged 50-74 years Women aged ≥75 years
Recommendation Individualize decision to begin biennial 
screening according to the patient’s 
circumstances and values. 
Grade: C Screen every 2 years. 
Risk AssessmentThis recommendation applies to women aged ≥40 years who are not at increased risk by 
virtue of a known genetic mutation or history of chest radiation. Increasing age is the most 
important risk factor for most women.   
Screening TestsStandardization of film mammography has led to improved quality. Refer patients to facilities 
certified under the Mammography Quality Standards Act (MQSA), listed at  
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfMQSA/mqsa.cfm  
Timing of ScreeningEvidence indicates that biennial screening is optimal. A biennial schedule preserves most

Timing of ScreeningEvidence indicates that biennial screening is optimal. A biennial schedule preserves most 
of the benefit of annual screening and cuts the harms nearly in half. A longer interval may 
reduce the benefit.   
Balance of Benefits and HarmsThere is convincing evidence that screening with film mammography reduces breast cancer 
mortality, with a greater absolute reduction for women aged 50 to 74 years than for younger 
women. 
Harms of screening include psychological harms, additional medical visits, imaging, and 
biopsies in women without cancer, inconvenience due to false-positive screening results, 
harms of unnecessary treatment, and radiation exposure. Harms seem moderate for each 
age group.
False-positive results are a greater concern for younger women; treatment of cancer that 
would not become clinically apparent during a woman’s life (overdiagnosis) is an increasing 
problem as women age.

problem as women age. 
Rationale for No Recommendation  
(I Statement) Among women 75 years or older, evidence 
of benefit is lacking.
RecommendationsUSPSTF recommendations on screening for genetic susceptibility for breast cancer and chemoprevention of breast cancer are available at 
 
1The U.S. Department of Health and Human Services, in implementing the Affordable Care Act under the standard it sets out in revised Section 2713(a)(5) of the Public Health Service Act, utilizes the 2002 recommendation on breast cancer screening  of the U.S. 
Preventive Services Task Force. For clinical summary of 2002 Recommendation, see Appendix F.
For a summary of the evidence systematically reviewed in making these recommendations, the full recommendation statement, and supporting documents, please go to

17Breast Cancer (Screening) 

Breastfeeding
Title Primary Care Interventions to Promote Breastfeeding
Population Pregnant women New mothersThe mother’s partner, other 
family members, and friendsInfants and young children
RecommendationPromote and support breastfeeding.
Grade: B 
Benefits of BreastfeedingMothers
Less likelihood of breast and ovarian 
cancerInfants
Fewer ear infections, lower-respiratory-
tract infections, and gastrointestinal 
infectionsYoung children
Less likelihood of asthma, type 2 
diabetes, and obesity
Interventions to Promote 
BreastfeedingInterventions to promote and support breastfeeding have been found to increase the rates of initiation, duration, and exclusivity 
of breastfeeding. Consider multiple strategies, including:
 ●Formal breastfeeding education for mothers and families

 ●Direct support of mothers during breastfeeding
 ●Training of primary care staff about breastfeeding and techniques for breastfeeding support
 ●Peer support
Interventions that include both prenatal and postnatal components may be most effective at increasing breastfeeding duration.
In rare circumstances, for example for mothers with HIV and infants with galactosemia, breastfeeding is not recommended. 
Interventions to promote breastfeeding should empower individuals to make informed choices supported by the best available 
evidence.
Implementation System-level interventions with senior leadership support may be more likely to be sustained over time.

18Carotid Artery Stenosis 
Title Screening for Carotid Artery Stenosis
Population Adult general population1
RecommendationDo not screen with ultrasound or other screening tests.
Grade: D
Risk AssessmentThe major risk factors for carotid artery stenosis (CAS) include: older age, male gender, hypertension, smoking, 
hypercholesterolemia, and heart disease.
However, accurate, reliable risk assessment tools are not available.
HarmsHarms outweigh benefits.
In the general population, screening with carotid duplex ultrasound would result in more false-positive results than true 
positive results. This would lead either to surgeries that are not indicated or to confirmatory angiography. As the result of 
these procedures, some people would suffer serious harms (death, stroke, and myocardial infarction) that outweigh the 
potential benefit surgical treatment may have in preventing stroke.
Recommendations from the

Recommendations from the 
USPSTFAdults should be screened for hypertension, hyperlipidemia, and smoking. Clinicians should discuss aspirin chemoprevention 
with patients at increased risk for cardiovascular disease.
These recommendations and related evidence are available at http://www.uspreventiveservicestaskforce.org .
1This recommendation applies to adults without neurological symptoms and without a history of transient ischemic attacks (TIA) or stroke. If otherwise eligible, an individual who has a carotid area TIA should be evaluated 
promptly for consideration of carotid endarterectomy.

19Cervical Cancer
Title Screening for Cervical Cancer
Population Women ages 21 to 65 Women ages 30 to 65Women younger than 
age 21Women older than 
age 65 who have 
had adequate prior 
screening and are not 
high riskWomen after 
hysterectomy with 
removal of the cervix 
and with no history of 
high-grade precancer 
or cervical cancerWomen younger than 
age 30
RecommendationScreen with cytology 
(Pap smear) every  
3 years.
Grade: AScreen with cytology 
every 3 years or co-
testing (cytology/HPV 
testing) every 5 years
Grade: ADo not screen. 
Grade: DDo not screen. 
Grade: DDo not screen with 
HPV testing (alone or 
with cytology)
Grade: D
Risk AssessmentHuman papillomavirus (HPV) infection is associated with nearly all cases of cervical cancer. Other factors that put a woman at increased risk of cervical 
cancer include HIV infection, a compromised immune system, in utero exposure to diethylstilbestrol, and previous treatment of a high-grade precancerous

cancer include HIV infection, a compromised immune system, in utero exposure to diethylstilbestrol, and previous treatment of a high-grade precancerous 
lesion or cervical cancer.
Screening Tests and 
IntervalScreening women ages 21 to 65 years every 3 years with cytology provides a reasonable balance between benefits and harms.  
Screening with cytology more often than every 3 years confers little additional benefit, with large increases in harms.
HPV testing combined with cytology (co-testing) every 5 years in women ages 30 to 65 years offers a comparable balance of benefits and harms, and is 
therefore a reasonable alternative for women in this age group who would prefer to extend the screening interval.
Timing of ScreeningScreening earlier than age 21 years, regardless of sexual history, leads to more harms than benefits. Clinicians and patients should base the decision to end

Timing of ScreeningScreening earlier than age 21 years, regardless of sexual history, leads to more harms than benefits. Clinicians and patients should base the decision to end 
screening on whether the patient meets the criteria for adequate prior testing and appropriate follow-up, per established guidelines.
InterventionsScreening aims to identify high-grade precancerous cervical lesions to prevent development of cervical cancer and early-stage asymptomatic invasive cervical 
cancer.  
High-grade lesions may be treated with ablative and excisional therapies, including cryotherapy, laser ablation, loop excision, and cold knife conization.  
Early-stage cervical cancer may be treated with surgery (hysterectomy) or chemoradiation.
Balance of Benefits 
and HarmsThe benefits of 
screening with 
cytology every 3 years 
substantially outweigh 
the harms.The benefits of 
screening with co-
testing) every 5 years 
outweigh the harms.The harms of screening

outweigh the harms.The harms of screening 
earlier than age 21 
years outweigh the 
benefits.The benefits of 
screening after age 65 
years do not outweigh 
the potential harms.The harms of screening 
after hysterectomy 
outweigh the benefits.The potential harms 
of screening with HPV 
testing (alone or with 
cytology) outweigh the 
potential benefits.
USPSTF 
RecommendationsThe USPSTF has made recommendations on screening for breast cancer and ovarian cancer, as well as genetic risk assessment and BRCA  mutation testing 
for breast and ovarian cancer susceptibility. These recommendations are available at http://www.uspreventiveservicestaskforce.org/ .

http://www.uspreventiveservicestaskforce.org/ .

20Chlamydial Infection
Title Screening for Chlamydial Infection
PopulationNon-pregnant women Pregnant women
Men24 years and 
younger25 years and older24 years and 
younger25 years and older
Includes 
adolescentsNot at increased 
riskAt increased riskIncludes 
riskAt increased risk
RecommendationScreen if sexually 
active. 
Grade: ADo not 
automatically 
screen.
Grade: CScreen.
Grade: AScreen.
Grade: BDo not 
screen.
Grade: BNo 
recommendation.
Grade: I 
(Insufficient 
Evidence1)
Risk AssessmentAge:  Women and men aged 24 years and younger are at greatest risk.
History of:  previous chlamydial infection or other sexually transmitted infections, new or multiple sexual partners, inconsistent condom use, sex work.
Demographics:  African-Americans and Hispanic women and men have higher prevalence rates than the general population in many communities.

Screening TestsNucleic acid amplification tests (NAATs) can identify chlamydial infection in asymptomatic women (non-pregnant and pregnant) and asymptomatic men. NAATs 
have high specificity and sensitivity and can be used with urine and vaginal swabs.
Screening 
IntervalsNon-Pregnant Women  
The optimal interval for screening is not known. The CDC 
recommends that women at increased risk be screened at least 
annually.2 Pregnant Women  
For women 24 years and younger and older women at increased 
risk: Screen at the first prenatal visit.  
For patients at continuing risk, or who are newly at risk: Screen in 
the 3rd trimester.Not applicable
TreatmentThe Centers for Disease Control and Prevention has outlined appropriate treatment at: http://www.cdc.gov/STD/treatment . Test and/or treat partners of patients 
treated for chlamydial infection.

1Chlamydial infection results in few sequelae in men. Therefore, the major benefit of screening men would be to reduce the likelihood that infected and untreated men would pass the infection to sexual partners. There is no evidence that screening men reduces the 
long-term consequences of chlamydial infection in women. Because of this lack of evidence, the USPSTF was not able to assess the balance of benefits and harms, and concluded that the evidence is insufficient to recommend for or against routinely screening 
men.
2Centers for Disease Control and Prevention, Sexually transmitted diseases treatment guidelines, 2006. MMWR  2006. 55(No. RR-11).

21Chronic Kidney Disease
Title Screening for Chronic Kidney Disease
Population Asymptomatic adults without diagnosed chronic kidney disease (CKD)
Recommendation No recommendation. 
Risk Assessment There is no generally accepted risk assessment tool for CKD or risk for complications of CKD. Diabetes and hypertension are 
well-established risk factors with strong links to CKD. Other risk factors for CKD include older age, cardiovascular disease, 
obesity, and family history. 
Screening Tests While there is insufficient evidence to recommend routine screening, the tests often suggested for screening that are feasible 
in primary care include testing the urine for protein (microalbuminuria or macroalbuminuria) and testing the blood for serum 
creatinine to estimate glomerular filtration rate. 
Harms The USPSTF could not determine the balance between the benefits and harms of screening for CKD in asymptomatic adults.

Harms The USPSTF could not determine the balance between the benefits and harms of screening for CKD in asymptomatic adults. 
Recommendations The USPSTF has made recommendations on screening for diabetes, hypertension, and obesity, as well as  
aspirin use for the prevention of cardiovascular disease. These recommendations are available at  

22Chronic Obstructive Pulmonary Disease
Title Screening for Chronic Obstructive Pulmonary Disease Using Spirometry
Population Adult general population
RecommendationDo not screen for chronic obstructive pulmonary disease using spirometry.
Grade: D 
Additional Population 
InformationThis screening recommendation applies to healthy adults who do not recognize or report respiratory symptoms to a clinician.  
It does not apply to individuals with a family history of alpha-1 antitrypsin deficiency.
Risk AssessmentRisk factors for COPD include:
 ●Current or past tobacco use.
 ●Exposure to occupational and environmental pollutants.
 ●Age 40 or older.
Screening Tests1Spirometry can be performed in a primary care physician’s office or a pulmonary testing laboratory. The USPSTF did not 
review evidence comparing the accuracy of spirometry performed in primary care versus referral settings.

For individuals who present to clinicians complaining of chronic cough, increased sputum production, wheezing, or dyspnea, 
spirometry would be indicated as a diagnostic test for COPD, asthma, and other pulmonary diseases.
Other Approaches to the 
Prevention of Pulmonary 
IllnessesThese services should be offered to patients regardless of COPD status:
 ●All current smokers should receive smoking cessation counseling and be offered pharmacologic therapies demonstrated 
to increase cessation rates.
 ●All patients 50 years of age or older should be offered influenza immunization  annually.
 ●All patients 65 years of age or older should be offered one-time pneumococcal immunization .
RecommendationsClinicians should screen all adults for tobacco use and provide tobacco cessation interventions for those who use tobacco

RecommendationsClinicians should screen all adults for tobacco use and provide tobacco cessation interventions for those who use tobacco 
products. The USPSTF tobacco cessation counseling recommendation and supporting evidence are available at  
http://www.uspreventiveservicestaskforce.org/uspstf/uspstbac.htm .
1The potential benefit of spirometry-based screening for COPD is prevention of one or more exacerbations by treating patients found to have an airflow obstruction previously undetected. However, even in groups with  
the greatest prevalence of airflow obstruction, hundreds of patients would need to be screened with spirometry to defer one exacerbation.

23Chronic Obstructive Pulmonary Disease
Grade: D 

Title Screening for Cognitive Impairment in Older Adults

Population Community-dwelling adults who are older than age 65 years and have no signs or symptoms of cognitive impairment
Grade: I statement
Risk AssessmentIncreasing age is the strongest known risk factor for cognitive impairment. Other reported risk factors for cognitive impairment 
include cardiovascular risk factors (such as diabetes, tobacco use, hypercholesterolemia, and hypertension), head trauma, 
learning disabilities (such as Down syndrome), depression, alcohol abuse, physical frailty, low education level, low social 
support, and having never been married.
Screening TestsScreening tests for cognitive impairment in the clinical setting generally include asking patients to perform a series of tasks

Screening TestsScreening tests for cognitive impairment in the clinical setting generally include asking patients to perform a series of tasks 
that assess 1 or more cognitive domains (memory, attention, language, and visuospatial or executive functioning). The most 
widely studied instrument is the Mini-Mental State Examination. 
Other instruments with more limited evidence include the Clock Draw Test, Mini-Cog, Memory Impairment Screen, 
Abbreviated Mental Test, Short Portable Mental Status Questionnaire, Free and Cued Selective Reminding Test, 7-Minute 
Screen, Telephone Interview for Cognitive Status, and Informant Questionnaire on Cognitive Decline in the Elderly.
TreatmentPharmacologic treatments approved by the U.S. Food and Drug Administration include acetylcholinesterase inhibitors 
and memantine. Nonpharmacologic interventions include cognitive training, lifestyle behavioral interventions, exercise,

and memantine. Nonpharmacologic interventions include cognitive training, lifestyle behavioral interventions, exercise, 
educational interventions, and multidisciplinary care interventions. Some interventions focus on the caregiver and aim to 
improve caregiver morbidity and delay institutionalization of persons with dementia.
HarmsThe evidence on screening for cognitive impairment is lacking, and the balance of benefits and harms cannot be determined.
RecommendationsThe USPSTF has made recommendations related to several of the risk factors for cognitive impairment, including counseling 
on tobacco cessation, alcohol use, healthful diet, physical activity, and falls prevention and screening for high cholesterol, 
hypertension, and depression. These recommendations are available at http://www.uspreventiveservicestaskforce.org/ .

24Colorectal Cancer
Title Screening for Colorectal Cancer
Population1Adults age 50 to 75 years Adults age 76 to 85 years Adults older than 85
RecommendationScreen with high sensitivity fecal occult 
blood testing (FOBT), sigmoidoscopy, or 
Grade: A Do not automatically screen.
Grade: CDo not screen. 
Grade: D
For all populations, evidence is insufficient to assess the benefits and harms of screening with computerized tomography 
colonography (CTC) and fecal DNA testing. 
Screening TestsHigh sensitivity FOBT, sigmoidoscopy with FOBT, and colonoscopy are effective in decreasing colorectal cancer mortality. 
The risks and benefits of these screening methods vary. 
Colonoscopy and flexible sigmoidoscopy (to a lesser degree) entail possible serious complications. 
Screening Test Intervals Intervals for recommended screening strategies: 
 ●Annual screening with high-sensitivity fecal occult blood testing

 ●Sigmoidoscopy every 5 years, with high-sensitivity fecal occult blood testing every 3 years
 ●Screening colonoscopy every 10 years
Balance of Benefits and HarmsThe benefits of screening outweigh the 
potential harms for 50- to 75-year-olds. The likelihood that detection and early intervention will yield a mortality benefit declines 
after age 75 because of the long average time between adenoma development and cancer 
diagnosis. 
ImplementationFocus on strategies that maximize the number of individuals who get screened. 
Practice shared decisionmaking; discussions with patients should incorporate information on test quality and availability.
Individuals with a personal history of cancer or adenomatous polyps are followed by a surveillance regimen, and screening guidelines are not 
applicable. 

RecommendationsThe USPSTF recommends against the use of aspirin or nonsteroidal anti-inflammatory drugs for the primary prevention of colorectal cancer. 
This recommendation is available at http://www.uspreventiveservicestaskforce.org .
1These recommendations do not apply to individuals with specific inherited syndromes (Lynch Syndrome or Familial Adenomatous Polyposis) or those with inflammatory bowel disease.

25Coronary Heart Disease (Risk Assessment, Nontraditional Risk Factors)
Title Using Nontraditional Risk Factors In Coronary Heart Disease Risk Assessment
Population Asymptomatic men and women with no history of coronary heart disease (CHD), diabetes, or any CHD risk equivalent
Risk AssessmentThis recommendation applies to adult men and women classified at intermediate 10-year risk for CHD (10% to 20%) by 
traditional risk factors. 
ImportanceCoronary heart disease (CHD) is the most common cause of death in adults in the United States. Treatment to prevent 
CHD events by modifying risk factors is currently based on the Framingham risk model. If the classification of individuals 
at intermediate risk could be improved by using additional risk factors, treatment to prevent CHD might be targeted more 
effectively.

effectively. 
Risk factors not currently part of the Framingham model (nontraditional risk factors) include high sensitivity C-reactive protein 
(hs-CRP), ankle-brachial index (ABI), leukocyte count, fasting blood glucose level, periodontal disease, carotid intima-media 
thickness, electron beam computed tomography, homocysteine level, and lipoprotein(a) level.
Balacne of Benefits and 
HarmsThere is insufficient evidence to determine the percentage of intermediate-risk individuals who would be reclassified by 
screening with nontraditional risk factors, other than hs-CRP and ABI. For individuals reclassified as high-risk on the basis of 
hs-CRP or ABI scores, data are not available to determine whether they benefit from additional treatments.

Little evidence is available to determine the harms of using nontraditional risk factors in screening. Potential harms include 
lifelong use of medications without proven benefit and psychological and other harms from being misclassified in a higher risk 
category.
Suggestions for practiceClinicians should continue to use the Framingham model to assess CHD risk and guide risk-based preventive therapy.
Adding nontraditional risk factors to CHD assessment would require additional patient and clinical staff time and effort. 
Routinely screening with nontraditional risk factors could result in lost opportunities to provide other important health services 
of proven benefit.
RecommendationsUSPSTF recommendations on risk assessment for CHD, the use of aspirin to prevent cardiovascular disease, and screening

RecommendationsUSPSTF recommendations on risk assessment for CHD, the use of aspirin to prevent cardiovascular disease, and screening 
for high blood pressure can be accessed at http://www.uspreventiveservicestaskforce.org .

26Coronary Heart Disease (Electrocardiography) 
Title Screening for Coronary Heart Disease with Electrocardiography
PopulationAsymptomatic adults at low risk for coronary heart disease 
(CHD) eventsAsymptomatic adults at intermediate or high risk for CHD 
events
Recommendation Do not screen with resting or exercise 
electrocardiography (ECG). 
Grade: I (Insufficient Evidence) 
Risk Assessment Several factors are associated with a higher risk for CHD events, including older age, male sex, high blood pressure, 
smoking, abnormal lipid levels, diabetes, obesity, and sedentary lifestyle. Calculators are available to ascertain a person’s 
10-year risk for a CHD event. 
Persons with a 10-year risk >20% are considered to be high-risk, those with a 10-year risk <10% are considered to be low-
risk, and those in the 10%–20% range are considered to be intermediate-risk.

risk, and those in the 10%–20% range are considered to be intermediate-risk. 
Screening Tests Several abnormalities on resting and exercise ECG are associated with an increased risk for a serious CHD event. However, 
the incremental information offered by screening asymptomatic adults at low risk for a CHD event with resting or exercise 
ECG (beyond that obtained with conventional CHD risk factors) is highly unlikely to result in changes in risk stratification that 
would prompt interventions and ultimately reduce CHD-related events. 
Harms The potential harms of screening for CHD with exercise or 
resting ECG equal or exceed the potential benefits in this 
population.The USPSTF could not determine the balance between the 
benefits and harms of screening for CHD with resting or 
exercise ECG in this population.

Recommendations The USPSTF has made recommendations on screening for carotid artery stenosis, high blood pressure,  
lipid disorders, peripheral arterial disease, and obesity. These recommendations are available at  

27Depression in Adults
Title Screening for Depression in Adults
Population Nonpregnant adults 18 years or older
RecommendationScreen when staff-assisted depression care supports1 
are in place to assure accurate diagnosis, effective 
treatment, and followup. 
Grade: BDo not automatically screen when staff-assisted 
depression care supports1 are not in place. 
Grade: C
Risk AssessmentPersons at increased risk for depression are considered at risk throughout their lifetime. Groups at increased risk include 
persons with other psychiatric disorders, including substance misuse; persons with a family history of depression; 
persons with chronic medical diseases; and persons who are unemployed or of lower socioeconomic status. Also, 
women are at increased risk compared with men. However, the presence of risk factors alone cannot distinguish 
depressed patients from nondepressed patients. 
Screening TestsSimple screening questions may perform as well as more

Screening TestsSimple screening questions may perform as well as more 
complex instruments. Any positive screening test result 
should trigger a full diagnostic interview using standard 
diagnostic criteria. 
Timing of ScreeningThe optimal interval for screening is unknown. In older 
adults, significant depressive symptoms are associated 
with common life events, including medical illness, 
cognitive decline, bereavement, and institutional 
placement in residential or inpatient settings. 
Balance of Benefits and Harms  Limited evidence suggests that screening for depression 
in the absence of staff-assisted depression care does not 
improve depression outcomes.
Suggestions for Practice“Staff-assisted depression care supports” refers to clinical staff that assists the primary care clinician by providing some 
direct depression care and/or coordination, case management, or mental health treatment.
Relevant USPSTF

Relevant USPSTF 
Recommendations Related USPSTF recommendations on screening for suicidality and screening children and adolescents for depression 
are available at http://www.uspreventiveservicestaskforce.org .
1Go to the Suggestions for Practice section of this figure for further explanation.

28Diabetes Mellitus
Title Screening for Type 2 Diabetes Mellitus in Adults
PopulationAsymptomatic adults with sustained blood pressure greater than 
135/80 mm HgAsymptomatic adults with sustained blood pressure 135/80 mm 
Hg or lower
RecommendationScreen for type 2 diabetes mellitus. 
Grade: BNo recommendation. 
Risk AssessmentThese recommendations apply to adults with no symptoms of type 2 diabetes mellitus or evidence of possible complications of diabetes.
Blood pressure measurement is an important predictor of cardiovascular complications in people with type 2 diabetes mellitus.  
The first step in applying this recommendation should be measurement of blood pressure (BP).  
Adults with treated or untreated BP >135/80 mm Hg should be screened for diabetes.
Screening Tests Three tests have been used to screen for diabetes:
 ●Fasting plasma glucose (FPG).
 ●2-hour postload plasma.
 ●Hemoglobin A1c.

The American Diabetes Association (ADA) recommends screening with FPG, defines diabetes as FPG ≥ 126 mg/dL, and recommends 
confirmation with a repeated screening test on a separate day.
Screening Intervals The optimal screening interval is not known. The ADA, on the basis of expert opinion, recommends an interval of every 3 years.
Suggestions for practice regarding 
insufficient evidenceWhen BP is ≤ 135/80 mm Hg, screening may be considered on an individual basis when knowledge of diabetes status would help inform 
decisions about coronary heart disease (CHD) preventive strategies, including consideration of lipid-lowering agents or aspirin.
To determine whether screening would be helpful on an individual basis, information about 10-year CHD risk must be considered. For

To determine whether screening would be helpful on an individual basis, information about 10-year CHD risk must be considered. For 
example, if CHD risk without diabetes was 17% and risk with diabetes was >20%, screening for diabetes would be helpful because 
diabetes status would determine lipid treatment. In contrast, if risk without diabetes was 10% and risk with diabetes was 15%, screening 
would not affect the decision to use lipid-lowering treatment.
Other relevant information from 
the USPSTF and the Community 
Preventive Services Task ForceEvidence and USPSTF recommendations regarding blood pressure, diet, physical activity, and obesity are available at  
The reviews and recommendations of the Community Preventive Services Task Force may be found at  
http://www.thecommunityguide.org .

29Falls in Older Adults
Title Prevention of Falls in Community-Dwelling Older Adults
PopulationCommunity-dwelling adults aged 65 years and older who are 
at increased risk for fallsCommunity-dwelling adults aged 65 years and older
Recommendation Provide intervention consisting of exercise or physical 
therapy and/or vitamin D supplementation to prevent 
falls. 
Grade: B Do not automatically perform an in-depth multifactorial 
risk assessment with comprehensive management of 
identified risks to prevent falls. 
Grade: C 
Risk Assessment Primary care clinicians can consider the following factors to identify older adults at increased risk for falls: a history of falls, a 
history of mobility problems, and poor performance on the timed Get-Up-and-Go test. 
Interventions Effective exercise and physical therapy interventions include group classes and at-home physiotherapy strategies and range 
in intensity from very low (≤9 hours) to high (>75 hours).

in intensity from very low (≤9 hours) to high (>75 hours). 
Benefit from vitamin D supplementation occurs by 12 months; the efficacy of treatment of shorter duration is unknown. The 
recommended daily allowance for vitamin D is 600 IU for adults aged 51 to 70 years and 800 IU for adults older than 70 
years. 
Comprehensive multifactorial assessment and management interventions include assessment of multiple risk factors for 
falls and providing medical and social care to address factors identified during the assessment. In determining whether this 
service is appropriate in individual cases, patients and clinicians should consider the balance of benefits and harms on the 
basis of the circumstances of prior falls, medical comorbid conditions, and patient values. 
Balance of Benefits and

Harms Exercise or physical therapy and vitamin D supplementation 
have a moderate benefit in preventing falls in older adults. Multifactorial risk assessment with comprehensive 
management of identified risks has at least a small benefit in 
preventing falls in older adults. 
Recommendations The USPSTF has made recommendations on screening for osteoporosis. These recommendations are available at  

30Folic Acid Supplementation
Title Folic Acid for the Prevention of Neural Tube Defects
Population Women planning a pregnancy or capable of becoming pregnant
Recommendation Take a daily vitamin supplement containing 0.4 to 0.8 mg (400 to 800 µg) of folic acid. 
Grade: A
Risk AssessmentRisk factors include:
 ●A personal or family history of a pregnancy affected by a neural tube defect
 ●The use of certain antiseizure medications
 ●Mutations in folate-related enzymes
 ●Maternal diabetes
 ●Maternal obesity
Note:  This recommendation does not apply to women who have had a previous pregnancy affected by neural tube 
defects or women taking certain antiseizure medicines. These women may be advised to take higher doses of folic acid. 
Timing of MedicationStart supplementation at least 1 month before conception.
Continue through first 2 to 3 months of pregnancy.

Continue through first 2 to 3 months of pregnancy. 
Recommendations of OthersACOG, AAFP, and most other organizations recommend 4 mg/d for women with a history of a pregnancy affected by a 
neural tube defect.
 
Abbreviations:  AAFP = American Academy of Family Physicians; ACOG = American College of Obstetricians and Gynecologists.

31Genital Herpes
Time Screening for Genital Herpes
Population Asymptomatic pregnant women Asymptomatic adolescents and adults
RecommendationDo not screen for herpes simplex virus.
Grade: DDo not screen for herpes simplex virus.
Grade: D
Screening TestsMethods for detecting herpes simplex virus include viral culture, polymerase chain reaction, and antibody-based tests, such 
as the western blot assay and type-specific glycoprotein G serological tests.
InterventionsThere is limited evidence that the use of antiviral therapy in 
women with a history of recurrent infection, or performance 
of cesarean delivery in women with active herpes lesions at 
the time of delivery, decreases neonatal herpes infection. 
There is also limited evidence of the safety of antiviral 
therapy in pregnant women and neonates.Antiviral therapy improves health outcomes in symptomatic 
persons (e.g., those with multiple recurrences); however, 
there is no evidence that the use of antiviral therapy

there is no evidence that the use of antiviral therapy 
improves health outcomes in those with asymptomatic 
infection. There are multiple efficacious regimens that may 
be used to prevent the recurrence of clinical genital herpes.
HarmsThe potential harms of screening asymptomatic pregnant 
women include false-positive test results, labeling, 
and anxiety, as well as false-negative tests and false 
reassurance, although these potential harms are not well 
studied. The USPSTF determined that there are no benefits 
associated with screening, and therefore the potential harms 
outweigh the benefits.The potential harms of screening asymptomatic adolescents 
and adults include false-positive test results, labeling, 
and anxiety, although these potential harms are not well 
studied. The USPSTF determined the benefits of screening 
are minimal, at best, and the potential harms outweigh the

are minimal, at best, and the potential harms outweigh the 
RecommendationsThe USPSTF has made recommendations on screening for chlamydia, gonorrhea, HIV, and several other sexually 
transmitted infections. These recommendations are available at http://www.uspreventiveservicestaskforce.org/ .

32Gestational Diabetes Mellitus
Title Screening for Gestational Diabetes Mellitus
Population Asymptomatic pregnant women after 24 weeks of gestation Asymptomatic pregnant women before 24 weeks of gestation
RecommendationScreen for gestational diabetes mellitus (GDM). 
Risk AssessmentRisk factors that increase a woman’s risk for developing GDM include obesity, increased maternal age, history of GDM, family 
history of diabetes, and belonging to an ethnic group with increased risk of developing type 2 diabetes mellitus (Hispanic, 
Native American, South or East Asian, African American, or Pacific Islands descent).
Screening TestsThere are 2 strategies used to screen for gestational diabetes in the United States. In the 2-step approach, the 50-g oral 
glucose challenge test is administered between 24 and 28 weeks of gestation in a nonfasting state. If the screening threshold

glucose challenge test is administered between 24 and 28 weeks of gestation in a nonfasting state. If the screening threshold 
is met or exceeded (7.22 mmol/L [130 mg/dL], 7.50 mmol/L [135 mg/dL], or 7.77 mmol/L [140 mg/dL]), patients receive the 
oral glucose tolerance test. A diagnosis of GDM is made when 2 or more glucose levels meet or exceed the specified glucose 
thresholds. In the 1-step approach, a 75-g glucose load is administered after fasting and plasma glucose levels are evaluated 
after 1 and 2 hours. GDM is diagnosed if 1 glucose value falls at or above the specified glucose threshold.
Other methods of screening include fasting plasma glucose and screening based on risk factors. However, there is limited 
evidence on these alternative screening approaches.
TreatmentInitial treatment includes moderate physical activity, dietary changes, support from diabetes educators and nutritionists, and

TreatmentInitial treatment includes moderate physical activity, dietary changes, support from diabetes educators and nutritionists, and 
glucose monitoring. If the patient’s glucose is not controlled after these initial interventions, she may be prescribed medication 
(either insulin or oral hypoglycemic agents), undergo increased surveillance in prenatal care, and have changes in delivery 
management.
Harms There is a moderate net benefit to screening for GDM 
after 24 weeks of gestation to reduce maternal and fetal 
complications.The evidence for screening for GDM before 24 weeks of 
gestation is insufficient, and the balance of benefits and 
harms of screening cannot be determined.
RecommendationsThe USPSTF has made recommendations on screening for type 2 diabetes. These recommendations are available at http://
www.uspreventiveservicestaskforce.org/ .

33Glaucoma
Title Screening for Glaucoma  
Population Adults without vision symptoms who are seen in primary care
Risk Assessment Important risk factors for open-angle glaucoma are increased intraocular pressure, older age, family history of glaucoma,  
and African American race. 
Screening Tests Diagnosis of glaucoma is usually made on the basis of several tests that, when combined, evaluate the biologic structure 
and function of the optic nerve and intraocular pressure. Most tests that are available in a primary care setting do not have 
acceptable accuracy to detect glaucoma. 
Treatment The immediate physiologic goal and measure of effect of primary treatment of glaucoma is reduction in intraocular pressure. 
Treatments that are effective in reducing intraocular pressure include medications, laser therapy, and surgery. However, these

Treatments that are effective in reducing intraocular pressure include medications, laser therapy, and surgery. However, these 
treatments have potential harms, and their effectiveness in reducing patient-perceived impairment in vision-related function is 
uncertain. 
Harms Evidence on the accuracy of screening tests, especially in primary care settings, and the benefits of screening or treatment to 
delay or prevent visual impairment or improve quality of life is inadequate. Therefore, the overall certainty of the evidence is 
low, and the USPSTF is unable to determine the balance of benefits and harms of screening for glaucoma in asymptomatic 
adults. 
Recommendations The USPSTF has made recommendations on screening for impaired visual acuity in older adults. These recommendations 
are available at http://www.uspreventiveservicestaskforce.org/ .

are available at http://www.uspreventiveservicestaskforce.org/ . 

34Gonorrhea
Title Screening for Gonorrhea
PopulationSexually active women, including 
those who are pregnant, who are 
at increased risk for infectionMen who are at increased risk for 
infectionMen and women who are at low 
risk for infectionPregnant women who are not 
at increased risk for infection
RecommendationScreen for gonorrhea. 
Grade: I  
(Insufficient Evidence)Do not screen for gonorrhea.
Grade: DNo recommendation. 
Grade: I  
(Insufficient Evidence)
Risk AssessmentWomen and men younger than age 25 years—including sexually active adolescents—are at highest risk for gonorrhea infection. Risk 
factors for gonorrhea include a history of previous gonorrhea infection, other sexually transmitted infections, new or multiple sexual partners, 
inconsistent condom use, sex work, and drug use. Risk factors for pregnant women are the same as for non-pregnant women.

Screening TestsVaginal culture is an accurate screening test when transport conditions are suitable. Newer screening tests, including nucleic acid amplification 
and hybridization tests, have demonstrated improved sensitivity and comparable specificity when compared with cervical culture. Some newer 
tests can be used with urine and vaginal swabs, which enables screening when a pelvic examination is not performed.
Timing of ScreeningScreening is recommended at the first prenatal visit for pregnant women who are in a high-risk group for gonorrhea infection. For pregnant 
women who are at continued risk, and for those who acquire a new risk factor, a second screening should be conducted during the third 
trimester. The optimal interval for screening in the non-pregnant population is not known.

InterventionsGenital gonorrhea infection in men and women, including pregnant women, may be treated with a third-generation cephalosporin. Because of 
increased prevalence of resistant organisms, fluoroquinolones should not be used to treat gonorrhea. Current guidelines for treating gonorrhea 
infection are available from the Centers for Disease Control and Prevention ( http://www.cdc.gov/std/treatment ).
Balance of Benefits and HarmsThe USPSTF concluded that 
the benefits of screening women 
at increased risk for gonorrhea 
infection outweigh the potential 
harms.The USPSTF could not 
determine the balance of benefits 
and harms of screening for 
gonorrhea in men at increased 
risk for infection.Given the low prevalence of 
gonorrhea infection in the 
general population, the USPSTF 
concluded that the potential 
harms of screening in low-
prevalence populations outweigh

prevalence populations outweigh 
the benefits.The USPSTF could not 
determine the balance 
between the benefits and 
harms of screening for 
gonorrhea in pregnant women 
who are not at increased risk 
for infection.
RecommendationsThe USPSTF has also made a recommendation on ocular prophylaxis in newborns for gonococcal ophthalmia neonatorum.  
This recommendation is available at http://www.uspreventiveservicestaskforce.org/ .

35Healthful Diet and Physical Activity 
TitleBehavioral Counseling Interventions to Promote A Healthful Diet and Physical Activity for Cardiovascular Disease 
Prevention in Adults  
Population General adult population without a known diagnosis of hypertension, diabetes, hyperlipidemia, or cardiovascular disease
Recommendation Although the correlation among healthful diet, physical activity, and the incidence of cardiovascular disease is 
strong, existing evidence indicates that the health benefit of initiating behavioral counseling in the primary care 
setting to promote a healthful diet and physical activity is small. Clinicians may choose to selectively counsel 
patients rather than incorporate counseling into the care of all adults in the general population. 
Considerations:  Issues to consider include other risk factors for cardiovascular disease, patient readiness for 
change, social support and community resources that support behavioral change, and other health care and

change, social support and community resources that support behavioral change, and other health care and 
preventive service priorities. 
Potential Harms:  Harms may include the lost opportunity to provide other services with a greater health effect. 
Grade: C
 
Risk Assessment If an individual’s risk for cardiovascular disease is uncertain, there are several calculators and models available to quantify 
a person’s 10-year risk for cardiac events, such as the Framingham-based Adult Treatment Panel III calculator (available at 
http://hp2010.nhlbihin.net/atpiii/calculator.asp ). Generally, persons with a 10-year risk greater than 20% are considered to 
be high-risk, those with a 10-year risk less than 10% are considered to be low-risk, and those in the 10% to 20% range are 
considered to be intermediate-risk. 
Interventions Medium- or high-intensity behavioral interventions to promote a healthful diet and physical activity may be provided

Interventions Medium- or high-intensity behavioral interventions to promote a healthful diet and physical activity may be provided 
to individual patients in primary care settings or in other sectors of the health care system after referral from a primary 
care clinician. In addition, clinicians may offer healthful diet and physical activity interventions by referring the patient to 
community-based organizations. Strong linkages between the primary care setting and community-based resources may 
improve the delivery of these services. 
Harms The USPSTF concludes with moderate certainty that medium- or high-intensity primary care behavioral counseling 
interventions to promote a healthful diet and physical activity have a small net benefit in adult patients without cardiovascular 
disease, hypertension, hyperlipidemia, or diabetes. 

Recommendations The USPSTF has made recommendations on screening for carotid artery stenosis, coronary heart disease,  
high blood pressure, lipid disorders, peripheral arterial disease, and obesity. These recommendations are available  
at http://www.uspreventiveservicestaskforce.org/ .
 
to http:// www.uspreventiveservicestaskforce.org/ .

36Hearing Loss in Older Adults 
Title Screening for Hearing Loss in Older Adults  
Population Asymptomatic adults aged 50 years or older
Risk Assessment Increasing age is the most important risk factor for hearing loss. Other risk factors include a history of exposure to loud noises 
or ototoxic agents, including occupational exposures, previous recurrent inner ear infections, genetic factors, and certain 
systemic diseases, such as diabetes.
Screening Tests Various screening tests are used in primary care settings to detect hearing loss in adults, including: 
 ●Whispered voice test 
 ●Finger rub test  
 ●Watch tick test  
 ●Single-item screening (for example, asking “Do you have difficulty with your hearing?”)  
 ●Multiple-item patient questionnaire (for example, Hearing Handicap Inventory for the Elderly—Screening Version)  
 ●Handheld audiometer

●Multiple-item patient questionnaire (for example, Hearing Handicap Inventory for the Elderly—Screening Version)  
Interventions Hearing aids can improve self-reported hearing, communication, and social functioning for some adults with age-related 
hearing loss. 
Harms There is inadequate evidence to determine the balance of benefits and harms of screening for hearing loss in adults aged 50 
years or older. 

37Hemochromatosis
Title Screening for Hemochromatosis
Population Asymptomatic general population
RecommendationDo not screen for hereditary hemochromatosis. 
Grade: D
Risk AssessmentClinically recognized hereditary hemochromatosis is primarily associated with mutations on the hemochromatosis ( HFE) 
gene. Although this is a relatively common mutation in the U.S. population, only a small subset will develop symptoms of 
hemochromatosis. An even smaller proportion of these individuals will develop advanced stages of clinical disease.
Screening TestsGenetic screening for HFE mutations can accurately identify individuals at risk for hereditary hemochromatosis. However, 
identifying an individual with the genotypic predisposition does not accurately predict the future risk for disease manifestation.
InterventionsTherapeutic phlebotomy is the main treatment for hereditary hemochromatosis. Phlebotomy is generally thought to have few 

Harms ●Screening could lead to identification of a large number of individuals who possess the high-risk genotype but may never 
manifest the clinical disease. This may result in unnecessary surveillance and diagnostic procedures, labeling, anxiety, 
and, potentially, unnecessary treatments. 
 ●There is poor evidence that early therapeutic phlebotomy improves morbidity and mortality in individuals with screening-
detected versus clinically-detected hemochromatosis. 
 ●The USPSTF concluded that the potential harms of genetic screening for hereditary hemochromatosis outweigh the 
RecommendationsThe USPSTF has also made recommendations on genetic testing for mutations in the breast cancer susceptibility gene to

RecommendationsThe USPSTF has also made recommendations on genetic testing for mutations in the breast cancer susceptibility gene to 
predict breast and ovarian cancer susceptibility. These recommendations are available at  

38Hepatitis B Virus Infection (Pregnant Women)
Title Screening for Hepatitis B Virus Infection in Pregnancy
Population All pregnant women
Recommendation Screen for hepatitis B virus (HBV) at the first prenatal visit. 
Grade: A
Screening TestsSerologic identification of hepatitis B surface antigen (HBsAg).
Reported sensitivity and specificity are greater than 98%. 
Timing of ScreeningOrder HBsAg testing at the first prenatal visit.
Re-screen women with unknown HBsAg status or new or continuing risk factors at admission to hospital, birth center, or 
other delivery setting.
InterventionsAdminister hepatitis B vaccine and hepatitis B immune globulin to HBV-exposed infants within 12 hours of birth.
Refer women who test positive for counseling and medical management.  
Counseling should include information about how to prevent transmission to sexual partners and household contacts. 
Reassure patients that breastfeeding is safe for infants who receive appropriate prophylaxis.

Implementation Establish systems for timely transfer of maternal HBsAg test results to the labor and delivery and newborn medical records.
RecommendationsUSPSTF recommendations on the screening of pregnant women for other infections, including asymptomatic bacteriuria, 
bacterial vaginosis, chlamydia, HIV, and syphilis, can be found at http://www.uspreventiveservicestaskforce.org . 

39Hepatitis C Virus Infection
Title Screening for Hepatitis C Virus Infection in Adults  
Population Persons at high risk for infection and adults born between 1945 and 1965
Recommendation Screen for hepatitis C virus (HCV) infection. 
Grade: B
 
Risk Assessment The most important risk factor for HCV infection is past or current injection drug use. Additional risk factors include receiving a 
blood transfusion before 1992, long-term hemodialysis, being born to an HCV-infected mother, incarceration, intranasal drug 
use, getting an unregulated tattoo, and other percutaneous exposures. 
Adults born between 1945 and 1965 are more likely to be diagnosed with HCV infection, either because they received 
a blood transfusion before the introduction of screening in 1992 or because they have a history of other risk factors for 
exposure decades earlier. 
Screening Tests Anti-HCV antibody testing followed by confirmatory polymerase chain reaction testing accurately identifies patients with

Screening Tests Anti-HCV antibody testing followed by confirmatory polymerase chain reaction testing accurately identifies patients with 
chronic HCV infection. Various noninvasive tests with good diagnostic accuracy are possible alternatives to liver biopsy for 
diagnosing fibrosis or cirrhosis. 
Screening Interval Persons with continued risk for HCV infection (such as injection drug users) should be screened periodically. Evidence on 
how often screening should occur in these persons is lacking. Adults born between 1945 and 1965 and persons who are at 
risk because of potential exposure before universal blood screening need only be screened once. 
Treatment Antiviral treatment prevents long-term health complications of HCV infection (such as cirrhosis, liver failure, and 
hepatocellular carcinoma). 
The combination of pegylated interferon ( a-2a or a-2b) and ribavirin is the standard treatment for HCV infection. In 2011,

The combination of pegylated interferon ( a-2a or a-2b) and ribavirin is the standard treatment for HCV infection. In 2011, 
the U.S. Food and Drug Administration approved the protease inhibitors boceprevir and telaprevir for the treatment of HCV 
genotype 1 infection (the predominant genotype in the United States). 
Harms On the basis of the accuracy of HCV antibody testing and the availability of effective interventions for persons with HCV 
infection, the USPSTF concludes that there is a moderate net benefit to screening in populations at high risk for infection. 
The USPSTF concludes that there is also a moderate net benefit to 1-time screening in all adults in the United States born 
between 1945 and 1965. 
Recommendations The USPSTF has made recommendations on screening for hepatitis B virus infection in adolescents, adults, and pregnant

Recommendations The USPSTF has made recommendations on screening for hepatitis B virus infection in adolescents, adults, and pregnant 
women. These recommendations are available at http://www.uspreventiveservicestaskforce.org/ . 
For a  summary of the ev idence systematically reviewed in making this recommendation, the full recommendation statement, and supporting documents, please go 
to http://www.uspreventi veservicestaskforce.org/ .

40High Blood Pressure in Adults
Title Screening for High Blood Pressure in adults
RecommendationScreen for high blood pressure.
Grade: A
Screening TestsHigh blood pressure (hypertension) is usually defined in adults as: systolic blood pressure (SBP) of 140 mm Hg or higher,  
or diastolic blood pressure (DBP) of 90 mm Hg or higher.
Due to variability in individual blood pressure measurements, it is recommended that hypertension be diagnosed only after 2 
or more elevated readings are obtained on at least 2 visits over a period of 1 to several weeks.
Screening IntervalsThe optimal interval for screening adults for hypertension is not known. 
The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) 
recommends:
 ●Screening every 2 years with BP <120/80.
 ●Screening every year with SBP of 120-139 mmHg or DBP of 80-90 mmHg.

TreatmentA variety of pharmacological agents are available to treat hypertension. JNC 7 guidelines for treatment of hypertension can 
be accessed at http://www.nhlbi.nih.gov/guidelines/hypertension/jncintro.htm . 
The following non-pharmacological therapies are associated with reductions in blood pressure:
 ●Reduction of dietary sodium intake.
 ●Potassium supplementation.
 ●Increased physical activity, weight loss.
 ●Stress management.
 ●Reduction of alcohol intake.
RecommendationsAdults with hypertension should be screened for diabetes. 
Adults should be screened for hyperlipidemia (depending on age, sex, risk factors) and smoking. Clinicians should discuss 
aspirin chemoprevention with patients at increased risk for cardiovascular disease.

1This recommendation applies to adults without known hypertension.

41HIV Infection
Title Screening for HIV  
PopulationAdolescents and adults aged 15 to 65 years, younger adolescents and older adults at increased risk for infection, and 
pregnant women
Recommendation Screen for HIV infection. 
Grade: A
Risk Assessment Men who have sex with men and active injection drug users are at very high risk for new HIV infection. Other persons at high 
risk include those who have acquired or request testing for other sexually transmitted infections. 
Behavioral risk factors for HIV infection include: 
 ●Having unprotected vaginal or anal intercourse 
 ●Having sexual partners who are HIV-infected, bisexual, or injection drug users 
 ●Exchanging sex for drugs or money 
The USPSTF recognizes that the above categories are not mutually exclusive, the degree of sexual risk is on a continuum, 
and individuals may not be aware of their sexual partners’ risk factors for HIV infection.

and individuals may not be aware of their sexual partners’ risk factors for HIV infection. 
Screening Tests The conventional serum test for diagnosing HIV infection is repeatedly reactive immunoassay, followed by confirmatory 
Western blot or immunofluorescent assay. Conventional HIV test results are available within 1 to 2 days from most 
commercial laboratories. 
Rapid HIV testing may use either blood or oral fluid specimens and can provide results in 5 to 40 minutes; however, initial 
positive results require confirmation with conventional methods.
Other U.S. Food and Drug Administration–approved tests for detection and confirmation of HIV infection include combination 
tests (for p24 antigen and HIV antibodies) and qualitative HIV-1 RNA. 
Interventions At present, there is no cure for chronic HIV infection. However, appropriately timed interventions in HIV-positive persons

Interventions At present, there is no cure for chronic HIV infection. However, appropriately timed interventions in HIV-positive persons 
can reduce risks for clinical progression, complications or death from the disease, and disease transmission. Effective 
interventions include antiretroviral therapy (ART) (specifically, the use of combined ART), immunizations, and prophylaxis for 
opportunistic infections. 
Harms The net benefit of screening for HIV infection in adolescents, adults, and pregnant women is substantial. 
Recommendations The USPSTF has made recommendations on behavioral counseling to prevent sexually transmitted infections. This 
recommendation is available at http://www.uspreventiveservicestaskforce.org/ . 

42Illicit Drug Use
Title Screening for Illicit Drug Use
Population Adolescents1, adults, and pregnant women not previously identified as users of illicit drugs
RecommendationNo recommendation.
Grade I: (Insufficient Evidence)
Screening TestsToxicologic tests of blood or urine can provide objective evidence of drug use, but do not distinguish occasional users from 
impaired drug users.
Valid and reliable standardized questionnaires are available to screen adolescents and adults for drug use or misuse.
There is insufficient evidence to evaluate the clinical utility of these instruments when widely applied in primary care settings.
HarmsThe USPSTF concludes that for adolescents, adults, and pregnant women, the evidence is insufficient to determine the 
benefits and harms of screening for illicit drug use.
Suggestions for Practice Clinicians should be alert to the signs and symptoms of illicit drug use in patients.

Treatment More evidence is needed on the effectiveness of primary care office-based treatments for illicit drug use/dependence.
RecommendationsThe USPSTF recommendation for screening and counseling interventions to reduce alcohol misuse by adults and pregnant 
women can be found at http://www.uspreventiveservicestaskforce.org/uspstf/uspsdrin.htm .
1For adolescents, see also Illicit and Prescription Drug Use in Children and Adolescents, Counseling

43Impaired Visual Acuity in Older Adults1
Title Screening for Impaired Visual Acuity in Older Adults1
Population Adults age 65 and older
Recommendation No recommendation.
Risk AssessmentOlder age is an important risk factor for most types of visual impairment. 
Additional risk factors include:
 ●Smoking, alcohol use, exposure to ultraviolet light, diabetes, corticosteroids, and black race (for cataracts).
 ●Smoking, family history, and white race (for age-related macular degeneration).
Screening TestsVisual acuity testing (for example, the Snellen eye chart) is the usual method for screening for impairment of visual acuity in 
the primary care setting.
Screening questions are not as accurate as a visual acuity test.
HarmsThere is no direct evidence that screening for vision impairment in older adults in primary care settings is associated with 
improved clinical outcomes.

There is evidence that early treatment of refractive error, cataracts, and age-related macular degeneration may lead to harms 
that are small.
The magnitude of net benefit for screening cannot be calculated because of a lack of evidence.
RecommendationsRecommendations on screening for glaucoma and on screening for hearing loss in older adults can be accessed at  
1This recommendation does not cover screening for glaucoma.

44Intimate Partner Violence and Elderly Abuse
Title Screening for Intimate Partner Violence and Abuse of Elderly and Vulnerable Adults
Population Asymptomatic women of childbearing age Elderly or vulnerable adults
Recommendation Screen women for intimate partner violence (IPV), 
and provide or refer women who screen positive to 
intervention services. 
Risk Assessment While all women are at potential risk for abuse, factors that elevate risk include young age, substance abuse, marital 
difficulties, and economic hardships. 
Interventions Adequate evidence from randomized trials support a variety of interventions for women of childbearing age that can be 
delivered or referred by primary care, including counseling, home visits, information cards, referrals to community services, 
and mentoring support. Depending on the type of intervention, these services may be provided by clinicians, nurses, social

and mentoring support. Depending on the type of intervention, these services may be provided by clinicians, nurses, social 
workers, nonclinician mentors, or community workers. 
Harms Screening and interventions for IPV in women of 
childbearing age are associated with moderate health 
improvements through the reduction of exposure to abuse, 
physical and mental harms, and mortality. The associated 
harms are deemed no greater than small. Therefore, the 
overall net benefit is moderate. The USPSTF was not able to estimate the magnitude of 
net benefit for screening all elderly or vulnerable adults 
(i.e., adults who are physically or mentally dysfunctional) 
for abuse and neglect because there were no studies on 
the accuracy, effectiveness, or harms of screening in this 
population. 
Recommendations The USPSTF has made recommendations on screening for depression in adults and screening and counseling to reduce

Recommendations The USPSTF has made recommendations on screening for depression in adults and screening and counseling to reduce 
alcohol misuse in adults. These recommendations are available at http://www.uspreventiveservicestaskforce.org/ .

45Lipid Disorders in Adults
Title Screening for Lipid Disorders in Adults
Population ●Men age 35 years and older 
 ●Women age 45 years and older 
who are at increased risk for 
coronary heart disease (CHD) ●Men ages 20 to 35 years who are 
at increased risk for CHD 
 ●Women ages 20 to 45 years who 
are at increased risk for CHD ●Men ages 20 to 35 years 
 ●Women age 20 years and older 
who are not at increased risk for 
CHD
RecommendationScreen for lipid disorders. 
Grade: AScreen for lipid disorders. 
screening
Grade: C
Risk AssessmentConsideration of lipid levels along with other risk factors allows for an accurate estimation of CHD risk. Risk factors for 
CHD include diabetes, history of previous CHD or atherosclerosis, family history of cardiovascular disease, tobacco use, 
hypertension, and obesity (body mass index ≥30 kg/m2).

Screening TestsThe preferred screening tests for dyslipidemia are measuring serum lipid (total cholesterol, high-density and low-denisty 
lipoprotein cholesterol) levels in non-fasting or fasting samples. Abnormal screening results should be confirmed by a 
repeated sample on a separate occasion, and the average of both results should be used for risk assessment.
Timing of ScreeningThe optimal interval for screening is uncertain. Reasonable options include every 5 years, shorter intervals for people 
who have lipid levels close to those warranting therapy, and longer intervals for those not at increased risk who have had 
repeatedly normal lipid levels.
An age at which to stop screening has not been established. Screening may be appropriate in older people who have never

An age at which to stop screening has not been established. Screening may be appropriate in older people who have never 
been screened; repeated screening is less important in older people because lipid levels are less likely to increase after age 
65 years.
InterventionsDrug therapy is usually more effective than diet alone in improving lipid profiles, but choice of treatment should consider 
overall risk, costs of treatment, and patient preferences. Guidelines for treating lipid disorders are available from the National 
Cholesterol Education Program of the National Institutes of Health ( http://www.nhlbi.nih.gov/about/ncep/ ).
Balance of Benefits and HarmsThe benefits of screening for and 
treating lipid disorders in men age 35 
and older and women age 45 and older 
at increased risk for CHD substantially 
outweigh the potential harms.The benefits of screening for and 
treating lipid disorders in young adults 
at increased risk for CHD moderately

at increased risk for CHD moderately 
outweigh the potential harms.The net benefits of screening for 
lipid disorders in young adults not at 
increased risk for CHD are not sufficient 
to make a general recommendation.
RecommendationsThe USPSTF has made recommendations on screening for lipid disorders in children and screening for carotid artery 
stenosis, coronary heart disease, high blood pressure, and peripheral arterial disease. These recommendations are available 

46Lung Cancer
Title Screening for Lung Cancer
PopulationAsymptomatic adults aged 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit 
smoking within the past 15 years
RecommendationScreen annually for lung cancer with low-dose computed tomography. 
Discontinue screening when the patient has not smoked for 15 years.
Grade: B
Risk AssessmentAge, total cumulative exposure to tobacco smoke, and years since quitting smoking are the most important risk factors 
for lung cancer. Other risk factors include specific occupational exposures, radon exposure, family history, and history of 
pulmonary fibrosis or chronic obstructive lung disease.
Screening TestsLow-dose computed tomography has high sensitivity and acceptable specificity for detecting lung cancer in high-risk persons 
and is the only currently recommended screening test for lung cancer.

Treatment Non–small cell lung cancer is treated with surgical resection when possible and also with radiation and chemotherapy.
Harms Annual screening for lung cancer with low-dose computed tomography is of moderate net benefit in asymptomatic persons 
who are at high risk for lung cancer based on age, total cumulative exposure to tobacco smoke, and years since quitting 
smoking.
RecommendationsThe USPSTF has made recommendations on counseling and interventions to prevent tobacco use and tobacco-caused 
disease. These recommendations are available at http://www.uspreventiveservicestaskforce.org/ .

47Menopausal Hormone Therapy 
Title Menopausal Hormone Therapy for the Primary Prevention of Chronic Conditions 
Population Postmenopausal women Postmenopausal women who have had a hysterectomy
Recommendation Do not prescribe combined estrogen and progestin for 
the prevention of chronic conditions. 
Grade: D Do not prescribe estrogen for the prevention of chronic 
Grade: D
 
Risk Assessment This recommendation applies to the average-risk population. Risk factors for a specific chronic disease or individual 
characteristics that affect the likelihood of a specific therapy-associated adverse event may cause a woman’s net balance of 
benefits and harms to differ from that of the average population. 
Preventive Medications Although combined estrogen and progestin therapy (specifically, oral conjugated equine estrogen, 0.625 mg/d, plus 
medroxyprogesterone acetate, 2.5 mg/d) decreases the risk for fractures in postmenopausal women, there is an

medroxyprogesterone acetate, 2.5 mg/d) decreases the risk for fractures in postmenopausal women, there is an 
accompanying increased risk for serious adverse events, such as stroke, invasive breast cancer, dementia, gallbladder 
disease, deep venous thrombosis, and pulmonary embolism. 
Estrogen therapy (specifically, oral conjugated equine estrogen, 0.625 mg/d) decreases the risk for fractures and has a small 
effect on the risk for invasive breast cancer, but it is also associated with important harms, such as an increased likelihood of 
stroke, deep venous thrombosis, and gallbladder disease. 
Neither combined estrogen and progestin therapy nor estrogen alone reduces the risk for coronary heart disease in 
postmenopausal women. 
Harms The chronic disease prevention benefits of combined 
estrogen and progestin do not outweigh the harms in most 
postmenopausal women. The chronic disease prevention benefits of estrogen are

postmenopausal women. The chronic disease prevention benefits of estrogen are 
unlikely to outweigh the harms in most postmenopausal 
women who have had a hysterectomy. 
Recommendations The USPSTF has made recommendations on screening for osteoporosis and the use of preventive medications for breast 
cancer, as well as other relevant interventions for the primary or secondary prevention of chronic diseases in women,  
such as medications for cardiovascular disease and screening for coronary heart disease, high blood pressure, lipid 
disorders, colorectal cancer, breast cancer, and dementia. These recommendations are available at  
 
For a summary of the evidence systematically reviewed in making this recommendation, the full recommendation statement, and supporting documents, please go

48Motor Vehicle Occupant Restraints
Title Primary Care Counseling for Proper Use of Motor Vehicle Occupant Restraints
Population General primary care population
InterventionsThere is good evidence that community and public health interventions, including legislation, law enforcement campaigns, 
car seat distribution campaigns, media campaigns, and other community-based interventions, are effective in improving the 
proper use of car seats, booster seats, and seat belts.
Suggestions for PracticeCurrent evidence is insufficient to assess the incremental benefit of counseling in primary care settings, beyond increases 
related to other interventions, in improving rates of proper use of motor vehicle occupant restraints.
Linkages between primary care and community interventions are critical for improving proper car seat, booster seat, and seat 
belt use. 
Relevant Recommendations 
from the Guide to Community

belt use. 
from the Guide to Community 
Preventive Services The Community Preventive Services Task Force has reviewed evidence of the effectiveness of selected population-based 
interventions to reduce motor vehicle occupant injuries, focusing on three strategic areas: 
 ●Increasing the proper use of child safety seats.
 ●Increasing the use of safety belts.
 ●Reducing alcohol-impaired driving.
Multiple interventions in these areas have been recommended. Recommendations can be accessed at  
http://www.thecommunityguide.org/mvoi/

49Obesity in Adults
Title Screening for and Management Of Obesity In Adults  
Population Adults aged 18 years or older
Recommendation Screen for obesity. Patients with a body mass index (BMI) of 30 kg/m2 or higher should be offered or referred to 
intensive, multicomponent behavioral interventions. 
Grade: B
 
Screening Tests Body mass index is calculated from the measured weight and height of an individual. Recent evidence suggests that waist 
circumference may be an acceptable alternative to BMI measurement in some patient subpopulations. 
Timing of Screening No evidence was found about appropriate intervals for screening. 
Interventions Intensive, multicomponent behavioral interventions for obese adults include the following components: 
 ●Behavioral management activities, such as setting weight-loss goals 
 ●Improving diet or nutrition and increasing physical activity 
 ●Addressing barriers to change 
 ●Self-monitoring 
 ●Strategizing how to maintain lifestyle changes

●Improving diet or nutrition and increasing physical activity 
 ●Strategizing how to maintain lifestyle changes 
Harms Adequate evidence indicates that intensive, multicomponent behavioral interventions for obese adults can lead to weight loss, 
as well as improved glucose tolerance and other physiologic risk factors for cardiovascular disease. 
Inadequate evidence was found about the effectiveness of these interventions on long-term health outcomes (for example, 
mortality, cardiovascular disease, and hospitalizations). 
Adequate evidence indicates that the harms of screening and behavioral interventions for obesity are small. Possible harms 
of behavioral weight-loss interventions include decreased bone mineral density and increased fracture risk, serious injuries 
resulting from increased physical activity, and increased risk for eating disorders.
Other relevant USPSTF

Other relevant USPSTF 
recommendations Recommendations on screening for obesity in children and adolescents can be found at  

50Oral Cancer 
Title Screening for Oral Cancer 
Population Asymptomatic adults aged 18 years or older
 
Risk Assessment The primary risk factors for oral cancer are tobacco and alcohol use. Additional risk factors include male sex, older age, use 
of betel quid, ultraviolet light exposure, infection with Candida  or bacterial flora, and a compromised immune system. 
Recently, sexually transmitted oral human papillomavirus infection has been recognized as an increasing risk factor for 
oropharyngeal cancer, another subset of head and neck cancer. 
Screening Tests The primary screening test for oral cancer is a systematic clinical examination, including inspection and palpation of the  
oral cavity. 
Treatment Suspected oral cancer or its precursors detected on examination require confirmation by tissue biopsy. Treatment for screen-
detected oral cancer includes surgery, radiotherapy, and chemotherapy.

detected oral cancer includes surgery, radiotherapy, and chemotherapy. 
Harms The USPSTF found inadequate evidence on the diagnostic accuracy, benefits, and harms of screening for oral cancer. 
Therefore, the USPSTF cannot determine the balance of benefits and harms of screening for oral cancer in asymptomatic 
adults. 
Recommendations The USPSTF has made recommendations on counseling to prevent tobacco use and screening for and counseling to reduce 
alcohol misuse. These recommendations are available at http://www.uspreventiveservicestaskforce.org/ . 

51Osteoporosis
Title Screening for Osteoporosis
PopulationWomen age ≥65 years without 
previous known fractures or secondary 
causes of osteoporosisWomen age <65 years whose 10-year 
fracture risk is equal to or greater than 
that of a 65-year-old white woman 
without additional risk factorsMen without previous known fractures 
or secondary causes of osteoporosis
Recommendation Screen for osteoporosis.
Grade: BNo recommendation.
Risk AssessmentAs many as 1 in 2 postmenopausal women and 1 in 5 older men are at risk for an osteoporosis-related fracture. 
Osteoporosis is common in all racial groups but is most common in white persons. Rates of osteoporosis increase with age. 
Elderly people are particularly susceptible to fractures. According to the FRAX fracture risk assessment tool, available at 
http://www.shef.ac.uk/FRAX/ , the 10-year fracture risk in a 65-year-old white woman without additional risk factors is 9.3%.

http://www.shef.ac.uk/FRAX/ , the 10-year fracture risk in a 65-year-old white woman without additional risk factors is 9.3%. 
Screening Tests Current diagnostic and treatment criteria rely on dual-energy x-ray absorptiometry of the hip and lumbar spine. 
Timing of Screening Evidence is lacking about optimal intervals for repeated screening. 
InterventionIn addition to adequate calcium and vitamin D intake and weight-bearing exercise, multiple U.S. Food and Drug 
Administration–approved therapies reduce fracture risk in women with low bone mineral density and no previous fractures, 
including bisphosphonates, parathyroid hormone, raloxifene, and estrogen. The choice of treatment should take into 
account the patient’s clinical situation and the tradeoff between benefits and harms. Clinicians should provide education 
about how to minimize drug side effects. 
Suggestions for Practice 
Regarding the I Statement for 
MenClinicians should consider:

 ●potential preventable burden: increasing because of the aging of the U.S. population
 ●potential harms: likely to be small, mostly opportunity costs
 ●current practice: routine screening of men not widespread
 ●costs: additional scanners required to screen sizeable populations
Men most likely to benefit from screening have a 10-year risk for osteoporotic fracture equal to or greater than that of a 
65-year-old white woman without risk factors. However, current evidence is insufficient to assess the balance of benefits 
and harms of screening for osteoporosis in men.

52Ovarian Cancer 
Title Screening for Ovarian Cancer  
Population Asymptomatic women without known genetic mutations that increase risk for ovarian cancer
Recommendation Do not screen for ovarian cancer. 
Grade: D
 
Risk Assessment Women with BRCA1  and BRCA2  genetic mutations, the Lynch syndrome (hereditary nonpolyposis colon cancer), or a family 
history of ovarian cancer are at increased risk for ovarian cancer. 
Women with an increased-risk family history should be considered for genetic counseling to further evaluate their potential 
risks. “Increased-risk family history” generally means having 2 or more first- or second-degree relatives with a history of 
ovarian cancer or a combination of breast and ovarian cancer; for women of Ashkenazi Jewish descent, it means having a 
first-degree relative (or 2 second-degree relatives on the same side of the family) with breast or ovarian cancer.

first-degree relative (or 2 second-degree relatives on the same side of the family) with breast or ovarian cancer. 
Screening Tests Transvaginal ultrasonography and serum cancer antigen (CA)–125 testing are the most commonly suggested screening 
modalities. 
Treatments Treatment of ovarian carcinoma includes surgical treatment (debulking) and intraperitoneal or systemic chemotherapy. 
Harms Annual screening with transvaginal ultrasonography and serum CA-125 testing in women does not decrease ovarian cancer 
mortality. Screening for ovarian cancer can lead to important harms, including major surgical interventions in women who do 
not have cancer. Therefore, the harms of screening for ovarian cancer outweigh the benefits. 
Recommendations The USPSTF has made a recommendation on genetic risk assessment and BRCA mutation testing for breast and ovarian

Recommendations The USPSTF has made a recommendation on genetic risk assessment and BRCA mutation testing for breast and ovarian 
cancer susceptibility. This recommendation is available at http://www.uspreventiveservicestaskforce.org/ .
 
53Peripheral Artery Disease
Title Screening for Peripheral Artery Disease and Cardiovascular Disease Risk Assessment with the Ankle Brachial Index 
in Adults  
PopulationAsymptomatic adults without a known diagnosis of peripheral artery disease (PAD), cardiovascular disease,  
severe chronic kidney disease, or diabetes
Risk Assessment Important risk factors for PAD include older age, diabetes, smoking, hypertension, high cholesterol level, obesity, and physical 
inactivity. Peripheral artery disease is more common in men than women and occurs at an earlier age in men. 
Screening Tests Resting ankle–brachial index (ABI) is the most commonly used test in screening for and detection of PAD in clinical 
settings. It is calculated as the systolic blood pressure obtained at the ankle divided by the systolic blood pressure obtained

settings. It is calculated as the systolic blood pressure obtained at the ankle divided by the systolic blood pressure obtained 
at the brachial artery while the patient is lying down. Physical examination has low sensitivity for detecting mild PAD in 
asymptomatic persons. 
Harms Evidence on screening for PAD with the ABI in asymptomatic adults with no known diagnosis of cardiovascular disease or 
diabetes is insufficient; therefore, the balance of benefits and harms cannot be determined. 
Recommendations The USPSTF has made recommendations on using nontraditional risk factors, including the ABI, in screening for coronary 
heart disease. These recommendations are available at http://www.uspreventiveservicestaskforce.org/ .
 
54Prostate Cancer 
Title Screening for Prostate Cancer 
Population Adult males
Recommendation Do not use prostate-specific antigen (PSA)-based screening for prostate cancer. 
Grade: D
 
Screening Tests Contemporary recommendations for prostate cancer screening all incorporate the measurement of serum PSA levels; other 
methods of detection, such as digital rectal examination or ultrasonography, may be included. 
There is convincing evidence that PSA-based screening programs result in the detection of many cases of asymptomatic 
prostate cancer, and that a substantial percentage of men who have asymptomatic cancer detected by PSA screening have 
a tumor that either will not progress or will progress so slowly that it would have remained asymptomatic for the man’s lifetime 
(i.e., PSA-based screening results in considerable overdiagnosis). 
Interventions Management strategies for localized prostate cancer include watchful waiting, active surveillance, surgery, and radiation 
therapy.

therapy. 
There is no consensus regarding optimal treatment. 
HarmsThe reduction in prostate cancer mortality 10 to 14 years after PSA-based screening is, at most, very small, even for men in 
the optimal age range of 55 to 69 years. 
The harms of screening include pain, fever, bleeding, infection, and transient urinary difficulties associated with prostate 
biopsy, psychological harm of false-positive test results, and overdiagnosis. 
Harms of treatment include erectile dysfunction, urinary incontinence, bowel dysfunction, and a small risk for premature 
death. Because of the current inability to reliably distinguish tumors that will remain indolent from those destined to be lethal, 
many men are being subjected to the harms of treatment for prostate cancer that will never become symptomatic.

many men are being subjected to the harms of treatment for prostate cancer that will never become symptomatic. 
The benefits of PSA-based screening for prostate cancer do not outweigh the harms. 
Recommendations Recommendations on screening for other types of cancer can be found at http://www.uspreventiveservicestaskforce.org/ .
 
go to http://www.uspreventiveservicestaskforce.org/ .

55Sexually Transmitted Infections
Title Behavioral Counseling to Prevent Sexually Transmitted Infections
Population All sexually active adolescents Adults at increased risk for STIsNon-sexually-active adolescents and 
adults not at increased risk for STIs
RecommendationOffer high-intensity counseling.
Grade: B Offer high-intensity counseling.
Risk AssessmentAll sexually active adolescents are at increased risk for STIs and should be offered counseling.
Adults should be considered at increased risk and offered counseling if they have:
 ●Current STIs or have had an STI within the past year.
 ●Multiple sexual partners.
In communities or populations with high rates of STIs, all sexually active patients in non-monogamous relationships may be 
considered at increased risk. 
InterventionsCharacteristics of successful high-intensity counseling interventions: 
 ●Multiple sessions of counseling.

 ●Frequently delivered in group settings.
Suggestions for PracticeHigh-intensity counseling may be delivered in primary care settings, or in other 
sectors of the health system and community settings after referral.  
 
Delivery of this service may be greatly improved by strong linkages between the 
primary care setting and community. Evidence is limited regarding 
counseling for adolescents who 
are not sexually active. Intensive 
counseling for all adolescents in order 
to reach those who are at risk but 
have not been appropriately identified 
is not supported by current evidence. 
Evidence is lacking regarding the 
effectiveness of counseling for adults 
not at increased risk for STIs.

Recommendations USPSTF recommendations on screening for chlamydial infection, gonorrhea, genital herpes, hepatitis B, hepatitis C, HIV, 
and syphilis can be found at http://www.uspreventiveservicestaskforce.org .
Abbreviation:  STI = Sexually Transmitted Infection

56Skin Cancer (Counseling)
Title Behavioral Counseling to Prevent Skin Cancer  
PopulationChildren, adolescents, and young adults aged 10 to 24 years 
with fair skinAdults older than age 24 years
Recommendation Provide counseling about minimizing exposure to 
ultraviolet radiation to reduce risk for skin cancer.
 
Risk Assessment Individuals with a fair skin type are at greatly increased risk for skin cancer. Fair skin type can be defined by eye and hair 
color; freckling; and historical factors, such as usual reaction to sun exposure (always or usually burning or infrequently 
tanning). 
Behavioral Counseling Effective counseling interventions were generally of low intensity and almost entirely accomplished within the primary care 
visit. 
Successful counseling interventions used cancer prevention or appearance-focused messages (such as stressing the aging

visit. 
Successful counseling interventions used cancer prevention or appearance-focused messages (such as stressing the aging 
effect of ultraviolet radiation on the skin) to reach specific audiences. 
Interventions Behavior change interventions are aimed at reducing ultraviolet radiation exposure. Sun-protective behaviors include the use 
of a broad-spectrum sunscreen with a sun protection factor ≥ 15, wearing hats or other shade-protective clothing, avoiding 
the outdoors during midday hours (10 a.m. to 3 p.m.), and avoiding the use of indoor tanning. 
Harms For children, adolescents, and young adults aged 10 to 24 
years with fair skin, primary care counseling interventions 
can increase the use of sun-protective behaviors by a 
moderate amount, with no appreciable harms. For adults older than 24 years, there is inadequate evidence 
to determine the effect of counseling on the use of sun-
protective behaviors. 

Recommendations The USPSTF has made recommendations on screening for skin cancer. These recommendations are available  
 
57Skin Cancer (Screening)
Title Screening for Skin Cancer
Risk AssessmentSkin cancer risks: family history of skin cancer, considerable history of sun exposure and sunburn.
Groups at increased risk for melanoma: 
 ●Fair-skinned men and women over the age of 65 years.
 ●Patients with atypical moles.
 ●Patients with more than 50 moles.
Screening TestsThere is insufficient evidence to assess the balance of benefits and harms of whole body skin examination by a clinician or 
patient skin self-examination for the early detection of skin cancer.
Suggestions for PracticeClinicians should remain alert for skin lesions with malignant features that are noted while performing physical examinations 
for other purposes. Features associated with increased risk for malignancy include: asymmetry, border irregularity, color

for other purposes. Features associated with increased risk for malignancy include: asymmetry, border irregularity, color 
variability, diameter >6mm (“A,” “B,” “C,” “D”), or rapidly changing lesions. Suspicious lesions should be biopsied. 
USPSTF and the Community 
Preventive Services Task 
ForceThe USPSTF has reviewed the evidence for counseling to prevent skin cancer. The recommendation statement and 
supporting documents can be accessed at http://www.uspreventiveservicestaskforce.org .
The Community Preventive Services Task Force has reviewed the evidence on public health interventions to reduce skin 
cancer. The recommendations can be accessed at http://www.thecommunityguide.org .
1The USPSTF does not examine outcomes related to surveillance of patients with familial syndromes, such as familial atypical mole and melanoma (FAM-M) syndrome.

58Suicide Risk
Title Screening for Suicide Risk
Population General population
Risk AssessmentThe strongest risk factors for attempted suicide include mood disorders or other mental disorders, comorbid substance 
abuse disorders, history of deliberate self-harm, and a history of suicide attempts. Deliberate self-harm refers to intentionally 
initiated acts of self-harm with a nonfatal outcome (including self-poisoning and self-injury). Suicide risk is assessed along a 
continuum ranging from suicidal ideation alone (relatively less severe) to suicidal ideation with a plan (more severe). Suicidal 
ideation with a specific plan of action is associated with a significant risk for attempted suicide.
Screening TestsThere is limited evidence on the accuracy of screening tools to identify suicide risk in the primary care setting, including

Screening TestsThere is limited evidence on the accuracy of screening tools to identify suicide risk in the primary care setting, including 
tools to identify those at high risk. The characteristics of the most commonly used screening instruments (Scale for Suicide 
Ideation, Scale for Suicide Ideation–Worst, and the Suicidal Ideation Questionnaire) have not been validated to assess 
suicide risk in primary care settings. 
InterventionsThere is insufficient evidence to determine if treatment of persons at high risk for suicide reduces suicide attempts or 
mortality.
HarmsThere is no evidence that screening for suicide risk reduces suicide attempts or mortality. There is insufficient evidence to 
determine if treatment of persons at high risk reduces suicide attempts or mortality. There are no studies that directly address 
the harms of screening and treatment for suicide risk.

the harms of screening and treatment for suicide risk. 
As a result, the USPSTF could not determine the balance of benefits and harms of screening for suicide risk in the primary 
care setting.
RecommendationsThe USPSTF has also made recommendations on screening for alcohol misuse, depression, and illicit drug use. These 
recommendations are available at http://www.uspreventiveservicestaskforce.org/ .

59Syphilis (Pregnant Women)
Title Screening for Syphilis Infection in Pregnancy  
Recommendation Screen for syphilis infection. 
Grade: A 
Screening TestsNontreponemal tests commonly used for initial screening include:
 ●Venereal Disease Research Laboratory (VDRL) 
 ●Rapid Plasma Reagin (RPR)
Confirmatory tests include:
 ●Fluorescent treponemal antibody absorbed (FTA-ABS)
 ●Treponema pallidum  particle agglutination (TPPA)
Timing of Screening Test all pregnant women at the first prenatal visit.
Other Clinical ConsiderationsMost organizations recommend testing high-risk women again during the third trimester and at delivery. Groups at increased 
risk include:
 ●Uninsured women
 ●Women living in poverty
 ●Sex workers
 ●Illicit drug users
 ●Those diagnosed with other sexually transmitted infections (STIs)
 ●Other women living in communities with high syphilis morbidity

●Women living in poverty
Prevalence is higher in southern U.S. and in metropolitan areas and in Hispanic and African American populations.
InterventionsThe Centers for Disease Control and Prevention (CDC) recommends treatment with parenteral benzathine penicillin G. 
Women with penicillin allergies should be desensitized and treated with penicillin.
Consult the CDC for the most up-to-date recommendations: http://www.cdc.gov/std/treatment/ .
RecommendationsRecommendations on screening for other STIs, and on counseling for STIs, can be found at  
http://www.uspreventiveservicestaskforce.org . 

60Testicular Cancer
Title Screening for Testicular Cancer
Population Adolescent and adult males
Grade: D
Screening TestsThere is inadequate evidence that screening asymptomatic patients by means of self-examination or clinician examination 
has greater yield or accuracy for detecting testicular cancer at more curable stages.
InterventionsManagement of testicular cancer consists of orchiectomy and may include other surgery, radiation therapy, or chemotherapy, 
depending on stage and tumor type. Regardless of disease stage, over 90% of all newly diagnosed cases of testicular cancer 
will be cured.
HarmsScreening by self-examination or clinician examination is unlikely to offer meaningful health benefits, given the very low 
incidence and high cure rate of even advanced testicular cancer. 
Potential harms include false-positive results, anxiety, and harms from diagnostic tests or procedures.

Recommendations Recommendations on screening for other types of cancer can be found at http://www.uspreventiveservicestaskforce.org . 

61Tobacco Use in Adults
TitleCounseling and Interventions to Prevent Tobacco Use and Tobacco-Caused Disease  
in Adults and Pregnant Women
Population Adults age ≥ 18 years Pregnant women of any age
Recommendation Ask about tobacco use. Provide tobacco cessation 
interventions to those who use tobacco products. 
Grade: A Ask about tobacco use. Provide augmented 
pregnancy-tailored counseling for women who smoke. 
Grade: A 
CounselingThe “5-A” framework provides a useful counseling strategy:
1. Ask about tobacco use.
2. Advise to quit through clear personalized messages.
3. Assess willingness to quit.
4. Assist to quit.
5. Arrange fol low-up and support.
Intensity of counseling matters: brief one-time counseling works; however, longer sessions or multiple sessions are more 
Telephone counseling “quit lines” also improve cessation rates.
PharmacotherapyCombination therapy with counseling and medications 
is more effective than either component alone. FDA-

approved pharmacotherapy includes nicotine replacement 
therapy, sustained-release bupropion, and varenicline.The USPSTF found inadequate evidence to evaluate the 
safety or efficacy of pharmacotherapy during pregnancy.
ImplementationSuccessful implementation strategies for primary care practice include:
 ●Instituting a tobacco user identification system.
 ●Promoting clinician intervention through education, resources, and feedback.
 ●Dedicating staff to provide treatment, and assessing the delivery of treatment in staff performance evaluations.
Recommendations Recommendations on other behavioral counseling topics are available at http://www.uspreventiveservicestaskforce.org .

Abbreviations:  FDA = U.S. Food and Drug Administration; USPSTF = U.S. Preventive Services Task Force

62Vitamin D and Calcium Supplementation to Prevent Fractures
Title Vitamin D and Calcium Supplementation to Prevent Fractures in Adults
Population Men or premenopausal womenCommunity-dwelling postmenopausal 
women at doses of >400 IU of vitamin 
D3 and >1,000 mg of calciumCommunity-dwelling postmenopausal 
women at doses of ≤400 IU of vitamin D3 
and ≤1,000 mg of calcium
Grade: I (Insufficient Evidence)No recommendation. 
Grade: I (Insufficient Evidence)Do not supplement. 
Grade: D recommendation 
Preventive Medications Appropriate intake of vitamin D and calcium are essential to overall health. However, there is inadequate evidence 
to determine the effect of combined vitamin D and calcium supplementation on the incidence of fractures in men or 
premenopausal women. 
There is adequate evidence that daily supplementation with 400 IU of vitamin D3 and 1,000 mg of calcium has no effect on 
the incidence of fractures in postmenopausal women.

There is inadequate evidence regarding the effect of higher doses of combined vitamin D and calcium supplementation on 
fracture incidence in community-dwelling postmenopausal women. 
Harms Evidence is lacking regarding the 
benefit of daily vitamin D and calcium 
supplementation for the primary 
prevention of fractures, and the 
balance of benefits and harms cannot 
be determined. Evidence is lacking regarding the 
benefit of daily supplementation with 
>400 IU of vitamin D3 and >1,000 mg 
of calcium for the primary prevention 
of fractures in postmenopausal 
women, and the balance of benefits 
and harms cannot be determined.Daily supplementation with ≤400 IU of 
vitamin D3 and ≤1,000 mg of calcium has 
no net benefit for the primary prevention of 
fractures.

Recommendations The USPSTF has made recommendations on screening for osteoporosis and vitamin D supplementation to prevent falls in 
community-dwelling older adults. These recommendations are available at http://www.uspreventiveservicestaskforce.org/ .
 
63Vitamin Supplementation to Prevent Cardiovascular Disease and Cancer
Title Vitamin, Mineral, and Multivitamin Supplements for the Primary Prevention of Cardiovascular Disease and Cancer
PopulationHealthy adults without special nutritional needs. This recommendation does not apply to children, women who are pregnant 
or may become pregnant, or persons who are chronically ill or hospitalized or have a known nutritional deficiency.
RecommendationMultivitamins: No recommendation.
Grade: I statementSingle- or paired-nutrient 
supplements: No recommendation.
Grade: I statementβ-carotene or vitamin E: Do not 
recommend. 
Grade: D
Preventive MedicationsEvidence on supplementation with multivitamins to reduce the risk for cardiovascular disease or cancer is inadequate, as is 
the evidence on supplementation with individual vitamins, minerals, or functional pairs. 
Supplementation with β-carotene or vitamin E does not reduce the risk for cardiovascular disease or cancer.

HarmsThe evidence is insufficient to determine 
the balance of benefits and harms of 
supplementation with multivitamins for 
the prevention of cardiovascular disease 
or cancer.The evidence is insufficient to 
determine the balance of benefits and 
harms of supplementation with single 
or paired nutrients for the prevention of 
cardiovascular disease or cancer.There is no net benefit of 
supplementation with vitamin E or 
β-carotene for the prevention of 
cardiovascular disease or cancer.
RecommendationsThe USPSTF has made several recommendations on the prevention of cardiovascular disease and cancer, including 
recommendations for smoking cessation; screening for lipid disorders, hypertension, diabetes, and cancer; obesity screening

recommendations for smoking cessation; screening for lipid disorders, hypertension, diabetes, and cancer; obesity screening 
and counseling; and aspirin use. These recommendations are available at http://www.uspreventiveservicestaskforce.org/ .

Clinical Summaries 
of Recommendations 
for Children and 

67Blood Lead Levels in Children and Pregnant Women
Title Screening for Elevated Blood Lead Levels in Children and Pregnant Women
PopulationAsymptomatic children ages 1 to 5 
years who are at increased riskAsymptomatic children ages 1 to 5 
years who are at average riskAsymptomatic pregnant women
Grade: I (Insufficient Evidence)Do not screen for elevated blood 
lead levels. 
Grade: DDo not screen for elevated blood 
Grade: D
Risk AssessmentChildren younger than age 5 years are at greater risk for elevated blood lead levels and lead toxicity because of increased 
hand-to-mouth activity, increased lead absorption from the gastrointestinal tract, and the greater vulnerability of the 
developing central nervous system.
Risk factors for increased blood lead levels in children and adults include: minority race/ethnicity; urban residence; low

Risk factors for increased blood lead levels in children and adults include: minority race/ethnicity; urban residence; low 
income; low educational attainment; older (pre-1950) housing; recent or ongoing home renovation or remodeling; pica; use of 
ethnic remedies, certain cosmetics, and exposure to lead-glazed pottery; occupational exposure; and recent immigration.
Additional risk factors for pregnant women include alcohol use and smoking.
Screening TestsVenous sampling accurately detects elevated blood lead levels. Screening questionnaires may be of value in identifying 
children at risk for elevated blood lead levels, but should be tailored for and validated in specific communities for clinical use.
InterventionsTreatment options for elevated blood lead levels include residential lead hazard-control efforts (i.e., counseling and 
education, dust or paint removal, and soil abatement), chelation, and nutritional interventions.

Community-based interventions for the prevention of lead exposure are likely to be more effective, and may be more cost-
effective, than office-based screening, treatment, and counseling. Relocating children who do not yet have elevated blood 
lead levels but who live in settings with high lead exposure may be especially helpful. 
HarmsThere is not enough evidence to 
assess the balance between the 
potential benefits and harms of routine 
screening for elevated blood lead 
levels in children at increased risk.Given the significant potential harms 
of treatment and residential lead 
hazard abatement, and no evidence 
of treatment benefit, the harms of 
levels in children at average risk 
outweigh the benefits.Given the significant potential harms 
hazard abatement, and no evidence

screening for elevated blood lead levels 
in asymptomatic pregnant women 
outweigh the benefits.

68Child Maltreatment
Title Primary Care Interventions to Prevent Child Maltreatment  
Population Children and adolescents aged 0 to 18 years without signs or symptoms of maltreatment
Risk Assessment There are numerous risk factors associated with child maltreatment, including but not limited to: 
 ●Young, single, or nonbiological parents 
 ●Parental lack of understanding of childrenís needs, child development, or parenting skills 
 ●Poor parent–child relationships/negative interactions 
 ●Parental thoughts or emotions that support maltreatment behaviors 
 ●Family dysfunction or violence 
 ●Parental history of abuse or neglect in family of origin 
 ●Substance abuse within the family 
 ●Social isolation, poverty, or other socioeconomic disadvantages 
 ●Parental stress and distress
Interventions Although the evidence is insufficient to recommend specific preventive interventions, most child maltreatment prevention

●Parental stress and distress
Interventions Although the evidence is insufficient to recommend specific preventive interventions, most child maltreatment prevention 
programs focus on home visitation. Home visitation programs usually comprise a combination of services provided by a nurse 
or paraprofessional in the family’s home on a regularly scheduled basis; most programs are targeted to families with young 
children and often begin in the prenatal or postnatal period. 
Harms The evidence on interventions in primary care to prevent child maltreatment among children without signs or symptoms of 
maltreatment is insufficient, and the balance of benefits and harms cannot be determined. 
Recommendations The USPSTF has made recommendations on screening for intimate partner violence and abuse of elderly and vulnerable 
adults. These recommendations are available at http://www.uspreventiveservicestaskforce.org/ .

adults. These recommendations are available at http://www.uspreventiveservicestaskforce.org/ . 

69Congenital Hypothyroidism
Title Screening for Congenital Hypothyroidism
Population All newborn infants1
RecommendationScreen for congenital hypothyroidism.
Grade: A 
Screening TestsTwo methods of screening are used most frequently in the United States:
 ●Primary TSH with backup T4.
 ●Primary T4 with backup TSH.
Screening for congenital hypothyroidism (CH) is mandated in all 50 states and the District of Columbia.
Clinicians should become familiar with the tests used in their area and the limitations of the screening strategies employed.
Timing of ScreeningInfants should be tested between 2 and 4 days of age.
Infants discharged from hospitals before 48 hours of life should be tested immediately before discharge.  
Specimens obtained in the first 24-48 hours of age may be falsely elevated for TSH regardless of the screening method 
used.
Suggestions for PracticeInfants with abnormal screens should receive confirmatory testing and begin appropriate treatment with thyroid hormone

used.
Suggestions for PracticeInfants with abnormal screens should receive confirmatory testing and begin appropriate treatment with thyroid hormone 
replacement within 2 weeks after birth.
Children with positive confirmatory testing in whom no permanent cause of CH is found should undergo a 30-day trial of 
reduced or discontinued thyroid hormone replacement therapy to determine if the hypothyroidism is permanent or transient. 
This trial of reduced or discontinued therapy should take place at some time after the child reaches 3 years of age.
USPSTFAdditional USPSTF recommendations regarding screening tests for newborns can be accessed at:  
http://www.uspreventiveservicestaskforce.org/recommendations.htm#pediatric
1This recommendation applies to all infants born in the U.S. Premature, very low birth weight and ill infants may benefit from additional screening. These conditions are associated with decreased sensitivity and specificity

of screening tests.

70Developmental Dysplasia of the Hip
Title Screening for Developmental Dysplasia of the Hip
Population Infants who do not have obvious hip dislocations or other abnormalities evident without screening
Risk AssessmentRisk factors for developmental dysplasia of the hip include female sex, family history, breech positioning, and in utero 
postural deformities. However, the majority of cases of developmental dysplasia of the hip have no identifiable risk factors.
Screening TestsScreening tests for developmental dysplasia of the hip have limited accuracy. The most common methods of screening are 
serial physical examinations of the hip and lower extremities, using the Barlow and Ortolani procedures, and ultrasonography.  
InterventionsTreatments for developmental dysplasia of the hip include both nonsurgical and surgical options. Nonsurgical treatment with

InterventionsTreatments for developmental dysplasia of the hip include both nonsurgical and surgical options. Nonsurgical treatment with 
abduction devices is used as early treatment and includes the commonly prescribed Pavlik method. 
Surgical intervention is used when the dysplasia is severe or diagnosed late, or after an unsuccessful trial of nonsurgical 
treatment. Avascular necrosis of the hip is the most common and most severe potential harm of both surgical and nonsurgical 
interventions, and can result in growth arrest of the hip and eventual joint destruction, with significant disability.
HarmsThe USPSTF was unable to assess the balance of benefits and harms of screening for developmental dysplasia of the hip 
due to insufficient evidence. There are concerns about the potential harms associated with treatment of infants identified by 
routine screening.

RecommendationsThe USPSTF has made recommendations on screening for hyperbilirubinemia, phenylketonuria, sickle cell disease, 
congenital hypothyroidism, and hearing loss in newborns. These recommendations are available at  

71Gonococcal Ophthalmia Neonatorum
Title Ocular Prophylaxis for Gonococcal Ophthalmia Neonatorum
Population All newborn infants
RecommendationProvide prophylactic ocular topical medication for the prevention of gonococcal ophthalmia 
neonatorum.
Grade: A
Risk AssessmentAll newborns should receive prophylaxis.
However, some newborns are at increased risk, including those with a maternal history of no prenatal care, 
sexually transmitted infections, or substance abuse.
Preventive InterventionsPreventive medications include 0.5% erythromycin ophthalmic ointment, 1.0% solution of silver nitrate, and 
1.0% tetracycline ointment. All are considered equally effective; however, the latter two are no longer available 
in the United States.
Timing of Intervention Within 24 hours after birth.
Other Relevant USPSTF Recommendations Several recommendations on screening and counseling for infectious diseases and perinatal care can be found 
at: http://www.uspreventiveservicestaskforce.org .

at: http://www.uspreventiveservicestaskforce.org . 

72Hearing Loss (Newborns)
Title Universal Screening for Hearing Loss in Newborns
RecommendationScreen for hearing loss in all newborn infants. 
Grade: B
Risk AssessmentThe prevalence of hearing loss in newborn infants with specific risk indicators is 10 to 20 times higher than in the general 
population of newborns.
Risk indicators associated with permanent bilateral congenital hearing loss include:
 ●Neonatal intensive care unit admission for 2 or more days.
 ●Family history of hereditary childhood sensorineural hearing loss.
 ●Craniofacial abnormalities.
 ●Certain congenital syndromes and infections.
Approximately 50% of newborns with permanent bilateral congenital hearing loss do not have any known risk indicators.
Screening TestsScreening programs should be conducted using a one-step or two-step validated protocol. A frequently-used 2-step

Screening TestsScreening programs should be conducted using a one-step or two-step validated protocol. A frequently-used 2-step 
screening process involves otoacoustic emissions followed by auditory brain stem response in newborns who fail the first 
test. Infants with positive screening tests should receive appropriate audiologic evaluation and follow-up after discharge.
Procedures for screening and follow-up should be in place for newborns delivered at home, birthing centers, or hospitals 
without hearing screening facilities.
Timing of ScreeningAll infants should have hearing screening before one month of age. Infants who do not pass the newborn screening should 
undergo audiologic and medical evaluation before 3 months of age. 
TreatmentEarly intervention services for hearing-impaired infants should meet the individualized needs of the infant and family, 
including acquisition of communication competence, social skills, emotional well-being, and positive self-esteem.

including acquisition of communication competence, social skills, emotional well-being, and positive self-esteem. 
Early intervention comprises evaluation for amplification or sensory devices, surgical and medical evaluation, and 
communication assessment and therapy. Cochlear implants are usually considered for children with severe-to-profound 
hearing loss only after inadequate response to hearing aids.
RecommendationsAdditional USPSTF recommendations regarding screening tests for newborns can be accessed at  
http://www.uspreventiveservicestaskforce.org/recommendations.htm#pediatric .

73High Blood Pressure (Children)
Title Screening for Primary Hypertension in Children and Adolescents  
Population Children and adolescents without symptoms of hypertension
 
Risk Assessment The strongest risk factor for primary hypertension in children is elevated body mass index. Other risk factors include low 
birthweight, male sex, ethnicity, and a family history of hypertension. 
Screening Tests Blood pressure screening with sphygmomanometry in the clinical setting may identify children and adolescents with 
hypertension with reasonable sensitivity; however, false-positive results may occur with normalization of subsequent blood 
pressure measurements. 
Treatment Stage 1 hypertension in children is treated with lifestyle and pharmacological interventions; medications are not 
recommended as first-line therapy. 

Harms The USPSTF found inadequate evidence on the diagnostic accuracy of screening for primary hypertension. The USPSTF 
also found inadequate evidence on the effectiveness of treatment and the harms of screening or treatment. Therefore, the 
USPSTF cannot determine the balance of benefits and harms of screening for hypertension in children and adolescents. 
Recommendations The USPSTF has made recommendations on screening for lipid disorders in children and adolescents. These 
recommendations are available at http://www.uspreventiveservicestaskforce.org/ . 

74Hyperbilirubinemia in Infants
Title Screening of Infants for Hyperbilirubinemia to Prevent Chronic Bilirubin Encephalopathy
Population Healthy newborn infants ≥35 weeks’ gestational age
Risk AssessmentRisk factors for hyperbilirubinemia include family history of neonatal jaundice, exclusive breastfeeding, bruising, cephalohematoma, ethnicity 
(Asian, black), maternal age >25 years, male gender, G6PD deficiency, and gestational age <36 weeks. 
The specific contribution of these risk factors to chronic bilirubin encephalopathy in healthy children is not well understood. 
ImportanceChronic bilirubin encephalopathy is a rare but devastating condition. Not all children with chronic bilirubin encephalopathy have a history of 
hyperbilirubinemia. 
Balance of Benefits and HarmsEvidence about the benefits and harms of screening is lacking. Therefore, the USPSTF could not determine the balance of benefits and harms

Balance of Benefits and HarmsEvidence about the benefits and harms of screening is lacking. Therefore, the USPSTF could not determine the balance of benefits and harms 
of screening newborns for hyperbilirubinemia to prevent chronic bilirubin encephalopathy.
Considerations for Practice In deciding whether to screen, clinicians should consider the following: 
 ●Potential preventable burden.  Bilirubin encephalopathy is a relatively rare disorder. Hyperbilirubinemia alone does not account for the 
neurologic condition of chronic bilirubin encephalopathy. There is no known screening test that will reliably identify all infants at risk of 
developing chronic bilirubin encephalopathy. 
 ●Potential harms.  Potential harms of screening are unmeasured but may be important. Evidence about the potential harms of 
phototherapy is lacking. Harms of treatment by exchange transfusion may include apnea, bradycardia, cyanosis, vasospasm, thrombosis,

phototherapy is lacking. Harms of treatment by exchange transfusion may include apnea, bradycardia, cyanosis, vasospasm, thrombosis, 
necrotizing enterocolitis, and, rarely, death.
 ●Current practice. Universal screening is widespread in the United States.
Screening TestsScreening may consist of risk-factor assessment, measurement of bilirubin level either in serum or by transcutaneous estimation, or a 
combination of methods.
InterventionsPhototherapy is commonly used to treat hyperbilirubinemia.
Exchange transfusion is used to treat extreme hyperbilirubinemia. 
RecommendationsUSPSTF recommendations on screening newborns for hearing loss, congenital hypothyroidism, hemoglobinopathies, and phenylketonuria 
(PKU) can be found at http://www.uspreventiveservicestaskforce.org . 

75Illicit and Prescription Drug Use in Children and Adolescents
TitlePrimary Care Behavioral Interventions to Reduce Illicit Drug and Nonmedical Pharmaceutical Use in Children and 
Population Children and adolescents younger than age 18 years who have not already been diagnosed with a substance use disorder
Behavioral InterventionsWhile the evidence is insufficient to recommend specific interventions in the primary care setting, those that have been 
studied include face-to-face counseling, videos, print materials, and interactive computer-based tools. Studies on these 
interventions were limited and findings on whether interventions significantly improved health outcomes were inconsistent.
HarmsThe evidence regarding primary care–based behavioral interventions to prevent or reduce illicit drug and nonmedical

HarmsThe evidence regarding primary care–based behavioral interventions to prevent or reduce illicit drug and nonmedical 
pharmaceutical use in children and adolescents is insufficient, and the balance of benefits and harms cannot be determined.
RecommendationsThe USPSTF has made recommendations on screening for and interventions to decrease the unhealthy use of other 
substances, including alcohol and tobacco. These recommendations are available at www.uspreventiveservicestaskforce.org .

76Iron Deficiency Anemia (Screening)
Title Part I: Screening for Iron Deficiency Anemia in Children and Pregnant Women
Population Asymptomatic children ages 6 to 12 months Asymptomatic pregnant women
Grade: I (Insufficient Evidence)Screen for iron deficiency anemia.
Grade: B
Risk AssessmentIndividuals considered to be at high risk for iron deficiency include adult women, recent immigrants, and, among adolescent 
females, fad dieters, as well as those who are obese. Premature and low birth weight infants are also at increased risk for 
iron deficiency. 
Screening TestsSerum hemoglobin or hematocrit is the primary screening test for identifying anemia. Hemoglobin is sensitive for iron 
deficiency anemia; however, it is not sensitive for iron deficiency because mild deficiency states may not affect hemoglobin 
levels. 
Potential harms of screening include false-positive results, anxiety, and cost.

levels. 
InterventionsIron deficiency anemia is usually treated with oral iron preparations. The likelihood that iron deficiency anemia identified by 
screening will respond to treatment is unclear, because many families do not adhere to treatment and because the rate of 
spontaneous resolution is high.
HarmsThe USPSTF was unable to determine the balance between 
the benefits and harms of routine screening for iron 
deficiency anemia in asymptomatic children ages 6 to 12 
months.The benefits of routine screening for iron deficiency anemia 
in asymptomatic pregnant women outweigh the potential 
harms.
RecommendationsThe USPSTF has also made recommendations on screening for blood lead levels in children and pregnant women. These 

77Iron Deficiency Anemia (Supplementation)
Title Part II: Iron Supplementation for Children and Pregnant Women
PopulationAsymptomatic children ages 6 to 12 
months who are at increased risk for iron 
deficiency anemiaAsymptomatic children ages 6 to 12 
months who are at average risk for iron 
deficiency anemiaPregnant women who are not anemic
RecommendationProvide routine iron supplementation.
Grade: I (Insufficient Evidence)No recommendation.
Risk AssessmentA validated risk assessment tool to guide primary care physicians in identifying individuals who would benefit from iron supplementation 
has not been developed.
MedicationIron supplementation, such as iron-fortified formula or iron supplements, may improve neurodevelopmental outcomes in children at 
increased risk for iron deficiency anemia. There is poor evidence that it improves neurodevelopmental or health outcomes in other 
populations.

Oral iron supplementation increases the risk for unintentional overdose and gastrointestinal symptoms. Given appropriate protection 
against overdose, these harms are small.
Balance of 
Benefits and 
HarmsThe moderate benefits of iron 
supplementation in asymptomatic 
children ages 6 to 12 months who are at 
increased risk for iron deficiency anemia 
outweigh the potential harms.The USPSTF was unable to determine 
the balance between the benefits and 
harms of iron supplementation in children 
ages 6 to 12 months who are at average 
risk for iron deficiency anemia.The USPSTF was unable to determine the 
balance between the benefits and harms of 
iron supplementation in non-anemic pregnant 
women.
USPSTF

women.
USPSTF 
RecommendationsThe USPSTF has also made recommendations on folic acid supplementation in women planning or capable of pregnancy and vitamin D 
supplementation to prevent cancer and fractures. These recommendations are available at http://www.uspreventiveservicestaskforce.org/ .
  
78Lipid Disorders in Children
Title Screening for Lipid Disorders in Children
Population Asymptomatic infants, children, adolescents, and young adults (age 20 years or younger)
Risk AssessmentRisk factors for dyslipidemia include overweight, diabetes, and a family history of common familial dyslipidemias (e.g., familial 
hypercholesterolemia).
Screening TestsSerum lipid (total cholesterol, high-density and low-density lipoprotein cholesterol) levels are accurate screening tests for 
childhood dyslipidemia, although many children with multifactorial types of dyslipidemia will have normal lipid levels in 
adulthood. The use of family history as a screening tool for dyslipidemia has variable accuracy, largely because definitions of 
a positive family history and lipid threshold values vary substantially.

InterventionsThe effectiveness of treatment interventions (diet, exercise, lipid-lowering agents) in improving health outcomes in children 
with dyslipidemia (including multifactorial dyslipidemia) remains a critical research gap. Potential harms of screening may 
include labeling of children whose dyslipidemia would not persist into adulthood or cause health problems. Adverse effects 
from lipid-lowering medications and low-fat diets, including potential long-term harms, have been inadequately evaluated in 
children.
HarmsThe USPSTF was unable to determine the balance between the potential benefits and harms of routinely screening children 
and adolescents for dyslipidemia.
RecommendationsThe USPSTF has made recommendations on high blood pressure and obesity in children and adolescents. These

RecommendationsThe USPSTF has made recommendations on high blood pressure and obesity in children and adolescents. These 
recommendations are available at http://www.uspreventiveservicestaskforce.org/ ..

79Major Depressive Disorder in Children and Adolescents
Title Screening and Treatment for Major Depressive Disorder in Children and Adolescents
Population Adolescents (12-18 years) Children (7-11 years)
Recommendation Screen when systems for diagnosis, treatment, and 
followup are in place. 
Grade: B No Recommendation 
Risk AssessmentRisk factors for major depressive disorder (MDD) include parental depression, having comorbid mental health or chronic 
medical conditions, and having experienced a major negative life event.
Screening TestsThe following screening tests have been shown to do well 
in teens in primary care settings: 
 ●Patient Health Questionnaire for Adolescents 
(PHQ-A).
 ●Beck Depression Inventory-Primary Care Version 
(BDI-PC).Screening instruments perform less well in younger 
children.
TreatmentsAmong pharmacotherapies fluoxetine, a selective 
serotonin reuptake inhibitor (SSRI), has been found

children.
serotonin reuptake inhibitor (SSRI), has been found 
efficacious. However, because of risk of suicidality, SSRIs 
should be considered only if clinical monitoring is possible. 
Various modes of psychotherapy, and pharmacotherapy 
combined with psychotherapy, have been found 
efficacious. Evidence on the balance of benefits and harms of 
treatment of younger children is insufficient for a 
 
80Obesity in Children and Adolescents
Title Screening for Obesity in Children and Adolescents
Population Children and adolescents 6 to 18 years of age
RecommendationScreen children aged 6 years and older for obesity.  
Offer or refer for intensive counseling and behavioral interventions.
Grade: B
Screening TestsBMI is calculated from the weight in kilograms divided by the square of the height in meters.  
Height and weight, from which BMI is calculated, are routinely measured during health maintenance visits.  
BMI percentile can be plotted on a chart or obtained from online calculators.  
Overweight = age- and gender-specific BMI at ≥85th to 94th percentile  
Obesity = age- and gender-specific BMI at ≥95th percentile
Timing of Screening No evidence was found on appropriate screening intervals.
InterventionsRefer patients to comprehensive moderate- to high-intensity programs that include dietary, physical activity, and behavioral 
counseling components.

HarmsModerate- to high-intensity programs were found to yield modest weight changes.  
Limited evidence suggests that these improvements can be sustained over the year after treatment.  
Harms of screening were judged to be minimal.
Recommendations Recommendations on other pediatric and behavioral counseling topics can be found at  

81Phenylketonuria (PKU)
Title Screening for Phenylketonuria
RecommendationScreen for Phenykeltonuria (PKU).
Grade: A
Screening TestsScreening for PKU is mandated in all 50 states. Methods of screening vary.
Three main methods are used to screen for PKU in the United States:
1. Guthrie Bacterial Inhibition Assay (BIA)
2. Automated fluorometric assay
3. Tandem mass spectrometry
Timing of ScreeningInfants who are tested within the first 24 hours after birth should receive a repeat screening test by 2 weeks of age.
Optimal timing of screening for premature infants and infants with illnesses is at or near 7 days of age, but in all cases before 
discharge from the newborn nursery.
Treatment It is essential that phenylalanine restrictions be instituted shortly after birth to prevent the neurodevelopmental effects of PKU.
RecommendationsAdditional USPSTF recommendations regarding screening tests for newborns can be accessed at:

RecommendationsAdditional USPSTF recommendations regarding screening tests for newborns can be accessed at:  

82Sickle Cell Disease
Title Screening for Sickle Cell Disease in Newborns
RecommendationScreen for sickle cell disease.
Grade: A
Screening TestsScreening for sickle cell disease in newborns is mandated in all 50 states and the District of Columbia.  
In most states, one of these tests is used for the initial screening:
 ●Thin-layer isoelectric focusing (IEF).
 ●High performance liquid chromatography (HPLC). 
Both IEF and HPLC have extremely high sensitivity and specificity for sickle cell anemia.
Timing of ScreeningAll newborns should undergo screening regardless of birth setting.  
Birth attendants should make arrangements for samples to be obtained.  
The first clinician to see the infant at an office visit should verify screening results.  
Confirmatory testing should occur no later than 2 months of age.
TreatmentInfants with sickle cell anemia should receive:
 ●Prophylactic penicillin starting by age 2 months.

 ●Pneumococcal immunizations at recommended intervals.
http://www.uspreventiveservicestaskforce.org/recommendations.htm#vision .

83Speech and Language Delay
Title Screening for Speech and Language Delay in Preschool Children
PopulationChildren ages 5 years and younger who have not already been identified as at increased risk for speech and language 
delays
Risk AssessmentThe most consistently reported risk factors include a family history of speech and language delay, male sex, and perinatal 
factors, such as prematurity and low birth-weight. Other risk factors reported less consistently include levels of parental 
education, specific childhood illnesses, birth order, and larger family size.
Screening TestsThere is insufficient evidence that brief, formal screening instruments that are suitable for use in primary care for assessing 
speech and language development can accurately identify children who would benefit from further evaluation and 
intervention.

HarmsThe USPSTF could not determine the balance of benefits and harms of using brief, formal screening instruments to screen 
for speech and language delay in the primary care setting.
RecommendationsThe USPSTF has also made recommendations on screening for hearing loss in newborns and vision impairment in children 
ages 1 to 5 years. These recommendations are available at http://www.uspreventiveservicestaskforce.org/ .

84Tobacco Use in Children and Adolescents
Title Primary Care Interventions to Prevent Tobacco Use in Children and Adolescents  
Population School-aged children and adolescents
Recommendation Provide interventions to prevent initiation of tobacco use. 
Grade: B
 
Risk Assessment The strongest factors associated with smoking initiation in children and adolescents are parental smoking and parental 
nicotine dependence. 
Other factors include low levels of parental monitoring, easy access to cigarettes, perception that peers smoke, and exposure 
to tobacco promotions. 
Interventions Behavioral counseling interventions, such as face-to-face or phone interaction with a health care provider, print materials, 
and computer applications, can reduce the risk for smoking initiation in school-aged children and adolescents. The type and 
intensity of effective behavioral interventions substantially varies. 

Harms There is a moderate net benefit to providing primary care interventions to prevent tobacco use in school-aged children and 
Recommendations The USPSTF has made recommendations on counseling and interventions to prevent tobacco use and tobacco-caused 
disease in adults and pregnant women. These recommendations are available at www.uspreventiveservicestaskforce.org/ .
 
85Visual Impairment in Children Ages 1 to 5
Title Screening for Visual Impairment in Children Ages 1 to 5
Population Children ages 3 to 5 years Children younger than 3 years of age
RecommendationProvide vision screening. 
Screening TestsVarious screening tests are used in primary care to identify visual impairment in children, including: 
 ●Visual acuity test
 ●Stereoacuity test
 ●Cover-uncover test
 ●Hirschberg light reflex test
 ●Autorefraction
 ●Photoscreening
Timing of Screening No evidence was found regarding appropriate screening intervals.
InterventionsPrimary treatment for amblyopia includes the use of corrective lenses, patching, or atropine therapy of the non-affected 
eye. Treatment may also consist of a combination of interventions.
Balance of Benefits and HarmsThere is adequate evidence that early treatment of amblyopia in children ages 3 to 5 years leads to improved visual

Balance of Benefits and HarmsThere is adequate evidence that early treatment of amblyopia in children ages 3 to 5 years leads to improved visual 
outcomes. There is limited evidence on harms of screening, including psychosocial effects, in children ages 3 years and 
older. 
There is inadequate evidence that early treatment of amblyopia in children younger than 3 years of age leads to 
improved visual outcomes.
Regarding the I StatementIn deciding whether to refer children younger than 3 years of age for screening, clinicians should consider: 
 ●Potential preventable burden:  screening later in the preschool years seems to be as effective as screening earlier
 ●Costs:  initial high costs associated with autorefractors and photoscreeners
 ●Current practice:  typical vision screening includes assessment of visual acuity, strabismus, and stereoacuity; 
children with positive findings should be referred for a comprehensive ophthalmologist exam

89Immunizations for Adults and Children
The USPSTF recognizes the importance of immunizations in primary disease 
prevention. However, the USPSTF does not wish to duplicate the significant 
investment of resources made by others to review new evidence on immunizations in 
a timely fashion and make recommendations. 
The Centers for Disease Control and Prevention’s (CDC’s) Advisory Committee 
on Immunization Practices (ACIP) publishes recommendations on immunizations 
for children and adults. The methods used by the ACIP to review evidence on 
immunizations may differ from the methods used by the USPTF . 
For the ACIP’s current recommendations on immunizations, please refer to the 
National Immunization Program Web site at www.cdc.gov/vaccines/recs/schedules/
default.htm .

93Topics in Progress
Each USPSTF recommendation goes through several stages of development. The 
review process takes into account input from the medical and research community, 
stakeholders, and the general public.
The length of time for the entire recommendation process varies depending on the 
amount and type of available evidence and the time required for compilation of data 
into a draft recommendation, public comment periods, consideration of comments, 
and in-depth review and discussions among USPSTF members.
The following topics are in review and are likely to be issued as drafts for public 
comment during 2014:
 ■Aspirin for the Prevention of Cardiovascular Disease
 ■Aspirin or NSAIDS for the Prevention of Colorectal Cancer, Preventive 
 ■Aspirin Use to Prevent Preeclampsia, Preventive Medications  
 ■Chlamydial Infection, Screening  
 ■Diabetes Mellitus, Screening
 ■Gonorrhea, Screening

 ■Healthy Diet and Physical Activity for Cardiovascular Disease Prevention in 
Adults at Risk, Counseling
 ■High Blood Pressure in Adults, Screening
 ■Iron Deficiency Anemia in Childhood and Pregnancy, Screening 
 ■Major Depressive Disorder in Children and Adolescents, Screening
 ■Sexually T ransmitted Infections, Counseling 
 ■Thyroid Disease, Screening  
 ■Vitamin D Deficiency, Screening
Recommendations on the following topics were published during the production 
of the 2014 Guide to Clinical Preventive Services or are in review and are likely to be 
published as final recommendations during 2014:
 ■Abdominal Aortic Aneurysm, Screening 
 ■Carotid Artery Stenosis, Screening  
 ■Dental Caries Prevention in Children From Birth to Age 5 Years, Screening 
and Preventive Medications

94 ■Hepatitis B Virus Infection in Nonpregnant Adolescents and Adults, Screening  
 ■Suicide Risk, Screening 
The following topics are in earlier stages of review and are likely to be issued as drafts 
or published as final recommendations sometime after 2014:
 ■Autism Spectrum Disorder in Young Children, Screening
 ■Breast Cancer, Screening 
 ■Chronic Obstructive Pulmonary Disease, Screening
 ■Colorectal Cancer, Screening
 ■Depression in Adults and in Pregnant and Postpartum Women, Screening
 ■Impaired Visual Acuity in Older Adults, Screening
 ■Lipid Disorders in Adults, Screening
 ■Lipid Disorders in Children, Screening
 ■Skin Cancer, Screening
 ■Speech and Language Delay and Disorders in Children Age 5 Years or Younger, 
Screening 
 ■Syphilis Infection, Screening
 ■Tobacco Cessation in Adults, Including Pregnant Women, Counseling

97Appendix A
How the U.S. Preventive Services Task Force Grades Its 
Recommendations
The Task Force assigns each of its recommendations a letter grade (A, B, C, or D) or 
issues an I statement, based on the certainty of the evidence and on the balance of 
benefits and harms of the preventive service as displayed in the recommendation grid 
below. The USPSTF changed its grade definitions based on a change in methods in 
May 2007.
U.S. Preventive Services Task Force Recommendation Grid: Letter Grade 
of Recommendation or Statement of Insufficient Evidence Assessing 
Certainty and Magnitude of Net Benefit 
Certainty of Net 
Benefit Magnitude of Net Benefit
Substantial Moderate Small Zero/negative
High A B C D
Moderate B B C D
Low Insufficient

98Grade Definitions
What the Grades Mean and Suggestions for Practice
The USPSTF updated its definitions of the grades it assigns to recommendations and 
now includes “suggestions for practice” associated with each grade. The USPSTF has 
also defined levels of certainty regarding net benefit.
Grade Definition Suggestions for Practice
AThe USPSTF recommends the service. 
There is high certainty that the net benefit is 
substantial.Offer or provide this service.
BThe USPSTF recommends the service. 
moderate or there is moderate certainty that 
the net benefit is moderate to substantial.Offer or provide this service.
CThe USPSTF recommends selectively 
offering or providing this service to individual 
patients based on professional judgment 
and patient preferences. There is at least 
moderate certainty that the net benefit is 
small.Offer or provide this service for selected 
patients depending on individual 
circumstances.

DThe USPSTF recommends against the 
service. There is moderate or high certainty 
that the service has no net benefit or that the 
harms outweigh the benefits.Discourage the use of this service.
I StatementThe USPSTF concludes that the current 
evidence is insufficient to assess the 
balance of benefits and harms of the service. 
Evidence is lacking, of poor quality, or 
conflicting, and the balance of benefits and 
harms cannot be determined.Read the clinical considerations section of 
USPSTF Recommendation Statement. If the 
service is offered, patients should understand 
the uncertainty about the balance of benefits 
and harms.

99Levels of Certainty Regarding Net Benefit
Level of Certainty* Description
HighThe available evidence usually includes consistent results from well-designed, 
well-conducted studies in representative primary care populations. These 
studies assess the effects of the preventive service on health outcomes. This 
conclusion is therefore unlikely to be strongly affected by the results of future 
studies.
ModerateThe available evidence is sufficient to determine the effects of the preventive 
service on health outcomes, but confidence in the estimate is constrained by 
such factors as: 
 ●The number, size, or quality of individual studies. 
 ●Inconsistency of findings across individual studies. 
 ●Limited generalizability of findings to routine primary care practice. 
 ●Lack of coherence in the chain of evidence. 
As more information becomes available, the magnitude or direction of the 
observed effect could change, and this change may be large enough to alter 
the conclusion.

LowThe available evidence is insufficient to assess effects on health outcomes. 
Evidence is insufficient because of: 
 ●The limited number or size of studies. 
 ●Important flaws in study design or methods. 
 ●Gaps in the chain of evidence. 
 ●Findings not generalizable to routine primary care practice. 
 ●Lack of information on important health outcomes. 
More information may allow estimation of effects on health outcomes.
* The USPSTF defines certainty as “likelihood that the USPSTF assessment of the net benefit of a preventive service is correct.” 
The net benefit is defined as benefit minus harm of the preventive service as implemented in a general, primary care population.

The net benefit is defined as benefit minus harm of the preventive service as implemented in a general, primary care population. 
The USPSTF assigns a certainty level based on the nature of the overall evidence available to assess the net benefit of a 
preventive service.

100Grade Definitions Prior to May 2007
The definitions below (of USPSTF grades and quality of evidence ratings) were in use 
prior to the update and apply to recommendations voted on by the USPSTF prior to 
May 2007.
A — Strongly Recommended:  The USPSTF strongly recommends that clinicians 
provide [the service] to eligible patients. The USPSTF found good evidence that [the 
service] improves important health outcomes and concludes that benefits substantially 
outweigh harms.
B — Recommended:  The USPSTF recommends that clinicians provide [the service] 
to eligible patients. The USPSTF found at least fair evidence that [the service] 
improves important health outcomes and concludes that benefits outweigh harms.
C — No Recommendation:  The USPSTF makes no recommendation for or against 
routine provision of [the service]. The USPSTF found at least fair evidence that [the 
service] can improve health outcomes but concludes that the balance of benefits and

service] can improve health outcomes but concludes that the balance of benefits and 
harms is too close to justify a general recommendation.
D — Not Recommended:  The USPSTF recommends against routinely providing 
[the service] to asymptomatic patients. The USPSTF found at least fair evidence that 
[the service] is ineffective or that harms outweigh benefits.
I — Insufficient Evidence to Make a Recommendation:  The USPSTF concludes 
that the evidence is insufficient to recommend for or against routinely providing 
[the service]. Evidence that [the service] is effective is lacking, of poor quality, or 
conflicting and the balance of benefits and harms cannot be determined.
Quality of Evidence Prior to May 2007
The USPSTF grades the quality of the overall evidence for a service on a 3-point scale 
(good, fair, poor):
Good: Evidence includes consistent results from well-designed, well-conducted

Good: Evidence includes consistent results from well-designed, well-conducted 
studies in representative populations that directly assess effects on health outcomes.
Fair: Evidence is sufficient to determine effects on health outcomes, but the strength 
of the evidence is limited by the number, quality, or consistency of the individual 
studies, generalizability to routine practice, or indirect nature of the evidence on 
health outcomes.
Poor:  Evidence is insufficient to assess the effects on health outcomes because of 
limited number or power of studies, important flaws in their design or conduct, gaps 
in the chain of evidence, or lack of information on important health outcomes.

101Appendix B
Members of the U.S. Preventive Services Task Force 2004-2014
Janet D. Allan, Ph.D., R.N., C.S.,
    F .A.A.N.School of NursingUniversity of Maryland, Baltimore
Baltimore, MD
Linda Ciofu Baumann, Ph.D., R.N.
School of Nursing and School of  
    Medicine & Public HealthUniversity of WisconsinMadison, WI
Alfred O. Berg, M.D., M.P .H.
University of Washington
Seattle, WA
Kirsten Bibbins-Domingo, Ph.D., 
    M.D.
San Francisco General HospitalUniversity of California,San Francisco, CA
Adelita Gonzales Cantu, R.N., Ph.D.
University of Texas Health Science  
    CenterSan Antonio, TX
Ned Calonge, M.D., M.P .H.
Colorado Department of Public Health 
    and EnvironmentDenver, CO
Susan J. Curry, Ph.D.
College of Public HealthUniversity of IowaIowa City, IA
Karina W . Davidson, Ph.D., M.A.Sc.
Center for Behavioral Cardiovascular

and EnvironmentDenver, CO
Center for Behavioral Cardiovascular  
    HealthColumbia University Medical CenterNew York, NYThomas G. DeWitt, M.D.Department of PediatricsChildren’s Hospital Medical CenterCincinnati, OHAllen J. Dietrich, M.D.Dartmouth Medical SchoolHanover, NH
Mark Ebell, M.D., M.S.
The University of GeorgiaAthens, GA
Glenn Flores, M.D.
University of TexasSouthwestern Medical Center and 
    Children’s Medical Center of DallasDallas, TX
Paul S. Frame, M.D.
Tri-County Family Medicine  
Cohocton, NY
Francisco A.R. García, M.D., M.P .H.
Pima County Department of HealthT ucson, AZ
Matthew W . Gillman, M.D., S.M.
Obesity Prevention ProgramHarvard Medical School and Harvard 
    Pilgrim Health Care InstituteBoston, MA
Leon Gordis, M.D., Dr.P .H.
Johns Hopkins Bloomberg School of 
    Public HealthBaltimore, MD
Kimberly D. Gregory, M.D., M.P .H.

Pilgrim Health Care InstituteBoston, MA
Cedars-Sinai Medical CenterLos Angeles, CA

102David Grossman, M.D., M.P .H.
Center for Health Studies, Group  
    Health Cooperative
Russell Harris, M.D., M.P .H.
University of North Carolina School  
    of Medicine
Chapel Hill, NC
Jessica Herzstein, M.D., M.P .H.
Air Products
Allentown, PA
George Isham, M.D., M.S.
HealthPartners
Minneapolis, MN
Mark S. Johnson, M.D., M.P .H.
New Jersey Medical School
University of Medicine and Dentistry of  
    New Jersey
Newark, NJ
Alex R. Kemper, M.D., M.P .H., M.S.
Pediatrics
Duke University Medical School
Durham, NC
Division of Children’s Primary Care 
Duke University
Durham, NC
Kenneth Kizer, M.D., M.P .H.
National Quality Forum
Washington, DC
Jonathan D. Klein, M.D., M.P .H.
University of Rochester
Rochester, NY
Ann E. Kurth, Ph.D., R.N., M.S.N.,  
    M.P .H.
College of Nursing and the Department  
    of Population Health
Global Institute of Public Health
New York University
New York, NYMichael L. LeFevre, M.D., M.S.P .H.

M.P .H.
University of Missouri School of  
    Medicine
Columbia, MO
Rosanne Leipzig, M.D., Ph.D.
Mount Sinai School of Medicine
New York, NY
Carol Loveland-Cherry, Ph.D., R.N.,  
    F .A.A.N.
School of Nursing
University of Michigan
Ann Arbor, MI
Lucy N. Marion, Ph.D., R.N.
Medical College of Georgia
Augusta, GA
Joy Melnikow, M.D., M.P .H.
University of California Davis
Sacramento, CA
Bernadette Melnyk, Ph.D., R.N., 
C.P .N.P ./N.P .P .
College of Nursing & Healthcare  
    Innovation
Arizona State University
Phoenix, AZ
Virginia A. Moyer, M.D., M.P .H.
    Center
Houston, TX
Wanda Nicholson, M.D., M.P .H., 
M.B.A.
Johns Hopkins School of Medicine and  
    Bloomberg School of Public Health
Judith K. Ockene, Ph.D., M.Ed.

Center
M.B.A.
University of Massachusetts Medical  
    School
Worcester, MA

103Douglas K. Owens, M.D., M.S.
VA Palo Alto Health Care System
Freeman Spogli Institute for  
    International Studies
Stanford University
Stanford, CA
Diana B. Petitti, M.D., M.P .H.
Fulton School of Engineering
Tempe, AZ
William R. Phillips, M.D., M.P .H.
Family Medicine and Health Services
Maureen G. Phipps, M.D., M.P .H.
Department of Obstetrics and 
Gynecology
Warren Alpert Medical School
Brown University, Providence, RI
Michael P . Pignone, M.D., M.P .H.
Division of General Internal Medicine
University of North Carolina
Carolina Reyes, M.D.
University of Southern California,  
    Los Angeles County/USC Medical  
    Center
Los Angeles, CAGeorge F . Sawaya, M.D.
University of California, San Francisco
San Francisco, CA
J. Sanford (Sandy) Schwartz, M.D.
University of Pennsylvania School of  
    Medicine and Wharton School
Philadelphia, PA
Albert L. Siu, M.D.
Mount Sinai Medical Center

Steven M. T eutsch, M.D., M.P .H.
Merck and Company, Inc.
West Point, PA
Timothy Wilt, M.D., M.P .H.
Minneapolis VA Medical Center
University of Minnesota
Barbara P . Yawn, M.D., M.S.P .H.,  
    M.Sc.
Olmstead Medical Center
Rochester, MN

104Appendix C
Acknowledgements
AHRQ Staff Supporting the USPSTF
Aileen Buckler, M.D., M.P .H.
Joel Boches
Joya Chowdhury, M.P .H.
Robert Cosby, Ph.D.
Jennifer Croswell, M.D., M.P .H.
Sandra K. Cummings
Farah Englert
Tina Fan, M.D., M.P .H.
Saeed Fatemi
Janice Genevro, Ph.D., M.S.W.
Margi Grady
Alison Hunt
William Hyde, M.L.S.
Kristie Kiser
Karen Lee, M.D., M.P .H.
Biff LeVee
Iris Mabry, M.D., M.P .H.
Corey Mackison, M.S.A.
Andrew Marshall
Robert McNellis, M.P .H., P .A.
David Meyers, M.D.
Tess Miller, Dr.P .H.
Emily Moser
Quyen Ngo-Metzger, M.D., M.P .H.
Lisa Nicolella
Linwood Norman, M.S.
Janine Payne, M.P .H.
Kathryn Ramage
Richard Ricciardi, Ph.D., N.P ., F .A.A.N.P .
Randie Siegel, M.S.
Rachel Weinstein
T racy Wolff, M.D., M.P .H.

105Evidence-based Practice Centers Supporting the USPSTF  
2014
Kaiser Permanente Research Affiliates Evidence-based Practice Center
Director, Evelyn P . Whitlock, M.D., M.P .H.
The Kaiser Permanente Research Affiliates EPC involves over 75 researchers from 
three integrated health care delivery systems: Kaiser Permanente, Group Health 
Research Institute, and HealthPartners Institute for Education and Research. The 
KPRA EPC is headquartered in Portland, Oregon, at the Kaiser Permanente Center 
for Health Research.  To learn more about the KPRA EPC, please visit:
http://www.kpchr.org/research/public/resEPC.htm
Pacific Northwest Evidence-based Practice Center
Director, Roger Chou, M.D.
The Pacific Northwest EPC is housed in the Department of Medical Informatics 
& Clinical Epidemiology, at the Oregon Health and Science University School of 
Medicine, with partners at the University of Washington CHASE Alliance in Seattle,

Medicine, with partners at the University of Washington CHASE Alliance in Seattle, 
and Spectrum Research, Inc., in Tacoma, Washington.  To learn more about the 
Pacific Northwest EPC, please visit:
http://www.ohsu.edu/xd/research/centers-institutes/evidence-based-practice-center/
RTI-UNC Evidence-based Practice Center
Director, Meena Viswanathan, Ph.D.
Co-Director, Dan Jonas, M.D., M.P .H.
RTI International, in collaboration with the five health professions schools and 
the Cecil G. Sheps Center for Health Services Research at the University of North 
Carolina at Chapel Hill, operates the RTI-UNC Evidence-based Practice Center. To 
learn more about the RTI-UNC EPC, please visit:
http://www.rti.org/page.cfm?objectid=4FA3323C-51CA-4DFE-A3E0246F90D5FA4B .
Vanderbilt Evidence-based Practice Center
Director, Melissa McPheeters, Ph.D., M.P .H.

Established in 2007, the Vanderbilt EPC is located in the Institute for Medicine and 
Public Health at Vanderbilt University. To learn more about the Vanderbilt EPC, 
please visit:
http://medicineandpublichealth.vanderbilt.edu/epc/ .

106Liaisons to the USPSTF
Primary care partners include:
 ■American Academy of Family Physicians (AAFP)
 ■American Academy of Nurse Practitioners (AANP)
 ■American Academy of Pediatrics (AAP)
 ■American Academy of Physician Assistants (AAPA)
 ■American Congress of Obstetricians and Gynecologists (ACOG)
 ■American College of Physicians (ACP)
 ■American College of Preventive Medicine (ACPM)
 ■American Osteopathic Association (AOA)
 ■National Association of Pediatric Nurse Practitioners (NAPNAP)
Policy, population, and quality improvement partners include:
 ■America’s Health Insurance Plans (AHIP)
 ■American Medical Association
 ■National Committee for Quality Assurance (NCQA)
 ■AARP
 ■Canadian Task Force on Preventive Health Care (CTFPHC)
 ■Community Preventive Services Task Force (CPSTF)
Federal partners include:
 ■Centers for Disease Control and Prevention (CDC)
 ■Centers for Medicare & Medicaid Services (CMS)
 ■Department of Defense/Military Health System (DoD/MHS)

 ■U.S. Food and Drug Administration (FDA)
 ■Health Resources and Services Administration (HRSA)
 ■Indian Health Service (IHS)
 ■National Institutes of Health (NIH)
 ■Veteran’s Health Administration (VHA)
 ■Substance Abuse & Mental Health Services Administration (SAMHSA)
 ■Office of the Assistant Secretary for Planning and Evaluation (ASPE)
 ■Office of Disease Prevention and Health Promotion  (ODPHP)
 ■Office of the Surgeon General

107Appendix D
About the U.S. Preventive Services Task Force
Overview
Created in 1984, the U.S. Preventive Services Task Force (USPSTF) is an 
independent group of national experts in prevention and evidence-based medicine 
that works to improve the health of all Americans by making evidence-based 
recommendations about clinical preventive services such as:
 ■Screenings
 ■Counseling services
 ■Preventive medications
The Task Force is made up of 16 volunteer members who serve 4-year terms. 
Members come from the fields of preventive medicine and primary care, including 
internal medicine, family medicine, pediatrics, behavioral health, obstetrics and 
gynecology, and nursing. The Task Force is led by a chair and two vice-chairs. 
Members are appointed by the Director of the Agency for Healthcare Research 
and Quality (AHRQ). Members must have no substantial conflicts of interest that 
could impair the integrity of the work of the Task Force. A list of current USPSTF

could impair the integrity of the work of the Task Force. A list of current USPSTF 
members, including their biographical information, can be found on the USPSTF 
Web site (www.USPreventiveServicesTaskForce.org).
Since 1998, through acts of the U.S. Congress, AHRQ has been authorized to 
convene the Task Force and to provide ongoing scientific, administrative, and 
dissemination support to the Task Force. 
The Task Force makes recommendations to help primary care clinicians and 
patients decide together whether a preventive service is right for a patient’s needs. 
Its recommendations apply to people who have no signs or symptoms of the 
specific disease or condition to which a recommendation applies and are for services 
prescribed, ordered, or delivered in the primary care setting. 
Task Force recommendations are based on a rigorous review of existing peer-reviewed

Task Force recommendations are based on a rigorous review of existing peer-reviewed 
evidence. The Task Force assesses the effectiveness of a clinical preventive service by 
evaluating and balancing the potential benefits and harms of the service. The potential 
benefits include early identification of disease leading to improvement in health. 
The potential harms can include adverse effects of the service itself or inaccurate test 
results that may lead to additional testing, additional risks, or unneeded treatment.

108The Task Force does not explicitly consider costs in its assessment of the effectiveness 
of a service. The Task Force assigns each recommendation a letter grade (A, B, C, or 
D grade or an I statement) based on the strength of the evidence and on the balance 
of benefits and harms of the preventive service. More information on USPSTF 
recommendation grades and a list of all current USPSTF recommendations can be 
found on the USPSTF Web site. 
The Recommendation Making Process
The USPSTF is committed to making its work as transparent as possible. As part of 
this commitment, the Task Force provides opportunities for the public to provide 
input during each phase of the recommendation process. 
The phases of the topic development process are described below and illustrated in 
“Steps the USPSTF Takes to Make a Recommendation” at the end of this appendix. 
T opic Nomination
The USPSTF considers a broad range of clinical preventive services for its

The USPSTF considers a broad range of clinical preventive services for its 
recommendations, focusing on screenings, counseling, and preventive medications. 
Anyone can nominate a topic for consideration by the Task Force. 
Research Plan Development
Once the USPSTF selects a topic for review, it works with an Evidence-based Practice 
Center (EPC) to develop a draft research plan, which guides the review process and 
includes key questions and target populations. A draft research plan is posted for 
public comment, and feedback is incorporated into a final research plan.
Evidence Report and Recommendation Statement Development
Using the final research plan as a guide, the EPC researchers independently gather, 
review, and analyze evidence on the topic and summarize their findings in a 
systematic evidence report.  The evidence report is sent to subject matter experts for

systematic evidence report.  The evidence report is sent to subject matter experts for 
peer review before it is shared with the Task Force.  
Then, the entire Task Force discusses and deliberates the evidence, weighs the benefits 
and harms, and uses the information to determine the effectiveness of a service.  The 
Task Force revises and finalizes a draft recommendation statement based on this 
discussion.   
The draft evidence report and draft recommendation statement are typically posted 
together on the Task Force Web site for a period of 4 weeks.  During the comment 
period, any member of the public may submit comments on either or both of the 
documents.

109Upon receiving all comments from experts, partners, and the public, the EPC 
researchers revise the draft evidence report.  Once final, the EPC begins to prepare a 
summary of the evidence report for submission to a peer-reviewed journal.  
Final Recommendation Statement
Then, Task Force members review all the comments received and use them to inform 
the development of the final recommendation statement. The recommendation 
statement is sent to all Task Force members for final ratification. 
The final recommendation statement and evidence summary are published at 
the same time in a peer-reviewed journal.  All recommendation statements and 
supporting evidence reports are made available on the Task Force Web site  
(www.USPreventiveServicesTaskForce.org ).
Please visit the Task Force Web site to learn how and when to nominate topics for 
consideration by the Task Force or to comment on topics in development.
Identifying High Priority Research Gaps

Identifying High Priority Research Gaps 
In the Patient Protection and Affordable Care Act of 2010, Congress has specifically 
charged the Task Force with identifying and reporting each year on areas where 
current evidence is insufficient to make a recommendation on the use of a clinical 
preventive service, with special attention to those areas where evidence is needed 
to make recommendations for specific populations and age groups. The USPSTF 
believes that identifying evidence gaps and highlighting them as priority areas for 
research will inspire public and private researchers to collaborate and target their 
efforts to generate new knowledge and address important health priorities. The 
Annual Report to Congress is available on the Task Force Web site.
Online Resources 
On the Task Force Web site, people can:

 ■View all current USPSTF recommendations, EPC reports, and supporting 
materials.
 ■View manuals, slides, videos, and commentaries about the methods and processes 
the Task Force uses.
 ■Learn how to interpret recommendations and use them in clinical primary care 
practice.
 ■Nominate a new USPSTF member or a topic for a consideration by the Task 
Force.
 ■Provide input on specific draft materials during public comment periods.
 ■Sign up for the USPSTF listserv to receive USPSTF updates.

110 ■Access the Electronic Preventive Services Selector (ePSS), a quick hands-on tool 
designed to help primary care clinicians and health care teams identify, prioritize, 
and offer the screening, counseling, and preventive medication services that are 
appropriate for their patients. The ePSS is available on the Web ( epss.ahrq.gov ) or 
as a mobile phone or PDA application.
 ■Access myhealthfinder. myhealthfinder is a tool for consumers that provides 
personalized recommendations for preventive services based on the U.S. 
Preventive Services Task Force; the Bright Futures  Guidelines; the Centers for 
Disease Control and Prevention’s Advisory Committee on Immunization Practices 
(ACIP); and the Institute of Medicine’s (IOM’s) Committee on Preventive 
Services for Women.

112Appendix E 
More Resources 
AHRQ’s Improving Primary Care Program 
AHRQ’s Improving Primary Care Program Web site ( www.ahrq.gov/
improvingprimarycare ) produces evidence and tools to transform the 
primary care delivery system, resulting in better care, better experiences, 
and better value. The Program’s Web site includes tools, resources, and 
materials to support health care organizations and engage the entire health 
care delivery system.
The Program includes two overall project areas with specific areas of focus:
 ■Improving Primary Care Practice
 –Capacity building
 –Care coordination
 –Clinical-community linkages
 –Health care/system redesign
 –Health information technology integration
 –Behavioral and mental health
 –Primary care practice-based research networks
 –Self-management support
 ■Evidence-Based Decisionmaking
 –Clinical decision support
 –Multiple chronic conditions
 –Research centers for excellence in clinical preventive services

–Self-management support
 –U.S. Preventive Services Task Force
myhealthfinder
A consumer-friendly resource, myhealthfinder (available at www.
healthfinder.gov ) helps people create a customized list of relevant 
recommendations for preventive services based on age, sex, and pregnancy 
status, along with explanations of each recommendation in plain 
language.

113
Stay Healthy Brochures 
Consumers can use the information in this series of brochures to learn 
which screening tests you need and when to get them, which medicines 
may prevent diseases, and daily steps to take for good health. The series 
includes Men Stay Healthy at Any Age, Women Stay Healthy at Any Age, 
Men Stay Healthy at 50+, and Women Stay Healthy at 50+ , all in English 
and Spanish. Go to http://www.ahrq.gov/patients-consumers/prevention/
lifestyle/index.html  for the list and choose the title you are interested in.
Community Preventive Services Task Force
Established in 1996 by the U.S. Department of Health and Human 
Services, the Community Preventive Services Task Force (CPSTF) 
complements the work of the USPSTF , by addressing preventive services 
at the community level. The CPSTF assists agencies, organizations, and 
individuals at all levels (national, State, community, school, worksite, 
and health care system) by providing evidence-based recommendations

and health care system) by providing evidence-based recommendations 
about community prevention programs and policies that are effective 
in saving lives, increasing longevity, and improving Americans’ quality 
of life. The recommendations of the CPSTF are available at www.
thecommunityguide.org .
Advisory Committee on Immunization Practices
The Advisory Committee on Immunization Practices, managed and 
supported by the Centers for Disease Control and Prevention, is a group 
of medical and public health experts that develops recommendations 
on how to use vaccines to control diseases in the United States. The 
recommendations stand as public health advice that will lead to a 
reduction in the incidence of vaccine preventable diseases and an increase 
in the safe use of vaccines and related biological products.  
The Substance Abuse and Mental Health Services Administration

The Substance Abuse and Mental Health Services Administration provides 
resources that help health care providers locate and utilize behavioral 
health services. The T reatment Locator (fi ndtreatment.samhsa.gov ) 
helps find alcohol and drug abuse treatment or mental health treatment 
facilities and programs around the country, and the National SBIRT 
Addiction Technology T ransfer Center ( ireta.org/ebpsbirt ) helps utilize the 
public health model of screening and counseling to patients on risky or 
harmful drug and alcohol use.

114
Healthy People 2020
Healthy People 2020 is an initiative from the U.S. Department of Health 
and Human Services that challenges individuals, communities, and 
professionals to take specific steps to ensure good health. Healthy People 
provides science-based, 10-year national objectives for improving the 
health of all Americans. Read more at www.healthypeople.gov/2020/
default.aspx .
National Guideline ClearinghouseTM
A public resource for evidence-based clinical practice guidelines, 
NGC ( guideline.gov/index.aspx ) was originally created by AHRQ in 
partnerships with the American Medical Association and the American 
Association of Health Plans (now America’s Health Insurance Plans). The 
NGC mission is to provide physicians and other health professionals, 
health care providers, health plans, integrated delivery systems, 
purchasers, and others an accessible mechanism for obtaining objective, 
detailed information on clinical practice guidelines and to further their

detailed information on clinical practice guidelines and to further their 
dissemination, implementation, and use of this information.
Canadian Task Force on Preventive Health Care
The Task Force was established by the Public Health Agency of Canada 
to develop clinical practice guidelines that support primary care providers 
in delivering preventive health care. The mandate of the Task Force is 
to develop and disseminate clinical practice guidelines for primary and 
preventive care, based on systematic analysis of scientific evidence. Read 
more at www.canadiantaskforce.ca/ .
Cancer Control P .L.A.N.E.T .
A service of the National Cancer Institute, the Cancer Control 
P .L.A.N.E.T. portal provides access to Web-based resources that can 
help planners, program staff, and researchers to design, implement, 
and evaluate evidence-based cancer control programs. Read more at

and evaluate evidence-based cancer control programs. Read more at 
cancercontrolplanet.cancer.gov/index.html .
HealthCare.gov
This Web site ( www.healthcare.gov ), managed by the U.S. Department of 
Health and Human Services, helps people take health care into their own 
hands. It provides information about insurance options, using insurance, 
the Affordable Care Act, comparing providers, and prevention and 
wellness—including which preventive services are covered under the Act.

115Breast Cancer (2002 Recommendation)*
Title Screening for Breast Cancer (2002 Recommendation)
Population Women ages 40 years and older
Screening TestMammography, with or without 
clinical breast examinationClinical breast examination alone Breast self-examination alone
RecommendationScreen every 1 to 2 years.
Risk AssessmentWomen who are at increased risk for breast cancer (e.g., those with a family history of breast cancer in a mother or sister, a 
previous breast biopsy revealing atypical hyperplasia, or first childbirth after age 30) are more likely to benefit from regular 
mammography than women at lower risk.
Screening TestsThere is fair evidence that mammography screening every 12 to 33 months significantly reduces mortality from breast 
cancer. Evidence is strongest for women ages 50 to 69 years. For women ages 40 to 49 years, the evidence that screening

cancer. Evidence is strongest for women ages 50 to 69 years. For women ages 40 to 49 years, the evidence that screening 
mammography reduces mortality from breast cancer is weaker, and the absolute benefit of mammography is smaller, than it is 
for older women.
Clinicians should refer patients to mammography screening centers with proper accreditation and quality assurance standards to 
ensure accurate imaging and radiographic interpretation. Clinicians should adopt office systems to ensure timely and adequate 
follow-up of abnormal results.
Balance of Benefits and HarmsThe precise age at which the benefits from screening mammography justify the potential harms is a subjective judgment and 
should take into account patient preferences. Clinicians should inform women about the potential benefits (reduced chance of 
dying from breast cancer), potential harms (false-positive results, unnecessary biopsies), and limitations of the test that apply to

dying from breast cancer), potential harms (false-positive results, unnecessary biopsies), and limitations of the test that apply to 
women their age. The balance of benefits and potential harms of mammography improves with increasing age for women ages 
40 to 70 years.
Clinicians who advise women to perform breast self-examination or who perform routine clinical breast examination to screen for 
breast cancer should understand that there is currently insufficient evidence to determine whether these practices affect breast 
cancer mortality, and that they are likely to increase the incidence of clinical assessments and biopsies.
RecommendationsThe USPSTF has made recommendations on screening for genetic susceptibility for breast cancer and chemoprevention of 
breast cancer. These recommendations are available at http://www.uspreventiveservicestaskforce.org/ .

*The U.S. Department of Health and Human Services, in implementing the Affordable Care Act, under the standard it sets out in revised Section 2713(a)(5) of the Public Health Service Act, utilizes the 
2002 recommendation on breast cancer screening of the U.S. Preventive Services Task Force.
http://www.uspreventiveservicestaskforce.org/ .Appendix F

117Index
2-hour postload plasma (see Diabetes Mellitus, Screening)
AAA (see Abdominal Aortic Aneurysm, Screening)
Abdominal Aortic Aneurysm, Screening  ........................................................... 7, 93
Anemia, Iron Deficiency (see Iron Deficiency Anemia, Screening)
Ankle Brachial Index (see Peripheral Artery Disease And Cardiovascular Risk 
Assessment, Screening)
Aspirin for the Prevention of Cardiovascular Disease, Preventive  
Medication  ................................................................................................... 9, 93
Aspirin or NSAIDS for Prevention of Colorectal Cancer, Preventive  
Medication  ................................................................................................. 10, 93
Aspirin Use to Prevent Preeclampsia, Preventive Medication  ....................................... 93

Asymptomatic Bacteriuria (see Bacteriuria, Screening)
Autism Spectrum Disorder in Young Children, Screening  ........................................... 93
Autorefraction (see Visual Impairment in Children Ages 1-5, Screening)
Bacterial Vaginosis in Pregnancy, Screening  ........................................................ 11
Bacteriuria, Screening  .......................................................................................... 12
Basal Cell Cancer (see Skin Cancer, Counseling OR Screening)
Bladder Cancer, Screening  ................................................................................... 13
Blood Pressure, High (see High Blood Pressure in Adults, Screening)
BMI Screening, Children and Adolescents (see Obesity in Children and Adolescents, 
Screening)

Bone Mineral Density (see Osteoporosis, Screening)
BRCA Mutation Testing (see BRCA-Related Cancer in Women, Screening)
*BRCA-Related Cancer in Women, Screening  ..................................................... 14
*Breast Cancer, Preventive Medications  ............................................................... 15
Breast Cancer, Screening  ................................................................................ 16, 94
Breast Self Examination [BSE] (see Breast Cancer, Screening)
Breastfeeding, Counseling  .................................................................................... 17
CA-125 Screening for Ovarian Cancer (see BRCA-Related Cancer in Women, 

118Calcium Supplements (see Vitamin D and Calcium Supplementation to Prevent 
Fractures, Preventive Medication)
Cancer
 (see Aspirin or NSAIDS for Prevention of Colorectal Cancer, Preventive 
Medication)
 (see Bladder Cancer, Screening)
 (see BRCA-Related Cancer in Women, Screening)
 (see Breast Cancer, Preventive Medications)
 (see Breast Cancer, Screening)
 (see Cervical Cancer, Screening)
 (see Colorectal Cancer, Screening)
 (see Lung Cancer Screening)
 (see Oral Cancer, Screening)
 (see Ovarian Cancer, Screening)
 (see Prostate Cancer, Screening)
 (see Skin Cancer, Counseling)
 (see Skin Cancer, Screening)
 (see Testicular Cancer, Screening)
Carotid Artery Stenosis, Screening  ................................................................. 18, 93
Cervical Cancer, Screening  ................................................................................... 19
Chest X-Ray (see Lung Cancer, Screening)

*Child Maltreatment, Interventions to Prevent  ................................................... 68
Chlamydial Infection, Screening  .................................................................... 20, 93
Chronic Bilirubin Encephalopathy (see Hyperbilirubinemia in Infants, Screening)
*Chronic Kidney Disease, Screening  ................................................................... 21
Chronic Obstructive Pulmonary Disease, Screening ...................................... 22, 94
Clinical Breast Examination [CBE] (see Breast Cancer, Screening)
*Cognitive Impairment in Older Adults, Screening  ............................................ 23
Colonoscopy (see Colorectal Cancer, Screening)
Colorectal Cancer, Aspirin/NSAIDS (see Aspirin or NSAIDS for Prevention of 
Colorectal Cancer, Preventive Medication)

Colorectal Cancer, Screening  .......................................................................... 24, 94
Congenital Hypothyroidism, Screening  .............................................................. 69
Coronary Heart Disease Prevention (see Aspirin for the Prevention of Cardiovascular 
Disease, Preventive Medication)

119Coronary Heart Disease (Risk Assessment, Nontraditional Risk Factors), 
Screening  .......................................................................................................... 25
*Coronary Heart Disease, Screening With Electrocardiography  ........................ 26
COPD (see Chronic Obstructive Pulmonary Disease, Screening)
CT (Computerized Tomography) for Lung Cancer (See Lung Cancer, Screening)
Cover-Uncover Test (see Visual Impairment in Children Ages 1-5, Screening)
Dementia (see Cognitive Impairment in Older Adults, Screening)
Dental Caries Prevention in Children from Birth to Age 5 Years, Screening and Preventive 
Medication  ......................................................................................................... 93
Depression in Adults, Screening  ..................................................................... 27, 94
Depression or Depressive Disorders in Children and Adolescents (see Major

Depression or Depressive Disorders in Children and Adolescents (see Major 
Depressive Disorder in Children and Adolescents, Screening)
Depression in Pregnant and Postpartum Women, Screening  ........................................ 94
Developmental Dysplasia of the Hip, Screening  ................................................. 70
Diabetes Mellitus, Screening  .......................................................................... 28, 93
Drug Use, Illicit (see Illicit Drug Use, Screening)
Drug Abuse (see Illicit Drug Use, Screening)
Dysplasia, Hip (see Developmental Dysplasia of the Hip, Screening)
Elevated Blood Lead Levels (see Blood Lead Levels in Children and Pregnant Women, 
Estrogen Therapy (see Menopausal Hormone Therapy for the Primary Prevention of 
Chronic Conditions, Preventive Medication)
*Falls in Older Adults, Counseling, Preventive Medication,

*Falls in Older Adults, Counseling, Preventive Medication,  
and Other Interventions  .................................................................................. 29
Fasting Plasma Glucose (see Diabetes Mellitus, Screening)
Fecal Occult Blood Testing [FOBT] (see Colorectal Cancer, Screening)
Folic Acid Supplementation to Prevent Neural T ube Defects,  
Preventive Medication  ..................................................................................... 30
Framingham-based Adult T reatment Panel III (see Lipid Disorders in Adults, 
Screening or Healthful Diet and Physical Activity, Counseling)
Genetic Risk Assessment and BRCA Mutation Testing (see BRCA-Related Cancer in 
Women, Screening)
Genital Herpes, Screening  .................................................................................... 31

*Gestational Diabetes Mellitus, Screening  .......................................................... 32
*Glaucoma, Screening  .......................................................................................... 33

120Glucose Challenge, Glucose Tolerance (see Gestational Diabetes Mellitus, Screening)
Gonorrhea, Screening  ..................................................................................... 34, 93
Healthy Diet and Physical Activity for Cardiovascular Disease Prevention in Adults at 
Risk, Counseling  ................................................................................................. 93
Hearing Loss in Newborns, Screening  ................................................................. 72
*Hearing Loss in Older Adults, Screening  ........................................................... 36
Heart Disease (see Coronary Heart Disease, Risk Assessment, Nontraditional Risk 
Factors)

Factors)
Hemochromatosis, Screening  ............................................................................... 37
Hemoglobin A1C (see Diabetes Mellitus, Screening)
Hepatitis B Virus Infection, Screening  ....................................................................... 94
Hepatitis B Virus Infection in Pregnant Women, Screening  ............................... 38
*Hepatitis C Virus Infection in Adults, Screening ............................................... 39
Hereditary Hemochromatosis (see Hemochromatosis, Screening)
Herpes Simplex Virus (see Genital Herpes, Screening)
High Blood Pressure in Adults, Screening  ...................................................... 40, 93
*High Blood Pressure in Children, Screening  ..................................................... 73

High Cholesterol (see Lipid Disorders in Adults OR in Children, Screening)
Hip Dysplasia (see Developmental Dysplasia of the Hip, Screening)
*HIV Infection, Screening  .................................................................................... 41
Hirschberg Light Reflex Test (see Visual Impairment in Children Ages 1-5, Screening)
Hormone Replacement Therapy (see Menopausal Hormone Therapy for the Primary 
Prevention of Chronic Conditions, Preventive Medication)
HPV Testing (see Cervical Cancer, Screening)
HT or HRT (see Menopausal Hormone Therapy for the Primary Prevention of 
Human Immunodeficiency Virus (see HIV Infection, Screening)
Hyperbilirubinemia in Infants, Screening  ........................................................... 74
Hyperlipidemia (see Lipid Disorders in Adults OR in Children, Screening)

Hypertension (see High Blood Pressure in Adults OR in Children, Screening)
Hypothyroidism, Congenital (see Congenital Hypothyroidism, Screening)
Illicit Drug Use, Screening  ................................................................................... 42

121*Illicit and Prescription Drug Use in Children and Adolescents, Counseling  ......75
Impaired Visual Acuity in Older Adults, Screening  ...................................... 43, 94
Iron Deficiency Anemia, Screening  ........................................................... 76, 77, 93
Iron Supplementation (see Iron Deficiency Anemia, Screening)
Lead Levels in Blood, Elevated (see Blood Lead Levels in Children and Pregnant 
Lipid Disorders in Adults, Screening  .............................................................. 45, 94
Lipid Disorders in Children, Screening  .......................................................... 78, 94
Low Dose Computerized Tomography (see Lung Cancer, Screening)
*Lung Cancer, Screening  ...................................................................................... 46

Major Depressive Disorder in Children and Adolescents, Screening  ............. 79, 93
Major Depressive Disorder in Adults (see Depression in Adults, Screening)
Mammography (see Breast Cancer, Screening)
Melanoma (see Skin Cancer, Counseling OR Screening)
*Menopausal Hormone Therapy for the Primary Prevention of Chronic 
Conditions, Preventive Medication  ................................................................. 47
Motor Vehicle Occupant Restraints, Counseling  ................................................ 48
Multivitamins (see Vitamin, Mineral, and Multivitamin Supplements for the Primary 
Prevention of Cardiovascular Disease and Cancer, Preventive Medication)
Neural T ube Defects (see Folic Acid Supplementation to Prevent Neural T ube 
Defects, Preventive Medication)

Newborn Hearing Screening (see Hearing Loss in Newborns, Screening)
Nonmedical Prescription Drug Use in Children and Adolescents (see Illicit and 
Prescription Drug Use in Children and Adolescents, Counseling) 
Non-Steroidal Anti-Inflammatories [NSAIDS] (see Aspirin or NSAIDs for 
Prevention of Colorectal Cancer, Preventive Medication)
*Obesity in Adults, Screening  .............................................................................. 49
Obesity in Children and Adolescents, Screening  ................................................. 80
*Oral Cancer, Screening  ....................................................................................... 50
Osteoporosis, Screening  ....................................................................................... 51

*Ovarian Cancer, Screening  ................................................................................. 52
Ovarian Cancer, Genetic Risk (see BRCA-Related Cancer in Women, Screening)
Overweight (see Obesity in Children and Adolescents, Screening)
Pap Smear (see Cervical Cancer, Screening)

122*Peripheral Artery Disease and Cardiovascular Risk Asssessment, Screening  ......53
Phenylketonuria (PKU), Screening  ..................................................................... 81
Photoscreening (see Visual Impairment in Children Ages 1-5, Screening)
PKU (see Phenylketonuria, Screening)
Postmenopausal Hormone Therapy (see Menopausal Hormone Therapy for the 
Primary Prevention of Chronic Conditions, Preventive Medication)
Prescription Drug Abuse (see Illicit and Prescription Drug Use in Children and 
Adolescents)
Progestin Therapy (see Menopausal Hormone Therapy for the Primary Prevention of 
*Prostate Cancer, Screening  ................................................................................. 54
PSA Screening for Prostate Cancer (see Prostate Cancer, Screening)
Sexually Transmitted Infections, Counseling  ................................................. 55, 93

Sickle Cell Disease in Newborns, Screening  ........................................................ 82
Sigmoidoscopy (see Colorectal Cancer, Screening)
*Skin Cancer, Counseling  .................................................................................... 56
Skin Cancer, Screening  ................................................................................... 57, 94
Speech and Language Delay, Screening  .......................................................... 83, 94
Squamous Cell Cancer (see Skin Cancer, Counseling OR Screening)
Smoking Cessation (see Tobacco Use in Adults, Counseling and Interventions OR 
Tobacco Use in Children and Adolescents, Primary Care Interventions)
Spirometry Screening for COPD (see Chronic Obstructive Pulmonary Disease, 
Sputum Cytology (see Lung Cancer, Screening)

Stereoacuity Test (see Visual Impairment in Children Ages 1-5, Screening)
STI or STD 
 (see Sexually T ransmitted Infections, Counseling)
 (see Chlamydial Infection, Screening)
 (see Gonorrhea, Screening)
 (see Genital Herpes, Screening)
 (see HIV Infection, Screening)
 (see Syphilis Infection (Pregnant Women), Screening)
Suicide Risk, Screening  ................................................................................... 58, 94
Syphilis Infection, Screening  ..................................................................................... 94

123Syphilis Infection (Pregnant Women), Screening  ................................................ 59
T4 (see Congenital Hypothyroidism, Screening)
T esticular Cancer, Screening  ................................................................................ 60
Thyroid Disease Screening  ........................................................................................ 93
*T obacco Use in Children and Adolescents, Primary Care Interventions  .......... 84
T obacco Use in Adults, Counseling and Interventions  ................................... 61, 94
TSH (see Congenital Hypothyroidism, Screening)
Ultrasonography (see Abdominal Aortic Aneurysm, Screening)
Urinalysis (see Bladder Cancer, Screening)
Urine Biomarkers (see Bladder Cancer, Screening)
Urine Culture (see Bacteriurias, Screening)
Urine Cytology (see Bladder Cancer, Screening)
Vaginosis, Bacterial (see Bacterial Vaginosis in Pregnancy, Screening)
Visual Acuity Test (see Visual Impairment in Children Ages 1-5, Screening)

Visual Impairment in Children Ages 1-5, Screening  ........................................... 85
*Vitamin D and Calcium Supplementation to Prevent Fractures, Preventive 
Medication  ....................................................................................................... 62
Vitamin D Deficiency, Screening  .............................................................................. 94
Vitamin D3 Supplement (see Vitamin D and Calcium Supplementation to Prevent 
Fractures, Preventive Medication or Falls in Older Adults)
*Vitamin, Mineral, and Multivitamin Supplements for the Primary Prevention  
of Cardiovascular Disease and Cancer, Preventive Medication  ...................... 63
* indicates new or updated recommendations released March 2012 to March 2014.

Bold  text indicates topic of recommendation.
Italic  text indicates topic in progress (new or update).

AHRQ’s Electronic Preventive Services 
Selector (ePSS)
Bringing the prevention information clinicians need—
recommendations, clinical considerations, and selected practice 
tools—to the point of care.
The ePSS helps you identify and select screening, counseling, and 
preventive medication services based on specific patient characteristics.
Available at
http://epss.ahrq.gov
on the Web and for mobile devices, including Android, BlackBerry, 
iPhone, Palm, and iPad.

The U.S. Preventive Services Task Force is always interested in making our 
resources and tools more useful to those implementing the recommendations in 
primary care, as well as educating health professions students and patients. Please 
send any comments to coordinator@USPSTF .net.

U.S. Department of Health and Human Services  
www.ahrq.gov
AHRQ Pub. No. 14-05158  
May 2014  
ISBN 978-1-58763-439-0

Revised: October 1, 2022 ADHD Medication Guide*
*Disclaimer: The ADHD Medication Guide was created by Dr. Andrew Adesman of Northwell Health, Inc. Northwell Health is not affiliated with the owner nor is an owner of any of the medications or brands referenced in this Guide. No endorsement or affiliation exists between Northwell Heath and the owner of the medications or brands.
The ADHD Medication Guide is a visual aid for professionals caring for individuals with ADHD. The Guide includes only medications indicated by the FDA for the treatment of ADHD. In clinical practice, this guide may be used to assist patients in identifying medications previously tried, and may allow clinicians to identify ADHD medication options

for the future.  Practitioners should refer to the FDA-approved product information to learn more about each medication. Although every effort has been made to depict the true size and color of each medication depicted, we cannot guarantee there are not minor distortions.
This Guide should not be used as an exclusive basis for decision-making. The user understands and accepts that if Northwell Health were to accept the risk of harm to the user from use of this Guide, it would not be able to make the Guide available because the cost to cover the risk of harm to all users would be too great. Thus, use of this 
ADHD Medication Guide is strictly voluntary and at the user’s sole risk.

Copyright 2006, 2016, 2017, 2019, 2020, 2021, 2022 by Northwell Health, Inc., New Hyde Park, New York.  All rights reserved. Reproduction of the ADHD Medication Guide or the creation of derivative works is not permitted without the written permission of Northwell Health. The sale of this Guide is strictly forbidden. Send inquiries to Office 
of Legal Affairs, Northwell Health, 2000 Marcus Avenue, New Hyde Park, NY 11042. This Guide is accurate as of October 1, 2022.♦Discontinued ADHD Medications: The following FDA-approved proprietary formulations are no longer available (though, in some cases, branded or generic equivalents are 
still available): Adhansia XR; Ritalin LA capsule (60mg); Metadate CD capsules (40mg, 60mg); Metadate ER tablet (10mg); Ritalin SR tablets (20mg); Methylin Chewable tablets

still available): Adhansia XR; Ritalin LA capsule (60mg); Metadate CD capsules (40mg, 60mg); Metadate ER tablet (10mg); Ritalin SR tablets (20mg); Methylin Chewable tablets 
(2.5mg, 5mg, 10mg); Dexedrine Spansules (5mg, 10mg); Dexedrine tablets (5mg, 10mg); DextroStat tablets (5mg, 10mg); LiquADD solution (5mg/5mL), and Cylert (pemoline).**Important Information: The age-specific dosing information listed for each medication reflects the FDA-approved prescribing information. “SD” refers to the FDA-recommended 
starting dose, which sometimes varies by age.  Practitioners should refer to the full prescribing information for each medication. Please note: medications have been arranged on 
the ADHD Medication Guide for ease of display and visual comparison; dosing comparability cannot be assumed.Administration Key:
 ¶ Orally disintegrating tablet
 † Must be swallowed whole
 § Chewable
 ¥ Can be mixed with yogurt, orange juice, or water

¶ Orally disintegrating tablet
 § Chewable
 ‡ Can open capsule and sprinkle medication on apple sauce
  Can open capsule and sprinkle medication into water or onto apple sauce
 ❢ Can open capsule and mix with apple sauce or yogurt 
 ❢ Indicates a generic formulation is also available; generic products are not shown
 ❢ Indicates a generic (but NOT a branded) formulation is available
6-17 Yrs: 10–30mg; SD: 10mg
(The color border around each patch reflects 
the packaging color, not the patch itself.)Daytrana®
 (patch)
1.5”x3.9”30mg
1.5”x2.6”20mg
1.5”x1.9”15mg
1.4”x1.4”10mg
Methylin® Solution (grape flavor)Focalin®
 (dexmethylphenidate)
Ritalin®Methylphenidate Formulations – Short Acting**     (Medications in this section are shown at actual size)
2.5mg2.5mg
5mg
5mg5mg
10mg
10mg
10mg/5mL10mg
20mg
5mg/5mLMethylphenidate
 Chewable§ (grape flavor )6–17 Yrs: Daily: 5–20mg, divided BID; SD: 2.5mg BID

5mg
5mg5mg
10mg
10mg
20mg
6–12 Yrs: Daily: 10–60mg; divided BID or TID; SD: 5mg BID 
Adults: Daily: 10–60mg, divided BID or TID6–12 Yrs: Daily: 10–60mg; divided BID or TID; SD: 5mg BID 
Adults: Daily: 10–60mg, divided BID or TID♦
♦ ♦ ♦Jornay  PM®‡Methylphenidate Formulations – Long Acting/Delayed Onset**     (Medications in this section are shown at actual size)
6 Yrs–Adults: 20–100mg (dosed in the evening); SD: 20mg20mg 40mg 60mg 80mg 100mg
Azstarys ®
(dexmethylphenidate + 
serdexmethylphenidate)Methylphenidate Pro-Drug Formulations - Long Acting**     (Medications in this section are shown at actual size)     
6-12 Yrs: 26.1/5.2 – 52.3/10.4; SD: 39.2/7.8 mg; 13 Yrs – 
Adult: 39.2/7.8 – 52.3/10.4; SD: 39.2/7.8mg26.1mg SDX / 
5.2mg d-MPH39.2mg SDX/

5.2mg d-MPH39.2mg SDX/ 
7.8mg d-MPH52.3mg SDX/ 
10.4mg d-MPH
Methylphenidate Formulations – Long Acting**       (Capsules and tablets in this section are shown at actual size)
6 Yrs-Adult: 20–60mg; SD: 20mg20mgMetadate® ER†
10mg
6-17 Yrs: 10–60mg; SD: 20mg
(biphasic – 30/70)♦ ♦ ♦
Metadate® CD‡ 
10mg 20mg 30mg 40mg 50mg 60mg
6-12 Yrs: 10–60mg; SD: 20mg
(biphasic – 50/50)♦
Ritalin® LA‡
10mg
 20mg 30mg 40mg
 60mg
6-17 Yrs: 5–30mg; SD: 5mg
18 Yrs-Adult: 5–30mg; SD: 5mg
(biphasic – 50/50)
Focalin® XR‡
 (dexmethylphenidate)5mg 15mg 20mg 30mg 35mg 40mg
 25mg
 10mg
6 Yrs–Adult: 20–60mg; SD: 20mg20mg 30mg 40mgQuillichew ER®§
 (cherry flavor)
6 Yrs–Adult: 20–60mg; SD: 20mg  25mg/5mL (5mg/mL)Quillivant XR®
 (banana flavor)
10mg
2mL20mg
4mL30mg
6mL40mg
8mL50mg
10mL60mg
12mL1 Bottle:
300mg
60mL1 Bottle:
600mg
120mL1 Bottle:
900mg
180mL2 Bottles:
750mg
150mL2 Bottles:
900mg

(banana flavor)
10mg
2mL20mg
4mL30mg
6mL40mg
8mL50mg
10mL60mg
300mg
600mg
900mg
750mg
900mg
600mg
120mL6-12 Yrs: 18-54mg; SD: 18mg
13-17 Yrs: 18-72mg; SD: 18mg
>18 Yrs: 18-72mg; SD: 18mg or 36mg+ Concerta®†
18mg 36mg 54mg 72mg 27mg
Methylphenidate ER 72mg
(bioequivalent to 2 x 36 mg Concerta tablets)
6 Yrs–Adult: 10–60mg; SD: 10mg
(biphasic – 40/60)10mg 20mg 30mg 40mg 50mg 60mgAptensio® XR‡
15mg
Cotempla XR-ODT® ¶
 (grape flavor) 17.3mg 25.9mg 8.6mg 34.6mg 51.8mg6-17 Yrs: 8.6–51.8mg; SD: 17.3mg
 + +
10mg
• Updated versions of the ADHD Medication Guide can be viewed at: www.ADHDMedicationGuide.com
• Laminated copies of the ADHD Medication Guide can be ordered on-line from the ADD Warehouse
• Contact Dr. Andrew Adesman with any comments or suggestions: ADHDMedGuide@Northwell.edu

80mg6–12 Yrs: 1-4mg; SD: 1mg
13–17 Yrs: 1-7mg; SD: 1mg
Weight-based dosing: SD: 0.05-0.08 mg/
kg/day; may increase to 0.12 mg/kg/day
10mg
0.1mg
1mg
18mg0.2mg
(only in 
dose pack)
2mg
25mg
3mg
40mg
4mg
60mg
 100mg
Intuniv®†
 (guanfacine, extended
  release)
Strattera®†
 (atomoxetine)Kapvay®†
 (clonidine, extended
  release)Non-Stimulants**    (Medications in this section are shown at actual size)    
6–17 Yrs: 0.1-0.2mg BID;
  SD: 0.1mg qHS
≤70kg: 0.5mg/kg x ≥ 3days, then 1.2mg/kg
(max:1.4mg/kg, not to exceed 100mg)
>70 kg: 40mg x ≥ 3days, then 80mg 
     (max:100mg)Amphetamine Formulations – Long Acting**       (Medications in this section are shown at actual size)       
Amphetamine Pro-Drug Formulations – Long Acting**     (Medications in this section are shown at actual size)
Amphetamine Formulations – Short Acting**    (Medications in this section are shown at actual size)    
ProCentra®
 (d-amphetamine sulfate) (bubblegum flavor)Zenzedi®
 (d-amphetamine sulfate)
Adderall®

Adderall®
 (mixed amphetamine salts)
30mg
30mg
 20mg
20mg
15mg
15mg
12.5mg
 10mg
10mg
10mg
7.5mg
7.5mg
5mg/5mL5mg
5mg
5mg
2.5mgEvekeo®
 (d- & l- amphetamine sulfate)
20mg 15mg 10mg 5mgEvekeo® ODT
 (d- & l- amphetamine sulfate)6–17 Yrs: 5-40mg divided BID;
  SD: 5mg 1-2x/day3–5 Yrs: SD: 2.5mg 1x/day
6–17 Yrs: 5-40mg divided BID;
  SD: 5mg 1-2x/day
3–5 Yrs: SD: 2.5mg 1x/day
6–16 Yrs: 5-40mg divided BID;
  SD: 5mg 1-2x/dayDexedrine Spansule®
 (d-amphetamine sulfate)15mg 10mg 5mg
6-17 Yrs: 10–60mg;
SD: 5mg 1-2x/day♦ ♦2.5mg
1mL17.5mg
7mL20mg
8mL12.5mg
5mL15mg
6mL10mg
4mL5mg
2mL7.5mg
3mL
Dyanavel® XR
 (d- & l-amphetamine sulfate)
 2.5mg/mL (bubblegum flavor)6 Yrs–Adults: 2.5–20mg;
SD: 2.5 or 5mg2.5mg 17.5mg 12.5mg 7.5mg
+
 +
 +

7mL20mg
8mL12.5mg
5mL15mg
6mL10mg
4mL5mg
2mL7.5mg
3mL
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 +
 +
20mg 15mg 10mg 5mgDyanavel® XR
Adderall XR®‡
 (mixed amphetamine salts)6–17 Yrs: 5–30mg; SD: 10mg
Adults: 5-30mg; SD: 20mg
 25mg 20mg 15mg 10mg 5mg 30mgAdzenys ER®
 (d- & l-amphetamine)
 1.25mg/mL (orange flavor)6–12 Yrs: 6.3–18.8mg; SD: 6.3mg
13–17 Yrs: 6.3–12.5mg; SD: 6.3mg
Adults: 12.5mg18.8mg
15mL12.5mg
10mL15.7mg
12.5mL9.4mg
7.5mL3.1mg
2.5mL6.3mg
5mL
Adzenys XR-ODT® ¶
 (orange flavor)6–12 Yrs: 3.1–18.8mg; SD: 6.3mg
13–17 Yrs: 3.1–12.5mg; SD: 6.3mg
Adults: 12.5mg
 3.1mg 6.3mg 9.4mg 12.5mg 15.7mg 18.8mg
Vyvanse®§ (chewables)
 (lisdexamfetamine)
 (strawberry flavor) 60mg 50mg 40mg 30mg 20mg 10mg
6 Yrs–Adults: 10–70mg; SD: 30mgVyvanse®¥ (capsules)
 (lisdexamfetamine)6 Yrs–Adults: 10–70mg; SD: 30mg

70mg 60mg 50mg 40mg 30mg 20mg 10mg
Mydayis®‡
 (mixed amphetamine salts)13–17 Yrs: 12.5–25mg; SD: 12.5mg
Adults: 12.5-50mg; SD: 12.5mg25mg 12.5mg 50mg 37.5mg
100mg 200mg 300mg 400mgQelbree®‡
 (viloxaxzine)6–11 Yrs: 100-400mg; SD: 100mg
12–17 Yrs: 200-400mg; SD: 200mg
Adults: 200-600mg; SD: 200mg+ +
6 Yrs–Adults: 2.5–20mg;
SD: 2.5 or 5mg